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Medicine › Oncology

Peptidase Inhibition and Analysis

Works Count: 61522

Description

This cluster of papers explores the role of fibroblast activation in cancer progression, focusing on the expression of fibroblast activation protein, immunosuppression in the tumor microenvironment, N-terminal acetylation of proteins, protease inhibitors for cancer therapy, angiogenesis, and PET imaging to target stromal cells in the tumor microenvironment.

Keywords

Fibroblast Activation Protein; Tumor Microenvironment; Immunosuppression; Cancer Therapy; N-terminal Acetylation; Protease Inhibitors; Angiogenesis; PET Imaging; Stromal Cells; Tumor Stroma

[13] Evolutionary families of metallopeptidases

1995-01-01
Neil D. Rawlings , A. John Barrett

Kinetics of association of serine proteinases with native and oxidized alpha-1-proteinase inhibitor and alpha-1-antichymotrypsin.

1980-05-01
K. Beatty , Joseph G. Bieth , James Travis
The association rate constants for the interaction of alpha-1-proteinase inhibitor, oxidized alpha-1-proteinase inhibitor, and alpha-1-antichymotrypsin with several mammalian serine proteinases have been determined. The results indicate that leukocyte elastase reacts … The association rate constants for the interaction of alpha-1-proteinase inhibitor, oxidized alpha-1-proteinase inhibitor, and alpha-1-antichymotrypsin with several mammalian serine proteinases have been determined. The results indicate that leukocyte elastase reacts more rapidly with alpha-1-proteinase inhibitor than any other proteinase tested, while leukocyte cathepsin G shows the strongest association with alpha-1-antichymotrypsin. Oxidation of the critical methionine residue of alpha-1-proteinase inhibitor reduces the association with leukocyte elastase by a factor of more than 2000 and also lowers the association with all of the other enzymes tested with the exception of chymotrypsin. Significantly, oxidation completely abolishes any interaction of alpha-1-proteinase inhibitor with porcine elastase, human plasmin or human thrombin. These data support previous results (Johnson, D., and Travis, J. (1979) J. Biol. Chem. 254, 4022-4026) which indicated that oxidation of human alpha-1-proteinase inhibitor in vivo could reduce the effectiveness of this inhibitor in controlling proteolysis. In the lung, in particular, oxidizing agents of both chemical and biological sources could, indirectly, augment elastolysis in this tissue, resulting in the development of pulmonary emphysema.

A new solid-state reagent to iodinate proteins

1982-09-01
Mary Ann K. Markwell

Handbook of Proteolytic Enzymes

2004-01-01
A. John Barrett , Neil D. Rawlings , J. Frederick Woessner

SV40-transformed Human Lung Fibroblasts Secrete a 92-kDa Type IV Collagenase Which Is Identical to That Secreted by Normal Human Macrophages

1989-10-01
S M Wilhelm , Ivan E. Collier , Barry L. Marmer +3 more
We have reported that SV40-transformed human lung fibroblasts secrete a 92-kDa metalloprotease which is not detectable in the parental cell line IMR-90. We now present the complete structure of this … We have reported that SV40-transformed human lung fibroblasts secrete a 92-kDa metalloprotease which is not detectable in the parental cell line IMR-90. We now present the complete structure of this enzyme along with the evidence that it is identical to the 92-kDa metalloprotease secreted by normal human alveolar macrophages, phorbol ester-differentiated monocytic leukemia U937 cells, fibrosarcoma HT1080 cells, and cultured human keratinocytes. A similar, perhaps identical, enzyme can be released by polymorphonuclear cells. The preproenzyme is synthesized as a polypeptide of predicted Mr 78,426 containing a 19 amino-acid-long signal peptide and secreted as a single 92,000 glycosylated proenzyme. The purified proenzyme complexes noncovalently with the tissue inhibitor of metalloproteases (TIMP) and can be activated by organomercurials. Activation with phenylmercuric chloride results in removal of 73 amino acids from the NH2 terminus of the proenzyme, yielding an active form capable of digesting native types IV and V collagen. The in vitro substrate specificity of the enzyme using these substrates was indistinguishable from that of the 72-kDa type IV collagenase. The 92-kDa type IV collagenase consists of five domains; the amino-terminal and zinc-binding domains shared by all members of the secreted metalloprotease gene family, the collagen-binding fibronectin-like domain also present in the 72-kDa type IV collagenase, a carboxyl-terminal hemopexin-like domain shared by all known enzymes of this family with the exception of PUMP-1, and a unique 54-amino-acid-long proline-rich domain homologous to the alpha 2 chain of type V collagen.

L-<i>trans</i>-Epoxysuccinyl-leucylamido(4-guanidino)butane (E-64) and its analogues as inhibitors of cysteine proteinases including cathepsins B, H and L

1982-01-01
A. John Barrett , A A Kembhavi , M A Brown +4 more
1. L-trans-Epoxysuccinyl-leucylamido(4-guanidino)butane (E-64) at a concentration of 0.5 mM had no effect on the serine proteinases plasma kallikrein and leucocyte elastase or the metalloproteinases thermolysin and clostridial collagenase. In contrast, … 1. L-trans-Epoxysuccinyl-leucylamido(4-guanidino)butane (E-64) at a concentration of 0.5 mM had no effect on the serine proteinases plasma kallikrein and leucocyte elastase or the metalloproteinases thermolysin and clostridial collagenase. In contrast, 10 muM-E-64 rapidly inactivated the cysteine proteinases cathepsins B, H and L and papain (t0.5 = 0.1-17.3s). The streptococcal cysteine proteinase reacted much more slowly, and there was no irreversible inactivation of clostripain. The cysteine-dependent exopeptidase dipeptidyl peptidase I was very slowly inactivated by E-64. 2. the active-site-directed nature of the interaction of cathepsin B and papain with E-64 was established by protection of the enzyme in the presence of the reversible competitive inhibitor leupeptin and by the stereospecificity for inhibition by the L as opposed to the D compound. 3. It was shown that the rapid stoichiometric reaction of the cysteine proteinases related to papain can be used to determine the operational molarity of solutions of the enzymes and thus to calibrate rate assays. 4. The apparent second-order rate constants for the inactivation of human cathepsins B and H and rat cathepsin L by a series of structural analogues of E-64 are reported, and compared with those for some other active-site-directed inhibitors of cysteine proteinases. 5. L-trans-Epoxysuccinyl-leucylamido(3-methyl)butane (Ep-475) was found to inhibit cathepsins B and L more rapidly than E-64. 6. Fumaryl-leucylamido(3-methyl)butane (Dc-11) was 100-fold less reactive than the corresponding epoxide, but was nevertheless about as effective as iodoacetate.
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Evolutionary families of peptidases

1993-02-15
Neil D. Rawlings , A. John Barrett
The available amino acid sequences of peptidases have been examined, and the enzymes have been allocated to evolutionary families. Some of the families can be grouped together in 'clans' that … The available amino acid sequences of peptidases have been examined, and the enzymes have been allocated to evolutionary families. Some of the families can be grouped together in 'clans' that show signs of distant relationship, but nevertheless, it appears that there may be as many as 60 evolutionary lines of peptidases with separate origins. Some of these contain members with quite diverse peptidase activities, and yet there are some striking examples of convergence. We suggest that the classification by families could be used as an extension of the current classification by catalytic type.
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Structure of the receptor for platelet-derived growth factor helps define a family of closely related growth factor receptors

1986-09-01
Yosef Yarden , J A Escobedo , Wun-Jing Kuang +7 more

The colorimetric determination of leucine aminopeptidase in urine and serum of normal subjects and patients with cancer and other diseases

1958-03-01
Julius A. Goldbarg , Alexander M. Rutenburg
FIRST demonstration of "leucylpepti-T dase" as a component of erepsin was made by measuring the rate of liberation of carboxyl groups from L-leucylglycine.6However, since this substrate was hydrolyzed by enzymes … FIRST demonstration of "leucylpepti-T dase" as a component of erepsin was made by measuring the rate of liberation of carboxyl groups from L-leucylglycine.6However, since this substrate was hydrolyzed by enzymes other than leucylpeptidase, L-leucinamide, a more specific substrate was synthesized.'Gomori4 developed a more precise colorimetric and histe chemical method to study tissue aminopeptidase, based on the formation of azo dyes from the naphthylamine moiety liberated by enzymatic hydrolysis of glycylor alanyl-p-naphthylamide. Green et a1.6 and Folk and Burstones assayed enzymatic activity of mammalian tissues and serum by measuring the p-naphthylamine liberated by hydrolysis of L-leucyl-P-naphthylamide hydrochloride.The present report deals with a new method for the colorimetric measurement of leucine aminopeptidase activity in urine and an improved procedure for the assay of enzymatic activity in tissues and serum, the kinetics o f the urinary and serum enzyme, and the assay of this enzyme in the urine and serum of normal subjects and patients with cancer and other diseases. METHODSReagents.The reagents used included the following: a substrate solution composed of a
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The N-end rule: functions, mysteries, uses.

1996-10-29
A Varshavsky
The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. Similar but distinct versions of the N-end rule operate in all organisms … The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. Similar but distinct versions of the N-end rule operate in all organisms examined, from mammals to fungi and bacteria. In eukaryotes, the N-end rule pathway is a part of the ubiquitin system. I discuss the mechanisms and functions of this pathway, and consider its applications.
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Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases

2002-11-08
James C. Powers , Juliana L. Asgian , Özlem Doǧan Ekici +1 more
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTIrreversible Inhibitors of Serine, Cysteine, and Threonine ProteasesJames C. Powers, Juliana L. Asgian, Özlem Doǧan Ekici, and Karen Ellis JamesView Author Information School of Chemistry and Biochemistry, … ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTIrreversible Inhibitors of Serine, Cysteine, and Threonine ProteasesJames C. Powers, Juliana L. Asgian, Özlem Doǧan Ekici, and Karen Ellis JamesView Author Information School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332-0400 Cite this: Chem. Rev. 2002, 102, 12, 4639–4750Publication Date (Web):November 8, 2002Publication History Received26 February 2002Published online8 November 2002Published inissue 1 December 2002https://pubs.acs.org/doi/10.1021/cr010182vhttps://doi.org/10.1021/cr010182vresearch-articleACS PublicationsCopyright © 2002 American Chemical SocietyRequest reuse permissionsArticle Views21661Altmetric-Citations869LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Inhibition,Inhibitors,Monomers,Peptides and proteins,Reaction products Get e-Alerts

Matrix Metalloproteinase Inhibitors and Cancer—Trials and Tribulations

2002-03-29
Lisa M. Coussens , Barbara Fingleton , Lynn M. Matrisian
For at least 30 years, matrix metalloproteinases (MMPs) have been heralded as promising targets for cancer therapy on the basis of their massive up-regulation in malignant tissues and their unique … For at least 30 years, matrix metalloproteinases (MMPs) have been heralded as promising targets for cancer therapy on the basis of their massive up-regulation in malignant tissues and their unique ability to degrade all components of the extracellular matrix. Preclinical studies testing the efficacy of MMP suppression in tumor models were so compelling that synthetic metalloproteinase inhibitors (MPIs) were rapidly developed and routed into human clinical trials. The results of these trials have been disappointing. Here we review the studies that brought MPIs into clinical testing and discuss the design and outcome of the trials in light of new information about the cellular source, substrates, and mode of action of MMPs at different stages of tumor progression. The important lessons learned from the MPI experience may be of great value for future studies of MPIs and for cancer drug development in general.

A New Group of Chromatin‐Associated Proteins with a High Content of Acidic and Basic Amino Acids

1973-09-01
Graham H. Goodwin , Clive Sanders , Ernest W. Johns
A new group of chromatin‐associated proteins having a high content of acidic and basic amino acids have been isolated from the 0.35 M NaCl‐extractable proteins from calf thymus. This new … A new group of chromatin‐associated proteins having a high content of acidic and basic amino acids have been isolated from the 0.35 M NaCl‐extractable proteins from calf thymus. This new group, designated “high‐mobility group” proteins have been partially separated and some interesting new proteins identified. One such protein contains over 55% acidic and basic amino acids.

Crystal structure of the human angiotensin-converting enzyme–lisinopril complex

2003-01-01
R. Natesh , Sylva L. U. Schwager , Edward D. Sturrock +1 more

Transforming growth factor beta 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis.

1991-08-01
T J Broekelmann , Andrew H. Limper , Thomas V. Colby +1 more
Idiopathic pulmonary fibrosis is an inexorably fatal disorder characterized by connective tissue deposition within the terminal air spaces resulting in loss of lung function and eventual respiratory failure. Previously, we … Idiopathic pulmonary fibrosis is an inexorably fatal disorder characterized by connective tissue deposition within the terminal air spaces resulting in loss of lung function and eventual respiratory failure. Previously, we demonstrated that foci of activated fibroblasts expressing high levels of fibronectin, procollagen, and smooth muscle actin and thus resembling those found in healing wounds are responsible for the connective tissue deposition and scarring in idiopathic pulmonary fibrosis. Using in situ hybridization and immunohistochemistry, we now demonstrate the presence of transforming growth factor beta 1 (TGF-beta 1), a potent profibrotic cytokine, in the foci containing these activated fibroblasts. These results suggest that matrix-associated TGF-beta 1 may serve as a stimulus for the persistent expression of connective tissue genes. One potential source of the TGF-beta 1 is the alveolar macrophage, and we demonstrate the expression of abundant TGF-beta 1 mRNA in alveolar macrophages in lung tissue from patients with idiopathic pulmonary fibrosis.
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Structural basis of substrate specificity in the serine proteases

1995-03-01
John J. Perona , Charles S. Craik
Abstract Structure‐based mutational analysis of serine protease specificity has produced a large database of information useful in addressing biological function and in establishing a basis for targeted design efforts. Critical … Abstract Structure‐based mutational analysis of serine protease specificity has produced a large database of information useful in addressing biological function and in establishing a basis for targeted design efforts. Critical issues examined include the function of water molecules in providing strength and specificity of binding, the extent to which binding subsites are interdependent, and the roles of polypeptide chain flexibility and distal structural elements in contributing to specificity profiles. The studies also provide a foundation for exploring why specificity modification can be either straightforward or complex, depending on the particular system.
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MEROPS: the database of proteolytic enzymes, their substrates and inhibitors

2011-11-15
Neil D. Rawlings , A. John Barrett , Alex Bateman
Peptidases, their substrates and inhibitors are of great relevance to biology, medicine and biotechnology. The MEROPS database (http://merops.sanger.ac.uk) aims to fulfill the need for an integrated source of information about … Peptidases, their substrates and inhibitors are of great relevance to biology, medicine and biotechnology. The MEROPS database (http://merops.sanger.ac.uk) aims to fulfill the need for an integrated source of information about these. The database has hierarchical classifications in which homologous sets of peptidases and protein inhibitors are grouped into protein species, which are grouped into families, which are in turn grouped into clans. Recent developments include the following. A community annotation project has been instigated in which acknowledged experts are invited to contribute summaries for peptidases. Software has been written to provide an Internet-based data entry form. Contributors are acknowledged on the relevant web page. A new display showing the intron/exon structures of eukaryote peptidase genes and the phasing of the junctions has been implemented. It is now possible to filter the list of peptidases from a completely sequenced bacterial genome for a particular strain of the organism. The MEROPS filing pipeline has been altered to circumvent the restrictions imposed on non-interactive blastp searches, and a HMMER search using specially generated alignments to maximize the distribution of organisms returned in the search results has been added.
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Cysteine proteases of parasitic organisms☆

2002-03-01
Mohammed Sajid , James H. McKerrow

Effects of Angiogenesis Inhibitors on Multistage Carcinogenesis in Mice

1999-04-30
Gabriele Bergers , Kashi Javaherian , Kin-Ming Lo +2 more
Solid tumors depend on angiogenesis for their growth. In a transgenic mouse model of pancreatic islet cell carcinogenesis (RIP1-Tag2), an angiogenic switch occurs in premalignant lesions, and angiogenesis persists during … Solid tumors depend on angiogenesis for their growth. In a transgenic mouse model of pancreatic islet cell carcinogenesis (RIP1-Tag2), an angiogenic switch occurs in premalignant lesions, and angiogenesis persists during progression to expansive solid tumors and invasive carcinomas. RIP1-Tag2 mice were treated so as to compare the effects of four angiogenesis inhibitors at three distinct stages of disease progression. AGM-1470, angiostatin, BB-94, and endostatin each produced distinct efficacy profiles in trials aimed at preventing the angiogenic switch in premalignant lesions, intervening in the rapid expansion of small tumors, or inducing the regression of large end-stage cancers. Thus, anti-angiogenic drugs may prove most efficacious when they are targeted to specific stages of cancer.

