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Capillary morphogenesis gene 2 (CMG2) mediates cell-matrix interactions to facilitate cell adhesion and migration. CMG2 has been implicated in the disease progression of breast cancer, prostate cancer and gastric cancer. The present study aims to determine the role of CMG2 in the disease progression and peritoneal metastasis of pancreatic cancer. Pancreatic tumour samples were collected from Peking University Cancer Hospital. CMG2 expression was determined using quantitative PCR. After the creation of knockdown and overexpression of CMG2 in pancreatic cancer cells, the effect of CMG2 on several cell functions and adhesion to the peritoneum was examined. Potential pathways regulated by CMG2 were found via proteomics analysis and drug tests. CMG2 was upregulated in pancreatic cancer tissues and associated with a poor prognosis. CMG2 was increased in metastatic lesions and those primary tumours with distant metastases. CMG2 promotes cell-cell, cell-matrix and cell-hyaluronic acid adhesion, which may be mediated by epidermal growth factor receptor (EGFR) and focal adhesion kinase (FAK) pathway activation.

Objective: To synthesise young person and family member perspectives on processes of change in family therapy for anorexia nervosa (AN), including systemic family therapy and manualised family-based treatments, to obtain an understanding of what helps and hinders positive change., Method: A systematic search of the literature was conducted to identify qualitative studies focussing on experiences of therapeutic change within family therapies for AN from the perspectives of young people and their families. Fifteen studies met inclusion criteria and underwent quality appraisal following which they were synthesised using a meta-synthesis approach., Results: Six overarching themes were generated: "A holistic focus on the young person's overall development"; "The therapeutic relationship as a vehicle for change"; "The therapist's confinement to a script and its impact on emotional attunement"; "A disempowering therapeutic context"; "Externalisation of the eating disorder (ED)"; and "The importance of family involvement". Positive change was helped by understanding and support given to the young person's overall development including their psychological, emotional, social and physical wellbeing, positive therapeutic relationships, relational containment within the family system and externalising conversations in which young people felt seen and heard. Positive change was hindered by inflexibility in the treatment approach, counter-effects of externalisation, negative experiences of the therapist, a narrow focus on food-intake and weight, as well as the neglect of family difficulties, emotional experiences, and psychological factors., Conclusions: Positive change regarding the young person's eating-related difficulties ensued in the context of positive relational changes between the young person, their family members, the therapist and treatment team, highlighting the significance of secure and trusting relationships. The findings of this review can be utilised by ED services to consider how they may adapt to the needs of young people and their families in order to improve treatment satisfaction, treatment outcomes, and in turn reduce risk for chronicity in AN., (© 2024. The Author(s).)

Background: A total of 30-40% of diffuse large B cell lymphoma (DLBCL) patients will either not respond to the standard therapy or their disease will recur. The first-line treatment for DLBCL is rituximab and combination chemotherapy. This treatment involves the chemotherapy-induced recruitment of tumor-associated macrophages that recognize and kill rituximab-opsonized DLBCL cells. However, we lack insights into the factors responsible for the recruitment and functionality of macrophages in DLBCL tumors., Methods: We have studied the effects of the immunomodulatory lipid sphingosine-1-phosphate (S1P) on macrophage activity in DLBCL, both in vitro and in animal models., Results: We show that tumor-derived S1P mediates the chemoattraction of both monocytes and macrophages in vitro and in animal models, an effect that is dependent upon the S1P receptor S1PR1. However, S1P inhibited M1 macrophage-mediated phagocytosis of DLBCL tumor cells opsonized with the CD20 monoclonal antibodies rituximab and ofatumumab, an effect that could be reversed by an S1PR1 inhibitor., Conclusions: Our data show that S1P signaling can modulate macrophage recruitment and tumor cell killing by anti-CD20 monoclonal antibodies in DLBCL. The administration of S1PR1 inhibitors could enhance the phagocytosis of tumor cells and improve outcomes for patients.

Abstract: Voice hearing experiences are commonly reported by patients with anorexia nervosa (AN) and are associated with negative outcomes. The "eating disorder voice" (EDV) can be understood within relational frameworks. Relating therapy (RT) has offered encouraging outcomes when targeted at voice hearing experiences transdiagnostically but has not been evaluated in the context of AN. This study aimed to offer a preliminary and mixed methods exploration of RT for the EDV. RT was delivered to three participants with a diagnosis of AN who were distressed by an EDV. Weight, negative impact of voices, and eating disorder cognitions were assessed at baseline, posttherapy and at brief follow-up. Participant experiences were explored through exit interviews. Therapy was completed by all participants. Weight gain was reported by two participants and maintained at brief follow-up. Positive changes were not reported on other measures. Qualitative data were suggestive of positive experiences that facilitated assertive responding., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Post-acute cardiac sequelae, following SARS-CoV-2 infection, are well recognized as complications of COVID-19. We have previously shown the persistence of autoantibodies against antigens in skin, muscle, and heart in individuals following severe COVID-19; the most common staining on skin tissue displayed an inter-cellular cement pattern consistent with antibodies against desmosomal proteins. Desmosomes play a critical role in maintaining the structural integrity of tissues. For this reason, we analyzed desmosomal protein levels and the presence of anti-desmoglein (DSG) 1, 2, and 3 antibodies in acute and convalescent sera from patients with COVID-19 of differing clinical severity. We find increased levels of DSG2 protein in sera from acute COVID-19 patients. Furthermore, we find that DSG2 autoantibody levels are increased significantly in convalescent sera following severe COVID-19 but not in hospitalized patients recovering from influenza infection or healthy controls. Levels of autoantibody in sera from patients with severe COVID-19 were comparable to levels in patients with non-COVID-19-associated cardiac disease, potentially identifying DSG2 autoantibodies as a novel biomarker for cardiac damage. To determine if there was any association between severe COVID-19 and DSG2, we stained post-mortem cardiac tissue from patients who died from COVID-19 infection. This confirmed DSG2 protein within the intercalated discs and disruption of the intercalated disc between cardiomyocytes in patients who died from COVID-19. Our results reveal the potential for DSG2 protein and autoimmunity to DSG2 to contribute to unexpected pathologies associated with COVID-19 infection., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Immunology.)

