Metallointercalator [Ru(dppz)2(PIP)]2+ Renders BRCA Wild-Type Triple-Negative Breast Cancer Cells Hypersensitive to PARP Inhibition

There is a need to improve and extend the use of clinically-approved poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi), including for BRCA wild-type triple-negative breast cancer (TNBC). The demonstration that ruthenium(II) polypyridyl complex (RPC) metallo-intercalators can rapidly stall DNA replication fork progression provides the rationale for their combination alongside DNA damage response (DDR) inhibitors to achieve synergism in cancer cells. The aim of the present study was to evaluate use of the multi-intercalator [Ru(dppz)2(PIP)]2+ (dppz = dipyrido[3,2-a:2′,3′-c]phenazine, PIP = (2-(phenyl)imidazo[4,5-f][1,10]phenanthroline, Ru-PIP) alongside the PARP inhibitors (PARPi) olaparib and NU1025. Cell proliferation and clonogenic survival assays indicated a synergistic relationship between Ru-PIP and olaparib in MDA-MB-231 TNBC and MCF7 human breast cancer cells. Strikingly, low dose Ru-PIP renders both cell lines hypersensitive to olaparib, with a 300-fold increase in olaparib potency in TNBC; the largest non-genetic PARPi enhancement effect described to date. Negligible impact on the viability of normal human fibroblasts was observed for any combination tested. Increased levels of DNA double-strand break (DSB) damage and olaparib abrogation of Ru-PIP activated pChk1 signalling is consistent with PARPi-facilitated collapse of Ru-PIP-associated stalled replication forks. This results in enhanced G2/M cell-cycle arrest, apoptosis and decreased cell motility for the combination treatment compared to single-agent conditions. This work establishes that an RPC metallo-intercalator can be combined with PARPi for potent synergy in BRCA-proficient breast cancer cells, including TNBC

Identification of the genomic mutation in Epha4rb-2J/rb-2J mice

The EphA4 receptor tyrosine kinase is involved in numerous cell-signalling activities during embryonic development. EphA4 has the ability to bind to both types of ephrin ligands, the ephrinAs and ephrinBs. The C57BL/6J-Epha4rb-2J/GrsrJ strain, denoted Epha4rb-2J/rb-2J, is a spontaneous mouse mutant that arose at The Jackson Laboratory. These mutants exhibited a synchronous hind limb locomotion defect or “hopping gait” phenotype, which is also characteristic of EphA4 null mice. Genetic complementation experiments suggested that Epha4rb-2J corresponds to an allele of EphA4, but details of the genomic defect in this mouse mutant are currently unavailable. We found a single base-pair deletion in exon 9 resulting in a frame shift mutation that subsequently resulted in a premature stop codon. Analysis of the predicted structure of the truncated protein suggests that both the kinase and sterile α motif (SAM) domains are absent. Definitive determination of genotype is needed for experimental studies of mice carrying the Epha4rb-2J allele, and we have also developed a method to ease detection of the mutation through RFLP. Eph-ephrin family members are reportedly expressed as numerous isoforms. Hence, delineation of the specific mutation in EphA4 in this strain is important for further functional studies, such as protein–protein interactions, immunostaining and gene compensatory studies, investigating the mechanism underlying the effects of altered function of Eph family of receptor tyrosine kinases on phenotype

External electrical and pharmacological cardioversion for atrial fibrillation, atrial flutter or atrial tachycardias:a network meta-analysis

