Miracle-dz/UniFAR-FTUs huggingface dataset:
A first‐in‐human phase I, multicenter, open‐label, dose‐escalation study of the oral RAF/VEGFR‐2 inhibitor (RAF265) in locally advanced or metastatic melanoma independent from BRAF mutation status

To establish the maximum tolerated dose (MTD), dose‐limiting toxicities (DLT), safety profile, and anti‐tumor efficacy of RAF265. We conducted a multicenter, open‐label, phase‐I, dose‐escalation trial of RAF265, an orally available RAF kinase/VEGFR‐2 inhibitor, in patients with advanced or metastatic melanoma. Pharmacokinetic (PK) analysis, pharmacodynamics (PD) and tumor response assessment were conducted. We evaluated metabolic tumor response by 18[F]‐fluorodeoxyglucose‐positron‐emission tomography (FDG‐PET), tissue biomarkers using immunohistochemistry (IHC), and modulators of angiogenesis. RAF265 has a serum half‐life of approximately 200 h. The MTD was 48 mg once daily given continuously. Among 77 patients, most common treatment‐related adverse effects were fatigue (52%), diarrhea (34%), weight loss (31%) and vitreous floaters (27%). Eight of 66 evaluable patients (12.1%) had an objective response, including seven partial and one complete response. Responses occurred in BRAF‐mutant and BRAF wild‐type (WT) patients. Twelve of 58 (20.7%) evaluable patients had a partial metabolic response. On‐treatment versus pretreatment IHC staining in 23 patients showed dose‐dependent p‐ERK inhibition. We observed a significant temporal increase in placental growth factor levels and decrease in soluble vascular endothelial growth factor receptor 2 (sVEGFR‐2) levels in all dose levels. RAF265 is an oral RAF/VEGFR‐2 inhibitor that produced antitumor responses, metabolic responses, and modulated angiogenic growth factor levels. Antitumor activity occurred in patients with BRAF‐mutant and BRAF‐WT disease. Despite low activity at tolerable doses, this study provides a framework for the development of pan‐RAF inhibitors and modulators of angiogenesis for the treatment of melanoma.
Why does starvation make bones fat?

Body fat, or adipose tissue, is a crucial energetic buffer against starvation in humans and other mammals, and reserves of white adipose tissue (WAT) rise and fall in parallel with food intake. Much less is known about the function of bone marrow adipose tissue (BMAT), which are fat cells found in bone marrow. BMAT mass actually increases during starvation, even as other fat depots are being mobilized for energy. This review considers several possible reasons for this poorly understood phenomenon. Is BMAT a passive filler that occupies spaces left by dying bone cells, a pathological consequence of suppressed bone formation, or potentially an adaptation for surviving starvation? These possibilities are evaluated in terms of the effects of starvation on the body, particularly the skeleton, and the mechanisms involved in storing and metabolizing BMAT during negative energy balance. Am. J. Hum. Biol., 2011. © 2011 Wiley‐Liss, Inc.
Prevention of cigarette smoke–induced lung tumors in mice by budesonide, phenethyl isothiocyanate, and N‐acetylcysteine

Lung cancer is the most important cause of death among neoplastic diseases worldwide, and cigarette smoke (CS) is the major risk factor for cancer. Complementarily to avoidance of exposure to CS, chemoprevention will lower the risk of cancer in passive smokers, ex‐smokers, and addicted current smokers who fail to quit smoking. Unfortunately, chemoprevention clinical trials have produced disappointing results to date and, until recently, a suitable animal model evaluating CS carcinogenicity was not available. We previously demonstrated that mainstream CS induces a potent carcinogenic response when exposure of mice starts at birth. In the present study, neonatal mice (strain H) were exposed to CS for 120 consecutive days, starting at birth. The chemopreventive agents budesonide (2.4 mg/kg diet), phenethyl isothiocyanate (PEITC, 1,000 mg/kg diet), and N‐acetyl‐L‐cysteine (NAC, 1,000 mg/kg body weight) were administered orally according to various protocols. The experiment was stopped after 210 days. Exposure to CS resulted in a high incidence and multiplicity of benign lung tumors and in significant increases of malignant lung tumors and other histopathological alterations. All three chemopreventive agents, administered to current smokers after weaning, were quite effective in protecting both male and female mice from CS pulmonary carcinogenicity. When given to ex‐smokers after withdrawal of exposure to CS, the protective capacity of budesonide was unchanged, while PEITC lost part of its cancer chemopreventive activity. In conclusion, the proposed experimental model provides convincing evidence that it is possible to prevent CS‐induced lung cancer by means of dietary and pharmacological agents.
High throughput sequencing identifies an imprinted gene, Grb10, associated with the pluripotency state in nuclear transfer embryonic stem cells

