Similar Protection Research Articles

Ablation of SigH+ pDCs in B6.Nba2 mice prevents lupus-like disease development only if started before disease is fully established.

Systemic lupus erythematosus is characterized by hyper-activation of the immune system, multi-organ inflammation, and end-organ damage. Type I interferons (IFN-I) have been strongly implicated a role in disease etiology as has the main IFN-I-producing cell subset, the plasmacytoid dendritic cell (pDC). The B6.Nba2 mouse model develops a lupus-like disease characterized by elevated IFN-I levels and pDC pathogenicity. We have previously shown that pDC ablation prior to disease development in B6.Nba2 mice effectively prevents disease; however, it remains unclear if a similar protection can be seen if pDC ablation is initiated during later disease stages. This is important as Systemic lupus erythematosus patients are rarely diagnosed until disease is well-established and thus preventative treatment is unlikely to take place. Here we show that ablation of pDCs in the B6.Nba2 mouse model must be initiated early in order to effectively block disease development and that sustained reduction in pDC numbers is necessary for sustained effects. Finally, targeting of pDCs have been hypothesized to affect immunity towards infectious agents, in particular virus and intracellular bacteria. We show here that pDC ablation in B6.Nba2 mice does not affect the anti-viral response to encephalomyocarditic virus or a model T-dependent antigen. In summary, pDC ablation does not affect general immunity, but needs to happen early and be sustained to prevent lupus-like disease development in B6.Nba2 mice.

Alcohol flush does not aid in endoscope channel drying but may serve as an adjunctive microbiocidal measure: A new take on an old assumption

Alcohol is perceived to aid flexible endoscope channel drying, however we previously showed alcohol increased the time required to dry some channels with forced air versus water alone. Yet, alcohol may prevent microorganism outgrowth during storage. Drying endoscope channels has been shown to prevent outgrowth, but it is unknown if incomplete drying (<10 µL remaining) provides similar protection. Endoscope channel test articles were used to determine the efficacy of 70%-30% alcohol flush for prevention of Pseudomonas aeruginosa outgrowth and drying efficiency. For non-alcohol flushed channels, the impact of forced air drying on outgrowth of P. aeruginosa was determined. Alcohol flush (70%-30%) prevented outgrowth with little to no recovery of P. aeruginosa during ambient storage. 70% alcohol increased channel drying time by 1.5 or 3-fold compared to 50% alcohol or water, respectively. Forced air drying of non-alcohol flushed channels greatly reduced the initial contamination level and prevented outgrowth. Incomplete drying of contaminated channels was akin to no application of forced air. Applying forced air for more time than necessary to remove residual liquid did not completely eliminate the low level recovery of P. aeruginosa. Flushing with reduced concentrations of alcohol may provide a strategy to prevent microbial outgrowth while reducing drying time.

Charring performance of timber structures protected by traditional lime-based plasters

There are limited performance data available on the fire resistance of lime-based plasters as a fire protection system for timber structures; no design values are given in the current fire part of Eurocode 5. This complicates the design and assessment of such (historic) building structures, as the contribution of lime plasters in case of fire is not clear. This paper aims to provide relevant data and assessment tools for the fire safety design and evaluation of the protection ability of lime-based plasters in combination with timber structures under standard fire exposure conditions. An overview of experimental studies in small and model-scale to determine the protection effect of various lime plaster systems is presented. The investigation is carried out in view of the design concept given in the European fire design standard with respect to the start time of charring of timber and the charring rate of timber behind the plaster system. Results present new knowledge and fire-related performance data of selected lime-based plasters regarding their protection ability under different heat exposure conditions and scales. References are made to the commonly used gypsum plasterboards and previous studies by the authors for an extended evaluation of test results. Obtained results demonstrate that thicker plaster coats are able to provide similar initial protection compared to the gypsum plasterboards for the start time of charring and the charring rate of protected timber until its fall-off.

The ketone body β-hydroxybutyrate mitigates ILC2-driven airway inflammation by regulating mast cell function.

