bluuebunny/crossref_metadata_2025 huggingface dataset:
Noncanonical role for Ku70/80 in the prevention of allergic airway inflammation via maintenance of airway epithelial cell organelle homeostasis
Authors: Rehman Rakhshinda , Vijayakumar Vijay Elakkya , Jaiswal Ashish , Jain Vaibhav , Mukherjee Shravani , Vellarikkal Shamsudheen Karuthedath , Dieffenbach Paul B. , Fredenburgh Laura E. , Prakash Y. S. , Ghosh Balaram , Agrawal Anurag , Mabalirajan Ulaganathan
Published: September 2020

Airway epithelial homeostasis is under constant threat due to continuous exposure to the external environment, and abnormally robust sensitivity to external stimuli is critical to the development of airway diseases, including asthma. Ku is a key nonhomologous end-joining DNA repair protein with diverse cellular functions such as VDJ recombination and telomere length maintenance. Here, we show a novel function of Ku in alleviating features of allergic airway inflammation via the regulation of mitochondrial and endoplasmic reticulum (ER) stress. We first determined that airway epithelial cells derived from both asthmatic lungs and murine asthma models demonstrate increased expression of 8-hydroxy-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage. Ku protein expression was dramatically reduced in the bronchial epithelium of patients with asthma as well as in human bronchial epithelial cells exposed to oxidative stress. Knockdown of Ku70 or Ku80 in naïve mice elicited mitochondrial collapse or ER stress, leading to bronchial epithelial cell apoptosis and spontaneous development of asthma-like features, including airway hyperresponsiveness, airway inflammation, and subepithelial fibrosis. These findings demonstrate an essential noncanonical role for Ku proteins in asthma pathogenesis, likely via maintenance of organelle homeostasis. This novel function of Ku proteins may also be important in other disease processes associated with organelle stress.
Novel roles of immunometabolism and nonmyocyte metabolism in cardiac remodeling and injury
Authors: Mouton Alan J. , Hall John E.
Published: September 2020

Changes in cardiomyocyte metabolism have been heavily implicated in cardiac injury and heart failure (HF). However, there is emerging evidence that metabolism in nonmyocyte populations, including cardiac fibroblasts, immune cells, and endothelial cells, plays an important role in cardiac remodeling and adaptation to injury. Here, we discuss recent advances and insights into nonmyocyte metabolism in the healthy and injured heart. Metabolic switching from mitochondrial oxidative phosphorylation to glycolysis is critical for immune cell (macrophage and T lymphocyte) and fibroblast phenotypic switching in the inflamed and fibrotic heart. On the other hand, cardiac endothelial cells are heavily reliant on glycolytic metabolism, and thus impairments in glycolytic metabolism underlie endothelial cell dysfunction. Finally, we review current and ongoing metabolic therapies for HF and the potential implications for nonmyocyte metabolism.
Exaggerated cortical representation of speech in older listeners: mutual information analysis
Authors: Zan Peng , Presacco Alessandro , Anderson Samira , Simon Jonathan Z.
Published: September 2020

Cortical representations of natural speech are investigated using a novel nonlinear approach based on mutual information. Cortical responses, phase-locked to the speech envelope, show an exaggerated level of mutual information associated with aging, appearing at several distinct latencies (∼50, ∼100, and ∼200 ms). Critically, for older listeners only, the ∼200 ms latency response components are correlated with specific behavioral measures, including behavioral inhibition and speech comprehension.
Toe walking in children with cerebral palsy: a possible functional role for the plantar flexors
Authors: Beyaert C. , Pierret J. , Vasa R. , Paysant J. , Caudron S.
Published: September 2020

Adaptation to walking in negative-heel shoes was similar in typically developing children and children with cerebral palsy: it featured ankle dorsiflexion upon initial contact, even though (in the latter group) the soleus was always spastic in a clinical examination. Hence, in children with cerebral palsy, the early deceleration of ankle dorsiflexion by the plantar flexors (promoted by early flattening of the foot, and regardless of the type of footwear) may have a functional role.
Improving Processing Time for the Location Algorithm of Robots
Authors: Chen Jing , Chen Liwen
Published: September 2020

The paper proposes an algorithm based on the Multi-State Constraint Kalman Filter (MSCKF) algorithm to construct the map for robots special in the poor GPS signal environment. We can calculate the position of the robots with the data collected by inertial measurement unit and the features extracted by the camera with MSCKF algorithm in a tight couple way. The paper focuses on the way of optimizing the position because we adopt it to compute Kalman gain for updating the state of robots. In order to reduce the processing time, we design a novel fast Gauss–Newton MSCKF algorithm to complete the nonlinear optimization. Compared with the performance of conventional MSCKF algorithm, the novel fast-location algorithm can reduce the processing time with the kitti datasets.
Dynamic Analysis of a Tumor-Immune System under Allee Effect
Authors: Zeng Chunmei , Ma Shaojuan
Published: September 2020

In this paper, we develop a definite tumor-immune model considering Allee effect. The deterministic model is studied qualitatively by mathematical analysis method, including the positivity, boundness, and local stability of the solution. In addition, we explore the effect of random factors on the transition of the tumor-immune system from a stable coexistence equilibrium point to a stable tumor-free equilibrium point. Based on the method of stochastic averaging, we obtain the expressions of the steady-state probability density and the mean first-passage time. And we find that the Allee effect has the greatest impact on the number of cells in the system when the Allee threshold value is within a certain range; the intensity of random factors could affect the likelihood of the system crossing from the coexistence equilibrium to the tumor-free equilibrium.
Completeness of b∼Metric Spaces and the Fixed Points of Generalized Multivalued Quasicontractions
Authors: Ali Basit , Abbas Mujahid , Sen Manuel de la
Published: September 2020

