Durable partial response to pembrolizumab, lenvatinib, and letrozole in a case of recurrent uterine carcinosarcoma with ESR1 gene amplification.

•ESR1 gene amplification occurs in 7% of uterine carcinosarcoma.•The presence of ESR1 gene amplification in recurrent uterine carcinosarcoma may be targeted by aromatase inhibitors.•ESR1 gene amplification may be identified through immunohistochemical staining for estrogen receptor followed by fluorescence in situ hybridization or tumor targeted gene sequencing.

Live Attenuated Vaccines against Tuberculosis: Targeting the Disruption of Genes Encoding the Secretory Proteins of Mycobacteria.

Tuberculosis (TB), a chronic infectious disease affecting humans, causes over 1.3 million deaths per year throughout the world. The current preventive vaccine BCG provides protection against childhood TB, but it fails to protect against pulmonary TB. Multiple candidates have been evaluated to either replace or boost the efficacy of the BCG vaccine, including subunit protein, DNA, virus vector-based vaccines, etc., most of which provide only short-term immunity. Several live attenuated vaccines derived from Mycobacterium tuberculosis (Mtb) and BCG have also been developed to induce long-term immunity. Since Mtb mediates its virulence through multiple secreted proteins, these proteins have been targeted to produce attenuated but immunogenic vaccines. In this review, we discuss the characteristics and prospects of live attenuated vaccines generated by targeting the disruption of the genes encoding secretory mycobacterial proteins.

ZMYND8 Is a Regulator of Sonic Hedgehog Signaling in ATRA-Mediated Differentiation of Neuroblastoma Cells.

Zinc Finger MYND (Myeloid, Nervy, and DEAF-1) type containing 8 (ZMYND8) is a crucial epigenetic regulator that plays a multifaceted role in governing a spectrum of vital cellular processes, encompassing proliferation, apoptosis, migration, tumor suppression, and differentiation. It has emerged as a key player in neuronal differentiation by orchestrating the expression of neuronal lineage-committed genes. The present study uncovers the role of ZMYND8 in regulating the Sonic Hedgehog (SHH) signaling axis, which is crucial for neuronal differentiation. Genetic deletion of ZMYND8 leads to a significant reduction in SHH pathway genes, GLI1, and PTCH1 expression during all-trans-retinoic acid (ATRA)-induced differentiation. ZMYND8 and RNA pol II S5P are found to co-occupy the GLI1 and PTCH1 gene promoters, positively impacting their gene transcription upon ATRA treatment. Interestingly, ZMYND8 is found to counteract the inhibitory effects of Cyclopamine that block the upstream SHH pathway protein SMO, resulting in enhanced neurite formation in neuroblastoma cells following their treatment with ATRA. These results indicate that ZMYND8 is an epigenetic regulator of the SHH signaling pathway and has tremendous therapeutic potential in ATRA-mediated differentiation of neuroblastoma.

Progress and prospect of nanotechnology for cardiac fibrosis treatment.

Cardiac fibrosis is the excessive accumulation of extracellular matrix components in the heart, leading to reduced cardiac functionality and heart failure. This review provides an overview of the therapeutic applications of nanotechnology for the treatment of cardiac fibrosis. We first delve into the fundamental pathophysiology of cardiac fibrosis, highlighting the key molecular players, including Matrix Metalloproteinases, Transforming Growth Factor-beta, and several growth factors, cytokines, and signaling molecules. Each target presents a unique opportunity to develop targeted nano-therapies. We then focus on recent advancements in nanotechnology and how nanoparticles can be engineered to deliver drugs or therapeutic genes. These advanced delivery approaches have shown significant potential to inhibit fibrosis-promoting factors, thereby mitigating the fibrotic response and potentially reversing disease progression. In addition, we discuss the challenges associated with developing and translating nanotechnology-based drug delivery systems, including ensuring biocompatibility, safety, and regulatory compliance. This review highlights how nanotechnology can bridge the gap between lab research and clinical practice for treating cardiac fibrosis.

Pathogenic mycoplasmas of humans regulate the long noncoding RNAs in epithelial cells.

