Trauma Functioning and Well-Being in Children Who Receive Mental Health Aid after Natural Disaster or War.

Background: There is worldwide consensus that providing secondary prevention to promote resilience and prevent mental health concerns after a disaster is important. However, data supporting this kind of intervention is largely lacking. The current study evaluates the effectiveness of OperationSAFE, an early intervention for children after community-wide trauma. Methods: Secondary data analyses of data collected during 158 OperationSAFE camps (a five day camp with a curriculum focused on coping with stressors) in five countries and ten disasters between 2015 and 2020 were performed. Data on child trauma-related functioning/well-being were collected by an OperationSAFE in-house developed symptom checklist and completed by counselors about children on the first and last day of the 5-day camp. Results: A total of 16,768 children participated in the camps (mean age 9.4 ± 2.36; 50% male). Trauma-related functioning/well-being improved from day 1 to day 5 (b = 8.44 ± 0.04; p < 0.0001). Older children improved more (b = 0.22 ± 0.01; p < 0.0001). Children in man-made ongoing trauma (war/refugees) situations responded stronger than those after natural disasters (b = 2.24 ± 0.05; p < 0.0001). Negligible effects for gender and the number of days between a traumatic event and the start of camp were found. Conclusions: This is the first study to show in a large and diverse sample that secondary prevention to promote resilience and prevent mental health concerns after a disaster for children is associated with improvements in trauma-related functioning/well-being. Delaying delivery of the intervention did not affect outcomes. Given the uncontrolled nature of the study and lack of long-term outcomes, more studies are needed to corroborate the current findings.

CREBBP/EP300 acetyltransferase inhibition disrupts FOXA1-bound enhancers to inhibit the proliferation of ER+ breast cancer cells.

Therapeutic targeting of the estrogen receptor (ER) is a clinically validated approach for estrogen receptor positive breast cancer (ER+ BC), but sustained response is limited by acquired resistance. Targeting the transcriptional coactivators required for estrogen receptor activity represents an alternative approach that is not subject to the same limitations as targeting estrogen receptor itself. In this report we demonstrate that the acetyltransferase activity of coactivator paralogs CREBBP/EP300 represents a promising therapeutic target in ER+ BC. Using the potent and selective inhibitor CPI-1612, we show that CREBBP/EP300 acetyltransferase inhibition potently suppresses in vitro and in vivo growth of breast cancer cell line models and acts in a manner orthogonal to directly targeting ER. CREBBP/EP300 acetyltransferase inhibition suppresses ER-dependent transcription by targeting lineage-specific enhancers defined by the pioneer transcription factor FOXA1. These results validate CREBBP/EP300 acetyltransferase activity as a viable target for clinical development in ER+ breast cancer.

Discovery of novel N-1 substituted pyrazolopyrimidinones as potent, selective PDE2 inhibitors.

A focused SAR study was conducted on a series of N1-substituted pyrazolopyrimidinone PDE2 inhibitors to reveal compounds with excellent potency and selectivity. The series was derived from previously identified internal leads and designed to enhance steric interactions with key amino acids in the PDE2 binding pocket. Compound 26 was identified as a lead compound with excellent PDE2 selectivity and good physicochemical properties.

Discovery of CPI-1612: A Potent, Selective, and Orally Bioavailable EP300/CBP Histone Acetyltransferase Inhibitor.

The histone acetyltransferases, CREB binding protein (CBP) and EP300, are master transcriptional co-regulators that have been implicated in numerous diseases, such as cancer, inflammatory disorders, and neurodegeneration. A novel, highly potent, orally bioavailable EP300/CBP histone acetyltransferase (HAT) inhibitor, CPI-1612 or 17, was developed from the lead compound 3. Replacement of the indole scaffold of 3 with the aminopyridine scaffold of 17 led to improvements in potency, solubility, and bioavailability. These characteristics resulted in a 20-fold lower efficacious dose for 17 relative to lead 3 in a JEKO-1 tumor mouse xenograft study.

