Alterations of the expression of TET2 and DNA 5-hmC predict poor prognosis in Myelodysplastic Neoplasms.

BACKGROUND: Myelodysplastic Neoplasms (MDS) are clonal stem cell disorders characterized by ineffective hematopoiesis and progression to acute myeloid leukemia, myelodysplasia-related (AML-MR). A major mechanism of pathogenesis of MDS is the aberration of the epigenetic landscape of the hematopoietic stem cells and/or progenitor cells, especially DNA cytosine methylation, and demethylation. Data on TET2, the predominant DNA demethylator of the hematopoietic system, is limited, particularly in the MDS patients from India, whose biology may differ since these patients present at a relatively younger age. We studied the expression and the variants of TET2 in Indian MDS and AML-MR patients and their effects on 5-hydroxymethyl cytosine (5-hmC, a product of TET2 catalysis) and on the prognosis of MDS patients. RESULTS: Of the 42 MDS patients, cytogenetics was available for 31 sub-categorized according to the Revised International Prognostic Scoring System (IPSS-R). Their age resembled that of the previous studies from India. Bone marrow nucleated cells (BMNCs) were also obtained from 13 patients with AML-MR, 26 patients with de-novo AML, and 11 subjects with morphologically normal bone marrow. The patients had a significantly lower TET2 expression which was more pronounced in AML-MR and the IPSS-R higher-risk MDS categories. The 5-hmC levels in higher-risk MDS and AML-MR correlated with TET2 expression, suggesting a possible mechanistic role in the loss of TET2 expression. The findings on TET2 and 5-hmC were also confirmed at the tissue level using immunohistochemistry. Pathogenic variants of TET2 were found in 7 of 24 patient samples (29%), spanning across the IPSS-R prognostic categories. One of the variants - H1778R - was found to affect local and global TET2 structure when studied using structural predictions and molecular dynamics simulations. Thus, it is plausible that some pathogenic variants in TET2 can compromise the structure of TET2 and hence in the formation of 5-hmC. CONCLUSIONS: IPSS-R higher-risk MDS categories and AML-MR showed a reduction in TET2 expression, which was not apparent in lower-risk MDS. DNA 5-hmC levels followed a similar pattern. Overall, a decreased TET2 expression and a low DNA 5-hmC level are predictors of advanced disease and adverse outcome in MDS in the population studied, i.e., MDS patients from India.

India's Opportunities and Challenges in Establishing a Twin Registry: An Unexplored Human Resource for the World's Second-Most Populous Nation.

Nature and nurture have always been a prerogative of evolutionary biologists. The environment's role in shaping an organism's phenotype has always intrigued us. Since the inception of humankind, twinning has existed with an unsettled parley on the contribution of nature (i.e. genetics) versus nurture (i.e. environment), which can influence the phenotypes. The study of twins measures the genetic contribution and that of the environmental influence for a particular trait, acting as a catalyst, fine-tuning the phenotypic trajectories. This is further evident because a number of human diseases show a spectrum of clinical manifestations with the same underlying molecular aberration. As of now, there is no definite way to conclude just from the genomic data the severity of a disease or even to predict who will get affected. This greatly justifies initiating a twin registry for a country as diverse and populated as India. There is an unmet need to set up a nationwide database to carefully curate the information on twins, serving as a valuable biorepository to study their overall susceptibility to disease. Establishing a twin registry is of paramount importance to harness the wealth of human information related to the biomedical, anthropological, cultural, social and economic significance.

Applications of Quantum Dots in Preventive Oncology.

QDs are semiconductor nanocrystalline materials with distinct optical and electronic characteristics due to their microscopic size and quantum mechanical properties. They are often composed of materials such as cadmium selenide (CdSe), cadmium telluride (CdTe), or indium phosphide (InP) and are typically in the size range of 2 to 10 nanometers in diameter. These tiny particles are used in various scientific and technological applications. Some key characteristics and applications of quantum dots are size-dependent Optical Properties with tunable emission. The color of light emitted by quantum dots highly depends on their size. Smaller QDs emit blue or green light, while larger ones emit red or near-infrared light. This tunability makes them valuable in various applications, especially in molecular medicine and oncology research. Quantum dots can exhibit a high quantum yield, meaning they efficiently emit light when excited, making them excellent fluorescent probes for non-invasive imaging. This review discusses the applications of QDs and their role in biomedical research and patient care, focusing on non-invasive imaging and preventive oncology.

