bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Raf-Competitive K-Ras Binder Can Fail to Functionally Antagonize Signaling
Authors: Kauke Monique J. , Tisdale Alison W. , Kelly Ryan L. , Braun Christian J. , Hemann Michael T. , Wittrup K. Dane 
Published: May 2018

Abstract
Mutated in approximately 30% of human cancers, Ras GTPases are the most common drivers of oncogenesis and render tumors unresponsive to many standard therapies. Despite decades of research, no drugs directly targeting Ras are currently available. We have previously characterized a small protein antagonist of K-Ras, R11.1.6, and demonstrated its direct competition with Raf for Ras binding. Here we evaluate the effects of R11.1.6 on Ras signaling and cellular proliferation in a panel of human cancer cell lines. Through lentiviral transduction, we generated cell lines that constitutively or through induction with doxycycline express R11.1.6 or a control protein YW1 and show specific binding by R11.1.6 to endogenous Ras through microscopy and co-immunoprecipitation experiments. Genetically encoded intracellular expression of this high-affinity Ras antagonist, however, fails to measurably disrupt signaling through either the MAPK or PI3K pathway. Consistently, cellular proliferation was unaffected as well. To understand this lack of signaling inhibition, we quantified the number of molecules of R11.1.6 expressed by the inducible cell lines and developed a simple mathematical model describing the competitive binding of Ras by R11.1.6 and Raf. This model supports a potential mechanism for the lack of biological effects that we observed, suggesting stoichiometric and thermodynamic barriers that should be overcome in pharmacologic efforts to directly compete with downstream effector proteins localized to membranes at very high effective concentrations. Mol Cancer Ther; 17(8); 1773–80. ©2018 AACR.
CAR-T Cells Surface-Engineered with Drug-Encapsulated Nanoparticles Can Ameliorate Intratumoral T-cell Hypofunction
Authors: Siriwon Natnaree , Kim Yu Jeong , Siegler Elizabeth , Chen Xianhui , Rohrs Jennifer A. , Liu Yarong , Wang Pin 
Published: May 2018

Abstract
One limiting factor of CAR T-cell therapy for treatment of solid cancers is the suppressive tumor microenvironment (TME), which inactivates the function of tumor-infiltrating lymphocytes (TIL) through the production of immunosuppressive molecules, such as adenosine. Adenosine inhibits the function of CD4+ and CD8+ T cells by binding to and activating the A2a adenosine receptor (A2aR) expressed on their surface. This suppression pathway can be blocked using the A2aR-specific small molecule antagonist SCH-58261 (SCH), but its applications have been limited owing to difficulties delivering this drug to immune cells within the TME. To overcome this limitation, we used CAR-engineered T cells as active chaperones to deliver SCH-loaded cross-linked, multilamellar liposomal vesicles (cMLV) to tumor-infiltrating T cells deep within the immune suppressive TME. Through in vitro and in vivo studies, we have demonstrated that this system can be used to effectively deliver SCH to the TME. This treatment may prevent or rescue the emergence of hypofunctional CAR-T cells within the TME. Cancer Immunol Res; 6(7); 812–24. ©2018 AACR.
Clinical Characteristics, Sex Differences, and Outcomes in Patients With Normal or Near‐Normal Coronary Arteries, Non‐Obstructive or Obstructive Coronary Artery Disease
Authors: Ouellette Michelle L. , Löffler Adrián I. , Beller George A. , Workman Virginia K. , Holland Eric , Bourque Jamieson M. 
Published: May 2018

Background

Normal or near‐normal coronary arteries (
NNCAs
) or nonobstructive coronary artery disease (
CAD)
are found on invasive coronary angiography in ≈55% of patients. Some attribute this to frequent referral of low‐risk patients. We sought to identify the referral indications, pretest risk, key clinical characteristics, sex, and outcomes in patients with
NNCAs
and nonobstructive
CAD
versus obstructive
CAD
on nonemergent invasive coronary angiography.

