Association between the clinical and histopathological classifications of actinic keratosis and the efficacy of topical imiquimod treatment

Abstract

We investigated the association between the clinical and histopathological classifications of actinic keratosis (AK) and the efficacy of topical imiquimod treatment. Forty patients (55 lesions) with AK were treated with topical 5% imiquimod and the efficacy of imiquimod for AK was evaluated based on the clinical/histopathological changes. The complete remission (CR) rates in patients with the different clinical classifications of AK were 85.4% (erythematous type) and 46.2% (hyperkeratotic type). The CR rates in the different histopathological classifications of AK were 80% (hypertrophic type), 81.8% (atrophic type) and 42.9% (bowenoid type). The results revealed that determining the clinical and histopathological type of AK was important for selecting a therapeutic method. The topical imiquimod treatment could be expected to be more effective for AK clinically classified as the erythematous type, or histopathologically classified as the atrophic or hypertrophic type. However, it would be expected to be less effective for the treatment of AK clinically classified as the hyperkeratotic type or histopathologically classified as the bowenoid type. Our observations suggest that we can predict the efficacy of topical imiquimod therapy in AK by determining its clinical and histopathological type.

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Purpura fulminans in congenital protein C deficiency successfully treated with fresh frozen plasma and thrombomodulin

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Case of subungual tumoral melanosis: The detection of melanoma cells and dermoscopic features

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Successful treatment with rituximab in a Japanese patient with systemic sclerosis-associated interstitial lung disease resistant to oral steroid and cyclophosphamide

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Diagnostic criteria, severity classification and guideline of lichen sclerosus et atrophicus

Abstract

We established diagnostic criteria and severity classification of lichen sclerosus et atrophicus, because there is no established diagnostic criteria or widely accepted severity classification of the disease. Also, there is no clinical guideline for lichen sclerosus et atrophicus in Japan, so we proposed its clinical guideline. The clinical guidelines were formulated by clinical questions and recommendations on the basis of evidence-based medicine according to the New Minds Clinical Practice Guideline Creation Manual (version 1.0). We aimed to make the guidelines easy to use and reliable including the newest evidence, and to present guidance for various clinical problems in treatment of lichen sclerosus et atrophicus.

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Intraoral ultrasonography to measure tumor thickness of oral cancer: A systematic review and meta-analysis

Publication date: February 2018
Source:Oral Oncology, Volume 77
Author(s): Thomas J.W. Klein Nulent, Rob Noorlag, Ellen M. Van Cann, Frank A. Pameijer, Stefan M. Willems, Adrian Yesuratnam, Antoine J.W.P. Rosenberg, Remco de Bree, Robert J.J. van Es
Early oral cancer is preferably treated by surgery. Its complete removal is essential for locoregional control and disease-free survival. Inadequate resection margins require adjuvant therapy such as re-resection or (chemo)radiation, that causes extra morbidity and oral discomfort. Intraoral ultrasonography (US) is reported to be of value in determining tumor thickness. Intraoperative visualization of the tumor may facilitate the resection and ensure adequate surgical margins. Furthermore, accurate prediction of tumor thickness could help determine the treatment strategy of the clinically node-negative neck, as thickness and depth of invasion are predictors of cervical metastasis as well as prognosticators of survival. The 8th edition of the American Joint Committee on Cancer staging system for oral squamous cell carcinoma has included depth of invasion as parameter for cT-stage. The aim of this review is to analyze the accuracy of intraoral US in determining tumor thickness in oral cancer.A systematic search was conducted, and the quality of the included papers was assessed using the QUADAS-2 tool for diagnostic accuracy studies. Subsequently, a meta-analysis was performed on the available individual participant data of 240 patients.Most of the twelve included studies focused on T1-2 tongue cancer (n = 129). Meta-analysis showed a high correlation in tumor thickness within this subgroup as measured by intraoral US and histopathology (r = 0.82, p < .001), with minor overestimation of 0.5 mm on US. It is concluded that intraoral US is very accurate in determining tumor thickness in early oral tongue cancer.



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Postoperative staging of the neck dissection using extracapsular spread and lymph node ratio as prognostic factors in HPV-negative head and neck squamous cell carcinoma patients

Publication date: February 2018
Source:Oral Oncology, Volume 77
Author(s): Katarina Majercakova, Cristina Valero, Montserrat López, Jacinto García, Nuria Farré, Miquel Quer, Xavier León
ObjectivesThe presence of nodes with extracapsular spread (ECS) and the lymph node ratio (LNR) have prognostic competence in the pathologic evaluation of patients with a head and neck squamous cell carcinoma (HNSCC) treated with a neck dissection. The purpose of this study is to assess the effect of ECS & LNR on prognosis of HPV negative HNSCC patients treated with neck dissection and to compare to 8th edition TNM/AJCC classification.Materials and methodsWe carried out a retrospective study of 1383 patients with HNSCC treated with a neck dissection between 1985 and 2013. We developed a classification of the patients according to the presence of nodes with ECS and the LNR value with a recursive partitioning analysis (RPA) model.ResultsWe obtained a classification tree with four terminal nodes: for patients without ECS (including patients pN0) the cut-off point for LNR was 1.6%, while for patients with lymph nodes with ECS it was 11.4%. The 5-year disease-specific survival for patients without ECS/LNR < 1.6% was 83.3%; for patients without ECS/LNR ≥ 1.6% it was 61.5%; for patients with ECS/LNR < 11.4% it was 33.7%; and for patients with ECS/LNR ≥ 11.4% it was 18.5%. The classification obtained with RPA had better discrimination between categories than the 8th edition of the TNM/AJCC classification.ConclusionECS status and LNR value proved high prognostic capacity in the pathological evaluation of the neck dissection. The combination of ECS and LNR improved the predictive capacity of the 8th edition of the TNM/AJCC classification in HPV-negative HNSCC patients.



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The Investigated Question and Study Design in Cross-sectional Studies Response to “Chronic Urticaria and the Metabolic Syndrome: a Cross-sectional Community-based Study of 11,261 Patients” Authors Reply

We read with interest the letter by Soria et al. We have been studying Chronic Urticaria (CU) for several years. During this time, we have evaluated the disease and associated conditions from several aspects. The study presented by Soria et al. compared the severity of CU between a small group of obese CU patients and another small group of non-obese CU patients, all recruited in inpatient clinics of a hospital setting.

This article is protected by copyright. All rights reserved.

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Two novel mutations in the TSC2 gene causing severe phenotype in nervous system and skin in a patient with tuberous sclerosis complex

Tuberous sclerosis complex (TSC1, OMIM 191100 and TSC2 OMIM 613254) is an autosomal dominant neurocutaneous disorder that affects multiple organs, associated with the development of wide spread hamartomatous lesions including brain, eyes, lungs, heart, liver, kidneys and skin. Mutations in the tumor suppressor genes, TSC1 at 9q34 and TSC2 at 16p13.3, which encode the proteins hamartin and tuberin respectively, detected in approximately 85-90% of the cases. The majority of cases occur sporadically, with a family history found in only 30% of patients.

This article is protected by copyright. All rights reserved.

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Hyperkalzämie

Zusammenfassung

Die Hyperkalzämie stellt ein häufiges klinisches Problem dar. Normalerweise ist die Kalziumkonzentration im Blutserum streng reguliert. Eine Hyperkalzämie tritt auf, wenn das Gleichgewicht zwischen intestinaler Kalziumaufnahme, renaler Kalziumexkretion und ossärem Kalziumstoffwechsel gestört ist. Der erste Schritt in der Evaluation der Hyperkalzämie besteht darin, diese durch eine wiederholte Messung zu bestätigen. Zusätzlich sollten Albumin und Eiweiß bestimmt werden, um ein korrigiertes Kalzium zu berechnen. Der nächste diagnostische Schritt ist die Messung des Serumparathormons, um zwischen einer nebenschilddrüsenbedingten und einer nicht nebenschilddrüsenbedingten Form zu unterscheiden. Bei den nebenschilddrüsenbedingten Hyperkalzämien stellt der primäre Hyperparathyreoidismus (PHPT) die mit Abstand häufigste Form dar. Ein symptomatischer PHPT sollte, wenn möglich, operativ saniert werden. Ein niedriger Wert (<20 pg/ml) für das intakte Parathormon (PTH) spricht hingegen für das Vorliegen einer nicht nebenschilddrüsenbedingten Hyperkalzämie. In einem solchen Fall empfiehlt sich die Bestimmung von Parathormon-related Protein (PTHrP) sowie der Vitamin-D-Metaboliten. In der überwiegenden Mehrzahl der Fälle mit dieser Konstellation liegt eine tumorbedingte Hyperkalzämie vor. 80–90 % aller Hyperkalzämien sind durch einen PHPT oder eine Tumorhyperkalzämie bedingt, während viele andere Ursachen entsprechend selten sind. Ist keine Operation beim PHPT gewünscht oder handelt es sich um eine Tumorhyperkalzämie, stehen medikamentöse Therapieformen zur Verfügung.

