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Biomedical subjects

Alexander Meves

Publications and source records attributed to Alexander Meves.

10 recordsLinked to original sources
PubMed2026

Shared ligand-blocking mechanism but distinct conformational modulation by α5-targeting antibodies BIIG2 and MINT1526A.

Integrins are heterodimeric receptors important for cell adhesion and signaling. Integrin α5β1 is a key mediator of angiogenesis and its dysregulation is associated with tumor progression and metastasis. Despite numerous efforts, α5β1-targeting therapeutics have been unsuccessful due to poor efficacy and off-target effects. A contributing factor is our limited understanding of how integrin conformation influences interactions with therapeutics. Using cell-based functional assays, patient-derived xenografts, biophysics, X-ray crystallography, and electron microscopy, we shed light on these relationships by characterizing two anti-α5β1 antibodies, BIIG2 and MINT1526A. We show that both antibodies bind α5β1 with nanomolar affinity, reduce tube formation in vitro, and bind overlapping epitopes that block fibronectin binding. However, using electron microscopy, we reveal that while BIIG2 binding does not substantially alter the conformational states, MINT1526A preferentially recognizes the bent conformation and restricts the conformational ensemble. These insights can guide which aspects to prioritize to improve the design of future integrin-targeted therapeutics.

angiogenesis↗
PubMed2025

Shared ligand-blocking mechanism but distinct conformational modulation by α5-targeting antibodies BIIG2 and MINT1526A.

Integrins are heterodimeric receptors important for cell adhesion and signaling. Integrin α5β1 is a key mediator of angiogenesis and its dysregulation is associated with tumor progression and metastasis. Despite numerous efforts, α5β1-targeting therapeutics have been unsuccessful due to poor efficacy and off-target effects. A contributing factor is our limited understanding of how integrin conformation influences interactions with therapeutics. Using cell-based functional assays, patient derived xenografts, biophysics, and electron microscopy, we shed light on these relationships by characterizing two anti-α5β1 antibodies, BIIG2 and MINT1526A. We show that both antibodies bind α5β1 with nanomolar affinity, reduce angiogenesis in vitro, and bind overlapping epitopes that block fibronectin binding. However, using cryoEM, we reveal that while BIIG2 binding doesn't alter the conformational states, MINT1526A restricts α5β1's range of flexibility. These insights can guide which aspects to prioritize and improve the design of future integrin-targeted therapeutics.

Journal Article↗
PubMed2006

Acute graft-versus-host disease after liver transplantation diagnosed by fluorescent in situ hybridization testing of skin biopsy specimens.

Acute graft-versus-host disease after orthotopic liver transplantation is an underrecognized entity with a guarded prognosis. We describe a patient who underwent orthotopic liver transplantation with an HLA-matched donor liver. She had an uneventful recovery from operation up until day 36 posttransplantation, when she developed a generalized, erythematous, mostly macular eruption, accompanied by ascites, diarrhea, and fever. The diagnosis of graft-versus-host disease was considered but a drug rash could not be excluded. A polymerase chain reaction-based chimerism assay failed to identify donor DNA in peripheral blood. A confirmatory fluorescent in situ hybridization analysis revealed significant numbers of donor lymphocytes in biopsied skin, with lesser amounts in biopsy specimens from the stomach and colon. Despite immunosuppressive treatment, the patient died of overwhelming sepsis 18 weeks after transplantation. We conclude that early testing of skin biopsy specimens using fluorescent in situ hybridization in sex-mismatched patients with orthotopic liver transplantation can serve as an early diagnostic tool for graft-versus-host disease.

Acute Disease↗
PubMed2005

Case reports and case series from Lancet had significant impact on medical literature.

