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Peter Schwartz

Publications and source records attributed to Peter Schwartz.

18 recordsLinked to original sources
PubMed2006

Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) induces apoptosis in ovarian cancer cells.

OBJECTIVES: Triapine (Vion Pharmaceuticals, New Haven, CT) is a potent ribonucleotide reductase inhibitor which exerts its antineoplastic activity by inhibiting DNA synthesis and repair. The objectives of this study were: (1) to determine whether Triapine has cytotoxic effects on epithelial ovarian cancer (EOC) cells; (2) to characterize the apoptotic cascade induced in response to this agent; and (3) to determine its utility in combination treatment with carboplatin and paclitaxel. METHODS: Five EOC cell lines were treated with tenfold dilutions of Triapine (0.1 to 100 microM) for 24 and 48 hours. Cell viability was determined by the CellTiter 96 AQueous One Solution Cell Proliferation Assay (Promega Corp, Madison, WI) and the morphologic features of apoptosis were observed using Hoechst staining. The apoptotic cascade was characterized by Western blot analyses. RESULTS: All EOC cell lines treated with Triapine showed decreased cell viability in a time- and dose-dependent manner. Hoechst staining revealed nuclear shrinkage and chromatin condensation and fragmentation, which correlated with the occurrence of apoptosis. Western blots demonstrated that Bid activation was one of the initiating signals involved in the cascade. In addition, cleavage of XIAP and down-regulation of Akt were observed. We also demonstrated that Triapine enhances the cytotoxic effects of carboplatin and paclitaxel. CONCLUSIONS: The present findings demonstrate that Triapine induces cell death through the induction of apoptosis. The initial activation of Bid indicates the involvement of the mitochondrial pathway. The demonstration that Triapine is an effective addition to a carboplatin regimen suggests the possibility of a new combination therapy for ovarian cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

The expression of mesenchymal, neural and haematopoietic stem cell markers in adult hepatocytes proliferating in vitro.

BACKGROUND/AIMS: Cultured adult hepatocytes may be stimulated into clonal expansion. We raise the question whether adult hepatocytes proliferating in vitro recapitulate the early process of hepatic development. METHODS: A non-enzymatic method was used to isolate hepatocytes free of contamination with non-parenchymal cells. Hepatocytes were stimulated into proliferation in the presence of mitogens and conditioned media from non-parenchymal cell and hepatocyte culture supernatants. Immunofluorescence methods and PCR analysis were used to demonstrate immunophenotypical characteristics and gene expression profiles similar to those of progenitor cells. RESULTS: Rapid growth occurred during the first 7 days of culture. Cells continued to express hepatic markers (phosphoenolpyruvate carboxykinase, cytokeratin 18, transferrin and dipeptidylpeptidase IV), but the gap junction protein connexin 32 was down-regulated. In the early stage of proliferation, cells started to express biliary and extrahepatic progenitor markers (cytokeratin 19, CD49b, CD49f, nestin, vimentin, Thy1 and c-kit), followed by cytokeratin 7, connexin 43, and neural cell adhesion molecule. Co-expression of the epithelial liver progenitor marker alpha-foetoprotein with either nestin (neural marker) or Thy1 (mesenchymal marker) was also demonstrated. CONCLUSIONS: Mature hepatocytes reveal their potential to regain a spectrum of progenitor markers from different germ layers, suggesting enormous plasticity and differentiation potential of adult liver cells.

Animals↗
PubMed2005

Family history as a co-factor for adenocarcinoma and squamous cell carcinoma of the uterine cervix: results from two studies conducted in Costa Rica and the United States.

