bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic associations with polycystic ovary syndrome: the role of the mitochondrial genome; a systematic review and meta-analysis
Authors: Moosa Almira , Ghani Meeladah , O'Neill Helen Claire 
Published: September 2022

BackgroundPolycystic ovary syndrome (PCOS) remains the most common female reproductive endocrine disorder. Genetic studies have predominantly focused on the role of the nuclear genome, while the contribution of mitochondrial genetics in PCOS remains largely unknown.AimThis study aims to systematically evaluate the literature regarding the associations between the mitochondrial genome and PCOS.MethodsA literature search focused on PCOS and mitochondrial genetics was conducted on (1) MEDLINE, (2) EMBASE and (3) The Cochrane Library (CENTRAL and Cochrane Reviews). Search results were screened for eligibility, and data involving genetic variants of mitochondrial DNA (mtDNA) were extracted. Quantitative data were presented in forest plots, and where this was not possible, data were analysed in a qualitative manner. Quality of studies was assessed using the Q-Genie tool.ResultsOf the 13 812 identified studies, 15 studies were eligible for inclusion, with 8 studies suitable for meta-analysis. Women with PCOS showed higher frequencies of a 9 bp deletion, and aberrant single nucleotide polymorphisms (SNPs) in the ND5, A6 and 7 transfer RNA-encoding genes. They also showed lower frequencies of two SNPs in the D-loop of the genome. Women with PCOS also exhibited significantly lowered mtDNA copy number.ConclusionWomen with PCOS harbour genetic variants in coding and non-coding regions of the mitochondrial genome. This may disrupt the electron transport chain and lead to oxidative stress, causing apoptosis of cells and further genetic damage. However, further studies of higher quality are required to confirm these associations.PROSPERO registration numberCRD42021267991.
Psychotherapy and change in mental health-related work disability: a prospective Finnish population-level register-based study with a quasi-experimental design
Authors: Kausto Johanna , Gluschkoff Kia , Turunen Jarno , Selinheimo Sanna , Peutere Laura , Väänänen Ari 
Published: September 2022

BackgroundMental disorders are a major cause of work disability among the working-age population. Psychotherapy has shown to be an effective treatment for mental disorders, but the evidence is mainly based on small-scale randomised trials with relatively short follow-ups. We used population-based register data to examine the association between statutory rehabilitative psychotherapy and change in depression or anxiety-related work disability.MethodsWe drew a nationally representative sample of the working-age population (aged 18–55 in 2010). The study group comprised all those who started rehabilitative psychotherapy in 2011–2014. A total of 10 436 participants who were followed from 3 years prior to 4 years after the onset of rehabilitative psychotherapy. This resulted in 83 488 observations. The annual total number of mental health-related work disability months (0 to 12) was calculated from the total number of annual compensated sickness absence and disability pension days. A quasi-experimental interrupted time series analysis was applied.ResultsThe onset of rehabilitative psychotherapy marked a decline in work disability in comparison to the counterfactual trend. Specifically, a 20% decrease in the level (incidence rate ratio, IRR 0.80; 95% CI 0.76 to 0.85) and a 48% decrease in the slope (IRR 0.52; 95% CI 0.50 to 0.54) of work disability were detected in comparison to the counterfactual scenario. No significant gender differences were observed. The decline in work disability was the steepest in the oldest age group.ConclusionsThis study suggests that statutory psychotherapy may decrease work disability at the population level. However, further evidence of causal inference and the potential heterogeneity of the association is required.
Personalized neoantigen vaccine combined with PD-1 blockade increases CD8+tissue-resident memory T-cell infiltration in preclinical hepatocellular carcinoma models
Authors: Chen Hengkai , Li Zhenli , Qiu Liman , Dong Xiuqing , Chen Geng , Shi Yingjun , Cai Linsheng , Liu Wenhan , Ye Honghao , Zhou Yang , Ouyang Jiahe , Cai Zhixiong , Liu Xiaolong 
Published: September 2022

