bluuebunny/crossref_metadata_2025_split huggingface dataset:
Angiotensin II causes cellular proliferation in infantile haemangioma via angiotensin II receptor 2 activation
Authors: Itinteang Tinte , Marsh Reginald , Davis Paul Frank , Tan Swee Thong 
Published: February 2015

AimsTo investigate the effect of the angiotensin peptides and their agonists and antagonists on cellular proliferation in proliferating infantile haemangioma (IH) in vitro explants.MethodsProliferating IH samples from six patients were cultured in vitro in the presence of angiotensin I (ATI) alone, or AT1 and the ACE inhibitor, ramipril, or ATII alone, or ATII with the ATII receptor 1 (ATIIR1) blocker, losartan, or ATII with the ATIIR2 blocker, PD123319, or the ATIIR2 agonist, CGP42112. After 6 days in culture, the IH tissue pieces were harvested, formalin-fixed and paraffin-embedded. The effect of each treatment type on cellular proliferation was evaluated by immunohistochemical staining of these tissue pieces using the proliferation marker, Ki67.ResultsThere was a significant increase in cellular proliferation in the ATI and ATII treated IH tissues compared with control samples. Their effect on cellular proliferation was reduced by adding ramipril and PD123319, respectively. CGP42112, but not losartan, significantly increased cellular proliferation.ConclusionsOur findings suggest a key regulatory role of ATI and ATII in promoting cellular proliferation in IH, and establish a role for ACE and ATIIR2 in the proliferation of this tumour.
Are fluoride levels in drinking water associated with hypothyroidism prevalence in England? A large observational study of GP practice data and fluoride levels in drinking water
Authors: Peckham S , Lowery D , Spencer S 
Published: February 2015

BackgroundWhile previous research has suggested that there is an association between fluoride ingestion and the incidence of hypothyroidism, few population level studies have been undertaken. In England, approximately 10% of the population live in areas with community fluoridation schemes and hypothyroidism prevalence can be assessed from general practice data. This observational study examines the association between levels of fluoride in water supplies with practice level hypothyroidism prevalence.MethodsWe used a cross-sectional study design using secondary data to develop binary logistic regression models of predictive factors for hypothyroidism prevalence at practice level using 2012 data on fluoride levels in drinking water, 2012/2013 Quality and Outcomes Framework (QOF) diagnosed hypothyroidism prevalence data, 2013 General Practitioner registered patient numbers and 2012 practice level Index of Multiple Deprivation scores.FindingsWe found that higher levels of fluoride in drinking water provide a useful contribution for predicting prevalence of hypothyroidism. We found that practices located in the West Midlands (a wholly fluoridated area) are nearly twice as likely to report high hypothyroidism prevalence in comparison to Greater Manchester (non-fluoridated area).InterpretationIn many areas of the world, hypothyroidism is a major health concern and in addition to other factors—such as iodine deficiency—fluoride exposure should be considered as a contributing factor. The findings of the study raise particular concerns about the validity of community fluoridation as a safe public health measure.
Case ascertainment of heat illness in the British Army: evidence of under-reporting from analysis of Medical and Command notifications, 2009–2013
Authors: Stacey Michael J , Brett S , Woods D , Jackson S , Ross D 
Published: February 2015

BackgroundHeat illness in the Armed Forces is considered preventable. The UK military relies upon dual Command and Medical reporting for case ascertainment, investigation of serious incidents and improvement of preventive practices and policy. This process could be vulnerable to under-reporting.ObjectivesTo establish whether heat illness in the British Army has been under-reported, by reviewing concordance of reporting to the Army Incident Notification Cell (AINC) and the Army Health Unit (AHU) and to characterise the burden of heat illness reported by these means.MethodsAnalysis of anonymised reporting databases held by the AHU and AINC, for the period 2009–2013.Results565 unique cases of heat illness were identified. Annual concordance of reporting ranged from 9.6% to 16.5%. The overall rate was 13.3%. July was the month with the greatest number of heat illness reports (24.4% of total reporting) and the highest concordance rate (30%). Reports of heat illness from the UK (n=343) exceeded overseas notifications (n=221) and showed better concordance (17.1% vs 12.8%). The annual rate of reported heat illness varied widely, being greater in full-time than reservist personnel (87 vs 23 per100 000) and highest in full-time untrained personnel (223 per100 000).ConclusionsThe risk of heat illness was global, year-round and showed dynamic local variation. Failure to dual-report casualties impaired case ascertainment of heat illness across Command and Medical chains. Current preventive guidance, as applied in training and on operations, should be critically evaluated to ensure that risk of heat illness is reduced as low as possible. Clear procedures for casualty notification and surveillance are required in support of this and should incorporate communication within and between the two reporting chains.
Open abdomen and VAC®in severe diffuse peritonitis
Authors: Mutafchiyski Ventsislav M , Popivanov G I , Kjossev K T , Chipeva S 
Published: February 2015

