Impact of coding risk variant IFNGR2 on the B cell-intrinsic IFN-γ signaling pathway in multiple sclerosis.

B cells of people with multiple sclerosis (MS) are more responsive to IFN-γ, corresponding to their brain-homing potential. We studied how a coding single nucleotide polymorphism (SNP) in IFNGR2 (rs9808753) co-operates with Epstein-Barr virus (EBV) infection as MS risk factors to affect the IFN-γ signaling pathway in human B cells. In both cell lines and primary cells, EBV infection positively associated with IFN-γ receptor expression and STAT1 phosphorylation. The IFNGR2 risk SNP selectively promoted downstream signaling via STAT1, particularly in transitional B cells. Altogether, EBV and the IFNGR2 risk SNP independently amplify IFN-γ signaling, potentially driving B cells to enter the MS brain.

Comparing Medicare Fee-for-Service Beneficiaries with ESKD who Switched to Medicare Advantage versus Remained in Traditional Medicare.

ABSTRACT: Patients choosing Medicare Advantage vs. Medicare fee-for-service (FFS) differ with respect to race, socioeconomic status, and burden of disease. However, it is unclear whether these differences also occur among patients with kidney failure, who were newly allowed to switch to Medicare Advantage after the 21st Century Cares Act. We used data from the United States Renal Data System (USRDS) to examine differences in characteristics of dialysis patients and kidney transplant recipients who switched from FFS to Medicare Advantage compared with those who stayed with FFS in 2021, the first year such switching was allowed. We used unadjusted and adjusted logistic regression to compare odds of switching among demographic and geographic subgroups. Among 411,513 patients with FFS coverage in 2020, 10.1% switched to Medicare Advantage in 2021. Switchers constituted 12% of the dialysis population and 5% of the kidney transplant population. In the dialysis population, patients of Black race and Hispanic ethnicity were more likely to switch than patients of White race (adjusted OR 1.69, 95% Confidence Interval [CI] 1.64, 1.73 and OR 1.42, 95% CI 1.40, 1.47, respectively), as were patients with dual eligibility for Medicaid (adjusted OR 1.12, 95% CI 1.09, 1.15). Patients living in the South were also more likely to switch to Medicare Advantage than those living in the West (adjusted OR 1.48, 95% CI 1.43, 1.52). Similar differences were observed among kidney transplant recipients. Patients who switched from FFS to Medicare Advantage were disproportionately from historically marginalized groups, including Black, Hispanic, and low income individuals. They were also more likely to live in the South. These differences may threaten the generalizability of USRDS data that relies on FFS insurance claims and suggest that comparisons of outcomes between FFS and MA beneficiaries with kidney failure should be adjusted for key patient characteristics.

Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer.

To delineate the mechanisms by which the ERK1 and ERK2 mitogen-activated protein kinases support mutant KRAS-driven cancer growth, we determined the ERK-dependent phosphoproteome in KRAS-mutant pancreatic cancer. We determined that ERK1 and ERK2 share near-identical signaling and transforming outputs and that the KRAS-regulated phosphoproteome is driven nearly completely by ERK. We identified 4666 ERK-dependent phosphosites on 2123 proteins, of which 79 and 66%, respectively, were not previously associated with ERK, substantially expanding the depth and breadth of ERK-dependent phosphorylation events and revealing a considerably more complex function for ERK in cancer. We established that ERK controls a highly dynamic and complex phosphoproteome that converges on cyclin-dependent kinase regulation and RAS homolog guanosine triphosphatase function (RHO GTPase). Our findings establish the most comprehensive molecular portrait and mechanisms by which ERK drives KRAS-dependent pancreatic cancer growth.

Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers.

How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal-regulated kinase (ERK)-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome (APC/C) and other components of the cell cycle machinery as key processes that drive pancreatic ductal adenocarcinoma (PDAC) growth. Our findings elucidate mechanistically the critical role of ERK in driving KRAS-mutant tumor growth and in resistance to KRAS-ERK MAPK targeted therapies.

Comparison of In-person Versus Online Comprehensive Pelvic Floor Rehabilitation Program Following Prostatectomy.

