bluuebunny/crossref_metadata_2025 huggingface dataset:
Liver GCN2 controls hepatic FGF21 secretion and modulates whole body postprandial oxidation profile under a low-protein diet
Authors: Chalvon-Demersay Tristan , Moro Joanna , Even Patrick C. , Chaumontet Catherine , Tomé Daniel , Averous Julien , Piedcoq Julien , Gaudichon Claire , Maurin Anne-Catherine , Fafournoux Pierre , Azzout-Marniche Dalila
Published: October 2019

General control nonderepressible 2 (GCN2) is a kinase that detects amino acid deficiency and is involved in the control of protein synthesis and energy metabolism. However, the role of hepatic GCN2 in the metabolic adaptations in response to the modulation of dietary protein has been seldom studied. Wild-type (WT) and liver GCN2-deficient (KO) mice were fed either a normo-protein diet, a low-protein diet, or a high-protein diet for 3 wk. During this period, body weight, food intake, and metabolic parameters were followed. In mice fed normo- and high-protein diets, GCN2 pathway in the liver is not activated in WT mice, leading to a similar metabolic profile with the one of KO mice. On the contrary, a low-protein diet activates GCN2 in WT mice, inducing FGF21 secretion. In turn, FGF21 maintains a high level of lipid oxidation, leading to a different postprandial oxidation profile compared with KO mice. Hepatic GCN2 controls FGF21 secretion under a low-protein diet and modulates a whole body postprandial oxidation profile.
No evidence of attenuation of placental insulin-stimulated Akt phosphorylation and amino acid transport in maternal obesity and gestational diabetes mellitus
Authors: Castillo-Castrejon Marisol , Jansson Thomas , Powell Theresa L.
Published: October 2019

Pregnancies complicated by obesity and/or gestational diabetes (GDM) are associated with peripheral insulin resistance; however, the insulin responsiveness of the placenta in these pregnancy complications remains largely unknown. We tested the hypothesis that primary human trophoblast cells and placental villous explants will be insulin responsive, characterized by amino acid transport, Akt and Erk activity with maternal obesity, and/or GDM. We evaluated term placentas from women with normal body mass index (BMI) (normal; n = 15), obesity (OB; n = 11), normal BMI with GDM (N-GDM; n = 11), and obesity with GDM (OB-GDM; n = 11). In a subgroup, primary human trophoblast cells (PHT) were isolated, and in an independent subgroup placental villous explants were exposed to varying concentrations of insulin. Amino acid transport capacity and insulin signaling activity were determined. Insulin significantly increased amino acid transport activity to a similar degree in PHT cells isolated from normal (+21%), N-GDM (+38%), OB (+37%), and OB-GDM (+35%) pregnancies. Insulin increased Akt and Erk phosphorylation in PHT cells (3-fold) and in villous explants (2-fold) in all groups to a similar degree. In contrast to the peripheral maternal insulin resistance commonly associated with obesity and/or GDM, we found that the placenta is insulin sensitive in these pregnancy complications. We suggest that elevated maternal insulin levels in pregnancies complicated by obesity and/or GDM promote critical placental functions, including amino acid transport. Insulin-stimulated placental nutrient delivery may contribute to the increased risk of fetal overgrowth and adiposity in these pregnancies. Moreover, our findings may inform efforts to optimize insulin regimens for women with GDM.
Fiber type-specific effects of acute exercise on insulin-stimulated AS160 phosphorylation in insulin-resistant rat skeletal muscle
Authors: Pataky Mark W. , Van Acker Sydney L. , Dhingra Rhea , Freeburg Marina M. , Arias Edward B. , Oki Kentaro , Wang Haiyan , Treebak Jonas T. , Cartee Gregory D.
Published: October 2019

Muscle is a heterogeneous tissue composed of multiple fiber types. Earlier research revealed fiber type-selective postexercise effects on insulin-stimulated glucose uptake (ISGU) from insulin-resistant rats (increased for type IIA, IIB, IIBX, and IIX, but not type I). In whole muscle from insulin-resistant rats, the exercise increase in ISGU is accompanied by an exercise increase in insulin-stimulated AS160 phosphorylation (pAS160), an ISGU-regulating protein. We hypothesized that, in insulin-resistant muscle, the fiber type-selective exercise effects on ISGU would correspond to the fiber type-selective exercise effects on pAS160. Rats were fed a 2-wk high-fat diet (HFD) and remained sedentary (SED) or exercised before epitrochlearis muscles were dissected either immediately postexercise (IPEX) or at 3 h postexercise (3hPEX) using an exercise protocol that previously revealed fiber type-selective effects on ISGU. 3hPEX muscles and SED controls were incubated ± 100µU/mL insulin. Individual myofibers were isolated and pooled on the basis of myosin heavy chain (MHC) expression, and key phosphoproteins were measured. Myofiber glycogen and MHC expression were evaluated in muscles from other SED, IPEX, and 3hPEX rats. Insulin-stimulated pAktSer473 and pAktThr308 were unaltered by exercise in all fiber types. Insulin-stimulated pAS160 was greater for 3hPEX vs. SED on at least one phosphosite (Ser588, Thr642, and/or Ser704) in type IIA, IIBX, and IIB fibers, but not in type I or IIX fibers. Both IPEX and 3hPEX glycogen were decreased versus SED in all fiber types. These results provided evidence that fiber type-specific pAS160 in insulin-resistant muscle may play a role in the previously reported fiber type-specific elevation in ISGU in some, but not all, fiber types.
The Impact of Residual O2, Temperature, and Light at Display on Sensory Attributes of Sliced, Packaged Salami
Authors: Øvrum Gaarder Mari , Carlehög Mats , Berg Per , Sørheim Oddvin , Larsen Hanne
Published: October 2019

