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2-(4-Benzyloxy-3-methoxyphenyl)-5-(carbethoxyethylene)-7-methoxy-benzofuran (BMBF), a benzofuran derivative, is an intermediate found in the process of total synthesis of ailanthoidol. Benzofuran derivatives are a class of compounds that possess various biological and pharmacological activities. The present study explored the anti-metastasis effects in hepatocellular carcinoma (HCC). Our preliminary findings indicate that BMBF suppresses the proliferation and changes the morphology of Huh7, an HCC cell line with a mutated p53 gene (Y220C). According to scratching motility assay, noncytotoxic concentrations of BMBF significantly inhibited the motility and migration in Huh7 cells. BMBF upregulated the expression of E-cadherin and downregulated the expression of vimentin, Slug, and MMP9, which are associated with epithelial-mesenchymal-transition (EMT) and metastasis in Huh7 cells. BMBF decreased the expression of integrin α7 and deactivated its downstream signal FAK/AKT and inhibited p53 protein levels. Cell transfection with p53 siRNA resulted in prevention of cell invasion because of the reduced expression of integrin α7, Slug, and MMP-9 in Huh7 cells. BMBF had anti-metastatic effects in PLC/PRF/5, an HCC cell line with R249S, a mutated p53 gene. Our findings indicate that BMBF has anti-metastatic effects in that it downregulates p53 and mediates the suppression of integrin α7, EMT, and MMP-9 in HCC cells with mutated p53 gene.

Supplementary Figure 1 lists the sequencing gene alignments separated into exons and depicting primer pairs used.

Table 1 lists patient demographics of tumor microarray. Table 2 lists univariate and multivariate analysis of tumor microarray.

Purpose: The transcriptional regulation mediating cancer cell differentiation into distinct molecular subtypes and modulating sensitivity to existing treatments is an enticing therapeutic target. Our objective was to characterize the ability of the forkhead/winged transcription factor FOXP3 to modulate the differentiation of bladder cancer.Experimental Design: Expression of FOXP3 was analyzed by immunohistochemistry in a tumor microarray of 587 samples and overall survival in a subset of 187 patients following radical cystectomy. Functional assays were performed in SW780 and HT1376 cell lines in vitro and in vivo and gene expression profiling performed by RNA-Seq. Validation was undertaken using gene expression profiles of 131 patients from The Cancer Genome Atlas (TCGA) consortium in bladder cancer.Results: FOXP3 expression correlates with bladder cancer stage and inversely with overall survival, with biased expression of the FOXP3Δ3 isoform. Functional assays of FOXP3Δ3 demonstrated resistance to chemotherapy in vitro, whereas subcutaneous xenografts overexpressing FOXP3Δ3 developed larger and more poorly differentiated bladder cancers. RNA expression profiling revealed a unique FOXP3Δ3 gene signature supporting a role in chemotherapy resistance. Accordingly, knockdown of Foxp3 by siRNA in HT1376 cells conferred sensitivity to cisplatin- and gemcitabine-induced cytotoxicity. Validation in TCGA dataset demonstrated increased expression of FOXP3 in subtypes II to IV and skewing of molecular subtypes based on FOXP3Δ3-specific gene expression.Conclusions: (i) Biased expression of the FOXP3Δ3 isoform in bladder cancer inversely correlates with overall survival, (ii) FOXP3Δ3 induces a unique gene program that mediates cancer differentiation, and (iii) FOXP3Δ3 may augment chemotherapy resistance. Clin Cancer Res; 22(21); 5349–61. ©2016 AACR.

Supplementary Figure 2 shows representative histology of tumor microarray and provides controls for immunoblot, qPCR, and antibodies. Supplementary Figure 3 characterizes the created SW780 overexpressed cell lines. Supplementary Figure 4 shows sample immunofluorescence depicting FOXP3 localization. Supplementary Figure 5 shows SW780 RNA Seq alignment statistics. Supplementary Figure 6 shows migration assay in SW780 overexpressed cells. Supplementary Figure 7 shows FOXP3del3 network analyses. Supplementary Figure 8 shows FOXP3 knockdown efficiency. Supplementary Figure 9 shows HT1376 RNA Seq alignment statistics. Supplementary Figure 10 shows dendrogram between FOXP3 overexpressed cells and TCGA.

