Miracle-dz/UniFAR-FTUs huggingface dataset:
Unraveling Triple-Negative Breast Cancer Tumor Microenvironment Heterogeneity: Towards an Optimized Treatment Approach

Abstract Background Recent efforts of gene expression profiling analyses recognized at least four different triple-negative breast cancer (TNBC) molecular subtypes. However, little is known regarding their tumor microenvironment (TME) heterogeneity. Methods Here, we investigated TME heterogeneity within each TNBC molecular subtype, including immune infiltrate localization and composition together with expression of targetable immune pathways, using publicly available transcriptomic and genomic datasets from a large TNBC series totaling 1512 samples. Associations between molecular subtypes and specific features were assessed using logistic regression models. All statistical tests were two-sided. Results We demonstrated that each TNBC molecular subtype exhibits distinct TME profiles associated with specific immune, vascularization, stroma, and metabolism biological processes together with specific immune composition and localization. The immunomodulatory subtype was associated with the highest expression of adaptive immune-related gene signatures and a fully inflamed spatial pattern appearing to be the optimal candidate for immune check point inhibitors. In contrast, most mesenchymal stem-like and luminal androgen receptor tumors showed an immunosuppressive phenotype as witnessed by high expression levels of stromal signatures. Basal-like, luminal androgen receptor, and mesenchymal subtypes exhibited an immune cold phenotype associated with stromal and metabolism TME signatures and enriched in margin-restricted spatial pattern. Tumors with high chromosomal instability and copy number loss in the chromosome 5q and 15q regions, including genomic loss of major histocompatibility complex related genes, showed reduced cytotoxic activity as a plausible immune escape mechanism. Conclusions Our results demonstrate that each TNBC subtype is associated with specific TME profiles, setting the ground for a rationale tailoring of immunotherapy in TNBC patients.
Decentralized Event-Triggered Control for a Class of Nonlinear-Interconnected Systems Using Reinforcement Learning

In this article, we propose a novel decentralized event-triggered control (ETC) scheme for a class of continuous-time nonlinear systems with matched interconnections. The present interconnected systems differ from most of the existing interconnected plants in that their equilibrium points are no longer assumed to be zero. Initially, we establish a theorem to indicate that the decentralized ETC law for the overall system can be represented by an array of optimal ETC laws for nominal subsystems. Then, to obtain these optimal ETC laws, we develop a reinforcement learning (RL)-based method to solve the Hamilton–Jacobi–Bellman equations arising in the discounted-cost optimal ETC problems of the nominal subsystems. Meanwhile, we only use critic networks to implement the RL-based approach and tune the critic network weight vectors by using the gradient descent method and the concurrent learning technique together. With the proposed weight vectors tuning rule, we are able to not only relax the persistence of the excitation condition but also ensure the critic network weight vectors to be uniformly ultimately bounded. Moreover, by utilizing the Lyapunov method, we prove that the obtained decentralized ETC law can force the entire system to be stable in the sense of uniform ultimate boundedness. Finally, we validate the proposed decentralized ETC strategy through simulations of the nonlinear-interconnected systems derived from two inverted pendulums connected via a spring.
Emerging Trends in Cigarette Sales in Ohio During First Year Implementation of the Smoking Ban

Objective: The Ohio smoking ban was passed by Ohio voters on November 7, 2006 and took effect on December 7, 2006. The reporting of violations to the Ohio smoking ban began on May 3, 2007 with the implementation of the civil penalties for the violations. The purpose of this study is to look at emerging trends in cigarette sales change from 2006 to 2007 for the 88 counties in Ohio following implementation of the smoking ban on December 7, 2006 based on geographical location, violation level, and tobacco production. Methods: Data was obtained from Claritas for the 2006 aggregate expenditure estimate on cigarettes and the 2007 aggregate expenditure estimate on cigarettes (Claritas, 2008). This data was used to calculate cigarette sales change and cigarette percent sales change for the state of Ohio. The independent variables used were county regional distinction, tobacco production, and smoking ban violation level per 1000 population. For each of these variables an analysis of descriptive statistics was used to look at cigarette percent sales change. The descriptive statistics included mean, median, standard deviation, range, minimum, and maximum. Results: Overall for the state of Ohio there was a decrease in the aggregate expenditure estimate on cigarettes from 2006 to 2007. The cigarette percent sales change for Ohio was -1.9%. The cigarette percent sales change for all regional distinctions decreased; Appalachian counties by -2.1%, rural non-Appalachian counties by -1.7%, metropolitan counties by -2.0%, and suburban counties by -1.1%. The cigarette percent sales change decreased for both violation distinctions; high violation counties by -1.9% and low violation counties by -1.7%. The cigarette percent sales change also decreased for all tobacco producing distinctions; -1.6% for high tobacco producing counties, -1.9% for low tobacco producing counties, and -1.7% for non-tobacco producing counties. Conclusion: Although the results can not draw concrete connections between cigarette sales change and the smoking ban this study does provide some insight into what has occurred in Ohio with cigarette sales since the implementation of the smoking ban and enforcement of violations. Cigarette sales in Ohio decreased in 95.45% of Ohio counties (84 of 88) ranging from 1.6% change to -5.2% change. Cigarette sales for the state of Ohio as a whole decreased from 2006 to 2007 by a total of $83,002,044 which is a -1.9% mean percentage cigarette sales change. This decrease in cigarette sales change provides support for the implementation of the smoking ban in Ohio and the positive impact it has had on the Ohio population in relation to a decrease in cigarette sales and. This study also shows the areas in Ohio which efforts can be focused to increase awareness of the negative effects of smoking and secondhand smoke along with the hope of increasing cessation rates and/or decreasing cigarette consumption in these areas to comparable levels of the other regions in Ohio. Emerging trends in cigarette sales 7
SCGN deficiency results in colitis susceptibility

