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Mishra R.,Angiogenesis and Nanomedicine Research | Thorat D.,Angiogenesis and Nanomedicine Research | Soundararajan G.,Angiogenesis and Nanomedicine Research | Pradhan S.J.,Angiogenesis and Nanomedicine Research | And 4 more authors.
Oncogene | Year: 2014

Semaphorin 3A (Sema 3A), a member of semaphorin family, serves as a guidance clue during embryonic development and is known as a candidate tumor suppressor that attenuates breast tumor progression by binding with its co-receptor, neuropilin-1 (NRP-1). However, the underlying mechanism by which Sema 3A suppresses breast tumor growth is still unexplored. In this study, we report that Sema 3A regulates phosphorylation and nuclear translocation of phosphatase and tensin homolog (PTEN) and FOXO 3a. Moreover, Sema 3A controls NRP-1-mediated PTEN-dependent FOXO 3a activation. Overexpression of PTEN and FOXO 3a enhances Sema 3A-induced attenuation of breast cancer cell migration. Chromatin immunoprecipitation and electrophoretic mobility shift assay data revealed that FOXO 3a regulates MelCAM at the transcriptional level. Furthermore, Sema 3A induces NRP-1-mediated MelCAM expression through PTEN and FOXO 3a. The data also showed that vascular endothelial growth factor-induced angiogenesis is inhibited by Sema 3A. Loss of or gain in function study revealed that Sema 3A modulates phosphorylation of PTEN and FOXO 3a and expression of MelCAM, leading to suppression of tumor growth and angiogenesis using in vivo mice model. Clinical specimen analysis revealed that reduced expression of Sema 3A and p-PTEN are correlated with enhanced breast cancer progression, further strengthening our in vitro and in vivo findings. Correlation of relapse-free survival of breast cancer patients (n=2878) with expression levels of Sema 3A, NRP-1, FOXO 3a and MelCAM were studied by Kaplan-Meier analysis. Statistical analysis revealed a close association between reduced expression of Sema 3A and MelCAM with that of poor patient's survival. Our study demonstrated a novel mechanism of regulation of tumor suppression by Sema 3A in coordination with a chain of tumor-suppressor genes, which in turn inhibits breast cancer cell migration, tumor growth and angiogenesis.Oncogene advance online publication, 14 April 2014; doi:10.1038/onc.2014.79.


Raja R.,Angiogenesis and Nanomedicine Research | Kale S.,Angiogenesis and Nanomedicine Research | Thorat D.,Angiogenesis and Nanomedicine Research | Soundararajan G.,Angiogenesis and Nanomedicine Research | And 4 more authors.
Oncogene | Year: 2014

Hypoxia is a salient feature of most solid tumors, and hypoxic adaptation of cancer cells has crucial implications in propagation of malignant clonal cell population. Osteopontin (OPN) has been identified as a hypoxia-responsive gene, but the mechanistic and regulatory role of OPN under hypoxia is less characterized. The present study identifies the existence of a positive inter-regulatory loop between hypoxia and OPN. We have shown that hypoxia induces OPN expression in breast cancer cells; however, the expression was found to be HIF1α independent. OPN enabled transcriptional upregulation of HIF1α expression both under normoxia and hypoxia, whereas stability of HIF1α protein in breast cancer cells remained unaffected. Moreover, we have shown that OPN induces integrin-linked kinase (ILK)/Akt-mediated nuclear factor (NF)-κB p65 activation leading to HIF1α-dependent vascular endothelial growth factor (VEGF) expression and angiogenesis in response to hypoxia. These in vitro data are biologically important as OPN expressing cells induce greater tumor growth and angiogenesis through enhanced expressions of proangiogenic molecules as compared with control. Immunohistochemical analysis of human breast cancer specimens revealed significant correlation between OPN and HIF1α but not HIF2α. Elevated expression of HIF1α and OPN was observed in pre-neoplastic and early stage infiltrating ductal carcinoma implicating the role of these proteins in neoplastic progression of breast cancer. Together, our results substantiate the prime role of OPN in cellular adaptation through ILK and NF-κB-mediated HIF1α-dependent VEGF expression in response to hypoxia that ultimately controls breast cancer progression and angiogenesis. Our study reinforces the fact that targeting OPN and its regulated signaling network hold important therapeutic implications. © 2014 Macmillan Publishers Limited.


Vaid S.,Grant Medical Foundation | Vaid N.,Kem Hospital | Rawat S.,Grant Medical Foundation | Ahuja A.T.,Chinese University of Hong Kong
Clinical Radiology | Year: 2011

The reference standard for preoperative imaging in functional endoscopic sinus surgery (FESS) is multiplanar high-resolution computed tomography (HRCT). Surgeons require a precise preoperative anatomical road map, and hence it is essential for radiologists to be familiar with the normal three-dimensional sinonasal anatomy and the normal variants encountered in this region. Sagittal imaging has recently emerged as an important tool to visualize additional details in this critical anatomical region. Radiologists also need to report these examinations with special focus on the surgeon's expectations. Constant communication between the radiologist and the surgeon helps to resolve specific issues and improve the overall quality of reports. This results in better preoperative patient counselling and in predicting postoperative improvement in clinical status. This review provides a basic structured format for reporting pre-FESS CT, which can be tailored to meet individual requirements. The CT reporting format follows the order in which the sinonasal structures are approached during surgery. © 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.


