Quinoxalinone substituted pyrrolizine (4h)-induced dual inhibition of AKT and ERK instigates apoptosis in breast and colorectal cancer by modulating mitochondrial membrane potential.

AKT and ERK 1/2 play a pivotal role in cancer cell survival, proliferation, migration, and angiogenesis. Therefore, AKT and ERK 1/2 are considered crucial targets for cancer intervention. In this study, we envisaged the role of AKT and ERK signaling in apoptosis regulation in presence of compound 4h, a novel synthetic derivative of quinoxalinone substituted spiropyrrolizines exhibiting substantial antiproliferative activity in various cancer cell lines. Structurally 4h is a spiropyrrolizine derivative. Molecular docking analysis revealed that compound 4h shows strong binding affinity with AKT-1 (-9.5 kcal/mol) and ERK2 (-9.0 kcal/mol) via binding at allosteric sites of AKT and active site of ERK2. The implications of 4h binding with these two survival kinases resulted in the obstruction for ATP binding, hence, hampering their phosphorylation dependent activation. We demonstrate that 4h mediated apoptotic induction via disruption in the mitochondrial membrane potential of MCF-7 and HCT-116 cells and 4h-mediated inhibition of survival pathways occurred in a wild type PTEN background and is diminished in PTEN-/- cells. In 4T1 mammary carcinoma model, 4h exhibited pronounced reduction in the tumor size and tumor volume at significantly low doses. Besides, 4h reached the highest plasma concentration of 5.8 µM within a period of 1 h in mice model intraperitoneally. Furthermore, 4h showed acceptable clearance with an adequate elimination half-life and satisfactory pharmacokinetic behaviour, thus proclaiming as a potential lead molecule against breast and colorectal cancer by specifically inhibiting simultaneously AKT and ERK1/2 kinases.

Diversity-Oriented Synthesis of Benzo[f][1,4]oxazepine-, 2H-Chromene-, and 1,2-Dihydroquinoline-Fused Polycyclic Nitrogen Heterocycles under Microwave-Assisted Conditions.

An efficient, diversity-oriented synthesis of oxazepino[5,4-b]quinazolin-9-ones, 6H-chromeno[4,3-b]quinolines, and dibenzo[b,h][1,6]naphthyridines was established involving a substrate-based approach under microwave-assisted and conventional heating conditions in high yields (up to 88%). The CuBr2-catalyzed, chemoselective cascade annulation of O-propargylated 2-hydroxybenzaldehydes and 2-aminobenzamides delivered oxazepino[5,4-b]quinazolin-9-ones involving a 6-exo-trig cyclization-air oxidation-1,3-proton shift-7-exo-dig cyclization sequence. This one-pot process showed excellent atom economy (-H2O) and constructed two new heterocyclic rings (six- and seven-membered) and three new C-N bonds in a single synthetic operation. On the other side of diversification, the reaction between O/N-propargylated 2-hydroxy/aminobenzaldehydes and 2-aminobenzyl alcohols delivered 6H-chromeno[4,3-b]quinolines and dibenzo[b,h][1,6]naphthyridines involving sequential imine formation-[4 + 2] hetero-Diels-Alder reaction-aromatization steps. The influence of microwave assistance was superior to conventional heating, where the reactions were clean, rapid, and completed in 15 min, and the conventional heating required a longer reaction time at a relatively elevated temperature.

"More than just checking the box": community-based organizations on their role in Medicaid redesigns.

New York and Massachusetts 1115 Medicaid demonstration waivers aimed to prioritize social determinants of health and engage community-based organizations to improve health outcomes. This is an evaluation of community-based organizations' public comments regarding their participation in social services delivery within the 1115 waivers. Both states solicited public comments on waiver implementation to date and potential improvements. The research team extracted all publicly available comments (n = 359) made by direct service providers between November 2016 and April 2019. The sample was then limited to only comments that discussed social service provision and health care-social service partnerships (n = 58). Findings are presented in 2 stages: (1) concerns regarding delivery system reform incentive payments funding levels, timing, and flow and (2) perspectives on how states and Medicaid administrators could improve health care-community organization relationships. Resource-dependent, community-based organizations protested insufficient funding. Additional comments identified specific design, structure, and implementation aspects of the 1115 waiver that could improve partnerships. Despite 1115 waivers prioritizing social service integration, community-based organizations still feel underfunded and disenfranchised. Aligning with health care standards requires significant time and effort. Given resource constraints, the state must facilitate these investments. Community organizations' feedback can also offer guidance on waiver strategies in other states.

