Miracle-dz/UniFAR-FTUs huggingface dataset:
Cost differential of immuno-oncology therapy delivered at community versus hospital clinics.

OBJECTIVES The site of cancer care delivery has been shown to be associated with the total cost of care. The magnitude of this effect in patients receiving expensive immuno-oncology (I-O) therapies has not been evaluated. We evaluated cost differentials between community-based and hospital-based outpatient clinics among patients receiving I-O therapies. STUDY DESIGN This was a retrospective analysis utilizing Truven MarketScan Commercial and Supplemental Medicare claims databases. METHODS Cost data for 3135 patients with non-small cell lung cancer, squamous cell carcinoma of the head and neck, bladder cancer, renal cell carcinoma, or melanoma who received pembrolizumab, nivolumab, and/or ipilimumab between January 1, 2015, and February 14, 2017, were analyzed as cost per patient per month (PPPM). Patients treated within a community setting were matched 2:1 with those treated at a hospital clinic based on cancer type, specific I-O therapy, receipt of radiation therapy, evidence of metastatic disease, gender, age, and evidence of surgery in the preindex period. RESULTS Mean (SD) total (medical plus pharmacy) PPPM cost was significantly lower for patients treated in a community- versus hospital-based clinic ($22,685 [$16,205] vs $26,343 [$22,832]; P <.001). Lower PPPM medical cost in the community versus hospital setting ($21,382 [$15,667] vs $24,831 [$22,102]; P <.001) was the major driver of this cost differential. Lower total cost was seen regardless of cancer type or I-O therapy administered. CONCLUSIONS Treatment with I-O therapies in community practice is associated with a lower total cost of care compared with that in hospital-based outpatient practices. With the expanding indications of these agents, future research is needed.
Structural and mechanistic insights into mechanoactivation of focal adhesion kinase

Significance Nonreceptor tyrosine kinases are major players in cell signaling. Among them, focal adhesion kinase (FAK) is the key integrator of signals from growth factors and cell adhesion. In cancer, FAK is frequently overexpressed, and by promoting adhesion to the tumor stroma and ECM, FAK provides important signals for tumor invasion and metastasis. Although autoinhibitory mechanisms have previously been described, FAK activation in response to force generated by ECM attachment is currently not understood. Here, we use experimental and computational approaches to demonstrate how mechanical forces can induce conformational changes in FAK that result in activation. This mechanistic insight enables the design of alternative strategies for the discovery of potential anticancer drugs that inhibit both catalytic and scaffolding functions of FAK. Focal adhesion kinase (FAK) is a key signaling molecule regulating cell adhesion, migration, and survival. FAK localizes into focal adhesion complexes formed at the cytoplasmic side of cell attachment to the ECM and is activated after force generation via actomyosin fibers attached to this complex. The mechanism of translating mechanical force into a biochemical signal is not understood, and it is not clear whether FAK is activated directly by force or downstream to the force signal. We use experimental and computational single-molecule force spectroscopy to probe the mechanical properties of FAK and examine whether force can trigger activation by inducing conformational changes in FAK. By comparison with an open and active mutant of FAK, we are able to assign mechanoactivation to an initial rupture event in the low-force range. This activation event occurs before FAK unfolding at forces within the native range in focal adhesions. We are also able to assign all subsequent peaks in the force landscape to partial unfolding of FAK modules. We show that binding of ATP stabilizes the kinase domain, thereby altering the unfolding hierarchy. Using all-atom molecular dynamics simulations, we identify intermediates along the unfolding pathway, which provide buffering to allow extension of FAK in focal adhesions without compromising functionality. Our findings strongly support that forces in focal adhesions applied to FAK via known interactions can induce conformational changes, which in turn, trigger focal adhesion signaling.
Assessing food safety and associated food hygiene and sanitary practices in food industries

