bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk Factors for Rubella Transmission in Kuyu District, Ethiopia, 2018: A Case-Control Study
Authors: Abdulkadir Abdulbari , Gebrehiwot Tsegaye Tewelde
Published: September 2019

Background. Rubella is a vaccine-preventable disease associated with a significant morbidity and adverse pregnancy outcomes, mainly if acquired in the first trimester of pregnancy with serious consequences to the fetus. Despite increased episodes of rubella epidemics (127 outbreaks in 2009–2015), rubella national vaccination is not yet introduced in Ethiopia. In January 2018, an increase of fever and rash cases was reported in Kuyu District of Oromia. We investigated the outbreak to confirm rubella, determine risk factors, and guide interventions. Methods. We identified rubella cases from health centers and conducted a case-control study (1 case : 2 controls) with 150 participants, from March 12 to 15, 2018. Cases were people who presented with fever and rash or laboratory-confirmed cases. Controls were age matched (<15 yrs) with neighbors selected purposively. We interviewed parents by a structured questionnaire and observed the housing condition. Variables include sex, age, vaccination status, family size, contact history, housing condition, and travel history. Simple logistic regression was used to select the candidate variable at a P value <0.25. We identified risk factors at P<0.05 with AOR and 95% CI by multivariate logistic regression. Results. We identified 50 cases (with no death), and out of them, seven (14%) were confirmed cases (rubella IgM positive). The mean age of the cases was 6 ± 3 years and of the controls was 8 ± 4 years. Family size >5 (AOR = 2.4; 95% CI: 1.5–4.11), not well-ventilated living room (AOR = 4.7; 95% CI: 3.43–8.12), history of contact with rash people (AOR = 2.2; 95% CI: 1.6 3.5), no history of diarrhea in the last 14 days (AOR = 0.8; 95% CI: 0.6–0.9), and no history of vitamin A supplementation (AOR = 2.9; 95% CI: 1.7–2.6) were significant factors for rubella infection. Conclusions. We identified rubella outbreak in the rural area. Crowded living condition, large family size, not receiving vitamin A in the last 6 months, and contact with people with symptoms of rubella were factors that drove the outbreak, while not having diarrhea in the last 14 days was the protective factor. We recommended the introduction of rubella immunization national programs and advocated the policy on rubella vaccine and strengthening surveillance for congenital rubella syndrome and rubella.
Does Moxa Smoke Have Significant Effect on the Acupuncturist’s Respiratory System? A Population-Based Study
Authors: Yu Chang , Zhang Ning , Zhu Weikang , Zhang Yueyue , Yang Jiao , Wang Yong , Song Xiaoge , Hu Ling , Wu Zijian , Liu Qi , Tang Yong , Wu Qiaofeng , Yu Shuguang
Published: September 2019

Objectives. To evaluate the safety of moxa smoke, especially to provide quantitative information and details for the occupational prevention of acupuncturists. Methods. We combined the questionnaire-based cross-sectional survey and lung function testing-based historical retrospective cohort research to investigate the safety of moxa smoke exposure (MSE) among acupuncturists. A mathematical regression model was established to quantitatively evaluate the relationship between moxa smoke exposure and the respiratory health of the acupuncturist. The smoke exposure time of the acupuncturist and the prevalence of abnormal respiratory symptoms or diseases were also evaluated. Results. (1) The cross-sectional research showed that the incidence of expectoration (18.7%) and rhinitis (22.7%) was the most common respiratory symptom and disease after MSE. No statistical difference was found between smoke exposure time of the acupuncturist and the prevalence of abnormal respiratory symptoms or diseases, except the prevalence of rhinitis and shortness of breath (P<0.01). Regression model for the incidence of first three symptoms (expectoration, shortness of breath, and wheezing) from the cross-sectional survey indicated that the weight coefficients of factors associated with moxa smoke were lower than those of factors unrelated to moxa smoke, such as gender and personal history of respiratory diseases. (2) Historical retrospective cohort research showed that there was no significant difference in the % predicted PEF. No statistic difference was found between the exposed and nonexposed group in large airway function indexes (% predicted FEV1, % predicted FVC, and % predicted FEV1/FVC) and small airway function indexes (% predicted FEF25, % predicted FEF50, % predicted FEF75, and % predicted MMEF), either. Especially, the % predicted MVV among males (106.23 ± 2.92 vs. 95.56 ± 1.92, P<0.01 and % predicted VC among females (100.70 ± 1.59 vs. 95.91 ± 1.61, P<0.05) between the two groups had statistical significance, but did not cause pulmonary ventilation dysfunction. Conclusions. MSE has no significant effect on the respiratory health of acupuncturists.
Cannabis-Induced Third-Degree AV Block
Authors: Van Keer Jan M.
Published: September 2019

Background. Cannabis (marijuana) is the most widely consumed illicit drug in Europe. However, many are unaware of its potential cardiovascular side effects. Case Report. A 19-year-old man presented to the emergency department with palpitations and presyncope after smoking cannabis. A third-degree atrioventricular block (complete heart block) was diagnosed. We believe cannabis exposure to have been the likely cause. Extensive work-up—including Borrelia and auto-immune serology, CT coronary angiography, magnetic resonance imaging, and electrophysiological study—was negative. The patient was initially treated with IV isoprenaline. Within one day, the bradycardia spontaneously resolved. The patient was advised to quit using cannabis. No further therapy was initiated. We discuss the clinical presentation, pathophysiology, and evidence from the literature linking cannabis exposure to bradycardia. Conclusion. We describe a case of third-degree atrioventricular block after cannabis use. Emergency physicians should be aware of the potential cardiovascular side effects of this drug.
Synchronous Choriocarcinoma and Epithelioid Trophoblastic Tumor Concurring at the Cesarean Scar: A Case Report and Review of the Literature
Authors: Zeng Chunyan , Rezai Shadi , Hughes Alexander C. , Henderson Cassandra E. , Liu Juan
Published: September 2019

