bluuebunny/crossref_metadata_2025 huggingface dataset:
Renal Involvement in Children with Dengue Fever: A Study in Tertiary Care Hospital of Bangladesh
Authors: Sultana Azmeri , Rumana Jubaida , Roy Smrity , Sonia Seikh Farzana , Rahat Farhana , Parvin Ruma , Afroze Sharmin
Published: January 2020

Background and Objective: Dengue has emerged globally as the most relevant viral infection transmitted by a mosquito bite and represents a major threat to public health. Dengue-related renal manifestations such as proteinuria, hematuria, acute kidney injury (AKI), and rhabdomyolysis are not uncommon, and acute kidney injury (AKI) is a serious complication of dengue fever. There is relatively few data on the renal manifestations of dengue fever in children. Hence, this study was conducted to evaluate the incidence, characteristics, and clinical outcome of dengue fever with renal manifestations. Method. This prospective cross sectional study was conducted in Dr. M R Khan Children Hospital and Institute of Child Health, Dhaka, over a period of 1 year from January 2018 to December 2018. The study was approved by the ethical committee of the institute. A total number of 316 patients were admitted with the diagnosis of dengue fever either NS1 positive or antibody IgM positive or both IgM and IgG positive. Data were collected in a structured questionnaire form and were analyzed by SPSS version 20.0. The disease severity was classified according to the World Health Organization criteria. Renal manifestations were divided into AKI groups using pRIFLE criteria. Proteinuria was defined as urinary protein >1+ (30 mg/dL) by dipstick test. Hematuria was defined as red blood cell (RBC) >5/μL in a fresh uncentrifuged urine specimen. Result. Among 316 dengue patients, thirty-one patients (9.8%) had renal involvement. Most of the patients (54.83%) with renal manifestations were aged between 1 and 5 years. A total of 14 patients were found to have proteinuria (4.4%). Nephrotic-range proteinuria was seen in only one patient (0.3%). AKI was defined by pRIFLE criteria and was seen in 13 patients (4.1%); among AKI 6 (46.15%) had risk, three patients (23.07%) had injury and 4 (30.7%) had failure and needed peritoneal dialysis. Death occurred in 3 patients (9.6%) in dengue with AKI who had failure. The incidence of renal manifestations (proteinuria, hematuria, and AKI) is as high as 9.8% among patients with dengue, and those with AKI had significant morbidity and mortality. Conclusion. Renal involvement in children with dengue is not uncommon. Dengue associated with AKI had significant mortality and morbidity.
Miso Soup Consumption Enhances the Bioavailability of the Reduced Form of Supplemental Coenzyme Q10
Authors: Takahashi Michiyo , Nagata Mayumi , Kaneko Takehiko , Suzuki Toshikazu
Published: January 2020

Coenzyme Q10 (CoQ10) is an essential compound that is involved in energy production and is a lipid-soluble antioxidant. Although it has been proposed as an antiaging and a health-supporting supplement, its low bioavailability remains a significant issue. Concurrent food intake enhances the absorption of orally administered CoQ10, but it has not been fully established whether specific food substances affect intestinal CoQ10 absorption. Therefore, to determine whether the bioavailability of supplemental CoQ10 is affected by diet, P30, a granulated and reduced form of CoQ10, was dispersed in four different foods, clear soup, miso soup, milk soup, and raw egg sauce. Those foods which contained CoQ10 were consumed on different occasions at intervals of 6–14 weeks by the same participants. Thirteen participants were recruited in the single-dose and repeated clinical study. When miso soup containing P30 was provided, the serum CoQ10 concentration increased faster than when participants consumed other P30-containing soups or a P30-containing raw egg sauce. The area under the curve for serum CoQ10 during the first 5 h after consumption of the P30-containing miso soup was approximately 1.5 times larger than those after the consumption of other P30-containing meals. These data imply that the absorption of CoQ10 supplements can be enhanced by consuming them with food and in particular with specific food substances, such as miso soup.
DNA-Detection Based Diagnostics for Taenia solium Cysticercosis in Porcine
Authors: Waema Maxwell W. , Misinzo Gerald , Kagira John M. , Agola Eric L. , Ngowi Helena A.
Published: January 2020

Porcine cysticercosis is a neglected and underestimated disease caused by metacestode stage of the tapeworm, Taenia solium (T. solium). Pigs are the intermediate hosts of T. solium while human are the only known definitive host. The disease has an economic consequence because the affected farmers lose 50−100 percent of the value of pigs if they are infected. Lack of affordable, easy to use, sensitive, and specific molecular diagnostic tools for detection of infections at the farm level hinders the control of porcine cysticercosis in endemic areas. A number of DNA based diagnostic assays for the detection of T. solium infections in pigs have been developed and evaluated but none is applicable at low-resource areas where this disease is an endemic. This review focuses mainly on DNA based diagnostic methods, their sensitivity, specificity, and utilization at low-resource areas. We summarized data from 65 studies on the current DNA-detection based diagnostic techniques for T. solium cysticercosis in porcine, published in English between the years 2000–2018, identified through PubMed search engine. Of the different polymerase chain reaction (PCR) assays developed for identification of T. solium, the most sensitive (97−100%) and specific (100%) one is nested PCR. One study utilized loop-mediated isothermal amplification (LAMP) as a diagnostic tool for the detection of T. solium infections though its field use was never determined. Recombinase polymerase amplification (RPA) has been evaluated as a diagnostic tool for a variety of diseases, but has never been exploited for the diagnosis of cysticercosis/taeniasis. In conclusion, several molecular methods have been developed and evaluated in lab settings. However, there is need to validate these methods as a diagnostic tool to diagnose porcine cysticercosis in low-resource areas.
Analytical Study of the Holographic Superconductor from Higher Derivative Theory
Authors: Wang Chunyan , Zhang Dan , Fu Guoyang , Wu Jian-Pin
Published: January 2020

