bluuebunny/crossref_metadata_2025_split huggingface dataset:
Boswellic acid acetate induces apoptosis through caspase-mediated pathways in myeloid leukemia cells
Authors: Xia Lijuan , Chen Duo , Han Rui , Fang Qicheng , Waxman Samuel , Jing Yongkui 
Published: February 2021

Abstract
The mechanism of the cytotoxic effect of boswellic acid acetate, a 1:1 mixture of α-boswellic acid acetate and β-boswellic acid acetate, isolated from Boswellia carterri Birdw on myeloid leukemia cells was investigated in six human myeloid leukemia cell lines (NB4, SKNO-1, K562, U937, ML-1, and HL-60 cells). Morphologic and DNA fragmentation assays indicated that the cytotoxic effect of boswellic acid acetate was mediated by induction of apoptosis. More than 50% of the cells underwent apoptosis after treatment with 20 μg/mL boswellic acid for 24 hours. This apoptotic process was p53 independent. The levels of apoptosis-related proteins Bcl-2, Bax, and Bcl-XL were not modulated by boswellic acid acetate. Boswellic acid acetate induced Bid cleavage and decreased mitochondrial membrane potential without production of hydrogen peroxide. A general caspase inhibitor (Z-VAD-FMK) and a specific caspase-8 inhibitor II (Z-IETD-FMK) blocked boswellic acid acetate–induced apoptosis. The mRNAs of death receptors 4 and 5 (DR4 and DR5) were induced in leukemia cells undergoing apoptosis after boswellic acid acetate treatment. These data taken together suggest that boswellic acid acetate induces myeloid leukemia cell apoptosis through activation of caspase-8 by induced expression of DR4 and DR5, and that the activated caspase-8 either directly activates caspase-3 by cleavage or indirectly by cleaving Bid, which in turn decreases mitochondria membrane potential.
Small interfering RNA targeting of S phase kinase–interacting protein 2 inhibits cell growth of oral cancer cells by inhibiting p27 degradation
Authors: Kudo Yasusei , Kitajima Shojiro , Ogawa Ikuko , Kitagawa Masae , Miyauchi Mutsumi , Takata Takashi 
Published: February 2021

Abstract
S phase kinase–interacting protein 2 (Skp2), an F box protein, is required for the ubiquitination and consequent degradation of p27. It is well known that reduced expression of p27 is frequently observed in various cancers including oral squamous cell carcinoma and is due to an enhancement of its protein degradation. Our previous study showed that overexpression of Skp2 was frequently found in oral squamous cell carcinoma and inversely correlated with p27 expression. Recently, a technique known as RNA interference has been successfully adapted to mammalian cells. In the present study, we investigated if small interfering RNA (siRNA)-mediated gene silencing of Skp2 can be employed in order to inhibit p27 down-regulation in oral squamous cell carcinoma. We used a siRNA plasmid vector, which has an advantage over synthetic siRNAs in determining the effects of decreasing the high constitutive levels of Skp2 protein in oral squamous cell carcinoma. We showed that Skp2 siRNA transfection decreased Skp2 protein and induced the accumulation of p27 protein in oral squamous cell carcinoma cells. Moreover, p27 protein in Skp2 siRNA-transfected cells is more stabilized than that in control siRNA-transfected cells. Interestingly, Skp2 siRNA inhibited the cell proliferation of oral squamous cell carcinoma cells both in vitro and in vivo. Our findings suggest that siRNA-mediated gene silencing of Skp2 can be a novel modality of cancer gene therapy for suppression of p27 down-regulation.
A recombinant, fully human, bispecific antibody neutralizes the biological activities mediated by both vascular endothelial growth factor receptors 2 and 3
Authors: Jimenez Xenia , Lu Dan , Brennan Laura , Persaud Kris , Liu Meilin , Miao Huaquan , Witte Larry , Zhu Zhenping 
Published: February 2021

