bluuebunny/crossref_metadata_2025 huggingface dataset:
Angiotensin-(1–7) reduces doxorubicin-induced cardiac dysfunction in male and female Sprague-Dawley rats through antioxidant mechanisms
Authors: Rahimi Omeed , Kirby Jay , Varagic Jasmina , Westwood Brian , Tallant E. Ann , Gallagher Patricia E.
Published: February 2020

Doxorubicin (Dox) is an effective chemotherapeutic for a variety of pediatric malignancies. Unfortunately, Dox administration often results in a cumulative dose-dependent cardiotoxicity that manifests with marked oxidative stress, leading to heart failure. Adjunct therapies are needed to mitigate Dox cardiotoxicity and enhance quality of life in pediatric patients with cancer. Angiotensin-(1–7) [Ang-(1–7)] is an endogenous hormone with cardioprotective properties. This study investigated whether adjunct Ang-(1–7) attenuates cardiotoxicity resulting from exposure to Dox in male and female juvenile rats. Dox significantly reduced body mass, and the addition of Ang-(1–7) had no effect. However, adjunct Ang-(1–7) prevented Dox-mediated diastolic dysfunction, including markers of decreased passive filling as measured by reduced early diastole mitral valve flow velocity peak ( E) ( P < 0.05) and early diastole mitral valve annulus peak velocity ( e′; P < 0.001) and increased E/e′ ( P < 0.001), an echocardiographic measure of diastolic dysfunction. Since Dox treatment increases reactive oxygen species (ROS), the effect of Ang-(1–7) on oxidative by-products and enzymes that generate or reduce ROS was investigated. In hearts of male and female juvenile rats, Dox increased NADPH oxidase 4 ( P < 0.05), a major cardiovascular NADPH oxidase isozyme that generates ROS, as well as 4-hydroxynonenal ( P < 0.001) and malondialdehyde ( P < 0.001), markers of lipid peroxidation; Ang-(1–7) prevented these effects of Dox. Cotreatment with Dox and Ang-(1–7) increased the antioxidant enzymes SOD1 (male: P < 0.05; female: P < 0.01) and catalase ( P < 0.05), which likely contributed to reduced ROS. These results demonstrate that Ang-(1–7) prevents diastolic dysfunction in association with a reduction in ROS, suggesting that the heptapeptide hormone may serve as an effective adjuvant to improve Dox-induced cardiotoxicity.

NEW & NOTEWORTHY Ang-(1–7) is a clinically safe peptide hormone with cardioprotective and antineoplastic properties that could be used as an adjuvant therapy to improve cancer treatment and mitigate the long-term cardiotoxicity associated with doxorubicin in pediatric patients with cancer.
Induction of SOCS Expression by EV71 Infection Promotes EV71 Replication
Authors: Gao Wenying , Hou Min , Liu Xin , Li Zhaolong , Yang Yongjun , Zhang Wenyan
Published: February 2020

Enterovirus 71 (EV71) is the causative pathogen of hand, foot, and mouth disease (HFMD). However, no effective antiviral therapy is currently available. Some viruses could escape the host’s innate immunity by upregulating suppressor of cytokine signaling (SOCS) proteins. Until now, whether EV71 evades the host immune system by regulating the expression of SOCS proteins remains unknown. In this study, we found that EV71 infection promoted SOCS expression at both mRNA and protein levels in vitro and in vivo. Consistently, the infectivity of EV71 was decreased significantly in the SOCS3 or SOCS1 knockdown cells, suggesting that SOCS1 and especially SOCS3 are crucial for EV71 infection. Further investigation showed that SOCS3 promoted virus infection by inhibiting interferon‐induced STAT3 phosphorylation. SOCS1 and SOCS3 mRNA expressions were independent on virus‐induced type I interferon expression but were blocked by the inhibitor of NF‐κB. Therefore, EV71 infection stimulates the expression of SOCS proteins in an interferon‐independent way and negatively regulates the JAK/STAT signaling pathway, thus escaping host immunity. All these results may add new information to the mechanism of EV71 in fighting against type I interferon responses.
Outrigger and Belt‐Truss System Design for High‐Rise Buildings: A Comprehensive Review Part II—Guideline for Optimum Topology and Size Design
Authors: Alhaddad Wael , Halabi Yahia , Xu Hu , Lei HongGang
Published: February 2020

This article is the second part of the series of the comprehensive review which is related to the outrigger and belt‐truss system design for tall buildings. In this part, by presenting and analyzing as much relevant excellent resources as possible, a guideline for optimum topology and size design of the outrigger system is provided. This guideline will give an explanation and description for the used theories, assumptions, concepts, and methods in the reviewed articles for optimum topology and size design. Finally, this part ended up with a summary for the findings of the reviewed studies, which is useful to understand how different parameters influence the optimum topology and size design of a tall building with outrigger and belt‐truss system.
Metabolic Biomarkers of Squamous Cell Carcinoma of the Aerodigestive Tract: A Systematic Review and Quality Assessment
Authors: Goh Yan Mei , Antonowicz Stefan S. , Boshier Piers , Hanna George B.
Published: February 2020

