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Cancer cachexia is a highly prevalent condition associated with poor quality of life and reduced survival 1 . Tumor-induced perturbations in the endocrine, immune and nervous systems drive anorexia and catabolic changes in adipose tissue and skeletal muscle, hallmarks of cancer cachexia 2 – 4 . However, the molecular mechanisms driving cachexia remain poorly defined, and there are currently no approved drugs for the condition. Elevation in circulating growth differentiation factor 15 (GDF15) correlates with cachexia and reduced survival in patients with cancer 5 – 8 , and a GDNF family receptor alpha like (GFRAL)–Ret proto-oncogene (RET) signaling complex in brainstem neurons that mediates GDF15-induced weight loss in mice has recently been described 9 – 12 . Here we report a therapeutic antagonistic monoclonal antibody, 3P10, that targets GFRAL and inhibits RET signaling by preventing the GDF15-driven interaction of RET with GFRAL on the cell surface. Treatment with 3P10 reverses excessive lipid oxidation in tumor-bearing mice and prevents cancer cachexia, even under calorie-restricted conditions. Mechanistically, activation of the GFRAL–RET pathway induces expression of genes involved in lipid metabolism in adipose tissues, and both peripheral chemical sympathectomy and loss of adipose triglyceride lipase protect mice from GDF15-induced weight loss. These data uncover a peripheral sympathetic axis by which GDF15 elicits a lipolytic response in adipose tissue independently of anorexia, leading to reduced adipose and muscle mass and function in tumor-bearing mice. Pharmacological inhibition of GFRAL–RET signaling in preclinical tumor models supports the therapeutic potential for reversing GDF15-dependent cachexia in people with cancer.

Playing three-dimensional (3D) video games enhances stereo acuity (i.e., the precision of stereopsis) in young adults with normal vision Here we asked whether the improvement in stereoacuity was the result of a reduced disparity pedestal, as indicated by a decreased subjective depth bias (i.e., the accuracy of stereopsis). Twenty-one healthy young participants with normal vision and limited previous video game experience, none had played 3D video games, played first-person-shooter action stereoscopic 3D video games for a total of 40 h. Depth detection performance was measured using random dot stereograms before and after the video game intervention. We found that playing stereoscopic 3D video games boosts the precision, but not the accuracy of depth perception, suggesting that the enhanced stereoacuity did not result from reducing the effects of a disparity pedestal. These types of video games have potential therapeutic applications for improving stereo vision in patients with binocular vision anomalies.

Purpose We performed a systematic review of the ethical, social, and cultural issues associated with delivery of genetic services in low- and middle-income countries (LMICs). Methods We searched 11 databases for studies addressing ethical, social, and/or cultural issues associated with clinical genetic testing and/or counselling performed in LMICs. Narrative synthesis was employed to analyze findings, and resultant themes were mapped onto the social ecological model (PROSPERO #CRD42016042894). Results After reviewing 13,308 articles, 192 met inclusion criteria. Nine themes emerged: (1) genetic counseling has a tendency of being directive, (2) genetic services have psychosocial consequences that require improved support, (3) medical genetics training is inadequate, (4) genetic services are difficult to access, (5) social determinants affect uptake and understanding of genetic services, (6) social stigma is often associated with genetic disease, (7) family values are at risk of disruption by genetic services, (8) religious principles pose barriers to acceptability and utilization of genetic services, and (9) cultural beliefs and practices influence uptake of information and understanding of genetic disease. Conclusion We identified a number of complex and interrelated ethical, cultural, and social issues with implications implications for further development of genetic services in LMICs.

