An epithelial–mesenchymal transition-related long noncoding RNA signature correlates with the prognosis and progression in patients with bladder cancer

Bladder cancer is a common malignant tumour worldwide. Epithelial–mesenchymal transition (EMT)-related biomarkers can be used for early diagnosis and prognosis of cancer patients. To explore, accurate prediction models are essential to the diagnosis and treatment for bladder cancer. In the present study, an EMT-related long noncoding RNA (lncRNA) model was developed to predict the prognosis of patients with bladder cancer. Firstly, the EMT-related lncRNAs were identified by Pearson correlation analysis, and a prognostic EMT-related lncRNA signature was constructed through univariate and multivariate Cox regression analyses. Then, the diagnostic efficacy and the clinically predictive capacity of the signature were assessed. Finally, Gene set enrichment analysis (GSEA) and functional enrichment analysis were carried out with bioinformatics. An EMT-related lncRNA signature consisting of TTC28-AS1, LINC02446, {"type":"entrez-nucleotide","attrs":{"text":"AL662844.4","term_id":"17978158","term_text":"AL662844.4"}}AL662844.4, {"type":"entrez-nucleotide","attrs":{"text":"AC105942.1","term_id":"18129419","term_text":"AC105942.1"}}AC105942.1, {"type":"entrez-nucleotide","attrs":{"text":"AL049840.3","term_id":"7406443","term_text":"AL049840.3"}}AL049840.3, SNHG26, USP30-AS1, PSMB8-AS1, {"type":"entrez-nucleotide","attrs":{"text":"AL031775.1","term_id":"4071041","term_text":"AL031775.1"}}AL031775.1, {"type":"entrez-nucleotide","attrs":{"text":"AC073534.1","term_id":"8655969","term_text":"AC073534.1"}}AC073534.1, {"type":"entrez-nucleotide","attrs":{"text":"U62317.2","term_id":"6862558","term_text":"U62317.2"}}U62317.2, C5orf56, {"type":"entrez-nucleotide","attrs":{"text":"AJ271736.1","term_id":"8979791","term_text":"AJ271736.1"}}AJ271736.1, and {"type":"entrez-nucleotide","attrs":{"text":"AL139385.1","term_id":"6996206","term_text":"AL139385.1"}}AL139385.1 was constructed. The diagnostic efficacy of the signature was evaluated by the time-dependent receiver-operating characteristic (ROC) curves, in which all the values of the area under the ROC (AUC) were more than 0.73. A nomogram established by integrating clinical variables and the risk score confirmed that the signature had a good clinically predict capacity. GSEA analysis revealed that some cancer-related and EMT-related pathways were enriched in high-risk groups, while immune-related pathways were enriched in low-risk groups. Functional enrichment analysis showed that EMT was associated with abundant GO terms or signaling pathways. In short, our research showed that the 14 EMT-related lncRNA signature may predict the prognosis and progression of patients with bladder cancer.     

Human papillomavirus seroprevalence in pregnant women following gender-neutral and girls-only vaccination programs in Finland: A cross-sectional cohort analysis following a cluster randomized trial

BackgroundCervical cancer elimination through human papillomavirus (HPV) vaccination programs requires the attainment of herd effect. Due to its uniquely high basic reproduction number, the vaccination coverage required to achieve herd effect against HPV type 16 exceeds what is attainable in most populations. We have compared how gender-neutral and girls-only vaccination strategies create herd effect against HPV16 under moderate vaccination coverage achieved in a population-based, community-randomized trial.Methods and findingsIn 2007–2010, the 1992–1995 birth cohorts of 33 Finnish communities were randomized to receive gender-neutral HPV vaccination (Arm A), girls-only HPV vaccination (Arm B), or no HPV vaccination (Arm C) (11 communities per trial arm). HPV16/18/31/33/35/45 seroprevalence differences between the pre-vaccination era (2005–2010) and post-vaccination era (2011–2016) were compared between all 8,022 unvaccinated women <23 years old and resident in the 33 communities during 2005–2016 (2,657, 2,691, and 2,674 in Arms A, B, and C, respectively). Post- versus pre-vaccination-era HPV seroprevalence ratios (PRs) were compared by arm. Possible outcome misclassification was quantified via probabilistic bias analysis. An HPV16 and HPV18 seroprevalence reduction was observed post-vaccination in the gender-neutral vaccination arm in the entire study population (PR₁₆ = 0.64, 95% CI 0.10–0.85; PR₁₈ = 0.72, 95% CI 0.22–0.96) and for HPV16 also in the herpes simplex virus type 2 seropositive core group (PR₁₆ = 0.64, 95% CI 0.50–0.81). Observed reductions in HPV31/33/35/45 seroprevalence (PR_31/33/35/45 = 0.88, 95% CI 0.81–0.97) were replicated in Arm C (PR_31/33/35/45 = 0.79, 95% CI 0.69–0.90).ConclusionsIn this study we only observed herd effect against HPV16/18 after gender-neutral vaccination with moderate vaccination coverage. With only moderate vaccination coverage, a gender-neutral vaccination strategy can facilitate the control of even HPV16. Our findings may have limited transportability to other vaccination coverage levels.Trial registrationClinicalTrials.gov number {"type":"clinical-trial","attrs":{"text":"NCT00534638","term_id":"NCT00534638"}}NCT00534638, https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT00534638","term_id":"NCT00534638"}}NCT00534638.     

