Miracle-dz/UniFAR-FTUs huggingface dataset:
Dose Titration of Ixazomib Maintenance Therapy in Transplant‐Ineligible Multiple Myeloma: Exposure–Response Analysis of the TOURMALINE‐MM4 Study

Ixazomib has been approved in several countries as single‐agent maintenance therapy in newly diagnosed multiple myeloma, in both posttransplant and transplant‐ineligible settings, based on two phase III studies. In these maintenance studies, patients were initially administered 3 mg ixazomib, escalating to 4 mg if the initial dose level was well tolerated through Cycles 1–4. Here, we report the results of exposure–response analyses of TOURMALINE‐MM4, wherein relationships between exposure and clinical response, dose adjustments, and selected adverse events were evaluated. Similar progression‐free survival benefits were observed across the range of ixazomib exposures achieved in the study. Moreover, increased ixazomib exposures corresponded to a higher probability of maintaining complete response. Exposure was not a significant predictor (P > 0.05) of hematological adverse events (anemia, neutropenia, thrombocytopenia) and peripheral neuropathy; however, higher exposures did correlate to increased probabilities of experiencing diarrhea, vomiting, nausea, rash, and fatigue. While ixazomib exposure was not predictive of dose reductions, lower apparent clearance values (corresponding to higher systemic exposures) were correlated with a reduced likelihood of escalating to the 4 mg dose. Thus, the dose titration approach balanced patient benefit and risk; it ensured that only patients for whom the 3 mg dose was safe/tolerable escalated to the higher dose, while maximizing the fraction of patients (85%) who were able to derive additional clinical benefit at 4 mg. Collectively, these results highlight the value of safety‐driven personalized dosing to maximize patient benefit/risk.
Pluronic-F-127-Passivated SnO2 Nanoparticles Derived by Using Polygonum cuspidatum Root Extract: Synthesis, Characterization, and Anticancer Properties

Nanotechnology has emerged as the most popular research topic with revolutionary applications across all scientific disciplines. Tin oxide (SnO2) has been gaining considerable attention lately owing to its intriguing features, which can be enhanced by its synthesis in the nanoscale range. The establishment of a cost-efficient and ecologically friendly procedure for its production is the result of growing concerns about human well-being. The novelty and significance of this study lie in the fact that the synthesized SnO2 nanoparticles have been tailored to have specific properties, such as size and morphology. These properties are crucial for their applications. Moreover, this study provides insights into the synthesis process of SnO2 nanoparticles, which can be useful for developing efficient and cost-effective methods for large-scale production. In the current study, green Pluronic-coated SnO2 nanoparticles (NPs) utilizing the root extracts of Polygonum cuspidatum have been formulated and characterized by several methods such as UV–visible, Fourier transform infrared spectroscopy (FTIR), energy dispersive X-ray (EDAX), transmission electron microscope (TEM), field emission-scanning electron microscope (FE-SEM), X-ray diffraction (XRD), photoluminescence (PL), and dynamic light scattering (DLS) studies. The crystallite size of SnO2 NPs was estimated to be 45 nm, and a tetragonal rutile-type crystalline structure was observed. FESEM analysis validated the NPs’ spherical structure. The cytotoxic potential of the NPs against HepG2 cells was assessed using the in vitro MTT assay. The apoptotic efficiency of the NPs was evaluated using a dual-staining approach. The NPs revealed substantial cytotoxic effects against HepG2 cells but failed to exhibit cytotoxicity in different liver cell lines. Furthermore, dual staining and flow cytometry studies revealed higher apoptosis in NP-treated HepG2 cells. Nanoparticle treatment also inhibited the cell cycle at G0/G1 stage. It increased oxidative stress and promoted apoptosis by encouraging pro-apoptotic protein expression in HepG2 cells. NP treatment effectively blocked the PI3K/Akt/mTOR axis in HepG2 cells. Thus, green Pluronic-F-127-coated SnO2 NPs exhibits enormous efficiency to be utilized as an talented anticancer agent.
Reporting of harms in clinical trials of esketamine in depression: a systematic review

