Miracle-dz/UniFAR-FTUs huggingface dataset:
Second-line cabozantinib after sorafenib treatment for advanced hepatocellular carcinoma: a subgroup analysis of the phase 3 CELESTIAL trial

Objective In the phase 3 CELESTIAL trial, cabozantinib improved overall survival (OS) and progression-free survival (PFS) compared with placebo in patients with previously treated advanced hepatocellular carcinoma (HCC). This subgroup analysis evaluated cabozantinib in patients who had received sorafenib as the only prior systemic therapy. Methods CELESTIAL randomised (2:1) patients with advanced HCC and Child–Pugh class A liver function to treatment with cabozantinib (60 mg daily) or placebo. Eligibility required prior treatment with sorafenib, and patients could have received ≤2 prior systemic regimens. The primary endpoint was OS. Outcomes in patients who had received sorafenib as the only prior therapy were analysed by duration of prior sorafenib (<3 months, 3 to <6 months and ≥6 months). Results Of patients who had received only prior sorafenib, 331 were randomised to cabozantinib and 164 to placebo; 136 patients had received sorafenib for <3 months, 141 for 3 to <6 months and 217 for ≥6 months. Cabozantinib improved OS relative to placebo in the overall second-line population who had received only prior sorafenib (median 11.3 vs 7.2 months; HR=0.70, 95% CI 0.55 to 0.88). This improvement was maintained in analyses by prior sorafenib duration with longer duration generally corresponding to longer median OS—median OS 8.9 vs 6.9 months (HR=0.72, 95% CI 0.47 to 1.10) for prior sorafenib <3 months, 11.5 vs 6.5 months (HR=0.65, 95% CI 0.43 to 1.00) for 3 to <6 months and 12.3 vs 9.2 months (HR=0.82, 95% CI 0.58 to 1.16) for ≥6 months. Cabozantinib also improved PFS in all duration subgroups. Safety data were consistent with the overall study population. Conclusion Cabozantinib improved efficacy outcomes versus placebo in the second-line population who had received only prior sorafenib irrespective of duration of prior sorafenib treatment, further supporting the utility of cabozantinib in the evolving treatment landscape of HCC. Clinical trial number NCT01908426.
Parental Microbiota Modulates Offspring Development, Body Mass and Fecundity in a Polyphagous Fruit Fly

The commensal microbiota is a key modulator of animal fitness, but little is known about the extent to which the parental microbiota influences fitness-related traits of future generations. We addressed this gap by manipulating the parental microbiota of a polyphagous fruit fly (Bactrocera tryoni) and measuring offspring developmental traits, body composition, and fecundity. We generated three parental microbiota treatments where parents had a microbiota that was non-manipulated (control), removed (axenic), or removed-and-reintroduced (reinoculation). We found that the percentage of egg hatching, of pupal production, and body weight of larvae and adult females were lower in offspring of axenic parents compared to that of non-axenic parents. The percentage of partially emerged adults was higher, and fecundity of adult females was lower in offspring of axenic parents relative to offspring of control and reinoculated parents. There was no significant effect of parental microbiota manipulation on offspring developmental time or lipid reserve. Our results reveal transgenerational effects of the parental commensal microbiota on different aspects of offspring life-history traits, thereby providing a better understanding of the long-lasting effects of host–microbe interactions.
Pharmacologic Properties and Preclinical Activity of Sasanlimab, A High-affinity Engineered Anti-Human PD-1 Antibody