The selective alpha7 nicotinic acetylcholine receptor agonist AR-R17779 does not affect ischemia–reperfusion brain injury in mice

Inflammation plays a central role in stroke-induced brain injury. The alpha7 nicotinic acetylcholine receptor (α7nAChR) can modulate immune responses in both the periphery and the brain. The aims of the present study were to investigate α7nAChR expression in different brain regions and evaluate the potential effect of the selective α7nAChR agonist AR-{"type":"entrez-nucleotide","attrs":{"text":"R17779","term_id":"771389"}}R17779 on ischemia–reperfusion brain injury in mice. Droplet digital PCR (ddPCR) was used to evaluate the absolute expression of the gene encoding α7nAChR (Chrna7) in hippocampus, striatum, thalamus and cortex in adult, naïve mice. Mice subjected to transient middle cerebral artery occlusion (tMCAO) or sham surgery were treated with α7nAChR agonist AR-{"type":"entrez-nucleotide","attrs":{"text":"R17779","term_id":"771389"}}R17779 (12 mg/kg) or saline once daily for 5 days. Infarct size and microglial activation 7 days after tMCAO were analyzed using immunohistochemistry. Chrna7 expression was found in all analyzed brain regions in naïve mice with the highest expression in cortex and hippocampus. At sacrifice, white blood cell count was significantly decreased in AR-{"type":"entrez-nucleotide","attrs":{"text":"R17779","term_id":"771389"}}R17779 treated mice compared with saline controls in the sham groups, although, no effect was seen in the tMCAO groups. Brain injury and microglial activation were evident 7 days after tMCAO. However, no difference was found between mice treated with saline or AR-{"type":"entrez-nucleotide","attrs":{"text":"R17779","term_id":"771389"}}R17779. In conclusion, α7nAChR expression varies in different brain regions and, despite a decrease in white blood cells in sham mice receiving AR-{"type":"entrez-nucleotide","attrs":{"text":"R17779","term_id":"771389"}}R17779, this compound does not affect stroke-induced brain injury.     

Mining the key genes for ventilator-induced lung injury using co-expression network analysis

Mechanical ventilation is extensively adopted in general anesthesia and respiratory failure management, but it can also induce ventilator-induced lung injury (VILI). Therefore, it is of great urgency to explore the mechanisms involved in the VILI pathogenesis, which might contribute to its future prevention and treatment. Four microarray datasets from the GEO database were selected in our investigation, and were subjected to the Weighted Gene Co-Expression Network Analysis (WGCNA) to identify the VILI-correlated gene modules. The limma package in R software was used to identify the differentially expressed genes (DEGs) between the VILI and control groups. WGCNA was constructed by merging the {"type":"entrez-geo","attrs":{"text":"GSE9314","term_id":"9314"}}GSE9314, {"type":"entrez-geo","attrs":{"text":"GSE9368","term_id":"9368"}}GSE9368, {"type":"entrez-geo","attrs":{"text":"GSE11434","term_id":"11434"}}GSE11434 and {"type":"entrez-geo","attrs":{"text":"GSE11662","term_id":"11662"}}GSE11662 datasets. A total of 49 co-expression network modules were determined as associated with VILI. The intersected genes between hub genes screened from DEGs for VILI and those identified using WGCNA were as follows: Tlr2, Hmox1, Serpine1, Mmp9, Il6, Il1b, Ptgs2, Fos and Atf3, which were determined to be key genes for VILI. Those key genes were validated by {"type":"entrez-geo","attrs":{"text":"GSE86229","term_id":"86229"}}GSE86229 and quantitative PCR (qPCR) experiment to have significantly statistical difference in their expression between the VILI and control groups. In a nutshell, nine key genes with expression differences in VILI were screened by WGCNA by integrating multiple datasets.     

Comparative palatability of orally disintegrating tablets (ODTs) of Praziquantel (L-PZQ and Rac-PZQ) versus current PZQ tablet in African children: A randomized,single-blind,crossover study

