, , and are the most frequently mutated splicing factor genes in the myelodysplastic syndromes (MDS). We have performed a comprehensive and systematic analysis to determine the effect of these commonly mutated splicing factors on pre-mRNA splicing in the bone marrow stem/progenitor cells and in the erythroid and myeloid precursors in splicing factor mutant MDS. Using RNA-seq, we determined the aberrantly spliced genes and dysregulated pathways in CD34 cells of 84 patients with MDS. Splicing factor mutations result in different alterations in splicing and largely affect different genes, but these converge in common dysregulated pathways and cellular processes, focused on RNA splicing, protein synthesis, and mitochondrial dysfunction, suggesting common mechanisms of action in MDS. Many of these dysregulated pathways and cellular processes can be linked to the known disease pathophysiology associated with splicing factor mutations in MDS, whereas several others have not been previously associated with MDS, such as sirtuin signaling. We identified aberrantly spliced events associated with clinical variables, and isoforms that independently predict survival in MDS and implicate dysregulation of focal adhesion and extracellular exosomes as drivers of poor survival. Aberrantly spliced genes and dysregulated pathways were identified in the MDS-affected lineages in splicing factor mutant MDS. Functional studies demonstrated that knockdown of the mitosis regulators and aberrantly spliced target genes of and mutations, respectively, led to impaired erythroid cell growth and differentiation. This study illuminates the effect of the common spliceosome mutations on the MDS phenotype and provides novel insights into disease pathophysiology.

VIA screening by primary health workers statistically significantly reduced cervical cancer mortality. Our study demonstrates the efficacy of an easily implementable strategy that could prevent 22000 cervical cancer deaths in India and 72600 deaths in resource-poor countries annually.

Purpose The MET receptor is involved in the pathogenesis and progression of non-small-cell lung cancer (NSCLC). Clinical trials with MET inhibitors in NSCLC are planned with patient selection based on immunohistochemistry (IHC) and/or gene copy number assessment. Therefore, a detailed understanding of relationship between these markers and prognosis is essential. Methods This study included tumors from 189 NSCLC patients who underwent pulmonary resection (median follow-up 5.3 years). MET expression was evaluated by IHC on tissue microarrays and scored according to hybrid (H) score (range: 0–400) and by scoring system used in the MetMAb trial (≥50% of cells with moderate or strong staining). MET gene copy number was assessed by silver in-situ hybridization (SISH, N=140 patients). Results Median MET IHC H-score was 60 (range: 0–400; N=174). There were no associations between clinical and pathological characteristics, disease-free or overall survival according to median value (P=0.36 and P=0.38, respectively) or other cut-points. According to MetMAb scoring criteria, IHC positivity rate was 25%, again with no associations to clinico-pathological features nor survival. In 140 tumors evaluable for MET copy number, three (2.1%) showed gene amplification and 14 (10%) had tumors with average of 5 or more copies/nucleus. There were no associations of MET copy number with clinical characteristics, disease-free or overall survival with any analyzed cut-points. Correlation between MET copy number and protein expression was significant (Pearson’s r=0.42, P<0.0001). Conclusions There is a significant correlation between MET protein expression and MET gene copy number in operable NSCLC, but neither is associated with prognosis.