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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. [ABSTRACT FROM AUTHOR]

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 < 0.001). There were also 1 month (1 M) to 2 month (2 M) reductions in dietary sodium intake (−1687 ± 297 mg; P < 0.001); thirst score (−4.4 ± 1.3; P = 0.003), xerostomia score (−6.7 ± 1.9; P = 0.002), SBP (−18.0 ± 3.6 mmHg; P < 0.001), DBP (−5.9 ± 2.0 mmHg; P = 0.008), and plasma phosphorus −1.55 ± 0.21 mg/dL; P = 0.005), as well as a 0 M to 2 M reduction in absolute volume overload (−1.08 ± 0.33 L; P = 0.025). However, there were no significant changes in serum or tissue sodium (all 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

Highlights: [•] Ferulic acid (FAA) exerts good water solubility and an antioxidant effect. [•] FAA reduces intracellular reactive oxygen species (ROS) effectively. [•] FAA attenuates the migration of lung cancer cells without inducing cytotoxicity. [ABSTRACT FROM AUTHOR]

Abstract: Feruloylated oligosaccharides (FOs), the ferulic acid ester of oligosaccharides, can be released either by the enzymatic or mild acid hydrolysis of arabinoxylans present in cereal bran, and are usually considered as natural antioxidants. However, no related research is available to explain their immunomodulatory effects. This report elucidated their immunomodulatory effects through the variations of pro-inflammatory mediators in vitro. FOs were obtained from the mild acid hydrolysis of rice bran. We found that FOs (0.1–100μg/ml) induced tumour necrosis factor alpha (TNF-α), IL-1β, IL-6, nitric oxide (NO) and PGE2 production in unstimulated macrophages, RAW264.7 cells. Furthermore, pre- and post-treated FOs (0.1–100μg/ml) dose-dependently suppressed TNF-α, IL-1β, IL-6 and NO production, and induced IL-10 production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells without exerting cytotoxicity. As a result anti-inflammatory and therapeutic activities were revealed. It is noteworthy that prostaglandin E2 (PGE2) production was significantly suppressed at an FO level of 100μg/ml. The in vitro assessment of inflammatory mediators should be useful in further characterising the effects of FOs on immunomodulation. Moreover, it will create the economical value of rice bran, which has long been considered as conventional agricultural wastes. [Copyright &y& Elsevier]

Abstract: An extracellular xylanase was purified to homogeneity from a culture of Aspergillus carneus M34. In contrast to xylanases from other microorganisms, only a low-molecular weight xylanase, approximately 18.8kDa with a pI value of 7.7–7.9, was purified in this investigation. The optimum temperature and pH of this purified xylanase activity were 50°C and 6, respectively. The xylanase was more stable under alkaline conditions and retained more than 50% activity after 12h incubation at pH 7–9. Considering of its characteristics and N-terminal sequence, this xylanase was concluded as a new one belonging to the group I of family 11 endoxylanases. In addition, hemicellulose of coba husk was selected as the substrate for xylooligosaccharide preparation owing to its higher specificity for this xylanase. Feruloyl xylooligosaccharides were separated and shown potential antioxidative capacity in a cell model of ultraviolet B (UVB)-induced oxidative damage to keratinocyte xb-2. [Copyright &y& Elsevier]

Abstract: Growth conditions, including incubation times, temperature, agitation rate and initial pH of medium, that affect xylanase production by Aspergillus carneus M34 were studied sequentially use the classical “change-one-factor-at-a-time” method. Our results showed that there was a similar trend between cellular xylanase activity and extracellular xylanase activity. The optimal conditions for xylanase production, different from their cell growth, were on the third day, 30°C, 100rpm and pH 4, respectively, in this test. Response surface methodology (RSM) was further introduced to optimize the cultivation conditions and to evaluate the significance of these factors. The optimal cultivation conditions predicted from canonical analysis of this model were achieved by incubation at 35.08°C with an agitation rate of 111.9rpm and an initial pH of 5.16. In addition, temperature was the most critical factor for xylanase production by A. carneus M34. Xylanase activity of 22.2U/mL was verified using the predicted optimal conditions and confirmed the fitness and applicability of the model. The optimal temperature and pH of the crude xylanase activity was observed at 60°C and acidic pH, respectively. Sustained xylanase activity in the crude extract was also detected over a broad range of pH from 3 to 10. Considering its higher specificity toward agricultural wastes, especially corn cob and coba husk, this strain can be used to develop low-cost media for the mass-production of xylanase. [Copyright &y& Elsevier]