Ketone bodies are increasingly understood to have regulatory effects on immune cell function, with β-hydroxybutyrate (BHB) exerting a predominantly anti-inflammatory response. Dietary strategies to increase endogenous ketone body availability such as the ketogenic diet (KD) have recently been shown to alleviate inflammation of the respiratory tract. However, the role of BHB has not been addressed. Here, we observe that BHB suppresses group 2 innate lymphoid cell (ILC2)-mediated airway inflammation. Central to this are mast cells, which support ILC2 proliferation through interleukin-2 (IL-2). Suppression of the mast cell/IL-2 axis by BHB attenuates ILC2 proliferation and the ensuing type 2 cytokine response and immunopathology. Mechanistically, BHB directly inhibits mast cell function in part through GPR109A activation. Similar effects are achieved with either the KD or 1,3-butanediol. Our data reveal the protective role of BHB in ILC2-driven airway inflammation, which underscores the potential therapeutic value of ketone body supplementation for the management of asthma.

Experimental and numerical evaluation of a new visor concept with aerodynamic sealing to protect medical professionals from contaminated droplets and aerosols.

The fast spreading of the SARS‐CoV‐2 virus led to a significant increase in the demand for personal protective equipment (PPE). Healthcare professionals, mainly dentists, work near the patients, increasing their risk of infection. This paper investigates the effectiveness of an air‐curtain sealing effect in a newly designed visor developed to reduce the risk of contracting a respiratory infection. This PPE was developed by computational fluid dynamics (CFD) modeling. CFD results show that the aerodynamic sealing in this PPE device effectively protects the user's face by 43% from a contaminated environment. The experiments considered two different tests: one using a tracer gas (CO2) to simulate a gaseous contaminant inside and outside the PPE face shield and a second test using smoke to simulate aerosol transport and evaluate the PPE efficiency. The particle concentration within the aerodynamically sealed PPE was evaluated and compared with the protection efficiency of other PPE. Results show similar protection levels for particles in the 1–5 μm range between the prototype and a KN95 respirator. The combined use of this novel PPE with aerodynamic sealing and a physical mask (KN95 or surgical) produced protection efficiency values within the range of 57%–70% for particles greater than 0.5 μm. This study reveals the potential of using an air curtain combined with a face shield to reduce the risks from contaminated environments.

Engineered DNA-encoded monoclonal antibodies targeting Plasmodium falciparum circumsporozoite protein confer single dose protection in a murine malaria challenge model

Novel approaches for malaria prophylaxis remain important. Synthetic DNA-encoded monoclonal antibodies (DMAbs) are a promising approach to generate rapid, direct in vivo host-generated mAbs with potential benefits in production simplicity and distribution coupled with genetic engineering. Here, we explore this approach in a malaria challenge model. We engineered germline-reverted DMAbs based on human mAb clones CIS43, 317, and L9 which target a junctional epitope, major repeat, and minor repeat of the Plasmodium falciparum circumsporozoite protein (CSP) respectively. DMAb variants were encoded into a plasmid vector backbone and their expression and binding profiles were characterized. We demonstrate long-term serological expression of DMAb constructs resulting in in vivo efficacy of CIS43 GL and 317 GL in a rigorous mosquito bite mouse challenge model. Additionally, we engineered an Fc modified variant of CIS43 and L9-based DMAbs to ablate binding to C1q to test the impact of complement-dependent Fc function on challenge outcomes. Complement knockout variant DMAbs demonstrated similar protection to that of WT Fc DMAbs supporting the notion that direct binding to the parasite is sufficient for the protection observed. Further investigation of DMAbs for malaria prophylaxis appears of importance.

Chronic developmental hypoxia alters mitochondrial oxidative capacity and reactive oxygen species production in the fetal rat heart in a sex-dependent manner.

