Paras Hospitals

Gurgaon, India

Paras Hospitals

Gurgaon, India
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Gupta P.,National Brain Research Center | Ghosh S.,National Brain Research Center | Nagarajan A.,National Brain Research Center | Mehta V.S.,Paras Hospitals | Sen E.,National Brain Research Center
Cellular Signalling | Year: 2013

The non-classical HLA class I antigen HLA-G contributes to immune escape mechanisms in glioblastoma multiforme (GBM). We have previously shown that IL-1β-HIF-1α axis connects inflammatory and oncogenic pathways in GBM. In this study, we investigated the role of IL-1β induced inflammation in regulating HLA-G expression. IL-1β increased HLA-G and Toll like receptor 4 (TLR4) expression in a HIF-1α dependent manner. Inhibition of TLR4 signaling abrogated IL-1β induced HLA-G. IL-1β increased HMGB1 expression and its interaction with TLR4. Inhibition of HMGB1 inhibited TLR4 and vice versa suggesting the existence of HMGB1-TLR4 axis in glioma cells. Interestingly, HMGB1 inhibition prevented IL-1β induced HLA-G expression. Elevated levels of HMGB1 and β-defensin 3 were observed in GBM tumors. Importantly, β-defensin-3 prevented IL-1β induced HLA-G, TLR4, HMGB1 expression and release of pro-inflammatory mediators. Our studies indicate that β-defensin-3 abrogates IL-1β induced HLA-G expression by negatively affecting key molecules associated with its regulation. © 2012 Elsevier Inc.

Dixit D.,National Brain Research Center | Sharma V.,National Brain Research Center | Ghosh S.,National Brain Research Center | Mehta V.S.,National Brain Research Center | And 2 more authors.
Cell Death and Disease | Year: 2012

Glioblastoma multiforme (GBM) are resistant to TNFα-induced apoptosis and blockade of TNFα-induced NF-κB activation sensitizes glioma cells to apoptosis. As Casein kinase-2 (CK2) induces aberrant NF-κB activation and as we observed elevated CK2 levels in GBM tumors, we investigated the potential of CK2 inhibitors (CK2-Is)-DRB and Apigenin in sensitizing glioma cells to TNFα-induced apoptosis. CK2-Is and CK2 small interfering RNA (siRNA) reduced glioma cell viability, inhibited TNFα-mediated NF-κB activation, and sensitized cell to TNFα-induced apoptosis. Importantly, CK2-Is activated p53 function in wild-type but not in p53 mutant cells. Activation of p53 function involved its increased transcriptional activation, DNA-binding ability, increased expression of p53 target genes associated with cell cycle progression and apoptosis. Moreover, CK2-Is decreased telomerase activity and increased senescence in a p53-dependent manner. Apoptotic gene profiling indicated that CK2-Is differentially affect p53 and TNFα targets in p53 wild-type and mutant glioma cells. CK2-I decreased MDM2-p53 association and p53 ubiquitination to enhance p53 levels. Interestingly, CK2-Is downregulated SIRT1 activity and over-expression of SIRT1 decreased p53 transcriptional activity and rescued cells from CK2-I-induced apoptosis. This ability of CK2-Is to sensitize glioma to TNFα-induced death via multiple mechanisms involving abrogation of NF-κB activation, reactivation of wild-type p53 function and SIRT1 inhibition warrants investigation. © 2012 Macmillan Publishers Limited. All rights reserved.

Sharma V.,National Brain Research Center | Dixit D.,National Brain Research Center | Koul N.,National Brain Research Center | Mehta V.S.,Paras Hospitals | Sen E.,National Brain Research Center
Journal of Molecular Medicine | Year: 2011

We observed elevated levels of pro-inflammatory cytokine IL-1β in glioblastoma multiforme tumor samples. Since hypoxia-inducible factor-1α (HIF-1α) plays a crucial role in linking inflammatory and oncogenic pathways, we investigated the effect of IL-1β on HIF-1α expression in glioma cells under normoxia. IL-1β-mediated elevation of HIF-1α transcriptional activity was dependent on Ras-induced NF-κB activation, as IL-1β failed to induce NF-κB and HIF-1α activity in cells transfected with dominant negative RasN17. Increased Ras expression was accompanied by increased phosphorylation of Ras effectors AKT, ERK, JNK, and p38MAPK. While inhibition of these effectors individually failed to block the IL-1β-mediated increase in HIF-1α induction, co-inhibition of both AKT and ERK resulted in a significant decrease in IL-1β-induced HIF-1α activation. Interestingly, IL-1β elevated Wnt-1 expression in a Ras-dependent manner, and small interfering RNA (siRNA)-mediated knockdown of Wnt-1 decreased HIF-1α activity. Although Wnt-1-mediated HIF-1α was independent of the canonical Wnt/β-catenin signaling pathway, it regulated HIF-1α through NF-κB. siRNA-mediated HIF-1α knockdown attenuated elevated IL-1β mRNA levels induced upon IL-1β treatment. This was accompanied by increased interaction of HIF-1α with HIF responsive element on the IL-1β promoter upon IL-1β treatment, under normoxia. Our studies highlights for first time that (1) Ras is a key mediator of IL-1β-induced NF-κB and HIF-1α activation, under normoxia; (2) Wnt-1 regulates IL-1β-mediated HIF-1α induction via NF-κB; (3) Ras and Wnt-1 are intermediaries in the canonical IL-1β-NF-κB signaling pathway downstream of MyD88; and (4) IL-1β-induced HIF-1α drives a HIF-1α-IL-1β autocrine loop to maintain persistently elevated IL-1β level. © 2010 Springer-Verlag.