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Endoscopic transpterygoid approach to a mass in a child

Publication date: Available online 18 December 2017
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Dong Hoon Lee, Hee Jo Baek, Tae Mi Yoon, Joon Kyoo Lee, Sang Chul Lim
The endoscopic transterygoid approach to the petrous apex is a feasible/alternative approach in carefully selected patients with specific favorable anatomy, even children. This approach, unlike traditional approaches, spares cochlear and vestibular function. We report a case of a six-year-old boy with embryonal rhabdomyosarcoma of the petrous apex that was diagnosed via the endoscopic transpterygoid approach.



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Timing of tracheostomy in patients with prolonged endotracheal intubation: a systematic review

Abstract

The objective of this article is to evaluate the appropriate timing of tracheostomy in patients with prolonged intubationregarding the incidence of hospital-acquired pneumonia, mortality, length of stay in intensive care unit (ICU) and duration of artificial ventilation. The study included published articles yielded by a search concerning timing of tracheostomy in adult and pediatric patients with prolonged intubation. The search was limited to articles published in English language in the last 30 years (between 1987 and 2017). For the 690 relevant articles, we applied our inclusion and exclusion criteria and only 43 articles were included. 41 studies in the adult age group including 222,501 patients and 2 studies in pediatric age group including 140 patients met our criteria. Studies in adult age group were divided into three groups according to the methodology of determining the cut off timing for early tracheostomy, they were divided into studies that considered early tracheostomy within the first 7, 14 or 21 days of endotracheal intubation, while in pediatric age group the cut off timing for early tracheostomy was within the first 7 days of endotracheal intubation. There was a significant difference in favor of early tracheostomy in adults' three groups and pediatric age group as early tracheostomy was superior regarding reduced duration of mechanical ventilation, with less mortality rates and less duration of stay in ICU. Regarding hospital-acquired pneumonia, it was significantly less in adult groups but with no significant difference in pediatric age group (3 patients out of 72 pediatric patient with early tracheostomy had pneumonia compared to 11 patients out of 68 with late tracheostomy). Studies defining early tracheostomy as that done within 7 days of intubation had better results than those defining early tracheostomy as that done within 14 or 21 days of intubation. In conclusion, early tracheostomy within 7 days of intubation should be done for both adults and pediatric patients with prolonged intubation.

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YouTube as a source of information on skin bleaching: a content analysis

Summary

Background

Skin bleaching is a common, yet potentially harmful body modification practice.

Aim

To describe the characteristics of the most widely viewed YouTube™ videos related to skin bleaching.

Methods

The search term 'skin bleaching' was used to identify the 100 most popular English-language YouTube videos relating to the topic. Both descriptive and specific information were noted.

Results

Among the 100 manually coded skin-bleaching YouTube videos in English, there were 21 consumer-created videos, 45 internet-based news videos, 30 television news videos and 4 professional videos. Excluding the 4 professional videos, we limited our content categorization and regression analysis to 96 videos. Approximately 93% (89/96) of the most widely viewed videos mentioned changing how you look and 74% (71/96) focused on bleaching the whole body. Of the 96 videos, 63 (66%) of videos showed/mentioned a transformation. Only about 14% (13/96) mentioned that skin bleaching is unsafe. The likelihood of a video selling a skin bleaching product was 17 times higher in internet videos compared with consumer videos (OR = 17.00, 95% CI 4.58–63.09, P < 0.001). Consumer-generated videos were about seven times more likely to mention making bleaching products at home compared with internet-based news videos (OR = 6.86, 95% CI 1.77–26.59, P < 0.01).

Conclusions

The most viewed YouTube video on skin bleaching was uploaded by an internet source. Videos made by television sources mentioned more information about skin bleaching being unsafe, while consumer-generated videos focused more on making skin-bleaching products at home.

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Increased infiltration of CD11c+/CD123+ dendritic cell subsets and upregulation of TLR/IFN-α signaling participate in pathogenesis of oral lichen planus

Publication date: Available online 18 December 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Yufeng Wang, Shu Shang, Qianqian Sun, Junjun Chen, Guanhuan Du, Hong Nie, Xiaozhe Han, Guoyao Tang
ObjectiveInvestigation of dendritic cell (DC) subsets and expression patterns of Toll-like receptors (TLRs) was conducted to understand the pathogenesis in oral lichen planus (OLP).Study DesignBlood, OLP lesion and control samples were collected. Four DC subsets (CD11c⁺CD123^-myeloid DC-mDC1, CD141⁺myeloid DC-mDC2, CD11c^-CD123⁺plasmacytoid DC-pDC and CD1a⁺CD207⁺Langerhans cells-LC) were investigated via flow cytometry (FCM) and immunohistochemical (IHC) staining. Expression patterns of TLRs and their downstream molecules were analyzed via qRT-PCR and IHC in situ.ResultsThirty-two samples were collected (9 controls and 23 OLP patients). FCM results showed the percentages of LC, mDC1, mDC2 and pDC in situ were 0.0119±0.0251%, 0.0064±0.0134%, 0.0005±0.0011%, and 0.0022±0.0019% in control mucosa, respectively. The mDC1 (0.0300±0.0276%) and pDC (0.0204±0.0186%) subsets were significantly increased in OLP lesions (p<0.01). No marked differences were evident, when comparing all four DC subsets from blood, between control and OLP groups. Significant upregulation of TLR7, TLR8 and TLR9 were disclosed in OLP (p<0.01), along with their downstream interferon-α(IFN-α) signaling molecules(IRF7 and IFN-α, p<0.01).ConclusionOur findings of increased infiltration of pDC and mDC1, along with upregulation of TLR/IFN-α signaling, provide valuable information for further understanding the immunity in OLP.



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An actionable test using loss of heterozygosity in identifying high-risk oral premalignant lesions

Publication date: Available online 18 December 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Kelly Y.P. Liu, X.J. David Lu, Yi-Shing L. Cheng, Hagen Klieb, Samson Ng, Kelly McNeil, Aly Karsan, Catherine F. Poh
Objectives.To develop an actionable test using fluorescent-labeled primers with capillary gel electrophoresis (FCE) to assess loss of heterozygosity (LOH) of histologically similar low-grade lesions (LGLs) to identify high-risk lesions for oral cancer progression.Study Design.To determine the cut-offs of LOH, the FCE results of 52 surgical margin samples were used to compare to the existing LOH results from the previously validated ³²P-GE approach. Using the developed FCE workflow, an independent set of 102 LGLs with known progression status was used to determine the LOH molecular risk (MR) patterns and associated risk of progression.Results.Using 65% cut-off LOH-FCE, the agreement of LOH-³²P-GE showed an average of 82.3% (76.8-87.8). Comparing to non-progressors (n=61), anatomical site, and MR patterns (LOH at 9p21, 3p14, or 17p13) were independent risk factors. High-risk profile of tongue and MR3 (LOH at 9p21 and/or 3p14, and 17p13) was significantly associated with progression (HR, 6.7; 95% CI, 2.6-17.6) with specificity of 98.4% at identifying progressors.Conclusions.We have developed an objective, fast, environmental-safe, and cost-effective test using LOH to stratify the risk of LGLs. With further validation, it can be used in the clinical settings to provide clinicians additional information guiding the management of these lesions.



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Tinea capitis mimicking dissecting cellulitis in three children

Abstract

Tinea capitis mimicking dissecting cellulitis is a rare presentation, and there is a paucity of information regarding this presentation in the literature. Three children 10-14 years of age who presented with an unusual clinical manifestation of tinea capitis that clinically resembled dissecting cellulitis are reported. The patients were treated with systemic antifungals for 3-4 months. Treatment success was measured according to repeat fungal cultures and clinical assessment of hair regrowth at follow-up visits. All three patients had resolution of infection, with negative repeat fungal cultures and complete hair regrowth without scarring. These cases highlight a rare inflammatory subtype of tinea capitis that can be easily misdiagnosed and therefore improperly treated, prolonging the duration of infection.

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Primary surgical management with radial forearm free flap reconstruction in T4 oropharyngeal cancer: Complications and functional outcomes

Functional outcomes and complication rates after open surgery for advanced-stage oropharyngeal cancers are rarely reported. These measures are critical for choice of treatment modality and patient counseling. We describe the long term functional outcomes and associated complications of primary surgical management of T4 oropharyngeal cancers reconstructed with radial forearm free flaps.