Development of antagonistic mAbs that specifically target the immune checkpoint receptor, programmed cell death protein-1 (PD-1), is of great interest for cancer immunotherapy. Here, we report the biophysical characteristics and nonclinical antagonistic activities of sasanlimab (PF-06801591), a humanized anti-PD-1 antibody of IgG4 isotype. We show that sasanlimab binds selectively and with similar high potency to human and cynomolgus monkey PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, with no detectable Fc-dependent effector function. The binding of sasanlimab to human and cynomolgus PD-1 is associated with the formation of a stable complex, which is likely to be the main driver of this high-affinity interaction. In vitro, sasanlimab significantly augmented T-cell proliferation and cytokine production in mixed lymphocyte reaction and superantigen stimulation assays. In vivo, sasanlimab accelerated the incidence of GvHD by enhancing T-cell proliferation and cytokine secretion in a xenogeneic model of acute GvHD and halted the growth of MC-38 colon adenocarcinoma tumors in human PD-1 knock-in mice. Pharmacokinetic and toxicokinetic findings from cynomolgus monkey showed that sasanlimab was active and well-tolerated. Taken together, the data presented here support the clinical development of sasanlimab for the treatment of patients with advanced cancers as a single agent or in combination with other immunotherapies.
The importance of Indigenous Peoples’ lands for the conservation of terrestrial mammals

Indigenous Peoples’ lands cover over one‐quarter of Earth's surface, a significant proportion of which is still free from industrial‐level human impacts. As a result, Indigenous Peoples and their lands are crucial for the long‐term persistence of Earth's biodiversity and ecosystem services. Yet, information on species composition on these lands globally remains largely unknown. We conducted the first comprehensive analysis of terrestrial mammal composition across mapped Indigenous lands based on data on area of habitat (AOH) for 4460 mammal species assessed by the International Union for Conservation of Nature. We overlaid each species’ AOH on a current map of Indigenous lands and found that 2695 species (60% of assessed mammals) had ≥10% of their ranges on Indigenous Peoples’ lands and 1009 species (23%) had >50% of their ranges on these lands. For threatened species, 473 (47%) occurred on Indigenous lands with 26% having >50% of their habitat on these lands. We also found that 935 mammal species (131 categorized as threatened) had ≥ 10% of their range on Indigenous Peoples’ lands that had low human pressure. Our results show how important Indigenous Peoples’ lands are to the successful implementation of conservation and sustainable development agendas worldwide.
Is improvement in depression in patients attending cardiac rehabilitation with new-onset depressive symptoms determined by patient characteristics?

Background Patients with cardiovascular disease (CVD) commonly experience depressive symptoms which is associated with adverse outcome and increased mortality. Examining the baseline characteristics of cardiac rehabilitation (CR) patients that determine Hospital Anxiety and Depression Scale (HADS) depression outcome may facilitate adjustments in CR programme delivery. This study aims to investigate whether comorbidities, demographic and clinical characteristics of patients, with new-onset post-cardiac event depressive symptoms, determine change in their depression following CR. Methods Analysing the routine practice data of British Heart Foundation National Audit of Cardiac Rehabilitation between April 2012 and March 2018, an observational study was conducted. Patients with new-onset post-cardiac event depressive symptoms and no previous documented history of depression constituted the study population. Results The analyses included 64 658 CR patients (66.24±10.69 years, 75% male) with new-onset HADS measures, excluding patients with a history of depression. The comorbidities determining reduced likelihood of improvement in depression outcomes after CR were angina, diabetes, stroke, emphysema and chronic back problems. In addition, higher total number of comorbidities, increased weight, a higher HADS anxiety score, smoking at baseline, physical inactivity, presence of heart failure and being single were other significant determinants. However, receiving coronary artery bypass graft treatment was associated with better improvement. Conclusion The study identified specific baseline comorbid conditions of patients with new-onset depressive symptoms including angina, diabetes, stroke, emphysema and chronic back problems that were determinants of poorer mental health outcomes (HADS) following CR. Higher total number of comorbidities, increased weight, physical inactivity, smoking, presence of heart failure and being single were other determinants of a negative change in depression. These findings could help CR programmes focus on tailoring the CR intervention around comorbidity, physical activity status, weight management and smoking cessation in patients with new-onset depressive symptoms.
Childhood Trauma and Maladaptive Daydreaming: Fantasy Functions and Themes In A Multi-Country Sample