Previous work suggests that cervical cancer may aggregate in families. We evaluated the association between a family history of gynecological tumors and risk of squamous cell and adenocarcinomas of the cervix in 2 studies conducted in Costa Rica and the United States. The Costa Rican study consisted of 2,073 women (85 diagnosed with CIN3 or cancer, 55 diagnosed with CIN2 and 1,933 controls) selected from a population-based study of 10,049 women. The U.S. study consisted of 570 women (124 with in situ or invasive adenocarcinomas, 139 with in situ or invasive squamous cell carcinomas of the cervix and 307 community-based controls) recruited as part of a multicentric case-control study in the eastern part of the United States. Information on family history of cervical and other cancers among first-degree relatives was ascertained via questionnaire. Information on other risk factors for cervical cancer was obtained via questionnaire. Human papillomavirus (HPV) exposure was assessed in both studies using broad spectrum HPV L1-based PCR testing of exfoliated cervicovaginal cells and in Costa Rica by additional testing of plasma collected from participants for antibodies against the L1 protein of HPV types 16, 18, 31 and 45 by ELISA. A family history of cervical cancer in a first-degree relative was associated with increased risk of squamous tumors in both studies (odds ration [OR] = 3.2 for CIN3/cancer vs. controls; 95% confidence interval [CI] = 1.1-9.4 in Costa Rica; OR = 2.6 for in situ/invasive squamous cell carcinoma cases vs. controls, 95% CI = 1.1-6.4 in the Eastern United States study). These associations were evident regardless of whether the affected relative was a mother, sister or daughter of the study participant. Furthermore, observed effects were not strongly modified by age. In Costa Rica, the effect persisted in analysis restricted to HPV-exposed individuals (OR = 3.0; 95% CI = 1.0-9.0), whereas in the Eastern United States study there was evidence of attenuation of risk in analysis of squamous carcinoma cases restricted to HPV positive women (OR = 1.4; 95% CI = 0.29-6.6). No significant association was observed between a family history of cervical cancer in a first-degree relative and adenocarcinomas (OR = 1.3; 95% CI = 0.43-3.9). History of gynecological tumors other than cervical cancer in a first-degree relative was not significantly associated with risk of disease in either study. These results are consistent with a role of host factors in the pathogenesis of squamous cell cervical cancer, although familial aggregation due to shared environmental exposures cannot be ruled out.

Adenocarcinoma↗
PubMed2005

Numerical computation of diffusion on a surface.

We present a numerical method for computing diffusive transport on a surface derived from image data. Our underlying discretization method uses a Cartesian grid embedded boundary method for computing the volume transport in a region consisting of all points a small distance from the surface. We obtain a representation of this region from image data by using a front propagation computation based on level set methods for solving the Hamilton-Jacobi and eikonal equations. We demonstrate that the method is second-order accurate in space and time and is capable of computing solutions on complex surface geometries obtained from image data of cells.

Biological Transport↗
PubMed2005

Serum protein markers for early detection of ovarian cancer.

Early diagnosis of epithelial ovarian cancer (EOC) would significantly decrease the morbidity and mortality from this disease but is difficult in the absence of physical symptoms. Here, we report a blood test, based on the simultaneous quantization of four analytes (leptin, prolactin, osteopontin, and insulin-like growth factor-II), that can discriminate between disease-free and EOC patients, including patients diagnosed with stage I and II disease, with high efficiency (95%). Microarray analysis was used initially to determine the levels of 169 proteins in serum from 28 healthy women, 18 women newly diagnosed with EOC, and 40 women with recurrent disease. Evaluation of proteins that showed significant differences in expression between controls and cancer patients by ELISA assays yielded the four analytes. These four proteins then were evaluated in a blind cross-validation study by using an additional 106 healthy females and 100 patients with EOC (24 stage I/II and 76 stage III/IV). Upon sample decoding, the results were analyzed by using three different classification algorithms and a binary code methodology. The four-analyte test was further validated in a blind binary code study by using 40 additional serum samples from normal and EOC cancer patients. No single protein could completely distinguish the cancer group from the healthy controls. However, the combination of the four analytes exhibited the following: sensitivity 95%, positive predictive value (PPV) 95%, specificity 95%, and negative predictive value (NPV) 94%, a considerable improvement on current methodology.

Aged↗
PubMed2005

Hierarchy of resistance to cervical neoplasia mediated by combinations of killer immunoglobulin-like receptor and human leukocyte antigen loci.

