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(a) Gating example of flow cytometric analysis for CXCR4+CD45+CD11b+ myeloid cells, neutrophils (CD45+CD11b+Ly6G+F480-.), and macrophages (CD45+CD11b+Ly6G-F480+). (b-d) Flow cytometric analysis of ILCs (CD45+Cd3-Cd90.2+), NK cells (CD45+CD3-NK1.1+) and B cells (CD45+CD3-b220+) in esophagus of different time point mice (n=4-7). (e) Flow cytometric analysis shows an increase trend of CXCR4+CD45+CD11b+ myeloid cell populations in spleen (n=3, age=12 months).

A trend appears that more CXCR4+proliferating cells are present in high-grade dysplasia mice.

Purpose: Barrett's esophagus represents an early stage in carcinogenesis leading to esophageal adenocarcinoma. Considerable evidence supports a major role for chronic inflammation and diverse chemokine pathways in the development of Barrett's esophagus and esophageal adenocarcinoma.Experimental Design: Here we utilized an IL1β transgenic mouse model of Barrett's esophagus and esophageal adenocarcinoma and human patient imaging to analyze the importance of CXCR4-expressing cells during esophageal carcinogenesis.Results: IL1β overexpression induces chronic esophageal inflammation and recapitulates the progression to Barrett's esophagus and esophageal adenocarcinoma. CXCR4 expression is increased in both epithelial and immune cells during disease progression in pL2-IL1β mice and also elevated in esophageal adenocarcinoma patient biopsy samples. Specific recruitment of CXCR4-positive (CXCR4+) immune cells correlated with dysplasia progression, suggesting that this immune population may be a key contributor to esophageal carcinogenesis. Similarly, with progression to dysplasia, there were increased numbers of CXCR4+ columnar epithelial cells at the squamocolumnar junction (SCJ). These findings were supported by stronger CXCR4-related signal intensity in ex vivo fluorescence imaging and autoradiography with advanced dysplasia. Pilot CXCR4-directed PET/CT imaging studies in patients with esophageal cancer demonstrate the potential utility of CXCR4 imaging for the diagnosis and staging of esophageal cancer.Conclusion: In conclusion, the recruitment of CXCR4+ immune cells and expansion of CXCR4+ epithelial cells in esophageal dysplasia and cancer highlight the potential of CXCR4 as a biomarker and molecular target for diagnostic imaging of the tumor microenvironment in esophageal adenocarcinoma. Clin Cancer Res; 24(5); 1048–61. ©2017 AACR.

CXCR4 immunohistochemistry of a patient with EAC that has been imaged by [68Ga]CXCR4-PET/CT showing moderate infiltration with immune cells (open arrow) expressing CXCR4. Only very few epithelial tumor cells were detectable within this biopsy and they did not express CXCR4 (solid arrow)

Supplementary Figure 3 from Use of Macrophages to Target Therapeutic Adenovirus to Human Prostate Tumors

Supplementary Figure 1 from Use of Macrophages to Target Therapeutic Adenovirus to Human Prostate Tumors

New therapies are required to target hypoxic areas of tumors as these sites are highly resistant to conventional cancer therapies. Monocytes continuously extravasate from the bloodstream into tumors where they differentiate into macrophages and accumulate in hypoxic areas, thereby opening up the possibility of using these cells as vehicles to deliver gene therapy to these otherwise inaccessible sites. We describe a new cell-based method that selectively targets an oncolytic adenovirus to hypoxic areas of prostate tumors. In this approach, macrophages were cotransduced with a hypoxia-regulated E1A/B construct and an E1A-dependent oncolytic adenovirus, whose proliferation is restricted to prostate tumor cells using prostate-specific promoter elements from the TARP, PSA, and PMSA genes. When such cotransduced cells reach an area of extreme hypoxia, the E1A/B proteins are expressed, thereby activating replication of the adenovirus. The virus is subsequently released by the host macrophage and infects neighboring tumor cells. Following systemic injection into mice bearing subcutaneous or orthotopic prostate tumors, cotransduced macrophages migrated into hypoxic tumor areas, upregulated E1A protein, and released multiple copies of adenovirus. The virus then infected neighboring cells but only proliferated and was cytotoxic in prostate tumor cells, resulting in the marked inhibition of tumor growth and reduction of pulmonary metastases. This novel delivery system employs 3 levels of tumor specificity: the natural “homing” of macrophages to hypoxic tumor areas, hypoxia-induced proliferation of the therapeutic adenovirus in host macrophages, and targeted replication of oncolytic virus in prostate tumor cells. Cancer Res; 71(5); 1805–15. ©2011 AACR.

Supplementary Figure 5 from Use of Macrophages to Target Therapeutic Adenovirus to Human Prostate Tumors

Supplementary Figure 2 from Use of Macrophages to Target Therapeutic Adenovirus to Human Prostate Tumors

Supplementary Figure 4 from Use of Macrophages to Target Therapeutic Adenovirus to Human Prostate Tumors

