bluuebunny/crossref_metadata_2025_split huggingface dataset:
Paracrine Hedgehog Signaling Drives Metabolic Changes in Hepatocellular Carcinoma
Authors: Chan Isaac S. , Guy Cynthia D. , Chen Yuping , Lu Jiuyi , Swiderska-Syn Marzena , Michelotti Gregory A. , Karaca Gamze , Xie Guanhua , Krüger Leandi , Syn Wing-Kin , Anderson Blair R. , Pereira Thiago A. , Choi Steve S. , Baldwin Albert S. , Diehl Anna Mae 
Published: October 2012

Abstract
Hepatocellular carcinoma (HCC) typically develops in cirrhosis, a condition characterized by Hedgehog (Hh) pathway activation and accumulation of Hh-responsive myofibroblasts. Although Hh signaling generally regulates stromal–epithelial interactions that support epithelial viability, the role of Hh-dependent myofibroblasts in hepatocarcinogenesis is unknown. Here, we used human HCC samples, a mouse HCC model, and hepatoma cell/myofibroblast cocultures to examine the hypothesis that Hh signaling modulates myofibroblasts' metabolism to generate fuels for neighboring malignant hepatocytes. The results identify a novel paracrine mechanism whereby malignant hepatocytes produce Hh ligands to stimulate glycolysis in neighboring myofibroblasts, resulting in release of myofibroblast-derived lactate that the malignant hepatocytes use as an energy source. This discovery reveals new diagnostic and therapeutic targets that might be exploited to improve the outcomes of cirrhotic patients with HCCs. Cancer Res; 72(24); 6344–50. ©2012 AACR.
A Novel Evolutionarily Conserved Element Is a General Transcriptional Repressor of p21WAF1/CIP1
Authors: Xu Weiguo , Zhu Qi , Wu Zhenghua , Guo Hao , Wu Fengjuan , Mashausi Dhahiri S. , Zheng Chengjie , Li Dawei 
Published: October 2012

Abstract
The effective induction of p21WAF1/CIP1/Cdkn1a (p21) expression in p53-negative cancer cells is an important avenue in cancer management. We investigated the ability of various common chemotherapeutic drugs to induce p21 expression in p53-negative cancer cells and showed that the induction of p21 expression by oxaliplatin is caused by the derepression of a previously unrecognized negative regulatory element with a Sp1/Sp3 palindrome sequence core at −216 to −236 of the p21 proximal promoter. Electrophoretic mobility shift and antibody super-shift assays confirmed the specific binding of Sp1/Sp3, and showed that the oxaliplatin-mediated derepression of p21 transcription was associated with an increased Sp1/Sp3 phosphorylation and binding affinity to the oxaliplatin-responsive element. A search of the ENCODE database for vertebrate-conserved genomic elements identified the Sp1/Sp3 palindrome element as the only vertebrate-conserved element within the 500-bp proximal p21 promoter region, indicating its fundamental importance. In in vivo competition assays, transfected synthetic Sp1/Sp3 palindrome elements derepressed the cotransfected or endogenous p21 promoter in a dosage-dependent manner. This derepression was not seen in oxaliplatin-treated cells, suggesting that the exogenous Sp1/Sp3 palindrome and oxaliplatin had the same downstream signaling target. Taken together, our results revealed, for the first time, this evolutionarily conserved Sp1/Sp3 palindrome element in the proximal p21 promoter that serves as a regulatory repressor to maintain p21 basal level expression. Cancer Res; 72(23); 6236–46. ©2012 AACR.
PIK3CA Mutation H1047R Is Associated with Response to PI3K/AKT/mTOR Signaling Pathway Inhibitors in Early-Phase Clinical Trials
Authors: Janku Filip , Wheler Jennifer J. , Naing Aung , Falchook Gerald S. , Hong David S. , Stepanek Vanda M. , Fu Siqing , Piha-Paul Sarina A. , Lee J. Jack , Luthra Rajyalakshmi , Tsimberidou Apostolia M. , Kurzrock Razelle 
Published: October 2012