In this paper, we analytically study the holographic superconductor models with the high derivative (HD) coupling terms. Using the Sturm-Liouville (S-L) eigenvalue method, we perturbatively calculate the critical temperature. The analytical results are in good agreement with the numerical results. It confirms that the perturbative method in terms of the HD coupling parameters is available. Along the same line, we analytically calculate the value of the condensation near the critical temperature. We find that the phase transition is second order with mean field behavior, which is independent of the HD coupling parameters. Then, in the low-temperature limit, we also calculate the conductivity, which is qualitatively consistent with the numerical one. We find that the superconducting energy gap is proportional to the value of the condensation. But we note that since the condensation changes with the HD coupling parameters, as the function of the HD coupling parameters, the superconducting energy gap follows the same change trend as that of the condensation.
Systematic Elucidation of the Potential Mechanism of Erzhi Pill against Drug‐Induced Liver Injury via Network Pharmacology Approach
Authors: Huang Shao-jie , Mu Fei , Li Fei , Wang Wen-jun , Zhang Wei , Lei Lu , Ma Yang , Wang Jing-wen
Published: January 2020

Objective. The purpose of this work was to investigate the bioactive compounds, core genes, and pharmacological mechanisms and to provide a further research orientation of Erzhi pill (EZP) on drug‐induced liver injury (DILI). Methods. At first, we collected information of bioactive compounds of EZP from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and previous studies. And then, the targets related to bioactive compounds and DILI were obtained from 4 public databases. At last, Cytoscape was used to establish a visual network. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses and network analysis were performed to investigate potential mechanism of EZP against DILI. Results. A total of 23 bioactive compounds and 89 major proteins of EZP were screened out as potential players against DILI. Association for bioactive compounds, core targets, and related pathways was analyzed, implying that core targets related to these pathways are ALB, AKT1, MAPK1, EGFR, SRC, MAPK8, IGF1, CASP3, HSP90AA1, and MMP9, and potential mechanisms of EZP acting on DILI are closely related to negative regulation of apoptosis process, improvement of lipid metabolism, and positive regulation of liver regeneration process. Conclusion. This study demonstrated the multicompound, multitarget, and multichannel characteristics of EZP, which provided a novel approach for further research the mechanism of EZP in the treatment of DILI.
The Correlation between Hormonal Disturbance in PCOS Women and Serum Level of Kisspeptin
Authors: Ibrahim Razaw O. , Omer Shirwan H. , Fattah Chro N.
Published: January 2020

Background. Kisspeptin is a neuropeptide that upregulates gonadotropin-releasing hormone (GnRH) secretion. It is an essential element for the luteinizing hormone (LH) surge and ovulation. Women with polycystic ovary syndrome (PCOS) expose alteration in both GnRH and LH secretion levels. Objective. This paper aims to evaluate serum kisspeptin levels in healthy and polycystic ovarian syndrome women. Furthermore, it investigates the effect of obesity and age on circulating kisspeptin levels in both normal and PCOS women. Moreover, it points out the correlation between kisspeptin and other hormonal parameters. Methods and Patients. One hundred women (60 are with PCOS and 40 are normal) were enrolled in the study. Five milliliter samples of blood from all the patients and control women were obtained twice during the menstrual cycle. All the study samples were classified depending on the age factor for several subgroups. Results. Kisspeptin levels were higher in PCOS patients than those in the normal group. Kisspeptin correlated with serum free testosterone level (r=0.26). In healthy women, preovulatory kisspeptin levels were higher than follicular kisspeptin levels (P<0.05), while this difference was insignificant in PCOS patients. The variation in serum kisspeptin levels between overweight/obese and normal-weight women was insignificant. In normal women, serum kisspeptin levels were higher in women >35 years than those <24 years at (P=0.03). Conclusion. The serum kisspeptin level is higher in PCOS women. Its levels fluctuate during the menstrual cycle, but these fluctuations are disturbed in PCOS women. The effect of BMI on serum kisspeptin levels is insignificant, and kisspeptin serum levels increase with age.
A Mobile Localization Method in Smart Indoor Environment Using Polynomial Fitting for Wireless Sensor Network
Authors: Wang Yan , Yan Yang , Li Zhengjian , Cheng Long
Published: January 2020

The main factor affecting the localization accuracy is nonline of sight (NLOS) error which is caused by the complicated indoor environment such as obstacles and walls. To obviously alleviate NLOS effects, a polynomial fitting-based adjusted Kalman filter (PF-AKF) method in a wireless sensor network (WSN) framework is proposed in this paper. The method employs polynomial fitting to accomplish both NLOS identification and distance prediction. Rather than employing standard deviation of all historical data as NLOS detection threshold, the proposed method identifies NLOS via deviation between fitted curve and measurements. Then, it processes the measurements with adjusted Kalman filter (AKF), conducting weighting filter in the case of NLOS condition. Simulations compare the proposed method with Kalman filter (KF), adjusted Kalman filter (AKF), and Kalman-based interacting multiple model (K-IMM) algorithms, and the results demonstrate the superior performance of the proposed method. Moreover, experimental results obtained from a real indoor environment validate the simulation results.
[Retracted] Calibration of the Live Load Factor for Highway Bridges with Different Requirements of Loading
Authors: Liu Lang , Ren Qingyang , Wang Xu
Published: January 2020

