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Biomedical subjects

E Rubin

Publications and source records attributed to E Rubin.

At least 19 recordsLinked to original sources
PubMed1999

The camptothecin-resistant topoisomerase I mutant F361S is cross-resistant to antitumor rebeccamycin derivatives. A model for topoisomerase I inhibition by indolocarbazoles.

DNA topoisomerase I is a major cellular target for antitumor indolocarbazole derivatives (IND) such as the antibiotic rebeccamycin and the synthetic analogue NB-506 which is undergoing phase I clinical trials. We have investigated the mechanism of topoisomerase I inhibition by a rebeccamycin analogue, R-3, using the wild-type human topoisomerase I and a well-characterized recombinant enzyme, F361S. The catalytic activity of this mutant remains fully intact, but the enzyme is resistant to inhibition by camptothecin (CPT). Here we show that the mutated enzyme is cross-resistant to the rebeccamycin analogue. Despite their profound structural differences, CPT and R-3 interfere similarly with the activity of the wild-type and mutant topoisomerase I enzymes, and the drug-induced cleavable complexes are equally sensitive to the NaCl concentration. CPT and IND likely recognize identical structural elements of the topoisomerase I-DNA covalent complex; however, differences do exist in terms of sequence-specificity of topoisomerase I-mediated DNA cleavage. For the first time, a molecular model showing that CPT and IND share common steric and electronic features is proposed. The model helps to identify a specific pharmacophore for topoisomerase I inhibitors.

Amino Acid Substitution↗
PubMed1999

Stomatocytosis is absent in "stomatin"-deficient murine red blood cells.

To examine the relationship between erythrocyte membrane protein 7. 2b deficiency and the hemolytic anemia of human hereditary stomatocytosis, we created 7.2b knock-out mice by standard gene targeting approaches. Immunoblots showed that homozygous knock-out mice completely lacked erythrocyte protein 7.2b. Despite the absence of protein 7.2b, there was no hemolytic anemia and mouse red blood cells (RBCs) were normal in morphology, cell indices, hydration status, monovalent cation content, and ability to translocate lipids. The absence of the phenotype of hereditary stomatocytosis implies that protein 7.2b deficiency plays no direct role in the etiology of this disorder and casts doubt on the previously proposed role of this protein as a mediator of cation transport in RBC.

Anemia, Hemolytic, Congenital↗
PubMed1999

Characteristics of medical students completing an honors program in pathology.

The Honors Program in pathology at Jefferson Medical College provides a voluntary enrichment opportunity for students who have demonstrated a superior ability to cope with the pathology curriculum and who rank in the upper fifth of their class. This study was performed to determine whether honor students possess cognitive and psychosocial attributes that distinguish them from their classmates. Students from five academic years (entering classes 1991 to 1995) were divided into 3 groups: (1) those who completed the Honors Program (n = 85), (2) those in the top 20% of the class who were offered the option but chose not to participate in the Honors Program (n = 128), and (3) students who did not qualify for the program (n = 953). Comparisons between these three groups were made on the basis of selected measures of academic achievement retrieved from the Jefferson Longitudinal Study database and psychosocial data obtained from a questionnaire completed during the first-year orientation. Students who completed the Honors Program in pathology had scored higher on the physical science section of the Medical College Admission Test (MCAT) and had obtained higher first-year grade point averages than students in both of the other groups. Subsequently, they attained higher second-year grade point averages and scored higher on Step 1 and Step 2 of the United States Medical Licensing Examination (USMLE), compared with their peers in the other groups. There were no significant differences in psychosocial measures between honor students and the rest of the cohort (group 3). However, students in the top 20% of the class who declined the invitation to participate in the Honors Program (group 2) showed higher scores on the Taylor Manifest Anxiety Scale and the Eysenck Emotional Instability (Neuroticism) Scale than did their classmates. Despite these differences, students who completed the Honors Program (group 1) and eligible students who declined participation (group 2) selected similar pathways of postgraduate residency training: both groups preferred internal medicine to family practice, and both were more likely than the rest of the cohort to begin residency training at a top-ranked academic/research medical center. Voluntary participation in an Honors Program is a self-selection system that identifies students who are most likely to succeed academically at the highest levels. Residency selection committees may wish to pay dose attention to student involvement in similar programs, because this information may provide insights into student personality and general aptitude.

Anxiety↗
PubMed1999

Topoisomerase-I inhibitors in gynecologic tumors.

