bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of Autophagy Enhances Anticancer Effects of Atorvastatin in Digestive Malignancies
Authors: Yang Pei-Ming , Liu Yuan-Ling , Lin Yi-Chu , Shun Chia-Tung , Wu Ming-Shiang , Chen Ching-Chow 
Published: September 2010

Abstract
Preclinical and clinical studies have shown that statins, the 3-hydroxy-3-methylglutaryl–CoA reductase inhibitors with cholesterol-lowering properties, exhibited anticancer effects. However, the underlying mechanisms remain ill defined. In this study, we showed that atorvastatin could inhibit the growth of hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) cells via induction of apoptosis. Atorvastatin also induced autophagy that is a physiologic process involved in the turnover of intracellular organelles. Atorvastatin-induced autophagy was found to be inhibited by AMP-activated protein kinase (AMPK) small interfering RNA. Examination of HCC patients showed the positive correlation between AMPK activity and autophagic marker (beclin-1). Atorvastatin-induced AMPK activation could induce p21 expression, which was also positively correlated with beclin-1 expression in CRC patients. AMPK/p21 signaling caused endoplasmic reticulum (ER) stress response leading to the induction of autophagy. Inhibition of autophagy by an autophagic inhibitor bafilomycin A1 or genetic knockout of autophagy-related gene 5 enhanced atorvastatin-induced cytotoxicity and apoptosis. In summary, activation of AMPK by atorvastatin enhances p21 expression and ER stress response, leading to autophagy, which promotes survival of cancer cells. Combinations of atorvastatin with bafilomycin A1 provide a novel and promising strategy to improve the treatment of digestive malignancies. Cancer Res; 70(19); 7699–709. ©2010 AACR.
Activity of the Novel Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 against T-Cell Acute Lymphoblastic Leukemia
Authors: Chiarini Francesca , Grimaldi Cecilia , Ricci Francesca , Tazzari Pier Luigi , Evangelisti Camilla , Ognibene Andrea , Battistelli Michela , Falcieri Elisabetta , Melchionda Fraia , Pession Andrea , Pagliaro Pasqualepaolo , McCubrey James A. , Martelli Alberto M. 
Published: September 2010

Abstract
Recent findings have highlighted that constitutively active phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it upregulates cell proliferation, survival, and drug resistance. These observations lend compelling weight to the application of PI3K/Akt/mTOR inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of the novel dual PI3K/mTOR inhibitor NVP-BEZ235, an orally bioavailable imidazoquinoline derivative, which has entered clinical trials for solid tumors, on both T-ALL cell lines and patient samples. NVP-BEZ235 was cytotoxic to a panel of T-ALL cell lines as determined by MTT assays. NVP-BEZ235 treatment resulted in cell cycle arrest and apoptosis. Western blots showed a dose- and time-dependent dephosphorylation of Akt and mTORC1 downstream targets in response to NVP-BEZ235. Remarkably, NVP-BEZ235 targeted the side population of both T-ALL cell lines and patient lymphoblasts, which might correspond to leukemia-initiating cells, and synergized with chemotherapeutic agents (cyclophosphamide, cytarabine, dexamethasone) currently used for treating T-ALL patients. NVP-BEZ235 reduced chemoresistance to vincristine induced in Jurkat cells by coculturing with MS-5 stromal cells, which mimic the bone marrow microenvironment. NVP-BEZ235 was cytotoxic to T-ALL patient lymphoblasts displaying pathway activation, where the drug dephosphorylated eukaryotic initiation factor 4E-binding protein 1, at variance with rapamycin. Taken together, our findings indicate that longitudinal inhibition at two nodes of the PI3K/Akt/mTOR network with NVP-BEZ235, either alone or in combination with chemotherapeutic drugs, may be an efficient treatment of those T-ALLs that have aberrant upregulation of this signaling pathway for their proliferation and survival. Cancer Res; 70(20); 8097–107. ©2010 AACR.
Pancreatic Cancer Screening in a Prospective Cohort of High-Risk Patients: A Comprehensive Strategy of Imaging and Genetics
Authors: Verna Elizabeth C. , Hwang Caroline , Stevens Peter D. , Rotterdam Heidrun , Stavropoulos Stavros N. , Sy Carolyn D. , Prince Martin A. , Chung Wendy K. , Fine Robert L. , Chabot John A. , Frucht Harold 
Published: September 2010

