Acknowledgement of reviewers 2016

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Genomic Analysis Reveals Distinct Subtypes in Two Rare Cases of Primary Ovarian Lymphoma

Publication date: Available online 3 January 2018
Source:Pathology - Research and Practice
Author(s): Pallavi Khattar, Puneet Bedi, Marion Gonzalez, Minghao Zhong, Changhong Yin, Weihua Huang, Humayun K. Islam, John T. Fallon
Primary (localized) non-Hodgkin lymphoma (NHL) of the ovary is extremely rare; only few cases have been reported in the literature. We report two cases of primary ovarian lymphoma (POL), one involving bilateral ovaries in a 15-year-old girl and other involving one ovary in a 5-year-old girl. This report describes detailed clinical, histopathological, and imaging findings, along with the review of literature of primary diffuse large B-cell lymphoma (DLBCL) arising from an ovary. In addition we describe findings of targeted capture panel sequencing on both tumors and identify the major genetic mutations that are recurrently mutated in pan-cancers. Compared to the genomic mutation features of major subtypes of DLBCL, we distinguish that each POL belongs to distinctive subtypes, GCB (germinal center B-cell type) DLBCL and ABC (activated B-cell type) DLBCL, respectively. The findings from the genomic analysis may help to understand the pathogenesis of POL and to guide potential targeted therapy in the future.



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Clinical value of survivin and its underlying mechanism in ovarian cancer: A bioinformatics study based on GEO and TCGA data mining

Publication date: Available online 2 January 2018
Source:Pathology - Research and Practice
Author(s): Xiao-jiao Li, Jin-shu Pang, Yao-mei Li, Farah Abdirahman Ahmed, Rong-quan He, Jie Ma, Fu-chao Ma, Gang Chen
ObjectiveAn increasing number of studies have confirmed that survivin (BIRC5) plays essential roles in ovarian cancer. Nevertheless, inconsistent or controversial results exist in some studies. In the present study, we sought to determine the clinical significance of survivin and its potential molecular pathways.MethodsThe correlation between survivin (BIRC5) expression and diagnostic value, prognostic value and clinicopathological features was assessed by meta-analysis with more than 4000 patients from literature, GEO and TCGA. In addition, the potential molecular mechanism of survivin in ovarian cancer was also determined.ResultsThe pooled sensitivity and specificity were 0.71 (95%CI: 0.68–0.74) and 0.97 (95%CI: 0.94–0.98), respectively. The AUC of sROC was 0.8765. The results showed that there was also a significant relationship between survivin expression and poor overall survival (HR: 1.24, 95%CI: 1.14–1.35, p < 0.001), disease-free survival (HR: 1.53, 95%CI: 0.57–4.09, p < 0.001), as well as higher recurrence rate (HR: 1.11, 95%CI: 0.97–1.27). Moreover, survivin expression was also associated with tumor progression (cancerous vs. benign, OR: 11.29, 95%CI: 8.96–14.24, p < 0.001), TNM stage (III + IV vs. I + II, OR: 5.38, 95%CI: 4.16–6.97, p < 0.001), histological grades (G3 vs. G1 ∼ G2, OR: 4.36, 95%CI: 3.29–5.77, p < 0.001), and lymphatic metastasis (metastasis vs. non-metastasis, 3.35, 95%CI 2.36–4.75, p < 0.001). Bioinformatics analysis revealed the 50 most frequently altered neighboring genes of survivin in OC, and then Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted. GO analysis showed that these genes were related to signal conduction, cell cycle, apoptosis, and metabolism. KEGG pathways analysis indicated that these genes were primarily enriched in mitotic prometaphase, PLK1 signaling events and the regulation of glucokinase by the glucokinase regulatory protein.ConclusionSurvivin (BIRC5) expression might become a specific but low-sensitivity biomarker in ovarian cancer patients, and its presence indicated poor prognosis and worse TNM stages. This protein might function as an oncoprotein by influencing specific pathways involving the 50 genes identified herein. Additional studies are needed to confirm these results.



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Analysis of the Proliferative Activity in Lung Adenocarcinomas with Specific Driver Mutations

Publication date: Available online 2 January 2018
Source:Pathology - Research and Practice
Author(s): Mark Kriegsmann, Alexander Harms, Daniel Kazdal, Sebastian Fischer, Albrecht Stenzinger, Jonas Leichsenring, Roland Penzel, Rémi Longuespée, Katharina Kriegsmann, Thomas Muley, Seyer Safi, Arne Warth
In the last decade it became evident that many lung adenocarcinomas (ADC) harbor key genetic alterations such as KRAS, EGFR or BRAF mutations as well as rearrangements of ROS1 or ALK that drive these tumors. In the present study we investigated whether different driver mutations of ADC result in different proliferation rates, which might have clinical impact, including resistance to therapy, recurrence and prognosis.



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Up-regulated Expression of SNHG6 Predicts Poor Prognosis in Colorectal Cancer

Publication date: Available online 3 January 2018
Source:Pathology - Research and Practice
Author(s): Min Li, Zehua Bian, Surui Yao, Jia Zhang, Guoying Jin, Xue Wang, Yuan Yin, Zhaohui Huang
Long non-coding RNAs (lncRNAs) have been shown to play important roles in tumor formation and development. Small nucleolar RNA host gene 6 (SNHG6) is a recently identified cancer-related lncRNA, and its role in colorectal cancer (CRC) remains to be explored. The aim of this study was to evaluate the expression and function of SNHG6 in CRC. The expression of SNHG6 was detected by real time quantitative RT-PCR (qRT-PCR) in 74 CRC tissues and matched noncancerous tissues (NCTs). Relationships between the expression levels of SNHG6 and various clinicopathological features were analyzed by Chi-square test. The Kaplan-Meier method and log-rank test were applied to compare the survival distribution between different groups. CCK8 assay and colony formation assay were used to measure the effect of SNGH6 on cell proliferation. Flow cytometric analysis was performed to measure the effect of SNHG6 on cell cycle and apoptosis. Our results showed that SNHG6 was up-regulated more than 1.5-fold in 50.0% (37/74) of CRC tissues compared with paired NCTs (P < 0.0001). High level of SNHG6 expression was strongly associated with advanced tumor stage (P = 0.026) and predicted poor prognosis of CRC (P = 0.0215). The Cox proportional hazards model demonstrated that SNHG6 expression was an independent prognostic factor for CRC (HR, 2.568; 95% CI, 1.055–6.252; P = 0.038). Furthermore, SNHG6 knockdown by siRNA could inhibit cell proliferation, cell cycle progression, and induce apoptosis. Taken together, SNHG6 functions as an oncogene in CRC and appears as a novel prognositic factor for CRC patients.



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Tumor Budding and Poorly-differentiated Cluster in Prognostication in Stage II Colon Cancer

Publication date: Available online 2 January 2018
Source:Pathology - Research and Practice
Author(s): Victor Wai Kwan Lee, Kui Fat Chan
Comparison between tumor budding (TB) and poorly-differentiated clusters (PDC) for prognostication in Stage II colon cancer was not extensively studied in literature. In this retrospective study, we assessed TB (according to the consensus statement in 2016) and PDC in 135 Stage II colon adenocarcinoma resection specimens. Counting of TB and PDC was performed on H&E slides. High-grade TB (Bd3 (>=10 tumor buds in 0.785 mm²)) and high-grade PDC (Grade 3 (>=10)) were found in 20% and 17% of cases respectively. High-grade TB was associated with pT4 (p = 0.008) and presence of lymphovascular invasion (p = 0.001). There was correlation between TB and PDC grades (p < 0.001), in which both grades were the same or one grade apart in majority of the cases (97%). Both TB and PDC correlated with 5-year disease-specific survival (DSS) and overall survival (OS) (DSS for TB: 89% (Bd1); 73% (Bd2); 52% (Bd3), p = 0.001) (DSS for PDC: 88% (Grade 1); 72% (Grade 2); 61% (Grade 3), p = 0.021). Survival curves of Stage II colon cancer could be further stratified by TB and PDC (log-rank tests: TB p < 0.001; PDC p = 0.009). Combining TB and PDC grades into single grading system (high-grade: Bd3 + G2, Bd2 + G3, Bd3 + G3; low-grade: other combinations) was found to have strong correlation with both 5-year DSS (p < 0.001) and OS (p = 0.006). Our study has confirmed TB and PDC as independent prognostic factors in Stage II colon cancer, and might help selecting high-risk patients for adjuvant chemotherapy.



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Whole-exome sequencing of chondroid hamartoma of lung identified no driver mutations

Publication date: Available online 2 January 2018
Source:Pathology - Research and Practice
Author(s): Su Hye Choi, Hyeon-Chun Park, Min Sung Kim, Yeun-Jun Chung, Sug Hyung Lee




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Cancers, Vol. 10, Pages 7: Clinical Implementation of Robust Optimization for Craniospinal Irradiation

Cancers, Vol. 10, Pages 7: Clinical Implementation of Robust Optimization for Craniospinal Irradiation

Cancers doi: 10.3390/cancers10010007

Authors: Alexandria Tasson Nadia Laack Chris Beltran

With robust optimization for spot scanning proton therapy now commercially available, the ability exists to account for setup, range, and interfield uncertainties during optimization. Robust optimization is particularly beneficial for craniospinal irradiation (CSI) where the large target volume lends itself to larger setup uncertainties and the need for robust match lines can all be handled with the uncertainty parameters found inside the optimizer. Suggested robust optimization settings, parameters, and image guidance for CSI patients using proton therapy spot scanning are provided. Useful structures are defined and described. Suggestions are given for perturbations to be entered into the optimizer in order to achieve a plan that provides robust target volume coverage and critical structure sparing as well as a robust match line. Interfield offset effects, a concern when using multifield optimization, can also be addressed within the robust optimizer. A robust optimizer can successfully be employed to produce robust match lines, target volume coverage, and critical structure sparing under specified uncertainties. The robust optimizer can also be used to reduce effects arising from interfield uncertainties. Using robust optimization, a plan robust against setup, range, and interfield uncertainties for craniospinal treatments can be created. Utilizing robust optimization allows one to ensure critical structures are spared and target volumes are covered under the desired uncertainty parameters.