The aim of the study was to examine if small amounts of oxygen (O2) causing discolouration of salami exposed to light in the grocery store also cause adverse changes in the flavour and odour sensory profile. Sensory properties of packaged sliced salami under different temperatures (4, 20°C, and 23°C), two lights sources (LED and fluorescent), and a low level of residual O2 in the headspace were evaluated. The experiment consisted of nine series, which were sensory-assessed after 3 and 6 days of display. A combination of light exposure and residual O2 causing discolouration resulted in substantial off-flavour and off-odour of the displayed salami, both on the upper slice exposed to light and the middle slice in the stack with no direct light exposure. Samples from all other series without O2 and those displayed in various light or stored in darkness showed no changes in quality compared with control samples stored in darkness. Temperature at display did not affect sensory attributes in the series without O2 in the headspace. Sensory results from 3 to 6 days display were similar. To minimize quality defects and food waste, producers and retailers are advised to store packages of sliced salami in darkness until nearly all residual O2 is consumed internally by the product before placing the packages upon light in the counter.
Strategies to Lower In-Hospital Mortality in STEMI Patients with Primary PCI: Analysing Two Years Data from a High-Volume Interventional Centre
Authors: Burlacu Alexandru , Tinica Grigore , Nedelciuc Igor , Simion Paul , Artene Bogdan , Covic Adrian
Published: October 2019

Objectives. We aimed to analyse data from our high-volume interventional centre (>1000 primary percutaneous coronary interventions (PCI) per year) searching for predictors of in-hospital mortality in acute myocardial infarction (MI) patients. Moreover, we looked for realistic strategies and interventions for lowering in-hospital mortality under the “5 percent threshold.” Background. Although interventional and medical treatment options are constantly expanding, recent studies reported a residual in-hospital mortality ranging between 5 and 10 percent after primary PCI. Current data sustain that mortality after ST-elevation MI will soon reach a point when cannot be reduced any further. Methods. In this retrospective observational single-centre cohort study, we investigated two-year data from a primary PCI registry including 2035 consecutive patients. Uni- and multivariate analysis were performed to identify independent predictors for in-hospital mortality. Results. All variables correlated with mortality in univariate analysis were introduced in a stepwise multivariate linear regression model. Female gender, hypertension, depressed left ventricular ejection fraction, history of MI, multivessel disease, culprit left main stenosis, and cardiogenic shock proved to be independent predictors of in-hospital mortality. The model was validated for sensitivity and specificity using receiver operating characteristic curve. For our model, variables can predict in-hospital mortality with a specificity of 96.60% and a sensitivity of 84.68% (p<0.0001, AUC = 0.93, 95% CI 0.922–0.944). Conclusions. Our analysis identified a predictive model for in-hospital mortality. The majority of deaths were due to cardiogenic shock. We suggested that in order to lower mortality under 5 percent, focus should be on creating a cardiogenic shock system based on the US experience. A shock hub-centre, together with specific transfer algorithms, mobile interventional teams, ventricular assist devices, and surgical hybrid procedures seem to be the next step toward a better management of ST-elevation MI patients and subsequently lower death rates.
Investigation of the Insulation Effect of Thermal Insulation Layer in the Seasonally Frozen Region Tunnel: A Case Study in the Zuomutai Tunnel, China
Authors: Zhao Pengyu , Chen Jianxun , Luo Yanbin , Chen Lijun , Li Yao , Wang Chuanwu
Published: October 2019

In this study, a field temperature test was performed to reveal the insulation effect of the thermal insulation layer installed at lining surface. The thermal insulation layer is made of polyphenolic, and the thickness is 7 cm. According to the test results, the temperature of the thermal insulation layer and lining continuously changes with the air temperature in the tunnel in an approximately trigonometric function. The temperature of tunnel lining without thermal insulation layer is close to the air temperature, which results in the lining frost in winter. The maximum temperature difference between the two sides of the thermal insulation layer can be 27°C. In the section whose buried depth is more than 11.4 m, the temperature of lining with thermal insulation layer in winter is mainly influenced by the cold air in the tunnel. When the monthly mean and lowest daily mean air temperature are lower than −10°C and −14.3°C in the coldest month, the temperature at the inner side of the thermal insulation layer is below 0°C. When the buried depth is less than 11.4 m, the temperature of lining is also influenced by the low temperature at ground surface. The temperature of lining is lower. The thicker thermal insulation layer and even active heat measure are needed. Therefore, the design of thermal insulation layer thickness should consider the air temperature distribution and tunnel buried depth along the tunnel length.
Study on the Evaluation Method of Green Construction Based on Ontology and BIM
Authors: Xu Zhao , Wang Xuerong , Zhou Wentao , Yuan Jingfeng
Published: October 2019

Many problems and issues affect the green construction process. Inaccurate assessment is one of the important factors for green construction. The objective of this study is to propose a BIM and ontology‐based approach that enables the evaluation information of green construction to be inferred from a knowledge base in order to achieve scheme optimization. To automate the inference, this study established the BIM ontology that consists of BIM shared ontology and BIM construction ontology. First, IFC extension is adopted in green construction assessment system to generate attribute sets. IFC‐based parameters stored in BIM models are mapped to OWL and will be used as the data source of the evaluation indicators. Then, BIM‐shared ontology and BIM construction ontology are defined. Protégé is employed to simulate the evaluation indicator system. Last, utilizing BIM knowledge base, through the construction of SWRL rule language and the Drools inference, the scores of evaluation indicators could be obtained. The experimental results demonstrated that BIM knowledge base for the evaluation of green construction could realize the sharing, maintenance, and acquisition of knowledge among different participants of the project and improve the management of green construction. The proposed ontological inference of evaluation item enables an automated search of the aspects needing improvements in green construction and assist project managers in using BIM data more easily and effectively.
Alignment between Business Requirement, Business Process, and Software System: A Systematic Literature Review
Authors: Habba Maryam , Fredj Mounia , Benabdellah Chaouni Samia
Published: October 2019

