Immediate-Early Genes and Delayed Primary Response Genes Regulated by NmU in SKBR3 HER-2 Positive Breast Cancer Cell Line

BackgroundBreast cancer is a heterogeneous disease that consists of varying genetic, cellular and molecular subtypes with unique characteristics. Due to the multiple subtypes and molecular markers of breast cancer, successful clinical treatment is hampered by the lack of reliable biomarkers. HER2-positive breast cancer is an aggressive subtype associated with poor patient prognosis. Although survival rates have dramatically increased due to the development of Trastuzumab in 1997, many patients develop a resistance to this therapeutic treatment and relapse over time. Rani et al. (2014), have associated the acquirement of resistance to HER2-treatment with Neuromedin U, but the mechanisms by which it works remain elusive. AimThe aim of this study was to investigate the effects of NmU on the regulation of immediate early and delayed primary response genes in HER2-positive SKBR3 breast cancer cells using RT-qPCR gene expression analysis. This information was then used to uncover related pathways that may be involved in the progression of this aggressive cancer due to NmU. ResultsTreatment of SKBR3 cells with endogenous NmU resulted in a significant change in the regulation of several cancer-associated genes. Jun expression was significantly downregulated after 30 minutes of NmU treatment, which increased significantly after 1 hour. EGR1 and NR4A1 expression levels were also significantly downregulated. EGR1 and NR4A1 act as tumour suppressors in certain human cancers, suggesting that NmU may drive cancer progression by inhibiting important tumour suppressors. Increasing regulation of SOD2 and DKK1 was observed due to NmU, suggesting that NmU plays a role in Wnt and MAPK signalling. ConclusionThis project has identified a number of critical genes that may induced by NmU. Through further research, this could lead to the potential development of alternative therapies for HER2-positive breast cancer by targeting these genes

Evaluation of perinatal outcome in high-risk pregnancy at tertiary care centre

Background: A high risk pregnancy is one in which mother, fetus or neonate is at increased risk of morbidity or mortality before or after delivery. Hence a relatively small percentage of high risk obstetric population gives rise to a disproportionately high percentage of perinatal and maternal morbidity and mortality. The perinatal outcome can be changed significantly by early detection and special intensive care to high risk pregnancies. Hence Identification of women at risk for these complicated pregnancies with poor outcome is fundamental to antenatal check-up.Methods: 86 high risk antenatal patients attending the outpatient department and labour room were recruited after informed consent.70 normal pregnancy was taken as control group. Perinatal outcomes were compared between high risk and normal pregnancies.Results: Adverse perinatal outcomes were more in high risk pregnancies as compared to normal pregnancies.Conclusions: This study emphasizes on pregnancy related complication leading to adverse perinatal outcome so evaluating patients for high risk factors, early diagnosis, proper antenatal care, prompt treatment, regular follow up, and timely management thus can improve maternal and perinatal outcome

Fatigue Behaviour Analysis Of Differently Heat Treated Medium Carbon Steel

The utility of medium carbon steel is well known now-a- days. It has got so many applications in different industries. The importance of fatigue failure of materials is a very important topic in the field of mechanical behavior of materials since 90% of failures resulted from mechanical causes is due to fatigue. In the present work fatigue of medium carbon steel (EN9 grade) has been studied. Since the mechanical properties are greatly influenced by heat-treatment techniques, the effect of various heat treatment operations (like annealing, normalizing, tempering) on fatigue life has been investigated. The emphasis has been given on the value of endurance limit. The change in the value of endurance limit of the material concerned as a result of various heat-treatment operations were studied thoroughly. It has been found that the specimens tempered at low temperature (2000C) exhibits the best results as far as fatigue strength is concerned

miR-630 targets IGF1R to regulate response to HER-targeting drugs and overall cancer cell progression in HER2 over-expressing breast cancer