Non-coding RNAs (ncRNAs), specifically long ncRNAs (lncRNAs), regulate cellular processes by affecting gene expression at the transcriptional, post-transcriptional, and epigenetic levels. Emerging evidence indicates that pathogenic microbes dysregulate the expression of host lncRNAs to suppress cellular defense mechanisms and promote survival. To understand whether the pathogenic human mycoplasmas dysregulate host lncRNAs, we infected HeLa cells with Mycoplasma genitalium (Mg) and Mycoplasma penumoniae (Mp) and assessed the expression of lncRNAs by directional RNA-seq analysis. HeLa cells infected with these species showed up-and-down regulation of lncRNAs expression, indicating that both species can modulate host lncRNAs. However, the number of upregulated (200 for Mg and 112 for Mp) and downregulated lncRNAs (30 for Mg and 62 for Mp) differ widely between these two species. GREAT analysis of the noncoding regions associated with differentially expressed lncRNAs showed that Mg and Mp regulate a discrete set of lncRNA plausibly related to transcription, metabolism, and inflammation. Further, signaling network analysis of the differentially regulated lncRNAs exhibited diverse pathways such as neurodegeneration, NOD-like receptor signaling, MAPK signaling, p53 signaling, and PI3K signaling, suggesting that both species primarily target signaling mechanisms. Overall, the study's results suggest that Mg and Mp modulate lncRNAs to promote their survival within the host but in distinct manners.

Mycobacterium smegmatis secreting methionine sulfoxide reductase A (MsrA) modulates cellular processes in mouse macrophages.

Methionine sulfoxide reductase A (MsrA) is an antioxidant repair enzyme that reduces the oxidized methionine (Met-O) in proteins to methionine (Met). Its pivotal role in the cellular processes has been well established by overexpressing, silencing, and knocking down MsrA or deleting the gene encoding MsrA in several species. We are specifically interested in understanding the role of secreted MsrA in bacterial pathogens. To elucidate this, we infected mouse bone marrow-derived macrophages (BMDMs) with recombinant Mycobacterium smegmatis strain (MSM), secreting a bacterial MsrA or M. smegmatis strain (MSC) carrying only the control vector. BMDMs infected with MSM induced higher levels of ROS and TNF-α than BMDMs infected with MSC. The increased ROS and TNF-α levels in MSM-infected BMDMs correlated with elevated necrotic cell death in this group. Further, RNA-seq transcriptome analysis of BMDMs infected with MSC and MSM revealed differential expression of protein and RNA coding genes, suggesting that bacterial-delivered MsrA could modulate the host cellular processes. Finally, KEGG pathway enrichment analysis identified the down-regulation of cancer-related signaling genes in MSM-infected cells, indicating that MsrA can potentially regulate the development and progression of cancer.

ZMYND8 suppresses MAPT213 LncRNA transcription to promote neuronal differentiation.

Zinc Finger transcription factors are crucial in modulating various cellular processes, including differentiation. Chromatin reader Zinc Finger MYND (Myeloid, Nervy, and DEAF-1) type containing 8 (ZMYND8), an All-Trans Retinoic Acid (ATRA)-responsive gene, was previously shown to play a crucial role in promoting the expression of neuronal-lineage committed genes. Here, we report that ZMYND8 promotes neuronal differentiation by positively regulating canonical MAPT protein-coding gene isoform, a key player in the axonal development of neurons. Additionally, ZMYND8 modulates gene-isoform switching by epigenetically silencing key regulatory regions within the MAPT gene, thereby suppressing the expression of non-protein-coding isoforms such as MAPT213. Genetic deletion of ZMYND8 led to an increase in the MAPT213 that potentially suppressed the parental MAPT protein-coding transcript expression related to neuronal differentiation programs. In addition, ectopic expression of MAPT213 led to repression of MAPT protein-coding transcript. Similarly, ZMYND8-driven transcription regulation was also observed in other neuronal differentiation-promoting genes. Collectively our results elucidate a novel mechanism of ZMYND8-dependent transcription regulation of different neuronal lineage committing genes, including MAPT, to promote neural differentiation.

Functional Characterization of lncRNA152 as an Angiogenesis-Inhibiting Tumor Suppressor in Triple-Negative Breast Cancers.

