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Importance Large language models (LLMs) like ChatGPT appear capable of performing a variety of tasks, including answering patient eye care questions, but have not yet been evaluated in direct comparison with ophthalmologists. It remains unclear whether LLM-generated advice is accurate, appropriate, and safe for eye patients. Objective To evaluate the quality of ophthalmology advice generated by an LLM chatbot in comparison with ophthalmologist-written advice. Design, Setting, and Participants This cross-sectional study used deidentified data from an online medical forum, in which patient questions received responses written by American Academy of Ophthalmology (AAO)–affiliated ophthalmologists. A masked panel of 8 board-certified ophthalmologists were asked to distinguish between answers generated by the ChatGPT chatbot and human answers. Posts were dated between 2007 and 2016; data were accessed January 2023 and analysis was performed between March and May 2023. Main Outcomes and Measures Identification of chatbot and human answers on a 4-point scale (likely or definitely artificial intelligence [AI] vs likely or definitely human) and evaluation of responses for presence of incorrect information, alignment with perceived consensus in the medical community, likelihood to cause harm, and extent of harm. Results A total of 200 pairs of user questions and answers by AAO-affiliated ophthalmologists were evaluated. The mean (SD) accuracy for distinguishing between AI and human responses was 61.3% (9.7%). Of 800 evaluations of chatbot-written answers, 168 answers (21.0%) were marked as human-written, while 517 of 800 human-written answers (64.6%) were marked as AI-written. Compared with human answers, chatbot answers were more frequently rated as probably or definitely written by AI (prevalence ratio [PR], 1.72; 95% CI, 1.52-1.93). The likelihood of chatbot answers containing incorrect or inappropriate material was comparable with human answers (PR, 0.92; 95% CI, 0.77-1.10), and did not differ from human answers in terms of likelihood of harm (PR, 0.84; 95% CI, 0.67-1.07) nor extent of harm (PR, 0.99; 95% CI, 0.80-1.22). Conclusions and Relevance In this cross-sectional study of human-written and AI-generated responses to 200 eye care questions from an online advice forum, a chatbot appeared capable of responding to long user-written eye health posts and largely generated appropriate responses that did not differ significantly from ophthalmologist-written responses in terms of incorrect information, likelihood of harm, extent of harm, or deviation from ophthalmologist community standards. Additional research is needed to assess patient attitudes toward LLM-augmented ophthalmologists vs fully autonomous AI content generation, to evaluate clarity and acceptability of LLM-generated answers from the patient perspective, to test the performance of LLMs in a greater variety of clinical contexts, and to determine an optimal manner of utilizing LLMs that is ethical and minimizes harm.

Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans 1 – 3 . In endogenous taurine metabolism, dedicated enzymes are involved in the biosynthesis of taurine from cysteine and in the downstream metabolism of secondary taurine metabolites 4 , 5 . One taurine metabolite is N -acetyltaurine 6 . Levels of N -acetyltaurine are dynamically regulated by stimuli that alter taurine or acetate flux, including endurance exercise 7 , dietary taurine supplementation 8 and alcohol consumption 6 , 9 . So far, the identities of the enzymes involved in N -acetyltaurine metabolism, and the potential functions of N -acetyltaurine itself, have remained unknown. Here we show that the body mass index associated orphan enzyme phosphotriesterase-related (PTER) 10 is a physiological N -acetyltaurine hydrolase. In vitro, PTER catalyses the hydrolysis of N -acetyltaurine to taurine and acetate. In mice, PTER is expressed in the kidney, liver and brainstem. Genetic ablation of Pter in mice results in complete loss of tissue N -acetyltaurine hydrolysis activity and a systemic increase in N -acetyltaurine levels. After stimuli that increase taurine levels, Pter knockout mice exhibit reduced food intake, resistance to diet-induced obesity and improved glucose homeostasis. Administration of N -acetyltaurine to obese wild-type mice also reduces food intake and body weight in a GFRAL-dependent manner. These data place PTER into a central enzymatic node of secondary taurine metabolism and uncover a role for PTER and N -acetyltaurine in body weight control and energy balance. The orphan enzyme phosphotriesterase-related (PTER) is identified as a mammalian N -acetyltaurine hydrolase that has roles in regulating body weight and energy balance.

Bonemetastasis involves dynamic interplay between tumor cells and the local stromal environment. In bones, local hypoxia and activation of the hypoxia-inducible factor (HIF)-1α in osteoblasts are essential to maintain skeletal homeostasis. However, the role of osteoblast-specific HIF signaling in cancer metastasis is unknown. Here, we show that osteoprogenitor cells (OPCs) are located in hypoxic niches in the bone marrow and that activation of HIF signaling in these cells increases bone mass and favors breast cancer metastasis to bone locally. Remarkably, HIF signaling in osteoblast-lineage cells also promotes breast cancer growth and dissemination remotely, in the lungs and in other tissues distant from bones. Mechanistically, we found that activation of HIF signaling in OPCs increases blood levels of the chemokine C-X-C motif ligand 12 (CXCL12), which leads to a systemic increase of breast cancer cell proliferation and dissemination through direct activation of the CXCR4 receptor. Hence, our data reveal a previously unrecognized role of the hypoxic osteogenic niche in promoting tumorigenesis beyond the local bone microenvironment. They also support the concept that the skeleton is an important regulator of the systemic tumor environment.

