Ruby Dhar’s research while affiliated with All India Institute of Medical Sciences Bhopal and other places

Postpartum depression (PPD) or baby blue refers to conditions in new mothers who experience depression, mood swings, and desperation. Affecting as many as 85% of mothers post-delivery, PPD is a serious health concern, especially in some vulnerable populations, precipitating postpartum psychosis leading to confusion, cognitive impairment, delusion, and disorganized behaviour. Left untreated, these may lead to suicidal episodes in some extreme situations. The first FDA-approved drug for PPD was brexanolone in 2019, which is infused over three days under medical supervision. A recent clinical trial using a single low dose of esketamine (0.2 mg/kg body weight), infused 40 minutes postdelivery, seems to significantly reduce symptoms in the treated groups. Affecting a large number of females, PPD is a major health concern that needs to be addressed promptly by healthcare professionals.

Cancer immunotherapy is a form of biotherapy (also called biological response modifier therapy) that refers to a broad array of anti-cancer therapies targeted to activate and trigger the body’s immune system against cancer. This includes targeted antibodies to specific cell surface entities on cancer cells, anti-cancer vaccines like vaccines against HPV in cervical cancer, cytolytic virus, adoptive cell transfer, biologicals like cytokines and other small molecular agents, and the most explored immune checkpoint inhibitors. Immunotherapies use immune modulatory materials from the same organism to fight disease, while some immunotherapy treatments use genetic engineering-based gene editing approaches to enhance the host immune system in an effort to eradicate the cancer cells and boost its cancer-fighting capabilities. Used in combination with surgery, chemotherapy, and radiotherapy, cancer immunotherapy improves their overall effectiveness. WHAT IS AN IMMUNE CHECKPOINT T cell activation involves the engagement of a number of signaling cascades, originating from the interaction between T cell receptors (TCR) with antigen-presenting cells (APC) that ultimately determine cell fate through regulating cytokine production, cell survival, proliferation, and differentiation. TCR alone is not sufficient to generate an adequate response. It needs the participation of coreceptors. Primary T cell activation involves the integration of three distinct signals (1) antigen recognition in the presence of APC, (2) costimulation, and (3) cytokine-mediated differentiation and expansion. To make sure that these activated T cells do not cross-react with self-antigens, these are rendered inactive by immune checkpoints. PDL on T cells and PDL1 on host cells engage in bringing about this. Programmed Cell Death Protein 1 (PD-1) inhibits immune responses by fostering a state of self-tolerance. This is achieved by activating apoptosis, anergy, and avoidance of antigen-specific T cells. The functional counterpart of PD-1, the Programmed Cell Death Ligand 1 (PD-L1), is a trans-membrane protein that acts as a coinhibitory immune response factor. This is what the cancer cells hijack for their survival. PD-L1 expressed on cancer cells attenuates the host T cell response transmitting negative signals. Therefore, the PD-1/PD-L1 axis is the main driver of cancer immune evasion, which needs serious attention. WHAT IS IMMUNE CHECKPOINT INHIBITORS These classes of molecules are designed to block the cross-talks between cancer cells expressing PD-L1 with T cells expressing PD-1 receptors. When the interaction is blocked, inhibitory influence on T-cells is circumvented, and an attack may be launched. Checkpoint inhibitors are used in cancer immunotherapy, including a wide range of cancers, such as melanoma, skin cancer, and lung cancer. Different drug classes block checkpoint proteins like CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors. Commercially checkpoint inhibitors include pembrolizumab (Keytruda), ipilimumab (Yervoy), nivolumab (Opdivo), and atezolizumab (Tecentriq). RAYS OF HOPE AND CAUTION Because checkpoint inhibitors stimulate the immune system and are immunomodulatory, their usage has significantly improved cancer treatment and management, extending the life span for numerous patients. However, we need to be cautious as they may cause immune cells to attack healthy cells, causing side effects such as fatigue, nausea, high fever, flu-like symptoms, and inflammation.

