Vitamin D Status Is Associated With Immune Checkpoint Inhibitor Efficacy and Immune-related Adverse Event Severity in Lung Cancer Patients: A Prospective Cohort Study.

Vitamin D (VitD) is potentially immunomodulatory, so here we aimed to explore the relationships between serum VitD levels, immune checkpoint inhibitor (ICI) efficacy, and immune-related adverse events (irAEs). Serum 25-hydroxyvitamin D [25(OH)D] levels were quantified before and after ICI treatment in prospectively enrolled patients with advanced lung cancers. Of 77 enrolled patients, 29 developed 42 irAEs. Baseline 25(OH)D levels of partial response (PRs) patients were significantly higher than non-PR patients (19.39±7.16 vs. 16.28±5.99 ng/mL, P =0.04). The area under the curve of 25(OH)D >15.73 ng/mL to identify PR was 0.63 (95% CI, 0.51-0.76, P =0.047), and baseline 25(OH)D levels >15.73 ng/mL (odds ratio: 2.93, 95% CI, 1.10-7.79, P =0.03) and prior targeted therapy (odds ratio: 0.30, 95% CI, 0.10-0.92, P =0.04) were independent predictors of PR as best efficacy by multivariable logistic regression. With respect to irAEs, baseline 25(OH)D levels were higher in grade 1 irAE patients than in grade 2/3/4 irAE patients (20.07±8.64 vs. 15.22±2.30 ng/mL, P =0.02). However, the area under the curve was only 0.56 (95% CI, 0.42-0.70, P =0.39) for a baseline 25(OH)D of 20.99 ng/mL for predicting irAE occurrence. There was a direct monotonic relationship and U-shaped relationship between baseline 25(OH)D levels and ICI efficacy and irAE occurrence, respectively. Overall survival was significantly different between VitD sufficient, insufficient, and deficient patients (log-rank P =0.01), which remained after adjustment in Cox proportional hazards regression models. Baseline 25(OH)D levels seem to be associated with ICI efficacy and prognosis, it might be helpful to assess the baseline VitD status, and supplementation with VitD might bring some benefit to enhance ICI efficacy and reduce moderate-severe irAEs.

Vitamin D3 and Lactobacillus rhamnosus GG/p40 Synergize to Protect Mice From Colitis by Promoting Vitamin D Receptor Expression and Epithelial Proliferation.

BACKGROUND: While vitamin D (VitD) levels are negatively correlated with inflammatory bowel disease (IBD) activity, VitD supplementation does not reduce IBD severity. The probiotic Lactobacillus rhamnosus GG (LGG), which secretes p40, can upregulate colonic VitD receptor (VDR) expression. We therefore evaluated synergy between VitD3 and LGG/p40 in the treatment of mouse colitis. METHODS: A dextran sulfate sodium (DSS) colitis model was established in Vdr+/+ and Vdr-/- mice, and mice were treated with VitD3, LGG, or p40 alone or in combination for 7 to 14 days. Colitis severity was assessed by weight loss, disease activity index (DAI), colon length, histology, and inflammatory cytokine expression together with VDR expression, proliferation, and apoptosis. In vitro, VDR expression and cell viability were assessed in HCT116 cells after stimulation with p40. RESULTS: Total and nuclear VDR protein expression were lower in DSS-treated Vdr+/+ mice compared with control mice (P < .05). Compared with the DSS group, VitD3 + LGG alleviated colitis as assessed by significantly improved DAI and histological scores, increased colon length, decreased colonic Tnf, and increased Il10 expression together with increased colonic VDR gene and protein expression and increased Ki-67 proliferation index (P < .05). In Vdr-/- mice, VitD3 + LGG had no effect on DSS colitis. In Vdr+/+ mice, VitD3 + p40 also reduced colitis severity according to clinicopathological and immunological metrics and increased VDR expression and epithelial proliferation (P < .05). In HCT116 cells, p40 stimulation increased VDR protein expression and viability (P < .05). CONCLUSIONS: VitD3 and LGG/p40 synergistically improve the severity of colitis by increasing colonic VDR expression and promoting colonic epithelial proliferation.

There is increasing evidence that vitamin D and its associated pathways may be a helpful adjunct to inflammatory bowel disease therapies. This experimental study shows that vitamin D may synergize with the probiotic Lactobacillus rhamnosus GG for enhanced therapeutic effect.

E-cadherin Mediates the Preventive Effect of Vitamin D3 in Colitis-associated Carcinogenesis.

