Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection.

Cytokine storm during viral infection is a prospective predictor of morbidity and mortality, yet the cellular sources remain undefined. Here, using genetic and chemical tools to probe functions of the S1P(1) receptor, we elucidate cellular and signaling mechanisms that are important in initiating cytokine storm. Whereas S1P(1) receptor is expressed on endothelial cells and lymphocytes within lung tissue, S1P(1) agonism suppresses cytokines and innate immune cell recruitment in wild-type and lymphocyte-deficient mice, identifying endothelial cells as central regulators of cytokine storm. Furthermore, our data reveal immune cell infiltration and cytokine production as distinct events that are both orchestrated by endothelial cells. Moreover, we demonstrate that suppression of early innate immune responses through S1P(1) signaling results in reduced mortality during infection with a human pathogenic strain of influenza virus. Modulation of endothelium with a specific agonist suggests that diseases in which amplification of cytokine storm is a significant pathological component could be chemically tractable.

Radiolabelling and preclinical characterisation of [89Zr]Zr-Df-ATG-101 bispecific to PD-L1/4-1BB.

PURPOSE: ATG-101, a bispecific antibody that simultaneously targets the immune checkpoint PD-L1 and the costimulatory receptor 4-1BB, activates exhausted T cells upon PD-L1 crosslinking. Previous studies demonstrated promising anti-tumour efficacy of ATG-101 in preclinical models. Here, we labelled ATG-101 with 89Zr to confirm its tumour targeting effect and tissue biodistribution in a preclinical model. We also evaluated the use of immuno-PET to study tumour uptake of ATG-101 in vivo. METHODS: ATG-101, anti-PD-L1, and an isotype control were conjugated with p-SCN-Deferoxamine (Df). The Df-conjugated antibodies were radiolabelled with 89Zr, and their radiochemical purity, immunoreactivity, and serum stability were assessed. We conducted PET/MRI and biodistribution studies on [89Zr]Zr-Df-ATG-101 in BALB/c nude mice bearing PD-L1-expressing MDA-MB-231 breast cancer xenografts for up to 10 days after intravenous administration of [89Zr]Zr-labelled antibodies. The specificity of [89Zr]Zr-Df-ATG-101 was evaluated through a competition study with unlabelled ATG-101 and anti-PD-L1 antibodies. RESULTS: The Df-conjugation and [89Zr]Zr -radiolabelling did not affect the target binding of ATG-101. Biodistribution and imaging studies demonstrated biological similarity of [89Zr]Zr-Df-ATG-101 and [89Zr]Zr-Df-anti-PD-L1. Tumour uptake of [89Zr]Zr-Df-ATG-101 was clearly visualised using small-animal PET imaging up to 7 days post-injection. Competition studies confirmed the specificity of PD-L1 targeting in vivo. CONCLUSION: [89Zr]Zr-Df-ATG-101 in vivo distribution is dependent on PD-L1 expression in the MDA-MB-231 xenograft model. Immuno-PET with [89Zr]Zr-Df-ATG-101 provides real-time information about ATG-101 distribution and tumour uptake in vivo. Our data support the use of [89Zr]Zr-Df-ATG-101 to assess tumour and tissue uptake of ATG-101.

Targeting of immune checkpoint regulator V-domain Ig suppressor of T-cell activation (VISTA) with 89Zr-labelled CI-8993.