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Cancers, Vol. 10, Pages 5: Oncogenic Signalling through Mechanistic Target of Rapamycin (mTOR): A Driver of Metabolic Transformation and Cancer Progression

Cancers, Vol. 10, Pages 5: Oncogenic Signalling through Mechanistic Target of Rapamycin (mTOR): A Driver of Metabolic Transformation and Cancer Progression

Cancers doi: 10.3390/cancers10010005

Authors: Ellie Rad James Murray Andrew Tee

Throughout the years, research into signalling pathways involved in cancer progression has led to many discoveries of which mechanistic target of rapamycin (mTOR) is a key player. mTOR is a master regulator of cell growth control. mTOR is historically known to promote cell growth by enhancing the efficiency of protein translation. Research in the last decade has revealed that mTOR's role in promoting cell growth is much more multifaceted. While mTOR is necessary for normal human physiology, cancer cells take advantage of mTOR signalling to drive their neoplastic growth and progression. Oncogenic signal transduction through mTOR is a common occurrence in cancer, leading to metabolic transformation, enhanced proliferative drive and increased metastatic potential through neovascularisation. This review focuses on the downstream mTOR-regulated processes that are implicated in the "hallmarks" of cancer with focus on mTOR's involvement in proliferative signalling, metabolic reprogramming, angiogenesis and metastasis.

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CCR5+ Myeloid-Derived Suppressor Cells Are Enriched and Activated in Melanoma Lesions

Accumulation of myeloid-derived suppressor cells (MDSC) in melanoma microenvironment is supported by chemokine receptor/chemokine signaling. Although different chemokines were suggested to be involved in this process, the role of CCR5 and its ligands is not established. Using a Ret transgenic mouse melanoma model, we found an accumulation of CCR5+ MDSCs in melanoma lesions associated with both increased concentrations of CCR5 ligands and tumor progression. Tumor-infiltrating CCR5+ MDSCs displayed higher immunosuppressive activity than their CCR5− counterparts. Upregulation of CCR5 expression on CD11b+Gr1+ myeloid cells was induced in vitro by CCR5 ligands and other inflammatory factors. In melanoma patients, CCR5+ MDSCs were enriched at the tumor site and correlated with enhanced production of CCR5 ligands. Moreover, they exhibited a stronger immunosuppressive pattern compared with CCR5− MDSCs. Blocking CCR5/CCR5 ligand interactions increased survival of tumor-bearing mice and was associated with reduced migration and immunosuppressive potential of MDSCs in tumor lesions. Our findings define a critical role for CCR5 in recruitment and activation of MDSCs, suggesting a novel strategy for melanoma treatment.Significance: These findings validate the importance of the CCR5/CCR5 ligand axis not only for MDSC recruitment but also for further activation of their immunosuppressive functions in the tumor microenvironment, with potentially broad therapeutic implications, given existing clinically available inhibitors of this axis. Cancer Res; 78(1); 157–67. ©2017 AACR.

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Convergence to Cure Cancer through Research: A Message from the New Editor-in-Chief

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Dendritic Cells Enhance Polyfunctionality of Adoptively Transferred T Cells That Target Cytomegalovirus in Glioblastoma

Median survival for glioblastoma (GBM) remains <15 months. Human cytomegalovirus (CMV) antigens have been identified in GBM but not normal brain, providing an unparalleled opportunity to subvert CMV antigens as tumor-specific immunotherapy targets. A recent trial in recurrent GBM patients demonstrated the potential clinical benefit of adoptive T-cell therapy (ATCT) of CMV phosphoprotein 65 (pp65)–specific T cells. However, ex vivo analyses from this study found no change in the capacity of CMV pp65-specific T cells to gain multiple effector functions or polyfunctionality, which has been associated with superior antitumor efficacy. Previous studies have shown that dendritic cells (DC) could further enhance tumor-specific CD8+ T-cell polyfunctionality in vivo when administered as a vaccine. Therefore, we hypothesized that vaccination with CMV pp65 RNA-loaded DCs would enhance the frequency of polyfunctional CMV pp65-specific CD8+ T cells after ATCT. Here, we report prospective results of a pilot trial in which 22 patients with newly diagnosed GBM were initially enrolled, of which 17 patients were randomized to receive CMV pp65-specific T cells with CMV-DC vaccination (CMV-ATCT-DC) or saline (CMV-ATCT-saline). Patients who received CMV-ATCT-DC vaccination experienced a significant increase in the overall frequencies of IFNγ+, TNFα+, and CCL3+ polyfunctional, CMV-specific CD8+ T cells. These increases in polyfunctional CMV-specific CD8+ T cells correlated (R = 0.7371, P = 0.0369) with overall survival, although we cannot conclude this was causally related. Our data implicate polyfunctional T-cell responses as a potential biomarker for effective antitumor immunotherapy and support a formal assessment of this combination approach in a larger randomized study.Significance: A randomized pilot trial in patients with GBM implicates polyfunctional T-cell responses as a biomarker for effective antitumor immunotherapy. Cancer Res; 78(1); 256–64. ©2017 AACR.

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Janet A. Houghton, PhD: In Memoriam (1952-2017)

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MUC1-C Induces PD-L1 and Immune Evasion in Triple-Negative Breast Cancer

The immune checkpoint ligand PD-L1 and the transmembrane mucin MUC1 are upregulated in triple-negative breast cancer (TNBC), where they contribute to its aggressive pathogenesis. Here, we report that genetic or pharmacological targeting of the oncogenic MUC1 subunit MUC1-C is sufficient to suppress PD-L1 expression in TNBC cells. Mechanistic investigations showed that MUC1-C acted to elevate PD-L1 transcription by recruitment of MYC and NF-κB p65 to the PD-L1 promoter. In an immunocompetent model of TNBC in which Eo771/MUC1-C cells were engrafted into MUC1 transgenic mice, we showed that targeting MUC1-C associated with PD-L1 suppression, increases in tumor-infiltrating CD8+ T cells and tumor cell killing. MUC1 expression in TNBCs also correlated inversely with CD8, CD69, and GZMB, and downregulation of these markers associated with decreased survival. Taken together, our findings show how MUC1 contributes to immune escape in TNBC, and they offer a rationale to target MUC1-C as a novel immunotherapeutic approach for TNBC treatment.Significance: These findings show how upregulation of the transmembrane mucin MUC1 contributes to immune escape in an aggressive form of breast cancer, with potential implications for a novel immunotherapeutic approach. Cancer Res; 78(1); 205–15. ©2017 AACR.

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KRAS Oncogenic Signaling Extends beyond Cancer Cells to Orchestrate the Microenvironment

KRAS is one of the most frequently mutated oncogenes in cancer, being a potent initiator of tumorigenesis, a strong inductor of malignancy, and a predictive biomarker of response to therapy. Despite the large investment to understand the effects of KRAS activation in cancer cells, pharmacologic targeting of KRAS or its downstream effectors has not yet been successful at the clinical level. Recent studies are now describing new mechanisms of KRAS-induced tumorigenesis by analyzing its effects on the components of the tumor microenvironment. These studies revealed that the activation of KRAS on cancer cells extends to the surrounding microenvironment, affecting the properties and functions of its constituents. Herein, we discuss the most emergent perspectives on the relationship between KRAS-mutant cancer cells and their microenvironment components. Cancer Res; 78(1); 7–14. ©2017 AACR.

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Results from the European Prospective Investigation into Cancer and Nutrition Link Vitamin B6 Catabolism and Lung Cancer Risk

Circulating pyridoxal-5′-phosphate (PLP) has been linked to lung cancer risk. The PAr index, defined as the ratio 4-pyridoxic acid/(pyridoxal + PLP), reflects increased vitamin B6 catabolism during inflammation. PAr has been defined as a marker of lung cancer risk in a prospective cohort study, but analysis of a larger numbers of cases are needed to deepen the significance of this study. Here, we conducted a nested case–control study within the European Prospective Investigation into Cancer and Nutrition (EPIC, n = 521,330), which included 892 incident lung cancer cases and 1,748 controls matched by center, gender, date of blood collection, and date of birth. The association of PAr with risk of lung cancer was evaluated by using conditional logistic regression. Study participants with elevated PAr experienced higher risk of lung cancer in a dose–response fashion, with a doubling in PAr levels associated with 52% higher odds of lung cancer after adjustment for tobacco smoking, serum cotinine levels, educational attainment, and BMI [OR, 1.52; 95% confidence interval (CI) 1.27–1.81; P < 0.001]. Additional adjustment for intake of vegetables and fruits and physical activity did not materially affect risk association. The association of PAr with lung cancer risk was similar in both genders but slightly stronger in former smokers and in participants diagnosed with squamous cell carcinoma. This study provides robust evidence that increased vitamin B6 catabolism is independently associated with a higher risk of future lung cancer.Significance: This large cohort study firmly establishes an association between an index of vitamin B6 levels with lung cancer risk. Cancer Res; 78(1); 302–8. ©2017 AACR.

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Interleukin-27 Exerts Its Antitumor Effects by Promoting Differentiation of Hematopoietic Stem Cells to M1 Macrophages

The interleukin IL27 promotes expansion and differentiation of hematopoietic stem cells into myeloid progenitor cells. Many tumor-infiltrating myeloid cells exert immunosuppressive effects, but we hypothesized that the myeloid cells induced by IL27 would have antitumor activity. In this study, we corroborated this hypothesis as investigated in two distinct mouse transplantable tumor models. Malignant mouse cells engineered to express IL27 exhibited reduced tumor growth in vivo. Correlated with this effect was a significant increase in the number of tumor-infiltrating CD11b+ myeloid cells exhibiting a reduced immunosuppressive activity. Notably, these CD11b+ cells were characterized by an activated M1 macrophage phenotype, on the basis of increased expression of inducible nitric oxide synthase and other M1 biomarkers. In vivo depletion of these cells by administering anti–Gr-1 eradicated the antitumor effects of IL27. When admixed with parental tumors, CD11b+ cells inhibited tumor growth and directly killed the tumor in a nitric oxide-dependent manner. Mechanistically, IL27 expanded Lineage−Sca-1+c-Kit+ cells in bone marrow. Transplant experiments in Ly5.1/5.2 congenic mice revealed that IL27 directly acted on these cells and promoted their differentiation into M1 macrophages, which mobilized into tumors. Overall, our results illustrated how IL27 exerts antitumor activity by enhancing the generation of myeloid progenitor cells that can differentiate into antitumorigenic M1 macrophages.Significance: These findings show how the interleukin IL27 exerts potent antitumor activity by enhancing the generation of myeloid progenitor cells that can differentiate into antitumorigenic M1 macrophages.Cancer Res; 78(1); 182–94. ©2017 AACR.

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Pleiotropic Roles for ZEB1 in Cancer

ZEB1 is a prime element of a network of transcription factors that controls epithelial-to-mesenchymal transition (EMT), a reversible embryonic transdifferentiation program that allows partial or complete transition from an epithelial to a mesenchymal state. Aberrant expression of ZEB1 has been reported in a variety of human cancers, where it is generally believed to foster migration, invasion, and metastasis. Over the past few years, in vitro and in vivo observations have highlighted unsuspected intrinsic oncogenic functions of ZEB1 that impact tumorigenesis from its earliest stages. Located downstream of regulatory processes that integrate microenvironmental signals and directly implicated in feedback loops controlled by miRNAs, ZEB1 appears to be a central switch that determines cell fate. Its expression fosters malignant transformation through the mitigation of critical oncosuppressive pathways and through the conferment of stemness properties. ZEB1 is also a key determinant of cell plasticity, endowing cells with the capacity to withstand an aberrant mitogenic activity, with a profound impact on the genetic history of tumorigenesis, and to adapt to the multiple constraints encountered over the course of tumor development. Cancer Res; 78(1); 30–35. ©2017 AACR.

