Overexpression of Bcl-2 is a potential mechanism for chemoresistance in acute leukemia and has been associated with unfavorable clinical outcome. We hypothesized that down-regulation of Bcl-2 would restore chemosensitivity in leukemic cells. To test this hypothesis, we performed a phase 1 study of G3139 (Genasense, Genta, Berkeley Heights, NJ), an 18-mer phosphorothioate Bcl-2 antisense, with fludarabine (FL), cytarabine (ARA-C), and granulocyte colony-stimulating factor (G-CSF) (FLAG) salvage chemotherapy in patients with refractory or relapsed acute leukemia. Twenty patients with refractory or relapsed acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) were enrolled. G3139 was delivered by continuous infusion on days 1 to 10. FLAG chemotherapy was administered on days 5 to 10. Common side effects of this combination included fever, nausea, emesis, electrolyte imbalance, and fluid retention that were not dose limiting. Plasma pharmacokinetics of G3139 demonstrated steady-state concentration (Css) within 24 hours. Of the 20 patients, 9 (45%) had disease response, 6 (5 AML, 1 ALL) with complete remission (CR) and 3 (2 AML and 1 ALL) with no evidence of disease but failure to recover normal neutrophil and/or platelet counts or to remain in remission for at least 30 days (incomplete remission). Bcl-2 mRNA levels were down-regulated in 9 of the 12 (75%) evaluable patients. This study demonstrates that G3139 can be administered safely with FLAG chemotherapy and down-regulate its target, Bcl-2. The encouraging clinical and laboratory results justify the current plans for a phase 3 study in previously untreated high-risk AML (ie, age at least 60 years).

G3139 can be administered safely in combination with intensive chemotherapy, and the degree of Bcl-2 downmodulation may correlate with response to therapy.

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We performed a meta-analysis to analyze the associations of depression with pre-diabetes (PreDM), undiagnosed diabetes (UDM), and previously diagnosed diabetes (PDM), and whether the association was affected by important study characteristics. We searched relevant articles published in PubMed and EMBASE up to August, 2015. Studies reporting cross-sectional associations of depression with PreDM, UDM, or PDM compared with normal glucose metabolism (NGM) were included. Odds ratios (ORs) were pooled with random-effect and fixed-effect models. Subgroup analyses by sex, study mean age, different degrees of adjustment, publication year, quality score, and depression assessment scales were also performed. Twenty studies were eligible and included in current analysis. Summary estimates showed that compared with NGM individuals, prevalence of depression was moderately increased in PreDM (random-effect odds ratio (OR) 1.11, 95 % confidence interval (CI) 1.03-1.19) and UDM (OR 1.27, 95 % CI 1.02-1.59), and markedly increased in PDM (OR 1.80, 95 % CI 1.40-2.31). Subgroup analyses showed that the positive association remained only among studies with mean age <60 years old but not among those with mean age ≥60 years old. Summary estimates of ORs with cardiovascular disease adjustment substantially attenuated the association. Our findings suggested that risk of prevalent depression was gradually increased with the deterioration of glucose metabolism among younger age groups but not among older age groups. Comorbid cardiovascular diseases might be an important intermediate factor underlying the association between depression and diabetes.

The validated hybridization enzyme-linked immunosorbent assay method is specific for quantitation of PS ODNs in biological samples to picomolar level. This method provides a powerful technique to evaluate plasma pharmacokinetics and intracellular uptake of PS ODNs in patients and shows its utility in clinical evaluations.

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Purpose: Down-regulation of Bcl-2 by the antisense G3139, currently under clinical evaluations, could restore chemosensitivity in otherwise resistant malignant cells. To date, the mechanism of intracellular accumulation of G3139 following in vivo administration remains to be elucidated.This study aimed to assess whether detectable intracellular concentrations of G3139 are achievable in vivo and how these relate to Bcl-2 down-regulation. Experimental Design: Cellular uptake of G3139 was studied in leukemia myeloid cell lines and blasts collected from treated patients using a newly developed, novel, and highly sensitive ELISAbased assay. Real-time reverse transcription-PCR was used to quantify Bcl-2 mRNA changes in treated cells. Results: The assay was fully validated and showed a limit of quantification of 50 pmol/L.When exposed to 0.33 to10 Amol/L G3139, K562 cells exhibited intracellular concentrations in the range of 2.1 to 11.4 pmol/mg protein. When G3139 was delivered with cationic lipids, a 10-to 25-fold increase of the intracellular concentrations was observed. There was an accumulation of G3139 in the nuclei, and the ratio of nucleus to cytoplasm was increased 7-fold by cationic lipids. Intracellular concentrations of G3139 were correlated with Bcl-2 mRNA down-regulation. Robust intracellular concentrations of G3139 were achieved in vivo in bone marrow (range, 3.4-40.6 pmol/mg protein) and peripheral blood mononuclear cells (range, 0.47-19.4 pmol/mg protein) from acute myeloid leukemia patients treated with G3139. Conclusions:This is the first evidence that measurable intracellular levels of G3139 are achievable in vivo in acute myeloid leukemia patients and that Bcl-2 down-regulation is likely to depend on the achievable intracellular concentrations rather than on plasma concentrations.

High waist hip ratio, triglyceride, fasting blood glucose, and metabolic syndrome were associated with increased risk factors for reflux esophagitis while high high-density lipoprotein for men correlated with a reduced risk of reflux esophagitis.