bluuebunny/crossref_metadata_2025 huggingface dataset:
Dual Targeting of Tissue Factor and CD105 for Preclinical PET Imaging of Pancreatic Cancer
Authors: Luo Haiming , England Christopher G. , Shi Sixiang , Graves Stephen A. , Hernandez Reinier , Liu Bai , Theuer Charles P. , Wong Hing C. , Nickles Robert J. , Cai Weibo
Published: March 2016

Purpose: Pancreatic adenocarcinoma is a highly aggressive cancer, currently treated with limited success and dismal outcomes. New diagnostic and treatment strategies offer the potential to reduce cancer mortality. Developing highly specific noninvasive imaging probes for pancreatic cancer is essential to improving diagnostic accuracy and monitoring therapeutic intervention.

Experimental Design: A bispecific heterodimer was synthesized by conjugating an anti-tissue factor (TF) Fab with an anti-CD105 Fab, via the bio-orthogonal “click” reaction between tetrazine (Tz) and trans-cyclooctene (TCO). The heterodimer was labeled with 64Cu for PET imaging of nude mice bearing BXPC-3 xenograft and orthotopic pancreatic tumors.

Results: PET imaging of BXPC-3 (TF/CD105+/+) xenograft tumors with 64Cu-labeled heterodimer displayed significantly enhanced tumor uptake (28.8 ± 3.2 %ID/g; n = 4; SD) at 30 hours postinjection, as compared with each of their monospecific Fab tracers (12.5 ± 1.4 and 7.1 ± 2.6 %ID/g; n = 3; SD). In addition, the activity–concentration ratio allowed for effective tumor visualization (tumor/muscle ratio 75.2 ± 9.4 at 30 hours postinjection.; n = 4; SD). Furthermore, 64Cu-NOTA-heterodimer enabled sensitive detection of orthotopic pancreatic tumor lesions with an uptake of 17.1 ± 4.9 %ID/g at 30 hours postinjection and tumor/muscle ratio of 72.3 ± 46.7.

Conclusions: This study demonstrates that dual targeting of TF and CD105 provided synergistic improvements in binding affinity and tumor localization of the heterodimer. Dual-targeted imaging agents of pancreatic and other cancers may assist in diagnosing pancreatic malignancies as well as reliable monitoring of therapeutic response. Clin Cancer Res; 22(15); 3821–30. ©2016 AACR.
Development and Validation of Urine-based Peptide Biomarker Panels for Detecting Bladder Cancer in a Multi-center Study
Authors: Frantzi Maria , van Kessel Kim E. , Zwarthoff Ellen C. , Marquez Mirari , Rava Marta , Malats Núria , Merseburger Axel S. , Katafigiotis Ioannis , Stravodimos Konstantinos , Mullen William , Zoidakis Jerome , Makridakis Manousos , Pejchinovski Martin , Critselis Elena , Lichtinghagen Ralph , Brand Korbinian , Dakna Mohammed , Roubelakis Maria G. , Theodorescu Dan , Vlahou Antonia , Mischak Harald , Anagnou Nicholas P.
Published: March 2016

Purpose: Urothelial bladder cancer presents high recurrence rates, mandating continuous monitoring via invasive cystoscopy. The development of noninvasive tests for disease diagnosis and surveillance remains an unmet clinical need. In this study, validation of two urine-based biomarker panels for detecting primary and recurrent urothelial bladder cancer was conducted.

Experimental Design: Two studies (total n = 1,357) were performed for detecting primary (n = 721) and relapsed urothelial bladder cancer (n = 636). Cystoscopy was applied for detecting urothelial bladder cancer, while patients negative for recurrence had follow-up for at least one year to exclude presence of an undetected tumor at the time of sampling. Capillary electrophoresis coupled to mass spectrometry (CE-MS) was employed for the identification of urinary peptide biomarkers. The candidate urine–based peptide biomarker panels were derived from nested cross-sectional studies in primary (n = 451) and recurrent (n = 425) urothelial bladder cancer.

Results: Two biomarker panels were developed on the basis of 116 and 106 peptide biomarkers using support vector machine algorithms. Validation of the urine-based biomarker panels in independent validation sets, resulted in AUC values of 0.87 and 0.75 for detecting primary (n = 270) and recurrent urothelial bladder cancer (n = 211), respectively. At the optimal threshold, the classifier for detecting primary urothelial bladder cancer exhibited 91% sensitivity and 68% specificity, while the classifier for recurrence demonstrated 87% sensitivity and 51% specificity. Particularly for patients undergoing surveillance, improved performance was achieved when combining the urine-based panel with cytology (AUC = 0.87).

Conclusions: The developed urine-based peptide biomarker panel for detecting primary urothelial bladder cancer exhibits good performance. Combination of the urine-based panel and cytology resulted in improved performance for detecting disease recurrence. Clin Cancer Res; 22(16); 4077–86. ©2016 AACR.
Apratoxin A Shows Novel Pancreas-Targeting Activity through the Binding of Sec 61
Authors: Huang Kuan-Chun , Chen Zhihong , Jiang Yimin , Akare Sandeep , Kolber-Simonds Donna , Condon Krista , Agoulnik Sergei , Tendyke Karen , Shen Yongchun , Wu Kuo-Ming , Mathieu Steven , Choi Hyeong-wook , Zhu Xiaojie , Shimizu Hajime , Kotake Yoshihiko , Gerwick William H. , Uenaka Toshimitsu , Woodall-Jappe Mary , Nomoto Kenichi
Published: March 2016