Background and ObjectivesThis scoping review aimed to chart the scientific literature on the association between workplace demands with cognitive health, and whether race and ethnicity have a direct or indirect relationship between occupational complexity and cognitive health.Research Design and MethodsPRISMA scoping review guided this study. Peer-reviewed articles were drawn from 5 databases. Inclusion criteria were populations aged 18 and older, U.S.-based studies, a comprehensive conceptualization of workplace demands, and cognitive health outcomes. All articles were screened by title and abstract; qualifying articles proceeded to full-text review.ResultsThe majority of studies drew from theories that did not interrogate heterogeneity and minority aging experiences. Consequently, the majority of studies did not include race and ethnicity in their analyses. A small and growing body of research drew from critical perspectives and interrogated cognitive health inequities by race and ethnicity within the context of workplace demands. The association between workplace demands and cognitive health is not linear when race and ethnicity are examined. Emerging evidence suggests interventions to improve substantive complexity among racial and ethnic minorities, and individuals with low education are a promising avenue for intervention research.Discussion and ImplicationsWe discuss integrating emerging theories, such as minority stress and revised social determinants of health frameworks, to sharpen the focus and broaden our understanding on racial and ethnic cognitive health inequities in an emerging area of prevention research. This research can advance our basic understanding of preventable health inequities as well as provide important information for interventions.

Gallbladder mucocele (GBM) is a common biliary disorder in dogs that can be categorized into 6 types, but the value of this classification scheme remains unknown. Cholecystectomy is associated with high death rates and warrants additional interrogation.Investigate the clinical value of ultrasonographic diagnosis of type of GBM and identify prognostic factors in dogs with GBM undergoing cholecystectomy.Two hundred sixteen dogs.Retrospective cohort study. Dogs with GBM diagnosed from 2014 to 2019 at 6 veterinary referral hospitals in Asia. Ultrasonogram images were reviewed and a GBM type (ie, types I-VI) assigned.Dogs with GBM type V as compared to I (OR, 8.6; 95% CI, 2.6-27.8; P .001) and III (OR, 10.0; 95% CI, 2.5-40.8; P = .001), and dogs with type VI compared to I (OR, 10.5; 95% CI, 1.8-61.2; P = .009) and III (OR, 12.3; 95% CI, 1.8-83.9; P = .01) were more likely to exhibit signs of biliary tract disease. Independent predictors of death after cholecystectomy included age (OR, 2.81; 95% CI, 1.41-5.59; P = .003) and intraoperative systolic blood pressure (SBP) nadir. There was an interaction between SBP nadir and gallbladder rupture; SBP nadir in dogs with (OR, 0.92; 95% CI, 0.89-0.94; P .001) and without (OR, 0.88; 95% CI, 0.82-0.93; P .001) gallbladder rupture.Increasing developmental stage of GBM could be associated with an increased likelihood of biliary tract related clinical signs. Nadir SBP deserves further investigation as a prognostic or potentially modifiable variable, particularly in the presence of gallbladder rupture.

Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

Simple methods for desalting HTL-derived biocrudes from food waste improve their properties and reduce hydrotreating demands, bringing them toward use as marine fuels.

To examine the relationship between craniofacial skeletal anatomy and objective measures of pharyngeal collapse obtained during drug‐induced sleep endoscopy. We hypothesized that transverse maxillary deficiency and an increased pharyngeal length will be associated with higher levels of pharyngeal collapsibility. Cross‐sectional analysis in a prospective cohort. University Hospital. A cross‐sectional analysis was conducted in a cohort of consecutive patients from the positive airway pressure (PAP) alternatives clinic who underwent computed tomography (CT) analysis and drug‐induced sleep endoscopy for characterization of upper airway collapsibility. PAP titration was used to determine pharyngeal critical pressure (PCRIT) and pharyngeal opening pressure (PhOP). CT metrics included: Transverse maxillary dimensions (interpremolar and intermolar distances) and pharyngeal length (posterior nasal spine to hyoid distance). The cohort (n = 103) of severe obstructive sleep apnea (Apnea and Hipopnea Index 32.1 ± 21.3 events/h) was predominantly male (71.8%), Caucasian (81.6%), middle‐aged (54.4 ± 14.3 years), and obese (body mass index [BMI] = 30.0 ± 4.9 kg/m2). Reduced transverse maxillary dimensions were associated with higher PCRIT (intermolar distance: β [95% confidence interval, CI] = −.25 [−0.14, −0.36] cmH2O/mm; p = .03) and PhOP (Interpremolar distance: β = −.25 [−0.14, −0.36] cmH2O/mm; p = .02). Longer pharyngeal length was also associated with higher PCRIT (β = .11 [0.08, 0.14] cmH2O/mm, p = .04) and PhOP (β [95% CI] = .06 [0.03, 0.09] cmH2O/mm, p = .04). These associations persisted after adjustments for sex, age, height, and BMI. Our results further the concept that skeletal restriction in the transverse dimension and hyoid descent are associated with elevations in pharyngeal collapsibility during sleep, suggesting a role of transverse deficiency in the pathogenesis of airway obstruction.

