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RPL32: From housekeeping gene to potential biomarker and therapeutic target in cancer and multiple system diseases.

Ribosomal protein L32 (RPL32) is a core component of the 60S ribosomal subunit and a stable reference gene. Mounting evidence shows that RPL32 is upregulated in hepatocellular carcinoma, lung cancer, breast cancer, prostate cancer, and other malignancies, correlating with poor prognosis. RPL32 promotes cancer cell proliferation, invasion, and progression partly through the MDM2-p53-autophagy axis, and its expression is regulated by promoter methylation, copy number variations, and transcription factors. RPL32 represents a promising prognostic biomarker and candidate intervention target for cancer. However, its clinical translation requires further validation regarding intervention efficacy, systemic toxicity, druggability, and companion diagnostics. This narrative review summarizes the structure, function, and regulatory mechanisms of RPL32, emphasizes its oncogenic roles and translational potential in cancer, and briefly describes its pathological implications in non-cancer diseases, providing a framework for future cancer research.

Humans↗

Vaccinology of classical swine fever: from lab to field.

There are two types of classical swine fever vaccines available: the classical live and the recently developed E2 subunit vaccines. The live Chinese strain vaccine is the most widely used. After a single vaccination, it confers solid immunity within a few days that appears to persist lifelong. The E2 subunit vaccine induces immunity from approximately 10-14 days after a single vaccination. The immunity may persist for more than a year, but is then not complete. The Chinese strain vaccine may establish a strong herd immunity 1-2 weeks earlier than the E2 vaccine. The ability of the Chinese vaccine strain to prevent congenital infection has not been reported, but the E2 subunit vaccine does not induce complete protection against congenital infection. Immunological mechanisms that underlie the protective immunity are still to be elucidated. Both types of vaccine are considered to be safe. A great advantage of the E2 subunit vaccine is that it allows differentiation of infected pigs from vaccinated pigs and is referred to as a DIVA vaccine. However, the companion diagnostic E(rns) ELISA to actually make that differentiation should be improved. Many approaches to develop novel vaccines have been described, but none of these is likely to result in a new DIVA vaccine reaching the market in the next 5-10 years. Countries where classical swine fever is endemic can best control the infection by systematic vaccination campaigns, accompanied by the normal diagnostic procedures and control measures. Oral vaccination of wild boar may contribute to lowering the incidence of classical swine fever, and consequently diminishing the threat of virus introduction into domestic pigs. Free countries should not vaccinate and should be highly alert to rapidly diagnose any new outbreak. Once a new introduction of classical swine fever virus in dense pig areas has been confirmed, an emergency vaccination programme should be immediately instituted, for maximum benefit. The question is whether the time is ripe to seriously consider global eradication of classical swine fever virus.

Animals↗

Diva vaccines that reduce virus transmission.

This brief review deals with the effect of diva (Differentiating Infected from VAccinated individuals) vaccines (also termed marker vaccines) on transmission of herpesviruses and pestiviruses in swine and cattle. Pseudorabies and bovine herpesvirus 1 diva vaccines have been demonstrated to reduce transmission of wild-type virus in populations of pigs and cattle in the laboratory as well as in the field. A subunit diva vaccine based on the immunodominant E2 protein of classical swine fever virus that is expressed in the baculovirus system may reduce transmission of wild-type virus among pigs and also transmission from mother to foetuses. A similar diva vaccine against bovine virus diarrhoea infections protected sheep against transplacental transmission of antigenically homologous wild-type virus. Diva vaccines along with their companion diagnostic tests can play a role in control of infections, ultimately leading to eradication of viruses.

Animals↗

Classical swine fever (CSF) marker vaccine. Trial I. Challenge studies in weaner pigs.