Methods and Results

Over 24 months, 925 consecutive patients were classified as having
NNCAs
(≤20% stenosis), nonobstructive
CAD
(21–49% stenosis), or obstructive
CAD
(≥50% stenosis). Outcomes included cardiac death, nonfatal myocardial infarction
,
and late revasclarization.
NNCAs
were found in 285 patients (31.0%), nonobstructive
CAD
in 125 (13.5%), and obstructive
CAD
in 513 (55.5%).
NNCAs
or nonobstructive
CAD
was found in 40.5% with stress ischemia, 27.9% after a non‐ST‐elevation myocardial infarction, and in 55.5% with stable or unstable angina. More women than men (53.5% versus 37.2%;
P
<0.001) had
NNCAs
or nonobstructive
CAD
across all referral indications. Pretest risk was high and
ICA
appropriate in 75.5% and 99.2% of patients, respectively. Annual rates of cardiac death or nonfatal
myocardial infarction
were 1.0%, 1.1%, and 6.7%, respectively, for patients with
NNCAs
, nonobstructive
CAD
, and obstructive
CAD
(
P
<0.001). No sex differences in outcomes were observed with either
NNCAs
, nonobstructive
CAD,
or obstructive
CAD
(
P
=0.84).

Conclusions

Many (44.5%) patients undergoing nonemergent invasive coronary angiography have
NNCAs
or nonobstructive
CAD
despite high pretest risk, including ischemia and troponin elevation. Although women had more
NNCAs
or nonobstructive
CAD
, there were no differences in event rates by sex. Patients with
NNCAs
and nonobstructive
CAD
had very low event rates.
Gene Transfer of Engineered Calmodulin Alleviates Ventricular Arrhythmias in a Calsequestrin‐Associated Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia
Authors: Liu Bin , Walton Shane D. , Ho Hsiang‐Ting , Belevych Andriy E. , Tikunova Svetlana B. , Bonilla Ingrid , Shettigar Vikram , Knollmann Bjorn C. , Priori Silvia G. , Volpe Pompeo , Radwański Przemysław B. , Davis Jonathan P. , Györke Sándor 
Published: May 2018

Background

Catecholaminergic polymorphic ventricular tachycardia (
CPVT
) is a familial arrhythmogenic syndrome characterized by sudden death. There are several genetic forms of
CPVT
associated with mutations in genes encoding the cardiac ryanodine receptor (RyR2) and its auxiliary proteins including calsequestrin (
CASQ
2) and calmodulin (CaM). It has been suggested that impairment of the ability of RyR2 to stay closed (ie, refractory) during diastole may be a common mechanism for these diseases. Here, we explore the possibility of engineering CaM variants that normalize abbreviated RyR2 refractoriness for subsequent viral‐mediated delivery to alleviate arrhythmias in non–CaM‐related
CPVT
.

Methods and Results

To that end, we have designed a CaM protein (
GSH
‐M37Q; dubbed as therapeutic CaM or T‐CaM) that exhibited a slowed N‐terminal Ca dissociation rate and prolonged RyR2 refractoriness in permeabilized myocytes derived from
CPVT
mice carrying the
CASQ
2 mutation R33Q. This T‐CaM was introduced to the heart of R33Q mice through recombinant adeno‐associated viral vector serotype 9. Eight weeks postinfection, we performed confocal microscopy to assess Ca handling and recorded surface ECGs to assess susceptibility to arrhythmias in vivo. During catecholamine stimulation with isoproterenol, T‐CaM reduced isoproterenol‐promoted diastolic Ca waves in isolated
CPVT
cardiomyocytes. Importantly, T‐CaM exposure abolished ventricular tachycardia in
CPVT
mice challenged with catecholamines.

Conclusions

Our results suggest that gene transfer of T‐CaM by adeno‐associated viral vector serotype 9 improves myocyte Ca handling and alleviates arrhythmias in a calsequestrin‐associated
CPVT
model, thus supporting the potential of a CaM‐based antiarrhythmic approach as a therapeutic avenue for genetically distinct forms of
CPVT
.
Association of Blood Pressure With Short- and Long-Term Functional Outcome After Stroke Thrombectomy
Authors: Schönenberger Silvia , Uhlmann Lorenz , Ungerer Matthias , Pfaff Johannes , Nagel Simon , Klose Christina , Bendszus Martin , Wick Wolfgang , Ringleb Peter A. , Kieser Meinhard , Möhlenbruch Markus A. , Bösel Julian 
Published: May 2018

Background and Purpose—
Outcome after mechanical thrombectomy for ischemic stroke may be influenced by blood pressure (BP). This study aims to assess the association of BP changes during general anesthesia versus conscious sedation with functional outcome after mechanical thrombectomy.