Abstract
PIK3CA mutations may predict response to PI3K/AKT/mTOR inhibitors in patients with advanced cancers, but the relevance of mutation subtype has not been investigated. Patients with diverse cancers referred to the Clinical Center for Targeted Therapy were analyzed for PIK3CA and, if possible, KRAS mutations. Patients with PIK3CA mutations were treated, whenever possible, with agents targeting the PI3K/AKT/mTOR pathway. Overall, 105 (10%) of 1,012 patients tested harbored PIK3CA mutations. Sixty-six (median 3 prior therapies) of the 105 PIK3CA-mutant patients, including 16 individuals (of 55 PIK3CA-mutant patients tested) with simultaneous KRAS mutations, were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor; 17% (11/66) achieved a partial response (PR). Patients with a PIK3CA H1047R mutation compared with patients who had other PIK3CA mutations or patients with wild-type PIK3CA treated on the same protocols had a higher PR rate (6/16, 38% vs. 5/50; 10% vs. 23/174, 13%, respectively; all P ≤ 0.02). None of the 16 patients with coexisting PIK3CA and KRAS mutations in codon 12 or 13 attained a PR (0/16, 0%). Patients treated with combination therapy versus single-agent therapies had a higher PR rate (11/38, 29% vs. 0/28, 0%; P = 0.002). Multivariate analysis showed that H1047R was the only independent factor predicting response [OR 6.6, 95% confidence interval (CI), 1.02–43.0, P = 0.047). Our data suggest that interaction between PIK3CA mutation H1047R versus other aberrations and response to PI3K/AKT/mTOR axis inhibitors warrants further exploration. Cancer Res; 73(1); 276–84. ©2012 AACR.
Evolutionary Approaches to Prolong Progression-Free Survival in Breast Cancer
Authors: Silva Ariosto S. , Kam Yoonseok , Khin Zayar P. , Minton Susan E. , Gillies Robert J. , Gatenby Robert A. 
Published: October 2012

Abstract
Many cancers adapt to chemotherapeutic agents by upregulating membrane efflux pumps that export drugs from the cytoplasm, but this response comes at an energetic cost. In breast cancer patients, expression of these pumps is low in tumors before therapy but increases after treatment. While the evolution of therapeutic resistance is virtually inevitable, proliferation of resistant clones is not, suggesting strategies of adaptive therapy. Chemoresistant cells must consume excess resources to maintain resistance mechanisms, so adaptive therapy strategies explicitly aim to maintain a stable population of therapy-sensitive cells to suppress growth of resistant phenotypes through intratumoral competition. We used computational models parameterized by in vitro experiments to illustrate the efficacy of such approaches. Here, we show that low doses of verapamil and 2-deoxyglucose, to accentuate the cost of resistance and to decrease energy production, respectively, could suppress the proliferation of drug-resistant clones in vivo. Compared with standard high-dose-density treatment, the novel treatment we developed achieved a 2-fold to 10-fold increase in time to progression in tumor models. Our findings challenge the existing flawed paradigm of maximum dose treatment, a strategy that inevitably produces drug resistance that can be avoided by the adaptive therapy strategies we describe. Cancer Res; 72(24); 6362–70. ©2012 AACR.
p38 MAPK in Myeloma Cells Regulates Osteoclast and Osteoblast Activity and Induces Bone Destruction
Authors: He Jin , Liu Zhiqiang , Zheng Yuhuan , Qian Jianfei , Li Haiyan , Lu Yong , Xu Jingda , Hong Bangxing , Zhang Mingjun , Lin Pei , Cai Zhen , Orlowski Robert Z. , Kwak Larry W. , Yi Qing , Yang Jing 
Published: October 2012

