Discovery and SAR of substituted 3-oxoisoindoline-4-carboxamides as potent inhibitors of poly(ADP-ribose) polymerase (PARP) for the treatment of cancer

Through conformational restriction of a benzamide by formation of a seven-membered hydrogen-bond with an oxindole carbonyl group, a series of PARP inhibitors was designed for appropriate orientation for binding to the PARP surface. This series of compounds with a 3-oxoisoindoline-4-carboxamide core structure, displayed modest to good activity against PARP-1 in both intrinsic and cellular assays. SAR studies at the lactam nitrogen of the pharmacophore have suggested that a secondary or tertiary amine is important for cellular potency. An X-ray structure of compound 1e bound to the protein confirmed the formation of a seven-membered intramolecular hydrogen bond. Though revealed previously in peptides, this type of seven-membered intramolecular hydrogen bond is rarely observed in small molecules. Largely due to the formation of the intramolecular hydrogen bond, the 3-oxoisoindoline-4-carboxamide core structure appears to be planar in the X-ray structure. An additional hydrogen bond interaction of the piperidine nitrogen to Gly-888 also contributes to the binding affinity of 1e to PARP-1.     

The alpha-ketoglutarate dehydrogenase complex in neurodegeneration

Altered energy metabolism is characteristic of many neurodegenerative disorders. Reductions in the key mitochondrial enzyme complex, the alpha-ketoglutarate dehydrogenase complex (KGDHC), occur in a number of neurodegenerative disorders including Alzheimer's Disease (AD). The reductions in KGDHC activity may be responsible for the decreases in brain metabolism, which occur in these disorders. KGDHC can be inactivated by several mechanisms, including the actions of free radicals (Reactive Oxygen Species, ROS). Other studies have associated specific forms of one of the genes encoding KGDHC (namely the DLST gene) with AD, Parkinson's disease, as well as other neurodegenerative diseases. Reductions in KGDHC activity can be plausibly linked to several aspects of brain dysfunction and neuropathology in a number of neurodegenerative diseases. Further studies are needed to assess mechanisms underlying the sensitivity of KGDHC to oxidative stress and the relation of KGDHC deficiency to selective vulnerability in neurodegenerative diseases.     

Light-regulated interaction of Dmoesin with TRP and TRPL channels is required for maintenance of photoreceptors

Recent studies in Drosophila melanogaster retina indicate that absorption of light causes the translocation of signaling molecules and actin from the photoreceptor's signaling membrane to the cytosol, but the underlying mechanisms are not fully understood. As ezrin-radixin-moesin (ERM) proteins are known to regulate actin-membrane interactions in a signal-dependent manner, we analyzed the role of Dmoesin, the unique D. melanogaster ERM, in response to light. We report that the illumination of dark-raised flies triggers the dissociation of Dmoesin from the light-sensitive transient receptor potential (TRP) and TRP-like channels, followed by the migration of Dmoesin from the membrane to the cytoplasm. Furthermore, we show that light-activated migration of Dmoesin results from the dephosphorylation of a conserved threonine in Dmoesin. The expression of a Dmoesin mutant form that impairs this phosphorylation inhibits Dmoesin movement and leads to light-induced retinal degeneration. Thus, our data strongly suggest that the light- and phosphorylation-dependent dynamic association of Dmoesin to membrane channels is involved in maintenance of the photoreceptor cells.     

The Price of a Neglected Zoonosis: Case-Control Study to Estimate Healthcare Utilization Costs of Human Brucellosis

