Miracle-dz/UniFAR-FTUs huggingface dataset:
Combinatorial Efficacy of Olaparib with Radiation and ATR Inhibitor Requires PARP1 Protein in Homologous Recombination–Proficient Pancreatic Cancer

PARP inhibitor monotherapy (olaparib) was recently FDA approved for the treatment of BRCA1/2-mutant, homologous recombination (HR) repair-deficient pancreatic cancer. Most pancreatic cancers, however, are HR proficient and thus resistant to PARP inhibitor monotherapy. We tested the hypothesis that combined therapy with radiation and ataxia telangiectasia and Rad3-related (ATR) inhibitor (AZD6738) would extend the therapeutic indication of olaparib to HR-proficient pancreatic cancers. We show that olaparib combined with AZD6738 significantly reduced radiation survival relative to either agent alone, regardless of HR status. Whereas catalytic inhibition of PARP with low concentrations of olaparib radiosensitized HR-deficient models, maximal sensitization in HR-proficient models required concentrations of olaparib that induce formation of PARP1–DNA complexes. Furthermore, CRISPR-Cas9–mediated PARP1 deletion failed to recapitulate the effects of olaparib on radiosensitivity and negated the combinatorial efficacy of olaparib and AZD6738 on radiosensitization, suggesting that PARP1–DNA complexes, rather than PARP catalytic inhibition, were responsible for radiosensitization. Mechanistically, therapeutic concentrations of olaparib in combination with radiation and AZD6738 increased DNA double-strand breaks. DNA fiber combing revealed that high concentrations of olaparib did not stall replication forks but instead accelerated replication fork progression in association with an ATR-mediated replication stress response that was antagonized by AZD6738. Finally, in HR-proficient tumor xenografts, the combination of olaparib, radiation, and AZD6738 significantly delayed tumor growth compared with all other treatments. These findings suggest that PARP1–DNA complexes are required for the therapeutic activity of olaparib combined with radiation and ATR inhibitor in HR-proficient pancreatic cancer and support the clinical development of this combination for tumors intrinsically resistant to PARP inhibitors.
News FLASH-RT: To Treat GBM and Spare Cognition, Fraction Size and Total Dose Matter

Data indicate that ultrahigh dose rate (>106 Gy/second) FLASH radiotherapy (FLASH-RT) delivery of radiation reduces normal tissue damage without compromising tumor response. Orthotopic glioblastoma mouse studies now demonstrate that radiation fraction size, total dose, and number of fractions are critical parameters for FLASH-RT cognitive sparing without compromising tumor response. See related article by Montay-Gruel et al., p. 775
Current understanding of primary biliary cholangitis

Primary biliary cholangitis (PBC) causes chronic and persistent cholestasis in the liver, eventually resulting in cirrhosis and hepatic failure without appropriate treatment. PBC mainly develops in middle-aged women, but it is also common in young women and men. PBC is considered a model of autoimmune disease because of the presence of disease-specific autoantibodies, that is, antimitochondrial antibodies (AMAs), intense infiltration of mononuclear cells into the bile ducts, and a high prevalence of autoimmune diseases such as comorbidities. Histologically, PBC is characterized by degeneration and necrosis of intrahepatic biliary epithelial cells surrounded by a dense infiltration of mononuclear cells, coined as chronic non-suppurative destructive cholangitis, which leads to destructive changes and the disappearance of small- or medium-sized bile ducts. Since 1990, early diagnosis with the detection of AMAs and introduction of ursodeoxycholic acid as first-line treatment has greatly altered the clinical course of PBC, and liver transplantation-free survival of patients with PBC is now comparable to that of the general population.
Spray-Dried Iron Fischer−Tropsch Catalysts. 2. Effect of Carburization on Catalyst Attrition Resistance

Spray drying has been recently used by this research team in the preparation of Fe Fischer−Tropsch catalysts with higher attrition resistance for use in slurry bubble column reactors. In the first paper in this series, the effects of the type, concentration, and network structure of SiO2 on the attrition resistance of two series of spray-dried Fe catalysts in their calcined state were explored and the dependence of catalyst attrition resistance on catalyst particle density was discussed. As a continuation of our previous effort, the effect of carburization on catalyst attrition resistance was studied and is presented in this paper. After carburization, the majority component of the catalysts, hematite (Fe2O3), was converted to iron carbides, mostly χ-carbide (Fe2C5). Breakage of individual catalyst particles and fines formation, which can be considered as evidence of chemical attrition, was only observed during carburization of the catalyst with low SiO2 concentration <9 wt %. With an increase in the tota.
Laryngeal Pathologies Associated with the Genre of Singing and Professional Singing Status in a Treatment‐Seeking Population

