Oxaliplatin induces drug resistance more rapidly than cisplatin in H69 small cell lung cancer cells

Cisplatin produces good responses in solid tumours including small cell lung cancer (SCLC) but this is limited by the development of resistance. Oxaliplatin is reported to show activity against some cisplatin-resistant cancers but there is little known about oxaliplatin in SCLC and there are no reports of oxaliplatin resistant SCLC cell lines. Studies of drug resistance mainly focus on the cellular resistance mechanisms rather than how the cells develop resistance. This study examines the development of cisplatin and oxaliplatin resistance in H69 human SCLC cells in response to repeated treatment with clinically relevant doses of cisplatin or oxaliplatin for either 4 days or 2h. Treatments with 200ng/ml cisplatin or 400ng/ml oxaliplatin for 4 days produced sublines (H69CIS200 and H69OX400 respectively) that showed low level (approximately 2-fold) resistance after 8 treatments. Treatments with 1000ng/ml cisplatin or 2000ng/ml oxaliplatin for 2h also produced sublines, however these were not stably resistant suggesting shorter treatment pulses of drug may be more effective. Cells survived the first five treatments without any increase in resistance, by arresting their growth for a period and then regrowing. The period of growth arrest was reduced after the sixth treatment and the H69CIS200 and H69OX400 sublines showed a reduced growth arrest in response to cisplatin and oxaliplatin treatment suggesting that "regrowth resistance" initially protected against drug treatment and this was further upregulated and became part of the resistance phenotype of these sublines. Oxaliplatin dose escalation produced more surviving sublines than cisplatin dose escalation but neither set of sublines were associated with increased resistance as determined by 5-day cytotoxicity assays, also suggesting the involvement of regrowth resistance. The resistant sublines showed no change in platinum accumulation or glutathione levels even though the H69OX400 subline was more sensitive to buthionine sulfoximine treatment. The H69CIS200 cells were cross-resistant to oxaliplatin demonstrating that oxaliplatin does not have activity against low level cisplatin resistance. Relative to the H69 cells, the H69CIS200 and H69OX400 sublines were more sensitive to paclitaxel and taxotere suggests the taxanes may be useful in the treatment of platinum resistant SCLC. These novel cellular models of cisplatin and oxaliplatin resistant SCLC will be useful in developing strategies to treat platinum-resistant SCLC

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

Palladium and Platinum 2,4-cis-amino Azetidine and Related Complexes

Seven N,N’-palladium(II) chloride complexes, one N,N’-palladium(II) acetate complex of 2,4-cis-azetidines where prepared and analyzed by single crystal XRD. Two platinum(II) chloride N,N’-complexes of 2,4-cis-azetidines where prepared and analyzed by single crystal XRD. Computational analysis and determination of the %Vbur was examined conducted. A CNN’ metallocyclic complex was prepared by oxidative addition of palladium(0) to an ortho bromo 2,4-cis-disubstituted azetidine and its crystal structure displays a slightly pyramidalized metal-ligand orientation

Verhinderung von Zwang und Förderung von Partizipation in der Psychiatrie durch Behandlungsvereinbarungen : Ergebnisse einer multizentrischen, randomisierten kontrollierten Studie und einer Sekundärdatenanalyse

Zielsetzung: Diese Dissertation untersucht, inwiefern Behandlungsvereinbarungen (BVen) in der Psychiatrie Zwang reduzieren und Partizipation fördern. Methoden: In einer Multicenter-RCT wurde die BV mit dem weniger aufwändigen Krisenpass verglichen. Primärer Endpunkt: kumulative Behandlungsdauer; weitere Endpunkte u.a.: Anzahl und Dauer von Zwangsmaßnahmen, subjektive Einschätzung der Maßnahme. Zudem erfolgte eine inhaltsanalytische Auswertung der BVen unter Berücksichtigung des Geschlechts. Ergebnisse: 266 Personen nahmen teil. Es wurden keine signifikanten Unterschiede bei der Behandlungsdauer oder Zwangsmaßnahmen gefunden. Eine Überlegenheit der BV zeigte sich bei der Mitgestaltung der Behandlung (p = 0,002) und dem Vertrauen ins Team (p = 0,002). Rückzug war die häufigste vereinbarte Intervention. Medikation könnte insbesondere für Männer hilfreich sein. Folgerungen: Die Ergebnisse legen nahe, dass BVen Partizipation und Selbstbestimmung fördern. Weitere Forschung ist notwendig

Diagnosis of obstructive coronary artery disease using computed tomography angiography in patients with stable chest pain depending on clinical probability and in clinically important subgroups: meta-analysis of individual patient data

