Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover.

Accumulating evidence has implicated impaired extracellular matrix (ECM) clearance as a key factor in fibrotic disease. Despite decades of research elucidating the effectors of ECM clearance, relatively little is understood regarding the upstream regulation of this process. Collagen is the most abundant constituent of normal and fibrotic ECM in mammalian tissues. Its catabolism occurs through extracellular proteolysis and cell-mediated uptake of collagen fragments for intracellular degradation. Given the paucity of information regarding the regulation of this latter process, here we execute unbiased genome-wide screens to understand the molecular underpinnings of cell-mediated collagen clearance. Using this approach, we discover a mechanism through which collagen biosynthesis is sensed by cells internally and directly regulates clearance of extracellular collagen. The sensing mechanism appears to be dependent on endoplasmic reticulum-resident protein SEL1L and occurs via a noncanonical function of this protein. This pathway functions as a homeostatic negative feedback loop that limits collagen accumulation in tissues. In human fibrotic lung disease, the induction of this collagen clearance pathway by collagen synthesis is impaired, thereby contributing to the pathological accumulation of collagen in lung tissue. Thus, we describe cell-autonomous, rheostatic collagen clearance as an important pathway of tissue homeostasis.

Effectiveness of Sublingual Immunotherapy in the Treatment of HDM-Induced Nasobronchial Allergies: A 3-Year Randomized Case-Control Study From Kashmir.

Allergen immunotherapy (AIT) is the only disease-modifying treatment for allergic disorders that induces immunological tolerance through administration of specific allergens. Studies on AIT for subcutaneous route are in abundance; however, the efficacy of AIT in tablet form through sublingual route has not been well elucidated. The present prospective, parallel-group, controlled study sought to compare the efficacy of sublingual immunotherapy (SLIT) tablets with pharmacotherapy (PT) in 332 house dust mite (HDM)-specific allergic asthma and/or rhinitis patients over a period of 3 years. Patients were followed up for a 6-month run-in period and then randomly stratified as those who would receive SLIT, SLIT in addition to PT (SLIT+PT), and PT alone. AIT was administered in the form of sublingual tablets. Symptom and medication scores were measured every 3 months. In vitro evaluation of serum total and HDM specific immunoglobulin E (HDM sIgE) levels was carried out every 3 months, whereas in vivo skin prick test was performed annually for 3 years. Our study demonstrated sustained clinical improvement, reduction in inhaled corticosteroid (ICS) dose and duration as well as prevention from development of neosensitization to other aero allergens in HDM-allergic asthmatics and/or rhinitis patients treated with 3 years SLIT. Despite a remarkable clinical improvement with AIT, we observed that SLIT did not significantly change the skin reactivity to HDM at 3 years and there was no significant change in the ratio of serum total and HDM sIgE. Given the immune and disease modifying effects of AIT in allergic diseases, the present study supports the notion of its sublingual mode being an effective long-term immunomodulator in HDM-sensitized nasobronchial allergies.

Galectin-1 as a predictive biomarker in ovarian cancer.

AIM: There is an urgent need to set up a useful biomarker for ovarian cancer. Galectin-1 is a promising carbohydrate-binding protein which plays a remarkable role in various malignancies yet its clinical significance is questionable. In this study, we have tested the clinical implications of serum Galectin-1 levels in patients with ovarian tumours. MAIN METHODS: Serum Galectin-1 levels were quantified in 84 newly diagnosed ovarian tumour patients and 20 healthy controls by Enzyme Linked Immuno Sorbent Assay during the course of the disease. Therefore the samples were taken at diagnosis, after surgery and after chemotherapy. KEY FINDINGS: The Galectin-1 levels were found to be associated with various variables of Ovarian Cancer patients. The levels were found to be prominently high in postmenopausal patients. Galectin-1 levels were raised in epithelial ovarian tumours with significantly high levels in serous subtype. A decrease in Galectin-1 levels post-surgical intervention and after receiving chemotherapy was found. Galectin-1 levels evidently distinguished between normal, benign, malignant and metastatic cases as compared to CA125 levels. Galectin-1 demonstrated to be a better biomarker than CA125 according to the Receiver Operating Characteristic (ROC) curve analysis. SIGNIFICANCE: The study emphasizes that serum Galectin-1 may serve as a better surrogate biomarker in Ovarian Cancer for early detection, discriminating between malignant and benign abdominal masses and monitoring the progression of the disease and response to treatment.

Improved pulmonary function test (PFT) after 1 one year of Sublingual Immunotherapy (SLIT) in unison with pharmacotherapy in mild allergic asthmatics.

BACKGROUND: Allergen immunotherapy (AIT) is a promising treatment for allergic disease that induces immunological tolerance through the administration of specific allergens. The study of AIT is in its early stage and its clinical effects are not well elucidated. The present study was aimed at determining the effect of AIT on pulmonary function and serum variables of mild allergic asthma patients. METHODS: A total of 80 patients with mild allergic asthma were recruited for the study. Allergen Specific Immunotherapy was administered in the form of Sublingual Immunotherapy and consisted of a build up phase followed by a maintenance phase (six months each respectively). Total serum IgE and vitamin D levels were quantified by ELISA. The percent eosinophill count was determined by cell analyzers. Pulmonary function test was performed at the baseline and after the end of study period. Subjective symptom score was recorded in the form of asthma control questionnaire score. RESULTS: There was a significant increase in the pre FEV1% and pre FEV1/FVC post AIT administration. A significant decrease in the total serum IgE was found post AIT. A decrease in Asthma control Questionnaire (ACQ) scores indicated an improvement in clinical symptoms. Besides there was a significant effect on ICS discontinuation after AIT. CONCLUSION: The study supports SLIT as an effective treatment for Immunomodulation in mild allergic asthmatics besides it gives us significant information regarding the safety and efficacy of SLIT in such patients.

Influence of single gene variants of FOXP3 on allergic asthma predisposition.

BACKGROUND: The role of FoxP3, a master regulator of T regulatory cells, in allergic diseases such as asthma is of immense importance yet the effect of its gene variants on the disease predisposition is not fully understood. We studied the association of FoxP3 polymorphisms (-2383C/T and -3279C/A) in allergic asthma patients and their correlation with serum IL-4, IL-13, Total IgE, and Vitamin D levels. METHODS: In this study 350 individuals were enrolled, 150 allergic asthma patients and 200 healthy controls. SNP analyses were performed by RFLP. IL-4, IL-13 vitamin D and Total IgE were measured by ELISA. RESULTS: The AA homozygous mutant of -3279C/A posed a three-fold risk [P < 0.005; OR, 3.52] whereas the -2383C/T variants TT genotype carried a fourfold risk [P = 0.002; OR, 4.04]. Haplotype analysis exhibited predisposition to allergic asthmawith CC/TT [P = 0.01; OR 5.93 (95%CI)], AA/CC [P = 0.01; OR 3.29] and AA/TT haplotypes [P = 0; OR 11.86 (1.31-85.87)]. A negative correlation between IgE and Vitamin D was found [r = -0.30p-value 0.001] but a negative correlation betweenIgE and Vit D was established in the haplotype CC/TT [r = -0.45P = 0.002] and CC/CT [r = -0.52P = 0.04]. In allergic patients, the eosinophils count was high [p = 0.003] and the mean levels of pro-inflammatory cytokines IL-4 and IL-13 were elevated [P < 0.001] as well. CONCLUSIONS: The study suggests SNP -3279 -AA genotype and, -2383-TT genotype in association with certain haplotypes pose a risk for allergy development. There was no correlation between different genotypes and serum levels of various cytokines.