bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ataxia telangiectasia mutated kinase deficiency impairs the autophagic response early during myocardial infarction
Authors: Thrasher Patsy R. , Scofield Stephanie L. C. , Dalal Suman , Crawford Claire C. , Singh Mahipal , Singh Krishna 
Published: April 2018

Ataxia telangiectasia mutated kinase (ATM) is activated in response to DNA damage. We have previously shown that ATM plays a critical role in myocyte apoptosis and cardiac remodeling after myocardial infarction (MI). Here, we tested the hypothesis that ATM deficiency results in autophagic impairment in the heart early during MI. MI was induced in wild-type (WT) and ATM heterozygous knockout (hKO) mice by ligation of the left anterior descending artery. Structural and biochemical parameters of the heart were measured 4 h after left anterior descending artery ligation. M-mode echocardiography revealed that MI worsens heart function, as evidenced by reduced percent ejection fraction and fractional shortening in both groups. However, MI-induced increase in left ventricular end-diastolic and end-systolic diameters and volumes were significantly lower in hKO hearts. ATM deficiency resulted in autophagic impairment during MI, as evidenced by decreased microtubule-associated protein light chain 3-II increased p62, decreased cathepsin D protein levels, and increased aggresome accumulation. ERK1/2 activation was only observed in WT-MI hearts. Activation of Akt and AMP-activated protein kinase (AMPK) was lower, whereas activation of glycogen synthase kinase (GSK)-3β and mammalian target of rapamycin (mTOR) was higher in hKO-MI hearts. Inhibition of ATM using KU-55933 resulted in autophagic impairment in cardiac fibroblasts, as evidenced by decreased light chain 3-II protein levels and formation of acidic vesicular organelles. This impairment was associated with decreased activation of Akt and AMPK but enhanced activation of GSK-3β and mTOR in KU-55933-treated fibroblasts. Thus, ATM deficiency results in autophagic impairment in the heart during MI and cardiac fibroblasts. This autophagic impairment may occur via the activation of GSK-3β and mTOR and inactivation of Akt and AMPK. NEW & NOTEWORTHY Ataxia telangiectasia mutated kinase (ATM) plays a critical role in myocyte apoptosis and cardiac remodeling after myocardial infarction (MI). Here, we provide evidence that ATM deficiency results in autophagic impairment during MI. Further investigation of the role of ATM in autophagy post-MI may provide novel therapeutic targets for patients with ataxia telangiectasia suffering from heart disease.
Dynamic cerebral autoregulation is impaired during submaximal isometric handgrip in patients with heart failure
Authors: Caldas J. R. , Panerai R. B. , Salinet A. M. , Seng-Shu E. , Ferreira G. S. R. , Camara L. , Passos R. H. , Galas F. R. B. G. , Almeida J. P. , Nogueira R. C. , de Lima Oliveira M. , Robinson T. G. , Hajjar L. A. 
Published: April 2018