Pancreatic ductal adenocarcinoma (PDAC) has a poor clinical outlook. Responses to immune checkpoint blockade are suboptimal and a much more detailed understanding of the tumor immune microenvironment is needed if this situation is to be improved. Here, we characterized tumor-infiltrating T-cell populations in patients with PDAC using cytometry by time of flight (CyTOF) and single-cell RNA sequencing. T cells were the predominant immune cell subset observed within tumors. Over 30% of CD4+ T cells expressed a CCR6+CD161+ Th17 phenotype and 17% displayed an activated regulatory T-cell profile. Large populations of CD8+ tissue-resident memory (TRM) T cells were also present and expressed high levels of programmed cell death protein 1 (PD-1) and TIGIT. A population of putative tumor-reactive CD103+CD39+ T cells was also observed within the CD8+ tumor-infiltrating lymphocytes population. The expression of PD-1 ligands was limited largely to hemopoietic cells whilst TIGIT ligands were expressed widely within the tumor microenvironment. Programmed death-ligand 1 and CD155 were expressed within the T-cell area of ectopic lymphoid structures and colocalized with PD-1+TIGIT+ CD8+ T cells. Combinatorial anti-PD-1 and TIGIT blockade enhanced IFNγ secretion and proliferation of T cells in the presence of PD-1 and TIGIT ligands. As such, we showed that the PDAC microenvironment is characterized by the presence of substantial populations of TRM cells with an exhausted PD-1+TIGIT+ phenotype where dual checkpoint receptor blockade represents a promising avenue for future immunotherapy., (©2023 The Authors; Published by the American Association for Cancer Research.)

Epstein-Barr virus (EBV), defined as a group I carcinogen by the World Health Organization (WHO), is present in the tumour cells of patients with different forms of B-cell lymphoma, including Burkitt lymphoma, Hodgkin lymphoma, post-transplant lymphoproliferative disorders, and, most recently, diffuse large B-cell lymphoma (DLBCL). Understanding how EBV contributes to the development of these different types of B-cell lymphoma has not only provided fundamental insights into the underlying mechanisms of viral oncogenesis, but has also highlighted potential new therapeutic opportunities. In this review, we describe the effects of EBV infection in normal B-cells and we address the germinal centre model of infection and how this can lead to lymphoma in some instances. We then explore the recent reclassification of EBV+ DLBCL as an established entity in the WHO fifth edition and ICC 2022 classifications, emphasising the unique nature of this entity. To that end, we also explore the unique genetic background of this entity and briefly discuss the potential role of the tumour microenvironment in lymphomagenesis and disease progression. Despite the recent progress in elucidating the mechanisms of this malignancy, much work remains to be done to improve patient stratification, treatment strategies, and outcomes.

S100A8/A9, also known as "calprotectin" or "MRP8/14," is an alarmin primarily secreted by activated myeloid cells with antimicrobial, proinflammatory, and prothrombotic properties. Increased plasma levels of S100A8/A9 in thrombo-inflammatory diseases are associated with thrombotic complications. We assessed the presence of S100A8/A9 in the plasma and lung autopsies from patients with COVID-19 and investigated the molecular mechanism by which S100A8/A9 affects platelet function and thrombosis. S100A8/A9 plasma levels were increased in patients with COVID-19 and sustained high levels during hospitalization correlated with poor outcomes. Heterodimeric S100A8/A9 was mainly detected in neutrophils and deposited on the vessel wall in COVID-19 lung autopsies. Immobilization of S100A8/A9 with collagen accelerated the formation of a fibrin-rich network after perfusion of recalcified blood at venous shear. In vitro, platelets adhered and partially spread on S100A8/A9, leading to the formation of distinct populations of either P-selectin or phosphatidylserine (PS)-positive platelets. By using washed platelets, soluble S100A8/A9 induced PS exposure but failed to induce platelet aggregation, despite GPIIb/IIIa activation and alpha-granule secretion. We identified GPIbα as the receptor for S100A8/A9 on platelets inducing the formation of procoagulant platelets with a supporting role for CD36. The effect of S100A8/A9 on platelets was abolished by recombinant GPIbα ectodomain, platelets from a patient with Bernard-Soulier syndrome with GPIb-IX-V deficiency, and platelets from mice deficient in the extracellular domain of GPIbα. We identified the S100A8/A9-GPIbα axis as a novel targetable prothrombotic pathway inducing procoagulant platelets and fibrin formation, in particular in diseases associated with high levels of S100A8/A9, such as COVID-19., (© 2022 by The American Society of Hematology.)