BACKGROUND: CI-8993 is a fully human IgG1κ monoclonal antibody (mAb) that binds specifically to immune checkpoint molecule VISTA (V-domain Ig suppressor of T-cell activation). Phase I safety has been established in patients with advanced cancer (NCT02671955). To determine the pharmacokinetics and biodistribution of CI-8993 in patients, we aimed to develop 89Zr-labelled CI-8993 and validate PET imaging and quantitation in preclinical models prior to a planned human bioimaging trial. METHODS: CI-8993 and human isotype IgG1 control were conjugated to the metal ion chelator p-isothiocyanatobenzyl-desferrioxamine (Df). Quality of conjugates were assessed by SE-HPLC, SDS-PAGE, and FACS. After radiolabelling with zirconium-89 (89Zr), radioconjugates were assessed for radiochemical purity, immunoreactivity, antigen binding affinity, and serum stability in vitro. [89Zr]Zr-Df-CI-8993 alone (1 mg/kg, 4.6 MBq) or in combination with 30 mg/kg unlabelled CI-8993, as well as isotype control [89Zr]Zr-Df-IgG1 (1 mg/kg, 4.6 MBq) were assessed in human VISTA knock-in female (C57BL/6 N-Vsirtm1.1(VSIR)Geno, huVISTA KI) or control C57BL/6 mice bearing syngeneic MB49 bladder cancer tumours; and in BALB/c nu/nu mice bearing pancreatic Capan-2 tumours. RESULTS: Stable constructs with an average chelator-to-antibody ratio of 1.81 were achieved. SDS-PAGE and SE-HPLC showed integrity of CI-8993 was maintained after conjugation; and ELISA indicated no impact of conjugation and radiolabelling on binding to human VISTA. PET imaging and biodistribution in MB49 tumour-bearing huVISTA KI female mice showed specific localisation of [89Zr]Zr-Df-CI-8993 to VISTA in spleen and tumour tissues expressing human VISTA. Specific tumour uptake was also demonstrated in Capan-2 xenografted BALB/c nu/nu mice. CONCLUSIONS: We radiolabelled and validated [89Zr]Zr-Df-CI-8993 for specific binding to huVISTA in vivo. Our results demonstrate that 89Zr-labelled CI-8993 is now suitable for targeting and imaging VISTA expression in human trials.

Practices and perceptions of strength and conditioning training in female golf: A cross-sectional survey study of high-level amateur players.

This study aims to ascertain an in-depth understanding of current practices and perceptions of S&C training in high-level amateur female golfers. A cross-sectional, explorative survey study was constructed which asked questions relating to four key areas: i) general participant information, ii) current strength and conditioning (S&C) practices, iii) the perceived influence of S&C training on golf performance, and iv) knowledge and awareness of S&C. Results showed that the majority of female players had participated in some form of S&C training in the past, with the majority believing that clubhead speed and carry distance were the primary golfing metrics which could be positively impacted. More specifically, 91-97% of the players "Strongly agreed" or "Agreed" that the key physical characteristics for golf were strength and power for the lower and upper body, and flexibility. Interestingly, 58% of the players believed that S&C training should mimic the movement of the golf swing, which based off current evidence, is not how drive metrics and ultimately shots gained, can be maximised. This survey study provides useful information relating to the practices and perceptions of S&C training in high-level female amateur players and areas where education may be able to further advance player understanding of physical preparation.

Consensus on a netball video analysis framework of descriptors and definitions by the netball video analysis consensus group.

Using an expert consensus-based approach, a netball video analysis consensus (NVAC) group of researchers and practitioners was formed to develop a video analysis framework of descriptors and definitions of physical, technical and contextual aspects for netball research. The framework aims to improve the consistency of language used within netball investigations. It also aims to guide injury mechanism reporting and identification of injury risk factors. The development of the framework involved a systematic review of the literature and a Delphi process. In conjunction with commercially used descriptors and definitions, 19 studies were used to create the initial framework of key descriptors and definitions in netball. In a two round Delphi method consensus, each expert rated their level of agreement with each of the descriptors and associated definition on a 5-point Likert scale (1-strongly disagree; 2-somewhat disagree; 3-neither agree nor disagree; 4-somewhat agree; 5-strongly agree). The median (IQR) rating of agreement was 5.0 (0.0), 5.0 (0.0) and 5.0 (0.0) for physical, technical and contextual aspects, respectively. The NVAC group recommends usage of the framework when conducting video analysis research in netball. The use of descriptors and definitions will be determined by the nature of the work and can be combined to incorporate further movements and actions used in netball. The framework can be linked with additional data, such as injury surveillance and microtechnology data.

A phase 1 safety and bioimaging trial of antibody DS-8895a against EphA2 in patients with advanced or metastatic EphA2 positive cancers.