Purpose: It 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. Methods: In 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. Conclusion: Application 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Eag (Kv10) and Erg (Kv11) belong to two distinct subfamilies of the ether-à-go-go K+ channel family (KCNH). While Erg channels are characterized by an inward-rectifying current-voltage relationship that results from a C-type inactivation, mammalian Eag channels display little or no voltage-dependent inactivation. Although the amino (N)-terminal region such as the eag domain is not required for the C-type inactivation of Erg channels, an N-terminal deletion in mouse Eag1 has been shown to produce a voltage-dependent inactivation. To further discern the role of the eag domain in the inactivation of Eag1 channels, we generated N-terminal chimeras between rat Eag (rEag1) and human Erg (hERG1) channels that involved swapping the eag domain alone or the complete cytoplasmic N-terminal region. Functional analyses indicated that introduction of the homologous hERG1 eag domain led to both a fast phase and a slow phase of channel inactivation in the rEag1 chimeras. By contrast, the inactivation features were retained in the reverse hERG1 chimeras. Furthermore, an eag domain-lacking rEag1 deletion mutant also showed the fast phase of inactivation that was notably attenuated upon co-expression with the rEag1 eag domain fragment, but not with the hERG1 eag domain fragment. Additionally, we have identified a point mutation in the S4–S5 linker region of rEag1 that resulted in a similar inactivation phenotype. Biophysical analyses of these mutant constructs suggested that the inactivation gating of rEag1 was distinctly different from that of hERG1. Overall, our findings are consistent with the notion that the eag domain plays a critical role in regulating the inactivation gating of rEag1. We propose that the eag domain may destabilize or mask an inherent voltage-dependent inactivation of rEag1 K+ channels. [ABSTRACT FROM AUTHOR]

Abstract: Aims of study: The habit of khat chewing has been associated with increased risk of systemic and oral disease. Although research has been conducted on the affects of khat on oral epithelial cells, little is known about its influence on immune cells. This study examined the biological effects of khat on the phenotype and function of peripheral blood mononuclear cells (PBMCs). Material and Methods: Khat-stimulated PBMCs were examined for signs of cytotoxicity, apoptosis and changes in cell surface receptor and cytokine expression. Khat-induced regulation of transcription factors and stress-related factors were examined, as was PBMC phagocytic activity against oral bacteria. Results: Khat was cytotoxic to PBMC in a dose- and time-dependent manner and cell death was mediated by apoptosis. Khat-treated PBMC showed increased expression of co-stimulatory molecules (CD80, CD86 and MHC II) and pattern recognition receptors (TLR-2, TLR-4 and TREM-1) but secretion of inflammatory cytokines (TNFα, IL-6, CCL5, CXCL8) was inhibited. In contrast, khat induced an increase in the anti-inflammatory cytokine IL-10 as well as IL-2, IFN-γ, FasL and HSP70. These khat-induced alterations were accompanied by increased expression of transcription factors p38 MAPK and HIF-1α, whilst expression of NFκB p65 was inhibited. Although the ability of PBMC to phagocytose dextran and oral bacteria was inhibited, production of reactive oxygen species was increased. Conclusion: These data suggest that khat may severely influence the effectiveness of immune surveillance and anti-microbial capacity of PBMCs. [Copyright &y& Elsevier]