Purpose The purpose of this cross-sectional study was to evaluate the level of knowledge, attitudes and practices of food handlers about food hygiene and sanitation in biscuit industry of central marketing company in Jessore, Bangladesh. Design/methodology/approach A self-administered, structured questionnaire was designed and data were collected during the period of April to July 2016 from 110 food handlers using simple random sampling. Findings The results show that the food handlers had excellent knowledge, attitude and good practices toward food hygiene and sanitation and food contamination related to food safety. The mean score (standard deviation) of knowledge, attitudes and practices were 20.1 (3.9), 18.6 (3.1) and 16.7 (3.3), respectively (p < 0.007). There was significant correlation between food safety training and knowledge, knowledge and attitude or knowledge and practices (p < 0.001). The majority (90.9 per cent) of the respondents stated that they intended to make sure that the prepared food was safe for consumers, which was significant (p < 0.007). Almost all of the food workers were aware of the critical role of general sanitary practices in the work place. The study suggests that the knowledge, attitude and practice level of food handlers were satisfactory. Originality/value Continuous education and training should be organized to strengthen food handlers’ knowledge in areas which seem to be deficient.
Clinical and Etiological Profile of Ischemic Stroke in Young Adults: A Prospective, Observational, Hospital based Study from Seacoast Population of South India

Objectives: To evaluate the clinical and etiological profile and outcome of the acute ischemic stroke in young adults in a tertiary-care hospital of south India. Methods: This study was conducted among 50 acute ischemic stroke patients (clinically and radiologically confirmed) irrespective of sex within the age group of 15-45 years admitted to Department of Neurology after clearance from Institutional Ethical Committee (IEC). A proforma for each of the acute ischemic stroke patients was maintained where all clinical information in brief including particulars of the subject, chief complaints, past history, proper general physical examination and systemic examinations etc were recorded. The patients had been undergone plain CT (computed tomography) scan/MRI (Magnetic Resonance Imaging) brain at admission for radiological confirmation and to localize the site of lesion in brain. All the included patients were followed upto 3 months of discharge to assess the outcome. Results: Hypertension (56%) was the most common risk factor among acute ischemic stroke in young adults. Majority of the acute ischemic stroke patients presented with motor weakness (94% - either in the form of hemiparesis or hemiplegia). Stroke of other determined etiology (62%) with predominant hypercoagulable disorders (Hyperhomocystinemia-55%) was the most common etiology. Beside, imaging findings confirmed right sided brain lesion in majority of the patients (60%) and middle cerebral artery circulation (80%) as the most common territory involved in the brain. Most patients had a good functional outcome after 3 months of discharge with NIHSS score of 0-5 in 90% and mRS score 0-2 in 92% patients. Conclusion: Most common clinical presentation is hemiplegia among the young onset acute ischemic stroke patients. Hypertension is most common risk factor and Stroke of other determined etiology is the most common etiology with middle cerebral arterial circulation being commonly involved and most patients had good functional outcome. Thus, the knowledge of the risk factors, clinical presentation and radiological findings and outcome of acute ischemic stroke in young adults can help in prevention, better understanding of pathogenesis and therapeutic decision making in the disease management.
Awareness of Type 2 diabetes mellitus in rural population of Mangalore, South India -

Background: As an emerging epidemic of the 21st century, diabetes would threaten to overwhelm the health-care system in the coming years posing a major challenges to patients and national economies. Currently, 415 million adults are found to be diabetic which is likely to cross 642 million by 2040. Awareness and health-seeking behavior are important in the reduction of burden of the disease and its long-term complications. Objectives: The objective of this study is to assess the awareness of Type 2 diabetes mellitus among the general and diabetic population in the rural community of Mangalore. Materials and Methods: A Community-based cross-sectional study was conducted in rural population among subjects aged 35 years and above. Based on the prevalence rate of 16.6% by Rao et al., 226 subjects were interviewed by systematic random sampling method, and among them, 64 were found to be diabetic at the time of the survey. Results: Of 226 persons interviewed, 28.8% were aware of symptoms, 31.9% were aware of risk factors, and among them, majority were aware of increased intake of sweets in association with diabetes, and 49.6% were aware of warning signs of hypoglycemia. Only 22.6% were aware of complications of diabetes. Mean awareness score was 21.23 among diabetics than compared with the general population, 17.07 (P < 0.05). Overall awareness of diabetes among the subjects was found to be
Elevated signature of a gene module coexpressed with CDC20 marks genomic instability in glioma