Aims: Thrombotic complications and vasculopathy have been extensively associated with severe COVID-19 infection; however, the mechanisms inducing endotheliitis and the disruption of endothelial integrity in the microcirculation are poorly understood. We hypothesized that within the vessel wall, pericytes preferentially take up viral particles and mediate the subsequent loss of vascular integrity., Methods and Results: Immunofluorescence of post-mortem patient sections was used to assess pathophysiological aspects of COVID-19 infection. The effects of COVID-19 on the microvasculature were assessed using a vascular organoid model exposed to live viral particles or recombinant viral antigens. We find increased expression of the viral entry receptor angiotensin-converting enzyme 2 on pericytes when compared to vascular endothelium and a reduction in the expression of the junctional protein CD144, as well as increased cell death, upon treatment with both live virus and/or viral antigens. We observe a dysregulation of genes implicated in vascular permeability, including Notch receptor 3, angiopoietin-2, and TEK. Activation of vascular organoids with interleukin-1β did not have an additive effect on vascular permeability. Spike antigen was detected in some patients' lung pericytes, which was associated with a decrease in CD144 expression and increased platelet recruitment and von Willebrand factor (VWF) deposition in the capillaries of these patients, with thrombi in large vessels rich in VWF and fibrin., Conclusion: Together, our data indicate that direct viral exposure to the microvasculature modelled by organoid infection and viral antigen treatment results in pericyte infection, detachment, damage, and cell death, disrupting pericyte-endothelial cell crosstalk and increasing microvascular endothelial permeability, which can promote thrombotic and bleeding complications in the microcirculation., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved.)

Background: The systemic inflammatory response post-SARS-CoV-2 infection increases pro-inflammatory cytokine production, multi-organ damage, and mortality rates. Mast cells (MC) modulate thrombo-inflammatory disease progression ( e.g. , deep vein thrombosis) and the inflammatory response post-infection., Objective: To enhance our understanding of the contribution of MC and their proteases in SARS-CoV-2 infection and the pathogenesis of the disease, which might help to identify novel therapeutic targets., Methods: MC proteases chymase (CMA1), carboxypeptidase A3 (CPA3), and tryptase beta 2 (TPSB2), as well as cytokine levels, were measured in the serum of 60 patients with SARS-CoV-2 infection (30 moderate and 30 severe; severity of the disease assessed by chest CT) and 17 healthy controls by ELISA. MC number and degranulation were quantified by immunofluorescent staining for tryptase in lung autopsies of patients deceased from either SARS-CoV-2 infection or unrelated reasons (control). Immortalized human FcεR1 + c-Kit + LUVA MC were infected with SARS-CoV-2, or treated with its viral proteins, to assess direct MC activation by flow cytometry., Results: The levels of all three proteases were increased in the serum of patients with COVID-19, and strongly correlated with clinical severity. The density of degranulated MC in COVID-19 lung autopsies was increased compared to control lungs. The total number of released granules and the number of granules per each MC were elevated and positively correlated with von Willebrand factor levels in the lung. SARS-CoV-2 or its viral proteins spike and nucleocapsid did not induce activation or degranulation of LUVA MC in vitro ., Conclusion: In this study, we demonstrate that SARS-CoV-2 is strongly associated with activation of MC, which likely occurs indirectly, driven by the inflammatory response. The results suggest that plasma MC protease levels could predict the disease course, and that severe COVID-19 patients might benefit from including MC-stabilizing drugs in the treatment scheme., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Krysko, Bourne, Kondakova, Galova, Whitworth, Newby, Bachert, Hill, Crispin, Stamataki, Cunningham, Pugh, Khan, Rayes, Vedunova, Krysko and Brill.)

Objectives: Recombinant granulocyte colony-stimulating factor (G-CSF) is frequently administered to patients with cancer to enhance granulocyte recovery post-chemotherapy. Clinical trials have also used G-CSF to modulate myeloid cell function in pregnancy and inflammatory diseases. Although the contribution of G-CSF to expanding normal granulocytes is well known, the effect of this cytokine on the phenotype and function of immunosuppressive granulocytic cells remains unclear. Here, we investigate the impact of physiological and iatrogenic G-CSF on an as yet undescribed granulocyte phenotype and ensuing outcome on T cells in the settings of cancer and pregnancy., Methods: Granulocytes from patients treated with recombinant G-CSF, patients with late-stage cancer and women enrolled on a trial of recombinant G-CSF were phenotyped by flow cytometry. The ability and mechanism of polarised granulocytes to suppress T-cell proliferation were assessed by cell proliferation assays, flow cytometry and ELISA., Results: We observed that G-CSF leads to a significant upregulation of CD14 expression on CD15 + granulocytes. These CD15 + CD14 + cells are identified in the blood of patients with patients undergoing neutrophil mobilisation with recombinant G-CSF, and physiologically in women early in pregnancy or in those treated as a part of a clinical trial. Immunohistochemistry of tumor tissue or placental tissue identified the expression of G-CSF. The G-CSF upregulates the release of reactive oxygen species (ROS) in CD15 + CD14 + cells leading to the suppression of T-cell proliferation., Conclusions: G-CSF induces a population of ROS + immunosuppressive CD15 + CD14 + granulocytes. Strategies for how recombinant G-CSF can be scheduled to reduce effects on T-cell therapies should be developed in future clinical studies., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Inflammasomes are cytosolic innate immune sensors of pathogen infection and cellular damage that induce caspase-1-mediated inflammation upon activation. Although inflammation is protective, uncontrolled excessive inflammation can cause inflammatory diseases and can be detrimental, such as in coronavirus disease (COVID-19). However, the underlying mechanisms that control inflammasome activation are incompletely understood. Here we report that the leucine-rich repeat (LRR) protein ribonuclease inhibitor (RNH1), which shares homology with LRRs of NLRP (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing) proteins, attenuates inflammasome activation. Deletion of RNH1 in macrophages increases interleukin (IL)-1β production and caspase-1 activation in response to inflammasome stimulation. Mechanistically, RNH1 decreases pro-IL-1β expression and induces proteasome-mediated caspase-1 degradation. Corroborating this, mouse models of monosodium urate (MSU)-induced peritonitis and lipopolysaccharide (LPS)-induced endotoxemia, which are dependent on caspase-1, respectively, show increased neutrophil infiltration and lethality in Rnh1 -/- mice compared with wild-type mice. Furthermore, RNH1 protein levels were negatively related with disease severity and inflammation in hospitalized COVID-19 patients. We propose that RNH1 is a new inflammasome regulator with relevance to COVID-19 severity., (© 2022 Bombaci et al.)