Killer immunoglobulin-like receptor (KIR) recognition of specific human histocompatibility leukocyte antigen (HLA) class I allotypes contributes to the array of receptor-ligand interactions that determine natural killer (NK) cell response to its target. Contrasting genetic effects of KIR/HLA combinations have been observed in infectious and autoimmune diseases, where genotypes associated with NK cell activation seem to be protective or to confer susceptibility, respectively. We show here that combinations of KIR and HLA loci also affect the risk of developing cervical neoplasia. Specific inhibitory KIR/HLA ligand pairs decrease the risk of developing neoplasia, whereas the presence of the activating receptor KIR3DS1 results in increased risk of disease, particularly when the protective inhibitory combinations are missing. These data suggest a continuum of resistance conferred by NK cell inhibition to susceptibility involving NK cell activation in the development of cervical neoplasia and underscore the pervasive influence of KIR/HLA genetic variation in human disease pathogenesis.

Case-Control Studies↗
PubMed2005

Zona pellucida characteristics and sperm-binding patterns of in vivo and in vitro produced porcine oocytes inseminated with differently prepared spermatozoa.

IVF of porcine oocytes has been carried out in many laboratories. However, polyspermic fertilization is still a major issue to be solved. It is well known that besides the nucleus, oocyte organelles and the cytoplasm have to undergo a final maturation process before they become fully competent for fertilization. Until now, it is still uncertain whether the zona pellucida (ZP) must also undergo a maturation process and what impact the maturation status may have on sperm recognition and monospermic fertilization. Our data show that the ZP undergoes biochemical changes in the final maturation phase of the oocyte prior to fertilization. During zona maturation, the induction of the acrosome reaction in spermatozoa bound to the zona pellucida shows a different time pattern. Additionally, it was shown by 2D gel electrophoresis that after maturation, ZPA moved 0.8 pI units and ZPB/ZPC 1.3 pI units in the direction of the anode, indicating increased acidity. These preliminary studies indicate that the maturation processes of the oocyte involves biochemical and functional alterations in the zona pellucida. In addition, the morphology of the porcine ZP was investigated before and after maturation at the GVI and metaphase II stage as well as 1h after onset of IVF. No significant consistent structural changes were seen between immature oocytes and those matured in vitro for 48 h. However, at 24 h, the zona structures were more similar to those in in vivo matured oocytes. This phenomenon needs to be elucidated. So far, the only way to avoid polyspermic penetration is to reduce the number of spermatozoa per oocyte used for IVF. The amount depends on the treatment of the sperm and has to be set for each individual boar.

Acrosome Reaction↗
PubMed2005

Weekly topotecan in heavily pretreated patients with recurrent epithelial ovarian carcinoma.

OBJECTIVE: To investigate weekly topotecan in heavily pretreated patients with recurrent ovarian cancer. METHODS: The records of patients with recurrent epithelial ovarian cancer who were treated with weekly topotecan after failure of > or =1 prior regimen were reviewed. Patients received topotecan (median starting dose approximately 2.5 mg/m(2)) on days 1, 8, and 15 of a 28-day cycle. Antitumor response was assessed after 2 cycles by serial CA-125 levels. RESULTS: Thirty-five heavily pretreated patients received a mean of 5 cycles of topotecan (range, 1-13 cycles). Thirty-two patients had definable platinum sensitivity (16 sensitive, 8 resistant, 8 refractory). Median age was 56 years. A total of 177 cycles (534 weeks) of topotecan was administered. Hematologic toxicity was generally mild, and no grade 4 toxicities were observed. Grade 3 hematologic toxicity, including leukopenia, neutropenia, thrombocytopenia, and anemia, was observed in 2, 2, 1, and 0 patients, respectively. No patients experienced grade 3 or 4 nonhematologic toxicity. Based on serial CA-125 measurements, there were 1 (3%) complete and 5 (15%) partial responses, with 1 of the partial responses in a patient with platinum-refractory disease. Stable disease was reported in 13 (38%) patients, including 5 patients with platinum-resistant/refractory disease. CONCLUSION: Weekly topotecan demonstrates activity and is well tolerated compared with historical data with the standard 5-day schedule. Higher doses may be warranted because of the high tolerability shown for weekly topotecan. Weekly topotecan may be an appropriate treatment option for patients with recurrent ovarian cancer, especially heavily pretreated patients who might require dosing schedules with improved tolerability.

