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M Haber

Publications and source records attributed to M Haber.

At least 109 records · Page 6Linked to original sources
PubMed1991

A generalized stochastic model for the analysis of infectious disease final size data.

A stochastic infectious disease model was developed by Ball (1986, Advances in Applied Probability 18, 289-310) in which the distribution of the length of the infectious period is allowed to have any distribution that can be described by its Laplace transform. We extend this model such that the infection can be transmitted within the population or from an unspecified source outside the population. Also, discrete heterogeneity in the population can be modeled to incorporate variable susceptibility, variable infectivity, and/or mixing behaviors. The model is fitted to serologic data from two influenza epidemics in Tecumseh, Michigan, using maximum likelihood estimation procedures. The estimates show a clustering pattern by age groups.

Adult↗
PubMed1990

Phenotypic and cytogenetic analysis of atypical multidrug resistance in human leukaemic cells selected with methotrexate at high concentration.

A series of CCRF-CEM sublines selected for extreme resistance to methotrexate has been shown previously to exhibit cross resistance to a number of agents belonging to the multidrug resistance phenotype. The mechanism(s) underlying resistance to vincristine, vinblastine and actinomycin D in the most resistant subline (CEM/MTX R3) has now been investigated. Efflux of [3H]vincristine was more rapid in CEM/MTX R3 than in either CCRF-CEM cells or a methotrexate-resistant subline not refractory to Vinca alkaloids. In addition, verapamil completely reversed resistance to vincristine, vinblastine and actinomycin D in the CEM/MTX R3 cells. While these results are suggestive of P-glycoprotein-mediated multidrug resistance, Northern analysis revealed no detectable expression of the mdr 1/gene in CEM/MTX R3 cells. Likewise, karyotypic analysis of the resistant subline, while revealing certain clonal abnormalities, provided no evidence of alteration in the mdr 1/gene locus on chromosome 7. The data suggest therefore the operation, in these cells, of a novel mechanism of resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Atypical multidrug resistance in CCRF-CEM cells selected for high level methotrexate resistance: reactivity to monoclonal antibody C219 in the absence of P-glycoprotein expression.

A series of CCRF-CEM sublines selected for extreme resistance to methotrexate has been shown previously to exhibit cross resistance to a number of agents belonging to the multidrug resistance phenotype (J.Natl.Cancer Inst.1989; 81, 1250-1254). The role of the mdr1 gene and its product (P-glycoprotein) in this atypical pattern of multidrug resistance has now been investigated. Southern and Northern analyses failed to demonstrate any amplification, rearrangement or over-expression of the mdr1 gene in the drug-resistant cells. Similarly, monoclonal antibodies MRK16 and JSB1 revealed no increase in the amount of P-glycoprotein present. By contrast, monoclonal antibody C219 detected a 170 kDa protein in all sublines, and in highest concentration in the most resistant cells. The results raise the possibility that a novel, C219-reactive protein may mediate resistance to both methotrexate and members of the multidrug resistance family.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Atypical multidrug resistance in a therapy-induced drug-resistant human leukemia cell line (LALW-2): resistance to Vinca alkaloids independent of P-glycoprotein.

