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Biomedical subjects

A Husain

Publications and source records attributed to A Husain.

At least 55 records · Page 3Linked to original sources
PubMed1998

BRCA1 up-regulation is associated with repair-mediated resistance to cis-diamminedichloroplatinum(II).

We sought to identify novel genes associated with cis-diamminedichloroplatinum(II) (CDDP) resistance, and by differential display analysis, we found that the human breast and ovarian cancer susceptibility gene BRCA1 was overexpressed in CDDP-resistant MCF-7 cells. A recent report that BRCA1 and human Rad51 colocalize in S-phase cells suggests a role for BRCA1 in DNA damage repair. We hypothesized that BRCA1 plays a role in DNA damage repair-mediated CDDP resistance. In CCDP-resistant variants of breast and ovarian carcinoma cell lines, MCF-7 CDDP/R and SKOV-3 CDDP/R, we found increased levels of BRCA1 protein, and we determined that the SKOV-3 CDDP/R cell line is significantly more proficient at DNA damage repair. Antisense inhibition of BRCA1 in this cell line resulted in an increased sensitivity to CDDP, a decreased proficiency of DNA repair, and an enhanced rate of apoptosis. These data support the hypothesis that BRCA1 is a gene involved in DNA damage repair.

Breast Neoplasms↗
PubMed1998

Lisofylline sensitizes p53 mutant human ovarian carcinoma cells to the cytotoxic effects of cis-diamminedichloroplatinum (II).

A novel approach to counteracting drug resistance is the development of nontoxic agents that are able to preferentially increase the sensitivity of tumor cells to the cytotoxicity of chemotherapy. The possibility that such an agent could be directed specifically against p53-defective tumor cells led us to study the new methylxanthine, Lisofylline, for its ability to sensitize ovary cancer cells to cis-diamminedichloroplatinum(II) (CDDP). In cell lines lacking functional p53 (SKOV3, SKOV3 CDDP-resistant, OVCAR3, and OVCAR432) Lisofylline (20-100 microM) enhanced the cytotoxicity of CDDP by approximately 50% as measured by the Alamar blue vital dye indicator assay. LSF had no effect on p53 wild-type cell lines: OVCAR 420, 429, and 433. Restoration of wild-type p53 phenotype by transfection of SKOV3 cells with a p53 cDNA expression vector showed reversal of sensitization by Lisofylline to CDDP cytotoxicity. While sensitization to DNA damaging agents by other methylxanthines is related to an abrogation of G2 delay, FACS data found no loss of CDDP-induced G2 block in the cell lines, demonstrating that Lisofylline enhanced sensitization. Cell death was examined by quantitative fluorescence microscopy but no increase in apoptosis attributable to Lisofylline exposure was observed. Our results show that the combination of CDDP and Lisofylline preferentially sensitizes p53-defective cancer cells to the cytotoxic effect of CDDP by a yet undetermined mechanism.

Adjuvants, Immunologic↗
PubMed1998

Gastrointestinal toxicity and Clostridium difficile diarrhea in patients treated with paclitaxel-containing chemotherapy regimens.

OBJECTIVE: The objective of this study was to determine the incidence of grade 3 and 4 gastrointestinal toxicity and the prevalence of Clostridium difficile-associated diarrhea (CDAD) in patients with gynecologic malignancies treated with paclitaxel-based chemotherapy regimens. METHODS: We retrospectively reviewed the medical records of all patients treated on the Gynecology Service at Memorial Sloan-Kettering Cancer Center from January 1, 1993 to July 1, 1996. We identified all patients treated with paclitaxel during this period and determined the total number of patients hospitalized for symptoms of gastrointestinal toxicity, including nausea, vomiting, diarrhea, and dehydration, within 4 weeks of chemotherapy, as well as the incidence of CDAD among these patients. RESULTS: Six hundred and twenty-four patients were treated with paclitaxel-containing chemotherapy regimens during the study period, including 55 patients who were treated on a "dose-dense" high-dose protocol for advanced ovarian cancer. Among these, 149 patients (24%) were hospitalized for symptoms of gastrointestinal toxicity. During the study period, a total of 40 cases of CDAD were reported among hospitalized patients on the Gynecology Service and 24 (60%) of these cases occurred in patients who had received paclitaxel within the prior 4 weeks. CONCLUSIONS: The occurrence of CDAD in patients receiving paclitaxel-containing chemotherapy is not rare and can result in severe dehydration requiring hospitalization. The risk of C. difficile colitis appears to be 2.2% in patients receiving standard-dose regimens and as high as 20% in patients receiving high-dose regimens. This etiology should be considered and treated early in patients presenting with symptoms of gastrointestinal toxicity subsequent to chemotherapy treatments.

