Alien Registration- Castonguay, Joseph T. (Caribou, Aroostook County)

https://digitalmaine.com/alien_docs/26145/thumbnail.jp

Organometallic iridium(III) anticancer complexes with new mechanisms of action: NCI-60 screening, mitochondrial targeting, and apoptosis

Platinum complexes related to cisplatin, cis-[PtCl2(NH3)2], are successful anticancer drugs; however, other transition metal complexes offer potential for combating cisplatin resistance, decreasing side effects, and widening the spectrum of activity. Organometallic half-sandwich iridium (IrIII) complexes [Ir(Cpx)(XY)Cl]+/0 (Cpx = biphenyltetramethylcyclopentadienyl and XY = phenanthroline (1), bipyridine (2), or phenylpyridine (3)) all hydrolyze rapidly, forming monofunctional G adducts on DNA with additional intercalation of the phenyl substituents on the Cpx ring. In comparison, highly potent complex 4 (Cpx = phenyltetramethylcyclopentadienyl and XY = N,N-dimethylphenylazopyridine) does not hydrolyze. All show higher potency toward A2780 human ovarian cancer cells compared to cisplatin, with 1, 3, and 4 also demonstrating higher potency in the National Cancer Institute (NCI) NCI-60 cell-line screen. Use of the NCI COMPARE algorithm (which predicts mechanisms of action (MoAs) for emerging anticancer compounds by correlating NCI-60 patterns of sensitivity) shows that the MoA of these IrIII complexes has no correlation to cisplatin (or oxaliplatin), with 3 and 4 emerging as particularly novel compounds. Those findings by COMPARE were experimentally probed by transmission electron microscopy (TEM) of A2780 cells exposed to 1, showing mitochondrial swelling and activation of apoptosis after 24 h. Significant changes in mitochondrial membrane polarization were detected by flow cytometry, and the potency of the complexes was enhanced ca. 5× by co-administration with a low concentration (5 μM) of the γ-glutamyl cysteine synthetase inhibitor L-buthionine sulfoximine (L-BSO). These studies reveal potential polypharmacology of organometallic IrIII complexes, with MoA and cell selectivity governed by structural changes in the chelating ligands

The snow must go on: Ground ice encasement, snow compaction and absence of snow differently cause soil hypoxia, CO2 accumulation and tree seedling damage in boreal forest

201

Trauma-related emotions and radical acceptance in dialectical behavior therapy for posttraumatic stress disorder after childhood sexual abuse

Background: Posttraumatic Stress Disorder (PTSD) related to childhood sexual abuse (CSA) is often associated with a wide range of trauma-related aversive emotions such as fear, disgust, sadness, shame, guilt, and anger. Intense experience of aversive emotions in particular has been linked to higher psychopathology in trauma survivors. Most established psychosocial treatments aim to reduce avoidance of trauma-related memories and associated emotions. Interventions based on Dialectical Behavior Therapy (DBT) also foster radical acceptance of the traumatic event. Methods: This study compares individual ratings of trauma-related emotions and radical acceptance between the start and the end of DBT for PTSD (DBT-PTSD) related to CSA. We expected a decrease in trauma-related emotions and an increase in acceptance. In addition, we tested whether therapy response according to the Clinician Administered PTSD-Scale (CAPS) for the DSM-IV was associated with changes in trauma-related emotions and acceptance. The data was collected within a randomized controlled trial testing the efficacy of DBT-PTSD, and a subsample of 23 women was included in this secondary data analysis. Results: In a multilevel model, shame, guilt, disgust, distress, and fear decreased significantly from the start to the end of the therapy whereas radical acceptance increased. Therapy response measured with the CAPS was associated with change in trauma-related emotions. Conclusions: Trauma-related emotions and radical acceptance showed significant changes from the start to the end of DBT-PTSD. Future studies with larger sample sizes and control group designs are needed to test whether these changes are due to the treatment. Trial registration: ClinicalTrials.gov, number NCT0048100