A proportion of individuals given an eating disorder diagnosis describe the experience of an eating disorder 'voice' (EDV). However, methods for working with this experience are currently lacking. Voice Dialogue (Stone & Stone, 1989) involves direct communication between a facilitator and parts of the self to increase awareness, understanding, and separation from inner voices. Adapted forms of this method have shown promise in working with voices in psychosis. This study aimed to explore the experience and acceptability of Voice Dialogue amongst individuals with anorexia nervosa who experience an EDV. Nine women participated in a semistructured interview following a single Voice Dialogue session. Interview transcripts were analysed using interpretative phenomenological analysis (IPA). Three overarching themes were identified as follows: (i) "separating from the EDV"; (ii) "better understanding of the EDV"; and (iii) "hopeful, motivated, and afraid of recovery". The majority of participants found Voice Dialogue acceptable and helpful for exploring their EDV. Whilst preliminary, the results suggest that Voice Dialogue has potential in terms of helping individuals establish a more constructive relationship with their EDV and motivating change. Further research is needed to build upon these findings. Implications for addressing the EDV using voice-focused interventions are explored., (© 2021 John Wiley & Sons, Ltd.)

Coronavirus disease 2019 (COVID-19) induces a hypercoagulatory state that frequently leads to thromboembolic complications. Whereas anticoagulation is associated with reduced mortality, the role of antiplatelet therapy in COVID-19 is less clear. We retrospectively analyzed the effect of anticoagulation and antiplatelet therapy in 578 hospitalized patients with COVID-19 and prospectively monitored 110 patients for circulating microthrombi and plasma markers of coagulation in the first week of admission. Moreover, we determined platelet shape change and also thrombi in postmortem lung biopsies in a subset of patients with COVID-19. We observed no association of antiplatelet therapy with COVID-19 survival. Adverse outcome in COVID-19 was associated with increased activation of the coagulation cascade, whereas circulating microthrombi did not increase in aggravated disease. This was in line with analysis of postmortem lung biopsies of patients with COVID-19, which revealed generally fibrin(ogen)-rich and platelet-low thrombi. Platelet spreading was normal in severe COVID-19 cases; however, plasma from patients with COVID-19 mediated an outcome-dependent inhibitory effect on naïve platelets. Antiplatelet medication disproportionally exacerbated this platelet impairment in plasma of patients with fatal outcome. Taken together, this study shows that unfavorable outcome in COVID-19 is associated with a profound dysregulation of the coagulation system, whereas the contribution of platelets to thrombotic complications is less clear. Adverse outcome may be associated with impaired platelet function or platelet exhaustion. In line, antiplatelet therapy was not associated with beneficial outcome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schrottmaier, Pirabe, Pereyra, Heber, Hackl, Schmuckenschlager, Brunnthaler, Santol, Kammerer, Oosterlee, Pawelka, Treiber, Khan, Pugh, Traugott, Schörgenhofer, Seitz, Karolyi, Jilma, Rayes, Zoufaly and Assinger.)

Thromboembolic complications are frequently observed in Coronavirus disease 2019 (COVID-19). While COVID-19 is linked to platelet dysregulation, the association between disease outcome and platelet function is less clear. We prospectively monitored platelet activation and reactivity in 97 patients during the first week of hospitalization and determined plasma markers of platelet degranulation and inflammation. Adverse outcome in COVID-19 was associated with increased basal platelet activation and diminished platelet responses, which aggravated over time. Especially GPIIb/IIIa responses were abrogated, pointing toward impeded platelet aggregation. Moreover, platelet-leukocyte aggregate formation was diminished, pointing toward abrogated platelet-mediated immune responses in COVID-19. No general increase in plasma levels of platelet-derived granule components could be detected, arguing against platelet exhaustion. However, studies on platelets from healthy donors showed that plasma components in COVID-19 patients with unfavorable outcome were at least partly responsible for diminished platelet responses. Taken together this study shows that unfavorable outcome in COVID-19 is associated with a hypo-responsive platelet phenotype that aggravates with disease progression and may impact platelet-mediated immunoregulation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Schrottmaier, Pirabe, Pereyra, Heber, Hackl, Schmuckenschlager, Brunnthaler, Santol, Kammerer, Oosterlee, Pawelka, Treiber, Khan, Pugh, Traugott, Schörgenhofer, Seitz, Karolyi, Jilma, Rayes, Zoufaly and Assinger.)