BACKGROUND AND OBJECTIVES: Case reports and case series are often the first evidence of innovative treatment, but clinical trials need to follow to substantiate this evidence. The objective of this article was to evaluate case reports or case series describing innovative treatment concerning their impact. METHODS: Case reports and case series (n < or = 10) from a high-impact journal, The Lancet, published from 1 January 1996 to 30 June 1997, were evaluated according to predefined criteria. To assess publication impact, Pubmed, Science Citation Index, the Register of Current Controlled Clinical Trials, and the Cochrance Controlled Clinical Trials Register were searched. RESULTS: Sixty-four case reports and 39 case series were identified. They were cited in average 17 times (median 6,5; range 0-336). Twenty-Four follow-up trials were identified, nine in the register of current controlled clinical trials. CONCLUSION: Case reports and case series can be well received, and have significant influence on subsequent literature and possibly on clinical practice. Many were followed by clinical trials. Often, though, they report rare conditions for which trials may not be feasible, and more or less explicitly transfer established treatment into other conditions. Overall, there is a strong publication bias favoring positive results, and opportunity should be created for publication of follow-up reports.

Bibliometrics↗
PubMed2004

Antipsoriatic drug anthralin induces EGF receptor phosphorylation in keratinocytes: requirement for H(2)O(2) generation.

Even though anthralin is a well-established topical therapeutic agent for psoriasis, little is known about its effects and biochemical mechanisms of signal transduction. In contrast to a previous report, we found that anthralin induced time- and concentration-dependent phosphorylation of epidermal growth factor receptor in primary human keratinocytes. Four lines of evidence show that this process is mediated by reactive oxygen species. First, we found that anthralin induces time-dependent generation of H(2)O(2). Second, there is a correlation between a time-dependent increase in anthralin-induced epidermal growth factor receptor phosphorylation and H(2)O(2) generation. Third, the structurally different antioxidants n-propyl gallate and N-acetylcysteine inhibited epidermal growth factor receptor phosphorylation induced by anthralin. Fourth, overexpression of catalase inhibited this process. The epidermal growth factor receptor-specific tyrosine kinase inhibitor PD153035 abrogated anthralin-induced epidermal growth factor receptor phosphorylation and activation of extracellular-regulated kinase 1/2. These findings establish the following sequence of events: (1) H(2)O(2) generation, (2) epidermal growth factor receptor phosphorylation, and (3) extracellular-regulated kinase activation. Our data identify anthralin-induced reactive oxygen species and, more specifically, H(2)O(2) as an important upstream mediator required for ligand-independent epidermal growth factor receptor phosphorylation and downstream signaling.

Acetylcysteine↗
PubMed2002

Vitamin C derivative ascorbyl palmitate promotes ultraviolet-B-induced lipid peroxidation and cytotoxicity in keratinocytes.

Among the preventative and protective strategies against the harmful effects of ultraviolet radiation to the skin is the application of antioxidants. Ascorbic acid has been shown to protect against sunburn, delay the onset of skin tumors, and reduce ultraviolet-B-radiation-induced skin wrinkling. In this work, we sought to determine the antioxidative properties of a lipid-soluble derivative of ascorbic acid, ascorbic acid-6-palmitate. We found that ascorbic acid-6-palmitate reduced cellular levels of reactive oxygen species following ultraviolet B irradiation. Treatment of keratinocytes with ascorbic acid-6-palmitate inhibited ultraviolet-B-mediated activation of epidermal growth factor receptor, extracellular regulated kinases 1 and 2, and p38 kinase because of its ability to prevent reduced glutathione depletion and scavenge hydrogen peroxide. Ascorbic acid-6-palmitate strongly promoted ultraviolet-B-induced lipid peroxidation, c-Jun N-terminal kinase activation, and cytotoxicity, however. End products of lipid peroxidation, such as 4-hydroxy-2-nonenal, have been reported to mediate stress-activated protein kinase activation and cell toxicity in epithelial cells. The lipid component of ascorbic acid-6-palmitate probably contributes to the generation of oxidized lipid metabolites that are toxic to epidermal cells. Our data suggest that, despite its antioxidant properties, ascorbic acid-6-palmitate may intensify skin damage following physiologic doses of ultraviolet radiation.

Antioxidants↗