We present a complicated case of recurrence of gestational trophoblastic neoplasms (GTN), mixed ETT and choriocarcinoma at an abdominal cesarean scar. This tumor consisted of typical morphologic and immunophenotypic features of ETT and choriocarcinoma. The tumor recurred despite the patient undergoing chemotherapy. The patient had this abdominal mass resected three times. The elements of ETT and coexisting choriocarcinoma varied each time. Due to re-recurrence of the tumor, the following decisions had been made: total abdominal hysterectomy, bilateral salpingectomy, right-sided inguinal lymph node biopsy. At the time of this report, recurrence was negative.
Vogt–Koyanagi–Harada Syndrome in a Ugandan: Diagnostic and Therapeutic Challenges
Authors: Bongomin Felix , Onen Francis S. , Kaddumukasa Mark
Published: September 2019

Background. Vogt–Koyanagi–Harada (VKH) syndrome is a multisystemic autoimmune disease of uncertain pathogenesis. Infectious aetiology has been proposed which is suggested to lead to the loss of melanocytes in the skin, inner ear, meninges, and uvea in those who are genetically predisposed. Information regarding VKH syndrome is scanty among the African population. Case Presentation. We report a 28-year-old HIV-uninfected Ugandan woman who had previously been well and presented with chronic bilateral panuveitis; symmetrical vitiligo patches on the head, trunk, and upper limbs; tinnitus; and poliosis of the scalp hair, eyelashes, and eyebrows. A flu-like syndrome preceded this. Several weeks of prednisolone and azathioprine therapy resulted in remarkable improvement of the ocular and inner ear symptoms. Conclusion. A high index of suspicion is required in diagnosing VKH syndrome, even in sub-Saharan Africa where the disease is reported to be rare. Initiation of prompt and appropriate treatment prevents blindness and other complications.
Factors Associated with the Technical Success of Bilateral Endoscopic Metallic Stenting with Partial Stent-In-Stent Placement in Patients with Malignant Hilar Biliary Obstruction
Authors: Fujita Toshihiro , Hashimoto Shinichi , Tanoue Shiroh , Tsuneyoshi Kengo , Nakamura Yoshitaka , Hinokuchi Makoto , Iwaya Hiromichi , Arima Shiho , Iwashita Yuji , Sasaki Fumisato , Taguchi Hiroki , Kanmura Shuji , Ido Akio
Published: September 2019

Background. Bilateral biliary drainage decreases the risk of cholangitis, but bilateral endoscopic metallic stenting is technically challenging. Aim. We retrospectively evaluated the factors associated with successful bilateral self-expanding metal stent (SEMS) placement using the partial stent-in-stent (PSIS) method for malignant hilar biliary obstruction and also assessed the safety and efficacy of this technique. Methods. From April 2010 to February 2016, 47 consecutive patients (mean age, 73.0±8.6 years; 32 males and 15 females) underwent PSIS placement for malignant hilar biliary obstruction in our hospital. The technical success of PSIS, clinical response, and complications were investigated. Factors associated with the technical success of PSIS were assessed. Using a propensity score-matched analysis, we compared the procedure time, clinical response, complications, stent patency, and survival time in 17 matched patients treated with bilateral SEMS placement using a SEMS delivery system of <6.0 or ≥6.0 Fr. Results. The technical success rate was 77%. The clinical response rate was 91%, and the complication rate was 26%. Regarding complications, pancreatitis occurred in 5 patients (11%), cholangitis in 6 (13%), and cholecystitis in 1 (2%). A multiple logistic regression analysis identified the use of a SEMS with a delivery system<6.0 Fr as a factor associated with technical success (P=0.033; odds ratio, 10.769; 95% confidence interval, 1.205-96.212). In the 17 matched patients assigned according to the SEMS delivery system size, the procedure time was significantly shorter in those with a delivery system size<6.0 Fr than in those with ≥6.0 Fr (P<0.01). There were no significant differences in the clinical response, complication rate, stent patency, or survival time between the two groups. Conclusion. Using a delivery system<6.0 Fr in size helped improve the technical success and reduced the procedure time for the placement of a SEMS by the PSIS method.
Transarterial Chemoembolization Combined with Radiofrequency Ablation in the Treatment of Stage B1 Intermediate Hepatocellular Carcinoma
Authors: Liu Furong , Chen Minshan , Mei Jie , Xu Li , Guo Rongping , Lin Xiaojun , Zhang Yaojun , Peng Zhenwei
Published: September 2019

