bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative efficacy and acceptability of psychotherapies for post-traumatic stress disorder in children and adolescents: a systematic review and network meta-analysis
Authors: Xiang Yajie , Cipriani Andrea , Teng Teng , Del Giovane Cinzia , Zhang Yuqing , Weisz John R. , Li Xuemei , Cuijpers Pim , Liu Xueer , Barth Jürgen , Jiang Yuanliang , Cohen David , Fan Li , Gillies Donna , Du Kang , Ravindran Arun V. , Zhou Xinyu , Xie Peng 
Published: October 2021

BackgroundAvailable evidence on the comparative efficacy and acceptability of psychotherapies for post-traumatic stress disorder (PTSD) in children and adolescents remains uncertain.ObjectiveWe aimed to compare and rank the different types and formats of psychotherapies for PTSD in children and adolescents.MethodsWe searched eight databases and other international registers up to 31 December 2020. The pairwise meta-analyses and frequentist network meta-analyses estimated pooled standardised mean differences (SMDs) and ORs with random-effects model. Efficacy at post-treatment and follow-up, acceptability, depressive and anxiety symptoms were measured.FindingsWe included 56 randomised controlled trials with 5327 patients comparing 14 different types of psychotherapies and 3 control conditions. For efficacy, cognitive processing therapy (CPT), behavioural therapy (BT), individual trauma-focused cognitive–behavioural therapy (TF-CBT), eye movement desensitisation and reprocessing, and group TF-CBT were significantly superior to all control conditions at post-treatment and follow-up (SMDs between −2.42 and −0.25). Moreover, CPT, BT and individual TF-CBT were more effective than supportive therapy (SMDs between −1.92 and −0.49). Results for depressive and anxiety symptoms were similar to the findings for the primary outcome. Most of the results were rated as ‘moderate’ to ‘very low’ in terms of confidence of evidence.ConclusionsCPT, BT and individual TF-CBT appear to be the best choices of psychotherapy for PTSD in young patients. Other types and different ways of delivering psychological treatment can be alternative options. Clinicians should consider the importance of each outcome and the patients’ preferences in real clinical practice.
Bispecific antibody-mediated redirection of NKG2D-CAR natural killer cells facilitates dual targeting and enhances antitumor activity
Authors: Zhang Congcong , Röder Jasmin , Scherer Anne , Bodden Malena , Pfeifer Serrahima Jordi , Bhatti Anita , Waldmann Anja , Müller Nina , Oberoi Pranav , Wels Winfried S 
Published: October 2021