Background: Clonidine is a frequently prescribed long-term antihypertensive medication in hemodialysis (HD) patients in the USA, but its safety and efficacy has not been clearly established in the HD population. Objective: To evaluate, we conducted a systematic review and meta-analysis on the safety and efficacy of clonidine in HD patients. Methods: Keyword search of “clonidine” and “dialysis” was conducted through April 2021 in PubMed, Cochrane Library, Web of Science, Scopus, and ClinicalTrials.gov databases. Inclusion criteria were as follows – study design: randomized controlled trials, cohort studies, prospective studies, retrospective studies, or case series; subjects: adult HD patients; main outcome: blood pressure (BP) and safety; language: English; and article type: peer-reviewed publications. Studies that examined the effects of clonidine in populations other than adult HD patients were excluded. Meta-analysis was performed on BP reduction outcomes. Results: Eight studies met the inclusion criteria for the systematic review, including prospective pre-post studies (2), double-blind controlled trial (1), single-blinded placebo-controlled trial (1), crossover open-label clinical trial (1), retrospective analysis (1), and case report series (2). Three studies included in the meta-analysis ranged from 2 to 12 weeks duration, with a collective sample size of 24 (ages 12–77 years). Risk of bias, assessed using the ROBINS-1 tool, was high for all included studies. Significant adverse effects reported included hypotension, light-headedness, drowsiness, dry mouth, rebound hypertension, and contact dermatitis from patch application. Short-term clonidine use was associated with significant improvement in systolic BP (pooled effect: −12.985 mm Hg, 95% CI [−7.878, −18.092], p < 0.001), while changes in diastolic BP were not statistically significant (−11.119 mm Hg, 95% CI [−22.725, 0.487], p = 0.060). No data currently support the long-term efficacy of clonidine in HD patients. This study was unfunded and was developed using PRISMA guidelines and registered on PROSPERO (CRD42018112042). Conclusions: There is no evidence supporting the long-term use of clonidine in the HD population and a significant side-effect profile. There is low-quality evidence demonstrating the efficacy of clonidine in lowering BP in HD patients in short-term use, but significant safety concerns remain. Fluid removal strategies and other antihypertensives should be used over clonidine for long-term BP control in the HD population.

Key points The ingestion of protein potentiates the stimulation of myofibrillar protein synthesis rates after an acute bout of resistance exercise. Protein supplementation (eating above the protein Recommended Dietary Allowance) during resistance training has been shown to maximize lean mass and strength gains in healthy young and older adults. Here, we assessed contractile, oxidative, and structural protein synthesis in skeletal muscle in response to a moderate or higher protein diet during the early adaptive phase of resistance training in middle-aged adults. We report that the stimulation of myofibrillar, mitochondrial, or collagen protein synthesis rates during 0-3 weeks of resistance training is not further enhanced by a higher protein diet. These results show that moderate protein diets are sufficient to support the skeletal muscle adaptive response during the early phase of a resistance training program. Abstract Protein ingestion augments muscle protein synthesis (MPS) rates acutely after resistance exercise and can offset age-related loss in muscle mass. Skeletal muscle contains a variety of protein pools, such as myofibrillar (contractile), mitochondrial (substrate oxidation), and collagen (structural support) proteins, and the sensitivity to nutrition and exercise seems to be dependent on the major protein fraction studied. However, it is unknown how free-living conditions of dietary protein density with habitual resistance exercise mediates muscle protein subfraction synthesis. Therefore, we investigated the effect of moderate (MOD: 1.06 ± 0.22 g·kg-1 ·d-1 ) or high (HIGH: 1.55 ± 0.25 g·kg-1 ·d-1 ) protein intake on daily MPS rates within the myofibrillar (MyoPS), mitochondrial (MitoPS), and collagen (CPS) protein fractions in middle-aged men and women (n = 20, 47 ± 1 y, BMI 28 ± 1 kg·m-2 ) during the early phase (0-3 wks) of a dietary counseling-controlled resistance training program. Participants were loaded with deuterated water, followed by daily maintenance doses throughout the intervention. Muscle biopsies were collected at baseline and after weeks 1, 2, and 3. MyoPS in the HIGH condition remained constant (P = 1.000), but MOD decreased over time (P = 0.023). MitoPS decreased after 0-3 wks when compared to 0-1 wks (P = 0.010) with no effects of protein intake (P = 0.827). A similar decline with no difference between groups (P = 0.323) was also observed for CPS (P = 0.007). Our results demonstrated that additional protein intake above moderate amounts does not potentiate the stimulation of longer-term MPS responses during the early stage of resistance training adaptations in middle-aged adults. This article is protected by copyright. All rights reserved.

The aim of this study was to identify a folate receptor-α (FRα)–selective PET agent potentially suitable for the selection of patients who might profit from FRα-targeted therapies. The 6R and 6S isomers of (18)F-aza-5-methyltetrahydrofolate (MTHF) were assessed regarding their binding to FRα and FRβ, expressed on cancer and inflammatory cells, respectively, and compared with (18)F-AzaFol, the folic acid–based analog. Methods: FR selectivity was investigated using FRα-transfected (RT16) and FRβ-transfected (D4) CHO cells. The cell uptake of (18)F-folate tracers was investigated, and receptor-binding affinities were determined with the nonradioactive analogs. In vitro autoradiography of the (18)F-folate tracers was performed using RT16 and D4 tissue sections. Biodistribution studies and PET/CT imaging of the radiotracers were performed on mice bearing RT16 and D4 xenografts. Results: The uptake of (18)F-6R-aza-5-MTHF was high when using RT16 cells (62% ± 10% of added activity) but much lower when using D4 cells (5% ± 2%). The FRα selectivity of (18)F-6R-aza-5-MTHF was further demonstrated by its approximately 43-fold higher binding affinity to FRα (half-maximal inhibitory concentration [IC(50)], 1.8 ± 0.1 nM) than to FRβ (IC(50), 77 ± 27 nM). The uptake of (18)F-6S-aza-5-MTHF and (18)F-AzaFol was equal in both cell lines (52%–70%), with similar affinities to FRα (IC(50), 2.1 ± 0.4 nM and 0.6 ± 0.3 nM, respectively) and FRβ (0.8 ± 0.2 nM and 0.3 ± 0.1 nM, respectively). The autoradiography signal obtained with (18)F-6R-aza-5-MTHF was 11-fold more intense for RT16 than for D4 tissue sections. Biodistribution data showed high uptake of (18)F-6R-aza-5-MTHF in RT16 xenografts (81% ± 20% injected activity per gram [IA]/g 1 h after injection) but significantly lower accumulation in D4 xenografts (7.3% ± 2.1% IA/g 1 h after injection), which was also visualized using PET. The uptake of (18)F-6S-aza-5-MTHF and (18)F-AzaFol was similar in RT16 (53% ± 10% IA/g and 45% ± 2% IA/g, respectively) and D4 xenografts (77% ± 10% IA/g and 52% ± 7% IA/g, respectively). Conclusion: This study demonstrated FRα selectivity for (18)F-6R-aza-5-MTHF but not for (18)F-6S-aza-5-MTHF or (18)F-AzaFol. This characteristic, together with its favorable tissue distribution, makes (18)F-6R-aza-5-MTHF attractive for clinical translation to enable detection of FRα-positive cancer while preventing undesired accumulation in FRβ-expressing inflammatory cells.