Abstract While previous systematic reviews of trials evaluating conventional antidepressants highlighted inadequacies and inconsistencies in adverse event (AE) reporting, no evaluation is available on esketamine in resistant depression. The objective of this review was to assess quality of reporting AEs in all published clinical trials studying esketamine. It also aimed to compare the proportions of AEs reported in journal articles to those recorded in the ClinicalTrial.gov Registers. Clinical trials evaluating the efficacy and safety of esketamine in depression were searched using Medline and ClinicalTrials.gov. The quality of reporting harms was assessed using a 21-item checklist from the CONSORT Extension of Harms (1 point by item). The total quality score was graded into four categories: high (17–21), moderate (12–16), low (7–11) and very low (0–6). Ten clinical trials were included in the analysis. Nine trials were classified as ‘low quality’ with regard to safety, one trial was classified as ‘moderate quality’. Compared to AEs recorded in ClinicalTrials.gov, we found that 41.5% of serious AEs and 39% of non-serious AEs were not reported in the published articles. Among them, the majority were psychiatric events but also cardiovascular events and 94% concerned patients from esketamine groups. Quality of AEs reporting in published clinical trials of esketamine was poor and harms were reported less frequently in journal publications than in ClinicalTrial.gov Registers. The study suggests that an assessment of the benefits/risks balance of esketamine based on the results reported in trial publications is flawed due to the poor accuracy and completeness of harm data.
Heterogeneous translational landscape of the endoplasmic reticulum revealed by ribosome proximity labeling and transcriptome analysis

The endoplasmic reticulum (ER) is a nexus for mRNA localization and translation, and recent studies have demonstrated that ER-bound ribosomes also play a transcriptome-wide role in regulating proteome composition. The Sec61 translocon (SEC61) serves as the receptor for ribosomes that translate secretory/integral membrane protein-encoding mRNAs, but whether SEC61 also serves as a translation site for cytosolic protein-encoding mRNAs remains unknown. Here, using a BioID proximity-labeling approach in HEK293T Flp-In cell lines, we examined interactions between ER-resident proteins and ribosomes in vivo. Using in vitro analyses, we further focused on bona fide ribosome interactors (i.e. SEC61) and ER proteins (ribophorin I, leucine-rich repeat–containing 59 (LRRC59), and SEC62) previously implicated in associating with ribosomes. We observed labeling of ER-bound ribosomes with the SEC61β and LRRC59 BioID reporters, comparatively modest labeling with the ribophorin I reporter, and no labeling with the SEC62 reporter. A biotin pulse-chase/subcellular fractionation approach to examine ribosome exchange at the SEC61β and LRRC59 sites revealed that, at steady state, ribosomes at these sites comprise both rapid- and slow-exchanging pools. Global translational initiation arrest elicited by the inhibitor harringtonine accelerated SEC61β reporter-labeled ribosome exchange. RNA-Seq analyses of the mRNAs associated with SEC61β- and LRRC59-labeled ribosomes revealed both site-enriched and shared mRNAs and further established that the ER has a transcriptome-wide role in regulating proteome composition. These results provide evidence that ribosomes interact with the ER membrane via multiple modes and suggest regulatory mechanisms that control global proteome composition via ER membrane-bound ribosomes.
Modelling The Growth Of AlgaeIn The Lagoon Of VeniceWith The Artificial Intelligence Tool GoldHorn

Classical construction of ecological models follows one of the following two approaches: (1) either the measured data are analyzed with a statistical approach and a black-box statistical model is constructed, or (2) the model is deduced from basic (physical, chemical, etc.) principles and the measured data are used to calibrate and validate the model. A combination of the both ways is used very rarely, although it could combine the benefits of both. Machine learning tools (ML), developed within the area of artificial intelligence (AI), are able to analyze a data base (perform data mining), using also some domain (expert) knowledge. As a result, ML tools can automatically, or with limited expert help, induce compact and easy to understand models from measured data. In this paper a description of the ML tool GoldHorn that induces differential or difference (algebraic) equations from measured time series data is given. Its successful application to the prediction of algae growth in the Lagoon of Venice, Italy, is also described in detail. The model was induced using some background knowledge, as the tackled domain was too complex for data mining alone. Our experiments show that for noisy and complex domains inducing difference equations models could be more effective than inducing differential equations models. The induced (discovered) difference equation model for predicting algae growth in the Lagoon contains only one difference equation in contrast to classical models which contain several differential equations. Nevertheless, the simulation and predictive accuracy of the discovered model is comparable to the best deductionistic models of the Lagoon.
On the Morse–Sard property and level sets of Wn,1 Sobolev functions on ℝn

We establish Luzin N and Morse–Sard properties for functions from the Sobolev space W n;1 . R n / . Using these results we prove that almost all level sets are ﬁnite disjoint unions of C 1 -smooth compact manifolds of dimension n (cid:0) 1 . These results remain valid also within the larger space of functions of bounded variation BV n . R n / . For the proofs we establish and use some new results on Luzin-type approximation of Sobolev and BV-functions by C k -functions, where the exceptional sets have small Hausdorff content.
Future Changes in Winter Precipitation around Japan Projected by Ensemble Experiments Using NHRCM

