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Proteomics has revolutionized the field of cancer biology because the use of a large number of in vivo (SILAC), in vitro (iTRAQ, ICAT, TMT, stable-isotope Dimethyl, and 18 O) labeling techniques or label-free methods (spectral counting or peak intensities) coupled with mass spectrometry enables us to profile and identify dysregulated proteins in diseases such as cancer. These proteome and genome studies have led to many challenges, such as the lack of consistency or correlation between copy numbers, RNA, and protein-level data. This review covers solely mass spectrometry-based approaches used for cancer biomarker discovery. It also touches on the emerging role of oncoproteogenomics or proteogenomics in cancer biomarker discovery and how this new area is attracting the integration of genomics and proteomics areas to address some of the important questions to help impinge on the biology and pathophysiology of different malignancies to make these mass spectrometry-based studies more realistic and relevant to clinical settings., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

In women globally, breast cancer ranks as the second most frequent cause of cancer-related deaths, making up about 25% of female cancer cases, which is pretty standard in affluent countries. Breast cancer is divided into subtypes based on aggressive, genetic and stage. The precise cause of the problem is still unknown. However, the following significant risk factors have been found: sex, age, heredity, not having children, breastfeeding, elevated hormone levels, and personal lifestyle. The presence or lack of three nuclear receptors ER, PR, and HER2/ERBB2 (triple negative) and the amplification of the HER2/ErbB2 gene are the clinical criteria used to classify breast cancer. Chemotherapy is still the cornerstone of treatment for triple-negative breast cancer (TNBC), even. If, for the first two groups of patients,receptor-specific therapy is used. The most often prescribed chemotherapy agents for the treatment of breast cancer include doxorubicin (DOX), curcumin paclitaxel (PTX), docetaxel (DCX), thioridazine (THZ), disulfiram (DSF), and camptothecin (CPT). Monoclonal antibodies (mAbs) were used in antibody-drug conjugates (ADCs) to bind tumor-associated target antigens selectively and deliver very effective cytotoxic agents. According to recent research, synthetic derivatives effectively combat both MCF- 7 and breast cancer cell lines that are resistant to many drugs. This review provides a wealth of information on the mechanism of action of synthetic derivatives on multidrug-resistant cell lines. This review includes information about how synthetic derivatives affect cancer cells that have developed multidrug resistance during chemotherapy. These mechanisms have been linked to factors such as increased drug efflux, genetic factors, growth factors, increased DNA repair capacity, and elevated xenobiotic metabolism. Because of this, more research is necessary to learn more about the effectiveness of synthetic derivatives against breast cancer and cell lines that are resistant to several drugs. This review aims to find recent prospects of various types of cellular signaling pathways (JAK/STAT, Akt, MAPK, etc.) involved in the progression of breast cancer disorder, and we also study different synthetic and natural drugs that are applied for treating breast cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Epithelial-Mesenchymal Transition (EMT) is a fundamental biological process involved in embryonic development, wound healing, and cancer progression. In lung cancer, EMT is a key regulator of invasion and metastasis, significantly contributing to the fatal progression of the disease. Age-related factors such as cellular senescence, chronic inflammation, and epigenetic alterations exacerbate EMT, accelerating lung cancer development in the elderly. This review describes the complex mechanism among EMT and age-related pathways, highlighting key regulators such as TGF-β, WNT/β-catenin, NOTCH, and Hedgehog signalling. We also discuss the mechanisms by which oxidative stress, mediated through pathways involving NRF2 and ROS, telomere attrition, regulated by telomerase activity and shelterin complex, and immune system dysregulation, driven by alterations in cytokine profiles and immune cell senescence, upregulate or downregulate EMT induction. Additionally, we highlighted pathways of transcription such as SNAIL, TWIST, ZEB, SIRT1, TP53, NF-κB, and miRNAs regulating these processes. Understanding these mechanisms, we highlight potential therapeutic interventions targeting these critical molecules and pathways., Competing Interests: Declaration of Competing Interest MKK received consultant honoraria from the CBRS, Noida. Rest of the author declares no financial interests., (Copyright © 2024. Published by Elsevier B.V.)

The blood plays a vital role in the human body and serves as an intermediary between various physiological systems and organs. White blood cells, which are a part of the immune system, defend against infections and regulate the body temperature and pH balance. Blood platelets play a crucial role in clotting, the prevention of excessive bleeding, and the promotion of healing. Blood also serves as a courier system that transports hormones to facilitate communication and synchronization between different organs and systems in the body. The circulatory system, comprised of arteries, veins, and capillaries, plays a crucial role in the efficient transportation and connection of vital nutrients and oxygen. Despite the importance of natural blood, there are often supply shortages, compatibility issues, and medical conditions, which make alternatives such as artificial blood necessary. This is particularly relevant in cancer treatment, which was the focus of our study. In this study, we investigated the potential of artificial blood in cancer therapy, specifically to address tumor hypoxia. We also examined the potential of red blood cell substitutes such as hemoglobin-based oxygen carriers and perfluorocarbons. Additionally, we examined the production of hemoglobin using E. coli and the role of hemoglobin in oncogenesis. Furthermore, we explored the potential use of artificial platelets for cancer treatment. Our study emphasizes the significance of artificial blood in improving cancer treatment outcomes., Competing Interests: Declarations. Ethics approval: This study involves review of literature and analysis and does not involve directly or indirectly any patient sample, cell line, or even patients or normal subjects for participation in the study. Consent to participate: The study does not involve any human subjects, so ethical approval and consent to participate is not applicable. Consent for publication: All the authors agree to the content of the manuscript and have no conflict of interest for authorship. Competing interests: MKK has received consultant honoraria from the CBRS, Noida. The rest of the authors declare that they have no financial interests., (© 2024. International Federation for Medical and Biological Engineering.)

Splicing factor 3b subunit 1 (SF3B1) is the largest subunit and core component of the spliceosome. Inhibition of SF3B1 was associated with an increase in broad intron retention (IR) on most transcripts, suggesting that IR can be used as a marker of spliceosome inhibition in chronic lymphocytic leukemia (CLL) cells. Furthermore, we separately analyzed exonic and intronic mapped reads on annotated RNA-sequencing transcripts obtained from B cells ( n  = 98 CLL patients) and healthy volunteers ( n  = 9). We measured intron/exon ratio to use that as a surrogate for alternative RNA splicing (ARS) and found that 66% of CLL-B cell transcripts had significant IR elevation compared with normal B cells (NBCs) and that correlated with mRNA downregulation and low expression levels. Transcripts with the highest IR levels belonged to biological pathways associated with gene expression and RNA splicing. A >2-fold increase of active pSF3B1 was observed in CLL-B cells compared with NBCs. Additionally, when the CLL-B cells were treated with macrolides (pladienolide-B), a significant decrease in pSF3B1, but not total SF3B1 protein, was observed. These findings suggest that IR/ARS is increased in CLL, which is associated with SF3B1 phosphorylation and susceptibility to SF3B1 inhibitors. These data provide additional support to the relevance of ARS in carcinogenesis and evidence of pSF3B1 participation in this process., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Esophageal cancer (EC) ranks as the 8 th most aggressive malignancy, and its treatment remains challenging due to the lack of biomarkers facilitating early detection. EC manifests in two major histological forms - adenocarcinoma (EAD) and squamous cell carcinoma (ESCC) - both exhibiting variations in incidence across geographically distinct populations. High-throughput technologies are transforming the understanding of diseases, including cancer. A significant challenge for the scientific community is dealing with scattered data in the literature. To address this, a simple pipeline is proposed for the analysis of publicly available microarray datasets and the collection of differentially regulated molecules between cancer and normal conditions. The pipeline can serve as a standard approach for differential gene expression analysis, identifying genes differentially expressed between cancer and normal tissues or among different cancer subtypes. The pipeline involves several steps, including Data preprocessing (involving quality control and normalization of raw gene expression data to remove technical variations between samples), Differential expression analysis (identifying genes differentially expressed between two or more groups of samples using statistical tests such as t-tests, ANOVA, or linear models), Functional analysis (using bioinformatics tools to identify enriched biological pathways and functions in differentially expressed genes), and Validation (involving validation using independent datasets or experimental methods such as qPCR or immunohistochemistry). Using this pipeline, a collection of differentially expressed molecules (DEMs) can be generated for any type of cancer, including esophageal cancer. This compendium can be utilized to identify potential biomarkers and drug targets for cancer and enhance understanding of the molecular mechanisms underlying the disease. Additionally, population-specific screening of esophageal cancer using this pipeline will help identify specific drug targets for distinct populations, leading to personalized treatments for the disease.