Background. Due to the heterogeneity of patients with Barcelona clinic liver cancer (BCLC) intermediate-stage hepatocellular carcinoma (HCC), Bolondi criteria were proposed and patients were divided into four substages. The purpose of this study was to compare the survival of substage B1 patients who were initially treated with a combination of transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) (TACE-RFA) or TACE alone. Methods. 404 patients with stage B1 HCC were retrospectively analyzed from January 2005 to December 2012. 209 patients received TACE-RFA, and 195 received TACE alone as initial treatment. The overall survival (OS) and progression-free survival (PFS) rates were estimated by the Kaplan–Meier method and compared by the log-rank test. Results. 1-, 3-, and 5-year OS rates were 83.7%, 45.8%, and 24.8% in the TACE-RFA group and 80.7%, 26.4%, and 16.7% in the TACE group, respectively (P=0.003). The corresponding PFS rates were 71.8%, 26.6%, and 13.0% and 59.1%, 11.0%, and 2.2% in the TACE-RFA group and TACE group, respectively (P<0.001). Multivariate regression analysis indicated that tumor size (OS: hazard ratio (HR) = 0.683, P=0.001; PFS: HR = 0.761, P=0.013), along with treatment allocation (OS: HR = 0.701, P=0.003; PFS: HR = 0.620, P<0.001), was the independent prognostic factor for both OS and PFS. Conclusions. Combination TACE and RFA treatment yielded better survival than TACE alone for patients with stage B1 HCC according to the Bolondi criteria.
Transcranial Magnetic Stimulation as a Potential Biomarker in Multiple Sclerosis: A Systematic Review with Recommendations for Future Research
Authors: Snow Nicholas J. , Wadden Katie P. , Chaves Arthur R. , Ploughman Michelle
Published: September 2019

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system. Disease progression is variable and unpredictable, warranting the development of biomarkers of disease status. Transcranial magnetic stimulation (TMS) is a noninvasive method used to study the human motor system, which has shown potential in MS research. However, few reviews have summarized the use of TMS combined with clinical measures of MS and no work has comprehensively assessed study quality. This review explored the viability of TMS as a biomarker in studies of MS examining disease severity, cognitive impairment, motor impairment, or fatigue. Methodological quality and risk of bias were evaluated in studies meeting selection criteria. After screening 1603 records, 30 were included for review. All studies showed high risk of bias, attributed largely to issues surrounding sample size justification, experimenter blinding, and failure to account for key potential confounding variables. Central motor conduction time and motor-evoked potentials were the most commonly used TMS techniques and showed relationships with disease severity, motor impairment, and fatigue. Short-latency afferent inhibition was the only outcome related to cognitive impairment. Although there is insufficient evidence for TMS in clinical assessments of MS, this review serves as a template to inform future research.
CD133 in Breast Cancer Cells: More than a Stem Cell Marker
Authors: Brugnoli Federica , Grassilli Silvia , Al-Qassab Yasamin , Capitani Silvano , Bertagnolo Valeria
Published: September 2019

Initially correlated with hematopoietic precursors, the surface expression of CD133 was also found in epithelial and nonepithelial cells from adult tissues in which it has been associated with a number of biological events. CD133 is expressed in solid tumors as well, including breast cancer, in which most of the studies have been focused on its use as a surface marker for the detection of cells with stem-like properties (i.e., cancer stem cells (CSCs)). Differently with other solid tumors, very limited and in part controversial are the information about the significance of CD133 in breast cancer, the most common malignancy among women in industrialized countries. In this review, we summarize the latest findings about the implication of CD133 in breast tumors, highlighting its role in tumor cells with a triple negative phenotype in which it directly regulates the expression of proteins involved in metastasis and drug resistance. We provide updates about the prognostic role of CD133, underlining its value as an indicator of increased malignancy of both noninvasive and invasive breast tumor cells. The molecular mechanisms at the basis of the regulation of CD133 levels in breast tumors have also been reviewed, highlighting experimental strategies capable to restrain its level that could be taken into account to reduce malignancy and/or to prevent the progression of breast tumors.
Emerging Perspective: Role of Increased ROS and Redox Imbalance in Skin Carcinogenesis
Authors: Xian Dehai , Lai Rui , Song Jing , Xiong Xia , Zhong Jianqiao
Published: September 2019

Strategies to battle malignant tumors have always been a dynamic research endeavour. Although various vehicles (e.g., chemotherapeutic therapy, radiotherapy, surgical resection, etc.) are used for skin cancer management, they mostly remain unsatisfactory due to the complex mechanism of carcinogenesis. Increasing evidence indicates that redox imbalance and aberrant reactive oxygen species (ROS) are closely implicated in the oncogenesis of skin cancer. When ROS production goes beyond their clearance, excessive or accumulated ROS could disrupt redox balance, induce oxidative stress, and activate the altered ROS signals. These would damage cellular DNA, proteins, and lipids, further leading to gene mutation, cell hyperproliferation, and fatal lesions in cells that contribute to carcinogenesis in the skin. It has been known that ROS-mediated skin carcinogenesis involves multiple ways, including modulating related signaling pathways, changing cell metabolism, and causing the instability of the genome and epigenome. Nevertheless, the exact role of ROS in skin cancer has not been thoroughly elucidated. In spite of ROS inducing skin carcinogenesis, toxic-dose ROS could trigger cell death/apoptosis and, therefore, may be an efficient therapeutic tool to battle skin cancer. Considering the dual role of ROS in the carcinogenesis and treatment of skin cancer, it would be essential to clarify the relationship between ROS and skin cancer. Thus, in this review, we get the related data together to seek the connection between ROS and skin carcinogenesis. Besides, strategies basing on ROS to fight skin cancer are discussed.
Changes in Soft-Tissue Sarcoma Treatment Patterns over Time: A Population-Based Study in a Country with Universal and Centralized Healthcare
Authors: Bozzo Anthony , Seow Hsien , Pond Gregory , Ghert Michelle
Published: September 2019

