Geographic distribution of racial differences in mortality in muscle-invasive bladder cancer patients: an opportunity for improvement.

OBJECTIVES: To determine the geographic distribution of muscle-invasive bladder cancer mortality according to race in the United States (US). African Americans (AAs) have up to two times the risk of bladder cancer mortality compared to Caucasians. Bladder cancer mortality increases exponentially once it invades the muscle. Geographic heterogeneity in bladder cancer mortality according to race remains to be determined. DESIGN: Analysis of Surveillance, Epidemiology, and End Results (SEER)-Medicare data for 6,044 patients aged 66-85 diagnosed with clinical stage T2-T4 N0M0 bladder cancer from 1 January 2002 to 31 December 2011. Fine and Gray-competing risks regression models were used to assess the association of race with bladder cancer-specific mortality (BCSM) according to tumor registry. RESULTS: Out of 6,044 patients, 5,408 (89.5%) were Caucasian, 352 (5.82%) were non-Hispanic AA, 85 (1.4%) were Hispanic, and 199 (3.29%) were other. Of the 18 registries, AAs with bladder cancer were largely concentrated in Louisiana (19%), New Jersey (17.9%), and Georgia (17.6%). New Jersey was the only registry where AAs had increased risk of BCSM than Caucasians and only for stage T2 disease: (AHR, 1.74; 95% CI 1.22-2.47, p = 0.002). According to treatment, AAs in New Jersey had worse BCSM than Caucasians when they underwent radical cystectomy (AHR, 2.05; 95% CI 1.26-3.35, p = 0.0039) and radiotherapy or chemotherapy alone (AHR, 1.55; 95% CI 1.03-2.35, p = 0.0367). CONCLUSIONS: We observed geographic variation in bladder cancer mortality which impacted only one registry with one of the largest population of AAs. These findings support further investigation into the social determinants of race (i.e., socioeconomic status and distance to healthcare facility) and culturally centered healthcare decision making which may drive these results.

Race reporting and disparities regarding clinical trials in bladder cancer: a systematic review.

PURPOSE: To systematically review the literature to investigate racial disparities among bladder cancer clinical trial enrollees. METHODS: A systematic review was conducted using Ovid, MEDLINE® to identify clinical trials between 1970 and 2020. Articles were reviewed and were included if they assessed race in their outcomes reporting among bladder cancer patients enrolled in clinical trials. The review was conducted in accordance with the PRISMA statement. RESULTS: We identified 544 clinical trials meeting our initial search criteria, with only 24 (4.4%) studies reporting racial demographic data. Enrollees were largely Caucasian (81-98%), with a strikingly small proportion of enrolled patients consisting of African-Americans (2-8%) and Hispanics (2-5%). Only one of the studies reported results on the efficacy and safety/tolerability of the tested treatment separately for racial groups and performed analyses stratified by race. CONCLUSION: Race is poorly studied in bladder cancer clinical trials. Trial cohorts may not reflect multicultural populations. The potential association between race and efficacy, safety or tolerability of the tested interventions is unknown. Given the up to twofold increase in bladder cancer-specific death among African-Americans, further research is needed to address the impact of race in clinical trials, while encompassing socioeconomic factors and disease risk factor exposures.

Peli1 signaling blockade attenuates congenital zika syndrome.

Zika virus (ZIKV) infects pregnant women and causes devastating congenital zika syndrome (CZS). How the virus is vertically transmitted to the fetus and induces neuronal loss remains unclear. We previously reported that Pellino (Peli)1, an E3 ubiquitin ligase, promotes p38MAPK activation in microglia and induction of lethal encephalitis by facilitating the replication of West Nile virus (WNV), a closely related flavivirus. Here, we found that Peli1 expression was induced on ZIKV-infected human monocytic cells, peripheral blood mononuclear cells, human first-trimester placental trophoblasts, and neural stem cell (hNSC)s. Peli1 mediates ZIKV cell attachment, entry and viral translation and its expression is confined to the endoplasmic reticulum. Moreover, Peli1 mediated inflammatory cytokine and chemokine responses and induced cell death in placental trophoblasts and hNSCs. ZIKV-infected pregnant mice lacking Peli1 signaling had reduced placental inflammation and tissue damage, which resulted in attenuated congenital abnormalities. Smaducin-6, a membrane-tethered Smad6-derived peptide, blocked Peli1-mediated NF-κB activation but did not have direct effects on ZIKV infection. Smaducin-6 reduced inflammatory responses and cell death in placental trophoblasts and hNSCs, and diminished placental inflammation and damage, leading to attenuated congenital malformations in mice. Collectively, our results reveal a novel role of Peli1 in flavivirus pathogenesis and suggest that Peli1 promotes ZIKV vertical transmission and neuronal loss by mediating inflammatory cytokine responses and induction of cell death. Our results also identify Smaducin-6 as a potential therapeutic candidate for treatment of CZS.

Synthesis of fluorescent heterocycles via a Knoevenagel/[4 + 1]-cycloaddition cascade using acetyl cyanide.

