Association between high-dose erythropoiesis-stimulating agents, inflammatory biomarkers, and soluble erythropoietin receptors

<p>Abstract</p> <p>Background</p> <p>High-dose erythropoiesis-stimulating agents (ESA) for anemia of chronic kidney disease (CKD) have been associated with adverse clinical outcomes and do not always improve erythropoiesis. We hypothesized that high-dose ESA requirement would be associated with elevated inflammatory biomarkers, decreased adipokines, and increased circulating, endogenous soluble erythropoietin receptors (sEpoR).</p> <p>Methods</p> <p>A cross-sectional cohort of anemic 32 CKD participants receiving ESA were enrolled at a single center and cytokine profiles, adipokines, and sEpoR were compared between participants stratified by ESA dose requirement (usual-dose darbepoetin-α (< 1 μg/kg/week) and high-dose (≥1 μg/kg/week)).</p> <p>Results</p> <p>Baseline characteristics were similar between groups; however, hemoglobin was lower among participants on high-dose (1.4 μg/kg/week) vs usual-dose (0.5 μg/kg/week) ESA.</p> <p>In adjusted analyses, high-dose ESA was associated with an increased odds for elevations in c-reactive protein and interleukin-6 (p < 0.05 for both). There was no correlation between high-dose ESA and adipokines. Higher ESA dose correlated with higher levels of sEpoR (r_s= 0.39, p = 0.03). In adjusted analyses, higher ESA dose (per μcg/kg/week) was associated with a 53% greater odds of sEpoR being above the median (p < 0.05).</p> <p>Conclusion</p> <p>High-dose ESA requirement among anemic CKD participants was associated with elevated inflammatory biomarkers and higher levels of circulating sEpoR, an inhibitor of erythropoiesis. Further research confirming these findings is warranted.</p> <p>Trial registration</p> <p>Clinicaltrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00526747">NCT00526747</a></p

Differential impact of LPG-and PG-deficient Leishmania major mutants on the immune response of human dendritic cells

<div><p>Background</p><p><i>Leishmania major</i> infection induces robust interleukin-12 (IL12) production in human dendritic cells (hDC), ultimately resulting in Th1-mediated immunity and clinical resolution. The surface of <i>Leishmania</i> parasites is covered in a dense glycocalyx consisting of primarily lipophosphoglycan (LPG) and other phosphoglycan-containing molecules (PGs), making these glycoconjugates the likely pathogen-associated molecular patterns (PAMPS) responsible for IL12 induction.</p><p>Methodology/Principal Findings</p><p>Here we explored the role of parasite glycoconjugates on the hDC IL12 response by generating <i>L</i>. <i>major</i> Friedlin V1 mutants defective in LPG alone, (FV1 <i>lpg1-</i>), or generally deficient for all PGs, (FV1 <i>lpg2-</i>). Infection with metacyclic, infective stage, <i>L</i>. <i>major</i> or purified LPG induced high levels of <i>IL12B</i> subunit gene transcripts in hDCs, which was abrogated with FV1 <i>lpg1-</i> infections. In contrast, hDC infections with FV1 <i>lpg2-</i> displayed increased <i>IL12B</i> expression, suggesting other PG-related/<i>LPG2</i> dependent molecules may act to dampen the immune response. Global transcriptional profiling comparing WT, FV1 <i>lpg1-</i>, FV1 <i>lpg2-</i> infections revealed that FV1 <i>lpg1-</i> mutants entered hDCs in a silent fashion as indicated by repression of gene expression. Transcription factor binding site analysis suggests that LPG recognition by hDCs induces IL-12 in a signaling cascade resulting in Nuclear Factor κ B (NFκB) and Interferon Regulatory Factor (IRF) mediated transcription.</p><p>Conclusions/Significance</p><p>These data suggest that <i>L</i>. <i>major</i> LPG is a major PAMP recognized by hDC to induce IL12-mediated protective immunity and that there is a complex interplay between PG-baring <i>Leishmania</i> surface glycoconjugates that result in modulation of host cellular IL12.</p></div

The Adventures of ScriptKitty: Teaching middle school students cyber awareness with comics on the Raspberry Pi