BackgroundPersonalized neoantigen vaccine could induce a robust antitumor immune response in multiple cancers, whose efficacy could be further enhanced by combining with programmed cell death 1 blockade (α-PD-1). However, the corresponding immune response and synergistic mechanisms remain largely unclear. Here, we aimed to develop clinically available combinational therapeutic strategy and further explore its potential antitumor mechanisms in hepatocellular carcinoma (HCC).MethodsNeoantigen peptide vaccine (NeoVAC) for murine HCC cell line Hepa1-6 was developed and optimized by neoantigen screening and adjuvant optimization. Then the synergistic efficacy and related molecular mechanisms of NeoVAC combined with α-PD-1 in HCC were evaluated by orthotopic HCC mouse model, single-cell RNA sequencing, tetramer flow cytometry, immunofluorescence, etc. The tumor-killing capacity of CD8+tissue-resident memory T cells (CD8+TRMs) was assessed by orthotopic HCC mouse model, and autologous patient-derived cells.ResultsNeoVAC, which consisted of seven high immunogenic neoantigen peptides and clinical-grade Poly(I:C), could generate a strong antitumor immune response in HCC mouse models. Significantly, its efficacy could be further improved by combining with α-PD-1, with 80% of durable tumor regression and long-term immune memory in orthotopic HCC models. Moreover, in-depth analysis of the tumor immune microenvironment showed that the percentage of CD8+TRMswas remarkedly increased in NeoVAC plus α-PD-1 treatment group, and positively associated with the antitumor efficacy. In vitro and in vivo T-cell cytotoxicity assay further confirmed the strong tumor-killing capacity of CD8+TRMssorting from orthotopic mouse HCC or patient’s HCC tissue.ConclusionsThis study showed that NeoVAC plus α-PD-1 could induce a strong antitumor response and long-term tumor-specific immune memory in HCC by increasing CD8+TRMsinfiltration, which might serve as a potential immune-therapeutic target for HCC.
Intratumoral administration of CD1c (BDCA-1)+and CD141 (BDCA-3)+myeloid dendritic cells in combination with talimogene laherparepvec in immune checkpoint blockade refractory advanced melanoma patients: a phase I clinical trial
Authors: Schwarze Julia Katharina , Tijtgat Jens , Awada Gil , Cras Louise , Vasaturo Angela , Bagnall Christopher , Forsyth Ramses , Dufait Inès , Tuyaerts Sandra , Van Riet Ivan , Neyns Bart 
Published: September 2022

BackgroundIntratumoral (IT) myeloid dendritic cells (myDCs) play a pivotal role in initiating antitumor immune responses and relicensing of anti-tumor cytotoxic T lymphocytes within the tumor microenvironment. Talimogene laherparepvec (T-VEC) induces immunogenic cell death, thereby providing maturation signals and enhancing the release of tumor antigens that can be captured and processed by CD1c (BDCA-1)+/ CD141 (BDCA-3)+myDCs, in order to reinvigorate the cancer-immunity cycle.MethodsIn this phase I trial, patients with advanced melanoma who failed standard therapy were eligible for IT injections of ≥1 non-visceral metastases with T-VEC on day 1 followed by IT injection of CD1c (BDCA-1)+myDCs +/- CD141 (BDCA-3)+myDCs on day 2. T-VEC injections were repeated on day 21 and every 14 days thereafter. The number of IT administered CD1c (BDCA-1)+myDCs was escalated from 0.5×106, to 1×106, to a maximum of 10×106cells in three sequential cohorts. In cohort 4, all isolated CD1c (BDCA-1)+/ CD141 (BDCA-3)+myDCs were used for IT injection. Primary objectives were safety and feasibility. Repetitive biopsies of treated lesions were performed.ResultsIn total, 13 patients were enrolled (cohort 1 n=2; cohort 2 n=2; cohort 3 n=3; cohort 4 n=6). Patients received a median of 6 (range 3–8) T-VEC injections. The treatment was safe with most frequent adverse events being fatigue (n=11 (85%)), fever (n=8 (62%)), and chills/influenza-like symptoms (n=6 (46%)). Nine (69%) and four patients (31%), respectively, experienced pain or redness at the injection-site. Clinical responses were documented in injected and non-injected lesions. Two patients (cohort 3) who previously progressed on anti-PD-1 therapy (and one patient also on anti-CTLA-4 therapy) developed a durable, pathologically confirmed complete response that is ongoing at 33 and 35 months following initiation of study treatment. One additional patient treated (cohort 4) had an unconfirmed partial response as best response; two additional patients had a mixed response (with durable complete responses of some injected and non-injected lesions). On-treatment biopsies revealed a strong infiltration by inflammatory cells in regressing lesions.ConclusionsIT coinjection of autologous CD1c (BDCA-1)++/- CD141 (BDCA-3)+myDCs with T-VEC is feasible, tolerable and resulted in encouraging early signs of antitumor activity in immune checkpoint inhibitor-refractory melanoma patients.Trial registration numberNCT03747744.
Oral beclomethasone dipropionate is an effective treatment for immune checkpoint inhibitor induced colitis
Authors: Alexander James L , Ibraheim Hajir , Richards Camellia , Shum Ben , Pavlidis Polychronis , Hunter Nikki , Teare Julian P , Wotherspoon Andrew , Furness Andrew , Turajlic Samra , Pickering Lisa , Larkin James , Speight Ally , Papa Sophie , Powell Nick 
Published: September 2022