Cardiotoxicity is a well-known adverse effect of cancer-related therapy that has a significant influence on patient outcomes and quality of life. The use of antineoplastic drugs to treat colorectal cancers (CRCs) is associated with a number of undesirable side effects including cardiac complications. For both sexes, CRC ranks second and accounts for four out of every ten cancer deaths. According to the reports, almost 39% of patients with colorectal cancer who underwent first-line chemotherapy suffered cardiovascular impairment. Although 5-fluorouracil is still the backbone of chemotherapy regimen for colorectal, gastric, and breast cancers, cardiotoxicity caused by 5-fluorouracil might affect anywhere from 1.5% to 18% of patients. The precise mechanisms underlying cardiotoxicity associated with CRC treatment are complex and may involve the modulation of various signaling pathways crucial for maintaining cardiac health including TKI ErbB2 or NRG-1, VEGF, PDGF, BRAF/Ras/Raf/MEK/ERK, and the PI3/ERK/AMPK/mTOR pathway, resulting in oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis, ultimately damaging cardiac tissue. Thus, the identification and management of cardiotoxicity associated with CRC drug therapy while minimizing the negative impact have become increasingly important. The purpose of this review is to catalog the potential cardiotoxicities caused by anticancer drugs and targeted therapy used to treat colorectal cancer as well as strategies focused on early diagnosing, prevention, and treatment of cardiotoxicity associated with anticancer drugs used in CRC therapy.

Drug development from herbal medicines or botanical sources is believed to have a prominent role in the exploration of novel counteractive drugs that has sparked much interest in recent times. Paederia foetida is one such medicinal plant used in both traditional and folkloric medicine. Several parts of the herb are locally utilised as a natural curative agent for several ailments since time immemorial. Paederia foetida indeed possesses anti-diabetic, anti-hyperlipidaemic, antioxidant, nephro-protective, anti-inflammatory, antinociceptive, antitussive, thrombolytic, anti-diarrhoeal, sedative-anxiolytic, anti-ulcer, hepatoprotective activity, anthelmintic and anti-diarrhoeal activity. Furthermore, growing evidence shows many of its active constituents to be effective in cancer, inflammatory diseases, wound healing and spermatogenesis as well. These investigations shed light on possible pharmacological targets and attempts to establish a mechanism of action for these pharmacological effects. These findings contrast the significance of this medicinal plant for further research and for the exploration of novel counteractive drugs to establish a mechanism of action before being employed to healthcare. Pharmacological activities of Paederia foetida and their mechanism of action., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The COVID-19 pandemic has changed many aspects of people's lives, including not only individual social behavior, healthcare procedures, and altered physiological and pathophysiological responses. As a result, some medical studies may be influenced by one or more hidden factors brought about by the COVID-19 pandemic. Using the literature review method, we are briefly discussing the studies that are confounded by COVID-19 and facemask-induced partiality and how these factors can be further complicated with other confounding variables. Facemask wearing has been reported to produce partiality in studies of ophthalmology (particularly dry eye and related ocular diseases), sleep studies, cognitive studies (such as emotion-recognition accuracy research, etc.), and gender-influenced studies, to mention a few. There is a possibility that some other COVID-19 related influences remain unrecognized in medical research. To account for heterogeneity, current and future studies need to consider the severity of the initial illness (such as diabetes, other endocrine disorders), and COVID-19 infection, the timing of analysis, or the presence of a control group. Face mask-induced influences may confound the results of diabetes studies in many ways., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Circular RNAs (circRNAs) are regulatory elements that are involved in orchestrating gene expression and protein functions and are implicated in various biological processes including cancer. Notably, breast cancer has a significant mortality rate and is one of the most common malignancies in women. CircRNAs have been demonstrated to contribute to the pathogenesis of breast cancer including its initiation, progression, metastasis, and resistance to drugs. By acting as miRNA sponges, circRNAs can indirectly influence gene expression by disrupting miRNA regulation of their target genes, ultimately altering the course of cancer development and progression. Additionally, circRNAs can interact with proteins and modulate their functions including signaling pathways involved in the initiation and development of cancer. Recently, circRNAs can encode peptides that play a role in the pathophysiology of breast cancer and other diseases and their potential as diagnostic biomarkers and therapeutic targets for various cancers including breast cancer. CircRNAs possess biomarkers that differentiate, such as stability, specificity, and sensitivity, and can be detected in several biological specimens such as blood, saliva, and urine. Moreover, circRNAs play an important role in various cellular processes including cell proliferation, differentiation, and apoptosis, all of which are integral factors in the development and progression of cancer. This review synthesizes the functions of circRNAs in breast cancer, scrutinizing their contributions to the onset and evolution of the disease through their interactions with exosomes and cancer-related intracellular pathways. It also delves into the potential use of circRNA as a biomarker and therapeutic target against breast cancer. It discusses various databases and online tools that offer crucial circRNA information and regulatory networks. Lastly, the challenges and prospects of utilizing circRNAs in clinical settings associated with breast cancer are explored., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

