48 results on '"Shivani Malik"'
Search Results
2. Histomorphological and Morphometric Evaluation of Microvessel Density in Nodal Non-Hodgkin Lymphoma Using CD34 and CD105
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Sant Prakash Kataria, Shivani Malik, Roomi Yadav, Raman Kapil, and Rajeev Sen
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angiogenesis ,cd105 ,microvessel density ,non-hodgkin lymphoma ,Medicine - Abstract
Background Expression of angiogenic markers determined by microvessel density (MVD) could be used as a reliable predictor of prognosis and as a potential target for antiangiogenic therapy in different categories of non-Hodgkin lymphoma (NHL). Aims The aim of this study was to evaluate MVD using immunohistochemical methods and computer-assisted quantitative image analysis in nodal NHL patients and compare CD34 and CD105 expression in lymph nodes of NHL patients. Materials and Methods The present study was conducted on 60 lymph node biopsies received in the Department of Pathology at our tertiary care center for histopathological examination. Representative paraffin-embedded tissue sections were stained with hematoxylin and eosin along with immunohistochemical stains for CD34 and CD105. MVDs were analyzed at 400× using automated image analyzer by two investigators independently. Statistical Analysis Data were calculated, tabulated, and statistically analyzed using SPSS (Statistical Package for Social Studies) statistical program version 18. The values entered were mean of morphometric parameters. In all tests, p-values below 0.05 were regarded as significant. Results MVD was determined by CD34 and CD105 antibody highly correlated with different categories of NHL. Higher MVD was observed in cases of aggressive NHL as compared with indolent NHL and the difference was statistically significantly. MVD using CD105 was correlated more strongly as compared to CD34 with different categories of NHL. Conclusion The present study concluded that NHL exhibits potent angiogenic activity that increased significantly with increasing aggressiveness. The study also demonstrated that CD105 is more specific than CD34 as a marker of neoangiogenesis in NHL.
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- 2021
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3. Evolution of a guarded decoy protease and its receptor in solanaceous plants
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Jiorgos Kourelis, Shivani Malik, Oliver Mattinson, Sonja Krauter, Parvinderdeep S. Kahlon, Judith K. Paulus, and Renier A. L. van der Hoorn
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Science - Abstract
Abstract Rcr3 is a secreted protease of tomato that is targeted by fungal effector Avr2, a secreted protease inhibitor of the fungal pathogen Cladosporium fulvum. The Avr2-Rcr3 complex is recognized by receptor-like protein Cf-2, triggering hypersensitive cell death (HR) and disease resistance. Avr2 also targets Rcr3 paralog Pip1, which is not required for Avr2 recognition but contributes to basal resistance. Thus, Rcr3 acts as a guarded decoy in this interaction, trapping the fungus into a recognition event. Here we show that Rcr3 evolved > 50 million years ago (Mya), whereas Cf-2 evolved
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- 2020
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4. A non-canonical BRD9-containing BAF chromatin remodeling complex regulates naive pluripotency in mouse embryonic stem cells
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Jovylyn Gatchalian, Shivani Malik, Josephine Ho, Dong-Sung Lee, Timothy W. R. Kelso, Maxim N. Shokhirev, Jesse R. Dixon, and Diana C. Hargreaves
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Science - Abstract
The BAF complex is a multi-subunit chromatin remodeling complex that plays important roles in transcription regulation. Here the authors provide evidence that BRD9 and GLTSCR1/BICRA or its paralog GLTSCR1-like/BICRAL define a non-canonical BAF complex that regulates naive pluripotency in mouse embryonic stem cells.
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- 2018
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5. Eosinophil-rich Variant of Follicular Dendritic Sarcoma of Cervical Lymph Node: An Extremely Rare Entity
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Rajeev Sen, Sumiti Gupta, Shivani Malik, Sunita Singh, Rajnish Kalra, and Vipul Bansal
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Follicular ,Dendritic sarcoma ,Eosinophil ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Follicular dendritic cell neoplasms are extremely rare. Information regarding the accurate treatment and prognosis is limited owing to their rarity; thus, this tumor encompasses a domain to be brought into focus. Clinical and pathological diagnoses warrant a high index of suspicion as this entity is not considered in routine clinical practice. Histopathologically it mimics various other neoplasms which lead to higher chances of misdiagnosis at initial evaluation. Use of follicular dendritic cell immunohistochemical markers CD 21 and CD 35 helps in rendering a definitive diagnosis.
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- 2018
6. Unilateral Malignant Pleural Effusion as an Initial Manifestation of Acute Lymphoblastic Leukemia: A Rare Case Report
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Sonia Chabbra, Rajneesh Kalra, Shivani Malik, Sunita Singh, Gurpreet Singh, Pansi Gupta, and Rajeev Sen
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Unilateral malignant pleural effusion as an initial manifestation that leads to the diagnosis of an underlying acute lymphoblastic leukemia is a rare event. Early and accurate diagnosis of this case is important for prompt and adequate therapy. We present the case of an18-year-old male who presented to the emergency department with severe respiratory distress. Chest X-ray revealed a unilateral massive right-sided pleural effusion. Cytological examination of the pleural fluid led to the diagnosis of underlying acute lymphoblastic leukemia. Subsequent hemogram, bone marrow aspirate and flow cytometry analysis confirmed the diagnosis of T-lineage acute lymphoblastic leukemia. The patient underwent induction chemotherapy which led to significant clinical improvement due to resolution of the pleural effusion. The patient is on follow up at present. This case report exemplifies and highlights the importance of cytopathological analysis of body cavity fluids in the diagnosis of underlying unsuspected malignancies.
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- 2015
7. Colloid goiter in ectopic thyroid tissue presenting as submandibular swelling with a coexisting functional orthotopic thyroid gland in a pregnant female
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Renuka Verma, Sumiti Gupta, Rajnish Kalra, Rajeev Sen, Swagatika Samal, Jyoti Sharma, and Shivani Malik
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Cytology ,QH573-671 - Published
- 2016
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8. A prospective randomized comparative study to evaluate the effect of palliative hypo-fractionated radiotherapy with concurrent chemotherapy versus hypo-fractionated radiotherapy alone in advanced and unresectable head and neck cancer with no metastasis
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Aditya Kumar Attam, Arun Kumar Yadav, Shreya Jalota, Renu Singh, Shivani Malik, and Ashok Kumar Arya
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Cancer Research ,Oncology - Published
- 2023
9. Tipifarnib potentiates the antitumor effects of PI3Kα inhibition inPIK3CA- andHRAS-dysregulated HNSCC via convergent inhibition of mTOR activity
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Alison E. Smith, Stacia Chan, Zhiyong Wang, Asako McCloskey, Quinn Reilly, Jayden Z. Wang, Hetika Vora Patel, Keiichi Koshizuka, Harris S. Soifer, Linda Kessler, Ashley Dayoub, Victoria Villaflor, Douglas Adkins, Justine Bruce, Alan Ho, Cesar Perez Batista, Glenn Hanna, Amaya Gascó Hernández, Andrew Saunders, Stephen Dale, J. Silvio Gutkind, Francis Burrows, and Shivani Malik
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Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival ranging from 6 to 18 months. For those who progress on standard of care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we targeted the key HNSCC drivers PI3K-mTOR and HRAS via the combination of tipifarnib, a farnesyltransferase inhibitor, and alpelisib, a PI3Kα inhibitor, in multiple molecularly defined subsets of HNSCC. We find that tipifarnib synergizes with alpelisib at the level of mTOR in PI3Kα-or HRAS-dependent HNSCCs, leading to marked cytotoxicityin vitroand tumor regressionin vivo. Based on these findings, we have launched the KURRENT-HN trial to evaluate the effectiveness of this combination in PIK3CA-mutant/amplified and/or HRAS-overexpressing R/M HNSCC. Preliminary evidence supports the clinical activity of this molecular biomarker-driven combination therapy.SignificanceBacked by strong mechanistic rationale, the combination of alpelisib and tipifarnib has the potential to benefit >45% of R/M HNSCC patients. By blocking feedback reactivation of mTORC1, tipifarnib may prevent adaptive resistance to additional targeted therapies, thereby enhancing their clinical utility.
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- 2023
10. Clinical Profile of Indian Children with Down Syndrome
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Inusha Panigrahi, Yogita Bhatt, Shivani Malik, Parminder Kaur, and Anupriya Kaur
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Down syndrome ,education.field_of_study ,Pediatrics ,medicine.medical_specialty ,business.industry ,Population ,030209 endocrinology & metabolism ,Retrospective cohort study ,Disease ,medicine.disease ,Atrial septal defects ,03 medical and health sciences ,0302 clinical medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Neonatal cholestasis ,education ,business ,Cardiac disorders ,030217 neurology & neurosurgery ,Genetics (clinical) - Abstract
This retrospective study was performed on 208 patients with Down syndrome (DS) from heterogeneous ethnic population and admitted under Genetics Metabolic Unit. The aim of the study was to look for phenotypic variability and associated complications in children and adolescents with DS. The average age of the evaluated DS patients was 34 months. Cardiac anomalies were found in 128 (62%) of the 208 cases. Among the cardiac disorders, atrial septal defects accounted for 30% of cases. Other complications observed were hypothyroidism and developmental delay in around 31% cases and neonatal cholestasis in 14% cases. Also, we report two cases with Moya-Moya disease and one case with atlanto-axial dislocation.
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- 2021
11. Abstract 1079: Combination of tipifarnib with KRAS G12C inhibitors to prevent adaptive resistance
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Hetika Vora Patel, Alison Smith, Stacia Chan, Linda Kessler, Francis Burrows, and Shivani Malik
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Cancer Research ,Oncology - Abstract
Selective KRAS G12C inhibitors, including AMG510 (sotorasib) and MRTX849 (adagrasib), have exhibited clinical activity in patients with non-small cell lung cancer (NSCLC); however, drug resistance and relapse inevitably occur through various mechanisms, which limits the ability of these therapeutic agents to achieve durable responses. Resistance mechanisms include feedback reactivation of compensatory, oncogenic signaling pathways and the attainment of a drug-tolerant state, each of which allows cancer cells to survive the anti-tumor effects of these highly active drugs. Compensatory mechanisms ameliorating KRAS blockade include HRAS/NRAS and the PI3K-AKT-mTOR pathway. Tipifarnib is a clinical stage farnesyltransferase inhibitor known to inhibit multiple farnesylation-dependent proteins in tumor cells. We have recently shown that tipifarnib can prevent feedback-mediated adaptive resistance to the PI3Kα inhibitor, alpelisib, through inhibition of both HRAS and RHEB, allowing simultaneous blockade of two key nodes of the oncogenic MAPK- and PI3K-signaling pathways. In another example, tipifarnib has been demonstrated by others to inhibit the ability of tumor cells to enter a drug-tolerant state induced by the EGFR inhibitor, osimertinib, in EGFR-mutant NSCLC models. In these models, inhibition of farnesylation of certain RHO proteins appear to contribute to the death of drug-tolerant cells prior to the emergence of acquired resistance mutations. Building on these two mechanisms of how tipifarnib may prevent adaptive resistance, we propose that tipifarnib can be used as an effective partner drug to delay or prevent the onset of adaptive resistance to KRAS G12C inhibitors. We have conducted in vitro 2D and 3D viability and regrowth experiments using combinations of tipifarnib with KRAS G12C inhibitors and have observed synergistic, anti-proliferative effects in KRAS G12C NSCLC cell lines as well as enhanced activity of combination in a KRAS G12C NSCLC PDX model. We are currently expanding the scope of in vitro and in vivo combination studies to further evaluate the molecular mechanism(s) of resistance that tipifarnib targets when combined with KRAS G12C inhibitors. Citation Format: Hetika Vora Patel, Alison Smith, Stacia Chan, Linda Kessler, Francis Burrows, Shivani Malik. Combination of tipifarnib with KRAS G12C inhibitors to prevent adaptive resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1079.