The first section of this article reviews recent studies that have clarified both the cellular role of topoisomerase I and the mechanisms of cytotoxicity of the topoisomerase inhibitors, the camptothecins. Different analogs of this new class of antitumor drug have been studied using various dose schedules in the treatment of refractory or recurrent gynecologic cancer. Response rates are between 13% and 25%. The main toxic effects are hematologic and gastrointestinal, the latter remains problematic. Radiotherapy, alkylate, platinum analogues, and topoisomerase II inhibitors are currently being studied in combination with camptothecins.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Leucovorin, 5-fluorouracil, and gemcitabine: a phase I study.

Gemcitabine is a chemotherapy agent with efficacy in the treatment of lung, pancreas, bladder and breast cancer. It inhibits DNA synthesis by interfering with cytidine triphosphate production and also inhibits the activity of ribonucleotide reductase. Gemcitabine may potentiate fluorouracil's inhibition of thymidylate synthase. This inhibition would be expected to be sequence dependent, occurring only if gemcitabine were administered following fluorouracil (5FU). The combination of leucovorin, 5-FU, and gemcitabine was assessed in this phase I trial. Eligibility requirements included refractory solid tumor malignancy; adequate hematologic, renal and hepatic reserve; no prior therapy with the combination of leucovorin and 5FU, or with gemcitabine; ECOG performance status 0-2, and signed informed consent. Eleven men and nine women were eligible. The median age was 52.5 years and the median performance status was 1. All but three patients had prior chemotherapy. The starting doses were leucovorin 20 mg/m2, 5FU 255 mg/m2 and gemcitabine 600 mg/m2. 5FU and gemcitabine were escalated in tandem to 340 mg/m2 and 800 mg/m2 and thereafter to 425 mg/m2 and 1000 mg/m2, respectively. Gemcitabine administration always followed that of 5FU by 30 minutes. The median number of cycles was 2 (range 1-32). Two patients at the starting dose had disease progression within the first cycle with one death on day 28. One patient with cholangiocarcinoma had a partial response and remained on study for 40 months. There were no other responses. The maximum tolerated dose is leucovorin 20 mg/m2, 5FU 340 mg/m2, and gemcitabine 800 mg/m2. The impact of drug sequence remains undetermined.

Adult↗
PubMed1999

Protein 4.1R-deficient mice are viable but have erythroid membrane skeleton abnormalities.

A diverse family of protein 4.1R isoforms is encoded by a complex gene on human chromosome 1. Although the prototypical 80-kDa 4.1R in mature erythrocytes is a key component of the erythroid membrane skeleton that regulates erythrocyte morphology and mechanical stability, little is known about 4.1R function in nucleated cells. Using gene knockout technology, we have generated mice with complete deficiency of all 4.1R protein isoforms. These 4.1R-null mice were viable, with moderate hemolytic anemia but no gross abnormalities. Erythrocytes from these mice exhibited abnormal morphology, lowered membrane stability, and reduced expression of other skeletal proteins including spectrin and ankyrin, suggesting that loss of 4. 1R compromises membrane skeleton assembly in erythroid progenitors. Platelet morphology and function were essentially normal, indicating that 4.1R deficiency may have less impact on other hematopoietic lineages. Nonerythroid 4.1R expression patterns, viewed using histochemical staining for lacZ reporter activity incorporated into the targeted gene, revealed focal expression in specific neurons in the brain and in select cells of other major organs, challenging the view that 4.1R expression is widespread among nonerythroid cells. The 4.1R knockout mice represent a valuable animal model for exploring 4.1R function in nonerythroid cells and for determining pathophysiological sequelae to 4.1R deficiency.

Animals↗
PubMed1999

Service use by elderly patients after psychiatric hospitalization.

The extent and source of services used by older adults discharged to a community setting after a psychiatric hospitalization were examined in a prospective follow-up study. Patients were asked about service use in structured telephone interviews one month after hospital discharge. Subjects had comorbid medical conditions and high levels of functional impairment. Service use was low, highly skewed, and spread across three sectors of care-mental health specialty care (38 percent of the services), general medical care (35 percent), and social services and formal aging services (27 percent). Most service episodes were related to mental disorder.

Aftercare↗
PubMed1999

Phase I clinical and pharmacologic study of 13-cis-retinoic acid, interferon alfa, and paclitaxel in patients with prostate cancer and other advanced malignancies.