Quantitative reactivity profiling predicts functional cysteines in proteomes

2010-11-17
Eranthie Weerapana , Chu Wang , Gabriel M. Simon +7 more
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Human aminopeptidase N is a receptor for human coronavirus 229E

1992-06-01
Curtis Yeager , Richard A. Ashmun , Richard K. Williams +4 more
Human coronaviruses (HCV) in two serogroups represented by HCV-229E and HCV-OC43 are an important cause of upper respiratory tract infections. Here we report that human aminopeptidase N, a cell-surface metalloprotease … Human coronaviruses (HCV) in two serogroups represented by HCV-229E and HCV-OC43 are an important cause of upper respiratory tract infections. Here we report that human aminopeptidase N, a cell-surface metalloprotease on intestinal, lung and kidney epithelial cells, is a receptor for human coronavirus strain HCV-229E, but not for HCV-OC43. A monoclonal antibody, RBS, blocked HCV-229E virus infection of human lung fibroblasts, immunoprecipitated aminopeptidase N and inhibited its enzymatic activity. HCV-229E-resistant murine fibroblasts became susceptible after transfection with complementary DNA encoding human aminopeptidase N. By contrast, infection of human cells with HCV-OC43 was not inhibited by antibody RBS and expression of aminopeptidase N did not enhance HCV-OC43 replication in mouse cells. A mutant aminopeptidase lacking the catalytic site of the enzyme did not bind HCV-229E or RBS and did not render murine cells susceptible to HCV-229E infection, suggesting that the virus-binding site may lie at or near the active site of the human aminopeptidase molecule.
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Dipeptidyl-Peptidase IV from Bench to Bedside: An Update on Structural Properties, Functions, and Clinical Aspects of the Enzyme DPP IV

2003-01-01
Anne‐Marie Lambeir , Christine Durinx , Simon Scharpé +1 more
Dipeptidyl-peptidase IV/CD26 (DPP IV) is a cell-surface protease belonging to the prolyloligopeptidase family. It selectively removes the N-terminal dipeptide from peptides with proline or alanine in the second position. Apart … Dipeptidyl-peptidase IV/CD26 (DPP IV) is a cell-surface protease belonging to the prolyloligopeptidase family. It selectively removes the N-terminal dipeptide from peptides with proline or alanine in the second position. Apart from its catalytic activity, it interacts with several proteins, for instance, adenosine deaminase, the HIV gp120 protein, fibronectin, collagen, the chemokine receptor CXCR4, and the tyrosine phosphatase CD45. DPP IV is expressed on a specific set of T lymphocytes, where it is up-regulated after activation. It is also expressed in a variety of tissues, primarily on endothelial and epithelial cells. A soluble form is present in plasma and other body fluids. DPP IV has been proposed as a diagnostic or prognostic marker for various tumors, hematological malignancies, immunological, inflammatory, psychoneuroendocrine disorders, and viral infections. DPP IV truncates many bioactive peptides of medical importance. It plays a role in glucose homeostasis through proteolytic inactivation of the incretins. DPP IV inhibitors improve glucose tolerance and pancreatic islet cell function in animal models of type 2 diabetes and in diabetic patients. The role of DPP IV/CD26 within the immune system is a combination of its exopeptidase activity and its interactions with different molecules. This enables DPP IV/CD26 to serve as a co-stimulatory molecule to influence T cell activity and to modulate chemotaxis. DPP IV is also implicated in HIV-1 entry, malignant transformation, and tumor invasion.Referee: Dr. Albert Adam, Faculté de Pharmace, Université de Montréal, 2900 Blvd. Edouard—Montpetit, CP succursale Centreville, Montreal, Quebec H3C 3J7, Canada

Dipeptidyl-peptidase IV (CD26)-role in the inactivation of regulatory peptides

1999-11-01
Rolf Mentlein

Predotar: A tool for rapidly screening proteomes for <b><i>N</i></b>‐terminal targeting sequences

2004-04-30
Ian Small , Nemo Peeters , Fabrice Legeai +1 more
Abstract Probably more than 25% of the proteins encoded by the nuclear genomes of multicellular eukaryotes are targeted to membrane‐bound compartments by N ‐terminal targeting signals. The major signals are … Abstract Probably more than 25% of the proteins encoded by the nuclear genomes of multicellular eukaryotes are targeted to membrane‐bound compartments by N ‐terminal targeting signals. The major signals are those for the endoplasmic reticulum, the mitochondria, and in plants, plastids. The most abundant of these targeted proteins are well‐known and well‐studied, but a large proportion remain unknown, including most of those involved in regulation of organellar gene expression or regulation of biochemical pathways. The discovery and characterization of these proteins by biochemical means will be long and difficult. An alternative method is to identify candidate organellar proteins via their characteristic N ‐terminal targeting sequences. We have developed a neural network‐based approach (Predotar – Prediction of Organelle Targeting sequences) for identifying genes encoding these proteins amongst eukaryotic genome sequences. The power of this approach for identifying and annotating novel gene families has been illustrated by the discovery of the pentatricopeptide repeat family.

Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein–α

2010-11-04
Matthew Kraman , Paul Bambrough , James N. Arnold +6 more
The stromal microenvironment of tumors, which is a mixture of hematopoietic and mesenchymal cells, suppresses immune control of tumor growth. A stromal cell type that was first identified in human … The stromal microenvironment of tumors, which is a mixture of hematopoietic and mesenchymal cells, suppresses immune control of tumor growth. A stromal cell type that was first identified in human cancers expresses fibroblast activation protein-α (FAP). We created a transgenic mouse in which FAP-expressing cells can be ablated. Depletion of FAP-expressing cells, which made up only 2% of all tumor cells in established Lewis lung carcinomas, caused rapid hypoxic necrosis of both cancer and stromal cells in immunogenic tumors by a process involving interferon-γ and tumor necrosis factor-α. Depleting FAP-expressing cells in a subcutaneous model of pancreatic ductal adenocarcinoma also permitted immunological control of growth. Therefore, FAP-expressing cells are a nonredundant, immune-suppressive component of the tumor microenvironment.

A novel heterodimeric cysteine protease is required for interleukin-1βprocessing in monocytes

1992-04-01
Nancy A. Thornberry , Herbert G. Bull , Jimmy Calaycay +7 more

A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences

1986-02-01
Dionisio Martı́n-Zanca , Stephen H. Hughes , Mariano Barbacid
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Families of zinc metalloproteases

1994-10-31
Nigel M. Hooper
A scheme based on the zinc binding site [1992, FEBS Lett. 312, 110–114] has been extended to classify zinc metalloproteases into distinct families. The gluzincins, defined by the HEXXH motif … A scheme based on the zinc binding site [1992, FEBS Lett. 312, 110–114] has been extended to classify zinc metalloproteases into distinct families. The gluzincins, defined by the HEXXH motif and a glutamic acid as the third zinc ligand, include the thermolysin, endopeptidase‐24.11, aminopeptidase, angiotensin converting enzyme, endopeptidase‐24.15, and tetanus and botulinum neurotoxin families. The metzincins, defined by the HEXXH motif, a histidine as the third zinc ligand and a Met‐turn, include the astacin, serralysin, reprolysin and matrixin families. The inverted zincin motif, HXXEH, defines the inverzincin family of insulin‐degrading enzymes, the HXXE motif defines the carboxypeptidase family, and the HXH Motif dd ‐carboxypeptidase.

(2<i>R</i>)-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-<i>a</i>]pyrazin- 7(8<i>H</i>)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: A Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes

2004-12-13
Dooseop Kim , Liping Wang , Maria Beconi +7 more
A novel series of β-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine … A novel series of β-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC50 = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes.

Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti–PD-L1 immunotherapy in pancreatic cancer

2013-11-25
Christine Feig , James O. Jones , Matthew Kraman +7 more
Significance Cancer immune evasion is well described. In some cases, this may be overcome by enhancing T-cell responses. We show that despite the presence of antitumor T cells, immunotherapeutic antibodies … Significance Cancer immune evasion is well described. In some cases, this may be overcome by enhancing T-cell responses. We show that despite the presence of antitumor T cells, immunotherapeutic antibodies are ineffective in a murine pancreatic cancer model recapitulating the human disease. Removing the carcinoma-associated fibroblast (CAF) expressing fibroblast activation protein (FAP) from tumors permitted immune control of tumor growth and uncovered the efficacy of these immunotherapeutic antibodies. FAP + CAFs are the only tumoral source of chemokine (C-X-C motif) ligand 12 (CXCL12), and administering AMD3100, an inhibitor of chemokine (C-X-C motif) receptor 4, a CXCL12 receptor, also revealed the antitumor effects of an immunotherapeutic antibody and greatly diminished cancer cells. These findings may have wide clinical relevance because FAP + cells are found in almost all human adenocarcinomas.
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The Electrophoretic α;<sub>1</sub>-Globulin Pattern of Serum in α;<sub>1</sub>-Antitrypsin Deficiency

1963-01-01
C.‐B. Laurell , Sten Eriksson
(1963). The Electrophoretic α;1-Globulin Pattern of Serum in α;1-Antitrypsin Deficiency. Scandinavian Journal of Clinical and Laboratory Investigation: Vol. 15, No. 2, pp. 132-140. (1963). The Electrophoretic α;1-Globulin Pattern of Serum in α;1-Antitrypsin Deficiency. Scandinavian Journal of Clinical and Laboratory Investigation: Vol. 15, No. 2, pp. 132-140.

Chemistry for peptide and protein PEGylation

2002-06-01
Michael J. Roberts , Michael D. Bentley , J. Milton Harris

Histone Deacetylase 4 Controls Chondrocyte Hypertrophy during Skeletogenesis

2004-11-01
Rick B. Vega , Koichi Matsuda , Jun‐Young Oh +7 more
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Multicenter Phase II Study of Erlotinib, an Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck

2003-12-30
Denis Soulières , Neil Senzer , Everett E. Vokes +3 more
To determine the efficacy and safety profiles of erlotinib in patients with advanced recurrent and/or metastatic squamous cell cancer of the head and neck (HNSCC).Patients with locally recurrent and/or metastatic … To determine the efficacy and safety profiles of erlotinib in patients with advanced recurrent and/or metastatic squamous cell cancer of the head and neck (HNSCC).Patients with locally recurrent and/or metastatic HNSCC, regardless of their HER1/EGFR status, were treated with erlotinib at an initial dose of 150 mg daily. Dose reductions or escalations were allowed based on tolerability of erlotinib.One-hundred fifteen patients were enrolled onto this study. Forty-seven percent of patients received erlotinib at 150 mg daily throughout the entire study, 6% had dose escalations, and 46% required dose reductions and/or interruptions. Five patients achieved partial responses on study, for an overall objective response rate of 4.3% (95% CI, 1.4% to 9.9%). Disease stabilization was maintained in 44 patients (38.3%) for a median duration of 16.1 weeks. The median progression-free survival was 9.6 weeks (95% CI, 8.1 to 12.1 weeks), and the median overall survival was 6.0 months (95% CI, 4.8 to 7.0 months). Subgroup analyses revealed a significant difference in overall survival favoring patients who developed at least grade 2 skin rashes versus those who did not (P =.045), whereas no difference was detected based on HER1/EGFR expression. Rash and diarrhea were the most common drug-related toxicities, encountered in 79% and 37% of patients, respectively, though the severity was mild to moderate in most cases.Erlotinib was well tolerated in this heavily pretreated HNSCC population and produced prolonged disease stabilization; hence, further evaluation of its role in this tumor type is warranted.
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Dipeptidyl‐peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon‐like peptide‐1(7–36)amide, peptide histidine methionine and is responsible for their degradation in human serum

1993-06-01
Rolf Mentlein , Baptist Gallwitz , Wolfgang E. Schmidt
Peptides of the glucagon/vasoactive‐intestinal‐peptide (VIP) peptide family share a considerable sequence similarity at their N‐terminus. They either start with Tyr‐Ala, His‐Ala or His‐Ser which might be in part potential targets … Peptides of the glucagon/vasoactive‐intestinal‐peptide (VIP) peptide family share a considerable sequence similarity at their N‐terminus. They either start with Tyr‐Ala, His‐Ala or His‐Ser which might be in part potential targets for dipeptidyl‐peptidase IV, a highly specialized aminopeptidase removing dipeptides only from peptides with N‐terminal penultimate proline or alanine. Growthhormone‐releasing factor(1–29)amide and gastric inhibitory peptide/glucose‐dependent insulinotropic peptide (GIP) with terminal Tyr‐Ala as well as glucagon‐like peptide‐1(7–36)amide/insulinotropin [GLP‐1(7–36)amide] and peptide histidine methionine (PHM) with terminal His‐Ala were hydrolysed to their des‐Xaa‐Ala derivatives by dipeptidyl‐peptidase IV purified from human placenta. VIP with terminal His‐Ser was not significantly degraded by the peptidase. The kinetics of the hydrolysis of GIP, GLP‐1(7–36)amide and PHM were analyzed in detail. For these peptides K m values of 4–34 μM and V max values of 0.6–3.8 μmol · min −1 · mg protein −1 were determined for the purified peptidase which should allow their enzymic degradation also at physiological, nanomolar concentrations. When human serum was incubated with GIP or GLP‐1(7–36)amide the same fragments as with the purified dipeptidyl‐peptidase IV, namely the des‐Xaa‐Ala peptides and Tyr‐Ala in the case of GIP or His‐Ala in the case of GLP‐1(7–36)amide, were identified as the main degradation products of these peptide hormones. Incorporation of inhibitors specific for dipeptidylpeptidase IV, 1 mM Lys‐pyrrolidide or 0.1 mM diprotin A (Ile‐Pro‐Ilc), completely abolished the production of these fragments by serum. It is concluded that dipeptidyl‐peptidase IV initiates the metabolism of GIP and GLP‐1(7–36)amide in human serum. Since an intact N‐terminus is obligate for the biological activity of the members of the glucagon/VIP peptide family [e. g. GIP(3–42) is known to be inactive to release insulin in the presence of glucose as does intact GIP], dipeptidyl‐peptidase‐IV action inactivates these peptide hormones. The relevance of this finding for their inactivation and their determination by immunoassays is discussed.
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Prostate-specific membrane antigen expression in normal and malignant human tissues.