Inflammatory bowel disease (IBD) affects 1.5–3.0 million people in the United States. IBD is genetically determined and many common risk alleles have been identified. Yet, a large proportion of genetic predisposition remains unexplained. In this study, we report the identification of an ultra rare missense variant (NM_006998.3:c.230G > A;p.Arg77His) in the SCGN gene causing Mendelian early-onset ulcerative colitis. SCGN encodes a calcium sensor that is exclusively expressed in neuroendocrine lineages, including enteroendocrine cells and gut neurons. SCGN interacts with the SNARE complex, which is required for vesicle fusion with the plasma membrane. We show that the SCGN mutation identified impacted the localization of the SNARE complex partner, SNAP25, leading to impaired hormone release. Finally, we show that mouse models of Scgn deficiency recapitulate impaired hormone release and susceptibility to DSS-induced colitis. Altogether, these studies demonstrate that functional deficiency in SCGN can result in intestinal inflammation and implicates the neuroendocrine cellular compartment in IBD.
Preventive and therapeutic approaches against hepatitis B virus by vaccine

Hepatitis B virus (HBV) infection is caused by a small enveloped DNA virus that infects the liver. Approximately 2 billion people of the world have been infected by HBV and 300-350 million of them are chronically infected with the virus. The annual global mortality rate from HBV infection and its sequelae is 1-2 million people. Control of HBV infection is a major challenge of contemporary virology, hepatology, immunology, and vaccinology. There are two important aspects of this problem. The first is the prevention of new HBV infection. Transmission of HBV from HBV-infected persons to uninfected healthy individuals can be blocked by interrupting the transmission cycle of the virus. But, this is extremely hard and time-consuming, especially in view of the socio-economic status and health care delivery system of most of the developing nations, where HBV carrier rate is high. Another practical solution to this problem is by immunoprophylaxis using vaccines against hepatitis B. Commercially available hepatitis B vaccines induce protective antibody against HBV in more than 90% of apparently healthy individuals. However, these vaccines are ineffective in about 5-10% of normal individuals, most immunosuppressed subjects and also in liver transplanted patients with HBV background. Accordingly, a more potent prophylactic vaccine against HBV is needed. The concept of using vaccine for treatment of chronic diseases (vaccine therapy) has existed for quite a long time, but very few clinical trials with vaccine therapy have been conducted to assess their efficacy and clinical usage. During the last decade, some studies have reported the use of hepatitis B vaccine to treat patients with chronic hepatitis B. The present regimen of vaccine therapy for patients with chronic hepatitis B is safe, but is not very effective as an independent therapeutic tool. This article reviews the development of more potent prophylactic vaccines against HBV and better regimens of therapeutic vaccines for patients with chronic hepatitis B with special reference to the recent developments in the relevant fields.
Cross-sectional study of the association between empathy and burnout and drug prescribing quality in primary care

Abstract Objective: The aim of this study was to assess whether burnout and empathy levels among general practitioners (GPs) might influence prescribing performance assessed using pharmaceutical prescription quality standard indicators. Design and Setting: Cross-sectional descriptive study of 108 GPs from 22 primary care centers in Lleida, Spain, and of centralized data corresponding to 183 600 patients under their care. The study was conducted between May and July 2014. Main Outcome Measures: Burnout and empathy were measured using the Spanish versions of the Maslach Burnout Inventory and the Jefferson Scale for Physician Empathy, and prescribing quality was measured using the Catalan Pharmaceutical Prescription Quality Standard (EQPF). Normal distribution of scores was verified using the Chi-square and Kolmogorov–Smirnov–Lilliefors tests. The effect of each of the variables was evaluated using crude odds ratios. Results: Older GPs scored significantly higher in the EQPF (P < 0.05). High empathy scores were positively associated with high EQPF scores. GPs with low burnout also performed better in the EQPF. Conclusions: More empathic, less burned-out, older GPs showed better prescribing performance according to quality indicators. However, further studies are needed to evaluate other factors influencing prescribing habits. The promotion of communication skills may increase empathy and reduce burnout, thus benefiting patients.
Extensive chondroid bone in juvenile duck limbs hints at accelerated growth mechanism in avian skeletogenesis

