Search Results (179)

The protein p53, often referred to as the “guardian of the genome,” is essential for preserving cellular balance and preventing cancerous transformations. As one of the most commonly altered genes in human cancers, its impaired function is associated with tumor initiation, development, and resistance to treatment. Exploring the diverse roles of p53, which include regulating the cell cycle, repairing DNA, inducing apoptosis, reprogramming metabolism, and modulating immunity, provides valuable insights into cancer mechanisms and potential treatments. This review integrates recent findings on p53′s dual nature, functioning as both a tumor suppressor and an oncogenic promoter, depending on the context. Wild-type p53 suppresses tumors by inducing cell cycle arrest or apoptosis in response to genotoxic stress, while mutated variants often lose these functions or gain novel pro-oncogenic activities. Emerging evidence highlights p53′s involvement in non-canonical pathways, such as regulating tumor microenvironment interactions, metabolic flexibility, and immune evasion mechanisms. For instance, p53 modulates immune checkpoint expression and influences the efficacy of immunotherapies, including PD-1/PD-L1 blockade. Furthermore, advancements in precision diagnostics, such as liquid biopsy-based detection of p53 mutations and AI-driven bioinformatics tools, enable early cancer identification and stratification of patients likely to benefit from targeted therapies. Therapeutic strategies targeting p53 pathways are rapidly evolving. Small molecules restoring wild-type p53 activity or disrupting mutant p53 interactions, such as APR-246 and MDM2 inhibitors, show promise in clinical trials. Combination approaches integrating gene editing with synthetic lethal strategies aim to exploit p53-dependent vulnerabilities. Additionally, leveraging p53′s immunomodulatory effects through vaccine development or adjuvants may enhance immunotherapy responses. In conclusion, deciphering p53′s complex biology underscores its unparalleled potential as a biomarker and therapeutic target. Integrating multi-omics analyses, functional genomic screens, and real-world clinical data will accelerate the translation of p53-focused research into precision oncology breakthroughs, ultimately improving patient outcomes. Full article

Background: The Human Papillomavirus (HPV) vaccine generates high antibody titers against targeted HPV types. This study investigated vaccine-induced anti-HPV18 immunoglobulin (IgG) antibody titers and subsequent HPV18/45 infections. Methods: We performed a nested matched case-control study leveraging a prospective longitudinal cohort of adolescent and young adult women (AYW) vaccinated with the quadrivalent HPV vaccine (4vHPV) attending the Mount Sinai Adolescent Health Center (MSAHC) in Manhattan, NY. The case individuals included AYW who had an incident detection of cervical HPV18 (n = 3) or HPV45 (n = 34) DNA after vaccination and were compared to two vaccinated control individuals (HPV18/45-negative); one random control (RC, n = 37) and one high-risk control (HRC, n = 37) selected from the upper quartile of a sexual risk behavior score. Serological titers against HPV18 were measured by end-point dilution and enzyme-linked immunosorbent assay (ELISA) in serum collected before the incident detection of HPV. Matching was performed based on age at first dose, follow-up time, and sexual risk behavior score. Conditional logistic regression was used to assess the association between case-control status and anti-HPV antibody titers, consistent with the matched-pair design. Results: Antibody titers for HPV18 were most different between AYW who developed an HPV18/45 infection compared to high-risk controls OR = 1.66, 95% CI: 0.96–2.85 (p = 0.1629). Analyses of pooled data from vaccinated recipients including who developed HPV16/31 or HPV18/45 infections demonstrated that the odds of a one-log unit increase in anti-HPV16 or 18 antibody titers, respectively, were 40% higher in the combined control groups (RC + HRC, n = 160) (OR = 1.40, 95% CI: 1.09–1.79, p = 0.0135) and 73% higher in the HRC (n = 80) (OR 1.73, 95% CI: 1.34, 2.52, p = 0.0117) compared to HPV16/18/31/45 cases (n = 80). Conclusions: Overall, these findings suggest that higher IgG antibodies to HPV16/18 after vaccination represent an increased likelihood of protection from homologous and cross-reactive HPV types (HPV16/18/31/45). These results show that differences in antibody titers are associated with breakthrough infection after vaccination, suggesting that further study of long-term antibody titers and infection should be pursued. Full article

