Miracle-dz/UniFAR-FTUs huggingface dataset:
Combination lenalidomide‐rituximab immunotherapy activates anti‐tumour immunity and induces tumour cell death by complementary mechanisms of action in follicular lymphoma

Chemotherapy plus rituximab has been the mainstay of treatment for follicular lymphoma (FL) for two decades but is associated with immunosuppression and relapse. In phase 2 studies, lenalidomide combined with rituximab (R2) has shown clinical synergy in front‐line and relapsed/refractory FL. Here, we show that lenalidomide reactivated dysfunctional T and Natural Killer (NK) cells ex vivo from FL patients by enhancing proliferative capacity and T‐helper cell type 1 (Th1) cytokine release. In combination with rituximab, lenalidomide improved antibody‐dependent cellular cytotoxicity in sensitive and chemo‐resistant FL cells, via a cereblon‐dependent mechanism. While single‐agent lenalidomide and rituximab increased formation of lytic NK cell immunological synapses with primary FL tumour cells, the combination was superior and correlated with enhanced cytotoxicity. Immunophenotyping of FL patient samples from a phase 3 trial revealed that R2 treatment increased circulating T‐ and NK‐cell counts, while R‐chemotherapy was associated with reduced cell numbers. Finally, using an in vitro model of myeloid differentiation, we demonstrated that lenalidomide caused a reversible arrest in neutrophil maturation that was distinct from a cytotoxic chemotherapeutic agent, which may help explain the lower rates of neutropenia observed with R2 versus R‐chemotherapy. Taken together, we believe these data support a paradigm shift in the treatment of FL – moving from combination immunochemotherapy to chemotherapy‐free immunotherapy.
Genetic Evolution and Molecular Selection of the HE Gene of Influenza C Virus

Influenza C virus (ICV) was first identified in humans and swine, but recently also in cattle, indicating a wider host range and potential threat to both the livestock industry and public health than was originally anticipated. The ICV hemagglutinin-esterase (HE) glycoprotein has multiple functions in the viral replication cycle and is the major determinant of antigenicity. Here, we developed a comparative approach integrating genetics, molecular selection analysis, and structural biology to identify the codon usage and adaptive evolution of ICV. We show that ICV can be classified into six lineages, consistent with previous studies. The HE gene has a low codon usage bias, which may facilitate ICV replication by reducing competition during evolution. Natural selection, dinucleotide composition, and mutation pressure shape the codon usage patterns of the ICV HE gene, with natural selection being the most important factor. Codon adaptation index (CAI) and relative codon deoptimization index (RCDI) analysis revealed that the greatest adaption of ICV was to humans, followed by cattle and swine. Additionally, similarity index (SiD) analysis revealed that swine exerted a stronger evolutionary pressure on ICV than humans, which is considered the primary reservoir. Furthermore, a similar tendency was also observed in the M gene. Of note, we found HE residues 176, 194, and 198 to be under positive selection, which may be the result of escape from antibody responses. Our study provides useful information on the genetic evolution of ICV from a new perspective that can help devise prevention and control strategies.
The Unusual Suspects: Multiple-Perpetrator and Multiple Concurrent Victim Sexual Homicide

Sexual homicide typically implies a crime involving two people: perpetrator and victim. Thus, multiple-perpetrator and multiple concurrent victim sexual murderers are unusual, empirically invisible due to their exclusion from (or burying within) research samples. The present study examines 21 such cases of male sexual murderers having perpetrated at least one sexual homicide either together with a co-offender or alone but killing two victims at once. The aim was to investigate just how unusual, or not, these cases may be in relation to current scientific understanding of sexual murderers and their crimes. A descriptive analysis of offenses (co-offender and offender–victim dynamics, modus operandi) and offender characteristics is presented. Main findings, that multiple-perpetrator and multiple concurrent victim sexual murderers are not so unusual in that they are well conceptualized through application of the established sexualized, grievance, and rape murderer typology, are discussed in relation to clinical and empirical implications.
A Radiomics Nomogram for the Preoperative Prediction of Lymph Node Metastasis in Bladder Cancer

