bluuebunny/crossref_metadata_2025 huggingface dataset:
A Methylation-based nomogram for predicting survival in patients with lung adenocarcinoma
Authors: Wang Xuelong , Zhou Bin , Xia Yuxin , Zuo Jianxin , Liu Yanchao , Bi Xin , Luo Xiong , Zhang Chengwei
Published: September 2020

Background
DNA methylation alteration is frequently observed in Lung adenocarcinoma (LUAD) and may play important roles in carcinogenesis, diagnosis, and prognosis. Thus, this study aimed to construct a reliable methylation-based nomogram, guiding prognostic classification screening and personalized medicine for LUAD patients.
Method:
The DNA methylation data, gene expression data and corresponding clinical information of lung adenocarcinoma samples were extracted from The Cancer Genome Atlas (TCGA) database. Differentially methylated sites (DMSs) and differentially expressed genes (DEGs) were obtained and then calculated expression correlation by pearson correlation coefficient. Functional enrichment analysis and Protein-protein interaction network were used to explore the biological roles of aberrant methylation genes. A prognostic risk score model was constructed using univariate Cox and LASSO analysis and was assessed in an independent cohort. A methylation-based nomogram that included the risk score and the clinical risk factors was developed, which was evaluated by concordance index and calibration curves.
Result
We identified a total of 1362 DMSs corresponding to 471 DEGs with significant negative correlation, including 752 hypermethylation sites and 610 hypomethylation sites. Univariate cox regression analysis showed that 59 DMSs were significantly associated with overall survival. Using LASSO method, we constructed a three-DMSs signature that was independent predictive of prognosis in the training cohort. Patients in high-risk group had a significant shorter overall survival than patients in low-risk group classified by three-DMSs signature (log-rank p = 1.9E-04). Multivariate cox regression analysis proved that the three-DMSs signature was an independent prognostic factor for LUAD in TCGA-LUAD cohort (HR = 2.29, 95%CI: 1.47–3.57, P = 2.36E-04) and GSE56044 cohort (HR = 2.16, 95%CI: 1.19–3.91, P = 0.011). Furthermore, a nomogram, combining the risk score with clinical risk factors, was developed with C-indexes of 0.71 and 0.70 in TCGA-LUAD and GSE56044 respectively.
Conclusions
The present study established a robust three-DMSs signature for the prediction of overall survival and further developed a nomogram that could be a clinically available guide for personalized treatment of LUAD patients.
A potent synthetic nanobody targets RBD and protects mice from SARS-CoV-2 infection
Authors: Li Dianfan , Li Tingting , Cai Hongmin , Yao Hebang , Zhou Bingjie , Zhang Ning , Gong Yuhuan , Zhao Yapei , Shen Quan , Qin Wenming , Hutter Cedric , Lai Yanling , Kuo Shu-Ming , Bao Juan , Lan Jiaming , Seeger Markus , Wong Gary , Bi Yuhai , LAVILLETTE Dimitri
Published: September 2020

SARS-CoV-2, the causative agent of COVID-191, recognizes host cells by attaching its receptor-binding domain (RBD) to the host receptor ACE22-7. Neutralizing antibodies that block RBD-ACE2 interaction have been a major focus for therapeutic development8-18. Llama-derived single-domain antibodies (nanobodies, ~15 kDa) offer advantages including ease of production and possibility for direct delivery to the lungs by nebulization19, which are attractive features for bio-drugs against the global respiratory disease. Here, we generated 99 synthetic nanobodies (sybodies) by in vitro selection using three libraries. The best sybody, MR3 bound to RBD with high affinity (KD = 1.0 nM) and showed high neutralization activity against SARS-CoV-2 pseudoviruses (IC50 = 0.40 μg mL-1). Structural, biochemical, and biological characterization of sybodies suggest a common neutralizing mechanism, in which the RBD-ACE2 interaction is competitively inhibited by sybodies. Various forms of sybodies with improved potency were generated by structure-based design, biparatopic construction, and divalent engineering. Among these, a divalent MR3 conjugated with the albumin-binding domain for prolonged half-life displayed highest potency (IC50 = 12 ng mL-1) and protected mice from live SARS-CoV-2 challenge. Our results pave the way to the development of therapeutic nanobodies against COVID-19 and present a strategy for rapid responses for future outbreaks.
Massive Hemothorax in A Pregnant Patient With Neurofibromatosis Type 1
Authors: Hashimoto Kumiko , Nomata Yuji , Fukui Takayuki , Takada Akira , Narita Kunio
Published: September 2020

Background: Spontaneous hemothorax in a patient with neurofibromatosis type 1 is a less common though lethal complication, and there is no report which occurred in the pregnant period. We here present the first case of hemothorax in a neurofibromatosis type 1 patient during pregnancy and discus on the difficulty in diagnosis and treatment choice.Case Presentation: A 39-year-old female at 34 weeks gestation presented with sudden left back pain and dyspnea. Chest radiography revealed massive left pleural effusion. Although the patient was hemodynamically stable, the fetus was in a critical condition. Emergency cesarean section and endovascular coil embolization of the aneurysm of the intercostal artery were performed successfully. The patient’s condition improved immediately, and she was discharged 1 month later. Conclusions: A neurofibromatosis type 1 patients have the potential to develop massive hemothorax without gross lesions, especially late in pregnancy and postpartum.
Exploring the Acceptability and Relevance of Tool-supported Advance Care Planning (ACP) for a Long-term Care (LTC) Home Environment
Authors: Sussman Tamara , Kaasalainen Sharon , Bimman Rennie , Punia Harveer , Edsell Nathaniel , Sussman Jess
Published: September 2020