Helicobacter pylori is a Gram-negative bacterium that infects almost half of the global population and is linked to gastric conditions like peptic ulcers and gastric cancer, as well as other diseases such as neurological disorders, cardiovascular problems, and iron deficiency anemia. Its survival in the acidic stomach environment is due to virulence factors like urease, flagella, and adhesion proteins (BabA, SabA). Current treatments involve a combination of antibiotics (clarithromycin, metronidazole, amoxicillin, tetracycline) and proton pump inhibitors, but increasing antibiotic resistance, especially to clarithromycin and metronidazole, poses a major challenge. Resistance mechanisms include mutations in drug targets, efflux pump overexpression, and enzymatic degradation of antibiotics. This has prompted exploration of alternative therapies targeting bacterial processes like urease activity, biofilm formation, and metabolic pathways (energy production, amino acid synthesis, iron acquisition). Natural compounds, such as chitosan and plant extracts, show promise in combating H. pylori growth and virulence. Vaccine development is also ongoing, with DNA vaccines showing potential for broad immune responses. However, no vaccine is yet close to widespread clinical use. Full article

Background/Objectives: Antibiotic resistance or antimicrobial resistance (AMR) in livestock is a growing global concern that threatens both human and animal health. The overuse and misuse of antibiotics in livestock production have led to an increased propensity for the development of AMR bacterial strains in animals, which can be spread to humans through the consumption of contaminated animal products, direct contact, or environmental exposure. This review aims to summarize the development and transmission of AMR in livestock, explore its underlying mechanisms and impact on human and animal health, and discuss current practices and potential strategies for mitigation and prevention. Methods: For this narrative review, we searched articles on PubMed and Google Scholar using the terms antibiotic resistance, livestock, and environment, alone or in combination. Results: The history of antibiotic use in livestock and its link to increased AMR, along with the involved mechanisms, including the enzymatic breakdown of antibiotics, alterations in bacterial targets, horizontal gene transfer, and efflux pumps, are important. Antibiotics in livestock are used for growth promotion, disease prevention and control, and metaphylactic use. The role of livestock and the environment as reservoirs for resistant pathogens, their impact on human health, chronic infections, allergic reactions, toxicity, and the development of untreatable diseases is important to understand AMR. Conclusions: Given the widespread use of antibiotics and the potential consequences of AMR, collaborative global efforts, increased public awareness, coordinated regulations, and advancements in biological technology are required to mitigate the threat AMR poses to human and animal health. Regulatory solutions and the development of new therapeutic alternatives like antimicrobial peptides and bacteriophage therapy, and preventive measures such as DNA and mRNA vaccines, are future perspectives. Full article

The emergence of complex and rapidly evolving pathogens necessitates innovative vaccine platforms that move beyond traditional methods. This review explores the transformative potential of next-generation vaccine technologies, focusing on the combined use of synthetic biology, nanotechnology, and systems immunology. Synthetic biology provides modular tools for designing antigenic components with improved immunogenicity, as seen in mRNA, DNA, and peptide-based platforms featuring codon optimization and self-amplifying constructs. At the same time, nanotechnology enables precise antigen delivery and controlled immune activation through engineered nanoparticles such as lipid-based carriers, virus-like particles, and polymeric systems to improve stability, targeting, and dose efficiency. Systems immunology aids these advancements by analyzing immune responses through multi-omics data and computational modeling, which assists in antigen selection, immune profiling, and adjuvant optimization. This approach enhances both humoral and cellular immunity, solving challenges like antigen presentation, response durability, and vaccine personalization. Case studies on SARS-CoV-2, Epstein–Barr virus, and Mycobacterium tuberculosis highlight the practical application of these platforms. Despite promising progress, challenges include scalability, safety evaluation, and ethical concerns with data-driven vaccine designs. Ongoing interdisciplinary collaboration is crucial to fully develop these technologies for strong, adaptable, globally accessible vaccines. This review emphasizes next-generation vaccines as foundational for future immunoprophylaxis, especially against emerging infectious diseases and cancer immunotherapy. Full article