Somatic cell nuclear transfer and transcription factor mediated reprogramming are two widely used techniques for somatic cell reprogramming. Both fully reprogrammed nuclear transfer embryonic stem cells and induced pluripotent stem cells hold potential for regenerative medicine, and evaluation of the stem cell pluripotency state is crucial for these applications. Previous reports have shown that the Dlk1-Dio3 region is associated with pluripotency in induced pluripotent stem cells and the incomplete somatic cell reprogramming causes abnormally elevated levels of genomic 5-methylcytosine in induced pluripotent stem cells compared to nuclear transfer embryonic stem cells and embryonic stem cells. In this study, we compared pluripotency associated genes Rian and Gtl2 in the Dlk1-Dio3 region in exactly syngeneic nuclear transfer embryonic stem cells and induced pluripotent stem cells with same genomic insertion. We also assessed 5-methylcytosine and 5-hydroxymethylcytosine levels and performed high-throughput sequencing in these cells. Our results showed that Rian and Gtl2 in the Dlk1-Dio3 region related to pluripotency in induced pluripotent stem cells did not correlate with the genes in nuclear transfer embryonic stem cells, and no significant difference in 5-methylcytosine and 5-hydroxymethylcytosine levels were observed between fully and partially reprogrammed nuclear transfer embryonic stem cells and induced pluripotent stem cells. Through syngeneic comparison, our study identifies for the first time that Grb10 is associated with the pluripotency state in nuclear transfer embryonic stem cells.
Examining the Effect of Playing an Arithmetic-based Game- “Chopsticks” on the Arithmetical Competencies of 5-year-old Children in Singapore

Abstract . In this study, the authors examined the effect of playing arithmetic-based game- “Chopsticks” has on young children’s arithmetical competencies. A total of 21 young children (Mean age: 4 years 11 months) were randomized to an experimental group ( n =10) or a control group ( n =11) from two typical early childhood settings in Singapore. Those in the experimental group attended the learning and playing sessions of “Chopsticks” for a 4-week period, while those in the control group did not attend. Pre-test and post-test, which comprised 10 simple addition items each, were administered to all participants. The statistical results revealed both groups of children performed the same level in the pre-test. However, after the 4-week playing session of “Chopsticks”, children in the experimental group solved more items and utilized a shorter time to solve the items than those children in the control group. Therefore, the authors suggested that playing “Chopsticks” enhances young children’s arithmetical competencies.
Fruit and vegetable intake in relation to risk of ischemic stroke.

CONTEXT Few studies have evaluated the relationship between fruit and vegetable intake and cardiovascular disease. OBJECTIVE To examine the associations between fruit and vegetable intake and ischemic stroke. DESIGN, SETTING, AND SUBJECTS Prospective cohort studies, including 75 596 women aged 34 to 59 years in the Nurses' Health Study with 14 years of follow-up (1980-1994), and 38683 men aged 40 to 75 years in the Health Professionals' Follow-up Study with 8 years of follow-up (1986-1994). All individuals were free of cardiovascular disease, cancer, and diabetes at baseline. MAIN OUTCOME MEASURE Incidence of ischemic stroke by quintile of fruit and vegetable intake. RESULTS A total of 366 women and 204 men had an ischemic stroke. After controlling for standard cardiovascular risk factors, persons in the highest quintile of fruit and vegetable intake (median of 5.1 servings per day among men and 5.8 servings per day among women) had a relative risk (RR) of 0.69 (95% confidence interval [CI], 0.52-0.92) compared with those in the lowest quintile. An increment of 1 serving per day of fruits or vegetables was associated with a 6% lower risk of ischemic stroke (RR, 0.94; 95 % CI, 0.90-0.99; P =.01, test for trend). Cruciferous vegetables (RR, 0.68 for an increment of 1 serving per day; 95% CI, 0.49-0.94), green leafy vegetables (RR, 0.79; 95% CI, 0.62-0.99), citrus fruit including juice (RR, 0.81; 95% CI, 0.68-0.96), and citrus fruit juice (RR, 0.75; 95% CI, 0.61-0.93) contributed most to the apparent protective effect of total fruits and vegetables. Legumes or potatoes were not associated with lower ischemic stroke risk. The multivariate pooled RR for total stroke was 0.96 (95% CI, 0.93-1.00) for each increment of 2 servings per day. CONCLUSIONS These data support a protective relationship between consumption of fruit and vegetables-particularly cruciferous and green leafy vegetables and citrus fruit and juice-and ischemic stroke risk.
Prevalence and Predictors of Elevated Aspartate Aminotransferase-to-Platelet Ratio Index in Latin American Perinatally HIV-infected Children