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Least Injurious Mechanical Ventilation in Pulmonary Resection Surgery

No abstract available

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To Clot or Not to Clot: Understanding Coagulopathy in Liver Disease

No abstract available

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Unadjusted Bivariate Two-Group Comparisons: When Simpler is Better

Hypothesis testing involves posing both a null hypothesis and an alternative hypothesis. This basic statistical tutorial discusses the appropriate use, including their so-called assumptions, of the common unadjusted bivariate tests for hypothesis testing and thus comparing study sample data for a difference or association. The appropriate choice of a statistical test is predicated on the type of data being analyzed and compared. The unpaired or independent samples t test is used to test the null hypothesis that the 2 population means are equal, thereby accepting the alternative hypothesis that the 2 population means are not equal. The unpaired t test is intended for comparing dependent continuous (interval or ratio) data from 2 study groups. A common mistake is to apply several unpaired t tests when comparing data from 3 or more study groups. In this situation, an analysis of variance with post hoc (posttest) intragroup comparisons should instead be applied. Another common mistake is to apply a series of unpaired t tests when comparing sequentially collected data from 2 study groups. In this situation, a repeated-measures analysis of variance, with tests for group-by-time interaction, and post hoc comparisons, as appropriate, should instead be applied in analyzing data from sequential collection points. The paired t test is used to assess the difference in the means of 2 study groups when the sample observations have been obtained in pairs, often before and after an intervention in each study subject. The Pearson chi-square test is widely used to test the null hypothesis that 2 unpaired categorical variables, each with 2 or more nominal levels (values), are independent of each other. When the null hypothesis is rejected, 1 concludes that there is a probable association between the 2 unpaired categorical variables. When comparing 2 groups on an ordinal or nonnormally distributed continuous outcome variable, the 2-sample t test is usually not appropriate. The Wilcoxon-Mann-Whitney test is instead preferred. When making paired comparisons on data that are ordinal, or continuous but nonnormally distributed, the Wilcoxon signed-rank test can be used. In analyzing their data, researchers should consider the continued merits of these simple yet equally valid unadjusted bivariate statistical tests. However, the appropriate use of an unadjusted bivariate test still requires a solid understanding of its utility, assumptions (requirements), and limitations. This understanding will mitigate the risk of misleading findings, interpretations, and conclusions.

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Anesthesia & Analgesia: Update and a Year in Review

No abstract available

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A Novel Method of Evaluating Key Factors for Success in a Multifaceted Critical Care Fellowship Using Data Envelopment Analysis

BACKGROUND: The current system of summative multi-rater evaluations and standardized tests to determine readiness to graduate from critical care fellowships has limitations. We sought to pilot the use of data envelopment analysis (DEA) to assess what aspects of the fellowship program contribute the most to an individual fellow's success. DEA is a nonparametric, operations research technique that uses linear programming to determine the technical efficiency of an entity based on its relative usage of resources in producing the outcome. DESIGN: Retrospective cohort study. SUBJECTS AND SETTING: Critical care fellows (n = 15) in an Accreditation Council for Graduate Medical Education (ACGME) accredited fellowship at a major academic medical center in the United States. METHODS: After obtaining institutional review board approval for this retrospective study, we analyzed the data of 15 anesthesiology critical care fellows from academic years 2013–2015. The input-oriented DEA model develops a composite score for each fellow based on multiple inputs and outputs. The inputs included the didactic sessions attended, the ratio of clinical duty works hours to the procedures performed (work intensity index), and the outputs were the Multidisciplinary Critical Care Knowledge Assessment Program (MCCKAP) score and summative evaluations of fellows. RESULTS: A DEA efficiency score that ranged from 0 to 1 was generated for each of the fellows. Five fellows were rated as DEA efficient, and 10 fellows were characterized in the DEA inefficient group. The model was able to forecast the level of effort needed for each inefficient fellow, to achieve similar outputs as their best performing peers. The model also identified the work intensity index as the key element that characterized the best performers in our fellowship. CONCLUSIONS: DEA is a feasible method of objectively evaluating peer performance in a critical care fellowship beyond summative evaluations alone and can potentially be a powerful tool to guide individual performance during the fellowship.

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Inadvertent Perioperative Hypothermia Induced by Spinal Anesthesia for Cesarean Delivery Might Be More Significant Than We Think: Are We Doing Enough to Warm Our Parturients?

No abstract available

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Society for Obstetric Anesthesia and Perinatology 2017 Meeting Report

No abstract available

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Efficiency, Paths, Goals, and Frontiers in Graduate Education: New Uses for Old Concepts

No abstract available

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Pentathol Postcards: Erratum

No abstract available

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Are You Down With TPP? Considering Transpulmonary Pressures as Opposed to Ventilator-Measured Pressures

No abstract available

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Repeated Administration of Duloxetine Suppresses Neuropathic Pain by Accumulating Effects of Noradrenaline in the Spinal Cord

BACKGROUND: Antidepressants are used to treat neuropathic pain and although the detailed mechanisms of their effects are unclear, the descending noradrenergic inhibitory system might play an important role. We tested our hypothesis that repeated administration of duloxetine suppresses neuropathic pain by restoring the descending noradrenergic inhibitory system in rats 6 weeks after spinal nerve ligation (SNL). METHODS: We subcutaneously injected SNL rats with duloxetine (10 mg kg−1 day−1) daily for 3 consecutive days and assessed behavioral hypersensitivity and noxious stimulus–induced analgesia (NSIA) activated by subcutaneous injection of capsaicin. We also performed microdialysis studies of the spinal cord, noradrenaline measurements of homogenized lumbar spinal tissue, and immunohistochemistry of the locus coeruleus. RESULTS: Three daily injections of duloxetine attenuated the mechanical hyperalgesia induced by SNL (SNL treated with vehicle: 88 ± 9.4 g versus SNL treated with duloxetine: 148 ± 13 g, P

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“However Beautiful the Strategy, You Should Occasionally Look at the Results”: Sir Winston Churchill and Medical Checklists

No abstract available

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Anaesthesia for the Elderly Patient, 2nd ed.

No abstract available

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Postoperative Atrial Fibrillation and Maslow’s Hammer

No abstract available

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In Response

No abstract available

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The Pediatric Elephant in the Room

No abstract available

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Risk of Cognitive Impairment by Sleep-Disordered Breathing

No abstract available

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The Eye of the Beholder

No abstract available

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Preventing Mistransfusions: An Evaluation of Institutional Knowledge and a Response

BACKGROUND: Blood product mistransfusions occur when a process error causes transfusion of incompatible blood products. These events are known sources of negative patient outcomes. One such event demonstrated an institutional knowledge gap and an opportunity to reduce this source of transfusion errors. The focus of this study was to evaluate the application of point of care cognitive aids to bridge potentially lethal knowledge gaps in blood product to patient compatibility. METHODS: A patient-donor ABO antigen compatibility grid for red blood cells (RBC) and fresh frozen plasma (FFP) was developed for creation of a cognitive aid and a blood product safety quiz. Participants included 117 registered nurses and postgraduate medical interns who were given 2 minutes to complete the quiz for establishing institutional controls. A separate group of 111 registered nurses and interns were given the same timed quiz twice, without and then with a blood product compatibility cognitive aid. An analysis of covariance was used to evaluate without cognitive aid versus with cognitive aid quiz results while taking the specialty (nurse versus interns) and baseline score into consideration. The blood bank adopted the grid as a forcing function to be completed before release of blood products. RESULTS: The correct RBC answer percentage increased from 84.7% to 98.3% without and with cognitive aid (average improvement 13.6%, standard deviation [SD] = 18.3%, 95% confidence interval, 10.1%–17.1%, P

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Insight Into Our Technologies: A New Series of Manuscripts in Anesthesia & Analgesia

No abstract available

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In Memorium - Professor Robin AJ Eady, MB BS Lond(1967) MRCP(1970) FRCP(1982) FMedSci(2002) MBE(2014) DSc. (b.29 November 1940 d.2 August 2017)

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Perception of ABC (Asymmetry, Borders and Color) Parameters in the Screening for Melanoma. Model Exercise with Experienced Dermatologists

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CXCR3/CXCL10 Axis Shapes Tissue Distribution of Memory Phenotype CD8+ T Cells in Nonimmunized Mice [IMMUNE SYSTEM DEVELOPMENT]

The preimmune repertoire consists of mature T lymphocytes that have not yet been stimulated in the periphery. Memory phenotype (MP) cells have been reported as part of the preimmune repertoire (i.e., T cells bearing memory markers despite lack of engagement with cognate Ag); however, little is known about their trafficking and function. In this study, we hypothesized that MP cells, naive to TCR stimulation, constitute a transient population that traffics to tissues during development. Using mutant and transgenic animals with a monospecific TCR, we discovered increased numbers of MP CD8⁺ T cells circulating in nonimmunized Cxcr3^–/– and Cxcl10^–/– mice compared with wild-type animals. Phenotypic differences included decreased numbers of preimmune MP Ag-specific T cells in the skin and thymus and a distinct pattern of activation upon TCR engagement. Our results show for the first time, to our knowledge, an important role for CXCR3 and CXCL10 in the tissue distribution of preimmune MP cells.

