bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of T-cell Receptors Targeting KRAS-Mutated Human Tumors
Authors: Wang Qiong J. , Yu Zhiya , Griffith Kayla , Hanada Ken-ichi , Restifo Nicholas P. , Yang James C. 
Published: January 2016

Abstract
KRAS is one of the most frequently mutated proto-oncogenes in human cancers. The dominant oncogenic mutations of KRAS are single amino acid substitutions at codon 12, in particular G12D and G12V present in 60% to 70% of pancreatic cancers and 20% to 30% of colorectal cancers. The consistency, frequency, and tumor specificity of these “neoantigens” make them attractive therapeutic targets. Recent data associate T cells that target mutated antigens with clinical immunotherapy responses in patients with metastatic melanoma, lung cancer, or cholangiocarcinoma. Using HLA-peptide prediction algorithms, we noted that HLA-A*11:01 could potentially present mutated KRAS variants. By immunizing HLA-A*11:01 transgenic mice, we generated murine T cells and subsequently isolated T-cell receptors (TCR) highly reactive to the mutated KRAS variants G12V and G12D. Peripheral blood lymphocytes (PBL) transduced with these TCRs could recognize multiple HLA-A*11:01+ tumor lines bearing the appropriate KRAS mutations. In a xenograft model of large established tumor, adoptive transfer of these transduced PBLs reactive with an HLA-A*11:01, G12D-mutated pancreatic cell line could significantly reduce its growth in NSG mice (P = 0.002). The success of adoptive transfer of TCR-engineered T cells against melanoma and other cancers supports clinical trials with these T cells that recognize mutated KRAS in patients with a variety of common cancer types. Cancer Immunol Res; 4(3); 204–14. ©2015 AACR.
Temporal Trends and Variation in Early Scheduled Follow-Up After a Hospitalization for Heart Failure
Authors: DeVore Adam D. , Cox Margueritte , Eapen Zubin J. , Yancy Clyde W. , Bhatt Deepak L. , Heidenreich Paul A. , Peterson Eric D. , Fonarow Gregg C. , Hernandez Adrian F. 
Published: January 2016

Background—
Previous data demonstrate early follow-up (ie, within 7 days of discharge) after a hospitalization for heart failure is associated with a lower risk of readmission, yet is uncommon and varies widely across hospitals. Limited data exist on whether the use of early follow-up after discharge has improved over time.

Methods and Results—

We used data from Get With The Guidelines-Heart Failure (GWTG-HF) linked to Medicare claims to examine temporal trends in early follow-up and to assess for patient and hospital characteristics associated with early scheduled follow-up. In the overall GWTG-HF cohort, we studied 52 438 patients discharged from 239 hospitals from 2009 to 2012. Scheduled early follow-up at the time of hospital discharge rose from 51% to 65% over time (
P
<0.001). After multivariable adjustment, patients with older age (odds ratio, 1.04; 95% confidence interval, 1.01–1.07), certain comorbidities (anemia, diabetes mellitus, and chronic kidney disease), and the use of anticoagulation at discharge (odds ratio, 1.16; 95% confidence interval, 1.11–1.22) were associated with greater likelihood for early scheduled follow-up. Patients treated in hospitals located in the Midwest (odds ratio, 0.67; 95% confidence interval, 0.50–0.91) were less likely to have early scheduled follow-up. In a subset of patients with linked Medicare claims, we observed smaller improvements in actual early follow-up visits over time from 26% to 30% (
P
=0.005).

