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PubMedDate not supplied

[Pharmacologic complications of the unequal reactivity of constituent elements of the myocardium to the parasympathetic system].

Pharmacological consequences of the unequal reactivity of the myocardial different parts to parasympathic system. The effects of acetylcholine on the various levels of cardiac automatism are studied on open chest dogs with extracorporeal circulation. This drug depresses the sinus node, and more specially the atrio-ventricular node (AV node), but does not alter the His bundle and the Purkinje fibers activity. The sensitivity of the intra-cardiac conduction to acetylcholine also depends upon the considered level of conduction: measured with a bipolar electrode situated upon the His bundle, this one is lowered electively in the atrio-ventricular part. So, the A, V. node can be considered as the elective place of action of acetylcholine on the double point of view of automatism and conduction. Drugs modifying the vagal tonus see their action altered, either in a plus way (antiarrhythmic agents), either in a minus way (cardiac glycosides, halogenated hydrocarbons).

Acetylcholine↗

PubMed1976

Tolerance development to cadmium-induced alteration of drug action.

Cadmium administration potentiates the duration of hexobarbital-induced hypnosis and inhibits the rate of hepatic microsomal metabolism of this drug in the male rat. The threshold dose of cadmium required to produce these alterations in drug action is 0.84 mg Ck/kg. If subthreshold doses of cadmium (0.21 or 0.42 mg Cd/kg) are administered prior to the 0.84 mg Cd/kg dose, the cadmium-induced alterations in drug action are no longer observed.

Animals↗

PubMed2026

Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC): An Aggressive Disease Course and Limitations for Personalized Oncology.

Neuroendocrine carcinoma (NEC) is a rare, aggressive malignancy with limited treatment options and poor prognosis. We report a male patient diagnosed with a gastroenteropancreatic (GEP)-NEC with synchronous liver metastasis at the time of surgery who underwent a radical resection attempt. Despite radical-intent surgery followed by adjuvant carboplatin/etoposide, early recurrence developed with progression through multiple subsequent chemotherapy lines. During the treatment process, genetic profiling was performed twice to identify actionable genomic targets, with inclusion in the national IMPRESS study as a last resort. Comprehensive genomic profiling revealed TP53 mutation and RB1 loss but no actionable alterations. A patient-derived organoid (PDO) was successfully established from resected tumor tissue and retained key neuroendocrine and proliferative features, with partial genomic concordance to the primary tumor. Differences between the primary and subsequent PDO in variant allele frequencies suggest clonal selection during culture. Exploratory metabolomic profiling of tryptophan pathway metabolites in patient serum and PDO-culture media indicated tumor-associated metabolic alterations. We present clinical and translational efforts in difficult-to-treat NEC, illustrating both the translational challenges and the potential role of PDOs in advancing personalized treatment strategies for a cancer with very limited treatment options.

Gastroenteropancreatic neuroendocrine carcinoma↗

PubMed2026

Genomic profiling by circulating tumor DNA in patients with hormone receptor-positive/HER2-negative advanced breast cancer: Prevalence of actionable mutations across treatment lines.