Two commercial marker vaccines against classical swine fever virus (CSFV) and companion diagnostic tests were examined in 160 conventional pigs. To test the vaccines in a "worst case scenario", group of 10 weaners were vaccinated using a single dose of an E2 (gp55) based vaccine at days -21, -14, -10 or -7, and subsequently challenged at day 0. The challenge virus was CSFV 277, originating from a recent outbreak of classical swine fever (CSF) in Germany. In all groups, only 5 out of 10 pigs were challenged; the remaining 5 pigs served as vaccinated contact controls. Also, three control groups, each consisting of 10 non-vaccinated pigs, were challenged in parallel to the vaccinated animals. CSFV could be isolated from all non-vaccinated pigs. Among these pigs 40% displayed a chronic course of the infection (virus positive for more than 10 days). Pigs vaccinated 21 or 14 days before challenge displayed no clinical signs of CSFV after challenge. However, they were still able to replicate CSFV when challenged, as measured by reisolation of CSFV from leukocytes of the directly challenged pigs. CSFV could be isolated from the leucocytes of 25% of the pigs vaccinated 21 days before challenge and 50% of the pigs vaccinated 14 days before challenge. Chronic infection was not observed, but transmission to one vaccinated contact pig occurred. From all pigs vaccinated 10 or 7 days before challenge, CSFV could be reisolated. We observed a chronic course of infection in 5% of pigs vaccinated 10 days before challenge and in 30% of pigs vaccinated 7 days before challenge. The mortality rate was 20% in the pigs vaccinated 10 days before challenge, and varied between 20 and 80% in pigs vaccinated 7 days prior to challenge. The contact animals had lower mortality (0-20%) than directly challenged pigs, probably mirroring the delayed time point of infection. There was thus some protection against clinical illness by both marker vaccines, but not a solid protection against infection and virus shedding. The efficacy of the vaccine was best if used 3 weeks before challenge and a clear correlation between time interval from vaccination to challenge and the level of virus shedding was observed. Each vaccine had its own accompanying discriminatory ELISA, but 18% of the virus positive pigs never seroconverted in these tests.

Animals↗

Advances in the development and evaluation of bovine herpesvirus 1 vaccines.

This review deals with conventional and modern bovine herpesvirus 1 (BHV1) vaccines. Conventional vaccines are widely used to prevent clinical signs of infectious bovine rhinotracheitis. The use of conventional vaccines, however, does not appear to have resulted in reduction of the prevalence of infection. Novel BHV1 marker vaccines comprise either mutants with a deletion in one of the non-essential genes, or subunit vaccines that contain one or more glycoproteins. These marker vaccines can be used in conjunction with companion diagnostic tests to differentiate between infected and vaccinated cattle. Their efficacy has been evaluated in vaccination-challenge experiments, transmission experiments and in field trials. The results demonstrate that the marker vaccines can contribute to the eventual eradication of BHV1. However, there remains room for improvement of BHV1 marker vaccines.

Animals↗

Bovine herpesvirus-1 vaccines.

Vaccination has been important in controlling a wide variety of viral and bacterial infections of man and animals. Vaccines to herpesvirus infection of cattle are no exception. The present review describes the different types of conventional vaccines that have been used to date and furthermore describes the novel approaches which are presently being implemented to develop more effective vaccines. These include subunit vaccines as well as genetically engineered modified live deletion mutants. Both these novel vaccine approaches appear to be more efficacious than conventional vaccines. Furthermore, these vaccines provide an additional dimension for control and eradication of infection by providing an opportunity to develop companion diagnostic tests to differentiate infected animals from vaccinated animals. This review summarizes these developments as well as present knowledge regarding the important host defence mechanisms required for preventing infection and aiding recovery from infection.

Animals↗

Pseudorabies virus eradication by area-wide vaccination is feasible.

This article reviews the rationale for using marker vaccines and companion diagnostic tests in the eradication of pseudorabies virus (PRV). Recent advances in vaccinology and epidemiology indicate that, despite the inability to induce complete immunity, vaccination is a useful tool in the battle against PRV. This review focuses on the effectiveness of vaccination under field conditions and on herd, management and regional factors that are associated with PRV introduction or transmission.

Animals↗

Present and future of veterinary viral vaccinology: a review.

This review deals briefly with some key developments in veterinary vaccinology, lists the types of vaccines that are used for vaccinations commonly performed in food animals as well as in companion animals, and indicates that the practising veterinarian can select the best vaccine by comparing the results of efficacy studies. Diva (Differentiating Infected from Vaccinated Animals; also termed marker) vaccines and companion diagnostic tests have been developed that can be used for progammes aimed to control or eradicate virus infections. Vaccine-induced herd immunity, which can be measured relatively easily when diva vaccines are used, is a crucial issue in such programmes. Current vaccine research follows many routes towards novel vaccines, which can be divided into non-replicating ('killed') and replicating ('live') vaccines. Promising trends are the development of DNA vaccination, vector vaccines, and attenuation of DNA and RNA viruses by DNA technology. The lack of (in vitro) correlates of vaccine protection markedly hampers progress in vaccine research. Various characteristics of an 'ideal' vaccine are listed, such as multivalency and the induction of lifelong immunity after one non-invasive administration in animals with maternal immunity. Future research should be aimed at developing vaccines that approach the ideal as closely as possible and which are directed against diseases not yet controlled by vaccination and against newly emerging diseases.