Purpose: To develop and validate a radiomics nomogram for the preoperative prediction of lymph node (LN) metastasis in bladder cancer. Experimental Design: A total of 118 eligible bladder cancer patients were divided into a training set (n = 80) and a validation set (n = 38). Radiomics features were extracted from arterial-phase CT images of each patient. A radiomics signature was then constructed with the least absolute shrinkage and selection operator algorithm in the training set. Combined with independent risk factors, a radiomics nomogram was built with a multivariate logistic regression model. Nomogram performance was assessed in the training set and validated in the validation set. Finally, decision curve analysis was performed with the combined training and validation set to estimate the clinical usefulness of the nomogram. Results: The radiomics signature, consisting of nine LN status–related features, achieved favorable prediction efficacy. The radiomics nomogram, which incorporated the radiomics signature and CT-reported LN status, also showed good calibration and discrimination in the training set [AUC, 0.9262; 95% confidence interval (CI), 0.8657–0.9868] and the validation set (AUC, 0.8986; 95% CI, 0.7613–0.9901). The decision curve indicated the clinical usefulness of our nomogram. Encouragingly, the nomogram also showed favorable discriminatory ability in the CT-reported LN-negative (cN0) subgroup (AUC, 0.8810; 95% CI, 0.8021–0.9598). Conclusions: The presented radiomics nomogram, a noninvasive preoperative prediction tool that incorporates the radiomics signature and CT-reported LN status, shows favorable predictive accuracy for LN metastasis in patients with bladder cancer. Multicenter validation is needed to acquire high-level evidence for its clinical application. Clin Cancer Res; 23(22); 6904–11. ©2017 AACR.
Comparison of dexmedetomidine and benzodiazepine for intraoperative sedation in elderly patients: a randomized clinical trial

Background and objectives Elderly individuals have a greater sensitivity to sedation, and the most commonly used drugs for sedation are benzodiazepines, which exhibit some complication. Therefore, this study aimed to compare the use of dexmedetomidine and midazolam regarding proper sedation and postoperative complications in elderly individuals who require intraoperative sedation. Methods This study was a parallel-randomized clinical trial, which included 120 patients aged >70 years undergoing regional anesthesia and sedation. The exclusion criteria consisted of bradycardia, heart failure, respiratory failure, a Glasgow Coma Scale ≤14, liver failure and refusal to participate. Patients were divided into two groups: the first group received midazolam (MDZ), while the second group received dexmedetomidine (DEX). The doses were titrated to achieve an intraoperative Richmond Agitation-Sedation Scale (RASS) score between −3 and −1. Incidences of complications were recorded. Results During a 120 min follow-up, the depth of sedation (RASS score) revealed variations less often in the DEX group (p=0.002). Patients in the DEX group (n=67) had lower rates of intraoperative complications (19.4% vs 73.6%, p<0.001). Intraoperatively, the incidence rates of psychomotor agitation (15.1% vs 1.5%, p=0.005), arterial hypotension (28.3% vs 3.0%, p<0.001) and respiratory depression (73.6% vs 0%, p<0.001) were higher in the MDZ group (n=53). During postanesthesia care, the incidence rates of shivering (p<0.001), residual sedation (p=0.04) and use of supplemental oxygen (p<0.001) were significantly lower in the DEX group. Conclusions The use of DEX for sedation during surgery provides better control over the depth of sedation and produces fewer complications in elderly individuals. Trial registration number NCT02878837.
Long-Term Changes of Symptoms of Anxiety, Depression, and Fatigue in Cancer Patients 6 Months After the End of Yoga Therapy

