bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heparanase Enhances Local and Systemic Osteolysis in Multiple Myeloma by Upregulating the Expression and Secretion of RANKL
Authors: Yang Yang , Ren Yongsheng , Ramani Vishnu C. , Nan Li , Suva Larry J. , Sanderson Ralph D. 
Published: October 2010

Abstract
Excessive bone destruction is a major cause of morbidity in myeloma patients. However, the biological mechanisms involved in the pathogenesis of myeloma-induced bone disease are not fully understood. Heparanase, an enzyme that cleaves the heparan sulfate chains of proteoglycans, is upregulated in a variety of human tumors, including multiple myeloma. We previously showed that heparanase promotes robust myeloma tumor growth and supports spontaneous metastasis of tumor cells to bone. In the present study, we show, for the first time, that the expression of heparanase by myeloma tumor cells remarkably enhances bone destruction locally within the tumor microenvironment. In addition, enhanced heparanase expression in the primary tumor also stimulated systemic osteoclastogenesis and osteolysis, thus mimicking the systemic osteoporosis often seen in myeloma patients. These effects occur, at least in part, as the result of a significant elevation in the expression and secretion of receptor activator of NF-κB ligand (RANKL) by heparanase-expressing myeloma cells. Moreover, analysis of bone marrow biopsies from myeloma patients reveals a positive correlation between the level of expression of heparanase and RANKL. Together, these discoveries reveal a novel and key role for heparanase in promoting tumor osteolysis and show that RANKL is central to the mechanism of heparanase-mediated osteolysis in myeloma. Cancer Res; 70(21); 8329–38. ©2010 AACR.
von Hippel-Lindau–Dependent Patterns of RNA Polymerase II Hydroxylation in Human Renal Clear Cell Carcinomas
Authors: Yi Ying , Mikhaylova Olga , Mamedova Aygun , Bastola Prabhat , Biesiada Jacek , Alshaikh Enas , Levin Linda , Sheridan Rachel M. , Meller Jarek , Czyzyk-Krzeska Maria F. 
Published: October 2010

Abstract
Purpose: We have previously shown that von Hippel-Lindau (VHL) regulates ubiquitylation and proline 1465 hydroxylation of the large subunit of RNA polymerase II, Rpb1, in human renal clear cell carcinoma (RCC) cell lines. Here, our goal was to determine the effect of this VHL function and the status of P1465 hydroxylation in human RCC tumors.
Experimental Design: Primary human tumors and matched normal kidney samples were probed for expression levels of the large subunit of RNA polymerase II (Rpb1), Rpb1 hydroxylated on P1465 [Rpb1(OH)], Rpb1 phosphorylated on Ser5 [Rpb1(S5P)], and proline hydroxylases PHD1, PHD2, and PHD3. Results from RCC tumors were categorized according to the status of VHL gene. Mechanistic analysis was performed in orthotopic xenograft model using 786-O RCC cells with wild-type (WT) VHL and knockdown of PHD2, characterized by high levels of Rpb1(OH) and PHD1.
Results: Levels of Rpb1(OH), PHD1, and PHD2 were significantly higher in RCC tumors compared with normal kidneys. RCC tumors with WT VHL had higher levels of Rpb1(OH) and PHD1 and lower levels of PHD2 than tumors with VHL gene alterations. Levels of Rpb1(OH) significantly correlated with levels of PHD1 in tumors and normal kidneys. Knockdown of PHD2 in 786-O VHL(+) cells resulted in a more malignant phenotype in orthotopic xenografts and higher expression of specific cell cycle regulators (CDC25A, cyclin-dependent kinase 2, CCNA2) compared with VHL(−) RCC cells.
Conclusions: Elevated PHD1 concomitant with decreased PHD2 are causatively related to Rpb1 hydroxylation and oncogenesis in human RCC tumors with WT VHL gene. Thus, P1465-hydroxylated Rpb1 and PHD1 represent attractive drug targets for new RCC treatments. Clin Cancer Res; 16(21); 5142–52. ©2010 AACR.
A Novel Correlation between LINE-1 Hypomethylation and the Malignancy of Gastrointestinal Stromal Tumors
Authors: Igarashi Shinichi , Suzuki Hiromu , Niinuma Takeshi , Shimizu Haruo , Nojima Masanori , Iwaki Hiroyuki , Nobuoka Takayuki , Nishida Toshirou , Miyazaki Yasuaki , Takamaru Hiroyuki , Yamamoto Eiichiro , Yamamoto Hiroyuki , Tokino Takashi , Hasegawa Tadashi , Hirata Koichi , Imai Kohzoh , Toyota Minoru , Shinomura Yasuhisa 
Published: October 2010

