Miracle-dz/UniFAR-FTUs huggingface dataset:
Programmed Death Receptor 1 (PD1) Knockout and Human Telomerase Reverse Transcriptase (hTERT) Transduction Can Enhance Persistence and Antitumor Efficacy of Cytokine-Induced Killer Cells Against Hepatocellular Carcinoma

Background The weak antitumor efficacy and limited lifespan are the main obstacles that hinder the therapeutic effect of cytokine-induced killer (CIK) cell immunotherapy. In the study, we enhanced the persistence and the antitumor efficacy of CIK cell through PD-1 knockout and hTERT transduction. Material/Methods CIK cells were cultured from patients with hepatocellular carcinoma and PD-1 gene was knocked out through the Cas9 ribonucleoproteins (Cas9 RNPs) electroporation. TIDE assay, T7E1 mismatch cleavage assay, and clone Sanger sequencing were used to detect PD-1 knockout efficiency. The immunophenotype was analyzed by flow cytometry. After PD-1 knockout, the hTERT gene was transduced into PD-1 KO/CIK cells with lentiviral transduction. The hTERT expression and persistence of hTERT/PD-1 KO/CIK cells were evaluated by Western blotting and proliferation curve. The antitumor efficacy was detected by ELISPOT and cytotoxicity assay. The telomere length was measured by the Q-FISH and qPCR method. The karyotype assay was used to analyze the chromosome structural stability. Results The optimal knockout efficiency of PD-1 gene in CIK cells could reach 41.23±0.52%. PD-1 knockout did not affect the immunophenotype of CIK cells. The hTERT transduction enhanced persistence and increased the telomere length. ELISPOT and cytotoxicity assay showed hTERT/PD-1 KO/CIK cells had an enhanced antitumor efficacy. Meanwhile, PD-1 KO/CIK cells transduced with hTERT showed a normal karyotype. Conclusions PD-1 knockout combined with hTERT transduction could prolong the lifespan and enhance antitumor efficacy of CIK cells against hepatocellular carcinoma cell line.
Modulation of the Cannabinoid System: A New Perspective for the Treatment of the Alzheimer’s Disease

The pathogenesis of Alzheimer’s disease (AD) is somewhat complex and has yet to be fully understood. As the ef-fectiveness of the therapy currently available for AD has proved to be limited, the need for new drugs has become increas-ingly urgent. The modulation of the endogenous cannabinoid system (ECBS) is one of the potential therapeutic approaches that is attracting a growing amount of interest. The ECBS consists of endogenous compounds and receptors. The receptors CB1 and CB2 have already been well characterized: CB1 receptors, which are abundant in the brain, particularly in the hip-pocampus, basal ganglia and cerebellum, regulate memory function and cognition. It has been suggested that the activation of CB1 receptors reduces intracellular Ca concentrations, inhibits glutamate release and enhances neurotrophin expression and neurogenesis. CB2 receptors are expressed, though to a lesser extent, in the central nervous system, particularly in the mi-croglia and immune system cells involved in the release of cytokines. CB2 receptors have been shown to be upregulated in neuritic plaque-associated microglia in the hippocampus and entorhinal cortex of patients, which suggests that these receptors play a role in the inflammatory pathology of AD. The role of the ECBS in AD is supported by cellular and animal models. By contrast, few clinical studies designed to investigate therapies aimed at reducing behaviour disturbances, especially night-time agitation, eating behaviour and aggressiveness, have yielded positive results. In this review, we will describe how the manipulation of the ECBS offers a potential approach to the treatment of AD.
Malignant Otitis Externa Outcomes: A Study of the University HealthSystem Consortium Database

Objective: To characterize factors that affect outcomes for patients with malignant otitis externa (MOE). Methods: Retrospective review of inpatients with MOE was performed. Patient demographics, comorbid conditions, complications, procedures, and mortalities were analyzed. Results: A total of 786 patients with MOE were identified. The mean hospitalization length of stay (LOS) was 18.6 days (SD = 19.7). The overall mortality rate was 2.5% (n = 20), and complication rate was 4.3% (n = 34). Increasing age significantly and positively correlated with the incidence of MOE (r = 0.979, P < .0001). Factors that were associated with an increased rate of mortality were sepsis (odds ratio [OR] = 18.5; ES = 0.94; 95% CI, 0.47-1.42), congestive heart failure (OR = 3.1; ES = 0.42; 95% CI, 0.02-0.82), weight loss (OR = 10.2; ES = 1.23; 95% CI, 0.61-1.85), and coagulopathy (OR = 8.8; ES = 1.84; 95% CI, 0.91-2.77). Surgical intervention was performed in 19.2% (n = 151) of patients. Facial nerve involvement was present in 15.5% (n = 122) of patients and was associated with a significantly longer LOS of 12.9 days (SD = 19.6; ES = 0.21; 95% CI, 0.03-0.41). Conclusions: This large multi-institutional database study of MOE demonstrates that several patient factors impact the LOS and mortality. Patients at risk for unfavorable outcomes include the elderly, male gender, comorbidities, or cranial nerve involvement.
Generating Better Queries for Systematic Reviews