Introduction: A growing body of evidence suggests the prognostic and therapeutic value of Androgen Receptors (AR) in Breast Cancer (BrCa), particularly Triple Negative BrCa (TNBC). The splice variants of AR (ARVs); notably full-length AR (AR-fl) of ~110 kDa and a C-terminally Ligand Binding Domain (LBD) truncated AR isoform (AR-V7) of ~67 kDa are present in a variety of tissues. The ligand-independent AR-V7 is constitutively expressed and confers castration resistance in prostate cancer. With the irrefutable role of ARVs in BrCa, we evaluated their expression profile in cell lines with their prevalence and clinicopathological correlation in BrCa patients from India. Methods: Breast Cancer cell lines MDA-MB-231, MCF7, and MDA-MB-453 were procured from American Type Culture Collection. Thirty-eight de novo cases of Breast Cancer undergoing surgical intervention at a tertiary healthcare center in India were recruited. Tumor and adjacent benign tissue were collected after informed consent. The ARVs expression at transcriptomic and proteomic levels was evaluated by qRT-PCR and western blotting & Immunohistochemistry (IHC) respectively. For functional annotation, ARVs were knocked down in vitro using differently targeting siRNAs facilitated by Lipofectamine 3000 based transfection. There was a strong complementarity observed in western blotting and IHC. Results: All the ARVs were significantly higher in MDA-MB-453 followed by MCF7 and MDA-MB-231 cells. The expression ratio of AR-V7 versus AR-fl is, however, elevated in highly aggressive TNBC cell line MDA-MB-231. 67% of patients recruited were immunostained positive for AR (n=38). A majority of patients were of Luminal phenotype (37%) expressing both the prominent ARVs. One-third of the TNBC fraction were AR positive. Following the TNBC cell line, a subset of patients' samples also exhibited a substantial upregulation of AR-V7 compared to AR-fl. These patients had poor prognoses and aggressive features. The siRNA knockdown of all the ARVs resulted in decreased invasion and Epithelial-mesenchymal transition (EMT). Interestingly knocking down of ARVs barring AR-V7, restored invasiveness suggesting the compensatory behavior of AR-V7. Conclusion: Our work demonstrates the presence of ARVs in BrCa with a particular focus on the AR-V7. The LBD truncated AR-V7 potentiates the growth in BrCa cell lines and patients. This study further encourages the ARVs expression screening with AR positive BrCa for a prognostic biomarker of aggressive phenotype and therapeutic resistance. Citation Format: Tryambak Pratap Srivastava, Ruby Dhar, Anurag Srivastava, SVS Deo, Rajinder Parshad, Subhradip Karmakar. Functional characterization of Androgen Receptor splice variants in breast cancer invasion and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6398.

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.

Synthetic biology is an emerging discipline of science, at the intersection of biology, engineering, and chemistry that involves redesigning organisms to have new phenotypes and customized abilities. While synthetic biology seems to have originated from genetic engineering, over the years, it has matured as well as diverged from it. It involves not just the transfer of genes from one or cell to another creating some variants, it also involves the assembly of an altogether novel organism or cell created part by part by the assembly of individual components of the desired function in a logical fashion. In this minireview, we will explore this new discipline and its possible applications and future promises to serve the humanity

Rapidly spreading Omicron (B1.1.529) poses a considerable health risk, despite being labeled as a mild SARS-CoV2 variant. The higher transmissibility, immune evasion properties along blunting the effect of vaccine are some of its unique features, a fact that should not be ignored, no matter how benign it might be. We suggest that our knowledge and experience in dealing with Omicron have been very less and its long-term health consequences are still not studied properly. Under these conditions, we must continue to remain vigilant following all safety measures and avoid down-sizing its impact.

Publish or perish has been the mantra for researchers and scientists. It is an aphorism describing the sheer pressure to publish academic work in order to succeed in an academic career. After all what good one has done if they didn’t even publish an article in a good journal. A good journal is the one with the highest impact factor. The Impact Factor is calculated by dividing the number of citations in the JCR year by the total number of articles published in the two previous years. An Impact Factor of 1.0 means that, on average, the articles published 1 or 2 years ago have been cited one time. While the impact factor metric is very unreliable to judge the quality of the journal or published paper, as numerous unfair and dubious means were frequently adopted to boost the journal impact factors. But still, the race is on with the psychology to publish in higher impact journals as it is often associated with greater academic rewards. What emerged out of this race is that journals and the publishing houses ramped the article processing charges (APC) to an astronomical level, which was unprecedented before. APC for a few BMC, MDPI, SAGE DOVE press journals on an average exceed 2000 USD, equivalent to few months salary of the Principle Investigtor. Journal publishing house often justifies high APC citing reasons for “open access” such that they are freely available for a wider range of readers free of cost or to meet their operational cost. Although apparently sound like a great initiative, a little more investigation reveals an underlying agenda, which is far from true when we find that a majority of this same. Publishing house ferociously opposes Sci-hub like 3d party platforms which genuinely gives free access to all readers worldwide. Recently, three major academic publishers Elsevier, Wiley, and American Chemical Society filed a copyright infringement suit in the Delhi High Court, India against “Sci-Hub” and “Libgen” which provide free access to millions of research papers/books. This clearly indicates that their intentions are misaligned with what they say. High APC is a means to just earn larger profit margins. Publishing house does mention a fee waiver for low-income countries but is exploited and abused instead of this as a helping gesture. Scientific research can hardly proceed in solo. It needs infrastructure, trained manpower, logistic support, and high-level coordination. Providing fee waivers for publication to countries that hardly can feed its starving populations makes little sense because either way, these countries are far behind to have material to publish or to engage in any credible research. Instead what is happening is what is called “author swapping” wherein the corresponding or co-corresponding authors are cherry-picked from these improvised nations for APC waiver without them anyway participating in the scientific study. This is surely unethical. Journals are also reported extorting authors who fail to pay the APC. There are other flip sides of APC. High APC skew only those rich and affluent labs/groups who may be able to afford them, something getting away even with mediocre articles while genuine data from less affluent labs may never be able to reach these journals. This trend is growing alarmingly high, filtering out publications only from wealthy labs. Though the scientific community is well aware of this, very little is actually done to prevent this as the nexus runs deep benefiting few who can afford it. Unless this chain is broken, future science may just be determined by those who can afford the high APC to get into the highest impact journals, and not by the quality of science.