Cyber security and on-line safety practices are not commonly taught in schools. However, there is an increasing need for education in these topics as children are joining the Internet community at a much earlier age than previous generations. It is crucial that young people understand the risks they may face on-line and how to mitigate them, ideally as soon as they begin using the Internet unsupervised. The Adventures of ScriptKitty (AOSK) introduces students to basic cyber security concepts using the Raspberry Pi, a single board computer that retails for $35.00. We created AOSK to help facilitate a culture of good cyber security practices and raise interest in STEM. The material is presented in the form of comics paired with instructional sections, including sections of more detailed technical information for readers who wish to learn more about key concepts. We piloted a portion of AOSK to a group of local middle school students. Our time with the students was limited, so we administered a short quiz, then discussed the Raspberry Pi. Next, students completed the packet sniffing exercise from Chapter 2, with the authors available to answer questions and help troubleshoot. Students were asked to re-take the quiz afterward. Our preliminary results show that students achieved a greater understanding of the material, with improved scores of 14%. A custom Pi image preloaded with Kali Linux and all needed software is included with the material. All the materials are published and available for free through GitBook at: https://suzannejmatthews.gitbooks.io/aosk/conten

Lessons from the ReMail prototypes

Electronic mail has become the most widely-used application for business productivity and communication, yet many people are frustrated with their email. Though email usage has changed, our email clients largely have not. In this paper, we describe a prototype email client developed out of a multi-year iterative design process aimed at providing those who “live in their email” with an improved, integrated email experience. We highlight innovative features and describe the user trials for each version of the prototype with resulting modifications. Finally, we discuss how these studies have recast our understanding of the email “habitat ” and user needs

Epstein–Barr virus-encoded LMP2A regulates viral and cellular gene expression by modulation of the NF-κB transcription factor pathway

Epstein–Barr virus (EBV)-associated malignancies display distinct patterns of virus latent gene expression that reflect the complex interplay between the virus and its host cell. In the EBV-associated epithelial tumor nasopharyngeal carcinoma (NPC), the virus-encoded latent membrane protein LMP2A is consistently expressed whereas the oncogenic LMP1 protein appears to be restricted to only a proportion of tumors. In an attempt to understand the contribution of LMP2A to the pathogenesis of NPC, we established carcinoma cell lines stably infected in vitro with either a wild-type recombinant EBV (rEBV) or a mutant rEBV in which LMP2A is deleted (rEBV-2A). An NPC-like pattern of EBV gene expression including LMP2A but not LMP1 was consistently observed in carcinoma cells infected with rEBV. However, carcinoma cells infected with rEBV-2A expressed high levels of LMP1 from the signal transducer and activator of transcription (STAT)-regulated L1-TR promoter. Consistent with this effect, basal STAT activity was reduced in rEBV-infected carcinoma cells, and this repression was relieved in the absence of LMP2A. This modulation of STAT activity correlated with the ability of LMP2A to inhibit the autocrine secretion of IL-6 from carcinoma cell lines. Exogenous IL-6 was able to induce expression of LMP1 by means of STAT3 activation both in rEBV-infected carcinoma cell lines and in the EBV-positive C666-1 NPC cell line. The LMP2A-mediated suppression of IL-6 was a consequence of NF-κB inhibition. These data reveal that LMP2A modulates two key transcription factor pathways in carcinoma cells and suggest that this finding may be important in the pathogenesis of EBV-associated tumors

Influence of radiation therapy parameters on outcome in children treated with radiation therapy for localized parameningeal rhabdomyosarcoma in Intergroup Rhabdomyosarcoma Study Group trials II through IV