Background. The clinical care of soft-tissue sarcoma (STS) patients is largely multidisciplinary involving clinicians from surgical disciplines, medical oncology, and radiation oncology. It is not clear if treatment patterns for STS have changed over time. We present population-level data on changes in treatment patterns of patients diagnosed with STS of all stages in Ontario, Canada. Methods. We performed a population-based cohort study using linked administrative databases in Ontario, Canada, of patients with STS between 2006 and 2015. Patients with the AJCC stage at the time of diagnosis were included. Patients were categorized into one of the seven treatment arms: single modality treatment (surgery, chemotherapy, or radiation therapy), bimodality therapy, or all three treatment modalities. Survival of STS patients of different stages is displayed with the Kaplan–Meier method. Results. A total of 4696 patients were diagnosed with biopsy-proven sarcoma during the study period including 1915 patients with stage information available. Treatment patterns for patients with Stage 1 and 2 disease were similar enough to allow for grouping. The use of radiation therapy in Stage 1 and 2 patients increased by 15% over the study period. None of the 7 treatment regimens for Stage 3 patients changed appreciably during the study period. We observed that the use of chemotherapy for Stage 4 STS patients increased 36% during the study period. Overall patient survival was, as expected, highest in Stage 1 patients and lowest in Stage 4 patients. Conclusion. This is the first population-level study reporting of 7 different STS treatment regimens in a country with universal and centralized healthcare. Radiation therapy for local disease control and chemotherapy for Stage 4 patients have recently become more utilized. Survival from STS is highly dependent on stage at presentation. Other population-based studies from other countries are needed to establish the current international treatment patterns.
Resectability of Rectal Neuroendocrine Tumors Using Endoscopic Mucosal Resection with a Ligation Band Device and Endoscopic Submucosal Dissection
Authors: Lim Hong Kyu , Lee Seong Jun , Baek Dong Hoon , Park Do Youn , Lee Bong Eun , Park Eun Young , Park Joon Woo , Kim Gwang Ha , Song Geun Am
Published: September 2019

Background. Rectal neuroendocrine tumors NETs<10 mm in diameter, limited to the submucosa without local or distant metastasis, can be treated endoscopically. Endoscopic mucosal resection with a ligation band device (EMR-L) and endoscopic submucosal dissection (ESD) have been employed to resect rectal NETs. We evaluated and compared the clinical outcomes of EMR-L and ESD for endoscopic resection of rectal NETs G1<10 mm in diameter. Methods. We conducted a retrospective study of 82 rectal NETs in 82 patients who underwent either EMR-L or ESD. Therapeutic outcomes (en bloc resection and complete resection rates), procedure time, and procedure-related adverse events were evaluated. Additionally, we measured the distance of the lateral and vertical margins from the border of the tumor in pathologic specimens and compared the resectability between EMR-L and ESD. Results. Sixty-six lesions were treated using EMR-L and 16 using ESD. En bloc resection was achieved in all patients. The complete resection rate with EMR-L was significantly higher than that with ESD (95.5% vs.75.0%, p=0.025). The prevalence of vertical margin involvement was significantly higher in the ESD group than in the EMR-L group (12.5% vs. 0%, p=0.036), and ESD was more time consuming than EMR-L (24.21±12.18 vs. 7.05±4.53 min, p<0.001). The lateral and vertical margins were more distant in the EMR-L group than in the ESD group (lateral margin distance, 1661±849 vs. 1514±948 μm; vertical margin distance, 277±308 vs. 202±171 μm). Conclusions. EMR-L is more favorable for small rectal NETs with respect to therapeutic outcomes, procedure time, and technical difficulties. Additionally, EMR-L enables achievement of sufficient vertical margin distances.
Optimal Midcourse Guidance Algorithm for Exoatmospheric Interception Using Analytical Gradients
Authors: Du Wenhao , Chen Wanchun , Yang Liang , Zhou Hao
Published: September 2019

This paper is aimed at providing a semianalytical method to solve the optimal exoatmospheric interception problem with the minimum fuel consumption. A nonlinear programming (NLP) problem with the minimum velocity increment, which involves Lambert’s problem with unspecified time-of-flight, is firstly formulated. Then, a set of Karush-Kuhn-Tucker conditions and the Jacobian matrix corresponding to those conditions are derived in an analytical manner, even though the derivatives are mathematically complicated and computationally onerous. Therefore, the Newton-Raphson method can be used to efficiently solve this problem. To further decrease computational cost, a near-optimal initialization method reducing the dimension of the search space is presented to provide a better initial guess. The performance of the proposed method is assessed by numerical experiments and comparison with other methods. The results show that this method is not only of high computational efficiency and accuracy but also applicable to onboard guidance.
An Application of a Three‐Stage XGBoost‐Based Model to Sales Forecasting of a Cross‐Border E‐Commerce Enterprise
Authors: Ji Shouwen , Wang Xiaojing , Zhao Wenpeng , Guo Dong
Published: September 2019

Sales forecasting is even more vital for supply chain management in e‐commerce with a huge amount of transaction data generated every minute. In order to enhance the logistics service experience of customers and optimize inventory management, e‐commerce enterprises focus more on improving the accuracy of sales prediction with machine learning algorithms. In this study, a C‐A‐XGBoost forecasting model is proposed taking sales features of commodities and tendency of data series into account, based on the XGBoost model. A C‐XGBoost model is first established to forecast for each cluster of the resulting clusters based on two‐step clustering algorithm, incorporating sales features into the C‐XGBoost model as influencing factors of forecasting. Secondly, an A‐XGBoost model is used to forecast the tendency with the ARIMA model for the linear part and the XGBoost model for the nonlinear part. The final results are summed by assigning weights to forecasting results of the C‐XGBoost and A‐XGBoost models. By comparison with the ARIMA, XGBoost, C‐XGBoost, and A‐XGBoost models using data from Jollychic cross‐border e‐commerce platform, the C‐A‐XGBoost is proved to outperform than other four models.
Circulating Tumor Cell-Neutrophil Tango along the Metastatic Process
Authors: Saini Massimo , Szczerba Barbara M. , Aceto Nicola
Published: September 2019

