Explore the vast range of titles available.

Circulating tumor cell (CTC) enumeration promises to be an important predictor of clinical outcome for a range of cancers. Established CTC enumeration methods primarily rely on affinity capture of cell surface antigens, and have been criticized for underestimation of CTC numbers due to antigenic bias. Emerging CTC capture strategies typically distinguish these cells based on their assumed biomechanical characteristics, which are often validated using cultured cancer cells. In this study, we developed a software tool to investigate the morphological properties of CTCs from patients with castrate resistant prostate cancer and cultured prostate cancer cells in order to establish whether the latter is an appropriate model for the former. We isolated both CTCs and cultured cancer cells from whole blood using the CellSearch® system and examined various cytomorphological characteristics. In contrast with cultured cancer cells, CTCs enriched by CellSearch® system were found to have significantly smaller size, larger nuclear-cytoplasmic ratio, and more elongated shape. These CTCs were also found to exhibit significantly more variability than cultured cancer cells in nuclear-cytoplasmic ratio and shape profile.

A key challenge in transfusion medicine research and clinical hematology is to develop a simple and non-destructive method to measure the quality of each blood unit prior to use. RBC deformability has long been proposed as an indicator of blood quality. We measured RBC deformability using the pressure required for single cells to transit through a micrometer scale constriction to examine longitudinal changes in RBC deformability, as well as the variability in blood quality and storage capacity across donors. We used a microfluidic device to monitor deformability changes in RBCs stored in plastic tubes and in blood bags over 14 and 56 days respectively. We found consistent storage based degradation of RBC deformability with statistically significant variability in both the initial RBC deformability and storage capacity among donors. Furthermore, all samples exhibited a transient recovery phenomenon. Deformability profiling of stored RBCs using transiting pressure showed significant donor variability in initial quality and storage capacity. This measurement approach shows promise as a rapid method to individually assess the quality of stored RBC units.

Human papillomavirus (HPV)–associated oropharyngeal squamous-cell carcinoma differs from oropharyngeal cancers caused by tobacco and other factors. In this study, patients with oropharyngeal cancer were treated with cisplatin plus radiation therapy; the 3-year rate of overall survival was 82.4% among patients with HPV-positive tumors and 57.1% among patients with HPV-negative tumors. HPV status is an independent prognostic factor for survival among patients with oropharyngeal squamous-cell carcinoma. Patients with oropharyngeal cancer were treated with cisplatin plus radiation therapy; the 3-year rate of overall survival was 82.4% among patients with HPV-positive tumors and 57.1% among patients with HPV-negative tumors. HPV status is an independent prognostic factor for survival among patients with oropharyngeal squamous-cell carcinoma. The majority of patients enrolled in therapeutic trials for squamous-cell carcinoma of the head and neck have oropharyngeal squamous-cell carcinoma, which in a subgroup of these patients is caused by infection with human papillomavirus (HPV). 1 This subgroup is defined by the presence of high-risk types of HPV in tumor cells, predominantly HPV type 16 (HPV-16). Expression of viral E6 and E7 oncoproteins that inactivate the tumor-suppressor proteins p53 and the retinoblastoma protein (pRb), respectively, is necessary for malignant behavior of these tumors. 2 Several retrospective case series have shown that among patients with oropharyngeal squamous-cell carcinoma, patients with HPV-positive tumors have . . .

Anhedonia remains a major clinical issue for which there is few effective interventions. Untreated or poorly controlled anhedonia has been linked to worse disease course and increased suicidal behavior across disorders. Taking a proof-of-mechanism approach under the auspices of the National Institute of Mental Health FAST-FAIL initiative, we were the first to show that, in a transdiagnostic sample screened for elevated self-reported anhedonia, 8 weeks of treatment with a kappa-opioid receptor (KOR) antagonist resulted in significantly higher reward-related activation in one of the core hubs of the brain reward system (the ventral striatum), better reward learning in the Probabilistic Reward Task (PRT), and lower anhedonic symptoms, relative to 8 weeks of placebo. Here, we performed secondary analyses of the PRT data to investigate the putative effects of KOR antagonism on anhedonic behavior with more precision by using trial-level model-based Bayesian computational modeling and probability analyses. We found that, relative to placebo, KOR antagonism resulted in significantly higher learning rate (i.e., ability to learn from reward feedback) and a more sustained preference toward the more frequently rewarded stimulus, but unaltered reward sensitivity (i.e., the hedonic response to reward feedback). Collectively, these findings provide novel evidence that in a transdiagnostic sample characterized by elevated anhedonia, KOR antagonism improved the ability to modulate behavior as a function of prior rewards. Together with confirmation of target engagement in the primary report (Krystal et al., Nat Med, 2020), the current findings suggest that further transdiagnostic investigation of KOR antagonism for anhedonia is warranted.

