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Biomedical subjects

N Cohen

Publications and source records attributed to N Cohen.

At least 37 records · Page 2Linked to original sources
PubMed2001

PML RING suppresses oncogenic transformation by reducing the affinity of eIF4E for mRNA.

The promyelocytic leukemia protein PML is organized into nuclear bodies which mediate suppression of oncogenic transformation and of growth. The biochemical functions of PML bodies are unknown, despite their involvement in several human disorders. We demonstrate that eukaryotic initiation factor 4E (eIF4E) directly binds the PML RING, a domain required for association with bodies and for suppression of transformation. Nuclear eIF4E functions in nucleocytoplasmic transport of a subset of transcripts including Cyclin D1. Present studies indicate that some PML requires the evolutionarily older eIF4E protein for association with nuclear bodies. Further more, PML RING modulates eIF4E activity by drastically reducing its affinity for its substrate, 5' m(7)G cap of mRNA. We demonstrate that eIF4E requires cap binding for transport of Cyclin D1 mRNA and subsequent transformation activity. Additionally, PML reduces the affinity of eIF4E for m(7)G mRNA cap, causing a reduction in Cyclin D1 protein levels and consequent transformation inhibition. PML is the first factor shown to modulate nuclear eIF4E function. These findings provide the first biochemical framework for understanding the transformation suppression activity of PML.

Cell Nucleus↗
PubMed2001

Subgroup of patients with Philadelphia-positive chronic myelogenous leukemia characterized by a deletion of 9q proximal to ABL gene: expression profiling, resistance to interferon therapy, and poor prognosis.

A major deletion of the region proximal to the rearranged ABL gene on 9q was found in 14/94 (15%) of chronic myelogenous leukemia Philadelphia-positive patients by interphase fluorescent in situ hybridization with the BCR/ABL extra signal dual-color probe. Preliminary results indicated that the prognosis of the deletion 9q patients is probably worse than that of the non-deletion 9q patients. Twelve of the 14 deletion 9q patients were treated with alpha-interferon and none had a major cytogenetic response. The median duration of the chronic phase in patients not undergoing BMT was significantly shorter for the deletion 9q patients as compared to the non-deletion 9q patients (p =.0144). DNA microarray technology was performed in order to compare the gene expression patterns between the two groups of patients. A number of genes exhibiting differential expression, especially involving cell adhesion and migration, were identified. This finding may identify a sub-group of CML patients with different cell properties and a relatively poor prognosis.

Antineoplastic Agents↗
PubMed2001

One-trial conditioning of the antibody response to hen egg lysozyme in rats.

In Wistar rats, reexposure to a novel conditioned stimulus (CS) previously paired with a protein antigen, hen egg lysozyme (HEL) on a single conditioning trial increased anti-HEL IgG levels relative to conditioned rats that were not reexposed to the CS, conditioned rats that were preexposed to the CS, and nonconditioned rats. These results confirm previous findings that a single exposure to a CS associated with immunization is sufficient to elicit an antibody response upon subsequent reexposure to the CS in the absence of exogenous antigen.

Animals↗
PubMed2001

Phylogenetic conservation of the molecular and immunological properties of the chaperones gp96 and hsp70.

The heat shock proteins (HSP) gp96 and hsp70 have been shown to have a critical role in eliciting adaptive immune responses to cancers and viruses. This role derives from (i) their ability to chaperone antigenic peptides generated in the cells from which the HSP are isolated, and (ii) their capacity to interact with antigen presenting cells (APC) which re-present the HSP-chaperoned peptides in context of MHC I molecules. We have asked whether the immunological properties of HSP extend beyond the mammals to other phyla. We report here the serological, biochemical, genetic, and immunological characterization of the Xenopus gp96. Like mammalian gp96, Xenopus gp96 forms non-covalent complexes with peptides. Immunization with gp96 and hsp70 purified from Xenopus tumors, elicits potent and specific anti-tumor immunity, which is dependent on their ability to chaperone peptides in vivo. An immunogenic peptide chaperoned by the Xenopus gp96 can be processed and presented by mouse APC, to antigen-specific CD8+ T cells of mice. The remarkable conservation of these essential immunological properties of gp96 and hsp70 between amphibians and mammals suggests the importance of HSP in the evolution of the vertebrate immune system.

Amino Acid Sequence↗
PubMed2001

Adequacy of anticoagulation in patients with atrial fibrillation: effect of various parameters.