BackgroundNatural killer group 2D (NKG2D) is an activating receptor of natural killer (NK) cells and other lymphocytes that mediates lysis of malignant cells through recognition of stress-induced ligands such as MICA and MICB. Such ligands are broadly expressed by cancer cells of various origins and serve as targets for adoptive immunotherapy with effector cells endogenously expressing NKG2D or carrying an NKG2D-based chimeric antigen receptor (CAR). However, shedding or downregulation of NKG2D ligands (NKG2DL) can prevent NKG2D activation, resulting in escape of cancer cells from NKG2D-dependent immune surveillance.MethodsTo enable tumor-specific targeting of NKG2D-expressing effector cells independent of membrane-anchored NKG2DLs, we generated a homodimeric recombinant antibody which harbors an N-terminal single-chain fragment variable (scFv) antibody domain for binding to NKG2D, linked via a human IgG4Fc region to a second C-terminal scFv antibody domain for recognition of the tumor-associated antigen ErbB2 (HER2). The ability of this molecule, termed NKAB-ErbB2, to redirect NKG2D-expressing effector cells to ErbB2-positive tumor cells of different origins was investigated using peripheral blood mononuclear cells, ex vivo expanded NK cells, and NK and T cells engineered with an NKG2D-based chimeric receptor.ResultsOn its own, bispecific NKAB-ErbB2 increased lysis of ErbB2-positive breast carcinoma cells by peripheral blood-derived NK cells endogenously expressing NKG2D more effectively than an ErbB2-specific IgG1mini-antibody able to induce antibody-dependent cell-mediated cytotoxicity via activation of CD16. Furthermore, NKAB-ErbB2 synergized with NK-92 cells or primary T cells engineered to express an NKG2D-CD3ζ chimeric antigen receptor (NKAR), leading to targeted cell killing and greatly enhanced antitumor activity, which remained unaffected by soluble MICA known as an inhibitor of NKG2D-mediated natural cytotoxicity. In an immunocompetent mouse glioblastoma model mimicking low or absent NKG2DL expression, the combination of NKAR-NK-92 cells and NKAB-ErbB2 effectively suppressed outgrowth of ErbB2-positive tumors, resulting in treatment-induced endogenous antitumor immunity and cures in the majority of animals.ConclusionsOur results demonstrate that combining an NKAB antibody with effector cells expressing an activating NKAR receptor represents a powerful and versatile approach to simultaneously enhance tumor antigen-specific as well as NKG2D-CAR and natural NKG2D-mediated cytotoxicity, which may be particularly useful to target tumors with heterogeneous target antigen expression.
Novel phosphatidylserine-binding molecule enhances antitumor T-cell responses by targeting immunosuppressive exosomes in human tumor microenvironments
Authors: Bhatta Maulasri , Shenoy Gautam N , Loyall Jenni L , Gray Brian D , Bapardekar Meghana , Conway Alexis , Minderman Hans , Kelleher Jr Raymond J , Carreno Beatriz M , Linette Gerald , Shultz Leonard D , Odunsi Kunle , Balu-Iyer Sathy V , Pak Koon Yan , Bankert Richard B 
Published: October 2021

BackgroundThe human tumor microenvironment (TME) is a complex and dynamic milieu of diverse acellular and cellular components, creating an immunosuppressive environment, which contributes to tumor progression. We have previously shown that phosphatidylserine (PS) expressed on the surface of exosomes isolated from human TMEs is causally linked to T-cell immunosuppression, representing a potential immunotherapeutic target. In this study, we investigated the effect of ExoBlock, a novel PS-binding molecule, on T-cell responses in the TME.MethodsWe designed and synthesized a new compound, (ZnDPA)6-DP-15K, a multivalent PS binder named ExoBlock. The PS-binding avidity of ExoBlock was tested using an in vitro competition assay. The ability of this molecule to reverse exosome-mediated immunosuppression in vitro was tested using human T-cell activation assays. The in vivo therapeutic efficacy of ExoBlock was then tested in two different human tumor xenograft models, the melanoma-based xenomimetic (X-)mouse model, and the ovarian tumor-based omental tumor xenograft (OTX) model.ResultsExoBlock was able to bind PS with high avidity and was found to consistently and significantly block the immunosuppressive activity of human ovarian tumor and melanoma-associated exosomes in vitro. ExoBlock was also able to significantly enhance T cell-mediated tumor suppression in vivo in both the X-mouse and the OTX model. In the X-mouse model, ExoBlock suppressed tumor recurrence in a T cell-dependent manner. In the OTX model, ExoBlock treatment resulted in an increase in the number as well as function of CD4 and CD8 T cells in the TME, which was associated with a reduction in tumor burden and metastasis, as well as in the number of circulating PS+ exosomes in tumor-bearing mice.ConclusionOur results establish that targeting exosomal PS in TMEs with ExoBlock represents a promising strategy to enhance antitumor T-cell responses.
Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors
Authors: Marcu Ana , Schlosser Andreas , Keupp Anne , Trautwein Nico , Johann Pascal , Wölfl Matthias , Lager Johanna , Monoranu Camelia Maria , Walz Juliane S , Henkel Lisa M , Krauß Jürgen , Ebinger Martin , Schuhmann Martin , Thomale Ulrich Wilhelm , Pietsch Torsten , Klinker Erdwine , Schlegel Paul G , Oyen Florian , Reisner Yair , Rammensee Hans-Georg , Eyrich Matthias 
Published: October 2021

BackgroundAtypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS tumors of infancy and early childhood. Hallmark is the surprisingly simple genome with inactivating mutations or deletions in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T cells. However, it is unclear which epitopes T cells might recognize on AT/RT cells.MethodsHere, we report a comprehensive mass spectrometry (MS)-based analysis of naturally presented human leukocyte antigen (HLA) class I and class II ligands on 23 AT/RTs. MS data were validated by matching with a human proteome dataset and exclusion of peptides that are part of the human benignome. Cryptic peptide ligands were identified using Peptide-PRISM.ResultsComparative HLA ligandome analysis of the HLA ligandome revealed 55 class I and 139 class II tumor-exclusive peptides. No peptide originated from the SMARCB1 region. In addition, 61 HLA class I tumor-exclusive peptide sequences derived from non-canonically translated proteins. Combination of peptides from natural and cryptic class I and class II origin gave optimal representation of tumor cell compartments. Substantial overlap existed with the cryptic immunopeptidome of glioblastomas, but no concordance was found with extracranial tumors. More than 80% of AT/RT exclusive peptides were able to successfully prime CD8+T cells, whereas naturally occurring memory responses in AT/RT patients could only be detected for class II epitopes. Interestingly, >50% of AT/RT exclusive class II ligands were also recognized by T cells from glioblastoma patients but not from healthy donors.ConclusionsThese findings highlight that AT/RTs, potentially paradigmatic for other pediatric tumors with a low mutational load, present a variety of highly immunogenic HLA class I and class II peptides from canonical as well as non-canonical protein sources. Inclusion of such cryptic peptides into therapeutic vaccines would enable an optimized mapping of the tumor cell surface, thereby reducing the likelihood of immune evasion.
Dual checkpoint blockade of CD47 and PD-L1 using an affinity-tuned bispecific antibody maximizes antitumor immunity
Authors: Chen Shih-Hsun , Dominik Pawel K , Stanfield Jessica , Ding Sheng , Yang Wenjing , Kurd Nadia , Llewellyn Ryan , Heyen Jonathan , Wang Carole , Melton Zea , Van Blarcom Thomas , Lindquist Kevin C , Chaparro-Riggers Javier , Salek-Ardakani Shahram 
Published: October 2021

BackgroundT cell checkpoint immunotherapies have shown promising results in the clinic, but most patients remain non-responsive. CD47-signal regulatory protein alpha (SIRPα) myeloid checkpoint blockade has shown early clinical activity in hematologic malignancies. However, CD47 expression on peripheral blood limits αCD47 antibody selectivity and thus efficacy in solid tumors.MethodsTo improve the antibody selectivity and therapeutic window, we developed a novel affinity-tuned bispecific antibody targeting CD47 and programmed death-ligand 1 (PD-L1) to antagonize both innate and adaptive immune checkpoint pathways. This PD-L1-targeted CD47 bispecific antibody was designed with potent affinity for PD-L1 and moderate affinity for CD47 to achieve preferential binding on tumor and myeloid cells expressing PD-L1 in the tumor microenvironment (TME).ResultsThe antibody design reduced binding on red blood cells and enhanced selectivity to the TME, improving the therapeutic window compared with αCD47 and its combination with αPD-L1 in syngeneic tumor models. Mechanistically, both myeloid and T cells were activated and contributed to antitumor activity of αCD47/PD-L1 bispecific antibody. Distinct from αCD47 and αPD-L1 monotherapies or combination therapies, single-cell RNA sequencing (scRNA-seq) and gene expression analysis revealed that the bispecific treatment resulted in unique innate activation, including pattern recognition receptor-mediated induction of type I interferon pathways and antigen presentation in dendritic cells and macrophage populations. Furthermore, treatment increased the Tcf7+stem-like progenitor CD8 T cell population in the TME and promoted its differentiation to an effector-like state. Consistent with mouse data, the compounds were well tolerated and demonstrated robust myeloid and T cell activation in non-human primates (NHPs). Notably, RNA-seq analysis in NHPs provided evidence that the innate activation was mainly contributed by CD47-SIRPα but not PD-L1-PD-1 blockade from the bispecific antibody.ConclusionThese findings provide novel mechanistic insights into how myeloid and T cells can be uniquely modulated by the dual innate and adaptive checkpoint antibody and demonstrate its potential in clinical development (NCT04881045) to improve patient outcomes over current PD-(L)1 and CD47-targeted therapies.
Bispecific antibody targeting TROP2xCD3 suppresses tumor growth of triple negative breast cancer
Authors: Liu Huicheng , Bai Lili , Huang Liu , Ning Na , Li Lin , Li Yijia , Dong Xuejiao , Du Qiuyang , Xia Minghui , Chen Yufei , Zhao Likun , Li Yanhu , Meng Qingwu , Wang Jing , Duan Yaqi , Ming Jie , Yuan Andy Qingan , Yang Xiang-Ping 
Published: October 2021