In this article, we present a completeness characterization of b∼metric space via existence of fixed points of generalized multivalued quasicontractions. The purpose of this paper is twofold: (a) to establish the existence of fixed points of multivalued quasicontractions in the setup of b∼ metric spaces and (b) to establish completeness of a b∼ metric space which is a topological property in nature with existence of fixed points of generalized multivalued quasicontractions. Further, a comparison of our results with comparable results shows that the results obtained herein improve and unify the existing results in the literature applicable to the case where existing results fail.
Experimental Study on Mechanical Properties of Fly Ash Stabilized with Cement
Authors: Zhou Shengquan , Zhang Yongfei , Zhou Dawei , Wang Weijian , Li Dongwei , Ke Zhaibang
Published: September 2020

Cement‐fly ash mixture has been commonly used for the foundation treatment projects in the fly ash stratum, as it is effective in improving foundation bearing capacity and reducing settlement of stratum. In order to figure out the effect of dynamic and static load on the mechanical properties exhibited by the cement‐fly ash and the reaction mechanism of cement‐fly ash, a combination of the unconfined compressive test, impact test, scanning electron microscopy (SEM), and X‐ray diffraction (XRD) method was adopted in this study to investigate the cement‐fly ash test samples. As demonstrated by the results, the observed growth rate of 0–60 days (d) is higher than that in the later stages and the typical stress‐strain curve can be divided into six sections under the unconfined compressive test. At the gas pressure of 0.2 MPa, the cement‐fly ash samples exhibited obvious plastic properties in early curing time (0–60 d), and brittle failure was observed in the final stage (90 d). It is obvious that the value of dynamic compressive strength (DCS) is higher than that of unconfined compressive strength (UCS). The analysis of XRD has revealed that the hydration products are primarily derived from the hydration reaction of cement in the early stage and the pozzolanic reaction in the late stage. The pores of cement‐fly ash are found to be filled with the hydration products, despite the presence of a mass of pores in the interior.
On Fully Degenerate Daehee Numbers and Polynomials of the Second Kind
Authors: Yun Sang Jo , Park Jin-Woo
Published: September 2020

In a study, Carlitz introduced the degenerate exponential function and applied that function to Bernoulli and Eulerian numbers and degenerate special functions have been studied by many researchers. In this paper, we define the fully degenerate Daehee polynomials of the second kind which are different from other degenerate Daehee polynomials and derive some new and interesting identities and properties of those polynomials.
[Retracted] Results and Lessons Learned on Robotic Assisted Kidney Transplantation
Authors: Musquera Mireia , Peri Lluis , Ajami Tarek , Revuelta Ignacio , Izquierdo Laura , Mercader Claudia , Sierra Alba , Diekmann Fritz , D’Anna Maurizio , Monsalve Concepción , Alcaraz Antonio
Published: September 2020

Introduction. Nowadays, minimally invasive surgery in kidney transplantation is a reality thanks to robotic assistance. In this paper, we describe our experience, how we developed the robotic assisted Kidney transplantation (RAKT) technique, and analyze our results. Material and Methods. This is a retrospective study of all RAKTs performed at our center between July 2015 and March 2020. We describe the donor selection, surgical technique, and analyze the surgical results and complications. A comparison between the first 20 cases and the following ones is performed. Results. During the aforementioned period, 82 living donor RAKTs were performed. The mean age was 47.4 ± 13.4 and 50 (61%) were male. Mean body mass index was 25 ± 4.7 and preemptive in 63.7% of cases. Right kidneys and multiple arteries were seen in 14.6% and 12.2%, respectively. Mean operative and rewarming time was 197 ± 42 and 47 ± 9.6 minutes, respectively. Five cases required conversion to open surgery because of abnormal kidney vascularization. Two patients required embolization for subcapsular and hypogastric artery bleeding without repercussion. Three kidneys were lost, two of them due to acute rejection and one because venous thrombosis. Late complications requiring surgery included one kidney artery stenosis, one ureteral stenosis, two lymphoceles, and three hernia repairs. We noticed a significant reduction in time between the first 20 cases and the following ones from 248.25 ± 38.1 to 189.75 ± 25.3 (p < 0.05). With a mean follow‐up time of 1.8 years (SD 1.3), the mean creatinine was 1.52 (SD 0.7) and RAKT graft survival was 98%. Conclusions. The robotic approach is an attractive, minimally invasive method for kidney transplantation, yielding good results. Further studies are needed to consider it a standard approach.
ARMC5 Primary Bilateral Macronodular Adrenal Hyperplasia Associated with a Meningioma: A Family Report
Authors: Ferreira M. J. , Pedro J. , Salazar D. , Costa C. , Aragão Rodrigues J. , Costa M. M. , Grangeia A. , Castedo J. L. , Carvalho D.
Published: September 2020