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- 2023
12. Abstract 1071: Tipifarnib synergizes with TKIs in clear cell renal cell carcinoma models
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Jovylyn Gatchalian, Linda Kessler, Stacia Chan, Francis Burrows, and Shivani Malik
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Cancer Research ,Oncology - Abstract
Clear cell renal cell carcinoma (ccRCC) is a highly vascularized tumor type, primarily due to loss of the Von Hippel-Lindau (VHL) gene, which is observed in ~88% of ccRCC cases. Deletion of VHL stabilizes hypoxia-inducible factor alpha protein (HIFα) to drive the hypoxic transcriptional response, including induction of VEGF and PDGF2 that mediate tumor angiogenesis. Anti-angiogenic tyrosine kinase inhibitors (TKIs) such as sunitinib and axitinib have demonstrated therapeutic benefit in patients with ccRCC by exploiting the critical dependency of ccRCC tumors on the vasculature for oxygen, nutrients, and growth factors. However, resistance to TKIs is commonly observed, leading to clinical relapse. Here, we report that the combination of the farnesyltransferase inhibitor (FTI), tipifarnib, and any of several anti-angiogenic TKIs results in deeper and more durable responses in the VHL-mutant 786-O CDX model and an RCC PDX model, compared to TKI alone. While the anti-angiogenic TKIs or tipifarnib alone merely slowed or occasionally arrested tumor growth, the TKI-tipifarnib combination induced marked tumor regressions in all treated animals. To investigate the mechanism of action, VHL-mutant RCC cell lines were subjected to hypoxia (1% O2) in vitro to mimic the hypoxic conditions induced by TKIs in vivo and were treated with tipifarnib to evaluate tipifarnib’s impact on signaling pathways in hypoxia-exposed cells. In the Caki2 cell line, hypoxia initially reduced mTOR signaling, but it rebounded strongly after 24 hours in hypoxia, suggesting that mTOR pathway reactivation is a potential mechanism of resistance to TKIs. Addition of tipifarnib blocked hypoxia-induced mTOR reactivation. Mechanistically, tipifarnib potently inhibits the farnesylation, and hence the activity, of an obligate farnesylated protein RHEB, a positive regulator of mTOR, suggesting that the synergy may arise through RHEB inhibition in this model. The mechanistic data in cell lines suggest that tipifarnib’s ability to inhibit mTOR reactivation observed in ccRCC cell lines under hypoxic stress contributes to the enhanced treatment durability observed in vivo. Because FTIs are pleiotropic drugs, there are likely additional cell intrinsic mechanisms that may influence synergy with TKIs. Further in vitro and in vivo studies are underway to establish the scope and mechanistic underpinnings of TKI-tipifarnib effects and strengthen the therapeutic rationale for combining TKIs with tipifarnib in the treatment of patients with ccRCC. Citation Format: Jovylyn Gatchalian, Linda Kessler, Stacia Chan, Francis Burrows, Shivani Malik. Tipifarnib synergizes with TKIs in clear cell renal cell carcinoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1071.
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- 2023
13. Evolution of a guarded decoy protease and its receptor in solanaceous plants
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Parvinderdeep S Kahlon, Sonja Krauter, Renier A. L. van der Hoorn, Judith K Paulus, Shivani Malik, Oliver Mattinson, and Jiorgos Kourelis
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0301 basic medicine ,Proteases ,medicine.medical_treatment ,Science ,General Physics and Astronomy ,Nicotiana benthamiana ,02 engineering and technology ,Plant disease resistance ,Genes, Plant ,Solanum ,Petunia ,General Biochemistry, Genetics and Molecular Biology ,Article ,Microbiology ,Host-Parasite Interactions ,Evolution, Molecular ,Fungal Proteins ,03 medical and health sciences ,Plant immunity ,Tobacco ,medicine ,Protease Inhibitors ,lcsh:Science ,Phylogeny ,Disease Resistance ,Plant Diseases ,Plant Proteins ,Pattern recognition receptors in plants ,Multidisciplinary ,Protease ,biology ,Effector ,fungi ,food and beverages ,General Chemistry ,021001 nanoscience & nanotechnology ,biology.organism_classification ,Protease inhibitor (biology) ,Effectors in plant pathology ,030104 developmental biology ,lcsh:Q ,0210 nano-technology ,Plant sciences ,Cladosporium ,medicine.drug ,Peptide Hydrolases - Abstract
Rcr3 is a secreted protease of tomato that is targeted by fungal effector Avr2, a secreted protease inhibitor of the fungal pathogen Cladosporium fulvum. The Avr2-Rcr3 complex is recognized by receptor-like protein Cf-2, triggering hypersensitive cell death (HR) and disease resistance. Avr2 also targets Rcr3 paralog Pip1, which is not required for Avr2 recognition but contributes to basal resistance. Thus, Rcr3 acts as a guarded decoy in this interaction, trapping the fungus into a recognition event. Here we show that Rcr3 evolved > 50 million years ago (Mya), whereas Cf-2 evolved, Avr2 is an effector secreted by the phytopathogen Cladosporium fulvum to inhibit Rcr3, an apoplastic protease of solanaceous plants. Here the authors show that this interaction predates the emergence of Cf-2, an R-gene that evolved in Solanum to co-opt an existing effector-target reaction and trigger resistance.
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- 2020
14. Abstract 1120: Tipifarnib potentiates the antitumor effects of PI3Ka blockade in HNSCC via convergent inhibition of mTOR activity
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Shivani Malik, Alison Smith, Stacia Chan, Asako McCloskey, Hetika Vora, Quinn Reilly, and Francis Burrows
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Cancer Research ,Oncology - Abstract
The PI3K-AKT-mTOR signaling cascade is the most frequently activated pathway in the head and neck squamous cell carcinomas (HNSCC). PIK3CA (encoding PI3K’s α catalytic subunit), is activated by gain-of-function mutation or amplification in approximately 30% of HNSCCs, making PI3Kα an attractive therapeutic candidate. While the PI3Kα inhibitor alpelisib has shown some promise in HNSCC in a phase I setting, its single agent efficacy will likely be limited by feedback reactivation of PI3K or compensatory parallel pathways, necessitating the development of rational combination strategies. Here, we utilize cell line and patient-derived xenograft (PDX) models to evaluate the therapeutic potential of the farnesyltransferase inhibitor (FTI) tipifarnib, in combination with alpelisib in the PIK3CA-dysregulated subset of HNSCC. Because FTIs potentially block hyperactivated growth factor signaling at multiple nodes, including HRAS and RHEB, we examined tipifarnib’s impact on growth of PIK3CA-altered HNSCC models in vitro and in vivo. In cell lines harboring PIK3CA mutation or amplification, tipifarnib reduced proliferation of both monolayer and spheroid cultures and when combined with alpelisib, induced cytotoxicity. Consistently, in PIK3CA mutant/amplified PDX models, the tipifarnib-alpelisib doublet led to deeper antitumor responses compared to alpelisib monotherapy. Simultaneous administration was superior to split intermittent dosing, hinting at cooperativity between the mechanistic targets of tipifarnib and alpelisib. To interrogate the mechanistic underpinnings of this synergy, we exposed HNSCC cell lines to tipifarnib, alpelisib, or the combination, and assessed their effect on RAS/PI3K pathway activity. In PIK3CA dysregulated lines, single agent tipifarnib or alpelisib reduced phosphorylation of p90 RSK, and mTOR substrates, particularly S6 kinase and ribosomal protein S6. Combination treatment effects were more robust and induced rapid apoptosis. In cells exposed to alpelisib alone, marked rebound of RSK and mTOR substrate phosphorylation occurred after 24 hours, correlating with restored AKT activity. In contrast, although AKT activity rebounded in cells treated with the combination, RSK phosphorylation and markers of mTOR activity (including 4EBP1) remained suppressed. Thus, tipifarnib appears to blunt both MAPK and mTOR reactivation following PI3K inhibition. This dual effect implies that the efficacy of tipifarnib in this context may stem from simultaneous defarnesylation of multiple targets, likely HRAS and RHEB, which converge upon mTOR and synergize with alpelisib to durably block tumor growth. We contend that combination of alpelisib and tipifarnib holds therapeutic potential for treatment of recurrent/metastatic HNSCCs harboring dysregulated PIK3CA, which will be evaluated in the recently initiated KURRENT clinical trial (NCT04997902). Citation Format: Shivani Malik, Alison Smith, Stacia Chan, Asako McCloskey, Hetika Vora, Quinn Reilly, Francis Burrows. Tipifarnib potentiates the antitumor effects of PI3Ka blockade in HNSCC via convergent inhibition of mTOR activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1120.
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- 2022
15. Mutant KRAS regulates transposable element RNA and innate immunity via KRAB zinc-finger genes
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Roman E. Reggiardo, Sreelakshmi Velandi Maroli, Haley Halasz, Mehmet Ozen, Eva Hrabeta-Robinson, Amit Behera, Vikas Peddu, David Carrillo, Erin LaMontagne, Lila Whitehead, Eejung Kim, Shivani Malik, Jason Fernandes, Georgi Marinov, Eric Collisson, Angela Brooks, Utkan Demirci, and Daniel H. Kim
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Proto-Oncogene Proteins p21(ras) ,Zinc ,Genes, ras ,Cell Line, Tumor ,Mutation ,DNA Transposable Elements ,Humans ,RNA ,General Biochemistry, Genetics and Molecular Biology ,Immunity, Innate - Abstract
RAS genes are the most frequently mutated oncogenes in cancer, yet the effects of oncogenic RAS signaling on the noncoding transcriptome remain unclear. We analyzed the transcriptomes of human airway and bronchial epithelial cells transformed with mutant KRAS to define the landscape of KRAS-regulated noncoding RNAs. We find that oncogenic KRAS signaling upregulates noncoding transcripts throughout the genome, many of which arise from transposable elements (TEs). These TE RNAs exhibit differential expression, are preferentially released in extracellular vesicles, and are regulated by KRAB zinc-finger (KZNF) genes, which are broadly downregulated in mutant KRAS cells and lung adenocarcinomas in vivo. Moreover, mutant KRAS induces an intrinsic IFN-stimulated gene (ISG) signature that is often seen across many different cancers. Our results indicate that mutant KRAS remodels the repetitive noncoding transcriptome, demonstrating the broad scope of intracellular and extracellular RNAs regulated by this oncogenic signaling pathway.