Objectives: Despite known benefits, advance care planning (ACP) is rarely a component of usual practice in long-term care (LTC). A series of tools and workbooks have been developed to support ACP uptake. Yet, their acceptability and relevance for LTC has yet to be examined. This study explored the extent to which available ACP materials hold promise in improving ACP engagement in LTC by (1) exploring LTC home staff’s reactions to tool supported ACP and (2) examining if available ACP tools include content of relevance to LTC. Methods: A combination of focus group deliberations with LTC home staff (N=32) and content analysis of publicly available ACP workbooks (N=32) were used to meet the study aims. Results: Focus group deliberations suggested that tool-directed ACP is a promising approach for LTC, provided tools include psychosocial elements and are paper-based. Content analysis of available tools revealed that only a handful of paper-based ACP tools (32/611, 5%) include, psychosocial content, with most encouraging psychosocially-oriented reflections (30/32, 84%), and far fewer providing direction around other elements of ACP such as communicating psychosocial preferences (14/32, 44%) or transforming preferences into a documented plan (7/32, 22%).Conclusions: Tool-supported ACP appears acceptable to LTC staff. To improve ACP uptake in LTC selected tools should include psychosocial content that can be supported by a range of clinical and non-clinical staff. Available ACP tools may require infusion of scenarios pertinent to frail older persons, and a better balance between psychosocial content that elicits reflections and psychosocial content that supports communication.
MIB1 Upregulates IQGAP1 and Promotes Pancreatic Cancer Progression by inducing ST7 Degradation
Authors: Liu Tao , Zhang Bin , jin xin , Cheng Xiang
Published: September 2020

BackgroundPancreatic cancer is a highly heterogeneous and has a poor prognosis. Elucidating the molecular mechanisms underlying pancreatic cancer progression is essential for improving patient survival. Although the E3 ubiquitin ligase mind bomb 1 (MIB1) is involved in cancer cell proliferation and is often overexpressed in pancreatic cancer, the role of MIB1 in pancreatic cancer progression remains unclear.Methods The relationship of MIB1 with the clinicopathological features of pancreatic tumors was bioinformatically investigated in different datasets. The protein levels of MIB1 and ST7 were assessed by Western blotting and immunohistochemistry. The role of MIB1 and ST7 in pancreatic cancer growth was assessed by MTS assays, colony formation assays, and experiments in mouse xenograft models. The interaction between MIB1 and ST7 was investigated by co-immunoprecipitation. The relationship between MIB1, ST7, and IQGAP1 levels was explored by Western blotting and quantitative real-time PCR.ResultsMIB1 expression was elevated in pancreatic cancer tissues, and its expression levels were associated with unfavorable prognosis. MIB1 overexpression enhanced pancreatic cancer proliferation and invasion in vitro and in vivo. We identified ST7 as a novel MIB1 target for proteasomal degradation. Further, we found that ST7 suppressed tumor growth by downregulating IQGAP1 in pancreatic cancer cells.ConclusionsThese data suggest that MIB1 promotes pancreatic cancer progression by inducing ST7 degradation. ST7 suppresses tumor growth by downregulating IQGAP1 in pancreatic cancer cells. Therefore, the MIB1/ST7/IQGAP1 axis is essential for pancreatic cancer progression, and MIB1 inhibition may improve the survival of pancreatic cancer patients.
The ‘Un-Shrunk’ Partial Correlation in Gaussian Graphical Models
Authors: Bernal Victor , Bischoff Rainer , Horvatovich Peter , Guryev Victor , Grzegorczyk Marco
Published: September 2020

Background: In systems biology, it is important to reconstruct regulatory networks from quantitative molecular profiles. Gaussian graphical models (GGMs) are one of the most popular methods to this end. A GGM consists of nodes (representing the transcripts, metabolites or proteins) inter-connected by edges (reflecting their partial correlations). Learning the edges from quantitative molecular profiles is statistically challenging, as there are usually fewer samples than nodes (‘high dimensional problem’). Shrinkage methods address this issue by learning a regularized GGM. However, it is an open question how the shrinkage affects the final result and its interpretation.Results: We show that the shrinkage biases the partial correlation in a non-linear way. This bias does not only change the magnitudes of the partial correlations but also affects their order. Furthermore, it makes networks obtained from different experiments incomparable and hinders their biological interpretation. We propose a method, referred to as the ‘un-shrunk’ partial correlation, which corrects for this non-linear bias. Unlike traditional methods, which use a fixed shrinkage value, the new approach provides partial correlations that are closer to the actual (population) values and that are easier to interpret. We apply the ‘un-shrunk’ method to two gene expression datasets from Escherichia coli and Mus musculus.Conclusions: GGMs are popular undirected graphical models based on partial correlations. The application of GGMs to reconstruct regulatory networks is commonly performed using shrinkage to overcome the “high-dimensional” problem. Besides it advantages, we have identified that the shrinkage introduces a non-linear bias in the partial correlations. Ignoring this type of effects caused by the shrinkage can obscure the interpretation of the network, and impede the validation of earlier reported results.
In Silico Mutagenesis Based Remodeling of SARs-CoV-1 Peptide (ATLQAIAS) to Inhibit SARs-CoV-2: Structural-dynamics and Free Energy Calculations
Authors: Khan Abbas , Umbreen Shaheena , Hameed Asma , Fatima Rida , Zahoor Ujala , Babar Zainib , Waseem Muhammad , Hussain Zahid , Rizwan Muhammad , Zaman Nasib , Ali Shahid , Suleman Muhammad , Shah Abdullah , Ali Liaqat , Ali Syed Shujait , Wei Dong-Qing
Published: September 2020

