bluuebunny/crossref_metadata_2025_split huggingface dataset:
Can Physical Examination Create a Stener Lesion?
Authors: Lankachandra Manesha , Eggers John P. , Bogener James W. , Hutchison Richard L. 
Published: August 2017

Background: The purpose of this study is to determine whether a Stener lesion can be created while testing stability of the ulnar collateral ligament (UCL) of the thumb. Testing was performed in a manner that reproduced clinical examination. Methods: Six fresh frozen hand and forearm specimens underwent sequential sectioning of the accessory UCL, the proper UCL, and the ulnar sagittal band. Measurements of radial deviation of the metacarpophalangeal (MCP) joint were taken with the thumb in neutral rotation, pronation and supination, both with 0 degrees and with 30 degrees of flexion of the MCP joint. Visual examination was performed to assess the presence of a Stener lesion. Results: No Stener lesion was created in any position as long as the fascial origin of the ulnar sagittal band at the adductor pollicis longus remained intact. After creating a defect in the ulnar sagittal band, a Stener lesion was created in two specimens, but only when the thumb was flexed and supinated. Pronation provided more stability, and supination provided less stability, with one or both components cut, especially when testing at 30° of flexion. Compared to both components cut without flexion or rotation, there was a statistically significant difference in angulation with the 30 degrees of MCP joint flexion in both neutral rotation in supination. Conclusions: Performing a physical examination to assess the amount of instability of an ulnar collateral ligament injury did not create a Stener lesion if the exam was performed in a controlled, gentle manner with the thumb held without rotation. If the thumb is held in neutral rotation during the exam, an iatrogenic Stener lesion should not be created.
Effect of ovariectomy on intracellular Ca2+ regulation in guinea pig cardiomyocytes
Authors: Yang Hsiang-Yu , Firth Jahn M. , Francis Alice J. , Alvarez-Laviada Anita , MacLeod Kenneth T. 
Published: August 2017

This study addressed the hypothesis that long-term deficiency of ovarian hormones after ovariectomy (OVx) alters cellular Ca2+-handling mechanisms in the heart, resulting in the formation of a proarrhythmic substrate. It also tested whether estrogen supplementation to OVx animals reverses any alterations to cardiac Ca2+ handling and rescues proarrhythmic behavior. OVx or sham operations were performed on female guinea pigs using appropriate anesthetic and analgesic regimes. Pellets containing 17β-estradiol (1 mg, 60-day release) were placed subcutaneously in selected OVx animals (OVx + E). Cardiac myocytes were enzymatically isolated, and electrophysiological measurements were conducted with a switch-clamp system. In fluo-4-loaded cells, Ca2+ transients were 20% larger, and fractional sarcoplasmic reticulum (SR) Ca2+ release was 7% greater in the OVx group compared with the sham group. Peak L-type Ca2+ current was 16% larger in OVx myocytes with channel inactivation shifting to more positive membrane potentials, creating a larger “window” current. SR Ca2+ stores were 22% greater in the OVx group, and these cells showed a higher frequency of Ca2+ sparks and waves and shorter wave-free intervals. OVx myocytes showed higher frequencies of early afterdepolarizations, and a greater percentage of these cells showed delayed afterdepolarizations after exposure to isoprenaline compared with sham myocytes. The altered Ca2+ regulation occurring in the OVx group was not observed in the OVx + E group. These findings suggest that long-term deprivation of ovarian hormones in guinea pigs lead to changes in myocyte Ca2+-handling mechanisms that are considered proarrhythmogenic. 17β-Estradiol replacement prevented these adverse effects. NEW & NOTEWORTHY Ovariectomized guinea pig cardiomyocytes have higher frequencies of Ca2+ waves, and isoprenaline-challenged cells display more early afterdepolarizations, delayed afterdepolarizations, and extra beats compared with sham myocytes. These alterations to Ca2+ regulation were not observed in myocytes from ovariectomized guinea pigs supplemented with 17β-estradiol, suggesting that ovarian hormone deficiency modifies cardiac Ca2+ regulation, potentially creating proarrhythmic substrates.
Anomalous baroreflex functionality inherent in floxed and Cre-Lox mice: an overlooked physiological phenotype
Authors: Tsai Ching-Yi , Poon Yan-Yuen , Chen Chang-Han , Chan Samuel H. H. 
Published: August 2017