BackgroundCurrently, the open abdomen technique is the widely recognised method for treatment of life-threatening trauma, intra-abdominal sepsis, abdominal compartment syndrome and wound dehiscence. The techniques for temporary closure using negative pressure have gained increasing popularity. Although negative pressure wound therapy has been proved as an effective method in trauma, the results in diffuse peritonitis are contradictory.MethodsOverall, 108 patients with diffuse peritonitis and open abdomen were prospectively enrolled from January 2006 to December 2013—69 treated with mesh-foil laparostomy without negative pressure and 49 with vacuum-assisted closure (VAC®) The primary endpoints were the rate of primary fascial closure and mortality. The secondary outcomes were the rate of complications—enteroatmospheric fistulas, intra-abdominal abscesses, wound infection and necrotising fasciitis, intensive care unit (ICU) and overall hospital stay.ResultsVAC was associated with higher overall (73% vs 53%) and late primary fascial closure rates (31% vs 7%), lower rates of necrotising fasciitis (2% vs 15%, p=0.012), intra-abdominal abscesses (10% vs 20%), enteroatmospheric fistulas (8% vs 19%), overall mortality (31% vs 53%, p<0.05), shorter ICU (6.1 vs 10.6 days, p=0.002) and hospital stay (15.1 vs 25.9 days, p=0.000).ConclusionsThe results clearly suggest the obvious advantage of VAC in comparison to the temporary abdominal closure without negative pressure in the cases with severe diffuse peritonitis. However, to a large extent, our results might be attributed to the combination of VAC with dynamic fascial closure.
Determination of the minimum infusion rate of alfaxalone during its co‐administration with midazolam in goats
Authors: Dzikiti T. B. , Ndawana P. S. , Zeiler G. , Bester L. , Dzikiti L. N. 
Published: February 2015

IntroductionThe minimum infusion rate (MIR) of alfaxalone when co‐administered with midazolam in goats was evaluated.Materials and methodsEight goats (four does and four wethers) were anaesthetised, on separate occasions, with alfaxalone at an initial dose of 9.6 mg/kg/hour combined with one of three midazolam treatments: a bolus of 0.1 mg/kg followed by constant rate infusion (CRI) of 0.1 mg/kg/hour (treatment LMID), 0.3 mg/kg followed by CRI of 0.3 mg/kg/hour (MMID), 0.9 mg/kg followed by CRI of 0.9 mg/kg/hour (HMID), intravenously. Responses to stimulation (clamping on the proximal part of one digit of the hoof with Vulsellum forceps for 60 seconds) were tested every 30 minutes. In the absence or presence of a response to stimulation, the infusion rate was reduced or increased by 1.9 mg/kg/hour. Alfaxalone MIR was calculated as the mean of the infusion rates that allowed and abolished movement. Cardiopulmonary parameters were measured.ResultsAlfaxalone MIR was 6.7 (6.7–8.6) mg/kg/hour, 6.7 (4.8–6.7) mg/kg/hour and 2.9 (1.0–4.8) mg/kg/hour for LMID, MMID and HMID respectively. Cardiopulmonary function was minimally affected, with hypoxaemia observed two minutes into anaesthesia during all treatments. Recovery from anaesthesia was excitement‐free.ConclusionsMidazolam causes a dose‐dependent reduction of alfaxalone MIR in goats. Oxygen supplementation is recommended during anaesthesia with alfaxalone and midazolam in goats.
Bridge numbers for virtual and welded knots
Authors: Boden Hans U. , Gaudreau Anne Isabel 
Published: February 2015

Using Gauss diagrams, one can define the virtual bridge number vb (K) and the welded bridge number wb (K), invariants of virtual and welded knots satisfying wb (K) ≤ vb (K). If K is a classical knot, Chernov and Manturov showed that vb (K) = br (K), the bridge number as a classical knot, and we ask whether the same thing is true for welded knots. The welded bridge number is bounded below by the meridional rank of the knot group GK, and we use this to relate this question to a conjecture of Cappell and Shaneson. We show how to use other virtual and welded invariants to further investigate bridge numbers. Among them are Manturov's parity and the reduced virtual knot group ḠK, and we apply these methods to address Questions 6.1–6.3 and 6.5 raised by Hirasawa, Kamada and Kamada in their paper [Bridge presentation of virtual knots, J. Knot Theory Ramifications 20(6) (2011) 881–893].
Small-Molecule ONC201/TIC10 Targets Chemotherapy-Resistant Colorectal Cancer Stem–like Cells in an Akt/Foxo3a/TRAIL–Dependent Manner
Authors: Prabhu Varun V. , Allen Joshua E. , Dicker David T. , El-Deiry Wafik S. 
Published: February 2015

