bluuebunny/crossref_metadata_2025 huggingface dataset:
Estrogen replacement enhances insulin-induced AS160 activation and improves insulin sensitivity in ovariectomized rats
Authors: Kawakami Mizuho , Yokota-Nakagi Naoko , Uji Masami , Yoshida Ken-ichi , Tazumi Shoko , Takamata Akira , Uchida Yuki , Morimoto Keiko
Published: September 2018

Menopause predisposes women to impaired glucose metabolism, but the role of estrogen remains unclear. In this study, we examined the effects of chronic estrogen replacement on whole body insulin sensitivity and insulin signaling in ovariectomized rats. Female Wistar rats aged 9 wk were ovariectomized under anesthesia. After 4 wk, pellets containing either 17β-estradiol (E2) or placebo (Pla) were subcutaneously implanted in the rats. After 4 wk of treatment, the intra-abdominal fat accumulation was greater in the Pla group than that in the E2 group. Hyperinsulinemic-euglycemic clamp analysis and intravenous glucose tolerance test revealed that insulin sensitivity was significantly lower in the Pla group than in the E2 group. In addition, Western blotting showed that in vivo insulin stimulation increased protein kinase B (Akt) phosphorylation to a similar degree in the gastrocnemius and liver of both groups, but phosphorylated Akt2 Ser474 was enhanced in the muscle of the E2 group compared with the Pla group. Moreover, insulin-stimulated phosphorylation of Akt substrate of 160 kDa (AS160) Thr642 was observed only in the E2 group, resulting in the difference between the two groups. Additionally, AS160 protein and mRNA levels were higher in muscle of the E2 group than the Pla group. In contrast, E2 replacement had no effect on glucose transporter 4 protein levels in muscle and glycogen synthase kinase-3β in muscle and liver. These results suggest that estrogen replacement improves insulin sensitivity by activating the Akt2/AS160 pathway in the insulin-stimulated muscle of ovariectomized rats.
Privacy-Preserving Sorting Algorithms Based on Logistic Map for Clouds
Authors: Dai Hua , Ren Hui , Chen Zhiye , Yang Geng , Yi Xun
Published: September 2018

Outsourcing data in clouds is adopted by more and more companies and individuals due to the profits from data sharing and parallel, elastic, and on-demand computing. However, it forces data owners to lose control of their own data, which causes privacy-preserving problems on sensitive data. Sorting is a common operation in many areas, such as machine learning, service recommendation, and data query. It is a challenge to implement privacy-preserving sorting over encrypted data without leaking privacy of sensitive data. In this paper, we propose privacy-preserving sorting algorithms which are on the basis of the logistic map. Secure comparable codes are constructed by logistic map functions, which can be utilized to compare the corresponding encrypted data items even without knowing their plaintext values. Data owners firstly encrypt their data and generate the corresponding comparable codes and then outsource them to clouds. Cloud servers are capable of sorting the outsourced encrypted data in accordance with their corresponding comparable codes by the proposed privacy-preserving sorting algorithms. Security analysis and experimental results show that the proposed algorithms can protect data privacy, while providing efficient sorting on encrypted data.
Tips and Tricks for Validation of Quality Control Analytical Methods in Good Manufacturing Practice Mesenchymal Stromal Cell Production
Authors: Viganò Mariele , Budelli Silvia , Lavazza Cristiana , Montemurro Tiziana , Montelatici Elisa , de Cesare Stefania , Lazzari Lorenza , Orlandi Anna Rosa , Lunghi Giovanna , Giordano Rosaria
Published: September 2018

Mesenchymal stromal cells (MSC) for cellular therapy in European Union are classified as advanced therapy medicinal products (ATMPs), and their production must fulfill the requirements of Good Manufacturing Practice (GMP) rules. Despite their classification as medicinal products is already well recognized, there is still a lack of information and indications to validate methods and to adapt the noncompendial and compendial methods to these peculiar biological products with intrinsic characteristics that differentiate them from classic synthetic or biologic drugs. In the present paper, we present the results of the validation studies performed in the context of MSC development as ATMPs for clinical experimental use. Specifically, we describe the validation policies followed for sterility testing, endotoxins, adventitious viruses, cell count, and immunophenotyping. Our work demonstrates that it is possible to fully validate analytical methods also for ATMPs and that a risk-based approach can fill the gap between the prescription of the available guidelines shaped on traditional medicinal products and the peculiar characteristics of these novel and extremely promising new drugs.
Successful Treatment of Olecranon Bursitis Caused byTrueperella bernardiae: Importance of Environmental Exposure and Pathogen Identification
Authors: Gowe Ivan , Parsons Christopher , Best Michael , Parsons Eveline , Prechter Scott , Vickery Stephen
Published: September 2018

A livestock farmer with a history of arthropathy presented with unilateral olecranon bursal swelling and tenderness. Multiple wound and intraoperative cultures revealed growth ofTrueperella bernardiae, a Gram-positive coccobacillus, with symptom resolution following appropriate antimicrobial therapy. To our knowledge, this is the first case report of olecranon bursitis caused by this organism. Coryneform bacteria are often regarded as contaminants in clinical cultures, but advanced techniques for species identification may reveal expanded pathogenic potential of individual species likeT. bernardiaeand elucidate epidemiologic clues for osteoarticular infections in these cases.
Usefulness of Magnetoinertial Wearable Devices in Neurorehabilitation of Children with Cerebral Palsy
Authors: Iosa Marco , de Sanctis Manuela , Summa Aurora , Bergamini Elena , Morelli Daniela , Vannozzi Giuseppe
Published: September 2018