Vitamin D3 is beneficial in ameliorating or preventing inflammation and carcinogenesis. Here, we evaluated if vitamin D3 has a preventive effect on colitis-associated carcinogenesis. Administration of azoxymethane (AOM), followed with dextran sulfate sodium (DSS), was used to simulate colitis-associated colon cancer in mice. The supplement of vitamin D3 at different dosages (15, 30, 60 IU·g·w), started before AOM or immediately after DSS treatment (post 60), was sustained to the end of the experiment. Dietary vitamin D3 significantly reduced the number of tumors and tumor burden in a dose-dependent manner. Of note, vitamin D3 in high doses showed significant preventive effects on carcinogenesis regardless of administration before or after AOM-DSS treatment. Cell proliferation decreased in vitamin D3 groups compared with the control group after inhibition of expression of ß-catenin and its downstream target gene cyclin D1 in the colon. In vitro, vitamin D3 reduced the transcriptional activity and nuclear level of ß-catenin, and it also increased E-cadherin expression and its binding affinity for ß-catenin. Moreover, repression of E-cadherin was rescued by supplemental vitamin D3 in mouse colons. Taken together, our results indicate that vitamin D3 effectively suppressed colonic carcinogenesis in the AOM-DSS mouse model. Our findings further suggest that upregulation of E-cadherin contributes to the preventive effect of vitamin D3 on ß-catenin activity.

Pellagra Secondary to Medication and Alcoholism: A Case Report and Review of the Literature.

Pellagra usually results from niacin deficiency and presents with the classic triad of dermatitis, diarrhea, and dementia. It is most commonly associated with malnutrition and poverty and is extremely rare in industrialized societies. Furthermore, pellagra can be induced by special clinical conditions that interfere with the intake, absorption, and metabolism of niacin. Because of its detrimental effects on health and its favorable prognosis after supplementation of nicotinamide, the importance of early diagnosis and treatment should be emphasized. Herein, we report a case of pellagra in a young alcoholic who underwent combined chemotherapy for tuberculosis. For the first time, a descriptive review of literature from 1957 to 2014 has been conducted to clarify potential etiologies of pellagra: alcoholism (35.24%, 37 articles), various medications (25.71%, 27 articles), inadequate oral intake (16.19%, 17 articles), malabsorption (13.33%, 14 articles), metabolic derangement (7.62%, 8 articles), excessive loss (0.95%, 1 article), and etiology unknown (0.95%, 1 article).

Therapeutic and immunoregulatory effect of GATA-binding protein-3/T-box expressed in T-cells ratio of astragalus polysaccharides on 2,4,6-trinitrobenzene sulfonic acid-induced colitis in rats.

OBJECTIVE: To analyze the immunological characteristics of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model and examine the therapeutic effects and mechanisms of Astragalus polysaccharides (APS) treatment. METHODS: Thirty-two male specific pathogen free Spragne-Dawley rats were randomly equally assigned to four groups: control, TNBS, APS and prednisone groups. Experimental colitis was induced by enema administration of TNBS. Then rats were treated with APS (0.5 g•kg-1•day-1, once daily) or prednisone (1.0 mg•kg-1•day-1, once daily) by gavage for 14 days. Macroscopic lesion and histological damage were determined, and activity of myeloperoxidase (MPO) was measured in the colonic tissues. Expressions of T-box expressed in T-cells (T-bet) and GATA-binding protein-3 (GATA-3) were determined by immunohistochemistry analysis and western blot. RESULTS: Both macroscopic lesion and histological colonic damage induced by TNBS were reduced by APS and prednisone treatment. These were accompanied by significant attenuation of MPO activity (P=0.03). TNBS intervention enhanced the expression of both GATA-3 and T-bet, but the expression of T-bet was significantly enhanced than that of GATA-3, resulting in significant reduction of GATA-3/T-bet ratio (P=0.025). APS administration enhanced the expression of T-bet (P=0.04) and GATA-3 (P=0.019) in comparison to TNBS group, and resulting in an up-regulated GATA-3/T-bet ratio. Prednisone treatment inhibited both expressions; however it also resulted in up-regulation of the GATA-3/T-bet ratio. CONCLUSIONS: These results demonstrated that APS exerted a beneficial immune regulatory effect on experimental colitis. It promoted the expression of T helper cell 1 (Th1) and T helper cell 2 (Th2) specific transcription factors but ultimately favor a shift toward Th2 phenotype, suggesting that APS possessed therapeutic potential in experimental colitis.

Nutrition Therapy for Mitochondrial Neurogastrointestinal Encephalopathy with Homozygous Mutation of the TYMP Gene.

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is characterized by significant gastrointestinal dysmotility. Early and long-term nutritional therapy is highly recommended. We report a case of MNGIE in a patient who was undergoing long-term nutrition therapy. The patient was diagnosed with a serious symptom of fatty liver and hyperlipidemia complications, along with homozygous mutation of the thymidine phosphorylase (TYMP) gene (c.217G > A). To our knowledge, this is the first report of such a case. Herein, we describe preventive measures for the aforementioned complications and mitochondrial disease-specific nutritional therapy.

1,25-hydroxyvitamin D relieves colitis in rats via down-regulation of toll-like receptor 9 expression.

