Ibrutinib as a potential therapeutic option for HER2 overexpressing breast cancer - the role of STAT3 and p21.

Treatment response rates to current anticancer therapies for HER2 overexpressing breast cancer are limited and are associated with severe adverse drug reactions. Tyrosine kinases perform crucial roles in cellular processes by mediating cell signalling cascades. Ibrutinib is a recently approved Tyrosine Kinase Inhibitor (TKI) that has been shown be an effective therapeutic option for HER2 overexpressing breast cancer. The molecular mechanisms, pathways, or genes that are modulated by ibrutinib and the mechanism of action of ibrutinib in HER2 overexpressing breast cancer remain obscure. In this study, we have performed a kinome array analysis of ibrutinib treatment in two HER2 overexpressing breast cancer cell lines. Our analysis shows that ibrutinib induces changes in nuclear morphology and causes apoptosis via caspase-dependent extrinsic apoptosis pathway with the activation of caspases-8, caspase-3, and cleavage of PARP1. We further show that phosphorylated STAT3Y705 is upregulated and phosphorylated p21T145 is downregulated upon ibrutinib treatment. We propose that STAT3 upregulation is a passive response as a result of induction of DNA damage and downregulation of phosphorylated p21 is promoting cell cycle arrest and apoptosis in the two HER2 overexpressing cell lines. These results suggest that inhibitors of STAT3 phosphorylation may be potential options for combination therapy to help increase the efficacy of ibrutinib against HER2-overexpressing tumors.

Identification of compounds for improved growth of Leptospira in culture and isolation.

Leptospirosis is a recurring global disease of severe illness involving pulmonary and renal involvement in cattle and humans that needs attention to cure. The major challenge in treating leptospirosis disease is the diagnosis of the disease. The culturing of an organism is a gold standard for confirmation of the disease. The growth and optimistic identification of an organism require at least 8 to 14 days because of its slow growth characteristics. We have investigated various media conditions that are prepared based on the wealth of information obtained from 'omic' studies and report a sustainable Leptospira growth medium comprising of serum equivalent elements and nutrients for pyrimidine biosynthesis, which allows a visible growth of organism within 2 days.

Investigation of potential zoonotic transmission of cryptosporidiosis in southern India.

The common species and subgenotypes causing cryptosporidiosis were studied in 394 children and 627 animals with diarrhea in Vellore in southern India. Although no zoonotic strains were identified in 13 infected children, 1 of 12 infected animals had C. hominis, indicating the potential for cross-species transmission. This study also reports C. xiaoi for the first time in India.

Pathotypes of diarrheagenic Escherichia coli in children attending a tertiary care hospital in South India.

The prevalence of diarrheagenic Escherichia coli (DEC) in children under 5 years was studied in children with diarrhea and controls in South India. Four polymerase chain reaction (PCR) "schemes" were used to detect genes of the 6 pathotypes of DEC. In 394 children with diarrhea, 203 (52%) DEC infections were found. Among the 198 controls, 126 (63%) DEC infections were found. Enteroaggregative E. coli was the most common pathotype by multiplex PCR both in cases (58, 14.7%) and controls (47, 23.7%), followed by enteropathogenic E. coli seen in 10% cases and 8% of controls. Enterotoxigenic E. coli (ETEC), enterohemorrhagic E. coli (EHEC), enteroinvasive E. coli (EIEC), and diffusely adherent E. coli (DAEC) were found in 4.1%, 2.0%, 1.0%, and 0.5% of cases, respectively. ETEC was found in 2.5% of controls, but EHEC, EIEC, and DAEC were not detected. Overall, no single assay worked well, but by discounting genes with a pathogenicity index of less than 1, it was possible to use the PCR assays to identify DEC in 75/394 (19%) cases and 12/198 (6.1%) controls, while mixed infection could be identified in 8/394 (2%) cases and 2/198 (1%) controls.