Conclusions—
From 2009 to 2012, there was improvement in early scheduled outpatient follow-up and, in the subset analyzed, improvement in actual early follow-up visits for hospitalized patients with heart failure. However, substantial opportunities remain for improving heart failure transitional care.
Efficacy and Safety of Available Protocols for Aspirin Hypersensitivity for Patients Undergoing Percutaneous Coronary Intervention
Authors: Bianco Matteo , Bernardi Alessandro , D’Ascenzo Fabrizio , Cerrato Enrico , Omedè Pierluigi , Montefusco Antonio , DiNicolantonio James J. , Zoccai Giuseppe Biondi , Varbella Ferdinando , Carini Giovanni , Moretti Claudio , Pozzi Roberto , Gaita Fiorenzo 
Published: January 2016

Background—
The most suitable approach for patients with aspirin hypersensitivity undergoing percutaneous coronary intervention remains to be assessed.

Methods and Results—
Pubmed, Google Scholar, and Cochrane were systematically searched for papers describing protocols about aspirin hypersensitivity in the percutaneous coronary intervention setting. Discharge from hospital with aspirin was the primary end point, whereas rates of adverse reactions being a secondary outcome. An online international survey was performed to critically analyze rates of aspirin hypersensitivity and its medical and interventional management. Eleven studies with 283 patients were included. An endovenous desensitization protocol was performed on one of them, with high efficacy rate (98%) and a low adverse reaction rate when compared with oral administration. No significant differences were reported among the oral protocols in terms of efficacy (less versus more fractionated [95.8% {95.4%–96.2%} versus 95.9% {95.2–96.5%}]), whereas higher incidence of rash and angioedema were reported for protocols with <6 doses escalation (2.6% [1.1%–4.1%] versus 2.6% [1.9%–3.2%]). In the survey, we collected answer from 86 physician of the 100 interviewed. Fifty-six percent of them managed aspirin hypersensitivity changing the therapeutic regimen (eg, clopidogrel monotherapy and indobufen). Despite the previous safety data, desensitization protocols were adopted by only 42% of surveyed cardiologist.

Conclusions—
Available protocols for aspirin hypersensitivity are effective and safe, representing a feasible approach for patients needing dual antiplatelet therapy.
Mitochondrial Reactive Oxygen Species Mediate Cardiac Structural, Functional, and Mitochondrial Consequences of Diet‐Induced Metabolic Heart Disease
Authors: Sverdlov Aaron L. , Elezaby Aly , Qin Fuzhong , Behring Jessica B. , Luptak Ivan , Calamaras Timothy D. , Siwik Deborah A. , Miller Edward J. , Liesa Marc , Shirihai Orian S. , Pimentel David R. , Cohen Richard A. , Bachschmid Markus M. , Colucci Wilson S. 
Published: January 2016

Background

Mitochondrial reactive oxygen species (
ROS
) are associated with metabolic heart disease (
MHD
). However, the mechanism by which
ROS
cause
MHD
is unknown. We tested the hypothesis that mitochondrial
ROS
are a key mediator of
MHD
.

Methods and Results

Mice fed a high‐fat high‐sucrose (
HFHS
) diet develop
MHD
with cardiac diastolic and mitochondrial dysfunction that is associated with oxidative posttranslational modifications of cardiac mitochondrial proteins. Transgenic mice that express catalase in mitochondria and wild‐type mice were fed an
HFHS
or control diet for 4 months. Cardiac mitochondria from
HFHS
‐fed wild‐type mice had a 3‐fold greater rate of H
2
O
2
production (
P
=0.001 versus control diet fed), a 30% decrease in complex
II
substrate–driven oxygen consumption (
P
=0.006), 21% to 23% decreases in complex I and
II
substrate–driven
ATP
synthesis (
P
=0.01), and a 62% decrease in complex
II
activity (
P
=0.002). In transgenic mice that express catalase in mitochondria, all
HFHS
diet–induced mitochondrial abnormalities were ameliorated, as were left ventricular hypertrophy and diastolic dysfunction. In
HFHS
‐fed wild‐type mice complex
II
substrate–driven
ATP
synthesis and activity were restored ex vivo by dithiothreitol (5 mmol/L), suggesting a role for reversible cysteine oxidative posttranslational modifications. In vitro site‐directed mutation of complex
II
subunit B Cys100 or Cys103 to redox‐insensitive serines prevented complex
II
dysfunction induced by
ROS
or high glucose/high palmitate in the medium.