PURPOSE: Recent studies demonstrate that retinoids decrease expression of the anti-apoptotic protein bcl-2, enhance the effect of chemotherapy, and act synergistically with interferon alfa (IFNalpha) to inhibit tumor cell growth in vitro. A phase I trial of 13-cis-retinoic acid (CRA), IFNalpha, and paclitaxel (TAX) was conducted to determine the toxicity and recommended phase II dose of this combination. Pharmacodynamic studies were performed to determine whether CRA and IFNalpha could modulate bcl-2 expression in vitro and in patients. PATIENTS AND METHODS: Twenty-two patients with prostate cancer or other advanced malignancies were treated with CRA/IFNalpha and escalating doses of TAX. The effect of CRA/IFNalpha on TAX pharmacokinetics was analyzed in both patients and human liver microsomes. The effect of CRA/IFNalpha on bcl-2 expression was assessed in vitro and in peripheral-blood mononuclear cells (PBMCs) by immunoblotting. RESULTS: CRA 1 mg/kg on days 1 to 4, IFNalpha 6 MU/m(2) subcutaneously on days 1 to 4, and TAX 175 mg/m(2) on day 3 was well tolerated. Pharmacokinetic studies demonstrated that CRA/IFNalpha caused a 33% decrease in TAX clearance and a 23% decrease in the area under the concentration-time curve values of the TAX metabolite 6-alfa-hydroxytaxol (6-HT). CRA alone reduced conversion of TAX to 6-HT by 41% in human liver microsomes. CRA/IFNalpha decreased bcl-2 expression in vitro and in PBMCs. CONCLUSION: CRA/IFNalpha and TAX is a well-tolerated regimen. CRA/IFNalpha increases TAX area under the concentration-time curve through an inhibitory effect of CRA on the metabolism of TAX to 6-HT. CRA/IFNalpha can modulate bcl-2 expression in vitro and demonstrates similar biologic activity in patients. Further studies will determine the activity of CRA/IFNalpha/TAX and validate the assessment of bcl-2 in PBMCs as a marker of tumor response.

Adult↗
PubMed1999

Sonographic evaluation of infiltrating lobular carcinoma.

OBJECTIVE: Infiltrating lobular carcinoma (ILC), which accounts for 7-10% of all breast malignancies, often poses diagnostic difficulties. The purpose of our study was to correlate the clinical, mammographic, and sonographic findings in each histologic subtype of ILC and to evaluate the sensitivity of sonography in its diagnosis. MATERIALS AND METHODS: We reviewed 208 cases of invasive lobular carcinoma. In 81 of these tumors, sonography was performed to further examine a mammographically invisible palpable abnormality or a mammographically subtle lesion. A dedicated breast pathologist classified each of these tumors as pure invasive lobular carcinoma or mixed invasive lobular and ductal carcinoma. Pure ILC tumors were further subclassified as one of five histologic subtypes. We retrospectively studied the clinical, mammographic, and sonographic findings in each histologic tumor subtype. RESULTS: The most common sonographic appearance of ILC was a heterogeneous, hypoechoic mass with angular or ill-defined margins and posterior acoustic shadowing, which was seen in 60.5% (49/81) of tumors. Of the remaining 32 tumors, 15% (12/81) showed focal shadowing without a discrete mass, 12% (10/81) appeared as a lobulated, well-circumscribed mass, and 12% (10/81) were sonographically invisible. Although considerable overlap occurred among histologic subtypes, classic ILC tended to present as focal shadowing without a discrete mass; pleomorphic ILC typically was seen as a shadowing mass; and, of all the tumor subtypes, signet, alveolar, and solid ILC were most likely to be revealed on sonography as a lobulated, well-circumscribed mass. In the 81 mammographically subtle or invisible lesions, sonography detected the tumor in 87.7% (71/81). The sensitivity of sonography in tumors smaller than 1 cm was 85.7% (12/14). CONCLUSION: High-resolution sonography of the breast is a useful adjunct in the evaluation of ILC, a neoplasm that frequently presents a clinical and mammographic diagnostic challenge.

Breast↗
PubMed1999

Communication and its disorders.

This article defines communication and describes its various disorders. Some of these disorders are associated with other DSM-IV conditions, such as mental retardation or pervasive developmental disorder. Others are specific to the language-learning process. The interactions between communication and psychiatric disorders are discussed. Suggestions for integrating treating approaches among communication disorders and mental health professionals are presented.

Child↗
PubMed1998

Protein phosphatase type 1, the product of the retinoblastoma susceptibility gene, and cell cycle control.

Cell cycle regulation--three words which conjure in the minds of those conducting research in this area a myriad of proteins and biochemical pathways. In this examination, an overview of the mammalian cell cycle is presented with emphasis on the function of the negative growth regulatory protein, the product of the retinoblastoma susceptibility gene, pRb. Since the activity of this protein itself is regulated by phosphorylation on serine and threonine residues, more elaborate discussions on the enzymes involved in placing the phosphates on, and taking them off, are provided. The focus here is on the activity of the members of the type 1 class of serine/threonine phosphatases. More specifically, the role of PP1 in regulating cell cycle progression by dephosphorylating pRb during mitosis, thereby activating the growth suppressing function of pRb, is presented. Suggested avenues for further investigation regarding the functional significance, and ultimately the effect on cell cycle progression, of the complex between pRb and the type 1 phosphatases are also discussed.

