Prognostic and Predictive Biomarkers in Breast Cancer: Past, Present and Future

Publication date: Available online 4 September 2017
Source:Seminars in Cancer Biology
Author(s): Andrea Nicolini, Paola Ferrari, Michael J. Duffy
Following a diagnosis of breast cancer, the most immediate challenges in patient management are the determination of prognosis and identification of the most appropriate adjuvant systemic therapy. Determining prognosis can best be addressed with a combination of traditional clinicopathological prognostic factors, biomarkers such as HER2/neu and specific multigene genes tests. Amongst the best validated prognostic multigene tests are uPA/PAI1, Oncotype DX and MammaPrint. Oncotype DX and MammaPrint, may be used for predicting outcome and aiding adjunct therapy decision making in patients with ER-positive, HER2-negative breast cancers that are either lymph node-negative or node positive (1-3 metastatic nodes), while uPA/PAI-1 may be similarly used in ER-positive, lymph node-negative patients. For selecting likely response to endocrine therapy, both estrogen receptors (ER) and progesterone receptors (PR) should be measured. On the other hand, for identifying likely response to anti-HER2 therapy, determination of HER2 gene amplification or overexpression is necessary. To identify new prognostic and predictive biomarkers for breast cancer, current research is focusing on tumor and circulating DNA (ctDNA) and RNA (e.g., micro RNAs) and circulating tumor cells. A promising ctDNA biomarker is the mutational status of ER (ESR1) for predicting the emergence of resistance to aromatase inhibitors. Challenges for future research include the identification of biomarkers for predicting response to radiotherapy and specific forms of chemotherapy.



http://ift.tt/2wCkSov

Deciding on Active Surveillance or Surgery for Primary Management of Low Risk Papillary Thyroid Cancer

Condition:   Thyroid Cancer Stage I
Intervention:  
Sponsors:   University Health Network, Toronto;   Ontario Ministry of Health and Long Term Care;   Canadian Cancer Society Research Institute (CCSRI)
Recruiting - verified August 2017

http://ift.tt/2iZgtap

Breathing-motion-compensated robotic guided stereotactic body radiation therapy

Abstract

Purpose

We retrospectively evaluated the patterns of failure for robotic guided real-time breathing-motion-compensated (BMC) stereotactic body radiation therapy (SBRT) in the treatment of tumors in moving organs.

Patients and methods

Between 2011 and 2016, a total of 198 patients with 280 lung, liver, and abdominal tumors were treated with BMC-SBRT. The median gross tumor volume (GTV) was 12.3 cc (0.1–372.0 cc). Medians of mean GTV BED_{α/β =10  Gy} (BED = biological effective dose) was 148.5 Gy₁₀ (31.5–233.3 Gy₁₀) and prescribed planning target volume (PTV) BED_{α/β =10  Gy} was 89.7 Gy₁₀ (28.8–151.2 Gy₁₀), respectively. We analyzed overall survival (OS) and local control (LC) based on various factors, including BEDs with α/β ratios of 15 Gy (lung metastases), 21 Gy (primary lung tumors), and 27 Gy (liver metastases).

Results

Median follow-up was 10.4 months (2.0–59.0 months). The 2‑year actuarial LC was 100 and 86.4% for primary early and advanced stage lung tumors, respectively, 100% for lung metastases, 82.2% for liver metastases, and 90% for extrapulmonary extrahepatic metastases. The 2‑year OS rate was 47.9% for all patients. In uni- and multivariate analysis, comparatively lower PTV prescription dose (equivalence of 3 × 12–13 Gy) and higher average GTV dose (equivalence of 3 × 18 Gy) to current practice were significantly associated with LC. For OS, Karnofsky performance score (100%), gender (female), and SBRT without simultaneous chemotherapy were significant prognostic factors. Grade 3 side effects were rare (0.5%).

Conclusions

Robotic guided BMC-SBRT can be considered a safe and effective treatment for solid tumors in moving organs. To reach sufficient local control rates, high average GTV doses are necessary. Further prospective studies are warranted to evaluate these points.

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Downregulated expression of miR-223 promotes Toll-like receptor-activated inflammatory responses in macrophages by targeting RhoB

Publication date: November 2017
Source:Molecular Immunology, Volume 91
Author(s): Ningjie Zhang, Liyao Fu, Yanhong Bu, Yao Yao, Yongjun Wang
Toll-like receptors (TLRs) induced-inflammatory response must be tightly regulated to avoid impairment in host itself. Numerous factors have been identified in regulation of TLR-triggered inflammatory response. Among these, microRNAs (miRNAs) are small non-coding RNA molecules which have got much attention. MiR-223, which highly expresses in myeloid cells of the bone marrow, has reported to participate in kinds of inflammatory responses by targeting inflammasome sensor-NLRP3 to repress production of IL-6 and IL-1β, and thus attenuate inflammatory response. However, the function of miR-223 in TLRs-activated inflammatory response of macrophages is not clear. Here we found miR-223 expression is dramatically reduced in macrophages by TLR ligand stimulation (e.g. LPS, CpG and poly (I:C)). The down-regulated miR-223 leads to the increase in the RhoB expression, which induce the activation of NF-κB and MAPK signaling, promoting TNF-α, IL-6 and IL-1β production upon LPS stimulation. In addition, the histone deacetylase inhibitor trichostatin A increased miR-223 expression obviously in TLR-triggered macrophages, which in turn suppressed RhoB expression and downstream IL-6 production, suggesting that the inhibition of miR-223 by histone deacetylation may be involved in the regulation of TLR-activated inflammatory response. Herein, our findings suggest that miR-223-RhoB axis might be a novel target for the treatment of inflammatory diseases.



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Sex and the elderly: Attitudes to long-lived women and men in early Anglo-Saxon England

Publication date: December 2017
Source:Journal of Anthropological Archaeology, Volume 48
Author(s): Christine M. Cave, Marc F. Oxenham
Currently, in the industrialised world, women have a higher life expectancy than men, a pattern often seen in the past as well. However, in Britain, from the Neolithic to medieval period, it has been suggested that men outlived women. One issue with such statistics is that age estimation techniques are often biased, underestimating the age of older individuals, while the oldest individuals in a sample often disappear into catch-all categories such as 50+ years. Here we employ an approach that renders visible the older individuals in three archaeological cemeteries (Great Chesterford; Mill Hill; Worthy Park) to assess gendered longevity and differential mortuary treatment of the elderly in Anglo-Saxon England. We find that women tended to outlive men and while some elderly females were respected in death, others were more likely to receive a non-normative burial than males. Old males tended to receive 'elaborate' burial, and were less likely to receive a deviant burial. It appears that ageing in Anglo-Saxon England was a gendered process, with some older women respected like their male counterparts, while others were possibly perceived less auspiciously.



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Scholar : These new articles for Norwegian Archaeological Review are available online

The online platform for Taylor & Francis Online content New for Norwegian Archaeological Review and online now on Taylor & Francis Online: Discussion The Two Cultures and a World Apart: Archaeology and Science at a New Crossroads Tim Flohr Sørensen Pages: 1-15 | DOI: 10.1080/00293652.2017.1367031 Original Articles Bronze Tooth Pendants from the Late Iron Age: Between Real and Fictional Zooarchaeology Tõnno Jonuks Pages: 1-14 | DOI: 10.1080/00293652.2017.1367838 To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Emotional and behavioural needs in children with specific language impairment and in children with autism spectrum disorder: The importance of pragmatic language impairment

Publication date: November 2017
Source:Research in Developmental Disabilities, Volume 70
Author(s): Wenche Andersen Helland, Turid Helland
BackgroundLanguage problems may negatively affect children's behaviour and have detrimental effects on the development of peer-relations.AimsWe investigated and compared emotional and behavioural profiles in children with SLI and in children with ASD aged 6–15 years and explored to what extent pragmatic language problems contributed to the emotional and behavioural needs (EBN) in these clinical groups.Methods and proceduresThe ASD group consisted of 23 children (19 boys; 4 girls) and the SLI group consisted of 20 children (18 boys; 2 girls). In order to assess EBN and language abilities, the Strength and Difficulties Questionnaire (SDQ) and the Children's Communication Checklist −2 (CCC-2) were filled out by parents.Outcomes and resultsOur main findings were that although EBN was common in both groups; the children in the ASD group were significantly impaired relative to the children in the SLI group. However, in both groups pragmatic language problems were found to be significantly associated with EBN.ImplicationsA comprehensive assessment of EBN as well as pragmatic language abilities should be an integral part of the assessment procedure. Considering the substantial influence of pragmatic language abilities on social function and in resolving interpersonal conflicts with peers further development of therapy plans and interventions targeting pragmatics is strongly needed.