Alignment is a very wide subject that can be used to support an organization’s information system. Many authors have dealt with this topic according to various dimensions, including the operational alignment dimension. Our work aims to review approaches that discuss the operational alignment by reducing the gap between business requirement, business process, and software system. Therefore, this study was conducted by a systematic literature review (SLR). In the first step, we gather 1846 papers relative to the subject. In the last step, we filter those articles and select only the most pertinent ones, which leave us with 63 studies to focus on. These primary studies were analyzed according to 9 quality assessment criteria.
Automatic Prediction of Meningioma Grade Image Based on Data Amplification and Improved Convolutional Neural Network
Authors: Zhu Hong , Fang Qianhao , He Hanzhi , Hu Junfeng , Jiang Daihong , Xu Kai
Published: October 2019

Meningioma is the second most commonly encountered tumor type in the brain. There are three grades of meningioma by the standards of the World Health Organization. Preoperative grade prediction of meningioma is extraordinarily important for clinical treatment planning and prognosis evaluation. In this paper, we present a new deep learning model for assisting automatic prediction of meningioma grades to reduce the recurrence of meningioma. Our model is based on an improved LeNet-5 model of convolutional neural network (CNN) and does not require the extraction of the diseased tissue, which can greatly enhance the efficiency. To address the issue of insufficient and unbalanced clinical data of meningioma images, we use an oversampling technique which allows us to considerably improve the accuracy of classification. Experiments on large clinical datasets show that our model can achieve quite high accuracy (i.e., as high as 83.33%) for the classification of meningioma images.
Detection of Alternative Drugs for Illegal Injection Based on Surface-Enhanced Raman Spectroscopy
Authors: Bao Lin , Han Siqingaowa , Sha Xuanyu , Zhao Hang , Liu Yuping , Lin Dianyang , Hasi Wuliji
Published: October 2019

Promethazine and scopolamine are two major components of a drug commonly used as a substitute for heroin addiction but with its own potential for abuse. Here, surface-enhanced Raman spectroscopy experiments were combined with density functional theory computations of the Raman frequencies of promethazine. The enhancement of the SERS substrate was optimized by contrast detection of silver nanoparticles. The optimized substrate was used to detect scopolamine, promethazine and their mixtures. Several mixtures of different concentrations were detected and analyzed. The approach of rapid identification and monitoring of drugs will become an important tool in the detection and control of illicit drug use.
El uso del análisis de caracterización de variables cualitativas en datos del programa de control de las helmintiasis Intestinales en Amazonas, Venezuela.
Authors: Gómez Medina Jesús Alberto , Rangel Tibisay , Trabucco Juan Carlos , Botto Carlos
Published: October 2019

Introducción: en este artículo se presenta un método original y poco conocido, que permite caracterizar una variable respuesta a partir de un conjunto de variables explicativas de tipo categórica. Métodos: el procedimiento consiste en realizar comparaciones entre proporciones para hallar las variables explicativas relacionadas, permite diferenciar grupos de la variable que se desea caracterizar, en base a las distintas categorías de las variables que se usan como explicativas. Esta técnica estadística se realizó con el apoyo del software SPAD, paquete estadístico empleado para realizar análisis de tipo multivariante. Resultados: se analizaron datos del programa de control de helmintos intestinales del estado Amazonas Venezuela, donde se evaluaron las prevalencias de los principales helmintos intestinales (Ascaris lumbricoides, Trichuris trichiura y anquilostomídeos). Conclusiones: el interés de usar esta metodología para la caracterización de las infecciones por helmintos intestinales, es que estas siguen siendo un serio problema de salud pública. Los resultados obtenidos, permitieron caracterizar los distintos niveles de prevalencia de estos helmintos, en función de las variables explicativas de tipo categórico usadas en el análisis.
The Role of Metabolic Plasticity in Blood and Brain Stem Cell Pathophysiology
Authors: Landis Catherine J. , McConathy Jonathan , Darley-Usmar Victor , Hjelmeland Anita B.
Published: October 2019

Our understanding of intratumoral heterogeneity in cancer continues to evolve, with current models incorporating single-cell signatures to explore cell–cell interactions and differentiation state. The transition between stem and differentiation states in nonneoplastic cells requires metabolic plasticity, and this plasticity is increasingly recognized to play a central role in cancer biology. The insights from hematopoietic and neural stem cell differentiation pathways were used to identify cancer stem cells in leukemia and gliomas. Similarly, defining metabolic heterogeneity and fuel-switching signals in nonneoplastic stem cells may also give important insights into the corresponding molecular mechanisms controlling metabolic plasticity in cancer. These advances are important, because metabolic adaptation to anticancer therapeutics is rooted in this inherent metabolic plasticity and is a therapeutic challenge to be overcome.
Disparities in Cancer Incidence and Trends among American Indians and Alaska Natives in the United States, 2010–2015
Authors: Melkonian Stephanie C. , Jim Melissa A. , Haverkamp Donald , Wiggins Charles L. , McCollum Jeffrey , White Mary C. , Kaur Judith S. , Espey David K.
Published: October 2019

Background:

Cancer incidence rates for American Indian and Alaska Native (AI/AN) populations vary by geographic region in the United States. The purpose of this study is to examine cancer incidence rates and trends in the AI/AN population compared with the non-Hispanic white population in the United States for the years 2010 to 2015.

