Gender-specific effects of comorbid depression and anxiety on the propensity to drink in negative emotional states.

Background And Aims: Depression and anxiety are often comorbid with alcoholism and contribute to craving and relapse. We aimed to estimate the prevalence of life-time diagnoses of major depressive disorder (MDD), substance-induced depression (SID), anxiety disorder (AnxD) and substance-induced anxiety (SIA), the effects of these comorbidities on the propensity to drink in negative emotional states (negative craving), and test whether these effects differ by sex.

Design: Secondary analyses of baseline data collected in a single-arm study of pharmacogenetic predictors of acamprosate response.

Characteristics of heart rate variability in alcohol-dependent subjects and nondependent chronic alcohol users.

Heart rate variability (HRV) is an objective and sensitive measure of integrated physiological functioning reflective of heart rhythm responsivity to internal and external demands. Reduced HRV is associated with vulnerability to stress and deterioration of medical and/or psychiatric conditions, while increased HRV is associated with a favorable treatment response and recovery from various medical and/or psychiatric conditions. Our previous review found that acute alcohol consumption caused decreased parasympathetic and increased sympathetic HRV effects in both nonalcoholic and chronic alcohol users.

Association of the PDYN gene with alcohol dependence and the propensity to drink in negative emotional states.

Synthetic κ-opioid receptor (KOR) agonists induce dysphoric and pro-depressive effects and variations in the KOR (OPRK1) and prodynorphin (PDYN) genes have been shown to be associated with alcohol dependence. We genotyped 23 single nucleotide polymorphisms (SNPs) in the PDYN and OPRK1 genes in 816 alcohol-dependent subjects and investigated their association with: (1) negative craving measured by a subscale of the Inventory of Drug Taking Situations; (2) a self-reported history of depression; (3) the intensity of depressive symptoms measured by the Beck Depression Inventory-II. In addition, 13 of the 23 PDYN and OPRK1 SNPs, which were previously genotyped in a set of 1248 controls, were used to evaluate association with alcohol dependence.

Association of GATA4 sequence variation with alcohol dependence.

To further explore reports of association of alcohol dependence and response to acamprosate treatment with the GATA4 rs13273672 single nucleotide polymorphism (SNP), we genotyped this and 10 other GATA4 SNPs in 816 alcohol-dependent cases and 1248 controls. We tested for association of alcohol dependence with the 11 SNPs individually and performed a global test for association using a principle components analysis. Our analyses demonstrate significant association between GATA4 and alcohol dependence at the gene level (P = 0.

Ataxia telangiectasia and rad3-related kinase contributes to cell cycle arrest and survival after cisplatin but not oxaliplatin.

The DNA cross-linking agents cisplatin and oxaliplatin are widely used in the treatment of human cancer. Lesions produced by these agents are widely known to activate the G1 and G2 cell cycle checkpoints. Less is known about the role of the intra-S-phase checkpoint in the response to these agents.

Müllerian inhibiting substance type II receptor (MISIIR): a novel, tissue-specific target expressed by gynecologic cancers.

Objective: Müllerian inhibiting substance type II receptor (MISIIR) is expressed by ovarian, breast, and prostate cancers [Masiakos PT, et al. Human ovarian cancer, cell lines, and primary ascites cells express the human Mullerian inhibiting substance (MIS) Type II Receptor, bind, and are responsive to MIS. Clin Cancer Res 1999;5:3488-99; Hoshiya Y, et al.

Mutations in the ataxia telangiectasia and rad3-related-checkpoint kinase 1 DNA damage response axis in colon cancers.

In response to certain types of DNA damage, ataxia telangiectasia and rad3-related (ATR) phosphorylates checkpoint kinase 1 (CHEK1) resulting in cell cycle arrest and subsequent DNA repair. ATR and CHEK1 contain mononucleotide microsatellite repeat regions, which are mutational targets in tumors with defective mismatch repair (MMR). This study examined the frequency of such mutations in colon cancers and their impact on biologic behavior.

Heterozygous ATR mutations in mismatch repair-deficient cancer cells have functional significance.

ATR (ataxia telangiectasia and Rad3-related) function is necessary for the proper response to commonly used chemotherapeutic agents. Heterozygous truncating mutations in exon 10 of the ATR gene have been described in numerous cancers exhibiting microsatellite instability. We show that truncating mutations of ATR are capable of acting in a dominant-negative manner to abrogate ATR-dependent Chk1 phosphorylation and cell-cycle arrests after DNA damage.

Lovastatin alters the isoprenoid biosynthetic pathway in acute myelogenous leukemia cells in vivo.

Lovastatin, a competitive inhibitor of hydroxymethylglutaryl coenzyme A reductase (HMGR), is used therapeutically to lower plasma cholesterol levels and has garnered attention for its cytotoxic effects in leukemia cells. In this study, escalating doses of lovastatin were administered to nine patients with acute myelogenous leukemia. Peripheral blood leukemia cells were drawn pre- and post-lovastatin dosing.

A phase I trial of perillyl alcohol administered four times daily for 14 days out of 28 days.

Purpose: Perillyl alcohol (POH) has been shown to have both chemopreventative and chemotherapeutic activities in preclinical studies. The underlying mechanism(s) of action of POH have yet to be delineated but may involve effects on the transforming growth factor beta (TGFbeta) and/or the Ras signaling pathways. A phase I study of POH for 14 days out of every 28 days in subjects with advanced malignancies was performed to evaluate dose escalation, toxicity, pharmacokinetics, and effects on TGFbeta and Ras.

S phase and G2 arrests induced by topoisomerase I poisons are dependent on ATR kinase function.

ATR, a human phosphatidylinositol 3-kinase-related kinase, is an important component of the cellular response to DNA damage. In the present study, we evaluated the role of ATR in modulating the response of cells to S phase-associated DNA double-stranded breaks induced by topoisomerase poisons. Prolonged exposure to low doses of the topoisomerase I poison topotecan (TPT) resulted in S phase slowing because of diminished DNA synthesis at late-firing replicons.