Insufficient oxygen supply (hypoxia) during fetal development leads to cardiac remodeling and a predisposition to cardiovascular disease in later life. Previous work has shown hypoxia causes oxidative stress in the fetal heart and alters the activity and expression of mitochondrial proteins in a sex‐dependent manner. However, the functional effects of these modifications on mitochondrial respiration remain unknown. Furthermore, while maternal antioxidant treatments are emerging as a promising new strategy to protect the hypoxic fetus, whether these treatments convey similar protection to cardiac mitochondria in the male or female fetus has not been investigated. Therefore, using an established rat model, we measured the sex‐dependent effects of gestational hypoxia and maternal melatonin treatment on fetal cardiac mitochondrial respiration, reactive oxygen species (ROS) production, and lipid peroxidation. Pregnant Wistar rats were subjected to normoxia or hypoxia (13% oxygen) during gestational days (GDs) 6–20 (term ~22 days) with or without melatonin treatment (5 µg/ml in maternal drinking water). On GD 20, mitochondrial aerobic respiration and H2O2 production were measured in fetal heart tissue, together with lipid peroxidation and citrate synthase (CS) activity. Gestational hypoxia reduced maternal body weight gain (p < .01) and increased placental weight (p < .05) but had no effect on fetal weight or litter size. Cardiac mitochondria from male but not female fetuses of hypoxic pregnancy had reduced respiratory capacity at Complex II (CII) (p < .05), and an increase in H2O2 production/O2 consumption (p < .05) without any changes in lipid peroxidation. CS activity was also unchanged in both sexes. Despite maternal melatonin treatment increasing maternal and fetal plasma melatonin concentration (p < .001), melatonin treatment had no effect on any of the mitochondrial parameters investigated. To conclude, we show that gestational hypoxia leads to ROS generation from the mitochondrial electron transport chain and affects fetal cardiac mitochondrial respiration in a sex‐dependent manner. We also show that maternal melatonin treatment had no effect on these relationships, which has implications for the development of future therapies for hypoxic pregnancies.

Orally Ingested Probiotics, Prebiotics, and Synbiotics as Countermeasures for Respiratory Tract Infections in Nonelderly Adults: A Systematic Review and Meta-Analysis.

The impact of gut microbiota-targeted interventions on the incidence, duration, and severity of respiratory tract infections (RTIs) in nonelderly adults, and factors moderating any such effects, are unclear. This systematic review and meta-analysis aimed to determine the effects of orally ingested probiotics, prebiotics, and synbiotics compared with placebo on RTI incidence, duration, and severity in nonelderly adults, and to identify potential sources of heterogeneity. Studies were identified by searching CENTRAL, PubMed, Scopus, and Web of Science up to December 2021. English-language, peer-reviewed publications of randomized, placebo-controlled studies that tested an orally ingested probiotic, prebiotic, or synbiotic intervention of any dose for ≥1 wk in adults aged 18-65y were included. Results were synthesized using intention-to-treat and per-protocol random-effects meta-analysis. Heterogeneity was explored by subgroup meta-analysis and meta-regression. Risk of bias was assessed using the Cochrane risk-of-bias assessment tool for randomized trials version 2 (RoB2). Forty-two manuscripts reporting effects of probiotics (n=38), prebiotics (n=2), synbiotics (n=1) or multiple -biotic types (n=1) were identified (n=9179 subjects). Probiotics reduced the risk of experiencing ≥1 RTI (relative risk=0.91; 95% CI: 0.84, 0.98; P=0.01), and total days (rate ratio=0.77; 95% CI: 0.71, 0.83; P<0.001), duration (Hedges' g = -0.23; 95% CI: -0.39, -0.08; P=0.004), and severity (Hedges' g = -0.16; 95% CI: -0.29, -0.03; P=0.02) of RTIs. Effects were relatively consistent across different strain combinations, doses, and durations, although reductions in RTI duration were larger with fermented dairy as the delivery matrix, and beneficial effects of probiotics were not observed in physically active populations. Overall risk of bias was rated as "some concerns" for most studies. In conclusion, orally ingested probiotics, relative to placebo, modestly reduce the incidence, duration, and severity of RTIs in nonelderly adults. Physical activity and delivery matrix may moderate some of these effects. Whether prebiotic and synbiotic interventions confer similar protection remains unclear due to few relevant studies. This trial was registered at https://www.crd.york.ac.uk/prospero/ as CRD42020220213.