Methods:

Cases diagnosed during 2010 to 2015 were identified from population-based cancer registries and linked with the Indian Health Service (IHS) patient registration databases to describe cancer incidence rates in non-Hispanic AI/AN persons compared with non-Hispanic whites (whites) living in IHS purchased/referred care delivery area counties. Age-adjusted rates were calculated for the 15 most common cancer sites, expressed per 100,000 per year. Incidence rates are presented overall as well as by region. Trends were estimated using joinpoint regression analyses.

Results:

Lung and colorectal cancer incidence rates were nearly 20% to 2.5 times higher in AI/AN males and nearly 20% to nearly 3 times higher in AI/AN females compared with whites in the Northern Plains, Southern Plains, Pacific Coast, and Alaska. Cancers of the liver, kidney, and stomach were significantly higher in the AI/AN compared with the white population in all regions. We observed more significant decreases in cancer incidence rates in the white population compared with the AI/AN population.

Conclusions:

Findings demonstrate the importance of examining cancer disparities between AI/AN and white populations. Disparities have widened for lung, female breast, and liver cancers.

Impact:

These findings highlight opportunities for targeted public health interventions to reduce AI/AN cancer incidence.
A Prospective Analysis of Red and Processed Meat Consumption and Risk of Colorectal Cancer in Women
Authors: Mehta Suril S. , Arroyave Whitney D. , Lunn Ruth M. , Park Yong-Moon Mark , Boyd Windy A. , Sandler Dale P.
Published: October 2019

Background:

Red and processed meats have been implicated as risk factors in the development of colorectal cancer in U.S. women, but associations with cooking practices are less well established.

Methods:

Data are from the Sister Study, a cohort of women ages 35 to 74 years from the United States and Puerto Rico who have a sister diagnosed with breast cancer. Red and processed meat consumption, meat cooking practices, and intake of common meat products were collected at baseline using self-administered questionnaires (N = 48,704). Multivariable HRs (HRadj) and 95% confidence intervals (95% CI) were estimated.

Results:

During a median 8.7 years' follow-up (range <1–12.7 years), 216 colorectal cancer cases were diagnosed. In categorical analyses, an increased risk of colorectal cancer was seen in the highest quartile of processed meat consumption compared with the lowest [HRadj = 1.52 (95% CI, 1.01–2.30); Ptrend = 0.02], and for specific meat products, including breakfast sausages [HRadj = 1.85 (95% CI, 1.30–2.64)] and bacon [HRadj = 1.46 (95% CI, 1.01–2.11)]. The HRadj for the highest quartile of red meat consumption was 1.04 (95% CI, 0.68–1.60), and little evidence of association was observed for cooking practices or doneness of red meat. We observed positive associations with specific red meat products when cooking methods were considered, for example, grilled/barbequed steaks [HRadj = 2.23 (95% CI, 1.20–4.14)] and hamburgers [HRadj = 1.98 (95% CI, 1.00–3.91)].

Conclusions:

Higher reported daily intake of processed meats and consumption of barbecued/grilled red meat products were associated with increased risk of colorectal cancer in women.

Impact:

Variability in colorectal risk risk by meat type and cooking method should be considered when evaluating meat consumption.
Differences in Pathology, Staging, and Treatment between HIV+ and Uninfected Patients with Microscopically Confirmed Hepatocellular Carcinoma
Authors: Torgersen Jessie , Taddei Tamar H. , Park Lesley S. , Carbonari Dena M. , Kallan Michael J. , Mitchell Richards Kisha , Zhang Xuchen , Jhala Darshana , Bräu Norbert , Homer Robert , D'Addeo Kathryn , Mehta Rajni , Skanderson Melissa , Kidwai-Khan Farah , Justice Amy C. , Lo Re Vincent
Published: October 2019

Background:

The incidence of hepatocellular carcinoma (HCC) is substantially higher among HIV-infected (HIV+) than uninfected persons. It remains unclear if HCC in the setting of HIV infection is morphologically distinct or more aggressive.

Methods:

We evaluated differences in tumor pathology in a cohort of HIV+ and uninfected patients with microscopically confirmed HCC in the Veterans Aging Cohort Study from 2000 to 2015. We reviewed pathology reports and medical records to determine Barcelona Clinic Liver Cancer stage (BCLC), HCC treatment, and survival by HIV status. Multivariable Cox regression was used to determine the hazard ratio [HR; 95% confidence interval (CI)] of death associated with HIV infection after microscopic confirmation.

Results:

Among 873 patients with HCC (399 HIV+), 140 HIV+ and 178 uninfected persons underwent liver tissue sampling and had microscopically confirmed HCC. There were no differences in histologic features of the tumor between HIV+ and uninfected patients, including tumor differentiation (well differentiated, 19% vs. 28%, P = 0.16) and lymphovascular invasion (6% vs. 7%, P = 0.17) or presence of advanced hepatic fibrosis (40% vs. 39%, P = 0.90). There were no differences in BCLC stage (P = 0.06) or treatment (P = 0.29) by HIV status. After adjustment for risk factors, risk of death was higher among HIV-infected than uninfected patients (HR = 1.37; 95% CI, 1.02–1.85).

Conclusions:

We found no differences in HCC tumor characteristics or background hepatic parenchyma by HIV status, yet HIV was associated with poorer survival. Of note, pathology reports often omitted these characteristics.

Impact:

Systematic evaluation of HCC pathology by HIV status is needed to understand tumor characteristics associated with improved survival.
Identification of FES as a Novel Radiosensitizing Target in Human Cancers
Authors: Kim Byoung Hyuck , Kim Yong Joon , Kim Myung-Ho , Na Yi Rang , Jung Daun , Seok Seung Hyeok , Kim Joon , Kim Hak Jae
Published: October 2019

Purpose:

The identification of novel targets for developing synergistic drug–radiation combinations would pave the way to overcome tumor radioresistance. We conducted cell-based screening of a human kinome siRNA library to identify a radiation-specific kinase that has a synergistic toxic effect with radiation upon inhibition and is not essential for cell survival in the absence of radiation.