Apratoxin A is a natural product with potent antiproliferative activity against many human cancer cell lines. However, we and other investigators observed that it has a narrow therapeutic window in vivo. Previous mechanistic studies have suggested its involvement in the secretory pathway as well as the process of chaperone-mediated autophagy. Still the link between the biologic activities of apratoxin A and its in vivo toxicity has remained largely unknown. A better understanding of this relationship is critically important for any further development of apratoxin A as an anticancer drug. Here, we describe a detailed pathologic analysis that revealed a specific pancreas-targeting activity of apratoxin A, such that severe pancreatic atrophy was observed in apratoxin A–treated animals. Follow-up tissue distribution studies further uncovered a unique drug distribution profile for apratoxin A, showing high drug exposure in pancreas and salivary gland. It has been shown previously that apratoxin A inhibits the protein secretory pathway by preventing cotranslational translocation. However, the molecule targeted by apratoxin A in this pathway has not been well defined. By using a 3H-labeled apratoxin A probe and specific Sec 61α/β antibodies, we identified that the Sec 61 complex is the molecular target of apratoxin A. We conclude that apratoxin A in vivo toxicity is likely caused by pancreas atrophy due to high apratoxin A exposure. Mol Cancer Ther; 15(6); 1208–16. ©2016 AACR.
Triptolide Induces Cell Killing in Multidrug-Resistant Tumor Cells via CDK7/RPB1 Rather than XPB or p44
Authors: Yi Jun-Mei , Huan Xia-Juan , Song Shan-Shan , Zhou Hu , Wang Ying-Qing , Miao Ze-Hong
Published: March 2016

Multidrug resistance (MDR) is a major cause of tumor treatment failure; therefore, drugs that can avoid this outcome are urgently needed. We studied triptolide, which directly kills MDR tumor cells with a high potency and a broad spectrum of cell death. Triptolide did not inhibit P-glycoprotein (P-gp) drug efflux and reduced P-gp and MDR1 mRNA resulting from transcription inhibition. Transcription factors including c-MYC, SOX-2, OCT-4, and NANOG were not correlated with triptolide-induced cell killing, but RPB1, the largest subunit of RNA polymerase II, was critical in mediating triptolide's inhibition of MDR cells. Triptolide elicited antitumor and anti-MDR activity through a universal mechanism: by activating CDK7 by phosphorylating Thr170 in both parental and MDR cell lines and in SK-OV-3 cells. The CDK7-selective inhibitor BS-181 partially rescued cell killing induced by 72-hour treatment of triptolide, which may be due to partial rescue of RPB1 degradation. We suggest that a precise phosphorylation site on RPB1 (Ser1878) was phosphorylated by CDK7 in response to triptolide. In addition, XPB and p44, two transcription factor TFIIH subunits, did not contribute to triptolide-driven RPB1 degradation and cell killing, although XPB was reported to covalently bind to triptolide. Several clinical trials are underway to test triptolide and its analogues for treating cancer and other diseases, so our data may help expand potential clinical uses of triptolide, as well as offer a compound that overcomes tumor MDR. Future investigations into the primary molecular target(s) of triptolide responsible for RPB1 degradation may suggest novel anti-MDR target(s) for therapeutic development. Mol Cancer Ther; 15(7); 1495–503. ©2016 AACR.
Targeted Drug Delivery with an Integrin-Binding Knottin–Fc–MMAF Conjugate Produced by Cell-Free Protein Synthesis
Authors: Currier Nicolas V. , Ackerman Shelley E. , Kintzing James R. , Chen Rishard , Filsinger Interrante Maria , Steiner Alexander , Sato Aaron K. , Cochran Jennifer R.
Published: March 2016

Antibody–drug conjugates (ADC) have generated significant interest as targeted therapeutics for cancer treatment, demonstrating improved clinical efficacy and safety compared with systemic chemotherapy. To extend this concept to other tumor-targeting proteins, we conjugated the tubulin inhibitor monomethyl-auristatin-F (MMAF) to 2.5F–Fc, a fusion protein composed of a human Fc domain and a cystine knot (knottin) miniprotein engineered to bind with high affinity to tumor-associated integrin receptors. The broad expression of integrins (including αvβ3, αvβ5, and α5β1) on tumor cells and their vasculature makes 2.5F-Fc an attractive tumor-targeting protein for drug delivery. We show that 2.5F-Fc can be expressed by cell-free protein synthesis, during which a non-natural amino acid was introduced into the Fc domain and subsequently used for site-specific conjugation of MMAF through a noncleavable linker. The resulting knottin–Fc–drug conjugate (KFDC), termed 2.5F-Fc-MMAF, had approximately 2 drugs attached per KFDC. 2.5F–Fc–MMAF inhibited proliferation in human glioblastoma (U87MG), ovarian (A2780), and breast (MB-468) cancer cells to a greater extent than 2.5F–Fc or MMAF alone or added in combination. As a single agent, 2.5F–Fc–MMAF was effective at inducing regression and prolonged survival in U87MG tumor xenograft models when administered at 10 mg/kg two times per week. In comparison, tumors treated with 2.5F–Fc or MMAF were nonresponsive, and treatment with a nontargeted control, CTRL–Fc–MMAF, showed a modest but not significant therapeutic effect. These studies provide proof-of-concept for further development of KFDCs as alternatives to ADCs for tumor targeting and drug delivery applications. Mol Cancer Ther; 15(6); 1291–300. ©2016 AACR.
Angiogenic Factors and Risks of Technique Failure and Cardiovascular Events in Patients Receiving Peritoneal Dialysis
Authors: Matsui Masaru , Samejima Ken-ichi , Takeda Yukiji , Morimoto Katsuhiko , Tagawa Miho , Onoue Kenji , Okayama Satoshi , Kawata Hiroyuki , Kawakami Rika , Akai Yasuhiro , Okura Hiroyuki , Saito Yoshihiko
Published: March 2016

