bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long Noncoding RNA LINC00092 Acts in Cancer-Associated Fibroblasts to Drive Glycolysis and Progression of Ovarian Cancer
Authors: Zhao Linjie , Ji Gaili , Le Xiaobing , Wang Chenlu , Xu Lian , Feng Min , Zhang Yaguang , Yang Huiliang , Xuan Yu , Yang Yanfei , Lei Lingzi , Yang Qilian , Lau Wayne Bond , Lau Bonnie , Chen Yi , Deng Xiangbing , Yao Shaohua , Yi Tao , Zhao Xia , Wei Yuquan , Zhou Shengtao 
Published: January 2017

Abstract
The majority of patients with epithelial ovarian cancer are diagnosed at a late stage when the peritoneal metastases exist; however, there is little knowledge of the metastatic process in this disease setting. In this study, we report the identification of the long noncoding RNA LINC00092 as a nodal driver of metastatic progression mediated by cancer-associated fibroblasts (CAF). Prometastatic properties of CAFs in vitro and in vivo were found to associate with elevated expression of the chemokine CXCL14. In clinical specimens, elevated levels of CXCL14 in CAFs also correlated with poor prognosis. Notably, CXCL14-high CAFs mediated upregulation of LINC00092 in ovarian cancer cells, the levels of which also correlated with poor prognosis in patients. Mechanistic studies showed that LINC00092 bound a glycolytic enzyme, the fructose-2,6-biphosphatase PFKFB2, thereby promoting metastasis by altering glycolysis and sustaining the local supportive function of CAFs. Overall, our study uncovered a positive feedback loop in the metabolism of CXCL14-positive CAFs and ovarian cancer cells that is critical for metastatic progression. Cancer Res; 77(6); 1369–82. ©2017 AACR.
U.S. FDA Approval Summary: Nivolumab for Treatment of Unresectable or Metastatic Melanoma Following Progression on Ipilimumab
Authors: Hazarika Maitreyee , Chuk Meredith K. , Theoret Marc R. , Mushti Sirisha , He Kun , Weis Shawna L. , Putman Alexander H. , Helms Whitney S. , Cao Xianhua , Li Hongshan , Zhao Hong , Zhao Liang , Welch Joel , Graham Laurie , Libeg Meredith , Sridhara Rajeshwari , Keegan Patricia , Pazdur Richard 
Published: January 2017

Abstract
On December 22, 2014, the FDA granted accelerated approval to nivolumab (OPDIVO; Bristol-Myers Squibb) for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on a clinically meaningful, durable objective response rate (ORR) in a non-comparative analysis of 120 patients who received 3 mg/kg of nivolumab intravenously every 2 weeks with at least 6-month follow-up in an ongoing, randomized, open-label, active-controlled clinical trial. The ORR as assessed by a blinded independent review committee per RECIST v1.1 was 31.7% (95% confidence interval, 23.5–40.8). Ongoing responses were observed in 87% of responding patients, ranging from 2.6+ to 10+ months. In 13 patients, the response duration was 6 months or longer. The risks of nivolumab, including clinically significant immune-mediated adverse reactions (imARs), were assessed in 268 patients who received at least one dose of nivolumab. The FDA review considered whether the ORR and durations of responses were reasonably likely to predict clinical benefit, the adequacy of the safety database, and systematic approaches to the identification, description, and patient management for imARs in product labeling. Clin Cancer Res; 23(14); 3484–8. ©2017 AACR.
Molecular Pathways: Targeting Protein Tyrosine Phosphatases in Cancer
Authors: Bollu Lakshmi Reddy , Mazumdar Abhijit , Savage Michelle I. , Brown Powel H. 
Published: January 2017

Abstract
The aberrant activation of oncogenic signaling pathways is a universal phenomenon in cancer and drives tumorigenesis and malignant transformation. This abnormal activation of signaling pathways in cancer is due to the altered expression of protein kinases and phosphatases. In response to extracellular signals, protein kinases activate downstream signaling pathways through a series of protein phosphorylation events, ultimately producing a signal response. Protein tyrosine phosphatases (PTP) are a family of enzymes that hydrolytically remove phosphate groups from proteins. Initially, PTPs were shown to act as tumor suppressor genes by terminating signal responses through the dephosphorylation of oncogenic kinases. More recently, it has become clear that several PTPs overexpressed in human cancers do not suppress tumor growth; instead, they positively regulate signaling pathways and promote tumor development and progression. In this review, we discuss both types of PTPs: those that have tumor suppressor activities as well as those that act as oncogenes. We also discuss the potential of PTP inhibitors for cancer therapy. Clin Cancer Res; 23(9); 2136–42. ©2017 AACR.
STXBP4 Drives Tumor Growth and Is Associated with Poor Prognosis through PDGF Receptor Signaling in Lung Squamous Cell Carcinoma
Authors: Otaka Yukihiro , Rokudai Susumu , Kaira Kyoichi , Fujieda Michiru , Horikoshi Ikuko , Iwakawa-Kawabata Reika , Yoshiyama Shinji , Yokobori Takehiko , Ohtaki Yoichi , Shimizu Kimihiro , Oyama Tetsunari , Tamura Jun'ichi , Prives Carol , Nishiyama Masahiko 
Published: January 2017