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IFC-EDITORIAL BOARD

Publication date: October 2017
Source:Research in Developmental Disabilities, Volume 69





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The role of physical activity in improving physical fitness in children with intellectual and developmental disabilities

Publication date: October 2017
Source:Research in Developmental Disabilities, Volume 69
Author(s): Kyla Collins, Kerri Staples
BackgroundOne in three children in North America are considered overweight or obese. Children with intellectual and developmental disabilities (IDD) are at an increased risk for obesity than their typically developing peers. Decreased physical activity (PA) and low physical fitness may be contributing factors to this rise in obesity.AimBecause children with IDD are at an increased risk of diseases related to inactivity, it is important to improve health-related physical fitness to complete activities of daily living and improve health.Methods and proceduresThe focus of this research is on improving the performance of physical fitness components through physical activity programming among a group of children with IDD, ages 7–12 years. The Brockport Physical Fitness Test was used assess levels of physical fitness of 35 children with IDD (25 boys, 10 girls) before and after participation in a 10-week program.Outcomes and resultsThe results of paired sampled t-tests showed participation in 15-h PA program can significantly increase aerobic capacity and muscular strength and endurance in children with IDD.Conclusions and implicationsThis study is aimed at understanding the role of PA in helping children with IDD to develop the fitness capacities essential to participation in a wide variety of activities.



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Letter in response to commentary by Small and Cronin

Publication date: 18 September 2017
Source:Vaccine, Volume 35, Issue 39
Author(s): Lisa Grohskopf, Ivo Foppa, Brendan Flannery, Alicia Fry




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Response to letter by Grohskopf et al. in response to commentary by Small and Cronin

Publication date: 18 September 2017
Source:Vaccine, Volume 35, Issue 39
Author(s): Brendan J. Cronin, Parker A. Small




http://ift.tt/2vHFSeM

Editorial Board/Aims and Scope

Publication date: 18 September 2017
Source:Vaccine, Volume 35, Issue 39





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Vaccination coverage among social and healthcare workers in ten countries of Samu-social international sites

Publication date: 18 September 2017
Source:Vaccine, Volume 35, Issue 39
Author(s): Esaie Marshall, Dominique Salmon, Nadia Bousfiha, Yacouba Togola, François Ouedraogo, Maud Santantonio, Coumba Khadidja Dieng, Suzanne Tartière, Xavier Emmanuelli
BackgroundWe aim to determine the vaccination coverage of social and healthcare workers in International sites of Samusocial, providing emergency care to homeless people, and to assess factors associated with having received necessary doses at adulthood.MethodsData on immunization coverage of social and healthcare workers were provided by a cross-sectional survey, conducted from February to April 2015 among 252 Samusocial workers in 10 countries. Vaccination status and characteristics of participants were collected through a self-administered questionnaire. Prevalence rate ratio (PRR) of vaccination status was calculated using Poisson regression models.ResultsAmong 252 Samusocial social and health workers who felt a questionnaire, median age was 39years, 42.1% were female, 88.9% were in contact with homeless beneficiaries (19.1% health workers). Overall, 90.1% of Samusocial staff felt adult vaccinations was useful and 70.2% wished to receive booster doses in future. Vaccination coverage at adulthood was satisfactory for diphtheria and poliomyelitis (96%), but low for influenza (20.8%), meningococcus (50.5%), hepatitis B (56.3%), yellow fever (58.1%), measles (81.3%) and pertussis (90.7%). The main reasons for not having received vaccination booster doses were forgetting the dates of booster doses (38.4%) and not having received the information (13.5%). In adjusted analysis, prevalence of up-to-date for vaccination schedule was 35% higher among health workers than among social workers (aPRR=1.35, 95%CI: 1.01–1.82, P=0.05) and was 56% higher among workers who had a documentary evidence of vaccination than in those who did not (aPRR=1.56, 95%CI: 1.19–2.02, P=0.001).ConclusionsThe Samusocial International workers vaccine coverage at adulthood was insufficient and disparate by region. It is necessary to strengthen the outreach of this staff and increase immunization policy for hepatitis B, diphtheria, tetanus, and measles, as well as for yellow fever, rabies and meningococcal ACYW135 vaccines in at risk regions.



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Ion channel functional protein kinase TRPM7 regulates Mg ions to promote the osteoinduction of human osteoblast via PI3K pathway: In vitro simulation of the bone-repairing effect of Mg-based alloy implant

Publication date: Available online 4 September 2017
Source:Acta Biomaterialia
Author(s): Xiuzhi Zhang, Haiyue Zu, Dewei Zhao, Ke Yang, Simiao Tian, Xiaoming Yu, Faqiang Lu, Baoyi Liu, Xiaobing Yu, Benjie Wang, Wei Wang, Shibo Huang, Yongxuan Wang, Zihua Wang, Zhaodong Zhang
Mg-based alloys, as the potential orthopaedic implant, can self-degrade to avoid second operation for its remove, and enable to promote bone repair; however, the underlying molecular mechanisms remain unclear. In the present study, we examined the effect of Mg ions on osteogenesis, chemotaxis and anti-alkaline stress in hFOB1.19 human osteoblast cells to simulate bone-repairing effect of a biodegradable Mg-based alloy implant in vitro, and explored the regulatory role of the transient receptor potential melastatin 7 (TRPM7)/phosphoinositide 3-kinase (PI3K) signalling pathway in the process of Mg ion-induced bone repair by knockdown of TRPM7 and antagonizing PI3K activity. Results indicate that Mg ions up-regulated the expression of Runx2 and alkaline phosphatase (ALP) through TRPM7/PI3K signalling pathway, which could significantly enhance the osteogenic activity of human osteoblasts. Furthermore, the expression levels of MMP2, MMP9 and vascular endothelial growth factor (VEGF) were increased by TRPM7/PI3K signalling pathway, which recruits osteoblasts from low- to high-Mg ion environments by inducing cell migration. Although an alkaline environment has antibacterial effects, alkaline stress can cause cytotoxicity and induce cell death. Finally, we found that Mg ions could activate PI3K phosphorylation to promote cell growth and survival, protecting cells against the alkaline-stress-induced cytotoxicity caused by the degradation of Mg-based alloy implants. Our study not only revealed the molecular mechanism of Mg in promoting bone repair but also explained the protective effects of Mg ions on osteoblasts in an alkaline environment, which provides a theoretical basis and new directionsfor the application of Mg-based alloy implant material in orthopaedics fixations and osteosarcoma treatment.Statements of SignificanceAs a potential biomaterial for orthopaedic implant, biodegradable magnesium has several advantages including self-degradation and bone repair promotion; however, the underlying mechanisms and effective concentration by which molecular regulates the bone repair remain unclear. The present study revealed that Mg ion and its effective concentration for activating PI3K phosphorylation via TRPM7, which causes three processes affecting bone repair, namely, osteoblast recruitment, osteogenesis and resistance to alkaline stress in human osteoblast. Therefore, our results have provided insight into the underlying molecular biological basis, and guidance for manipulating degradation rate, such as surface modification, of orthopaedic Mg-based implants.

Graphical abstract

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Avoid mitochondrion-toxic antiepileptic drugs in glycine encephalopathy

Publication date: Available online 4 September 2017
Source:Brain and Development
Author(s): Josef Finsterer, Sinda Zarrouk-Mahjoub




http://ift.tt/2gIMtPx

Kritische Betrachtung der Leitlinie der Europäischen Gesellschaft für Neuroonkologie (EANO) zur Diagnostik und Behandlung von adulten astrozytären und oligodendroglialen Gliomen

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Variable domain glycosylation of ACPA-IgG: A missing link in the maturation of the ACPA response?

Publication date: Available online 5 September 2017
Source:Clinical Immunology
Author(s): Ayla C. Kempers, Lise Hafkenscheid, Hans Ulrich Scherer, René E.M. Toes
Anti-citrullinated Protein Antibodies (ACPA) are excellent markers for Rheumatoid arthritis (RA) and are postulated to have a pathogenic role in the disease process. A multistep model for the evolution of the ACPA response in RA was proposed in which an initial break of tolerance causes, as "first hit", "silent" production of ACPA without any clinical symptoms. The model further proposes that the ACPA immune response matures upon a certain (unknown) trigger, a "second hit", which leads to epitope spreading, an increase in ACPA titres and extended isotype usage before clinical RA manifestations. These occurrences are indicative of an expansion of the citrulline-specific B cell response, though ACPA remain of low avidity even in established disease. This persistence of low avidity is puzzling, as the typical signs of maturation of the immune response seem to be uncoupled from the classical process of affinity maturation. In fact, it suggests that B cells expressing ACPA could bypass selection mechanisms that otherwise control the expansion of auto-reactive B cells. In the established, chronic phase, we recently found that ACPA-IgG are extensively glycosylated in the variable (Fab) domain. More than 90% of ACPA-IgG molecules carry Fab glycans that are highly sialylated. This molecular feature is striking and may provide a missing link in our understanding of the maturation of the ACPA immune response. This review, therefore, describes the current knowledge about ACPA Fab glycosylation in the pathogenesis of RA.



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Antibodies targeting BTLA or TIM-3 enhance HIV-1 specific T cell responses in combination with PD-1 blockade

Publication date: Available online 4 September 2017
Source:Clinical Immunology
Author(s): Katharina Grabmeier-Pfistershammer, Carmen Stecher, Markus Zettl, Sandra Rosskopf, Armin Rieger, Gerhard J. Zlabinger, Peter Steinberger
Persistent stimulation with antigens derived from viruses that establish chronic infections or tumour antigens results in the exhaustion of T cells. Coinhibitory receptors like PD-1 and CTLA-4 function as immune checkpoints on exhausted T cells. Blocking these molecules with antibodies improve immunity to cancer cells. Immune checkpoint inhibitors targeting other coinhibitory receptors might have a similar role in improving T cell function and thus also utility in cancer therapy.Using HIV-specific T cells as a model for exhaustion we have evaluated the capacity of antibodies targeting TIM-3, BTLA, CD160, LAG-3 and CTLA-4 alone or in combination with a PD-1 antibody to enhance proliferation and cytokine production in response to Gag and Nef peptides.Antibodies targeting BTLA and TIM-3 enhanced CD8 T cell proliferation. Moreover, our results indicate that blocking BTLA and TIM-3 in combination with PD-1 might be especially effective in enhancing responses of exhausted human T cells.

