A study on clinico immuno pathological correlation of skin and pulmonary involvement in systemic sclerosis

INTRODUCTION: Systemic sclerosis is a chronic autoimmune connective tissue disease of unknown etiology involving multiple systems. It is characterized by significant dysfunction of the microvasculature, immune system and connective tissue. The currently used classification of Systemic Sclerosis is by the extent of skin involvement1. The extent of skin disease correlates with the disease course. Though many internal organs are involved, lung involvement is the major cause of morbidity and mortality in SSc. While some studies regard skin involvement as a surrogate marker for pulmonary involvement, there are studies that have shown improvement of sclerosis occurring spontaneously or as a result of treatment and therefore it does not reflect the pulmonary fibrosis. In addition several cutaneous features have been found to be associated with clinical and serological manifestations in systemic sclerosis. In a recent study2 elevated serum level of MMP-12 correlated with the severity of skin fibrosis and activity of interstitial lung disease in systemic sclerosis, suggesting the common pathogenesis between them. So the skin can be useful marker for early diagnosis and to assess pulmonary involvement. AIMS AND OBJECTIVES: 1. To study the skin and pulmonary manifestations in Systemic Sclerosis. 2. To study the correlation of the clinical, pathological, immunological features of skin and pulmonary involvement in Systemic Sclerosis. MATERIALS AND METHODS: SUBJECTS: Patients attending the Rheumatology Care Centre (RCC) outpatient and inpatient of Rajiv Gandhi Government General Hospital, Chennai were recruited from the period of June 2011 to February 2013. 55 eligible cases who fulfilled the inclusion criteria were enrolled. All subjects gave a written informed consent to enroll in this study. The Ethical committee approval was obtained. INCLUSION CRITERIA: American College of Rheumatology preliminary classification criteria. Major criteria or two minor criteria for diagnosis. Major criteria: Scleroderma proximal to the metacarpophalangeal joints. Minor Criteria: 1. Sclerodactyly. 2. Digital pitting scars or loss of finger pad substance. 3. Bibasilar pulmonary fibrosis. EXCLUSION CRITERIA Overlap syndrome, mixed connective tissue disease, other scleroderma spectrum disorders. RESULTS: Total number of cases were 55. The mean age was 35.5 years. The range was from 20-56 years. Majority were females 49 (89.1%) while males were 6 (10.9%). The mean disease duration was 3.1 years with range 4 months to 10 years. CONCLUSION: In this study on Systemic sclerosis there was a female gender Predominance (8:1). • The limited cutaneous SSc were more than diffuse cutaneous type in this study. • There was positive correlation between disease duration and PHT. • 43.6% of the study group were in the 7-15 MRSS Range. • Presence of salt and pepper had significant association with MRSS in this study. • Dyspnea was the most common respiratory symptom and it correlated positively with MRSS. • The MRSS was significantly associated with presence of ILD in the study group. • ILD was more common in diffuse cutaneous type and the mean MRSS was significantly associated with ILD in diffuse cutaneous type. • There was no association between MRSS and PHT in this study. • There was significant association between MRSS and the Medsger disease severity of lung. • Digital pitted scars and Raynaud‟s Phenomenon positively correlated with ILD in this study group. • ANA positivity was seen in 80% of the cases

mTORC2 signaling drives the development and progression of pancreatic cancer

mTOR signaling controls several critical cellular functions and is deregulated in many cancers, including pancreatic cancer. To date, most efforts have focused on inhibiting the mTORC1 complex. However, clinical trials of mTORC1 inhibitors in pancreatic cancer have failed, raising questions about this therapeutic approach. We employed a genetic approach to delete the obligate mTORC2 subunit Rictor and identified the critical times during which tumorigenesis requires mTORC2 signaling. Rictor deletion resulted in profoundly delayed tumorigenesis. Whereas previous studies showed most pancreatic tumors were insensitive to rapamycin, treatment with a dual mTORC1/2 inhibitor strongly suppressed tumorigenesis. In late-stage tumor-bearing mice, combined mTORC1/2 and PI3K inhibition significantly increased survival. Thus, targeting mTOR may be a potential therapeutic strategy in pancreatic cancer