Experimental Design:

Unbiased RNAi screening was performed by transfecting A549 cells with a human kinome siRNA library followed by irradiation. Radiosensitizing effects of a target gene and involved mechanisms were examined.

Results:

We identified the nonreceptor protein tyrosine kinase FES (FEline Sarcoma oncogene) as a radiosensitizing target. The expression of FES was increased in response to irradiation. Cell viability and clonogenic survival after irradiation were significantly decreased by FES knockdown in lung and pancreatic cancer cell lines. In contrast, FES depletion alone did not significantly affect cell proliferation without irradiation. An inducible RNAi mouse xenograft model verified in vivo radiosensitizing effects. FES-depleted cells showed increased apoptosis, DNA damage, G2–M phase arrest, and mitotic catastrophe after irradiation. FES depletion promoted radiation-induced reactive oxygen species formation, which resulted in phosphorylation of S6K and MDM2. The radiosensitizing effect of FES knockdown was partially reversed by inhibition of S6K activity. Consistent with the increase in phosphorylated MDM2, an increase in nuclear p53 levels was observed, which appears to contribute increased radiosensitivity of FES-depleted cells.

Conclusions:

We uncovered that inhibition of FES could be a potential strategy for inducing radiosensitization in cancer. Our results provide the basis for developing novel radiosensitizers.
Whole–Genome Sequencing of Childhood Cancer Survivors Treated with Cranial Radiation Therapy Identifies 5p15.33 Locus for Stroke: A Report from the St. Jude Lifetime Cohort Study
Authors: Sapkota Yadav , Cheung Yin Ting , Moon Wonjong , Shelton Kyla , Wilson Carmen L. , Wang Zhaoming , Mulrooney Daniel A. , Zhang Jinghui , Armstrong Gregory T. , Hudson Melissa M. , Robison Leslie L. , Krull Kevin R. , Yasui Yutaka
Published: October 2019

Purpose:

To identify genetic factors associated with risk of stroke among survivors of childhood cancer treated with cranial radiotherapy (CRT).

Experimental Design:

We analyzed whole-genome sequencing (36.8-fold) data of 686 childhood cancer survivors of European ancestry [median (range), 40.4 (12.4–64.7) years old; 54% male] from the St. Jude Lifetime Cohort study treated with CRT, of whom 116 (17%) had clinically diagnosed stroke. Association analyses (single-variant and Burden/SKAT tests) were performed, adjusting for demographic characteristics and childhood cancer treatment exposures.

Results:

We identified a genome-wide significant association between 5p15.33 locus and stroke [rs112896372: HR = 2.55; P = 1.42 × 10–8], with a stronger association (HR = 3.68) among survivors treated with CRT dose 25–50 Gray (Gy) and weaker associations among those treated with CRT doses <20 or 20–25 or >50 Gy (HRs = 2.14, 2.40, and 2.28). The association was replicated in 90 CRT-exposed African survivors (HR = 3.05; P = 0.034). In CRT-exposed Europeans, rs112896372 significantly (P < 0.001) improved predictive ability (AUC = 0.717) for determining stroke risk than nongenetic factors alone (AUC = 0.663) at 30 years since diagnosis, with significant improvement among African survivors (P = 0.047). SNP rs112896372 was further evaluated in three independent datasets including 1,641 European (HR = 1.54; P = 0.055) and 316 African survivors (HR = 1.88; P = 0.283) not treated with CRT, and 166,988 males in the UK Biobank (OR = 1.0012; P = 0.042).

Conclusions:

A novel locus 5p15.33 is associated with stroke risk among childhood cancer survivors, with a possible CRT dose-specific effect. The locus is of potential clinical utility in characterizing individuals who may benefit from surveillance and intervention strategies.
Acquired On-Target Clinical Resistance Validates FGFR4 as a Driver of Hepatocellular Carcinoma
Authors: Hatlen Megan A. , Schmidt-Kittler Oleg , Sherwin Cori Ann , Rozsahegyi Emily , Rubin Nooreen , Sheets Michael P. , Kim Joseph L. , Miduturu Chandrasekhar , Bifulco Neil , Brooijmans Natasja , Shi Hongliang , Guzi Timothy , Boral Andy , Lengauer Christoph , Dorsch Marion , Kim Richard D. , Kang Yoon-Koo , Wolf Beni B. , Hoeflich Klaus P.
Published: October 2019

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide with no clinically confirmed oncogenic driver. Although preclinical studies implicate the FGF19 receptor FGFR4 in hepatocarcinogenesis, the dependence of human cancer on FGFR4 has not been demonstrated. Fisogatinib (BLU-554) is a potent and selective inhibitor of FGFR4 and demonstrates clinical benefit and tumor regression in patients with HCC with aberrant FGF19 expression. Mutations were identified in the gatekeeper and hinge-1 residues in the kinase domain of FGFR4 upon disease progression in 2 patients treated with fisogatinib, which were confirmed to mediate resistance in vitro and in vivo. A gatekeeper-agnostic, pan-FGFR inhibitor decreased HCC xenograft growth in the presence of these mutations, demonstrating continued FGF19–FGFR4 pathway dependence. These results validate FGFR4 as an oncogenic driver and warrant further therapeutic targeting of this kinase in the clinic.