Background: Placental growth factor (PlGF) is a member of the vascular endothelial growth factor family that acts as a pleiotropic cytokine capable of stimulating angiogenesis and accelerating atherogenesis. Soluble fms-like tyrosine kinase-1 (sFlt-1) antagonizes PlGF action. Higher levels of PlGF and sFlt-1 have been associated with cardiovascular events in patients with chronic kidney disease, yet little is known about their relationship with adverse outcomes in patients on peritoneal dialysis (PD). The aim of this study was to investigate the association of PlGF and sFlt-1 with technique survival and cardiovascular events. Methods: We measured serum levels of PlGF and plasma levels of sFlt-1 in 40 PD patients at Nara Medical University. Results: PlGF and sFlt-1 levels were significantly correlated with the dialysate-to-plasma ratio of creatinine (r = 0.342, p = 0.04 and r = 0.554, p < 0.001) although PlGF and sFlt-1 levels were not correlated with total creatinine clearance and total Kt/V. Additionally, both PlGF and sFlt-1 levels were significantly higher in patients with high transport membranes compared to those without (p = 0.039 and p < 0.001, respectively). Patients with PlGF levels above the median had lower technique survival and higher incidence of cardiovascular events than patients with levels below the median, with hazard ratios of 11.9 and 7.7, respectively, in univariate Cox regression analysis. However, sFlt-1 levels were not associated with technique survival or cardiovascular events (p = 0.11 and p = 0.10, respectively). Conclusion: Elevated PlGF and sFlt-1 are significantly associated with high transport membrane status. PlGF may be a useful predictor of technique survival and cardiovascular events in PD patients.
Improved Vision from Severe Compressive Optic Neuropathy by Apical Cavernous Hemangioma
Authors: Kang Hyera , Takahashi Yasuhiro , Nishimura Kunihiro , Yasuda Muneyoshi , Akutsu Hiroyoshi , Kakizaki Hirohiko
Published: March 2016

A 59-year-old woman had a 1-year history of right vision loss. Her visual acuity was then 0.01 OD, and the critical flicker frequency (CFF) was 8 Hz OD. Goldmann perimetry examination showed inferior suppression of the right visual field center. Funduscopic examination revealed normal coloring of the right optic disc. Imaging studies showed an apical oval tumor. The optic nerve was compressed by both the tumor and the superior rectus muscle/levator palpebrae superioris complex. The tumor was dissected from the surrounding tissues and completely extracted. Histopathologic examination confirmed a cavernous hemangioma. The patient underwent three cycles of postoperative steroid pulse therapy. One year after the surgery, her visual acuity and CFF improved to 1.0 and 32 Hz OD, respectively. Her right visual field was within the normal range.
5‐Lipoxygenase Gene Variants Are Not Associated With Atherosclerosis or Incident Coronary Heart Disease in the Multi‐Ethnic Study of Atherosclerosis Cohort
Authors: Tsai Michael Y. , Cao Jing , Steffen Brian T. , Weir Natalie L. , Rich Stephen S. , Liang Shuang , Guan Weihua
Published: March 2016

Background

The arachidonate 5‐lipoxygenase enzyme plays a crucial role in mediating inflammation to maintain homeostasis, yet certain allelic variants of the 5‐lipoxygenase gene,

ALOX
5

, may increase risk of atherosclerosis and coronary heart disease (
CHD
). Further, relations between

ALOX
5

and disease outcomes may be enhanced or attenuated depending on the bioavailability of 5‐lipoxygenase enzyme substrates. By using a candidate gene approach in 6153 Multi‐Ethnic Study of Atherosclerosis (
MESA
) participants, associations were determined among 1348

ALOX
5

single nucleotide polymorphisms (
SNP
s) and carotid intima‐media thickness (
cIMT
) as well as incident
CHD
, and interactions with plasma concentrations of arachidonic acid, eicosapentaenoic acid, or docosahexaenoic acid were tested.

Methods and Results

Multivariable linear regression was used to test for associations between
cIMT
and

ALOX
5

SNP
s, and Cox regression was used for incident
CHD
. Bonferroni correction was used for multiple hypothesis testing. No significant associations between

ALOX
5

SNP
s and
cIMT
or
CHD
events were observed. Levels of arachidonic acid, eicosapentaenoic acid, or docosahexaenoic acid concentrations did not modify the relations of

ALOX
5

with either outcome.

Conclusions

ALOX
5

gene variants do not appear to be related to clinical
CHD
events or subclinical atherosclerosis regardless of bioavailable enzyme substrate levels in this multiethnic cohort. Further studies that directly examine protein expression or enzyme activity may better define the arachidonate 5‐lipoxygenase pathway in disease development and progression.
Identification of
PTCSC3
as a Novel Locus for Large‐Vessel Ischemic Stroke: A Genome‐Wide Association Study
Authors: Lee Tsong‐Hai , Ko Tai‐Ming , Chen Chien‐Hsiun , Lee Ming‐Ta Michael , Chang Yeu‐Jhy , Chang Chien‐Hung , Huang Kuo‐Lun , Chang Ting‐Yu , Lee Jiann‐Der , Chang Ku‐Chou , Yang Jen‐Tsung , Wen Ming‐Shien , Wang Chao‐Yung , Chen Ying‐Ting , Hsieh Chia‐San , Chou Shu‐Yu , Liu Yi‐Min , Chen Hui‐Wen , Liao Hung‐Ting , Wang Chia‐Wen , Chen Shih‐Ping , Lu Liang‐Suei , Chen Yuan‐Tsong , Wu Jer‐Yuarn
Published: March 2016

Background

Ischemic stroke is a major cause of death and disability in the world. A major ischemic stroke subtype, large‐vessel ischemic stroke (large artery atherosclerosis;
LAA
), has been shown to have some genetic components in individuals of European ancestry. However, it is not clear whether the genetic predisposition to
LAA
stroke varies among ethnicities. We sought to identify genetic factors that contribute to
LAA
stroke in 2 independent samples of Han Chinese individuals.

