Exploring the possible link between the spike protein immunoglobulin G4 antibodies and cancer progression

Repeated inoculation with messenger RNA (mRNA) vaccines elicits immunoglobulin G4 (IgG4) antibody production. Such an increase in the concentration of specific and non-specific IgG4 antibodies allows the growth of some types of cancer by blocking the activation of effector immune cells. This work proposes the hypothesis that cancer growth may be indirectly promoted by increased concentrations of non-specific IgG4 antibodies by the following mechanisms: 1) IgG4 antibodies can bind to anti-tumor IgG1 antibodies and block their interaction with receptors located on effector cells, thus preventing the destruction of cancer cells, 2) IgG4 can interact with fragment crystallizable gamma receptor IIb (FcγRIIB) inhibitory receptors, thus reducing effector functions of innate immune cells, and 3) targeting of specific epitopes by IgG4 could be oncogenic by inducing the production of a microenvironment that can promote cancer development. This article reviews the supporting literature and suggests several experimental protocols to evaluate this hypothesis in the context of repeated inoculation with mRNA vaccines. Additionally, this work proposes some management options aimed at reducing the unfavorable molecular consequences that could mediate cancer development when encountering high concentrations of IgG4 antibodies

Bioequivalence study of 2.5 mg film-coated bisoprolol tablets in healthy volunteers

Wstęp: Bisoprolol jest jednym z najczęściej stosowanych beta-adrenolityków cechujących się kardioselektywnością i pozbawionym wewnętrznej aktywności sympatykomimetycznej. Jest powszechnie stosowany w leczeniu choroby niedokrwiennej serca czy niewydolności serca. Cel: Celem pracy była ocena równoważności biologicznej tabletek powlekanych zawierających bisoprolol w dawce 2,5 mg (Bisocard® — lek badany) w odniesieniu do oryginalnego produktu leczniczego (Concor Cor 2.5® — lek referencyjny). Metody: Przeprowadzono badanie otwarte z randomizacją w schemacie krzyżowym, po pojedynczym podaniu na czczo zdrowym ochotnikom rasy białej bisolprololu w dawce 10 mg (4 tabletki po 2,5 mg). Próbki krwi pobierano do 60. godziny po podaniu leku. Stężenie bisoprololu w osoczu oznaczono zwalidowaną metodą LC-MS/MS. Produkty lecznicze uznano za równoważne biologicznie, gdy 90-procentowe przedziały ufności (CI) stosunków średnich geometrycznych (produkt badany/referencyjny) dla zlogarytmowanych AUC(0–t), AUC(0–∞) i Cmax mieściły się w granicach 80–125%. Działania niepożądane monitorowano na podstawie parametrów klinicznych i zgłoszeń ochotników. Wyniki: Dwudziestu sześciu zdrowych ochotników obu płci (średnia wieku ok. 29 lat, wskaźnik masy ciała 22,7 kg/m2) zostało włączonych do badania, a 24 z nich ukończyło część kliniczną badania. Otrzymano następujące stosunki średnich geometrycznych (produkt badany/referencyjny): AUC(0–t) 95,16% (90% CI 92,52–97,87%), AUC(0–∞) 95,08% (90% CI 92,40–97,83%) oraz Cmax 100,00% (90% CI 94,83–105,45%). Nie zaobserwowano istotnych statystycznie różnic w ocenianych parametrach farmakokinetycznych między produktami badanym i referencyjnym. Nie stwierdzono poważnych zdarzeń niepożądanych w badanej populacji. Wnioski: W badanej populacji stwierdzono równoważność biologiczną leku generycznego (Bisocard®) z produktem referencyjnym (Concor Cor 2.5®). Oba produkty cechują się porównywalną, dobrą tolerancją i bezpieczeństwem.Background: Bisoprolol is one of the most widely used beta-blockers characterised by cardioselectivity, and it has no intrinsic sympathomimetic activity. It is commonly used in the treatment of coronary heart disease and heart failure.   Aim: The aim of study was to assess the bioequivalence of the film-coated tablets containing 2.5 mg of bisoprolol (Bisocard® — the medicinal product) to the original medicinal product (Concor Cor 2.5® — the reference).   Methods: A randomised, open-label, two-period, crossover, single-dose, relative bioavailability study was conducted in fasted healthy Caucasian volunteers. A single 10-mg oral dose (four tablets of 2.5 mg) of the test or reference product was followed by a 14-day wash-out period, after which the subjects received the alternative product. Blood was sampled within a period of 60 h post administration in pre-specified time points. Bisoprolol concentrations were determined by a validated LC-MS/MS method. The products were considered bioequivalent if the 90% confidence interval (CI) of the log-transformed geometric mean ratios (test vs. reference) for AUC(0–t), AUC(0–∞), and Cmax were within 80–125% limits. Adverse events were monitored during the study based on the subject claims and clinical parameters.   Results: Twenty-six healthy male and female volunteers (mean age ca. 29 years; body mass index 22.7 kg/m2) were in­cluded in the study, and 24 completed the clinical part. The geometric mean ratios (test/reference) for the log-transformed AUC(0–t), AUC(0–∞), and Cmax were 95.16% (90% CI 92.52–97.87%), 95.08% (90% CI 92.40–97.83%), and 100.00% (90% CI 94.83–105.45%), respectively. There were no significant differences in the pharmacokinetic parameters between the test and reference formulations. No serious adverse events were reported.   Conclusions: The results of this single-dose study in healthy Caucasian volunteers indicate that Bisocard®; 2.5 mg film-coated tablets are bioequivalent to the reference product — Concor Cor 2.5®; 2.5 mg film-coated tablets. Both products had similar safety profile and have been well tolerated.  