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- 2020
16. SMARCA4 supports the oncogenic landscape of KRAS-driven lung tumors
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Shivani Malik, Masaya Oshima, Nilotpal Roy, Swati Kaushik, Ora Kuvshinova, Wei Wu, John E. Greer, Shon Green, Martin McMahon, Kuang-Yu Jen, Matthias Hebrok, Sourav Bandyopadhyay, Diana C. Hargreaves, and Eric A. Collisson
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0303 health sciences ,cells ,genetic processes ,Cancer ,macromolecular substances ,Biology ,medicine.disease ,medicine.disease_cause ,3. Good health ,03 medical and health sciences ,enzymes and coenzymes (carbohydrates) ,0302 clinical medicine ,Cell culture ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,medicine ,SMARCA4 ,Chromatin maintenance ,Adenocarcinoma ,KRAS ,biological phenomena, cell phenomena, and immunity ,Gene ,030304 developmental biology - Abstract
Cancer resequencing studies identify recurrent mutations in the switch/sucrose non-fermentable (SWI/SNF) complex at an unexpectedly high frequency across many cancer types. Some SWI/SNF mutations appear to be loss-of-function events, implying that the intact SWI/SNF complex is tumor suppressive. We examined the distribution and function of SMARCA4 mutations, the most frequently mutated SWI/SNF complex gene in lung adenocarcinoma, using human cancers, cell lines and mouse model systems. We found that lung adenocarcinomas harboring activated oncogenes have fewer deleterious mutations in SMARCA4 and express higher levels of the mRNA than cancers without activated oncogenes, indicating distinct dependencies on SMARCA4 in these two settings. Surprisingly, intact Smarca4 promoted the growth and tumorgenicity of KrasG12D-driven mouse lung tumors and human cells. Mechanistically, we found that Smarca4 supports the oncogenic transcriptional/signaling landscape of KrasG12D-driven mouse lung cancer. This dependency on the chromatin maintenance machinery in established cancer cells support treatments directed towards pathogenic SWI/SNF complexes in lung adenocarcinoma and other malignancies.
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- 2020
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17. Morphological Patterns of Anaemia and Prevalence of Haemoglobinopathy in State of Haryana
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Richa Pawar, Shivani Malik, Sunita Singh, Sonia Kaur Singh, Rinky Langan, and Rajiv Sen
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Pediatrics ,medicine.medical_specialty ,Thalassemia Minor ,business.industry ,Thalassemia ,medicine.disease ,Hemoglobinopathy ,medicine ,Trait ,General Earth and Planetary Sciences ,Population study ,Statistical analysis ,Thalassemia intermedia ,business ,General Environmental Science - Abstract
Background: Hemoglobinopathies including thalassemias are important prevalent group of erythrocytic genetic disorders found in various parts of the world and are important cause of morbidity and mortality. Methods: Samples were run on 5 part differential cell counter and after analyzing various RBC parameters and peripheral smear, the appropriate sample on biorad HPLC for hemoglobinopathy and mutation study was done. Statistical analysis performed. Study population included two groups- anemic pregnant women and students. Result: Out of 361 cases; 27 were positive for haemoglobinopathies giving a prevalence of 7.5 % in anemic mothers. Positive cases included 22 cases of β-thalassemia trait, 2 HbS trait, 1 case of HbD trait, 1 case of HbE trait and 1 case of HbE homozygous. Out of a total of 630 cases, 38 were found positive for various haemoglobinopathies including 36 cases of β-thalassemia trait, 1 case of thalassemia intermedia and 1 case of HbLepore. DNA analysis was done for 10 cases in which the common mutation found was IVSI-5 followed by codon 41/42 and codon 8/9 Conclusion: Proper screening studies should be done to diagnose the cases and reduce the prevalence of thalassemia major by informing and educating such cases.
- Published
- 2018
18. CXCL12 in Pancreatic Cancer: Its Function and Potential as a Therapeutic Drug Target
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Shivani Malik, Jill M. Westcott, Rolf A. Brekken, and Francis J. Burrows
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CXCR4 ,Cancer Research ,endocrine system diseases ,Oncology ,cancer-associated fibroblast ,pancreatic cancer ,tumor microenvironment ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Hypothesis ,CXCL12 ,RC254-282 ,digestive system diseases - Abstract
Simple Summary Pancreatic cancer is a challenging disease to treat effectively. Fibroblasts associated with pancreatic cancer contribute to disease progression by secreting factors that enhance tumor cell survival and help tumor cells avoid detection by the immune system. This overview focuses on a chemokine, CXCL12, produced by cancer-associated fibroblasts and how CXCL12 signaling enhances pancreatic cancer progression by contributing to various hallmarks of cancer including, but not limited to, tumor growth and evasion of immune response. These pro-oncogenic functions of CXCL12 make it an attractive target in pancreatic cancer. We discuss the different approaches in development to therapeutically target CXCL12 and finally propose a novel approach, the use of the farnesyl transferase inhibitor tipifarnib to inhibit CXCL12 expression in pancreatic fibroblasts. Abstract Pancreatic ductal adenocarcinoma (PDAC) is a disease with limited therapeutic options and dismal long-term survival. The unique tumor environment of PDAC, consisting of desmoplastic stroma, immune suppressive cells, and activated fibroblasts, contributes to its resistance to therapy. Activated fibroblasts (cancer-associated fibroblasts and pancreatic stellate cells) secrete chemokines and growth factors that support PDAC growth, spread, chemoresistance, and immune evasion. In this review, we focus on one such chemokine, CXCL12, secreted by the cancer-associated fibroblasts and discuss its contribution to several of the classical hallmarks of PDAC and other tumors. We review the various therapeutic approaches in development to target CXCL12 signaling in PDAC. Finally, we propose an unconventional use of tipifarnib, a farnesyl transferase inhibitor, to inhibit CXCL12 production in PDAC.
- Published
- 2021
19. Abstract P123: Antitumor activity of tipifarnib and PI3K pathway inhibitors in HRAS-associated HNSCC
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Francis Burrows, Shivani Malik, Stacia Chan, Asako Mccloskey, Zhiyong Wang, Mara Gilard, and Silvio Gutkind
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Cancer Research ,Oncology - Abstract
HRAS-MAPK and PI3K-AKT-mTOR are important oncogenic pathways in head and neck squamous cell carcinoma (HNSCC) and other squamous cell carcinomas (SCCs). HRAS is mutated in ~5% and overexpressed in approximately 30% of HNSCC patients, raising the possibility that some HRAS wild-type (WT) HNSCCs may also display a degree of dependence on HRAS. RAS proteins undergo several post-translational modifications, including the addition of a farnesyl isoprenoid moiety by the enzyme farnesyltransferase (FT), which facilitate their attachment to membranes. This dependence prompted the development of selective inhibitors (FTIs) for the treatment of RAS-driven cancers. Tipifarnib is a potent and selective FTI that has demonstrated antitumor activity in recurrent/metastatic HNSCC carrying HRAS mutations. Based on these data, a pivotal study (NCT03719690) evaluating the efficacy of tipifarnib in HRAS mutant HNSCC (AIM-HN) is currently ongoing. PIK3CA (the catalytic subunit of PI3K), another prominent driver in HNSCC, is commonly activated either by gain of function mutations or gene amplification with some overlap between the two subsets. Multiple reports indicate that HRAS and PIK3CA pathways cooperate and crosstalk in driving tumor progression in SCCs and resistance to inhibitors of respective pathways. In this study, we explored whether combined inhibition of HRAS farnesylation (by tipifarnib) and inhibition of PI3K pathway signaling (with inhibitors of PI3K-a, AKT or mTORC1/2) would be more effective in CDX and PDX models of HRAS-associated SCCs relative to the monotherapy approaches. In a panel of HNSCC cell lines harboring HRAS and/or PIK3CA alterations (mutation, overexpression or amplification), tipifarnib reduced cell growth and, in combination with PI3K-a inhibitor alpelisib, induced cytotoxicity. Consistent with in vitro findings, robust inhibition of tumor growth was observed in majority of animals treated with the combination of tipifarnib and alpelisib. Similar activity was noted with the AKT inhibitor uprosertib and the mTORC1/2 inhibitor sapanisertib. Regressions with the FTI-PI3K-a inhibitor doublet were observed both in tumors that were HRAS mutant or HRAS overexpressed with or without mutation or amplification of the PIK3CA gene or carried the latter without alterations in HRAS, suggesting that concomitant blockade of both targets may have surprisingly broad and potent anti-tumor activity in HNSCC. In dose-scheduling experiments in PDX models, simultaneous blockade of both targets was superior to split intermittent dosing of the two drugs, underlining the cooperativity of the two pathways in these models. Mechanistically, tipifarnib repressed the compensatory MAPK pathway activation induced by alpelisib at the level of phosphorylated ribosomal S6 protein. Impact of tipifarnib and alpelisib combination on additional MAPK and AKT signaling mediators will be reported. Citation Format: Francis Burrows, Shivani Malik, Stacia Chan, Asako Mccloskey, Zhiyong Wang, Mara Gilard, Silvio Gutkind. Antitumor activity of tipifarnib and PI3K pathway inhibitors in HRAS-associated HNSCC [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P123.