Background. Despite the increasing use of wearable magnetoinertial measurement units (MIMUs) for gait analysis, the efficacy of MIMU-based assessment for planning rehabilitation has not been adequately documented yet. Methods. The usefulness of a MIMU-based assessment was evaluated comparing the data acquired by three MIMUs located at the pelvis, sternum, and head levels in 12 children with cerebral palsy (CP, age: 2–9 years) and 12 age-matched children with typical development (TD). Gait stability was quantified in terms of acceleration attenuation coefficients from pelvis to head, pelvis to sternum, and sternum to head. Children with CP were randomly divided in two groups: in the first group (CPI), MIMU-based parameters were used by therapists for planning patient-tailored rehabilitation programs, whereas in the second group (CPB), therapists were blind to the MIMU-based assessment results. Both CPI and CPB were tested before and after the relevant neurorehabilitation program. Ad hoc questionnaires were also administered to therapists of the CPI group to assess the degree of usefulness perceived about the information provided by the MIMU-based assessment. Results. Significant differences were found between children with CP and those with TD for the acceleration attenuation coefficient from pelvis to head (p=0.048) and from pelvis to sternum (p=0.021). After neurorehabilitation, this last parameter increased more in CPI (35%) than in CPB (6%, p=0.017 for the interaction group per time). The results of the questionnaires showed that therapists agreed with the usability (100% judged it as “easy to use”) and usefulness of the MIMU-based assessment in defining patient-oriented interventions (87%). Conclusions. There is a large debate in literature about the efficacy of classical gait analysis that should be enlarged to new technological approaches, such as that based on MIMUs. This study is a first proof of concept about the efficacy of this approach for neurorehabilitation of children with CP.
A Passenger Flow Control Method for Subway Network Based on Network Controllability
Authors: Zeng Lu , Liu Jun , Qin Yong , Wang Li , Yang Jie
Published: September 2018

The volume of passenger flow in urban rail transit network operation continues to increase. Effective measures of passenger flow control can greatly alleviate the pressure of transportation and ensure the safe operation of urban rail transit systems. The controllability of an urban rail transit passenger flow network determines the equilibrium state of passenger flow density in time and space. First, a passenger flow network model of urban rail transit and an evaluation index of the alternative set of flow control stations are proposed. Then, the controllable determination model of the urban rail transit passenger flow network is formed by converting the passenger flow distribution into a system state equation based on system control theory. The optimization method of passenger flow control stations is established via driver node matching to realize the optimized control of network stations. Finally, a real-world case study of the Beijing subway network is presented to demonstrate that the passenger flow network is controllable when driver nodes compose 25.3% of the entire network. The optimization of the flow control station, set during the morning peak, proves the efficiency and validity of the proposed model and algorithm.
Malignant Transformation of an Ovarian Endometrioma during Endometriosis Treatment: A Case Report
Authors: Takagi Hiroaki , Takata Emi , Sakamoto Jinichi , Fujita Satoko , Takakura Masahiro , Sasagawa Toshiyuki
Published: September 2018

Dienogest (DNG) is considered to be effective against ovarian endometrioma (OMA). We report a rare case of OMA transformation to ovarian cancer during long-term endometriosis treatment with a periodic administration of a gonadotropin-releasing hormone agonist (Gn-RH agonist) and DNG. The patient was a 41-year-old Japanese woman. OMA and adenomyosis of the uterus were revealed via computed tomography. Consequently, she underwent conservative treatment without undergoing surgery because her overall status was poor. She received cyclic therapy (Gn-RH agonist and DNG) for approximately eight years. However, she reported lumbago and underwent close medical examination at our hospital after about eight years of treatment. Under the suspicion of malignant transformation, she underwent surgery. The pathological diagnosis was clear cell carcinoma of the right ovary (stage 2B). After surgery, she received six courses of chemotherapy (conventional TC). No evidence of disease was observed after chemotherapy. Our findings suggest that malignant transformation of OMA can occur during DNG treatment. Since the delayed detection of ovarian cancer greatly affects the prognosis, women older than 40 with OMA are encouraged to undergo regular check-ups every few months.
The Role of Oxidative Stress, Selected Metals, and Parameters of the Immune System in Male Fertility
Authors: Dobrakowski Michał , Kaletka Zbigniew , Machoń-Grecka Anna , Kasperczyk Sławomir , Horak Stanisław , Birkner Ewa , Zalejska-Fiolka Jolanta , Kasperczyk Aleksandra
Published: September 2018

The aim of the study was to investigate the associations between standard semen parameters and the parameters reflecting oxidative stress intensity, antioxidant defense functions, levels of selected macro and trace elements, and parameters characterizing immune system function. The study group consisted of 103 fertile males. Based on semen volume, sperm concentration, total sperm count, and percentage of motile sperm at 1 hour postcollection, the individuals were divided into two equal groups—those with excellent (EX) semen quality and those with mediocre (ME) semen quality. The remaining measured parameters characterizing motility and the percentage of normal morphology were higher in the EX group than in the ME group; however, the seminal plasma pH did not differ between the examined groups. The phosphate level was 31% lower in the EX group than in the ME group, whereas there was a tendency toward a 25% lower level of Fe in the EX group than in the ME group (p = 0.064). The activities of enzymes involved in antioxidant defense, CuZn‐SOD, CAT, and G6PD, were 14%, 63%, and 39%, respectively, higher in the EX group than in the ME group. However, the level of alpha‐tocopherol was 32% lower in the EX group than in the ME group. The other measured parameters characterizing antioxidant defense and the parameters of oxidative stress intensity and immune system function were not significantly different. The value of seminal plasma pH is not related to the semen quality of fertile males. Higher fertility potential estimated based on standard semen parameters in fertile males is associated with lower levels of Fe and higher activities of some antioxidant enzymes.
Antidiabetic and Neuroprotective Effect of the N‐Butanol Extract of Fragaria nilgerrensis Schlecht. in STZ‐Induced Diabetic Mice
Authors: Gao Liangcai , Wang Xinyi , Lin Zejie , Song Ningning , Liu Xinnan , Chi Xinxin , Shao Tiange
Published: September 2018

