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Key PointsCD28 delivers a pro-survival signal to MM cells via regulation of PI3K/Akt, FoxO3a, and Bim. Blockade of CD28:CD80/CD86 in vivo resensitizes MM cells to chemotherapy and significantly reduces tumor burden.

Abstract Rationale Daily azithromycin decreases acute exacerbations of chronic obstructive pulmonary disease (AECOPD), but long-term side effects are unknown. Objectives To identify the types of exacerbations most likely to be reduced and clinical subgroups most likely to benefit from azithromycin, 250 mg daily, added to usual care. Methods Enrollment criteria included irreversible airflow limitation and AECOPD requiring corticosteroids, emergency department visit, or hospitalization in the prior year or use of supplemental oxygen. Recurrent events and cumulative incidence analyses compared treatment received for AECOPD by randomization group, stratified by subgroups of interest. Cox proportional hazards models estimated treatment effects in subgroups adjusted for age, sex, smoking status, FEV1% predicted, concomitant COPD medications, and oxygen use. Measurements and Main Results Azithromycin was most effective in reducing AECOPD requiring both antibiotic and steroid treatment (n = 1,113; cumulative incidence analysis, P = 0.0002; recurrent events analysis, P = 0.002). No difference in treatment response by sex (P = 0.75), presence of chronic bronchitis (P = 0.19), concomitant inhaled therapy (P = 0.29), or supplemental oxygen use (P = 0.23) was observed. Older age and milder Global Initiative for Chronic Obstructive Lung Disease stage were associated with better treatment response (P = 0.02 and 0.04, respectively). A significant interaction between treatment and current smoking was seen (P = 0.03) and azithromycin did not reduce exacerbations in current smokers (hazard ratio, 0.99; 95% confidence interval, 0.71–1.38; P = 0.95). Conclusions Azithromycin is most effective in preventing AECOPD requiring both antibiotic and steroid treatment. Adjusting for confounders, we saw no difference in efficacy by sex, history of chronic bronchitis, oxygen use, or concomitant COPD therapy. Greater efficacy was seen in older patients and milder Global Initiative for Chronic Obstructive Lung Disease stages. We found little evidence of treatment effect among current smokers. Clinical trial registered with www.clinicaltrials.gov (NCT0011986 and NCT00325897).

Abstract TGF-β2 is a potent immunoregulatory mediator that influences B cell, T cell, and macrophage function. To test whether this cytokine alters pathology in a model of virus-induced demyelinating disease, we treated SJL/J mice with TGF-β2 either before or after infection with Theiler’s murine encephalomyelitis virus. Treatment continued three times weekly through day 35 postinfection. TGF-β2 administration resulted in significantly smaller lesions and fewer virus Ag-positive cells in the spinal cords of infected SJL/J mice. Mice treated with TGF-β2 had similar levels of virus-specific IgG as infected, control-treated mice. TGF-β2 administration significantly increased the level of non-virus-specific activated CTLs, but had no effect on virus-specific CTLs. TUNEL revealed a decrease in the number of apoptotic nuclei in the spinal cord white matter of mice treated in vivo with TGF-β2. Immunostaining with an Ab to F4/80 revealed that TGF-β2-treated mice had significantly fewer F4/80-positive cells in the white matter of the spinal cord as compared with infected control-treated mice. These data suggest that TGF-β2 may control virus-induced demyelination via an immunomodulatory mechanism that reduces macrophage infiltration.

Abstract We have investigated the genetic basis of the immune response to dietary gluten in HCD4/DQ8 and HCD4/DQ6 double transgenic mice. Mice were immunized with gluten i.p. or individual peptides s.c. and spleen or draining lymph node T cells were challenged in vitro. Strong proliferative responses to gluten were seen in the HCD4/DQ8 mice, whereas the HCD4/DQ6 mice responded to gluten poorly. A series of overlapping peptides spanning gliadin were synthesized. The HCD4/DQ8 mice reacted to many of the individual peptides of gliadin, while the HCD4/DQ6 mice were relatively unresponsive. T cells isolated from HCD4/DQ8 mice also responded well to modified (deamidated) versions of the gliadin peptides, whereas HCD4DQ6 mice did not. The T cell response to gluten was CD4 dependent and DQ restricted and led to the production of cytokines IL-6, TGF-β, and IL-10. Finally, intestinal lymphocytes isolated from gluten-fed HCD4/DQ8 mice displayed an activated phenotype. These data suggest that this HLA class II transgenic murine model of gluten sensitivity may provide insight into the initiation of the MHC class II-restricted gluten sensitivity in celiac disease.