Methods and Results

Novel genetic variants that predispose individuals to
LAA
stroke were identified using a genome‐wide association study (
GWAS
) of 444 individuals with
LAA
stroke and 1727 controls in a Han Chinese population residing in Taiwan. The study was replicated in an independent Han Chinese population comprising an additional 319 cases and 1802 controls. We identified 5 single‐nucleotide polymorphisms, including rs2415317 (
P
=3.10×10
−8
), rs934075 (
P
=4.00×10
−9
), rs944289 (
P
=3.57×10
−8
), rs2787417 (
P
=1.76×10
−8
), and rs1952706 (
P
=2.92×10
−8
), at one novel locus on chromosome 14q13.3 within

PTCSC
3

(encoding papillary thyroid carcinoma susceptibility candidate 3) that were associated with
LAA
stroke at genome‐wide significance (
P
<5×10
−8
).

Conclusions

Our data provide strong support for future studies on the role of
PTCSC
3 in the pathogenesis of
LAA
stroke and the association between
LAA
stroke development and thyroid function. In addition, these findings provide insights into the genetic basis of
LAA
stroke and identify a novel pathway that might be applicable for future therapeutic intervention.
Ischemic Stroke Risk in Patients With Atrial Fibrillation and CHA
2
DS
2
-VASc Score of 1
Authors: Joundi Raed A. , Cipriano Lauren E. , Sposato Luciano A. , Saposnik Gustavo ,   on behalf of the Stroke Outcomes Research Working Group
Published: March 2016

Background and Purpose—

The CHA
2
DS
2
-VASc score aims to improve risk stratification of ischemic stroke among patients with atrial fibrillation to identify those who can safely forego oral anticoagulation. Oral anticoagulation treatment guidelines remain uncertain for CHA
2
DS
2
-VASc score of 1. We conducted a systematic review and meta-analysis of the risk of ischemic stroke for patients with atrial fibrillation and CHA
2
DS
2
-VASc score of 0, 1, or 2 not treated with oral anticoagulation.

Methods—

We searched MEDLINE, Embase, PubMed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science from the start of the database up until April 15, 2015. We included studies that stratified the risk of ischemic stroke by CHA
2
DS
2
-VASc score for patients with nonvalvular atrial fibrillation. We estimated the summary annual rate of ischemic stroke using random effects meta-analyses and compared the estimated stroke rates with published net-benefit thresholds for initiating anticoagulants.

Results—

1162 abstracts were retrieved, of which 10 met all inclusion criteria for the study. There was substantial heterogeneity among studies. The summary estimate for the annual risk of ischemic stroke was 1.61% (95% confidence interval 0%–3.23%) for CHA
2
DS
2
-VASc score of 1, meeting the theoretical threshold for using novel oral anticoagulants (0.9%), but below the threshold for warfarin (1.7%). The summary incident risk of ischemic stroke was 0.68% (95% confidence interval 0.12%–1.23%) for CHA
2
DS
2
-VASc score of 0 and 2.49% (95% confidence interval 1.16%–3.83%) for CHA
2
DS
2
-VASc score of 2.

Conclusions—

Our meta-analysis of ischemic stroke risk in atrial fibrillation patients suggests that those with CHA
2
DS
2
-VASc score of 1 may be considered for a novel oral anticoagulant, but because of high heterogeneity, the decision should be based on individual patient characteristics.
Gender-specific differences in gene expression profiles in gynogenetic Pengze crucian carp
Authors: Zheng Yao , Chen Jiazhang , Bing Xuwen , Yang Yanping , Liang Hongwei , Wang Zaizhao
Published: March 2016

Gynogenesis is a form of asexual reproduction that is used to obtain all-female fish stocks. In this study, we were interested in studying gender-specific differences in gene expression profiles in gynogenetic teleosts, using a carp species. The four-month old gynogenetic Pengze crucian carp F1 (Carassius auratus var. pengzensis, Pcc) showed a high ratio of males under laboratory culture condition. The present study aimed to investigate the differences between males and females. The gonadosomatic index of the females was significantly higher than that of the males. Moreover, the hepatosomatic index of the females was significantly lower than that of the males. Vitellogenin B mRNA was abnormally highly expressed in male hepatopancreas and testes compared to females. Similarly, zona pellucida 2 expressed at a significantly high level in the testes. For the sex related genes, dosage-sensitive sex reversal, adrenal hypoplasia congenital critical region on the X-chromosome gene 1, doublesex and mab-3 related transcription factor 1a, nuclear receptor subfamily 5, group A, member 1b and SRY-box containing gene 9a had significantly higher expression levels in the males than in the females, whereas there was no difference in expression of anti-Müllerian hormone, cytochrome P450 family 19 subfamily A member 1A and forkhead box L2 transcripts between the two genders. The females showed higher levels of estrogen but no significant difference in testosterone compared to the males. The data suggest remarkable differences between the two genders of the Pengze crucian carp.
New botanical discoveries in Eugenia (Myrtaceae) from Bolivia and Brazil
Authors: VILLARROEL DANIEL , FARIA JAIR E. Q. , BELMONT ALÉXIA MORAES , GOMES SUELI MARIA , PROENÇA CAROLYN E. B.
Published: March 2016

Eugenia michaelneei is a new Bolvian species endemic to the Meseta de Chochís and the Serranía de Santiago de Chiquitos in eastern Santa Cruz Department. It is closely related to E. sonderiana, but differs mainly by its small height, low number of secondary veins, midvein glabrescent on the abaxial surface and glabrous on the adaxial surface, and few ovules per locule. Nineteen differences in their leaf anatomy were also recorded although they share a dorsiventral mesophyll. Eugenia repanda and E. corrientina are reported as new occurrences for Bolivia and Brazil respectively.
Prevalence of Voice Disturbances in the Pediatric Craniofacial Patient Population
Authors: Fritz Mark A. , Rickert Scott M.
Published: March 2016

Objective

To report on the prevalence of voice disturbances in the pediatric craniofacial population and to prove that the pediatric Voice Handicap Index (pVHI) is a useful questionnaire for this unique population.