OBJECTIVE: To compare continence outcomes in post-prostatectomy patients undergoing supervised in-person versus online pelvic floor muscle training and pelvic floor education (iPMFT vs oPFMT/PFE). Despite the proven benefit of in-person PFMT for urinary incontinence (UI) following prostatectomy, numerous barriers impede access. We developed a comprehensive online program to deliver oPFMT/PFE. METHODS: We performed a retrospective review of patients receiving iPFMT versus oPFMT/PFE with minimum 12-month follow-up. Outcomes were assessed at 3 weeks, 3-, 6-, and 12 months following robotic-assisted laparoscopic prostatectomy using validated ICIQ-MLUTS and IIQ-7 questionnaires and additional items (daily pad use [PPD] and satisfaction). The primary study outcome was ICIQ-MLUTS SUI domain score (SDS). Secondary outcomes were PPD, PPD cure (0 PPD at 12 months), SUI cure (12-month SDS=baseline score), and QOL score (IIQ-7 Sum). RESULTS: Analysis included 41 men. Though men enrolled in oPFMT/PFE demonstrated lower SUI domain scores than iPFMT at most time points (3wk P <.01, 3 mo P = .04, 6 mo P = .15, 12 mo P = .04), the rate of improvement from 3 weeks to other time points was similar between groups (P = NS at all time points). SDS Cure was no different for oPFMT/PFE (75%, 15/20) compared to iPFMT (60%, 12/20, P = .3). PPD and IIQ-7 were also similar at all time points and demonstrated a similar rate of decrease over time through 12 months. CONCLUSION: Significant and similar improvements in UI and QOL are seen both in men completing iPFMT or oPFMT/PFE programs. Our novel online program provides another option to improve PFMT/PFE access in men undergoing RALP.

Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability.

The tumor microenvironment is a determinant of cancer progression and therapeutic efficacy, with nutrient availability playing an important role. Although it is established that the local abundance of specific nutrients defines the metabolic parameters for tumor growth, the factors guiding nutrient availability in tumor compared to normal tissue and blood remain poorly understood. To define these factors in renal cell carcinoma (RCC), we performed quantitative metabolomic and comprehensive lipidomic analyses of tumor interstitial fluid (TIF), adjacent normal kidney interstitial fluid (KIF), and plasma samples collected from patients. TIF nutrient composition closely resembles KIF, suggesting that tissue-specific factors unrelated to the presence of cancer exert a stronger influence on nutrient levels than tumor-driven alterations. Notably, select metabolite changes consistent with known features of RCC metabolism are found in RCC TIF, while glucose levels in TIF are not depleted to levels that are lower than those found in KIF. These findings inform tissue nutrient dynamics in RCC, highlighting a dominant role of non-cancer-driven tissue factors in shaping nutrient availability in these tumors.

Cancer cells convert nutrients into energy differently compared to healthy cells. This difference in metabolism allows them to grow and divide more quickly and sometimes to migrate to different areas of the body. The environment around cancer cells ­ known as the tumor microenvironment ­ contains a variety of different cells and blood vessels, which are bathed in interstitial fluid. This microenvironment provides nutrients for the cancer cells to metabolize, and therefore influences how well a tumor grows and how it might respond to treatment. Recent advances with techniques such as mass spectrometry, which can measure the chemical composition of a substance, have allowed scientists to measure nutrient levels in the tumor microenvironments of mice. However, it has been more difficult to conduct such studies in humans, as well as to compare the tumor microenvironment to the healthy tissue the tumors arose from. Abbott, Ali, Reinfeld et al. aimed to fill this gap in knowledge by using mass spectrometry to measure the nutrient levels in the tumor microenvironment of 55 patients undergoing surgery to remove kidney tumors. Comparing the type and levels of nutrients in the tumor interstitial fluid, the neighboring healthy kidney and the blood showed that nutrients in the tumor and healthy kidney were more similar to each other than those in the blood. For example, both the tumor and healthy kidney interstitial fluids contained less glucose than the blood. However, the difference between nutrient composition in the tumor and healthy kidney interstitial fluids was insignificant, suggesting that the healthy kidney and its tumor share a similar environment. Taken together, the findings indicate that kidney cancer cells must adapt to the nutrients available in the kidney, rather than changing what nutrients are available in the tissue. Future studies will be required to investigate whether this finding also applies to other types of cancer. A better understanding of how cancer cells adapt to their environments may aid the development of drugs that aim to disrupt the metabolism of tumors.

Level of BPA contamination in resin composites determines BPA release.