Background:The prolific spread of COVID-19 caused by a novel coronavirus (SARS-CoV-2) from its epicenter in Wuhan, China, to every nook and cranny of the world after December 2019, jeopardize the prevailing health system in the world and has raised serious concerns about human safety. To date efforts are continuing to design small molecule inhibitor, vaccines and many other therapeutic options are practiced but their final therapeutic potential is still to be tested. Using the old drug or vaccine or peptides could aid this process to avoid such long experimental procedure. Results:Hence, here we have repurposed a small peptide (ATLQAIAS) from the previous study which reported the inhibitory effects of this peptide. We used in silico mutagenesis approach to design more peptides from the native wild peptide, which revealed that substitutions (T2W, T2Y, L3R and A5W) could increase the binding affinity of the peptide towards the 3CLpro. Furthermore, using MD simulation and free energy calculation confirmed its dynamics stability and stronger binding affinities. Per-residues energy decomposition analysis revealed that the specified substitution significantly increased the binding affinity at residue level. Conclusion:Our wide-ranging analyses of binding affinities disclosed that our designed peptide owns the potential to hinder the SARS-CoV-2 and will reduce the progression of SARs-CoV-2-borne pneumonia. Our analysis strongly suggests the experimental and clinical validation of these peptides to curtail the recent corona outbreak.
Is Maternal Obesity Associated With Fetal Congenital Lung Malformations?
Authors: Stocker Linden , Wellseley Diana , Parasuraman Rajeswari , Stanton Michael , Howe David
Published: September 2020

BackgroundPrevious data demonstrated an increased incidence in congenital lung malformations (CLM) and hypothesised a link with maternal obesity.MethodA retrospective case-control study (1994-2017) including all cases of CLM and matched controls (N=114 pregnancies). For each diagnosis of a baby diagnosed antenatally with CLM, two controls were selected. Primary outcome measure was mean Body Mass Index of women of affected pregnancies.ResultsThe women in affected pregnancies had a greater BMI (26.7 ±5.2kg/m2 (n=38)) than the control women (24.6±4.7 kg/m2 (n=76)) (p=0.03). 60.5% (n=46) of women in the control group and 39.5% (n=15) women in the CLM group had a normal BMI (<25kg/m2). Women with a BMI > 25kg/m2 had a 1.53 relative risk (RR) of having an affected baby (p=0.02, 95% CI 1.05-2.24). ConclusionObesity is not associated with increased rates of CLM. There is a small clinical difference in the BMI of women affected by CLM.
Sorting nexin 3 induces myocardial injury via promoting retromer-dependent nuclear trafficking of STAT3
Authors: Lu Jing , Xu Suowen , Huo Yuqing , Hu Yuehuai , Wang Juanjian , Zhang Xiaolei , Sun Duanping , Wang Panxia , Li Zhuo-Ming , Liang Mengya , Wu Zhongkai , Liu Peiqing
Published: September 2020

Sorting nexins (SNXs), the retromer-associated cargo binding proteins, have emerged as critical regulators of the trafficking of proteins involved in the pathogenesis of diverse diseases. However, studies of SNXs in the development of cardiovascular diseases, especially pathological cardiac hypertrophy, are lacking. Here, we asked whether SNX3, the simplest structured isoform in the SNXs family, may act as a key inducer of myocardial injury. We reported that increased level of SNX3 was observed in failing hearts from human patients and mice. Cardiac-specific Snx3 knockout (Snx3-cKO) in mice significantly protected against isoproterenol (ISO) -induced cardiac injury at 12 weeks. Conversely, cardiac-specific Snx3 transgenic (Snx3-cTg) mice were more susceptible to ISO-induced cardiac injury at 12 weeks, and showed aggravated cardiac injury even heart failure at 24 weeks. Immunoprecipitation-based mass spectrometry (IP-MS), immunofluorescent staining, co-immunoprecipitation and localized surface plasmon resonance (LSPR) were performed to examine the direct interaction of SNX3-retromer with STAT3. STAT3 was discovered as a new interacting partner of SNX3-retromer, and SNX3-retromer served as an essential platform for assembling gp130/JAK2/STAT3 complexes and subsequent phosphorylation of STAT3 by direct combination at early endosomes. SNX3-retromer and STAT3 complexes were transiently imported into the nucleus after hypertrophic stimuli. Moreover, SNX3-retromer promoted importin α3-mediated STAT3 nuclear trafficking and ultimately leading to cardiac injury. Also, pharmacological inhibition of STAT3 reversed SNX3 overexpression-induced myocardial injury in vivo and in vitro. Taken together, our study reveals that SNX3 plays a key role in cardiac function and implicates SNX3 as a potential therapeutic target for cardiac hypertrophy and heart failure.
No-touch Harvesting in Off-pump Coronary Artery Bypass Grafting With Sequential Saphenous Vein Graft: A Single-center Prospective Randomized Controlled Trial
Authors: Hou Xuejian , Zhang Kui , Liu Taoshuai , Li Yang , Zhao Yang , Song Bangrong , Huang Zhuhui , Xu Shijun , Winata William Adiwignya , Zheng Jubing , Dong Ran
Published: September 2020

