Three-dimensional printing of a low-cost, high-fidelity laryngeal dissection station

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A clicking larynx: Diagnostic and therapeutic challenges

A clicking larynx can be described as a clicking sensation in the neck on swallowing or when moving the head, often associated with a tender or painful area in the neck. Diagnosis and therapy are challenging. In this article, we present a case report and overview of the current literature. The clicking larynx most often is reported to be a result of a displaced cornu superior of the thyroid cartilage, an enlarged greater cornu of the hyoid bone, or a short distance between the thyroid cartilage and hyoid bone. If a possible cause is identified, surgery can be offered to the patient, although an explanation of the possible underlying anatomical cause also could be satisfying for the patient and avert surgery. Laryngoscope, 2017

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The Visual Agnosias and Related Disorders.

Background: There are many disorders of higher visual processing that result from damage to specific areas of the cerebral cortex that have a specific role in processing certain aspects (modalities) of vision. These can be grouped into those that affect the ventral, or "what?", pathway (e.g., object agnosia, cerebral achromatopsia, prosopagnosia, topographagnosia, and pure alexia), and those that affect the dorsal, or "where?", pathway (e.g., akinetopsia, simultanagnosia, and optic ataxia). Evidence Acquisition: This article reviews pertinent literature, concentrating on recent developments in basic science research and studies of individual patients. Results: An overview of the current understanding of higher cerebral visual processing is followed by a discussion of the various disorders listed above. Conclusions: There has been considerable progress in the understanding of how the extrastriate visual cortex is organized, specifically in relation to functionally specialized visual areas. This permits a better understanding of the individual visual agnosias resulting from damage to these areas. (C) 2017 by North American Neuro-Ophthalmology Society

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Atlas of Anatomy, Third Edition, Latin Nomenclature Edited by A. Gilroy and B. MacPherson. Illustrations by Markus Voll and Karl Wesker. New York, Stuttgart, Delhi, and Rio de Janeiro: Thieme Medical Publishers 2017.

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The Effect of Acute Taurine Ingestion on Human Maximal Voluntary Muscle Contraction.

Purpose: To examine the effect of taurine ingestion on maximal voluntary muscle torque and power in trained male athletes with different caffeine habits. Methods: Fourteen male athletes aged 21.8 +/- 2.5 years were separated into caffeine and non-caffeine consumers to control for the effect of caffeine withdrawal on muscle function. On separate occasions, participants performed four isokinetic or three maximal isometric knee extensions with and without taurine (40 mg/kg body mass) following a double blind, counterbalanced design. Muscle contractile performances were compared between the first sets as well as between the sets where these variables scored best. Results: In response to isokinetic contraction, taurine treatment in the non-caffeine consumers resulted in a significant fall in first (-16.1%; p=0.013) and best peak torque (-5.0%; p=0.016) as well as in first (-17.7%; p=0.015) and best power output (-8.0%; p=0.008). In the caffeine consumers deprived of caffeine, taurine intake improved best power (5.2%; p=0.045). With respect to the isometric variables, there was a significant decrease in the first (-5.1%; p=0.002) and best peak torque (-4.3%; p=0.032) in the non-caffeine group, but no effect in the group of caffeine consumers deprived of caffeine. Taurine ingestion increased blood taurine levels, but had no effect on plasma amino acid levels. Conclusion: Taurine ingestion is detrimental to maximal voluntary muscle power and both maximal isokinetic and isometric peak torque in non-caffeine consumers, whereas taurine ingestion in caffeine-deprived caffeine consumers improves maximal voluntary muscle power but has not effect on other aspects of contractile performance. (C) 2017 American College of Sports Medicine

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High expression of Bruton’s tyrosine kinase (BTK) is required for EGFR-induced NF-κB activation and predicts poor prognosis in human glioma

Malignant glioma is the most common primary brain tumor in adults and has a poor prognosis. However, there are no effective targeted therapies for glioma patients. Thus, the development of novel targeted thera...

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Traumatic Brain Injury in a Community-Based Cohort of Homeless and Vulnerably Housed Individuals

Journal of Neurotrauma , Vol. 0, No. 0.


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Clinical impact of tumor location on the colon cancer survival and recurrence: analyses of pooled data from three large phase III randomized clinical trials

Abstract

The aim of the present study was to determine whether or not the overall survival (OS) and disease-free survival (DFS) were affected by the tumor location in patients who underwent curative resection for colon cancer in a pooled analysis of three large phase III studies performed in Japan. In total, 4029 patients were included in the present study. Patients were classified as having right-side colon cancer (RC) if the primary tumor was located in the cecum, ascending colon, hepatic flexure or transverse colon, and left-side colon cancer (LCC) if the tumor site was within the splenic flexure, descending colon, sigmoid colon or recto sigmoid junction. The risk factors for the OS and DFS were analyzed. In the present study, 1449 patients were RC, and 2580 were LCC. The OS rates at 3 and 5 years after surgery were 87.6% and 81.6% in the RC group and 91.5% and 84.5% in the LCC group, respectively. Uni- and multivariate analyses showed that RRC increased the risk of death by 19.7% (adjusted hazard ratio = 1.197; 95% confidence interval, 1.020–1.408; P = 0.0272). In contrast, the DFS was similar between the two locations. The present study confirmed that the tumor location was a risk factor for the OS in patients who underwent curative treatment for colon cancer. Tumor location may, therefore, need to be considered a stratification factor in future phase III trials of colon cancer.

The present study confirmed that the tumor location was a risk factor for the OS in patients who underwent curative treatment for colon cancer. Tumor location may, therefore, need to be considered a stratification factor in future phase III trials of colon cancer.

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CT imaging features associated with recurrence in non-small cell lung cancer patients after stereotactic body radiotherapy

Predicting recurrence after stereotactic body radiotherapy (SBRT) in non-small cell lung cancer (NSCLC) patients is problematic, but critical for the decision of following treatment. This study aims to investi...

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Comparative study of the effects of different radiation qualities on normal human breast cells

As there is a growing number of long-term cancer survivors, the incidence of carcinogenesis as a late effect of radiotherapy is getting more and more into the focus. The risk for the development of secondary m...

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Comparative anatomy on 3-D MRI of the urogenital sinus and the periurethral area before and during the second stage of labor during childbirth

Abstract

Purpose of the study

To describe the observable MRI changes in the urogenital sinus during the second stage of labor and delivery by comparing the changes in the positions of the anatomical structures of the maternal perineum using MRI-based vector 3-D models.

Materials and methods

Seven pregnant women underwent 3-D MRI sequences using a Philips 1 T Panorama open MRI during the pre-labor period and during the second stage of labor. A 3-D vector reconstruction platform (BABYPROGRESS, France) enabled the transformation of volumes of 2-D images into finite element meshes. The polygonal meshes labeled with the principal components of the urogenital sinus were used as part of a biomechanical study of the pressure exerted on the perineum during fetal descent.

Results

The expansion of the urogenital sinus was observed in all patients. Qualitative stretching was observed toward the rear and bottom of the iliococcygeus, pubococcygeus, puborectalis and obturator internus muscles. Significant length differences were measured along the iliococcygeus and pubococcygeus muscles but not along the tendinous arch of the levator ani or the puborectalis muscle. The inversion of the levator ani muscle curvature was accompanied by the transmission of pressure generated during fetal descent to the pubic muscle insertions and the descent of the tendinous arch of the levator ani.

Conclusion

Mechanical pressures responsible for the tensioning of the constituent muscles of the urogenital sinus were qualitatively identified during the second stage of labor. MRI-based vector 3-D models allow the quantitative assessment of levator ani muscle stretching during labor, but 2-D MRI is not sufficient for describing perineal expansion. Vector 3-D models from larger scale studies have the potential to aid in the calibration of a realistic simulation based on the consideration of the reaction of each muscular element. These models offer perspectives to enhance our knowledge regarding perineal expansion during childbirth as a risk factor for postpartum perineal defects.

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Practical aspects of immunoglobulin replacement

A woman was diagnosed with common variable immunodeficiency (CVID) at the age of 42 years. She began having infections when she was 24 years of age. Her history included chronic sinusitis and 3 bacterial pneumonias at different times in both lungs. Her infections necessitated antibiotic therapy almost every other month. A specialist in allergy and immunology finally made the diagnosis of immune deficiency and, specifically, CVID on testing. Her immunoglobulin levels were extremely low: serum IgG, 250 mg/dL; IgA, less than 7 mg/dL; and IgM, 40 mg/dL.

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Idiopathic CD4 lymphocytopenia

Idiopathic CD4 lymphocytopenia (ICL) is a rare condition characterized by an unexplained deficit of circulating CD4 T cells leading to increased risk of serious opportunistic infections. The pathogenesis, etiology, clinical presentation, and best treatment options remain unclear.

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Kounis syndrome should be excluded when physicians treat patients with anaphylaxis

The article, "Epinephrine Use for Anaphylaxis: Too Seldom, Too Late," by Chooniedass et al1 was an interesting read. Therefore, we would like to introduce Kounis syndrome, which is defined as the concurrence of acute coronary syndromes with conditions associated with mast cell and platelet activation and involving interrelated and interacting inflammatory cells in the setting of allergic or hypersensitivity and anaphylactic or anaphylactoid insults.2 Akoz et al3 reported that the annual incidence of Kounis syndrome at the emergency department among all admissions and patients with allergy was 19.4 per 100,000 (27 of 138,911) and 3.4% (27 of 793), respectively.

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Expression of immunoglobulin D is increased in chronic rhinosinusitis

Immunoglobulin (Ig) D is largely localized to the upper airway and reacts with colonizing respiratory pathogens.

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Instructions for Authors

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Comparison of fractional exhaled nitric oxide levels measured using the NIOX VERO and NOA 280i

Fractional exhaled nitric oxide (FeNO) is a type 2 biomarker of eosinophilic airway inflammation and predicts the likelihood of corticosteroid responsiveness in patients with eosinophilic asthma.1,2 Several devices are available to measure FeNO levels for research purposes or in clinical practice worldwide, including the Sievers Nitric Oxide Analyzer (NOA 280i; GE Analytical Instruments, Boulder, Colorado), a stationary chemiluminescence analyzer, and the NIOX VERO (Aerocrine AB, Solna, Sweden), a portable electrochemical analyzer.