Graphical abstract

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HLA class Ia and Ib molecules and FOXP3+ TILs in relation to the prognosis of malignant melanoma patients

Publication date: Available online 4 September 2017
Source:Clinical Immunology
Author(s): Wenna Nascimento, Lasse Lindholm Johansen, Jørgen Lock-Andersen, Nille Behrendt, Jens Ole Eriksen, Michael Bzorek, Thomas Scheike, Thomas Vauvert F. Hviid
HLA class Ia (HLA-ABC) and HLA class Ib (HLA-E, -F and -G) molecules and FOXP3+ tumor-infiltrating lymphocytes (TILs) are often reported as relevant factors of tumor immune regulation. We investigated their expression as prognostic factors in 200 patients with primary cutaneous melanoma (PCM). In our cohort, patients with tumors showing upregulation of HLA-ABC molecules had significantly thicker tumors (32% vs 7%, P<0.001), frequent ulceration (20% vs 6%, P=0.007) and frequent nodular melanomas (20% vs 4%, P=0.001). Additionally, high expression of HLA-G in the tumor was a sign of bad prognosis for the patients, being associated with thick tumors (30% vs 12%, P=0.017), ulceration (24% vs 5%, P<0.001) and positive sentinel node (13% vs 6%, P=0.015). HLA-E, HLA-F and FOXP3+ TILs were not indicative of the prognosis in PCM. High HLA-ABC and HLA-G were associated with tumor aggressiveness and could be relevant predictive markers for effective immunotherapy of melanoma tumors.



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DOCK8 and STAT3 dependent inhibition of IgE isotype switching by TLR9 ligation in human B cells

Publication date: Available online 4 September 2017
Source:Clinical Immunology
Author(s): Michel J. Massaad, Brittney Cangemi, Waleed Al-Herz, Gérard LeFranc, Alexandra Freeman, Sachin Baxi, Sevgi Keles, Ayse Metin, Majid Dasouki, Ali Sobh, Maria Kanariou, Nashat Al-Sukaiti, Ahmet Ozen, Hans Ochs, Talal A. Chatila, John P. Manis, Raif Geha




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Airborne radionuclides in the proglacial environment as indicators of sources and transfers of soil material

Publication date: November 2017
Source:Journal of Environmental Radioactivity, Volumes 178–179
Author(s): Edyta Łokas, Przemysław Wachniew, Paweł Jodłowski, Michał Gąsiorek
A survey of artificial (¹³⁷Cs, ²³⁸Pu, ^239+240Pu, ²⁴¹Am) and natural (²²⁶Ra, ²³²Th, ⁴⁰K, ²¹⁰Pb) radioactive isotopes in proglacial soils of an Arctic glacier have revealed high spatial variability of activity concentrations and inventories of the airborne radionuclides. Soil column ¹³⁷Cs inventories range from below the detection limit to nearly 120 kBq m⁻², this value significantly exceeding direct atmospheric deposition. This variability may result from the mixing of materials characterised by different contents of airborne radionuclides. The highest activity concentrations observed in the proglacial soils may result from the deposition of cryoconites, which have been shown to accumulate airborne radionuclides on the surface of glaciers. The role of cryoconites in radionuclide accumulation is supported by the concordant enrichment of the naturally occurring airborne ²¹⁰Pb in proglacial soil cores showing elevated levels of artificial radionuclides. The lithogenic radionuclides show less variability than the airborne radionuclides because their activity concentrations are controlled only by the mixing of material derived from the weathering of different parent rocks. Soil properties vary little within and between the profiles and there is no unequivocal relationship between them and the radionuclide contents. The inventories reflect the pathways and time variable inputs of soil material to particular sites of the proglacial zone. Lack of the airborne radionuclides reflects no deposition of material exposed to the atmosphere after the 1950s or its removal by erosion. Inventories above the direct atmospheric deposition indicate secondary deposition of radionuclide-bearing material. Very high inventories indicate sites where transport pathways of cryoconite material terminated.



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Overexpression of Exportin-5 Overrides the Inhibitory Effect of miRNAs Regulation Control and Stabilize Proteins via Posttranslation Modifications in Prostate Cancer

Publication date: October 2017
Source:Neoplasia, Volume 19, Issue 10
Author(s): Naseruddin Höti, Shuang Yang, Paul Aiyetan, Binod Kumar, Yingwei Hu, David Clark, Arife Unal Eroglu, Punit Shah, Tamara Johnson, Wasim H. Chowdery, Hui Zhang, Ronald Rodriguez
Although XPO5 has been characterized to have tumor-suppressor features in the miRNA biogenesis pathway, the impact of altered expression of XPO5 in cancers is unexplored. Here we report a novel "oncogenic" role of XPO5 in advanced prostate cancer. Using prostate cancer models, we found that excess levels of XPO5 override the inhibitory effect of the canoncial miRNA-mRNA regulation, resulting in a global increase in proteins expression. Importantly, we found that decreased expression of XPO5 could promote an increase in proteasome degradation, whereas overexpression of XPO5 leads to altered protein posttranslational modification via hyperglycosylation, resulting in cellular protein stability. We evaluated the therapeutic advantage of targeting XPO5 in prostate cancer and found that knocking down XPO5 in prostate cancer cells suppressed cellular proliferation and tumor development without significantly impacting normal fibroblast cells survival. To our knowledge, this is the first report describing the oncogenic role of XPO5 in overriding the miRNAs regulation control. Furthermore, we believe that these findings will provide an explanation as to why, in some cancers that express higher abundance of mature miRNAs, fail to suppress their potential protein targets.



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Molecular Imaging of Colorectal Tumors by Targeting Colon Cancer Secreted Protein-2 (CCSP-2)

Publication date: October 2017
Source:Neoplasia, Volume 19, Issue 10
Author(s): Jaeil Kim, Eun-ju Do, Helen Moinova, Sang Mun Bae, Ja Young Kang, Seung-Mo Hong, Stephen P. Fink, Jinmyoung Joo, Young-Ah Suh, Se Jin Jang, Sung Wook Hwang, Sang Hyoung Park, Dong-Hoon Yang, Byong Duk Ye, Jeong-Sik Byeon, Jaewon Choe, Suk-Kyun Yang, Sanford D. Markowitz, Sang-Yeob Kim, Seung-Jae Myung
A versatile biomarker for detecting colonic adenoma and colon cancer has yet to be developed. Colon cancer secreted protein-2 (CCSP-2) is a protein specifically expressed and secreted in colon adenomas and cancers. We developed a fluorescent imaging method based on CCSP-2 targeting for a more sensitive and specific detection of colorectal tumors. CCSP-2 expression was evaluated in human colon adenoma and colorectal specimens. Anti–CCSP-2 antibody was labeled with a near-infrared fluorescent dye, FPR-675, and molecular imaging of surgical human colorectal tumors was performed. Immunohistochemistry identified CCSP-2 expression in 87.0% of colorectal cancer specimens and 89.5% of colon adenoma specimens. Fluorescence imaging of surgical human colon specimens after spraying treatment with the probe permitted a clear distinction of cancer from paired normal colon tissue (target-to-background ratio, 4.09±0.42; P<.001). CCSP-2 targeting imaging was also evaluated in patient-derived colon cancer xenograft mouse and liver metastasis murine models. CCSP-2–positive colon cancer xenografts and liver metastases were visualized by near-infrared fluorescence imaging after intravenous injection of the probe, which showed significantly higher fluorescence. Our results show that CCSP-2 is a promising marker for colorectal tumor detection in clinical settings and that a CCSP-2–targeting molecular imaging strategy might improve the diagnosis of colorectal tumors in metastatic or recurrent cancers and aid in early colonoscopic detection of premalignant lesions.