Anti-Bacterial Agents↗
PubMed1998

Nutritional issues and therapy in inflammatory bowel disease.

Nutritional issues in inflammatory bowel disease (IBD) often receive inadequate attention both in regard to therapy and nutritionally related complications of IBD. This article reviews much of the research that has evaluated the role of diet in the causation, primary treatment, and adjunctive therapy of both ulcerative colitis (UC) and Crohn's disease (CD). Benefits have been demonstrated in the use of elemental diets or polymeric diets in CD in both acute flare up or maintenance of IBD. A careful team approach can overcome problems in implementing nutritional therapy. Nutrition also has a critical benefit in postoperative CD and perioperative UC. Numerous easily corrected, nutritional abnormalities are often overlooked in patients with IBD, which may have significant consequences. Nutritional therapy may have a central place in the hierarchy of treatment in IBD and further research is critical in this area to better define the benefits of nutrition in IBD.

Adult↗
PubMed1997

Distinct multisite synergistic interactions determine substrate specificities of human chymase and rat chymase-1 for angiotensin II formation and degradation.

Human chymase and rat chymase-1 are mast cell serine proteases involved in angiotensin II (Ang II) formation and degradation, respectively. Previous studies indicate that both these enzymes have similar P1 and P2 preferences, which are the major determinants of specificity. Surprisingly, despite the occurrence of optimal P2 and P1 residues at the Phe8 downward arrow and Tyr4 downward arrow bonds (where downward arrow, indicates the scissile bond in peptide substrates) in Ang I (DRVYIHPFHL), human chymase cleaves the Phe8 downward arrow bond with an approximately 750-fold higher catalytic efficiency (kcat/Km) than the Tyr4 downward arrow bond in Ang II (DRVYIHPF), whereas rat chymase-1 cleaves the Tyr4 downward arrow bond with an approximately 20-fold higher catalytic efficiency than the Phe8 downward arrow bond. Differences in the acyl groups IHPF and DRVY at the Phe8 downward arrow and Tyr4 downward arrow bonds, respectively, are chiefly responsible for the preference of human chymase for the Phe8 downward arrow bond. We show that the IHPF sequence forms an optimal acyl group, primarily through synergistic interactions between neighboring acyl group residues. In contrast to human chymase, rat chymase-1 shows a preference for the Tyr4 downward arrow bond, mainly because of a catalytically productive interaction between the enzyme and the P'1 Ile5. The overall effect of this P'1 Ile interaction on catalytic efficiency, however, is influenced by the structure of the acyl group and that of the other leaving group residues. For human chymase, the P'1 Ile interaction is not productive. Thus, specificity for Ang II formation versus Ang II degradation by these chymases is produced through synergistic interactions between acyl or leaving group residues as well as between the acyl and leaving groups. These observations indicate that nonadditive interactions between the extended substrate binding site of human chymase or rat chymase-1 and the substrate are best explained if the entire binding site is taken as an entity rather than as a collection of distinct subsites.

Amino Acid Sequence↗
PubMed1997

Selective reporter expression in mast cells using a chymase promoter.

Primate alpha-chymases are mast cell neutral proteases that are involved in regulating several regulatory peptides including angiotensin II. Because of significant substrate specificity differences among the chymase group of enzymes, animal models that overexpress primate chymases are crucial for delineating the in vivo function of these enzymes. Activation of alpha-prochymase requires processing enzymes and proteoglycans found in mast cell secretory granules. Thus, the development of models overexpressing active primate chymase requires a mast cell-specific promoter. We show that the 571-base pair (bp) 5'-upstream sequence of the baboon chymase gene, which encodes an alpha-chymase, coupled to the prokaryotic lacZ gene allows the targeting of beta-galactosidase to mast cells in transgenic mice. Tissue expression of the transgene is similar to the expression of the endogenous mouse alpha-chymase mouse mast cell protease-5. A mouse mast cell line that endogenously expresses mouse mast cell protease-5 (JKras mast cells) also selectively supports the expression of this transgene. In vitro transcription studies in JKras mast cells shows the critical role of a GATA cis-regulatory motif in baboon chymase promoter, located approximately 430-bp upstream of the transcription start site. These results suggest that the 571-bp domain of the baboon chymase promoter contains most, if not all, of the mast cell-specific region of the promoter. We describe here for the first time a promoter that directs expression of transgenes specifically to mouse mast cells. This promoter should be generally applicable for dominant expression of mast cell regulatory proteins.

