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Biomedical subjects

P Joseph

Publications and source records attributed to P Joseph.

At least 19 recordsLinked to original sources
PubMed2001

Integration of tuberculosis screening at an HIV voluntary counselling and testing centre in Haiti.

OBJECTIVE: To describe the integration of tuberculosis screening into the activities of an HIV voluntary counselling and testing (VCT) centre in a country with endemic tuberculosis. SETTING: An HIV VCT centre in Port au Prince, Haiti. DESIGN: All patients presenting for HIV VCT who reported cough received same-day evaluation for active tuberculosis. Of the 1327 adults presenting to the centre for the first time between January and April 1997, 263 (20%) reported cough and of these 241 (92%) were evaluated. RESULTS: Of the 241 patients evaluated for cough, 76 (32%) were diagnosed with pulmonary tuberculosis. Of the 76 patients diagnosed with pulmonary tuberculosis, 28 (37%) had a positive smear for acid-fast bacilli (AFB), 14 (18%) had a negative AFB smear but a positive sputum culture for Mycobacterium tuberculosis, and 34 (45%) had culture-negative tuberculosis. Also, 31 out of 241 (13%) VCT clients evaluated for cough were diagnosed with bacterial pneumonia. CONCLUSION: This report confirms that in areas with a high HIV and tuberculosis prevalence, a high proportion of VCT clients have active pulmonary tuberculosis. The integration of tuberculosis screening offers several benefits, including the diagnosis and treatment of large numbers of individuals with tuberculosis, a decreased risk of nosocomial tuberculosis transmission, and the opportunity to provide tuberculosis prophylaxis to HIV-positive patients in whom tuberculosis has been excluded. Future studies are needed to determine the cost-effectiveness of integrated tuberculosis and HIV VCT services, and whether integration should be recommended in all countries with high HIV and tuberculosis rates.

AIDS Serodiagnosis↗
PubMed2001

Variation in delivery of palliative radiotherapy to persons dying of cancer in nova scotia, 1994 to 1998.

PURPOSE: To examine sociodemographic and clinical variables associated with provision of palliative radiotherapy (RT) to persons dying of cancer. METHODS: The Nova Scotia Cancer Registry was used to identify 9,978 adults who were dying of cancer between 1994 and 1998 in the Canadian province of Nova Scotia. RT records from between April 1992 and December 1998 were obtained from the provincial treatment database. Multivariate analysis identified factors associated with two sequential decisions determining provision of palliative RT in the last 9 months of life: likelihood of receiving an RT consultation with a radiation oncologist and, given a consultation, likelihood of being treated with palliative RT. RESULTS: The likelihood of having a consultation decreased with age (20 to 59 years v. 80+ years: odds ratio [OR], 4.43 [95% confidence interval, 3.80 to 5.15]), increased with community median household income (> $50,000 v. < $20,000: OR, 1.31 [1.02 to 1.70]), was higher for residents closer to the cancer center (< 25 km v 200+ km: OR, 2.47 [2.16 to 2.83]), increased between 1994 and 1998 (OR, 1.34 [1.16 to 1.56]), varied by cause of death (relative to thoracic cancers, head and neck: OR, 1.75 [1.31 to 2.33]; gynecologic: OR, 0.35 [0.27 to 0.44]), and was greater for those who had prior RT (OR, 2.20 [1.89 to 2.56]). Similar associations were observed when outcome was the provision of palliative RT given a consult, with one notable exception: prior RT was associated with a lower likelihood of receiving palliative RT (OR, 0.48 [0.40 to 0.58]). CONCLUSION: Variations observed in delivery of palliative RT should prompt further investigation into equity of access to clinically appropriate, palliative radiation consultation and treatment.

Adult↗
PubMed2001

Gene expression profile in BALB/c-3T3 cells transformed with beryllium sulfate.