Kumar V.,National Center for Cell Science | Behera R.,National Center for Cell Science | Lohite K.,Grant Medical Foundation | Karnik S.,Grant Medical Foundation | Kundu G.C.,National Center for Cell Science
Cancer Research | Year: 2010

p38 kinases activated by growth factors, hormones, and environmental stresses exert diverse functions in regulating normal and malignant cell pathophysiology. Enhanced levels of activated p38 isoforms have been linked with poor prognosis in breast cancer, although the mechanistic basis for this association is poorly understood. In this study, we report that p38 activation in cervical cancer cells is driven by osteopontin (OPN), an extracellular matrix-associated cytokine that drives invasive progression. OPN regulates CD44-mediated p38 phosphorylation that induces NF-κB activation and NF-κB-dependent expression of furin, an extracellular protease implicated in human papilloma virus (HPV) processing that enhances cervical cancer cell motility. OPN induces CD44-mediated MKK3/6 phosphorylation which in turn phosphorylates p38 in these cells. OPN-induced furin expression and cell motility was impeded by blockades to MKK3/6, p38α/β or NF-κB signaling. In a mouse xenograft model of human cervical cancer, tumor growth was enhanced by OPN overexpression and blocked by short hairpin RNA (shRNA)-mediated OPN silencing. Furin overexpression similarly augmented tumor growth in the model, whereas blocking MKK3/6, p38, or furin reduced OPN-induced cervical tumor growth. Analysis of clinical specimens revealed that enhanced expression of OPN, phosphorylated NF-κB, p65, and furin correlated with cervical cancer progression, further strengthening the in vitro and in vivo results. In summary, our findings offer a proof of concept for targeting OPN and its downstream p38 signaling as a novel therapeutic strategy to manage cervical cancer. ©2010 AACR.


Vaid S.,Grant Medical Foundation | Vaid N.,Kem Hospital | Rathod S.,Grant Medical Foundation
Otology and Neurotology | Year: 2012

Objective: To highlight the importance of imaging the geniculate fossa in patients with solitary infranuclear facial palsy. Study Design: Prospective. Setting: Tertiary referral center. ELIGIBILITY CRITERIA: Patients with solitary infranuclear facial palsy sent for imaging. INTERVENTION: Diagnostic. MAIN OUTCOME MEASURE: Imaging specifics concerning high-resolution computed tomography (HRCT) and magnetic resonance imaging (MRI) are described in detail for evaluation of the intratemporal part of the facial nerve with special focus on the geniculate fossa. Results: Normal appearances of the geniculate fossa on HRCT and MRI and its normal anatomic variant, that is, dehiscence of the overlying bone are described. Imaging findings in a range of pathologies involving the geniculate fossa in a clinical setting of infranuclear facial nerve palsy is demonstrated. These include infections (tuberculosis), trauma, schwannoma, hemangioma, meningioma, and perineural spread of parotid malignancy. Conclusion: The geniculate fossa is a small bony hiatus in the temporal bone and is situated at the junction of the labyrinthine and the tympanic segments of the intratemporal facial nerve canal. It houses important neural structures and is best visualized by a combination of HRCT and high-resolution MRI examination of the temporal bone. It is therefore imperative for imaging specialists to be familiar with the normal appearance of this structure on HRCT and MRI examinations of the temporal bone as subtle imaging findings involving the geniculate fossa can be indicators of a variety of abnormalities. © 2012, Otology & Neurotology, Inc.


Behera R.,National Center for Cell Science | Kumar V.,National Center for Cell Science | Lohite K.,Grant Medical Foundation | Karnik S.,Grant Medical Foundation | Kundu G.C.,National Center for Cell Science
Carcinogenesis | Year: 2010

