Plasticity of neoplasia, whereby cancer cells attain stem-cell-like properties, is required for disease progression and represents a major therapeutic challenge. We report that in breast cancer cells ...NANOG, SNAIL and NODAL transcripts manifest multiple isoforms characterized by different 5' Untranslated Regions (5'UTRs), whereby translation of a subset of these isoforms is stimulated under hypoxia. The accumulation of the corresponding proteins induces plasticity and "fate-switching" toward stem cell-like phenotypes. Mechanistically, we observe that mTOR inhibitors and chemotherapeutics induce translational activation of a subset of NANOG, SNAIL and NODAL mRNA isoforms akin to hypoxia, engendering stem-cell-like phenotypes. These effects are overcome with drugs that antagonize translational reprogramming caused by eIF2α phosphorylation (e.g. ISRIB), suggesting that the Integrated Stress Response drives breast cancer plasticity. Collectively, our findings reveal a mechanism of induction of plasticity of breast cancer cells and provide a molecular basis for therapeutic strategies aimed at overcoming drug resistance and abrogating metastasis.
A non-empty set \(S\) together with the ternary operation denoted by juxtaposition is said to be ternary semigroup if it satisfies the associativity property \(ab(cde)=a(bcd)e=(abc)de\) for all ...\(a,b,c,d,e\in S\). The global set of a ternary semigroup \(S\) is the set of all non empty subsets of \(S\) and it is denoted by \(P(S)\). If \(S\) is a ternary semigroup then \(P(S)\) is also a ternary semigroup with a naturally defined ternary multiplication. A natural question arises: "Do all properties of \(S\) remain the same in \(P(S)\)?" The global determinism problem is a part of this question. A class \(K\) of ternary semigroups is said to be globally determined if for any two ternary semigroups \(S_1\) and \(S_2\) of \(K\), \(P(S_1)\cong P(S_2)\) implies that \(S_1\cong S_2\). So it is interesting to find the class of ternary semigroups which are globally determined. Here we will study the global determinism of ternary \(\ast\)-band.
Background: Gestational diabetes mellitus (GDM) is associated with hypertension, preeclampsia, stillbirth, macrosomia, unexplained intrauterine death, instrumental and traumatic delivery leading to ...both maternal and foetal injuries, and increased risk of maternal and neonatal infections. The present study was conducted at Rajendra Institute of Medical Sciences, Ranchi to determine the prevalence of Gestational Diabetes Mellitus(GDM) and its associated risk factors in tribal population of Jharkhand.
Aims and Objectives: The aim of the study was to determine the prevalence of GDM and to analyze its association with various risk factors.
Materials and Methods: Detailed history of all patients was taken with emphasis on genetic and family history and history of the previous pregnancies. All the patients were screened by the single step 75 gm 2 hours oral glucose tolerance test (OGTT) as recommended by the World Health Organization. GDM was diagnosed if 2 hours PG is ≥140 mg/dL.
Results: Most patients of GDM were from upper middle class 45.45%, followed by lower middle class (27.27%) and upper lower class (18.18%). For the non-GDM patients, most patients were from upper lower class (55.055%), followed by upper middle (24.71%). The prevalence of GDM was 12.12 % in the tribal population as compared to non-tribal population (10.44 %). In present study, in majority (89.00 %) of study subjects, result of 75 gm OGTT was negative. Result of 75 gm OGTT was positive in only 11 out of 100 study subjects (11.00 %).
Conclusion: Tribal population in Jharkhand has very poor access to health-care services of the state. This study is first of its kind in our state which will set as an eye opener to further deliver better health-care facilities at grassroot level in Jharkhand.
Interactions between immune and tumor cells in the tumor microenvironment (TME) often impact patient outcome, yet remain poorly understood. In addition, the effects of biophysical features such as ...hypoxia low oxygen (O
) on cells within the TME may lead to tumor evasion. Gamma delta T cells (γδTcs) naturally kill transformed cells and are therefore under development as immunotherapy for various cancers. Clinical trials have proven the safety of γδTc immunotherapy and increased circulating γδTc levels correlate with improved patient outcome. Yet, the function of γδTc tumor infiltrating lymphocytes in human breast cancer remains controversial. Breast tumors can be highly hypoxic, thus therapy must be effective under low O
conditions. We have found increased infiltration of γδTc in areas of hypoxia in a small cohort of breast tumors; considering their inherent plasticity, it is important to understand how hypoxia influences γδTc function.
