Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacodynamic measures within tumors expose differential activity of PD(L)-1 antibody therapeutics

Significance Success with immune checkpoint therapy has led to a proliferation of antibody therapeutics with distinct biophysical and pharmacological properties. Antibodies experience poor penetration in solid tumors because of their size, and blood-based measurements fail to reflect their activity at the tumor. While of fundamental importance to establish dose–exposure–response relationships, pharmacologic activity of antibodies within tumors is technically challenging to study in real time because of the lack of quantitative tools. Here, we show that target pharmacodynamics can yield insights into pharmacologic activity of antibodies in tumors and elucidate therapeutic response. Our approach of using small-molecule probes for rapid quantification of target pharmacodynamics to interrogate the pharmacologic activity of antibodies has broad implications for drug development and guiding therapy. Macromolecules such as monoclonal antibodies (mAbs) are likely to experience poor tumor penetration because of their large size, and thus low drug exposure of target cells within a tumor could contribute to suboptimal responses. Given the challenge of inadequate quantitative tools to assess mAb activity within tumors, we hypothesized that measurement of accessible target levels in tumors could elucidate the pharmacologic activity of a mAb and could be used to compare the activity of different mAbs. Using positron emission tomography (PET), we measured the pharmacodynamics of immune checkpoint protein programmed-death ligand 1 (PD-L1) to evaluate pharmacologic effects of mAbs targeting PD-L1 and its receptor programmed cell death protein 1 (PD-1). For PD-L1 quantification, we first developed a small peptide-based fluorine-18–labeled PET imaging agent, [18F]DK222, which provided high-contrast images in preclinical models. We then quantified accessible PD-L1 levels in the tumor bed during treatment with anti–PD-1 and anti–PD-L1 mAbs. Applying mixed-effects models to these data, we found subtle differences in the pharmacodynamic effects of two anti–PD-1 mAbs (nivolumab and pembrolizumab). In contrast, we observed starkly divergent target engagement with anti–PD-L1 mAbs (atezolizumab, avelumab, and durvalumab) that were administered at equivalent doses, correlating with differential effects on tumor growth. Thus, we show that measuring PD-L1 pharmacodynamics informs mechanistic understanding of therapeutic mAbs targeting PD-L1 and PD-1. These findings demonstrate the value of quantifying target pharmacodynamics to elucidate the pharmacologic activity of mAbs, independent of mAb biophysical properties and inclusive of all physiological variables, which are highly heterogeneous within and across tumors and patients.
Bivariate small‐area estimation for binary and gaussian variables based on a conditionally specified model

Many large‐scale surveys collect both discrete and continuous variables. Small‐area estimates may be desired for means of continuous variables, proportions in each level of a categorical variable, or for domain means defined as the mean of the continuous variable for each level of the categorical variable. In this paper, we introduce a conditionally specified bivariate mixed‐effects model for small‐area estimation, and provide a necessary and sufficient condition under which the conditional distributions render a valid joint distribution. The conditional specification allows better model interpretation. We use the valid joint distribution to calculate empirical Bayes predictors and use the parametric bootstrap to estimate the mean squared error. Simulation studies demonstrate the superior performance of the bivariate mixed‐effects model relative to univariate model estimators. We apply the bivariate mixed‐effects model to construct estimates for small watersheds using data from the Conservation Effects Assessment Project, a survey developed to quantify the environmental impacts of conservation efforts. We construct predictors of mean sediment loss, the proportion of land where the soil loss tolerance is exceeded, and the average sediment loss on land where the soil loss tolerance is exceeded. In the data analysis, the bivariate mixed‐effects model leads to more scientifically interpretable estimates of domain means than those based on two independent univariate models.
Regulation and role of glycophagy in skeletal muscle energy metabolism