Abstract
Self-renewing colorectal cancer stem/progenitor cells (CSC) contribute to tumor maintenance and resistance to therapy. Therapeutic targeting of CSCs could improve treatment response and prolong patient survival. ONC201/TIC10 is a first-in-class antitumor agent that induces TRAIL pathway–mediated cell death in cancer cells without observed toxicity. We have previously described that ONC201/TIC10 exposure leads to transcriptional induction of the TRAIL gene via transcription factor Foxo3a, which is activated by dual inactivation of Akt and ERK. The Akt and ERK pathways serve as important targets in CSCs. Foxo3a is a key mediator of Akt and ERK-mediated CSC regulation. We hypothesized that the potent antitumor effect of ONC201/TIC10 in colorectal cancer involves targeting CSCs and bulk tumor cells. ONC201/TIC10 depletes CD133+, CD44+, and Aldefluor+ cells in vitro and in vivo. TIC10 significantly inhibits colonosphere formation of unsorted and sorted 5-fluorouracil–resistant CSCs. ONC201/TIC10 significantly reduces CSC-initiated xenograft tumor growth in mice and prevents the passage of these tumors. ONC201/TIC10 treatment also decreased xenograft tumor initiation and was superior to 5-fluorouracil treatment. Thus, ONC201/TIC10 inhibits CSC self-renewal in vitro and in vivo. ONC201/TIC10 inhibits Akt and ERK, consequently activating Foxo3a and significantly induces cell surface TRAIL and DR5 expression in both CSCs and non-CSCs. ONC201/TIC10-mediated anti-CSC effect is significantly blocked by the TRAIL sequestering antibody RIK-2. Overexpression of Akt, DR5 knockdown, and Foxo3a knockdown rescues ONC201/TIC10-mediated depletion of CD44+ cells and colonosphere inhibition. In conclusion, ONC201/TIC10 is a promising agent for colorectal cancer therapy that targets both non-CSCs and CSCs in an Akt–Foxo3a–TRAIL–dependent manner. Cancer Res; 75(7); 1423–32. ©2015 AACR.
Usp28 Counteracts Fbw7 in Intestinal Homeostasis and Cancer
Authors: Diefenbacher Markus E. , Chakraborty Atanu , Blake Sophia M. , Mitter Richard , Popov Nikita , Eilers Martin , Behrens Axel 
Published: February 2015

Abstract
The stability of several oncoproteins, including c-Myc, is regulated by ubiquitin-dependent degradation mediated by the SCF(Fbw7) ubiquitin ligase. This activity is antagonized by the deubiquitinase Usp28, which is highly expressed in murine and human intestinal cancers. Usp28 was previously shown to interact with its substrates via a “piggyback” interaction with Fbw7, which suggested that Fbw7 is required for Usp28 activity. Unexpectedly, we found that genetic deletion of Usp28 rescued the lethality of Fbw7-deficient primary fibroblasts. Moreover, Usp28 inactivation in the intestine (Usp28ΔIEC) ameliorated the hyperproliferation and the impaired goblet and Paneth cell differentiation observed in Fbw7ΔIEC mice. The aggressive intestinal tumor formation of APCMin/+; Fbw7ΔIEC mice was restrained when Usp28 was inactivated concomitantly. In both fibroblasts and intestinal cells, Usp28 deficiency corrected the accumulation of SCF(Fbw7) substrate proteins, including NICD1, c-Jun, and c-Myc. These findings suggested that Usp28 function does not depend on the presence of Fbw7, but instead independently recognizes and deubiquitylates the same substrates as SCF(Fbw7). Fbw7 binds to a phosphorylated motif termed the phosphodegron and we found that Usp28 also interacted with this same motif, but only when it is unphosphorylated, offering a mechanistic explanation for identical substrate selection by Fbw7 and Usp28. Our results indicate an unusually direct antagonism between an E3 ligase and a deubiquitinase, Fbw7 and Usp28, in modulating intestinal homeostasis and cancer. Cancer Res; 75(7); 1181–6. ©2015 AACR.
MyD88-Dependent Signaling Decreases the Antitumor Efficacy of Epidermal Growth Factor Receptor Inhibition in Head and Neck Cancer Cells
Authors: Koch Adam T. , Love-Homan Laurie , Espinosa-Cotton Madelyn , Stanam Aditya , Simons Andrean L. 
Published: February 2015