Background: Chronic liver disease has emerged as an important problem in adults with longstanding HIV infection, but data are lacking for children. We characterized elevated aspartate aminotransferase-to-platelet ratio index (APRI), a marker of possible liver fibrosis, in perinatally HIV-infected children. Methods: The National Institute of Child Health and Human Development International Site Development Initiative enrolled HIV-infected children (ages 0.1–20.1 years) from 5 Latin American countries in an observational cohort from 2002 to 2009. Twice yearly visits included medical history, physical examination and laboratory evaluations. The prevalence (95% confidence interval) of APRI > 1.5 was calculated, and associations with demographic, HIV-related and liver-related variables were investigated in bivariate analyses. Results: APRI was available for 1012 of 1032 children. APRI was >1.5 in 32 (3.2%, 95% confidence interval: 2.2%–4.4%) including 2 of 4 participants with hepatitis B virus infection. Factors significantly associated with APRI > 1.5 (P < 0.01 compared with APRI ⩽ 1.5) included country, younger age, past or current hepatitis B virus, higher alanine aminotransferase, lower total cholesterol, higher log10 current viral load, lower current CD4 count, lower nadir CD4 count, use of hepatotoxic nonantiretroviral (ARV) medications and no prior ARV use. Rates of APRI > 1.5 varied significantly by current ARV regimen (P = 0.0002), from 8.0% for no ARV to 3.2% for non–protease inhibitor regimens to 1.5% for protease inhibitor–based regimens. Conclusions: Elevated APRI occurred in approximately 3% of perinatally HIV-infected children. Protease inhibitor–based ARVs appeared protective whereas inadequate HIV control appeared to increase risk of elevated APRI. Additional investigations are needed to better assess potential subclinical, chronic liver disease in HIV-infected children.
Probabilistic Pursuit of Adversarial Evaders Blind Submission

The pursuit-evasion problem consists of a team of pursuers maneuvering to capture one or more evaders. Solutions to the pursuit-evasion problem help search and rescue teams quickly find survivors, sentries protect against intruders, and law enforcement apprehend suspects. Early work considered the case of adversarial evaders, though these approaches become prohibitively expensive when scaling to large environments and/or multiple pursuers. More recently, probabilistic pursuit methods have yielded computationally efficient approaches, but have sacrificed the ability to deal with adversarial evaders. We describe a new probabilistic method that solves the adversarial pursuit-evasion problem without the need for costly adversarial searches (e.g., minimax). In particular, we show how a random-walk model of evaders can be transformed into a model that reflects the behavior of an adversarial agent. Our approach allows pursuers to characterize their opponents’ cunning, allowing faster capture times in the case of sub-optimal evaders. Finally, we demonstrate our algorithm’s performance on a number of benchmark problems, and verify our implementation on a robot.
Effects of inner ear trauma on the risk of pneumococcal meningitis.

OBJECTIVE To examine the risk of pneumococcal meningitis in healthy rats that received a severe surgical trauma to the modiolus and osseous spiral lamina or the standard insertion technique for acute cochlear implantation. DESIGN Interventional animal studies. SUBJECTS Fifty-four otologically normal adult Hooded-Wistar rats. INTERVENTIONS Fifty-four rats (18 of which received a cochleostomy alone; 18, a cochleostomy and acute cochlear implantation using standard surgical techniques; and 18, a cochleostomy followed by severe inner ear trauma) were infected 4 weeks after surgery with Streptococcus pneumoniae via 3 different routes (hematogenous, middle ear, and inner ear) to represent all potential routes of bacterial infection from the upper respiratory tract to the meninges in cochlear implant recipients with meningitis. RESULTS Severe trauma to the osseous spiral lamina and modiolus increased the risk of pneumococcal meningitis when the bacteria were given via the middle or inner ear (Fisher exact test, P<.05). However, the risk of meningitis did not change when the bacteria were given via the hematogenous route. Acute electrode insertion did not alter the risk of subsequent pneumococcal meningitis for any route of infection. CONCLUSIONS Severe inner ear surgical trauma to the osseous spiral lamina and modiolus can increase the risk of pneumococcal meningitis. Therefore, every effort should be made to ensure that cochlear implant design and insertion technique cause minimal trauma to the bony structures of the inner ear to reduce the risk of pneumococcal meningitis.
The urinary 1H‐NMR metabolomics profile of an italian autistic children population and their unaffected siblings

