bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional and biochemical responses of skeletal muscle following a moderate degree of systemic iron loading in mice
Authors: Liang Chen , Mickey Marisa C. , Receno Candace N. , Atalay Mustafa , DeRuisseau Keith C. 
Published: January 2019

Excessive iron loading may cause skeletal muscle atrophy and weakness because of its free radical generating properties. To determine whether a clinically relevant degree of iron loading impairs skeletal muscle function, young male mice received injections of iron dextran (4 mg iron/200 µl) or 2 mM d-glucose (control) 5 days/week for 2 weeks ( n = 10/group). Systemic iron loading induced an approximate fourfold increase in the skeletal muscle nonheme iron concentration. Soleus specific tension (1, 30–250 Hz) was lower among iron-loaded animals compared with controls despite similar body mass and muscle mass. Soleus lipid peroxidation (4-hydroxynonenal adducts) and protein oxidation (protein carbonyls) levels were similar between groups. In gastrocnemius muscle, reduced glutathione (GSH) and glutathione peroxidase activity were similar but glutathione disulfide (GSSG) and the GSSG/GSH ratio were greater in iron-loaded muscle. A greater protein expression level of endogenous thiol antioxidant thioredoxin (TRX) was observed among iron-loaded muscle whereas its endogenous inhibitor thioredoxin-interacting protein (TXNip) and the TRX/TXNip ratio were similar. Glutaredoxin2, a thiol-disulfide oxidoreductase activated by GSSG-induced destabilization of its iron-sulfur [2Fe-2S] cluster, was lower following iron loading. Additionally, protein levels of α-actinin and αII-spectrin at 240 kDa were lower in the iron-loaded group. Ryanodine receptor stabilizing subunit calstabin1 was also lower following iron loading. In summary, the contractile dysfunction that resulted from moderate iron loading may be mediated by a disturbance in the muscle redox balance and from changes arising from an increased proteolytic response and aberrant sarcoplasmic reticulum Ca2+ release. NEW & NOTEWORTHY Although severe iron loading is known to cause muscle oxidative stress and dysfunction, the effects of a moderate degree of systemic iron loading on muscle contractile function and biochemical responses remain unclear. This study demonstrates that a pathophysiological elevation in the skeletal muscle iron load leads to force deficits that coincide with impaired redox status, structural integrity, and lower ryanodine receptor-associated calstabin1 in the absence of muscle mass changes or oxidative damage.
Remote ischemic preconditioning increases accumulated oxygen deficit in middle-distance runners
Authors: Paull Emily J. , Van Guilder Gary P. 
Published: January 2019

The mediators underlying the putative benefits of remote ischemic preconditioning (IPC) on dynamic whole body exercise performance have not been widely investigated. Our objective was to test the hypothesis that remote IPC improves supramaximal exercise performance in National Collegiate Athletic Association (NCAA) Division I middle-distance runners by increasing accumulated oxygen deficit (AOD), an indicator of glycolytic capacity. A randomized sham-controlled crossover study was employed. Ten NCAA Division I middle-distance athletes [age: 21 ± 1 yr; maximal oxygen uptake (V̇o2max): 65 ± 7 ml·kg−1·min−1] completed three supramaximal running trials (baseline, after mock IPC, and with remote IPC) at 110% V̇o2max to exhaustion. Remote IPC was induced in the right arm with 4 × 5 min cycles of brachial artery ischemia with 5 min of reperfusion. Supramaximal AOD (ml/kg) was calculated as the difference between the theoretical oxygen demand required for the supramaximal running bout (linear regression extrapolated from ~12 × 5 min submaximal running stages) and the actual oxygen demand for these bouts. Remote IPC [122 ± 38 s, 95% confidence interval (CI): 94–150] increased ( P < 0.001) time to exhaustion 22% compared with baseline (99 ± 23 s, 95% CI: 82–116, P = 0.014) and sham (101 ± 30 s, 95% CI: 80–123, P = 0.001). In the presence of IPC, AOD was 47 ± 36 ml/kg (95% CI: 20.8–73.9), a 29% increase compared with baseline (36 ± 28 ml/kg, 95% CI: 16.3–56.9, P = 0.008) and sham (38 ± 32 ml/kg, 95% CI: 16.2–63.0, P = 0.024). Remote IPC considerably improved supramaximal exercise performance in NCAA Division I middle-distance athletes. Greater glycolytic capacity, as estimated by increased AOD, is a potential mediator for these performance improvements. NEW & NOTEWORTHY Our novel findings indicate that ischemic preconditioning enhanced glycolytic exercise capacity, enabling National Collegiate Athletic Association (NCAA) middle-distance track athletes to run ~22 s longer before exhaustion compared with baseline and mock ischemic preconditioning. The increase in “all-out” performance appears to be due to increased accumulated oxygen deficit, an index of better supramaximal capacity. Of note, enhanced exercise performance was demonstrated in a specific group of in-competition NCAA elite athletes that has already undergone substantial training of the glycolytic energy systems.
Two weeks of ischemic conditioning improves walking speed and reduces neuromuscular fatigability in chronic stroke survivors
Authors: Durand Matthew J. , Boerger Timothy F. , Nguyen Jennifer N. , Alqahtani Saad Z. , Wright Michael T. , Schmit Brian D. , Gutterman David D. , Hyngstrom Allison S. 
Published: January 2019