We performed a systematic review and meta-analysis to investigate the use of machine learning techniques for predicting stone-free rates following Shockwave Lithotripsy (SWL). Eight papers (3264 patients) were included. Two studies used decision-tree approaches, five studies utilised Artificial Neural Networks (ANN), and one study combined a variety of approaches. The summary true positive rate was 79%, summary false positive rate was 14%, and Receiver Operator Characteristic (ROC) was 0.90 for machine learning approaches. Machine learning algorithms were at least as good as standard approaches. Further prospective evidence is needed to routinely apply machine learning algorithms in clinical practice., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Early stages of colorectal cancer (CRC) development are characterized by a complex rewiring of transcriptional networks resulting in changes in the expression of multiple genes. Here, we demonstrate that the deletion of a poorly studied tetraspanin protein Tspan6 in Apc min/+ mice, a well-established model for premalignant CRC, resulted in increased incidence of adenoma formation and tumor size. We demonstrate that the effect of Tspan6 deletion results in the activation of EGF-dependent signaling pathways through increased production of the transmembrane form of TGF-α (tmTGF-α) associated with extracellular vesicles. This pathway is modulated by an adaptor protein syntenin-1, which physically links Tspan6 and tmTGF-α. In support of this, the expression of Tspan6 is frequently decreased or lost in CRC, and this correlates with poor survival. Furthermore, the analysis of samples from the epidermal growth factor receptor (EGFR)-targeting clinical trial (COIN trial) has shown that the expression of Tspan6 in CRC correlated with better patient responses to EGFR-targeted therapy involving Cetuximab. Importantly, Tspan6-positive patients with tumors in the proximal colon (right-sided) and those with KRAS mutations had a better response to Cetuximab than the patients that expressed low Tspan6 levels. These results identify Tspan6 as a regulator of CRC development and a potential predictive marker for EGFR-targeted therapies in CRC beyond RAS pathway mutations., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Objective: Recent years have seen a significant and rapid increase in the provision of tele-therapies. Chairwork methods such as empty-chair dialogues and role-play represent a "common" category of therapeutic interventions which are utilized in many psychotherapeutic approaches. However, guidelines for facilitating chairwork in tele-therapy are currently lacking. The aim of this study was to survey expert providers regarding how chairwork is best provided in internet-delivered psychotherapy. Method: Forty one experts were recruited from a range of therapeutic backgrounds including cognitive behaviour therapy, compassion focused therapy, emotion focused therapy, psychodrama, schema therapy, and voice dialogue. Participants completed a brief questionnaire survey exploring the delivery of tele-chairwork. Responses were analysed using thematic analysis. Results: Five themes were identified: (i) divided opinion; (ii) convergence between therapy and home; (iii) disconnection and depth; (iv) practical impediments and benefits; and (v) revising and re-visioning chairwork. Overall, results indicate that chairwork can be successfully incorporated into tele-therapy, but requires adaption and special considerations. Discussion: Despite challenges, tele-chairwork appears to be a feasible method of psychotherapeutic intervention. Preliminary guidelines for initiating, facilitating, and concluding tele-chairwork are presented, alongside future directions for research.

Background: The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC., Methods: We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 × 10-06. Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided., Results: The genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P < 5 × 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor-positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 × 10-30)., Conclusions: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men., (© The Author(s) 2020. Published by Oxford University Press.)

Rates of loco-regional recurrence and distant metastasis remain high among head and neck squamous cell carcinoma (HNSCC) patients, despite advancing cancer treatment modalities and therapeutic agents. One area that has generated considerable interest is the immune landscape of the tumour, heralding a wave of immune checkpoint inhibitors with notable efficacy in recurrent/metastatic HNSCC patients. However, HNSCC remains poorly served by biomarkers that can direct treatment in a personalised fashion to target the tumour heterogeneity seen between patients. Detection and analysis of circulating tumour cells (CTCs) in HNSCC has provided a previously unseen view of the metastasis forming cells that are potentially contributing to poor clinical outcomes. In particular, identifying CTC expression of phenotypic and druggable protein markers has allowed CTC sub-populations to be defined that hold prognostic value or are potential therapeutic targets themselves. The aim of this systematic review was to examine the role of CTC immune-marker expression as prognostic/therapeutic biomarkers in HNSCC by evaluating progress to date and discussing areas for future research. Our results highlight how few studies have been able to demonstrate prognostic significance of immune-marker expression in CTCs. As expected, the immune checkpoint PD-L1 was the most widely investigated marker. However, no studies evaluated CTC target immune marker expression in immunotherapy cohorts. Despite these findings, the data presented demonstrate promise that CTCs may be a source of future biomarkers for immunotherapy and will provide valuable information regarding the potential immune evasion of these metastasis forming cells.