GDNF receptor alpha-like is a brainstem-restricted receptor for growth and differentiation factor 15, regulating appetite and body weight in non-homeostatic conditions by activating the emergency circuit response to disease and toxin stresses. Brainstem receptor regulates body mass loss Growth and differentiation factor 15 (GDF15) acts on feeding centres in the brain to cause anorexia, leading to loss of both lean and fat mass and eventually cachexia. GDF15 levels rise in response to tissue stress and injury, and higher levels are associated with weight loss in numerous chronic human diseases, including cancer. Bernard Allan and colleagues now show that glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) is a GDF15 receptor in the brainstem. The structure of GDF15 and its interaction with GFRAL together with biochemical experiments and analysis of Gfral knockout mice demonstrate that regulation of body weight by GFRAL is independent of previously characterized pathways. Unlike hormones from gut and adipose tissue that activate receptors mostly in the hypothalamus, GDF15 increases in response to tissue damage and activates GFRAL-expressing neurons in the brainstem. Gfral knockout mice overate under stressed conditions and were resistant to chemotherapy-induced anorexia and weight loss. These findings provide therapeutic opportunities for disorders with altered energy demands. Under homeostatic conditions, animals use well-defined hypothalamic neural circuits to help maintain stable body weight, by integrating metabolic and hormonal signals from the periphery to balance food consumption and energy expenditure 1 , 2 . In stressed or disease conditions, however, animals use alternative neuronal pathways to adapt to the metabolic challenges of altered energy demand 3 . Recent studies have identified brain areas outside the hypothalamus that are activated under these ‘non-homeostatic’ conditions 4 , 5 , 6 , but the molecular nature of the peripheral signals and brain-localized receptors that activate these circuits remains elusive. Here we identify glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as a brainstem-restricted receptor for growth and differentiation factor 15 (GDF15). GDF15 regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses; we show that Gfral knockout mice are hyperphagic under stressed conditions and are resistant to chemotherapy-induced anorexia and body weight loss. GDF15 activates GFRAL-expressing neurons localized exclusively in the area postrema and nucleus tractus solitarius of the mouse brainstem. It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala, which constitute part of the ‘emergency circuit’ that shapes feeding responses to stressful conditions 7 . GDF15 levels increase in response to tissue stress and injury, and elevated levels are associated with body weight loss in numerous chronic human diseases 8 , 9 . By isolating GFRAL as the receptor for GDF15-induced anorexia and weight loss, we identify a mechanistic basis for the non-homeostatic regulation of neural circuitry by a peripheral signal associated with tissue damage and stress. These findings provide opportunities to develop therapeutic agents for the treatment of disorders with altered energy demand.

BackgroundTeduglutide, a glucagon-like peptide 2 analog, has demonstrated efficacy in treating adult patients with short bowel syndrome (SBS) and dependence on parenteral nutrition (PN), but its role in chronic malabsorptive states that do not necessitate PN remains uncertain.AimsTo evaluate teduglutide use beyond its approved indications and to discuss the results of this adjunctive treatment in patients resistant to established therapy.ResultsThis series reports four patients treated with teduglutide off-label. The first case had Crohn’s disease (CD) with persistent colocutaneous fistulae that demonstrated complete closure after 8 months of teduglutide therapy. The second case involved a PN-dependent CD patient with persistent fistulae and intra-abdominal abscesses who weaned off PN and had a significant improvement in her nutritional status after 3 months of teduglutide therapy. The third case had CD complicated by severe malnutrition and previous PN-associated line infections, but by 9 months of teduglutide therapy, she gained 5 kg and no longer required re-initiation of PN. The fourth case had a high-output diverting ileostomy with resultant impaired healing of a stage IV decubitus ulcer, and after 2 months of therapy, the patient’s pre-albumin increased by 250% and the ulcer had decreased by 40% in size.ConclusionThe use of teduglutide might be broadened to include patients with functional SBS not meeting strict criteria for intestinal failure. Further studies should evaluate the efficacy of teduglutide in patients who may require short-term small intestine rehabilitation or who have chronically impaired absorptive capacity not yet requiring PN.

Three-dimensional (3D) hydrogel structures are finding use in fundamental studies of self-assembly, rheology, and 3D cell culture. Most techniques for 3D hydrogel formation are ‘single pot’, in which gels are not addressable after formation. For many applications, it would be useful to be able to form arrays of gels bearing mixtures of constituents and/or formed from composites of different gel materials. Here, in response to this challenge, we introduce a digital microfluidic method for ‘on-demand’ formation of arrays of microgels bearing arbitrary contents and shapes. On formation of the gels, each microgel is individually addressable for reagent delivery and analysis. We demonstrate the utility of the method for 3D cell culture and higher-order tissue formation by implementing the first sub-microlitre recapitulation of 3D kidney epithelialization. We anticipate this platform will enable new research that can exploit the flexible nature of this technique for forming and addressing arrays of hydrogels with unique geometries and contents. Traditional methods for forming hydrogel particles are limited by geometry and lack of addressability after synthesis. Here the authors use digital microfluidics to form individually addressable gels with customisable shapes and compositions.

To evaluate CD200 expression in B-cell proliferative disorders. We analyzed 180 recent specimens of B-cell neoplasms for CD200 expression by flow cytometric immunophenotypic analysis, which is better able to assess relative intensity of staining than immunohistochemical staining. We found that hairy cell leukemia exhibits a high level of staining for CD200 in comparison to other B-cell lymphoproliferative disorders, including hairy cell leukemia-variant (HCL-V), marginal zone lymphoma, and lymphoplasmacytic lymphoma. We confirmed this observation by semiquantitative immunohistochemical staining. Assessment of the CD200 expression level is helpful to distinguish HCL from HCL-V and other B-cell lymphoproliferative disorders and in the differential diagnosis of B-cell neoplasms in general.