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Evidence for Kaposi Sarcoma Originating from Mesenchymal Stem Cell through KSHV-induced Mesenchymal-to-Endothelial Transition

The major transmission route for Kaposi sarcoma–associated herpesvirus (KSHV) infection is the oral cavity through saliva. Kaposi sarcoma (KS) frequently occurs in the oral cavity in HIV-positive individuals and is often the first presenting sign of AIDS. However, the oral target cells for KSHV infection and the cellular origin of Kaposi sarcoma remain unknown. Here we present clinical and experimental evidences that Kaposi sarcoma spindle cells may originate from virally modified oral mesenchymal stem cells (MSC). AIDS-KS spindle cells expressed neuroectodermal stem cell marker (Nestin) and oral MSC marker CD29, suggesting an oral/craniofacial MSC lineage of AIDS-associated Kaposi sarcoma. Furthermore, oral MSCs were highly susceptible to KSHV infection, and infection promoted multilineage differentiation and mesenchymal-to-endothelial transition (MEndT). KSHV infection of oral MSCs resulted in expression of a large number of cytokines, a characteristic of Kaposi sarcoma, and upregulation of Kaposi sarcoma signature and MEndT-associated genes. These results suggest that Kaposi sarcoma may originate from pluripotent MSC and KSHV infection transforms MSC to Kaposi sarcoma–like cells through MEndT.Significance: These findings indicate that Kaposi sarcomas, which arise frequently in AIDS patients, originate from neural crest-derived mesenchymal stem cells, with possible implications for improving the clnical treatment of this malignancy. Cancer Res; 78(1); 230–45. ©2017 AACR.

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Adaptive Evolution of the GDH2 Allosteric Domain Promotes Gliomagenesis by Resolving IDH1R132H-Induced Metabolic Liabilities

Hotspot mutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in a number of human cancers and confer a neomorphic enzyme activity that catalyzes the conversion of α-ketoglutarate (αKG) to the oncometabolite D-(2)-hydroxyglutarate (D2HG). In malignant gliomas, IDH1R132H expression induces widespread metabolic reprogramming, possibly requiring compensatory mechanisms to sustain the normal biosynthetic requirements of actively proliferating tumor cells. We used genetically engineered mouse models of glioma and quantitative metabolomics to investigate IDH1R132H-dependent metabolic reprogramming and its potential to induce biosynthetic liabilities that can be exploited for glioma therapy. In gliomagenic neural progenitor cells, IDH1R132H expression increased the abundance of dipeptide metabolites, depleted key tricarboxylic acid cycle metabolites, and slowed progression of murine gliomas. Notably, expression of glutamate dehydrogenase GDH2, a hominoid-specific enzyme with relatively restricted expression to the brain, was critically involved in compensating for IDH1R132H-induced metabolic alterations and promoting IDH1R132H glioma growth. Indeed, we found that recently evolved amino acid substitutions in the GDH2 allosteric domain conferred its nonredundant, glioma-promoting properties in the presence of IDH1 mutation. Our results indicate that among the unique roles for GDH2 in the human forebrain is its ability to limit IDH1R132H-mediated metabolic liabilities, thus promoting glioma growth in this context. Results from this study raise the possibility that GDH2-specific inhibition may be a viable therapeutic strategy for gliomas with IDH mutations.Significance: These findings show that the homonid-specific brain enzyme GDH2 may be essential to mitigate metabolic liabilities created by IDH1 mutations in glioma, with possible implications to leverage its therapeutic management by IDH1 inhibitors. Cancer Res; 78(1); 36–50. ©2017 AACR.

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Rapid Intraoperative Diagnosis of Pediatric Brain Tumors Using Stimulated Raman Histology

Accurate histopathologic diagnosis is essential for providing optimal surgical management of pediatric brain tumors. Current methods for intraoperative histology are time- and labor-intensive and often introduce artifact that limit interpretation. Stimulated Raman histology (SRH) is a novel label-free imaging technique that provides intraoperative histologic images of fresh, unprocessed surgical specimens. Here we evaluate the capacity of SRH for use in the intraoperative diagnosis of pediatric type brain tumors. SRH revealed key diagnostic features in fresh tissue specimens collected from 33 prospectively enrolled pediatric type brain tumor patients, preserving tumor cytology and histoarchitecture in all specimens. We simulated an intraoperative consultation for 25 patients with specimens imaged using both SRH and standard hematoxylin and eosin histology. SRH-based diagnoses achieved near-perfect diagnostic concordance (Cohen's kappa, κ > 0.90) and an accuracy of 92% to 96%. We then developed a quantitative histologic method using SRH images based on rapid image feature extraction. Nuclear density, tumor-associated macrophage infiltration, and nuclear morphology parameters from 3337 SRH fields of view were used to develop and validate a decision-tree machine-learning model. Using SRH image features, our model correctly classified 25 fresh pediatric type surgical specimens into normal versus lesional tissue and low-grade versus high-grade tumors with 100% accuracy. Our results provide insight into how SRH can deliver rapid diagnostic histologic data that could inform the surgical management of pediatric brain tumors.Significance: A new imaging method simplifies diagnosis and informs decision making during pediatric brain tumor surgery. Cancer Res; 78(1); 278–89. ©2017 AACR.

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CBX8 Exhibits Oncogenic Activity via AKT/{beta}-Catenin Activation in Hepatocellular Carcinoma

Deregulation of polycomb proteins influences the development and progression of hepatocellular carcinoma. Here we show that chromobox 8 (CBX8) expression is increased in hepatocellular carcinoma and correlates with poor outcome in two independent cohorts containing a total of 879 cases. Ectopic expression of CBX8 facilitated tumor growth and metastasis, whereas CBX8 silencing suppressed these effects. CBX8 efficiently activated AKT/β-catenin signaling via upregulation of the transcription factor EGR1 and miR-365-3p in a noncanonical manner: CBX8 directly bound the EGR1 promoter to enhance its activity. In the nucleus, CBX8 also interacted with EGR1 to prevent its degradation. Furthermore, CBX8 increased the transcription of miR-365a-3p, which promoted the nuclear localization of β-catenin by targeting the 3′-UTR ZNRF1. Inhibiting either EGR1 or miR-365a-3p partially rescued CBX8-mediated malignant phenotypes. In clinical samples, CBX8 expression closely correlated with EGR1, miR-365a-3p, and nuclear β-catenin. Collectively, our results show that CBX8 functions as an oncogene to upregulate EGR1 and miR-365-3p to stimulate the AKT/β-catenin pathway. This newly identified signaling axis may suggest new therapeutic strategies against hepatocellular carcinoma.Significance: Elucidation of a key new element of the β-catenin signaling pathway in liver cancer may suggest new therapeutic targets. Cancer Res; 78(1); 51–63. ©2017 AACR.

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Highlights from Recent Cancer Literature

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MYC Targeted Long Noncoding RNA DANCR Promotes Cancer in Part by Reducing p21 Levels

The MYC oncogene broadly promotes transcription mediated by all nuclear RNA polymerases, thereby acting as a positive modifier of global gene expression. Here, we report that MYC stimulates the transcription of DANCR, a long noncoding RNA (lncRNA) that is widely overexpressed in human cancer. We identified DANCR through its overexpression in a transgenic model of MYC-induced lymphoma, but found that it was broadly upregulated in many human cancer cell lines and cancers, including most notably in prostate and ovarian cancers. Mechanistic investigations indicated that DANCR limited the expression of cell-cycle inhibitor p21 (CDKN1A) and that the inhibitory effects of DANCR loss on cell proliferation could be partially rescued by p21 silencing. In a xenograft model of human ovarian cancer, a nanoparticle-mediated siRNA strategy to target DANCR in vivo was sufficient to strongly inhibit tumor growth. Our observations expand knowledge of how MYC drives cancer cell proliferation by identifying DANCR as a critical lncRNA widely overexpressed in human cancers.Significance: These findings expand knowledge of how MYC drives cancer cell proliferation by identifying an oncogenic long noncoding RNA that is widely overexpressed in human cancers. Cancer Res; 78(1); 64–74. ©2017 AACR.

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YAP1 and COX2 Coordinately Regulate Urothelial Cancer Stem-like Cells

Overcoming acquired drug resistance remains a core challenge in the clinical management of human cancer, including in urothelial carcinoma of the bladder (UCB). Cancer stem-like cells (CSC) have been implicated in the emergence of drug resistance but mechanisms and intervention points are not completely understood. Here, we report that the proinflammatory COX2/PGE2 pathway and the YAP1 growth-regulatory pathway cooperate to recruit the stem cell factor SOX2 in expanding and sustaining the accumulation of urothelial CSCs. Mechanistically, COX2/PGE2 signaling induced promoter methylation of let-7, resulting in its downregulation and subsequent SOX2 upregulation. YAP1 induced SOX2 expression more directly by binding its enhancer region. In UCB clinical specimens, positive correlations in the expression of SOX2, COX2, and YAP1 were observed, with coexpression of COX2 and YAP1 particularly commonly observed. Additional investigations suggested that activation of the COX2/PGE2 and YAP1 pathways also promoted acquired resistance to EGFR inhibitors in basal-type UCB. In a mouse xenograft model of UCB, dual inhibition of COX2 and YAP1 elicited a long-lasting therapeutic response by limiting CSC expansion after chemotherapy and EGFR inhibition. Our findings provide a preclinical rationale to target these pathways concurrently with systemic chemotherapy as a strategy to improve the clinical management of UCB.Significance: These findings offer a preclinical rationale to target the COX2 and YAP1 pathways concurrently with systemic chemotherapy to improve the clinical management of UCB, based on evidence that these two pathways expand cancer stem-like cell populations that mediate resistance to chemotherapy. Cancer Res; 78(1); 168–81. ©2017 AACR.

