Here we report the NMR structure of the actin-binding domain contained in the cell adhesion protein palladin. Previously we demonstrated that one of the immunoglobulin domains of palladin (Ig3) is both necessary and sufficient for direct F-actin binding in vitro. In this study, we identify two basic patches on opposite faces of Ig3 that are critical for actin binding and crosslinking. Sedimentation equilibrium assays indicate that the Ig3 domain of palladin does not self-associate. These combined data are consistent with an actin crosslinking mechanism that involves concurrent attachment of two actin filaments by a single palladin molecule by an electrostatic mechanism. Palladin mutations that disrupt actin binding show altered cellular distributions and morphology of actin in cells, revealing a functional requirement for the interaction between palladin and actin in vivo.
BACKGROUND Gut microbial diversity is associated with improved response to immune checkpoint inhibitors (ICI). Based on the known detrimental impact that antibiotics have on microbiome diversity, we hypothesized that antibiotic receipt prior to ICI would be associated with decreased survival. METHODS Patients with stage III and IV melanoma treated with ICI between 2008 and 2019 were selected from an institutional database. A window of antibiotic receipt within 3 months prior to the first infusion of ICI was pre-specified. The primary outcome was overall survival (OS) and secondary outcomes were melanoma-specific mortality and immune-mediated colitis requiring intravenous (IV) steroids. All statistical tests were two-sided. RESULTS There were 568 patients in our database, of which 114 received antibiotics prior to ICI. 35.9% of patients had stage III disease. On multivariable Cox proportional hazards analysis of patients with stage IV disease, the antibiotic-exposed group had statistically significantly worse OS (hazard ratio [HR] 1.81, 95% confidence interval [CI] 1.27-2.57, p<.001). The same effect was observed among antibiotic-exposed patients with stage III disease (HR 2.78, 95% CI 1.31-5.87, p=.007). When limited to only patients who received adjuvant ICI (N = 89), antibiotic-exposed patients also had statistically significantly worse OS (HR 4.84, 95% CI 1.09-21.50, p=.04). The antibiotic group had a greater incidence of colitis (HR 2.14, 95% CI 1.02-4.52, p=.046). CONCLUSION Patients with stage III and IV melanoma exposed to antibiotics prior to ICI had statistically significantly worse OS than unexposed patients. Antibiotic exposure was associated with greater incidence of moderate to severe immune-mediated colitis. Given the large number of antibiotics prescribed annually, physicians should be judicious with their use in cancer populations likely to receive ICI.
King SL, Mohiuddin JJ, Dekaney CM. Paneth cells expand from newly created and preexisting cells during repair after doxorubicin-induced damage. Am J Physiol Gastrointest Liver Physiol 305: G151-G162, 2013. First published May 9, 2013 doi:10.1152/ajpgi.00441.2012.-Paneth cell numbers increase following intestinal damage, but mechanisms driving this process are not understood. We hypothesized that the increase in Paneth cell numbers is due to recruitment of cells from a preexisting pool of secretory progenitors. Mice were given a single injection of doxorubicin (Dox), and intestinal tissue was collected 0 -168 h after treatment. Paneth, goblet, and intermediate cells were counted and evaluated for cell morphology. Quantitative RT-PCR was used to measure expression of various genes associated with Paneth cell allocation and maturation. Paneth cells were birth dated using incorporation of thymidine analogs given before or after Dox. Staining revealed "intermediate" cells, which were rarely observed in control crypts but increased significantly in number 96 and 120 h after Dox treatment. Birth dating of intermediate cells 5 days after Dox treatment revealed that 24% of these cells took up thymidine analog given prior to Dox treatment and 36% took up thymidine analog given after Dox treatment. Quantitative RT-PCR demonstrated a significant increase in Spdef, Atoh1, Sox9, EphB3, Mist, Wnt5a, FGF-9, and FGF-18 mRNAs and a significant decrease in Indian hedgehog mRNA. Expansion of the Paneth cell compartment after Dox treatment is due to generation of new cells and recruitment of cells from an existing pool. These cells express Paneth and goblet biomarkers and are found only during repair. Expansion of these cells correlates temporally with reduced Indian hedgehog and increased FGF and Wnt mRNA. These findings are significant, as they provide a first step in understanding mechanisms of Paneth cell expansion during mucosal repair. Paneth cell; doxorubicin; intermediate cell PANETH CELLS ARE ONE OF FOUR differentiated cell lineages that arise from intestinal stem cells (ISC), and unlike the other three cell lineages found in small intestinal epithelium, they migrate toward and reside in the base of intestinal crypts (5, 6). Paneth cells are part of the innate mucosal immune system in the intestine and protect against microbial infection and overgrowth. Antimicrobial peptides, including cryptdins (␣-defensins), lysozyme, secretory phospholipase A 2 , and matrilysin [matrix metalloproteinase 7 (MMP-7)], are secreted from granules localized to the apical membrane of Paneth cells upon bacterial stimulation (2,25). At the crypt base, Paneth cells are adjacent to and intercalated among ISC and are, therefore, in an advantageous position to influence the stem cell microenvironment (5, 6). In addition to secreting numerous antimicrobial factors, Paneth cells synthesize and secrete factors that are capable of influencing proliferation and migration of intestinal epithelial cells, including EGF, granulocyte-macrophage colony-stimul...
