bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Circulating Tumor DNA in Evaluating Clinical Tumor Burden and Predicting Survival in Chinese Metastatic Colorectal Cancer Patients
Authors: xu xiaojing , yu yiyi , shen minna , liu menglin , wu shengchao , liang li , huang fei , zhang chenlu , guo wei , liu tianshu
Published: August 2020

Background:The aim of this study was to further explore the utility of ctDNA in the evaluation of clinical tumor burden and survival in Chinese metastatic CRC (mCRC) patients and to preliminarily summarize some metastatic characteristics associated with mutations in ctDNA. Patients and Methods:A four-gene mutation testing panel covering a total 197 mutation hotspots of KRAS, NRAS, BRAF and PIK3CA was used to evaluate their mutant status via next-generation sequencing of plasma from patients with mCRC. Clinical markers including CEA, CA199, CA125,NSE and LDH in serum and the sum of all tumor diameters on CT or PET/CT were collected to indicate clinical tumor burden. The correlations between cfDNA levels and clinical tumor burden were analyzed using Pearson correlation and linear regression models. The median PFS and 1-year OS rates were calculated by Kaplan–Meier (K–M) survival analysis. Results：The study enrolled 126 mCRC patients for ctDNA testing. Wild-type patients accounted for 54.8% (69/126) of the total patients, and mutated patients accounted for 45.2% (57/126) of the total patients. Mutations in KRAS, NRAS, BRAF and PIK3CA were detected in 37.3% (47/126), 1.6% (2/126), 3.2% (4/126) and 13.5% (17/126) of patients, respectively. The overall concordance rate of gene status between ctDNA and matched tissues was 78.6% (99/126). The concentration of cfDNA was significantly correlated with the levels of clinical markers, especially CEA (P<0.0001, Pearson r = 0.81), LDH (P<0.0001, Pearson r = 0.84) and the sum of tumor diameters (P<0.0001, Pearson r = 0.80). The median PFS (11.7 versus 6.6 months, P<0.0001) and 1-year OS rates (94% versus 56%, P<0.0001) were significantly different between patients with a low cfDNA concentration (≤17.91 ng/ml) and those with a high cfDNA concentration (>17.91 ng/ml). The most common metastatic site was liver (77.8%), followed by lymph nodes (62.7%), lung (40.5%), peritoneum (14.3%) and bone (10.3%), in all patients. There was no significant difference in metastasis regardless of gene status. Conclusion:These results suggested that the level of cfDNA could be a quantitative biomarker of tumor burden and could predict survival in Chinese patients with mCRC. Patients with gene mutations had a similar metastatic pattern to those with wild-type genes.
Statistical Design of Phase II/III Clinical Trials for Testing Therapeutic Interventions in COVID-19 Patients
Authors: Rai Shesh , Qian Chen , Pan Jianmin , Seth Anand , Srivast Deo K , Bhatnagar Aruni
Published: August 2020

Background Due to unknown features of the COVID-19 disease and complexity of the patient population, standard clinical trial designs on treatments may not be optimal in such patients. We propose two independent clinical trials designs based on careful grouping of patient and outcome measures.Methods Using the World Health Organization ordinal scale on patient status, we classify treatable patients (Stages 3-7) into two risk groups. Patients in Stages 3, 4 and 5 are categorized as the intermediate-risk group while patients in Stages 6 and 7 are categorized as the high-risk group. To ensure that an intervention, if deemed efficacious, is promptly made available to vulnerable patients, we propose a group sequential design incorporating four factors stratification, two interim analyses, and a toxicity monitoring rule for the intermediate-risk group. The primary response variable (binary variable) is based on the proportion of patients discharged from hospital by the 15th day. The goal is to detect a meaningful improvement in this response rate. For the high-risk group, we propose a group sequential design incorporating three factors stratification, two interim analyses, and without toxicity monitoring. The primary response variable for this design is the 30 days mortality, and the goal is to detect a meaning reduction in mortality rate.Results Required sample size and toxicity boundaries are calculated for each scenario. Sample size requirements for the designs with interim analyses are marginally greater than the ones without. In addition, for both the intermediate-risk group and the high-risk group, conducting two interim analyses have almost identical required sample size compared with just one interim analysis. Conclusions We recommend using binary outcome with composite endpoints for those in Stages 3, 4 and 5 with a power of 90% to detect an improvement of 20% in response rate, and 30 days mortality rate outcome for those in Stages 6 and 7 with a power of 90% to detect 15% (effect size) reduced mortality rate, in the trial design. For the intermediate-risk group, two interim analyses for efficacy evaluation along with toxicity monitoring are encouraged. For the high-risk group, two interim analyses without toxicity monitoring is advised.
Predictive equations for evaluation for resting energy expenditure in Brazilian patients with type 2 diabetes: What can we use?
Authors: Grassi Thaiciane , Boeno Francesco Pinto , de Freitas Mauren Minuzzo , de Paula Tatiana Pedroso , Viana Luciana Vercoza , de Oliveira Alvaro Reischak , Steemburgo Thais
Published: August 2020

