bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of the SRC Kinase HCK Impairs STAT3-Dependent Gastric Tumor Growth in Mice
Authors: Poh Ashleigh R. , Dwyer Amy R. , Eissmann Moritz F. , Chand Ashwini L. , Baloyan David , Boon Louis , Murrey Michael W. , Whitehead Lachlan , O'Brien Megan , Lowell Clifford A. , Putoczki Tracy L. , Pixley Fiona J. , O'Donoghue Robert J.J. , Ernst Matthias 
Published: January 2020

Abstract

Persistent activation of the latent transcription factor STAT3 is observed in gastric tumor epithelial and immune cells and is associated with a poor patient prognosis. Although targeting STAT3-activating upstream kinases offers therapeutically viable targets with limited specificity, direct inhibition of STAT3 remains challenging. Here we provide functional evidence that myeloid-specific hematopoietic cell kinase (HCK) activity can drive STAT3-dependent epithelial tumor growth in mice and is associated with alternative macrophage activation alongside matrix remodeling and tumor cell invasion. Accordingly, genetic reduction of HCK expression in bone marrow–derived cells or systemic pharmacologic inhibition of HCK activity suppresses alternative macrophage polarization and epithelial STAT3 activation, and impairs tumor growth. These data validate HCK as a molecular target for the treatment of human solid tumors harboring excessive STAT3 activity.
Control of Metastases via Myeloid CD39 and NK Cell Effector Function
Authors: Yan Juming , Li Xian-Yang , Roman Aguilera Amelia , Xiao Christos , Jacoberger-Foissac Celia , Nowlan Bianca , Robson Simon C. , Beers Courtney , Moesta Achim K. , Geetha Nishamol , Teng Michele W.L. , Smyth Mark J. 
Published: January 2020

AbstractNatural killer (NK) cell protection from tumor metastases is a critical feature of the host immune response to cancer, but various immunosuppression mechanisms limit NK cell effector function. The ectoenzyme, CD39, expressed on tumor-infiltrating myeloid cells, granulocytes, and lymphocytes, including NK cells, converts extracellular ATP (eATP) into AMP and, thus, potentially suppresses eATP-mediated proinflammatory responses. A CD39-targeting monoclonal antibody (mAb) that inhibits the mouse ectoenzyme CD39 suppressed experimental and spontaneous metastases in a number of different tumor models and displayed superior antimetastatic activity compared with the CD39 inhibitor POM1 and inhibitors and mAbs that block other members of the adenosinergic family (e.g., A2AR and CD73). The antimetastatic activity of anti-CD39 was NK cell and IFNγ dependent, and anti-CD39 enhanced the percentage and quantity of IFNγ produced and CD107a expression in lung-infiltrating NK cells following tumor challenge and anti-CD39 therapy. Using conditional Cd39 gene–targeted mouse strains and adoptive NK cell transfers, we showed that CD39 expressed on bone marrow–derived myeloid cells was essential for anti-CD39′s antimetastatic activity, but NK cell expression of CD39 was not critical. The eATP receptor P2X7 and the NALP3 inflammasome, including downstream IL18, were critical in the mechanism of action of anti-CD39, and the frequency of P2X7 and CD39 coexpressing lung alveolar macrophages was specifically reduced 1 day after anti-CD39 therapy. The data provide a mechanism of action involving NK cells and myeloid cells, and anti-CD39 combined with anti–PD-1, NK cell–activating cytokines IL15 or IL2, or an inhibitor of A2AR to effectively suppress tumor metastases.
Predictive Value of the Get With The Guidelines Heart Failure Risk Score in Unselected Cardiac Intensive Care Unit Patients
Authors: Lyle Melissa , Wan Siu‐Hin , Murphree Dennis , Bennett Courtney , Wiley Brandon M. , Barsness Gregory , Redfield Margaret , Jentzer Jacob 
Published: January 2020

Background

The cardiac intensive care unit (
CICU
) population is no longer composed of only patients with acute coronary syndromes, and includes those with acute heart failure and multiple comorbidities. We hypothesized that the
GWTG
‐
HF
(Get With The Guidelines–Heart Failure) risk score that predicts inpatient mortality in hospitalized patients with heart failure would predict mortality in
CICU
patients.