Adult↗
PubMed2004

Functional analysis of seven genes encoding eight translation initiation factor 4E (eIF4E) isoforms in Drosophila.

The Drosophila genome-sequencing project has revealed a total of seven genes encoding eight eukaryotic initiation factor 4E (eIF4E) isoforms. Four of them (eIF4E-1,2, eIF4E-3, eIF4E-4 and eIF4E-5) share exon/intron structure in their carboxy-terminal part and form a cluster in the genome. All eIF4E isoforms bind to the cap (m7GpppN) structure. All of them, except eIF4E-6 and eIF4E-8 were able to interact with Drosophila eIF4G or eIF4E-binding protein (4E-BP). eIF4E-1, eIF4E-2, eIF4E-3, eIF4E-4 and eIF4E-7 rescued a yeast eIF4E-deficient mutant in vivo. Only eIF4E-1 mRNAs and, at a significantly lower level, eIF4E3 and eIF4E-8 are expressed in embryos and throughout the life cycle of the fly. The transcripts of the remaining isoforms were detected from the third instar larvae onwards. This indicates the cap-binding activity relies mostly on eIF4E-1 during embryogenesis. This agrees with the proteomic analysis of the eIF4F complex purified from embryos and with the rescue of l(3)67Af, an embryonic lethal mutant for the eIF4E-1,2 gene, by transgenic expression of eIF4E-1. Overexpression of eIF4E-1 in wild-type embryos and eye imaginal discs results in phenotypic defects in a dose-dependent manner.

Aging↗
PubMed2004

Somatic D-loop mitochondrial DNA mutations are frequent in uterine serous carcinoma.

The mitochondria plays a role in apoptosis. Its genome is also more susceptible to mutations because of high levels of reactive oxygen species and limited repair mechanisms. The D-loop of mitochondrial DNA (mtDNA) contains essential transcription and replication elements, and mutations in this region might alter the rate of DNA replication. We examined genetic alterations in the D-loop region of mtDNA in uterine serous carcinoma (USC) samples and their paired normal adjacent endometrium. DNA was extracted after laser-capture microdissection of paraffin-embedded tissues from eight patients with USC. The entire D-loop genome was amplified using nine pairs of overlapping primers. Denatured polymerase chain reaction (PCR) products were subjected to single-strand conformation polymorphism (SSCP) analysis. Somatic mtDNA alterations were detected in five tumours (63%). Our study indicates that mtDNA D-loop sequence alterations occur at a high frequency in USC suggesting that mtDNA mutations may play a role in the development of USC.

Aged↗
PubMed2004

Apoptosis-based evaluation of chemosensitivity in ovarian cancer patients.

OBJECTIVE: Induction of apoptosis in target cells is a key mechanism by which chemotherapy induces cell killing. We have established an in vitro system for determining the chemosensitivity of epithelial ovarian cancer cells to carboplatin and paclitaxel (Taxol). Practical assays to predict the likelihood of individual tumor sensitivity are needed to facilitate the choice of adequate treatment. We sought to determine whether epithelial ovarian cancer cells (EOC) collected from the ascites fluid of patients known to be clinically chemosensitive or chemoresistant to carboplatin and paclitaxel would show a similar response to chemotherapeutic drugs after in vitro treatment. METHODS: Thirteen patients with stage III and IV ovarian cancer treated with carboplatin and paclitaxel were studied. Caspase-3 activation was used as a surrogate marker for activation of chemotherapy-induced programmed cell death. We compared the in vitro apoptotic response to the clinical response of the patients from whom the tumor cells were isolated. Clinical sensitivity was defined as no evidence of disease recurrence for 6 months after optimal debulking surgery and completion of chemotherapy. RESULTS: Of seven chemosensitive patients, five cell samples treated in vitro had increased caspase-3 activity in response to both carboplatin and paclitaxel. Five of six chemoresistant cases did not show caspase-3 activity in response to only one or to neither agent. CONCLUSION: Quantifiable markers of apoptosis such as caspase-3 activation have the potential to predict the clinical response to chemotherapy. Application of this assay in clinical laboratories could optimize the potential for efficient treatment and avoid the toxicities of ineffective drugs.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Osteoclast-independent bone resorption by fibroblast-like cells.