Looking both ways

On the occasion of the 25th anniversary of the journal, Psychotherapy Research, three former editors first look back at: (i) the controversial persistence of the Dodo verdict (i.e., the observation that all bona fide therapies seem equally effective); (ii) the connection between process and outcome; (iii) the move toward methodological pluralism; and (iv) the politicization of the field around evidence-based practice and treatment guidelines. We then look forward to the next 25 years, suggesting that it would be promising to focus on three areas: (i) systematic theory-building research; (ii) renewed attention to fine-grained study of therapist techniques; and (iii) politically expedient research on the outcomes of marginalized or emerging therapies

Measuring Flexicurity: Precautionary Notes, a New Framework, and an Empirical Example

Recently, there has been an increase and abundance of literature measuring flexicurity across countries. However, there is yet to be any agreement on the definition of the key concepts of flexicurity as well as the framework in which to base one’s research. Due to this, the outcomes found in the existing studies are rather diverse, far from reaching a consensus, and can be misleading. This paper addresses the issues by first introducing a framework, namely, the various levels and stages of flexicurity, as well as introducing some key issues that should be addressed when doing flexicurity indicators research. In addition, an empirical example is given to show how the framework derived can be used to carry out flexicurity research, and to show how by not regarding these frameworks one can come to misleading outcomes

Knowledge, interest, and anticipated barriers of pre-exposure prophylaxis uptake and adherence among gay, bisexual, and men who have sex with men who are incarcerated

Criminal justice (CJ) settings disproportionately include populations at high risk for acquiring HIV, and CJ-involved individuals are often at the intersection of multiple overlapping risk factors. However, few studies have examined attitudes about pre-exposure prophylaxis (PrEP) among incarcerated men who have sex with men (MSM). This study explored interest in, knowledge of, and barriers to PrEP uptake among gay, bisexual, and other men who have sex with men at the Rhode Island Department of Corrections. Using semi-structured interviews, 26 MSM were interviewed about PrEP knowledge, interest, timing preferences for provision (e.g. before or after release), and barriers to uptake and adherence during community re-entry. Interviews were coded and analyzed using a general inductive approach. Participants demonstrated low initial knowledge of PrEP but high interest after being told more about it. Participants self-identified risk factors for HIV acquisition, including condom-less sex and substance use. In addition, participants preferred provision of PrEP prior to release. Post-release barriers to PrEP uptake and adherence included 1) concerns about costs of PrEP medications; 2) anticipated partner or family disapproval; 3) lack of access to transportation; 4) unstable housing; 5) compounding impacts of multiple hardships leading to a de-prioritization of PrEP and 6) fears of future re-incarceration. These results point to the need for future PrEP interventions among incarcerated populations that address incarceration and PrEP related barriers during community re-entry via wraparound services that address PrEP and incarceration-related barriers

River histories : A thematic review

Peer reviewe

Bortezomib in combination with celecoxib in patients with advanced solid tumors: a phase I trial

<p>Abstract</p> <p>Background</p> <p>COX-2 inhibitors, such as celecoxib, and ubiquitin-proteasome pathway inhibitors, such as bortezomib, can down-regulate NF-κB, a transcription factor implicated in tumor growth. The objective of this study was to determine the maximum tolerated dose and dose-limiting toxicities of bortezomib in combination with celecoxib in patients with advanced solid tumors.</p> <p>Methods</p> <p>Patients received escalating doses of bortezomib either on a weekly schedule (days 1, 8, 15, 22, and 29 repeated every 42 days) or on a twice-weekly administration schedule (days 1, 4, 8, and 11 repeated every 21 days), in combination with escalating doses of celecoxib twice daily throughout the study period from 200 mg to 400 mg twice daily.</p> <p>Results</p> <p>No dose-limiting toxicity was observed during the study period. Two patients had stable disease lasting for four and five months each, and sixteen patients developed progressive disease.</p> <p>Conclusion</p> <p>The combination of bortezomib and celecoxib was well tolerated, without dose limiting toxicities observed throughout the dosing ranges tested, and will be studied further at the highest dose levels investigated.</p> <p>Trial registration number</p> <p>NCT00290680.</p