Ferulic acid and vinpocetine intake improves memory function by enhancing insulin sensitivity and reducing neuroinflammation and oxidative stress in type 2 diabetic animals with induced Alzheimer's disease

• Vinpocetine and ferulic acid intakes suppressed the memory deficits by hippocampal amyloid-β infusion in diabetic rats. • Vinpocetine and ferulic acid intake lowered systemic insulin resistance than the rats without amyloid-β infusion. • Vinpocetine and ferulic acid intake potentiated hippocampal insulin signaling and reduced neuroinflammation. • Ferulic acid intake additionally decreased oxidative stress in the hippocampus. • Ferulic acid intake improved memory deficit as much as the rats without amyloid-β infusion. We aimed to examine the hypothesis that dietary ferulic acid and vinpocetine intake improve the memory deficits caused by hippocampal amyloid-β accumulation in type 2 diabetic(T2DM) rats with induced Alzheimer’s disease(AD). Their mechanisms were also tested. Partial pancreatectomized animals with hippocampal amyloid-β(25–35) infusion representing Asian T2DM developed AD (AD rats; memory deficit). After the eight-week intervention, memory impairment was impeded in the AD-FRA fed ferulic acid(50 mg/kg BW) and AD-VPC vinpocetine(50 mg/kg BW; AD-VPC) through the inhibition of amyloid-β deposition and neuroinflammation compared to the AD-CON. The AD-FRA showed less amyloid-β deposition than the AD-VPC group. The AD-FRA and AD-VPC groups showed an inhibited attenuation of the hippocampal phosphorylated Akt → glycogen-synthase kinase(GSK)-3β → forkhead box protein O1(FOXO1) pathway, and AD-FRA showed similar protection as CON. No adverse effects in AD-FRA and AD-VPC were detected. In conclusion, vinpocetine and ferulic acid supplementation suppressed the memory deficits in T2DM rats with AD, and ferulic acid showed better improvement than vinpocetine, similar to no AD-induced rats.

The Shifting Approach of the Court of Justice of the European Union towards the Principle of Mutual Trust and the Impact of the Rule of Law

Summary The principle of mutual trust is based on the idea that there is mutual confidence between Member States that their national legal systems are in line with the European Union law and are able to provide similar protection of the shared values. However, the experience of last years has brought multiple challenges questioning these fundamental building blocs. This article focuses on understanding the role of fundamental rights and the rule of law in limiting the principle of mutual trust as suggested by the case law of the Court of Justice of the European Union (CJEU). It discusses the shift in the approach of the CJEU towards the limitations, exploring whether the recent case law suggests that the current crises of values, including the systemic violations of the rule of law and fundamental rights play a crucial role in widening the limits of mutual trust.

COVID-19 cases, hospitalizations and deaths after vaccination: a cohort event monitoring study, Islamic Republic of Iran.

ObjectiveTo investigate the incidence of coronavirus disease 2019 (COVID-19) cases, hospitalizations and deaths in Iranians vaccinated with either AZD1222 Vaxzevria, CovIran® vaccine, SARS-CoV-2 Vaccine (Vero Cell), Inactivated (lnCoV) or Sputnik V.MethodsWe enrolled individuals 18 years or older receiving their first COVID-19 vaccine dose between April 2021 and January 2022 in seven Iranian cities. Participants completed weekly follow-up surveys for 17 weeks (25 weeks for AZD1222) to report their COVID-19 status and hospitalization. We used Cox regression models to assess risk factors for contracting COVID-19, hospitalization and death.FindingsOf 89 783 participants enrolled, incidence rates per 1 000 000 person-days were: 528.2 (95% confidence interval, CI: 514.0–542.7) for contracting COVID-19; 55.8 (95% CI: 51.4–60.5) for hospitalization; and 4.1 (95% CI: 3.0–5.5) for death. Compared with SARS-CoV-2 Vaccine (Vero Cell), hazard ratios (HR) for contracting COVID-19 were: 0.70 (95% CI: 0.61−0.80) with AZD1222; 0.73 (95% CI: 0.62–0.86) with Sputnik V; and 0.73 (95% CI: 0.63–0.86) with CovIran®. For hospitalization and death, all vaccines provided similar protection 14 days after the second dose. History of COVID-19 protected against contracting COVID-19 again (HR: 0.76; 95% CI: 0.69–0.84). Diabetes and respiratory, cardiac and renal disease were associated with higher risks of contracting COVID-19 after vaccination.ConclusionThe rates of contracting COVID-19 after vaccination were relatively high. SARS-CoV-2 Vaccine (Vero Cell) provided lower protection against COVID-19 than other vaccines. People with comorbidities had higher risks of contracting COVID-19 and hospitalization and should be prioritized for preventive interventions.

