Isoprinosine as a foot-and-mouth disease vaccine adjuvant elicits robust host defense against viral infection through immunomodulation.

Background: Commercial foot-and-mouth disease (FMD) vaccines have limitations, such as local side effects, periodic vaccinations, and weak host defenses. To overcome these limitations, we developed a novel FMD vaccine by combining an inactivated FMD viral antigen with the small molecule isoprinosine, which served as an adjuvant (immunomodulator). Method: We evaluated the innate and adaptive immune responses elicited by the novel FMD vaccine involved both in vitro and in vivo using mice and pigs. Results: We demonstrated isoprinosine-mediated early, mid-term, and long-term immunity through in vitro and in vivo studies and complete host defense against FMD virus (FMDV) infection through challenge experiments in mice and pigs. We also elucidated that isoprinosine induces innate and adaptive (cellular and humoral) immunity via promoting the expression of immunoregulatory gene such as pattern recognition receptors [PRRs; retinoic acid-inducible gene (RIG)-I and toll like receptor (TLR)9], transcription factors [T-box transcription factor (TBX)21, eomesodermin (EOMES), and nuclear factor kappa B (NF-kB)], cytokines [interleukin (IL)-12p40, IL-23p19, IL-23R, and IL-17A)], and immune cell core receptors [cluster of differentiation (CD)80, CD86, CD28, CD19, CD21, and CD81] in pigs. Conclusion: These findings present an attractive strategy for constructing novel FMD vaccines and other difficult-to-control livestock virus vaccine formulations based on isoprinosine induced immunomodulatory functions.

Bestatin, A Pluripotent Immunomodulatory Small Molecule, Drives Robust and Long-Lasting Immune Responses as an Adjuvant in Viral Vaccines.

An inactivated whole-virus vaccine is currently used to prevent foot-and-mouth disease (FMD). Although this vaccine is effective, it offers short-term immunity that requires regular booster immunizations and has several side effects, including local reactions at the vaccination site. To address these limitations, herein, we evaluated the efficacy of bestatin as a novel small molecule adjuvant for inactivated FMD vaccines. Our findings showed that the FMD vaccine formulated with bestatin enhanced early, intermediate-, and particularly long-term immunity in experimental animals (mice) and target animals (pigs). Furthermore, cytokines (interferon (IFN)α, IFNß, IFNγ, and interleukin (IL)-29), retinoic acid-inducible gene (RIG)-I, and T-cell and B-cell core receptors (cluster of differentiation (CD)28, CD19, CD21, and CD81) markedly increased in the group that received the FMD vaccine adjuvanted with bestatin in pigs compared with the control. These results indicate the significant potential of bestatin to improve the efficacy of inactivated FMD vaccines in terms of immunomodulatory function for the simultaneous induction of potent cellular and humoral immune response and a long-lasting memory response.

The role of zinc sulfate in enhancing cellular and humoral immune responses to foot-and-mouth disease vaccine.

Foot-and-mouth disease (FMD) is a rapidly propagating infectious disease of cloven-hoofed animals, especially cattle and pigs, affecting the productivity and profitability of the livestock industry. Presently, FMD is controlled and prevented using vaccines; however, conventional FMD vaccines have several disadvantages, including short vaccine efficacy, low antibody titers, and safety issues in pigs, indicating the need for further studies. Here, we evaluated the efficacy of a novel bivalent vaccine containing zinc sulfate as an immunostimulant and FMD type O and A antigens (O PA2 and A YC, respectively) against FMD virus in mice and pigs. Zinc sulfate induced cellular immunity in murine peritoneal exudate cells (PECs) and porcine peripheral blood mononuclear cells (PBMCs) by increasing IFNγ secretion. Additionally, FMD vaccine containing O PA2 and A YC antigens and zinc sulfate induced early, mid-, and long-term immune responses in mice and pigs, and enhanced cellular and humoral immunity by regulating the expression of pathogen recognition receptors (PRRs), transcription factors, co-stimulatory molecules, and cytokines in porcine PBMCs from vaccinated pigs. Overall, these results indicated that the novel immunostimulant zinc sulfate induced potent cellular and humoral immune responses by stimulating antigen-presenting cells (APCs) and T and B cells, and enhanced long-term immunity by promoting the expression of co-stimulatory molecules. These outcomes suggest that zinc sulfate could be used as a novel vaccine immunostimulant for difficult-to-control viral diseases, such as African swine fever (ASF) or COVID-19.