OBJECTIVES: Resin composites may release bisphenol A (BPA) due to impurities present in the monomers. However, there is a lack of knowledge regarding the leaching characteristics of BPA from resin composites. Therefore, experimental resin composites were prepared with known amounts of BPA. The objective of this study was (1) to determine which amount of BPA initially present in the material leaches out in the short term and, (2) how this release is influenced by the resin composition. METHODS: BPA (0, 0.001, 0.01, or 0.1 wt%) was added to experimental resin composites containing 60 mol% BisGMA, BisEMA(3), or UDMA, respectively, as base monomer and 40 mol% TEGDMA as diluent monomer. Polymerized samples (n = 5) were immersed at 37 °C for 7 days in 1 mL of water, which was collected and refreshed daily. BPA release was quantified with UPLC-MS/MS after derivatization with pyridine-3-sulfonyl chloride. RESULTS: Between 0.47 to 0.67 mol% of the originally added BPA eluted from the resin composites after 7 days. Similar elution trends were observed irrespective of the base monomer. Two-way ANOVA showed a significant effect of the base monomer on BPA release, but the differences were small and not consistent. SIGNIFICANCE: The released amount of BPA was directly proportional to the quantity of BPA present in the resin composite as an impurity. BPA release was mainly diffusion-based, while polymer composition seemed to play a minor role. Our results underscore the importance for manufacturers only to use monomers of the highest purity in dental resin composites to avoid unnecessary BPA exposure in patients.

Exploring the influence of activity participation on the economic value of nature-based recreation in the Sierra Nevada.

A more comprehensive understanding of how recreational values and forest visitation rates vary across different activities enables forest managers to tailor conservation and management strategies to align with preferences among visitors, ensuring more effective allocation of budgetary resources. However, current research often focuses on only a few recreational activities, resulting in limited insights for forest managers. This study aims to expand the nature-based activities considered so that management can better serve the broader public. We conduct a travel cost analysis using a large survey-based dataset to estimate the value of nature-based recreation in national forests in the Sierra Nevada region and assess how these values differ across main activities. We categorize recreational activities into five broad groups (Passive, Active, Camping, Winter, and Other) to offer a comprehensive view of recreational preferences. A truncated negative binomial regression accounting for endogenous stratification is used to analyze the relationship between the number of trips to the forests, travel cost, activity categories, and socio-demographic variables. Our results suggest a mean consumer surplus (CS) of $65 per visit per person to national forests in the Sierra Nevada. Aggregated over annual per person visits, the total CS is approximately $313.3 million per year. Our findings reveal variations in CS across activity groups, with winter activities (e.g., skiing, snowboarding) and active activities (e.g., hiking, fishing) attracting the highest number of visits, and the highest total CS. Our results provide valuable insights for national forest managers, facilitating the strategic allocation of limited resources to recreational activities that maximize societal welfare.

Magnet-assisted endoscopic removal of ferromagnetic metallic gastric foreign bodies in 4 dogs.

OBJECTIVE: Describe presenting signs, diagnostic findings, and magnet-assisted endoscopic removal method of ferromagnetic gastric foreign bodies (FBs) in dogs. CLINICAL PRESENTATION: Four dogs presented with ingestion of sharp metallic FBs. The presence of gastric FBs was confirmed by abdominal radiography. RESULTS: In 3 cases, initial attempts at endoscopic removal were unsuccessful because of ingesta and fluid in the stomach. A magnet contained within a Roth net was introduced endoscopically. Magnet and attached objects were successfully removed from the stomach. In the fourth case, removal with a magnet was judged to be the most expedient method of removal because multiple metallic objects were present. CLINICAL RELEVANCE: An endoscopic technique was used for the removal of difficult-to-visualize or multiple metallic FBs. The use of this technique allows the removal of ferromagnetic gastric FBs without surgery or risk of complications associated with the passage of sharp material through the gastrointestinal (GI) tract.

Effects of feeding α-amylase-expressed corn silage and grain on performance, enteric methane production, and carcass characteristics in beef steers.