ABSTRACT Glycophagy is the autophagic degradation of glycogen via the lysosomal enzyme GAA/alpha-acid glucosidase. Glycophagy is considered a housekeeping process to degrade poorly branched glycogen particles, but the regulation and role of glycophagy in skeletal muscle metabolism remains enigmatic. Herein, prior muscle contraction promoted glycogen supercompensation 24 and 48 h post contraction, an effect associated with reduced glycophagy. Moreover, NOTCH or cAMP signaling promoted glycophagy, whereas acute glycophagy deficiency rewired cell metabolism by reducing glycolysis and enhancing AMPK and PPAR signaling and fatty acid and glutamine metabolism. These metabolic adaptations were associated with reduced inflammation and triglyceride content but enhanced phosphoinositide 3-kinase (PI3K)-AKT/protein kinase B signaling and insulin action, the latter of which was abolished by exogenous oxidative stress. Collectively, these data suggest glycophagy is dynamically regulated, while the function of glycophagy can be extended beyond a housekeeping process to having an additional role in regulating energy metabolism and insulin action. Abbreviations: AMPK, AMP-activated protein kinase; ASM, acid soluble metabolites; cAMP, cyclic adenosine monophosphate; EPS, electrical pulse stimulation; FCCP, carbonyl cyanide-p-trifluoromethoxyphenylhydrazone; GAA, glucosidase, alpha, acid; mTOR, mechanistic target of rapamycin kinase; NAD, nicotinamide adenine dinucleotide; PARP, poly (ADP-ribose) polymerase family; PI3K, phosphoinositide 3-kinase; PPAR, peroxisome proliferator activated receptor ; PYGM, muscle glycogen phosphorylase; STBD1, starch binding domain 1; TFEB, transcription factor EB.
From Victims to Perpetrators of Bullying: The Role of Irrational Cognitions, Externalizing Problems, and Parental Attachment

The transition from bullying victimization to bullying perpetration is well documented in the literature. However, the mechanisms linking bullying victimization to perpetration are not fully understood. The main aim of the current study was to conduct a preliminary research investigating the indirect effects of youths bullying victimization on bullying perpetration through irrational cognitions and externalizing problems. The second aim of the study was to explore the moderating role of the type of parental attachment (secure vs. insecure) in the proposed model in explaining the association of bullying victimization and bullying perpetration. Data were collected from 269 adolescents (11-15 years; M = 11.98, SD = .68), enrolled in middle public schools from Romania. Path analysis and moderated path analysis were conducted to explore the direct and indirect effects and moderating effects, respectively. Study findings indicate that bullying victimization was indirectly related to bullying perpetration separately through youths’ irrational cognition as well as through externalizing problems. The serial indirect pathway from victimization to perpetration through irrational cognitions leading further to externalizing problems was also significant. However, the type of attachment that adolescents reported having toward their parents failed to moderate the indirect pathways, since all the interaction terms were nonsignificant. These findings advance the field prevention and intervention by identifying irrational cognitions and externalizing problems as important targets that anti-bullying programs should address to stop the transition from victims of bullying to perpetrators.
Self-Assessment of Therapeutic Decision-Making Skills in Pharmacy Students

Objective. The ability of pharmacy students to self-regulate and reflect on knowledge and skills is important as proficient self-assessment skills guide learning strategies and prompt students to bridge their knowledge gaps. The objectives for this study were to determine how well third-year pharmacy students self-assess, explore the rationales behind their self-assessments and determine whether there is a correlation between self-assessment accuracy and academic performance. Methods. A quasi-experimental one-group pre-/post-test design was conducted with third-year pharmacy students. Examiner grades, student self-assessment grades, comparative reports, and end-of-semester grades were collected. Students were categorized into tertiles based on academic performance for data analysis. Paired t tests, Pearson r and percentage agreements were conducted to investigate self-assessment accuracy. Correlational statistical tests were implemented to examine the relationships between self-assessment accuracy and academic performance. Results. One hundred sixty-two third-year pharmacy students were included. On average, students demonstrated poor self-evaluation skills and underestimated themselves by 4.9%. Lower performing students were generally overconfident in evaluating their performance. There was no significant correlation between students’ self-assessment accuracy and academic performance on the subsequent end-of-semester examination questions. Conclusion. Overall, students tended to underestimate their academic performance. Further research on self-assessment is needed to better understand how students think about their performance, which may help to improve education methods, such as inclusion of reflective practices after case-based activities.
Family Members’ Understanding of the End-of-Life Wishes of People Undergoing Maintenance Dialysis