Background: Coronary artery bypass grafting (CABG) materials comprise the combination of the left internal mammary artery and saphenous vein. The patency rate of vein grafts is considered not ideal; more studies support that the no-touch (NT) procedure can improve the patency rate of vein grafts. However, it is not clear that the NT technology is used in the sequential saphenous vein grafting during off-pump coronary artery bypass surgery. This study explored whether the NT technique is safety and efficacy compared to the conventional manner in the off-pump coronary artery bypass surgery using sequential vein graft.Methods: This was a prospective single-center randomized controlled clinical trial. A total of 200 patients undergoing off-pump coronary artery bypass grafting in the sequential saphenous graft were randomly assigned to two groups: The no-touch(NT) and the conventional (CON) groups. Perioperative and postoperative data were collected prospectively during the hospital stay. The occlusion of sequential grafts was measured by cardiac computed tomography angiography (CCTA) 3-months post CABG. Leg wound complications were followed up. The mean diameter of sequential grafts for the first 100 patients was measured using CCTA, 3-months after the operation.Results: The primary endpoint was that there was no difference in occlusion of sequential venous grafts between the two groups (NT: 9/180 (4.4%), CON: 5/194 (1.5%), p=0.22). Similarly, there were no differences in composite clinical events (NT: 2/91 (2.2%), CON: 1/96 (1.0%), p=0.96). There was no difference in the leg wound complications between the two groups (NT: 8/91 (8.8%), CON: 4/96 (4.2%), p=0.20). However, there was a significant difference in the average diameter of sequential grafts between the two groups (NT: (2.98±0.42), CON: (3.26±0.51), p=0.005).Conclusions: The early clinical results suggest that the NT technique is safety and efficacy compared to the conventional technique in sequential grafting in off-pump coronary artery bypass surgery. The sequential grafts early expansion in the NT technique is not as pronounced as the conventional technique, which may have a long-term protective effect on the grafts.Trial Registration: Registered 1 November 2018, ClinicalTrials.gov NCT03729531, http://www.clinicaltrials.gov
Comparison Between IGS and Three ITRS Realizations
Authors: Liu Jiao , Chen Junping , Liu Peizhao , Tan Weijie , Dong Danan , Qu Weijing
Published: September 2020

Four space geodetic techniques (IGS, SLR, VLBI and DORIS) contribute to the realizations of International Terrestrial Reference System (ITRS). The GNSS-derived terrestrial reference frame generated from the second reprocessing campaign (repro2), named IG2, act as the IGS input to the most recently three realizations (ITRF2014, DTRF2014 and JTRF2014). Its origin and orientation are aligned to the IGb08, and its scale is defined by using the igs08.atx satellite antenna phase center offset (PCO) values. To study the consistencies and discrepancies between IGS solutions and the three ITRS realizations, we corrected the IG2 solutions to be uniform with the IGS14 frame and perform Helmert transformation to compare the IGS frame and the three ITRS realizations. Results indicate that IGS frame is more stable than the two secular frames especially in the periods after 2015. The similarity transformation parameters between the corrected IGS solutions and ITRF2014 show excellent agreement with a notable mean z-offset of around 1 mm. The transformation parameters between the corrected IGS solutions and DTRF2014 show linear discrepancies in the three categories parameters, where the origin offsets are around less than 5.5 mm, rotational alignment is consistent at the level of 4.5 uas/yr (about 0.15 mm/yr) and the scale exhibits a stable offset of 0.16 ppb. Unlike the two secular frames, distinct seasonal signals and interannual variations of translation time series can be observed from the comparison between JTRF2014 and the IGS solutions. The orientation of JTRF2014 is in worst agreement with the IGS solutions, which is related to biased no-net-rotation (NNR) condition due to weekly center of network (CN) variations. Moreover, the scale defined by JTRF2014 suffer from large instability variations over time.
The Prevalence of Iron Deficiency and Anemia and Their Impact on Survival in Patients at a Cardio-Oncology Clinic
Authors: Ciburiene Egle , Celutkiene J. , Aidietiene S. , Scerbickaite G. , Lyon Alexander R.
Published: September 2020

Background. Iron deficiency (ID) and anemia are common in both heart failure (HF) and cancer patients and are associated with poor quality of life and survival. The aims of this study were (1) to evaluate the prevalence, types, and confounding factors of ID and anemia in patients referred to cardio-oncology clinic, and (2) identify the association between iron metabolism parameters and survival of cardio-oncology patients.Methods. We assessed iron, ferritin, hemoglobin concentrations, transferrin saturation (TSAT), cancer type, brain natriuretic peptide (BNP), left ventricular ejection fraction (LVEF), kidney function, cardiovascular risk factors and survival in 599 patients who were referred to cardio-oncology clinic from 2011 to 2017.ID was defined by a TSAT < 20%, absolute iron deficiency (AID) with a serum ferritin level <100 μg/L while serum ferritin level of ≥100 µg/L was considered as functional iron deficiency (FID) and TSAT ≥20% was considered as no ID.Results. The prevalence of ID, AID, and FID was 46%, 31%, and 15% of study patients, respectively. Anemia was present in approximately half (54%) of the patients with any ID.Multivariate Cox analyses showed that male gender (HR 1.704 [1.207–2.404] p=0.002); previous cancer history (HR 1.879 [1.079–3.272] p=0.026); elevated BNP (HR 2.126 [1.258–3.590] p=0.005); TSAT<20% (HR 1.721 [1.214–2.439] p=0.002); ferritin c100 µg/L (HR 2.008 [1.088–3.706] p=0.026); serum iron concentration <12 µmol/L (HR 2.292 [1.614–3.255] p<0.001); FID (HR 2.538 [1.1618–3.981] p<0.001) and anemia (HR 2.462 [1.734–3.495] p<0.001) were significantly associated with increased risk of all-cause death.Conclusions. About half of cardio-oncology patients had anemia and iron deficiency, with the absolute type being twice as prevalent as the functional one. Patients with breast, gastrointestinal, and genitourinary cancer were affected more often. Both anemia and iron deficiency independently predicted all-cause mortality. Future studies are required to confirm ID as a risk factor and evaluate the clinical benefits of iron replacement therapy.
Combination of Pre-Exposure and Postexposure Prophylaxes Used for an Occupational Exposure to HIV: A Case Report
Authors: Zhao Rugang , Ding Rui , Zhang Qiang
Published: September 2020