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Scholar : European Competition Journal, Volume 13, Issue 1, May 2017 is now available online on Taylor & Francis Online

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The online platform for Taylor & Francis Online content European Competition Journal, Volume 13, Issue 1, May 2017 is now available online on Taylor & Francis Online. This new issue contains the following articles: Articles Behavioural economics: the lessons for regulators Mike Walker Pages: 1-27 | DOI: 10.1080/17441056.2017.1298338 A new horizon in European sports law: the application of the EU state aid rules meets the specific nature of sport Borja García , An Vermeersch & Stephen Weatherill Pages: 28-61 | DOI: 10.1080/17441056.2017.1311146 Out of the box: illegal tying and Google's suite of apps for the Android OS Patrick F. Todd Pages: 62-92 | DOI: 10.1080/17441056.2017.1314136 The Italian pharmaceutical antitrust (r)evolution and its most recent example: the Aspen case Patrick Actis Perinetto Pages: 93-116 | DOI: 10.1080/17441056.2017.1362864 Defining non-economic activities in competition law | Erik Kloosterhuis Pages: 117-149 | DOI: 10.1080/17441056.2017.1362865 To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Scholar : These new articles for Research in Dance Education are available online

The online platform for Taylor & Francis Online content New for Research in Dance Education and online now on Taylor & Francis Online: Original Articles Negotiating meanings and examining practice of 'arts across the curriculum' Ralph Buck & Barbara Helen Snook Pages: 1-14 | DOI: 10.1080/14647893.2017.1370450 To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Growth characteristics and nutrient removal capability of eco-ditch plants in mesocosm sediment receiving primary domestic wastewater

Abstract

Eco-ditches are being explored to maximize their capability of capturing pollutants and mitigate any harmful side effects in rivers. In this study, mesocosm plastic drum sediment and field experiments were set up to screen 18 plant species found in ditches and identify those with potential for high biomass production and nutrients removal. Terrestrial plants grown in the mesocosm system were shown to be able to acclimate to aquatic conditions and to survive in primary domestic sewage. About 73–95% increase in plant biomass was recorded. Removal efficiencies for total nitrogen, total phosphorus, and ammonium-nitrogen from the sewage of 72–99%, 64–99%, and 75–100%, respectively, were recorded. Furthermore, complete removal of the applied nitrate-nitrogen load was achieved in mesocosm systems. Findings also show that all species, but especially Acorus calamus, Canna indica, Canna lily, Cyperus alternifolius, Colocasia gigantea, Eichhornia crassipes, Iris sibirica, and Typha latifolia had the highest efficiencies for nitrogen and phosphorous removal. The N and P mass balance analysis demonstrated that plant uptake and sediment N and P accumulation accounted for 41–86% and 18–49% of the total influent TN and TP loads, respectively. In addition, the amounts of nitrogen and phosphorous uptake by these plant species were influenced significantly by biomass. The field-culture experiment further identified Canna indica followed by Cyperus alternifolius as the most promising for high biomass production and nutrients uptake. Therefore, these plants may be recommended for extensive use in treating highly eutrophicated rivers. Outcomes of this work can be useful for model design specifications in eco-ditch mitigation of sewage pollution.

http://ift.tt/2iZ8GJO

Regulation of Hypothalamic CRH Neuron Excitability by Oxytocin

Abstract

Oxytocin (OT) is a neuropeptide that exerts multiple actions throughout the brain and periphery. Within the brain, OT regulates diverse neural populations, including neural networks controlling responses to stress. Local release of OT within the paraventricular nucleus (PVN) of the hypothalamus has been suggested to regulate stress responses by modulating the excitability of neighboring corticotropin-releasing hormone (CRH) neurons. However, the mechanisms by which OT regulates CRH neuron excitability are unclear. Here, we investigated the morphological relationship between OT and CRH neurons and determined the effects of OT on CRH neuron excitability. Morphological analysis revealed that the processes of OT and CRH neurons were highly intermingled within the PVN, possibly allowing for local cell-to-cell cross talk. Whole-cell patch-clamp recordings from CRH neurons was used to study the impact of OT on postsynaptic excitability and synaptic innervation. Bath-applied OT did not alter CRH neuron holding current, spiking output or any action potential parameters. Recordings of evoked excitatory and inhibitory postsynaptic currents (EPSCs/IPSCs) revealed no net effect of OT on current amplitude, however, subgroups of CRH neurons appeared to respond differentially to OT. Analysis of spontaneous EPSC events uncovered a significant reduction in spontaneous EPSC frequency but no change in spontaneous EPSC amplitude in response to OT. Together these data demonstrate that OT exerts a subtle modulation of synaptic transmission onto CRH neurons providing one potential mechanism by which OT could suppress CRH neuron excitability and stress axis activity.

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Opioid Prescribing Education in Surgical Residencies: A Program Director Survey

Publication date: Available online 4 September 2017
Source:Journal of Surgical Education
Author(s): Brian K. Yorkgitis, Elizabeth Bryant, Desiree Raygor, Gabriel Brat, Douglas S. Smink, Marie Crandall
BackgroundOpioid abuse and misuse is a public health crisis. A national effort to reduce this phenomenon is ongoing. Residents represent a large pool of opioid prescribers but, are often not the target for opioid prescribing education (OPE). We developed a survey to assess current opioid prescribing practices and education among surgical residents.Study DesignAn Institutional Review Board and Association of Program Directors in Surgery approved survey was electronically mailed to surgical program directors (PDs). The survey included questions regarding residency type, location, number of graduates per year, perceived value of OPE, residency policy on prescribing outpatients controlled substances, presence of OPE, and preferred method of OPE.Materials and MethodsA total of 248 PDs were e-mailed the survey with 110 complete responses (44.4%). Of all 104 (94.5%) allow residents to prescribe outpatient opioids with 24 (23.1%) limiting the opioid class prescribed. A total of 29 (27.9%) programs require residents to obtain their own Drug Enforcement Administration registration.Only 22 (20.0%) programs had in place mandatory OPE, 7 (6.4%) PDs were unsure if OPE was a mandatory educational requirement. Furthermore, 70 (79.5%) of programs currently without OPE are considering adding it. Didactic lecture (18, 81.8%) is the most common modality for OPE. The mode time dedicated to OPE was 1 hour. When PDs were asked about which method would be best to deliver OPE, the most common response was case-based scenarios (39, 35.5%). Bivariate statistics were performed and no association was found between OPE and program characteristics'.ConclusionsMost surgical residency programs allow residents to prescribe outpatient opioids, very few require OPE. The most common method of OPE was didactic lectures. To enhance a resident's knowledge in prescribing opioids, programs should incorporate OPE into their curriculum.



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Scholar : Contemporary French and Francophone Studies, Volume 21, Issue 2, March 2017 is now available online on Taylor & Francis Online

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The online platform for Taylor & Francis Online content Contemporary French and Francophone Studies, Volume 21, Issue 2, March 2017 is now available online on Taylor & Francis Online. This new issue contains the following articles: Introduction Editors' Introduction Roger Célestin & Eliane DalMolin Pages: 129-132 | DOI: 10.1080/17409292.2017.1357921 Articles Stratification of the Urban Space in Contemporary Paris: Modiano, Vasset, and the Data Centers of Memory Morgane Cadieu Pages: 133-141 | DOI: 10.1080/17409292.2017.1356008 Le Roman scarabée ou l'écriture du traumatisme dans Anima de Wajdi Mouawad Laurence Aubry Pages: 142-149 | DOI: 10.1080/17409292.2017.1335995 Le Cinéma français filme l'altérité en Corée du Nord : Le Cas du film Voir le pays du Matin Calme Antoine Coppola Pages: 150-158 | DOI: 10.1080/17409292.2017.1344032 Où maintenant ? Quand maintenant ? La difficulté de localiser un tiers texte entre les autotraductions de L'Innommable / The Unnamable de Samuel Beckett Lily Robert-Foley Pages: 159-168 | DOI: 10.1080/17409292.2017.1361609 L'Indécidabilité de genre (gender) dans le premier roman du cycle de Marie, de Jean-Philippe Toussaint Marie-Françoise Berthu-Courtivron Pages: 169-180 | DOI: 10.1080/17409292.2017.1343013 Speaking from the Grave: Deadly Echoes in Le Village de l'Allemand ou le journal des frères Schiller Anneka Haddix Pages: 181-188 | DOI: 10.1080/17409292.2017.1356105 Passeurs de douleurs chez Sylvie Germain Laurence Enjolras Pages: 189-196 | DOI: 10.1080/17409292.2017.1356037 Amour Fou and the Informe: Jacques Prévert, the Popular Front, and the Forestalling of a People to Come Colin Gardner Pages: 197-205 | DOI: 10.1080/17409292.2017.1356011 Les Réseaux d'édition française en Asie 1840 – 1940 Mathilde Kang Pages: 206-214 | DOI: 10.1080/17409292.2017.1346945 Extrait de Jeune fille Anne Wiazemsky Pages: 215-219 | DOI: 10.1080/17409292.2017.1354488 Excerpt from A Young Girl Anne Wiazemsky & Translation by Dawn M. Cornelio Pages: 220-224 | DOI: 10.1080/17409292.2017.1354487 Editorial Assistants Editorial Assistants Pages: 225-225 | DOI: 10.1080/17409292.2017.1366157 Acknowledgments Acknowledgments Pages: 226-226 | DOI: 10.1080/17409292.2017.1366158 Interested in the political-economic topics surrounding China? You wouldn't want to miss this exclusive collection. To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Sleep, Sleep Apnea and Atrial Fibrillation: Questions and Answers

Sleep apnea (SA) is a common sleep disorder increasingly recognized as a risk for cardiovascular disease. Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with significant morbidity and mortality. An increasing number of investigations in recent years have linked SA to AF. In this review, we aim to provide a critical overview of the existing evidence in a question and answer format by addressing the following: What is the prevalent association between the two conditions (separating nocturnally detected AF episodes from AF as a prevalent condition)? Is SA a risk factor for incident AF? Is SA a risk factor for recurrence of AF following cardioversion/catheter-based ablation? What is the association between SA and AF in patients with heart failure? Are there signature electrocardiographic markers of AF found in patients with SA? Are there electrophysiology-based studies supporting the link between SA and AF? What other sleep characteristics (beyond SA) are found in patients with AF? What is the impact of SA treatment on AF? What is the effect of AF treatment on sleep? Finally, we address unsolved questions and suggest future directions to enhance our understanding of the AF-sleep apnea relationship.