BACKGROUND: Despite reported evidence of the vital importance of appropriate anticoagulation in patients with chronic atrial fibrillation for stroke prevention, this treatment modality still lags behind optimal requirements. HYPOTHESIS: Our objectives were to evaluate various doctor or patient-related factors that influence quality of control and to assess the adequacy of anticoagulation provided by physicians in the community. METHODS: In a retrospective study, International Normalized Ratio (INR) values obtained immediately on admission to hospital were considered representative of previous long-term control. RESULTS: Only 42% of the relevant 385 patient population fell within the protective anticoagulation range of INR 1.91-4.1. The respective figures for patients with poor (INR < 1.5) or suboptimal (INR 1.51-1.9) control, as well as those whose INR values risked bleeding (INR > 4.1), were 28.3, 14.1, and 15.6%. Patient involvement in treatment positively influenced quality of control. By contrast, age 70-80 years or absence of congestive heart failure negatively affected quality of anticoagulation [p = 0.07, odds ratio (OR), 1.7 (95% confidence interval. 0.94-3.08), p = 0.014, OR, 2.06 (95% confidence interval, 1.15-3.7) respectively]. The percentage of patients admitted with stroke who had been adequately anticoagulated was significantly lower than that of patients who had no stroke (21 vs. 44.4%). Adequacy of anticoagulation in patients with cardiac prosthetic valves was superior compared with the rest of the patient population (56.7 vs. 42% with optimal, and only 14.5 vs. 28.3% with poor anticoagulation, respectively), indicating that under the same conditions a better quality of treatment could be achieved. CONCLUSIONS: Adequacy of anticoagulation in patients with atrial fibrillation lags behind actual recommendations. Better control is required and achievable.

Aged↗
PubMed2001

Detection of unidentified chromosome abnormalities in human neuroblastoma by spectral karyotyping (SKY).

Spectral karyotyping (SKY) is a novel technique based on the simultaneous hybridization of 24 fluorescently labeled chromosome painting probes. It provides a valuable addition to the investigation of many tumors that can be difficult to define by conventional banding techniques. One such tumor is neuroblastoma, which is often characterized by poor chromosome morphology and complex karyotypes. Ten primary neuroblastoma tumor samples initially analyzed by G-banding were analyzed by SKY. In 8/10 tumors, we were able to obtain additional cytogenetic information. This included the identification of complex rearrangements and material of previously unknown origin. Structurally rearranged chromosomes can be identified even in highly condensed metaphase chromosomes. Following the SKY results, the G-banding findings were reevaluated, and the combination of the two techniques resulted in a more accurate karyotype. This combination allows identification not only of material gained and lost, but also of breakpoints and chromosomal associations. The use of SKY is therefore a powerful tool in the genetic characterization of neuroblastoma and can contribute to a better understanding of the molecular events associated with this tumor.

Child↗
PubMed2001

Acute inflammatory myopathy with severe subcutaneous edema, a new variant? Report of two cases and review of the literature.

Acute inflammatory myopathy with severe subcutaneous edema is extremely rare and has been reported in only a handful of cases. We describe two similar patients presenting with this disorder and generalized rash. Unlike the five previously reported cases, the clinical and histologic features of our two patients are more suggestive of dermatomyositis than polymyositis. Nevertheless, scrutinizing all seven reported patients, a number of specific characteristics could be defined. All patients were adult males. Dysphagia was present in four. In six patients, acute inflammatory myopathy was idiopathic while malignancy was present in one. Two patients died despite intensive therapy, three improved on corticosteroid treatment, and two recovered spontaneously. In all patients, limb involvement with marked subcutaneous edema was present, clinically mimicking deep vein thrombosis in both our patients. The presence of severe subcutaneous edema may be a hallmark of a distinctive variant of acute inflammatory myopathy. More cases are needed to discern subtypes of this general entity and to establish guidelines for treatment and prognosis.

Acute Disease↗
PubMed2001

In vitro thymocyte differentiation in MHC class I-negative Xenopus larvae.

CTX is a surface antigen whose expression in larval and adult Xenopus is primarily restricted to MHC class I-negative immature cortical thymocytes. In adult Xenopus, surface expression of CTX marks a population of MHC class I(-) CD8(+) immature thymocytes that appears to be the equivalent of the mammalian CD4CD8 double positive subset. The present study reveals that transient in vitro exposure of immature CTX(+) thymocytes from MHC class I-negative tadpoles to suboptimal mitogenic concentrations of phorbol ester (PMA) plus ionomycin, induces larval cells to differentiate into more mature T-lymphoblasts that express high level of surface CD5 and CD45. These T-lymphoblasts have downregulated CTX, Rag 1 and TdT genes, whereas TCR-beta genes remain actively transcribed. Signaling induced by PMA/ionomycin modulates both class I and class II expression of MHC class I/II-negative larval thymocytes. This study also reveals that larval T-lymphoblasts are composed of two distinct subsets: CD5(high)CD8(-) and CD5 (high)CD8 (high).

