bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early interventions for the prevention of post-traumatic stress symptoms in survivors of critical illness: protocol for a systematic review
Authors: Glaspey Lindsey J , Roberts Michael B , Mazzarelli Anthony , Trzeciak Stephen , Roberts Brian W 
Published: September 2017

IntroductionPost-traumatic stress disorder (PTSD) is being increasingly reported among survivors of critical illness and injury. Previous work has demonstrated that PTSD reduces patient quality of life and ability to return to work, as well as increases healthcare costs. As such, identifying interventions aimed at preventing the development of critical illness-related PTSD could have an important public health impact. The objective of this systematic review is to collate the world’s literature on early interventions aimed at preventing PTSD among survivors of critical illness.Methods and analysisWe will perform a qualitative systematic review of human clinical trials of interventions aimed at preventing or reducing critical illness-related PTSD symptoms. We will methodically search CENTRAL, MEDLINE, Embase and CINAHL. We will also search websites containing details on clinical trials registration (National Library of Medicine’s ClinicalTrials.gov and the WHO’s International Clinical Trials Registry Platform), as well as screen reference lists of the articles we select for inclusion to identify additional studies for potential inclusion. Two authors will independently review all search results. After identification and inclusion of articles, we will use a standardised form for data extraction. We will use tables to describe the study type, populations, interventions tested and timing of interventions, outcome measures and effects of interventions on outcome measures compared with control groups. This review will be completed between 1 August 2017 and 31 August 2017.Ethics and disseminationThe proposed systematic review will not collect individual patient level data and does not require ethical approval. Results of this study will contribute to the understanding of critical illness-related PTSD and help prompt future research aimed at further developing interventions to prevent PTSD symptoms in survivors of critical illness.PROSPERO registration numberThis systematic review is registered in the PROSPERO international prospective register of systematic reviews (registration number CRD42017069672).
Feasibility and acceptability of a patient-reported outcome intervention in chronic heart failure
Authors: Kane Pauline M , Daveson Barbara A , Ryan Karen , Ellis-Smith Clare I , Mahon Niall G , McAdam Brendan , McQuilllan Regina , Tracey Cecelia , Howley Christine , O’Gara Geraldine , Raleigh Caroline , Higginson Irene J , Koffman Jonathan , Murtagh Fliss E M 
Published: September 2017

Patients with chronic heart failure (CHF) have symptoms and concerns which are inadequately addressed. Patient-reported outcome measures (PROMs) can potentially improve the identification and management of advanced symptoms and palliative concerns. However, these have not been used in CHF.ObjectivesTo examine the feasibility and acceptability of using a PROM—the Integrated Palliative care Outcome Scale (IPOS)—together with heart failure nurse education and training to improve the identification and management of symptoms and concerns among patients with CHF.MethodsA parallel, mixed methods design with an embedded qualitative component was used to examine the feasibility of recruitment, retention, intervention adherence/compliance and follow-up assessment completion (symptom burden, quality of life, psychological well-being). Patient and nurse qualitative semistructured interviews explored intervention and study design feasibility and its acceptability.ResultsConversion to consent was 46.9% (372 screened, 81 approached, 38 recruited). 66% of patient participants completed the IPOS; 6% of IPOS questionnaire items were missing (non-response). Over two-thirds (65.6%) of these missing items related to three patients. No item was consistently missing; appetite was the most frequent missing item (1.4%). 92% of participants who completed the IPOS completed all follow-up assessments (1–2 days, 1–2 weeks and 4–6 weeks post-IPOS completion) with no missing data. The a priori feasibility objectives were met. Patients and nurses reported the intervention and study design feasible and acceptable.ConclusionsA palliative-specific PROM-based intervention is feasible and acceptable to both patients with CHF and nurses in nurse-led disease management clinics for the purposes of both clinical care and research.
Anatomical and clinical predictors of valve dysfunction and aortic dilation in bicuspid aortic valve disease
Authors: Evangelista Arturo , Gallego Pastora , Calvo-Iglesias Francisco , Bermejo Javier , Robledo-Carmona Juan , Sánchez Violeta , Saura Daniel , Arnold Roman , Carro Amelia , Maldonado Giuliana , Sao-Avilés Augusto , Teixidó Gisela , Galian Laura , Rodríguez-Palomares José , García-Dorado David 
Published: September 2017