3T3 Cells↗
PubMed1997

Partial nephrectomy for pediatric renal cell carcinoma: an unusual case presentation.

Nine years after successful treatment of Stage IV neuroblastoma, a 10-year-old white girl was demonstrated to have a complex cystic mass in the upper pole of her solitary right kidney. Partial nephrectomy was performed, disclosing a renal cell carcinoma, predominantly clear cell type. No metastases were detected. Renal cell carcinoma is a rare cause of secondary malignancy. Partial nephrectomy can be used successfully to treat renal cell carcinoma in children.

Carcinoma, Renal Cell↗
PubMed1997

Association of antral mucosal levels of interleukin 8 and reactive oxygen radicals in patients infected with Helicobacter pylori.

1. Helicobacter pylori infection is characterized by an infiltration of neutrophils in the gastric mucosa. Neutrophil activation is an important source of reactive oxygen radicals, which cause tissue damage. Studies have shown that in Helicobacter pylori-infected patients there is increased mucosal production of interleukin 8. However, the role of interleukin 8 in the Helicobacter pylori-related inflammatory process and its relationship with reactive oxygen radicals remains to be clarified. The aims of this study were to investigate if there is any association between antral mucosal levels of interleukin 8 and reactive oxygen radicals and their relationship to gastric antral inflammation. 2. Fifty-two patients referred for endoscopy were recruited into the study. Gastric antral biopsies were taken for histology, culture and measurement of interleukin 8 and chemiluminescence (measuring reactive oxygen radicals). Interleukin 8 was measured by ELISA and the result expressed as pg/mg biopsy. Luminol-enhanced chemiluminescence was measured as mV min-1 mg-1 biopsy. Antral inflammation was assessed by a pathologist in a blinded fashion. 3. Antral mucosal levels of interleukin 8 and reactive oxygen radicals were significantly higher in Helicobacter pylori-colonized mucosa than in Helicobacter pylori-negative mucosa. After the eradication of Helicobacter pylori in patients with duodenal ulcer the median values (ranges) of interleukin 8 and reactive oxygen radicals fell from 1.21 (0.10-2.40) to 0.65 (0.00-1.60) and from 110.0 (10.0-959.0) to 14.5 (0.0-85.0) respectively. There was a positive correlation between interleukin 8 concentration and chemiluminescence response in the antral mucosa (r = 0.72). A higher interleukin 8 concentration was associated with greater neutrophil infiltration (r = 0.72) and mononuclear cell infiltration (r = 0.55); the magnitude of the chemiluminescence response was also positively associated with neutrophil (r = 0.77) and mononuclear cell infiltration (r = 0.59). 4. Interleukin 8 concentration is associated with an infiltration of neutrophils and mononuclear cells and is correlated with the production of reactive oxygen radicals in antral gastric mucosa infected with Helicobacter pylori. These findings suggest that interleukin 8 may be important in attracting and activating phagocytes to release reactive oxygen radicals, thereby causing mucosal damage.

Duodenal Ulcer↗
PubMed1997

Perinatal myocardial infarction in a newborn with a structurally normal heart.

Myocardial infarction in a newborn infant in the absence of congenital heart disease and anomalous coronary artery anatomy is extremely rare. We report a case of a newborn with a structurally normal heart who presented shortly after birth with congestive heart failure and cardiovascular collapse suggestive of a hypoplastic left ventricle or critical aortic stenosis. This newborn had a massive myocardial infarction caused by thromboembolic occlusion of the left main coronary artery. Clinical, laboratory, and autopsy data suggest the event occurred in utero.

Adult↗
PubMed1997

Polycyclic aromatic hydrocarbons in food products originating from locally reared animals in Kuwait.

Analysis for the presence of 12 polycyclic aromatic hydrocarbons (PAHs) in 327 foodstuff samples originating from locally reared animals was carried out. The data revealed that non-carcinogenic PAHs were detected in considerable amounts in several food commodities. The carcinogenic PAH concentrations were relatively low in most of the samples investigated. Among the carcinogenic PAHs detected, chrysene had the highest concentration.

Animals↗
PubMed1997

Relationship between the mucosal production of reactive oxygen radicals and density of Helicobacter pylori in patients with duodenal ulcer.