Abstract
Purpose: Expression of the ΔN isoform of p63 (ΔNp63) is a diagnostic marker highly specific for lung squamous cell carcinoma (SCC). We previously found that Syntaxin Binding Protein 4 (STXBP4) regulates ΔNp63 ubiquitination, suggesting that STXBP4 may also be an SCC biomarker. To address this issue, we investigated the role of STXBP4 expression in SCC biology and the impact of STXBP4 expression on SCC prognosis.
Experimental Design: We carried out a clinicopathologic analysis of STXBP4 expression in 87 lung SCC patients. Whole transcriptome analysis using RNA-seq was performed in STXBP4-positive and STXBP4-negative tumors of lung SCC. Soft-agar assay and xenograft assay were performed using overexpressing or knockdown SCC cells.
Results: Significantly higher levels of STXBP4 expression were correlated with accumulations of ΔNp63 in clinical lung SCC specimens (Spearman rank correlation ρ = 0.219). Notably, STXBP4-positive tumors correlated with three important clinical parameters: T factor (P &lt; 0.001), disease stage (P = 0.030), and pleural involvement (P = 0.028). Whole transcriptome sequencing followed by pathway analysis indicated that STXBP4 is involved in functional gene networks that regulate cell growth, proliferation, cell death, and survival in cancer. Platelet-derived growth factor receptor alpha (PDGFRα) was a key downstream mediator of STXBP4 function. In line with this, shRNA mediated STXBP4 and PDGFRA knockdown suppressed tumor growth in soft-agar and xenograft assays.
Conclusions: STXBP4 plays a crucial role in driving SCC growth and is an independent prognostic factor for predicting worse outcome in lung SCC. These data suggest that STXBP4 is a relevant therapeutic target for patients with lung SCC. Clin Cancer Res; 23(13); 3442–52. ©2017 AACR.
TNF Signaling through RIP1 Kinase Enhances SN38-Induced Death in Colon Adenocarcinoma
Authors: Cabal-Hierro Lucia , O'Dwyer Peter J. 
Published: January 2017

Abstract
Elucidation of TNF-directed mechanisms for cell death induction and maintenance of tumor growth has revealed a role for receptor-interacting protein kinases 1 and 3 (RIPK1/RIP1 and RIPK3/RIP3), components of the necrosome complex, as determinants of cell fate. Here, the participation of TNF signaling was analyzed with regard to the cytotoxic action of different DNA-damaging agents in a panel of colon cancer cells. While most of these cell lines were insensitive to TNF, combination with these drugs increased sensitivity by inducing cell death and DNA damage, especially in the case of the topoisomerase inhibitor SN38. Changes in levels of RIP1 and RIP3 occurred following monotherapy with SN38 or in combination with TNF. Downregulation of RIP1 resulted in increased resistance to SN38, implying a requirement for RIP1 in mediating cytotoxicity through the TNF/TNFR signaling pathway. Downregulation of RIP1 in a xenograft model impaired tumor growth inhibition from SN38 treatment, suggesting the potential of RIP1 to determine the clinical outcome of irinotecan treatment. These results indicate that TNF plays a key role in determining the cytotoxic effectiveness of SN38 in colorectal cancer and suggests a re-evaluation of TNF-based interventions to enhance therapeutic efficacy.
Implications: The capacity of RIP1 to influence drug sensitivity suggests RIP1 may have biomarker potential. Mol Cancer Res; 15(4); 395–404. ©2017 AACR.
International Variation in Outcomes Among People with Cardiovascular Disease or Cardiovascular Risk Factors and Impaired Glucose Tolerance: Insights from the NAVIGATOR Trial
Authors: Harumi Higuchi dos Santos Marilia , Sharma Abhinav , Sun Jie‐Lena , Pieper Karen , McMurray John J.V. , Holman Rury R. , Lopes Renato D. 
Published: January 2017

Background
Regional differences in risk of diabetes mellitus and cardiovascular outcomes in people with impaired glucose tolerance are poorly characterized. Our objective was to evaluate regional variation in risk of new‐onset diabetes mellitus, cardiovascular outcomes, and treatment effects in participants from the NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) trial.

