bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reticuloendotheliosis Virus Strain T Induces miR-155, Which Targets JARID2 and Promotes Cell Survival
Authors: Bolisetty Mohan T. , Dy George , Tam Wayne , Beemon Karen L. 
Published: September 2009

ABSTRACTThe oncogenic microRNA miR-155 is upregulated by several oncogenic viruses. The precursor of miR-155, termedbic, was first observed to cooperate withmycin chicken B-cell lymphomas induced by avian leukosis proviral integrations. We identified another oncogenic retrovirus, reticuloendotheliosis virus strain T (REV-T), that upregulates miR-155 in chicken embryo fibroblasts. We also observed very high levels of miR-155 in REV-T-induced B-cell lymphomas. To study the role of miR-155 in these tumors, we identified JARID2/Jumonji, a cell cycle regulator and part of a histone methyltransferase complex, as a target of miR-155. The overexpression of miR-155 decreased levels of endogenous JARID2 mRNA. We confirmed that miR-155 directly targets both human and chicken JARID2 by assaying the repression of reporters containing the JARID2 3′-untranslated regions. Further, the overexpression of a sponge complementary to miR-155 in a tumor cell line increased endogenous JARID2 mRNA levels. The overexpression of JARID2 in chicken fibroblasts led to decreased cell numbers and an increase in apoptotic cells. The overexpression of miR-155 rescued cells undergoing cytopathic effect caused by infection with subgroup B avian retroviruses. Therefore, we propose that miR-155 has a prosurvival function that is mediated through the downregulation of targets including JARID2.
Dephosphorylation of eIF2α Mediated by the γ
1
34.5 Protein of Herpes Simplex Virus 1 Facilitates Viral Neuroinvasion
Authors: Verpooten Dustin , Feng Zongdi , Valyi-Nagy Tibor , Ma Yijie , Jin Huali , Yan Zhipeng , Zhang Cuizhu , Cao Youjia , He Bin 
Published: September 2009

ABSTRACT

The γ
1
34.5 protein, a virulence factor of herpes simplex viruses, redirects protein phosphatase 1 to dephosphorylate the α subunit of translation initiation factor 2 (eIF2α). Additionally, it inhibits the induction of antiviral genes by TANK-binding kinase 1. Nevertheless, its precise role in vivo remains to be established. Here we show that eIF2α dephosphorylation by γ
1
34.5 is crucial for viral neuroinvasion. V
193
E and F
195
L substitutions in γ
1
34.5 abrogate viral replication in the eye and spread to the trigeminal ganglia and brain. Intriguingly, inhibition of antiviral gene induction by γ
1
34.5 is not sufficient to exhibit viral virulence.
Maribavir Inhibits Epstein-Barr Virus Transcription in Addition to Viral DNA Replication
Authors: Wang Fu-Zhang , Roy Debasmita , Gershburg Edward , Whitehurst Christopher B. , Dittmer Dirk P. , Pagano Joseph S. 
Published: September 2009

ABSTRACT

Although many drugs inhibit the replication of Epstein-Barr virus (EBV) in cell culture systems, there is still no drug that is effective and approved for use in primary EBV infection. More recently, maribavir (MBV), an
l
-ribofuranoside benzimidazole, has been shown to be a potent and nontoxic inhibitor of EBV replication and to have a mode of action quite distinct from that of acyclic nucleoside analogs such as acyclovir (ACV) that is based primarily on MBV's ability to block the phosphorylation of target proteins by EBV and human cytomegalovirus protein kinases. However, since the antiviral mechanisms of the drug are complex, we have carried out a comprehensive analysis of the effects of MBV on the RNA expression levels of all EBV genes with a quantitative real-time reverse transcription-PCR-based array. We show that in comparisons with ACV, the RNA expression profiles produced by the two drugs are entirely different, with MBV causing a pronounced inhibition of multiple viral mRNAs and with ACV causing virtually none. The results emphasize the different modes of action of the two drugs and suggest that the action of MBV may be linked to indirect effects on the transcription of EBV genes through the interaction of BGLF4 with multiple viral proteins.
A Role for the Clock Gene Per1 in Prostate Cancer
Authors: Cao Qi , Gery Sigal , Dashti Azadeh , Yin Dong , Zhou Yan , Gu Jiang , Koeffler H. Phillip 
Published: September 2009