Abstract
Purpose: Gastrointestinal stromal tumors (GIST) are the most important mesenchymal tumors of the gastrointestinal tract. The vast majority of GISTs exhibit activating mutations of KIT or PDGFRA, but epigenetic alteration of GISTs is largely unknown. In this study, we aimed to clarify the involvement of DNA methylation in GIST malignancy.
Experimental Design: A total of 106 GIST specimens were studied. Levels of LINE-1 methylation were analyzed using bisulfite pyrosequencing. In addition, methylation of three other repetitive sequences (Alu Yb8, Satellite-α, and NBL2) was similarly analyzed, and CpG island hypermethylation was analyzed using MethyLight. Array-based comparative genomic hybridization (array CGH) was carried out in 25 GIST specimens.
Results: LINE-1 hypomethylation was significantly correlated with risk, and high-risk GISTs exhibited significantly lower levels of LINE-1 methylation than low-risk (61.3% versus 53.2%; P = 0.001) or intermediate-risk GISTs (60.8% versus 53.2%; P = 0.002). Hypomethylation of Satellite-α and NBL2 was also observed in high-risk GISTs. By contrast, promoter hypermethylation was relatively infrequent (CDH1, 11.2%; MLH1, 9.8%; SFRP1, 1.2%; SFRP2, 11.0%; CHFR, 9.8%; APC, 6.1%; CDKN2A, 0%; RASSF1A, 0%; RASSF2, 0%) and did not correlate with LINE-1 methylation or risk. Array CGH analysis revealed a significant correlation between LINE-1 hypomethylation and chromosomal aberrations.
Conclusions: Our data suggest that LINE-1 hypomethylation correlates significantly with the aggressiveness of GISTs and that LINE-1 methylation could be a useful marker for risk assessment. Hypomethylation may increase the malignant potential of GISTs by inducing accumulation of chromosomal aberrations. Clin Cancer Res; 16(21); 5114–23. ©2010 AACR.
Cis-dichlorodiammineplatinum Upregulates Angiotensin II Type 1 Receptors through Reactive Oxygen Species Generation and Enhances VEGF Production in Bladder Cancer
Authors: Tanaka Nobuyuki , Miyajima Akira , Kosaka Takeo , Shirotake Suguru , Hasegawa Masanori , Kikuchi Eiji , Oya Mototsugu 
Published: October 2010

