bluuebunny/crossref_metadata_2025_split huggingface dataset:
RARγ Downregulation Contributes to Colorectal Tumorigenesis and Metastasis by Derepressing the Hippo–Yap Pathway
Authors: Guo Peng-Da , Lu Xing-Xing , Gan Wen-Juan , Li Xiu-Ming , He Xiao-Shun , Zhang Shen , Ji Qing-Hua , Zhou Feng , Cao Yue , Wang Jing-Ru , Li Jian-Ming , Wu Hua 
Published: June 2016

Abstract
The Hippo–Yap pathway conveys oncogenic signals, but its regulation during cancer development is not well understood. Here, we identify the nuclear receptor RARγ as a regulator of the Hippo–Yap pathway in colorectal tumorigenesis and metastasis. RARγ is downregulated in human colorectal cancer tissues, where its expression correlates inversely with tumor size, TNM stage, and distant metastasis. Functional studies established that silencing of RARγ drove colorectal cancer cell growth, invasion, and metastatic properties both in vitro and in vivo. Mechanistically, RARγ controlled Hippo–Yap signaling to inhibit colorectal cancer development, acting to promote phosphorylation and binding of Lats1 to its transcriptional coactivator Yap and thereby inactivating Yap target gene expression. In clinical specimens, RARγ expression correlated with overall survival outcomes and expression of critical Hippo–Yap pathway effector molecules in colorectal cancer patients. Collectively, our results defined RARγ as tumor suppressor in colorectal cancer that acts by restricting oncogenic signaling by the Hippo–Yap pathway, with potential implications for new approaches to colorectal cancer therapy. Cancer Res; 76(13); 3813–25. ©2016 AACR.
CSN1 Somatic Mutations in Penile Squamous Cell Carcinoma
Authors: Feber Andrew , Worth Daniel C. , Chakravarthy Ankur , de Winter Patricia , Shah Kunal , Arya Manit , Saqib Muhammad , Nigam Raj , Malone Peter R. , Tan Wei Shen , Rodney Simon , Freeman Alex , Jameson Charles , Wilson Gareth A. , Powles Tom , Beck Stephan , Fenton Tim , Sharp Tyson V. , Muneer Asif , Kelly John D. 
Published: June 2016

Abstract
Other than an association with HPV infection, little is known about the genetic alterations determining the development of penile cancer. Although penile cancer is rare in the developed world, it presents a significant burden in developing countries. Here, we report the findings of whole-exome sequencing (WES) to determine the somatic mutational landscape of penile cancer. WES was performed on penile cancer and matched germline DNA from 27 patients undergoing surgical resection. Targeted resequencing of candidate genes was performed in an independent 70 patient cohort. Mutation data were also integrated with DNA methylation and copy-number information from the same patients. We identified an HPV-associated APOBEC mutation signature and an NpCpG signature in HPV-negative disease. We also identified recurrent mutations in the novel penile cancer tumor suppressor genes CSN1(GPS1) and FAT1. Expression of CSN1 mutants in cells resulted in colocalization with AGO2 in cytoplasmic P-bodies, ultimately leading to the loss of miRNA-mediated gene silencing, which may contribute to disease etiology. Our findings represent the first comprehensive analysis of somatic alterations in penile cancer, highlighting the complex landscape of alterations in this malignancy. Cancer Res; 76(16); 4720–7. ©2016 AACR.
Molecular Pathology of Patient Tumors, Patient-Derived Xenografts, and Cancer Cell Lines
Authors: Guo Sheng , Qian Wubin , Cai Jie , Zhang Likun , Wery Jean-Pierre , Li Qi-Xiang 
Published: June 2016