IntroductionSystemic corticosteroids are the mainstay of treatment for immune checkpoint inhibitor induced (CPI) colitis but are associated with complications including life-threatening infection. The topically acting oral corticosteroid beclomethasone dipropionate (BD) is an effective treatment for mild to moderate flares of ulcerative colitis, and has fewer side effects than systemic corticosteroids. We hypothesized that BD would be an effective treatment for CPI-induced colitis.MethodsWe performed a retrospective analysis of all patients who started BD for CPI-induced colitis at three UK cancer centers between November 2017 and October 2020. All patients underwent endoscopic assessment and biopsy. The initial regimen of BD was 5 mg once daily for 28 days. Data were collected from electronic patient records. Clinical outcomes were assessed at 28 days after initiation of treatment.ResultsTwenty-two patients (14 male) with a median age of 64 (range 45–84) with CPI-induced colitis were treated with BD. At baseline, the median number of loose stools in a 24-hour period was six (common terminology criteria for adverse events, CTCAE grade diarrhea=2). Thirteen patients (59%) were dependent on systemic corticosteroids prior to starting BD. Baseline sigmoidoscopy showed moderate inflammation (Mayo Endoscopic Score (MES) = 2) in two patients (9%), mild inflammation (MES=1) in nine patients (41%) and normal findings (MES=0) in eleven patients (50%). Twenty patients (91%) had histopathological features of inflammation. All 22 patients (100%) had a clinical response to BD and 21 (95%) achieved clinical remission with a return to baseline stool frequency (CTCAE diarrhea=0). Ten patients (45%) had symptomatic relapse on cessation of BD, half within 7 days of stopping. All patients recaptured response on restarting BD. No adverse events were reported in patients treated with BD.ConclusionsTopical BD represents an appealing alternative option to systemic immunosuppressive treatments to treat colonic inflammation. In this study, BD was effective and safe at inducing remission in CPI-induced colitis, which was refractory to systemic corticosteroids. Further randomized studies are needed to confirm these findings and determine the optimum dosing regimen.
Comprehensive RNA and protein functional assessments contribute to the clinical interpretation ofMSH2variants causing in-frame splicing alterations
Authors: Meulemans Laëtitia , Baert Desurmont Stéphanie , Waill Marie-Christine , Castelain Gaia , Killian Audrey , Hauchard Julie , Frebourg Thierry , Coulet Florence , Martins Alexandra , Muleris Martine , Gaildrat Pascaline 
Published: September 2022

BackgroundSpliceogenic variants in disease-causing genes are often presumed pathogenic since most induce frameshifts resulting in loss of function. However, it was recently shown in cancer predisposition genes that some may trigger in-frame anomalies that preserve function. Here, we addressed this question by usingMSH2, a DNA mismatch repair gene implicated in Lynch syndrome, as a model system.MethodsEighteenMSH2variants, mostly localised within canonical splice sites, were analysed by using minigene splicing assays. The impact of the resulting protein alterations was assessed in a methylation tolerance-based assay. Clinicopathological characteristics of variant carriers were collected.ResultsThree in-frame RNA biotypes were identified based on variant-induced spliceogenic outcomes: exon skipping (E3, E4, E5 and E12), segmental exonic deletions (E7 and E15) and intronic retentions (I3, I6, I12 and I13). The 10 corresponding protein isoforms exhibit either large deletions (49–93 amino acids (aa)), small deletions (12 or 16 aa) or insertions (3–10 aa) within different functional domains. We showed that all these modifications abrogate MSH2 function, in agreement with the clinicopathological features of variant carriers.ConclusionAltogether, these data demonstrate that MSH2 function is intolerant to in-frame indels caused by the spliceogenic variants analysed in this study, supporting their pathogenic nature. This work stresses the importance of combining complementary RNA and protein approaches to ensure accurate clinical interpretation of in-frame spliceogenic variants.
Identification of variants in genes associated with autoinflammatory disorders in a cohort of patients with psoriatic arthritis
Authors: Atschekzei Faranaz , Dubrowinskaja Natalia , Anim Manfred , Thiele Thea , Witte Torsten , Sogkas Georgios 
Published: September 2022