OBJECTIVE: To determine whether coronary computed tomography angiography (CTA) should be performed in patients with any clinical probability of coronary artery disease (CAD), and whether the diagnostic performance differs between subgroups of patients. DESIGN: Prospectively designed meta-analysis of individual patient data from prospective diagnostic accuracy studies. DATA SOURCES: Medline, Embase, and Web of Science for published studies. Unpublished studies were identified via direct contact with participating investigators. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Prospective diagnostic accuracy studies that compared coronary CTA with coronary angiography as the reference standard, using at least a 50% diameter reduction as a cutoff value for obstructive CAD. All patients needed to have a clinical indication for coronary angiography due to suspected CAD, and both tests had to be performed in all patients. Results had to be provided using 2×2 or 3×2 cross tabulations for the comparison of CTA with coronary angiography. Primary outcomes were the positive and negative predictive values of CTA as a function of clinical pretest probability of obstructive CAD, analysed by a generalised linear mixed model; calculations were performed including and excluding non-diagnostic CTA results. The no-treat/treat threshold model was used to determine the range of appropriate pretest probabilities for CTA. The threshold model was based on obtained post-test probabilities of less than 15% in case of negative CTA and above 50% in case of positive CTA. Sex, angina pectoris type, age, and number of computed tomography detector rows were used as clinical variables to analyse the diagnostic performance in relevant subgroups. RESULTS: Individual patient data from 5332 patients from 65 prospective diagnostic accuracy studies were retrieved. For a pretest probability range of 7-67%, the treat threshold of more than 50% and the no-treat threshold of less than 15% post-test probability were obtained using CTA. At a pretest probability of 7%, the positive predictive value of CTA was 50.9% (95% confidence interval 43.3% to 57.7%) and the negative predictive value of CTA was 97.8% (96.4% to 98.7%); corresponding values at a pretest probability of 67% were 82.7% (78.3% to 86.2%) and 85.0% (80.2% to 88.9%), respectively. The overall sensitivity of CTA was 95.2% (92.6% to 96.9%) and the specificity was 79.2% (74.9% to 82.9%). CTA using more than 64 detector rows was associated with a higher empirical sensitivity than CTA using up to 64 rows (93.4% v 86.5%, P=0.002) and specificity (84.4% v 72.6%, P<0.001). The area under the receiver-operating-characteristic curve for CTA was 0.897 (0.889 to 0.906), and the diagnostic performance of CTA was slightly lower in women than in with men (area under the curve 0.874 (0.858 to 0.890) v 0.907 (0.897 to 0.916), P<0.001). The diagnostic performance of CTA was slightly lower in patients older than 75 (0.864 (0.834 to 0.894), P=0.018 v all other age groups) and was not significantly influenced by angina pectoris type (typical angina 0.895 (0.873 to 0.917), atypical angina 0.898 (0.884 to 0.913), non-anginal chest pain 0.884 (0.870 to 0.899), other chest discomfort 0.915 (0.897 to 0.934)). CONCLUSIONS: In a no-treat/treat threshold model, the diagnosis of obstructive CAD using coronary CTA in patients with stable chest pain was most accurate when the clinical pretest probability was between 7% and 67%. Performance of CTA was not influenced by the angina pectoris type and was slightly higher in men and lower in older patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42012002780

Efectividad de un programa educativo en el nivel de conocimiento del cuidador primario en la prevención de las úlceras por presión en los servicios de medicina de un hospital nacional

Un programa educativo es una gran herramienta para fortalecer conocimientos, para aprender algo nuevo y permite sensibilizar a las personas por eso, el estudio tiene como objetivo determinar la efectividad de un Programa Educativo en el Nivel de conocimiento del Cuidador Primario sobre la Prevención de las Úlceras por Presión en pacientes con permanencia prolongada en cama hospitalizados en los servicios de medicina del Hospital Nacional Cayetano Heredia. El estudio fue cuantitativo, pre experimental, la intervención se hizo mediante la aplicación de un programa educativo y se midió su efectividad aplicando un instrumento antes y después. La población estuvo constituida por 55 familiares o cuidadores primarios de los servicio de medicina. La técnica fue la entrevista y el instrumento aplicado un cuestionario de 20 preguntas cerradas. Resultados: antes de la intervención educativa prevaleció el nivel de conocimiento medio con el 47.3%, seguido del alto con el 41.8%, y un 10.9% presentó bajo nivel de conocimientos. Después de la intervención educativa, el 100.0% de los cuidadores primarios presentaron alto nivel de conocimiento sobre la prevención de las úlceras por presión en pacientes con permanencia prolongada en cama. Conclusión: que el nivel de conocimientos de los cuidadores primarios de pacientes con permanencia prolongada en cama mejoró después de recibir el programa educativo sobre prevención de las Úlceras por Presión

Análisis institucional y propuesta de mejora del sistema administrativo de gestión de recursos humanos, en la Dirección Regional de Salud Huánuco durante el periodo del 2019 – 2021

El presente trabajo de investigación titulado “Análisis institucional y propuesta de mejora del Sistema Administrativo de Gestión de Recursos Humanos, en la Dirección Regional de Salud Huánuco, durante el periodo del 2018 -2020”, centra su foco en un aspecto muy importante dentro de la gestión pública, el mismo que se refiere a la gestión de los Recursos Humanos, más aún, cuando a través de las personas o servidores públicos se trasladan los servicios que las entidades públicas desarrollan hacia los ciudadanos en general