bluuebunny/crossref_metadata_2025_split huggingface dataset:
p27 as a Transcriptional Regulator: New Roles in Development and Cancer
Authors: Razavipour Seyedeh Fatemeh , Harikumar Kuzhuvelil B. , Slingerland Joyce M. 
Published: April 2020

Abstract
p27 binds and inhibits cyclin-CDK to arrest the cell cycle. p27 also regulates other processes including cell migration and development independent of its cyclin-dependent kinase (CDK) inhibitory action. p27 is an atypical tumor suppressor–deletion or mutational inactivation of the gene encoding p27, CDKN1B, is rare in human cancers. p27 is rarely fully lost in cancers because it can play both tumor suppressive and oncogenic roles. Until recently, the paradigm was that oncogenic deregulation results from either loss of growth restraint due to excess p27 proteolysis or from an oncogenic gain of function through PI3K-mediated C-terminal p27 phosphorylation, which disrupts the cytoskeleton to increase cell motility and metastasis. In cancers, C-terminal phosphorylation alters p27 protein–protein interactions and shifts p27 from CDK inhibitor to oncogene. Recent data indicate p27 regulates transcription and acts as a transcriptional coregulator of cJun. C-terminal p27 phosphorylation increases p27-cJun recruitment to and action on target genes to drive oncogenic pathways and repress differentiation programs. This review focuses on noncanonical, CDK-independent functions of p27 in migration, invasion, development, and gene expression, with emphasis on how transcriptional regulation by p27 illuminates its actions in cancer. A better understanding of how p27-associated transcriptional complexes are regulated might identify new therapeutic targets at the interface between differentiation and growth control.
DGKA Provides Platinum Resistance in Ovarian Cancer Through Activation of c-JUN–WEE1 Signaling
Authors: Li Jie , Pan Chaoyun , Boese Austin C. , Kang JiHoon , Umano Anna D. , Magliocca Kelly R. , Yang Wenqing , Zhang Yu , Lonial Sagar , Jin Lingtao , Kang Sumin 
Published: April 2020

Abstract

Purpose:
Although platinum compounds are the first-line treatment for ovarian cancer, the majority of patients relapse and develop resistance to treatment. However, the mechanism underlying resistance is unclear. The goal of our study is to decipher the mechanism by which a metabolic kinase, diacylglycerol kinase alpha (DGKA), confers platinum resistance in ovarian cancer.

Experimental Design:
Metabolic kinase RNAi synthetic lethal screening was used to identify a cisplatin resistance driver in ovarian cancer. DGKA variants were used to demonstrate the need for DGKA activity in cisplatin resistance. Phospho-proteomic and genomic screens were performed to identify downstream effectors of DGKA. Therapeutic efficacy of targeting DGKA was confirmed and clinical relevance of DGKA signaling was validated using ovarian cancer patient-derived tumors that had different responses to platinum-based therapy.

Results:
We found that platinum resistance was mediated by DGKA and its product, phosphatidic acid (PA), in ovarian cancer. Proteomic and genomic screens revealed that DGKA activates the transcription factor c-JUN and consequently enhances expression of a cell-cycle regulator, WEE1. Mechanistically, PA facilitates c-JUN N-terminal kinase recruitment to c-JUN and its nuclear localization, leading to c-JUN activation upon cisplatin exposure. Pharmacologic inhibition of DGKA sensitized ovarian cancer cells to cisplatin treatment and DGKA–c-JUN–WEE1 signaling positively correlated with platinum resistance in tumors derived from patients with ovarian cancer.

Conclusions:
Our study demonstrates how the DGKA-derived lipid messenger, PA, contributes to cisplatin resistance by intertwining with kinase and transcription networks, and provides preclinical evidence for targeting DGKA as a new strategy in ovarian cancer treatment to battle cisplatin resistance.
Single-Cell Circulating Tumor Cell Analysis Reveals Genomic Instability as a Distinctive Feature of Aggressive Prostate Cancer
Authors: Malihi Paymaneh D. , Graf Ryon P. , Rodriguez Angel , Ramesh Naveen , Lee Jerry , Sutton Ramsay , Jiles Rhett , Ruiz Velasco Carmen , Sei Emi , Kolatkar Anand , Logothetis Christopher , Navin Nicholas E. , Corn Paul , Aparicio Ana M. , Dittamore Ryan , Hicks James , Kuhn Peter , Zurita Amado J. 
Published: April 2020

