julilili42/papers huggingface dataset:
Repetitive sensorimotor mu-alpha phase-targeted afferent stimulation produces no phase-dependent plasticity related changes in somatosensory evoked potentials or sensory thresholds
2023-10-30

Phase-dependent plasticity has been proposed as a neurobiological mechanism by which oscillatory phase-amplitude cross-frequency coupling mediates memory process in the brain. Mimicking this mechanism, real-time EEG oscillatory phase-triggered transcranial magnetic stimulation (TMS) has successfully induced LTP-like changes in corticospinal excitability in the human motor cortex. Here we asked whether EEG phase-triggered afferent stimulation alone, if repetitively applied to the peaks, troughs, or random phases of the sensorimotor mu-alpha rhythm, would be sufficient to modulate the strength of thalamocortical synapses as assessed by changes in somatosensory evoked potential (SEP) N20 and P25 amplitudes and sensory thresholds (ST). Specifically, we applied 100 Hz triplets of peripheral electrical stimulation (PES) to the thumb, middle, and little finger of the right hand in pseudorandomized trials, with the afferent input from each finger repetitively and consistently arriving either during the cortical mu-alpha trough or peak or at random phases. No significant changes in SEP amplitudes or ST were observed across the phase-dependent PES intervention. We discuss potential limitations of the study and argue that suboptimal stimulation parameter choices rather than a general lack of phase-dependent plasticity in thalamocortical synapses are responsible for this null finding. Future studies should further explore the possibility of phase-dependent sensory stimulation.
A comprehension on structure guided alignment dependent 3D-QSAR modelling, and molecular dynamics simulation on 2,4-thiazolidinediones as aldose reductase inhibitors for the management of diabetic complications
2023-10-30

Aldose reductase is an oxo-reductase enzyme belonging to the aldo-keto reductase class. Compounds having thiazolidine-2,4-dione scaffold are reported as potential aldose reductase inhibitors for diabetic complications. The present work uses structure-guided alignment-dependent Gaussian field- and atom-based 3D-QSAR on a dataset of 84 molecules. 3D-QSAR studies on two sets of dataset alignment have been carried out to understand the favourable and unfavourable structural features influencing the affinity of these inhibitors towards the enzyme. Using common pharmacophore hypotheses, the five-point pharmacophores for aldose reductase favourable features were generated. The molecular dynamics simulations (up to 100 ns) were performed for the potent molecule from each alignment set (compounds 24 and 65) compared to reference standard tolrestat and epalrestat to study target-ligand complexes' binding energy and stability. Compound 65 was most stable with better interactions in the aldose reductase binding pocket than tolrestat. The MM-PBSA study suggests compound 65 possessed better binding energy than reference standard tolrestat, i.e. -87.437 ± 19.728 and -73.424 ± 12.502 kJ/mol, respectively. The generated 3D-QSAR models provide information about structure-activity relationships and ligand-target binding energy. Target-specific stability data from MD simulation would be helpful for rational compound design with better aldose reductase activity.Communicated by Ramaswamy H. Sarma.
Health-Related Quality-of-Life Effects of Rectus Repair during Body Contouring Surgery in Postbariatric Patients: A Prospective Study
2023-10-30

Background: Massive weight loss after bariatric surgery often leads to psychological and physical dissatisfaction, resulting in an increased demand for body contouring surgery (BCS). As a result of these operations, health-related quality of life (HRQL) is improved. However, little is known about the impact of rectus plication during BCS on HRQL. Methods: This multicenter prospective cohort study included postbariatric primary BCS patients with a minimum follow-up period of 12 months between January of 2016 and December of 2019. Patients were divided into 2 groups based on plication status. Using the BODY-Q, a patient-reported outcome measure, HRQL was measured preoperatively and at least 12 months postoperatively. Six HRQL domains were investigated: body image, physical function, psychological function, sexual function, social function, and physical symptoms. Results: A total of 305 patients were included in this study: 201 of these patients (66%) did not undergo plication, whereas 104 patients (34%) did. HRQL improved significantly 12 months after BCS in all measured domains, regardless of plication status. Delta scores were significantly higher in the plication group in all HRQL domains. After adjusting for baseline score and other significant variables through multivariate linear regression, 3 scales remained significant: body image ( P = 0.001), psychological function ( P = 0.035), and sexual function ( P = 0.035). Conclusions: Three of 6 HRQL domains showed significant improvement after BCS with rectus plication, predominantly body image. Preoperative counseling and surgical planning could benefit from this information. The long-term effects of rectus plication on HRQL should be explored in future research. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.
Individual-level deviations from normative brain morphology in violence, psychosis, and psychopathy
2023-10-30

