Role of long non-coding RNA lincNMR in nucleotide metabolism in cancer

Whole transcriptome analysis of the human genome has revealed that the majority of the genome gives rise to non-protein-encoding or simply non-coding RNAs (ncRNAs). Long non-coding RNAs (lncRNAs) ranging from 200 nt to >100 kb represent a large subgroup of ncRNAs. They have emerged as critical players for not only regulating various physiological and developmental processes but also various cancers including liver cancer. Global cancer statistics report of 2018 has shown liver cancer to be the fourth leading cause of cancer-related deaths worldwide and has predicted it to be the sixth most commonly diagnosed cancer. Notably, advanced stage liver cancer has a poor overall survival rate of less than 20 % - thus warranting further investigations into the understanding of molecular mechanisms driving hepatocarcinogenesis, contributing to the discovery of improved diagnostic, prognostic and treatment modalities. Here, I performed a transcriptome-wide profiling of lncRNAs in liver cancer and identified a novel lncRNA, which I named lincNMR (long intergenic non-coding RNA - Nucleotide Metabolism Regulator). LincNMR was induced six-fold in hepatocellular carcinoma compared to normal liver tissue. Depletion of lincNMR in multiple liver cancer cell lines invoked a strong proliferation defect and lead to an induction of senescence. This phenotype was also observed in multiple breast and lung cancer cell lines suggesting cancer-wide role of lincNMR. Silencing of lincNMR caused a strong depletion of the key dNTP synthesizing enzymes RRM2, TK1 and TYMS implicating lincNMR in regulation of nucleotide metabolism. Notably, dNTP levels were significantly decreased in liver cancer cells upon the loss of lincNMR. Importantly, the proliferation defect induced by downregulation of lincNMR could be rescued by bathing the cells in exogenous pools of extracellular dNTPs. An in vivo RNA Antisense Purification combined with mass spectrometry (RAP-MS) approach identified YBX1 as a direct interaction partner of lincNMR. Furthermore, I show YBX1 as a regulator of RRM2, TK1 and TYMS gene expression and found lincNMR to control the transactivational activity of YBX1 as measured in luciferase assays. Lastly, I established the relevance of lincNMR for tumor growth in vivo using the Chick Chorioallantoic Membrane (CAM) model. LincNMR-depleted tumors were significantly smaller in size and weight. In summary, I discovered a novel lncRNA, lincNMR, which regulates tumor cell proliferation through a YBX1-RRM2-TK1-TYMS axis governing nucleotide metabolism

The lncRNA lincNMR regulates nucleotide metabolism via a YBX1 - RRM2 axis in cancer

Despite some well-characterized functions in cancer, the impact of most long non-coding RNAs remains unknown. Here, the authors discover the lncRNA lincNMR which is upregulated in cancer and drives cell proliferation by interacting with YBX1 and controlling nucleotide metabolism

Cost of implementing the QualityRights programme in public hospitals in Gujarat providing mental healthcare

Background & objectives: Investment in mental health is quite meagre worldwide, including in India. The costs of new interventions must be clarified to ensure the appropriate utilization of available resources. The government of Gujarat implemented QualityRights intervention at six public mental health hospitals. This study was aimed to project the costs of scaling up of the Gujarat QualityRights intervention to understand the additional resources needed for a broader implementation. Methods: Economic costs of the QualityRights intervention were calculated using an ingredients-based approach from the health systems' perspective. Major activities within the QualityRights intervention included assessment visits, meetings, training of trainers, provision of peer support and onsite training. Results: Total costs of implementing the QualityRights intervention varied from Indian Rupees (₹) 0.59 million to ₹ 2.59 million [1United States Dollars (US $) = ₹ 74.132] across six intervention sites at 2020 prices with 69-79 per cent of the cost being time cost. Scaling up the intervention to the entire State of Gujarat would require about two per cent increase in financial investment, or about 7.5 per cent increase in total cost including time costs over and above the costs of usual care for people with mental health conditions in public health facilities across the State. Interpretation & conclusions: The findings of this study suggest that human resources were the major cost contributor of the programme. Given the shortage of trained human resources in the mental health sector, appropriate planning during the scale-up phase of the QualityRights intervention is required to ensure all staff members receive the required training, and the treatment is not compromised during this training phase. As only about two per cent increase in financial cost can improve the quality of mental healthcare significantly, the State government can plan for its scale-up across the State