Background: Symptoms of anxiety, depression, and cancer-related fatigue are commonly associated with cancer. Cancer patients increasingly use complementary and alternative treatments, such as yoga, to cope with psychological and physical impairments. In the present article, long-term changes of anxiety, depression, and fatigue in cancer are examined 6 months after a yoga intervention. Method: We used an observational design based on a randomized controlled study in cancer patients with mixed diagnoses to evaluate long-term changes of symptoms of anxiety, depression, and fatigue 6 months after the end of yoga therapy. We measured anxiety symptoms with the Generalized Anxiety Disorder scale (GAD-7), depressive symptoms with the Patient Health Questionnaire–2 (PHQ-2), and fatigue with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Fatigue Scale (EORTC QLQ-FA13). Yoga therapy was provided in yoga classes of 60 minutes each once a week for 8 weeks in total. The exercises provided contained both body and breathing activities as well as meditation. Results: A total of 58 patients participated in the study. Six months after the end of yoga therapy, symptoms of anxiety, depression, and fatigue were significantly reduced compared with baseline. However, symptoms of anxiety and fatigue slightly increased during the follow-up period, whereas symptoms of depression remained stable. Conclusion: Our results are promising and support the integration of yoga interventions in supportive cancer treatment concepts but should be confirmed by randomized controlled trials. Long-term effects of yoga therapy on cancer patients should be the subject of further research.
Transgender Children and the Right to Transition: Medical Ethics When Parents Mean Well but Cause Harm

In this article, I argue that (1) transgender adolescents should have the legal right to access puberty-blocking treatment (PBT) without parental approval, and (2) the state has a role to play in publicizing information about gender dysphoria. Not only are transgender children harmed psychologically and physically via lack of access to PBT, but PBT is the established standard of care. Given that we generally think that parental authority should not go so far as to (1) severally and permanently harm a child and (2) prevent a child from access to standard physical care, then it follows that parental authority should not encompass denying gender-dysphoric children access to PBT. Moreover, transgender children without supportive parents cannot be helped without access to health care clinics and counseling to facilitate the transition. Hence there is an additional duty of the state to help facilitate sharing this information with vulnerable teens.
Human inborn errors of the actin cytoskeleton affecting immunity: way beyond WAS and WIP

Inherited defects in genes encoding for proteins that are involved in the assembly and dynamics of the actin skeleton have increasingly been identified in patients presenting with primary immunodeficiencies. In this review, we summarize a subset of the recently described conditions, emphasizing the clinical features as well as the immunophenotype and pathophysiology.
Defining and overcoming the contact resistance challenge in scaled carbon nanotube transistors

In this work, we define the relevant aspects of a CNTFET contact and the corresponding resistances, putting them into the proper context for a sub-10 nm technology node. Also, new results on the use of different metal-CNT contacts and how they impact the Rc vs. Lc scaling is presented.
CBT for schizophrenia: a critical viewpoint

In England and Wales, cognitive behavioral therapy (cognitive therapy, CBT) has been part of official treatment guidelines for schizophrenia since 2002 (NICE, 2009, p. 212). The 2014 NICE guideline (NICE, 2014), which is based on the same meta-analytic evidence as its predecessor in 2009, recommends that it be offered to all people with schizophrenia, including first-episode patients and those with established illness, and to patients who are actively symptomatic and in remission. Similar recommendations are to be found in the Scottish SIGN guideline (SIGN, 2013) as well as those of several other countries (Rathod et al., 2010). In 2012, however, the Cochrane collaboration sounded a discordant note, concluding that ‘[t]rial-based evidence suggests no clear and convincing advantage for cognitive behavioural therapy over other–and sometimes much less sophisticated–therapies for people with schizophrenia’ (Jones et al., 2012). A further challenge came from a 2014 meta-analysis carried out by ourselves (Jauhar et al., 2014), which found end of treatment effect sizes (ESs) that were uniformly in the small range [overall symptoms: 0.33 (95% CI 0.19–0.47), 34 studies; positive symptoms: 0.25 (95% CI 0.13–0.37), 33 studies; negative symptoms: 0.13 (95% CI 0.01–0.25), 34 studies] (note these and all further ESs are shown as a positive sign favoring CBT). A 2018 network meta-analysis of various psychological interventions to reduce positive symptoms in schizophrenia (Bighelli et al., 2018), carried out on a rather different dataset of 27 studies than us, again found pooled ESs for CBT in the small range, though this time at the upper end of this [v. treatment as usual (TAU): 0.30 (95% CI 0.14–0.45), 18 trials; v. inactive control interventions: 0.29 (95% CI 0.03–0.55), seven trials] (Bighelli et al., 2018). Most recently, a 2018 update of the 2012 Cochrane meta-analysis has continued to find no clear or convincing evidence of superiority on any measure apart from leaving the study early (Jones et al., 2018). In the wake of a ‘viewpoint’ article examining whether it is right to continue to regard CBT as a gold standard for depression and anxiety (Leichsenring and Steinert, 2017), we consider the current status of this form of therapy in schizophrenia and the related psychotic disorders that are typically included in trials (schizoaffective disorder, delusional disorder, and psychosis not otherwise specified). We draw on what can legitimately be regarded as the two best sources of evidence, namely meta-analyses and large, well-conducted individual trials.
Access pattern-aware cache management for improving data utilization in GPU