Abstract Background Neuroimaging research has shown brain morphological abnormalities associated with violence and psychosis, but individual differences are substantial and results not consistent across studies. Recently developed normative modeling of brain MRI-features provides a possibility to parse this heterogeneity by mapping inter-individual brain characteristics, which has not yet been explored in forensic psychiatry. Methods We explored brain heterogeneity in persons with a history of severe violence with or without a schizophrenia spectrum disorder (HoV, n=58), non-violent patients with schizophrenia spectrum disorders (SSD-NV, n=138), and healthy non-violent controls (HC) from lifetime normative trajectories of cortical thickness, surface area, and subcortical volumes. Normative models were based on Freesurfer derived regions of interest from 58,836 individuals (ages 2-100) from 82 sites. Group differences and associations between brain deviations and psychopathy traits (PCL-R scores) were investigated. Results Across groups, we found an overall heterogeneous pattern of individual-level deviations, with a significantly higher frequency of extreme negative deviations in HoV ( p =.020, d =.31) and SSD-NV ( p =.019, d= . 48) , than HC. Group differences were mostly present in subcortical volumes and cortical area, but not thickness, with significant regional group-level differences within the subcallosal and insular cortices, and the cerebellum, and no significant associations to psychopathy traits. Conclusion By applying normative modeling, this proof-of-concept study demonstrates the heterogeneous pattern of brain morphometry deviations associated with violence and psychosis. While the results warrant replication, studies addressing individual brain deviations may contribute to improved understanding of the complex underpinnings of violence in forensic psychiatry.
Role (in-)congruity and the Catch 22 for female executives: how stereotyping contributes to the gender pay gap at top executive level
2023-10-30

We examine to what extent the gender pay gap at top executive level is linked to gender stereotypes, i.e. to societal beliefs about the attributes women and men possess and the roles they ought to perform. We theorize that, even at the highest hierarchical level of an organization, executive functions are gender stereotyped: some (such as IT) are considered typically 'masculine', while others (such as human resources) are considered typically 'feminine'. We argue gender stereotyping at the executive level to be related to pay such that masculine functions are paid more than feminine ones. Referring to role congruity theory, we further argue that women are paid better when they hold less masculine and therefore more role congruous functions. We find supportive evidence for both predictions when studying large European companies across the years 2014 to 2018. Pay data for 353 executives were linked to results of a survey in which participants were asked to rate the masculinity of the areas of responsibility of different executive functions. We find an empirical pattern that reflects a Catch 22 situation in which women executives appear unable to increase their pay by switching to more masculine functions that are, on average, better paid.
A further case of AFG2B‐related neurodevelopmental disorder with hearing loss and microcephaly allows further clarification of pathogenicity of the variant c.1313T>C, p.(Leu438Pro)
2023-10-30

Abstract Background Bi‐allelic variants in AFG2B (previously known as SPATA5L1 ) have recently been associated with a neurodevelopmental disorder with hearing loss and spasticity, as well as isolated hearing loss. We report on a 6 1/2‐year‐old girl with a history of global developmental delay, subsequent intellectual disability without relevant language acquisition, sensorineural hearing loss, muscular hypotonia and microcephaly. Methods We performed trio exome sequencing on the patient and her parents. Results Trio exome sequencing revealed likely pathogenic compound heterozygous missense variants in AFG2B [c.527G&gt;T, p.(Gly176Val) and c.1313T&gt;C, p.(Leu438Pro)] in the patient. Conclusion Of note, the change c.1313T&gt;C, p.(Leu438Pro) has been observed in a previously published patient as part of a complex disease allele along with a second homozygous missense change, so the exact contribution of the two alterations to this patient's disease had initially remained unclear. Our results support the pathogenic relevance of the c.1313T&gt;C, p.(Leu438Pro) allele while providing detailed insights into the disease manifestation of a further patient.
Impact of the extent of lymph node dissection on survival outcomes in clinically lymph node‐positive bladder cancer
2023-10-31