Primary bilateral adrenal macronodular hyperplasia is characterized by functioning adrenal macronodules and variable cortisol secretion. Familial clustering suggests a genetic cause that has been confirmed with the identification of some genetic mutations, including inactivating germline mutations, in armadillo repeat containing 5 (ARMC5) gene. The identification of the pathogenic variant enables the physician to identify and treat these patients earlier and more effectively. It has also been noticed that patients with germline causative variants show a different clinical spectrum, presenting specific clinical characteristics, as the association with the presence of meningiomas.
A Spatial Interpolation of Meteorological Parameters considering Geographic Semantics
Authors: Wu Wenjun , Gan Ruijie , Li Junli , Cao Xiu , Ye Xinxin , Zhang Jie , Qu Hongjiao
Published: September 2020

Spatial interpolation of meteorological parameters, closely related to the earth surface, plays important roles in climatological study. However, most of traditional spatial interpolation methods ignore the geographic semantics of interpolation sample points in practical application. This paper attempts to propose an improved inverse-distance weighting interpolation algorithm considering geographic semantics (S-IDW), which adds geographic semantic similarity to the traditional IDW formula and adjusts weight coefficient. In the interpolation process, the geographic semantic differences between sample points and estimation points are considered comprehensively. In this study, 3 groups of land surface temperature data from 2 different areas were selected for experiments, and several commonly used spatial interpolation methods were compared. Experimental results indicated that S-IDW outperformed IDW and several existing spatial interpolation methods, but there were also some abnormal value and interpolation outliers. This method provides a new insight toward the estimation accuracy, data missing, and error correction of spatial attributes related to meteorological parameters.
Research on Energy-Saving Design of Rural Building Wall in Qinba Mountains Based on Uniform Radiation Field
Authors: Zhao Qin , Fan Xiaona , Wang Qing , Sang Guochen , Zhu Yiyun
Published: September 2020

How to create a healthy and comfortable indoor environment without causing a substantial increase in energy consumption has become a strategic problem that the development of all countries must face and solve. According to the climatic conditions of Qinba Mountains in China, combined with the characteristics of local rural residential buildings and residents’ living habits, the field survey and theoretical analysis were used to study the thermal environment status and the heating energy consumption condition of local rural residential buildings. The thermal design method of walls for the local rural energy-saving buildings based on the indoor uniform radiation field was explored by using the outdoor comprehensive temperature function expressed by the fourth-order harmonic Fourier series as the boundary condition of the wall thermal analysis. ANSYS CFX was adopted to study the suitability of the energy-saving wall structure designed by the above method. The results show that the indoor thermal environment of local rural residential buildings in winter is not ideal and the heating energy consumption is high, but this area has the geographical advantage to develop solar energy buildings. It is proposed that the indoor thermal comfort temperature of local rural residential buildings in winter should not be lower than 14°C. When the internal surface temperature of the external walls in different orientations are equally based on the design principle of uniform radiation field, the heat transfer coefficient of the east wall, the west wall, and the north wall of the local rural residential buildings is 1.13 times, 1.06 times, and 1.14 times of the south wall heat transfer coefficient, respectively. The energy-saving structural wall with KPI porous brick as the main material and the south wall heat transfer coefficient of 0.9 W/(m2·K) is the most suitable energy-saving wall for local rural residential buildings.
A Green Demand-Responsive Airport Shuttle Service Problem with Time-Varying Speeds
Authors: Wei Ming , Jing Binbin , Yin Jian , Zang Yang
Published: September 2020

This study proposes a multiobjective mixed integer linear programming (MOMILP) model for a demand-responsive airport shuttle service. The approach aims to assign a set of alternative fuel vehicles (AFVs) located at different depots to visit each demand point within the specified time and transport all of them to the airport. The proposed model effectively captures the interactions between path selection and environmental protection. Moreover, users with flexible pick-up time windows, the time-varying speed of vehicles on the road network, and the limited fuel for the route duration are also fully considered in this model. The work aims at simultaneously minimizing the operating cost, vehicle fuel consumption, and CO2 emissions. Since this task is an NP-hard problem, a heuristic-based nondominated sorting genetic algorithm (NSGA-II) is also presented to find Pareto optimal solutions in a reasonable amount of time. Finally, a real-world example is provided to illustrate the proposed methodology. The results demonstrate that the model not only selects an optimal depot for each AFV but also determines its route and timetable plan. A sensitivity analysis is also given to assess the effect of early/late arrival penalty weights and the number of AFVs on the model performance, and the difference in quality between the proposed and traditional models is compared.
Vascular Changes in Cancer Treatment—Seeing Is Believing
Authors: Tomaszewski Michal R.
Published: September 2020

Understanding the effects of novel cancer drugs on the tumor microenvironment will be crucial for their successful use in patients. In this issue of Cancer Research, Ghosh and colleagues discuss the effect of two promising heme-targeting agents on the vascular network in mouse models of lung cancer, utilizing emerging optoacoustic imaging approaches. The findings demonstrating significant, dynamic modulation of tumor hypoxia with the heme-targeting drug treatments create important opportunities for image-guided combination therapy.