SKping cell cycle regulation: role of ubiquitin ligase SKP2 in hematological malignancies.

SKP2 (S-phase kinase-associated protein 2) is a member of the F-box family of substrate-recognition subunits in the SCF ubiquitin-protein ligase complexes. It is associated with ubiquitin-mediated degradation in the mammalian cell cycle components and other target proteins involved in cell cycle progression, signal transduction, and transcription. Being an oncogene in solid tumors and hematological malignancies, it is frequently associated with drug resistance and poor disease outcomes. In the current review, we discussed the novel role of SKP2 in different hematological malignancies. Further, we performed a limited in-silico analysis to establish the involvement of SKP2 in a few publicly available cancer datasets. Interestingly, our study identified Skp2 expression to be altered in a cancer-specific manner. While it was found to be overexpressed in several cancer types, few cancer showed a down-regulation in SKP2. Our review provides evidence for developing novel SKP2 inhibitors in hematological malignancies. We also investigated the effect of SKP2 status on survival and disease progression. In addition, the role of miRNA and its associated families in regulating Skp2 expression was explored. Subsequently, we predicted common miRNAs against Skp2 genes by using miRNA-predication tools. Finally, we discussed current approaches and future prospective approaches to target the Skp2 gene by using different drugs and miRNA-based therapeutics applications in translational research.

The issues and challenges with cancer biomarkers.

A biomarker is a measurable indicator used to distinguish precisely/objectively either normal biological state/pathological condition/response to a specific therapeutic intervention. The use of novel molecular biomarkers within evidence-based medicine may improve the diagnosis/treatment of disease, improve health outcomes, and reduce the disease's socio-economic impact. Presently cancer biomarkers are the backbone of therapy, with greater efficacy and better survival rates. Cancer biomarkers are extensively used to treat cancer and monitor the disease's progress, drug response, relapses, and drug resistance. The highest percent of all biomarkers explored are in the domain of cancer. Extensive research using various methods/tissues is carried out for identifying biomarkers for early detection, which has been mostly unsuccessful. The quantitative/qualitative detection of various biomarkers in different tissues should ideally be done in accordance with qualification rules laid down by the Early Detection Research Network (EDRN), Program for the Assessment of Clinical Cancer Tests (PACCT), and National Academy of Clinical Biochemistry. Many biomarkers are presently under investigation, but lacunae lie in the biomarker's sensitivity and specificity. An ideal biomarker should be quantifiable, reliable, of considerable high/low expression, correlate with the outcome progression, cost-effective, and consistent across gender and ethnic groups. Further, we also highlight that these biomarkers' application remains questionable in childhood malignancies due to the lack of reference values in the pediatric population. The development of a cancer biomarker stands very challenging due to its complexity and sensitivity/resistance to the therapy. In past decades, the cross-talks between molecular pathways have been targeted to study the nature of cancer. To generate sensitive and specific biomarkers representing the pathogenesis of specific cancer, predicting the treatment responses and outcomes would necessitate inclusion of multiple biomarkers.

New immune horizons in therapeutics and diagnostic approaches to Preeclampsia.