INTRODUCTION: Plasma next-generation sequencing (NGS) is endorsed by ESMO as an alternative to tissue testing in advanced hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2- mBC), particularly after progression on endocrine therapy plus CDK4/6 inhibitors. However, prospective real-world data across distinct therapeutic contexts remain limited. PATIENTS AND METHODS: In this prospective observational study conducted within a nationwide cancer network in Brazil, centralized plasma NGS, and tissue NGS when available, was performed in two independent cohorts: prior to initiation of first-line endocrine therapy in the metastatic setting (Cohort 1) and at progression on endocrine therapy plus a CDK4/6 inhibitor (Cohort 2). The primary objective was to evaluate plasma-detected ESR1 mutation prevalence across these therapeutic contexts, and secondarily to assess other actionable drivers detected by plasma or tissue NGS. RESULTS: Among 86 collected plasma samples, 72 (84%) had evaluable NGS results (Cohort 1, n = 37; Cohort 2, n = 35). ESR1 mutations were identified in 18.9% of patients in Cohort 1 and 40.0% in Cohort 2, mostly at low variant allele fractions (<0.5%), corresponding to an absolute prevalence difference of 21.1 percentage points (95% CI, -0.2 to 40.3; P value=0.07). When considering any actionable alteration detected by plasma, including ESR1, PIK3CA, AKT1, PTEN, BRCA1, BRCA2, and ERBB2, prevalences were 43.2% and 68.6%, respectively (P value=0.04). Only four patients had ESR1 mutations identified in tissue, three in metastatic samples. Plasma-tissue concordance was higher for PIK3CA mutations (85.1%). CONCLUSION: Plasma NGS identified clinically meaningful ESR1 mutation rates across both contexts, supporting guideline-endorsed plasma-based genomic profiling in HR+/HER2- mBC.

CDK4/6 inhibitors↗

PubMed2026

Multiregion profiling of genomic and transcriptional heterogeneity in head and neck squamous-cell carcinoma.

BACKGROUND: Intratumoral heterogeneity (ITH) is thought to contribute to tumour evolution and treatment resistance but its biological and clinical significance in localised head and neck squamous-cell carcinoma (HNSCC) remains incompletely understood. PATIENTS AND METHODS: In the prospective SCANDARE study, we analysed 87 patients with resectable HNSCC treated with upfront surgery. Two to five spatially distinct tumour regions per patient underwent pathological evaluation, targeted DNA sequencing, and bulk RNA sequencing. Genomic ITH (gITH) was quantified using clonal deconvolution and Shannon diversity indices, whereas transcriptional heterogeneity (tITH) was assessed using the intratumour expression distance metric. Associations between ITH, molecular features, tumour microenvironment composition, and clinical outcomes were explored using multivariable statistical models. RESULTS: Pathology-based spatial heterogeneity showed limited prognostic value. gITH was common, with 37% of tumours displaying regionally heterogeneous pathogenic variants, including spatially actionable alterations in 10% of patients. In an initial multivariable Cox model, higher gITH was associated with shorter disease-free survival. However, after Ridge-penalised modelling and bootstrap internal validation, the effect size was attenuated [corrected hazard ratio 1.42, 95% confidence interval (CI) 0.91-2.75]. The overall model retained moderate discriminative performance (optimism-corrected C-index 0.69, 95% CI 0.59-0.79). gITH was associated with tumour cellularity, reduced estimated endothelial cell infiltration, and alterations in KMT2C and PIK3CA. tITH differed according to human papillomavirus (HPV) status, with lower tITH in HPV-positive tumours, and was associated with distinct biological pathways and genomic alterations. Genomic and tITH were not correlated. CONCLUSIONS: This prospective multiregion study provides a comprehensive characterisation of genomic and tITH in localised HNSCC. Our findings highlight substantial spatial molecular diversity within primary tumours and suggest potential associations between heterogeneity, tumour biology, and clinical outcome that warrant validation in independent cohorts.

head and neck squamous-cell carcinoma (HNSCC)↗

PubMed2026

The future of blood-based biomarkers in liver cancer.

Liquid biomarkers hold substantial promise in liver cancer, with potential applications in risk stratification, surveillance and early detection, therapeutic decision-making, and treatment-response monitoring. In parallel with oncologic advances, liquid biopsy has gained increasing attention. However, despite expanded research efforts, prospective clinical validation remains limited. While cell-free DNA-based detection of actionable alterations has entered clinical practice in select contexts, most candidate liquid biomarkers still require rigorous evaluation through translational research embedded in clinical trials and prospective cohort studies. In this review, we summarise the current landscape of blood-based biomarkers across the cancer care continuum for individuals at risk, or diagnosed with hepatocellular carcinoma and biliary tract cancers, and discuss the key challenges and opportunities that lie ahead.