ABSTRACT We analyzed responses of 539 adults who met an evidence-based criterion for probable maladaptive daydreaming (MD). Their reported childhood traumata were associated with the utilization of MD to distract from painful memories. A history of childhood physical and emotional neglect as well as emotional abuse was associated with daydreaming aimed to regulate emotional pain. Childhood exposure to physical and emotional abuse was associated with an increased likelihood of daydreaming about an idealized version of their original families. Themes of emotional suffering were associated with exposure to childhood emotional abuse. A range of morbid imageries and trauma-related reenacting behaviors featured in the fantasies of our respondents. Childhood emotional abuse was related to daydreaming about death, physical violence as a victim, being a captor, being rescued, and being a rescuer. Childhood sexual abuse was correlated with themes of sexual violence as a victim, being a captive, and being rescued. Childhood emotional neglect was linked with daydreaming about taking revenge, and a childhood history of physical abuse was associated with current fantasies about being captive. MD fantasy among adults exposed to childhood trauma may not only serve as mere coping mechanisms but potentially manifest a pathological preoccupation with unresolved childhood adversities.
Altered Expression of the m6A Methyltransferase METTL3 in Alzheimer’s Disease

Abstract Cognitive impairment in Alzheimer’s disease (AD) is associated with dysregulation of the RNA and protein expression profiles in the brain. Recent studies have highlighted the importance of RNA post-transcriptional regulation (epitranscriptomics) in higher order brain functions. Specifically, N6-methyladenosine (m6A), which controls RNA stability, splicing, translation and trafficking, plays an important role in learning and memory. This raises the question of whether m6A signaling is perturbed in AD. To address this, we investigated the expression profile of known m6A-regulatory genes using a public RNA-seq dataset and identified a subset of genes which were significantly dysregulated in the human AD brain. Among these, genes encoding the m6A methyltransferase, METTL3, and a member of the m6A methyltransferase complex (MACOM), RBM15B, were downregulated and upregulated in the hippocampus, respectively. These findings were validated at the protein level using an independent cohort of postmortem human brain samples. Unexpectedly, we observed an accumulation of methyltransferase-like 3 (METTL3), but not RBM15B, in the insoluble fractions, which positively correlated with the levels of insoluble Tau protein in the postmortem human AD samples. Aberrant expression and distribution of METTL3 in the hippocampus of the AD brain may therefore represent an epitranscriptomic mechanism underlying the altered gene expression patterns associated with disease pathogenesis.
Multi-Fidelity Nonideality Simulation and Evaluation Framework for Resistive Neuromorphic Computing

While ReRAM crossbar arrays (RCAs) can perform matrix-vector multiplication (MVM) operations with great efficiency, they often suffer functional inaccuracy due to hardware nonidealities, making the functional evaluation of RCA-based systems a central challenge for system designers. Along with a taxonomy of RCA modeling approaches, this paper presents NIXSim, a nonideality-aware simulation and evaluation frame-work for RCA-based neural network accelerators with an em-phasis on accuracy and speed tradeoff. We also present crossbar-and network-level comparisons with previous work, and offline training examples demonstrating the usefulness of our framework for designing RCA-based neural network accelerators.11Code is available at https://github.com/QCH170308/NIXSim.
Application of Spatio-Temporal Context and Convolution Neural Network (CNN) in Grooming Behavior of Bactrocera minax (Diptera: Trypetidae) Detection and Statistics

