In vivo compartmentalization of functionally distinct, rapidly responsive antigen-specific T-cell populations in DNA-immunized or Salmonella enterica serovar Typhimurium-infected mice

The location and functional properties of antigen-specific memory T-cell populations in lymphoid and nonlymphoid compartments following DNA immunization or infection with Salmonella were investigated. Epitope-specific CD8+-T-cell expansion and retention during the memory phase were analyzed for DNA-immunized mice by use of a 5-h peptide restimulation assay. These data revealed that epitope-specific gamma interferon (IFN-{gamma})-positive CD8+ T cells occur at higher frequencies in the spleen, liver, and blood than in draining or peripheral lymph nodes during the expansion phase. Moreover, this distribution is maintained into long-term memory. The location and function of both CD4+ and CD8+ Salmonella-specific memory T cells in mice who were given a single dose of Salmonella enterica serovar Typhimurium was also quantitated by an ex vivo restimulation with bacterial lysate to detect the total Salmonella-specific memory pool. Mice immunized up to 6 months previously with S. enterica serovar Typhimurium had bacterium-specific CD4+ T cells that were capable of producing IFN-{gamma} or tumor necrosis factor alpha (TNF-{alpha}) at each site analyzed. Similar findings were observed for CD8+ T cells that were capable of producing IFN-{gamma}, while a much lower frequency and more restricted distribution were associated with TNF-{alpha}-producing CD8+ T cells. This study is the first to assess the frequencies, locations, and functions of both CD4+ and CD8+ memory T-cell populations in the same Salmonella-infected individuals and demonstrates the organ-specific functional compartmentalization of memory T cells after Salmonella infection

Maternal Vitamin D Status and Infant Infection

Maternal vitamin D status during pregnancy may modulate fetal immune system development and infant susceptibility to infections. Vitamin D deficiency is common during pregnancy, particularly among African American (AA) women. Our objective was to compare maternal vitamin D status (plasma 25(OH)D concentration) during pregnancy and first-year infections in the offspring of African American (AA) and non-AA women. We used medical records to record frequency and type of infections during the first year of life of 220 term infants (69 AA, 151 non-AA) whose mothers participated in the Kansas University DHA Outcomes Study. AA and non-AA groups were compared for maternal 25(OH)D by Mann–Whitney U-test. Compared to non-AA women, AA women were more likely to be vitamin D deficient (<50 nmol/L; 84 vs. 37%, p < 0.001), and more of their infants had at least one infection in the first 6 months (78.3% and 59.6% of infants, respectively, p = 0.022). We next explored the relationship between maternal plasma 25(OH)D concentration and infant infections using Spearman correlations. Maternal 25(OH)D concentration was inversely correlated with the number of all infections (p = 0.033), eye, ear, nose, and throat (EENT) infections (p = 0.043), and skin infection (p = 0.021) in the first 6 months. A model that included maternal education, income, and 25(OH)D identified maternal education as the only significant predictor of infection risk in the first 6 months (p = 0.045); however, maternal education, income, and 25(OH)D were all significantly lower in AA women compared to non-AA women . The high degree of correlation between these variables does not allow determination of which factor is driving the risk of infection; however, the one that is most easily remediated is vitamin D status. It would be of value to learn if vitamin D supplementation in this at-risk group could ameliorate at least part of the increased infection riskThis work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Development (R01 HD047315 [to SC])the Kansas Intellectual and Developmental Disabilities Research Center (P30 HD002528 [to SC and JC]