BackgroundPraziquantel (PZQ) is currently the only recommended drug for infection and disease caused by the schistosome species that infects humans; however, the current tablet formulation is not suitable for pre-school age children mainly due to its bitterness and the large tablet size. We assessed the palatability of two new orally disintegrating tablet (ODT) formulations of PZQ.MethodologyThis randomized, single-blind, crossover, swill-and-spit palatability study ({"type":"clinical-trial","attrs":{"text":"NCT02315352","term_id":"NCT02315352"}}NCT02315352) was carried out at a single school in Tanzania in children aged 6–11 years old, with or without schistosomiasis infection as this was not part of the assessment. Children were stratified according to age group (6–8 years or 9–11 years) and gender, then randomized to receive each formulation in a pre-specified sequence. Over 2 days, the children assessed the palatability of Levo-Praziquantel (L-PZQ) ODT 150 mg and Racemate Praziquantel (Rac-PZQ) ODT 150 mg disintegrated in the mouth without water on the first day, and L-PZQ and Rac-PZQ dispersed in water and the currently available PZQ 600 mg formulation (PZQ-Cesol) crushed and dispersed in water on the second day. The palatability of each formulation was rated using a 100 mm visual analogue scale (VAS) incorporating a 5-point hedonic scale, immediately after spitting out the test product (VAS_{t = 0} primary outcome) and after 2–5 minutes (VAS_{t = 2–5}).Principal findingsIn total, 48 children took part in the assessment. Overall, there was no reported difference in the VAS_{t = 0} between the two ODT formulations (p = 0.106) without water. Higher VAS_{t = 0} and VAS_{t = 2–5} scores were reported for L-PZQ ODT compared with Rac-PZQ ODT in older children (p = 0.046 and p = 0.026, respectively). The VAS_{t = 0} and VAS_{t = 2–5} were higher for both ODT formulations compared with the standard formulation (p<0.001 for both time points). No serious adverse events were reported.Conclusions/SignificanceThe new paediatric-friendly formulations dispersed in water were both found to be more palatable than the existing standard formulation of PZQ. There may be gender and age effects on the assessment of palatability. Further research is needed for assessing efficacy and tolerability of the newly ODTs Praziquantel drug in younger children.Trial registrationThe trial was registered on ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT02315352","term_id":"NCT02315352"}}NCT02315352) and in the Pan African Clinical Trials Registry (PACTR201412000959159).     

Optimal protamine dosing after cardiopulmonary bypass: The PRODOSE adaptive randomised controlled trial

BackgroundThe dose of protamine required following cardiopulmonary bypass (CPB) is often determined by the dose of heparin required pre-CPB, expressed as a fixed ratio. Dosing based on mathematical models of heparin clearance is postulated to improve protamine dosing precision and coagulation. We hypothesised that protamine dosing based on a 2-compartment model would improve thromboelastography (TEG) parameters and reduce the dose of protamine administered, relative to a fixed ratio.Methods and findingsWe undertook a 2-stage, adaptive randomised controlled trial, allocating 228 participants to receive protamine dosed according to a mathematical model of heparin clearance or a fixed ratio of 1 mg of protamine for every 100 IU of heparin required to establish anticoagulation pre-CPB. A planned, blinded interim analysis was undertaken after the recruitment of 50% of the study cohort. Following this, the randomisation ratio was adapted from 1:1 to 1:1.33 to increase recruitment to the superior arm while maintaining study power. At the conclusion of trial recruitment, we had randomised 121 patients to the intervention arm and 107 patients to the control arm. The primary endpoint was kaolin TEG r-time measured 3 minutes after protamine administration at the end of CPB. Secondary endpoints included ratio of kaolin TEG r-time pre-CPB to the same metric following protamine administration, requirement for allogeneic red cell transfusion, intercostal catheter drainage at 4 hours postoperatively, and the requirement for reoperation due to bleeding. The trial was listed on a clinical trial registry (ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03532594","term_id":"NCT03532594"}}NCT03532594).Participants were recruited between April 2018 and August 2019. Those in the intervention/model group had a shorter mean kaolin r-time (6.58 [SD 2.50] vs. 8.08 [SD 3.98] minutes; p = 0.0016) post-CPB. The post-protamine thromboelastogram of the model group was closer to pre-CPB parameters (median pre-CPB to post-protamine kaolin r-time ratio 0.96 [IQR 0.78–1.14] vs. 0.75 [IQR 0.57–0.99]; p < 0.001). We found no evidence of a difference in median mediastinal/pleural drainage at 4 hours postoperatively (140 [IQR 75–245] vs. 135 [IQR 94–222] mL; p = 0.85) or requirement (as a binary outcome) for packed red blood cell transfusion at 24 hours postoperatively (19 [15.8%] vs. 14 [13.1%] p = 0.69). Those in the model group had a lower median protamine dose (180 [IQR 160–210] vs. 280 [IQR 250–300] mg; p < 0.001).Important limitations of this study include an unblinded design and lack of generalisability to certain populations deliberately excluded from the study (specifically children, patients with a total body weight >120 kg, and patients requiring therapeutic hypothermia to <28°C).ConclusionsUsing a mathematical model to guide protamine dosing in patients following CPB improved TEG r-time and reduced the dose administered relative to a fixed ratio. No differences were detected in postoperative mediastinal/pleural drainage or red blood cell transfusion requirement in our cohort of low-risk patients.Trial registrationClinicalTrials.gov Unique identifier {"type":"clinical-trial","attrs":{"text":"NCT03532594","term_id":"NCT03532594"}}NCT03532594.