Background: Evaluation of the resting energy expenditure (REE) is essential to ensure an appropriate dietary prescription for patients with type 2 diabetes. The aim of this record was to evaluate the accuracy of predictive equations for REE estimation in patients with type 2 diabetes, considering indirect calorimetry (IC) as the reference method.Methods: A cross-sectional study was performed in outpatients with type 2 diabetes. Clinical, body composition by electrical bioimpedance and laboratory variables were evaluated. The REE was measured by IC (QUARK RMR, Cosmed, Rome, Italy) and estimated by eleven predictive equations. Data were analyzed using Bland–Altman plots, paired t-tests, and Pearson’s correlation coefficients.Results: 62 patients were evaluated [50% female; mean age 63.1 ± 5.2 years; diabetes duration of 11 (1-36) years, and mean A1C of 7.6 ± 1.2%]. There was a wide variation in the accuracy of REE values predicted by equations when compared to IC REE measurement. In all patients, Ikeda and Mifflin St-Jeor equations were that most underestimated REE. And, the equations that overestimated the REE were proposed by Dietary Reference Intakes and Huang. The most accurate equations were FAO/WHO/UNO in women (-1.8% difference) and Oxford in men (-1.3% difference).Conclusion: In patients with type 2 diabetes, in the absence of IC, FAO/WHO/UNO and Oxford equations provide the best REE prediction in comparison to measured REE for women and men, respectively.
Emission factor, relative ozone formation potential and relative carcinogenic risk assessment of VOCs emitted from manufacturing industries
Authors: Yang Hsi-Hsien , Gupta Sunil Kumar , Dhital Narayan Babu
Published: August 2020

Manufacturing industries are one of the important emission sectors of anthropogenic volatile organic compounds (VOCs). In this study, VOC emission factors, relative ozone formation potential (ROFP) and relative carcinogenic risk (RCR) were estimated for some important manufacturing industries (n = 13) located in central Taiwan. Emission samples were collected in stainless steel canisters and were analyzed with a system of gas chromatography-mass spectroscopy. Higher emission factors of total VOCs (∑VOCs) were observed for stencil printing (423 mg-VOC kg-1) compared to other emission industries. Alkanes constituted the most prominent group of VOCs for steel foundry (41.6%), aluminum foundry (25.1%) and synthetic resin industries (25.0%). Oxygenated VOCs were obtained as the most abundant group in the organic solvent (80.3%), polyester resin (80.0%) and PU leather (75.0%) industries. Moreover, emissions from acrylic resin manufacturing had higher contributions from aromatic compounds (> 95%). Toluene was the topmost compound in terms of its contribution to ∑VOCs in plastic tape manufacturing (44.4%), aluminum foundry (39.6%), steel foundry (11.6%), plastic coating (64.3%) and stencil printing (35.3%). Analysis of ozone formation potentials showed that the metal product and machinery acrylic resin manufacturing and stencil printing had a higher normalized ROFP index and belonged to Level-I emission sources. However, in terms of the RCR, integrated iron and steel manufacturing had the highest normalized RCR index belonged to level-I emission sources. Level-I represents the most important VOC emission sources. This study provides a reactivity- and carcinogenicity-based approach to identify high-priority VOC emission sources. The results of this study would help formulate emission reduction policies and strategies for manufacturing industries.
Operative invasiveness does not affect the prognosis of patients with non-small cell lung cancer
Authors: Motono Nozomu , Iwai Shun , Iijima Yoshihito , Usuda katsuo , Uramoto Hidetaka
Published: August 2020

Background: The relationship between operative invasiveness and the prognosis in non-small cell lung cancer (NSCLC) patients who have undergone surgery has been controversial.Methods: Clinical data were analyzed for 463 NSCLC patients. Operative invasiveness was defined by wound length, operation time, and the postoperative C-reactive protein (postCRP) level. The operative approach was divided into video-assisted thoracic surgery (VATS) and thoracotomy.Results: The wound length and operation time were significantly correlated with the postCRP level (correlation coefficient (CC) = 0.39, p<0.01; CC = 0.54, p<0.01, respectively). The postCRP level in the VATS group was significantly lower than that in the thoracotomy group (12.2 mg/dl vs 20.58 mg/dl, p<0.01). The relapse-free survival differed significantly based on wound length (p<0.01), operation time (p=0.01), CRP level (p<0.01), and operative approach (p<0.01). The carcinoembryonic antigen level (hazard ratio [HR], 1.58; p = 0.02), pathological stage (pStage) (HR, 2.57; p < 0.01), vascular invasion (HR, 1.95; p = 0.01), and preoperative CRP level (preCRP) (HR, 1.91; p < 0.01) were identified as significant prognostic factors for relapse-free survival in a multivariate analysis. Furthermore, the multivariate analysis showed that smoking history (HR, 2.36; p = 0.03), pStage (HR, 3.26; p < 0.01), and preCRP level were significant prognostic factors for overall survival.Conclusion: Preoperative CRP level was associated with poor prognosis. Although the VATS approach might be less invasive procedure for NSCLC patients, operative invasiveness does not affect the prognosis. Trial registrationThe Institutional Review Boards of Kanazawa Medical University approved the protocol (approval number: I392), and written informed consent was obtained from all of the patients.
A Finite Element Analysis of Sacroiliac Joint Displacements and Ligament Strains in Response to Three Manipulations
Authors: Xu Zhun , Li Yikai , Zhang Shaoqun , Liao Liqing , Wu Kai , Feng Ziyu , Liu Dan
Published: August 2020

BackgroundClinical studies have found that manipulations have a good clinical effect on sacroiliac joint (SIJ) pain without specific causes. However, the specific mechanisms underlying the effect of manipulations are still unclear. The purpose of this study was to investigate the effects of three common manipulations on the stresses and displacements of the SIJ and the strains of the surrounding ligaments.MethodsA three-dimensional finite element model of the pelvis-femur was developed. The manipulations of hip and knee flexion (MHKF), oblique pulling (MOP), and lower limb hyperextension (MLLH) were simulated. The stresses and displacements of the SIJ and the strains of the surrounding ligaments were analyzed during the three manipulations.ResultsMOP produced the highest stress on the left SIJ, at 6.6 MPa, while MHKF produced the lowest stress on the right SIJ, at 1.5 MPa. The displacements of the SIJ were all less than 1 mm during the three manipulations. The three manipulations caused different degrees of ligament strain around the SIJ, and MOP produced the greatest straining of the ligaments.ConclusionThe three manipulations all produced small displacements of the SIJ and different degrees of ligament strains, which might be the mechanism through which they relieve SIJ pain. MOP may be the most effective of these manual therapies.
Hepatitis C Core Antigen Testing to Diagnose Active Hepatitis C Infection Among Haemodialysis Patients
Authors: Wong XZ , Gan CC , M R , Y R , G S , Tan SS , Lim SK
Published: August 2020

