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1.
D. A. B. Rex Shobha Dagamajalu Richard K. Kandasamy Rajesh Raju T. S. Keshava Prasad 《Journal of cell communication and signaling》2021,15(4):601
Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has been declared a pandemic by WHO. The clinical manifestation and disease progression in COVID-19 patients varies from minimal symptoms to severe respiratory issues with multiple organ failure. Understanding the mechanism of SARS-CoV-2 interaction with host cells will provide key insights into the effective molecular targets for the development of novel therapeutics. Recent studies have identified virus-mediated phosphorylation or activation of some major signaling pathways, such as ERK1/2, JNK, p38, PI3K/AKT and NF-κB signaling, that potentially elicit the cytokine storm that serves as a major cause of tissue injuries. Several studies highlight the aggressive inflammatory response particularly ‘cytokine storm’ in SARS-CoV-2 patients. A depiction of host molecular dynamics triggered by SARS-CoV-2 in the form of a network of signaling molecules will be helpful for COVID-19 research. Therefore, we developed the signaling pathway map of SARS-CoV-2 infection using data mined from the recently published literature. This integrated signaling pathway map of SARS-CoV-2 consists of 326 proteins and 73 reactions. These include information pertaining to 1,629 molecular association events, 30 enzyme catalysis events, 43 activation/inhibition events, and 8,531 gene regulation events. The pathway map is publicly available through WikiPathways: https://www.wikipathways.org/index.php/Pathway:WP5115.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12079-021-00632-4. 相似文献
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Penelope Gray Hanna Kann Ville N. Pimenoff Tiina Eriksson Tapio Luostarinen Simopekka Vnsk Helj-Marja Surcel Helena Faust Joakim Dillner Matti Lehtinen 《PLoS medicine》2021,18(6)
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 (PR31/33/35/45 = 0.88, 95% CI 0.81–0.97) were replicated in Arm C (PR31/33/35/45 = 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 , https://clinicaltrials.gov/ct2/show/ NCT00534638. NCT00534638相似文献
3.
William Stohl Joan T. Merrill R. John Looney Jill Buyon Daniel J. Wallace Michael H. Weisman Ellen M. Ginzler Blaire Cooke Donna Holloway Arunan Kaliyaperumal Kameswara Rao Kuchimanchi Tsui Chern Cheah Erik Rasmussen John Ferbas Shelley S. Belouski Wayne Tsuji Debra J. Zack 《Arthritis research & therapy》2015,17(1)
IntroductionBlisibimod is a potent B cell-activating factor (BAFF) antagonist that binds to both cell membrane-expressed and soluble BAFF. The goal of these first-in-human studies was to characterize the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of blisibimod in subjects with systemic lupus erythematosus (SLE).MethodsSLE subjects with mild disease that was stable/inactive at baseline received either a single dose of blisibimod (0.1, 0.3, 1, or 3 mg/kg subcutaneous [SC] or 1, 3, or 6 mg/kg intravenous [IV]) or placebo (phase 1a; N = 54), or four weekly doses of blisibimod (0.3, 1, or 3 mg/kg SC or 6 mg/kg IV) or placebo (phase 1b; N = 63). Safety and tolerability measures were collected, and B cell subset measurements and pharmacokinetic analyses were performed.ResultsAll subjects (93 % female; mean age 43.7 years) carried the diagnosis of SLE for ≥ 1 year. Single- and multiple-dose treatment with blisibimod produced a decrease in the number of naïve B cells (24–76 %) and a transient relative increase in the memory B cell compartment, with the greatest effect on IgD-CD27+; there were no notable changes in T cells or natural killer cells. With time, memory B cells reverted to baseline, leading to a calculated 30 % reduction in total B cells by approximately 160 days after the first dose. In both the single- and multiple-dosing SC cohorts, the pharmacokinetic profile indicated slow absorption, dose-proportional exposure from 0.3 through 3.0 mg/kg SC and 1 through 6 mg/kg IV, linear pharmacokinetics across the dose range of 1.0–6.0 mg/kg, and accumulation ratios ranging from 2.21 to 2.76. The relative increase in memory B cells was not associated with safety signals, and the incidence of adverse events, anti-blisibimod antibodies, and clinical laboratory abnormalities were comparable between blisibimod- and placebo-treated subjects.ConclusionsBlisibimod changed the constituency of the B cell pool and single and multiple doses of blisibimod exhibited approximate dose-proportional pharmacokinetics across the dose range 1.0–6.0 mg/kg. The safety and tolerability profile of blisibimod in SLE was comparable with that of placebo. These findings support further studies of blisibimod in SLE and other B cell-mediated diseases.