Lachlan Miles and co-workers report on a randomized controlled trial seeking to optimise protamine dosing after cardiopulmonary bypass.     

Seroprevalence of chikungunya virus infection among HIV-infected adults in French Caribbean Islands of Martinique and Guadeloupe in 2015: A cross-sectional study

BackgroundIn 2014, a first outbreak of chikungunya hit the Caribbean area where chikungunya virus (CHIKV) had never circulated before.Methodology/Principal findingsWe conducted a cross-sectional study to measure the seroprevalence of CHIKV immediately after the end of the 2014 outbreak in HIV-infected people followed up in two clinical cohorts at the University hospitals of Guadeloupe and Martinique. Study patients were identified during the first months of 2015 and randomly selected to match the age and sex distribution of the general population in the two islands. They were invited to complete a survey that explored the symptoms consistent with chikungunya they could have developed during 2014 and to have a blood sample drawn for CHIKV serology.The study population consisted of 377 patients (198 in Martinique and 179 in Guadeloupe, 178 men and 199 women), 182 of whom reported they had developed symptoms consistent with chikungunya. CHIKV serology was positive in 230 patients, which accounted for an overall seroprevalence rate of 61% [95%CI 56–66], with only 153 patients who reported symptoms consistent with chikungunya. Most frequent symptoms included arthralgia (94.1%), fever (73.2%), myalgia (53.6%), headache (45.8%), and skin rash (26.1%).Conclusions/SignificanceThis study showed that the seroprevalence of CHIKV infection was 61% after the 2014 outbreak, with one third of asymptomatic infections.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT 02553369","term_id":"NCT02553369"}}NCT 02553369.     

Diagnostic performance of a Recombinant Polymerase Amplification Test—Lateral Flow (RPA-LF) for cutaneous leishmaniasis in an endemic setting of Colombia

BackgroundControl of cutaneous leishmaniasis by public health systems in the Americas relies on case identification and treatment. Point-of-care diagnostics that can be performed by health workers within or near affected communities could effectively bring the health system to the resource-limited sites providing early diagnosis and treatment, reducing morbidity and the burden of disease.Methodology/principal findingsA cross-sectional study was undertaken to evaluate the diagnostic test performance of Isothermal Recombinase Polymerase Amplification (RPA) targeting Leishmania kinetoplast DNA, coupled with a lateral flow (LF) immunochromatographic strip, in a field setting and a laboratory reference center. Minimally invasive swab and FTA filter paper samples were obtained by community health workers and highly trained technicians from ulcerated lesions of > 2 weeks’ evolution from 118 patients’ ≥ 2 years of age in the municipality of Tumaco, Nariño. Extracted DNA was processed by RPA-LF at a reference center or in a primary health facility in the field. Evaluation was based on a composite “gold standard” that included microscopy, culture, biopsy and real-time polymerase chain reaction detection of Leishmania 18S rDNA. Standard of care routine diagnostic tests were explored as comparators.Sensitivity and specificity of RPA-LF in the reference lab scenario were 87% (95%CI 74–94) and 86% (95%CI 74–97), respectively. In the field scenario, the sensitivity was 75% (95%CI 65–84) and specificity 89% (95%CI 78–99). Positive likelihood ratios in both scenarios were higher than 6 while negative likelihood ratios ranged to 0.2–0.3 supporting the usefulness of RPA-LF to rule-in and potentially to rule-out infection.Conclusions/significanceThe low complexity requirements of RPA-LF combined with non-invasive sampling support the feasibility of its utilization by community health workers with the goal of strengthening the diagnostic capacity for cutaneous leishmaniasis in Colombia.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT04500873","term_id":"NCT04500873"}}NCT04500873.     

Identification of novel biomarkers and candidate small molecule drugs in rheumatoid arthritis and osteoarthritis based on bioinformatics analysis of high‐throughput data

Background: Rheumatoid arthritis (RA) and osteoarthritis (OA) are two major types of joint diseases. The present study aimed to identify hub genes involved in the pathogenesis and further explore the potential treatment targets of RA and OA.Methods: The gene expression profile of {"type":"entrez-geo","attrs":{"text":"GSE12021","term_id":"12021"}}GSE12021 was downloaded from Gene Expression Omnibus (GEO). Total 31 samples (12 RA, 10 OA and 9 NC samples) were used. The differentially expressed genes (DEGs) in RA versus NC, OA versus NC and RA versus OA groups were screened using limma package. We also verified the DEGs in {"type":"entrez-geo","attrs":{"text":"GSE55235","term_id":"55235"}}GSE55235 and {"type":"entrez-geo","attrs":{"text":"GSE100786","term_id":"100786"}}GSE100786. Functional annotation and protein–protein interaction (PPI) network construction of OA‐ and RA‐specific DEGs were performed. Finally, the candidate small molecules as potential drugs to treat RA and OA were predicted in CMap database.Results: 165 up-regulated and 163 down-regulated DEGs between RA and NC samples, 73 up-regulated and 293 down-regulated DEGs between OA and NC samples, 92 up-regulated and 98 down-regulated DEGs between RA and OA samples were identified. Immune response and TNF signaling pathway were significantly enriched pathways for RA‐ and OA‐specific DEGs, respectively. The hub genes were mainly associated with ‘Primary immunodeficiency’ (RA vs. NC group), ‘Ribosome’ (OA vs. NC group), and ‘Chemokine signaling pathway’ (RA vs. OA group). Arecoline and Cefamandole were the most promising small molecule to reverse the RA and OA gene expression.Conclusion: Our findings suggest new insights into the underlying pathogenesis of RA and OA, which may improve the diagnosis and treatment of these intractable chronic diseases.     