Methods and Results

We retrospectively analyzed
CICU
patients at a tertiary care hospital from 2007 to 2015. The
GWTG
‐
HF
risk score was calculated at
CICU
admission. As a secondary analysis, the
EFFECT (Enhanced Feedback for Effective Cardiac Treatment)
, OPTIMIZE‐HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure), and
ADHERE (Acute Decompensated Heart Failure National Registry)
risk scores were calculated. Kaplan–Meier survival analysis and the area under the receiver operating characteristic curve value were determined for inpatient and 1‐year mortality. The
GWTG
‐
HF
risk score was calculated in 9532 (95%) patients, with a median value of 40 (interquartile range, 35–47). Inpatient mortality occurred in 824 (8.6%) patients, and 2075 (21.8%) patients died by 1 year. Patients who died in hospital had a significantly higher mean
GWTG
‐
HF
score (47.7 versus 40.2;
P
<0.001). Inpatient and 1‐year mortality increased in each
GWTG
‐
HF
risk score quartile (
P
<0.0001). Discrimination of the
GWTG
‐
HF
,
EFFECT, OPTIMIZE‐HF, and ADHERE
risk scores was assessed using
area under the receiver operating characteristic curve
values for hospital mortality, and were similar for all risk scores (0.72–0.74;
P
>0.05). The Hosmer–Lemeshow statistic suggested poor calibration for hospital mortality by the
GWTG
‐
HF
risk score (
P
<0.001).

Conclusions

The
GWTG
‐
HF
risk score and other heart failure prediction tools demonstrate good discrimination for inpatient and 1‐year mortality in a heterogeneous cohort of
CICU
patients. Our study emphasizes that prognostic variables overlap in cardiac patients, regardless of the admission diagnosis.
Effects of Intracoronary Alteplase on Microvascular Function in Acute Myocardial Infarction
Authors: Maznyczka Annette M. , McCartney Peter J. , Oldroyd Keith G. , Lindsay Mitchell , McEntegart Margaret , Eteiba Hany , Rocchiccioli Paul , Good Richard , Shaukat Aadil , Robertson Keith , Kodoth Vivek , Greenwood John P. , Cotton James M. , Hood Stuart , Watkins Stuart , Macfarlane Peter W. , Kennedy Julie , Tait R. Campbell , Welsh Paul , Sattar Naveed , Collison Damien , Gillespie Lynsey , McConnachie Alex , Berry Colin 
Published: January 2020

Background

Impaired microcirculatory reperfusion worsens prognosis following acute
ST
‐segment–elevation myocardial infarction. In the T‐
TIME
(A Trial of Low‐Dose Adjunctive Alteplase During Primary PCI) trial, microvascular obstruction on cardiovascular magnetic resonance imaging did not differ with adjunctive, low‐dose, intracoronary alteplase (10 or 20 mg) versus placebo during primary percutaneous coronary intervention. We evaluated the effects of intracoronary alteplase, during primary percutaneous coronary intervention, on the index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio.

Methods and Results

A prespecified physiology substudy of the T‐
TIME
trial. From 2016 to 2017, patients with
ST
‐segment–elevation myocardial infarction ≤6 hours from symptom onset were randomized in a double‐blind study to receive alteplase 20 mg, alteplase 10 mg, or placebo infused into the culprit artery postreperfusion, but prestenting. Index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio were measured after percutaneous coronary intervention. Cardiovascular magnetic resonance was performed at 2 to 7 days and 3 months. Analyses in relation to ischemic time (<2, 2–4, and ≥4 hours) were prespecified. One hundred forty‐four patients (mean age, 59±11 years; 80% male) were prospectively enrolled, representing 33% of the overall population (n=440). Overall, index of microcirculatory resistance (median, 29.5; interquartile range, 17.0–55.0), coronary flow reserve(1.4 [1.1–2.0]), and resistive reserve ratio (1.7 [1.3–2.3]) at the end of percutaneous coronary intervention did not differ between treatment groups. Interactions were observed between ischemic time and alteplase for coronary flow reserve (
P
=0.013), resistive reserve ratio (
P
=0.026), and microvascular obstruction (
P
=0.022), but not index of microcirculatory resistance.

Conclusions

In
ST
‐segment–elevation myocardial infarction with ischemic time ≤6 hours, there was overall no difference in microvascular function with alteplase versus placebo.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov
. Unique identifier:
NCT
02257294.
Training and Certifying Users of the National Institutes of Health Stroke Scale
Authors: Anderson Ariana , Klein John , White Brian , Bourgeois Marianne , Leonard Anne , Pacino Al , Hill John , Lyden Patrick 
Published: January 2020

Background and Purpose—
The National Institutes of Health Stroke Scale, designed and validated for use in clinical stroke trials, is now required for all patients with stroke at hospital admission. Recertification is required annually but no data support this frequency; the effect of mandatory training before recertification is unknown.