Abstract
Purpose: Pancreatic cancer is a virtually uniformly fatal disease. We aimed to determine if screening to identify curable neoplasms is effective when offered to patients at high risk.
Experimental Design: Patients at high risk of pancreatic cancer were prospectively enrolled into a screening program. Endoscopic ultrasound (EUS), magnetic resonance imaging (MRI), and genetic testing were offered by a multidisciplinary team according to each patient's risk.
Results: Fifty-one patients in 43 families were enrolled, with mean age of 52 years, 35% of whom were male. Of these patients, 31 underwent EUS and 33 MRI. EUS revealed two patients with pancreatic cancer (one resectable, one metastatic), five with intraductal papillary mucinous neoplasms (IPMN), seven with cysts, and six with parenchymal changes. Five had pancreatic surgery (one total pancreatectomy for pancreatic cancer, three distal and one central pancreatectomy for pancreatic intraepithelial neoplasia 2 and IPMN). A total of 24 (47%) had genetic testing (19 for BRCA1/2 mutations, 4 for CDKN2A, 1 for MLH1/MSH2) and 7 were positive for BRCA1/2 mutations. Four extrapancreatic neoplasms were found: two ovarian cancers on prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy, one carcinoid, and one papillary thyroid carcinoma. Overall, 6 (12%) of the 51 patients had neoplastic lesions in the pancreas and 9 (18%) had neoplasms in any location. All were on the initial round of screening. All patients remain alive and without complications of screening.
Conclusions: Pancreatic cancer screening for high-risk patients with a comprehensive strategy of imaging and genetics is effective and identifies curable neoplasms that can be resected. Ongoing study will better define who will benefit from screening and what screening strategy will be the most effective. Clin Cancer Res; 16(20); 5028–37. ©2010 AACR.
Pharmacologic Inactivation of Kinase Suppressor of Ras1 Sensitizes Epidermal Growth Factor Receptor and Oncogenic Ras-Dependent Tumors to Ionizing Radiation Treatment
Authors: Xiao Hongyan , Zhang Qingbei , Shen Jikun , Bindokas Vytas , Xing H. Rosie 
Published: September 2010

AbstractSelective enhancement of tumor response to radiation therapy is a highly attractive objective, but it has not been met clinically. Gain-of-function Ras (gf) signaling via hyperactivation of receptor tyrosine kinases, such as the epidermal growth factor receptor (EGFR), or via oncogenic mutation of Ras is shown to confer radioresistance and requires the engagement of the Raf/MEK/ERK pathway. However, upstream mediators of such interaction in cancer cells that could be targeted for radiosensitization have not been identified and characterized. Here, we provide original observations both in vitro and in vivo that kinase suppressor of Ras1 (KSR1) is a new target for reversing gf Ras-mediated radioresistance. We employed EGFR-dependent A431 squamous cell carcinoma (SCC) and genetically defined the molecular function of KSR1 in irradiation-induced Raf/MEK/ERK activation. In vitro KSR1 inactivation via genetic inhibition of its expression or kinase function abrogated ionizing radiation–induced activation of the Raf/MEK/ERK2 cascade, enhanced the cytotoxic effect of radiation, and achieved radiosensitization associated with inhibition of DNA damage repair and enhancement of clonogenic death. In vivo pharmacologic inactivation of KSR1 by KSR1 AS-ODN infusion leads to radiosensitization in EGFR-dependent A431 SCC and in oncogenic K-Ras-driven A549 human non–small cell lung carcinoma. These observations collectively establish KSR1 as a novel target for radiosensitization and show the feasibility of using KSR1 AS-ODN as a radiosensitizer for treating gf Ras-dependent human malignancies. Identification of such mediators of gf Ras signaling in response to irradiation holds promises for improving the therapeutic efficacy of radiation therapy and our ability to eradicate tumor. Mol Cancer Ther; 9(10); 2724–36. ©2010 AACR.
Efficacy of the Multi-Kinase Inhibitor Enzastaurin Is Dependent on Cellular Signaling Context
Authors: Kuo Wen-Liang , Liu Jing , Mauceri Helena , Vokes Everett E. , Weichselbaum Ralph , Rosner Marsha Rich , Cohen Ezra Eddy Wyssam 
Published: September 2010