See related article by Ghosh et al., p. 3542
An RNA-Binding Protein, Hu-antigen R, in Pancreatic Cancer Epithelial to Mesenchymal Transition, Metastasis, and Cancer Stem Cells
Authors: Dong Ruochen , Chen Ping , Polireddy Kishore , Wu Xiaoqing , Wang Tao , Ramesh Remya , Dixon Dan A. , Xu Liang , Aubé Jeffrey , Chen Qi
Published: September 2020

Pancreatic cancer has poor prognosis and treatment outcomes due to its highly metastatic nature and resistance to current treatments. The RNA-binding protein (RBP) Hu-antigen R (HuR) is a central player in posttranscriptional regulation of cancer-related gene expression, and contributes to tumorigenesis, tumor growth, metastasis, and drug resistance. HuR has been suggested to regulate pancreatic cancer epithelial-to-mesenchymal transition (EMT), but the mechanism was not well understood. Here, we further elucidated the role HuR plays in pancreatic cancer cell EMT, and developed a novel inhibitor specifically interrupting HuR–RNA binding. The data showed that HuR binds to the 3′-UTR of the mRNA of the transcription factor Snail, resulting in stabilization of Snail mRNA and enhanced Snail protein expression, thus promoted EMT, metastasis, and formation of stem-like cancer cells (CSC) in pancreatic cancer cells. siRNA silencing or CRISPR/Cas9 gene deletion of HuR inhibited pancreatic cancer cell EMT, migration, invasion, and inhibited CSCs. HuR knockout cells had dampened tumorigenicity in immunocompromised mice. A novel compound KH-3 interrupted HuR–RNA binding, and KH-3 inhibited pancreatic cancer cell viability, EMT, migration/invasion in vitro. KH-3 showed HuR-dependent activity and inhibited HuR-positive tumor growth and metastasis in vivo.
Therapeutic Targeting of Mitochondrial One-Carbon Metabolism in Cancer
Authors: Dekhne Aamod S. , Hou Zhanjun , Gangjee Aleem , Matherly Larry H.
Published: September 2020

One-carbon (1C) metabolism encompasses folate-mediated 1C transfer reactions and related processes, including nucleotide and amino acid biosynthesis, antioxidant regeneration, and epigenetic regulation. 1C pathways are compartmentalized in the cytosol, mitochondria, and nucleus. 1C metabolism in the cytosol has been an important therapeutic target for cancer since the inception of modern chemotherapy, and “antifolates” targeting cytosolic 1C pathways continue to be a mainstay of the chemotherapy armamentarium for cancer. Recent insights into the complexities of 1C metabolism in cancer cells, including the critical role of the mitochondrial 1C pathway as a source of 1C units, glycine, reducing equivalents, and ATP, have spurred the discovery of novel compounds that target these reactions, with particular focus on 5,10-methylene tetrahydrofolate dehydrogenase 2 and serine hydroxymethyltransferase 2. In this review, we discuss key aspects of 1C metabolism, with emphasis on the importance of mitochondrial 1C metabolism to metabolic homeostasis, its relationship with the oncogenic phenotype, and its therapeutic potential for cancer.
Tumor-Infiltrating Regulatory T-cell Accumulation in the Tumor Microenvironment Is Mediated by IL33/ST2 Signaling
Authors: Son Jimin , Cho Jae-Won , Park Hyo Jin , Moon Jihyun , Park Seyeon , Lee Hoyoung , Lee Jeewon , Kim Gamin , Park Su-Myeong , Lira Sergio A. , Mckenzie Andrew N. , Kim Hye Young , Choi Cheol Yong , Lim Yong Taik , Park Seong Yong , Kim Hye Ryun , Park Su-Hyung , Shin Eui-Cheol , Lee Insuk , Ha Sang-Jun
Published: September 2020

Regulatory T cells (Treg) are enriched in the tumor microenvironment (TME) and suppress antitumor immunity; however, the molecular mechanism underlying the accumulation of Tregs in the TME is poorly understood. In various tumor models, tumor-infiltrating Tregs were highly enriched in the TME and had significantly higher expression of immune checkpoint molecules. To characterize tumor-infiltrating Tregs, we performed bulk RNA sequencing (RNA-seq) and found that proliferation-related genes, immune suppression–related genes, and cytokine/chemokine receptor genes were upregulated in tumor-infiltrating Tregs compared with tumor-infiltrating CD4+Foxp3− conventional T cells or splenic Tregs from the same tumor-bearing mice. Single-cell RNA-seq and T-cell receptor sequencing also revealed active proliferation of tumor infiltrating Tregs by clonal expansion. One of these genes, ST2, an IL33 receptor, was identified as a potential factor driving Treg accumulation in the TME. Indeed, IL33-directed ST2 signaling induced the preferential proliferation of tumor-infiltrating Tregs and enhanced tumor progression, whereas genetic deletion of ST2 in Tregs limited their TME accumulation and delayed tumor growth. These data demonstrated the IL33/ST2 axis in Tregs as one of the critical pathways for the preferential accumulation of Tregs in the TME and suggests that the IL33/ST2 axis may be a potential therapeutic target for cancer immunotherapy.
Adenomyomatosis of the Common Bile Duct and Ampulla of Vater
Authors: Gouveia Catarina , Fidalgo Catarina , Loureiro Rui , Oliveira Helena , Maio Rui , Cravo Marília
Published: September 2020