Background: Pre-exposure prophylaxis (PrEP), the usage of antiretroviral medications in HIV-uninfected individuals to prevent acquisition of HIV, has been identified to be sufficient and safe for HIV prevention. Case presentation: A surgeon was prescribed Tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) as pre-exposure prophylaxis before he performed a surgery for HIV positive patient. After occupational exposure, he was prescribed TDF/FTC and Raltegravir as postexposure prophylaxis. Serology confirmed no HIV infection at follow-ups. Conclusion: This brief report presents a case who received PrEP and PEP in an occupational exposure to indicate the feasibility of the use of PrEP in occupational exposure.
Mitochondrial Genome Regulator TFAM Modulates Head and Neck Tumorigenesis Through Activation of Intracellular Metabolic Reprogramming and Oncogenic Effectors
Authors: Hsieh Yi-Ta , Tu Hsi-Feng , Yang Muh-Hwa , Chen Yi-Fen , Huang Chien-Ling , Chen Hsin-Ming , Li Wan-Chun
Published: September 2020

Background: Mitochondrial defect is often observed in cancers while, in comparison with other metabolic cues, mitochondria mediated regulations in controlling tumorigenesis are less emphasized. Mitochondrial transcriptional factor A (TFAM) acts as a key regulatory factor to control mitochondrial DNA (mtDNA) replication and packing; the role of TFAM in modulating carcinogenesis, however, is controversial. Current study therefore aims to define TFAM mediated regulations in head and neck cancer (HNC) development. Methods: Multifaceted analyses in HNC cells genetically manipulated for TFAM were performed. Clinical correlations of TFAM and its downstream Electron Transport Chain (ETC) associated factors in regulating HNC progression were also examined in HNC specimens and different clinical databasesResults: At the cellular level, it was demonstrated that shRNA mediated TFAM silencing resulted in an enhanced cell proliferation, both in vitro and in vivo; in contrast, TFAM overexpression suppressed cell growth. Moreover, TFAM loss also facilitated cell migration and chemodrug resistance. At the molecular basis, TFAM mediated phenotypic changes could be resulting from metabolic reprogramming by directing HNC metabolism towards aerobic glycolysis, based on the detection of less respiratory capacity in accompany with greater extracellular acidification in response to TFAM loss. Interestingly, it was also found that TFAM loss upregulated ERK1/2 and Akt-mTORC-S6 signaling activity, revealing a potential "mitochondrion-to-cytoplasm" retrograde regulatory cue in controlling HNC malignancy. Clinical impact of TFAM and its downstream targets was further examined in clinical HNC tissues while the results showed that TFAM expression and mtDNA copy numbers were significant dropped in HNC tissues compared with their normal counterparts. By using clinical databases, HNC subjects with higher TFAM expression and less genetic alteration(s) exhibited better survival rates. Conclusion: Collectively, Current study uncovered a tumor suppressing role of TFAM and mitochondrial genome in determining HNC oncogenicity. This TFAM mediated regualtions are through intracellular metabolic reprogramming and mitochondria-to-cytoplasm cross-talk to activate oncogenic signals.
Machine Learning-assisted Identification of Bioindicators Predicts Medium-chain Carboxylate Production Performance of an Anaerobic Mixed Culture
Authors: Liu Bin , Sträuber Heike , Saraiva Joao , Harms Hauke , Silva Sandra Godinho , Kleinsteuber Sabine , Rocha Ulisses
Published: September 2020

Background: The ability to quantitatively predict ecophysiological functions of microbial communities provides an important step to engineer microbiota for desired functions related to specific biochemical conversions. Here, we present the quantitative prediction of medium-chain carboxylate production in two continuous anaerobic bioreactors from 16S rRNA gene dynamics in enrichment cultures. Results: By progressively shortening the hydraulic retention time from 8 days to 2 days with different temporal schemes in both bioreactors operated for 211 days, we achieved higher productivities and yields of the target products n-caproate and n-caprylate. The datasets generated from each bioreactor were applied independently for training and testing in machine learning. A predictive model was generated by employing the random forest algorithm using 16S rRNA amplicon sequencing data. More than 90% accuracy in the prediction of n-caproate and n-caprylate productivities was achieved. Four inferred bioindicators belonging to the genera Olsenella, Lactobacillus, Syntrophococcus and Clostridium IV suggest their relevance to the higher carboxylate productivity at shorter hydraulic retention time. The recovery of metagenome-assembled genomes of these bioindicators confirmed their genetic potential to perform key steps of medium-chain carboxylate production.Conclusions: Shortening the hydraulic retention time of the continuous bioreactor systems allows to shape the communities with desired chain elongation functions. Using machine-learning, we demonstrated that 16S rRNA amplicon sequencing data can be used to predict bioreactor process performance quantitatively and accurately. Characterising and harnessing bioindicators holds promise to manage reactor microbiota towards selection of the target processes. Our mathematical framework is transferrable to other ecosystem processes and 3 microbial systems where community dynamics is linked to key functions. The general methodology can be adapted to data types of other functional categories such as genes, transcripts, proteins or metabolites.
Genetic Structure in 21 Remnant Phoebe Sheareri Populations in Southern China: Implications for Genetic Resource Conservation
Authors: Wang Yang , Lu Yunfeng , Xu Wenting , Han Xiao , Yang An’na , Lou Luhuan , Tong Zaikang , Zhang Junhong
Published: September 2020