1997-01-01
Donald Silver , I Pellicer , W R Fair +2 more
Prostate-specific membrane antigen is a type II membrane protein with folate hydrolase activity produced by prostatic epithelium. The expression of this molecule has also been documented in extraprostatic tissues, including … Prostate-specific membrane antigen is a type II membrane protein with folate hydrolase activity produced by prostatic epithelium. The expression of this molecule has also been documented in extraprostatic tissues, including small bowel and brain. In the present study, an extensive immunohistochemical analysis was performed on a panel of well-characterized normal and malignant human tissues to further define the pattern of prostate-specific membrane antigen (PSMA) expression. Detectable PSMA levels were identified in prostatic epithelium, duodenal mucosa, and a subset of proximal renal tubules. A subpopulation of neuroendocrine cells in the colonic crypts also exhibited PSMA immunoreactivity. All other normal tissues, including cerebral cortex and cerebellum, had undetectable levels of PSMA. Thirty-three of 35 primary prostate adenocarcinomas and 7 of 8 lymph node metastases displayed tumor cell PSMA immunostaining. Eight of 18 prostate tumors metastatic to bone expressed PSMA. All of the other nonprostatic primary tumors studied had undetectable PSMA levels. However, intense staining was observed in endothelial cells of capillary vessels in peritumoral and endotumoral areas of certain malignancies, including 8 of 17 renal cell carcinomas, 7 of 13 transitional cell carcinomas, and 3 of 19 colon carcinomas. Extraprostatic PSMA expression appears to be highly restricted. Nevertheless, its diverse anatomical distribution implies a broader functional significance than previously suspected. The decrease in PSMA immunoreactivity noted in advanced prostate cancer suggests that expression of this molecule may be linked to the degree of tumor differentiation. The neoexpression of PSMA in endothelial cells of capillary beds in certain tumors may be related to tumor angiogenesis and suggests a potential mechanism for specific targeting of tumor neovasculature.

Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC

2013-03-01
V. Stalin Raj , Huihui Mou , Saskia L. Smits +7 more
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Paclitaxel–Carboplatin Alone or with Bevacizumab for Non–Small-Cell Lung Cancer

2006-12-13
Alan Sandler , Robert J. Gray , Michael C. Perry +5 more
Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has been shown to benefit patients with a variety of cancers.Between July 2001 and April 2004, the Eastern Cooperative Oncology Group … Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has been shown to benefit patients with a variety of cancers.Between July 2001 and April 2004, the Eastern Cooperative Oncology Group (ECOG) conducted a randomized study in which 878 patients with recurrent or advanced non-small-cell lung cancer (stage IIIB or IV) were assigned to chemotherapy with paclitaxel and carboplatin alone (444) or paclitaxel and carboplatin plus bevacizumab (434). Chemotherapy was administered every 3 weeks for six cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous-cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or performance status (ECOG performance status, >1) were excluded. The primary end point was overall survival.The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (hazard ratio for death, 0.79; P=0.003). The median progression-free survival in the two groups was 6.2 and 4.5 months, respectively (hazard ratio for disease progression, 0.66; P<0.001), with corresponding response rates of 35% and 15% (P<0.001). Rates of clinically significant bleeding were 4.4% and 0.7%, respectively (P<0.001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including 5 from pulmonary hemorrhage.The addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with non-small-cell lung cancer has a significant survival benefit with the risk of increased treatment-related deaths. (ClinicalTrials.gov number, NCT00021060.)
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Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function

2007-10-01
Francis G. Spinale
It is now becoming apparent that dynamic changes occur within the interstitium that directly contribute to adverse myocardial remodeling following myocardial infarction (MI), with hypertensive heart disease and with intrinsic … It is now becoming apparent that dynamic changes occur within the interstitium that directly contribute to adverse myocardial remodeling following myocardial infarction (MI), with hypertensive heart disease and with intrinsic myocardial disease such as cardiomyopathy. Furthermore, a family of matrix proteases, the matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPs), has been recognized to play an important role in matrix remodeling in these cardiac disease states. The purpose of this review is fivefold: 1) to examine and redefine the myocardial matrix as a critical and dynamic entity with respect to the remodeling process encountered with MI, hypertension, or cardiomyopathic disease; 2) present the remarkable progress that has been made with respect to MMP/TIMP biology and how it relates to myocardial matrix remodeling; 3) to evaluate critical translational/clinical studies that have provided a cause-effect relationship between alterations in MMP/TIMP regulation and myocardial matrix remodeling; 4) to provide a critical review and analysis of current diagnostic, prognostic, and pharmacological approaches that utilized our basic understanding of MMP/TIMPs in the context of cardiac disease; and 5) most importantly, to dispel the historical belief that the myocardial matrix is a passive structure and supplant this belief that the regulation of matrix protease pathways such as the MMPs and TIMPs will likely yield a new avenue of diagnostic and therapeutic strategies for myocardial remodeling and the progression to heart failure.

Proteolytic activation of latent transforming growth factor-beta from fibroblast-conditioned medium.

1988-05-01
Russette M. Lyons , Jorma Keski‐Oja , Harold L. Moses
Transforming growth factor-beta (TGF beta) is produced by most cultured cells in an inactive form. Potential activation mechanisms of latent TGF beta were studied using fibroblastic (NRK-49F and AKR-MCA) cell-conditioned … Transforming growth factor-beta (TGF beta) is produced by most cultured cells in an inactive form. Potential activation mechanisms of latent TGF beta were studied using fibroblastic (NRK-49F and AKR-MCA) cell-conditioned medium as a model. Active TGF beta was monitored by radioreceptor and soft agar assays as well as by antibody inhibition and immunoprecipitation. Little or no TGF beta was detected in untreated conditioned medium. Treatment of the medium with extremes of pH (1.5 or 12) resulted in significant activation of TGF beta as shown by radioreceptor assays, while mild acid treatment (pH 4.5) yielded only 20-30% of the competition achieved by pH 1.5. In an effort to define more physiological means of TGF beta activation, the effects of some proteases were tested. Plasmin and cathepsin D were found to generate 25-kD bands corresponding to the active form of TGF beta as shown by immunoprecipitation analysis of radiolabeled cell-conditioned medium. Plasmin treatment of the medium resulted in activity that was quantitatively similar to that of mild acid treatment as measured by radioreceptor and soft agar assays. In addition, the plasmin-generated activity was inhibited by anti-TGF beta antibodies. Sequential treatments of AKR-MCA cell-conditioned medium with mild acid followed by plasmin or plasmin followed by mild acid gave activation comparable to either treatment alone. The data suggest that conditioned medium may contain at least two different pools of latent TGF beta. One pool is resistant to mild acid and/or plasmin and requires strong acid or alkali treatment for activation. A second pool is activated by mild pH change and/or plasmin. Activation of this form of latent TGF beta may take place by dissociation or proteolytic digestion from a precursor molecule or hypothetical TGF beta-binding protein complex.
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Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer

2003-10-07
Arundhati Ghosh , Warren D.W. Heston
Abstract Prostate specific membrane antigen (PSMA), is a unique membrane bound glycoprotein, which is overexpressed manifold on prostate cancer as well as neovasculature of most of the solid tumors, but … Abstract Prostate specific membrane antigen (PSMA), is a unique membrane bound glycoprotein, which is overexpressed manifold on prostate cancer as well as neovasculature of most of the solid tumors, but not in the vasculature of the normal tissues. This unique expression of PSMA makes it an important marker as well as a large extracellular target of imaging agents. PSMA can serve as target for delivery of therapeutic agents such as cytotoxins or radionuclides. PSMA has two unique enzymatic functions, folate hydrolase and NAALADase and found to be recycled like other membrane bound receptors through clathrin coated pits. The internalization property of PSMA leads one to consider the potential existence of a natural ligand for PSMA. In this review we have discussed the regulation of PSMA expression within the cells, and significance of its expression in prostate cancer and metastasis. © 2003 Wiley‐Liss, Inc.

Aminopeptidase N is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis.

2000-02-01
Renata Pasqualini , Erkki Koivunen , Renate Kain +7 more
Phage that display a surface peptide with the NGR sequence motif home selectively to tumor vasculature in vivo. A drug coupled to an NGR peptide has more potent antitumor effects … Phage that display a surface peptide with the NGR sequence motif home selectively to tumor vasculature in vivo. A drug coupled to an NGR peptide has more potent antitumor effects than the free drug [W. Arap et al., Science (Washington DC), 279: 377-380, 1998]. We show here that the receptor for the NGR peptides in tumor vasculature is aminopeptidase N (APN; also called CD13). NGR phage specifically bound to immunocaptured APN and to cells engineered to express APN on their surface. Antibodies against APN inhibited in vivo tumor homing by the NGR phage. Immunohistochemical staining showed that APN expression is up-regulated in endothelial cells within mouse and human tumors. In another tissue that undergoes angiogenesis, corpus luteum, blood vessels also expressed APN, but APN was not detected in blood vessels of various other normal tissues stained under the same conditions. APN antagonists specifically inhibited angiogenesis in chorioallantoic membranes and in the retina and suppressed tumor growth. Thus, APN is involved in angiogenesis and can serve as a target for delivering drugs into tumors and for inhibiting angiogenesis.

Tumors: Wounds That Do Not Heal

1986-12-25
Jeffrey S. Flier , Lisa H. Underhill , Harold F. Dvorak
SOLID tumors are composed of two discrete but interdependent compartments: the malignant cells themselves and the stroma that they induce and in which they are dispersed.1 , 2 In tumors … SOLID tumors are composed of two discrete but interdependent compartments: the malignant cells themselves and the stroma that they induce and in which they are dispersed.1 , 2 In tumors of epithelialcell origin — carcinomas — a basement membrane is often interposed between the tumor cells and the stroma, but in other types of tumors, malignant cells directly abut on or intermingle with stromal elements.1 , 3 An appreciation of tumor stroma is essential to an understanding of the biology of tumor growth; all solid tumors, regardless of their site of origin, require stroma if they are to grow beyond a minimal size of . . .

The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database

2017-10-30
Neil D. Rawlings , A. John Barrett , Paul D. Thomas +3 more
The MEROPS database (http://www.ebi.ac.uk/merops/) is an integrated source of information about peptidases, their substrates and inhibitors. The hierarchical classification is: protein-species, family, clan, with an identifier at each level. The … The MEROPS database (http://www.ebi.ac.uk/merops/) is an integrated source of information about peptidases, their substrates and inhibitors. The hierarchical classification is: protein-species, family, clan, with an identifier at each level. The MEROPS website moved to the EMBL-EBI in 2017, requiring refactoring of the code-base and services provided. The interface to sequence searching has changed and the MEROPS protein sequence libraries can be searched at the EMBL-EBI with HMMER, FastA and BLASTP. Cross-references have been established between MEROPS and the PANTHER database at both the family and protein-species level, which will help to improve curation and coverage between the resources. Because of the increasing size of the MEROPS sequence collection, in future only sequences of characterized proteins, and from completely sequenced genomes of organisms of evolutionary, medical or commercial significance will be added. As an example, peptidase homologues in four proteomes from the Asgard superphylum of Archaea have been identified and compared to other archaean, bacterial and eukaryote proteomes. This has given insights into the origins and evolution of peptidase families, including an expansion in the number of proteasome components in Asgard archaeotes and as organisms increase in complexity. Novel structures for proteasome complexes in archaea are postulated.
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Functions and mechanisms of non-histone protein acetylation

2018-11-22
Takeo Narita , Brian T. Weinert , Chunaram Choudhary

<sup>68</sup>Ga-FAPI PET/CT: Tracer Uptake in 28 Different Kinds of Cancer

2019-04-06
Clemens Kratochwil , Paul Flechsig , Thomas Lindner +7 more
The recent development of quinoline-based PET tracers that act as fibroblast-activation-protein inhibitors (FAPIs) demonstrated promising preclinical and clinical results. FAP is overexpressed by cancer-associated fibroblasts of several tumor entities. Here, … The recent development of quinoline-based PET tracers that act as fibroblast-activation-protein inhibitors (FAPIs) demonstrated promising preclinical and clinical results. FAP is overexpressed by cancer-associated fibroblasts of several tumor entities. Here, we quantify the tumor uptake on <sup>68</sup>Ga-FAPI PET/CT of various primary and metastatic tumors to identify the most promising indications for future application. <b>Methods:</b><sup>68</sup>Ga-FAPI PET/CT scans were requested by various referring physicians according to individual clinical indications that were considered insufficiently covered by <sup>18</sup>F-FDG PET/CT or other imaging modalities. All PET/CT was performed 1 h after injection of 122–312 MBq of <sup>68</sup>Ga-FAPI-04. We retrospectively identified 80 patients with histopathologically proven primary tumors or metastases or radiologically unequivocal metastatic lesions of histologically proven primary tumors. Tumor uptake was quantified by SUV<sub>max</sub> and SUV<sub>mean</sub> (60% isocontour). <b>Results:</b> Eighty patients with 28 different tumor entities (54 primary tumors and 229 metastases) were evaluated. The highest average SUV<sub>max</sub> (&gt;12) was found in sarcoma, esophageal, breast, cholangiocarcinoma, and lung cancer. The lowest <sup>68</sup>Ga-FAPI uptake (average SUV<sub>max</sub> &lt; 6) was observed in pheochromocytoma, renal cell, differentiated thyroid, adenoid cystic, and gastric cancer. The average SUV<sub>max</sub> of hepatocellular, colorectal, head–neck, ovarian, pancreatic, and prostate cancer was intermediate (SUV 6–12). SUV varied across and within all tumor entities. Because of low background in muscle and blood pool (SUV<sub>max</sub> &lt; 2), the tumor-to-background contrast ratios were more than 3-fold in the intermediate and more than 6-fold in the high-intensity uptake group. <b>Conclusion:</b> Several highly prevalent cancers presented with remarkably high uptake and image contrast on <sup>68</sup>Ga-FAPI PET/CT. The high and rather selective tumor uptake may open up new applications for noninvasive tumor characterization, staging examinations, or radioligand therapy.
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Human α1-proteinase inhibitor

