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Articles by S Kumar
Total Records ( 12 ) for S Kumar
  S Kumar , E. Y Chang , J Frankhouse , P. B Dorsey , R. G Lee and N. Johnson
 

Background  Microsatellite instability (MSI) and lymphocytic infiltrate (LI) in colon cancer are associated with less aggressive biological characteristics. Patients with stage II disease who are negative for MSI and LI have been found to have a less favorable prognosis. These patients may be candidates for more aggressive adjuvant therapy.

Objective  To evaluate the outcomes of patients with colon cancer treated with and without adjuvant chemotherapy on the basis of stage, MSI, and LI.

Design  Prospective evaluation of MSI and LI status with retrospective analysis of chemotherapy regimen.

Setting  Community hospital system.

Patients  A total of 167 patients with colon cancer.

Intervention  Definitive resection of colorectal cancer with or without chemotherapy.

Main Outcome Measure  Disease-free survival (DFS) with and without chemotherapy according to combined MSI and LI status.

Results  Data on MSI and LI status and chemotherapeutic regimens were available for 140 patients. The 5-year DFS was 50% for patients with stage II disease who underwent chemotherapy vs 76% for those who did not (P = .02). In the group negative for MSI and LI, 5-year DFS was 29% for those undergoing chemotherapy and 91% for those who did not (P = .001).

Conclusions  Forgoing adjuvant chemotherapy should be considered in patients with stage II colon cancer who are negative for MSI and LI. The MSI and LI status shows promise as a combined prognostic marker and may prove particularly useful in selecting patients with stage II disease for adjunctive therapy.

  M. S Randall , F. M McKevitt , S Kumar , T. J Cleveland , K Endean , G. S Venables and P. A. Gaines
 

Background— Limited data are available about the long-term outcomes of the use of carotid artery stents in symptomatic patients and the impact of patient variables on the durability of endovascular carotid procedures. Outcome data previously reported from registry series mix symptomatic and asymptomatic patients. We present analysis of long-term follow-up, with independent neurological assessment, for patients with symptomatic high-grade carotid lesions undergoing stenting to identify patients at risk of recurrence.

Methods and Results— Prospectively collected data on 563 carotid stenting procedures in a single center were analyzed. Univariate and multivariate techniques were used to identify risk groups and beneficial technical adaptations. Ipsilateral stroke rates for all patients were 4.8%, 7.0%, and 9.5% at 30 days, 1 year, and 4 years, respectively. The rates improved to 2.7%, 4.1%, and 4.5% when patients were treated with optimal therapy. Retinal events had a lower risk of long-term recurrent ipsilateral stroke (hazard ratio=0.228, CI=0.082 to 0.632, P=0.004) than cerebral events. A recurrent or residual stenosis of >50% had a statistically significant effect on long-term stroke recurrence in multivariate analysis (hazard ratio=2.187, CI=1.173 to 4.078, P=0.014).

Conclusions— Patients with retinal presentations are a lower risk group to treat. Residual stenosis or restenosis >50% has a statistically significant trend to an increased risk of recurrence for ipsilateral stroke in the long term in this population. In our patients, a combination of procedural modifications and pharmacological changes seems to improve outcomes.

  S Kumar , H Qiu , N Oezguen , H Herlyn , J. R Halpert and L. Wojnowski
 

For currently unknown reasons, the evolution of CYP3A4 underwent acceleration in the human lineage after the split from chimpanzee. We investigated the significance of this event by comparing Escherichia coli-expressed CYP3A4 from humans, chimpanzee, and their most recent common ancestor. The expression level of chimpanzee CYP3A4 was ~50% of the human CYP3A4, whereas ancestral CYP3A4 did not express in E. coli. Steady-state kinetic analysis with 7-benzyloxyquinoline, 7-benzyloxy-4-(trifluoromethyl)coumarin (7-BFC), and testosterone showed no significant differences between human and chimpanzee CYP3A4. Upon addition of -naphthoflavone (25 µM), human CYP3A4 showed a slightly decreased substrate concentration at which 50% of the maximal rate Vmax is reached for 7-BFC, whereas chimpanzee CYP3A4 showed a >2-fold increase. No significant differences in inhibition/activation were found for a panel of 43 drugs and endogenous compounds, suggesting that the wide substrate spectrum of human CYP3A4 precedes the human-chimpanzee split. A striking exception was the hepatotoxic secondary bile acid lithocholic acid, which at saturation caused a 5-fold increase in 7-BFC debenzylation by human CYP3A4 but not by chimpanzee CYP3A4. Mutagenesis of human CYP3A4 revealed that at least four of the six amino acids positively selected in the human lineage contribute to the activating effect of lithocholic acid. In summary, the wide functional conservation between chimpanzee and human CYP3A4 raises the prospect that phylogenetically more distant primate species such as rhesus and squirrel monkey represent suitable models of the human counterpart. Positive selection on the human CYP3A4 may have been triggered by an increased load of dietary steroids, which led to a novel defense mechanism against cholestasis.