Adenomyomatosis is a rare benign lesion that has been observed in different sites throughout the gastrointestinal tract, most frequently in the gallbladder. Few cases have been described in the stomach, small bowel, bile ducts, and ampullary region. Adenomyomas of the vaterian system (ampulla and common bile duct) have important clinical consequences, since the majority of these lesions present with biliary tract obstruction and mimic malignant behavior. As a consequence, considering the diagnostic difficulty of these lesions, patients are often treated with extensive surgery (pancreaticoduodenectomy). We report 2 cases of adenomyomatosis: one of the ampulla of Vater and the other of the common bile duct, as well as a review of reported cases in the literature. Both of our patients presented with epigastralgia and had laboratory or endoscopic evidence of biliary obstruction. Both patients underwent endoscopic ultrasound, one of them with fine-needle aspiration; however, it was not possible to exclude the possibility of cancer. The diagnosis of adenomyoma was only confirmed by the surgical specimen after pancreaticoduodenectomy.
Murine Skin Carcinogenesis and the Role of Immune System Dysregulation in the Tumorigenicity of 2-Ethylhexyl Acrylate
Authors: Elmets Craig A. , Yusuf Nabiha
Published: September 2020

Some chemicals act as human carcinogens in various organ systems including the skin. Mice have been an ideal model to study a wide variety of chemical carcinogens because the pathogenesis in that species often mirrors that in humans. However, different mouse strains vary in their susceptibility to these agents. Thus, reliance on a single strain may lead to inaccurate findings. 2-Ethylhexyl acrylate (2-EHA) is an acrylate used as a co-monomer in the production of polymer resins for adhesives, latex paints, cross-linking agents, finishes for textiles and leather, and paper coatings. Monomer exposure may occur in occupational settings where it is produced or used; the only exposure that may occur to consumers or construction personnel is trace amounts in the final polymer product. There are no reports of cancer in humans caused by exposure to 2-EHA. However, 2-EHA has been reported to cause cancer in one strain of mice. This is an important issue since recommendations about its safety in humans depend, in part, on information derived from animal studies. We reviewed the literature on the preclinical effects of acrylates on skin carcinogenesis in C3H/HeJ mice, which can be criticized because of peculiarities in the immunological composition of that strain, the lack of rigorous histopathologic characterization of tumors that developed, the high doses of 2-EHA that were used for evaluation, and the lack of reproducibility in a second strain of mice. The C3H/HeJ mouse model is not ideal as it has a mutation in Toll-like receptor 4 (TLR4) that impairs its innate and adaptive immune responses. Inconsistencies in the histological evaluation of tumors induced in C3H/HeJ mice provide further evidence that the tumorigenic effect of 2-EHA was strain specific, a result of chronic inflammation during the promotion stage and/or a skewed immune response caused by the TLR4 mutation. In conclusion, 2-EHA has not convincingly been demonstrated to have skin carcinogenic activity to date. More relevant mouse models that mimic human squamous cell carcinoma, basal cell carcinoma, and melanoma with amounts that do not exceed a maximum tolerated dose are needed to assess the carcinogenic effects of 2-EHA.
A New Pathogenic Variant in the TRIOBP Associated with Profound Deafness Is Remediable with Cochlear Implantation
Authors: Tekin Ahmet M. , de Ceulaer Geert , Govaerts Paul , Bayazit Yıldırım , Wuyts Wim , Van de Heyning Paul , Topsakal Vedat
Published: September 2020

Background and Objectives: A rare type of nonsyndromic autosomal recessive hereditary hearing loss is caused by pathogenic mutations in the TRIOBP gene mostly involving exons 6 and 7. These mutations cause hearing loss originating from dysfunction of sensory inner ear hair cells. Of all the affected siblings, 2 brothers and 1 sister, part of an Afghan family, were referred to our clinic for diagnostic workup and candidacy selection for cochlear implantation (CI). Methods: Molecular analysis showed a homozygous c.1342C > T p. (Arg448*) pathogenic variant in exon 7 of the TRIOBP gene (reference sequence NM_001039141.2) in all 3 affected siblings. Clinical audiometry demonstrated profound sensorineural hearing loss in all 3 affected siblings (2 males and 1 female), and they were implanted unilaterally. Results: One month after activation, the pure-tone averages with the CI processor were between 30 and 23 dBHL. Ten months after the first activation of the implant, open-set speech audiometry test could be performed for the first time in the 2 younger CI recipients (S5 and S9), and they could identify up to a maximum 77% phonemes correctly. The oldest brother (S12) could not yet perform open-set speech audiometry at that moment. Conclusions: Implant outcomes are better with normal inner ear anatomy in general. The earlier congenital patients are implanted, the better their outcomes. Here, we demonstrate both statements are true in a homozygous c.1342C > T p. (Arg448*) pathogenic variant in the TRIOBP gene in all 3 affected siblings.
Effect of Cochlear Implantation on Hearing Fluctuation in Patients with Biallelic SLC26A4 Variants
Authors: Na Gina , Lee Jeon Mi , Lee Hyun Jin , Jeong Yeonsu , Jung Jinsei , Choi Jae Young
Published: September 2020