Humans↗

PubMed2026

Detection of a Rare Intra-ALK Inversion and ALK Rearrangement in a Lung Adenocarcinoma Patient by FoundationOne Liquid CDx and Successful Treatment with Alectinib: Case Report.

A 50-year-old woman with stage IVB lung adenocarcinoma tested negative for driver mutations using the Oncomine Dx Target Test Multi-CDx system (Thermo Fisher Scientific, Waltham, MA). After undergoing chemotherapy and immunotherapy, FoundationOne Liquid CDx (Foundation Medicine, Inc., Cambridge, MA) identified a rare EML4-ALK gene rearrangement. Treatment with alectinib led to rapid clinical improvement and sustained disease control for more than 7 months. This case highlights the value of next-generation sequencing-based profiling in detecting rare actionable alterations missed by standard tests. We also include a discussion on why the EML4-AKL fusion was not detected in the usual test.

ALK-EML4 rearrangement↗

PubMed2025

Next-generation sequencing in breast cancer: current clinical applications and future directions.

INTRODUCTION: Breast cancer is a heterogeneous disease that claims 670,000 lives by 2022. Omic technologies, particularly next generation sequencing (NGS) offers promising avenues for precision medicine. American Society of Clinical Oncology (ASCO) outlines genomic testing's utility, emphasizing prognostic and diagnostic potential. OBJECTIVES: This review succinctly explores NGS's evolution and clinical applications of NGS in breast cancer, thereby guiding future research to enhance patient care. METHODS: Comprehensive literature searches were conducted using databases such as PubMed, Google Scholar, and ResearchGate, focusing on keywords including breast cancer, HER-2 low breast cancer, circulating tumour DNA, single-cell RNA sequencing, and next-generation sequencing. Peer-reviewed, high-quality articles published in English were selected for inclusion. RESULTS: Previous studies have explored the evolution of NGS technology and its clinical applications in breast cancer, including genomic and transcriptomic characterization, treatment guidance, and resistance prediction. Molecular profiling of challenging entities such as early-onset breast cancer and HER-2 low tumours was summarized, with key findings highlighted. This review also discusses emerging technologies, including circulating DNA and single-cell sequencing, as promising avenues for discovery. CONCLUSION: NGS has revealed the genomic and transcriptomic diversity of breast cancer, identifying actionable alterations associated with chemotherapy response and resistance to therapies such as trastuzumab, TKIs, and CDK4/6 inhibitors. Circulating tumour DNA (ctDNA) shows potential for diagnosis, prediction, prognosis, and monitoring, despite tumour heterogeneity. Single-cell analysis enables exploration of individual cell transcriptomes, though high costs and low throughput remain barriers to widespread adoption. HER2-low tumours continue to pose significant research challenges.

Humans↗

PubMed2026

Liquid biopsy for biliary tract cancer: available evidence and future research directions.

INTRODUCTION: Biliary tract cancers (BTCs) are molecularly heterogeneous, and early genomic profiling is becoming increasingly important for treatment decisions. Because tissue sampling is often limited or inadequate, there is a clear need for minimally invasive biomarkers that can support treatment selection and longitudinal disease assessment. AREAS COVERED: This narrative review summarizes current and emerging liquid-biopsy (LB) applications in BTC, with a primary focus on plasma circulating tumor DNA (ctDNA). The evidence base was assembled through targeted searches of PubMed/MEDLINE and Embase up to 1 February 2026, supported by selective ClinicalTrials.gov searches for ongoing biomarker-driven studies. We discuss ctDNA-based molecular profiling for actionable alterations, its prognostic role including minimal residual disease assessment, and its use in serial monitoring of treatment response and acquired resistance. We also consider how LB may support clinical-trial enrichment and biomarker-guided endpoints, and briefly review complementary approaches using bile and other analytes, while highlighting current evidence gaps. EXPERT OPINION: In BTC, ctDNA is best viewed as a complement to tissue-based profiling, especially when tissue is inadequate or when rapid genotyping is needed. Its broader clinical impact will depend on assay standardization, clearer interpretation frameworks for low-shedding disease, and prospective studies showing that ctDNA-guided decisions improve patient outcomes.