Near diploid leukemic T-cells (LALW-2), exposed to cytotoxic drugs only as a consequence of therapy administered to the donor patient, have been maintained by serial xenograft in nude mice. In comparison with the leukemic line CCRF-CEM, using a growth inhibition assay, LALW-2 cells were resistant to Vinca alkaloids and actinomycin D (relative resistance, 200-fold or more), were slightly resistant to Adriamycin (relative resistance, 4-fold), and showed no resistance to daunorubicin or teniposide. By comparison, a vincristine-resistant CEM subline developed in our laboratory (CEM/VCR R) was resistant to all these agents by at least 30-fold. The VCR R subline served as a positive control, confirming the previously reported correlation between multidrug resistance and amplification of the P-glycoprotein gene. Comparison of CEM, CEM/VCR R, and LALW-2 cells establish that the P-glycoprotein gene was not amplified or overexpressed in the LALW-2 cells; neither could the gene product be detected by immunoblotting in extracts from these cells. The LALW-2 cells were further distinguished from CEM/VCR R cells due to the lack of increased vincristine efflux by the xenografted cells, an effect readily demonstrable in the CEM/VCR R cells. However, although LALW-2 cells efflux vincristine at the same rate as CCRF-CEM cells, the xenografted cells exhibited a reduced rate of vincristine accumulation. Uptake of daunorubicin by LALW-2 cells was not distinguished from that by CEM cells, consistent with similar 50% inhibitory dose levels for this drug in both cell populations, and differentiating both from CEM/VCR R cells. Thus, clinical resistance in this case appears to be an "atypical" form of multidrug resistance specifically distinguished by resistance to Vinca alkaloids and actinomycin D occurring in the absence of increased amounts of P-glycoprotein and manifesting decreased drug uptake.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Resistance to drugs associated with the multidrug resistance phenotype following selection with high-concentration methotrexate.

To study patterns of resistance at extreme but nevertheless clinically relevant drug concentrations, we developed a series of methotrexate-selected CCRF-CEM sublines, all of which were highly resistant to this antifolate (relative resistance, 10(2)- to greater than 10(5)-fold). The least methotrexate-resistant subline was completely sensitive to drugs associated with the multidrug resistance phenotype. However, more highly methotrexate-resistant sublines were significantly cross-resistant to vincristine, vinblastine, and dactinomycin (maximum relative resistance, 40-fold). These sublines were not cross-resistant to doxorubicin, daunorubicin, and teniposide. Regression analysis indicated that relative resistance to methotrexate was correlated with relative resistance to vincristine (r = 0.96) and vinblastine (r = 0.99). Such cross-resistance in highly methotrexate-resistant cells may have important clinical implications.

Antineoplastic Agents↗
PubMed1989

Therapy-induced drug resistance in a human leukemia line (LALW-2). A clinically relevant model.

A human leukemic T-cell line, LALW-2, established by xenografting in nude mice, has been maintained through 14 serial passages. The cells display consistent morphologic features, immunophenotype, and karyotypic aberrations (including an 11;14 translocation) and exhibit rearrangement of the T-cell receptor beta-chain gene. The growth rate of LALW-2 xenografts was differentially affected by drugs administered to host mice, the cells being resistant to cytotoxic agents (particularly methotrexate and doxorubicin) used in treatment of the donor patient. In short-term in vitro culture, LALW-2 cells exhibited extreme resistance to methotrexate and were also resistant to vincristine, vinblastine, dactinomycin, and doxorubicin. The findings differ from those obtained with laboratory-derived methotrexate or multidrug-resistant cell lines. The response of LALW-2 cells, in both the nude mouse model and in vitro, is consistent with acquisition of drug-resistance as a result of clinical treatment.

Animals↗
PubMed1989

Protecting adults with mental retardation: a model statute.

On February 1, 1985, the Abuse Investigation Division of the Office of Protection and Advocacy was created by Section 19a-458 of the Connecticut General Statutes. This division was designed to receive and investigate allegations of the abuse and neglect of adults with mental retardation and to ensure that necessary protective services are provided by appropriate agencies. The major components of the law were discussed, and data were reported concerning type of abuse and neglect, perpetrators, and locations in which it occurs.

Adult↗
PubMed1988

Statistical inference for infectious diseases. Risk-specific household and community transmission parameters.

A statistical model is presented for the analysis of infectious disease data from family studies in the community. The model partitions the sources of infection into those from within the household and those from the community at large. The parameters reflecting these sources of infection are estimated as functions of the risk factors. This new model is used to overcome problems associated with the lack of independence of observations in infectious disease data and negative confounding due to the association of unmeasured exposures and immunity. An example of how this new statistical model is used to provide a clearer and less confounded description of risk factor effects is presented for data from influenza A(H3N2) epidemic seasons in the Tecumseh Respiratory Illness Study. The risk factors examined are age and pre-epidemic season antibody level as measured by the hemagglutination-inhibition test, while the outcome is the infection rate. A standard analysis of the data indicates that the efficacy of protective antibodies is 70% in children and only 47% in adults. However, such an efficacy measurement is negatively confounded by past exposure which is age dependent. By means of the model, the true, unconfounded, efficacy of protective antibodies is shown to be 90% in both adults and children.