Abstract
EGFR is upregulated in the majority of head and neck squamous cell carcinomas (HNSCC). However, many patients with HNSCC respond poorly to the EGFR inhibitors (EGFRI) cetuximab and erlotinib, despite tumor expression of EGFR. Gene expression analysis of erlotinib-treated HNSCC cells revealed an upregulation of genes involved in MyD88-dependent signaling compared with their respective vehicle-treated cell lines. We therefore investigated whether MyD88-dependent signaling may reduce the antitumor efficacy of EGFRIs in HNSCC. Erlotinib significantly upregulated IL6 secretion in HNSCC cell lines, which our laboratory previously reported to result in reduced drug efficacy. Suppression of MyD88 expression blocked erlotinib-induced IL6 secretion in vitro and increased the antitumor activity of erlotinib in vivo. There was little evidence of Toll-like receptor or IL18 receptor involvement in erlotinib-induced IL6 secretion. However, suppression of IL1R signaling significantly reduced erlotinib-induced IL6 production. A time-dependent increase of IL1α but not IL1β was observed in response to erlotinib treatment, and IL1α blockade significantly increased the antitumor activity of erlotinib and cetuximab in vivo. A pan-caspase inhibitor reduced erlotinib-induced IL1α secretion, suggesting that IL1α was released because of cell death. Human HNSCC tumors showed higher IL1α mRNA levels compared with matched normal tissue, and IL1α was found to be negatively correlated with survival in patients with HNSCC. Overall, the IL1α/IL1R/MYD88/IL6 pathway may be responsible for the reduced antitumor efficacy of erlotinib and other EGFRIs, and blockade of IL1 signaling may improve the efficacy of EGFRIs in the treatment of HNSCC. Cancer Res; 75(8); 1657–67. ©2015 AACR.
Dietary Microbes Modulate Transgenerational Cancer Risk
Authors: Poutahidis Theofilos , Varian Bernard J. , Levkovich Tatiana , Lakritz Jessica R. , Mirabal Sheyla , Kwok Caitlin , Ibrahim Yassin M. , Kearney Sean M. , Chatzigiagkos Antonis , Alm Eric J. , Erdman Susan E. 
Published: February 2015

AbstractEnvironmental factors are suspected in the increase of obesity and cancer in industrialized countries but are poorly understood. Here, we used animal models to test how future generations may be affected by Westernized diets. We discover long-term consequences of grandmothers' in utero dietary exposures, leading to high rates of obesity and frequent cancers of lung and liver in two subsequent generations of mice. Transgenerational effects were transplantable using diet-associated bacteria communities alone. Consequently, feeding of beneficial microbes was sufficient to lower transgenerational risk for cancer and obesity regardless of diet history. Targeting microbes may be a highly effective population-based approach to lower risk for cancer. Cancer Res; 75(7); 1197–204. ©2015 AACR.
PDK1 and SGK3 Contribute to the Growth of BRAF-Mutant Melanomas and Are Potential Therapeutic Targets
Authors: Scortegagna Marzia , Lau Eric , Zhang Tongwu , Feng Yongmei , Sereduk Chris , Yin Hongwei , De Surya K. , Meeth Katrina , Platt James T. , Langdon Casey G. , Halaban Ruth , Pellecchia Maurizio , Davies Michael A. , Brown Kevin , Stern David F. , Bosenberg Marcus , Ronai Ze'ev A. 
Published: February 2015

Abstract
Melanoma development involves members of the AGC kinase family, including AKT, PKC, and, most recently, PDK1, as elucidated recently in studies of Braf::Pten mutant melanomas. Here, we report that PDK1 contributes functionally to skin pigmentation and to the development of melanomas harboring a wild-type PTEN genotype, which occurs in about 70% of human melanomas. The PDK1 substrate SGK3 was determined to be an important mediator of PDK1 activities in melanoma cells. Genetic or pharmacologic inhibition of PDK1 and SGK3 attenuated melanoma growth by inducing G1 phase cell-cycle arrest. In a synthetic lethal screen, pan-PI3K inhibition synergized with PDK1 inhibition to suppress melanoma growth, suggesting that focused blockade of PDK1/PI3K signaling might offer a new therapeutic modality for wild-type PTEN tumors. We also noted that responsiveness to PDK1 inhibition associated with decreased expression of pigmentation genes and increased expression of cytokines and inflammatory genes, suggesting a method to stratify patients with melanoma for PDK1-based therapies. Overall, our work highlights the potential significance of PDK1 as a therapeutic target to improve melanoma treatment. Cancer Res; 75(7); 1399–412. ©2015 AACR.
The Ovarian Cancer Chemokine Landscape Is Conducive to Homing of Vaccine-Primed and CD3/CD28–Costimulated T Cells Prepared for Adoptive Therapy
Authors: Zsiros Emese , Duttagupta Priyanka , Dangaj Denarda , Li Hongzhe , Frank Renee , Garrabrant Thomas , Hagemann Ian S. , Levine Bruce L. , June Carl H. , Zhang Lin , Wang Ena , Marincola Francesco M. , Bedognetti Davide , Powell Daniel J. , Tanyi Janos , Feldman Michael D. , Kandalaft Lana E. , Coukos George 
Published: February 2015