The last two decades have seen the emergence of Cre-Lox recombination as one of the most powerful and versatile technologies for cell-specific genetic engineering of mammalian cells. Understandably, the primary concerns in the practice of Cre-Lox recombination are whether the predicted genome has been correctly modified and the targeted phenotypes expressed. Rarely are the physiological conditions of the animals routinely examined because the general assumption is that they are normal. Based on corroborative results from radiotelemetric recording, power spectral analysis, and magnetic resonance imaging/diffusion tensor imaging in brain-derived neurotrophic factor-floxed mice, the present study revealed that this assumption requires amendment. We found that despite comparable blood pressure and heart rate with C57BL/6 or Cre mice under the conscious state, floxed and Cre-Lox mice exhibited diminished baroreflex-mediated sympathetic vasomotor tone and cardiac vagal baroreflex. We further found that the capacity and plasticity of baroreflex of these two strains of mice under isoflurane anesthesia were retarded, as reflected by reduced connectivity between the nucleus tractus solitarii and rostral ventrolateral medulla or nucleus ambiguus. The identification of anomalous baroreflex functionality inherent in floxed and Cre-Lox mice points to the importance of incorporating physiological phenotypes into studies that engage gene manipulations such as Cre-Lox recombination. NEW & NOTEWORTHY We established that anomalous baroreflex functionality is inherent in floxed and Cre-Lox mice. These two mouse strains exhibited diminished baroreflex-mediated sympathetic vasomotor tone and cardiac vagal baroreflex under the conscious state, retarded capacity and plasticity of baroreflex under isoflurane anesthesia, and reduced connectivity between key nuclei in the baroreflex neural circuits.
EZH2 Palmitoylation Mediated by ZDHHC5 in p53-Mutant Glioma Drives Malignant Development and Progression
Authors: Chen Xueran , Ma Huihui , Wang Zhen , Zhang Shangrong , Yang Haoran , Fang Zhiyou 
Published: August 2017

Abstract
Gliomas with mutant p53 occurring in 30% of glioma patients exhibit therapeutic resistance and poor outcomes. In this study, we identify a novel mechanism through which mutant p53 drives cancer cell survival and malignant growth. We documented overexpression of the zinc finger protein ZDHHC5 in glioma compared with normal brain tissue and that this event tightly correlated with p53 mutations. Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y. These events contributed to the development of glioma by promoting the self-renewal capacity and tumorigenicity of glioma stem-like cells, by altering the palmitoylation and phosphorylation status of the tumor suppressor EZH2. Taken together, our work highlighted ZDHHC5 as a candidate therapeutic target for management of p53-mutated gliomas. Cancer Res; 77(18); 4998–5010. ©2017 AACR.
Bypassing Drug Resistance Mechanisms of Prostate Cancer with Small Molecules that Target Androgen Receptor–Chromatin Interactions
Authors: Dalal Kush , Che Meixia , Que Nanette S. , Sharma Aishwariya , Yang Rendong , Lallous Nada , Borgmann Hendrik , Ozistanbullu Deniz , Tse Ronnie , Ban Fuqiang , Li Huifang , Tam Kevin J. , Roshan-Moniri Mani , LeBlanc Eric , Gleave Martin E. , Gewirth Daniel T. , Dehm Scott M. , Cherkasov Artem , Rennie Paul S. 
Published: August 2017

Abstract
Human androgen receptor (AR) is a hormone-activated transcription factor that is an important drug target in the treatment of prostate cancer. Current small-molecule AR antagonists, such as enzalutamide, compete with androgens that bind to the steroid-binding pocket of the AR ligand–binding domain (LBD). In castration-resistant prostate cancer (CRPC), drug resistance can manifest through AR-LBD mutations that convert AR antagonists into agonists, or by expression of AR variants lacking the LBD. Such treatment resistance underscores the importance of novel ways of targeting the AR. Previously, we reported the development of a series of small molecules that were rationally designed to selectively target the AR DNA-binding domain (DBD) and, hence, to directly interfere with AR–DNA interactions. In the current work, we have confirmed that the lead AR DBD inhibitor indeed directly interacts with the AR-DBD and tested that substance across multiple clinically relevant CRPC cell lines. We have also performed a series of experiments that revealed that genome-wide chromatin binding of AR was dramatically impacted by the lead compound (although with lesser effect on AR variants). Collectively, these observations confirm the novel mechanism of antiandrogen action of the developed AR-DBD inhibitors, establishing proof of principle for targeting DBDs of nuclear receptors in endocrine cancers. Mol Cancer Ther; 16(10); 2281–91. ©2017 AACR.
Development of Aggressive Pancreatic Ductal Adenocarcinomas Depends on Granulocyte Colony Stimulating Factor Secretion in Carcinoma Cells
Authors: Pickup Michael W. , Owens Philip , Gorska Agnieszka E. , Chytil Anna , Ye Fei , Shi Chanjuan , Weaver Valerie M. , Kalluri Raghu , Moses Harold L. , Novitskiy Sergey V. 
Published: August 2017