It has been 2 years plus that the global pandemic has shadowed every aspect of human life. We have witnessed multiple waves of invasion by the different mutated versions of SARS-CoV-2, with each wave specific predominant symptoms and casualties. At present, we are witnessing the rage of Omicron, another mutated version of the virus, carrying 32 alterations in its spike proteins. What makes Omicron unique is its extremely high transmissibility, spreading like wildfire across the globe, with its footprints in over 90 countries infecting over several million. The high mutational burden of Omicron is perhaps the outcome of the selection pressure that this virus has been encountering while infecting its hosts. Added to that is also the effect of vaccination contributing to the emergence of different variants. What is spectacular is that Omicron is relatively less lethal than the previous variants though it contains many more alterations. This may be pointing toward a scenario of mutational exhaustion as well the status of an enhanced host immune surveillance. Under these conditions, it is conceivable that the virus will run out ofall its maximal capacity to mutate. We must accept the fact that the virus and its variants will keep on coming and time and often they might take an upper hand but over years, we will get used to this and learn ways to coexist.We must adjust our vaccine development pipelines and other risk mitigation tools to evade the risk. This has been the case with the influenza virus and it is likely that SARS-CoV-2 will follow the same. Let’s look at the other examples of this kind. How did other pandemics that affect humankind before has ended? The viruses did not go away completely, the modern H1N1, a descendent of the Spanish flu virus, circulates as H3N2 even today. Humans did not completely develop a herd immunity and knocked it off. That simply did not happen. Rather, the viruses became endemic and we will learn to live together. Both sides will develop safety nets so that none affects the other beyond a point of mutual coexistence. A better infectious agent evolves to ensure the survival of its host so that it can sustain itself without killing it. SARS-CoV-2 seems getting educated along these lines too. SARS-CoV-2 evolution to Omicron is perhaps a step in that direction.

Cell to Cell communications is the pivot for life processes. Any event that disrupts this leads to the loss of physiological function, eventually leading to cell death. Evolutionarily, cells developed an elaborate mechanism to undertake this paramount responsibility through cell surface glycocalyx, receptors, integrins, and other recognition molecules. Cells also exchange through local acting soluble mediators as well as through vesicles and exosomes. Recent development in this field led to the identification of a spectacular network of membrane process that seems to be the supremo of all that was known about cellular communications. These are called membrane nanotubes or tunneling nanotubes (TNT). Cellular communication can be subdivided into contact and contactless. The former provides more rapid and molecule transfer as compared to the latter. Tunneling nanotubes (TNTs) are a novel type of contact-based communication. TNTs are straight, thin membrane extensions connecting cells over long distances first reported in PC12 cells in 2004. TNT is believed to form from actin-based membrane protrusion. There are three different models of TNT formation. a>Protrusions from one cell grow and extend until it reaches the other cell, followed by a membrane fusion. b> Membrane protrusions grow from both cells until they meet and establish a connection c> TNT formation by cell dislodgement when cells migrate further apart from each other, and during this movement, TNT is formed. It is possible that all these three models may be operational depending on cell types and context. Tunneling nanotubes (TNT) are dynamic connections between cells, representing a novel route for cell-to-cell communication. TNT was reported in various cell types, like epithelial cells, neuronal cells, mesenchyma cells, and immune cells engaged in intercellular exchanges of molecules, subcellular organelles, and pathogen and viruses transport routes. TNT can extend up to 200 µm in length and about 50 nm to 1500 nm in diameter in macrophages. TNT can be established between similar cell types (homo-TNT) or between one cell type and another ( hetro TNT) and thus may be involved in the initiation and growth of cancer as well as dissemination of cancer cells. TNTs are also assumed to play a role in treatment resistance, e.g., in chemotherapy treatment of cancer. Recently, TNT has been used to hijack mitochondria from healthy cells by the cancer cells as a source of energy. TNT was also reported to transport miRNA and other RNA to the surrounding stroma creating an environment suitable for cancer growth. More research in this discipline is needed to understand the full function of these wonderful nanostructures.

Most viruses–including SARS-CoV-2, seem to have evolved over time. The lack of stringent proofreading mechanisms makes viral DNA/RNA replication error-prone. When a virus replicates, it sometimes changes a little bit, which is called mutations. Any virus with one or more new mutations can be referred to as a “variant” of the original virus. The last 2 years have witnessed the emergence of a large number of variants. Since the pandemic’s beginning, the SARS-CoV-2 coronavirus has mutated extensively, resulting in the emergence of different variants of the virus. One of these is the delta variant (arising from Pango lineage B.1.617.2) that took the word in a storm this year (February-July). The current a variant of concern is the B.1.1.529 (Omicron) variant reported first from South Africa on November 24, 2021. In recent weeks, infections have been widely reported, along with the increased detection of the B.1.1.529 variant. We reviewed the emergence of the new variant (B1.1.529) and its possible outcomes.