Animals↗
PubMed2001

In vitro enzyme evolution: the screening challenge of isolating the one in a million.

The generation of large mutant libraries for in vitro enzyme evolution presents the challenge of effectively screening libraries of 10(4)-10(7) mutants on the basis of simultaneously assaying their biocatalytic activity. In this review, we highlight the main steps involved in this process, describe the alternative approaches to address this challenge, survey the state-of-the-art technology and assess achievements already made. It is anticipated that, as a result of the expected accomplishment of further improvements in high-throughput screening that will allow routine screening of whole libraries, the number of useful new and improved enzymes derived through in vitro enzyme evolution will expand rapidly in the near future.

Cells, Immobilized↗
PubMed2001

The effect of social desirability trait on self-reported dietary measures among multi-ethnic female health center employees.

PURPOSE: To evaluate the effect of social desirability trait, the tendency to respond in a manner consistent with societal expectations, on self-reported fruit, vegetable, and macronutrient intake. METHODS: A 61-item food frequency questionnaire (FFQ), 7-item fruit and vegetable screener, and a single question on combined fruit and vegetable intake were completed by 132 female employees at five health centers in eastern Massachusetts. Intake of fruit and vegetables derived from all three methods and macronutrients from the FFQ were fit as dependent variables in multiple linear regression models (overall and by race/ethnicity and education); independent variables included 3-day mean intakes derived from 24-hour recalls (24HR) and score on the 33-point Marlowe-Crowne Social Desirability scale (the regression coefficient for which reflects its effect on estimates of dietary intake based on the comparison method relative to 24HR). RESULTS: Results are based on the 93 women with complete data and FFQ-derived caloric intake between 450 and 4500 kcal/day. In women with college education, FFQ-derived estimates of total caloric were associated with under-reporting by social desirability trait (e.g., the regression coefficient for total caloric intake was -23.6 kcal/day/point in that group versus 36.1 kcal/day/point in women with education less than college) (difference = 59.7 kcal/day/point, 95% confidence interval (CI) = 13.2, 106.2). Except for the single question on which women with college education tended to under-report (difference =.103 servings/day/point, 95% CI = 0.003, 0.203), there was no association of social desirability trait with self-reported fruit and vegetable intake. CONCLUSIONS: The effect of social desirability trait on FFQ reports of macronutrient intake appeared to differ by education, but not by ethnicity or race. The results of this study may have important implications for epidemiologic studies of diet and health in women.

Adult↗
PubMed2001

Hypotrichosis with juvenile macular dystrophy is caused by a mutation in CDH3, encoding P-cadherin.

Congenital hypotrichosis associated with juvenile macular dystrophy (HJMD; MIM601553) is an autosomal recessive disorder of unknown etiology, characterized by hair loss heralding progressive macular degeneration and early blindness. We used homozygosity mapping in four consanguineous families to localize the gene defective in HJMD to 16q22.1. This region contains CDH3, encoding P-cadherin, which is expressed in the retinal pigment epithelium and hair follicles. Mutation analysis shows in all families a common homozygous deletion in exon 8 of CDH3. These results establish the molecular etiology of HJMD and implicate for the first time a cadherin molecule in the pathogenesis of a human hair and retinal disorder.

Adolescent↗
PubMed2001

The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA.

Mitochondrial DNA (mtDNA)-depletion syndromes (MDS; OMIM 251880) are phenotypically heterogeneous, autosomal-recessive disorders characterized by tissue-specific reduction in mtDNA copy number. Affected individuals with the hepatocerebral form of MDS have early progressive liver failure and neurological abnormalities, hypoglycemia and increased lactate in body fluids. Affected tissues show both decreased activity of the mtDNA-encoded respiratory chain complexes (I, III, IV, V) and mtDNA depletion. We used homozygosity mapping in three kindreds of Druze origin to map the gene causing hepatocerebral MDS to a region of 6.1 cM on chromosome 2p13, between markers D2S291 and D2S2116. This interval encompasses the gene (DGUOK) encoding the mitochondrial deoxyguanosine kinase (dGK). We identified a single-nucleotide deletion (204delA) within the coding region of DGUOK that segregates with the disease in the three kindreds studied. Western-blot analysis did not detect dGK protein in the liver of affected individuals. The main supply of deoxyribonucleotides (dNTPs) for mtDNA synthesis comes from the salvage pathway initiated by dGK and thymidine kinase-2 (TK2). The association of mtDNA depletion with mutated DGUOK suggests that the salvage-pathway enzymes are involved in the maintenance of balanced mitochondrial dNTP pools.