Targeting PDE4B (Phosphodiesterase-4 Subtype B) for Cardioprotection in Acute Myocardial Infarction via Neutrophils and Microcirculation.

Timely and complete restoration of blood flow is the most effective intervention for patients with acute myocardial infarction. However, the efficacy is limited by myocardial ischemia-reperfusion (MI/R) injury. PDE4 (phosphodiesterase-4) hydrolyzes intracellular cyclic adenosine monophosphate and it has 4 subtypes A-D. This study aimed to delineate the role of PDE4B (phosphodiesterase-4 subtype B) in MI/R injury. Mice were subjected to 30-minute coronary artery ligation, followed by 24-hour reperfusion. Cardiac perfusion was assessed by laser Doppler flow. Vasomotor reactivities were determined in mouse and human coronary (micro-)arteries. Cardiac expression of PDE4B, but not other PDE4 subtypes, was increased in mice following reperfusion. PDE4B was detected primarily in endothelial and myeloid cells of mouse and human hearts. PDE4B deletion strikingly reduced infarct size and improved cardiac function 24-hour or 28-day after MI/R. PDE4B in bone marrow-derived cells promoted MI/R injury and vascular PDE4B further exaggerated this injury. Mechanistically, PDE4B mediated neutrophil-endothelial cell interaction and PKA (protein kinase A)-dependent expression of cell adhesion molecules, neutrophil cardiac infiltration, and release of proinflammatory cytokines. Meanwhile, PDE4B promoted coronary microcirculatory obstruction and vascular permeability in MI/R, without affecting flow restriction-induced thrombosis. PDE4B blockade increased flow-mediated vasodilatation and promoted endothelium-dependent dilatation of coronary arteries in a PKA- and nitric oxide-dependent manner. Furthermore, postischemia administration with piclamilast, a PDE4 pan-inhibitor, improved cardiac microcirculation, suppressed inflammation, and attenuated MI/R injury in mice. Incubation with sera from patients with acute myocardial infarction impaired acetylcholine-induced relaxations in human coronary microarteries, which was abolished by PDE4 inhibition. Similar protection against MI/R-related coronary injury was recapitulated in mice with PDE4B deletion or inhibition, but not with the pure vasodilator, sodium nitroprusside. PDE4B is critically involved in neutrophil inflammation and microvascular obstruction, leading to MI/R injury. Selective inhibition of PDE4B might protect cardiac function in patients with acute myocardial infarction designated for reperfusion therapy.

COVID-19 After Vaccination in Lung Transplant Recipients: Real-Life Data.

The effectiveness of COVID-19 vaccines in lung transplant recipients is unclear. We retrospectively analyzed lung transplant recipients vaccinated with an inactivated virus vaccine (CoronaVac) and the mRNA vaccine BNT162b2 used against the SARS-CoV-2 virus in Turkey and shared their effects on COVID-19. Demographic data of lung transplant recipients followed up for >3 months were collected, and vaccination dates and status against the SARS-CoV-2 virus were recorded. Recipients who received at least 3 doses of CoronaVac or 2 doses of BNT162b2, or 1 dose of CoronaVac plus 2 doses of BNT162b2, or 2 doses of CoronaVac plus 1 dose of BNT162b2 were considered fully vaccinated; those who were vaccinated less than this number were considered partially vaccinated. Patients with positive SARS-CoV-2 reverse transcription-polymerase chain reaction tests from respiratory tract samples were accepted as positive for COVID-19. Recipients were classified by number and type of vaccine, and groups were compared for infection, need for intensive care, and death as a result of COVID-19. Of the 53 lung transplant recipients, 51 were vaccinated (7 partially vaccinated, 44 fully vaccinated) and 2 were not vaccinated. Of fully vaccinated recipients, 13/44 received the inactivated vaccine, 5/44 received the mRNA vaccine, and 26/44 had a combination of the 2 vaccines. During the follow-up period, 13 patients (2/2 not vaccinated, 2/7 [28.5%] partially vaccinated, 9/44 [20.5%] fully vaccinated) were diagnosed with COVID-19. There was no significant difference in protection against infection between the inactivated, the mRNA, and combined vaccine groups. There was no significant association in cycle threshold values that determine the infection load and COVID-19 severity between transplant recipients who died and those who did not. In lung transplant recipients, 3 doses of inactivated vaccine, 2 doses of mRNA vaccine, or the combined heterologous vaccine provided similar protection. Prevention of exposure is one of the most crucial steps.