A concise one-pot three-component reaction that affords fluorescent indolizines, benzo[d]pyrrolo[2,1-b]thiazoles, and pyrrolo[1,2-a]pyrazines is reported. The methodology involves the formation of a heterocyclic 1-aza-1,3-diene derived from a Knoevenagel condensation between an aldehyde and 2-methyl-ene-cyano aza-heterocycles, followed by [4 + 1] cycloaddition of acetyl cyanide behaving as a non-classical isocyanide replacement.

Zeta Inhibitory Peptide Disrupts Electrostatic Interactions That Maintain Atypical Protein Kinase C in Its Active Conformation on the Scaffold p62.

Atypical protein kinase C (aPKC) enzymes signal on protein scaffolds, yet how they are maintained in an active conformation on scaffolds is unclear. A myristoylated peptide based on the autoinhibitory pseudosubstrate fragment of the atypical PKCζ, zeta inhibitory peptide (ZIP), has been extensively used to inhibit aPKC activity; however, we have previously shown that ZIP does not inhibit the catalytic activity of aPKC isozymes in cells (Wu-Zhang, A. X., Schramm, C. L., Nabavi, S., Malinow, R., and Newton, A. C. (2012) J. Biol. Chem. 287, 12879-12885). Here we sought to identify a bona fide target of ZIP and, in so doing, unveiled a novel mechanism by which aPKCs are maintained in an active conformation on a protein scaffold. Specifically, we used protein-protein interaction network analysis, structural modeling, and protein-protein docking to predict that ZIP binds an acidic surface on the Phox and Bem1 (PB1) domain of p62, an interaction validated by peptide array analysis. Using a genetically encoded reporter for PKC activity fused to the p62 scaffold, we show that ZIP inhibits the activity of wild-type aPKC, but not a construct lacking the pseudosubstrate. These data support a model in which the pseudosubstrate of aPKCs is tethered to the acidic surface on p62, locking aPKC in an open, signaling-competent conformation. ZIP competes for binding to the acidic surface, resulting in displacement of the pseudosubstrate of aPKC and re-engagement in the substrate-binding cavity. This study not only identifies a cellular target for ZIP, but also unveils a novel mechanism by which scaffolded aPKC is maintained in an active conformation.

(Z)-Stereoselective Synthesis of Mono- and Bis-heterocyclic Benzimidazol-2-ones via Cascade Processes Coupled with the Ugi Multicomponent Reaction.

Several novel cascade reactions are herein reported that enable access to a variety of unique mono- and bis-heterocyclic scaffolds. The sequence of cascade events are mediated through acid treatment of an Ugi adduct that affords 1,5-benzodiazepines which subsequently undergo an elegant rearrangement to deliver (E)-benzimidazolones, which through acid-promoted tautomerization convert to their corresponding (Z)-isomers. Moreover, a variety of heterocycles tethered to (Z)-benzimidazole-2-ones are also accessible through similar domino-like processes, demonstrating a general strategy to access significantly new scaffold diversity, each containing four points of potential diversification. Final structures of five scaffolds have been definitively proven by X-ray crystallography.

The Synthesis of Stable, Complex Organocesium Tetramic Acids through the Ugi Reaction and Cesium-Carbonate-Promoted Cascades.

Two structurally unique organocesium carbanionic tetramic acids have been synthesized through expeditious and novel cascade reactions of strategically functionalized Ugi skeletons delivering products with two points of potential diversification. This is the first report of the use of multicomponent reactions and subsequent cascades to access complex, unprecedented organocesium architectures. Moreover, this article also highlights the first use of mild cesium carbonate as a cesium source for the construction of cesium organometallic scaffolds. Relativistic DFT calculations provide an insight into the electronic structure of the reported compounds.

Synthesis of diverse nitrogen-enriched heterocyclic scaffolds using a suite of tunable one-pot multicomponent reactions.

Five elegant and switchable three-component reactions which enable access to a new series of nitrogen-containing heterocycles are reported. A novel one-step addition of an isocyanide to a hydrazine derived Schiff base affords unique six-membered pyridotriazine scaffolds (A and E). With slight modification of reaction conditions and replacement of the nucleophilic isocyanide moiety with different electrophiles (i.e., isocyanates, isothiocyanates, cyclic anhydrides, and acyl chlorides) five-membered triazolopyridine scaffolds (B, D, F, G) are generated in a single step. Furthermore, the use of phenyl hydrazine enables access to dihydroindazole-carboxamides, devoid of a bridge-head nitrogen (C). All protocols are robust and tolerate a diverse collection of reactants, and as such, it is expected that the new scaffolds and associated chemistry will garner high interest from medicinal chemists involved in either file enhancement or specific target-related drug discovery campaigns.

A simple one-pot 2-step N-1-alkylation of indoles with α-iminoketones toward the expeditious 3-step synthesis of N-1-quinoxaline-indoles.

