Analysis of patients with endometrial carcinoma using the ProMise classifier: a pilot study from India.

BACKGROUND: Molecular subtyping of endometrial carcinomas (EC) has been shown to classify tumors into prognostically relevant groups. Characterizing EC with a limited number of markers viz., POLE mutations, p53 mutations, and MMR status, can provide valuable information. DESIGN: Paraffin sections of a cohort of 48 EC from a tertiary care center were characterized for the above-mentioned molecular markers and analyzed in the context of survival. METHODS: Formalin fixed paraffin embedded tissues from 48 EC were characterized for POLE mutations by Sanger sequencing (exons 9-14), for MMR (MLH1, MH2, MSH6) using immunohistochemistry (IHC) and copy number (high/low) using p53 IHC. Mutational status was integrated along with the clinicopathological details and survival analysis performed. RESULTS: Eleven (22.9%) patients were MMR deficient, 3 (6.3%) had POLE mutation, while 2 (4.1%) had both POLE and P53 mutations (regarded as multiple classifiers). Twelve (25%) patients were found to have P53 mutations, while the remaining 20 (41.7%) had no specific molecular profile (NSMP). Median follow-up duration was 43.5 (2-62) months with 8 recurrences and 9 deaths. Tumors with POLE mutation had the most favorable prognosis followed by the NSMP and the MMR mutated group while the P53 and multiple classifier groups had the worst prognosis in terms of OS (Log-rank p: 0.006) and PFS (Log-rank p: 0.001). CONCLUSION: The integration of molecular-clinicopathologic data for endometrial cancer classification, through cost-effective, clinically applicable assays appears to be a highly objective tool that can be adopted even in resource-limited settings. It has the potential to cause a shift in the paradigm of EC pathology and management practice.

Novel peptide-based inhibitor for targeted inhibition of T cell function.

Novel immunosuppressants are sought to overcome the side effects of currently used drugs. T cells play a central role in the functioning of the immune system; hence, drugs that specifically inhibit T cell function are expected to be better immunosuppressants with fewer side effects than the ones currently used. Peptides that interfere with crucial protein-protein interactions (PPIs) have been shown to influence cell physiology and have therapeutic potential. In this study, we designed a peptide, GVITAA, which specifically inhibits the function of lymphocyte-specific protein kinase (LCK), a signaling molecule that is mainly expressed in T cells and is responsible for positively regulating T cell function. Aspartate Histidine -Histidine Cysteine (DHHC21) -LCK is an important PPI present in T cells; DHHC21 interacts with LCK and targets the kinase to membrane rafts by adding a palmitoyl group. GVITAA is a ten amino acid peptide that interferes with the DHHC21-LCK interaction, prevents the membrane localization of LCK, and inhibits LCK-mediated initiation of complex signal transduction pathways required for T cell activation. In this study, we present evidence that the GVITAA peptide when conjugated with a cell-penetrating peptide-human immunodeficiency virus transactivator of transcription (TAT) and incubated with mouse T cells specifically inhibits LCK-mediated T cell receptor signaling, cytokine secretion, and T cell proliferation. This peptide does not affect other non-T cell functions and is non-toxic. A similar strategy was also tested and demonstrated in human peripheral T cells.