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Information for Readers

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An analysis of insurance and other factors associated with asthma-related emergency department visits, 2009–2014

Asthma is a common chronic airway disorder characterized by periods of reversible airflow obstruction known as asthma attacks. Although no cure for asthma is known, control of the frequency and intensity of exacerbations and associated functional limitations is desirable. Uncontrolled asthma has a significant cost to families and society, including costs associated with work and school absenteeism, emergency department (ED) visits, and hospitalizations. Costs associated with asthma, including costs of children and adults missing school or work after an asthma attack, continue to increase.

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Risk factors for severe anaphylaxis in the United States

Anaphylaxis is an acute systemic allergic reaction and may be life-threatening.

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Contemporary issues in anaphylaxis and the evolution of epinephrine autoinjectors

Food allergy and anaphylaxis appear to be increasing in the United States, especially in young children, and preparedness is paramount to successful emergency management in the community. Although the treatment of choice for anaphylaxis is epinephrine delivered by autoinjection, some devices are challenged by less user-friendly designs or pose the risk of injury, especially in young patients. Human factors engineering has played a larger role in the development of more recent epinephrine autoinjector technologies and will continue to play a role in the evolution and future design of epinephrine autoinjectors.

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Influence of rhinitis control and inspiratory loop flattening on perceived asthma control

Patient-reported outcome measures in asthma and rhinitis are important tools for acute and longitudinal disease monitoring. The Asthma Control Test (ACT)1,2 and the Rhinitis Control Assessment Test (RCAT)3 are 2 brief, valid measures that can be used to monitor the assessment of patient control of these respective conditions. Children and adults with asthma are frequently noted to have comorbid allergic or chronic (nonallergic) rhinitis and vice-versa.4 These conditions can influence each other, and there are emerging hypotheses that suggest there is "one airway" from nose to lung.

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This book is a comprehensive collection of the experimental techniques that are most commonly used for...

This book is a comprehensive collection of the experimental techniques that are most commonly used for basic science research. It is divided into 15 chapters, each chapter representing a different laboratory technique. Within every chapter is a detailed and well-rounded discussion of that particular research method, including descriptions of relevant scientific principles, basic science concepts, and laboratory protocols. The book provides a bridge between basic research and clinical science by including relevant applications, typical scenarios or case studies, and potential limitations, with troubleshooting tips for each experimental method.

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Table of Contents

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Disseminated Mycobacterium avium intracellulare leading to protein-losing enteropathy in an elderly man with idiopathic CD4 lymphocytopenia

Idiopathic CD4 lymphocytopenia (ICL) is a clinical diagnosis in which CD4+ T lymphocytes constitute fewer than 300 cells/μL or fewer than 20% of total T cells without evidence of human immunodeficiency virus (HIV) or any defined immunodeficiency or therapy associated with decreased levels of CD4+ T cells.1 Mycobacterium is one of the most common opportunistic infections in ICL. We report on a unique case of a 64-year-old man with ICL who developed protein-losing enteropathy (PLE) secondary to disseminated Mycobacterium avium intracellulare (MAI) infection that resolved with successful treatment of the mycobacterium infection.

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Editorial Board

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Effects of Respiratory Muscle Strength Training in Classically Trained Singers

Many voice pedagogy practices revolve around the notion of controlling airflow and lung volumes and focus heavily on the concepts of breath support and breath control. Despite this emphasis, the effects of increased respiratory muscle strength on airflow and phonation patterns in trained singers remain unknown. This study addressed whether singers could increase respiratory muscle strength with progressive threshold training and whether respiratory muscle strength increases had measurable effect on voice outcomes.

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Investigation of Flexible High-Speed Video Nasolaryngoscopy

High-speed videolaryngoscopy is widely used in voice practices as a complement to videostroboscopy, especially when it is desired to visualize asymmetric and nonperiodic vocal fold vibration or voice onset and offset. Because of the requirement for greater illumination at higher frame rates, the high-speed exam is usually performed with a rigid transoral laryngoscope. Although it is possible to obtain color high-speed video images with a flexible fiberoptic nasoendoscope, the results are often disappointing because of the inability to provide adequate lighting inside the larynx.

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Judgments of Intelligence and Likability of Young Adult Female Speakers of American English: The Influence of Vocal Fry and the Surrounding Acoustic-Prosodic Context

Vocal fry is a prevalent speech feature in college-aged American women living in the United States. However, there is currently little consensus about how its use influences listener judgments of the speaker. This study investigated how vocal fry influences judgments of intelligence and the likability of young adult female speakers of American English while taking into account the surrounding acoustic-prosodic context, specifically voice pitch and speech rate.

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Emotional response of undergraduates to cadaver dissection

Abstract

Introduction The most effective way to learn human anatomy is through cadaver dissection. Historically, cadaver dissection has been the provenance of professional schools. Increasingly, cadaver-based courses in human anatomy are shifting to the undergraduate level, which creates both problems and opportunities because of differences between undergraduate and graduate student populations. Anxiety associated with dissecting cadavers can create a barrier to learning, and ultimately, entry into the health and medical sciences for some demographic subpopulations of undergraduates.

Methods We surveyed 76 students in 2007 and 51 students in 2009 at four times in the semester to investigate the timing and sociodemographic predictors of anxiety over cadaver dissection. We followed this with a second survey of 44 students in 2014 to test the effect of humanization of cadaver donors (providing information about donor occupation and cause of death) to reduce student anxiety.

Results Students experienced anxiety upon first exposure to cadaver dissection. Female students experienced greater anxiety than male students upon first exposure to cadavers but this effect was short-lived. Self-identified non-white, non-Christian students experienced sustained anxiety throughout the semester, likely because cadaver stress compounded social and financial stressors unique to international students. Humanization was effective in reducing anxiety in non-white, non-Christian students but had the unexpected effect of increasing anxiety in female students.

Conclusions We recommend that humanizing information be offered to students who seek it out, but not forced upon students for whom the information would only add to their stress. This article is protected by copyright. All rights reserved.

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NY-ESO-1 Vaccination in Combination with Decitabine Induces Antigen-Specific T-Lymphocyte Responses in Patients with Myelodysplastic Syndrome

Purpose: Treatment options are limited for patients with high-risk myelodysplastic syndrome (MDS). The azanucleosides, azacitidine and decitabine, are front-line therapy for MDS that induce promoter demethylation and gene expression of the highly immunogenic tumor antigen NY-ESO-1. We demonstrated that AML patients receiving decitabine exhibit induction of NY-ESO-1 expression in circulating blasts. We hypothesized that vaccinating against NY-ESO-1 in MDS patients receiving decitabine would capitalize upon induced NY-ESO-1 expression in malignant myeloid cells to provoke an NY-ESO-1-specific-MDS directed cytotoxic T-cell immune response. Experimental Design: In a phase I study, 9 MDS patients received an HLA unrestricted NY-ESO-1 vaccine (CDX-1401 + poly-ICLC) in a non-overlapping schedule every four weeks with standard dose decitabine. Results: Analysis of samples serially obtained from the 7 patients who reached the end-of-study demonstrated induction of NY-ESO-1 expression in 7/7 patients and NY-ESO-1 specific CD4+ and CD8+ T-lymphocyte responses in 6/7 and 4/7 of the vaccinated patients respectively. Myeloid cells expressing NY-ESO-1, isolated from a patient at different time-points during decitabine therapy, were capable of activating a cytotoxic response from autologous NY-ESO-1-specific T-lymphocytes. Vaccine responses were associated with a detectable population of CD141Hi conventional dendritic cells, which are critical for the uptake of NY-ESO-1 vaccine and have a recognized role in anti-tumor immune responses. Conclusion: These data indicate that vaccination against induced NY-ESO-1 expression can produce an antigen-specific immune response in a relatively non-immunogenic myeloid cancer and highlight the potential for induced-antigen directed immunotherapy in a group of patients with limited options.

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Discrimination of germline EGFR T790M mutations in plasma cell-free DNA allows study of prevalence across 31,414 cancer patients

Purpose: Plasma cell-free DNA (cfDNA) analysis is increasingly used clinically for cancer genotyping, but may lead to incidental identification of germline risk alleles. We studied EGFR T790M mutations in non-small cell lung cancer (NSCLC) toward the aim of discriminating germline and cancer-derived variants within cfDNA. Experimental Design: Patients with EGFR-mutant NSCLC, some with known germline EGFR T790M, underwent plasma genotyping. Separately, deidentified genomic data and buffy coat specimens from a clinical plasma next-generation sequencing (NGS) laboratory were reviewed and tested. Results: In patients with germline T790M mutations, the T790M allelic fraction (AF) in cfDNA approximates 50%, higher than that of EGFR driver mutations. Review of plasma NGS results reveals three groups of variants: a low AF tumor group, a heterozygous group (~50% AF), and a homozygous group (~100% AF). As the EGFR driver mutation AF increases, the distribution of the heterozygous group changes, suggesting increased copy number variation from increased tumor content. Excluding cases with high copy number variation, mutations can be differentiated into somatic variants and incidentally identified germline variants. We then developed a bioinformatic algorithm to distinguish germline and somatic mutations; blinded validation in 21 cases confirmed a 100% positive predictive value for predicting germline T790M. Querying a database of 31,414 patients with plasma NGS, we identified 48 with germline T790M, 43 with non-squamous NSCLC (p<0.0001). Conclusion: With appropriate bioinformatics, plasma genotyping can accurately predict the presence of incidentally detected germline risk alleles. This finding in patients indicates a need for genetic counseling and confirmatory germline testing.

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Cytoplasmic Cyclin E Mediates Resistance to Aromatase Inhibitors in Breast Cancer

Purpose: Preoperative aromatase inhibitor (AI) therapy has demonstrated efficacy in hormone receptor (HR)-positive postmenopausal breast cancer. However, many patients have disease that is either intrinsically resistant to AIs or that responds initially but develops resistance after prolonged exposure. We have shown that patients with breast tumors expressing the deregulated forms of cyclin E (low molecular weight forms [LMW-E]) have poor overall survival. Herein, we hypothesize that LMW-E expression can identify HR-positive tumors that are unresponsive to neoadjuvant AI therapy due to the inability of AIs to induce a cytostatic effect. Experimental Design: LMW-E was examined in breast cancer specimen from 58 patients enrolled in the American College of Surgeons Oncology Group Z1031, a neoadjuvant AI clinical trial. The mechanisms of LMW-E mediated resistance to AI were evaluated in vitro and in vivo using an inducible model system of cyclin E (full-length and LMW-E) in aromatase-overexpressing MCF7 cells. Results: Breast cancer recurrence-free interval was significantly worst in LMW-E positive patients who received AI neoadjuvant therapy. Upon LMW-E induction, MCF7 xenografts were unresponsive to letrozole in vivo, resulting in increased tumor volume after treatment with AIs. LMW-E expression overcame cell cycle inhibition by AIs in a CDK2/Rb-dependent manner and inhibition of CDK2 by dinaciclib reversed LMW-E-mediated resistance, while treatment with palbociclib, a CDK4/6 inhibitor, did not. Conclusion: Collectively, these findings suggest that cell cycle deregulation by LMW-E mediates resistance to AIs and a combination of CDK2 inhibitors and AIs may be an effective treatment in patients with HR-positive tumors that express LMW-E.