BACKGROUND Haem oxygenase (HO)-1 is a rate-limiting enzyme for degrading haem into carbon monoxide. Subjects with longer GT repeats in the HO-1 gene (HMOX1) promoter are more likely to have coronary artery disease (CAD) and cardiovascular events. METHODS We retrospectively enrolled CAD subjects with an abnormal ejection fraction (EF) 30 repeats). In Cox regression analysis, carrier of S allele (hazard ratio 0.665, p = 0.027), a higher EF (hazard ratio 0.037, p = 0.001), and revascularization with PCI were all negatively associated with all-cause death in subjects with CAD and abnormal EF. CONCLUSIONS Carrier of shorter (GT)n repeats of HMOX1 gene promoter was negatively correlated with death events in CAD patients with abnormal EF.

As we anticipate a growing population of older adults, we will see an increase in chronic conditions such as dementia and falls. To meet these public health needs, we must systematically provide screening, education, preventive care, and supportive care for older patients and their caregivers in a primary care setting. This will require a workforce trained in providing for the complex medical and psychosocial needs of an older adult population in an interprofessional and collaborative fashion. By integrating geriatric screening tools into an interdisciplinary Annual Wellness Visit teaching clinic, we were able to successfully improve rates of geriatric screening for dementia, depression, falls, medication reconciliation and advance care planning. We also saw improvements in patient care and satisfaction and provided the opportunity for interprofessional collaboration and education for students in medicine, nursing, pharmacy and social work.

The stemness and metastasis of cancer cells are crucial features in determining cancer progression. Argonaute-2 (AGO2) overexpression was reported to be associated with microRNA (miRNA) biogenesis, supporting the self-renewal and differentiation characteristics of cancer stem cells (CSCs). Ursolic acid (UA), a triterpene compound, has multiple biological functions, including anticancer activity. In this study, we find that UA inhibits the proliferation of MDA-MB-231 and MCF-7 breast cancer cell lines using the CCK-8 assay. UA induced a significant decrease in the fraction of CSC in which it was examined by changes in the expression of stemness biomarkers, including the Nanog and Oct4 genes. UA altered invasion and migration capacities by significant decreases in the levels of epithelial-to-mesenchymal transition (EMT) proteins of slug and vimentin. Furthermore, the co-reduction in oncogenic miRNA levels (miR-9 and miR-221) was a result of the down-modulation in AGO2 in breast cancer cells in vitro. Mechanically, UA increases PTEN expression to inactivate the FAK/PI3K/Akt/mTOR signaling pathway and the decreased level of c-Myc in quantitative RT-PCR and Western blot imaging analyses. Our current understanding of the anticancer potential of UA in interrupting between EMT programming and the state of CSC suggests that UA can contribute to improvements in the clinical practice of breast cancer.

The canonical β-catenin-dependent wingless (Wnt) pathway is associated with endothelial function. We examined the effect of plasma dickkopf-1 (DKK-1), an inhibitor of the Wnt pathway, on the prediction of major adverse cardiac events (MACEs). We enrolled patients who had undergone selective coronary angiography for angina. DKK-1 levels were determined using plasma collected at the outpatient visit after fasting. MACEs served as the primary endpoint. All 470 enrolled patients were divided into four groups according to their median plasma DKK-1 levels and the presence of obstructive coronary artery disease (CAD). Forty-eight patients reached the primary endpoint during a median follow-up time of 4.8 years. Kaplan–Meier survival analysis indicated that the group with high DKK-1 and obstructive CAD had a significantly higher mortality rate than the other three groups (log-rank test p = 0.001). Compared with the low plasma DKK-1 without significant coronary obstruction group, the high DKK-1 with obstructive CAD group had a hazard ratio of 10.640 (95% confidence interval: 1.350–83.874) for MACEs, as determined by multivariable Cox proportional hazard regression analysis. In conclusion, we observed a synergistic effect between high plasma DKK-1 and obstructive CAD on the prediction of MACEs in patients with angina.

Objectives With the development of percutaneously inserted devices, peripheral nerve stimulation (PNS) has been gaining attention within chronic pain literature as a less invasive neurostimulation alternative to spinal column and dorsal root ganglion stimulation. A majority of current PNS literature focuses on targeting individual distal nerves to treat individual peripheral mononeuropathies, limiting its applications. This article discusses our experience treating dermatomal pain with neurostimulation without needing to access the epidural space by targeting the proximal spinal nerve with peripheral nerve stimulation under ultrasound-guidance. Materials and methods A temporary, percutaneous PNS was used to target the proximal spinal nerve in 11 patients to treat various dermatomal pain syndromes in patients seen in an outpatient chronic pain clinic. Four patients received stimulation targeting the lumbar spinal nerves and seven patient received stimulation targeting the cervical or thoracic spinal nerves. Results The case series presents 11 cases of PNS of the proximal spinal nerve. Seven patients, including a majority of the patients with lumbar radiculopathy, had analgesia during PNS. Four patients, all of whom targeted the cervical or thoracic spinal nerves, did not receive analgesia from PNS. Conclusion PNS of the proximal spinal nerve may be an effective modality to treat dermatomal pain in patients who are not candidates for other therapies that require access to the epidural space. This technique was used to successfully treat lumbar radiculopathy, post-herpetic neuralgia, and complex regional pain syndrome.