Study Design

Case series with chart review.

Setting

Tertiary care center.

Subjects

Pediatric patients seen by a pediatric otolaryngologist in a craniofacial clinic.

Methods

Consecutive patients (N = 366) seen by a single pediatric otolaryngologist in a craniofacial clinic from July 2011 to September 2012 were included. Any patient specifically referred for airway problems or voice difficulties completed a pVHI questionnaire. Patients each underwent an evaluation including flexible fiberoptic laryngoscopy and videostroboscopy. Voice disturbance was further characterized into dysphonia, hypernasality, or hyponasality.

Results

Of all the patients evaluated, 280 (77%) were specifically referred for airway problems or voice disturbance. Of those referred, 39 (10.7%) were found to have an organic vocal fold pathology causing dysphonia, as seen on the videostroboscopic examination; 53.7% of these lesions were attributable to potential iatrogenic causes. Hypernasality and hyponasality were seen in 116 (31.7%) and 78 (21.3%) patients, respectively. The pVHI was 3.95, 26.3, 11.34, and 10.53 for those with no voice disturbance, dysphonia, hypernasality, and hyponasality, respectively.

Conclusion

Pediatric patients with craniofacial disorders have a higher prevalence of dysphonia than the general pediatric population. The majority of causes of dysphonia in these patients are possibly iatrogenic in origin. The pVHI serves as a useful questionnaire in this unique patient cohort to quantify the disability from not only dysphonia but also hypernasality and hyponasality.
Laryngeal Preservation in Glottic Cancer
Authors: Mandelbaum Rachel S. , Abemayor Elliot , Mendelsohn Abie H.
Published: March 2016

Objective

When total laryngectomy is not required, organ preservation surgery or radiotherapy is considered the standard of care for primary glottic cancer. These accepted treatment options are available for early and advanced glottic cancers due to equivalent locoregional control and survival rates. However, in today’s climate of accountable care, the financial burden of treatment choices continues to increase in significance. We therefore compared hospital charges and treatment‐related morbidity between organ‐preserving surgery and radiation with or without chemotherapy—herein, (chemo)radiation—in the primary treatment of glottic cancer.

Study Design

Nationwide Inpatient Sample Database was analyzed to assess clinical and financial information.

Setting

Population‐based analysis.

Subjects

Patients (N = 5499) with primary glottic cancer undergoing treatment with laryngeal preservation strategies.

Methods

Patients were subdivided by ICD‐9 codes into 3 treatment groups: endoscopic resection, open partial laryngectomy, and (chemo)radiation. Treatment‐related outcomes, charges, and length of hospitalization were analyzed among treatment groups.

Results

When adjusting for sex, age, race, comorbidity, and primary payer, (chemo)radiotherapy was associated with increased direct charges (P <. 001; coefficient, $23,658.99; 95% confidence interval [95% CI]: $10,227.15‐$37,090.84) and length of hospitalization (P <. 001; hazard ratio, 0.593; 95% CI: 0.502‐0.702) when compared with endoscopic surgery. As compared with open surgery, endoscopic surgery was associated with reduced hospital charges (P =. 012; coefficient, $11,967.01; 95% CI: $2,784.17‐$21,249.85) and duration of hospitalization (P <. 001; hazard ratio, 0.749; 95% CI: 0.641‐0.876).

Conclusions

This analysis suggests that increased utilization of endoscopic surgery in patients with primary glottic cancer not requiring total laryngectomy may lead to reduced financial burden and duration of hospitalization when compared with open surgery or (chemo)radiation therapy.
Noninvasive neurostimulation methods for migraine therapy: The available evidence
Authors: Schoenen Jean , Roberta Baschi , Magis Delphine , Coppola Gianluca
Published: March 2016

Background

Migraine is one of the most disabling neurological disorders. The current pharmacological armamentarium is not satisfying for a large proportion of patients because the responder rate does not exceed 50% on average and the most effective drugs often induce intolerable side effects. During recent years, noninvasive central and peripheral neuromodulation methods have been explored for migraine treatment.

Overview

A review of the available evidence suggests that noninvasive neuromodulation techniques could be beneficial for migraine patients. The transcranial stimulation methods allow modulating selectively cortical activity and can thus be curtailed to the patient’s pathophysiological profile, while transcutaneous stimulation of pericranial nerves likely modulates central pain control centers. Occipital single-pulse transcranial magnetic stimulation and transcutaneous supraorbital stimulation have the strongest evidence respectively for acute and preventive treatment. Transcranial direct current stimulation and repetitive magnetic stimulation are promising in pilot studies, but large sham-controlled trials are not yet available.