Autism spectrum disorders (ASD) make a dishomogeneous group of psychiatric diseases having either genetic and environmental components, including changes of the microbiota. The rate of diagnosis, based on a series of psychological tests and observed behavior, dramatically increased in the past few decades. Currently, no biological markers are available and the pathogenesis is not defined. The purpose of this study was to evaluate the potential use of 1H‐NMR metabolomics to analyze the global biochemical signature of ASD patients (n = 21) and controls (n = 21), these being siblings of autistic patients. A multivariate model has been used to extrapolate the variables of importance. The discriminating urinary metabolites were identified; in particular, significantly increased levels of hippurate, glycine, creatine, tryptophan, and d‐threitol and decreased concentrations of glutamate, creatinine, lactate, valine, betaine, and taurine were observed in ASD patients. Based on the identified discriminant metabolites, the attention was focused on two possible mechanisms that could be involved in ASD: oxidative stress conditions and gut microflora modifications. In conclusion, nuclear magnetic resonance‐based metabolomics analysis of the urine seems to have the potential for the identification of a metabolic fingerprint of ASD phenotypes and appears to be suitable for further investigation of the disease mechanisms. Autism Res 2017. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 1058–1066. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.
Moving Past Exploration and Adoption: Considering Priorities for Implementing Mobile Learning by Nurses

Successful implementation of mobile technology for informal learning and continuing professional development within healthcare settings cannot be achieved or sustained, until end-users recognise that the benefits of using this innovation, outweigh the issues of non-use. At a systems level there is a need for standards, guidelines and codes of conduct to support deployment of mobile technology at an individual level. The aim of this research was to explore findings of a previous focus group study to elucidate priorities for action, provide evidence and focus impetus for advocating progression of the installation of standards and guidelines at an organisation level. The study confirms nurse supervisors' preparedness and readiness to employ mobile learning at point of care. However, successful implementation requires organisations engaging with, and embracing the evolving digital landscape, and supporting this new andragogy. Organisational level commitment will promote contemporary nursing practice, support the best clinical outcomes for patients, and provide educational support for nurses. Nurse leaders and professional bodies must drive and guide development of robust standards, guidelines, and codes of conduct to prioritise mobile learning as a component of digital professionalism within healthcare organisations.
Effect of Exercise Training on Adiponectin Receptor Expression and Insulin Resistance in Mice Fed a High Fat Diet

Problem statement: Adiponectin is an adipocyte secreted hormones, exerts its effects via the specific receptors. AdipoR1 and adipoR2 and plays a pivotal role in lipid and glucose metabolism. Approach: We investigated the effect of increased physical activities on insulin resistance and if this effect is modulated through adiponectin receptor expression. Results: We also assessed the effect of High Fat Diet (HFD) on adipoRs expression. Mice were subjected to 16 weeks of HFD protocol then to 4, 6 and 8 weeks of exercise training. Following the experimental protocol the fasting plasma glucose, insulin and index of Homeostasis Model Assessment of insulin Resistance (HOMA-R) were evaluated. The mRNA expression of adiponectin receptors genes were also analyzed using reverse transcription RT-PCR. The consumption of high fat diet by the mice for 16 weeks resulted in a significant increase in weight associated with insulin resistance and associated with significant decrease in adiponectin receptors R1 and R2 expression in both liver and skeletal muscle. Exercise training for 4 weeks resulted in a significant improvement in the insulin resistance state, significant increase in expression of AdipoR1 and AdipoR2 in both liver and skeletal muscles. On increasing duration of exercise training for 6 weeks and 8 weeks there was significant improvement in insulin resistance and significant increase in the expression of AdipoR1 in liver, AdipoR1 and AdipoR2 in muscle, whereas liver AdipoR2 expression was significantly decreased. Conclusion/Recommendations: we conclude that the exercise training improves insulin sensitivity and up-regulates mRNA expression of AdipoR1 in both skeletal muscle and liver in mice and AdiopR2 in muscle and this suggests that the insulin sensitizing effect of exercise training may be mediated even partially through increased adiponectin receptor expression and up regulation of adiponectin receptors reaches certain level and increasing the duration of exercise adds no more improvement to insulin sensitivity or adiponectin receptor expression.
A Novel Neural Network Model for Blood Pressure Estimation Using Photoplethesmography without Electrocardiogram