Hypertensive disorders of pregnancy (HDP) are one of the commonest maladies, affecting 5%-10% of pregnancies worldwide. The American College of Obstetricians and Gynecologists (ACOG) identifies four categories of HDP, namely gestational hypertension (GH), Preeclampsia (PE), chronic hypertension (CH), and CH with superimposed PE. PE is a multisystem, heterogeneous disorder that encompasses 2%-8% of all pregnancy-related complications, contributing to about 9% to 26% of maternal deaths in low-income countries and 16% in high-income countries. These translate to 50 000 maternal deaths and over 500 000 fetal deaths worldwide, therefore demanding high priority in understanding clinical presentation, screening, diagnostic criteria, and effective management. PE is accompanied by uteroplacental insufficiency leading to vascular and metabolic changes, vasoconstriction, and end-organ ischemia. PE is diagnosed after 20 weeks of pregnancy in women who were previously normotensive or hypertensive. Besides shallow trophoblast invasion and inadequate remodeling of uterine arteries, dysregulation of the nonimmune system has been the focal point in PE. This results from aberrant immune system activation and imbalanced differentiation of T cells. Further, a failure of tolerance toward the semi-allogenic fetus results due to altered distribution of Tregs such as CD4+FoxP3+ or CD4+CD25+CD127(low) FoxP3+ cells, thereby creating a cytotoxic environment by suboptimal production of immunosuppressive cytokines like IL-10, IL-4, and IL-13. Also, intracellular production of complement protein C5a may result in decreased FoxP3+ regulatory T cells. With immune system dysfunction as a major driver in PE pathogenesis, it is logical that therapeutic targeting of components of the immune system with pharmacologic agents like anti-inflammatory and immune-modulating molecules are either being used or under clinical trial. Cholesterol synthesis inhibitors like Pravastatin may improve placental perfusion in PE, while Eculizumab (monoclonal antibody inhibiting C5) and small molecular inhibitor of C5a, Zilucoplan are under investigation. Monoclonal antibody against IL-17(Secukinumab) has been proposed to alter the Th imbalance in PE. Autologous Treg therapy and immune checkpoint inhibitors like anti-CTLA-4 are emerging as new candidates in immune horizons for PE management in the future.

Monosodium Glutamate Perturbs Human Trophoblast Invasion and Differentiation through a Reactive Oxygen Species-Mediated Pathway: An In-Vitro Assessment.

The overproduction of reactive oxygen species (ROS) has been associated with various human diseases. ROS exert a multitude of biological effects with both physiological and pathological consequences. Monosodium glutamate (MSG), a sodium salt of the natural amino acid glutamate, is a flavor-enhancing food additive, which is widely used in Asian cuisine and is an ingredient that brings out the "umami" meat flavor. MSG consumption in rats is associated with ROS generation. Owing to its consumption as part of the fast-food culture and concerns about its possible effects on pregnancy, we aimed to study the impact of MSG on placental trophoblast cells. MSG exposure influenced trophoblast invasion and differentiation, two of the most critical functions during placentation through enhanced production of ROS. Similar findings were also observed on MSG-treated placental explants, as confirmed by elevated Nrf2 levels. Ultrastructural studies revealed signs of subcellular injury by MSG exposure. Mechanistically, MSG-induced oxidative stress with endoplasmic reticulum stress pathways involving Xbp1s and IRE1α was observed. The effect of MSG through an increased ROS production indicates that its long-term exposure might have adverse health effect by compromising key trophoblast functions.

Fenofibrate mediated activation of PPARα negatively regulates trophoblast invasion.

The Peroxisome Proliferator-Activated Receptor-alpha (PPARα) is a member of the ligand-dependent nuclear receptor superfamily known for their crucial role in lipid metabolism. The expression and role of PPARα in trophoblast cells are not very well known. Trophoblast invasion is one of the most critical processes required for successful implantation of the developing embryo into the maternal endometrium. Defects in this process are associated with adverse pregnancy outcomes such as FGR(Fetal Growth Restriction), Preeclampsia, and choriocarcinoma. In this present study, we investigated the role of the ligand-activated transcription factor, Peroxisome proliferator-activated receptor (PPARα) in regulating trophoblast cell invasion using cell lines and explants-based models. Immunohistological localization of PPARα in human placental tissues showed a gestational variation with relatively low expression at term as compared to early trimester. PCR and Western Blot also confirmed this. Further to delineate the effect of PPAR alpha on trophoblast invasion, EVT derived HTR8/SVneo cell lines were stimulated with PPARα agonist, i.e., fenofibrate (FF). Fenofibrate stimulation led to an increased activation and nuclear translocation of PPARα, followed by reduced migration and invasion of these cells in a matrigel invasion assay (Boyden chamber). PPAR alpha stimulation also led to a reduced MMP-2/9 expression following our previous observation. Thus, we may conclude that PPARα to be playing a very important regulatory role in orchestrating the invasive trophoblast programme and hence it seems plausible for it to be associated with PE, which is often characterized by a shallow trophoblast invasion.