Differential gene expression was studied to understand the potential molecular mechanism responsible for cell transformation and tumorigenesis induced by beryllium. Cell lines were derived from tumors developed in nude mice injected subcutaneously with BALB/c-3T3 cells morphologically transformed with beryllium sulfate. Using the Atlas mouse 1.2 cDNA expression microarray, the expression profiles of 1176 genes, belonging to several different functional categories, were studied in the tumor cells as well as in the nontransformed control cells. Expression of 18 genes belonging to two functional groups was found to be consistently and reproducibly different (at least twofold) in the tumor cells compared with the control cells. The functional groups and the differentially expressed genes are as follows: The cancer-related genes (nine genes) were the ets-related transcription factor activated by ras, colony-stimulating factor, A-myb, sky, cot1, c-fos, c-jun, c-myc, and R-ras proto-oncogenes. The DNA synthesis, repair, and recombination genes (nine genes) were the DNA replication licensing factor MCM4, the DNA replication licensing factor MCM5, the DNA mismatch repair gene PMS2, the DNA excision repair gene, the DNA mismatch repair gene MSH2, the ultraviolet excision repair gene Rad23 DNA ligase 1, Rad51, and Rad52. The differential gene expression profile was confirmed with reverse transcription-polymerase chain reaction using primers specific for the differentially expressed genes. In general, expression of the cancer-related genes was upregulated, while expression of genes involved in DNA synthesis, repair, and recombination was downregulated in the tumor cells compared with the control cells. Using c-fos and c-jun, two of the differentially expressed genes, as model genes, we have found that in the nontransformed BALB/c-3T3 cells, the beryllium-induced transcriptional activation of these genes was dependent on pathways of protein kinase C and mitogen-activated protein kinase and independent of reactive oxygen species. These results indicate that beryllium-induced cell transformation and tumorigenesis are accompanied by and are possibly a product of alterations in expression of genes related to cancer and to DNA synthesis, repair, and recombination.

3T3 Cells↗
PubMed2001

Cadmium-induced cell transformation and tumorigenesis are associated with transcriptional activation of c-fos, c-jun, and c-myc proto-oncogenes: role of cellular calcium and reactive oxygen species.

The molecular mechanisms of carcinogenesis by cadmium were studied using BALB/c-3T3 cell transformation and nude mouse tumorigenesis models. BALB/c-3T3 cells transformed with cadmium chloride were subcutaneously injected into nude mice to develop tumors and the cell lines derived from these tumors were used in the present study. The proto-oncogenes c-fos and c-jun were overexpressed in 100% (10 out of 10) of the cell lines, while a statistically significant overexpression of c-myc was observed in 40% (4 out of 10) of the cell lines. Analysis of tumor cells stained with fluorescent dyes specific for reactive oxygen species revealed that these cells possessed markedly higher levels of superoxide anion and hydrogen peroxide compared with the nontransformed cells. Similarly, the intracellular calcium level was higher in the tumor cells compared with the nontransformed cells. Overexpression of the proto-oncogenes in these cells was blocked by treating the cells with superoxide dismutase, catalase, and 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetra acetoxy methyl ester (BAPTA/AM), which are scavengers of superoxide anion, hydrogen peroxide, and calcium, respectively. This confirmed that the overexpression of the proto-oncogenes in the tumor cells required elevated intracellular levels of reactive oxygen species and calcium. In addition to the scavengers of reactive oxygen species and calcium, inhibitors specific for transcription (actinomycin D), protein kinase C (RO-31-8220), and MAP kinase (PD 98059) also blocked the cadmium-induced overexpression of the proto-oncogenes in the tumor cells. Exposure of the nontransformed BALB/c-3T3 cells to 20 microM cadmium chloride for 1 h caused elevated intracellular levels of superoxide anion, hydrogen peroxide, and calcium, with corresponding increases in the expression levels of c-fos, c-jun, and c-myc. As in the case of the tumor cells, treating the nontransformed cells with the various modulators prior to their exposure to cadmium chloride resulted in inhibition in the expression of the proto-oncogenes. Based on these data, we conclude that the cadmium-induced overexpression of cellular proto-oncogenes is mediated by the elevation of intracellular levels of superoxide anion, hydrogen peroxide, and calcium. Further, the cadmium-induced overexpression of the proto-oncogenes is dependent on transcriptional activation as well as on pathways involving protein kinase C and MAP kinase.

3T3 Cells↗
PubMed2001

Community mental health team management in severe mental illness: a systematic review.