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4-1BB agonist focuses CD8+ tumor-infiltrating T-cell growth into a distinct repertoire capable of tumor recognition in pancreatic cancer

Purpose: Survival for pancreatic ductal adenocarcinoma (PDAC) patients is extremely poor and improved therapies are urgently needed. Tumor-infiltrating lymphocyte (TIL) adoptive cell therapy (ACT) has shown great promise in other tumor types, such as metastatic melanoma where overall response rates of 50% have been seen. Given this success and the evidence showing that T-cell presence positively correlates with overall survival in PDAC, we sought to enrich for CD8+ TIL capable of autologous tumor recognition. Additionally, we explored the phenotype and TCR repertoire of the CD8+ TIL in the tumor microenvironment. Experimental Design: We used an agonistic 4-1BB mAb during the initial tumor fragment culture to provide 4-1BB co-stimulation and assessed changes in TIL growth, phenotype, repertoire, and anti-tumor function. Results: Increased CD8+ TIL growth from PDAC tumors was achieved with the aid of an agonistic 4-1BB mAb. Expanded TIL were characterized by an activated but not terminally differentiated phenotype. Moreover, 4-1BB stimulation expanded a more clonal and distinct CD8+ TIL repertoire than IL-2 alone. TIL from both culture conditions displayed MHC class I-restricted recognition of autologous tumor targets. Conclusions: Co-stimulation with an anti-4-1BB mAb increases the feasibility of TIL therapy by producing greater numbers of these tumor-reactive T cells. These results suggest that TIL ACT for PDAC is a potential treatment avenue worth further investigation for a patient population in dire need of improved therapy.

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Long-term results of temperature-controlled endobiliary radiofrequency ablation in a normal swine model

Endobiliary radiofrequency ablation (EB-RFA) is a new adjunctive method for biliary drainage restoration. However, a concern remains about long-term adverse events of this procedure, such as biliary stricture, perforation and hemorrhage. Therefore, we aimed to assess the long-term effects of in vivo EB-RFA in a swine model.

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The impact of advanced endoscopic imaging on Barrett’s esophagus in daily clinical practice

Several advanced imaging techniques have been proposed to improve the visualization of dysplastic regions within Barrett's epithelium, with some evidence for the use of narrow-band imaging and acetic acid chromo-endoscopy.

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Restricted delivery of talazoparib across the blood-brain barrier limits the sensitizing effects of poly (ADP-ribose) polymerase inhibition on temozolomide therapy in glioblastoma

Poly (ADP-ribose) polymerase PARP inhibitors, including talazoparib (TAL), potentiate temozolomide (TMZ) efficacy in multiple tumor types, however TAL-mediated sensitization has not been evaluated in orthotopic glioblastoma (GBM) models. This study evaluates TAL ± TMZ in clinically relevant GBM models. TAL at 1-3 nmol/L sensitized T98G, U251 and GBM12 cells to TMZ, and enhanced DNA damage signaling and G2/M arrest in vitro. In vivo cyclical therapy with TAL (0.15 mg/kg twice daily) combined with low dose TMZ (5 mg/kg daily) was well tolerated. This TAL/TMZ regimen prolonged tumor stasis more than TMZ alone in heterotopic GBM12 xenografts [median time to endpoint: 76 days vs. 50 days TMZ (p=0.005), 11 days placebo (p <0.001)]. However, TAL/TMZ did not accentuate survival beyond that of TMZ alone in corresponding orthotopic xenografts (median survival 37 vs. 30 days with TMZ (p=0.93), 14 days with placebo, p<0.001). Average brain and plasma TAL concentrations at 2 hours after a single dose (0.15 mg/kg) were 0.49±0.07 ng/g and 25.5±4.1 ng/ml, respectively. The brain/plasma distribution of TAL in Bcrp-/- versus WT mice did not differ, while the brain/plasma ratio in Mdr1a/b-/- mice was higher than WT mice (0.23 vs. 0.02, p<0.001). Consistent with the in vivo brain distribution, overexpression of MDR1 decreased TAL accumulation in MDCKII cells. These results indicate that TAL has significant MDR1 efflux liability that may restrict delivery across the blood-brain barrier, and this may explain the loss of TAL-mediated TMZ sensitization in orthotopic versus heterotopic GBM xenografts.

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The DNA repair inhibitor Dbait is specific for malignant hematologic cells in blood

Hematologic malignancies are rare cancers that develop refractory disease upon patient relapse, resulting in decreased life expectancy and quality of life. DNA repair inhibitors are promising strategy to treat cancer but are limited by their hematologic toxicity in combination with conventional chemotherapies. Dbait are large molecules targeting the signaling of DNA damage and inhibiting all the double-strand DNA break pathways. Dbait have been shown to sensitize resistant solid tumors to radiotherapy and Platinium salts. Here, we analyze the efficacy and lack of toxicity of AsiDNA, a cholesterol form of Dbait, in hematologic malignancies. We show that AsiDNA, enters cells via LDL receptors and activates its molecular target, the DNA dependent protein kinase (DNA-PKcs) in 10 lymphoma and leukemia cell lines (Jurkat-E6.1, MT-4, MOLT-4, 174xCEM.T2, Sup-T1, HuT-78, Raji, IM-9, THP-1 and U-937) and in normal primary human PBMCs, resting or activated T-cells, and CD34+ progenitors. The treatment with AsiDNA induced necrotic and mitotic cell death in most cancer cell lines and had no effect on blood or bone marrow cells, including immune activation, proliferation or differentiation. Sensitivity to AsiDNA was independent of p53 status. Survival to combined treatment with conventional therapies (etoposide, cyclophosphamides, vincristine, or radiotherapy) was analyzed by isobolograms and combination index. AsiDNA synergized with all treatments, except vincristine, without increasing their toxicity to normal blood cells. AsiDNA is a novel, potent, and wide range drug with the potential to specifically increase DNA damaging treatment toxicity in tumor without adding toxicity in normal hematologic cells or inducing immune dysregulation.

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PD-1 expression in head and neck squamous cell carcinomas derives primarily from functionally anergic CD4+ TILs in the presence of PD-L1+ TAMs

Oral tongue squamous cell carcinoma (OTSCC) is the most common oral cavity tumor. In this study, we examined the basis for the activity of PD-1-based immune checkpoint therapy that is being explored widely in head and neck cancers. Using multispectral imaging, we systematically investigated the OTSCC tumor microenvironment (TME) by evaluating the frequency of PD-1 expression in CD8+, CD4+ and FoxP3+ tumor-infiltrating lymphocytes (TIL). We also defined the cellular sources of PD-L1 to evaluate the utility of PD-1:PD-L1 blocking antibody therapy in this patient population. PD-L1 was expressed in 79% of the OTSCC specimens examined within the TME. Expression of PD-L1 was associated with moderate to high levels of CD4+ and CD8+ TIL. We found that CD4+ TIL were present in equal or greater frequencies than CD8+ TIL in 94% of OTSCC, and that CD4+ FOXP3neg TIL were co-localized with PD-1/PD-L1/CD68 more frequently than CD8+ TIL. However, both CD4+PD1+ and CD8+PD1+ TIL were anergic in the setting of PD-L1 expression. Overall, our results highlight the importance of CD4+ TIL as pivotal regulators of PD-L1 levels and in determining the responsiveness of OTSCC to PD1-based immune checkpoint therapy.

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Skp2-mediated stabilization of MTH1 promotes survival of melanoma cells upon oxidative stress

MTH1 helps prevent misincorporation of ROS-damaged dNTPs into genomic DNA, however, there is little understanding of how MTH1 itself is regulated. Here we report that MTH1 is regulated by polyubiquitination mediated by the E3 ligase Skp2. In melanoma cells, MTH1 was upregulated commonly mainly due to its improved stability caused by K63-linked polyubiquitination. While Skp2 along with other components of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex were physically associated with MTH1, blocking the SCF function ablated MTH1 ubiquitination and expression. Conversely, overexpressing Skp2 elevated levels of MTH1 associated with an increase in its K63-linked ubiquitination. In melanoma cell lines and patient specimens, we observed a positive correlation of Skp2 and MTH1 expression. Mechanistic investigations showed that Skp2 limited DNA damage and apoptosis triggered by oxidative stress and that MAPK upregulated Skp2 and MTH1 to render cells more resistant to such stress. Collectively, our findings identify Skp2-mediated K63-linked polyubiquitination as a critical regulatory mechanism responsible for MTH1 upregulation in melanoma, with potential implications to target the MAPK/Skp2/MTH1 pathway to improve its treatment.

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Integrated analysis of whole-genome ChIP-Seq and RNA-Seq data of primary head and neck tumor samples associates HPV integration sites with open chromatin marks

Chromatin alterations mediate mutations and gene expression changes in cancer. Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) has been utilized to study genome-wide chromatin structure in human cancer cell lines, yet numerous technical challenges limit comparable analyses in primary tumors. Here we have developed a new whole-genome analytical pipeline to optimize ChIP-Seq protocols on patient-derived xenografts from human papillomavirus-related (HPV+) head and neck squamous cell carcinoma (HNSCC) samples. We further associated chromatin aberrations with gene expression changes from a larger cohort of the tumor and normal samples with RNA-Seq data. We detect differential histone enrichment associated with tumor-specific gene expression variation, sites of HPV integration in the human genome, and HPV-associated histone enrichment sites upstream of cancer driver genes, which play central roles in cancer associated pathways. These comprehensive analyses enable unprecedented characterization of the complex network of molecular changes resulting from chromatin alterations that drive HPV-related tumorigenesis.