Helicobacter pylori (H. pylori) is a Gram-negative bacterium that colonizes the human stomach and is associated with several gastric diseases, including gastritis, peptic ulcer disease, and gastric cancer. The bacterium’s ability to thrive in the harsh gastric environment is due, to some extent, to its stress response mechanisms, with its heat shock proteins (HSPs) playing a putative, yet not fully understood, role in these adaptive processes. HSPs are a family of molecules, highly conserved throughout phylogenesis, that assist in protein folding, prevent aggregation, and ensure cellular homeostasis under stressful conditions. In H. pylori, HSPs contribute to survival in the stomach’s acidic environment and oxidative stress. Furthermore, they aid in the bacterium’s ability to adhere to gastric epithelial cells, modulate the host immune response, and form biofilms, all contributing to chronic infection and pathogenicity. The role of microbial HSPs in antibiotic resistance has also emerged as a critical area of research, as these proteins help stabilize efflux pumps, protect essential proteins targeted by antibiotics, and promote biofilm formation, thereby reducing the efficacy of antimicrobial treatments. Among bacterial HSPs, GroEL and DnaK are probably the major proteins that control most of the H. pylori’s functioning. Indeed, both proteins possess remarkable acid resistance, high substrate affinity, and dual roles in protein homeostasis and host interaction. These features make them critical for H. pylori’s adaptation, persistence, and pathogenicity in the gastric niche. In addition, recent findings have also highlighted the involvement of HSPs in the crosstalk between H. pylori and gastric epithelial cells mediated by the release of bacterial outer membrane vesicles and host-derived exosomes, both of these extracellular vesicles being part of the muco-microbiotic layer of the stomach and influencing cellular signalling and immune modulation. Considering their critical role in the survival and persistence of bacteria, microbial HSPs also represent potential therapeutic targets. Strategies aimed at inhibiting microbial HSP function, combined with conventional antibiotics or developing vaccines targeting microbial HSPs, could provide new avenues for the treatment of H. pylori infections and combat antibiotic resistance. This review explores the multifaceted roles of microbial HSPs in the pathogenesis of H. pylori, highlighting their contributions to bacterial adhesion, immune evasion, stress response, and antibiotic resistance. Full article

Cervical cancer ranks third in mortality and fourth in incidence among women worldwide as one of the leading causes of death from cancer in females. The main reason behind cervical carcinogenesis is long-term infection with high-risk human papillomavirus (HPV) genotypes, particularly HPV16 and HPV18. This review investigates HPV distribution across the world, along with cervical cancer molecular development mechanisms and current treatment strategies. Epidemiological data show that disease patterns vary significantly between different geographic regions because underdeveloped nations bear a higher disease burden. The molecular mechanisms of oncogenes E6 and E7 disrupt tumor suppressor pathways, while epigenetic modifications through DNA methylation and miRNA dysregulation promote malignant cell transformation. The reduction in HPV infection through prophylactic vaccination has shown promise, yet barriers related to accessibility and coverage still exist. The therapeutic technologies of gene expression inhibitors together with immunotherapies and epigenetic targeting agents show promise but require optimization to achieve specific targeting while minimizing off-target effects. A combined approach that integrates HPV vaccination with early diagnosis and molecular-specific therapies represents the most effective method to manage cervical cancer impact. The future care of patients will require increased translational research along with better immunization programs to drive prevention and therapeutic outcomes. Full article

