PARP16 is a tail-anchored endoplasmic reticulum protein required for the PERK- and IRE1α-mediated unfolded protein response

Poly(ADP-ribose) polymerases (PARPs; also known as ADP-ribosyl transferase D proteins) modify acceptor proteins with ADP-ribose modifications of varying length (reviewed in refs 1, 2, 3). PARPs regulate key stress response pathways, including DNA damage repair and the cytoplasmic stress response. Here, we show that PARPs also regulate the unfolded protein response (UPR) of the endoplasmic reticulum (ER). Human PARP16 (also known as ARTD15) is a tail-anchored ER transmembrane protein required for activation of the functionally related ER stress sensors PERK and IRE1α during the UPR. The third identified ER stress sensor, ATF6, is not regulated by PARP16. As is the case for other PARPs that function during stress, the enzymatic activity of PARP16 is upregulated during ER stress when it ADP-ribosylates itself, PERK and IRE1α. ADP-ribosylation by PARP16 is sufficient for activating PERK and IRE1α in the absence of ER stress, and is required for PERK and IRE1α activation during the UPR. Modification of PERK and IRE1α by PARP16 increases their kinase activities and the endonuclease activity of IRE1α. Interestingly, the carboxy-terminal luminal tail of PARP16 is required for PARP16 function during ER stress, suggesting that it transduces stress signals to the cytoplasmic PARP catalytic domain.National Cancer Institute (U.S.) (Cancer Center Support Core Grant P30-CA14051)National Institutes of Health (U.S.) (Grant 5R01 GM087465-02)Kathy and Curt Marble Cancer Research FundJeptha H. and Emily V. Wade FundVirginia and D.K. Ludwig Fund for Cancer Researc

Cetuximab Augments Cytotoxicity with Poly (ADP-Ribose) Polymerase Inhibition in Head and Neck Cancer

Overexpression of the epidermal growth factor receptor (EGFR) is a hallmark of head and neck cancers and confers increased resistance and inferior survival rates. Despite targeted agents against EGFR, such as cetuximab (C225), almost half of treated patients fail this therapy, necessitating novel therapeutic strategies. Poly (ADP-Ribose) polymerase (PARP) inhibitors (PARPi) have gained recent attention due to their unique selectivity in killing tumors with defective DNA repair. In this study, we demonstrate that C225 enhances cytotoxicity with the PARPi ABT-888 in UM-SCC1, UM-SCC6, and FaDu head and neck cancer cells. The mechanism of increased susceptibility to C225 and PARPi involves C225-mediated reduction of non-homologous end-joining (NHEJ)- and homologous recombination (HR)-mediated DNA double strand break (DSB) repair, the subsequent persistence of DNA damage, and activation of the intrinsic apoptotic pathway. By generating a DSB repair deficiency, C225 can render head and neck tumor cells susceptible to PARP inhibition. The combination of C225 and the PARPi ABT-888 can thus be an innovative treatment strategy to potentially improve outcomes in head and neck cancer patients. Furthermore, this strategy may also be feasible for other EGFR overexpressing tumors, including lung and brain cancers

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

Varenicline: A review of the literature and place in therapy

Evidence regarding the health consequences of smoking is undeniable, yet 21% of the American population continues to smoke. In addition to behavioral modifications, first-line treatment options include nicotine replacement therapies and bupropion SR. Varenicline, which was recently approved by the Food and Drug Administration (FDA), offers a novel mechanism of action for smoking cessation. This article reviews current first-line smoking cessation aids and evaluates the clinical trials pertaining to the efficacy and safety of varenicline. Additionally, the authors attempt to establish the role of varenicline in smoking cessation therapy and determine whether varenicline should be used prior to other first-line smoking cessation aids, particularly considering the lower costs of generic alternatives. At present, clinical studies have not established the efficacy of varenicline after repeated courses, following bupropion failures, or in various unstudied populations. Relatively poor study outcomes emphasize the need to provide patients with behavioral counseling throughout each quit attempt and for 1 year past the quit date

Evaluation of patient perceptions and outcomes related to anticoagulation point-of-care testing in ambulatory care clinics

Until recently, Prothrombin Time/International Normalized Ratio (PT/INR) measurements have typically been used to monitor patients on warfarin through institutional laboratories via venous puncture. The Point-of-Care Testing (POCT) device has revolutionized the patient care process by allowing for laboratory testing outside of the central laboratory. Objective: To analyze humanistic and clinical outcomes in patients currently treated with warfarin and monitored through a pharmacist-managed anticoagulation clinic using point-of-care testing (POCT) device versus venipuncture within ambulatory care clinics at our institution. Methods: All patients currently treated with warfarin therapy who were managed by clinical pharmacists for anticoagulation monitoring at the Medical University of South Carolina (MUSC) Family Medicine Center and University Diagnostic Center, were enrolled. Patients were asked to complete a satisfaction survey regarding their anticoagulation monitoring. In addition, data related to emergency department (ED) visits, hospitalizations and percent of time in the INR therapeutic range for 6 months pre- and post-implementation of POCT device was collected. This information was obtained through an electronic patient information database, Oacis. Results: A total of 145 patients were included in the data collection from the two clinics. The majority (41%) of these patients were taking warfarin for atrial fibrillation. Satisfaction surveys were completed by 86 (59 %) of patients. The surveys revealed that POCT device was preferred over venipuncture in 95% of patients. Reasons for the preference included more face-to-face interaction, less wait time, less pain, less blood needed, and quicker results. Of the 145 patients who were included in the objective data analysis, no significant differences were found in the number of hospitalizations, ED visits, or percent of time in the INR therapeutic range pre- and post- implementation of POCT device.Conclusion: The results of this study demonstrate improvement in patient satisfaction with POCT compared to venipuncture, with limited value in clinical outcomes

Assessment of patient knowledge of diabetic goals, self-reported medication adherence, and goal attainment

Background: Medication adherence is an integral aspect of disease state management for patients with chronic illnesses, including diabetes mellitus. It has been hypothesized that patients with diabetes who have poor medication adherence may have less knowledge of overall therapeutic goals and may be less likely to attain these goals. Objective: The purpose of this study was to assess self-reported medication adherence, knowledge of therapeutic goals (hemoglobin A1C [A1C], low density lipoprotein cholesterol [LDL-C] and blood pressure [BP]), and goal attainment in adult patients with diabetes. Methods: A survey was created to assess medication adherence, knowledge of therapeutic goals, and goal attainment for adult patients with diabetes followed at an internal medicine or a family medicine clinic. Surveys were self-administered prior to office visits. Additional data were collected from the electronic medical record. Statistical analysis was performed. Results: A total of 149 patients were enrolled. Knowledge of therapeutic goals was reported by 14%, 34%, and 18% of survived patients for LDL-C, BP, and A1C, respectively. Forty-six percent, 37%, and 40% of patients achieved LDL-C, BP, and A1C goals, respectively. Low prescribing of cholesterol-lowering medications was an interesting secondary finding; 36% of patients not at LDL-C goal had not been prescribed a medication targeted to lower cholesterol. Forty-eight percent of patients were medication non-adherent; most frequently reported reasons for non-adherence were forgot (34%) and too expensive (14%). Patients at A1C goal were more adherent than patients not at goal (p=0.025). Conclusion: The majority did not reach goals and were unknowledgeable of goals; however, most were provided prescriptions to treat these parameters. Goal parameters should be revisited often amongst multidisciplinary team members with frequent and open communications. Additionally, it is imperative that practitioners discuss the importance of medication adherence with every patient at every visit