Diabetes has been associated with neurodegenerative disorders that are accompanied by memory loss and cognitive impairments, but there is no effective treatment for it at present. Fragaria nilgerrensis Schlecht. (FNS), a well‐known Chinese materia medica, has been traditionally used for the folkloric treatment of diabetes and other diseases. However, its effects are poorly documented. Here, we investigated the antidiabetic and neuroprotective effect of FNS in diabetic mice. Thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) evaluations of N‐butanol extract of Fragaria nilgerrensis Schlecht. (N‐FNS) showed the presence of flavonoid and its structure is similar to scutellarin. For the first time, we show the potential neuroprotective and antidiabetic effects of FNS. After 4 weeks of FNS intervention, a significant decrease in blood glucose, increase in body weight, and amelioration in glucose tolerance were observed in FNS treated diabetic mice. In the acute study, FNS enhanced motor activity in the open field task and significantly prevented spatial‐learning deficits in Morris water maze tests. Besides, synapse ultrastructure of the hippocampus showed that the mitochondrial morphology was basically restored and all the synaptic structural parameters were gradually normalized after treatment with FNS. Importantly, we found that the activities of SOD and CAT in liver and hippocampus of diabetic mice significantly increased after FNS administration. In vitro, FNS and scutellarin showed high DPPH radical scavenging activity. The study suggests that FNS exerted significant antidiabetic and neuroprotective effects which may be attributed to its antioxidant property.
Incarcerated Uterus Presenting as Short Cervix and Placenta Previa
Authors: Alhousseini Ali , Zeineddine Salam , Alsamsam Adham , Gonik Bernard , Abramowicz Jacques , Puder Karoline , Saker Homam , Hernandez-Andrade Edgar
Published: September 2018

Introduction. Incarcerated uterus is a rare complication of pregnancy, usually associated with retroversion. Case. A 26-year-old woman presents at 19 4/7 weeks for evaluation of a short cervix and placenta previa. On ultrasound scan, the placenta was considered previa and the cervix was not visualized. The cervix was not identified by pelvic examination and the presumptive diagnosis of short cervix was done. The patient was followed up closely and remained asymptomatic. Retrospective analysis of the ultrasound images showed a retroverted uterus with an elongated cervix compressed towards the anterior vaginal wall. At 26 weeks of gestation, ultrasound showed a cervical length of 41 mm and a fundal placenta and the diagnosis of spontaneous correction of an incarcerated uterus was made. The patient had an uncomplicated vaginal delivery at 39 3/7 weeks. Comment. Identification and close follow-up of incarcerated uterus may potentially help in avoiding serious obstetrical and surgical complications.
Pulmonary Metastases from an Undifferentiated Embryonal Sarcoma of the Liver: A Case Report and Review
Authors: Shi Mingxia , Xu Hongzhi , Sangster Guillermo P. , Gu Xin
Published: September 2018

Undifferentiated embryonal sarcoma of the liver (UESL) is a rare malignant hepatic tumor that occurs primarily in children. Only a limited number of cases have been reported in the literature due to low incidence of one per million, and reports of metastatic lesion of UESL are even rarer. We hereby describe the case of a 13-year-old male who presented with a palpable mass with imaging findings suggestive of a large complex tumor in the right lobe of the liver. He underwent extended right hepatectomy followed by adjuvant chemotherapy. The tumor was confirmed to be UESL by postoperative pathology and immunohistochemical staining analysis. Four years later, surveillance imaging revealed a small lung nodule in the left lower lobe. Complete removal of the lung tumor by wedge resection was performed, and a histological diagnosis of metastatic UESL was made. The patient also received postoperative adjuvant chemotherapy and is currently in a good general condition and tumor-free in the present eight-month period. This case is presented with emphasis on clinicopathological and immunohistochemical findings of the primary UESL and lung metastases with the aim of collecting more data and expanding our understanding of this rare malignancy.
New Quantization Approach for the Anomaly: The Increase in Time Float following Consumption
Authors: Su Zhixiong , Wei Hanying
Published: September 2018

Anomalous scenarios in projects with generalized precedence relations (GPRs) have been arousing widely interest. A recent relevant discovery of anomaly under GPRs is that an activity’s time float increases following its consumption. The scenario is contrary to a common idea for plan management, and it also changes relationships between time floats and maximum prolongations of activity durations. Classic computations may be invalid to time parameters under GPRs. This study tests the fact that the current analysis on the anomaly has limitations so that it may provide improper guidelines for project scheduling and lead to undesirable effects. A new quantization algorithm is presented for the anomaly that overcomes the limitations of the current works. In particular, the algorithm confirms accurate time parameters and maximum duration prolongations of activities under constraints that retain project duration. The accuracy of quantization for the anomaly is particularly important for project scheduling with GPRs. Moreover, an application of the anomaly is developed in the resource-constrained project scheduling with activity splitting and GPRs, and an illustration is provided to test the fact that the new quantization result of the anomaly is an essential guarantee to achieve optimal solutions.
Statin Use and Cancer Incidence in Patients with Type 2 Diabetes Mellitus: A Network Meta-Analysis
Authors: Hu Yi-Bing , Hu En-De , Fu Rong-Quan
Published: September 2018