The incidence of neurological complications, including stroke and cognitive dysfunction, is elevated in patients with heart failure (HF) with reduced ejection fraction. We hypothesized that the cerebrovascular response to isometric handgrip (iHG) is altered in patients with HF. Adults with HF and healthy volunteers were included. Cerebral blood velocity (CBV; transcranial Doppler, middle cerebral artery) and arterial blood pressure (BP; Finometer) were continuously recorded supine for 6 min, corresponding to 1 min of baseline and 3 min of iHG exercise, at 30% maximum voluntary contraction, followed by 2 min of recovery. The resistance-area product was calculated from the instantaneous BP-CBV relationship. Dynamic cerebral autoregulation (dCA) was assessed with the time-varying autoregulation index estimated from the CBV step response derived by an autoregressive moving-average time-domain model. Forty patients with HF and 23 BP-matched healthy volunteers were studied. Median left ventricular ejection fraction was 38.5% (interquartile range: 0.075%) in the HF group. Compared with control subjects, patients with HF exhibited lower time-varying autoregulation index during iHG, indicating impaired dCA ( P < 0.025). During iHG, there were steep rises in CBV, BP, and heart rate in control subjects but with different temporal patterns in HF, which, together with the temporal evolution of resistance-area product, confirmed the disturbance in dCA in HF. Patients with HF were more likely to have impaired dCA during iHG compared with age-matched control subjects. Our results also suggest an impairment of myogenic, neurogenic, and metabolic control mechanisms in HF. The relationship between impaired dCA and neurological complications in patients with HF during exercise deserves further investigation. NEW & NOTEWORTHY Our findings provide the first direct evidence that cerebral blood flow regulatory mechanisms can be affected in patients with heart failure during isometric handgrip exercise. As a consequence, eventual blood pressure modulations are buffered less efficiently and metabolic demands may not be met during common daily activities. These deficits in cerebral autoregulation are compounded by limitations of the systemic response to isometric exercise, suggesting that patients with heart failure may be at greater risk for cerebral events during exercise.
ME1 Regulates NADPH Homeostasis to Promote Gastric Cancer Growth and Metastasis
Authors: Lu Yun-Xin , Ju Huai-Qiang , Liu Ze-Xian , Chen Dong-Liang , Wang Yun , Zhao Qi , Wu Qi-Nian , Zeng Zhao-lei , Qiu Hai-Bo , Hu Pei-Shan , Wang Zhi-Qiang , Zhang Dong-Sheng , Wang Feng , Xu Rui-Hua 
Published: April 2018

Abstract
Genomic alterations of tumor suppressorsoften encompass collateral protein-coding genes that create therapeutic vulnerability to further inhibition of their paralogs. Here, we report that malic enzyme 2 (ME2) is frequently hemizygously codeleted with SMAD4 in gastric cancer. Its isoenzyme ME1 was upregulated to replenish the intracellular reducing equivalent NADPH and to maintain redox homeostasis. Knockdown of ME1 significantly depleted NADPH, induced high levels of reactive oxygen species (ROS), and ultimately cell apoptosis under oxidative stress conditions, such as glucose starvation and anoikis, in ME2-underexpressed cells. Moreover, ME1 promoted tumor growth, lung metastasis, and peritoneal dissemination of gastric cancer in vivo. Intratumoral injection of ME1 siRNA significantly suppressed tumor growth in cell lines and patient-derived xenograft–based models. Mechanistically, ME1 was transcriptionally upregulated by ROS in an ETV4-dependent manner. Overexpression of ME1 was associated with shorter overall and disease-free survival in gastric cancer. Altogether, our results shed light on crucial roles of ME1-mediated production of NADPH in gastric cancer growth and metastasis.
Significance: These findings reveal the role of malic enzyme in growth and metastasis.
Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/8/1972/F1.large.jpg. Cancer Res; 78(8); 1972–85. ©2018 AACR.
Resistance to Antibody–Drug Conjugates
Authors: García-Alonso Sara , Ocaña Alberto , Pandiella Atanasio 
Published: April 2018

Abstract
Antibody–drug conjugates (ADC) are multicomponent molecules constituted by an antibody covalently linked to a potent cytotoxic agent. ADCs combine high target specificity provided by the antibody together with strong antitumoral properties provided by the attached cytotoxic agent. At present, four ADCs have been approved and over 60 are being explored in clinical trials. Despite their effectiveness, resistance to these drugs unfortunately occurs. Efforts to understand the bases underlying such resistance are being carried out with the final purpose of counteracting them. In this review, we report described mechanisms of resistance to ADCs used in the clinic along with other potential ones that may contribute to resistance acquisition. We also discuss strategies to overcome resistance to ADCs. Cancer Res; 78(9); 2159–65. ©2018 AACR.
Mitotic Exit Dysfunction through the Deregulation of APC/C Characterizes Cisplatin-Resistant State in Epithelial Ovarian Cancer
Authors: Belur Nagaraj Anil , Kovalenko Olga , Avelar Rita , Joseph Peronne , Brown Annalyn , Surti Arshia , Mantilla Sandra , DiFeo Analisa 
Published: April 2018