BackgroundAtrial fibrillation (AF) is the most frequent sustained arrhythmia. Cardioversion is a rhythm control strategy torestore normal/sinus rhythm, and can be achieved through drugs (pharmacological) or a synchronized electricshock (electrical cardioversion).ObjectivesTo assess the efficacy and safety of pharmacological and electrical cardioversion for AF.Search methodsWe searched CENTRAL, MEDLINE, Embase, Conference Proceedings Citation Index-Science (CPCI-S) andthree trials registers (ClinicalTrials.gov, WHO ICTRP and ISRCTN) on 14 February 2023.Selection criteriaWe included randomised controlled trials (RCTs) at individual patient level. Patient populations were aged ≥18years with AF of any type and duration, atrial flutter or other sustained related atrial arrhythmias, not occurring asa result of reversible causes.Data collection and analysisWe used standard Cochrane methodology to collect data and performed a network meta-analysis using thestandard frequentist graph-theoretical approach using the netmeta package in R. We used GRADE to assess thequality of the evidence which we presented in in our summary of findings with a judgement on certainty. Wecalculated differences using risk ratios (RR) and 95% confidence intervals (CI) as well as ranking treatmentsusing a P-score. We assessed clinical and statistical heterogeneity and split the networks for the primaryoutcome and acute procedural success due to concerns about violating the transitivity assumption.Main resultsWe included 112 RCTs (139 records), from which we pooled data from 15,968 patients. Average age was 47 to72 years and proportion of male patients was 38%-92%.79 trials were considered high risk of bias for at least one domain, 32 had no high risk of bias domains, but hadat least one domain classified as uncertain risk, and one study was considered low risk for all domains.For paroxysmal AF (35 trials), when compared to Placebo, AA/AP BTE incremental cardioversion (RR: 2.42;95%CI 1.65 to 3.56), quinidine (RR: 2.23; 95%CI 1.49 to 3.34), ibutilide (RR: 2.00; 95%CI 1.28 to 3.12),propafenone (RR: 1.98; 95%CI 1.67 to 2.34), amiodarone (RR: 1.69; 95%CI 1.42 to 2.02), sotalol (RR: 1.58;95%CI 1.08 to 2.31) and procainamide (RR: 1.49; 95%CI 1.13 to 1.97) likely result in a large increase inmaintenance of sinus rhythm until hospital discharge or end of study follow-up (certainty of evidence: moderate).The effect size was larger for AA/AP incremental and was progressively smaller for the subsequent interventions.Despite low certainty of evidence Antazoline may result in a large increase (RR: 28.60; 95%CI 1.77 to 461.30) inthis outcome. Similarly, low certainty evidence suggests a large increase on this outcome for flecainide (RR: 2.17;95%CI 1.68 to 2.79), vernakalant (RR: 2.13; 95%CI 1.52 to 2.99), and magnesium (RR: 1.73; 95%CI 0.79 to 3.79)on this outcome.For persistent AF (26 trials), one network was created for electrical cardioversion and showed that whencompared to AP BTE incremental energy with patches, AP BTE maximum energy with patches (RR 1.35, 95%CI1.17 to 1.55) likely results in large increase and Active compression AP BTE incremental energy with patches(RR: 1.14, 95%CI 1.00 to 1.131) likely results in an increase in maintenance of sinus rhythm at hospital dischargeor end of study follow-up (certainty of evidence: high). Use of AP BTE incremental with paddles (RR: 1.03, 95%CI0.98 to 1.09; certainty of evidence: low) may lead to a little increase, and AP MDS Incremental paddles (RR: 0.95,95%CI 0.86 to 1.05; certainty of evidence: low) may lead to a little decrease in efficacy. On the other hand, APMDS incremental energy using patches (RR: 0.78, 95%CI 0.70 to 0.87), AA RBW incremental energy withpatches (RR: 0.76, 95%CI 0.66 to 0.88), AP RBW incremental energy with patches (RR: 0.76, 95%CI 0.68 to0.86), AA MDS incremental energy with patches (RR: 0.76, 95%CI 0.67 to 0.86) and AA MDS incremental energywith paddles (RR: 0.68, 95%CI 0.53 to 0.83) probably result in a decrease on this outcome when compared to APBTE incremental energy with patches (certainty of evidence: moderate). The network for pharmacologicalcardioversion showed that Bepridil (RR: 2.29, 95%CI 1.26 to 4.17) and Quindine (RR: 1.53, (95%CI 1.01 to 2.32)probably result in large increase in maintenance of sinus rhythm at hospital discharge or end of study follow-upwhen compared to amiodarone (certainty of evidence: moderate). Dofetilide (RR: 0.79, 95%CI 0.56 to 1.44),Sotalol (RR: 0.89, 95%CI 0.67 to 1.18), Propafenone (RR: 0.79, 95%CI 0.50 to 1.25) and Pilsicainide (RR: 0.39,95%CI 0.02 to 7.01) may result in a reduction of this outcome when compared to amiodarone, but certainty ofevidence is lowFor atrial flutter (14 trials) a network could be created only for antiarrhythmic drugs. Using Placebo as thecommon comparator, ibutilide (RR: 21.45, 95%CI 4.41 to 104.37), propafenone (RR: 7.15, 95%CI 1.27 to 40.10),dofetilide (RR: 6.43, 95%CI 1.38 to 29.91), and sotalol (RR: 6.39, 95%CI 1.03 to 39.78) probably result in a largeincrease in maintenance of sinus rhythm at hospital discharge or end of study follow-up (certainty of evidence:moderate), and procainamide (RR: 4.29, 95%CI 0.63 to 29.03), flecainide (RR 3.57, 95%CI 0.24 to 52.30) andvernakalant (RR: 1.18, 95%CI 0.05 to 27.37) may result in a large increase of maintenance of sinus rhythm athospital discharge or end of study follow-up at (certainty of evidence: low) All tested electrical cardioversionstrategies for atrial flutter had very high efficacy (97.9% to 100%).Mortality (14 deaths) and Stroke or systemic embolism (3 events) at 30 days was extremely low.Data on quality of life were scarce and of uncertain clinical significance. No information was available regardingheart failure readmissions. Data on duration of hospitalization was scarce, low quality, & could not be pooled.Authors' conclusionsDespite the low quality of evidence, this systematic review provides important information on electrical andpharmacological strategies to help patients and physicians deal with AF and atrial flutter.Assessing the patient comorbidity profile, antiarrhythmic drug onset of action & side effect profile vs. need for aphysician with experience in sedation, or anaesthetics support, for electrical cardioversion are key aspects whenchoosing the cardioversion method