Abstract

Purpose:
Aggressive variant prostate cancer (AVPC) represents a clinical subset distinguished by therapy resistance and poor prognosis, linked to combined losses of the tumor suppressor genes (TSG) PTEN, RB1, and TP53. Circulating tumor cells (CTC) provide a minimally invasive opportunity for identification and molecular characterization of AVPC. We aimed to evaluate the incidence and clinical significance of compound (2+)TSG losses and genomic instability in prostate cancer CTC, and to expand the set genomic biomarkers relevant to AVPC.

Experimental Design:
Genomic analysis of chromosomal copy-number alterations (CNA) at single-cell resolution was performed in CTC from patients with and without AVPC before initiating chemotherapy with cabazitaxel or cabazitaxel and carboplatin. We evaluated associations between single-CTC genomics and clinical features, progression-free survival, and overall survival.

Results:
A total of 257 individual CTC were sequenced from 47 patients (1–22 CTC/patient). Twenty patients (42.6%) had concurrent 2+TSG losses in at least one CTC in association with poor survival and increased genomic instability, inferred by high large-scale transitions scores. Higher LST in CTC were independent of CTC enumerated, clinically more indicative of aggressive behavior than co-occurring TSG losses, and molecularly associated with gains in chromosomal regions including PTK2, Myc, and NCOA2; increased androgen receptor expression; and BRCA2 loss. In 57 patients with matched cell-free tumor DNA data, CTC were more frequently detectable and evaluable for CNA analysis (in 73.7% vs. 42.1%, respectively).

Conclusions:
Our findings suggest that genomic instability in CTC is a hallmark of advanced prostate cancer aggressiveness, and support single-CTC sequencing as a compelling tool to noninvasively characterize cancer heterogeneity.
Patients with Cancer Appear More Vulnerable to SARS-CoV-2: A Multicenter Study during the COVID-19 Outbreak
Authors: Dai Mengyuan , Liu Dianbo , Liu Miao , Zhou Fuxiang , Li Guiling , Chen Zhen , Zhang Zhian , You Hua , Wu Meng , Zheng Qichao , Xiong Yong , Xiong Huihua , Wang Chun , Chen Changchun , Xiong Fei , Zhang Yan , Peng Yaqin , Ge Siping , Zhen Bo , Yu Tingting , Wang Ling , Wang Hua , Liu Yu , Chen Yeshan , Mei Junhua , Gao Xiaojia , Li Zhuyan , Gan Lijuan , He Can , Li Zhen , Shi Yuying , Qi Yuwen , Yang Jing , Tenen Daniel G. , Chai Li , Mucci Lorelei A. , Santillana Mauricio , Cai Hongbing 
Published: April 2020

Abstract

The novel COVID-19 outbreak has affected more than 200 countries and territories as of March 2020. Given that patients with cancer are generally more vulnerable to infections, systematic analysis of diverse cohorts of patients with cancer affected by COVID-19 is needed. We performed a multicenter study including 105 patients with cancer and 536 age-matched noncancer patients confirmed with COVID-19. Our results showed COVID-19 patients with cancer had higher risks in all severe outcomes. Patients with hematologic cancer, lung cancer, or with metastatic cancer (stage IV) had the highest frequency of severe events. Patients with nonmetastatic cancer experienced similar frequencies of severe conditions to those observed in patients without cancer. Patients who received surgery had higher risks of having severe events, whereas patients who underwent only radiotherapy did not demonstrate significant differences in severe events when compared with patients without cancer. These findings indicate that patients with cancer appear more vulnerable to SARS-CoV-2 outbreak.

Significance:
Because this is the first large cohort study on this topic, our report will provide much-needed information that will benefit patients with cancer globally. As such, we believe it is extremely important that our study be disseminated widely to alert clinicians and patients.
This article is highlighted in the In This Issue feature, p. 747
Sleep Characteristics and Measures of Glucose Metabolism in Blacks: The Jackson Heart Study
Authors: Yano Yuichiro , Gao Yan , Johnson Dayna A. , Carnethon Mercedes , Correa Adolfo , Mittleman Murray A. , Sims Mario , Mostofsky Elizabeth , Wilson James G. , Redline Susan 
Published: April 2020

Background
Characterizing associations of sleep characteristics with blood‐glucose–level factors among blacks may clarify the underlying mechanisms of impaired glucose metabolism and help identify treatment targets to prevent diabetes mellitus in blacks.