Simple Summary Traditional manual insect grooming behavior statistical methods are time-consuming, labor-intensive, and error-prone. In response to this problem, we proposed a method for detecting the grooming behavior of Bactrocera minax based on computer vision and artificial intelligence. Using this method to detect the grooming behavior of Bactrocera minax can save a lot of manpower, the detection accuracy is above 95%, and the difference was less than 15% when compared with the results of manual observation. The experimental results show that the method in this paper greatly reduces the time of manual observation and at the same time ensures the accuracy of insect behavior detection and analysis, which proposes a new informatization analysis method for the behavior statistics of Bactrocera minax. At the same time, it also has a positive effect on pest control research. Abstract Statistical analysis and research on insect grooming behavior can find more effective methods for pest control. Traditional manual insect grooming behavior statistical methods are time-consuming, labor-intensive, and error-prone. Based on computer vision technology, this paper uses spatio-temporal context to extract video features, uses self-built Convolution Neural Network (CNN) to train the detection model, and proposes a simple and effective Bactrocera minax grooming behavior detection method, which automatically detects the grooming behaviors of the flies and analysis results by a computer program. Applying the method training detection model proposed in this paper, the videos of 22 adult flies with a total of 1320 min of grooming behavior were detected and analyzed, and the total detection accuracy was over 95%, the standard error of the accuracy of the behavior detection of each adult flies was less than 3%, and the difference was less than 15% when compared with the results of manual observation. The experimental results show that the method in this paper greatly reduces the time of manual observation and at the same time ensures the accuracy of insect behavior detection and analysis, which proposes a new informatization analysis method for the behavior statistics of Bactrocera minax and also provides a new idea for related insect behavior identification research.
Increased Risk of Squamous Cell Carcinoma of the Skin and Lymphoma Among 5,739 Patients with Bullous Pemphigoid: A Swedish Nationwide Cohort Study

Evidence about the association of bullous pemphigoid and the risk of cancer is conflicting. Patients diagnosed with bullous pemphigoid (n = 5,739) between 2005 and 2016 were matched with a control cohort from the general population (n = 17,168) to estimate their over-all and specific risk of cancer. The risk of squamous cell cancer of the skin (cSCC) was increased in patients with bullous pemphigoid (hazard ratio (HR) 1.3; 95% confidence interval (CI) 1.1–1.6). The risk of lymphoma within one year after bullous pemphigoid diagnosis was also increased (HR 3.1; 95% CI 1.3–7.6). While overall cancer risk prior to diagnosis of bullous pemphigoid was similar in cases and controls (prevalence odds ratio (POR) 1.0; 95% CI 0.9–1.0), the risk of male genital cancer within one year prior to diagnosis of bullous pemphigoid was lower in cases (POR 0.4; 95% CI 0.2–0.8). Clinicians must be aware of the increased risk of cSCC and lymphoma in patients with bullous pemphigoid.
Erratum to “Inter-Channel Nonlinear Interference Noise in the Presence of PDL”

We presented analytical model which predicts the statistical properties of nonlinear interference noise (NLIN) in fiber links which are affected by polarization dependent loss (PDL) [1]. Although the model and results shown in [1] are correct, we found several typos and omissions in the analytical derivation. While the final results presented in the paper are correct, these errors may hinder anyone trying to reproduce the mathematical steps of the derivation. Hence, we correct them here.
Ultra-processed foods and early childhood caries in 0–3‐year‐olds enrolled at Primary Healthcare Centers in Southern Brazil

Abstract Objective: To investigate the relationship between ultra-processed food consumption and early childhood caries. Design: Cross-sectional analysis of baseline data from a cluster randomised controlled study. Outcomes included the prevalence of children with non-cavitated and cavitated caries. The main exposure was the total daily consumption of ultra-processed foods (up to three times and four times or more), assessed through a FFQ. Potential confounders were socio-demographic characteristics of the child and caregiver/family, child breast-feeding, oral hygiene and use of dental services. Poisson regression using robust variance adjustment was used to estimate prevalence ratios (PR) and their respective 95 % CI. Setting: Primary Healthcare Centers in an urban area of Pelotas, Southern Brazil. Participants: Children aged 0–3 years (n 309). Results: Consumption of ultra-processed foods four times or more a day was found in 67·6 % of children; 24·4 and 12·0 % presented non-cavitated and cavitated caries, respectively. After adjustment, children who consumed ultra-processed foods four times or more a day were more likely to present both non-cavitated caries (PR 2·25, 95 % CI 1·19, 4·27, P = 0·013) and cavitated caries (PR 3·48, 95 % CI 1·18, 10·30, P = 0·024) compared with those who have consumed them up to three times a day. Conclusions: Consumption of ultra-processed foods is associated with early childhood caries. Interventions aiming at reducing ultra-processed food consumption should be implemented to improve children’s oral health.
Analysis of Phenotypic Features in a Large Cohort of Individuals with Prader-Willi syndrome: Differences between Gender, Molecular Type, Growth Hormone Exposure in Various Age Groups