AbstractWe previously reported that angiotensin II type 1 receptor (AT1R) antagonists enhanced the cytotoxity of cis-dichlorodiammineplatinum (CDDP) in a bladder cancer xenograft model. To elucidate the synergistic mechanism, we investigated whether reactive oxygen species (ROS) generation induced by CDDP may affect the regulation of AT1R expression. Five invasive human bladder cancer cell lines, T24, UMUC-3, 5637, KU-1, and KU-19-19, were used in the in vitro study. For the in vivo study, T24 cells were used. We also examined AT1R and vascular endothelial growth factor (VEGF) expression in human bladder cancer specimens that had been treated with CDDP-based chemotherapy. The in vitro study showed that AT1R expression was significantly upregulated by CDDP in T24, KU-1, and KU-19-19 cells. On the other hand, AT1R expression was not changed in UMUC-3 and 5637 cells. ROS generation was also significantly upregulated by CDDP in T24, KU-1, and KU-19-19 cells. The upregulation of AT1R expression induced by CDDP was significantly suppressed by scavenging free radicals. Angiotensin II induced VEGF production in CDDP-treated cells; however, the AT1R antagonist significantly inhibited the increase in VEGF. The in vivo study results also showed that CDDP treatment upregulated AT1R expression, resulting in increased VEGF. Clinical specimens from patients who underwent cystectomy after neoadjuvant CDDP-based chemotherapy showed significantly higher AT1R and VEGF expression than corresponding transurethral resection specimens. Our findings indicate that CDDP upregulates AT1R expression though ROS generation and enhances VEGF production. Therefore, AT1R blockade may be an effective strategy for bladder cancer in combination with CDDP-based chemotherapy. Mol Cancer Ther; 9(11); 2982–92. ©2010 AACR.
Dual Inhibition of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor is an Effective Chemopreventive Strategy in the Mouse 4-NQO Model of Oral Carcinogenesis
Authors: Zhou Guolin , Hasina Rifat , Wroblewski Kristen , Mankame Tanmayi P. , Doçi Colleen L. , Lingen Mark W. 
Published: October 2010

Abstract
Despite recent therapeutic advances, several factors, including field cancerization, have limited improvements in long-term survival for oral squamous cell carcinoma (OSCC). Therefore, comprehensive treatment plans must include improved chemopreventive strategies. Using the 4-nitroquinoline 1-oxide (4-NQO) mouse model, we tested the hypothesis that ZD6474 (Vandetanib, ZACTIMA) is an effective chemopreventive agent. CBA mice were fed 4-NQO (100 μg/mL) in their drinking water for 8 weeks and then randomized to no treatment or oral ZD6474 (25 mg/kg/d) for 24 weeks. The percentage of animals with OSCC was significantly different between the two groups (71% in control and 12% in the ZD6474 group; P ≤ 0.001). The percentage of mice with dysplasia or OSCC was significantly different (96% in the control and 28% in the ZD6474 group; P ≤ 0.001). Proliferation and microvessel density scores were significantly decreased in the ZD6474 group (P ≤ 0.001 for both). Although proliferation and microvessel density increased with histologic progression in control and treatment cohorts, epidermal growth factor receptor and vascular endothelial growth factor receptor-2 phosphorylation was decreased in the treatment group for each histologic diagnosis, including mice harboring tumors. OSCC from ZD6474-treated mice exhibited features of epithelial to mesenchymal transition, as shown by loss E-cadherin and gain of vimentin protein expression. These data suggest that ZD6474 holds promise as an OSCC chemopreventive agent. They further suggest that acquired resistance to ZD6474 may be mediated by the expression of an epithelial to mesenchymal transition phenotype. Finally, the data suggests that this model is a useful preclinical platform to investigate the mechanisms of acquired resistance in the chemopreventive setting. Cancer Prev Res; 3(11); 1493–502. ©2010 AACR.
Clinical laboratory measurement of direct factor Xa inhibitors: Anti-Xa assay is preferable to prothrombin time assay
Authors: Wang Zhaoqing , Frost Charles , Shenker Andrew , Barrett Yu Chen 
Published: October 2010