Early Drug-Discovery Efforts towards the Identification of EP300/CBP Histone Acetyltransferase (HAT) Inhibitors.

EP300 and CBP (KAT3A/3B) are two highly homologous, multidomain, epigenetic coregulators that play central roles in transcription through the acetylation of lysine residues on histones and other proteins. Both enzymes have been implicated in human diseases, especially cancer. From a high-throughput screen of 191 000 compounds searching for EP300/CBP histone acetyltransferase (HAT) inhibitors, 18 compounds were characterized by a suite of biochemical enzymatic assays and biophysical methods, including X-ray crystallography and native mass spectrometry. This work resulted in the discovery of three distinct mechanistic classes of EP300/CBP HAT inhibitors, including two classes not previously described. The profiles of an example of each class of inhibitor are described in detail. A subsequent medicinal chemistry effort led to the development of a novel class of orally bioavailable AcCoA-competitive EP300/CBP HAT inhibitors with in vivo activity. We believe that this work will prove to be a useful guide for other groups interested in the development of HAT inhibitors.

Discovery and development of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists for the treatment of diabetes.

A novel series of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists are described. The series was designed to address the suboptimal PK (pharmacokinetic) and off-target profile of a class of N-aryl-benzo-[1,4]-oxazepine-4-carboxamides, represented by 1, that were identified from a high-throughput screen of the Merck compound collection for GPR142 agonists. This work led to the discovery of 3-phenoxy-benzo-[1,2,4]-triazolo-[1,4]-oxazepine 47, a potent GPR142 agonist with an off-target and PK profile suitable for in vivo studies. This compound and a related analogue 40 were shown to be active in mouse oral glucose tolerance tests (OGTTs). Furthermore, a GPR142 knock-out mouse OGTT study with compound 40 provides evidence that its glucose-lowering effect is mediated by GPR142.

Discovery of Novel Indoline Cholesterol Ester Transfer Protein Inhibitors (CETP) through a Structure-Guided Approach.

Using the collective body of known (CETP) inhibitors as inspiration for design, a structurally novel series of tetrahydroquinoxaline CETP inhibitors were discovered. An exemplar from this series, compound 5, displayed potent in vitro CETP inhibition and was efficacious in a transgenic cynomologus-CETP mouse HDL PD (pharmacodynamic) assay. However, an undesirable metabolic profile and chemical instability hampered further development of the series. A three-dimensional structure of tetrahydroquinoxaline inhibitor 6 was proposed from (1)H NMR structural studies, and this model was then used in silico for the design of a new class of compounds based upon an indoline scaffold. This work resulted in the discovery of compound 7, which displayed potent in vitro CETP inhibition, a favorable PK-PD profile relative to tetrahydroquinoxaline 5, and dose-dependent efficacy in the transgenic cynomologus-CETP mouse HDL PD assay.

Routine revascularization is unnecessary in the majority of patients requiring zone II coverage during thoracic endovascular aortic repair: a longitudinal outcomes study using United States Medicare population data.

OBJECTIVE: We aimed to evaluate outcomes of thoracic endovascular aortic repair (TEVAR) with left subclavian artery (LSA) coverage without bypass (TEVAR + SUB) to TEVAR with coverage of the LSA with a bypass at the time of the initial procedure or later at a separate procedure (TEVAR + SUB + BYPASS). METHODS: The Centers for Medicare & Medicaid Services inpatient claims for 2006-2007 were queried using Current Procedural Terminology codes for TEVAR, TEVAR + SUB, TEVAR + SUB + BYPASS or later as a separate procedure. RESULTS: A total of 2676 patients underwent TEVAR; 869 (32.5%) underwent TEVAR + SUB and 49 (5.6%) TEVAR + SUB + BYPASS. At the time of the initial procedure, TEVAR + SUB + BYPASS was associated with a higher incidence of stroke compared to TEVAR + SUB (12.8% vs. 3.8 %; p = 0.0033). Among TEVAR + SUB, only 1.93% (50 patients) had a subsequent bypass performed during a one-year follow-up. Overall rates of morbidity (p = 0.004) and mortality (p = 0.011) trended towards significance in favor of TEVAR + SUB. CONCLUSIONS: TEVAR + SUB were associated with lower rates of mortality and complications. Only a small percentage of TEVAR + SUB required a bypass at one year after procedure. Our data suggest that routine LSA bypass during TEVAR is unnecessary and associated with increase morbidity and mortality.