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Editorial Board

Publication date: 25 September 2017
Source:Journal of Proteomics, Volume 168





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Thyroid-associated orbitopathy and tears: A proteomics study

Publication date: Available online 5 September 2017
Source:Journal of Proteomics
Author(s): Edina Kishazi, Marianne Dor, Simone Eperon, Aurélie Oberic, Mehrad Hamedani, Natacha Turck
To date, Thyroid-Associated Orbitopathy (TAO), an autoimmune inflammatory disease affecting the eye, remains poorly characterised and its diagnosis challenging. The aim of this study was to investigate the tears of the TAO patients in order to identify potential biomarkers. Two independent quantitative Tandem Mass Tag™ 6-plex experiments were done. After in-solution digestion and isoelectric fractionation, the 12 fractions were analysed with a LTQ Orbitrap Velos coupled to a liquid chromatography. Raw files were searched against Swiss-Prot-AC database using Proteome Discoverer software, with a false discovery rate of 1% at peptide and protein levels. The differential proteins were then verified using orthogonal approaches in independent patients. Globally, 712 tear proteins were quantified with 2 unique peptides. Interestingly, cystatin c (TAO/controls ratio: 1.53) alpha-1 antichymotrypsin (ratio: 1.70) and retinal dehydrogenase (ratio: 0.68), displaying differential levels in the tears of TAO patients using proteomics experiments emerged as highly promising biomarkers after verification. In conclusion, this proteomics study supports the idea that tears reflect biological modifications occurring in a disease context and can therefore be a promising fluid for biomarker discovery. Moreover, our study identified three candidates that could in the future open new avenues in the diagnosis of TAO disease.SignificanceThyroid associated orbitopathy (TAO) is the most common disease affecting the orbit, moreover, the later, severe stages of the disease can be sight threating [1]. On the other hand, the early sign and symptoms can be mistaken with other ocular pathologies [2]. Here we explore the modification of the tear content of the TAO patients using proteomics strategies and we proposed three new biomarker candidates, which could allow the early diagnosis of the disease and prompt action to prevent more severe stages. Moreover, our findings could also help to better understand the pathophysiology of the disease.

Graphical abstract

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RNA interference-mediated knockdown of SIRT1 and/or SIRT2 in melanoma: Identification of downstream targets by large-scale proteomics analysis

Publication date: Available online 5 September 2017
Source:Journal of Proteomics
Author(s): Melissa J. Wilking-Busch, Mary A. Ndiaye, Xiaoqi Liu, Nihal Ahmad
Melanoma is the most notorious and fatal of all skin cancers and the existing treatment options have not been proven to effectively manage this neoplasm, especially the metastatic disease. Sirtuin (SIRT) proteins have been shown to be differentially expressed in melanoma. We have shown that SIRTs 1 and 2 were overexpressed in melanoma and inhibition of SIRT1 imparts anti-proliferative responses in human melanoma cells. To elucidate the impact of SIRT 1 and/or 2 in melanoma, we created stable knockdowns of SIRTs 1, 2, and their combination using shRNA mediated RNA interference in A375 human melanoma cells. We found that SIRT1 and SIRT1&2 combination knockdown caused a decreased cellular proliferation in melanoma cells. Further, the knockdown of SIRT 1 and/or 2 resulted in a decreased colony formation in melanoma cells. To explore the downstream targets of SIRTs 1 and/or 2, we employed a label-free quantitative nano-LC-MS/MS proteomics analysis using the stable lines. We found aberrant levels of proteins involved in many vital cellular processes, including cytoskeletal organization, ribosomal activity, oxidative stress response, and angiogenesis. These findings provide clear evidence of cellular systems undergoing alterations in response to sirtuin inhibition, and have unveiled several excellent candidates for future study.SignificanceMelanoma is the deadliest form of skin cancer, due to its aggressive nature, metastatic potential, and a lack of sufficient treatment options for advanced disease. Therefore, detailed investigations into the molecular mechanisms of melanoma growth and progression are needed. In the search for candidate genes to serve as therapeutic targets, the sirtuins show promise as they have been found to be upregulated in melanoma and they regulate a large number of proteins involved in cellular processes known to affect tumor growth, such as DNA damage repair, cell cycle arrest, and apoptosis. In this study, we used a large-scale label-free comparative proteomics system to identify novel protein targets that are affected following knockdown of SIRT1 and/or 2 in A375 metastatic melanoma cell line. Our study offers important insight into the potential downstream targets of SIRTs 1 and/or 2. This may unravel new potential areas of exploration in melanoma research.

Graphical abstract

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Malonylome analysis in developing rice (Oryza sativa) seeds suggesting that protein lysine malonylation is well-conserved and overlaps with acetylation and succinylation substantially

Publication date: Available online 4 September 2017
Source:Journal of Proteomics
Author(s): Hana Mujahid, Xiaoxi Meng, Shihai Xing, Xiaojun Peng, Cailin Wang, Zhaohua J. Peng
In recent years, lysine malonylation has garnered wide spread interest due to its potential regulatory roles. While studies have been performed in bacteria, mouse, and human, the involvement and the biological function of this modification in plant are still largely unknown. We examined the global proteome profile of lysine malonylation in developing rice seeds using affinity enrichment followed by LC-MS/MS analysis. We identified 421 malonylated lysine sites across 247 proteins. Functional analyses showed predominant presence of malonylated proteins in metabolic processes, including carbon metabolism, glycolysis/gluconeogenesis, TCA cycle, as well as photosynthesis. Malonylation was also detected on enzymes in starch biosynthesis pathway in developing rice seeds. In addition, we found a remarkable overlap among the malonylated, succinylated and acetylated sites identified in rice. Furthermore, malonylation at conserved sites of homologous proteins was observed across organisms of different kingdoms, including mouse, human, and bacteria. Finally, distinguished motifs were identified when the rice malonylation sites were analyzed and conserved motifs were observed from bacterium to human and rice. Our results provide an initial understanding of the lysine malonylome in plants. The study has critical reference value for future understanding of the biological function of protein lysine malonylation in plants.Biological significanceLysine malonylation is a newly discovered acylation with functional potential in regulating cellular metabolisms and activities. However, the malonylation status has not been reported in plants. Grain yield and quality, mainly determined during cereal seed development, are closely related to food security, human health and economic value. To evaluate malonylation level in plant and the possible regulatory functions of malonylation in seed development, we conducted comprehensive analyses of malonylome in developing rice seeds. A total of 421 malonylated lysine sites from 247 proteins were identified, which involved in multiple critical metabolic processes, including central carbon metabolism, lipid metabolism, photosynthesis, and starch biosynthesis. We found that charged amino acids lysine and arginine were the preferred residues in positions flanking the modified lysines. Highly conserved modification sites on both histone and non-histone proteins were observed among different organisms through sequence alignment analysis. More interestingly, a large number of modification sites shared by malonylation, acetylation and succinylation were identified in rice. The study presents a comprehensive understanding of malonylome in plants, which will serve as an initial platform for further investigation of the functions of lysine malonylation, especially in cereal seeds development.

Graphical abstract

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Cost-effectiveness analysis of PET-CT-guided management for locally advanced head and neck cancer

Publication date: November 2017
Source:European Journal of Cancer, Volume 85
Author(s): A.F. Smith, P.S. Hall, C.T. Hulme, J.A. Dunn, C.C. McConkey, J.K. Rahman, C. McCabe, H. Mehanna
BackgroundA recent large United Kingdom (UK) clinical trial demonstrated that positron-emission tomography–computed tomography (PET-CT)-guided administration of neck dissection (ND) in patients with advanced head and neck cancer after primary chemo-radiotherapy treatment produces similar survival outcomes to planned ND (standard care) and is cost-effective over a short-term horizon. Further assessment of long-term outcomes is required to inform a robust adoption decision. Here we present results of a lifetime cost-effectiveness analysis of PET-CT-guided management from a UK secondary care perspective.MethodsInitial 6-month cost and health outcomes were derived from trial data; subsequent incidence of recurrence and mortality was simulated using a de novo Markov model. Health benefit was measured in quality-adjusted life years (QALYs) and costs reported in 2015 British pounds. Model parameters were derived from trial data and published literature. Sensitivity analyses were conducted to assess the impact of uncertainty and broader National Health Service (NHS) and personal social services (PSS) costs on the results.ResultsPET-CT management produced an average per-person lifetime cost saving of £1485 and an additional 0.13 QALYs. At a £20,000 willingness-to-pay per additional QALY threshold, there was a 75% probability that PET-CT was cost-effective, and the results remained cost-effective over the majority of sensitivity analyses. When adopting a broader NHS and PSS perspective, PET-CT management produced an average saving of £700 and had an 81% probability of being cost-effective.ConclusionsThis analysis indicates that PET-CT-guided management is cost-effective in the long-term and supports the case for wide-scale adoption.



