Ethyl (2R,3S)-2-benzoyl-3-(4-bromo­phen­yl)-4-nitro­butano­ate

The title compoud, C19H18BrNO5, was synthesized by an organocatalytic reaction. The aymmetric unit contains two independent mol­ecules, in each of which the carbon between the two carbonyl groups adopts an R configuration, while the adjacent C atom has an S configuration. The dihedral angle between the two benzene rings is different in the two mol­ecules [11.64 (3) and 58.96 (4)°]

Abnormal Calcium Handling and Exaggerated Cardiac Dysfunction in Mice with Defective Vitamin D Signaling

Aim Altered vitamin D signaling is associated with cardiac dysfunction, but the pathogenic mechanism is not clearly understood. We examine the mechanism and the role of vitamin D signaling in the development of cardiac dysfunction. Methods and Results: We analyzed 1α-hydroxylase (1α-OHase) knockout (1α-OHase−/−) mice, which lack 1α-OH enzymes that convert the inactive form to hormonally active form of vitamin D. 1α-OHase−/− mice showed modest cardiac hypertrophy at baseline. Induction of pressure overload by transverse aortic constriction (TAC) demonstrated exaggerated cardiac dysfunction in 1α-OHase−/− mice compared to their WT littermates with a significant increase in fibrosis and expression of inflammatory cytokines. Analysis of calcium (Ca2+) transient demonstrated profound Ca2+ handling abnormalities in 1α-OHase−/− mouse cardiomyocytes (CMs), and treatment with paricalcitol (PC), an activated vitamin D3 analog, significantly attenuated defective Ca2+ handling in 1α-OHase−/− CMs. We further delineated the effect of vitamin D deficiency condition to TAC by first correcting the vitamin D deficiency in 1α-OHase−/− mice, followed then by either a daily maintenance dose of vitamin D or vehicle (to achieve vitamin D deficiency) at the time of sham or TAC. In mice treated with vitamin D, there was a significant attenuation of TAC-induced cardiac hypertrophy, interstitial fibrosis, inflammatory markers, Ca2+ handling abnormalities and cardiac function compared to the vehicle treated animals. Conclusions: Our results provide insight into the mechanism of cardiac dysfunction, which is associated with severely defective Ca2+ handling and defective vitamin D signaling in 1α-OHase−/− mice

H2O2-responsive molecularly engineered polymer nanoparticles as ischemia/reperfusion-targeted nanotherapeutic agents

The main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury is the overproduction of reactive oxygen species (ROS). Hydrogen peroxide (H2O2), the most abundant form of ROS produced during I/R, causes inflammation, apoptosis and subsequent tissue damages. Here, we report H2O2-responsive antioxidant nanoparticles formulated from copolyoxalate containing vanillyl alcohol (VA) (PVAX) as a novel I/R-targeted nanotherapeutic agent. PVAX was designed to incorporate VA and H2O2-responsive peroxalate ester linkages covalently in its backbone. PVAX nanoparticles therefore degrade and release VA, which is able to reduce the generation of ROS, and exert anti-inflammatory and anti-apoptotic activity. In hind-limb I/R and liver I/R models in mice, PVAX nanoparticles specifically reacted with overproduced H2O2 and exerted highly potent anti-inflammatory and anti-apoptotic activities that reduced cellular damages. Therefore, PVAX nanoparticles have tremendous potential as nanotherapeutic agents for I/R injury and H2O2-associated diseases

The Relative Importance of Clinical, Economic, Patient Values and Feasibility Criteria in Cancer Drug Reimbursement in Canada:A Revealed Preferences Analysis of Recommendations of the Pan-Canadian Oncology Drug Review 2011–2017

Background: Most Canadian provinces and territories rely on the pan-Canadian Oncology Drug Review (pCODR) to provide recommendations regarding public reimbursement of cancer drugs. The pCODR review process considers four dimensions of value—clinical benefit, economic evaluation, patient-based values and adoption feasibility—but they do not define weights for individual decision criteria or an acceptable threshold for any of the criteria. Given this implicit review process, it is of interest to understand which factors appear to carry the most weight in pCODR recommendations using a revealed preferences approach. Methods: Using publicly available decision summaries (n = 91) describing submissions and resulting recommendations 2011–2017, we extracted ten attributes that characterized each submission. Using logistic regression, we identified statistically significant attributes and estimated their relative impact in final recommendations. Results: Clinical aspects appear to carry the greatest weight in the decision to reject or not reject, along with aspects of patient value (treatments with no alternatives were less likely to be rejected). Cost effectiveness does not appear to play a role in the initial decision to reject or not reject but is critical in full versus conditional approvals. There is evidence of a maximum acceptable threshold of around $Can140,000 per quality-adjusted life-year (QALY) gained. Conclusion: A set of factors driving pCODR recommendations is identifiable, supporting the consistency of the review process. However, the implicit nature of the review process and the difficulty of extracting and interpreting some of the attribute levels used in the analysis suggests that the process may still lack full transparency

