Publications by authors named "Clifford Stephan"

Article Synopsis
  • Protein/protein interactions (PPI) are important for brain functions, but their use as drug targets for brain disorders is not fully explored.
  • A small molecule called compound 1028 has been identified that targets the FGF14/Na1.6 PPI and affects the channel's activity, resulting in increased excitability of neurons.
  • Administering compound 1028 can enhance motivation under challenging conditions, and its effects are linked to changes in dopamine levels in the brain, suggesting a new way to impact behaviors related to neuropsychiatric disorders.
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Immune checkpoint inhibitor-associated myocarditis is the most lethal side effect of immune checkpoint blockade. Myocarditis leads to persistently increased mortality and lacks effective treatments. The development of patient-relevant disease models may enable disease prediction, increased understanding of disease pathophysiology, and the development of effective treatment strategies.

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Background: is frequently mutated in the tumors of patients with metastatic colorectal cancer (mCRC) and thus represents a valid target for therapy. However, the strategies of targeting KRAS directly and targeting the downstream effector mitogen-activated protein kinase kinase (MEK) via monotherapies have shown limited efficacy. Thus, there is a strong need for novel, effective combination therapies to improve MEK-inhibitor efficacy in patients with -mutated mCRC.

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Adult type ovarian granulosa cell tumors (AGCTs) are rare malignancies with the near universal c.C402G (p.Cys134Trp) somatic mutation in FOXL2, a Forkhead box-family transcription factor important for ovarian function.

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The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g.

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  • - Myotonic dystrophy type 1 (DM1) is caused by a CTG triplet repeat expansion that leads to the production of RNA with excessive CUG repeats, which accumulate and form structures in cell nuclei; the mechanisms behind their expression and accumulation aren't fully understood.
  • - Researchers discovered that HSP90 plays a crucial role in modifying RNA foci levels in DM1 cells, with its inhibition leading to increased RNA foci and mRNA levels, supported by experiments where HSP90 was either knocked down or overexpressed.
  • - In differentiated DM1 cells, HSP90 inhibition caused a decrease in mRNA levels through a mechanism that doesn't involve p-STAT3, highlighting the complexity of HSP90's role
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Toxins TcdA and TcdB are the main virulence factors of Clostridioides difficile, a leading cause of hospital-acquired diarrhea. Despite their importance, there is a significant knowledge gap of druggable targets for inhibiting toxin production. To address this, we screened nonantibiotic phytochemicals to identify potential chemical genetic probes to discover antivirulence drug targets.

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Background: is frequently mutated in the tumors of patients with metastatic colorectal cancer (mCRC) and thus represents a valid target for therapy. However, the strategies of targeting KRAS directly and targeting the downstream effector mitogen-activated protein kinase kinase (MEK) via monotherapies have shown limited efficacy. Thus, there is a strong need for novel, effective combination therapies to improve MEK-inhibitor efficacy in patients with -mutated mCRC.

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Cystic fibrosis (CF) is a single-gene disorder that affects the lung, digestive system, and other organs. Mutations in the CF transmembrane conductance regulator (CFTR) gene are classified into several classes based on their pathogenic mechanism and clinical severity. The distinct and heterogeneous clinical behavior of each CF class and the respective CFTR mutations have made the development of a durable therapy for all CF patients extremely challenging.

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Triple negative breast cancer (TNBC) accounts for 15-20% of breast cancer cases in the United States. Systemic neoadjuvant chemotherapy (NACT), with or without immunotherapy, is the current standard of care for patients with early-stage TNBC. However, up to 70% of TNBC patients have significant residual disease once NACT is completed, which is associated with a high risk of developing recurrence within two to three years of surgical resection.

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Endometrial cancer is the most frequent malignant tumor of the female reproductive tract but lacks effective therapy. EphA2, a receptor tyrosine kinase, is overexpressed by various cancers including endometrial cancer and is associated with poor clinical outcomes. In preclinical models, EphA2-targeted drugs had modest efficacy.

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Triple-negative breast cancer (TNBC) poses significant challenges due to its aggressive nature and limited treatment options. In this study, we investigated the impact of urea-based compounds on TNBC cells to uncover their mechanisms of action and therapeutic potential. Notably, polypharmacology urea analogues were found to work via p53-related pathways, and their cytotoxic effects were amplified by the modulation of oxidative phosphorylation pathways in the mitochondria of cancer cells.

