Miracle-dz/UniFAR-FTUs huggingface dataset:
Rindopepimut with Bevacizumab for Patients with Relapsed EGFRvIII-Expressing Glioblastoma (ReACT): Results of a Double-Blind Randomized Phase II Trial

Purpose: Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma. Patients and Methods: In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2. Results: Between May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control (P = 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage [HR, 0.53; 95% confidence interval (CI), 0.32–0.88; two-sided log-rank P = 0.01], a higher ORR [30% (9/30) vs. 18% (6/34; P = 0.38)], median duration of response [7.8 months (95% CI, 3.5–22.2) vs. 5.6 (95% CI, 3.7–7.4)], and ability to discontinue steroids for ≥6 months [33% (6/18) vs. 0% (0/19)]. Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (≥1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07–0.45; P < 0.0001). Conclusions: Our randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM. See related commentary by Wick and Wagener, p. 1535
Beyond physical entrainment: competitive and cooperative mental stances during identical joint-action tasks differently affect inter-subjective neural synchrony and judgments of agency

ABSTRACT Little work has examined how mental stance alone, apart from physical entrainment, affects between-participant neural synchrony during joint social interaction. We report the first findings on how cooperative and competitive mental stances, even during identical visuomotor joint-action tasks, result in distinct neural oscillatory signatures in low beta and theta band between-participant phase synchrony. Two participants jointly controlled a cursor and were instructed to either compete or cooperate to move it to one of three targets. The visuomotor output was identical for both the compete and cooperate conditions because participants were privately given the same target for experimental trials. Cooperation enhanced theta band between-participant phase-locking value (PLV) midtrial at 1-2 seconds, reflecting activation of systems for social coordination to move the cursor in a shared direction. Competition enhanced low beta between-participant PLV, shifting from temporal to frontal regions, indicating that participants focused only on their target and later evaluated self-agency as winner or loser. This interpretation of the neural signature was corroborated by participants’ greater post-trial ratings of the degree of control over the cursor during competition. Top-down cooperative and competitive mental stances shape perceptions of social context and affect interpersonal neural synchrony important for representation of self and others’ actions.
Targeting Insulin-Like Growth Factor 1 Receptor Delays M-Phase Progression and Synergizes with Aurora B Inhibition to Suppress Cell Proliferation

The insulin-like growth factor 1 receptor (IGF1R) is a receptor-type tyrosine kinase that transduces signals related to cell proliferation, differentiation, and survival. IGF1R expression is often misregulated in tumor cells, but the relevance of this for cancer progression remains unclear. Here, we examined the impact of IGF1R inhibition on cell division. We found that siRNA-mediated knockdown of IGF1R from HeLa S3 cells leads to M-phase delays. Although IGF1R depletion causes partial exclusion of FoxM1 from the nucleus, quantitative real-time PCR revealed that the transcription of M-phase regulators is not affected by decreased levels of IGF1R. Moreover, a similar delay in M phase was observed following 2 h of incubation with the IGF1R inhibitors OSI-906 and NVP-ADW742. These results suggest that the M-phase delay observed in IGF1R-compromised cells is not caused by altered expression of mitotic regulators. Live-cell imaging revealed that both prolonged prometaphase and prolonged metaphase underlie the delay and this can be abrogated by the inhibition of Mps1 with AZ3146, suggesting activation of the Spindle Assembly Checkpoint when IGF1R is inhibited. Furthermore, incubation with the Aurora B inhibitor ZM447439 potentiated the IGF1R inhibitor-induced suppression of cell proliferation, opening up new possibilities for more effective cancer chemotherapy.
Safety of synthetic and biological DMARDs: a systematic literature review informing the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis

Objectives To perform a systematic literature review (SLR) concerning the safety of synthetic (s) and biological (b) disease-modifying anti rheumatic dugs (DMARDs) to inform the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis (RA). Methods An SLR of observational studies comparing safety outcomes of any DMARD with another intervention for the management of RA. A comparator group was required for inclusion. For treatments still without registry data (eg, sarilumab and the Janus kinase (JAK) inhibitors baricitinib, upadacitinib), randomised controlled trials (RCTs) and long-term extensions (LTEs) were used. Risk of bias (RoB) was assessed according to standard procedures. Results Forty-two observational studies fulfilled the inclusion criteria, addressing safety outcomes with bDMARDs and sDMARDs. Nine studies showed no difference in the risk of serious infections across bDMARDs and two studies (high RoB) showed an increased risk with bDMARDs compared with conventional synthetic (cs) DMARDs (adjusted incidence rate ratio 3.1–3.9). The risk of Herpes zoster infection was similar across bDMARDs, but one study showed an increased risk with tofacitinib compared with abatacept (adjusted HR (aHR) 2.0). Five studies showed no increased risk of cancer for bDMARDs compared with csDMARDs. An increased risk of lower intestinal perforation was found for tocilizumab compared with csDMARDs (aHR 4.5) and tumour necrosis factor inhibitor (TNFi) (aHR 2.6–4.0). Sixty manuscripts reported safety data from RCTs/LTEs. Overall, no unexpected safety outcomes were found, except for the possibly increased risk of venous thromboembolism (VTE) with JAK inhibitors. Conclusion Data obtained by this SLR confirm the known safety profile of bDMARDs. The risk of VTE in RA, especially in patients on JAK inhibitors, needs further evaluation.
A Simplified Method for Simultaneous Determination of α-Lipoic Acid and Low-Molecular-Mass Thiols in Human Plasma

