To compare disease burden and biologic use among psoriatic arthritis (PsA) or rheumatoid arthritis (RA) patients recruited to the Corrona registry. Retrospective study of patients with PsA or RA enrolled in Corrona between January 2002 and March 2013 and grouped in 2-year intervals. Clinical outcomes and biologic use were assessed. Biologic use increased over time in both cohorts, with 62 and 52% of patients with PsA and RA, respectively, receiving biologics by 2012-2013. However, 25 and 35% of patients with PsA and RA, respectively, continued to experience moderate/high disease activity. Overall, the progressive increase in biologic use accompanied progressive decreases in Clinical Disease Activity Index (from 14.2 to 10.4 for RA, and 12.4 to 8.1 for PsA) and mean Health Assessment Questionnaire score (from 0.36 to 0.34, and 0.3 to 0.24). Mean patient pain, the proportion of patients reporting morning stiffness, and the mean duration of morning stiffness remained similar for both cohorts. PsA and RA treated in the rheumatology setting had a comparable impact on patient quality of life and functional ability. Disease burden improved with increased biologic utilization in both groups; however, moderate/severe disease remains in a significant proportion of PsA and RA patients.

Nuclear receptor coregulators are master regulators of transcription and selectively interact with the vitamin D receptor (VDR) to modulate cell differentiation, cell proliferation and calcium homeostasis. Herein, we report the syntheses and evaluation of highly potent and selective VDR-coactivator inhibitors based on a recently identified 3-indolylmethanamine scaffold. The most active compound, PS121912, selectively inhibited VDR-mediated transcription among eight other nuclear receptors tested. PS121912 is also selectively disrupting the binding between VDR and the third nuclear receptor interaction domain of the coactivator SRC2. Genetic studies revealed that PS121912 behaves like a VDR antagonist by repressing 1,25-(OH)₂D₃ activated gene transcription. In addition, PS121912 induced apoptosis in HL-60.

OBJECTIVE: To assess the prevalence and correlates of prescription of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and/or glucagon-like peptide 1 receptor agonists (GLP1-RA) in individuals with type 2 diabetes mellitus (T2DM) with and without chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS: This was a cross-sectional analyses of SGLT2i and GLP1-RA prescriptions from 1 January 2019 to 31 December 2020 in the Veterans Health Administration System. The likelihood of prescriptions was examined by the presence or absence of CKD and by predicted risks of atherosclerotic cardiovascular disease (ASCVD) and end-stage kidney disease (ESKD). RESULTS: Of 1,197,880 adults with T2DM, SGLT2i and GLP1-RA were prescribed to 11% and 8% of patients overall, and to 12% and 10% of those with concomitant CKD, respectively. In adjusted models, patients with severe albuminuria were less likely to be prescribed SGLT2i or GLP1-RA versus nonalbuminuric patients with CKD, with odds ratios (ORs) of 0.91 (95% CI 0.89, 0.93) and 0.97 (0.94, 1.00), respectively. Patients with a 10-year ASCVD risk >20% (vs. <5%), had lower odds of SGLT2i use (OR 0.66 [0.61, 0.71]) and GLP1-RA prescription (OR 0.55 [0.52, 0.59]). A 5-year ESKD risk >5%, compared with <1%, was associated with lower likelihood of SGLT2i prescription (OR 0.63 [0.59, 0.67]) but higher likelihood of GLP1-RA prescription (OR 1.53 [1.46, 1.61]). CONCLUSIONS: Among a large cohort of patients with T2DM, prescription of SGLT2i and GLP1-RA was low in those with CKD. We observed a risk-treatment paradox, whereby patients with higher risk of adverse outcomes were less likely to receive these therapies.

Aim

Guideline-directed medical therapy (GDMT) is designed to improve clinical outcomes. The study aim was to assess GDMT prescribing rates and prescribing-persistence predictors in patients with diabetes and chronic kidney disease (CKD) from the Center for Kidney Disease Research, Education, and Hope Registry.

Materials and methods

Data were obtained from adults ≥18 years old with diabetes and CKD between 1 January 2019 and 31 December 2020 (N = 39 158). Baseline and persistent (≥90 days) prescriptions for GDMT, including angiotensin converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB), sodium-glucose cotransporter-2 (SGLT2) inhibitor and glucagon-like peptide 1 (GLP-1) receptor agonist were assessed.

Results

The population age (mean ± SD) was 70 ± 14 years, and 49.6% (n = 19 415) were women. Baseline estimated glomerular filtration rate (2021 CKD-Epidemiology Collaboration creatinine equation) was 57.5 ± 23.0 ml/min/1.73 m² and urine albumin/creatinine 57.5 mg/g (31.7-158.2; median, interquartile range). Baseline and ≥90-day persistent prescribing rates, respectively, were 70.7% and 40.4% for ACE inhibitor/ARB, 6.0% and 5.0% for SGLT2 inhibitors, and 6.8% and 6.3% for GLP-1 receptor agonist (all p < .001). Patients lacking primary commercial health insurance coverage were less likely to be prescribed an ACE inhibitor/ARB [odds ratio (OR) = 0.89; 95% confidence interval (CI) 0.84-0.95; p < .001], SGLT2 inhibitor (OR 0.72; 95% CI 0.64-0.81; p < .001) or GLP-1 receptor agonist (OR 0.89; 95% CI 0.80-0.98; p = .02). GDMT prescribing rates were lower at Providence than UCLA Health.

Conclusions

Prescribing for GDMT was suboptimal and waned quickly in patients with diabetes and CKD. Type of primary health insurance coverage and health system were associated with GDMT prescribing.

