bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dietary Heterocyclic Amine Intake and Colorectal Adenoma Risk: A Systematic Review and Meta-analysis
Authors: Martínez Góngora Victoria , Matthes Katarina L. , Castaño Patricia Rodríguez , Linseisen Jakob , Rohrmann Sabine 
Published: October 2018

Abstract

Background:
Heterocyclic amines (HCA) are potent carcinogenic substances formed in meat. Because of their mutagenic activity, they may increase the risk of colorectal adenomas, which are the precursors of colorectal cancer, one of the most prevalent cancers worldwide. The aim of this meta-analysis was to synthesize the knowledge about the intake of HCAs and its associations with CRA.

Methods:
We conducted a systematic search in PubMed and EMBASE. We used odds ratios (OR); or relative risks, RR) from every reported intake and compared the highest versus lowest level of dietary HCAs. In addition, we assessed a dose–response relationship.

Results:
Twelve studies on HCA intake and risk of CRA were included in our analysis. We observed a statistically significant association when comparing top versus bottom intake category of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine [PhIP; OR = 1.20; 95% confidence interval (CI) = 1.12–1.29], 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx; OR = 1.20; 95% CI = 1.08–1.34), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx; OR = 1.16; 95% CI = 1.05–1.27), benzo(a)pyrene (BaP; OR = 1.15; 95% CI = 1.04–1.27), and mutagenicity index (OR = 1.22; 95% CI = 1.06–1.41). Furthermore, we observed a significant dose–response effect for PhIP, MeIQx, and mutagenicity index.

Conclusions:
This meta-analysis suggests that there is a positive association of HCAs, BaP, mutagenicity index with risk of CRA. In addition, our dose–response analyses showed an increased risk of CRA for PhIP, MeIQx, and mutagenicity index.

Impact:
This study provides evidence for a positive association between the dietary intake of meat mutagens and CRA risk.
Multilevel Regression for Small-Area Estimation of Mammography Use in the United States, 2014
Authors: Berkowitz Zahava , Zhang Xingyou , Richards Thomas B. , Sabatino Susan A. , Peipins Lucy A. , Holt James , White Mary C. 
Published: October 2018

Abstract

Background:
The U.S. Preventive Services Task Force recommends biennial screening mammography for average-risk women aged 50–74 years. County-level information on population measures of mammography use can inform targeted intervention to reduce geographic disparities in mammography use. County-level estimates for mammography use nationwide are rarely presented.

Methods:
We used data from the 2014 Behavioral Risk Factor Surveillance System (BRFSS; n = 130,289 women), linked it to the American Community Survey poverty data, and fitted multilevel logistic regression models with two outcomes: mammography within the past 2 years (up-to-date), and most recent mammography 5 or more years ago or never (rarely/never). We poststratified the data with U.S. Census population counts to run Monte Carlo simulations. We generated county-level estimates nationally and by urban–rural county classifications. County-level prevalence estimates were aggregated into state and national estimates. We validated internal consistency between our model-based state-specific estimates and urban–rural estimates with BRFSS direct estimates using Spearman correlation coefficients and mean absolute differences.

Results:
Correlation coefficients were 0.94 or larger. Mean absolute differences for the two outcomes ranged from 0.79 to 1.03. Although 78.45% (95% confidence interval, 77.95%–78.92%) of women nationally were up-to-date with mammography, more than half of the states had counties with &gt;15% of women rarely/never using a mammogram, many in rural areas.

Conclusions:
We provided estimates for all U.S. counties and identified marked variations in mammography use. Many states and counties were far from the 2020 target (81.1%).

Impact:
Our results suggest a need for planning and resource allocation on a local level to increase mammography uptake.
Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial
Authors: Sudhan Dhivya R. , Schwarz Luis J. , Guerrero-Zotano Angel , Formisano Luigi , Nixon Mellissa J. , Croessmann Sarah , González Ericsson Paula I. , Sanders Melinda , Balko Justin M. , Avogadri-Connors Francesca , Cutler Richard E. , Lalani Alshad S. , Bryce Richard , Auerbach Alan , Arteaga Carlos L. 
Published: October 2018

