Targeting PGLYRP1 promotes antitumor immunity while inhibiting autoimmune neuroinflammation.

Co-inhibitory and checkpoint molecules suppress T cell function in the tumor microenvironment, thereby rendering T cells dysfunctional. Although immune checkpoint blockade is a successful treatment option for multiple human cancers, severe autoimmune-like adverse effects can limit its application. Here, we show that the gene encoding peptidoglycan recognition protein 1 (PGLYRP1) is highly coexpressed with genes encoding co-inhibitory molecules, indicating that it might be a promising target for cancer immunotherapy. Genetic deletion of Pglyrp1 in mice led to decreased tumor growth and an increased activation/effector phenotype in CD8+ T cells, suggesting an inhibitory function of PGLYRP1 in CD8+ T cells. Surprisingly, genetic deletion of Pglyrp1 protected against the development of experimental autoimmune encephalomyelitis, a model of autoimmune disease in the central nervous system. PGLYRP1-deficient myeloid cells had a defect in antigen presentation and T cell activation, indicating that PGLYRP1 might function as a proinflammatory molecule in myeloid cells during autoimmunity. These results highlight PGLYRP1 as a promising target for immunotherapy that, when targeted, elicits a potent antitumor immune response while protecting against some forms of tissue inflammation and autoimmunity.

Effect of Beam Oscillation on Microstructure and Mechanical Properties of Electron Beam Welded EN25 Steel.

EN25 steels have been found to be applicable in shafts, gears, etc., but welding of EN25 steel was performed using electron beam welding with different oscillation beam diameters varying from 2 mm to 0.5 mm. The present study reports the effect of beam oscillation on the evolution of nonmetallic inclusions, microstructures, and mechanical properties of EN25 steel. Heat input calculations showed that the application of beam oscillations resulted in significantly lower heat inputs compared to their non-oscillating counterparts. The highest fraction of the retained austenite (9.35%) was observed in a weld prepared with beam oscillation at a 2-mm oscillation diameter, and it decreased to 3.27% at an oscillating diameter of 0.5 mm, and it further reduced to 0.36% for non-oscillating beam cases. Residual stresses were compressive in the fusion zone, irrespective of beam oscillation. Beam oscillation resulted in equiaxed grain in the recenter region of the fusion zone, attributed to heat mixing and the evolution of random texture. The application of beam oscillations resulted in a significant decrease in the size of the nonmetallic inclusions to 0.1-0.5 compared to 5-20 mm in base metal. All tensile samples failed in the base metal, indicating good strength of the weld. Fusion zone hardness (250-670 HNV) and wear properties (COF 0.7 to COF 0.45) improved irrespective of with and without beam oscillation.

Case report: Later onset of NRAS-mutant metastatic melanoma in a patient with a partially-excised giant congenital melanocytic nevus.

Despite recent advances in treatment and surveillance, metastatic melanoma still carries a poor prognosis. Large/giant congenital melanocytic nevi (CMNs) constitute a known risk factor for the condition, with the greatest risk for malignant transformation thought to be during childhood (median age at diagnosis of 3 years in a previous cohort). Herein, we present the case of a 30-year-old male who, after undergoing multiple excision/grafting procedures for a giant CMN as a child, was diagnosed with an NRAS-mutant, MDM2-amplified metastatic melanoma more than 20 years later. Response to ipilimumab/nivolumab immunotherapy, cisplatin/vinblastine/temozolomide chemotherapy, and nivolumab/relatlimab immunotherapy was poor. This case highlights the importance of lifetime monitoring with once-yearly dermatological examination (including lymph node palpation) in large/giant CMN patients, as well as the need for further clinical trials evaluating novel therapies for NRAS-mutant melanoma.

Metabolic modeling of single Th17 cells reveals regulators of autoimmunity.