Broadband stealth composite metastructure with high penetration protection

Microwave absorption plays an important role in modern electromagnetic protection and compatibility. However, lack of mechanical and impact design restricts their practical applications. Herein, a composite armor (CA) incorporating metastructure design with mixed characteristic periods was optimized by embedded genetic algorithms and inversion framework of equivalent impedance derivation. The −10 dB absorption bandwidth was covered from 2 GHz to 18 GHz. The impact-penetration ballistic experiments and simulation verified the penetration protection of CA against large caliber armor-piercing incendiary (API) with target impact speed of more than 745.1 m/s. The CA fabricated by ultra-high molecular weight polyethylene fiber reinforced polymer (UFRP), carbon fiber reinforced polymer (CFRP) and alumina ceramics showed better penetration protection performance than the counterparts with titanium and aluminum alloys with the same weight. Compared with traditional armor steel with similar protection performance, more than 30% weight is reduced for the proposed composite armor.

Extending Animal Cruelty Protections to Scientific Research

Extending Animal Cruelty Protections to Scientific Research

A Snakeskin-Inspired, Soft-Hinge Kirigami Metamaterial for Self-Adaptive Conformal Electronic Armor.

A majority of soft-body creatures evolve armor or shells to protect themselves. Similar protection demand is for flexible electronics working in complex environments. Existing works mainly focus on improving the sensing capabilities such as electronic skin (E-skin). Inspired by snakeskin, a novel electronic armor (E-armor) is proposed, which not only possesses mechanical flexibility and electronic functions similar to E-skin, but is also able to protect itself and the underlying soft body from external physical damage. The geometry of the kirigami mechanical metamaterial (Kiri-MM) ensures auxetic stretchability and meanwhile large areal coverage for sufficient protection. Moreover, to suppress the inherent but undesired out-of-plane buckling of conventional Kiri-MMs for conformal applications, soft hinges are used to form a distinct soft (hinges)-rigid (tiles) configuration. Analytical, computational, and experimental studies of the mechanical behaviors of the soft-hinge Kiri-MM E-armor demonstrate the merits of this design, i.e., stretchability, conformability, and protectability, as applied to flexible electronics. Deploying a conductive soft material at the hinges enables facile wiring strategies for large-scale circuit arrays. Functional E-armor systems for controllable display and sensing purposes provide simple examples of a wide spectrum of applications of this concept.

El secreto comercial made in Paraguay: los alcances y límites en el derecho laboral y en el derecho penal

In Paraguayan Law there is not a single norm which regulates the confidential information that should be kept “in secret”. Instead, there are several regulations on the “confidential information” that should be kept “in secret”. Moreover, these different regulations come from different areas of the legal arena, as the Civil Law, Labor Law, Criminal Law and Public Law. Furthermore, in Paraguayan Law there are known several “levels” of secrecy, namely, “professional secrecy”, “industrial secrecy”, “business secret”, “trade secrets”, “classified matters”, etc. Even though these names suggest a unique o at least a similar protection. But in fact, these “levels” of secrecy differ in its legal protection, namely in its scope as in its quality.In this work the “legal secrecy obligation” will be analyzed from both the Labor Law and Criminal Law points of view, taking in consideration the ‘General Principles of Law’ and the rules of other legal areas like Civil Law or Public Law, aiming the proper reach of the labor and criminal regulations on the “legal secrecy obligation (considering the fact that “trade secrets” sometimes are not the same as “professional secrecy” and so on).