Abstract
The survival rate for pancreatic ductal adenocarcinoma (PDAC) remains low. More therapeutic options to treat this disease are needed, for the current standard of care is ineffective. Using an animal model of aggressive PDAC (Kras/p48TGFβRIIKO), we discovered an effect of TGFβ signaling in regulation of G-CSF secretion in pancreatic epithelium. Elevated concentrations of G-CSF in PDAC promoted differentiation of Ly6G+ cells from progenitors, stimulated IL10 secretion from myeloid cells, and decreased T-cell proliferation via upregulation of Arg, iNOS, VEGF, IL6, and IL1b from CD11b+ cells. Deletion of csf3 in PDAC cells or use of a G-CSF–blocking antibody decreased tumor growth. Anti–G-CSF treatment in combination with the DNA synthesis inhibitor gemcitabine reduced tumor size, increased the number of infiltrating T cells, and decreased the number of Ly6G+ cells more effectively than gemcitabine alone. Human analysis of human datasets from The Cancer Genome Atlas and tissue microarrays correlated with observations from our mouse model experiments, especially in patients with grade 1, stage II disease. We propose that in aggressive PDAC, elevated G-CSF contributes to tumor progression through promoting increases in infiltration of neutrophil-like cells with high immunosuppressive activity. Such a mechanism provides an avenue for a neoadjuvant therapeutic approach for this devastating disease. Cancer Immunol Res; 5(9); 718–29. ©2017 AACR.
Role for High-Affinity IgE Receptor in Prognosis of Lung Adenocarcinoma Patients
Authors: Ly Dalam , Zhu Chang-Qi , Cabanero Michael , Tsao Ming-Sound , Zhang Li 
Published: August 2017

Abstract
Cancer development and biology is influenced by the host immune system. Emerging data indicate that the context of immune cell infiltrates may contribute to cancer prognosis. However, the types of infiltrating immune cells that are critical for cancer development remain controversial. In attempts to gain insights into the immune networks that regulate and/or predict tumor progression, gene expression analysis was conducted on microarray datasets of resected tumor samples from 128 early-stage non–small cell lung cancer (NSCLC) adenocarcinoma patients. By limiting analysis to immune-related genes, we identified a 9-gene signature using MAximizing R Square Algorithm that selected for the greatest separation between favorable and adverse prognostic patient subgroups. The prognostic value of this 9-gene signature was validated in 10 additional independently published microarray datasets of lung adenocarcinoma [n = 1,097; overall survival hazard ratio (HR), 2.05; 95% confidence interval, 1.64–2.56; P &lt; 0.0001] and was found to be an independent prognostic indicator relative to tumor stage (overall survival HR, 2.09, 95% confidence interval, 1.65–2.66; P &lt; 0.0001). Network analysis revealed that genes associated with Fcϵ complex (FCER1, MS4A2) formed the largest and most significant pathway of the signature. Using immunohistochemistry, we validated that MS4A2, the β subunit of the IgE receptor expressed on mast cells, is a favorable prognostic indicator and show that MS4A2 gene expression is an independent prognostic marker for early-stage lung cancer patient survival. Cancer Immunol Res; 5(9); 821–9. ©2017 AACR.
First Selective 12-LOX Inhibitor, ML355, Impairs Thrombus Formation and Vessel Occlusion In Vivo With Minimal Effects on Hemostasis
Authors: Adili Reheman , Tourdot Benjamin E. , Mast Katherine , Yeung Jennifer , Freedman John C. , Green Abigail , Luci Diane K. , Jadhav Ajit , Simeonov Anton , Maloney David J. , Holman Theodore R. , Holinstat Michael 
Published: August 2017

Objective—
Adequate platelet reactivity is required for maintaining hemostasis. However, excessive platelet reactivity can also lead to the formation of occlusive thrombi. Platelet 12(S)-lipoxygenase (12-LOX), an oxygenase highly expressed in the platelet, has been demonstrated to regulate platelet function and thrombosis ex vivo, supporting a key role for 12-LOX in the regulation of in vivo thrombosis. However, the ability to pharmacologically target 12-LOX in vivo has not been established to date. Here, we studied the effect of the first highly selective 12-LOX inhibitor, ML355, on in vivo thrombosis and hemostasis.