Ephrin type-A 2 (EphA2) is a transmembrane receptor expressed in epithelial cancers. We report on a phase I dose escalation and biodistribution study of DS-8895a, an anti-EphA2 antibody, in patients with advanced EphA2 positive cancers. DS-8895a was administered at 1, 3, 10 or 20 mg/kg every 2 weeks to determine safety, pharmacokinetics and anti-tumor efficacy. All patients underwent 89Zr trace-labelled infusion of DS-8895a (89Zr-DS-8995a) positron emission tomography imaging to determine the biodistribution of DS-8895a, and correlate findings with EphA2 expression, receptor saturation and response. Nine patients were enrolled on study. Of patients enrolled, seven patients received at least one infusion of DS-8895a: four patients received 1 mg/kg dose (Cohort 1) and three patients received 3 mg/kg dose (Cohort 2). Median age was 67.0 years (range 52-81), majority male (71%), and median number of prior systemic therapies was three (range 0-8). The primary cancer diagnosis was colorectal cancer (two patients) and one patient each had gastric, head and neck, high-grade serous adenocarcinoma, lung, and pancreatic cancers. No dose-limiting toxicities or treatment-related adverse events reported. The best response for the patients in Cohort 1 was stable disease and in Cohort 2 was progressive disease. 89Zr-DS-8895a demonstrated no normal tissue uptake and specific low-grade uptake in most tumours. DS-8895a had limited therapeutic efficacy at doses evaluated and 89Zr-DS-8895a demonstrated low tumour uptake. The biodistribution data from this study were key in halting further development of DS-8895a, highlighting the importance of biodistribution studies in drug development. (Trial registration: ClinicalTrials.gov Identifier NCT02252211).

Development of dihydropyrrolopyridinone-based PKN2/PRK2 chemical tools to enable drug discovery.

The Protein Kinase N proteins (PKN1, PKN2 and PKN3) are Rho GTPase effectors. They are involved in several biological processes such as cytoskeleton organization, cell mobility, adhesion, and cell cycle. Recently PKNs have been reported as essential for survival in several tumor cell lines, including prostate and breast cancer. Here, we report the development of dihydropyrrolopyridinone-based inhibitors for PKN2 and its closest homologue, PKN1, and their associated structure-activity relationship (SAR). Our studies identified a range of molecules with high potency exemplified by compound 8 with Ki = 8 nM for PKN2 and 14x selectivity over PKN1. Membrane permeability and target engagement for PKN2 were assessed by a NanoBRET cellular assay. Importantly, good selectivity across the wider human kinome and other kinase family members was achieved. These compounds provide strong starting points for lead optimization to PKN1/2 development compounds.

Radiolabelling and preclinical characterization of 89Zr-Df-radiolabelled bispecific anti-PD-L1/TGF-ßRII fusion protein bintrafusp alfa.

PURPOSE: Τhis study aimed to optimize the 89Zr-radiolabelling of bintrafusp alfa investigational drug product and controls, and perform the in vitro and in vivo characterization of 89Zr-Df-bintrafusp alfa and 89Zr-Df-control radioconjugates. METHODS: Bintrafusp alfa (anti-PD-L1 human IgG1 antibody fused to TGF-ß receptor II (TGF-ßRII), avelumab (anti-PD-L1 human IgG1 control antibody), isotype control (mutated inactive anti-PD-L1 IgG1 control antibody), and trap control (mutated inactive anti-PD-L1 human IgG1 fused to active TGF-ßRII) were chelated with p-isothiocyanatobenzyl-desferrioxamine (Df). After radiolabelling with zirconium-89 (89Zr), radioconjugates were assessed for radiochemical purity, immunoreactivity, antigen binding affinity, and serum stability in vitro. In vivo biodistribution and imaging studies were performed with PET/CT to identify and quantitate 89Zr-Df-bintrafusp alfa tumour uptake in a PD-L1/TGF-ß-positive murine breast cancer model (EMT-6). Specificity of 89Zr-Df-bintrafusp alfa was assessed via a combined biodistribution and imaging experiment in the presence of competing cold bintrafusp alfa (1 mg/kg). RESULTS: Nanomolar affinities for PD-L1 were achieved with 89Zr-Df-bintrafusp alfa and 89Zr-avelumab. Biodistribution and imaging studies in PD-L1- and TGF-ß-positive EMT-6 tumour-bearing BALB/c mice demonstrated the biologic similarity of 89Zr-Df-bintrafusp alfa and 89Zr-avelumab indicating the in vivo distribution pattern of bintrafusp alfa is driven by its PD-L1 binding arm. Competition study with 1 mg of unlabelled bintrafusp alfa or avelumab co-administered with trace dose of 89Zr-labelled bintrafusp alfa demonstrated the impact of dose and specificity of PD-L1 targeting in vivo. CONCLUSION: Molecular imaging of 89Zr-Df-bintrafusp alfa biodistribution was achievable and allows non-invasive quantitation of tumour uptake of 89Zr-Df-bintrafusp alfa, suitable for use in bioimaging clinical trials in cancer patients.