Introduction Patients with kidney failure undergoing maintenance hemodialysis (HD) therapy are routinely counseled to reduce dietary sodium intake to ameliorate sodium retention, volume overload, and hypertension. However, low-sodium diet trials in HD are sparse and indicate that dietary education and behavioral counseling are ineffective in reducing sodium intake. This study aimed to determine whether 4 weeks of low-sodium, home-delivered meals in HD patients reduces interdialytic weight gain (IDWG). Secondary outcomes included changes in dietary sodium intake, thirst, xerostomia, blood pressure, volume overload, and muscle sodium concentration. Methods Twenty HD patients (55 ± 12 years, body mass index [BMI] 40.7 ± 16.6 kg/m2 ) were enrolled in this study. Participants followed a usual (control) diet for the first 4 weeks followed by 4 weeks of three low-sodium, home-delivered meals per day. We measured IDWG, hydration status (bioimpedance), standardized blood pressure (BP), food intake (3-day dietary recall), and muscle sodium (magnetic resonance imaging) at baseline (0 M), after the 4-week period of usual diet (1 M), and after the meal intervention (2 M). Findings The low-sodium meal intervention significantly reduced IDWG when compared to the control period (-0.82 ± 0.14 kg; 95% confidence interval, -0.55 to -1.08 kg; P 0.05). Discussion Low-sodium, home-meal delivery appears to be an effective method for improving volume control and blood pressure in HD patients. Future studies with larger sample sizes are needed to examine the long-term effects of home-delivered meals on these outcomes and to assess cost-effectiveness.

PurposeIt was previously demonstrated that radiation effects can enhance the therapy outcome of immune checkpoint inhibitors. In this study, a syngeneic breast tumor mouse model was used to investigate the effect of [177Lu]Lu-DOTA-folate as an immune stimulus to enhance anti-CTLA-4 immunotherapy.MethodsIn vitro and in vivo studies were performed to characterize NF9006 breast tumor cells with regard to folate receptor (FR) expression and the possibility of tumor targeting using [177Lu]Lu-DOTA-folate. A preclinical therapy study was performed over 70 days with NF9006 tumor-bearing mice that received vehicle only (group A); [177Lu]Lu-DOTA-folate (5 MBq; 3.5 Gy absorbed tumor dose; group B); anti-CTLA-4 antibody (3 × 200 μg; group C), or both agents (group D). The mice were monitored regarding tumor growth over time and signs indicating adverse events of the treatment.Results[177Lu]Lu-DOTA-folate bound specifically to NF9006 tumor cells and tissue in vitro and accumulated in NF9006 tumors in vivo. The treatment with [177Lu]Lu-DOTA-folate or an anti-CTLA-4 antibody had only a minor effect on NF9006 tumor growth and did not substantially increase the median survival time of mice (23 day and 19 days, respectively) as compared with untreated controls (12 days). [177Lu]Lu-DOTA-folate sensitized, however, the tumors to anti-CTLA-4 immunotherapy, which became obvious by reduced tumor growth and, hence, a significantly improved median survival time of mice (> 70 days). No obvious signs of adverse effects were observed in treated mice as compared with untreated controls.ConclusionApplication of [177Lu]Lu-DOTA-folate had a positive effect on the therapy outcome of anti-CTLA-4 immunotherapy. The results of this study may open new perspectives for future clinical translation of folate radioconjugates.

Chronic inflammation induces Barrett’s Esophagus (BE) which can advance to esophageal adenocarcinoma. Elevated levels of interleukin (IL)-1b, IL-6 and IL-8 together with activated nuclear factor-kappaB (NF-κB), have been identified as important mediators of tumorigenesis. The inflammatory milieu apart from cancer cells and infiltrating immune cells contains myofibroblasts (MFs) that express aSMA and Vimentin. As we observed that increased NF-κB activation and inflammation correlates with increased MF recruitment and an accelerated phenotype we here analyze the role of NF-κB in MF during esophageal carcinogenesis in our L2-IL-1B mouse model. To analyze the effect of NF-κB signaling in MFs, we crossed L2-IL-1B mice to tamoxifen inducible Vim-Cre (Vim-CreTm) mice and floxed RelA (p65fl/fl) mice to specifically eliminate NF-κB signaling in MF (IL-1b.Vim-CreTm.p65fl/fl). The interaction of epithelial cells and stromal cells was further analyzed in mouse BE organoids and patient-derived human organoids. Histological scoring of IL-1b.Vim-CreTm.p65fl/fl mice showed a significantly attenuated phenotype compared with L2-IL-1B mice, with mild inflammation, decreased metaplasia and no dysplasia. This correlated with decreased proliferation and increased differentiation in cardia tissue of IL-1b.Vim-CreTm.p65fl/fl compared with L2-IL-1B mice. Distinct changes of cytokines and chemokines within the local microenvironment in IL-1b.Vim-CreTm.p65fl/fl mice reflected the histopathological abrogated phenotype. Co-cultured NF-κB inhibitor treated MF with mouse BE organoids demonstrated NF-κB-dependent growth and migration. MFs are essential to form an inflammatory and procarcinogenic microenvironment and NF-κB signaling in stromal cells emerges as an important driver of esophageal carcinogenesis. Our data suggest anti-inflammatory approaches as preventive strategies during surveillance of BE patients.