ObjectiveBicuspid aortic valve (BAV) is associated with early valvular dysfunction and proximal aorta dilation with high heterogeneity. This study aimed to assess the determinants of these complications.MethodsEight hundred and fifty-two consecutive adults diagnosed of BAV referred from cardiac outpatient clinics to eight echocardiographic laboratories of tertiary hospitals were prospectively recruited. Exclusion criteria were aortic coarctation, other congenital disorders or intervention. BAV morphotype, significant valve dysfunction and aorta dilation (≥2 Z-score) at sinuses and ascending aorta were established.ResultsThree BAV morphotypes were identified: right–left coronary cusp fusion (RL) in 72.9%, right–non-coronary (RN) in 24.1% and left–non-coronary (LN) in 3.0%. BAV without raphe was observed in 18.3%. Multivariate analysis showed aortic regurgitation (23%) to be related to male sex (OR: 2.80, p<0.0001) and valve prolapse (OR: 5.16, p<0.0001), and aortic stenosis (22%) to BAV-RN (OR: 2.09, p<0.001), the presence of raphe (OR: 2.75, p<0.001), age (OR: 1.03; p<0.001), dyslipidaemia (OR: 1.77, p<0.01) and smoking (OR: 1.63, p<0.05). Ascending aorta was dilated in 76% without differences among morphotypes and associated with significant valvular dysfunction. By contrast, aortic root was dilated in 34% and related to male sex and aortic regurgitation but was less frequent in aortic stenosis and BAV-RN.ConclusionsNormofunctional valves are more prevalent in BAV without raphe. Aortic stenosis is more frequent in BAV-RN and associated with some cardiovascular risk factors, whereas aortic regurgitation (AR) is associated with male sex and sigmoid prolapse. Although ascending aorta is the most commonly dilated segment, aortic root dilation is present in one-third of patients and associated with AR. Remarkably, BAV-RL increases the risk for dilation of the proximal aorta, whereas BAV-RN spares this area.
Impact of presynaptic sympathetic imbalance in long-QT syndrome by positron emission tomography
Authors: Zumhagen Sven , Vrachimis Alexis , Stegger Lars , Kies Peter , Wenning Christian , Ernsting Marko , Müller Jovanca , Seebohm Guiscard , Paul Matthias , Schäfers Klaus , Stallmeyer Birgit , Schäfers Michael , Schulze-Bahr Eric 
Published: September 2017

ObjectiveWe investigated the impact of cardiac presynaptic norepinephrine recycling in patients with long-QT syndrome (LQTS) using positron emission tomography (PET) with 11C-meta-hydroxyephedrine ([11C]mHED-PET).Methods[11C]mHED-PET was performed in 25 patients with LQTS (LQT1: n=14; LQT2: n=11) and 20 healthy controls and correlated with clinical parameters. [11C]mHED-PET images were analysed for global and regional retention indices (RI) and washout rates (WO) reflecting dynamic parameters of the tracer activity.ResultsGlobal and regional RI values were similar between patients with LQTS and controls. Although the global WO rates were similar between these groups, regional WO rates were on average higher in the lateral left ventricle (LV) wall in patients with LQTS (dose, mean ±SD; 0.08±0.14 vs 0.00%±0.09% min–1; p=0.033). In addition, patients with LQTS with a longer QTc interval showed a higher global WO rate. Clinical symptoms correlated with higher global WO rates. In the presence of normal global WO rates, asymptomatic LQTS patients showed higher global RI values.ConclusionThe increased regional WO rate of [11C]mHED in the lateral LV suggests an imbalance of presynaptic catecholamine reuptake and release, resulting in a higher synaptic catecholamine concentration, in particular in LQT1 patients. This might enhance β-adrenoceptor signalling and thereby aggravate inherited ion channel dysfunction and may facilitate occurrence of ventricular tachyarrhythmias. Detection of regional differences in LV sympathetic nervous function may modify disease expression and potentially serve as a non-invasive risk marker in congenital LQTS.Trial registration number2006-002767-41;Results.
Trajectories and characteristics of work disability before and after acute myocardial infarction
Authors: Wang Mo , Vaez Marjan , Dorner Thomas Ernst , Tiihonen Jari , Voss Margaretha , Ivert Torbjörn , Mittendorfer-Rutz Ellenor 
Published: September 2017

