Mintu Pal

Predictive and prognostic biomarkers in colorectal cancer: A systematic review of recent advances and challenges

BACKGROUND Colorectal cancer (CRC) is one of the leading cause of cancer deaths worldwide. Since CRC is largely asymptomatic until alarm features develop to advanced stages, the implementation of the screening programme is very much essential to reduce cancer incidence and mortality rates. CRC occurs predominantly from accumulation of genetic and epigenetic changes in colon epithelial cells, which later gets transformed into adenocarcinomas. SCOPE OF REVIEW The current challenges of screening paradigm and diagnostic ranges are from semi-invasive methods like colonoscopy to non-invasive stool-based test, have resulted in over-diagnosis and over-treatment of CRC. Hence, new screening initiatives and deep studies are required for early diagnosis of CRC. In this regard, we not only summarise current predictive and prognostic biomarkers with their potential for diagnostic and therapeutic applications, but also describe current limitations, future perspectives and challenges associated with the progression of CRC. MAJOR CONCLUSIONS Currently many potential biomarkers have already been successfully translated into clinical practice eg. Fecal haemoglobin, Carcinoembryonic antigen (CEA) and CA19.9, although these are not highly promising diagnostic target for personalized medicine. So there is a critical need for reliable, minimally invasive, highly sensitive and specific genetic markers of an individualised and optimised patient treatment at the earliest disease stage possible. GENERAL SIGNIFICANCE Identification of a new biomarker, or a set of biomarkers to the development of a valid, and clinical sensible assay that can be served as an alternative tool for early diagnosis of CRC and open up promising new targets in therapeutic intervention strategies.

Impedimetric immunosensor for detection of cardiovascular disorder risk biomarker

We report the construction and characterization of a novel, level free impedimetric immunosensor for rapid, sensitive and selective detection of myoglobin (Mb). Monoclonal anti-myoglobin (anti-Mb-IgG) antibody was immobilized on screen-printed multiwalled carbon nanotubes electrode for signal amplification without the need of natural enzymes. The fabrication of resulting immunosensor was extensively characterized by using scanning electron microscopy (SEM), fourier transform infrared (FT-IR) spectroscopy, cyclic voltammetry (CV), differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS). Electrochemical impedance spectroscopy (EIS) technique offered a linear detection range (0.1-90ngmL(-1)) of myoglobin with sensitivity of 0.74kΩngmL(-1) (correlation coefficient, R(2)=0.97) and detection limit of 0.08ngmL(-1) (S/N=3). The mean percentage recovery of Mb in serum samples using this working biosensor is 97.33%. Furthermore, the proposed strategy can be a promising alternative for detection of Mb related cardiovascular disorders.

Diagnostic and Prognostic Biomarkers in ovarian cancer and the potential roles of cancer stem cells – An updated review

Abstract Ovarian carcinomas relate to highest death rate in gynecologic malignancies as absence of symptoms shield the disease in the early stage. Current evidences have been devoted to discovering early effective screening mechanism prior to the onset of clinical symptoms. Therefore, biomarkers are the crucial tools that are capable of predicting progression, risk stratification and overall therapeutic benefit to fight against this deadly disease. Although recent studies have revealed serum protein markers, CA‐125, HE4, mesothelin etc. have higher sensitivity and specificity at the early stages of the cancer; the critical questions arise regarding the applicability and reproducibility of genomic profiling across different patient groups. Hence, our hypothesis is that the panels of signature biomarkers will be much more effective to improve the diagnosis and prediction of patient survival outcome with high sensitivity and specificity. Ovarian cancer is heterogeneous in nature and contain a sub‐population of stem cell‐like characteristics that has the ability to grow as anchorage‐independent manner and subsequently is able to metastasize. Highly tumorigenic and chemotherapy‐resistant cancer stem cells (CSCs)‐specific biomarkers therefore reflects the interesting possibilities to be targeted to minimize the high frequency of relapse and resistance to drugs. Several putative ovarian CSC markers such as CD24, CD44, CD133, SSEA have already been proposed in recent studies, yet, a large panel of updated biomarkers have high clinical relevance to define the prospective isolation of viable circulating CSCs. Therefore, this review highlights current evidence based updated ovarian cancer specific prognostic and diagnostic biomarkers and potential importance of CSCs in context of tumorigenicity and metastatic activity for fundamental biological and clinical implications. HighlightsCurrent updated potential prognostic and diagnostic biomarkers in ovarian cancer.Potential importance of cancer stem cells in tumorigenesis and metastasis.Signature biomarkers improve the prediction of survival in cancer patients.