Trial registration
Clinicaltrials.gov . Registered 11 May 2015. NCT02443506 Registered 7 April 2015. NCT02411136相似文献4.
Elodie Curlier Laurence Fagour Ccile Herrmann-Storck Adrien Staelen Ingrid Vingadassalom Sbastien Breurec Sylvie Abel Sandrine Pierre-Franois Janick Jean-Marie Cdric Laounan Raymond Csaire Bruno Hoen Andr Cabi 《PLoS neglected tropical diseases》2021,15(4)
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 . NCT 02553369相似文献
5.
Philipp Reddiess Stefanie Aeschbacher Pascal Meyre Michael Coslovsky Michael Kühne Nicolas Rodondi Oliver Baretella Jürg H. Beer Richard Kobza Giorgio Moschovitis Marcello Di Valentino Cyrill Müller Fabienne Steiner Leo H. Bonati Christian Sticherling Stefan Osswald David Conen 《CMAJ》2021,193(4):E117
BACKGROUND:Little is known about the association between alcohol consumption and risk of cardiovascular events in patients with established atrial fibrillation (AF). The main aim of the current study was to investigate the associations of regular alcohol intake with incident stroke or systemic embolism in patients with established AF.METHODS:To assess the association between alcohol consumption and cardiovascular events in patients with established AF, we combined data from 2 comparable prospective cohort studies that followed 3852 patients with AF for a median of 3.0 years. Patients were grouped into 4 categories of daily alcohol intake (none, > 0 to < 1, 1 to < 2 and ≥ 2 drinks/d). The primary outcome was a composite of stroke and systemic embolism. Secondary outcomes were all-cause mortality, myocardial infarction, hospital admission for acute heart failure, and a composite of major and clinically relevant nonmajor bleeding. Associations were assessed using time-updated, multivariable-adjusted Cox proportional hazards models.RESULTS:Mean age (± standard deviation) was 71 ± 10 years (28% were women and 84% were on oral anticoagulants). We observed 136 confirmed strokes or systemic emboli. Compared with nondrinkers, adjusted hazard ratios for the primary outcome event were 0.87, 95% confidence interval (CI) 0.55–1.37 for > 0 to < 1 drinks/d; 0.70, 95% CI 0.39–1.25 for 1 to < 2 drinks/d; and 0.96, 95% CI 0.56–1.67 for ≥ 2 drinks/d (p for linear [quadratic] trend 0.71 [0.22]). There was no significant association between alcohol consumption and bleeding, but there was a nonlinear association with heart failure (p for quadratic trend 0.01) and myocardial infarction (p for quadratic trend 0.007).INTERPRETATION:In patients with AF, we did not find a significant association between low to moderate alcohol intake and risk of stroke or other cardiovascular events. Our findings do not support special recommendations for patients with established AF with regard to alcohol consumption. Trial registration:ClinicalTrials.gov, no. An association between excessive alcohol intake and atrial arrhythmias was described about 40 years ago as “holiday heart syndrome.” NCT021058441 Since then, several studies have shown that even low amounts of regular alcohol intake are independently associated with an increased risk of incident atrial fibrillation (AF).2–4In contrast, little is known about the effects of alcohol intake on the risk of adverse events among patients with established AF.5 These patients have a high risk of stroke.6,7 The use of oral anticoagulation significantly decreases stroke risk,8 but a residual risk persists and the risk of bleeding is increased. As alcohol consumption has been associated with stroke risk in non-AF populations, reduced alcohol consumption may help to further mitigate stroke risk in patients with AF. In addition, alcohol consumption may interfere with adherence to oral anticoagulation, increase bleeding risk and lead to more frequent falls, such that the effects of alcohol intake on stroke risk observed in other populations may be not be generalizable to patients with AF.9–14For all these reasons, many physicians recommend to patients with established AF to fully abstain from alcohol. However, these recommendations are largely based on expert opinions, and prospective data are needed to address this important gap in knowledge. Therefore, the main aim of our study was to investigate the association of regular alcohol intake with incident stroke or systemic embolism in patients with established AF. As secondary objectives, we also assessed the associations of alcohol intake with incident death, hospital admission for heart failure, myocardial infarction and bleeding. 相似文献