Introduction: Fluctuating hearing loss is a distinctive feature caused by SLC26A4 variants. We investigated whether cochlear implantation had protective or deleterious effect on hearing fluctuation in patients with biallelic SLC26A4 variants. Methods: Patients with biallelic SLC26A4 variants (N = 16; age = 10.24 ± 9.20 years) who had unilateral cochlear implantation and consecutive postsurgical, bilateral pure-tone audiograms more than 3 times were selected. We retrospectively reviewed the patients’ medical records from 2008 to 2019 obtained from a tertiary medical center and used the auditory threshold change (Shift) over time as a marker of hearing fluctuation. Fluctuation events were counted, and the Shift of the implanted and contralateral ears was compared using logistic regression with a generalized estimating equation and linear mixed model. A total of 178 values were included. Results: The odds of fluctuating hearing frequency were 11.185-fold higher in the unimplanted ears than in the implanted ears postoperatively (p = 0.001). The extent of fluctuation at 250 and 500 Hz was also significantly lower in the implanted ears than in the unimplanted ears after adjusting for every other effect (p = 0.003 and p < 0.001, respectively). Notably, higher residual hearing was rather associated with lesser fluctuation in frequency and the extent of fluctuation at 500 Hz, indicating residual hearing function is not the positive predictor for hearing fluctuation. Conclusion: In patients with biallelic SLC26A4 variants, cochlear implantation may reduce the frequency and extent of hearing fluctuations.
Liraglutide Improves the Kidney Function in a Murine Model of Chronic Kidney Disease
Authors: Ougaard Maria E. , Sembach Frederikke E. , Jensen Henrik E. , Pyke Charles , Knudsen Lotte B. , Kvist Peter H.
Published: September 2020

Background: Chronic kidney disease (CKD) is a global health burden, and the current treatment options only slow down the disease progression. GLP-1 receptor agonists (GLP-1 RA) have shown a renal protective effect in models of CKD; however, the mechanism behind the beneficial effect is not understood. In this study, we investigate the effect of the GLP-1 RA liraglutide in the nephrotoxic serum nephritis (NTN) CKD model. Moreover, we compare the gene expression pattern of liraglutide-treated mice to the gene expression pattern of mice treated with the angiotensin converting enzyme inhibitor, enalapril. Methods: The effect of liraglutide was tested in the NTN model by evaluating the glomerular filtration rate (GFR), albuminuria, mesangial expansion, renal fibrosis, and renal inflammation. Furthermore, the regulation of selected genes involved in CKD and in glomerular, cortical tubulointerstitial, and whole kidney structures was analyzed using a gene expression array on samples following laser capture microdissection. Results: Treatment with liraglutide improved CKD hallmarks including GFR, albuminuria, mesangial expansion, renal inflammation, and renal fibrosis. The gene expression revealed that both liraglutide and enalapril reversed the regulation of several fibrosis and inflammation associated genes, which are also regulated in human CKD patients. Furthermore, liraglutide and enalapril both regulated genes in the kidney involved in blood pressure control. Conclusions: Treatment with liraglutide improved the kidney function and diminished renal lesions in NTN-induced mice. Both liraglutide and enalapril reversed the regulation of genes involved in CKD and regulated genes involved in blood pressure control.
Transcription Factor 7-Like-2 (TCF7L2) rs7903146 (C/T) Polymorphism in Patients with Type 2 Diabetes Mellitus
Authors: Bahaaeldin Ahmed Mohamed , Seif Arig Aly , Hamed Amira Ibrahim , Kabiel Walaa Ahmed Yousry
Published: September 2020

Introduction: Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by the incapability of pancreas to increase insulin secretion to compensate for insulin resistance in the peripheral tissues. T2DM is a multifactorial disease including several environmental factors with the presence of genetic predisposition. The transcription factor 7-like-2 gene (TCF7L2) rs7903146 (C/T) polymorphism is one of the most susceptible genes to T2DM discovered to date, with contribution to the disease through the Wnt/β-catenin signaling pathway affecting pancreatic islet development, expression of several genes involved in insulin granules exocytosis, and the incretin glucagon-like peptide 1 (GLP-1) gene. Then, TCF7L2 gene seems to affect diabetes susceptibility through B-cell dysfunction that is why we studied its association with T2DM in particular. Objectives: To investigate the potential association of the transcription factor 7-like-2 (TCF7L2) rs7903146 (C/T) gene polymorphism in patients with T2DM. Methods: A case-control study conducted on 70 T2DM patients recruited from the endocrinology clinic at Ain Shams University Hospitals, and 30 non-diabetic healthy controls age- and sex-matched with the patients. All subjects underwent full history taking; thorough clinical examination; routine laboratory investigations including hemoglobin A1c, total cholesterol, triglycerides, high-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol; and determination of TCF7L2 gene polymorphism by qRT-PCR. Results: The minor T allele of the rs7903146(C/T) SNP was associated with high risk of development of T2DM with an OR of 1.35 (95% CI: 0.68–2.6) and the heterozygous genotype (CT) with an OR 1.16 (95% CI: 0.49–2.7); however, they were statistically insignificant (p value >0.05). Conclusion: Our study did not confirm the presence of significant association between the TCF7L2 rs7903146(C/T) polymorphism and T2DM; however, it pointed out the possibility of presence of high risk of development of T2DM in patients with TT genotype. Further studies with higher sample size are needed to clarify the association.
Cerebral Venous Thrombosis: A Comprehensive Review
Authors: Idiculla Pretty Sara , Gurala Dhineshreddy , Palanisamy Manikandan , Vijayakumar Rajendran , Dhandapani Sindhu , Nagarajan Elanagan
Published: September 2020