BackgroundTriple negative breast cancer (TNBC) is a subtype of breast cancers with poor prognosis and targeted drug therapies are limited. To develop novel and efficacious therapies for TNBC, we developed a bispecific antibody F7AK3 that recognizes both trophoblast cell surface antigen 2 (TROP2) and CD3 and evaluated its antitumor activities both in vitro and in vivo.MethodsThe binding affinities of F7AK3 to the two targets, TROP2 and CD3, were evaluated by surface plasmon resonance. Binding of F7AK3 to TNBC cells and T cells were evaluated by flow cytometry. Immunofluorescent staining was performed to demonstrate the interactions between T cells with TNBC cells. The cytotoxicity of T cells against TNBC cell lines and primary tumor cells mediated by F7AK3 were determined in vitro. In vivo antitumor activity of F7AK3 was investigated in a xenograft TNBC tumor model, using immunodeficient mice that were reconstituted with human peripheral blood mononuclear cells.ResultsWe demonstrated that F7AK3 binds specifically to human TROP2 and CD3 antigens, as well as TNBC cell lines and primary tumor cells. Human T cells can only be activated by F7AK3 in the presence of target tumor cells. F7AK3 recruits T cells to TROP2+ tumor cells in vitro and into tumor tissues in vivo. Antitumor growth activity of F7AK3 is observed in a xenograft TNBC tumor model.ConclusionThis study showed the antitumor potential of an anti-TROP2xCD3 bispecific antibody F7AK3 to TNBC tumor cells both in vitro and in vivo. These data demonstrate that F7AK3 has the potential to treat TNBC patients, which warrants further preclinical and clinical evaluation of the F7AK3 in advanced or metastatic TNBC patients.
Association Between Anatomical Features and Anterior Knee Pain in a “Fit” Service Population
Authors: Hand C. J. , Spalding J. W. 
Published: October 2021

AbstractAnterior knee pain and overuse sports type injuries have been associated with anatomical factors. Specific diagnosis in knee pain is difficult, most service patients are grouped together as “Patello-Femoral Stress Syndrome”. Knee pain incidence within the service population is unknown, but thought to be greater than those presenting to General Practitioners. 293 active duty service men (100 Army and 193 Royal Navy) were interviewed and examined in relation to their knees. 138 measurements were made on each subject.118 admitted to knee problems. Six had specific diagnoses, ranging from patellar tendonitis to ACL deficiency (with marked anterior instability). The remaining 112 individuals formed the study group and examination findings were compared with the 175 without Patello-Femoral Stress Syndrome. The results have been analysed to determine normal ranges and predictors of knee pain.Age, years in the military and results of patello-femoral compression tests were consistently significantly different between the groups.This survey provides useful information on normal values at examination. Q angle measurement was a poor predictor of knee pain. There was no clinically detectable anatomical variant that correlated with the Patello-Femoral Stress Syndrome. There was poor correlation between Tegner activity score and the perceived limitation on sport or work, as assessed on a visual analogue scale.
Critical Care Retrieval Revisited
Authors: Bateman R. M. 
Published: October 2021

