Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer. NEPC arises de novo only rarely; the disease predominantly develops from adenocarcinoma in response to drug-induced ...androgen receptor signalling inhibition, although the mechanisms behind this transdifferentiation are a subject of debate. The survival of patients with NEPC is poor, and few effective treatment options are available. To improve clinical outcomes, understanding of the biology and molecular mechanisms regulating NEPC development is crucial. Various NEPC molecular drivers make temporal contributions during NEPC development, and despite the limited treatment options available, several novel targeted therapeutics are currently under research.
Single-cell transcriptomic analysis is widely used to study human tumors. However, it remains challenging to distinguish normal cell types in the tumor microenvironment from malignant cells and to ...resolve clonal substructure within the tumor. To address these challenges, we developed an integrative Bayesian segmentation approach called copy number karyotyping of aneuploid tumors (CopyKAT) to estimate genomic copy number profiles at an average genomic resolution of 5 Mb from read depth in high-throughput single-cell RNA sequencing (scRNA-seq) data. We applied CopyKAT to analyze 46,501 single cells from 21 tumors, including triple-negative breast cancer, pancreatic ductal adenocarcinoma, anaplastic thyroid cancer, invasive ductal carcinoma and glioblastoma, to accurately (98%) distinguish cancer cells from normal cell types. In three breast tumors, CopyKAT resolved clonal subpopulations that differed in the expression of cancer genes, such as KRAS, and signatures, including epithelial-to-mesenchymal transition, DNA repair, apoptosis and hypoxia. These data show that CopyKAT can aid in the analysis of scRNA-seq data in a variety of solid human tumors.
Immune evasion and altered metabolism, where glucose utilization is diverted to increased lactic acid production, are two fundamental hallmarks of cancer. Although lactic acid has long been ...considered a waste product of this alteration, it is now well accepted that increased lactic acid production and the resultant acidification of the tumor microenvironment (TME) promotes multiple critical oncogenic processes including angiogenesis, tissue invasion/metastasis, and drug resistance. We and others have hypothesized that excess lactic acid in the TME is responsible for suppressing anticancer immunity. Recent studies support this hypothesis and provide mechanistic evidence explaining how lactic acid and the acidic TME impede immune cell functions. In this review, we consider lactic acid's role as a critical immunoregulatory molecule involved in suppressing immune effector cell proliferation and inducing immune cell de-differentiation. This results in the inhibition of antitumor immune responses and the activation of potent, negative regulators of innate and adaptive immune cells. We also consider the role of an acidic TME in suppressing anticancer immunity. Finally, we provide insights to help translate this new knowledge into impactful anticancer immune therapies.
Abstract
Tumor necrosis commonly exists and predicts poor prognoses in many cancers. Although it is thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved ...cell death remain obscure. Here, we show that necrosis in glioblastoma (GBM) involves neutrophil-triggered ferroptosis. In a hyperactivated transcriptional coactivator with PDZ-binding motif-driven GBM mouse model, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens necrosis. Neutrophils isolated from mouse brain tumors kill cocultured tumor cells. Mechanistically, neutrophils induce iron-dependent accumulation of lipid peroxides within tumor cells by transferring myeloperoxidase-containing granules into tumor cells. Inhibition or depletion of myeloperoxidase suppresses neutrophil-induced tumor cell cytotoxicity. Intratumoral glutathione peroxidase 4 overexpression or acyl-CoA synthetase long chain family member 4 depletion diminishes necrosis and aggressiveness of tumors. Furthermore, analyses of human GBMs support that neutrophils and ferroptosis are associated with necrosis and predict poor survival. Thus, our study identifies ferroptosis as the underlying nature of necrosis in GBMs and reveals a pro-tumorigenic role of ferroptosis. Together, we propose that certain tumor damage(s) occurring during early tumor progression (i.e. ischemia) recruits neutrophils to the site of tissue damage and thereby results in a positive feedback loop, amplifying GBM necrosis development to its fullest extent.
Non‐technical summary MicroRNA (miRNA) molecules are essential intracellular mediators of numerous biological processes including angiogenesis, inflammation, and mitochondrial metabolism. Recently, ...it has been shown that miRNAs are secreted into the bloodstream and that circulating miRNAs (c‐miRNAs) may serve important endocrine functions. This study examined plasma profiles of specific c‐miRNAs in healthy competitive athletes at rest and during exhaustive exercise testing, before and after a 90 day period of exercise training. In this setting, we observed four distinct patterns of c‐miRNA response to exercise: (1) c‐miRNAs up‐regulated by acute exhaustive exercise before and after sustained exercise training, (2) c‐miRNAs responsive to acute exhaustive exercise before but not after sustained exercise training, (3) c‐miRNAs responsive only to sustained exercise training, and (4) non‐responsive c‐miRNAs. These findings set the stage for further work aimed at defining the role of c‐miRNAs as fitness biomarkers and physiological mediators of exercise‐induced cardiovascular adaptation.