1984-08-01
Hartmut Loebermann , R. Tokuoka , J. Deisenhofer +1 more

<i>MEROPS</i>: the database of proteolytic enzymes, their substrates and inhibitors

2013-10-23
Neil D. Rawlings , Matthew A. Waller , A. John Barrett +1 more
Peptidases, their substrates and inhibitors are of great relevance to biology, medicine and biotechnology. The MEROPS database (http://merops.sanger.ac.uk) aims to fulfill the need for an integrated source of information about … Peptidases, their substrates and inhibitors are of great relevance to biology, medicine and biotechnology. The MEROPS database (http://merops.sanger.ac.uk) aims to fulfill the need for an integrated source of information about these. The database has hierarchical classifications in which homologous sets of peptidases and protein inhibitors are grouped into protein species, which are grouped into families, which are in turn grouped into clans. Recent developments include the following. A community annotation project has been instigated in which acknowledged experts are invited to contribute summaries for peptidases. Software has been written to provide an Internet-based data entry form. Contributors are acknowledged on the relevant web page. A new display showing the intron/exon structures of eukaryote peptidase genes and the phasing of the junctions has been implemented. It is now possible to filter the list of peptidases from a completely sequenced bacterial genome for a particular strain of the organism. The MEROPS filing pipeline has been altered to circumvent the restrictions imposed on non-interactive blastp searches, and a HMMER search using specially generated alignments to maximize the distribution of organisms returned in the search results has been added.
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MEROPS: the peptidase database

1999-01-01
Neil D. Rawlings , A. John Barrett
The MEROPS database (http://www.bi.bbsrc.ac.uk/Merops/Merops.htm) provides a catalogue and structure-based classification of peptidases (i.e. all proteolytic enzymes). This is a large group of proteins (∼2% of all gene products) that is … The MEROPS database (http://www.bi.bbsrc.ac.uk/Merops/Merops.htm) provides a catalogue and structure-based classification of peptidases (i.e. all proteolytic enzymes). This is a large group of proteins (∼2% of all gene products) that is of particular importance in medicine and biotechnology. An index of the peptidases by name or synonym gives access to a set of files termed PepCards each of which provides information on a single peptidase. Each card file contains information on classification and nomenclature, and hypertext links to the relevant entries in online databases for human genetics, protein and nucleic acid sequence data and tertiary structure. Another index provides access to the PepCards by organism name so that the user can retrieve all known peptidases from a particular species. The peptidases are classified into families on the basis of statistically significant similarities between the protein sequences in the part termed the 'peptidase unit' that is most directly responsible for activity. Families that are thought to have common evolutionary origins and are known or expected to have similar tertiary folds are grouped into clans. The MEROPS database provides sets of files called FamCards and ClanCards describing the individual families and clans. Each FamCard document provides links to other databases for sequence motifs and secondary and tertiary structures, and shows the distribution of the family across the major kingdoms of living creatures. Release 3.03 of MEROPS contains 758 peptidases, 153 families and 22 clans. We suggest that the MEROPS database provides a model for a way in which a system of classification for a functional group of proteins can be developed and used as an organizational framework around which to assemble a variety of related information.
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MEROPS: the peptidase database

2009-11-05
Neil D. Rawlings , A. John Barrett , Alex Bateman
Peptidases, their substrates and inhibitors are of great relevance to biology, medicine and biotechnology. The MEROPS database (http://merops.sanger.ac.uk) aims to fulfil the need for an integrated source of information about … Peptidases, their substrates and inhibitors are of great relevance to biology, medicine and biotechnology. The MEROPS database (http://merops.sanger.ac.uk) aims to fulfil the need for an integrated source of information about these. The database has a hierarchical classification in which homologous sets of peptidases and protein inhibitors are grouped into protein species, which are grouped into families, which are in turn grouped into clans. The classification framework is used for attaching information at each level. An important focus of the database has become distinguishing one peptidase from another through identifying the specificity of the peptidase in terms of where it will cleave substrates and with which inhibitors it will interact. We have collected over 39 000 known cleavage sites in proteins, peptides and synthetic substrates. These allow us to display peptidase specificity and alignments of protein substrates to give an indication of how well a cleavage site is conserved, and thus its probable physiological relevance. While the number of new peptidase families and clans has only grown slowly the number of complete genomes has greatly increased. This has allowed us to add an analysis tool to the relevant species pages to show significant gains and losses of peptidase genes relative to related species.
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Dampak Mutasi HMPV pada Pasien Kanker : Scoping Review

2025-06-25
Shofi Marsya , Arvi Aliviani , Dian Tiranie +7 more | Jurnal Kesehatan Ilmiah Indonesia (Indonesian Health Scientific Journal)
Human Metapneumovirus (HMPV) adalah virus RNA dari keluarga Paramyxoviridae yang menyebabkan infeksi saluran pernapasan dan dapat mengalami mutasi, meningkatkan risiko penyakit serius. Penelitian ini bertujuan untuk menggambarkan dampak mutasi HMPV … Human Metapneumovirus (HMPV) adalah virus RNA dari keluarga Paramyxoviridae yang menyebabkan infeksi saluran pernapasan dan dapat mengalami mutasi, meningkatkan risiko penyakit serius. Penelitian ini bertujuan untuk menggambarkan dampak mutasi HMPV terhadap keparahan infeksi pada pasien kanker. Metode penelitian menggunakan scoping review dengan sumber data dari Google Scholar, PubMed, dan Semantic Scholar, menggunakan kata kunci mutasi HMPV, kanker, dan dampak. Kriteria inklusi mencakup artikel berbahasa Indonesia dan Inggris, pasien kritis, artikel full-text/open access, serta publikasi tahun 2015–2025 yang relevan dengan topik. Analisis dilakukan menggunakan diagram PRISMA untuk menyeleksi artikel yang sesuai. Hasil penelitian menunjukkan bahwa infeksi HMPV pada pasien kanker dapat memperburuk kondisi akibat penurunan sistem imun yang disebabkan oleh terapi kanker seperti kemoterapi atau transplantasi sel punca. Infeksi ini juga berisiko menimbulkan komplikasi serius, seperti pneumonia dan gagal napas, serta menghambat pengobatan kanker yang sedang berlangsung. Mengingat status imun yang terganggu, pasien kanker lebih rentan terhadap dampak mutasi virus ini. Oleh karena itu, penelitian lebih lanjut diperlukan untuk memahami konsekuensi klinis mutasi HMPV guna mengoptimalkan strategi pencegahan dan penanganan.

Combined Targeting of PD-1 and TIM-3 in Patients with Locally Advanced or Metastatic Melanoma: AMBER Cohorts 1c, 1e, and 2A

2025-06-24
Diwakar Davar , Zeynep Eroglu , Casilda Llácer Pérez +7 more | Clinical Cancer Research
The phase I, open-label, multicenter AMBER study (NCT02817633) is evaluating cobolimab, an anti-T-cell immunoglobulin and mucin-domain containing protein-3 humanized mAb, as a monotherapy and combination therapy in patients with solid … The phase I, open-label, multicenter AMBER study (NCT02817633) is evaluating cobolimab, an anti-T-cell immunoglobulin and mucin-domain containing protein-3 humanized mAb, as a monotherapy and combination therapy in patients with solid tumors. In this study, the safety and efficacy of cobolimab plus dostarlimab, a PD-1 inhibitor, in patients with locally advanced/metastatic melanoma who were either immunotherapy-naïve or had progressed on prior anti-PD-(L)1 therapy, are reported. Adults with adequate organ function and either immunotherapy-naïve (parts 1c/1e) or anti-PD-(L)1 relapsed or refractory (part 2A) melanoma were enrolled and received cobolimab 100, 300, or 900 mg and dostarlimab 500 mg every 3 weeks. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or death (whichever occurred sooner). Endpoints included safety, tolerability, overall response rate, and disease control rate. The current integrated analysis included 28 patients who received treatment in parts 1c/1e and 43 patients who received treatment in part 2A. Treatment-related serious adverse events were observed in 14.3% and 9.3% of patients in parts 1c/1e and 2A, respectively. The overall response rate (95% confidence interval) was 42.9% (24.5-62.8) and 4.7% (0.6-15.8) for patients in parts 1c/1e and 2A, respectively, and the disease control rate (95% confidence interval) was 53.6% (33.9-72.5; 1c/1e) and 20.9% (10.0-36.0; 2A). In this exploratory setting, cobolimab plus dostarlimab was well tolerated, with reported preliminary efficacy similar to other anti-T-cell immunoglobulin and mucin-domain containing protein-3 treatments in patients with locally advanced/metastatic melanoma. See related article by Davar et al., p. XX.

Combined Targeting of PD-1 and TIM-3 in Patients with Locally Advanced or Metastatic Non–Small Cell Lung Cancer: AMBER Part 2B

2025-06-24
Diwakar Davar , Zeynep Eroglu , Mohammed Milhem +7 more | Clinical Cancer Research
Treatment options for patients with non-small cell lung cancer (NSCLC) who have progressed on anti-PD-(L)1 treatment are lacking. In preclinical models, blockade of the inhibitory immune receptor T-cell immunoglobulin and … Treatment options for patients with non-small cell lung cancer (NSCLC) who have progressed on anti-PD-(L)1 treatment are lacking. In preclinical models, blockade of the inhibitory immune receptor T-cell immunoglobulin and mucin-domain containing protein 3 (TIM-3) is associated with an antitumor response. AMBER (NCT02817633) part 2B assessed the safety and efficacy of cobolimab, an anti-TIM-3 humanized monoclonal antibody, plus PD-1 inhibitor dostarlimab in patients with locally advanced or metastatic NSCLC who had progressed on anti-PD-(L)1 treatment. Adult patients with anti-PD-(L)-1 treated locally advanced or metastatic NSCLC were included. Patients received cobolimab 100, 300, or 900 mg and dostarlimab 500 mg every 3 weeks. Treatment continued until disease progression, unacceptable toxicity, patient withdrawal, investigator's decision, or death. Endpoints included overall response rate, disease control rate, and safety. Post hoc biomarker assessments of pretreatment tumor biopsies were also assessed. In total, 85 patients were enrolled and 84 received treatment. Treatment-emergent and treatment-related adverse events occurred in 98.8% and 52.4% of patients, respectively; no treatment-related deaths occurred. Across all three cobolimab doses, overall response rate was 8.3% (95% confidence interval, 3.4-16.4) and disease control rate was 21.4% (95% confidence interval, 13.2-31.7); both were highest in the 300 mg cohort (n = 41; 9.8% and 22.0%). Pretreatment TIM-3 expression was significantly greater in patients with partial or stable responses versus progressive disease. Cobolimab plus dostarlimab showed preliminary efficacy and tolerability in a subset of patients with locally advanced/metastatic NSCLC. See related article by Davar et al., p. XX.

AARS1 Serves as Prognostic Predictor and Implicates CD8+ T Cell Infiltration in Head and Neck Squamous Cell Carcinoma

2025-06-24
Zibin Tian | International Journal of Oral and Maxillofacial Surgery

Diagnostic Value of [18F]-FDG and [68 Ga]-FAPI-04 PET/MRI for Lymph Node Metastasis in Papillary Thyroid Cancer

2025-06-24
Tingting Han , Zhiyong Quan , Hongliang Wei +7 more | Molecular Imaging and Biology

Diagnosing Organ Involvement in Juvenile Systemic Sclerosis with<sup>68</sup>Ga-FAPI-46 PET/CT

2025-06-24
Tobias Krickau , Joachim Woelfle , Michael Beck +4 more | Journal of Nuclear Medicine Technology
We sought to assess the diagnostic value of 68Ga-fibroblast activation protein inhibitor (FAPI)-46 PET/CT for obtaining information on organ involvement in the process of inflammation and fibrosis in patients with … We sought to assess the diagnostic value of 68Ga-fibroblast activation protein inhibitor (FAPI)-46 PET/CT for obtaining information on organ involvement in the process of inflammation and fibrosis in patients with juvenile systemic sclerosis (jSSc). Methods: In this retrospective study, 4 children with a diagnosis of jSSc underwent 68Ga-FAPI-46 PET/CT imaging, 3 immediately after the diagnosis and before implementing immunmodulatory drugs and 1 a few years after active disease. Results: In this case series, 68Ga-FAPI-46 PET/CT detected all clinically known organ manifestations of jSSc. Additionally, this diagnostic tool provided previously unknown information about cardiac and muscular involvement in jSSc. Conclusion: 68Ga-FAPI-46 PET/CT provides valuable information to better assess disease activity and detect organ involvement. Further studies using 68Ga-FAPI-46 PET/CT in patients with jSSc are encouraged.

Preclinical and first-in-human of purinostat mesylate, a novel selective HDAC I/IIb inhibitor, in relapsed/refractory multiple myeloma and lymphoma

2025-06-23
Linyu Yang , Qiang Qiu , Jie Wang +7 more | Signal Transduction and Targeted Therapy
Abstract Simultaneously targeting key pathogenic drivers and remodeling of the tumor microenvironment represents a critical therapeutic strategy for relapsed or refractory (r/r) multiple myeloma (MM) and lymphoma. Purinostat mesylate (PM), … Abstract Simultaneously targeting key pathogenic drivers and remodeling of the tumor microenvironment represents a critical therapeutic strategy for relapsed or refractory (r/r) multiple myeloma (MM) and lymphoma. Purinostat mesylate (PM), a highly selective HDAC I/II binhibitor, exhibits excellent antitumor activity in MM and lymphoma cell lines and mouse models, outperforming the pan-HDAC inhibitor panobinostat or first-line/second-line multi-drug combinations. Different from panobinostat, bulk RNA-seq analysis revealed that PM suppressed essential tumor survival factors and triggered inflammation and interferon responses. The scRNA-seq of 5TMM models further indicated that PM enhanced antitumor immunity by boosting monocyte- and T cell-mediated immune responses. In a phase I trial (NCT05526313; N = 29) of PM at doses up to 15 mg/m², treatment-related Grade ≥3 adverse events predominantly comprised hematologic toxicities: thrombocytopenia (75.9%), neutropenia (55.2%), leukopenia (41.4%), and lymphopenia (31.0%), with no dose-limiting toxicities observed. PM monotherapy achieved a disease control rate of 72.7% (8/11) and an objective response rate (ORR) of 9.1% (1/11) in r/r MM. Notably, r/r lymphoma patients showed an ORR of 61.6% (11/18), particularly reaching 63.6% (7/11) with 6 complete responses in diffuse large B-cell lymphoma (DLBCL). Treatment responders exhibited enhanced immune activation, with elevated CD3 + CD8 + T cells and increased cytokine levels, such as IFN-γ and CXCL10. Overall, PM is safe and moderately effective in MM, but highly effective in lymphoma. Additionally, PM combined with pomalidomide and dexamethasone showed strong synergistic activity in r/r MM treatment. These findings support further open-label, multicenter phase Ib/IIa trials of PM combination therapy with immunomodulators for r/r MM, as well as phase II monotherapy trials for r/r DLBCL and r/r T-cell lymphoma.