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, contractile, oxidative, and structural protein synthesis were assessed in skeletal muscle in response to a moderate or higher protein diet during the early adaptive phase of resistance training in middle‐aged adults.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 programme. 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 with high dietary protein density and habitual resistance exercise mediates muscle protein subfraction synthesis. Therefore, we investigated the effect of moderate (MOD: 1.06 ± 0.22 g kg−1 day−1) or high (HIGH: 1.55 ± 0.25 g kg−1 day−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 years, BMI 28 ± 1 kg m–2) during the early phase (0–3 weeks) of a dietary counselling‐controlled resistance training programme. 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 weeks when compared to 0–1 week (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. 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, contractile, oxidative, and structural protein synthesis were assessed in skeletal muscle in response to a moderate or higher protein diet during the early adaptive phase of resistance training in middle‐aged adults.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 programme. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC), but its cellular origin and mechanism of neoplastic progression remain unresolved. Notch signaling, which plays a key role in regulating intestinal stem cell maintenance, has been implicated in a number of cancers. The kinase Dclk1 labels epithelial post-mitotic tuft cells at the squamo-columnar junction (SCJ), and has also been proposed to contribute to epithelial tumor growth. Here, we find that genetic activation of intracellular Notch signaling in epithelial Dclk1-positive tuft cells resulted in the accelerated development of metaplasia and dysplasia in a mouse model of BE (pL2.Dclk1.N2IC mice). In contrast, genetic ablation of Notch receptor 2 in Dclk1-positive cells delayed BE progression (pL2.Dclk1.N2fl mice), and led to increased secretory cell differentiation. The accelerated BE progression in pL2.Dclk1.N2IC mice correlated with changes to the transcriptomic landscape, most notably for the activation of oncogenic, proliferative pathways in BE tissues, in contrast to upregulated Wnt signalling in pL2.Dclk1.N2fl mice. Collectively, our data show that Notch activation in Dclk1-positive tuft cells in the gastric cardia can contribute to BE development. [ABSTRACT FROM AUTHOR]

Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC), but its cellular origin and mechanism of neoplastic progression remain unresolved. Notch signaling, which plays a key role in regulating intestinal stem cell maintenance, has been implicated in a number of cancers. The kinase Dclk1 labels epithelial post-mitotic tuft cells at the squamo-columnar junction (SCJ), and has also been proposed to contribute to epithelial tumor growth. Here, we find that genetic activation of intracellular Notch signaling in epithelial Dclk1-positive tuft cells resulted in the accelerated development of metaplasia and dysplasia in a mouse model of BE (pL2.Dclk1.N2IC mice). In contrast, genetic ablation of Notch receptor 2 in Dclk1-positive cells delayed BE progression (pL2.Dclk1.N2fl mice), and led to increased secretory cell differentiation. The accelerated BE progression in pL2.Dclk1.N2IC mice correlated with changes to the transcriptomic landscape, most notably for the activation of oncogenic, proliferative pathways in BE tissues, in contrast to upregulated Wnt signalling in pL2.Dclk1.N2fl mice. Collectively, our data show that Notch activation in Dclk1-positive tuft cells in the gastric cardia can contribute to BE development. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 -13C6]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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Voltage-gated ClC-2 channels are essential for chloride homeostasis. Complete knockout of mouse ClC-2 leads to testicular degeneration and neuronal myelin vacuolation. Gain-of-function and loss-of-function mutations in the ClC-2-encoding human CLCN2 gene are linked to the genetic diseases aldosteronism and leukodystrophy, respectively. The protein homeostasis (proteostasis) mechanism of ClC-2 is currently unclear. Here, we aimed to identify the molecular mechanism of endoplasmic reticulum-associated degradation of ClC-2, and to explore the pathophysiological significance of disease-associated anomalous ClC-2 proteostasis. In both heterologous expression system and native neuronal and testicular cells, ClC-2 is subject to significant regulation by cullin-RING E3 ligase-mediated polyubiquitination and proteasomal degradation. The cullin 4 (CUL4)-damage-specific DNA binding protein 1 (DDB1)-cereblon (CRBN) E3 ubiquitin ligase co-exists in the same complex with and promotes the degradation of ClC-2 channels. The CRBN-targeting immunomodulatory drug lenalidomide and the cullin E3 ligase inhibitor MLN4924 promotes and attenuates, respectively, proteasomal degradation of ClC-2. Analyses of disease-related ClC-2 mutants reveal that aldosteronism and leukodystrophy are associated with opposite alterations in ClC-2 proteostasis. Modifying CUL4 E3 ligase activity with lenalidomide and MLN4924 ameliorates disease-associated ClC-2 proteostasis abnormality. Our results highlight the significant role and therapeutic potential of CUL4 E3 ubiquitin ligase in regulating ClC-2 proteostasis. [ABSTRACT FROM AUTHOR]