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KIT suppresses BRAFV600E-mutant melanoma by attenuating oncogenic RAS/MAPK signaling

The receptor tyrosine kinase KIT promotes survival and migration of melanocytes during development, and excessive KIT activity hyperactivates the RAS/MAPK pathway and can drive formation of melanomas, most notably of rare melanomas that occur on volar and mucosal surfaces of the skin. The much larger fraction of melanomas that occur on sun-exposed skin is driven primarily by BRAF or NRAS activating mutations, but these melanomas exhibit a surprising loss of KIT expression, which raises the question of whether loss of KIT in these tumors facilitates tumorigenesis. To address this question, we introduced a kit(lf) mutation into a strain of Tg(mitfa:BRAFV600E); p53(lf) melanoma-prone zebrafish. Melanoma onset was accelerated in kit(lf); Tg(mitfa:BRAFV600E); p53(lf) fish. Tumors from kit(lf) animals were more invasive and had higher RAS/MAPK pathway activation. KIT knockdown also increased RAS/MAPK pathway activation in a BRAFV600E-mutant human melanoma cell line. We found that pathway stimulation upstream of BRAFV600E could paradoxically reduce signaling downstream of BRAFV600E, and wild-type BRAF was necessary for this effect, suggesting that its activation can dampen oncogenic BRAFV600E signaling. In vivo, expression of wild-type BRAF delayed melanoma onset, but only in a kit-dependent manner. Together, these results suggest that KIT can activate signaling through wild-type RAF proteins, thus interfering with oncogenic BRAFV600E-driven melanoma formation.

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Combined CDK4/6 and PI3K{alpha} inhibition is synergistic and immunogenic in triple negative breast cancer

New treatments for triple-negative breast cancer (TNBC) are urgently needed. Despite there being little evidence of clinical activity as single-agent therapies, we show that dual blockade of PI3Kα and CDK4/6 is synergistically effective against multiple RB1-wildtype TNBC models. Combined PI3Kα and CDK4/6 inhibition significantly increased apoptosis, cell cycle arrest, and tumor immunogenicity and generated immunogenic cell death in human TNBC cell lines. Combination treatment also significantly improved disease control in human xenograft models compared with either monotherapy. Combined PI3Kα and CDK4/6 inhibition significantly increased tumor-infiltrating T cell activation and cytotoxicity and decreased the frequency of immunosuppressive myeloid-derived suppressor cells in a syngeneic TNBC mouse model. Notably, combined PI3Kα and CDK4/6 inhibition, along with inhibition of immune checkpoints PD-1 and CTLA-4, induced complete and durable regressions (>1 year) of established TNBC tumors in vivo. Overall, our results illustrate convergent mechanisms of PI3Kα and CDK4/6 blockade on cell cycle progression, DNA damage response, and immune-modulation and may provide a novel therapeutic approach for TNBC.

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Survival outcomes in cancer patients predicted by a partial EMT gene expression scoring metric

Metastasis is a significant contributor to morbidity and mortality for many cancer patients and remains a major obstacle for effective treatment. In many tissue types, metastasis is fueled by the epithelial-to-mesenchymal transition (EMT), a dynamic process characterized by phenotypic and morphologic changes concomitant with increased migratory and invasive potential. Recent experimental and theoretical evidence suggests that cells can be stably halted en route to EMT in a hybrid E/M phenotype. Cells in this phenotype tend to move collectively, forming clusters of circulating-tumor-cells that are key tumor-initiating agents. Here we developed an inferential model built on the gene expression of multiple cancer subtypes to devise an EMT metric that characterizes the degree to which a given cell line exhibits hybrid E/M features. Our model identified drivers and fine-tuners of epithelial-mesenchymal plasticity and recapitulates the behavior observed in multiple in vitro experiments across cancer types. We also predicted and experimentally validated the hybrid E/M status of certain cancer cell lines, including DU145 and A549. Lastly, we demonstrated the relevance of predicted EMT scores to patient survival and observed that the role of the hybrid E/M phenotype in characterizing tumor aggressiveness is tissue- and subtype-specific. Our algorithm is a promising tool to quantify the EMT spectrum, to investigate the correlation of EMT score with cancer treatment response and survival, and to provide an important metric for systematic clinical risk stratification and treatment.

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A new all-purpose bilateral cleft lip repair: bilateral cheiloplasty suitable for most conditions

Only experienced surgeons are able to produce satisfactory results with most of the current surgical methods for bilateral cleft lip repair. The existing methods require not only preoperative orthodontic maneuvers but also accurate measurements for surgical design. We describe an easy-to-design and simple-to-execute general purpose surgical technique to repair most bilateral cleft lips.

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Assessing outcome following levatorplasty: when east meets west editorial on paper “transcutaneous aponeurotic repair with small detachment of the levator aponeurosis for aponeurotic blepharoptosis in japanese patients”

In this well-written paper [insert reference] the authors convincingly argue for combining a long skin incision with a limited aponeurosis dissection for involutional ptosis in East Asian patients instead of the small incision, external levator repair or excision currently in vogue. This makes sense as a longer incision allows for the creation of a smooth double eyelid crease which this surgeon seems to have achieved in a high percentage (> 86%) of patients. Why less than two-thirds of patients were satisfied with the overall result, where one functional, and 3 aesthetic criteria were applied, is much harder to explain and comes as a surprise.

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Debunking the myth of e-cigarettes: a case of free flap compromise due to e-cigarette use within the first 24 hours

Nicotine abstinence for free flap patients has long been the dictum for good reason: nicotine induced vasoconstriction can cause spasm and subsequent thrombosis, ultimately resulting in flap loss.(1) Electronic cigarettes (E-cig) have become much more common, and are routinely seen as being the "lesser" of two evils when compared to "traditional" smoking among the general population. This stigma if e-cigarettes being an "acceptable alternative" to smoking, particularly in individuals attempting to abstain from smoking, has persisted despite debate among healthcare providers.

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Evaluation of the effect of an innovative automated text messaging service on patient experience in day-case hand trauma surgery

Hand trauma makes up a significant proportion of the acute caseload of plastic surgery departments in the UK. At least 1.36 million hand injuries are assessed in Accident and Emergency (A&E) departments each year and approximately 2425 patients per 500,000 population require specialist care [1,2]. Our unit runs a full hand trauma list every day treating several thousand patients per year. Despite high demand for services, there is limited operating capacity in most units, increasing pressure on the operating teams.

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Comparing sensation of common donor site regions for autologous breast reconstruction to a healthy breast.

Autologous breast reconstruction has become standard care for breast cancer patients. Although excellent cosmetic results can be achieved, most reconstructed breasts fail to regain normal sensation. Nerve coaptation of the flap has been suggested to improve sensation, the effect of the donor flap native sensory threshold, on the degree of sensory restoration has yet to be determined. The aim of this study is to evaluate the differences in sensation between various potential donor site regions in comparison to sensation of the healthy breast.

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Blocking CGRP in migraine patients – a review of pros and cons

Migraine is the most prevalent neurological disorder worldwide and it has immense socioeconomic impact. Currently, preventative treatment options for migraine include drugs developed for diseases other than mi...

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The molecular genetics of chemotherapy–induced peripheral neuropathy: A systematic review and meta-analysis

Publication date: Available online 25 September 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): J. Cliff, A.L. Jorgensen, R. Lord, F. Azam, L. Cossar, D.F. Carr, M. Pirmohamed
Chemotherapy-induced peripheral neuropathy (CIPN) can adversely affect completion of systemic anti-cancer treatment and cause long-term morbidity. Increasingly pharmacogenetic studies have been performed to explore susceptibility to this important adverse effect.A systematic review was conducted to identify pharmacogenetic studies, assess their quality and findings and undertake meta-analysis where possible.93 studies were included. Notable methodological issues included lack of standardisation and detail in phenotype definition and acknowledgement of potential confounding factors. Insufficient data was presented in many studies meaning only a minority could be included in meta-analysis showing mainly non-significant effects. Nonetheless, SNPs in CYP2C8, CYP3A4, ARHGEF10, EPHA and TUBB2A genes (taxanes), FARS2, ACYP2 and TAC1 (oxaliplatin), and CEP75 and CYP3A5 (vincristine) are of potential interest. These require exploration in large cohort studies with robust methodology and well-defined phenotypes.Seeking standardisation of phenotype, collaboration and subsequently, individual-patient-data meta-analysis may facilitate identifying contributory SNPs which could be combined in a polygenic risk score to predict those most at risk of CIPN.



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32 Consecutive Cases of Whipple’s Operation with Single-Layer End to Side Dunking Pancreatojejunostomy Without Any Pancreatic Fistula: Our Institutional Experience

Abstract

The aim of this paper is to study the outcome of single-layer end to side dunking pancreatojejunostomy technique in 32 patients of malignant pancreatic disease undergoing Whipple's surgery in a tertiary care oncology centre in India. From January 2013 to January 2016, 32 consecutive patients who underwent pancreatoduodenectomy for malignant diseases were analysed retrospectively. All the patients underwent standard Whipple's operation. Pancreatojejunostomy was established in a single-layer end to side dunking manner with PDS 4-0. Various patient data, i.e. preoperative symptoms and demography, intra-operative time, blood loss and need of blood transfusion, postoperative hospital stay and complications, were noted. Mean operative time was 3.5 h approximately. Mean blood loss was 328 ml approx (range 150–600 ml). Postoperative delayed gastric emptying was observed in 8 (25%) patients. Three (9.4%) patients developed superficial surgical site infection. Mean hospital stay was 16.5 days (range 13–20 days). There were no pancreatic leak or fistula and no perioperative mortality. It is a feasible technique. It achieved zero leak rates, zero mortality and minimal morbidity without compromising any oncologic principles.

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Non-Union Rates in Fibula Free-Flap Reconstruction of Head and Neck Oncologic Defects

Publication date: October 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 10, Supplement
Author(s): S.T. Claiborne, D. Kademani, K. Patel, M.R. Idle




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A Cluster Randomized Controlled Clinical Trial to Evaluate Fate and Volumetric Shrinkage of Interposed Pedicled Buccal Pad of Fat and Abdominal Fat in the Treatment of TMJ Ankylosis

Publication date: October 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 10, Supplement
Author(s): A. Roychoudhury, S. Acharya, O. Bhutia, A. Seith Bhalla, S. Manchanda, R. Pandey




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Masthead

Publication date: October 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 10





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Effectiveness, Safety, and Predictors of Response to Botulinum Toxin Type A in Refractory Masticatory Myalgia: A Retrospective Study

Publication date: October 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 10, Supplement
Author(s): S.N. Khawaja, S.J. Scrivani, N. Holland, D.A. Keith




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Does Increased Crown-to-Implant Ratio Predispose Towards Implant or Implant Supported Prosthesis Failure in Mandibular Reconstruction with Fibula Free Flaps?

