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PubMed | St. Mary's University, START and Texas A&M University
Type: Journal Article | Journal: Behavioral sciences (Basel, Switzerland) | Year: 2015

The Internet Process Addiction Test (IPAT) was created to screen for potential addictive behaviors that could be facilitated by the internet. The IPAT was created with the mindset that the term Internet addiction is structurally problematic, as the Internet is simply the medium that one uses to access various addictive processes. The role of the internet in facilitating addictions, however, cannot be minimized. A new screening tool that effectively directed researchers and clinicians to the specific processes facilitated by the internet would therefore be useful. This study shows that the Internet Process Addiction Test (IPAT) demonstrates good validity and reliability. Four addictive processes were effectively screened for with the IPAT: Online video game playing, online social networking, online sexual activity, and web surfing. Implications for further research and limitations of the study are discussed.


Tap W.D.,University of California at Los Angeles | Demetri G.,Harvard University | Barnette P.,Primary Childrens Medical Center | Desai J.,Royal Melbourne Hospital | And 11 more authors.
Journal of Clinical Oncology | Year: 2012

Purpose: Ganitumab is a fully human monoclonal antibody against type-1 insulin-like growth factor receptor (IGF1R). An open-label phase II study was conducted to evaluate the efficacy and safety of ganitumab monotherapy in patients with metastatic Ewing family tumors (EFT) or desmoplastic small round cell tumors (DSRCT). Patients and Methods: Patients ≥16 years of age with relapsed or refractory EFT or DSRCT received 12 mg/kg of ganitumab every 2 weeks. Objective response rate (ORR) was the primary end point. Secondary end points included clinical benefit rate (CBR = complete + partial responses + stable disease [SD] ≥ 24 weeks) and safety and pharmacokinetic profiles of ganitumab. The relationship between tumor response and EWS gene translocation status and IGF-1 levels was evaluated. Results: Thirty-eight patients (22 with EFT; 16 with DSRCT) received one or more doses of ganitumab. Twenty-four patients (63%) experienced ganitumab-related adverse events. Grade 3 related events included hyperglycemia (n = 2), thrombocytopenia (n = 5), neutropenia (n = 2), leukopenia (n = 1), and transient ischemic attack (n = 1). There were no grade 4 or 5 treatment-related events. Of 35 patients assessed for response, two had partial responses (ORR, 6%) and 17 (49%) had SD. Four patients had SD ≥ 24 weeks, contributing to a CBR of 17%. The pharmacokinetic profile of ganitumab was similar to that observed in the first-in-human trial. Elevation of IGF-1 levels was observed postdose. EWS-Fli1 translocations were analyzed by RNA sequencing and fluorescent in situ hybridization, and novel translocations were observed in EFT and DSCRT. No apparent relationship between tumor response and IGF-1 levels or EWS gene translocations was observed. Conclusion: Ganitumab was well tolerated and demonstrated antitumor activity in patients with advanced recurrent EFT or DSRCT. © 2012 by American Society of Clinical Oncology.


Patnaik A.,START | Tolcher A.,START | Beeram M.,START | Nemunaitis J.,Mary Crowley | And 10 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2015

Purpose: RG7112, the first selective small-molecule MDM2 antagonist in clinical testing, is a non-genotoxic oral p53 activator. To optimize its dose and schedule, a number of clinical pharmacology characteristics were explored in this multicenter trial in patients with advanced solid tumors. Method: In part 1, the impact of high-energy/high-fat meal and formulations (crystalline and amorphous) on relative bioavailability was examined in single-dose crossover designs. In part 2, schedule optimization (4 schedules of drug administration under fasting condition and 2 cohorts with liquid supplementation) was investigated in parallel, dose escalation designs. Clinical endpoints were pharmacokinetics (PK), pharmacodynamics (PD) including MIC-1 elevation and platelet reduction, and safety/tolerability. Results: With a single-dose treatment, a high-fat/high-energy meal and a new formulation under fasting condition, respectively, enhanced overall bioavailability of RG7112 slightly over twofold. Following multiple-dose administrations, all four schedules yielded the comparable per-cycle (28-d) exposure (AUC), as designed; liquid supplements also enhanced bioavailability. High-dose treatments of consecutive daily dosing for 5 and 3 days resulted in higher on-treatment-day exposure to RG7112 than both weekly and low-dose/long-duration (20-day) daily schedules. Serum MIC-1 and blood platelet profiles showed similar patterns to those of PK when the clinical pharmacology conditions were varied, suggesting the relative importance of treatment-day exposure than overall per-cycle AUC. Conclusion: Food (both high-fat and low-fat meals) and new formulation enhanced bioavailability. High-dose consecutive daily treatment for 3-5 days is superior to weekly and low-dose/long-duration (20-day) daily schedules in yielding the sufficiently high drug exposure and PD effects potentially required for cancer treatment efficacy. © 2015 Springer-Verlag Berlin Heidelberg.