BACKGROUND: Community mental health teams are now generally recommended for the management of severe mental illness but a comparative evaluation of their effectiveness is lacking. AIMS: To assess the benefits of community mental health team management in severe mental illness. METHOD: A systematic review was conducted of community mental health team management compared with other standard approaches. RESULTS: Community mental health team management is associated with fewer deaths by suicide and in suspicious circumstances (odds ratio=0.32, 95% Cl 0.09-1.12), less dissatisfaction with care (odds ratio=0.34, 95% Cl 0.2-0.59) and fewer drop-outs (odds ratio=0.61, 95% Cl 0.45-0.83). Duration of in-patient psychiatric treatment is shorter with community team management and costs of care are less, but there are no gains in clinical symptomatology or social functioning. CONCLUSIONS: Community mental health team management is superior to standard care in promoting greater acceptance of treatment, and may also reduce hospital admission and avoid deaths by suicide. This model of care is effective and deserves encouragement.

Adolescent↗
PubMed2000

Effect of post-treatment isoniazid on prevention of recurrent tuberculosis in HIV-1-infected individuals: a randomised trial.

BACKGROUND: Patients with HIV-1 infection respond well to treatment for active tuberculosis, but whether such patients are at increased risk of disease recurrence after complete cure is uncertain. We did a randomised trial in Port au Prince, Haiti, to determine whether recurrent tuberculosis after curative tuberculosis treatment is more common in HIV-1-infected individuals than HIV-1-uninfected individuals, and to determine whether post-treatment isoniazid prophylaxis decreases the risk of recurrent tuberculosis. METHODS: Patients older than 18 years who were diagnosed with a first episode of tuberculosis at the national HIV testing centre in Haiti, and who successfully completed a 6-month rifampicin-containing regimen for active pulmonary tuberculosis, were randomly assigned 1 year of post-treatment isoniazid prophylaxis or placebo. The primary outcome measure was rate of recurrent tuberculosis after at least 24 months. An intention-to-treat analysis was used. FINDINGS: Of 354 patients with active pulmonary tuberculosis, 274 successfully completed treatment, and 233 were randomised. Of 142 HIV-1-positive patients, 68 were assigned isoniazid and 74 placebo. Of 91 HIV-1-negative individuals, 51 were assigned isoniazid and 40 placebo. The rate of recurrent tuberculosis was 4.8 per 100 person-years in HIV-1-infected individuals and 0.4 per 100 person-years in uninfected individuals (relative risk 10.7 [95% CI 1.4-81.6]). Among HIV-1-positive patients receiving isoniazid, the tuberculosis recurrence rate was 1.4 per 100 person-years, and among HIV-1-positive patients receiving placebo, it was 7.8 per 100 person-years (0.18 [0.04-0.83]). Among HIV-1-positive individuals, all cases of recurrent tuberculosis occurred in individuals with a history of HIV-1-related symptoms before initial tuberculosis diagnosis. INTERPRETATION: The rate of recurrent tuberculosis is higher in HIV-1-positive individuals than in HIV-1-negative individuals, and is strongly associated with a history of symptomatic HIV-1 disease before initial tuberculosis diagnosis. Post-treatment isoniazid prophylaxis decreases the risk of recurrence in HIV-1-positive individuals, and should be considered for HIV-1-positive individuals with a history of HIV-1-related symptoms at the time of tuberculosis diagnosis.

AIDS-Related Opportunistic Infections↗
PubMed2000

Role of NAD(P)H:quinone oxidoreductase 1 (DT diaphorase) in protection against quinone toxicity.