BACKGROUNDHepatitis C virus (HCV) infects more than 71 million people worldwide and chronic HCV infection increases the risk of liver cirrhosis and failure. Haemodialysis (HD) is one of the renal replacement therapies with risk of HCV transmission. Anti-HCV antibodies are the serological screening test for HCV infection that does not detect active phase of infection. Majority HCV infected HD patients in Malaysia do not have further HCV RNA performed due to high cost and thus HCV treatment is less frequently offered. HCV Core Antigen (HCV Ag) can potentially be used to diagnose active HCV infection in HD population in comparison to HCV RNA, at lower cost. METHODS We conducted a cross-sectional study to assess the correlation between HCV Ag and HCV RNA and to identify the prevalence of active HCV infection among HCV seropositive HD patients from dialysis centres across West Malaysia from July 2019 to May 2020. Pre-dialysis blood was taken and tested for both HCV Ag and HCV RNA tests. HCV Ag was tested with Abbott ARCHITECT HCV Ag test.RESULTS We recruited 112 seropositive HD patients from 17 centres with mean age of 54.04±11.62 years, HD vintage of 14.1±9.7 years, and male constitute 59.8% (67) of the study population. HCV Ag correlates well with HCV RNA (Spearman test coefficient 0.833, p<0.001). The sensitivity was 90.7%, specificity 100%, positive predictive value (PPV) 100%, negative predictive value (NPV) 76.5%, and accuracy 92.9%. For HCV RNA level >3000 IU/mL, HCV Ag had a higher sensitivity of 95.1% and greater correlation (Spearman test coefficient 0.897, p<0.001). The prevalence of active HCV infection was 76.8% among HCV seropositive HD patients. CONCLUSIONS Although HCV Ag is less sensitive, it shows an excellent correlation with HCV RNA and has 100% PPV. HCV Ag can be considered as an alternative diagnostic tool for chronic active HCV infection among HD cohort, who can then be considered for HCV treatment. For seropositive HD patient with negative HCV Ag, we recommend to follow-up with HCV RNA test.
Von Willebrand Factor:Antigen And Adamts-13 Level, But Not Soluble P-Selectin, Are Risk Factors For The First Asymptomatic Deep Vein Thrombosis In Cancer Patients Undergoing Chemotherapy
Authors: Setiawan Budi , Permatadewi Cecilia Oktaria , de Samakto Baringin , Bugis Ashar , Naibaho Ridho M. , Pangarsa Eko Adhi , Santosa Damai , Suharti Catharina
Published: August 2020

METHODS: We measured sP-selectin, vWF:Ag and ADAMTS-13 levels at baseline RESULTS: Forty patients with cancer were included in the study, all were recuited before their first chemotherapy induction. vWF:Ag and ADAMTS-13 were significantly associated with cancer chemotherapy accounting to increased RR for first asymptomatic DVT in the logistic regression model.﻿CONCLUSIONS: Further research is needed to determine whether incorporating vWF:Ag and ADAMTS-13 levels wil find use in everyday clinical practice. Once validated, these results may specify particular cancer patients to be treated with prophylactic anticoagulant.
Fully automated radiosynthesis of [18F]LBT999 on TRACERlab FXFN and AllinOne modules, a PET radiopharmaceutical for imaging the dopamine transporter in human brain
Authors: Vala Christine , Mothes Céline , Chicheri Gabrielle , Magadur Pauline , Viot Gilles , Deloye Jean-Bernard , Maia Serge , Bouvet Yann , Dupont Anne-Claire , Arlicot Nicolas , Guilloteau Denis , Emond Patrick , Vercoullie Johnny
Published: August 2020

Background: Fluorine labelled 8-((E)-4-fluoro-but-2-enyl)-3b-p-tolyl-8-aza-bicyclo[3.2.1]octane-2b-carboxylic acid methyl ester ([18F]LBT999) is a selective radioligand for the in vivo neuroimaging and quantification of the dopamine transporter by Positron Emission Tomography (PET). [18F]LBT999 was produced on a TRACERlab FXFN for the Phase I study but for Phase III and a potent industrial production transfer, production was also implemented on an AllinOne (AIO) system requiring a single use cassette. Both production methods are reported herein. Results: Automation of [18F]LBT999 radiosynthesis on FXFN was carried out in 35% yield (decay-corrected) in 65 min (n=16), with a radiochemical purity higher than 99 % and a molar activity of 158 GBq/µmol at the end of synthesis. The transfer to the AIO platform followed by optimizations allowed the production of [18F]LBT999 in 32.7% yield (decay-corrected) within 48 min (n=5), with a radiochemical purity better than 98% and a molar activity above 154 GBq/µmol on average at the end of synthesis. Quality controls of both methods met the specification for clinical application.Conclusion: Both modules allow efficient and reproducible radiosynthesis of [18F]LBT999 with good radiochemical yields and a reasonable synthesis time. The developments made on AIO, such as its ability to meet pharmaceutical criteria and to more easily comply with GMP requirements, make it an optimal approach for the potent industrial production of [18F]LBT999 and future wider use.
Bioconversion of biphenyl to a polyhydroxyalkanoate copolymer by Alcaligenes denitrificans A41
Authors: Yajima Taito , Nagatomo Mizuki , Wakabayashi Aiko , Sato Michio , Taguchi Seiichi , Maeda Michihisa
Published: August 2020