Systematic reviews form the cornerstone of evidence based medicine, aiming to answer complex medical questions based on all evidence currently available. Key to the effectiveness of a systematic review is an (often large) Boolean query used to search large publication repositories. These Boolean queries are carefully crafted by researchers and information specialists, and often reviewed by a panel of experts. However, little is known about the effectiveness of the Boolean queries at the time of formulation. In this paper we investigate whether a better Boolean query than that defined in the protocol of a systematic review, can be created, and we develop methods for the transformation of a given Boolean query into a more effective one. Our approach involves defining possible transformations of Boolean queries and their clauses. It also involves casting the problem of identifying a transformed query that is better than the original into: (i) a classification problem; and (ii) a learning to rank problem. Empirical experiments are conducted on a real set of systematic reviews. Analysis of results shows that query transformations that are better than the original queries do exist, and that our approaches are able to select more effective queries from the set of possible transformed queries so as to maximise different target effectiveness measures.
Influence of the intensity of galvanic vestibular stimulation and cutaneous stimulation on the soleus H-reflex in healthy individuals

Modulation of the soleus H-reflex following galvanic vestibular stimulation (GVS) has been used to evaluate vestibulospinal tract function. It is not known whether this modulation is because of vestibular stimulation and/or cutaneous stimulation, and the suitable stimulating intensity of GVS for the modulation is not established. We investigated the influence of GVS intensity and cutaneous stimulation on the soleus H-reflex in healthy adults. We applied cathodal GVS (at 1, 2, and 3 mA) or 3-mA cutaneous stimulation as a conditioning stimulation in a random order to 17 individuals in the prone position with the head facing forward, and we examined the changes in the right soleus H-reflex amplitude. We maintained the interval between the conditioning stimulation’s onset and the tibial nerve stimulation evoking the soleus H-reflex constant at 100 ms. The amplitude of all conditioned H-reflexes was significantly larger than that of the unconditioned H-reflexes. The greatest facilitation of the H-reflex occurred when 3-mA GVS was applied. The degree of facilitation of the H-reflex by 3-mA GVS was significantly larger than that produced by the 3-mA cutaneous stimulation. These findings indicate that (a) the facilitation of the soleus motor neuron pool excitability by GVS is derived from both vestibular stimulation and cutaneous stimulation, and (b) the intensity of GVS affects the degree of facilitation. When this technique is used to examine vestibulospinal tract function, no less than 3 mA GVS may be appropriate as the conditioning stimulation.
A Systematic Review and Meta-Analysis of the Association between Water, Sanitation, and Hygiene Exposures and Cholera in Case–Control Studies

Abstract. Case–control studies are conducted to identify cholera transmission routes. Water, sanitation, and hygiene (WASH) exposures can facilitate cholera transmission (risk factors) or interrupt transmission (protective factors). To our knowledge, the association between WASH exposures and cholera from case–control studies has not been systematically analyzed. A systematic review was completed to close this gap, including describing the theory of risk and protection, developing inclusion criteria, searching and selecting studies, assessing quality of evidence, and summarizing associations between cholera and seven predicted WASH protective factors and eight predicted WASH risk factors using meta-analysis and sensitivity analysis. Overall, 47 articles describing 51 individual studies from 30 countries met the inclusion criteria. All eight predicted risk factors were associated with higher odds of cholera (odds ratio [OR] = 1.9–5.6), with heterogeneity (I2) of 0–92%. Of the predicted protective factors, five of seven were associated with lower odds of cholera (OR = 0.35–1.4), with heterogeneity of 57–91%; exceptions were insignificant associations for improved water source (OR = 1.1, heterogeneity 91%) and improved sanitation (OR = 1.4, heterogeneity 68%). Results were robust; 3/70 (5%) associations changed directionality or significance in sensitivity analysis. Meta-analysis results highlight that predicted risk factors are associated with cholera; however, predicted protective factors are not as consistently protective. This variable protection is attributed to 1) cholera transmission via multiple routes and 2) WASH intervention implementation quality variation. Water, sanitation, and hygiene interventions should address multiple transmission routes and be well implemented, according to international guidance, to ensure that field effectiveness matches theoretical efficacy. In addition, future case–control studies should detail WASH characteristics to contextualize results.
Nosocomial Staphylococcal Toxic Shock. Case Report

