Miracle-dz/UniFAR-FTUs huggingface dataset:
CScape-somatic: distinguishing driver and passenger point mutations in the cancer genome

Abstract Motivation Next-generation sequencing technologies have accelerated the discovery of single nucleotide variants in the human genome, stimulating the development of predictors for classifying which of these variants are likely functional in disease, and which neutral. Recently, we proposed CScape, a method for discriminating between cancer driver mutations and presumed benign variants. For the neutral class, this method relied on benign germline variants found in the 1000 Genomes Project database. Discrimination could, therefore, be influenced by the distinction of germline versus somatic, rather than neutral versus disease driver. This motivates this article in which we consider predictive discrimination between recurrent and rare somatic single point mutations based solely on using cancer data, and the distinction between these two somatic classes and germline single point mutations. Results For somatic point mutations in coding and non-coding regions of the genome, we propose CScape-somatic, an integrative classifier for predictively discriminating between recurrent and rare variants in the human cancer genome. In this study, we use purely cancer genome data and investigate the distinction between minimal occurrence and significantly recurrent somatic single point mutations in the human cancer genome. We show that this type of predictive distinction can give novel insight, and may deliver more meaningful prediction in both coding and non-coding regions of the cancer genome. Tested on somatic mutations, CScape-somatic outperforms alternative methods, reaching 74% balanced accuracy in coding regions and 69% in non-coding regions, whereas even higher accuracy may be achieved using thresholds to isolate high-confidence predictions. Availability and implementation Predictions and software are available at http://CScape-somatic.biocompute. org.uk/. Contact mark.f. rogers.phd@gmail.com or C.Campbell@bristol.ac. uk Supplementary information Supplementary data are available at Bioinformatics online.
Neurotrophic factors in bipolar disorders patients with manic episode

Background/aim Neurotrophins are one of the most important molecule groups affecting cerebral neuroplasticity. The amount of evidence about the role of changes in neuroplasticity in the pathophysiology of bipolar disease is growing. Materials and methods We measured serum levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), glial cell-line derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), fibroblast growth factor (FGF)-2, neuritin 1 (Nrn 1) in bipolar 1 manic episode patients (n = 45) and healthy control group. Results When controlled for age, BMI and cortisol, it was found that the serum levels of BDNF, NGF, NT-3, VEGF and FGF-2 of bipolar manic episode patients were not statistically different compared to those of the control group. GDNF level and Nrn 1 levels were significantly lower (P = 0.003 and P = 0.025 respectively) while IGF-1 levels were significantly higher than the control group (P = 0.0001). ROC analysis was performed and the area under the the curve was calculated as 0.737, 0.766 for GDNF, IGF-1 respectively. Conclusion The changes in the levels of GDNF, IGF-1 and Nrn 1 might be involved in pathopysiology of bipolar disorder, and GDNF, IGF-1 may be considered as state markers in bipolar manic episode.
Fecal Recovery of Probiotics Administered as a Multi-Strain Formulation during Antibiotic Treatment

The present study aimed to investigate whether probiotic recovery is affected when consumed together with antibiotics. Fecal samples were collected from an earlier antibiotic associated diarrhea, randomized, placebo-controlled study with a product consisting of a combination of Lactobacillus acidophilus NCFM, Lactobacillus paracasei Lpc-37, and Bifidobacterium lactis Bi-07, B. lactis Bl-04 at equal numbers and at a total dose of 1010 CFU. Fecal samples were collected during the screening visit (T0), i.e., at the time of antibiotic prescription, and then on the last day of the antibiotic treatment (T1) as well as seven days after the subject had stopped taking the antibiotic treatment (T2) and at two weeks after completing antibiotic treatment and one week after probiotic/placebo consumption stopped (T3). Samples were analyzed for the presence of the four administered strains. The study was registered at clinicaltrials.gov as NCT01596829. Detection levels of all four strains were significantly increased from T0 to T1 and returned to baseline level from T2 to T3. There were also significantly more subjects with detectable levels of L. paracasei Lpc-37, B. lactis Bi-07, and B. lactis Bl-04 at T1 and T2 compared to T0 and T3, and compared to placebo. Each of the four strains could be detected in the feces of patients apparently unaffected by the simultaneous consumption of antibiotics.
When Can One Vaccinate with a Live Vaccine after Wild-Type Dengue Infection?