Modern altricial birds are the fastest growing vertebrates, whereas various degrees of precocity (functional maturity) result in slower growth. Diaphyseal osteohistology, the best proxy for inferring relative growth rates in fossils, suggests that in the earliest birds, posthatching growth rates were more variable than in modern representatives, with some showing considerably slow growth that was attributed to their assumed precocial flight abilities. For finding clues how precocial or altricial skeletogenesis and related growth acceleration could be traced in avian evolution, as a case study we investigated the growing limb diaphyseal histology in an ontogenetic series of ducks which, among several other avian taxa, show a combination of altricial wing and precocial leg development. Here we report the unexpected discovery that chondroid bone, a skeletal tissue family intermediate between cartilage and bone, extensively contributes to the development of limb bone shaft in ducks up to at least 30 days posthatching age. To our knowledge, chondroid bone has never been reported in such quantities and with an ontogenetically extended deposition period in post‐embryonic, non‐pathological periosteal bone formation of any tetrapod limb. It shows transitional cellular/lacunar morphologies and matrix staining properties between cartilage and woven bone and takes a significant part in the diametric growth of the limb bone shaft. Its amount and distribution through duckling ontogeny seems to be associated with the disparate functional and growth trajectories of the altricial wings vs. precocial legs characteristic of duck limb development. The presence of isogenous cell groups in the periosteal chondroid bone implies that cartilage‐like interstitial growth took place before matrix mineralization complementing appositional bone growth. Based on these characteristics and on its fast formation rate in all previously reported normal as well as pathological cases, we suggest that chondroid bone in ducks significantly accelerates diametric limb bone growth. Related to this growth acceleration, we hypothesize that chondroid bone may be generally present in the growing limb bones of modern birds and hence may have key skeletogenic importance in achieving extreme avian growth rates and placing birds among the fastest growing vertebrates. Thus, we encourage future studies to test this hypothesis by investigating the occurrence of chondroid bone in a variety of precocial and altricial bird species, and to explore the presence of similar tissues in the growing limbs of other extant and extinct tetrapods in order to understand the evolutionary significance of chondroid bone in accelerated appendicular skeletogenesis.
Large tunability of strain in WO3 single-crystal microresonators controlled by exposure to H2 gas.

Strain engineering is one of the most effective approaches to manipulate the physical state of materials, control their electronic properties, and enable crucial functionalities. Because of their rich phase diagrams arising from competing ground states, quantum materials are an ideal playground for on-demand material control, and can be used to develop emergent technologies, such as adaptive electronics or neuromorphic computing. It was recently suggested that complex oxides could bring unprecedented functionalities to the field of nanomechanics, but the possibility of precisely controlling the stress state of materials is so far lacking. Here we demonstrate the wide and reversible manipulation of the stress state of single-crystal WO3 by strain engineering controlled by catalytic hydrogenation. Progressive incorporation of hydrogen in freestanding ultra-thin structures determines large variations of their mechanical resonance frequencies and induces static deformation. Our results demonstrate hydrogen doping as a new paradigm to reversibly manipulate the mechanical properties of nanodevices based on materials control.
Efficacy and safety of dabrafenib–trametinib in the treatment of unresectable advanced/metastatic melanoma with BRAF‐V600 mutation: A systematic review and network meta‐analysis

The current systematic review aimed to evaluate and compare the efficacy and safety of dabrafenib–trametinib with those of other therapeutic alternatives in the treatment of patients with unresectable advanced/metastatic melanoma with BRAF‐V600 mutation. The search was carried out on four databases up to July 2018. Two separate network meta‐analyses (NMA) were performed using the frequentist method (random effects): one with an exclusive population with BRAF‐V600 mutation (NMA‐pBRAFV600) and another with mixed population (with or without the mutation: NMA‐pMixed). An evidence profile was included using the GRADE method for NMA. The validity of the final estimator in the NMA‐pMixed was assessed via a sensitivity analysis. Nine clinical trials were included in the NMA‐pBRAFV600. Dabrafenib–trametinib was found to have a favorable effect on overall survival (OS) and progression‐free survival (PFS) compared with dabrafenib, vemurafenib, and dacarbazine and on partial response rate (PRR) and overall response rate compared with dacarbazine and vemurafenib. In the NMA‐pMixed, dabrafenib–trametinib was found to have a positive effect on OS versus ipilimumab 3 mg/kg and on PFS and PRR versus ipilimumab, nivolumab, and pembrolizumab. However, dabrafenib–trametinib and vemurafenib–cobimetinib significantly differed in terms of efficacy. In addition, dabrafenib–trametinib has a favorable effect on Grades 3 and 4 adverse events.
Secular trends in weight, height and weight for height among children under 7 years in nine cities of China, 1975–2015: results from five repeated cross-sectional surveys