Adolescent↗
PubMed1988

Models for the statistical analysis of infectious disease data.

The Longini-Koopman model (1982, Biometrics 38, 115-126) describes the process underlying the transmission of an infectious disease in terms of household and community level transmission probabilities. This model is generalized by allowing for different transmission probabilities that may correspond to various levels of risk factors on both the household and community levels. Two types of models are considered: (i) models for household data, where the numbers of susceptible and infected members in each household are known along with the values of household level risk factors; and (ii) models for individual data, where the infection status and risk factor level are known for each individual in the household. Although the type (i) models can be expressed as special cases of the type (ii) models, they deserve special attention as they can be represented and analyzed as log-linear models. Both types of models can be analyzed using maximum likelihood methods, while the type (i) models, when expressed as log-linear models, can also be analyzed by the weighted least squares method. Data from influenza epidemics in Tecumseh, Michigan and Seattle, Washington are used to illustrate these methods.

Adult↗
PubMed1986

Two-stage incorporation of thymidine triphosphate into mammalian DNA as indicated by chromatography on benzoylated DEAE-cellulose.

Replicating DNA contains single-stranded regions as indicated by the extent of its recovery in the final fraction, following stepwise elution of sheared preparations from benzoylated DEAE-cellulose using 0.3 M sodium chloride, 1.0 M sodium chloride and caffeine solutions, respectively. In preparations of hepatic DNA, isolated up to 60 min after administration of [3H]thymidine to rats subjected earlier to partial hepatectomy, the proportion of radioactivity contained in the caffeine-eluted fraction progressively decreased. This change was attributable to migration of incorporated radioactivity from replicating forms to mature (double-stranded) DNA, the latter being recovered from the column in 1.0 M sodium chloride. In terms of the same chromatograms, the relative size of the 0.3 M sodium chloride-eluted fraction also decreased, this fraction of radioactivity co-eluting from benzoylated DEAE-cellulose with thymidine triphosphate. The precursor--intermediate--product relationship between the three products separated by benzoylated DEAE-cellulose chromatography was confirmed using DNA isolated from cultured mammalian cells. Early eluting radioactivity co-chromatographed with thymidine triphosphate on thin-layer cellulose, whilst the intermediate status of caffeine-eluted radioactivity was confirmed following pulse-chase labelling procedures. Utilizing stepwise chromatography of such DNA on benzoylated DEAE-cellulose, the effect of three inhibitors could thus be described as affecting either an early or late stage of DNA synthesis. Such an approach offers a simple quantitative method of monitoring influences on DNA synthesis.

Animals↗
PubMed1986

Digestion of repair sites in rat liver DNA by endogenous nucleases.

The proportion of sheared rat liver DNA recovered from benzoylated DEAE-cellulose in the final stage following stepwise elution with NaCl and caffeine solutions was dependent upon the DNA isolation procedure. An increase in the proportion of DNA containing single stranded regions, consequent upon delay or addition of Mg2+ prior to phenol extraction, suggested nuclease mediated degradation. Administration of methyl methanesulphonate to rats resulted in a consistent proportional increase in the caffeine-eluted fraction. The results of caffeine gradient elution of control and alkylated DNA from benzoylated DEAE-cellulose were consistent with repair-associated single stranded regions being substrates for endogenous single strand-specific exonucleases.

Animals↗
PubMed1986

Testing for pairwise independence.

This article presents a method for testing the hypothesis of mutual pairwise independence of k events. The method, which is based on the weighted least squares approach (Grizzle, Starmer, and Koch, 1969, Biometrics 25, 489-504) can be generalized to two types of incomplete data: the multiple-recapture census, where one of the cells of the corresponding 2k contingency table cannot be observed, and situations allowing an "unknown" response to the question designed to determine whether an event has occurred.