The metabolic addiction of cancer stem cells.

Cancer stem cells (CSC) are the minor population of cancer originating cells that have the capacity of self-renewal, differentiation, and tumorigenicity (when transplanted into an immunocompromised animal). These low-copy number cell populations are believed to be resistant to conventional chemo and radiotherapy. It was reported that metabolic adaptation of these elusive cell populations is to a large extent responsible for their survival and distant metastasis. Warburg effect is a hallmark of most cancer in which the cancer cells prefer to metabolize glucose anaerobically, even under normoxic conditions. Warburg's aerobic glycolysis produces ATP efficiently promoting cell proliferation by reprogramming metabolism to increase glucose uptake and stimulating lactate production. This metabolic adaptation also seems to contribute to chemoresistance and immune evasion, a prerequisite for cancer cell survival and proliferation. Though we know a lot about metabolic fine-tuning in cancer, what is still in shadow is the identity of upstream regulators that orchestrates this process. Epigenetic modification of key metabolic enzymes seems to play a decisive role in this. By altering the metabolic flux, cancer cells polarize the biochemical reactions to selectively generate "onco-metabolites" that provide an added advantage for cell proliferation and survival. In this review, we explored the metabolic-epigenetic circuity in relation to cancer growth and proliferation and establish the fact how cancer cells may be addicted to specific metabolic pathways to meet their needs. Interestingly, even the immune system is re-calibrated to adapt to this altered scenario. Knowing the details is crucial for selective targeting of cancer stem cells by choking the rate-limiting stems and crucial branch points, preventing the formation of onco-metabolites.

Loss of TET2 with reduced genomic 5-hmC is associated with adverse-risk AML.

While considerable information exists on the ten-eleven translocation 2 (TET2) mutational landscape in AML, the information on TET2 expression is limiting. So, we aimed to study the TET2 expression at mRNA and protein levels in AML patients compared to healthy controls. To achieve this, we recruited 70 non-M3, de novo AML patients and 20 healthy controls. The expression of TET2 was checked at mRNA and protein levels by qPCR and ELISA respectively and the TET activity was checked by the 5-hmC assay. TET2 mRNA expression was correlated with clinicopathological parameters and overall survival. We found a significant downregulation of TET2 mRNA and protein and significantly lower DNA 5-hmC levels in AML patients compared to controls. TET2 downregulation was more in patients with high blast counts and patients of the adverse-risk ELN category. We also found a significant upregulation of DNMT1 and DNMT3a suggesting a hypermethylation phenotype in de novo AML.

Fault Lines in India's COVID-19 Management: Lessons Learned and Future Recommendations.

With about 0.4-0.5 million COVID cases diagnosed every single day in a row over the past three weeks back in May 2021, India was at the epicenter of the global viral rampage. The catastrophe of this crisis was unprecedented, pushing the health care system to its breaking point. Although significant progress has been made in identifying these highly transmissible variants, what is somewhat lacking is the competence to exploit this information for risk mitigation and effective disease management through an integrated nationwide coordinated approach. With a positivity rate of 15-20% (April-May 2021) and the healthcare system pushed to its limit, accompanied by increased mortality, the situation was rather grim then. Though the central command scrambled all its resources and logistics to streamline the supply chain, the efforts were insufficient in response to the ongoing crisis due to a disproportionate rise in the case. We examined the current scenario emerging from this 2nd COVID wave and identified the possible lacunae. We also suggested few recommendations that may be adopted to avoid similar failures in the future.

Balancing Healthcare and Economy Amidst the COVID-19 Pandemic: An Indian Experience.