ObjectiveScientific knowledge on work disability in terms of sickness absence and disability pension (SA/DP) among patients with acute myocardial infarction (AMI) is scarce. The study aimed to investigate trajectories of SA/DP among individuals with or without AMI and examined the associations between sociodemographic, morbidity and coronary revascularisation characteristics with such trajectories among patients with AMI.MethodsThis is a population-based cohort study of 10 255 individuals aged 30–60 years who had a first AMI during 2008–2010 and were alive 30 days after AMI. Each case was matched by sociodemographics to one control without AMI. Trajectories of annual SA/DP months over a 6-year period for cases and controls were analysed by group-based trajectory modelling. Associations of characteristics with trajectory groups were estimated by Χ2 test and multinomial logistic regression.ResultsThe majority of patients (59%) had slightly increased annual levels of SA/DP (1 month) at the time of AMI, which returned to no SA/DP 2 years after the event. One group (4%) had increasing SA/DP months preceding and after AMI. Three groups showed constant SA/DP months on low (14%), medium (9%) and high (15%) levels. Sex, unemployment, education, musculoskeletal disorders and prescription of antidepressants were the strongest factors discriminating the SA/DP trajectories (R2difference=0.02–0.03, p<0.01).ConclusionsThe majority of patients with AMI have a good outcome in terms of low levels of work disability within 2 years after AMI. Patterns of SA/DP before AMI, sex, socioeconomic status as well as comorbid musculoskeletal and mental disorders provide crucial clinical information on work disability after AMI.
Krüppel-like factor 5 is essential for maintenance of barrier function in mouse colon
Authors: Liu Yang , Chidgey Martyn , Yang Vincent W. , Bialkowska Agnieszka B. 
Published: September 2017

Krüppel-like factor 5 (KLF5) is a member of the zinc finger family of transcription factors that regulates homeostasis of the intestinal epithelium. Previous studies suggested an indispensable role of KLF5 in maintaining intestinal barrier function. In the current study, we investigated the mechanisms by which KLF5 regulates colonic barrier function in vivo and in vitro. We used an inducible and a constitutive intestine-specific Klf5 knockout mouse models ( Villin-CreERT2;Klf5fl/fldesignated as Klf5ΔINDand Villin-Cre;Klf5fl/flas Klf5ΔIS) and studied an inducible KLF5 knockdown in Caco-2 BBe cells using a lentiviral Tet-on system (Caco-2 BBe KLF5ΔIND). Specific knockout of Klf5 in colonic tissues, either inducible or constitutive, resulted in increased intestinal permeability. The phenotype was accompanied by a significant reduction in Dsg2, which encodes desmoglein-2, a desmosomal cadherin, at both mRNA and protein levels. Transmission electron microscopy showed alterations of desmosomal morphology in both KLF5 knockdown Caco-2 BBe cells and Klf5 knockout mouse colonic tissues. Inducible knockdown of KLF5 in Caco-2BBe cells grown on Transwell plates led to impaired barrier function as evidenced by decreased transepithelial electrical resistance and increased paracellular permeability to fluorescein isothiocyanate-4 kDa dextran. Furthermore, DSG2 was significantly decreased in KLF5 knockdown cells, and DSG2 overexpression partially rescued the impaired barrier function caused by KLF5 knockdown. Electron microscopy studies demonstrated altered desmosomal morphology after KLF5 knockdown. In combination with chromatin immunoprecipitation analysis and promoter study, our data show that KLF5 regulates intestinal barrier function by mediating the transcription of DSG2, a gene encoding a major component of desmosome structures.NEW & NOTEWORTHY The study is original research on the direct function of a Krüppel-like factor on intestinal barrier function, which is commonly exerted by cell junctions, including tight junctions, adherens junctions, and desmosomes. Numerous previous studies were focused on tight junctions and adherens junctions. However, this study provided a new perspective on how the intestinal barrier function is regulated by KLF5 through DSG2, a component of desmosome complexes.
Dual Inhibition of Hedgehog and c-Met Pathways for Pancreatic Cancer Treatment
Authors: Rucki Agnieszka A. , Xiao Qian , Muth Stephen , Chen Jianlin , Che Xu , Kleponis Jennifer , Sharma Rajni , Anders Robert A. , Jaffee Elizabeth M. , Zheng Lei 
Published: September 2017

