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Articles by S Sharma
Total Records ( 6 ) for S Sharma
  S Sharma , T. K Kelly and P. A. Jones

Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Global changes in the epigenetic landscape are a hallmark of cancer. The initiation and progression of cancer, traditionally seen as a genetic disease, is now realized to involve epigenetic abnormalities along with genetic alterations. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer including DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs, specifically microRNA expression. The reversible nature of epigenetic aberrations has led to the emergence of the promising field of epigenetic therapy, which is already making progress with the recent FDA approval of three epigenetic drugs for cancer treatment. In this review, we discuss the current understanding of alterations in the epigenetic landscape that occur in cancer compared with normal cells, the roles of these changes in cancer initiation and progression, including the cancer stem cell model, and the potential use of this knowledge in designing more effective treatment strategies.

  C Widera , R Horn Wichmann , T Kempf , K Bethmann , B Fiedler , S Sharma , R Lichtinghagen , H Leitolf , B Ivandic , H. A Katus , E Giannitsis and K. C. Wollert

Background: Follistatin-like 1 (FSTL1) is a 308–amino acid secreted glycoprotein. Tissue levels of FSTL1 are induced in animal models and patients with chronic inflammatory and cardiovascular disease. We hypothesized that FSTL1 can be measured in the human circulation and used as a biomarker in acute coronary syndrome (ACS).

Methods: We developed an immunoluminometric assay (ILMA), assessed the preanalytic characteristics of FSTL1, and determined circulating FSTL1 concentrations in 120 apparently healthy individuals and 216 patients with ACS.

Results: The assay had a limit of detection of 0.17 µg/L, limit of quantification of 1.02 µg/L, intraassay imprecision of ≤12.7%, and interassay imprecision of ≤15.4%. Selectivity was demonstrated with size-exclusion chromatography and lack of cross-reactivity with related proteins. The assay was not appreciably influenced by unrelated biological substances. FSTL1 in serum or whole blood was stable at room temperature for 48 h and was resistant to 4 freeze-thaw cycles. Measured FSTL1 concentrations in citrated plasma and heparin-treated plasma were 18% and 17% lower, respectively, than concentrations measured in serum. Apparently healthy individuals presented with a median FSTL1 serum concentration of 7.18 (range 1.06–18.49) µg/L. Serum FSTL1 concentrations were increased in ACS and related to the risk of all-cause mortality during follow-up.

Conclusions: The ILMA permits detection of FSTL1 in human serum and plasma. We expect that the favorable preanalytic characteristics of FSTL1 and the reference limits defined here for apparently healthy individuals will facilitate future studies of FSTL1 as a biomarker in various disease settings, including ACS.

  A Gulati , A Sinha , S. C Jordan , P Hari , A. K Dinda , S Sharma , R. N Srivastava , A Moudgil and A. Bagga

Background and objectives: The treatment of idiopathic nephrotic syndrome is often complicated by a refractory and relapsing course, with risk of drug toxicity and progressive renal failure. We report the efficacy and safety of rituximab in patients with steroid-resistant (SRNS) and steroid-dependent nephrotic syndrome (SDNS) refractory to standard therapy.

Design, setting, participants, & measurements: This was a cohort study in academic, tertiary care centers in India and the United States. Patients with SRNS or SDNS, not responding to medications or showing calcineurin inhibitor toxicity, treated with two to four doses of intravenous rituximab, and followed ≥12 months were included. Remission was termed as complete, partial, or no response.

Results: Thirty-three patients with SRNS (24 initial, 9 late resistance) and 24 with SDNS, with mean ages of 12.7 ± 9.1 and 11.7 ± 2.9 years, respectively, were included. Six months after rituximab therapy, 9 (27.2%) patients with SRNS showed complete remission, 7 (21.2%) had partial remission, and 17 (51.5%) had no response. At 21.5 ± 11.5 months, remission was sustained in 15 (complete: 7, partial: 8) patients. Of 24 patients with SDNS, remission was sustained in 20 (83.3%) at 12 months and in 17 (71%) at follow-up of 16.8 ± 5.9 months. The mean difference in relapses before and 12 months after treatment with rituximab was 3.9 episodes/patient per year.