Significance:

Our study is the first to demonstrate on-target FGFR4 kinase domain mutations as a mechanism of acquired clinical resistance to targeted therapy. This further establishes FGF19–FGFR4 pathway activation as an oncogenic driver. These findings support further investigation of fisogatinib in HCC and inform the profile of potential next-generation inhibitors.

See related commentary by Subbiah and Pal, p. 1646.

This article is highlighted in the In This Issue feature, p. 1631
First-in-Human Phase I Study of Fisogatinib (BLU-554) Validates Aberrant FGF19 Signaling as a Driver Event in Hepatocellular Carcinoma
Authors: Kim Richard D. , Sarker Debashis , Meyer Tim , Yau Thomas , Macarulla Teresa , Park Joong-Won , Choo Su Pin , Hollebecque Antoine , Sung Max W. , Lim Ho-Yeong , Mazzaferro Vincenzo , Trojan Joerg , Zhu Andrew X. , Yoon Jung-Hwan , Sharma Sunil , Lin Zhong-Zhe , Chan Stephen L. , Faivre Sandrine , Feun Lynn G. , Yen Chia-Jui , Dufour Jean-Francois , Palmer Daniel H. , Llovet Josep M. , Manoogian Melissa , Tugnait Meera , Stransky Nicolas , Hagel Margit , Kohl Nancy E. , Lengauer Christoph , Sherwin Cori Ann , Schmidt-Kittler Oleg , Hoeflich Klaus P. , Shi Hongliang , Wolf Beni B. , Kang Yoon-Koo
Published: October 2019

Outcomes for patients with advanced hepatocellular carcinoma (HCC) remain poor despite recent progress in drug development. Emerging data implicate FGF19 as a potential HCC driver, suggesting its receptor, FGFR4, as a novel therapeutic target. We evaluated fisogatinib (BLU-554), a highly potent and selective oral FGFR4 inhibitor, in a phase I dose-escalation/dose-expansion study in advanced HCC using FGF19 expression measured by IHC as a biomarker for pathway activation. For dose escalation, 25 patients received 140 to 900 mg fisogatinib once daily; the maximum tolerated dose (600 mg once daily) was expanded in 81 patients. Fisogatinib was well tolerated; most adverse events were manageable, grade 1/2 gastrointestinal events, primarily diarrhea, nausea, and vomiting. Across doses, the overall response rate was 17% in FGF19-positive patients [median duration of response: 5.3 months (95% CI, 3.7–not reached)] and 0% in FGF19-negative patients. These results validate FGFR4 as a targetable driver in FGF19-positive advanced HCC.

Significance:

Fisogatinib elicited clinical responses in patients with tumor FGF19 overexpression in advanced HCC. These results validate the oncogenic driver role of the FGFR4 pathway in HCC and the use of FGF19 as a biomarker for patient selection.

See related commentary by Subbiah and Pal, p. 1646.

This article is highlighted in the In This Issue feature, p. 1631
Sustained-Release Triamcinolone Acetonide Hydrogels Reduce Hearing Threshold Shifts in a Model for Cochlear Implantation with Hearing Preservation
Authors: Honeder Clemens , Zhu Chengjing , Gausterer Julia Clara , Schöpper Hanna , Ahmadi Navid , Saidov Nodir , Nieratschker Michael , Gabor Franz , Arnoldner Christoph
Published: October 2019

Introduction: In recent years, the preservation of residual hearing has become a major factor in patients undergoing cochlear implantation (CI). In studies attempting to pharmaceutically improve hearing preservation rates, glucocorticoids (GCs) applied perioperatively in many institutions have emerged as a promising treatment regimen. Although dexamethasone is most commonly used and has been applied successfully by various research groups, recently pharmacological properties have been reported to be relatively unsuitable for topical delivery to the inner ear. Consequently other glucocorticoids merit further evaluation. The aim of this study was therefore to evaluate the otoprotective effects of the topical application of a sustained-release triamcinolone acetonide (TAAC) hydrogel in CI with hearing preservation. Methods: Normal-hearing pigmented guinea pigs were randomized into a group receiving a single dose of a 6% TAAC poloxamer 407 hydrogel, a group receiving a 30% TAAC hydrogel and a control group. All hydrogel applications were performed 1 day prior to CI. After a cochleostomy was drilled, a specifically designed silicone electrode was inserted into the scala tympani for 5 mm. Frequency-specific compound action potentials of the auditory nerve (0.5–32 kHz) were measured pre- and directly postoperatively as well as on days 3, 7, 14, 21, and 28. Finally, temporal bones were harvested for histological evaluation. Results: Application of the TAAC hydrogels resulted in significantly reduced hearing threshold shifts in low, middle and high frequencies and improved spiral ganglion cell survival in the second turn of the cochlea. Outer hair cell numbers in the basal and second turn of the cochlea were slightly reduced after TAAC application. Conclusion: In summary, we were able to demonstrate functional benefits of a single preoperative application of a TAAC hydrogel in a guinea pig model for CI, which persisted until the end of the observational period, that is, 28 days after surgery.
Vitreoretinal Surgery and Panretinal Photocoagulation in a Patient with Multiple Large Retinal Capillary Hemangiomas (von Hippel-Lindau Disease): A Novel Approach
Authors: Sturzeneker Guilherme , Maia André , Morales Melina , N. Belfort Rubens
Published: October 2019