Leucine is regarded as an anabolic trigger for the mTORC1 pathway and the stimulation muscle protein synthesis rates. More recently, there has been an interest in underpinning the relevance of branched-chain amino acid (BCAA)-containing dipeptides and their intact absorption into circulation to regulate muscle anabolic responses. We investigated the effects of dileucine and leucine ingestion on postprandial muscle protein turnover. Ten healthy young men (age: 23 ± 3 yr) consumed either 2 g of leucine (LEU) or 2 g of dileucine (DILEU) in a randomized crossover design. The participants underwent repeated blood and muscle biopsy sampling during primed continuous infusions of l-[

Introduction Skeletal muscle loss is common in patients with renal failure who receive maintenance hemodialysis (MHD) therapy. Regular ingestion of protein-rich meals are recommended to help offset muscle protein loss in MHD patients, but little is known about the anabolic potential of this strategy. Methods Eight MHD patients (age: 56 ± 5 years; body mass index [BMI]: 32 ± 2 kg/m2) and 8 nonuremic control subjects (age: 50 ± 2 years: BMI: 31 ± 1 kg/m2) received primed continuous L-[ring-2H5]phenylalanine and L-[1-13C]leucine infusions with blood and muscle biopsy sampling on a nondialysis day. Participants consumed a mixed meal (546 kcal; 20-g protein, 59-g carbohydrates, 26-g fat) with protein provided as L-[5,5,5-2H3]leucine-labeled eggs. Results Circulating dietary amino acid availability was reduced in MHD patients (41 ± 5%) versus control subjects (61 ± 4%; P = 0.03). Basal muscle caspase-3 protein content was elevated (P = 0.03) and large neutral amino acid transporter 1 (LAT1) protein content was reduced (P = 0.02) in MHD patients versus control subjects. Basal muscle protein synthesis (MPS) was ∼2-fold higher in MHD patients (0.030 ± 0.005%/h) versus control subjects (0.014 ± 0.003%/h) (P = 0.01). Meal ingestion failed to increase MPS in MHD patients (absolute change from basal: 0.0003 ± 0.007%/h), but stimulated MPS in control subjects (0.009 ± 0.002%/h; P = 0.004). Conclusions MHD patients demonstrated muscle anabolic resistance to meal ingestion. This blunted postprandial MPS response in MHD patients might be related to high basal MPS, which results in a stimulatory ceiling effect and/or reduced plasma dietary amino acid availability after mixed-meal ingestion.

Purpose The incidence of esophageal adenocarcinoma (EAC) has been increasing for decades without significant improvements in treatment. Barrett’s esophagus (BE) is best established risk factor for EAC, but current surveillance with random biopsies cannot predict progression to cancer in most BE patients due to the low sensitivity and specificity of high-definition white light endoscopy. Methods Here, we evaluated the membrane-bound highly specific Hsp70-specific contrast agent Tumor-Penetrating Peptide (Hsp70-TPP) in guided fluorescence molecular endoscopy biopsy. Results Hsp70 was significantly overexpressed as determined by IHC in dysplasia and EAC compared with non-dysplastic BE in patient samples (n = 12) and in high-grade dysplastic lesions in a transgenic (L2-IL1b) mouse model of BE. In time-lapse microscopy, Hsp70-TPP was rapidly taken up and internalized by human BE dysplastic patient–derived organoids. Flexible fluorescence endoscopy of the BE mouse model allowed a specific detection of Hsp70-TPP-Cy5.5 that corresponded closely with the degree of dysplasia but not BE. Ex vivo application of Hsp70-TPP-Cy5.5 to freshly resected whole human EAC specimens revealed a high (> 4) tumor-to-background ratio and a specific detection of previously undetected tumor infiltrations. Conclusion In summary, these findings suggest that Hsp70-targeted imaging using fluorescently labeled TPP peptide may improve tumor surveillance in BE patients.

Barrett’s esophagus (BE) is the main known precursor condition of esophageal adenocarcinoma (EAC). BE is defined by the presence of metaplasia above the normal squamous columnar junction and has mainly been attributed to gastroesophageal reflux disease and chronic reflux esophagitis. Thus, the rising incidence of EAC in the Western world is probably mediated by chronic esophageal inflammation, secondary to gastroesophageal reflux disease in combination with environmental risk factors such as a Western diet and obesity. However, (at present) risk prediction tools and endoscopic surveillance have shown limited effectiveness. Chemoprevention as an adjunctive approach remains an attractive option to reduce the incidence of neoplastic disease. Here, we investigate the feasibility of chemopreventive approaches in BE and EAC via inhibition of inflammatory signaling in a transgenic mouse model of BE and EAC (L2-IL1B mice), with accelerated tumor formation on a high-fat diet (HFD). L2-IL1B mice were treated with the IL-1 receptor antagonist Anakinra and the nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin or Sulindac. Interleukin-1b antagonism reduced tumor progression in L2-IL1B mice with or without a HFD, whereas both NSAIDs were effective chemoprevention agents in the accelerated HFD-fed L2-IL1B mouse model. Sulindac treatment also resulted in a marked change in the immune profile of L2-IL1B mice. In summary, anti-inflammatory treatment of HFD-treated L2-IL1B mice acted protectively on disease progression. These results from a mouse model of BE support results from clinical trials that suggest that anti-inflammatory medication may be effective in the chemoprevention of EAC.

OBJECTIVES: Yes-Associated Protein (YAP) is implicated as a regulator of the post-exercise skeletal muscle response through mechanical transduction. We recently observed that resistance exercise (RE) increased both total (t) and phosphorylated (p) muscle YAP content, which correlated with extracellular signal-regulated kinase 1/2 (Erk1/2). Other anabolic signaling pathways (i.e., mTORC1) are known to be potentiated by the combined stimuli of RE and protein ingestion during post-exercise recovery. However, the impact of protein ingestion on t- and p-muscle YAP content during recovery from RE is unknown. Therefore, we aimed to determine the nutrient sensitivity of YAP in both an acute and chronic exercise setting in aging skeletal muscle. METHODS: Acute study: 13 untrained older women (59.8 ± 0.5 y) were randomized to perform an acute bout of unilateral RE (3 sets × 12 repetitions at 65% of one repetition maximum) followed by the ingestion of whey protein (0.3 g/kg lean body mass) or water. Muscle biopsies of both the rested and exercised legs were collected before and during the postprandial period. Chronic study: 20 untrained middle-aged men and women (47.5 ± 0.3 y) performed 3 weeks of whole body RE (3 d/wk) with moderate or high protein intake set at 1.2 g/kg/d or 1.6 g/kg/d, respectively. Muscle biopsies were taken weekly in the rested state. Total and phosphorylated YAP(Ser127) and Erk1/2(Thr202/Tyr204) were examined by western blotting. RESULTS: Acute study: Protein ingestion decreased t- and p-YAP compared to the water condition in the non-exercised leg (main effect: P 0.05). There was a decrease in t-Erk1/2 irrespective of condition (P = 0.04). There was no change in p/t ratio of Erk1/2 throughout training. There was a significant correlation between t-Erk1/2 and t-YAP (r = 0.741 and P

