Miracle-dz/UniFAR-FTUs huggingface dataset:
Why is PTEN an important tumor suppressor?

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) was originally cloned as a tumor suppressor for brain tumors. Now it is known as a tumor suppressor for many tumor types. In this review, we ask the simple question: why is PTEN such a common and important tumor suppressor? The most obvious answer is that there are no other family members that can replace PTEN. As a result, several pathways critical for cell transformation are misregulated. The most important of these is the phosphoinositide 3‐kinase (P13K) PI3K‐Akt pathway, which has downstream effects on transcription, proliferation, cell survival, invasiveness, and angiogenesis. In addition, PTEN is linked via several mechanisms to the p53 tumor suppressor. Through p53 and additional mechanisms, loss of PTEN leads to genomic instability. Hence, PTEN is important because its loss misregulates multiple Akt‐dependent and ‐independent pathways critical for the development of cancer. J. Cell. Biochem. 102: 1368–1374, 2007. © 2007 Wiley‐Liss, Inc.
Biological drug use: US perspectives on indications and monitoring

An estimated 20% of patients with rheumatoid arthritis (RA) receive tumour necrosis factor (TNF) inhibitor treatment. This paper presents the results of an online survey of US rheumatologists (1023 respondents) conducted in April 2005 on issues relating to use of TNF inhibitors in RA. The primary determinant of TNF inhibitor use among the participating rheumatologists was physician preference rather than patient preference or payor guidelines. Qualitative (rather than quantitative measures) assessments (physician overall assessment, symptom review, etc.) and laboratory measures were more frequently employed when assessing and treating patients with RA. Clinical assessments with hepatic enzymes and complete blood count as an additional safety tool were most commonly employed to monitor drug safety. Nearly all the rheumatologists (⩾92%) felt that a partial purified derivative (PPD) test was indicated when using a TNF inhibitor, but were equally split with regard to those with a history of PPD positivity or BCG vaccination. The frequency of serious adverse events was estimated and included tuberculosis, systemic fungal infection, demyelinating disorders, cytopenia, drug induced lupus, lymphoma, and hepatic failure. Among 454 RA patients who became pregnant while receiving biological therapy there were 378 normal deliveries, 9 premature babies, 5 therapeutic abortions, and 25 miscarriages. It was concluded that a greater than expected number of US rheumatologists are familiar with biologicals and TNF inhibitor therapies, but uncertainties and educational gaps still exist regarding their use and monitoring.
Dehydroepiandrosterone 7α‐ and 7β‐Hydroxylation in Mouse Brain Microsomes. Effects of Cytochrome P450 Inhibitors and Structure‐Specific Inhibition by Steroid Hormones

Presently, several works question the effects of dehydroepiandrosterone (DHEA) reported in vivo and designate its 7‐hydroxylated metabolites as native antiglucocorticoids and potent mediators in the triggering of immune response. Among mouse tissues and organs, and second to liver, the largest production of 7α‐and 7β‐hydroxylated derivatives of DHEA takes place in brain microsomes. To contribute to identification of cytochromes P450 (CYPs) responsible for 7α‐ and 7β‐hydroxy‐DHEA production, effects of CYP inhibitors and of several steroid hormones on DHEA 7‐hydroxylation were examined. Using mouse brain microsomes as a source of enzyme, we report now that strong and smaller inhibitions of DHEA 7α‐hydroxylation were obtained with ketoconazole and α‐naphthoflavone, respectively, and that neither changed DHEA 7β‐hydroxylation. Metyrapone and antipyrine also inhibited 7α‐hydroxylation, but by contrast, significantly increased 7β‐hydroxylation of DHEA. This indicated that at least, two different CYPs were responsible for 7α‐ and 7β‐hydroxylation of DHEA. Steroids sharing a 3β‐hydroxylated structure with DHEA, namely pregnenolone, 5‐androstene‐3β,17β‐diol and 3β‐hydroxy‐5α‐androstan‐17‐one, were strong inhibitors of DHEA 7α‐hydroxylation (non‐competitive inhibition with pregnenolone, Ki=2.0±0.3 μM). In contrast, 7β‐hydroxylation yields were not decreased by the 3β‐hydroxysteroids tested. Moderate inhibition of 7α‐ and 7β‐hydroxylation was obtained with 3‐oxosteroids, namely testosterone, progesterone, corticosterone and 4‐androsten‐3,17‐dione. Taken together, these data indicate specific inhibition patterns of DHEA 7α‐ and 7β‐hydroxylation by CYP inhibitors and steroid hormones in mouse brain microsomes and may be used as criteria necessary for identification of the responsible CYP species.
Molecular characteristics of mitochondrial DNA and phylogenetic analysis of the loach (Misgurnus anguillicaudatus) from the Poyang Lake