Abstract Staphylococcal toxic shock syndrome (STSS) is a rare, potentially lethal infection, with a clinical picture of multiple organ dysfunction and shock. The etiology is Staphylococcus aureus exotoxin, while enterotoxins act as superantigens. Most cases are identified in women using a vaginal tampon. A 51-year-old female, with a past medical history of biliary dyskinesia, presented in the emergency room complaining of sudden onset of abdominal pain, vomiting, headache, myalgia, and chills. The initial diagnosis was biliary colic and was treated parenterally with Amoxi-clavulanate and fluid replacement. Initially, progress was unsatisfactory. Four days after admission she developed a systemic inflammatory syndrome, diffuse rash, jaundice, oliguria, confusion, persistent hypotension and biological evidence of thrombocytopenia, nitrogen retention, and cholestasis. She was admitted to the intensive care unit. A gluteal phlegmon induced after intramuscular injections was identified and surgically treated. Blood bacteriological cultures were negative, though MRSA was isolated in phlegmon pus. A diagnosis of STSS was based on CDC criteria. The risks of similar infections could be prevented by limiting intramuscular treatments and monitoring invasive procedures.
Immunohistochemical analysis of neutrophils, interleukin‐17, matrix metalloproteinase‐9, and neoformed vessels in oral squamous cell carcinoma

BACKGROUND Tumor-associated neutrophils (TAN), matrix metalloproteinase-9 (MMP-9), interleukin-17 (IL-17), and angiogenesis have been proposed as prognostic biomarkers of malignant tumors. The purpose of this study was to investigate these inflammatory markers as prognostic factors for oral squamous cell carcinoma (OSCC). METHODS Specimens of OSCC (n = 30), healthy oral mucosa (negative control, n = 10), oral leukoplakia (n = 10), and apical granuloma with abscess (positive inflammatory controls, n = 10) were immunostained for CD66b (neutrophils), MMP-9, IL-17, and CD105 (neoformed microvessels). Semiquantitative (IL-17) and quantitative (CD66b, IL-17, MMP-9, and CD105) analyses were performed. Clinical information (TNM stage, metastasis, recurrence, and survival) and tumor histological grade were also obtained. RESULTS Positivity for TAN, MMP-9, IL-17, and CD105 was higher in OSCC than in the negative control (P < 0.05) and oral leukoplakia, but similar to the positive inflammatory control. Coincident high counts of inflammatory markers (CD66b, MMP-9, IL-17, and CD105) were associated with lymph node metastasis of OSCC. Associations between high numbers of neoformed microvessels and advanced clinical stage and a higher degree of malignancy were also demonstrated. CONCLUSIONS Combined positivity for TAN, MMP-9, IL-17, and CD105 appears to be associated with the metastasis-prone phenotype of OSCC.
Response to the letter by Dr. Förster and Pitkanen regarding our manuscript “Incidence and related factors for intraoperative failed spinal anaesthesia for lower limb arthroplasty”

We thank Dr. Förster and Dr. Pitkanen for their interest in our studies. The current study regarding failed spinal anaesthesia (FSA) confirms previous small‐scale studies, by using real‐life data from high‐volume expert orthopaedic centres with standardized anaesthetic technique. Our study confirms that FSA is indeed an unpredictable clinical problem in a minor proportion of patients. We look forward to future studies on how to solve the pre‐operative risk assessment for FSA.
Transcriptomic Characterization of Endometrioid, Clear Cell, and High-Grade Serous Epithelial Ovarian Carcinoma

