Background: Breast cancer is the second most common malignancy among Nepalese women, accounting for 60% of the total cancer cases in females. Women diagnosed with germline mutations in BRCA1 like 185delAG, 1294del40 develop breast and/or ovarian cancer with a lifelong likelihood of up to 85% whereas presence of a mutation increases the risk for mutations to occur in other genes. The major objective of this study was to find the prevalence of these mutations in Nepalese cancer patients. Materials and Methods: This prospective study was carried out at two cancer hospitals in the Kathmandu valley over a period of 11 months. Irrespective of age group and stage of canceran appropriate amount of blood was withdrawn from 50 breast cancer patients and 20 controls. DNA was extracted manually and subjected to PCR using primers for 185delAG and 1294del40 mutations. PCR products were then digested with restriction enzyme (DdeII) followed by electrophoresis. Results: Prevalence of 185delAG in reference breast cancer patients was found to be 4/50 (8%) but no 1294del40 was apparent. Conclusions: Several mutations occurring in different exons of BRCA1 as well as mutations in other genes like BRCA2, for example, should also be taken in account.
Immune cells are generated from hematopoietic stem cells (HSCs) in the bone marrow (BM). Immune stimulation can rapidly activate HSCs out of their quiescent state to accelerate the generation of immune cells. HSCs' activation follows various viral or bacterial stimuli, and we sought to investigate the hypersensitivity immune response. Surprisingly, the Ova-induced hypersensitivity peritonitis model finds no significant changes in BM HSCs. HSC markers cKIT, SCA1, CD48, CD150, and the Fgd5-mCherry reporter showed no significant difference from control. Functionally, hypersensitivity did not alter HSCs' potency, as assayed by transplantation. We further characterized the possible impact of hypersensitivity using RNA-sequencing of HSCs, finding minor changes at the transcriptome level. Moreover, hypersensitivity induced no significant change in the proliferative state of HSCs. Therefore, this study suggests that, in contrast to other immune stimuli, hypersensitivity has no impact on HSCs.
33Cancer cells have an altered transcriptome which contributes to their altered behaviors compared 34 to normal cells. Indeed, many tumors express high levels of genes participating in meiosis or 35 kinetochore biology, but the role of this high expression has not been fully elucidated. In this study 36 we explore the relationship between this overexpression and genome instability and transformation 37 capabilities of cancer cells. For this, we obtained expression data from 5 different cancer types 38which were analyzed using computational information-theoretic analysis. We were able to show 39 that highly expressed meiotic/kinetochore genes were enriched in the altered gene networks 40 characterizing unstable cancer types with high chromosome instability (CIN). However, altered 41 networks characterizing the cancers with low CIN did not include meiotic and kinetochore genes. 42Representative gene candidates, found by the analysis to be correlated with a CIN phenotype, were 43 further explored by transfecting genomically-stable (HCT116) and unstable (MCF7) cancer cell 44 lines with vectors overexpressing those genes. This overexpression resulted in abnormal cell 45 divisions, defective spindle formation and increased transformation properties in stable cancer 46 HCT116 cells. Interestingly the genome stability properties of the unstable MCF7 cancer cells 47 were less affected by gene overexpression. Our results indicate that overexpression of both meiosis 48 and kinetochore genes drives genomic instability and cancer progression.
Myeloid progenitors are intermediates between Hematopoietic Stem Cells (HSCs) and Myeloid effector progeny. In mouse bone marrow, they are part of the Lineage− cKit+ Sca1− (LK) compartment. To date, most researchers used CD34 and FcγR surface markers for the dissection of this compartment into various populations. Surprisingly, however, this approach does not provide distinct separation by fluorescence-activated cell sorting (FACS). In this study, we suggest using CD150 instead of FcγR. We re-analyzed published single-cell RNA-Seq data and found that CD34/CD150 provides better sub-populations separation, compared to the “classical” CD34/FcγR-based approach. We confirm our findings by independent FACS analysis. We demonstrate comparable differentiation potential of the newly-obtained LK sub-populations, like previous “classical” ones. Therefore, we suggest the CD34/CD150 gating strategy, utilizing commonly-used surface markers, as a robust and reproducible separation of the LK compartment into distinct sub-populations.
Adult Hematopoietic Stem Cells (HSCs) are quiescent in the bone marrow (BM). Following perturbations, such as blood loss or infection, HSCs may activate to accelerate the production of needed effector blood and immune cells. Surprisingly little is known about the earliest stages of HSCs activation. We utilize surface markers of HSC activation, CD69 and CD317, revealing very early response in as little as 2 h. The dynamic expression of HSC activation markers varies between viral-like (poly-Inosinic-poly-Cytidylic) or bacterial-like (Lipopolysaccharide) immune stimuli. We further quantify the dose-response, demonstrating a low-threshold and similar sensitivity of HSCs like other progenitors in the BM. Finally, we find a positive correlation between surface activation markers expression and the early exit from quiescence into proliferation following immune stimulation. Our data show that premier response of adult stem cells to immune stimulation is rapid, sensitive, and directly leading towards proliferation.
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