Introduction. Aerodigestive squamous cell carcinomas (ASCC) constitute a major source of global cancer deaths. Patients typically present with advanced, incurable disease, so new means of detecting early disease are a research priority. Metabolite quantitation is amenable to point-of-care analysis and can be performed in ASCC surrogates such as breath and saliva. The purpose of this systematic review is to summarise progress of ASCC metabolomic studies, with an emphasis on the critical appraisal of methodological quality and reporting. Method. A systematic online literature search was performed to identify studies reporting metabolic biomarkers of ASCC. This review was conducted in accordance with the recommendations of the Cochrane Library and MOOSE guidelines. Results. Thirty studies comprising 2117 patients were included in the review. All publications represented phase-I biomarker discovery studies, and none validated their findings in an independent cohort. There was heterogeneity in study design and methodological and reporting quality. Sensitivities and specificities were higher in oesophageal and head and neck squamous cell carcinomas compared to those in lung squamous cell carcinoma. The metabolic phenotypes of these cancers were similar, as was the kinetics of metabolite groups when comparing blood, tissue, and breath/saliva concentrations. Deregulation of amino acid metabolism was the most frequently reported theme. Conclusion. Metabolite analysis has shown promising diagnostic performance, especially for oesophageal and head and neck ASCC subtypes, which are phenotypically similar. However, shortcomings in study design have led to inconsistencies between studies. To support future studies and ultimately clinical adoption, these limitations are discussed.
Kai‐Xin‐San, a Chinese Herbal Decoction, Accelerates the Degradation of β‐Amyloid by Enhancing the Expression of Neprilysin in Rats
Authors: Wang Na , Jia Yongming , Zhang Bo , Li Yan , Murtaza Ghulam , Huang Shuming , Liu Xuewei
Published: February 2020

This study aimed to investigate the mechanisms of Kai‐Xin‐San (KXS, a famous Chinese herbal decoction used to treat amnesia) on the degradation of Aβ and further elucidate the mechanism of KXS on Aβ‐induced memory dysfunction. After pretreatment with KXS (1.08 g/kg/day) for two weeks, Aβ42 (2 μL, 200 μM) was injected into rat hippocampus to induce cognitive dysfunction. Morris water maze (MWM) test was developed to evaluate cognitive performance in rats. Hippocampal neurons were observed by histological staining using Hematoxylin‐Eosin (HE) methods. Levels of exogenous Aβ42, which was injected into the hippocampus, were continually measured through a special Enzyme‐linked immunoassay (ELISA) kit to observe the catabolic process of Aβ in the brain. Similarly, Aβ degradation in PC12 cells was also investigated using the ELISA kit. The expressions of Aβ degeneration enzymes, including neprilysin (NEP), angiotensin‐converting enzyme (ACE), and endothelin‐converting enzyme (ECE), were detected by western blotting to elucidate Aβ reduction mechanism. Our results showed that KXS prevented Aβ42‐induced cognitive impairment and attenuated hippocampus neuronal damage caused by Aβ42. Moreover, KXS could accelerate Aβ42 degradation in Aβ42 injected rats. Furthermore, NEP, an Aβ degradation enzyme, was increased in the hippocampus while ECE and ACE, other two Aβ‐degrading enzymes, were not changed. KXS accelerated Aβ degradation in PC12 cells. Our findings revealed that KXS facilitated the degradation of Aβ42 by increasing the expression of NEP in rat hippocampus. By reducing the Aβ burdens, KXS protected hippocampal neurons, leading to the improvement of cognitive function in rats.
Diagnostic Pitfall of Platypnea-Orthodeoxia Syndrome Caused by Atrial Septal Defect after Right Pneumonectomy
Authors: Bohren Y. , Lopez M. , Santelmo N. , Ristorto J. , Billaud P. , Canuet M. , Mertes P. M. , Collange O.
Published: February 2020

We describe a case of platypnea-orthodeoxia syndrome (POS) due to atrial septal defect (ASD) occurring in the early postoperative course of a right pneumonectomy. Deformation of the atrial septum after right pneumonectomy deviates the blood from the inferior vena cava to ASD during the sitting position creating, a massive right-to-left shunt. Diagnosis can initially be missed by making contrast bubble test through the superior vena cava. The atrial septal defect was then closed using the surgical technique, allowing an instantaneous improvement of hematosis.
Practical Synthesis and Field Application of the Synthetic Sex Pheromone of Rice Stem Borer, Chilo suppressalis (Lepidoptera: Pyralidae)
Authors: Liu Bin , Syu Kun-Jie , Zhang Yuan-Xin , Gupta Sachin , Shen Yu-Jhe , Chien Wei-Jynn , Tseng Jui-Chang , Lou Da Wei
Published: February 2020

Rice stem borer, Chilo suppressalis, is a common and major serious pest of rice, maize, and wheat crops across Asia, Europe, and Oceania countries. Its sex pheromone consists of three analogously compounds, i.e., (Z)-hexadec-11-enal (1), (Z)-octadec-13-enal (2), and (Z)-hexadec-9-enal (3), as long-chain aliphatic internal cis-alkenyl aldehydes. In order to perform an economic and widespread pest control management of rice stem borer, a versatile and efficient synthetic strategy is required. A versatile and efficient synthesis using a common synthetic route for cis-alkenals with high overall yields is described. Commercially available inexpensive aliphatic diols were chosen as starting materials. Two key steps were employed to synthesize the long-chain aliphatic internal cis-alkenes in excellent yields, including the alkylation of terminal alkynes without the utilization of a highly polar aprotic cosolvent and the versatile cis-selective semihydrogenation for the reduction of internal alkynes with excellent stereoselectivity. The results of field tests showed that the synthetic sex pheromone blend was highly effective for the capture of rice stem borer.
Levels of Intestinal Inflammation and Fibrosis in Resection Specimens after Preoperative Anti-Tumor Necrosis Factor Alpha Treatment in Patients with Crohn’s Disease: A Comparative Pilot Study
Authors: Torle J. , Dabir P. D. , Korsgaard U. , Christiansen J. , Qvist N. , El-Hussuna A.
Published: February 2020