Abstract
Purpose: Acquired resistance to cisplatin is a major barrier to success in treatment of various cancers, and understanding mitotic mechanisms unique to cisplatin-resistant cancer cells can provide the basis for developing novel mitotic targeted therapies aimed at eradicating these cells.
Experimental Design: Using cisplatin-resistant models derived from primary patient epithelial ovarian cancer (EOC) cells, we have explored the status of mitotic exit mechanisms in cisplatin-resistant cells.
Results: We have uncovered an unexpected role of long-term cisplatin treatment in inducing mitotic exit vulnerability characterized by increased spindle checkpoint activity and functional dependency on Polo-like kinase 1 (PLK1) for mitotic exit in the presence of anaphase promoting complex/cyclosome (APC/C) dysfunction in a cisplatin-resistant state. Accordingly, PLK1 inhibition decreased the survival of cisplatin-resistant cells in vitro and in vivo and exacerbated spindle checkpoint response in these cells. APC/CCDC20 inhibition increased sensitivity to pharmacologic PLK1 inhibition, further confirming the existence of APC/C dysfunction in cisplatin-resistant cells. In addition, we uncovered that resistance to volasertib, PLK1 inhibitor, is due to maintenance of cells with low PLK1 expression. Accordingly, stable PLK1 downregulation in cisplatin-resistant cells induced tolerance to volasertib.
Conclusions: We provide the first evidence of APC/C dysfunction in cisplatin-resistant state, suggesting that understanding APC/C functions in cisplatin-resistant state could provide a basis for developing novel mitotic exit–based therapies to eradicate cisplatin-resistant cancer cells. Our results also show that PLK1 downregulation could underlie emergence of resistance to PLK1-targeted therapies in cancers. Clin Cancer Res; 24(18); 4588–601. ©2018 AACR.
Induced Telomere Damage to Treat Telomerase Expressing Therapy-Resistant Pediatric Brain Tumors
Authors: Sengupta Satarupa , Sobo Matthew , Lee Kyungwoo , Senthil Kumar Shiva , White Angela R. , Mender Ilgen , Fuller Christine , Chow Lionel M.L. , Fouladi Maryam , Shay Jerry W. , Drissi Rachid 
Published: April 2018

Abstract
Brain tumors remain the leading cause of cancer-related deaths in children and often are associated with long-term sequelae among survivors of current therapies. Hence, there is an urgent need to identify actionable targets and to develop more effective therapies. Telomerase and telomeres play important roles in cancer, representing attractive therapeutic targets to treat children with poor-prognosis brain tumors such as diffuse intrinsic pontine glioma (DIPG), high-grade glioma (HGG), and high-risk medulloblastoma. We have previously shown that DIPG, HGG, and medulloblastoma frequently express telomerase activity. Here, we show that the telomerase-dependent incorporation of 6-thio-2′deoxyguanosine (6-thio-dG), a telomerase substrate precursor analogue, into telomeres leads to telomere dysfunction–induced foci (TIF) along with extensive genomic DNA damage, cell growth inhibition, and cell death of primary stem-like cells derived from patients with DIPG, HGG, and medulloblastoma. Importantly, the effect of 6-thio-dG is persistent even after drug withdrawal. Treatment with 6-thio-dG elicits a sequential activation of ATR and ATM pathways and induces G2–M arrest. In vivo treatment of mice bearing medulloblastoma xenografts with 6-thio-dG delays tumor growth and increases in-tumor TIFs and apoptosis. Furthermore, 6-thio-dG crosses the blood–brain barrier and specifically targets tumor cells in an orthotopic mouse model of DIPG. Together, our findings suggest that 6-thio-dG is a promising novel approach to treat therapy-resistant telomerase-positive pediatric brain tumors. Mol Cancer Ther; 17(7); 1504–14. ©2018 AACR.
Caspase-1 from Human Myeloid-Derived Suppressor Cells Can Promote T Cell–Independent Tumor Proliferation
Authors: Zeng Qi , Fu Juan , Korrer Michael , Gorbounov Mikhail , Murray Peter J. , Pardoll Drew , Masica David L. , Kim Young J. 
Published: April 2018