ABSTRACTObjectives:Limited data suggest complete mucosal healing in treated children with celiac disease (CD), but recent data from adult endoscopic biopsies have shown substantial numbers with persistent mucosal injury. We aimed to assess the rate of mucosal healing and indications for repeat small bowel (SB) biopsy in children with CD.Methods:We retrospectively reviewed records of children (ages 1–18 years) with CD who underwent a second SB biopsy. All of the children were seen at Mayo Clinic (Rochester, MN) from January 1997 through June 2013.Results:Forty children were identified (14 boys); average age at diagnosis was 8.5 years. Indications for second SB biopsy were abdominal pain (n = 20), diarrhea (n = 7), constipation (n = 5), non–celiac‐related concern (n = 2), follow‐up (n = 5), and persistent serology (n = 1). Average time between biopsies was 24 months (range 4–120 months). Histology on the second biopsy showed complete healing (n = 25), intraepithelial lymphocytes (n = 9), and persistent villous atrophy (n = 6). Of these, 3 patients had partial villous atrophy and 3 had with complete villous atrophy. Persistent villous atrophy was observed in 2 of 20 patients with abdominal pain and 1 of 7 with diarrhea. All of the patients with persistent constipation (n = 5) had complete resolution.Conclusions:Mucosal healing in children with CD may not be complete as previously assumed. Abdominal pain was the most common indication for repeating the SB biopsy. Persistence of abdominal pain, diarrhea, and constipation was poorly associated with persistence of mucosal injury.

ABSTRACTBackground:The purpose of this study was to identify the frequency of fat‐soluble vitamin deficiencies in children with celiac disease (CD) and to determine the value of routine testing for these deficiencies.Methods:We conducted a retrospective medical record review of patients with a confirmed diagnosis of CD and fat‐soluble vitamin levels measured at diagnosis between 1995 and 2012 at Mayo Clinic. Patients' demographics, fat‐soluble vitamin levels, and pertinent clinical factors at the time of diagnosis were collected.Results:Eighty‐three patients were included in the final analysis: 51 girls and 32 boys, with an average age at diagnosis of 12.8 years in girls and 13.0 years in boys. The most commonly reported symptoms were abdominal pain in 49 patients and diarrhea in 30 patients. Family history of CD was reported in 32 patients. Average vitamin levels for vitamin E, 25‐hydroxyvitamin D (25 (OH) D), and vitamin A were 7.5 mg/L, 32.8 ng/mL, and 334.5 μg/dL, respectively. No patients had vitamin A deficiency, 2 patients had vitamin E deficiency, and 9 patients had mild‐to‐moderate vitamin D deficiency (none had severe deficiency). Both patients with vitamin E deficiency were symptomatic and had complete villous atrophy. Thirty‐one patients had insufficiency of 25 (OH) D, which was less than the reported frequency of vitamin D insufficiency in the general pediatric population in the United States in 2004. None of the patients were receiving vitamin supplements at the time of diagnosis.Conclusions:Fat‐soluble vitamin deficiencies are uncommon in children with new diagnosis of CD. Routine measuring of fat‐soluble vitamins levels may not be necessary.

BACKGROUNDSince 2002, priority Model for End‐stage Liver Disease (MELD) exception status has been given to patients with hepatocellular carcinoma (HCC) who meet the Milan criteria. Since then, the number of liver transplantations performed in patients with HCC has increased, but to the authors' knowledge, few studies to date have examined the effect of MELD exception recommendations on therapy use and survival rates in a nationwide sample. The current study examines therapy use and long‐term survival rates among patients with HCC tumors meeting the Milan criteria in the post‐MELD exception era.METHODSThe current study is a retrospective cohort study of 2179 patients with localized HCC meeting the Milan criteria who were registered between 2004 and 2007 in the Surveillance, Epidemiology, and End Results database.RESULTSA total of 43% of patients did not receive any specific therapy. Overall, the 5‐year relative survival rate for patients receiving only supportive care was dismal at 24% (95% confidence interval [95% CI], 21%‐27%), whereas that for patients undergoing liver transplantation was 77% (95% CI, 71%‐82%). Long‐term survival was found to be dependent on age, race/ethnicity, and type of therapy received. A multivariate Cox proportional hazards model adjusted for age, race/ethnicity, and type of therapy received demonstrated that, compared with white patients, black patients had significantly poorer survival outcomes (hazards ratio, 1.23; 95% CI, 1.03‐1.47 [P = .02]), whereas Asian/Pacific Islander patients had significantly better survival rates when compared with white patients (HR, 0.66; 95% CI, 0.57‐0.77 [P < .001]).CONCLUSIONSDespite having localized disease that met transplantation criteria, nearly 50% of the large nationwide cohort of patients with HCC in the current study received only supportive care and had dismal 5‐year relative survival rates, especially among black patients. Cancer 2014;120:1725–1732. © 2014 American Cancer Society.