The crosstalk between cancer cells and the immune system is crucial for disease progression and its therapeutic targeting is providing exciting results, in particular with newly developed immune checkpoint inhibitors. Current approaches primarily focus on cellular interactions occurring between tumor cells and T lymphocytes; however, recent data highlight a crucial role of neutrophils in support of tumor progression and suggest yet unexplored treatment opportunities. In this review, we summarize the current understanding of those interactions that occur between neutrophils and cancer cells, focusing on both protumor and antitumor activities of neutrophils at different stages of cancer progression. These include infiltration of neutrophils into the primary tumor, their interactions with circulating tumor cells (CTC) within the bloodstream, and their involvement in the establishment of a metastatic niche. Additionally, we discuss how further investigation of CTCs and their interacting immune cell partners may point towards novel immune checkpoint inhibition strategies and provide new insights on the efficacy of already existing immunotherapies.
Bioactivation of Napabucasin Triggers Reactive Oxygen Species–Mediated Cancer Cell Death
Authors: Froeling Fieke E.M. , Swamynathan Manojit Mosur , Deschênes Astrid , Chio Iok In Christine , Brosnan Erin , Yao Melissa A. , Alagesan Priya , Lucito Matthew , Li Juying , Chang An-Yun , Trotman Lloyd C. , Belleau Pascal , Park Youngkyu , Rogoff Harry A. , Watson James D. , Tuveson David A.
Published: September 2019

Purpose:

Napabucasin (2-acetylfuro-1,4-naphthoquinone or BBI-608) is a small molecule currently being clinically evaluated in various cancer types. It has mostly been recognized for its ability to inhibit STAT3 signaling. However, based on its chemical structure, we hypothesized that napabucasin is a substrate for intracellular oxidoreductases and therefore may exert its anticancer effect through redox cycling, resulting in reactive oxygen species (ROS) production and cell death.

Experimental Design:

Binding of napabucasin to NAD(P)H:quinone oxidoreductase-1 (NQO1), and other oxidoreductases, was measured. Pancreatic cancer cell lines were treated with napabucasin, and cell survival, ROS generation, DNA damage, transcriptomic changes, and alterations in STAT3 activation were assayed in vitro and in vivo. Genetic knockout or pharmacologic inhibition with dicoumarol was used to evaluate the dependency on NQO1.

Results:

Napabucasin was found to bind with high affinity to NQO1 and to a lesser degree to cytochrome P450 oxidoreductase (POR). Treatment resulted in marked induction of ROS and DNA damage with an NQO1- and ROS-dependent decrease in STAT3 phosphorylation. Differential cytotoxic effects were observed, where NQO1-expressing cells generating cytotoxic levels of ROS at low napabucasin concentrations were more sensitive. Cells with low or no baseline NQO1 expression also produced ROS in response to napabucasin, albeit to a lesser extent, through the one-electron reductase POR.

Conclusions:

Napabucasin is bioactivated by NQO1, and to a lesser degree by POR, resulting in futile redox cycling and ROS generation. The increased ROS levels result in DNA damage and multiple intracellular changes, one of which is a reduction in STAT3 phosphorylation.
Lessons Learned from Deescalation Trials in Favorable Risk HPV-Associated Squamous Cell Head and Neck Cancer–A Perspective on Future Trial Designs
Authors: Ventz Steffen , Trippa Lorenzo , Schoenfeld Jonathan D.
Published: September 2019

In recent years several clinical studies have investigated deintensified treatments in human papillomavirus (HPV)-associated head and neck squamous cell carcinoma. Two large phase III trials, RTOG 1016 and De-ESCALaTE, which attempted to reduce toxicity by replacing radiotherapy in combination with cisplatin with the use of cetuximab in combination with radiotherapy, recently suggested that radiotherapy + cetuximab leads to inferior survival compared with standard therapy (observed HRs of 1.45 and 5 in RTOG 1016 and De-ESCALaTE), as well as increased rates of locoregional failure. These unexpected results should prompt a careful examination of deintensification trials, both in HPV-associated oropharyngeal cancer and in other contexts. Statistical designs for deintensification studies should be consistent with the study aims of reducing toxicities while maintaining survival nearly identical to the standard of care. We suggest criteria to design future deintensification trials and discuss important operating characteristics, including tradeoffs between power and stringent early stopping rules to reduce the number of patients exposed to inferior treatments. Using retrospective analyses of previous clinical studies, we compared designs with different operating characteristics. As an example, using outcomes data from RTOG 1016 and De-ESCALaTE, we conducted analyses to determine advantages of (i) stringent futility early-stopping rules and of (ii) study designs that leverage both toxicity and efficacy endpoints for interim analyses. We show that increasing the frequency of interim-futility analyses has little impact on power, but the average study duration and number of subjects enrolled before the trial is closed for inferiority can decrease substantially (from 57.8 to 18 months, and from 764 to 645 subjects). Moreover, the number of observed deaths during the study can be reduced by up to 68%.
Dilution of Molecular–Pathologic Gene Signatures by Medically Associated Factors Might Prevent Prediction of Resection Status After Debulking Surgery in Patients With Advanced Ovarian Cancer
Authors: Heitz Florian , Kommoss Stefan , Tourani Roshan , Grandelis Anthony , Uppendahl Locke , Aliferis Constantin , Burges Alexander , Wang Chen , Canzler Ulrich , Wang Jinhua , Belau Antje , Prader Sonia , Hanker Lars , Ma Sisi , Ataseven Beyhan , Hilpert Felix , Schneider Stephanie , Sehouli Jalid , Kimmig Rainer , Kurzeder Christian , Schmalfeldt Barbara , Braicu Elena I. , Harter Philipp , Dowdy Sean C. , Winterhoff Boris J. , Pfisterer Jacobus , du Bois Andreas
Published: September 2019

Purpose:

Predicting surgical outcome could improve individualizing treatment strategies for patients with advanced ovarian cancer. It has been suggested earlier that gene expression signatures (GES) might harbor the potential to predict surgical outcome.