BackgroundThe relationship between atherosclerosis and endotypes of myocardial ischaemia with no obstructive coronary artery disease (INOCA) is unclear. We investigated potential associations between cumulative atherosclerotic plaque burden quantified using the Gensini score, novel invasive indices of coronary microvascular function (microvascular resistance reserve (MRR); resistive reserve ratio (RRR)) and related INOCA endotypes.MethodsCoronary angiography and invasive coronary function tests were simultaneously acquired in the CorMicA cohort. A comprehensive physiological assessment was performed using both a thermodilution-based diagnostic guidewire and intracoronary acetylcholine provocation testing. Angiograms were examined for luminal stenosis in each segment of the SYNTAX coronary model. Cumulative plaque burden was quantified using the Gensini score, which incorporated both the number of diseased coronary segments and stenosis severity. Results were compared with indices of microvascular function and INOCA endotypes. Angiographic analyses were performed blind to coronary physiology findings.ResultsIn 151 participants (median age 61 years; 73.5% female) without flow-limiting coronary artery disease, medical history included 41.7% smoking, 63.6% hypertension and 19.2% diabetes mellitus. The left anterior descending artery underwent diagnostic guidewire testing in 85.4%, and 55.0% of participants had abnormal coronary flow reserve (CFR) and/or Index of Microcirculatory Resistance (IMR). The median Gensini score was 6.0 (IQR 2.5–11.0). CFR (p=0.012), MRR (p=0.026) and RRR (p=0.026), but not IMR (p=0.445), were univariably associated with raised Gensini scores. These significant effects persisted in multivariable models controlling for potential confounders. Considering INOCA endotypes, Gensini scores differed among participants with microvascular angina (MVA) (7.0 (2.5–11.0)), vasospastic angina (VSA) (4.5 (2.0–10.0)), mixed MVA/VSA (9.0 (5.0–11.5)) and non-cardiac symptoms (3.5 (1.5–8.0)); Kruskal-Wallis p=0.030.ConclusionsReduced CFR, MRR and RRR, and MVA were associated with increased coronary atherosclerotic plaque burden, as evidenced by higher Gensini scores. These novel findings provide a mechanistic link between INOCA and cardiovascular events, reinforcing the importance of antiatherosclerosis therapy in patients with MVA.

There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19 + B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were 48.6% for both. The 1-year overall survival and progression-free survival were 68% and 32%, respectively. Patients who achieved OR had higher levels and longer persistence of CAR-NK cells. Receiving CAR-NK cells from a cord blood unit (CBU) with nucleated red blood cells ≤ 8 × 10 7 and a collection-to-cryopreservation time ≤ 24 h was the most significant predictor for superior outcome. NK cells from these optimal CBUs were highly functional and enriched in effector-related genes. In contrast, NK cells from suboptimal CBUs had upregulation of inflammation, hypoxia and cellular stress programs. Finally, using multiple mouse models, we confirmed the superior antitumor activity of CAR/IL-15 NK cells from optimal CBUs in vivo. These findings uncover new features of CAR-NK cell biology and underscore the importance of donor selection for allogeneic cell therapies. ClinicalTrials.gov identifier: NCT03056339 . In the final report of a phase 1/2 trial evaluating allogeneic CD19-specific CAR-NK cells armored with IL-15 in patients with CD19 + hematologic malignancies, the therapy was shown to be safe and efficacious with distinct cord blood features associated with response.

Patterning of the mouse embryo along the anteroposterior axis during body plan development requires migration of the distal visceral endoderm (DVE) towards the future anterior side by a mechanism that has remained unknown. Here we show that Nodal signalling and the regionalization of its antagonists are required for normal migration of the DVE. Whereas Nodal signalling provides the driving force for DVE migration by stimulating the proliferation of visceral endoderm cells, the antagonists Lefty1 and Cerl determine the direction of migration by asymmetrically inhibiting Nodal activity on the future anterior side.

PurposeNeratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated systemic efficacy and intracranial activity in various stages of HER2+breast cancer. NALA was a phase III randomized trial that assessed the efficacy and safety of neratinib+capecitabine (N+C) against lapatinib+capecitabine (L+C) in HER2+ metastatic breast cancer (mBC) patients who had received ≥ 2 HER2-directed regimens. Descriptive analysis results of the Asian subgroup in the NALA study are reported herein.Methods621 centrally assessed HER2+ mBC patients were enrolled, 202 of whom were Asian. Those with stable, asymptomatic brain metastases (BM) were eligible for study entry. Patients were randomized 1:1 to N (240 mg qd) + C (750 mg/m2 bid, day 1–14) with loperamide prophylaxis or to L (1250 mg qd) + C (1000 mg/m2 bid, day 1–14) in 21-day cycles. Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints included time to intervention for central nervous system (CNS) disease, objective response rate, duration of response (DoR), clinical benefit rate, and safety.Results104 and 98 Asian patients were randomly assigned to receive N+C or L+C, respectively. Median PFS of N+C and L+C was 7.0 and 5.4 months (P = 0.0011), respectively. Overall cumulative incidence of intervention for CNS disease was lower with N+C (27.9 versus 33.8%; P = 0.039). Both median OS (23.8 versus 18.7 months; P = 0.185) and DoR (11.1 versus 4.2 months; P < 0.0001) were extended with N+C, compared to L+C. The incidences of grade 3/4 treatment emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation were mostly comparable between the two arms. Diarrhea and palmar-plantar erythrodysesthesia were the most frequent TEAEs in both arms, similar to the overall population in incidence and severity.ConclusionConsistent with the efficacy profile observed in the overall study population, Asian patients with HER2+ mBC, who had received ≥ 2 HER2-directed regimens, may also benefit from N+C. No new safety signals were noted.Clinical trial registrationNCT01808573

Heart failure is caused in part by cardiac remodeling processes that include the death of cardiac myocytes and their replacement by cardiac fibroblasts. Here, we hypothesize that cardiac fibroblasts may harbor epigenetic contexts in which heart disease-associated non-coding SNPs perturb gene expression relevant to disease. To test this, we utilized male primary cardiac fibroblasts to generate high-resolution Hi-C data and integrate it with functional genomic information to annotate and link putative distal regulatory elements in heart disease-associated loci to gene promoters. We identify several target genes with established roles in cardiac fibrosis and/or heart disease ( GJA1 , TBC1D32, CXCL12 , IL6R , and FURIN ). We perform Perturb-seq in immortalized male cardiac fibroblasts to knock out putative regulatory elements, confirming regulatory relationships involving GJA1 , CXCL12 , and FURIN . Our results demonstrate that multi-omic approaches can delineate pathophysiologically relevant regulatory circuits connecting protein-coding genes to non-coding genetic variants associated with disease. Heart failure can be caused by cardiac fibroblasts replacing myocytes. Here, the authors use functional genomic data from fibroblasts, genetic signals enriched in people with heart disease, and gene perturbation analyses to link disease-associated regulatory elements to protein-coding genes.

Direct quantification of terrestrial biosphere responses to global change is crucial for projections of future climate change in Earth system models. Here, we synthesized ecosystem carbon-cycling data from 1,119 experiments performed over the past four decades concerning changes in temperature, precipitation, CO 2 and nitrogen across major terrestrial vegetation types of the world. Most experiments manipulated single rather than multiple global change drivers in temperate ecosystems of the USA, Europe and China. The magnitudes of warming and elevated CO 2 treatments were consistent with the ranges of future projections, whereas those of precipitation changes and nitrogen inputs often exceeded the projected ranges. Increases in global change drivers consistently accelerated, but decreased precipitation slowed down carbon-cycle processes. Nonlinear (including synergistic and antagonistic) effects among global change drivers were rare. Belowground carbon allocation responded negatively to increased precipitation and nitrogen addition and positively to decreased precipitation and elevated CO 2 . The sensitivities of carbon variables to multiple global change drivers depended on the background climate and ecosystem condition, suggesting that Earth system models should be evaluated using site-specific conditions for best uses of this large dataset. Together, this synthesis underscores an urgent need to explore the interactions among multiple global change drivers in underrepresented regions such as semi-arid ecosystems, forests in the tropics and subtropics, and Arctic tundra when forecasting future terrestrial carbon-climate feedback. A synthesis of global change experiments that manipulated temperature, precipitation, carbon dioxide or nitrogen identifies a need to consider site-specific factors and interactions in Earth system models.