bluuebunny/crossref_metadata_2025_split huggingface dataset:
Radiation Enhancement of Head and Neck Squamous Cell Carcinoma by the Dual PI3K/mTOR Inhibitor PF-05212384
Authors: Leiker Andrew J. , DeGraff William , Choudhuri Rajani , Sowers Anastasia L. , Thetford Angela , Cook John A. , Van Waes Carter , Mitchell James B. 
Published: February 2015

Abstract
Purpose: Radiation remains a mainstay for the treatment of nonmetastatic head and neck squamous cell carcinoma (HNSCC), a malignancy characterized by a high rate of PI3K/mTOR signaling axis activation. We investigated the ATP-competitive dual PI3K/mTOR inhibitor, PF-05212384, as a radiosensitizer in preclinical HNSCC models.
Experimental Design: Extent of radiation enhancement of two HNSCC cell lines (UMSCC1-wtP53 and UMSCC46-mtP53) and normal human fibroblast (1522) was assessed by in vitro clonogenic assay with appropriate target inhibition verified by immunoblotting. Radiation-induced DNA damage repair was evaluated by γH2AX Western blots with the mechanism of DNA double-strand break repair abrogation investigated by cell cycle analysis, immunoblotting, and RT-PCR. PF-05212384 efficacy in vivo was assessed by UMSCC1 xenograft tumor regrowth delay, xenograft lysate immunoblotting, and tissue section immunohistochemistry.
Results: PF-05212384 effectively inhibited PI3K and mTOR, resulting in significant radiosensitization of exponentially growing and plateau-phase cells with 24-hour treatment following irradiation, and variable radiation enhancement with 24-hour treatment before irradiation. Tumor cells radiosensitized to a greater extent than normal human fibroblasts. Postirradiation PF-05212384 treatment delays γH2AX foci resolution. PF-05212384 24-hour exposure resulted in an evident G1–S phase block in p53-competent cells. Fractionated radiation plus i.v. PF-05212384 synergistically delayed nude mice bearing UMSCC1 xenograft regrowth, with potential drug efficacy biomarkers identified, including pS6, pAkt, p4EBP1, and Ki67.
Conclusions: Taken together, our results of significant radiosensitization both in vitro and in vivo validate the PI3K/mTOR axis as a radiation modification target and PF-05212384 as a potential clinical radiation modifier of nonmetastatic HNSCC. Clin Cancer Res; 21(12); 2792–801. ©2015 AACR.
High Turnover of Tissue Factor Enables Efficient Intracellular Delivery of Antibody–Drug Conjugates
Authors: de Goeij Bart E.C.G. , Satijn David , Freitag Claudia M. , Wubbolts Richard , Bleeker Wim K. , Khasanov Alisher , Zhu Tong , Chen Gary , Miao David , van Berkel Patrick H.C. , Parren Paul W.H.I. 
Published: February 2015

Abstract
Antibody–drug conjugates (ADC) are emerging as powerful cancer treatments that combine antibody-mediated tumor targeting with the potent cytotoxic activity of toxins. We recently reported the development of a novel ADC that delivers the cytotoxic payload monomethyl auristatin E (MMAE) to tumor cells expressing tissue factor (TF). By carefully selecting a TF-specific antibody that interferes with TF:FVIIa-dependent intracellular signaling, but not with the procoagulant activity of TF, an ADC was developed (TF-011-MMAE/HuMax-TF-ADC) that efficiently kills tumor cells, with an acceptable toxicology profile. To gain more insight in the efficacy of TF-directed ADC treatment, we compared the internalization characteristics and intracellular routing of TF with the EGFR and HER2. Both in absence and presence of antibody, TF demonstrated more efficient internalization, lysosomal targeting, and degradation than EGFR and HER2. By conjugating TF, EGFR, and HER2-specific antibodies with duostatin-3, a toxin that induces potent cytotoxicity upon antibody-mediated internalization but lacks the ability to induce bystander killing, we were able to compare cytotoxicity of ADCs with different tumor specificities. TF-ADC demonstrated effective killing against tumor cell lines with variable levels of target expression. In xenograft models, TF-ADC was relatively potent in reducing tumor growth compared with EGFR- and HER2-ADCs. We hypothesize that the constant turnover of TF on tumor cells makes this protein specifically suitable for an ADC approach. Mol Cancer Ther; 14(5); 1130–40. ©2015 AACR.
Frequent Loss of NISCH Promotes Tumor Proliferation and Invasion in Ovarian Cancer via Inhibiting the FAK Signal Pathway
Authors: Li Jing , He Xiaoying , Dong Ruofan , Wang Yuan , Yu Jinjin , Qiu Haifeng 
Published: February 2015

