Background We evaluated whether oral vitamin D supplementation during the winter and early spring reduces the incidence of influenza and upper respiratory infections in patients with inflammatory bowel disease (IBD). Methods A randomized, double-blind, controlled trial was conducted to compare the effects of vitamin D supplementation (500 IU/day) and a placebo. The primary outcome was the incidence of influenza; the secondary outcome was the incidence of upper respiratory infection. Prespecified subgroup analyses were performed according to 25-hydroxyvitamin D (25-OHD) levels (low <20 ng/mL or high ≥20 ng/mL) and whether ulcerative colitis (UC) or Crohn’s disease (CD) was present. We also used the Lichtiger clinical activity index for patients with UC and the Crohn’s Disease Activity Index (CDAI) for patients with CD before and after interventions. Results We included 223 patients with IBD and randomized them into 2 groups: vitamin D supplementation (n = 108) and placebo (n = 115). The incidence of influenza did not differ between the groups. However, the incidence of upper respiratory infection was significantly lower in the vitamin D group (relative risk [RR], 0.59; 95% confidence interval (CI), 0.35–0.98; P = 0.042). This effect was enhanced in the low 25-OHD level subgroup (RR, 0.36; 95% CI, 0.14–0.90; P = 0.02). With respect to adverse events, the Lichtiger clinical activity index score was significantly worse in the vitamin D group ( P = 0.002) and remained significant only in the high 25-OHD level subgroup. Conclusions Vitamin D supplementation may have a preventative effect against upper respiratory infection in patients with IBD but may worsen the symptoms of UC.
Pancreatic cancer is a highly aggressive and notoriously difficult to treat. As the vast majority of patients are diagnosed at advanced stage of the disease, only a small population is curative by surgical resection. Although gemcitabine-based chemotherapy is typically offered as standard of care, most patients do not survive longer than 6 months. Thus, new therapeutic approaches are needed. Pancreatic cancer cells that develop gemcitabine resistance would still be suitable targets for immunotherapy. Therefore, one promising treatment approach may be immunotherapy that is designed to target pancreatic-cancer-associated antigens. In this paper, we detail recent work in immunotherapy and the advances in concept of combination therapy of immunotherapy and chemotherapy. We offer our perspective on how to increase the clinical efficacy of immunotherapies for pancreatic cancer.
OBJECTIVE. Reliable indicators of the risk of lymph node metastasis (LNM) in superficial esophageal squamous cell carcinoma (sESCC: intramucosal and submucosal invasive carcinoma) may contribute to assist optimal clinical decision-making for treating sESCC. In esophageal cancer, there is a possibility of metastasis, even in sESCC, and careful evaluation is needed when making a pathological diagnosis. In this study, we objectively evaluated predictive factors of LNM. MATERIALS AND METHODS. A total of 110 consecutive sESCC cases were obtained. We evaluated candidate predictive factors of LNM as follows: (1) maximum tumor diameter; (2) macroscopic type; (3) depth of tumor invasion; (4) histological differentiation; (5) infiltrative growth pattern; (6) tumor budding; (7) lymphatic invasion; (8) venous invasion and (9) lympho-vascular invasion (LVI). Both Elastica-Van Gieson staining (EVG) and immunohistochemistry (IHC: D2-40, CD31, CD34) were used to evaluate invasion into the lympho-vascular spaces. For statistical analyses, single and multiple logistic regression were performed. RESULTS. LNM was observed in 37 cases (33.6%). LVI using EVG and IHC was the strongest independent predictor of LNM with an odds ratio of 12.01. Analysis of the relationship between LVI using EVG and IHC and LNM showed a negative predictive value of 94.6%. CONCLUSIONS. Evaluation of LVI using EVG and IHC may contribute to predict LNM in sESCC.
Induction of antitumor immunity by dendritic cell (DC)-tumor fusion cells (DC/tumor) can be modulated by their activation status. In this study, to address optimal status of DC/tumor to induce efficient antigen-specific cytotoxic T lymphocytes (CTLs), we have created various types of DC/tumor: 1) un-activated DC/tumor; 2) penicillin-killed Streptococcus pyogenes (OK-432; TLR4 agonist)-activated DC/tumor; 3) protein-bound polysaccharides isolated from Coriolus versicolor (PSK; TLR2 agonist)-activated DC/tumor; and 4) Combined OK-432- and PSK-activated DC/tumor. Moreover, we assessed the effects of TGF-β1 derived from DC/tumor on the induction of MUC1-specific CTLs. Combined TLR2- and TLR4-activated DC/tumor overcame immune-suppressive effect of TGF-β1 in comparison to those single activated or un-activated DC/tumor as demonstrated by: 1) up-regulation of MHC class II and CD86 expression on DC/tumor; 2) increased fusion efficiency; 3) increased production of fusions derived IL-12p70; 4) activation of CD4+ and CD8+ T cells that produce high levels of IFN-γ; 5) augmented induction of CTL activity specific for MUC1; and 6) superior efficacy in inhibiting CD4+CD25+Foxp3+ T cell generation. However, DC/tumor-derived TGF-β1 reduced the efficacy of DC/tumor vaccine in vitro. Incorporating combined TLRs-activation and TGF-β1-blockade of DC/tumor may enhance the effectiveness of DC/tumor-based cancer vaccines and have the potential applicability to the field of adoptive immunotherapy.
Previous work has demonstrated that intestinal bacteria, such as Fusobacterium varium (F. varium), contribute to the clinical activity in ulcerative colitis (UC); thus, an antibiotic combination therapy (amoxicillin, tetracycline, and metronidazole (ATM)) against F. varium can induce and maintain UC remission. Therefore, we investigated whether ATM therapy induces a long-term alteration of intestinal microbiota in patients with UC. Patients with UC were enrolled in a multicenter, randomized, double-blind, placebo-controlled study. Biopsy samples at the beginning of the trial and again at 3 months after treatment completion were randomly obtained from 20 patients. The terminal restriction fragment length polymorphism (T-RFLP) in mucosa-associated bacterial components was examined to assess the alteration of the intestinal microbiota. Profile changes of T-RFLP in mucosa-associated bacterial components were found in 10 of 12 patients in the treatment group and in none of 8 in the placebo group. Dice similarity coefficients using the unweighted pair group method with arithmetic averages (Dice-UPGMA) confirmed that the similarity of mucosal microbiota from the descending colon was significantly decreased after the ATM therapy, and this change was maintained for at least 3 months. Moreover, at 3 months after treatment completion, the F. varium/β-actin ratio, examined by real-time PCR using nested PCR products from biopsy samples, was reduced less than 40% in 8 of 12 treated patients, which was higher, but not significantly, than in 4 of 8 patients in the placebo group. Together, these results suggest that ATM therapy induces long-term alterations in the intestinal microbiota of patients with UC, which may be associated, at least in part, with clinical effects of the therapy.
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