AbstractPurpose:The phase III ExteNET trial showed improved invasive disease-free survival in patients with HER2+ breast cancer treated with neratinib versus placebo after trastuzumab-based adjuvant therapy. The benefit from neratinib appeared to be greater in patients with ER+/HER2+ tumors. We thus sought to discover mechanisms that may explain the benefit from extended adjuvant therapy with neratinib.Experimental Design: Mice with established ER+/HER2+ MDA-MB-361 tumors were treated with paclitaxel plus trastuzumab ± pertuzumab for 4 weeks, and then randomized to fulvestrant ± neratinib treatment. The benefit from neratinib was evaluated by performing gene expression analysis for 196 ER targets, ER transcriptional reporter assays, and cell-cycle analyses.Results:Mice receiving “extended adjuvant” therapy with fulvestrant/neratinib maintained a complete response, whereas those treated with fulvestrant relapsed rapidly. In three ER+/HER2+ cell lines (MDA-MB-361, BT-474, UACC-893) but not in ER+/HER2− MCF7 cells, treatment with neratinib induced ER reporter transcriptional activity, whereas treatment with fulvestrant resulted in increased HER2 and EGFR phosphorylation, suggesting compensatory reciprocal crosstalk between the ER and ERBB RTK pathways. ER transcriptional reporter assays, gene expression, and immunoblot analyses showed that treatment with neratinib/fulvestrant, but not fulvestrant, potently inhibited growth and downregulated ER reporter activity, P-AKT, P-ERK, and cyclin D1 levels. Finally, similar to neratinib, genetic and pharmacologic inactivation of cyclin D1 enhanced fulvestrant action against ER+/HER2+ breast cancer cells.Conclusions:These data suggest that ER blockade leads to reactivation of ERBB RTKs and thus extended ERBB blockade is necessary to achieve durable clinical outcomes in patients with ER+/HER2+ breast cancer.
The Role of Angiogenesis in Hepatocellular Carcinoma
Authors: Morse Michael A. , Sun Weijing , Kim Richard , He Aiwu Ruth , Abada Paolo B. , Mynderse Michelle , Finn Richard S. 
Published: October 2018

Abstract
Hepatocellular carcinoma (HCC) accounts for about 90% of all primary liver cancers and is the second leading cause of cancer-related deaths worldwide. The hypervascular nature of most HCC tumors underlines the importance of angiogenesis in the pathobiology of these tumors. Several angiogenic pathways have been identified as being dysregulated in HCC, suggesting they may be involved in the development and pathogenesis of HCC. These data provide practical targets for systemic treatments such as those targeting the vascular endothelial growth factor receptor and its ligand. However, the clinical relevance of other more recently identified angiogenic pathways in HCC pathogenesis or treatment remains unclear. Research into molecular profiles and validation of prognostic or predictive biomarkers will be required to identify the patient subsets most likely to experience meaningful benefit from this important class of agents.
Targeting Resistance against the MDM2 Inhibitor RG7388 in Glioblastoma Cells by the MEK Inhibitor Trametinib
Authors: Berberich Anne , Kessler Tobias , Thomé Carina M. , Pusch Stefan , Hielscher Thomas , Sahm Felix , Oezen Iris , Schmitt Lara-Marie , Ciprut Sara , Hucke Nanina , Ruebmann Petra , Fischer Manuel , Lemke Dieter , Breckwoldt Michael O. , von Deimling Andreas , Bendszus Martin , Platten Michael , Wick Wolfgang 
Published: October 2018

Abstract

Purpose:
Resistance is an obstacle of glioma therapy. Despite targeted interventions, tumors harbor primary resistance or become resistant over short course of treatment. This study examined the mouse double minute 2 (MDM2) inhibitor RG7388 together with radiotherapy and analyzed strategies to overcome acquired MDM2 inhibitor resistance in glioblastoma.

Experimental Design:
Effects of RG7388 and radiotherapy were analyzed in p53 wild-type glioblastoma cell lines and glioma-initiating cells. RG7388 resistant cells were generated by increasing RG7388 doses over 3 months. Regulated pathways were investigated by microarray, qRT-PCR, and immunoblot analysis and specifically inhibited to evaluate rational salvage therapies at RG7388 resistance. Effects of RG7388 and trametinib treatment were challenged in an orthotopical mouse model with RG7388 resistant U87MG glioblastoma cells.