Noggin is an antagonist of bone morphogenetic proteins (BMP), being indispensable for certain developmental events. The present study aimed to examine the role of Noggin in the development and prognosis of gastric cancer (GC) and to elucidate the underlying mechanisms. The expression of Noggin in GC was evaluated by RT‑qPCR, immunohistochemistry and by the analyses of publicly available databases. The effects of Noggin on proliferation, cell cycle, adhesion, invasion, colony formation and tumour spheroid were examined following both the knockdown and overexpression of Noggin in GC cell lines. The involvement of epidermal growth factor receptor (EGFR) signalling was examined by western blot analysis and by using small molecule inhibitors. As a result, a higher expression of Noggin in GC was found to be associated with a poorer overall survival. Noggin overexpression promoted the proliferation and colony formation of GC cells by promoting cell cycle progression. The knockdown of Noggin in HGC27 cells exerted an opposite effect on proliferation, colony formation and cell cycle progression. Noggin expression positively correlated with EGFR expression in both GC cell line models and The Cancer Genome Atlas human GC cohort. Targeting EGFR and its downstream pathways diminished cell proliferation which was promoted by Noggin. Furthermore, Noggin overexpression resulted in an enhanced nuclear translocation of β‑catenin, leading to an upregulation of EGFR. Thus, the findings of the present study demonstrate that Noggin promotes the proliferation of GC cells by upregulating EGFR and enhancing a vicious circle formed by β‑catenin, EGFR, ERK and Akt.

Background & Aims: Cancer therapy with immune checkpoint inhibitors can cause colitis and colon perforation. We investigated whether infection with Epstein Barr virus (EBV) associates with development and severity of colitis in patients receiving immune checkpoint inhibitor therapies., Methods: We performed a retrospective analysis of fixed colon tissues from 16 patients (12 men, 4 women, median age, 69.5 y) with colitis after immune checkpoint inhibitor therapy (9 patients treated with anti-CTLA4, 3 patients treated with anti-PD1, and 4 patients received a combination). Ten tissue samples were biopsies and 6 were collected during resection (4 surgeries for colon perforation). Patients were treated between 2010 and 2018 in the United Kingdom. The tissues were analyzed by pathology, in situ hybridization (to detect EBV-encoded small RNAs [EBERs]), and immunohistochemistry. Clinical data were also collected., Results: Colon tissues from 4 of the 13 patients who received anti-CTLA4 (alone or in combination, 4 with colon perforation) had EBV-positive lymphoproliferations that manifested as florid ulcers associated with polymorphous infiltrates containing EBV-positive blasts (CD30+ or CD30-negative, CD20+, CD3-negative, and EBER+), plasma cells (CD138+, CD20-negative, and EBER+ or EBER-negative), and small B cells (CD20+, CD3-negative, and EBER+ or EBER-negative), consistent with EBV-positive mucocutaneous ulcers (EBVMCUs). In analyses of biopsies collected from 2 patients with EBVMCUs over multiple time points, we found that earlier biopsies had no or only a few EBV-positive cells, whereas 1 later biopsy had EBVMCU and co-infection with cytomegalovirus. EBVMCUs were associated with steroid-refractory colitis (100% of EBV-positive patients vs 12.5% of EBV-negative patients; P = .008) and colon perforation (100% of EBV-positive patients vs no EBV-negative patients; P = .001)., Conclusions: We found that colon tissues from 4/13 patients with colitis after anti-CTLA4 therapy (4/6 patients who underwent resection and 4/4 patients with colon perforation) contained EBVMCUs. EBVMCUs seem to arise secondarily in areas of inflamed colon due to immunosuppressive treatment for colitis. EBVMCUs are associated with steroid-refractory colitis and colon perforation., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: The coronavirus pandemic has led to a dramatically different way of working for many therapists working with eating disorders, where telehealth has suddenly become the norm. However, many clinicians feel ill equipped to deliver therapy via telehealth, while adhering to evidence-based interventions. This article draws together clinician experiences of the issues that should be attended to, and how to address them within a telehealth framework., Method: Seventy clinical colleagues of the authors were emailed and invited to share their concerns online about how to deliver cognitive-behavioral therapy for eating disorders (CBT-ED) via telehealth, and how to adapt clinical practice to deal with the problems that they and others had encountered. After 96 hr, all the suggestions that had been shared by 22 clinicians were collated to provide timely advice for other clinicians., Results: A range of themes emerged from the online discussion. A large proportion were general clinical and practical domains (patient and therapist concerns about telehealth; technical issues in implementing telehealth; changes in the environment), but there were also specific considerations and clinical recommendations about the delivery of CBT-ED methods., Discussion: Through interaction and sharing of ideas, clinicians across the world produced a substantial number of recommendations about how to use telehealth to work with people with eating disorders while remaining on track with evidence-based practice. These are shared to assist clinicians over the period of changed practice., (© 2020 The Authors. International Journal of Eating Disorders published by Wiley Periodicals, Inc.)