, the cell density of expanded primary healthy donor blood-derived human γδTc decreased in response to hypoxia (2% O
) compared to normoxia (20% O
). However, the secretion of macrophage inflammatory protein 1α (MIP1α)/MIP1β, regulated on activation, normal T cell expressed and secreted (RANTES), and CD40L by γδTc were increased after 40 h in hypoxia compared to normoxia concomitant with the stabilization of hypoxia inducible factor 1-alpha protein. Mechanistically, we determined that natural killer group 2, member D (NKG2D) on γδTc and the NKG2D ligand MHC class I polypeptide-related sequence A (MICA)/B on MCF-7 and T47D breast cancer cell lines are important for γδTc cytotoxicity, but that MIP1α, RANTES, and CD40L do not play a direct role in cytotoxicity. Hypoxia appeared to enhance the cytotoxicity of γδTc such that exposure for 48 h increased cytotoxicity of γδTc against breast cancer cells that were maintained in normoxia; conversely, breast cancer lines incubated in hypoxia for 48 h prior to the assay were largely resistant to γδTc cytotoxicity. MICA/B surface expression on both MCF-7 and T47D remained unchanged upon exposure to hypoxia; however, ELISAs revealed increased MICA shedding by MCF-7 under hypoxia, potentially explaining resistance to γδTc cytotoxicity. Despite enhanced γδTc cytotoxicity upon pre-incubation in hypoxia, these cells were unable to overcome hypoxia-induced resistance of MCF-7. Thus, such resistance mechanisms employed by breast cancer targets must be overcome to develop more effective γδTc immunotherapies.
Gamma delta (γδ) T cells kill transformed cells, and increased circulating γδ T cells levels correlate with improved outcome in cancer patients; however, their function within the breast tumor ...microenvironment (TME) remains controversial. As tumors progress, they begin to express stem-cell associated proteins, concomitant with the emergence of therapy resistant metastatic disease. For example, invasive breast cancers often secrete the embryonic morphogen, NODAL. NODAL has been shown to promote angiogenesis, therapy resistance and metastasis in breast cancers. However, to date, little is known about how this secreted protein may interact with cells in the TME. Herein we explore how NODAL in the TME may influence γδ T cell function. We have assessed the proximity of γδ T cells to NODAL in a cohort of triple negative breast tumors. In all cases in which γδ T cells could be identified in these tumors, γδ T cells were found in close proximity to NODAL-expressing tumor cells. Migration of γδ and αβ T cells was similar toward MDA-MB-231 cells in which NODAL had been knocked down (shN) and MDA-MB-231 scrambled control cells (shC). Furthermore, Vδ1 γδ T cells did not migrate preferentially toward conditioned medium from these cell lines. While 24-h exposure to NODAL did not impact CD69, PD-1, or T cell antigen receptor (TCR) expression on γδ T cells, long term exposure resulted in decreased Vδ2 TCR expression. Maturation of γδ T cells was not significantly influenced by NODAL stimulation. While neither short- nor long-term NODAL stimulation impacted the ability of γδ T cells to kill MCF-7 breast cancer cells, the absence of NODAL resulted in greater sensitivity of targets to γδ T cell cytotoxicity, while overexpression of NODAL conferred resistance. This appeared to be at least in part due to an inverse correlation between NODAL and surface MICA/B expression on breast cancer target lines. As such, it appears that NODAL may play a role in strategies employed by breast cancer cells to evade γδ T cell targeting, and this should be considered in the development of safe and effective γδ T cell immunotherapies.