Methods—
SIESTA (Sedation vs Intubation for Endovascular Stroke Treatment) was a monocentric randomized trial of general anesthesia versus conscious sedation during mechanical thrombectomy involving BP target protocols. In this post hoc analysis, BP measurements were divided into 4 phases: preintervention, prerecanalization, postrecanalization, and postintervention. We examined the association between BP and functional outcomes (defined by improvement of 24-hour National Institutes of Health Stroke Scale [NIHSS] and 3-month modified Rankin Scale).

Results—

We found no association between the difference in systolic BP, diastolic BP, and mean arterial pressure from baseline to the different phases of intervention and NIHSS change after 24 hours. Only baseline diastolic BP was associated with a reduced improvement in NIHSS (β=0.17,
P
<0.01). There was no association of BP drops with a change in modified Rankin Scale at 3 months. About sedation, only baseline mean arterial pressure preintervention revealed significant associations (β=0.16,
P
<0.01) with less change in 24-hour NIHSS in conscious sedation group. Otherwise, there was no association for differences of any of the BP measurements with a change in 24-hour NIHSS and long-term functional outcome either in general anesthesia or the conscious sedation group when analyzed separately, consistent with our findings in the entire cohort. Doses of propofol (β=0.84,
P
=0.04) and norepinephrine (β=1.87,
P
=0.01) administered during intervention before recanalization were associated with reduced improvement of NIHSS at 24 hours.

Conclusions—
In a setting, where both sedation regimes general anesthesia and conscious sedation were performed according to strict protocols directed at avoiding BP extremes, our findings suggest that peri-interventional BP drops were not associated with either early neurological improvement or long-term functional outcome.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02126085.
Prediction of Tissue Outcome and Assessment of Treatment Effect in Acute Ischemic Stroke Using Deep Learning
Authors: Nielsen Anne , Hansen Mikkel Bo , Tietze Anna , Mouridsen Kim 
Published: May 2018

Background and Purpose—
Treatment options for patients with acute ischemic stroke depend on the volume of salvageable tissue. This volume assessment is currently based on fixed thresholds and single imagine modalities, limiting accuracy. We wish to develop and validate a predictive model capable of automatically identifying and combining acute imaging features to accurately predict final lesion volume.

Methods—

Using acute magnetic resonance imaging, we developed and trained a deep convolutional neural network (CNN
deep
) to predict final imaging outcome. A total of 222 patients were included, of which 187 were treated with rtPA (recombinant tissue-type plasminogen activator). The performance of CNN
deep
was compared with a shallow CNN based on the perfusion-weighted imaging biomarker Tmax (CNN
Tmax
), a shallow CNN based on a combination of 9 different biomarkers (CNN
shallow
), a generalized linear model, and thresholding of the diffusion-weighted imaging biomarker apparent diffusion coefficient (ADC) at 600×10
−6
mm
2
/s (ADC
thres
). To assess whether CNN
deep
is capable of differentiating outcomes of ±intravenous rtPA, patients not receiving intravenous rtPA were included to train CNN
deep,
−rtpa
to access a treatment effect. The networks’ performances were evaluated using visual inspection, area under the receiver operating characteristic curve (AUC), and contrast.

Results—

CNN
deep
yields significantly better performance in predicting final outcome (AUC=0.88±0.12) than generalized linear model (AUC=0.78±0.12;
P
=0.005), CNN
Tmax
(AUC=0.72±0.14;
P
<0.003), and ADC
thres
(AUC=0.66±0.13;
P
<0.0001) and a substantially better performance than CNN
shallow
(AUC=0.85±0.11;
P
=0.063). Measured by contrast, CNN
deep
improves the predictions significantly, showing superiority to all other methods (
P
≤0.003). CNN
deep
also seems to be able to differentiate outcomes based on treatment strategy with the volume of final infarct being significantly different (
P
=0.048).