Pemphigus is a chronic dermatological disorder caused by an autoimmune response and is associated with a high proportion of comorbidities and fatalities. The aim of this study was to investigate the risk of depression in patients with pemphigus. Data were derived from the National Health Insurance Research Database recorded during the period 2000&ndash, 2010 in Taiwan. Multivariate Cox proportional hazards regression models were used to analyze the data and assess the effects of pemphigus on the risk of depression after adjusting for demographic characteristics and comorbidities. Patients with pemphigus were 1.98 times more likely to suffer from depression than the control group (pemphigus, adjusted HR: 1.99, 95% CI = 1.37&ndash, 2.86). People aged &ge, 65 years were 1.69 times more likely to suffer from depression than those aged 20&ndash, 49 years (&ge, 65 years, adjusted HR: 1.42, 95% CI = 0.92&ndash, 2.21). Female and male patients with pemphigus were respectively 2.02 and 1.91 times more likely to suffer from depression than the control group (female, adjusted HR: 2.09, 95% CI = 1.24&ndash, 3.54, male, adjusted HR: 1.87, 95% CI = 0.97&ndash, 3.60). People with HTN, hyperlipidemia, asthma/COPD, and chronic liver disease were respectively 1.73, 2.3, 2.2, and 1.69 times more likely to suffer from depression than those without these comorbidities (HTN, adjusted HR: 0.75, 95% CI = 0.41&ndash, 1.42, hyperlipidemia, adjusted HR: 1.48, 95% CI = 0.78&ndash, 2.82, asthma/COPD, adjusted HR: 1.4, 95% CI = 0.72&ndash, 2.69, and chronic liver disease, adjusted HR: 1.61, 95% CI = 1.07&ndash, 2.43). There was a significant association between pemphigus and increased risk of depression. Female patients had a higher incidence of depression.

INTRODUCTION Chronic volume overload is a persistent problem in hemodialysis (HD) patients. The purpose of this study was to investigate the impacts of comprehensive volume reduction protocol on HD patient's hydration status and blood pressure (BP). METHODS Twenty-three HD patients (age = 55.7 ± 13.3 years) completed a 6-month comprehensive volume control protocol consisting of: reducing postdialysis weight; reducing BP medication prescriptions; and weekly intradialytic counseling to reduce dietary sodium intake and interdialytic weight gain (IDWG). The primary outcome was volume overload (VO) measured by bioelectrical impedance spectroscopy. Secondary outcomes included: IDWG, postdialysis weight, estimated dry weight (EDW), dietary sodium intake, BP and BP medication prescriptions. FINDINGS From baseline (0M) to 6 months (6M), significant improvements were noted in: VO (0M 3.9 ± 3.9 L vs. 6M 2.6 ± 3.4 L, P = 0.003), postdialysis weight (0M 89.4 ± 23.1 kg vs. 6M 87.6 ± 22.2 kg; P = 0.012), and EDW (0M 89.0 ± 23.2 vs. 6M 86.7 ± 22.5 kg., P = 0.009). There was also a trend for a reduction in monthly averaged IDWG (P = 0.053), and sodium intake (0M 2.9 ± 1.6 vs. 6M 2.3 ± 1.1 g/d, P = 0.125). Neither systolic BP (0M 162 ± 27 vs. 6M 157 ± 23 mmHg, P = 0.405) nor diastolic BP (0M 82 ± 21 vs. 6M 82 ± 19 mmHg, P = 0.960) changed, though there was a significant reduction in the total number of BP medications prescribed (0M 3.0 ± 1.0 vs. 6M 1.5 ± 1.0 BP meds; P = 0.004). DISCUSSION Our volume reduction protocol significantly improved HD patient's hydration status. While BP did not change, the reduction in prescribed BP medication number suggests improved BP control. Despite these overall positive findings, the magnitude of change in most variables was modest. Comprehensive changes in HD clinics may be necessary to realize more clinically significant results.

During a traditional set configuration of resistance exercise (TRD), characterized by a continuous completion of repetitions, a decrease in power output tends to occur throughout a set of repetitions. Inclusion of intraset rest, otherwise known as a cluster set configuration (CLU), counteracts this power decline. However, the effect of a CLU configuration on postexercise myofibrillar protein synthesis rates (MPS) and anabolic signaling has not been investigated. PURPOSE We aimed to determine if any mechanistic differences exist between TRD and CLU signaling events associated with muscle anabolism. METHODS In randomized crossover trials, eight resistance-trained participants (23 ± 1 yr, 81 ± 4.7 kg, body fat: 18% ± 1.9%; 1 repetition maximum [1RM], 150 ± 9.1 kg) performed an acute bout of CLU (4 sets × (2 × 5) repetitions, 30-s intraset rest, 90-s interset rest) and TRD (4 sets × 10 repetitions, 120-s interset rest) barbell back squats at approximately 70% 1RM with total volume load equated during primed continuous L-[ring-C6]phenylalanine infusions. Blood and muscle biopsy samples were collected at rest and after exercise at 0, 2, and 5 h. RESULTS There was no difference in postexercise MPS between the CLU and TRD condition (P > 0.05) and no changes in phosphorylation of mTORC1 downstream targets (p70S6K and 4EBP1). Total and phosphorylated yes-associated protein on Ser127 transiently increased (P < 0.01) immediately after exercise (t = 0) in CLU (~2.1-fold) and TRD condition (~2.2-fold). CONCLUSIONS Our results show that CLU is a viable anabolic option by preserving power output with similar MPS stimulation when compared with the TRD condition in trained young adults.