Biometry↗
PubMed1985

Single-strand-specific degradation of DNA during isolation of rat liver nuclei.

We have investigated structural change in rat liver DNA produced by different isolation procedures and specifically compared the integrity of DNA derived by phenol extraction from isolated and purified nuclei with preparations extracted immediately from a crude liver homogenate containing intact nuclei. As indicated by stepwise elution from benzoylated DEAE-cellulose, most structural change in DNA was evident following nuclei isolation. Damage principally involved generation of single-stranded regions in otherwise double-stranded DNA fragments; totally single-stranded DNA was not detected by hydroxylapatite chromatography. Caffeine gradient elution suggested formation of single-stranded regions extending for up to several kilobases. In neutral sucrose gradients, differences in sedimentation rates of respective DNA samples consequent upon S1 nuclease digestion could be detected after isolation of nuclei, though not in other circumstances. The observed single-strand-specific nuclease digestion of DNA could apparently be reduced if steps were taken to reduce autodigestion during nuclei isolation by reduction of temperature and covalent cation concentration. The results are discussed in terms of the use of exogenous and endogenous nucleases in chromatin fractionation studies involving isolated nuclei and possible artifactual findings that may be generated by single-strand-specific autodigestion.

Animals↗
PubMed1985

Oncogenes. A possible role for cancer genes in human malignant disease.

A small class of normal cellular genes has the potential to transform cells malignantly. These cellular oncogenes have been identified by their similarity to the transforming genes of oncogenic RNA viruses (retroviruses), and by their ability, under certain circumstances, to transform cells into which they have been transferred. Cellular oncogenes are not normally tumorigenic and, indeed, appear to be critically involved in normal cellular processes, possibly at the level of growth regulation. However, it appears that a number of mechanisms exist whereby these oncogenes can become malignantly activated, leading to uncontrolled cellular proliferation. The evidence implicating cellular oncogenes in human malignant disease is reviewed.

Animals↗
PubMed1985

Dose-dependent persistence of alkylation-induced single stranded regions in rat liver DNA in vivo.

Single stranded regions in DNA, presumed to be indicative of DNA repair, may be readily detected in rat liver DNA following injections of non-necrotizing single doses of methyl methanesulfonate, dimethylnitrosamine and diethylnitrosamine. The present study concerns persistence of such structural defects in vivo, as determined by benzoylated DEAE-cellulose chromatography, in relation to the dose of alkylating agent. For all these agents, the period during which structural damage may be detected is markedly dependent upon dose: prolonged persistence only occurs after the highest dose. The findings, in relation to other data, implicate reaction processes involving the final stages of repair as being critical to prolongation of this type of genomic damage in vivo.

Alkylating Agents↗
PubMed1985

Patterns of structural change in DNA during tissue necrosis indicated by benzoylated DEAE-cellulose chromatography.

Structural change in liver DNA, isolated following administration of a necrogenic dose of carbon tetrachloride to rats, was examined by benzoylated DEAE-cellulose (BD-cellulose) chromatography. Greatest increase in the amount of DNA exhibiting single stranded character was detected 48 h after treatment, at which time massive necrosis was evident histologically. By 72 h after dosing, normal hepatic architecture had been restored and gross structural change in DNA could no longer be detected. The extent of single stranded regions in DNA isolated at various times after carbon tetrachloride intoxication was assessed by caffeine gradient elution of respective samples from BD-cellulose. By this criterion, structural damage to DNA was again most marked 48 h after treatment at which time single stranded regions extending over several kilobases were apparent. At earlier times such lesions were considerably shorter. Single stranded regions of discrete length detected 72 h after administration of the hepatotoxin appeared to be associated with cell division. Structural damage to DNA coincident with toxic injury was further characterized using BD-cellulose, by caffeine gradient elution of preparations subjected to denaturation before chromatography. The data indicate that production of single stranded regions is a major feature of DNA degradation during tissue necrosis. Whilst such degradation might otherwise confound interpretation of structural analyses based only upon strand breakage, the size of these regions suggests a basis for distinguishing between them and lesions specifically associated with repair, replication and transcription of DNA.

Animals↗