OBJECTIVE: To investigate the associations between the mucosal production of reactive oxygen radicals (RORs) in the gastric antrum and duodenum, Helicobacter pylori density and duodenal ulcer (DU). PATIENTS: Forty-seven endoscoped patients, comprising 22 with DU and 25 non-ulcer subjects, were included in the study. METHODS: Antral and duodenal biopsies were taken for histology, Helicobacter pylori culture and measurement of chemiluminescence. Biopsies were homogenized and cultured on Columbia blood agar plate. Colonies of H. pylori were counted and bacterial density expressed as colony-forming units (cfu)/mg of biopsy. Chemiluminescence was measured by luminometry and the results expressed as millivolt (mV)/min/mg of biopsy, after subtraction of background count. RESULTS: Thirty-one of 47 (66%) patients had antral H. pylori and 6/47 (12.8%) had proven duodenal colonization. Increased chemiluminescence (median (interquartile)) was found in H. pylori-infected patients compared to those without H. pylori in antral (90.0 (26.0, 249.0) vs. 7.0 (0.0, 10.0), P<0.001) and duodenal mucosa (22.0 (10.0, 100.0) vs. -2.5 (-10.0, 0.0) P<0.001). A positive correlation was found between antral H. pylori density and chemiluminescence response in both the antrum (r=0.77) and duodenum (r=0.52). DU patients showed an increased chemiluminescence compared to those non-ulcer subjects with or without H. pylori infection in antrum (163.5 (44.5, 297.8) vs. 33.0 (8.7, 168.0) (P=0.046) vs. 2.7 (0.1, 10.0), P<0.01) and duodenum (45.0 (17.5, 100.0) vs. 15.0 (-1.25, 22.5) vs. -2.5 (-10, 0.0), P<0.01). CONCLUSION: Increased production of RORs in the antrum and duodenum was found to be related to antral H. pylori density and associated with duodenal ulceration. The association between antral H. pylori and ROR release in the duodenum may be important in the pathogenesis of duodenal ulceration.

Biopsy↗
PubMed1997

UCN-01 in ovary cancer cells: effective as a single agent and in combination with cis-diamminedichloroplatinum(II)independent of p53 status.

Our goal was to determine the cytotoxicity of 7-OH-hydroxystaurosporine (UCN-01) as a single agent and in combination with cis-diamminedichloroplatinum(II) (CDDP) in a panel of ovarian carcinoma cells. We sought to examine the role of p53 gene function and alterations in cell cycle progression or other mechanisms of action of UCN-01 including perturbation of the apoptosis pathway mediated by NF-kappaB and Bcl-2/Bax. Cytotoxicity was determined from dose-response curves established by the Alamar blue vital dye indicator assay. Restoration of wild-type p53 in a p53 null cell line, SKOV 3, was achieved by transfection of a p53 expression vector. Cell cycle distribution was measured by fluorescence-activated cell sorting analysis of ethidium bromide-stained nuclei. Apoptosis was measured by quantitative fluorescence microscopy. NF-kappaB DNA binding activity was measured by electrophoretic mobility shift assay. Bcl-2 and Bax levels were determined by Western immunoblotting. UCN-01 was effective as a cytotoxic agent alone and in combination with CDDP in all cell lines studied, regardless of p53 status. The degree of sensitization to CDDP conferred by UCN-01, however, was found to correlate with p53 gene status. p53 wild-type cells seem to be more sensitive to the cytotoxic effects of the combination of UCN-01 + CDDP than the p53 mutant cells. This was confirmed in cells in which p53 wild-type function was restored by transfection of p53 cDNA, but these cells are also significantly more sensitive to CDDP alone. The effects of UCN-01 on cell cycle progression also appear to be p53 dependent but may not be the primary mechanism of action. The rate of apoptosis is increased 4-fold in UCN-01 + CDDP-treated cells compared to either agent alone. UCN-01 does not effect NF-kappaB DNA binding activity or Bcl-2 and Bax levels. UCN-01 enhances CDDP cytotoxicity and apoptosis in ovary cancer cells. This occurs regardless of p53 status, but wild-type p53 seems to increase the degree of sensitization.

Alkaloids↗
PubMed1996

The active state of the AT1 angiotensin receptor is generated by angiotensin II induction.

In the current model of receptor activation, the given hormone is not involved in the conversion of the inactive receptor (R) to the fully active state (R*). Rather, it preferentially selects the activated receptor conformation, thereby shifting the equilibrium toward R*. The hormone angiotensin II (Ang II) contains two residues, Tyr4 and Phe8, that are essential for agonism. We show that the conserved Asn111 in transmembrane helix III of the AT1 angiotensin receptor directly interacts with the Tyr4 side chain. A decrease in the size of the Asn111 side chain induces an intermediate activated receptor conformation (R'). The Ang II analogue [Sar1,Ile4,Ile8]Ang II fully activates the N111G mutant, indicating that either the transition from R' to R* or the stabilization of the R* state requires binding by Ang II but not its Tyr4 and Phe8 side chains. In contrast, [Sar1,Ile4,Ile8]Ang II binds to but does not activate the wild-type AT1 receptor (R), suggesting that in the wild-type receptor spontaneous occurrence of R' and R* states is rare. Thus, Ang II through interactions involving Tyr4 and Phe8 induces a transition from R to R' and through unspecified interactions induces transition from R' to R* states rather than stabilizing the spontaneously generated R* state by "conformational, selection".