Conclusion

Mitochondrial
ROS
are pathogenic in
MHD
and contribute to mitochondrial dysfunction, at least in part, by causing oxidative posttranslational modifications of complex I and
II
proteins including reversible oxidative posttranslational modifications of complex
II
subunit B Cys100 and Cys103.
Intravenous Lipid Infusion Induces Endoplasmic Reticulum Stress in Endothelial Cells and Blood Mononuclear Cells of Healthy Adults
Authors: Tampakakis Emmanouil , Tabit Corey E. , Holbrook Monika , Linder Erika A. , Berk Brittany D. , Frame Alissa A. , Bretón‐Romero Rosa , Fetterman Jessica L. , Gokce Noyan , Vita Joseph A. , Hamburg Naomi M. 
Published: January 2016

Background

Endoplasmic reticulum (
ER
) stress and the subsequent unfolded protein response may initially be protective, but when prolonged, have been implicated in atherogenesis in diabetic conditions. Triglycerides and free fatty acids (
FFAs
) are elevated in patients with diabetes and may contribute to
ER
stress. We sought to evaluate the effect of acute
FFA
elevation on
ER
stress in endothelial and circulating white cells.

Methods and Results

Twenty‐one healthy subjects were treated with intralipid (20%; 45 mL/h) plus heparin (12 U/kg/h) infusion for 5 hours. Along with increased triglyceride and
FFA
levels, intralipid/heparin infusion reduced the calf reactive hyperemic response without a change in conduit artery flow‐mediated dilation consistent with microvascular dysfunction. To investigate the short‐term effects of elevated triglycerides and
FFA
, we measured markers of
ER
stress in peripheral blood mononuclear cells (
PBMC
s) and vascular endothelial cells (
VEC
s). In
VEC
s, activating transcription factor 6 (
ATF
6) and phospho‐inositol requiring kinase 1 (
pIRE
1) proteins were elevated after infusion (both
P
<0.05). In
PBMC
s,
ATF
6 and spliced X‐box‐binding protein 1 (
XBP
‐1) gene expression increased by 2.0‐ and 2.5‐fold, respectively (both
P
<0.05), whereas
CHOP
and
GADD
34 decreased by ≈67% and 74%, respectively (both
P
<0.01).
ATF
6 and
pIRE
1 protein levels also increased (both
P
<0.05), and confocal microscopy revealed the nuclear localization of
ATF
6 after infusion, suggesting activation.

Conclusions

Along with microvascular dysfunction, intralipid infusion induced an early protective
ER
stress response evidenced by activation of
ATF
6 and
IRE
1 in both leukocytes and endothelial cells. Our results suggest a potential link between metabolic disturbances and
ER
stress that may be relevant to vascular disease.
Galectin‐3 Is Elevated and Associated With Adverse Outcomes in Patients With Single‐Ventricle Fontan Circulation
Authors: Opotowsky Alexander R. , Baraona Fernando , Owumi Justin , Loukas Brittani , Singh Michael N. , Valente Anne Marie , Wu Fred , Cheng Susan , Veldtman Gruschen , Rimm Eric B. , Landzberg Michael J. 
Published: January 2016

Background
Galectin‐3 may play a role in cardiac and noncardiac fibrosis, and elevated circulating levels of this protein predict adverse outcomes in patients with heart failure who do not have congenital heart disease. We investigated galectin‐3 in adults with single‐ventricle Fontan circulation, patients who are prone to premature clinical deterioration in the context of extensive multiorgan fibrosis.