BACKGROUND Stereotactic body radiotherapy (SBRT) is a newer treatment option for patients with localized prostate cancer. The rates of diffusion of this technology across the United States are unknown. The goal of the current study was to describe the use of SBRT among patients with prostate cancer based on different risk groups (low, intermediate, or high risk) and by type of facility (community cancer program, comprehensive community cancer program, or academic program) in which patients were treated. METHODS Using the National Cancer Data Base, a national registry that contains approximately 70% of patients with cancer in the United States, the authors identified 274,466 men between the ages of 40 to 80 years who were diagnosed from 2004 to 2012 with localized prostate cancer and received radiation therapy (RT) as their initial treatment. The authors described the prevalence of SBRT use each year, and multivariable analysis was used to examine factors associated with the receipt of SBRT. RESULTS In 2004, SBRT use was low (<1% in all patient groups), and was observed to increase steadily each year. By 2012, 8.8% of low‐risk patients treated at academic centers with RT received SBRT. Uptake of SBRT was highest in patients with low‐risk or intermediate‐risk disease. Multivariable analysis demonstrated that year of diagnosis, type of center, risk group, and race were all significantly associated with the use of SBRT. CONCLUSIONS To the authors' knowledge, the current study is the first report of the adoption of SBRT for localized prostate cancer across the United States. Diffusion was noted to be slowest at community cancer programs, reflecting potential barriers of cost or expertise for this new technology. Adoption of SBRT was found to be highest among patients with low‐risk or intermediate‐risk disease, in accordance with the bulk of patients included in published SBRT studies. Cancer 2016;122:2234–41. © 2016 American Cancer Society.
Background Multiple clinical trials have shown that neoadjuvant systemic therapy has a benefit in women who are borderline lumpectomy candidates and in those with locally-advanced breast cancers by reducing the mastectomy rate and making inoperable tumors operable. The study aim was to examine the patterns of neoadjuvant chemotherapy and endocrine therapy use among younger women in the US treated at different types of cancer centers. Study Design Data from the National Cancer Data Base for 118,086 women younger than 65 with clinical stage IIA (T2N0 only) to IIIC breast cancer. Following the National Comprehensive Cancer Network guideline categorization, patients were grouped into those who were borderline lumpectomy candidates (clinical stage IIA [T2N0 only], IIB, or IIIA [T3N1 only]) or those with locally-advanced disease (clinical stage IIIA [T0-3N2 only], IIIB, or IIIC). The main outcome was the proportion of women who received neoadjuvant systemic therapy. Results Use of neoadjuvant chemotherapy ranged from 17% (stage IIA) to 79% (stage IIIB). Across almost all stage and receptor subtypes, the use was lower in community vs. academic centers. On multivariable analysis, use of neoadjuvant chemotherapy was decreased in community vs. academic centers (borderline lumpectomy candidates, aRR 0.73, 95% CI 0.69–0.77; locally-advanced disease, aRR 0.78, 95% CI 0.74–0.83). Conclusions Use of guideline-concordant neoadjuvant chemotherapy is significantly higher among women treated at academic vs. community centers in young and healthy women who do not commonly have contraindications to this treatment. Our study identified a potential disparity in cancer care by type of center where patients receive treatment.
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