Conclusions

The noninvasive neurostimulation methods are promising for migraine treatment and devoid of serious adverse effects allowing their combination with drug therapies. Their application in clinical practice will depend on the industry’s capacity to develop portable and user-friendly devices, and on the scientists’ capacity to prove their efficacy in randomized sham-controlled trials.
Emerging in play: Collectives, ownership, and everyday rules in a low-income neighborhood in Boston
Authors: Vidart-Delgado Maria
Published: March 2016

Play in public space pauses the everyday and allows for fictional collective worlds to emerge. In this article I focus on the unintended ‘frictions’ triggered by these collective fictions. When players inhabit these fantastical worlds, they tend to become more aware of the invisible rules of ownership and property that shape their everyday. This article questions play as an open-ended modality of emergence. I argue that these fictions are ephemeral instances of collective awareness, and by definition preclude sustained forms of collective action to enact long-lasting, structural change; yet they are potentially transformative. I draw on my work as co-founder of Department of Play, a Boston-based interdisciplinary group that works at the intersection of art, urban theory and ethnography. I reflect on the organization and implementation of Boxtopia, a recent play project in a low-income neighborhood of Boston that sits along a ‘development corridor’.
The antiallodynic action of pregabalin in neuropathic pain is independent from the opioid system
Authors: Kremer Mélanie , Yalcin Ipek , Nexon Laurent , Wurtz Xavier , Ceredig Rhian Alice , Daniel Dorothée , Hawkes Rachael Aredhel , Salvat Eric , Barrot Michel
Published: March 2016

Background

Clinical management of neuropathic pain, which is pain arising as a consequence of a lesion or a disease affecting the somatosensory system, partly relies on the use of anticonvulsant drugs such as gabapentinoids. Therapeutic action of gabapentinoids such as gabapentin and pregabalin, which act by the inhibition of calcium currents through interaction with the α2δ-1 subunit of voltage-dependent calcium channels, is well documented. However, some aspects of the downstream mechanisms are still to be uncovered. Using behavioral, genetic, and pharmacological approaches, we tested whether opioid receptors are necessary for the antiallodynic action of acute and/or long-term pregabalin treatment in the specific context of neuropathic pain.

Results

Using the cuff model of neuropathic pain in mice, we show that acute pregabalin administration at high dose has a transitory antiallodynic action, while prolonged oral pregabalin treatment leads to sustained antiallodynic action, consistent with clinical observations. We show that pregabalin remains fully effective in μ-opioid receptor, in δ-opioid receptor and in κ-opioid receptor deficient mice, either female or male, and its antiallodynic action is not affected by acute naloxone. Our work also shows that long-term pregabalin treatment suppresses tumor necrosis factor-α overproduction induced by sciatic nerve constriction in the lumbar dorsal root ganglia.

Conclusions

We demonstrate that neither acute nor long-term antiallodynic effect of pregabalin in a context of neuropathic pain is mediated by the endogenous opioid system, which differs from opioid treatment of pain and antidepressant treatment of neuropathic pain. Our data are also supportive of an impact of gabapentinoid treatment on the neuroimmune aspect of neuropathic pain.
Behavioral Styles of Path-Goal Theory
Authors: Phillips Antoinette S. , Phillips Carl R.
Published: March 2016

Path-goal theory is firmly established as a robust, comprehensive leadership model. Its applicability makes it attractive to students and practitioners alike. We have designed an exercise with two main goals: first, to help students better understand the path-goal behaviors (directive, supportive, participative, achievement-oriented), particularly those in which they feel weakest; and second, to provide practice modeling each behavior through generating explicit sample statements for the various behaviors that can be used in various leadership situations. The exercise is ideal for use by instructors of upper level or graduate organizational behavior or leadership classes, or in leadership training contexts. We provide focused discussion activities centered on situational diagnosis (when to use which behavior) and guidelines for conducting a behavioral styles exercise. Using the suggested video examples aids in teaching the concepts and is very helpful in preparing students for the exercise.
Intraspecific variation in physiological performance of a benthic elasmobranch challenged by ocean acidification and warming
Authors: Di Santo Valentina
Published: March 2016

Elucidating the combined effects of increasing temperature and ocean acidification on performance of fishes is central to our understanding of how species will respond to global climate change. Measuring the metabolic costs associated with intense and short activities such as those required to escape predators, is key to quantify changes in performance and estimate potential effects of environmental stressors on survival. In this study, juvenile little skate Leucoraja erinacea from two neighboring locations (Gulf of Maine, or northern location, and Georges Bank, or southern location) were developmentally acclimatized and reared at current and projected temperatures (15, 18, or 20°C) and acidification conditions (pH of 8.1 or 7.7), and their escape performance was tested by employing a chasing protocol. Results from this study suggest variation in growth between skates from the two locations, while the optimum for escape performance was at a lower temperature in individuals from the northern latitudes, which could be related to adaptation to the local thermal environment. Aerobic performance and scope declined in skates from the northern latitudes at simulated ocean warming and acidification conditions. Overall, the southern skates showed lower sensitivity to these climatic stressors. This study demonstrates that even mobile organisms from neighboring locations can exhibit substantial differences in energetic costs of exercise and that skates from the northern part of the geographic range may be more sensitive to the directional increase in temperature and acidification expected by the end of the century.
A tool for reproducible research: From data analysis (in R) to a typeset laboratory notebook (as .pdf) using the text editor Emacs with the 'mp' package
Authors: Dardis Christopher , Woolf Eric C , Scheck Adrienne C
Published: March 2016

Software

Much scientific research makes use of commonly available 'office' software. While numerous more fully-featured open-source alternatives exist, the integration of diverse tools and platforms which their use often entails can be challenging. The mp package for Emacs aims to bring together a number of these elements with the goal of simplifying the process of converting an .R file, as used for data analysis, to a nicely formatted .pdf which includes the complete description of the methods and interpretation. We discuss the rationale for development of the package and illustrate its applications and options with a series of experiments from our laboratory.