Objective To determine the oncological impact of extended pelvic lymph node dissection (ePLND) vs standard PLND (sPLND) during radical cystectomy (RC) in clinically lymph node‐positive (cN+) bladder cancer (BCa). Patients and Methods In this retrospective, multicentre study we included 969 patients who underwent RC with sPLND (internal/external iliac and obturator lymph nodes) or ePLND (sPLND plus common iliac and presacral nodes) with or without platin‐based peri‐operative chemotherapy for cTany N1‐3 M0 BCa between 1991 and 2022. We assessed the impact of ePLND on recurrence‐free survival (RFS) and the distribution of recurrences (locoregional and distant recurrences). The secondary endpoint was overall survival (OS). We performed propensity‐score matching using covariates associated with the extent of PLND in univariable logistic regression analysis. The association of the extent of PLND with RFS and OS was investigated using Cox regression models. Results Of 969 cN+ patients, 510 were 1:1 matched on propensity scores. The median (interquartile range [IQR]) time to recurrence was 8 (4–16) months, and median (IQR) follow‐up of alive patients was 30 (13–51) months. Disease recurrence was observed in 104 patients in the ePLND and 107 in the sPLND group. Of these, 136 (27%), 47 (9.2%) and 19 patients (3.7%) experienced distant, locoregional, or both distant and locoregional disease recurrence, respectively. When stratified by the extent of PLND, we did not find a difference in recurrence patterns ( P &gt; 0.05). ePLND improved neither RFS (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.70–1.19; P = 0.5) nor OS (HR 0.78, 95% CI 0.60–1.01; P = 0.06) compared to sPLND. Stratification by induction chemotherapy did not change outcomes. Conclusion Performing an ePLND at the time of RC in cN+ patients improved neither RFS nor OS compared to sPLND, regardless of induction chemotherapy status. Pretreatment risk stratification is paramount to identify ideal candidates for RC with ePLND as part of a multimodal treatment approach.
Special Issue: Digital Truth-Making: Anthropological Perspectives on Right-wing Politics and Social Media in "Post-truth" Societies
2023-10-31

How do users of social media platforms produce, shape and share truths online? In this introduction, we outline our understanding of digital truth-making as a process that builds on the affordances of digital infrastructures to entangle information with social, cultural and emotional dynamics in a way that co-constitutes beliefs and convictions about the world. The contributions to the special issue illuminate how different variations of this process can be illuminated with the help of digital ethnography and additional empirical methods. In doing so, they exemplify how digital anthropology can contribute to ongoing debates about populism and right-wing politics in “post-truth” digital societies.
Cost-effectiveness of endovascular treatment versus best medical management in basilar artery occlusion stroke: A U.S. healthcare perspective
2023-10-31

Introduction: Two recent studies showed clinical benefit for endovascular treatment (EVT) in basilar artery occlusion (BAO) stroke up to 12 h (ATTENTION) and between 6 and 24 h from onset (BAOCHE). Our aim was to investigate the cost-effectiveness of EVT from a U.S. healthcare perspective. Materials and Methods: Clinical input data were available for both trials, which were analyzed separately. A decision model was built consisting of a short-run model to analyze costs and functional outcomes within 90 days after the index stroke and a long-run Markov state transition model (cycle length of 12 months) to estimate expected lifetime costs and outcomes from a healthcare and a societal perspective. Incremental cost-effectiveness ratios (ICER) were calculated, deterministic (DSA) and probabilistic (PSA) sensitivity analyses were performed. Results: EVT in addition to best medical management (BMM) resulted in additional lifetime costs of 7690 in the BAOCHE trial (societal perspective). From a healthcare perspective, EVT led to incremental costs and effectiveness of 3516 and 1.9 QALYs (BAOCHE), compared to BMM alone. The ICER values were 15,867/QALY (ATTENTION) from a societal perspective. In each trial, PSA showed EVT to be cost-effective in most calculations (99.9%) for a willingness-to-pay threshold of $100,000/QALY. Cost of EVT and age at stroke represented the greatest impact on the ICER. Discussion: From an economic standpoint with a lifetime horizon, EVT in addition to BMM is estimated to be highly effective and cost-effective in BAO stroke.
1365 An immunocytokine with target cell-restricted IL-15 activity for induction of anti-tumor immunity against acute myeloid leukemia
2023-10-31