- Published
- 2021
20. Potential of Farnesyl Transferase Inhibitors in Combination Regimens in Squamous Cell Carcinomas
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Linda Kessler, Francis Burrows, Shivani Malik, and Mollie Leoni
- Subjects
Cisplatin ,Cancer Research ,farnesyl transferase ,Cetuximab ,business.industry ,Farnesyl Transferase Inhibitor ,Cell ,tipifarnib ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,combination regimen ,Context (language use) ,Hypothesis ,medicine.disease ,HNSCC ,Head and neck squamous-cell carcinoma ,stomatognathic diseases ,medicine.anatomical_structure ,Oncology ,Cancer research ,Medicine ,Tipifarnib ,HRAS ,business ,RC254-282 ,medicine.drug - Abstract
Simple Summary Current therapies for recurrent and metastatic squamous cell carcinomas (SCCs) are associated with poor patient outcomes, and options for later lines of treatment are very limited. In cases where single-agent therapy may be insufficient to eradicate the tumor, thus allowing outgrowth of resistant cells, a well-chosen combination of therapeutic agents may enable improved outcomes. Tipifarnib, a farnesyl transferase inhibitor, is a small molecule drug candidate that has demonstrated promising clinical activity in HRAS-mutant head and neck squamous cell carcinoma (HNSCC). New molecular analyses suggest that HRAS may also be important in some HNSCC cases where it is not mutated, which might allow tipifarnib to be active in a broader population of HNSCC patients when used in combination with other agents such as cisplatin, cetuximab, or alpelisib. Other non-HRAS oncoproteins that can also be blocked by tipifarnib may offer alternative approaches to combination regimens for SCCs. Abstract Current therapies for recurrent and metastatic SCC are associated with poor outcomes, and options for later lines of treatment are limited. Insights into potential therapeutic targets, as well as mechanisms of resistance to available therapies, have begun to be elucidated, creating the basis for exploration of combination approaches to drive better patient outcomes. Tipifarnib, a farnesyl transferase inhibitor (FTI), is a small molecule drug that has demonstrated encouraging clinical activity in a genetically-defined subset of head and neck squamous cell carcinoma (HNSCC)–specifically, tumors that express a mutation in the HRAS protooncogene. More recently, bioinformatic analyses and results from patient-derived xenograft modeling indicate that HRAS pathway dependency may extend to a broader subpopulation of SCCs beyond HRAS mutants in the context of combination with agents such as cisplatin, cetuximab, or alpelisib. In addition, tipifarnib can also inactivate additional farnesylated proteins implicated in resistance to approved therapies, including immunotherapies, through a variety of distinct mechanisms, suggesting that tipifarnib could serve as an anchor for combination regimens in SCCs and other tumor types.
- Published
- 2021
21. Which are online shopping determinants Analysing ease and convenience to use, prior shopping experience, online benefits, social influence in India
- Author
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Shivani Malik, Navneet Gera, Rinki Garg, and Davide Di Fatta
- Subjects
Value (ethics) ,Marketing ,Point (typography) ,business.industry ,Questionnaire ,Advertising ,Usability ,Field (computer science) ,Exploratory factor analysis ,Management Information Systems ,Order (business) ,Business ,Business and International Management ,Social influence - Abstract
Online shopping is growing day by day with the help of technology and customer support. Provided that India is the second largest country in terms of internet users, the purpose of the study is to examine online shopping determinants. This topic is original and up to date not only from the academic point of view, but also from the practical one. Indeed, to attract internet users to the online shopping, retailers need to understand the drivers of such phenomenon. In order to reach the goal, primary data was collected through a questionnaire survey wherein judgemental sampling method has been used. Then an exploratory factor analysis was performed. Results highlight that 'ease of use and convenience' is the most relevant factor for online shopping since it represents 32% of total variance. This study not only will help online shopping business man to formulate their strategies, but also will add value to theoretical research field.
- Published
- 2021
22. Abstract B08: Therapeutic inhibition of YAP1 expression by next-generation antisense oligonucleotides leads to antitumor activity in head and neck squamous cell carcinoma with YAP1 activation
- Author
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Youngsoo Kim, A. Robert MacLeod, Stephanie Klein, Rachel Fleming, Joanna Schmidt, Xiaolin Luo, Shivani Malik, and Jian Li
- Subjects
YAP1 ,Cancer Research ,Hippo signaling pathway ,Cell growth ,Cancer ,Biology ,medicine.disease ,Head and neck squamous-cell carcinoma ,Oncology ,CYR61 ,Survivin ,medicine ,Cancer research ,Molecular Biology ,FAT1 - Abstract
As the final effector of the Hippo pathway, YAP1 plays a driver role in promoting growth of a variety of tumor types. Unlike other oncogenic pathways, however, genetic alterations on the core components of the Hippo pathway leading to YAP1 activation are rare and have not been well characterized. Therefore, identifying alternate pathway alterations leading to YAP1-dependent tumors will be critical for clinical success of potential YAP1-targeted therapies. Recent reports have suggested that frequent mutations of tumor suppressor FAT1 might contribute to the progression of YAP1-dependent head and neck squamous cell carcinoma (HNSCC). In this study, we have investigated the underlying mechanisms for YAP1 activation in HNSCC, developed a therapeutic agent for the specific suppression of YAP expression, and identified a HNSCC subtype that is highly sensitive to YAP1 inhibition. We first screened and identified active human YAP1 antisense oligonucleotides (ASOs) with next-generation (constrained ethyl=cEt) chemistry and then evaluated them in a broad panel of human HNSCC lines in vitro. The majority of HNSCC lines were highly amenable to ASO free uptake (without any transfection agents), resulting in strong reductions of YAP1 and its downstream target genes such as CTGF, Cyr61, and Survivin in a dose-dependent manner. However, phenotypic consequences of YAP1 depletion varied significantly among the cell lines and were dependent upon the levels of functional FAT1 protein. Cell proliferation was strongly reduced by YAP1 ASOs in the cell lines harboring homozygous copy loss or nonsense mutations of FAT1, while minimal antiproliferative activity was observed in cells with wild-type FAT1 or YAP1 amplification. Importantly, the nuclear localization of YAP1 appeared to be a key determining factor for the sensitivity of HNSCC cells to YAP1 ASOs. Unexpectedly, in contrast to oral tongue SCC (OTSCC) lines that were generally sensitive to YAP1 ASOs, proliferation of FAT1 mutant HNSCC lines originated from larynx were minimally affected by YAP1 inhibition even with near-complete depletion of YAP1, suggesting variable dependency of tumor cells on YAP1 for their growth among different subtypes of HNSCC. Moreover, when systemically administered into mice bearing OTSCC with FAT1 mutations, YAP1 ASOs greatly reduced YAP1 expression in tumors and suppressed tumor growth in subcutaneous and more notably oral orthotopic xenograft models. These results suggest that OTSCC with YAP1 activation due to FAT1 loss is highly dependent on YAP1 for growth and that YAP1 ASOs have promise for the treatment of this cancer. Finally, through an extensive selection process the human YAP1 ASO clinical development compound, YAP1Rx, has been identified. Citation Format: Xiaolin Luo, Youngsoo Kim, Joanna Schmidt, Jian Li, Rachel Fleming, Shivani Malik, Stephanie Klein, A. Robert MacLeod. Therapeutic inhibition of YAP1 expression by next-generation antisense oligonucleotides leads to antitumor activity in head and neck squamous cell carcinoma with YAP1 activation [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B08.
- Published
- 2020
23. Total output and switching in category fluency successfully discriminates Alzheimer's disease from Mild Cognitive Impairment, but not from frontotemporal dementia
- Author
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Kavita Shivani Malik, Jwala Narayanan, Tanya Perpetua D'Souza, Siddharth Ramanan, and Ellajosyula Ratnavalli
- Subjects
medicine.medical_specialty ,switching ,Cognitive Neuroscience ,verbal fluency ,Disease ,Original Articles ,Audiology ,medicine.disease ,Sensory Systems ,lcsh:RC321-571 ,Fluency ,mild cognitive impairment ,Neurology ,medicine ,Dementia ,Verbal fluency test ,Neurology (clinical) ,Geriatrics and Gerontology ,Cognitive impairment ,Psychology ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Cognitive psychology ,Frontotemporal dementia ,clustering ,dementia - Abstract
Verbal fluency tasks require generation of words beginning with a letter (phonemic fluency; PF) or from a category (category fluency; CF) within a limited time period. Generally, total output on CF has been used to discriminate Mild Cognitive Impairment (MCI) from Alzheimer's disease (AD), while poor PF has been used as a marker for behavioral-variant frontotemporal dementia (bvFTD). However, in the absence of this disparate performance, further characterization of the task becomes necessary.We examined whether fluency, as well as its components, clustering (successively generated words belonging to a category) and switching (shifting between categories) carried diagnostic utility in discriminating AD from MCI and bvFTD.PF (letter 'P') and CF ('animals') tasks were administered in English to patients with MCI (n=25), AD (n=37), and bvFTD (n=17). Clustering and switching scores were calculated using established criteria.Our findings suggested that up to 85% of AD and MCI could be successfully discriminated based on total number of responses and switching in CF alone. PF-CF disparity was not noted in AD or bvFTD. Performance on clustering or switching also proved insufficient to discriminate AD from bvFTD.Switching was found to be useful when differentiating AD from MCI. In AD and bvFTD, the course of progression of the disease may lead to attenuation of total number of responses produced on both tasks to an extent where clustering and switching may not be useful measures to discriminate these dementias from each other.Tarefas de fluência verbal requerem geração de palavras iniciadas por letras (fluência fonêmica; FF) ou por categoria (fluência por categoria; FC) dentro de um período limitado de tempo. Geralmente, a produção total na FC tem sido usada para discriminar o comprometimento cognitivo leve (CCL) da doença de Alzheimer, enquanto que, uma produção pobre em FF tem sido usada como marcador da variante comportamental da demência frontotemporal (vcDFT). Todavia, na ausência desta desproporção melhor caracterização torna-se necessária.Examinar se a fluência e seus componentes, agrupamentos (geração sucessiva de palavras pertencentes a uma categoria) e mudança (alternância entre categorias) teriam utilidade na discriminação entre DA, CCL e vcDFT.Tarefas de FF (letra P) e FC (animais) foram administradas em inglês a pacientes com CCL (n=25), DA (n=37) e vcDFT (n=17). Escores de agrupamentos e alternância foram calculados através dos critérios estabelecidos.Nossos achados sugeriram que 85% dos DA e CCL puderam ser discriminados com sucesso, baseando-se no número total de respostas e alternância na FC. A disparidade FF e FC não foi notada em DA ou vcDFT. O desempenho em agrupamento ou alternância também se provaram insuficientes para discriminar DA de vcDFT.Alternância foi útil na diferenciação DA de CCL. Em pacientes com DA e vcDFT a progressão das doenças podem levar à atenuação do número total de respostas produzidas em ambas as tarefas de modo que o agrupamento e alternância podem não ser medidas úteis na discriminação destas demências entre si.