Background: Clinical guidelines emphasize identifying atrial fibrillation (AF) as a strategy to reduce stroke risk. Cardiac implantable electronic device (CIED) interrogation at the point of care may facilitate AF detection, increasing opportunities to identify patients at high risk for stroke., Objectives: This study sought to quantify AF prevalence and assess stroke risk in patients with a CIED who presented to the emergency department (ED)., Methods: This noninterventional, retrospective observational study included adult patients who presented at a single facility ED that incorporated device interrogation as a routine standard practice for all patients with a CIED. Interrogations were conducted in 494 unique patients, and relevant demographic/clinical information was captured from electronic medical records., Results: AF was detected via CIED interrogation in 54.8% (271/494) of the unique patient population that presented to the ED. Device interrogation detected the presence of AF in 110 patients without a documented past history or current diagnosis of AF, representing 22.3% (110/494) of total unique patients. Based on CHA 2 DS 2 -VASc (Congestive heart failure, Hypertension, Age > 75 years, Diabetes mellitus, prior Stroke or transient ischemic attack or thromboembolism, Vascular disease, Age 65-74 years, Sex category [female]) risk scoring methodology, over three-quarters of these newly detected AF patients (78.2%, 86/110) were classified in a high stroke risk category that reflected a > 2.2% annualized risk, and over half (57.3%, 63/110) presented to the ED for reasons unrelated to cardiac/dysrhythmia problems., Conclusions: The use of technology-assisted device interrogation of CIEDs at the point of care has promise in identifying patients with asymptomatic AF. Results suggest consideration of routine device interrogation of CIEDs in the ED, regardless of reason for admission or history of AF., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Competing Interests: The authors report no conflicts of interest.

Individuals with anorexia nervosa often describe experiencing an internal "voice" of their disorder, which previous research has associated with multiple dimensions of eating pathology. This pilot study examined whether eating disorder measures use invoice characteristics at the outset of outpatient therapy predicted changes in disordered eating over the course of treatment. Participants were 14 individuals meeting ICD-10 criteria for anorexia nervosa. Participants completed measures relating to the severity of disordered eating and voice-related characteristics (perceived voice power and metacognitive appraisals about its nature) at the start and end of therapy. Results indicated that the perceived power of the eating disorder was reduced over the course of outpatient therapy, although its other characteristics remained stable. Greater levels of voice power, omnipotence and benevolence at the outset of therapy were related to greater improvements in eating attitudes. No voice-related characteristics were associated with changes in weight. These findings suggest that voice-related appraisals do not obstruct the effectiveness of outpatient therapies for anorexia nervosa. Further studies are needed to ratify these preliminary findings.

Many individuals diagnosed with eating disorders describe their disorder as being represented by an internal 'voice'. In line with cognitive models of voice-hearing, previous research has identified associations between voice appraisals and eating psychopathology in anorexia nervosa. Whether these findings generalise to other eating disorder subtypes remains unknown. The aetiology of the internal eating disorder voice also remains unclear. Traumatic-dissociative models of voice-hearing, which link such experiences to decontexualised material arising from early traumatic events, might also be relevant to eating disorder groups. To determine whether cognitive models of trauma and voice-hearing apply across eating disorder subtypes, 85 individuals fulfilling ICD-10 criteria for an eating disorder completed self-report measures regarding eating disorder cognitions, voice-related appraisals, childhood trauma, and dissociation. The relative power of the eating disorder voice was found to be positively associated with experiences of childhood emotional abuse, and this relationship was partly mediated by dissociation. In addition, eating disorder voices appraised as powerful and benevolent predicted more negative attitudes towards eating across diagnostic groups, but were unrelated to disordered eating behaviours or weight. These findings suggest that the eating disorder voice plays a meaningful role in eating pathology across diagnoses and that this experience might be related, in part, to experiences of childhood maltreatment. Therapeutic implications are discussed., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Context: - Pleural pathology has been dominated by discussions relating to the diagnosis, prognosis, etiology, and management of malignant mesothelioma. However, there exists a diverse group of other neoplasms that involve the pleura; the most common by far is metastatic carcinoma, usually of pulmonary origin. Other metastatic tumors of varied histogenesis do occur but are less common. Primary pleural neoplasms other than diffuse malignant mesothelioma are either uncommon or rare and have received less attention., Objective: - To provide a review of those diverse tumors that can involve the pleura other than mesothelioma in order to facilitate their accurate diagnosis., Data Sources: - Review of relevant literature published via PubMed and other search engines., Conclusions: - A wide variety of tumors can involve the pleura. In most cases, the approach of considering the morphologic features with appropriate immunohistochemistry, in the correct clinical context, allows for a confident diagnosis. For a number of those soft tissue tumors that are well recognized in the pleura, such as solitary fibrous tumor, desmoid-type fibromatosis, synovial sarcoma, and epithelioid hemangioendothelioma, novel markers now exist based on an understanding of the individual tumors' molecular characteristics. Primary pleural lymphomas are rare with poor prognosis. They represent localized specific diffuse large B-cell lymphomas, with either post-germinal center B-cell or plasma cell lineage, arising in the context of either immunodeficiency or immune sequestration and with viral infection.

In common with individuals experiencing a number of disorders, people with anorexia nervosa report experiencing an internal 'voice'. The anorexic voice comments on the individual's eating, weight and shape and instructs the individual to restrict or compensate. However, the core characteristics of the anorexic voice are not known. This study aimed to develop a parsimonious model of the voice characteristics that are related to key features of eating disorder pathology and to determine whether patients with anorexia nervosa fall into groups with different voice experiences. The participants were 49 women with full diagnoses of anorexia nervosa. Each completed validated measures of the power and nature of their voice experience and of their responses to the voice. Different voice characteristics were associated with current body mass index, duration of disorder and eating cognitions. Two subgroups emerged, with 'weaker' and 'stronger' voice experiences. Those with stronger voices were characterized by having more negative eating attitudes, more severe compensatory behaviours, a longer duration of illness and a greater likelihood of having the binge-purge subtype of anorexia nervosa. The findings indicate that the anorexic voice is an important element of the psychopathology of anorexia nervosa. Addressing the anorexic voice might be helpful in enhancing outcomes of treatments for anorexia nervosa, but that conclusion might apply only to patients with more severe eating psychopathology. Copyright © 2016 John Wiley & Sons, Ltd., Key Practitioner Message: Experiences of an internal 'anorexic voice' are common in anorexia nervosa. Clinicians should consider the role of the voice when formulating eating pathology in anorexia nervosa, including how individuals perceive and relate to that voice. Addressing the voice may be beneficial, particularly in more severe and enduring forms of anorexia nervosa. When working with the voice, clinicians should aim to address both the content of the voice and how individuals relate and respond to it., (Copyright © 2016 John Wiley & Sons, Ltd.)