NQO1-/- mice, along with Chinese hamster ovary (CHO) cells, were used to determine the in vivo role of NAD(P)H:quinone oxidoreductase 1 (NQO1) in cellular protection against quinone cytotoxicity, membrane damage, DNA damage, and carcinogenicity. CHO cells permanently expressing various levels of cDNA-derived P450 reductase and NQO1 were produced. Treatment of CHO cells overexpressing P450 reductase with menadione, benzo[a]pyrene-3,6-quinone (BPQ), and benzoquinone led to increased cytotoxicity as compared with CHO cells expressing endogenous P450 reductase. In a similar experiment, overexpression of NQO1 significantly protected CHO cells against the cytotoxicity of these quinones. Knockout (NQO1-/-) mice deficient in NQO1 protein and activity had been generated previously in our laboratory and were used in the present studies. Wild-type (NQO1+/+) and knockout (NQO1-/-) mice were given i.p. injections of menadione and BPQ, followed by analysis of membrane damage and DNA damage. Both menadione and BPQ induced lipid peroxidation in hepatic and non-hepatic tissues, indicating increased membrane damage. Exposure to BPQ also resulted in increased hepatic DNA adducts in NQO1-/- mice as compared with NQO1+/+ mice. The skin application of BPQ alone and BPQ + 12-O-tetradecanoylphorbol-13-acetate (TPA) failed to induce papillomas, or other lesions, for up to 50 weeks in either NQO1+/+ or NQO1-/- mice. The various results from CHO cells and NQO1-/- mice indicated that NQO1 protects against quinone-induced cytotoxicity, as well as DNA and membrane damage. The absence of BPQ-induced skin carcinogenicity in NQO1-/- mice may be related to the strain (C57BL/6) of mice used in the present study and/or due to poor BPQ absorption into the skin and/or due to detoxification of BPQ by cytosolic NRH:quinone oxidoreductase 2 (NQO2).

Animals↗
PubMed2000

Community mental health teams (CMHTs) for people with severe mental illnesses and disordered personality.

BACKGROUND: Closure of asylums and institutions for the mentally ill, coupled with government policies focusing on reducing the number of hospital beds for people with severe mental illness in favour of providing care in a variety of non-hospital settings underpins the rationale behind care in the community. A major thrust towards community care has been the development of community mental health teams (CMHT). OBJECTIVES: To evaluate the effects of community mental health team (CMHT) treatment for anyone with serious mental illness. SEARCH STRATEGY: Electronic searches of Biological Abstracts (1982-1997), the Cochrane Library (1998, Issue 2), EMBASE (1980-1997), MEDLINE (1966-1997), PsycLIT (1974-1997) and SCISEARCH (1997) were undertaken. The Journal of Personality Disorders was hand searched, and contact was made with colleagues at ENMESH, ISSPD and in forensic psychiatry. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials of CMHT management versus non-team standard care. DATA COLLECTION AND ANALYSIS: The selection of trials, assessment of quality and data extraction was undertaken independently and in parallel by two reviewers. Where possible the data were entered into RevMan and an intention-to-treat analysis undertaken. Tests of heterogeneity were undertaken. MAIN RESULTS: CMHT management may be associated with fewer deaths by suicide and in suspicious circumstances (OR 0.32 CI 0.09-1.12). It causes less people to be dissatisfied with their care (OR 0.34 CI 0.2-0.59) and to leave the studies early (OR 0.61 CI 0.45-0.83). No clear difference was found in admission rates, overall clinical outcomes and duration of in-patient hospital treatment, although this was partly a consequence of poorly presented data. REVIEWER'S CONCLUSIONS: Community mental health team management is not inferior to non-team standard care in any important respects and is superior in promoting greater acceptance of treatment. It may also be superior in reducing hospital admission and avoiding death by suicide.

Community Mental Health Services↗
PubMed2000

A unique cytosolic activity related but distinct from NQO1 catalyses metabolic activation of mitomycin C.

Mitomycin C (MMC) is a prototype bioreductive drug employed to treat a variety of cancers including head and neck cancer. Among the various enzymes, dicoumarol inhibitable cytosolic NAD(P)H:quinone oxidoreductase1 (NQO1) was shown to catalyse bioreductive activation of MMC leading to cross-linking of the DNA and cytotoxicity. However, the role of NQO1 in metabolic activation of MMC has been disputed. In this report, we present cellular and animal models to demonstrate that NQO1 may play only a minor role in metabolic activation of MMC. We further demonstrate that bioreductive activation of MMC is catalysed by a unique cytosolic activity which is related but distinct from NQO1. Chinese hamster ovary (CHO) cells were developed that permanently express higher levels of cDNA-derived NQO1. These cells showed significantly increased protection against menadione toxicity. However, they failed to demonstrate higher cytotoxicity due to exposure to MMC under oxygen (normal air) or hypoxia, as compared to the wild-type control CHO cells. Disruption of the NQO1 gene by homologous recombination generated NQO1-/- mice that do not express the NQO1 gene resulting in the loss of NQO1 protein and activity. The cytosolic fractions from liver and colon tissues of NQO1-/- mice showed similar amounts of DNA cross-linking upon exposure to MMC, as observed in NQO1+/+ mice. The unique cytosolic activity that activated MMC in cytosolic fractions of liver and colon tissues of NQO1-/- mice was designated as cytosolic MMC reductase. This activity, like NQO1, was inhibited by dicoumarol and immunologically related to NQO1.