Background. Type 2 diabetes mellitus (T2DM) patients are involved closely with cancer. This work aims to conduct a systematic review and network meta-analysis (NMA) to examine the effect of different types of statins on cancer incidence in patients with T2DM.Methods. We systematically searched the Cochrane Library, PubMed, Embase, and Wanfang databases from January 1999 to March 2017. We performed a pairwise meta-analysis to estimate the pooled ratios (ORs) and 95% confidence intervals (CIs). A NMA was performed to compare different types of statins.Results. Seven publications were included. In pairwise meta-analysis, the incidence of cancer in T2DM patients was reduced when simvastatin, atorvastatin, pravastatin, fluvastatin, lovastatin, rosuvastatin, and pitavastatin were used. In the result of NMA, the usage of simvastatin (RR 0.30 and 95% CI 0.16–0.56), atorvastatin (RR 0.29 and 95% CI 0.09–0.88), pravastatin (RR 0.34 and 95% CI 0.12–0.93), fluvastatin (RR 0.27 and 95% CI 0.09–0.83), rosuvastatin (RR 0.22 and 95% CI 0.10–0.49), and pitavastatin (RR 0.33 and 95% CI 0.20–0.57) was superior to the nonstatin groups. When compared with six other statins, rosuvastatin appeared to be the best one.Conclusions. Different statins can reduce the risk of cancer in patients with T2DM. Our analyses suggest that rosuvastatin may be more effective than others.
Polymorphic Variants of TNFR2 Gene in Schizophrenia and Its Interaction with -308G/A TNF-α Gene Polymorphism
Authors: Suchanek-Raif Renata , Raif Paweł , Kowalczyk Małgorzata , Paul-Samojedny Monika , Kucia Krzysztof , Merk Wojciech , Kowalski Jan
Published: September 2018

Aim. Many data showed a role of inflammation and dysfunction of immune system as important factors in the risk of schizophrenia. The TNFR2 receptor is a molecule that adapts to both areas. Tumor necrosis factor receptor 2 (TNFR2) is a receptor for the TNF-α cytokine which is a strong candidate gene for schizophrenia. The serum level of TNFR2 was significantly increased in schizophrenia and associated with more severe symptoms of schizophrenia. Methods. We examined the association of the three single nucleotide polymorphisms (rs3397, rs1061622, and rs1061624) in TNFR2 gene with a predisposition to and psychopathology of paranoid schizophrenia in Caucasian population. The psychopathology was measured by a five-factor model of the PANSS scale. We also assessed a haplotype analysis with the -308G/A of TNF-α gene. Results. Our case-control study (401 patients and 657 controls) revealed that the genetic variants of rs3397, rs1061622, and rs1061624 in the TNFR2 gene are associated with a higher risk of developing schizophrenia and more severe course in men. However, the genotypes with polymorphic allele for rs3397 SNP are protective for women. The rs1061624 SNP might modulate the appearance of the disease in relatives of people with schizophrenia. The CTGG haplotype build with tested SNPs of TNFR2 and SNP -308G/A of TNF-α has an association with a risk of schizophrenia in Caucasian population depending on sex. Our finding is especially true for the paranoid subtypes of schizophrenia.
The Impact of Noncavity-Distorting Intramural Fibroids on the Efficacy of In Vitro Fertilization-Embryo Transfer: An Updated Meta-Analysis
Authors: Wang Xiaodan , Chen Li , Wang Hengyu , Li Qin , Liu Xiru , Qi Hongbo
Published: September 2018

Aim. To address the impact of noncavity-distorting intramural fibroids on the efficacy of in vitro fertilization-embryo transfer (IVF-ET) outcomes. Methods. The PubMed, Web of Science, Embase, Cochrane Library, and China National Knowledge Infrastructure were searched systematically. A meta-analysis was performed based on comparative or cohort studies that explored the impact of noncavity-distorting intramural fibroids on the efficacy of IVF-ET treatment. The IVE-ET outcomes of study group (women with noncavity-distorting intramural fibroids) and control group (women without fibroids) were compared, including live birth rate (LBR), clinical pregnancy rate (cPR), implantation rate (IR) , miscarriage rate (MR), and ectopic pregnancy rate (ePR). Results. A total of 28 studies involving 9189 IVF cycles were included. Our meta-analysis showed a significant reduction of LBR in the study group compared to control group (RR = 0.82, 95% CI: 0.73-0.92, and P = 0.005). In addition, it indicated that study group had a significant reduction in cPR (RR = 0.86, 95% CI: 0.80-0.93, P = 0.0001) and IR (RR = 0.90, 95% CI: 0813-1.00, P = 0.04) and have a significantly increase in MR (RR = 1.27, 95% CI: 1.08-1.50, and P = 0.004) compared with control group. Conclusions. The present evidence suggests that noncavity-distorting intramural fibroids would significantly reduce the IR, cRP, and LBR and significantly increase the MR after IVF treatment, but it would not significantly increase the ePR.
Prevalence of Subclinical Hypothyroidism in Acute Coronary Syndrome in Nondiabetics: Detailed Analysis from Consecutive 1100 Patients from Eastern India
Authors: Mukherjee Sudeb , Datta Suhana , Mandal S. C.
Published: September 2018

Background. The association between subclinical thyroid dysfunction (defined by no symptoms or clinical features of hypothyroidism but biochemically TSH level in the range of above 5 miu/ml but below 10 miu/ml with normal FT4 level) and Acute Coronary Syndrome (ACS) is not known so far. This study was done to calculate the prevalence of subclinical thyroid dysfunction in patients with ACS. Methods. A retrospective chart review of 1100 consecutive patients was done who presented to Emergency Department with symptoms suggestive of ACS and admitted. They were later classified in 3 categories that includes Acute ST Elevated Myocardial Infarction (STEMI), Unstable Angina (UA), and Acute Non-ST Elevated Myocardial Infarction (NSTEMI). Thyroid function test (FT4, TSH) and antithyroid peroxidase (TPO) were done and evaluated properly. Results. Of 1100 consecutive patients 168 (15.27%) patients had the biochemical features of subclinical thyroid dysfunction. These 168 patients include 60 STEMI, 66 NSTEMI, and 42 Unstable Angina patients. There were no statistically significant differences in terms of left ventricular ejection fraction (LVEF) and catheterisation results considering thyroid dysfunction. Conclusions. Subclinical thyroid dysfunction is quite prevalent in ACS patients. There are no significant associations between STEMI, Unstable Angina, or NSTEMI patients in terms of thyroid dysfunction neither in single vessel versus multivessel disease involvement. The causative role and outcomes of treatment are still uncertain and need further follow-up.
Melatonin Ameliorates the Progression of Atherosclerosis via Mitophagy Activation and NLRP3 Inflammasome Inhibition
Authors: Ma Sai , Chen Jiangwei , Feng Jing , Zhang Ran , Fan Miaomiao , Han Dong , Li Xiang , Li Congye , Ren Jun , Wang Yabin , Cao Feng
Published: September 2018

