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MAbs 2023CD40 agonism by systemic administration of CD40 monoclonal antibodies has been explored in clinical trials for immunotherapy of cancer, uncovering enormous potential,...
CD40 agonism by systemic administration of CD40 monoclonal antibodies has been explored in clinical trials for immunotherapy of cancer, uncovering enormous potential, but also dosing challenges in terms of systemic toxicity. CD40-dependent activation of antigen presenting cells is dependent on crosslinking of the CD40 receptor. Here we exploited this requisite by coupling crosslinking to cancer-receptor density by dual-targeting of CD40 and platelet-derived growth factor receptor beta (PDGFRB), which is highly expressed in the stroma of various types of tumors. A novel PDGFRBxCD40 Fc-silenced bispecific AffiMab was developed to this end to test whether it is possible to activate CD40 in a PDGFRB-targeted manner. A PDGFRB-binding Affibody molecule was fused to each heavy chain of an Fc-silenced CD40 agonistic monoclonal antibody to obtain a bispecific "AffiMab". Binding of the AffiMab to both PDGFRB and CD40 was confirmed by surface plasmon resonance, bio-layer interferometry and flow cytometry, through analysis of cells expressing respective target. In a reporter assay, the AffiMab displayed increased CD40 potency in the presence of PDGFRB-conjugated beads, in a manner dependent on PDGFRB amount/bead. To test the concept in immunologically relevant systems with physiological levels of CD40 expression, the AffiMab was tested in human monocyte-derived dendritic cells (moDCs) and B cells. Expression of activation markers was increased in moDCs specifically in the presence of PDGFRB-conjugated beads upon AffiMab treatment, while the Fc-silenced CD40 mAb did not stimulate CD40 activation. As expected, the AffiMab did not activate moDCs in the presence of unconjugated beads. Finally, in a co-culture experiment, the AffiMab activated moDCs and B cells in the presence of PDGFRB-expressing cells, but not in co-cultures with PDGFRB-negative cells. Collectively, these results suggest the possibility to activate CD40 in a PDGFRB-targeted manner . This encourages further investigation and the development of such an approach for the treatment of solid cancers.
Topics: Humans; Receptor, Platelet-Derived Growth Factor beta; CD40 Antigens; Neoplasms; Antibodies, Monoclonal; Monocytes
PubMed: 37332119
DOI: 10.1080/19420862.2023.2223750 -
Frontiers in Neuroscience 2019Several control conditions, such as penetrating sham acupuncture and non-penetrating placebo needles, have been used in clinical trials on acupuncture effects in chronic... (Review)
Review
Several control conditions, such as penetrating sham acupuncture and non-penetrating placebo needles, have been used in clinical trials on acupuncture effects in chronic pain syndromes. All these control conditions are surprisingly effective with regard to their analgesic properties. These findings have fostered a discussion as to whether acupuncture is merely a placebo. Meta-analyses on the clinical effectiveness of placebo revealed that placebo interventions in general have minor, clinically important effects. Only in trials on pain and nausea, including acupuncture studies, did placebo effects vary from negligible to clinically important. At the same time, individual patient meta-analyses confirm that acupuncture is effective for the treatment of chronic pain, including small but statistically significant differences between acupuncture and sham acupuncture. All acupuncture control conditions induce , a distinct stimulation associated with pain and needling which has been shown to be a nociceptive/pain stimulus. Acupuncture therefore probably activates the pain matrix in the brain in a bottom-up fashion via the spino-thalamic tract. Central nervous system effects of acupuncture can be modulated through expectations, which are believed to be a central component of the placebo response. However, further investigation is required to determine how strong the influence of placebo on the attenuation of activity in the pain matrix really is. A meta-analysis of individual participant functional magnetic imaging data reveals only weak effects of placebo on the activity of the pain network. The clinical acupuncture setting is comprised of a combination of a distinct neurophysiological stimulus, the needling stimulus/experience, and a complex treatment situation. A broader definition of placebo, such as that proposed by Howick (2017) acknowledges a role for expectation, treatment context, emotions, learning, and other contextual variables of a treatment situation. The inclusion of particular treatment feature as a definitional element permits a contextual definition of placebo, which in turn can be helpful in constructing future clinical trials on acupuncture.