A polyhydroxyalkanoate (PHA) copolymer, poly(3-hydroxybutyrate-co-3-hydroxyvalerate) [P(3HB-co-3HV)], was biosynthesized from biphenyl as the sole carbon source using Alcaligenes (currently Achromobacter) denitrificans A41. This strain is capable of degrading polychlorinated biphenyls (PCBs) and biphenyl. This proof-of-concept of the conversion of aromatic chemicals such as the environmental pollutant PCBs/biphenyl to eco-friendly products such as biodegradable polyester PHA was inspired by the uncovering of two genes encoding PHA synthases in the A. denitrificans A41 genome. When the carbon/nitrogen (C/N) ratio was set at 21, the cellular P(3HB-co-3HV) content in strain A41 reached its highest value of 10.1% of the cell dry weight (CDW). A two-step cultivation protocol improved the accumulation of P(3HB-co-3HV) by up to 26.2% of the CDW, consisting of 13.0 mol% 3HV when grown on minimum salt medium without nitrogen sources. The highest cellular content of P(3HB-co-3HV) (47.6% of the CDW) was obtained through the two-step cultivation of strain A41 on biphenyl as the sole carbon source. The purified copolymer had ultra-high molecular weight (weight-average molecular weight of 3.5 × 106), as revealed through gel-permeation chromatography. Based on the genomic information related to both polymer synthesis and biphenyl degradation, we finally proposed a metabolic pathway for the production of P(3HB-co-3HV) associated with the degradation of biphenyl by strain A41.
Closing-wedge Distal Femoral Osteotomy Combined with Medial Patellofemoral Ligament Reconstruction for Recurrent Patellar Dislocation with Genu Valgum
Authors: Jing Lizhong , Wang Xiaole , Liu Kun , Wang Xiaotan , Jiang Lu , Wu Di , Zhang Zhiwei , Li Zhuang , Yu Le , Wang Shaoshan , Yang Jiushan
Published: August 2020

Background: Medial patellofemoral ligament reconstruction (MPFLR) is a well-established procedure for addressing recurrent patellar dislocation (RPD) in young patients. However, for RPD with genu valgum, simultaneous MPFLR and closing-wedge distal femoral osteotomy (CWDFO) may be a promising procedure yet rarely reported. This study’s purpose was to observe and analyse the clinical and imaging findings of CWDFO combined with MPFLR for RPD with genu valgum.Methods: From May 2015 to Apirl 2018, 25 patients with RPD and genu valgum were surgically treated in our department. Anteroposterior long-leg, weight-bearing, lower-extremity radiographs, lateral radiographs and computed tomography (CT) scans of the patellofemoral joint were obtained, and the femorotibial angle (FTA), mechanical lateral distal femoral angle (mLDFA), weight-bearing line rate (WBLR), patellar height, patellar lateral shift (PLS) and tibial tubercle–trochlear groove (TT-TG) distance were analysed. Validated knee scores, such as the Kujala, Lysholm, visual analogue scale (VAS) scores and Tegner socres, were evaluated preoperatively and 2 years postoperatively.Results: 25 patients, with an average age of 19.8 years (14–27), were evaluated. All patients had been able to achieve a better sports level without any problems during the 2-year follow-up period. There has been no recurrence of patellar instability. Compared with preoperation, the FTA, mLDFA, WBLR and PLS showed statistically significant improvement following the procedure (p < 0.001). Meanwhile, no significant differences in the Insall index and TT-TG distance was found. The mean Kujala score, average Lysholm score, VAS score and Tegner socres showed significant improvement postoperatively.Conclusions: CWDFO combined with MPFLR is a suitable treatment for RPD with genu valgum, as it leads to significant improvement in the clinical and imaging findings of the knee in the short term.
De novo mosaic and partial monosomy of chromosome 21 in a case with superior vena cava duplication
Authors: Azad Abul Kalam , Yanakakis Lindsay , Issleb Samantha , Turina Jessica , Drabik Kelli , Bonner Christina , Simi Eve , Wagner Andrew , Fiddler Morry , Naeem Rizwan
Published: August 2020

Background: Full or partial monosomy of chromosome (chr) 21 is a very rare abnormal cytogenetic finding. It is characterized by variable sizes and deletion breakpoints on the long arm (q) of chr 21 that lead to a broad spectrum of phenotypes that include an increased risk of birth defects, developmental delay and intellectual deficit.Case presentation: We report a 37-year-old G1P0 woman initially screened by non-invasive prenatal testing with no positive findings that was followed by an 18-week anatomy scan with a fetal finding of duplication of the superior vena cava (SVC). The medical and family history was otherwise uneventful. After appropriate genetic counseling, amniocentesis was performed to evaluate suspected chromosomal anomalies.Conclusions: Interphase fluorescent in situ hybridization revealed loss of one chr 21 signal that was further delineated by chromosomal microarray analysis on uncultured amniocytes as a terminal 10 Mb deletion on chr 21q. Karyotype and microarrays on cultured amniocytes showed two cell lines for a mosaic 21q terminal deletion and monosomy 21. The combined molecular cytogenetics results reported following the ISCN 2016 guideline as mos 46,XX,del(21)(q22)dn[20]/45,XX,-21dn[10].nuc ish(D21S342/D21S341/D21S259x1)[100].arr[GRCh37] 21q11.2q22.12(15412676_36272993)x1~2,21q22.12q22.3(36431283_47612400)x1. Parental chromosomal analysis revealed normal karyotypes. Thus, this was a de novo mosaic full and partial monosomy of chr 21 in a case with SVC duplication. Despite the association of congenital heart disease with monsomy 21 we could not find any published literature or online databases for this cytogenetic abnormality. The patient terminated the pregnancy following the abnormal molecular cytogenetic results due to the possible challenges the baby would face if carried to term.
LINC00649 underexpression is an adverse prognostic marker in acute myeloid leukemia
Authors: Guo Chao , Gao Ya-yue , Ju Qian-qian , Zhang Chun-xia , Gong Ming , Li Zhen-ling
Published: August 2020

