Functional Analysis of the TAN-1 Gene, a Human Homolog of Drosophila Notch

The TAN-1 gene was originally discovered at the breakpoint of a recurrent (7;9)(q34;q34.3) chromosomal translocation found in a subset of human T-lymphoblastic leukemias (Reynolds et al. 1987; Smith et al. 1988; Ellisen et al. 1991). This translocation joins roughly the 3′ half of TAN-1 head-to-head with the 3′ portion of the β T-cell-receptor gene (TCRB) beginning at the 5′ boundary of one or the other J segment. Intact TAN-1 is normally transcribed into an 8.2-kb transcript that is present in many tissues, most abundantly in developing thymus and spleen (Ellisen et al. 1991). This tissue distribution and the apparent involvement of an altered version of the gene in T-cell cancers have suggested that TAN-1 normally has some special function in lymphocytes or their precursors

Features of the primary wall CESA complex in wild type and cellulose-deficient mutants of Arabidopsis thaliana

Evidence from genetics, co-precipitation and bimolecular fluorescence complementation suggest that three CESAs implicated in making primary wall cellulose in Arabidopsis thaliana form a complex. This study shows the complex has a Mr of approximately 840 kDa in detergent extracts and that it has undergone distinctive changes when extracts are prepared from some cellulose-deficient mutants. The mobility of CESAs 1, 3, and 6 in a Triton-soluble microsomal fraction subject to blue native polyacrylamide gel electrophoresis was consistent with a Mr of about 840 kDa. An antibody specific to any one CESA pulled down all three CESAs consistent with their occupying the same 840 kDa complex. In rsw1, a CESA1 missense mutant, extracts of seedlings grown at the permissive temperature have an apparently normal CESA complex that was missing from extracts of seedlings grown at the restrictive temperature where CESAs precipitated independently. In prc1-19, with no CESA6, CESAs 1 and 3 were part of a 420 kDa complex in extracts of light-grown seedlings that was absent from extracts of dark-grown seedlings where the CESAs precipitated independently. Two CESA3 missense mutants retained apparently normal CESA complexes as did four cellulose-deficient mutants defective in proteins other than CESAs. The 840 kDa complex could contain six CESA subunits and, since loss of plasma membrane rosettes accompanies its loss in rsw1, the complex could form one of the six particles which electron microscopy reveals in rosettes

Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia

The BCR-ABL kinase inhibitor imatinib has shown significant efficacy in chronic myeloid leukemia (CML) and is the standard front-line therapy for patients in chronic phase. However, a substantial number of patients are either primarily refractory or acquire resistance to imatinib. While a number of mechanisms are known to confer resistance to imatinib, increasing evidence has demonstrated a role for BCR-ABL–independent pathways. The Src-family kinases (SFKs) are one such pathway and have been implicated in imatinib resistance. Additionally, these kinases are key to the progression of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The dual SFK/BCR-ABL inhibitor dasatinib is now clinically available and has markedly greater potency compared with imatinib against native BCR-ABL and the majority of imatinib resistant BCR-ABL mutants. Therefore, this agent, as well as other dual SFK/BCR-ABL inhibitors under development, could provide added therapeutic advantages by overcoming both BCR-ABL– dependent (i.e., BCR-ABL mutations) and – independent forms of imatinib resistance and delaying transition to advanced phase disease. In this review, we discuss the preclinical and clinical evidence demonstrating the involvement of SFKs in imatinib resistance and the progression of CML and Ph+ ALL, as well as the potential role of dual SFK/BCR-ABL inhibition in the management of these diseases

Mental accounting, access motives, and overinsurance

People exercising mental accounting have an additional motive for buying insurance. They perceive a risk of having insufficient funds available to self-insure. In this way insurance protects the consumption value of the insured asset beyond the expenditure to acquire/replace it. This complements previous approaches based on probability weighting and loss aversion to explain the high profitability of warranties and an aversion toward deductibles. It helps to account for why the value of a warranty is found to be positively related to the value of the product and why there is seemingly contradictory empirical evidence on how household income affects demand for warranties. The adapted model rationalizes a strong aversion to deductibles, and explains the observed sensitivity of this aversion to the insurance context. Finally, it predicts a strong impact of how an insurer pays out benefits on the value and cost of insurance. This can explain both the evidence on strong deductible aversion for flood insurance and the lack of such evidence for long-term care insurance