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TP 53-mutant acute myeloid leukemia (AML) remains the ultimate therapeutic challenge. Epichaperomes, formed in malignant cells, consist of heat shock protein 90 (HSP90) and associated proteins that support the maturation, activity, and stability of oncogenic kinases and transcription factors including mutant p53. High-throughput drug screening identified HSP90 inhibitors as top hits in isogenic TP53-wild-type (WT) and -mutant AML cells.

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Article Synopsis
  • Mutations in the KRAS gene are prevalent in over 50% of metastatic colorectal cancer (mCRC) cases, making effective treatment challenging due to the ineffectiveness of direct and single-agent therapies targeting it.
  • Recent research utilized high-throughput screening to discover that combining trametinib, a MEK inhibitor, with vincristine significantly enhances anti-cancer effects in KRAS-mutant colorectal cancer cells.
  • The synergistic combination works by increasing vincristine accumulation and inhibiting crucial cell survival pathways, showing promising results in preclinical models and suggesting potential for future clinical trials.
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  • Idiopathic pulmonary fibrosis (IPF) is a severe lung disease characterized by the replacement of healthy lung tissue with dense fibrotic tissue, leading to progressive respiratory failure.
  • Research utilizing single-cell RNA sequencing has uncovered a specific type of stem cell in IPF patients that is capable of converting normal lung cells into harmful myofibroblasts, suggesting a critical role in disease progression.
  • Drug testing revealed that this profibrotic stem cell variant may be targeted with specific inhibitors, indicating potential new therapeutic approaches for treating IPF.
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  • Cisplatin (CDDP) is commonly used to treat advanced head and neck cancers, but many tumors develop resistance through changes in their metabolism.
  • Researchers studied CDDP-resistant cancer cell clones using advanced techniques, revealing that mutations in KEAP1 lead to increased Nrf2 activity, which is linked to drug resistance.
  • The study found that resistant cells show metabolic shifts that reduce energy production while enhancing biomass generation, suggesting new potential treatments could target these specific metabolic pathways.
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Metastatic colorectal cancer (mCRC) is the second leading cause of cancer deaths in the United States. More than 50% of patients with mCRC harbor mutations of the oncogenic driver RAS (KRAS or NRAS). Because directly targeting most mutations of RAS is technically challenging, researchers have concentrated on targeting MEK, a downstream mediator of RAS.

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EphA2 tyrosine kinase is upregulated in many cancers and correlated with poor survival of patients, including those with endometrial cancer. EphA2-targeted drugs have shown modest clinical benefit. To improve the therapeutic response to such drugs, we performed a high-throughput chemical screen to discover novel synergistic partners for EphA2-targeted therapeutics.

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Drug repurposing can overcome both substantial costs and the lengthy process of new drug discovery and development in cancer treatment. Some Food and Drug Administration (FDA)-approved drugs have been found to have the potential to be repurposed as anti-cancer drugs. However, the progress is slow due to only a handful of strategies employed to identify drugs with repurposing potential.

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  • Pediatric ependymoma (EPN) frequently recurs, with a study tracking 30 patients showing they experienced an average of 3.67 relapses over 13 years.
  • The research identified stable molecular subtypes and significant patterns in DNA methylation that change during relapses, highlighting specific genes that are differentially expressed and might play a role in the disease's progression.
  • Findings include potential biomarkers for predicting relapses found in primary tumors, along with a detailed epigenetic profile to support future studies on EPN biology and treatment approaches.
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The AP1 transcription factor ΔFOSB, a splice variant of FOSB, accumulates in the brain in response to chronic insults such as exposure to drugs of abuse, depression, Alzheimer's disease and tardive dyskinesias, and mediates subsequent long-term neuroadaptations. ΔFOSB forms heterodimers with other AP1 transcription factors, e.g.

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Purpose: Human papillomavirus (HPV) causes >5% of cancers, but no therapies uniquely target HPV-driven cancers.

Experimental Design: We tested the cytotoxic effect of 864 drugs in 16 HPV-positive and 17 HPV-negative human squamous cancer cell lines. We confirmed apoptosis in vitro and in vivo using patient-derived xenografts.

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Much has been written and said about the promise and excitement of microphysiological systems, miniature devices that aim to recreate aspects of human physiology on a chip. The rapid explosion of the offerings and persistent publicity placed high expectations on both product manufacturers and regulatory agencies to adopt the data. Inevitably, discussions of where this technology fits in chemical testing paradigms are ongoing.

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