Inhibition of the ULK1 protein complex suppresses Staphylococcus-induced autophagy and cell death.

Autophagy plays multiple roles in host cells challenged with extracellular pathogens. Here, we aimed to explore whether autophagy inhibition could prevent bacterial infections. We first confirmed widely distinct patterns of autophagy responses in host cells infected with Staphylococcus aureus, as compared with Salmonella Only infection with Staphylococcus produced strong accumulation of lipidated autophagy-related protein LC3B (LC3B-II). Infection with virulent Staphylococcus strains induced formation of p62-positive aggregates, suggestive of accumulated ubiquitinated targets. During Salmonella infection, bacteria remain enclosed by lysosomal-associated membrane protein 2 (LAMP2)-positive lysosomes, whereas virulent Staphylococcus apparently exited from enlarged lysosomes and invaded the cytoplasm. Surprisingly, Staphylococcus appeared to escape from the lysosome without generation of membrane-damage signals as detected by galectin-3 recruitment. In contrast, Salmonella infection produced high levels of lysosomal damage, consistent with a downstream antibacterial xenophagy response. Finally, we studied the Unc-51-like autophagy-activating kinase 1 (ULK1) regulatory complex, including the essential subunit autophagy-related protein 13 (ATG13). Infection of cells with either Staphylococcus or Salmonella led to recruitment of ATG13 to sites of cytosolic bacterial cells to promote autophagosome formation. Of note, genetic targeting of ATG13 suppressed autophagy and the ability of Staphylococcus to infect and kill host cells. Two different ULK1 inhibitors also prevented Staphylococcus intracellular replication and host cell death. Interestingly, inhibition of the ULK1 pathway had the opposite effect on Salmonella, sensitizing cells to the infection. Our results suggest that ULK1 inhibitors may offer a potential strategy to impede cellular infection by S. aureus.

Development of 2-(4-pyridyl)-benzimidazoles as PKN2 chemical tools to probe cancer.

Kinases are signalling proteins which have proven to be successful targets for the treatment of a variety of diseases, predominantly in cancers. However, only a small proportion of kinases (<20%) have been investigated for their therapeutic viability, likely due to the lack of available chemical tools across the kinome. In this work we describe initial efforts in the development of a selective chemical tool for protein kinase N2 (PKN2), a relatively unexplored kinase of interest in several types of cancer. The most successful compound, 5, has a measured IC50 of 0.064 µM against PKN2, with ca. 17-fold selectivity over close homologue, PKN1.

Determinants of ovarian function after response-adapted therapy in patients with advanced Hodgkin's lymphoma (RATHL): a secondary analysis of a randomised phase 3 trial.