Background. Strictures are a common complication in Crohn’s disease (CD), found in more than 50% of patients. They are characterized by the excessive deposition of extracellular proteins in the tissue as a result of the chronic inflammatory process. The effect of anti-tumor necrosis factor alpha (TNF-α) therapy on the development of fibrosis is not yet fully understood. Aim. To investigate whether the degree of intestinal inflammation and fibrosis is correlated with preoperative anti-TNF-α therapy in patients with CD who are undergoing bowel resection. Methods. This unblinded, prospective, single tertiary center, pilot cohort study included all adult patients with CD who underwent elective, laparoscopic, or open intestinal resection. Preoperative investigations included measurement of blood TNF-α concentration, specific antidrug antibodies, and the concentration of selected inflammatory cytokines. Three pathologists independently examined the specimens and assessed the degree of inflammation and fibrosis. Results. Histopathological specimens from 10 patients with CD who underwent ileocecal or ileocolic resections were retrieved. Four of those patients were on anti-TNF-α treatment prior to surgery. The last dose of the anti-TNF-α agent was administered 1–9 weeks prior to bowel resection. Patients on anti-TNF-α treatment had a higher fibrosis score than controls (p=0.01). Anti-TNF-α treatment was not associated with an increase in CD68- or CD163-positive macrophages. There was no significant relationship between the time from the final preoperative anti-TNF-α dose to surgery and the fibrosis score. No significant association was found between the concentration of major inflammatory cytokines, including TNF-α, and the fibrosis score or degree of inflammation. Conclusions. Patients who underwent preoperative anti-TNF-α treatment had a higher fibrosis score than controls.
Parathormone Levels in a Middle-Eastern Healthy Population Using 2nd and 3rd Generation PTH Assays
Authors: Gannagé-Yared Marie-Hélène , Kallas-Chémaly Marie-Noëlle , Sleilaty Ghassan
Published: February 2020

Background. The purpose of the current study is to determine PTH reference values in vitamin-D-replete Lebanese adults using 2nd and 3rd generation PTH assays and to look at the factors that affect PTH variations. Methods. Fasting PTH was measured using 2nd and 3rd generation Diasorin PTH assays in 339 vitamin-D-replete healthy subjects aged 18 to 63 years (230 men and 109 women) who have normal calcium levels and an eGFR ≥60 ml/mn. 25-OH vitamin D (25(OH)D) was measured using the Diasorin assay. Results. For the 2nd PTH generation, median (IQR) levels were 48.9 (34.9–66.0) pg/ml, and its 2.5th–97.5th percentile values were 19.7–110.5 pg/ml for 25(OH)D values between 20 and 30 ng/ml, and 19.7–110.7 pg/ml for 25(OH)D values ≥30 ng/ml. For the 3rd PTH generation, the median (IQR) values were 23.9 (17.7–30.5) pg/ml, and its 2.5th–97.5th percentile values were, respectively, 9.2 and 50.2 pg/ml for 25(OH)D values between 20 and 30 ng/ml, and 8.4 and 45.4 pg/ml for 25(OH)D values ≥30 ng/ml. The median (IQR) serum 25(OH)D levels were 27.5 (23.8–32.7) ng/ml. 2nd and 3rd generation PTH values are strongly correlated (r = 0.96, p<0.0001), but poorly concordant (Lin’s concordance coefficient 0.365, 95% CI: 0.328–0.401) with observations beyond the 95% Bland–Altman limits of agreement. 2nd and 3rd generation PTH levels did not differ according to gender and were significantly correlated with age but not with 25(OH)D and serum calcium levels. Conclusion. Lebanese adult healthy subjects have higher 2nd and 3rd generation PTH levels compared with the reference range provided by the manufacturer. The reference range was not influenced by changing the 25(OH)D cutoff. The clinical significance of the higher PTH levels in our population should be investigated.
Bcl-2 Proteins Regulate Mitophagy in Lipopolysaccharide-Induced Acute Lung Injury via PINK1/Parkin Signaling Pathway
Authors: Zhang Zhihao , Chen Zhugui , Liu Ruimeng , Liang Qingchun , Peng Zhiyong , Yin Shuang , Tang Jing , Gong Ting , Liu Youtan
Published: February 2020

Mitophagy is involved in sepsis-induced acute lung injury (ALI). Bcl-2 family proteins play an important role in mitochondrial homeostasis. However, whether targeting Bcl-2 proteins (Bcl-2 and Bad) could influence mitophagy in ALI remains unclear. In this study, lipopolysaccharide (LPS) was used to induce injury in A549 cells and ALI in mice. LPS treatment resulted in elevated cell apoptosis, enhanced mitophagy, decreased Bcl-2 expression, increased Bad expression, and activation of PINK1/Parkin signaling in cells and lung tissues. Both Bcl-2 overexpression and Bad knockdown attenuated LPS-induced injury, inhibited cell apoptosis and mitophagy, and improved survival. Atg5 knockout (KO) inhibited LPS-induced cell apoptosis. Furthermore, Bcl-2 proteins regulated mitophagy by modulating the recruitment of Parkin from the cytoplasm to mitochondria via direct protein-protein interactions. These results were further confirmed in Park2 KO cells and Park2-/- mice. This is the first study to demonstrate that Bcl-2 proteins regulated mitophagy in LPS-induced ALI via modulating the PINK1/Parkin signaling pathway, promoting new insights into the mechanisms and investigation of therapeutic strategies for a septic patient with ALI.
Early Aggressive Immunotherapy Improves Functional Outcome in Chronic Immune Sensory Polyradiculopathy
Authors: Koh Jasmine Shimin , Tung James Wei Min , Tan-Yu Genevieve Lynn Yu , Umapathi Thirugnanam
Published: February 2020