Purpose: Barrett's esophagus represents an early stage in carcinogenesis leading to esophageal adenocarcinoma. Considerable evidence supports a major role for chronic inflammation and diverse chemokine pathways in the development of Barrett's esophagus and esophageal adenocarcinoma. Experimental Design: Here we utilized an IL1β transgenic mouse model of Barrett's esophagus and esophageal adenocarcinoma and human patient imaging to analyze the importance of CXCR4-expressing cells during esophageal carcinogenesis. Results: IL1β overexpression induces chronic esophageal inflammation and recapitulates the progression to Barrett's esophagus and esophageal adenocarcinoma. CXCR4 expression is increased in both epithelial and immune cells during disease progression in pL2-IL1β mice and also elevated in esophageal adenocarcinoma patient biopsy samples. Specific recruitment of CXCR4-positive (CXCR4+) immune cells correlated with dysplasia progression, suggesting that this immune population may be a key contributor to esophageal carcinogenesis. Similarly, with progression to dysplasia, there were increased numbers of CXCR4+ columnar epithelial cells at the squamocolumnar junction (SCJ). These findings were supported by stronger CXCR4-related signal intensity in ex vivo fluorescence imaging and autoradiography with advanced dysplasia. Pilot CXCR4-directed PET/CT imaging studies in patients with esophageal cancer demonstrate the potential utility of CXCR4 imaging for the diagnosis and staging of esophageal cancer. Conclusion: In conclusion, the recruitment of CXCR4+ immune cells and expansion of CXCR4+ epithelial cells in esophageal dysplasia and cancer highlight the potential of CXCR4 as a biomarker and molecular target for diagnostic imaging of the tumor microenvironment in esophageal adenocarcinoma. Clin Cancer Res; 24(5); 1048–61. ©2017 AACR.

In-depth knowledge of the mechanisms induced by early postischemic cardiac endogenous mesenchymal stem cells (MSCs) in the acutely ischemic heart could advance our understanding of cardiac regeneration. Herein, we aimed to identify, isolate, and initially characterize the origin, kinetics and fate of cardiac MSCs. This was facilitated by in vivo genetic cell fate mapping through green fluorescent protein (GFP) expression under the control of vimentin induction after acute myocardial infarction (MI). Following permanent ligation of the left anterior descending coronary artery in CreER+ mTom/mGFP+ mice, vimentin/GFP+ cells revealed ischemia-responsive activation, survival, and local enrichment inside the peri-infarction border zone. Fluorescence-activated cell sorting (FACS)-isolated vimentin/GFP+ cells could be strongly expanded in vitro with clonogenic precursor formation and revealed MSC-typical cell morphology. Flow-cytometric analyses demonstrated an increase in cardiac vimentin/GFP+ cells in the ischemic heart, from a 0.6% cardiac mononuclear cell (MNC) fraction at 24 h to 1.6% at 72 h following MI. Sca-1+CD45– cells within the vimentin/GFP+ subtype of this MNC fraction increased from 35.2% at 24 h to 74.6% at 72 h after MI. The cardiac postischemic vimentin/GFP+ MNC subtype showed multipotent adipogenic, chondrogenic, and osteogenic differentiation potential, which is distinctive for MSCs. In conclusion, we demonstrated a seemingly proliferative first response of vimentin- induced cardiac endogenous MSCs in the acutely ischemic heart. Genetically, GFP-targeted in vivo cell tracking, isolation, and in vitro expansion of this cardiac MSC subtype could help to clarify their reparative status in inflammation, fibrogenesis, cell turnover, tissue homeostasis, and myocardial regeneration.

OBJECTIVES: There is a myth that obesity equals overnutrition. We conducted a study to examine whether obese people had a higher chance of adherence to recommended daily intake. METHODS: A retrospective cross-sectional study was conducted using data from the Nutrition and Health Survey in Taiwan (NAHSIT) 2014–2016. NAHSIT is a nationwide representative survey aimed to investigate and monitor the nutritional status of Taiwanese people. Fourteen nutrient intakes, including vitamin A, C, D, E, B1, B2, B3, B6, B12, Fe, Mg, Zn, Ca, and P, were evaluated using 24-hour dietary recall. Logistic regression models will be used to determine whether obesity was related to the higher chance of adherence to recommended daily intakes. Stratified analyses were conducted by sex. Obese (body mass index (BMI) ≥ 27 kg/m(2)) and normal-weight (18.5 kg/m(2) ≤ BMI

Background: Physical inactivity is prevalent and linked with a variety of unfavorable clinical outcomes in hemodialysis patients. To increase physical activity (PA) and improve quality of life in this population, intradialytic and out-of-clinic exercise interventions have been implemented in many studies. However, there is still a lack of consensus in the literature on which type of exercise intervention is more feasible and effective. Summary: This review provides a brief overview of intradialytic and out-of-clinic exercise protocols utilized in previous studies. We also examine data related to the feasibility of each approach, and their efficacy for improving cardiovascular health, muscle mass, strength, and physical function. Key Messages: The benefits from most intradialytic and out-of-center exercise training interventions published to date have been modest or inconsistent. Furthermore, neither appears to provide a significant advantage over the other in terms of benefits for cardiovascular health, muscle mass, strength, and physical function. A significant concern is that most intradialytic and out-of-center exercise interventions are mandated exercise prescriptions that include either endurance or resistance training exercises, performed at low-moderate intensities, for a total of 60–135 min of exercise/week. This volume, intensity, and variety of exercise are far less than what is recommended in most PA guidelines. This type of structured activity is also boring for most patients. To enhance the effectiveness of exercise interventions, we suggest using the intradialytic period to provide patients guidance on how they can best incorporate more activity into their lives, based on their individual needs and barriers.