ObjectivesBesides adaptive immunity genes, genetic risk factors for psoriatic arthritis (PsA) include innate immunity loci, which suggests an autoinflammatory disease mechanism, at least in a subset of patients. Here, we aimed at investigating the autoinflammatory genetic background of PsA.MethodsA total of 120 patients with PsA visiting the outpatient clinics of the Hannover University hospital underwent targeted next-generation sequencing, searching for variations in genes linked with inborn errors of immunity classified as autoinflammatory disorders (AIDs). Deleteriousness of rare variants was evaluated through in silico analysis.ResultsWe found 45 rare predicted deleterious variants in 37 out of 120 (30.8%) patients with PsA. Relatively common were variants in AP1S3, PLCG2, NOD2 and NLRP12. All 45 variants were monoallelic and 25 of them, identified in 20 out of 120 (16.7%) patients, were localised in genes associated with autosomal dominant (AD) disorders. Detection of those variants is associated with pustular psoriasis or a coexisting inflammatory bowel disease (IBD).ConclusionsApproximately 30% of patients with PsA harboured at least one variant in a gene associated with an AID, suggesting an autoinflammatory disease mechanism. Detection of variants in genes linked to AD-AIDs may explain extra-articular manifestations of PsA, such as pustular psoriasis and IBD.
The seismic network of Ischia island from 1993 to 2021
Authors: Tramelli Anna , Orazi Massimo , Nardone Lucia , Bobbio Antonella , Benincasa Aldo , Buonocunto Ciro , Capello Marco , Caputo Antonio , Castellano Mario , D'Auria Luca , De Cesare Walter , Di Filippo Alessandro , Galluzzo Danilo , Gaudiosi Guido , Giudicepietro Flora , Liguoro Francesco , Lo Bascio Domenico , Martini Marcello , Martino Claudio , Peluso Rosario , Ricciolino Patrizia , Scarpato Giovanni , Torello Vincenzo , Bianco Francesca 
Published: September 2022

Abstract

The volcanic island of Ischia has shown to have an important seismogenic potential, being the location of several destructive earthquakes, e.g. 1881, 1883 and 2017. The damage caused by these earthquakes was more connected to the proximity of the source to the surface than to their magnitude (M
w
< 5.2). The need to monitor and model this seismicity required the installation of a dense and modern seismic network. The first modern seismic station on the island was installed in 1993, and the network was successively increased with time. A meaningful improvement to the network was made after the earthquake that occurred on the 21 of August 2017. The network currently has 11 sites with velocimeters and some of them with accelerometers installed too. We analysed the seismic network configuration in comparison with the seismicity that characterizes the area to mark a starting point for future seismological analysis. The network is currently able to locate shallow earthquakes with duration magnitude greater or equal to 0 in the whole island.
A Preclinical and Phase Ib Study of Palbociclib plus Nab-Paclitaxel in Patients with Metastatic Adenocarcinoma of the Pancreas
Authors: Hidalgo Manuel , Garcia-Carbonero Rocio , Lim Kian-Huat , Messersmith Wells A. , Garrido-Laguna Ignacio , Borazanci Erkut , Lowy Andrew M. , Medina Rodriguez Laura , Laheru Daniel , Salvador-Barbero Beatriz , Malumbres Marcos , Shields David J. , Grossman Joseph E. , Huang Xin , Tammaro Meggan , Martini Jean-François , Yu Yanke , Kern Kenneth , Macarulla Teresa 
Published: September 2022