With its 1.3 billion population and faced with the COVID-19 pandemic, India is at the junction of two crucial decisions, balancing healthcare and the economy. To prevent the community spread of the virus, the Indian Government imposed a nationwide lockdown. Though initially successful to some extent in containing the disease spread, the extended lockdown eventually leads to a spiraling out effect resulting in the slowdown of the economy, which, in turn, lead to widespread consequences affecting the lives of millions of people, mostly those at the base of the social pyramid. We investigated the implications of few government policies taken during this pandemic and their impact on society, thereby suggesting short-term crisis management with long-term solutions. Here, we present a comprehensive account of Indian policy in dealing with the COVID-19 crisis, balancing both economic and public health. We also explored a future contingency plan for risk mitigation along with few recommendations. This viewpoint will be useful for effective healthcare management and the economy in Asia's populous nation in the COVID-19 and prepare for a future crisis of this nature.

Heat Shock Proteins and Their Role in Pregnancy: Redefining the Function of "Old Rum in a New Bottle".

Pregnancy in humans is a multi-step complex physiological process comprising three discrete events, decidualization, implantation and placentation. Its overall success depends on the incremental advantage that each of the preceding stages passes on to the next. The success of these synchronized sequels of events is an outcome of timely coordination between them. The pregnancy events are coordinated and governed primarily by the ovarian steroid hormones, estrogen and progesterone, which are essentially ligand-activated transcription factors. It's well known that intercellular signaling of steroid hormones engages a plethora of adapter proteins that participate in executing the biological functions. This involves binding of the hormone receptor complex to the DNA response elements in a sequence specific manner. Working with Drosophila melanogaster, the heat shock proteins (HSPs) were originally described by Ferruccio Ritossa back in the early 1960s. Over the years, there has been considerable advancement of our understanding of these conserved families of proteins, particularly in pregnancy. Accumulating evidence suggests that endometrial and uterine cells have an abundance of HSP27, HSP60, HSP70 and HSP90, implying their possible involvement during the pregnancy process. HSPs have been found to be associated with decidualization, implantation and placentation, with their dysregulation associated with implantation failure, pregnancy loss and other feto-maternal complications. Furthermore, HSP is also associated with stress response, specifically in modulating the ER stress, a critical determinant for reproductive success. Recent advances suggest a therapeutic role of HSPs proteins in improving the pregnancy outcome. In this review, we summarized our latest understanding of the role of different members of the HSP families during pregnancy and associated complications based on experimental and clinical evidences, thereby redefining and exploring their novel function with new perspective, beyond their prototype role as molecular chaperones.

TETology: Epigenetic Mastermind in Action.

Cytosine methylation is a well-explored epigenetic modification mediated by DNA methyltransferases (DNMTs) which are considered "methylation writers"; cytosine methylation is a reversible process. The process of removal of methyl groups from DNA remained unelucidated until the discovery of ten-eleven translocation (TET) proteins which are now considered "methylation editors." TET proteins are a family of Fe(II) and alpha-ketoglutarate-dependent 5-methyl cytosine dioxygenases-they convert 5-methyl cytosine to 5-hydroxymethyl cytosine, and to further oxidized derivatives. In humans, there are three TET paralogs with tissue-specific expression, namely TET1, TET2, and TET3. Among the TETs, TET2 is highly expressed in hematopoietic stem cells where it plays a pleiotropic role. The paralogs also differ in their structure and DNA binding. TET2 lacks the CXXC domain which mediates DNA binding in the other paralogs; thus, TET2 requires interactions with other proteins containing DNA-binding domains for effectively binding to DNA to bring about the catalysis. In addition to its role as methylation editor of DNA, TET2 also serves as methylation editor of RNA. Thus, TET2 is involved in epigenetics as well as epitranscriptomics. TET2 mutations have been found in various malignant hematological disorders like acute myeloid leukemia, and non-malignant hematological disorders like myelodysplastic syndromes. Increasing evidence shows that TET2 plays an important role in the non-hematopoietic system as well. Hepatocellular carcinoma, gastric cancer, prostate cancer, and melanoma are some non-hematological malignancies in which a role of TET2 has been implicated. Loss of TET2 is also associated with atherosclerotic vascular lesions and endometriosis. The current review elaborates on the role of structure, catalysis, physiological functions, pathological alterations, and methods to study TET2, with specific emphasis on epigenomics and epitranscriptomics.

Exploring the Role of Gut Microbiome in Colon Cancer.