The NLRP3 (nucleotide‐binding domain and leucine‐rich repeat pyrin domain containing 3) inflammasome‐mediated inflammatory responses are critically involved in the progression of atherosclerosis (AS), which is the essential cause for cardiovascular diseases. Melatonin has anti‐inflammatory properties. However, little is known about the potential effects of melatonin in the pathological process of AS. Herein, we demonstrate that melatonin suppressed prolonged NLRP3 inflammasome activation in atherosclerotic lesions by reactive oxygen species (ROS) scavenging via mitophagy in macrophages. The atherosclerotic mouse model was induced with a high‐fat diet using ApoE−/− mice. Melatonin treatment markedly attenuated AS plaque size and vulnerability. Furthermore, melatonin decreased NLRP3 inflammasome activation and the consequent IL‐1β secretion within atherosclerotic lesions. Despite the unchanged protein expression, the silent information regulator 3 (Sirt3) activity was elevated in the atherosclerotic lesions in melatonin‐treated mice. In ox‐LDL‐treated macrophages, melatonin attenuated the NLRP3 inflammasome activation and the inflammatory factors secretion, while this protective effect was abolished by either Sirt3 silence or autophagy inhibitor 3‐MA. Mitochondrial ROS (mitoROS), which was a recognized inducer for NLRP3 inflammasome, was attenuated by melatonin through the induction of mitophagy. Both Sirt3‐siRNA and autophagy inhibitor 3‐MA partially abolished the beneficial effects of melatonin on mitoROS clearance and NLRP3 inflammasome activation, indicating the crucial role of Sirt3‐mediated mitophagy. Furthermore, we demonstrated that melatonin protected against AS via the Sirt3/FOXO3a/Parkin signaling pathway. In conclusion, the current study demonstrated that melatonin prevented atherosclerotic progression, at least in part, via inducing mitophagy and attenuating NLRP3 inflammasome activation, which was mediated by the Sirt3/FOXO3a/Parkin signaling pathway. Collectively, our study provides insight into melatonin as a new target for therapeutic intervention for AS.
Efficacy of Shear-Wave Elastography for Detecting Postoperative Cervical Lymph Node Metastasis in Papillary Thyroid Carcinoma
Authors: Kim Hye Jeong , Choi In Ho , Jin So-Young , Park Hyeong Kyu , Byun Dong Won , Suh Kyoil , Yoo Myung Hi
Published: September 2018

Aims. To evaluate shear-wave elastography (SWE) as a tool to detect postoperative cervical lymph node (LN) metastasis in patients with papillary thyroid carcinoma (PTC). Methods. Forty-three LNs of 43 patients with PTC undergoing ultrasound (US) and SWE before ultrasound-guided fine-needle aspiration (FNA) for the evaluation of postoperative cervical LN recurrences were analyzed. The mean (EMean), minimum (EMin), maximum (EMax), and standard deviation (ESD) of SWE elasticity indices were measured. Results. Among 43 indeterminate or suspicious LNs, 12 were malignant and 31 were benign. The EMean, EMin, EMax, and ESD values were significantly higher in malignant LNs than in benign LNs (EMean: 37.1 kPa in malignant versus 11.8 kPa in benign LNs, P<0.001; EMin: 11.3 kPa versus 5.1 kPa, P=0.046; EMax: 50.5 kPa versus 23.7 kPa, P<0.001; and ESD: 7.8 kPa versus 4.1 kPa, P=0.006). EMax had the highest accuracy (93.0%) when applied with a cut-off value of 37.5 kPa. It had a positive likelihood ratio of 25.83 and a diagnostic odds ratio of 150.0. Conclusions. The shear elasticity index of EMax, with higher likelihood ratios for malignant LNs, may help identify postoperative cervical LN metastasis in PTC patients with indeterminate or suspicious LNs.
Pyogenic Liver Abscess with No Predisposing Risk Factors
Authors: Chadwick Matthew , Shamban Leonid , Neumann Michael
Published: September 2018

Pyogenic liver abscesses (PLA) are an uncommon cause of hospitalization in the United States. The majority of such cases are polymicrobial and are most commonly caused by seeding of infection from the biliary system. PLA is frequently associated with specific comorbidities such as diabetes mellitus, history of liver transplant, underlying hepatobiliary, or pancreatic disease. Herein, we describe a 47-year-old healthy male with no known risk factors associated with PLA who presented to the hospital with acute fever, abdominal pain, and dark colored urine. Initially the patient had a negative right upper quadrant ultrasound. However, the patient continued to have persistent fevers and abnormal liver biochemistries with negative liver serology that led to checking a magnetic resonance cholangiopancreatography which suggested multiple liver abscesses. Computer tomography guided aspiration revealed a monobacterial Streptococcus species within the abscess, which is commonly associated with arterial bacteremia as a source of PLA. Arterial bacteremia is one of most rare causes of PLA. The patient’s septic workup was negative for any source of infection. This case demonstrates a patient with no risk factors who was diagnosed with PLA caused by apparent arterial bacteremia with no clear source of infection.
Elevation of Stromal-Derived Mediators of Inflammation Promote Prostate Cancer Progression in African-American Men
Authors: Gillard Marc , Javier Rodrigo , Ji Yuan , Zheng S. Lilly , Xu Jianfeng , Brendler Charles B. , Crawford Susan E. , Pierce Brandon L. , Griend Donald J. Vander , Franco Omar E.
Published: September 2018