Abstract
The number of targeted small molecules being developed in oncology is increasing rapidly. Many of these are designed to inhibit multiple kinases, and thus the mechanisms of responsiveness and predictive biomarkers can be difficult to discern. In fact, with few exceptions, multi-kinase inhibitors are developed with limited mechanism-based patient selection. Enzastaurin is a multi-kinase inhibitor being studied in several malignancies that we hypothesized would be active in squamous cell carcinoma of the head and neck, because it inhibits classic and novel protein kinase C isoforms. Indeed, enzastaurin reduced the growth of SQ-20B and CAL27 tumor xenografts, decreased proliferation in these cell lines, inhibited putative target phosphorylation, and induced cell cycle arrest. Gene expression arrays confirmed that expression of cell cycle genes, including cyclins D and E, were significantly altered by exposure to enzastaurin. However, testing a panel of squamous cell carcinoma of the head and neck cell lines revealed variable sensitivity to enzastaurin, which correlated significantly with baseline cyclin D1 protein expression. Moreover, sensitivity and resistance could be reversed, respectively, by expression or depletion of cyclin D1. Furthermore, analysis of sensitive and resistant cell lines revealed distinct differences in cyclin D1 regulation. Enzastaurin modulated cyclin D1 synthesis through an Akt-regulated pathway in the former, whereas high-level CCND1 gene amplification was present in the latter. These results underscore the critical relevance of cellular signaling context in developing cancer therapies in general and suggest that enzastaurin in particular would be most effective in tumors where baseline cyclin D1 expression is low to moderate and physiologically regulated. Mol Cancer Ther; 9(10); 2814–24. ©2010 AACR.
Colon Tumor Cell Growth–Inhibitory Activity of Sulindac Sulfide and Other Nonsteroidal Anti-Inflammatory Drugs Is Associated with Phosphodiesterase 5 Inhibition
Authors: Tinsley Heather N. , Gary Bernard D. , Thaiparambil Jose , Li Nan , Lu Wenyan , Li Yonghe , Maxuitenko Yulia Y. , Keeton Adam B. , Piazza Gary A. 
Published: September 2010

Abstract
Nonsteroidal anti-inflammatory drugs (NSAID) display promising antineoplastic activity, but toxicity resulting from cyclooxygenase (COX) inhibition limits their clinical use for chemoprevention. Studies suggest that the mechanism may be COX independent, although alternative targets have not been well defined. Here, we show that the NSAID sulindac sulfide (SS) inhibits cyclic guanosine 3′,5′-monophosphate (cGMP) phosphodiesterase (PDE) activity in colon tumor cell lysates at concentrations that inhibit colon tumor cell growth in vitro and in vivo. A series of chemically diverse NSAIDs also inhibited cGMP hydrolysis at concentrations that correlate with their potency to inhibit colon tumor cell growth, whereas no correlation was observed with COX-2 inhibition. Consistent with its selectivity for inhibiting cGMP hydrolysis compared with cyclic AMP hydrolysis, SS inhibited the cGMP-specific PDE5 isozyme and increased cGMP levels in colon tumor cells. Of numerous PDE isozyme–specific inhibitors evaluated, only the PDE5-selective inhibitor MY5445 inhibited colon tumor cell growth. The effects of SS and MY5445 on cell growth were associated with inhibition of β-catenin–mediated transcriptional activity to suppress the synthesis of cyclin D and survivin, which regulate tumor cell proliferation and apoptosis, respectively. SS had minimal effects on cGMP PDE activity in normal colonocytes, which displayed reduced sensitivity to SS and did not express PDE5. PDE5 was found to be overexpressed in colon tumor cell lines as well as in colon adenomas and adenocarcinomas compared with normal colonic mucosa. These results suggest that PDE5 inhibition, cGMP elevation, and inhibition of β-catenin transcriptional activity may contribute to the chemopreventive properties of certain NSAIDs. Cancer Prev Res; 3(10); 1303–13. ©2010 AACR.
Ancestry as a Determinant of Mean Population C-Reactive Protein Values
Authors: Shah Tina , Newcombe Paul , Smeeth Liam , Addo Juliet , Casas Juan P. , Whittaker John , Miller Michelle A. , Tinworth Lorna , Jeffery Steve , Strazzullo Pasquale , Cappuccio Francesco P. , Hingorani Aroon D. 
Published: September 2010

Background—
Eligibility for rosuvastatin treatment for cardiovascular disease prevention includes a C-reactive protein (CRP) concentration >2 mg/L. Most observational studies of CRP and cardiovascular disease have been in Europeans. We evaluated the influence of ancestry on population CRP concentration to assess the implications for statin targeting in non-Europeans.