Abstract
Vascular endothelial growth factors (VEGF) and their receptors (VEGFR) have been implicated to play important roles in tumor-associated angiogenesis and lymphangiogenesis, and hence in tumor growth and metastasis. We previously produced a number of fully human antibodies directed against VEGF receptor 2 (VEGFR2) and VEGF receptor 3 (VEGFR3) and showed that these antibodies are capable of inhibiting growth factor (VEGF and VEGF-C)-induced receptor activation, migration, and proliferation of human endothelial cells. In this report, we constructed and produced a bispecific antibody, a diabody, using the variable domain genes of two neutralizing antibodies, IMC-1121 to VEGFR2 and hF4-3C5 to VEGFR3. The diabody binds to both VEGFR2 and VEGFR3 in a dose-dependent manner, and blocks interaction between VEGF/VEGFR2, VEGF-C/VEGFR2, and VEGF-C/VEGFR3. In cell-based assays, the diabody neutralized both VEGF and VEGF-C-stimulated activation of VEGFR2, VEGFR3, and p44/p42 mitogen-activated protein kinase in endothelial cells. Furthermore, the diabody was able to inhibit both VEGF and VEGF-C-induced migration of endothelial cells. Taken together, our results suggest that a dual blockade of both VEGFR2 and VEGFR3 simultaneously may represent a more potent approach to effective cancer therapy.
Microfibrillar-Associated Protein 4 Regulates Stress-Induced Cardiac Remodeling
Authors: Dorn Lisa E. , Lawrence William , Petrosino Jennifer M. , Xu Xianyao , Hund Thomas J. , Whitson Bryan A. , Stratton Matthew S. , Janssen Paul M. L. , Mohler Peter J. , Schlosser Anders , Sorensen Grith L. , Accornero Federica 
Published: February 2021

Rationale:
Cardiac hypertrophy, a major risk factor for heart failure, occurs when cardiomyocytes remodel in response to complex signaling induced by injury or cell stress. Although cardiomyocytes are the ultimate effectors of cardiac hypertrophy, nonmyocyte populations play a large yet understudied role in determining how cardiomyocytes respond to stress.

Objective:
To identify novel paracrine regulators of cardiomyocyte hypertrophic remodeling.

Methods and Results:
We have identified a novel role for a nonmyocyte-derived and TGFβ1 (transforming growth factor β1)–induced extracellular matrix protein MFAP4 (microfibrillar-associated protein 4) in the pathophysiology of cardiac remodeling. We have determined that nonmyocyte cells are the primary sources of MFAP4 in the heart in response to TGFβ1 stimulation. Furthermore, we have demonstrated a crucial role of MFAP4 in the cardiac adaptation to stress. Global knockout of MFAP4 led to increased cardiac hypertrophy and worsened cardiac function following chronic pressure overload. Also, one week of angiotensin-mediated neurohumoral stimulation was sufficient to exacerbate cardiomyocyte hypertrophy in MFAP4 null mice. In contrast, administration of exogenous MFAP4 to isolated cardiomyocytes blunted their phenylephrine-induced hypertrophic growth through an integrin-dependent mechanism. Finally, MFAP4 deficiency leads to dysregulated integration of G protein-coupled receptor and integrin signaling in the heart.

Conclusions:
Altogether, our results demonstrate a critical paracrine role of MFAP4 in the development of cardiac hypertrophy and could inform future treatment options for patients with heart failure.
Atherosclerosis Regression and Cholesterol Efflux in Hypertriglyceridemic Mice
Authors: Josefs Tatjana , Basu Debapriya , Vaisar Tomas , Arets Britt , Kanter Jenny E. , Huggins Lesley-Ann , Hu Yunying , Liu Jianhua , Clouet-Foraison Noemie , Heinecke Jay W. , Bornfeldt Karin E. , Goldberg Ira J. , Fisher Edward A. 
Published: February 2021

Rationale:
Hypertriglyceridemia and low HDL-C (high-density lipoprotein cholesterol), both of which are regulated by LpL (lipoprotein lipase) activity, associate with increased cardiovascular disease. Genetic regulators of LpL actions track with cardiovascular disease risk in humans. Whether this is due to changes in HDL-C or function or circulating triglyceride levels is unresolved.