Long noncoding RNAs have been implicated in many of the hallmarks of cancer. Herein, we found that the expression of lncRNA152 (lnc152; a.k.a. DRAIC), which we annotated previously, is highly upregulated in luminal breast cancer (LBC) and downregulated in triple-negative breast cancer (TNBC). Knockdown of lnc152 promotes cell migration and invasion in LBC cell lines. In contrast, ectopic expression of lnc152 inhibits growth, migration, invasion, and angiogenesis in TNBC cell lines. In mice, lnc152 inhibited the growth of TNBC cell xenografts, as well as metastasis of TNBC cells in an intracardiac injection model. Transcriptome analysis of the xenografts indicated that lnc152 downregulates genes controlling angiogenesis. Using pull down assays followed by LC/MS-MS, we identified RBM47, a known tumor suppressor in breast cancer, as a lnc152-interacting protein. The effects of lnc152 in TNBC cells are mediated, in part, by regulating the expression of RBM47. Collectively, our results demonstrate that lnc152 is an angiogenesis-inhibiting tumor suppressor that attenuates the aggressive cancer-related phenotypes found in TNBC. IMPLICATIONS: This study identifies lncRNA152 as an angiogenesis-inhibiting tumor suppressor that attenuates the aggressive cancer-related phenotypes found in TNBC by upregulating the expression of the tumor suppressor RBM47. As such, lncRNA152 may serve as a biomarker to track aggressiveness of breast cancer, as well as therapeutic target for treating TNBC.

Harnessing the Immune System with Cancer Vaccines: From Prevention to Therapeutics.

Prophylactic vaccination against infectious diseases is one of the most successful public health measures of our lifetime. More recently, therapeutic vaccination against established diseases such as cancer has proven to be more challenging. In the host, cancer cells evade immunologic regulation by multiple means, including altering the antigens expressed on their cell surface or recruiting inflammatory cells that repress immune surveillance. Nevertheless, recent clinical data suggest that two classes of antigens show efficacy for the development of anticancer vaccines: tumor-associated antigens and neoantigens. In addition, many different vaccines derived from antigens based on cellular, peptide/protein, and genomic components are in development to establish their efficacy in cancer therapy. Some vaccines have shown promising results, which may lead to favorable outcomes when combined with standard therapeutic approaches. This review provides an overview of the innate and adaptive immune systems, their interactions with cancer cells, and the development of various different vaccines for use in anticancer therapeutics.

The paradigm of drug resistance in cancer: an epigenetic perspective.

Innate and acquired resistance towards the conventional therapeutic regimen imposes a significant challenge for the successful management of cancer for decades. In patients with advanced carcinomas, acquisition of drug resistance often leads to tumor recurrence and poor prognosis after the first therapeutic cycle. In this context, cancer stem cells (CSCs) are considered as the prime drivers of therapy resistance in cancer due to their 'non-targetable' nature. Drug resistance in cancer is immensely influenced by different properties of CSCs such as epithelial-to-mesenchymal transition (EMT), a profound expression of drug efflux pump genes, detoxification genes, quiescence, and evasion of apoptosis, has been highlighted in this review article. The crucial epigenetic alterations that are intricately associated with regulating different mechanisms of drug resistance, have been discussed thoroughly. Additionally, special attention is drawn towards the epigenetic mechanisms behind the interaction between the cancer cells and their microenvironment which assists in tumor progression and therapy resistance. Finally, we have provided a cumulative overview of the alternative treatment strategies and epigenome-modifying therapies that show the potential of sensitizing the resistant cells towards the conventional treatment strategies. Thus, this review summarizes the epigenetic and molecular background behind therapy resistance, the prime hindrance of present day anti-cancer therapies, and provides an account of the novel complementary epi-drug-based therapeutic strategies to combat drug resistance.

Characterization of the Testis-specific LINC01016 Gene Reveals Isoform-specific Roles in Controlling Biological Processes.