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most chemotherapy- and radiotherapy-resistant tumors. The c-Met and Hedgehog (Hh) pathways have been shown previously by our group to be key regulatory pathways in the primary tumor growth and metastases formation. Targeting both the HGF/c-Met and Hh pathways has shown promising results in preclinical studies; however, the benefits were not readily translated into clinical trials with PDAC patients. In this study, utilizing mouse models of PDAC, we showed that inhibition of either HGF/c-Met or Hh pathways sensitize the PDAC tumors to gemcitabine, resulting in decreased primary tumor volume as well as significant reduction of metastatic tumor burden. However, prolonged treatment of single HGF/c-Met or Hh inhibitor leads to resistance to these single inhibitors, likely because the single c-Met treatment leads to enhanced expression of Shh, and vice versa. Targeting both the HGF/c-Met and Hh pathways simultaneously overcame the resistance to the single-inhibitor treatment and led to a more potent antitumor effect in combination with the chemotherapy treatment. Mol Cancer Ther; 16(11); 2399–409. ©2017 AACR.
Inhibition of Discoidin Domain Receptor 1 Reduces Collagen-mediated Tumorigenicity in Pancreatic Ductal Adenocarcinoma
Authors: Aguilera Kristina Y. , Huang Huocong , Du Wenting , Hagopian Moriah M. , Wang Zhen , Hinz Stefan , Hwang Tae Hyun , Wang Huamin , Fleming Jason B. , Castrillon Diego H. , Ren Xiaomei , Ding Ke , Brekken Rolf A. 
Published: September 2017

Abstract
The extracellular matrix (ECM), a principal component of pancreatic ductal adenocarcinoma (PDA), is rich in fibrillar collagens that facilitate tumor cell survival and chemoresistance. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that specifically binds fibrillar collagens and has been implicated in promoting cell proliferation, migration, adhesion, ECM remodeling, and response to growth factors. We found that collagen-induced activation of DDR1 stimulated protumorigenic signaling through protein tyrosine kinase 2 (PYK2) and pseudopodium-enriched atypical kinase 1 (PEAK1) in pancreatic cancer cells. Pharmacologic inhibition of DDR1 with an ATP-competitive orally available small-molecule kinase inhibitor (7rh) abrogated collagen-induced DDR1 signaling in pancreatic tumor cells and consequently reduced colony formation and migration. Furthermore, the inhibition of DDR1 with 7rh showed striking efficacy in combination with chemotherapy in orthotopic xenografts and autochthonous pancreatic tumors where it significantly reduced DDR1 activation and downstream signaling, reduced primary tumor burden, and improved chemoresponse. These data demonstrate that targeting collagen signaling in conjunction with conventional cytotoxic chemotherapy has the potential to improve outcome for pancreatic cancer patients. Mol Cancer Ther; 16(11); 2473–85. ©2017 AACR.
mTOR Kinase Inhibition Effectively Decreases Progression of a Subset of Neuroendocrine Tumors that Progress on Rapalog Therapy and Delays Cardiac Impairment
Authors: Orr-Asman Melissa A. , Chu Zhengtao , Jiang Min , Worley Mariah , LaSance Kathleen , Koch Sheryl E. , Carreira Vinicius S. , Dahche Hanan M. , Plas David R. , Komurov Kakajan , Qi Xiaoyang , Mercer Carol A. , Anthony Lowell B. , Rubinstein Jack , Thomas Hala E. 
Published: September 2017

Abstract
Inhibition of mTOR signaling using the rapalog everolimus is an FDA-approved targeted therapy for patients with lung and gastroenteropancreatic neuroendocrine tumors (NET). However, patients eventually progress on treatment, highlighting the need for additional therapies. We focused on pancreatic NETs (pNET) and reasoned that treatment of these tumors upon progression on rapalog therapy, with an mTOR kinase inhibitor (mTORKi), such as CC-223, could overcome a number of resistance mechanisms in tumors and delay cardiac carcinoid disease. We performed preclinical studies using human pNET cells in vitro and injected them subcutaneously or orthotopically to determine tumor progression and cardiac function in mice treated with either rapamycin alone or switched to CC-223 upon progression. Detailed signaling and RNA sequencing analyses were performed on tumors that were sensitive or progressed on mTOR treatment. Approximately 57% of mice bearing pNET tumors that progressed on rapalog therapy showed a significant decrease in tumor volume upon a switch to CC-223. Moreover, mice treated with an mTORKi exhibited decreased cardiac dilation and thickening of heart valves than those treated with placebo or rapamycin alone. In conclusion, in the majority of pNETs that progress on rapalogs, it is possible to reduce disease progression using an mTORKi, such as CC-223. Moreover, CC-223 had an additional transient cardiac benefit on valvular fibrosis compared with placebo- or rapalog-treated mice. These results provide the preclinical rationale to further develop mTORKi clinically upon progression on rapalog therapy and to further test their long-term cardioprotective benefit in those NET patients prone to carcinoid syndrome. Mol Cancer Ther; 16(11); 2432–41. ©2017 AACR.
A CRISPR/Cas9–Based Screening for Non-Homologous End Joining Inhibitors Reveals Ouabain and Penfluridol as Radiosensitizers
Authors: Du Jie , Shang Jun , Chen Fei , Zhang Yushuo , Yin Narui , Xie Ting , Zhang Haowen , Yu Jiahua , Liu Fenju 
Published: September 2017