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Live Attenuated Leishmania donovani Centrin Gene-Deleted Parasites Induce IL-23-Dependent IL-17-Protective Immune Response against Visceral Leishmaniasis in a Murine Model [IMMUNOTHERAPY AND VACCINES]

No vaccine exists against visceral leishmaniasis. To develop effective vaccines, we have previously reported protective role of live attenuated centrin gene–deleted Leishmania donovani (LdCen^–/–) parasites through induction of Th1 type immune response in mice, hamsters, and dogs. In this study, we specifically explored the role of Th17 cells in LdCen^–/–-induced host protection in mice. Our results showed that compared with wild-type L. donovani infection, LdCen^–/– parasites induce significantly higher expression of Th17 differentiation cytokines in splenic dendritic cells. There was also induction of IL-17 and its promoting cytokines in total splenocytes and in both CD4 and CD8 T cells following immunization with LdCen^–/–. Upon challenge with wild-type parasites, IL-17 and its differentiating cytokines were significantly higher in LdCen^–/–-immunized mice compared with nonimmunized mice that resulted in parasite control. Alongside IL-17 induction, we observed induction of IFN-–producing Th1 cells as reported earlier. However, Th17 cells are generated before Th1 cells. Neutralization of either IL-17 or IFN- abrogated LdCen^–/–-induced host protection further confirming the essential role of Th17 along with Th1 cytokines in host protection. Treatment with recombinant IL-23, which is required for stabilization and maintenance of IL-17, heightened Th17, and Tc17 responses in immunized mice splenocytes. In contrast, Th17 response was absent in immunized IL-23R^–/– mice that failed to induce protection upon virulent Leishmania challenge suggesting that IL-23 plays an essential role in IL-17–mediated protection by LdCen^–/– parasites. This study unveiled the role of IL-23–dependent IL-17 induction in LdCen^–/– parasite-induced immunity and subsequent protection against visceral leishmaniasis.

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A Novel Pkhd1 Mutation Interacts with the Nonobese Diabetic Genetic Background To Cause Autoimmune Cholangitis [IMMUNOGENETICS]

We previously reported that NOD.c3c4 mice develop spontaneous autoimmune biliary disease (ABD) with anti-mitochondrial Abs, histopathological lesions, and autoimmune T lymphocytes similar to human primary biliary cholangitis. In this article, we demonstrate that ABD in NOD.c3c4 and related NOD ABD strains is caused by a chromosome 1 region that includes a novel mutation in polycystic kidney and hepatic disease 1 (Pkhd1). We show that a long terminal repeat element inserted into intron 35 exposes an alternative polyadenylation site, resulting in a truncated Pkhd1 transcript. A novel NOD congenic mouse expressing aberrant Pkhd1, but lacking the c3 and c4 chromosomal regions (NOD.Abd3), reproduces the immunopathological features of NOD ABD. RNA sequencing of NOD.Abd3 common bile duct early in disease demonstrates upregulation of genes involved in cholangiocyte injury/morphology and downregulation of immunoregulatory genes. Consistent with this, bone marrow chimera studies show that aberrant Pkhd1 must be expressed in the target tissue (cholangiocytes) and the immune system (bone marrow). Mutations of Pkhd1 produce biliary abnormalities in mice but have not been previously associated with autoimmunity. In this study, we eliminate clinical biliary disease by backcrossing this Pkhd1 mutation onto the C57BL/6 genetic background; thus, the NOD genetic background (which promotes autoimmunity) is essential for disease. We propose that loss of functional Pkhd1 on the NOD background produces early bile duct abnormalities, initiating a break in tolerance that leads to autoimmune cholangitis in NOD.Abd3 congenic mice. This model is important for understanding loss of tolerance to cholangiocytes and is relevant to the pathogenesis of several human cholangiopathies.

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Modulation of the Alternative Pathway of Complement by Murine Factor H-Related Proteins [INNATE IMMUNITY AND INFLAMMATION]

Factor H (FH) is a key alternative pathway regulator that controls complement activation both in the fluid phase and on specific cell surfaces, thus allowing the innate immune response to discriminate between self and foreign pathogens. However, the interrelationships between FH and a group of closely related molecules, designated the FH-related (FHR) proteins, are currently not well understood. Whereas some studies have suggested that human FHR proteins possess complement regulatory abilities, recent studies have shown that FHR proteins are potent deregulators. Furthermore, the roles of the FHR proteins have not been explored in any in vivo models of inflammatory disease. In this study, we report the cloning and expression of recombinant mouse FH and three FHR proteins (FHR proteins A–C). Results from functional assays show that FHR-A and FHR-B proteins antagonize the protective function of FH in sheep erythrocyte hemolytic assays and increase cell-surface C3b deposition on a mouse kidney proximal tubular cell line (TEC) and a human retinal pigment epithelial cell line (ARPE-19). We also report apparent K_D values for the binding interaction of mouse C3d with mouse FH (3.85 μM), FHR-A (136 nM), FHR-B (546 nM), and FHR-C (1.04 μM), which directly correlate with results from functional assays. Collectively, our work suggests that similar to their human counterparts, a subset of mouse FHR proteins have an important modulatory role in complement activation. Further work is warranted to define the in vivo context-dependent roles of these proteins and determine whether FHR proteins are suitable therapeutic targets for the treatment of complement-driven diseases.

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IL-33-Responsive Group 2 Innate Lymphoid Cells Are Regulated by Female Sex Hormones in the Uterus [INNATE IMMUNITY AND INFLAMMATION]

Group 2 innate lymphoid cells (ILC2s) reside in multiple organs in the body, where they play roles in immunity, tissue homeostasis, and metabolic regulation. However, little is known about the regulatory mechanisms of ILC2s in different organs. Here, we identified ILC2s in the mouse uterus and found that they express cell surface molecules, including the IL-33 receptor, ST2, that are roughly comparable to those expressed by lung ILC2s. Both in vivo and in vitro treatment with IL-33 induced type 2 cytokine production in uterine ILC2s, suggesting that they respond to IL-33 in a manner similar to ILC2s in other organs. Importantly, uterine ILC2s were nearly absent in ovariectomized mice and were increased in wild-type mice by estrogen administration, whereas lung ILC2s were unaffected by both ovariectomy and estrogen administration. Likewise, a marked reduction in uterine ILC2s was observed in mice deficient in estrogen receptor α or estrogen receptor β. Furthermore, uterine ILC2s highly expressed estrogen receptor α, and in vitro culture of isolated uterine ILC2s with 17β-estradiol modified expression of a number of genes. Finally, an increased prevalence in neonatal mortality was observed in litters from dams lacking the IL-33 receptor, ST2. Taken together, our findings indicate that unlike lung IL2Cs, uterine ILC2s are regulated by female sex hormones, which may specialize them for specific physiological functions.

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A Beginners Guide to Analyzing and Visualizing Mass Cytometry Data [IMMUNOLOGY NOTES AND RESOURCES]

Mass cytometry has revolutionized the study of cellular and phenotypic diversity, significantly expanding the number of phenotypic and functional characteristics that can be measured at the single-cell level. This high-dimensional analysis platform has necessitated the development of new data analysis approaches. Many of these algorithms circumvent traditional approaches used in flow cytometric analysis, fundamentally changing the way these data are analyzed and interpreted. For the beginner, however, the large number of algorithms that have been developed, as well as the lack of consensus on best practices for analyzing these data, raise multiple questions: Which algorithm is the best for analyzing a dataset? How do different algorithms compare? How can one move beyond data visualization to gain new biological insights? In this article, we describe our experiences as recent adopters of mass cytometry. By analyzing a single dataset using five cytometry by time-of-flight analysis platforms (viSNE, SPADE, X-shift, PhenoGraph, and Citrus), we identify important considerations and challenges that users should be aware of when using these different methods and common and unique insights that can be revealed by these different methods. By providing annotated workflow and figures, these analyses present a practical guide for investigators analyzing high-dimensional datasets. In total, these analyses emphasize the benefits of integrating multiple cytometry by time-of-flight analysis algorithms to gain complementary insights into these high-dimensional datasets.

