bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteomic Characterization of Head and Neck Cancer Patient–Derived Xenografts
Authors: Li Hua , Wheeler Sarah , Park Yongseok , Ju Zhenlin , Thomas Sufi M. , Fichera Michele , Egloff Ann M. , Lui Vivian W. , Duvvuri Umamaheswar , Bauman Julie E. , Mills Gordon B. , Grandis Jennifer R. 
Published: December 2015

Abstract
Despite advances in treatment approaches for head and neck squamous cell carcinoma (HNSCC), survival rates have remained stagnant due to the paucity of preclinical models that accurately reflect the human tumor. Patient-derived xenografts (PDX) are an emerging model system where patient tumors are implanted directly into mice. Increased understanding of the application and limitations of PDXs will facilitate their rational use. Studies to date have not reported protein profiles of PDXs. Therefore, we developed a large cohort of HNSCC PDXs and found that tumor take rate was not influenced by the clinical, pathologic, or processing features. Protein expression profiles, from a subset of the PDXs, were characterized by reverse-phase protein array and the data was compared with The Cancer Genome Atlas HNSCC data. Cluster analysis revealed that HNSCC PDXs were more similar to primary HNSCC than to any other tumor type. Interestingly, while a significant fraction of proteins were expressed similarly in both primary HNSCC and PDXs, a subset of proteins/phosphoproteins were expressed at higher (or lower) levels in PDXs compared with primary HNSCC. These findings indicate that the proteome is generally conserved in PDXs, but mechanisms for both positive and negative model selection and/or differences in the stromal components exist.
Implications: Proteomic characterization of HNSCC PDXs demonstrates potential drivers for model selection and provides a framework for improved utilization of this expanding model system. Mol Cancer Res; 14(3); 278–86. ©2015 AACR.
Cyclin A2 and CDK2 as Novel Targets of Aspirin and Salicylic Acid: A Potential Role in Cancer Prevention
Authors: Dachineni Rakesh , Ai Guoqiang , Kumar D. Ramesh , Sadhu Satya S. , Tummala Hemachand , Bhat G. Jayarama 
Published: December 2015

Abstract
Data emerging from the past 10 years have consolidated the rationale for investigating the use of aspirin as a chemopreventive agent; however, the mechanisms leading to its anticancer effects are still being elucidated. We hypothesized that aspirin's chemopreventive actions may involve cell-cycle regulation through modulation of the levels or activity of cyclin A2/cyclin-dependent kinase-2 (CDK2). In this study, HT-29 and other diverse panel of cancer cells were used to demonstrate that both aspirin and its primary metabolite, salicylic acid, decreased cyclin A2 (CCNA2) and CDK2 protein and mRNA levels. The downregulatory effect of either drugs on cyclin A2 levels was prevented by pretreatment with lactacystin, an inhibitor of proteasomes, suggesting the involvement of 26S proteasomes. In-vitro kinase assays showed that lysates from cells treated with salicylic acid had lower levels of CDK2 activity. Importantly, three independent experiments revealed that salicylic acid directly binds to CDK2. First, inclusion of salicylic acid in naïve cell lysates, or in recombinant CDK2 preparations, increased the ability of the anti-CDK2 antibody to immunoprecipitate CDK2, suggesting that salicylic acid may directly bind and alter its conformation. Second, in 8-anilino-1-naphthalene-sulfonate (ANS)-CDK2 fluorescence assays, preincubation of CDK2 with salicylic acid dose-dependently quenched the fluorescence due to ANS. Third, computational analysis using molecular docking studies identified Asp145 and Lys33 as the potential sites of salicylic acid interactions with CDK2. These results demonstrate that aspirin and salicylic acid downregulate cyclin A2/CDK2 proteins in multiple cancer cell lines, suggesting a novel target and mechanism of action in chemoprevention.
Implications: Biochemical and structural studies indicate that the antiproliferative actions of aspirin are mediated through cyclin A2/CDK2. Mol Cancer Res; 14(3); 241–52. ©2015 AACR.
Myocardial Fibrosis Quantified by Extracellular Volume Is Associated With Subsequent Hospitalization for Heart Failure, Death, or Both Across the Spectrum of Ejection Fraction and Heart Failure Stage
Authors: Schelbert Erik B. , Piehler Kayla M. , Zareba Karolina M. , Moon James C. , Ugander Martin , Messroghli Daniel R. , Valeti Uma S. , Chang Chung‐Chou H. , Shroff Sanjeev G. , Diez Javier , Miller Christopher A. , Schmitt Matthias , Kellman Peter , Butler Javed , Gheorghiade Mihai , Wong Timothy C. 
Published: December 2015

Background

Myocardial fibrosis (
MF
) in noninfarcted myocardium may be an interstitial disease pathway that confers vulnerability to hospitalization for heart failure, death, or both across the spectrum of heart failure and ejection fraction. Hospitalization for heart failure is an epidemic that is difficult to predict and prevent and requires potential therapeutic targets associated with outcomes.