Background: Endometrioid carcinoma (EC) and clear cell carcinoma (CC) histotypes of epithelial ovarian cancer are understudied compared with the more common high-grade serous carcinomas (HGSC). We therefore sought to characterize EC and CC transcriptomes in relation to HGSC. Methods: Following bioinformatics processing and gene abundance normalization, differential expression analysis of RNA sequence data collected on fresh-frozen tumors was completed with nonparametric statistical analysis methods (55 ECs, 19 CCs, 112 HGSCs). Association of gene expression with progression-free survival (PFS) was completed with Cox proportional hazards models. Eight additional multi-histotype expression array datasets (N = 852 patients) were used for replication. Results: In the discovery set, tumors generally clustered together by histotype. Thirty-two protein-coding genes were differentially expressed across histotype (P < 1 × 10−10) and showed similar associations in replication datasets, including MAP2K6, KIAA1324, CDH1, ENTPD5, LAMB1, and DRAM1. Nine genes associated with PFS (P < 0.0001) showed similar associations in replication datasets. In particular, we observed shorter PFS time for CC and EC patients with high gene expression for CCNB2, CORO2A, CSNK1G1, FRMD8, LIN54, LINC00664, PDK1, and PEX6, whereas, the converse was observed for HGSC patients. Conclusions: The results suggest important histotype differences that may aid in the development of treatment options, particularly those for patients with EC or CC. Impact: We present replicated findings on transcriptomic differences and how they relate to clinical outcome for two of the rarer ovarian cancer histotypes of EC and CC, along with comparison with the common histotype of HGSC. Cancer Epidemiol Biomarkers Prev; 27(9); 1101–9. ©2018 AACR.
TFE3 translocation and protein expression in renal cell carcinoma are correlated with poor prognosis

Since Xp11.2 translocation‐associated renal cell carcinoma (TRCC) was first recognised, its morphological features and the clinical significance of TFE3 expression, frequency of gene translocation and diagnostic criteria have been the subject of limited studies. The present retrospective analysis aimed to evaluate the correlation between TFE3 immunoreactivity and its gene translocation status using fluorescence in‐situ hybridisation (FISH) and determine how TFE3 translocation and expression affect patient prognosis differently.
Study on the mechanism behind lncRNA MEG3 affecting clear cell renal cell carcinoma by regulating miR‐7/RASL11B signaling

The goal of this research was to study the relationships between maternally expressed gene 3 (MEG3), microRNA‐7 (miR‐7), and RASL11B, and explore their influence on the progression of clear cell renal cell carcinoma (CCRCC). Microarray analysis was conducted using the data provided by The Cancer Genome Atlas. The expression levels of MEG3 and miR‐7 in CCRCC and adjacent tissue samples were ascertained by quantitative real‐time polymerase chain reaction (qRT‐PCR). The cell proliferation activity was unmasked by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay, and cell apoptosis and cell cycle were investigated by flow cytometry. A dual luciferase reporter assay was used to verify target relationships. Wound healing assay and transwell assay were used to detect cell migration and invasion ability. Decreased MEG3 expression was observed in CCRCC tissues and cells. Overexpression of MEG3 accelerated apoptosis; inhibited cell proliferation, migration and invasion; and induced G0/G1 phase cell cycle arrest in CCRCC. MiR‐7, directly binding to MEG3, was overexpressed in the CCRCC tissues and could inhibit the apoptosis and promote the migration and invasion of CCRCC cells. RASL11B, lowly expressed in CCRCC, was a target of miR‐7. After the overexpression of RASL11B, G0/G1 phase cell cycle arrest was induced; cell apoptosis was promoted; and the proliferation, invasion, and migration of CCRCC cells were inhibited. MEG3 could up‐regulate RASL11B to inhibit the cell proliferation, invasion, and migration; induce G0/G1 cell cycle arrest; and promote cell apoptosis by suppressing miR‐7 in CCRCC.
Determinants of quality of life as measured with variants of SF-36 in patients with predialysis chronic kidney disease