Recommendations have been issued for vaccinating with the Sanofi Pasteur tetravalent dengue vaccine (CYD-TDV, Dengvaxia®) individuals aged from 9 to 45/60 years old with a prior dengue virus (DENV) infection and living in endemic countries/areas. One question linked to these recommendations is to determine when it is possible to start vaccination after laboratory confirmed wild-type DENV infection, and this question can be relevant to any live vaccine to be used in endemic areas. To address it, we reviewed and discussed the immunological and practical considerations of live vaccination in this context. Firstly, the nature and kinetics of immune responses triggered by primary or secondary DENV infection may positively or negatively impact subsequent live vaccine take and associated clinical benefit, depending on when vaccination is performed after infection. Secondly, regarding practical aspects, the “easiest” situation would correspond to a confirmed acute dengue fever, only requiring knowing when the patient should come back for vaccination. However, in most cases, it will not be possible to firmly establish the actual date of infection and vaccination may have to take place during well-defined periods, regardless of when prior infection occurred. Evidence that informs health authorities and medical practitioners in formulating vaccine policies and implementing vaccine programs is thus needed. The present work reviewed the different elements of the guidance and proposes some key conclusions and recommendations.
The ABC of Major Histocompatibility Complexes and T Cell Receptors in Health and Disease

A seminal discovery of major histocompatibility complex (MHC) restriction in T cell recognition by Peter Doherty and Rolf Zinkernagel has led to 45 years of exciting research on the mechanisms governing peptide MHC (pMHC) recognition by T cell receptors (TCRs) and their importance in health and disease. T cells provide a significant level of protection against viral, bacterial, and parasitic infections, as well as tumors, hence, the generation of protective T cell responses is a primary goal for cell-mediated vaccines and immunotherapies. Understanding the mechanisms underlying generation of optimal high-avidity effector T cell responses, memory development, maintenance, and recall is of major importance for the rational design of preventative and therapeutic vaccines/immunotherapies. In this review, we summarize the lessons learned over the last four decades and outline our current understanding of the basis and consequences of pMHC/TCR interactions on T cell development and function, and TCR diversity and composition, driving better clinical outcomes and prevention of viral escape. We also discuss the current models of T cell memory formation and determinants of immunodominant T cell responses in animal models and humans. As TCR composition and diversity can affect both the protective capacity of T cells and protection against viral escape, defining the spectrum of TCR selection has implications for improving the functional efficacy of effector T cell responsiveness and memory formation.
Nurse Practitioners’ Knowledge, Attitudes, and Perceptions Regarding Irritable Bowel Syndrome and Treatment

Contact Information [1] International Foundation for Functional Gastrointestinal Disorders, Inc. (IFFGD). Retrieved from http://www.aboutibs. org/facts-about-ibs/statistics.html [2] Chey, W. , D. (2015). Irritable bowel syndrome: A clinical review. Journal of the American Medical Association313(9), 949-958. [3] Olafsdottir, L. , B. , Gudjonsson, H. , Jonsdottir, H. , H. , Jonsson, J., S. , Bjornsson, E. , & Thjodleifsson, B. ( 2012). Irritable Bowel Syndrome: Physicians’ awareness and patients’ experience. World Journal of Gastroenterology 18(28), 3715-3720. http://dx.doi/org/10.3748/wjg.v18. i28.3715 [4] Drossman, D. , A. (2016). Functional gastrointestinal disorders: History, pathophysiology, clinical features, and Rome IV. Gastroenterology150(6), 1262-1279. [5] Gikas, A. , & Triantafillidis, J. (2014). The role of primary care physicians in early diagnosis and treatment of chronic gastrointestinal diseases. International Journal of General Medicine 7, 159-173. [6] Ford, A. , C. , Speigel, B. , M. , R. , Talley, N. , J., & Moayyedi, P. (2009). Small intestinal bacterial overgrowth in irritable bowel syndrome: Systematic review and meta-analysis. Clinical Gastroenterology and Hepatology7(1),12791286.http://dx.doi. org/10.1016/j.cgh. 2009.06. 031 Results .
Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells

Mitotane is the only drug approved for the treatment of adrenocortical carcinoma (ACC). The regimen to be added to mitotane is a chemotherapy including etoposide, doxorubicin, and cisplatin. This pharmacological approach, however, has a limited efficacy and significant toxicity. Evidence indicates that ACC seems to be sensitive to alkylating agents. Trabectedin is an anti-tumor drug that acts as an alkylating agent with a complex mechanism of action. Here, we investigated whether trabectedin could exert a cytotoxic activity in in vitro cell models of ACC. Cell viability was evaluated by MTT assay on ACC cell lines and primary cell cultures. The gene expression was evaluated by q-RT-PCR, while protein expression and localization were studied by Western blot and immunocytochemistry. Combination experiments were performed to evaluate their interaction on ACC cell line viability. Trabectedin demonstrated high cytotoxicity at sub-nanomolar concentrations in ACC cell lines and patient-derived primary cell cultures. The drug was able to reduce /β catenin nuclear localization, although it is unclear whether this effect is involved in the observed cytotoxicity. Trabectedin/mitotane combination exerted a synergic cytotoxic effect in NCI-H295R cells. Trabectedin has antineoplastic activity in ACC cells. The synergistic cytotoxic activity of trabectedin with mitotane provides the rationale for testing this combination in a clinical study.
Functional diversity between HSP70 paralogs caused by variable interactions with specific co-chaperones

Heat shock protein 70 (HSP70) chaperones play a central role in protein quality control and are crucial for many cellular processes, including protein folding, degradation, and disaggregation. Human HSP70s compose a family of 13 members that carry out their functions with the aid of even larger families of co-chaperones. A delicate interplay between HSP70s and co-chaperone recruitment is thought to determine substrate fate, yet it has been generally assumed that all Hsp70 paralogs have similar activities and are largely functionally redundant. However, here we found that when expressed in human cells, two highly homologous HSP70s, HSPA1A and HSPA1L, have opposing effects on cellular handling of various substrates. For example, HSPA1A reduced aggregation of the amyotrophic lateral sclerosis–associated protein variant superoxide dismutase 1 (SOD1)–A4V, whereas HSPA1L enhanced its aggregation. Intriguingly, variations in the substrate-binding domain of these HSP70s did not play a role in this difference. Instead, we observed that substrate fate is determined by differential interactions of the HSP70s with co-chaperones. Whereas most co-chaperones bound equally well to these two HSP70s, Hsp70/Hsp90-organizing protein (HOP) preferentially bound to HSPA1L, and the Hsp110 nucleotide-exchange factor HSPH2 preferred HSPA1A. The role of HSPH2 was especially crucial for the HSPA1A-mediated reduction in SOD1-A4V aggregation. These findings reveal a remarkable functional diversity at the level of the cellular HSP70s and indicate that this diversity is defined by their affinities for specific co-chaperones such as HSPH2.
Cannabis use disorder and the lungs.

Cannabis is one of the world's most widely used recreational drugs and the second most commonly smoked substance. Research on cannabis and the lungs has been limited by its illegal status, the variability in strength and size of cannabis cigarettes (joints), and the fact that most cannabis users also smoke tobacco making the effects hard to separate. Despite these difficulties, the available evidence indicates that smoking cannabis causes bronchitis and is associated with changes in lung function. The pattern of effects is surprisingly different from that of tobacco. Whereas smoking cannabis appears to increase the risk of severe bronchitis at quite low exposure, there is no convincing evidence that this leads to chronic obstructive pulmonary disease. Instead cannabis use is associated with increased central airway resistance, lung hyperinflation, and higher vital capacity with little evidence of airflow obstruction or impairment of gas transfer. There are numerous reports of severe bullous lung disease and pneumothorax among heavy cannabis users, but convincing epidemiological data of an increased risk of emphysema or alveolar destruction are lacking. An association between cannabis and lung cancer remains unproven with studies providing conflicting findings.
Illustrations in the Journal of Craniofacial Surgery.