<h3>Background</h3> Despite the significant progress achieved in cancer treatment by the use of antitumor antibodies, there remains an urgent need to optimize their therapeutic efficacy. We recently completed a phase I trial evaluating safety/tolerability and preliminary efficacy of an Fc-optimized FLT3/CD135 antibody (FLYSYN, NCT02789254) to induce NK cell anti-leukemia reactivity against AML cells. Besides by reinforcing the capability of antibodies to induce antibody-dependent cellular cytotoxicity (ADCC), NK cell immunity can be further increased using cytokines like IL-15. However, the application of clinically effective doses of IL-15 is hindered by significant side effects caused by nonspecific immune activation. <h3>Methods</h3> We generated a modified immunocytokine (MIC) consisting of our Fc-optimized CD135 antibody fused to mutated IL-15 with abolished binding to IL-15 receptor alpha (MIC135). This abrogated binding allows to substitute the trans-presentation of IL-15, which physiologically is required to stimulate the IL-15 receptor beta/gamma on NK cells, by binding of the antibody part to CD135 on leukemic cells. The efficacy of our construct was evaluated in various <i>in vitro</i> assays using primary AML cells as targets. <h3>Results</h3> Functional analysis revealed that MIC135 exhibited significantly greater induction of target-restricted NK cell anti-leukemia reactivity compared to the Fc-optimized FLYSYN mAb. Notably, in stark contrast to FLYSYN, MIC135 induced pronounced NK cell proliferation, and target cell killing was likewise clearly superior. Analyses regarding off-target toxicity confirmed that MIC135 exhibited target-antigen restricted efficacy, in contrast to anti-CD135 immunocytokines with wildtype IL-15 (IC135). MIC135 did not induce unwanted effects against healthy FLT3 expressing cells. <h3>Conclusions</h3> MIC135 induces NK cell reactivity against leukemia cells in a target cell-restricted manner and exhibits superior efficacy compared to Fc-optimized antibodies, thus constituting a promising treatment option for AML. <h3>Ethics Approval</h3> The studies involving human participants were reviewed and approved by IRB (ethics committee of the Faculty of Medicine of the Eberhard Karls Universität Tübingen) at the University Hospital Tübingen and was conducted in accordance with the Declaration of Helsinki; reference number 13/2007V. <h3>Consent</h3> Human material was collected after obtaining informed consent. The patients/participants provided their written informed consent to participate in this study.
965 NFAT2 drives the cytoskeletal remodeling of leukemia cells, which regulates their vulnerability to perforin-mediated killing
2023-10-31