Significance Genomic instability fuels tumor progression and treatment resistance in cancer. Causative factors and means for clinical detection of genomic instability in the bulk of gliomas have been inadequately explored. We identify a conserved gene coexpression module centered on CDC20 (CDC20-M) in glioma transcriptomes that encompasses broad activities of cell proliferation and genome maintenance. We show that high CDC20-M expression robustly predicts poor prognosis and severe chromosomal instability and mutation burden in glioma. Core members of CDC20-M, including AURKA, are dysregulated and may provide new therapeutic targets in glioma. These data suggest that the CDC20-M signature could be applied for risk stratification and for the development of treatment protocols for glioma and other cancers. Genomic instability (GI) drives tumor heterogeneity and promotes tumor progression and therapy resistance. However, causative factors underlying GI and means for clinical detection of GI in glioma are inadequately identified. We describe here that elevated expression of a gene module coexpressed with CDC20 (CDC20-M), the activator of the anaphase-promoting complex in the cell cycle, marks GI in glioma. The CDC20-M, containing 139 members involved in cell proliferation, DNA damage response, and chromosome segregation, was found to be consistently coexpressed in glioma transcriptomes. The coexpression of these genes was conserved across multiple species and organ systems, particularly in human neural stem and progenitor cells. CDC20-M expression was not correlated with the morphological subtypes, nor with the recently defined molecular subtypes of glioma. CDC20-M signature was an independent and robust predictor for poorer prognosis in over 1,000 patients from four large databases. Elevated CDC20-M signature enabled the identification of individual glioma samples with severe chromosome instability and mutation burden and of primary glioma cell lines with extensive mitotic errors leading to chromosome mis-segregation. AURKA, a core member of CDC20-M, was amplified in one-third of CDC20-M–high gliomas with gene-dosage–dependent expression. MLN8237, a Food and Drug Administration-approved AURKA inhibitor, selectively killed temozolomide-resistant primary glioma cells in vitro and prolonged the survival of a patient-derived xenograft mouse model with a high–CDC20-M signature. Our findings suggest that application of the CDC20-M signature may permit more selective use of adjuvant therapies for glioma patients and that dysregulated CDC20-M members may provide a therapeutic vulnerability in glioma.
One-Pot FDCA Diester Synthesis from Mucic Acid and Their Solvent-Free Regioselective Polytransesterification for Production of Glycerol-Based Furanic Polyesters

A one pot-two step procedure for the synthesis of diethyl furan-2,5-dicarboxylate (DEFDC) starting from mucic acid without isolation of the intermediate furan dicarboxylic acid (FDCA) was studied. Then, the production of three different kinds of furan-based polyesters— polyethylene-2,5-furan dicarboxylate (PEF), polyhydropropyl-2,5-furan dicarboxylate(PHPF) and polydiglycerol-2,5-furandicarboxylate (PDGF)—was realized through a Co(Ac)2·4H2O catalyzed polytransesterification performed at 160 °C between DEFDC and a defined diol furan-based prepolymer or pure diglycerol. In parallel to polymerization process, an unattended regioselective 1-OH acylation of glycerol by direct microwave-heated FDCA diester transesterification led to the formation of a symmetric prepolymer ready for further polymerization and clearly identified by 2D NMR sequences. Furthermore, the synthesis of a more soluble and hydrophilic diglycerol-based furanic polyester was also achieved. The resulting biobased polymers were characterized by NMR, FT-IR spectroscopy, DSC, TGA and XRD. The morphologies of the resulted polymers were observed by FE-SEM and the purity of the material by EDX.
Long-term effects of high intensity resistance and endurance exercise on plasma leptin and ghrelin in overweight individuals: the RESOLVE Study.