Animal Diseases↗

Predictive Biomarkers for Immune Checkpoint Inhibitor Efficacy: Challenges, Innovations, and a Pathway to Precision Medicine in the Era of Cancer Immunotherapy.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed oncology practice. However, treatment response remains heterogeneous, rendering predictive biomarkers critical for optimal patient care. The 3 established biomarkers, programmed death-ligand 1, tumor mutational burden (TMB), and microsatellite instability-high/deficient mismatch repair, are approved and clinically validated but are modest predictors of benefit. As a result, multiple novel predictive biomarkers remain under investigation. CONTENT: This review highlights established and investigational predictive ICI efficacy biomarkers. For established biomarkers, we describe biology, assay modalities, approved companion diagnostics, landmark studies, and notable limitations. Due to the multisystem nature of antitumor immune effects, investigational biomarkers span multiple domains, including tumor genomic biomarkers (e.g., mutational signatures, TMB, neoantigen clonality), tumor microenvironment (e.g., tumor-infiltrating lymphocytes [TILs], tertiary lymphoid structures), systemic immune biomarkers (e.g., cytokines, autoantibodies, glycoproteins, peripheral blood mononuclear cells), and the microbiome (e.g., gastrointestinal microbial diversity, responder-enriched taxa). SUMMARY: The established biomarkers PD-L1, TMB, and microsatellite instability-high/deficient mismatch repair inform ICI use in clinical practice but have important limitations. Multiple investigational biomarkers show promise in refining patient selection and optimizing therapy. Moving forward, increased assay harmonization, prospective validation, and standardized parameters may improve performance. Composite models integrating complementary signals across domains may further individualize treatment and lead to an era of personalized cancer immunotherapy.

Humans↗

Survey on the current status of novel cancer drug therapies for gynecological cancers in Japan: a nationwide survey by the Japan Society of Obstetrics and Gynecology (JSOG).

OBJECTIVE: To characterize real-world implementation of novel therapies in gynecological oncology in Japan and identify actionable gaps through a nationwide survey. METHODS: A cross-sectional questionnaire was distributed to Japan Society of Obstetrics and Gynecology-affiliated institutions. The items covered institution characteristics; use of poly (ADP-ribose) polymerase (PARP) inhibitors, immune checkpoint inhibitors (ICIs), kinase inhibitors, and antibody-based agents; local adverse event (AE) manuals; availability of expert panels and immune-related adverse event (irAE) teams; and perceptions of educational sufficiency. RESULTS: Valid responses were obtained from 245 institutions, spanning universities, cancer centers, and general hospitals. Most institutions reported the routine use of PARP inhibitors, ICIs, kinase inhibitors, and antibody drugs. However, only 40.4% of institutions had an in-hospital irAE management team, 57.1% had an AE/irAE manual, and 31.0% and 12.2% considered prior educational opportunities sufficient for physicians and nurses/other medical staff, respectively. High-volume institutions and academic centers were significantly more likely to have medical oncology support, expert-panel access, irAE teams, manuals, and higher self-rated evidence-based management capacity. The majority favored e-learning and society-led case conferences, and 76.3% supported the development of drug therapy subspecialties in gynecologic oncology. CONCLUSION: Innovative drug modalities are widely implemented across Japanese gynecological oncology services. However, critical gaps persist in multidisciplinary irAE management, standardized manuals, and practical education. Coordinated society-led programs to expand irAE teams, streamline companion diagnostics, disseminate ready-to-use algorithms, and provide credential-targeted training may enhance safety, equity, and evidence-concordant care nationwide.

Immune Checkpoint Inhibitors↗

[Biotechnology for the benefit of vaccination against viral diseases: a review].