Gut dysbiosis is a major contributor to adverse chronic kidney disease (CKD) progression, and microbiota-based strategies could be considered as a novel therapeutic and preventative target. In this study, a probiotic screening platform based on gut-derived uremic toxin-reducing probiotics was developed and the underlying mechanism was further verified through a 0.2% adenine-induced CKD mouse model. Two strains (Lactobacillus paracasei and Lactobacillus plantarum) were selected due to their high clearance ability and named Lactobacillus mix (Lm). The results showed that Lm significantly improved the kidney function by reducing kidney injury and fibrotic-related proteins. Furthermore, Lm decreased oxidative stress and proinflammatory reactions and elevated immune responses in the kidney. Importantly, Lm reversed gut dysbiosis and restored the abundance of commensal bacteria, especially short-chain fatty acid producers, leading to improved intestinal barrier integrity via modulation of microbial composition and metabolite production. Taken together, these findings provided evidence that Lm could be a preventive approach against CKD.

Objective Asian Americans are underutilizing mental health services. The aim of the current systematic review was to identify protective and risk factors of mental health help-seeking patterns among the disaggregated Asian Americans and to classify types of help. Methods A systematic literature review was conducted using the PRISMA guidelines. The Health Belief Model served as the theoretical framework for this review. Thirty-four articles were reviewed, and the studies investigated one of the following Asian ethnic subgroups: Chinese, Filipino, Asian Indian, Korean, or Vietnamese. Data were extracted based on the study characteristics, sample characteristics, and protective and risk factors to mental health help-seeking patterns. Results Predisposing factors like female gender, higher levels of English proficiency, and history of mental illness increased the likelihood for help-seeking across several ethnic groups. Interestingly, cues to action and structural factors were under-examined. However, cues to action like having a positive social network did increase the likelihood of using formal support services among Chinese and Filipinx participants. Structural factors like lacking ethnic concordant providers and access to healthcare served as barriers for Korean and Vietnamese participants. Discussion The findings showed a need for ethnic tailored approaches when supporting mental health help-seeking patterns. Asian ethnic group’s immigration status, acculturation level, and psychological barriers to help-seeking should continue to be emphasized. Psychoeducational groups can be beneficial to expand the knowledge base surrounding mental illness and to link group members to culturally responsive resources.

Diabetic retinopathy (DR) is a pathophysiologic vasculopathic process with obscure mechanisms and limited effective therapeutic strategies. Aryl hydrocarbon receptor (AhR) is an important regulator of xenobiotic metabolism and an environmental sensor. The aim of the present study was to investigate the role of AhR in the development of DR and elucidate the molecular mechanism of its downregulation. DR was evaluated in diabetes-induced retinal injury in wild type and AhR knockout (AhR-/-) mice. Retinal expression of AhR was determined in human donor and mice eyes by immunofluorescence since AhR activity was examined in diabetes. AhR knockout (AhRKO) mice were used to induce diabetes with streptozotocin, high-fat diet, or genetic double knockout with diabetes spontaneous mutation (Leprdb) (DKO; AhR-/-×Leprdb/db) for investigating structural, functional, and metabolic abnormalities in vascular and epithelial retina. Structural molecular docking simulation was used to survey the pharmacologic AhR agonists targeting phosphorylated AhR (Tyr245). Compared to diabetic control mice, diabetic AhRKO mice had aggravated alterations in retinal vasculature that amplified hallmark features of DR like vasopermeability, vascular leakage, inflammation, blood-retinal barrier breakdown, capillary degeneration, and neovascularization. AhR agonists effectively inhibited inflammasome formation and promoted AhR activity in human retinal microvascular endothelial cells and pigment epithelial cells. AhR activity and protein expression was downregulated, resulting in a decrease in DNA promoter binding site of pigment epithelium-derived factor (PEDF) by gene regulation in transcriptional cascade. This was reversed by AhR agonists. Our study identified a novel of DR model that target the protective AhR/PEDF axis can potentially maintain retinal vascular homeostasis, providing opportunities to delay the development of DR.