The goal of our study was to investigate the molecular characteristics of mitochondrial DNA (mtDNA) and phylogenetic construction of the weather loach (Misgurnus anguillicaudatus) in Poyang Lake. The complete mitochondrial genome was 16,634 bp, and the gene order was identical to that of teleost fishes. Compared with the previous reported weather loach in China, there were numerous nucleotide substitutions and length polymorphisms on the structural genes of mitochondrial DNA in the loach from the Poyang Lake. The Phylogenetic tree indicated that the loach had its own molecular characteristics and was somewhat different from those in other regions of China. Fourteen unique haplotypes of the cytochrome b (cyt b) gene were obtained from 300 weather loaches. The Phylogenetic tree based on the cyt b gene showed that the loaches were substructured into two different populations in The Poyang Lake. Results indicated that the loaches in Poyang Lake not only showed the same phylogeny as the loaches in other areas of China, but also generated its own unique phylogenetic relationships.
International Environmental Agreements: Incentives and Political Economy

International environmental agreements are increasingly important in a globalised economy. Beyond their specific interest, these agreements are also important in the context of coalition formation theory. Given the incentives to free ride, associated to the environment as a public good and to the presence of spillovers, the profitability and the optimality of environmental agreements are separated from their stability (i.e. self-enforcement): hence, a whole set of political economy issues. This paper reviews the recent advances in this area. In particular it discusses mechanisms and strategies aimed at offsetting the incentives to free ride and increasing welfare, such as transfers, issue linkages, threats and multiple agreements. The main results show that partial coalitions and multiple agreements tend to prevail among subsets of players, and that agreements among all players are most unlikely to exist. The design of the agreements, moreover, can be crucial in determining the number of signatory countries.
The analysis of customer density, tenant placement and coupling inside a shopping centre with GIS

Abstract The spatial arrangement of tenants is currently one of the main topics in shopping centre research. This paper shows how a Geographic Information System (GIS) can be used to analyse the tenant structure. Given the recommendations in the literature, the analysis may help to improve the situation within a certain shopping centre. Therefore, we introduce the variable clumping method and kernel density estimation into shopping centre research in order to analyse retail category concentrations, customer flows and coupling in a shopping centre. Applying these techniques to a German shopping centre showed that spatial concentration can be observed within the retail categories of food, health & body and fashion and that the pass ratio declines according to the distance from the central point of the shopping centre. Also, shops in the same retail category have higher coupling than those of different categories, and unexpectedly spatially separated shops have a slightly higher coupling than non-spatially separated ones. Overall, the use of GIS improves the quality and the speed of spatially based analysis, and thus should be used more frequently in scientific shopping centre research and shopping centre management.
Replication of Subgenomic Hepatitis C Virus Replicons in Mouse Fibroblasts Is Facilitated by Deletion of Interferon Regulatory Factor 3 and Expression of Liver-Specific MicroRNA 122