A straightforward procedure for the preparation of N-quinoxaline-indoles is presented. A base-catalyzed one-pot addition of indoles to a preformed α-iminoketone proceeds on the N-1 indole and the subsequent adduct undergoes an acid-mediated deprotection of an internal amino nucleophile, intramolecular cyclization and final oxidation generating N-1-quinoxaline-indoles in good yield.

2,4-Diphenyl-6-trifluoro-methyl-2,3-dihydro-1H,5H-pyrrolo-[3,4-c]pyrrole-1,3-dione.

The asymmetric unit of the title compound, C(19)H(11)F(3)N(2)O(2), contains two crystallographically unique mol-ecules which differ in the rotation of a phenyl ring and a -CF(3) substituent. The dihedral angles involving the pyrrole ring and the attached phenyl ring are 62.82 (8) and 71.54 (7)° in the two molecules. The difference in the rotation of the CF(3) groups with respect to the pyrrolo rings to which they are attached is 23.5(1)°. For one mol-ecule, there is a close contact between an H atom and the centroid of the phenyl ring of an adjacent mol-ecule (2.572 Å). A similar contact is lacking in the second mol-ecule. In the crystal, N-H⋯O inter-actions connect adjacent mol-ecules into a chain normal to (01[Formula: see text]). Crystallographically unique mol-ecules alternate along the hydrogen-bonded chains.

Factors Associated With Urgency Urinary Incontinence Among Older Mexican American Women Aged 65 years and Older.

The purpose of this study was to determine which socio-demographic, clinical, or functional factors are associated with urgency urinary incontinence (UUI) over 20-years of follow-up in a community-dwelling sample of Mexican American women aged 65 years and older without UUI at baseline. We included 1,358 women participants from the Hispanic Established Population for the Epidemiologic Study of the Elderly study conducted in the southwestern of US (Arizona, California, Colorado, New Mexico, and Texas). Measures included self-reported UUI, socio-demographics, smoking status, body mass index, medical conditions, depressive symptoms, physical and cognitive function, and handgrip strength. We used generalized estimating equation models to estimate the odds ratio (OR) and 95% Confidence Interval (CI) of UUI as a function of socioeconomic, clinical, and functional factors. Self-reported UUI increased from 3.1% to 21.9% from baseline (1993/1994) to follow-up (2012/2013). Current smokers, obesity, arthritis, previous heart attacks, and depressive symptoms were factors associated with greater odds of UUI over time. Identification of these factors can help clinicians determine those at high risk of developing UUI. Preventing and/or treating the risk factors early may delay UUI and increase quality of life in this underserved population.

One-Pot Two-Step Multicomponent Process of Indole and Other Nitrogenous Heterocycles or Amines toward α-Oxo-acetamidines.

A cesium carbonate promoted three-component reaction of N-H containing heterocycles, primary or secondary amines, arylglyoxaldehydes, and anilines is reported. The key step involves a tandem sequence of N-1 addition of a heterocycle or an amine to preformed α-iminoketones, followed by an air- or oxygen-mediated oxidation to form α-oxo-acetamidines. The scope of the reaction is enticingly broad, and this novel methodology is applied toward the synthesis of various polycyclic heterocycles.

Recent advances in allosteric androgen receptor inhibitors for the potential treatment of castration-resistant prostate cancer.

Prostate cancer (PC) is the second most frequent cause of male cancer death in the USA. As such, the androgen receptor (AR) plays a crucial role in PC, making AR the major therapeutic target for PC. Current antiandrogen chemotherapy prevents androgen binding to the ligand-binding pocket (LBP) of AR. However, PC frequently recurs despite treatment and it progresses to castration-resistant prostate cancer. Behind this regression is renewed AR signaling initiated via mutations in the LBP. Hence, there is a critical need to improve the therapeutic options to regulate AR activity in sites other than the LBP. Herein, recently disclosed (2010-2015) allosteric AR inhibitors are summarized and a perspective on the potential pharmaceutical intervention at these sites is provided.

Crystal structures of N-tert-butyl-3-(4-fluoro-phenyl)-5-oxo-4-[2-(tri-fluoro-meth-oxy)phen-yl]-2,5-di-hydro-furan-2-carboxamide and 4-(2H-1,3-benzodioxol-5-yl)-N-cyclo-hexyl-5-oxo-3-[4-(tri-fluoro-meth-yl)phen-yl]-2,5-di-hydro-furan-2-carboxamide.

The title compounds, C22H19F4NO4, (I), and C25H22F3NO5, (II), each contain a central nearly planar di-hydro-furan-one ring. The r.m.s. deviation from planarity of these rings is 0.015 Šin (I) and 0.027 Šin (II). The mol-ecules are T-shaped, with the major conformational difference being the O-C-C-O torsion angle [-178.9 (1) in (I) and 37.7 (2)° in (II)]. In the crystal of (I), mol-ecules are linked by N-H⋯O hydrogen bonds, forming chains along [001] while in (II) mol-ecules are linked by N-H⋯O hydrogen bonds, forming chains along [010]. In (II), the tri-fluoro-methyl substituent is disordered over two sets of sites, with refined occupancies of 0.751 (3) and 0.249 (3).