- Published
- 2015
24. Primary breast mucormycosis: FNAC diagnosis of a rare entity
- Author
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Sant Prakash Kataria, Jyoti Sharma, Gajender Singh, Vinod Kumar, Shivani Malik, and Sanjay Kumar
- Subjects
Mucorales ,Pathology ,medicine.medical_specialty ,Angioinvasion ,Histology ,biology ,business.industry ,030231 tropical medicine ,Mucormycosis ,Rare entity ,General Medicine ,Disease ,medicine.disease ,biology.organism_classification ,Thrombosis ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Tissue necrosis ,030212 general & internal medicine ,Young female ,business - Abstract
Mucormycosis is the common name given to several different diseases caused by fungi in the order of mucorales. The clinical hallmark of these opportunistic pathogens in invasive mucormycosis is tissue necrosis resulting from angioinvasion and subsequent thrombosis. Rarely the disease may affect immunocompetent individuals. In addition, the breast involvement in this disease is very rare. Herein, we describe a case of primary breast mucormycosis diagnosed on fine needle aspiration cytology (FNAC), in an immunocompetent young female, which is extremely rare. Diagn. Cytopathol. 2016;44:761-763. © 2016 Wiley Periodicals, Inc.
- Published
- 2016
25. UNFOLDING THE LITERATURE OF A RARE CASE OF TRICHILEMMAL CARCINOMA
- Author
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Rajeev Sen, Anil Kumar Dhull, Shivani Malik, Rajeev Atri, and Vivek Kaushal
- Subjects
medicine.medical_specialty ,lcsh:R5-130.5 ,business.industry ,Trichilemmal Carcinoma ,TLCA ,Radiation-Induced ,Skin Neoplasms ,medicine.disease ,Dermatology ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Rare case ,Medicine ,Trichilemmal carcinoma ,030212 general & internal medicine ,business ,lcsh:General works - Abstract
A rare case of trichilemmal carcinoma in a 40-year-young female is reported. She presented with a horny ulcerated lesion over anterior aspect of left arm. Strong history of exposure to sun, which is the main contributory factor for its aetiopathogenesis is present. Patient underwent wide surgical excision and diagnosis was established on histopathological examination with positive surgical margins. Hence adjuvant radical radiotherapy was administered. She is now on disease free followup for last 4 years.
- Published
- 2016
26. Eukaryotic Gene Expression by RNA Polymerase II
- Author
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Geetha Durairaj, Shivani Malik, and Sukesh R. Bhaumik
- Subjects
0301 basic medicine ,biology ,Chemistry ,Eukaryotic transcription ,RNA-dependent RNA polymerase ,RNA polymerase II ,Molecular biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,biology.protein ,RNA polymerase I ,Transcription factor II D ,RNA polymerase II holoenzyme ,030217 neurology & neurosurgery ,Small nuclear RNA ,Polymerase - Published
- 2017
27. Regulation of active genome integrity and expression by Rad26p
- Author
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Sukesh R. Bhaumik and Shivani Malik
- Subjects
musculoskeletal diseases ,Premature aging ,DNA Repair ,Transcription, Genetic ,DNA repair ,Review ,Biology ,Cockayne syndrome ,chemistry.chemical_compound ,Transcription (biology) ,medicine ,Humans ,Cockayne Syndrome ,Poly-ADP-Ribose Binding Proteins ,Genetics ,Regulation of gene expression ,Genome, Human ,DNA Helicases ,Cell Biology ,medicine.disease ,Chromatin ,DNA Repair Enzymes ,Gene Expression Regulation ,chemistry ,Mutation ,Human genome ,DNA - Abstract
Rad26p is a SWI/SNF-like ATPase in yeast, and is conserved among eukaryotes. Both Rad26p and its human homolog CSB (Cockayne syndrome group B) are involved in regulation of chromatin structure, transcription and DNA repair. Thus, mutations or malfunctions of these proteins have significant effects on cellular functions. Mutations in CSB are associated with Cockayne syndrome (CS) that is characterized by heterogeneous pathologies such as mental and physical retardation, sun sensitivity, premature aging, muscular and skeletal abnormalities, and progressive decline in neurological and cognitive functions. Therefore, many research groups focused their studies to understand the mechanisms of Rad26p/CSB functions to illuminate the molecular bases of CS. These studies have provided significant functional and mechanistic insights of Rad26p/CSB in regulation of gene expression and genome integrity as described here.
- Published
- 2014
28. Rrd1p, an RNA polymerase II-specific prolyl isomerase and activator of phosphoprotein phosphatase, promotes transcription independently of rapamycin response
- Author
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Bhawana Uprety, Shweta Lahudkar, Shivani Malik, Sukesh R. Bhaumik, Rwik Sen, and Sarah Frankland-Searby
- Subjects
Transcriptional Activation ,Saccharomyces cerevisiae Proteins ,Transcription, Genetic ,Response element ,RNA polymerase II ,Stimulation ,Biology ,Biochemistry ,Galactokinase ,Transcription (biology) ,Gene Expression Regulation, Fungal ,Genetics ,Prolyl isomerase ,Coding region ,Promoter Regions, Genetic ,Gene ,Molecular Biology ,Transcription Initiation, Genetic ,Regulation of gene expression ,Phosphoprotein phosphatase ,Sirolimus ,General transcription factor ,Activator (genetics) ,Intracellular Signaling Peptides and Proteins ,Promoter ,Peptidylprolyl Isomerase ,Molecular biology ,3. Good health ,biology.protein ,Trans-Activators ,RNA Polymerase II ,Biotechnology - Abstract
Rrd1p (resistance to rapamycin deletion 1) has been previously implicated in controlling transcription of rapamycin-regulated genes in response to rapamycin treatment. Intriguingly, we show here that Rrd1p associates with the coding sequence of a galactose-inducible and rapamycin non-responsive GAL1 gene, and promotes the association of RNA polymerase II with GAL1 in the absence of rapamycin treatment following transcriptional induction. Consistently, nucleosomal disassembly at GAL1 is impaired in the absence of Rrd1p, and GAL1 transcription is reduced in the Δrrd1 strain. Likewise, Rrd1p associates with the coding sequences of other rapamycin non-responsive and inducible GAL genes to promote their transcription in the absence of rapamycin treatment. Similarly, inducible, but rapamycin-responsive, non-GAL genes such as CTT1, STL1 and CUP1 are also regulated by Rrd1p. However, transcription of these inducible GAL and non-GAL genes is not altered in the absence of Rrd1p when the steady-state is reached after long transcriptional induction. Consistently, transcription of the constitutively active genes is not changed in the Δrrd1 strain. Taken together, our results demonstrate a new function of Rrd1p in stimulation of initial rounds of transcription, but not steady-state/constitutive transcription, of both rapamycin-responsive and non-responsive genes independently of rapamycin treatment.
- Published
- 2014
29. PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance
- Author
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Yan Song, Jeanine M. Ruggeri, Mats Ljungman, Christopher V.E. Wright, David K. Chang, Laura Leonhardt, Howard C. Crawford, Matthias Hebrok, David W. Dawson, Shan Gao, Shivani Malik, Kenneth K. Takeuchi, Joey H. Li, Megan T. Hoffman, Sapna Puri, Nilotpal Roy, Andrew V. Biankin, Christopher J. Halbrook, and Peter Bailey
- Subjects
0301 basic medicine ,endocrine system diseases ,pancreatic cancer ,Pancreatic Intraepithelial Neoplasia ,pancreatitis ,Acinar Cells ,medicine.disease_cause ,Cell Transformation ,Medical and Health Sciences ,Mice ,Tumor Cells, Cultured ,2.1 Biological and endogenous factors ,Aetiology ,skin and connective tissue diseases ,Cancer ,Cultured ,EMT ,Biological Sciences ,Chromatin ,Tumor Cells ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Cell Transformation, Neoplastic ,Pancreatic Ductal ,PDX1 ,Pancreas ,Research Paper ,Carcinoma, Pancreatic Ductal ,medicine.medical_specialty ,endocrine system ,education ,Biology ,digestive system ,03 medical and health sciences ,Rare Diseases ,Internal medicine ,Pancreatic cancer ,Genetics ,Acinar cell ,medicine ,Animals ,Humans ,Neoplastic transformation ,Homeodomain Proteins ,Neoplastic ,Carcinoma ,dedifferentiation ,Psychology and Cognitive Sciences ,medicine.disease ,Pancreatic Neoplasms ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,Tissue Array Analysis ,Cancer research ,Trans-Activators ,Carcinogenesis ,Digestive Diseases ,Gene Deletion ,Developmental Biology - Abstract
Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression.
- Published
- 2016
30. Inspirational decoys: a new hunt for effector targets
- Author
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Shivani Malik and Renier A. L. van der Hoorn
- Subjects
0301 basic medicine ,Binding Sites ,Full Paper ,Physiology ,Effector ,Research ,fungi ,food and beverages ,Plant Science ,Full Papers ,BED domain ,Biology ,Fight-or-flight response ,03 medical and health sciences ,030104 developmental biology ,Humans ,nucleotide‐binding and leucine‐rich repeat domain (NLR) ,plant immunity ,decoy ,genome ,Neuroscience - Abstract
Summary Plant immune receptors of the class of nucleotide‐binding and leucine‐rich repeat domain (NLR) proteins can contain additional domains besides canonical NB‐ARC (nucleotide‐binding adaptor shared by APAF‐1, R proteins, and CED‐4 (NB‐ARC)) and leucine‐rich repeat (LRR) domains. Recent research suggests that these additional domains act as integrated decoys recognizing effectors from pathogens. Proteins homologous to integrated decoys are suspected to be effector targets and involved in disease or resistance.Here, we scrutinized 31 entire plant genomes to identify putative integrated decoy domains in NLR proteins using the Interpro search. The involvement of the Zinc Finger–BED type (ZBED) protein containing a putative decoy domain, called BED, in rice (Oryza sativa) resistance was investigated by evaluating susceptibility to the blast fungus Magnaporthe oryzae in rice over‐expression and knock‐out mutants.This analysis showed that all plants tested had integrated various atypical protein domains into their NLR proteins (on average 3.5% of all NLR proteins). We also demonstrated that modifying the expression of the ZBED gene modified disease susceptibility.This study suggests that integration of decoy domains in NLR immune receptors is widespread and frequent in plants. The integrated decoy model is therefore a powerful concept to identify new proteins involved in disease resistance. Further in‐depth examination of additional domains in NLR proteins promises to unravel many new proteins of the plant immune system., See also the Commentary on this article by Malik & Van der Hoorn, 210: 371–373.