Results:
MDM2 inhibition required functional p53 and showed synergistic activity with radiotherapy in first-line treatment. Long-term exposure to RG7388 induced resistance by activation of the extracellular signal-regulated kinases 1/2 (ERK1/2)–insulin growth factor binding protein 1 (IGFBP1) signaling cascade, which was specifically overcome by ERK1/2 pathway inhibition with trametinib and knockdown of IGFBP1. Combining trametinib with continued RG7388 treatment enhanced antitumor effects at RG7388 resistance in vitro and in vivo.

Conclusions:
These data provide a rationale for combining RG7388 and radiotherapy as first-line therapy with a specific relevance for tumors insensitive to alkylating standard chemotherapy and for the addition of trametinib to continued RG7388 treatment as salvage therapy after acquired resistance against RG7388 for clinical practice.
RON Receptor Tyrosine Kinase as a Therapeutic Target for Eradication of Triple-Negative Breast Cancer: Efficacy of Anti-RON ADC Zt/g4-MMAE
Authors: Suthe Sreedhar Reddy , Yao Hang-Ping , Weng Tian-Hao , Hu Chen-Yu , Feng Liang , Wu Zhi-Gang , Wang Ming-Hai 
Published: October 2018

Abstract
Triple-negative breast cancer (TNBC) is a highly diverse group of malignant neoplasia with poor outcome. Currently, the lack of effective therapy has fostered a major effort to discover new targets to treat this malignant cancer. Here we identified the RON receptor tyrosine kinase as a therapeutic target for potential TNBC treatment. We analyzed RON expression in 168 primary TNBC samples via tissue microarray using anti-RON IHC staining and demonstrated that RON was widely expressed in 76.8% TNBC samples with overexpression in 76 cases (45.2%). These results provide the molecular basis to target RON for TNBC therapy. To this end, anti-RON monoclonal antibody Zt/g4-drug monomethyl auristatin E conjugate (Zt/g4-MMAE) was developed with a drug to antibody ratio of 3.29 and tested in a panel of TNBC cell lines with different phenotypes. In vitro, Zt/g4-MMAE rapidly induced RON internalization, resulted in cell-cycle arrest followed by massive cell death. The calculated IC50 values ranged from 0.06 to 3.46 μg/mL dependent on individual TNBC cell lines tested. Zt/g4-MMAE also effectively killed TNBC stem-like cells with RON+/CD44+/CD24− phenotypes and RON-negative TNBC cells through the bystander effect. In vivo, Zt/g4-MMAE at 10 mg/kg in a Q12 × 2 regimen completely eradicated TNBC xenografts without the regrowth of xenograft tumors. In conclusion, increased RON expression is a pathogenic feature in primary TNBC samples. Zt/g4-MMAE is highly effective in eradicating TNBC xenografts in preclinical models. These findings lay the foundation for using anti-RON Zt/g4-MMAE in clinical trials as a novel strategy for TNBC treatment.
Efficacy of a Covalent ERK1/2 Inhibitor, CC-90003, in KRAS-Mutant Cancer Models Reveals Novel Mechanisms of Response and Resistance
Authors: Aronchik Ida , Dai Yumin , Labenski Matt , Barnes Carmen , Jones Terri , Qiao Lixin , Beebe Lisa , Malek Mehnaz , Elis Winfried , Shi Tao , Mavrommatis Konstantinos , Bray Gordon L. , Filvaroff Ellen H. 
Published: October 2018

Abstract

As a critical signaling node, ERK1/2 are attractive drug targets, particularly in tumors driven by activation of the MAPK pathway. Utility of targeting the MAPK pathway has been demonstrated by clinical responses to inhibitors of MEK1/2 or RAF kinases in some mutant BRAF-activated malignancies. Unlike tumors with mutations in BRAF, those with mutations in KRAS (&gt;30% of all cancers and &gt;90% of certain cancer types) are generally not responsive to inhibitors of MEK1/2 or RAF. Here, a covalent ERK1/2 inhibitor, CC-90003, was characterized and shown to be active in preclinical models of KRAS-mutant tumors. A unique occupancy assay was used to understand the mechanism of resistance in a KRAS-mutant patient-derived xenograft (PDX) model of colorectal cancer. Finally, combination of CC-90003 with docetaxel achieved full tumor regression and prevented tumor regrowth after cessation of treatment in a PDX model of lung cancer. This effect corresponded to changes in a stemness gene network, revealing a potential effect on tumor stem cell reprograming.

