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At least 19 recordsLinked to original sources
PubMed2025

Integrated proteomic network analysis reveals PTPRC as a central hub protein orchestrating co-expression modules and metabolic dysregulation in renal carcinoma: PTPRC protein molecular action.

The occurrence of renal carcinoma is closely related to a variety of molecular mechanisms and metabolic disorders. PTPRC (protein tyrosine phosphatase receptor C), as an important regulatory protein, was studied to reveal the role of PTPRC in renal carcinoma through comprehensive proteomic network analysis, especially its core position in the coordination of co-expression modules and metabolic disorders. This study was the first to download and process multiple publicly available renal cancer transcriptome data to conduct differential gene expression analysis across datasets. Functional enrichment and disease ontology analysis were performed on the transcriptome of renal cancer, and weighted gene co-expression network (WGCNA) was constructed. The results showed that comprehensive principal component analysis revealed significant differences in the transcriptome of renal cancer, and functional annotation revealed specific pathways associated with renal cancer. WGCNA analysis identified tumor-associated co-expression modules, while multi-omics analysis further identified core regulatory networks including PTPRC. As a central hub protein, PTPRC plays an important coordinating role in the co-expression module and metabolic dysregulation of renal carcinoma. This discovery provides a new perspective for understanding the molecular mechanism of kidney cancer.

Humans↗
PubMed2019

Estrogen-independent molecular actions of mutant estrogen receptor 1 in endometrial cancer.

Estrogen receptor 1 (ESR1) mutations have been identified in hormone therapy-resistant breast cancer and primary endometrial cancer. Analyses in breast cancer suggest that mutant ESR1 exhibits estrogen-independent activity. In endometrial cancer, ESR1 mutations are associated with worse outcomes and less obesity, however, experimental investigation of these mutations has not been performed. Using a unique CRISPR/Cas9 strategy, we introduced the D538G mutation, a common endometrial cancer mutation that alters the ligand binding domain of ESR1, while epitope tagging the endogenous locus. We discovered estrogen-independent mutant ESR1 genomic binding that is significantly altered from wild-type ESR1. The D538G mutation impacted expression, including a large set of nonestrogen-regulated genes, and chromatin accessibility, with most affected loci bound by mutant ESR1. Mutant ESR1 is distinct from constitutive ESR1 activity because mutant-specific changes are not recapitulated with prolonged estrogen exposure. Overall, the D538G mutant ESR1 confers estrogen-independent activity while causing additional regulatory changes in endometrial cancer cells that are distinct from breast cancer cells.

CRISPR-Cas Systems↗
PubMedDate not supplied

Sequiterpene lactones. Part XXV. Studies on the mode of action. The cellular and molecular basis of cytostatic action.

Two compounds, derivatives of the sesquiterpene lactones (SL), ALA and URSA, on the basis of the high antitumor activity in vitro and in vivo systems, were selected as models, in order to study the mechanism of action of this drug class. Using cytologic, morphologic and isotopic methods the following were demonstrated: 1) At a subtoxic conc., 0.28 microM, arrest the HeLa cell in its interphase (G1, and/or S, G2). 2) At a higher conc. of 28.0 microM, complete and irreversible cytotoxic effects with pyknosis and karyorrhexis. 3) At a conc. of 56.0 microM, inhibition of protein biosynthesis by 94% and RNA by 81--92%. 4) At a conc. of 2.5 microM inhibition by 80% of translation processes. Inhibition of DNA biosynthesis seems to be doubtful. A preliminary hypothetical model of the cellular and molecular mechanism of SL, partly explanatory also of the cytostatic effect, has been proposed.

Antineoplastic Agents, Phytogenic↗
PubMed1979

GABA receptors in clonal cell lines: a model for study of benzodiazepine action at molecular level.

A "recptor unit" for gamma-aminobutyric acid (GABA), which includes brainlike receptor binding sites for tritium-labeled GABA and benzodiazepines (diazepam, clonazepam, and flunitrazepam) and a thermostable endogenous protein (GABA modulin) that inhibits both GABA and benzodiazepine binding, has been demonstrated in membranes prepared from NB2a neuroblastoma and C6 glioma clonal cell lines. In these cells, as in brain, diazepam (1 micromolar) prevents the effect of GABA modulin, and in turn GABA (0.oma and, to a lesser extent, the glioma cells represent a suitable model to study the interactions and the sequence of membrane and intracellular events triggered by the stimulation of benzodiazepine and GABA receptors.

