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Currently approved checkpoint inhibitors are antibodies that block the function of three key proteins expressed on the surface of T cells: CTLA-4, PD-1 and PD-L1. Under normal conditions, these proteins function as brakes to prevent immune-related toxicity from arising because of persistent T cell activity. Cancer hijacks this essential function   of immune homeostasis to protect itself from immune- mediated elimination [1, 2]. By expressing high levels of PD- L1, tumor cells engage PD-1 receptors on T cells, suppressing  their anti-tumor activity and escaping T cell-mediated killing. By blocking PD-1 and PD-L1 signaling, the checkpoint inhibitors remove the brakes on T cells imposed by the tumor and enhance their anti-tumor activity

Currently approved checkpoint inhibitors are antibodies that block the function of three key proteins expressed on the surface of T cells: CTLA-4, PD-1 and PD-L1.

Under normal conditions, these proteins function as brakes to prevent immune-related toxicity from arising because of persistent T cell activity. Cancer hijacks this essential function of immune homeostasis to protect itself from immune-mediated elimination [1, 2]. By expressing high levels of PD-L1, tumor cells engage PD-1 receptors on T cells, suppressing their anti-tumor activity and escaping T cell-mediated killing. By blocking PD-1 and PD-L1 signaling, the checkpoint inhibitors remove the brakes on T cells imposed by the tumor and enhance their anti-tumor activity [3].

Indu Sharma, Varun Sharma, Akbar Khan, Parvinder Kumar, Ekta Rai, Rameshwar N. K. Bamezai, Miguel Vilar & Swarkar Sharma

Jammu and Kashmir (J&K), the Northern most State of India, has been under-represented or altogether absent in most of the phylogenetic studies carried out in literature, despite its strategic location in the Himalayan region. Nonetheless, this region may have acted as a corridor to various migrations to and from mainland India, Eurasia or northeast Asia. The belief goes that most of the migrations post-late Pleistocene were mainly male dominated, primarily associated with population invasions, where female migration may thus have been limited. To evaluate female-centered migration patterns in the region, we sequenced 83 complete mitochondrial genomes of unrelated individuals belonging to different ethnic groups from the state. We observed a high diversity in the studied maternal lineages, identifying 19 new maternal sub-haplogroups (HGs). High maternal diversity and our phylogenetic analyses suggest that the migrations post-Pleistocene were not strictly paternal, as described in the literature. These preliminary observations highlight the need to carry out an extensive study of the endogamous populations of the region to unravel many facts and find links in the peopling of India.

Muthusamy B, Selvan LDN, Nguyen TT, Manoj J, Stawiski EW, Jaiswal BS, Wang W, Raja R, Ramprasad VL, Gupta R, Murugan S, Kadandale JS, Prasad TSK, Reddy K, Peterson A, Pandey A, Seshagiri S, Girimaji SC, Gowda H, OMICS, 2017 May;21(5):295-303.

Robust diagnostics for many human genetic disorders are much needed in the pursuit of global personalized medicine. Next- generation sequencing now offers new promise for biomarker and diagnostic discovery, in developed as well as resource-limited countries. In this broader global health context, X-linked intellectual disability (XLID) is an inherited genetic disorder that is associated with a range of phenotypes impacting societies in both developed and developing countries. Although intellectual disability arises due to diverse causes, a substantial proportion is caused by genomic alterations. Studies have identified causal XLID genomic alterations in more than 100 protein-coding genes located on the X-chromosome. However, the causes for a substantial number of intellectual disability and associated phenotypes still remain unknown. Identification of causative genes and novel mutations will help in early diagnosis as well as genetic counseling of families. Advent of next-generation sequencing methods has accelerated the discovery of new genes involved in mental health disorders. In this study, we analyzed the exomes of three families from India with nonsyndromic XLID comprising seven affected individuals. The affected individuals had varying degrees of intellectual disability, microcephaly, and delayed motor and language milestones. We identified potential causal variants in three XLID genes, including PAK3 (V294M), CASK (complex structural variant), and MECP2 (P354T). Our findings reported in this study extend the spectrum of mutations and phenotypes associated with XLID, and calls for further studies of intellectual disability and mental health disorders with use of next-generation sequencing technologies.

Sunita Bijarnia-Mahay, Deepti Gupta, V L Ramprasad, Sakthivel Murugan, Renu Saxena, Sudha Kohli, Seiji Yamaguchi, Yosuke Shigematsu and I C Verma, Genetic Clinics 2017, January – March, Vol 10, Issue 1.

Next generation sequencing has changed the approach to genetic diagnosis and testing in recent times. The days have arrived when a molecular genetic diagnosis can be attempted even without the availability of the proband or affected person. However this requires additional strong evidence of diagnosis in the proband, such as biochemical or radiological hallmarks. Needless to say, this attempt should always be made during counseling to make the family aware of the fallacies and limitation involved due to non-availability of the sample of the proband. Since many recessive disorders are either fatal or severely debilitating and burdensome, with no easy treatment, the NGS technology has provided a much needed relief in terms of testing and prevention in family by enabling prenatal diagnosis, at least in a few cases. Encouraging results have been shown upon testing of the proband directly. However, the final word remains to be said on complete reliability of the method for carrier testing, performed without availability of the proband. We present two similar cases, of methyl malonic acidemia, where use of NGS resulted in contrasting outcomes after genetic testing for carrier status, thus highlighting the utility and the futility of the test in certain situations. While a correct identification of mutations in the first couple (in the MMAB gene) resulted in successful prenatal diagnosis and prevention of recurrence, an inability to identify the disease and mutation resulted in birth of an affected baby with MMA in the second family.

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