Abstract
The Cancer Genome Atlas (TCGA) project has generated abundant genomic data for human cancers of various histopathology types and enabled exploring cancer molecular pathology per big data approach. We developed a new algorithm based on most differentially expressed genes (DEG) per pairwise comparisons to calculate correlation coefficients to be used to quantify similarity within and between cancer types. We systematically compared TCGA cancers, demonstrating high correlation within types and low correlation between types, thus establishing molecular specificity of cancer types and an alternative diagnostic method largely equivalent to histopathology. Different coefficients for different cancers in study may reveal that the degree of the within-type homogeneity varies by cancer types. We also performed the same calculation using the TCGA-derived DEGs on patient-derived xenografts (PDX) of different histopathology types corresponding to the TCGA types, as well as on cancer cell lines. We, for the first time, demonstrated highly similar patterns for within- and between-type correlation between PDXs and patient samples in a systematic study, confirming the high relevance of PDXs as surrogate experimental models for human diseases. In contrast, cancer cell lines have drastically reduced expression similarity to both PDXs and patient samples. The studies also revealed high similarity between some types, for example, LUSC and HNSCC, but low similarity between certain subtypes, for example, LUAD and LUSC. Our newly developed algorithm seems to be a practical diagnostic method to classify and reclassify a disease, either human or xenograft, with better accuracy than traditional histopathology. Cancer Res; 76(16); 4619–26. ©2016 AACR.
Preclinical Efficacy of Bevacizumab with CRLX101, an Investigational Nanoparticle–Drug Conjugate, in Treatment of Metastatic Triple-Negative Breast Cancer
Authors: Pham Elizabeth , Yin Melissa , Peters Christian G. , Lee Christina R. , Brown Donna , Xu Ping , Man Shan , Jayaraman Lata , Rohde Ellen , Chow Annabelle , Lazarus Douglas , Eliasof Scott , Foster F. Stuart , Kerbel Robert S. 
Published: June 2016

Abstract
VEGF pathway–targeting antiangiogenic drugs, such as bevacizumab, when combined with chemotherapy have changed clinical practice for the treatment of a broad spectrum of human cancers. However, adaptive resistance often develops, and one major mechanism is elevated tumor hypoxia and upregulated hypoxia-inducible factor-1α (HIF1α) caused by antiangiogenic treatment. Reduced tumor vessel numbers and function following antiangiogenic therapy may also affect intratumoral delivery of concurrently administered chemotherapy. Nonetheless, combining chemotherapy and bevacizumab can lead to improved response rates, progression-free survival, and sometimes, overall survival, the extent of which can partly depend on the chemotherapy backbone. A rational, complementing chemotherapy partner for combination with bevacizumab would not only reduce HIF1α to overcome hypoxia-induced resistance, but also improve tumor perfusion to maintain intratumoral drug delivery. Here, we evaluated bevacizumab and CRLX101, an investigational nanoparticle–drug conjugate containing camptothecin, in preclinical mouse models of orthotopic primary triple-negative breast tumor xenografts, including a patient-derived xenograft. We also evaluated long-term efficacy of CRLX101 and bevacizumab to treat postsurgical, advanced metastatic breast cancer in mice. CRLX101 alone and combined with bevacizumab was highly efficacious, leading to complete tumor regressions, reduced metastasis, and greatly extended survival of mice with metastatic disease. Moreover, CRLX101 led to improved tumor perfusion and reduced hypoxia, as measured by contrast-enhanced ultrasound and photoacoustic imaging. CRLX101 durably suppressed HIF1α, thus potentially counteracting undesirable effects of elevated tumor hypoxia caused by bevacizumab. Our preclinical results show pairing a potent cytotoxic nanoparticle chemotherapeutic that complements and improves concurrent antiangiogenic therapy may be a promising treatment strategy for metastatic breast cancer. Cancer Res; 76(15); 4493–503. ©2016 AACR.
OncomiR or Tumor Suppressor? The Duplicity of MicroRNAs in Cancer
Authors: Svoronos Alexander A. , Engelman Donald M. , Slack Frank J. 
Published: June 2016