Unraveling the Role of <scp>WDR91</scp>: Case Report of a Previously Unrecognized Clinical Entity

2025-06-23
Nikolaos M. Marinakis , Afrodite Kampouraki , Danai Veltra +7 more | Clinical Genetics
WDR91, a WD40 repeat domain-containing protein, is a key regulator of endosomal trafficking, lysosomal function, and autophagy. It acts as a Rab7 effector, forming a complex with WDR81 to modulate … WDR91, a WD40 repeat domain-containing protein, is a key regulator of endosomal trafficking, lysosomal function, and autophagy. It acts as a Rab7 effector, forming a complex with WDR81 to modulate phosphatidylinositol 3-kinase (PI3K) activity, endosomal maturation, and lysosome homeostasis. Loss-of-function variants in WDR91 are considered related to endosomal accumulation, impaired cargo degradation, and neurodegeneration. In this report, an autosomal recessive neurodevelopmental disorder is proposed, associated with WDR91 loss-of-function in a consanguineous family. The patient presented with severe microcephaly, dysmorphic features, and organomegaly, along with early onset psychomotor delay, hypotonia, sensorineural hearing impairment, and visual impairment. Whole-exome sequencing (WES) identified a homozygous splice site variant, NM_014149.4:c.1395+1G>A, predicted to disrupt the donor site and classified as likely pathogenic (PVS1, PM2). The variant was absent from population databases and our internal in-house cohort. Functional analysis supports a pathogenic role for the variant. WDR91 deficiency results in neuronal loss, cortical thinning, and impaired brain development, as evidenced in Wdr91 knockout models. Our study expands the clinical and genetic spectrum of WDR91-related disorders and highlights the need for further investigations to elucidate the precise molecular mechanisms underlying WDR91-associated pathogenesis.

Predictive value of [68Ga]Ga-FAPI-04 PET/CT on pathologic response to neoadjuvant chemoimmunotherapy for locally advanced resectable oral squamous cell carcinoma

2025-06-23
Yaqun Jiang , Zi‐Li Yu , Yanan Sun +6 more | European Journal of Nuclear Medicine and Molecular Imaging

Investigating Inflammation and Tissue Remodeling in ILD with [11C]NES and [68Ga]Ga-FAPI-46 PET Imaging

2025-06-22
Olivia Wegrzyniak , Emil Ekbom , Jens Ellingsen +7 more | medRxiv (Cold Spring Harbor Laboratory)
Interstitial lung diseases (ILDs) encompass a large number of conditions that affect the lungs, characterized by varying degrees of inflammation and fibrosis. Accurate diagnosis and monitoring of ILDs remain challenging … Interstitial lung diseases (ILDs) encompass a large number of conditions that affect the lungs, characterized by varying degrees of inflammation and fibrosis. Accurate diagnosis and monitoring of ILDs remain challenging due to the complex nature of ILDs and the limitations of conventional diagnostic methods such as high-resolution computed tomography and pulmonary function tests. Methods: Fourteen patients with different ILDs and four healthy controls underwent positron emission tomography (PET) imaging using [11C]NES followed by [68Ga]Ga-FAPI-46, to visualize and quantify neutrophil elastase and fibroblast activated protein in the lungs, respectively. On the same day of the PET examination, blood samples were collected from the participant to measure various immune biomarkers in order to compare between PET results, serum biomarker levels, and clinical observations. Results: Uptake of both radiotracers were higher in the lungs of ILD patients compared to healthy controls, with particularly strong uptake in regions showing CT features of fibrosis. [68Ga]Ga-FAPI-46 generally exhibited higher uptake than [11C]NES in these fibrotic areas. Despite the elevation of several immune biomarkers compared to healthy controls, no clear correlation was found between these biomarkers and PET imaging results. Conclusion: These preliminary results support the potential of [11C]NES and [68Ga]Ga-FAPI-46 PET/CT imaging as promising non-invasive methods for assessing neutrophil-mediated inflammation and tissue remodeling activity in the lungs of ILD patients.

Protein-based Radiopharmaceuticals that target fibroblast activation protein alpha: a review of current progress

2025-06-21
Abdelrahman Homedan , Darpan N. Pandya , Nicholas Schnicker +1 more | EJNMMI Radiopharmacy and Chemistry
Abstract Background Fibroblast activation protein alpha (FAP) is a serine protease that is expressed at basal levels in benign tissues but is overexpressed in a variety of pathologies, including cancer. … Abstract Background Fibroblast activation protein alpha (FAP) is a serine protease that is expressed at basal levels in benign tissues but is overexpressed in a variety of pathologies, including cancer. Consequently, significant research efforts have been expended to develop diagnostic radiopharmaceuticals and effective radiotherapies that target this protein. The aim of this review is to summarize the current progress on the development of protein-based radiopharmaceuticals that target FAP. Main body A literature survey spanning nearly 40 years was conducted to assess the historical development and current progress in protein-based radiopharmaceuticals that target FAP. To date, more than 20 publications have been introduced that describe these agents in preclinical and clinical settings. This review summarizes the development and evaluation of radiopharmaceuticals involving antibodies, antibody fragments, and single domain antibodies. Conclusion The results of this literature review demonstrate that while significant research efforts have been expended on peptide-based radiopharmaceuticals and small molecule FAP inhibitors, the development of protein-based radiopharmaceuticals that target FAP remains an active research area that has yet to reach its full potential.

[68Ga]FAPI PET/CT reveals increased pulmonary fibroblast activation protein expression in long COVID patients after ICU discharge

2025-06-21
Bram van Leer , Mark Londema , Ömer Kasalak +7 more | European Journal of Nuclear Medicine and Molecular Imaging
Abstract Purpose Post-acute sequelae of COVID-19 (PASC) has emerged as a major healthcare problem. A comprehensive mechanism of disease remains to be elucidated. In this study we aimed to explore … Abstract Purpose Post-acute sequelae of COVID-19 (PASC) has emerged as a major healthcare problem. A comprehensive mechanism of disease remains to be elucidated. In this study we aimed to explore pulmonary and muscle fibroblast activation protein (FAP) activity in former critical COVID-19 patients with persistent dyspnea, using [ 68 Ga]FAPI-46 PET/CT. Methods In this single center prospective observational study we included former critical COVID-19 patients reporting complaints of dyspnea &gt; 3 months after hospital discharge. A [ 68 Ga]FAPI PET/CT scan was performed including a high-resolution CT scan, lung function test, EQ-5D questionnaire, 6 min walking test and inflammatory markers. Age and sex-matched subjects, without pulmonary pathology, served as controls. The [ 68 Ga]FAPI uptake was corrected for lean body mass and the target-to-background ratio (TBR) was calculated. Results Eighteen PASC patients and 15 controls (median age 59 and 63 years and BMI of 34.6 and 25.2 kg/m 2 ) were included. The interval between hospital discharge and study visit was 30 months. Increased pulmonary FAP expression was observed in PASC, (TBR 0.79 ± 0.23) compared to controls (TBR 0.40 ± 0.13, P &lt; 0.001). Increased FAP expression was also observed in the paravertebral muscles (PASC: TBR 1.17 and controls TBR 1.00, P = 0.03). Forced expiratory volume and forced vital capacity showed moderate negative correlation with the pulmonary TBR, while the percentage of ground glass opacities showed a moderate positive correlation. Conclusion [ 68 Ga]FAPI PET/CT demonstrated elevated FAP expression in PASC. These findings provide insight into possible pathophysiological mechanisms of PASC and a potential new diagnostic modality.

Rapid and specific immunoPET imaging of Nectin-4 in gastric cancer and non-small cell lung cancer using [64Cu]Cu-NOTA-EV-F(ab’)2

2025-06-21
Wenpeng Huang , Xinyao Sun , Xiaoyan Li +7 more | European Journal of Nuclear Medicine and Molecular Imaging
Abstract Purpose This study aimed to develop and evaluate [ 64 Cu]Cu-NOTA-EV-F(ab’) 2 as a rapid and specific immunoPET imaging probe targeting Nectin-4 in gastric cancer (GC) and non-small cell … Abstract Purpose This study aimed to develop and evaluate [ 64 Cu]Cu-NOTA-EV-F(ab’) 2 as a rapid and specific immunoPET imaging probe targeting Nectin-4 in gastric cancer (GC) and non-small cell lung cancer (NSCLC). Materials and methods F(ab’) 2 fragments were generated from enfortumab vedotin (EV) using IdeS protease and conjugated with p -SCN-Bn-NOTA for radiolabeling with 64 CuCl 2 . The radiochemical yield was 85.40 ± 2.43% ( n = 5). In vitro binding affinity and specificity were assessed via flow cytometry and cell uptake assays using Nectin-4-positive (NCI-N87, H1975) and Nectin-4-low (HGC-27, H520) cell lines. In vivo PET imaging and biodistribution studies were conducted in murine models of GC and NSCLC to evaluate tumor targeting efficiency and tracer pharmacokinetics. Results [ 64 Cu]Cu-NOTA-EV-F(ab’) 2 demonstrated rapid tumor accumulation, with peak uptake observed at 4 h post-injection (10.23 ± 0.70%ID/g in NCI-N87 tumors, 3.03 ± 0.35%ID/g in HGC-27, 11.56 ± 1.12%ID/g in H1975, 2.77 ± 0.47%ID/g in H520). Compared to full-length EV, the tracer exhibited faster blood clearance and reduced off-target uptake. Blocking with excess EV-F(ab’) 2 significantly reduced subsequent tumor uptake (6.27 ± 0.49%ID/g in NCI-N87, P = 0.0029; 5.23 ± 0.31%ID/g in H1975, P = 0.00074), confirming Nectin-4 specificity. Ex vivo biodistribution analysis supported high tumor retention consistent with in vivo imaging findings. Conclusions [ 64 Cu]Cu-NOTA-EV-F(ab’) 2 offers rapid, specific, and high-contrast immunoPET imaging of Nectin-4-expressing tumors in GC and NSCLC models, highlighting its potential as a non-invasive diagnostic tool for Nectin-4-targeted cancer imaging.

Accurate de novo design of high-affinity protein-binding macrocycles using deep learning

2025-06-20
Stephen Rettie , David Juergens , Victor Adebomi +7 more | Nature Chemical Biology
Abstract Developing macrocyclic binders to therapeutic proteins typically relies on large-scale screening methods that are resource intensive and provide little control over binding mode. Despite progress in protein design, there … Abstract Developing macrocyclic binders to therapeutic proteins typically relies on large-scale screening methods that are resource intensive and provide little control over binding mode. Despite progress in protein design, there are currently no robust approaches for de novo design of protein-binding macrocycles. Here we introduce RFpeptides, a denoising diffusion-based pipeline for designing macrocyclic binders against protein targets of interest. We tested 20 or fewer designed macrocycles against each of four diverse proteins and obtained binders with medium to high affinity against all targets. For one of the targets, Rhombotarget A (RbtA), we designed a high-affinity binder ( K d &lt; 10 nM) despite starting from the predicted target structure. X-ray structures for macrocycle-bound myeloid cell leukemia 1, γ-aminobutyric acid type A receptor-associated protein and RbtA complexes match closely with the computational models, with a Cα root-mean-square deviation &lt; 1.5 Å to the design models. RFpeptides provides a framework for rapid and custom design of macrocyclic peptides for diagnostic and therapeutic applications.

Statement of Retraction: Dihydroartemisinin represses oral squamous cell carcinoma progression through downregulating mitochondrial calcium uniporter

2025-06-20
| Bioengineered

In Salmonella Typhimurium and Bacillus subtilis, Nucleoid-Associated HU Proteins Are N-Terminally Acetylated

2025-06-20
Anastacia R. Parks , J. Will , Liju G. Mathew +3 more | Pathogens
Here we report that the Salmonella Typhimurium NatB (SeNatB) protein N-terminal acetyltransferase acetylated the N-terminal methionine of the nucleoid-associated HU proteins. Our findings were supported by an in vitro analysis … Here we report that the Salmonella Typhimurium NatB (SeNatB) protein N-terminal acetyltransferase acetylated the N-terminal methionine of the nucleoid-associated HU proteins. Our findings were supported by an in vitro analysis of acetylation of the HUα and HUβ proteins and lysine-null (K-null) variants, and by an in vivo analysis of the effect of acetylation on HU-mediated transcriptional regulation of a known target of HU, the hilA promoter. SeNatB did not acetylate the initiating methionines of HU proteins that were oxidized to methionine sulfoxide, but the reduction of these methionine sulfoxide residues restored the acetylation of HU proteins by SeNatB. These results demonstrate that the SeHU proteins are bona fide substrates for the methionine sulfoxide reductases MsrA and MsrB. Finally, we showed that the Bacillus subtilis acetyltransferase, YfmK, is a functional homolog of SeNatB, and that BsYfmK acetylates the Nα amino group of the initiating methionine of the B. subtilis HU protein (HBsu).

Efficacy and safety of Sacituzumab govitecan in solid tumors: a systematic review and meta-analysis

2025-06-20
Ya‐Ping Zhang , Jian Chen , Xiaoyan Wang +4 more | Frontiers in Oncology
Background Sacituzumab govitecan (SG) is an antibody-drug conjugate (ADC) that targets trophoblast cell-surface antigen 2 and is conjugated to SN-38, a potent topoisomerase I inhibitor. SG has demonstrated promising activity … Background Sacituzumab govitecan (SG) is an antibody-drug conjugate (ADC) that targets trophoblast cell-surface antigen 2 and is conjugated to SN-38, a potent topoisomerase I inhibitor. SG has demonstrated promising activity against various solid tumors. However, comprehensive evaluations of its efficacy and safety remain limited, and outcomes across studies have shown inconsistency. This systematic review and meta-analysis aimed to assess the therapeutic efficacy and associated adverse events (AEs) of SG in the treatment of solid tumors. Methods A systematic search of PubMed, Embase, and the Cochrane Library was conducted to identify randomized controlled trials (RCTs) and single-arm studies published up to February 14, 2025. The primary outcomes included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related AEs. Results Five RCTs comparing SG with chemotherapy were included in the analysis. SG significantly improved OS (risk ratio [RR] = 0.720; 95% confidence interval [CI]: 0.587–0.882; P = 0.002), PFS (RR = 0.682; 95% CI: 0.516–0.901; P = 0.007), and DCR (RR = 1.286; 95% CI: 1.034–1.599; P = 0.024). However, higher incidences of neutropenia, leukopenia, diarrhea, and anemia were observed in the SG group. In the single-arm meta-analysis, 16 cohorts from five trials were included. The pooled ORR was 21% (95% CI: 16%–27%), DCR was 62% (95% CI: 56%–69%), and the clinical benefit rate was 33% (95% CI: 26%–39%). The median pooled PFS, duration of response, and OS were 4.41 months (95% CI: 3.61–5.22 months), 7.40 months (95% CI: 5.99–8.82 months), and 10.29 months (95% CI: 7.75–12.83 months), respectively. Conclusion Although SG demonstrates superior OS, PFS, and DCR compared to chemotherapy in patients with solid tumors, this benefit is accompanied by an increased risk of specific adverse events. Subgroup analyses indicate that SG confers a more substantial clinical benefit in breast and urothelial cancers than in other tumor types.