Background: While the treatment of HER2 over-expressing breast cancer with recent HER-targeted drugs has been highly effective for some patients, primary (also known as innate) or acquired resistance limits the success of these drugs. microRNAs have potential as diagnostic, prognostic and predictive biomarkers, as well as replacement therapies. Here we investigated the role of microRNA-630 (miR-630) in breast cancer progression and as a predictive biomarker for response to HER-targeting drugs, ultimately yielding potential as a therapeutic approach to add value to these drugs. Methods: We investigated the levels of intra- and extracellular miR-630 in cells and conditioned media from breast cancer cell lines with either innate- or acquired- resistance to HER-targeting lapatinib and neratinib, compared to their corresponding drug sensitive cell lines, using qPCR. To support the role of miR-630 in breast cancer, we examined the clinical relevance of this miRNA in breast cancer tumours versus matched peritumours. Transfection of miR-630 mimics and inhibitors was used to manipulate the expression of miR-630 to assess effects on response to HER-targeting drugs (lapatinib, neratinib and afatinib). Other phenotypic changes associated with cellular aggressiveness were evaluated by motility, invasion and anoikis assays. TargetScan prediction software, qPCR, immunoblotting and ELISAs, were used to assess miR-630’s regulation of mRNA, proteins and their phosphorylated forms. Results: We established that introducing miR-630 into cells with innate- or acquired- resistance to HER-drugs significantly restored the efficacy of lapatinib, neratinib and afatinib; through a mechanism which we have determined to, at least partly, involve miR-630’s regulation of IGF1R. Conversely, we demonstrated that blocking miR-630 induced resistance/insensitivity to these drugs. Cellular motility, invasion, and anoikis were also observed as significantly altered by miR-630 manipulation, whereby introducing miR-630 into cells reduced cellular aggression while inhibition of miR-630 induced a more aggressive cellular phenotype. Conclusions: Taken together, our findings suggest miR-630 as a key regulator of cancer cell progression in HER2 over-expressing breast cancer, through targeting of IGF1R. This study supports miR-630 as a diagnostic and a predictive biomarker for response to HER-targeted drugs and indicates that the therapeutic addition of miR-630 may enhance and improve patients’ response to HER-targeting drugs

Mesenchymal stromal cells (MSCs) and colorectal cancer - a troublesome twosome for the anti-tumour immune response?

The tumour microenvironment (TME) is an important factor in determining the growth and metastasis of colorectal cancer, and can aid tumours by both establishing an immunosuppressive milieu, allowing the tumour avoid immune clearance, and by hampering the efficacy of various therapeutic regimens. The tumour microenvironment is composed of many cell types including tumour, stromal, endothelial and immune cell populations. It is widely accepted that cells present in the TME acquire distinct functional phenotypes that promote tumorigenesis. One such cell type is the mesenchymal stromal cell (MSC). Evidence suggests that MSCs exert effects in the colorectal tumour microenvironment including the promotion of angiogenesis, invasion and metastasis. MSCs immunomodulatory capacity may represent another largely unexplored central feature of MSCs tumour promoting capacity. There is considerable evidence to suggest that MSCs and their secreted factors can influence the innate and adaptive immune responses. MSC-immune cell interactions can skew the proliferation and functional activity of T-cells, dendritic cells, natural killer cells and macrophages, which could favour tumour growth and enable tumours to evade immune cell clearance. A better understanding of the interactions between the malignant cancer cell and stromal components of the TME is key to the development of more specific and efficacious therapies for colorectal cancer. Here, we review and explore MSC- mediated mechanisms of suppressing anti-tumour immune responses in the colon tumour microenvironment. Elucidation of the precise mechanism of immunomodulation exerted by tumour-educated MSCs is critical to inhibiting immunosuppression and immune evasion established by the TME, thus providing an opportunity for targeted and efficacious immunotherapy for colorectal cancer growth and metastasis

Clinical significance of unexplained elevated maternal serum alpha feto-protein in second trimester of pregnancy

Background: Alpha-fetoprotein (AFP) is the major serum protein in the embryonic stage and in the early fetal stage. The aim of this study was to measure maternal serum AFP levels in second trimester between 15-20 weeks of gestation and to determine whether unexplained elevated MSAFP levels is an effective predictor of adverse pregnancy outcome among Indian population.Methods: This study was a prospective observational study, carried out on 400 pregnant women. Maternal serum alpha-fetoprotein (MSAFP) was measured between 15 and 20 weeks of gestation after excluding congenital malformation or birth defects. MSAFP level was determined by using a radio-immunoassay technique. Women with MSAFP level >2.0 MoM was considered as abnormal while MSAFP level≤ 2.0 MoM was considered as normal. All women were followed up till delivery and pregnancy outcomes were noted and compared between two groups.Results: Women with elevated MSAFP had significantly higher adverse pregnancy outcomes (75.4%) compared to women with MSAFP ≤2.0 MoM (26.1%) (p<0.0001 with relative risk of 2.89, 95% confidence interval 2.276 -3.667).Conclusions: Unexplained elevated MSAFP has high sensitivity, specificity, positive predictive value and negative predictive value in predicting adverse pregnancy outcomes. It would, therefore be worthwhile screening pregnant women in second trimester for maternal serum alpha-fetoprotein levels as it would help to identify high risk pregnancies and allow close antenatal survillence for better pregnancy outcome