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Avoiding harm and supporting autonomy are under-prioritised in cancer-screening policies and practices

Publication date: November 2017
Source:European Journal of Cancer, Volume 85
Author(s): Lisa Parker, Stacy Carter, Jane Williams, Kristen Pickles, Alexandra Barratt
The ethical principles of avoiding harm and supporting autonomy are relevant to cancer-screening policy. We argue that more attention needs to be given to implementing them. Cancer screening may deliver excessive harms due to low-value or outdated screening programs and from poorly communicated screening options that leave people with heavy burdens of decision-making. Autonomy is inadequately supported due to limited opportunities for people to understand downsides of screening and because of institutional and societal pressures in favour of screening.Members of screening policy committees may have differing ideas about the goals of screening or have conflicts of interest that prevent them from addressing policy questions in a neutral way. We recommend the following: 1. Committees should be required to discern and discuss the values of individual members and the wider public; 2. Committee membership and voting procedures should be more carefully constructed to reduce the likelihood that committee members' interests are placed above public interests; 3. Committees should explain their policy decisions with reference to values as well as evidence, so that values considered in decision-making can be interrogated and challenged if necessary. These changes would increase the likelihood that cancer-screening policy decisions are in keeping with public views about what is important.



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Value of a short-term imaging follow-up after a benign result in a one-stop breast unit: Is it still useful?

Publication date: November 2017
Source:European Journal of Cancer, Volume 85
Author(s): Johanna Daroles, Isabelle Borget, Voichita Suciu, Chafika Mazouni, Suzette Delaloge, Corinne Balleyguier
IntroductionA short-term radiologic follow-up after a benign breast biopsy or fine needle aspiration (FNA) is recommended in many guidelines. However, the current trend is to reduce imaging investigations, radiation dose and costs. The objectives of this study were to evaluate the cancer detection rate at short-term follow-up and to estimate its cost.MethodsWe retrospectively assessed all consecutive patients referred to our 'one-stop' breast unit between 2004 and 2012, with a benign histological or cytological result and at least one short-term follow-up within 3–12 months after the initial diagnosis. We evaluated the number of cancers detected, as well as the mean cost to detect each cancer and per patient.ResultsAbout 1366 patients were eligible for this study. Ten patients were diagnosed with cancers (0.73%) at short-term follow-up; six of 10 were low-grade tumours or ductal carcinoma in situ. The cost for detecting one cancer was 19,043€, with mean cost per patient of 139€.ConclusionThe cancer detection rate at short-term follow-up after benign biopsy or FNA was low and was similar to that of most national screening programs. The cost of cancer detection appeared high, considering that most cancers were indolent. This suggests that radiologic follow-up could reasonably be carried out at a later point in time.



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Societal challenges of precision medicine: Bringing order to chaos

Publication date: October 2017
Source:European Journal of Cancer, Volume 84
Author(s): Roberto Salgado, Helen Moore, John W.M. Martens, Tracy Lively, Shakun Malik, Ultan McDermott, Stefan Michiels, Jeffrey A. Moscow, Sabine Tejpar, Tawnya McKee, Denis Lacombe
The increasing number of drugs targeting specific proteins implicated in tumourigenesis and the commercial promotion of relatively affordable genome-wide analyses has led to an increasing expectation among patients with cancer that they can now receive effective personalised treatment based on the often complex genomic signature of their tumour. For such approaches to work in routine practice, the development of correspondingly complex biomarker assays through an appropriate and rigorous regulatory framework will be required. It is becoming increasingly evident that a re-engineering of clinical research is necessary so that regulatory considerations and procedures facilitate the efficient translation of these required biomarker assays from the discovery setting through to clinical application. This article discusses the practical requirements and challenges of developing such new precision medicine strategies, based on leveraging complex genomic profiles, as discussed at the Innovation and Biomarkers in Cancer Drug Development meeting (8th–9th September 2016, Brussels, Belgium).



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Time trends (2006–2015) of quality indicators in EUSOMA-certified breast centres

Publication date: November 2017
Source:European Journal of Cancer, Volume 85
Author(s): P.A. van Dam, M. Tomatis, L. Marotti, J. Heil, R.E. Mansel, M. Rosselli del Turco, P.J. van Dam, D. Casella, L.G. Bassani, M. Danei, A. Denk, D. Egle, G. Emons, K. Friedrichs, N. Harbeck, M. Kiechle, R. Kimmig, U. Koehler, S. Kuemmel, N. Maass, C. Mayr, A. Prové, C. Rageth, L. Regolo, F. Lorenz-Salehi, D. Sarlos, C. Singer, C. Sohn, G. Staelens, C. Tinterri, R. Audisio, A. Ponti
Aim of the studyThe European Society of Breast Cancer Specialists (EUSOMA) has fostered a voluntary certification process for breast centres to establish minimum standards and ensure specialist multidisciplinary care. Prospectively collected anonymous information on primary breast cancer cases diagnosed and treated in the units is transferred annually to a central EUSOMA data warehouse for continuous monitoring of quality indicators (QIs) to improve quality of care. Units have to comply with the EUSOMA Breast Centre guidelines and are audited by peers. The database was started in 2006 and includes over 110,000 cancers from breast centres located in Germany, Switzerland, Belgium, Austria, The Netherlands, Spain, Portugal and Italy. The aim of the present study is assessing time trends of QIs in EUSOMA-certified breast centres over the decade 2006–2015.Materials and methodsPreviously defined QIs were calculated for 22 EUSOMA-certified breast centres (46122 patients) during 2006–2015.ResultsOn the average of all units, the minimum standard of care was achieved in 8 of 13 main EUSOMA QIs in 2006 and in all in 2015. All QIs, except removal of at least 10 lymph nodes at axillary clearance and oestrogen receptor–negative tumours (T > 1 cm or N+) receiving adjuvant chemotherapy, improved significantly in this period. The desirable target was reached for two QIs in 2006 and for 7 of 13 QIs in 2015.ConclusionThe EUSOMA model of audit and monitoring QIs functions well in different European health systems and results in better performance of QIs over the last decade. QIs should be evaluated and adapted on a regular basis, as guidelines change over time.



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Orphan Drug Regulation: A missed opportunity for children and adolescents with cancer

Publication date: October 2017
Source:European Journal of Cancer, Volume 84
Author(s): Gilles Vassal, Pam Kearns, Patricia Blanc, Nicole Scobie, Delphine Heenen, Andy Pearson
BackgroundOncology represents a major sector in the field of orphan drug development in Europe. The objective was to evaluate whether children and adolescents with cancer benefited from the Orphan Drug Regulation.MethodsData on orphan drug designations (ODDs) and registered orphan drugs from 8th August 2000 to 10th September 2016 were collected from the Community Register of medicinal products for human use. Assessment history, product information and existence of paediatric investigation plans were searched and retrieved from the European Medicine Agency website.ResultsOver 16 years, 272 of 657 oncology ODDs (41%) concerned a malignant condition occurring both in adults and children. The five most common were acute myeloid leukaemia, high-grade glioma, acute lymphoblastic leukaemia, graft-versus-host disease and soft-tissue sarcomas. 74% of 31 marketing authorisations (MAs) for an indication both in adults and children (26 medicines) had no information for paediatric use in their Summary of Product Characteristics (SmPC) at the time of the first MA. Furthermore, 68% still have no paediatric information in their most recently updated SmPC, at a median of 7 years after. Only 15 ODDs (2%) pertained to a malignancy occurring specifically in children and only two drugs received an MA: Unituxin for high-risk neuroblastoma and Votubia for sub-ependymal giant-cell astrocytoma.ConclusionThe Orphan Drug Regulation failed to promote the development of innovative therapies for malignancies occurring in children. Major delays and waivers occurred through the application of the Paediatric Medicines Regulation. The European regulatory environment needs to be improved to accelerate innovation for children and adolescents dying of cancer.



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Hormone replacement therapy after risk-reducing salpingo-oophorectomy minimises endocrine and sexual problems: A prospective study

Publication date: October 2017
Source:European Journal of Cancer, Volume 84
Author(s): Ravi F.M. Vermeulen, Marc van Beurden, Jacobien M. Kieffer, Eveline M.A. Bleiker, Heiddis B. Valdimarsdottir, Leon F.A.G. Massuger, Marian J.E. Mourits, Katja N. Gaarenstroom, Eleonora B.L. van Dorst, Hans W.H.M. van der Putten, Neil K. Aaronson
BackgroundThere has been some doubts raised in earlier studies about the efficacy of hormone replacement therapy (HRT) in reducing endocrine and sexual problems in women who have undergone a risk-reducing salpingo-oophorectomy (RRSO).MethodsIn this prospective, observational study, we recruited 178 premenopausal women with a high risk for ovarian cancer. Fifty-seven women opted for RRSO and 121 for gynaecological screening (GS). Women completed questionnaires before surgery (T1) and 3 (T2) and 9 (T3) months post surgery, or at equivalent time points for the GS-group. Menopausal symptoms were assessed with the Functional Assessment of Cancer Therapy–Endocrine Subscale (FACT-ES) and sexual functioning with the Sexual Activity Questionnaire (SAQ). Groups were compared using repeated measures mixed effect models for continuous variables, and generalised estimating equations for longitudinal ordered categorical data.ResultsTwenty-seven women who underwent RRSO used HRT after surgery (HRT-users) and 30 did not (HRT-non-users). There were no significant group differences at baseline on the outcome variables. Compared to the HRT-users, the HRT-non-users exhibited a significant increase in overall endocrine symptoms (p = 0.001, effect size (ES) = −0.40 and p < 0.001, ES = −0.59 at T1 and T2, respectively), and in sexual discomfort (p < 0.001, ES = 0.74 and p < 0.001, ES = 1.17). The effect size provides an indication of the magnitude of the observed group differences. An effect size of 0.50 or greater is generally considered to be clinically relevant. No significant differences over time were observed between the HRT-users and the GS-group on any of the outcomes.ConclusionOur results suggest that HRT use in the first year after RRSO has beneficial effects in terms of minimising endocrine symptoms and sexual symptoms in premenopausal women who have undergone RRSO.



