A Randomized Placebo-Controlled Trial of Varenicline for Smoking Cessation Allowing Flexible Quit Dates

Introduction: Current smoking cessation guidelines recommend setting a quit date prior to starting pharmacotherapy. However, providing flexibility in the date of quitting may be more acceptable to some smokers. The objective of this study was to compare varenicline 1 mg twice daily (b.i.d.) with placebo in subjects using a flexible quit date paradigm after starting medication. Methods: In this double-blind, randomized, placebo-controlled international study, smokers of ≥10 cigarettes/day, aged 18-75 years, and who were motivated to quit were randomized (3:1) to receive varenicline 1 mg b.i.d. or placebo for 12 weeks. Subjects were followed up through Week 24. Subjects were instructed to quit between Days 8 and 35 after starting medication. The primary endpoint was carbon monoxide-confirmed continuous abstinence during Weeks 9-12, and a key secondary endpoint was continuous abstinence during Weeks 9-24. Results: Overall, 493 subjects were randomized to varenicline and 166 to placebo. Continuous abstinence was higher for varenicline than for placebo subjects at the end of treatment (Weeks 9-12: 53.1% vs. 19.3%; odds ratio [OR] 5.9; 95% CI, 3.7-9.4; p < .0001) and through 24 weeks follow-up (Weeks 9-24: 34.7% vs. 12.7%; OR 4.4; 95% CI, 2.6-7.5; p < .0001). Serious adverse events occurred in 1.2% varenicline (none were psychiatric) and 0.6% placebo subjects. Fewer varenicline than placebo subjects reported depression-related adverse events (2.3% vs. 6.7%, respectively). Conclusions: Varenicline 1 mg b.i.d. using a flexible quit date paradigm had similar efficacy and safety compared with previous fixed quit date studies. © The Author 2011. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco

Selective Down-Regulation of Nuclear Poly(ADP-Ribose) Glycohydrolase

The formation of ADP-ribose polymers on target proteins by poly(ADP-ribose) polymerases serves a variety of cell signaling functions. In addition, extensive activation of poly(ADP-ribose) polymerase-1 (PARP-1) is a dominant cause of cell death in ischemia-reperfusion, trauma, and other conditions. Poly(ADP-ribose) glycohydrolase (PARG) degrades the ADP-ribose polymers formed on acceptor proteins by PARP-1 and other PARP family members. PARG exists as multiple isoforms with differing subcellular localizations, but the functional significance of these isoforms is uncertain.Primary mouse astrocytes were treated with an antisense phosphorodiamidate morpholino oligonucleotide (PMO) targeted to exon 1 of full-length PARG to suppress expression of this nuclear-specific PARG isoform. The antisense-treated cells showed down-regulation of both nuclear PARG immunoreactivity and nuclear PARG enzymatic activity, without significant alteration in cytoplasmic PARG activity. When treated with the genotoxic agent MNNG to induced PARP-1 activation, the antisense-treated cells showed a delayed rate of nuclear PAR degradation, reduced nuclear condensation, and reduced cell death.These results support a preferentially nuclear localization for full-length PARG, and suggest a key role for this isoform in the PARP-1 cell death pathway

A 22-year single institution review of 119 cases of salivary duct carcinoma.

OBJECTIVE: Salivary duct carcinoma (SDC) is a rare and aggressive salivary gland malignancy. Herein, we present the largest single-institution review of SDC to date. METHODS: This is a retrospective cohort study of all histologically confirmed cases of SDC seen at our institution from January 1, 2002, to August 1, 2022. Patient demographics, treatment, histological characteristics, tumor staging, and outcomes were extracted from the electronic medical record. Kaplan-Meier and Cox regression survival analyses were performed. RESULTS: This study included 119 patients with a mean age of 66.2 years. Most primary tumors arose from the parotid gland (72.3%), and 23.5% were noted to be carcinoma ex-pleomorphic adenoma. 57.1% of patients presented with regional lymph node metastasis, whereas 23.5% presented with distant disease. Kaplan-Meier analysis demonstrated a 62.4% 5-year overall survival (OS) and a 69.0% 5-year disease-specific survival (DSS). Univariate analyses indicated that presence of regional lymph node disease (p&lt;.001), distant metastasis (p&lt;.001), perineural invasion (p = .027), and lymphovascular invasion (p = .018) were predictive of decreased OS and DSS. Trastuzumab administration was not associated with survival in HER-2-positive patients receiving chemotherapy. Multivariate analyses demonstrated that presence of nodal disease (HR 30.337, 95% CI 2.782-330.851, p = .005) and carcinoma ex pleomorphic adenoma (HR 5.54, 95% CI 1.024-29.933, p = .047) were associated with decreased OS. CONCLUSION: Our patients had more favorable survival rates compared to prior studies, which may be due to lower incidence of nodal disease. Factors associated with worse survival included nodal and distant metastases, perineural invasion, lymphovascular invasion, and tumor size. LEVEL OF EVIDENCE: Level 3

Altered Expression of the Poly(ADP-Ribosyl)ation Enzymes in Uveal Melanoma and Regulation of PARG Gene Expression by the Transcription Factor ERM

International audiencePurpose.: Poly(ADP-ribosyl)ation is a reversible post-translational modification that requires the contribution of the enzymes poly(ADP-ribose) polymerase-1 (PARP-1) and poly(ADP-ribose) glycohydrolase (PARG). Our study explores expression and activity of PARP-1 and PARG in uveal melanoma cell lines with varying tumorigenic properties.Methods.: Gene profiling on microarrays was conducted using RNA prepared from the uveal melanoma cell lines T97, T98, T108, and T115. The activity of PARP-1 and PARG was monitored by enzymatic assays, whereas their expression was measured by Western blot and PCR. The PARG promoter was analyzed using promoter deletions and site-specific mutagenesis in transfection analyses. The transcription factors binding the PARG promoter were studied by electrophoretic mobility shift assay (EMSA) analyses. Suppression of PARP-1 and PARG expression was performed in T97 and T115 cells by RNAi, and their tumorigenic properties monitored by injections into athymic mice.Results.: Expression of PARP-1 was found to vary considerably between uveal melanoma cell lines with distinctive tumorigenic properties in vivo. Sp1 and the ETS protein ERM were shown to bind to the PARG gene promoter to ensure basal transcription in uveal melanoma. Importantly, suppression of PARG gene expression in T97 and T115 cells increased their capacity to form tumors in athymic mice, whereas suppression of PARP-1 significantly reduced or almost entirely abolished tumor formation.Conclusions.: Our results suggest that while overexpression of PARP-1 may confer a proliferative advantage to aggressive uveal melanoma tumors, PARG may, on the other hand, support a tumor suppressor function in vivo

Water-in-Trichloroethylene Emulsions Stabilized by Uniform Carbon Microspheres

Uniform hard carbon spheres (HCS), synthesized by the hydrothermal decomposition of sucrose followed by pyrolysis, are effective at stabilizing water-in-trichloroethylene (TCE) emulsions. The irreversible adsorption of carbon particles at the TCE-water interface resulting in the formation of a monolayer around the water droplet in the emulsion phase is identified as the key reason for emulsion stability. Cryogenic scanning electron microscopy was used to image the assembly of carbon particles clearly at the TCE-water interface and the formation of bilayers in regions of droplet-droplet contact. The results of this study have potential implications to the subsurface injection of carbon submicrometer particles containing zero-valent iron nanoparticles to treat pools of chlorinated hydrocarbons that are sequestered in fractured bedrock. © 2011 American Chemical Society