MYC-induced oncogenesis is dependent on acidic patches within its N-terminal intrinsically disordered domain.

2025-06-19
Víctor Llombart , David O’Connor , Jonas Demeulemeester +7 more | bioRxiv (Cold Spring Harbor Laboratory)
ABSTRACT MYC is one of the most enticing therapeutic targets for cancer but clinical-grade inhibitors are still lacking. By site-saturation mutagenesis screening, we identified several evolutionarily conserved acidic patches within … ABSTRACT MYC is one of the most enticing therapeutic targets for cancer but clinical-grade inhibitors are still lacking. By site-saturation mutagenesis screening, we identified several evolutionarily conserved acidic patches within the intrinsically-disordered MYC N-terminus that were confirmed to be functionally essential in different cell models and in vivo. Beyond modulating MYC’s global transcriptional activity, these negatively charged patches regulate the interaction with chromatin-modifying complexes including those with histone acetyl-transferase activity. One of the key interactions is established with the co-factor TRRAP, a subunit shared between several Histone Acetyl-Transferase complexes. The protein-protein binding between MYC and TRRAP predominantly relies on two of the N-terminal negative clusters that are located outside MYC-Box-II (MBII) and drive oncogenesis. Our work identifies a new multivalent MYC subdomain that presents new therapeutic vulnerabilities providing invaluable insights for the development of new therapeutic approaches.

Porto‐sinusoidal vascular disorder in a pediatric patient with prolidase deficiency: A case report

2025-06-19
Melissa Castro , Christian Hederich Martínez , Carole Brathwaite +3 more | JPGN Reports
Abstract Prolidase deficiency (PD) is a rare autosomal recessive disorder affecting collagen turnover, leading to diverse clinical manifestations including dermatologic lesions, hepatosplenomegaly, and vascular anomalies. Liver involvement in PD is … Abstract Prolidase deficiency (PD) is a rare autosomal recessive disorder affecting collagen turnover, leading to diverse clinical manifestations including dermatologic lesions, hepatosplenomegaly, and vascular anomalies. Liver involvement in PD is poorly understood, with few reported cases. We present a child with early‐onset non‐cirrhotic portal hypertension and PD. The patient initially presented with neonatal hemolytic anemia and hepatosplenomegaly. At age 9, recurrent epistaxis and splenomegaly led to splenectomy. Liver biopsy revealed sinusoidal dilation and parenchymal nodularity, later progressing to esophageal varices. Genetic testing identified pathogenic variants in peptidase‐D gene, suggestive of PD, and biochemical testing confirmed the diagnosis. Given suspected vasculopathy, tocilizumab was initiated with clinical improvement. This case suggests a potential link between PD and porto‐sinusoidal vascular disorder (PSVD), particularly nodular regenerative hyperplasia. Further research is needed to explore prolidase's role in vascular remodeling and its contribution to PSVD‐related liver pathology. Early recognition may improve management and outcomes.

Fibulin-4 is highly expressed in metastatic breast cancer and can serve as a target of peptide-based imaging probes and experimental therapeutics

2025-06-19
Alexes C. Daquinag , Solmaz AghaAmiri , Stephen M. Farmer +7 more | bioRxiv (Cold Spring Harbor Laboratory)
Abstract We have previously reported a cyclic peptide CRAGVGRGC (termed BLMP6) that homes to disseminating tumor cells in mouse cancer models and could be used for metastasis detection and intervention. … Abstract We have previously reported a cyclic peptide CRAGVGRGC (termed BLMP6) that homes to disseminating tumor cells in mouse cancer models and could be used for metastasis detection and intervention. Here, based on BLMP6 similarity to latent transforming growth factor beta binding protein 4 (LTBP4), we discovered fibulin-4 as a BLMP6 target. We show that BLMP6 mimics the LTBP4 domain binding to fibulin-4 and selectively binds to fibulin-4 in vitro. Fibulin-4 knockout in mouse 4T1 cancer cells abrogated BLMP6 homing to lung metastases. Fibulin-4 expression was found to be increased in invasive and metastatic human breast cancer. AZDye555 fluorophore-labeled BLMP6 was developed as a reagent selectively binding to invasive and metastatic human breast cancer cells in tissue sections and homing to MDA-MB-231 metastases in mice. We show that radiolabeling BLMP6 with 68 Ga can be used for the detection of MDA-MB-231 metastases. We designed a peptide-drug conjugate consisting of monomethyl auristatin E (MMAE) and BLMP6 that preferentially kills aggressive cancer cells. Cytotoxicity of MMAE-BLMP6 against MDA-MB-231 tumors was confirmed in vivo . In an immunocompetent mouse model of B16F10 experimental lung metastases, treatment with MMAE-BLMP6 suppressed metastasis growth and improved survival. There was also a trend for metastasis suppression and survival improvement in the MDA-MB-231 experimental metastasis model. Our results suggest that fibulin-4 and BLMP6 may be further developed for the detection and targeting of metastatic human cancers. Statement of significance This study identifies fibulin-4 as a protein highly expressed in breast cancer metastasis. It evaluates the application of peptide conjugates targeting fibulin-4 in mouse models as non-invasive probes for metastasis detection and cytotoxic drug delivery.

Development of Cysteic Acid-Modified FAP Radioligands for Enhanced Renal Clearance: From Preclinical Optimization to First-in-Human Study

2025-06-18
Simin Peng , Baoyuan Li , Mingming Sun +7 more | Journal of Medicinal Chemistry
Fibroblast activation protein (FAP)-targeting radioligands hold promise for cancer theranostics. Cyclic peptide-based DOTA-FAP-2286 radioligands have demonstrated high kidney uptake and retention, raising concerns regarding potential nephrotoxicity. Hence, we aimed to … Fibroblast activation protein (FAP)-targeting radioligands hold promise for cancer theranostics. Cyclic peptide-based DOTA-FAP-2286 radioligands have demonstrated high kidney uptake and retention, raising concerns regarding potential nephrotoxicity. Hence, we aimed to design three cysteic acid-modified FAP-targeting cyclic peptide ligands (DOTA-C1/C2/C3-FAP-2286) for reducing renal retention and optimizing pharmacokinetic properties. Competitive binding assays revealed maintained potent affinity for FAP (IC50 < 150 nM). Following systematic preclinical evaluation, [68Ga]Ga-C1-FAP-2286 exhibited optimal biodistribution characteristics, reducing renal uptake by 50% (2.12 ± 0.19% ID/g, P < 0.05), while maintaining tumor accumulation (7.08 ± 0.35 vs 6.26 ± 0.82% ID/g for [68Ga]Ga-FAP-2286), yielding a significantly improved tumor-to-kidney ratio (3.34 ± 0.15 vs 1.59 ± 0.53% ID/g). First-in-human PET/CT imaging in a metastatic gastric cancer patient demonstrated superior diagnostic performance compared to [18F]FDG, with intense uptake in primary lesions (SUVmax = 3.0), including [18F]FDG-negative and metastatic lesions. Thus, [68Ga]Ga-C1-FAP-2286 is a clinically translatable tracer for imaging FAP-expressing malignancies.

Study about fluostatins: efficient preparation of fluostatin A and discovery of fluostatin derivatives from Streptomyces sp. TA-3391

2025-06-18
Shigehiro Tohyama , Seiji Nukui , Masaki Hatano +3 more | The Journal of Antibiotics

Prognostic and Clinical Significance of MetAP2 Overexpression in Head and Neck Cancer

2025-06-18
Bhavna Kumar , Chandra Pandi , Vijayashree Priyadharsini Jayaseelan +1 more | Indian Journal of Otolaryngology and Head & Neck Surgery

Targeting fibroblast activation protein in rheumatoid arthritis: from molecular imaging to precision therapeutics

2025-06-18
Yupeng Huang , Yang Wu , Huan Liu +3 more | Frontiers in Immunology
Rheumatoid arthritis (RA), a chronic inflammatory disorder characterized by synovitis and joint destruction, remains a global health challenge. Activated fibroblast-like synoviocytes (FLS), which play a crucial role in the progression … Rheumatoid arthritis (RA), a chronic inflammatory disorder characterized by synovitis and joint destruction, remains a global health challenge. Activated fibroblast-like synoviocytes (FLS), which play a crucial role in the progression of RA, demonstrate tumor-like invasiveness and secrete inflammatory mediators. Fibroblast activation protein (FAP), a type II transmembrane serine protease, has been extensively studied in oncology for decades and has yielded significant clinical benefits. FAP is highly expressed in tumor-associated fibroblasts and plays a pivotal role in tumor growth, dissemination, and immune escape. In cancer imaging, small-molecule FAP inhibitor (FAPI) PET/CT has demonstrated superior sensitivity for detecting primary tumors and metastases. Additionally, FAP-targeted radionuclide therapy has emerged as a promising strategy for delivering precise radiation to tumors, while sparing healthy tissues. Beyond oncology, research on FAP in non-malignant diseases is rapidly advancing. In RA, FAP is overexpressed in RA-FLS but scarce in normal tissues. Thus, FAPI PET/CT can accurately visualize synovitis and monitor the treatment response in patients with RA. Similarly, FAP imaging is used to assess extra-articular manifestations, such as interstitial lung disease and cardiac fibrosis, by mapping fibroblast activity, offering a non-invasive tool. Moreover, emerging therapies, such as FAP-targeted photodynamic therapy, selectively eliminate pathogenic cells in RA models, highlighting their therapeutic potential. This review highlights the advances in FAP-targeted imaging for RA, specifically focusing on FAP as a key biomarker for diagnosis, disease evaluation, and potential therapeutic use in RA.

Biodistribution and Radiation Dosimetry for [<sup>68</sup>Ga]Ga-LNTH-1363S, a Probe Targeting Fibroblast Activation Protein α

2025-06-18
Johanna S. Enke , Bradley W. Schuller , Lisa Glantschnig +7 more | Journal of Nuclear Medicine
The objective of this study is to evaluate the PET biodistribution and radiation dosimetry of the fibroblast activation protein (FAP)-targeted tracer [68Ga]Ga-LNTH-1363S in cancer patients. Methods: Five patients with oncologic … The objective of this study is to evaluate the PET biodistribution and radiation dosimetry of the fibroblast activation protein (FAP)-targeted tracer [68Ga]Ga-LNTH-1363S in cancer patients. Methods: Five patients with oncologic diseases (breast cancer, papillary thyroid carcinoma) were injected intravenously with 153-184 MBq of [68Ga]Ga-LNTH-1363S. PET/CT imaging was performed at 10, 60, and 180 min after administration of [68Ga]Ga-LNTH-1363S. Normal tissue dosimetry was performed following the MIRD dosimetry formalism. SUV analysis of normal tissues and tumors was performed. Results: The biodistribution of [68Ga]Ga-LNTH-1363S demonstrated rapid tumor uptake and efficient clearance from nontarget tissues, resulting in high tumor-to-background ratios at all imaging time points. The kidneys received the highest absorbed dose among normal tissues (0.038 ± 0.01 mGy/MBq), followed by the pancreas and salivary glands. The tumor SUVmax peaked at 10 min after injection (18.6 ± 7.2) and remained high at later time points. No adverse events were observed during follow-up, and the effective dose (0.013 ± 0.002 mSv/MBq) was consistent with other FAP tracers. Conclusion: [68Ga]Ga-LNTH-1363S offers favorable dosimetry and biodistribution profiles, comparable with other FAP-targeted tracers.

Clinical Pathological Significance and Biological Function of APIP in Hepatocellular Carcinoma

2025-06-18
Cong Yu , Jianghua Huang , Rui Zhang +2 more | Research Square (Research Square)
<title>Abstract</title> <bold>Background &amp; aims</bold> With a high incidence and fatality rate, hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors in the world. In addition to examining its … <title>Abstract</title> <bold>Background &amp; aims</bold> With a high incidence and fatality rate, hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors in the world. In addition to examining its clinical pathogenic importance in HCC, our goal is to study the expression of Apaf-1-interacting protein(<italic>APIP)</italic> in HCC and investigate its effects on the biological functions of HCC cells and the underlying mechanisms. <bold>Methods</bold> To determine the expression level and clinical significance of <italic>APIP</italic> in HCC, we employed internal tissue samples for Real-time quantitative polymerase chain reaction,(RT-qPCR) and immunohistochemistry(IHC) procedures. In order to verify the findings, we obtained external datasets. We investigated the upstream regulatory transcription factors of <italic>APIP</italic> and talked about the molecular mechanism of the biological role of <italic>APIP</italic> in HCC through experiments on cell proliferation, cell cycle, and cell apoptosis as well as scratch and transwell assays to assess the effects of <italic>APIP</italic> on the proliferation, apoptosis, migration, and invasion capabilities of HCC cells. <bold>Results</bold> We discovered that HCC tissues exhibited higher levels of <italic>APIP</italic> expression than nearby non-tumor tissues, and that <italic>APIP</italic> could differentiate HCC from healthy liver tissues. Additionally, the age, gender, and poor prognosis of individuals with HCC were linked to <italic>APIP </italic>expression. In the meantime, down regulating <italic>APIP</italic> may encourage HCC cells to undergo apoptosis and prevent their growth, migration, and invasion. Furthermore, the transcription factor Serum response factor(SRF) and <italic>APIP</italic> may have a regulatory connection. <bold>conclusion</bold> By influencing the proliferation, apoptosis, migration, and invasion of HCC cells, <italic>APIP </italic>plays a significant role in the formation and progression of HCC and may provide a novel therapeutic target.

99mTc-FAPI-46 Scintigraphy in Genital Tract Carcinosarcoma

2025-06-17
Nasrin Raeisi , Amin Saber Tanha , Kamran Aryana +2 more | Clinical Nuclear Medicine
A 47-year-old woman presenting with abdominal pain and constipation was diagnosed with high-grade mucinous adenocarcinoma of the genital tract after undergoing extensive surgery. Six months after adjuvant chemotherapy, she developed … A 47-year-old woman presenting with abdominal pain and constipation was diagnosed with high-grade mucinous adenocarcinoma of the genital tract after undergoing extensive surgery. Six months after adjuvant chemotherapy, she developed recurrent symptoms and a large pelvic mass, leading to cytoreductive surgery, which histopathologic evaluation revealed carcinosarcoma. Postsurgery, 99m Tc-FAPI-46 scintigraphy indicated heterogeneous uptake in the tumoral masses and diffuse uptake in peritoneal carcinomatosis, which was not detected on contrast-enhanced CT (CeCT) scan. This case demonstrates the superior diagnostic performance of FAPI-targeted imaging over CeCT in assessing tumor extent in genital tract carcinosarcoma and suggests 177 Lu-FAPI as a potential therapeutic approach.