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Muhidin K. Mahende Eric Huber Elly Kourany-Lefoll Ali Ali Brooke Hayward Deon Bezuidenhout Wilhelmina Bagchus Abdunoor M. Kabanywanyi 《PLoS neglected tropical diseases》2021,15(6)
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 () 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 (VASt = 0 primary outcome) and after 2–5 minutes (VASt = 2–5).Principal findingsIn total, 48 children took part in the assessment. Overall, there was no reported difference in the VASt = 0 between the two ODT formulations (p = 0.106) without water. Higher VASt = 0 and VASt = 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 VASt = 0 and VASt = 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 ( NCT02315352) and in the Pan African Clinical Trials Registry ( NCT02315352PACTR201412000959159). 相似文献
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Andre Tsin Chih Chen Fabio Payo Aline Lopes Chagas Regiane Saraiva De Souza Melo Alencar Claudia Megumi Tani Karina Gondim Moutinho da Conceio Vasconcelos Manoel de Souza Rocha Heloisa de Andrade Carvalho Paulo Marcelo Gehm Hoff Flair Jos Carrilho 《Reports of Practical Oncology and Radiotherapy》2021,26(2):226
9.
Wojciech Szczeklik Yannick LeManach Jakub Fronczek Kamil Polok David Conen Finlay A. McAlister Sadeesh Srinathan Pablo Alonso-Coello Bruce Biccard Emmanuelle Duceppe Diane Heels-Ansdell Jacek Grka Shirley Pettit Pavel S. Roshanov P.J. Devereaux 《CMAJ》2020,192(49):E1715
BACKGROUND:Postoperative atrial fibrillation (POAF) is associated with clinically significant short- and long-term complications after noncardiac surgery. Our aim was to describe the incidence of clinically important POAF after noncardiac surgery and establish the prognostic value of N-terminal pro–brain-type natriuretic peptide (NT-proBNP) in this context.METHODS:The Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) Study was a prospective cohort study involving patients aged 45 years and older who had inpatient noncardiac surgery that was performed between August 2007 and November 2013. We determined 30-day incidence of clinically important POAF (i.e., resulting in angina, congestive heart failure, symptomatic hypotension or requiring treatment) using logistic regression models to analyze the association between preoperative NT-proBNP and POAF.RESULTS:In 37 664 patients with no history of atrial fibrillation, we found that the incidence of POAF was 1.0% (95% confidence interval [CI] 0.9%–1.1%; 369 events); 3.2% (95% CI 2.3%–4.4%) in patients undergoing major thoracic surgery, 1.3% (95% CI 1.2%–1.5%) in patients undergoing major nonthoracic surgery and 0.2% (95% CI 0.1%–0.3%) in patients undergoing low-risk surgery. In a subgroup of 9789 patients with preoperative NT-proBNP measurements, the biomarker improved the prediction of POAF risk over conventional prognostic factors (likelihood ratio test p < 0.001; fraction of new information from NT-proBNP was 16%). Compared with a reference NT-proBNP measurement set at 100 ng/L, adjusted odds ratios for the occurrence of POAF were 1.31 (95% CI 1.15–1.49) at 200 ng/L, 2.07 (95% CI 1.27–3.36) at 1500 ng/L and 2.39 (95% CI 1.26–4.51) at 3000 ng/L.INTERPRETATION:We determined that the incidence of clinically important POAF after noncardiac surgery was 1.0%. We also found that preoperative NT-proBNP levels were associated with POAF independent of established prognostic factors. Trial registration: ClinicalTrials.gov, no. Postoperative atrial fibrillation (POAF) is the most common arrhythmia that occurs after noncardiac surgery NCT005121091 and is associated with prolonged hospital stays and an increased risk of stroke and