Experimental work

We demonstrate the inhibitory effects of the ketone body \emph{beta}-hydroxybutyrate (BHB) on the growth and motility of a cancer cell line. BHB is produced endogenously; levels may be increased in certain medial conditions e.g. diabetic ketoacidosis. They may also be raised voluntarily e.g. by adopting the ketogenic diet. 

BHB is known to inhibit the growth of other neoplastic cell lines. However the finding that it can do so in a cell line selected for their propensity to metastasize to the brain is novel. Given the challenges in treating patients with melanoma metastatic to brain, this work strengthens the rationale for investigating the ketogenic diet as a potential adjunct to treatment in such cases.
Monoclonal antibodies against muscle actin isoforms: epitope identification and analysis of isoform expression by immunoblot and immunostaining in normal and regenerating skeletal muscle
Authors: Chaponnier Christine , Gabbiani Giulio
Published: March 2016

Higher vertebrates express six different highly conserved actin isoforms that can be classified in three subgroups: 1) sarcomeric actins, α-skeletal (α-SKA) and α-cardiac (α-CAA), 2) smooth muscle actins (SMAs), α-SMA and γ-SMA, and 3) cytoplasmic actins (CYAs), β-CYA and γ-CYA. The variations among isoactins, in each subgroup, are due to 3-4 amino acid differences located in their acetylated N-decapeptide sequence. The first monoclonal antibody (mAb) against an actin isoform (α-SMA) was produced and characterized in our laboratory in 1986 (Skalli et al., 1986). We have further obtained mAbs against the 5 other isoforms. In this report, we focus on the mAb anti-α-SKA and anti-α-CAA obtained after immunization of mice with the respective acetylated N-terminal decapeptides using the Repetitive Immunizations at Multiple Sites Strategy (RIMMS). In addition to the identification of their epitope by immunoblotting, we describe the expression of the 2 sarcomeric actins in mature skeletal muscle and during muscle repair after micro-lesions. In particular, we analyze the expression of α-CAA, α-SKA and α-SMA by co-immunostaining in a time course frame during the muscle repair process. Our results indicate that a restricted myocyte population expresses α-CAA and suggest a high capacity of self-renewal in muscle cells. These antibodies may represent a helpful tool for the follow-up of muscle regeneration and pathological changes.
A failure to reproduce: How bad biomedical science is holding us back
Authors: Jaafar Hussein , Maweni Robert M.
Published: March 2016

Irreproducibility is a common problem in the biomedical sciences. Numerous studies have revealed the systemic and chronic nature of the problem, yet not enough is being down to combat it. The financial cost is estimated to be 28 billion dollars in the United States alone. Combine this financial cost with the time spent on irreproducible studies and the net effect is staggering. The factors for this lack of reproducibility are however identifiable and concrete steps can be taken to improve the situation. This article describes some of the factors leading to irreproducibility in the biomedical sciences and how stakeholders at every level of the field can act to reverse them.
Interprofessional graduate programme for nursing-paramedicine degree graduates: work outcomes and participant experience
Authors: Considine Julie , Walker Tony
Published: March 2016

The 2011/12 interprofessional graduate programme (IPG) was Australia's first programme for graduates of double degrees in nursing and paramedicine.

Aims:

The aim of this study was to examine the employment outcomes and participant experience of the first cohort of 10 IPG participants.

Methods:

Data were collected by repeated surveys (6 months prior to, 6 months and 18 months following IPG completion) and interviews.

Results:

There were 10 IPG participants, nine completed all surveys and nine agreed to be interviewed. Two were males and the average age was 23.7 years (SD=1.3). At IPG completion, all participants were employed by Ambulance Victoria: five participants were working casual shifts in emergency nursing. Themes related to career choice were that casual employment was easier in nursing and paramedicine had higher levels of freedom and more regular shift patterns. Mean scores for involvement decreased (p<0.018) and manager control increased (p<0.018). The four themes related to participant experience were: i) best of emergency health care; ii) knowledge and experience; iii) understanding and respect; and iv) chopping and changing.

Conclusions:

Participants' experience of IPG were mostly positive. Traditional professional and industrial structures still prevent double degree graduates using their skills and knowledge to their full capability.
Credits granted for professional education of paramedics and nurses at at US colleges with paired programmes
Authors: Phelps Scott
Published: March 2016

Aims:

To compare professional education requirements for Commission on Accreditation of Allied Health Educations Programs (CAAHEP)-accredited community college paramedic programs and associate degree registered nurse programmes at the same institution.

Methods:

All CAAHEP-accredited community college paramedic programmes were identified from the CAAHEP website. The college website was visited to determine credits granted for paramedic professional education, followed by a search of the college website to determine if there was an associate degree registered nursing programme. If there was, the credits granted for registered nurse professional education was determined and the pair was recorded.

Results:

At the 259 community colleges in the United States that had both a CAAHEP-accredited paramedic and registered nursing education programme that were offered for college credit, paramedic professional education was granted more college credit than nursing professional education at the individual college level 81% of the time. At the national level, median (48 versus 40 college credits) of paramedic professional education exceeded associate degree registered nursing professional education by 20%.