Method and Results

We quantified
MF
with cardiovascular magnetic resonance extracellular volume fraction (
ECV
) measures in 1172 consecutive patients without amyloidosis or hypertrophic or stress cardiomyopathy and assessed associations with outcomes using Cox regression.
ECV
ranged from 16.6% to 47.8%. Over a median of 1.7 years, 111 patients experienced events after cardiovascular magnetic resonance, 55 had hospitalization for heart failure events, and there were 74 deaths.
ECV
was more strongly associated with outcomes than “nonischemic”
MF
observed with late gadolinium enhancement, thus
ECV
quantified
MF
in multivariable models. Adjusting for age, sex, renal function, myocardial infarction size, ejection fraction, hospitalization status, and heart failure stage, higher
ECV
was associated with hospitalization for heart failure (hazard ratio 1.77; 95%
CI
1.32 to 2.36 for every 5% increase in
ECV
), death (hazard ratio 1.87 95%
CI
1.45 to 2.40) or both (hazard ratio 1.85, 95%
CI
1.50 to 2.27).
ECV
improved classification of persons at risk and improved model discrimination for outcomes (eg, hospitalization for heart failure: continuous net reclassification improvement 0.33, 95%
CI
0.05 to 0.66;
P
=0.02; 0.16, 95%
CI
0.01 to 0.33;
P
=0.02; integrated discrimination improvement 0.037, 95%
CI
0.008 to 0.073;
P
<0.01).

Conclusion

MF
measured by
ECV
is associated with hospitalization for heart failure, death, or both.
MF
may represent a principal phenotype of cardiac vulnerability that improves risk stratification. Because
MF
can be reversible, cells and enzymes regulating collagen could be potential therapeutic targets.
Proteinuria Is an Independent Risk Factor for First Incident Stroke in Adults Under Treatment for Hypertension in China
Authors: Zhang Chunyan , Wang Xiaobin , He Mingli , Qin Xianhui , Tang Genfu , Xu Xin , Wang Yu , Huo Yong , Cai Yefeng , Fu Jia , Zhao Gang , Dong Qiang , Xu Xiping , Wang Binyan , Hou Fan Fan 
Published: December 2015

Background

Conflicting evidence exists regarding whether reduced estimated glomerular filtration rate (
eGFR
) and proteinuria are independent risk factors for stroke and its subtypes in hypertensive patients. This study investigated the association of these renal measures with first incident stroke in adults under treatment for hypertension in China.

Methods and Results

The study included 19 599 adults aged 45 to 75 years who participated in the China Stroke Primary Prevention Trial. Baseline
eGFR
was calculated using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. Proteinuria was assessed by qualitative dipstick urinalysis and in a subset by the quantitative albumin–creatinine ratio method. Cox regression analysis was used to examine the effects of
eGFR
and proteinuria on the risk of first incident stroke. During a median of 4.5 years of follow‐up, a total of 585 first strokes (472 ischemic strokes) were identified. Compared to participants without proteinuria, participants with proteinuria (trace or more by dipstick) had a 35% increased risk of first stroke: the adjusted hazard ratio (
HR
) (95%
CI
) was 1.35 (1.09–1.66,
P
=0.005). The results were robust in subgroup analyses. In a subset with data on proteinuria measured by quantitative albumin–creatinine ratio, a similar association was found. In both independent and combined analyses with proteinuria,
eGFR
was not significantly associated with stroke.

Conclusions

In adults under treatment for hypertension in China, baseline proteinuria measured by dipstick or quantitative albumin–creatinine ratio, but not reduced
eGFR
, was found to be an independent risk factor for first incident stroke and ischemic stroke.
Growth rates of black caiman (Melanosuchus niger) in the Rupununi region of Guyana
Authors: Taylor Peter , Li Fernando , Holland Ashley , Martin Michael , Rosenblatt Adam E. 
Published: December 2015