OBJECTIVE To evaluate the effects of high intensity resistance and endurance exercise on body composition and plasma leptin and ghrelin concentrations in overweight individuals. METHODS 100 participants were randomly assigned to three exercise interventions: high resistance-low aerobic (Re), low resistance-high aerobic (rE), low resistance-low aerobic (re). Interventions began with 3 weeks of residential supervision (Phase1) after which participants had to manage the physical activity programs individually (Phase2). Body composition and plasma variables were measured at baseline and after Phase 1 as well as after 3, 6, and 12 months. RESULTS Significant decreases in body weight and fat were observed after Phase 1 (p<0.001), and continued at a lower rate for up to 3 months, and then remained stable for the rest of the protocol. Once a body weight plateau was reached, body fat loss after the Re and rE conditions exceeded the fat loss observed in the re condition by 1.5-2 kg (p<0.05). Leptin was significantly decreased after Day 21 and Month 3 (p<0.001) and remained stable for the rest of the study. Ghrelin was significantly increased after Day 21 and Month 3 (p<0.001) and returned to a level comparable to baseline between Month 6 and 12 when body weight and fat had reached a plateau. CONCLUSIONS This study reinforces the idea that an increase in exercise intensity may accentuate body fat loss before the occurrence of a body weight plateau. Resistance to further fat loss was accompanied by a decrease in plasma leptin and an increase in plasma ghrelin.
Revisiting Histone Deacetylases in Human Tumorigenesis: The Paradigm of Urothelial Bladder Cancer

Urinary bladder cancer is a common malignancy, being characterized by substantial patient mortality and management cost. Its high somatic-mutation frequency and molecular heterogeneity usually renders tumors refractory to the applied regimens. Hitherto, methotrexate-vinblastine-adriamycin-cisplatin and gemcitabine-cisplatin represent the backbone of systemic chemotherapy. However, despite the initial chemosensitivity, the majority of treated patients will eventually develop chemoresistance, which severely reduces their survival expectancy. Since chromatin regulation genes are more frequently mutated in muscle-invasive bladder cancer, as compared to other epithelial tumors, targeted therapies against chromatin aberrations in chemoresistant clones may prove beneficial for the disease. “Acetyl-chromatin” homeostasis is regulated by the opposing functions of histone acetyltransferases (HATs) and histone deacetylases (HDACs). The HDAC/SIRT (super-)family contains 18 members, which are divided in five classes, with each family member being differentially expressed in normal urinary bladder tissues. Since a strong association between irregular HDAC expression/activity and tumorigenesis has been previously demonstrated, we herein attempt to review the accumulated published evidences that implicate HDACs/SIRTs as critical regulators in urothelial bladder cancer. Moreover, the most extensively investigated HDAC inhibitors (HDACis) are also analyzed, and the respective clinical trials are also described. Interestingly, it seems that HDACis should be preferably used in drug-combination therapeutic schemes, including radiation.
Quantitative analysis of the effects of nicotinamide phosphoribosyltransferase induction on the rates of NAD+ synthesis and breakdown in mammalian cells using stable isotope-labeling combined with mass spectrometry

NAD+ is mainly synthesized from nicotinamide (Nam) by the rate-limiting enzyme Nam phosphoribosyltransferase (Nampt) and degraded to Nam by NAD+-degrading enzymes in mammals. Numerous studies report that tissue NAD+ levels decrease during aging and age-related diseases and suggest that NAD+ replenishment promotes healthy aging. Although increased expression of Nampt might be a promising intervention for healthy aging, forced expression of Nampt gene, inducing more than 10-fold increases in the enzyme protein level, has been reported to elevate NAD+ levels only 40–60% in mammalian cells. Mechanisms underlying the limited increases in NAD+ levels remain to be determined. Here we show that Nampt is inhibited in cells and that enhanced expression of Nampt activates NAD+ breakdown. Combined with the measurement of each cell’s volume, we determined absolute values (μM/h) of the rates of NAD+ synthesis (RS) and breakdown (RB) using a flux assay with a 2H (D)-labeled Nam, together with the absolute NAD+ concentrations in various mammalian cells including primary cultured cardiomyocytes under the physiological conditions and investigated the relations among total cellular Nampt activity, RS, RB, and the NAD+ concentration. NAD+ concentration was maintained within a narrow range (400–700 μM) in the cells. RS was much smaller than the total Nampt activity, indicating that NAD+ synthesis from Nam in the cells is suppressed. Forced expression of Nampt leading to 6-fold increase in total Nampt activity induced only a 1.6-fold increase in cellular NAD+ concentration. Under the conditions, RS increased by 2-fold, while 2-fold increase in RB was also observed. The small increase in cellular NAD+ concentration is likely due to both inhibited increase in the NAD+ synthesis and the activation of its breakdown. Our findings suggest that cellular NAD+ concentrations do not vary dramatically by the physiological fluctuation of Nampt expression and show the tight link between the NAD+ synthesis and its breakdown.
Suboptimal Nutrition and Low Physical Activity Are Observed Together with Reduced Plasma Brain-Derived Neurotrophic Factor (BDNF) Concentration in Children with Severe Cerebral Palsy (CP)