Genome-wide pleiotropy and shared biological pathways for resistance to bovine pathogens

<div><p>Host genetic architecture is a major factor in resistance to pathogens and parasites. The collection and analysis of sufficient data on both disease resistance and host genetics has, however, been a major obstacle to dissection the genetics of resistance to single or multiple pathogens. A severe challenge in the estimation of heritabilities and genetic correlations from pedigree-based studies has been the confounding effects of the common environment shared among relatives which are difficult to model in pedigree analyses, especially for health traits with low incidence rates. To circumvent this problem we used genome-wide single-nucleotide polymorphism data and implemented the Genomic-Restricted Maximum Likelihood (G-REML) method to estimate the heritabilities and genetic correlations for resistance to 23 different infectious pathogens in calves and cows in populations undergoing natural pathogen challenge. Furthermore, we conducted gene-based analysis and generalized gene-set analysis to understand the biological background of resistance to infectious diseases. The results showed relatively higher heritabilities of resistance in calves than in cows and significant pleiotropy (both positive and negative) among some calf and cow resistance traits. We also found significant pleiotropy between resistance and performance in both calves and cows. Finally, we confirmed the role of the B-lymphocyte pathway as one of the most important biological pathways associated with resistance to all pathogens. These results both illustrate the potential power of these approaches to illuminate the genetics of pathogen resistance in cattle and provide foundational information for future genomic selection aimed at improving the overall production fitness of cattle.</p></div

Can We Breed Cattle for Lower bovine TB Infectivity?

Publication history: Accepted - 22 November 2018; Published - 7 December 2018.Host resistance and infectivity are genetic traits affecting infectious disease transmission. This Perspective discusses the potential exploitation of genetic variation in cattle infectivity, in addition to resistance, to reduce the risk, and prevalence of bovine tuberculosis (bTB). In bTB, variability in M. bovis shedding has been previously reported in cattle and wildlife hosts (badgers and wild boars), but the observed differences were attributed to dose and route of infection, rather than host genetics. This article addresses the extent to which cattle infectivity may play a role in bTB transmission, and discusses the feasibility, and potential benefits from incorporating infectivity into breeding programmes. The underlying hypothesis is that bTB infectivity, like resistance, is partly controlled by genetics. Identifying and reducing the number of cattle with high genetic infectivity, could reduce further a major risk factor for herds exposed to bTB. We outline evidence in support of this hypothesis and describe methodologies for detecting and estimating genetic parameters for infectivity. Using genetic-epidemiological predictionmodels we discuss the potential benefits of selection for reduced infectivity and increased resistance in terms of practical field measures of epidemic risk and severity. Simulations predict that adding infectivity to the breeding programme could enhance and accelerate the reduction in breakdown risk compared to selection on resistance alone. Therefore, given the recent launch of genetic evaluations for bTB resistance and the UK government’s goal to eradicate bTB, it is timely to consider the potential of integrating infectivity into breeding schemes.This work was carried out with funding from the Biotechnology and Biological Sciences Research Council Institute Strategic Programme grants BB/J004235/1 (ISP1) and BB/P013740/1 (ISP2) (OA, AD-W, GB and JW), and the European Union FP7 project FISHBOOST (KBBE - 7-613611) (ST). GB was also supported by the Rural and Environment Science and Analytical Services Division of the Scottish Government

Use of genomic tools to improve cattle health in the context of infectious diseases

Although infectious diseases impose a heavy economic burden on the cattle industry, the etiology of many disorders that affect livestock is not fully elucidated, and effective countermeasures are often lacking. The main tools available until now have been vaccines, antibiotics and antiparasitic drugs. Although these have been very successful in some cases, the appearance of parasite and microbial resistance to these treatments is a cause of concern. This review describes the rapid gains achieved to track disease progression, identify the pathogens involved, and map pathogen interactions with the host. Next-generation sequencing provides important opportunities to tackle problems associated with pathogenic illnesses. Use of novel genomic tools subsequently aids in treatment development, as well as successful creation of breeding programs aimed towards less susceptible livestock. These may be important tools for mitigating the long term effects of combating infection and helping reduce the reliance on antibiotic treatment

A glimpse of the future in animal nutrition science. 1. Past and future challenges

If the world population continues to increase exponentially, wealth and education inequalities might become more pronounced in the developing world. Thus, offering affordable, high-quality protein food to people will become more important and daunting than ever. Past and future challenges will increasingly demand quicker and more innovative and efficient solutions. Animal scientists around the globe currently face many challenging issues: from ensuring food security to prevent excess of nutrient intake by humans, from animal welfare to working with genetic-engineered animals, from carbon footprint to water footprint, and from improved animal nutrition to altering the rumen microbiome. Many of these issues are most likely to continue (or to exacerbate further) in the coming years, but animal scientists have many options to surmount the obstacles posed to the livestock industry through tools that are presently available. The frequency, interval, and intensity of livestock impacts, however, differ across regions, production systems, and among livestock species. These differences are such that the generalization of these issues is impossible and dangerous. For instance, when we discuss domesticated ruminant nutrition in the human food context, we look for the most efficient ruminant feeds that complement, rather than compete with, grains grown for direct human nutrition. Greater scrutiny and standardization are needed when developing and validating methodologies to assess short- and long-term impacts of livestock production. Failure in correctly quantifying these impacts may lead to disregard and disbelief by the livestock industry, increased public confusion, and the development of illusionary solutions that may amplify the impacts, thereby invalidating its original intent