BACKGROUND: Adverse effects on reproductive function are a key concern in young women treated with chemotherapy for advanced Hodgkin's lymphoma. We aimed to identify risk factors for the extent of ovarian damage in women with Hodgkin's lymphoma treated with different chemotherapy regimens to inform accurate advice on options for fertility preservation. METHODS: We recruited female participants from the randomised phase 3 RATHL trial, aged 18-45 years, based on availability of participants at recruiting sites in the UK. The RATHL trial key inclusion criteria were histologically confirmed classic Hodgkin's lymphoma, stage IIB-IV or IIA with adverse features (bulky disease or more than two sites of involvement), no previous treatments, and a performance status of 0-3. As part of RATHL, participants were treated with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or AVD followed by an interim PET-CT scan. Participants who had negative interim scans (PET score of 1 to 3 according to the Lugano classification) were randomly assigned (1:1) by use of minimisation, stratified by interim PET score and study centre, to continue ABVD or AVD for four more cycles. Participants with positive scans (PET score of 4 or 5) were escalated to treatment with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone (BEACOPP-14 or escalated BEACOPP) for four cycles. For the protocol-driven prospective cohort substudy, ovarian function was assessed before treatment, during chemotherapy, and then annually for 3 years by use of serum antimüllerian hormone and follicle-stimulating hormone measurements. The RATHL study is registered with ClinicalTrials.gov, number NCT00678327. FINDINGS: Between Dec 13, 2010, and Dec 19, 2012, 67 eligible participants were recruited for this prospective cohort study; 57 had received ABVD or AVD (ABVD-AVD group) and ten BEACOPP-14 or escalated BEACOPP (BEACOPP group). Follow-up was fixed at 3 years. Antimüllerian hormone concentrations decreased during both chemotherapy regimens. At 1 year after chemotherapy, antimüllerian hormone concentrations recovered to a median of 10·5 pmol/L (IQR 4·3-17·3) in the ABVD-AVD group, but little recovery was seen after BEACOPP (median 0·11 pmol/L [0·07-0·20]). Age also affected the extent of ovarian function recovery, with antimüllerian hormone recovery in participants aged 35 years or older in the ABVD-AVD group to 37% (SD 10) of their before treatment concentrations, compared with full recovery to 127% (SD 12) in those younger than 35 years (p<0·0001). Follicle-stimulating hormone recovery to less than 25 IU/L occurred for 95% of women younger than 35 years in the ABVD-AVD group by 2 years and was also dependent on age (hazard ratio 0·49, 95% CI 0·37-0·65; p<0·0001). INTERPRETATION: Reduced recovery of ovarian function observed in women older than 35 years treated with ABVD or AVD compared with younger women indicates that treatment could reduce their reproductive lifespan and supports discussion of fertility preservation before treatment. Women treated with BEACOPP should be informed of its potential high gonadotoxicity. These findings warrant further investigation in large, prospective studies with fertility and reproductive lifespan as outcomes. FUNDING: Medical Research Foundation and Cancer Research UK.

Transnitrosylation of XIAP regulates caspase-dependent neuronal cell death.

X-linked inhibitor of apoptosis (XIAP) is a potent antagonist of caspase apoptotic activity. XIAP also functions as an E3 ubiquitin ligase, targeting caspases for degradation. However, molecular pathways controlling XIAP activities remain unclear. Here, we report that nitric oxide (NO) reacts with XIAP by S-nitrosylating its RING domain (forming SNO-XIAP), thereby inhibiting E3 ligase and antiapoptotic activity. NO-mediated neurotoxicity and caspase activation have been linked to several neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases. We find significant SNO-XIAP formation in brains of patients with these diseases, implicating this reaction in the etiology of neuronal damage. Conversely, S-nitrosylation of caspases is known to inhibit apoptotic activity. Unexpectedly, we find that SNO-caspase transnitrosylates (transfers its NO group) to XIAP, forming SNO-XIAP, and thus promotes cell injury and death. These findings provide insights into the regulation of caspase activation in neurodegenerative disorders mediated, at least in part, by nitrosative stress.

Epidemiology of autism in adults across age groups and ability levels.

BACKGROUND: The epidemiology of autism in adults has relied on untested projections using childhood research. AIMS: To derive representative estimates of the prevalence of autism and key associations in adults of all ages and ability levels. METHOD: Comparable clinical diagnostic assessments of 7274 Adult Psychiatric Morbidity Survey participants combined with a population case-register survey of 290 adults with intellectual disability. RESULTS: The combined prevalence of autism in adults of all ages in England was 11/1000 (95% CI 3-19/1000). It was higher in those with moderate to profound intellectual disability (odds ratio (OR) = 63.5, 95% CI 27.4-147.2). Male gender was a strong predictor of autism only in those with no or mild intellectual disability (adjusted OR = 8.5, 95% CI 2.0-34.9; interaction with gender, P = 0.03). CONCLUSIONS: Few adults with autism have intellectual disability; however, autism is more prevalent in this population. Autism measures may miss more women with autism.

Galectin 3 regulates HCC cell invasion by RhoA and MLCK activation.