Methods and Results
Cross‐sectional analyses were conducted in 789 blacks who completed home sleep apnea testing and 7‐day wrist actigraphy in 2012–2016. Sleep‐disordered breathing measurements included respiratory event index associated with 4% oxygen desaturation and minimum oxygen saturation. Sleep patterns on actigraphy included fragmented sleep indices. Associations between sleep characteristics (8 exposures) and measures of glucose metabolism (3 outcomes) were determined using multivariable linear regression. Mean (SD) age of the participants was 63 (11) years; 581 (74%) were women; 198 (25%) were diabetes mellitus, and 158 (20%) were taking antihyperglycemic medication. After multivariable adjustment, including antihyperglycemic medication use, the betas (95% CI) for fasting glucose and hemoglobin A1c, respectively, for each SD higher level were 0.13 (0.02, 0.24) mmol/L and 1.11 (0.42, 1.79) mmol/mol for respiratory event index associated with 4% oxygen desaturation and 0.16 (0.05, 0.27) mmol/L and 0.77 (0.10, 1.43) mmol/mol for fragmented sleep indices. Among 589 participants without diabetes mellitus, the betas (95% CI) for homeostatic model assessment of insulin resistance for each SD higher level were 1.09 (1.03, 1.16) for respiratory event index associated with 4% oxygen desaturation, 0.90 (0.85, 0.96) for minimum oxygen saturation, and 1.07 (1.01, 1.13) for fragmented sleep indices.

Conclusions
Sleep‐disordered breathing, overnight hypoxemia, and sleep fragmentation were associated with higher blood glucose levels among blacks.
A Geometric Interpretation of Zonostrophic Instability
Authors: Kontogiannis Georgios , Bakas Nikolaos A. 
Published: April 2020

AbstractThe zonostrophic instability that leads to the emergence of zonal jets in barotropic beta-plane turbulence is analyzed through a geometric decomposition of the eddy stress tensor. The stress tensor is visualized by an eddy variance ellipse whose characteristics are related to eddy properties. The tilt of the ellipse principal axis is the tilt of the eddies with respect to the shear, and the eccentricity of the ellipse is related to the eddy anisotropy, and its size is related to the eddy kinetic energy. Changes of these characteristics are directly related to the vorticity fluxes forcing the mean flow. The statistical state dynamics of the turbulent flow closed at second order is employed as it provides an analytic expression for both the zonostrophic instability and the stress tensor. For the linear phase of the instability, the stress tensor is analytically calculated at the stability boundary. For the nonlinear equilibration of the instability the tensor is calculated in the limit of small supercriticality in which the amplitude of the jet velocity follows Ginzburg–Landau dynamics. It is found that, dependent on the characteristics of the forcing, the jet is accelerated either because the jet primarily anisotropizes the eddies so as to produce upgradient fluxes, or because the jet changes the eddy tilt. The instability equilibrates as these changes are partially reversed by the nonlinear jet–eddy dynamics.
The Influence of Perioperative Nerve Block on Strength and Functional Return to Sports After Anterior Cruciate Ligament Reconstruction
Authors: Kew Michelle E. , Bodkin Stephan G. , Diduch David R. , Smith Marvin K. , Wiggins Anthony , Brockmeier Stephen F. , Werner Brian C. , Gwathmey F. Winston , Miller Mark D. , Hart Joseph M. 
Published: April 2020