Characteristics of patients with atrial fibrillation prescribed edoxaban in Belgium and the Netherlands: insights from the ETNA-AF-Europe study

BackgroundStudies on the use of non-vitamin K antagonist oral anticoagulants in unselected patients with atrial fibrillation (AF) show that clinical characteristics and dosing practices differ per region, but lack data on edoxaban.MethodsWith data from Edoxaban Treatment in routiNe clinical prActice for patients with AF in Europe (ETNA-AF-Europe), a large prospective observational study, we compared clinical characteristics (including the dose reduction criteria for edoxaban: creatinine clearance 15–50 ml/min, weight ≤60 kg, and/or use of strong p‑glycoprotein inhibitors) of patients from Belgium and the Netherlands (BeNe) with those from other European countries (OEC).ResultsOf all 13,639 patients in ETNA-AF-Europe, 2579 were from BeNe. BeNe patients were younger than OEC patients (mean age: 72.3 vs 73.9 years), and had lower CHA₂DS₂-VASc (mean: 2.8 vs 3.2) and HAS-BLED scores (mean: 2.4 vs 2.6). Patients from BeNe less often had hypertension (61.6% vs 80.4%), and/or diabetes mellitus (17.3% vs 23.1%) than patients from OEC. Moreover, relatively fewer patients in BeNe were prescribed the reduced dose of 30 mg edoxaban (14.8%) than in OEC (25.4%). Overall, edoxaban was dosed according to label in 83.1% of patients. Yet, 30 mg edoxaban was prescribed in the absence of any dose reduction criteria in 36.9% of 30 mg users (5.5% of all patients) in BeNe compared with 35.5% (9.0% of all patients) in OEC.ConclusionThere were several notable differences between BeNe and OEC regarding clinical characteristics and dosing practices in patients prescribed edoxaban, which are relevant for the local implementation of dose evaluation and optimisation.Trial registration{"type":"clinical-trial","attrs":{"text":"NCT02944019","term_id":"NCT02944019"}}NCT02944019; Date of registration 24 October 2016Electronic supplementary materialThe online version of this article (10.1007/s12471-020-01518-7) contains supplementary material, which is available to authorized users.     

High expression of COL5A2, a member of COL5 family,indicates the poor survival and facilitates cell migration in gastric cancer

Background: Gastric cancer (GC) metastasis determines the prognosis of patients, and exploring the molecular mechanism of GC metastasis is expected to provide a theoretical basis for clinical treatment. Recent studies have shown that extracellular matrix protein is closely related to GC metastasis. The present study aimed to explore the expression profile and role of COL5A2, as an extracellular matrix protein, in GC.Methods: The expression, overall survival, and progression-free survival data of COL5 family members were extracted from The Cancer Genome Atlas (TCGA) database, respectively. Weighted gene co-expression network analysis of the {"type":"entrez-geo","attrs":{"text":"GSE62229","term_id":"62229"}}GSE62229 database was performed out to identify modules and associated genes.Results: COL5A2 was selected as our research target in the TCGA database, and was also verified in the {"type":"entrez-geo","attrs":{"text":"GSE62229","term_id":"62229"}}GSE62229 and {"type":"entrez-geo","attrs":{"text":"GSE15459","term_id":"15459"}}GSE15459 datasets. COL5A2 was up-regulated in GC tissues by paraffin immunohistochemistry and RT-qPCR. The prognosis of patients with low COL5A2 expression was better than that of patients with high COL5A2 expression. Scratch and migration experiments showed that knockdown of COL5A2 decreased the migration ability of gastric cancer cells compared with the control group. In vivo, mice with tail vein injection COL5A2 knockdown had fewer and smaller metastatic nodules in liver. GSEA results showed that the TCGA and {"type":"entrez-geo","attrs":{"text":"GSE62229","term_id":"62229"}}GSE62229 samples were significantly enriched in several well-known cancer-related pathways, such as the TGF-β, MAPK, and JAK2 signaling pathways.Conclusion: COL5A2 was most closely related to advanced GC among COL5 family members. High COL5A2 expression is associated with a poor prognosis, and may be a novel therapeutic target for GC.     