Methods and Results

We measured plasma galectin‐3 concentrations in 70 ambulatory adult Fontan patients and 21 age‐ and sex‐matched control participants. Galectin‐3 level was significantly higher in the Fontan group (11.85 ng/mL, interquartile range 9.9 to 15.0 ng/mL) versus the control group (9.4 ng/mL, interquartile range 8.2 to 10.8 ng/mL;
P
<0.001). Among Fontan patients, galectin‐3 was positively correlated with age, uric acid, and high‐sensitivity C‐reactive protein and negatively correlated with estimated glomerular filtration rate. There was no significant relationship between galectin‐3 and oxygen saturation, Fontan type, or ventricular morphology. Over a median follow‐up of 461 days, 15 events occurred among the Fontan patients: 12 nonelective hospitalizations (with 2 subsequent deaths) and 3 deaths without prior hospitalization. Patients with elevated galectin‐3 (n=19, defined as >2
SD
above the control group mean value) had a higher risk of nonelective hospitalization or death (hazard ratio 6.0, 95%
CI
2.1 to 16.8,
P
<0.001). This relationship persisted after individual adjustment for covariates including age, New York Heart Association functional class, C‐reactive protein, and estimated glomerular filtration rate and after multivariable adjustment for independently predictive covariates (hazard ratio 9.2, 95%
CI
2.4 to 35.2,
P
=0.001).

Conclusions
Galectin‐3 concentrations are elevated among adults with a Fontan circulation, and elevated galectin‐3 is associated with an increased risk of nonelective cardiovascular hospitalization or death.
Hidden biodiversity revealed by collections-based research—Laboulbeniales in millipedes: genus Rickia
Authors: Santamaria Sergi , Enghoff Henrik , Reboleira Ana Sofia 
Published: January 2016

Nine new species of the genus Rickia parasitizing Diplopoda are described: R. appendicifera from Iran on Chiraziulus, R. candelabriformis from Australia and New Zealand on several Spirostreptida, R. galatheae from New Zealand on Eumastigonus, R. gigas from Tanzania on ‘Spirostreptus’ and Archispirostreptus, R. lophophora from Tanzania on some genera of Spirostreptidae, R. obelostrepti from Tanzania on Obelostreptus, R. odontopygiidarum from Tanzania on Odontopygidae, R. platessa from Singapore and Thailand on Pachybolidae, and R. rhynchophora from Australia on Trigoniulus. This nearly triples the previously known number of species of Rickia species on millipedes; all 14 species are treated in this study with photomicrographs, additional observations on previously described taxa and comments. A key to these species is also provided. The Laboulbeniales species were found on millipede specimens preserved mostly at the Natural History Museum of Denmark, from samples collected between 1916 to the present.
Influence of Canopy Seasonal Changes on Turbulence Parameterization within the Roughness Sublayer over an Orchard Canopy
Authors: Shapkalijevski M. , Moene A. F. , Ouwersloot H. G. , Patton E. G. , Vilà-Guerau de Arellano J. 
Published: January 2016

Abstract
In this observational study, the role of tree phenology on the atmospheric turbulence parameterization over 10-m-tall and relatively sparse deciduous vegetation is quantified. Observations from the Canopy Horizontal Array Turbulence Study (CHATS) field experiment are analyzed to establish the dependence of the turbulent exchange of momentum, heat, and moisture, as well as kinetic energy on canopy phenological evolution through widely used parameterization models based on 1) dimensionless gradients or 2) turbulent kinetic energy (TKE) in the roughness sublayer. Observed vertical turbulent fluxes and gradients of mean wind, temperature, and humidity, as well as velocity variances, are used in combination with empirical dimensionless functions to calculate the turbulent exchange coefficient. The analysis shows that changes in canopy phenology influence the turbulent exchange of all quantities analyzed in this study. The turbulent exchange coefficients of those quantities are twice as large near the canopy top for a leafless canopy than for a full-leaf canopy under unstable and near-neutral conditions. This turbulent exchange coefficient difference is related to the differing penetration depths of the turbulent eddies organized at the canopy top, which increase for a canopy without leaves. The TKE and dissipation analysis under near-neutral atmospheric conditions additionally shows that TKE exchange increases for a leafless canopy because of reduced TKE dissipation efficiency relative to that when the canopy is in full-leaf stage. The study closes with discussion surrounding the implications of these findings for parameterizations used in large-scale models.
Mechanisms Contributing to Suppressed Precipitation in Mt. Hua of Central China. Part I: Mountain Valley Circulation
Authors: Yang Yan , Fan Jiwen , Leung L. Ruby , Zhao Chun , Li Zhanqing , Rosenfeld Daniel 
Published: January 2016