Background: Phoebe sheareri (Lauraceae) is a valuable and endemic tree species in China, with limited large natural communities remnant. Genetic diversity and differentiation analysis are essential to manage their conservation and utilization. To provide a conservation and utilization strategy of P. sheareri based on sound genetic diversity and differentiation data.Results: We found medium level of genetic diversity and low inbreeding. Nei's gene diversity and Shannon’s information index value showed medium genetic diversity in nature populations of P. sheareri, which was higher than other two Phoebe species. AMOVA showed the genetic differentiation among populations was significantly, and 21.2% of genetic variation was among populations. Bayesian clustering, obtained with STRUCTURE, grouped the populations into four genetic clusters, whereas UPGMA analysis distinguished three main groups approximately in line with the geographic area of occurrence.Conclusion: Based on the study results, the establishment of gene conservation units must be considered in nature conserves in order to protect the genetic diversity of the species, and the proposal of sampling strategies for ex situ conservation and reforestation.
Cardiac Arrests and Outcomes at Accident and Emergency (A&E) Department in A Tertiary Care Hospital of Sri Lanka.
Authors: Jayasekera Priyamali , Dassanayake Gayani , Bandara Kasthuri , Vithanage Wiraj
Published: September 2020

Background : Witnessed cardiac arrest is a common occurrence in an A&E department. The reported incidence of witnessed cardiac arrest is variable around the world. The overall unadjusted survival to hospital discharge rate was18.4% at the time of performing this study [1]. Methods: This descriptive study was conducted between January 1, 2016 to December 31, 2016 ( one year) at the A&E department of Provincial General Hospital Kurunegala. The objective was to assess the aetiology, factors associated in outcomes of witnessed cardiac arrests, and the rate of occurrence of cardiac arrest at the A&E of Provincial General Hospital Kurunegala (PGHK). Survivors were followed up on for a one-year period following the study’s conclusion. Results: There were 123 witnessed cardiac arrests (mean age 64 (+/- 15.9) years, 64% male), out of which 25 patients were successfully resuscitated and transferred to intensive care units for further care. However, only 6 (4.9%) patients were discharged from the hospital. The three-month and one-year survival numbers were 6 (4.9%) (males: 4, females: 2) and 4 (3.3%) (males: 3, female: 1) respectively. The age of the sole female survivor after one year was 43 years and the ages of the three male survivors were 46, 54, and 55 years respectively. The most common aetiology for cardiac arrest was myocardial infarction (43.1%) while the most common initial rhythm was non-shockable (82%). The initial rhythm was shockable in all 6 survivors. Conclusion: The overall ratio of survival to discharge in this study was much lower in comparison to international figures. The poor survival rate in this study may be due a very high rate of cardiac arrests with initial non-shockable rhythms in this study’s population.
Participation in Cardiovascular Health Awareness Program (CHAP) by the Elderly Residents of Social Housing in Quebec: Social Network Analysis
Authors: Deville-Stoetzel Nadia , Kaczorowski Janusz , Agarwal Gina , Lussier Marie-Thérèse , Girard Magali
Published: September 2020

Background: The Cardiovascular Health Awareness Program (CHAP) was originally developed and evaluated as a community-based cardiovascular disease (CVD) prevention program in small to medium size communities in Ontario. Recently, CHAP has been adapted to target older individuals living in 14 social housing buildings in Ontario (7) and Quebec (7). The participation rates in the 10-months program varied across buildings in Quebec from 23.5% to 49.1%. Social network analysis (SNA) has been successfully used to assess and strengthen participation in health promotion programs. We applied SNA methods to investigate whether interpersonal relationships between tenants within buildings influence the participation in CHAP. Methods: We used sociometric questionnaires and complete network analysis, supplemented by qualitative interviews to examine relational dynamics of two buildings in Quebec with a low and a high attendance rates. All residents of the two buildings were eligible to be interviewed for the sociometric questionnaire. The participants for the qualitative part of the study were selected at random. Results: In total, 69 seniors participated in the study, including qualitative interviews. Among study participants selected for qualitative interviews, 10 attended almost all CHAP sessions, 10 attended once and 12 did not attend any. Quantitative results helped to identify well-known and appreciated local leaders. In building 1 which had a high attendance rate (34.3%), there was a main leader (In-degree or ‘named by others’ frequency 23.2%) who attended all sessions. In building 2 which had a low attendance rate (23.9%), none of the leaders had participated in CHAP sessions. Qualitative analysis showed that tenants who did not attend CHAP sessions (or other activities in the building) generally preferred to avoid conflicts, retaliation and gossip and did not want to get involved in clans and politics within the buildings. Conclusion: In order to increase attendance at CHAP sessions among residents of subsidized housings for seniors, we identified 4 potential strategies: increase participant confidentiality; deploy community peer-networks to enhance recruitment; pair attendants to ensure their future participation; intervene through an opinion leader or through bridging individuals.
Epimedokoreanin C, A Prenylated Flavonoid Isolated from Epimedium Koreanum, Induces Non-Apoptotic Cell Death with the Characteristics of Methuosis in Lung Cancer Cells
Authors: Liu Xiaoqing , Wang Shuqi , Zheng Hao , Liu Qingying , Shen Tao , Wang Xiaoning , Ren Dongmei
Published: September 2020