A Secondary Analysis of a Randomized Clinical Trial

This work is licensed under a Creative Commons Attribution 4.0 International License.Importance The blood pressure–lowering property of docosahexaenoic acid (DHA) in children and adults is known, and an observational study from the Netherlands has linked higher intrauterine DHA exposure to lower childhood blood pressure. However, the association of prenatal intake of DHA supplement with childhood blood pressure has not been evaluated in randomized clinical trials. Objective To determine the effect of DHA supplementation during pregnancy on childhood blood pressure. Design, Setting, and Participants This prespecified secondary analysis of the Kansas University DHA Outcome Study (KUDOS), a phase 3, double-blind, randomized, placebo-controlled clinical trial was conducted at several local hospitals in the Kansas City, Kansas, metropolitan area. Pregnant women (n = 350) were enrolled in the KUDOS trial between January 10, 2006, and November 17, 2009, and were followed up until their children were 18 months of age. During pregnancy, the women received either 3 capsules per day of placebo or 600 mg per day of DHA from a mean (SD) of 14.5 (3.7) weeks’ (all before 20 weeks) gestation until birth. The parents of 190 children consented to additional follow-up of their children until 6 years, which ended April 29, 2016. Study personnel involved in testing were blind to the randomization until all children had completed the trial. Data analysis was performed from May 23, 2017, to July 10, 2018. Interventions Pregnant women were assigned to either 600 mg per day of DHA or a placebo that was half soy and half corn oil. Both placebo and DHA were provided in 3 capsules per day. Main Outcomes and Measures Childhood blood pressure was a planned secondary outcome of a study powered to measure cognitive development. The hypothesis was that DHA would lower blood pressure prior to data analysis. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured at 4, 4.5, 5, 5.5, and 6 years and were analyzed for possible covariates using mixed models to generate a final model. Results In total, 171 children (88 [51.5%] female) were included in this analysis. Of these children, 89 (52.0%) were randomized to the DHA group and 82 (47.9%) to the placebo group. A statistically significant interaction was found between treatment (placebo or DHA) and child weight status (5-year body mass index ≤85th or >85th percentile) for both SBP and DBP. Children who were overweight or obese whose mothers received placebo during pregnancy had higher SBP and DBP compared with children who were overweight or obese whose mothers received DHA (mean [SE] SBP, 104.28 [1.37] mm Hg vs 100.34 [1.02] mm Hg; DBP, 64.7 [1.23] mm Hg vs 59.76 [0.91] mm Hg). No differences in the SBP and DBP were found between children who were overweight or obese whose mothers received DHA and children who were not overweight or obese. In the mixed model analysis, the child’s age at blood pressure measurement and the maternal prepregnancy body mass index were the only other statistically significant variables (child age, SBP: F = 7.385; P = .001; DBP: F = 7.39; P = .001; prepregnancy BMI, SBP: r = 0.284; P = .001; DBP: r = 0.216; P = .01). Conclusions and Relevance Maternal docosahexaenoic acid intake during pregnancy appeared to mitigate the association between childhood overweight condition or obesity and blood pressure

Potential Role of Platelet-Derived Growth Factor Receptor Inhibition Using Imatinib in Combination with Docetaxel in the Treatment of Recurrent Non-small Cell Lung Cancer

Introduction:Platelet-derived growth factor receptor (PDGFR) is expressed in lung cancer and is involved in angiogenesis. Preclinical models demonstrated that imatinib (Im) regulates angiogenesis through PDGFR inhibition and enhances efficacy of chemotherapy. Hypothesis: We hypothesized that Im plus docetaxel (D) would have a synergistic effect detectable by an increase in response rate in patients with recurrent non-small cell lung cancer (NSCLC).Methods:A phase II trial to evaluate Im in combination with D in patients with recurrent NSCLC was conducted. The primary end point was response rate, using a Simon two-stage design. Eligible patients had measurable disease and no more than two chemotherapy regimens. D was given at 30 mg/m2/wk intravenously ×3 every 4 weeks and oral Im at 600 mg daily for four cycles. Patients required two cycles to be evaluable for response. Nonprogressors after four cycles continued with Im maintenance until progression or for a total of 12 months.Results:Twenty-three patients were enrolled in the first stage. Toxicity was mainly nonhematologic. We observed one partial response (5.5%), four stable disease (22.2%), and 13 progressed (72.2%). Median time to progression was 1.9 months, and median overall survival was 6.1 months. Two patients who went on Im maintenance had time to progression of 7.78 months and 15.8 months.Conclusion:Im in combination with D did not achieve its primary objective of improving response rate in patients with recurrent NSCLC. An increased understanding of the complex PDGFR pathway in lung cancer and alternative strategies to inhibit it are needed

Multidisciplinary Group Clinic Appointments: The Self-Management and Care of Heart Failure (SMAC-HF) Trial