Abstractp38 mitogen-activated protein kinase (MAPK), which is constitutively activated in human myeloma, has been implicated in bone destruction by this cancer, but the processes it recruits are obscure. In this study, we show that p38 activity in myeloma inhibits osteoblast differentiation and bone formation, but also enhances osteoclast maturation and bone resorption. p38 regulated the expression and secretion of the Wnt pathway antagonist DKK-1 and the monocyte chemoattractant MCP-1. Attenuating p38, DKK-1, or MCP-1 were each sufficient to reduce bone lesions in vivo. Although it is well known that DKK-1 inhibits osteoblast differentiation, we found that together with MCP-1, it could also promote osteoclast differentiation and bone resorption. The latter effects were mediated by enhancing expression of RANK in osteoclast progenitor cells and by upregulating secretion of its ligand RANKL from stromal cells and mature osteoblasts. In summary, our study defined the mechanisms by which p38 signaling in myeloma cells regulates osteoblastogenesis, osteoclastogenesis, and bone destruction. Our findings, which may have implications for bone invasion by other cancers where p38 is elevated, strongly suggests that targeting p38 for inhibition may offer an effective therapeutic approach to treat osteolytic bone lesions in patients with myeloma. Cancer Res; 72(24); 6393–402. ©2012 AACR.
Targeting Hypoxia, HIF-1, and Tumor Glucose Metabolism to Improve Radiotherapy Efficacy
Authors: Meijer Tineke W.H. , Kaanders Johannes H.A.M. , Span Paul N. , Bussink Johan 
Published: October 2012

Abstract
Radiotherapy, an important treatment modality in oncology, kills cells through induction of oxidative stress. However, malignant tumors vary in their response to irradiation as a consequence of resistance mechanisms taking place at the molecular level. It is important to understand these mechanisms of radioresistance, as counteracting them may improve the efficacy of radiotherapy. In this review, we describe how the hypoxia-inducible factor 1 (HIF-1) pathway has a profound effect on the response to radiotherapy. The main focus will be on HIF-1–controlled protection of the vasculature postirradiation and on HIF-1 regulation of glycolysis and the pentose phosphate pathway. This aberrant cellular metabolism increases the antioxidant capacity of tumors, thereby countering the oxidative stress caused by irradiation. From the results of translational studies and the first clinical phase I/II trials, it can be concluded that targeting HIF-1 and tumor glucose metabolism at several levels reduces the antioxidant capacity of tumors, affects the tumor microenvironment, and sensitizes various solid tumors to irradiation. Clin Cancer Res; 18(20); 5585–94. ©2012 AACR.
Predicting Drug Targets and Biomarkers of Cancer via Genome-Scale Metabolic Modeling
Authors: Jerby Livnat , Ruppin Eytan 
Published: October 2012

Abstract
The metabolism of cancer cells is reprogrammed in various ways to support their growth and survival. Studying these phenomena to develop noninvasive diagnostic tools and selective treatments is a promising avenue. Metabolic modeling has recently emerged as a new way to study human metabolism in a systematic, genome-scale manner by using pertinent high-throughput omics data. This method has been shown in various studies to provide fairly accurate estimates of the metabolic phenotype and its modifications following genetic and environmental perturbations. Here, we provide an overview of genome-scale metabolic modeling and its current use to model human metabolism in health and disease. We then describe the initial steps made using it to study cancer metabolism and how it may be harnessed to enhance ongoing experimental efforts to identify drug targets and biomarkers for cancer in a rationale-based manner. Clin Cancer Res; 18(20); 5572–84. ©2012 AACR.
p53 Arg72Pro Polymorphism, HPV Status and Initiation, Progression, and Development of Cervical Cancer: A Systematic Review and Meta-Analysis
Authors: Habbous Steven , Pang Vincent , Eng Lawson , Xu Wei , Kurtz Goldie , Liu Fei-Fei , Mackay Helen , Amir Eitan , Liu Geoffrey 
Published: October 2012