Metformin is being actively repurposed for the treatment of gynecologic malignancies including ovarian cancer. We investigated if metformin induces analogous metabolic changes across ovarian cancer ...cells. Functional metabolic analysis showed metformin caused an immediate and sustained decrease in oxygen consumption while increasing glycolysis across A2780, C200, and SKOV3ip cell lines. Untargeted metabolomics showed metformin to have differential effects on glycolysis and TCA cycle metabolites, while consistent increased fatty acid oxidation intermediates were observed across the three cell lines. Metabolite set enrichment analysis showed alpha-linolenic/linoleic acid metabolism as being most upregulated. Downstream mediators of the alpha-linolenic/linoleic acid metabolism, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were abundant in all three cell lines. EPA was more effective in inhibiting SKOV3 and CaOV3 xenografts, which correlated with inhibition of inflammatory markers and indicated a role for EPA-derived specialized pro-resolving mediators such as Resolvin E1. Thus, modulation of the metabolism of omega-3 fatty acids and their anti-inflammatory signaling molecules appears to be one of the common mechanisms of metformin's antitumor activity. The distinct metabolic signature of the tumors may indicate metformin response and aid the preclinical and clinical interpretation of metformin therapy in ovarian and other cancers.
Mechanistic studies contribute greatly to our understanding of γδ T cell (γδTc) biology, aiding development of these cells as immunotherapeutic agents. The antibody blocking assay is an accepted ...method to determine the receptors involved in γδTc killing of tumor targets. Effectors and/or targets are preincubated with microgram quantities of monoclonal antibodies (mAb), often described by commercial sources to be useful for blocking assays. We and others have used such assays extensively in the past, correlating decreases in cytotoxicity against specific targets with involvement of the blocked receptor(s). However, we wondered whether other mechanisms might be at play beyond cytotoxicity inhibition. Indeed, administration of certain "blocking" mAb to the γδ T cell antigen receptor (γδTCR) induced γδTc death. Upon further investigation, we discovered that γδTc underwent apoptosis triggered by incubation with mAb to the γδTCR. This effect was specific, as no apoptosis was observed when αβ T cells (αβTc) were incubated with these mAb. Apoptosis was further potentiated by the presence of interleukin (IL)-2, often included in cytotoxicity assays; however, exogenous interleukin-2 (IL-2) did not contribute significantly to γδTc cytotoxicity against breast cancer cell lines. Here, we have investigated the usefulness of four mAb for use in blocking assays by assessing blocking properties in conjunction with their propensity to induce apoptosis in cultured primary human γδTc. We found that the 5A6.E9 clone was usually a better alternative to the commonly used B1 (or B1.1) and 11F2 clones; however, some variability in susceptibility to apoptosis induction was observed among donor cultures. Thus, viability assessment of primary effector cells treated with mAb alone should be undertaken in parallel with cytotoxicity assays employing blocking antibodies, to account for cytotoxicity reduction caused by effector cell death. Previous findings should be reassessed in this light.
Objective: The reduction in potency and inter-birth interval can decrease the chances of newborn and maternal death. With the execution of the national fertility program, there is a reduction in ...fertility rates considerably, but it persists in endemic groups in rural parts of India. This study was conducted to evaluate the knowledge of contraception and practice by type in tribal women in Jharkhand. Methods and Materials: This is a cross-sectional study carried out in a tribal area of Jharkhand. In this study, 200 pregnant women were included. With the observation of a single characteristic complex analyses were conducted to know the number and characteristics of people living in this area and behavioural factors related to the understanding of contraceptive methods. Results: All the tribal women were well acquainted with female sterilization. Few of the women around 40% knew about temporary contraception and 35% of the women did not know where to get them. The majority of the women knew about copper T (34%), but only 29.1% had knowledge of oral contraceptives and condoms (12%). Temporary contraception was utilized by 3% of the women. Conclusion: This study evaluated less or no awareness and usage of temporary contraceptive methods among tribal people in Jharkhand. The main aim is to make them aware of the different contraceptive methods for inter-birth intervals and should focus on young women. Recommendation: Awareness of various methods of contraception needs to be mass introduced to people in tribal regions. Therefore, this research shows the requirement for complete education and encouragement related to temporary methods of contraception in tribal women.
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