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Toxoplasma gondii Inactivates Human Plasmacytoid Dendritic Cells by Functional Mimicry of IL-10 [INFECTIOUS DISEASE AND HOST RESPONSE]

Plasmacytoid dendritic cells (pDCs) are the major producers of IFN-α, an antiviral cytokine involved in immunomodulation and control of HIV type 1 replication, whereas Toxoplasma gondii is a life-threatening opportunistic infection in AIDS patients. During infection with HIV type 1, human pDCs decrease in circulation and remaining pDC produce lower amounts of IFN-α in response to viral stimulation. In this study, we investigated the impact of coinfection with T. gondii on the innate virus-directed responses of human pDCs. Using intracellular flow cytometry and fluorescence microscopy, we determined that T. gondii invaded but did not induce IFN-α or TNF-α in human pDC. However, T. gondii inhibited IFN-α and TNF-α produced in response to HSV and HIV, thus functionally inactivating pDC. IFN-α production was inhibited only in cells infected by T. gondii, which inhibited neither uptake of GFP-HSV nor localization of TLR9 in CD71⁺ endosomes, directing us to investigate downstream events. Using imaging flow cytometry, we found that both T. gondii and IL-10 inhibited virus-induced nuclear translocation, but not phosphorylation, of IFN response factor 7. Blockade of IFN response factor 7 nuclear translocation and inhibition of the IFN-α response was partially reversed by a deficiency in the T. gondii–derived ROP16 kinase, known to directly phosphorylate STAT3, a critical mediator of IL-10's anti-inflammatory effects. Taken together, our results indicate that T. gondii suppresses pDC activation by mimicking IL-10's regulatory effects through an ROP16 kinase-dependent mechanism. Our findings further imply a convergent mechanism of inhibition of TLR signaling by T. gondii and IL-10 and suggest potential negative consequences of HIV/T. gondii coinfection.

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The Reign of Antibodies: A Celebration of and Tribute to Michael Potter and His Homogeneous Immunoglobulin Workshops [PILLARS OF IMMUNOLOGY]

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Embryonic Lethality and Host Immunity of RelA-Deficient Mice Are Mediated by Both Apoptosis and Necroptosis [INNATE IMMUNITY AND INFLAMMATION]

In mammalian cells, signaling pathways triggered by TNF can be switched from NF-B activation to apoptosis and/or necroptosis. The in vivo mechanisms underlying the mutual regulation of these three signaling pathways are poorly understood. In this article, we report that the embryonic lethality of RelA-deficient mice is partially prevented by the deletion of Rip3 or Mlkl, but it is fully rescued by the combined ablation of Fadd and Rip3 or Mlkl or by blocking RIP1 kinase activity (RIP1^K45A). RelA^–/–Fadd^–/–Rip3^–/– triple-knockout (TKO) and RelA^–/–Rip1^K45A/K45A mice displayed bacterial pneumonia leading to death ~2 wk after birth. Moreover, RelA^–/–Rip1^K45A/K45A mice, but not TKO mice, developed severe inflammation associated with inflammatory skin lesion. Antibiotic treatment improved bacterial pneumonia, extended the lifespan of TKO and RelA^–/–Rip1^K45A/K45A mice, and alleviated skin inflammation in RelA^–/–Rip1^K45A/K45A mice. These results show the mechanisms underlying the in vivo mutual regulation between NF-B activation and the cell death pathway and provide new insights into this interplay in embryonic development and host immune homeostasis.

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Pillars Article: Evidence for Amino Acid Sequence Differences among Proteins Resembling the L-chain Subunits of Immunoglobulins. J. Mol. Biol. 1965. 12: 81-87 [PILLARS OF IMMUNOLOGY]

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In This Issue [IN THIS ISSUE]

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Salmonella Vaccines: Conduits for Protective Antigens [BRIEF REVIEWS]

Vaccines afford a better and more cost-effective approach to combatting infectious diseases than continued reliance on antibiotics or antiviral or antiparasite drugs in the current era of increasing incidences of diseases caused by drug-resistant pathogens. Recombinant attenuated Salmonella vaccines (RASVs) have been significantly improved to exhibit the same or better attributes than wild-type parental strains to colonize internal lymphoid tissues and persist there to serve as factories to continuously synthesize and deliver rAgs. Encoded by codon-optimized pathogen genes, Ags are selected to induce protective immunity to infection by that pathogen. After immunization through a mucosal surface, the RASV attributes maximize their abilities to elicit mucosal and systemic Ab responses and cell-mediated immune responses. This article summarizes many of the numerous innovative technologies and discoveries that have resulted in RASV platforms that will enable development of safe efficacious RASVs to protect animals and humans against a diversity of infectious disease agents.

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The IFN Response in Bats Displays Distinctive IFN-Stimulated Gene Expression Kinetics with Atypical RNASEL Induction [INFECTIOUS DISEASE AND HOST RESPONSE]

Bats host a large number of zoonotic viruses, including several viruses that are highly pathogenic to other mammals. The mechanisms underlying this rich viral diversity are unknown, but they may be linked to unique immunological features that allow bats to act as asymptomatic viral reservoirs. Vertebrates respond to viral infection by inducing IFNs, which trigger antiviral defenses through IFN-stimulated gene (ISG) expression. Although the IFN system of several bats is characterized at the genomic level, less is known about bat IFN-mediated transcriptional responses. In this article, we show that IFN signaling in bat cells from the black flying fox (Pteropus alecto) consists of conserved and unique ISG expression profiles. In IFN-stimulated cells, bat ISGs comprise two unique temporal subclusters with similar early induction kinetics but distinct late-phase declines. In contrast, human ISGs lack this decline phase and remained elevated for longer periods. Notably, in unstimulated cells, bat ISGs were expressed more highly than their human counterparts. We also found that the antiviral effector 2-5A–dependent endoribonuclease, which is not an ISG in humans, is highly IFN inducible in black flying fox cells and contributes to cell-intrinsic control of viral infection. These studies reveal distinctive innate immune features that may underlie a unique virus–host relationship in bats.

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The Role of MHC-E in T Cell Immunity Is Conserved among Humans, Rhesus Macaques, and Cynomolgus Macaques [ANTIGEN RECOGNITION AND RESPONSES]

MHC-E is a highly conserved nonclassical MHC class Ib molecule that predominantly binds and presents MHC class Ia leader sequence-derived peptides for NK cell regulation. However, MHC-E also binds pathogen-derived peptide Ags for presentation to CD8⁺ T cells. Given this role in adaptive immunity and its highly monomorphic nature in the human population, HLA-E is an attractive target for novel vaccine and immunotherapeutic modalities. Development of HLA-E–targeted therapies will require a physiologically relevant animal model that recapitulates HLA-E–restricted T cell biology. In this study, we investigated MHC-E immunobiology in two common nonhuman primate species, Indian-origin rhesus macaques (RM) and Mauritian-origin cynomolgus macaques (MCM). Compared to humans and MCM, RM expressed a greater number of MHC-E alleles at both the population and individual level. Despite this difference, human, RM, and MCM MHC-E molecules were expressed at similar levels across immune cell subsets, equivalently upregulated by viral pathogens, and bound and presented identical peptides to CD8⁺ T cells. Indeed, SIV-specific, Mamu-E–restricted CD8⁺ T cells from RM recognized antigenic peptides presented by all MHC-E molecules tested, including cross-species recognition of human and MCM SIV-infected CD4⁺ T cells. Thus, MHC-E is functionally conserved among humans, RM, and MCM, and both RM and MCM represent physiologically relevant animal models of HLA-E–restricted T cell immunobiology.

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The Activation of Human Dermal Microvascular Cells by Poly(I:C), Lipopolysaccharide, Imiquimod, and ODN2395 Is Mediated by the Fli1/FOXO3A Pathway [INNATE IMMUNITY AND INFLAMMATION]

Endothelial cell (EC) dysfunction has been associated with inflammatory and autoimmune diseases; however, the factors contributing to this dysfunction have not been fully explored. Because activation of TLRs has been implicated in autoimmune diseases, the goal of this study was to determine the effects of TLR ligands on EC function. Human dermal microvascular ECs (HDMECs) treated with TLR3 [Poly(I:C)], TLR4 (LPS), and TLR7 (imiquimod) agonists showed decreased proliferation and a reduced total number of branching tubules in three-dimensional human dermal organoid ex vivo culture. In contrast, the TLR9 ligand class C, ODN2395, increased angiogenesis. The antiproliferative effects of TLR3, TLR4, and TLR7 ligands correlated with significant downregulation of a key regulator of vascular homeostasis, Fli1, whereas TLR9 increased Fli1 levels. Furthermore, Poly(I:C) and LPS induced endothelial to mesenchymal transition that was reversed by the pretreatment with TGF-β neutralizing Ab or re-expression of Fli1. We showed that Fli1 was required for the HDMEC proliferation by transcriptionally repressing FOXO3A. In contrast to TLR9, which suppressed activation of the FOXO3A pathway, TLR3, TLR4, and TLR7 ligands activated FOXO3A as indicated by decreased phosphorylation and increased nuclear accumulation. The inverse correlation between Fli1 and FOXO3A was also observed in the vasculature of scleroderma patients. This work revealed opposing effects of TLR9 and TLR3, TLR4, and TLR7 on the key angiogenic pathways, Fli1 and FOXO3A. Our results provide a mechanistic insight into the regulation of angiogenesis by TLRs and confirm a central role of Fli1 in regulating vascular homeostasis.