The authors present a novel surgical approach for the treatment of retinal capillary hemangiomas (RCHs) secondary to von Hippel-Lindau (VHL) disease. This is a case report of a 23-year-old male patient with VHL that presented with multiple large RCHs and a thick epiretinal membrane (ERM) in his left eye, with best-corrected visual acuity (BCVA) of 20/80. This condition was surgically addressed with 23-gauge pars plana vitrectomy, ERM and internal limiting membrane peeling, and panretinal photocoagulation. Three monthly intravitreal injections of bevacizumab were administered after surgery. In a 14-month follow-up period, hemangiomas have regressed after laser therapy, macular anatomy has improved, retina remained completely attached, and there has been no development of new tumors or proliferative vitreoretinopathy. The patient achieved a BCVA of 20/40 in the treated eye. Panretinal photocoagulation combined with pars plana vitrectomy may be useful to reduce development of new capillary hemangiomas and reduce overall occurrence of complications in patients with VHL disease. Postoperative intravitreal injections of bevacizumab may have a role in this positive outcome.
Factors Impacting on Decision-Making towards Prophylactic Surgeries in BRCA Mutation Carriers and Women with Familial Predisposition
Authors: Segerer Robin , Peschel Clara , Kämmerer Ulrike , Häussler Sebastian , Wöckel Achim , Segerer Sabine
Published: October 2019

Background/Objectives: BRCA mutation carriers and women at high risk of breast/ovarian cancer are faced with the intricate question to opt for prophylactic surgeries and/or a periodic screening. The aim of this study was therefore to identify objective and emotional factors that have an impact on the decision-making process. Methods: Ninety-five women with BRCA mutations or women at increased breast/ovarian cancer lifetime risk were counseled at our outpatient department and either opted for prophylactic surgery or periodic screening. To identify the psychological factors that could have influenced the decision-making, a standardized questionnaire was applied. Additionally, clinical data were collected and were reviewed by a personal talk. Results: Seventy-one of the patients opted for an increased surveillance only, 21 for prophylactic surgeries. Positive predictors for prophylactic surgeries were sociodemographic characteristics such as parity and objective variables such as verified mutation status. Hierarchical regression analysis revealed that the need for safety in health issues has been the only significant psychological predictor of surgery beyond the objective factors. Fear of surgical procedures, menopausal symptoms after surgery, loss of attractiveness, or fear of interferences with sexual life did not significantly affect decision-making. Conclusion: Decision-making towards prophylactic surgeries is influenced by objective but also emotional factors. Knowing that fear and anxiety also have an important impact on decision-making, distinct counselling about the procedures, the subsequent risk reduction as well as the psychological effects of prophylactic surgeries are essential.
Novel Assay Analyzing Tropism between Adipose-Derived Stem Cells and Breast Cancer Cells Reveals a Low Oncogenic Response
Authors: Sauter Matthias A. , Brett Elizabeth , Müller Christina M. , Machens Hans-Günther , Duscher Dominik
Published: October 2019

Introduction: In the surgical world of breast cancer reconstruction, fat grafting is commonly viewed as an oncogenic risk. Scientific studies add confusion, given the stark lack of clinical evidence suggesting pro-oncogenic links. Typically, classic migration assays (e.g., Boyden chamber) between adipose-derived stem cells and breast cancer cells define this cell relationship as pro-oncogenic. Objective: We sought to develop a new migration model which better explains existing clinical data. Methods: Silicon chambers were used to seed isolated populations of cells simultaneously in culture dish. Once cells had adhered, chambers were removed and cells were allowed to follow natural trophic cues. Multiple permutations of MDA-MB-231, MCF-7, HS-27, and ASCs were engineered. Cells were stained with MitoTracker for fluorescent visualization. A human cytokine array (RayBiotech) was performed on the media of migrating assays. Cellular tropism and blot intensity were quantitatively measured in Image J. Results: An in vitromodel was successfully constructed where ASCs reproducibly and freely migrated. Cytokine arrays reveal higher levels of IL-6 and CCL2 in the media of Boyden chambers containing ASCs and MDA-MB-231, compared to the novel assay, comprised of the same cell numbers, types, and incubation times. Conclusion: These data collectively show for the first time the attraction of ASCs to malignant breast cancer cells; a phenomenon which many ASC studies infer. The cytokine profile of the novel system described is less oncogenic than the commonly described Boyden chamber. These data integrate better into the clinical data, which fail to link cancer recurrence with fat grafting.
Estudo da mineralização de cobre em basaltos do Grupo Serra Geral, utilizando difratometria de raios X, microscopia eletrônica de varreduraespectroscopia por energia dispersiva e tomografia com nêutrons
Authors: Garda Gianna Maria , Filgueira Diego Arruda , Pugliesi Reynaldo , Pereira Marco Antônio Stanojev , Sayeg Isaac Jamil
Published: October 2019

Mineralizações de cobre do tipo Michigan ocorrem nos derrames basálticos do Grupo Serra Geral na região de Nova Prata do Iguaçu, sudoeste do estado do Paraná. Nessas mineralizações, o cobre nativo é o principal mineral de minério e, com a alteração supérgena, transforma-se em óxidos de cobre, malaquita e crisocola, sendo esta encontrada na forma de um precipitado gelatinoso que preenche amígdalas e impregna fraturas no basalto, além de recobrir minerais secundários e outros produtos de alteração. Neste estudo, foram utilizadas as técnicas de difratometria de raios X e microscopia eletrônica de varredura-espectroscopia por energia dispersiva (MEV-EDS) para a caracterização do grau de cristalinidade e composição química da crisocola e a identificação de outros materiais hidrogenados, como subsídio para o imageamento 3D por tomografia com nêutrons. A crisocola destacou-se como um eficiente atenuador de nêutrons, obtendo-se coeficiente de atenuação linear da ordem de 0,8–1,3 cm-1, ao passo que, para o corpo de minério (basalto), obteve-se 0,5–0,6 cm-1. O contraste entre os coeficientes permitiu a obtenção de imagens tomográficas e filmes de boa resolução, em que se pôde visualizar a distribuição da crisocola na amostra de basalto e estimar como fração volumétrica de crisocola no corpo de minério valores entre 0,9 e 1,4%, obtendo-se o valor de 7,8% em volume de crisocola para uma das amostras. A utilização integrada das três técnicas analíticas demonstrou que esta pode ser uma ferramenta para avaliação do potencial mineral nas fases iniciais da prospecção mineral, especialmente quando as substâncias de interesse são ricas em hidrogênio.
O parque agroambiental como nova categoria de sistema de espaços livres
Authors: Queiroz Alessandra Natali , Queiroga Eugênio Fernandes , Merlin José Roberto
Published: October 2019