Serum Uric Acid in Acute Ischemic Stroke

PURPOSE: To estimate the level of serum uric acid in patients with acute ischemic stroke, to find out its association with diabetes and hypertension, to correlate with age and gender and to study its significance in the out come of the stroke patients. METHODS: A cross section study was designed after institutional ethical clearance to screen acute ischemic stroke patients admitted to the hospital within 48 hours of stroke who satisfied a rigid inclusion and exclusion criteria. Another 40 members with similar variables without stroke were taken as control. The serum uric acid level was measured by uricase method. The outcome in the stroke patients was analysed at the end of 2 weeks while in hospital. The data were entered in microsoft excel spread sheet and analysed statistically. RESULTS: There were 102 stroke patients. Among them there were 66 males and 36 females. Their age varied from 30 to 70 years and the mean age was 56.72 years. The uric acid level among the stroke cases varied from 4.12 to 7.2 mg/dL and the mean serum uric acid level was 5.66 mg/dL. It was elevated significantly than the control group (P< 0.001). Stroke patients with diabetics and hypertension had elevated serum uric acid level than the counter parts in the control and the difference was significant statistically (P<0.001). Those stroke cases with elevated uric acid had poor outcome and statistically was significant (P < 0.001). CONCLUSION: Serum uric acid level was increased in stroke patients and was independent of age and gender. Uric acid level among stroke cases was independent of their diabetic and hypertensive status. All the stroke cases who had poor outcome were found to have elevated uric acid level which may be a response to oxidative stress and hence it can be considered as biochemical marker in stroke patients

Secure Digital Information Forward Using Highly Developed AES Techniques in Cloud Computing

Nowadays, in communications, the main criteria are ensuring the digital information and communication in the network. The normal two users' communication exchanges confidential data and files via the web. Secure data communication is the most crucial problem for message transmission networks. To resolve this problem, cryptography uses mathematical encryption and decryption data on adaptation by converting data from a key into an unreadable format. Cryptography provides a method for performing the transmission of confidential or secure communication. The proposed AES (Advanced Encryption Standard)-based Padding Key Encryption (PKE) algorithm encrypts the Data; it generates the secret key in an unreadable format. The receiver decrypts the data using the private key in a readable format. In the proposed PKE algorithm, the sender sends data into plain Text to cypher-text using a secret key to the authorized person; the unauthorized person cannot access the data through the Internet; only an authorized person can view the data through the private key. A method for identifying user groups was developed. Support vector machines (SVM) were used in user behaviour analysis to estimate probability densities so that each user could be predicted to launch applications and sessions independently. The results of the proposed simulation offer a high level of security for transmitting sensitive data or files to recipients compared to other previous methods and user behaviour analysis

Glycans as receptors for influenza pathogenesis

Influenza A viruses, members of the Orthomyxoviridae family, are responsible for annual seasonal influenza epidemics and occasional global pandemics. The binding of viral coat glycoprotein hemagglutinin (HA) to sialylated glycan receptors on host epithelial cells is the critical initial step in the infection and transmission of these viruses. Scientists believe that a switch in the binding specificity of HA from Neu5Acα2-3Gal linked (α2-3) to Neu5Acα2-6Gal linked (α2-6) glycans is essential for the crossover of the viruses from avian to human hosts. However, studies have shown that the classification of glycan binding preference of HA based on sialic acid linkage alone is insufficient to establish a correlation between receptor specificity of HA and the efficient transmission of influenza A viruses. A recent study reported extensive diversity in the structure and composition of α2-6 glycans (which goes beyond the sialic acid linkage) in human upper respiratory epithelia and identified different glycan structural topologies. Biochemical examination of the multivalent HA binding to these diverse sialylated glycan structures also demonstrated that high affinity binding of HA to α2-6 glycans with a characteristic umbrella-like structural topology is critical for efficient human adaptation and human-human transmission of influenza A viruses. This review summarizes studies which suggest a new paradigm for understanding the role of the structure of sialylated glycan receptors in influenza virus pathogenesis.National Institute of General Medical Sciences (U.S.) (Glue Grant U54 GM62116)National Institutes of Health (U.S.) (Grant GM57073)Singapore-MIT Alliance for Research and Technolog

Investigating the Potential Antihyperlipidemic Properties of Ultra-High Dilutions of Guatteria Gaumeri: An Experimental Approach

The traditional medicinal plant known as Guatteria gaumeri, also referred to as G. leiophylla Safford, is a member of the Anonaceae family. It has historically been employed by indigenous populations for addressing hyperlipidemia, a condition that heightens the risk of atherosclerosis and atherosclerotic cardiovascular disease, which ranks as the leading cause of global and national mortality. This investigation presents the effectiveness of various homeopathic dilutions of Guatteria gaumeri, including 30C, 12C, and the Mother Tincture, in the reduction of cholesterol levels. The research was conducted using Hubbard broiler chickens, with each group consisting of four chickens. The chickens received Guatteria gaumeri Mother Tincture, 12C, or 30C twice daily for a duration of 35 days. On the 36th day, serum lipid parameters such as total cholesterol, triglycerides, LDL, HDL, and VLDL were measured and compared to a control group. The results revealed a significant decrease in blood triglycerides, total cholesterol, LDL, and VLDL levels, along with an increase in HDL levels, following 35 days of Guatteria gaumeri Mother Tincture, 12C, and 30C intervention. In conclusion, these findings suggest that Guatteria gaumeri, as a homeopathic remedy, possesses noteworthy anti-hyperlipidemic properties and holds promise as a potential therapeutic agent for metabolic correction and lipid level

