bluuebunny/crossref_metadata_2025_split huggingface dataset:
Albendazole induces immunotherapy response by facilitating ubiquitin-mediated PD-L1 degradation
Authors: Zhu Lin , Kuang Xinwei , Zhang Guanxiong , Liang Long , Liu Dandan , Hu Bin , Xie Zuozhong , Li Hui , Liu Hong , Ye Mao , Chen Xiang , Liu Jing 
Published: May 2022

BackgroundImmune checkpoint inhibitors (ICIs) have been increasingly used in patients with various cancers and have shown efficient therapeutic outcomes. However, fewer than 40% of cases across multiple cancer types show a response to ICIs. Therefore, developing more efficient combinational approaches with ICIs and revealing the underlying mechanisms are important goals for achieving rapid clinical transformation and application.MethodsThe effects on antitumor immunity activity of albendazole (ABZ) and the synergistic effects of ABZ with CD73 blockade were investigated in the melanoma B16F10 and the Lewis lung cancer tumor-bearing immune-competent mice models. The mechanism of ABZ reducing PD-L1 protein level through suppressing UBQLN4 was identified and validated through immunoprecipitation-mass spectrometry and molecular methods. Bioinformatics and anti-PD-1 therapy melanoma patients samples analysis were used to assess the level of UBQLN4/PD-L1 in the therapeutic efficacy of anti-PD-1 therapy.ResultsABZ induces CD8+T cell activity and subsequent immunotherapy response associated with suppression of PD-L1 protein level. Mechanistically, we revealed that ABZ promotes ubiquitin-mediated degradation of PD-L1 via suppressing UBQLN4, which was bound to PD-L1 and stabilized PD-L1 protein. Preclinically, genetic deletion or target inhibition of CD73 showed synergistic effects with ABZ treatment in the immune-competent mice models. Significantly, UBQLN4 and PD-L1 levels were higher in the tumor region of responders versus non-responders and correlated with better progression-free survival and overall survival in anti-PD-1 therapy melanoma patients.ConclusionsOur findings revealed a previously unappreciated role of ABZ in antitumor immunity by inducing ubiquitin-mediated PD-L1 protein degradation, identified predictors for assessing the therapeutic efficacy of anti-PD-1 therapy, and provided novel therapeutic possibility by combination treatment of ABZ and CD73 blockade in cancers.
Salt-inducible kinase 3 protects tumor cells from cytotoxic T-cell attack by promoting TNF-induced NF-κB activation
Authors: Sorrentino Antonio , Menevse Ayse Nur , Michels Tillmann , Volpin Valentina , Durst Franziska Christine , Sax Julian , Xydia Maria , Hussein Abir , Stamova Slava , Spoerl Steffen , Heuschneider Nicole , Muehlbauer Jasmin , Jeltsch Katharina Marlene , Rathinasamy Anchana , Werner-Klein Melanie , Breinig Marco , Mikietyn Damian , Kohler Christian , Poschke Isabel , Purr Sabrina , Reidell Olivia , Martins Freire Catarina , Offringa Rienk , Gebhard Claudia , Spang Rainer , Rehli Michael , Boutros Michael , Schmidl Christian , Khandelwal Nisit , Beckhove Philipp 
Published: May 2022