SummaryApixaban and other factor Xa (FXa) inhibitors are in late-stage clinical development for prevention and treatment of thromboembolic diseases. Although routine monitoring will not be required, in certain situations assessment of drug level may be helpful. This study evaluated the suitability of commercially available prothrombin time/international normalised ratio (PT/INR) and anti-FXa activity assays to measure FXa inhibitors in plasma. Twelve PT (ISI 0.89ﺹ1.88) and three anti-Xa assays were evaluated in vitro using human plasma spiked with four FXa inhibitors (0ﺹ2,000 ng/ml). Assay variability and correlation with drug plasma exposure were evaluated in patients with venous thromboembolism (VTE) treated with apixaban. All FXa inhibitors prolonged PT; however, assay sensitivity was dependent on thromboplastin reagents used and FXa inhibitors tested. To achieve a doubling of PT, the concentration of each FXa inhibitor varied 2.6- to 8-fold between thromboplastin reagents. The rank order of a FXa inhibitor’s effect on PT ratio varied across thromboplastin reagents. Conversion to INR increased variability. Different anti-Xa assays showed different dynamic ranges for each FXa inhibitor; however, their rank order was consistent. For apixaban, the dynamic range of <7.8–240 ng/ml, and inter- and intra-assay precision of <6% coefficient of variation by Rotachrom assay appeared suitable for the anticipated apixaban plasma concentrations with 2.5 and 5 mg bid clinical doses. The stronger correlation between apixaban plasma concentration and anti-Xa activity (r2 = 0.88–0.89) compared with PT/INR (r2 = 0.36) in patients undergoing VTE treatment suggested that anti-Xa activity was the better indicator of apixaban plasma concentrations.
Facilitators and Barriers to Self-management of Type 2 Diabetes Among Urban African American Adults
Authors: Orr Chlebowy Diane , Hood Sula , LaJoie A. Scott 
Published: October 2010

Purpose The purpose of this study was to identify facilitators and barriers to self-management of type 2 diabetes mellitus (T2DM) among urban African American adults. Methods Thirty-eight African American adults with T2DM were recruited from 1 of 3 health care agencies in a midsized city in the southeastern United States. Qualitative data were obtained using focus groups, wherein each participant engaged in a 60- to 90-minute audio-recorded session. Focus group data were transcribed and analyzed using Atlas ti 6 ® data analysis software. Demographic and medical history information was also collected. Results Factors relating to external locus of control primarily facilitated adherence to T2DM self-management behaviors. Support from family, peers, and health care providers positively influenced adherence behaviors by providing cues to action, direct assistance, reinforcement, and knowledge. Internal factors were primarily described as barriers to self-management behaviors and included fears associated with glucose monitoring, lack of self-control over dietary habits, memory failure, and perceived lack of personal control over diabetes. Conclusions African Americans perceived external factors as facilitators of their T2DM management behaviors and internal factors as barriers to self-management. Further research is necessary to design and test interventions that capitalize on the external facilitators while helping African Americans to overcome perceived barriers identified in this study.
Spatio-temporal expression of a novel neuron-derived neurotrophic factor (NDNF) in mouse brains during development
Authors: Kuang Xiu-Li , Zhao Xiao-Mei , Xu Hai-Fang , Shi Yuan-Yuan , Deng Jin-Bo , Sun Guo-Tao 
Published: October 2010

Abstract

Background
Neuron-derived neurotrophic factor (NDNF) is evolutionarily well conserved, being present in invertebrate animals such as the nematode, Caenorhabditis elegans, as well as in the fruit fly, Drosophila melanogaster. Multiple cysteines are conserved between species and secondary structure prediction shows that NDNF is mainly composed of beta-strands. In this study, we aimed to investigate the function of NDNF.

Results
NDNF is a glycosylated, disulfide-bonded secretory protein that contains a fibronectin type III domain. NDNF promoted migration and growth and elicited neurite outgrowth of mouse hippocampal neurons in culture. NDNF also protected cultured hippocamal neurons against excitotoxicity and amyloid beta-peptide toxicity. Western blotting showed that NDNF was exclusively expressed in the brain and spinal cord. Immunostaining indicated that NDNF was expressed by neurons and not by astrocytes. Cajal-Retzius cells, cortex neurons, hippocampus neurons, olfactory mitral cells, cerebellar purkinje cells, cerebellar granular cells and spinal neurons were found to be NDNF-positive. NDNF expression was observed in the neurons during development.