Background & Aims Studies are needed to determine the mechanism by which Barrett’s esophagus (BE) progresses to esophageal adenocarcinoma (EAC). Notch signaling maintains stem cells in the gastrointestinal tract and is dysregulated during carcinogenesis. We explored the relationship between Notch signaling and goblet cell maturation, a feature of BE, during EAC pathogenesis. Methods We measured goblet cell density and levels of Notch messenger RNAs in BE tissues from 164 patients, with and without dysplasia or EAC, enrolled in a multicenter study. We analyzed the effects of conditional expression of an activated form of NOTCH2 (pL2.Lgr5.N2IC), conditional deletion of NOTCH2 (pL2.Lgr5.N2fl/fl), or loss of nuclear factor κB (NF-κB) (pL2.Lgr5.p65fl/fl), in Lgr5+ (progenitor) cells in L2-IL1B mice (which overexpress interleukin 1 beta in esophagus and squamous forestomach and are used as a model of BE). We collected esophageal and stomach tissues and performed histology, immunohistochemistry, flow cytometry, transcriptome, and real-time polymerase chain reaction analyses. Cardia and forestomach tissues from mice were cultured as organoids and incubated with inhibitors of Notch or NF-kB. Results Progression of BE to EAC was associated with a significant reduction in goblet cell density comparing nondysplastic regions of tissues from patients; there was an inverse correlation between goblet cell density and levels of NOTCH3 and JAG2 messenger RNA. In mice, expression of the activated intracellular form of NOTCH2 in Lgr5+ cells reduced goblet-like cell maturation, increased crypt fission, and accelerated the development of tumors in the squamocolumnar junction. Mice with deletion of NOTCH2 from Lgr5+ cells had increased maturation of goblet-like cells, reduced crypt fission, and developed fewer tumors. Esophageal tissues from in pL2.Lgr5.N2IC mice had increased levels of RelA (which encodes the p65 unit of NF-κB) compared to tissues from L2-IL1B mice, and we found evidence of increased NF-κB activity in Lgr5+ cells. Esophageal tissues from pL2.Lgr5.p65fl/fl mice had lower inflammation and metaplasia scores than pL2.Lgr5.N2IC mice. In organoids derived from pL2-IL1B mice, the NF-κB inhibitor JSH-23 reduced cell survival and proliferation. Conclusions Notch signaling contributes to activation of NF-κB and regulates differentiation of gastric cardia progenitor cells in a mouse model of BE. In human esophageal tissues, progression of BE to EAC was associated with reduced goblet cell density and increased levels of Notch expression. Strategies to block this pathway might be developed to prevent EAC in patients with BE.

Summary Background Both psoriasis and asthma are chronic immune-mediated inflammatory diseases. Objectives To evaluate the risk of developing asthma in patients with psoriasis compared with controls. Methods This cohort study was conducted using data from the Taiwan National Health Insurance Research Database. Patients with psoriasis (n = 10 288) and matched comparison patients without psoriasis (n = 41 152) were evaluated. A Cox proportional hazard regression analysis was used to determine the risk of asthma in patients with and without psoriasis. Results The risk of asthma was 1·38-fold higher [95% confidence interval (CI) 1·23–1·54] in the cohort with psoriasis than in the reference cohort, after adjusting for age, sex and comorbidities. The incidence of asthma in men and women with psoriasis exhibited nonsignificant differences. Among all patients aged > 50 years, psoriasis was associated with a higher risk of asthma compared with not having psoriasis [adjusted hazard ratio (HR) 1·49; 95% CI 1·18–1·88 (in patients aged 50–64 years); adjusted HR 1·63; 95% CI 1·34–1·99 (in patients aged > 65 years)]. Conclusions Our results indicate that patients with psoriasis are associated with a increased risk of developing asthma.

Background & Aims: Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Progression from BE to cancer is associated with obesity, possibly due to increased abdominal pressure and gastroesophageal reflux disease, although this pathogenic mechanism has not been proven. We investigated whether environmental or dietary factors associated with obesity contribute to the progression of BE to EAC in mice. Methods: Tg(ED-L2-IL1RN/IL1B)#Tcw mice (a model of BE, called L2-IL1B mice) were fed a chow (control) or high-fat diet (HFD) or were crossbred with mice that express human interleukin (IL) 8 (L2-IL1B/IL8 mice). Esophageal tissues were collected and analyzed for gene expression profiles and by quantitative polymerase chain reaction, immunohistochemistry, and flow cytometry. Organoids were established from BE tissue of mice and cultured with serum from lean or obese individuals or with neutrophils from L2-IL1B mice. Feces from mice were analyzed by 16s ribosomal RNA sequencing and compared to 16s sequencing data from patients with dysplasia or BE. L2-IL1B were mice raised in germ-free conditions. Results: L2-IL1B mice fed an HFD developed esophageal dysplasia and tumors more rapidly than mice fed the control diet; the speed of tumor development was independent of body weight. The acceleration of dysplasia by the HFD in the L2-IL1B mice was associated with a shift in the gut microbiota and an increased ratio of neutrophils to natural killer cells in esophageal tissues compared with mice fed a control diet. We observed similar differences in the microbiomes from patients with BE that progressed to EAC vs patients with BE that did not develop into cancer. Tissues from dysplasias of L2-IL1B mice fed the HFD contained increased levels of cytokines that are produced in response to CXCL1 (the functional mouse homolog of IL8, also called KC). Serum from obese patients caused organoids from L2-IL1B/IL8 mice to produce IL8. BE tissues from L2-IL1B mice fed the HFD and from L2-IL1B/IL8 mice contained increased numbers of myeloid cells and cells expressing Cxcr2 and Lgr5 messenger RNAs (epithelial progenitors) compared with mice fed control diets. BE tissues from L2-IL1B mice raised in germ-free housing had fewer progenitor cells and developed less dysplasia than in L2-IL1 mice raised under standard conditions; exposure of fecal microbiota from L2-IL1B mice fed the HFD to L2-IL1B mice fed the control diet accelerated tumor development. Conclusions: In a mouse model of BE, we found that an HFD promoted dysplasia by altering the esophageal microenvironment and gut microbiome, thereby inducing inflammation and stem cell expansion, independent of obesity., German Research Foundation (Grant SFB 824)