Abstract
Purpose: Chemokines are implicated in T-cell trafficking. We mapped the chemokine landscape in advanced stage ovarian cancer and characterized the expression of cognate receptors in autologous dendritic cell (DC)–vaccine primed T cells in the context of cell-based immunotherapy.
Experimental Design: The expression of all known human chemokines in patients with primary ovarian cancer was analyzed on two independent microarray datasets and validated on tissue microarray. Peripheral blood T cells from five HLA-A2 patients with recurrent ovarian cancer, who previously received autologous tumor DC vaccine, underwent CD3/CD28 costimulation and expansion ex vivo. Tumor-specific T cells were identified by HER2/neu pentamer staining and were evaluated for the expression and functionality of chemokine receptors important for homing to ovarian cancer.
Results: The chemokine landscape of ovarian cancer is heterogeneous with high expression of known lymphocyte-recruiting chemokines (CCL2, CCL4, and CCL5) in tumors with intraepithelial T cells, whereas CXCL10, CXCL12, and CXCL16 are expressed quasi-universally, including in tumors lacking tumor-infiltrating T cells. DC-vaccine primed T cells were found to express the cognate receptors for the above chemokines. Ex vivo CD3/CD28 costimulation and expansion of vaccine-primed Tcells upregulated CXCR3 and CXCR4, and enhanced their migration toward universally expressed chemokines in ovarian cancer.
Conclusions: DC-primed tumor-specific T cells are armed with the appropriate receptors to migrate toward universal ovarian cancer chemokines, and these receptors are further upregulated by ex vivo CD3/CD28 costimulation, which render T cells more fit for migrating toward these chemokines. Clin Cancer Res; 21(12); 2840–50. ©2015 AACR.
Intracellular Targeting of the Oncogenic MUC1-C Protein with a Novel GO-203 Nanoparticle Formulation
Authors: Hasegawa Masanori , Sinha Raj Kumar , Kumar Manoj , Alam Maroof , Yin Li , Raina Deepak , Kharbanda Akriti , Panchamoorthy Govind , Gupta Dikshi , Singh Harpal , Kharbanda Surender , Kufe Donald 
Published: February 2015

Abstract
Purpose: The MUC1-C oncoprotein is an intracellular target that is druggable with cell-penetrating peptide inhibitors. However, development of peptidyl drugs for treating cancer has been a challenge because of unfavorable pharmacokinetic parameters and limited cell-penetrating capabilities.
Experimental Design: Encapsulation of the MUC1-C inhibitor GO-203 in novel polymeric nanoparticles was studied for effects on intracellular targeting of MUC1-C signaling and function.
Results: Our results show that loading GO-203 into tetrablock polylactic acid (PLA)-polyethylene glycol (PEG)-polypropylene glycol (PPG)-PEG copolymers is achievable and, notably, is enhanced by increasing PEG chain length. In addition, we found that release of GO-203 from these nanoparticles is controllable over at least 7 days. GO-203/nanoparticle treatment of MUC1-C–positive breast and lung cancer cells in vitro was more active with less frequent dosing than that achieved with nonencapsulated GO-203. Moreover, treatment with GO-203/nanoparticles blocked MUC1-C homodimerization, consistent with on-target effects. GO-203/nanoparticle treatment was also effective in downregulating TIGAR, disrupting redox balance, and inhibiting the self-renewal capacity of cancer cells. Significantly, weekly administration of GO-203/nanoparticles to mice bearing syngeneic or xenograft tumors was associated with regressions that were comparable with those found when dosing on a daily basis with GO-203.
Conclusions: These findings thus define an effective approach for (i) sustained administration of GO-203 in polymeric PLA-(PEG-PPG-PEG) nanoparticles to target MUC1-C in cancer cells and (ii) the potential delivery of other anticancer peptide drugs. Clin Cancer Res; 21(10); 2338–47. ©2015 AACR.