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PDF file - 2.5MB, LEF binding elements are prevalent in human breast cancer NOS2-associated gene expression

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PDF file - 2.2MB, NO signaling results in PP2A-c phosphorylation and decreased phosphatase activity

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Increased inducible nitric oxide synthase (NOS2) expression in breast tumors is associated with decreased survival of estrogen receptor negative (ER−) breast cancer patients. We recently communicated the preliminary observation that nitric oxide (NO) signaling results in epidermal growth factor receptor (EGFR) tyrosine phosphorylation. To further define the role of NO in the pathogenesis of ER− breast cancer, we examined the mechanism of NO-induced EGFR activation in human ER− breast cancer. NO was found to activate EGFR and Src by a mechanism that includes S-nitrosylation. NO, at physiologically relevant concentrations, induced an EGFR/Src-mediated activation of oncogenic signal transduction pathways (including c-Myc, Akt, and β-catenin) and the loss of PP2A tumor suppressor activity. In addition, NO signaling increased cellular EMT, expression and activity of COX-2, and chemoresistance to adriamycin and paclitaxel. When connected into a network, these concerted events link NO to the development of a stem cell–like phenotype, resulting in the upregulation of CD44 and STAT3 phosphorylation. Our observations are also consistent with the finding that NOS2 is associated with a basal-like transcription pattern in human breast tumors. These results indicate that the inhibition of NOS2 activity or NO signaling networks may have beneficial effects in treating basal-like breast cancer patients. Mol Cancer Res; 10(9); 1203–15. ©2012 AACR.

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Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

本文报道一例腮腺来源的睾丸核蛋白（nuclear protein in testis，NUT）中线癌患者，为35岁男性，因“发现右侧腮腺区肿物3年，增大2周”入院，行腮腺浅叶切除术，手术标本免疫组化及分子检测结果为NUT中线癌。患者术后接受放化疗联合靶向药物治疗，随访10个月内无疾病复发或其他不良事件。腮腺来源的NUT中线癌临床罕见，易发生误诊、漏诊，目前诊断方式依赖免疫组化（NUT抗体阳性）以及分子检测（

We aimed at investigating the expression of Long non-coding RNA (LncRNA) PGM5-AS1 and its facilitating effects on proliferation and invasion of colorectal cancer by sponging miR-100-5p.qRT-PCR was performed to detect the expressions of PGM5-AS1 and SMAD4 in human colorectal cancer tissues and cells. CCK-8 assay was performed to evaluate the SW403 cells proliferation and transwell assay was performed to evaluate the SW403 cells migration. The correlation between miR-100-5p and PGM5-AS1 was detected by statistical analysis. Bioinformatics prediction and Luciferase assay were performed to explore the interaction and binding site of PGM5-AS1 and miR-100-5p, miR-100-5p and SMAD4, respectively.We found that both PGM5-AS1 and SMAD4 were downregulated in human colorectal cancer tissues and cells. qRT-PCR and CCK-8 assay showed that PGM5-AS1 expression is associated with the proliferation of colorectal cancer cells. Transwell assay showed that PGM5-AS1 regulated the migration ability of colorectal cancer cells. The bioinformatics prediction and Luciferase assay demonstrated that by sponging miR-100-5p, PGM5-AS1 can serve as a molecular sponge to further regulate the expression of SMAD4.In this study, we found that lncRNA-PGM5-AS1 was low expressed in human colorectal cancer cells, which could promote tumor proliferation, migration and invasion by serving as a molecular sponge and by modulating the inhibitory effect of miR-100-5p on tumor suppressor gene SMAD4.

Recent findings suggest that co-expression of NOS2 and COX2 is a strong prognostic indicator in triple-negative breast cancer patients. These two key inflammation-associated enzymes are responsible for the biosynthesis of NO and PGE , respectively, and can exert their effect in both an autocrine and paracrine manner. Impairment of their physiological regulation leads to critical changes in both intra-tumoural and intercellular communication with the immune system and their adaptation to the hypoxic tumour micro-environment. Recent studies have also established a key role of NOS2-COX2 in causing metabolic shift. This review provides an extensive overview of the role of NO and PGE in shaping communication between the tumour micro-environment composed of tumour and immune cells that in turn favours tumour progression and metastasis. LINKED ARTICLES: This article is part of a themed section on Nitric Oxide 20 Years from the 1998 Nobel Prize. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.2/issuetoc.