AIM: To investigate the therapeutic and immunoregulatory effects of 1,25-dihydroxyvitamin D (1,25(OH)D3) on 2,4,6-trinitrobenzenesulfonic acid (TNBS) -induced colitis in rats. METHODS: Experimental colitis induced by enema administration of TNBS plus ethanol was treated with 5-aminosalicylic acid (5-ASA) and/or 1,25(OH)D3. Disease activity was measured using the disease activation index (DAI), colon macroscopic damage index (CMDI), histological colonic damage score, and myeloperoxidase (MPO) activity. The expression of toll-like receptor 9 (TLR9) in the colon was determined by reverse transcription-polymerase chain reaction and immunohistochemistry. RESULTS: Rats with TNBS-induced colitis had significantly elevated DAI, CMDI, histological colonic damage score, and MPO activity (all P<0.001) compared to rats without colitis. Treatment with 5-ASA or 1,25(OH)D3 ameliorated colitis by lowering CMDI (P=0.049, P=0.040, respectively), histological colonic damage score (P=0.010, P=0.005, respectively), and MPO activity (P=0.0003, P=0.0013, respectively) compared with the TNBS group. Combined treatment with 5-ASA and 1,25(OH)D3 significantly decreased MPO activity (P=0.003). 1,25(OH)D3 attenuated colitis without causing hypercalcemia or renal insufficiency. TNBS significantly increased the number of TLR9 positive cells compared to control (P<0.010), while 5-ASA, 1,25(OH)D3, and combined treatment with 5-ASA and 1,25(OH)D3 significantly decreased it compared to TNBS group (all P<0.010). In TNBS group a moderate correlation was observed between MPO activity and the number of TLR9-positive cells (r=0.654, P<0.001). CONCLUSION: TLR9 expression correlates with the extent of inflammation in TNBS-induced colitis. 1,25(OH)D3 relieves this inflammation possibly by decreasing TLR9 expression.

Randomized phase II trial of lyophilized strawberries in patients with dysplastic precancerous lesions of the esophagus.

Dysplasia is a histologic precursor of esophageal squamous cell carcinoma (SCC). We previously showed that dietary freeze-dried, or lyophilized, strawberry powder inhibits N-nitrosomethylbenzylamine-induced SCC in the rat esophagus. On the basis of this observation, we conducted a randomized (noncomparative) phase II trial in China to investigate the effects of two doses of freeze-dried strawberries in patients with esophageal dysplastic lesions in a high-risk area for esophageal cancer. We randomly assigned 75 patients identified by endoscopy to have dysplastic esophageal premalignant lesions to receive freeze-dried strawberry powder at either 30 g/d (37 patients) or 60 g/d (38 patients) for six months; the powder was mixed with water and drunk. After six months, we assessed the changes in histologic grade of these lesions (primary endpoint) in a blinded fashion. The dose of 30 g/d, did not significantly affect histology or any other measured parameter. The dose of 60 g/d, however, reduced the histologic grade of dysplastic premalignant lesions in 29 (80.6%) of the 36 patients at this dose who were evaluated for histology (P < 0.0001). The strawberry powder was well tolerated, with no toxic effects or serious adverse events. Strawberries (60 g/d) also reduced protein expression levels of inducible nitric oxide synthase (iNOS) by 79.5% (P < 0.001), cyclooxygenase-2 (COX-2) by 62.9% (P < 0.001), phospho-nuclear factor kappa B (NFκB)-p65 (pNFκB-p65) by 62.6% (P < 0.001), and phospho-S6 (pS6) by 73.2% (P < 0.001). Freeze-dried strawberries (60 g/d) also significantly inhibited the Ki-67 labeling index by 37.9% (P = 0.023). Our present results indicate the potential of freeze-dried strawberry powder for preventing human esophageal cancer, supporting further clinical testing of this natural agent in this setting.

Protective effects of rhubarb on experimental severe acute pancreatitis.

AIM: To investigate the effects of rhubarb on severe acute pancreatitis (SAP) in rats. METHODS: Severe acute pancreatitis was induced by two intraperitoneal injections of cerulein (40 microg/kg body weight) plus 5-h restraint water-immersion stress. Rhubarb (75-150 mg/kg) was orally fed before the first cerulein injection. The degree of pancreatic edema, serum amylase level, local pancreatic blood flow (PBF), and histological alterations were investigated. The effects of rhubarb on pancreatic exocrine secretion in this model were evaluated by comparing with those of somatostatin. RESULTS: In the Cerulein+Stress group, severe edema and diffuse hemorrhage in the pancreas were observed, the pancreatic wet weight (11.60+/-0.61 g/Kg) and serum amylase (458 490+/-43 100 U/L) were markedly increased (P<0.01 vs control). In the rhubarb (150 mg/kg) treated rats, necrosis and polymorphonuclear neutrophil (PMN) infiltration in the pancreas were significantly reduced (P<0.01), and a marked decrease (50%) in serum amylase levels was also observed (P<0.01). PBF dropped to 38% (93+/-5 mL/min per 100 g) of the control in the Cerulein+Stress group and partly recovered in the Cerulein+Stress+Rhubarb 150 mg group (135+/-12 mL/min per 100 g) (P<0.01). The pancreatic exocrine function was impaired in the SAP rats. The amylase levels of pancreatic juice were reduced in the rats treated with rhubarb or somatostatin, comparing with that of untreated SAP group. The bicarbonate concentration of pancreatic juice was markedly elevated only in the rhubarb-treated group (P<0.01). CONCLUSION: Rhubarb can exert protective effects on SAP, probably by inhibiting the inflammation of pancreas, improving pancreatic microcirculation, and altering exocrine secretion.