  S Kumar , H Qiu , N Oezguen , H Herlyn , J. R Halpert and L. Wojnowski
 

For currently unknown reasons, the evolution of CYP3A4 underwent acceleration in the human lineage after the split from chimpanzee. We investigated the significance of this event by comparing Escherichia coli-expressed CYP3A4 from humans, chimpanzee, and their most recent common ancestor. The expression level of chimpanzee CYP3A4 was ~50% of the human CYP3A4, whereas ancestral CYP3A4 did not express in E. coli. Steady-state kinetic analysis with 7-benzyloxyquinoline, 7-benzyloxy-4-(trifluoromethyl)coumarin (7-BFC), and testosterone showed no significant differences between human and chimpanzee CYP3A4. Upon addition of -naphthoflavone (25 µM), human CYP3A4 showed a slightly decreased substrate concentration at which 50% of the maximal rate Vmax is reached for 7-BFC, whereas chimpanzee CYP3A4 showed a >2-fold increase. No significant differences in inhibition/activation were found for a panel of 43 drugs and endogenous compounds, suggesting that the wide substrate spectrum of human CYP3A4 precedes the human-chimpanzee split. A striking exception was the hepatotoxic secondary bile acid lithocholic acid, which at saturation caused a 5-fold increase in 7-BFC debenzylation by human CYP3A4 but not by chimpanzee CYP3A4. Mutagenesis of human CYP3A4 revealed that at least four of the six amino acids positively selected in the human lineage contribute to the activating effect of lithocholic acid. In summary, the wide functional conservation between chimpanzee and human CYP3A4 raises the prospect that phylogenetically more distant primate species such as rhesus and squirrel monkey represent suitable models of the human counterpart. Positive selection on the human CYP3A4 may have been triggered by an increased load of dietary steroids, which led to a novel defense mechanism against cholestasis.

  P. D Keightley , U Trivedi , M Thomson , F Oliver , S Kumar and M. L. Blaxter
 

We inferred the rate and properties of new spontaneous mutations in Drosophila melanogaster by carrying out whole-genome shotgun sequencing-by-synthesis of three mutation accumulation (MA) lines that had been maintained by close inbreeding for an average of 262 generations. We tested for the presence of new mutations by generating alignments of each MA line to the D. melanogaster reference genome sequence and then compared these alignments base by base. We determined empirically that at least five reads at a site within each line are required for accurate single nucleotide mutation calling. We mapped a total of 174 single-nucleotide mutations, giving a single nucleotide mutation rate of 3.5 x 10–9 per site per generation. There were no false positives in a random sample of 40 of these mutations checked by Sanger sequencing. Variation in the numbers of mutations among the MA lines was small and nonsignificant. Numbers of transition and transversion mutations were 86 and 88, respectively, implying that transition mutation rate is close to 2x the transversion rate. We observed 1.5x as many G or C -> A or T as A or T -> G or C mutations, implying that the G or C -> A or T mutation rate is close to 2x the A or T -> G or C mutation rate. The base composition of the genome is therefore not at an equilibrium determined solely by mutation. The predicted G + C content at mutational equilibrium (33%) is similar to that observed in transposable element remnants. Nearest-neighbor mutational context dependencies are nonsignificant, suggesting that this is a weak phenomenon in Drosophila. We also saw nonsignificant differences in the mutation rate between transcribed and untranscribed regions, implying that any transcription-coupled repair process is weak. Of seven short indel mutations confirmed, six were deletions, consistent with the deletion bias that is thought to exist in Drosophila.