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Deficiency in Protein Tyrosine Phosphatase PTP1B Shortens Lifespan and Leads to Development of Acute Leukemia

Protein tyrosine phosphatase PTP1B is a critical regulator of signaling pathways controlling metabolic homeostasis, cell proliferation, and immunity. In this study, we report that global or myeloid-specific deficiency of PTP1B in mice decreases lifespan. We demonstrate that myeloid-specific deficiency of PTP1B is sufficient to promote the development of acute myeloid leukemia. LysM-PTP1B−/− mice lacking PTP1B in the innate myeloid cell lineage displayed a dysregulation of bone marrow cells with a rapid decline in population at midlife and a concomitant increase in peripheral blood blast cells. This phenotype manifested further with extramedullary tumors, hepatic macrophage infiltration, and metabolic reprogramming, suggesting increased hepatic lipid metabolism prior to overt tumor development. Mechanistic investigations revealed an increase in anti-inflammatory M2 macrophage responses in liver and spleen, as associated with increased expression of arginase I and the cytokines IL10 and IL4. We also documented STAT3 hypersphosphorylation and signaling along with JAK-dependent upregulation of antiapoptotic proteins Bcl2 and BclXL. Our results establish a tumor suppressor role for PTP1B in the myeloid lineage cells, with evidence that its genetic inactivation in mice is sufficient to drive acute myeloid leukemia.Significance: This study defines a tumor suppressor function for the protein tyrosine phosphatase PTP1B in myeloid lineage cells, with evidence that its genetic inactivation in mice is sufficient to drive acute myeloid leukemia. Cancer Res; 78(1); 75–87. ©2017 AACR.

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Type I IFN Receptor Signaling Controls IL7-Dependent Accumulation and Activity of Protumoral IL17A-Producing {gamma}{delta}T Cells in Breast Cancer

The protumoral activity of γδT17 cells has recently emerged in a wide variety of solid malignancies, including breast cancer. These cells exert their detrimental functions by promoting tumor growth, angiogenesis, and subsequent metastasis development. However, the intratumoral factors that regulate the biology of γδT17cells within the tumor microenvironment are less well understood. Here, using two experimental models of breast cancer, we reinforced the concept that tumor-infiltrating γδT17 cells are endowed with protumoral functions, which promote tumor progression and metastasis development. More importantly, we demonstrated a critical role for type I IFN signaling in controlling the preferential accumulation in the tumor bed of a peculiar subset of γδT17 cells displaying a CD27− CD3bright phenotype (previously associated with the invariant Vγ6Vδ1+ TCR). Interestingly, this effect was indirect and partially relied on the IFNAR1-dependent control of IL7 secretion, a factor that triggers proliferation and activating functions of deleterious γδT17 cells. Our work therefore identifies a key role of the type I IFN/IL7 axis in the regulation of intratumoral γδT17-cell functions and in the development of primary breast tumor growth and metastasis.Significance: Tumor-derived IL7 can represent a therapeutic target to prevent accumulation of immune cells endowed with potent protumoral activities. Cancer Res; 78(1); 195–204. ©2017 AACR.

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TGF{beta} Promotes Genomic Instability after Loss of RUNX3

Studies of genomic instability have historically focused on intrinsic mechanisms rather than extrinsic mechanisms based in the tumor microenvironment (TME). TGFβ is the most abundantly secreted cytokine in the TME, where it imparts various aggressive characteristics including invasive migration, drug resistance, and epithelial-to-mesenchymal transition (EMT). Here we show that TGFβ also promotes genomic instability in the form of DNA double strand breaks (DSB) in cancer cells that lack the tumor suppressor gene RUNX3. Loss of RUNX3 resulted in transcriptional downregulation of the redox regulator heme oxygenase-1 (HO-1 or HMOX1). Consequently, elevated oxidative DNA damage disrupted genomic integrity and triggered cellular senescence, which was accompanied by tumor-promoting inflammatory cytokine expression and acquisition of the senescence-associated secretory phenotype (SASP). Recapitulating the above findings, tumors harboring a TGFβ gene expression signature and RUNX3 loss exhibited higher levels of genomic instability. In summary, RUNX3 creates an effective barrier against further TGFβ-dependent tumor progression by preventing genomic instability. These data suggest a novel cooperation between cancer cell–extrinsic TGFβ signaling and cancer cell–intrinsic RUNX3 inactivation as aggravating factors for genomic instability.Significance: RUNX3 inactivation in cancer removes an antioxidant barrier against DNA double strand breaks induced by TGFβ expressed in the tumor microenvironment. Cancer Res; 78(1); 88–102. ©2017 AACR.

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Concurrent Diffuse Large B-Cell Lymphoma and Epstein-Barr Virus-Associated Smooth Muscle Tumour in the Small Bowel of an HIV-Positive Adult—a Case Report and Review of the Literature

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CRISPR/Cas9 Editing of the Mouse Thra Gene Produces Models with Variable Resistance to Thyroid Hormone

Thyroid , Vol. 0, No. 0.


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The Hobnail Variant of Papillary Thyroid Carcinoma: Clinical/Molecular Characteristics of a Large Monocentric Series and Comparison with Conventional Histotypes

Thyroid , Vol. 0, No. 0.


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Stable Isotope Pharmacokinetic Studies Provide Insight into Effects of Age, Sex, and Weight on Levothyroxine Metabolism

Thyroid , Vol. 0, No. 0.


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Repurposing of the CDK inhibitor PHA-767491 as a NRF2 inhibitor drug candidate for cancer therapy via redox modulation

Summary

Oxidative stress and cellular response mechanisms such as NRF2-mediated antioxidant responses play differential roles in healthy and diseased cells. Constant generation and elimination of high levels of reactive oxygen species is a hallmark of many cancer cell types; this phenomenon is not observed during steady state of healthy cells. Manipulation of NRF2 transcriptional activity and the cellular redox homeostasis therefore has potential to be therapeutically exploitable for cancer therapy by preferentially targeting cancer cells for induction of oxidative stress. We found that the NRF2 inhibitor brusatol triggered increased oxidative stress while compromising viability and proliferation of multiple myeloma cells. Using a repurposing approach we discovered that the Cdc7/CDK9 inhibitor PHA-767491 is also a potent inhibitor of NRF2 transcriptional activity. The molecule was identified by high throughput screening of a library of about 5900 drug-like molecules. Screening assays included two cell-based assays using HepG2 hepatocellular carcinoma cells: a) A NRF2 nuclear translocation assay, and b) A NRF2 luciferase reporter assay. Validation assays were performed in multiple myeloma cells and included detection of mitochondrial superoxide levels and MTS assays. We found that PHA-767491 treatment of multiple myeloma cells was associated with inhibition of nuclear translocation of NRF2, increased mitochondrial superoxide levels and inhibition of cell growth. Our findings suggest that PHA-767491 is a promising drug candidate for cancer therapy with NRF2 inhibitory potency contributing to its anti-cancer properties.

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Local changes in computational non-rapid eye movement sleep depth in infants

Publication date: February 2018
Source:Clinical Neurophysiology, Volume 129, Issue 2
Author(s): Anna-Liisa Satomaa, Outi Saarenpää-Heikkilä, Eero Huupponen, Turkka Kirjavainen, Juhani Heinonen, Sari-Leena Himanen
ObjectiveDeep NREM sleep and its hallmark EEG phenomenon slow wave activity (SWA) are under homeostatic control in adults. SWA is also locally regulated as it increases in the brain areas that have been used intensively. Moreover, in children, SWA is a marker of cortical maturation. In the present study the local properties of NREM sleep depth were evaluated using the quantitative mean frequency method. We aimed to study if age is related to NREM sleep depth in young infants. In addition, we studied if young infants have local differences in their NREM sleep.MethodsAmbulatory over-night polysomnographies were recorded in 59 healthy and full-term infants at the age of one month. The infants were divided into two age groups (<44 weeks and ≥44 weeks) to allow maturational evaluations.ResultsThe quantitative sleep depth analysis showed differences between the age groups. In addition, there were local sleep depth differences within the age groups.ConclusionsThe sleep depth change with age is most likely related to cortical maturation, whereas the local sleep depth gradients might also reflect the use-dependent properties of SWA.SignificanceThe results support the idea that young infants have frontal cortical processing.



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Predictors of deep brain stimulation outcome in tremor patients

Publication date: Available online 2 January 2018
Source:Brain Stimulation
Author(s): Claire Sandoe, Vibhor Krishna, Diellor Basha, Francesco Sammartino, Joao Tatsch, Marina Picillo, Lazzaro di Biase, Yu-Yan Poon, Clement Hamani, Duemani Reddy, Renato P. Munhoz, Andres M. Lozano, William D. Hutchison, Alfonso Fasano
BackgroundDeep brain stimulation of the ventro-intermedius nucleus of the thalamus is an established treatment for tremor of differing etiologies but factors that may predict the short- and especially long-term outcome of surgery are still largely unknown.MethodsWe retrospectively investigated the clinical, pharmacological, electrophysiological and anatomical features that might predict the initial response and preservation of benefit in all patients who underwent deep brain stimulation for tremor. Data were collected at the following time points: baseline (preoperative), one-year post-surgery, and most recent visit. Tremor severity was recorded using the Fahn-Tolosa-Marin Tremor Rating Scale and/or the Unified Parkinson's Disease Rating Scale.ResultsA total of 52 patients were included in the final analysis: 31 with essential tremor, 15 with cerebellar tremor of different etiologies, and 6 with Parkinson's disease. Long-term success (mean follow-up duration 34.7 months, range 1.7–121.1 months) was reported in 63.5%. Predictors of long-term benefit were: underlying tremor etiology (best outcome in Parkinson's disease, worst outcome in cerebellar tremor); age at surgery (the older the better); baseline tremor severity (the greater the better); lack of response to benzodiazepines; a more anterior electrode placement and single-unit beta power (the greater the better).ConclusionsSpecific patients' features (including single unit beta activity) and electrode locations may predict the short- and long-term benefit of thalamic stimulation for tremor. Future prospective studies enrolling a much larger sample of patients are needed to substantiate the associations detected by this retrospective study.



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Effects of Acoustic Environment on Tinnitus Behavior in Sound-Exposed Rats

Abstract

Laboratory studies often rely on a damaging sound exposure to induce tinnitus in animal models. Because the time course and ultimate success of the induction process is not known in advance, it is not unusual to maintain sound-exposed animals for months while they are periodically assessed for behavioral indications of the disorder. To demonstrate the importance of acoustic environment during this period of behavioral screening, sound-exposed rats were tested for tinnitus while housed under quiet or constant noise conditions. More than half of the quiet-housed rats developed behavioral indications of the disorder. None of the noise-housed rats exhibited tinnitus behavior during 2 months of behavioral screening. It is widely assumed that the "phantom sound" of tinnitus reflects abnormal levels of spontaneous activity in the central auditory pathways that are triggered by cochlear injury. Our results suggest that sustained patterns of noise-driven activity may prevent the injury-induced changes in central auditory processing that lead to this hyperactive state. From the perspective of laboratory studies of tinnitus, housing sound-exposed animals in uncontrolled noise levels may significantly reduce the success of induction procedures. From a broader clinical perspective, an early intervention with sound therapy may reduce the risk of tinnitus in individuals who have experienced an acute cochlear injury.

