RAC1(P29S) Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance

RAC1 P29 is the third most commonly mutated codon in human cutaneous melanoma, after BRAF V600 and NRAS Q61. Here, we study the role of RAC1P29S in melanoma development and reveal that RAC1P29S activates PAK, AKT, and a gene expression program initiated by the SRF/MRTF transcriptional pathway, which results in a melanocytic to mesenchymal phenotypic switch. Mice with ubiquitous expression of RAC1P29S from the endogenous locus develop lymphoma. When expressed only in melanocytes, RAC1P29S cooperates with oncogenic BRAF or with NF1-loss to promote tumorigenesis. RAC1P29S also drives resistance to BRAF inhibitors, which is reversed by SRF/MRTF inhibitors. These findings establish RAC1P29S as a promoter of melanoma initiation and mediator of therapy resistance, while identifying SRF/MRTF as a potential therapeutic target

Mitochondrial polymorphisms and susceptibility to type 2 diabetes-related traits in Finns

Mitochondria play an integral role in ATP production in cells and are involved in glucose metabolism and insulin secretion, suggesting that variants in the mitochondrial genome may contribute to diabetes susceptibility. In a study of Finnish families ascertained for type 2 diabetes mellitus (T2DM), we genotyped single nucleotide polymorphisms (SNPs) based on phylogenetic networks. These SNPs defined eight major haplogroups and subdivided groups H and U, which are common in Finns. We evaluated association with both diabetes disease status and up to 14 diabetes-related traits for 762 cases, 402 non-diabetic controls, and 465 offspring of genotyped females. Haplogroup J showed a trend toward association with T2DM affected status (OR 1.69, P =0.056) that became slightly more significant after excluding cases with affected fathers (OR 1.77, P =0.045). We also genotyped non-haplogroup-tagging SNPs previously reported to show evidence for association with diabetes or related traits. Our data support previous evidence for association of T16189C with reduced ponderal index at birth and also show evidence for association with reduced birthweight but not with diabetes status. Given the multiple tests performed and the significance levels obtained, this study suggests that mitochondrial genome variants may play at most a modest role in glucose metabolism in the Finnish population. Furthermore, our data do not support a reported maternal inheritance pattern of T2DM but instead show a strong effect of recall bias.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47596/1/439_2005_Article_46.pd

A study on clinical profile and outcome of low birth weight neonates admitted to NICU in a tertiary care hospital

Background: Neonatal period is the first 28 days of life since birth. it is considered as the most susceptible period for mortality and morbidity [1]. Neonatal mortality accounts for 2/3 rd of the infant mortality. Objectives:1. To study clinical profile of LBW neonates2. To evaluate morbidity and mortality in LBW neonates3. To analyse the risk factors for mortality in LBW neonatesMaterial & methods: Study Design: Prospective hospital based observational study.Study area: The Neonatal Intensive Care Unit, Department of Paediatrics, Alluri SitaRamaRaju Academy of Medical Sciences, Malkapuram, Eluru, West Godavari (dist.), Andhra Pradesh. Study Period: September 2020 to September 2021. Study population: All neonates with birth weight less than 2,500 grams admitted to NICU. Sample size: study consisted a total of 46 cases. Sampling method: Simple Random sampling method. Study tools and Data collection procedure: All neonates less than 2500gms irrespective of gestational age, examined and a detailed Antenatal, Natal and Postnatal history was obtained and recorded in a predesigned proforma. Neonate’s birth weight, gestational age, sex, mode of delivery, indication for any interventions, immediate postnatal events like APGAR score and if any resuscitation done, were recorded in a predesigned proforma. Results: The Most common morbidity found in this study subjects were RDS (30.4%), followed by EONS (28.3%), NNJ (13%), NEC (6.5%), HYPOGLYCEMIA(6.5%), BIRTHASPHYXIA (4.3%), DIC & MAS (2.2%). Pre term LBW babies were more effected by these morbidities than the term LBW babies, but there was no statistical significance in our study. Conclusion: RDS and Sepsis were the most common factors associated with LBW. The factors associated with mortality were found to be Birth asphyxia, Sepsis, RDS

Correlation of NGS <i>KRAS</i> mutant allele frequency with digital PCR <i>KRAS</i> mutant allele frequency detected in the appropriate multiplex assay for FFPE tissue DNA and cell line gDNA samples.

<p>Correlation of NGS <i>KRAS</i> mutant allele frequency with digital PCR <i>KRAS</i> mutant allele frequency detected in the appropriate multiplex assay for FFPE tissue DNA and cell line gDNA samples.</p

<i>KRAS</i> mutations observed in human NSCLC in order of decreasing frequency (http://www.sanger.co.uk/cosmic; accessed 14^th July 2015).

<p><i>KRAS</i> mutations observed in human NSCLC in order of decreasing frequency (<a href="http://www.sanger.co.uk/cosmic" target="_blank">http://www.sanger.co.uk/cosmic</a>; accessed 14^th July 2015).</p

<i>KRAS</i> mutations observed in human cancer in order of decreasing frequency (http://www.sanger.co.uk/cosmic; accessed 14^th July 2015).

<p><i>KRAS</i> mutations observed in human cancer in order of decreasing frequency (<a href="http://www.sanger.co.uk/cosmic" target="_blank">http://www.sanger.co.uk/cosmic</a>; accessed 14^th July 2015).</p

<i>KRAS</i> multiplex digital PCR assays A-C and corresponding duplex assays.

<p>Multiplex A (top left panel) is an assay combination of 900 nM primers and 500 nM G13C probe (red dashed square), 450 nM primers and 250 nM G12C probe (blue dashed square) and 225 nM primers and 125 nM G12V probe (yellow dashed square). Multiplex B (top middle panel) is an assay combination of 675 nM primers and 375 nM G12S probe (red dashed square), 450 nM primers and 250 nM G12D probe (blue dashed square) and 225 nM primers and 125 nM G13D probe (yellow dashed square). Multiplex C (top right panel) is an assay combination of 675 nM primers and 375 nM G12R probe (red dashed square), 450 nM primers and 250 nM G12A probe (blue dashed square) and 900 nM primers and 500 nM Q61H probe (yellow dashed square). Multiplex C has 900 nM primers and 500 nM Q61H wild-type probe in addition to a G12C wild-type assay. All other wild-type droplet populations shown, except in the Q61H duplex assay, are 450 nM primers and 250 nM G12C wild-type probe. All panels in the left and centre columns show a FAM amplitude up to 18000 and an HEX amplitude up to 6000. Panels in the right column have a FAM amplitude up to 18000 and a HEX amplitude up to 11000.</p

<i>KRAS</i> duplex assays at optimal annealing temperature.

<p>Droplet populations observed for each duplex assay tested with wild-type and relevant mutant cell line gDNA or oligonucleotide at the optimal annealing temperature e.g. G12V panel top left shows droplet populations seen with WT for G12V assay, G12V assay, NCI-H727 gDNA and NCI-H1975 gDNA present. HEX amplitude is up to 6000 on the x axis and FAM amplitude up to 11000 on the y-axis of each panel. Key: Black drops- empty droplets, blue- mutant DNA FAM positive droplets, green- wild-type DNA HEX positive droplets, brown—wild-type and mutant DNA double positive droplets.</p