Modeling neurocognitive and neurobiological recovery in addiction

This book focuses on "what to know" and "how to apply" information, prioritizing novel principles and delineating cutting-edge assessment, phenotyping and treatment tools

Hydrogen peroxide-activatable antioxidant prodrug as a targeted therapeutic agent for ischemia-reperfusion injury

Overproduction of hydrogen peroxide (H2O2) causes oxidative stress and is the main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury. Suppression of oxidative stress is therefore critical in the treatment of I/R injury. Here, we report H2O2-activatable antioxidant prodrug (BRAP) that is capable of specifically targeting the site of oxidative stress and exerting anti-inflammatory and anti-apoptotic activities. BRAP with a self-immolative boronic ester protecting group was designed to scavenge H2O2 and release HBA (p-hydroxybenzyl alcohol) with antioxidant and anti-inflammatory activities. BRAP exerted potent antioxidant and anti-inflammatory activity in lipopolysaccharide (LPS)- and H2O2-stimulated cells by suppressing the generation of ROS and pro-inflammatory cytokines. In mouse models of hepatic I/R and cardiac I/R, BRAP exerted potent antioxidant, anti-inflammatory and anti-apoptotic activities due to the synergistic effects of H2O2-scavenging boronic esters and therapeutic HBA. In addition, administration of high doses of BRAP daily for 7 days showed no renal or hepatic function abnormalities. Therefore BRAP has tremendous therapeutic potential as H2O2-activatable antioxidant prodrug for the treatment of I/R injuries

Pediatric supracondylar fractures of the distal humerus

Supracondylar fractures of the humerus are a common pediatric elbow injury that are historically associated with morbidity due to malunion, neurovascular complications, and compartment syndrome. True anteroposterior and lateral radiographs are essential not only for an accurate diagnosis, but also for creating a treatment plan for these injuries. A staging system (based on the lateral radiograph) for classifying the severity of the fracture helps guide definitive management. Nondisplaced fractures are treated initially with a posterior splint, followed by a long-arm casting. Closed reduction and percutaneous pinning is the preferred treatment for displaced or unstable fractures. If there is any question about fracture stability, patients should be seen within 5 days postoperatively for repeat radiographs to ensure that the reduction and pin fixation has been maintained. Understanding the anatomy, radiographic findings, management options, and complications associated with this fracture allow physicians to limit the morbidity associated with this relatively common pediatric injury

Biomarkers of Targeted Therapy and Immuno-Oncology in Cancers Metastatic to the Breast.

The breast is a rare site for metastases, and their molecular characteristics have not been studied yet. Intrinsic molecular genetics, cancer characteristics, and breast tissue immune responses in diverse metastases to the breast have not been previously studied. We identified 64 patients with cancers metastatic to the breast: 51 carcinomas and 13 melanomas. Programmed death ligand 1 (PD-L1), steroid receptors, and HER2/neu expressions were evaluated using immunohistochemistry. Gene sequencing, copy number alterations, microsatellite instability, and tumor mutational burden were performed using next-generation sequencing platforms. The 3 most common primary sites for metastatic carcinomas were lung (37%), ovary (29%), and fallopian tubes/peritoneum (14%). TP53 mutations were commonly (50%) observed among the carcinoma cases, while other mutations were characteristic for the primary cancers (VHL in renal, BRCA1 in the fallopian tube, and BRAF in melanomas). High tumor mutational burden was detected in 5/14 carcinomas and 3/7 melanomas. Tumor cell PD-L1 expression was detected in 6 carcinomas, but not in any of the melanomas, whereas immune cells' expression of PD-L1 was seen in 17 carcinomas and 6 melanomas. Estrogen receptor status was positive in 13/49 carcinomas including 12 adenocarcinomas originating from the ovary and fallopian tube or peritoneum and 1 duodenal neuroendocrine carcinoma. No carcinoma was HER2/neu positive. Intrinsic genetic characteristics of the metastases to the breast followed the pattern commonly seen in primary tumors. Biomarkers of potential benefit to immune checkpoint inhibition therapy were limited to PD-L1-positive non-small cell lung cancer. No common characteristics of the heterogeneous group of tumor metastases to this organ were identified