death,2–8 both of which raise societal costs.9 The reported incidence of POAF ranges from 3.7% to 21.0% in patients undergoing thoracic surgery3,10 and from less than 0.5% to 10.0% in patients undergoing noncardiac, nonthoracic surgery (Appendix 1, Supplementary Table 1, available at www.cmaj.ca/lookup/doi/10.1503/cmaj.200840/tab-related-content).6,11Brain-type natriuretic peptide (BNP) is a neurohormone released by cardiomyocytes in response to volume and pressure overload.12 This biomarker has an established role in the diagnosis and management of heart failure and in predicting cardiovascular morbidity and mortality.13 Although natriuretic peptides have been shown to predict new-onset atrial fibrillation (AF) in the nonsurgical setting reliably,14–18 their value in predicting POAF after noncardiac surgery is unclear.19–21The Vascular events In non-cardiac Surgery patIents cOhort evaluatioN (VISION) Study was a prospective international cohort study involving a representative sample of adults who underwent noncardiac surgery that required an overnight hospital stay. One of the predefined objectives in VISION was to determine the incidence of new-onset, clinically important POAF. We aimed to describe the overall and surgery-specific incidence of POAF after noncardiac surgery and to investigate the association between preoperative N-terminal pro–brain-type natriuretic peptide (NT-proBNP) and POAF. We hypothesized that measurement of NT-proBNP would improve POAF risk prediction beyond conventional prognostic factors. 相似文献
10.
Fosciclopirox suppresses growth of high-grade urothelial cancer by targeting the γ-secretase complex
Scott J. Weir Prasad Dandawate David Standing Sangita Bhattacharyya Prabhu Ramamoorthy Parthasarathy Rangarajan Robyn Wood Amanda E. Brinker Benjamin L. Woolbright Mehmet Tanol Tammy Ham William McCulloch Michael Dalton Gregory A. Reed Michael J. Baltezor Roy A. Jensen John A. Taylor III Shrikant Anant 《Cell death & disease》2021,12(6)
Ciclopirox (CPX) is an FDA-approved topical antifungal agent that has demonstrated preclinical anticancer activity in a number of solid and hematologic malignancies. Its clinical utility as an oral anticancer agent, however, is limited by poor oral bioavailability and gastrointestinal toxicity. Fosciclopirox, the phosphoryloxymethyl ester of CPX (Ciclopirox Prodrug, CPX-POM), selectively delivers the active metabolite, CPX, to the entire urinary tract following parenteral administration. We characterized the activity of CPX-POM and its major metabolites in in vitro and in vivo preclinical models of high-grade urothelial cancer. CPX inhibited cell proliferation, clonogenicity and spheroid formation, and increased cell cycle arrest at S and G0/G1 phases. Mechanistically, CPX suppressed activation of Notch signaling. Molecular modeling and cellular thermal shift assays demonstrated CPX binding to γ-secretase complex proteins Presenilin 1 and Nicastrin, which are essential for Notch activation. To establish in vivo preclinical proof of principle, we tested fosciclopirox in the validated N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) mouse bladder cancer model. Once-daily intraperitoneal administration of CPX-POM for four weeks at doses of 235 mg/kg and 470 mg/kg significantly decreased bladder weight, a surrogate for tumor volume, and resulted in a migration to lower stage tumors in CPX-POM treated animals. This was coupled with a reduction in the proliferation index. Additionally, there was a reduction in Presenilin 1 and Hes-1 expression in the bladder tissues of CPX-POM treated animals. Following the completion of the first-in-human Phase 1 trial (), the pharmacologic activity of fosciclopirox is currently being characterized in a Phase 1 expansion cohort study of muscle-invasive bladder cancer patients scheduled for cystectomy ( NCT03348514) as well as a Phase 2 trial of newly diagnosed and recurrent urothelial cancer patients scheduled for transurethral resection of bladder tumors ( NCT04608045).Subject terms: NCT04525131Bladder cancer, Pharmacodynamics 相似文献
11.