PURPOSE: To evaluate the impact of radiation treatment parameters on cancer control outcomes for children with parameningeal rhabdomyosarcoma (PM-RMS) treated on Intergroup Rhabdomyosarcoma Study Group protocols II through IV (including IRS-IV pilot). MATERIALS AND METHODS: Radiation therapy (RT) treatment quality was assessed by contemporary review of portal radiographs, simulation films, treatment plans, and, in most cases, cross-sectional diagnostic imaging data for patients treated on Intergroup Rhabdomyosarcoma Study Group protocols II through IV. Five hundred ninety-five patients with PM-RMS were registered on these 4 studies between 1978 and 1997. Most of these patients (95%) had Group III disease. Radiation doses varied over the span of these trials with protocol doses ranging from 40 Gy to 50.4 Gy on IRS-II and IRS-III and 50.4 Gy to 59.4 Gy (hyperfractionated) on IRS-IV pilot and IRS-IV. Patients with high-risk signs of meningeal impingement, including cranial nerve palsy (CNP) or cranial base bone erosion (CBBE) with or without intracranial extension (ICE), were required to start radiotherapy at the time of study entry (Day 0). Among 595 patients reviewed, 385 (65%) had diagnostic images submitted to the Quality Assurance Review Center for assessment of target volume coverage. Only 123 (21%) patients, 49 (40%) of whom were treated on IRS-II, received whole brain RT. RESULTS: The estimated overall survival and failure-free survival rates were 73% and 69% at 5 years, respectively. The estimated 5-year local failure (LF) rate was 17%. The detection of ICE increased from 24% to 41% as more cross-sectional diagnostic images became available. For patients with any sign of meningeal impingement, starting RT (n = 315) had 18% LF compared to 33% LF if started \u3e2 weeks after diagnosis (n = 43) (p = 0.03). For patients with ICE, starting RT (n = 177) resulted in LF in 16% compared to 37% among those who started \u3e2 weeks after (n = 19) (p = 0.07). For patients with CNP and/or CBBE, starting RT (n = 138) resulted in 21% LF compared to 30% among those that started \u3e2 weeks (n = 23) (p = 0.23). In none of these circumstances was the 5-year failure-free survival significantly impacted by this increase in LF. The estimated 3-year survival after local failure was 17% (95% CI, 10%-25%). For patients without signs of meningeal impingement, there was no difference in local control whether they started radiation therapy earlier or later than 10 weeks. Patients with large (\u3e or =5 cm) Group III tumors had an LF rate of 35% if they received less than 47.5 Gy compared to an LF rate of 18% in patients who received less than 47.5 Gy with smaller tumors or a rate of 15% if they received more than 47.5 Gy, irrespective of tumor size (p = 0.14). There was no evidence that whole brain radiation therapy affected LF or reduced central nervous system (CNS) relapse. Multivariate analysis of RT parameters and clinical factors demonstrated that a radiation dose of \u3e47.5 Gy was associated with lower LF. The presence of ICE, CNP, or CBBE and age \u3e10 years at diagnosis were significantly associated with higher rates of local failure. CONCLUSIONS: The availability of cross-sectional diagnostic images (CT or MRI) has improved detection of ICE. Starting radiation therapy within 2 weeks of diagnosis for patients with signs of meningeal impingement was associated with lower rates of local failure. When no signs of meningeal impingement were present, delay of radiation therapy for more than 10 weeks did not impact local failure rates. Whole brain radiation therapy is unnecessary in PM-RMS. A dose of at least 47.5 Gy seems to be associated with lower rates of local failure, especially when tumor diameter is \u3e or =5 cm

Gender Imbalance in U.S. Geoscience Academia

Geoscientists explain women’s under-representation in our field along three dominant themes: the structure of academia, historically low numbers of women, and women’s views and choices. Which factor they perceive as most important depends overwhelmingly on their gender

Influence of noncompliance with radiation therapy protocol guidelines and operative bed recurrences for children with rhabdomyosarcoma and microscopic residual disease: a report from the Children\u27s Oncology Group

PURPOSE: Postoperative radiation therapy (RT) is recommended for patients with rhabdomyosarcoma having microscopic disease. Sometimes RT dose/volume is reduced or omitted in an attempt to avoid late effects, particularly in young children. We reviewed operative bed recurrences to determine if noncompliance with RT protocol guidelines influenced local-regional control. METHODS AND MATERIALS: All operative bed recurrences among 695 Group II rhabdomyosarcoma patients in Intergroup Rhabdomyosarcoma Study Group (IRS) I through IV were reviewed for deviation from RT protocol. Major/minor dose deviation was defined as \u3e10% or 6-10% of the prescribed dose (40-60 Gy), respectively. Major/minor volume deviation was defined as tumor excluded from the RT field or treatment volume not covered by the specified margin (preoperative tumor volume and 2- to 5-cm margin), respectively. No RT was a major deviation. RESULTS: Forty-six of 83 (55%) patients with operative bed recurrences did not receive the intended RT (39 major and 7 minor deviations). RT omission was the most frequent RT protocol deviation (19/46, 41%), followed by dose (17/46, 37%), volume (9/46, 20%), and dose and volume deviation (1/46, 2%). Only 7 operative bed recurrences occurred in IRS IV (5% local-regional failure) with only 3 RT protocol deviations. Sixty-three (76%) patients with recurrence died of disease despite retrieval therapy, including 13 of 19 nonirradiated children. CONCLUSION: Over half of the operative bed recurrences were associated with noncompliance; omission of RT was the most common protocol deviation. Three fourths of children die when local-regional disease is not controlled, emphasizing the importance of RT in Group II rhabdomyosarcoma