In recent years, drug manufacturers and researchers have begun to consider the nanobiotechnology approach to improve the drug delivery system for tumour and cancer diseases. In this article, we review current strategies to improve tumour and cancer drug delivery, which mainly focuses on sustaining biocompatibility, biodistribution, and active targeting. The conventional therapy using cornerstone drugs such as fludarabine, cisplatin etoposide, and paclitaxel has its own challenges especially not being able to discriminate between tumour versus normal cells which eventually led to toxicity and side effects in the patients. In contrast to the conventional approach, nanoparticle-based drug delivery provides target-specific delivery and controlled release of the drug, which provides a better therapeutic window for treatment options by focusing on the eradication of diseased cells via active targeting and sparing normal cells via passive targeting. Additionally, treatment of tumours associated with the brain is hampered by the impermeability of the blood-brain barriers to the drugs, which eventually led to poor survival in the patients. Nanoparticle-based therapy offers superior delivery of drugs to the target by breaching the blood-brain barriers. Herein, we provide an overview of the properties of nanoparticles that are crucial for nanotechnology applications. We address the potential future applications of nanobiotechnology targeting specific or desired areas. In particular, the use of nanomaterials, biostructures, and drug delivery methods for the targeted treatment of tumours and cancer are explored., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Purpose: The COVID-19 pandemic has drastically disrupted global healthcare systems. With the higher demand for healthcare and misinformation related to COVID-19, there is a need to explore alternative models to improve communication. Artificial Intelligence (AI) and Natural Language Processing (NLP) have emerged as promising solutions to improve healthcare delivery. Chatbots could fill a pivotal role in the dissemination and easy accessibility of accurate information in a pandemic. In this study, we developed a multi-lingual NLP-based AI chatbot, DR-COVID, which responds accurately to open-ended, COVID-19 related questions. This was used to facilitate pandemic education and healthcare delivery., Methods: First, we developed DR-COVID with an ensemble NLP model on the Telegram platform (https://t.me/drcovid_nlp_chatbot). Second, we evaluated various performance metrics. Third, we evaluated multi-lingual text-to-text translation to Chinese, Malay, Tamil, Filipino, Thai, Japanese, French, Spanish, and Portuguese. We utilized 2,728 training questions and 821 test questions in English. Primary outcome measurements were (A) overall and top 3 accuracies; (B) Area Under the Curve (AUC), precision, recall, and F1 score. Overall accuracy referred to a correct response for the top answer, whereas top 3 accuracy referred to an appropriate response for any one answer amongst the top 3 answers. AUC and its relevant matrices were obtained from the Receiver Operation Characteristics (ROC) curve. Secondary outcomes were (A) multi-lingual accuracy; (B) comparison to enterprise-grade chatbot systems. The sharing of training and testing datasets on an open-source platform will also contribute to existing data., Results: Our NLP model, utilizing the ensemble architecture, achieved overall and top 3 accuracies of 0.838 [95% confidence interval (CI): 0.826-0.851] and 0.922 [95% CI: 0.913-0.932] respectively. For overall and top 3 results, AUC scores of 0.917 [95% CI: 0.911-0.925] and 0.960 [95% CI: 0.955-0.964] were achieved respectively. We achieved multi-linguicism with nine non-English languages, with Portuguese performing the best overall at 0.900. Lastly, DR-COVID generated answers more accurately and quickly than other chatbots, within 1.12-2.15 s across three devices tested., Conclusion: DR-COVID is a clinically effective NLP-based conversational AI chatbot, and a promising solution for healthcare delivery in the pandemic era., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yang, Ng, Lei, Tan, Wang, Yan, Pargi, Zhang, Lim, Gunasekeran, Tan, Lee, Yeo, Tan, Ho, Tan, Wong, Kwek, Goh, Liu and Ting.)

In underdeveloped nations, colorectal carcinogenesis (CRC) is a significant health issue. It is the third most common outcome of cancer death. Despite a variety of therapy options, new medications are needed to lessen the severity of this condition. In the colon, adenomatous polyps are the most common cause of CRC, occurring in 45 percent of cases, particularly in patients over 60 years old. Inflammatory polyps are acquiring popularity in CRC, as well as inflammation appears to exert a function in the disease, according to mounting research. The azoxymethane, dimethyl hydrazine, APC min/+ mouse model, and a combination of sulfated polysaccharides composed of dextran and sulfated and dimethylhydrazine are among the experimental models used to study CRC in animals. Numerous signal transduction pathways are engaged as CRC progresses. The p53, TGF-β, Delta-Notch, Salvador-Warts-Hippo (SWH), and Kelch-like ECH associated protein 1 pathways are among the key signal transduction pathways. To decide cell destiny, several signalling pathways work in tandem with the death of cell modalities, such as autophagy, necroptosis, and apoptosis. In our lab, we have spent a lot of time looking into the cell signalling and mechanisms of cell death in CRC. The pathogenesis of CRC, as well as the associated cell death and cell signalling pathways, are summarised in this study., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Multiple myeloma (MM) is the 2nd most frequently diagnosed blood cancer after non-Hodgkin's lymphoma. The present study aimed to identify the differentially expressed genes (DEGs) between the control and pristimerin-treated MM cell lines. We examined the GSE14011 microarray dataset and screened DEGs with GEO2R statistical tool using the inbuilt limma package. We used a bioinformatics pipeline to identify the differential networks, signaling cascades, and the survival of the hub genes. We implemented two different enrichment analysis including ClueGO and Metacore™, to get accurate annotation for most significant DEGs. We screened the most significant 408 DEGs from the dataset based on p-values and logFC values. Using protein network analysis, we found the genes UBC, HSP90AB1, HSPH1, HSPA1B, HSPA1L, HSPA6, HSPD1, DNAJB1, HSPE1, DNAJC10, BAG3, and DNAJC7 had higher node degree distribution. In contrast, the functional annotation provided that the DEGs were predominantly enriched in B-cell receptor signaling, unfolded protein response, positive regulation of phagocytosis, HSP70, and HSP40-dependent folding, and ubiquitin-proteasomal proteolysis. Using network algorithms, and comparing enrichment analysis, we found the hub genes enriched were INHBE, UBC, HSPA1A, HSP90AB1, IKBKB, and BAG3. These DEGs were further validated with overall survival and gene expression analysis between the tumor and control groups. Finally, pristimerin effects were validated independently in a cell line model consisting of IM9 and U266 MM cells. Pristimerin induced in vitro cytotoxicity in MM cells in a dose-dependent manner. Pristimerin inhibited NF-κB, induced accumulation of ubiquitinated proteins and inhibited HSP60 in the validation of bioinformatics findings, while pristimerin-induced caspase-3 and PARP cleavage confirmed cell death. Taken together, we found that the identified DEGs were strongly associated with the apoptosis induced in MM cell lines due to pristimerin treatment, and combinatorial therapy derived from pristimerin could act as novel anti-myeloma multifunctional agents., (Copyright © 2023. Published by Elsevier Inc.)

Ovarian cancer is characterized by the establishment of tolerance, the recurrence of disease, as well as a poor prognosis. Gene signatures in ovarian cancer cells enable cancer medicine research, therapy, prevention, & management problematic. Notwithstanding advances in tumor puncture surgery, novel combinations regimens, and abdominal radiation, which can provide outstanding reaction times, the bulk of gynecological tumor patients suffer from side effects & relapse. As a consequence, more therapy alternatives for individuals with ovarian cancer must always be studied to minimize side effects and improve progression-free and total response rates. The development of cancer medications is presently undergoing a renaissance in the quest for descriptive and prognostic ovarian cancer biomarkers. Nevertheless, abnormalities in the BRCA2 or BRCA1 genes, a variety of hereditary predispositions, unexplained onset and progression, molecular tumor diversity, and illness staging can all compromise the responsiveness and accuracy of such indicators. As a result, current ovarian cancer treatments must be supplemented with broad-spectrum & customized targeted therapeutic approaches. The objective of this review is to highlight recent contributions to the knowledge of the interrelations between selected ovarian tumor markers, various perception signs, and biochemical and molecular signaling processes, as well as one's interpretation of much more targeted and effective treatment interventions., Competing Interests: The authors declare no potential conflicts of interest concerning the research, authorship, and/or publication of this article., (Thieme. All rights reserved.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Pancreatic cancer is one of the most difficult cancers to detect early and most patients die from complications arising due to distant organ metastases. The lack of bona fide early biomarkers is one of the primary reasons for late diagnosis of pancreatic cancer. It is a multifactorial disease and warrants a novel approach to identify early biomarkers., Methods: In order to characterize the proteome, Extracellular vesicles (EVs) isolated from different in vitro conditions mimicking tumor-microenvironment interactions between pancreatic cancer epithelial and stromal cells were analyzed using high throughput mass spectrometry. The biological activity of the secreted EVome was analyzed by investigating changes in distant organ metastases and associated early changes in the microbiome. Candidate biomarkers (KIF5B, SFRP2, LOXL2, and MMP3) were selected and validated on a mouse-human hybrid Tissue Microarray (TMA) that was specifically generated for this study. Additionally, a human TMA was used to analyze the expression of KIF5B and SFRP2 in progressive stages of pancreatic cancer., Results: The EVome of co-cultured epithelial and stromal cells is different from individual cells with distinct protein compositions. EVs secreted from stromal and cancer cells cultures could not induce significant changes in Pre-Metastatic Niche (PMN) modulation, which was assessed by changes in the distant organ metastases. However, they did induce significant changes in the early microbiome, as indicated by differences in α and β-diversities. KIF5B and SFRP2 show promise for early detection and investigation in progressive pancreatic cancer. These markers are expressed in all stages of pancreatic cancer such as low grade PanINs, advanced cancer, and in liver and soft tissue metastases., Conclusions: Proteomic characterization of EVs derived from mimicking conditions of epithelial and stromal cells in the tumor-microenvironment resulted in the identification of several proteins, some for the first time in EVs. These secreted EVs cannot induce changes in distant organ metastases in in vivo models of EV education, but modulate changes in the early murine microbiome. Among all the proteins that were analyzed (MMP3, KIF5B, SFRP2, and LOXL2), KIF5B and SFRP2 show promise as bona fide early pancreatic cancer biomarkers expressed in progressive stages of pancreatic cancer., (© 2022. The Author(s).)