PubMed: 31680841
DOI: 10.3389/fnins.2019.01110 -
JAMA Network Open Mar 2023High-dose docosahexaenoic acid (DHA), a long-chain polyunsaturated fatty acid, may affect the risk of bronchopulmonary dysplasia (BPD). However, high-level summative... (Meta-Analysis)
Meta-Analysis
Association Between Enteral Supplementation With High-Dose Docosahexaenoic Acid and Risk of Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review and Meta-analysis.
IMPORTANCE
High-dose docosahexaenoic acid (DHA), a long-chain polyunsaturated fatty acid, may affect the risk of bronchopulmonary dysplasia (BPD). However, high-level summative evidence supporting such clinical association in very preterm infants is lacking.
OBJECTIVE
To examine the association between enteral supplementation with high-dose DHA during the neonatal period and the risk of BPD in preterm infants born at less than 29 weeks' gestation.
DATA SOURCES
PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, medRxiv, and ClinicalTrials.gov were searched from inception to August 1, 2022, for eligible articles with no language restrictions.
STUDY SELECTION
Randomized clinical trials (RCTs) were eligible for inclusion (1) if their interventions involved direct administration of a minimum DHA supplementation of 40 mg/kg/d or breast milk or formula feeding of at least 0.4% of total fatty acids, and (2) if they reported data on either BPD, death, BPD severity, or a combined outcome of BPD and death.
DATA EXTRACTION AND SYNTHESIS
Two investigators completed independent review of titles and abstracts, full text screening, data extraction, and quality assessment using the Cochrane Risk of Bias 2.0. Risk ratios (RRs) with 95% CIs were pooled using random-effect meta-analyses.
MAIN OUTCOMES AND MEASURES
Primary outcome was BPD using trial-specific definitions, which was further stratified for RCTs that used a more stringent BPD definition based on systematic pulse oximetry assessment at 36 weeks' postmenstrual age. Other outcomes were BPD, death, BPD severity, or combined BPD and death.
RESULTS
Among the 2760 studies screened, 4 RCTs were included, which involved 2304 infants (1223 boys [53.1%]; mean [SD] gestational age, 26.5 [1.6] weeks). Enteral supplementation with high-dose DHA was associated with neither BPD (4 studies [n = 2186 infants]; RR, 1.07 [95% CI, 0.86-1.34]; P = .53; I2 = 72%) nor BPD or death (4 studies [n = 2299 infants]; RR, 1.04 [95% CI, 0.91-1.18]; P = .59; I2 = 61%). However, an inverse association with BPD was found in RCTs that used a more stringent BPD definition (2 studies [n = 1686 infants]; RR, 1.20 [95% CI, 1.01-1.42]; P = .04; I2 = 48%). Additionally, DHA was inversely associated with moderate-to-severe BPD (3 studies [n = 1892 infants]; RR, 1.16 [95% CI, 1.04-1.29]; P = .008; I2 = 0%).
CONCLUSIONS AND RELEVANCE
Results of this study showed that enteral supplementation with high-dose DHA in the neonatal period was not associated overall with BPD, but an inverse association was found in the included RCTs that used a more stringent BPD definition. These findings suggest that high-dose DHA supplementation should not be recommended to prevent BPD in very preterm infants.
Topics: Infant, Newborn; Infant; Male; Female; Humans; Adult; Docosahexaenoic Acids; Bronchopulmonary Dysplasia; Infant, Premature; Gestational Age; Infant, Premature, Diseases; Fetal Growth Retardation; Dietary Supplements
PubMed: 36943265
DOI: 10.1001/jamanetworkopen.2023.3934 -
Plants (Basel, Switzerland) Jun 2023The interaction between genotypes and environments plays an important role in selecting superior genotypes for target locations. The main objectives of the present study...