Deregulation of signal transducer and activator of transcription (STAT)-3 signaling plays crucial role in oncogenesis of various cancers. However, the molecular mechanism by which osteopontin (OPN), a chemokine-like extracellular matrix-associated protein, regulates STAT3 activation that leads to tumor progression and inhibits apoptosis in breast cancer cells is not well understood. In this study, we for the first time report that OPN upregulates αvβ3 integrin-mediated Janus kinase 2 (JAK2) phosphorylation and STAT3 activation in breast cancer (MDA-MB-468 and MCF-7) cells. Pretreatment of cells with JAK2 inhibitor (AG 490) suppresses OPN-induced STAT3 phosphorylation, its nuclear localization and DNA binding indicating that JAK2 is involved in this process. Transfection of cells with wild-type (wt) STAT3 enhanced whereas mutant STAT3 (STAT3 Y705F) suppressed OPNinduced breast tumor cell migration. Treatment of cells with OPN followed by staurosporine (STS) showed that OPN protects the cells from STS-induced apoptosis. Moreover, transfection of cells with wt STAT3 upregulates whereas STAT3 Y705F downregulates Bcl2 and cyclin D1 expressions in response to OPN. Interestingly, STAT3-overexpressing cells when injected to non-obese diabetic/severe combined immunodeficiency mice followed by OPN treatment, the mice developed enhanced tumor growth as compared with STAT3 Y705F-injected mice or mice injected with OPN alone. The levels of Bcl2 and cyclin D1 in wt STAT3 tumors were significantly higher than controls. Clinical specimen analysis revealed that increased OPN and pSTAT3 expressions correlate with enhanced breast tumor progression. Thus, targeting OPN and its regulated STAT3 signaling could be a potent therapeutic approach and understanding these mechanisms may form the basis of new therapeutic regimen for the management of breast cancer. © The Author 2009. Published by Oxford University Press.


Vaid N.,Kem Hospital | Vaid S.,Grant Medical Foundation | Manikoth M.,Dr Manojs Superspeciality ENT Institute
Cochlear Implants International | Year: 2013

One of the most dreaded complications after cochlear implantation is infection. These infections are a challenge due to lack of any data regarding optimal methods of investigation and management. More often than not, these patients have to undergo explantation and revision surgery. This paper presents a case report and literature review which focuses on the role of antibiotics and the need for early explantation in most biofilm-related infections of cochlear implants. © W. S. Maney & Son Ltd 2013.


Vaid S.,Grant Medical Foundation | Lee Y.Y.P.,The Chinese University of Hongkong | Rawat S.,Grant Medical Foundation | Luthra A.,Grant Medical Foundation | And 2 more authors.
Clinical Radiology | Year: 2010

The aim of the present review is to illustrate the pathogenesis and imaging findings of tuberculosis in specific head and neck regions to avoid pitfalls in diagnosis. It is imperative to be aware of, and provide an early diagnosis for, extra-pulmonary tubercular lesions in the head and neck. A high index of suspicion combined with an appropriate clinical setting serves as an important background to diagnose tubercular lesions in the head and neck region and differentiate them from malignancy and other disease entities. Early diagnosis and treatment can prevent irreversible and debilitating complications and mortality from disseminated tuberculosis. © 2009 The Royal College of Radiologists.


Vaid N.,Kem Hospital | Thomas Roland J.,Otolaryngology and Neurosurgery | Thomas Roland J.,Cochlear Implant Center | Vaid S.,Grant Medical Foundation
Cochlear Implants International | Year: 2011

Extra-cochlear electrode extrusion is a potentially under-recognized complication of cochlear implantation. As the age of implantation becomes younger, electrode extrusion is of concern due to future skull growth. Extrusion of several electrodes may compromise performance and thus require surgical reinsertion of the electrodes. Almost 60% of patients with electrode extrusion have required revision surgery. This paper presents a case report and literature review which discusses factors which contribute to electrode extrusion and emphasizes the need for a high degree of suspicion in certain situations. Surgical steps such as electrode fixation techniques are highlighted in order to attempt to reduce the occurrence of this complication. © W.S. Maney & Son Ltd. 2011.


PubMed | National Center for Cell Science, CSIR - National Chemical Laboratory, Grant Medical Foundation, Indian Institute of Technology Kharagpur and Wipro GE Healthcare
Type: Journal Article | Journal: Proteomics | Year: 2016

Globally, breast cancer is the second most common cancer among women. Although biomarker discoveries through various proteomic approaches of tissue and serum samples have been studied in breast cancer, urinary proteome alterations in breast cancer are least studied. Urine being a noninvasive biofluid and a significant source of proteins, it has the potential in early diagnosis of breast cancer. This study used complementary quantitative gel-based and gel-free proteomic approaches to find a panel of urinary protein markers that could discriminate HER2 enriched (HE) subtype breast cancer from the healthy controls. A total of 183 differentially expressed proteins were identified using three complementary approaches, namely 2D-DIGE, iTRAQ, and sequential window acquisition of all theoretical mass spectra. The differentially expressed proteins were subjected to various bioinformatics analyses for deciphering the biological context of these proteins using protein analysis through evolutionary relationships, database for annotation, visualization and integrated discovery, and STRING. Multivariate statistical analysis was undertaken to identify the set of most significant proteins, which could discriminate HE breast cancer from healthy controls. Immunoblotting and MRM-based validation in a separate cohort testified a panel of 21 proteins such as zinc-alpha2-glycoprotein, A2GL, retinol-binding protein 4, annexin A1, SAP3, SRC8, gelsolin, kininogen 1, CO9, clusterin, ceruloplasmin, and 1-antitrypsin could be a panel of candidate markers that could discriminate HE breast cancer from healthy controls.

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