Hepatocellular carcinoma (HCC) carries a poor prognosis with no effective treatment available other than liver transplantation for selected patients. Vascular invasion of HCC is one of the most important negative predictor of survival. As the regulation of invasion of HCC cells is not well understood, our aim was to study the mechanisms by which galectin 3, a ß-galactosidase-binding lectin mediates HCC cell migration. HCC was induced by N-diethylnitrosamine in wild-type and galectin 3(-/-) mice, and tumor formation, histology, and tumor cell invasion were assessed. The galectin 3(-/-) mice developed significantly smaller tumor burden with a less invasive phenotype than the wild-type animals. Galectin 3 was upregulated in the wild-type HCC tumor tissue, but not in the surrounding parenchyma. Galectin 3 expression in HCC was induced by NF-κB transactivation as determined by chromatin immunoprecipitation assays. In vitro studies assessed the pro-migratory effects of galectin 3. The migration of hepatoma cells was significantly decreased after transfection by the galectin 3 siRNA and also after using the Rho kinase inhibitor Y-27632. The reorganization of the actin cytoskeleton, RhoA GTPase activity and the phosphorylation of MLC2 (myosin light chain 2) were decreased in the galectin 3 siRNA-transfected cells. In addition, in vitro and in vivo evidence showed that galectin 3 deficiency reduced hepatoma cell proliferation and increased their apoptosis rate. In conclusion, galectin 3 is an important lectin that is induced in HCC cells, and promotes hepatoma cell motility and invasion by an autocrine pathway. Targeting galectin 3 therefore could be an important novel treatment strategy to halt disease progression.

Integral membrane protease fibroblast activation protein sensitizes fibrosarcoma to chemotherapy and alters cell death mechanisms.

Fibroblast activation protein (FAP), an integral membrane serine protease, is found on fibro- and osteo-sarcoma and on myofibroblasts in epithelial carcinoma, but rarely on other adult tissue. FAP has been demonstrated to be an excellent target for tumor imaging in clinical trials, and antibodies and other FAP-targeting drugs are in development. Here we have shown that FAP overexpression increased the growth of HT1080 fibrosarcoma cells in vitro and in vivo, and found that the expression of FAP affects response to chemotherapy. When treated with doxorubicin, expression of FAP increased susceptibility to the drug. In spite of this, FAP-HT1080 cells had fewer markers of classical apoptosis than HT1080 cells and neither necrosis nor necroptosis were enhanced. However, levels of early mitochondrial and lysosomal membrane permeability markers were increased, and autophagy switched from a protective function in HT1080 cells to part of the cell death mechanism with FAP expression. Therefore, FAP may affect how the tumor responds to chemotherapeutic drugs overall, which should be considered in targeted drug development. The overexpression of FAP also alters cell signaling and responses to the environment in this cell line. This includes cell death mechanisms, changing the response of HT1080 cells to doxorubicin from classical apoptosis to an organelle membrane permeability-dependent form of cell death.

The Fas-FADD death domain complex structure unravels signalling by receptor clustering.

The death inducing signalling complex (DISC) formed by Fas receptor, FADD (Fas-associated death domain protein) and caspase 8 is a pivotal trigger of apoptosis. The Fas-FADD DISC represents a receptor platform, which once assembled initiates the induction of programmed cell death. A highly oligomeric network of homotypic protein interactions comprised of the death domains of Fas and FADD is at the centre of DISC formation. Thus, characterizing the mechanistic basis for the Fas-FADD interaction is crucial for understanding DISC signalling but has remained unclear largely because of a lack of structural data. We have successfully formed and isolated the human Fas-FADD death domain complex and report the 2.7 A crystal structure. The complex shows a tetrameric arrangement of four FADD death domains bound to four Fas death domains. We show that an opening of the Fas death domain exposes the FADD binding site and simultaneously generates a Fas-Fas bridge. The result is a regulatory Fas-FADD complex bridge governed by weak protein-protein interactions revealing a model where the complex itself functions as a mechanistic switch. This switch prevents accidental DISC assembly, yet allows for highly processive DISC formation and clustering upon a sufficient stimulus. In addition to depicting a previously unknown mode of death domain interactions, these results further uncover a mechanism for receptor signalling solely by oligomerization and clustering events.