RNA splicing is the fundamental process that brings diversity at the transcriptome and proteome levels. The spliceosome complex regulates minor and major processes of RNA splicing. Aberrant regulation is often associated with different diseases, including diabetes, stroke, hypertension, and cancer. In the majority of cancers, dysregulated alternative RNA splicing (ARS) events directly affect tumor progression, invasiveness, and often lead to poor survival of the patients. Alike the rest of the gastrointestinal malignancies, in hepatocellular carcinoma (HCC), which alone contributes to ~ 75% of the liver cancers, a large number of ARS events have been observed, including intron retention, exon skipping, presence of alternative 3'-splice site (3'SS), and alternative 5'-splice site (5'SS). These events are reported in spliceosome and non-spliceosome complexes genes. Molecules such as MCL1, Bcl-X, and BCL2 in different isoforms can behave as anti-apoptotic or pro-apoptotic, making the spliceosome complex a dual-edged sword. The anti-apoptotic isoforms of such molecules bring in resistance to chemotherapy or cornerstone drugs. However, in contrast, multiple malignant tumors, including HCC that target the pro-apoptotic favoring isoforms/variants favor apoptotic induction and make chemotherapy effective. Herein, we discuss different splicing events, aberrations, and antisense oligonucleotides (ASOs) in modulating RNA splicing in HCC tumorigenesis with a possible therapeutic outcome., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The microbiota has been associated with different cancer and may vary from patient to patient. A specific microbial strain can alter the progression of cancer and therapeutic outcome in response to anti-cancer therapy. The variations in microbiota contributed due to the individual microbiome of the microorganism are responsible for diverse clinical outcomes. The expansion of microbiota subpopulation during dysbiosis can lead to toxin production, inducing inflammation and cancer. The microbiota can be a dual-edged sword because it can be tumor-suppressive or oncogenic in the case of the gut. The transition of cancer cells from early to late-stage also impacts the composition of the microbiota, and this alteration could change the behavior of cancer. Multi-omics platforms derived data from an individual's multi-dimensional data (DNA, mRNA, microRNA, protein, metabolite, microbiota, and microbiome), i.e., individualome, to exploit it for personalized tailored treatment for different cancers in a precise manner. A number of studies suggest the importance of microbiota and its add-in suitability to existing treatment options for different malignancies. Furthermore, in vitro, and in vivo studies and cancer clinical trials suggest that probiotics have driven modulation of gut microbiota and other sites discourage the aggressive behavior and progression of different cancers., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Since the identification of the genomic sequence of SARS-CoV-2, an unprecedented effort is being made until this date for the development of a safe and effective vaccine by pharma companies and laboratories worldwide. To attain herd immunity and quite possibly recover from this pandemic, which has claimed the life of about 4.23 million people, an exceptional effort has been made by the scientific community for the development of a vaccine. Various vaccines have been developed based on different platforms and each of them seems to possess its own merits and demerits based on its safety, immunogenicity, the durability of immunity, dosing schedule, technological platform, and ease of manufacture and transport. Based on these parameters this review aims to critically assess the efficacy of Covaxin and compare it with other vaccines in the WHO EUL list and perform a comparative analysis of COVID-19 vaccines which are in phase 3 and phase 4 of clinical trials. This will help us determine where COVAXIN stands against other vaccines and vaccine candidates based on these parameters which will ultimately help us determine the best vaccine that could potentially eradicate the COVID-19 pandemic., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Alterations in RNA splicing are associated with different malignancies, including leukemia, lymphoma, and solid tumors. The RNA splicing modulators such as FD-895 and pladienolide B have been investigated in different malignancies to target/modulate spliceosome for therapeutic purpose. Different cell lines were screened using an RNA splicing modulator to test in vitro cytotoxicity and the ability to modulate RNA splicing capability via induction of intron retention (using RT-PCR and qPCR). The Cignal Finder Reporter Array evaluated [pathways affected by the splice modulators in HeLa cells. Further, the candidates associated with the pathways were validated at protein level using western blot assay, and gene-gene interaction studies were carried out using GeneMANIA. We show that FD-895 and pladienolide B induces higher apoptosis levels than conventional chemotherapy in different solid tumors. In addition, both agents modulate Wnt signaling pathways and mRNA splicing. Specifically, FD-895 and pladienolide B significantly downregulates Wnt signaling pathway-associated transcripts (GSK3β and LRP5) and both transcript and proteins including LEF1, CCND1, LRP6, and pLRP6 at the transcript, total protein, and protein phosphorylation's levels. These results indicate FD-895 and pladienolide B inhibit Wnt signaling by decreasing LRP6 phosphorylation and modulating mRNA splicing through induction of intron retention in solid tumors.