Humans↗

PubMed2026

Matched targeted therapy use after broad genomic profiling in advanced Non-Small cell lung cancer.

INTRODUCTION: While broad genomic profiling is increasingly used in advanced NSCLC (aNSCLC), the impact of test results on subsequent guideline-concordant targeted therapy selection remains incompletely understood. METHODS: Using a merged dataset of two large, nationwide, patient-level databases, we identified patients who were diagnosed with aNSCLC 2017-2023, had potentially actionable genomic profiling findings, and initiated systemic therapy. Patients were categorized into actionability subgroups based on contemporaneous regulatory approvals and NCCN guideline recommendations. Within each subgroup, we assessed receipt of guideline-concordant targeted therapy within 24 months, including potential underuse (non-receipt of recommended treatment) and overuse (receipt of non-recommended treatment). RESULTS: Among 6620 patients (67.4% ≥65 years, 54.6% female, 68.9% White), guideline-concordant targeted therapy use varied substantially by actionability category: 2313 (89.6%) of 2582 patients with available 1st-line on-label options received them (10.4% underuse), while 212 (67.3%) of 315 patients with available later-line on-label options received them after 1st-line (32.7% underuse). Among 441 patients with available guideline-concordant off-label options, only 122 (27.7%) received them (72.3% underuse). Conversely, 238 (8.6%) of 3282 patients received matched but guideline-discordant off-label options, representing overuse of ineffective or unestablished therapies. Smoking history, squamous histology, and high PD-L1 expression were associated with lower targeted therapy receipt. CONCLUSIONS: In this cohort study of aNSCLC care, the guideline concordance of targeted therapy use varied by clinical actionability of molecular testing results. Underuse was more common in patients with later-line and off-label targeted therapy options. Patients with classical smoking-related risk profiles were substantially less likely to receive targeted therapy even when actionable alterations were identified.

Journal Article↗

PubMed2026

Circulating Tumor DNA in Breast Cancer: A Liquid Biopsy Revolution for Non-Invasive Genomic Profiling and Clinical Decision-Making.

Breast cancer remains the most frequently diagnosed cancer and a leading cause of cancer-related mortality among women worldwide, underscoring the need for accurate, minimally invasive biomarkers to support precision oncology. Conventional tissue biopsy remains the standard for molecular characterization but is limited by its invasiveness, inability to capture spatial and temporal tumor heterogeneity, and challenges in serial monitoring. Circulating tumor DNA (ctDNA), a tumor-derived fraction of cell-free DNA, has emerged as a promising liquid biopsy biomarker capable of providing real-time genomic information throughout disease progression. This narrative review examines recent advances in ctDNA biology, analytical technologies, clinical applications, current limitations, and future directions in breast cancer management. A structured literature search of PubMed/MEDLINE, Scopus, Embase, Web of Science, and Google Scholar identified relevant English-language publications from 2015 to 2026. Current evidence indicates that highly sensitive platforms, including digital PCR, BEAMing, and next-generation sequencing, can detect clinically actionable alterations in genes such as PIK3CA, ESR1, TP53, ERBB2, AKT1, and BRCA1/2. ctDNA has demonstrated particular utility in identifying minimal residual disease, monitoring therapeutic response, detecting emerging resistance mechanisms, and guiding targeted treatment selection in advanced breast cancer. However, applications in early cancer detection, population screening, and artificial intelligence-assisted clinical decision-making remain investigational. Widespread clinical implementation is constrained by low ctDNA abundance in early-stage disease, analytical variability, limited assay standardization, and cost considerations. Continued technological innovation, prospective multicenter validation, standardized testing protocols, and evidence-based clinical guidelines are essential to fully integrate ctDNA into routine precision breast cancer care.

breast cancer↗

PubMed1975

[Peculiarities of the development of chloramine induced pulmonary edema in rabbits in various age periods].