Bovine viral diarrhea (BVD) is caused by bovine viral diarrhea virus (BVDV), a member of the genus Pestivirus and in the family Flaviviridae. According to some studies, the disease incurs USD 1.5–2.5 billion per year and USD 0.50 to USD 687.80 per cow loss in beef and dairy farms, respectively. Using vaccines is among the strategies to prevent the disease. However, complete protection requires vaccines that target both the humoral and cellular immune responses of the adaptive immune system. A comprehensive literature review was made to provide insights into the interaction of BVDV with host immunity, vaccine applications, and the limitation of the currently available vaccines, as well as explore strategies used to advance the vaccines. BVDV causes immunosuppression by interfering with the innate and adaptive immune systems in a manner that is species and biotype-dependent. Interferon production, apoptosis, neutrophil activity, and antigen-processing and presenting cells are significantly affected during the viral infection. Despite maternal antibodies (MatAbs) being crucial to protect calves from early-age infection, a higher level of MatAbs are counterproductive during the immunization of calves. There are numerous inactivated or modified BVDV vaccines, most of which are made of cytopathic BVDV 1 and 2 and the BVDV 1a subgenotypes. Furthermore, subunit, marker, DNA and mRNA vaccines are made predominantly from E2, E^rns, and NS₃ proteins of the virus in combination with modern adjuvants, although the vaccines have not yet been licensed for use and are in the experimental stage. The existing BVDV vaccines target the humoral immune system, which never gives the full picture of protection without the involvement of the cell-mediated immune system. Several limitations were associated with conventional and next-generation vaccines that reduce BVDV vaccine efficiency. In general, providing complete protection against BVDV is very complex, which requires a multi-pronged approach to study factors affecting vaccine efficacy and strategies needed to improve vaccine efficacy and safety. Full article

Background/Objectives: The surveillance of viral strain evolution is needed during prophylactic HPV vaccination programs against cervical cancer and necessitates safely archiving and storing cervical samples while maintaining the long-term stability of HPV DNA to carry out molecular diagnosis. The present proof-of-concept study aimed to assess DNA stability for HPV molecular detection from veils resuspended in a universal transport medium (UTM) and conserved at different temperatures after long-term storage. Methods: The detection and quantification of HPV DNA were evaluated in female genital secretions self-collected using veils and conserved in Cyt-All^® UTM at −30 °C, +4 °C, and +25 °C after long-term 27-month storage. Results: A slight degradation of the ubiquitous single-copy cellular DNA TOP3 gene was assessed using multiplex real-time PCR (BMRT Human Papillomavirus Genotyping Real Time PCR Kit, Bioperfectus Technologies Co., Ltd., Taizhou, Jiangsu, China) at positive temperatures (+4 °C and +25 °C) but not at a frozen temperature (−30 °C) after 27 months of storage. Nevertheless, HPV DNA preservation was sufficient at the three storage temperatures to detect and quantify HPV DNA, with a similar rate of HPV detection, a similar level of cumulative HPV viral loads, high sensitivity and specificity, and perfect concordance in HPV genotype detection after the long period of 27 months of storage. Finally, the conservation of genital samples for a prolonged period in the Cyt-All^® medium, even at room temperature, allows for the detection and quantification of any HPV and HR-HPV with high accuracy. Conclusions: The combination of veil-based self-sampling of female genital secretions and their elution and conservation in UTM may be used in the field to carry out longitudinal molecular epidemiology surveys of circulating HPV. Full article

Background: Tuberculosis (TB) is a respiratory infectious disease, and the current TB vaccine has low local lung protection. We aim to optimize immune pathways to improve the immunogenicity of vaccines. Methods: In the immunogenicity study, 50 BALB/c mice were randomly divided into the following: (1) phosphate buffered saline (PBS)+intramuscular injection combined with electroporation (EP) group (100 μL), (2) pVAX1+EP group (50 μg/100 μL), (3) ag85ab+EP group (50 μg/100 μL), (4) pVAX1+pulmonary delivery (PD) group (50 μg/50 μL), and (5) ag85ab+PD group (50 μg/50 μL). Immunization was given once every 2 weeks for a total of three times. The number of IFN-γ-secreting lung and spleen lymphocytes was determined by enzyme-linked immunospot assay (ELISPOT). The levels of Th1, Th2, and Th17 cytokines in the culture supernatants of lung and spleen lymphocytes were detected with the Luminex method. The proportion of FoxP3 regulatory T cells in splenocytes was determined by flow cytometry. The levels of IgG-, IgG1-, and IgG2a-specific antibodies in plasma and IgA antibody in bronchoalveolar lavage fluid (BALF) were determined by enzyme-linked immunosorbent assay (ELISA). Results: The PD and EP routes of Mycobacterium tuberculosis (M. tb) ag85ab DNA vaccine can effectively induce the responses of IFN-γ-secreting lung and spleen lymphocytes, and induce dominant Th1 and Th17 cell immune responses. The PD route can induce earlier, greater numbers and stronger responses of pulmonary effector T cells, with higher levels of the specific antibody IgA detected in BALF. High levels of the specific antibodies IgG, IgG1, and IgG2α were detected in the plasma of mice immunized by the EP route. Conclusions: The PD route of DNA vaccines can more effectively stimulate the body to produce strong cellular and mucosal immunity than the EP route, especially local cellular immunity in the lungs, which can provide early protection for the lungs. It can significantly improve the immunogenicity of the ag85ab DNA vaccine, suggesting a feasible and effective approach to DNA immunization. Full article