Approach and Results—

ML355 dose-dependently inhibited human platelet aggregation and 12-LOX oxylipin production, as confirmed by mass spectrometry. Interestingly, the antiplatelet effects of ML355 were reversed after exposure to high concentrations of thrombin in vitro. Ex vivo flow chamber assays confirmed that human platelet adhesion and thrombus formation at arterial shear over collagen were attenuated in whole blood treated with ML355 comparable to aspirin. Oral administration of ML355 in mice showed reasonable plasma drug levels by pharmacokinetic assessment. ML355 treatment impaired thrombus growth and vessel occlusion in FeCl
3
-induced mesenteric and laser-induced cremaster arteriole thrombosis models in mice. Importantly, hemostatic plug formation and bleeding after treatment with ML355 was minimal in mice in response to laser ablation on the saphenous vein or in a cremaster microvasculature laser–induced rupture model.

Conclusions—
Our data strongly support 12-LOX as a key determinant of platelet reactivity in vivo, and inhibition of platelet 12-LOX with ML355 may represent a new class of antiplatelet therapy.
Association of Concentric Left Ventricular Hypertrophy With Subsequent Change in Left Ventricular End-Diastolic Volume
Authors: Garg Sonia , de Lemos James A. , Matulevicius Susan A. , Ayers Colby , Pandey Ambarish , Neeland Ian J. , Berry Jarett D. , McColl Roderick , Maroules Christopher , Peshock Ronald M. , Drazner Mark H. 
Published: August 2017

Background
In the conventional paradigm of the progression of left ventricular hypertrophy, a thick-walled left ventricle (LV) ultimately transitions to a dilated cardiomyopathy. There are scant data in humans demonstrating whether this transition occurs commonly without an interval myocardial infarction.

Methods and Results

Participants (n=1282) from the Dallas Heart Study underwent serial cardiac magnetic resonance ≈7 years apart. Those with interval cardiovascular events and a dilated LV (increased LV end-diastolic volume [EDV] indexed to body surface area) at baseline were excluded. Multivariable linear regression models tested the association of concentric hypertrophy (increased LV mass and LV mass/volume
0.67
) with change in LVEDV. The study cohort had a median age of 44 years, 57% women, 43% black, and 11% (n=142) baseline concentric hypertrophy. The change in LVEDV in those with versus without concentric hypertrophy was 1 mL (−9 to 12) versus −2 mL (−11 to 7), respectively,
P
<0.01. In multivariable linear regression models, concentric hypertrophy was associated with larger follow-up LVEDV (
P
≤0.01). The progression to a dilated LV was uncommon (2%, n=25).

Conclusions
In the absence of interval myocardial infarction, concentric hypertrophy was associated with a small, but significantly greater, increase in LVEDV after 7-year follow-up. However, the degree of LV enlargement was minimal, and few participants developed a dilated LV. These data suggest that if concentric hypertrophy does progress to a dilated cardiomyopathy, such a transition would occur over a much longer timeframe (eg, decades) and may be less common than previously thought.

Clinical Trial Registration

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00344903.
Variation in the Echocardiographic Surveillance of Primary Mitral Regurgitation
Authors: Tanguturi Varsha K. , Hidrue Michael K. , Picard Michael H. , Atlas Steven J. , Weilburg Jeffrey B. , Ferris Timothy G. , Armstrong Katrina , Wasfy Jason H. 
Published: August 2017

Background—
Clinical outcomes after surgical treatment of mitral regurgitation are worse if intervention occurs after deterioration of left ventricular size and function. Transthoracic echocardiographic (TTE) surveillance of patients with mitral regurgitation is indicated to avoid adverse ventricular remodeling. Overly frequent TTEs can impair patient access and reduce value in care delivery. This balance between timely surveillance and overutilization of TTE in valvular disease provides a model to study variation in the delivery of healthcare services. We investigated patient and provider factors contributing to variation in TTE utilization and hypothesized that variation was attributable to provider practice even after adjustment for patient characteristics.

Methods and Results—
We obtained records of all TTEs from 2001 to 2016 completed at a large echocardiography laboratory. The outcome variable was time interval between TTEs. We constructed a mixed-effects linear regression model with the individual physician as the random effect in the model and used intraclass correlation coefficient to assess the proportion of outcome variation because of provider practice. Our study cohort was 55 773 TTEs corresponding to 37 843 intervals ordered by 635 providers. The mean interval between TTEs was 12.4 months, 17.0 months, 18.3 months, and 17.4 months for severe, moderate, mild, and trace mitral regurgitation, respectively, with 20% of providers deemed overutilizers of TTEs and 25% underutilizers.