α-Lipoic acid, glutathione, cysteine, and cysteinylglycine can be applied as therapeutic agents in civilization diseases such as diabetes mellitus, cardiovascular diseases, and cancers. On the other hand, a higher concentration of homocysteine can result in health problems and has been indicated as an independent risk factor for cardiovascular disease and accelerated atherosclerosis. Here, the first simplified HPLC-UV assay that enables simultaneous determination of α-lipoic acid and low-molecular-mass thiols in plasma, reduces the number of steps, shortens the total time of sample preparation, and limits the amount of single-use polypropylene laboratory materials is described. The assay is based on reversed-phase high performance liquid chromatography with UV detection and simultaneous reduction of disulfide bound with tris(2-carboxyethyl)phosphine and the selective pre-column derivatization of the thiol group with 1-benzyl-2-chloropyridinium bromide. Linearity in the detector responses for plasma samples were observed in ranges: 0.12–5.0 nmol mL−1 for α-lipoic acid; 2.0–20.0 nmol mL−1 for glutathione, cysteinylglycine, and homocysteine; and 40.0–400.0 for cysteine. The LODs for α-lipoic acid and low-molecular-mass thiols were 0.08 and 0.12 nmol mL−1, respectively, while LOQs were 0.12 and 0.16 nmol mL−1, respectively. The usefulness of the proposed method has been proven by its application to real samples.
Effects of a Futsal Game on Metabolic, Hormonal, and Muscle Damage Indicators of Male Futsal Players

Abstract Bekris, E, Gioldasis, A, Gissis, I, Katis, A, Mitrousis, I, and Mylonis, E. Effects of a futsal game on metabolic, hormonal and muscle damage indicators of male futsal players. J Strength Cond Res 36(2): 545–550, 2022—The aim of this study was to examine the effects of a futsal game on several metabolic, hormonal, and muscle damage indicators. Twenty-one male top-level futsal players participated in the study. Players were divided into 2 groups according to playing time: the long playing time (LPT) group and the short playing time (SPT) group. Game intensity parameters such as percentage of the HRmax and blood lactate concentration, as well as metabolic, hormonal, and muscle damage indicators were examined before and after a futsal game. The results showed that during the game, the intensity was up to 93% of HRmax and lactate concentrations ranged from 5.8 to 21.8 mmol·L−1. The LPT group showed an increased lactate dehydrogenase level compared with the SPT group (p < 0.05). Similarly, creatine kinase was significantly increased in the LPT group (p < 0.05) after the game. By contrast, nonsignificant differences were observed between groups for alanine transaminase (ALT-SGPT), aspartate transaminase (AST-SGOT), and gamma-glutamyl transferase enzymes (p > 0.05). The testosterone/cortisol ratio (T/C) reduced for both groups after the game (p < 0.05). The results of this study indicated that a futsal game have a significantly effect on several hormonal, metabolic, and muscle damage indicators for players who participate for a longer playing time in the game. Therefore, the evaluation of these volumes could assist coaches to organize specific, effective, and individualized training programs.
Dynamics of stunting from childhood to youthhood in Ethiopia: Evidence from the Young Lives panel data