Objective:
We created hypertriglyceridemia and HDL-C reduction in atherosclerotic mice to allow the assessment of how hypertriglyceridemia and reduced HDL-C affect regression of atherosclerosis and the phenotype of plaque macrophages.

Methods and Results:

Atherosclerosis regression was studied in control LpL floxed (
Lpl

fl/fl

) mice and tamoxifen-inducible whole-body LpL knockout (
iLpl
−/−
) mice with hypertriglyceridemia (≈500 mg/dL) and reduced HDL-C (≈50% reduction). Atherosclerosis regression was studied using 2 models in which advanced plaques resulting from hypercholesterolemia are exposed to normal LDL-C (low-density lipoprotein cholesterol) levels using aortic transplantation or treatments with oligonucleotides. In a subset of mice, we expressed hCETP (human cholesterol ester transfer protein) to humanize the relationship between apoB-lipoproteins and HDL. HDL particle number, cholesterol efflux capacity, and HDL proteome were measured in hypertriglyceridemia mice and humans. Surprisingly, hypertriglyceridemia and reduced HDL-C levels due to loss of LpL did not affect atherosclerosis lesion size or macrophage content (CD68+cells) in either model. Expression of hCETP and further reduction of HDL-C did not alter lesions. Sera from
iLpl
−/−
mice had a decrease in total cholesterol efflux capacity, but not ABCA1 (ATP-binding cassette transporter A1)-mediated cholesterol efflux capacity. Hypertriglyceridemic humans, including those with LpL deficiency, had greater ABCA1-mediated cholesterol efflux capacity and total cholesterol efflux capacity per HDL particle number.

Conclusions:
Atherosclerosis regression in mice is driven by LDL-C reduction and is not affected by hypertriglyceridemia and plasma HDL-C levels.
<strong><em>Pandea</em>, a new replacement name for <em>Udaria</em> D.K. Singh, S. Majumdar &amp; D. Singh (Marchantiophyta, Lophocoleaceae)</strong>
Authors: DESHMUKH UMAKANT  BHOOPATI 
Published: February 2021

The generic name Udaria Gupta (1996:103) was established by Gupta (1996) with two fossil fungi species Udaria singhii Gupta (1996:103) and U. saxenae Gupta (1996:104) from Lower Tertiary sediments of Himachal Pradesh, India. Later on, Singh et al. (2018) described the new genus of liverworts, Udaria Singh, Majumdar & Singh (2018: 1537) with the single species Udaria lamellicaulis Singh, Majumdar & Singh (2018: 1537) to the family Lophocoleaceae Vanden Berghen (1956: 208) from Arunachal Pradesh and Sikkim in Eastern Himalaya, India. After a thorough scrutiny of literature and type specimens, it was found that the liverwort genus name, Udaria Singh, Majumdar & Singh (2018: 1537) is illegitimate as it is a later homonym of the fossil fungi genus Udaria Gupta (1996:103). Therefore, a new replacement name Pandea U. B. Deshmukh is proposed with a new combination for the type species here in accordance with article 53.1 of Shenzhen Code (Turland et al. 2018).
Constructing High-Resolution, Bias-Corrected Climate Products: A Comparison of Methods
Authors: Holthuijzen Maike F. , Beckage Brian , Clemins Patrick J. , Higdon Dave , Winter Jonathan M. 
Published: February 2021