<h3>Background</h3> Cytoskeletal remodeling is crucial for migration, infiltration and metastasis and overall tumor aggressiveness. In addition, cytoskeleton remodeling protects from cell membrane damage, e.g. in case of cytotoxic lymphocytes from content of their own cytotoxic granules, but also by preventing perforin/granzyme-induced lysis in case of tumor cells. Antibody dependent cellular cytotoxicity (ADCC) a major effector mechanism by which Rituximab that is routinely used for treatment of chronic lymphocytic leukemia (CLL) mediates lysis of tumor cells and thus therapeutic efficacy. We previously demonstrated that in CLL patients loss of the transcription factor NFAT2 (NFATc1) correlates with an aggressive disease course. NFAT2 further is involved in regulating cytoskeleton reorganization of immune cells. Here we investigated the role of NFAT2 with regard to susceptibility of CLL cells to perforin-induced lysis. <h3>Methods</h3> To investigate whether and how loss of NFAT2 affects ADCC in CLL, we generated a CRISPR/Cas9 based NFAT2 knockout (KO) in MEC-1 CLL cells. Cytotoxicity assays revealed profoundly higher resistance of NFAT2 KO CLL cells to NK cell killing compared to scrambled control (SCR) CLL cells, without affecting the level of recognition as revealed by analyses of NK cell activation, degranulation and IFNy release. <h3>Results</h3> Next, we investigated the role of NFAT2 in the Eμ-TCL1 mouse model for CLL by inducing a conditional B cell specific NFAT2 knockout. Using this model, we show that CLL cells of TCL1 NFAT2<sup>–/–</sup> mice are less susceptible to perforin lysis compared to that of TCL1 NFAT2<sup>+/+</sup> mice. When we classified CLL patients into NFAT2-low and NFAT2-high cases according to the NFAT2 transcript level, CLL cells of NFAT2-low patients showed higher resistance to perforin-mediated lysis and less perforin binding in the cell membrane, confirming our findings obtained with MEC-1 and murine CLL cells. Finally, inhibition of CDC42, a key regulator of actin cytoskeleton remodeling, with ZCL278 resensitized MEC-1 NFAT2 KO cells to perforin mediated lysis. Similar effects were observed with the tubulin cytoskeleton stabilizing agent Paclitaxel, indicating that cytoskeletal remodeling is crucial for perforin resistance. <h3>Conclusions</h3> Together, our results demonstrate that loss of NFAT2 allows CLL cells to evade NK cell effector function. This holds true for both, constitutive cytotoxicity and therapeutically induced ADCC and is due to lowered susceptibility to perforin-mediated membrane permeabilization, which can be overcome by inhibiting cytoskeletal rearrangement. Thus, NFAT2 loss facilitates resistance of CLL cells to immunotherapeutic treatment modalities. <h3>Ethics Approval</h3> The study was approved by the ethics committee at the Medical Faculty of the Eberhard Karls University and the University Hospital Tuebingen (reference number 13/2007V). Human material was collected after obtaining informed consent in accordance with the Helsinki protocol.
1423 Novel immunotherapy based on commensal-derived peptides to drive an effective CD8 T Cell response against selected tumor-associated antigens (TAAs)
2023-10-31

<h3>Background</h3> Efficacy demonstration of a unique peptide-based immunotherapy as potent approach for cancer treatment. This strategy relies on the activation of commensal-specific T cells which cross-react against peptides derived from Tumor-Associated Antigens (TAAps) found in various solid tumors, including glioblastoma, adrenocortical carcinoma and colorectal cancer. The same strategy is also used to target lineage-specific markers in hematologic cancers such as B cell malignancies. <h3>Methods</h3> The gut microbiota has the outstanding ability of regulating the human immune system through commensal antigens. Since specific microbiota peptides exhibit significant homology with particular TAAs, the full potential of cross-reactive CD8+ T cells that recognize both commensal peptides and poorly immunogenic tumor antigens can thus be harnessed against tumor cells. We identified a specific set of commensal derived peptides, referred to as OncoMimicsTM (OMP) peptides, which elicit cross-reactive cytotoxic CD8+ T cell responses against TAAps owing to their strong sequence homology. The capacity of these OMPs to induce TAAps-specific cross-reactive CD8+ T cell responses in humans is evaluated through peptide-MHC multimer staining and flow cytometry-based cytotoxic assays. <h3>Results</h3> Experiments conducted on human peripheral blood mononuclear cells (PBMCs) demonstrate that OMPs can be recognized by CD8 T cells in a significant proportion of healthy individuals. Upon <i>in vitro</i> stimulation, OMPs induce the expansion of CD8+ T cells that recognize homologous peptides derived from tumor antigen targets. Importantly, these T cells display cytotoxic capabilities against tumor cells presenting the corresponding TAAps on their surface. Further support for this approach comes from ongoing clinical trials, since we displayed that CD8+ T cells from indolent Non-Hodgkin Lymphoma (iNHL) patients treated with EO2463 immunotherapy (SIDNEY, EONHL1–20 phase 1/2 trial) are cytotoxic against TAA protein-expressing tumor cell lines.<sup>1</sup> <h3>Conclusions</h3> These data provide compelling evidence that OncoMimic peptides sharing a high degree of homology with TAAps can be utilized to generate an effective anti-tumor immune response. <h3>Reference</h3> https://www.enterome.com/clinical-trials/ <h3>Ethics Approval</h3> Buffy coats from healthy donors were provided from the Blood Bank (Etablissement français du sang (EFS)) of Rungis. This study was performed according to established ethical guidelines, and all blood donors gave informed consent. Patient cells are coming from the ongoing EONHL1–20 phase 1/2 trial.