We conducted a study of black caiman (Melanosuchus niger) growth rates using data from a long-term mark-recapture study carried out in the Rupununi region of Guyana between 2005 and 2015. In contrast to previous studies, growth rates of black caiman declined with increasing size and this decline occurred more rapidly for females. Size-at-age models predicted that males and females reach asymptotic sizes of 178.2-189.0 cm SVL and 140.1-143.4 cm SVL, respectively. Our results suggest that growth rates of black caiman in the Rupununi region follow the same general patterns as for other crocodilians, and that disparities with previous black caiman studies may be largely related to density-dependent factors, among other possibilities. However, future studies that include large black caiman of known ages are needed to validate our findings.
“Please Check for Grammar.”: Code-Alternations in a Language Learning Blogging Community
Authors: Buendgens-Kosten Judith 
Published: December 2015

This paper looks at code-alternations in the language-learning blogging community “Lang-8”. In this community, users write blog posts in their target language and receive feedback and corrections from native speakers. 116 blog posts with the target language English are analyzed in detail. Around 2/3 of those blog posts avoided all code-alternations. Among the remaining third, the most frequently observed type of code-alternation involved translation of part or all of the blog post (interlinear translation and en bloc translation), or switches motivated by lexical need (complex lexical gaps). Quoting, other sentence-level switches and word-level switches for meta-linguistic discussion were rare.
The author argues that technological affordances, different understandings of one’s audience and of the language learning process, and, to a limited degree, community norms, shape code-alternations and their avoidance.
25-Hydroxyvitamin D C3-epimer is universally present in neonatal Western Australian samples but is unlikely to contribute to diagnostic misclassification
Authors: Cooke David J , Cooke Brian R , Bell Damon A , Vasikaran Samuel D , Glendenning Paul 
Published: December 2015

Background The presence of C3-epimer (C-3-epi-25-hydroxyvitamin D) in infant serum may complicate 25-hydroxyvitamin D (25(OH)D) measurement when using liquid chromatography tandem mass spectrometry assays that do not separately measure the epimer. We measured the concentration of C3-epi-25(OH)D in neonatal samples in Western Australian using umbilical cord blood samples and a liquid chromatography tandem mass spectrometry assay that separately quantifies 25(OH)D and C3-epi-25(OH)D. Methods A total of 120 anonymized cord blood samples were analysed using a liquid chromatography tandem mass spectrometry assay that utilizes two CSH fluoro-phenyl columns in series. Chromatography was performed on a Waters Acquity Ultra Performance Liquid system, and quantification was using a Waters Quattro Premier XE mass spectrometer. Results C3-epi-25(OH)D3 was detected in all umbilical cord blood samples (median 5.2 nmol/L, IQR 3.7–6.6 nmol/L) and contributed 6.6% (SD 2.6, 95% CI [6.1, 7.1]) of the total 25(OH)D concentration. Mean 25(OH)D3 measured in cord blood was 79.1 nmol/L (SD 22.7 nmol/L). A positive relationship (R2 = 0.35, P < 0.0005) between 25(OH)D3 levels and C3-epi-25(OH)D3 was noted in this cohort. No samples contained 25(OH)D2 or C3-epi-25(OH)D2. Conclusion C3-epi-25(OH)D3 is present in all neonatal samples but contributes <10% of the total 25(OH)D concentration which is unlikely to be clinically significant. Liquid chromatography tandem mass spectrometry assays that do not separately quantify C3-epi-25(OH)D3 from other vitamin D metabolites may potentially overestimate neonatal 25(OH)D levels, but diagnostic misclassification in neonates is unlikely.
Impact of carbon dioxide tension during cardiopulmonary bypass on tissue perfusion in neonates undergoing cardiac surgery using autologous umbilical cord blood
Authors: Chasovskyi Kyrylo , Yemets Illya 
Published: December 2015