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Nickel accumulation and its effect on growth, physiological and biochemical parameters in millets and oats

Abstract

With the boom in industrialization, there is an increase in the level of heavy metals in the soil which drastically affect the growth and development of plants. Nickel is an essential micronutrient for plant growth and development, but elevated level of Ni causes stunted growth, chlorosis, nutrient imbalance, and alterations in the defense mechanism of plants in terms of accumulation of osmolytes or change in enzyme activities like guiacol peroxidase (POD), catalase (CAT), and superoxide dismutase (SOD). Ni-induced toxic response was studied in seedlings of finger millet, pearl millet, and oats in terms of seedling growth, lipid peroxidation, total chlorophyll, proline content, and enzymatic activities. On the basis of germination and growth parameters of the seedling, finger millet was found to be the most tolerant. Nickel accumulation was markedly lower in the shoots as compared to the roots, which was the highest in finger millet and the lowest in shoots of oats. Plants treated with a high concentration of Ni showed significant reduction in chlorophyll and increase in proline content. Considerable difference in level of malondialdehyde (MDA) content and activity of antioxidative enzymes indicates generation of redox imbalance in plants due to Ni-induced stress. Elevated activities of POD and SOD were observed with high concentrations of Ni while CAT activity was found to be reduced. It was observed that finger millet has higher capability to maintain homeostasis by keeping the balance between accumulation and ROS scavenging system than pearl millet and oats. The data provide insight into the physiological and biochemical changes in plants adapted to survive in Ni-rich environment. This study will help in selecting the more suitable crop species to be grown on Ni-rich soils.

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cGAS Conducts Micronuclei DNA Surveillance

Publication date: Available online 4 September 2017
Source:Trends in Cell Biology
Author(s): Carina C. de Oliveira Mann, Philip J. Kranzusch
DNA damage elicits a potent proinflammatory immune response. A collection of four papers now reveals that micronuclear DNA is a new cell intrinsic immunostimulatory molecule, and that accumulation of the immune sensor cyclic GMP–AMP synthase (cGAS) in micronuclei leads to a cell-cycle-dependent proinflammatory response following DNA damage.



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Proinflammatory Signals as Fuel for the Fire of Hematopoietic Stem Cell Emergence

Publication date: Available online 4 September 2017
Source:Trends in Cell Biology
Author(s): Raquel Espin-Palazon, Bart Weijts, Victor Mulero, David Traver
Hematopoietic stem cells (HSCs) have the extraordinary ability to both self-renew and generate all mature blood cell lineages. The ability to produce or expand patient-derived HSCs in vitro would greatly improve the outcome for patients with blood disorders that are currently treated with allogeneic HSC transplantation. Many laboratories have been working to identify the signals required for HSC emergence in their native environments to apply this knowledge in vitro. Recently, several signals traditionally known to underlie classical inflammation have emerged as essential regulators of HSC development. In this review we synthesize the findings that have established inflammatory cues as key regulators of HSC development.



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High prevalence of papillary thyroid carcinoma in nodular Hashimoto’s thyroiditis at the first diagnosis and during the follow-up

Abstract

Background

The association between Hashimoto's thyroiditis (HT) and papillary thyroid carcinoma (PTC) remains to be elucidated.

Materials and methods

A total of 484 HT patients were retrospectively subdivided into two groups: 243 without thyroid nodules, TNs (HTN−) and 241 with TNs (HTN+). Fine-needle aspiration cytology was available in 152 HTN+ patients. This group was compared to a group of 161 patients with nodular goiter (NG) without HT. Finally, 70 HTN+ and 37 NG patients underwent surgery.

Results

A very high prevalence of suspicious/malignant cytology (Thy 4–5) at the first diagnosis (38/124; 31%) and during the follow-up (6/28; 22%) was found in HTN+ group. In HTN- group, 22/130 (17%) patients developed TN, but none showed malignant features during the follow-up. HTN+ patients had higher prevalence of Thy 4–5 (44/152 = 28.9%) compared to NG patients (12/161 = 7.4%, p < 0.0001). Increased independent odds ratio (OR) for malignancy was conferred by serum TSH > 1.0 μUI/ml, [OR 1.93, 95% confidence interval (CI) 1.41–2.64, p < 0.0001], male sex (OR 3.44, CI 1.48–8.02, p = 0.004) and HT (OR 3.14; CI 1.08–9.31, p < 0.05). Malignant histology (mostly PTC) was confirmed higher in HTN+ (48/70, 68.6%) compared to NG (15/37, 40.5%; p < 0.05). Higher prevalence of extrathyroidal infiltration (24/48, 50%) and vascular invasion (25/48, 52%) was found in HTN+ vs NG (2/15, 1.3% p < 0.01), (3/16, 1.8% p < 0.05), respectively.

Conclusions

This study confirms higher prevalence of suspicious/malignant cytology and PTC at histology in nodular HT compared to NG, without evidence of malignancy in non-nodular HT patients during the follow-up.

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Serial Dependence in Audition: Free, Fast, and Featureless?

Publication date: Available online 4 September 2017
Source:Trends in Cognitive Sciences
Author(s): Benjamin James Dyson




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Quality of life in patients with vitiligo using the short form 36

Vitiligo is an acquired pigmentary disorder affecting 0.5-1% of the world's population. Affected individuals often have low self-esteem, and poor quality of life (QOL) due to the disfigurement caused by the disease [1]. Vitiligo's impact on QOL compared to other diseases using general health questionnaires like the Short Form 36 (SF-36) is not well understood. We performed a cross-sectional study of patients with vitiligo and controls using the SF-36 and compared our scores to studies of patients with depression, chronic lung disease, psoriasis, atopic dermatitis, arthritis, cancer, congestive heart failure, myocardial infarction, type 2 diabetes, hypertension, and healthy adults.

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Development of an electrochemical immunosensor for the diagnostic testing of spotted fever using synthetic peptides

Publication date: 15 February 2018
Source:Biosensors and Bioelectronics, Volume 100
Author(s): Isis C. Prado, Mônica E.T.A. Chino, Antonia L. dos Santos, André L.A. Souza, Luciano G. Pinho, Elba R.S. Lemos, Salvatore G. De-Simone
Spotted fever is a rare acute and multisystemic febrile infectious disease with a mortality rate of ≥50% without adequate antibiotic treatment, and in diagnosed and treated cases, of approximately 2.5%. Currently, the applied test to diagnose this disease is the indirect immunofluorescence reaction, however two samples of paired sera are necessary to confirm the diagnosis, since using only one sample may allow for confusion with cross reactions. OmpA is an outer membrane protein present in the R. rickettsia, the etiological agent of spotted fever, able to activate dendritic and macrophage cells. It also presents immunogenicity properties, and is considered a target for the development of diagnostic tests for spotted fever. In this context, an amperometric immunosensor was developed for the identification of sera antibodies (human IgG) from patients with spotted fever aimed at improving sensitivity and minimize sample volume. The development of the immunosensor was conducted using a synthetic peptide, derivative from the H6PGA4 R. rickettsia protein, homologous to OmpA. Amperometric responses were generated at −0.6 to 0.6V, at a scan rate of 0.025Vs⁻¹ for 20 cycles, a limit of detection of approximately 10ngmL⁻¹ for the synthetic peptides and 0.01µgmL⁻¹ for the humam serum, a sensitivity of 2.59µA, adequate for the detection of spotted fever antibodies. The construction of this immunosensor, capable of identifying circulating antibodies in real time, can also be applied in the diagnosis of other infectious-parasitic diseases.