This pilot study examined whether ischemic conditioning (IC), a noninvasive, cost-effective, and easy-to-administer intervention, could improve gait speed and paretic leg muscle function in stroke survivors. We hypothesized that 2 wk of IC training would increase self-selected walking speed, increase paretic muscle strength, and reduce neuromuscular fatigability in chronic stroke survivors. Twenty-two chronic stroke survivors received either IC or IC Sham on their paretic leg every other day for 2 wk (7 total sessions). IC involved 5-min bouts of ischemia, repeated five times, using a cuff inflated to 225 mmHg on the paretic thigh. For IC Sham, the cuff inflation pressure was 10 mmHg. Self-selected walking speed was assessed using the 10-m walk test, and paretic leg knee extensor strength and fatigability were assessed using a Biodex dynamometer. Self-selected walking speed increased in the IC group (0.86 ± 0.21 m/s pretest vs. 1.04 ± 0.22 m/s posttest, means ± SD; P < 0.001) but not in the IC Sham group (0.92 ± 0.47 m/s pretest vs. 0.96 ± 0.46 m/s posttest; P = 0.25). Paretic leg maximum voluntary contractions were unchanged in both groups (103 ± 57 N·m pre-IC vs. 109 ± 65 N·m post-IC; 103 ± 59 N·m pre-IC Sham vs. 108 ± 67 N·m post-IC Sham; P = 0.81); however, participants in the IC group maintained a submaximal isometric contraction longer than participants in the IC Sham group (278 ± 163 s pre-IC vs. 496 ± 313 s post-IC, P = 0.004; 397 ± 203 s pre-IC Sham vs. 355 ± 195 s post-IC Sham; P = 0.46). The results from this pilot study thus indicate that IC training has the potential to improve walking speed and paretic muscle fatigue resistance poststroke. NEW & NOTEWORTHY This pilot study is the first to demonstrate that ischemic conditioning can improve self-selected walking speed and reduce paretic muscle fatigue in stroke survivors. Ischemic conditioning has been shown to be safe in numerous patient populations, can be accomplished at home or at the bedside in only 45 min, and requires no specialized training. Future larger studies are warranted to determine the efficacy of ischemic conditioning as a neurorehabilitation therapy poststroke.
Exercise intensity independently modulates thermal behavior during exercise recovery but not during exercise
Authors: Vargas Nicole T. , Chapman Christopher L. , Johnson Blair D. , Gathercole Rob , Schlader Zachary J. 
Published: January 2019