- Published
- 2016
31. Etiological Profile of Plasmacytosis on Bone Marrow Aspirates
- Author
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Sunita Singh, Promil Jain, Monika Gupta, Veena Gupta, Rajeev Sen, Rajnish Kalra, Nisha Sharma, Shivani Malik, University of Health Sciences, Department of Pathology, and 0-Belirlenecek
- Subjects
Gynecology ,Pathology ,medicine.medical_specialty ,lcsh:R5-920 ,bone marrow ,Kemik iliği ,business.industry ,Plasmacytosis ,lcsh:R ,lcsh:Medicine ,Reaktif plazmasitoz,kemik iliği,multipl miyelom,megaloblastik anemi ,medicine.disease ,Reactive plasmacytosis ,medicine.anatomical_structure ,Megaloblastik anemi ,Multiple myeloma ,Reaktif plazmasitoz ,medicine ,Bone marrow ,business ,multiple myeloma ,lcsh:Medicine (General) ,Megaloblastic anaemia ,Multipl miyelom - Abstract
Objective: In recent years, during routine examination of bone marrow aspirates, an increased plasma cell percentage has been noted in a good number of cases which included both neoplastic and non-neoplastic diseases. An attempt has been made to observe the spectra of conditions with plasmacytosis in bone marrow.Methods: The present study was conducted in the department of pathology over a period of one year. A total of 114 bone marrow aspirates that showed increased plasma cells (>3.5%) constitute the study material. A detailed relevant clinical examination followed by complete blood count, peripheral smear examination and bone marrow aspiration was done in all cases.Results: There was slight female predominance with male to female ratio of 1:1.1. The majority of patients were in 4th decade. The plasma cell concentration ranged from 5% to 36%. As far as the etiology is concerned, 96 cases (84.2%) were non-neoplastic and 18 cases (15.7%) had neoplastic etiology.Conclusion: Bone marrow plasmacytosis can present as diagnostic dilemma and some time can be challenging to differentiate reactive from neoplastic condition as there is an overlap both in counts and morphology. Each case with plasmacytosis especially in the overlap range requires complete clinical evaluation, individualized investigations and more specific tests like immunoelectrophoresis and bone marrow biopsy with immunohistochemistry to arrive at a final diagnosis for patient management.Key words: Reactive plasmacytosis, bone marrow, multiple myeloma, megaloblastic anaemia, Amaç: Son yıllarda rutin kemik iliği aspiratı incelemelerinde saptanan neoplastik ve non-neoplastik hastalıklarda giderek artan oranlarda plazma hücrelerine rastlanmaktadır. Bu çalışmada kemik iliği aspiratında plazmasitoz saptanan durumların bir spektrumu çıkarılmaya çalışılmıştır.Yöntemler: Sunulan çalışma bir yıllık süre içinde Patoloji Bölümünde gerçekleştirildi. Çalışma materyalini artmış oranda plazma hücresi (>%3,5) gösteren toplam 114 kemik iliği aspiratı oluşturmaktadır. Tüm olgularda ayrıntılı bir klinik muayene ve takiben tam kan sayımı, periferik yayma ve kemik iliği aspirasyonu yapıldı.Bulgular: Erkek / Kadın oranı açısından hafif bir kadın üstünlüğü görüldü (1 / 1,1). Vakaların çoğu 40’lı yaşlarda idi. Plazma hücre yoğunluğu %5-36 arasında değişmekte idi. Etyoloji açısından 96 (%84,2) olguda non-neoplastik, 18 (%15,8) olguda ise neoplastik bir etyoloji saptandı.Sonuç: Kemik iliği plazmasitozu tanısal bir karmaşaya yol açarak, özellikle sayı ve morfolojik görünümlerinde çakışma olan reaktif patolojilerin neoplastik durumlardan ayırt edilmesini bazen zorlaştırabilir. Özellikle çakışma aralıklarındakiler başta olmak üzere, plazmasitozlu her hastada bireyselleştirilmiş araştırmalar ve immunelektroforez ve immunhistokimya ile boyanmış kemik iliği aspiratı incelemesi ile sonuç tanısı konabilir ve hasta yönetimi gerçekleştirilebilir
- Published
- 2016
32. Review of the Rpt3 Genes Encoding Part of the 26S Proteasome Associated with Loci Underlying Disease Resistance in Soybean
- Author
-
Shivani Malik, Sukesh Bhaumik and David A. Lightfoot
- Subjects
SCN ,Proteasome ,lcsh:Biology (General) ,QTL ,Glycine max ,soybean ,SDS ,lcsh:QH301-705.5 ,Rpt3 - Abstract
The 26S proteasomal complex is a multifunctional proteolyticmachinery of the cell. The proteasome plays role in myriadof cellular functions, which have been further diversified byits separable proteolytic and non-proteolytic sub-complexes.Protein quality control and turnover, cell cycle regulation,gene regulation and DNA repair are among the key processescontrolled by the proteasome. Disease resistance inplants invokes changes in all the processes controlled by the26S proteasome. In this review, the potential contribution ofgenes encoding the proteasome to disease resistance in soybean(Glycine max L. Merr.) was examined.
- Published
- 2012
33. Primary breast mucormycosis: FNAC diagnosis of a rare entity
- Author
-
Sant Prakash, Kataria, Jyoti, Sharma, Gajender, Singh, Sanjay, Kumar, Shivani, Malik, and Vinod, Kumar
- Subjects
Adult ,Biopsy, Fine-Needle ,Humans ,Mucormycosis ,Female ,Breast - Abstract
Mucormycosis is the common name given to several different diseases caused by fungi in the order of mucorales. The clinical hallmark of these opportunistic pathogens in invasive mucormycosis is tissue necrosis resulting from angioinvasion and subsequent thrombosis. Rarely the disease may affect immunocompetent individuals. In addition, the breast involvement in this disease is very rare. Herein, we describe a case of primary breast mucormycosis diagnosed on fine needle aspiration cytology (FNAC), in an immunocompetent young female, which is extremely rare. Diagn. Cytopathol. 2016;44:761-763. © 2016 Wiley Periodicals, Inc.
- Published
- 2015
34. The 19S proteasome subcomplex promotes the targeting of NuA4 HAT to the promoters of ribosomal protein genes to facilitate the recruitment of TFIID for transcriptional initiation in vivo
- Author
-
Bhawana Uprety, Shivani Malik, Sukesh R. Bhaumik, and Shweta Lahudkar
- Subjects
Ribosomal Proteins ,Transcriptional Activation ,Proteasome Endopeptidase Complex ,Saccharomyces cerevisiae Proteins ,Transcription, Genetic ,Telomere-Binding Proteins ,macromolecular substances ,Gene Regulation, Chromatin and Epigenetics ,Shelterin Complex ,Histone H4 ,03 medical and health sciences ,0302 clinical medicine ,Ribosomal protein ,Genetics ,Promoter Regions, Genetic ,Transcription factor ,Histone Acetyltransferases ,030304 developmental biology ,0303 health sciences ,biology ,Activator (genetics) ,Promoter ,Histone acetyltransferase ,Molecular biology ,Cell biology ,Transcription Factor TFIID ,biology.protein ,Chromatin immunoprecipitation ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
Previous studies have implicated SAGA (Spt-Ada-Gcn5-acetyltransferase) and TFIID (Transcription factor-IID)-dependent mechanisms of transcriptional activation in yeast. SAGA-dependent transcriptional activation is further regulated by the 19S proteasome subcomplex. However, the role of the 19S proteasome subcomplex in transcriptional activation of the TFIID-dependent genes has not been elucidated. Therefore, we have performed a series of chromatin immunoprecipitation, mutational and transcriptional analyses at the TFIID-dependent ribosomal protein genes such as RPS5, RPL2B and RPS11B. We find that the 19S proteasome subcomplex is recruited to the promoters of these ribosomal protein genes, and promotes the association of NuA4 (Nucleosome acetyltransferase of histone H4) co-activator, but not activator Rap1p (repressor-activator protein 1). These observations support that the 19S proteasome subcomplex enhances the targeting of co-activator at the TFIID-dependent promoter. Such an enhanced targeting of NuA4 HAT (histone acetyltransferase) promotes the recruitment of the TFIID complex for transcriptional initiation. Collectively, our data demonstrate that the 19S proteasome subcomplex enhances the targeting of NuA4 HAT to activator Rap1p at the promoters of ribosomal protein genes to facilitate the recruitment of TFIID for transcriptional stimulation, hence providing a new role of the 19S proteasome subcomplex in establishing a specific regulatory network at the TFIID-dependent promoter for productive transcriptional initiation in vivo.
- Published
- 2011
35. Regulation of Chromatin Assembly/Disassembly by Rtt109p, a Histone H3 Lys56-specific Acetyltransferase, in Vivo
- Author
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Priyasri Chaurasia, Geetha Durairaj, Shweta Lahudkar, Sukesh R. Bhaumik, Shivani Malik, and Abhijit Shukla
- Subjects
Saccharomyces cerevisiae Proteins ,Transcription, Genetic ,Saccharomyces cerevisiae ,Biology ,Biochemistry ,Histones ,Galactokinase ,Histone H3 ,Histone H1 ,Gene Expression Regulation, Fungal ,Histone H2A ,Histone methylation ,Histone H2B ,Histone code ,Gene Regulation ,RNA, Messenger ,Histone octamer ,Molecular Biology ,Histone Acetyltransferases ,Acetylation ,RNA, Fungal ,Cell Biology ,Chromatin Assembly and Disassembly ,Molecular biology ,carbohydrates (lipids) ,Histone methyltransferase ,RNA Polymerase II - Abstract
Rtt109p, a histone acetyltransferase, associates with active genes and acetylates lysine 56 on histone H3 in Saccharomyces cerevisiae. However, the functional role of Rtt109p or H3 Lys(56) acetylation in chromatin assembly/disassembly (and hence gene expression) immediately switching transcription on or off has not been clearly elucidated in vivo. Here, we show that Rtt109p promotes the eviction of histone H3 from a fast inducible yeast gene, GAL1, following transcriptional initiation via histone H3 Lys(56) acetylation. Conversely, the deposition of histone H3 to GAL1 is significantly decreased in the presence of Rtt109p following transcriptional termination. Intriguingly, we also find that the deposition of histone H2B on preexisting non-acetylated histone H3 Lys(56) at GAL1 in Δrtt109 is significantly increased independently of histone H3 deposition immediately following transcriptional termination subsequent to a short induction. Consistently, histone H2B is not efficiently evicted from GAL1 in the absence of Rtt109p immediately following transcriptional induction. Furthermore, we show that the stimulated eviction or reduced deposition of histones by Rtt109p promotes the association of RNA polymerase II with GAL1 and hence the synthesis of GAL1 mRNA. These results, taken together, support the fact that Rtt109p regulates the deposition/eviction of histone H2B in addition to its role in stimulating histone H3 eviction, thus providing insight into chromatin assembly/disassembly and hence gene expression in vivo.