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Efficacy and the toxicity of the interstitial high-dose-rate brachytherapy in the management of recurrent keloids: 5-year outcomes

Publication date: Available online 2 January 2018
Source:Brachytherapy
Author(s): Ping Jiang, Matthias Geenen, Frank-André Siebert, Julia Bertolini, Bjoern Poppe, Ulf Luetzen, Juergen Dunst, Daniel Druecke
PurposeRecurring keloids are a clinical challenge. Interdisciplinary treatments are required in most cases. Owing to the wide variety of concepts, the optimal treatment regime remains unclear. Our clinic established a protocol of perioperative interstitial high-dose-rate brachytherapy with three fractions of 6 Gy and achieved an excellent 2-year local control rate of 94% (In search of the optimal treatment of keloids: Report of a series and a review of the literature). This report is an update on our long-term results of prospective study. Twenty-nine patients were included with a median followup of 5 years.Methods and MaterialsFrom 2009 to 2015, 29 patients with 37 recurrent keloids were treated with perioperative interstitial high-dose-rate brachytherapy; 3 patients had been previously treated with adjuvant external beam radiotherapy and presented with recurrences in the pretreated area. Brachytherapy was given in three fractions with a single dose of 6 Gy in 5-mm tissue depth and covered the scar in total length. Followup visits were scheduled at 6 weeks, 3 months, 6 months, 1 year, and annually thereafter. Therapeutic outcome was assessed in terms of recurrence, acute and late complications, and cosmetic results.ResultsNo procedure-related complications occurred. Improvement of keloid-related symptoms was noticed in all patients after treatment. After a median followup of 49.7 months (range: 7.9–91.9 months), three keloid recurrences and two hypertrophied scars were observed.ConclusionsOur results suggest that brachytherapy may be advantageous in the management of high-risk keloids, even after failure of external beam radiotherapy and other treatment procedures. Our three-fraction treatment schedule reduces the treatment period to 2 days and is therefore convenient for the patients.



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5 tips for securing a patient's airway

One of the first concerns an EMS provider should have about a patient with significant facial trauma is whether the patient has a patent airway and will be able to maintain that airway. Bleeding, soft tissue swelling, broken teeth and other fractures can all create partial or complete obstruction to the patient's airway. Care must be paid to how the airway is managed in these patients to strike ...

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Clinical scenario: Patient with facial trauma

Rescue 7, Engine 2, respond Code 3 to the intersection of Maple and Division. Multiple callers are reporting a cyclist struck by a vehicle at that location. You arrive on scene where law enforcement is already maintaining manual stabilization of the patient's head and neck. According to the first arriving officer, witnesses state that the patient was riding his bicycle through the intersection ...

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Effects of Acoustic Environment on Tinnitus Behavior in Sound-Exposed Rats

Abstract

Laboratory studies often rely on a damaging sound exposure to induce tinnitus in animal models. Because the time course and ultimate success of the induction process is not known in advance, it is not unusual to maintain sound-exposed animals for months while they are periodically assessed for behavioral indications of the disorder. To demonstrate the importance of acoustic environment during this period of behavioral screening, sound-exposed rats were tested for tinnitus while housed under quiet or constant noise conditions. More than half of the quiet-housed rats developed behavioral indications of the disorder. None of the noise-housed rats exhibited tinnitus behavior during 2 months of behavioral screening. It is widely assumed that the "phantom sound" of tinnitus reflects abnormal levels of spontaneous activity in the central auditory pathways that are triggered by cochlear injury. Our results suggest that sustained patterns of noise-driven activity may prevent the injury-induced changes in central auditory processing that lead to this hyperactive state. From the perspective of laboratory studies of tinnitus, housing sound-exposed animals in uncontrolled noise levels may significantly reduce the success of induction procedures. From a broader clinical perspective, an early intervention with sound therapy may reduce the risk of tinnitus in individuals who have experienced an acute cochlear injury.

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Idalopirdine, a selective 5-HT 6 receptor antagonist, reduces food intake and body weight in a model of excessive eating

Abstract

Obesity, from early childhood onwards, is a common societal problem. The overconsumption of sweet, salty and high-fat products are the main factors that cause excessive weight gain. It is therefore necessary to search for new drugs that affect satiety centers and reduce the sense of hunger and caloric intake. It has been suggested that the blockade of 5-HT₆ receptors may reduce food intake, and since idalopirdine is a clinically tested, selective 5HT₆ receptor antagonist, it was chosen to be examined in animal models of obesity. The activity of idalopirdine was measured in the rat model of excessive eating. Animals were on a high caloric diet that consisted of milk chocolate with nuts, cheese, salted peanuts and condensed milk. During a four-week experiment, the rats had constant access to standard feed and water ad libitum. Idalopirdine was administered intraperitoneally at a dose 5 mg/kg b.w./day. To establish whether idalopirdine would effectively suppress the rebound hyperphagia that accompanies refeeding, it was administered after a 20 h food deprivation period. Pica behavior was evaluated after the administration of idalopirdine to confirm that the suppression of food intake was not caused by visceral illness. The effect of the four-week treatment with idalopirdine on the amount of peritoneal adipose tissue, and on lipid and carbohydrate profiles in rats was also examined. The statistical significance was calculated using the one-way ANOVA post-hoc Tukey Multiple Comparison Test or the two-way ANOVA post-hoc Bonferroni Multiple Comparison Test. Idalopirdine significantly reduced caloric intake and prevented the development of obesity in tested animals. Rats, that received idalopirdine, had a smaller amount of adipose tissue in the peritoneum as well as lower glucose, triglyceride and cholesterol levels in comparison to the control group. Moreover, an anorectic action was not caused by abnormalities of the gastrointestinal tract, such as nausea. The obtained results indicate that idalopirdine reduces caloric intake and could be considered for further tests as a potential treatment of obesity.

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Bone marrow-derived mesenchymal stromal cells promote colorectal cancer cell death under low-dose irradiation

Bone marrow-derived mesenchymal stromal cells promote colorectal cancer cell death under low-dose irradiation

Bone marrow-derived mesenchymal stromal cells promote colorectal cancer cell death under low-dose irradiation, Published online: 02 January 2018; doi:10.1038/bjc.2017.415

Bone marrow-derived mesenchymal stromal cells promote colorectal cancer cell death under low-dose irradiation

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Reply to ‘Comment on ‘Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system”

Reply to 'Comment on 'Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system"

Reply to 'Comment on 'Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system", Published online: 02 January 2018; doi:10.1038/bjc.2017.426

Reply to 'Comment on 'Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system"

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Silencing of HMGA2 reverses retardance of cell differentiation in human myeloid leukaemia

Silencing of HMGA2 reverses retardance of cell differentiation in human myeloid leukaemia

Silencing of HMGA2 reverses retardance of cell differentiation in human myeloid leukaemia, Published online: 02 January 2018; doi:10.1038/bjc.2017.403

Silencing of HMGA2 reverses retardance of cell differentiation in human myeloid leukaemia

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Comment on ‘Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system’

Comment on 'Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system'

Comment on 'Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system', Published online: 02 January 2018; doi:10.1038/bjc.2017.343

Comment on 'Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system'

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Mechanisms of resistance to immune checkpoint inhibitors

Mechanisms of resistance to immune checkpoint inhibitors

Mechanisms of resistance to immune checkpoint inhibitors, Published online: 02 January 2018; doi:10.1038/bjc.2017.434

Mechanisms of resistance to immune checkpoint inhibitors

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MTOR inhibitor-based combination therapies for pancreatic cancer

MTOR inhibitor-based combination therapies for pancreatic cancer

MTOR inhibitor-based combination therapies for pancreatic cancer, Published online: 02 January 2018; doi:10.1038/bjc.2017.421

MTOR inhibitor-based combination therapies for pancreatic cancer

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Comparison of mobility and user satisfaction between a microprocessor knee and a standard prosthetic knee: a summary of seven single-subject trials

Insufficient evidence of the benefits provided by costlier microprocessor knees (MPKs) over nonmicroprocessor knees (NMPKs) often causes concern when considering MPK prescription. Thus, more studies are needed to demonstrate differences between MPKs and NMPKs and define sensitive outcomes to guide MPK prescription. The aim of this study was to evaluate the impact of switching from NMPK to MPK on measures of mobility and preference. Seven long-term NMPK users (all men, ages 50–84, 3–64 years postamputation) participated in this study, which use a single-subject design (ABA or BAB; A=NMPK, B=MPK). Mobility was assessed with the Amputee Mobility Predictor, Berg Balance Scale (BBS), L-Test, 6-Min Walk Test (6MWT) with Physiological Cost Index, and self-selected normal and very fast gait speeds. The preference between NMPK and MPK was evaluated by the Prosthesis Evaluation Questionnaire (PEQ) and the visual analog scale. Mobility improved with the MPK in six of seven participants, which was most often captured with BBS (median: +6 points) and 6MWT (median: +63 m). These improvements typically exceeded minimal clinically important difference or minimal detectable change thresholds. Most participants scored the MPK higher on the PEQ (median: +20 points) and six of seven expressed a global preference toward MPK. In the BAB group, the Amputee Mobility Predictor and BBS correlated with perception of change on several PEQ domains (Ρ≥0.59). In conclusion, MPKs may provide better outcomes and user satisfaction, particularly in those with lower mobility function. BBS and 6MWT were found to be the most sensitive measures to capture changes in mobility while using MPK for several weeks. Correspondence to Charla L. Howard, PhD, Methodist Rehabilitation Center, 1350 E. Woodrow Wilson Drive, Jackson, MS 39216, USA Tel: +1 601 364 3314; fax: +1 601 364 3305; e-mail: research@mmrcrehab.org Received June 15, 2017 Accepted November 6, 2017 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Use of clinical measures to document the effect of passive cycling on knee extensor spasticity and the ability to perform activities of daily living in spinal cord injury: a case report

The effects, on spasticity-related clinical measure results [initial knee flexion velocity during the pendulum test (F1-VEL); Spinal Cord Injury Spasticity Evaluation Tool (SCI-SET) scores], of a 5-week passive cycling program were assessed in a 67-year-old man with chronic, complete, thoracic-level SCI. Three weekly evaluations were performed before and after training, at the start, middle, and end of the training (ET), and 24 h following ET. The F1-VEL increased significantly from baseline, from ET to the 2-week follow-up evaluation. A trend was found for an improvement from baseline in SCI-SET scores, from middle of training onwards. These findings, which can inform clinical decisions and clinical trial development, suggest that the F1-VEL pendulum test result may be used to document the effect on knee extensor spasticity of a passive cycling program in chronic, complete, thoracic-level SCI. Whether this is also true for the SCI-SET requires future confirmation. Correspondence to Désirée B. Maltais, PhD, PT, Department of Rehabilitation, Université Laval; 1050, avenue de la médecine, Room 4457, Quebec City, QC, Canada G1V 0A6 Tel: 418 656 2131 x7964; fax: 418 656 5476; e-mail: desiree.maltais@rea.ulaval.ca Received November 8, 2017 Accepted December 13, 2017 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Effects of rehabilitation aftercare on work participation in patients with musculoskeletal disorders: a propensity score-matched analysis