The interaction between genotypes and environments plays an important role in selecting superior genotypes for target locations. The main objectives of the present study were to analyze the effect of the genotype-by-environment interaction (GEI) and identify superior, newly developed, and promising barley genotypes for cold regions in Iran. For these purposes, a set of genotypes obtained from breeding programs for cold climates in Iran, along with two reference genotypes, were investigated at eight research stations (Tabriz, Ardabil, Arak, Miandoab, Mashhad, Jolge Rokh, Karaj, and Hamadan) during two consecutive growing seasons (2019-2020 and 2020-2021). The results of the freezing test (LT) showed that most of the tested genotypes had significant cold tolerance at the seedling stage. Based on the additive main effect and multiplicative interaction (AMMI) analysis, environment (E) and GEI effects explained 49.44% and 16.55% of the total variation in grain yield, respectively. Using AMMI1 and AMMI2 models, G2 and G20 were found to be superior genotypes in terms of grain yield and stability. Moreover, AMMI-based stability parameters considered the G20 genotype to be the ideal genotype. A two-plot analysis of the genotype-by-environment interaction (GGE) biplot showed that the 16 experimental environments were grouped into 2 mega-environments. Of the test environments, ARK1 and KAJ2 had the highest discriminating power and representativeness ability, and these were identified as ideal environments for testing advanced genotypes for yield and stability performance during early barley breeding practices in cold areas in Iran. In conclusion, both AMMI and GGE biplot models identified several superior genotypes, among which G20, with a high average yield relative to the overall average yield and the lowest IPC1 score, was found to have high yield stability and is recommended for inclusion in breeding programs for cold climates in Iran.
PubMed: 37446971
DOI: 10.3390/plants12132410 -
PloS One 2022The uropathogens is the main cause of urinary tract infection (UTI). The aim of the study was to isolate bacteria from urine samples of UTI patients and find out the... (Clinical Trial)
Clinical Trial
The uropathogens is the main cause of urinary tract infection (UTI). The aim of the study was to isolate bacteria from urine samples of UTI patients and find out the susceptibility of isolated bacteria. Bacteria were identified using both conventional and molecular methods. Sanger sequence procedure used for 16S ribosomal RNA and phylogenetic analysis was performed using Molecular Evolutionary Genetics Analysis (MEGA-7) software. In this study, Escherichia coli, Klebsiella pneumonia, Staphylococcus were reported as 58, 28 and 14.0% respectively. Phylogenetic tree revealed that 99% of sample No. Ai (05) is closely related to E. coli to (NR 114042.1 E. coli strain NBRC 102203). Aii (23) is 99% similar to K. pneumoniae to (NR 117686.1 K. pneumonia strain DSM 30104) and 90% Bi (48) is closely linked to S. aureus to (NR 113956.1 S. aureus strain NBRC 100910). The antibiotic susceptibility of E. coli recorded highest resistance towards ampicillin (90%) and least resistant to ofloxacin (14%). Some of the other antibiotics such amoxicillin, ciprofloxacin, gentamicin, ceftazidime, cefuroxime and nitrofurantoin resistance were observed 86, 62, 24, 55, 48 and 35% respectively. The cefuroxime showed the highest antibiotic resistance against K. pneumoniae with 85% followed by amoxicillin, ciprofloxacin, gentamicin, ceftazidime, ampicillin and nitrofurantoin resulted in 60, 45, 67, 70, 75 and 30% respectively. The resistance of S. aureus against erythromycin, cefuroxime and ampicillin were found with 72%. The resistance against amoxicillin, gentamicin, ceftazidime and ceftriaxone found 57, 43, 43 and 15% respectively. Phylogenetic analysis shows that sequences are closely related with the reference sequences and E. coli is the dominant bacteria among UTI patients and is resistant to the commercially available antibiotics.
Topics: Anti-Bacterial Agents; Bacteria; Bacterial Infections; Drug Resistance, Bacterial; Female; Humans; Male; Microbial Sensitivity Tests; Phylogeny; Urinary Tract Infections
PubMed: 35089940
DOI: 10.1371/journal.pone.0262952 -
Heliyon Nov 2023Increasing production requires the development of high yielding cultivars adapted to various environments. Multi-environment trials (MET) remains the best approach to...
Increasing production requires the development of high yielding cultivars adapted to various environments. Multi-environment trials (MET) remains the best approach to assess the performance of accessions across environments. The objective of this study was to select the best performing and stable accessions of sesame across different environments in Benin Republic. Nineteen sesame accessions were evaluated across eight environments using a randomized complete block design with four replicates. The accessions were evaluated for three traits: days to 50% flowering (D50F), thousand-seed weight (TSW), and seed yield (SY) during 2020 growing season. The stable and top-performing accessions across environments were determined using AMMI (Additive main effects and multiplicative interaction), GGE (Genotype main effect and genotype × environment interaction), and MTSI (Multi-trait stability index). AMMI analysis of variance showed a significant difference across environments for the three traits. The accessions were affected by environmental conditions for the three traits. The broad-sense heritability estimates were high (>0.60) for all the traits, indicating the improvement is achievable through selection. AMMI1 and AMMI2 biplots identified G10 and G13 as high seed yielding accessions adapted to environments E1, E2. The GGE biplot showed two mega-environments for TSW and three mega-environments for D50F and SY. For SY, G11 and G13 were the best accessions in the first mega-environment, G10 the best accession in the second mega-environment; G3 and G8 were the best accessions in the third mega-environment. AMMI and GGE analyses identified G10, G5, G12 as high seed yielding and stable accessions across environments. GGE biplot revealed that E1 and E2 were the most suitable environments for multi-location trials based on their discriminating ability and representativeness. MTSI indicated G10, G13, G19 as promising germplasm to be recommended for breeding program.