Sterol lipids are widely present in eukaryotes and play essential roles in signaling and modulating membrane fluidity. Although rare, some bacteria also produce sterols, but their function in bacteria is not known. Moreover, many more species, including pathogens and commensal microbes, acquire or modify sterols from eukaryotic hosts through poorly understood molecular mechanisms. The aerobic methanotroph Methylococcus capsulatus was the first bacterium shown to synthesize sterols, producing a mixture of C-4 methylated sterols that are distinct from those observed in eukaryotes. C-4 methylated sterols are synthesized in the cytosol and localized to the outer membrane, suggesting that a bacterial sterol transport machinery exists. Until now, the identity of such machinery remained a mystery. In this study, we identified three novel proteins that may be the first examples of transporters for bacterial sterol lipids. The proteins, which all belong to well-studied families of bacterial metabolite transporters, are predicted to reside in the inner membrane, periplasm, and outer membrane of M. capsulatus, and may work as a conduit to move modified sterols to the outer membrane. Quantitative analysis of ligand binding revealed their remarkable specificity for 4-methylsterols, and crystallographic structures coupled with docking and molecular dynamics simulations revealed the structural bases for substrate binding by two of the putative transporters. Their striking structural divergence from eukaryotic sterol transporters signals that they form a distinct sterol transport system within the bacterial domain. Finally, bioinformatics revealed the widespread presence of similar transporters in bacterial genomes, including in some pathogens that use host sterol lipids to construct their cell envelopes. The unique folds of these bacterial sterol binding proteins should now guide the discovery of other proteins that handle this essential metabolite.

With the approval of the antibody-drug conjugate enfortumab vedotin (EV), NECTIN4 has emerged as a bona fide therapeutic target in urothelial carcinoma (UC). Here, we report the development of a NECTIN4-directed chimeric antigen receptor (CAR) T cell, which exhibits reactivity across cells expressing a range of endogenous NECTIN4, with enhanced activity in high expressors. We demonstrate that the PPARγ pathway, critical for luminal differentiation, transcriptionally controls NECTIN4 , and that the PPARγ agonist rosiglitazone primes and augments NECTIN4 expression, thereby increasing sensitivity to NECTIN4-CAR T cell-mediated killing. NECTIN4-CAR T cells have potent anti-tumor activity even against EV resistant cells, which largely retain NECTIN4 expression, including in a post-EV biopsy cohort. Our results elucidate a therapeutically actionable mechanism that UC cells use to control NECTIN4 expression and suggest therapeutic approaches that leverage PPARγ agonists for rational combinations with NECTIN4-targeting agents in UC, as well as future potential treatment options for EV-refractory patients. Enfortumab vedotin (EV) is the current standard treatment for advanced bladder cancer, but resistance typically develops within a year, highlighting the need for new therapies. This study demonstrates that NECTIN4-targeting CAR T cells are effective against bladder cancer, including EV-resistant cells, and their potency can be further enhanced by using rosiglitazone to boost NECTIN4 expression.

Genomic sequencing of thousands of tumors has revealed many genes associated with specific types of cancer. Similarly, large scale CRISPR functional genomics efforts have mapped genes required for cancer cell proliferation or survival in hundreds of cell lines. Despite this, for specific disease subtypes, such as metastatic prostate cancer, there are likely a number of undiscovered tumor specific driver genes that may represent potential drug targets. To identify such genetic dependencies, we performed genome-scale CRISPRi screens in metastatic prostate cancer models. We then created a pipeline in which we integrated pan-cancer functional genomics data with our metastatic prostate cancer functional and clinical genomics data to identify genes that can drive aggressive prostate cancer phenotypes. Our integrative analysis of these data reveals known prostate cancer specific driver genes, such as AR and HOXB13 , as well as a number of top hits that are poorly characterized. In this study we highlight the strength of an integrated clinical and functional genomics pipeline and focus on two top hit genes, KIF4A and WDR62 . We demonstrate that both KIF4A and WDR62 drive aggressive prostate cancer phenotypes in vitro and in vivo in multiple models, irrespective of AR-status, and are also associated with poor patient outcome. It is hypothesized that there are a number of tumor specific driver genes for metastatic prostate cancer. Here, the authors perform genome-wide CRISPRi screens and integrate these data with metastatic prostate cancer functional and clinical genomics data to show that KIF4A and WDR62 drive aggressive prostate cancer phenotypes.