Efficacy and safety of apatinib for the treatment of AFP-producing gastric cancer

BackgroundAlpha-fetoprotein-producing gastric cancer (AFPGC) poses a therapeutic challenge worldwide because of its poor prognosis. This study aimed to evaluate the efficacy and safety of antiangiogenic drug apatinib in advanced AFPGC in a real-world setting.MethodsFrom September 2015 to December 2017, twenty-one patients identified with AFPGC from the clinical trial AHEAD-G202, an open-label, prospective, multicenter, non-interventional study of apatinib for advanced metastatic gastric cancer, were enrolled to perform this analysis. Patients received oral apatinib as monotherapy or combination therapy. A treatment cycle was defined as 28 days. The primary outcome was progression-free survival (PFS) and overall survival (OS), and the secondary outcomes included safety, objective response rate (ORR), and disease control rate (DCR).ResultsTwenty patients were evaluated for the apatinib efficacy analysis. The ORR of apatinib was 10%, whereas the DCR was 70%. The median PFS was 3.5 months [95%confidence interval (CI): 2.34–4.66]. The median OS was 4.5 months (95%CI: 3.49–5.51). Median OS of AFPGC patients without carcinoembryonic antigen (CEA) elevation achieved 30.8 months. CEA elevation was considered to be a potential independent predictive factor for OS (P = 0.030) and PFS (P = 0.047) by the analysis of multivariate analysis. The most common grade 3 to 4 adverse events (AEs) were hypertension (4.8%), hand-foot syndrome (4.8%), anorexia (4.8%), and vomiting and nausea (4.8%).ConclusionApatinib showed promising efficacy and an acceptable safety profile in patients with advanced AFPGC. Antiangiogenic therapy may be a good strategy for the treatment of AFPGC as a rare sub-type of gastric cancer.Trial registrationAHEAD-G202 ({"type":"clinical-trial","attrs":{"text":"NCT02668380","term_id":"NCT02668380"}}NCT02668380).     

PfSPZ-CVac efficacy against malaria increases from 0% to 75% when administered in the absence of erythrocyte stage parasitemia: A randomized,placebo-controlled trial with controlled human malaria infection

PfSPZ-CVac combines ‘PfSPZ Challenge’, which consists of infectious Plasmodium falciparum sporozoites (PfSPZ), with concurrent antimalarial chemoprophylaxis. In a previously-published PfSPZ-CVac study, three doses of 5.12x10⁴ PfSPZ-CVac given 28 days apart had 100% vaccine efficacy (VE) against controlled human malaria infection (CHMI) 10 weeks after the last immunization, while the same dose given as three injections five days apart had 63% VE. Here, we conducted a dose escalation trial of similarly condensed schedules. Of the groups proceeding to CHMI, the first study group received three direct venous inoculations (DVIs) of a dose of 5.12x10⁴ PfSPZ-CVac seven days apart and the next full dose group received three DVIs of a higher dose of 1.024x10⁵ PfSPZ-CVac five days apart. CHMI (3.2x10³ PfSPZ Challenge) was performed by DVI 10 weeks after the last vaccination. In both CHMI groups, transient parasitemia occurred starting seven days after each vaccination. For the seven-day interval group, the second and third vaccinations were therefore administered coincident with parasitemia from the prior vaccination. Parasitemia was associated with systemic symptoms which were severe in 25% of subjects. VE in the seven-day group was 0% (7/7 infected) and in the higher-dose, five-day group was 75% (2/8 infected). Thus, the same dose of PfSPZ-CVac previously associated with 63% VE when given on a five-day schedule in the prior study had zero VE here when given on a seven-day schedule, while a double dose given on a five-day schedule here achieved 75% VE. The relative contributions of the five-day schedule and/or the higher dose to improved VE warrant further investigation. It is notable that administration of PfSPZ-CVac on a schedule where vaccine administration coincided with blood-stage parasitemia was associated with an absence of sterile protective immunity.Clinical trials registration: {"type":"clinical-trial","attrs":{"text":"NCT02773979","term_id":"NCT02773979"}}NCT02773979.     

SARS-CoV-2 outbreak in a tri-national urban area is dominated by a B.1 lineage variant linked to a mass gathering event