PubMed: 38034689
DOI: 10.1016/j.heliyon.2023.e21656 -
Journal of Cosmetic Dermatology Jul 2022Hyaluronic acid (HA) plays an important role in cellular and extracellular matrix (ECM) homeostasis. Recent studies demonstrate that low molecular weight (MW) HA has...
INTRODUCTION
Hyaluronic acid (HA) plays an important role in cellular and extracellular matrix (ECM) homeostasis. Recent studies demonstrate that low molecular weight (MW) HA has pro-inflammatory characteristics while high MW HA is considered anti-inflammatory and regenerative. In formulating a topical HA product, the possibility of creating a focused high MW HA technology was posed, combining external surface high MW HA constituents with active agents promoting fibroblast production of high MW in the depths of the dermis.
METHODS
Human dermal fibroblasts and keratinocytes were treated with various agents, and RNA sequencing (RNA-seq) was conducted to identify genes involved in HA synthesis. HA production by fibroblasts was assessed by collecting the culture supernatant, concentrating the protein, and conducting polyacrylamide gel electrophoresis (PAGE). The gel was stained with Stains-All to identify bands relative to known HA products of different MWs. Subsequently, the supernatants were treated with hyaluronidase to confirm the bands corresponded to HA.
RESULTS
The RNA-seq results revealed a variety of agents upregulated HA-related genes. However, a potent upregulation of HA synthesis gene was observed by hexapeptide-11 in the keratinocytes and a newly identified proprietary octapeptide in the fibroblasts. PAGE demonstrated not only robust production of HA by octapeptide, but significantly, the HA produced was ~2 Mega Daltons in size. Octapeptide was the most potent stimulator among the tested agents.
CONCLUSION
Comprehensive in vitro testing identified a group of active agents that stimulated high MW HA production. This novel approach to HA topical application with exclusively high MW HA production should maximize hydration capacity while encouraging regenerative activity within the ECM. Multi-center trials are underway.
Topics: Fibroblasts; Humans; Hyaluronic Acid; Hyaluronoglucosaminidase; Molecular Weight; Technology
PubMed: 35486441
DOI: 10.1111/jocd.15027 -
Nature Communications Dec 2022Booster doses for the ongoing COVID-19 pandemic are under consideration in many countries. We report a three-month follow-up of 700 participants in a fourth vaccine dose...
Booster doses for the ongoing COVID-19 pandemic are under consideration in many countries. We report a three-month follow-up of 700 participants in a fourth vaccine dose study, comparing BNT162b2 and mRNA1273, administered four months after a third BNT162b2 dose. The primary outcomes are the levels of IgG, neutralizing antibodies, and microneutralization and the secondary outcomes are the levels of IgA and T cell activation, and clinical outcomes of SARS-CoV-2 infection and substantial symptomatic disease. Waning of the immune response is evident during follow-up, with an 11% (β = 0.89, 95% CI, 0.88-0.9) and 21% (β = 0.79, 95% CI, 0.76-0.82) multiplicative decay per week of IgG and neutralizing antibodies, respectively, in the mRNA1273 group, and of 14% (β = 0.86, 95% CI, 0.86-0.87) and 26% (β = 0.74, 95% CI, 0.72-0.76), respectively, in the BNT162b2 group. Direct neutralization of Omicron variants is low relative to ancestral strains. Cumulatively over the study period, both vaccines show little efficacy against infection but were highly efficacious against substantial symptomatic disease [89% [(IRR 0.11, 95% CI, 0.02-0.37) and 71% (IRR 0.29, 95% CI, 0.13-0.57) for mRNA1273 and BNT162b2, respectively]. These results are informative for further boosting policy-making. Trial registration numbers (clinicaltrials.gov): NCT05231005 and NCT05230953.