Long latency of memory operation is a prominent performance bottleneck in graphics processing units (GPUs). The small data cache that must be shared across dozens of warps (a collection of threads) creates significant cache contention and premature data eviction. Prior works have recognized this problem and proposed warp throttling which reduces the number of active warps contending for cache space. In this paper we discover that individual load instructions in a warp exhibit four different types of data locality behavior: (1) data brought by a warp load instruction is used only once, which is classified as streaming data (2) data brought by a warp load is reused multiple times within the same warp, called intra-warp locality (3) data brought by a warp is reused multiple times but across different warps, called inter-warp locality (4) and some data exhibit both a mix of intra- and inter-warp locality. Furthermore, each load instruction exhibits consistently the same locality type across all warps within a GPU kernel. Based on this discovery we argue that cache management must be done using per-load locality type information, rather than applying warp-wide cache management policies. We propose Access Pattern-aware Cache Management (APCM), which dynamically detects the locality type of each load instruction by monitoring the accesses from one exemplary warp. APCM then uses the detected locality type to selectively apply cache bypassing and cache pinning of data based on load locality characterization. Using an extensive set of simulations we show that APCM improves performance of GPUs by 34% for cache sensitive applications while saving 27% of energy consumption over baseline GPU.
Expression pattern of microRNAs related with response to trastuzumab in breast cancer

Although an immense effort has been made to develop a novel biomarker for response to trastuzumab, no reliable biomarkers are available to guide management, expect for HER2. The aim of this study was to examine the relationship between microRNA (miRNA) expression and resistance to trastuzumab.
Morphometric analysis of spinal cord termination in Cavalier King Charles Spaniels

Background There is an association between Chiari malformations, syringomyelia (CMSM) and tethered cord syndrome (TCS) in people, suggesting Cavalier King Charles Spaniels (CKCS) with CMSM could also have TCS. Currently there are no data on the position of the caudal spinal cord structures in CKCS. Objective To describe and compare location of spinal cord termination in CKCS with weight‐matched controls and to examine the relationship between SM and spinal cord termination. Animals Thirty‐nine CKCS and 33 controls with thoracolumbar MRIs; 34 of 39 CKCS also had cervical MRIs. Methods Blinded retrospective study. Spinal cord and dural sac termination were determined from T2‐weighted sagittal and transverse images and half‐Fourier acquisition single‐shot turbo spin echo sequences. Intra‐observer reliability was determined using kappa analysis. Presence of SM was compared with location of spinal cord and dural sac termination. Results Intra‐observer reliability was moderate for identifying spinal cord termination (Kappa = 0.6) and good for dural sac termination (Kappa = 0.8). The spinal cord terminated at lumbar vertebra 6 (L6) in 1, 7 (L7) in 22, and sacrum in 16 CKCS versus 9 at L6, 23 at L7, 1 at sacrum in controls. Spinal cord (P < .001) and dural sac (P = .002) termination were significantly more caudal in CKCS compared to controls. The presence of thoracolumbar SM was associated with more caudal dural sac termination in CKCS (P = .03). Conclusions and Clinical Importance The relationship between TL SM and possible spinal cord tethering because of a more caudal dural sac termination should be investigated.
Retinal microglia signaling affects Müller cell behavior in the zebrafish following laser injury induction