Experimental Design:

Data derived from high-grade serous tumor tissue of FIGO stage IIIC/IV patients of AGO-OVAR11 trial were used to generate a transcriptome profiling. Previously identified molecular signatures were tested. A theoretical model was implemented to evaluate the impact of medically associated factors for residual disease (RD) on the performance of GES that predicts RD status.

Results:

A total of 266 patients met inclusion criteria, of those, 39.1% underwent complete resection. Previously reported GES did not predict RD in this cohort. Similarly, The Cancer Genome Atlas molecular subtypes, an independent de novo signature and the total gene expression dataset using all 21,000 genes were not able to predict RD status. Medical reasons for RD were identified as potential limiting factors that impact the ability to use GES to predict RD. In a center with high complete resection rates, a GES which would perfectly predict tumor biological RD would have a performance of only AUC 0.83, due to reasons other than tumor biology.

Conclusions:

Previously identified GES cannot be generalized. Medically associated factors for RD may be the main obstacle to predict surgical outcome in an all-comer population of patients with advanced ovarian cancer. If biomarkers derived from tumor tissue are used to predict outcome of patients with cancer, selection bias should be focused on to prevent overestimation of the power of such a biomarker.

See related commentary by Handley and Sood, p. 9
Tumor Microenvironment Dynamics in Clear-Cell Renal Cell Carcinoma
Authors: Vuong Lynda , Kotecha Ritesh R. , Voss Martin H. , Hakimi A. Ari
Published: September 2019

Renal cell carcinoma stands out as one of the most immune-infiltrated tumors in pan-cancer comparisons. Features of the tumor microenvironment heavily affect disease biology and may affect responses to systemic therapy. With evolving frontline options in the metastatic setting, several immune checkpoint blockade regimens have emerged as efficacious, and there is growing interest in characterizing features of tumor biology that can reproducibly prognosticate patients and/or predict the likelihood of their deriving therapeutic benefit. Herein, we review pertinent characteristics of the tumor microenvironment with dedicated attention to candidate prognostic and predictive signatures as well as possible targets for future drug development.

Significance:

Tumor microenvironment features broadly characterizing angiogenesis and inflammatory signatures have shown striking differences in response to immune checkpoint blockade and antiangiogenic agents. Integration of stromal and immune biomarkers may hence produce predictive and prognostic signatures to guide management with existing regimens as well as future drug development.
Blockade of β-Adrenergic Receptors Improves CD8+ T-cell Priming and Cancer Vaccine Efficacy
Authors: Daher Clara , Vimeux Lene , Stoeva Ralitsa , Peranzoni Elisa , Bismuth Georges , Wieduwild Elisabeth , Lucas Bruno , Donnadieu Emmanuel , Bercovici Nadège , Trautmann Alain , Feuillet Vincent
Published: September 2019

β-Adrenergic receptor (β-AR) signaling exerts protumoral effects by acting directly on tumor cells and angiogenesis. In addition, β-AR expression on immune cells affects their ability to mount antitumor immune responses. However, how β-AR signaling impinges antitumor immune responses is still unclear. Using a mouse model of vaccine-based immunotherapy, we showed that propranolol, a nonselective β-blocker, strongly improved the efficacy of an antitumor STxBE7 vaccine by enhancing the frequency of CD8+ T lymphocytes infiltrating the tumor (TIL). However, propranolol had no effect on the reactivity of CD8+ TILs, a result further strengthened by ex vivo experiments showing that these cells were insensitive to adrenaline- or noradrenaline-induced AR signaling. In contrast, naïve CD8+ T-cell activation was strongly inhibited by β-AR signaling, and the beneficial effect of propranolol mainly occurred during CD8+ T-cell priming in the tumor-draining lymph node. We also demonstrated that the differential sensitivity of naïve CD8+ T cells and CD8+ TILs to β-AR signaling was linked to a strong downregulation of β2-AR expression related to their activation status, since in vitro–activated CD8+ T cells behaved similarly to CD8+ TILs. These results revealed that β-AR signaling suppresses the initial priming phase of antitumor CD8+ T-cell responses, providing a rationale to use clinically available β-blockers in patients to improve cancer immunotherapies.
Predictors for Favorable Cognitive Outcome Post-Stroke: A-Seven-Year Follow-Up Study
Authors: Hagberg Guri , Fure Brynjar , Thommessen Bente , Ihle-Hansen Håkon , Øksengård Anne-Rita , Nygård Ståle , Pendlebury Sarah T. , Beyer Mona K. , Wyller Torgeir Bruun , Ihle-Hansen Hege
Published: September 2019