Background: Cerebral sinus venous thrombosis (CSVT) is a relatively rare, potentially fatal neurological condition that can be frequently overlooked due to the vague nature of its clinical and radiological presentation. A literature search on PubMed using the keyword “Cerebral sinus venous thrombosis” was performed. We searched for the epidemiology, risk factors, pathophysiology, clinical features, diagnosis, and treatment of CSVT. All full-text articles in the last 10 years, in adults (>18 years), and the English language were included. We aim to give a comprehensive review of CSVT, with a primary focus on the management of the disease. Summary: The literature search revealed 404 articles that met our criteria. CSVT is a relatively rare condition that accounts for approximately 1% of all forms of stroke. They can be subdivided into acute, subacute, and chronic forms based on the time of onset of clinical symptoms. It is a multifactorial disease, and the major forms of clinical presentation include isolated intracranial hypertension syndrome, focal neurological deficits, and cavernous sinus syndrome. MRI with magnetic resonance venogram (MRV) is considered the gold standard for diagnosis. Anticoagulation with heparin or low-molecular-weight heparin is the mainstay of treatment. Endovascular management is indicated for those cases with severe symptoms or worsening of symptoms despite anticoagulation therapy. Favorable outcomes have been reported in patients who receive early diagnosis and treatment. Conclusion: CSVT is a potentially fatal neurological condition that is often under-diagnosed due to its nonspecific presentation. Timely diagnosis and treatment can reduce morbidity and mortality, remarkably improving the outcome in affected individuals.
Intrauterine Growth Restriction and Hypertrophic Cardiomyopathy as Prenatal Ultrasound Findings in a Case of Leprechaunism
Authors: Perge Kevin , Massoud Mona , Gauthier-Moulinier Hélène , Lascols Olivier , Pangaud Nicolas , Villanueva Carine , Pons Linda
Published: September 2020

Donohue syndrome (leprechaunism; OMIM *246200) is a rare and often lethal autosomal recessive disease caused by mutations in the INSR gene. We report the case of a 29-year-old pregnant woman, primigravida, who was referred at 33 weeks of gestation for severe intrauterine growth restriction (IUGR). Ultrasound examination found severe IUGR associated with an obstructive hypertrophic cardiomyopathy (HCM), confirmed postnatally. The newborn’s blood glucose level fluctuated from fasting hypoglycemia to postprandial hyperglycemia. The infant was found to be homozygous for a novel missense pathogenic variant, c.632C>T (p.T211l), in exon 2 of the INSR gene, predicted to result in an abnormal insulin receptor. To our knowledge, this is the first report of leprechaunism being revealed by IUGR and HCM during the prenatal period. Clinicians should keep in mind that the association of these prenatal signs could indicate leprechaunism and specific early neonatal management could be proposed, in particular with recombinant human insulin-like growth factor-I.
A Prospective Study on the Usefulness of Initial Voriconazole Dose Adjustment Based on CYP2C19 Gene Polymorphism Analysis
Authors: Tanaka Ryota , Fujioka Takashi , Suzuki Yosuke , Iwao Motoshi , Itoh Hiroki
Published: September 2020

Genetic polymorphism exists for CYP2C19, a dominant metabolic enzyme of voriconazole (VRCZ), and VRCZ pharmacokinetics has been shown to fluctuate according to the CYP2C19 phenotype. Although dosages for different phenotypes have been recommended in various retrospective studies, few reports have adjusted the initial VRCZ dose based on CYP2C19 phenotype determined prior to administration. In this study, we prospectively evaluated the usefulness of CYP2C19 polymorphism analysis in adjusting the initial VRCZ maintenance dose. The study enrolled 19 patients who underwent analysis of CYP2C19 polymorphism prior to VRCZ administration. Subjects were classified into 3 phenotype subgroups: extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM). The initial VRCZ maintenance doses given twice daily were proposed as follows: approximately 8, 6, and 4 mg/kg/day for EM, IM and PM, respectively, according to previous reports. In EM, the initial maintenance dose was 8.0 ± 0.5 mg/kg/day, and trough level was 6.6 ± 2.4 μg/mL. By contrast, the initial maintenance doses in IM and PM were 5.5 ± 0.7 and 4.1 ± 0.3 mg/kg/day, and the initial trough concentrations were 2.9 ± 1.2 and 2.6 ± 0.4 μg/mL, respectively. The attainment rate of target trough concentration of 1–6 μg/mL was 50% in EM, and was 100% in IM and PM. Determining the initial dose of VRCZ only by phenotype based on CYP2C19 gene polymorphism was found to be challenging. However, decreasing the initial maintenance dose in IM and PM may be important for adjusting the initial trough level to target range.
First Trimester Screening for Common Trisomies and Microdeletion 22q11.2 Syndrome Using Cell-Free DNA: A Prospective Clinical Study
Authors: Kagan Karl Oliver , Hoopmann Markus , Pfaff Theresa , Prodan Natalia , Wagner Philipp , Schmid Maximilian , Dufke Andreas , Mau-Holzmann Ulrike , Brucker Sara , Marcato Livia , Malvestiti Barbara , Grati Francesca Romana
Published: September 2020