Rabbits under three weeks of age were found to be less tolerant to chloramine (CA) than adult rabbits. For them the lethal dose of CA was 40--50 mg/kg. They perished from intoxication with the symptoms of protracted collapse without any manifestations of edema. For older rabbits the lethal dose of CA was 60--70 mg/kg. Death occurred with phenomena of acute and sharp edema of the lungs. In young rabbits atypical edema of the lungs occurred only with the administration of very high doses of CA--200--250 mg/kg. Edematous fluid is present in small amount only; there is a prevalence of hemorrhage, this being possibly caused by a direct alterating action of the CA excreted through the lungs on the walls of the arterioles and capillaries of the vascular system of the lungs.

Age Factors↗

PubMed1978

[Effect of ionizing radiation on cerebral phosphodiesterase].

The authors examined the influence of x-ray irradiation on phosphodiesterase system in the brain of rats and the sensitivity of the enzyme to inhibitors (caffeine, theophyline, thyopental) and activators (imidozol). The animals (Wistar with weights of 150--200 gm/were irradiated singly with a dose of 737 r. Phosphodiesterase activity (PD) was determined by the method of Filburn and Carn (1972) at two substrate concentrations (1 and 100 microM). X-ray irradiation did not change PD with high Km, while the enzyme with low Km was reduced significantly and transitionaly. Caffeine, theophyline and thyopental inhibited more PD with low Km in the irradiated rats in comparison with the control nonirradiated rats. The activating effect of imidazol on PD with low Km was more marked in irradiated rats. These data could be interpreted in the light of the molecular mechanisms, determining the altered action of some drugs after x-ray irradiation.

Animals↗

PubMedDate not supplied

Sex-related differences in cadmium-induced alteration of drug action in the rat.

3 days after pretreatment of rats of both sexes with cadmium (2 mg/kg, 1.p.) the duration of hypnosis induced by hexobarbital (75 mg/kg, 1.p.) was potentiated in males but not females. Likewise similar treatment with cadmium leads to significant inhibition of the metabolism of hexobarbital by hepatic microsomal enzymes obtained from male but not female animals. These data suggest that there is a sex-related difference in the ability of cadmium to alter drug action in rats.

Animals↗

PubMed2026

Tumor Mutational Landscape and Its Correlation With Histopathological Characteristics in Breast Cancer.

BACKGROUND/AIM: In breast cancer, knowledge of the associations between clinicopathologic characteristics, genetic changes, and subtype-specific patterns is expanding. This study investigated how pathological and clinical variables affect the actionability of Next Generation Sequencing (NGS)-based tumor molecular data. MATERIALS AND METHODS: 227 breast cancer patients referred to Genekor's laboratory for tumor molecular profile analysis were included in the study. Pathology records were used to assess critical clinicopathological features, including HER2, ER, PR, Ki67, grade, metastatic site, and age. A 1021-gene NGS-based multigene panel was utilized to assess tumor biology alongside tumor mutational burden (TMB) and microsatellite instability (MSI). RESULTS: Comprehensive genomic profiling revealed that 95.6% of the patients harbored at least one oncogenic or likely oncogenic alteration, highlighting the high diagnostic yield of NGS-based testing. Distinct subtype-specific patterns were observed: HR+/HER2- tumors were enriched for PIK3CA and ESR1 gene alterations, whereas triple-negative breast cancer (TNBC) was dominated by TP53 alterations. Clinically actionable alterations were most common in HR+/HER2- tumors (~60% on-label), whereas TNBC more often harbored off-label or trial-associated targets. The inclusion of tumor-agnostic biomarkers (TMB/MSI) increased on-label actionability up to 64.5% in HR+/HER2- tumors, primarily driven by TMB-high cases. Median TMB values were low, and age was the only independent predictor. Furthermore, the presence of actionable alterations was significantly higher in metastatic tumors, and TP53 alterations were associated with aggressive tumor characteristics. CONCLUSION: Comprehensive NGS-based genomic profiling identifies clinically actionable alterations in over half of breast cancer patients, with substantial variability across molecular subtypes. The HR+/HER2- subtype demonstrates the highest prevalence of on-label actionable biomarkers. These findings support the routine implementation of comprehensive genomic profiling, especially in metastatic HER2-negative breast cancer, to guide precision oncology strategies and enable enrollment in biomarker-driven clinical trials.