Animals↗
PubMedDate not supplied

[Molecular aspects of the action of insulin].

Molecular aspects of the insulin action in an organism are discussed. The following mechanisms of the hormone effect are considered: induction of the synthesis of glycolytic enzymes in cell-targets under effect of insulin; mechanisms of the insulin reception in cell-enzymes in cell-targets; the possible role of cyclic nucleotides as mediators in the effect of insulin in cell targets.

Adipose Tissue↗
PubMed1975

Molecular mechanisms in the actions of morphine and viminol (R2) on rat striatum.

Analgesic doses of morphine and viminol R2 increase the turnover rate of dopamine (DA) in rat striatum but fail to increase the striatal concentration of adenosine 3',5'-monophosphate (cAMP) or the affinity of tyrosine hydroxylase (TH) for the pteridine cofactor. When morphine is added to striatal homogenates, it changes neither the basal activity of adenylate cyclase nor the enzyme activation by DA. Similarly to morphine, haloperidol enhances the turnover rate of striatal DA, but unlike morphine it increases the affinity of TH for the pteridine cofactor and blocks the in vitro activation of striatal adenylacte cyclase by DA. Morphine (52 mumol/kg i.p.), viminol R2 (7 mumol/kg i.p.) or haloperidol (2.6 mumol/kg i.p.) fails to increase the striatal cAMP contrations. However (+)-amphetamine (4.8 mumol/kg i.p.) increases DA turnover rate and the striatal cAMP content, but, in doses up to 12.8 mumol/kg i.p., it fails to change the affinity of TH for the pteridine cofactor. This study shows that although (+)-amphetamine, haloperidol and morphine increase the turnover rate of striatal DA each drug possesses a specific profile in its action on molecular mechanisms that control the function of striatal dopaminergic synapses.

Animals↗
PubMed2026

Large cell neuroendocrine carcinoma of the lung: Current standards, emerging targets, and translational foundations.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is one of the most complex and heterogenous clinical entities in thoracic oncology, sharing features with both non-small cell lung cancer (NSLC) and neuroendocrine lung cancers. LCNEC diagnosis and classification relies on evolving histopathological and molecular criteria that define its diagnostic boundaries. Recent advances have confirmed the dual nature of LCNEC, with distinct small cell-like and non-small cell-like molecular characteristics, which guide treatment decisions. In this review, we synthesize current evidence on the diagnosis, molecular characterization, and multimodality management of LCNEC to provide a comprehensive framework for clinical and translational decision-making. A comprehensive literature search was conducted using the PubMed database with no date restrictions, last updated on 12th of April 2026. Articles were selected based on relevance to the diagnosis, molecular characterization, and management of pulmonary LCNEC. Emphasis was placed on studies providing clinical, pathological, and molecular insights into the field. In this review, we summarize contemporary diagnostic approaches, including the expanding role of immunohistochemistry, next‑generation sequencing, and integrated morpho‑molecular assessment. This review represents a consolidated update on LCNEC genomic and transcriptional landscapes, and actionable molecular alterations that are anticipated to impact treatment decisions. Additionally, it provides a state-of-the-art overview of multimodality management, covering surgical approaches, radiotherapy, perioperative therapy, systemic treatment, and the emerging role of immunotherapy. Despite incremental progress, LCNEC remains constrained by limited prospective data and lack of consensus on optimal treatment pathways. By conducting literature review, we identified persistent gaps in LCNEC published data and hereby highlight key priorities for future research.

Humans↗
PubMed1976

Neurochemistry and behavior in man.

The distribution and functions of certain neurotransmitter substances seem to correlate with clinical, anatomical and physiological evidence about the mediation of normal and abnormal behaviors in man, though much remains to be learned. The biosynthetic and metabolic pathways, receptors and reuptake mechanisms, and relationships to cyclic nucleotides for several major neurotransmitters are characterized, as well as the specific actions of many behavior-modifying drugs employed clinically. Experimental systems, including nerve cells in culture, permit tests of molecular actions inferred from biochemical and neurophysiological analyses in intact brain. This selective review emphasizes advances in neurochemistry which provide a context for current and future research on neurological and psychiatric disorders encountered in clinical practice.