Animals↗
PubMed1998

Natural history of alcoholic myopathy: a 5-year study.

Chronic myopathy is a common complication of alcoholism, but its natural history has not been well described. We, therefore, studied muscle structure and function in a 5-year study of 30 chronic alcoholics who became abstinent and 20 who relapsed, and 40 control subjects. The mean strength of the abstaining alcoholics increased from 18.6 to 23.2 kg; but, after 5 years, they were still substantially weaker than controls. In a subset who showed histological myopathy, the strength of half of the patients remained two standard deviations below that of controls. Alcoholics who relapsed tended to become progressively weaker (21.7 kg vs. 18.2 kg) and develop histological evidence of myopathy. Thus, continued alcohol abuse was generally reflected in deterioration of muscle strength and the appearance of histological injury to muscle. Importantly, almost half of the sober patients did not recover to normal levels, indicating that alcoholic myopathy is only partially reversible. We also unexpectedly found that, in some alcoholics, a substantial reduction in the amount of alcohol consumed may be as effective as complete abstinence in improving muscle strength or preventing its deterioration.

Alcoholism↗
PubMed1997

The human integrin beta3 gene is 63 kb and contains a 5'-UTR sequence regulating expression.

The human blood platelet fibrinogen receptor, integrin alphaIIbbeta3 (glycoprotein IIb-IIIa) is an archetypal member of the integrin family of adhesive molecules and is the only integrin encoded by genes physically linked in the genome. Because studies on the normal and abnormal expression of any gene require a thorough understanding of its organization, the initial goals of the current study were to determine the size and complete the genomic organization for the beta3 gene. We now report the isolation of the entire beta3 gene in a single P1 plasmid and for the first time have linked the first and second exons on a contiguous fragment of DNA. Using pulsed-field gel analysis, we determined the full size of the beta3 gene to be 63 kb and show a large (16.7 kb) first intron; based on this information, we propose a uniform numbering system for the beta3 exons. We have completed the 5' genomic structure and generated a long-range restriction map. The promoter and the 5' end of the first intron were found to have approximately 50% sequence identity with a region of the avian beta3 gene known to possess functional transcriptional activity. Analysis of three different homologous regions led to the identification of a sequence in the 5'-UTR of the human gene, CCGCGGGAGG, which shares 90% identity with the avian gene and which bound nuclear proteins in DNaseI and electrophoretic mobility shift assay studies. Mutating this sequence caused a 2.6-fold reduction in reporter gene activity. In these studies we have (1) determined the full length and 5' organization of the beta3 gene, (2) identified a large region of homology between the 5' regions of the avian and human genes, and (3) identified a sequence in the 5'-UTR that augments gene expression. Knowing the genomic structure of beta3 has permitted the uncovering of new mechanisms of mutagenesis causing Glanzmann thrombasthenia (Jin et al, J Clin Invest 98:1745, 1996), and our findings will be valuable for such genetic analyses as well as for studies on the transcriptional regulation of beta3 and other integrin genes.

Antigens, CD↗
PubMed1997

Temporal lobe epilepsy: correlation of proton magnetic resonance spectroscopy and 18F-fluorodeoxyglucose positron emission tomography.

Proton magnetic resonance spectroscopy (MRS) has demonstrated reduction of N-acetylaspartate (NAA) in the epileptogenic temporal lobe. However, the correlation of NAA reduction with cerebral metabolic abnormalities is unknown in temporal lobe epilepsy (TLE). Proton MRS and 18F-fluorodeoxyglucose positron emission tomography (FDG/PET) were used to study 12 unilateral TLE patients with medically intractable seizures and 26 age-matched healthy volunteers. The epileptogenic temporal lobe of each patient was determined by both electroencephalography and FDG/PET. The NAA/choline-plus-creatine (NAA/(Cho+Cr)) ratio correlated significantly with the interictal glucose metabolism (r = 0.54, P < 0.01) in 12 TLE patients. The mean NAA/(Cho+Cr) ratio in the epileptogenic temporal lobe was significantly less than that in the contralateral side (P < 0.01), and less than that in normal control temporal lobes (P < 0.0001). These results suggest that quantitative MRS abnormalities reflect underlying metabolic pathology in TLE.

Adult↗