This study was designed to compare the safety and efficacy of sirolimus-eluting stents (SESs) to paclitaxel-eluting stents (PESs) in percutaneous intervention of saphenous vein graft (SVG) lesions. SVGs develop atherosclerosis at high rates and often require repeat revascularization. Percutaneous intervention with drug-eluting stents has become the preferred method of revascularization due to higher restenosis with bare metal stents and increased morbidity and mortality with repeat coronary artery bypass grafting. We sought to compare the rate of major adverse cardiac events and stent thrombosis between SESs and PESs in patients undergoing SVG intervention. A multicenter analysis of 172 patients with SVG lesions treated with SESs or PESs was performed. The 30-day and 1-year clinical outcomes of 102 patients receiving SESs were compared to those of 70 patients receiving PESs. There was no significant difference in baseline demographic, angiographic, and procedural characteristics between the SES and PES treatment groups. There was no statistical difference in major adverse cardiac events at 30 days and at 1 year (hazard ratio [HR] 1.58, 95% confidence interval [CI] 0.77 to 3.23, log-rank p = 0.21). There was also no difference in survival (HR 1.28, 95% CI 0.39 to 4.25, log-rank p = 0.69) or target vessel revascularization (HR 2.54, 95% CI 0.84 to 7.72, log-rank p = 0.09). In conclusion, this multicenter analysis of real-world patients demonstrated that SESs and PESs have similar clinical outcomes when used in SVG intervention.

Objectives

To evaluate the clinical outcomes in patients with chronic renal insufficiency (CRI) who undergo saphenous vein graft (SVG) intervention with drug-eluting stents (DES).

Background

Patients with CRI have higher rates of major adverse cardiac events (MACE) after percutaneous revascularization. SVG intervention is associated with increased rates of MACE compared with percutaneous revascularization of native arteries. However, the impact of CRI on SVG intervention with DES has not been well delineated.

Methods

Consecutive patients who underwent SVG intervention with DES at five medical centers from April 2003 to December 2007 were included in this analysis.

Results

A total of 172 patients, 39 patients with CRI and a serum creatinine > or =1.5 mg dL(-1), and 133 patients without CRI, underwent SVG intervention with DES. Patients with CRI were more often older, diabetic, and had a longer mean total stent length. At 1 year, patients with CRI had a higher MACE rate (35.9% vs. 15.8%, hazard ratio [HR] 2.48, 95% confidence interval [CI] 1.26-4.88, log rank P = 0.009), mainly driven by higher mortality (20.5% vs. 9.8%, HR 3.41, 95% CI 1.10-10.58, log rank P = 0.024). There was a trend toward higher rates of target vessel revascularization in the CRI group (21.8% vs. 10.3%, HR 2.42, 95% CI 0.94-6.24, log rank P = 0.059). Stent thrombosis rates were not different between patients with and without CRI (2.6% vs. 2.3%, P = 0.8). Multivariable analysis revealed that CRI was the only significant predictor of 1-year MACE (HR 2.2, 95% CI 1.1-4.3; P = 0.03).

Conclusions

Patients with CRI who underwent SVG intervention with DES had higher risks of MACE and death compared with patients with preserved renal function. Further treatment strategies are needed in this high-risk group who undergo SVG intervention with DES.

Leishmaniases are a collection of neglected tropical diseases caused by kinetoplastid parasites in the genus Leishmania. Current chemotherapies are severely limited, and the need for new antileishmanials is of pressing international importance. Bromodomains are epigenetic reader domains that have shown promising therapeutic potential for cancer therapy and may also present an attractive target to treat parasitic diseases. Here, we investigate Leishmania donovani bromodomain factor 5 (LdBDF5) as a target for antileishmanial drug discovery. LdBDF5 contains a pair of bromodomains (BD5.1 and BD5.2) in an N-terminal tandem repeat. We purified recombinant bromodomains of L. donovani BDF5 and determined the structure of BD5.2 by X-ray crystallography. Using a histone peptide microarray and fluorescence polarization assay, we identified binding interactions of LdBDF5 bromodomains with acetylated peptides derived from histones H2B and H4. In orthogonal biophysical assays including thermal shift assays, fluorescence polarization, and NMR, we showed that BDF5 bromodomains bind to human bromodomain inhibitors SGC-CBP30, bromosporine, and I-BRD9; moreover, SGC-CBP30 exhibited activity against Leishmania promastigotes in cell viability assays. These findings exemplify the potential BDF5 holds as a possible drug target in Leishmania and provide a foundation for the future development of optimized antileishmanial compounds targeting this epigenetic reader protein.

Calcium dependent protein kinase 1 (CDPK1) is an essential enzyme in the opportunistic pathogen Toxoplasma gondii. CDPK1 controls multiple processes that are critical to the intracellular replicative cycle of T. gondii including secretion of adhesins, motility, invasion, and egress. Remarkably, CDPK1 contains a small glycine gatekeeper residue in the ATP binding pocket making it sensitive to ATP-competitive inhibitors with bulky substituents that complement this expanded binding pocket. Here we explored structure-activity relationships of a series of pyrazolopyrimidine inhibitors of CDPK1 with the goal of increasing selectivity over host enzymes, improving antiparasite potency, and improving metabolic stability. The resulting lead compound 24 exhibited excellent enzyme inhibition and selectivity for CDPK1 and potently inhibited parasite growth in vitro. Compound 24 was also effective at treating acute toxoplasmosis in the mouse, reducing dissemination to the central nervous system, and decreasing reactivation of chronic infection in severely immunocompromised mice. These findings provide proof of concept for the development of small molecule inhibitors of CDPK1 for treatment of CNS toxoplasmosis.