Background: Patients often have quadriceps or hamstring weakness after anterior cruciate ligament reconstruction (ACLR), despite postoperative physical therapy regimens; however, little evidence exists connecting nerve blocks and ACLR outcomes. Purpose: To compare muscle strength at return to play in patients who received a nerve block with ACLR and determine whether a specific block type affected subjective knee function. Study Design: Cohort study; Level of evidence, 3. Methods: Patients were recruited 5 to 7 months after primary, isolated ACLR and completed bilateral isokinetic strength tests of the knee extensor/flexor groups as a single-session return-to-sport test. Subjective outcomes were assessed with the International Knee Documentation Committee (IKDC) score. Strength was expressed as torque normalized to mass (N·m/kg) and limb symmetry index as involved/uninvolved torque. Chart review was used to determine the type of nerve block and graft used. Nerve block types were classified as knee extensor motor (femoral nerve), knee flexor motor (sciatic nerve), or isolated sensory (adductor canal block/saphenous nerve). A 1-way analysis of covariance controlling for graft type was used. Results: A total of 169 patients were included. Graft type distribution consisted of 102 (60.4%) ipsilateral bone–patellar tendon–bone (BTB) and 67 (39.6%) ipsilateral hamstring tendon. Nerve block type distribution consisted of 38 (22.5%) femoral, 25 (14.8%) saphenous, 45 (26.6%) femoral and sciatic, and 61 (36.1%) saphenous and sciatic. No significant difference was found in knee extensor strength ( P = .113) or symmetry ( P = .860) between patients with knee extensor motor blocks (1.57 ± 0.45 N·m/kg; 70.1% ± 15.3%) and those without (1.47 ± 0.47 N·m/kg; 69.6% ± 18.8%). A significant difference was found between patients with knee flexor motor blocks (0.83 ± 0.26 N·m/kg) and those without (0.92 ± 0.27 N·m/kg) for normalized knee flexor strength ( P = .21) but not knee flexor symmetry ( P = .592). Controlling for graft type, there were no differences in subjective knee function (IKDC score) between all nerve block groups ( P = .57). Conclusion: Our data showed that use of a sciatic nerve block with ACLR in patients with hamstring and BTB grafts influences persistent knee flexor strength deficits at time of return to sports. Although the cause of postoperative muscular weakness is multifactorial, this study adds to the growing body of evidence suggesting that perioperative nerve blocks affect muscle strength and functional rehabilitation after ACLR.
Complete response after ceritinib treatment in non-small cell lung cancer in an elderly patient
Authors: Sengul Samanci Nilay , Celik Emir , Akovalı Burak , Sager Sait , Demirelli Fuat Hulusi 
Published: April 2020

Introduction Ceritinib is a selective second-generation ALK inhibitor that is highly sensitive to echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) molecule. Case report In this paper, we report a 68-year-old female that was diagnosed with stage 4 ALK-positive non-small cell lung cancer (NSCLC). Management and outcome: She was treated with crizotinib first-line, cisplatin and gemcitabine as second-line. And for third-line, ceritinib was started. She had complete response over 3.5 years under ceritinib treatment. And she is still receiving ceritinib with no adverse event. Discussion Cases achieving complete response with ceritinib treatment are rare. In this paper, we aimed to emphasize the complete response in stage 4 NSCLC in an elderly patient.
Primary and revision total hip arthroplasty with uncemented acetabular components in patients with Paget’s disease
Authors: Tibbo Meagan E , Brown Timothy S , Hanssen Arlen D , Lewallen David G , Sim Franklin H , Abdel Matthew P 
Published: April 2020

Introduction: Paget’s disease affects 3–4% of the population; however, literature describing outcomes of total hip arthroplasty (THA) in this population are limited. Given the known concerns with bleeding, heterotopic ossification (HO), and component loosening, we describe our results with primary and revision THAs in Paget’s disease with emphasis on implant survivorship, radiographic results, and clinical outcomes. Methods: We identified 25 THAs performed with contemporary uncemented acetabular components in patients with Paget’s disease from 1999 to 2014. Mean age and follow-up were 78 and 7 years. Results: In primary THAs, survivorship free from aseptic acetabular and femoral loosening was 100% and 94% at 8 years. 7 patients (41%) received blood transfusions. HO was seen in 9 (53%). Mean Harris Hip Score (HHS) improved from 49 to 76. In revision THAs, survivorship free from acetabular and/or femoral aseptic loosening was 100% at 5 years. 3 patients (38%) received a transfusion. HO was seen in 5 (63%). Mean HHS improved from 52 to 77. There were no radiographic signs of aseptic loosening among unrevised cases in either group. Discussion: Our investigation demonstrates that concerns with acetabular fixation in Paget’s disease have been mitigated with contemporary uncemented acetabular components. Complications previously noted, namely intraoperative bleeding and HO, continue to be of concern.
A prospective cohort study of predictors of upper extremity arteriovenous fistula maturation
Authors: Waheed Aiza , Masengu Agnes , Skala Tomas , Li Guiyun , Jastrzebski Jacek , Zalunardo Nadia 
Published: April 2020