Long noncoding RNAs (lncRNAs) have emerged as critical regulators of biological processes. However, the aberrant expression of an isoform from the same lncRNA gene could lead to RNA with altered functions due to changes in their conformations, leading to diseases. Here, we describe a detailed characterization of the gene that encodes long intergenic non-protein-coding RNA 01016 (LINC01016, also known as LncRNA1195) with a focus on its structure, exon usage, and expression in human and macaque tissues. In this study we show that it is among the highly expressed lncRNAs in the testis, exclusively conserved among nonhuman primates, suggesting its recent evolution and is processed into 12 distinct RNAs in testis, cervix, and uterus tissues. Further, we integrate de novo annotation of expressed LINC01016 transcripts and isoform-dependent gene expression analyses to show that human LINC01016 is a multiexon gene, processed through differential exon usage with isoform-specific roles. Furthermore, in cervical, testicular, and uterine cancers, LINC01016 isoforms are differentially expressed, and their expression is predictive of survival in these cancers. This study has revealed an essential aspect of lncRNA biology, rarely associated with coding RNAs, that lncRNA genes are precisely processed to generate isoforms with distinct biological roles in specific tissues.

Mycoplasma genitalium and M. pneumoniae Regulate a Distinct Set of Protein-Coding Genes in Epithelial Cells.

Mycoplasma genitalium and M. pneumoniae are two significant mycoplasmas that infect the urogenital and respiratory tracts of humans. Despite distinct tissue tropisms, they both have similar pathogenic mechanisms and infect/invade epithelial cells in the respective regions and persist within these cells. However, the pathogenic mechanisms of these species in terms of bacterium-host interactions are poorly understood. To gain insights on this, we infected HeLa cells independently with M. genitalium and M. pneumoniae and assessed gene expression by whole transcriptome sequencing (RNA-seq) approach. The results revealed that HeLa cells respond to M. genitalium and M. pneumoniae differently by regulating various protein-coding genes. Though there is a significant overlap between the genes regulated by these species, many of the differentially expressed genes were specific to each species. KEGG pathway and signaling network analyses revealed that the genes specific to M. genitalium are more related to cellular processes. In contrast, the genes specific to M. pneumoniae infection are correlated with immune response and inflammation, possibly suggesting that M. pneumoniae has some inherent ability to modulate host immune pathways.

TCF19 and p53 regulate transcription of TIGAR and SCO2 in HCC for mitochondrial energy metabolism and stress adaptation.

Alteration in glucose homeostasis during cancer metabolism is an important phenomenon. Though several important transcription factors have been well studied in the context of the regulation of metabolic gene expression, the role of epigenetic readers in this regard remains still elusive. Epigenetic reader protein transcription factor 19 (TCF19) has been recently identified as a novel glucose and insulin-responsive factor that modulates histone posttranslational modifications to regulate glucose homeostasis in hepatocytes. Here we report that TCF19 interacts with a non-histone, well-known tumor suppressor protein 53 (p53) and co-regulates a wide array of metabolic genes. Among these, the p53-responsive carbohydrate metabolic genes Tp53-induced glycolysis and apoptosis regulator (TIGAR) and Cytochrome C Oxidase assembly protein 2 (SCO2), which are the key regulators of glycolysis and oxidative phosphorylation respectively, are under direct regulation of TCF19. Remarkably, TCF19 can form different transcription activation/repression complexes which show substantial overlap with that of p53, depending on glucose-mediated variant stress situations as obtained from IP/MS studies. Interestingly, we observed that TCF19/p53 complexes either have CBP or HDAC1 to epigenetically program the expression of TIGAR and SCO2 genes depending on short-term high glucose or prolonged high glucose conditions. TCF19 or p53 knockdown significantly altered the cellular lactate production and led to increased extracellular acidification rate. Similarly, OCR and cellular ATP production were reduced and mitochondrial membrane potential was compromised upon depletion of TCF19 or p53. Subsequently, through RNA-Seq analysis from patients with hepatocellular carcinoma, we observed that TCF19/p53-mediated metabolic regulation is fundamental for sustenance of cancer cells. Together the study proposes that TCF19/p53 complexes can regulate metabolic gene expression programs responsible for mitochondrial energy homeostasis and stress adaptation.

PARP-1 Regulates Estrogen-Dependent Gene Expression in Estrogen Receptor α-Positive Breast Cancer Cells.