To date, mesenchymal cells have only been associated with bone resorption indirectly, and it has been hypothesized that the degradation of bone is associated exclusively with specific functions of osteoclasts. Here we show, in aseptic prosthesis loosening, that aggressive fibroblasts at the bone surface actively contribute to bone resorption and that this is independent of osteoclasts. In two separate models (a severe combined immunodeficient mouse coimplantation model and a dentin pit formation assay), these cells produce signs of bone resorption that are similar to those in early osteoclastic resorption. In an animal model of aseptic prosthesis loosening (i.e. intracranially self-stimulated rats), it is shown that these fibroblasts acquire their ability to degrade bone early on in their differentiation. Upon stimulation, such fibroblasts readily release acidic components that lower the pH of their pericellular milieu. Through the use of specific inhibitors, pericellular acidification is shown to involve the action of vacuolar type ATPases. Although fibroblasts, as mesenchymal derived cells, are thought to be incapable of resorbing bone, the present study provides the first evidence to challenge this widely held belief. It is demonstrated that fibroblast-like cells, under pathological conditions, may not only enhance but also actively contribute to bone resorption. These cells should therefore be considered novel therapeutic targets in the treatment of bone destructive disorders.

Adult↗
PubMed2003

Evidence of woven bone formation in heart valve disease.

The pathogenesis of acquired cardiac valve disease still remains a matter of controversy. In this work, scanning electron and polarised light microscopic investigations in addition to energy dispersive X-ray microanalyses (EDAX) were carried out on explanted human aortic and mitral valves to determine the morphology and element composition of calcified areas in valvular lesions. Biopsies were taken from aortic valves removed from 28 male patients (average age, 75+/-1 years) and 46 females (68+/-3 years) and from mitral valves obtained from 18 male patients (72+/-3 years) and 8 females (71+/-6 years). By means of scanning electron microscopy, multiple foci of calcified areas were identified. Endothelial cells in these areas appeared swollen and displayed reduced cell-cell contacts. The calcium deposits were separated from the adjacent tissue by layers of collagen fibers. Often a layer of woven bone tissue separated intravalvular inclusions from hyperplastic collagen fibers. Using EDAX analysis, calcium and phosphorus were detected in these valvular lesions. The major finding of our study is the presence of woven bone tissue in explanted cardiac valves, which may result from pathological strains or mechanical overloading of the collagen fibers.

Aged↗
PubMed2002

Sertraline treatment of major depression in patients with acute MI or unstable angina.

CONTEXT: Major depressive disorder (MDD) occurs in 15% to 23% of patients with acute coronary syndromes and constitutes an independent risk factor for morbidity and mortality. However, no published evidence exists that antidepressant drugs are safe or efficacious in patients with unstable ischemic heart disease. OBJECTIVE: To evaluate the safety and efficacy of sertraline treatment of MDD in patients hospitalized for acute myocardial infarction (MI) or unstable angina and free of other life-threatening medical conditions. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled trial conducted in 40 outpatient cardiology centers and psychiatry clinics in the United States, Europe, Canada, and Australia. Enrollment began in April 1997 and follow-up ended in April 2001. PATIENTS: A total of 369 patients with MDD (64% male; mean age, 57.1 years; mean 17-item Hamilton Depression [HAM-D] score, 19.6; MI, 74%; unstable angina, 26%). INTERVENTION: After a 2-week single-blind placebo run-in, patients were randomly assigned to receive sertraline in flexible dosages of 50 to 200 mg/d (n = 186) or placebo (n = 183) for 24 weeks. MAIN OUTCOME MEASURES: The primary (safety) outcome measure was change from baseline in left ventricular ejection fraction (LVEF); secondary measures included surrogate cardiac measures and cardiovascular adverse events, as well as scores on the HAM-D scale and Clinical Global Impression Improvement scale (CGI-I) in the total randomized sample, in a group with any prior history of MDD, and in a more severe MDD subgroup defined a priori by a HAM-D score of at least 18 and history of 2 or more prior episodes of MDD. RESULTS: Sertraline had no significant effect on mean (SD) LVEF (sertraline: baseline, 54% [10%]; week 16, 54% [11%]; placebo: baseline, 52% [13%]; week 16, 53% [13%]), treatment-emergent increase in ventricular premature complex (VPC) runs (sertraline: 13.1%; placebo: 12.9%), QTc interval greater than 450 milliseconds at end point (sertraline: 12%; placebo: 13%), or other cardiac measures. All comparisons were statistically nonsignificant (P> or = .05). The incidence of severe cardiovascular adverse events was 14.5% with sertraline and 22.4% with placebo. In the total randomized sample, the CGI-I (P =.049), but not the HAM-D (P =.14), favored sertraline. The CGI-I responder rates for sertraline were significantly higher than for placebo in the total sample (67% vs 53%; P =.01), in the group with at least 1 prior episode of depression (72% vs 51%; P =.003), and in the more severe MDD group (78% vs 45%; P =.001). In the latter 2 groups, both CGI-I and HAM-D measures were significantly better in those assigned to sertraline. CONCLUSION: Our results suggest that sertraline is a safe and effective treatment for recurrent depression in patients with recent MI or unstable angina and without other life-threatening medical conditions.