Chronic immune sensory polyradiculopathy (CISP) is an uncommon and treatable inflammatory disorder of the proximal sensory nerve roots. Patients typically present with severe sensory ataxia, normal motor examination, unsteady gait, and normal nerve conduction studies (NCS). We describe an elderly man who presented with a two-week history of progressive numbness of both legs and recurrent falls. He had hyporeflexia, normal strength, severe proprioceptive, and vibration sense loss in both lower limbs and was unable to stand or walk because of severe sensory ataxia. The NCS and MR scan of the spine were normal. Tibial somatosensory evoked potentials revealed proximal conduction defect and localized the pathology to the lumbar sensory nerve roots proximal to the dorsal root ganglion. Cerebrospinal fluid showed cytoalbuminergic dissociation suggestive of inflammation. CISP was diagnosed; he was given aggressive immunotherapy consisting sequentially of corticosteroids with mycophenolate mofetil and three cycles of intravenous immunoglobulin after which he regained independent mobility. Unlike previous reports where patients presented months-years after symptom onset and improved after single-line immunotherapy, our patient presented fairly acutely and made dramatic improvement only after aggressive combination therapy. We urge physicians to recognize this uncommon neurologic cause of sensory ataxia where early aggressive treatment is crucial for better functional outcomes.
Numerical Investigation on Flapping Aerodynamic Performance of Dragonfly Wings in Crosswind
Authors: Wang Chao , Zhang Rui , Zhou Chaoying , Sun Zhenzhong
Published: February 2020

Numerical simulations are performed to investigate the influence of crosswind on the aerodynamic characteristics of rigid dragonfly-like flapping wings through the solution of the three-dimensional unsteady Navier-Stokes equations. The aerodynamic forces, the moments, and the flow structures of four dragonfly wings are examined when the sideslip angleϑbetween the crosswind and the flight direction varied from 0oto 90o. The stability of the dragonfly model in crosswind is analyzed. The results show that the sideslip angleϑhas a little effect on the total time-average lift force but significant influence on the total time-average thrust force, lateral force, and three-direction torques. An increase in the sideslip angle gives rise to a larger total time-average lateral force and yaw moment. These may accelerate the lateral skewing of the dragonfly, and the increased rolling and pitching moments will further aggravate the instability of the dragonfly model. The vorticities and reattached flow on the wings move laterally to one side due to the crosswind, and the pressure on wing surfaces is no longer symmetrical and hence, the balance between the aerodynamic forces of the wings on two sides is broken. The effects of the sideslip angleϑon each dragonfly wing are different, e.g.,ϑhas a greater effect on the aerodynamic forces of the hind wings than those of the fore wings. When sensing a crosswind, it is optimal to control the two hind wings of the bionic dragonfly-like micro aerial vehicles.
Development and Validation of Improved Impedance Functions for Roads with Mixed Traffic Using Taxi GPS Trajectory Data and Simulation
Authors: Zhao Fei , Fu Liping , Zhong Ming , Liu Shaobo , Wang Xudong , Huang Junda , Ma Xiaofeng
Published: February 2020

This paper proposes an improved impedance function for roads with mixed traffic. It is known that only limited studies consider the impact of nonmotorized traffic on travel impedance of a road segment, and a comparison of the impedance considering nonmotorized traffic with the classic BPR function, which does not consider the former, is scarce. Most of the previous studies targeted road conditions in developed countries, where the presence of nonmotorized traffic is negligible, and therefore limited efforts have been invested to develop improved impedance function considering mixed traffic. To overcome this limitation, this paper develops an improved impedance function and carries out a case study for a road in the city of Wuhan, China. The improved impedance function explicitly considers the interaction between motorized and nonmotorized traffic. Taxi GPS data from the case study road is used to extract and analyze the travel time of the “probe vehicles” running through the sampled segment at any time during a sampling day. The capacity of the road segment is measured, and the traffic flow of motorized vehicles and nonmotorized vehicles on the segment is counted. Based on the above data, the classic BPR function and the improved one proposed in this paper are calibrated. After comparing and analyzing the observed road impedance based on both analytical and simulation results, the classic BPR function and the proposed impedance function, the proposed impedance function is found to be more accurate to simulate the observed road impedance, with the error reducing from 14.83 s with the classic BPR impedance function to 6.50 s with the improved function. The proposed impedance function possesses a simple structure and high flexibility, and the parameters calibrated in this paper can be applied to similar roads to provide more realistic impedance than the previous ones based on the classic BPR function. The calibrated improved impedance function’s transferability to other similar roads is validated by applying it to another road and the results show that the percentage error between the predicted travel times and the observed ones is only 3.8%.
Sulfonamide‐Based Azaheterocyclic Schiff Base Derivatives as Potential Carbonic Anhydrase Inhibitors: Synthesis, Cytotoxicity, and Enzyme Inhibitory Kinetics
Authors: Abas Mujahid , Rafique Hummera , Shamas Shazia , Roshan Sadia , Ashraf Zaman , Iqbal Zafar , Raza Hussain , Hassan Mubashir , Afzal Khurram , Rizvanov Albert A. , Asad Muhammad Hassham Hassan Bin
Published: February 2020

A series of sulfonamide‐bearing azaheterocyclic Schiff base derivatives 3(a-j) were synthesized as carbonic anhydrase inhibitors. The substituted benzene sulfonyl chlorides 1(a-d) were reacted with N2H4 to get aromatic sulfonyl hydrazides 2(a-d). The intermediate hydrazides 2(a-d) were treated with substituted aldehydes to afford azaheterocyclic sulfonamide Schiff bases 3(a-j). The spectral data of synthesized compounds confirmed the formation of the final products. The inhibitory effects of 3(a-j) on carbonic anhydrase activity were determined, and it was found that derivative 3c exhibited the most potent activity with IC500.84 ± 0.12 μM among all other derivatives and is also more active than standard acetazolamide (IC500.91 ± 0.12). The enzyme inhibitory kinetics results determined by Lineweaver‐Burk plots revealed that compound 3c inhibits the enzyme by noncompetitive mode of inhibition with Ki value 8.6 μM. The molecular docking investigations of the synthesized analogues 3(a-j) were evaluated which assured that synthesized compounds bind well inside the active binding site of the target enzyme. Cytotoxicity on human keratinocyte (HaCaT) and MCF‐7 cell lines was performed, and it was found that most of the synthesized analogues were nontoxic on these cell lines and the toxic effects follow the dose‐dependent manner. Based on our investigations, it was suggested that analogue 3c may serve as core structure to project carbonic anhydrase inhibitors with greater potency.
Impact of the Glycemic Control and Duration of Type 2 Diabetes on Vitamin D Level and Cardiovascular Disease Risk
Authors: Alaidarous Thuraya A. , Alkahtani Noura M. , Aljuraiban Ghadeer S. , Abulmeaty Mahmoud M. A.
Published: February 2020