Drawing upon the concept of student-led live broadcasting tour (LBT), this study aims to construct and empirically test the Input-Process-Output (IPO) framework that links inputs, processes, and outputs within online tourism educational context. The sample involved students who are currently studying a tourism program in the Greater Bay Area, China. One group of students was invited as the audience with another group of students acting as tour guides to lead a live broadcasting tour. Upon completion of the tour, the audience group was invited to fill in the questionnaire survey. The data were gathered through the questionnaire survey from December 2022 to March 2023. The survey instruments were designed based on existing research and the IPO framework. The quantitative data were analysed by SPSS and SmartPLS. 5 hypotheses were developed based on the IPO framework. The results confirmed that students perceived student-led LBT positively in terms of input dimensions (intrinsic motivation and resources support), process dimension (learning climate) and output dimension (learning outcomes and satisfaction). This study gives implications to educators on how student-led LBT can be designed and implemented under the constraints of travel. The utilisation of technology offers educators the possibility to enrich the learning experience of tourism students in a more affordable and effective way.

Human blood brain barrier (BBB) models derived from induced pluripotent stem cells (iPSCs) have become an important tool for the discovery and preclinical evaluation of central nervous system (CNS) targeting cell and gene-based therapies. Chimeric antigen receptor (CAR)-T cell therapy is a revolutionary form of gene-modified cell-based immunotherapy with potential for targeting solid tumors, such as glioblastomas. Crossing the BBB is an important step in the systemic application of CAR-T therapy for the treatment of glioblastomas and other CNS malignancies. In addition, even CAR-T therapies targeting non-CNS antigens, such as the well-known CD19-CAR-T therapies, are known to trigger CNS side-effects including brain swelling due to BBB disruption. In this study, we used iPSC-derived brain endothelial-like cell (iBEC) transwell co-culture model to assess BBB extravasation of CAR-T based immunotherapies targeting U87MG human glioblastoma (GBM) cells overexpressing the tumor-specific mutated protein EGFRvIII (U87vIII). Two types of anti-EGFRvIII targeting CAR-T cells, with varying tonic signaling profiles (CAR-F263 and CAR-F269), and control Mock T cells were applied on the luminal side of BBB model in vitro. CAR-F263 and CAR-F269 T cells triggered a decrease in transendothelial electrical resistance (TEER) and an increase in BBB permeability. CAR-T cell extravasation and U87vIII cytotoxicity were assessed from the abluminal compartment using flow cytometry and Incucyte real-time viability imaging, respectively. A significant decrease in U87vIII cell viability was observed over 48 h, with the most robust cytotoxicity response observed for the constitutively activated CAR-F263. CAR-F269 T cells showed a similar cytotoxic profile but were approximately four fold less efficient at killing the U87vIII cells compared to CAR-F263, despite similar transmigration rates. Visualization of CAR-T cell extravasation across the BBB was further confirmed using BBTB-on-CHIP models. The described BBB assay was able to discriminate the cytotoxic efficacies of different EGFRvIII-CARs and provide a measure of potential alterations to BBB integrity. Collectively, we illustrate how BBB models in vitro can be a valuable tool in deciphering the mechanisms of CAR-T–induced BBB disruption, accompanying toxicity and effector function on post-barrier target cells.

IntroductionIn an increasingly globalised and interconnected world, evidence to evaluate complex interventions may be generated in multiple languages. However, despite its influence in shaping the evidence base, there is little literature explicitly connecting the translation process to the goals and processes of implementation research. This study aims to explore the processes and experience of an international implementation research team conducting a process evaluation of a complex intervention in Tibet Autonomous Region, China.MethodsThis study uses a collaborative autoethnographic approach to explore the translation process from Chinese or Tibetan to English of key stakeholder interview transcripts. In this approach, multiple researchers and translators contributed their reflections, and conducted joint analysis through dialogue, reflection and with consideration of multiple perspectives. Seven researchers involved with the translation process contributed their perspectives through in-depth interviews or written reflections and jointly analysed the resulting data.ResultsWe describe the translation process, synthesise key challenges including developing a ‘voice’ and tone as a translator, conveying the depth of idioms across languages, and distance from the study context. We further offer lessons learnt including the importance of word banks with unified translations of words and phrases created iteratively during the translation process, the need to collaborate between translators and the introspective work necessary for translators to explore their positionality and reflexivity during the work. We then offer a summary of these learnings for other implementation research teams.ConclusionOur findings emphasise that in order to ensure rigour in their work, implementation research teams using qualitative data should make concerted effort to consider both the translation process as well as its outcomes. Given the numerous multinational or multilingual implementation research studies using qualitative methods, there is a need for further consideration and reflection on the translation process.