Methods and Results

NAVIGATOR
randomized people with impaired glucose tolerance and cardiovascular risk factors or with established cardiovascular disease to valsartan (or placebo) and to nateglinide (or placebo) with a median 5‐year follow‐up. Data from the 9306 participants were categorized by 5 regions: Asia (n=552); Europe (n=4909); Latin America (n=1406); North America (n=2146); and Australia, New Zealand, and South Africa (n=293). Analyzed outcomes included new‐onset diabetes mellitus; cardiovascular death; a composite cardiovascular outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke; and treatment effects of valsartan and nateglinide. Respective unadjusted 5‐year risks for new‐onset diabetes mellitus, cardiovascular death, and the composite cardiovascular outcome were 33%, 0.4%, and 4% for Asia; 34%, 2%, and 6% for Europe; 37%, 4%, and 8% for Latin America; 38%, 2%, and 6% for North America; and 32%, 4%, and 8% for Australia, New Zealand, and South Africa. After adjustment, compared with North America, European participants had a lower risk of new‐onset diabetes mellitus (hazard ratio 0.86, 95%
CI
0.78–0.94;
P
=0.001), whereas Latin American participants had a higher risk of cardiovascular death (hazard ratio 2.68, 95%
CI
1.82–3.96;
P
<0.0001) and the composite cardiovascular outcome (hazard ratio 1.48, 95%
CI
1.15–1.92;
P
=0.003). No differential interactions between treatment and geographic location were identified.

Conclusions

Major regional differences regarding the risk of new‐onset diabetes mellitus and cardiovascular outcomes in
NAVIGATOR
participants were identified. These differences should be taken into account when planning global trials.

Clinical Trial Registration

URL:
http://www.ClinicalTrials.gov
. Unique identifier:
NCT
00097786.
Clinical Selection Strategies to Identify Ischemic Stroke Patients With Large Anterior Vessel Occlusion
Authors: Scheitz Jan F. , Abdul-Rahim Azmil H. , MacIsaac Rachael L. , Cooray Charith , Sucharew Heidi , Kleindorfer Dawn , Khatri Pooja , Broderick Joseph P. , Audebert Heinrich J. , Ahmed Niaz , Wahlgren Nils , Endres Matthias , Nolte Christian H. , Lees Kennedy R. 
Published: January 2017

Background and Purpose—
The National Institutes of Health Stroke Scale (NIHSS) correlates with presence of large anterior vessel occlusion (LAVO). However, the application of the full NIHSS in the prehospital setting to select patients eligible for treatment with thrombectomy is limited. Therefore, we aimed to evaluate the prognostic value of simple clinical selection strategies.

Methods—
Data from the Safe Implementation of Thrombolysis in Stroke International Stroke Thrombolysis Registry (January 2012–May 2014) were analyzed retrospectively. Patients with complete breakdown of NIHSS scores and documented vessel status were included. We assessed the association of prehospital stroke scales and NIHSS symptom profiles with LAVO (internal carotid artery, carotid-terminus or M1-segment of the middle cerebral artery).

Results—
Among 3505 patients, 23.6% (n=827) had LAVO. Pathological finding on the NIHSS item best gaze was strongly associated with LAVO (adjusted odds ratio 4.5, 95% confidence interval 3.8–5.3). All 3 face–arm–speech–time test (FAST) items identified LAVO with high sensitivity. Addition of the item best gaze to the original FAST score (G-FAST) or high scores on other simplified stroke scales increased specificity. The NIHSS symptom profiles representing total anterior syndromes showed a 10-fold increased likelihood for LAVO compared with a nonspecific clinical profile. If compared with an NIHSS threshold of ≥6, the prehospital stroke scales performed similarly or even better without losing sensitivity.

Conclusions—
Simple modification of the face–arm–speech–time score or evaluating the NIHSS symptom profile may help to stratify patients’ risk of LAVO and to identify individuals who deserve rapid transfer to comprehensive stroke centers. Prospective validation in the prehospital setting is required.
Splenectomy Does Not Improve Long-Term Outcome After Stroke
Authors: Zierath Dannielle , Shen Angela , Stults Astiana , Olmstead Theresa , Becker Kyra J. 
Published: January 2017

Background and Purpose—
Immune responses to brain antigens after stroke contribute to poor outcome. We hypothesized that splenectomy would lessen the development of such responses and improve outcome.