Matthijs Kox Lucas T. van Eijk Tim Verhaak Tim Frenzel Harmke D. Kiers Jelle Gerretsen Johannes G. van der Hoeven Lilian Kornet Avram Scheiner Peter Pickkers 《Arthritis research & therapy》2015,17(1)
IntroductionVagus nerve stimulation (VNS) exerts beneficial anti-inflammatory effects in various animal models of inflammation, including collagen-induced arthritis, and is implicated in representing a novel therapy for rheumatoid arthritis. However, evidence of anti-inflammatory effects of VNS in humans is very scarce. Transvenous VNS (tVNS) is a newly developed and less invasive method to stimulate the vagus nerve. In the present study, we determined whether tVNS is a feasible and safe procedure and investigated its putative anti-inflammatory effects during experimental human endotoxemia.MethodsWe performed a randomized double-blind sham-controlled study in healthy male volunteers. A stimulation catheter was inserted in the left internal jugular vein at spinal level C5–C7, adjacent to the vagus nerve. In the tVNS group (n = 10), stimulation was continuously performed for 30 minutes (0–10 V, 1 ms, 20 Hz), starting 10 minutes before intravenous administration of 2 ng kg−1Escherichia coli lipopolysaccharide (LPS). Sham-instrumented subjects (n = 10) received no electrical stimulation.ResultsNo serious adverse events occurred throughout the study. In the tVNS group, stimulation of the vagus nerve was achieved as indicated by laryngeal vibration. Endotoxemia resulted in fever, flu-like symptoms, and hemodynamic changes that were unaffected by tVNS. Furthermore, plasma levels of inflammatory cytokines increased sharply during endotoxemia, but responses were similar between groups. Finally, cytokine production by leukocytes stimulated with LPS ex vivo, as well as neutrophil phagocytosis capacity, were not influenced by tVNS.ConclusionstVNS is feasible and safe, but does not modulate the innate immune response in humans in vivo during experimental human endotoxemia.
Trial registration
Clinicaltrials.gov . Registered 12 September 2013. NCT01944228相似文献12.
Jean-Philippe Bertocchio Coralie Barbe Sylvie Lavaud Olivier Toupance Pierre Nazeyrollas Frederic Jaisser Philippe Rieu 《PloS one》2016,11(4)
BackgroundAnimal studies have highlighted the role of vascular mineralocorticoid receptor during Cyclosporine A-induced nephrotoxicity. Mineralocorticoid receptor antagonists could improve kidney survival but are not commonly used during renal impairment and in association with several immunosuppressive drugs due to a supposed higher risk of adverse events. We tested the tolerance of eplerenone according to its expected adverse events: hyperkalemia, metabolic acidosis, hypotension, acute kidney failure, or any other adverse event.MethodsWe conducted a single-center, prospective, open-label study in 31 kidney-transplant recipients with impaired renal function (30 and 50 mL/min/1.73m2) and receiving cyclosporine A. All patients received eplerenone 25 mg/d for 8 weeks. Serum potassium, renal function and expected adverse events were closely monitored.ResultsEight patients experienced mild hyperkalemia (>5 mmol/L), one moderate hyperkalemia (>5.5 mmol/L) and had to receive potassium-exchange resin. No severe hyperkalemia (>6 mmol/L) occurred. One acute kidney failure was observed, secondary to diarrhea. Basal serum potassium and bicarbonate were independently associated with a higher risk of developing mild hyperkalemia (>5 mmol/L) under treatment (OR 6.5, p = 0.003 and 0.7, p = 0.007, respectively). A cut-off value of 4.35 mmol/L for basal serum potassium was the best factor to predict the risk of developing mild hyperkalemia (>5 mmol/L).ConclusionsUntil eGFR falls to 30 mL/min/1.73m2, eplerenone could be safely given to kidney-transplant recipients receiving cyclosporine A, if kalemia is closely monitored. When renal function is impaired and if basal kalemia is >4.35 mmol/L, then clinicians should properly balance risk and benefit of eplerenone use and offer dietary advice. An adequately powered prospective randomized study is now needed to test its efficiency (and safety) in this population.
Trial Registration
ClinicalTrials.gov NCT01834768相似文献13.