O presente artigo tem como tema o estudo de sistemas de espaços livres e a urbanização contemporânea na região de Limeira, integrante da Região Administrativa de Campinas - SP. De especial atenção é a configuração do território, como unidade de projeto para um “parque regional contemporâneo” ou, como se propôs chamar, “parque agroambiental”. O “parque agroambiental” não é uma solução simples, mas uma possibilidade de pensar e agir. Pode-se, por meio dele, ajustar o foco de leitura da realidade local, buscando-se mecanismos mais coerentes para nela atuar. Diferentemente de outras regiões de importantes recursos naturais, como a região metropolitana de São Paulo, o conceito do parque objetiva trabalhar uma área econômica e socialmente uniforme, onde a fauna e a flora são quase inexistentes, visto terem sido substituídas pela urbanização e pelas áreas destinadas à produção agrícola para o mercado global. O desafio aqui proposto é tornar o parque regional contemporâneo objeto de debate para políticas públicas de atendimento às necessidades sociais e ambientais. Podem ser práticas de lazer, esportes e/ou contemplativas, atividades culturais de identidade regional, de produção agrícola ou florestal, de conservação de ecossistemas, por meio das quais se definem diferentes níveis e escalas de intervenção e de acessibilidade aos lugares. Propõe-se o conceito de “parque agroambiental” como instrumento de planejamento regional e ambiental.
The Philippines in 2018: a Year of Disruption and Consolidation
Authors: Aguirre Arjan
Published: October 2019

2018 is a year of so much uneasiness and tension in Philippine politics. It saw one of the greatest crises in the Supreme Court, the bloodiest period in local politics of late, and successive attempts to silence critics of the president and the government. This year also witnessed major political alignments in the Duterte administration: a change in the leadership of the Senate, the election of Gloria Macapagal Arroyo as Speaker of the House, the rivalry between Hugpong ng Pagbabago and Partido Demokratiko ng Pilipinas-Lakas ng Bayan, and the eventual termination of the alliance with the radical left. This review aims to understand these developments in Philippine politics. It seeks to know why are there so many rifts and shifts in the political rule of Duterte. These changes can be interpreted as part of an ongoing transition toward democratic regression under the Duterte regime. The disruptive events that ensued throughout the year should be understood as the offshoot of the extant efforts to alter the political status quo since the election of Duterte in 2016. The administration uses these events to consolidate its power by rallying its supporters for the 2019 midterm elections and reconfiguring the alignments within the Duterte bloc.
Revision of the circumglobal genus Barathronus (Ophidiiformes, Bythitidae) with a new species from the eastern North Atlantic Ocean
Authors: NIELSEN JØRGEN G.
Published: October 2019

The viviparous genus Barathronus Goode & Bean, 1886 is known from 11 species. Examination of 68 specimens, not earlier published upon, and re-examination of older material have resulted in taxonomical changes and new distributions. B. unicolor Nielsen, 1984 has become a junior synonym of B. pacificus Nielsen & Eagle, 1974, now known from the Atlantic and Pacific Oceans. The number of specimens of B. parfaiti Vaillant, 1888 is restricted to the holotype and a specimen from off the Azores (MOM P01-0003665), often referred to B. parfaiti, represents a new species, B. roulei, herein described. B. diaphanus Brauer, 1906 is now recorded from off Madagascar eastwards to Tonga and Fiji Islands.
The Chinese Hecalina (Hemiptera: Cicadellidae: Deltocephalinae: Hecalini) with descriptions of a new genus and seven new species
Authors: HE ZHIQIANG , ZHANG YALIN , MCKAMEY STUART H. , ZAHNISER JAMES N.
Published: October 2019

The Chinese Hecalina (Deltocephalinae: Hecalini), which consists of five genera, is reviewed. Coloration and shape of the head and body, venation of forewing, and genitalia structures are the main morpological characters utilized to distinguish taxa. Fangamanus gen. n. is proposed for Parabolocratus tripunctatus Matsumura (type species of the new genus) and two other species. A key to the five genera of the Chinese Hecalina (Fangamanus gen. n., Hecalus Stål, Hecalusina He et al., Linnavuoriella Evans, and Thomsonia Signoret) is given, and seven new species from China are described: Hecalus changjiaotus, H. feithailandus, H. nadanus, H. triundosus, H. yuanmouensis, Thomsonia breviaea, and T. daliensis. In addition, four new combinations are proposed: Thomsonia nitobei (Matsumura), Fangamanus rufofascianus (Li), F. tripunctatus (Matsumura) (n. rec.), and F. morrisoni (Kwon and Lee). Only seven previously described species from China remain in Hecalus Stål: H. bifurcatus Cai & Wang, H. furcatus Morrison, H. henanus Cai & Shen, H. katoi Metcalf, H. prasinus (Matsumura), H. thailandensis Morrison, and H. wallengreni (Stål) plus two species (H. paykulli Stål and H. lefroyi Distant) previously recorded but unconfirmed here from China. Four species are redescribed: Fangamanus rufofascianus, F. tripunctatus, Thomsonia porrecta, and the first description and illustration of the male of T. nitobei (Matsumura) are provided.