Understanding the role of structural integrity and differential expression of integrin profiling to identify potential therapeutic targets in breast cancer.

Breast cancer is found to be the most prevalent neoplasm in women worldwide. Despite the function of physically tethering cells to the matrix, transmembrane protein integrins are crucially involved in diverse cellular functions such as cell differentiation, proliferation, invasion, migration, and metastasis. Dysregulation of integrins and their interactions with the cells and their microenvironment can trigger several signaling cues that determine the cell fate decision. In this review, we spotlight all pre‐existing integrin molecules, their structure, molecular interactions motifs, and function through several cross talks with kinase receptors. We also discuss the role of these integrins as potential prognostic and therapeutic targets and also in the regulation of breast cancer cells differentiation. Understanding of integrin structure and their motifs for ligand interactions in this context will enable the development of new therapeutic approaches to sensitize the tumors and their microenvironment to conventional therapy and overall suppress their metastatic phenotype.

Cadherin profiling for therapeutic interventions in Epithelial Mesenchymal Transition (EMT) and tumorigenesis

ABSTRACT The major hallmarks of Epithelial‐Mesenchymal Transition (EMT) is the loss of epithelial cell polarity and loss of expression of the cell‐ cell adhesion molecule like E‐cadherin and acquired mesenchymal cells marker called N‐Cadherin. This phenotypical changes of E‐M plasticity of cells is extensively considered to be a crucial factor for tumor cells invasion and cancer metastasis; landmark events for transforming a locally growing tumor (benign tumor) into a systemic and live‐threatening disease (malignant tumor). Cadherin molecules are adherens junction proteins and expressed as multiple isoforms. Cadherin switching occurs during normal tissue developmental processes; also recapitulates the increasing aggressive behavior and metastatic nature of cancer cells when E‐Cadherin converts to N‐Cadherin, in particular. There are several mechanisms established that cadherin switching and some of the underlying pathways involves multiple steps associated with migration and invasion of cancer cells, and finally colonization of micro metastatic lesions to form macro‐metastasis. Inhibition of metastasis is complicated by the plasticity of cancer cells behaviors and the evolving nature of microenvironment. Although there is no clear evidence how that dynamic structural switching of cadherin family member occurs, stabilized and eventually influence cell behavior, phenotypic transformations and initiate tumorigenesis. Therefore, we emphasize here the major functions of over 20 existing human cadherins in tissue integrity and stability as well as mechanistic understanding on recent work of cadherin ectodomain‐mediated adhesion, functional studies of the cell‐cell adhesion through key signaling intermediates interacting with other binding partners. We hope understanding on how the dynamic all existing cadherins influence the cell behavior can be targeted to design possible therapeutic interventions to combat its activity and prevent tumor cell growth, invasion and metastasis.

Selective deletion of PPARβ/δ in fibroblasts causes dermal fibrosis by attenuated LRG1 expression

Connective tissue diseases of the skin are characterized by excessive collagen deposition in the skin and internal organs. Fibroblasts play a pivotal role in the clinical presentation of these conditions. Nuclear receptor peroxisome-proliferator activated receptors (PPARs) are therapeutic targets for dermal fibrosis, but the contribution of the different PPAR subtypes are poorly understood. Particularly, the role of fibroblast PPARβ/δ in dermal fibrosis has not been elucidated. Thus, we generated a mouse strain with selective deletion of PPARβ/δ in the fibroblast (FSPCre-Pparb/d−/−) and interrogated its epidermal and dermal transcriptome profiles. We uncovered a downregulated gene, leucine-rich alpha-2-glycoprotein-1 (Lrg1), of previously unknown function in skin development and architecture. Our findings suggest that the regulation of Lrg1 by PPARβ/δ in fibroblasts is an important signaling conduit integrating PPARβ/δ and TGFβ1-signaling networks in skin health and disease. Thus, the FSPCre-Pparb/d−/− mouse model could serve as a novel tool in the current gunnery of animal models to better understand dermal fibrosis.