Objective: Previously, we reported that the oxyhemoglobin dissociation curve is shifted leftward in patients who receive autologous umbilical cord blood (UCB) during neonatal open heart surgery. In this study, we assessed whether allowing the pCO2 to rise during hypothermic cardiopulmonary perfusion would shift the curve back to the right and improve tissue oxygenation. Methods: The study population included prenatally diagnosed patients with transposition of the great arteries. The study cohort was divided into two groups and consisted of early patients originally managed with lower pCO2 levels (Group I, n=42, 2009-12) and later patients subsequently managed with higher pCO2 levels (Group II, n=38, 2012-14). Results: Patients received similar volumes of collected autologous UCB (Group I, 80 ml; Group II, 75ml, p=0.207) with a similar mean level of HbF during CPB (Group I, 90±8%; Group II, 87±9%, p=0.310). Higher levels of pCO2 during CPB (Group I, 31 mmHg; Group II, 37 mmHg, p=0.011) resulted in a rightward shift of the oxyhemoglobin dissociation curve (increased p50O2) (Group I, 19.5±3.4 mmHg; Group II, 22.5±2.2 mmHg, p=0.011). The use of a higher pCO2 strategy was associated with decreased serum lactate during CPB (Group I, 4.7±2 mmol/l; Group II, 2.8±1.4 mmol/l, p=0.001), decreased duration of mechanical ventilation (Group I, 46h; Group II, 22h, p<0.001) and decreased of length of intensive care unit (ICU) stay (Group I, 7.6±2.6, Group II, 5.6±2.2, p=0.003) Conclusions: A higher pCO2 during CPB in neonates who underwent open heart surgery using UCB resulted in a rightward shift of the oxyhemoglobin dissociation curve and was associated with improved serum lactate levels.
The effects of acute and preventive migraine therapies in a mouse model of chronic migraine
Authors: Tipton Alycia F , Tarash Igal , McGuire Brenna , Charles Andrew , Pradhan Amynah A 
Published: December 2015

Background The development of novel migraine therapies has been slow, in part because of the small number of clinically relevant animal models. We have recently developed a new mouse model of chronic migraine using chronic intermittent nitroglycerin, a known human migraine trigger. The objective of this study was to validate this model by testing known and potential migraine-preventive treatments. Methods Migraine therapies were administered to male and female mice for 11 days. On day 3, mice were tested with nitroglycerin every second day for nine days. Basal and nitroglycerin-evoked mechanical hypersensitivity was evaluated using von Frey filaments. Results Chronic intermittent nitroglycerin produced acute hyperalgesia with each administration, and progressive and sustained basal hypersensitivity. The established preventive migraine therapy propranolol effectively blocked the development of acute and chronic nitroglycerin-induced hyperalgesia, while valproate had no effect. Potential migraine-preventive therapies were also tested: Amiloride inhibited nitroglycerin-induced acute and chronic hyperalgesia; while memantine was ineffective. We also tested the acute migraine therapy sumatriptan, which did not alter nitroglycerin-induced hyperalgesia, but instead resulted in acute and chronic hyperalgesia similar to that observed following nitroglycerin administration. Conclusions This study establishes the chronic nitroglycerin model as an additional screening tool to test novel migraine-preventive therapies.
Pain Management After Outpatient Anterior Cruciate Ligament Reconstruction
Authors: Secrist Eric S. , Freedman Kevin B. , Ciccotti Michael G. , Mazur Donald W. , Hammoud Sommer 
Published: December 2015

Background: Effective pain management after anterior cruciate ligament (ACL) reconstruction improves patient satisfaction and function. Purpose: To collect and evaluate the available evidence from randomized controlled trials (RCTs) on pain control after ACL reconstruction. Study Design: Systematic review. Methods: A systematic literature review was performed using PubMed, Medline, Google Scholar, UpToDate, Cochrane Reviews, CINAHL, and Scopus following PRISMA guidelines (July 2014). Only RCTs comparing a method of postoperative pain control to another method or placebo were included. Results: A total of 77 RCTs met inclusion criteria: 14 on regional nerve blocks, 21 on intra-articular injections, 4 on intramuscular/intravenous injections, 12 on multimodal regimens, 6 on oral medications, 10 on cryotherapy/compression, 6 on mobilization, and 5 on intraoperative techniques. Single-injection femoral nerve blocks provided superior analgesia to placebo for up to 24 hours postoperatively; however, this also resulted in a quadriceps motor deficit. Indwelling femoral catheters utilized for 2 days postoperatively provided superior analgesia to a single-injection femoral nerve block. Local anesthetic injections at the surgical wound site or intra-articularly provided equivalent analgesia to regional nerve blocks. Continuous-infusion catheters of a local anesthetic provided adequate pain relief but have been shown to cause chondrolysis. Cryotherapy improved analgesia compared to no cryotherapy in 4 trials, while in 4 trials, ice water and water at room temperature provided equivalent analgesic effects. Early weightbearing decreased pain compared to delayed weightbearing. Oral gabapentin given preoperatively and oral zolpidem given for the first week postoperatively each decreased opioid consumption as compared to placebo. Ibuprofen reduced pain compared to acetaminophen. Oral ketorolac reduced pain compared to hydrocodone-acetaminophen. Conclusion: Regional nerve blocks and intra-articular injections are both effective forms of analgesia. Cryotherapy-compression appears to be beneficial, provided that intra-articular temperatures are sufficiently decreased. Early mobilization reduces pain symptoms. Gabapentin, zolpidem, ketorolac, and ibuprofen decrease opioid consumption. Despite the vast amount of high-quality evidence on this topic, further research is needed to determine the optimal multimodal approach that can maximize recovery while minimizing pain and opioid consumption. Clinical Relevance: These results provide the best available evidence from RCTs on pain control regimens after ACL reconstruction.
An In Vitro Robotic Assessment of the Anterolateral Ligament, Part 1
Authors: Rasmussen Matthew T. , Nitri Marco , Williams Brady T. , Moulton Samuel G. , Cruz Raphael Serra , Dornan Grant J. , Goldsmith Mary T. , LaPrade Robert F. 
Published: December 2015