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Method optimization for heavy metal determination in milk powder: application to milk samples from Greece

Abstract

The scope of this study was the development, optimization and validation of an analytical method for the determination of selected heavy metals and trace elements (As, Hg, Se, Cd, Cu, Pb, Mn, Fe, Ni, Zn, Cr) in milk powder, using microwave-assisted digestion. A statistical experimental design approach using central composite design (CCD) was carried out, to investigate the effects of three independent pretreatment variables (final digestion temperature (°C), HNO₃ concentration (in % w/v), microwave hold time) on the heavy metal recovery of spiked undigested milk powder sample and to calculate the variable factor values which produce the optimum recovery. CCD results revealed that the optimum digestion conditions, with respect to maximum recovery were as follows: temperature 190 °C, HNO₃ 56.8% w/v, and digestion time of 8.47 min. The method was fully validated. Recoveries for all metals ranged between 92 and 108% while intra-day repeatability was below 6.59% (rsd). A certified reference material (ERM BD 150) that included 8 out of the total 11 heavy metals of the present study (Hg, Se, Cd, Cu, Pb, Mn, Ni, and Zn) was used to test the accuracy of the method where acceptable recovery values ranging between 96 and 107% were obtained. High heavy metal recoveries, short digestion time, and low acid consumption were the advantages of the pretreatment method. The analytical process was successfully applied for the determination of heavy metals in different milk samples from the Greek market. Heavy metal concentrations for Ni, Cr, Pb, Cd, Se, Mn, and Cu measured in this study reached 307, 102, 8.01, 5.96, 60.2, 519, and 438 μg/kg wet weight (ww), respectively. Zn and Fe were found at concentrations ranging 3.21–8.39 and 0.170–10.1 mg/kg ww, respectively. Risk assessment based on the WHO tolerable daily intake levels and the calculated target hazard quotients revealed that the consumption of the selected milk samples is considered safe.

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Evaluating the potential genotoxicity of phthalates esters (PAEs) in perfumes using in vitro assays

Abstract

We previously reported high levels of phthalate esters (PAEs) added as solvents or fixatives in 47 brands of perfumes. Diethyl phthalate was the most abundant compound (0.232–23,649 ppm), and 83.3% of the perfumes had levels >1 ppm, the threshold limit cited by a Greenpeace investigation. All samples had dimethyl phthalate levels higher than its threshold limit of 0.1 ppm, and 88, 38, and 7% of the perfumes had benzyl butyl phthalate, di(2-ethylhexyl) phthalate, and dibutyl phthalate levels, respectively, above their threshold limits. The role of PAEs as endocrine disruptors has been well documented, but their effect on genotoxic behavior has received little attention. We used in vitro single-cell gel electrophoresis (comet) and micronucleus (MN) assays with human lymphoblastoid TK6 cells to evaluate the genotoxic potency of 42 of the same perfumes and to determine its association with PAEs. All perfumes induced more DNA damage than a negative control (NEG), ≥ 90% of the samples caused more damage than cells treated with the vehicles possibly used in perfume's preparations such as methanol (ME) and ethanol (ET), and 11.6% of the perfumes caused more DNA damage than a positive control (hydrogen peroxide). Chromosome breakage expressed as MN frequency was higher in cells treated with 71.4, 64.3, 57.1, and 4.8% of the perfumes than in NEG, cells treated with ME or ET, and another positive control (x-rays), respectively. The genotoxic responses in the comet and MN assays were not correlated. The comet assay indicated that the damage in TK6 cells treated with five PAEs at concentrations of 0.05 and 0.2 ppm either individually or as a mixture did not differ significantly from the damage in cells treated with the perfumes. Unlike the comet assay, the sensitivity of the MN assay to PAEs was weak at both low and high concentrations, and MN frequencies were generally low. This study demonstrates for the first time the possible contribution of PAEs in perfumes to DNA damage and suggests that their use as solvents or fixatives should be regulated. Other ingredients with mutagenic/genotoxic properties, however, may also have contributed to the DNA damage. Future studies should focus on applying a series of assays that use different cellular models with various endpoints to identify the spectrum of genotoxic mechanisms involved.

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Long-term clinical safety of high-dose proton radiotherapy delivered with pencil beam scanning technique for extracranial chordomas and chondrosarcomas in adult patients: Clinical evidence of spinal cord tolerance

Publication date: Available online 4 September 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sonja Stieb, James W. Snider, Lorenzo Placidi, Ulrike Kliebsch, Anthony J. Lomax, Ralf A. Schneider, Damien C. Weber
Purpose/ObjectivesTo assess the radiation dose tolerance of the spinal cord, we reviewed our institutional experience regarding the incidence of radiation-induced spinal cord toxicity following high dose, pencil beam scanning proton therapy (PBSPT).Materials/MethodsSeventy-six patients (median age, 53 years; range: 23–79), treated for spinal chordoma (n=55) or chondrosarcoma (n=21) met the following criteria and were retrospectively analyzed: PBSPT only, no re-irradiation or concomitant chemotherapy, maximum dose (Dmax) to the spinal cord of ≥45 Gy(RBE), ≥18 years of age, and follow-up of ≥12 months. The delivered dose was 59.4–75.2 Gy(RBE) (median, 73.9) delivered with conventional fractionation between 2000–2014. The Dmax, D2%, V40–V60 of the surface (sSC) and center (cSC) of the spinal cord were recorded. Toxicity was scored according to the Common Toxicity Criteria of Adverse Events (CTCAE v4.03).ResultsMedian follow-up was 65.5 months (range, 13–173). Patients received a mean Dmax and D2% to the sSC of 59.0 (median 58.7, range: 48.3 – 75.9), and 55.3 Gy(RBE) (median, 52.7, range: 43.1 – 73.8), respectively. The corresponding values for the cSC were 52.3 (median, 52.7, range: 32.3 – 73.3) and 51.1 Gy(RBE) (median, 52.0, range: 25.3 – 73.1), respectively. Four patients (5%) developed acute radiation-induced neurotoxicity (G1, n=1; G2, n=3). Twelve patients (16%) experienced late neurologic toxicities (G1, n=7; G2, n=4; G4, n=1). One patient with a history of pre-PBSPT symptomatic spinal cord compression redeveloped tetraplegia (G4) after receiving a Dmax of 57.8 Gy(RBE) to the sSC and 54.1 Gy(RBE) to the cSC. No significant correlation was found between sSC Dmax and D2%, cSC Dmax and D2%, or the length of CTV and toxicity.ConclusionsHigh-dose conformal PBSPT may be delivered safely in close proximity to the spinal cord with minimal neurotoxicity. Dose constraints of 64 Gy(RBE) as D2% for the sSC and 54 Gy(RBE) for the cSC appear appropriate for clinical use.

Teaser

Limited clinical data to define the radiotherapy tolerance of the spinal cord are available to clinicians. To add further clarity, we retrospectively evaluated our patients treated with proton therapy only for spinal chordomas and chondrosarcomas, who received a spinal cord dose in excess of 45 Gy(RBE) with special regard to neurotoxicity. Radiation doses reaching 64 Gy(RBE) to the surface of the spinal cord were associated with limited toxicity, defining this cut-off dose level as a safe threshold for appropriate clinical use.


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Serum microRNA Signature Predicts Response to High-dose Radiotherapy in Locally Advanced Non-Small-Cell Lung Cancer

Publication date: Available online 4 September 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Yilun Sun, Peter G. Hawkins, Nan Bi, Robert T. Dess, Muneesh Tewari, Jason W.D. Hearn, James A. Hayman, Gregory P. Kalemkerian, Theodore S. Lawrence, Randall K. Ten Haken, Martha M. Matuszak, Feng-Ming Kong, Shruti Jolly, Matthew J. Schipper
PurposeWhile efforts to improve control of locally-advanced non-small-cell lung cancer (NSCLC) by escalating radiation dose in unselected patients have been unsuccessful, we hypothesized that a subset of patients may derive benefit. Circulating serum microRNAs (c-miRNAs) have shown promise as prognostic and predictive biomarkers. We assessed the utility of c-miRNAs to predict response to high-dose radiotherapy.Methods and MaterialsData from 80 patients treated from 2004 to 2013 with definitive standard- or high-dose radiotherapy for stages II-III NSCLC as part of four prospective institutional clinical trials were evaluated. Pretreatment serum levels of 62 miRNAs were measured by quantitative reverse-transcription polymerase chain reaction array. We combined miRNA data and clinical factors to generate a Dose Response Score (DRS) for predicting overall survival (OS) following high-dose versus standard-dose radiotherapy. Elastic net Cox regression was used for variable selection and parameter estimation. Model assessment and tuning parameter selection were performed through full cross validation. DRS was also correlated with local progression, distant metastasis, and grade 3 or higher cardiac toxicity using Cox regression; and grade 2 or higher esophageal and pulmonary toxicity using logistic regression.ResultsEleven predictive miRNAs were combined with clinical factors to generate a DRS for each patient. In patients with low DRS, high-dose radiotherapy was associated with significantly improved OS compared to treatment with standard-dose radiotherapy (HR 0.22). In these patients, high-dose radiation also conferred lower risk of distant metastasis and local progression, although the latter association was not statistically significant. Patients with high DRS exhibited similar rates of OS regardless of dose (HR 0.78). DRS did not correlate with treatment-related toxicity.ConclusionsUsing c-miRNA signature and clinical factors, we developed a DRS that identified a subset of patients with locally-advanced NSCLC who derive an OS benefit from high-dose radiotherapy. This DRS may guide dose-escalation in a patient-specific manner.

Teaser

Escalation of radiation dose has not been beneficial in unselected patients with locally-advanced non-small-cell lung cancer. We hypothesized that a subset of patients may derive benefit and sought to identify a dose-response biomarker by analyzing patients treated with varying doses of radiotherapy on four institutional clinical trials. We identified a micro-RNA signature that, when combined with clinical factors, identified a subset of patients who exhibited an overall survival benefit following high-dose radiotherapy.


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Graphical Abstracts

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