Background Long noncoding RNAs (lncRNA) play a role in leukemogenesis, maintenance, development, and therapeutic resistance of AML. While few studies have focused on the prognostic significance of LINC00649 in AML, which we aim to investigate in this present study. Methods We compared the expression level of LINC00649 between AML patients and healthy controls. The Kaplan-Meier curves of AML patients expressing high versus low level of LINC00649 was performed. The LINC00649 correlated genes/miRNAs/lncRNAs and methylation CpG sites were screened by Pearson correlation analysis with R (version 3.6.0), using TCGA-LAML database. The LINC00649 associated ceRNA network was established using lncBase 2.0 and miRWalk 2.0 online tools, combining results from correlation analysis. Finally, a prediction model was constructed using LASSO-Cox regression. Results LINC00649 was underexpressed in bone marrow of AML group than that in healthy control group. The patients of LINC00649-low group have significantly inferior PFS and OS. A total of 154 mRNAs, 31 miRNAs, 28 lncRNAs and 1590 methylated CpG sites were identified to be significantly correlated with LINC00649. Furthermore, the network of ceRNA was established with 6 miRNAs and 122 mRNAs. The Lasso-Cox model fitted OS/PFS to novel prediction models, which integrated clinical factors, ELN risk stratification, mRNA/miRNA expression and methylation profiles. The analysis of time-dependent ROC for our model showed a superior AUC (AUC = 0.916 at 1 year, AUC = 0.916 at 3 years, and AUC = 0.891 at 5 years). Conclusions Low expression of LINC00649 is a potential unfavorable prognostic marker for AML patients, which requires the further validation. The analysis by LASSO-COX regression identified a novel comprehensive model with a superior diagnostic utility, which integrated clinical and genetic variables.
Interferon-beta enhances sensitivity to gemcitabine in pancreatic cancer
Authors: Blaauboer Amber , Booy Stephanie , Koetsveld Peter M. van , Karels Bas , Dogan Fadime , Zwienen Suzanne van , Eijck Casper H.J. van , Hofland Leo J.
Published: August 2020

Background: Adjuvant gemcitabine for pancreatic cancer has limited efficacy in the clinical setting. Impaired drug metabolism is associated with treatment resistance. We aimed to evaluate the chemosensitising effect of interferon-beta (IFN-β).Methods: BxPC-3, CFPAC-1, and Panc-1 cells were pre-treated with IFN-β followed by gemcitabine monotherapy. The effect on cell growth, colony formation, and cell cycle was determined. RT-qPCR was used to measure gene expression. BxPC-3 cells were used in a heterotopic subcutaneous mouse model. Results: IFN-β increased sensitivity to gemcitabine (4-, 7.7-, and 1.7-fold EC50 decrease in BxPC-3, CFPAC-1, and Panc-1, respectively; all P<0.001). Findings were confirmed when assessing colony formation. The percentage of cells in the S-phase was significantly increased after IFN-β treatment only in BxPC-3 and CFPAC-1 by 12% and 7%, respectively (p<0.001 and p<0.05, respectively). Thereby, IFN-β upregulated expression of the drug transporters SLC28A1 in BxPC-3 (252%) and SLC28A3 in BxPC-3 (127%) and CFPAC-1 (223%) (all p<0.001). In vivo, combination therapy reduced tumor volume with 45% (P=0.01). Both ex vivo and in vivo data demonstrate a significant reduction in the number of proliferating cells, whereas apoptosis was increased. Conclusions: For the first time, we validated the chemosensitising effects of IFN-β when combined with gemcitabine in vitro, ex vivo, and in vivo. This was driven by cell cycle modulation and associated with an upregulation of genes involving intracellular uptake of gemcitabine. The use of IFN-β in combination with gemcitabine seems promising in patients with pancreatic cancer and needs to be further explored.
Role of interleukin 6 as a predictive factor for a severe course of Covid-19: retrospective data analysis of patients from a Long-term Care Facility during Covid-19 Outbreak
Authors: Sabaka Peter , Koščálová Alena , Straka Igor , Hodosy Julius , Lipták Robert , Kmotorková Barbora , Kachlíková Mária , Kušnírová Alica
Published: August 2020

Background: Covid-19 is a disease with high morbidity and mortality among elderly residents of long-term care facilities (LTCF). During an outbreak of SARS-CoV-2 infection in the LTCF an effective screening tool is essential to identify the patients at risk for severe illness and death. We explored the role of interleukin 6 (IL-6) as a predictor for severe disease during the outbreak of Covid-19 in one LTCF in Slovakia.Methods: We conducted a retrospective data analysis of cases of COVID-19, diagnosed during the outbreak in one LTCF in Slovakia between April 11, 2020, and May 5, 2020. Within 24 hours after the diagnosis of Covid-19, clinical and laboratory screening was performed in the LTCF to identify patients in need of hospitalization. Patients with oxygen saturation below 90% were immediately referred to the hospital. Patients staying in the LFTC were monitored daily and those that developed hypoxemia were transferred to the hospital. We analyzed the association between the IL-6 at the initial assessment and development of hypoxemia during follow up and determined the cut-off of the IL-6 able to predict the development of hypoxemia requiring oxygen therapy.Results: Fifty-three patients (11 men, 42 women) with diagnosed Covid-19 were included in the analysis. 19 (53%) patients developed hypoxemia during the disease. Patients with hypoxemia had significantly higher concentrations of IL-6, C-reactive protein, procalcitonin, fibrinogen, total bilirubin, aspartate aminotransferase and alanine aminotransferase at initial screening. ROC analyses identified IL-6 as the most robust predictor of hypoxemia. The concentration of IL-6 > 24 pg/mL predicted the development of hypoxemia with the sensitivity of 100% and specificity of 88.9%. The positive and negative predictive values were 76.9%, and 100% respectively.Conclusions: The concentration of IL-6 > 24 pg/mL at initial assessment predicted the development of hypoxemia requiring hospitalization with excellent sensitivity and good specificity. IL-6 appears as a potential predictor for the development of the severe Covid-19 and might serve for early identification of patients in need of hospitalization. Further studies are needed to evaluate the robustness of the use of IL-6 as an effective screening tool for the severe course of Covid-19.
Performance Analysis of Power-Splitting Relaying Protocol in SWIPT Based Cooperative NOMA Systems
Authors: Tran Quy-Huu , Phan Ca V , Vien Quoc-Tuan
Published: August 2020