Virji H.,START | Padgham J.,START | Seipt C.,START
Current Opinion in Environmental Sustainability | Year: 2012

Sustained action by society to support timely and effective actions to deal with global environmental changes must be underpinned by systems of knowledge generation and exchange that are capable of engaging a wide range of decision makers. Building more robust knowledge systems to support resilient development requires significant and well-targeted investments in education and training that bolster scientific capacities, and in communication approaches that foster better interaction of scientists with practitioner and policy communities. Reflecting on nearly two decades of capacity building experience of START and its partner institutions, we review the key principles that should underlie long-term capacity building efforts. We note that investments in capacity building are in themselves an effective adaptation response to global change. Strong and well-supported scientific networks are an indispensible component of capacity building, as they are a key source for new knowledge that enables continual and dynamic adaptation practice. We illustrate guiding principles and priority areas for capacity building that promote an integrated and comprehensive approach to capacity building in the context of the emerging Earth System Science Initiative and other programs, such as Integrated Research on Disaster Reduction, Climate Change, Agriculture, and Food Security, People and Ecosystem Services, and the Program of Research on Climate Change Vulnerability, Impacts and Adaptation. © 2012 Elsevier B.V.


Patnaik A.,START | Haluska P.,Mayo Medical School | Tolcher A.W.,START | Erlichman C.,Mayo Medical School | And 18 more authors.
Clinical Cancer Research | Year: 2016

Purpose: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer. Experimental Design: The study design consisted of a doseescalation phase performed in a 3+3 design (Part A; n = 54), two dose-confirmation phases [Part B at 420 mg (n=18) and Part C at 300 mg (n = 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor- positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle. Results: Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose-dependent manner. After a single dose, ralimetinib inhibited p38 MAPK-induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for ≥ 6 cycles. Conclusions: Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. © 2015 American Association for Cancer Research.


Patent
Start | Date: 2012-08-28

The proposed device enables to improve cushioning properties, increase ball flying speed, improve twisting of a ball. The said technical effect is achieved owing to that the proposed bat comprises a base, a handle and an elastic pad connected to the base outer surface. Protrusions on the elastic pad are distributed evenly. The said protrusions are made T-shaped, in the form of a leg and a head combined with the said leg. The legs are connected to the elastic pad. The heads of the neighboring T-shaped protrusions are brought into contact therebetween.


Stroh M.,Merck And Co. | Talaty J.,Merck And Co. | Sandhu P.,Merck And Co. | McCrea J.,Merck And Co. | And 12 more authors.
Journal of Clinical Pharmacology | Year: 2014

Ridaforolimus, a unique non-prodrug analog of rapamycin, is a potent inhibitor of mTOR under development for cancer treatment. In vitro data suggest ridaforolimus is a reversible and time-dependent inhibitor of CYP3A. A model-based evaluation suggested an increase in midazolam area under the curve (AUC0-) of between 1.13- and 1.25-fold in the presence of therapeutic concentrations of ridaforolimus. The pharmacokinetic interaction between multiple oral doses of ridaforolimus and a single oral dose of midazolam was evaluated in an open-label, fixed-sequence study, in which cancer patients received a single oral dose of 2 mg midazolam followed by 5 consecutive daily single oral doses of 40 mg ridaforolimus with a single dose of 2 mg midazolam with the fifth ridaforolimus dose. Changes in midazolam exposure were minimal [geometric mean ratios and 90% confidence intervals: 1.23 (1.07, 1.40) for AUC0 and 0.92 (0.82, 1.03) for maximum concentrations (Cmax), respectively]. Consistent with model predictions, ridaforolimus had no clinically important effect on midazolam pharmacokinetics and is not anticipated to be a perpetrator of drug-drug interactions (DDIs) when coadministered with CYP3A substrates. Model-based approaches can provide reasonable estimates of DDI liability, potentially obviating the need to conduct dedicated DDI studies especially in challenging populations like cancer patients. © 2014, The American College of Clinical Pharmacology.


PubMed | START, Mayo Medical School, inVentiv Health and Eli Lilly and Company
Type: Journal Article | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016

p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer.The study design consisted of a dose-escalation phase performed in a 3+3 design (Part A; n = 54), two dose-confirmation phases [Part B at 420 mg (n = 18) and Part C at 300 mg (n = 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor-positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle.Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose-dependent manner. After a single dose, ralimetinib inhibited p38 MAPK-induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for 6 cycles.Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer.

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