Visual Abstract Background and objectives People receiving maintenance dialysis must often rely on family members and other close persons to make critical treatment decisions toward the end of life. Contemporary data on family members’ understanding of the end-of-life wishes of members of this population are lacking. Design, setting, participants, & measurements Among 172 family members of people undergoing maintenance dialysis, we ascertained their level of involvement in the patient’s care and prior discussions about care preferences. We also compared patient and family member responses to questions about end-of-life care using percentage agreement and the κ-statistic. Results The mean (SD) age of the 172 enrolled family members was 55 (±17) years, 136 (79%) were women, and 43 (25%) were Black individuals. Sixty-seven (39%) family members were spouses or partners of enrolled patients. A total of 137 (80%) family members had spoken with the patient about whom they would want to make medical decisions, 108 (63%) had spoken with the patient about their treatment preferences, 47 (27%) had spoken with the patient about stopping dialysis, and 56 (33%) had spoken with the patient about hospice. Agreement between patient and family member responses was highest for the question about whether the patient would want cardiopulmonary resuscitation (percentage agreement 83%, κ=0.31), and was substantially lower for questions about a range of other aspects of end-of-life care, including preference for mechanical ventilation (62%, 0.21), values around life prolongation versus comfort (45%, 0.13), preferred place of death (58%, 0.07), preferred decisional role (54%, 0.15), and prognostic expectations (38%, 0.15). Conclusions Most surveyed family members reported they had spoken with the patient about their end-of-life preferences but not about stopping dialysis or hospice. Although family members had a fair understanding of patients’ cardiopulmonary resuscitation preferences, most lacked a detailed understanding of their perspectives on other aspects of end-of-life care.
Anomalous high temperature crystal structure behaviour of PrCo 0.5 Cr 0.5 O 3

Mixed praseodymium cobaltite-chromite PrCo 0.5 Cr 0.5 O 3 with dimensionally (pseudo)-cubic orthorhombic perovskite structure was obtained by solid state reaction in air at 1573 K. Crystal structure parameters were derived from high-resolution X-ray synchrotron powder diffraction data collected in situ in a broad temperature range of 298–1173 K. Analysis of the results obtained revealed anomalous thermal expansion of PrCo 0.5 Cr 0.5 O 3 , which is reflected in a sigmoidal temperature dependence of the unit cell dimensions and in abnormal increase of the thermal expansion coefficients with a broad maxima near 870 K. The observed anomalies are associated with the changes of spin state of Co3+ ions and temperature induced insulator-metal transition occurred in PrCo 0.5 Cr 0.5 O 3 .
Zincated Nanoclay Polymer Composites (ZNCPCs): Synthesis, Characterization, Biodegradation and Controlled Release Behaviour in Soil

ABSTRACT Novel zincated nanoclay polymer composites (ZNCPCs) with variable percentage of commercial bentonite and nanobentonite (8%, 10% and 12% of monomer for each case) were synthesized. Polyacrylic acid-Polyacrylamide copolymer was synthesized using N, N-Methylene bisacrylamide as crosslinker and ammonium persulfate as initiator. Clays as well as ZNCPCs were characterized by XRD, SEM, TEM and FTIR. 12% nanoclay containing formulation showed slowest release rate. ZNCPCs containing 8% clay recorded highest Zn content as well as highest equilibrium water absorbency. Biodegradation study revealed that Aspergillus spp was more effective as compared with Trichoderma spp in degradation of ZNCPCs. GRAPHICAL ABSTRACT
Helicobacter pylori cholesterol-α-glucosyltransferase manipulates cholesterol for bacterial adherence to gastric epithelial cells