Background—This trial tested the effects of multidisciplinary group clinic appointments on the primary outcome of time to first heart failure (HF) rehospitalization or death. Methods and Results—HF patients (n=198) were randomly assigned to standard care or standard care plus multidisciplinary group clinics. The group intervention consisted of 4 weekly clinic appointments and 1 booster clinic at month 6, where multidisciplinary professionals engaged patients in HF self-management skills. Data were collected prospectively for 12 months beginning after completion of the first 4 group clinic appointments (2 months post randomization). The intervention was associated with greater adherence to recommended vasodilators (P=0.04). The primary outcome (first HF-related hospitalization or death) was experienced by 22 (24%) in the intervention group and 30 (28%) in standard care. The total HF-related hospitalizations, including repeat hospitalizations after the first time, were 28 in the intervention group and 45 among those receiving standard care. The effects of treatment on rehospitalization varied significantly over time. From 2 to 7 months post randomization, there was a significantly longer hospitalization-free time in the intervention group (Cox proportional hazard ratio=0.45 (95% confidence interval, 0.21–0.98; P=0.04). No significant difference between groups was found from month 8 to 12 (hazard ratio=1.7; 95% confidence interval, 0.7–4.1). Conclusions—Multidisciplinary group clinic appointments were associated with greater adherence to selected HF medications and longer hospitalization-free survival during the time that the intervention was underway. Larger studies will be needed to confirm the benefits seen in this trial and identify methods to sustain these benefits

Optimizing Retrieval of Biospecimens Using the Curated Cancer Clinical Outcomes Database (C3OD)

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.To fully support their role in translational and personalized medicine, biorepositories and biobanks must continue to advance the annotation of their biospecimens with robust clinical and laboratory data. Translational research and personalized medicine require well-documented and up-to-date information, but the infrastructure used to support biorepositories and biobanks can easily be out of sync with the host institution. To assist researchers and provide them with accurate pathological, epidemiological, and bio-molecular data, the Biospecimen Repository Core Facility (BRCF) at the University of Kansas Medical Center (KUMC) merges data from medical records, the tumor registry, and pathology reports using the Curated Cancer Clinical Outcomes Database (C3OD). In this report, we describe the utilization of C3OD to optimally retrieve and dispense biospecimen samples using these 3 data sources and demonstrate how C3OD greatly increases the efficiency of obtaining biospecimen samples for the researchers.National Cancer Institute (NCI) Cancer Center Support Grant P30 CA168524Biostatistics and Informatics Shared Resource (BISR)Biospecimen Shared Resource (BSR

Long-Lived Plasma Cells in Mice and Men

Even though more than 30 years have passed since the eradication of smallpox, high titers of smallpox-specific antibodies are still detected in the blood of subjects vaccinated in childhood. In fact, smallpox-specific antibody levels are maintained in serum for more than 70 years. The generation of life-long immunity against infectious diseases such as smallpox and measles has been thoroughly documented. Although the mechanisms behind high persisting antibody titers in the absence of the causative agent are still unclear, long lived plasma cells (LLPCs) play an important role. Most of the current knowledge on LLPCs is based on experiments performed in mouse models, although the amount of data derived from human studies is increasing. As the results from mouse models are often directly extrapolated to humans, it is important to keep in mind that there are differences. These are not only the obvious such as the life span but there are also anatomical differences, for instance the adiposity of the bone marrow (BM) where LLPCs reside. Whether these differences have an effect on the function of the immune system, and in particular on LLPCs, are still unknown. In this review, we will briefly discuss current knowledge of LLPCs, comparing mice and humans

Adjacent thoracic lymph node metastases originating from two separate primary cancers: case report

Reported is an unusual case of adjacent thoracic lymph nodes demonstrating metastases from two different primary malignancies. A 51 year-old woman with a previous history of bilateral breast cancer underwent a radical gastro-oesophagectomy for adenocarcinoma of the lower third of the oesophagus. The resection specimen demonstrated breast and oesophageal metastases in adjacent thoracic lymph nodes. Mechanisms for this phenomenon, including the known local immune suppression on lymphoid cells by oesophageal carcinoma cells, are discussed