Conclusions—
The considerable prediction improvement accuracy over current state of the art increases the potential for automated decision support in providing recommendations for personalized treatment plans.
Hypoxia-Inducible Factor-1α (HIF-1α) Expression on Endothelial Cells in Juvenile Nasopharyngeal Angiofibroma: A Review of 70 cases and Tissue Microarray Analysis
Authors: Song Xiaole , Yang Chenhe , Zhang Huankang , Wang Jingjing , Sun Xicai , Hu Li , Liu Zhuofu , Wang Dehui 
Published: May 2018

Objective: To examine the expression of hypoxia-inducible factor-1α (HIF-1α) and its related molecules (cellular repressor of E1A-stimulated genes [CREG], osteopontin [OPN], proto-oncogene tyrosine-protein kinase Src [c-Src], and vascular endothelial growth factor [VEGF]) in juvenile nasopharyngeal angiofibroma (JNA) and explore the correlation between clinical prognosis and HIF-1α expression. Methods: The study performed a retrospective review of the clinical records of patients with JNA treated between 2003 and 2007. Specimens were analyzed by immunohistochemistry for HIF-1α, CREG, OPN, c-Src, and VEGF expression, and microvessel density (MVD) was assessed by tissue microarray. The correlation between expression levels and clinicopathological features including age, tumor stage, intraoperative blood loss, and recurrence was analyzed. Results: HIF-1α, CREG, OPN, c-Src, and VEGF were upregulated in endothelial cells (ECs) of patients with JNA, and strong correlations in the expression of these molecules were observed. HIF-1α expression was higher in young patients ( P = .032) and in recurrent cases ( P = .01). Survival analysis showed that low HIF-1α levels in ECs predicted longer time to recurrence (log rank test P = .006). Receiver operating characteristic curve analysis showed that HIF-1α was a prognostic factor for recurrence (area under the curve = 0.690, P = .019). No correlation was found between the expression of molecules and Radkowski stage or intraoperative blood loss. Conclusion: In cases of JNA treated surgically, HIF-1α expression in ECs is a useful prognostic factor for tumor recurrence.
Double Carina: A Novel Tracheo-Bronchial Anomaly Found During a Pediatric Airway Evaluation
Authors: Mildenhall Nicholas R. , Raynor Eileen M. 
Published: May 2018

Objectives: To present a novel pediatric airway anomaly encountered on direct laryngoscopy and bronchoscopy, further characterized with computed tomography imaging of the chest. Study Design: Case report and literature review. Methods: Review of the clinical presentation, operative findings, and imaging findings of an infant who presented with respiratory distress in the setting of multiple congenital abnormalities. A brief literature review supplements the case presentation. Results: While multiple tracheobronchial anomalies have long been reported, this is the first report of a double or false carina: a system of symmetric paired upper and lower bronchi connected by a central conduit. Operative evaluation was limited given the narrow lumen, and postoperative imaging aided in further characterization of the pediatric airway. Conclusions: This is the first report of a novel tracheobronchial anomaly presenting as a double carina. Tracheobronchial anomalies are diverse and should be considered when performing operative airway evaluations. Imaging can be a helpful adjunct with anatomic characterization.
Integrating Visual Mnemonics and Input Feedback With Passphrases to Improve the Usability and Security of Digital Authentication
Authors: Juang Kevin , Greenstein Joel 
Published: May 2018

Objective: We developed a new authentication system based on passphrases instead of passwords. Our new system incorporates a user-generated mnemonic picture displayed during login, definition tooltips, error correction to reduce typographical errors, a decoy-based input masking technique, and random passphrase generation using either a specialized wordlist or a sentence template. Background: Passphrases exhibit a greater level of security than traditional passwords, but their wider adoption has been hindered by human factors issues. Our assertion is that the added features of our system work particularly well with passphrases and help address these shortcomings. Method: We conducted a study to evaluate our new system with a customized 1,450-word list and our new system with a 6-word sentence structure against the control conditions of a user-created passphrase of at least 24 characters and a system-generated passphrase using a 10,326-word list. Fifty participants completed two sessions so that we could measure the usability and security of the authentication schemes. Results: With the new system conditions, memorability was improved, and security was equivalent to or better than the control conditions. Usability and overall ratings also favored the new system conditions over the control conditions. Conclusion: Our research presents a new authentication system using innovative techniques that improve on the usability and security of existing password and passphrase authentication systems. Application: In computer security, drastic changes should never happen overnight, but we recommend that our contributions be incorporated into current authentication systems to help facilitate a transition from passwords to usable passphrases.
Screening for colorectal cancer in defunctioned colons
Authors: Akbar Fayyaz , Quyn Aaron , Steele Robert 
Published: May 2018