Conclusions
The results of this study indicated that NDNF is a novel neurotrophic factor derived from neurons that may be useful in the treatment of neuronal degeneration diseases and nerve injuries.
Increased spinal prodynorphin gene expression in reinflammation-associated hyperalgesia after neonatal inflammatory insult
Authors: Lin Jack Yu-Shih , Cheng Yu-Che , Chen Julia Yi-Ru , Chien Chih-Cheng , Lin Shih-Chang , Wen Yeong-Ray , Tsou Tsung-Shan , Ling Qing-Dong 
Published: October 2010

AbstractBackgroundNeuroplasticity induced by neonatal inflammation is the consequence of a combination of activity-dependent changes in neurons. We investigated neuronal sensitivity to a noxious stimulus in a rat model of neonatal hind-paw peripheral inflammation and assessed changes in pain behaviour at the physiological and molecular levels after peripheral reinflammation in adulthood.ResultsA decrease in paw withdrawal latency (PWL) after a heat stimulus was documented in rats that received inflammatory injections in their left hind paws on postnatal day one (P1) and a reinflammation stimulus at postnatal 6-8 weeks of age, compared with normal rats. An increase in the expression of the prodynorphin (proDYN) gene was noted after reinflammation in the spinal cord ipsilateral to the afferents of the neonatally treated hind paw. The involvement of the activation of extracellular signal-regulated kinases (ERK) in peripheral inflammatory pain hypersensitivity was evidenced evident by the increase in phospho-ERK (pERK) activity after reinflammation.ConclusionsOur results indicate that peripheral inflammation in neonates can permanently alter the pain processing pathway during the subsequent sensory stimulation of the region. Elucidation of the mechanism underlying the developing pain circuitry will provide new insights into the understanding of the early pain behaviours and the subsequent adaptation to pain.
Risk of placental abruption in relation to migraines and headaches
Authors: Sanchez Sixto E , Williams Michelle A , Pacora Percy N , Ananth Cande V , Qiu Chungfang , Aurora Sheena K , Sorensen Tanya K 
Published: October 2010

AbstractBackgroundMigraine, a common chronic-intermittent disorder of idiopathic origin characterized by severe debilitating headaches and autonomic nervous system dysfunction, and placental abruption, the premature separation of the placenta, share many common pathophysiological characteristics. Moreover, endothelial dysfunction, platelet activation, hypercoagulation, and inflammation are common to both disorders. We assessed risk of placental abruption in relation to maternal history of migraine before and during pregnancy in Peruvian women.MethodsCases were 375 women with pregnancies complicated by placental abruption, and controls were 368 women without an abruption. During in-person interviews conducted following delivery, women were asked if they had physician-diagnosed migraine, and they were asked questions that allowed headaches and migraine to be classified according to criteria established by the International Headache Society. Logistic regression procedures were used to calculate odds ratios (aOR) and 95% confidence intervals (CI) adjusted for confounders.ResultsOverall, a lifetime history of any headaches or migraine was associated with an increased odds of placental abruption (aOR = 1.60; 95% CI 1.16-2.20). A lifetime history of migraine was associated with a 2.14-fold increased odds of placental abruption (aOR = 2.14; 95% CI 1.22-3.75). The odds of placental abruption was 2.11 (95% CI 1.00-4.45) for migraineurs without aura; and 1.59 (95% 0.70-3.62) for migraineurs with aura. A lifetime history of tension-type headache was also increased with placental abruption (aOR = 1.61; 95% CI 1.01-2.57).ConclusionsThis study adds placental abruption to a growing list of pregnancy complications associated with maternal headache/migraine disorders. Nevertheless, prospective cohort studies are needed to more rigorously evaluate the extent to which migraines and/or its treatments are associated with the occurrence of placental abruption.
Aberrant expression and constitutive activation of STAT3 in cervical carcinogenesis: implications in high-risk human papillomavirus infection
Authors: Shukla Shirish , Shishodia Gauri , Mahata Sutapa , Hedau Suresh , Pandey Arvind , Bhambhani Suresh , Batra Swaraj , Basir Seemi F , Das Bhudev C , Bharti Alok C 
Published: October 2010