Abstract
MicroRNAs (miRNA) are short, noncoding RNAs whose dysregulation has been implicated in most, if not all, cancers. They regulate gene expression by suppressing mRNA translation and reducing mRNA stability. To this end, there is a great deal of interest in modifying miRNA expression levels for the treatment of cancer. However, the literature is fraught with inconsistent accounts as to whether various miRNAs are oncogenic or tumor suppressive. In this review, we directly examine these inconsistencies and propose several mechanisms to explain them. These mechanisms include the possibility that specific miRNAs can simultaneously produce competing oncogenic and tumor suppressive effects by suppressing both tumor suppressive mRNAs and oncogenic mRNAs, respectively. In addition, miRNAs can modulate tumor-modifying extrinsic factors, such as cancer-immune system interactions, stromal cell interactions, oncoviruses, and sensitivity to therapy. Ultimately, it is the balance between these processes that determines whether a specific miRNA produces a net oncogenic or net tumor suppressive effect. A solid understanding of this phenomenon will likely prove valuable in evaluating miRNA targets for cancer therapy. Cancer Res; 76(13); 3666–70. ©2016 AACR.
Functional Flow Patterns and Static Blood Pooling in Tumors Revealed by Combined Contrast-Enhanced Ultrasound and Photoacoustic Imaging
Authors: Bar-Zion Avinoam , Yin Melissa , Adam Dan , Foster F. Stuart 
Published: June 2016

Abstract
Alterations in tumor perfusion and microenvironment have been shown to be associated with aggressive cancer phenotypes, raising the need for noninvasive methods of tracking these changes. Dynamic contrast–enhanced ultrasound (DCEUS) and photoacoustic (PA) imaging serve as promising candidates—one has the ability to measure tissue perfusion, whereas the other can be used to monitor tissue oxygenation and hemoglobin concentration. In this study, we investigated the relationship between the different functional parameters measured with DCEUS and PA imaging, using two morphologically different hind-limb tumor models and drug-induced alterations in an orthotopic breast tumor model. Imaging results showed some correlation between perfusion and oxygen saturation maps and the ability to sensitively monitor antivascular treatment. In addition, DCEUS measurements revealed different vascular densities in the core of specific tumors compared with their rims. Noncorrelated perfusion and hemoglobin concentration measurements facilitated discrimination between blood lakes and necrotic areas. Taken together, our results illustrate the utility of a combined contrast-enhanced ultrasound method with photoacoustic imaging to visualize blood flow patterns in tumors. Cancer Res; 76(15); 4320–31. ©2016 AACR.
Cholesterol Metabolism and Prostate Cancer Lethality
Authors: Stopsack Konrad H. , Gerke Travis A. , Sinnott Jennifer A. , Penney Kathryn L. , Tyekucheva Svitlana , Sesso Howard D. , Andersson Swen-Olof , Andrén Ove , Cerhan James R. , Giovannucci Edward L. , Mucci Lorelei A. , Rider Jennifer R. 
Published: June 2016

Abstract
Cholesterol metabolism has been implicated in prostate cancer pathogenesis. Here, we assessed the association of intratumoral mRNA expression of cholesterol synthesis enzymes, transporters, and regulators in tumor specimen at diagnosis and lethal prostate cancer, defined as mortality or metastases from prostate cancer in contrast to nonlethal disease without evidence of metastases after at least 8 years of follow-up. We analyzed the prospective prostate cancer cohorts within the Health Professionals Follow-up Study (n = 249) and the Physicians' Health Study (n = 153) as well as expectantly managed patients in the Swedish Watchful Waiting Study (n = 338). The expression of squalene monooxygenase (SQLE) was associated with lethal cancer in all three cohorts. Men with high SQLE expression (&gt;1 standard deviation above the mean) were 8.3 times (95% confidence interval, 3.5 to 19.7) more likely to have lethal cancer despite therapy compared with men with the mean level of SQLE expression. Absolute SQLE expression was associated with lethal cancer independently from Gleason grade and stage, as was a SQLE expression ratio in tumor versus surrounding benign prostate tissue. Higher SQLE expression was tightly associated with increased histologic markers of angiogenesis. Collectively, this study establishes the prognostic value of intratumoral cholesterol synthesis as measured via SQLE, its second rate-limiting enzyme. SQLE expression at cancer diagnosis is prognostic for lethal prostate cancer both after curative-intent prostatectomy and in a watchful waiting setting, possibly by facilitating micrometastatic disease. Cancer Res; 76(16); 4785–90. ©2016 AACR.
Bevacizumab Targeting Diffuse Intrinsic Pontine Glioma: Results of 89Zr-Bevacizumab PET Imaging in Brain Tumor Models
Authors: Jansen Marc H.A. , Lagerweij Tonny , Sewing A. Charlotte P. , Vugts Danielle J. , van Vuurden Dannis G. , Molthoff Carla F.M. , Caretti Viola , Veringa Susanna J.E. , Petersen Naomi , Carcaboso Angel M. , Noske David P. , Vandertop W. Peter , Wesseling Pieter , van Dongen Guus A.M.S. , Kaspers Gertjan J.L. , Hulleman Esther 
Published: June 2016

