Distinct sub-second dopamine signaling in dorsolateral striatum measured by a genetically-encoded fluorescent sensor

The development of genetically encoded dopamine sensors such as dLight has provided a new approach to measuring slow and fast dopamine dynamics both in brain slices and in vivo, possibly enabling dopamine measurements in areas like the dorsolateral striatum (DLS) where previously such recordings with fast-scan cyclic voltammetry (FSCV) were difficult. To test this, we first evaluated dLight photometry in mouse brain slices with simultaneous FSCV and found that both techniques yielded comparable results, but notable differences in responses to dopamine transporter inhibitors, including cocaine. We then used in vivo fiber photometry with dLight in mice to examine responses to cocaine in DLS. We also compared dopamine responses during Pavlovian conditioning across the striatum. We show that dopamine increases were readily detectable in DLS and describe transient dopamine kinetics, as well as slowly developing signals during conditioning. Overall, our findings indicate that dLight photometry is well suited to measuring dopamine dynamics in DLS

Health-Related Quality of Life and Experiences of Sarcoma Patients during the COVID-19 Pandemic

Sarcomas are rare cancers with a spectrum of clinical needs and outcomes. We investigated care experiences and health-related quality of life (HRQoL) in sarcoma patients during the COVID-19 pandemic. Patients with appointments during the first two months of the UK lockdown were invited to complete a survey. Questions included views on care modifications, COVID-19 worry and psychosocial impact, and EORTC-QLQ-C30 items. 350 patients completed the survey; median age 58 (16–92) years. Care modifications included telemedicine (74%) and postponement of appointments (34%), scans (34%) or treatment (10%). Most felt the quality of care was not affected (72%), however, social life (87%) and emotional wellbeing (41%) were affected. Worry about COVID-19 infection was moderately high (mean 5.8/10) and significantly related to higher cancer-related worry; associated with lower emotional functioning irrespective of treatment intent. Curative patients (44%) with low resilient coping scores had significantly higher COVID-19 worry. Patients who did not know their treatment intent (22%) had significantly higher COVID-19 worry and insomnia. In summary, care experiences were generally positive; however, cancer-related worry, low resilient coping and uncertainty about treatment intent were associated with COVID-19 worry. These patients may benefit from additional psychological support during the pandemic and beyond.</jats:p

Prevalence estimation of significant fibrosis because of NASH in Spain combining transient elastography and histology

Acord transformatiu CRUE-CSICBackground & Aims: Non-alcoholic fatty liver disease (NAFLD) has become a major public health problem, but the prevalence of fibrosis associated with non-alcoholic steatohepatitis (NASH) is largely unknown in the general population. This study aimed to provide an updated estimation of the prevalence of NASH fibrosis in Spain. Methods: This was an observational, retrospective, cross-sectional, population-based study with merged data from two Spanish datasets: a large (N = 12 246) population-based cohort (ETHON), including transient elastography (TE) data, and a contemporary multi-centric biopsy-proven NASH cohort with paired TE data from tertiary centres (N = 501). Prevalence for each NASH fibrosis stage was estimated by crossing TE data from ETHON dataset with histology data from the biopsy-proven cohort. Results: From the patients with valid TE in ETHON dataset (N = 11 440), 5.61% (95% confidence interval [95% CI]: 2.53-11.97) had a liver stiffness measurement (LSM) ≥ 8 kPa. The proportion attributable to NAFLD (using clinical variables and Controlled Attenuation Parameter) was 57.3% and thus, the estimated prevalence of population with LSM ≥ 8 kPa because of NAFLD was 3.21% (95% CI 1.13-8.75). In the biopsy-proven NASH cohort, 389 patients had LSM ≥ 8 kPa. Among these, 37% did not have significant fibrosis (F2-4). The estimated prevalence of NASH F2-3 and cirrhosis in Spain's adult population were 1.33% (95% CI 0.29-5.98) and 0.70% (95% CI 0.10-4.95) respectively. Conclusions: These estimations provide an accurate picture of the current prevalence of NASH-related fibrosis in Spain and can serve as reference point for dimensioning the therapeutic efforts that will be required as NASH therapies become available

Machine Learning Detects Pan-cancer Ras Pathway Activation in The Cancer Genome Atlas.