Background: A substantial proportion of arteriovenous fistulas fail to function adequately for hemodialysis. Existing studies on arteriovenous fistula failure prediction assess patency rather than the more clinically relevant outcome of arteriovenous fistula function. We hypothesized that preoperative demographic and ultrasound characteristics, and postoperative assessment by an experienced vascular access nurse would predict which arteriovenous fistulas will not function adequately for hemodialysis. Methods: Prospective cohort study of chronic kidney disease patients at a tertiary care center in Vancouver, Canada, with arteriovenous fistula creation between 2009 and 2013. Pre and postoperative clinical assessment and ultrasound blood vessel mapping were performed by an experienced vascular access nurse. The primary outcome was failure to achieve a fistula used successfully for hemodialysis (FUSH). Results: Outcomes were assessed in 200 patients; 123 (61.5%) arteriovenous fistulas were radiocephalic. Overall, 26.5% of arteriovenous fistulas had FUSH failure (34.1% of lower arm vs 14.3% of upper arm, p = 0.002). Univariate predictors of FUSH failure included older age (p = 0.03), female sex (p = 0.05), smaller arterial diameter (p ⩽ 0.001), lower artery volume flow (p = 0.04), and smaller vein diameter (p = 0.01). In multivariable analysis, artery diameter (odds ratio: 0.44, 95% confidence interval: 0.28–0.68) most significantly predicted FUSH failure. Vascular access nurse assessment 6 weeks postoperatively correctly predicted outcome in 83.8% of FUSH and 65.0% of FUSH failure. Conclusion: Smaller artery diameter most strongly predicted FUSH failure. Early postoperative nursing assessment was more useful to predict FUSH than FUSH failure, and as such was insufficient in determining which arteriovenous fistulas should be abandoned as many predicted to fail could be salvaged with further intervention.
Hybrid electrospun nanofibrous membranes: Influence of layer arrangement and composition ratio on tensile and transport properties
Authors: Sangtabi Meisam S , Dolatabadi Mehdi K , Gorji Mohsen , Gharehaghaji Ali A , Rashidi Abosaid 
Published: April 2020

The present research aimed to investigate the influence of layer arrangement and composition ratio on tensile and transport properties in bi-constituent electrospun nanofibrous membranes composed of polyurethane nanofibers with a hydrophobic nature and poly(2-acrylamido-2-methylpropanesulfonic acid) with a hydrophilic nature. Different hybrid electrospun nanofibrous membranes were produced based on different layer arrangement and composition ratios. To evaluate the membrane performance, their tensile strength, wind, and waterproof performance were measured. By adding 50% poly(2-acrylamido-2-methylpropanesulfonic acid) to polyurethane, the pore size of the hybrid electrospun nanofibrous membranes decreased by 47.64%. As a result, compared with pristine polyurethane membranes, hybrid electrospun nanofibrous membranes showed a good (9.6 mm s−1) windproof performance. Adding poly(2-acrylamido-2-methylpropanesulfonic acid) nanofibers to the polyurethane resulted in a decrease in mechanical properties and waterproof performance. The results show that the volume fraction of the poly(2-acrylamido-2-methylpropanesulfonic acid) and the electrospinning scenarios have a great influence on the mechanical properties of the samples. The results also show that the mechanical properties of hybrid electrospun nanofibrous membranes can be predicted based on the geometrical properties of each component. Computational fluid dynamics were used to simulate air flow through a virtual medium and the results of simulation were compared with the experimental measurement and predicted permeability; then, the best models for predicting air permeability were determined. In addition, based on different types of use, duration of use, and relative humidity level, a bi-functional membrane can be obtained by regulating layer arrangement and composition ratios to suit various applications, for example, in medical disposable clothing, wound dressing, filtering industries, and protective clothing.