Abstract
Cervical cancer develops through progression from normal cervical epithelium through squamous intraepithelial lesions (SIL) to invasive cancer. Cervical cancer is associated with oncogenic human papillomavirus (HPV). The HPV E6 oncoprotein binds to the tumor suppressor gene product p53, promoting its degradation; the Arg allele of p53 Arg72Pro polymorphism binds more ardently with HPV E6 than the Pro variant. Here we evaluate the role of p53 Arg72Pro polymorphism and HPV status on the initiation, progression, and development of cervical cancer. A systematic review and meta-analysis were conducted. Events of interest were the initiation of neoplasia (SIL vs. normal), progression to invasive cancer (cervical cancer vs. SIL), and risk of invasive cancer (cervical cancer vs. normal) by HPV status. OR were extracted from individual studies and pooled using generic inverse variance and random effects modeling. Forty-nine studies were included. In individuals showing HPV positivity, there was a significantly higher odds of progression from SIL to cervical cancer with the p53 Arg allele [OR 1.37; 95% confidence intervals (CI), 1.15–1.62; P &lt; 0.001]. This association was not seen in HPV-negative individuals. p53 Arg72Pro was not associated with the risk of cervical cancer or initiation of SIL in either HPV-positive or HPV-negative patient subsets. The Arg variant of p53 Arg72Pro is associated with progression of SIL to cervical cancer only in the presence of HPV positivity. There were no associations of this variant with overall risk or initiation of cancer in either HPV-positive or HPV-negative patients. Clin Cancer Res; 18(23); 6407–15. ©2012 AACR.
Accelerating Cancer Therapy Development: The Importance of Combination Strategies and Collaboration. Summary of an Institute of Medicine Workshop
Authors: LoRusso Patricia M. , Canetta Renzo , Wagner John A. , Balogh Erin P. , Nass Sharyl J. , Boerner Scott A. , Hohneker John 
Published: October 2012

Abstract
Cancer cells contain multiple genetic changes in cell signaling pathways that drive abnormal cell survival, proliferation, invasion, and metastasis. Unfortunately, patients treated with single agents inhibiting only one of these pathways—even if showing an initial response—often develop resistance with subsequent relapse or progression of their cancer, typically via the activation of an alternative uninhibited pathway. Combination therapies offer the potential for inhibiting multiple targets and pathways simultaneously to more effectively kill cancer cells and prevent or delay the emergence of drug resistance. However, there are many unique challenges to developing combination therapies, including devising and applying appropriate preclinical tests and clinical trial designs, prioritizing which combination therapies to test, avoiding overlapping toxicity of multiple agents, and overcoming legal, cultural, and regulatory barriers that impede collaboration among multiple companies, organizations, and/or institutions. More effective strategies to efficiently develop combination cancer therapies are urgently needed. Thus, the Institute of Medicine's National Cancer Policy Forum recently convened a workshop with the goal of identifying barriers that may be impeding the development of combination investigational cancer therapies, as well as potential solutions to overcome those barriers, improve collaboration, and ultimately accelerate the development of promising combinations of investigational cancer therapies. Clin Cancer Res; 18(22); 6101–9. ©2012 AACR.
Dominant Role of the Protein-Tyrosine Phosphatase CD148 in Regulating Platelet Activation Relative to Protein-Tyrosine Phosphatase-1B
Authors: Mori Jun , Wang Ying-Jie , Ellison Stuart , Heising Silke , Neel Benjamin G. , Tremblay Michel L. , Watson Steve P. , Senis Yotis A. 
Published: October 2012

Objective—

The receptor-like protein-tyrosine phosphatase (PTP) CD148 and the nontransmembrane PTP1-B have been shown to be net positive regulators of Src family kinases in platelets. In the present study, we compared the relative contributions of these PTPs in platelet activation by the major glycoprotein, glycoprotein VI, α
IIb
β
3
, and C-type lectin-like receptor 2 (CLEC-2).