BackgroundCancer immunotherapeutic strategies showed unprecedented results in the clinic. However, many patients do not respond to immuno-oncological treatments due to the occurrence of a plethora of immunological obstacles, including tumor intrinsic mechanisms of resistance to cytotoxic T-cell (TC) attack. Thus, a deeper understanding of these mechanisms is needed to develop successful immunotherapies.MethodsTo identify novel genes that protect tumor cells from effective TC-mediated cytotoxicity, we performed a genetic screening in pancreatic cancer cells challenged with tumor-infiltrating lymphocytes and antigen-specific TCs.ResultsThe screening revealed 108 potential genes that protected tumor cells from TC attack. Among them, salt-inducible kinase 3 (SIK3) was one of the strongest hits identified in the screening. Both genetic and pharmacological inhibitions of SIK3 in tumor cells dramatically increased TC-mediated cytotoxicity in several in vitro coculture models, using different sources of tumor and TCs. Consistently, adoptive TC transfer of TILs led to tumor growth inhibition of SIK3-depleted cancer cells in vivo. Mechanistic analysis revealed that SIK3 rendered tumor cells susceptible to tumor necrosis factor (TNF) secreted by tumor-activated TCs. SIK3 promoted nuclear factor kappa B (NF-κB)nuclear translocation and inhibited caspase-8 and caspase-9 after TNF stimulation. Chromatin accessibility and transcriptome analyses showed that SIK3 knockdown profoundly impaired the expression of prosurvival genes under the TNF–NF-κBaxis. TNF stimulation led to SIK3-dependent phosphorylation of the NF-κB upstream regulators inhibitory-κB kinase and NF-kappa-B inhibitor alpha on the one side, and to inhibition of histone deacetylase 4 on the other side, thus sustaining NF-κB activation and nuclear stabilization. A SIK3-dependent gene signature of TNF-mediated NF-κB activation was found in a majority of pancreatic cancers where it correlated with increased cytotoxic TC activity and poor prognosis.ConclusionOur data reveal an abundant molecular mechanism that protects tumor cells from cytotoxic TC attack and demonstrate that pharmacological inhibition of this pathway is feasible.
Immune cell infiltration pattern in non-small cell lung cancer PDX models is a model immanent feature and correlates with a distinct molecular and phenotypic make-up
Authors: Oswald Eva , Bug Daniel , Grote Anne , Lashuk Kanstantsin , Bouteldja Nassim , Lenhard Dorothee , Löhr Anne , Behnke Anke , Knauff Volker , Edinger Anna , Klingner Kerstin , Gaedicke Simone , Niedermann Gabriele , Merhof Dorit , Feuerhake Friedrich , Schueler Julia 
Published: May 2022

BackgroundThe field of cancer immunology is rapidly moving towards innovative therapeutic strategies, resulting in the need for robust and predictive preclinical platforms reflecting the immunological response to cancer. Well characterized preclinical models are essential for the development of predictive biomarkers in the oncology as well as the immune-oncology space. In the current study, gold standard preclinical models are being refined and combined with novel image analysis tools to meet those requirements.MethodsA panel of 14 non-small cell lung cancer patient-derived xenograft models (NSCLC PDX) was propagated in humanized NOD/Shi-scid/IL-2Rnull mice. The models were comprehensively characterized for relevant phenotypic and molecular features, including flow cytometry, immunohistochemistry, histology, whole exome sequencing and cytokine secretion.ResultsModels reflecting hot (>5% tumor-infiltrating lymphocytes/TILs) as opposed to cold tumors (<5% TILs) significantly differed regarding their cytokine profiles, molecular genetic aberrations, stroma content, and programmed cell death ligand-1 status. Treatment experiments including anti cytotoxic T-lymphocyte-associated protein 4, anti-programmed cell death 1 or the combination thereof across all 14 models in the single mouse trial format showed distinctive tumor growth response and spatial immune cell patterns as monitored by computerized analysis of digitized whole-slide images. Image analysis provided for the first time qualitative evaluation of the extent to which PDX models retain the histological features from their original human donors.ConclusionsDeep phenotyping of PDX models in a humanized setting by combinations of computational pathology, immunohistochemistry, flow cytometry and proteomics enables the exhaustive analysis of innovative preclinical models and paves the way towards the development of translational biomarkers for immuno-oncology drugs.
Tissue-resident memory T cells from a metastatic vaginal melanoma patient are tumor-responsive T cells and increase after anti-PD-1 treatment
Authors: Pizzolla Angela , Keam Simon Paul , Vergara Ismael A , Caramia Franco , Thio Niko , Wang Minyu , Kocovski Nikolce , Tantalo Daniela , Jabbari Jafar , Au-Yeung George , Sandhu Shahneen , Gyorki David E , Weppler Alison , Perdicchio Maurizio , McArthur Grant A , Papenfuss Anthony T , Neeson Paul Joseph 
Published: May 2022