Primary chondrosarcoma of the breast: report of a case and review of the literature.

Sarcomas of the breast are rare, comprising 1% of all breast tumors. Primary chondrosarcomas of the breast account for an extremely rare subset of such tumors, with few reports in the literature. We report the case of a 52 year-old woman with a primary chondrosarcoma of the breast and review the current literature.

Highly regioselective palladium-catalyzed direct arylation of oxazole at C-2 or C-5 with aryl bromides, chlorides, and triflates.

Complementary palladium-catalyzed methods for direct arylation of oxazole with high regioselectivity (>100:1) at both C-5 and C-2 have been developed for a wide range of aryl and heteroaryl bromides, chlorides, iodides, and triflates. C-5 arylation is preferred in polar solvents with phosphines 5 or 6, whereas C-2 arylation is preferred by nonpolar solvents and phosphine 3. This represents the first general method for C-5 selective arylation of oxazole and should see broad applicability in the synthesis of biologically active molecules. Additionally, potential mechanisms for these two competing arylation processes are proposed on the basis of mechanistic observations.

Enantioselective aldehyde alpha-nitroalkylation via oxidative organocatalysis.

The first enantioselective organocatalytic alpha-nitroalkylation of aldehydes has been accomplished. The aforementioned process involves the oxidative coupling of an enamine intermediate, generated transiently via condensation of an amine catalyst with an aldehyde, with a silyl nitronate to produce a beta-nitroaldehyde. Two methods, one that furnishes the syn beta-nitroaldehyde and a second that provides access to the anti isomer, have been developed. Data are presented to support a hypothesis that explains this phenomenon in terms of a silyl group-controlled change in mechanism. Finally, a three-step procedure for the synthesis of both syn- and anti-alpha,beta-disubstituted beta-amino acids is presented.

Whole blood aggregation and coagulation in db/db and ob/ob mouse models of type 2 diabetes.

Type 2 diabetes in humans is associated with a significant hypercoagulable state; however, the effects of this on stroke and cardiovascular disease are not completely understood. The genetic mutations in db/db and ob/ob mice produce metabolic abnormalities similar to type 2 diabetes, but little is known about their platelet or coagulation properties. The objective of this study was therefore to examine platelet function and coagulation in db/db and ob/ob mice to determine the degree of alteration induced by type 2 diabetes. Male db/db and ob/ob mice, 8-16 weeks old, and their respective genetic control mice were used for all experiments. To examine platelet function and coagulation, we measured ADP-induced whole blood aggregation at baseline and after inhibition with aspirin and fucoidan, whole blood coagulation by thromboelastography, and platelet CD61 expression by flow cytometry. Both db/db and ob/ob mice demonstrated significantly less ADP-induced whole blood aggregation compared with control mice (db/db mice, P < 0.001; ob/ob mice, P < 0.01). Aggregation was significantly inhibited with aspirin in all groups; however, fucoidan inhibited aggregation only in control mice. The db/db and ob/ob mice demonstrated significantly less maximal clot strength compared with control mice (P < 0.01), and ob/ob mice demonstrated premature clot fibrinolysis measured by thromboelastography. In conclusion, the db/db and ob/ob type 2 diabetes mouse models do not demonstrate a hypercoagulable state similar to humans with this disease. We caution their use for studying cardiovascular and cerebrovascular disease in the setting of type 2 diabetes.