Highway bridge load rating has been moving toward structural reliability since the issuance of AASHTO LRFR specifications; however, the recommended load factors were carried out by a few reliable truck data. The objective of this study is to calibrate the live load factor in AASHTO LRFR Rating Specification by using huge amount of WIM data collected in California for more than ten years between 2001 and 2013. Since traffic volumes, vehicular overloads, and traffic components are highly related to the load effect induced, a set of calibration equations is proposed here, in which the nominal standard load effect models are used and different requirements of loading are taken into account. By the analytical model of platoons of trucks and the extrapolation of the gathered WIM data over a short period of time to remote future over a longer time period, the expected maximum live load effects over the rating period of 5 years are also obtained. Then, the live load factor is calibrated as the product of the codified value multiplied by the ratio between the nominal standard load effect and the expected mean value. The results show that the products of the two ratios present rather constant, implying the proposed method and load configurations selected are effective. In the end, the live load factors of 1.0 and 0.7 along with load configurations are recommended for a simple span length less than 300 ft. The recommended calibration method and live load factors will eliminate the unnecessary overconservatism in rating specifications.
Sex-Specific Associations of Trimethylamine-N-Oxide and Zonulin with Signs of Depression in Carbohydrate Malabsorbers and Nonmalabsorbers
Authors: Meinitzer Sophie , Baranyi Andreas , Holasek Sandra , Schnedl Wolfgang J. , Zelzer Sieglinde , Mangge Harald , Herrmann Markus , Meinitzer Andreas , Enko Dietmar
Published: January 2020

Background.The microbiome-derived trimethylamine-N-oxide (TMAO) and the intestinal permeability marker zonulin are considered to be linked with depression. Moreover, carbohydrate malabsorption (CMA) was shown to be associated with signs of depression. This study is aimed at investigating possible sex-specific associations between TMAO and zonulin and the presence of depressive signs in individuals with and without CMA.Methods.Serum concentrations of TMAO and zonulin were determined in 115 and 136 individuals with the presence or absence of CMA. All 251 study participants underwent lactase gene C/T-13910polymorphism genotyping and fructose H2/CH4breath testing. Additionally, they filled in the Beck Depression Inventory (BDI-II) questionnaire.Results.The median TMAO and zonulin serum concentrations were 2.66 (1.93–4.14)μmol/L and 40.83 (34.73–47.48) ng/mL. Serum TMAO levels were positively correlated with depressive symptoms (P=0.011,ρ=0.160). The strongest correlations were observed in 87 females (P=0.010,ρ=0.274) and 49 males (P=0.027,ρ=0.315) without CMA, whereas 115 patients with CMA showed no significant correlations. Zonulin tended to be negatively correlated with the BDI-II score in 49 males without CMA (P=0.062,ρ=−0.269).Conclusion.This study demonstrates a positive correlationship between the serum TMAO concentrations and the severity of depressive symptoms in females and males without CMA. Serum zonulin levels were negatively correlated with signs of depression in males without CMA. These findings suggest a gender-specific relationship between the serum TMAO and zonulin concentrations, depression, and CMA.
Linkage between Neighborhood Social Cohesion and BMI of South Asians in the Masala Study
Authors: Gill Gagandeep , Lancki Nicola , Randhawa Manjit , Mann Semran K. , Arechiga Adam , Smith Robin D. , Soret Samuel , Kanaya Alka M. , Kandula Namratha
Published: January 2020

Introduction. South Asians in the United States have a high prevalence of obesity and an elevated risk for cardiometabolic diseases. Yet, little is known about how aspects of neighborhood environment influence cardiometabolic risk factors such as body mass index (BMI) in this rapidly growing population. We aimed to investigate the association between perceived neighborhood social cohesion and BMI among South Asians. Methods. We utilized cross-sectional data from the MASALA study, a prospective community-based cohort of 906 South Asian men and women from the San Francisco Bay area and the greater Chicago area. Multivariable linear regression models, stratified by sex, were used to examine the association between perceived level of neighborhood social cohesion and individual BMI after adjusting for sociodemographics. Results. Participants were 54% male, with an average age of 55 years, 88% had at least a bachelor’s degree, and the average BMI was 26.0 kg/m2. South Asian women living in neighborhoods with the lowest social cohesion had a significantly higher BMI than women living in neighborhoods with the highest cohesion (β coefficient = 1.48, 95% CI 0.46–2.51, p=0.02); however, the association was not statistically significant after adjusting for sociodemographic factors (β coefficient = 1.06, 95% CI −0.01–2.13, p=0.05). There was no association between level of neighborhood social cohesion and BMI in South Asian men. Conclusion. Perceived neighborhood social cohesion was not significantly associated with BMI among South Asians in our study sample. Further research is recommended to explore whether other neighborhood characteristics may be associated with BMI and other health outcomes in South Asians and the mechanisms through which neighborhood may influence health.
Data-Driven Models for Capacity Allocation of Inpatient Beds in a Chinese Public Hospital
Authors: Zhu Ting , Liao Peng , Luo Li , Ye Heng-Qing
Published: January 2020