We tested the hypothesis that thermal behavior is greater during and after high- compared with moderate-intensity exercise. In a 27°C, 20% relative humidity environment, 20 participants (10 women, 10 men) cycled for 30 min at moderate [53% (SD 6) peak oxygen uptake (V̇o2peak) or high [78% (SD 6) V̇o2peak] intensity, followed by 120 min of recovery. Mean skin and core temperatures and mean skin wettedness were recorded continuously. Participants maintained thermally comfortable neck temperatures with a custom-made neck device. Neck device temperature provided an index of thermal behavior. The weighted average of mean skin and core temperatures and mean skin wettedness provided an indication of the afferent stimulus to thermally behave. Mean skin and core temperatures were greater at end-exercise in high intensity ( P < 0.01). Core temperature remained elevated in high intensity until 70 min of recovery ( P = 0.03). Mean skin wettedness and the afferent stimulus were greater at 10–20 min of exercise in high intensity ( P ≤ 0.03) and remained elevated until 60 min of recovery ( P < 0.01). Neck device temperature was lower during exercise in high versus moderate intensity ( P ≤ 0.02). There was a strong relation between the afferent stimulus and neck device temperature during exercise (high: R2 = 0.82, P < 0.01; moderate: R2 = 0.95, P < 0.01) and recovery (high: R2 = 0.97, P < 0.01; moderate: R2 = 0.93, P < 0.01). During exercise, slope ( P = 0.49) and y-intercept ( P = 0.91) did not differ between intensities. In contrast, slope was steeper ( P < 0.01) and y-intercept was higher ( P < 0.01) during recovery from high-intensity exercise. Thermal behavior is greater during high-intensity exercise because of the greater stimulus to behave. The withdrawal of thermal behavior is augmented after high-intensity exercise. NEW & NOTEWORTHY This is the first study to determine the effects of exercise intensity on thermal behavior. We show that exercise intensity does not independently modulate thermal behavior during exercise but is dependent on the magnitude of afferent stimuli. In contrast, the withdrawal of thermal behavior after high-intensity exercise is augmented. This may be a consequence of an attenuated perceptual response to afferent stimuli, which may be due to processes underlying postexercise hypoalgesia.
Ezrin Promotes Stem Cell Properties in Pancreatic Ductal Adenocarcinoma
Authors: Penchev Vesselin R. , Chang Yu-Tai , Begum Asma , Ewachiw Theodore , Gocke Christian , Li Joey , McMillan Ross H. , Wang Qiuju , Anders Robert , Marchionni Luigi , Maitra Anirban , Uren Aykut , Rasheed Zeshaan , Matsui William 
Published: January 2019

AbstractSelf-renewal maintains the long-term clonogenic growth that is required for cancer relapse and progression, but the cellular processes regulating this property are not fully understood. In many diseases, self-renewal is enhanced in cancer stem cells (CSC), and in pancreatic ductal adenocarcinoma (PDAC), CSCs are characterized by the surface expression of CD44. In addition to cell adhesion, CD44 impacts cell shape and morphology by modulating the actin cytoskeleton via Ezrin, a member of the Ezrin/Radixin/Moesin (ERM) family of linker proteins. We examined the expression of Ezrin in PDAC cells and found higher levels of both total and activated Ezrin in CSCs compared with bulk tumor cells. We also found that the knockdown of Ezrin in PDAC cells decreased clonogenic growth, self-renewal, cell migration, and CSC frequency in vitro as well as tumor initiation in vivo. These effects were associated with cytoskeletal changes that are similar to those occurring during the differentiation of normal stem cells, and the inhibition of actin remodeling reversed the impact of Ezrin loss. Finally, targeting Ezrin using a small-molecule inhibitor limited the self-renewal of clinically derived low-passage PDAC xenografts. Our findings demonstrate that Ezrin modulates CSCs properties and may represent a novel target for the treatment of PDAC.Implications:Our findings demonstrate that Ezrin modulates CSCs' properties and may represent a novel target for the treatment of PDAC.
Estrogen-Induced Apoptosis in Breast Cancers Is Phenocopied by Blocking Dephosphorylation of Eukaryotic Initiation Factor 2 Alpha (eIF2α) Protein
Authors: Sengupta Surojeet , Sevigny Catherine M. , Bhattacharya Poulomi , Jordan V. Craig , Clarke Robert 
Published: January 2019

Abstract

Approximately 30% of aromatase-inhibitor–resistant, estrogen receptor–positive patients with breast cancer benefit from treatment with estrogen. This enigmatic estrogen action is not well understood and how it occurs remains elusive. Studies indicate that the unfolded protein response and apoptosis pathways play important roles in mediating estrogen-triggered apoptosis. Using MCF7:5C cells, which mimic aromatase inhibitor resistance, and are hypersensitive to estrogen as evident by induction of apoptosis, we define increased global protein translational load as the trigger for estrogen-induced apoptosis. The protein kinase RNA-like endoplasmic reticulum kinase pathway was activated followed by increased phosphorylation of eukaryotic initiation factor-2 alpha (eIF2α). These actions block global protein translation but preferentially allow high expression of specific transcription factors, such as activating transcription factor 4 and C/EBP homologous protein that facilitate apoptosis. Notably, we recapitulated this phenotype of MCF7:5C in two other endocrine therapy–resistant cell lines (MCF7/LCC9 and T47D:A18/4-OHT) by increasing the levels of phospho-eIF2α using salubrinal to pharmacologically inhibit the enzymes responsible for dephosphorylation of eIF2α, GADD34, and CReP. RNAi-mediated ablation of these genes induced apoptosis that used the same signaling as salubrinal treatment. Moreover, combining 4-hydroxy tamoxifen with salubrinal enhanced apoptotic potency.