68Ga-FAPI-04 PET Differentiates Benign From Malignant in a Patient With 18F-FDG-Avid Colon Lesion

2025-06-17
Na Qi , Haiyan Wang , Jie Ding +2 more | Clinical Nuclear Medicine
Lesions exhibiting heightened 18 F-FDG uptake in colorectal PET scans may be indicative of either benign or malignant processes, thus necessitating gastroscopic biopsy or pathologic assessment for diagnostic clarification. Herein, … Lesions exhibiting heightened 18 F-FDG uptake in colorectal PET scans may be indicative of either benign or malignant processes, thus necessitating gastroscopic biopsy or pathologic assessment for diagnostic clarification. Herein, we reported intense 18 F-FDG uptake but negative 68 Ga-FAPI-04 PET uptake in a 65-year-old man with sigmoid colon tubular adenoma. This case underscores the utility of FAPI PET in preoperatively discerning between colorectal carcinoma and adenoma, potentially influencing treatment strategies.

Discovery of APH02174 as a Highly Selective and Orally Bioavailable IRAK4 Degrader for the Treatment of Inflammatory Diseases

2025-06-17
Xi‐Wei Wu , Zhaomin Chen , Cui Gao +7 more | Journal of Medicinal Chemistry
Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role as a key regulator in systemic inflammatory diseases, acting as a central mediator in the downstream signaling cascades of Toll-like receptors … Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role as a key regulator in systemic inflammatory diseases, acting as a central mediator in the downstream signaling cascades of Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs). Herein, we describe the design and synthesis of novel IRAK4 degraders based on a proteolysis-targeting chimera (PROTAC) strategy. Twenty-one PROTACs 3-5, 7-14, 22, 30-36 and 39 showed strong IRAK4 degradation (DC50 < 5 nM and Dmax > 85%), APH02174 (36) was identified as the lead compound exhibiting highly selective IRAK4 degradation in vitro and in vivo, along with favorable drug metabolism and oral pharmacokinetic properties. Further studies indicated that APH02174 demonstrated significant therapeutic efficacy by effectively alleviating imiquimod-induced psoriasis-like skin inflammation and antiarthritic activity in mouse models. These results highlight the potential of APH02174 as a highly selective and orally bioavailable IRAK4 PROTAC degrader in the treatment of inflammatory diseases mediated by IRAK4 signaling.

The MUC5B promoter variant results in proteomic changes in the non-fibrotic lung

2025-06-17
Jeremy Herrera , Mark Maslanka , Rachel Z. Blumhagen +7 more | JCI Insight
The gain-of-function MUC5B promoter variant is the dominant risk factor for the development of idiopathic pulmonary fibrosis (IPF). However, its impact on protein expression in both non-fibrotic control and IPF … The gain-of-function MUC5B promoter variant is the dominant risk factor for the development of idiopathic pulmonary fibrosis (IPF). However, its impact on protein expression in both non-fibrotic control and IPF lung specimens have not been well characterized. Utilizing laser capture microdissection coupled to mass spectrometry (LCM-MS), we investigated the proteomic profiles of airway and alveolar epithelium in non-fibrotic controls (n = 12) and IPF specimens (n = 12), stratified by the MUC5B promoter variant. Through qualitative and quantitative analyses, as well as pathway analysis and immunohistological validation, we have identified a distinct MUC5B-associated protein profile. Notably, the non-fibrotic control alveoli exhibited substantial MUC5B-associated protein changes, with an increase of IL-3 signaling. Additionally, we found that epithelial cells overlying IPF fibroblastic foci cluster closely to alveolar epithelia and express proteins associated with cellular stress pathways. In conclusion, our findings suggest that the MUC5B promoter variant leads to protein changes in alveolar and airway epithelium that appears to be associated with initiation and progression of lung fibrosis.

Added value of dual-phase 99mTc-HYNIC-FAPI-04 SPECT/CT in postoperative follow-up of colorectal cancer

2025-06-16
Donghua Sun , Yan Liu , Rui Hou +3 more | Frontiers in Oncology
Objective To assess the added value of dual-phase 99m Tc-HYNIC-FAPI-04 single-photon emission computed tomography/computed tomography (SPECT/CT) compared with single-phase imaging in postoperative follow-up of colorectal cancer (CRC). Methods Early and … Objective To assess the added value of dual-phase 99m Tc-HYNIC-FAPI-04 single-photon emission computed tomography/computed tomography (SPECT/CT) compared with single-phase imaging in postoperative follow-up of colorectal cancer (CRC). Methods Early and delayed 99m Tc-HYNIC-FAPI-04 SPECT/CT imaging were undertaken in 21 patients with CRC after surgery. The mean radioactivity count of the lesion site and abdominal aorta in secondary imaging was delineated and measured. The early and delayed target background ratio (TBR) and retention index (RI) were calculated, respectively. The results of biopsy or postoperative pathology, clinical and imaging follow-up were used as the “gold standard” of tumor metastasis. Lesions were divided into “benign” and “malignant” groups. The uptake rate and metabolic rate of 99m Tc-HYNIC-FAPI-04 in the two groups were observed. The diagnostic efficiency of early imaging, delayed imaging, and their combination for prediction of benign and malignant lesions was compared using receiver operating characteristic (ROC) curves. Results Fifty-five lesions with abnormal uptake of 99m Tc-HYNIC-FAPI-04 were found by SPECT/CT. Compared with TBR-early, TBR-delayed in malignant group was increased (4.07 ± 1.65 vs . 4.36 ± 1.86, P = 0.040), whereas TBR-delayed in the benign group was decreased significantly (2.96 ± 0.85 vs . 2.66 ± 0.77, P &amp;lt; 0.001). The mean count of radioactivity in the delayed phase, TBR-early, TBR-delayed, and RI in the malignant group were higher than those in the benign group ( P = 0.005, &amp;lt;0.001, and &amp;lt;0.001, respectively). ROC curves showed that combined application of TBR-early, TBR-delayed, and RI had an AUC of 0.889, specificity of 0.900, and sensitivity of 0.844, and its diagnostic efficiency was superior to that of TBR-delayed ( P = 0.026) and TBR-early ( P &amp;lt; 0.001). Conclusions Dual-phase 99m Tc-HYNIC-FAPI-04 SPECT/CT could be used for the detection of metastatic lesions after CRC surgery. It has a higher auxiliary role than single-phase imaging for the differential diagnosis of benign and malignant lesions after CRC surgery.

Loss of PDE10A is associated with metastasis of colon adenocarcinoma.

2025-06-16
Sumaita Arowa , Nicholas Nuechterlein , Vinny Ha +6 more | PubMed
Phosphodiesterase 10A (PDE10A), located on cytoband 6q27, acts as a haploinsufficient tumor suppressor in glioblastoma, where its loss drives aggressive tumor behavior and is associated with a proneural-to-mesenchymal (PN-MES) shift. … Phosphodiesterase 10A (PDE10A), located on cytoband 6q27, acts as a haploinsufficient tumor suppressor in glioblastoma, where its loss drives aggressive tumor behavior and is associated with a proneural-to-mesenchymal (PN-MES) shift. Leveraging bioinformatic analyses of The Cancer Genome Atlas (TCGA) pan-cancer dataset, we identified gastrointestinal carcinomas, specifically stomach adenocarcinoma and colon adenocarcinoma, as cancers where 6q27/PDE10A loss is prognostic. In both stomach adenocarcinoma and colon adenocarcinoma, PDE10A loss was associated with reduced overall survival (OS) and progression-free survival (PFS). Additionally, PDE10A loss correlated with increased lymphatic invasion and higher AJCC pathologic nodal stage in colon adenocarcinoma. In an independent institutional cohort, immunohistochemical analysis showed lower PDE10A expression in metastatic colon adenocarcinomas compared to primary tumors. Furthermore, PDE10A loss and decreased protein expression corresponded with an epithelial-to-mesenchymal transition (EMT) phenotype in both cohorts, consistent with the known PN-MES shift observed in glioblastoma. In summary, PDE10A loss in colon adenocarcinoma is associated with decreased OS and PFS, more frequent lymphatic invasion, higher pathologic nodal stage, metastatic disease, and an EMT phenotype.

Dipeptidyl peptidase‐4 in the tumor microenvironment of the digestive system: Molecular mechanisms and therapeutic targets

2025-06-16
Jingting Wang , Lei Zhao , Duo Yun +3 more | International Journal of Cancer
Abstract Digestive system cancers represent nearly half of all global cancer cases and are associated with high mortality rates. Although immunotherapy has ushered in a new era for the treatment … Abstract Digestive system cancers represent nearly half of all global cancer cases and are associated with high mortality rates. Although immunotherapy has ushered in a new era for the treatment of digestive system cancers, the complexity and diversity of the immunosuppressive tumor microenvironment (TME) pose significant challenges to effective immunotherapy for digestive tumors. Dipeptidyl peptidase 4 (DPP4), also known as CD26, has garnered considerable attention for its role within the TME, where it plays a crucial role in the initiation and progression of digestive system cancers and serves as a predictive biomarker for certain cancers. Additionally, it is involved in regulating immune responses, angiogenesis, ferroptosis activation, tumor‐associated inflammation, neurotransmission, and metastasis. Thus, DPP4 inhibitors play a pivotal role in modulating the intricate tumor ecosystem, contributing to the control of digestive system cancer development. Therefore, a deeper understanding of DPP4's mechanisms in the TME holds promise for establishing essential theoretical frameworks for developing novel treatment strategies for digestive system cancers. This review explores the regulatory role of DPP4 in the TME of digestive system cancers and its clinical implications, aiming to provide insights into potential advancements in oncological therapies.

Design, Structure Optimization, and Preclinical Evaluation of <sup>188</sup>Re-Labeled FAPI for Targeted Radionuclide Therapy

2025-06-16
Mengxin Xu , Hanbo Song , Jie Cai +7 more | Journal of Medicinal Chemistry
Rhenium-188 (188Re) is a promising theranostic radionuclide due to its cost-effectiveness, therapeutic β- emissions, and SPECT-compatible γ rays. However, Re's complex coordination chemistry challenges stable bifunctional chelator development. Despite sharing … Rhenium-188 (188Re) is a promising theranostic radionuclide due to its cost-effectiveness, therapeutic β- emissions, and SPECT-compatible γ rays. However, Re's complex coordination chemistry challenges stable bifunctional chelator development. Despite sharing Group 7 traits with technetium, substituting 99mTc with 188Re is hindered by ReO4-'s lower reducibility. In this study, we designed, synthesized, and systematically evaluated four triamidomonothiol (N3S) tetradentate donor type related radiotracers: 188Re-labeled MAS3-FAPI, MAS3-DOTA-FAPI, MAE3-FAPI, and MAE3-DOTA-FAPI. All the radiotracers exhibited efficient radiolabeling with yields exceeding 80%. MAE3-based chelators demonstrated good stability (RCP >90% at 6 h). In vitro studies also confirmed the FAP-specific binding. In vivo performance through SPECT/CT imaging and biodistribution studies in HT1080-FAP xenografts revealed distinct pharmacokinetic profiles: DOTA-modified tracers (MAS3-DOTA-FAPI and MAE3-DOTA-FAPI) showed enhanced tumor uptake and prolonged retention with significantly reduced hepatic/intestinal accumulation. Notably, [188Re]Re-MAE3-DOTA-FAPI achieved high tumor specificity, sustained intralesional retention, and potent therapeutic efficacy, underscoring strong potential for clinical translation.

Disruption of oncogenic MCL-1-BAX/BAK interaction using integrase inhibitors: insights from a molecular docking and dynamic exploration

2025-06-15
Lateef O. Anifowose , Fikayo N. Adegboyega , Oludare M. Ogunyemi +4 more | Discover Chemistry.

Targeted inhibition of Ninjurin2 promotes chemosensitivity in chemoresistant gastric cancer by suppressing cancer-initiating cells

2025-06-15
Hyo Shik Shin , Jae-Il Choi , Hye Won Chung +4 more | Biomarker Research

Assessing the Suitability of Deubiquitylases As Substrates For Targeted Protein Degradation

2025-06-14
Joel Tong , J. Watkins , James M. Burke +1 more | bioRxiv (Cold Spring Harbor Laboratory)
The development of selective inhibitors of Deubiquitylase enzymes (DUBs) is difficult due to a high level of homology in the active sites of the ≈ 100 such enzymes in the … The development of selective inhibitors of Deubiquitylase enzymes (DUBs) is difficult due to a high level of homology in the active sites of the ≈ 100 such enzymes in the human proteome. A potentially attractive strategy to achieve this goal would be to develop PROTACs or molecular glues that engage the target DUB in a less conserved region outside of the catalytic domain. However, this raises the concern that auto-deubiquitylation would make DUBs poor substrates for this modality. Here we describe a chemical genetics system to evaluate this issue. We find that some Dubs are readily degradable via the Ubiquitin-proteasome pathway and some are not. Of the latter category, some resist turnover through auto-deubiquitylation and some are simply poor proteasome substrates.

Correction: Development and validation of an ARID1A-related immune genes risk model in evaluating prognosis and immune therapeutic efficacy for gastric cancer patients: a translational study

2025-06-13
Jiangtao Zhang , Jingting Li , Shangfeng Yang +7 more | Frontiers in Immunology

861-P: Targeting Activin Type II Receptors—Develop Monoclonal Antibodies LAE102, LAE103, and LAE123 as Candidate Therapeutics for Muscle Growth and Fat Reduction

2025-06-13
R Zhang , Mengxue Yang , Jianxin Gu +6 more | Diabetes
Introduction and Objective: Ligands of the TGF-β superfamily including myostatin, activins, and GDFs, are known to negatively regulate skeletal muscle mass and lipolysis via Activin Type II receptors (ActRII) signaling. … Introduction and Objective: Ligands of the TGF-β superfamily including myostatin, activins, and GDFs, are known to negatively regulate skeletal muscle mass and lipolysis via Activin Type II receptors (ActRII) signaling. This study aims to investigate the effects of ActRII receptor antagonist antibodies on promoting muscle growth and fat reduction. Methods: We have developed three monoclonal antibodies: LAE102, specific to ActRIIA; LAE103, specific to ActRIIB; and LAE123, bi-specific to both ActRIIA and ActRIIB. The roles of ActRIIA and ActRIIB signaling in skeletal muscle and adipose tissue are being investigated using cell-based functional assays, lean mouse, and diet-induced obesity mouse models. Results: LAE102, LAE103, and LAE123 are high-affinity functional antagonists. They can completely inhibit the signaling transduced by ligands such as activin A, B, AB, and myostatin, all of which are known to contribute to muscle atrophy. In addition, they also inhibit activin E and GDF3, which promote lipid accumulation. In mouse models, LAE102 alone significantly induced muscle growth and reduced fat mass, while LAE103 had much less effect. Notably, a synergistic effect on muscle increase and fat loss was observed when combining LAE102 with LAE103, achieving the maximal effect comparable to the bi-specific antibody LAE123. Conclusion: The findings indicate that ActRIIA is a major regulator of muscle growth and fat loss. LAE102 shows great potential as muscle preserving weight loss management with a favorable safety profile. On the other hand, LAE123 could be utilized to treat diseases requiring completely inhibition of both ActRIIA and ActRIIB, such as spinal muscle atrophy. Disclosure R. Zhang: None. M. Yang: None. J. Gu: None. M. Hu: None. J. Chen: None. W.A. Li: None. L. Xiaofen: None. X. Zhang: None. C. Lu: None.