Meta-analyses of rehabilitation studies in chronic back pain patients in Germany showed a lack of sustainability of rehabilitation programs. The German Pension Insurance therefore developed an intensified aftercare program to support rehabilitation outcomes. The aim of this study was to compare disability pension rates, income from regular employment, and duration of welfare benefits in patients with and without rehabilitation aftercare. We used administrative data on finished rehabilitation services. Patients were included if they were aged 18–60 years, had musculoskeletal disorders, and attended an outpatient or an inpatient rehabilitation program during the first term of 2007. Patients were excluded if they received an old-age pension, started a disability pension before January 2008, or died during the follow-up period. Patients with rehabilitation aftercare were matched by propensity scores with patients without rehabilitation aftercare. Estimation of the propensity score considered 20 potential confounders. There were no differences in the cumulative probability of receiving a disability pension. Moreover, patients with and without aftercare did not differ in their income from regular employment and the duration of different types of welfare benefits during the follow-up period. However, stratified analyses found a positive effect of an aftercare program on income in patients who attended a postacute rehabilitation program and patients who were at least 3 months absent because of sickness during the year preceding the initial rehabilitation program. Only patients with strong impairments benefit from attending an aftercare program. Allocation to aftercare programs and the focus on exercise only have to be reconsidered and revised. Correspondence to Dr Matthias Bethge, Institute of Social Medicine and Epidemiology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany Tel: +49 451 500 51280; fax: +49 451 500 51204; e-mail: matthias.bethge@uksh.de Received July 25, 2017 Accepted December 4, 2017 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Erratum to “Experience with a simplified eucapnic voluntary hyperventilation (EVH) device for diagnosis of exercise-induced bronchospasm”

In the abstract P205, "Experience with a simplified eucapnic voluntary hyperventilation (EVH) device for diagnosis of exercise-induced bronchospasm" (Ann Allergy Asthma Immunol. 2017;119(Suppl 1):S50-S51), the first author was mistakenly left off the abstract. The author list should read: C. Randolph1, R. Rosenthal*2, 1. Waterbury, CT; 2. Great Falls, VA.

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Incidence of anterior disc displacement without reduction of the temporomandibular joint in patients with dentofacial deformity

The aim of this study was to investigate the incidence of anterior disc displacement without reduction (ADDwoR) of the temporomandibular joint (TMJ) in patients with dentofacial deformity. Eighty-eight female patients (176 joints) with skeletal class III malocclusion and 33 female patients (66 joints) with skeletal class II malocclusion, with or without anterior open bite and asymmetry, were evaluated. Magnetic resonance imaging (MRI) of the TMJ was used to diagnose ADDwoR. A statistical analysis was performed to examine the relationship between ADDwoR and skeletal structure.

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Actigraphy data in pediatric research: The role of sleep diaries

When assessing children's sleep using actigraphy, researchers usually rely on a sleep diary completed by a parent as an aid in scoring actigraphic data. However, parental non-adherence in completing the sleep diary may significantly reduce the amount of available data. The current study examined the agreement between actigraphic data scored with and without a sleep diary in order to evaluate the impact of not using a sleep diary when studying children's sleep with actigraphy.

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Bleaching and enamel surface interactions resulting from the use of highly-concentrated bleaching gels

Publication date: March 2018
Source:Archives of Oral Biology, Volume 87
Author(s): Guillermo Grazioli, Lisia Lorea Valente, Cristina Pereira Isolan, Helena Alves Pinheiro, Camila Gonçalves Duarte, Eliseu Aldrighi Münchow
Tooth bleaching is considered a non-invasive treatment, although the use of highly-concentrated products may provoke increased surface roughness and enamel demineralization, as well as postoperative sensitivity. Thus, the aim of this study was to investigate whether hydrogen peroxide (H2O2) concentration would affect tooth bleaching effectiveness and the enamel surface properties. Enamel/dentin bovine specimens (6 × 4 mm) were immersed in coffee solution for 7 days and evaluated with a spectrophotometer (Easyshade; baseline), using the CIEL^*a^*b^* color parameters. Hardness was measured using a hardness tester. The specimens were randomly assigned into four groups: one negative control, in which the specimens were not bleached, but they were irradiated with a laser-light source (Whitening Lase II, DMC Equipments); and three groups using distinct H2O2 concentration, namely LP15% (15% Lase Peroxide Lite), LP25% (25% Lase Peroxide Sensy), and LP35% (35% Lase Peroxide Sensy), all products from DMC. The bleached specimens were also irradiated with the laser-light source. After bleaching, all specimens were evaluated using scanning electron microscopy (SEM). pH kinetics and rate was monitored during bleaching. The data were analyzed using ANOVA and Tukey's test (p < 0.05). All bleaching gels produced similar color change (p > 0.05). Concerning hardness, only the LP25% and LP35% significantly reduced hardness after bleaching; also, there was a progressive tendency for a greater percentage reduction in hardness with increased H2O2 concentration of the gel (R² = 0.9973, p < 0.001). SEM showed that LP25% and LP35% produced an etching pattern on enamel with prism rods exposure. In conclusion, H2O2 concentration above the 15% level does not increase bleaching effectiveness, and may increase the possibility for alteration of enamel hardness, surface morphology, and acidity of the medium. When using H2O2-based bleaching agents, dental practitioners should choose for less concentrated gels, e.g., around the 15% level.



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Identifying mechanisms of stance control: A single stimulus multiple output model-fit approach

Publication date: 15 February 2018
Source:Journal of Neuroscience Methods, Volume 296
Author(s): Adam D. Goodworth, Robert J. Peterka
BackgroundPosture control models are instrumental to interpret experimental data and test hypotheses. However, as models have increased in complexity to include multi-segmental dynamics, discrepancy has arisen amongst researchers regarding the accuracy and limitations of identifying neural control parameters using a single stimulus.New methodThe current study examines this topic using simulations with a parameterized model-fit approach. We first determine if the model-fit approach can identify parameters in the theoretical situation with no noise. Then, we measure variability and bias of parameter estimates when realistic noise is included. We also address how the accuracy is influenced by the frequency bandwidth of the stimulus, signal-to-noise of the data, and fitting procedures.ResultsWe found perfect identification of parameters in the theoretical model without noise. With realistic noise, bias errors were 4.4% and 7.6% for fits that included frequencies 0.02–1.2 Hz and 0.02–0.4 Hz, respectively. Fits between 0.02–1.2 Hz also had the lowest variability in parameter estimates compared to other bandwidths. Parameters with the lowest variability tended to have the largest influence on body sways. Results also demonstrated the importance of closely examining model fits because of limitations in fitting algorithms.Comparison with existing methodThe single-input model-fit approach may be a simpler and more practical method for identifying neural control mechanisms compared to a multi-stimulus alternative.ConclusionsThis study provides timely theoretical and practical considerations applicable to the design and analysis of experiments contributing to the identification of mechanisms underlying stance control of a multi-segment body.



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Evaluation of an artifact reduction strategy for electrically evoked auditory steady-state responses: Simulations and measurements

Publication date: 15 February 2018
Source:Journal of Neuroscience Methods, Volume 296
Author(s): Andreas Bahmer, Sabrina Pieper, Uwe Baumann
BackgroundElectrically evoked steady-state response (EASSR) recording is a measure of neuronal response strength after continuous electrical stimulation of the auditory system. In order to suppress the large electrical artifact generated by intracochlear electrical stimulation, a sophisticated artifact reduction processing strategy ("Hofmann procedure") has been proposed (Hofmann and Wouters, 2010). So far, EASSR recordings with artifact reduction procedures were reported only in cochlear implant (CI) users implanted with Cochlear devices (Macquarie, Australia).New methodHere, we demonstrate the application of the Hofmann procedure in CI users implanted with MED-EL (Innsbruck, Austria) devices. To demonstrate potential limitations of the procedure, we calculated discrete time Fourier transformations (DTFT) of various pulse patterns which may be used for EASSR.ResultsEASSR recordings were obtained in three subjects and processed with the Hofmann procedure. Neural response amplitude growth functions and phase for modulated and unmodulated pulse trains at various stimulation rates could be assessed. Simulations of three different interpolation methods aimed to suppress the electrical artifact show that the interpolation of a sinusoidal signal in a temporal window between 0 and 1 ms has demonstrated negligible impact on the spectral amplitude of the signal with a superior performance of a spline interpolation.Comparison with existing methodThe Hofmann procedure, initially developed for recording EASSRs with CIs from the manufacturer Cochlear, was validated for MED-EL devices.ConclusionIt is feasible to record EASSRs with the described measurement setup and CIs from the manufacturer MED-EL.



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Isolation of Satellite Glial Cells for High-Quality RNA purification

Publication date: Available online 2 January 2018
Source:Journal of Neuroscience Methods
Author(s): Sara Buskbjerg Jager, Lone Tjener Pallesen, Christian Bjerggaard Vaegter
BackgroundSatellite glial cells (SGCs) envelope the neuronal somas in the dorsal root ganglia (DRG) and are believed to provide important neuronal support. Animal models of peripheral nerve injury, diabetes or chemotherapy all demonstrate activation of SGCs, suggesting important physiological roles for SGCs in various states of peripheral neuropathy. However, the biology of these glial cells is only poorly characterized under normal as well as pathological conditions due to suboptimal isolation methods.New MethodThe method presented here allows complete dissociation and isolation of highly pure SGCs from rat DRGs by fluorescence-activated cell sorting (FACS) using SGC-specific antibodies. The method further allows purification of high-quality RNA from the fixed and permeabilized cells.ResultsThe purified RNA shows very little degradation, demonstrated by RNA integrity number (RIN) analysis with an average value of 8. The purified RNA, therefore, lends itself very well to downstream applications such as qPCR and transcriptome analysis.Comparison with existing methodsPrimary SGC cultures have previously been established for in vitro studies. Unfortunately, SGCs quickly change morphology and gene expression in vitro, complicating biologically meaningful interpretation of the obtained results. In contrast, this method allows the investigation of SGC gene regulation in vivo by isolation of high-quality RNA.ConclusionsThis method enables investigation of SGC transcriptional response in vivo by isolation and analysis of mRNA expression, allowing a more detailed investigation of SGC biology under normal as well as pathological conditions.



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Machine-Learning neuroimaging challenge for automated diagnosis of mild cognitive impairment: Lessons learnt

Publication date: Available online 2 January 2018
Source:Journal of Neuroscience Methods
Author(s): Isabella Castiglioni, Christian Salvatore, Javier Ramirez, Juan Manuel Górriz Sáez




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Preterm infants have narrowed upper airways, which may explain higher obstructive sleep apnea risk

Infants born preterm have significantly lower nasopharyngeal and oropharyngeal volumes, compared with newborn peers carried to full term, and those lower airway volumes are independent of the infants' gender, ethnicity or weight, according to a study published online Dec. 16, 2017 in Clinical Imaging.