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Superoxide Production by NADPH Oxidase Intensifies Macrophage Antiviral Responses during Diabetogenic Coxsackievirus Infection [AUTOIMMUNITY]

Coxsackievirus B infections are suspected environmental triggers of type 1 diabetes (T1D) and macrophage antiviral responses may provide a link to virus-induced T1D. We previously demonstrated an important role for NADPH oxidase (NOX)–derived superoxide production during T1D pathogenesis, as NOX-deficient NOD mice (NOD.Ncf1^m1J) were protected against T1D due, in part, to impaired proinflammatory TLR signaling in NOD.Ncf1^m1J macrophages. Therefore, we hypothesized that loss of NOX-derived superoxide would dampen diabetogenic antiviral macrophage responses and protect from virus-induced diabetes. Upon infection with a suspected diabetogenic virus, Coxsackievirus B3 (CB3), NOD.Ncf1^m1J mice remained resistant to virus-induced autoimmune diabetes. A concomitant decrease in circulating inflammatory chemokines, blunted antiviral gene signature within the pancreas, and reduced proinflammatory M1 macrophage responses were observed. Importantly, exogenous superoxide addition to CB3-infected NOD.Ncf1^m1J bone marrow–derived macrophages rescued the inflammatory antiviral M1 macrophage response, revealing reduction-oxidation–dependent mechanisms of signal transducer and activator of transcription 1 signaling and dsRNA viral sensors in macrophages. We report that superoxide production following CB3 infection may exacerbate pancreatic β cell destruction in T1D by influencing proinflammatory M1 macrophage responses, and mechanistically linking oxidative stress, inflammation, and diabetogenic virus infections.

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Granzyme A in Human Platelets Regulates the Synthesis of Proinflammatory Cytokines by Monocytes in Aging [INNATE IMMUNITY AND INFLAMMATION]

Dysregulated inflammation is implicated in the pathobiology of aging, yet platelet–leukocyte interactions and downstream cytokine synthesis in aging remains poorly understood. Platelets and monocytes were isolated from healthy younger (age <45, n = 37) and older (age ≥65, n = 30) adults and incubated together under autologous and nonautologous conditions. Synthesis of inflammatory cytokines by monocytes, alone or in the presence of platelets, was examined. Next-generation RNA-sequencing allowed for unbiased profiling of the platelet transcriptome in aging. Basal IL-8 and MCP-1 synthesis by monocytes alone did not differ between older and younger adults. However, in the presence of autologous platelets, monocytes from older adults synthesized greater IL-8 (41 ± 5 versus 9 ± 2 ng/ml, p < 0.0001) and MCP-1 (867 ± 150 versus 216 ± 36 ng/ml, p < 0.0001) than younger adults. Platelets from older adults were sufficient for upregulating the synthesis of inflammatory cytokines by monocytes. Using RNA-sequencing of platelets followed by validation via RT-PCR and immunoblot, we discovered that granzyme A (GrmA), a serine protease not previously identified in human platelets, increases with aging (~9-fold versus younger adults, p < 0.05) and governs increased IL-8 and MCP-1 synthesis through TLR4 and caspase-1. Inhibiting GrmA reduced excessive IL-8 and MCP-1 synthesis in aging to levels similar to younger adults. In summary, human aging is associated with changes in the platelet transcriptome and proteome. GrmA is present and bioactive in human platelets, is higher in older adults, and controls the synthesis of inflammatory cytokines by monocytes. Alterations in the platelet molecular signature and signaling to monocytes may contribute to dysregulated inflammatory syndromes in older adults.

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Essential Role of CARD14 in Murine Experimental Psoriasis [AUTOIMMUNITY]

Caspase recruitment domain family member 14 (CARD14) was recently identified as a psoriasis-susceptibility gene, but its immunological role in the pathogenesis of psoriasis in vivo remains unclear. In this study, we examined the role of CARD14 in murine experimental models of psoriasis induced by either imiquimod (IMQ) cream or recombinant IL-23 injection. In all models tested, the psoriasiform skin inflammation was abrogated in Card14^–/– mice. Comparison of the early gene signature of the skin between IMQ-cream–treated Card14^–/– mice and Tlr7^–/–Tlr9^–/– mice revealed not only their similarity, but also distinct gene sets targeted by IL-23. Cell type–specific analysis of these mice identified skin Langerin^high Langerhans cells as a potent producer of IL-23, which was dependent on both TLR7 and TLR9 but independent of CARD14, suggesting that CARD14 is acting downstream of IL-23, not TLR7 or TLR9. Instead, a bone marrow chimera study suggested that CARD14 in radio-sensitive hematopoietic cells was required for IMQ-induced psoriasiform skin inflammation, controlling the number of V4⁺ T cells producing IL-17 or IL-22 infiltrating through the dermis to the inflamed epidermis. These data indicate that CARD14 is essential and a potential therapeutic target for psoriasis.

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Identity and Diversity of Human Peripheral Th and T Regulatory Cells Defined by Single-Cell Mass Cytometry [SYSTEMS IMMUNOLOGY]

Human CD3⁺CD4⁺ Th cells, FOXP3⁺ T regulatory (Treg) cells, and T regulatory type 1 (Tr1) cells are essential for ensuring peripheral immune response and tolerance, but the diversity of Th, Treg, and Tr1 cell subsets has not been fully characterized. Independent functional characterization of human Th1, Th2, Th17, T follicular helper (Tfh), Treg, and Tr1 cells has helped to define unique surface molecules, transcription factors, and signaling profiles for each subset. However, the adequacy of these markers to recapitulate the whole CD3⁺CD4⁺ T cell compartment remains questionable. In this study, we examined CD3⁺CD4⁺ T cell populations by single-cell mass cytometry. We characterize the CD3⁺CD4⁺ Th, Treg, and Tr1 cell populations simultaneously across 23 memory T cell–associated surface and intracellular molecules. High-dimensional analysis identified several new subsets, in addition to the already defined CD3⁺CD4⁺ Th, Treg, and Tr1 cell populations, for a total of 11 Th cell, 4 Treg, and 1 Tr1 cell subsets. Some of these subsets share markers previously thought to be selective for Treg, Th1, Th2, Th17, and Tfh cells, including CD194 (CCR4)⁺FOXP3⁺ Treg and CD183 (CXCR3)⁺T-bet⁺ Th17 cell subsets. Unsupervised clustering displayed a phenotypic organization of CD3⁺CD4⁺ T cells that confirmed their diversity but showed interrelation between the different subsets, including similarity between Th1–Th2–Tfh cell populations and Th17 cells, as well as similarity of Th2 cells with Treg cells. In conclusion, the use of single-cell mass cytometry provides a systems-level characterization of CD3⁺CD4⁺ T cells in healthy human blood, which represents an important baseline reference to investigate abnormalities of different subsets in immune-mediated pathologies.

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The Loss of TET2 Promotes CD8+ T Cell Memory Differentiation [IMMUNE REGULATION]

T cell differentiation requires appropriate regulation of DNA methylation. In this article, we demonstrate that the methylcytosine dioxygenase ten-eleven translocation (TET)2 regulates CD8⁺ T cell differentiation. In a murine model of acute viral infection, TET2 loss promotes early acquisition of a memory CD8⁺ T cell fate in a cell-intrinsic manner without disrupting Ag-driven cell expansion or effector function. Upon secondary recall, TET2-deficient memory CD8⁺ T cells demonstrate superior pathogen control. Genome-wide methylation analysis identified a number of differentially methylated regions in TET2-deficient versus wild-type CD8⁺ T cells. These differentially methylated regions did not occur at the loci of differentially expressed memory markers; rather, several hypermethylated regions were identified in known transcriptional regulators of CD8⁺ T cell memory fate. Together, these data demonstrate that TET2 is an important regulator of CD8⁺ T cell fate decisions.