Methods and Results—

PTP-1B–deficient mouse platelets responded normally to the glycoprotein VI–specific agonist collagen-related peptide and antibody-mediated CLEC-2 activation. However, they exhibited a marginal reduction in α
IIb
β
3
-mediated Src family kinase activation and tyrosine phosphorylation. In contrast, CD148-deficient platelets exhibited a dramatic reduction in activation by glycoprotein VI and α
IIb
β
3
and a marginal reduction in response to activation by CLEC-2, which was further enhanced in the absence of PTP-1B. These defects were associated with reduced activation of Src family kinase and spleen tyrosine kinase, suggesting a causal relationship. Under arteriolar flow conditions, there was defective aggregate formation in the absence of PTP-1B and, to a greater extent, CD148 and a severe abrogation of both adhesion and aggregation in the absence of both PTPs.

Conclusion—
Findings from this study demonstrate that CD148 plays a dominant role in activating Src family kinases in platelets relative to PTP-1B. Both PTPs are required for optimal platelet activation and aggregate formation under high arterial shear rates.
Myeloid Krüppel-Like Factor 4 Deficiency Augments Atherogenesis in ApoE
−/−
Mice—Brief Report
Authors: Sharma Nikunj , Lu Yuan , Zhou Guangjin , Liao Xudong , Kapil Parul , Anand Puneet , Mahabeleshwar Ganapati H. , Stamler Jonathan S. , Jain Mukesh K. 
Published: October 2012

Objective—
To investigate the role of Krüppel-like factor 4 (KLF4), an essential transcriptional regulator of macrophage polarization (M1/M2), in the pathogenesis of atherosclerosis.

Methods and Results—

Despite the acknowledged importance of macrophages in atherosclerosis, the role of M1 (classically activated or proinflammatory) versus M2 (alternatively activated or anti-inflammatory) macrophages in this process remains incompletely understood. We recently identified KLF4 as a regulator of macrophage subset specification; that is, KLF4 promotes M2 and inhibits M1 phenotype. Here, we provide evidence that KLF4-deficient macrophages exhibit enhanced proinflammatory activation and foam cell formation in response to oxidized lipids. In vivo, myeloid KLF4-deficient mice (ApoE
−/−
background) develop significantly more vascular inflammation and atherosclerotic lesion formation.

Conclusion—
Our findings identify myeloid KLF4 as an essential regulator of vascular inflammation and experimental atherogenesis.
Low Prevalence of Mutations in Known Loci for Autosomal Dominant Hypercholesterolemia in a Multiethnic Patient Cohort
Authors: Ahmad Zahid , Adams-Huet Beverley , Chen Chiyuan , Garg Abhimanyu 
Published: October 2012

Background—

Autosomal dominant hypercholesterolemia (ADH), characterized by elevated plasma levels of low-density lipoprotein (LDL)-cholesterol, is caused by variants in at least 3 different genes: LDL receptor (
LDLR
), apolipoprotein B-100, and proprotein convertase subtilisin-like kexin type 9. There is paucity of data about the molecular basis of ADH among ethnic groups other than those of European or Japanese descent. Here, we examined the molecular basis of ADH in a multiethnic patient cohort from lipid clinics in a large, urban US city.

Methods and Results—

A total of 38 men and 53 women, aged 22 to 76 years, met modified Simon-Broome criteria for ADH and were screened for mutations in the exons and consensus splice sites of
LDLR
, and in selected exons of apolipoprotein B-100 and proprotein convertase subtilisin-like kexin type 9. Deletions and duplications of
LDLR
exons were detected with multiplex ligation-dependent probe amplification. Heterozygous variants in
LDLR
were identified in 30 patients and in apolipoprotein B-100 in 1 patient. The remaining 60 patients (65%) had unexplained ADH. A higher proportion of blacks (77%) than either non-Hispanic whites (57%) or Hispanics (53%) had unexplained ADH. Compared with patients with
LDLR
variants, those with unexplained ADH had lower levels of LDL-cholesterol (292±47 mg/dL versus 239±42 mg/dL, respectively;
P
<0.0001) and higher levels of high-density lipoprotein cholesterol (45±12 mg/dL versus 54±13 mg/dL, respectively;
P
=0.003).