This paper investigates a relay assisted simultaneous wireless information and power transfer (SWIPT) for downlink in cellular systems. Cooperative non-orthogonal multiple access (C-NOMA) is employed along with power splitting (PS) protocol to enable both energy harvesting (EH) and information processing (IP). A downlink model consisting of a base station (BS) and two users is considered, in which the near user (NU) is selected as a relay to forward the received signal from the BS to the far user (FU). Maximum ratio combining is then employed at the FU to combine both the signals received from the BS and NU. Closed form expressions of outage probability (OP), throughput, ergodic rate and energy efficiency (EE) are firstly derived for the SWIPT based C-NOMA considering both scenarios of having and without having direct link between the BS and FU. The impacts of EH time, EH efficiency, power-splitting ratio, source data rate and distance between different nodes on the performance are then investigated. The simulation results show that the C-NOMA with direct link achieves an outperformed performance over C-NOMA without direct link. Moreover, the performance of C-NOMA with direct link is also higher than that for OMA. Specifically, (i) the outage probability for C-NOMA in both direct and relaying link cases is always lower than that for OMA. (ii) the outage probability, throughput and ergodic rate vary according to b, (iii) the EE of both users can obtain in SNR range of from -10 to 5 dB and it decreases linearly as SNR increases. Numerical results are provided to verify the findings.
Bridging Heterogeneous Mutation Data to Enhance Disease-Gene Discovery
Authors: Zhou Kaiyin , Wang Yuxing , Cohen Kevin Bretonnel , Kim Jin-Dong , Ma Xiaohang , Shen Zhixue , Meng Xiangyu , Xia Jingbo
Published: August 2020

Background: Bridging heterogeneous mutation data fills in the gap between various data categories and propels discovery of disease-related genes. It is known that genome-wide association study (GWAS) infers significant mutation associations which link genotype and phenotype, and it is under-powered for pinpointing causal genes due to high false positive or negative rate. In the meantime, mutation events widely reported in literature unveil typical functional biological process, including mutation types like gain-of-function and loss-of-function. Methods: To bring together the heterogeneous mutation data, we propose a pipeline, “Gene-Disease Association prediction by Mutation Data Bridging (GDAMDB)”, with a statistic generative model. The model learns the distribution parameters of mutation associations and mutation types, and recovers false negative GWAS mutations which fail to pass significant test but represent supportive evidences of functional biological process in literature. Results: Eventually, GDAMDB is applied in Alzheimer’s disease which is a common inheritable neurodegenerative disorder with unknown pathological mechanism, and it predicted 79 AD-associated genes. Besides 12 of them come from the original GWAS study, 57 of them are supported to be AD-related by other GWAS or literature report. Conclusion: Our model is capable of enhancing the GWAS-based gene association discovery by well combining text mining results. The positive result indicates that bridging the heterogeneous mutation data is contributory for the novel disease-related gene discovery.
Classification of OCT Images for Detecting Diabetic Retinopathy Disease Using Machine Learning
Authors: Aldahami Marwan , Alqasemi Umar
Published: August 2020

Background Optical Coherence Tomography (OCT) imaging aids in retinal abnormality detection by showing the tomographic retinal layers. OCT images are a useful tool for detecting Diabetic Retinopathy (DR) disease because of their capability of capturing micrometer-resolution.Method An automated technique was introduced to differentiate DR images from normal ones. 214 images were subjected to the experiment, of which 160 images were used for classifiers’ training, and 54 images were used for testing. Different features were extracted to feed our classifiers, including statistical features and local binary pattern (LBP) features.Results The experimental results demonstrated that our classifiers were able to discriminate DR retina from the normal retina with ROC Area Under the Curve (AUC) of 100%.Conclusions The retinal OCT images have common texture patterns and using a powerful tool for pattern analysis like LBP features has a significant impact on the achieved results. The result has better performance than previously proposed methods in the literature.
Regional Binding of Tau and Amyloid Pet Tracers in Down Syndrome Autopsy Brain Tissue
Authors: Lemoine Laetitia , Ledreux Aurelie , Mufson Elliott J , Perez Sylvia E , Simic Goran , Doran Eric , Lott Ira , Carroll Steven , Bharani Krishna , Thomas Sarah , Gilmore Anah , Hamlett Eric D , Nordberg Agneta , Granholm Ann-Charlotte
Published: August 2020