MN/CA9 is a cell surface glycoprotein and a tumor-associated antigen. It plays a crucial role in the regulation of cell proliferation and oncogenesis. There is no ideal tumor marker currently available for renal cell carcinoma (RCC) with sufficient sensitivity and specificity. Therefore, we studied MN/CA9 gene expression in the tumor tissue, apparently normal kidney tissue, preoperative blood, and urine samples of patients with RCC. We included thirty cases of renal tumors (26 RCC and 4 benign tumors) in the study. We applied an RT-PCR assay for MN/CA9 gene expression to 26 RCC kidney tumor samples and four benign kidney tumor tissue samples. We also evaluated MN/CA9 gene expression in preoperative blood and urine samples of 15 of these cases. Additionally, thirty-five grossly normal renal tissue samples, including 21 from kidneys with RCC, were also evaluated for gene expression. The RT-PCR analysis revealed that twenty-one out of 26 RCC tissue samples showed MN/CA9 gene expression compared to three out of 35 non-malignant renal tissue samples (p < 0.05). Two out of four benign renal tissue samples also expressed this gene. We also observed MN/CA9 gene expression in nine out of 15 blood samples and four out of 15 urine samples. All patients with urinary MN/CA9 gene expression showed expression in blood and tumor tissue samples. We found a correlation in terms of MN/CA9 expression between blood and tumor tissue samples of RCC patients as those who exhibit MN/CA9 expression in blood were also positive at the tumor tissue levels. The difference in MN/CA9 gene expression in tumor tissue, blood, and urine samples in relation to the stage of the disease, nuclear grade, and histological cell-type was not statistically significant. However, all the three patients who had metastatic RCC had MN/CA9 gene expression in their blood. The existence of a tumor-associated antigen such as MN/CA9 may present a possible target for molecular diagnosis and management of RCC., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Esophageal squamous cell carcinoma (ESCC) remains a serious concern globally due to many factors that including late diagnosis, lack of an ideal biomarker for diagnosis and prognosis, and high rate of mortality. In this study, we aimed to identify the essential dysregulated genes and molecular signatures associated with the progression and development of ESCC. The dataset with 15 ESCCs and the 15 adjacent normal tissue samples from the surrounding histopathologically tumor-free mucosa was selected. We applied bioinformatics pipelines including various topological parameters from MCODE, CytoNCA, and cytoHubba to prioritize the most significantly associated DEGs with ESCC. We performed functional enrichment annotation for the identified DEGs using DAVID and MetaCore™ GeneGo platforms. Furthermore, we validated the essential core genes in TCGA and GTEx datasets between the normal mucosa and ESCC for their expression levels. These DEGs were primarily enriched in positive regulation of transferase activity, negative regulation of organelle organization, cell cycle mitosis/S-phase transition, spindle organization/assembly, development, and regulation of angiogenesis. Subsequently, the DEGs were associated with the pathways such as oocyte meiosis, cell cycle, and DNA replication. Our study identified the eight-core genes (AURKA, AURKB, MCM2, CDC20, TPX2, PLK1, FOXM1, and MCM7) that are highly expressed among the ESCC, and TCGA dataset. The multigene comparison and principal component analysis resulted in elevated signals for the AURKA, MCM2, CDC20, TPX2, PLK1, and FOXM1. Overall, our study reported GO profiles and molecular signatures that might help researchers to grasp the pathological mechanisms underlying ESCC development and eventually provide novel therapeutic and diagnostic strategies., Competing Interests: Conflict of interest The authors have declared that no conflicts of interest exist., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Human SARS Coronavirus-2 (SARS-CoV-2) has infected more than 170 million people worldwide and resulted in more than 3.5 million deaths so far. The infection causes Coronavirus disease (COVID-19) in people of all age groups, notably diabetic and old age people, at a higher risk of infectivity and fatality. Around 35% of the patients who have died of the disease were diabetic. The infection is associated with weakening immune response, chronic inflammation, and potential direct pancreatic impairment. There seems to be a three-way association of the SARS-CoV-2 infection with diabetes and aging. The COVID-19 infection causes metabolism complications, which may induce diabetes and accelerate aging in healthy individuals. How does diabetes elevate the likelihood of the infection is not clearly understood. we summarize mechanisms of accelerated aging in COVID-19 and diabetes, and the possible correlation of these three diseases. Various drug candidates under different stages of pre-clinical or clinical developments give us hope for the development of COVID-19 therapeutics, but there is no approved drug so far to treat this disease. Here, we explored the potential of anti-diabetic and anti-aging natural compounds for the COVID-19 treatment. We have also reviewed different therapeutic strategies with plant-based natural products that may be used to cure patients infected with SARS-CoV-2 and post-infection syndrome., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Habitability has been generally defined as the capability of an environment to support life. Ecologists have been using Habitat Suitability Models (HSMs) for more than four decades to study the habitability of Earth from local to global scales. Astrobiologists have been proposing different habitability models for some time, with little integration and consistency among them, being different in function to those used by ecologists. Habitability models are not only used to determine whether environments are habitable, but they also are used to characterize what key factors are responsible for the gradual transition from low to high habitability states. Here we review and compare some of the different models used by ecologists and astrobiologists and suggest how they could be integrated into new habitability standards. Such standards will help improve the comparison and characterization of potentially habitable environments, prioritize target selections, and study correlations between habitability and biosignatures. Habitability models are the foundation of planetary habitability science, and the synergy between ecologists and astrobiologists is necessary to expand our understanding of the habitability of Earth, the Solar System, and extrasolar planets.

Reversion of tumor to a normal differentiated cell once considered a dream is now at the brink of becoming a reality. Different layers of molecules/events such as microRNAs, transcription factors, alternative RNA splicing, post-transcriptional, post-translational modifications, availability of proteomics, genomics editing tools, and chemical biology approaches gave hope to manipulation of cancer cells reversion to a normal cell phenotype as evidences are subtle but definitive. Regardless of the advancement, there is a long way to go, as customized techniques are required to be fine-tuned with precision to attain more insights into tumor reversion. Tumor regression models using available genome-editing methods, followed by in vitro and in vivo proteomics profiling techniques show early evidence. This review summarizes tumor reversion developments, present issues, and unaddressed challenges that remained in the uncharted territory to modulate cellular machinery for tumor reversion towards therapeutic purposes successfully. Ongoing research reaffirms the potential promises of understanding the mechanism of tumor reversion and required refinement that is warranted in vitro and in vivo models of tumor reversion, and the potential translation of these into cancer therapy. Furthermore, therapeutic compounds were reported to induce phenotypic changes in cancer cells into normal cells, which will contribute in understanding the mechanism of tumor reversion. Altogether, the efforts collectively suggest that tumor reversion will likely reveal a new wave of therapeutic discoveries that will significantly impact clinical practice in cancer therapy.

Since the first case reports in Wuhan, China, the SARS-CoV-2 has caused a pandemic and took lives of > 8,35,000 people globally. This single-stranded RNA virus uses Angiotensin-converting enzyme 2 (ACE2) as a receptor for entry into the host cell. Overexpression of ACE2 is mainly observed in hypertensive, diabetic and heart patients that make them prone to SARS-CoV-2 infection. Mitigations strategies were opted globally by the governments to minimize transmission of SARS-CoV-2 via the implementation of social distancing norms, wearing the facemasks, and spreading awareness using digital platforms. The lack of an approved drug treatment regimen, and non-availability of a vaccine, collectively posed a challenge for mankind to fight against the SARS-CoV-2 pandemic. In this scenario, repurposing of existing drugs and old treatment options like convalescent plasma therapy can be one of the potential alternatives to treat the disease. The drug repurposing provides a selection of drugs based on the scientific rationale and with a shorter cycle of clinical trials, while plasma isolated from COVID-19 recovered patients can be a good source of neutralizing antibody to provide passive immunity. In this review, we provide in-depth analysis on these two approaches currently opted all around the world to treat COVID-19 patients. For this, we used "Boolean Operators" such as AND, OR & NOT to search relevant research articles/reviews from the PUBMED for the repurposed drugs and the convalescent plasma in the COVID-19 treatment. The repurposed drugs like Chloroquine and Hydroxychloroquine, Tenofovir, Remdesivir, Ribavirin, Darunavir, Oseltamivir, Arbidol (Umifenovir), Favipiravir, Anakinra, and Baricitinib are already being used in clinical trials to treat the COVID-19 patients. These drugs have been approved for a different indication and belong to a diverse category such as anti-malarial/anti-parasitic, anti-retroviral/anti-viral, anti-cancer, or against rheumatoid arthritis. Although, the vaccine would be an ideal option for providing active immunity against the SARS-CoV-2, but considering the current situation, drug repurposing and convalescent plasma therapy and repurposed drugs are the most viable option against SARS-CoV-2.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of cancers. Collectively, HNSCC ranks sixth in incidence rate worldwide. Apart from classical risk factors like tobacco and alcohol, infection of human papillomavirus (HPV) is emerging as a discrete risk factor for HNSCC. HPV-positive HNSCC represent a distinct group of diseases that differ in their clinical presentation. These lesions are well-differentiated, occur at an early age, and have better prognosis. Epidemiological studies have demonstrated a specific increase in the proportions of the HPV-positive HNSCC. HPV-positive and HPV-negative HNSCC lesions display different disease progression and clinical response. For tumorigenic-transformation, HPV essentially requires a permissive cellular environment and host cell factors for induction of viral transcription. As the spectrum of host factors is independent of HPV infection at the time of viral entry, presumably entry of HPV only selects host cells that are permissive to establishment of HPV infection. Growing evidence suggest that HPV plays a more active role in a subset of HNSCC, where they are transcriptionally-active. A variety of factors provide a favorable environment for HPV to become transcriptionally-active. The most notable are the set of transcription factors that have direct binding sites on the viral genome. As HPV does not have its own transcription machinery, it is fully dependent on host transcription factors to complete the life cycle. Here, we review and evaluate the current evidence on level of a subset of host transcription factors that influence viral genome, directly or indirectly, in HNSCC. Since many of these transcription factors can independently promote carcinogenesis, the composition of HPV permissive transcription factors in a tumor can serve as a surrogate marker of a separate molecularly-distinct class of HNSCC lesions including those cases, where HPV could not get a chance to infect but may manifest better prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Aggarwal, Yadav, Thakur, Bibban, Chhokar, Tripathi, Bhat, Singh, Jadli, Singh, Kashyap and Bharti.)