Objectives: To determine the average health-related quality of life (HRQOL) score levels and their determinants in patients with predialysis chronic kidney disease (CKD). Methods: A systematic literature search was conducted for relevant observational studies published between April 2007 and April 2017 in MEDLINE, EBSCOhost, and CINAHL databases. Results: Thirteen observational studies with a total sample of 8635 subjects comprising 53.3% male with an aggregate mean age of 59.5 (SD 14.9) years were included in this review. Of the 8 generic HRQOL domains of the Short-Form Health Surveys, Social Functioning had the highest mean score whereas General Health had the lowest mean score in patients with predialysis CKD. Physical component summary (PCS) was more impaired than mental component summary (MCS). The determinants of poor HRQOL in predialysis CKD patients included both modifiable risk factors such as comorbidities (namely anxiety and depression), low serum hemoglobin level, sedentary lifestyle, unemployment and non-modifiable risk factors such as poor glomerular filtration rate, female gender, and older age. The risk factors impeded PCS more than MCS. Conclusion: Several risk factors influence HRQOL impairment in patients with predialysis CKD, with PCS being more impacted than MCS. The risk factors for poor HRQOL are important for future research and for improving renal care in patients with predialysis CKD. PROSPERO registration number: CRD42018093385
[Characteristics of N2O Release and Influencing Factors in Grass-type and Algae-type Zones of Taihu Lake During Summer].

Spatial heterogeneity of N2O generation and emissions in multi-ecotype lakes limited the accurate estimation of the N2O fluxes in lakes, but few studies on the characteristics of N2O generation and emissions have been conducted. In this study, N2O flux at the water-gas interface, dissolved N2O concentration in the water column, and N2O flux at the sediment-water interface in typical grass-type and algal-type zones of Taihu Lake were analyzed during summer, and indoor micro-environment experiments were conducted to illustrate the main factors affecting the generation and emissions of N2O. The results showed that the N2O fluxes at the water-gas interface, dissolved N2O concentration, and N2O fluxes at the sediment-water interface of the emergent macrophyte type area was higher than the algae-type area and submerged macrophyte area during the summer. , with N2O fluxes at the water-gas interface of (115.807±7.583), (79.768±1.842), and (3.685±0.295) μmol ·(m2 ·h)-1, respectively. The dissolved N2O concentration in the water column were (0.051±0), (0.029±0.001), and (0.018±0) μmol ·L-1, respectively; and the N2O fluxes at the sediment-water interface were (178.275±3.666), (160.685±0.642), and (75.665±1.016) μmol ·(m2 ·h)-1, respectively. The spatial difference could be attributed to dominant plants and the concentration of inorganic nitrogen in the water column. The results of micro-environment experiments showed that nitrate and organic carbon sources could significantly increase the N2O production potential of sediments, the high concentration of NH4+-N in the water column might inhibit the N2O production in sediments, and the production rates of N2O in the sediment increased remarkably when the incubation temperature increased, suggesting that the generation and emissions of N2O were mainly restricted by nitrate, organic carbon, and temperature in summer.
Dynamics of Genome Alterations in Crohn's Disease–Associated Colorectal Carcinogenesis

Purpose: Patients with inflammatory bowel diseases, that is, ulcerative colitis and Crohn's disease (CD), face an increased risk of developing colorectal cancer (CRC). Evidence, mainly from ulcerative colitis, suggests that TP53 mutations represent an initial step in the progression from inflamed colonic epithelium to CRC. However, the pathways involved in the evolution of CRC in patients with CD are poorly characterized. Experimental Design: Here, we analyzed 73 tissue samples from 28 patients with CD-CRC, including precursor lesions, by targeted next-generation sequencing of 563 cancer-related genes and array-based comparative genomic hybridization. The results were compared with 24 sporadic CRCs with similar histomorphology (i.e., mucinous adenocarcinomas), and to The Cancer Genome Atlas data (TCGA). Results: CD-CRCs showed somatic copy-number alterations (SCNAs) similar to sporadic CRCs with one notable exception: the gain of 5p was significantly more prevalent in CD-CRCs. CD-CRCs had a distinct mutation signature: TP53 (76% in CD-CRCs vs. 33% in sporadic mucinous CRCs), KRAS (24% vs. 50%), APC (17% vs. 75%), and SMAD3 (3% vs. 29%). TP53 mutations and SCNAs were early and frequent events in CD progression, while APC, KRAS, and SMAD2/4 mutations occurred later. In four patients with CD-CRC, at least one mutation and/or SCNAs were already present in non-dysplastic colonic mucosa, indicating occult tumor evolution. Conclusions: Molecular profiling of CD-CRCs and precursor lesions revealed an inflammation-associated landscape of genome alterations: 5p gains and TP53 mutations occurred early in tumor development. Detection of these aberrations in precursor lesions may help predicting disease progression and distinguishes CD-associated from sporadic colorectal neoplasia. Clin Cancer Res; 24(20); 4997–5011. ©2018 AACR.