Background and Aims. To investigate the impact of glycemic control and T2D duration on vitamin D status and cardiovascular disease (CVD) risk among Saudi patients. Methods. This case-control study was conducted in King Faisal Specialist Hospital, Saudi Arabia. A total of 25 nondiabetic controls and 92 patients with confirmed T2D, aged 20–60 years, were included. Patients with T2D were divided into the following groups based on disease duration (newly diagnosed: ≈6 months and long duration: ≥5 years) and glycemic control based on their glycated hemoglobin (HbA1C) level with a threshold of ≤0.053 mol/mol: newly diagnosed controlled (NC, n=25), newly diagnosed uncontrolled (NU, n=17), long duration controlled (LC, n=25), and long duration uncontrolled (LU, n=25). Blood levels of fasting blood glucose, HbA1C, lipid profile, and serum 25-hydroxyvitamin D (25(OH)D) were assessed and used to define the CVD risk score. Results. Our study showed that T2D duration was an independent predictor of vitamin D deficiency. The longer disease duration, the lower odds of being vitamin D deficient (odds ratio (OR) = 0.05, 95% CI: 0.01–0.29, p<0.05). No significant association was observed between vitamin D and HbA1C levels. In the NU group, CVD risk scores were directly correlated with serum 25(OH)D (r=0.53, p<0.05). On the contrary, 25(OH)D was moderately inversely correlated with CVD risk score in the LU group (r=−0.45, p<0.05). Conclusion. Duration of diabetes rather than glycemic control is associated with vitamin D deficiency. Glycemic uncontrol may augment vitamin D deficiency-associated CVD risk in both newly diagnosed and old patients with type 2 diabetes.
Herpes Simplex Virus-2 Hepatitis: A Case Report and Review of the Literature
Authors: Ahmed Amna , Granillo Alejandro , Burns Ethan , Glassner Kerri , Naseem Nishath , Force Christopher , Crumley Suzanne M. , Drews Ashley
Published: February 2020

Herpes simplex virus (HSV) is a rare cause of hepatitis in pregnancy and the chronically immunosuppressed, with a high propensity to progress to acute liver failure (ALF) and death. Patients typically present with a nonspecific clinical picture that often delays diagnosis and treatment, contributing to the high mortality rate. We present a case of a young female on chronic prednisone and hydroxychloroquine for systemic lupus erythematosus (SLE) who was diagnosed with HSV-2 hepatitis after presenting with right-sided chest and abdominal discomfort. Despite early clinical deterioration, prompt initiation of therapy with intravenous acyclovir and methylprednisolone led to rapid improvement.
Essential Oils-Loaded Electrospun Biopolymers: A Future Perspective for Active Food Packaging
Authors: Ataei Shahla , Azari Pedram , Hassan Aziz , Pingguan-Murphy Belinda , Yahya Rosiyah , Muhamad Farina
Published: February 2020

The growth of global food demand combined with the increased appeal to access different foods from every corner of the globe is forcing the food industry to look for alternative technologies to increase the shelf life. Essential oils (EOs) as naturally occurring functional ingredients have shown great prospects in active food packaging. EOs can inhibit the growth of superficial food pathogens, modify nutritious values without affecting the sensory qualities of food, and prolong the shelf life when used in food packaging as an active ingredient. Since 2016, various reports have demonstrated that combinations of electrospun fibers and encapsulated EOs could offer promising results when used as food packaging. Such electrospun platforms have encapsulated either pure EOs or their complexation with other antibacterial agents to prolong the shelf life of food products through sustained release of active ingredients. This paper presents a comprehensive review of the essential oil-loaded electrospun fibers that have been applied as active food packaging material.
Preoperative Portal Vein Embolization in Hepatic Surgery: A Review about the Embolic Materials and Their Effects on Liver Regeneration and Outcome
Authors: Luz Jose Hugo M. , Gomes Filipe V. , Coimbra Elia , Costa Nuno V. , Bilhim Tiago
Published: February 2020

Liver volume and function after hepatectomies are directly correlated to postoperative complications and mortality. Consequently contemporary liver surgery has focused on reaching an adequate future liver remnant so as to diminish postoperative morbidity and mortality. Portal vein embolization has evolved and is the standard of care as a liver regenerative strategy in many surgery departments worldwide before major liver resections. Different embolic materials have been used for portal vein embolization including gelfoam, ethanol, polyvinyl-alcohol particles, calibrated microspheres, central vascular plugs, coils, n-butyl-cyanoacrylate glue, fibrin glue, polidocanol-foam, alcoholic prolamin solution, and ethylene vinyl alcohol copolymer, as sole occluders or in varied combinations. While to date there has been no prospective controlled trial comparing the efficacy of different embolic materials in portal vein embolization, retrospective data insinuates that the use of n-butyl-cyanoacrylate and absolute ethanol produces higher contralateral liver hypertrophies. In this review, we evaluated publications up to August 2019 to assess the technical and regenerative results of portal vein embolization accomplished with different embolic materials. Special attention was given to specific aspects, advantages, and drawbacks of each embolic agent used for portal vein embolization, its liver regenerative performance, and its influence on patient outcome.
A Novel Improved Local Binary Pattern and Its Application to the Fault Diagnosis of Diesel Engine
Authors: Cai Yanping , Xu Guanghua , Li Aihua , Wang Xu
Published: February 2020