Abstract
Circadian rhythms regulate diverse physiologic processes, including homeostatic functions of steroid hormones and their receptors. Perturbations of these rhythms are associated with pathogenic conditions, such as depression, diabetes, and cancer. Androgens play an important role in both normal development and carcinogenesis of the prostate. In the present study, we investigated a potential role for the core clock factor Per1 in the pathogenesis of prostate cancer. Serum-shocked synchronized prostate cancer cells displayed disrupted circadian rhythms compared with the normal prostate tissue. Using Oncomine to perform a meta-analysis of microarray expression studies, we found that Per1 is down-regulated in human prostate cancer samples compared with normal prostates. Reporter assays showed that Per1 inhibited transactivation of the androgen receptor (AR) both in 293T cells overexpressing the AR and in the prostate cancer cell line LNCaP. Forced expression of Per1 in LNCaP cells diminished the expression of known androgen-sensitive genes following stimulation with dihydrotestosterone. We showed that Per1 physically interacted with AR; in addition, we found that Per1 itself is regulated by androgens in prostate cancer cells. Overexpression of Per1 in prostate cancer cells resulted in significant growth inhibition and apoptosis. Our results support the emerging role of circadian genes as key players in malignant transformation. Further elucidating the connections between clock genes and the AR pathway could benefit the development of new therapeutic strategies for prostate cancer as well as provide insights into chronotherapy as a way to optimize current therapies. [Cancer Res 2009;69(19):7619–25]
Lessons from Applied Ecology: Cancer Control Using an Evolutionary Double Bind
Authors: Gatenby Robert A. , Brown Joel , Vincent Thomas 
Published: September 2009

Abstract
Because the metastatic cascade is largely governed by the ability of malignant cells to adapt and proliferate at the distant tissue site, we propose that disseminated cancers are analogous in many important ways to the evolutionary and ecological dynamics of exotic species. Although pests can be decimated through the application of chemical toxins, this strategy virtually never achieves robust control as evolution of resistant phenotypes typically permits population recovery to pretreatment levels. In general, biological strategies that introduce predators, parasitoids, or pathogens have achieved more durable control of pest populations even after emergence of resistant phenotypes. From this we propose that long term outcome from any treatment strategy for invasive pests, including cancer, is not limited by evolution of resistance, but rather by the phenotypic cost of that resistance. If a cancerous cell's adaptation to therapy is achieved by upregulating xenobiotic metabolism or a redundant signaling pathway, the required investment in resources is small, and the original malignant phenotype remains essentially intact. As a result, the cancer cells' initial high level of fitness is little changed and unconstrained proliferation will resume once resistance evolves. Robust population control is possible if resistance to therapy requires a substantial and costly phenotypic adaptation that also significantly reduces the organism's fitness in its original niche: an evolutionary double bind. [Cancer Res 2009;69(19):7499–502]
Metformin Selectively Targets Cancer Stem Cells, and Acts Together with Chemotherapy to Block Tumor Growth and Prolong Remission
Authors: Hirsch Heather A. , Iliopoulos Dimitrios , Tsichlis Philip N. , Struhl Kevin 
Published: September 2009

Abstract
The cancer stem cell hypothesis suggests that, unlike most cancer cells within a tumor, cancer stem cells resist chemotherapeutic drugs and can regenerate the various cell types in the tumor, thereby causing relapse of the disease. Thus, drugs that selectively target cancer stem cells offer great promise for cancer treatment, particularly in combination with chemotherapy. Here, we show that low doses of metformin, a standard drug for diabetes, inhibits cellular transformation and selectively kills cancer stem cells in four genetically different types of breast cancer. The combination of metformin and a well-defined chemotherapeutic agent, doxorubicin, kills both cancer stem cells and non–stem cancer cells in culture. Furthermore, this combinatorial therapy reduces tumor mass and prevents relapse much more effectively than either drug alone in a xenograft mouse model. Mice seem to remain tumor-free for at least 2 months after combinatorial therapy with metformin and doxorubicin is ended. These results provide further evidence supporting the cancer stem cell hypothesis, and they provide a rationale and experimental basis for using the combination of metformin and chemotherapeutic drugs to improve treatment of patients with breast (and possibly other) cancers. [Cancer Res 2009;69(19):7507–11]
Wnt Antagonist Gene DKK2 Is Epigenetically Silenced and Inhibits Renal Cancer Progression through Apoptotic and Cell Cycle Pathways
Authors: Hirata Hiroshi , Hinoda Yuji , Nakajima Koichi , Kawamoto Ken , Kikuno Nobuyuki , Kawakami Kazumori , Yamamura Soichiro , Ueno Koji , Majid Shahana , Saini Sharanjot , Ishii Nobuhisa , Dahiya Rajvir 
Published: September 2009