Abstract
Immunosuppressive myeloid-derived suppressive cells (MDSCs) are characterized by their phenotypic and functional heterogeneity. To better define their T cell–independent functions within the tumor, sorted monocytic CD14+CD11b+HLA-DRlow/– MDSCs (mMDSC) from squamous cell carcinoma patients showed upregulated caspase-1 activity, which was associated with increased IL1β and IL18 expression. In vitro studies demonstrated that mMDSCs promoted caspase-1–dependent proliferation of multiple squamous carcinoma cell lines in both human and murine systems. In vivo, growth rates of B16, MOC1, and Panc02 were significantly blunted in chimeric mice adoptively transferred with caspase-1 null bone marrow cells under T cell–depleted conditions. Adoptive transfer of wild-type Gr-1+CD11b+ MDSCs from tumor-bearing mice reversed this antitumor response, whereas caspase-1 inhibiting thalidomide-treated MDSCs phenocopied the antitumor response found in caspase-1 null mice. We further hypothesized that MDSC caspase-1 activity could promote tumor-intrinsic MyD88-dependent carcinogenesis. In mice with wild-type caspase-1, MyD88-silenced tumors displayed reduced growth rate, but in chimeric mice with caspase-1 null bone marrow cells, MyD88-silenced tumors did not display differential tumor growth rate. When we queried the TCGA database, we found that caspase-1 expression is correlated with overall survival in squamous cell carcinoma patients. Taken together, our findings demonstrated that caspase-1 in MDSCs is a direct T cell–independent mediator of tumor proliferation. Cancer Immunol Res; 6(5); 566–77. ©2018 AACR.
Electrical Substrates Driving Response to Cardiac Resynchronization Therapy
Authors: Huntjens Peter R. , Ploux Sylvain , Strik Marc , Walmsley John , Ritter Philippe , Haissaguerre Michel , Prinzen Frits W. , Delhaas Tammo , Lumens Joost , Bordachar Pierre 
Published: April 2018

Background:
The predictive value of interventricular versus intraventricular dyssynchrony for response to cardiac resynchronization therapy (CRT) remains unclear. We investigated the relative importance of both ventricular electrical substrate components for left ventricular (LV) hemodynamic function.

Methods and Results:

First, we used the cardiovascular computational model CircAdapt to characterize the isolated effect of intrinsic interventricular and intraventricular activation on CRT response (ΔLVdP/dt
max
). Simulated ΔLVdP/dt
max
(range: 1.3%–26.5%) increased considerably with increasing interventricular dyssynchrony. In contrast, the isolated effect of intraventricular dyssynchrony in either the LV or right ventricle was limited (ΔLVdP/dt
max
range: 12.3%–18.3% and 14.1%–15.7%, respectively). Effects of activation during biventricular pacing on ΔLVdP/dt
max
were small. Second, electrocardiographic imaging–derived activation characteristics of 51 CRT candidates were used to personalize ventricular activation in CircAdapt. The individualized models were subsequently used to assess the accuracy of ΔLVdP/dt
max
prediction based on the electrical data. The model-predicted ΔLVdP/dt
max
was close to the actual value in patients with left bundle branch block (measured−simulated: 2.7±9.0%) when only intrinsic interventricular dyssynchrony was personalized. Among patients without left bundle branch block, ΔLVdP/dt
max
was systematically overpredicted by CircAdapt (measured−simulated: 9.2±7.1%). Adding intraventricular activation to the model did not improve the accuracy of the response prediction.