Purpose

PS121912 has been developed as selective vitamin D receptor (VDR)-coregulator inhibitor starting from a high throughput screening campaign to identify new agents that modulate VDR without causing hypercalcemia. Initial antiproliferative effects of PS121912 were observed that are characterized herein to enable future in vivo investigation with this molecule.

Methods

Antiproliferation and apoptosis were determined using four different cancer cell lines (DU145, Caco2, HL-60 and SKOV3) in the presence of PS121912, 1,25-(OH)₂D₃, or a combination of 1,25-(OH)₂D₃ and PS121912. VDR si-RNA was used to identify the role of VDR during this process. The application of ChIP enabled us to determine the involvement of coregulator recruitment during transcription, which was investigated by RT-PCR with VDR target genes and those affiliated with cell cycle progression. Translational changes of apoptotic proteins were determined with an antibody array. The preclinical characterization of PS121912 includes the determination of metabolic stability and CYP3A4 inhibition.

Results

PS121912 induced apoptosis in all four cancer cells, with HL-60 cells being the most sensitive. At sub-micromolar concentrations, PS121912 amplified the growth inhibition of cancer cells caused by 1,25-(OH)₂D₃ without being antiproliferative by itself. A knockout study with VDR si-RNA confirmed the mediating role of VDR. VDR target genes induced by 1,25-(OH)₂D₃ were down-regulated with the co-treatment of PS121912. This process was highly dependent on the recruitment of coregulators that in case of CYP24A1 was SRC2. The combination of PS121912 and 1,25-(OH)₂D₃ reduced the presence of SRC2 and enriched the occupancy of corepressor NCoR at the promoter site. E2F transcription factors 1 and 4 were down-regulated in the presence of PS121912 and 1,25-(OH)₂D₃ that in turn reduced the transcription levels of cyclin A and D, thus arresting HL-60 cells in the S or G2/M phase. In addition, proteins with hematopoietic functions such as cyclin-dependent kinase 6, histone deacetylase 9 and transforming growth factor beta 2 and 3 were down-regulated as well. Elevated levels of P21 and GADD45, in concert with cyclin D1, also mediated the antiproliferative response of HL-60 in the presence of 1,25-(OH)₂D₃ and PS121912. Studies at higher concentration of P121912 identified a VDR-independent pathway of antiproliferation that included the enzymatic and transcriptional activation of caspase 3/7.

Conclusion

Overall, we conclude that PS121912 behaves like a VDR antagonist at low concentrations but interacts with more targets at higher concentrations leading to apoptosis mediated by caspase 3/7 activation. In addition, PS121912 showed an acceptable metabolic stability to enable in vivo cancer studies.

Objective

For infants with single ventricle malformations undergoing staged repair, interstage mortality is reported at 2% to 20%. The Single Ventricle Reconstruction trial randomized subjects with a single morphologic right ventricle undergoing a Norwood procedure to a modified Blalock-Taussig shunt (MBTS) or a right ventricle-to-pulmonary artery shunt (RVPAS). The aim of this analysis was to explore the associations of interstage mortality and shunt type, and demographic, anatomic, and perioperative factors.

Methods

Participants in the Single Ventricle Reconstruction trial who survived to discharge after the Norwood procedure were included (n = 426). Interstage mortality was defined as death postdischarge after the Norwood procedure and before the stage II procedure. Univariate analysis and multivariable logistic regression were performed adjusting for site.

Results

Overall interstage mortality was 50 of 426 (12%)-13 of 225 (6%) for RVPAS and 37 of 201 (18%) for MBTS (odds ratio [OR] for MBTS, 3.4; P < .001). When moderate to severe postoperative atrioventricular valve regurgitation (AVVR) was present, interstage mortality was similar between shunt types. Interstage mortality was independently associated with gestational age less than 37 weeks (OR, 3.9; P = .008), Hispanic ethnicity (OR, 2.6; P = .04), aortic atresia/mitral atresia (OR, 2.3; P = .03), greater number of post-Norwood complications (OR, 1.2; P = .006), census block poverty level (P = .003), and MBTS in subjects with no or mild postoperative AVVR (OR, 9.7; P < .001).

Conclusions

Interstage mortality remains high at 12% and is increased with the MBTS compared with the RVPAS if postoperative AVVR is absent or mild. Preterm delivery, anatomic, and socioeconomic factors are also important. Avoiding preterm delivery when possible and close surveillance after Norwood hospitalization for infants with identified risk factors may reduce interstage mortality.

Aim

To investigate the in vivo effects of 3-indolylmethanamines 31B and PS121912 in treating ovarian cancer and leukemia, respectively.

Materials and methods

Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and western blotting were applied to demonstrate the induction of apoptosis. Xenografted mice were investigated to show the antitumor effects of 3-indolylmethanamines. (13)C-Nuclear magnetic resource (NMR) and western blotting were used to demonstrate inhibition of glucose metabolism.

Results

31B inhibited ovarian cancer cell proliferation and activated caspase-3, cleaved poly (ADP-ribose) polymerase 1 (PARP1), and phosphorylated mitogen-activated protein kinases (MAPK), JUN N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38. 31B reduced ovarian cancer xenograft tumor growth and PS121912 inhibited the growth of HL-60-derived xenografts without any sign of toxicity. Compound 31B inhibited de novo glycolysis and lipogenesis mediated by the reduction of fatty acid synthase and lactate dehydrogenase-A expression.

Conclusion

3-Indolylmethanamines represent a new class of antitumor agents. We have shown for the first time the in vivo anticancer effects of 3-indolylmethanamines 31B and PS121912.