Nano-therapeutic Approaches for Targeting Cancer Stem Cells

Emerging evidences suggest that a small population of highly tumorigenic cancer stem-like cells (CSC) or tumor-initiating cells (TICs) is responsible for sustaining multiple types of tumor. Like normal stem cells, CSCs can self-renew and differentiate to other tumor cell types and give rise to non-tumorigenic daughter cells that constitute the tumor bulk. These cells are highly resistant to chemo- and radiotherapies causing drug resistance, tumor recurrence, and the formation of distant metastases. CSCs often overexpress drug efflux transporters, and consequently, CSCs can escape conventional chemotherapies. Therefore, CSCs offer an attractive target for therapeutic intervention. Nanocarrier-based therapeutics is being targeted to CSCs for elimination and prevention of recurrence and metastasis of tumors in addition to achieving prolonged blood circulation times, stability, and bioavailability over current therapies. In this chapter, we focus on the problems in delivering drugs to the CSCs, and current status of CSCs therapy including inhibition of drug efflux transporters, targeting tumor microenvironment and nanometric drug delivery approaches to prevent tumor recurrence.

Origins based clinical and molecular complexities of epithelial ovarian cancer

Ovarian cancer is the most lethal of all common gynaecological malignancies in women worldwide. Ovarian cancer comprises of >15 distinct tumor types and subtypes characterized by histopathological features, environmental and genetic risk factors, precursor lesions and molecular events during oncogenesis. Recent studies on gene signature profiling of different subtypes of ovarian cancer have revealed significant genetic heterogeneity between and within each ovarian cancer histological subtype. Thus, an immense interest have shown towards a more personalized medicine for understanding the clinical and molecular complexities of four major types of epithelial ovarian cancer (serous, endometrioid, clear cell, and mucinous). As such, further in depth studies are needed for identification of molecular signalling network complexities associated with effective prognostication and targeted therapies to prevent or treat metastasis. Therefore, understanding the metastatic potential of primary ovarian cancer and therapeutic interventions against lethal ovarian cancer for the development of personalized therapies is very much indispensable. Consequently, in this review we have updated the key dysregulated genes of four major subtypes of epithelial carcinomas. We have also highlighted the recent advances and current challenges in unravelling the complexities of the origin of tumor as well as genetic heterogeneity of ovarian cancer.

Functionalized graphene oxides for drug loading, release and delivery of poorly water soluble anticancer drug: A comparative study

In this work, the modification of graphene oxides (GOs) have been done with hydrophilic and biodegradable polymer, polyvinylpyrrolidone (PVP) and other excipient β -cyclodextrin (β-CD) through covalent functionalization for efficient loading and compatible release of sparingly water soluble aromatic anticancer drug SN-38 (7-ethyl-10-hydroxy camptothecin). The drug was loaded onto both GO-PVP and GO-β-CD through the π-π interactions.The release of drug from both the nanocarriers were analyzed in different pH medium of pH 7 (water, neutral medium), pH 5 (acidic buffer) and pH 12 (basic buffer). The loading capacity and the cell killing activity of SN-38 loaded on functionalized GO were investigated comprehensively in human breast cancer cells MCF-7.Our findings shown that the cytotoxicity of SN-38 loaded to the polymer modified GO was comparatively higher than free SN-38. In particular, SN-38 loaded GO-PVP nanocarrier has more cytotoxic effect than GO-β-CD nanocarrier against MCF-7 cells, indicating that SN-38 loaded GO-PVP nanocarrier can be used as promising material for drug delivery and biological applications.