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Articles by P Sharma
Total Records ( 4 ) for P Sharma
  C. J Fabian , B. F Kimler , C. M Zalles , J. R Klemp , B. K Petroff , Q. J Khan , P Sharma , K. D. R Setchell , X Zhao , T. A Phillips , T Metheny , J. R Hughes , H. W Yeh and K. A. Johnson
 

Preclinical and correlative studies suggest reduced breast cancer with higher lignan intake or blood levels. We conducted a pilot study of modulation of risk biomarkers for breast cancer in premenopausal women after administration of the plant lignan secoisolariciresinol given as the diglycoside (SDG). Eligibility criteria included regular menstrual cycles, no oral contraceptives, a >3-fold increase in 5-year risk, and baseline Ki-67 of ≥2% in areas of hyperplasia in breast tissue sampled by random periareolar fine-needle aspiration (RPFNA) during the follicular phase of the menstrual cycle. SDG (50 mg/d) was given for 12 months, followed by repeat RPFNA. The primary end point was change in Ki-67. Secondary end points included change in cytomorphology, mammographic breast density, serum bioavailable estradiol and testosterone insulin-like growth factor-I and IGF-binding protein-3, and plasma lignan levels. Forty-five of 49 eligible women completed the study with excellent compliance (median = 96%) and few serious side effects (4% grade 3). Median plasma enterolactone increased ~9-fold, and total lignans increased 16-fold. Thirty-six (80%) of the 45 evaluable subjects showed a decrease in Ki-67, from a median of 4% (range, 2-16.8%) to 2% (range, 0-15.2%; P < 0.001, Wilcoxon signed rank test). A decrease from baseline in the proportion of women with atypical cytology (P = 0.035) was also observed. Based on favorable risk biomarker modulation and lack of adverse events, we are initiating a randomized trial of SDG versus placebo in premenopausal women. Cancer Prev Res; 3(10); 1342–50. ©2010 AACR.

  B Asthana , P Sharma , R Ranjan , P Jain , A Aravindan , P Chandra Mishra and R. Saxena
 

Bleeding disorders constitute a large proportion of referrals to hematology departments. Worldwide, acquired causes of bleeding are commoner than inherited ones. To identify the spectrum of these disorders, we evaluated all referrals for bleeding encountered in this tertiary care centre over a one-year period. Of the total 1342 cases, 1040 (77.5%) had underlying exclusively acquired causes, whereas inherited causes constituted 302 cases (22.5%). Amongst acquired causes, disseminated intravascular coagulation was seen in 297 (28.6%), hepatic coagulopathy in 218 (20.9%), neurosurgical causes (intracranial bleeds) in 154 (14.8%), malignancy in 89 (8.6%), and miscellaneous multiple acquired causes including those due to anticoagulant drug overdose in 282 patients (27.1%). Referrals for isolated prolonged prothrombin time or thrombocytopenia were common, but were excluded from this study because not all presented with bleeding. Prompt laboratory work-up and precise identification of acquired causes of bleeding is the key to planning appropriate patient management including transfusion support.

  P Sharma and R. Saxena
 

The role of quantitative D-dimer assay in screening for and diagnosing overt disseminated intravascular coagulation (DIC), conventionally diagnosed by the International Society of Thrombosis and Haemostasis’ (ISTH) score, was evaluated. Of patients with clinical conditions associated with overt DIC, 142 with ISTH scores ≥5 (compatible with overt DIC) and 61 with ISTH scores <5 (suggestive of nonovert DIC) underwent the quantitative D-dimer assay. Accuracy indices, receiver operating characteristic (ROC) curve—derived cutoffs, and areas under curve were compared. Mean D-dimer level in overt DIC was 4147.2 ± 2707 ng/mL. In nonovert DIC, it was 1678.9 ± 1888.3 ng/mL. Both were higher than healthy controls (229.6 ± 129.9 ng/mL). An optimized cutoff (2040 ng/mL) had relatively low sensitivity (75.4%) and specificity (73.8%). Extensive overlap between groups at this cutoff reduced diagnostic utility. Lowered cutoffs increased sensitivity (eg, 91.5% at 1000 ng/mL) but diminished specificity (59%), limiting use of screening. In conclusion, the quantitative D-dimer as a stand-alone assay has a limited role in diagnosis of overt DIC.

  J. J Paxman , N. A Borg , J Horne , P. E Thompson , Y Chin , P Sharma , J. S Simpson , J Wielens , S Piek , C. M Kahler , H Sakellaris , M Pearce , S. P Bottomley , J Rossjohn and M. J. Scanlon
 

Oxidative protein folding in Gram-negative bacteria results in the formation of disulfide bonds between pairs of cysteine residues. This is a multistep process in which the dithiol-disulfide oxidoreductase enzyme, DsbA, plays a central role. The structure of DsbA comprises an all helical domain of unknown function and a thioredoxin domain, where active site cysteines shuttle between an oxidized, substrate-bound, reduced form and a DsbB-bound form, where DsbB is a membrane protein that reoxidizes DsbA. Most DsbA enzymes interact with a wide variety of reduced substrates and show little specificity. However, a number of DsbA enzymes have now been identified that have narrow substrate repertoires and appear to interact specifically with a smaller number of substrates. The transient nature of the DsbA-substrate complex has hampered our understanding of the factors that govern the interaction of DsbA enzymes with their substrates. Here we report the crystal structure of a complex between Escherichia coli DsbA and a peptide with a sequence derived from a substrate. The binding site identified in the DsbA-peptide complex was distinct from that observed for DsbB in the DsbA-DsbB complex. The structure revealed details of the DsbA-peptide interaction and suggested a mechanism by which DsbA can simultaneously show broad specificity for substrates yet exhibit specificity for DsbB. This mode of binding was supported by solution nuclear magnetic resonance data as well as functional data, which demonstrated that the substrate specificity of DsbA could be modified via changes at the binding interface identified in the structure of the complex.

 
 
 
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