Conclusions: Therapy with rituximab was safe and effective in inducing and maintaining remission in a significant proportion of patients with difficult SRNS and SDNS.

  C. M Contreras , E. A Akbay , T. D Gallardo , J. M Haynie , S Sharma , O Tagao , N Bardeesy , M Takahashi , J Settleman , K. K Wong and D. H. Castrillon
  Cristina M. Contreras, Esra A. Akbay, Teresa D. Gallardo, J. Marshall Haynie, Sreenath Sharma, Osamu Tagao, Nabeel Bardeesy, Masaya Takahashi, Jeff Settleman, Kwok-Kin Wong, and Diego H. Castrillon

Endometrial cancer – the most common malignancy of the female reproductive tract – arises from the specialized epithelial cells that line the inner surface of the uterus. Although significant advances have been made in our understanding of this disease in recent years, one significant limitation has been the lack of a diverse genetic toolkit for the generation of mouse models. We identified a novel endometrial-specific gene, Sprr2f, and developed a Sprr2f-Cre transgene for conditional gene targeting within endometrial epithelium. We then used this tool to generate a completely penetrant Lkb1 (also known as Stk11)-based mouse model of invasive endometrial cancer. Strikingly, female mice with homozygous endometrial Lkb1 inactivation did not harbor discrete endometrial neoplasms, but instead underwent diffuse malignant transformation of their entire endometrium with rapid extrauterine spread and death, suggesting that Lkb1 inactivation was sufficient to promote the development of invasive endometrial cancer. Mice with heterozygous endometrial Lkb1 inactivation only rarely developed tumors, which were focal and arose with much longer latency, arguing against the idea – suggested by some prior studies – that Lkb1 is a haploinsufficient tumor suppressor. Lastly, the finding that endometrial cancer cell lines were especially sensitive to the mTOR (mammalian target of rapamycin) inhibitor rapamycin prompted us to test its efficacy against Lkb1-driven endometrial cancers. Rapamycin monotherapy not only greatly slowed disease progression, but also led to striking regression of pre-existing tumors. These studies demonstrate that Lkb1 is a uniquely potent endometrial tumor suppressor, but also suggest that the clinical responses of some types of invasive cancers to mTOR inhibitors may be linked to Lkb1 status.

  J. E Craig , A. W Hewitt , A. E McMellon , A. K Henders , L Ma , L Wallace , S Sharma , K. P Burdon , P. M Visscher , G. W Montgomery and S. MacGregor

Genome-wide association studies (GWAS) have now successfully identified important genetic variants associated with many human traits and diseases. The high cost of genotyping arrays in large data sets remains the major barrier to wider utilization of GWAS. We have developed a novel method in which whole blood from cases and controls, respectively, is pooled prior to DNA extraction for genotyping. We demonstrate proof of principle by clearly identifying the associated variants for eye color, age-related macular degeneration, and pseudoexfoliation syndrome in cohorts not previously studied. Blood pooling has the potential to reduce GWAS cost by several orders of magnitude and dramatically shorten gene discovery time. This method has profound implications for translation of modern genetic approaches to a multitude of diseases and traits yet to be analyzed by GWAS, and will enable developing nations to participate in GWAS.

  D Yadav , J Chandra , S Sharma and V. Singh

First-line therapies of acute and chronic idiopathic thrombocytopenic purpura (ITP) include intravenous immunoglobulin, IV anti-D and corticosteroids. A short-course high-dose dexamethasone (HDD-SC) therapy has recently been reported to be efficacious in acute ITP. The present study was conducted to assess the efficacy of HDD-SC in children with chronic ITP. Over a period of 10 months, 13 patients with chronic ITP were given HDD-SC (20 mg m–2 IV daily for 4 days, four cycles repeated every 15 days). Of the 12 patients who could be evaluated, complete response was observed in 8 (66.6%) and moderate response in 2 (17%) patients, whereas 2 (17%) patients had no response. HDD-SC appears to be a safe and effective therapy in childhood ITP.

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