Implications:
Here, a covalent ERK1/2 inhibitor (CC-90003) is demonstrated to have preclinical efficacy in models of KRAS-mutant tumors, which present a therapeutic challenge for currently available therapies.
High Prevalence of Hereditary Cancer Syndromes and Outcomes in Adults with Early-Onset Pancreatic Cancer
Authors: Bannon Sarah A. , Montiel Maria F. , Goldstein Jennifer B. , Dong Wenli , Mork Maureen E. , Borras Ester , Hasanov Merve , Varadhachary Gauri R. , Maitra Anirban , Katz Matthew H. , Feng Lei , Futreal Andrew , Fogelman David R. , Vilar Eduardo , McAllister Florencia 
Published: October 2018

Abstract
Introduction: We aimed to determine the prevalence and landscape of germline mutations among patients with young-onset pancreatic ductal adenocarcinoma (PDAC) as well as their influence in prognosis.
Methods: Patients from two cohorts were studied, the high-risk cohort (HRC), which included 584 PDAC patients who received genetic counseling at The University of Texas MD Anderson Cancer Center, and a general cohort (GC) with 233 metastatic PDAC patients. We defined germline DNA sequencing on 13 known pancreatic cancer susceptibility genes. The prevalence and landscape of mutations were determined, and clinical characteristics including survival were analyzed.
Results: A total of 409 patients underwent genetic testing (277 from HRC and 132 from GC). As expected, the HRC had higher prevalence of germline mutations compared with the GC: 17.3% versus 6.81%. The most common mutations in both cohorts were in BRCA1/2 and mismatch-repair (MMR) genes. Patients younger than 60 years old had significantly higher prevalence of germline mutations in both the HRC [odds ratios (OR), 1.93 ± 1.03–3.70, P = 0.039] and GC (4.78 ± 1.10–32.95, P = 0.036). Furthermore, PDAC patients with germline mutations in the GC had better overall survival than patients without mutations (HR, 0.44; 95% CI of HR, 0.25–0.76, P = 0.030).
Discussion: Germline mutations are highly prevalent in patients with PDAC of early onset and can be predictive of better outcomes. Considering emerging screening strategies for relatives carrying susceptibility genes as well as impact on therapy choices, genetic counseling and testing should be encouraged in PDAC patients, particularly those of young onset. Cancer Prev Res; 11(11); 679–86. ©2018 AACR.
Clinical Significance of Pancreatic Atrophy Induced by Immune-Checkpoint Inhibitors: A Case–Control Study
Authors: Eshet Yael , Baruch Erez Nissim , Shapira-Frommer Ronnie , Steinberg-Silman Yael , Kuznetsov Teodor , Ben-Betzalel Guy , Daher Sameh , Gluck Iris , Asher Nethanel , Apter Sara , Schachter Jacob , Bar Jair , Boursi Ben , Markel Gal 
Published: October 2018

Abstract
Immune-checkpoint inhibitor (ICI)–related diarrhea is attributed to inflammatory colitis, with no other drug-related differential diagnosis. Here, we investigated the occurrence of pancreatic atrophy (PA) in ICI-treated cancer patients and its correlation to exocrine pancreatic insufficiency (EPI). Metastatic melanoma, non–small cell lung carcinoma, and head and neck squamous cell carcinoma patients (n = 403) treated with anti–PD-1 (n = 356) or anti–CTLA-4 (n = 47) were divided into a case group (radiologic evidence of PA); control group matched by age, gender, and previous lines of treatment; and colitis group (ICI-induced colitis). Quantitative pancreatic volumetry was used for calculation of the decrease in pancreatic volume over time (atrophy rate). Thirty-one patients (7.7%) developed PA compared with 41 matched controls (P = 0.006). Four patients developed EPI, all from the anti–PD-1–treated group, which resolved with oral enzyme supplementation. The atrophy rate did not correlate with EPI (P = 0.87). EPI-related diarrhea presented at a median of 9 months, whereas the diarrhea of anti–PD-1–induced colitis patients (n = 22) was presented at a median of 2 months (P = 0.029). ICI-induced PA is irreversible and can result in EPI. EPI should be suspected in cases of late-onset steroid-resistant diarrhea with features of steatorrhea and treated with oral enzyme supplements.
Effect of Upper- and Lower-Level Baroclinicity on the Persistence of the Leading Mode of Midlatitude Jet Variability
Authors: Robert Loïc , Rivière Gwendal , Codron Francis 
Published: October 2018