Hospital beds are a critical but limited resource shared between distinct classes of elective patients. Urgent elective patients are more sensitive to delays and should be treated immediately, whereas regular patients can wait for an extended time. Public hospitals in countries like China need to maximize their revenue and at the same time equitably allocate their limited bed capacity between distinct patient classes. Consequently, hospital bed managers are under great pressure to optimally allocate the available bed capacity to all classes of patients, particularly considering random patient arrivals and the length of patient stay. To address the difficulties, we propose data-driven stochastic optimization models that can directly utilize historical observations and feature data of capacity and demand. First, we propose a single-period model assuming known capacity; since it recovers and improves the current decision-making process, it may be deployed immediately. We develop a nonparametric kernel optimization method and demonstrate that an optimal allocation can be effectively obtained with one year’s data. Next, we consider the dynamic transition of system state and extend the study to a multiperiod model that allows random capacity; this further brings in substantial improvement. Sensitivity analysis also offers interesting managerial insights. For example, it is optimal to allocate more beds to urgent patients on Mondays and Thursdays than on other weekdays; this is in sharp contrast to the current myopic practice.
Dexmedetomidine Postconditioning Alleviates Hypoxia/Reoxygenation Injury in Senescent Myocardial Cells by Regulating lncRNA H19 and m6A Modification
Authors: Zhang Xuan , Fu Qiang , Xu Longhe , Yang Yitian , Zhao Weixing , Zhang Yunliang , Li Hao , Mi Weidong
Published: January 2020

H19, a long noncoding RNA (lncRNA), reportedly protects myocardial cells (H9c2 cell line) against hypoxia-reoxygenation- (H/R-) induced injury. Dexmedetomidine (Dex) has an important myocardial protective effect, although its function and mechanism in cardiac ischemia/reperfusion (I/R) injury, especially for senile patients, requires further study. RNA N6-methyladenosine (m6A) is the most abundant endogenous RNA modification. However, the effect of Dex postconditioning on RNA m6A modification has rarely been reported. The aim of this study was to evaluate roles of H19 and m6A modification in Dex postconditioning of aged cardiomyocytes. Hydrogen peroxide (H2O2) was used to induce senescence of H9c2 cells. After 6 h of hypoxia, H9c2 cells were exposed to different concentrations of dexmedetomidine (0, 500 nM, 1 μM, and 2 μM) for 6 h. After knockdown or overexpression of H19 and its downstream gene miR-29b-3p and cellular inhibitor of apoptosis protein 1 (cIAP1), Dex postconditioning experiments were performed to examine effects on myocardial cell injury. Global m6A levels after H/R with or without Dex postconditioning were measured with a colorimetric m6A RNA Methylation Quantification Kit. The mechanism by which RNA m6A methylation regulated genes mediating H19 expression was verified by m6A RNA immunoprecipitation (MeRIP), and the function of Dex postconditioning of aged cardiomyocytes was investigated. Dex postconditioning protected against H/R-induced injury of aged myocardial cells through H19/miR-29b-3p/cIAP1, increased methylation of RNA m6A elicited by H/R, and attenuated H/R-induced injury by suppressing expression of the RNA m6A demethylase gene alkB homolog 5 (ALKBH5). In addition, AKLBH5 regulated the expression of H19, and Dex postconditioning attenuated H/R-induced injury via ALKBH5 in aged cardiomyocytes.
Bacterial Diversity in the Intestinal Mucosa of Dysbiosis Diarrhea Mice Treated with Qiweibaizhu Powder
Authors: Long Cheng-Xing , Shao Hao-Qing , Luo Cheng-Yu , Yu Rong , Tan Zhou-Jin
Published: January 2020

The current research tried to explore the effect of Qiweibaizhu powder (QWBZP) on the bacterial diversity and community structure of the intestinal mucosa of dysbiosis diarrhea mice and provide a scientific basis for the efficacy of QWBZP on antibiotic-induced diarrhea. A dysbiosis diarrhea mouse model was constructed with broad-spectrum antibiotics through a mixture of cephradine capsules and gentamicin sulfate (23.33 mL·kg-1·d-1). Intestinal mucosa was collected, and DNA was extracted from each group. The bacterial characteristics in intestinal mucosa were analyzed by MiSeq sequencing based on the 16S rRNA sequencing platform. There were no significant differences in alpha diversity indices among the three groups. The sample distributions in both the normal and QWBZP groups were relatively concentrated, and the distance among individuals was close. However, an opposite result was obtained in the model group. Furthermore, the composition and abundance of species were similar between the normal group and the QWBZP group at both the phylum and genus levels. After treatment with QWBZP, the abundance of Lactobacillus increased, and Proteobacteria decreased, and the Firmicutes/Bacteroidetes ratio decreased to a normal level. Our results indicate that QWBZP can help repair mucosal bacterial structure and recover mucosal microbiota. Specifically, QWBZP increased the abundance of Lactobacillus and Bacteroidales S24-7 group norank.
Epidural Needle Extension through the Ligamentum Flavum Using the Standard versus the CompuFlo®-Assisted Loss of Resistance to Saline Technique: A Simulation Study
Authors: Capogna E. , Coccoluto A. , Velardo M.
Published: January 2020

Background. The CompuFlo® epidural system has been recently introduced and validated as an objective and sensible tool to detect the epidural space. We aimed to verify whether the high sensitivity of the instrument may help the anesthesiologist to identify the epidural space very early, limiting the extension of the Tuohy needle into the epidural space. Methods. In this prospective, simulation study, we evaluated the Tuohy needle extension through a simulated ligamentum flavum during the epidural procedure performed by 52 expert anesthesiologists by using the CompuFlo® epidural instrument or their standard loss of resistance to saline technique (LORT). Results. The mean (SD) needle extension length was 3.90 (3.71) mm in the standard technique group and 0.68 (0.46) mm in the CompuFlo® group (P<000001). The extremely reduced variability of the data in the CompuFlo® group (F test 0.01) made the results obtained with this instrument highly predictable. Conclusions. Puncturing high-resistance material that simulated the ligamentum flavum, the use of CompuFlo® has determined the arrest of the needle more precociously when compared with the traditional LORT.
Undermining Glutaminolysis Bolsters Chemotherapy While NRF2 Promotes Chemoresistance in KRAS-Driven Pancreatic Cancers
Authors: Mukhopadhyay Suman , Goswami Debanjan , Adiseshaiah Pavan P. , Burgan William , Yi Ming , Guerin Theresa M. , Kozlov Serguei V. , Nissley Dwight V. , McCormick Frank
Published: January 2020