Background and Purpose: Knowledge of the burden and development of post-stroke cognitive impairments (CIs) in the long-term after the first event is limited. We aimed to assess the prevalence of mild CI (MCI) and dementia 7 years after first-ever stroke or transient ischemic attack (TIA), to subclassify the impairments, and to identify predictors for a favorable cognitive outcome. Materials and Methods: During 2007 and 2008, 208 patients with first-ever stroke or TIA without preexisting CI were included. After 1 and 7 years, survivors were invited to a follow-up. Transitions of cognitive status from 1 to 7 years were recorded based on the 3 categories dementia, MCI, or none. Etiologic subclassification was based on clinical cognitive profile, magnetic resonance imaging (MRI) findings, and biomarkers at both time points. Favorable outcome was defined as normal cognitive function or MCI after 7 years with exclusion of those who had progression from normal to MCI. Results: Eighty patients died during follow-up, 12 patients refused further participation. After 7 years, 109 completed follow-up of whom 40 (37%) were diagnosed with MCI and 24 (22%) with dementia. Of the 64 patients diagnosed with CI, 9 were subclassified with degenerative cognitive disease, 13 with vascular disease, and 42 had mixed cognitive disease. In all, 65 patients (60%) had a favorable outcome. In multivariable logistic regression analysis, lower age and lower medial temporal lobe atrophy (MTLA) grade on MRI at 12 months were independently associated with a favorable outcome, adjusted OR (95% CI), 0.94 (0.86–0.92), and 0.55 (0.35–0.85), respectively. Conclusions: Sixty percent of stroke survivors have a favorable cognitive outcome. Lower age and lower MTLA grade on MRI were associated with favorable outcome.
Precipitating Factors for Hospitalization with Heart Failure: Prevalence and Clinical Impact Observations from the Gulf CARE (Gulf aCute heArt failuRe rEgistry)
Authors: Salam Amar M. , Sulaiman Kadhim , Alsheikh-Ali Alawi A. , Singh Rajvir , AlHabib Khalid F. , Al-Zakwani Ibrahim , Asaad Nidal , Al-Qahtani Awad , Al-Jarallah Mohammed , AlMahmeed Wael , Bulbanat Bassam , Ridha Mustafa , Bazargani Nooshin , Amin Haitham , Al-Motarreb Ahmed , Panduranga Prashanth , AlFaleh Husam , Shehab Abdulla , Al Suwaidi Jassim
Published: September 2019

Objective: Despite the expanding burden of heart failure (HF) worldwide, data on HF precipitating factors (PFs) in developing countries, particularly the Middle East, are very limited. We examined PFs in patients hospitalized with acute HF in a prospective multicenter HF registry from 7 countries in the Middle East. Method: Data were derived from the Gulf CARE (Gulf aCute heArt failuRe rEgistry) for a prospective, multinational, multicenter study of consecutive patients hospitalized with HF in 47 hospitals in 7 Middle Eastern countries between February 2012 and November 2012. PFs were determined by the treating physician from a predefined list at the time of hospitalization. Results: The study included 5,005 patients hospitalized with acute HF, 2,276 of whom (45.5%) were hospitalized with acute new-onset HF (NOHF) and 2,729 of whom (54.5%) had acute decompensated chronic HF (DCHF). PFs were identified in 4,319 patients (86.3%). The most common PF in the NOHF group was acute coronary syndromes (ACS) (39.2%). In the DCHF group, it was noncompliance with medications (27.8%). Overall, noncompliance with medications was associated with a lower inhospital mortality (OR 0.47; 95% CI 0.28–0.80; p = 0.005) but a higher 1-year mortality (OR 1.43; 95% CI 1.1–1.85; p = 0.007). ACS was associated with higher inhospital mortality (OR 1.84; 95% CI 1.26–2.68; p = 0.002) and higher 1-year mortality (OR 1.62; 95% CI 1.27–2.06; p = 0.001). Conclusion: Preventive and therapeutic interventions specifically directed at noncompliance with medications and ACS are warranted in our region.
Predictive Performance of PlGF (Placental Growth Factor) for Screening Preeclampsia in Asymptomatic Women
Authors: Agrawal Swati , Shinar Shiri , Cerdeira Ana Sofia , Redman Christopher , Vatish Manu
Published: September 2019

Preeclampsia is a systemic syndrome that seems to originate from the placenta and is associated with an imbalance between angiogenic factors in the maternal circulation. One of the well-studied and widely used factors is PlGF (placental growth factor), the levels of which drop in women destined to develop preeclampsia. This drop is known to precede the development of actual signs and symptoms of preeclampsia, thus proving to be a useful screening tool in predicting the disease. The literature varies widely in terms of the clinical usefulness of the test. We conducted a meta-analysis to study the predictive accuracy of PlGF in asymptomatic women. Our analysis included 40 studies with 3189 cases of preeclampsia and 89 498 controls. The overall predictive odds ratio of the test was 9 (6–13). Subgroup analysis evaluating various PlGF thresholds demonstrated that the predictive values were highest for PlGF levels between 80 and 120 pg/mL with a high predictive odds ratio of 25 (7–88), a sensitivity of 0.78 (95% CI, 0.67–0.86), a specificity of 0.88 (95% CI, 0.75–0.95), a positive likelihood ratio of 6.3 (95% CI, 2.7–14.7), and a negative likelihood ratio of 0.26 (95% CI, 0.16–0.42). Additionally, the accuracy was higher when the test was performed after 14 weeks of gestation (OR, 10 [7–15]) and for prediction of early onset preeclampsia (OR, 18 [9–37]). We conclude that PlGF is a useful screening tool to predict preeclampsia. Nonetheless, its utility should be judged with caution and randomized controlled trials are warranted to explore if its implementation improves perinatal outcomes in asymptomatic women.
Impact of the Duration and Degree of Hypertension and Body Weight on New-Onset Atrial Fibrillation
Authors: Kim Yun Gi , Han Kyung-Do , Choi Jong-Il , Yung Boo Ki , Kim Do Young , Oh Suk-Kyu , Lee Kwang-No , Shim Jaemin , Kim Jin Seok , Kim Young-Hoon
Published: September 2019