Abstract
NISCH encodes the imidazoline receptor Nischarin and is a known tumor suppressor in many human malignancies; however, its roles in ovarian cancer are still largely unknown. Here, we aim to investigate the biologic functions of NISCH in ovarian cancer. We found that NISCH was significantly downregulated, which correlated considerably with advanced tumor stage, poor differentiation, lymph node metastasis, and the serous/mucinous subtypes in a panel of ovarian cancer tissues. Moreover, NISCH gene silencing was mainly the product of promoter hypermethylation, which could be reversed by treatment with 5-aza-dC. In vitro, NISCH overexpression suppressed cell proliferation and colony formation by hindering cell-cycle progression, whereas the opposite was observed in NISCH knockdown counterparts. In vivo, abundant NISCH expression hindered the growth of HO8910 xenografts, whereas NISCH knockdown accelerated the growth of SKOV3 xenografts. In addition, NISCH significantly attenuated cell invasion by inhibiting the phosphorylation of FAK and ERK, which could be neutralized by PF-562271 (a FAK/Pyk2 inhibitor). Accordingly, NISCH knockdown xenografts exhibited increased peritoneal/pelvic metastases that were not present in counterparts treated with PF-562271. Furthermore, NISCH expression in primary ovarian cancer cells predicted a cellular resistance to PF-562271. In conclusion, we showed that NISCH was frequently silenced by promoter hypermethylation in human ovarian cancer. NISCH manipulated cellular proliferation and invasion by arresting cell cycle and inhibiting the FAK signal. Our findings revealed the biologic functions of NISCH in ovarian cancer, and might be useful for treating patients with aberrant expression of NISCH. Mol Cancer Ther; 14(5); 1202–12. ©2015 AACR.
βIII-Tubulin Regulates Breast Cancer Metastases to the Brain
Authors: Kanojia Deepak , Morshed Ramin A. , Zhang Lingjiao , Miska Jason M. , Qiao Jian , Kim Julius W. , Pytel Peter , Balyasnikova Irina V. , Lesniak Maciej S. , Ahmed Atique U. 
Published: February 2015

AbstractBrain metastases occur in about 10% to 30% of breast cancer patients, which culminates in a poor prognosis. It is, therefore, critical to understand the molecular mechanisms underlying brain metastatic processes to identify relevant targets. We hypothesized that breast cancer cells must express brain-associated markers that would enable their invasion and survival in the brain microenvironment. We assessed a panel of brain-predominant markers and found an elevation of several neuronal markers (βIII-tubulin, Nestin, and AchE) in brain metastatic breast cancer cells. Among these neuronal predominant markers, in silico analysis revealed overexpression of βIII-tubulin (TUBB3) in breast cancer brain metastases (BCBM) and its expression was significantly associated with distant metastases. TUBB3 knockdown studies were conducted in breast cancer models (MDA-Br, GLIM2, and MDA-MB-468), which revealed significant reduction in their invasive capabilities. MDA-Br cells with suppressed TUBB3 also demonstrated loss of key signaling molecules such as β3 integrin, pFAK, and pSrc in vitro. Furthermore, TUBB3 knockdown in a brain metastatic breast cancer cell line compromised its metastatic ability in vivo, and significantly improved survival in a brain metastasis model. These results implicate a critical role of TUBB3 in conferring brain metastatic potential to breast cancer cells. Mol Cancer Ther; 14(5); 1152–61. ©2015 AACR.
The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression
Authors: Rabender Christopher S. , Alam Asim , Sundaresan Gobalakrishnan , Cardnell Robert J. , Yakovlev Vasily A. , Mukhopadhyay Nitai D. , Graves Paul , Zweit Jamal , Mikkelsen Ross B. 
Published: February 2015