Aiming at the feature extraction difficulty of vibration signals, an improved local binary pattern- (ILBP-) based diesel engine fault diagnosis approach is proposed. To effectively make use of the component spatial information in time-frequency images, local binary pattern (LBP) algorithm is applied. Also, in view of the problems that traditional LBP coding is easily interfered by singular pixel points and the relative spatial information is not prominent, an improved coding rule of the LBP operator is put forward in this paper. Compared with some typical LBP algorithms, computational complexity of the proposed ILBP algorithm is greatly reduced, and the coding sparsity is greatly improved. The ILBP operator is applied to fault diagnosis of BF4L1011F diesel engine with eight different valve conditions. For comparison, six kinds of time-frequency distribution are used to convert raw vibration signals into time-frequency images, and then circular LBP, rotation-invariant LBP, uniform LBP, and ILBP operator are applied for texture coding. Finally, nearest neighbor classifier (NNC) and support vector machine (SVM) are used for fault identification. The classification results show that the ILBP operator proposed in this paper can better describe the texture feature information in vibration time-frequency images of the diesel engine, and a good diagnostic effect can be achieved by combining wavelet packet (WP) distribution and ILBP.
iNOS Regulates the Therapeutic Response of Pancreatic Cancer Cells to Radiotherapy
Authors: Pereira Patricia M.R. , Edwards Kimberly J. , Mandleywala Komal , Carter Lukas M. , Escorcia Freddy E. , Campesato Luis Felipe , Cornejo Mike , Abma Lolkje , Mohsen Abu-Akeel , Iacobuzio-Donahue Christine A. , Merghoub Taha , Lewis Jason S.
Published: February 2020

Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to radiotherapy, chemotherapy, or a combination of these modalities, and surgery remains the only curative intervention for localized disease. Although cancer-associated fibroblasts (CAF) are abundant in PDAC tumors, the effects of radiotherapy on CAFs and the response of PDAC cells to radiotherapy are unknown. Using patient samples and orthotopic PDAC biological models, we showed that radiotherapy increased inducible nitric oxide synthase (iNOS) in the tumor tissues. Mechanistic in vitro studies showed that, although undetectable in radiotherapy-activated tumor cells, iNOS expression and nitric oxide (NO) secretion were significantly increased in CAFs secretome following radiotherapy. Culture of PDAC cells with conditioned media from radiotherapy-activated CAFs increased iNOS/NO signaling in tumor cells through NF-κB, which, in turn, elevated the release of inflammatory cytokines by the tumor cells. Increased NO after radiotherapy in PDAC contributed to an acidic microenvironment that was detectable using the radiolabeled pH (low) insertion peptide (pHLIP). In murine orthotopic PDAC models, pancreatic tumor growth was delayed when iNOS inhibition was combined with radiotherapy. These data show the important role that iNOS/NO signaling plays in the effectiveness of radiotherapy to treat PDAC tumors.

Significance:

A radiolabeled pH-targeted peptide can be used as a PET imaging tool to assess therapy response within PDAC and blocking iNOS/NO signaling may improve radiotherapy outcomes.
Efficacy, Safety, and Biomarkers of Toripalimab in Patients with Recurrent or Metastatic Neuroendocrine Neoplasms: A Multiple-Center Phase Ib Trial
Authors: Lu Ming , Zhang Panpan , Zhang Yanqiao , Li Zhongwu , Gong Jifang , Li Jie , Li Jian , Li Yan , Zhang Xiaotian , Lu Zhihao , Wang Xicheng , Zhou Jun , Peng Zhi , Wang Weifeng , Feng Hui , Wu Hai , Yao Sheng , Shen Lin
Published: February 2020

Purpose:

Patients with recurrent or metastatic neuroendocrine neoplasms (NEN) had a poor prognosis and few treatment options. Toripalimab, a humanized IgG4 antibody specific for human PD-1 receptor, was first approved to treat second-line metastatic melanoma in China in 2018.

Patients and Methods:

The multiple-center phase Ib trial enrolled patients with NENs (Ki-67 ≥ 10%) after failure of first-line therapy received 3 mg/kg toripalimab once every two weeks. The primary objective was objective response rate (ORR) and safety. PD-L1 expression and whole-exome sequencing were performed on tumor biopsies. Secondary objectives included duration of response (DOR), disease control rate (DCR), and progression-free survival and overall survival.

Results:

Of 40 patients included from April 2017 to December 2018, 8 partial responses and 6 stable diseases were observed, for a 20% ORR and a 35% DCR. The median DOR was 15.2 months. Patients with PD-L1 expression (≥10%) or high tumor mutational burden (TMB) had better ORR than PD-L1 <10% (50.0% vs. 10.7%, P = 0.019) and TMB-low patients (75.0% vs. 16.1%, P = 0.03). Three of 8 (37.5%) responders harbored ARID1A mutations, whereas only 1 of 27 nonresponders had mutations (P = 0.03). Of note, 1 exceptional responder with TMB-L, microsatellite stable (MSS), and PD-L1–negative had multiple genomic arrangements with high prediction score for neoantigens.