An experiment was conducted to evaluate the effects of feeding Enogen feed corn (EFC) silage or EFC grain with different grain processing (dry-rolled corn vs. whole-shelled corn) in feedlot cattle diets. Total 68 Angus cross-bred steers were blocked by body weight and the treatments (diets) were randomly assigned to steers in each block: a basal diet with isoline corn silage and isoline dry-rolled corn grain (IIR); the basal diet with EFC silage and isoline dry-rolled corn grain (EIR); the basal diet with EFC silage and EFC dry-rolled grain (EER); and the basal diet with EFC silage and EFC whole-shelled grain (EEW). Isoline refers to the isogenic counterpart of Enogen corn silage or grain. Steers received the assigned treatment over 32 wk of the entire experiment (backgrounding and finishing) until harvested. Part of the steers (eight blocks) in each treatment were used to measure CH4 production (g/d) using the GreenFeed and CH4 production per unit of DMI. All data were analyzed using a mixed procedure of SAS in a randomized complete block design, considering diet as a fixed effect and block as a random effect. Steers fed the EIR diet increased (P = 0.03) DMI compared to IIR during the backgrounding phase. However, feeding EFC silage or grain did not affect body weight, average daily gain, and feed efficiency during backgrounding and finishing phases. Feeding EEW decreased (P ≤ 0.05) body weight, average daily gain, feed efficiency, and tended to decrease (P = 0.06) hot carcass weight compared to EER during the finishing phase. Methane production per unit of DMI decreased (P = 0.02) for steers fed EIR compared with steers fed IIR only during the backgrounding phase. Feeding EFC grain had no effect on CH4 production (g/d) in both phases. In conclusion, feeding EFC silage or grain did not improve the performance of beef steers during the backgrounding and finishing phases in the current experiment condition. Methane production per unit of DMI was reduced for steers fed EFC silage compared with isoline corn silage only during the backgrounding phase.

A cohort study of sodium-glucose cotransporter-2 inhibitors after acute kidney injury among Veterans with diabetic kidney disease.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce the risk for several adverse outcomes among patients with diabetic kidney disease. Yet, optimal timing for SGLT2i after acute kidney injury (AKI) is uncertain, as are the providers responsible for post-AKI SGLT2i initiation. Using a retrospective cohort of United States Veterans with diabetes mellitus type 2 and proteinuria, we examined encounters by provider specialty before SGLT2i initiation and subsequent all-cause mortality after hospitalization with AKI, defined by a 50% or more rise in serum creatinine. Covariates included recovery, defined by return to a 110% or less of baseline creatinine, and time since AKI hospitalization. Among 21,330 eligible Veterans, 7,798 died (37%) and 6,562 received a SGLT2i (31%) over median follow-up of 2.1 years. Post-AKI SGLT2i use was associated with lower mortality risk [adjusted hazard ratio 0.63 (95% confidence interval 0.58-0.68)]. Compared with neither SGLT2i use nor recovery, mortality risk was similar with recovery without SGLT2i use [0.97 (0.91-1.02)] but was lower without recovery prior to SGLT2i use [0.62 (0.55-0.71)] and with SGLT2i use after recovery [0.60 (0.54-0.67)]. Finally, the effect of SGLT2i was stable over time (P for time-interaction 0.19). Thus, we observed reduced mortality with SGLT2i use after AKI among Veterans with diabetic kidney disease whether started earlier or later or before or after observed recovery. Hence, patients with diabetic kidney disease who receive a SGLT2i earlier after AKI experience no significant harm impacting mortality and experience a lower mortality risk than those who do not.

Broad evidence of xylazine in the UK illicit drug market beyond heroin supplies: Triangulating from toxicology, drug-testing and law enforcement.

BACKGROUND AND AIMS: Xylazine is a non-opioid sedative which has spread rapidly throughout the US illicit drug supply. This study aimed to describe the spread of xylazine throughout the UK illicit drug supply. METHODS: Xylazine detections in human biological samples were collated from toxicology laboratories operating in the United Kingdom with the date, location, case type, xylazine concentration and co-detected drugs (with quantifications where performed) detailed, where permitted, by the corresponding coroner. Drug-testing cases positive for xylazine were collated from the Welsh Emerging Drugs and Identification of Novel Substances (WEDINOS) drug-testing postal service with the date, location, purchase intent and co-detected drugs detailed. Drug seizures made by UK law enforcement were communicated by the Office for Health Improvement and Disparities with the date and location detailed. RESULTS: By the end of August 2023, xylazine was detected in 35 cases from throughout toxicology, drug-testing and drug seizure sources covering England, Scotland and Wales. There were no cases reported from Northern Ireland. Xylazine was detected in biological samples from 16 people. In most cases where full toxicology results were provided, xylazine was detected with heroin and/or a strong opioid (n = nine of 11), but this polydrug use pattern was not evident in all cases (n = two of 11), suggesting a wider circulation of xylazine in the UK illicit drug market beyond heroin supplies. Evidence from WEDINOS supports this claim, as all 14 drug samples (100%) submitted from across the UK contained xylazine; however, in none of these cases was heroin the purchase intent but rather counterfeit prescription medication tablets (n = 11 of 14), tetrahydrocannabinol (THC) vapes (n = two of 14) or white powder (n = one of 14). Additional evidence for the spread of illicit xylazine comes from five drug seizures made by law enforcement. CONCLUSIONS: Xylazine has penetrated the UK illicit drug market and is not limited to heroin supplies.