As a newly exfoliated magnetic 2D material from hematite, hematene is the most far-reaching ultrathin magnetic indirect bandgap semiconductor. We have carried out a detailed structural analysis of hematene via prefacing strain by means of first-principles calculations based on density functional theory (DFT). Hematene in the pristine form emerges out to be a magnetic semiconductor with a bandgap of 1.0/2.0 eV for the majority/minority spin channel. The dependence of magnetic anisotropy energy (MAE), T C , and the bandgap on compressive and tensile strains has been scanned exclusively. It is examined that T C depends firmly on the compressive strain and increases up to 21.1% at a compressive strain of 6% whereas it decreases significantly for tensile strain. The MAE is negatively correlated with the tensile and compressive strain. The value of MAE for all compressive strain cases is more than that of the pristine hematene. These results summarize that the studied 2D hematene has broad application prospects in spintronics, memory-based devices, and valleytronics., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The search for different life forms elsewhere in the universe is a fascinating area of research in astrophysics and astrobiology. Currently, according to the NASA Exoplanet Archive database, 3876 exoplanets have been discovered. The Earth Similarity Index (ESI) is defined as the geometric mean of radius, density, escape velocity, and surface temperature and ranges from 0 (dissimilar to Earth) to 1 (similar to Earth). The ESI was created to index exoplanets on the basis of their similarity to Earth. In this paper, we examined rocky exoplanets whose physical conditions are potentially suitable for the survival of rock-dependent extremophiles, such as the cyanobacteria Chroococcidiopsis and the lichen Acarospora. The Rock Similarity Index (RSI) is first introduced and then applied to 1659 rocky exoplanets. The RSI represents a measure for Earth-like planets on which physical conditions are potentially suitable for rocky extremophiles that can survive in Earth-like extreme habitats (i.e., hot deserts and cold, frozen lands)., Competing Interests: The authors declare no conflict of interest. The parties who funded this study had no role in its design, in the collection, analyses, or interpretation of the data, or in the writing of the manuscript and the decision to publish the results.

We investigated the U-Ni-B and Nb-Ni-B systems to search for possible new heavy fermion compounds and superconducting materials. The formation, crystal chemistry, and physical properties of U 2 Ni 21 B 6 and Nb 3- y Ni 20+ y B 6 [ternary derivatives of the cubic Cr 23 C 6 -type ( cF 116, Fm 3̅ m )] have been studied; the formation of the hypothetical "U 3 Ni 20 B 6 " and "Nb 2 Ni 21 B 6 " has been disproved. U 2 Ni 21 B 6 [ a = 10.6701(2) Å] crystallizes in the ordered W 2 Cr 21 C 6 -type, whereas Nb 3- y Ni 20+ y B 6 [ a = 10.5842(1) Å] adopts the Mg 3 Ni 20 B 6 -type. Ni in U 2 Ni 21 B 6 can be substituted by U, leading to the solid solution U 2+ x Ni 21- x B 6 (0 ≤ x ≤ 0.3); oppositely, Nb in Nb 3 Ni 20 B 6 is partially replaced by Ni, forming the solution Nb 3- y Ni 20+ y B 6 (0 ≤ y ≤ 0.5), none of them reaching the limit corresponding to the hypothetically ordered "U 3 Ni 20 B 6 " and "Nb 2 Ni 21 B 6 ". These results prompted us to investigate quaternary compounds U 2- z Nb z Ni 21 B 6 and U δ Nb 3-δ Ni 20 B 6 : strong competition in the occupancy of the 4 a and 8 c sites by U, Nb, and Ni atoms has been observed, with the 4 a site occupied by U/Ni atoms only and the 8 c site filled by U/Nb atoms only. U 2 Ni 21 B 6 , U 2.3 Ni 20.7 B 6 , and Nb 3 Ni 20 B 6 are Pauli paramagnets. Interestingly, Nb 2.5 Ni 20.5 B 6 shows ferromagnetism with T C ≈ 11 K; the Curie-Weiss fit gives an effective magnetic moment of 2.78 μ B /Ni, suggesting that all Ni atoms in the formula unit contribute to the total magnetic moment. The M ( H ) data at 2 K further corroborate the ferromagnetic behavior with a saturation moment of 10 μ B /fu (≈0.49 μ B /Ni). The magnetic moment of Ni at the 4 a site induces a moment in all of the Ni atoms of the whole unit cell (32 f and 48 h sites), with all atoms ordering ferromagnetically at 11 K. Density functional theory (DFT) shows that the formation of U 2 Ni 21 B 6 and Nb 3 Ni 20 B 6 is energetically preferred. The various electronic states generating ferromagnetism on Nb 2.5 Ni 20.5 B 6 and Pauli paramagnetism on U 2 Ni 21 B 6 and Nb 3 Ni 20 B 6 have been identified.