Dysbiosis of the gut microbiome has been associated with the development of colorectal cancer (CRC). Gut microbiota is involved in the metabolic transformations of dietary components into oncometabolites and tumor-suppressive metabolites that in turn affect CRC development. In a healthy colon, the major of microbial metabolism is saccharolytic fermentation pathways. The alpha-bug hypothesis suggested that oncogenic bacteria such as enterotoxigenic Bacteroides fragilis (ETBF) induce the development of CRC through direct interactions with colonic epithelial cells and alterations of microbiota composition at the colorectal site. Escherichia coli, E. faecalis, F. nucleatum, and Streptococcus gallolyticus showed higher abundance whereas Bifidobacterium, Clostridium, Faecalibacterium, and Roseburia showed reduced abundance in CRC patients. The alterations of gut microbiota may be used as potential therapeutic approaches to prevent or treat CRC. Probiotics such as Lactobacillus and Bifidobacterium inhibit the growth of CRC through inhibiting inflammation and angiogenesis and enhancing the function of the intestinal barrier through the secretion of short-chain fatty acids (SCFAs). Crosstalk between lifestyle, host genetics, and gut microbiota is well documented in the prevention and treatment of CRC. Future studies are required to understand the interaction between gut microbiota and host to the influence and prevention of CRC. However, a better understanding of bacterial dysbiosis in the heterogeneity of CRC tumors should also be considered. Metatranscriptomic and metaproteomic studies are considered a powerful omic tool to understand the anti-cancer properties of certain bacterial strains. The clinical benefits of probiotics in the CRC context remain to be determined. Metagenomic approaches along with metabolomics and immunology will open a new avenue for the treatment of CRC shortly. Dietary interventions may be suitable to modulate the growth of beneficial microbiota in the gut.

Cancer immunotherapy: Recent advances and challenges.

Immunotherapy is a treatment that uses specific components of a person's immune system to fight diseases. This is usually done by stimulating or assisting one's immune system is attacking the offending agent - for instance, in the case of cancer - the target of immunotherapy will be cancer cells. Some types of immunotherapy are also called biologic therapy or biotherapy. One of the fundamental challenges that a living cell encounters are to accurately copy its genetic material to daughter cells during every single cell cycle. When this process goes haywire, genomic instability ensues, and genetic alterations ranging from nucleotide changes to chromosomal translocations and aneuploidy occur. Genomic instability arising out of DNA structural changes (indels, rearrangements, etc.,) can give rise to mutations predisposing to cancer. Cancer prevention refers to actions taken to mitigate the risk of getting cancer. The past decade has encountered an explosive rate of development of anticancer therapy ranging from standard chemotherapy to novel targeted small molecules that are nearly cancer specific, thereby reducing collateral damage. However, a new class of emerging therapy aims to train the body's defense system to fight against cancer. Termed as "cancer immunotherapy" is the new approach that has gained worldwide acceptance. It includes using antibodies that bind to and inhibit the function of proteins expressed by cancer cells or engineering and boosting the person's own T lymphocytes to target cancer. In this review, we summarized the recent advances and developments in cancer immunotherapy along with their shortcoming and challenges.

Oxidative stress-induced impairment of trophoblast function causes preeclampsia through the unfolded protein response pathway.

Pre-eclampsia (PE) is a pregnancy-specific disorder, characterized by hypertension and proteinuria. In PE, trophoblasts mediated inadequate remodeling of uterine spiral arteries seem to interrupt uteroplacental blood flow, one of the hallmarks in the early onset of PE (EO-PE). This, in turn, results in placental ischemia-reperfusion injury during hypoxia and reoxygenation episodes, leading to the generation of reactive oxygen species (ROS) and oxidative stress (OS). But still it is debatable if OS is a cause or consequence of PE. In this present study, we have investigated the effects of OS on PE placentae and trophoblast cell functions using BeWo and HTR8/SVneo cell lines. PE placental tissues showed abnormal ultrastructure, high level of reactive oxygen species (ROS) with altered unfolded protein responses (UPR) in compare with term placental tissues. Similar to PE placentae, during OS induction, the trophoblast cells showed altered invasion and migration properties with significantly variable expression of differentiation and invasion markers, e.g., syncytin and MMPs. The effect was rescued by antioxidant, N-acetyl cysteine, thereby implying a ROS-specific effect and in the trophoblast cells, OS triggers UPR pathway through IRE1α-XBP1 axis. Taken together, these findings highlight the harmful effect of unfolded protein response, which was induced due to OS on trophoblast cells and deformed invasion and differentiation programme and can be extended further to clinical settings to identify clinically approved antioxidants during pregnancy as a therapeutic measure to reduce the onset of PE.