Base Sequence↗
PubMed2001

Red eye syndrome: clinical and experimental experience in a new aspect of diffuse eosinophilic infiltration?

Twenty-two of 24 hemodialysis patients dialyzed simultaneously with a new batch of cellulose acetate dialyzers promptly developed a spectrum of symptoms and physical signs including red eyes, hearing loss, tinnitus, and bone pain, previously described as red eye syndrome. We subsequently injected 4 rabbits with an eluate from a dialyzer of the same or a control batch. Six hours following exposure, the animals developed, in addition to red eyes, diffuse eosinophilic infiltration of various organs as well as myopathic changes and moderate brain edema. On the basis of these data, we suggest that it cannot be concluded whether the underlying pathophysiological mechanisms were toxic, allergic or both and that the occurrence of relevant symptomatology in 2 or more simultaneously dialyzed patients is a strong argument against unnecessary diagnostic or therapeutic procedures. Finally, a second exposure in a given patient should be avoided.

Animals↗
PubMed2001

Duffy antigen/receptor for chemokines (DARC): genotypes in Ashkenazi and non-Ashkenazi Jews in Israel.

Duffy genotypes were studied in Ashkenazi and non-Ashkenazi groups in Israel. The prevalence of the genotypes for the known polymorphic FY*A, FY*B, and FY*B(GATA-) alleles was similar in the two groups. The recently described FY*B(G298A) and FY*B(C265T) alleles were also found to be polymorphic. FY*B(G298A) was significantly more prevalent in the non-Ashkenazi group than in the Ashkenazi group (in 20% and 10% of FY*B, respectively). FY*B(C265T), which markedly diminishes the expression of Fy(b) antigen, was found in 3.5% of FY*B alleles, but only together with FY*B(G298A), consistent with previous suggestions that FY*B(C265T) occurred in the FY*B(G298A) allele. No difference in Duffy genotype distribution was found between schizophrenic and control groups. Duffy antigens are receptors for chemokines and bind Plasmodium vivax. Study of Duffy genotypes in additional populations might help in elucidating the possible functional significance of Duffy allele polymorphism.

Antigens, Protozoan↗
PubMed2001

Association of egg zona pellucida glycoprotein mZP3 with sperm protein sp56 during fertilization in mice.

Purified mouse sperm receptor, a zona pellucida glycoprotein called mZP3, binds to plasma membrane overlying acrosome-intact sperm heads (P.M. Wassarman, 1999, Cell 96, 175-183). Some evidence suggests that mZP3 binds to sp56, a protein reported to be associated peripherally with the plasma membrane of acrosome-intact sperm heads (J.D. Bleil and P.M. Wassarman, 1990, Proc. Natl. Acad. Sci., USA 87, 7215-7219; A. Cheng et al., 1994, J. Cell Biol. 125, 867-878). Here, we report that membrane vesicles prepared from acrosome-intact sperm contain sp56. When these vesicles are incubated with eggs they inhibit binding of sperm to eggs in vitro (ID50 approximately 50-100 microg protein/ml). On the other hand, a monoclonal antibody directed against sp56 relieves the inhibition of binding of sperm to eggs by membrane vesicles. As expected, incubation of intact sperm with the antibody directed against sp56 inhibits binding of the sperm to eggs. Results of immunoprecipitation of sperm extracts incubated with mZP3, by either a polyclonal antibody directed against mZP3 or a monoclonal antibody directed against sp56, suggest that mZP3 is specifically associated with sp56. Results of laser scanning confocal microscopy of fixed sperm probed with antibodies directed against either sp56 or a approximately 155 kDa acrosomal protein, suggest that the two proteins are present in the acrosome, but with different distributions. Furthermore, confocal images of sperm, fixed after exposure to purified mZP3 and probed with antibodies against mZP3 and sp56, reveal overlap between mZP3 and sp56 at the surface of the sperm head. The possible implications of these results are discussed in the context of mammalian fertilization.

Animals↗