During the current outbreak of Marburg virus disease (MVD) in Rwanda, we synthesized evidence from the literature to improve case management. Accordingly, experimental treatment was offered to patients under close follow-up. Remdesivir alone or in combination with monoclonal antibody treatment (MBP091) complemented with supportive care has improved the clinical outcomes of patients. Additionally, we have identified several experimental therapies currently under investigation, including antiviral drugs such as favipiravir, galidesivir, obeldesivir, and remdesivir, along with monoclonal and polyclonal antibodies (e.g., polyclonal IgG, monoclonal antibody MR-78-N; MR82-N; MR191-N; monoclonal antibodies MR186-YTE and MBP091). Furthermore, substantial progress is being made in vaccine development, with promising candidates including adenovirus-vectored vaccines, DNA vaccines, and the recombinant vesicular stomatitis virus (rVSV) vaccine. Moreover, innovative preventive and treatment strategies—such as synthetic hormones like estradiol benzoate, small interfering RNA (siRNA), interferon-β therapy, and phosphorodiamidate morpholino oligomers—are emerging as potential options for MVD management. Further investment is needed to accelerate research and optimize these therapeutics and preventive modalities. Additional epidemiological, preclinical, and clinical studies are warranted to generate the evidence required to inform policymaking, resource mobilization, and the implementation of cost-effective interventions for the prevention, control, and treatment of MVD. Full article

Background: The majority of antigen-based SARS-CoV-2 (SCV2) vaccines utilized in the clinic have had the Spike protein or domains thereof as the immunogen. While the Spike protein is highly immunogenic, it is also subject to genetic drift over time, which has led to a series of variants of concern that continue to evolve, requiring yearly updates to the vaccine formulations. In this study, we investigate the potential of the N-terminal ectodomain of the ORF3a protein encoded by the orf3a gene of SCV2 to be an evolution-resistant vaccine antigen. This domain is highly conserved over time, and, unlike many other SCV2 conserved proteins, it is present on the exterior of the virion, making it accessible to antibodies. ORF3a is also important for eliciting robust anti-SARS-CoV-2 T-cell responses. Methods: We designed a DNA vaccine by fusing the N-terminal ectodomain of orf3a to macrophage-inflammatory protein 3α (MIP3α), which is a chemokine utilized in our laboratory that enhances vaccine immunogenicity by targeting an antigen to its receptor CCR6 present on immature dendritic cells. The DNA vaccine was tested in mouse immunogenicity studies, vaccinating by intramuscular (IM) electroporation and by intranasal (IN) with CpG adjuvant administrations. We also tested a peptide vaccine fusing amino acids 15–28 of the ectodomain to immunogenic carrier protein KLH, adjuvanted with Addavax. Results: The DNA IM route was able to induce 3a-specific splenic T-cell responses, showing proof of principle that the region can be immunogenic. The DNA IN route further showed that we could induce ORF3a-specific T-cell responses in the lung, which are critical for potential disease mitigation. The peptide vaccine elicited a robust anti-ORF3a antibody response systemically, as well as in the mucosa of the lungs and sinus cavity. Conclusions: These studies collectively show that this evolutionarily stable region can be targeted by vaccination strategies, and future work will test if these vaccines, alone or in combination, can result in reduced disease burden in animal challenge models. Full article