Poly(ADP-ribose) polymerase-1 (PARP-1) has gained considerable attention as a target for therapeutic inhibitors in breast cancers. Previously we showed that PARP-1 localizes to active gene promoters to regulate histone methylation and RNA polymerase II activity (Pol II), altering the expression of various tumor-related genes. Here we report a role for PARP-1 in estrogen-dependent transcription in estrogen receptor alpha (ERα)-positive (ER+) breast cancers. Global nuclear run-on and sequencing analyses functionally linked PARP-1 to the direct control of estrogen-regulated gene expression in ER+ MCF-7 breast cancer cells by promoting transcriptional elongation by Pol II. Furthermore, chromatin immunoprecipitation sequencing analyses revealed that PARP-1 regulates the estrogen-dependent binding of ERα and FoxA1 to a subset of genomic ERα binding sites, promoting active enhancer formation. Moreover, we found that the expression levels of the PARP-1- and estrogen-coregulated gene set are enriched in the luminal subtype of breast cancer, and high PARP-1 expression in ER+ cases correlates with poor survival. Finally, treatment with a PARP inhibitor or a transcriptional elongation inhibitor attenuated estrogen-dependent growth of multiple ER+ breast cancer cell lines. Taken together, our results show that PARP-1 regulates critical molecular pathways that control the estrogen-dependent gene expression program underlying the proliferation of ER+ breast cancer cells. IMPLICATIONS: PARP-1 regulates the estrogen-dependent genomic binding of ERα and FoxA1 to regulate critical gene expression programs by RNA Pol II that underlie the proliferation of ER+ breast cancers, providing a potential therapeutic opportunity for PARP inhibitors in estrogen-responsive breast cancers.

Implications of Enhancer Transcription and eRNAs in Cancer.

Despite extensive progress in developing anticancer therapies, therapy resistance remains a major challenge that promotes disease relapse. The changes that lead to therapy resistance can be intrinsically present or may be initiated during treatment. Genetic and epigenetic heterogeneity in tumors make it more challenging to deal with therapy resistance. Recent advances in genome-wide analyses have revealed that the deregulation of distal gene regulatory elements, such as enhancers, appears in several pathophysiological conditions, including cancer. Beyond the conventional function of enhancers in recruiting transcription factors to gene promoters, enhancer elements are also transcribed into noncoding RNAs known as enhancer RNAs (eRNA). Accumulating evidence suggests that uncontrolled enhancer activity with aberrant eRNA expression promotes oncogenesis. Interestingly, tissue-specific, transcribed eRNAs from active enhancers can serve as potential therapeutic targets or biomarkers in several cancer types. This review provides a comprehensive overview of the mechanisms of enhancer transcription and eRNAs as well as their potential roles in cancer and drug resistance.

Suppression of poised oncogenes by ZMYND8 promotes chemo-sensitization.

The major challenge in chemotherapy lies in the gain of therapeutic resistance properties of cancer cells. The relatively small fraction of chemo-resistant cancer cells outgrows and are responsible for tumor relapse, with acquired invasiveness and stemness. We demonstrate that zinc-finger MYND type-8 (ZMYND8), a putative chromatin reader, suppresses stemness, drug resistance, and tumor-promoting genes, which are hallmarks of cancer. Reinstating ZMYND8 suppresses chemotherapeutic drug doxorubicin-induced tumorigenic potential (at a sublethal dose) and drug resistance, thereby resetting the transcriptional program of cells to the epithelial state. The ability of ZMYND8 to chemo-sensitize doxorubicin-treated metastatic breast cancer cells by downregulating tumor-associated genes was further confirmed by transcriptome analysis. Interestingly, we observed that ZMYND8 overexpression in doxorubicin-treated cells stimulated those involved in a good prognosis in breast cancer. Consistently, sensitizing the cancer cells with ZMYND8 followed by doxorubicin treatment led to tumor regression in vivo and revert back the phenotypes associated with drug resistance and stemness. Intriguingly, ZMYND8 modulates the bivalent or poised oncogenes through its association with KDM5C and EZH2, thereby chemo-sensitizing the cells to chemotherapy for better disease-free survival. Collectively, our findings indicate that poised chromatin is instrumental for the acquisition of chemo-resistance by cancer cells and propose ZMYND8 as a suitable epigenetic tool that can re-sensitize the chemo-refractory breast carcinoma.

The Interrelation of Neurological and Psychological Symptoms of COVID-19: Risks and Remedies.