Ferulic acid (FA), a phenolic compound, is an abundant dietary antioxidant and exerts the mitogenic effect on cells. Recently, we isolated an active FA derivative, namely feruloyl- l -arabinose (FAA), from coba husk. The aim of this study was to investigate the effects of FAA on the proliferation, migration and invasion of H1299 human lung cancer cells. Our results showed a strong antioxidant potential of FAA. Additionally, FAA inhibited the migration and invasion ability, while causing a significant accumulation of G2/M-population, of H1299 tumor cells in a dose-dependent manner, whereas no significant change on cell proliferation was observed. Results from the wound healing assay revealed that cell migration ability was markedly inhibited by FAA treatments. Similarly, results of gelatin zymography study showed that FAA treatments significantly decreased the activities of matrix metalloproteinase (MMP)-2 and MMP-9, suggesting that FAA-mediated inhibition on migration and invasion of lung cancer cells may be achieved by the down-regulation of the MMPs activities. Taken together, our present work provides a new insight into the novel inhibitory function of FAA on cell migration in H1299 cells, suggesting its promising role in the chemoprevention of lung cancer.

Trans-ferulic (FA) acid exhibits antioxidant effects in vitro. However, the underlying mechanism of trans-FA activity in cellular physiology, especially cancer physiology, remains largely unknown. This study investigated the cellular physiological effects of trans-FA on the H1299 human lung cancer cell line. The 2,2-diphenyl-1-picrylhydrazyl assay was used to determine free radical scavenging capability. Assessment of intracellular reactive oxygen species (ROS) was evaluated using oxidized 2ʹ,7ʹ-dichlorofluorescin diacetate and dihydroethidium staining. Trypan blue exclusion, colony formation, and anchorage-independent growth assays were used to determine cellular proliferation. Annexin V staining assay was used to assess cellular apoptosis by flow cytometry. Wound healing and Boyden’s well assays were used to detect the migration and invasion of cells. Gelatin zymography was used to detect matrix metalloproteinase (MMP-2 and MMP-9) activity. Western blotting was used to detect expression levels of various signaling pathway proteins. DPPH assay results indicated that trans-FA exerted potent antioxidant effects. However, trans-FA increased intracellular ROS levels, including hydrogen peroxide and superoxide anion, in H1299 cells. Trans-FA treatment inhibited cellular proliferation and induced moderate apoptotic cell death at the highest concentration used (0.6 mM). Furthermore, trans-FA moderately inhibited the migration of H1299 cells at the concentrations of 0.3 and 0.6 mM and attenuated MMP-2 and MMP-9 activity. Trans-FA caused the phosphorylation of β-catenin, resulting in proteasomal degradation of β-catenin. Conversely, trans-FA treatment increased the expression of pro-apoptotic factor Bax and decreased the expression of pro-survival factor survivin. Various concentrations (0.06–0.6 mM) of trans-FA exert both anti-proliferation and anti-migration effects in the human lung cancer cell line H1299.

Ischemia exists in many diseased tissues, including arthritic joints, atherosclerotic plaques, and malignant tumors. Macrophages accumulate in these sites and up-regulate hypoxia-inducible transcription factors (HIFs) 1 and 2 in response to the hypoxia present. Here we show that the gene expression profile in primary human and murine macrophages changes markedly when they are exposed to hypoxia for 18 hours. For example, they were seen to up-regulate the cell surface receptors, CXCR4 and GLUT1, and the potent, tumor-promoting cytokines, vascular endothelial growth factor A, interleukin (IL)-1β and IL-8, adrenomedullin, CXCR4, and angiopoietin-2. Hypoxia also stimulated their expression and/or phosphorylation of various proteins in the nuclear factor-κB (NF-κB) signaling pathway. We then used both genetic and pharmacologic methods to manipulate the levels of HIFs-1α and 2α or NF-κB in primary macrophages to elucidate their role in the hypoxic induction of many of these key genes. These studies showed that both HIF-1 and -2, but not NF-κB, are important transcriptional effectors regulating the responses of macrophages to such a period of hypoxia. Further studies using experimental mouse models are now warranted to investigate the role of such macrophage responses in the progression of various diseased tissues, such as malignant tumors.

Objective: The objective of this study was to determine whether a new diagnosis of asthma is associated with a later diagnosis of herpes zoster (HZ) in a nationwide, retrospective, non-age limited, population-based cohort. Methods: We used data from the National Health Insurance Research Database in Taiwan. The asthma group consisted of all 40 069 patients in the database with newly diagnosed asthma and using asthma medications from 2000 through 2005. The nonasthma group comprised 40 069 age- and sex-matched patients without any asthma diagnosis. Cox proportional hazards regression analysis was applied to calculate the hazard ratio of HZ in the patients with asthma relative to those without asthma. Results: During a mean follow-up period of 8.77 years, the risk of HZ was 1.48-fold higher in the asthma group compared with that in the nonasthma group after adjustment for sex, age, comorbidities, inhaled and systemic corticosteroid use, and annual outpatient department visits to dermatologists. Additional stratified analyses revealed that the risk of HZ was significantly higher in patients of both sexes and those aged older than 21 years. Conclusions: Newly diagnosed adult patients with asthma have a significantly higher risk of developing HZ than do those without asthma.

Additional file 1. DPPH radical-scavenging capacity of vitamin C as a positive control. (A) Vitamin C as a positive control in DPPH assay. (B) Quantificative analysis of (A). The radical-scavenging capacity of Vitamin C at indicated concentrations was quantified as the percentage decrease in absorbance at 492 nm against the blank control. *P