Since the introduction of prophylactic HPV vaccines, both HPV infection rates and cervical cancer rates have subsequently dropped. Yet, cervical cancer remains the fourth most common cancer diagnosis in women globally. As HPV and its role in the development of cervical cancer become better understood, vaccines have emerged as a front runner for improved therapeutic cervical cancer treatment. Recent studies have shown that protein and DNA vaccines may be effectively delivered via the use of several different vectors, while combination therapy with immune checkpoint inhibitors provides even more effective treatment. Further investigation and additional clinical studies into specific vaccine strategies are necessary to determine how effective vaccines are as therapeutic treatment for cervical cancer. This review intends to summarize some of the most promising research on cervical cancer vaccines. Such a study may be helpful for gynecologists to prevent and manage patients with HPV infection. Full article

Background: Next-generation vaccines against coronavirus disease 2019 (COVID-19) focus on inducing a long-lasting immune response against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its emerging variants. To achieve this, antigens other than spike proteins have been proposed, and different platforms have been evaluated. Nucleic acid-based vaccines are fundamental for this process. Preclinical data have shown that the SARS-CoV-2 nucleocapsid protein induces a protective cellular immune response, and when combined with the spike protein, the resulting humoral and cellular immune responses are effective against some SARS-CoV-2 variants. Methods: We designed a DNA vaccine against the spike and nucleocapsid proteins of SARS-CoV-2 to generate fusion proteins based on the Delta and Omicron B.5 strains. The most immunogenic regions of the spike and nucleocapsid proteins of the Delta and Omicron B strains were selected using bioinformatics. The nucleotide sequences were cloned into pcDNA3.1, and named pcDNA3.1/D-S1, pcDNA3.1/D-S1N, and pcDNA3.1/O-SN. The immunogenicity of the generated fusion proteins was evaluated by analyzing the humoral and cellular responses elicited after the immunization of BALB/c mice. Results: DNA immunization induced antibody production, neutralization activity, and IFN-γ production. The inclusion of the nucleocapsid regions in the plasmid greatly enhanced the immune response. Moreover, cross-reactions with the variants of interest were confirmed. Conclusions: Plasmids-encoding fusion proteins combining the most immunogenic regions of the spike and nucleocapsid proteins present a promising strategy for designing new and effective vaccines against SARS-CoV-2. Full article

Human papillomavirus (HPV) is a major global health issue and is recognized as the leading cause of cervical cancer. While prophylactic vaccination programs have led to substantial reductions in both HPV infection rates and cervical cancer incidence, considerable burdens of HPV-related diseases persist, particularly in developing countries with inadequate vaccine coverage and uptake. The development of therapeutic vaccines for HPV represents an emerging strategy that has the potential to bolster the fight against cervical cancer. Unlike current prophylactic vaccines designed to prevent new infections, therapeutic vaccines aim to eradicate or treat existing HPV infections, as well as HPV-associated precancers and cancers. This review focuses on clinical studies involving therapeutic HPV vaccines for cervical cancer, specifically in three key areas: the treatment of cervical intraepithelial neoplasia; the treatment of cervical cancer in combination with or without chemotherapy, radiotherapy, or immune checkpoint inhibitors; and the role of prophylaxis following completion of treatment. Currently, there are no approved therapeutic HPV vaccines worldwide; however, active progress is being made in clinical research and development using multiple platforms such as peptides, proteins, DNA, RNA, bacterial vectors, viral vectors, and cell-based, each offering relative advantages and limitations for delivering HPV antigens and generating targeted immune responses. We outline preferred vaccine parameters, including indications, target populations, safety considerations, efficacy considerations, and immunization strategies. Lastly, we emphasize that therapeutic vaccines for HPV that are currently under development could be an important new tool in fighting against cervical cancer. Full article