Objectives: The aims of the study were to assess the false-positive and uninformative test rate with first trimester cell-free DNA (cfDNA) screening for common trisomies and microdeletion 22q11.2 (22q11.2DS) and to examine women’s attitudes toward such an approach. Methods: This is a prospective study at the Prenatal Medicine Department of the University of Tübingen, Germany, at 11–13 weeks. In all pregnancies, a detailed ultrasound examination was carried out, followed by a cfDNA analysis for common trisomies and 22q11.2DS. In cases where the cfDNA analysis indicated 22q11.2DS, invasive prenatal diagnostic testing and parental testing were performed. After delivery, a detailed neonatal clinical examination was carried out including further genetic testing. Prior to counselling about the study, we asked the pregnant women who were potentially eligible for the study to anonymously report on their knowledge about 22q11.2DS. Results: A total of 1,127 pregnancies were included in the final analysis of the study. The first cfDNA test was uninformative in 15 (1.33%) pregnancies. In 10 (0.89%) cases, the test remained uninformative, even after the second blood sample. There were 3 (0.27%) cases with a positive cfDNA test for 22q11.2DS. In all, 983 women returned the anonymous questionnaire prior to study participation. Only 80 (8.1%) women responded that they felt familiar or very familiar with 22q11.2DS. Conclusion: The addition of 22q11.2DS in first trimester cfDNA screening for common trisomies is feasible. The uninformative test rate for common trisomies and 22q11.2DS is 0.9%, and the false-positive rate for 22q11.2DS is 0.3%. Awareness and education around 22q11.2DS should be improved.
The Genetics of Circulating Resistin Level, A Biomarker for Cardiovascular Diseases, Is Informed by Mendelian Randomization and the Unique Characteristics of African Genomes
Authors: Meeks Karlijn A.C. , Doumatey Ayo P. , Bentley Amy R. , Gouveia Mateus H. , Chen Guanjie , Zhou Jie , Lei Lin , Adeyemo Adebowale A. , Rotimi Charles N.
Published: September 2020

Background- Resistin, a protein linked with inflammation and cardiometabolic diseases, is one of few proteins for which GWAS consistently report variants within and near the coding gene (RETN). Here, we took advantage of the reduced linkage disequilibrium in African populations to infer genetic causality for circulating resistin levels by performing GWAS, whole-exome analysis, fine-mapping, Mendelian randomization and transcriptomic data analyses.

Methods- GWAS and fine-mapping analyses for resistin were performed in 5621 African ancestry individuals, including 3754 continental Africans (AF) and 1867 African Americans (AA). Causal variants identified were subsequently used as an instrumental variable in Mendelian randomization analyses for homeostatic modelling (HOMA) derived insulin resistance index, BMI and type 2 diabetes.

Results- The lead variant (rs3219175, in the promoter region ofRETN) for the single locus detected was the same for AF (P-value 5.0×10-111) and for AA (9.5×10-38), respectively explaining 12.1% and 8.5% of variance in circulating resistin. Fine-mapping analyses and functional annotation revealed this variant as likely causal affecting circulating resistin levels as acis-eQTL increasingRETNexpression. Additional variants regulating resistin levels were upstream ofRETNwith genesPCP2,STXBP2andXAB2showing the strongest association using integrative analysis of GWAS with transcriptomic data. Mendelian randomization analyses did not provide evidence for resistin increasing insulin resistance, BMI or type 2 diabetes risk in African-ancestry populations.

Conclusions- Taking advantage of the fine-mapping resolution power of African genomes, we identified a single variant (rs3219175) as the likely causal variant responsible for most of the variability in circulating resistin levels. In contrast to findings in some other ancestry populations, we showed that resistin does not seem to increase insulin resistance and related cardiometabolic traits in African-ancestry populations.
Clinical Characteristics and Outcomes From Percutaneous Coronary Intervention of Last Remaining Coronary Artery
Authors: Shoaib Ahmad , Rashid Muhammad , Kontopantelis Evangelos , Sharp Andrew , Fahy Eoin F. , Nolan James , Townend John , Ludman Peter , Ratib Karim , Azam Ziyad A. , Ahmad Ayesha , McEntegart Margaret , Mohamed Mohamed , Kinnaird Tim , Mamas Mamas A. ,   on behalf of the British Cardiovascular Intervention Society (BCIS) and the National Institute for Cardiovascular Outcomes Research (NICOR)
Published: September 2020

Background:

Patients with complex high-risk coronary anatomy, such as those with a last remaining patent vessel (LRPV), are increasingly revascularized with percutaneous coronary intervention (PCI) in contemporary practice. There are limited data on the outcomes of these high-risk procedures.

Methods:

We analyzed a large longitudinal PCI cohort (2007–2014, n=501 841) from the British Cardiovascular Intervention Society database. Clinical, demographic, procedural, and outcome data were analyzed by dividing patients into 2 groups; LRPV group (n=2432) and all other PCI groups (n=506 691).

Results:

Patients in the LRPV PCI group were older, had more comorbidities, and higher prevalence of moderate-severe left ventricular systolic dysfunction. Mortality was higher in the LRPV PCI group during hospital admission (12 % versus 1.5 %,
P
<0.001), at 30 days (15% versus 2%,
P
<0.001), and at one-year (24% versus 5%,
P
<0.001). In a propensity score matching analysis the adjusted risk of mortality during index admission (odds ratio, 2.05 [95% CI, 1.65–2.44],
P
<0.001), at 30 days (odds ratio, 2.13 [95% CI, 1.78–2.5],
P
<0.001), at 1 year (odds ratio, 1.81 [95% CI, 1.59–2.03],
P
<0.001), and in-hospital major adverse cardiovascular events (odds ratio, 1.8 [95% CI, 1.42–2.19],
P
<0.001) were higher in LRPV PCI group as compared to control group. In sensitivity analyses, similar clinical outcomes were observed irrespective of which major epicardial coronary artery was treated.

Conclusions:

In this contemporary cohort, patients who had PCI to their LRPV had a higher-risk profile and more adverse clinical outcomes, irrespective of the vessel treated.