Objective To analyse the secular trends in mean value and distribution of weight, height and weight for height in children under 7 years in developed regions in China. Design Five repeated cross-sectional surveys were conducted using the same methods at the same sites during 1975–2015. Setting Nine cities in northern, central and southern regions of China. Population Healthy children under 7 years; the sample sizes were 94 496 in 1975, 79 177 in 1985, 79 152 in 1995, 69 760 in 2005 and 83 583 in 2015. Main outcome measures Weight and height were measured by the same methods in the five surveys. Results The increasing trends in the mean value of weight, height and weight for height were observed and their distribution was found to have shifted upwards. There were unbalanced increments in various centiles and the relative increments in the 3rd centile of height for children under 7 years were larger than those in the 50th and 97th centiles. Although the relative increments in the 3rd centile of weight for children under 2 years were larger than those in the 50th and 97th centiles, the increments in the 97th centile for children older than 2 years became the largest compared with other centiles. The changes in each centile of weight for height were similar with those of weight. The annual increments of height and weight increased over time and were more significant between birth and 2 years of age for height and between ages 4 years and 6 years for weight. The per-decade increments in 1975–1985, 1985–1995 and 1995–2005 became larger, while those in 2005–2015 slowed down. Conclusions The rapid increasing trends of weight, height and weight for height had slowed down since 2005 in developed regions of China. The relative increments in the low centile of height were more significant, while the high centile of weight and weight for height increased more significantly in older children.
A Single Dose of The Mango Leaf Extract Zynamite® in Combination with Quercetin Enhances Peak Power Output During Repeated Sprint Exercise in Men and Women

The mango leaf extract rich in mangiferin Zynamite® improves exercise performance when combined with luteolin or quercetin ingested at least 48 h prior to exercise. To determine whether a single dose of Zynamite® administered 1 h before exercise increases repeated-sprint performance, 20 men and 20 women who were physically active were randomly assigned to three treatments following a double-blind cross-over counterbalanced design. Treatment A, 140 mg of Zynamite®, 140 mg of quercetin, 147.7 mg of maltodextrin, and 420 mg of sunflower lecithin; Treatment B, 140 mg of Zynamite®, 140 mg of quercetin, and 2126 mg of maltodextrin and Treatment C, 2548 mg of maltodextrin (placebo). Subjects performed three Wingate tests interspaced by 4 min and a final 15 s sprint after ischemia. Treatments A and B improved peak power output during the first three Wingates by 2.8% and 3.8%, respectively (treatment x sprint interaction, p = 0.01). Vastus Lateralis oxygenation (NIRS) was reduced, indicating higher O2 extraction (treatment × sprint interaction, p = 0.01). Improved O2 extraction was observed in the sprints after ischemia (p = 0.008; placebo vs. mean of treatments A and B). Blood lactate concentration was 5.9% lower after the ingestion of Zynamite® with quercetin in men (treatment by sex interaction, p = 0.049). There was a higher Vastus Lateralis O2 extraction during 60 s ischemia with polyphenols (treatment effect, p = 0.03), due to the greater muscle VO2 in men (p = 0.001). In conclusion, a single dose of Zynamite® combined with quercetin one hour before exercise improves repeated-sprint performance and muscle O2 extraction and mitochondrial O2. consumption during ischemia. No advantage was obtained from the addition of phospholipids.
Unmet need for family planning and barriers to contraceptive use in Kaduna, Nigeria: culture, myths and perceptions

Abstract In 2017, just one-fifth of all married women of reproductive age reported using contraception in Kaduna state, Nigeria, while many more experienced unmet need for contraception. These realities drive risky fertility behaviours and compromise reproductive rights. This study explored the determinants of low modern contraceptive uptake and persistent unmet need among women in the state. Nine focus group discussions were conducted with married women who met study criteria for unmet need, and who had different levels of access to contraception. Discussions confirmed that many women in Kaduna do not feel empowered to make contraceptive decisions. Yet there is a growing preference for smaller families and decreased stigmatisation of contracepting women. Barriers at home, in the community and in health facilities impose a ceiling on the extent to which women’s fertility desires may be achieved. These include cultural, normative, social and financial factors, such as the need for husband’s permission to access services, service providers’ insistence on spousal consent, subtle and overt pressures to use folkloric approaches by religious leaders, and high real, or perceived, out-of-pocket costs. These findings suggest that Kaduna is on the cusp of social change and study findings can be translated into programmatic interventions to improve voluntary uptake of contraception.