Conclusions—
We conclude that there is substantial variation in follow-up intervals for TTE assessment of mitral regurgitation, despite risk-adjustment for patient variables, likely because of provider factors.
Association of High‐Density Lipoprotein‐Cholesterol Versus Apolipoprotein A‐I With Risk of Coronary Heart Disease: The European Prospective Investigation Into Cancer‐Norfolk Prospective Population Study, the Atherosclerosis Risk in Communities Study, and the Women's Health Study
Authors: van Capelleveen Julian C. , Bochem Andrea E. , Boekholdt S. Matthijs , Mora Samia , Hoogeveen Ron C. , Ballantyne Christie M. , Ridker Paul M , Sun Wensheng , Barter Philip J. , Tall Alan R. , Zwinderman Aeilko H. , Kastelein John J. P. , Wareham Nick J. , Khaw Kay‐Tee , Hovingh G. Kees 
Published: August 2017

Background

The contribution of apolipoprotein A‐I (apoA‐I) to coronary heart disease (
CHD
) risk stratification over and above high‐density lipoprotein cholesterol (
HDL
‐C) is unclear. We studied the associations between plasma levels of
HDL
‐C and apoA‐I, either alone or combined, with risk of
CHD
events and cardiovascular risk factors among apparently healthy men and women.

Methods and Results

HDL
‐C and apoA‐I levels were measured among 17 661 participants of the
EPIC
(European Prospective Investigation into Cancer)‐Norfolk prospective population study. Hazard ratios for
CHD
events and distributions of risk factors were calculated by quartiles of
HDL
‐C and apoA‐I. Results were validated using data from the
ARIC
(Atherosclerosis Risk in Communities) and
WHS
(Women's Health Study) cohorts, comprising 15 494 and 27 552 individuals, respectively. In
EPIC
‐Norfolk, both
HDL
‐C and apoA‐I quartiles were strongly and inversely associated with
CHD
risk. Within
HDL
‐C quartiles, higher apoA‐I levels were not associated with lower
CHD
risk; in fact,
CHD
risk was higher within some
HDL
‐C quartiles. ApoA‐I levels were associated with higher levels of
CHD
risk factors: higher body mass index, HbA1c, non‐
HDL
‐C, triglycerides, apolipoprotein B, systolic blood pressure, and C‐reactive protein, within fixed
HDL
‐C quartiles. In contrast,
HDL
‐C levels were consistently inversely associated with overall
CHD
risk and
CHD
risk factors within apoA‐I quartiles (
P
<0.001). These findings were validated in the
ARIC
and
WHS
cohorts.

Conclusions

Our findings demonstrate that apoA‐I levels do not offer predictive information over and above
HDL
‐C. In fact, within some
HDL
‐C quartiles, higher apoA‐I levels were associated with higher risk of
CHD
events, possibly because of the unexpected higher prevalence of cardiovascular risk factors in association with higher apoA‐I levels.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov
. Unique identifier:
NCT
00000479.
Modality-specific Changes in Motor Cortex Excitability After Visuo-proprioceptive Realignment
Authors: Munoz-Rubke Felipe , Mirdamadi Jasmine L. , Lynch Anna K. , Block Hannah J. 
Published: August 2017

Abstract
Spatial realignment of visual and proprioceptive estimates of hand position is necessary both to keep the estimates in register over time and to compensate for sensory perturbations. Such realignment affects perceived hand position, which the brain must use to plan hand movements. We would therefore expect visuo-proprioceptive realignment to affect the motor system at some level, but the physiological basis of this interaction is unknown. Here, we asked whether activity in primary motor cortex (M1), a well-known substrate of motor control, shows evidence of change after visuo-proprioceptive realignment. In two sessions each, 32 healthy adults experienced spatially misaligned or veridical visual and proprioceptive information about their static left index finger. Participants indicated perceived finger position with no performance feedback or knowledge of results. Using TMS over the M1 representation of the misaligned finger, we found no average difference between sessions. However, regression analysis indicated that, in the misaligned session only, proprioceptive realignment was linked with a decrease in M1 activity and visual realignment was linked with an increase in M1 activity. Proprioceptive and visual realignment were inversely related to each other. These results suggest that visuo-proprioceptive realignment does indeed have a physiological impact on the motor system. The lack of a between-session mean difference in M1 activity suggests that the basis of the effect is not the multisensory realignment computation itself, independent of modality. Rather, the changes in M1 are consistent with a modality-specific neural mechanism, such as modulation of somatosensory cortex or dorsal stream visual areas that impact M1.