MicroRNAs (miRNAs) are intracellular mediators of essential biological functions. Recently, plasma‐based ‘circulating’ miRNAs (c‐miRNAs) have been shown to control cellular processes, but the c‐miRNA response to human exercise remains unknown. We sought to determine whether c‐miRNAs are dynamically regulated in response to acute exhaustive cycling exercise and sustained rowing exercise training using a longitudinal, repeated measures study design. Specifically, c‐miRNAs involved in angiogenesis (miR‐20a, miR‐210, miR‐221, miR‐222, miR‐328), inflammation (miR‐21, miR‐146a), skeletal and cardiac muscle contractility (miR‐21, miR‐133a), and hypoxia/ischaemia adaptation (miR‐21, miR‐146a, and miR‐210) were measured at rest and immediately following acute exhaustive cycling exercise in competitive male rowers (n= 10, age = 19.1 ± 0.6 years) before and after a 90 day period of rowing training. Distinct patterns of c‐miRNA response to exercise were observed and adhered to four major profiles: (1) c‐miRNA up‐regulated by acute exercise before and after sustained training (miR‐146a and miR‐222), (2) c‐miRNA responsive to acute exercise before but not after sustained training (miR‐21 and miR‐221), (3) c‐miRNA responsive only to sustained training (miR‐20a), and (4) non‐responsive c‐miRNA (miR‐133a, miR‐210, miR‐328). Linear correlations were observed between peak exercise levels of miR‐146a and (r= 0.63, P= 0.003) and between changes in resting miR‐20a and changes in (pre‐training vs. post‐training, r= 0.73; P= 0.02). Although future work is required, these results suggest the potential value of c‐miRNAs as exercise biomarkers and their possible roles as physiological mediators of exercise‐induced cardiovascular adaptation.
•Obesity is an important risk factor for atrial fibrillation.•Despite “obesity paradox” in atrial fibrillation, patient weight loss preferred.•Oral anticoagulants may be more efficacious in patients ...with higher body mass indices.•Similar efficacy/safety with novel anticoagulants versus warfarin in obese patients.
Four non-vitamin K antagonist oral anticoagulants (NOACs) are approved for use to reduce the risk of stroke and systemic embolism in patients with atrial fibrillation (AF). However, data are limited regarding the use of NOACs in the obese population. This manuscript summarizes current concepts regarding obesity in patients with AF and reviews in depth the data on the efficacy and safety of NOACs in obese patients with AF. The Pubmed database was searched for relevant articles. When evaluating obese patients with AF, weight loss is important to reduce disease burden. Recent analyses of the four NOAC versus warfarin trials (RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48) stratified by body mass index (BMI) demonstrate preserved efficacy with NOACs versus warfarin in obese patients, with similar risk of major bleeding. Although the data are limited in class III obese patients (body mass index ≥40kg/m2), the efficacy and safety of apixaban or edoxaban appears to be similar to warfarin in patients with BMI 40-50kg/m2. In conclusion, these new data should be considered in updated guidelines, which currently provide limited, and sometimes conflicting recommendations regarding the use of NOACs in obese patients, particularly in severely obese patients.
The deadliest anaplastic thyroid cancer (ATC) often transforms from indolent differentiated thyroid cancer (DTC); however, the complex intratumor transformation process is poorly understood. We ...investigated an anaplastic transformation model by dissecting both cell lineage and cell fate transitions using single-cell transcriptomic and genetic alteration data from patients with different subtypes of thyroid cancer. The resulting spectrum of ATC transformation included stress-responsive DTC cells, inflammatory ATC cells (iATCs), and mitotic-defective ATC cells and extended all the way to mesenchymal ATC cells (mATCs). Furthermore, our analysis identified 2 important milestones: (a) a diploid stage, in which iATC cells were diploids with inflammatory phenotypes and (b) an aneuploid stage, in which mATCs gained aneuploid genomes and mesenchymal phenotypes, producing excessive amounts of collagen and collagen-interacting receptors. In parallel, cancer-associated fibroblasts showed strong interactions among mesenchymal cell types, macrophages shifted from M1 to M2 states, and T cells reprogrammed from cytotoxic to exhausted states, highlighting new therapeutic opportunities for the treatment of ATC.