 

Story published on Science Daily

Materials provided by Children's National Health System

Journal Reference: Clinical Imaging

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Bone marrow-derived mesenchymal stromal cells promote colorectal cancer cell death under low-dose irradiation

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Mechanisms of resistance to immune checkpoint inhibitors

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Reply to ‘Comment on ‘Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system”

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MTOR inhibitor-based combination therapies for pancreatic cancer

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Comment on ‘Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system’

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Silencing of HMGA2 reverses retardance of cell differentiation in human myeloid leukaemia

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Length of Recovery From Sports-Related Concussions in Pediatric Patients Treated at Concussion Clinics

Objectives: We quantified the length of recovery time by week in a cohort of pediatric sports–related concussion patients treated at concussion clinics, and examined patient and injury characteristics associated with prolonged recovery. Design: A retrospective, cohort design. Setting: Seven concussion clinics at a Midwest children's hospital. Patients: Patients aged 10 to 17 years with a diagnosed sports-related concussion presenting to the clinic within 30 days of injury. Main Outcome Measures: Length of recovery by week. Methods: Unadjusted and adjusted multinomial logistic regression analyses were used to model the effect of patient and injury characteristics on length of recovery by week. Results: Median length of recovery was 17 days. Only 16.3% (299/1840) of patients recovered within one week, whereas 26.4% took longer than four weeks to recover. By 2 months postinjury, 6.7% of patients were still experiencing symptoms. Higher symptom scores at injury and initial visit were significantly associated with prolonged symptoms by week. Patients who presented to the clinic more than 2 weeks postinjury or who had 2 or more previous concussions showed increased risk for prolonged recovery. Females were at greater risk for prolonged recovery than males (odds ratio = 2.08, 95% confidence interval = 1.49-2.89). Age was not significantly associated with recovery length. Conclusions: High symptom scores at injury and initial visit, time to initial clinical presentation, presence of 2 or more previous concussions, and female sex are associated with prolonged concussion recovery. Further research should aim to establish objective measures of recovery, accounting for treatment received during the recovery. Clinical Relevance: The median length of recovery is 17 days among pediatric sports–related concussion patients treated at concussion clinics. Only 16.3% of patients recovered within one week, whereas 26.4% took longer than 4 weeks to recover.

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Safety and Prognostic Utility of Provocative Exercise Testing in Acutely Concussed Adolescents: A Randomized Trial

Objective: To evaluate (1) systematic assessment of exercise tolerance in adolescents shortly after sport-related concussion (SRC) and (2) the prognostic utility of such assessment. Design: Prospective randomized controlled trial. Setting: University and community sports medicine centers. Participants: Adolescents with SRC (1–9 days from injury). Sixty-five were randomized and 54 completed the study (mean age 15 years, 4 days after injury). Interventions: Buffalo Concussion Treadmill Test (BCTT, n = 27) or not (controls, n = 27) on visit day #1. Heart rate threshold (HRt) at symptom exacerbation represented level of exercise tolerance. Participants reported symptoms daily for 14 days and then had follow-up BCTT (n = 54). Recovery was defined as returning to normal level of symptoms and exercise tolerance, verified by independent physician examination. Main Outcome Measures: Days to recovery and typical (≤21 days) versus prolonged recovery (>21 days). Mixed effects linear models and linear regression techniques examined symptom reports and time to recovery. Linear regression assessed the association of HRt with recovery time. Results: Days to recovery (P = 0.7060) and typical versus prolonged recovery (P = 0.1195) were not significantly different between groups. Symptom severity scores decreased in both groups over 14 days (P

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In Response to: Use of Head Guards in AIBA Boxing Tournaments—A Cross-Sectional Observational Study

No abstract available

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Ultrasound Guidance Does Not Improve the Results of Shock Wave for Plantar Fasciitis or Calcific Achilles Tendinopathy: A Randomized Control Trial

Objective: To establish whether the use of ultrasound to direct shock waves to the area of greater calcification in calcaneal enthesopathies was more effective than the common procedure of directing shock waves to the point where the patient has the most tenderness. Design: Two-armed nonblinded randomized control trial with allocation concealment. Setting: The Sports Clinic at Sydney University. Patients: Participants 18 years or older with symptomatic plantar fasciitis (PF) (with heel spur) or calcific Achilles tendinopathy (CAT). Seventy-four of 82 cases completed treatment protocol and 6-month follow-up. Interventions: Patients were randomized to receive either ultrasound-guided (UG) or patient-guided (PG) shock wave at weekly intervals over 3 to 5 weeks. Main Outcome Measures: Reduced pain on visual analog scale (VAS) and improved functional score on Maryland Foot Score (MFS) (for PF) or Victorian Institute of Sport Assessment-Achilles (VISA-A) (for CAT). Follow-up was at 6 weeks and 3 and 6 months. Results: Comparative 6-month improvements in MFS for the 47 PF cases were PG +20/100 and UG +14/100 (P = 0.20). Comparative 6-month improvement in VISA-A score for the 27 CAT cases were PG +35/100 and UG +27/100 (P = 0.37). Comparative (combined PF and CAT) 6-month improvement in VAS pain scores for all 38 PG cases were +38/100 with +37/100 for all 36 UG shock wave cases. Conclusions: Although both treatment groups had good clinical outcomes in this study, results for the 2 study groups were almost identical. Clinical Relevance: This study shows that there is no major advantage in the addition of ultrasound for guiding shock waves when treating calcaneal enthesopathies (PF and CAT).

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Smartphone-Enabled Heart Rate Variability and Acute Mountain Sickness

Introduction: The autonomic system and sympathetic activation appears integral in the pathogenesis of acute mountain sickness (AMS) at high altitude (HA), yet a link between heart rate variability (HRV) and AMS has not been convincingly shown. In this study we investigated the utility of the smartphone-derived HRV score to predict and diagnose AMS at HA. Methods: Twenty-one healthy adults were investigated at baseline at 1400 m and over 10 days during a trek to 5140 m. HRV was recorded using the ithlete HRV device. Results: Acute mountain sickness occurred in 11 subjects (52.4%) at >2650 m. HRV inversely correlated with AMS Scores (r = −0.26; 95% CI, −0.38 to −0.13: P 5 had a sensitivity of 83% and specificity of 60% to identify severe AMS (likelihood ratio 1.9). Baseline HRV at 1400 m was not predictive of either AMS at higher altitudes. Conclusions: The ithlete HRV score can be used to help in the identification of severe AMS; however, a baseline score is not predictive of future AMS development at HA.

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The Efficacy of Dynamic Contract-Relax Stretching on Delayed-Onset Muscle Soreness Among Healthy Individuals: A Randomized Clinical Trial

Objective: To evaluate the efficacy of dynamic contract-relax stretching on delayed-onset muscle soreness (DOMS) in the calf muscle of healthy individuals. Design: Randomized clinical trial. Setting: Research laboratory. Participants: Three groups of 16 healthy participants (n = 48) were recruited by convenience sampling. Interventions: Three sets of resisted bilateral heel-raising exercises until exhaustion were conducted to initiate DOMS. Participants were randomly allocated into control group without any interventions, dynamic contract-relax stretching (DS), or static stretching (SS) groups. Dynamic contract-relax stretching and SS groups performed DS and SS, respectively, on the dominant leg twice a day for 5 consecutive days (before time points of outcome measurements at 24, 48, 72, 96, and 120 hours postexercise, respectively). Main Outcome Measures: Muscle soreness, lower leg girth, pressure pain threshold (PPT), range of motion (ROM), and muscle strength were measured before exercise, immediately after, and at 24, 48, 72, 96, and 120 hours postexercise. Results: There was a significant effect of time in all outcome measures including muscle soreness, lower leg girth, PPT, ROM, and muscle strength; however, there were no significant group differences or group by time interactions. Conclusions: The effect of DS on relieving DOMS in the calf muscle is insignificant in this study. Further evidence is needed to prove the efficacy of DS on DOMS. Clinical Relevance: Stretching is commonly recommended before and after exercise; however, this study showed no significant impact of DS or SS in treating DOMS.

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Why Professional Football Players Chose Not to Reveal Their Concussion Symptoms During a Practice or Game

Objective: To determine why professional football players in Canada decided not to seek medical attention during a game or practice when they believed they had suffered a concussion. Design: Retrospective survey. Setting: Preseason Canadian Football League training camps. Participants: Four hundred fifty-four male professional football players. Main Outcome Measures: Reasons athletes did not seek medical attention for a presumed concussion during the previous season, how often this occurred and how important these reasons were in the decision process. Results: One hundred six of the 454 respondents (23.4%) believed they had suffered a concussion during their previous football season and 87 of the 106 (82.1%) did not seek medical attention for a concussion at least once during that season. The response "Did not feel the concussion was serious/severe and felt you could still continue to play with little danger to yourself" was the most commonly listed reason (49/106) for not seeking medical attention for a presumed concussion. Many players answered that they did not seek medical attention because they did not want to be removed from a game (42/106) and/or they did not want to risk missing future games (41/106) by being diagnosed with a concussion. Conclusions: Some professional football players who believed they had suffered a concussion chose not to seek medical attention at the time of injury. Players seemed educated about the concussion evaluation process and possible treatment guidelines, but this knowledge did not necessarily translate into safe and appropriate behavior at the time of injury.

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First-Aid Treatment for Friction Blisters: “Walking Into the Right Direction?”

Objective: Blisters are common foot injuries during and after prolonged walking. However, the best treatment remains unclear. The aim of the study was to compare the effect of 2 different friction blister treatment regimens, wide area fixation dressing versus adhesive tape. Design: A prospective observational cohort study. Setting: The 2015 Nijmegen Four Days Marches in the Netherlands. Participants: A total of 2907 participants (45 ± 16 years, 52% men) were included and received 4131 blister treatments. Interventions: Blisters were treated with either a wide area fixation dressing or adhesive tape. Main Outcome Measures: Time of treatment application was our primary outcome. In addition, effectiveness and satisfaction were evaluated in a subgroup (n = 254). During a 1-month follow-up period, blister healing, infection and the need for additional medical treatment were assessed in the subgroup. Results: Time of treatment application was lower (41.5 minutes; SD = 21.6 minutes) in the wide area fixation dressing group compared with the adhesive tape group (43.4 minutes; SD = 25.5 minutes; P = 0.02). Furthermore, the wide area fixation dressing group demonstrated a significantly higher drop-out rate (11.7% vs 4.0%, P = 0.048), delayed blister healing (51.9% vs 35.3%, P = 0.02), and a trend toward lower satisfaction (P = 0.054) when compared with the adhesive tape group. Conclusions: Wide area fixation dressing decreased time of treatment application by 2 minutes (4.5%) when compared with adhesive tape. However, because of lower effectiveness and a trend toward lower satisfaction, we do not recommend the use of wide area fixation dressing over adhesive tape in routine first-aid treatment for friction blisters.