AbstractThe role of the VEGF inhibitor bevacizumab in the treatment of diffuse intrinsic pontine glioma (DIPG) is unclear. We aim to study the biodistribution and uptake of zirconium-89 (89Zr)-labeled bevacizumab in DIPG mouse models. Human E98-FM, U251-FM glioma cells, and HSJD-DIPG-007-FLUC primary DIPG cells were injected into the subcutis, pons, or striatum of nude mice. Tumor growth was monitored by bioluminescence imaging (BLI) and visualized by MRI. Seventy-two to 96 hours after 89Zr-bevacizumab injections, mice were imaged by positron emission tomography (PET), and biodistribution was analyzed ex vivo. High VEGF expression in human DIPG was confirmed in a publically available mRNA database, but no significant 89Zr-bevacizumab uptake could be detected in xenografts located in the pons and striatum at an early or late stage of the disease. E98-FM, and to a lesser extent the U251-FM and HSJD-DIPG-007 subcutaneous tumors, showed high accumulation of 89Zr-bevacizumab. VEGF expression could not be demonstrated in the intracranial tumors by in situ hybridization (ISH) but was clearly present in the perinecrotic regions of subcutaneous E98-FM tumors. The poor uptake of 89Zr-bevacizumab in xenografts located in the brain suggests that VEGF targeting with bevacizumab has limited efficacy for diffuse infiltrative parts of glial brain tumors in mice. Translating these results to the clinic would imply that treatment with bevacizumab in patients with DIPG is only justified after targeting of VEGF has been demonstrated by 89Zr-bevacizumab immuno-PET. We aim to confirm this observation in a clinical PET study with patients with DIPG. Mol Cancer Ther; 15(9); 2166–74. ©2016 AACR.
ST-11: A New Brain-Penetrant Microtubule-Destabilizing Agent with Therapeutic Potential for Glioblastoma Multiforme
Authors: Cherry Allison E. , Haas Brian R. , Naydenov Alipi V. , Fung Susan , Xu Cong , Swinney Katie , Wagenbach Michael , Freeling Jennifer , Canton David A. , Coy Jonathan , Horne Eric A. , Rickman Barry , Vicente Juan Jesus , Scott John D. , Ho Rodney J.Y. , Liggitt Denny , Wordeman Linda , Stella Nephi 
Published: June 2016