Animals↗
PubMed2000

Common coding in symbolic matching tasks with humans: training with a common consequence or antecedent.

The present experiments explored the importance of training with a common antecedent or consequence for common coding in symbolic matching-to-sample tasks with human subjects using reversal and transfer tests. Experiment 1 assessed common coding following training in many-to-one (MTO) and one-to-many (OTM) symbolic matching-to-sample tasks by comparing learning of partial and total reversals of these contingencies. Experiment 2 assessed common coding in MTO and OTM tasks by comparing performances in transfer tests when the common coding relations in the transfer phase were either consistent or inconsistent with those present during initial training. Evidence for common coding in the MTO and OTM discriminations was obtained in both experiments, although the amount of common coding was greater in the MTO discrimination in Experiment 1. These data are discussed in terms of associative mediational approaches to common coding phenomena. It is suggested that a basic requirement of an associative theory is that common coding should be more likely to occur when the stimuli are trained with a common consequence than when they are trained with a common antecedent, and that this requirement has been at least partly satisfied in the present studies.

Adult↗
PubMed1999

[Severe digestive complications after heart surgery using extracorporeal circulation].

PURPOSE: To determine the incidence, circumstances of occurrence and evolution of gastrointestinal complications after cardiac surgery with extracorporeal circulation (ECC). METHODS: Retrospective chart study of gastrointestinal complications in 6.281 patients undergoing ECC between january 1994 and December 1997. RESULTS: Sixty patients developed 68 gastrointestinal complications (1%). Complications included: upper gastrointestinal bleeding (n = 23), intestinal ischemia (n = 19), cholecystitis (n = 7), pancreatitis (n = 6), and paralytic ileus (n = 16). The incidence of these complications was low after coronary artery (0.4%) or valvular surgery (0.8%) and high after cardiac transplantation (6%) and after surgery for acute aortic dissection (9%). Compared with a control population, patients with gastrointestinal complication had a higher Parsonnet score (29 +/- 15 vs 13 +/- 12 points; P = 0.002), were more frequently operated upon as an emergency (40/60, 66% vs 1120/6221, 18%; P = 0.01), underwent ECC of longer duration (114 +/- 66 vs 74 +/- 42 min; P = 0.01), and presented more frequently with low cardiac output after surgery (45/60, 75% vs 435/6221, 7%; P = 0.001). The mortality rate after gastrointestinal complications was 52%. The major factor associated with mortality was the occurrence of sepsis (OR = 38.7). Other factors were: renal failure (OR = 7.9), age > 75 yr (OR = 3.5), mechanical ventilation for more than seven days (OR = 2.7), associated cerebral damage (OR = 3.9). CONCLUSION: Gastrointestinal complications after ECC occur in high risk surgical patients. These complications are frequently associated with other complications leading to a high mortality rate.

Adult↗
PubMed1999

Changing conditions and treatments in a dynamic cohort of ambulatory HIV patients: the HIV outpatient study (HOPS).