Abstract
The sensitivity of the variability of an eddy-driven jet to the upper- and lower-level baroclinicity of the mean state is analyzed using a three-level quasigeostrophic model on the sphere. The model is forced by a relaxation in temperature to a steady, zonally symmetric profile with varying latitude and intensity of the maximum baroclinicity. The leading EOF of the zonally and vertically averaged zonal wind is characterized by a meridional shift of the eddy-driven jet. While changes in the upper-level baroclinicity have no significant impact on the persistence of this leading EOF, an increase in lower-level baroclinicity leads to a reduced persistence. For small lower-level baroclinicity, the leading EOF follows a classical zonal index regime, for which the meridional excursions of the zonal wind anomalies are maintained by a strong positive eddy feedback. For strong lower-level baroclinicity, the jet enters a poleward-propagation regime, for which the eddy forcing continuously acts to push the jet poleward and prevents its maintenance at a fixed latitude. The enhanced poleward propagation when the lower-level baroclinicity increases is interpreted as resulting from the broader and weaker potential vorticity gradient that enables the waves to propagate equatorward and facilitates the poleward migration of the critical latitude. Finally, the decrease in the persistence of the leading EOF as the lower-level baroclinicity increases is shown not to result from the impact of changes in the mean climatological jet latitude.
Impact of the Extended Boreal Summer Intraseasonal Oscillation on Western North Pacific Tropical Cloud Cluster Genesis Productivity
Authors: Zhao Haikun , Chen Shaohua , Klotzbach Philip J. , Raga G. B. 
Published: October 2018

AbstractTropical cloud clusters (TCCs) are traditionally viewed as precursors of tropical cyclone (TC) genesis. Most studies have focused on the impact of the extended boreal summer intraseasonal oscillation (ISO) on TC activity over the western North Pacific (WNP), while the modulation of the ISO on WNP TCC genesis productivity (TCCGP), that is, the ratio of TC to TCC counts, has been investigated much less frequently. This study suggests that the extended boreal summer ISO modulates WNP TCCGP, with higher (lower) TCCGP during convectively active (inactive) ISO phases. Changes in TCCGP are found to be closely associated with changes of large-scale environmental factors. During the convectively active ISO phase, significantly increased TCCGP is associated with strengthened low-level cyclonic circulation anomalies and increased midlevel relative humidity anomalies over the WNP basin. The genesis potential index (GPI) contains several large-scale environmental variables demonstrated to relate to TCs and TCCs. The GPI can adequately depict the ISO modulation of WNP TCCGP through its alterations of large-scale parameters. Low-level vorticity makes the largest contribution to the change of TCCGP with a secondary contribution from midlevel relative humidity. Interestingly, the nonlinear GPI terms make comparable contributions, which can be partly explained by the synoptic-scale wave activity associated with the ISO mode. Stronger (weaker) 3–8-day synoptic-scale wave train intensity and increased (decreased) low-level eddy kinetic energy are found to be associated with the enhanced (weakened) monsoon circulation over the WNP basin during convectively active (inactive) ISO phases.
Need for guidelines for the combined management of pregnancy and dengue: a retrospective study from an Indian tertiary care maternity hospital
Authors: Kallur Sailaja Devi , Surapaneni Tarakeswari , Boorugu Hari Kishan , Aziz Nuzhat , Gala Anisha Ramniklal , Donnuri Swathi 
Published: October 2018

The incidence of dengue has risen in India in recent years. Evidence suggests that dengue in pregnancy may be associated with adverse maternal and fetal outcomes. The aim of our study was to analyse outcomes in pregnant women with confirmed dengue infection who had the benefit of close monitoring and intensive management at a tertiary maternity facility. We reviewed hospital data of 44 (0.11%) such women at Fernandez Hospital, a tertiary maternity unit, during the five-year period from 2011 to 2016. Maternal and fetal variables were collected from case sheets. Dengue haemorrhagic fever was seen in 15.9% and dengue shock syndrome in one fatal case (2.2%). Thrombocytopenia was seen in 31 cases (70.4%) and 14 (31.81%) received platelets transfusions. Fetal outcomes in our series were favourable, except for one stillbirth, with 45.4% preterm deliveries and 15.9% small for gestational age babies. Dengue in pregnancy is definitely associated with maternal and fetal morbidity and mortality. A high index of suspicion of dengue is required in pregnant women with pyrexia and thrombocytopenia.