Background: Methuosis is a novel type of non-apoptotic cell death characterized by accumulation of cytoplasmic vacuoles. Identification of molecules that induce methuosis may provide alternative therapeutics for cancers that are refractory to apoptosis. Epimedokoreanin C (EKC) is a prenylated flavonoid isolated from a Chinese herb Epimedium koreanum. Methods: In this study, MTT assay, real-time cell analysis monitoring of cell growth and wound-healing assay were used for cell viability and migration evaluation. Flow cytometry was performed to assess apoptosis. Immunoblot analysis, immunofluorescence, pull-down assays and live cell imaging with fluorescent tracers were utilized to evaluate the regulation of signaling pathways.Results: EKC reduced cell viability accompanied by extreme vacuolation in lung cancer NCI-H292 cells. The EKC-induced cell death was clarified as non-apoptosis based on the absence of apoptotic changes. The vacuoles stimulated by EKC were supposed to be derived from macropinocytosis based on the engulfment of extracellular fluid tracer, Lucifer Yellow. The vacuoles acquired some characteristics of late endosomes supported that EKC-induced cell death could be described as methuosis. Rac1 and Arf6 were found to be regulated inversely after EKC treatment. Blocking Rac1 activation with the specific Rac1 inhibitor EHT 1864 prevented the accumulation of vacuoles induced by EKC markedly, suggested that the regulation of Rac1 and Arf6 was at least partial mechanism involved in EKC induced methuosis. EKC synergized the effects of doxorubicin and etoposide, demonstrating the effectiveness of using EKC to synergize conventional chemotherapy. Conclusions: Collectively, EKC was demonstrated as a methuosis-like cell death inducer in NCI-H292 cells. It has the potential to be used as an attractive prototype for developing drugs that could kill apoptosis-resistant cancer cells.
Serial Assessment of Circulating T lymphocyte Phenotype and Receptor Repertoire During Treatment of Non-Muscle Invasive Bladder Cancer with Adoptive T Cell Immunotherapy
Authors: Wang Xiaoli , Qiao Guoliang , Jiang Ni , Morse Michael A , Zhou Xinna , Wang Shuo , Wu Jiangping , Song Yuguang , Zhao Yanjie , Zhou Lei , Yuan Yanhua , Hobeika Amy , Ren Jun , Lyerly Herbert Kim
Published: September 2020

Background: Recurrence and progression of non-muscle-invasive bladder cancer (NMIBC) are frequent despite intravesical therapy. We hypothesized that administration of an activated T cell immunotherapy (ACT) at times when immunosuppressive populations were noted to have increased in peripheral blood would prevent recurrence of disease.Method: This was an N-of-1 study. A subject with multiple primary bladder high grade urothelial carcinomas who had initially completed standard resection and chemotherapy was enrolled. ACT consisted of dendritic cells mixed with cytokine induced killer cells (DC/CIK)) which were infused intravenously 18 times over a 6 year period in response to observed increases in peripheral blood immunosuppressive CD8+/CD28- cells. Peripheral blood was analyzed for T cell phenotype by flow cytometry, T cell receptor (TCR) repertoire, and circulating tumor DNA (ctDNA) by next generation sequencing (NGS) at the time of each infusion. Standard of care cystoscopy and pelvic CT scans have been performed at routine intervals. Results: The patient’s resected bladder tumors did not express PD-1 or PD-L1. There has been no recurrence of urothelial carcinoma. Peripheral blood cytotoxic T cells and unique TCR clones increased and suppressive T cell populations decreased after DC/CIK infusions. ctDNA detected mutations in six tumor relevant genes (ARID1B, MYCN, CDH23, SETD2, NOTCH4 and FAT1) at baseline but all of them disappeared after the DC-CIK infusions.Conclusion: DC/CIK infusions were associated with beneficial changes in T cell phenotype, TCR repertoire, decreases in circulating tumor DNA and sustained recurrence-free survival.
Protective Effects of Berberine on Rat Model of Polycystic Ovary Syndrome Through the PI3K/AKT Pathway
Authors: Yu Jia , Ding Caifei , Hua Zhoujia , Jiang Xuejuan , Wang Chenye
Published: September 2020

Background: Berberine (Ber), a Chinese herbal monomer has been reported to exhibit an array of pharmacological activities relating to the lowering of blood glucose and the treatment of polycystic ovarian syndrome (PCOS). However, the related mechanism underlying these activites is not clear. In the current study, we aimed to elucidate the effect of Ber on rat model of PCOS by PI3K/AKT signaling pathway.Methods: A letrozole-induced rat PCOS model and primary ovarian granulosa cells model to explore the protective effect and the mechanism of action of Ber. In PCOS rats, the values of fasting blood glucose (FBG) insulin resistance (HOMA-IR), fasting insulin (FINS) values and the serum hormone levels were measured. The ovarian tissues were stained with HE and TUNEL to undergo pathological and apoptosis examination. Moreover, the effect of Ber on proliferation and apoptosis of granulosa cells was detected by CCK-8 and flow cytometry. And then the influence of Ber on granulosa cells was confirmed by blockade of the PI3K/AKT pathway. In addition, the modulatory effect on the expression of related proteins by blockade of PI3K/AKT was demonstrated via western blot.Results: We found that Ber was able to recover the serum hormone levels and improve insulin resistance (IR) in PCOS rat model. The morphological lesion and apoptosis of the ovary was also restored with the Ber treatment. Blockade of the PI3K/AKT pathway attenuated the influences of Ber on proliferation and apoptosis of granulosa cells. Due to this, we discovered a correlation between the PI3K/AKT signaling pathway and the beneficial effects of Ber, demonstrating that its application could alter the expression levels of key proteins in the PI3K/APT pathway.Conclusion: The beneficial effects of Ber on PCOS, including alter serum hormone levels, recover ovary morphological lesions, improve IR, improve cell viability and inhibition of apoptosis, which is mediated through the PI3K/AKT pathway.
Optimal Time Period of Wearing Protective Collar After Anterior Cervical Discectomy and Fusion
Authors: Qian Yu , Yu Zhiwei , Liu Zhenlei , Duan Wanru , Zhao Zhongjing , Zheng Hongyu , Jian Fengzeng
Published: September 2020