Progress in prostate cancer racial disparity research has been hampered by a lack of appropriate research tools and better understanding of the tumor biology. Recent gene expression studies suggest that the tumor microenvironment (TME) may contribute to racially disparate clinical outcomes in prostate cancer. Analysis of the prostate TME has shown increased reactive stroma associated with chronic inflammatory infiltrates in African-American (AA) compared with European-American (EA) patients with prostate cancer. To better understand stromal drivers of changes in TME, we isolated prostate fibroblasts (PrF) from AA (PrF−AA) and EA (PrF−EA) prostate cancer tissues and studied their functional characteristics. PrF−AA showed increased growth response to androgens FGF2 and platelet-derived growth factor. Compared with PrF−EA, conditioned media from PrF−AA significantly enhanced the proliferation and motility of prostate cancer cell lines. Expression of markers associated with myofibroblast activation (αSMA, vimentin, and tenascin-C) was elevated in PrF−AA. In vivo tumorigenicity of an AA patient–derived prostatic epithelial cell line E006AA was significantly increased in the presence of PrF−AA compared with PrF−EA, and RNA-seq data and cytokine array analysis identified a panel of potential proinflammatory paracrine mediators (BDNF, CHI3L1, DPPIV, FGF7, IL18BP, IL6, and VEGF) to be enriched in PrF−AA. E006AA cell lines showed increased responsiveness to BDNF ligand compared with EA-derived LNCaP and C4-2B cells. Addition of a TrkB-specific antagonist significantly reduced the protumorigenic effects induced by PrF−AA compared with PrF−EA. These findings suggest that fibroblasts in the TME of AA patients may contribute to the health disparity observed in the incidence and progression of prostate cancer tumors.

Significance: These findings suggest that stromal cells in the tumor microenvironment of African-American men promote progression of prostate cancer by increasing levels of a specific set of pro-inflammatory molecules compared with European-American men.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/21/6134/F1.large.jpg. Cancer Res; 78(21); 6134–45. ©2018 AACR.
Contribution of Adrenal Glands to Intratumor Androgens and Growth of Castration-Resistant Prostate Cancer
Authors: Mostaghel Elahe A. , Zhang Ailin , Hernandez Susana , Marck Brett T. , Zhang Xiaotun , Tamae Daniel , Biehl Heather E. , Tretiakova Maria , Bartlett Jon , Burns John , Dumpit Ruth , Ang Lisa , Matsumoto Alvin M. , Penning Trevor M. , Balk Steven P. , Morrissey Colm , Corey Eva , True Lawrence D. , Nelson Peter S.
Published: September 2018

Purpose:

Tumor androgens in castration-resistant prostate cancer (CRPC) reflect de novo intratumoral synthesis or adrenal androgens. We used C.B.-17 SCID mice in which we observed adrenal CYP17A activity to isolate the impact of adrenal steroids on CRPC tumors in vivo.

Experimental Design:

We evaluated tumor growth and androgens in LuCaP35CR and LuCaP96CR xenografts in response to adrenalectomy (ADX). We assessed protein expression of key steroidogenic enzymes in 185 CRPC metastases from 42 patients.

Results:

Adrenal glands of intact and castrated mice expressed CYP17A. Serum DHEA, androstenedione (AED), and testosterone (T) in castrated mice became undetectable after ADX (all P < 0.05). ADX prolonged median survival (days) in both CRPC models (33 vs. 179; 25 vs. 301) and suppressed tumor steroids versus castration alone (T 0.64 pg/mg vs. 0.03 pg/mg; DHT 2.3 pg/mg vs. 0.23 pg/mg; and T 0.81 pg/mg vs. 0.03 pg/mg, DHT 1.3 pg/mg vs. 0.04 pg/mg; all P ≤ 0.001). A subset of tumors recurred with increased steroid levels, and/or induction of androgen receptor (AR), truncated AR variants, and glucocorticoid receptor (GR). Metastases from 19 of 35 patients with AR positive tumors concurrently expressed enzymes for adrenal androgen utilization and nine expressed enzymes for de novo steroidogenesis (HSD3B1, CYP17A, AKR1C3, and HSD17B3).

Conclusions:

Mice are appropriate for evaluating adrenal impact of steroidogenesis inhibitors. A subset of ADX-resistant CRPC tumors demonstrate de novo androgen synthesis. Tumor growth and androgens were suppressed more strongly by surgical ADX than prior studies using abiraterone, suggesting reduction in adrenally-derived androgens beyond that achieved by abiraterone may have clinical benefit. Proof-of-concept studies with agents capable of achieving true “nonsurgical ADX” are warranted.
Crebbp Loss Drives Small Cell Lung Cancer and Increases Sensitivity to HDAC Inhibition
Authors: Jia Deshui , Augert Arnaud , Kim Dong-Wook , Eastwood Emily , Wu Nan , Ibrahim Ali H. , Kim Kee-Beom , Dunn Colin T. , Pillai Smitha P.S. , Gazdar Adi F. , Bolouri Hamid , Park Kwon-Sik , MacPherson David
Published: September 2018

CREBBP, encoding an acetyltransferase, is among the most frequently mutated genes in small cell lung cancer (SCLC), a deadly neuroendocrine tumor type. We report acceleration of SCLC upon Crebbp inactivation in an autochthonous mouse model. Extending these observations beyond the lung, broad Crebbp deletion in mouse neuroendocrine cells cooperated with Rb1/Trp53 loss to promote neuroendocrine thyroid and pituitary carcinomas. Gene expression analyses showed that Crebbp loss results in reduced expression of tight junction and cell adhesion genes, including Cdh1, across neuroendocrine tumor types, whereas suppression of Cdh1 promoted transformation in SCLC. CDH1 and other adhesion genes exhibited reduced histone acetylation with Crebbp inactivation. Treatment with the histone deacetylase (HDAC) inhibitor Pracinostat increased histone acetylation and restored CDH1 expression. In addition, a subset of Rb1/Trp53/Crebbp-deficient SCLC exhibited exceptional responses to Pracinostat in vivo. Thus, CREBBP acts as a potent tumor suppressor in SCLC, and inactivation of CREBBP enhances responses to a targeted therapy.