Prognostic value of mismatch repair deficiency in patients with advanced gastric cancer, treated by surgery and adjuvant 5-fluorouracil and leucovorin chemoradiotherapy.

OBJECTIVE: The predictive value of mismatch repair protein deficiency (MMRD) for chemoradiotherapeutic outcome has rarely been reported in gastric cancer. This study investigated the clinical significance of MMRD as a prognostic factor for tumor recurrence, and as a predictor of response to adjuvant chemoradiotherapy in advanced gastric cancer patients. METHODS: Between 1995 and 2008, tissue specimens of 881 patients who underwent radical gastrectomy for stage II and III gastric cancer were analyzed. MMRD was assessed using immunohistochemical stains for MLH1, PMS2, MSH2, and MSH6. Patients were divided into two groups according to adjuvant treatment: a 5-fluorouracil/leucovorin (FL) adjuvant chemoradiotherapy group and a surgery alone group. Disease-free survival (DFS) was compared between the two groups correlated to MMRD. Risk factors for tumor recurrence were analyzed using multivariate analysis. RESULTS: Of the 881 gastric cancer patients, 88 (10.0%) exhibited MMRD and 398 (45.2%) patients received adjuvant FL chemoradiotherapy. The multivariate analysis revealed that MMRD was a good independent prognostic factor (hazard ratio, 0.572; 95% confidence interval, 0.370-0.883; P = 0.012). For stage III gastric cancer displaying mismatch repair protein proficiency (MMRP), adjuvant FL chemoradiotherapy after surgery resulted in better DFS than surgery alone (P = 0.001). Among the stage II gastric cancer patients, adjuvant FL chemoradiotherapy did not show survival benefit, regardless of MMRD. CONCLUSION: MMRD is a good independent prognostic factor in advanced gastric cancer. Adjuvant FL chemoradiotherapy was beneficial in patients with stage III gastric cancer with MMRP but not in those with MMRD.

Synergistic effect of ribavirin and vaccine for protection during early infection stage of foot-and-mouth disease.

In many countries, vaccines are used for the prevention of foot-and-mouth disease (FMD). However, because there is no protection against FMD immediately after vaccination, research and development on antiviral agents is being conducted to induce protection until immunological competence is produced. This study tested whether well-known chemicals used as RNA virus treatment agents had inhibitory effects on FMD viruses (FMDVs) and demonstrated that ribavirin showed antiviral effects against FMDV in vitro/in vivo. In addition, it was observed that combining the administration of the antiviral agents orally and complementary therapy with vaccines synergistically enhanced antiviral activity and preserved the survival rate and body weight in the experimental animals. Antiviral agents mixed with an adjuvant were inoculated intramuscularly along with the vaccines, thereby inhibiting virus replication after injection and verifying that it was possible to induce early protection against viral infection prior to immunity being achieved through the vaccine. Finally, pigs treated with antiviral agents and vaccines showed no clinical signs and had low virus excretion. Based on these results, it is expected that this combined approach could be a therapeutic and preventive treatment for early protection against FMD.

Adjuvant Chemotherapy Versus Chemoradiotherapy Versus Surgery Alone for Early Gastric Cancer with One or Two Lymph Node Metastasis.