Pancreatic cancer is a disease with limited therapeutic options. Resistance to chemotherapies poses a significant clinical challenge for patients with pancreatic cancer and contributes to a high rate of recurrence. Oncogenic KRAS, a critical driver of pancreatic cancer, promotes metabolic reprogramming and upregulates NRF2, a master regulator of the antioxidant network. Here, we show that NRF2 contributed to chemoresistance and was associated with a poor prognosis in patients with pancreatic cancer. NRF2 activation metabolically rewired and elevated pathways involved in glutamine metabolism. This curbed chemoresistance in KRAS-mutant pancreatic cancers. In addition, manipulating glutamine metabolism restrained the assembly of stress granules, an indicator of chemoresistance. Glutaminase inhibitors sensitized chemoresistant pancreatic cancer cells to gemcitabine, thereby improving the effectiveness of chemotherapy. This therapeutic approach holds promise as a novel therapy for patients with pancreatic cancer harboring KRAS mutation.

Significance:

These findings illuminate the mechanistic features of KRAS-mediated chemoresistance and provide a rationale for exploiting metabolic reprogramming in pancreatic cancer cells to confer therapeutic opportunities that could be translated into clinical trials.
Nudix Hydrolase NUDT16 Regulates 53BP1 Protein by Reversing 53BP1 ADP-Ribosylation
Authors: Zhang Fan , Lou Lihong , Peng Bo , Song Xiaotian , Reizes Ofer , Almasan Alexandru , Gong Zihua
Published: January 2020

53BP1 controls two downstream subpathways, one mediated by PTIP and Artemis and the other by RIF1 and MAD2L2/Shieldin, to coordinate DNA repair pathway choices. However, the upstream regulator(s) of 53BP1 function in DNA repair remain unknown. We and others recently reported that TIRR associates with 53BP1 to stabilize it and prevents 53BP1 localization to DNA damage sites by blocking 53BP1 Tudor domain binding to H4K20me2 sites. Here, we report that the Nudix hydrolase NUDT16, a TIRR homolog, regulates 53BP1 stability. We identified a novel posttranslational modification of 53BP1 by ADP-ribosylation that is targeted by a PAR-binding E3 ubiquitin ligase, RNF146, leading to 53BP1 polyubiquitination and degradation. In response to DNA damage, ADP-ribosylated 53BP1 increased significantly, resulting in its ubiquitination and degradation. These data suggest that NUDT16 plays a major role in controlling 53BP1 levels under both normal growth conditions and during DNA damage. Notably, overexpression of a NUDT16 catalytically inactive mutant blocked 53BP1 localization to double-strand breaks because (i) the mutant binding to TIRR increased after IR; (ii) the mutant enhanced 53BP1 Tudor domain binding to TIRR, and (iii) the mutant impaired the interaction of 53BP1 Tudor domain with H4K20me2. Moreover, NUDT16's catalytic hydrolase activity was required for 53BP1 de–ADP-ribosylation, 53BP1 protein stability, and its function in cell survival. In summary, we demonstrate that NUDT16 regulates 53BP1 stability and 53BP1 recruitment at double-strand breaks, providing yet another mechanism of 53BP1 regulation.

Significance:

This study provides a novel mechanism of 53BP1 regulation by demonstrating that NUDT16 has hydrolase activities that remove ADP-ribosylation of 53BP1 to regulate 53BP1 stability and 53BP1 localization at DSBs.
A Bis-Indole–Derived NR4A1 Antagonist Induces PD-L1 Degradation and Enhances Antitumor Immunity
Authors: Karki Keshav , Wright Gus A. , Mohankumar Kumaravel , Jin Un-Ho , Zhang Xing-Han , Safe Stephen
Published: January 2020

PD-L1 is expressed in tumor cells and its interaction with PD-1 plays an important role in evading immune surveillance; this can be overcome using PD-L1 or PD-1 immunotherapy antibodies. This study reports a novel approach for targeting PD-L1. In human breast cancer cell lines and 4T1 mouse mammary tumor cells, PD-L1 expression was regulated by the nuclear receptor NR4A1/Sp1 complex bound to the proximal germinal center (GC)-rich region of the PD-L1 gene promoter. Treatment of breast cancer cells with bis-indole–derived NR4A1 antagonists including 1,1-bis(3′-indolyl)-1-(3-chloro-4-hydroxy-5-methoxyphenyl)methane (Cl-OCH3) decreased expression of PD-L1 mRNA, promoter-dependent luciferase activity, and protein. In in vivo studies using a syngeneic mouse model bearing orthotopically injected 4T1 cells, Cl-OCH3 decreased tumor growth and weight and inhibited lung metastasis. Cl-OCH3 also decreased expression of CD3+/CD4+/CD25+/FoxP3+ regulatory T cells and increased the Teff/Treg ratio. Therefore, the potent anticancer activities of NR4A1 antagonists are also accompanied by enhanced antitumor immunity in PD-L1–expressing triple-negative breast cancer and thus represent a novel class of drugs that mimic immunotherapy.