Publication date: October 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 10, Supplement
Author(s): N.R. Kenning, K.S. Ettinger, K. Arce, E. Keller, T. Salinas, E.J. Moore




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Prevalence of Oral Cancer at a Tertiary Care Hospital in Northern India

Publication date: October 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 10, Supplement
Author(s): A. Gupta, K. Dimri, A.K. Pandey, G. Lehl




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Editorial Board Page

Publication date: October 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 10





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The Bioresorption and Guided Bone Regeneration of Absorbable Hydroxyapatite(HA) Coated Magnesium Mesh

Publication date: October 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 10, Supplement
Author(s): S.H. Byun, Hallym University, H.K. Lim, J.Y. Kang, J.W. Kim, B.E. Yang, J.H. Lee




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Defining Mandibular Morphology in Robin Sequence

Publication date: October 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 10, Supplement
Author(s): S.M. Susarla, N. Vasilakou, H. Kapadia, M.A. Egbert, R.A. Hopper, K.N. Evans




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Effects of Orthognathic Surgery on TMJ Function and Dysfunction

Publication date: October 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 10, Supplement
Author(s): V. Arya, P. Kadagad, W. Alvarez, R. Chigurupati, P. Mehra




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Table of Contents

Publication date: October 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 10





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Analysis of Buccal Bone Changes and Positional Accuracy of Immediately Placed and Provisionalized Single Implants in the Maxilla Using Computer-Guided Templates: A Prospective Study.

Publication date: October 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 10, Supplement
Author(s): A.P. Sharma, J. Lozada, J. Kan, D. Smith, D. Rice




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AAOMS Author Disclosure forms

Publication date: October 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 10





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Detection of Secondary Pathology Utilizing PET Scanning in Patients with Head and Neck Cancer

Publication date: October 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 10, Supplement
Author(s): M.R. Idle




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The Microsurgical Approach in Primary Cleft Lip Rhinoplasty – an Anthropometric Analysis

Publication date: October 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 10, Supplement
Author(s): F. Bschorer, D. Schneider, M. Hennig, G. Schön, R. Bschorer




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Report of Sinonasal Undifferentiated Carcinoma (SNUC) in a Pediatric Patient: Clinical and Molecular Zebras

Publication date: October 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 10, Supplement
Author(s): V. Palermo




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Adverse Local Tissue Responses to Failed Temporomandibular Joint Implants

Publication date: October 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 10
Author(s): Louis G. Mercuri, Robert M. Urban, Deborah J. Hall, Mathew T. Mathew
PurposeThe purpose of this study was to determine whether failed alloplastic temporomandibular joint replacement (TMJR) devices can elicit the aseptic lymphocyte-dominated vasculitis-associated lesion (ALVAL) reaction seen in some patients with metal-on-metal hip arthroplasties.Materials and MethodsThis study involved analysis of paraffin-embedded sections of peri-implant tissue from failed TMJ implant cases obtained from 3 independent sources. Hematoxylin and eosin staining, conventional and polarized light microscopy, back-scattered electron imaging, and energy-dispersive x-ray analysis were used. Immunohistochemical methods were used to identify T and B lymphocytes and macrophages.ResultsThe total TMJR device specimens showed primary macrophage and lymphocytic responses similar to responses reported previously for failed total hip implants, including ALVAL. No chronic or acute inflammation was apparent in the failed hemiarthroplasty TMJR cases.ConclusionIn this limited preliminary study, the local tissue responses to the failed TMJR implants showed similar primary macrophage and lymphocyte responses to previously reported failed metal-on-metal and metal-on-polyethylene orthopedic total joint replacement devices. No such local inflammatory responses were seen with the failed TMJR hemiarthroplasty devices.



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Dental Care for the Working Poor—We Need Answers

Publication date: October 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 10
Author(s): James R. Hupp




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Senior Oral and Maxillofacial Surgery Resident Confidence in Performing Invasive Temporomandibular Joint Procedures

Publication date: October 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 10
Author(s): Mohmedvasim Momin, Michael Miloro, Louis G. Mercuri, Alexander Munaretto, Michael R. Markiewicz
PurposeThe purpose of this study was to evaluate the level of confidence that senior-level oral and maxillofacial surgery (OMS) residents have in the management of temporomandibular joint (TMJ) disorders, determine their exposure to various invasive TMJ procedures during training, and assess their confidence in performing those procedures on completion of residency.Materials and MethodsA questionnaire was designed, and a link to a University of Illinois at Chicago Qualtrics Survey platform (Qualtrics, Provo, UT) was e-mailed to all program directors at Commission on Dental Accreditation–accredited OMS training programs in the United States. The program directors were asked to forward the 20–multiple-choice question anonymous survey to their senior-level residents for completion. The survey included the program's demographic characteristics, resident's confidence in assessing and managing patients with temporomandibular disorders (TMDs), resident's experience performing various invasive TMJ procedures, and whether the resident believed he or she had received sufficient education and clinical experience in the management of TMJ disorders. The data were collected and summarized by use of a standard spreadsheet analysis, as well as appropriate descriptive and analytical statistical tests.ResultsThe response rate was 28.0%. Of the 56 respondents, 52 (92.9%) reported having received instruction in nonsurgical management of TMDs. All respondents confirmed that invasive TMJ procedures were performed in their program. The most commonly performed procedure was TMJ arthrocentesis (mean rating, 3.11), followed by open TMJ surgery (mean rating, 2.82). The least-performed invasive surgical procedure was autogenous total TMJ replacement surgery (mean rating, 1.39). Eighty percent of residents reported being comfortable managing the TMD patient. The only procedure with which the respondents were highly confident was TMJ arthrocentesis (mean rating, 3.89).ConclusionsThis study suggests that confidence levels in the management of the TMD patient are related directly to the invasive TMJ procedure experience obtained during residency. This finding may have implications on the practice patterns of OMS surgeons as it relates to access to care for the TMD patient.



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A Review of Maxillary and Orbital Bone Pathology in the Pediatric Population

Publication date: October 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 10, Supplement
Author(s): R. Daniel, T.A. Turvey




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TNFα-YAP/p65-HK2 axis mediates breast cancer cell migration

TNFα-YAP/p65-HK2 axis mediates breast cancer cell migration

Oncogenesis 6, e383 (September 2017). doi:10.1038/oncsis.2017.83

Authors: Y Gao, Y Yang, F Yuan, J Huang, W Xu, B Mao, Z Yuan & W Bi

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Xanthine dehydrogenase downregulation promotes TGFβ signaling and cancer stem cell-related gene expression in hepatocellular carcinoma

Xanthine dehydrogenase downregulation promotes TGFβ signaling and cancer stem cell-related gene expression in hepatocellular carcinoma

Oncogenesis 6, e382 (September 2017). doi:10.1038/oncsis.2017.81

Authors: G-L Chen, T Ye, H-L Chen, Z-Y Zhao, W-Q Tang, L-S Wang & J-L Xia

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PRAS40 promotes NF-κB transcriptional activity through association with p65

PRAS40 promotes NF-κB transcriptional activity through association with p65

Oncogenesis 6, e381 (September 2017). doi:10.1038/oncsis.2017.80

Authors: G Zhu, Q Qi, J J Havel, Z Li, Y Du, X Zhang & H Fu

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Spatial distribution of disease-associated variants in three-dimensional structures of protein complexes

Spatial distribution of disease-associated variants in three-dimensional structures of protein complexes

Oncogenesis 6, e380 (September 2017). doi:10.1038/oncsis.2017.79

Authors: A Gress, V Ramensky & O V Kalinina

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Adjuvant therapy for locally advanced gastric cancer

Abstract

D2 gastrectomy is now the globally accepted surgical standard for locally advanced gastric cancer. However, since 2000, different evidence has emerged regarding the efficacy of adjuvant chemoradiation, perioperative adjuvant chemotherapy, and postoperative chemotherapy for locally advanced gastric cancer. This review summarizes the background, current status, and future perspectives of adjuvant therapy for locally advanced gastric cancer. The Intergroup 0116 study was the first to show the significant overall survival benefits of adjuvant (chemoradiation) therapy for gastric cancer. The second study was the MAGIC trial, which showed the efficacy of perioperative adjuvant chemotherapy. Although the findings from the Intergroup 0116 study and the MAGIC trial were positive, recent studies, such as the ARTIST and EORTC 40954 studies, found no survival benefit for patients who had undergone D2 gastrectomy for gastric cancer. Regarding the adjuvant chemotherapy strategy, two pivotal phase III trials: the ACTS-GC and the CLASSIC, demonstrated the efficacy of postoperative adjuvant chemotherapy following D2 gastrectomy. However, more intensive chemotherapy is necessary to improve the survival rate. Several studies have analyzed the effectiveness of molecular-targeted therapy against metastatic gastric or gastroesophageal junction carcinoma. Further studies should focus on the survival benefit of more-intensive adjuvant therapy with D2 resection, or with concurrent molecular-targeted therapy.

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Sphingosine-1-phosphate/sphingosine kinase 1-dependent lymph node metastasis in esophageal squamous cell carcinoma

Abstract

Purpose

To establish whether Sphingosine-1-phosphate (S1P) and sphingosine kinase 1 (SphK1) contribute to lymph node metastasis in esophageal squamous cell carcinoma.<?oxy_comment_start comment="Author: Author details: Kindly check and confirm whether the corresponding affiliation is correctly identified and amend if necessary."?><?oxy_comment_end ?><?oxy_comment_start comment="There is no correction point."?><?oxy_comment_end ?>

Methods

Immunohistochemical analysis of SphK1 expression was performed using a tissue microarray containing 177 thoracic squamous cell esophageal cancer specimens resected at surgery, to investigate the association between intratumoral SphK1 expression and lymph node metastasis. Serum S1P levels and intratumoral SphK1 mRNA and protein expression were also evaluated in mice with vs. mice without lymph node metastasis in a murine lymph node metastasis model.<?oxy_comment_start comment="Author: Please check the edits made to the article title and amend if necessary."?><?oxy_comment_end ?><?oxy_comment_start comment="There is no correction point."?><?oxy_comment_end ?>

Results

Among 177 esophageal cancer patients, 127 (72%) were defined as being SphK1-positive. In univariate and multivariate analyses, SphK1 expression status was a significant factor contributing to lymph node metastasis and poorer 5-year overall survival. In the murine lymph node metastasis model, there was no difference in tumor volume or weight between the lymph node metastasis-negative and lymph node metastasis-positive groups. However, levels of SphK1 mRNA and protein and serum S1P levels were all much higher in the metastasis-positive group.