PURPOSE: Most HIV-infected persons are now treated as ambulatory patients. Obtaining continually updated data about these patients' changing conditions, therapies, and reimbursement is essential to health care provision and planning. The systematic tracking of patient medical and laboratory information in an ongoing commercial data collection program (The Health Research Network) allows clinicians to better understand health outcomes, practice patterns, and epidemiologic trends for their patients. METHODS: To evaluate trends in conditions and therapies of ambulatory HIV-infected patients, we analyzed such data electronically and prospectively collected in the HIV Outpatient Study (HOPS) from 1992 through 1996 from 1876 patients seen in 11,755 clinic visits to ten HIV clinical practices. RESULTS: Patients were as likely to be diagnosed with Mycobacterium avium complex ([MAC] 5.4 cases per 100 person-years) or wasting syndrome (7.8 cases per 100 person-years), as Pneumocystis carinii pneumonia ([PCP]; 7.6 cases per 100 person-years) or Kaposi sarcoma ([KS]; 6.9 cases per 100 person-years). A nested analysis showed that HIV-infected cigarette smokers were at substantially greater risk of pneumonia (relative hazard [RH] = 2.3), bronchitis (RH = 1.7) and hairy leukoplakia (RH = 1.9) than nonsmokers. By 1996, 35 (56%) of 62 patients with PCP, 9 (30%) of 30 patients with other pneumonias, 28 (90%) of 31 patients with KS, 35 (73%) of 48 patients with MAC, and 24 (63%) of 38 patients with cytomegalovirus retinitis were treated without hospitalization. CONCLUSIONS: The HOPS provides continually updated information on the changing characteristics, conditions, and therapy of ambulatory HIV-infected patients.

Adult↗
PubMed1999

Intravesical instillation of capsaicin in urology: A review of the literature.

OBJECTIVES: Interest in the intravesical instillation of capsaicin is growing among urologists. Its efficacy on detrusor hyperreflexia, hypersensitive bladder disorders and bladder pain has been reported in several studies. However, the lack of common evaluation parameters and the absence of consensus concerning a protocol of instillation hamper the interpretation of results. The purpose of this review is to better delineate the indications and optimum protocol for intravesical use of capsaicin. METHODS: Eight open and two placebo-controlled human clinical trials were analyzed. All 200 patients involved had lower urinary tract disorders. RESULTS: Clinical or urodynamic symptoms improved in 84.3% of the patients who received intravesical capsaicin for neurogenic hyperreflexic bladder, a significantly greater efficacy than that of placebo. Capsaicin may also be beneficial in patients who have non-neurogenic disorders. Whether or not the patients has a neurologic deficit, side effects appear during and in the period immediately following instillation. CONCLUSIONS: Intravesical capsaicin appears to be indicated in neurogenic hyperreflexic bladder, but is less effective against detrusor instability, hypersensitive bladder disorders or pelvic pain. The best instillation protocol and long-term tolerance remain to be established.

Administration, Intravesical↗
PubMed1999

An assessment of the value of midfinger smears in multibacillary leprosy patients.

In view of the different opinions on fingers as sites for persisting bacilli in multibacillary leprosy patients, it was decided to examine the midfingers for the presence of acid-fast bacilli (AFB) and establish its usefulness. Sixty-nine multibacillary leprosy patients, [lepromatous (LL) and borderline lepromatous (BL)] treated with multidrug therapy for fixed duration (2 years) were analysed. The bacillary load in the midfinger sites was lower when compared to that in the 'compulsory' (both earlobes) and 'optional' (four active lesions) sites. The midfinger bacterial index (BI) was higher among LL patients when compared to BL patients (p < 0.001). However, the difference in mean BI in 'optional' and 'compulsory sites' was not significant. The overall fall in BI was gradual and on expected lines for all sites, including midfingers, during treatment and follow-up period. Except in one case, at no time were the smears from midfinger sites positive when all other sites were negative, and their inclusion did not contribute to the early detection of relapse. Furthermore, the collection of blood-free smears from this site is technically difficult and often painful for the patient. The inclusion of midfinger smears in this study in patients in South India did not contribute useful information to that which is routinely available from smears of earlobes and other active sites.

Bacteriological Techniques↗
PubMed1999

Paclitaxel and concurrent radiation therapy for locally advanced adenocarcinomas of the pancreas, stomach, and gastroesophageal junction.