We investigate future changes in winter precipitation around Japan and their uncertainties using the downscalings of a non-hydrostatic regional climate model (NHRCM) with 20-km grid spacing according to global climate projections. The global climate projections were conducted by the atmospheric general circulation model with three patterns of sea surface temperature changes in the Coupled Model Intercomparison Project Phase 5 under the Representative Concentration Pathway 8.5. Moreover, three cumulus convective parameterizations were applied in the present and future climate experiments. The ensemble mean of nine future NHRCM experiments shows decreases in the winter precipitation on the coast of the Sea of Japan and over the Pacific Ocean in the south of the Japanese archipelago. The former decrease in precipitation results from a weakened winter monsoon. The latter corresponds to changes in extratropical cyclone number around Japan, which have a large uncertainty. On the other hand, winter precipitation increases over the northernmost part of Japan (Hokkaido) and the northeastern Asian continent. The strengthened northwesterly around Hokkaido, which results from the reduction of sea ice in the Sea of Okhotsk, causes increased precipitation in the inland area of Hokkaido. In addition, moistening due to global warming relates to increased precipitation in extremely cold regions. These signals are common to most experiments.
Extension and torsion of incompressible non-linearly elastic solid circular cylinders

The problem of torsion superimposed on axial extension of a solid circular cylinder composed of an incompressible isotropic hyperelastic material has been extensively investigated in the literature on non-linear elasticity following the pioneering theoretical investigations of Rivlin. The classical results of Rivlin were given in terms of a general strain—energy density that depends on the principal invariants of the Cauchy—Green deformation tensor. Here we reformulate these results in terms of a general strain—energy density that depends on alternative invariants, namely the invariants of the stretch tensor. Such an approach was carried out in a paper in this journal by Rivlin for the special case of pure torsion. As was remarked there, this is a relatively straightforward procedure and is a viable alternative to development of the theory from first principles in terms of the invariants of the stretch tensor. As an illustrative example, we consider the well-known Varga model for incompressible materials. For this material model, it is shown that the stretched circular cylinder always tends to further elongate on twisting. The special case of pure torsion is also briefly considered. The resultant axial force necessary to maintain pure torsion is compressive for the Varga model. In the absence of such a force, the bar tends to elongate on twisting, reflecting the celebrated Poynting effect.
The Influence of Perceptions of Competence on Motor Skills and Physical Activity in Middle Childhood: A Test of Mediation

The mediating effect of perceptions of physical competence (PPC) on the relationship between motor competence and physical activity levels is documented in adolescence. However, it is unclear at what age this begins. In this study, we examined whether PPC mediated the relationship between moderate–vigorous physical activity (MVPA) or sedentary behaviour and motor competence in middle childhood. The participants were 129 children (mean age = 8.3 years) from eight elementary schools. MVPA and sedentary behaviour were measured using Actigraph accelerometers, and motor competence was assessed using the Test of Gross Motor Development, Second Edition. The Pictorial Scale of Perceived Competence and Social Acceptance for Young Children and The Self-Perception Profile for Children were used to assess PPC. In this study, PPC did not predict either MVPA or engagement in sedentary behaviours. Further, structural equation modelling revealed that PPC did not mediate the relationship between motor competence and MVPA or between motor competence and sedentary behaviour. These results suggest that at 8 years of age, children’s perceptions do not influence their participation in physical activities. It is possible that factors influencing PPC, such as peer comparisons and performance outcomes, have more impact in later childhood or adolescence. In turn, those perceptions may affect children’s or adolescents’ choices to opt in or out of physical activities.
Upper-Limb Kinematic Behavior and Performance Fatigability of Elderly Participants Performing an Isometric Task: A Quasi-Experimental Study

Simple Summary The purpose of this research was to understand how upper-limb kinetics behaves alongside activity time during a position-sustained isometric task and how upper-limb kinetics relates to performance fatigability. As hypothesized, there were changes in acceleration behavior indicative of the displacement of the upper limb in the direction of shoulder extension, especially in the second half of the task, and also an increasing variation of acceleration, and, thus, in movement variability, alongside activity time. However, these changes showed different behaviors between men and women, suggesting greater performance fatigability in women. Results also showed that performance fatigability was positively related to average acceleration in an early phase of activity only in men, meaning that early movement adjustments were apparently sufficient to increase activity time and, consequently, performance. According to the results of our study, upper-limb acceleration measured through a single IMU can be a useful and easy strategy to identify fatigue early. Abstract Upper-limb position-sustained tasks (ULPSIT) are involved in several activities of daily living and are associated with high metabolic and ventilatory demand and fatigue. In older people, this can be critical to the performance of daily living activities, even in the absence of a disability. Objectives: To understand the ULPSIT effects on upper-limb (UL) kinetics and performance fatigability in the elderly. Methods: Thirty-one (31) elderly participants (72.61 ± 5.23 years) performed an ULPSIT. The UL average acceleration (AA) and performance fatigability were measured using an inertial measurement unit (IMU) and time-to-task failure (TTF). Results: The findings showed significant changes in AA in the X- and Z-axes (p < 0.05). AA differences in women started earlier in the baseline cutoff in the X-axis, and in men, started earlier between cutoffs in the Z-axis. TTF was positively related to AA in men until 60% TTF. Conclusions: ULPSIT produced changes in AA behavior, indicative of movement of the UL in the sagittal plane. AA behavior is sex related and suggests higher performance fatigability in women. Performance fatigability was positively related to AA only in men, where movement adjustments occurred in an early phase, though with increased activity time.
White Coat Effect: Is It Because of the Hospital Setting, or Is It Physician-Induced?