Objectives Population-based colorectal (bowel) cancer screening using faecal occult blood tests leads to a reduction in cause-specific mortality. However, in people where the colon is defunctioned, the use of standard faecal occult blood test is not appropriate. The aim of this study was to examine the current trends of clinical practice for colorectal cancer screening in people with defunctioned colons. Methods An online survey was performed using SurveyMonkey. All members of the Association of Coloproctology of Great Britain and Ireland were invited by email to participate. Reminders were sent to non-responders and partial responders till six weeks. All responses were included in our analysis. Results Of the 206 (34.59%) questionnaires completed, all questions were answered in 110 (55.8%). Among responders, 94 (85.4%) were colorectal consultant surgeons, 72% had worked in their current capacity for more than five years, and 105 (50.9%) had encountered colorectal cancer in defunctioned colons during their career. Some 72.2% of responders stated that a screening test for colorectal cancer in patients with defunctioned colons was currently not offered, or that they did not know whether or not it was offered in their area. Conclusions Bowel screening in the United Kingdom is currently not offered to 72.2% of the age appropriate population with defunctioned colons. Among responding colorectal surgeons, 50% had encountered colorectal cancer in such patients. There is considerable variability in clinical practice regarding the optimal age for onset of screening, time interval, and the optimal modality to offer for screening in such cases.
Demythologising the ‘Liberalisation’ of Clinical Trial Regulations in India: A Practitioner’s Perspective
Authors: Regal Brijesh 
Published: May 2018

Recent history of clinical trials in India has been mired in avoidable controversies. Negative public perception and consequent reactions by government and judiciary have led to a virtual blockade of clinical trials in the country. This article dispassionately analyses the fiascos that happened in the past few years, describes how folklore disseminated by media, civil society and experts created a myth about ‘liberalisation’ of regulations and presents facts about regulatory amendments. The causes of recent non-compliances are discussed and real fault-lines are identified. The article posits that territorial laws must remain harmonised with contemporary international standards for regulating global activities like clinical trials. Fixing what was not broken has already caused substantial harm and Indian regulators have done well by reversing the unnecessary tinkering recommended by some quasi-experts. Professional self-regulation along with implementation of existing regulations are proposed as the best solutions for gaining India’s place on the global clinical trials’ growth curve.
Informed Consent in Pediatric Oncology
Authors: Alahmad Ghiath 
Published: May 2018

Objective: Obtaining informed consent in pediatric cancer research can be subject to important ethical challenges because of the difficulty in distinguishing between care and research, which are interrelated. Pediatric oncologists also often conduct research, such as clinical trials, on their own patients, which may influence voluntary informed consent. This review aims to determine the ethical issues encountered in obtaining informed consent in pediatric oncology by identifying and summarizing the findings of existing qualitative studies on this topic. Methods: A systematic review of qualitative studies was conducted. Medline, Embase, CINAHL, and PubMed were searched using the following terms: (oncolog* or cancer or hematol* or haematol* or leuk* or malign* or neoplasm*) and (child* or adolescent* or minor* or young people or pediatr* or paediatr*) and ethic* or moral*) and (qualitative or interview). Other sources were also mined to identify all relevant studies. The data analysis method used was thematic analysis. Results: At the end of the search process, 2361 studies were identified. Duplicates were removed and irrelevant studies were excluded. After screening the full text of the remaining studies against our inclusion and exclusion criteria, 13 studies were included in the qualitative analysis. All studies were qualitative studies using semistructured and structured interviews, qualitative analysis of open-ended questions, and observation of informed consent conferences. Four themes were identified: parental comprehension of the trial and medical terms, influence of parental distress on decision-making, no offer of an alternative treatment, and influence of the doctor–parent relationship. Conclusion: Many ethical challenges affect the informed consent process. These challenges may include a lack of parental understanding, the potential influence of treating doctors, and vulnerability because of psychological status. All of these result in parents being unable to give well-informed and voluntary consent. Researchers are encouraged to adopt a stepwise approach during the informed consent process.