Significance: Our findings demonstrate that CREBBP loss in SCLC reduces histone acetylation and transcription of cellular adhesion genes, while driving tumorigenesis. These effects can be partially restored by HDAC inhibition, which exhibited enhanced effectiveness in Crebbp-deleted tumors. These data provide a rationale for selectively treating CREBBP-mutant SCLC with HDAC inhibitors. Cancer Discov; 8(11); 1422–37. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 1333
The BRAF Status May Predict Response to Sorafenib in Gastrointestinal Stromal Tumors Resistant to Imatinib, Sunitinib, and Regorafenib: Case Series and Review of the Literature
Authors: Franck Caspar , Rosania Rosa , Franke Sabine , Haybaeck Johannes , Canbay Ali , Venerito Marino
Published: September 2018

Background: Sorafenib has shown efficacy in patients with imatinib-, sunitinib-, and regorafenib-resistant gastrointestinal stromal tumors (GISTs). No biomarker is currently available for predicting response to sorafenib in patients with GIST. Methods: We herein report 3 patients with imatinib-, sunitinib-, and regorafenib-resistant metastasized GISTs, who were treated with sorafenib. Besides receptor tyrosine kinase KIT and platelet-derived growth factor receptor α, also BRAF was tested for mutations. Results: Sorafenib therapy induced a long-term disease control in 2 out of 3 patients over a period of 49 and 19 months, respectively. Sorafenib-responsive GISTs were BRAF wild-type, whereas the sorafenib-resistant GIST carried a BRAF V600E mutation. Conclusion: We confirm sorafenib as an effective therapeutic option in patients with imatinib-, sunitinib-, and regorafenib-resistant GISTs. Larger studies are required to corroborate whether BRAF mutation may predict sorafenib resistance in GISTs.
Smoking and Drinking Did Not Increase the Failure of Therapeutic Helicobacter pylori Eradication by Vonoprazan, Clarithromycin, and Amoxicillin
Authors: Takara Yoshimichi , Endo Hiroyoshi , Nakano Ryo , Kawachi Kojiro , Hidaka Hidenori , Matsunaga Takuya , Tsuruoka Nanae , Sakata Yasuhisa , Shimoda Ryo , Hara Megumi , Fujimoto Kazuma
Published: September 2018

Aims: The influence of lifestyle-related factors, including smoking and drinking, was evaluated for Helicobacter pylori eradication therapy with vonoprazan or proton pump inhibitors (PPIs). Methods: Between 2012 and 2016, the medical records of 620 patients receiving H. pylori eradication therapy at Saiseikai Karatsu Hospital were evaluated. Patients had received vonoprazan (20 mg) or PPIs with 200 mg clarithromycin and 750 mg amoxicillin twice daily for 7 days. The influence of lifestyle-related factors on eradication failure was determined in the 2 groups. Results: The eradication rates for vonoprazan and lansoprazole, rabeprazole, and esomeprazole were, respectively, 91.0, 73.8, 72.0, and 84.6%. The vonoprazan eradication rate was significantly higher than those for the PPIs (p < 0.01). Habitual smoking and drinking did not increase eradication failure, and smoking and drinking during the eradication period did not reduce the eradication rate. Metabolic syndrome-related factors including obesity, hypertension, and diabetes mellitus had no negative influence on the eradication rate. Eradication with vonoprazan was more effective compared with that achieved through the use of PPIs. Conclusion: Lifestyle-related factors including smoking and drinking did not exacerbate the H. pylori eradication failure, and vonoprazan was more effective than the PPIs.
ВПЛИВ КОРВІТИНУ НА ПОКАЗНИКИ ГУМОРАЛЬНОГО ІМУНІТЕТУ ЗА УМОВИ РОЗВИТКУ ЕКСПЕРИМЕНТАЛЬНОЇ ПНЕВМОНІЇ
Authors: Chuhay O. О.
Published: September 2018

Специфічна імунна відповідь дуже важлива для захисту легень від патогенних мікроорганізмів, що зазнали розладу фагоцитозу (мікобактерій, грибів, вірусів), та позаклітинних організмів, які досить стійкі до фагоцитозу (інкапсульовані бактерії). Мікробні інфекції, які уникають природних захисних механізмів, виробляють значну кількість антигенів, що призводить до розвитку антиген-специфічної імунної відповіді. Зокрема, прикладом є антиген-специфічна проліферація та диференціація В-лімфоцитів.На сьогодні біофлавоноїди часто використовують в якості супровідної терапії для виправлення порушень, викликаних тривалим запальним процесом. Флавоноїди мають антиоксидантні, мембранозахисні, ангіопротективні, протизапальні, імуномодулюючі властивості.Мета – дослідити вплив корвітину на показники клітинно-опосередкованого та гуморального імунітету при розвитку експериментальних пневмоній (ЕП).Матеріал і методи. Експериментальне дослідження проводили на 30 морських свинках (самцях) вагою 180–220 г, яких було поділено на 2 групи по 15 тварин у кожній:I група – морські свинки з ЕП на 20 день;II група – морські свинки, у яких застосовували корвітин.Цей антиоксидант вводили в дозі 40 мг/кг внутрішньочеревно протягом 7 днів (з 13 до 20 дня).Експериментальна пневмонія була індукована інтраназальним введенням тваринам культури Staphylococcus aureus методом В. Н. Шляпнікова та співавторів. Тварини були декапітовані на 20 день розвитку ЕП. Кількість Т- та В-лімфоцитів у крові визначали методом Е. Ф. Чернушенко, Л. С. Когосова. Рівень циркулюючих імунних комплексів визначали методом В. Хаскова, Я. Касліка.Отримані результати статистично оцінювали за допомогою t-критерію Стьюдента.Результати. Деякі принципи були виявлені після проведеної терапії. Зокрема, рівні В-лімфоцитів та ЦІК достовірно знизилися на 26,34 % та 17,54 % (р<0,05) відповідно, порівняно з показниками морських свинок на 20 день без лікування. Таким чином, введення препарату "Корвітин" мало профілактичний ефект у зв'язку з подальшим формуванням дисбалансу імунної відповіді, що підтвердило його протизапальну та імуномодулюючу дію.Висновки. Препарат "Корвітин" запобігає подальшому розвитку дисбалансу імунної системи, обмежуючи запальні реакції. Цей ефект може бути викликаний протизапальними та імуномодулюючими властивостями вказаного препарату. Корвітин може бути рекомендований у якості супровідної терапії при пневмонії.
ЕКСПРЕСІЯ ЕНДОТЕЛІАЛЬНОГО ФАКТОРА РОСТУ СУДИН У КОРІ ВЕЛИКОГО МОЗКУ ПРИ ПОРУШЕННЯХ КРОВООБІГУ ЗА УМОВ ПОПЕРЕДНЬОЇ СЕНСИБІЛІЗАЦІЇ МОЗКОВИМ АНТИГЕНОМ ТА ІМУНОКОРЕКЦІЇ
Authors: Yaremenko L. M. , Shepelev S. E. , Grabovoу A. N.
Published: September 2018