ABSTRACT Hepatitis C virus (HCV) infection causes significant morbidity, and efficient mouse models would greatly facilitate virus studies and the development of effective vaccines and new therapeutic agents. Entry factors, innate immunity, and host factors needed for viral replication represent the initial barriers that restrict HCV infection of mouse cells. Experiments in this paper consider early postentry steps of viral infection and investigate the roles of interferon regulatory factors (IRF-3 and IRF-9) and microRNA (miR-122) in promoting HCV replication in mouse embryo fibroblasts (MEFs) that contain viral subgenomic replicons. While wild-type murine fibroblasts are restricted for HCV RNA replication, deletion of IRF-3 alone can facilitate replicon activity in these cells. This effect is thought to be related to the inactivation of the type I interferon synthesis mediated by IRF-3. Additional deletion of IRF-9 to yield IRF-3−/− IRF-9−/− MEFs, which have blocked type I interferon signaling, did not increase HCV replication. Expression of liver-specific miR-122 in MEFs further stimulated the synthesis of HCV replicons in the rodent fibroblasts. The combined effects of miR-122 expression and deletion of IRF-3 produced a cooperative stimulation of HCV subgenome replication. miR-122 and IRF-3 are independent host factors that are capable of influencing HCV replication, and our findings could help to establish mouse models and other cell systems that support HCV growth and particle formation.
Cochlear Implantation: Relationships with Research on Auditory Deprivation and Acclimatization

&NA; This paper reviews research on cochlear implantation relevant to deprivation and acclimatization with acoustical hearing aids. The term “deprivation” is used in its everyday sense to refer to the bilateral absence of acoustic stimulation. Results are reviewed from several sources, with detailed evidence presented from three groups of postlingually deafened adult patients and one group of prelingually deafened child patients, all implanted at the University of Iowa. Outcomes from implantation reveal consistent effects of deprivation, evidenced by significant negative correlations between accuracy of speech perception and the duration of profound/total deafness before implantation. Outcomes also show acclimatization in the form of significant improvements in performance over time after implantation. For adult patients, the level of performance measured shortly after implantation on average is about half the level measured eventually. Individually, 80% of the adult patients implanted in Iowa show significant performance improvements with time. On average, performance reached asymptote after 30 to 40 mo of implant use, although individual differences in the rate and amount of improvement are large. Absolute accuracy of speech perception with implants by adults is believed to be related to preoperative measures in three domains: 1) the number and physiological responsiveness of auditory ganglion cells and nerve fibers, indexed by measures of hearing sensitivity, duration of deafness, and age; 2) the responsiveness of the central nervous system, indexed by measures of cognitive and linguistic ability, and possibly also by age and duration of deafness; and 3) the motivation to learn to use the implant. Preliminary analyses suggest that the measures in the first domain are more strongly associated with the immediate benefit from implantation than with the subsequent improvement in performance over time. (Ear & Hearing 1996;17;38S‐50S)
Pharmacokinetics of trimethoprim and sulfamethoxazole in normal subjects and in patients with renal failure.

The pharmacokinetics of trimethoprim (TMP) and sulfamethoxazole (SMZ) were studied in subjects with normal and impaired renal function after single doses of the drugs administered separately and in combination. Serum levels and urinary excretion of TMP and free and conjugated SMZ were fitted to appropriate pharmacokinetic models by nonlinear least-squares methods. Neither drug influenced the pharmacokinetics of the other, and the acid and alkaline loading used did not markedly affect the clearance of either drug from serum. Rates of elimination and urinary concentrations of both drugs were significantly reduced in uremic subjects. Levels of SMZ in serum were slightly lower in uremic than in normal subjects. Levels of TMP in serum were similar in both groups but tended to be higher in uremic subjects from 5 hr after dosing. Distribution of free SMZ in tissues increased during renal insufficiency, probably due to reduced binding to serum proteins, whereas distribution of TMP in tissues showed little apparent change. A dosage regimen involving reduced doses of both drugs, with an interval between doses of approximately 12 hr, is proposed for patients with severe renal failure.
Towards entrepreneurship education: Empowering township members to take ownership of the township economy