Efficacy of RTS,S/AS01E malaria vaccine administered according to different full, fractional, and delayed third or early fourth dose regimens in children aged 5–17 months in Ghana and Kenya: an open-label, phase 2b, randomised controlled trial

SummaryBackgroundControlled infection studies in malaria-naive adults suggest increased vaccine efficacy for fractional-dose versus full-dose regimens of RTS,S/AS01. We report first results of an ongoing trial assessing different fractional-dose regimens in children, in natural exposure settings.MethodsThis open-label, phase 2b, randomised controlled trial is conducted at the Malaria Research Center, Agogo, Ashanti Region (Ghana), and the Kenya Medical Research Institute and the US Centers for Disease Control and Prevention site in Siaya County (Kenya). We enrolled children aged 5–17 months without serious acute or chronic illness who had previously received three doses of diphtheria, tetanus, pertussis, and hepatitis B vaccine and at least three doses of oral polio vaccine. Children were randomly assigned (1:1:1:1:1) using a web-based randomisation system with a minimisation procedure accounting for centre to receive rabies control vaccine (M012 schedule) or two full doses of RTS,S/AS01E at month 0 and month 1, followed by either full doses at months 2 and 20 (group R012-20 [standard regimen]), full doses at months 2, 14, 26, and 38 (R012-14), fractional doses at months 2, 14, 26, and 38 (Fx012-14), or fractional doses at months 7, 20, and 32 (Fx017-20). The fractional doses were administered as one fifth (0·1 mL) of the full RTS,S dose (0·5 mL) after reconstitution. All vaccines were administered by intramuscular injection in the left deltoid. The primary outcome was occurrence of clinical malaria cases from month 2·5 until month 14 for the Fx012-14 group versus the pooled R012-14 and R012-20 groups in the per-protocol set. We assessed incremental vaccine efficacy of the Fx012-14 group versus the pooled R012-14 and R012-20 group over 12 months after dose three. Safety was assessed in all children who received at least one vaccine dose. This trial is registered with ClinicalTrials.gov, NCT03276962.FindingsBetween Sept 28, 2017, and Sept 25, 2018, 2157 children were enrolled, of whom 1609 were randomly assigned to a treatment group (322 to each RTS,S/AS01E group and 321 to the rabies vaccine control group). 1500 children received at least one study vaccine dose and the per-protocol set comprised 1332 children. Over 12 months after dose three, the incremental vaccine efficacy in the Fx012-14 group versus the pooled R012-14 and R12-20 groups was −21% (95% CI −57 to 7; p=0·15). Up to month 21, serious adverse events occurred in 48 (16%) of 298 children in the R012-20 group, 45 (15%) of 294 in the R012-14 group, 47 (15%) of 304 in the Fx012-14 group, 62 (20%) of 311 in the Fx017-20 group, and 71 (24%) of 293 in the control group, with no safety signals observed.InterpretationThe Fx012-14 regimen was not superior to the standard regimen over 12 months after dose three. All RTS,S/AS01E regimens provided substantial, similar protection against clinical malaria, suggesting potential flexibility in the recommended dosing regimen and schedule. This, and the effect of annual boosters, will be further evaluated through 50 months of follow-up.FundingGlaxoSmithKline Biologicals; PATH's Malaria Vaccine Initiative.

Vaccination with fractional doses: promise or illusion?