Conclusions:
Computer simulations revealed that intrinsic interventricular dyssynchrony is the dominant component of the electrical substrate driving the response to CRT. Intrinsic intraventricular dyssynchrony and any dyssynchrony during biventricular pacing play a minor role in this respect. This may facilitate patient-specific modeling for prediction of CRT response.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01270646.
OMBUDSMANLIK MEKANİZMASININ GELİŞİMİ: AVRUPA BİRLİĞİ VE TÜRKİYE BAĞLAMINDA DEĞERLENDİRİLMESİ
Authors: ÖZEKİCİOĞLU Seda 
Published: April 2018

Tarihsel süreç içinde, yöneten
tarafta yer alan iktidar ile yönetilen halk arasındaki sorunlara ilişkin yaşanan
gelişmeler, kamu kesiminin denetlenmesini bir ihtiyaç haline getirmiştir. Özellikle
1950’lerden sonra kamu kesiminde hesap verebilirlik ve mali saydamlık ilkelerinin
artan önemi, kamu kesiminde denetim yöntemlerinin çeşitlenmesini sağlamıştır. Denetim
alanındaki gelişmelere paralel olarak kurulan Ombudsmanlık Kurumu, vatandaşların
bilgi edinme hakkını karşılama ve kamu kaynaklarının verimli, etkin ve tutumlu
kullanılması adına kamu kurum ve kuruluşlarının denetlenmesi görevini yerine
getirmektedir.

Ombudsmanlık
Kurumu, Türkiye’de kamu yönetiminin daha iyi konuma taşınması ile birlikte
Avrupa Birliği Uyum Süreci için de önem arz eden bir kimliğe sahiptir. Bu
bağlamda çalışmada, ombudsmanlık mekanizmasının tarihsel gelişimine; Avrupa
Birliği ve Türkiye’de Ombudsmanlık Kurumu’nın işleyişine ve Türkiye’de
ombudsmanlık mekanizmasının daha etkin işleyebilmesi için bazı önerilere yer
verilmektedir.
Biliary ascariasis presenting with gangrenous perforation of the gall bladder: report of a case and brief review of literature
Authors: Sharma Ankush , Jariwala Priyansh , Kaur Navneet 
Published: April 2018

The most common cause of gallbladder perforation is calculous cholecystitis. Rarer causes include trauma, iatrogenic injuries, biliary stasis and gall bladder ischemia. We report a case of gall bladder gangrene with perforation, secondary to extensive ascariasis. A 45-year-old woman presented with acute intestinal obstruction and jaundice. She had abdominal distension and right hypochondrial tenderness. Abdominal radiography showed dilated bowel loops and ultrasonogram showed worms in the small intestine and biliary tree. On exploration, a bolus of worms 2 feet proximal to the ileocaecal junction was found causing obstruction. Worms were also present in the bile duct and gallbladder causing gangrene and perforation. She underwent cholecystectomy, bile-duct exploration and enterotomy. However, she died on the third postoperative day of overwhelming sepsis. Enteric complications of ascaris leading to bowel obstruction are well-known. Hepatobiliary complications such as cholangitis and obstructive jaundice are rare. However, such an extreme degree of infestation leading to gangrene and perforation of the gall bladder is extremely rare.
The Role of Managers in Employee Wellness Programs: A Mixed-Methods Study
Authors: Passey Deborah G. , Hammerback Kristen , Huff Aaron , Harris Jeffrey R. , Hannon Peggy A. 
Published: April 2018