Physician–Patient Communication About Prescription Medication Nonadherence: A 50-state Study of America’s Seniors

CONTEXT: Understanding and improving the quality of medication management is particularly important in the context of the Medicare prescription drug benefit that took effect last January 2006. OBJECTIVE: To determine the prevalence of physician–patient dialogue about medication cost and medication adherence among elderly adults nationwide. DESIGN: Cross-sectional survey. PARTICIPANTS: National stratified random sample of community-dwelling Medicare beneficiaries aged 65 and older. MAIN OUTCOME MEASURES: Rates of physician–patient dialogue about nonadherence and cost-related medication switching. RESULTS: Forty-one percent of seniors reported taking five or more prescription medications, and more than half has 2 or more prescribing physicians. Thirty-two percent overall and 24% of those with 3 or more chronic conditions reported not having talked with their doctor about all their different medicines in the last 12 months. Of seniors reporting skipping doses or stopping a medication because of side effects or perceived nonefficacy, 27% had not talked with a physician about it. Of those reporting cost-related nonadherence, 39% had not talked with a physician about it. Thirty-eight percent of those with cost-related nonadherence reported switching to a lower priced drug, and in a multivariable model, having had a discussion about drug cost was significantly associated with this switch (odds ratio [OR] 5.04, 95% confidence interval [CI] 4.28–5.93, P < .001). CONCLUSIONS: We show that there is a communication gap between seniors and their physicians around prescription medications. This communication problem is an important quality and safety issue, and takes on added salience as physicians and patients confront new challenges associated with coverage under new Medicare prescription drug plans. Meeting these challenges will require that more attention be devoted to medication management during all clinical encounters

Modulation of the virus-receptor interaction by mutations in the V5 loop of feline immunodeficiency virus (FIV) following in vivo escape from neutralising antibody

&lt;b&gt;BACKGROUND:&lt;/b&gt; In the acute phase of infection with feline immunodeficiency virus (FIV), the virus targets activated CD4+ T cells by utilising CD134 (OX40) as a primary attachment receptor and CXCR4 as a co-receptor. The nature of the virus-receptor interaction varies between isolates; strains such as GL8 and CPGammer recognise a "complex" determinant on CD134 formed by cysteine-rich domains (CRDs) 1 and 2 of the molecule while strains such as PPR and B2542 require a more "simple" determinant comprising CRD1 only for infection. These differences in receptor recognition manifest as variations in sensitivity to receptor antagonists. In this study, we ask whether the nature of the virus-receptor interaction evolves in vivo.&lt;p&gt;&lt;/p&gt; &lt;b&gt;RESULTS:&lt;/b&gt; Following infection with a homogeneous viral population derived from a pathogenic molecular clone, a quasispecies emerged comprising variants with distinct sensitivities to neutralising antibody and displaying evidence of conversion from a "complex" to a "simple" interaction with CD134. Escape from neutralising antibody was mediated primarily by length and sequence polymorphisms in the V5 region of Env, and these alterations in V5 modulated the virus-receptor interaction as indicated by altered sensitivities to antagonism by both anti-CD134 antibody and soluble CD134.&lt;p&gt;&lt;/p&gt; &lt;b&gt;CONCLUSIONS:&lt;/b&gt; The FIV-receptor interaction evolves under the selective pressure of the host humoral immune response, and the V5 loop contributes to the virus-receptor interaction. Our data are consistent with a model whereby viruses with distinct biological properties are present in early versus late infection and with a shift from a "complex" to a "simple" interaction with CD134 with time post-infection.&lt;p&gt;&lt;/p&gt

Aberrant signaling in T-cell acute lymphoblastic leukemia: biological and therapeutic implications

T-cell acute lymphoblastic leukemia (T-ALL) is a biologically heterogeneous disease with respect to phenotype, gene expression profile and activation of particular intracellular signaling pathways. Despite very significant improvements, current therapeutic regimens still fail to cure a portion of the patients and frequently implicate the use of aggressive protocols with long-term side effects. In this review, we focused on how deregulation of critical signaling pathways, in particular Notch, PI3K/Akt, MAPK, Jak/STAT and TGF-beta, may contribute to T-ALL. Identifying the alterations that affect intracellular pathways that regulate cell cycle and apoptosis is essential to understanding the biology of this malignancy, to define more effective markers for the correct stratification of patients into appropriate therapeutic regimens and to identify novel targets for the development of specific, less detrimental therapies for T-ALL