Controlling the properties of heavy element complexes, such as those containing berkelium, is challenging because relativistic effects, spin-orbit and ligand-field splitting, and complex metal-ligand bonding, all dictate the final electronic states of the molecules. While the first two of these are currently beyond experimental control, covalent M‒L interactions could theoretically be boosted through the employment of chelators with large polarizabilities that substantially shift the electron density in the molecules. This theory is tested by ligating Bk^III with 4'-(4-nitrophenyl)-2,2':6',2"-terpyridine (terpy*), a ligand with a large dipole. The resultant complex, Bk(terpy*)(NO₃)₃(H₂O)·THF, is benchmarked with its closest electrochemical analog, Ce(terpy*)(NO₃)₃(H₂O)·THF. Here, we show that enhanced Bk‒N interactions with terpy* are observed as predicted. Unexpectedly, induced polarization by terpy* also creates a plane in the molecules wherein the M‒L bonds trans to terpy* are shorter than anticipated. Moreover, these molecules are highly anisotropic and rhombic EPR spectra for the Ce^III complex are reported.

Vulvar squamous cell cancer (VSC) accounts for 90% of vulvar cancers. Next-generation sequencing studies of VSC imply human papillomavirus (HPV) and p53 status play separate roles in carcinogenesis and prognosis. We sought to describe the genomic landscape and analyze the immunologic profiles of VSC with respect to HPV and p53 status. A total of 443 VSC tumors underwent tumor profiling. Next-generation sequencing was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor samples. PD-L1, microsatellite instability were tested by fragment analysis, IHC, and next-generation sequencing. Tumor mutational burden-high was defined as >10 mutations per MB. HPV 16/18 positive (HPV+) status was determined using whole exome sequencing on 105 samples. Three cohorts were identified from 105 samples with known HPV: HPV+, HPV-/p53wt, and HPV-/p53mt. Where HPV and p53 status were examined, TP53 mutations were exclusive of HPV+ tumors. In all, 37% of samples were HPV+. Among the 66 HPV- tumors, 52 (78.8%) were HPV-/p53mt and 14 (21.2%) were HPV-/p53wt. The HPV-/p53wt cohort had a higher rate of mutations in the PI3KCA gene (42.9% HPV-/p53wt vs 26.3% HPV+ vs. 5.8% HPV-/p53mt, q =0.028) and alterations in the PI3K/AkT/mTOR pathway (57.1% HPV-/p53wt vs. 34.2% HPV+ vs. 7.7% HPV-/p53mt, q =0.0386) than the other 2 cohorts. Ninety-eight VSC tumors with HPV16/18 information underwent transcriptomic analysis and immune deconvolution method. No differences were observed in immune profiles. The HPV-/p53wt VSC tumors had significantly higher rates of mutations in the PI3KCA gene and alterations in the PI3K/AkT/mTOR pathway, a potential target that merits further investigation in this subgroup.

Purpose

We investigated racial disparities in survival by histology in cervical cancer and examined the factors contributing to these disparities.

Methods

Non-Hispanic Black and non-Hispanic White (hereafter known as Black and White) patients with stage I-IV cervical carcinoma diagnosed between 2004 and 2017 in the National Cancer Database were studied. Survival differences were compared using Cox modeling to estimate hazard ratio (HR) or adjusted HR (AHR) and 95% confidence interval (CI). The contribution of demographic, socioeconomic and clinical factors to the Black vs White differences in survival was estimated after applying propensity score weighting in patients with squamous cell carcinoma (SCC) or adenocarcinoma (AC).

Results

This study included 10,111 Black and 43,252 White patients with cervical cancer. Black patients had worse survival than White cervical cancer patients (HR = 1.40, 95% CI = 1.35-1.45). Survival disparities between Black and White patients varied significantly by histology (HR = 1.20, 95% CI = 1.15-1.24 for SCC; HR = 2.32, 95% CI = 2.12-2.54 for AC, interaction p < 0.0001). After balancing the selected demographic, socioeconomic and clinical factors, survival in Black vs. White patients was no longer different in those with SCC (AHR = 1.01, 95% CI 0.97-1.06) or AC (AHR = 1.09, 95% CI = 0.96-1.24). In SCC, the largest contributors to survival disparities were neighborhood income and insurance. In AC, age was the most significant contributor followed by neighborhood income, insurance, and stage. Diagnosis of AC (but not SCC) at ≥65 years old was more common in Black vs. White patients (26% vs. 13%, respectively).

Conclusions

Histology matters in survival disparities and diagnosis at ≥65 years old between Black and White cervical cancer patients. These disparities were largely explained by modifiable factors.