Singers have high vocal demands and are at increased risk of developing voice disorders. Different singing genres place different technical demands on the voice. However, differences in laryngeal pathology based on genre have not been well‐researched. The purpose of this study was to determine the prevalence of laryngeal pathology in different genres of professional and amateur singers who present with a voice complaint.
Moonlighting in drug metabolism

Abstract Drug metabolizing enzymes catalyze the biotransformation of many of drugs and chemicals. The drug metabolizing enzymes are distributed among several evolutionary families and catalyze a range of detoxication reactions, including oxidation/reduction, conjugative, and hydrolytic reactions that serve to detoxify potentially toxic compounds. This detoxication function requires that drug metabolizing enzymes exhibit substrate promiscuity. In addition to their catalytic functions, many drug metabolizing enzymes possess functions unrelated to or in addition to catalysis. Such proteins are termed ‘moonlighting proteins’ and are defined as proteins with multiple biochemical or biophysical functions that reside in a single protein. This review discusses the diverse moonlighting functions of drug metabolizing enzymes and the roles they play in physiological functions relating to reproduction, vision, cell signaling, cancer, and transport. Further research will likely reveal new examples of moonlighting functions of drug metabolizing enzymes.
Meta‐analysis as a system of springs

Meta‐analysis results are usually presented in forest plots, which show the individual study results and the summary effect along with their confidence intervals. In this paper, we propose a system of linear springs as a mechanical analogue of meta‐analysis that enables visualization and enhances intuition. The length of a spring corresponds to a study treatment effect and the stiffness of the spring corresponds to its inverse variance. To synthesize study springs we use two main operations: connection in parallel and connection in series. We show the equivalence between meta‐analysis and linear springs for fixed effect and random effects pairwise meta‐analysis and we also derive indirect treatment effects. We use examples to illustrate the different meta‐analytical schemes using the corresponding system of springs. The proposed visualization can serve as an educational tool, especially useful for researchers with no statistical background. The analogy between meta‐analysis and springs facilitates intuition for notions such as heterogeneity and the differences between fixed and random effects meta‐analysis.
Incidence of Symptomatic Submucous Cleft Palate in the Netherlands: A Retrospective Cohort Study Over a Period of 22 Years

Objective: To analyze the incidence of submucous cleft palate (SMCP) in a large national database and raise awareness among referring providers: pediatricians, speech pathologists, and dentists to minimize delay in diagnosis. Design: Retrospective cohort study. Setting: Tertiary setting. Patients: Patients were extracted from the “Dutch Association for Cleft and Craniofacial Anomalies” database. A total of 6916 patients were included from 1997 until 2018 and divided into 2 groups (ie, SMCP versus cleft palate [CP]). Patients born before 1997 and adopted patients were excluded. Interventions: Clefts were classified as either hard of soft palatal involvement based on anatomical landmarks at first consultation. Main Outcome Measures: Primary outcomes were the patient characteristics in both groups (ie, gender, birth weight, gestational age, and additional anomalies). Secondary outcome was the time of diagnosis among subgroups. Results: In total, 532 patients were diagnosed with SMCP (7.7%). Birth weight, gestational age, and additional anomalies did not differ between subgroups, but there were more males in the SMCP group (P < .001). The median age of diagnosis of the SMCP group was significantly higher than of the CP group (987 vs 27 days; P < .001). Over the course of 22 years, the time of diagnosis for SMCP did not decrease. Conclusion: Submucous cleft palate represents <10% of the Dutch cleft population and 19.4% of all CP. Time of diagnosis for SMCP is significantly longer when compared with time of diagnosis of CP, and this has not changed over the study period of 22 years.
Association of weight loss and weight loss maintenance following diabetes diagnosis by screening and incidence of cardiovascular disease and all‐cause mortality: An observational analysis of the ADDITION‐Europe trial

Short‐term weight loss may lead to remission of type 2 diabetes but the effect of maintained weight loss on cardiovascular disease (CVD) is unknown. We quantified the associations between changes in weight 5 years following a diagnosis of diabetes, and incident CVD events and mortality up to 10 years after diagnosis.
Effects of Pre-Calving Body Condition and Different post partum Concentrate Feed Proportions on Immune-Associated and Hematological Parameters in Pluriparous Dairy Cows