Abstract
Here, evidence suggests that nitric oxide synthases (NOS) of tumor cells, in contrast with normal tissues, synthesize predominantly superoxide and peroxynitrite. Based on high-performance liquid chromatography analysis, the underlying mechanism for this uncoupling is a reduced tetrahydrobiopterin:dihydrobiopterin ratio (BH4:BH2) found in breast, colorectal, epidermoid, and head and neck tumors compared with normal tissues. Increasing BH4:BH2 and reconstitution of coupled NOS activity in breast cancer cells with the BH4 salvage pathway precursor, sepiapterin, causes significant shifts in downstream signaling, including increased cGMP-dependent protein kinase (PKG) activity, decreased β-catenin expression, and TCF4 promoter activity, and reduced NF-κB promoter activity. Sepiapterin inhibited breast tumor cell growth in vitro and in vivo as measured by a clonogenic assay, Ki67 staining, and 2[18F]fluoro-2-deoxy-d-glucose–deoxyglucose positron emission tomography (FDG-PET). In summary, using diverse tumor types, it is demonstrated that the BH4:BH2 ratio is lower in tumor tissues and, as a consequence, NOS activity generates more peroxynitrite and superoxide anion than nitric oxide, resulting in important tumor growth–promoting and antiapoptotic signaling properties.
Implications: The synthetic BH4, Kuvan, is used to elevate BH4:BH2 in some phenylketonuria patients and to treat diseases associated with endothelial dysfunction, suggesting a novel, testable approach for correcting an abnormality of tumor metabolism to control tumor growth. Mol Cancer Res; 13(6); 1034–43. ©2015 AACR.
American Heart Association's Life's Simple 7 and Risk of Venous Thromboembolism: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study
Authors: Olson Nels C. , Cushman Mary , Judd Suzanne E. , McClure Leslie A. , Lakoski Susan G. , Folsom Aaron R. , Safford Monika M. , Zakai Neil A. 
Published: February 2015

Background

The American Heart Association's Life's Simple 7 metric is being used to track the population's cardiovascular health (
CVH
) toward a 2020 goal for improvement. The metric includes body mass index (
BMI
), blood pressure, cholesterol, glucose, physical activity (
PA
), cigarette smoking, and diet. We hypothesized a lower risk of venous thromboembolism (
VTE
) with favorable Life's Simple 7 scores.

Methods and Results

REGARDS
recruited 30 239 black and white participants ≥45 years of age across the United States in 2003–2007. A 14‐point summary score for Life's Simple 7 classified participants into inadequate (0 to 4 points), average (5 to 9 points), and optimal (10 to 14 points) categories. Hazard ratios (
HR
s) of incident
VTE
were calculated for these categories, adjusting for age, sex, race, income, education, and region of residence. For comparison,
HR
s of
VTE
were calculated using the Framingham 10‐year coronary risk score. There were 263 incident
VTE
cases over 5.0 years of follow‐up; incidence rates per 1000 person‐years declined from 2.9 (95% confidence interval [
CI
], 2.3 to 3.7) among those in the inadequate category to 1.8 (95%
CI
, 1.4 to 2.4) in the optimal category. Compared to the inadequate category, participants in the average category had a 38% lower
VTE
risk (95%
CI
, 11 to 57) and participants in the optimal category had a 44% lower risk (95%
CI
, 18 to 62). The individual score components related to lower
VTE
risk were ideal
PA
and
BMI
. There was no association of Framingham Score with
VTE
.

Conclusions

Life's Simple 7, a
CVH
metric, was associated with reduced
VTE
risk. Findings suggest that efforts to improve the population's
CVH
may reduce
VTE
incidence.
Tinnitus Holistic Simplified Classification (THoSC)
Authors: Cianfrone Giancarlo , Mazzei Filippo , Salviati Massimo , Turchetta Rosaria , Orlando Maria Patrizia , Testugini Valeria , Carchiolo Laura , Cianfrone Francesca , Altissimi Giancarlo 
Published: February 2015

Objective: One of the most debated topics in tinnitus is its standard and practical classification. The most popular classification distinguishes subjective from objective tinnitus. Other classifications are based on different features. On the whole, they seem incomplete, and the diagnostic and therapeutic algorithms are often difficult for practical purposes. The aim of this work is to develop a new diagnostic and therapeutic algorithm. Methods: Our model is based on 10 years of experience. In particular, the starting point is the data retrieved from 212 consecutive patients in our Tinnitus Unit between May and December 2013: We found a clear auditory disorder in 74.5% of the population, muscolo-skeletal disorders and/or trigeminal disease in 57.1%, and psychiatric comorbidities in 43.8%. Different features coexisted in 59.9% of the population. Results: Following such data we propose the Tinnitus Holistic Simplified Classification, which takes into account the different tinnitogenic mechanisms and the interactions between them. It differentiates tinnitus that arises from: (1) auditory alterations (Auditory Tinnitus), (2) complex auditory-somatosensory interactions (Somatosensory Tinnitus), (3) psychopathological-auditory interactions (Psychopathology-related Tinnitus), and (4) 2 or all of the previous mechanisms (Combined Tinnitus). Conclusions: In our opinion this classification provides an accurate and easy tailored path to manage tinnitus patients.
Salivary cortisol and cortisone responses to tetracosactrin (synacthen)
Authors: Cornes Michael P , Ashby Helen L , Khalid Yasmeen , Buch Harit N , Ford Clare , Gama Rousseau 
Published: February 2015