Angina, Unstable↗
PubMed2002

Women's choice between sentinel lymph node biopsy and axillary clearance.

PURPOSE: To determine whether women would choose sentinel lymph node biopsy (SLNB) or axillary clearance (AC) for breast cancer treatment when they are given a single choice based on clear information about morbidity and mortality. METHODS: The expected 5-year survival rate of women with breast cancer after either SLNB or AC was calculated using a utility analysis of established literature. The difference in survival was one in 1000. This and other detailed information on SLNB and AC was presented in a questionnaire, which provided subjects with a scenario and a choice between SLNB and AC. After a pilot study of 40 subjects, the questionnaire was mailed to 400 women (who had no mammographic abnormality) attending Breast Screen and handed to 100 women (who were over 40 years of age and had breast symptoms but not cancer) attending the rooms of two surgical specialists. RESULTS: One hundred and twenty one of the 243 respondents to the mailed questionnaires (49.8%) chose SLNB and 35% of the 100 consulting room subjects chose SLNB rather than AC. CONCLUSIONS: Women faced with the possibility of having breast cancer seem to be very conservative in their choice of treatment, many choosing the increased morbidity of AC rather than the very small (one in 1000) increased risk of death at 5 years from SLNB. This raises questions about proposals to offer SLNB as standard treatment and demands that women are fully informed about any increased risk of death when making their choice between SLNB and AC.

Adult↗
PubMed2002

A dose-finding study of aspirin for chemoprevention utilizing rectal mucosal prostaglandin E(2) levels as a biomarker.

Epidemiological and experimental evidence indicates that aspirin can protect against colorectal cancer. Aspirin inhibits cyclooxygenase enzymes and blocks prostaglandin (PG) biosynthesis. Using rectal PGE(2) levels as a mucosal biomarker, we sought to determine the optimal aspirin dose that would significantly suppress PGE(2) levels for chemoprevention trials. We conducted a randomized, double-blinded study in 60 subjects with prior sporadic colorectal adenoma(s) and evaluated three aspirin doses (81, 325, and 650 mg) or placebo taken daily for 4 weeks. PGE(2) levels in rectal biopsies performed at baseline and week 4 were analyzed by competitive immunoassay. Plasma salicylate levels, pill counts, and subject calendars were used to assess compliance. The 81-mg aspirin dose significantly suppressed PGE(2) levels relative to placebo (P = 0.005) and did so to an equivalent extent as did higher doses (P > 0.4) in evaluable subjects (n = 55) over a 4-week treatment period. Serum salicylate levels were associated with aspirin dose (P = 0.0002). Pill counts and calendars indicated that >98% of doses were taken by all subjects. No adverse events occurred in this short-term study. The 81-mg daily aspirin dose suppressed PGE(2) levels to an equivalent extent as did the 650-mg dose and supports the use of this dose for chemoprevention trials.

Adult↗