Diet and physical activity interventions to improve cardiovascular disease risk factors in liver transplant recipients: Systematic review and meta-analysis.

BACKGROUND AND AIMS: Cardiovascular disease, associated risk factors and obesity are prevalent after liver transplant and modifiable through lifestyle changes. Understanding what lifestyle interventions and their respective components are effective is essential for translation to clinical practice. We aimed to investigate the effects of diet and physical activity interventions on weight, body mass index and other cardiovascular disease risk factors in liver transplant recipients, and systematically describe the interventions. METHODS: We systematically searched Embase, MEDLINE, Psycho Info, CINAHL, Cochrane central register of controlled trials, PeDro, AMED, BNI, Web of Science, OpenGrey, ClinicalTrials.gov and the international clinical trials registry from inception to 31 May 2023. Search results were screened by two independent reviewers: randomised control trials with interventions that targeted diet and physical activity behaviours in liver transplant recipients were considered eligible. Two independent reviewers extracted and synthesised data for study, participant and intervention details and results. We used the Revised Cochrane Risk of Bias Tool for Randomised Trials to assess risk of bias for outcomes and the GRADE approach to rate the quality of the body of evidence. When two or more studies reported findings for an outcome, we pooled data using random-effects meta-analysis. RESULTS: Six studies were included, reporting three physical activity and three combined diet and physical activity interventions. Participants were 2 months-4 years post-transplant. Interventions lasted 12 weeks-10 months and were delivered remotely and/or in-person, most commonly delivered to individual participants by health care or sports professionals. Five studies described individual tailoring, e.g. exercise intensity. Adherence to interventions ranged from 51% to 94%. No studies reported fidelity. Intervention components were not consistently reported. In meta-analysis, diet and physical activity interventions did not significantly reduce weight or body mass index compared to control groups, however no studies targeted participants with obesity. Diet and physical activity interventions reduced percentage body fat and triglycerides compared to control groups but did not reduce total cholesterol or increase activity. The GRADE quality of evidence was low or very low. CONCLUSION: Diet and physical activity interventions reduced percentage body fat and triglycerides in liver transplant recipients. Further good quality research is needed to evaluate their effect on other cardiovascular disease risk factors, including weight and BMI. Interventions need to be better described and evaluated to improve evidence base and inform patient care.

Elution from direct composites for provisional restorations.

Purpose To assess elution from direct composite materials for provisional restorations and compare them with elution from direct restorative composites for permanent restorations.Methods Two dual-cure (Integrity Multi-Cure and Tempsmart DC) and two self-curing composites (Protemp 4 and Structur 3) were used, with Essentia serving as a reference. Cylindrical specimens (n=20) were cured according to the manufacturer's instructions; the dual-cure materials were prepared in both self- and dual-curing modes. Elution experiments were performed using water and absolute ethanol. The samples were incubated at 37 °C for either 24 h or four weeks; the extraction solvents were refreshed weekly. The eluted BisEMA (-3 / -6 / -10), BisGMA, CQ, UDMA, and TEGDMA were quantified using UHPLC-MS/MS.Results Monomer elution was detected in all provisional composites at 24 h and four weeks, but the amounts released did not exceed those released by the reference composite. When prepared in self-curing mode, Integrity Multi-Cure exhibited significantly higher elution of BisEMA-3, -6, and -10 in ethanol both after 24 h and cumulatively after four weeks. Self-cured Tempsmart DC released significantly more CQ, TEGDMA, and UDMA in both water and ethanol after immersion for 24 h and four weeks, along with significantly more BisGMA in ethanol both after 24 h and four weeks comparison to dual-cured Tempsmart DC (two-way ANOVA, post-hoc Tukey, P < 0.05).Conclusions Provisional composite materials did not elute higher amounts of monomers than a restorative composite. Dual-cured materials, prepared in the self-curing mode, show a trend towards higher monomer elution.

Long-term outcomes of revision total hip arthroplasty with the Zimmer Modular Revision hip system.