Purpose:To assess the preclinical efficacy, clinical safety and efficacy, and MTD of palbociclib plus nab-paclitaxel in patients with advanced pancreatic ductal adenocarcinoma (PDAC).Experimental Design:Preclinical activity was tested in patient-derived xenograft (PDX) models of PDAC. In the open-label, phase I clinical study, the dose-escalation cohort received oral palbociclib initially at 75 mg/day (range, 50‒125 mg/day; modified 3+3 design; 3/1 schedule); intravenous nab-paclitaxel was administered weekly for 3 weeks/28-day cycle at 100‒125 mg/m2. The modified dose–regimen cohorts received palbociclib 75 mg/day (3/1 schedule or continuously) plus nab-paclitaxel (biweekly 125 or 100 mg/m2, respectively). The prespecified efficacy threshold was 12-month survival probability of ≥65% at the MTD.Results:Palbociclib plus nab-paclitaxel was more effective than gemcitabine plus nab-paclitaxel in three of four PDX models tested; the combination was not inferior to paclitaxel plus gemcitabine. In the clinical trial, 76 patients (80% received prior treatment for advanced disease) were enrolled. Four dose-limiting toxicities were observed [mucositis (n = 1), neutropenia (n = 2), febrile neutropenia (n = 1)]. The MTD was palbociclib 100 mg for 21 of every 28 days and nab-paclitaxel 125 mg/m2 weekly for 3 weeks in a 28-day cycle. Among all patients, the most common all-causality any-grade adverse events were neutropenia (76.3%), asthenia/fatigue (52.6%), nausea (42.1%), and anemia (40.8%). At the MTD (n = 27), the 12-month survival probability was 50% (95% confidence interval, 29.9–67.2).Conclusions:This study showed the tolerability and antitumor activity of palbociclib plus nab-paclitaxel treatment in patients with PDAC; however, the prespecified efficacy threshold was not met.Trial Registration:Pfizer Inc (NCT02501902)Significance:In this article, the combination of palbociclib, a CDK4/6 inhibitor, and nab-paclitaxel in advanced pancreatic cancer evaluates an important drug combination using translational science. In addition, the work presented combines preclinical and clinical data along with pharmacokinetic and pharmacodynamic assessments to find alternative treatments for this patient population.
Toward Network Intelligence
Authors: Pentland Alex 
Published: September 2022

AbstractThis article proposes a conceptual framework to guide research in neural computation by relating it to mathematical progress in other fields and to examples illustrative of biological networks. The goal is to provide insight into how biological networks, and possibly large artificial networks such as foundation models, transition from analog computation to an analog approximation of symbolic computation. From the mathematical perspective, I focus on the development of consistent symbolic representations and optimal policies for action selection within network settings. From the biological perspective, I give examples of human and animal social network behavior that may be described using these mathematical models.
Capacity Limitations of Visual Search in Deep Convolutional Neural Networks
Authors: Põder Endel 
Published: September 2022

Abstract
Deep convolutional neural networks (CNN) follow roughly the architecture of biological visual systems and have shown a performance comparable to human observers in object classification tasks. In this study, three deep neural networks pretrained for image classification were tested in visual search for simple features and for feature configurations. The results reveal a qualitative difference from human performance. It appears that there is no clear difference between searches for simple features that pop out in experiments with humans and for feature configurations that exhibit strict capacity limitations in human vision. Both types of stimuli reveal comparable capacity limitations in the neural networks tested here.
Rwandan Perceptions of Jews, Judaism, and Israel
Authors: Beloff Jonathan R. 
Published: September 2022

Abstract
Religious studies of Rwanda typically focus on Christi26662531anity’s involvement before, during, and after the 1994 Genocide against the Tutsi, also referred to as the Rwandan Genocide. Rwanda’s postgenocide reconstruction has witnessed new and changing political and social commitments by previously established religious organisations such as the Roman Catholic, Protestant, and Adventist Churches. The Rwandan government has taken a more progressive stance on divisions of power and religious institutions, and the promotion of religious freedoms that has benefitted the domestic Muslim population. This essay examines how Judaism, a previously unknown religion in the region, is impacting Rwandan identity formation. Jewish identity is increasingly being tied to the nation’s own reconstructed identity, with a strong focus on historical persecution, rebuilding after genocide, and development. This essay suggests that Rwandan identity and religious studies should include the ever-growing ties with Jews and Israel to better understand its political and social reconstruction since 1994.
‘Wash and Pray’
Authors: Muyambo Tenson , Sande Nomatter , Tendere Jane 
Published: September 2022

Abstract
‘Continue to wash your hands, continue to wear your mask, continue to sanitize, continue to maintain social distance, and lastly continue to pray’. These were the closing remarks of a pastor who was preaching online to his congregants in the context of the second and third waves of COVID-19 variants. This article focuses on the church’s utilisation (or lack) of both religion and science under the ‘wash’ and ‘pray’ theology. The article raises this fundamental question: to what extent is the church embracing scientific knowledge in its efforts to deal with COVID-19? Data was collected through an online questionnaire survey, review of available literature, listening to clerics on YouTube, follow-up WhatsApp interviews, as well as overt and covert observations. The article argues that religion and science differ on a number of issues but in the context of COVID-19 and as indicated by this study, they must learn from each other and pool resources to combat COVID-19. COVID-19 calls for undivided attention, and when religion and science unify humanity vastly benefit. The article adds to the continuous debate on the relationship between science (wash) and religion (pray), arguing for the significance of religious ideas that make science effective in addressing the pandemic and vice versa.