The aim of this study is to analyze the medical illustrations that appeared in the Journal of Craniofacial Surgery (JCFS) during the last 3 years (2016-2018). All illustrations in 2676 articles from 24 issues were analyzed.In total, 363 articles (13.6%) contained illustrations (for total of 589 illustrations), and 38 articles (1.4%) cited illustrations from other articles. The number of illustrations increased over time (152 in 2016, 181 in 2017, and 256 in 2018; P = 0.007). The signature of the illustrator appeared in 16.5% of the illustrations, and the illustrator's name was acknowledged in 7.6%. The most frequent contents of the 589 illustrations were surgical procedures (55.4%), followed by anatomy (34.1%). Among the 555 illustrations showing regions of the body, the most frequently illustrated region was the oral cavity (41.6%), followed by the eye and periorbital region (18.4%), the nose (12.4%), and the head (11.4%). Of the 555 illustrations showing tissue, the tissue most frequently depicted was bone (52.8%), followed by soft tissue (42.5%). The mean score for clarity of the intended message was 3.5 ± 1.2. The mean score for artistic skill was 3.2 ± 1.0. As the number of illustrations in JCFS increases, it is increasingly important that information on the illustrators be given. The journal editor should recommend that authors provide the illustrators' information. From the author's perspective, the best illustration is one that tells the story the author wants to convey to readers. Therefore, the crucial point is the expression of the author's goal, rather than the esthetics of the illustration.
Follicular Thyroid Neoplasms

In follicular thyroid neoplasms without invasion, a diagnosis of atypical adenoma (AA) (follicular tumor of uncertain malignant potential) may be rendered if atypical features (indefinite capsular/vascular invasion, necrosis, solid growth, increased mitoses) are present. This study compares clinical, histologic, and molecular features of patients with AAs (n=31), nonmetastatic follicular thyroid carcinoma (nmFTC) (n=18), and metastatic follicular thyroid carcinoma (mFTC) (n=38). Patients with mFTC were older. Mitotic activity in areas of solid growth was greatest in mFTC (P=0.05). Oncocytic tumors tended to show solid growth (P=0.04). The presence or frequency of capsular and/or vascular invasion was not different between nmFTC and mFTC. TERT promoter mutations were higher in patients with mFTC (50%) than nmFTC (25%) and AA (10%) (P=0.02). TERT promoter mutation was associated with necrosis (P=0.01) and solid growth plus increased mitoses (P=0.03). Necrosis and TERT promoter mutations were identified in all groups, most frequently in mFTC. The combination of solid growth with increased mitoses, necrosis, and TERT promoter mutation was only seen in follicular carcinomas. Poorly differentiated features, vascular invasion, and TERT promoter mutation correlated with metastasis in FTC. Given the low frequency of necrosis and TERT promoter mutation in AAs, close clinical follow-up is recommended in patients with these findings, especially if additional atypical features (such as solid growth plus mitoses) are present.
Apoptosis induction by α-mangostin-loaded nanoparticles in human cervical carcinoma cells

Abstract The compound α-mangostin (AMG) extracted from Garcinia mangostana L. has potent anticancer properties but its clinical application is limited because of its poor solubility. In this study, AMG-loaded nanoparticles (NMG) were synthesized using a new formula and their apoptosis activity against human cervical carcinoma (HeLa) cells was investigated in comparison with organic solvent-soluble AMG in free form. The NMG was successfully synthesized with a particle size of <50 nm, polydispersity index <0.3, and zeta potential of −35.2 mV. At a concentration of 10 μg/mL, AMG reduced cell survival by 60%, whereas NMG treatment resulted in >90% cell death (p < 0.05). The AMG- or NMG-treated cells also showed changes in the size and shape and exhibited enhanced intensity of blue-stained nuclei, as well as decreased cell density, especially in NMG-treated cells. After 24 h of incubation with AMG or NMG, the cells went through late apoptosis at a rate of approximately 34% in 20 μg/mL AMG treatment and 27% in 10 μg/mL NMG treatment (p < 0.05). Thus, HeLa cells underwent more pronounced cell death through apoptosis induction caused by the NMG treatment compared to that caused by AMG. Clearly, the new NMG improved AMG bioavailability while maintaining the desired activity.
Effect of the ligands of thyroid hormone receptor on non-alcoholic fatty liver disease