Introduction: White coat hypertension (WCH) patients are those individuals who have high blood pressure (BP) in the medical environment but are normal during their daily activities. White coat hypertensive patients with normal daytime ambulatory blood pressure monitoring (ABPM) rapidly progress to sustained hypertension. WCH is mainly treated with non-pharmacological methods. Alpha-1 agonists and beta blockers are logical treatment choices for patients with fixed hypertension with the White Coat Effect (WCE). Masked hypertension patients are those individuals who have normal values at the doctor’s office but elevated BP at home or during 24-hour ABPM (24-hour or daytime). ABPM is a more practical and reliable method for detecting patients with WCH. Material and methods: This observational study was conducted at Dayanand Medical College & Hospital, Ludhiana, over the course of one year (December 2015 to November 2016). The primary objective of the study was to determine whether there was a difference in blood pressure readings between the home setting and the hospital setting. The secondary objective was to determine whether the difference, if present, between the hospital and home readings was due to the hospital setting, physician presence, or a combination of both. Patients with stage 1 hypertension were included in the study, irrespective of antihypertensive treatment. Patients with ischemic heart disease, chronic liver failure, and chronic kidney disease who could not follow protocol instructions were excluded. Results: In our study, the mean age of patients was 53.91±12.86 years. The patient’s mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) readings at the hospital were higher than their home readings (p-0.012; p-0.001, respectively). Mean hospital SBP and DBP readings recorded by the physician were higher than readings recorded by patients alone at home (p-0.002; p-0.014, respectively) and alone at the hospital (p-0.004; p-0.001, respectively). BP readings taken by the physician with a manual sphygmomanometer were significantly lower than those taken with a digital sphygmomanometer by patients and physicians in all settings (p<0.05). The mean rise in BP was significant in both the physician's presence and the hospital environment (p<0.05 for both), and this rise was more significantly associated with the hospital effect than the physician effect (p<0.05). Conclusion: Misdiagnosis of hypertension results in inappropriate prescription and overuse of antihypertensive medications for individuals who are not persistently hypertensive. So it is very important to rule out WCH in both the hospital setting and the physician's presence, more precisely by ABPM. WCH can be diagnosed with regular BP monitoring by a digital sphygmomanometer at home.
Low‐dose aspirin reduces hypoxia‐induced sFlt1 release via the JNK/AP‐1 pathway in human trophoblast and endothelial cells

Pre‐eclampsia (PE) is a serious hypertensive disorder of pregnancy that remains a leading cause of perinatal and maternal morbidity and mortality worldwide. Placental ischemia/hypoxia and the secretion of soluble fms‐like tyrosine kinase 1 (sFlt1) into maternal circulation are involved in the pathogenesis of PE. Although low‐dose aspirin (LDA) has beneficial effects on the prevention of PE, the exact mechanisms of action of LDA, particularly on placental dysfunction, and sFlt1 release, have not been well investigated. This study aimed to determine whether LDA exists the protective effects on placental trophoblast and endothelial functions and prevents PE‐associated sFlt1 release. First, we observed that LDA mitigated hypoxia‐induced trophoblast apoptosis, showed positive effects on trophoblast cells migration and invasion activity, and increased the tube‐forming activity of human umbilical vein endothelial cells (HUVECs). In addition, LDA decreased hypoxia‐induced sFlt1 production, and the c‐Jun NH2‐terminal kinase/activator protein‐1 (JNK/AP‐1) pathway was shown to mediate the induction of sFlt1. Moreover, the transcription factor AP‐1 was confirmed to regulate the Flt1 gene expression by directly binding to the Flt1 promoter in luciferase assays. The result of chromatin immunoprecipitation assays further demonstrated that LDA could directly decrease the expression of the transcription factor AP‐1, and thus decrease sFlt1 production. Finally, the effects of LDA on sFlt1 production were proved in human placental explants. Taken together, our data show the protective effects of LDA against trophoblast and endothelial cell dysfunction and reveal that the LDA‐mediated inhibition of sFlt1 via the JNK/AP‐1 pathway may be a potential cellular/molecular mechanism for the prevention of PE.