Significance:

These findings show that the orphan nuclear receptor NR4A1 controls PD-L1 expression and identify a chemical probe capable of disrupting this regulatory axis.
Multifactorial Deep Learning Reveals Pan-Cancer Genomic Tumor Clusters with Distinct Immunogenomic Landscape and Response to Immunotherapy
Authors: Xie Feng , Zhang Jianjun , Wang Jiayin , Reuben Alexandre , Xu Wei , Yi Xin , Varn Frederick S. , Ye Yongsheng , Cheng Junwen , Yu Miao , Wang Yue , Liu Yufeng , Xie Mingchao , Du Peng , Ma Ke , Ma Xin , Zhou Penghui , Yang Shengli , Chen Yaobing , Wang Guoping , Xia Xuefeng , Liao Zhongxing , Heymach John V. , Wistuba Ignacio I. , Futreal P. Andrew , Ye Kai , Cheng Chao , Xia Tian
Published: January 2020

Purpose:

Tumor genomic features have been of particular interest because of their potential impact on the tumor immune microenvironment and response to immunotherapy. Due to the substantial heterogeneity, an integrative approach incorporating diverse molecular features is needed to characterize immunologic features underlying primary resistance to immunotherapy and for the establishment of novel predictive biomarkers.

Experimental Design:

We developed a pan-cancer deep machine learning model integrating tumor mutation burden, microsatellite instability, and somatic copy-number alterations to classify tumors of different types into different genomic clusters, and assessed the immune microenvironment in each genomic cluster and the association of each genomic cluster with response to immunotherapy.

Results:

Our model grouped 8,646 tumors of 29 cancer types from The Cancer Genome Atlas into four genomic clusters. Analysis of RNA-sequencing data revealed distinct immune microenvironment in tumors of each genomic class. Furthermore, applying this model to tumors from two melanoma immunotherapy clinical cohorts demonstrated that patients with melanoma of different genomic classes achieved different benefit from immunotherapy. Interestingly, tumors in cluster 4 demonstrated a cold immune microenvironment and lack of benefit from immunotherapy despite high microsatellite instability burden.

Conclusions:

Our study provides a proof for principle that deep learning modeling may have the potential to discover intrinsic statistical cross-modality correlations of multifactorial input data to dissect the molecular mechanisms underlying primary resistance to immunotherapy, which likely involves multiple factors from both the tumor and host at different molecular levels.
Characterization of Immune Dysfunction and Identification of Prognostic Immune-Related Risk Factors in Acute Myeloid Leukemia
Authors: Tang Lu , Wu Jianghua , Li Cheng-Gong , Jiang Hui-Wen , Xu Min , Du Mengyi , Yin Zhinan , Mei Heng , Hu Yu
Published: January 2020

Purpose:

This study aims to provide comprehensive insights into longitudinal immune landscape in acute myeloid leukemia (AML) development and treatment, which may contribute to predict prognosis and guide clinical decisions.

Experimental Design:

Periphery blood samples from 79 patients with AML (at diagnosis or/and after chemotherapy or at relapse) and 24 healthy controls were prospectively collected. We performed phenotypic and functional analysis of various lymphocytes through multiparametric flow cytometry and investigated prognostic immune-related risk factors.

Results:

Immune defects in AML were reflected in T and natural killer (NK) cells, whereas B-cell function remained unaffected. Both CD8+ T and CD4+ T cells exhibited features of senescence and exhaustion at diagnosis. NK dysfunction was supported by excessive maturation and downregulation of NKG2D and NKP30. Diseased γδ T cells demonstrated a highly activated or even exhausted state through PD-1 upregulation and NKG2D downregulation. Effective therapeutic response following chemotherapy correlated with T and NK function restoration. Refractory and relapsed patients demonstrated even worse immune impairments, and selective immune signatures apparently correlated clinical outcomes and survival. PD-1 expression in CD8+ T cells was independently predictive of poor overall survival and event-free survival.

Conclusions:

T-cell senescence and exhaustion, together with impaired NK and γδ T-cell function, are dominant aspects involved in immune dysfunction in AML. Noninvasive immune testing of blood samples could be applied to predict therapeutic reactivity, high risk for relapse, and unfavorable prognosis.
Efficacy of FGFR Inhibitors and Combination Therapies for Acquired Resistance in FGFR2-Fusion Cholangiocarcinoma
Authors: Krook Melanie A. , Lenyo Alexandria , Wilberding Max , Barker Hannah , Dantuono Mikayla , Bailey Kelly M. , Chen Hui-Zi , Reeser Julie W. , Wing Michele R. , Miya Jharna , Samorodnitsky Eric , Smith Amy M. , Dao Thuy , Martin Dorrelyn M. , Ciombor Kristen K. , Hays John , Freud Aharon G. , Roychowdhury Sameek
Published: January 2020

The fibroblast growth factor receptor (FGFR) signaling pathway is aberrantly activated in approximately 15% to 20% of patients with intrahepatic cholangiocarcinoma. Currently, several FGFR kinase inhibitors are being assessed in clinical trials for patients with FGFR-altered cholangiocarcinoma. Despite evidence of initial responses and disease control, virtually all patients eventually develop acquired resistance. Thus, there is a critical need for the development of innovative therapeutic strategies to overcome acquired drug resistance. Here, we present findings from a patient with FGFR2-altered metastatic cholangiocarcinoma who enrolled in a phase II clinical trial of the FGFR inhibitor, infigratinib (BGJ398). Treatment was initially effective as demonstrated by imaging and tumor marker response; however, after 8 months on trial, the patient exhibited tumor regrowth and disease progression. Targeted sequencing of tumor DNA after disease progression revealed the FGFR2 kinase domain p.E565A and p.L617M single-nucleotide variants (SNV) hypothesized to drive acquired resistance to infigratinib. The sensitivities of these FGFR2 SNVs, which were detected post-infigratinib therapy, were extended to include clinically relevant FGFR inhibitors, including AZD4547, erdafitinib (JNJ-42756493), dovitinib, ponatinib, and TAS120, and were evaluated in vitro. Through a proteomics approach, we identified upregulation of the PI3K/AKT/mTOR signaling pathway in cells harboring the FGFR2 p.E565A mutation and demonstrated that combination therapy strategies with FGFR and mTOR inhibitors may be used to overcome resistance to FGFR inhibition, specific to infigratinib. Collectively, these studies support the development of novel combination therapeutic strategies in addition to the next generation of FGFR inhibitors to overcome acquired resistance in patients.
Association of Longitudinal Change in High-Sensitivity Troponin with All-Cause Mortality in Coronary Artery Disease: The Heart and Soul Study
Authors: Desai Yaanik B. , Mishra Rakesh K. , Fang Qizhi , Whooley Mary A. , Schiller Nelson B.
Published: January 2020