Abstract
Purpose: Wnt/β-catenin signaling is involved in renal cancer. DKK2, a Wnt antagonist, is silenced in some cancers, although its function has not been investigated. We hypothesized that DKK2 may be epigenetically silenced and inhibits progression of renal cell carcinoma (RCC).
Experimental Design: RCC cell lines and a normal kidney cell line were used for methylation and chromatin immunoprecipitation assays. To assess various functions of DKK2, we established stable DKK2-transfected cells and examined them with regard to cell viability, colony formation, apoptosis, cell cycle, and invasive capability. A total of 52 patients with confirmed conventional RCC were enrolled in this study.
Results: RCC cell lines had decreased levels of DKK2, which were significantly increased after treatment with 5-Aza-2′-deoxycytidine alone or 5-Aza-2′-deoxycytidine and trichostatin A. In chromatin immunoprecipitation assay, the levels of acetyl H3, acetyl H4, and dimethylated H3K4 were decreased, whereas the level of dimethylated H3K9 was increased in RCC cell lines compared with HK2 cells. Increased methylation in RCC tissues was associated with higher grades, pathologic stages, and pathologic tumor in RCC. Functional analysis showed that the numbers of viable A498 cells were significantly decreased in DKK2-transfected cells compared with mock cells. The number of apoptotic cells and S/G2-M phase cells was significantly increased and decreased after DKK2 transfection, respectively. Corresponding to these results, Bcl2 and cyclin D1 expression were also decreased in DKK2-overexpressing cells.
Conclusion: DKK2 is epigenetically silenced by methylation in higher grades and stages of RCC. These results suggest that DKK2 inhibits renal cancer progression through apoptotic and cell cycle pathways. (Clin Cancer Res 2009;15(18):5678–87)
Conversion of Minors to Islam in Malaysia
Authors: Muda Mohd Zamro , Kusrin Zuliza Mohd 
Published: September 2009

AbstractMalaysia constitutes a multicultural, multi-ethnic and multi-religious society and legally recognizes the right of freedom of religion among its subjects who have reached the age of maturity, that is, eighteen years of age. There are cases where minors change their religion due to their parents' conversion or through their own choice and this needs special consideration. This article aims to focus and discuss some issues of conversion of minors to Islam, commencing from the definition of minor, the law that relates to the conversion and some relevant cases.
Proteinases in Catabolism and Malnutrition
Authors: Hörl Walter H. , Wanner Christoph , Schollmeyer Peter 
Published: September 2009

Protein synthesis and degradation are particularly sensitive to malnutrition and catabolic states. Intracellular protein degradation is determined by the conformation, molecular weight, isoelectric point, and carbohydrate content of the proteins. ATP‐stimulated endoproteases appear to catalyse the rate‐limiting steps. In the liver, proteolysis is reduced by amino acids and/or insulin, whereas glucagon stimulates protein degradation, probably due to depletion of intracellular gluconeogenic amino acids. In the muscle, protein degradation is promoted by interleukin‐1 and inhibited by Ep‐475, which specifically inactivates cathepsin B,H, and L. Myofibrillar alkaline protemase activity increases postoperatively and in patients suffering from malignant tumors, whereas normal proteinase values were observed in these patients following total parenteral nutrition. Increased alkaline proteinase activity is also observed in diabetes mellitus and is normalized by insulin. Extracellular proteolysis has been reported in patients with hypercatabolic acute renal failure and in patients with sepsis or acute pancreatitis. Plasma fractions obtained from hypercatabolic patients with postoperative acute renal failure were proteolytic. Plasma proteinase activity decreases during hemodialysis due to elimination of a metallo‐proteinase. Plasma α2‐macroglobulin decreases in patients with acute renal failure and also during acute pancreatitis. Proteolytic degradation of parathyroid hormone by sera obtained from patients with acute pancreatitis has been observed. Also, there is a decrease of high molecular weight kininogen during experimental acute pancreatitis. Granulocyte elastase increases postoperatively, mainly in patients with sepsis. Sepsis also causes increased proteolytic activity in the urine.In conclusion, intracellular protein degradation can supply important precursors for hepatic and renal gluconeogenesis during malnutrition. Selective and nonspecific proteolysis may occur in patients with severe injury, sepsis, or acute renal failure, and result in the consumption of various plasma proteins. (Journal of Parenteral and Enteral Nutrition 11:98S‐103S, 1987)
Determinants of Nutritional Status in Hospital Patients in Italy
Authors: Mobarhan S. , Maiani G. , Ferro‐Luzzi A. , Pitassi F. , Trentini P. , Pappalardo G. , Nicastro A. , Azzini E. , Dalla Torre S. , Jama M.A. , Spigliati P. , Toico G. , Morabito S. 
Published: September 2009