INTRODUCTION: Tau pathology is a major age-related event in Down syndrome with Alzheimer’s disease (DS-AD). Although recently, several different Tau PET tracers have been developed as biomarkers for AD, these tracers showed different binding properties in Alzheimer disease and other non-AD tauopathies. They have not been yet investigated in tissue obtained postmortem for DS-AD cases. Here, we evaluated the binding characteristics of two Tau PET tracers (3H-MK6240 and 3H-THK5117) and one amyloid (3H-PiB) ligand in the medial frontal gyrus (MFG) and hippocampus (HIPP) in tissue from adults with DS-AD and DS cases with mild cognitive impairment (MCI) compared to sporadic AD. METHODS: Tau and amyloid autoradiography were performed on paraffin-embedded sections. To confirm respective ligand targets, adjacent sections were immunoreacted for phospho-Tau (AT8) and stained for amyloid staining using Amylo-Glo. RESULTS: The two Tau tracers showed a significant correlation with each other and with AT8, suggesting that both tracers were binding to Tau deposits. 3H-MK6240 Tau binding correlated with AT8 immunostaining but to a lesser degree than the 3H-THK5117 tracer, suggesting differences in binding sites between the two Tau tracers. 3H-THK5117, 3H-MK6240 and 3H-PIB displayed dense laminar binding in the HIPP and MFG in adult DS brains. A regional difference in Tau binding between adult DS and AD was observed suggesting differential regional Tau deposition in adult DS compared to AD, with higher THK binding density in the MFG in adult with DS compared to AD. No significant correlation was found between 3H-PiB and Amylo-Glo staining in adult DS brains suggesting that the amyloid PIB tracer binds to additional sites. CONCLUSIONS: This study provides new insights into the regional binding distribution of a first-generation and a second-generation Tau tracer in limbic and neocortical regions in adults with DS, as well as regional differences in Tau binding in adult with DS vs. those with AD. These findings provide new information about the binding properties of two Tau radiotracers for the detection of Tau pathology in adults with DS in vivo and provide valuable data regarding Tau vs. amyloid binding in adult DS compared to AD.
SARS-CoV-2 infection induces robust germinal center CD4 T follicular helper cell responses in rhesus macaques
Authors: Elizaldi Sonny , Lakshmanappa Yashavanth Shaan , Roh Jamin , Schmidt Brian , Carroll Timothy , Weaver Kourtney , Smith Justin , Deere Jesse , Dutra Joseph , Stone Mars , Franz Sergej , Sammak Rebecca , Olstad Katherine , Reader J. Rachel , Ma Zhong-Min , Nguyen Nancy , Watanabe Jennifer , Usachenko Jodie , Immareddy Ramya , Yee JoAnn , Weiskopf Daniela , Sette Alessandro , Hartigan-O'Connor Dennis , McSorley Stephen , Morrison John , Tran Nam , Simmons Graham , Busch Michael , Kozlowsk Pamela , Rompay Koen van , Miller Christopher , Iyer Smita
Published: August 2020

CD4 T follicular helper (Tfh) cells are important for the generation of durable and specific humoral protection against viral infections. The degree to which SARS-CoV-2 infection generates Tfh cells and stimulates the germinal center response is an important question as we investigate vaccine options for the current pandemic. Here we report that SARS-CoV-2 infection resulted in transient accumulation of pro-inflammatory monocytes and proliferating Tfh cells with a Th1 profile in peripheral blood. CD4 helper cell responses were skewed predominantly toward a Th1 response in blood, lung, and lymph nodes. We observed the generation of germinal center Tfh cells specific for the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins, and a corresponding early appearance of antiviral serum IgG antibodies. Our data suggest that a vaccine promoting Th1-type Tfh responses that target the S protein may lead to protective immunity.
Oxysterols Present in Alzheimer’s Disease Braininduce Synaptoxicity by Activating Astrocytes: A Major Role for Lipocalin-2
Authors: Staurenghi Erica , Cerrato Valentina , Gamba Paola , Testa Gabriella , Giannelli Serena , Leoni Valerio , Caccia Claudio , Buffo Annalisa , Noble Wendy , Perez-Nievas Beatriz Gomez , Leonarduzzi Gabriella
Published: August 2020

Background: Among Alzheimer’s disease (AD) brain hallmarks, the presence of reactive astrocytes was demonstrated to correlate with neuronal loss and cognitive deficits. Evidence indeed supports the role of reactive astrocytes as mediators of changes in neurons, including synapses. However, the complexity and the outcomes of astrocyte reactivity are far from being completely elucidated. Another key role in AD pathogenesis is played by alterations in brain cholesterol metabolism. Oxysterols (cholesterol oxidation products) are crucial for brain cholesterol homeostasis, and we previously demonstrated that changes in the brain levels of various oxysterols correlate with AD progression. Moreover, oxysterols have been shown to contribute to various pathological mechanisms involved in AD pathogenesis.In order to deepen the role of oxysterols in AD, we investigated whether they could contribute to astrocyte reactivity, and consequently impact on neuronal health.Methods: Mouse primary astrocyte cultures were used to test the effect of two oxysterol mixtures, that represent the oxysterol composition respectively of mild or severe AD brains, on astrocyte morphology, markers of reactivity, and secretion profile. Co-culture experiments were performed to investigate the impact of oxysterol-treated astrocytes on neurons. Neuronal cultures were exposed to astrocyte conditioned media (ACM) deprived of lipocalin-2 (Lcn2) to investigate the contribution of this mediator to synaptotoxicity.Results: Results showed that oxysterols induce a clear morphological change in astrocytes, accompanied by the upregulation of some reactive astrocyte markers, including Lcn2. Moreover, ACM analysis revealed a significant increase in the release of Lcn2, cytokines, and chemokines in response to oxysterols. A significant reduction of postsynaptic density protein 95 (PSD95) and a concurrent increase in cleaved caspase-3 protein levels have been demonstrated in neurons co-cultured with oxysterol-treated astrocytes, pointing out that mediators released by astrocytes have an impact on neurons. Among these mediators, Lcn2 has been demonstrated to play a major role on synapses, affecting neurite morphology and decreasing dendritic spine density. Conclusions: These data demonstrated that oxysterols present in the AD brain promote astrocyte reactivity, determining the release of several mediators that affect neuronal health and synapses. Lcn2 has been shown to exert a key role in mediating the synaptotoxic effect of oxysterol-treated astrocytes.
Short-term efficacy of trial medicine treatment may play a predictive value for the choice of therapy methods among brain abscess patients
Authors: Liu Zengjin , Guo Shewei , Sun Hongwei , Liu Xianzhi
Published: August 2020