Background: Serial increases in high-sensitivity cardiac troponin (hs-cTnT) have been associated with death in community-dwelling adults, but the association remains uninvestigated in those with coronary artery disease (CAD). Methods: We measured hs-cTnT at baseline and after 5 years in 635 ambulatory Heart and Soul Study patients with CAD. We also performed echocardiography at rest and after treadmill exercise at baseline and after 5 years. Participants were subsequently followed for the outcome of death. We used a multivariable-adjusted Cox proportional hazards model to evaluate the association between 5-year change in hs-cTnT and subsequent all-cause mortality. Results: Of the 635 subjects, there were 386 participants (61%) who had an increase in hs-cTnT levels between baseline and year 5 measurements (median increase 5.6 pg/mL, IQR 3.2–9.9 pg/mL). There were 182 deaths after a mean 4.2-year follow-up after the year 5 visit. After adjusting for clinical variables, a >50% increase in hs-cTnT between baseline and year 5 was associated with a nearly 2-fold increased risk of death from any cause (hazard ratio 1.7, 95% confidence interval 1.1–2.7). When addition of year 5 hs-cTnT was compared to a model including clinical variables and baseline hs-cTnT, there was a modest but statistically significant increase in C-statistic from 0.82 to 0.83 (p = 0.04). Conclusion: In ambulatory patients with CAD, serial increases in hs-cTnT over time are associated with an increased risk of death.
Immunoadsorption for Recurrent Primary Focal Segmental Glomerulosclerosis on Kidney Allografts: A Single-Center Experience and Literature Review
Authors: Naciri Bennani Hamza , Bonzi Juste Yérémandé , Noble Johan , Terrec Florian , Motte Lionel , Imerzoukene Farida , Bugnazet Mathilde , Giovannini Diane , Janbon Bénédicte , Malvezzi Paolo , Rostaing Lionel , Jouve Thomas
Published: January 2020

Introduction: Primary focal and segmental glomerulosclerosis (FSGS) frequently reoccurs on kidney transplants and may lead to premature allograft loss. There are no guidelines for treating FSGS recurrence on allografts; treatment is based on apheresis (plasma exchange plasmapheresis [PP], semi-specific immunoadsorption [IA] with reusable columns) plus rituximab. Objective: We aimed to assess the efficacy of IA to treat recurrent FSGS. Methods: We report on 7 patients with recurrent FSGS on kidney allograft (proteinuria ≥3 g/g of urinary creatinine or ≥3 g/day); they all received IA. Our primary objective was to reduce proteinuria by >50%. Patients’ mean age was 45 ± 10 years. Postoperative immunosuppression relied on steroids, mycophenolate mofetil, tacrolimus, with an induction therapy of basiliximab or antithymocyte globulins. Prophylaxis to prevent FSGS recurrence was either rituximab alone (n = 3), rituximab plus either PP or IA (n = 3), or no treatment (n = 1). Mean follow-up was 20 ± 13 months. There was a median of 72 (14–101) IA sessions per patient, that is, a mean of 14 ± 1 sessions per IA column. Results: At 12 months after starting IA, all patients had partial (n = 6) or complete (n = 1) remission, and allograft survival was 100%. The mean reduction in proteinuria within an IA session was 45 ± 15%. At last follow-up, 2 patients are in remission without IA, 3 patients are in partial remission that is IA dependent, and 2 patients lost their allograft due to FSGS recurrence. The most frequent adverse event was cytomegalovirus reactivation (n = 13), which subsided after valganciclovir therapy. Conclusions: We show that recurrence of FSGS can be controlled long term with IA plus rituximab. However, some patients remained dependent on IA.
Responses to Spatial and Temporal Variation in Food Availability on the Feeding Ecology of Proboscis Monkeys (Nasalis larvatus) in West Kalimantan, Indonesia
Authors: Feilen Katie L. , Marshall Andrew J.
Published: January 2020

Folivorous primates have long been assumed to experience food competition less acutely than frugivores due to their ability to eat leaves, an abundant resource in most forest systems. Consequently, the behavioural responses of leaf-eating primates to variation in food availability are less well characterised than those of frugivores. Recent empirical studies have demonstrated that many colobine species are more affected by food availability and distribution than previously thought; they employ multiple strategies to survive during periods of food scarcity. We studied a population of proboscis monkeys (Nasalis larvatus) over 16 months in three forest types in West Kalimantan, Indonesia, to examine their responses to temporal fluctuation and spatial variation in food availability. We examined how feeding behaviour was influenced by the availability of plants in botanical plots to identify important and preferred foods of proboscis monkeys across months and in different forest types. Proboscis monkeys consumed foods from 68 genera, comprising 35% young leaves, 27% unripe fruit, 12% flowers and 6% mature leaves. Consumption of plant parts and genera by proboscis monkeys varied in response to monthly changes in food availability but did not vary among forest types despite substantial differences in phenology and floristics among them. The monkeys preferred unripe fruits and flowers and used young and mature leaves as fallback foods in mangrove forests. Documentation of proboscis monkey responses to variation in food availability contributes to our understanding of how monkeys respond to changes in their environments due to climate change and habitat degradation.
The Long Noncoding RNA, Growth Arrest-Specific 5, Suppresses Gastric Cancer by Downregulating miR-21 Expression
Authors: Li Wenjun , Peng Xiaonu , Wang Zhaoyang , Zhang Hongwei , Huang Haibo , Liu Huimin , Cai Li
Published: January 2020