AbstractHigh-resolution, bias-corrected climate data are necessary for climate impact studies at local scales. Gridded historical data are convenient for bias correction but may contain biases resulting from interpolation. Long-term, quality-controlled station data are generally superior climatological measurements, but because the distribution of climate stations is irregular, station data are challenging to incorporate into downscaling and bias-correction approaches. Here, we compared six novel methods for constructing full-coverage, high-resolution, bias-corrected climate products using daily maximum temperature simulations from a regional climate model (RCM). Only station data were used for bias correction. We quantified performance of the six methods with the root-mean-square-error (RMSE) and Perkins skill score (PSS) and used two ANOVA models to analyze how performance varied among methods. We validated the six methods using two calibration periods of observed data (1980–89 and 1980–2014) and two testing sets of RCM data (1990–2014 and 1980–2014). RMSE for all methods varied throughout the year and was larger in cold months, whereas PSS was more consistent. Quantile-mapping bias-correction techniques substantially improved PSS, while simple linear transfer functions performed best in improving RMSE. For the 1980–89 calibration period, simple quantile-mapping techniques outperformed empirical quantile mapping (EQM) in improving PSS. When calibration and testing time periods were equivalent, EQM resulted in the largest improvements in PSS. No one method performed best in both RMSE and PSS. Our results indicate that simple quantile-mapping techniques are less prone to overfitting than EQM and are suitable for processing future climate model output, whereas EQM is ideal for bias correcting historical climate model output.
Tropical Cyclone Resistance to Strong Environmental Shear
Authors: Dai Yi , Majumdar Sharanya J. , Nolan David S. 
Published: February 2021

AbstractIt is widely known that strong vertical wind shear (exceeding 10 m s−1) often weakens tropical cyclones (TCs). However, in some circumstances, a TC is able to resist this strong shear and even restrengthen. To better understand this phenomenon, a series of idealized simulations are conducted, followed by a statistical investigation of 40 years of Northern Hemisphere TCs. In the idealized simulations, a TC is embedded within a time-varying point-downscaling framework, which is used to gradually increase the environmental vertical wind shear to 14 m s−1 and then hold it constant. This controlled framework also allows for the separation of the TC-induced flow from the prescribed environmental flow. The TC-induced outflow is found to withstand the strong upper-tropospheric environmental flow, and this is manifested in the TC-induced shear difference (TCSD) vector. The TCSD vector, together with the environmental shear vector, defines an azimuthal range within which most of the asymmetric convection is located. The statistical analysis confirms the findings from the idealized simulations, and the results are not strongly sensitive to the TC intensity or basin. Moreover, compared with total shear, the inclusion of TCSD information creates a slightly better correlation with TC intensity change. Overall, the TCSD vector serves as a diagnostic to explain the ability of a TC to resist strong environmental shear through its outflow, and it could potentially be used as a parameter to predict future intensity change.
Risk Factors Associated With Readmission After Pancreatectomy: A Single-Institution Retrospective Cohort Study
Authors: Bonds Morgan , Garwe Tabitha , Rozich Noah , Oluborode Babawale , Sarwar Zoona , Postier Russell G , Morris Katherine T 
Published: January 2021

Background Pancreatectomy has a significant rate of procedure-specific morbidity which can result in readmission. Readmission has been proposed as a measure of quality. The goal of this study is to determine what factors are associated with readmission after pancreatectomy and whether readmission can be prevented. Methods A retrospective review of a single institution’s pancreatectomies between January 2011 and April 2015 was performed. Demographic, perioperative, and outpatient data were collected from the medical record. Primary outcome was 90-day readmission. Univariate and multivariable analyses were performed to determine which factors were associated with increased risk for readmission. Results A total of 257 patients met inclusion criteria; the 90-day readmission rate was 32.7%. The median time to readmission was 13 days. Readmitted patients were more likely to have a postoperative pancreatic fistula (POPF) on univariate analysis. Surgical site infections were more common in readmitted patients (18% vs 6.4%, P = .0138). Upon multivariable adjustment, only POPF ( P = .0005) remained significant. A positive dose-response relationship was noted between POPF grade and the odds of readmission with odds ratios (ORs) ranging from 1.6 (95% Confidence Interval (CI): .6-4.1) for grade A to 16.7 (95% CI: 1.8-156.8) for grade C, albeit with limited precision. Conclusions Readmission after pancreatectomy is a common occurrence despite the many advancements in perioperative care. Our data suggest that POPF is a risk factor for readmission after pancreatectomy. Presently, this factor is not clearly preventable. This suggests that readmission may not be the best measure of quality to utilize in the evaluation of pancreatic surgery.
Emergency Medical Service Transport Time and Trauma Outcomes at an Urban Level 1 Trauma Center: Evaluation of Prehospital Emergency Medical Service Response
Authors: Elkbuli Adel , Dowd Brianna , Sanchez Carol , Shaikh Saamia , Sutherland Mason , McKenney Mark 
Published: January 2021