Abstract P3-04-28: Inhibition of FASN and ACC1 as a Potential Treatment for Advanced Endocrine Therapy-Resistant Breast Cancer

2025-06-13
Henriette Balinda , Avani Gunuganti , Avani Sinha +4 more | Clinical Cancer Research
Abstract Introduction: Over the past decade, there have been substantial advancements in improving survival rates for estrogen receptor alpha (ERα) positive breast cancer. Treatments such as selective estrogen receptor down-regulators … Abstract Introduction: Over the past decade, there have been substantial advancements in improving survival rates for estrogen receptor alpha (ERα) positive breast cancer. Treatments such as selective estrogen receptor down-regulators and modulators (SERMs) like fulvestrant and tamoxifen, mTOR inhibitors like everolimus, aromatase inhibitors (AIs), and cyclin-dependent kinase inhibitors such as palbociclib, ribociclib, and abemaciclib have all contributed to extending the overall survival of breast cancer patients. Unfortunately, resistance to endocrine therapy is a common occurrence and all patients will eventually succumb to their disease. Metabolic rewiring is a biological hallmark of all cancers, yet there are currently no therapies that specifically target cancer metabolism. Fatty acid synthase (FASN) is a key enzyme in lipid metabolism and is overexpressed in more aggressive and therapy-resistant tumors, including breast cancers. FASN inhibitor, TVB-2640, has been evaluated in multiple tumor cell lines and in a phase 1 clinical study, and showed partial responses in 5 patients and multiple patients with prolonged stable disease (≥16 weeks). Acetyl-CoA-carboxylase-1 (ACC1/ACACA) is an enzyme that functions upstream of FASN to provide malonyl-CoA, a rate-limiting step in de novo long-chain fatty acid synthesis and is overexpressed in cancer. Previously, we showed that FASN inhibition in tamoxifen-resistant cells leads to inhibition of proliferation and reduced tumor growth through induction of endoplasmic reticulum stress. We therefore assessed the effects of FASN and ACC1 inhibition in fulvestrant- and palbociclib-resistant breast cancer. Methods: We generated fulvestrant-resistant MCF7 cells by long term exposure to fulvestrant (MCF7/FR cells), and palbociclib-resistant (MCF7/RB1Crispr and ZR75/RB1Crispr) cells were generated through CRISPR/Cas9 knockout of the retinoblastoma (RB) gene. We assessed the impact of FASN inhibitor, TVB-3166, (and analog of TVB-2640 with slightly lower molecular weight for in vitro use), and ACC1 inhibitor, PF05175157 on proliferation, viability, cell cycle, and apoptosis in these cells, and tumor growth in xenografts. RNA sequencing of fulvestrant-, and palbociclib-resistant cells was performed to investigate gene expression. Unfolded protein response signaling protein levels were analyzed by western blotting after treatment with TVB and PF05175157. Results: Inhibition of FASN and ACC1 lead to a marked inhibition of proliferation in fulvestrant- and palbociclib-resistant cells compared to the parental cells. However, inhibiting both FASN and ACC1 did not appear to produce an additive effect in these cell lines. TVB increased cells in the G1 phase, whereas PF05175157 increased the number of cells in the S-phase in fulvestrant-resistant cells. Both TVB and PF05175157 increased the number of apoptotic cells in fulvestrant- and palbociclib-resistant cells. RNA sequencing of fulvestrant-resistant and palbociclib-resistant cells showed that treatment with TVB results in alteration in unfolded protein response (UPR) pathway. Additionally, TVB and PF05175157 significantly inhibited tumor growth in mice to untreated controls. Conclusion: Our preclinical data provide evidence that FASN inhibition by TVB-3166 or ACC1 inhibition by PF057175157 present promising therapeutic strategies for treatment of endocrine-resistant breast cancer. Further clinical development of FASN and ACC1 inhibitors for endocrine resistant breast cancer should be considered. Citation Format: Henriette Balinda, Avani Gunuganti, Asmita Sinha, Suryavathi Viswanadhapalli, Gangadhara Sareddy, Ratna Vadlamudi, Andrew Brenner. Inhibition of FASN and ACC1 as a Potential Treatment for Advanced Endocrine Therapy-Resistant Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-04-28.

Abstract P2-10-28: COMPASS-TNBC - A phase Ib/II, open-label, modular, dose-finding and dose-expansion study to explore safety and anti-tumor activity of novel therapeutics in patients with early relapsed mTNBC. Module 1: Dato-DXd &amp; Module 2: Dato-DXd + durvalumab

2025-06-13
Thomas Grinda , Rasha Cheikh-Hussin , Magali Lacroix‐Triki +7 more | Clinical Cancer Research
Abstract Background: Approximately half of all patients (pts) who develop metastatic triple negative breast cancer (mTNBC) after standard neo/adjuvant systemic treatment (NAST) experience a relapse occurring during or within 12 … Abstract Background: Approximately half of all patients (pts) who develop metastatic triple negative breast cancer (mTNBC) after standard neo/adjuvant systemic treatment (NAST) experience a relapse occurring during or within 12 months following the completion of curative treatments, defined as early relapse. Early relapsed mTNBC is a distinct aggressive entity, often resistant to standard therapies and with a poor prognosis (median overall survival, [OS] &amp;lt; 10 months). Given the limited effectiveness of currently available options, new treatment strategies are hardly awaited in this situation. COMPASS-TNBC has been co-designed with a patients’ association and wishes to broaden inclusion criteria to meet the important medical need in this situation. It assesses the efficacy of new treatment strategies and conducts translational analyses across different modules, in patients with early relapse mTNBC. The first 2 phase II modules are: Module 1 - Datopotamab deruxtecan (Dato-DXd, an anti-TROP2 antibody-drug conjugate (ADC) with a cleavable linker, and a topoisomerase I inhibitory payload) as monotherapy; Module 2 - Dato-DXd + durvalumab, an anti–PD-L1 monoclonal antibody (mAb). Methods: Eligible pts are aged ≥18 years, have untreated unresectable or metastatic TNBC (ER and PR &amp;lt; 10%, HER2 non 3+ and non-amplified), have received NAST at the localized stage and have radiological (RECIST) and histological evidence of early relapse (≤12 months from the end of curative treatments). Pts must have an ECOG PS of 0-2, adequate organ function, and ≥1 nonirradiated measurable lesion. Stable CNS metastases (including leptomeningeal disease) are allowed. Pts are excluded if they have clinically significant corneal disease, a history of interstitial lung disease/pneumonitis, active immune disease, or prior treatment with an anti-TROP2-ADC. Pts are randomized in a 1:1 ratio to receive either Dato-DXd (6 mg/kg) (Module 1) or Dato-DXd (6 mg/kg) combined with durvalumab (1120 mg) (Module 2), both administered intravenously every 3 weeks until disease progression or unacceptable toxicity. Each arm will include 25 pts and is designed using the Bayesian optimal phase 2 (BOP2) design. An intermediate analysis will be performed after 12 pts in each module. The primary endpoint is the objective response rate (ORR) at six months, determined and assessed every six weeks using RECIST v1.1 by the investigator. Secondary endpoints include investigator-assessed duration of response (DOR), progression-free survival (PFS), clinical benefit rate (CBR), OS, safety, patient-reported outcomes (EORTC QLQ-C30 and QLQ-BR45), and treatment-emergent antidrug antibodies (ADA). Tumor and blood samples are longitudinally collected at baseline, on treatment (C1D3 or C2D3), and at the end of treatment. Planned exploratory analyses include treatment-specific biomarkers/mechanisms of response and resistance using high-throughput imaging mass cytometry, RNA sequencing, and whole exome sequencing, on tumor samples, circulating tumor DNA (ctDNA), and circulating tumor cells (CTCs). Additionally, patient-derived organoids will be generated to test and develop novel treatment strategies. In modules 1 and 2, saliva and mouth swab will also longitudinally collected to determine predictors of oral mucositis in patients treated with Dato-DXd. Study enrollment started in June 2024 and is currently ongoing. Clinical trial information: EU CT Number: 2023-503606-36-00 Citation Format: Thomas Grinda, Rasha Cheikh-Hussin, Magali Lacroix-Triki, Kamar Serhal, Chayma Bousrih, Elie Rassy, Francoise Farace, Marianne Oulhen, Jean-Luc Perfettini, Awatef Allouch, Guillaume Montagnac, Fernanda Mosele, Ines Vaz-Luis, Joana M Ribeiro, Alessandro Viansone, Benjamin Verret, Suzette Delaloge, Jacqueline Deneuve, Claude Coutier, Juliette Gouenard, Fabrice André, Stefan Michiels, Barbara Pistilli. COMPASS-TNBC - A phase Ib/II, open-label, modular, dose-finding and dose-expansion study to explore safety and anti-tumor activity of novel therapeutics in patients with early relapsed mTNBC. Module 1: Dato-DXd &amp; Module 2: Dato-DXd + durvalumab [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-10-28.

Fibroblast activation protein expression in tumour microenvironment is crucial in differentiation and survival prediction of recurrent gliomas: a head-to-head comparison of 68Ga-FAPI-04 and 18F-FET in PET/CT imaging

2025-06-13
Tao Hua , Qi Huang , Weiyan Zhou +5 more | Research Square (Research Square)
<title>Abstract</title> <bold>Background</bold>—The accurate differentiation of recurrent glioma from treatment-related changes, such as pseudoprogression or radiation necrosis, is crucial for treatment planning and remains a critical challenge. Fibroblast activation protein (FAP) … <title>Abstract</title> <bold>Background</bold>—The accurate differentiation of recurrent glioma from treatment-related changes, such as pseudoprogression or radiation necrosis, is crucial for treatment planning and remains a critical challenge. Fibroblast activation protein (FAP) expressed by cancer-associated fibroblasts can be targeted with PET tracers for in vivo visualization and quantification. This research aims to evaluate the diagnostic and survival predictive efficacy of FAP expression in possible recurrent glioma patients with a head-to-head comparison of [gallium-68] FAP inhibitor-04 and [fluoride-18] fluoroethyl-L-tyrosine PET/CT imaging. 30 post-treatment glioma patients with possible recurrent signs under regular MRI follow-up were enrolled. PET-based semiquantitative parameters and clinical factors were obtained for analysis. <bold>Results</bold>—Univariate logistic regression indicated the initial pathological diagnosis has a borderline differential efficacy (P=0.053). In Multivariate logistic regression analysis of PET-based semiquantitative parameters, MTV<sub>FAPI</sub>:MTV<sub>FET</sub> ratio showed borderline differential efficacy (P=0.094). When including PET parameters and initial pathological diagnosis, the effectiveness of initial pathological diagnosis was significant (P = 0.045), and the MTV<sub>FAPI</sub>:MTV<sub>FET </sub>ratio enhanced the area under the receiver operating characteristic curve (AUC) (P=0.040). When the initial diagnosis was replaced with the WHO grade, both the MTV<sub>FAPI</sub>:MTV<sub>FET </sub>ratio (P=0.081) and the WHO grade (P=0.086) showed borderline efficacy, while the MTV<sub>FAPI</sub>:MTV<sub>FET</sub> ratio improved the AUC (P=0.016). After factoring in age and gender, the initial pathological diagnosis remained significant (P=0.038). Three parameters, including gender (P=0.057), MTV<sub>FAPI</sub>:MTV<sub>FET</sub> ratio (P=0.076), and MTV-FAPI (P=0.093), demonstrated borderline efficacy, with the MTV<sub>FAPI</sub>:MTV<sub>FET </sub>ratio enhancing the AUC (P=0.039). Similarly, after replacing the initial pathological diagnosis with the initial WHO grade, the initial WHO grade (P=0.072), MTV<sub>FAPI</sub>:MTV<sub>FET</sub> ratio (P=0.079), and gender (P=0.089) presented with borderline differential efficacy, and the MTV<sub>FAPI</sub>:MTV<sub>FET</sub> ratio similarly significantly enhanced the AUC of the model (P=0.046). The survival analysis indicated that MTV-FAPI significantly affects the overall survival (P=0.027, hazard ratio=1.103, 95% CI: 1.011-1.204). <bold>Conclusions</bold>—This head-to-head study illustrated FAP expression volume percentage of the post-treatment glioma patients has potential in the differentiation between glioma recurrence and treatment-related changes. Glioma FAP expression volume is an independent risk factor that could significantly influence the overall survival of this glioma cohort.

Activity‐enhancing mutations in an LmrR‐based artificial metalloenzyme destabilize the protein scaffold and alter its conformational plasticity

2025-06-13
Adil Safeer , Fabrizio Casilli , Wouter Beugelink +3 more | ChemBioChem
Artificial metalloenzymes (ArM) hold great potential for the sustainable catalysis of complex new‐to‐nature reactions. To efficiently improve the catalytic efficacy of ArMs a rational approach is desirable, requiring detailed molecular … Artificial metalloenzymes (ArM) hold great potential for the sustainable catalysis of complex new‐to‐nature reactions. To efficiently improve the catalytic efficacy of ArMs a rational approach is desirable, requiring detailed molecular insight into their conformational landscape. Lactococcal multidrug resistance regulator (LmrR) is a multi‐purpose ArM scaffold protein that when bound to the Cu(II)‐phenanthroline cofactor catalyzes the Friedel‐Crafts Alkylation (FCA) of indoles. Previously, the M8D and A92E mutations were found to increase the efficiency of this reaction, but a molecular explanation has been lacking. We here determined the impact of these two activating mutations on the conformational landscape of LmrR in its apo, cofactor‐ and substrate‐bound state. We found that the mutations cause a marked destabilization of the dimerization interface, resulting in a more opened central hydrophobic cavity and a dynamic equilibrium between dimer and monomer LmrR. While mutant and wild‐type have similar pocket conformation in the cofactor‐bound state, the mutant shows a distinct interaction with the substrate. Our results suggest that increased retention of the catalytic cofactor and widened plasticity improve activity of the mutant. Ultimately, these results help elucidating the intricate relationships between conformational dynamics of the protein scaffold, cofactor and substrates that define catalytic activity.