Implications:
These results not only elucidate the mechanism of estrogen-induced apoptosis but also identify a drugable target for potential therapeutic intervention that can mimic the beneficial effect of estrogen in some breast cancers.
Interaction Between MUC1 and STAT1 Drives IFITM1 Overexpression in Aromatase Inhibitor–Resistant Breast Cancer Cells and Mediates Estrogen-Induced Apoptosis
Authors: Escher Taylor E. , Lui Asona J. , Geanes Eric S. , Walter Katherine R. , Tawfik Ossama , Hagan Christy R. , Lewis-Wambi Joan 
Published: January 2019

Abstract

The human oncoprotein, mucin 1 (MUC1), drives tumorigenesis in breast carcinomas by promoting epithelial-to-mesenchymal transition (EMT), epigenetic reprogramming, and evasion of immune response. MUC1 interacts with STAT1, through JAK/STAT signaling, and stimulates transcription of IFN-stimulated genes, specifically IFN-induced transmembrane protein 1 (IFITM1). Our laboratory has previously shown that IFITM1 overexpression in aromatase inhibitor (AI)-resistant breast cancer cells promotes aggressiveness. Here, we demonstrate that differential regulation of MUC1 in AI-sensitive (MCF-7 and T-47D) compared with AI-resistant (MCF-7:5C) cells is critical in mediating IFITM1 expression. A tumor microarray of 94 estrogen receptor–positive human breast tumors correlated coexpression of MUC1 and IFITM1 with poor recurrence-free survival, poor overall survival, and AI-resistance. In this study, we investigated the effects of MUC1/IFITM1 on cell survival and proliferation. We knocked down MUC1 levels with siRNA and pharmacologic inhibitors, which abrogated IFITM1 mRNA and protein expression and induced cell death in AI-resistant cells. In vivo, estrogen and ruxolitinib significantly reduced tumor size and decreased expression of MUC1, P-STAT1, and IFITM1.

Implications:
MUC1 and IFITM1 overexpression drives AI resistance and can be targeted with currently available therapies.
Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/5/1180/F1.large.jpg.
Long-Term Impact of Iatrogenic Bile Duct Injury
Authors: Schreuder Anne Marthe , Busch Olivier R. , Besselink Marc G. , Ignatavicius Povilas , Gulbinas Antanas , Barauskas Giedrius , Gouma Dirk J. , van Gulik Thomas M. 
Published: January 2019

<b><i>Background:</i></b> Bile duct injury (BDI) is a devastating complication following cholecystectomy. After initial management of BDI, patients stay at risk for late complications including anastomotic strictures, recurrent cholangitis, and secondary biliary cirrhosis. <b><i>Methods:</i></b> We provide a comprehensive overview of current literature on the long-term outcome of BDI. Considering the availability of only limited data regarding treatment of anastomotic strictures in literature, we also retrospectively analyzed patients with anastomotic strictures following a hepaticojejunostomy (HJ) from a prospectively maintained database of 836 BDI patients. <b><i>Results:</i></b> Although clinical outcomes of endoscopic, radiologic, and surgical treatment of BDI are good with success rates of around 90%, quality of life (QoL) may be impaired even after “clinically successful” treatment. Following surgical treatment, the incidence of anastomotic strictures varies from 5 to 69%, with most studies reporting incidences around 10–20%. The median time to stricture formation varies between 11 and 30 months. Long-term BDI-related mortality varies between 1.8 and 4.6%. Of 91 patients treated in our center for anastomotic strictures after HJ, 81 (89%) were treated by percutaneous balloon dilatation, with a long-term success rate of 77%. Twenty-four patients primarily or secondarily underwent surgical revision, with recurrent strictures occurring in 21%. <b><i>Conclusions:</i></b> The long-term impact of BDI is considerable, both in terms of clinical outcomes and QoL. Treatment should be performed in tertiary expert centers to optimize outcomes. Patients require a long-term follow-up to detect anastomotic strictures. Strictures should initially be managed by percutaneous dilatation, with surgical revision as a next step in treatment.
Expansive Vascular Remodeling and Increased Vascular Calcification Response to Cholecalciferol in a Murine Model of Obesity and Insulin Resistance
Authors: Carmo Luciana S. , Burdmann Emmanuel A. , Fessel Melissa R. , Almeida Youri E. , Pescatore Luciana A. , Farias-Silva Elisangela , Gamarra Lionel F. , Lopes Gabriel H. , Aloia Thiago P.A. , Liberman Marcel 
Published: January 2019

Objective—
We hypothesized that ob/ob mice develop expansive vascular remodeling associated with calcification.