Background The use of helicopter emergency medical services (HEMS) for trauma patients has been debated since its introduction. We aim to compare outcomes for trauma patients transported by ground EMS (GEMS) vs. HEMS using raw and adjusted mortality in a level 1 trauma center. Methods A 6-year retrospective cohort study utilizing our level 1 trauma center registry for patients transferred by GEMS or HEMS was performed. Demographics and outcome measures were compared. Raw and adjusted mortality was evaluated. Adjusted mortality was determined incorporating confounders, including patient demographics, comorbid conditions, mechanism of injury, injury severity score (ISS), Glasgow Coma Scale score, and EMS transport time. Chi-square, multivariable logistic regression, and independent sample T-test were utilized with significance, defined as P < .05. Results Of 12 633 patients, 10 656 were transported via GEMS and 1977 with HEMS. Mean age was 55 for GEMS and 40 for HEMS ( P < .001). Mean ISS was 9.29 and 11.73 for GEMS and HEMS ( P < .001). Mean Revised Trauma Score was higher (less severe) for GEMS vs. HEMS (7.6 vs. 7.12, P < .001). Mean transport times for GEMS and HEMS was 39.45 vs. 47.29 minutes ( P = .02). Raw mortality was 2.55% (307/10 656) for GEMS and 6.78% (134/1977) for HEMS. Adjusted mortality revealed a 16.6% increased mortality for GEMS compared to HEMS (adjusted odds ratio = 1.166, 95% CI: .815-1.668). Conclusions Air-lifted trauma patients were younger, more severely injured, and more hemodynamically unstable and required longer transport time but experienced lower adjusted mortality. Future research is needed to investigate whether reducing transport times and augmenting the advanced care already implemented by HEMS crews can improve outcomes.
Change in Neutrophil-to-Lymphocyte Ratio During Neoadjuvant Treatment Does Not Predict Pathological Response and Survival in Resectable Pancreatic Ductal Adenocarcinoma
Authors: Strong James S. , Vos Elvira L. , Mcintyre Caitlin A. , Chou Joanne F. , Gonen Mithat , Tang Laura H. , Soares Kevin C. , Balachandran Vinod P. , Kingham T. Peter , D'Angelica Michael I. , Jarnagin William R. , Drebin Jeffrey , Kunstman John W. , Allen Peter J. , Wei Alice C. 
Published: January 2021

Background Neutrophil-to-lymphocyte ratio (NLR) has been reported as prognostic in pancreatic ductal adenocarcinoma (PDAC). Data about NLR changes during neoadjuvant therapy (NAT) and its relationship with pathological tumor response and survival are lacking. Methods Pancreatic ductal adenocarcinoma patients with NAT followed by resection between 2009 and 2015 were identified from a prospective database. Neutrophil-to-lymphocyte ratio was collected prior to NAT (baseline), on chemotherapy (prior to cycle 3), and prior to surgery. Baseline NLR, and changes in NLR between baseline and on chemotherapy (delta 1) and between baseline and surgery (delta 2) were compared with pathologic response (<90% and ≥90% defined as poor and good), overall (OS), and disease-free survival (DFS) using Wilcoxon rank-sum and Cox proportional hazard models. Results Of 93 patients, 17% had good pathological response. Median (interquartile range) NLR at baseline, third cycle, and surgery were 2.7 (2.0-3.7), 2.5 (1.9-4.1), and 3.1 (2.1-5.3), respectively. Median change in NLR from baseline to third cycle was .06 ( P = .72), and .6 from baseline to surgery ( P < .01). Baseline NLR, delta 1, and delta 2 were not associated with pathological response, OS, or DFS. Discussion Neutrophil-to-lymphocyte ratio increased after NAT, but a significant association between NLR and pathological response, OS, and DFS in resected PDAC patients was not observed.
The Accuracy of Point-of-Care Ultrasound in the Diagnosis of Acute Cholecystitis
Authors: Wehrle Chase J. , Talukder Asif , Tien Lillie , Parikh Soham , Devarakonda Aditya , Holsten Steven B. , Fox Elizabeth D. , Lawson Andrew 
Published: January 2021