Introduction Stunting continues to be a public health challenge with grave health, cognitive and economic consequences. Yet, its dynamics along the life course remain not well investigated in Ethiopia and beyond. Methods Longitudinal data generated by following two (younger and older) cohorts of about 3000 children for nearly 15 years were analyzed to investigate the longitudinal dynamics of stunting in Ethiopia. The cross-sectional prevalence of stunting in each round, longitudinal prevalence, and transition probabilities were determined. Multilevel mixed effects ordinal regression was applied to identify the determinants of stunting accounting for child-level and cluster-level variations. Results The cross-sectional prevalence of severe stunting for the younger cohort fluctuated between 21% and 6%, while for the older cohort it fluctuated between 12% and 3%. Moderate stunting fluctuated between 23% and 16% for the younger cohort and between 22% and 8% for the older cohort. The longitudinal prevalence of severe stunting was 10% in both the younger and older cohorts, whereas that of moderate stunting was 20% for the younger cohort and 18% for the older cohort. Children not stunted at baseline had very high probabilities of remaining not stunted through youthhood (87% for the younger and 90% for the older cohorts). Conversely, children with moderate stunting at baseline had high probabilities either remaining moderately stunted or progressing to severe stunting. Furthermore, children who had severe stunting at baseline had high probabilities of either remaining severely stunted or transitioning to moderate stunting. In both cohorts, older age of the child, female sex, having an educated mother, and being from a household with educated head significantly reduced the risk of stunting. Children from households in the top wealth tertile had a significantly lower risk of stunting in the younger cohort, but not in the older cohort. Similarly, Productive Safety Net Programme reduced the risk of stunting in the younger cohort, but not in the older cohort. Conclusion Children not stunted early in life are highly likely to grow into non-stunted adults while children stunted early in life are highly likely to grow into stunted adults. Several child-level, maternal, household and programmatic factors affect the risk of stunting. Efforts to prevent stunting shall commence early in life.
Dramatically diverse Schizosaccharomyces pombe wtf meiotic drivers all display high gamete-killing efficiency

Meiotic drivers are selfish alleles that can force their transmission into more than 50% of the viable gametes made by heterozygotes. Meiotic drivers are known to cause infertility in a diverse range of eukaryotes and are predicted to affect the evolution of genome structure and meiosis. The wtf gene family of Schizosaccharomyces pombe includes both meiotic drivers and drive suppressors and thus offers a tractable model organism to study drive systems. Currently, only a handful of wtf genes have been functionally characterized and those genes only partially reflect the diversity of the wtf gene family. In this work, we functionally test 22 additional wtf genes for meiotic drive phenotypes. We identify eight new drivers that share between 30–90% amino acid identity with previously characterized drivers. Despite the vast divergence between these genes, they generally drive into >85% of gametes when heterozygous. We also identify three wtf genes that suppress other wtf drivers, including two that also act as autonomous drivers. Additionally, we find that wtf genes do not underlie a weak (64% allele transmission) meiotic driver on chromosome 1. Finally, we find that some Wtf proteins have expression or localization patterns that are distinct from the poison and antidote proteins encoded by drivers and suppressors, suggesting some wtf genes may have non-meiotic drive functions. Overall, this work expands our understanding of the wtf gene family and the burden selfish driver genes impose on S. pombe.
The challenge of RNA branching prediction: a parametric analysis of multiloop initiation under thermodynamic optimization

Prediction of RNA base pairings yields insight into molecular structure, and therefore function. The most common methods predict an optimal structure under the standard thermodynamic model. One component of this model is the equation which governs the cost of branching, where three or more helical “arms” radiate out from a multiloop (also known as a junction). The multiloop initiation equation has three parameters; changing those values can significantly alter the predicted structure. We give a complete analysis of the prediction accuracy, stability, and robustness for all possible parameter combinations for a diverse set of tRNA sequences, and also for 5S rRNA. We find that the accuracy can often be substantially improved on a per sequence basis. However, simultaneous improvement within families, and most especially between families, remains a challenge.
Association between Generalized Anxiety Disorder and Premenstrual Dysphoric Disorder in a Diagnostic Interviewing Study

Background: Premenstrual dysphoric disorder (PMDD) demonstrates predictable, cyclic, affective and somatic symptoms that are aggravated in the late luteal phase and are resolved by menstruation. Generalized anxiety disorder (GAD) is characterized by excessive and persistant worry. The present study aims to evaluate the association between PMDD and GAD. The fluctuations of behavior inhibition, anxiety, depression, and irritability were also evaluated during the menstrual cycle among women with PMDD and healthy women. Methods: There were 100 women diagnosed with PMDD based on a psychiatric interview and on a prospective evaluation in three menstrual cycles. A total of 96 healthy women were recruited as controls. Each individual’s GAD diagnosis, behavior inhibition, behavior activation, depression, anxiety, and irritability were assessed in both luteal and follicular phases. Results: The odds ratio of women with GAD having PMDD was 7.65 (95% CI: 1.69–34.63) in relation to those without it. This association was partially mediated by behavior inhibition and irritability and was completely mediated by depression. Women with PMDD and GAD had higher anxiety during the luteal phase and higher PMDD severity, depression, and irritability than those without GAD in the follicular phase. There is no difference in anxiety, depression, or irritability between the luteal and follicular phases among women with PMDD and GAD. Conclusions: Women with GAD were more likely to have PMDD. Anxiety, depression, and irritability symptoms in women with PMDD and GAD were not relieved in the follicular phase. Thus, GAD should be assessed for women with PMDD. Their anxiety, depression, and irritability should be intervened not only in the luteal phase, but also in the follicular phase. Depression, irritability and behavior inhibition mediated the association between PMDD and GAD. Intervening with these mediators to attenuate GAD and PMDD comorbidity should be researched in the future.
How long is the tail end of the learning curve? Results from 1000 consecutive endoscopic endonasal skull base cases following the initial 200 cases.