Abstract
Glioblastoma multiforme is a devastating and intractable type of cancer. Current antineoplastic drugs do not improve the median survival of patients diagnosed with glioblastoma multiforme beyond 14 to 15 months, in part because the blood–brain barrier is generally impermeable to many therapeutic agents. Drugs that target microtubules (MT) have shown remarkable efficacy in a variety of cancers, yet their use as glioblastoma multiforme treatments has also been hindered by the scarcity of brain-penetrant MT-targeting compounds. We have discovered a new alkylindole compound, ST-11, that acts directly on MTs and rapidly attenuates their rate of assembly. Accordingly, ST-11 arrests glioblastoma multiforme cells in prometaphase and triggers apoptosis. In vivo analyses reveal that unlike current antitubulin agents, ST-11 readily crosses the blood–brain barrier. Further investigation in a syngeneic orthotopic mouse model of glioblastoma multiforme shows that ST-11 activates caspase-3 in tumors to reduce tumor volume without overt toxicity. Thus, ST-11 represents the first member of a new class of brain-penetrant antitubulin therapeutic agents. Mol Cancer Ther; 15(9); 2018–29. ©2016 AACR.
MET-Driven Resistance to Dual EGFR and BRAF Blockade May Be Overcome by Switching from EGFR to MET Inhibition inBRAF-Mutated Colorectal Cancer
Authors: Pietrantonio Filippo , Oddo Daniele , Gloghini Annunziata , Valtorta Emanuele , Berenato Rosa , Barault Ludovic , Caporale Marta , Busico Adele , Morano Federica , Gualeni Ambra Vittoria , Alessi Alessandra , Siravegna Giulia , Perrone Federica , Di Bartolomeo Maria , Bardelli Alberto , de Braud Filippo , Di Nicolantonio Federica 
Published: June 2016

AbstractA patient with metastatic BRAF-mutated colorectal cancer initially responded to combined EGFR and BRAF inhibition with panitumumab plus vemurafenib. Pre-existing cells with increased MET gene copy number in the archival tumor tissue likely underwent clonal expansion during treatment, leading to the emergence of MET amplification in the rebiopsy taken at progression. In BRAF-mutated colorectal cancer cells, ectopic expression of MET conferred resistance to panitumumab and vemurafenib, which was overcome by combining BRAF and MET inhibition. Based on tumor genotyping and functional in vitro data, the patient was treated with the dual ALK–MET inhibitor crizotinib plus vemurafenib, thus switching to dual MET and BRAF blockade, with rapid and marked effectiveness of such strategy. Although acquired resistance is a major limitation to the clinical efficacy of anticancer agents, the identification of molecular targets emerging during the first treatment may afford the opportunity to design the next line of targeted therapies, maximizing patient benefit.Significance: MET amplification is here identified—clinically and preclinically—as a new mechanism of resistance to EGFR and BRAF dual/triple block combinations in BRAF-mutated colorectal cancer. Switching from EGFR to MET inhibition, while maintaining BRAF inhibition, resulted in clinical benefit after the occurrence of MET-driven acquired resistance. Cancer Discov; 6(9); 963–71. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932
Sick Populations and Sick Subpopulations
Authors: Lu Yuan , Ezzati Majid , Rimm Eric B. , Hajifathalian Kaveh , Ueda Peter , Danaei Goodarz 
Published: June 2016

Background:
Cardiovascular disease (CVD) death rates are much higher in blacks than whites in the United States. It is unclear how CVD risk and events are distributed among blacks versus whites and how interventions reduce racial disparities.

Methods:
We developed risk models for fatal and for fatal and nonfatal CVD using 8 cohorts in the United States. We used 6154 adults who were 50 to 69 years of age in the National Health and Nutrition Examination Survey 1999 to 2012 to estimate the distributions of risk and events in blacks and whites. We estimated the total and disparity impacts of a range of population-wide, targeted, and risk-based interventions on 10-year CVD risks and event rates.

Results:
Twenty-five percent (95% confidence interval [CI], 22–28) of black men and 12% (95% CI, 10–14) of black women were at ≥6.67% risk of fatal CVD (almost equivalent to 20% risk of fatal or nonfatal CVD) compared with 10% (95% CI, 8–12) of white men and 3% (95% CI, 2–4) of white women. These high-risk individuals accounted for 55% (95% CI, 49–59) of CVD deaths among black men and 42% (95% CI, 35–46) in black women compared with 30% (95% CI, 24–35) in white men and 18% (95% CI, 13–22) in white women. We estimated that an intervention that treated multiple risk factors in high-risk individuals could reduce black-white difference in CVD death rate from 1659 to 1244 per 100 000 in men and from 1320 to 897 in women. Rates of fatal and nonfatal CVD were generally similar between black and white men. In women, a larger proportion of women were at ≥7.5% risk of CVD (30% versus 19% in whites), and an intervention that targeted multiple risk factors among this group was estimated to reduce black-white differences in CVD rates from 1688 to 1197 per 100 000.