Hypertension and obesity are known risk factors for atrial fibrillation (AF). However, it is unclear whether uncontrolled, long-standing hypertension has a particularly profound effect on AF. Because they have a similar underlying pathophysiology, hypertension and obesity could act synergistically in the context of AF. We evaluated how various stages of hypertension and body weight status affect new-onset AF. We analyzed a total of 9 797 418 participants who underwent a national health checkup. Hypertension was classified into 5 stages: nonhypertension, prehypertension, hypertension without medication, hypertension with medication <5 years, and hypertension with medication ≥5 years. The participants were also stratified based on body mass index and waist circumference. During the 80 130 161 person×years follow-up, a total of 196 136 new-onset AF cases occurred. The incidence of new-onset AF gradually increased among the 5 stages of hypertension: the adjusted hazard ratio for each group was 1 (reference), 1.145, 1.390, 1.853, and 2.344 for each stage of hypertension. A graded escalation in the risk of new-onset AF was also observed in response to increased systolic and diastolic blood pressure. The incidence of new-onset AF correlated with body mass index and waist circumference, with obese people having a higher risk than others. Hypertension and obesity acted synergistically: obese people with hypertension on medication ≥5 years had the highest risk of AF. In conclusion, the degree and duration of hypertension, as well as the presence of hypertension, were important factors for new-onset AF. Body weight status was significantly associated with new-onset AF and acted synergistically with hypertension.
Integrating Flexible Normalization into Midlevel Representations of Deep Convolutional Neural Networks
Authors: Giraldo Luis Gonzalo Sánchez , Schwartz Odelia
Published: September 2019

Deep convolutional neural networks (CNNs) are becoming increasingly popular models to predict neural responses in visual cortex. However, contextual effects, which are prevalent in neural processing and in perception, are not explicitly handled by current CNNs, including those used for neural prediction. In primary visual cortex, neural responses are modulated by stimuli spatially surrounding the classical receptive field in rich ways. These effects have been modeled with divisive normalization approaches, including flexible models, where spatial normalization is recruited only to the degree that responses from center and surround locations are deemed statistically dependent. We propose a flexible normalization model applied to midlevel representations of deep CNNs as a tractable way to study contextual normalization mechanisms in midlevel cortical areas. This approach captures nontrivial spatial dependencies among midlevel features in CNNs, such as those present in textures and other visual stimuli, that arise from tiling high-order features geometrically. We expect that the proposed approach can make predictions about when spatial normalization might be recruited in midlevel cortical areas. We also expect this approach to be useful as part of the CNN tool kit, therefore going beyond more restrictive fixed forms of normalization.
Capturing the Forest but Missing the Trees: Microstates Inadequate for Characterizing Shorter-Scale EEG Dynamics
Authors: Shaw Saurabh Bhaskar , Dhindsa Kiret , Reilly James P. , Becker Suzanna
Published: September 2019

The brain is known to be active even when not performing any overt cognitive tasks, and often it engages in involuntary mind wandering. This resting state has been extensively characterized in terms of fMRI-derived brain networks. However, an alternate method has recently gained popularity: EEG microstate analysis. Proponents of microstates postulate that the brain discontinuously switches between four quasi-stable states defined by specific EEG scalp topologies at peaks in the global field potential (GFP). These microstates are thought to be “atoms of thought,” involved with visual, auditory, salience, and attention processing. However, this method makes some major assumptions by excluding EEG data outside the GFP peaks and then clustering the EEG scalp topologies at the GFP peaks, assuming that only one microstate is active at any given time. This study explores the evidence surrounding these assumptions by studying the temporal dynamics of microstates and its clustering space using tools from dynamical systems analysis, fractal, and chaos theory to highlight the shortcomings in microstate analysis. The results show evidence of complex and chaotic EEG dynamics outside the GFP peaks, which is being missed by microstate analysis. Furthermore, the winner-takes-all approach of only one microstate being active at a time is found to be inadequate since the dynamic EEG scalp topology does not always resemble that of the assigned microstate, and there is competition among the different microstate classes. Finally, clustering space analysis shows that the four microstates do not cluster into four distinct and separable clusters. Taken collectively, these results show that the discontinuous description of EEG microstates is inadequate when looking at nonstationary short-scale EEG dynamics.
Mutual Inhibition with Few Inhibitory Cells via Nonlinear Inhibitory Synaptic Interaction
Authors: Weissenberger Felix , Gauy Marcelo Matheus , Zou Xun , Steger Angelika
Published: September 2019

In computational neural network models, neurons are usually allowed to excite some and inhibit other neurons, depending on the weight of their synaptic connections. The traditional way to transform such networks into networks that obey Dale's law (i.e., a neuron can either excite or inhibit) is to accompany each excitatory neuron with an inhibitory one through which inhibitory signals are mediated. However, this requires an equal number of excitatory and inhibitory neurons, whereas a realistic number of inhibitory neurons is much smaller. In this letter, we propose a model of nonlinear interaction of inhibitory synapses on dendritic compartments of excitatory neurons that allows the excitatory neurons to mediate inhibitory signals through a subset of the inhibitory population. With this construction, the number of required inhibitory neurons can be reduced tremendously.