BackgroundVaginal melanoma (VM) is a rare cancer and has a poor response to immune checkpoint blockade (ICB). CD8+Tissue Resident Memory (TRM) T cells proliferate in response to ICB and correlate with longer survival in metastatic cutaneous melanoma. However, their capacity to respond to VM and their neoantigens is not known.MethodsUsing longitudinal samples, we explored the evolution of VM mutations by whole-exome sequencing and RNAseq, we also defined the immune context using multiplex immunohistochemistry and nanostring pan cancer immune profile. Then using fresh single cell suspensions of the metastatic samples, we explored VM T cells via mass cytometry and single cell RNAseq and T cell receptor sequencing (TCRseq). Finally, we investigated TRM, pre-TRM and exhausted T cell function against melanoma neo-antigens and melanoma differentiation antigens in vitro.ResultsPrimary VM was non-inflamed and devoid of CD8+TRM cells. In contrast, both metastases showed proliferating CD8+TRM were clustered at the tumor margin, with increased numbers in the second ICB-refractory metastasis. The first metastasis showed dense infiltration of CD8+T cells, the second showed immune exclusion with loss of melanoma cell Major histocompatibility complex (MHC)-I expression associated with downregulation of antigen presentation pathway gene expression. CD8+TRM from both metastases responded to autologous melanoma cells more robustly than all other CD8+T cell subsets. In addition, CD8+TRM shared TCR clones across metastases, suggesting a response to common antigens, which was supported by recognition of the same neoantigen by expanded tumor infiltrating lymphocytes.ConclusionsIn this study, we identified TRM clusters in VM metastases from a patient, but not primary disease. We showed TRM location at the tumor margin, and their superior functional response to autologous tumor cells, predicted neoantigens and melanoma differentiation antigens. These CD8+TRM exhibited the highest tumor-responsive potential and shared their TCR with tumor-infiltrating effector memory T cells. This suggests VM metastases from this patient retain strong antitumor T cell functional responses; however, this response is suppressed in vivo. The loss of VG MHC-I expression is a common immune escape mechanism which was not addressed by anti-PD-1 monotherapy; rather an additional targeted approach to upregulate MHC-I expression is required.
Can brain signals and anatomy refine contact choice for deep brain stimulation in Parkinson’s disease?
Authors: Xu San San , Lee Wee-Lih , Perera Thushara , Sinclair Nicholas C , Bulluss Kristian J , McDermott Hugh J , Thevathasan Wesley 
Published: May 2022

IntroductionSelecting the ideal contact to apply subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease is time-consuming and reliant on clinical expertise. The aim of this cohort study was to assess whether neuronal signals (beta oscillations and evoked resonant neural activity (ERNA)), and the anatomical location of electrodes, can predict the contacts selected by long-term, expert-clinician programming of STN-DBS.MethodsWe evaluated 92 hemispheres of 47 patients with Parkinson’s disease receiving chronic monopolar and bipolar STN-DBS. At each contact, beta oscillations and ERNA were recorded intraoperatively, and anatomical locations were assessed. How these factors, alone and in combination, predicted the contacts clinically selected for chronic deep brain stimulation at 6 months postoperatively was evaluated using a simple-ranking method and machine learning algorithms.ResultsThe probability that each factor individually predicted the clinician-chosen contact was as follows: ERNA 80%, anatomy 67%, beta oscillations 50%. ERNA performed significantly better than anatomy and beta oscillations. Combining neuronal signal and anatomical data did not improve predictive performance.ConclusionThis work supports the development of probability-based algorithms using neuronal signals and anatomical data to assist programming of deep brain stimulation.
Increasing incidence and prevalence of multiple sclerosis in the Greater Hobart cohort of Tasmania, Australia
Authors: Simpson-Yap Steve , Atvars Roberts , Blizzard Leigh , van der Mei Ingrid , Taylor Bruce V 
Published: May 2022