Methods and Results—
In a systematic review and meta-analysis among 221 287 people from 89 studies, geometric mean CRP was 2.6 mg/L (95% credible interval, 2.27 to 2.96) in blacks resident in the United States (n=18 585); 2.51 mg/L (95% CI, 1.18 to 2.86) in Hispanics (n=5049); 2.34 mg/L (95% CI, 1.99 to 2.8) in South Asians (n=1053); 2.03 mg/L (95% CI, 1.77 to 2.3) in whites (n=104 949); and 1.01 mg/L (95% CI, 0.88 to 1.18) in East Asians (n=39 521). Differences were not explained by study design or CRP assay and were preserved after adjustment for age and body mass index. At age 60 years, fewer than half of East Asians but more than two thirds of Hispanics were estimated to have CRP values exceeding 2 mg/L. HapMap frequencies of CRP polymorphisms known to associate with CRP concentration but not coronary heart disease events differed by ancestry. In participant data from the Wandsworth Heart and Stroke Study including European, South Asian and African, and Caribbean-descent subjects, body mass index, systolic blood pressure, and smoking contributed to between-group differences in CRP, but the majority of the difference in CRP was unexplained.

Conclusions—
Differences in CRP concentration in populations of diverse ancestry are sufficiently large to affect statin eligibility, based on a single CRP threshold of 2 mg/L, and only partially influenced by differences in variables related to cardiovascular risk. A single threshold value of CRP for cardiovascular risk prediction could lead to inequalities in statin eligibility that may not accurately reflect underlying levels of cardiovascular risk.
Use of the Internet and Ratings of Information Sources for Medical Decisions: Results from the DECISIONS Survey
Authors: Couper Mick P. , Singer Eleanor , Levin Carrie A. , Fowler Floyd J. , Fagerlin Angela , Zikmund-Fisher Brian J. 
Published: September 2010

Background The rise in Internet use for seeking health information raises questions about the role the Internet may play in how patients make medical decisions. Objective To examine Internet use and perceived importance of different sources of information by patients making 9 specific medical decisions covering prescription medication initiation, cancer screening, and elective surgery. Setting National sample of US adults identified by random-digit dialing. Design Cross-sectional survey conducted between November 2006 and May 2007. Participants The final sample comprised 2575 English-speaking US adults aged 40 y and older who had either undergone 1 of 9 medical procedures or tests or talked with a health care provider about doing so during the previous 2 y. Measurements Participants indicated if they or other family members used the Internet to seek information related to each of the specific medical decisions and rated how important the health care provider, the Internet (if used), family and friends, and the media (newspapers, magazines, and television) were in providing information to help make the medical decision. Results Use of the Internet for information related to specific decisions among adults 40 y and older was generally low (28%) but varied across decisions, from 17% for breast cancer screening to 48% for hip/knee replacement. Internet use was higher at younger ages, rising from 14% among those aged 70 y and older to 38% for those aged 40 to 49 y. Internet users consistently rated health care providers as the most influential source of information for medical decisions, followed by the Internet, family and friends, and media. Limitations Telephone surveys are limited by coverage and nonresponse. The authors excluded health-related Internet use not associated with the 9 target decisions. Conclusions A minority of patients reported using the Internet to make specific common medical decisions, but use varied widely by type of decision. Perhaps reflecting perceived risk and uncertainty, use was lowest for screening decisions and highest for surgical decisions.
Decision-Making Processes for Breast, Colorectal, and Prostate Cancer Screening: The DECISIONS Survey
Authors: Hoffman Richard M. , Lewis Carmen L. , Pignone Michael P. , Couper Mick P. , Barry Michael J. , Elmore Joann G. , Levin Carrie A. , Van Hoewyk John , Zikmund-Fisher Brian J. 
Published: September 2010

