P53 tumor suppressor gene mutations in hepatocellular carcinoma patients in India

Background: Specific mutations of the p53 tumor suppressor gene in hepatocellular carcinoma (HCC) have been reported from several parts of the world, but to the authors' knowledge to date the status of this gene has not been studied in HCC patients in India, where HCC is one of the major cancers and the frequency of chronic hepatitis B virus (HBV) as well as hepatitis C virus (HCV) infection and exposure to dietary aflatoxin B1 is very high. The most frequent mutation of the p53 gene in HCC is an AGGArg to AGTSer missense mutation at codon 249 of exon 7. Methods: Liver biopsy specimens from 21 HCC patients and 10 healthy controls were obtained through surgery or by needle biopsy technique. Phenol-chloroform-extracted DNA specimens were employed for the detection of HBV infection and p53 gene mutations. Nucleotide mutations of exons 4-9 of the p53 gene were analyzed by polymerase chain reaction (PCR), single strand confirmation polymorphism, and direct sequencing. Third-generation sandwich enzyme-linked immunosorbent assay (ELISA) was used for the serologic detection of HBV and HCV infection. Results: Analysis of exons 4-9 of the p53 gene revealed only 3 mutations (3 of 21 specimens, 14.28%; 95% confidence interval, -0.7-29.3), 2 mutations at codon 249 showing G→T transversions, and 1 mutation (4.7%) at codon 250 with a C→T transition. The base substitutions at the third base of codon 249 resulted in a missense mutation leading to a change in amino acid from arginine to serine whereas at codon 250 it caused a change from proline to serine. Dot blot hybridization and PCR for HBV DNA from HCCs revealed 58.8% (10 of 17 specimens) and 90.47% (19 of 21 specimens), positivity, respectively. ELISA for hepatitis B virus surface antigen in serum showed a positivity of 71.42% (15 of 21 specimens), but there was only 40% positivity (8 of 20 specimens) for hepatitis B virus envelope antigen whereas 6 of 17 patients (35.29%) showed the presence of antibodies against hepatitis B virus envelope protein. No patient was found to be positive for the HCV antibody. Conclusions: The very low frequency of p53 mutations and the extremely high frequency of HBV infection (> 90%) in HCC indicate that the mutations in the p53 gene frequently found in HCC reported from different endemic areas of the world may not play a direct role in the development of HCC in India. HBV infection and, possibly, exposure to the dietary aflatoxin B1 appear to play major roles in the molecular pathogenesis of HCC in India

Developmental origins for kidney disease due to Shroom3 deficiency

CKD is a significant health concern with an underlying genetic component. Multiple genome-wide association studies (GWASs) strongly associated CKD with the shroomfamilymember 3 (SHROOM3) gene, which encodes an actin-associated protein important in epithelial morphogenesis. However, the role of SHROOM3 in kidney development and function is virtually unknown. Studies in zebrafish and rat showed that alterations in Shroom3 can result in glomerular dysfunction. Furthermore, human SHROOM3 variants can induce impaired kidney function in animal models. Here, we examined the temporal and spatial expression of Shroom3 in the mammalian kidney. We detected Shroom3 expression in the condensing mesenchyme, Bowman\u27s capsule, and developing and mature podocytes in mice. Shroom3 null (Shroom3Gt/Gt) mice showed marked glomerular abnormalities, including cystic and collapsing/degenerating glomeruli, and marked disruptions in podocyte arrangement and morphology. These podocyte-specific abnormalities are associated with altered Rho-kinase/myosin II signaling and loss of apically distributed actin. Additionally, Shroom3 heterozygous (Shroom3Gt/+) mice showed developmental irregularities that manifested as adult-onset glomerulosclerosis and proteinuria. Taken together, our results establish the significance of Shroom3 in mammalian kidney development and progression of kidney disease. Specifically, Shroom3 maintains normal podocyte architecture in mice via modulation of the actomyosin network, which is essential for podocyte function. Furthermore, our findings strongly support the GWASs that suggest a role for SHROOM3 in human kidney disease

IFNγ-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment

Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival. Single-cell RNA sequencing (RNA-seq) reveals enrichment of homeostatic modules in monocytes and DCs from human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role. These findings link immune homeostasis to key determinants of anti-tumoral immunity and escape, revealing co-opting of tissue-specific immune development in the tumor microenvironment. Keywords: dendritic cells; homeostasis; differentiation; IFNγ; tumor microenvironment; melanoma tolerance; immunotherapy; suppressor-of-cytokine-signaling 2 (SOCS2); tissue mononuclear phagocyte

Inverted T waves on electrocardiogram: myocardial ischemia versus pulmonary embolism.

Electrocardiogram (ECG) is of limited diagnostic value in patients suspected with pulmonary embolism (PE). However, recent studies suggest that inverted T waves in the precordial leads are the most frequent ECG sign of massive PE (Chest 1997;11:537). Besides, this ECG sign was also associated with the best sensitivity, specificity, and positive and negative predictive values for diagnosing PE. We report 2 cases with similar ECG findings that were referred to us as unstable angina. Both were hemodynamically stable and had moderate-size pulmonary emboli. The ECG findings reverted to normal within a week of anticoagulation treatment. Our observation suggests that even a moderate-size PE can cause these ECG changes

Prevalence of diabetes and pre-diabetes and assessments of their risk factors in urban slums of Bangalore

Background: To determine the prevalence of diabetes and pre-diabetes and to assess the risk factors associated with diabetes and pre-diabetes in the urban slums of Bangalore. Materials and Methods: A cross-sectional study was conducted in four slums of Bangalore in the age group of 35 years and above comprising of total 2013 subjects. Risk factors like age, sex, family history, behavior, physical activity, BMI, waist hip ration, diet habits were assessed to find their association with diabetes. Results: Prevalence of diabetes was 12.33% and of pre-diabetes was 11.57%. Prevalence was more among the females compared to males. Increasing age, over weight and obesity, sedentary life style, tobacco consumption, diet habits showed statistically significant association with prevalence of diabetes and pre-diabetes. Conclusion: Physical activity like regular exercises both at the office and at home, fibers-rich diet, blood sugar estimation after 35 years are some of the recommendations which can control diabetes

Differentiating acute viral hepatitis B from first episode of reactivation of chronic hepatitis B

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