BackgroundThe Greater Hobart region (42.5°S) of Tasmania has consistently had the highest recorded prevalence and incidence rates of multiple sclerosis (MS) in Australia. We reassessed MS epidemiology in 2009–2019 and assessed longitudinal changes over 68 years.MethodsCases recruited from clinic-based datasets and multiple other data sources. 2019 prevalence and 2009–2019 annual incidence and mortality rates estimated, and differences assessed using Poisson regression.Results436 MS cases resident on prevalence day were identified, and 130 had symptom onset within 2009–2019. Prevalence 197.1/100 000 (95% CI 179.4 to 216.5; 147.2/100 000 age standardised, 95% CI 126.5 to 171.3), a 36% increase since 2001 and 3.1-fold increase since 1961. 2009–2019 incidence rate=5.9/100 000 person-years, 95% CI 5.0 to 7.0 (6.1/1000 000 age standardised, 95% CI 4.7 to 7.9), a 2.8-fold increase since 1951–1961 and 65% since 2001–2009. 2009–2019 mortality rate=1.5/100 000 person-years, 95% CI 1.1 to 2.2 (0.9/100 000 age standardised, 95% CI 0.4 to 1.7), comparable to 2001–2009 (1.0/100 000) but reduced by 61% from 1951 to 1959 (2.1/100 000). 2001–2009 standardised mortality ratio=1.0 in 2009–2019, decreased from 2.0 in 1971–1979. Female:male prevalence sex ratio was 2.8, comparable to the 2009 value (2.6); incidence sex ratio (2.9) increased from 2001 to 9 (2.1). Comparisons with Newcastle, Australia (latitude=32.5°S) demonstrate a near complete abrogation of the latitudinal gradients for prevalence (ratio=1.0) and incidence (ratio=1.1), largely attributable to changing Hobart demography.ConclusionsPrevalence and incidence of MS continue to increase significantly in Hobart, alongside marked reductions in mortality and increased case longevity. The marked increase in incidence is of particular note and may reflect longstanding changes in MS risk behaviours including changing sun exposure, obesity rates, and smoking behaviours, particularly in females. Falling mortality contributes to increase longevity and prevalence, likely reflecting improved overall MS healthcare and implementation of disease-modifying therapy.
Effect of sodium phenylbutyrate/taurursodiol on tracheostomy/ventilation-free survival and hospitalisation in amyotrophic lateral sclerosis: long-term results from the CENTAUR trial
Authors: Paganoni Sabrina , Hendrix Suzanne , Dickson Samuel P , Knowlton Newman , Berry James D , Elliott Michael A , Maiser Samuel , Karam Chafic , Caress James B , Owegi Margaret Ayo , Quick Adam , Wymer James , Goutman Stephen A , Heitzman Daragh , Heiman-Patterson Terry D , Jackson Carlayne , Quinn Colin , Rothstein Jeffrey D , Kasarskis Edward J , Katz Jonathan , Jenkins Liberty , Ladha Shafeeq S , Miller Timothy M , Scelsa Stephen N , Vu Tuan H , Fournier Christina , Johnson Kristin M , Swenson Andrea , Goyal Namita , Pattee Gary L , Babu Suma , Chase Marianne , Dagostino Derek , Hall Meghan , Kittle Gale , Eydinov Mathew , Ostrow Joseph , Pothier Lindsay , Randall Rebecca , Shefner Jeremy M , Sherman Alexander V , Tustison Eric , Vigneswaran Prasha , Yu Hong , Cohen Joshua , Klee Justin , Tanzi Rudolph , Gilbert Walter , Yeramian Patrick , Cudkowicz Merit 
Published: May 2022

BackgroundCoformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS).ObjectiveDetermine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial.MethodsAdults with El Escorial Definite ALS ≤18 months from symptom onset were randomised to PB/ TURSO or placebo for 6 months. Those completing randomised treatment could enrol in an open-label extension (OLE) phase and receive PB/TURSO for ≤30 months. Times to the following individual or combined key events were compared in the originally randomised treatment groups over a period spanning trial start through July 2020 (longest postrandomisation follow-up, 35 months): death, tracheostomy, permanent assisted ventilation (PAV) and first hospitalisation.ResultsRisk of any key event was 47% lower in those originally randomised to PB/TURSO (n=87) versus placebo (n=48, 71% of whom received delayed-start PB/TURSO in the OLE phase) (HR=0.53; 95% CI 0.35 to 0.81; p=0.003). Risks of death or tracheostomy/PAV (HR=0.51; 95% CI 0.32 to 0.84; p=0.007) and first hospitalisation (HR=0.56; 95% CI 0.34 to 0.95; p=0.03) were also decreased in those originally randomised to PB/TURSO.ConclusionsEarly PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS.Trial registration numberNCT03127514;NCT03488524.
Primary care physician leaders’ perspectives on opportunities and challenges in healthcare leadership: a qualitative study
Authors: Stephenson Amber L , Sullivan Erin E , Hoffman Aaron R 
Published: May 2022

BackgroundThere is an increasing demand for physicians to assume leadership roles in hospitals, health systems, clinics and community settings, given the documented positive outcomes of physician leadership and the systemic shifts towards value-based care. The purpose of this study is to examine how primary care physicians (PCPs) perceive and experience leadership roles. Better understanding how PCPs perceive leadership affords the opportunity to influence changes in primary care training in order to more adequately prepare and support physicians for current and future leadership roles.MethodsThis study used qualitative interviews, conducted from January to May 2020. The participants included 27 PCPs, recruited via the Harvard Medical School Center for Primary Care newsletters and through snowball sampling techniques. Participants worked in 22 different organisations, including major urban health systems, corporate pharmacy, public health departments and academic medical centres.ResultsUsing content analysis and qualitative comparative analysis methodologies, three major themes and seven subthemes emerged from the interviews. The primary themes included the advantage PCPs have in leadership positions, the lack of leadership training and development, and disincentives to leading.ConclusionsWhile PCPs perceive primary care to hold a unique position that would incline them towards leadership, the lack of training and other noted disincentives are barriers to leadership. Therefore, health organisations should seek to invest in, better train and promote PCPs in leadership.
‘Climate change mitigation is a hot topic, but not when it comes to hospitals’: a qualitative study on hospital stakeholders’ perception and sense of responsibility for greenhouse gas emissions
Authors: Quitmann Claudia , Sauerborn Rainer , Danquah Ina , Herrmann Alina 
Published: May 2022