Conclusions

S1P/SphK1 may be novel targets for inhibiting lymph node metastasis in esophageal squamous cell carcinoma, and may provide the basis for a therapeutic strategy to suppress lymph node metastasis.

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Semantic and Phonological Encoding Times in Adults Who Stutter: Brain Electrophysiological Evidence

Purpose

Some psycholinguistic theories of stuttering propose that language production operates along a different time course in adults who stutter (AWS) versus typically fluent adults (TFA). However, behavioral evidence for such a difference has been mixed. Here, the time course of semantic and phonological encoding in picture naming was compared in AWS (n = 16) versus TFA (n = 16) by measuring 2 event-related potential (ERP) components: NoGo N200, an ERP index of response inhibition, and lateralized readiness potential, an ERP index of response preparation.

Method

Each trial required a semantic judgment about a picture in addition to a phonemic judgment about the target label of the picture. Judgments were mapped onto a dual-choice (Go–NoGo/left–right) push-button response paradigm. On each trial, ERP activity time-locked to picture onset was recorded at 32 scalp electrodes.

Results

NoGo N200 was detected earlier to semantic NoGo trials than to phonemic NoGo trials in both groups, replicating previous evidence that semantic encoding generally precedes phonological encoding in language production. Moreover, N200 onset was earlier to semantic NoGo trials in TFA than in AWS, indicating that semantic information triggering response inhibition became available earlier in TFA versus AWS. In contrast, the time course of N200 activity to phonemic NoGo trials did not differ between groups. Lateralized readiness potential activity was influenced by strategic response preparation and, thus, could not be used to index real-time semantic and phonological encoding.

Conclusion

NoGo N200 results point to slowed semantic encoding in AWS versus TFA. Discussion considers possible factors in slowed semantic encoding in AWS and how fluency might be impacted by slowed semantic encoding.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://article/doi/10.1044/2017_JSLHR-L-16-0309/2656220/Semantic-and-Phonological-Encoding-Times-in-Adults

Myriad Applications of Circulating Cell-Free DNA in Precision Organ Transplant Monitoring

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S237-S241, September 2017.


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Epithelial Barrier Regulation by Hypoxia-Inducible Factor

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S233-S236, September 2017.


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Assessment of Lungs for Transplant Recovered from Uncontrolled Donation after Circulatory Determination of Death Donors

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S251-S251, September 2017.


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Mechanisms of Graft Rejection and Immune Regulation after Lung Transplant

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S216-S219, September 2017.


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Immune Tolerance, Xenografts, and Large-Animal Studies in Transplantation

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S220-S225, September 2017.


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Bioactive Lipid Mediators Regulate Lung Epithelial and Mesenchymal Cell Reparative Processes In Vitro

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S252-S253, September 2017.


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Pharmacologic Protection of Mitochondrial DNA Integrity May Afford a New Strategy for Suppressing Lung Ischemia-Reperfusion Injury

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S210-S215, September 2017.


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Introduction to the 59th Annual Thomas L. Petty Aspen Lung Conference. Lung Transplantation: Opportunities for Repair and Regeneration

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S209-S209, September 2017.


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Opportunities for Lung Repair and Regeneration: An Overview

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S247-S250, September 2017.


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List of Abstracts and Posters Presented at the 59th Thomas L. Petty Aspen Lung Conference

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S254-S261, September 2017.


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Cell-Free Hemoglobin-mediated Increases in Vascular Permeability. A Novel Mechanism of Primary Graft Dysfunction and a New Therapeutic Target

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S251-S252, September 2017.


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Gene Expression Profiling of Bronchoalveolar Lavage Cells Preceding a Clinical Diagnosis of Chronic Lung Allograft Dysfunction

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S252-S252, September 2017.


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Host–Pathogen Interactions and Chronic Lung Allograft Dysfunction

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S242-S246, September 2017.


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Lymphatic Vessels: The Next Frontier in Lung Transplant

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S226-S232, September 2017.


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Correlation among ocular surface disease, xerostomia, and nasal symptoms in patients with differentiated thyroid carcinoma subjected to radioiodine therapy: A prospective comparative study

Abstract

Background

Some complications of radioiodine therapy have been reported, but the involvement of the eyes and adnexa is rarely discussed. The purpose of this study was to determine the correlation among ocular surface changes, xerostomia, and changes in the nasal mucosa associated with radioiodine therapy.

Methods

Patients subjected to radioiodine therapy (group 1) or not subjected (group 2) were prospectively evaluated by examinations of the ocular surface and tear film, saliva production, and nasal endoscopy. Ocular and nasal symptoms and xerostomia were evaluated using questionnaires.

Results

Evaluation of the ocular surface did not indicate significant differences between the groups. Nasal endoscopy revealed higher mucosal pallor in group 1 and worsening of the endoscopic appearance. Worsening of ocular symptoms and nasal symptoms, xerostomia, and a significant decrease in salivary production was also observed in group 1.

Conclusion

Subjective worsening of xerostomia, xerophthalmia, nasal symptoms, and changes in the nasal mucosa in group 1 was observed.

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Prognostic nomogram for disease-specific survival of carcinoma ex pleomorphic adenoma of the salivary gland

Abstract

Background

The purpose of this study was to establish an effective prognostic nomogram for carcinoma ex pleomorphic adenoma (Ca-ex-PA) of the salivary gland.

Methods

The nomogram was based on a retrospective study on 223 patients who underwent surgical operation for Ca-ex-PA from 2001 to 2010. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve. The results were validated using bootstrap resampling and a prospective study on 111 patients operated on from 2011 to 2012.

Results

On multivariate analysis of the primary cohort, independent factors for disease-specific survival (DSS) were age, tumor diameter, degree of capsule invasion, lymph node metastasis, and the interaction between tumor site and histological subtype, which were all selected into the nomogram. The C-index of the nomogram for predicting DSS was 0.90 and 0.86 in the primary cohort and validation cohort, respectively.

Conclusion

The proposed nomogram resulted in more accurate prognostic predictions for patients with Ca-ex-PA.

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Survival outcomes for stage-matched endoscopic and open resection of olfactory neuroblastoma

Abstract

Background

Advanced-stage olfactory neuroblastoma requires multimodal therapy for optimal outcomes. Debate exists over endoscopic endonasal surgery in this situation. Stage-matched open and endoscopic surgical therapy were compared.

Methods

Patients from 6 cancer institutions were assessed. Stratification included dural involvement, Kadish stage, nodal disease, Hyams' grade, approach, and margin status. At follow-up, local control, nodal status, and evidence of distant metastases were recorded with any subsequent therapy. Statistical analyses to identify risk factors for developing recurrence and survival differences were performed.

Results

One hundred nine patients were assessed (age 49.2 ± 13.0 years; 46% women) representing Kadish A stage (10%), Kadish B stage (25%), and Kadish C stage (65%). The majority of the patients (61.5%) underwent endoscopic resection, 53.5% within Kadish C stage. Within-stage survival analysis favored endoscopic subgroup for Kadish C stage (log-rank P = .017) nonsignificant for Kadish B stage (log-rank P = .39).

Conclusion

Stage-matched survival was better for the endoscopically treated group compared to the open surgery group, with high negative margin resections obtained.

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Upregulation of pAKT(Ser473) expression is involved in progression of HPV-positive oropharyngeal squamous cell carcinoma

Abstract

Background

PIK3CA alterations have been shown to be a frequent event in oropharyngeal squamous cell cancer (SCC), especially in human papillomavirus (HPV)-related tumors.

Methods

Tissue microarrays (TMAs) were used to evaluate pAKT(Ser473)/(Thr308), total protein kinase B (AKT)(pan) and phosphatase and tensin homolog (PTEN) expression in primary tumors and corresponding nodal disease in oropharyngeal SCC. The HPV status was determined in regard of HPV16 DNA and RNA. Survival analysis was performed by using Kaplan-Meier curves, log-rank testing, and multivariate Cox regression analysis.

Results

HPV16 is a prognostic predictive marker for advanced oropharyngeal SCC. pAKT(Ser473) and PTEN are highly expressed in HPV-related oropharyngeal SCCs in contrast to pAKT(Thr308). The pAKT(Ser473) expression increased from primary tumors to progressive nodal disease (21.1%; P < .011).

Conclusion

Activation of phosphoinositide 3-kinase (PI3K)/pAKT(Ser473) frequently occurs in advanced HPV-positive oropharyngeal SCC and elevated pAKT(Ser473) levels represent a feature during progression of oropharyngeal SCC, indicating a critical role of the mammalian target of rapamycin (mTOR) complex. Further studies are required to evaluate specific drugs targeting PI3K/AKT/mTOR in consideration of PIK3CA alterations.

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Prognostic biomarkers in patients with human immunodeficiency virus-positive disease with head and neck squamous cell carcinoma

Abstract

Background

We examined the prognostic value of a panel of biomarkers in patients with squamous cell carcinoma of the head and neck (SCCHN) who were human immunodeficiency virus (HIV) positive (HIV-positive head and neck cancer) and HIV negative (HIV-negative head and neck cancer).

Methods

Tissue microarrays (TMAs) were constructed using tumors from 41 disease site-matched and age-matched HIV-positive head and neck cancer cases and 44 HIV-negative head and neck cancer controls. Expression of tumor biomarkers was assessed by immunohistochemistry (IHC) and correlations examined with clinical variables.

Results

Expression levels of the studied oncogenic and inflammatory tumor biomarkers were not differentially regulated by HIV status. Among patients with HIV-positive head and neck cancer, laryngeal disease site (P = .003) and Clavien-Dindo classification IV (CD4) counts <200 cells/μL (P = .01) were associated with poor prognosis. Multivariate analysis showed that p16 positivity was associated with improved overall survival (OS; P < .001) whereas increased expression of transforming growth factor-beta (TGF-β) was associated with poor clinical outcome (P = .001).