Effectiveness of biological activated carbon (BAC) filter in removing disinfection byproducts (DBPs) precursors of micro-polluted lake water for one year was conducted. The formation potential (FP) of DBPs (trihalomethanes (THMs), haloacetic acids (HAAs) and Nitrosamines (NAs)), dissolved organic carbon (DOC), molecular weight (MW) distribution and excitation emission matrix fluorescence (EEM) of dissolved organic material (DOM) in the influent and effluent of BAC were determined. The results indicated that the removal efficiency (RE) of DOC ranged from 42.9-28.3%. Neither virgin GAC nor long-term operated BAC could efficiently dispose of THMs and HAAs precursors (RE from 35.2-18.8%, from 42 to 8.4%, respectively), however, BAC still showed good ability in removal of NAs precursors after a year operation, of which RE just dropped from 81.7-69.6%. There was strong correlation between RE of NAs precursors and DOC with small MW (0.5 kDa). The removal of HAAs precursors showed relatively close relation to aromatic protein-like components and soluble microbial pollutants (SMPs). Weak direct relationship was found between the water quality parameters and THMs precursors.

Purpose The purpose of this paper is to examine the business-government nexus in Hong Kong as a special case, thereby contributing to a comparative examination of various significant variables affecting the study of political and economic developments in East Asia. Design/methodology/approach The paper considers the privileged position afforded to the major business groups in Hong Kong’s political system as part of the pro-Beijing United Front. It adopts a historical perspective, relying on existing literature including media reports. As the author is both an academic and a long-term pro-democracy activist, his actual experiences and extensive interviews with various important participants in Hong Kong’s business and political communities offer valuable perspectives. Findings In the past, the business-government nexus was perceived to be a positive factor that contributed to the territory’s economic growth. In the past decade or so, though, increasing dissatisfaction with the Hong Kong government’s performance and the widening gap between the rich and the poor have led to the emergence of a legitimacy deficit on the part of the government, resulting in rising demands for democracy which have not been met. Divisions on these issues within the local business community have posed a severe challenge to the continuation of the business-government nexus. Originality/value The author’s actual experiences and his interviews with other participants in Hong Kong’s politics provide observations of significant value. The Occupy Central campaign, which took off in the territory in 2014, demands serious consideration in terms of its political development and a key element for consideration is the response of the business-government nexus to it.

Purpose To investigate the prognostic significance of (18)F-FDG PET imaging in patients with bone and soft tissue sarcoma, a meta-analysis was conducted. Methods Comprehensive literature searches were performed in PubMed, Embase, Web of Science and Cochrane Library. Pooled hazard ratio (HR) values were calculated to assess the correlations of pre-chemotherapy SUV (SUV1), post-chemotherapy SUV (SUV2), SUV Ratio, total lesion glycolysis (TLG) and metabolic tumor volume (MTV) with event-free survival (EFS) and overall survival (OS). Results Twenty-three studies with 1261 patients were identified. The combined HRs for EFS were 1.84 (95% CI: 1.54–2.20) for SUV1, 2.92 (95% CI: 2.15–3.97) for SUV2, 1.90 (95% CI: 1.43–2.52) for SUV Ratio, 3.01 (95% CI: 1.36–6.67) for TLG and 2.32 (95% CI: 1.44–3.75) for MTV. The pooled HRs for OS were 1.85 (95% CI: 1.49–2.30) for SUV1, 2.00 (95% CI: 1.39–2.88) for SUV2, 2.20 (95% CI: 1.18–4.10) for SUV Ratio, 6.19 (95% CI: 2.17–17.66) for TLG and 2.67 (95% CI: 1.52–4.68) for MTV. Besides, high SUV1 was found to be significantly associated with higher rate of metastasis (RR 5.55, 95% CI: 2.75–11.18) and local recurrence (RR 1.87 95% CI: 1.28–2.72). Conclusion (18)F-FDG PET parameters of SUV1, SUV2, SUV Ratio, TLG and MTV may have effective prognostic significance for patients with bone and soft tissue sarcoma. (18)F-FDG PET imaging may be a promising tool to help predict survival outcomes of these patients.