Conclusions:
A substantially larger proportion of blacks have a high risk of fatal CVD and bear a large share of CVD deaths. A risk-based intervention that reduces multiple risk factors could substantially reduce overall CVD rates and racial disparities in CVD death rates.
Composite Vascular Pedicled Middle Turbinate Flap for Reconstruction of Sellar Defects
Authors: Amin Sameh M , Fawzy Tamer O , Hegazy Ahmed A 
Published: June 2016

Objectives: Herein, we describe our experience in simple harvest of the vascular pedicled middle turbinate flap (MTF) sufficient for sellar defect reconstruction. Methods: An anatomical feasibility study is done in 10 sides of 5 preserved injected cadaveric heads. The middle turbinate is separated from the skull base and the basal lamella with or without retrograde dissection of its tail as a composite flap based on the middle turbinate and posterolateral nasal arteries. The technique was applied in 25 cases of cerebrospinal fluid (CSF) leak after endoscopic transsphenoidal surgery. Results: The mean area of MTF with and without medial mucosal dissection was 9.53 cm2 and 7.6 cm2, respectively. The mean length between anterior end of MT and basal lamella and the latter and the sella was 3.67 cm and 2.33 cm, respectively. The mean area of sella was 2.2 cm2. The MTF covered the sella, planum, and tuberculum sella corridors in 10 head sides. Partial dissection of MT medial mucosa was needed in 3 head sides to cover sella, planum, and tuberculum sella. Follow-up for 26 to 37 month revealed control of CSF leak in 24 cases. Conclusion: Composite MTF is a simple rapid reproducible option for sellar defects reconstruction.
A Cross-sectional Study of Depressive Symptoms and Diabetes Self-care in African Americans and Hispanics/Latinos With Diabetes
Authors: Hernandez Rosalba , Ruggiero Laurie , Prohaska Thomas R. , Chavez Noel , Boughton Seth W. , Peacock Nadine , Zhao Weihan , Nouwen Arie 
Published: June 2016

Purpose The purpose of this study is to examine the relationship between depressive symptoms and diabetes self-care in African American and Hispanic/Latino patients with type 2 diabetes and whether the association, if any, is mediated by diabetes-related self-efficacy. Methods The sample included self-report baseline data of African American and Hispanic/Latino patients with type 2 diabetes who were aged ≥18 years and enrolled in a diabetes self-management intervention study. Depressive symptoms were assessed with the 9-item Patient Health Questionnaire. The Summary of Diabetes Self-care Activities measured engagement in healthy eating, physical activity, blood glucose checking, foot care, and smoking. The Diabetes Empowerment Scale–Short Form assessed diabetes-related psychosocial self-efficacy. Indirect effects were examined with the Baron and Kenny regression technique and Sobel testing. Results Sample characteristics (n = 250) were as follows: mean age of 53 years, 68% women, 54% African American, and 74% with income <$20 000. Depressive symptoms showed a significant inverse association with the self-care domains of general diet, specific diet, physical activity, and glucose monitoring in the African American group. In Hispanics/Latinos, depression was inversely associated with specific diet. Self-efficacy served a significant mediational role in the relation between depression and foot care among African Americans. Conclusions Self-efficacy mediated the relationship between depression and foot care in the African American group but was not found to be a mediator of any self-care areas within the Hispanic/Latino group. In clinical practice, alleviation of depressive symptoms may improve self-care behavior adherence. Diabetes education may consider inclusion of components to build self-efficacy related to diabetes self-care, especially among African American patients.