AbstractIn 2000, the Journal of the Royal Naval Medical Service published an account of critical care retrieval experience written by Adrian Mellor and based on his time spent with CareFlight in Sydney, Australia. Having recently completed a term with the same organisation. I wanted to reiterate the usefulness of such an attachment.The purpose of this article is therefore to compare my experiences with those of Surgeon Commander Mellor and to provide an update on the work involved in critical care retrieval within New South Wales.
Case Report: Use of a Remifentanil Infusion with the Tri-Service Anaesthetic Apparatus
Authors: Bateman R. , Wedgwood J. , Henning J. 
Published: October 2021

AbstractDuring a recent deployment to Iraq, it was noticed that patients’ recovery times from general anaesthesia were significantly prolonged. We postulated that this was because of a lack of nitrous oxide – thereby creating a requirement for greater concentrations of volatile agent to maintain adequate depth of anaesthesia. We chose to adopt the technique of running a remifentanil infusion with the Tri-Service apparatus in an attempt to reduce the administered volatile and thus shorten recovery times.
Non-contrast head CT alone for thrombectomy in acute ischemic stroke: analysis of the ANGEL-ACT registry
Authors: Ren Zeguang , Ma Gaoting , Mokin Maxim , Jadhav Ashutosh P , Jia Baixue , Tong Xu , Bauer Clayton , Liu Raynald , Wang Anxin , Zhang Xuelei , Mo Dapeng , Ma Ning , Gao Feng , Song Ligang , Sun Xuan , Huo Xiaochuan , Deng Yiming , Liu Lian , Luo Gang , Luo Xiang , Peng Ya , Gui Liqiang , Song Cunfeng , Wu Jin , Wang Leyuan , Li Chunlei , Jovin Tudor G , Wang Yilong , Wang Yongjun , Miao Zhongrong 
Published: October 2021

BackgroudThe goal of this study was to determine if the choice of imaging paradigm performed in the emergency department influences the procedural or clinical outcomes after mechanical thrombectomy (MT).MethodsThis is a retrospective comparative outcome study which was conducted from the ANGEL-ACT registry. Comparisons were made between baseline characteristics and clinical outcomes of patients with acute ischemic stroke undergoing MT with non-contrast head computed tomography (NCHCT) alone versus patients undergoing NCHCT plus non-invasive vessel imaging (NVI) (including CT angiography (with or without CT perfusion) and magnetic resonance angiography). The primary outcome was the modified Rankin Scale (mRS) score at 90 days. Secondary outcomes included change in mRS score from baseline to 90 days, the proportions of mRS 0–1, 0–2, and 0–3, and dramatic clinical improvement at 24 hours. The safety outcomes were any intracranial hemorrhage (ICH), symptomatic ICH, and mortality within 90 days.ResultsA total of 894 patients met the inclusion criteria; 476 (53%) underwent NCHCT alone and 418 (47%) underwent NCHCT + NVI. In the NCHCT alone group, the door-to-reperfusion time was shorter by 47 min compared with the NCHCT + NVI group (219 vs 266 min, P<0.001). Patients in the NCHCT alone group showed a smaller increase in baseline mRS score at 90 days (median 3 vs 2 points; P=0.004) after adjustment. There were no significant differences between groups in the remaining clinical outcomes.ConclusionsIn patients selected for MT using NCHCT alone versus NCHCT + NVI, there were improved procedural outcomes and smaller increases in baseline mRS scores at 90 days.
Changes in ST segment elevation myocardial infarction hospitalisations in China from 2011 to 2015
Authors: Zhou Tianna , Li Xi , Lu Yuan , Murugiah Karthik , Bai Xueke , Hu Shuang , Gao Yan , Masoudi Frederick A , Krumholz Harlan M , Li Jing 
Published: October 2021