Methods—
Male Lewis rats (275–350 g) underwent 2-hour middle cerebral artery occlusion immediately after splenectomy or sham splenectomy. Animals were survived to 4 weeks (672 hrs), and immune responses to myelin basic protein determined at euthanasia. Infarct volume was determined in a subset of animals euthanized at 72 hours. Behavioral outcomes were assessed to 672 hours.

Results—
Splenectomy was associated with worse neurological scores early after stroke, but infarct size at 72 hours was similar in both groups. Behavioral outcomes and immune responses to myelin basic protein were also similar among splenectomized and sham-operated animals 672 hours after middle cerebral artery occlusion.

Conclusions—
Splenectomy did not alter the immune responses to brain antigens or improve outcome after stroke. Differences between this study and other studies of splenectomy and stroke are examined.
In Vivo Estimates of the Position of Advanced Bionics Electrode Arrays in the Human Cochlea
Authors: Skinner Margaret W. , Holden Timothy A. , Whiting Bruce R. , Voie Arne H. , Brunsden Barry , Neely J. Gail , Saxon Eugene A. , Hullar Timothy E. , Finley Charles C. 
Published: January 2017

Objectives: A new technique for determining the position of each electrode in the cochlea is described and applied to spiral computed tomography data from 15 patients implanted with Advanced Bionics HiFocus I, Ij, or Helix arrays. Methods: ANALYZE imaging software was used to register 3-dimensional image volumes from patients' preoperative and postoperative scans and from a single body donor whose unimplanted ears were scanned clinically, with micro computed tomography and with orthogonal-plane fluorescence optical sectioning (OPFOS) microscopy. By use of this registration, we compared the atlas of OPFOS images of soft tissue within the body donor's cochlea with the bone and fluid/tissue boundary available in patient scan data to choose the midmodiolar axis position and judge the electrode position in the scala tympani or scala vestibuli, including the distance to the medial and lateral scalar walls. The angular rotation 0° start point is a line joining the midmodiolar axis and the middle of the cochlear canal entry from the vestibule. Results: The group mean array insertion depth was 477° (range, 286° to 655°). The word scores were negatively correlated (r = −0.59; p = .028) with the number of electrodes in the scala vestibuli. Conclusions: Although the individual variability in all measures was large, repeated patterns of suboptimal electrode placement were observed across subjects, underscoring the applicability of this technique.
The effect of nitisinone on homogentisic acid and tyrosine: a two-year survey of patients attending the National Alkaptonuria Centre, Liverpool
Authors: Milan Anna M , Hughes Andrew T , Davison Andrew S , Devine Jean , Usher Jeannette , Curtis Sarah , Khedr Milad , Gallagher James A , Ranganath Lakshminarayan R 
Published: January 2017

BackgroundAlkaptonuria is a rare, debilitating autosomal recessive disorder affecting tyrosine metabolism. Deficiency of homogentisate 1,2-dioxygenase leads to increased homogentisic acid which is deposited as ochronotic pigment. Clinical sequelae include severe early onset osteoarthritis, increased renal and prostate stone formation and cardiac complications. Treatment has been largely based on analgaesia and arthroplasty. The National Alkaptonuria Centre in Liverpool has been using 2 mg nitisinone (NTBC) off-license for all patients in the United Kingdom with alkaptonuria and monitoring the tyrosine metabolite profiles.MethodsPatients with confirmed alkaptonuria are commenced on 2 mg dose (alternative days) of NTBC for three months with daily dose thereafter. Metabolite measurement by LC-MS/MS is performed at baseline, day 4, three-months, six-months and one-year post-commencing NTBC. Thereafter, monitoring and clinical assessments are performed annually.ResultsUrine homogentisic acid concentration decreased from a mean baseline 20,557 µmol/24 h (95th percentile confidence interval 18,446–22,669 µmol/24 h) by on average 95.4% by six months, 94.8% at one year and 94.1% at two year monitoring. A concurrent reduction in serum homogentisic acid concentration of 83.2% compared to baseline was also measured. Serum tyrosine increased from normal adult reference interval to a mean ± SD of 594 ± 184 µmol /L at year-two monitoring with an increased urinary excretion from 103 ± 81 µmol /24 h at baseline to 1071 ± 726 µmol /24 h two years from therapy.ConclusionsThe data presented represent the first longitudinal survey of NTBC use in an NHS service setting and demonstrate the sustained effect of NTBC on the tyrosine metabolite profile.
Comparison of method-related reference intervals for thyroid hormones: studies from a prospective reference population and a literature review
Authors: Barth Julian H , Luvai Ahai , Jassam Nuthar , Mbagaya Wycliffe , Kilpatrick Eric S , Narayanan Deepa , Spoors Shirley 
Published: January 2017