Aims: There are limited long-term studies reporting on outcomes of the Zimmer Modular Revision (ZMR) stem, and concerns remain regarding failure. Our primary aim was to determine long-term survival free from all-cause revision and stem-related failure for this modular revision stem in revision total hip arthroplasty (THA). Secondary aims included evaluating radiological and functional outcomes. Methods: We retrospectively identified all patients in our institutional database who underwent revision THA using the ZMR system from January 2000 to December 2007. We included 106 patients (108 hips) with a mean follow-up of 14.5 years (2.3 to 22.3). Mean patient age was 69.2 years (37.0 to 89.4), and 51.9% were female (n = 55). Indications for index revision included aseptic loosening (73.1%), infection (16.7%), fracture (9.3%), and stem fracture (0.9%). Kaplan-Meier analysis was used to determine the all-cause and stem-related failure revision-free survival. At most recent follow-up, Oxford Hip Scores (OHS) were collected, and radiological stem stability was determined using the Engh classification. Results: A total of 17 hips (15.7%) underwent re-revision of any component. Indications for re-revision were stem failure (35.3%; n = 6), infection (29.4%; n = 5), instability (29.4%; n = 5), and acetabular aseptic loosening (5.9%; n = 1). The five- and 15-year all-cause survival was 89.7% (95% confidence interval (CI) 86.7 to 92.7) and 83.3% (95% CI 79.6 to 87.0), respectively. There were six re-revisions (5.6%) for stem failure; five for stem fracture and one for aseptic loosening. The five- and 15-year survival free from stem-related failure was 97.2% (95% CI 95.6 to 98.8) and 94.0% (95% CI 91.6 to 96.4), respectively. At final follow-up, the mean OHS was 36.9 (8.0 to 48.0) and 95.7% (n = 66) of surviving modular revision stems were well-fixed in available radiographs. Conclusion: Femoral revision with the ZMR offers satisfactory long-term all-cause revision-free survival, good survival free of stem-related failure, and favourable clinical outcomes. Stem fracture was the most common reason for stem-related failure and occurred both early and late. This highlights the importance of both early and long-term surveillance for stem-related failure.

FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy.

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma1-4, but the efficacy of CAR T cell therapy in solid tumours has been limited5. This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more 'stem-like' phenotype and increased mitochondrial mass6-8. We therefore sought to identify transcription factors that could enhance CAR T cell fitness and efficacy against solid tumours. Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours.

Twin study dissects CXCR3+ memory B cells as non-heritable feature in multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS), B cells are considered main triggers of the disease, likely as the result of complex interaction between genetic and environmental risk factors. Studies on monozygotic twins discordant for MS offer a unique way to reduce this complexity and reveal discrepant subsets. METHODS: In this study, we analyzed B cell subsets in blood samples of monozygotic twins with and without MS using publicly available data. We verified functional characteristics by exploring the role of therapy and performed separate analyses in unrelated individuals. FINDINGS: The frequencies of CXCR3+ memory B cells were reduced in the blood of genetically identical twins with MS compared to their unaffected twin siblings. Natalizumab (anti-VLA-4 antibody) was the only treatment regimen under which these frequencies were reversed. The CNS-homing features of CXCR3+ memory B cells were supported by elevated CXCL10 levels in MS cerebrospinal fluid and their in vitro propensity to develop into antibody-secreting cells. CONCLUSIONS: Circulating CXCR3+ memory B cells are affected by non-heritable cues in people who develop MS. This underlines the requirement of environmental risk factors such as Epstein-Barr virus in triggering these B cells. We propose that after CXCL10-mediated entry into the CNS, CXCR3+ memory B cells mature into antibody-secreting cells to drive MS. FUNDING: This work was supported by Nationaal MS Fonds (OZ2021-016), Stichting MS Research (19-1057 MS, 20-490f MS, and 21-1142 MS), the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program grant agreement no. 882424, and the Swiss National Science Foundation (733 310030_170320, 310030_188450, and CRSII5_183478).

Plant-based diets in patients with chronic kidney disease.

Dietary protein restriction has been considered to be a nutritional-related strategy to reduce risk for end-stage kidney disease among patients with non-dialysis-dependent chronic kidney disease (CKD). However, there is insufficient evidence to recommend a particular type of protein to slow down the CKD progression. Recently, various plant-based diets could demonstrate some additional benefits such as a blood pressure-lowering effect, a reduction of metabolic acidosis as well as hyperphosphatemia, and gut-derived uremic toxins. Furthermore, the former concerns about the risk of undernutrition and hyperkalemia observed with plant-based diets may be inconsistent in real clinical practice. In this review, we summarize the current evidence of the proposed pleiotropic effects of plant-based diets and their associations with clinical outcomes among pre-dialysis CKD patients.