Methods—
To clarify optimal recertification frequency and training effect, we assessed users’ mastery of the National Institutes of Health Stroke Scale over several years using correct scores (accuracy) on each scale item of the 15-point scale. We also constructed 9 technical errors that could result from misunderstanding the scoring rules. We measured accuracy and the frequency of these technical errors over time. Using multivariable regression, we assessed the effect of time, repeat testing, and profession on user mastery.

Results—

The final dataset included 1.3×10
6
examinations. Data were consistent among all 3 online vendors that provide training and certification. Test accuracy showed no significant changes over time. Technical error rates were remarkably low, ranging from 0.48 to 1.36 per 90 test items. Within 2 vendors (that do not require training), the technical error rates increased negligibly over time (
P
<0.05). In data from a third vendor, mandatory training before recertification improved (reduced) technical errors but not accuracy.

Conclusions—
The data suggest that mastery of National Institutes of Health Stroke Scale scoring rules is stable over time, and the recertification interval should be lengthened. Mandatory retraining may be needed after unsuccessful recertifications, but not routinely otherwise.
Reconstructing Forearm Free Flap Donor Sites Using Full‐Thickness Skin Grafts Harvested from the Ipsilateral Arm
Authors: Krane Natalie A. , Mowery Alia , Azzi James , Petrisor Daniel , Wax Mark K. 
Published: January 2020

ObjectiveTo compare morbidity and aesthetic outcomes of full‐thickness skin grafts (FTSGs) and split‐thickness skin grafts (STSGs) in the reconstruction of the forearm free flap donor site.Study DesignCase series, retrospective chart review.SettingInstitutional microvascular database.Subjects and MethodsSubjects who underwent forearm free flaps and FTSGs for donor site reconstruction from April 2016 to November 2017 were included. FTSGs were obtained from the donor forearm with a proximal S‐shaped incision, thereby avoiding additional wound creation. Morbidity outcomes were compared to 68 consecutive patients with STSG reconstruction from January 2009 to May 2010. Complications, including tendon exposure, subjective functional impairment, complete graft loss, partial graft loss, infection, paresthesias, and hematoma/seroma, were evaluated, as were aesthetic outcomes.ResultsSixty‐eight patients underwent FTSG reconstruction. No significant differences between FTSGs and STSGs were demonstrated in terms of graft loss ≥40% (4% vs 4%, P = 1.000), partial graft loss (<40%) (29% vs 40%, P =. 207), tendon exposure (9% vs 12%, P =. 573), infection (15% vs 13%, P =. 805), paresthesias (12% vs 7%, P =. 382), subjective functional impairment (0% vs 2%, P =. 316), or hematoma/seroma (2% vs 0%, P =. 316). Aesthetic outcomes were better in the FTSG group compared to the STSG group, as determined by both patients (P =. 004) and surgeon (P <. 001).ConclusionsOur results advocate for the consideration of FTSGs in the reconstruction of the forearm free flap donor site given superior aesthetic results without additional donor site morbidity or additional wound creation when compared to STSGs.
A Critical Analysis of the Information Available Online for Ménière’s Disease
Authors: Bojrab Dennis I. , Fritz Christian , Babu Seilesh , Lin Kenny F. 
Published: January 2020