COVID-19 has catastrophically affected the world's panoramic view of human well-being in terms of healthcare and management. With the increase in the number of cases worldwide, neurological symptoms and psychological illnesses from COVID-19 have increasingly upsurged. Mental health illness and affective disorders, including depression, obsessive-compulsive disorder, anxiety, phobia, and panic disorders, are highly impacted due to social distress. The COVID-19 pandemic not only affected people with pre-existing mental and affective illnesses, but also healthy individuals with anxiety, worrying, and panic symptoms, and fear conditioning. In addditon, the novel coronavirus is known to impact the central nervous system in the brain, resulting in severe and certain long-lasting neurological issues. Owing to the significance of neurological and psychological events, the present perspective has been an attempt to disseminate the impact of COVID-19 on neural injury through inflammation, and its interrelation with psychological symptoms. In this current review, we synthesize the literature to highlight the critical associations between SARS-CoV-2 infection and the nervous system, and mental health illness, and discuss potential mechanisms of neural injury through psycho-neuroimmunity.

Hypoxanthine Phosphoribosyl Transferase 1 Is Upregulated, Predicts Clinical Outcome and Controls Gene Expression in Breast Cancer.

Hypoxanthine phosphoribosyl transferase 1 (HPRT1) is traditionally believed to be a housekeeping gene; however, recent reports suggest that it is upregulated in several cancers and is associated with clinical outcomes. HPRT1 is located on chromosome X and encodes the HPRT enzyme, which functions in recycling nucleotides to supply for DNA and RNA synthesis in actively dividing cells. Here, we used transcriptomic analyses to interrogate its expression across all known cancer types and elucidated its role in regulating gene expression in breast cancer. We observed elevated HPRT1 RNA levels in malignant tissues when compared to normal controls, indicating its potential as a diagnostic and prognostic marker. Further, in breast cancer, the subtype-specific analysis showed that its expression was highest in basal and triple-negative breast cancer, and HPRT1 knockdown in breast cancer cells suggested that HPRT1 positively regulates genes related to cancer pathways. Collectively, our results essentially highlight the importance of and change the way in which HPRT1's function is studied in biology, warranting careful examination of its role in cancer.

Emerging Roles of Estrogen-Regulated Enhancer and Long Non-Coding RNAs.

Genome-wide RNA sequencing has shown that only a small fraction of the human genome is transcribed into protein-coding mRNAs. While once thought to be "junk" DNA, recent findings indicate that the rest of the genome encodes many types of non-coding RNA molecules with a myriad of functions still being determined. Among the non-coding RNAs, long non-coding RNAs (lncRNA) and enhancer RNAs (eRNA) are found to be most copious. While their exact biological functions and mechanisms of action are currently unknown, technologies such as next-generation RNA sequencing (RNA-seq) and global nuclear run-on sequencing (GRO-seq) have begun deciphering their expression patterns and biological significance. In addition to their identification, it has been shown that the expression of long non-coding RNAs and enhancer RNAs can vary due to spatial, temporal, developmental, or hormonal variations. In this review, we explore newly reported information on estrogen-regulated eRNAs and lncRNAs and their associated biological functions to help outline their markedly prominent roles in estrogen-dependent signaling.

Structure and expression of the long noncoding RNA gene MIR503 in humans and non-human primates.

Recent technical and other advances in genomics provide unique opportunities to improve our understanding of human physiology and disease predisposition through a detailed analysis of gene structure and expression by examining data in public genome and gene-expression repositories. Yet, the vast majority of human genes remain understudied. This is particularly true of genes for long noncoding RNAs (lncRNAs). Here, we describe the detailed characterization of MIR503HG, a lncRNA gene found on the X chromosome in humans. Using information extracted from public databases, we show that human MIR503HG is a 5-exon gene, and that it is highly conserved among 5 non-human primates spanning over 85 million years ago of evolutionary diversification. MIR503HG is transcribed and processed into multiple distinct RNAs in each of these species through differential exon use and alternative RNA splicing, with a higher abundance of transcripts being found in reproductive tissues, especially during the early stages of ovary and testis development, indicating a possible role in reproductive biology. Furthermore, in select reproductive system cancers, MIR503HG transcripts are downregulated, with higher levels of RNA expression being associated with clinical outcomes. Collectively, these investigations show how the use of genomic, gene expression, and other genetic resources can lead to new insights about human biology and disease, and argue that MIR503HG is worthy of additional study.