How does gender influence the recognition of cardiovascular risk and adherence to self-care recommendations? : a study in polish primary care

Background: Studies have shown a correlation between gender and an ability to change lifestyle to reduce the risk of disease. However, the results of these studies are ambiguous, especially where a healthy lifestyle is concerned. Additionally, health behaviors are strongly modified by culture and the environment. Psychological factors also substantially affect engagement with disease-related lifestyle interventions. This study aimed to examine whether there are differences between men and women in the frequency of health care behavior for the purpose of reducing cardiovascular risk (CVR), as well as cognitive appraisal of this type of risk. We also aimed to identify the psychological predictors of engaging in recommended behavior for reducing the risk of cardiovascular disease after providing information about this risk in men and women. Methods: A total of 134 consecutive eligible patients in a family practice entered a longitudinal study. At initial consultation, the individual’s CVR and associated health burden was examined, and preventive measures were recommended by the physician. Self-care behavior, cognitive appraisal of risk, and coping styles were then assessed using psychological questionnaires. Six months after the initial data collection, the frequency of subjects’ self-care behavior was examined. Results: We found an increase in health care behavior after providing information regarding the rate of CVR in both sexes; this increase was greater for women than for men. Women followed self-care guidelines more often than men, particularly for preventive measures and dietary advice. Women were more inclined to recognize their CVR as a challenge. Coping style, cognitive appraisal, age, level of health behaviors at baseline and CVR values accounted for 48% of the variance in adherence to self-care guidelines in women and it was 52% in men. In women, total risk of CVD values were most important, while in men, cognitive appraisal of harm/loss was most important. Conclusions: Different predictors of acquisition of health behavior are encountered in men and women. Our results suggest that gender-adjusted motivation models influencing the recognition process need to be considered to optimize compliance in patients with CVR