EMTiness in pseudo-malignant behavior of trophoblasts during embryo implantation.

Implantation in humans is a multistep process that involves apposition, adhesion, and invasion of the developing blastocyst into the receptive maternal endometrium. Though significant volume of research in this direction has identified important players orchestrating this delicate process, there are still gaps in our understanding of all the sequence of events during embryo implantation. Also, the early pregnancy-related complications that lead to fetal loss and miscarriage often occur in this critical window of implantation, which is primarily defined as the time when the maternal endometrium is supposed to be most receptive to the free blastocyst that emerges out from the zona pellucida. Studies in humans and rodents have identified several mediators like folliculin, LIF, IL11Ra, splicing factor SC35, etc. to be essential for early implantation. Trophoblasts, that form the outer epithelial layer of the blastocyst, participate in the formation of the placenta. During placentation, invasive extravillous trophoblasts (EVTs), migrate into the endometrium, and a transient epithelial to mesenchymal transition (EMT) and remodel the uterine arteries for blood and nutrient exchange.

Potential SARS-CoV-2 interactions with proteins involved in trophoblast functions - An in-silico study.

BACKGROUND: Though a large number of pregnant females have been affected by COVID-19, there is a dearth of information on the effects of SARS-CoV-2 infection on trophoblast function. We explored in silico, the potential interactions between SARS-CoV-2 proteins and proteins involved in the key functions of placenta. METHODS: Human proteins interacting with SARS-CoV-2 proteins were identified by Gordon et al. (2020). Genes that are upregulated in trophoblast sub-types and stages were obtained by gene-expression data from NCBI-GEO and by text-mining. Genes altered in pathological states like pre-eclampsia and gestational diabetes mellitus were also identified. Genes crucial in placental functions thus identified were compared to the SARS-CoV-2 interactome for overlaps. Proteins recurring across multiple study scenarios were analyzed using text mining and network analysis for their biological functions. RESULTS: The entry receptors for SARS-CoV-2 - ACE2 and TMPRSS2 are expressed in placenta. Other proteins that interact with SARS-CoV-2 like LOX, Fibulins-2 and 5, NUP98, GDF15, RBX1, CUL3, HMOX1, PLAT, MFGE8, and MRPs are vital in placental functions like trophoblast invasion and migration, syncytium formation, differentiation, and implantation. TLE3, expressed across first trimester placental tissues and cell lines, is involved in formation of placental vasculature, and is important in SARS-CoV (2003) budding and exit from the cells by COPI vesicles. CONCLUSION: SARS-CoV-2 can potentially interact with proteins having crucial roles in the placental function. Whether these potential interactions identified in silico have effects on trophoblast functions in biological settings needs to be addressed by further in vitro and clinical studies.

Genomic analysis of estrogen cascade reveals histone variant H2A.Z associated with breast cancer progression.

We demonstrate an integrated approach to the study of a transcriptional regulatory cascade involved in the progression of breast cancer and we identify a protein associated with disease progression. Using chromatin immunoprecipitation and genome tiling arrays, whole genome mapping of transcription factor-binding sites was combined with gene expression profiling to identify genes involved in the proliferative response to estrogen (E2). Using RNA interference, selected ERalpha and c-MYC gene targets were knocked down to identify mediators of E2-stimulated cell proliferation. Tissue microarray screening revealed that high expression of an epigenetic factor, the E2-inducible histone variant H2A.Z, is significantly associated with lymph node metastasis and decreased breast cancer survival. Detection of H2A.Z levels independently increased the prognostic power of biomarkers currently in clinical use. This integrated approach has accelerated the identification of a molecule linked to breast cancer progression, has implications for diagnostic and therapeutic interventions, and can be applied to a wide range of cancers.