Thrombotic complications occur at high rates in hospitalized patients with COVID‐19, yet the impact of intensive antithrombotic therapy on mortality is uncertain. We examined in‐hospital mortality ...with intermediate‐ compared to prophylactic‐dose anticoagulation, and separately with in‐hospital aspirin compared to no antiplatelet therapy, in a large, retrospective study of 2785 hospitalized adult COVID‐19 patients. In this analysis, we established two separate, nested cohorts of patients (a) who received intermediate‐ or prophylactic‐dose anticoagulation (“anticoagulation cohort”, N = 1624), or (b) who were not on home antiplatelet therapy and received either in‐hospital aspirin or no antiplatelet therapy (“aspirin cohort”, N = 1956). To minimize bias and adjust for confounding factors, we incorporated propensity score matching and multivariable regression utilizing various markers of illness severity and other patient‐specific covariates, yielding treatment groups with well‐balanced covariates in each cohort. The primary outcome was cumulative incidence of in‐hospital death. Among propensity score‐matched patients in the anticoagulation cohort (N = 382), in a multivariable regression model, intermediate‐ compared to prophylactic‐dose anticoagulation was associated with a significantly lower cumulative incidence of in‐hospital death (hazard ratio 0.518 0.308–0.872). Among propensity‐score matched patients in the aspirin cohort (N = 638), in a multivariable regression model, in‐hospital aspirin compared to no antiplatelet therapy was associated with a significantly lower cumulative incidence of in‐hospital death (hazard ratio 0.522 0.336–0.812). In this propensity score‐matched, observational study of COVID‐19, intermediate‐dose anticoagulation and aspirin were each associated with a lower cumulative incidence of in‐hospital death.
Challenges in using cytokine data are limiting Coronavirus Disease 2019 (COVID-19) patient management and comparison among different disease contexts. We suggest mitigation strategies to improve the ...accuracy of cytokine data, as we learn from experience gained during the COVID-19 pandemic.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Anaplastic thyroid carcinoma (ATC) historically has a 4-month median overall survival (OS) from time of diagnosis, with disease-specific mortality approaching 100%. The association between recent ...major advancements in treatment and OS has yet to be evaluated.
To evaluate rates of OS in patients with ATC over the last 2 decades.
Retrospective cohort study in a single tertiary care institution. Patients with histopathological confirmation of ATC from January 2000 to October 2019 were included and divided into 3 groups according to date of presentation: 2000-2013, 2014-2016, and 2017-2019.
Overall survival compared among different treatment eras and differing therapies, including targeted therapy, immunotherapy, and surgery.
Of 479 patients (246 men 51%; median age, 65.0 range, 21.1-92.6 years) with ATC evaluated, 52 (11%) were stage IVA, 172 (36%) stage IVB, and 255 (53%) stage IVC at presentation. The median OS of the entire cohort was 0.79 years (9.5 months), ranging from 0.01 to 16.63. The OS at 1 and 2 years was 35% (95% CI, 29%-42%) and 18% (95% CI, 13%-23%) in the 2000-2013 group (n = 227), 47% (95% CI, 36%-56%) and 25% (95% CI, 17%-34%) in the 2014-2016 group (n = 100), and 59% (95% CI, 49%-67%) and 42% (95% CI, 30%-53%) in the 2017-2019 group (n = 152), respectively (P < .001). The hazard ratio was 0.50 (95% CI, 0.38-0.67) for the 2017-2019 group compared with the 2000-2013 patients (P < .001). Factors associated with improved OS included targeted therapy (hazard ratio, 0.49; 95% CI, 0.39-0.63; P < .001), the addition of immunotherapy to targeted therapy (hazard ratio, 0.58; 95% CI, 0.36-0.94; P = .03), and surgery following neoadjuvant BRAF-directed therapy (hazard ratio, 0.29; 95% CI, 0.10-0.78; P = .02). Patients undergoing surgery following neoadjuvant BRAF-directed therapy (n = 20) had a 94% 1-year survival with a median follow-up of 1.21 years.
In this large single-institution cohort study spanning nearly 20 years, changes in patient management appear to be associated with significant increase in survival. The era of untreatable ATC is progressively being replaced by molecular-based personalized therapies, with integration of multidisciplinary therapies including surgery and radiation therapy.
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