Richard A. Koup Mario Roederer Laurie Lamoreaux Jennifer Fischer Laura Novik Martha C. Nason Brenda D. Larkin Mary E. Enama Julie E. Ledgerwood Robert T. Bailer John R. Mascola Gary J. Nabel Barney S. Graham the VRC VRC Study Teams 《PloS one》2010,5(2)
Background
Induction of HIV-1-specific T-cell responses relevant to diverse subtypes is a major goal of HIV vaccine development. Prime-boost regimens using heterologous gene-based vaccine vectors have induced potent, polyfunctional T cell responses in preclinical studies.Methods
The first opportunity to evaluate the immunogenicity of DNA priming followed by recombinant adenovirus serotype 5 (rAd5) boosting was as open-label rollover trials in subjects who had been enrolled in prior studies of HIV-1 specific DNA vaccines. All subjects underwent apheresis before and after rAd5 boosting to characterize in depth the T cell and antibody response induced by the heterologous DNA/rAd5 prime-boost combination.Results
rAd5 boosting was well-tolerated with no serious adverse events. Compared to DNA or rAd5 vaccine alone, sequential DNA/rAd5 administration induced 7-fold higher magnitude Env-biased HIV-1-specific CD8+ T-cell responses and 100-fold greater antibody titers measured by ELISA. There was no significant neutralizing antibody activity against primary isolates. Vaccine-elicited CD4+ and CD8+ T-cells expressed multiple functions and were predominantly long-term (CD127+) central or effector memory T cells and that persisted in blood for >6 months. Epitopes mapped in Gag and Env demonstrated partial cross-clade recognition.Conclusion
Heterologous prime-boost using vector-based gene delivery of vaccine antigens is a potent immunization strategy for inducing both antibody and T-cell responses.Trial Registration
ClinicalTrails.gov , NCT00102089 NCT00108654相似文献14.
Ramya Rangan Andrew M Watkins Jose Chacon Rachael Kretsch Wipapat Kladwang Ivan N Zheludev Jill Townley Mats Rynge Gregory Thain Rhiju Das 《Nucleic acids research》2021,49(6):3092
The rapid spread of COVID-19 is motivating development of antivirals targeting conserved SARS-CoV-2 molecular machinery. The SARS-CoV-2 genome includes conserved RNA elements that offer potential small-molecule drug targets, but most of their 3D structures have not been experimentally characterized. Here, we provide a compilation of chemical mapping data from our and other labs, secondary structure models, and 3D model ensembles based on Rosetta''s FARFAR2 algorithm for SARS-CoV-2 RNA regions including the individual stems SL1-8 in the extended 5′ UTR; the reverse complement of the 5′ UTR SL1-4; the frameshift stimulating element (FSE); and the extended pseudoknot, hypervariable region, and s2m of the 3′ UTR. For eleven of these elements (the stems in SL1–8, reverse complement of SL1–4, FSE, s2m and 3′ UTR pseudoknot), modeling convergence supports the accuracy of predicted low energy states; subsequent cryo-EM characterization of the FSE confirms modeling accuracy. To aid efforts to discover small molecule RNA binders guided by computational models, we provide a second set of similarly prepared models for RNA riboswitches that bind small molecules. Both datasets (‘FARFAR2-SARS-CoV-2’, https://github.com/DasLab/FARFAR2-SARS-CoV-2; and ‘FARFAR2-Apo-Riboswitch’, at https://github.com/DasLab/FARFAR2-Apo-Riboswitch’) include up to 400 models for each RNA element, which may facilitate drug discovery approaches targeting dynamic ensembles of RNA molecules. 相似文献
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Yi-Zhou Jiang Yin Liu Yi Xiao Xin Hu Lin Jiang Wen-Jia Zuo Ding Ma Jiahan Ding Xiaoyu Zhu Jianjun Zou Claire Verschraegen Daniel G. Stover Virginia Kaklamani Zhong-Hua Wang Zhi-Ming Shao 《Cell research》2021,31(2):178
Triple-negative breast cancer (TNBC) is a highly heterogeneous disease, and molecular subtyping may result in improved diagnostic precision and targeted therapies. Our previous study classified TNBCs into four subtypes with putative therapeutic targets. Here, we conducted the FUTURE trial (ClinicalTrials.gov identifier: ), a phase Ib/II subtyping-based and genomic biomarker-guided umbrella trial, to evaluate the efficacy of these targets. Patients with refractory metastatic TNBC were enrolled and stratified by TNBC subtypes and genomic biomarkers, and assigned to one of these seven arms: (A) pyrotinib with capecitabine, (B) androgen receptor inhibitor with CDK4/6 inhibitor, (C) anti PD-1 with nab-paclitaxel, (D) PARP inhibitor included, (E) and (F) anti-VEGFR included, or (G) mTOR inhibitor with nab-paclitaxel. The primary end point was the objective response rate (ORR). We enrolled 69 refractory metastatic TNBC patients with a median of three previous lines of therapy (range, 1–8). Objective response was achieved in 20 (29.0%, 95% confidence interval (CI): 18.7%–41.2%) of the 69 intention-to-treat (ITT) patients. Our results showed that immunotherapy (arm C), in particular, achieved the highest ORR (52.6%, 95% CI: 28.9%–75.6%) in the ITT population. Arm E demonstrated favorable ORR (26.1%, 95% CI: 10.2%–48.4% in the ITT population) but with more high grade (≥ 3) adverse events. Somatic mutations of TOP2A and CD8 immunohistochemical score may have the potential to predict immunotherapy response in the immunomodulatory subtype of TNBC. In conclusion, the phase Ib/II FUTURE trial suggested a new concept for TNBC treatment, demonstrating the clinical benefit of subtyping-based targeted therapy for refractory metastatic TNBC.Subject terms: NCT03805399Breast cancer, Targeted therapies 相似文献
17.