The first case of SARS-CoV-2 in Basel, Switzerland was detected on February 26^th 2020. We present a phylogenetic study to explore viral introduction and evolution during the exponential early phase of the local COVID-19 outbreak from February 26^th until March 23^rd. We sequenced SARS-CoV-2 naso-oropharyngeal swabs from 746 positive tests that were performed at the University Hospital Basel during the study period. We successfully generated 468 high quality genomes from unique patients and called variants with our COVID-19 Pipeline (COVGAP), and analysed viral genetic diversity using PANGOLIN taxonomic lineages. To identify introduction and dissemination events we incorporated global SARS-CoV-2 genomes and inferred a time-calibrated phylogeny. Epidemiological data from patient questionnaires was used to facilitate the interpretation of phylogenetic observations. The early outbreak in Basel was dominated by lineage B.1 (83·6%), detected first on March 2^nd, although the first sample identified belonged to B.1.1. Within B.1, 68·2% of our samples fall within a clade defined by the SNP C15324T (‘Basel cluster’), including 157 identical sequences at the root of the ‘Basel cluster’, some of which we can specifically trace to regional spreading events. We infer the origin of B.1-C15324T to mid-February in our tri-national region. The other genomes map broadly over the global phylogenetic tree, showing several introduction events from and/or dissemination to other regions of the world via travellers. Family transmissions can also be traced in our data. A single lineage variant dominated the outbreak in the Basel area while other lineages, such as the first (B.1.1), did not propagate. A mass gathering event was the predominant initial source of cases, with travel returners and family transmissions to a lesser extent. We highlight the importance of adding specific questions to epidemiological questionnaires, to obtain data on attendance of large gatherings and their locations, as well as travel history, to effectively identify routes of transmissions in up-coming outbreaks. This phylogenetic analysis in concert with epidemiological and contact tracing data, allows connection and interpretation of events, and can inform public health interventions.Trial Registration: ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT04351503","term_id":"NCT04351503"}}NCT04351503.     

An open label,randomized clinical trial to compare the tolerability and efficacy of ivermectin plus diethylcarbamazine and albendazole vs. diethylcarbamazine plus albendazole for treatment of brugian filariasis in Indonesia

Improved treatments for lymphatic filariasis (LF) could accelerate the global elimination program for this disease. A triple drug combination of the anti-filarial drugs ivermectin, diethylcarbamazine (DEC) and albendazole (IDA) has been shown to be safe and effective for achieving sustained clearance of microfilariae (Mf) of the filarial parasite Wuchereria bancrofti from human blood. However, the triple drug combination has not been previously been evaluated for treatment of brugian filariasis, which accounts for about 10% of the global LF burden. This hospital-based clinical trial compared the safety and efficacy of IDA with that of the standard treatment (DEC plus albendazole, DA) in persons with Brugia timori infections on Sumba island, Indonesia. Fifty-five asymptomatic persons with B. timori Mf were treated with either a single oral dose of IDA (28 subjects) or with DEC plus albendazole (DA, 27 subjects). Participants were actively monitored for adverse events (AE) for two days after treatment by nurses and physicians who were masked regarding treatment assignments. Passive monitoring was performed by clinical teams that visited participant’s home villages for an additional five days. Microfilaremia was assessed by membrane filtration of 1 ml night blood at baseline, at 24h and one year after treatment. IDA was more effective than DA for completely clearing Mf at 24 hours (25/28, 89% vs. 8/27, 30%, P < 0.001). By 12 months after treatment, only one of 27 IDA recipients had Mf in their blood (4%) vs. 10 of 25 (40%) in persons treated with DA (P = 0.002). Approximately 90% of participants had antibodies to recombinant filarial antigen BmR1 at baseline. Antibody prevalence decreased to approximately 30% in both treatment groups at 12 months. About 45% of persons in both treatment groups experienced AE such as fever, muscle aches, lower back, joint and abdominal pain. These were mostly mild and most common during the first two days after treatment. No participant experienced a severe or serious AE. This study showed that IDA was well-tolerated and significantly more effective for clearing B. timori Mf from the blood than DA. Larger studies should be performed to further assess the safety and efficacy of IDA as a mass drug administration regimen to eliminate brugian filariasis.Trial Registration: {"type":"clinical-trial","attrs":{"text":"NCT02899936","term_id":"NCT02899936"}}NCT02899936.     

Miltefosine for the treatment of cutaneous leishmaniasis—A pilot study from Ethiopia

BackgroundCutaneous leishmaniasis (CL) in Ethiopia, caused by Leishmania aethiopica, is often severe and hard to treat compared to CL caused by other species elsewhere. Miltefosine is the only oral anti-leishmanial drug, with a favorable side-effect profile compared to routinely available sodium stibogluconate (SSG), but evidence about its use for L. aethiopica is lacking.Methodology and principal findingsIn an observational cohort study, treatment outcomes, safety and adherence among CL patients who required systemic treatment and received miltefosine for 28 days in Boru Meda Hospital and University of Gondar Hospital were studied. Patient cure was defined as 100% flattening for non-ulcerated lesions and 100% flattening and 100% re-epithelization for ulcerated lesions. Outcomes were documented for day 28, 90 and 180, both per site, and pooled, adjusting for site as a fixed effect with effect coding. Among 94 included patients (32 in Gondar, 62 in Boru Meda), median lesion duration was 12 months, median size six cm, and mucosal involvement (46.8%) and diffuse (30.9%) lesions were common. Adherence to miltefosine was good, and side-effects were tolerable. Initial outcomes at day 28 were promising, with 68.8% and 94.0% of patients having good improvement or cure in Gondar and Boru Meda respectively. In Boru Meda, outcomes were good with 72.7% and 72.9% cure at day 90 and day 180 respectively. In Gondar, results were less promising, with only 12.5% and 26.7% cure at day 90 and day 180, although confidence intervals were wide. In pooled estimates, 48.7% of patients reached cure at day 180, and 32.3% relapsed. Outcomes were better in Boru Meda Hospital, for smaller lesions and for mucosal lesions.Conclusions/SignificanceBased on miltefosine’s good initial response, tolerable side-effects, tablet-form, we propose to include miltefosine for future clinical trials using extended treatment schedules, combination therapy, or targeting specific subgroups.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT04004754","term_id":"NCT04004754"}}NCT04004754.     