Simple Summary Dairy cows have to cope with physiological, metabolic and endocrine challenges during the transition from late gestation to lactation. This period is characterized by a negative energy balance. Concentrate feed proportion of the rations is often increased to compensate the energy deficit. This can lead to acidotic conditions in the rumen, which might trigger the release of lipopolysaccharides from bacteria and result in inflammatory responses. An unfavorable pre-calving body condition is known to cause health problems after calving. Cows with a higher body condition (expressed as score, BCS, at a five-point scale) prior to calving might respond differently to either low or high concentrate feed proportions after calving with regard to hematological traits as indicators for possible interactions between nutritional status and immune system. For testing this hypothesis, cows were split into two classes (higher and adequate BCS) six weeks prior to calving according to their actual BCS and fed either a low- or high-energy-dense diet after calving. Neither BCS class nor dietary energy concentration influenced markedly hematological traits, including immune cell phenotypes, and inflammatory markers, such as haptoglobin. The overall covered individual BCS range and the post partum concentrate feed challenge did not overstress physiological adaptability. Abstract The present study aimed at evaluating the influences of different concentrate feed proportions in the ration offered to dairy cows post partum with different body condition scores (BCS) before calving. Therefore, 60 pluriparous cows were divided 42 days before expected calving into two groups with a higher or an adequate BCS. After calving, both groups were further subdivided into a group fed a ration with either a low concentrate feed proportion (C, 35% at dry matter basis) or a high (60% at dry matter basis) one. It was hypothesized that different BCS would lead to different reactions concerning varying concentrate feed proportions. Isolated BCS effects were detected in the white blood profile only before calving. Neither low nor high concentrate feed proportions affected hematological, blood immune cell phenotypes and inflammatory markers consistently irrespective of BCS group. It was concluded, that the assessed BCS span covered a range in which the capability of cows to cope with different dietary post partum energy supply remained unchanged.
The impact of solid-state form, water content and surface area of magnesium stearate on lubrication efficiency, tabletability, and dissolution

Abstract Magnesium stearate (MgSt) is a widely used pharmaceutical lubricant in tablet manufacturing. However, batch-to-batch variability in hydrate form and surface area can lead to inconsistency in tablet performance. In this work, several unique MgSt samples were studied: traditional monohydrate samples with high surface area, dihydrate forms with high and low surface area, and disordered forms with low and medium water content. The effects of solid-state form and particle properties on lubrication efficiency, tabletability and dissolution were studied for tablets in a model direct compression formulation. It was found that the monohydrate and dihydrate forms had good lubrication efficiency compared to the disordered form, while the disordered form had the best tabletability. The dissolution rate correlated with surface area, where slower dissolution rates corresponded with higher MgSt surface areas. The dihydrate sample with lower surface area had the best performance for this model formulation, in terms of lubrication efficiency, tabletability and dissolution. Overall, it is concluded that the choice of the most appropriate grade of MgSt for a particular formulation depends on a comprehensive evaluation of the impact of MgSt properties on lubrication efficiency, tabletability and dissolution.
Cytokine Storm

From the Department of Medicine, Division of Translational Medicine and Human Genetics, Center for Cytokine Storm Treatment and Laboratory (D.C.F.), and the Center for Cellular Immunotherapies and the Parker Institute for Cancer Immunotherapy (C.H.J.), Perelman School of Medicine, University of Pennsylvania, Philadelphia. Address reprint requests to Dr. Fajgenbaum at davidfa@ pennmedicine . upenn . edu or to Dr. June at cjune@ upenn . edu.
Nootkatone, a Dietary Fragrant Bioactive Compound, Attenuates Dyslipidemia and Intramyocardial Lipid Accumulation and Favorably Alters Lipid Metabolism in a Rat Model of Myocardial Injury: An In Vivo and In Vitro Study

In the present study, we assessed whether nootkatone (NKT), a sesquiterpene in edible plants, can provide protection against dyslipidemia, intramyocardial lipid accumulation, and altered lipid metabolism in a rat model of myocardial infarction (MI) induced by subcutaneous injections of isoproterenol (ISO, 85 mg/kg) on days 9 and 10. The rats were pre- and co-treated with NKT (10 mg/kg, p.o.) administered daily for 11 days. A significant reduction in the activities of myocardial creatine kinase and lactate dehydrogenase, as well as non-enzymatic antioxidants, and alterations in lipids and lipoproteins, along with a rise in plasma lipid peroxidation and intramyocardial lipid accumulation, were observed in ISO-treated rats. ISO administration induced alterations in the activities of enzymes/expressions that played a significant role in altering lipid metabolism. However, NKT treatment favorably modulated all biochemical and molecular parameters altered by ISO and showed protective effects against oxidative stress, dyslipidemia, and altered lipid metabolism, attributed to its free-radical-scavenging and antihyperlipidemic activities in rats with ISO-induced MI. Additionally, NKT decreased the accumulation of lipids in the myocardium as evidenced from Oil red O staining. Furthermore, the in vitro observations demonstrate the potent antioxidant property of NKT. The present study findings are suggestive of the protective effects of NKT on dyslipidemia and the underlying mechanisms. Based on our findings, it can be suggested that NKT or plants rich in NKT can be promising for use as a phytopharmaceutical or nutraceutical in protecting the heart and correcting lipid abnormalities and dyslipidemia, which are risk factors for ischemic heart diseases.
The expression of repulsive guidance molecule a (RGMa) after traumatic brain injury: Time-course changes in gene expression in a murine model of controlled cortical impact.