Purpose: The purpose of this study is to evaluate managers’ barriers and facilitators to supporting employee participation in the Washington State Wellness program. Design: Exploratory sequential mixed methods. Setting: Four Washington State agencies located in Olympia and Tumwater, Washington. Participants: State employees in management positions (executive, middle, and line), whose job includes supervision of subordinates and responsibility for the performance and conduct of a subunit or group. Methods: We interviewed 23 managers and then used the results to create a survey that was fielded to all managers at the 4 agencies. The survey response rate was 65% (n = 607/935). Analysis: We used qualitative coding techniques to analyze interview transcripts and descriptive statistics to summarize survey data. We used the Total Worker Health framework to organize our findings and conclusions. Results: Managers support the wellness program, but they also face challenges with accommodating employees’ participation due to workload, scheduling inflexibility, and self-efficacy to discuss wellness with direct reports. About half the managers receive support from the manager above them, and most have not received training on the wellness program. Conclusion: Our findings point to several strategies that can strengthen managers’ role in supporting the wellness program: the provision of training, targeted messages, formal expectations, and encouragement (from the manager above) to support employees’ participation.
A case of Gila monster (Heloderma suspectum) bite
Authors: Wong Oi Fung , Cheung Wing Hang , Fung Hin Tat , Lam Shing Kit Tommy , Chan Wing Lun William 
Published: April 2018

Introduction:A variety of exotic reptiles are kept as “pets” and the ownership of these animals is rising in Hong Kong. Two lizard species are known to be venomous: the Gila monster (Heloderma suspectum) and the Mexican Beaded Lizard (Heloderma horridum). Both of them are native to the North America but are traded in the pet markets. Bites from these lizards are capable of causing severe envenomation in humans.Case presentation:A 41‐year‐old man presented to the emergency department after bitten by his exotic pet. His right hand was bitten by a Gila monster resulting in local swelling and intense pain. The local envenomation lasted for about 12 hours and then gradually improved.Discussion:Bite by Gila monster could result in local and systemic envenomation. Local envenomation includes intense pain of the injured site, edema and paraesthesia. Systemic envenomation including hypotension and airway edema occurs in severe envenomation.Conclusion:With the increasing popularity of keeping exotic pets in Hong Kong, envenomation by exotic venomous animals may be encountered by the emergency physicians. Knowledge about the potential envenomation effects of these exotic animals is essential for proper management of the patients.
Giant gastric ulcers: Malignancy yield and predictors from a 10‐year retrospective single centre cohort
Authors: Lord Richard , El-Feki Mohammed , Tomos Lea , Mohammed Noor , Subramanian Venkat , Rembacken Bjorn J 
Published: April 2018

Background and study aimsGastric cancer is known to reside in some gastric ulcers but what predicts this association is still unclear. Historically it has been thought that the increasing size of gastric ulcers may be a predictor for harbouring malignancy. Giant gastric ulcers are arbitrarily defined as ≥3 cm. The aim of this retrospective study was to examine patients with giant gastric ulcers within a single tertiary centre over a 10‐year period. Our primary outcomes included the malignancy yield in giant gastric ulcers and to determine if any demographic, clinical or endoscopic predictors for malignancy exist. Secondary outcomes included the 30‐day and 12‐month mortality.MethodPatients with giant gastric ulcers ≥3 cm presenting from September 2005 to December 2015 were included in the study. Malignancy yield was obtained by looking at histology reports. Predictors for malignancy were tested using binary logistic regression, after demographic, clinical and endoscopic variables were tested using univariate analysis and for collinearity.ResultsA cohort of 111 patients was included for the final analysis. Forty‐two giant gastric ulcers were malignant, equating to a yield of 37.8% (95% CI 28.8–46.8). Binary logistic regression revealed predictors for malignancy included: ulcer location being within the fundus, cardia or incisura (odds ratio (OR) 4.417; 95% CI 1.10–17.76; P = 0.036); younger age of patient (OR 0.202; 95% CI 0.06–0.71; P = 0.013); and endoscopic ‘non‐suspicion’ (OR 0.138; 95% CI 0.049–0.39; P < 0.001). Patient's 12‐month mortality for giant gastric ulcer was 61.9% (26/42) for malignant and 21.9% (11/73) for benign histology.ConclusionWe have shown a high malignancy yield of 37.8% (95% CI 28.8–46.8) and a 12‐month mortality of 61.9% for malignant giant gastric ulcers and 21.9% for benign giant gastric ulcers. Predictors for malignancy in patients with giant gastric ulcers include ulcer location, patient's age and endoscopist's ‘suspicion’ during endoscopy.