Introduction Reference intervals are dependent on the reference population, the analytical methods and the way the data are handled statistically. Individual method-related differences have been studied but the comparative differences in reference intervals have not. Methods We studied a reference population of healthy adult subjects and measured free thyroxine and thyroid-stimulating hormone by the four most commonly used analytical platforms used in the UK. Subjects were excluded if they were > 65 years or had positive thyroid peroxidase antibodies. We also performed a systematic literature review of thyroid hormone reference interval studies in non-pregnant adults. Results In total, 303 subjects were recruited and 42 excluded. The central 95th centile values for thyroid-stimulating hormone (mIU/L) were Abbott Architect (0.51–3.67); Beckman Unicel DxI (0.57–3.60); Roche Cobas (0.60–4.31) and Siemens Advia Centaur XP (0.63–4.29). The 95th centile values for thyroxine (pmol/L) were Abbott Architect (10.6–15.5); Beckman Unicel DxI (7.9–13.0); Roche Cobas (12.5–19.6) and Siemens Advia Centaur XP (11.8–19.0). We identified 55 papers describing thyroid reference intervals in male and non-pregnant female adults. The values for upper and lower reference intervals by manufacturer varied but were not significantly different for thyroid-stimulating hormone but were for thyroxine. Discussion Our study demonstrates clearly that there are marked variations in the reference intervals for thyroid hormones between analytical platforms. There is an urgent need for standardization of thyroid hormone assays to permit transferability of results. Until then, guidelines will need to reflect this method-related difference.
Clinical Studies on the Effect of Laevulose on the Rate of Metabolism of Ethyl Alcohol
Authors: Patel A. R. , Paton A. M. , Rowan T. , Lawson D. H. , Linton A. L. 
Published: January 2017

A study of the effect of laevulose upon the rate of metabolism of ethyl alcohol was undertaken. The rate of disappearance of ethyl alcohol from the blood of normal volunteers was estimated under normal conditions and also following the administration of oral and intravenous laevulose. These results were compared with the rate of disappearance of ethyl alcohol from the blood of inebriated patients under normal circumstances and following intravenous laevulose. The investigation confirms that ethyl alcohol is metabolised at a constant rate which varies from individual to individual and that the administration of laevulose significantly increases this rate of metabolism. It is suggested that laevulose is helpful in the management of inebriated patients in whom there is clinical suspicion of accompanying head injury.
The Pathogenesis of Diabetes Mellitus
Authors: Clarke B. F. 
Published: January 2017

The precise aetiology of diabetes mellitus remains unknown. There is clearly both a genetic element which is almost certainly multifactorial, due to the multiple and additive effects of genes especially in younger patients, together with environmental factors, especially in older patients. Evidence is increasing that the genetic element is associated with an underlying defect of the beta cells with a characteristic delayed and subnormal insulin secretion in response to glucose or other insulinogenic stimuli. The same hyposecretory response can often be found in many close relatives and in ‘prediabetes’ where standard carbohydrate tolerance is still normal. The nature of the defect of the beta cell, its link with the genetic mechanism, and the mechanism leading to total islet failure in some diabetics is not known. Many factors may be involved simultaneously in a single individual and apart from multiple genes, certain non-genetic factors such as obesity, pregnancy, infection and other stress which result in increased insulin antagonism, lead to additive strains on islet cell function, and may determine the onset of the overt disease in hereditarily predisposed individuals.
Behavior of Cotton and Polynosic Fabrics Treated by the Poly-Set Process
Authors: Ohe Hideo , Matsuki Shintaro , Terai Mamoru , Kuroda Haruki , Matsukawa Saburo 
Published: January 2017

A study was made of the relations between crease recovery and various physical properties of cotton and polynosic fibers treated by the two-step poly-set process. These relations fall in two different groups (step I and step II) in the case of cotton; for polynosics, the relations show the same grouping in wet and alkali-swollen states. In order to explain the different types of links that form in the poly-set process as well as the dominant influence of the water-sensitive links on treated polynosics in the dry state, it is postulated that the crease-recovery increment is due to new covalent links and those in place of the water-sensitive links. The different effects of MMM and DMEU finishes are discussed