Brain-derived neurotrophic factor (BDNF) is a mediator of exercise and nutrition-induced neural plasticity. In children with cerebral palsy (CP), neuromuscular deficits and mobility impairment have a negative impact on their physical activity level and nutritional status, but whether these children have reduced BDNF concentrations is unknown. Therefore, the aim of the present study was to investigate the plasma BDNF concentration, nutritional status, and physical activity level in children with mild to severe CP. Blood sampling, dietary registration, and questionnaires were completed for children with mild CP (gross motor function classification system (GMFCS) I–II, n = 31, age 10.6 ± 0.6 years), severe CP (GMFCS IV–V, n = 14, age 10.9 ± 1.1 years) and typically developed (TD) children (n = 22, age 10.9 ± 0.6 years). Children with severe CP had ~40% lower plasma BDNF concentration than TD children (p < 0.05). Furthermore, children with severe CP had lower daily physical activity level than TD children (p < 0.01), and a daily intake of energy, n-3 fatty acids, and dietary fibers that was only ~50% of TD (p > 0.001). Reduced plasma BDNF concentrations were observed in children with severe CP. This may be of significance for optimal neural growth and plasticity. This was observed together with low physical activity levels and a suboptimal intake of energy, n-3 fatty acids, and dietary fibers.
Prevalence and characteristics of the metabolic syndrome in patients with chronic pancreatitis

Objective: Chronic pancreatitis (CP) and metabolic syndrome (MS) share a bidirectional cause and effect relation. We investigated the prevalence and characteristics of MS in patients with CP and compared the same between alcoholic CP and tropical CP (TCP). Materials and Methods: In this cross-sectional, observational study, we included serial patients of CP presented to our hospital. We excluded CP patients with other known systemic disorders, long-term intake of drugs that could affect the lipids and also excluded patients with features of exocrine deficiency. The study population is grouped as alcoholic CP (Group 1; n = 65) and TCP (Group 2; n = 37). A fasting blood sample was checked for all the biochemical parameters, and MS was defined as per the Asian modification of the National Cholesterol Education Program Adult Treatment Panel III definition. The results were analyzed by appropriate statistical methods. Results: The study participants (85 male and 17 female) had a mean age 40.8 ± 12.6 years, CP duration 3.7 ± 4.7 year, and body mass index of 22.5 ± 3.2 kg/m2. A total of 27 (26%) out of 102 patients had the presence of the MS, which was similar in frequency between both the groups (P = 0.0991). Hyperglycemia and low high-density lipoprotein cholesterol (HDL-C) were the common features in alcoholic CP, whereas TCP patents showed hyperglycemia, abdominal obesity, and low HDL-C. None of the participants had all the five components, and seven patients had no features of the MS. Conclusion: MS is seen in a quarter of patients with CP, and the prevalence is same irrespective of the underlying etiology.
Alkynes as Synthetic Equivalents of Ketones and Aldehydes: A Hidden Entry into Carbonyl Chemistry

The high energy packed in alkyne functional group makes alkyne reactions highly thermodynamically favorable and generally irreversible. Furthermore, the presence of two orthogonal π-bonds that can be manipulated separately enables flexible synthetic cascades stemming from alkynes. Behind these “obvious” traits, there are other more subtle, often concealed aspects of this functional group’s appeal. This review is focused on yet another interesting but underappreciated alkyne feature: the fact that the CC alkyne unit has the same oxidation state as the -CH2C(O)- unit of a typical carbonyl compound. Thus, “classic carbonyl chemistry” can be accessed through alkynes, and new transformations can be engineered by unmasking the hidden carbonyl nature of alkynes. The goal of this review is to illustrate the advantages of using alkynes as an entry point to carbonyl reactions while highlighting reports from the literature where, sometimes without full appreciation, the concept of using alkynes as a hidden entry into carbonyl chemistry has been applied.