The prevalence of protein‐calorie malnutrition (PCM) and micronutrient deficiency (MND) at the time of admission and discharge from hospital was evaluated in 91 patients consecutively admitted to the Surgery Clinic of the University Hospital of Rome.Anthropometric parameters and circulating levels of vitamins (A, E, C, B1, and B2) and visceral proteins [retinol‐binding protein (RBP, prealbumin (PA), and transferrin] were measured. Twenty‐one patients (23%) had moderate to severe PCM, and 70 patients (77%) had normal nutritional status (NNS) at admission. Two patients with PCM died in the hospital. At discharge, the prevalence of PCM was unchanged in the remaining 19 patents. Single or multiple MND was observed initially in 71% of patients with PCM and in 36% with apparently normal nutritional status. Despite vitamin supplementation, MND was present at the time of discharge in 73% of patients with PCM and 44% with NNS.Nutritional status at the time of admission was assessed in hospitals in six different Italian cities. The criterion for admission to the study was the diagnosis of chronic (>1 yr duration) illness (excluding cancer and multiple organ disorders). Two hundred eighty‐four patients (145 males, 139 females), ages 25–88 yr, were selected. The findings indicated a high prevalence of MND (64%). Also, in disorders that usually do not have significant alterations of digestion or absorption, such as uncomplicated cardiorespiratory disease, the prevalence of MND was high (9–38%). The prevalence of MND was not related to body mass index (BMI). PCM was more common among patients with chronic gastrointestinal disease. There was a high level of obesity among cardiac patients (BMI>24–25), even though one‐third of them had MND. The prevalence of MND was not related to anthropometric indicators of PCM. (Journal of Parenteral and Enteral Nutrition 11:122S‐125S, 1987)
Extracorporeal shockwave for hip necrosis in systemic lupus erythematosus
Authors: Wang CJ , Ko JY , Chan YS , Lee MS , Chen JM , Wang FS , Yang KD , Huang CC 
Published: September 2009

Patients with systemic lupus erythematosus (SLE) frequently received corticosteroid therapy, resulting in osteonecrosis of the femoral head (ONFH). Prior studies demonstrated the effectiveness of extracorporeal shockwave treatment (ESWT) for ONFH.. This study evaluated the effectiveness of ESWT for ONFH in patients with SLE. We studied 39 patients, including 15 patients with SLE (26 hips) and 24 controls (29 hips). To each affected hip we applied ESWT (6000 impulses at 28 kV in a single session). Patients were ambulated with partial weight bearing for 4–6 weeks. The primary endpoint was the need for hip replacement. The secondary endpoints were improvement in hip pain and function and image changes on X-ray and MRI. Patients received total hip replacement in 12% of patients with SLE and in 14% of controls ( P = 0.802). There was no statistically significant difference in pain scores (0.86 vs. 0.89; P = 0.467) and function scores (89% vs. 91%; P = 0.194) between patients with SLE and controls. SLE response to ESWT for ONFH is comparable with ONFH in patients without SLE.
The effects of previous hysterectomy on lupus
Authors: Namjou B , Scofield RH , Kelly JA , Goodmon EL , Aberle T , Bruner GR , Harley JB 
Published: September 2009