Objective: Internal "anorexic voices" are commonly described by individuals with eating disorders. This study examines whether the perceived power and nature of that voice are related to eating pathology in anorexia nervosa., Method: Sixty-three women and one man with an ICD-10 diagnosis of anorexia nervosa participated in this study (mean age = 27.3 years; mean BMI = 16.0). Participants completed questionnaires measuring severity of eating pathology, perceived voice power, and beliefs about voices, either at the start or during treatment., Results: A more powerful anorexic voice was associated with more negative eating attitudes in this clinical group. However, BMI was related to a moderating effect, with the interaction of greater voice power and malevolence being associated with a lower BMI., Discussion: These findings suggest the anorexic voice may function as a maintenance factor in anorexia nervosa. Cognitive models of hearing voices may be applicable to disorders other than psychosis. Further explorations are warranted. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:622-625)., (© 2016 Wiley Periodicals, Inc.)

Whilst cognitive-behavioural therapy has demonstrated efficacy in the treatment of eating disorders, therapy outcomes and current conceptualizations still remain inadequate. In light of these shortcomings there has been growing interest in the utility of schema therapy applied to eating pathology. The present article first provides a narrative review of empirical literature exploring schemas and schema processes in eating disorders. Secondly, it critically evaluates outcome studies assessing schema therapy applied to eating disorders. Current evidence lends support to schema-focused conceptualizations of eating pathology and confirms that eating disorders are characterised by pronounced maladaptive schemas. Treatment outcomes also indicate that schema therapy, the schema-mode approach, and associated techniques are promising interventions for complex eating disorders. Implications for clinical practice and future directions for research are discussed., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Evidence-based cognitive-behavioural therapy (CBT) for the eating disorders has an early focus on behavioural changes around food intake. However, patients' anxiety around such change might account for why they often seem unmotivated in treatment. In order to determine the impact of changing intake, this pilot study of patients with bulimic disorders (N = 19) or anorexia nervosa (N = 9) used a mixed quantitative and qualitative design to retrospectively examine their perspectives of the short- and long-term pros and cons of such change. As expected, change was seen negatively in the short-term (with particularly high numbers reporting anxiety), but there were few reports of long-term negative outcomes. In contrast, there were both short- and long-term benefits of changing eating. The patients described what was helpful in making changes and what they had learned as a result. In both cases, their descriptions mapped closely onto the content and process of evidence-based CBT for the eating disorders. Although there is a need for more extensive research, these findings suggest that patients (and therapists) might benefit from being aware of the contrast between the short- and the long-term pros and cons of changing eating within CBT for the eating disorders., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objectives: Although empathy is considered by many to be fundamental to psychotherapeutic practice, little is known about how working with an interpreter may affect empathy in clinical work. Accordingly, the present study aims to provide an exploration of mental health professionals' experiences of empathy in clinical work with an interpreter., Design: A qualitative methodology was utilized in order to provide a rich understanding of participants' shared experiences of empathy in work with an interpreter. Data were gathered using a semi-structured interviewing approach. Interpretative phenomenological analysis (IPA) was chosen as the method of analysis as this would provide a highly descriptive and in-depth account of participants' experiences., Method: Interviews were conducted with 10 mental health professionals regularly working with linguistic interpreters. Interviews were transcribed and analysed using IPA., Results: The analysis yielded four major themes which described the effects of translation upon empathic dialogues with service-users; changes in the quality of empathic communication with service-users; the effects of cultural similarities and dissimilarities upon empathy within client-interpreter and client-professional dyads; and opportunities for the interpreter to enrich participants' understanding of service-users' perspectives., Conclusions: The difficulties participants encountered in work with an interpreter highlight a need for training in cross-language empathy for interpreters and mental health professionals, and encourage the use of transcultural models of psychotherapy in work with non-English speaking service-users. Some of the difficulties associated with adopting traditional humanistic models of empathy, which tend to centralize the therapist within empathic processes, when working with interpreters are also discussed.

A Diels-Alder/thiol-olefin co-oxygenation approach to the synthesis of novel bicyclic endoperoxides 17a-22b is reported. Some of these endoperoxides (e.g., 17b, 19b, 22a and 22b) have potent nanomolar in vitro antimalarial activity equivalent to that of the synthetic antimalarial agent arteflene. Iron(II)-mediated degradation of sulfone-endoperoxide 19b and spin-trapping with TEMPO provide a spin-trapped adduct 25 indicative of the formation of a secondary carbon centered radical species 24. Reactive C-radical intermediates of this type may be involved in the expression of the antimalarial effect of these bicyclic endoperoxides.