This article explores the role of effective entrepreneurial education in township communities, to address some of the economic challenges facing poor township communities. Effective entrepreneurial education has the potential to ignite economic transformation in township communities. This effective entrepreneurial enterprise should be based on the understanding of whole education principles. This article also explores the role of the social missional entrepreneurial church by applying effective enterprises that would run entrepreneurial activities in township communities. The social missional entrepreneurial church understands that it should approach its mission holistically; ‘holistic’ here referring to the spiritual, physical, mental, social, emotional and economic spheres. This explorative study aims at understanding how to implement the social missional entrepreneurial enterprises in township communities. It explores effective entrepreneurial programmes that could be an engine in transforming the township communities. It focuses on the definition of education, specifically entrepreneurship education, and how can it be implemented effectively. This entrepreneurship education should resonate with those who live in township communities. It should address the needs and challenges that face township communities. The article will also explore the meaning of the township economy. It will examine the role of Churchpreneur, which refers to the social missional entrepreneurial church in the spotlight, and how this kind of church can be a place where entrepreneurial education is promoted.
Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group.

PURPOSE To compare the efficacy and tolerability of tamoxifen with that of letrozole, an oral aromatase inhibitor, with tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. PATIENTS AND METHODS Nine hundred seven patients were randomly assigned letrozole 2.5 mg once daily (453 patients) or tamoxifen 20 mg once daily (454 patients). Patients had estrogen receptor- and/or progesterone receptor-positive tumors, or both receptors were unknown. Recurrence during adjuvant antiestrogen therapy or within the following 12 months or prior endocrine therapy for advanced disease precluded enrollment. One prior chemotherapy regimen for metastatic disease was allowed. The primary end point was time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, rate and duration of clinical benefit, time to treatment failure (TTF), overall survival, and tolerability. RESULTS TTP was significantly longer for letrozole than for tamoxifen (median, 41 v 26 weeks). Treatment with letrozole reduced the risk of progression by 30% (hazards ratio, 0.70; 95% confidence interval, 0.60 to 0.82, P =.0001). TTP was significantly longer for letrozole irrespective of dominant site of disease, receptor status, or prior adjuvant antiestrogen therapy. Similarly, TTF was significantly longer for letrozole (median, 40 v 25 weeks). ORR was higher for letrozole (30% v 20%; P =.0006), as was the rate of clinical benefit (49% v 38%; P =.001). Survival data are currently immature and not reported here. Both treatments were well tolerated. CONCLUSION Letrozole was significantly superior to tamoxifen in TTP, TTF, ORR, and clinical benefit rate. Our results support its use as first-line endocrine therapy in postmenopausal women with advanced breast cancer.
Correlation between circulating CD27high plasma cells and disease activity in patients with systemic lupus erythematosus.

OBJECTIVE Disease activity in systemic lupus erythematosus (SLE) is usually assessed with complex disease activity scores comprising a variety of different parameters. In order to determine whether SLE disease activity correlates with abnormal B lymphocyte activity, B cell subsets were analyzed, and their relationship to clinical and humoral measures of disease activity was assessed. METHODS The distribution of B cell subsets was determined by fluorescence-activated cell sorting analysis and assessed in relation to the autoantibody profile, disease activity measured by the SLE Disease Activity Index (SLEDAI) and the European Consensus Lupus Activity Measure scores, disease duration, and therapy. RESULTS The number and frequency of CD27(high) plasma cells were significantly correlated with the SLE disease activity indices and with the titer of anti-double-stranded DNA (anti-dsDNA) autoantibodies. Circulating B cell subsets were not influenced by age or sex, but appeared to relate to the duration of disease and the therapeutic regimen, with the number and frequency of CD27(high) plasma cells increasing and those of CD27- naive B cells decreasing over time. Patients were divided into those with a SLEDAI score of 0-8 (low disease activity) and those with SLEDAI score >8 (high disease activity). Patients with high disease activity had an increased frequency of both CD19+ B cells and CD27(high) plasma cells. By using a nonparametric data sieving algorithm, we observed that these B cell abnormalities provided predictive values for nonactive and active disease of 78.0% and 78.9%, respectively. The predictive value of the B cell abnormalities (78.9%) was greater than that of the humoral/clinical data pattern (71.4%), including anti-dsDNA antibody levels, circulating immune complexes, increased erythrocyte sedimentation rate, mucocutaneous involvement, and acute renal involvement. CONCLUSION Flow cytometric monitoring of B cell subsets in the peripheral blood provides new insights into abnormalities of B cell function in SLE and may also be a diagnostically valuable option for monitoring the activity of this autoimmune disease.
Nrf2 Activation Protects the Liver From Ischemia/Reperfusion Injury in Mice