Background: Recent investigations have described the structural and functional behavior of the anterolateral ligament (ALL) of the knee through pull-apart and isolated sectioning studies. However, the secondary stabilizing role of the ALL in the setting of a complete anterior cruciate ligament (ACL) tear has not been fully defined for common simulated clinical examinations, such as the pivot-shift, anterior drawer, and internal rotation tests. Hypothesis: Combined sectioning of the ALL and ACL would lead to increased internal rotation and increased axial plane translation during a pivot-shift test when compared with isolated sectioning of the ACL. Study Design: Controlled laboratory study. Methods: Ten fresh-frozen human cadaveric knees were subjected to a simulated pivot-shift test with coupled 10-N·m valgus and 5-N·m internal rotation torques from 0° to 60° of knee flexion and a 5-N·m internal rotation torque and an 88-N anterior tibial load, both from 0° to 120° of knee flexion via a 6 degrees of freedom robotic system. Kinematic changes were measured and compared with the intact state for isolated sectioning of the ACL and combined sectioning of the ACL and ALL. Results: Combined sectioning of the ACL and ALL resulted in a significant increase in axial plane tibial translation during a simulated pivot shift at 0°, 15°, 30°, and 60° of knee flexion and a significant increase in internal rotation at 0°, 15°, 30°, 45°, 60°, 75°, 90°, 105°, and 120° when compared with the intact and ACL-deficient states. Based on the model results, ALL sectioning resulted in an additional 2.1 mm (95% CI, 1.4-2.9 mm; P < .001) of axial plane translation during the pivot shift when compared with ACL-only sectioning, when pooling evidence over all flexion angles. Likewise, when subjected to IR torque, the ACL+ALL-deficient state resulted in an additional 3.2° of internal rotation (95% CI, 2.4°-4.1°; P < .001) versus the intact state, and the additional sectioning of the ALL increased internal rotation by 2.7° (95% CI, 1.8°-3.6°; P < .001) versus the ACL-deficient state. Conclusion: The results of this study confirm the ALL as an important lateral knee structure that provides rotatory stability to the knee. Specifically, the ALL was a significant secondary stabilizer throughout flexion during an applied internal rotation torque and simulated pivot-shift test in the context of an ACL-deficient knee. Clinical Relevance: Residual internal rotation and a positive pivot shift after ACL reconstruction may be attributed to ALL injury. For these patients, surgical treatment of an ALL tear may be considered.
Synergic development of pharmacokinetics and bioanalytical methods as support of pharmaceutical research
Authors: Marzo M , Ciccarelli R , Di Iorio P , Giuliani P , Caciagli F , Marzo A 
Published: December 2015

The development of pharmacokinetics led this science to achieve a relevant role in the investigation of new chemical entities for therapeutic application, and has allowed a series of new useful realizations of out of patent drugs like prolonged release and delayed release formulations, therapeutic delivery system (TDS) for drugs to be active in systemic circulation avoiding the first pass effect, orodispersible and effervescent formulations, intramuscular and subcutaneous depot formulations acting over a long period, oral inhalatory systems, and drug association at fixed dose. The above applications had pharmacokinetics as protagonist and have required the support from bioanalytical methods to assay drug concentrations, even in pg·mL−1 of plasma, that really have paralleled the synergic development of pharmacokinetics. The complexity of the above realizations required specific guidelines from the regulatory authorities, mainly the US FDA and EU EMA, which have normalized and, in most cases, simplified the above applications admitting some waivers of in vivo bioequivalence. However, this review highlights some critical points, not yet focused on by operating guidelines, which need to be clarified by regulatory authorities. One of the most relevant issues is about the planning and conducting bioavailability and bioequivalence trials with endogenous substances, that possess own homeostatic equilibria with fluctuations, in some cases with specific rhythms, like melatonin and female sex hormones. The baseline subtraction required by guidelines to define the net contribute to the exogenous absorbed drug in most cases is a non-solvable problem.