Conclusions—
Our findings suggest that additional loci may contribute to ADH, especially in understudied populations such as blacks.
Health Status and Depression Remission in Patients With Chronic Heart Failure
Authors: Xiong Glen L. , Fiuzat Mona , Kuchibhatla Maragatha , Krishnan Ranga , O’Connor Christopher M. , Jiang Wei ,   on behalf of the SADHART-CHF Investigators
Published: October 2012

Background—
Depression is a common comorbidity in heart failure and is strongly associated with increased mortality, morbidity, and reduced health status. Whether depression treatment may result in improvement of health status in heart failure patients with comorbid depression remains unknown.

Methods and Results—

The Sertraline Against Depression and Heart Disease in Chronic Heart Failure study randomized 469 participants with chronic heart failure (left ventricular ejection fraction 45% and New York Heart Association class II) and major depressive disorder based on Diagnostic Statistics Manual fourth edition criteria to sertraline or placebo for 12 weeks. The Kansas City Cardiomyopathy Questionnaire, 36-Item Short-Form Health Survey, and 6-minute walk test were used to assess health status. Health status changes between treatment arms and remission status were evaluated adjusting for baseline variables and treatment assignment. The final Hamilton Depression Rating Scale scores were 3.50±2.08 and 12.97±4.33 in the remission and nonremission groups, respectively (
P
value=0.0001). Of 469 total participants, 378 (80.6%) completed the 6-minute walk test and 285 (70.1%) completed Kansas city cardiomyopathy questionnaire and 36-item short-form health survey, at baseline and at week 12. Depression remission was significantly associated with higher improvements in Kansas City Cardiomyopathy Questionnaire subscale scores (
P
<0.001) except on the Self-Efficacy (
P
=0.18) and Symptom Stability (
P
=0.91). On the 36-Item Short-Form Health Survey, depression remission was associated with significant improvement in subscales of the physical and mental component summary except the Pain Index (
P
=0.34). The 6-minute walk test improved more in depression remission compared with nonremission group (difference from baseline: 63.51±238.78 versus 16.24±115.70 m,
P
=0.03).

Conclusions—
Patients with heart failure whose depressive symptoms remitted had significantly greater improvement in physical function, social function, and quality of life.
Evaluating Treatment Efficacy by Multiple End Points in Phase II Acute Heart Failure Clinical Trials
Authors: Sun Hengrui , Davison Beth A. , Cotter Gad , Pencina Michael J. , Koch Gary G. 
Published: October 2012

Background—
To assess concomitant simultaneous effects on multiple end points using global statistical methods in phase II acute heart failure studies.

Methods and Results—
Using simulations we have assessed different statistical methods to evaluate concomitant effects of a new intervention on dyspnea relief (using 2 measures), length of hospital stay, worsening heart failure to 5 days, mortality, and heart failure readmission to 30 days. Treatment effect scenarios included large (20% to 28% relative improvements) and very large (30% to 43% relative improvements) effects among others. Placebo responses and correlations among end points typical in recent acute heart failure clinical trials were used. Powers for the average Z score exceeded 70% with ≥75 patients per group for 35% relative improvement across all 6 end points. Assessing dyspnea alone generally provides lower power than the average Z score approach, with power deducted ≈50% under most of scenarios. Other approaches generally provide lower power than the average Z score method.

Conclusions—
Assessing the effects of new therapies on multiple clinical end points using the average Z score enables detection of therapeutic efficacy using sample sizes of 100 to 150 patients per group, approximately double the power achievable assessing the effects on dyspnea alone.