ABSTRACT Helicobacter pylori infection is associated with several gastrointestinal diseases, including gastritis, peptic ulcers, and gastric cancer. Infection of cells with H. pylori is dependent on lipid rafts, which are cholesterol-rich microdomains located in the cell membrane. H. pylori cholesterol-α-glucosyltransferase (CGT) catalyzes the conversion of membrane cholesterol to cholesteryl glucosides, which can be incorporated into the bacterial cell wall, facilitating evasion from immune defense and colonization in the host. However, the detailed mechanisms underlying this process remain to be explored. In this study, we discovered for the first time that H. pylori CGT could promote adherence to gastric epithelial cells in a cholesterol-dependent manner. Externalization of cell membrane phosphatidylserine (PS) is crucial for enhancement of binding of H. pylori to cells by CGT and for cytotoxin-associated gene A (CagA)-induced pathogenesis. Furthermore, exogenous cholesterol interferes with the actions of H. pylori CGT to catalyze cellular cholesterol, which impedes bacterial binding to cells and attenuates subsequent inflammation, indicating that the initial attachment of H. pylori to cells is closely dependent on host cholesterol. These results provide evidence that CGT contributes to H. pylori infectivity and it may serve as a key target for the treatment of H. pylori-associated diseases.
Visually guided movement with increasing time-on-task: Differential effects on movement preparation and movement execution

Top-down cognitive control seems to be sensitive to the detrimental effects of fatigue induced by time-on-task (ToT). The planning and preparation of the motor responses may be especially vulnerable to ToT. Yet, effects of ToT specific to the different phases of movements have received little attention. Therefore, in three experiments, we assessed the effect of ToT on a mouse-pointing task. In Experiment 1, there were 16 possible target positions with variable movement directions. In Experiment 2, the layout of the targets was simplified. In Experiment 3, using cuing conditions, we examined whether the effects of ToT on movement preparation and execution were caused by an increased orientation deficit or decreased phasic alertness. In each experiment, initiation of movement (preparatory phase) became slower, movement execution became faster and overall response time remained constant with increasing ToT. There was, however, no significant within-person association between the preparatory and execution phases. In Experiments 1 and 2, we found a decreasing movement time/movement error ratio, suggesting a more impulsive execution of the pointing movement. In addition, ToT was also accompanied with imprecise movement execution as indicated by the increased errors, mainly in Experiment 2. The results of Experiment 3 indicated that ToT did not induce orientation and phasic alerting deficits but rather was accompanied by decreased tonic alertness.
Efficacy and safety of Sodium-Glucose-Transporter-2 inhibitors in kidney transplant patients

Purpose of review This review discusses current evidence and future perspectives for use of SLT2 inhibitors in kidney transplant recipients (KTRs). Recent findings Sodium-Glucose-Transporter-2 inhibitors (SGLT2is) lower plasma glucose in patients with type 2 diabetes, and protect against heart failure and progression of chronic kidney disease by a glucose-independent mechanism. Most of the current studies with SGLT2is in kidney transplant patients are however short-term retrospective case studies. These, together with one small randomized clinical trial, show that SGLT2is lower glucose also in KTRs with type 2 diabetes or posttransplant diabetes mellitus. Larger reductions in HbA1c (−0.5 to 1.5% points) are seen only in patients with estimated GFR > 60 ml/min/1.73m2 and HbA1c > 8%. With lower gomerular filtration rate (GFR) or glycated hemoglobin (HbA1c) the glucose-lowering effect is trivial. However, a reduction in body weight, blood pressure and uric acid is also seen, whereas the frequency of side effects (mycotic or urinary tract infections) does not seem to exceed what is seen in nontransplanted patients. Long-term effects on GFR have not been studied in kidney transplanted patients, but SGLT2is induce an early dip in GFR also in these patients. This could signal a beneficial long-term effect on renal hemodynamics. Summary SGLT2is lower glucose safely also in patients with single kidney grafts, but long-term kidney function and patient survival are yet to be explored.
Participation in a Chronic Limb Threatening Ischemia Randomized Trial Is Inversely Correlated With Regional Amputation Rate in Limb Threatening Ischemia Patients

