Background: Breast cancer (BC) is the most leading cause of cancer and the second most common cause of cancer-related death among females worldwide. The survival time of the disease and its risk factors are important for physicians.
Background: Thalassemia major (TM) is a severe disease and the most common anemia worldwide. The survival time of the disease and its risk factors are of importance for physicians. The present study was conducted to apply the semi-parametric Cox PH model and use parametric proportional hazards (PH) and accelerated failure time (AFT) models to identify the risk factors related to survival of TM patients. Methods: The data of this historical cohort study (296 patients with TM) were collected during 1994 and 2013 in Zafar Clinic in Tehran. Gompertz PH and Weibull AFT models were used for survival analysis (SA) of these patients. Data analysis was performed using R3.2.2 software. Results: 153 (51.7%) of patients were female; the mean (±SD) age of the patients was 29.11 (±0.47) years. One-year survival rate for males and females was 0.963±0.007 and 0.973±0.013, respectively; and 3-year survival rate for males and females was 0.711±0.057 and 0.733±0.114, respectively. In the Gompertz model, birthplace and age at onset of the disease were significant factors (p= 0.035, and p= 0.005) in survival time. Also, in the Weibull model, birth place and age at onset of the disease were significant factors (p= 0.013, and p= 0.008) in survival time. The Akaike Information Criterion (AIC) for Weibull model was 158.51, which was lower than other parametric models. Conclusion: According to the results, the Weibull AFT model was found to be a better model for identifying the risk factors related to survival of patients with TM disease. Informing parents, especially mothers and paying attention to blood screening for early diagnosis may increase the survival rate of patients.
Summary. Asthma is one of the most prevalent atopic diseases in childhood. It is characterized by infl ammation of conductive airways and bronchial hyperresponsiveness. Environmental factors introduced to child in early years of life may have a protective or harmful role in developing atopic diseases. To evaluate the infl uence of some environmental factors such as cat or dog ownership, smoking of mother or father and environmental pollution on prevalence of wheezing in children. Subjects and methods: This was a cross sectional retrospective study. A questionnaire was designed based on International Study of Asthma and Allergies in Childhood (ISAAC). Parents of the subjects were asked to fi ll in the questionnaires. Children's wheezing association with keeping cats and dogs, smoking mother and father and frequency of truck passing in place of residence was investigated. 545 children were recruited in our study. Prevalence of wheezing was 9%. Keeping cats in fi rst year of life and last year was associated with less wheezing. But the latter association was not statistically signifi cant. Keeping dogs was so scarce in area of our study, so we could not perform a rightful analysis. Frequency of truck passing was signifi cantly higher in those with wheezing. Keeping cats in fi rst year of life was a signifi cant protective factor, whereas residence in an area with frequent truck passing increased wheezing in children. Results of our study can emphasize the need to keep children away from polluted areas. Further studies are needed to investigate whether keeping a pet in household can benefi t children regarding all possible concerns and benefi ts.
Chronic graft-vs-host disease (cGVHD) is a major obstacle to the success of allogeneic hematopoietic stem cell transplantation (HCT) in patients. This debilitating condition is characterized by chronic inflammation, cell-mediated and humoral immunity, and ultimately tissue fibrosis. There is currently little or no understanding of the molecular pathogenesis of chronic cGVHD resulting in poor effective treatment strategies. Sclerodermatous GVHD (sclGVHD) is one of the more severe forms of cGVHD associated with poor prognosis and low sensitivity to immune suppressive therapy. Methods: To address the current gap in knowledge pertaining to the underlying pathophysiology of sclGVHD we used single cell RNA sequencing analyses on fresh patient biopsy specimens. In vivo studies were carried out by sub lethal irradiation of BALB.k recipients which underwent HCT from miAg-mismatched AKR/J donors. Recipient sclerodermatous-tissues were analyzed using FACS, IHC and IF staining. Human studies were conducted on (i) Primary samples from patients with severe sclGVHD using tissue microarrays (TMA) by Immuno-histofluorescence (IHF) and IF. (ii) Dermal fibroblasts from sclGVHD samples were subjected to ATACseq and ChiPseq CRISPR-Cas9 JUN deletion. (iii) Also, dermal fibroblasts from human scl-GVHD were implanted under the kidney capsule of NSG mice to study the effects of inhibiting pro-fibrotic pathways in vivo. Results: We show for the first time that in a mouse model of sclGVHD (male), recipients of female T-cell replete grafts developed severe scleroderma with massive skin thickening and collagen deposition. Fibroblasts strongly expressed JUN, which is part of AP-1, a transcription factor involved in the acute phase response that regulates gene expression in response to stimuli from cytokines, growth factors and pathogens. We have previously demonstrated JUN as a key player in the molecular pathogenesis of other fibrotic diseases (Wernig G et al. PNAS 2017, Cui et al. Nature comm. 2020, Lerbs et al. JCI i 2020). Likewise, CD47, an immune checkpoint protein that prevents removal of Mϕ, was strongly co-expressed in fibroblasts in sclGVHD - but not in the control mice (Fig A+B). Here we show that (i) In humans, (n = 45 sclGVHD patients), there is a strong expression and activation of JUN and CD47 in dermal fibroblasts which was not observed in control samples. Mixed inflammatory infiltrates were dominated by Mϕ and granulocytes. (ii) Isolated primary fibroblasts from fresh human sclGVHD skin biopsies analyzed for chromatin accessibility across the genome by ATAC-seq showed wide open accessibility to the JUN promoter, IL-6 promoter and CD47 enhancer and promoter indicating that they play a critical role in regulating the pathogenesis of sclGVHD. In contrast, normal fibroblasts displayed only minimal accessibility to the JUN promoter. We further validated our data using CRISPR-Cas9 knock-down studies on sclGVHD fibroblasts and show that the IL-6 promoter, enhancer and promoter of CD47 are regulated by JUN, with JUN deletion resulting in significant decrease in the promoter binding accessibility to IL-6 and CD47 (Fig C). Further, JUN activity appears to regulate key members of the Hh signaling pathway (GLI1, PTCH1 and PTCH2), as their chromatin accessibility was decreased with JUN deletion. These correlative findings were confirmed by JUN ChIP seq, an assay that identifies binding sites of DNA-associated proteins. (iii) To test our findings in vivo we established xenograft models of primary human sclGVHD by implanting cells under the kidney capsule of NSG mice.All treatments (except placebo) resulted in decreased fibrosis (Fig D), presumably by blocking the activation of JUN (pJUN) and its profibrotic downstream pathway members IL-6 and pSTAT3, as assessed by phospho flow. Conclusion: In our studies we demonstrate that in established SclGVHD, combinatorial therapy consisting of anti-CD47 antibody together with IL6 blockade has the highest potential to translate into a therapeutic intervention given its ability to be more effective than currently used antifibrotic and anti-inflammatory agents in clinic. The findings from our study are significant because we show an important mechanism underlying SclGVHD onset, identify a novel genetic signature that can be targeted, describe a new mouse model and a clinical assay that has a high throughput readout and suggest a treatment regimen for patients. Figure 1 Figure 1. Disclosures Arai: Magenta Therapeutics: Research Funding. Shizuru: Forty seven Inc: Other: Inventor on a patent licenses by Forty Seven. Forty seven was acquired by Gilead in 2020; Jasper Therapeutics, Inc.: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Chair of scientific advisory board.
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