  S Kumar , M. P Suleski , G. J Markov , S Lawrence , A Marco and A. J. Filipski
 

As the cost of DNA sequencing drops, we are moving beyond one genome per species to one genome per individual to improve prevention, diagnosis, and treatment of disease by using personal genotypes. Computational methods are frequently applied to predict impairment of gene function by nonsynonymous mutations in individual genomes and single nucleotide polymorphisms (nSNPs) in populations. These computational tools are, however, known to fail 15%–40% of the time. We find that accurate discrimination between benign and deleterious mutations is strongly influenced by the long-term (among species) history of positions that harbor those mutations. Successful prediction of known disease-associated mutations (DAMs) is much higher for evolutionarily conserved positions and for original–mutant amino acid pairs that are rarely seen among species. Prediction accuracies for nSNPs show opposite patterns, forecasting impediments to building diagnostic tools aiming to simultaneously reduce both false-positive and false-negative errors. The relative allele frequencies of mutations diagnosed as benign and damaging are predicted by positional evolutionary rates. These allele frequencies are modulated by the relative preponderance of the mutant allele in the set of amino acids found at homologous sites in other species (evolutionarily permissible alleles [EPAs]). The nSNPs found in EPAs are biochemically less severe than those missing from EPAs across all allele frequency categories. Therefore, it is important to consider position evolutionary rates and EPAs when interpreting the consequences and population frequencies of human mutations. The impending sequencing of thousands of human and many more vertebrate genomes will lead to more accurate classifiers needed in real-world applications.

  P Deepak , S Kumar , D Kishore and A. Acharya
 

Dalton's lymphoma (DL) is a transplantable T-cell lymphoma of spontaneous origin, characterized by highly invasive and immunosuppressive property. Progression of DL cells results into an imbalance of T helper type 1 (Th1)/T helper type 2 (Th2)-type cytokine in the host, which is partly responsible for DL-induced severe immunosuppression and DL cell progression. In this study, we have shown the role of IL-13 in the regulation of Th1 immunity in both normal healthy and DL-bearing host. IL-13 pre-treatment inhibits the induction of 2,4-dinitro-1-fluorobenzene-induced contact hypersensitivity and delayed-type hypersensitivity (DTH) in antigen-challenged mice, which have been confirmed by neutralizing IL-13 by systemic delivery of non-signaling decoy receptor IL-13R2. Furthermore, IL-13 neutralization enhances the splenocyte proliferation, which has been inhibited by IL-13 administration. Adoptive transfer of splenocyte from IL-13-pre-treated mice and macrophages incubated with IL-13 and pulsed with antigens suppresses the DTH as well in antigen-challenged recipient mice. In addition, it also suppresses the production of pro-inflammatory cytokine and C–C chemokine in DTH footpad. Furthermore, IL-13 neutralization not only enhances the DTH reaction but also increases longevity and survival of DL-bearing host, which suggests that blocking/inactivating systemic IL-13 enhances Th1 immunity, and therefore, effects to diminish IL-13 production may have therapeutic value in a host bearing T-cell lymphoma.

  S Kumar , R Budhwar , A Nigam and S. Priya
 

Alpha-lipoic acid (LA), the metabolic antioxidant, was evaluated for its potential to protect against Cr6+-induced DNA damage. Potassium dichromate was administered to Swiss albino mice orally ad libitum at the doses of 5, 10 or 25 mg/kg body weight in drinking water to set DNA damage in cells, which was characterized in mouse peripheral blood mononuclear cells and bone marrow cells using single-cell gel electrophoresis and analyses of generated comets for Tail moment, Tail DNA and Tail length. DNA damage was dose dependent. Cytoprotection by LA was remarkable. LA (5, 10 and 25 mg/kg body weight intraperitoneally) in pre-, co- and post-toxicant administration schedule abrogated DNA damage substantially in both cell types. Protection by LA was also dose dependent. LA annulled DNA damage by Cr6+ in plasmid relaxation assay. A negligible DNA damage resulted during interaction of Cr6+ and LA. Compared to ascorbate, LA emerged as a better antioxidant and least DNA damaging. In conclusion, our study advocated an experimental therapeutic research potential in LA against Cr6+-induced DNA damage for reduction of occupational cancer risk in humans.