The renin-angiotensin system (RAS) plays a central role in the regulation of homeostasis and blood pressure. This involves an important enzyme called angiotensin-converting enzyme that leads to the conversion of angiotensin I into angiotensin II. RAS has been reported to show association with inflammation, and in sporadic studies, with cancer. In particular, angiotensin II has been reported to be prevalent in the hypoxic microenvironment and associated with cancer signaling pathways. In a recent study, Bratlie et al. (Proteomics Clin. Appl. 2019, 4, 1800102) is shown to exploit 2D gel electrophoresis, and mass spectrometry (MS) to identify differentially expressed proteins by comparing low-grade dysplasia in Barrett's Esophagus (BE) following administration of agents that interfere with RAS, that is, enalapril and candesartan, and identified specific modulation of HSP60, PDIA3, and PPA1. Though 2D gel coupled with MS is a commonly-used tool for studying proteomes, it still has limitations in terms of a comprehensive analysis due to lack of absolute quantitation in a high-throughput manner. Despite technical limitations and the small size of the study, preliminary data emerging from the investigation show interference caused by clinically approved RAS inhibitors resulting in alteration of molecular markers associated with tumorigenicity. The authors propose potential factors that may influence the progression of the disease. However, these are conspicuous changes in high-abundance proteins only. Therefore, there is a need to carry out detailed experimental studies either using an in vitro labeling technique (isobaric labeling for relative and absolute quantitation) for tissues or an in vivo labeling technique (stable isotope labeling in animal cell culture) coupled with LC-MS/MS to identify differentially-regulated proteins to delineate the role of RAS in BE., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Finding life on other worlds is a fascinating area of astrobiology and planetary sciences. Presently, over 3800 exoplanets, representing a very wide range of physical and chemical environments, are known. Scientists are not only looking for traces of life outside Earth, but they are also trying to find out which of Earth's known organisms (ex: tardigrades (water bears)) would be able to survive on other planets. In our study, we have established a metric tool for distinguishing the potential survivability of active and cryptobiotic tardigrades on rocky-water and water-gas planets in our solar system and exoplanets, taking into consideration the geometrical means of six physical parameters such as radius, density, escape velocity, revolution period, surface temperature, and surface pressure of the considered planets. More than 3800 exoplanets are available as the main sample from Planetary Habitable Laboratory - Exoplanet Catalog (PHL-EC), from which we have chosen 57 exoplanets in our study including Earth and Mars, with water composition as reference. The Active Tardigrade Index (ATI) and Cryptobiotic Tardigrade Index (CTI) are two metric indices with minimum value 0 (= tardigrades cannot survive) and maximum 1 (= tardigrades will survive in their respective state). Values between 0 and 1 indicate a percentage chance of the active or cryptobiotic tardigrades surviving on a given exoplanet. Among known planets some of the exoplanets are tabulated as ATI and CTI indices for sample representation like: Kepler-100d, Kepler-48d, Kepler-289b, TRAPPIST-1 f and Kepler-106e. The results with Mars as the threshold indicates that Mars could be the only rock-water composition planet that could be more suitable for tardigrades than other considered exoplanets., (Copyright © 2018. Published by Elsevier Ltd.)

Esophageal cancer (EC) is the eighth most aggressive malignancy and its treatment remains a challenge due to the lack of biomarkers that can facilitate early detection. EC is identified in two major histological forms namely - Adenocarcinoma (EAC) and Squamous cell carcinoma (ESCC), each showing differences in the incidence among populations that are geographically separated. Hence the detection of potential drug target and biomarkers demands a population-centric understanding of the molecular and cellular mechanisms of EC. To provide an adequate impetus to the biomarker discovery for ESCC, which is the most prevalent esophageal cancer worldwide, here we have developed ESCC ATLAS, a manually curated database that integrates genetic, epigenetic, transcriptomic, and proteomic ESCC-related genes from the published literature. It consists of 3475 genes associated to molecular signatures such as, altered transcription (2600), altered translation (560), contain copy number variation/structural variations (233), SNPs (102), altered DNA methylation (82), Histone modifications (16) and miRNA based regulation (261). We provide a user-friendly web interface ( http://www.esccatlas.org , freely accessible for academic, non-profit users) that facilitates the exploration and the analysis of genes among different populations. We anticipate it to be a valuable resource for the population specific investigation and biomarker discovery for ESCC.

Cherubism is a rare benign, autosomal-dominant inherited fibro-osseous lesion of jaw characterized by excessive bone degradation of the upper and lower jaws followed by the development of fibrous tissue masses. It is usually self-limiting; it starts in early childhood and involutes by puberty. The purpose of this clinical report is to describe a nonfamilial case of cherubism on a teenager female patient first treated by calcitonin nasal spray followed by surgical resection and recontouring after puberty., Competing Interests: There are no conflicts of interest.

Esophageal cancer is one of the most common types of cancer, which is a leading cause of cancer-related death worldwide. Based on histological behavior, it is mainly of two types (i) Esophageal squamous cell carcinoma (ESCC), and (ii) esophageal adenocarcinoma (EAD or EAC). In astronomically immense majority of malignancies, receptor tyrosine kinases (RTKs) have been kenned to play a consequential role in cellular proliferation, migration, and metastasis of the cells. The post-translational modifications (PTMs) including phosphorylation of tyrosine (pY) residue of the tyrosine kinase (TK) domain have been exploited for treatment in different malignancies. Lung cancer where pY residues of EGFR have been exploited for treatment purpose in lung adenocarcinoma patients, but we do not have such kind of felicitously studied and catalogued data in ESCC patients. Thus, the goal of this review is to summarize the studies carried out on ESCC to explore the role of RTKs, tyrosine kinase inhibitors, and their pertinence and consequentiality for the treatment of ESCC patients.

The vast majority of esophageal cancers in China, India and Iran are esophageal squamous cell carcinomas (ESCC). A timely diagnosis provides surgical removal as the main therapeutic option for patients with ESCC. Currently, there are no targeted therapies available for ESCC. We carried out reverse phase protein array-based protein expression profiling of seven ESCC-derivedcell lines and a non-neoplastic esophageal epithelial cell line (Het-1A) to identify differentially expressed proteins in ESCC. SYK non-receptortyrosine kinase was overexpressed in six out of seven ESCC cell lines that were used in the study. We evaluated the role of SYK in ESCC using the pharmacological inhibitor entospletinib (GS-9973) and siRNA-based knock down studies. Entospletinib is a selective inhibitor of SYK, which is currently being evaluated in phase II clinical trials for hematological malignancies. Using in vivo subcutaneous tumor xenografts in mice, we demonstrate that treatment with entospletinib significantly inhibits tumor growth. Further clinical studies are needed to prove the efficacy of entospletinib as a targeted therapeutic agent for treating ESCC., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Since its discovery in 1977, the study of alternative RNA splicing has revealed a plethora of mechanisms that had never before been documented in nature. Understanding these transitions and their outcome at the level of the cell and organism has become one of the great frontiers of modern chemical biology. Until 2007, this field remained in the hands of RNA biologists. However, the recent identification of natural product and synthetic modulators of RNA splicing has opened new access to this field, allowing for the first time a chemical-based interrogation of RNA splicing processes. Simultaneously, we have begun to understand the vital importance of splicing in disease, which offers a new platform for molecular discovery and therapy. As with many natural systems, gaining clear mechanistic detail at the molecular level is key towards understanding the operation of any biological machine. This minireview presents recent lessons learned in this emerging field of RNA splicing chemistry and chemical biology., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL)-microenvironment interaction. Overexpression of CXCR4 has been reported in different hematological malignancies including CLL. Binding of the pro-survival chemokine CXCL12 with its cognate receptor CXCR4 induces cell migration. CXCL12/CXCR4 signaling axis promotes cell survival and proliferation and may contribute to the tropism of leukemia cells towards lymphoid tissues and bone marrow. Therefore, we hypothesized that targeting CXCR4 with an IgG1 antibody, PF-06747143, may constitute an effective therapeutic approach for CLL., Methods: Patient-derived primary CLL-B cells were assessed for cytotoxicity in an in vitro model of CLL microenvironment. PF-06747143 was analyzed for cell death induction and for its potential to interfere with the chemokine CXCL12-induced mechanisms, including migration and F-actin polymerization. PF-06747143 in vivo efficacy was determined in a CLL murine xenograft tumor model., Results: PF-06747143, a novel-humanized IgG1 CXCR4 antagonist antibody, induced cell death of patient-derived primary CLL-B cells, in presence or absence of stromal cells. Moreover, cell death induction by the antibody was independent of CLL high-risk prognostic markers. The cell death mechanism was dependent on CXCR4 expression, required antibody bivalency, involved reactive oxygen species production, and did not require caspase activation, all characteristics reminiscent of programmed cell death (PCD). PF-06747143 also induced potent B-CLL cytotoxicity via Fc-driven antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity activity (CDC). PF-06747143 had significant combinatorial effect with standard of care (SOC) agents in B-CLL treatment, including rituximab, fludarabine (F-ara-A), ibrutinib, and bendamustine. In a CLL xenograft model, PF-06747143 decreased tumor burden and improved survival as a monotherapy, and in combination with bendamustine., Conclusions: We show evidence that PF-06747143 has biological activity in CLL primary cells, supporting a rationale for evaluation of PF-06747143 for the treatment of CLL patients.