Conclusions:

Professional education for paramedics is granted more college credit that the professional ed-ucation for associate degree registered nurses.
Protecting businesses during a transfer: facing TUPE issues
Authors: Bernstein Adam
Published: March 2016

If ownership of your care home is set to change hands, you'll have to contend with Transfer of Undertakings (Protection of Employment) Regulations (TUPE) regulations. Adam Bernstein looks at their potential impact and any pitfalls to avoid
Improved Oral Pharmacokinetics of Diclofenac Sodium from SNEDDS in Human Volunteers
Authors: Kumar Gannu Praveen , Rambhau Devaraj , Apte Shashank Shridhar
Published: March 2016

The pharmacokinetics of diclofenac sodium in SNEDDS formulation and tablet were compared in healthy human volunteers. In this, randomized study with a cross over design, diclofenac sodium was administered as a single dose to subjects before food. Blood samples were obtained before dosing as a control and at 0.5, 1, 1.5, 2, 4, 8, 12 and 24 hours after dosing. The serum concentrations were determined by high performance liquid chromatography. Possible adverse events were monitored during the entire study. After log-transformation of the comparable variables, statistically significant differences were found between the two formulations with respect to the time between dosing and the appearance of the drug in serum, time to reach maximum concentration, elimination half-life, absorption rate constant and mean residence time. The extent of absorption was assessed by estimating the area under the serum concentration-time curve (AUC). AUC0-8hr and AUMC0-24hr was statistically significantly higher for diclofenac sodium (DFS) self nanoemulsifying drug delivery systems (SNEDDS) (6.428mcg.hr/ml, 218.83mcg.hr/ml) than for voveran tablet (5.869mcg.hr/ml, 52.19mcg.hr/ml). No significant differences were found in AUC0-24hr. SNEDDS of diclofenac sodium showed a statistically significant higher maximum serum concentration than voveran tablet (2.289mcg/ml and 1.375mcg/ml for SNEDDS and tablet, respectively). The results of the present study suggest that SNEDDS of diclofenac sodium could be a clinically useful rapid release formulation for immediate relief without causing gastric ulcers.
Extracting Electronic Health Record Data in a Practice-Based Research Network:
Lessons Learned from Collaborations with Translational Researchers
Authors: Cole Allison M. , Stephens Kari A. , Keppel Gina A. , Estiri Hossein , Baldwin Laura-Mae
Published: March 2016

Context: The widespread adoption of electronic health records (EHRs) offers
significant opportunities to conduct research with clinical data from patients outside
traditional academic research settings. Because EHRs are designed primarily for clinical
care and billing, significant challenges are inherent in the use of EHR data for
clinical and translational research. Efficient processes are needed for translational
researchers to overcome these challenges. The Data QUEST Coordinating Center (DQCC),
which oversees Data QUEST – a primary care EHR data sharing infrastructure – created
processes that that guide EHR data extraction for clinical and translational research
across these diverse practices. We describe these processes and their application in a
case example.Case Description: The DQCC process for developing EHR data extractions not
only supports researchers access to EHR data, but supports this access for the purpose
of answering scientific questions. This process requires complex coordination across
multiple domains, including: 1) understanding the context of EHR data; 2) creating and
maintaining a governance structure to support exchange of EHR data; and 3) defining data
parameters that are used in order to extract data from the EHR.1,2,3,4 We use the
Northwest-Alaska Pharmacogenomics Research Network (NWA-PGRN) as a case example that
focuses on pharmacogenomic discovery and clinical applications to describe the DQCC
process. The NWA-PGRN collaborates with Data QUEST to explore ways to leverage primary
care EHR data to support pharmacogenomics research.Findings: Preliminary analysis on the
case example shows that initial decisions about how researchers define the study
population can influence study outcomes.Major Themes and Conclusions: The experience of
the DQCC demonstrates that Coordinating Centers provide expertise in helping researchers
understand the context of EHR data, create and maintain governance structures, and guide
the definition of parameters for data extractions. This expertise is critical to support
research with EHR data. Replication of these strategies through Coordinating Centers may
lead to more efficient translational research. Investigators must also consider the
impact of initial decisions in defining study groups that may potentially affect
outcomes.
Veränderte Landschaften
Authors: Straube Robert
Published: March 2016

Ausgehend von der Feststellung, dass Landschaft auch für viele Gedichte aus der DDR eine zentrale Bezugsgröße darstellt, diskutiert Robert Straube die Frage, wie diese literarische Tradition ebenso weitergeschrieben wie gezielt für politische Inhalte umfunktioniert wurde. Durch einen detaillierten Blick auf die Texte stellt er verkürzenden Interpretationen mit Fokus auf Stellungnahmen zum Staatswesen ein breites Spektrum an lyrischen Landschaftsbildern gegenüber. Er zeigt: Neben bekannten Legitimationsmustern lassen sich affirmative Bezüge auf Vorstellungen von Heimat genauso beobachten wie die Distanznahme zu politischen Rahmensetzungen.
Berührungen
Authors: Egert Gerko
Published: March 2016

Heben, streifen, halten, stoßen - die Weisen der Berührung im Tanz sind vielfältig. Ausgehend von der Annahme, dass die Berührung mehr als bloß der Kontakt zweier Körper ist, entwirft Gerko Egert ein Denken der Berührung als komplexes Zusammenspiel von Bewegungen, Erfahrungen und Affekten. In detaillierten Analysen zeitgenössischer Tanzaufführungen und der Auseinandersetzung mit Konzepten des Rhythmus, des Ereignisses und des Gefüges entstehen so neue Perspektiven auf Körper, Wahrnehmung und Bewegung. Dieses Buch eröffnet nicht nur die Frage der Berührung für die Tanzwissenschaft, sondern leistet ebenso einen zentralen Beitrag für eine prozessorientierte Theorie der Berührung.
Theater zwischen Ich und Welt
Authors: Hentschel Ingrid
Published: March 2016

Theater für Kinder und Jugendliche - ebenso wie von und mit ihnen - erweist sich vor dem Hintergrund kultur- und theatertheoretischer Reflexionen als Seismograf gesellschaftlicher Verschiebungen zwischen den Generationen und deren jeweiligen Weltverhältnissen. Dieser Band versammelt erstmals Ingrid Hentschels wichtigste Beiträge zu den Entwicklungen und Formaten sowie zur Theorie und Praxis des Kinder- und Jugendtheaters seit den 1980er Jahren.