To address Medicaid enrollees' social needs, New York and Massachusetts have led the way in aiming to integrate community-based organizations into Medicaid policy and financing. In an evaluation examining public comments submitted by community-based organizations to state Medicaid offices, perspectives on participating in 1115 Medicaid demonstration waivers revealed 2 themes (1) financial concerns about funding, timing, and flow of payments and (2) nonfinancial suggestions for enhancing health care and community-based organization partnerships through standardized partnership standards, enhanced governance, and tailored metrics to better address social determinants of health.

Fluorescence "Turn-Off" and Colorimetric Sensor for Fe2+, Fe3+, and Cu2+ Ions Based on a 2,5,7-Triarylimidazopyridine Scaffold.

Two cyanoimidazopyridine-based sensors (SS1 and SS2) were explored for the colorimetric and fluorometric detection of Fe2+, Fe3+, and Cu2+ ions in the semi-aqueous medium. The "turn-off" fluorescence response of both sensors to these ions was due to the restriction in internal charge transfer. Job's plot and semi-empirical calculations revealed that SS1 and SS2 complexed with Cu2+ ions in a 1:1 ratio and Fe2+/3+ ions in a 2:1 ratio, respectively. The sensors were found to have high binding constant (K a) values and low detection limit values. FMO analysis using the semi-empirical quantum mechanics method revealed the decrease in energy gap after complexation with metal ions. Sensor-coated filter paper strips were prepared and analyzed, where the color changes in the strips could be utilized for the real-time detection of Fe2+, Fe3+, and Cu2+ ions.

Experimental Studies of Inter-Rater Agreement in Traditional Chinese Medicine: A Systematic Review.

Objectives: It has been recommended that clinical trials of Traditional Chinese Medicine (TCM) would be more ecologically valid if its characteristic mode of diagnostic reasoning were integrated into their design. In that context, however, it is also widely held that demonstrating a high level of agreement on initial TCM diagnoses is necessary for the replicability that the biomedical paradigm requires for the conclusions from such trials. Our aim was to review, summarize, and critique quantitative experimental studies of inter-rater agreement in TCM, and some of their underlying assumptions. Design: Systematic electronic searches were conducted for articles that reported a quantitative measure of inter-rater agreement across a number of rating choices based on examinations of human subjects in person by TCM practitioners, and published in English language peer-reviewed journals. Publications in languages other than English were not included, nor those appearing in other than peer-reviewed journals. Predefined categories of information were extracted from full texts by two investigators working independently. Each article was scored for methodological quality. Outcome measures: Design features across all studies and levels of inter-rater agreement across studies that reported the same type of outcome statistic were compared. Results: Twenty-one articles met inclusion criteria. Fourteen assessed inter-rater agreement on TCM diagnoses, two on diagnostic signs found upon traditional TCM examination, and five on novel rating schemes derived from TCM theory and practice. Raters were students of TCM colleges or graduates of TCM training programs with 3 or more years experience and licensure. Type of outcome statistic varied. Mean rates of pairwise agreement averaged 57% (median 65, range 19-96) across the 9 studies reporting them. Mean Cohen's kappa averaged 0.34 (median 0.34, range 0.07-0.59) across the seven studies reporting them. Meta-analysis was not possible due to variations in study design and outcome statistics. High risks of bias and confounding, and deficits in statistical reporting were common. Conclusions: With a few exceptions, the levels of agreement were low to moderate. Most studies had significant deficits of both methodology and reporting. Results overall suggest a few design features that might contribute to higher levels of agreement. These should be studied further with better experimental controls and more thorough reporting of outcomes. In addition, methods of complex systems analysis should be explored to more adequately model the relationship between clinical outcomes, and the series of diagnoses and treatments that are the norm in actual TCM practice.