Amino Acid Sequence↗
PubMed1996

Angiotensin II-forming activity in a reconstructed ancestral chymase.

The current model of serine protease diversity theorizes that the earliest protease molecules were simple digestive enzymes that gained complex regulatory functions and restricted substrate specificities through evolution. Among the chymase group of serine proteases are enzymes that convert angiotensin I to angiotensin II, as well as others that simply degrade angiotensins. An ancestral chymase reconstructed with the use of phylogenetic inference, total gene synthesis, and protein expression had efficient and specific angiotensin II-forming activity (turnover number, about 700 per second). Thus, angiotensin II-forming activity is the more primitive state for chymases, and the loss of such activity occurred later in the evolution of some of these serine proteases.

Amino Acid Sequence↗
PubMed1996

Long-term outcome following curative surgery for malignant large bowel obstruction.

This study determined whether the long-term outcome of patients with obstructing colorectal cancer could be related to conventional pathological prognostic variables or to other clinical, operative or histological features. Ninety-eight patients with bowel obstruction who had undergone potentially curative surgery and survived the postoperative period were studied. Features related to poor long-term outcome after a median follow-up of 5 years included bowel perforation at initial operation (P = 0.007), advanced tumour stage (P < 0.001), poor tumour differentiation (P = 0.02), mucin production by tumour (P = 0.004) and the presence of vascular (P = 0.08) and neural (P = 0.004) invasion. Outcome was not significantly related to the seniority of the operating surgeon (P = 0.52), even when this was adjusted for potentially confounding variables (adjusted hazard rate ratio for trainee surgeons 1.4 (95 per cent confidence interval 0.9-2.4), P = 0.16). Conventional prognostic features may help to identify the majority of patients with obstructed colorectal cancer at high risk of tumour recurrence and death.

Adult↗
PubMed1996

The practice of surgical staging and its impact on adjuvant treatment recommendations in patients with stage I endometrial carcinoma.

A survey of American gynecologic oncologists was undertaken to assess their compliance with current surgical staging criteria in patients with early endometrial carcinoma. One hundred forty-four members of the Society of Gynecologic Oncologists responded to the survey. Respondents treated an average of 22 new cases annually. Tumor grade and intraoperative determination of depth of myometrial invasion were demonstrated to influence the frequency of lymphatic dissection. In grade 1, 2, and 3 lesions, 76, 60, and 34% of responders, respectively, indicated that depth of invasion influenced their decision to perform lymphadenectomy. In addition, depth of invasion was important in determining type and extent of lymphatic resection. Further, the impact of pathologic lymph node status on postoperative adjuvant radiation therapy recommendations was evaluated for various stratifications of endometrial adenocarcinoma confined to the corpus. The greatest differences in treatment recommendations were noted in the 50-66% invasion category. For grade 1 and 2 cancers, adjuvant therapy recommendations were reduced by 23 and 16% respectively when comparing pelvic and combined therapy versus none and vaginal therapy. The effect of surgical staging data on clinical decisions is clearly evident. The knowledge of pathologically negative lymph node status reduces the recommendation for postoperative adjuvant radiotherapy in patients with adenocarcinoma otherwise confined to the uterine corpus.

Chemotherapy, Adjuvant↗
PubMed1996

Removal of intramedullary nails from the femur: a review of 45 cases.

The excellent biocompatibility of titanium and its alloys may result in osseointegration. In order to determine if this presents an obstacle to removal of intramedullary nails, we retrospectively reviewed a series of 45 cases of isolated removal of a femoral nail. Indications for removal were persistent pain and discomfort, request of an asymptomatic patient, or skeletal immaturity. Twenty-three nails were titanium, and 22 were stainless steel. Although removal of the titanium nails had a significantly longer operative time (110 vs. 84 min), analysis of variance indicated that this was due to a greater number of crosslocking screws in the titanium nails (2.2 vs. 0.6) and a tendency to set the titanium nails deeper in the femur. The use of the titanium material per se did not pose a risk factor for difficulty in late removal of an intramedullary nail.

Adult↗