Affective Symptoms↗
PubMed2026

Systemic treatment of advanced pancreatic cancer: A Comprehensive Review.

IMPORTANCE: Pancreatic adenocarcinoma (PDAC) is an uncommon but potentially catastrophic diagnosis with historically poor prognosis. It is the tenth most prevalent cancer in the US & UK. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide, with a five-year survival rate of approximately 10%. Despite increasing understanding of its molecular biology, systemic treatment options for advanced disease remain limited, and survival outcomes have improved only modestly over the past decade. OBSERVATIONS: This narrative review traces the evolution of systemic therapy for advanced PDAC from gemcitabine monotherapy through the landmark FOLFIRINOX (PRODIGE trial) and gemcitabine/nab-paclitaxel (MPACT trial) combination regimens, which remain the standard of care. Second-line options including liposomal irinotecan plus 5-FU/LV (NAPOLI-1) and maintenance olaparib for germline BRCA1/2-mutated disease (POLO) are also reviewed. Emerging data on sequential treatment strategies (SEQUENCE trial), biomarker-driven treatment selection (PRIMUS-001, PASS-01), and precision medicine approaches targeting actionable molecular subgroups, including dMMR/MSI-H, NTRK fusions, and homologous recombination deficiency are discussed. Real-world evidence comparing FOLFIRINOX and gemcitabine/nab-paclitaxel is critically appraised, including the challenges of patient selection, tolerance, and applicability outside clinical trial settings. CONCLUSION AND RELEVANCE: Despite incremental progress, the treatment landscape of advanced PDAC remains challenging. Molecular stratification and biomarker-driven precision oncology represent the most promising path forward. This review serves as a clinical reference for physicians managing advanced pancreatic cancer, highlighting current evidence, evidence limitations, and future research priorities including prospective biomarker-driven trials and improved access to genomic testing.

Biomarkers↗
PubMed2026

Integrated Clinicopathologic and Multiomic Profiling Reveals MEIS1-Rearranged Sarcoma as a Distinct Entity With 2 Prognostic Subgroups.

Sarcomas with MEIS1 fusions represent a rare, recently recognized group of mesenchymal neoplasms with a predilection for genitourinary and gynecologic sites. A subset exhibits skeletal muscle differentiation resembling spindle cell rhabdomyosarcoma. Existing literature is limited to case reports and small series, with scant comprehensive clinicopathologic, molecular, and outcome data. In this study, we analyzed a multi-institutional cohort of 20 MEIS1-rearranged sarcomas using integrated clinicopathologic review, genomic profiling, and DNA methylation analysis. The tumors occurred in 17 females and 3 males (median age, 41 years; range, 6-58 years), arising mainly in the uterus/vagina (n = 12), vulva/perineum (n = 4), bone (n = 2), and kidney (n = 2), with a median size of 9 cm (range, 2.5-20 cm). Histology showed mostly bland spindle cells in fascicles/storiform patterns, alternating cellularity, fibromyxoid stroma, prominent vascularity, and adipose metaplasia (45%). A subset of cases featured high-grade morphology with epithelioid cells and increased mitotic activity. Skeletal muscle markers were variably positive in 9 cases. Fusions involved MEIS1 with NCOA2 (16/20), NCOA1 (3/20), or FOXO1 (1/20). Recurrent additional genomic alterations included CTNNB1 mutations (31.6%) and MDM2 amplification (15%). DNA methylation profiling showed that MEIS1-rearranged sarcomas formed a unifying cluster comprising 2 subgroups, regardless of rhabdomyosarcomatous phenotype, clearly separated from other mesenchymal neoplasms, including various rhabdomyosarcoma subtypes and uterine sarcomas. The 2 DNA methylation (Meth) subgroups correlated with differences in genome-wide copy number variation (CNV) status (Meth-CNV high vs Meth-CNV low), with Meth-CNV high tumors characterized by high mitotic rate, frequent tumor necrosis, recurrent co-occurring CTNNB1 and MDM2 alterations, and recurrent chromosomal arm-level changes. Most importantly, this subgroup exhibited significantly worse overall survival (P = .027) and disease-free survival (median, 5 vs 99 months; P = .017). This study establishes MEIS1-rearranged sarcoma as a distinct entity with generally indolent but potentially aggressive behavior. The 2 methylation/CNV subgroups provide potential utility for prognostic stratification and highlight actionable molecular targets in high-risk cases.