Histologic variant (HV) subtypes of bladder cancer are clinically aggressive tumors that are more resistant to standard therapy compared to conventional urothelial carcinoma (UC). Little is known about the transcriptional programs that account for their biological differences. Here we show using single cell analysis that HVs harbor a tumor cell state characterized by expression of MUC16 (CA125), MUC4 , and KRT24 . This cell state is enriched in metastases, predicted to be highly resistant to chemotherapy, and linked with poor survival. We also find enriched expression of TM4SF1 , a transmembrane protein, in HV tumor cells. Chimeric antigen receptor (CAR) T cells engineered against TM4SF1 protein demonstrated in vitro and in vivo activity against bladder cancer cell lines in a TM4SF1 expression-dependent manner, highlighting its potential as a therapeutic target. Single cell analysis of histologic variant bladder tumors detects a shared CA125+ tumor cell state associated with aggressive clinical features and reveals enriched expression of TM4SF1, a membrane protein that can be targeted with CAR T cells.

Background/AimsAn altered haemodynamic profile for various ocular posterior segment capillary beds has been documented in primary open-angle glaucoma (POAG). POAG may also involve abnormal non-ocular blood flow, and the nailfold capillaries, which are not affected by elevated intraocular pressure (IOP), are readily assessable.MethodsWe measured resting nailfold capillary blood flow in 67 POAG and 63 control subjects using video capillaroscopy. Masked readers tracked blood column voids between consecutive, registered image sequence frames, measured vessel diameter and calculated blood flow. We used multiple logistic regression to investigate the relation between nailfold capillary blood flow and POAG. In secondary analyses, we stratified cases by maximum IOP and concurrent topical beta-blocker use.ResultsMean (±SD) blood flow in picolitres per second was 26.8±17.6 for POAG cases and 50.1±24.2 for controls (p<0.0001). After adjustment for demographic and clinical factors including blood pressure and pulse, every picolitre per second increase in resting nailfold blood flow was associated with a 6% (95% CI 0.92 to 0.96) reduced odds of POAG (p<0.0001). Similar relations between nailfold capillary blood flow and POAG were found for cases stratified by maximum known IOP and for cases stratified by concurrent topical beta-blocker use.ConclusionReduced resting nailfold capillary blood flow is present in POAG independent of covariates such as blood pressure, pulse and IOP.

Key Points The extracellular matrix (ECM) is a dynamic structure that is constantly remodelled to control tissue homeostasis. The ECM in mammals is composed of around 300 proteins, known as the core matrisome. Metalloproteinases are the main endopeptidases responsible for ECM degradation. These enzymes can also generate ECM fragments with different bioactive properties than their full-length proteins. These matrikines regulate many processes such as migration, adhesion and differentiation. ECM remodelling is important during organogenesis and development of the intestine, mammary and salivary glands and lung. Dysregulation of the ECM composition and structure and mutations in genes that affect ECM remodeling can lead to several severe human conditions, including fibrosis and cancer. ECM components and the proteins that regulate ECM remodelling represent promising therapeutic targets. Additional preclinical and clinical studies are required to fully understand the role of the ECM in human disease. The extracellular matrix (ECM) regulates many cellular functions, and its remodelling by enzymes such as metalloproteinases has a crucial role during development, as exemplified by intestinal, lung, mammary gland and submandibular gland morphogenesis. ECM structure and composition are important therapeutic targets, as their dysregulation contributes to conditions such as fibrosis and invasive cancer. The extracellular matrix (ECM) is a highly dynamic structure that is present in all tissues and continuously undergoes controlled remodelling. This process involves quantitative and qualitative changes in the ECM, mediated by specific enzymes that are responsible for ECM degradation, such as metalloproteinases. The ECM interacts with cells to regulate diverse functions, including proliferation, migration and differentiation. ECM remodelling is crucial for regulating the morphogenesis of the intestine and lungs, as well as of the mammary and submandibular glands. Dysregulation of ECM composition, structure, stiffness and abundance contributes to several pathological conditions, such as fibrosis and invasive cancer. A better understanding of how the ECM regulates organ structure and function and of how ECM remodelling affects disease progression will contribute to the development of new therapeutics.

Metastasis, the main cause of cancer-related death, has traditionally been viewed as a late-occurring process during cancer progression. Using the MMTV-PyMT luminal B breast cancer model, we demonstrate that the lung metastatic niche is established early during tumorigenesis. We found that matrix metalloproteinase 9 (MMP9) is an important component of the metastatic niche early in tumorigenesis and promotes circulating tumor cells to colonize the lungs. Blocking active MMP9, using a monoclonal antibody specific to the active form of gelatinases, inhibited endogenous and experimental lung metastases in the MMTV-PyMT model. Mechanistically, inhibiting MMP9 attenuated migration, invasion, and colony formation and promoted CD8 + T cell infiltration and activation. Interestingly, primary tumor burden was unaffected, suggesting that inhibiting active MMP9 is primarily effective during the early metastatic cascade. These findings suggest that the early metastatic circuit can be disrupted by inhibiting active MMP9 and warrant further studies of MMP9-targeted anti-metastatic breast cancer therapy.