- Published
- 2010
36. Mixed lineage leukemia: histone H3 lysine 4 methyltransferases from yeast to human
- Author
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Shivani Malik and Sukesh R. Bhaumik
- Subjects
Histone H3 Lysine 4 ,Cell Biology ,Biology ,complex mixtures ,Biochemistry ,Histone H3 ,Histone H1 ,Histone methyltransferase ,Histone H2A ,Histone methylation ,bacteria ,Histone code ,Histone octamer ,Molecular Biology - Abstract
The fourth lysine of histone H3 is post-translationally modified by a methyl group via the action of histone methyltransferase, and such a covalent modification is associated with transcriptionally active and/or repressed chromatin states. Thus, histone H3 lysine 4 methylation has a crucial role in maintaining normal cellular functions. In fact, misregulation of this covalent modification has been implicated in various types of cancer and other diseases. Therefore, a large number of studies over recent years have been directed towards histone H3 lysine 4 methylation and the enzymes involved in this covalent modification in eukaryotes ranging from yeast to human. These studies revealed a set of histone H3 lysine 4 methyltransferases with important cellular functions in different eukaryotes, as discussed here.
- Published
- 2010
37. The 19 S Proteasome Subcomplex Establishes a Specific Protein Interaction Network at the Promoter for Stimulated Transcriptional Initiation in Vivo
- Author
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Payel Sen, Shivani Malik, Sukesh R. Bhaumik, and Abhijit Shukla
- Subjects
Proteasome Endopeptidase Complex ,Saccharomyces cerevisiae Proteins ,Transcription, Genetic ,Promoter ,Saccharomyces cerevisiae ,Cell Biology ,Proteasome complex ,Biology ,Biochemistry ,Molecular biology ,Cell biology ,Upstream activating sequence ,Proteasome ,Transcription (biology) ,Mutation ,Transcription preinitiation complex ,Transcription, Chromatin, and Epigenetics ,Promoter Regions, Genetic ,Molecular Biology ,Transcription factor ,Chromatin immunoprecipitation ,Transcription Factors - Abstract
The 26 S proteasome complex that comprises the 20 S core and 19 S regulatory (with six ATPases) particles is engaged in an ATP-dependent degradation of a variety of key regulatory proteins and, thus, controls important cellular processes. Interestingly, several recent studies have implicated the 19 S regulatory particle in controlling eukaryotic transcriptional initiation or activation independently of the 20 S core particle. However, the mechanism of action of the 19 S proteasome subcomplex in regulation of eukaryotic transcriptional activation is not clearly understood in vivo. Here, using a chromatin immunoprecipitation assay in conjunction with mutational and transcriptional analyses in Saccharomyces cerevisiae, we show that the 19 S proteasomal subcomplex establishes a specific protein interaction network at the upstream activating sequence of the promoter. Such an interaction network is essential for formation of the preinitiation complex at the core promoter to initiate transcription. Furthermore, we demonstrate that the formation of the transcription complex assembly at the promoter is dependent on 19 S ATPase activity. Intriguingly, 19 S ATPases appear to cross-talk for stimulation of the assembly of transcription factors at the promoter. Together, these results provide significant insights as to how the 19 S proteasome subcomplex regulates the formation of the active transcription complex assembly (and, hence, transcriptional initiation) at the promoter in vivo.
- Published
- 2009
38. Elongating RNA Polymerase II Is Disassembled through Specific Degradation of Its Largest but Not Other Subunits in Response to DNA Damage in Vivo
- Author
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Zhen Duan, Sukesh R. Bhaumik, Priyasri Chaurasia, Shruti Bagla, and Shivani Malik
- Subjects
Transcriptional Activation ,Saccharomyces cerevisiae Proteins ,Time Factors ,DNA Repair ,Transcription, Genetic ,DNA polymerase ,DNA polymerase II ,RNA-dependent RNA polymerase ,RNA polymerase II ,Saccharomyces cerevisiae ,Models, Biological ,Biochemistry ,Open Reading Frames ,Gene Expression Regulation, Fungal ,RNA polymerase I ,Molecular Biology ,RNA polymerase II holoenzyme ,Polymerase ,biology ,RNA-Binding Proteins ,Cell Biology ,Molecular biology ,4-Nitroquinoline-1-oxide ,biology.protein ,RNA Polymerase II ,Genome, Fungal ,Transcription factor II D ,DNA Damage ,Mutagens - Abstract
Although previous biochemical studies have demonstrated global degradation of the largest subunit, Rpb1p, of RNA polymerase II in response to DNA damage, it is still not clear whether the initiating or elongating form of Rpb1p is targeted for degradation in vivo. Further, whether other components of RNA polymerase II are degraded in response to DNA damage remains unknown. Here, we show that the Rpb1p subunit of the elongating, but not initiating, form of RNA polymerase II is degraded at the active genes in response to 4-nitroquinoline-1-oxide-induced DNA damage in Saccharomyces cerevisiae. However, other subunits of RNA polymerase II are not degraded in response to DNA damage. Further, we show that Rpb1p is essential for RNA polymerase II assembly at the active gene, and thus, the degradation of Rpb1p following DNA damage disassembles elongating RNA polymerase II. Taken together, our data demonstrate that Rpb1p but not other subunits of elongating RNA polymerase II is specifically degraded in response to DNA damage, and such a degradation of Rpb1p is critical for the disassembly of elongating RNA polymerase II at the DNA lesion in vivo.
- Published
- 2008
39. Diverse Regulatory Mechanisms of Eukaryotic Transcriptional Activation by the Proteasome Complex
- Author
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Shivani Malik and Sukesh R. Bhaumik
- Subjects
Transcriptional Activation ,Proteasome Endopeptidase Complex ,Cell ,Eukaryotic gene ,26S Proteasome Complex ,Proteolytic degradation ,Proteasome complex ,Protein degradation ,Biology ,Biochemistry ,Cell biology ,Eukaryotic Cells ,medicine.anatomical_structure ,Proteasome ,19S regulatory particle ,medicine ,Animals ,Humans ,Molecular Biology - Abstract
The life of any protein within a cell begins with transcriptional activation, and ends with proteolytic degradation. Intriguingly, the 26S proteasome complex, a non-lysosomal protein degradation machine comprising the 20S proteolytic core and 19S regulatory particles, has been implicated in intimate regulation of eukaryotic transcriptional activation through diverse mechanisms in a proteolysis-dependent as well as independent manner. Here, we discuss the intricate mechanisms of such proteasomal regulation of eukaryotic gene activation via multiple pathways.
- Published
- 2008
40. SIRT7 inactivation reverses metastatic phenotypes in epithelial and mesenchymal tumors
- Author
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Nilotpal Roy, Eriko Michishita-Kioi, Shinji Tanaka, Jonathan R. Pollack, Elisabeth Berber, Misato Aonuma, Katrin F. Chua, Shivani Malik, and Lidia Villanova
- Subjects
Epithelial-Mesenchymal Transition ,Bioinformatics ,Article ,Metastasis ,Epigenesis, Genetic ,Cell Line, Tumor ,Medicine ,Humans ,Sirtuins ,Neoplasm Metastasis ,Multidisciplinary ,biology ,business.industry ,Mesenchymal stem cell ,Epithelial Cells ,Sarcoma ,medicine.disease ,Prognosis ,Phenotype ,Primary tumor ,Chromatin ,3. Good health ,Cancer cell ,Sirtuin ,Cancer research ,biology.protein ,Disease Progression ,business ,Reprogramming - Abstract
Metastasis is responsible for over 90% of cancer-associated mortality. In epithelial carcinomas, a key process in metastatic progression is the epigenetic reprogramming of an epithelial-to-mesenchymal transition-like (EMT) change towards invasive cellular phenotypes. In non-epithelial cancers, different mechanisms must underlie metastatic change, but relatively little is known about the factors involved. Here, we identify the chromatin regulatory Sirtuin factor SIRT7 as a key regulator of metastatic phenotypes in both epithelial and mesenchymal cancer cells. In epithelial prostate carcinomas, high SIRT7 levels are associated with aggressive cancer phenotypes, metastatic disease and poor patient prognosis and depletion of SIRT7 can reprogram these cells to a less aggressive phenotype. Interestingly, SIRT7 is also important for maintaining the invasiveness and metastatic potential of non-epithelial sarcoma cells. Moreover, SIRT7 inactivation dramatically suppresses cancer cell metastasis in vivo, independent of changes in primary tumor growth. Mechanistically, we also uncover a novel link between SIRT7 and its family member SIRT1, providing the first demonstration of direct interaction and functional interplay between two mammalian sirtuins. Together with previous work, our findings highlight the broad role of SIRT7 in maintaining the metastatic cellular phenotype in diverse cancers.
- Published
- 2015
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41. Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation
- Author
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Eric A. Collisson, Karina E. Villanueva, Guido von Figura, Xinyuan Lu, Atsushi Urano, David W. Dawson, E. Scott Seeley, Nilotpal Roy, Shivani Malik, and Matthias Hebrok
- Subjects
endocrine system diseases ,pancreatic cancer ,Pancreatic Intraepithelial Neoplasia ,Tumor initiation ,Cell Transformation ,medicine.disease_cause ,Medical and Health Sciences ,Mice ,Brg1 ,Tumor Cells, Cultured ,2.1 Biological and endogenous factors ,Aetiology ,Cancer ,Cultured ,EMT ,Nuclear Proteins ,SOX9 Transcription Factor ,Azepines ,Biological Sciences ,Tumor Cells ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,Pancreatic Ductal ,KRAS ,Carcinoma, Pancreatic Ductal ,medicine.medical_specialty ,education ,Biology ,Proto-Oncogene Proteins p21(ras) ,Rare Diseases ,Pancreatic cancer ,Internal medicine ,Genetics ,medicine ,Animals ,Humans ,Neoplastic transformation ,Epigenetics ,Neoplastic ,Intraductal papillary mucinous neoplasm ,IPMN ,Carcinoma ,dedifferentiation ,Psychology and Cognitive Sciences ,DNA Helicases ,Triazoles ,Stem Cell Research ,medicine.disease ,Pancreatic Neoplasms ,Endocrinology ,Gene Expression Regulation ,Kras ,Cancer research ,Digestive Diseases ,Carcinogenesis ,Developmental Biology ,Transcription Factors - Abstract
Pancreatic ductal adenocarcinoma (PDA) develops predominantly through pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) precursor lesions. Pancreatic acinar cells are reprogrammed to a “ductal-like” state during PanIN-PDA formation. Here, we demonstrate a parallel mechanism operative in mature duct cells during which functional cells undergo “ductal retrogression” to form IPMN-PDA. We further identify critical antagonistic roles for Brahma-related gene 1 (Brg1), a catalytic subunit of the SWI/SNF complexes, during IPMN-PDA development. In mature duct cells, Brg1 inhibits the dedifferentiation that precedes neoplastic transformation, thus attenuating tumor initiation. In contrast, Brg1 promotes tumorigenesis in full-blown PDA by supporting a mesenchymal-like transcriptional landscape. We further show that JQ1, a drug that is currently being tested in clinical trials for hematological malignancies, impairs PDA tumorigenesis by both mimicking some and inhibiting other Brg1-mediated functions. In summary, our study demonstrates the context-dependent roles of Brg1 and points to potential therapeutic treatment options based on epigenetic regulation in PDA.