The term non-alcoholic fatty liver disease (NAFLD) has been used as a general name for conditions ranging from simple steatosis to steatohepatitis, advanced fibrosis and cirrhosis. End-stage NAFLD cirrhosis carries a substantial risk for early hepatocellular carcinoma development. Therefore, there is an increasing need for new therapeutic approaches for the treatment of this liver disease. Here, we examined the effect of the thyroid hormone triiodothyronine (T3) and the agonist of the thyroid hormone receptor β isoform (TRβ), GC-1, on fatty liver and steatohepatitis induced in rodents by a choline-deficient, methionine-restricted (CMD) diet. Male Fischer rats fed the CMD diet for 1 week developed a marked fatty liver and mild hepatitis. Concurrent administration of T3 resulted in a complete prevention of the fatty change associated with increased mitochondrial and peroxisomal fatty acid beta-oxidation. To investigate whether T3 could also reverse fully established fatty liver, rats were fed the CMD diet for 10 weeks and then cofed T3 for 1 week. Coadministration of T3 resulted in a complete regression of liver steatosis associated with a decrease of lipid peroxidation, cyclooxygenase-2 expression, and activation of phospho-STAT3 and phospho-SAPK/JNK. Finally, additional experiments showed that GC-1, which has no significant side effects on heart rate, prevented and reverted CMD-induced fat accumulation. These results indicate that TR agonists have the potential to inhibit or reverse hepatic steatosis induced by a nutritional model.
Endothelial dysfunction in South African youth living with perinatally acquired HIV on antiretroviral therapy.

BACKGROUND HIV and antiretroviral therapy (ART) confer cardiovascular disease (CVD) risk in adults living with HIV. Few studies have assessed endothelial dysfunction (ED), an early marker of subclinical CVD risk, in youth living with perinatally acquired HIV (YLPHIV). METHODS Using peripheral arterial tonometry (EndoPAT), we compared ED in YLPHIV and age-matched youth without HIV. A reactive hyperaemic index (RHI) ≤1.35 was defined as ED. Eligible participants included those aged 9-14 years and on ART ≥6 months at enrollment. RESULTS Overall, 431 YLPHIV and 93 youth without HIV with median age 14.1 vs. 13.9 years, respectively, were included. YLPHIV had lower body mass index z-score (BMIZ) (-0.2 vs 0.4, p<0.01) but higher rates of hypercholesterolemia (10% vs 1%, p=0.01) compared to youth without HIV. Among YLPHIV, mean log viral load (VL) was 4.83 copies/ml with 21.7% having a CD4 count <500 cell/mm3; median duration on ART was 9.8 years with 38% initiating at <2 years of age. YLPHIV had higher rates of ED compared to youth without HIV (50% vs. 34%, p=0.01); this relationship persisted after adjusting for age, sex, BMIZ, elevated BP, and hypercholesterolemia (RR 1.43, p=0.02). Among YLPHIV CD4 count >500 cell/mm3 (RR 1.04, p=0.76), VL (RR 1.01, p=0.78) and current ART class (protease inhibitor-based vs. non-nucleoside inhibitor-based, RR 0.90, p=0.186) were not associated with ED after adjustment. CONCLUSIONS Even after adjusting for physiologic differences, YLPHIV appear to be at increased risk for ED compared to age-matched youth without HIV. These findings have important implications for the life course of YLPHIV who may be at increased risk of premature CVD and complications.
Cloth masks versus medical masks for COVID-19 protection.

Lazarski University, Warsaw, Poland; Polish Society of Disaster Medicine, Warsaw, Poland Department of Emergency Medical Service, Wroclaw Medical University, Wroclaw, Poland; Polish Society of Disaster Medicine, Warsaw, Poland 1 Chair and Department of Cardiology, Medical University of Warsaw, Poland Department of Emergency Medicine, Medical University of Bialystok, Poland; Polish Society of Disaster Medicine, Warsaw, Poland 1 Department of Cardiology, Medical University of Gdansk, Poland