Humans↗

PubMed1978

Zinc-induced protection against cadmium alteration of drug action.

Pretreatment of male rats with cadmium acetate potentiates the duration of hexobarbital hypnosis and inhibits the rate of hepatic microsomal drug metabolism. Pretreatment of rats with zinc acetate protects against these alterations in drug action elicited by cadmium.

Animals↗

PubMed2026

Accelerating Lung Cancer Management Through Previsit Liquid Biopsy: Results From the LUNG-FAST Pilot Study.

BACKGROUND: Timely molecular profiling is essential for treatment selection in non-small cell lung cancer (NSCLC), yet delays in biomarker testing remain common. We evaluated the feasibility and early clinical impact of a nurse navigator-driven workflow to initiate liquid biopsy before the initial oncology visit. METHODS: LUNG-FAST (Liquid Biopsy for Urgent Neoplastic Genomic Profiling Focused Accelerated Stratification and Testing) was a 4-month prospective pilot at a tertiary cancer center. Intake nurse navigators identified eligible patients with suspected or newly diagnosed lung cancer and facilitated previsit liquid biopsy ordering. Feasibility, turnaround times, genomic findings, and early clinical outcomes were assessed. RESULTS: Among 64 patients, intake nurse navigators identified 94% (60/64) of eligible cases. Liquid biopsy was ordered in 58 patients, with 62% (36/58) placed before the initial oncology visit. Median turnaround time from blood draw to results was 8.5 days for commercial testing and 12.5 days for institutional testing. FDA-actionable genomic alterations were identified in 34% (22/64) of patients, while an additional 11% (7/64) harbored clinically relevant, non-FDA-actionable alterations. Overall, FDA-actionable or clinically relevant alterations were identified in 45% (29/64), with 22% detected by liquid biopsy and an additional 23% by tissue-only profiling. Median time from new patient visit to systemic therapy was 26 days. CONCLUSIONS: A nurse navigator-driven workflow enabling previsit liquid biopsy is feasible and identifies actionable genomic alterations in a substantial proportion of patients with lung cancer. Plasma and tissue profiling are complementary, and earlier plasma-based testing may expedite treatment decision-making while highlighting opportunities to optimize biomarker testing workflows.

Humans↗

PubMed1979

Alterations in insulin action by endotoxin in vitro.

Fat cells isolated from epididymal fat pads of Sprague-Dawley rats were exposed to E coli endotoxin in vitro, and after washing the ensuing alterations in glucose oxidation and antilipolysis were studied. Although endotoxin (500 microgram/ml) exhibited an insulin-like effect on basal glucose oxidation, it diminished insulin stimulation of glucose oxidation, seemingly inducing an insulin-resistant state. On the other hand, identical doses of insulin elicited significantly greater antilipolytic effects in endotoxin-treated cells, than in untreated cells. Thus, endotoxin exposure (in a range of 0.05-200 microgram/0.5 ml cell suspension) rendered adipocytes more sensitive to the antilipolytic effect of insulin. Results of this study indicate that the different physiologic actions of insulin on adipocytes are not affected in a uniform manner by endotoxin exposure in vitro.

Adipose Tissue↗