NF-κB-mediated lncRNA AC007271.3 promotes carcinogenesis of oral squamous cell carcinoma by regulating miR-125b-2-3p/Slug

Oral squamous cell carcinoma (OSCC) is the most common oral cancer. The molecular mechanisms of this disease are not fully understood. Our previous studies confirmed that dysregulated function of long non-coding RNA (lncRNA) {"type":"entrez-nucleotide","attrs":{"text":"AC007271.3","term_id":"7408074","term_text":"AC007271.3"}}AC007271.3 was associated with a poor prognosis and overexpression of {"type":"entrez-nucleotide","attrs":{"text":"AC007271.3","term_id":"7408074","term_text":"AC007271.3"}}AC007271.3 promoted cell proliferation, migration, invasion, and inhibited cell apoptosis in vitro, and promoted tumor growth in vivo. However, the underlying mechanisms of {"type":"entrez-nucleotide","attrs":{"text":"AC007271.3","term_id":"7408074","term_text":"AC007271.3"}}AC007271.3 dysregulation remained obscure. In this study, our investigation showed that {"type":"entrez-nucleotide","attrs":{"text":"AC007271.3","term_id":"7408074","term_text":"AC007271.3"}}AC007271.3 functioned as competing endogenous RNA by binding to miR-125b-2-3p and by destabilizing primary miR-125b-2, resulted in the upregulating expression of Slug, which is a direct target of miR-125b-2-3p. Slug also inhibited the expression of E-cadherin but N-cadherin, vimentin, and β-catenin had no obvious change. The expression of {"type":"entrez-nucleotide","attrs":{"text":"AC007271.3","term_id":"7408074","term_text":"AC007271.3"}}AC007271.3 was promoted by the canonical nuclear factor-κB (NF-κB) pathway. Taken together, these results suggested that the classical NF-κB pathway-activated {"type":"entrez-nucleotide","attrs":{"text":"AC007271.3","term_id":"7408074","term_text":"AC007271.3"}}AC007271.3 regulates EMT by miR-125b-2-3p/Slug/E-cadherin axis to promote the development of OSCC, implicating it as a novel potential target for therapeutic intervention in this disease.Subject terms: Metastasis, Oral cancer     

Adherence at 2 years with distribution of essential medicines at no charge: The CLEAN Meds randomized clinical trial

BackgroundAdherence to medicines is low for a variety of reasons, including the cost borne by patients. Some jurisdictions publicly fund medicines for the general population, but many jurisdictions do not, and such policies are contentious. To our knowledge, no trials studying free access to a wide range of medicines have been conducted.Methods and findingsWe randomly assigned 786 primary care patients who reported not taking medicines due to cost between June 1, 2016 and April 28, 2017 to either free distribution of essential medicines (n = 395) or to usual medicine access (n = 391). The trial was conducted in Ontario, Canada, where hospital care and physician services are publicly funded for the general population but medicines are not. The trial population was mostly female (56%), younger than 65 years (83%), white (66%), and had a low income from wages as the primary source (56%). The primary outcome was medicine adherence after 2 years. Secondary outcomes included control of diabetes, blood pressure, and low-density lipoprotein (LDL) cholesterol in patients taking relevant treatments and healthcare costs over 2 years. Adherence to all appropriate prescribed medicines was 38.7% in the free distribution group and 28.6% in the usual access group after 2 years (absolute difference 10.1%; 95% confidence interval (CI) 3.3 to 16.9, p = 0.004). There were no statistically significant differences in control of diabetes (hemoglobin A1c 0.27; 95% CI −0.25 to 0.79, p = 0.302), systolic blood pressure (−3.9; 95% CI −9.9 to 2.2, p = 0.210), or LDL cholesterol (0.26; 95% CI −0.08 to 0.60, p = 0.130) based on available data. Total healthcare costs over 2 years were lower with free distribution (difference in median CAN$1,117; 95% CI CAN$445 to CAN$1,778, p = 0.006). In the free distribution group, 51 participants experienced a serious adverse event, while 68 participants in the usual access group experienced a serious adverse event (p = 0.091). Participants were not blinded, and some outcomes depended on participant reports.ConclusionsIn this study, we observed that free distribution of essential medicines to patients with cost-related nonadherence substantially increased adherence, did not affect surrogate health outcomes, and reduced total healthcare costs over 2 years.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02744963","term_id":"NCT02744963"}}NCT02744963.