The prevention, evaluation, and treatment of hypertension have attracted increasing attention in recent years. As photoplethysmography (PPG) technology has been widely applied to wearable sensors, the noninvasive estimation of blood pressure (BP) using the PPG method has received considerable interest. In this paper, a method for estimating systolic and diastolic BP based only on a PPG signal is developed. The multitaper method (MTM) is used for feature extraction, and an artificial neural network (ANN) is used for estimation. Compared with previous approaches, the proposed method obtains better accuracy; the mean absolute error is 4.02 ± 2.79 mmHg for systolic BP and 2.27 ± 1.82 mmHg for diastolic BP.
Translation initiation without IF2-dependent GTP hydrolysis

Translation initiation factor IF2 is a guanine nucleotide-binding protein. The free energy change associated with guanosine triphosphate hydrolase (GTPase) activity of these proteins is believed to be the driving force allowing them to perform their functions as molecular switches. We examined role and relevance of IF2 GTPase and demonstrate that an Escherichia coli IF2 mutant bearing a single amino acid substitution (E571K) in its 30S binding domain (IF2-G3) can perform in vitro all individual translation initiation functions of wild type (wt) IF2 and supports faithful messenger RNA translation, despite having a reduced affinity for the 30S subunit and being completely inactive in GTP hydrolysis. Furthermore, the corresponding GTPase-null mutant of Bacillus stearothermophilus (E424K) can replace in vivo wt IF2 allowing an E. coli infB null mutant to grow with almost wt duplication times. Following the E571K (and E424K) mutation, which likely disrupts hydrogen bonding between subdomains G2 and G3, IF2 acquires a guanosine diphosphate (GDP)-like conformation, no longer responsive to GTP binding thereby highlighting the importance of interdomain communication in IF2. Our data underlie the importance of GTP as an IF2 ligand in the early initiation steps and the dispensability of the free energy generated by the IF2 GTPase in the late events of the translation initiation pathway.
Effects of multidisciplinary interventions on weight loss and health outcomes in children and adolescents with morbid obesity

Morbid obesity is the fastest growing subcategory of childhood obesity, associated with an increased health risk that persists into adulthood. There is an urgent need to develop multifaceted interventions that target initial and long‐term lifestyle changes. This review investigates the effects of multidisciplinary interventions on weight loss and health outcomes in children and adolescents with morbid obesity. The influence of age, gender and family participation on health outcomes and intensive treatment alternatives are explored.
Distribution of human CMV‐specific memory T cells among the CD8pos. subsets defined by CD57, CD27, and CD45 isoforms

Chronic antigenic stimulation has been associated with peripheral blood expansions of CD8pos. T cells characterized by CD57 expression, loss of CD27 expression, and reversal of the CD45RObright /RAdim phenotype usually associated with immunological memory towards a CD45ROdim /RAbright phenotype. However, the relationship and functional significance of these subset(s) has remained controversial. Here, this issue was addressed using a novel flow cytometric technique that allows simultaneous detection of human cytomegalovirus (HCMV)‐specific CD8pos. memory T cells by rapid (< 6 h) HCMV peptide‐specific induction of cytokine synthesis, and their phenotypic characterization, including CD57, CD27 and CD45RA/RO. The vast majority of resting CD8pos. T cells capable of rapid induction of IFN‐γ and TNF‐α synthesis in response to HCMV peptides were found in a subset characterized by intermediate to high expression of CD57, down‐regulation/loss of CD27, and varying degrees of reversal of the classical “memory” CD45RObright /RAdim phenotype. This subpopulation likely includes the fully differentiated memory cells responsible for the long‐term immune defense against HCMV reactivation.