Abstract
A significant reduction in precipitation in the past decades has been documented over many mountain ranges such as those in central and eastern China. Consistent with the increase of air pollution in these regions, it has been argued that the precipitation trend is linked to the aerosol microphysical effect on suppressing warm rain. Rigorous quantitative investigations on the reasons responsible for the precipitation reduction are lacking. In this study, an improved Weather Research and Forecasting (WRF) Model with online coupled chemistry (WRF-Chem) is applied and simulations are conducted at the convection-permitting scale to explore the major mechanisms governing changes in precipitation from orographic clouds in the Mt. Hua area in central China. It is found that anthropogenic pollution contributes to a ~40% reduction of precipitation over Mt. Hua during the 1-month summertime period. The reduction is mainly associated with precipitation events associated with valley–mountain circulation and a mesoscale cold-front event. In this paper (Part I), the mechanism leading to a significant reduction for the cases associated with valley–mountain circulation is scrutinized. It is found that the valley breeze is weakened by aerosols as a result of absorbing aerosol-induced warming aloft and cooling near the surface as a result of aerosol–radiation interaction (ARI). The weakened valley breeze and the reduced water vapor in the valley due to reduced evapotranspiration as a result of surface cooling significantly reduce the transport of water vapor from the valley to mountain and the relative humidity over the mountain, thus suppressing convection and precipitation in the mountain.
Female sexual dysfunction in female genital mutilation
Authors: Elneil Sohier 
Published: January 2016

Female genital mutilation (FGM), otherwise known as female genital cutting (FGC), is currently very topical and has become a significant global political issue. The impact of FGM on the lives of women and girls is enormous, as it often affects both their psychology and physical being. Among the complications that are often under-reported and not always acknowledged is female sexual dysfunction (FSD). FSD presents with a complex of symptoms including lack of libido, arousability and orgasm. This often occurs in tandem with chronic urogenital pain and anatomical disruption due to perineal scarring. To treat FSD in FGM each woman needs specifically directed holistic care, geared to her individual case. This may include psychological support, physiotherapy and, on occasion, reconstructive surgery. In many cases the situation is complicated by symptoms of chronic pelvic pain, which can make treatment increasingly difficult as this issue needs a defined multidisciplinary approach for its effective management in its own right. The problems suffered by women with FGM are wholly preventable, as the practice need not happen. The current global momentum to address the social, cultural, economic and medical issues of FGM is being supported by communities, governments, non-governmental agencies (NGOs) and healthcare providers. It is only by working together that the practice can be abolished and women and girls may be free from this practice and its associated consequences.
Long-term Results After Hyaluronan-based MACT for the Treatment of Cartilage Lesions of the Patellofemoral Joint
Authors: Kon Elizaveta , Filardo Giuseppe , Gobbi Alberto , Berruto Massimo , Andriolo Luca , Ferrua Paolo , Crespiatico Ilaria , Marcacci Maurilio 
Published: January 2016