Microglia are the resident tissue macrophages of the central nervous system including the retina. Under pathophysiological conditions, microglia can signal to Müller cells, the major glial component of the retina, affecting their morphological, molecular, and functional responses. Microglia–Müller cell interactions appear to be bidirectional shaping the overall injury response in the retina. Hence, microglia and Müller cell responses to disease and injury have been ascribed both positive and negative outcomes. However, Müller cell reactivity and survival in the absence of immune cells after injury have not been investigated in detail in adult zebrafish. Here, we develop a model of focal retinal injury combined with pharmacological treatments for immune cell depletion in zebrafish. The retinal injury was induced by a diode laser to damage photoreceptors. Two pharmacological treatments were used to deplete either macrophage–microglia (PLX3397) or selectively eliminate peripheral macrophages (clodronate liposomes). We show that PLX3397 treatment hinders retinal regeneration in zebrafish, which is reversed by microglial repopulation. On the other hand, selective macrophage elimination did not affect the kinetics of retinal regeneration. The absence of retinal microglia and macrophages leads to dysregulated Müller cell behavior. In the untreated fish, Müller cells react after injury induction showing glial fibrillary acidic protein (GFAP), Phospho‐p44/42 MAPK (Erk1/2), and PCNA upregulation. However, in the immunosuppressed animals, GFAP and phospho‐p44/42 MAPK (Erk1/2) expression was not upregulated overtime and the reentry in the cell cycle was not affected. Thus, microglia and Müller cell signaling is pivotal to unlock the regenerative potential of Müller cells in order to repair the damaged retina.
The stromal cell-derived factor-1 α (SDF-1α)/cysteine-X-cysteine chemokine receptor 4 (CXCR4) axis: a possible prognostic indicator of acute ischemic stroke

Objective The stromal cell-derived factor-1α/cysteine-X-cysteine chemokine receptor 4 (SDF-1α/CXCR4) axis promotes neuroprotection and angiogenesis in animal studies. Few studies have investigated the potential clinical implications of the SDF-1α/CXCR4 axis in patients with acute ischemic stroke (AIS). We evaluated the prognostic values of the SDF-1α/CXCR4 axis in patients with proximal middle cerebral artery occlusion. Methods Fifty-five patients and 18 age- and sex-matched volunteers were enrolled. Baseline clinical characteristics and risk factors of stroke were recorded. Peripheral whole blood cells were double stained with anti-CD34 and anti-CXCR4 (CD184). CD34+CXCR4+ cells were analyzed by flow cytometry. Plasma SDF-1α levels were measured by enzyme-linked immunosorbent assay. Results In the AIS group, plasma SDF-1α levels and the number of circulating CD34+CXCR4+ cells were significantly higher than those in controls. Day 1 SDF-1α levels were negatively correlated with infarct volume (r = −0.521) and the initial National Institutes of Health Stroke Scale score (r = −0.489). SDF-1α levels (day 1: r = −0.514; day 3: r = −0.275; day 7: r = −0.375) and circulating CD34+CXCR4+ cells (day 7: r = −0.282) were inversely associated with the 90-day modified Rankin Scale score. Conclusion The SDF-1α/CXCR4 axis has potential applications for predicting the clinical outcome of AIS.
Clinical delineation of GTPBP2‐associated neuro‐ectodermal syndrome: Report of two new families and review of the literature

The GTPBP2 gene encodes a guanosine triphosphate (GTP)‐binding protein of unknown function. Biallelic loss‐of‐function variants in the GTPBP2 gene have been previously reported in association with a neuro‐ectodermal clinical presentation in six individuals from four unrelated families. Here, we provide detailed descriptions of three additional individuals from two unrelated families in the context of the previous literature. Both families carry nonsense variants in GTPBP2: homozygous p.(Arg470*) and compound heterozygous p.(Arg432*)/p.(Arg131*). Key features of this clinically recognizable condition include prenatal onset microcephaly, tone abnormalities, and movement disorders, epilepsy, dysmorphic features, retinal dysfunction, ectodermal dysplasia, and brain iron accumulation. Our findings suggest that some aspects of the clinical presentation appear to be age‐related; brain iron accumulation may appear only after childhood, and the ectodermal findings and peripheral neuropathy are most prominent in older individuals. In addition, we present prenatal and neonatal findings as well as the first Caucasian and black African families with GTPBP2 biallelic variants. The individuals described herein provide valuable additional phenotypic information about this rare, novel, and progressive neuroectodermal condition.