ObjectivePatients increasingly rely on online resources for medical information; however, the Internet is unregulated and prone to misinformation. This study analyzes the reliability, quality, and readability of websites for Ménière’s disease.Study DesignA Google search was performed using keywords Ménière’s disease. The first 5 pages (50 results) were reviewed. Websites were sorted into 5 categories: academic institutions, government agencies, professional organizations, medical information websites, and miscellaneous. The reliability, quality, and readability of each website were evaluated using the DISCERN instrument and Flesch‐Kincaid Grade Level (FKGL). DISCERN assesses reliability and quality by scoring 15 questions on a scale from 1 (low) to 3 (high). The reliability score emphasizes clear objectives and sources, as well as lack of bias, whereas the quality score emphasizes information on treatment options. The FKGL of each website was calculated using a formula to determine the equivalent US grade reading level.SettingAmbulatory.SubjectsNone.ResultsForty‐two websites were analyzed. Academic institutions were the most common (n = 13, 31%) but scored the lowest using DISCERN at 1.75 ± 0.13. Medical information websites scored highest at 2.24 ± 0.09 (P =. 024 compared to academic institutions). The average FKGL of all websites was 10.12 ± 0.57 with medical information websites being the easiest to read at 8.84 ± 0.83. Only 5 (13%) of websites scored below the eighth‐grade reading level.ConclusionsMost top online search results for Ménière’s disease are deficient in quality and readability. Medical information websites are generally the most reliable and easy to read.
Renal Replacement Therapy in Patients With Stage IV Cancer Admitted to the Intensive Care Unit With Acute Kidney Injury at a Comprehensive Cancer Center Was Not Associated With Survival
Authors: Abudayyeh Ala , Song Juhee , Abdelrahim Maen , Dahbour Ibrahim , Page Valda D. , Zhou Shouhao , Shen Chan , Zhao Bo , Pai Rima N. , Amaram-Davila Jaya , Manzano Joanna-Grace , George Marina C. , Yennu Sriram , Mandayam Sreedhar A. , Nates Joseph L. , Moss Alvin H. 
Published: January 2020

Introduction: In patients with advanced cancer, prolongation of life with treatment often incurs substantial emotional and financial expense. Among hospitalized patients with cancer since acute kidney injury (AKI) is known to be associated with much higher odds for hospital mortality, we investigated whether renal replacement therapy (RRT) use in the intensive care unit (ICU) was a significant independent predictor of worse outcomes. Methods: We retrospectively reviewed patients admitted in 2005 to 2014 who were diagnosed with stage IV solid tumors, had AKI, and a nephrology consult. The main outcomes were survival times from the landmark time points, inpatient mortality, and longer term survival after hospital discharge. Logistic regression and Cox proportional regression were used to compare inpatient mortality and longer term survival between RRT and non-RRT groups. Propensity score-matched landmark survival analyses were performed with 2 landmark time points chosen at day 2 and at day 7 from ICU admission. Results: Of the 465 patients with stage IV cancer admitted to the ICU with AKI, 176 needed RRT. In the multivariate logistic regression model after adjusting for baseline serum albumin and baseline maximum Sequential Organ Failure Assessment (SOFA), the patients who received RRT were not significantly different from non-RRT patients in inpatient mortality (odds ratio: 1.004 [95% confidence interval: 0.598-1.684], P = .9892). In total, 189 patients were evaluated for the impact of RRT on long-term survival and concluded that RRT was not significantly associated with long-term survival after discharge for patients who discharged alive. Landmark analyses at day 2 and day 7 confirmed the same findings. Conclusions: Our study found that receiving RRT in the ICU was not significantly associated with inpatient mortality, survival times from the landmark time points, and long-term survival after discharge for patients with stage IV cancer with AKI.
Dr N. R. Madhava Menon on Inclusion and Equity for Rural and Tribal India
Authors: Schukoske Jane Ellen 
Published: January 2020

This article examines some of Dr N. R. Madhava Menon’s key messages to the legal education community about the need to thoughtfully prepare lawyers to serve the rural and tribal communities of India. Dr Menon raised the issue on multiple platforms, including newspaper opinion editorials for the general public, lectures to fellow legal educators, in his expert recommendations for legal education in the National Education Policy 2019, and in a book on inclusion, opportunity and equity published by the World Bank and co-edited by Menon and other development experts. Dr Menon envisioned the characteristics of lawyers effectively prepared to serve rural and tribal people. They need to be familiar with the legal issues relevant to rural and tribal community members, including laws about land, natural resources, forests, and agriculture. They need to be fluent in local languages spoken by rural and tribal communities, sensitive to tribal and rural cultures, and expert in representation in the forums and departments where problems of the communities would be resolved. Dr Menon broadly designed the support that would be required of the legal profession in terms of corporate social responsibility funding and formation of legal cooperatives. Dr Menon’s road map for preparing the legal profession to better serve the majority of India’s population will continue to inspire legal educators, law students, legal services authorities, and other advocates for rural and tribal communities.
Contralateral Lateral Femoral Condyle Allografts Provide an Acceptable Surface Match for Simulated Classic Osteochondritis Dissecans Lesions of the Medial Femoral Condyle
Authors: Salka Nabeel , Grant John A. 
Published: January 2020