Abstract
Non-homologous end joining (NHEJ) is the major pathway responsible for the repair of ionizing radiation (IR)–induced DNA double-strand breaks (DSB), and correspondingly regulates the cellular response to IR. Identification of NHEJ inhibitors could substantially enhance the tumor radiosensitivity and improve the therapeutic efficiency of radiotherapy. In this study, we demonstrated a screening for NHEJ inhibitors using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and high-resolution melting (HRM) analysis. Because NHEJ is regarded as an error-prone mechanism, the NHEJ-mediated ligation of the site-specific DSB induced by Cas9 nuclease would eventually cause the mutation of the targeted sequence. Then, HRM analysis, a reliable and rapid assay for detecting sequence variation, was performed to evaluate the mutation efficiency of the targeted site. Validating analysis confirmed the NHEJ activities were positively correlated with the mutation frequencies. Next, an approved drug library containing 1,540 compounds was interrogated by using this screening strategy. Our results identified ouabain, a cardiotonic agent, and penfluridol, an antipsychotic agent, have the capacity to restrain NHEJ activity. Further experiments in vitro revealed the radiosensitizing effects of these compounds. Overall, we presented a cell-based screening for NHEJ inhibitors, which could promote the discovery of novel radiosensitizers. Mol Cancer Ther; 17(2); 419–31. ©2017 AACR.
See all articles in this MCT Focus section, “Developmental Therapeutics in Radiation Oncology.”
Recurrent Tumor Cell–Intrinsic and –Extrinsic Alterations during MAPKi-Induced Melanoma Regression and Early Adaptation
Authors: Song Chunying , Piva Marco , Sun Lu , Hong Aayoung , Moriceau Gatien , Kong Xiangju , Zhang Hong , Lomeli Shirley , Qian Jin , Yu Clarissa C. , Damoiseaux Robert , Kelley Mark C. , Dahlman Kimberley B. , Scumpia Philip O. , Sosman Jeffrey A. , Johnson Douglas B. , Ribas Antoni , Hugo Willy , Lo Roger S. 
Published: September 2017

Abstract
Treatment of advanced BRAFV600-mutant melanoma using a BRAF inhibitor or its combination with a MEK inhibitor typically elicits partial responses. We compared the transcriptomes of patient-derived tumors regressing on MAPK inhibitor (MAPKi) therapy against MAPKi-induced temporal transcriptomic states in human melanoma cell lines or murine melanoma in immune-competent mice. Despite heterogeneous dynamics of clinical tumor regression, residual tumors displayed highly recurrent transcriptomic alterations and enriched processes, which were also observed in MAPKi-selected cell lines (implying tumor cell–intrinsic reprogramming) or in bulk mouse tumors (and the CD45-negative or CD45-positive fractions, implying tumor cell–intrinsic or stromal/immune alterations, respectively). Tumor cell–intrinsic reprogramming attenuated MAPK dependency, while enhancing mesenchymal, angiogenic, and IFN-inflammatory features and growth/survival dependence on multi-RTKs and PD-L2. In the immune compartment, PD-L2 upregulation in CD11c+ immunocytes drove the loss of T-cell inflammation and promoted BRAFi resistance. Thus, residual melanoma early on MAPKi therapy already displays potentially exploitable adaptive transcriptomic, epigenomic, immune-regulomic alterations.
Significance: Incomplete MAPKi-induced melanoma regression results in transcriptome/methylome-wide reprogramming and MAPK-redundant escape. Although regressing/residual melanoma is highly T cell–inflamed, stromal adaptations, many of which are tumor cell–driven, could suppress/eliminate intratumoral T cells, reversing tumor regression. This catalog of recurrent alterations helps identify adaptations such as PD-L2 operative tumor cell intrinsically and/or extrinsically early on therapy. Cancer Discov; 7(11); 1248–65. ©2017 AACR.
See related commentary by Haq, p. 1216.
This article is highlighted in the In This Issue feature, p. 1201