Humans↗
PubMed2025

Deep immune profiling of intrahepatic cholangiocarcinoma with CODEX multiplexed imaging.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) may be genomically subclassified by the presence of potentially actionable molecular aberrations, of which pathogenic alterations in isocitrate dehydrogenase (IDH)1 and fibroblast growth factor receptor (FGFR)2 are the most frequently observed. The impact of these molecular alterations on the tumor immune microenvironment remains incompletely understood. METHODS: We performed a high-parameter spatial immune phenotyping of iCCA samples with pathogenic FGFR2 or IDH1 alterations and FGFR2/IDH1 wild-type controls at the single-cell level using CO-Detection by indEXing. RESULTS: A total of 24 tumors were examined. Tumors with FGFR2 alterations were characterized by fewer CD8+ T cells and "M2-like" macrophages but higher levels of polymorphonuclear myeloid-derived suppressor cells as compared to FGFR2 wild-type tumors. Spatial relationships between polymorphonuclear myeloid-derived suppressor cells and multiple other cell types in the tumor microenvironment (including tumor cells, CD4+, and CD8+ T cells) were enriched in tumors with FGFR2 alterations. Tumors with IDH1 mutations had a trend toward more fibroblasts and were characterized by a closer proximity of tumor cells to CD4+ T cells, and between macrophages and multiple structural tumor microenvironment components as compared to other subtypes. CONCLUSIONS: iCCAs with pathogenic FGFR2 fusions/rearrangements and IDH1 mutations have distinct immunophenotypes. Tailoring immunotherapeutic approaches to specific molecular subsets could improve treatment outcomes across the divergent molecularly defined iCCA subtypes.

Humans↗
PubMed1979

Transformation and translocation of 17 beta-estradiol receptor in rat pituitary.

The association of 17 beta-(3H)-estradiol with its pituitary cytosol receptor is described. The transformation products of this 8 S receptor complex at high salt concentration was analyzed by 5-20% linear sucrose gradients. KCl was found to reversibly convert the 8 S moiety into a 4-5 S species. The transformation by CaCl2 and trypsin was found to be irreversible. In addition, the nuclear translocation of the estrogen-receptor complex was investigated in vitro. Translocation was found to be temperature-dependent, since a 6 S nuclear receptor complex could be extracted from crude nuclei only after incubation of whole pituitaries at 37 degrees C and not at 4 degrees C incubation temperature. Similarly, a 6 S species was found upon sucrose gradient analysis of nuclear extract after a cell free incubation of isolated nuclei and cytosol with 17 beta-(3H)-estradiol. Maximal translocation was observed in this in vitro system within 60 to 90 min, resulting in a concomitant loss of cytosol receptor. The present data combine to suggest that nuclear translocation resembles one of the early events involved in the molecular action of estrogen at the pituitary level.

Animals↗
PubMed1979

The molecular mode of action of Clostridium perfringens enterotoxin.

While certain strains of Clostridium perfringens have been associated with food poisoning outbreaks for the past 30 years, it has been only during the past 10 years that progress has been made in describing the disease process. And only within the past 5 years has meaningful progress been made in understanding the mechanism by which the disease is caused. Early observations, that the protein enterotoxin can cause erythema, increase capillary permeability, and exhibit parasympathomimetic properties, have been greatly added to in more recent studies. It is now believed tht the enterotoxin can alter intestinal transport of fluid, ions, and glucose, cause tissue damage in the gut and inhibit metabolic processes in intestinal tissue. Furthermore, the enterotoxin is thought to act very quickly (in a matter of minutes, compared to hours for other known enteropathogenic factors) and to affect basic function (macromolecular synthesis) and structure (membrane damage to microvillus brush borders) of individual cells. These findings have opened up many new questions that hopefully, when answered, will further the understanding of how this enterotoxin acts, as well as other enterotoxins being studied today.

Animals↗