AbstractBackgroundRecent observations indicate potential role of transcription factor STAT3 in cervical cancer development but its role specifically with respect to HPV infection is not known. Present study has been designed to investigate expression and activation of STAT3 in cervical precancer and cancer in relation to HPV infection during cervical carcinogenesis. Established cervical cancer cell lines and prospectively-collected cervical precancer and cancer tissues were analyzed for the HPV positivity and evaluated for STAT3 expression and its phosphorylation by immunoblotting and immunohistochemistry whereas STAT3-specific DNA binding activity was examined by gel-shift assays.ResultsAnalysis of 120 tissues from cervical precancer and cancer lesions or from normal cervix revealed differentially high levels of constitutively active STAT3 in cervical precancer and cancer lesions, whereas it was absent in normal controls. Similarly, a high level of constitutively active STAT3 expression was observed in HPV-positive cervical cancer cell lines when compared to that of HPV-negative cells. Expression and activity of STAT3 were found to change as a function of severity of cervical lesions from precancer to cancer. Expression of active pSTAT3 was specifically high in cervical precancer and cancer lesions found positive for HPV16. Interestingly, site-specific accumulation of STAT3 was observed in basal and suprabasal layers of HPV16-positive early precancer lesions which is indicative of possible involvement of STAT3 in establishment of HPV infection. In HPV16-positive cases, STAT3 expression and activity were distinctively higher in poorly-differentiated lesions with advanced histopathological grades.ConclusionWe demonstrate that in the presence of HPV16, STAT3 is aberrantly-expressed and constitutively-activated in cervical cancer which increases as the lesion progresses thus indicating its potential role in progression of HPV16-mediated cervical carcinogenesis.
Intravenous Opioids for Severe Acute Pain in the Emergency Department
Authors: Patanwala Asad E , Keim Samuel M , Erstad Brian L 
Published: October 2010

Objective:To review clinical trials of intravenous opioids for severe acute pain in the emergency department (ED) and to provide an approach for optimization of therapy.Data Sources:Articles were identified through a search of Ovid/MEDLINE (1948-August 2010), PubMed (1950-August 2010), Cochrane Central Register of Controlled Trials (1991-August 2010), and Google Scholar (1900-August 2010). The search terms used were pain, opioid, and emergency department.Study Selection and Data Extraction:The search was limited by age group to adults and by publication type to comparative studies. Studies comparing routes of administration other than intravenous or using non-opioid comparators were not included. Bibliographies of all retrieved articles were reviewed to obtain additional articles. The focus of the search was to identify original research that compared intravenous opioids used for treatment of severe acute pain for adults in the ED.Data Synthesis:At equipotent doses, randomized controlled trials have not shown clinically significant differences in analgesic response or adverse effects between opioids studied. Single opioid doses less than 0.1 mg/kg of intravenous morphine, 0.015 mg/kg of intravenous hydromorphone, or 1 μg/kg of intravenous fentanyl are likely to be inadequate for severe, acute pain and the need for additional doses should be anticipated. In none of the randomized controlled trials did patients develop respiratory depression requiring the use of naloxone. Future trials could investigate the safety and efficacy of higher doses of opioids. Implementation of nurse-initiated and patient-driven pain management protocols for opioids in the ED has shown improvements in timely provision of appropriate analgesics and has resulted in better pain reduction.Conclusions:Currently, intravenous administration of opioids for severe acute pain in the ED appears to be inadequate. Opioid doses in the ED should be high enough to provide adequate analgesia without additional risk to the patient. EDs could implement institution-specific protocols to standardize the management of pain.