This review deals briefly with some key developments in veterinary viral vaccinology, lists the types of vaccines that are used for vaccinations commonly performed in food animals as well as in companion animals, and indicates that the practising veterinarian can select the best vaccine by comparing the results of efficacy studies. Diva (Differentiating Infected from Vaccinated Animals; also termed marker) vaccines and companion diagnostic tests have been developed that can be used for progam aimed to control or eradicate virus infections. Vaccine-induced herd immunity, which can be measured relatively easily when diva vaccines are used, is a crucial issue in such programmes. Current vaccine research follows many routes towards novel vaccines, which can he divided into non-replicating ('killed') and replicating ('live') vaccines. Promising trends are the development of DNA vaccination, vector vaccines, and attenuation of DNA and RNA viruses by DNA technology. The lack of (in vitro) correlates of vaccine protection markedly hampers progress in vaccine research. Various characteristics of an 'ideal' vaccine are listed, such as multivalency and the induction of lifelong immunity after one non-invasive administration in animals with maternal immunity. Future research should he aimed at developing vaccines that approach the ideal as closely as possible and which are directed against diseases not yet controlled by vaccination and against newly emerging diseases.

Animals↗

Regulatory considerations for emergency use of vaccines in the European Union.

From a regulatory perspective foot-and-mouth disease (FMD) vaccines represent a special case due to the number and antigenic diversity of strains that might be used alone or in combination within the context of an authorisation. New guidelines have been developed proposing that an FMD vaccine should be defined as a formulation of ingredients including defined amounts of one or more antigens that vary only in the number and types of antigen present. These new guidelines are in line with those previously proposed for equine influenza vaccines. Slaughter policies being less and less popular in the European Union, there is a tendency to use so-called marker vaccines associated with a companion diagnostic test. Such methodology has already been used for vaccination against pseudo-rabies and infectious bovine rhinotracheitis. Sub-unit marker vaccines against classical swine fever have also been developed; such vaccines are also envisaged against foot-and-mouth disease; it would permit, if satisfying defined criteria, to distinguish vaccinated from infected animals.

Animal Diseases↗

Emergency vaccination against classical swine fever.

At present, emergency vaccination against classical swine fever is not practised in Western countries. However, stamping out and pre-emptive culling policies are increasingly meeting greater resistance. Consequently, emergency vaccination is a re-emerging subject of debate. There are highly efficacious classical live vaccines that induce early immunity, but their use precludes the serological discrimination of infected and vaccinated pigs. Therefore, E2 subunit DIVA vaccines have been developed that allow this discrimination. However, their efficacy is lower than that of the live vaccines and the companion diagnostic differential test, the E(rns) ELISA, has its limitations. Modern biotechnological methods enabled researchers to develop a variety of candidate vaccines that have been shown to induce immunity in pigs. However, it is not expected that one of them will enter the marketplace in less than five to 10 years. The current vaccines should therefore be used, if emergency vaccination programmes to eradicate classical swine fever are to be implemented in the near future. Two possible scenarios for emergency vaccinations are discussed.

Animals↗

Veterinary vaccines for animal and public health.

Vaccination is without doubt the most useful single measure available to prevent animal infectious diseases. The advantages of vaccination are numerous. It is the only available method to prevent, or sometimes cure, viral animal infections in the absence of broad spectrum antivirals and avoids the alternative of mass slaughtering of livestock. Antibiotic or anthelmintic resistance, and the problem of pharmaceutical residues, promote the use of vaccines rather than chemotherapy. Vaccines are environmentally friendly and increase animal welfare by preventing suffering from disease resulting from treatment for a cure which may result in antibiotic resistance and pharmaceutical residues in food. For the management of livestock health vaccines are the best tool to achieve sustainability. Veterinary vaccines cannot only be used to protect animal health but also human health from zoonotic infections through animal vaccination as exemplified by wildlife vaccination against rabies. In animal health the focus is now on animal infections rather than on animal diseases. Vaccines should be designed to prevent infection rather than to prevent clinical signs of disease and should, wherever possible, produce sterile immunity. Available technologies allow us to design "marker" vaccines together with their companion diagnostic tests which permit the distinction between vaccinated and infected animals even if the latter were previously vaccinated. Examples will be given of foot-and-mouth disease, classical swine fever, and herpesvirus infections of livestock such as pseudorabies or infectious bovine rhinotracheitis where carrier state or latency remain an issue after vaccination.

Animal Diseases↗

DIVA--a vaccination strategy enabling the detection of field exposure to avian influenza.