Precision oncology uses genomic evidence to match patients with treatment but often fails to identify all patients who may respond. The transcriptome of these "hidden responders" may reveal responsive molecular states. We describe and evaluate a machine-learning approach to classify aberrant pathway activity in tumors, which may aid in hidden responder identification. The algorithm integrates RNA-seq, copy number, and mutations from 33 different cancer types across The Cancer Genome Atlas (TCGA) PanCanAtlas project to predict aberrant molecular states in tumors. Applied to the Ras pathway, the method detects Ras activation across cancer types and identifies phenocopying variants. The model, trained on human tumors, can predict response to MEK inhibitors in wild-type Ras cell lines. We also present data that suggest that multiple hits in the Ras pathway confer increased Ras activity. The transcriptome is underused in precision oncology and, combined with machine learning, can aid in the identification of hidden responders

Patients' preferences for subcutaneous trastuzumab versus conventional intravenous infusion for the adjuvant treatment of HER2-positive early breast cancer: final analysis of 488 patients in the international, randomized, two-cohort PrefHer study

PrefHer revealed compelling and consistent patient preference for subcutaneous (s.c.) trastuzumab, regardless of delivery by single-use injection device or hand-held syringe. s.c. trastuzumab was well-tolerated and safety data, including immunogenicity, were consistent with previous reports. No new safety signals were identified compared with the known intravenous trastuzumab profile in early breast cance

Artesunate may attenuate the effects of Cytokine Release Syndrome (CRS) in Covid-19 Disease by targeting Interleukin-6 and associated inflammatory response pathways

The coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an unprecedented global health challenge for which safe, effective and affordable treatments need to be rapidly identified. Although in the majority of patients, the natural history of COVID-19 infection is self limiting, a small proportion of patients develop a cytokine release syndrome (CRS)/cytokine storm (CS) with raised Interleukin-6 (IL-6) and associated inflammatory cytokines. Dysregulated continual synthesis of IL-6 can contribute to multi-organ failure (MOF). Artesunate is an established antimalarial with an excellent tolerability and safety profile. Artesunate is able to modulate pro-inflammatory cytokine pathways and in doing so prevent multi-organ failure in models of lung, myocardial and renal injury in a number of cell line and animal models. Robust clinical trials are indicated to test this hypothesis

A genetic predisposition for Cytokine Storm in life-threatening COVID-19 infection

The COVID-19 pandemic is a cause of serious morbidity and mortality and is placing a significant burden on healthcare systems globally. The clinical manifestations of COVID-19 disease form a wide spectrum, from mild symptoms to life threatening disease. A small subset of patients develop Cytokine Release Syndrome (CRS)/Cytokine Storm (CS) that results in hyper inflammation, clinical deterioration and multi-organ failure. There is growing evidence that Interleukin-6 (IL-6) is a central mediator of CS. Evidence of an inflammatory Kawasaki-like syndrome in children with severe COVID-19 is also emerging. Familial Mediterranean Fever (FMF) and Glucose-6-phosphate Dehydrogenase (G6PD) deficiency are 2 common gene polymorphisms that predispose to hyper inflammatory states. Countries with high mortality rates for COVID-19 deaths (such as Spain, Italy and France) or the Middle East (Iran) also have a high number of carriers of mutations in the Mediterranean Fever gene (MEFV), which causes Familial Mediterranean Fever (FMF). G6PD deficiency, a common enzymopathy caused by X-linked gene polymorphisms that reduce the ability of cells to deal with oxidant stress also has a global distribution affecting Black, Asian and Minority Ethnic (BAME) groups. In combination with acquired causes of inflammation such as obesity, these genetic variations may predispose to increased risk of severe COVID-19. Mendelian randomisation studies are needed to establish if there is a contribution to higher mortality rates in certain populations due to genetic factors such as MEFV or G6PD mutations and related genes and if these may represent predictive and prognostic biomarkers