  S Jajoo , D Mukherjea , S Kumar , S Sheth , T Kaur , L. P Rybak and V. Ramkumar
 

Exposure of cells to adenosine receptor (AR) agonists leads to receptor uncoupling from G proteins and downregulation of the A1AR. The receptor levels on the cell surface generally recover on withdrawal of the agonist, because of either translocation of the sequestered A1AR back to plasma membrane or de novo synthesis of A1AR. To examine the mechanism(s) underlying A1AR downregulation and recovery, we treated ductus deferens tumor (DDT1 MF-2) cells with the agonist R-phenylisopropyladenosine (R-PIA) and showed a decrease in membrane A1AR levels by 24 h, which was associated with an unexpected 11-fold increase in A1AR mRNA. Acute exposure of these cells to R-PIA resulted in a rapid translocation of β-arrestin1 to the plasma membrane. Knockdown of β-arrestin1 by short interfering RNA (siRNA) blocked R-PIA-mediated downregulation of the A1AR, suppressed R-PIA-dependent ERK1/2 and activator protein-1 (AP-1) activity, and reduced the induction of A1AR mRNA. Withdrawal of the agonist after a 24-h exposure resulted in rapid recovery of plasma membrane A1AR. This was dependent on the de novo protein synthesis and on the activity of ERK1/2 but independent of β-arrestin1 and nuclear factor-B. Together, these data suggest that exposure to A1AR agonist stimulates ERK1/2 activity via β-arrestin1, which subserves receptor uncoupling and downregulation, in addition to the induction of A1AR expression. We propose that such a pathway ensures both the termination of the agonist signal and recovery by priming the cell for rapid de novo synthesis of A1AR once the drug is terminated.

  N. M Dagia , G Agarwal , D. V Kamath , A Chetrapal Kunwar , R. D Gupte , M. G Jadhav , S. S Dadarkar , J Trivedi , A. A Kulkarni Almeida , F Kharas , L. C Fonseca , S Kumar and M. R. Bhonde
 

A promising therapeutic approach to diminish pathological inflammation is to inhibit the increased production and/or biological activity of proinflammatory cytokines (e.g., TNF-, IL-6). The production of proinflammatory cytokines is controlled at the gene level by the activity of transcription factors, such as NF-B. Phosphatidylinositol 3-kinase (PI3K), a lipid kinase, is known to induce the activation of NF-B. Given this, we hypothesized that inhibitors of PI3K activation would demonstrate anti-inflammatory potential. Accordingly, we studied the effects of a preferential p110/ PI3K inhibitor (compound 8C; PIK-75) in inflammation-based assays. Mechanism-based assays utilizing human cells revealed that PIK-75-mediated inhibition of PI3K activation is associated with dramatic suppression of downstream signaling events, including AKT phosphorylation, IKK activation, and NF-B transcription. Cell-based assays revealed that PIK-75 potently and dose dependently inhibits in vitro and in vivo production of TNF- and IL-6, diminishes the induced expression of human endothelial cell adhesion molecules (E-selectin, ICAM-1, and VCAM-1), and blocks human monocyte-endothelial cell adhesion. Most importantly, PIK-75, when administered orally in a therapeutic regimen, significantly suppresses the macroscopic and histological abnormalities associated with dextran sulfate sodium-induced murine colitis. The efficacy of PIK-75 in attenuating experimental inflammation is mediated, at least in part, due to the downregulation of pertinent inflammatory mediators in the colon. Collectively, these results provide first evidence that PIK-75 possesses anti-inflammatory potential. Given that PIK-75 is known to exhibit anti-cancer activity, the findings from this study thus reinforce the cross-therapeutic functionality of potential drugs.

  J Zhu , X Wu , S Goel , N. M Gowda , S Kumar , G Krishnegowda , G Mishra , R Weinberg , G Li , M Gaestel , T Muta and D. C. Gowda
 

Proinflammatory responses induced by Plasmodium falciparum glycosylphosphatidylinositols (GPIs) are thought to be involved in malaria pathogenesis. In this study, we investigated the role of MAPK-activated protein kinase 2 (MK2) in the regulation of tumor necrosis factor- (TNF-) and interleukin (IL)-12, two of the major inflammatory cytokines produced by macrophages stimulated with GPIs. We show that MK2 differentially regulates the GPI-induced production of TNF- and IL-12. Although TNF- production was markedly decreased, IL-12 expression was increased by 2–3-fold in GPI-stimulated MK2–/– macrophages compared with wild type (WT) cells. MK2–/– macrophages produced markedly decreased levels of TNF- than WT macrophages mainly because of lower mRNA stability and translation. In the case of IL-12, mRNA was substantially higher in MK2–/– macrophages than WT. This enhanced production is due to increased NF-B binding to the gene promoter, a markedly lower level expression of the transcriptional repressor factor c-Maf, and a decreased binding of GAP-12 to the gene promoter in MK2–/– macrophages. Thus, our data demonstrate for the first time the role of MK2 in the transcriptional regulation of IL-12. Using the protein kinase inhibitors SB203580 and U0126, we also show that the ERK and p38 pathways regulate TNF- and IL-12 production, and that both inhibitors can reduce phosphorylation of MK2 in response to GPIs and other toll-like receptor ligands. These results may have important implications for developing therapeutics for malaria and other infectious diseases.

 
 
 
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