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Amplifying IFN-{gamma} Signaling in Dendritic Cells by CD11c-Specific Loss of SOCS1 Increases Innate Immunity to Infection while Decreasing Adaptive Immunity [INFECTIOUS DISEASE AND HOST RESPONSE]

Although prophylactic vaccines provide protective humoral immunity against infectious agents, vaccines that elicit potent CD8 T cell responses are valuable tools to shape and drive cellular immunity against cancer and intracellular infection. In particular, IFN-–polarized cytotoxic CD8 T cell immunity is considered optimal for protective immunity against intracellular Ags. Suppressor of cytokine signaling (SOCS)1 is a cross-functional negative regulator of TLR and cytokine receptor signaling via degradation of the receptor–signaling complex. We hypothesized that loss of SOCS1 in dendritic cells (DCs) would improve T cell responses by accentuating IFN-–directed immune responses. We tested this hypothesis using a recombinant Listeria monocytogenes vaccine platform that targets CD11c⁺ DCs in mice in which SOCS1 is selectively deleted in all CD11c⁺ cells. Unexpectedly, in mice lacking SOCS1 expression in CD11c⁺ cells, we observed a decrease in CD8⁺ T cell response to the L. monocytogenes vaccine. NK cell responses were also decreased in mice lacking SOCS1 expression in CD11c⁺ cells but did not explain the defect in CD8⁺ T cell immunity. We found that DCs lacking SOCS1 expression were functional in driving Ag-specific CD8⁺ T cell expansion in vitro but that this process was defective following infection in vivo. Instead, monocyte-derived innate TNF-α and inducible NO synthase–producing DCs dominated the antibacterial response. Thus, loss of SOCS1 in CD11c⁺ cells skewed the balance of immune response to infection by increasing innate responses while decreasing Ag-specific adaptive responses to infectious Ags.

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Downregulation of NFAT3 Due to Lack of T-Box Transcription Factor TBX5 Is Crucial for Cytokine Expression in T Cells [IMMUNE REGULATION]

The NFAT family transcription factors play crucial roles in immunological and other biological activities. NFAT3 is rarely expressed in T cells, and the mechanisms and significance of the specific NFAT3 downregulation in T cells have been unknown. In human CD4⁺ T cells, overexpression of NFAT1 and NFAT3 enhanced and suppressed IL-2 expression, respectively. NFAT3 downregulation in Jurkat cells using RNA interference technology augmented IL-2 expression, whereas a knockdown of NFAT1, NFAT2, and NFAT4 suppressed it. The promoter/enhancer activity of the NFAT-binding site in the IL-2 gene was upregulated and downregulated by NFAT1 and NFAT3, respectively. A study employing NFAT1/NFAT3 chimeric molecules revealed that the region in NFAT3 responsible for NFAT promoter activity inhibition was located within its N-terminal transactivation domain, Ca²⁺-regulatory domain, and DNA-binding domain. Downregulation of NFAT3 expression in T cells is mediated by lower chromatin accessibility and enhancer activity in its promoter in comparison with aortic smooth muscle cells expressing endogenous NFAT3. The binding sites of T-box transcription factor TBX5 and NK-2 transcription factor–related locus 5 Nkx2.5, which were expressed at higher levels in aortic smooth muscle cells than in T cells, were located within the –387 to +97 NFAT3 promoter region, exhibiting the maximum enhancer activity. Mutating the binding site of TBX5 but not Nkx2.5 diminished the NFAT3 promoter activity, whereas the overexpression of TBX5 enhanced it. Introduction of TBX5 into CD4⁺ T cells enhanced the expression of NFAT3 and suppressed that of IL-2. TBX5 deficiency-mediated downregulation of NFAT3 is crucial for the high cytokine-producing activity of T cells.

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NOX2-Derived Reactive Oxygen Species Control Inflammation during Leishmania amazonensis Infection by Mediating Infection-Induced Neutrophil Apoptosis [INFECTIOUS DISEASE AND HOST RESPONSE]

Reactive oxygen species (ROS) produced by NADPH phagocyte oxidase isoform (NOX2) are critical for the elimination of intracellular pathogens in many infections. Despite their importance, the role of ROS following infection with the eukaryotic pathogen Leishmania has not been fully elucidated. We addressed the role of ROS in C57BL/6 mice following intradermal infection with Leishmania amazonensis. Despite equivalent parasite loads compared with wild-type (WT) mice, mice deficient in ROS production by NOX2 due to the absence of the gp91 subunit (gp91^phox–/–) had significantly more severe pathology in the later stages of infection. Pathology in gp91^phox–/– mice was not associated with alterations in CD4⁺ T cell–mediated immunity but was preceded by enhanced neutrophil accumulation at the dermal infection site. Ex vivo analysis of infected versus uninfected neutrophils revealed a deficiency in infection-driven apoptosis in gp91^phox–/– mice versus WT mice. gp91^phox–/– mice presented with higher percentages of healthy or necrotic neutrophils but lower percentages of apoptotic neutrophils at early and chronic time points. In vitro infection of gp91^phox–/– versus WT neutrophils also revealed reduced apoptosis and CD95 expression but increased necrosis in infected cells at 10 h postinfection. Provision of exogenous ROS in the form of H₂O₂ reversed the necrotic phenotype and restored CD95 expression on infected gp91^phox–/– neutrophils. Although ROS production is typically viewed as a proinflammatory event, our observations identify the importance of ROS in mediating appropriate neutrophil apoptosis and the importance of apoptosis in inflammation and pathology during chronic infection.

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The WNT7B protein promotes the migration and differentiation of human dental pulp cells partly through WNT/beta-catenin and c-Jun N-terminal kinase signalling pathways

Publication date: March 2018
Source:Archives of Oral Biology, Volume 87
Author(s): Hongyang Lv, Jing Yang, Chenglin Wang, Fanyuan Yu, Dingming Huang, Ling Ye
ObjectiveThe aim of this study is to investigate the role of the WNT7B protein in the migration and differentiation of human dental pulp cells (HDPCs).DesignThe effect of recombinant human WNT7B (rhWNT7B) on the proliferation and migration of HDPCs was evaluated by 5-ethynyl-2′-deoxyuridine (EdU), immunofluorescence staining of Ki67, flow cytometry and scratch assay; the differentiation of HDPCs was measured by alkaline phosphatase (ALP) staining, alizarin red staining, ALP activity, qPCR and western blot. The activation of the WNT/beta-catenin (WNT/β-catenin) and c-Jun N-terminal kinase (JNK) pathways was analysed by western blot, immunocytochemistry and dual luciferase assays. XAV939 and SP600125，the inhibitors of the WNT/β-catenin and JNK pathways, were further applied to verify the mechanism.ResultsrhWNT7B repressed the proliferation but did not affect the apoptosis of HDPCs. In the presence of rhWNT7B, ALP and alizarin red staining were increased substantially in the HDPCs with osteogenic induction; the gene expression of Runx2 and Col1 in HDPCs was quite elevated compared with that induced in osteogenic medium without WNT7B measured by qPCR; The ALP activity was also increased with rhWNT7B stimulation in HDPCs after 7-day odontogenic culture; Western blot revealed that the expression of dentin sialophosphoprotein (DSPP) of HDPCs was up-regulated significantly with the addition of WNT7B as well. Further study showed that rhWNT7B activated the WNT/β-catenin and JNK signalling pathways in the differentiation of HDPCs. XAV939 and SP600125 can partly offset the effect of the WNT7B-induced differentiation of HDPCs.ConclusionWNT7B promoted the differentiation of HDPCs partly through the WNT/β-catenin and JNK signalling pathways.



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The WNT7B protein promotes the migration and differentiation of human dental pulp cells partly through WNT/beta-catenin and c-Jun N-terminal kinase signalling pathways

Publication date: March 2018
Source:Archives of Oral Biology, Volume 87
Author(s): Hongyang Lv, Jing Yang, Chenglin Wang, Fanyuan Yu, Dingming Huang, Ling Ye
ObjectiveThe aim of this study is to investigate the role of the WNT7B protein in the migration and differentiation of human dental pulp cells (HDPCs).DesignThe effect of recombinant human WNT7B (rhWNT7B) on the proliferation and migration of HDPCs was evaluated by 5-ethynyl-2′-deoxyuridine (EdU), immunofluorescence staining of Ki67, flow cytometry and scratch assay; the differentiation of HDPCs was measured by alkaline phosphatase (ALP) staining, alizarin red staining, ALP activity, qPCR and western blot. The activation of the WNT/beta-catenin (WNT/β-catenin) and c-Jun N-terminal kinase (JNK) pathways was analysed by western blot, immunocytochemistry and dual luciferase assays. XAV939 and SP600125，the inhibitors of the WNT/β-catenin and JNK pathways, were further applied to verify the mechanism.ResultsrhWNT7B repressed the proliferation but did not affect the apoptosis of HDPCs. In the presence of rhWNT7B, ALP and alizarin red staining were increased substantially in the HDPCs with osteogenic induction; the gene expression of Runx2 and Col1 in HDPCs was quite elevated compared with that induced in osteogenic medium without WNT7B measured by qPCR; The ALP activity was also increased with rhWNT7B stimulation in HDPCs after 7-day odontogenic culture; Western blot revealed that the expression of dentin sialophosphoprotein (DSPP) of HDPCs was up-regulated significantly with the addition of WNT7B as well. Further study showed that rhWNT7B activated the WNT/β-catenin and JNK signalling pathways in the differentiation of HDPCs. XAV939 and SP600125 can partly offset the effect of the WNT7B-induced differentiation of HDPCs.ConclusionWNT7B promoted the differentiation of HDPCs partly through the WNT/β-catenin and JNK signalling pathways.