BACKGROUND: Limited studies exist comparing clinical outcomes by adjuvant treatment for pT1N1 gastric cancer. This study compared the disease-free survival (DFS) of patients with pT1N1 gastric cancer according to the type of adjuvant treatment-surgery alone, chemotherapy (CTx), and chemoradiotherapy (CCRTx)-and evaluated risk factors for tumor recurrence. METHODS: Between 1995 and 2015, 738 patients underwent radical gastrectomy for pT1N1 gastric cancer and were divided into three groups: surgery alone (n = 355), CTx (n = 214), and CCRTx (n = 169). Chronological changes in adjuvant treatment type and chemotherapeutic regimens were evaluated and DFS was compared. Risk factors for tumor recurrence were analyzed. RESULTS: The proportion of patients who underwent surgery alone was more than 50% until 2001, and the proportion of those who had either CTx or CCRTx was more than 50% from 2002 to 2011, after which the proportion who underwent surgery alone increased again. The main chemotherapeutic agent was 5-fluorouracil with leucovorin. The 5-year DFS was 96.5% in the surgery-alone group, 96.0% in the CTx group, and 95.8% in the CCRTx group (no significant difference). The various chemotherapeutic regimens did not show differences in DFS. In univariate and multivariate analyses, adjuvant CTx and CCRTx showed no beneficial effect with regard to tumor recurrence. CONCLUSIONS: Because adjuvant CTx and CCRTx did not show any benefit with regard to tumor recurrence, these treatment strategies might be unnecessary for pT1N1 gastric cancer after gastrectomy. Further studies are necessary to reveal pT1N1 gastric cancer patient subgroups who might benefit from adjuvant treatments.

A Randomized Controlled Trial of Vagus Nerve-preserving Distal Gastrectomy Versus Conventional Distal Gastrectomy for Postoperative Quality of Life in Early Stage Gastric Cancer Patients.

OBJECTIVE: To compare the postoperative quality of life of vagus nerve preserving distal gastrectomy (VPG) vs conventional distal gastrectomy (CG) in patients with early-stage gastric cancer. DESIGN: Randomized controlled clinical trial. SETTING: Large tertiary comprehensive cancer center in Korea. PARTICIPANTS: One hundred sixty-three patients with early gastric cancer 18 years of age or older expected to undergo curative gastric resection. INTERVENTION: Patients were randomized 1:1 to VPG (n = 85) or CG (n = 78). MAIN OUTCOME MEASURES: European Organization for Research and Treatment of Cancer (EORTC) gastric module (STO22). RESULTS: Patients assigned to VPG showed less diarrhea 3 and 12 months after surgery (P = 0.040 and 0.048, respectively) and less appetite loss at 12 months (P = 0.011) compared with those assigned to CG. In both groups, fatigue, anxiety, eating restriction, and body image deteriorated at 3 months after surgery and did not regain baseline levels 12 months after surgery. There were no significant differences between the 2 groups in cancer recurrence and death over 5 years of follow-up. CONCLUSIONS: Early gastric cancer patients undergoing VPG reported significantly less diarrhea and appetite loss at 12 months postsurgery compared with those undergoing CG, with no differences in long-term clinical outcomes. VPG may improve the quality of life after gastrectomy in early gastric cancer patients compared with CG.

Benign paroxysmal positional vertigo secondary to inner ear disease.

OBJECTIVES: To contrast clinical characteristics of secondary benign paroxysmal positional vertigo (s-BPPV) with idiopathic BPPV (i-BPPV). STUDY DESIGN: Case series with chart review. SETTING: University hospital. SUBJECTS AND METHODS: A total of 718 patients whose medical records were reviewed had BPPV. Sixty-nine patients had existing inner ear diseases and thus were considered to have s-BPPV. We reviewed demographics, concurrent causative disorders, involved area, and response to particle repositioning maneuvers for these s-BPPV patients in comparison with i-BPPV subjects. RESULTS: Female subjects with i-BPPV outnumbered male subjects by a ratio of 1.9:1, but there was no significant sex difference for s-BPPV patients. The diseases associated with s-BPPV were idiopathic sudden sensory hearing loss (ISSHL, 50.7%), Ménière's disease (MD, 28.9%) and unilateral vestibulopathy such as acute vestibular neuronitis and herpes zoster oticus (20.2%). The posterior canal was most commonly involved in both i-BPPV and s-BPPV. The horizontal canal was the second most common, followed by multi-canal involvement. However, MD-associated BPPV most commonly involved the lateral canal. The mean durations of treatment for i-BPPV and s-BPPV were 2.28 and 4.87 days, respectively. The mean duration of treatment was 6.28 days for ISSHL with BPPV, 5.07 days for BPPV with unilateral vestibulopathy, and 2.28 days for BPPV with MD. CONCLUSION: The mean duration of treatment for BPPV with ISSHL or unilateral vestibulopathy was longer than for other groups. The different pathophysiologies of s-BPPV associated with different inner ear diseases may explain its diverse clinical features and courses.