'It's not always textbook social anxiety': A survey-based study investigating the nature of social anxiety and experiences of therapy in autistic people.

LAY ABSTRACT: The nature of social anxiety has been widely researched in non-autistic people. This existing research has allowed therapists to develop effective therapy for social anxiety in non-autistic people. Meanwhile, some research suggests that autistic people may have different experiences of anxiety compared to non-autistic people. In addition, there is some evidence that modified therapy may help autistic people with social anxiety, although we also know that many autistic people feel failed by existing mental health services.This article provides a detailed picture of social anxiety in autistic people. This includes similarities and differences compared to non-autistic people. In terms of similarities, people often described feeling afraid that others would judge them, and this would have negative consequences. In terms of differences, autistic people commonly reported a clash between their traits and their social environment, which caused them distress and discomfort. This included factors only rarely reported by non-autistic people (such as struggling with too much sensory stimulation or inaccessible forms of communication and encountering discrimination for these problems). Based on this, we propose a 'distinct' model of social anxiety with particular relevance to autistic people. In addition, many participants reported negative experiences in therapy for social anxiety. They thought therapists wrongly viewed their fears of social situations as irrational and ungrounded. They thought therapists did not adapt the therapy process in an individualised way and did not understand neurodiversity or recognise neurodivergence.Standard approaches for social anxiety may not always suit autistic people, so this needs further exploration. We highlight several practical recommendations for therapists offering therapy for social anxiety to autistic people.

Relationships and Within-Group Differences in Physical Attributes and Golf Performance in Elite Amateur Female Players.

The aim of the present study was to examine the association between a comprehensive physical testing battery and measures of golf performance in elite female amateur players. Nineteen category one (handicap ≤ 5) or better golfers (age: 16.26 ± 1.28 years, height: 166.26 ± 3.62 cm, mass: 64.04 ± 11.27 kg, wingspan: 146.53 ± 15.59 cm, handicap: +1.45 ± 0.7) volunteered to participate in this investigation. All golfers attended a single 90 min testing session where golf shot data (clubhead speed [CHS], ball speed, carry distance, and smash factor) were measured with a Trackman 4 launch monitor and a battery of physical assessments were carried out. These included anthropometric data and assessments for seated thoracic rotation, the isometric mid-thigh pull (IMTP), isometric bench press, countermovement jump (CMJ), and seated medicine ball throws for distance. Pearson's r correlations showed CHS was the golf metric that most commonly demonstrated large associations with physical testing data, most notably with force at 100 ms during the isometric bench press (r = 0.70). Median split analysis was also conducted for the IMTP (force at 200 ms), isometric bench press (force at 100 ms), and CMJ (positive impulse). The results showed that players who produced more force at 200 ms during the IMTP exhibited a greater CHS (g = 1.13), ball speed (g = 0.90), and carry distance (g = 1.01). In addition, players with a greater positive impulse during the CMJ showed a greater ball speed (g = 0.93), carry distance (g = 1.29), and smash factor (g = 1.27). Collectively, these results highlight the relevance of explosive force production capabilities in both the lower and upper body for female golfers. This information can be used by practitioners to better target key physical attributes during testing and training of female players.

An Anti-VEGF-B Antibody Reduces Abnormal Tumor Vasculature and Enhances the Effects of Chemotherapy.

The vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are key regulators of blood vessel formation, including in tumors, where their deregulated function can promote the production of aberrant, leaky blood vessels, supporting tumor development. Here we investigated the VEGFR1 ligand VEGF-B, which we demonstrate to be expressed in tumor cells and in tumor stroma and vasculature across a range of tumor types. We examined the anti-VEGF-B-specific monoclonal antibody 2H10 in preclinical xenograft models of breast and colorectal cancer, in comparison with the anti-VEGF-A antibody bevacizumab. Similar to bevacizumab, 2H10 therapy was associated with changes in tumor blood vessels and intra-tumoral diffusion consistent with normalization of the tumor vasculature. Accordingly, treatment resulted in partial inhibition of tumor growth, and significantly improved the response to chemotherapy. Our studies indicate the importance of VEGF-B in tumor growth, and the potential of specific anti-VEGF-B treatment to inhibit tumor development, alone or in combination with established chemotherapies.