Sinha S.,National Brain Research Center | Ghildiyal R.,National Brain Research Center | Mehta V.S.,Paras Hospitals | Sen E.,National Brain Research Center
Cell Death and Disease | Year: 2013

Gliomas are resistant to radiation therapy, as well as to TNFα induced killing. Radiation-induced TNFα triggers Nuclear factor κB (NFκB)-mediated radioresistance. As inhibition of NFκB activation sensitizes glioma cells to TNFα-induced apoptosis, we investigated whether TNFα modulates the responsiveness of glioma cells to ionizing radiation-mimetic Neocarzinostatin (NCS). TNFα enhanced the ability of NCS to induce glioma cell apoptosis. NCS-mediated death involved caspase-9 activation, reduction of mitochondrial copy number and lactate production. Death was concurrent with NFκB, Akt and Erk activation. Abrogation of Akt and NFκB activation further potentiated the death inducing ability of NCS in TNFα cotreated cells. NCS-induced p53 expression was accompanied by increase in TP53-induced glycolysis and apoptosis regulator (TIGAR) levels and ATM phosphorylation. siRNA-mediated knockdown of TIGAR abrogated NCS-induced apoptosis. While DN-IjB abrogated NCS-induced TIGAR both in the presence and absence of TNFα, TIGAR had no effect on NFκB activation. Transfection with TIGAR mutant (i) decreased apoptosis and γH2AX foci formation (ii) decreased p53 (iii) elevated ROS and (iv) increased Akt/Erk activation in cells cotreated with NCS and TNFα. Heightened TIGAR expression was observed in GBM tumors. While NCS induced ATM phosphorylation in a NFκB independent manner, ATM inhibition abrogated TIGAR and NFκB activation. Metabolic gene profiling indicated that TNFα affects NCS-mediated regulation of several genes associated with glycolysis. The existence of ATM-NFκB axis that regulate metabolic modeler TIGAR to overcome prosurvival response in NCS and TNFα cotreated cells, suggests mechanisms through which inflammation could affect resistance and adaptation to radiomimetics despite concurrent induction of death. © 2013 Macmillan Publishers Limited. All rights reserved.

Tewari R.,National Brain Research Center | Choudhury S.R.,National Brain Research Center | Mehta V.S.,Paras Hospitals | Sen E.,National Brain Research Center
Molecular Biology Reports | Year: 2012

Resistance of glioblastoma multiforme (GBM) to TNFα induced apoptosis is attributed to NFκB activation. As TNF-receptor family member CD40 regulates NFκB activation, we investigated the role of CD40 in NFκB activation in GBM. We observed elevated CD40 levels in human glioma samples as compared to the surrounding normal tissue. Treatment with TNFα elevated CD40 levels in glioma cells and inhibition of CD40 signaling failed to abrogate TNFα induced NFκΒ activity. While TNFα increased the interaction between TRAF2/6, IκBα, IKKα/β in the CD40 signalosome, the level of CD40 in the signalosome remained unaffected upon TNFα treatment. Interestingly, TNFα decreased the spatial localization of CD40 and increased TRAF2/6 co-localization with lipid raft marker Caveolin. As localization of CD40 signalosome in lipid raft is crucial for NFκB activation, TNFα mediated decreased clustering of CD40 in lipid rafts could have possibly contributed to its non-involvement in NFκB activation. © 2012 Springer Science+Business Media B.V.

Tewari R.,National Brain Research Center | Choudhury S.R.,National Brain Research Center | Ghosh S.,National Brain Research Center | Mehta V.S.,Paras Hospitals | Sen E.,National Brain Research Center
Journal of Molecular Medicine | Year: 2012

The precise role of different toll-like receptor (TLR) superfamily members is just beginning to get elucidated in glioblastoma multiforme (GBM). In this study, we observed heightened TLR4 levels in GBM tumor samples as compared to adjacent normal tissue. Since the pro-inflammatory cytokine tumor necrosis factor (TNF)α induces NF-κB activation in GBM, and as several common signaling mediators are involved in TNFα and TLR4- mediated NF-κB activation, we investigated the role of TLR4 in the regulation of NF-κB activation and inflammatory responses in TNFα-treated glioma cells. TNFα elevated TLR4 expression and inhibition of TLR4 signaling by either signaling inhibitor, neutralizing antibody, or small interfering RNA (siRNA)-attenuated TNFα-induced NF- κB activation. TLR4-mediated NF-κB activation was independent of canonical myeloid differentiation factor 88 signaling but involved toll/IL-1R homology domaincontaining adaptor protein-inducing interferon-β. Inhibition of TLR4 signaling abrogated TNFα-induced increase in (1) transcription factors interferon (IFN) regulatory factor 3 and STAT-1 and (2) IFNβ and inflammatory cytokines/chemokines expression. Furthermore, TNFα-induced TLR4-dependent increase in AKT activation and HIF-1α transcriptional activation suggested the existence of TLR4-AKT-HIF-1α axis. Importantly, TNFα-induced TLR4 was abrogated in cells transfected with dominant negative IκB and HIF-1α siRNA. Our studies indicate that TNFα triggered TLR4-HIF-1α and NF-κB-TLR4 feed-forward loops act in tandem to sustain inflammatory response in glioma. © Springer-Verlag 2011.