In The Lancet Infectious Diseases, Aaron M Samuels and colleagues 1 Samuels AM Ansong D Kariuki SK et al. Efficacy of RTS,S/AS01E malaria vaccine administered according to different full, fractional, and delayed third or early fourth dose regimens in children aged 5–17 months in Ghana and Kenya: an open-label, phase 2b, randomised controlled trial. Lancet Infect Dis. 2022; (published online June 23.)https://doi.org/10.1016/S1473-3099(22)00273-0 Summary Full Text Full Text PDF PubMed Google Scholar assessed the efficacy of fractional RTS,S/AS01E (hereafter referred to as RTS,S) vaccines doses against malaria. The study design of this clinical trial was based on findings from a phase 2a controlled human malaria infection (CHMI) study assessing vaccine efficacy in adults, 2 Regules JA Cicatelli SB Bennett JW et al. Fractional third and fourth dose of RTS,S/AS01 malaria candidate vaccine: a phase 2a controlled human malaria parasite infection and immunogenicity study. J Infect Dis. 2016; 214: 762-771 Crossref PubMed Scopus (117) Google Scholar and from a study evaluating the effect of a change in the vaccine regimen on the quality of antibody responses. 3 Moon JE Ockenhouse C Regules JA et al. A phase IIa controlled human malaria infection and immunogenicity study of RTS,S/AS01E and RTS,S/AS01B delayed fractional dose regimens in malaria-naive adults. J Infect Dis. 2020; 222: 1681-1691 Crossref PubMed Scopus (7) Google Scholar Efficacy of RTS,S/AS01E malaria vaccine administered according to different full, fractional, and delayed third or early fourth dose regimens in children aged 5–17 months in Ghana and Kenya: an open-label, phase 2b, randomised controlled trialThe Fx012-14 regimen was not superior to the standard regimen over 12 months after dose three. All RTS,S/AS01E regimens provided substantial, similar protection against clinical malaria, suggesting potential flexibility in the recommended dosing regimen and schedule. This, and the effect of annual boosters, will be further evaluated through 50 months of follow-up. Full-Text PDF Open Access

Abstract 1856: Adaptation to dopamine impairs the anti-cancer effect of ONC201 and ONC206

Abstract ONC201 (originally discovered as TRAIL-Inducing Compound #10 or TIC10) and analogue ONC206 have been found to induce an integrated stress response with suggested primary targets and mechanisms involving agonist activity against mitochondrial ClpP and antagonism of dopamine receptors D2/3 (DRD2/3). We hypothesized that dopamine, the agonist of DRD2, may compete with ONC201 or ONC206 for DRD2/3 and impair the anti-cancer effect of ONC201 or ONC206. We therefore pre-treated cancer cells from different tissue origins including breast cancer, pancreatic cancer, colorectal cancer, lung cancer, GBM, and DIPG with dopamine for 12 hours, 24 hours or 48 hours, respectively, followed by treatment of ONC201 or ONC206 for 72hours. Cell viability was determined by the CellTiter Glo assay. Single treatment with dopamine did not increase cell viability. We observed that 48 hours of pre-treatment with dopamine at 50 μM, 100 μM or 200 μM impaired the cell viability suppression effect of ONC201 at 4 μM and 8 μM, while ONC206 at 0.5 μM, 1 μM and 2 μM led to similar protection for loss of cell viability in pancreatic cancer cells. The impairment of the anti-cancer effect by dopamine was also observed in colorectal cancer cells with 48 hours pre-treatment with dopamine at 50 μM, 100 μM, 200 μM or 400 μM and treatment with ONC201 at 4 μM and 8 μM, or ONC206 at 0.5 μM, 1 μM, or 2 μM. In addition, we treated pancreatic cancer and colorectal cancer cells with ONC212 after 48 hours pre-treatment with dopamine and observed a similar impairment of the anti-cancer effect, even though ONC212 is not a DRD2 antagonist. We pre-treated pancreatic cancer and colorectal cancer cells with specific DRD2 agonist, sumanirole, for 48 hours followed by treatment of ONC201, ONC206, or ONC212 for 72 hours, and no impairment was seen. We pre-treated multiple cancer cell lines with 2 μM or 10 μM dopamine for one week followed by ONC201, ONC206, or ONC212 treatment and performed colony assays. Pre-treatment with dopamine at 10 μM impaired the anti-cancer effect of ONC201 or ONC206 in pancreatic cancer. Pre-treatment with dopamine at 2 μM or 10 μM impaired the anti-tumor effect of ONC201 in GBM cells. By contrast to the cell viability result, no impairment of ONC212 effect from dopamine was seen in pancreatic cancer cells. Western blotting was conducted to investigate whether dopamine pre-treatment impacted signaling pathways reported to be affected by ONC201. Dopamine pre-treatment did not impact changes induced by ONC201 in ATF4, CHOP, DR5, ClpX, clpP, pERK, pAkt and pS6. We are pursuing whether the protective effect of dopamine is due to the agonism of DRD2 or alternative pro-survival mechanisms. Citation Format: Yiqun Zhang, Wafik S. El-Deiry. Adaptation to dopamine impairs the anti-cancer effect of ONC201 and ONC206 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1856.