Background: Osteochondral allograft transplantation is an effective technique for repairing large lesions of the medial femoral condyle (MFC), but its use is limited by graft availability. Purpose/Hypothesis: The present study aimed to determine whether contralateral lateral femoral condyle (LFC) allografts can provide an acceptable surface match for posterolateral MFC lesions characteristic of classic osteochondritis dissecans (OCD). The hypothesis was that LFC and MFC allografts will provide similar surface contour matches in all 4 quadrants of the graft for posterolateral MFC lesions characteristic of OCD. Study Design: Controlled laboratory study. Methods: Ten fresh-frozen recipient human MFCs were each size-matched to 1 ipsilateral medial and 1 contralateral LFC donor (N = 30 condyles). After a nano–computed tomography (nano-CT) scan of the native recipient condyle, a 20-mm circular osteochondral “defect” was created 1 cm posterior and 1 cm medial to the roof of the intercondylar notch (n = 10). A size-matched, random-order donor MFC or LFC plug was then harvested, transplanted, and scanned with nano-CT. Nano-CT scans were then reconstructed, registered to the initial scan of the recipient MFC, and processed in MATLAB to determine the height deviation ( d RMS) between the native and donor surfaces and percentage area unacceptably (>1 mm) proud (% A proud) and sunken (% A sunk). Circumferential step-off height ( h RMS) and percentage circumference unacceptably (>1 mm) proud (% C proud) and sunken (% C sunk) were measured using DragonFly software. The process was then repeated for the other allograft plug. Results: Both MFC and LFC plugs showed acceptable step-off heights in all 4 quadrants (range, 0.53-0.94 mm). Neither allograft type nor location within the defect had a significant effect on step-off height ( h RMS), surface deviation ( d RMS), % A proud, or % A sunk. In general, plugs were more unacceptably sunken than proud (MFC, 13.4% vs 2.4%; LFC, 13.2% vs 8.1%), although no significant differences in % C sunk were seen between allograft types or locations within the defect. In LFC plugs, % C proud in the lateral quadrant (28.0% ± 26.1%) was significantly greater compared with all other quadrants ( P = .0002). Conclusion: The present study demonstrates that 20-mm contralateral LFC allografts provide an acceptable surface match for posterolateral MFC lesions characteristic of OCD. Clinical Relevance: With comparable surface matching, MFC and LFC allografts can be expected to present similar stresses on the knee joint and achieve predictably positive clinical outcomes, thus improving donor availability and reducing surgical wait times for matches.
A comparison of curated gene sets versus transcriptomics-derived gene signatures for detecting pathway activation in immune cells
Authors: Liu Bin , Lindner Patrick , Jirmo Adan Chari , Maus Ulrich , Illig Thomas , DeLuca David S. 
Published: January 2020

Abstract
Background
Despite the significant contribution of transcriptomics to the fields of biological and biomedical research, interpreting long lists of significantly differentially expressed genes remains a challenging step in the analysis process. Gene set enrichment analysis is a standard approach for summarizing differentially expressed genes into pathways or other gene groupings. Here, we explore an alternative approach to utilizing gene sets from curated databases. We examine the method of deriving custom gene sets which may be relevant to a given experiment using reference data sets from previous transcriptomics studies. We call these data-derived gene sets, “gene signatures” for the biological process tested in the previous study. We focus on the feasibility of this approach in analyzing immune-related processes, which are complicated in their nature but play an important role in the medical research.

Results
We evaluate several statistical approaches to detecting the activity of a gene signature in a target data set. We compare the performance of the data-derived gene signature approach with comparable GO term gene sets across all of the statistical tests. A total of 61 differential expression comparisons generated from 26 transcriptome experiments were included in the analysis. These experiments covered eight immunological processes in eight types of leukocytes. The data-derived signatures were used to detect the presence of immunological processes in the test data with modest accuracy (AUC = 0.67). The performance for GO and literature based gene sets was worse (AUC = 0.59). Both approaches were plagued by poor specificity.

Conclusions
When investigators seek to test specific hypotheses, the data-derived signature approach can perform as well, if not better than standard gene-set based approaches for immunological signatures. Furthermore, the data-derived signatures can be generated in the cases that well-defined gene sets are lacking from pathway databases and also offer the opportunity for defining signatures in a cell-type specific manner. However, neither the data-derived signatures nor standard gene-sets can be demonstrated to reliably provide negative predictions for negative cases. We conclude that the data-derived signature approach is a useful and sometimes necessary tool, but analysts should be weary of false positives.