INTRODUCTION Repulsive guidance molecule a (RGMa) is a key protein that negatively regulates neuronal regeneration as its inhibition enhances axonal growth and promotes functional recovery in animal models of spinal cord injury. However, the role of RGMa in traumatic brain injury (TBI) remains elusive. This study aimed to clarify TBI-responsive RGMa expression in a murine model. METHODS Adult male C57Bl/6J mice were subjected to controlled cortical impact. Brains were extracted 6 hours and 1, 3, 7, 14 and 21 days after injury (n=6 in each group). Changes in the mRNA expression of RGMa and its receptor, neogenin, were evaluated by quantitative polymerase chain reaction in the damaged area of the cortex and contralateral cortex, along with expression measurement of inflammation-related molecules. Neurological deficit was also assessed by the cylinder test. RESULTS Neurological score was consistently lower in the TBI group compared to the sham group throughout the experimental period. mRNA expressions of representative inflammatory cytokine TNF-alpha and chemokine CCR2 were remarkably increased in the injured cortex on day 1 and gradually decreased over time, although remaining at higher values at least until day 14. mRNA expressions of RGMa and neogenin were significantly suppressed in the damaged cortex until day 3. Interestingly, RGMa expression was suppressed most on day 1 and recovered over time. CONCLUSION In the acute phase of TBI, gene expression of inflammatory cytokines significantly increased, and gene expressions of RGMa and neogenin significantly decreased in the inflammatory milieu of the damaged area. Despite the subsequent remission of inflammation, RGMa gene expression recovered to the normal level one week after TBI. Intrinsic regenerative response to acute brain injury might be hampered by the following recovery of RGMa expression, hinting at the possibility of functional RGMa inhibition as a new, effective maneuver against TBI.
The Exploration of Novel Regulatory Relationships Drives Haloarchaeal Operon-Like Structural Dynamics over Short Evolutionary Distances

Operons are a dominant feature of bacterial and archaeal genome organization. Numerous investigations have related aspects of operon structure to operon function, making operons exemplars for studies aimed at deciphering Nature’s design principles for genomic organization at a local scale. We consider this understanding to be both fundamentally important and ultimately useful in the de novo design of increasingly complex synthetic circuits. Here we analyze the evolution of the genomic context of operon-like structures in a set of 76 sequenced and annotated species of halophilic archaea. The phylogenetic depth and breadth of this dataset allows insight into changes in operon-like structures over shorter evolutionary time scales than have been studied in previous cross-species analysis of operon evolution. Our analysis, implemented in the updated software package JContextExplorer finds that operon-like context as measured by changes in structure frequently differs from a sequence divergence model of whole-species phylogeny and that changes seem to be dominated by the exploration of novel regulatory relationships.
Analysis of efficacy of lenvatinib treatment in highly advanced hepatocellular carcinoma with tumor thrombus in the main trunk of the portal vein or tumor with more than 50% liver occupation: A multicenter analysis

To assess the safety, efficacy, and prognostic impact of clinical factors associated with lenvatinib treatment in highly advanced hepatocellular carcinoma (HCC) with tumor thrombus in the main portal vein trunk (VP4) or tumor with more than 50% liver occupation (tm50%LO).
Thermal Impedance Characterization Using Optical Measurement Assisted by Multi-Physics Simulation for Multi-Chip SiC MOSFET Module

In this paper, an approach to determine the thermal impedance of a multi-chip silicon carbide (SiC) power module is proposed, by fusing optical measurement and multi-physics simulations. The tested power module consists of four parallel SiC metal-oxide semiconductor field-effect transistors (MOSFETs) and four parallel SiC Schottky barrier diodes. This study mainly relies on junction temperature measurements performed using fiber optic temperature sensors instead of temperature-sensitive electrical parameters (TESPs). However, the fiber optics provide a relatively slow response compared to other available TSEP measurement methods and cannot detect fast responses. Therefore, the region corresponding to undetected signals is estimated via multi-physics simulations of the power module. This method provides a compensated cooling curve. We analyze the thermal resistance using network identification by deconvolution (NID). The estimated thermal resistance is compared to that obtained via a conventional method, and the difference is 3.8%. The proposed fusion method is accurate and reliable and does not require additional circuits or calibrations.
Multimedia resources to support the recruitment of committed hematopoietic stem cell donors: Perspectives of the most‐needed donors

Recruitment of committed unrelated hematopoietic stem cell donors from the most‐needed demographics remains a challenge for donor recruitment organizations worldwide. Multimedia resources are gaining attention as a modality to support recruitment efforts; however, there is a lack of guidance for the development of such tools. This qualitative study explores the perspectives of eligible stem cell donors on an educational whiteboard video about stem cell donation, generating insights into how whiteboard videos and related multimedia may be optimized for donor recruitment.