Purpose Acute cholecystitis (AC) affects 50-200 000 patients per year. Early surgery is the treatment of choice for AC. Therefore, timely diagnosis is important to begin proper management. Recently, emergency departments have adopted point-of-care ultrasound (POCUS) for the initial evaluation of AC. The accuracy of POCUS for AC has not been well studied. Methods Patients receiving POCUS for evaluation of AC in the emergency department at our tertiary care institution for 2 years were considered. Patients with previous biliary diagnoses were excluded. Patients were deemed to have AC from a recorded POCUS result or 2/3 of the following POCUS findings: pericholecystic fluid, gallbladder wall hyperemia, and sonographic Murphy’s sign. Formal ultrasound and final diagnosis from surgical and pathology reports were used as gold standards for comparison. Results In total, 147 patients met inclusion criteria. POCUS had a sensitivity and specificity of .4 (95% CI: .1216-.7376) and .99 (.9483-.9982), respectively, when compared to a final diagnosis and .33 (.0749-.7007) and .94 (.8134-.9932) when compared to formal US. The modified Tokyo guidelines for suspicion of AC had a sensitivity of .2 (.0252-.5561) and specificity of .88 (.8173-.931) compared to the final diagnosis. Conclusion Point-of-care ultrasound was not a better screening test than the modified Tokyo guidelines. We recommend a simplified screening approach for AC using clinical findings and laboratory data, followed by confirmatory formal imaging. This strategy could prevent unnecessary delays in surgical management and use of physician resources.
Is There an Age Cutoff for Intracranial Pressure Monitoring?: A Propensity Score Matched Analysis of the National Trauma Data Bank
Authors: Liveris Anna , Parsikia Afshin , Melvin Jeffrey , Chao Edward , Reddy Srinivas H , Teperman Sheldon , Stone Melvin E 
Published: January 2021

Background Despite mostly favorable past evidence for use of intracranial pressure monitoring (ICPM), more recent data question not only the indications but also the utility of ICPM. The Fourth Edition Brain Trauma Foundation guidelines offer limited indications for ICPM. Evidence supports ICPM for reducing mortality in patients with severe traumatic brain injury (TBI) and cites decreased survival in elderly patients. Methods All patients ≥ 18 years of age with isolated TBI, head Abbreviated Injury Scale (AIS) ≥ 3, and a Glasgow Coma Scale (GCS) ≤ 8 between 2008 and 2014 were included from the National Trauma Data Bank. Exclusion criteria were head AIS = 6 and death within 24 hours. Patients with and without ICPM were compared using TBI-specific variables. Patients were then matched via propensity-score matching (PSM), and the odds ratio (OR) of death with ICPM was determined using logistic regression modeling for 8 different age strata. Results A total of 23,652 patients with a mean age of 56 years, median head AIS of 4, median GCS of 3, and overall mortality of 29.2% were analyzed. After PSM, ICPM was associated with death beginning at the age stratum of 56-65 years. Intracranial pressure monitoring was associated with survival beginning at the age-group 36-45 years. Discussion Based on a large propensity-matched sample of TBI patients, ICPM was not associated with improved survival for TBI patients above 55 years of age. Until level 1 evidence is available, this age threshold should be considered for further prospective study in determining indications for ICPM.