Detection of spontaneous CD4+ T-cell responses in melanoma patients against a tyrosinase-related protein-2-derived epitope identified in HLA-DRB1*0301 transgenic mice.

PURPOSE: The frequently expressed differentiation antigen tyrosinase-related protein-2 (TRP-2) has repeatedly been described as a target of spontaneous cytotoxic T-cell responses in melanoma patients, suggesting that it might be an ideal candidate antigen for T cell-based immunotherapy. As a prerequisite for immunization, T-cell epitopes have to be identified. Whereas a number of HLA class I-presented TRP-2-derived epitopes are known, information about HLA class II-presented antigenic ligands recognized by CD4+ T helper (Th) cells is limited. EXPERIMENTAL DESIGN: The search for TRP-2-derived Th epitopes was carried out by competitive in vitro peptide binding studies with predicted HLA-DRB1*0301 ligands in combination with peptide and protein immunizations of HLA-DRB1*0301 transgenic mice. In vivo selected candidate epitopes were subsequently verified for their immunogenicity in human T-cell cultures. RESULTS: This strategy led to the characterization of TRP-2(60-74) as an HLA-DRB1*0301-restricted Th epitope. Importantly, TRP-2(60-74)-reactive human CD4+ Th cell lines, specifically recognizing target cells loaded with recombinant TRP-2 protein, could be established by repeated peptide stimulation of peripheral blood lymphocytes from several HLA-DRB1*03+ melanoma patients. Even short-term peptide stimulation of patients' peripheral blood lymphocytes showed the presence of TRP-2(60-74)-reactive T cells, suggesting that these T cells were already activated in vivo. CONCLUSION: Peptide TRP-2(60-74) might be a useful tool for the improvement of immunotherapy and immune monitoring of melanoma patients.     

How Does the Gus Schumacher Nutrition Incentive Program Work? A Theory of Change

Increased fruit and vegetable (FV) intake is associated with decreased risk of nutrition-related chronic diseases. Sociodemographic disparities in FV intake indicate the need for strategies that promote equitable access to FVs. The United States Department of Agriculture’s Gus Schumacher Nutrition Incentive Program (GusNIP) supports state and local programs that offer nutrition incentives (NIs) that subsidize purchase of FVs for people participating in the Supplemental Nutrition Assistance Program (SNAP). While a growing body of research indicates NIs are effective, the pathways through which GusNIP achieves its results have not been adequately described. We used an equity-focused, participatory process to develop a retrospective Theory of Change (TOC) to address this gap. We reviewed key program documents; conducted a targeted NI literature review; and engaged GusNIP partners, practitioners, and participants through interviews, workshops, and focus groups in TOC development. The resulting TOC describes how GusNIP achieves its long-term outcomes of increased participant FV purchases and intake and food security and community economic benefits. GusNIP provides NIs and promotes their use, helps local food retailers develop the capacity to sell FVs and accept NIs in accessible and welcoming venues, and supports local farmers to supply FVs to food retailers. The TOC is a framework for understanding how GusNIP works and a tool for improving and expanding the program.     

Circulating tumor DNA predicts efficacy of a dual AKT/p70S6K inhibitor (LY2780301) plus paclitaxel in metastatic breast cancer: plasma analysis of the TAKTIC phase IB/II study

The phosphatidylinositol‐3‐kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently activated in HER2‐negative breast cancer and may play a role in taxane resistance. The phase IB/II TAKTIC trial ({"type":"clinical-trial","attrs":{"text":"NCT01980277","term_id":"NCT01980277"}}NCT01980277) has shown that combining a dual AKT and p70 ribosomal protein S6 kinase (p70S6K) inhibitor (LY2780301) taken orally with weekly paclitaxel in HER2‐negative advanced breast cancer is feasible, with preliminary evidence of efficacy. We wanted to explore whether circulating tumor DNA (ctDNA) may be a surrogate marker of treatment efficacy in this setting. Serial plasma samples were collected and cell‐free DNA was sequenced using low‐coverage whole‐genome sequencing, and analysis was completed with droplet digital polymerase chain reaction (PCR) for some patients with driver mutations. Baseline tumor fraction (TF) and TF after 7 weeks on treatment were compared to progression‐free survival (PFS) and the overall response rate. We also explored circulating copy number alterations associated with treatment failure. Of the 51 patients enrolled in the TAKTIC trial, at least one plasma sample was available for 44 cases (96 timepoints). All patients with tumor TP53, PI3KCA, or AKT1 mutations harbored at least one of these alterations in plasma. TF at inclusion was correlated with PFS (6m‐PFS was 92% for ctDNAneg patients vs 68% for ctDNApos cases; hazard ratio [HR] = 3.45, 95% confidence interval [CI] [1.34–8.90], P = 0.007). ctDNA status at week 7 was not correlated with prognosis. Even though most circulating copy number alterations were conserved at disease progression, some genomic regions of interest were altered in post‐progression samples. In conclusion, ctDNA detection at baseline was associated with shorter PFS in patients included in the TAKTIC trial. Plasma‐based copy number analysis may help to identify alterations involved in resistance to treatment.     

Mechanisms behind flare of renal lupus during murine pregnancy

The outcome of pregnancy in systemic lupus erythematosus is still controversial. The authors recently reported the disappearance of the manifestation of the skin disease but a diminished survival rate in lupus-prone animals undergoing several pregnancies. It was postulated that lupus-prone animals must have subclinical renal symptoms at an early age and that immune and hormonal changes during pregnancy exacerbate immune reactions in the kidneys, leading to a shortened life span. Here, the authors analysed changes at day 14 of pregnancy in lupus-prone LPR (MRL/lpr) mice and MRL controls regarding cytokines, regulatory T (Treg) cells and deposition of immunocomplexes. Worsened kidney function was observed during pregnancy, even in the absence of lupus signs. This was accompanied by renal inflammation and higher interferon-gamma and interleukin-10 levels. C3 and immunoglobulin G deposition was enhanced in kidney and placenta from lupus-prone pregnant animals. Pregnancy enhanced the levels of Treg cells in control animals but not in lupus-prone animals. As pregnancy-induced Treg cells were shown to be specific for paternal antigens it is not to be expected that these Treg cells can help to destroy autoreactive cells. The authors conclude that early subclinical kidney disease in lupus-prone animals exacerbates during pregnancy. Albeit obtained with an experimental animal model, their data are potentially of importance for lupus patients of reproductive age.     

To the point: medical education reviews--providing feedback

Formative feedback is an essential component of effective teaching and learning. Without it, the learner flounders. Furthermore, the Liaison Committee on Medical Education requires formative feedback within the clerkship and specifies that students must have the time and ability to remediate deficiencies before completing the clerkship. Few articles in the medical literature address how to give effective feedback. However, the themes within these articles are consistent. Formative feedback should be an interactive activity between the teacher and learner. Feedback must be approached with mutual respect and should be provided in a safe environment. Quality feedback is timely, specific to the situation, constructive, based on direct observation and nonjudgmental. With effective feedback, learners (and teachers) can discover what to improve, as well as which behaviors and skills to reinforce and augment. Learners appreciate and request specific feedback. In addition, learners tend to rate teachers who provide feedback more highly than they rate teachers who do not provide feedback. This article in the "To the Point" series will focus on the components of effective feedback and provide a practical and effective approach to giving feedback.     

Weibliches Genitale

Ohne Zusammenfassung     

Syphilis. Therapie

Ohne Zusammenfassung     

Syphilis. Symptomatologie

Ohne Zusammenfassung