Conclusion

Disease site has significant effect on the expression of biomarkers. Expression of tumor TGF-β could be a valuable addition to the conventional risk stratification equation for improving head and neck cancer disease management strategies.

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Remyelinating Pharmacotherapies in Multiple Sclerosis

Abstract

We have witnessed major successes in the development of effective immunomodulatory therapies capable of reducing adaptive immune-mediated myelin damage in MS over the last 30 years. However, until it is possible to prevent MS or initiate treatment before it has already caused lesions there is a need to repair myelin damage to prevent further axonal loss. The past decade has brought remarkable advances in our understanding of oligodendrocyte biology and the related search for remyelinating therapies in humans. In this review, we first outline the basic biology of central nervous system myelin and remyelination, including a discussion of the major identified pathways and targets that might help yield CNS remyelinating drugs. In conjunction, we provide an overview of techniques that have helped identify compounds capable of promoting oligodendrocyte precursor cell differentiation and myelination. This includes the methods for both initial in vitro screening and subsequent in vivo confirmation of the target. We then review methods proposed to quantify human remyelination in vivo, including visual evoked potentials and putative imaging modalities. As the remyelination era approaches, with the announcement of the first positive trial in remyelination, we are now tasked with answering new questions regarding patient-specific factors (e.g., age) that may influence the extent and optimal therapeutic window for remyelination.

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Can multi-positional magnetic resonance imaging be used to evaluate angular parameters in cervical spine? A comparison of multi-positional MRI to dynamic plain radiograph

Abstract

Purpose

To test the reliability and validity of the multi-positional magnetic resonance imaging (MRI) in measuring cervical angular parameter using the standard dynamic cervical X-ray as a reference.

Methods

All patients who underwent both cervical dynamic plain radiograph and multi-positional MRI on the same day between 2010 and 2016 were included in this study. The C2–7 angle and the segmental angles of the C2–3 to C6–7 segments were measured in all three positions (neutral, flexion, and extension) using multi-positional MRI and dynamic radiograph. The Pearson's correlation coefficients and linear regression analysis were used for statistical analysis.

Results

46 patients were enrolled in this study. All angular parameters showed significant positive correlation between multi-positional MRI and dynamic X-ray (p < 0.05). The angle of C2–7 showed significantly positive correlation between multi-positional MRI and X-ray (r = 0.552–0.756). All segmental angles from C2–3 to C6–7 showed moderate correlation (r = 0.401–0.636). The linear regression analysis showed that C2–7 angles and all angular parameters had significant correlation between multi-positional MRI and dynamic X-ray (p < 0.05, R ² = 0.107–0.571).

Conclusions

The C2–7 angle and segmental cervical angles measured by multi-positional MRI were valid, and reliability substituted the dynamic X-ray measurement within the acceptable range of error. Multi-positional MRI can be used as a reliable tool for angular parameter measurement and detection of angular instability in the cervical spine.

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Evaluation of 18 F-FDG PET/CT Parameters for Detection of Lymph Node Metastasis in Cutaneous Melanoma

Abstract

Purpose

The purpose of this study was to investigate the value of ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) parameters in the detection of regional lymph node (LN) metastasis in patients with cutaneous melanoma.

Methods

We evaluated patients with cutaneous melanoma who underwent FDG PET/CT for initial staging or recurrence evaluation. A total of 103 patients were enrolled, and 165 LNs were evaluated. LNs that were confirmed pathologically or by follow-up imaging were included in this study. PET parameters, including maximum standardized uptake value (SUVmax), total lesion glycolysis and tumour-to-liver ratio, were used to determine the presence of metastases, and the results were compared with CT-determined LN metastasis. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off values of the FDG PET parameters.

Results

A total of 93 LNs were malignant, and 84 LNs were smaller than 10 mm. In all 165 LNs, an SUVmax of >2.51 showed a sensitivity of 73.1%, a specificity of 88.9%, and an accuracy of 80.0% in detecting metastatic LNs. CT showed a higher specificity (87.3%) and lower accuracy (65.5%). For non-enlarged regional LNs (<10 mm), an SUVmax cut-off value of 1.4 showed the highest negative predictive value (81.3%). For enlarged LNs (≥10 mm), an SUVmax cut-off value of 2.4 showed the highest sensitivity (90.7%) and accuracy (88.9%) in detecting metastatic LNs.

Conclusions

In patients with cutaneous melanoma, an SUVmax of >2.4 showed a high sensitivity (91%) and accuracy (89%) in detecting metastasis in LNs ≥1 cm, and LNs <1 cm with an SUVmax <1.4 were likely to be benign.

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Corrigendum to “Place dependent stimulation rates improve pitch perception in cochlear implantees with single-sided deafness” [Hear. Res. 339 (2016) 94–103]

Publication date: October 2017
Source:Hearing Research, Volume 354
Author(s): Tobias Rader, Julia Döge, Youssef Adel, Tobias Weissgerber, Uwe Baumann




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Are You a Slave to Your E-mail?

Do you find yourself constantly checking it throughout the day? Does it keep you from getting other more important tasks done? If so, you may want to read Paul Argenti's Harvard Business Review's article titled Stop Letting Email Control Your Work Day. Professor Argenti first suggests taking a look at all your work tasks and dividing them up into four categories.

Tweet

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On Protecting Young People's Brains

Publication date: December 2017
Source:World Neurosurgery, Volume 108
Author(s): Mark A. Spatola




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Simplified conditions for storing and cryopreservation of dental pulp stem cells

Publication date: December 2017
Source:Archives of Oral Biology, Volume 84
Author(s): Nam Cong-Nhat Huynh, Son Hoang Le, Vu Nguyen Doan, Lan Thi Quynh Ngo, Ha Le Bao Tran
ObjectivesThis study aimed to simplify the collection, isolation and cryopreservation procedure of human dental pulp stem cells (DPSCs) to ease the establishment of dental stem cell banking.DesignExtracted third molars were collected and stored either in growth medium or in gentamicin-saline (480μg/ml) for 6, 9 or 12h. DPSCs were isolated and subjected to cryopreservation by a controlled-rate or rapid freezing method in 5 or 10% DMSO. Flow cytometry and growth pattern of DPSCs before and after cryopreservation were conducted.ResultsRate of contamination by which the extracted teeth were stored in control and gentamicin-saline were 9.1% (N=33) and 2.3% (N=43), respectively. Successful cell isolation rate of teeth preserved in gentamicin-saline at 6h (92.9%) was comparable to those of growth media group (90.3%). At 9 and 12h, the rates dropped significantly to 75% and 54%, respectively. Cryopreservation by controlled-rate freezing either in 5 or 10% DMSO resulted in a significantly higher percentage of viable cells than by rapid freezing. Cells conserved by controlled-rate freezing in 5% DMSO showed a pattern of growth similar to control unfrozen cells; 10% DMSO significantly deteriorated the growth pattern of the cells. After thawing, DPSCs conserved by controlled-rate freezing still expressed stemness characteristics, although hematopoietic stem cell markers were slightly increased.ConclusionGentamicin-saline was effective in preserving human teeth for DPSC isolation. Controlled-rate freezing in 5% DMSO gave the highest rate of cell viability. This study simplifies the storage conditions and proposes a simple method for cryopreservation of DPSCs.



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Bacterial Biofilms in Chronic Rhinosinusitis and Their Implications for Clinical Management

Abstract

To study the microbiological profile in patients with chronic rhino-sinusitis. To correlate disease severity with the presence of biofilms and host risk factors. To assess outcome of Sinus Surgery 2 weeks post operatively in terms of presence of bacteria and their ability to form biofilm. Prospective study. 50 cases of chronic rhino-sinusitis requiring Functional Endoscopic Sinus Surgery admitted in SDM Hospital, Dharwad, Karnataka were studied using intra-operative mucosal samples for microbiological analysis. The organisms isolated were tested for biofilm forming ability using three in vitro tests. Severity of disease was assessed using SNOT 22 scoring system. Of 50 cases studied, 66% showed presence of chronic rhino-sinusitis with polyposis and had higher SNOT scores compared to those without polyps. Bacterial isolates were obtained from only 17 samples. Staphylococcus species was isolated from 16 samples and Klebsiella pneumoniae from one. 11 Staph spp. isolates showed biofilm forming ability in vitro. Postoperative events in 3 cases yielded biofilm-forming Staphylococcus. Staphylococcus was the most dominant organism isolated and 11 isolates were biofilm formers. Thus the detection of biofilm forming organisms can be considered as a negative prognostic indicator and should forewarn the surgeon about the risk of recurrence.

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Hörrehabilitation mithilfe von Cochleaimplantaten und kognitive Fähigkeiten

Zusammenfassung

Die Untersuchung kognitiver Fähigkeiten erlangt vor dem Hintergrund des demografischen Wandels zunehmend Relevanz. Die Frage nach dem Effekt einer Cochleaimplantation bei taub geborenen Kindern im Vergleich zu Hörgesunden stand noch bis vor wenigen Jahren im Fokus. Es stellt sich heute die Frage, ob eine Hörrehabilitation bei Älteren, z. B. mithilfe eines Cochleaimplantats (CI), einen protektiven Effekt auf die kognitiven Fähigkeiten und damit auch auf das Demenzrisiko besitzt. Die vorliegende Übersichtsarbeit behandelt die Verknüpfungen der kognitiven Fähigkeiten mit Hörstörungen und Cochleaimplantation. Historische Aspekte der Intelligenztestung werden beschrieben. In der aktuellen Literatur sind Erkenntnisse über kognitive Aspekte bei älteren hörgestörten Patienten und CI-Trägern rar. Erste Untersuchungsergebnisse weisen einen positiven Zusammenhang von Hörverbesserung und Kognition aus. Im Umgang mit kognitiven Defiziten und hörgestörten Patienten sind weitere Untersuchungen zur Erarbeitung von Handlungsempfehlungen dringend erforderlich.