Conclusions:

Toripalimab had antitumor activity and safety in treating recurrent or metastatic NENs. Patients with positive PD-L1 expression, TMB-H (top 10%), and/or microsatellite instable (MSI-H) might preferentially benefit from the treatment. The genomic mutation of ARID1A and high genomic rearrangements might be correlated with clinical benefit.
Relapse-Fated Latent Diagnosis Subclones in Acute B Lineage Leukemia Are Drug Tolerant and Possess Distinct Metabolic Programs
Authors: Dobson Stephanie M. , García-Prat Laura , Vanner Robert J. , Wintersinger Jeffrey , Waanders Esmé , Gu Zhaohui , McLeod Jessica , Gan Olga I. , Grandal Ildiko , Payne-Turner Debbie , Edmonson Michael N. , Ma Xiaotu , Fan Yiping , Voisin Veronique , Chan-Seng-Yue Michelle , Xie Stephanie Z. , Hosseini Mohsen , Abelson Sagi , Gupta Pankaj , Rusch Michael , Shao Ying , Olsen Scott R. , Neale Geoffrey , Chan Steven M. , Bader Gary , Easton John , Guidos Cynthia J. , Danska Jayne S. , Zhang Jinghui , Minden Mark D. , Morris Quaid , Mullighan Charles G. , Dick John E.
Published: February 2020

Disease recurrence causes significant mortality in B-progenitor acute lymphoblastic leukemia (B-ALL). Genomic analysis of matched diagnosis and relapse samples shows relapse often arising from minor diagnosis subclones. However, why therapy eradicates some subclones while others survive and progress to relapse remains obscure. Elucidation of mechanisms underlying these differing fates requires functional analysis of isolated subclones. Here, large-scale limiting dilution xenografting of diagnosis and relapse samples, combined with targeted sequencing, identified and isolated minor diagnosis subclones that initiate an evolutionary trajectory toward relapse [termed diagnosis Relapse Initiating clones (dRI)]. Compared with other diagnosis subclones, dRIs were drug-tolerant with distinct engraftment and metabolic properties. Transcriptionally, dRIs displayed enrichment for chromatin remodeling, mitochondrial metabolism, proteostasis programs, and an increase in stemness pathways. The isolation and characterization of dRI subclones reveals new avenues for eradicating dRI cells by targeting their distinct metabolic and transcriptional pathways before further evolution renders them fully therapy-resistant.

Significance:

Isolation and characterization of subclones from diagnosis samples of patients with B-ALL who relapsed showed that relapse-fated subclones had increased drug tolerance and distinct metabolic and survival transcriptional programs compared with other diagnosis subclones. This study provides strategies to identify and target clinically relevant subclones before further evolution toward relapse.

See related video: https://vimeo.com/442838617

See related article by E. Waanders et al .
Increased Lipid Accumulation under Hypoxia in SZ95 Human Sebocytes
Authors: Choi KeunOh , Jin Mirim , Zouboulis Christos C. , Lee YoungJoo
Published: February 2020

Background: Excessive sebum is produced by specialized cells called sebocytes and is considered a cause or consequence of acne, sebaceous cysts, hyperplasia, and sebaceous adenoma. Objective: To report changes in lipid accumulation in human sebocytes under hypoxia, which occurs under conditions of seborrhea. Methods: Sebocytes from the immortalized human gland cell line SZ95 were cultured under conditions of hypoxia for 48 h; lipid formation was confirmed by Nile red and Oil Red O staining. To investigate whether HIF-1α plays a role in lipid accumulation, SZ95 cells transfected or treated with dimethyloxalylglycine (DMOG) were assessed by Nile red. For protein expression of the sterol regulatory element-binding protein-1 (SREBP-1) and perilipin 2 (PLIN2), Western blot analysis was performed. Differentially expressed genes (DEGs) in SZ95 sebocytes under hypoxia were revealed by RNA-Seq analyses, and the statistical significance of the correlation between hypoxic and acne/non-acne skin was evaluated using gene set enrichment analysis. Results: Hypoxia induces lipid accumulation in SZ95 sebocytes. In addition, the levels of SREBP-1 and PLIN2 were regulated by HIF-1α in SZ95 sebocytes under hypoxia. RNA-Seq analyses of DEGs in SZ95 sebocytes under hypoxia revealed 256 DEGs, including several lipid droplet-associated genes. DEGs between acne and non-acne skin are significantly enriched in hypoxia gene sets. We also detected 93 differentially expressed inflammatory mediators. Conclusions: To the best of our knowledge, this study is the first to show that a hypoxic microenvironment can increase lipogenesis and provides a link between seborrhea and inflammation.
B7-H3 and B7-H4 Expression in Breast Cancer and Their Association with Clinicopathological Variables and T Cell Infiltration
Authors: Kim Nah Ihm , Park Min Ho , Kweon Sun-Seog , Lee Ji Shin
Published: February 2020

Objectives: B7-H3 and B7-H4 proteins are expressed in breast cancer tissues, but their relationships with respect to tumor immune surveillance and outcomes in breast cancer are not conclusive. Methods: We first examined B7-H3 and B7-H4 mRNA expression in the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. Next, mRNA and protein expression were assessed by RNAscope in situ hybridization (ISH) and immunohistochemistry in 10 pairs of breast cancer and matched normal tissues. Immunohistochemical staining of B7-H3, B7-H4, CD3, and CD8 was performed in tissue microarray slides containing 198 breast cancer samples. Association of B7-H3 and B7-H4 expression with survival was verified using the publicly accessible BreastMark tool. Results: B7-H3 and B7-H4 mRNA expression were significantly higher in breast cancer samples in the TCGA dataset than in normal breast tissues in the GTEx dataset. RNAscope ISH and immunohistochemistry showed that B7-H3 and B7-H4 mRNA and protein appeared to be mainly expressed in cancer cells. Expression of B7-H3 and B7-H4 tended to be associated with low-density scores of stromal tumor-infiltrating lymphocytes (TILs) as well as molecular subtypes. Expressions of B7-H3 and B7-H4 were negatively correlated with stromal CD3+ and CD8+ T cell infiltration density. B7-H3 and B7-H4 expression was not associated with survival, which was verified by BreastMark analysis. Conclusion: Expression levels of B7-H3 and B7-H4 were independent of clinical outcomes of breast cancer. There was an inverse relationship between the expression of B7-H3 and B7-H4 in breast cancer and the density of stromal TILs and CD8+ T lymphocytes. This inverse relationship may represent a promising target in the field of breast cancer immunotherapy.
Acute Susac Syndrome in a Recent User of Adulterated Cocaine: Levamisole as a Triggering Factor?
Authors: De Baerdemaeker Klara , Mabiglia Chiara , Hantson Philippe , Di Fazio Vincent , Duprez Thierry , Kozyreff Alexandra , van Pesch Vincent , Sellimi Amina
Published: February 2020