Background Patients should understand the risks and benefits of cancer screening in order to make informed screening decisions. Objectives To evaluate the extent of informed decision making in patient-provider discussions for colorectal (CRC), breast (BrCa), and prostate (PCa) cancer screening. Setting National sample of US adults identified by random-digit dialing. Design Cross-sectional survey conducted between November 2006 and May 2007. Participants English-speaking US adults aged 50 y and older who had discussed cancer screening with a health care provider within the previous 2 y. Measurements Cancer screening survey modules that asked about demographic characteristics, cancer knowledge, the importance of various sources of information, and self-reported cancer screening decision-making processes. Results Overall, 1082 participants completed 1 or more of the 3 cancer modules. Although participants generally considered themselves well informed about screening tests, half or more could not correctly answer even 1 open-ended knowledge question for any given module. Participants consistently overestimated risks for being diagnosed with and dying from each cancer and overestimated the positive predictive values of prostate-specific antigen tests and mammography. Providers were the most highly rated information source, usually initiated screening discussions (64%–84%), and often recommended screening (73%–90%). However, participants reported that providers elicited their screening preferences in only 31% (CRC women) to 57% (PCa) of discussions. Although more than 90% of the discussions addressed the pros of screening, only 19% (BrCa) to 30% (PCa) addressed the cons of screening. Limitations Recall bias is possible because screening process reports were not independently validated. Conclusions Cancer screening decisions reported by patients who discussed screening with their health care providers consistently failed to meet criteria for being informed. Given the high ratings for provider information and frequent recommendations for screening, providers have important opportunities to ensure that informed decision making occurs for cancer screening decisions.
How Does Feeling Informed Relate to Being Informed? The DECISIONS Survey
Authors: Sepucha Karen R. , Fagerlin Angela , Couper Mick P. , Levin Carrie A. , Singer Eleanor , Zikmund-Fisher Brian J. 
Published: September 2010

Background An important part of delivering high-quality, patient-centered care is making sure patients are informed about decisions regarding their health care. The objective was to examine whether patients’ perceptions about how informed they were about common medical decisions are related to their ability to answer various knowledge questions. Methods A cross-sectional survey was conducted November 2006 to May 2007 of a national sample of US adults identified by random-digit dialing. Participants were 2575 English-speaking US adults aged 40 and older who had made 1 of 9 medication, cancer screening, or elective surgery decisions within the previous 2 years. Participants rated how informed they felt on a scale of 0 (not at all informed) to 10 (extremely well-informed), answered decision-specific knowledge questions, and completed standard demographic questions. Results Overall, 36% felt extremely well informed (10), 30% felt well informed (8–9), and 33% felt not at all to somewhat informed (0–7). Multivariate logistic regression analyses showed no overall relationship between knowledge scores and perceptions of being extremely well informed (odds ratio [OR] = 0.94, 95% confidence interval [CI] 0.63–1.42, P = 0.78). Three patterns emerged for decision types: a negative relationship for cancer screening decisions (OR = 0.58, CI 0.33–1.02, P = 0.06), no relationship for medication decisions (OR = 0.99, CI 0.54–1.83, P = 0.98), and a positive relationship for surgery decisions (OR = 3.07, 95% CI 0.90–10.54, P = 0.07). Trust in the doctor was associated with feeling extremely well-informed for all 3 types of decisions. Lower education and lower income were also associated with feeling extremely well informed for medication and screening decisions. Retrospective survey data are subject to recall bias, and participants may have had different perspectives or more factual knowledge closer to the time of the decision. Conclusions Patients facing common medical decisions are not able to accurately assess how well informed they are. Clinicians need to be proactive in providing adequate information to patients and testing patients’ understanding to ensure informed decisions.
The Chinese Reform Experience: A Critical Assessment
Authors: Hart-Landsberg Martin 
Published: September 2010

The consensus among economists is that China’s post-1978 market reform policies have produced one of the world’s greatest economic success stories. Some progressives believe that China is now capable of serving as an anchor for a new (non-U.S. dominated) global economy. A few claim that the reform experience demonstrates the workability (and desirability) of market socialism. This article is critical of these views. Its four main conclusions are as follows: first, the reforms have led to the restoration of capitalism, not a new form of market socialism. Second, the gains attributed to the reforms have been seriously overstated. Early successes were largely due to the economic foundation established during the pre-reform Mao era. Moreover, the reform process has begun to undermine this foundation, increasing the country’s dependence on foreign investment, technology, and markets. Third, the reforms have produced an increasingly exploitative growth process, one that generates considerable wealth for a minority at unacceptably high cost for the majority. Finally, the reforms also produced a growth process whose logic led it to become enmeshed in, and dependent upon, a broader process of transnational restructuring, one controlled by transnational capital. As a result, China is not only incapable of serving as an anchor for an alternative global economy, its accumulation dynamics actually contribute to the strengthening of existing structures of power and the global imbalances and tensions they generate. JEL classification:O53, P30, F23