Background To establish cutoff values for salivary liquid chromatography tandem mass spectroscopy cortisol and cortisone in defining adequate adrenocortical function during a standard synacthen test. Methods We compared salivary liquid chromatography tandem mass spectroscopy cortisol and cortisone responses to those of serum cortisol measured on the Roche E170 immunoassay analyser and the Abbott Architect i2000 before and 30 min and 60 min following 0.25 mg of intravenous synacthen. Results Correlations of salivary cortisol and cortisone were bimodal and linear, respectively. Based on these correlations, adequate salivary cortisol and cortisone responses to synacthen were extrapolated from a serum cortisol (Roche) cut-off of 550 nmol/L and defined as 15 nmol/L and 45 nmol/L, respectively. The Abbott method correlated well with the Roche but gave results that were about 20% lower than the Roche method. Conclusions Measurement of salivary cortisol and cortisone responses offers an alternative to those of serum cortisol during a synacthen test in the investigation of adrenal hypofunction.
Distriktssköterskors beskrivningar av sjukdomsförebyggande arbete i daglig verksamhet och strukturella förutsättningar för detta arbete
Authors: Eriksson Annelie , Engström Maria 
Published: February 2015

Background There is much research about district nurses’ preventive work, effects of it and their perceptions of the preventive work. Less is known about how district nurses perceive their preventive work in relation to structural conditions for this work. Aim The aim was to describe district nurses’ perceptions of their preventive work in daily practice; and structural conditions for this using Kanter’s theory of structural empowerment. Methods Interviews were conducted 2012 with nine Swedish district nurses. Data were analysed using qualitative content analysis. Findings The analysis resulted in one theme; ‘To experience stimulation versus frustration; a consistency versus a discrepancy between will and structural conditions’. District nurses who worked with specialized tasks felt that they mostly had the structural conditions required to work in a preventive manner and that they could prioritize which unhealthy living habits to discuss with their patients. District nurses without specialized tasks described that their structural conditions for preventive work was limited in the present streamlined organization. This in turn led to a feeling of frustration. Conclusion Preventive work is described as stimulating when district nurses have the conditions required, yet the conditions required are sometimes lacking and especially for district nurses without specialized tasks. There is a will to work in a preventive manner but structural conditions need to be improved.
Transcriptional Activity of HPV in Inverted Papilloma Demonstrated by In Situ Hybridization for E6/E7 mRNA
Authors: Stoddard David G. , Keeney Michael G. , Gao Ge , Smith David I. , García Joaquín J. , O’Brien Erin K. 
Published: February 2015

ObjectiveAssess human papilloma virus (HPV) transcriptional activity in inverted Schneiderian papillomas (IPs).Study DesignCase series with chart review.SettingAcademic tertiary care center.Subjects and MethodsRetrospective clinicopathologic review of 19 cases of IP in patients undergoing surgical excision from 1995 to 2013 at Mayo Clinic in Rochester, Minnesota. Surgical pathology archival material was histopathologically reviewed using hematoxylin and eosin–stained slides. Formalin‐fixed, paraffin‐embedded material from each case was evaluated for p16 expression using immunohistochemistry as well as HPV DNA and E6/E7 messenger RNA (mRNA) transcription using polymerase chain reaction (PCR) and in situ hybridization (via RNAscope technology), respectively.ResultsEight patients were female (42%), with an average age of 53 years (range, 23‐82 years). Three demonstrated malignancy, and 5 subsequently recurred. Average follow‐up was 49 months (range, 0‐200 months), and 1 patient died from squamous cell carcinoma arising from the IP. RNAscope detected HPV mRNA transcripts exclusively within IP in 100% of cases; however, in 11 patients (58%), less than 1% of cells exhibited transcriptional activity. Only 2 of 19 cases (11%) demonstrated mRNA activity in 50% or more cells. HPV DNA was detected in only 2 specimens by PCR.ConclusionsThis study reveals wide prevalence but limited transcriptional activity of HPV in IP. No correlation between HPV transcriptional activity and progression, recurrence, or malignant transformation was identified. These data suggest that transcription of HPV may contribute to the pathogenesis of IP, but prospective data are needed to definitively demonstrate this connection. These results also suggest that RNAscope may be more sensitive than PCR in detecting HPV activity in IP.
Reconstruction of the Naso‐orbital‐ethmoid (NOE) Complex Using the Osteocutaneous Radial Forearm Flap (OCRFF)
Authors: Cannady Steven B. , Friedman Oren , Chalian Ara A. , Newman Jason G. , Cook Ted , Wax Mark K. 
Published: February 2015