ObjectivePhysical and mental well-being are threatened by climate change. Since hospitals in high-income countries contribute significantly to climate change through their greenhouse gas (GHG) emissions, the medical ethics imperative of ‘do no harm’ imposes a responsibility on hospitals to decarbonise. We investigated hospital stakeholders’ perceptions of hospitals’ GHG emissions sources and the sense of responsibility for reducing GHG emissions in a hospital.MethodsWe conducted 29 semistructured qualitative expert interviews at one of Germany’s largest hospitals, Heidelberg University Hospital. Five patients, 12 clinical and 12 administrative employees on different levels were selected using purposive maximum variation sampling. Interviews were transcribed verbatim and analysed using the framework approach.ResultsConcerning GHG emissions, hospital stakeholders perceived energy and waste as most relevant emission sources followed by mobility. Climate change mitigation in general was considered as important. However, in their role as patients or employees, hospital stakeholders felt less responsible for climate change mitigation. They saw providing best possible medical care to be the top priority in hospitals and were often concerned that patients’ health could be jeopardised by climate change mitigation measures.ConclusionPerceptions of most important emission sources did not coincide with those in literature, highlighting the need to inform stakeholders, for instance, about pharmaceuticals as important emission source. A frequently perceived conflict between reducing emissions and providing high-quality medical care could be eased, if reducing emissions would not only be justified as a contribution to mitigation, but also as a contribution to preventing ill health—a basic principle of medical ethics.
Surgery should be routinely videoed
Authors: Jesudason Edwin 
Published: May 2022

Video recording is widely available in modern operating rooms. Here, I argue that, if patient consent and suitable technology are in place, video recording of surgery is an ethical duty. I develop this as aduty to protect,arguing for professional and institutional duties, as distinguished forduties of rescue.A professional duty to protect is described in mental healthcare. Practitioners have to take reasonable steps to prevent serious, foreseeable harm to their clients and others, even if that entails a non-consensual breach of confidentiality. I argue surgeons have a similar duty to patients which means that, provided the patient consents, surgery should be routinely videoed. This avoids non-consensual breaches of patient confidentiality and is aligned with stated professional obligations.An institutional duty to protect means institutions have to take reasonable steps to prevent serious, foreseeable harm at the hands of their surgeons. Rulli and Millum highlighted how institutions can meet their duty using a more consequentialist approach that balances wider interests.To test the force and scope of such duties, I examine potential impacts of routine videoing on aspects of autonomy, justice, beneficence and non-maleficence. I find routine videoing can benefit areas including safety, candour, consent and fairness in access (to surgical careers and expertise). Countervailing claims, for example, on liability, confidentiality and privacy can be resisted—such that where consent and the technology are in place, routine videoing meets aduty of easy protection. In other words, its use should be standard of care.
Paraneoplastic encephalitis: clinically based approach on diagnosis and management
Authors: Vaišvilas Mantas , Ciano-Petersen Nicolás Lundahl , Macarena Villagrán-García M D , Muñiz-Castrillo Sergio , Vogrig Alberto , Honnorat Jérôme 
Published: May 2022

Abstract
Paraneoplastic neurological syndromes (PNSs) comprise a subset of immune-mediated nervous system diseases triggered by an underlying malignancy. Each syndrome usually shows a distinct clinical presentation and outcome according to the associated neural antibodies. PNSs generally have a subacute onset with rapid progression and severe neurological disability. However, some patients may have hyperacute onset or even show chronic progression mimicking neurodegenerative diseases. Updated diagnostic criteria for PNS have been recently established in order to increase diagnostic specificity and to encourage standardisation of research initiatives related to PNS. Treatment for PNS includes oncological therapy and immunomodulation to halt neurological deterioration although current treatment options are seldom effective in reversing disability. Nevertheless, growing knowledge and better understanding of PNS pathogenesis promise better recognition, earlier diagnosis and novel treatment strategies. Considering that PNSs provide a model of effective anticancer immunity, the impact of these studies will extend far beyond the field of neurology.