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FDA OKs Tofacitinib (Xeljanz) for Active Psoriatic Arthritis

The JAK inhibitor is indicated for patients who have failed to respond adequately or are intolerant to methotrexate or other disease-modifying antirheumatic drugs.
FDA Approvals

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Primary surgical management with radial forearm free flap reconstruction in T4 oropharyngeal cancer: Complications and functional outcomes

Publication date: Available online 18 December 2017
Source:American Journal of Otolaryngology
Author(s): John R. Sims, Eric J. Moore
PurposeFunctional outcomes and complication rates after open surgery for advanced-stage oropharyngeal cancers are rarely reported. These measures are critical for choice of treatment modality and patient counseling. We describe the long term functional outcomes and associated complications of primary surgical management of T4 oropharyngeal cancers reconstructed with radial forearm free flaps.Materials and methodsA retrospective review was performed of 40 patients with T4 oropharyngeal cancers treated between 2005 and 2015 at a tertiary care center.ResultsForty patients with T4 oropharyngeal cancers underwent open surgical resection and radial forearm free flap reconstruction at the time of surgery. Mandibulotomy was required in 33 (82.5%) cases. Thirty-five (87.5%) patients received adjuvant radiation or combined chemotherapy and radiation. Tracheostomy was performed in all patients, but every patient was eventually decannulated. Twenty (57.1%) patients required gastrostomy tube placement at some point during treatment; however, 91.4% were on a completely oral diet with a mean FOSS score of 1.6 by 1year after completion of treatment. The addition of adjuvant treatment was the only factor significantly associated with poorer FOSS scores. The overall rates of short and long-term complications were 60.0% and 57.1% respectively. The most common short and long-term complications were infection (30.0%) and velopharyngeal insufficiency (25.7%) respectively.ConclusionsTraditional open surgical approaches to large tumors of the oropharynx carry higher complication rates than more recent advanced transoral approaches. However, they can still be utilized with excellent long-term functional results in certain cases of advance oropharyngeal cancers not amenable to transoral approaches. With careful reconstruction of oropharyngeal defects, over 90% of patients can achieve a completely oral diet.



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IL-6 and IL-10 are associated with good prognosis in early stage invasive breast cancer patients

Abstract

Macrophage-associated cytokines play an important role in cancer metastasis; however, the functions of interleukins (IL) 6 and 10 in breast cancer (BC) progression and metastasis are not clear. In this study the roles of IL-6/IL-10 in regulating vascular invasion and their prognostic significance in BC are investigated. MDA-MB-231 and MCF-7 migration (± IL-6 or IL-10) was assessed by scratch wound assay. Cancer cell adhesion to IL-6/IL-10 stimulated blood and lymphatic endothelial cells (EC) was investigated. Expression of IL-6 /IL-10 was assessed using immunohistochemistry in an annotated cohort of early stage BC (n = 1380) and associations with clinicopathological variables and clinical outcome evaluated. IL-6 did not alter BC cell migration however a dose-dependent inhibition in MDA-MB-231 migration with IL-10 treatment was observed (P = 0.03). BC cells were more adhesive to blood vs lymphatic EC, however, IL-6/IL-10 had no effect on adhesion patterns. High expression of IL-6/IL-10 was associated with clinicopathological criteria (e.g. hormone receptor status, all P < 0.05), improved disease-free survival (DFS; P < 0.05) and improved BC-specific survival (BCSS; only IL-6, P = 0.017). However, neither IL-6 nor IL-10 expression were independent prognostic factors from multivariate analysis. In BC subgroups, IL-6 and IL-10 were good prognosticators in terms of DFS in non-basal, non-triple-negative (non-TN), ER-positive, PgR-positive (only IL-10), and Her-2-negative (only IL-6) BC (all P < 0.05). IL-6 was associated with improved BCSS in non-basal, ER-positive and non-TN BC (all P < 0.05).

http://ift.tt/2CBRgro

Adaptive Dose-Escalated Multi-modality Image-guided RadiothErapy

Condition:   Head and Neck Cancer
Intervention:   Radiation: Adaptive dose-Escalated multi-modality image-guided radiotherapy
Sponsor:   The Netherlands Cancer Institute
Recruiting

http://ift.tt/2yTmJ6c

The Effects of Preoperative Prayer on Postoperative Quality of Recovery in Patients Undergoing Thyroidectomy

Condition:   Thyroid Cancer
Interventions:   Behavioral: Prayer;   Behavioral: non-prayer
Sponsor:   Yonsei University
Not yet recruiting

http://ift.tt/2B95G69

A Study of Epacadostat in Combination With Pembrolizumab and Chemotherapy in Subjects With Advanced or Metastatic Solid Tumors (ECHO-207/KEYNOTE-723)

Conditions:   Advanced or Metastatic Solid Tumors;   Advanced or Metastatic Colorectal Cancer (CRC);   Pancreatic Ductal Adenocarcinoma (PDAC);   Non-Small Cell Lung Cancer (NSCLC; Squamous or Nonsquamous);   Advanced or Metastatic Solid Tumor That Progressed on Previous Therapy With a Programmed Cell Death Protein 1 (PD-1) Inhibitor;   Advanced or Metastatic Solid Tumor That Progressed on Previous Therapy With a Programmed Cell Death Ligand 1 (PD-L1) Inhibitor;   Advanced or Metastatic Urothelial Carcinoma (UC);   Advanced or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)
Interventions:   Drug: Epacadostat;   Drug: Pembrolizumab;   Drug: Oxaliplatin;   Drug: Leucovorin;   Drug: 5-Fluorouracil;   Drug: Gemcitabine;   Drug: nab-Paclitaxel;   Drug: Carboplatin;   Drug: Paclitaxel;   Drug: Pemetrexed;   Drug: Cyclophosphamide;   Drug: Cisplatin
Sponsor:   Incyte Corporation
Recruiting

http://ift.tt/2yThhQX

Right Internal Jugular Vein Phlebectasia: A Rare Cause of Neck Swelling

Internal jugular vein (IJV) phlebectasia is a rare condition presenting as a self-reducible soft tissue swelling of the neck due to fusiform dilation of the venous wall. We report the case of a 7-year-old boy who presented with painless soft mass in the side of the neck which appears during coughing and straining and reduces spontaneously. Diagnosis was confirmed by Doppler ultrasonography and magnetic resonance imaging of the neck. Conservative management and regular follow-up were considered. In this case report, we highlight this rare benign condition as an uncommon differential of neck swellings in order to avoid unnecessary diagnostic workup and interventions.

http://ift.tt/2BtWd6D

Anatomical variant of the meniscus related to posterior junction: a case report

There are several reports on anatomical differences of the meniscus. However, there are only a few reports on abnormalities in both menisci and anatomical differences in anterior cruciate ligament insertions.

http://ift.tt/2jaAF6p

Asynchronous Bilateral Ovarian Torsion: Three Cases, Three Lessons

Background. Ovarian torsion (OT) is a serious condition, and delay in surgical intervention may result in loss of the ovary. Children and adolescents who have suffered from ovarian torsion may be at risk for asynchronous torsion of the contralateral ovary. Study objective. Three cases of asynchronous bilateral ovarian torsion were reported to analyse clinical history of three patients, to review the current literature, and to draw a conclusion for future treatment. Design. Case reports and review of the literature. Result. When a prepubertal girl presents with an ovarian torsion, several considerations have to be taken in account in order to preserve her future fertility; in particular, the pediatric surgeon/gynecologist has to preserve as much as possible the twisted ovary in addition to considering the fate of the contralateral ovary. Summary and Conclusions. Pelvic pain in a young girl has always raised the clinical suspect of an ovarian torsion; the possibility of asynchronous bilateral ovarian torsion is rare, but it is described in the literature and has catastrophic consequences; this condition has to be known and treated in the proper way by pediatric surgeons as well as by gynecologists in order to maximize the future fertility of the young patients.

http://ift.tt/2APJJ83

Cover Image

The cover image, by Erez Shmuel Davidi et al., is based on the Original Article Cisplatin-conjugated gold nanoparticles as a theranostic agent for head and neck cancer, DOI: 10.1002/hed.24935.

http://ift.tt/2yRtjtZ

Issue Information

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