An effective locoregional therapy is needed for adenocarcinomas of the pancreas, stomach, and gastroesophageal junction. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) may enhance the effect of radiation therapy (RT). Paclitaxel synchronizes cells at G2/M, a relatively radiosensitive phase of the cell cycle. We have shown that response to paclitaxel and concurrent RT (paclitaxel/RT) was not affected by p53 mutations in non-small cell lung cancer. This finding suggested that paclitaxel/RT was a rational treatment approach for other malignancies that frequently harbor p53 mutations, such as upper gastrointestinal malignancies. We completed a phase I study of paclitaxel/RT for locally advanced pancreatic and gastric cancer. The maximum tolerated dose of paclitaxel was 50 mg/m2/wk for 6 weeks with abdominal RT. The dose-limiting toxicities were abdominal pain within the radiation field, nausea, and anorexia. Phase II studies are now under way. Twenty-five patients with locally advanced pancreatic cancer have been entered at the phase II dose level of paclitaxel 50 mg/m2/wk with concurrent RT (total dose, 50 Gy). Thus far, the only grade 3/4 toxicities have been hypersensitivity reactions (n = 2), asymptomatic grade 4 neutropenia (n = 3), and nonneutropenic biliary sepsis (n = 1). Of the first 18 assessable patients with pancreatic cancer treated on the phase II study, six obtained a partial response, for a preliminary response rate of 33%. In the phase II study for locally advanced gastric cancer, 20 patients have been enrolled. Of the first 19 patients who have completed treatment, nine (47%) had grade 3/4 toxicities, including nausea, anorexia, esophagitis, and gastritis. Of the first 16 patients with gastric cancer, complete and partial responses have been observed in one and eight patients, respectively, for a preliminary response rate of 56%. We have also completed treatment on 24 patients with potentially resectable adenocarcinomas of the gastroesophageal junction with neoadjuvant paclitaxel 60 mg/m2 and cisplatin 25 mg/m2, weekly for 4 weeks, with concurrent RT (total dose, 40 Gy) followed by surgical resection. Ten patients (41%) had grade 3/4 toxicities, including neutropenia, nausea, and dehydration. Of 24 patients, four complete responses (17%) and 14 partial responses (58%) were observed, for an overall response rate of 75%. Severe esophagitis was uncommon, making this a well-tolerated outpatient regimen for adenocarcinomas of the distal esophagus. These findings demonstrate that paclitaxel-based chemoradiation for locally advanced upper gastrointestinal malignancies is well-tolerated with substantial activity.

Adenocarcinoma↗
PubMed1998

Abnormal microsomal detoxification implicated in Fanconi anemia group C by interaction of the FAC protein with NADPH cytochrome P450 reductase.

The FAC protein encoded by the Fanconi anemia (FA) complementation group C gene is thought to function in the cytoplasm at a step before DNA repair. Because FA cells are susceptible to mitomycin C, we considered the possibility that FAC might interact with enzymes involved in the bioreductive activation of this drug. Here we report that FAC binds to NADPH cytochrome-P450 reductase (RED), a microsomal membrane protein involved in electron transfer, in both transfected COS-1 and normal murine liver cells. FAC-RED interaction requires the amino-terminal region of FAC and the cytosolic, membrane-proximal domain of the reductase. The latter contains a known binding site for flavin mononucleotide (FMN). Addition of FMN to cytosolic lysates disrupts FAC-reductase complexes, while flavin dinucleotide, which binds to a distinct carboxy-terminal domain, fails to alter FAC-RED complexes at concentrations similar to FMN. FAC is also functionally coupled to this enzyme as its expression in COS-1 cells suppresses the ability of RED to reduce cytochrome c in the presence of NADPH. We propose that FAC plays a fundamental role in vivo by attenuating the activity of RED, thereby regulating a major detoxification pathway in mammalian cells.

Animals↗
PubMed1998

Disruption of the DT diaphorase (NQO1) gene in mice leads to increased menadione toxicity.

NAD(P)H:quinone oxidoreductase 1 (NQO1) is a flavoenzyme that catalyzes two-electron reductive metabolism and detoxification of quinones and their derivatives leading to protection of cells against redox cycling and oxidative stress. To examine the in vivo role of NQO1, a NQO1-null mouse was produced using targeted gene disruption. Mice lacking NQO1 gene expression showed no detectable phenotype and were indistinguishable from wild-type mice. However, NQO1-null mice exhibited increased toxicity when administered menadione compared with wild-type mice. These results establish a role for NQO1 in protection against quinone toxicity. The NQO1-null mice are a model for NQO1 deficiency in humans and can be used to determine the role of this enzyme in sensitivity to toxicity and carcinogenesis.

Alanine Transaminase↗