ObjectiveAccess to acute cardiovascular care has improved and health services capacity has increased over the past decades. We assessed national changes in (1) patient characteristics, (2) in-hospital management and (3) patient outcomes among patients presenting with ST segment elevation myocardial infarction (STEMI) in 2011–2015 in China.MethodsIn a nationally representative sample of hospitals in China, we created two random cohorts of patients in 2011 and 2015 separately. We weighted our findings to estimate nationally representative numbers and assessed changes from 2011 to 2015. Data were abstracted from medical charts centrally using standardised definitions.ResultsWhile the proportion of patients with STEMI among all patients with acute myocardial infarction decreased over time from 82.5% (95% CI 81.7 to 83.3) in 2011 to 68.5% (95% CI 67.7 to 69.3) in 2015 (p<0.0001), the weighted national estimate of patients with STEMI increased from 210 000 to 380 000. The rate of reperfusion eligibility among patients with STEMI decreased from 49.3% (95% CI 48.1 to 50.5) to 42.2% (95% CI 41.1 to 43.4) in 2015 (p<0.0001); ineligibility was principally driven by larger proportions with prehospital delay exceeding 12 hours (67.4%–76.7%, p<0.0001). Among eligible patients, the proportion receiving reperfusion therapies increased from 54% (95% CI 52.3 to 55.7) to 59.7% (95% CI 57.9 to 61.4) (p<0.0001). Crude and risk-adjusted rates of in-hospital death did not differ significantly between 2011 and 2015.ConclusionsIn this most recent nationally representative study of STEMI in China, the use of acute reperfusion increased, but no significant improvement occurred in outcomes. There is a need to continue efforts to prevent cardiovascular diseases, to monitor changes in in-hospital treatments and outcomes, and to reduce prehospital delay.
‘No-Barriers’ tobacco product? Selling smokeless tobacco to women, people of colour and the LGBTQ+ community in the USA
Authors: Hendlin Yogi Hale , Small Sarah , Ling Pamela M 
Published: October 2021

BackgroundIn both Sweden and the USA, smokeless tobacco (ST) is legal and used predominantly by men. Starting in the 1970s, US tobacco companies attempted to expand the ST market to women, African Americans, Hispanic Americans and lesbian, gay, bisexual, transgender, queer and other sexual orientation (LGBTQ+) people.DesignWe analysed industry documents from the Truth Tobacco Industry Documents Library triangulating findings with recent ST advertising and publicly available literature.FindingsWe found tobacco companies used design innovations such as pouched moist snuff, snus and dissolvable products to expand the market. In addition, diverse advertising campaigns targeted women, people of colour (Hispanic, African American) and LGBTQ+ communities with identity-targeted messages emphasising novelty, convenience, cleanliness and use in smoke-free environments. However, stereotypes of ST users as rural white males endured, perpetuated by continued marketing aimed at this customer base, which created cognitive dissonance and stymied marketer’s hopes that pouch products would ‘democratize’ ST.ConclusionThese failed campaigns suggest novel products such as nicotine pouch products may provide a ‘clean slate’ to similarly target women and other low-ST-using groups. Based on this history, the risk of new tobacco and nicotine products to increase health disparities should be closely monitored.
Heterogeneous HER2 Amplification—a New Clinical Category of HER2-Positive Breast Cancer?
Authors: Okines Alicia F.C. , Turner Nicholas C. 
Published: October 2021

Abstract

Summary:
HER2 amplification heterogeneity is associated with resistance to trastuzumab emtansine in the neoadjuvant setting, emphasizing the importance of assessing whether heterogeneous HER2-positive cancers require different treatment pathways.
See related article by Metzger Filho et al., p. 2474.