Вступ. Ендотеліальний фактор росту судин (VEGF) є сигнальним протеїном, який стимулює ангіогенез та виконує трофічні функції, у тому числі в нервовій системі. Зазначений фактор росту впливає на процеси розвитку та міграції нервових клітин, їх виживання.Мета дослідження – оцінити зміни експресії VEGF у корі великих півкуль головного мозку при порушеннях кровообігу за умов попередньої сенсибілізації мозковим антигеном та імунокорекції.Матеріал і методи. При моделюванні транзиторної ішемії та корекції нейродегенеративних змін імунофаном був проведений експеримент на 135 білих статевозрілих щурах-самцях масою 260–290 г. Були застосовані гістологічні, імуногістохімічний, морфометричний та статистичний методи дослідження.Результати. Проведені спостереження показали, що сенсибілізація мозковим антигеном очікувано призводить у сенсомоторній корі до виразних нейродегенеративних змін та вірогідного зниження експресії VEGF у нейро­цитах. Емболія судин гемомікроциркуляторного русла на фоні попередньої сенсибілізації характеризується посиленням нейродегенеративних та деструктивних змін у корі мозку та більш суттєвим зменшенням експресії VEGF у нейроцитах. При цьому часткове її відновлення після порушення кровообігу на фоні сенсибілізації відбувається повільніше, ніж тоді, коли остання не проводилася. Це можна розглядати як імунозалежне пригнічення компенсаторно-відновлювальних процесів, індукованих сенсибілізацією. Збільшення кількості гліоцитів, що спостерігалося після ішемічної атаки, супроводжувалося зростанням у них експресії VEGF.Імунофан вірогідно зменшує виразність нейродегенеративних змін та зниження експресії VEGF, викликаних як порушенням кровообігу в корі мозку, так і сенсибілізацією. Це може бути пов’язано як з прямим впливом імунофану, обумовленим його антиоксидантними властивостями, так і опосередковано, за рахунок відносної активації системи Т-регуляторних клітин, яка є одним із нейропротекторних факторів, що активуються після ішемії.Висновки. Сенсибілізація мозковим антигеном призводить до виразних нейродегенеративних змін у сенсомоторній корі та зниження експресії VEGF у нейроцитах.Емболія судин гемомікроциркуляторного русла на фоні попередньої сенсибілізації характеризується посиленням нейродегенеративних та деструктивних змін у корі мозку, виразнішим зменшенням експресії VEGF та уповільненням відновлювальних процесів.Імунофан вірогідно зменшує виразність нейродегенеративних змін та зниження експресії VEGF, викликаних як порушенням кровообігу в корі мозку, так і сенсибілізацією.
СТАН ПРОТЕОЛІЗУ І АНТИПРОТЕОЛІТИЧНОГО ЗАХИСТУ ПРИ ОСТЕОАРТРОЗІ НА ТЛІ ЕКСКРЕТОРНОЇ НЕДОСТАТНОСТІ ПІДШЛУНКОВОЇ ЗАЛОЗИ
Authors: Babinets L. S. , Galabitska I. M. , Kotsaba Yu. Ya.
Published: September 2018

У статті розглянуті сучасні погляди на патогенез первинного остеоартрозу і проблему коморбідності первинного остеоартрозу та захворювань, що супроводжуються порушенням зовнішньосекреторної функції підшлункової залози. Проаналізовано рівень активації системи протеолізу і системи антипротеолітичного захисту. Дослідниками було встановлено наявність більш глибокого порушення екскреторної функції підшлункової залози (тяжкого ступеня) при остеоартрозі з  коморбідними патологіями шлунково-кишкового тракту із зовнішньосекреторною недостатністю підшлункової залози, а також наявність зовнішньосекреторної недостатності підшлункової залози легкого ступеня у І групі хворих на первинний остеоартроз. У хворих на первинний ОА, що перебігав ізольовано або у поєднанні із захворюваннями, що супроводжуються порушенням зовнішньосекреторної функції підшлункової залози, було встановлено статистично значиму активацію загального протеолізу за рівнем протеолітичної активності плазми. Також аналіз засвідчив наявність підвищення специфічного протеолізу, або кініногенезу, за рівнем протеолітичного ферменту калікреїну. Встановлено зниження неактивного попередника калікреїну – прекалікреїну. Був підвищений рівень α1-інгібітора протеїназ, який здійснює контроль за активністю протеолізу, зв’язуючи трипсин та протеолітичні ферменти ендо- та екзогенного походження. Виявлено зниження рівня α2-макроглобуліну, що свідчить про виснаження інгібіторного захисту організму, адже даний показник блокує кініногеназну дію калікреїну і виводить активні портеїнази ендо- та екзогенного походження. Також було виявлено зниження активності кінінази–ІІ, що свідчить про ослаблення захисних реакцій організму через гіперпродукцію кінінів.