Background: There is still no consensus on the time period of wearing collar after anterior cervical discectomy and fusion (ACDF). We aim to investigate the optimal time period of wearing protective collar.Methods: We retrospectively reviewed patients with cervical spondylosis who underwent one to two segment ACDF during January 2016 and December 2017, and included 97 patients who meet inclusion and exclusion criterion. Patients were divided into three groups according to the actual time period of wearing collar after ACDF including 1-4 week group, 5-8 week group, and 9-12 week group. We analyzed Japanese Orthopedic Association (JOA) score, Axial Symptom (AS) score and Neck Disability Index (NDI) before surgery and at post-operative 3 months to investigate the optimal time period of wearing collar.Results: JOA score: All three groups have a better post-operative JOA score compared with that before surgery (paired t test, p<0.05). There is no significant difference among the three groups with respect to post-operative JOA (ANOVA, p>0.05).AS score: The post-operative AS scores of 1-4 week group and 5-8 week group were significantly better than that before surgery (paired t test, p>0.05). While the post-operative AS score of 9-12 week group was significantly worse than preoperative AS score (paired t test, p<0.05).NDI: All three groups have a better post-operative NDI compared with that before surgery (McNemar test, p<0.05). Of note, in 5-8 week group, the percentage of no deficit increased by 45%, and the percentage of mild deficit decreased by 45% accordingly. That percentage is 26% and 31% in 1-4 week group and 9-12 week group, respectively. There was significant difference among these three groups (Fisher's exact probability test, p<0.05)Conclusions: For cervical spondylosis patients who underwent 1-2 segment ACDF, the optimal time period of wearing protective is 5-8 weeks. This time period results in comparable neurological outcome, least axial symptom risk, and highest chance of no deficit on neck function.
Risk of QT Prolongation through Drug-drug Interactions between Hydroxychloroquine and Concomitant Drugs Prescribed in Real-world Practice
Authors: Choi Byung Jin , Koo Yeryung , Kim Tae Young , Chung Wou Young , Jung Yun Jung , Park Ji Eun , Lim Hong-Seok , Park Bumhee , Yoon Dukyong
Published: September 2020

Background: Hydroxychloroquine has recently received attention as a treatment for COVID-19. However, hydroxychloroquine may prolong the QTc interval, thus increasing the risk of life-threatening arrhythmia. Many patients with COVID-19 have comorbidities, necessitating the use of several drugs simultaneously with hydroxychloroquine. However, the risk of QT prolongation due to drug-drug interactions (DDIs) between hydroxychloroquine and these co-medications has not been identified. Therefore, it is necessary to investigate the risk of QT interval prolongation due to DDIs between hydroxychloroquine and frequently used concurrent drugs.Methods and Results: Using 447,632 patients and 1,040,752 electrocardiograms, we investigated the risk of QT prolongation due to DDIs between hydroxychloroquine and 118 concurrent drugs frequently used in real-world practice. In the analysis, we observed that 11 drugs (trimebutine, tacrolimus, tramadol, rosuvastatin, ciclosporin, sulfasalazine, rofecoxib, diltiazem, piperacillin/tazobactam, and isoniazid) show DDIs with hydroxychloroquine in the direction of QT prolongation.Conclusions: We found 11 drugs that show significant (p <0.05) DDIs with hydroxychloroquine, thereby increasing the risk of QT prolongation in patients. It is necessary to consider prescribing alternative drugs that have less DDI when these drugs are concurrently administered with hydroxychloroquine. Further investigation is needed to assess more profoundly the risk of QT prolongation due to DDI with hydroxychloroquine of each drug that we found in this analysis.
Tropospheric carbonyl sulfide mass-balance based on direct measurements of sulfur isotopes
Authors: Davidson Chen , Amrani Alon , Angert Alon
Published: September 2020

Carbonyl sulfide (COS) is the major long-lived sulfur bearing gas in the atmosphere and a promising proxy for terrestrial gross primary production (GPP; CO2 uptake). However, large uncertainties in estimating the relative magnitude of the COS sources and sinks limit this approach. Isotopic measurements have been suggested as a novel tool to constrain COS sources, yet such measurements are currently scarce. Here we present, for the first time, a complete data-based tropospheric COS isotopic mass balance, which allows improved partition of the sources. We found an isotopic (δ34S±SE) value of 13.9±0.1‰ (versus V-CDT standard) for the troposphere, with an isotopic seasonal cycle driven by plant uptake. This seasonality agrees with a fractionation of -1.9±0.3‰ which we measured in plant-chamber experiments. Anthropogenic-influenced air samples indicated an anthropogenic COS isotopic signal of 8±1‰. Samples of seawater-equilibrated-air indicate that marine COS emissions have an isotopic signal of 13±0.4‰. Using our new data-based mass balance, we constrained the relative contribution of the two main tropospheric COS sources resulting in 26±11% for the anthropogenic source and 74±23% for the oceanic source. This constraint is important for a better understanding of the global COS budget and its improved use for GPP determination.