This article examines, through the theoretical framework of realism, China’s articulation and implementation of its new model of major power relationships (NMMPR), its rationale, objectives and the strategies involved. The study will concentrate on the model’s application to Sino-American relations, though it will also briefly survey its application to China’s relations with other major powers. The Chinese leadership’s assessment of the global power configuration and its trends of evolution will be considered. The articulation of the NMMPR also reflects new variables in Chinese foreign policy and Sino-US relations. They include Xi Jinping’s distinctive leadership style, the arrival of a less favourable international environment, the concern about potential deterioration in Sino-US relations, and the increasing inclination of China’s neighbours to adopt a hedging strategy, including the strengthening of security co-operation with the US.

In line with the principle of ‘small government, big society', the Chinese authorities are likely to considerably expand the service delivery role of NGOs which do not intend to challenge the Party-state. These NGOs could be allowed a respected place in society, and they would have the financial resources from the government to offer needed services. On the other hand, NGOs which are perceived to pose a threat to the Party-state will continue to be suppressed. United front tactics are likely to be adopted, and leaders of these NGOs will be induced to alter their mode of operation into one acceptable to the Chinese authorities — i.e. both carrots and sticks are applied. Meanwhile, civil society will continue to grow quantitatively and qualitatively. Optimistic estimates are that, at this stage, China has about 7‒8 million social organizations involving about 300 million people, about one-fifth of China's total population. This critical mass is still inadequate to exert pressure on the Party-state t...

This volume attempts to understand China's rise and the China model, adopting an analytical framework linking China's domestic political economy order and the global system. Ming Wan's clearly defi...

This is a book based on a doctoral dissertation completed in 2007. Like other good books of this nature, it demonstrates serious research efforts and valuable data collection, and therefore should ...

The ASEAN–China Free Trade Area (ACFTA) is the first of the free trade agreements signed by ASEAN with its major trade partners, and is generally considered a success. However, while liberalization of trade among ASEAN countries has historically not provoked any major issues, things went differently concerning the ACFTA, and complaints have been raised that the treaty allows China too many trade benefits. The purpose of this article is to evaluate, using trade gravity equations, if there is any evidence that the ACFTA has been responsible for the growing trade imbalance between China and Indonesia. The model has not produced any conclusive results about the negative effects on the ACFTA for Indonesia. Given the relevance of this treaty for the ongoing regional integration in Asia, however, the coming years will be crucial in determining the form of it among the existing options and the outcome now seems more uncertain than ever.

This article examines China’s concern to prevent terrorism and maintain stability in Central Asia through the SCO. The situation in Afghanistan has raised concerns among SCO member countries and strengthened common interests to maintain the regional organization, regime stability, and economic co-operation within it.

There are now many books and articles on China’s global rise, and authors have to work hard to produce a new volume that is attractive and worth reading.The authors consider that the existing liter...

Congenital cleft palate causes a serious obstacle to children with regard to language and eating function. The aim of the current study was to examine the clinical application of a type of palatoplasty that has a reduced impact on the maxillary growth and good function in velopharyngeal competence. A total of 37 patients with cleft palate were treated with levator veli palatini retropositioning combined with Buccinator myomucosal island flap. The patients were successfully treated in the first phase and were followed up for 1-3 years. Speech intelligibility was satisfactory and no fistula occurred. In conclusion, the results suggested that levator veli palatini retropositioning combined with the Buccinator myomucosal island flap may restore normal anatomic structure and location of the levator veli palatini, obtain good velopharyngeal competence, and decrease the incidence rate thereof. Thus, levator veli palatini retropositioning combined with the Buccinator myomucosal island flap is a functional procedure for cleft palate repair.

This volume claims to be the first of its kind to be published since the 1970s; this is probably an exaggeration but the claim reflects that China’s relations with Africa have been a relatively neg...

With the variation of resources and norms in society, the effects of resources and norms on the well-being of individuals are likely to change. People’s age, education, family income, religiosity, voluntary organizational membership, and even protest participation can be considered resources and can maintain fits to local and global liberal norms. Specifically, local norms rest on popularity and valuation in societies. This paper studies the hypothesized effects of resources and normative fits and analyzes data collected from the World Values Survey of 2252 adults in 2005 and 2014 in Hong Kong, China. Results mostly support the resource and normative fit hypotheses. Age, family income, and active voluntary organizational membership are more salutary in 2014 than in 2005. By contrast, education and religious affiliation became less salutary in 2014 than in 2005. In support of the normative fit hypothesis but against the resource hypothesis, protest participation appeared to diminish well-being. Results present implications for enhancing well-being by fostering resources and normative fits.