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Associations Between Pedometer-Determined Physical Activity and Adiposity in Children and Adolescents: Systematic Review

Objective: The present review sought to examine the evidence on the associations between pedometer-determined physical activity and adiposity. Design: Of 304 potentially eligible articles, 36 were included. A search for observational studies was carried out using Cochrane Library (CENTRAL), the OVID (MEDLINE, Embase, and PsycINFO), EBSCOhost (Sportdiscus), and PEDro database from their commenced to July 2015. Of 304 potentially eligible articles, 36 were included. Results: Most studies (30/36; 83%) were cross sectional and all used proxies for adiposity, such as body mass index (BMI) or BMI z-score as the outcome measure. Few studies (2/36; 6%) focused on preschool children. There was consistent evidence of negative associations between walking and adiposity; significant negative associations were observed in 72% (26/36) of studies overall. Conclusions: The present review supports the hypothesis that higher levels of walking are protective against child and adolescent obesity. However, prospective longitudinal studies are warranted; there is a need for more research on younger children and for more "dose-response" evidence.

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Do Neurocognitive SCAT3 Baseline Test Scores Differ Between Footballers (Soccer) Living With and Without Disability? A Cross-Sectional Study

Objective: To determine if baseline Sport Concussion Assessment Tool, third Edition (SCAT3) scores differ between athletes with and without disability. Design: Cross-sectional comparison of preseason baseline SCAT3 scores for a range of England international footballers. Setting: Team doctors and physiotherapists supporting England football teams recorded players' SCAT 3 baseline tests from August 1, 2013 to July 31, 2014. Participants: A convenience sample of 249 England footballers, of whom 185 were players without disability (male: 119; female: 66) and 64 were players with disability (male learning disability: 17; male cerebral palsy: 28; male blind: 10; female deaf: 9). Assessment and Outcome Measures: Between-group comparisons of median SCAT3 total and section scores were made using nonparametric Mann–Whitney–Wilcoxon ranked-sum test. Main Results: All footballers with disability scored higher symptom severity scores compared with male players without disability. Male footballers with learning disability demonstrated no significant difference in the total number of symptoms, but recorded significantly lower scores on immediate memory and delayed recall compared with male players without disability. Male blind footballers' scored significantly higher for total concentration and delayed recall, and male footballers with cerebral palsy scored significantly higher on balance testing and immediate memory, when compared with male players without disability. Female footballers with deafness scored significantly higher for total concentration and balance testing than female footballers without disability. Conclusions: This study suggests that significant differences exist between SCAT3 baseline section scores for footballers with and without disability. Concussion consensus guidelines should recognize these differences and produce guidelines that are specific for the growing number of athletes living with disability.

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Twenty-Year Systematic Review of the Hip Pathology, Risk Factors, Treatment, and Clinical Outcomes in Artistic Athletes—Dancers, Figure Skaters, and Gymnasts

Objective: To identify (1) the predominant level of evidence of the clinical studies regarding the hip pathology, risk factors, treatment, and clinical outcomes in artistic athletes (dancers, figure skaters, and gymnasts) (2) the most commonly reported hip pathology, risk factors, treatments, and clinical outcomes in dancers, figure skaters, and gymnasts. Methods: To conduct this systematic review PubMed, EMBASE, and Scopus databases were searched for relevant studies and pertinent data were collected from the eligible articles. Included were studies which reported hip injuries in artistic athletes, the risk factors, treatment, and/or the clinical outcomes. We excluded case reports or irrelevant studies. No meta-analysis was performed because of study heterogeneity. The methodical index for nonrandomized studies (MINORS) criteria were used for quality control. Main Results: Thirty-eight studies were included in the analysis. The mean MINORS score was 13.6 ± 4.6 points indicating fair quality of evidence of the included articles. The predominant level of evidence was level IV. Chondrolabral pathology and muscle injuries were the most commonly reported pathologies. We found only 2 risk factor analysis studies; however, many studies reported risk correlation between artistic sports or imaging findings and hip pathology. Treatment strategies were reported in only 7 studies, clinical outcomes are significantly underreported. Conclusion: Chondrolabral pathology was the most commonly reported hip pathology in artistic athletes, however, prospective cohort studies are necessary to really understand these injuries and their associated risk factors. The lack of clinical outcomes is significant and future data collection is required to assess the effectiveness of the various treatments.

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Service Providers' Attitudes Toward Athletes With Eating Disorders

Objective: This study explored the nature and extent of Athlete Support Personnel's (ASP's) attitudes and beliefs toward athletes with symptoms of anorexia nervosa (AN) compared with those with symptoms of depression. Design: A cross-sectional study with a survey instrument. Setting: Sport and Exercise Science Professional Bodies and Associations in the Republic of Ireland, Northern Ireland, and mainland United Kingdom. Participants: One hundred fifty-two ASP. Main Outcome Measures: Participants read 2 vignettes describing a fictional female athlete with symptoms of AN or depression after which they completed an on-line survey examining attitudes toward such athletes. Results: Significant differences in patterns of responses were found between the 2 mental health conditions. The athlete with AN was viewed as significantly more difficult to communicate with F(1,148) = 18.17, P = 0.000, η2 = 0.11, more likely to be using her disorder to gain attention F(1,148) = 21.69, P = 0.000, η2 = 0.13, personally responsible for her condition F(1,148) = 10.10, P = 0.00, η2 = 0.06, and less likely to recover F(1,148) = 23.03, P = 0.000, η2 = 0.14 than the athlete with depression. Male service providers were more likely to believe that the athletes depicted were attention seeking F(1,148) = 10.69, P = 0.001, η2 = 0.07 and only had themselves to blame for their mental health condition F(1,148) = 12.97, P = 0.000, η2 = 0.08. Conclusions: Athlete support personnel report stigmatizing attitudes toward athletes with eating disorders such as AN. Male service providers hold greater negative attitudes toward athletes with mental health conditions.

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Reply

No abstract available

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The associations of sleep disturbances with dimensional psychotic experiences and quality of life in patients with schizophrenia spectrum disorders

Introduction: Sleep disturbances are distressing complaints commonly reported in individuals with psychotic disorders. Whilst increasing evidence suggests the continuum of psychosis, there has been a paucity of data on the association of sleep disturbances, including insomnia and nightmares, with specific dimensional psychotic experiences. The objectives of this study were to examine sleep disturbances in relation to dimensional psychotic experiences and quality of life in patients diagnosed with schizophrenia spectrum disorders.

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Lasting effects of early postnatal use of clomipramine on sleep-wakefulness cycle are ameliorated by ICV microinjection of Orexin-a (Hypocretin-1) and Orexin-b (Hypocretin-2)

Introduction: The main goal of present study was to consider hypothalamic Orexin (Hypocretin) producing neurons as the neurochemicaly identified cell population functional over-activation of which will contribute to the normalization of sleep-wakefulness disturbances produced in adult rats by their early postnatal exposure to Clomipramine. Pre-clinical studies have shown before that early postnatal exposure of rat pups to Clomipramine have lasting effects manifested in adult age in behavioral and sleep disturbances alike to disorders characteristic for major depressive disease (MDD).

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Factors influencing compliance to continuous positive airway pressure treatment in obstructive sleep apnea and mortality associated with treatment failure

Background and objectives: Poor compliance to therapy with continuous positive airway pressure (CPAP) treatment in patients with obstructive sleep apnea (OSA) is a major clinical problem. The aim of this study was to identify risk factors for and protective factors against discontinuation of CPAP and to estimate the mortality risk associated with CPAP treatment failure.

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Severity of REM sleep muscle atonia loss in idiopathic REM sleep behaviour disorder correlates with the degree of abnormalities in the vestibular evoked myogenic potentials

Introduction: The aim of this research is to correlate the severity of REM atonia loss in idiopathic REM sleep behavior disorder (iRBD) with vestibular-evoked myogenic potentials (VEMP) scores, which provide an indirect measure of severity of VEMP alterations. Brainstem dysfunction in established Parkinson's Disease (PD) has been associated with a consistent VEMP impairment, with alterations reported even in the early stages of the disease1,2. A misfunction of complex neurotransmitter connections within the brainstem probably accounts for the pathophysiology of iRBD, which is thought to predate synucleinopathies, such as PD, by many years3.

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The circadian rhythms of oxidative stress markers and melatonin metabolite in patients with autistic spectrum disorders

Introduction: Patients with autistic spectrum disorder (ASD) often have sleep problems, such as having difficulties in falling asleep, awakening frequently during night and waking up early in the morning. The relation between melatonin and sleep problems in ASD patients has been reported. Oxidative stress originates from an imbalance between the production of reactive oxygen species and reactive nitrogen species, and the antioxidant capacities of cells and organs. The relationship between oxidative stress and neurodegenerative disease has been reported.

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Perceived sleep quality of sleep profiles derived from connected sleep detector data

Introduction: The advance of connected sleep detection devices enables collecting sleep data automatically in free-living settings of large cohorts over long periods. This data is valuable in understanding which sleep patterns are most important for perceived sleep quality, which can in turn help people effectively improve their sleep.

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Comorbid insomnia and sleep apnoea is associated with greater neurocognitive impairment compared with OSA alone

Introduction: Comorbid insomnia with sleep apnoea (COMISA) affects as many as 30% of patients with obstructive sleep apnoea (OSA) and may compound the negative health consequences associated with both conditions. The aim of this study was to compare neurocognitive function between patients with COMISA to patients with OSA alone.

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Open your mouth! Should the somnologist care more about your teeth? Relations between sleep bruxism distribution and non-restorative sleep

Introduction: Beyond increased and abnormal teeth attrition, Sleep Bruxism (SB) may also directly impact sleep quality and related symptoms. We aimed at unraveling the existing relationships between nocturnal SB events (i.e. type, duration and sleep stage incidence) and structured clinical evaluations regarding sleep related daytime symptoms.

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Respiratory-related leg movements are associated with serotonergic antidepressants but not bupropion

Introduction: Respiratory-related leg movements (RRLMs) are contractions of the anterior tibialis occurring at the termination of respiratory events. Respiratory events terminating with such a leg movement produce larger heart rate increases than events without a leg movement, suggesting that RRLMs may potentially be a marker for the increased cardiovascular risk associated with obstructive sleep apnea (OSA). Selective serotonin reuptake inhibitors (SSRIs) and venlafaxine, but not bupropion, increase the risk for periodic limb movements of sleep (PLMS).

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