Topics: Humans; COVID-19 Vaccines; BNT162 Vaccine; Follow-Up Studies; Pandemics; COVID-19; SARS-CoV-2; Antibodies, Neutralizing; Immunoglobulin G; Antibodies, Viral
PubMed: 36513665
DOI: 10.1038/s41467-022-35480-2 -
Journal of Dental Anesthesia and Pain... Apr 2023Extrusion of debris is a major factor that results in postoperative pain during root canal treatment with various instruments and instrumentation techniques. Therefore,...
Incidence of postoperative pain after using single continuous, single reciprocating, and full sequence continuous rotary file system: a prospective randomized clinical trial.
BACKGROUND
Extrusion of debris is a major factor that results in postoperative pain during root canal treatment with various instruments and instrumentation techniques. Therefore, instrumentation techniques that extrude minimal debris into the periapical area while reducing pain are desirable. This study aimed to compare the incidence of postoperative pain and intake of analgesic medication (frequency and quantity) after endodontic treatment of mandibular posterior teeth using two single files and full-sequence continuous rotary systems with different kinematic motions.
METHODS
Thirty-five of 105 patients were assigned equally to three groups according to the instrumentation system used: ProTaper Next (PN) X2, 25/06 (Dentsply, Maillefer, Ballaigues, Switzerland), One Shape (OS), #0.25/06 (Micro Mega, Besancon, France), and Wave One Gold (WG), Red - #0.25, 0.07 (Dentsply, Maillefer, Ballaigues, Switzerland). Five specialists were included in this study design; each professional prepared 21 teeth, and randomly selected 7 per instrument system. The VAS sheet ranging from 0 to 10 was used to record the initial and postoperative pains at 24, 48, and 72 h, and 7 day after single visit endodontic treatment in mandibular premolars and molars with a diagnosis of asymptomatic irreversible pulpitis with or without apical periodontitis. Postoperatively, an analgesic, ibuprofen 400 mg was administered for intolerable pain at a dose of 1 tablet for 6 h. The patients were asked over the telephone regarding postoperative pain at intervals of 24, 48, and 72 h, and 7 day using a visual analogue scale.
RESULT
There were no statistically significant differences among the PN, OS, and WG systems (P > 0.05) with regard to the incidence of postoperative pain at any of the four time points assessed.
CONCLUSION
The intensity of postoperative pain, frequency, and analgesic intake were similar across all three types of instrument systems; however, the reciprocating single file (WG) was associated with less postoperative pain than the full sequence continuous rotary file.
PubMed: 37034837
DOI: 10.17245/jdapm.2023.23.2.91 -
Advances in Therapy Jun 2022Unmet expectations are a major cause of perceived treatment failure and discontinuation of treatment. To enable evidence-based counselling of patients on realistic...
INTRODUCTION
Unmet expectations are a major cause of perceived treatment failure and discontinuation of treatment. To enable evidence-based counselling of patients on realistic expectations, we determined the chance of patients with overactive bladder becoming free of a given symptom upon treatment with a muscarinic antagonist in a non-interventional setting.
METHODS
Two non-interventional studies included 1335 and 745 patients, respectively, who received 30 or 45 mg q.d. propiverine ER for 12 weeks. They were monitored for becoming free of urgency, urinary incontinence, frequency, or nocturia. Analyses were also performed in subgroups defined by basal symptom severity, age, and gender. Categorical data are shown as a percentage of the respective population. Continuous data are expressed as means or as median depending on whether the variability was considered to exhibit a normal distribution.
RESULTS
The probability of becoming symptom-free was largest for incontinence and frequency (about 50%), but lesser for urgency (about 20%) and nocturia (about 10%). Greater basal severity of a symptom reduced the chance to become free of that symptom upon treatment, but the chance to become free of incontinence and frequency was still considerable. Age and gender had only minor if any effects on the chance of becoming symptom-free. These findings are in line with those of a limited number of randomized controlled trials.
CONCLUSION
These data provide an evidence base for the counselling of patients with overactive bladder on realistic expectations of treatment outcomes. We propose that realistic expectations can lead to greater long-term adherence.
Topics: Benzilates; Humans; Motivation; Nocturia; Treatment Outcome; Urinary Bladder, Overactive; Urinary Incontinence
PubMed: 35325367
DOI: 10.1007/s12325-022-02114-4