Supplemental Digital Content is available in the text Objective: The National Health Service demonstrated that regions of the United Kingdom with the highest number of patients enrolled in research studies had the lowest risk-adjusted mortality when patients were admitted to the hospital. Our goal was to investigate if this correlation was evident for patients with chronic limb threatening ischemia (CLI) treated in the United States (US). Accordingly, we examined correlations among sites participating in the Best Endovascular versus best Surgical Therapy in patients with Critical (BEST-CLI) trial, a multicenter, National Institute of Health-sponsored, international randomized controlled trial (RCT) comparing revascularization strategies in patients with CLI, and regional rates of major amputation from CLI. Methods: We measured regional participation in the BEST-CLI trial by evaluating trial participation and enrollment rosters. To determine regional rates of lower limb amputation, we queried the Medicare database (2007–2016) for patients with concurrent peripheral arterial disease (PAD) and diabetes, then assessed how many had lower extremity amputations. Correlation of regional amputation rates with distribution of BEST-CLI sites in four US geographical regions was calculated using Pearson's correlation coefficients. Simple regression equations were used to calculate the significance of these correlation coefficients. Results: Of 9,231,909 CLI patients, 342,406 underwent amputation in the Medicare dataset. Amputation rates per 1000 CLI patients differed by region (South 40.42, Midwest 40.12, West 34.81, Northeast 31.14). There were 116 US vascular centers, selected by volume and expertise that participated in BEST-CLI with the following distribution: South (n = 30, 26%), Midwest (n = 26, 22%), West (n = 29, 25%), and Northeast (n = 31, 27%). There was a negative correlation between the number of amputations per 1000 for Medicare CLI patients with diabetes and PAD and the number of BEST-CLI sites in the region which trended toward significance (Pearson R= −0.61, P = 0.39). Conclusions: Amputation rate among Medicare CLI patients is inversely correlated with US BEST-CLI site distribution. Higher participation in clinical research, especially within large RCTs, may be a marker of optimal PAD management.
Interpersonal violence victimisation, HIV-related behaviours and STIs among adult, urban Indigenous and non-Indigenous gay, bisexual and other men who have sex with men in Guatemala

Abstract Gay, bisexual and other men who have sex with men are disproportionately affected by HIV in Guatemala; interpersonal violence may increase behaviours that augment the risk of HIV in this group. Although 44% of Guatemalans identify as Indigenous, little information exists on the experiences of Indigenous sexual minority individuals. In this study, we sought to compare different forms of violence and HIV-related behaviours by Indigenous identity among gay, bisexual and other men who have sex with men; and determine if associations between violence and HIV-related behaviours differed by Indigenous identity. We used cross-sectional survey data from 716 Spanish-speaking, adult men recruited from urban centres to examine the prevalence of and relationship between different forms of interpersonal violence and HIV-related behaviours using logistic regression analyses, including the moderating effect of Indigenous identity. In general, fewer Indigenous participants reported interpersonal violence victimisation and HIV-related behaviours compared to their non-Indigenous counterparts. In weighted multivariable analyses, non-Indigenous participants who reported physical and/or sexual violence were over five times as likely to report transactional sex (OR = 5.17, 95% CI 2.11–12.68, p < 0.001), but the relationship was not significant for Indigenous participants. Findings suggest that Indigenous sexual minority men have unique contexts and that additional strengths-based research is needed to ensure that actions and efforts to promote violence and HIV prevention meet their needs.