Elbow medial collateral ligament injuries

Elbow medial collateral ligament sprain occurs when the elbow is subjected to a valgus force exceeding the tensile properties of the medial collateral ligament (MCL). This is an injury seen more often in throwing athletes. Understanding the differential diagnosis of medial elbow pain is paramount to diagnose MCL injury as well as addressing other medial elbow pathology. A natural evolution regarding MCL injury has occurred over the past 20 years, with modifications of the original surgical procedure, specificity and sensitivity analysis of imaging modalities, and physical exam maneuvers to diagnose MCL pathology. In order for the MCL literature to advance further, more biomechanical and long-term clinical outcome data for the respective surgical modifications are needed. This review describes MCL injury pathophysiology, patient evaluation, reconstruction indications/contraindications, and current and evolving surgical techniques

First report of field evolved resistance to agrochemicals in dengue mosquito, Aedes albopictus (Diptera: Culicidae), from Pakistan

<p>Abstract</p> <p>Background</p> <p>Agrochemicals have been widely used in Pakistan for several years. This exposes mosquito populations, particularly those present around agricultural settings, to an intense selection pressure for insecticide resistance. The aim of the present study was to investigate the toxicity of representative agrochemicals against various populations of <it>Aedes albopictus </it>(Skuse) collected from three different regions from 2008-2010.</p> <p>Results</p> <p>For organophosphates and pyrethroids, the resistance ratios compared with susceptible Lab-PK were in the range of 157-266 fold for chlorpyrifos, 24-52 fold for profenofos, 41-71 fold for triazofos, and 15-26 fold for cypermethrin, 15-53 fold for deltamethrin and 21-58 fold for lambdacyhalothrin. The resistance ratios for carbamates and new insecticides were in the range of 13-22 fold for methomyl, 24-30 fold for thiodicarb, and 41-101 fold for indoxacarb, 14-27 fold for emamectin benzoate and 23-50 fold for spinosad. Pair wise comparisons of the log LC_50sof insecticides revealed correlation among several insecticides, suggesting a possible cross resistance mechanism. Moreover, resistance remained stable across 3 years, suggesting field selection for general fitness had also taken place for various populations of <it>Ae. albopictus</it>.</p> <p>Conclusion</p> <p>Moderate to high level of resistance to agrochemicals in Pakistani field populations of <it>Ae. albopictus </it>is reported here first time. The geographic extent of resistance is unknown but, if widespread, may lead to problems in future vector control.</p

Assessing the perceptions of a biostatistics and epidemiology module: Views of Year 2 medical students from a Malaysian university. A cross-sectional survey

Background In the era of evidence based medicine, biostatistics and epidemiology are considered as the main elements aiding the health professional to design a research study, understand the literature, and make decisions about patient care. The aim of the study is to explore students' perception about this subject because it plays an important role in determining educational outcome. Methods Data were collected from a self-administered questionnaire distributed among 164 Year 2 medical students. The 5-point Likert scale anchored by Strongly disagree = 1 and Strongly agree = 5 included 36 questions in four domains designed to assess the perception of a biostatistics and epidemiology module amongst students. Results 138 students with ages ranging from 20 to 24 years (Mean = 20.7; SD = 0.62) returned their responses to the questionnaire. This was a response rate of 84.14%. Of the 138 students, 80.7% realized the relevance of the subject to real health issues at the end of the module, while 89.8% believed the module focused on interpretation more than calculation. More than three quarters (78.1%) agreed that lack of practicing exercises was the cause for declining interest in the subject, while only 26.1% believed that lectures were not interesting. Another three quarters (75.4%) believed that there were too many lectures for one day of teaching activities, while 84.6% recommended practical sessions for designing research and data collection. Conclusions This study found that students perceived the relevance of biostatistics and epidemiology to real health issues. The major cause of poor interest in the subject was attributed to the short duration of the course, lack of practicing exercises, and the need for practical data collection sessions. Emphasis should be given to early introduction of projects for data collection and analysis