Susac syndrome (SS) is a central nervous system vasculitis characterized by the clinical triad of encephalopathy, sensorineural hearing loss, and visual disturbance caused by branch retinal artery occlusion. It is considered as an inflammatory disorder, and an autoimmune etiology is suggested. A 29-year-old man with a history of recent cocaine abuse developed the clinical features of SS. Toxicological analysis including hair testing revealed that cocaine had been adulterated with levamisole. After an initial clinical improvement following corticosteroid therapy, the introduction of mycophenolate mofetil was justified a few weeks later by the progression (or relapse) of the retinal injury, followed by complete recovery. The presence of levamisole has been documented in patients with multifocal inflammatory leukoencephalopathy (MIL). Further investigations are needed to determine if levamisole as an adulterant of cocaine could also play a role in the development of rapidly progressive leukoencephalopathy in young men, with Susac or Susac-like syndromes as possible variants of MIL.
New Nutraceutical Combination Reduces Blood Pressure and Improves Exercise Capacity in Hypertensive Patients Via a Nitric Oxide–Dependent Mechanism
Authors: Carrizzo Albino , Moltedo Ornella , Damato Antonio , Martinello Katiuscia , Di Pietro Paola , Oliveti Marco , Acernese Fausto , Giugliano Giuseppe , Izzo Raffaele , Sommella Eduardo , Migliarino Serena , Piazza Ornella , Izzo Carmine , Virtuoso Nicola , Strianese Andrea , Trimarco Valentina , Campiglia Pietro , Fucile Sergio , Puca Annibale , Trimarco Bruno , Vecchione Carmine
Published: February 2020

Background

High blood pressure (
BP
) has long been recognized as a major health threat and, particularly, a major risk factor for stroke, cardiovascular disease, and end‐organ damage. However, the identification of a novel, alternative, integrative approach for the control of
BP
and cardiovascular protection is still needed.

Methods and Results

Sixty‐nine uncontrolled hypertension patients, aged 40 to 68 years, on antihypertensive medication were enrolled in 2 double‐blind studies. Forty‐five were randomized to placebo or a new nutraceutical combination named AkP05, and
BP
, endothelial function, and circulating nitric oxide were assessed before and at the end of 4 weeks of treatment. Twenty‐four patients were randomized to diuretic or AkP05 for 4 weeks and underwent a cardiopulmonary exercise test to evaluate the effects of AkP05 on functional capacity of the cardiovascular, pulmonary, and muscular systems. Vascular and molecular studies were undertaken on mice to characterize the action of the single compounds contained in the AkP05 nutraceutical combination. AkP05 supplementation reduced
BP
, improved endothelial function, and increased nitric oxide release; cardiopulmonary exercise test revealed that AkP05 increased maximum O
2
uptake, stress tolerance, and maximal power output. In mice, AkP05 reduced
BP
and improved endothelial function, evoking increased nitric oxide release through the
PKC
α/Akt/endothelial nitric oxide synthase pathway and reducing reactive oxygen species production via
NADPH
‐oxidase inhibition. These effects were mediated by synergism of the single compounds of AkP05.

Conclusions

This is the first study reporting positive effects of a nutraceutical combination on the vasculature and exercise tolerance in treated hypertensive patients. Our findings suggest that AkP05 may be used as an adjunct for the improvement of cardiovascular protection and to better control
BP
in uncontrolled hypertension.
A Qumran Cave 4 Fragment with Psalm 41:10–11 (4Q98h = 4QPsy)
Authors: Tigchelaar Eibert
Published: February 2020

PAM 43.680 frag. 46 provides the first textual evidence of a manuscript with Psalm 41 among the Qumran scrolls and offers an additional example of stichometrically arranged psalms with one-colon lines.
Rapid Warming in Summer Wet Bulb Globe Temperature in China with Human-Induced Climate Change
Authors: Li Chao , Sun Ying , Zwiers Francis , Wang Dongqian , Zhang Xuebin , Chen Gang , Wu Hui
Published: February 2020

On the basis of a newly developed observational dataset and a suite of climate model simulations, we evaluate changes in summer mean wet bulb globe temperature (WBGT) in China from 1961 through 2080. We show that summer mean WBGT has increased almost everywhere across China since 1961 as a result of human-induced climate change. Consequently, hot summers as measured by summer mean WBGT are becoming more frequent and more conducive to heat stress. Hot summers like the hottest on record during 1961–2015 in western or eastern China are now expected occur once every 3–4 years. These hot WBGT summers have become more than 140 times as likely in eastern China in the present decade (2010s) as in the 1961–90 baseline period and more than 1000 times as likely in western China. The substantially larger influence in western China is associated with its stronger warming signal, which is likely due to the high Bowen ratio of sensible to latent heat fluxes of dry soils and increases in absorbed solar radiation from the decline in mountain snow cover extent. Observation-constrained projections of future summer mean WBGT under the RCP8.5 emissions scenario indicate that, by the 2040s, almost every summer in China will be at least as hot as the hottest summer in the historical record, and by the 2060s it will be common (on average, every other year) for summers to be as much as 3.0°C hotter than the historical record, pointing to potentially large increases in the likelihood of human heat stress and to a massive adaption challenge.