Sudhir Kumar Qiqing Tao Steven Weaver Maxwell Sanderford Marcos A Caraballo-Ortiz Sudip Sharma Sergei L K Pond Sayaka Miura 《Molecular biology and evolution》2021,38(8):3046
Global sequencing of genomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continued to reveal new genetic variants that are the key to unraveling its early evolutionary history and tracking its global spread over time. Here we present the heretofore cryptic mutational history and spatiotemporal dynamics of SARS-CoV-2 from an analysis of thousands of high-quality genomes. We report the likely most recent common ancestor of SARS-CoV-2, reconstructed through a novel application and advancement of computational methods initially developed to infer the mutational history of tumor cells in a patient. This progenitor genome differs from genomes of the first coronaviruses sampled in China by three variants, implying that none of the earliest patients represent the index case or gave rise to all the human infections. However, multiple coronavirus infections in China and the United States harbored the progenitor genetic fingerprint in January 2020 and later, suggesting that the progenitor was spreading worldwide months before and after the first reported cases of COVID-19 in China. Mutations of the progenitor and its offshoots have produced many dominant coronavirus strains that have spread episodically over time. Fingerprinting based on common mutations reveals that the same coronavirus lineage has dominated North America for most of the pandemic in 2020. There have been multiple replacements of predominant coronavirus strains in Europe and Asia as well as continued presence of multiple high-frequency strains in Asia and North America. We have developed a continually updating dashboard of global evolution and spatiotemporal trends of SARS-CoV-2 spread (http://sars2evo.datamonkey.org/). 相似文献
18.
Alexandra Cossio Jimena Jojoa María del Mar Castro Ruth Mabel Castillo Lyda Osorio Thomas R. Shelite Nancy Gore Saravia Peter C. Melby Bruno L. Travi 《PLoS neglected tropical diseases》2021,15(4)
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 . NCT04500873相似文献
19.
Lachlan F. Miles Christiana Burt Joseph Arrowsmith Mikel A. McKie Sofia S. Villar Pooveshnie Govender Ruth Shaylor Zihui Tan Ravi De Silva Florian Falter 《PLoS medicine》2021,18(6)
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: ).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 NCT03532594.Lachlan Miles and co-workers report on a randomized controlled trial seeking to optimise protamine dosing after cardiopulmonary bypass. NCT03532594相似文献
20.
Sandhya Vasan Sarah J. Schlesinger Zhiwei Chen Arlene Hurley Angela Lombardo Soe Than Phumla Adesanya Catherine Bunce Mark Boaz Rosanne Boyle Eddy Sayeed Lorna Clark Daniel Dugin Mar Boente-Carrera Claudia Schmidt Qing Fang Lei Yaoxing Huang Gerasimos J. Zaharatos David F. Gardiner Marina Caskey Laura Seamons Martin Ho Len Dally Carol Smith Josephine Cox Dilbinder Gill Jill Gilmour Michael C. Keefer Patricia Fast David D. Ho 《PloS one》2010,5(1)