OBJECTIVE Endoscopic endonasal approaches (EEAs) to the skull base have evolved over the last 20 years to become an essential component of a comprehensive skull base practice. Many case series show a learning curve from the earliest cases, in which the authors were inexperienced or were not using advanced closure techniques. It is generally accepted that once this learning curve is achieved, a plateau is reached with little incremental improvement. Cases performed during the early steep learning curve were eliminated to examine whether the continued improvement exists over the "tail end" of the curve. METHODS A prospectively acquired database of all EEA cases performed by the senior authors at Weill Cornell Medicine/NewYork-Presbyterian Hospital was reviewed. The first 200 cases were eliminated and the next 1000 consecutive cases were examined to avoid the bias created by the early learning curve. RESULTS Of the 1000 cases, the most common pathologies included pituitary adenoma (51%), meningoencephalocele or CSF leak repair (8.6%), meningioma (8.4%), craniopharyngioma (7.3%), basilar invagination (3.1%), Rathke's cleft cyst (2.8%), and chordoma (2.4%). Use of lumbar drains decreased from the first half to the second half of our series (p <0.05) as did the authors' use of fat alone (p <0.005) or gasket alone (p <0.005) for dural closure, while the use of a nasoseptal flap increased (p <0.005). Although mean tumor diameter was constant (on average), gross-total resection (GTR) increased from 60% in the first half to 73% in the second half (p <0.005). GTR increased for all pathologies but most significantly for chordoma (56% vs 100%, p <0.05), craniopharyngioma (47% vs 0.71%, p <0.05) and pituitary adenoma (67% vs 75%, p <0.05). Hormonal cure for secreting adenomas also increased from 83% in the first half to 89% in the second half (p <0.05). The rate of any complication was unchanged at 6.4% in the first half and 6.2% in the latter half of cases, and vascular injury occurred in only 0.6% of cases. Postoperative CSF leak occurred in 2% of cases and was unchanged between the first and second half of the series. CONCLUSIONS This study demonstrates that contrary to popular belief, the surgical learning curve does not plateau but can continue for several years depending on the complexity of the endpoints considered. These findings may have implications for clinical trial design, surgical education, and patient safety measures.
Flexible functional interactions between G-protein subunits contribute to the specificity of plant responses.

Plants being sessile integrate information from a variety of endogenous and external cues simultaneously to optimize growth and development. This necessitates the signaling networks in plants to be highly dynamic and flexible. One such network involves heterotrimeric G-proteins comprised of Gα, Gβ and Gγ subunits, which influences many aspects of growth, development and stress response pathways. In plants such as Arabidopsis, a relatively simple repertoire of G-proteins comprised of one canonical and three extra-large Gα, one Gβ and three Gγ subunits exists. Because the Gβ and Gγ proteins form obligate dimers, the phenotypes of plants lacking the sole Gβ or all Gγ genes are similar, as expected. However, the Gα proteins can exist both as monomers or in complex with Gβγ, and the details of combinatorial genetic and physiological interactions of different Gα proteins with the sole Gβ remain unexplored. To evaluate such flexible, signal-dependent interactions and their contribution towards eliciting specific response, we have generated Arabidopsis mutants lacking specific combinations of Gα and Gβ genes, performed extensive phenotypic analysis, and evaluated the results in the context of subunit usage and interaction specificity. Our data show that multiple mechanistic modes, and in some cases complex epistatic relationships exist, depending on the signal-dependent interactions between the Gα and Gβ proteins. This suggests that despite their limited numbers, the inherent flexibility of plant G-protein networks provides for the adaptability needed to survive under continuously changing environments.
New Materials for 3D-Printing Based on Polycaprolactone with Gum Rosin and Beeswax as Additives

In this work, different materials for three-dimensional (3D)-printing were studied, which based on polycaprolactone with two natural additives, gum rosin, and beeswax. During the 3D-printing process, the bed and extrusion temperatures of each formulation were established. After, the obtained materials were characterized by mechanical, thermal, and structural properties. The results showed that the formulation with containing polycaprolactone with a mixture of gum rosin and beeswax as additive behaved better during the 3D-printing process. Moreover, the miscibility and compatibility between the additives and the matrix were concluded through the thermal assessment. The mechanical characterization established that the addition of the mixture of gum rosin and beeswax provides greater tensile strength than those additives separately, facilitating 3D-printing. In contrast, the addition of beeswax increased the ductility of the material, which makes the 3D-printing processing difficult. Despite the fact that both natural additives had a plasticizing effect, the formulations containing gum rosin showed greater elongation at break. Finally, Fourier-Transform Infrared Spectroscopy assessment deduced that polycaprolactone interacts with the functional groups of the additives.