Background: Traditionally, brain abscess with diameter beyond 2.5cm is considered to be treated with surgical methods, however in some cases medical treatment alone also got good results. Which patients with the abscess diameter beyond 2.5cm could be treated with medicine alone? Objective: 32 brain abscess patients accepted one week of trial medicine therapy and were divided into surgical group and conservative group according the ultimate therapy method. Methods: Some clinical factors including Glasgow Coma Scale (GCS), Karnofsky performance scores (KPS), and mini-mental state examination (MMSE), abscess sizes and edema indexes (EI) were recorded, and these factors were analyzed to observe the differences between the two groups.Results: The surgical group had larger abscess sizes (4.21±0.62cm vs 2.85±0.98cm p<0.001), lower GCS (10.00±1.04 vs 11.44±1.92 p=0.017), lower KPS (40.71±12.69 vs 52.78±20.24 p=0.061), and lower MMSE scores (8.57±1.40 vs 11.67±2.38 p=0.0008) before treatment than the conservative group. After trial therapy, the conservative group got higher extent of MMSE improvement (10.06±2.67 vs 4.86±0.66 p<0.0001) and abscesses sizes decline (0.7±0.40cm vs 0.15 ± 0.18cm p=0.0002) than surgical group, logistic analysis indicated consecutive variation of MMSE and change of abscess sizes during trial treatment might correlated closely to the ultimate treatment methods (p=0.027; p=0.019). Conclusions: These data might provide some clues for the selection of treatment methods for brain abscess patients.
Early Spot Sign is Associated with Functional Outcomes in Primary Intracerebral Hemorrhage Survivors
Authors: Hsiao Ming Yen , Tseng Wen-Che , Wang Yu-Fen , Wang Tyng-Guey
Published: August 2020

Background The computed tomography angiography (CTA) spot sign is a validated predictor of hematoma expansion and 30-day mortality in intracerebral hemorrhage (ICH). However, whether the spot sign predicts worse functional outcomes among ICH survivors remains unclear. This study investigated the frequency of the spot sign and its association with functional outcomes and length of hospital stay among ICH survivors.Methods This was a retrospective analysis of consecutive patients with primary ICH who received CTA within 24 h from presentation to admission to the emergency department of a single medical center between January 2007 and December 2017. Patients who died before discharge and those referred from other hospitals were excluded. CTAs with motion artifacts were excluded from the analysis. The presence of a spot sign was examined by an experienced neuroradiologist. Functional outcomes were determined based on the modified Rankin Scale (mRS) score and Barthel Index (BI). Severe dependency in activities of daily living (ADL) was defined as BI of ≤60 and severe disability as an mRS score of ≥4. Odds ratio (OR) and multiple linear regression were used as measures of association.Results In total, 66 patients met the inclusion criteria, of whom 9 (13.64%) were positive for a spot sign. No significant differences were observed in baseline characteristics between patients with and without a spot sign. Patients with a spot sign tended to be severely dependent in ADL at discharge (66.67% vs 41.07%; OR = 2.87; p = 0.15) and were more likely to require ICH-related surgery (66.67% vs 24.56%; OR = 6.14; p = 0.01). In multiple linear regression, patients with a higher spot sign score had a significantly longer hospital stay (coefficient = 9.57; 95% CI = 2.11–17.03; p = 0.013).Conclusions The presence of a spot sign is a common finding and is associated with longer hospital stay and possibly worse functional outcomes in ICH survivors.
Predictors of neurological deterioration during admission for patients with cerebellar strokes
Authors: Amornpojnimman Thanyalak , Sathirapanya Pornchai , Intusoma Utcharee , Sanghan Nuttha , Kaewborisutsakul Anukoon
Published: August 2020

Background: Despite less common, cerebellar stroke frequently results in unfavorable outcomes, especially after deterioration. Therefore, this study was aimed to identify the significant predictors of neurological deterioration during admission (NDDA) in ischemic and hemorrhagic cerebellar strokes.Materials and methods: We retrospectively reviewed all medical records of the patients diagnosed with ischemic and hemorrhagic cerebellar strokes during 2002-2018 in Songklanagarind hospital. Comparison of patients’ demographic data, initial clinical presentations, neuroradiological results, timing and signs of NDDA, and outcomes between cerebellar strokes were descriptively analyzed. Logistic regression model was applied for determining the significant predictors of NDDA from initial clinical presentations.Results: 74 of 100 patients were eligible. They comprised of 42 (57%) cerebellar ischemia (CI) and 32 (43%) cerebellar hemorrhage (CH). Elevated diastolic blood pressure (DBP) and the neuro-radiological evidences suggesting increased posterior cranial fossa pressure were significantly prevalent in neurological deterioration patients. NDDA was found in 31 patients (42%) without significant difference between CI and CH. 42 (56.8%) patients had poor neurological outcomes. The independent predictors for NDDA were DBP B 120 mmHg (adjusted odds ratio [adj. OR] 15.39, 95% CI 1.58-149.59; p = 0.004), time from onset to arrival (adj. OR 0.98, 95% CI 0.97-1.00; p = 0.044), and hemispheric cerebellar signs (adj. OR 0.22, 95% CI 0.06-0.75; p = 0.012).Conclusions: CH was not an independent predictor of NDDA in overall cerebellar strokes. Only high DBP predicted NDDA, whereas time to arrival and hemispheric signs showed protective impact.