Mutations in the Epidermal growth factor receptor (EGFR) kinase domain, such as the L858R missense mutation and deletions spanning the conserved sequence 747 LREA 750 , are sensitive to tyrosine kinase inhibitors (TKIs). The gatekeeper site residue mutation, T790M accounts for around 60% of acquired resistance to EGFR TKIs. The first generation EGFR TKIs, erlotinib and gefitinib, and the second generation inhibitor, afatinib are FDA approved for initial treatment of EGFR mutated lung adenocarcinoma. The predominant biomarker of EGFR TKI responsiveness is the presence of EGFR TKI-sensitizing mutations. However, 30-40% of patients with EGFR mutations exhibit primary resistance to these TKIs, underscoring the unmet need of identifying additional biomarkers of treatment response. Here, we sought to characterize the dynamics of tyrosine phosphorylation upon EGFR TKI treatment of mutant EGFR-driven human lung adenocarcinoma cell lines with varying sensitivity to EGFR TKIs, erlotinib and afatinib. We employed stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative mass spectrometry to identify and quantify tyrosine phosphorylated peptides. The proportion of tyrosine phosphorylated sites that had reduced phosphorylation upon erlotinib or afatinib treatment correlated with the degree of TKI-sensitivity. Afatinib, an irreversible EGFR TKI, more effectively inhibited tyrosine phosphorylation of a majority of the substrates. The phosphosites with phosphorylation SILAC ratios that correlated with the TKI-sensitivity of the cell lines include sites on kinases, such as EGFR-Y1197 and MAPK7-Y221, and adaptor proteins, such as SHC1-Y349/350, ERRFI1-Y394, GAB1-Y689, STAT5A-Y694, DLG3-Y705, and DAPP1-Y139, suggesting these are potential biomarkers of TKI sensitivity. DAPP1, is a novel target of mutant EGFR signaling and Y-139 is the major site of DAPP1 tyrosine phosphorylation. We also uncovered several off-target effects of these TKIs, such as MST1R-Y1238/Y1239 and MET-Y1252/1253. This study provides unique insight into the TKI-mediated modulation of mutant EGFR signaling, which can be applied to the development of biomarkers of EGFR TKI response., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Upregulation of antiapoptotic Bcl-2 proteins in certain tumors confers cancer cell resistance to chemotherapy or radiations. Members of the antiapoptotic Bcl-2 proteins, including Bcl-2, Mcl-1, Bcl-xL, Bcl-w, and Bfl-1, inhibit apoptosis by selectively binding to conserved α-helical regions, named BH3 domains, of pro-apoptotic proteins such as Bim, tBid, Bad, or NOXA. Five antiapoptotic proteins have been identified that interact with various selectivity with BH3 containing pro-apoptotic counterparts. Cancer cells present various and variable levels of these proteins, making the design of effective apoptosis based therapeutics challenging. Recently, BH3 profiling was introduced as a method to classify cancer cells based on their ability to resist apoptosis following exposure to selected BH3 peptides. However, these studies were based on binding affinities measured with model BH3 peptides and Bcl-2-proteins taken from mouse sequences. While the majority of these interactions are conserved between mice and humans, we found surprisingly that human NOXA binds to human Bfl-1 potently and covalently via conserved Cys residues, with over 2 orders of magnitude increased affinity over hMcl-1. Our data suggest that some assumptions of the original BH3 profiling need to be revisited and that perhaps further targeting efforts should be redirected toward Bfl-1, for which no suitable specific inhibitors or pharmacological tools have been reported. In this regard, we also describe the initial design and characterizations of novel covalent BH3-based agents that potently target Bfl-1. These molecules could provide a novel platform on which to design effective Bfl-1 targeting therapeutics.

The dysregulation of RNA splicing is a molecular hallmark of disease, including different and often complex cancers. While gaining recognition as a target for therapeutic discovery, understanding the complex mechanisms guiding RNA splicing remains a challenge for chemical biology. The discovery of small molecule splicing modulators has recently enabled an evaluation of the mechanisms of aberrant splicing. We now report on three unique features within the selectivity of splicing modulators. First, we provide evidence that structural modifications within a splicing modulator can alter the splicing of introns in specific genes differently. These studies indicate that structure activity relationships not only have an effect on splicing activity but also include specificity for specific introns within different genes. Second, we find that these splicing modulators also target the mRNAs encoding components of the spliceosome itself. Remarkably, this effect includes the genes for the SF3B complex, a target of pladienolide B and related splicing modulators. Finally, we report on the first observation of a temporal phenomenon associated with small molecule splicing modulation. Combined, these three observations provide an important new perspective for the exploration of splicing modulation in terms of both future medicinal chemistry programs as well as understanding the key facets underlying its timing.

Small-molecule splice modulators have recently been recognized for their clinical potential for diverse cancers. This, combined with their use as tools to study the importance of splice-regulated events and their association with disease, continues to fuel the discovery of new splice modulators. One of the key challenges found in the current class of materials arises from their instability, where rapid metabolic degradation can lead to off-target responses. We now describe the preparation of bench-stable splice modulators by adapting carbohydrate motifs as a central scaffold to provide rapid access to potent splice modulators.

Malignant B cells accumulate in the peripheral blood, bone marrow, and lymphoid organs of patients with chronic lymphocytic leukemia (CLL). In the tissue compartments, CLL shape a protective microenvironment by coopting normal elements. The efficacy of drugs that target these interactions further underscores their importance in the pathogenesis of CLL. While the B cell receptor (BCR) pathway clearly plays a central role in the CLL microenvironment, there is also rationale to evaluate agents that inhibit other aspects or modulate the immune cells in the microenvironment. Here we review the main cellular components, soluble factors, and signaling pathways of the CLL microenvironment, and highlight recent clinical advances. As the BCR pathway is reviewed elsewhere, we focus on other aspects of the microenvironment., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The CXCR4 receptor (Chemokine C-X-C motif receptor 4) is highly expressed in different hematological malignancies including chronic lymphocytic leukemia (CLL). The CXCR4 ligand (CXCL12) stimulates CXCR4 promoting cell survival and proliferation, and may contribute to the tropism of leukemia cells towards lymphoid tissues. Therefore, strategies targeting CXCR4 may constitute an effective therapeutic approach for CLL. To address that question, we studied the effect of Ulocuplumab (BMS-936564), a fully human IgG4 anti-CXCR4 antibody, using a stroma--CLL cells co-culture model. We found that Ulocuplumab (BMS-936564) inhibited CXCL12 mediated CXCR4 activation-migration of CLL cells at nanomolar concentrations. This effect was comparable to AMD3100 (Plerixafor--Mozobil), a small molecule CXCR4 inhibitor. However, Ulocuplumab (BMS-936564) but not AMD3100 induced apoptosis in CLL at nanomolar concentrations in the presence or absence of stromal cell support. This pro-apoptotic effect was independent of CLL high-risk prognostic markers, was associated with production of reactive oxygen species and did not require caspase activation. Overall, these findings are evidence that Ulocuplumab (BMS-936564) has biological activity in CLL, highlight the relevance of the CXCR4-CXCL12 pathway as a therapeutic target in CLL, and provide biological rationale for ongoing clinical trials in CLL and other hematological malignancies.