Objective:To investigate the role of Nrf2 in the pathogenesis of hepatic ischemia-reperfusion (I/R) injury. Background:Hepatic I/R injury is a serious complication that leads to liver failure after liver surgery. NF-E2-related factor 2 (Nrf2) is a transcription factor that plays a critical role in protecting cells against oxidative stress. Therefore, it is suggested that Nrf2 activation protects the liver from I/R injury. Methods:Wild-type and Nrf2-deficient mice were treated with 15-deoxy-&Dgr;12,14–prostaglandin J2 (15d-PGJ2), or a vehicle. Subsequently, these mice were subjected to 60-minute hepatic 70% ischemia, followed by reperfusion. Liver and blood samples were collected to evaluate liver injury and mRNA expressions. Results:After hepatic I/R, Nrf2-deficient livers exhibited enhanced tissue damage; impaired GSTm1, NQO1, and GCLc inductions; disturbed redox state; and aggravated tumor necrosis factor &agr; mRNA expression in comparison with wild-type livers. 15d-PGJ2 treatment protected the livers of wild-type mice from I/R injury via increased expressions of GSTm1, NQO1, and GCLc; maintained redox status; and decreased tumor necrosis factor &agr; induction. These effects induced by 15d-PGJ2 were not seen in the livers of Nrf2−/− mice and were not annulled by peroxisome proliferator-activated receptor &ggr; antagonist in Nrf2+/+ mice, suggesting that the protective effect of 15d-PGJ2 is mediated by Nrf2-dependent antioxidant response. Conclusions:Nrf2 plays a critical role in the mechanism of hepatic I/R injury and would be a new therapeutic target for preventing hepatic I/R injury during liver surgery.
Hsp90 Inhibitor 17-Allylamino-17-Demethoxygeldanamycin Prevents Synovial Sarcoma Proliferation via Apoptosis in In vitro Models

Synovial sarcoma is a soft tissue malignancy with a poor prognosis; many patients will die from this disease within 10 years of diagnosis, despite treatment. Gene expression profiling and immunohistochemistry studies have identified oncogenes that are highly expressed in synovial sarcoma. Included in this group are receptor tyrosine kinases such as epidermal growth factor receptor, insulin-like growth factor receptor 1, fibroblast growth factor receptor 3, KIT, and HER2. Inhibitors of these growth-promoting receptors are likely to inhibit proliferation of synovial sarcoma; however, the effect of receptor tyrosine kinase inhibitors on synovial sarcoma is largely unknown. We assessed the ability of the following receptor tyrosine kinase inhibitors to halt proliferation and induce apoptosis in synovial sarcoma monolayer and three dimensional spheroid in vitro models: gefitinib (Iressa), NVP-AEW541, imatinib mesylate (Gleevec), SU5402, PRO-001, trastuzumab (Herceptin), and 17-allylamino-17-demethoxygeldanamycin (17-AAG). Gefitinib, NVP-AEW541, and imatinib inhibited proliferation only at relatively high concentrations, which are not clinically applicable. 17-AAG, which destabilizes multiple receptor tyrosine kinases and other oncoproteins through heat shock protein 90 inhibition, prevented proliferation and induced apoptosis in synovial sarcoma monolayer models at concentrations achievable in human serum. 17-AAG treatment was also associated with receptor tyrosine kinase degradation and induction of apoptosis in synovial sarcoma spheroid models. 17-AAG was more effective than doxorubicin, particularly in the spheroid models. Here we provide in vitro evidence that 17-AAG, a clinically applicable drug with known pharmacology and limited toxicity, inhibits synovial sarcoma proliferation by inducing apoptosis, and thus has potential as a systemic therapy for this disease.