Author(s): Leonenko, Anna | Advisor(s): Kimonis, Virginia E | Abstract: Prader-Willi syndrome (PWS) is a rare and complex genetic condition. It is characterized by distinct phenotypical features, short stature and morbid obesity, growth hormone (GH) deficiency and hypogonadism. The purpose of this study (N=355 individuals) was to describe differences in PWS phenotypic features by gender, molecular PWS subtype (deletion vs. UPD), and the use of GH and sex hormone (SH) treatments. Hypotheses include 1) Individuals with deletion versus UPD have an increased frequency and more severe features, 2) Individuals treated with GH or SH have normalization of features, 3) The age at the GH or SH treatment initiation impacts the effects of treatment. Individuals with deletions were found to have more frequent incidence of features such as: flat occiput, strabismus, almond shaped eyes, etc. They also tend to be heavier and with smaller head circumferences. Individuals who were treated with GH had lower incidences of some phenotypic features such as: prominent occiput, almond shaped eyes, exotropia, etc. This study has also confirmed that PWS individuals who were treated with GH on average are taller, with lower BMIs, and longer hands and feet. Initiating GH treatment below the age 4 years also demonstrated lower incidence rate of phenotypic features such as micrognathia, slit-like eyes, abdominal fat distribution, etc.The effect of the SH treatment is less obvious and requires further investigation.The results of this study support the benefit of GH treatment for individuals diagnosed with PWS and supports the benefits of starting the GH treatment at a younger age.
Characterization of In Vivo Function(s) of Members of the Plant Mitochondrial Carrier Family

Although structurally related, mitochondrial carrier family (MCF) proteins catalyze the specific transport of a range of diverse substrates including nucleotides, amino acids, dicarboxylates, tricarboxylates, cofactors, vitamins, phosphate and H+. Despite their name, they do not, however, always localize to the mitochondria, with plasma membrane, peroxisomal, chloroplast and thylakoid and endoplasmic reticulum localizations also being reported. The existence of plastid-specific MCF proteins is suggestive that the evolution of these proteins occurred after the separation of the green lineage. That said, plant-specific MCF proteins are not all plastid-localized, with members also situated at the endoplasmic reticulum and plasma membrane. While by no means yet comprehensive, the in vivo function of a wide range of these transporters is carried out here, and we discuss the employment of genetic variants of the MCF as a means to provide insight into their in vivo function complementary to that obtained from studies following their reconstitution into liposomes.
Deep Brain Stimulation of Nucleus Accumbens with Anterior Capsulotomy for Drug Addiction: A Case Report

Background: Drug addiction is one of the most prevalent and costly health problems worldwide. Over the past decade, deep brain stimulation (DBS) has increasingly been used for the treatment of drug addiction. Simultaneous DBS of nucleus accumbens (NAc) and the anterior limb of the internal capsule (ALIC) has successfully been used for preventing heroin relapse. However, the excessive energy consumption speeds up battery depletion, which puts a burden on patients. By comparison, anterior capsulotomy is usually more convenient for patients and its clinical efficacy is similar to that of ALIC DBS. Accordingly, NAc DBS combined with anterior capsulotomy may also be an effective, yet more convenient, intervention for drug addiction and relapse prevention. Case Description: The patient was a 28-year-old man with a polysubstance use disorder (bucinnazine, morphine, and hypnotics) for 13 years. After bilateral NAc DBS combined with bilateral anterior capsulotomy, his craving for the three drugs decreased markedly, and he remained abstinent throughout the follow-up period of approximately 1-year. Moreover, psychiatric and neuropsychological assessments showed significant improvements in depression, anxiety, sleep, quality of life, and most aspects of cognitive functioning. His overall health status was also improved. Conclusions: NAc DBS combined with anterior capsulotomy is a promising surgical treatment for drug addiction.