Metabolism is a major regulator of immune cell function, but it remains difficult to study the metabolic status of individual cells. Here, we present Compass, an algorithm to characterize cellular metabolic states based on single-cell RNA sequencing and flux balance analysis. We applied Compass to associate metabolic states with T helper 17 (Th17) functional variability (pathogenic potential) and recovered a metabolic switch between glycolysis and fatty acid oxidation, akin to known Th17/regulatory T cell (Treg) differences, which we validated by metabolic assays. Compass also predicted that Th17 pathogenicity was associated with arginine and downstream polyamine metabolism. Indeed, polyamine-related enzyme expression was enhanced in pathogenic Th17 and suppressed in Treg cells. Chemical and genetic perturbation of polyamine metabolism inhibited Th17 cytokines, promoted Foxp3 expression, and remodeled the transcriptome and epigenome of Th17 cells toward a Treg-like state. In vivo perturbations of the polyamine pathway altered the phenotype of encephalitogenic T cells and attenuated tissue inflammation in CNS autoimmunity.

Anogenital lichen sclerosus.

Lichen sclerosus (LS) was first described by Hallopeau in 1887. It is a chronic inflammatory condition most commonly involving the anogenital region with a relapsing course and a potential for destruction, functional impairment, atrophy, and malignant changes. LS affects both sexes with a female preponderance of 5:1. The exact prevalence of the disease is difficult to predict as the lesions are asymptomatic in the initial phase and later when the complications arise patients might visit the surgeon, pediatrician, gynecologist, or urologist. The etiology of LS has a complex interplay of genetic factors, autoimmunity, infections, and trauma. Physical examination to assess the extent of the disease and decide the line of management is the most crucial step in the management. Corticosteroids, calcineurin inhibitor, retinoids, phototherapy, and surgery can be helpful. Self-examination and long-term follow-up are necessary.

Childhood acute lymphoblastic leukaemia relapse with atypical localised presentation mimicking ankle trauma in a 28-year-old man.

Acute lymphoblastic leukaemia (ALL) is a common paediatric cancer with a tendency to relapse, usually within 3 years of remission. Most patients present with hepatomegaly, splenomegaly, pallor, fever and bruising. Localised muskuloskeletal presentation is extremely rare. Here, we present a case of leukaemia relapse in the bone marrow of a 28-year-old man 9 years after achieving remission, presenting only with ankle pain and normal routine labs besides mild hypercalcemia, and no signs of disease in common bone marrow biopsy sites. This highly localised presentation is unusual and would hopefully inform clinicians to have a high index of suspicion for relapse in an adult patient who has had childhood ALL.

Determinants of urban-rural differences in cardiovascular risk factors in middle-aged women in India: a cross-sectional study.

OBJECTIVES: Cardiovascular diseases (CVD) are the most important cause of death amongst middle-aged Indian women. To determine prevalence of CVD risk factors and their determinants we performed a nationwide study. METHODS: Population based studies amongst women 35-70 years were performed in four urban and five rural locations in India. Location based stratified sampling was performed and we enrolled 4624 (rural 2616, urban 2008) of eligible 8000 women (58%). Demographic details, medical history, diet, physical activity and anthropometry were recorded using standardised techniques. Blood haemoglobin, glucose and total cholesterol were determined. Risk factors were diagnosed using current guidelines. Descriptive statistics are reported. Stepwise multivariate logistic regression was performed to identify determinants of urban-rural differences. RESULTS: In urban women mean body mass index (BMI), waist circumference, waist-hip ratio (WHR), systolic BP, haemoglobin, fasting glucose and cholesterol were significantly greater (p<0.01). Age-adjusted prevalence of risk factors (%) in urban vs rural was of obesity BMI ≥ 25 kg/m(2) (45.6 vs 22.5), truncal obesity WHR>0.9 (44.3 vs 13.0), hypertension (37.5 vs 29.3), hypercholesterolemia ≥ 200 mg/dl (27.7 vs 13.5), and diabetes (15.1 vs 4.3) greater whilst any tobacco use (19.6 vs 41.6) or smoking lower. Significant determinants of urban-rural differences were greater income and literacy, dietary fats, low physical activity, obesity and truncal obesity (p<0.01). CONCLUSIONS: Greater prevalence of CVD risk factors in urban middle-aged women is explained by greater income and literacy, dietary fat, low physical activity and obesity.