Background: Gastric cancer has become the second major cause of cancer death. The aim of the present study was to explore the relationship between miR-21 and the long noncoding RNA growth arrest-specific 5 (GAS5) in gastric cancer and the effect on gastric cancer cells. Methods: The expression of miR-21 and GAS5 mRNA was analyzed by quantitative real-time-PCR. Overexpression of GAS5 was used to investigate the biological functions of GAS5 in cells. The cell proliferation was detected by cell counting kit-8 assay and the cell migration and invasion were detected by Transwell. Cell apoptosis was evaluated by Annexin V-FITC/PI staining and apoptosis-related proteins were detected by western blot. The mechanism of GAS5 in vivo was evaluated by the tumorigenesis of nude mice, and dual luciferase reporter was used to determine if miR-21 is a GAS5 target. The inhibition of miR-21 and the simultaneous overexpression of GAS5 and miR-21 were further performed, and the above indicators were detected again. Results: GAS5 was low expression and miR-21 was high expression in gastric cancer tissues and cells. GAS5 overexpression reduced the proliferation, migration, and invasion of gastric cancer cells and increased the apoptosis of gastric cancer cells. The growth rate of GAS5 group slowed down and the volume of tumor decreased. miR-21 is a GAS5 target and GAS5 inhibits the proliferation of gastric cancer cells by targeting miR-21. Conclusion: Our research shown that overexpression of GAS5 can significantly inhibit the proliferation, migration, invasion and tumor formation of gastric cancer cells, and promote the apoptosis of gastric cancer cells, which may be related to the targeting inhibition of miR-21 expression by GAS5.
Estimation of Worldwide Burden of Smoking-Related Asthma
Authors: Mattiuzzi Camilla , Lippi Giuseppe
Published: January 2020

Background: Although there is solid evidence that active cigarette-smoking interplays with asthma, no recent information has been published on the worldwide burden of smoking-related asthma. Methods: An electronic search was carried out in the Global Health Data Exchange (GHDx) registry, using the keywords “asthma” and “smoking.” Asthma-related population burden was expressed as disability-adjusted life years (DALYs). Results: Although smoking-related DALYs for asthma has consistently declined by approximately 20% over the last 3 decades, the burden remains high, accounting for 9.3% of the cumulative 22.8 million DALYs caused by asthma around the world. Across all ages, the burden of smoking-related DALYs for asthma is greater in men than in women and reaches a peak in both sexes at the age of 55–70 years. Europe is the continent with the greatest burden of smoking-related DALYs for asthma, followed by western Pacific nations and Southeast Asia, whilst the least burden is seen in Africa. Conclusions: The specific asthmatic populations identified with our search shall be specifically targeted with health care policies aimed at decreasing the impact of cigarette-smoking on their asthma condition and thereby contributing to lower the clinical, societal, and economic burden of smoking-related asthma.
A Case of Idiopathic Orbital Inflammation with Shallow Anterior Chamber and Choroidal Detachment
Authors: Sato Yohei , Mano Natsuko , Watanabe Hiroko , Miyamoto Makiko , Shimizu Kazuhiro , Mukai Noriko , Mimura Masashi , Oku Hidehiro , Ikeda Tsunehiko
Published: January 2020

We report a case of idiopathic orbital inflammation with a shallow anterior chamber and choroidal detachments. This study involved an 87-year-old female patient who presented at our department after becoming aware of the progression of diplopia. Examination of the patient’s right eye revealed proptosis, as well as conjunctival edema with dilated and tortuous blood vessels. The right-eye anterior chamber was shallow, and fundus examination revealed marked choroidal detachments. Magnetic resonance imaging revealed enlargement of the right-orbit extraocular muscles and a suspected compression of the right-orbit superior and inferior ophthalmic veins, yet no expansion of the cavernous sinus. We diagnosed the patient as having idiopathic orbital inflammation in her right orbit, and subsequently started corticosteroid therapy. One week after initiating treatment, the anterior chamber was found to be nearing a normal depth, and the choroidal detachments were found to have disappeared. Our findings revealed that the inflammatory swelling of the extraocular muscle due to idiopathic orbital inflammation resulted in compression of the right-orbit superior and inferior ophthalmic veins, thus leading to an apparent choroidal circulation disorder that presented with a shallow anterior chamber and marked choroidal detachments.
Late-Stage Failures of Monoclonal Antibody Drugs: A Retrospective Case Study Analysis
Authors: Sun Amy , Benet Leslie Z.
Published: January 2020

Aim: To analyze the late-stage failures of monoclonal antibody drugs. The later a drug fails in development, the more time and expense is incurred by the sponsor. Methods: We review the late stage, Phase III, failures of 21 monoclonal antibody drugs between 2014 and 2019 using published and publicly available information to characterize the reasons for these failures. Results: In some cases, the failures are unavoidable due to the lack of adequate science, but in others, we characterize the causes of such failures and recommend how such failures may have been avoided. Conclusion: By learning from previous mistakes and adhering to the principles and recommendations provided, it is possible to avoid these common pitfalls, increasing the likelihood of success in phase III clinical trials, and thus securing regulatory approval.