ObjectivesDescribe the utility of osteocutaneous forearm flaps in reconstruction of naso‐orbito‐ethmoid (NOE) defects.Study DesignCase series with chart review.SettingTertiary medical centers.Subjects and MethodsThe study was conducted on patients treated between the years 2000 and 2014 undergoing NOE resection with reconstruction using the radial forearm flap. Decision making, technical feasibility, need for revisions, and patient disease outcomes were included to assess the durability of reconstruction over remaining survival period.ResultsFifteen patients underwent NOE reconstruction in the timeframe studied. Five recent patients reported poor nasal airway but no diplopia or immediately clinically evident enopthalmus after NOE reconstruction in mean follow‐up of 17.3 months. One‐third of patients succumbed to disease in the study period, 3 without revision, and all but 2 surviving patients required revisions.ConclusionOsteocutaneous radial forearm flap (OCRFF) is a cosmetically acceptable method of reconstructing NOE defects. Though a 1‐step reconstruction can be serviceable without multiple additional procedures, longer surviving patients frequently receive revision surgery as with more traditional planned staged procedures.
Sensitization of the trigeminovascular system following environmental irritant exposure
Authors: Kunkler Phillip Edward , Zhang LuJuan , Pellman Jessica Joan , Oxford Gerry Stephen , Hurley Joyce Harts 
Published: February 2015

Background Air pollution is linked to increased emergency room visits for headache, and migraine patients frequently cite chemicals or odors as headache triggers, but the association between air pollutants and headache is not well understood. We previously reported that nasal administration of environmental irritants acutely increases meningeal blood flow via a TRPA1-dependent mechanism involving the trigeminovascular system. Here, we examine whether chronic environmental irritant exposure sensitizes the trigeminovascular system. Methods Male rats were exposed to acrolein, a TRPA1 agonist, or room air by inhalation for four days prior to meningeal blood flow measurements. Some animals were injected daily with a TRPA1 antagonist, AP-18, or vehicle prior to inhalation exposure. Trigeminal ganglia were isolated following blood flow measurements for immunocytochemistry and/or qPCR determination of TRPV1, TRPA1 and CGRP levels. Results Acrolein inhalation exposure potentiated blood flow responses both to TRPA1 and TRPV1 agonists compared to room air. Acrolein exposure did not alter TRPV1 or TRPA1 mRNA levels or TRPV1 or CGRP immunoreactive cell counts in the trigeminal ganglion. Acrolein sensitization of trigeminovascular responses to a TRPA1 agonist was attenuated by pre-treatment with AP-18. Interpretation These results suggest trigeminovascular sensitization as a mechanism for enhanced headache susceptibility after chemical exposure.
Mechanisms of glyceryl trinitrate provoked mast cell degranulation
Authors: Pedersen Sara Hougaard , Ramachandran Roshni , Amrutkar Dipak Vasantrao , Petersen Steffen , Olesen Jes , Jansen-Olesen Inger 
Published: February 2015

Background Migraine patients develop attacks several hours after intravenous infusion of glyceryl trinitrate. Due to the short half-life of nitric oxide, this delayed migraine cannot be caused by a direct action of nitric oxide derived from glyceryl trinitrate. The involvement of meningeal inflammation and dural mast cell degranulation is supported by the effectiveness of prednisolone on glyceryl trinitrate-induced delayed headache. Methods Using a newly developed rat model mimicking the human glyceryl trinitrate headache model, we have investigated the occurrence of dural mast cell degranulation after a clinically relevant dose of glyceryl trinitrate. Results A 6-fold increase in degranulation was observed starting at 2 hours after glyceryl trinitrate infusion. Interestingly, pre-treatment with the effective anti-migraine substances L-nitro-arginine methyl ester and sumatriptan prevented glyceryl trinitrate-induced mast cell degranulation whereas the calcitonin gene-related peptide-receptor antagonist olcegepant and the substance P receptor antagonist L-733,060 did not affect mast cell degranulation. However, topical application of two different nitric oxide donors did not cause mast cell degranulation ex vivo. Conclusions Direct application of an exogenous nitric oxide donor on dural mast cells does not cause mast cell degranulation ex vivo. In vivo application of the nitric oxide donor glyceryl trinitrate leads to a prominent level of degranulation via a yet unknown mechanism. This effect can be completely blocked by inhibition of the endogenous nitric oxide production and by 5-HT1B/1D receptor agonists but is unaffected by calcitonin gene-related peptide and substance P receptor antagonists.