The present paper reports on the development, validation and field application of a control strategy for avian influenza infections in poultry. The "DIVA" (Differentiating Infected from Vaccinated Animals) strategy is based on the use of an inactivated oil emulsion vaccine containing the same haemagglutinin (H) subtype as the challenge virus, but a different neuraminidase (N). The possibility of using the heterologous N subtype, to differentiate between vaccinated and naturally infected birds, was investigated through the development of an "ad hoc" serological test based on the detection of specific anti-N antibodies. This test is based on an indirect fluorescent antibody assay, using as an antigen a baculovirus expressing recombinant N proteins. The vaccination strategy has been tested in the laboratory and shown to be efficacious both against challenge with highly pathogenic AI viruses and with low pathogenicity AI viruses, ensuring clinical protection, reduction of duration and titre of shedding. In addition, vaccination resulted in an increased resistance to infection. The companion diagnostic tests directed to the detection of anti-N1 and anti-N3 antibodies have been validated in the laboratory and using field samples. The serological assay showed an "almost perfect agreement" (Kappa value) with the HI test, with relative sensitivity and specificity values of 98.1 and 95.7, respectively. The results of the present investigation suggest that the "DIVA" control strategy may represent a tool to support the eradication of avian influenza infections in poultry.

Animals↗

The place of marker vaccines in control and eradication of animal diseases--aspects of comparative interest.

Smallpox is the first viral infection to have been eradicated world-wide. This remarkable success is due to several factors including the availability of an efficacious vaccine and the absence of a wildlife reservoir. The only animal virus disease sharing these characteristics is rinderpest, for which there are several efficacious vaccines. Other animal viral infections do not share the same characteristics, either due to the lack of an efficacious vaccine (African swine fever), or to the existence of wildlife reservoirs such as the wild boar for classical swine fever, the African buffalo for foot-and-mouth disease, bats for lyssavirus infections, etc. These diseases are more prone to regional elimination than a complete worldwide eradication. Two methods are used to eliminate an animal viral infection, either vaccination or the strict application of hygienic measures including stamping out and incineration, or the combination of both methods. Public opinion is more and more concerned about stamping out, even when necessary such as when dealing with emerging zoonoses. On the other hand, generalised vaccination (i.e. against foot-and-mouth disease, classical swine fever, etc.) may be discontinued despite its efficacy, for macro-economical reasons. The solution may come from the use of marker vaccines associated with companion diagnostic tests to make a distinction between infected and immunised animals by serological examination. Current control and eradication programmes against these and other diseases, the role of marker vaccines, and the limitations of such programmes are being discussed.

Animal Diseases↗

[Aujeszky's disease in swine in The Netherlands, A.D. 1991].

Aujeszky's disease is caused by a herpesvirus. The pig is the natural host and sole source of dissemination of the virus. After a primary infection, during which the pig excretes virus for 10-14 days, the virus remains latent in the host. Eradication has been achieved in individual herds, areas and countries with a low prevalence. The crucial question is whether it is feasible to eradicate the virus in heavily infected areas. Using so-called marker vaccines in conjunction with companion diagnostic test kits the virus was eliminated in individual herds. The preliminary results of extensive field studies to investigate whether intensive vaccination curtails the circulation of virus are encouraging.

Animals↗

Diagnostic imaging in companion animal theriogenology.

Clinical assessment of reproductive problems in companion animals is greatly enhanced by the availability of various imaging modalities. Specifically, survey radiography, contrast radiography, real-time ultrasonography, and ultrasound-guided biopsy and/or aspiration cytology, alone or in various combinations, offer sophisticated methods of extension of the physical examination of the reproductive systems of dogs and cats. In particular, real-time ultrasonography offers invaluable assistance. It is nonionizing, largely noninvasive, rapid, and capable of providing certain dynamic information that is not conveniently available in any other way. Judging from its rapid growth in recent years, it has apparently become an integral part of the complete reproductive assessment of domestic animals. This is not to slight the importance of some of the contrast radiographic procedures that have been developed and refined. Some of them, such as maximum distention retrograde urothrocystography, provide unique information not available with presently routinely used ultrasound techniques. Other imaging modalities, such as magnetic resonance imaging, have heretofore provided limited benefit to theriogenology; that will probably change in years to come.

Animals↗