Approach and Results—

We quantified and investigated mechanisms of vascular remodeling and vascular calcification in ob/ob mice after vitamin D
3
(VD) stimulation or PBS (control), compared with C57BL/6 mice. Both ob/ob (OBVD [VD-treated ob/ob mice]) and C57BL/6 (C57VD [VD-treated C57BL/6 mice]) received 8×10
3
IU/day of intraperitoneal VD for 14 days. Control ob/ob (OBCT [PBS-treated ob/ob mice]) and C57BL/6 (C57CT [PBS-treated C57BL/6 mice]) received intraperitoneal PBS for 14 days. Hypervitaminosis D increased the external and internal elastic length in aortae from OBVD, resulting in increased total vascular area and lumen vascular area, respectively, which characterizes expansive vascular remodeling. OBVD decreased the aortic wall thickness, resulting in hypotrophic vascular remodeling. We demonstrated increased collagen deposition, elastolysis, and calcification in aortae from OBVD. Our results showed a positive correlation between expansive vascular remodeling and vascular calcification in OBVD. We demonstrated increased serum calcium levels, augmented Bmp (bone morphogenetic protein)-2 and osteochondrogenic proteins expression in OBVD aortae. Furthermore, aortae from OBVD increased oxidative stress, coincidently with augmented in situ MMP (matrix metalloproteinase) activity and exhibited no VDR (VD receptor) inhibition after VD.

Conclusions—
Our data provide evidence that obese and insulin-resistant mice (ob/ob) developed expansive hypotrophic vascular remodeling correlated directly with increased vascular calcification after chronic VD stimulation. Positive hypotrophic vascular remodeling and vascular calcification in this mouse model is possibly mediated by the convergence of absence VDR downregulation after VD stimulation, increased reactive oxygen species generation, and MMP activation.
Relationship Between Operator Volume and Long-Term Outcomes After Percutaneous Coronary Intervention
Authors: Fanaroff Alexander C. , Zakroysky Pearl , Wojdyla Daniel , Kaltenbach Lisa A. , Sherwood Matthew W. , Roe Matthew T. , Wang Tracy Y. , Peterson Eric D. , Gurm Hitinder S. , Cohen Mauricio G. , Messenger John C. , Rao Sunil V. 
Published: January 2019

Background:
Although many studies show an inverse association between operator procedural volume and short-term adverse outcomes after percutaneous coronary intervention (PCI), the association between procedural volume and longer-term outcomes is unknown.

Methods:
Using the National Cardiovascular Data Registry CathPCI registry data linked with Medicare claims data, we examined the association between operator PCI volume and long-term outcomes among patients ≥65 years of age. Operators were stratified by average annual PCI volume (counting PCIs performed in patients of all ages): low- (<50 PCIs), intermediate- (50–100), and high- (>100) volume operators. One-year unadjusted rates of death and major adverse coronary events (MACEs; defined as death, readmission for myocardial infarction, or unplanned coronary revascularization) were calculated with Kaplan-Meier methods. The proportional hazards assumption was not met, and risk-adjusted associations between operator volume and outcomes were calculated separately from the time of PCI to hospital discharge and from hospital discharge to 1-year follow-up.

Results:

Between July 1, 2009, and December 31, 2014, 723 644 PCI procedures were performed by 8936 operators: 2553 high-, 2878 intermediate-, and 3505 low-volume operators. Compared with high- and intermediate-volume operators, low-volume operators more often performed emergency PCI, and their patients had fewer cardiovascular comorbidities. Over 1-year follow-up, 15.9% of patients treated by low-volume operators had a MACE compared with 16.9% of patients treated by high-volume operators (
P
=0.004). After multivariable adjustment, intermediate- and high-volume operators had a significantly lower rate of in-hospital death than low-volume operators (odds ratio, 0.91; 95% CI, 0.86–0.96 for intermediate versus low; odds ratio, 0.79; 95% CI, 0.75–0.83 for high versus low). There were no significant differences in rates of MACEs, death, myocardial infarction, or unplanned revascularization between operator cohorts from hospital discharge to 1-year follow-up (adjusted hazard ratio for MACEs, 0.99; 95% CI, 0.96–1.01 for intermediate versus low; hazard ratio, 1.01; 95% CI, 0.99–1.04 for high versus low).

Conclusions:
Unadjusted 1-year outcomes after PCI were worse for older adults treated by operators with higher annual volume; however, patients treated by these operators had more cardiovascular comorbidities. After risk adjustment, higher operator volume was associated with lower in-hospital mortality and no difference in postdischarge MACEs.