- Published
- 2015
42. Role of morphometry and proliferative parameters in grading of urothelial neoplasms
- Author
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Sunita Singh, M. S. Sangwan, Sonia Singh, Rajeev Sen, Ramesh Lamba, Sonia Chabbra, Praveen Rana, Santosh Kumar, and Shivani Malik
- Subjects
Original Paper ,mitotic activity index ,Reproducibility ,Pathology ,medicine.medical_specialty ,proliferative parameters ,Papillary Urothelial Neoplasm ,business.industry ,Maximum correlation ,Histopathological grading ,Nuclear area ,General Medicine ,urothelial tumors ,Mitotic activity index ,medicine ,Who classification ,business ,Grading (tumors) ,morphometry - Abstract
Introduction Mean nuclear area of 10 nuclei (MNA–10), mitotic activity index (MAI) and Ki–67 are highly reproducible and can be routinely used as adjuncts to histopathological grading in classifying tumors. Assays of these biomarkers are non–invasive, rapid, easy to perform, more objective and accurate, with high sensitivity and specificity, and correlate well with tumor grade. Material and methods This study was conducted at the Department of Pathology PGIMS, Rohtak on 50 cases, of which 25 cases were high–grade, 15 low–grade, 6 Papillary Urothelial Neoplasm of Low Malignant Potentialand 4 reactive lesions as per the 2004 ISUP/WHO classification. MNA–10, MAI and Ki–67 immunoquantitation were performed on stained sections. Results The age of the patients varied from 35 to 87 years. Male: female ratio was 3.5:1. The mean MNA–10 (µm 2 ) for High Grade Malignant Potential was 104.52 ±25.64 µm 2 , which was significantly higher than in PUNLMP (47.64 ±10.23) and LMP (51.57 ±15.66). MAI (/10 HPF) showed an increasing trend from reactive lesions to HMP, with a mean of (3 ±1.16)/10 HPF to (21.36 ±5.31)/10 HPF respectively. Ki–67 labelling index, a proliferative marker, revealed increasing trend lowest with reactive lesions (10 ±2.83%) and highest in high grade tumors (65.96 ±14.44). Spearman’s correlation showed maximum correlation between MAI and Ki–67 and the increasing grade of tumor. Conclusions MNA–10 in combination with Ki–67 and MAI was found to be stronger than MNA–10 alone. MAI has high reproducibility in differentiating low and high grade, with simple assessment in paraffin embedded sections allowing adequate histopathological analysis and visualization of proliferating cells simultaneously. This multivariate grading model should be applied in routine grading to overcome interob server variability and to increase reproducibility of grading.
- Published
- 2015
43. Mechanisms of antisense transcription initiation from the 3' end of the GAL10 coding sequence in vivo
- Author
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Sukesh R. Bhaumik, Shivani Malik, and Geetha Durairaj
- Subjects
Saccharomyces cerevisiae Proteins ,Genes, Fungal ,RNA polymerase II ,Saccharomyces cerevisiae ,RNA, Antisense ,Molecular Biology ,RNA polymerase II holoenzyme ,Transcription Initiation, Genetic ,Mediator Complex ,biology ,General transcription factor ,RNA, Fungal ,Cell Biology ,Articles ,TATA-Box Binding Protein ,Molecular biology ,DNA-Binding Proteins ,TAF1 ,TAF2 ,Mutation ,biology.protein ,Trans-Activators ,Transcription Factor TFIIB ,RNA Polymerase II ,Transcription factor II D ,Transcription Initiation Site ,Transcription factor II B ,Transcription factor II A ,Transcription Factors - Abstract
In spite of the important regulatory functions of antisense transcripts in gene expression, it remains unknown how antisense transcription is initiated. Recent studies implicated RNA polymerase II in initiation of antisense transcription. However, how RNA polymerase II is targeted to initiate antisense transcription has not been elucidated. Here, we have analyzed the association of RNA polymerase II with the antisense initiation site at the 3' end of the GAL10 coding sequence in dextrose-containing growth medium that induces antisense transcription. We find that RNA polymerase II is targeted to the antisense initiation site at GAL10 by Reb1p activator as well as general transcription factors (e.g., TFIID, TFIIB, and Mediator) for antisense transcription initiation. Intriguingly, while GAL10 antisense transcription is dependent on TFIID, its sense transcription does not require TFIID. Further, the Gal4p activator that promotes GAL10 sense transcription is dispensable for antisense transcription. Moreover, the proteasome that facilitates GAL10 sense transcription does not control its antisense transcription. Taken together, our results reveal that GAL10 sense and antisense transcriptions are regulated differently and shed much light on the mechanisms of antisense transcription initiation.
- Published
- 2013
44. Rad26p, a transcription-coupled repair factor, promotes the eviction and prevents the reassociation of histone H2A-H2B dimer during transcriptional elongation in vivo
- Author
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Shivani Malik and Sukesh R. Bhaumik
- Subjects
Adenosine Triphosphatases ,animal structures ,Saccharomyces cerevisiae Proteins ,DNA Repair ,Biology ,Biochemistry ,Molecular biology ,Article ,Chromatin ,Histones ,Histone H1 ,Bacterial Proteins ,Histone methyltransferase ,Histone methylation ,Histone H2A ,embryonic structures ,Histone code ,Histone octamer ,Protein Multimerization ,Transcriptional Elongation Factors ,DNA, Fungal ,Chromatin immunoprecipitation ,Transcription Factors - Abstract
We have recently demonstrated the formation of an atypical histone H2A–H2B dimer-enriched chromatin at the coding sequence of the active gene in the absence of Rad26p in vivo. However, the mechanisms for such a surprising observation remain unknown. Here, using a ChIP assay, we demonstrate that Rad26p promotes the eviction of histone H2A–H2B dimer and prevents the reassociation of the dimer with naked DNA in the wake of elongating RNA polymerase II at the coding sequence of the active GAL1 gene. Thus, the absence of Rad26p leads to the generation of an atypical histone H2A–H2B dimer-enriched chromatin at the active coding sequence in vivo.
- Published
- 2012
45. A novel role of Rad26 in dynamic chromatin disassembly during transcriptional elonagtion in vivo
- Author
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Sukesh R. Bhaumik, Priyasri Chaurasia, and Shivani Malik
- Subjects
Chromatin Disassembly ,In vivo ,Chemistry ,Genetics ,Molecular Biology ,Biochemistry ,Biotechnology ,Cell biology - Published
- 2011
46. Malignant solitary fibrous tumor of the thigh in a young female: A rare case report
- Author
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Divya Srivastava, Shivani Malik, Rajeev Sen, and Hemant Yadav
- Subjects
Solitary fibrous tumor ,Pathology ,medicine.medical_specialty ,business.industry ,Soft tissue ,Malignant Solitary Fibrous Tumor ,General Medicine ,Thigh ,medicine.disease ,Lesion ,medicine.anatomical_structure ,Medicine ,Differential diagnosis ,Presentation (obstetrics) ,medicine.symptom ,business ,Young female - Abstract
Solitary fibrous tumor (SFT) is a mesenchymal origin tumor mainly confined to pleura and peritoneum. The extrapulmonary location is rare in incidence up to the level that fewer than 40 cases are described in literature in soft parts of extremities most of which are benign in nature with a mean age of presentation 52 years. The extrapulmonary SFT with malignant features at young age is an extremely rare mesenchymal neoplasm. A 20 years old female presented with a mass in the left thigh. The positron emission tomography scan performed, showed a hypermetabolic lesion at medial side of the left thigh. Subsequently, en bloc excision of mass was done along with adductor longus and brevis. Based on the histomorphology and immunohistochemical markers, diagnosis of malignant SFT was made. We report this case because of its rarity and to add on to literature and list of differential diagnosis of soft tissue tumors in the extremities.
- Published
- 2015
47. Metastatic Esophageal Squamous Cell Carcinoma in the Kidney
- Author
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Sonia Chhabra, Padam Parmar, Shivani Malik, Sunita Singh, Megha Ralli, and Pansi Gupta
- Subjects
Pathology ,medicine.medical_specialty ,Kidney ,Visceral metastasis ,medicine.anatomical_structure ,business.industry ,Metastatic Esophageal Squamous Cell Carcinoma ,Medicine ,Autopsy ,urologic and male genital diseases ,business ,Renal metastasis ,Esophageal squamous cell carcinoma - Abstract
Metastases from esophageal cancers represent only 4.8 per cent of secondary renal tumors. The kidney is known to be the 4th or 5th most common visceral metastasis site of esophageal carcinomas. More than 50% of renal metastases typically show bilateral involvement. Solitary, unilateral renal metastasis is extremely rare. Therefore, the diagnosis of renal metastases is very difficult. We report a case of solitary unilateral renal metastases in an esophageal squamous cell carcinoma in a 66 year old man’s autopsy.
- Published
- 2014
48. Total output and switching in ategory fluency successfully iscriminates Alzheimer's disease from Mild Cognitive Impairment, but not from frontotemporal dementia
- Author
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Siddharth Ramanan, Jwala Narayanan, Tanya Perpetua D'Souza, Kavita Shivani Malik, and Ellajosyula Ratnavalli
- Subjects
verbal fluency ,clustering ,switching ,dementia ,mild cognitive impairment ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Verbal fluency tasks require generation of words beginning with a letter (phonemic fluency; PF) or from a category (category fluency; CF) within a limited time period. Generally, total output on CF has been used to discriminate Mild Cognitive Impairment (MCI) from Alzheimer's disease (AD), while poor PF has been used as a marker for behavioral-variant frontotemporal dementia (bvFTD). However, in the absence of this disparate performance, further characterization of the task becomes necessary. Objective: We examined whether fluency, as well as its components, clustering (successively generated words belonging to a category) and switching (shifting between categories) carried diagnostic utility in discriminating AD from MCI and bvFTD. Methods: PF (letter 'P') and CF ('animals') tasks were administered in English to patients with MCI (n=25), AD (n=37), and bvFTD (n=17). Clustering and switching scores were calculated using established criteria. Results: Our findings suggested that up to 85% of AD and MCI could be successfully discriminated based on total number of responses and switching in CF alone. PF-CF disparity was not noted in AD or bvFTD. Performance on clustering or switching also proved insufficient to discriminate AD from bvFTD. Conclusion: Switching was found to be useful when differentiating AD from MCI. In AD and bvFTD, the course of progression of the disease may lead to attenuation of total number of responses produced on both tasks to an extent where clustering and switching may not be useful measures to discriminate these dementias from each other.
- Full Text
- View/download PDF
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