Sharma V.,VMMC and Safdarjung Hospital | Dogra A.,Paras Hospitals
Journal of Clinical Orthopaedics and Trauma | Year: 2011

Calcaneum the largest tarsal bone accounts for 60% of all tarsal bone injuries and 2% of all fractures. The management of the calcaneal fractures is still a challenge to orthopedic surgeons. The aim of this study was to establish the best treatment, non-surgical or surgical for Sanders type II fractures.It is a prospective study in which a total of 30 patients in age group of 18-60 years were randomized (by envelope) into non-operative (group A) 15 patients and operative (group B) 15 patients. All type II fractures confirmed on CT were included in the study. Patients with any other associated injuries or with any co-morbidity were excluded from this study. The results were evaluated using Bohler's angle, Kerr Atkins, AOFAS, and visual analog scale.In our series, mode of injury was fall from height in 27 (90%) and road traffic accident (RTA) in 3 (10%). There were 21 males and 9 females. The mean Kerr Atkins score in operative group was 66.12 and in conservative group was 60.22. The mean AOFAS in operative group was 72.13 and in conservative group was 71.16. The visual analog scale in operative group was 1.83 and in conservative group was 2.12. The mean follow-up was 28.1 months. Bohler's angle is a good predictor of morbidity and the improvement after surgery was not statistically significant.It was concluded that there is no significant difference in outcome of treatment, surgical or conservative, and results were equivalent in both groups. © 2011 Delhi Orthopedic Association.

Dhawan S.,Sir Ganga Ram Hospital | Jain D.,Sir Ganga Ram Hospital | Mehta V.S.,Paras Hospitals
Journal of Neurosurgery: Spine | Year: 2013

Balantidium coli is a ciliated protozoan parasite that primarily infects primates and pigs. It is the largest protozoan to infect humans and is a well-known cause of diarrhea and dysentery. Extraintestinal disease is uncommon, and extraintestinal spread to the peritoneal cavity, appendix, genitourinary tract, and lung has rarely been reported. The authors describe a case of vertebral osteomyelitis with secondary cervical cord compression caused by B. coli. The patient was a 60-year-old immunocompetent man presenting with quadriplegia of short duration. Magnetic resonance imaging of the cervical spine showed extradural and prevertebral abscess at the C3-4 level. Drainage of the abscess, C3-4 discectomy, and iliac bone grafting were performed. Histologically B. coli was confirmed in an abscess sample. To the best of the authors' knowledge, involvement of bone by B. coli has never been reported, and this case is the first documented instance of cervical cord compression due to B. coli osteomyelitis of the spine in the literature. © 2013 AANS.

Mittal S.,Sir Ganga Ram Hospital | Jain D.,Sir Ganga Ram Hospital | Roy S.,Sir Ganga Ram Hospital | Mehta V.S.,Paras Hospitals
International Journal of Surgical Pathology | Year: 2012

Prediction of tumor behavior in meningiomas based on morphological features alone remains difficult. Several immunohistochemical biomarkers have been proposed to assist conventional methods. However, no single immunohistochemical marker can unequivocally discriminate between benign and aggressive meningiomas. There is only 1 study available in the literature that correlates p63 expression with overall histological grade of the meningioma. The present study is undertaken to assess the correlation between p63 expression and histological grade of meningiomas. For this purpose, the authors studied and analyzed the immunohistochemical expression of p63 in 85 cases of meningioma, including WHO grade I (63), grade II (11), and grade III (11) cases. Correlation between histological grade and nuclear immunoreactivity to p63 antibody was performed. Furthermore, expression of p63 protein was correlated with short clinical follow-up and Ki-67 proliferation index. Among 85 patients analyzed, there were 61 women (71.7 %) and 24 men (28.2%) between 7 and 75 years old. Expression of p63 protein was found in 34.9% of grade I cases, but in grade II and III, 63.6% of cases each were immunoreactive. Correlation between histological grade and p63 immunoreactivity was significant (P =.02). p63-positive grade I meningiomas did not show elevated Ki-67 index. The present study contradicts earlier reports because there are a considerable number of grade I meningiomas that express p63. Although p63 expression is significantly associated with higher histological grade of meningiomas, it may not be considered as a sole biomarker to assess aggressive behavior of the tumor. © The Author(s) 2012.

News Article | December 12, 2016

Healthcare group Paras Healthcare, which runs Paras Hospitals in north India, has started talks with private equity (PE) funds to raise about Rs350-400 crore to finance expansion, two people aware of the matter said.

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