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Inactivated Sendai Virus Particles upregulate cancer cell ICAM-1 expression with enhancing NK cell sensitivity on cancer cell

Summary

We have already reported that the inactivated Sendai virus (hemagglutinating virus of Japan; HVJ) envelope (HVJ-E) has multiple anti-cancer effects, including induction of cancer-selective cell death and activation of anti-cancer immunity. HVJ-E stimulates dendritic cells (DCs) to produce cytokines and chemokines such as IFN-β, IL-6, CCL5 and CXCL10, which activate both CD8⁺ T cells and NK cells and recruit them to the tumor microenvironment. However, the effect of HVJ-E on modulating the sensitivity of cancer cells to immune cell attack has yet to be investigated. In this study, we found that HVJ-E induced the production of intercellular adhesion molecule-1 (ICAM-1, CD54), a ligand of LFA-1, in several cancer cell lines through the activation of NF-κB downstream of retinoic acid-inducible gene I (RIG-I) and the mitochondrial antiviral signaling (MAVS) pathway. The upregulation of ICAM-1 on the surface of cancer cells increased the sensitivity of cancer cells to NK cells. Knocking out expression of ICAM-1 in MDA-MB-231 cells using the CRISPR/Cas9 method significantly reduced the killing effect of NK cells on ICAM-1-depleted MDA-MB-231 cells. HVJ-E suppressed tumor growth in MDA-MB-231 tumor-bearing SCID mice, and the HVJ-E anti-tumor effect was impaired when NK cells were depleted by treatment with the anti-asialo-GM1 antibody. Our findings suggest that HVJ-E enhances NK cell sensitivity against cancer cells by increasing ICAM-1 expression on the cancer cell surface.

This article is protected by copyright. All rights reserved.

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Characterization of ascites-derived tumor cells from an endometrial cancer patient

Summary

Improved treatment outcomes for the endometrial cancer patient required precision methods to investigate the biology of this disease and clinically relevant models to test treatment drugs. Hence, we applied a personalized platform to investigate whether in vitro and in vivo models could accurately predict effective treatment regimens. We successfully expanded ascites-derived tumor cells from an endometrial cancer patient with malignant ascites using ascites collected prior to chemotherapy treatment. H&E and IHC staining of ascites-derived tumor cells confirmed the source of endometrial cancer cells. Ascites-derived tumor cells were sensitive to cisplatin and doxorubicin single-agent treatments in CCK8 assay and 3D culture, a condition that more closely mimics in vivo environment. We further demonstrated that ascites-derived tumor cells from this patient could form tumors in NOD/SCID mice with preserved morphological characteristics. A remarkable concordance between the clinical response of cisplatin and the results of in vitro and in vivo drug test reflected the reliability of our personalized approach in this case. Together, our results indicated that an effective platform for ex vivo and in vivo culture of ascites-derived tumor cells from our endometrial cancer patient could be applied to identify treatment options, and may be commonly used in treating cancer patients with malignant ascites in the future.

This article is protected by copyright. All rights reserved.

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Differences in the Impact of Prognostic Factors for Hepatocellular Carcinoma Over Time

Summary

To evaluate the prognostic significance of serum markers that reflect tumor progression, liver function, or liver fibrosis in patients with hepatocellular carcinoma (HCC), focusing on how their impact changes over time after diagnosis. Alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP), albumin-bilirubin (ALBI) score, aspartate aminotransferase to platelet ratio index (APRI), and FIB-4 index were measured at the time of initial non-recurrent HCC diagnosis in 1669 patients between 1997 and 2016. Survival rates after diagnosis were compared after stratifying patients by these markers. Time-dependent receiver-operating characteristics (ROC) analysis was performed to assess how these markers predict patient survival or death. Serum AFP and DCP levels, ALBI score, APRI, and FIB-4 index were strongly correlated with HCC progression, liver function, and degree of liver fibrosis, respectively. Survival rates after diagnosis were significantly different when patients were stratified by these markers. In the time-dependent ROC analysis, AFP and DCP had a high prognostic impact within 3 years of diagnosis but the impact decreased thereafter. In contrast, APRI and FIB-4 index had higher prognostic impact 10 years after diagnosis. ALBI score had a high prognostic impact throughout the study period. Time-dependent ROC analysis clearly showed changes in the prognostic importance of serum markers based on the duration after diagnosis. Whereas the prognostic impact of tumor progression markers was strong in the short term, liver fibrosis markers had higher prognostic impact long after diagnosis. Liver function had constant prognostic impact on patient survival after diagnosis.

This article is protected by copyright. All rights reserved.

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MALT lymphoma arising on a background of reactive pulmonary lymphoid hyperplasia in a patient with Systemic Lupus Erythematosus

Abstract

Interstitial lung diseases are not infrequently complicated by development of malignancies and whilst most cases are carcinomas, rare cases of lymphoma have been reported,^{1 2} these being diffuse large B-cell lymphomas and often associated with connective tissue disorders (CTDs). Reactive pulmonary lymphoid hyperplasia (RPLH), typically in the form of lymphoid interstitial pneumonia (LIP) often arises in patients with CTDs and only rarely shows malignant transformation,³ with many of the early putative cases of transformation to MALT (mucosa-associated lymphoid tissue) lymphoma from LIP being lymphoma 'de novo'.⁴ Herein we present a case of pulmonary non-Hodgkin lymphoma of MALT origin arising on a background RPLH with coexistent amyloidosis, confirmed by immunohistochemical and clonality studies. A 57 year old Caucasian female presented with chest pain and breathlessness at rest. She also described intermittent cough with small amounts of sputum, intermittent sweats, fatigue and joint pain in hands, feet, wrists, knees. She was known to have systemic lupus erythematosus (SLE) and SLE-related antiphospholipid syndrome for which she received immunosuppressive therapy including mycophenolate, prednisolone and hydroxychloroquin.

This article is protected by copyright. All rights reserved.

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Clinical evaluation of macrophages in cancer: role in treatment, modulation and challenges

Abstract

The focus of immunotherapeutics has been placed firmly on anti-tumour T cell responses. Significant progress has been made in the treatment of both local and systemic malignancies, but low response rates and rising toxicities are limiting this approach. Advancements in the understanding of tumour immunology are opening up a new range of therapeutic targets, including immunosuppressive factors in the tumour microenvironment. Macrophages are a heterogeneous group of cells that have roles in innate and adaptive immunity and tissue repair, but become co-opted by tumours to support tumour growth, survival, metastasis and immunosuppression. Macrophages also support tumour resistance to conventional therapy. In preclinical models, interference with macrophage migration, macrophage depletion and macrophage re-education have all been shown to reduce tumour growth and support anti-tumour immune responses. Here we discuss the role of macrophages in prognosis and sensitivity to therapy, while examining the significant progress which has been made in modulating the behaviour of these cells in cancer patients.

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Clinical evaluation of macrophages in cancer: role in treatment, modulation and challenges

Abstract

The focus of immunotherapeutics has been placed firmly on anti-tumour T cell responses. Significant progress has been made in the treatment of both local and systemic malignancies, but low response rates and rising toxicities are limiting this approach. Advancements in the understanding of tumour immunology are opening up a new range of therapeutic targets, including immunosuppressive factors in the tumour microenvironment. Macrophages are a heterogeneous group of cells that have roles in innate and adaptive immunity and tissue repair, but become co-opted by tumours to support tumour growth, survival, metastasis and immunosuppression. Macrophages also support tumour resistance to conventional therapy. In preclinical models, interference with macrophage migration, macrophage depletion and macrophage re-education have all been shown to reduce tumour growth and support anti-tumour immune responses. Here we discuss the role of macrophages in prognosis and sensitivity to therapy, while examining the significant progress which has been made in modulating the behaviour of these cells in cancer patients.

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Nano-Pulse Stimulation Induces Potent Immune Responses, Eradicating Local Breast Cancer while Reducing Distant Metastases

Abstract

Nano-Pulse Stimulation (NPS) as a developing technology has been studied for minimally invasive, non-thermal local cancer elimination for more than a decade. Here we show that a single NPS treatment results in complete regression of the poorly immunogenic, metastatic 4T1-Luc mouse mammary carcinoma. Impressively, spontaneous distant organ metastases were largely prevented, even in those animals with incomplete tumor regression. All tumor-free mice were protected from secondary tumor cell challenge, demonstrating a vaccine-like effect. NPS treatment induced anti-tumor immunity, long-term memory T cells, destruction of tumor microenvironment and reversal of the massive increase of immune suppressor cells in the tumor microenvironment and blood. NPS-treated 4T1 cells exhibited release of damage-associated molecular patterns (DAMPs), including calreticulin, HMGB1 and ATP, and activated dendritic cells. Those findings suggest that NPS is a potent immunogenic cell death inducer that elicits anti-tumor immunity to prevent distant metastases in addition to local tumor eradication. This article is protected by copyright. All rights reserved.

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Expression of miRNA-26b-5p and its target TRPS1 is associated with radiation exposure in post-Chernobyl breast cancer

Abstract

Ionising radiation is a well-recognised risk factor for the development of breast cancer, however, it is unknown whether radiation-specific molecular oncogenic mechanisms exist. We investigated post-Chernobyl breast cancers from radiation-exposed female clean-up workers and non-exposed controls for molecular changes. Radiation-associated alterations identified in the discovery cohort (n=38) were subsequently validated in a second cohort (n=39). Increased expression of hsa-miR-26b-5p was associated with radiation exposure in both of the cohorts. Moreover, downregulation of the TRPS1 protein, which is a transcriptional target of hsa-miR-26b-5p was associated with radiation exposure. Since TRPS1 overexpression is common in sporadic breast cancer its observed downregulation in radiation-associated breast cancer warrants clarification of the specific functional role of TRPS1 in the radiation context. For this purpose, the impact of TRPS1 on the transcriptome was characterised in two radiation-transformed breast cell culture models after siRNA-knockdown. Deregulated genes upon TRPS1 knockdown were associated with DNA-repair, cell cycle, mitosis, cell migration, angiogenesis and EMT pathways. Furthermore, we identified the interaction partners of TRPS1 from the transcriptomic correlation networks derived from gene expression data on radiation-transformed breast cell culture models and sporadic breast cancer tissues provided by the TCGA database. The genes correlating with TRPS1 in the radiation-transformed breast cell lines were primarily linked to DNA damage response and chromosome segregation, whilst the transcriptional interaction partners in the sporadic breast cancers were mostly associated with apoptosis. Thus, upregulation of hsa-miR-26b-5p and downregulation of TRPS1 in radiation-associated breast cancer tissue samples suggests these molecules representing radiation markers in breast cancer. This article is protected by copyright. All rights reserved.

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