Human brucellosis has reemerged as a serious public health threat to the Bedouin population of southern Israel in recent years. Little is known about its economic implications derived from elevated healthcare utilization (HCU). Our objective was to estimate the HCU costs associated with human brucellosis from the insurer perspective. A case-control retrospective study was conducted among Clalit Health Services (CHS) enrollees. Brucellosis cases were defined as individuals that were diagnosed with brucellosis at the Clinical Microbiology Laboratory of Soroka University Medical Center in the 2010–2012 period (n = 470). Control subjects were randomly selected and matched 1:3 by age, sex, clinic, and primary physician (n = 1,410). HCU data, demographic characteristics and comorbidities were obtained from CHS computerized database. Mean±SD age of the brucellosis cases was 26.6±17.6 years. 63% were male and 85% were Bedouins. No significant difference in Charlson comorbidity index was found between brucellosis cases and controls (0.41 vs. 0.45, respectively, P = 0.391). Before diagnosis (baseline), the average total annual HCU cost of brucellosis cases was slightly yet significantly higher than that of the control group ($439 vs. $382, P<0.05), however, no significant differences were found at baseline in the predominant components of HCU, i.e. hospitalizations, diagnostic procedures, and medications. At the year following diagnosis, the average total annual HCU costs of brucellosis cases was significantly higher than that of controls ($1,327 vs. $380, respectively, P<0.001). Most of the difference stems from 7.9 times higher hospitalization costs (p<0.001). Additional elevated costs were 3.6 times higher laboratory tests (P<0.001), 2.8 times higher emergency room visits (P<0.001), 1.8 times higher medication (P<0.001) and 1.3 times higher diagnostic procedures (P<0.001). We conclude that human brucellosis is associated with elevated HCU costs. Considering these results in cost-effective analyses may be crucial for both reducing health inequities and optimal allocation of health systems’ scarce resources.     

Incongruity between Affinity Patterns Based on Mandibular and Lower Dental Dimensions following the Transition to Agriculture in the Near East,Anatolia and Europe

While it has been suggested that malocclusion is linked with urbanisation, it remains unclear as to whether its high prevalence began 8,000 years earlier concomitant with the transition to agriculture. Here we investigate the extent to which patterns of affinity (i.e., among-population distances), based on mandibular form and dental dimensions, respectively, match across Epipalaeolithic, Mesolithic, and Neolithic samples from the Near East/Anatolia and Europe. Analyses were conducted using morphological distance matrices reflecting dental and mandibular form for the same 292 individuals across 21 archaeological populations. Thereafter, statistical analyses were undertaken on four sample aggregates defined on the basis of their subsistence strategy, geography, and chronology to test for potential differences in dental and mandibular form across and within groups. Results show a clear separation based on mandibular morphology between European hunter-gatherers, European farmers, and Near Eastern transitional farmers and semi-sedentary hunter-gatherers. In contrast, the dental dimensions show no such pattern and no clear association between the position of samples and their temporal or geographic attributes. Although later farming groups have, on average, smaller teeth and mandibles, shape analyses show that the mandibles of farmers are not simply size-reduced versions of earlier hunter-gatherer mandibles. Instead, it appears that mandibular form underwent a complex series of shape changes commensurate with the transition to agriculture that are not reflected in affinity patterns based on dental dimensions. In the case of hunter-gatherers there is a correlation between inter-individual mandibular and dental distances, suggesting an equilibrium between these two closely associated morphological units. However, in the case of semi-sedentary hunter-gatherers and farming groups, no such correlation was found, suggesting that the incongruity between dental and mandibular form began with the shift towards sedentism and agricultural subsistence practices in the core region of the Near East and Anatolia.     

The Impact of a 24 Month Housing First Intervention on Participants’ Body Mass Index and Waist Circumference: Results from the At Home / Chez Soi Toronto Site Randomized Controlled Trial

Research suggests that individuals experiencing homelessness have high rates of overweight and obesity. Unhealthy weights and homelessness are both associated with increased risk of poor health and mortality. Using longitudinal data from 575 participants at the Toronto site of the At Home/Chez Soi randomized controlled trial, we investigate the impact of receiving a Housing First intervention on the Body Mass Index (BMI) and waist circumference of participants with moderate and high needs for mental health support services. The ANCOVA results indicate that the intervention resulted in no significant change in BMI or waist circumference from baseline to 24 months. The findings suggest a need for a better understanding of factors contributing to overweight, obesity, and high waist circumference in populations who have histories of housing precarity and experience low-income in tandem with other concerns such as mental illness and addictions.

Trial Registration

International Standard Randomized Control Trial Number Register ISRCTN42520374