RSK1 dependency in FLT3-ITD acute myeloid leukemia

Internal tandem duplications (ITD) in fms-like tyrosine kinase 3 (FLT3) represent the most common genetic alteration in de novo acute myeloid leukemia (AML). Here, we identify ribosomal protein s6 kinase a1 (RSK1) as a core dependency in FLT3-ITD AML and unveil the existence of crucial bi-directional regulation. RSK1 perturbation resulted in marked apoptosis and abrogated phosphorylation of FLT3 and associated downstream signaling cascades in FLT3-ITD AML cell lines. Using cycloheximide, MG-132, and ubiquitination assays, we further demonstrate mechanistically that RSK1 regulates FLT3-ITD activity, and protein stability through deubiqutinase USP1, which we identify as a second dependency. Importantly, multivariate analysis revealed heightened expression of RPS6KA1 and USP1 to be associated with poor patient prognosis, and these effectors may serve as biomarkers predictive of patient survival and therapeutic response to FLT3-ITD inhibitors. Lastly, RSK1 inhibition utilizing a first-in-class RSK inhibitor, PMD-026, that is currently undergoing Phase 2 development for breast cancer, diminished leukemic disease burden in MV4-11 xenograft and syngeneic Flt

CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response.

Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition affects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all of the immune cell types that participate in an integrated immune response. Inhibiting CXCR4 in an experimental cancer medicine study by 1-wk continuous infusion of the small-molecule inhibitor AMD3100 (plerixafor) induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immune-mediated damage to noninfected tissues: Rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human pancreatic ductal adenocarcinoma and colorectal cancer by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.Stand Up 2 Cancer, Lustgarten Foundation, NIH

Associations of the built environment with type 2 diabetes in Asia: a systematic review

Objectives Our study aimed to systematically review the literature and synthesise findings on potential associations of built environment characteristics with type 2 diabetes (T2D) in Asia. Design Systematic review of the literature. Data sources Online databases Medline, Embase and Global Health were used to identify peer-reviewed journal articles published from inception to 23 January 2023. Eligibility criteria Eligible studies included cohort, cross-sectional and case–control studies that explored associations of built environment characteristics with T2D among adults 18 years and older in Asia. Data extraction and synthesis Covidence online was used to remove duplicates and perform title, abstract and full-text screening. Data extraction was carried out by two independent reviewers using the OVID database and data were imported into MS Excel. Out of 5208 identified studies, 28 studies were included in this systematic review. Due to heterogeneity in study design, built environment and outcome definitions, a semiqualitative analysis was conducted, which synthesised results using weighted z-scores. Results Five broad categories of built environment characteristics were associated with T2D in Asia. These included urban green space, walkability, food environment, availability and accessibility of services such as recreational and healthcare facilities and air pollution. We found very strong evidence of a positive association of particulate matter (PM2.5, PM10), nitrogen dioxide and sulfur dioxide (p<0.001) with T2D risk. Conclusion Several built environment attributes were significantly related to T2D in Asia. When compared with Western countries, very few studies have been conducted in Asia. Further research is, therefore, warranted to establish the importance of the built environment on T2D. Such evidence is essential for public health and planning policies to (re)design neighbourhoods and help improve public health across Asian countries

CSF1R+ Macrophages Sustain Pancreatic Tumor Growth through T Cell Suppression and Maintenance of Key Gene Programs that Define the Squamous Subtype.

Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapies including single-agent immunotherapy and has a dense desmoplastic stroma, and most patients present with advanced metastatic disease. We reveal that macrophages are the dominant leukocyte population both in human PDAC stroma and autochthonous models, with an important functional contribution to the squamous subtype of human PDAC. We targeted macrophages in a genetic PDAC model using AZD7507, a potent selective inhibitor of CSF1R. AZD7507 caused shrinkage of established tumors and increased mouse survival in this difficult-to-treat model. Malignant cell proliferation diminished, with increased cell death and an enhanced T cell immune response. Loss of macrophages rewired other features of the TME, with global changes in gene expression akin to switching PDAC subtypes. These changes were markedly different to those elicited when neutrophils were targeted via CXCR2. These results suggest targeting the myeloid cell axis may be particularly efficacious in PDAC, especially with CSF1R inhibitors