Background: Cartilage lesions of the patellofemoral joint are a challenging condition. Hyaluronan-based matrix-assisted autologous chondrocyte transplantation (MACT) has been shown to offer a significant improvement in the short term but has a tendency to worsen at midterm follow-up. Hypothesis: Patients treated with MACT for lesions of the articular surface of the patellofemoral joint will present further clinical worsening at long-term follow-up. Study Design: Case series; Level of evidence, 4. Methods: Thirty-two patients with full-thickness chondral lesions in the patellofemoral joint were treated with hyaluronan-based MACT and were prospectively evaluated preoperatively and at 2-, 5-, and 10-year follow-up. The mean defect size was 4.45 cm2. There were 20 lesions located on the patella and 8 on the trochlea, and 4 patients had multiple lesions: 3 with patellar and trochlear lesions and 1 with patellar and lateral femoral condyle lesions. Results were evaluated using International Knee Documentation Committee (IKDC) subjective scores, EuroQol visual analog scale (EQ VAS) scores, and Tegner scores. Surgical and clinical failures were documented. Results: All scores showed a statistically significant improvement at 2-, 5-, and 10-year follow-up with respect to the preoperative level. No worsening was observed at the last follow-up, and results were stable up to 10 years. The improvement in mean (±SD) outcome scores from preoperatively to 2-, 5-, and 10-year follow-up was as follows: IKDC, from 46.0 ± 19.8 to 77.1 ± 17.4, 72.0 ± 20.4, and 78.6 ± 16.4, respectively; Tegner, from 2.5 ± 1.4 to 4.7 ± 1.8, 4.7 ± 1.6, and 4.4 ± 1.5, respectively; and EQ VAS, from 56.9 ± 18.4 to 81.7 ± 13.2, 79.2 ± 17.9, and 78.9 ± 1.7, respectively. Four patients did not achieve significant clinical improvement, and 1 of these patients required further surgical treatment. All failures were female patients with patellar defects, and 3 of them had degenerative lesions and underwent a previous or combined realignment procedure. Conclusion: The clinical results of hyaluronan-based MACT treatment of chondral lesions of the patellofemoral joint do not worsen over time but remain stable and show a low rate of failure at long-term follow-up.
Serum neurofilament light chain in early relapsing remitting MS is increased and correlates with CSF levels and with MRI measures of disease severity
Authors: Kuhle Jens , Barro Christian , Disanto Giulio , Mathias Amandine , Soneson Charlotte , Bonnier Guillaume , Yaldizli Özguer , Regeniter Axel , Derfuss Tobias , Canales Mathieu , Schluep Myriam , Du Pasquier Renaud , Krueger Gunnar , Granziera Cristina 
Published: January 2016

Background/objectives: Neurofilament light chain (NfL) levels in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients correlate with the degree of neuronal injury. To date, little is known about NfL concentrations in the serum of relapsing remitting multiple sclerosis (RRMS) patients and their relationship with CSF levels and magnetic resonance imaging (MRI) measures of disease severity. We aimed to validate the quantification of NfL in serum samples of RRMS, as a biofluid source easily accessible for longitudinal studies. Methods: A total of 31 RRMS patients underwent CSF and serum sampling. After a median time of 3.6 years, 19 of these RRMS patients, 10 newly recruited RRMS patients and 18 healthy controls had a 3T MRI and serum sampling. NfL concentrations were determined by electrochemiluminescence immunoassay. Results: NfL levels in serum were highly correlated to levels in CSF ( r = 0.62, p = 0.0002). Concentrations in serum were higher in patients than in controls at baseline ( p = 0.004) and follow-up ( p = 0.0009) and did not change over time ( p = 0.56). Serum NfL levels correlated with white matter (WM) lesion volume ( r = 0.68, p < 0.0001), mean T1 ( r = 0.40, p = 0.034) and T2* relaxation time ( r = 0.49, p = 0.007) and with magnetization transfer ratio in normal appearing WM ( r = −0.41, p = 0.029). Conclusion: CSF and serum NfL levels were highly correlated, and serum concentrations were increased in RRMS. Serum NfL levels correlated with MRI markers of WM disease severity. Our findings further support longitudinal studies of serum NfL as a potential biomarker of on-going disease progression and as a potential surrogate to quantify effects of neuroprotective drugs in clinical trials.