Hysterectomy is one of the most common surgical procedures performed in United States, and currently, one in three women in United States has had a hysterectomy by the age of 60 years. Systemic lupus erythematosus (SLE) is a common autoimmune disease and especially targets women of childbearing age at least 10 times higher than men, which reflects the major role of female sex hormones. In this retrospective study, we evaluate the potential effects of previous hysterectomy in our lupus cohort. Data collected from study subject questionnaires were obtained from the Lupus Family Registry and Repository (LFRR) at the Oklahoma Medical Research Foundation. Hysterectomy data were available from 3389 subjects. SLE patients with a positive history of hysterectomy have been selected and compared with matched lupus patients with a negative history of hysterectomy and healthy controls. Association analyses were performed, and the P values and adjusted odds ratios (ORs) were calculated. SLE patients with a negative history of hysterectomy more likely had kidney nephritis or positive anti-dsDNA than age-matched SLE patients with a history of hysterectomy before disease onset. This effect was independent of ethnicity with an OR of 6.66 (95% CI = 3.09–14.38, P = 1.00 × 10−8) in European patients and 2.74 (95% CI = 1.43–5.25, P = 0.001) in African-Americans. SLE patients with a positive history of hysterectomy before disease onset also had a later age of disease onset ( P = 0.0001) after adjustment for age and race. Our findings support the notion that the influence of female sex hormones in SLE and various clinical findings are tremendous and that surgical menopause such as this could significantly affect the outcome of disease and clinical manifestations.
Factors Associated with Arterial Vascular Events in PROFILE: A Multiethnic Lupus Cohort
Authors: Bertoli AM , Vilá LM , Alarcón GS , McGwin G , Edberg JC , Petri M , Ramsey-Goldman R , Reveille JD , Kimberly RP ,   for the PROFILE Study Group
Published: September 2009

The objective of this study was to determine the factors associated with the occurrence of arterial vascular events in a multiethnic systemic lupus erythematosus (SLE) cohort. The PROFILE cohort, comprised SLE patients ( n = 1333) of defined ethnicity from five different US institutions, was studied to determine demographic, clinical and biological variables associated with vascular events. An arterial vascular event (first episode) was either a myocardial infarction, angina pectoris and/or a vascular procedure for myocardial infarction, stroke, claudication and/or evidence of gangrene. Patient characteristics were analyzed by univariable and multivariable Cox proportional hazards regression analyses. One-hundred twenty-three (9.8%) patients had at least one incident arterial event. Age at cohort enrollment (HR = 1.04, 95% CI 1.03–1.06), smoking (HR = 2.20, 95% CI 1.40–3.46) and the CRP2* C alleles (HR = 1.91, 95% CI 1.04–3.49) were associated with a shorter time-to-the occurrence of arterial vascular events. Some clinical manifestations of disease activity were associated with a shorter time-to-occurrence [psychosis (HR = 2.21, 95% CI 1.10–4.44), seizures (HR = 1.85, 95% CI 1.00–3.24) and anaemia (HR = 1.83, 95% CI 1.02–3.31)], but others were not [arthritis (HR = 0.32, 95% CI 0.18–0.58)]. In conclusion, older patients, especially in the context of a predisposing environmental factor (smoking) and severe clinical manifestations, are at higher risk of having arterial vascular events. The genetic contribution of the variation at the CRP locus was not obscured by demographic or clinical variables. Awareness of these factors should lead to more effective management strategies of patients at risk for arterial vascular events.
Colour Doppler ultrasound of the ocular circulation in patients with systemic lupus erythematosus identifies altered microcirculatory haemodynamics
Authors: Wright SA , O’Prey FM , Hamilton PK , Lockhart CJ , McCann A , McHenry MT , McGivern RC , Plumb R , Finch MB , Bell AL , McVeigh GE 
Published: September 2009

We assessed whether quantitative analysis of Doppler flow velocity waveforms is able to identify subclinical microvascular abnormalities in SLE and whether eigenvector analysis can detect changes not detectable using the resistive index (RI). Fifty-four SLE patients with no conventional cardiovascular risk factors, major organ involvement or retinopathy were compared to 32 controls. Flow velocity waveforms were obtained from the ophthalmic artery (OA), central retinal artery (CRA) and common carotid artery (CA). The waveforms were analysed using eigenvector decomposition and compared between groups at each arterial site. The RI was also determined. The RI was comparable between groups. In the OA and CRA, there were significant differences in the lower frequency sinusoidal components ( P < 0.05 for each component). No differences were apparent in the CA between groups. Eigenvector analysis of Doppler flow waveforms, recorded in proximity of the terminal vascular bed, identified altered ocular microvascular haemodynamics in SLE. Altered waveform structure could not be identified by changes in RI, the traditional measure of downstream vascular resistance. This analytical approach to waveform analysis is more sensitive in detecting preclinical microvascular abnormalities in SLE. It may hold potential as a useful tool for assessing disease activity, response to treatment, and predicting future vascular complications.