Observations reveal that People's Congress elections at the county/district and town/township levels in China in 2003, 2006–07 and 2011–12 were not entirely free and just. There are many loopholes, and they had been fully exploited by the Chinese authorities to control the elections. The problem does not lie in the specific provisions of the Election Law; the fundamental question is that the Chinese leadership has no intention to conduct free and just elections at the grassroots level. Its most important consideration is to control, or to maintain political stability, and this consideration became even stronger in 2011–12 because of the domestic political difficulties.

OBJECTIVE To examine the interaction effect of anxiety and depression on the intentional forgetting of positive and negative valence words. METHODS One hundred fifty-five grade 7 to grade 10 students participated in the study. The item-method directed forgetting paradigm was used to examine the intentional forgetting of positive-valence, negative-valence, and neutral-valence words. RESULTS Negative-valence words were recognized better than either positive-valence or neutral-valence words. The results revealed an anxiety main effect (p = .01, LLCI = -.09, and ULCI = -.01) and a depression main effect (p = .04, LLCI = .00, and ULCI = .24). The anxiety score was negative, whereas the depression score was positively related to the directed forgetting of negative-valence words. Regression-based moderation analysis revealed a significant anxiety × depression interaction effect on the directed forgetting of positive-valence words (p = .02, LLCI = .00, and ULCI = .01). Greater anxiety was associated with more directed forgetting of positive-valance words only among participants with high depression scores. With negative-valence words, the anxiety × depression interaction effect was not significant (p = .15, LLCI = - .00, and ULCI = .01). CONCLUSION Therapeutic strategies to increase positive memory bias may reduce anxiety symptoms only among those with high depression scores. Interventions to reduce negative memory bias may reduce anxiety symptoms irrespective of levels of depression.

20S-hydroxyvitamin D3 [20S(OH)D3] is anti-inflammatory and not hypercalcemic, suggesting its potential as a lead compound. In this study, side chain modified 20S(OH)D3 analogs (4, 13, 23 and 33) together with their 1α-OH derivatives were synthesized and their metabolism and biological activities tested. 4, 13 and 23 are good substrates for CYP27B1, enabling enzymatic synthesis of their 1α-OH derivatives 5, 14 and 24. However, 33 could not be hydroxylated by CYP27B1 and acts as an inhibitor. All analogs were poorer substrates for CYP24A1 than calcitriol, indicating improved catabolic stability. While the parent analogs showed minimal VDR stimulating activity, their 1α-OH derivatives were potent VDR agonists. 4, 5, 14 and 24 significantly upregulated the expression of CYP24A1 at the mRNA level, consistent with their VDR activation abilities and indicating that 1α-hydroxylation is required to produce analogs with strong activity. These analogs have anti-inflammatory activities that are influenced by side chain composition and by 1α-hydroxylation. To understand their molecular interactions with the VDR, 20S(OH)D3, 4 and 33 were co-crystalized with the VDR ligand binding domain, which revealed subtle differences to the calcitriol-bound receptor. This study demonstrates the potential of the 20S(OH)D3 scaffold for the development of novel anti-inflammatory agents.

Student creation of educational materials has the capacity both to enhance learning and to decrease costs. Three successive honors-style classes of undergraduate students in a cancer genetics class worked with a new software system, CuboCube, to create an e-textbook. CuboCube is an open-source learning materials creation system designed to facilitate e-textbook development, with an ultimate goal of improving the social learning experience for students. Equipped with crowdsourcing capabilities, CuboCube provides intuitive tools for nontechnical and technical authors alike to create content together in a structured manner. The process of e-textbook development revealed both strengths and challenges of the approach, which can inform future efforts. Both the CuboCube platform and the Cancer Genetics E-textbook are freely available to the community.

The economic rise of the BRICS (Brazil, Russia, India, China and South Africa) inevitably leads to a redistribution of power in the international system. Chinese leaders today accord a considerable priority to this group, and there are elements of realism, liberalism/institutionalism and constructivism in their approach. This article intends to study China's policy towards BRICS and examine the above elements so as to better understand how the Chinese leadership perceives China's role in the international system, and how it seeks to articulate its interests and enhance its influence.