Genetic Variants with Gene Regulatory Effects are Associated with Diisocyanate Asthma

Publication date: Available online 30 June 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): David I. Bernstein, Zana L. Lummus, Banu Kesavalu, Jianbo Yao, Leah Kottyan, Daniel Miller, André Cartier, Maria-Jesús Cruz, Catherine Lemiere, Xavier Muñoz, Santiago Quirce, Susan Tarlo, Joaquin Sastre, Louis Philippe Boulet, Matthew T. Weirauch, Kenneth Kaufman
BackgroundIsocyanates are major causes of occupational asthma but susceptibility and mechanisms of Diisocyanate Asthma (DA) remain uncertain.ObjectiveThe aim of this study is to identify DA-associated functional genetic variants via next generation sequencing (NGS), bioinformatics, and functional assays.MethodsNGS was performed in 91 workers with DA. Fourteen loci with known DA associated single nucleotide polymorphisms (SNPs) were sequenced and compared to data from 238 unexposed subjects. Ranking of DA associated SNPs based on their likelihood to affect gene regulatory mechanisms in the lung yielded 21 prioritized SNPs. Risk (R) and non-risk (NR) oligonucleotides were tested for binding of nuclear extracts from A549, BEAS 2B, and IMR-90 lung cell lines by electrophoretic mobility shift assays (EMSA). DNA constructs were cloned into a pGL3-promoter vector for luciferase gene reporter assays.ResultsNGS detected 130 risk variants associated with DA (3.1 x10^-6 – 6.21x10^-4), of which 129 were located in non-coding regions. The 21 SNPs prioritized by functional genomic data sets were in or proximal to five genes: CDH17 (n=10), ATF3 (n=7), FAM71A (n=2), TACR1 (n=1), and ZBTB16 (n=1). EMSA detected allele-dependent nuclear protein binding in A549 cells for 8 of 21 variants. In the luciferase assay, 4 of the 21 SNPs exhibited allele-dependent changes in gene expression. DNA affinity precipitation and mass spectroscopy of rs147978008 revealed allele-dependent binding of H1 histones, which was confirmed by Western blot.ConclusionsWe identified five DA associated potential regulatory SNPs. Four variants exhibited effects on gene regulation (ATF rs11571537, CDH17 rs2446824, rs2513789, and TACR1 rs2287231). A fifth variant (FAM71A rs147978008) showed non-risk allele preferential binding to H1 histones. These results demonstrate that many DA-associated genetic variants likely act by modulating gene regulation.

Teaser

This study advances knowledge of genetic mechanisms of occupational asthma by identification of a role for regulatory genetic variants associated with diisocyanate-induced asthma.


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Evaluation of food allergy candidate loci in the Genetics of Food Allergy Study

Publication date: Available online 30 June 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Ingo Marenholz, Sarah Grosche, Franz Rüschendorf, Birgit Kalb, Katharina Blumchen, Rupert Schlags, Neda Harandi, Mareike Price, Gesine Hansen, Jürgen Seidenberg, Songül Yürek, Georg Homuth, Carsten O. Schmidt, Markus M. Nöthen, Norbert Hubner, Bodo Niggemann, Kirsten Beyer, Young-Ae Lee

Teaser

A recent genome-wide association study suggested novel candidate loci for food allergy. Apart from the established locus at 11q13, these revealed no association with food allergy in the Genetics Of Food Allergy Study.


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Postoperative temporomandibular dysfunction in patients with fractures of the zygomatic complex: a prospective follow-up study

Publication date: Available online 30 June 2018
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): H. Rajantie, J. Snäll, H. Thorén
The aim of this prospective follow-up study was to clarify the incidence and characteristics of dysfunction of the temporomandibular joint (TMJ) in patients treated surgically for fractures of the zygomatic complex. Patients were evaluated on presentation and six months after injury to assess the function of the masticatory system using the Helkimo index, which incorporates two complementary subindices: the subjective symptomatic (anamnestic) index (Ai) and the objective clinical dysfunction index (Di). Forty-five patients (12 women and 33 men, mean (range) age 44 (21-83)years) completed the study. Six patients developed subjective symptoms of dysfunction of the TMJ during follow-up, in four of whom they were severe. Clinical findings were noted in 38 patients but without significant association with subjective symptoms.Dysfunction of the TMJ is common six months after surgical treatment of a fracture of the zygomatic complex, and patients with such fractures should be evaluated for temporomandibular dysfunction during follow-up and referred for treatment when necessary.



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Clinical analysis of second primary gingival squamous cell carcinoma after radiotherapy

Publication date: September 2018
Source:Oral Oncology, Volume 84
Author(s): Xiaoyan Fu, Shuwei Chen, Weichao Chen, Zhongyuan Yang, Ming Song, Hao Li, Huayong Zhang, Fan Yao, Xuan Su, Tianrun Liu, An-Kui Yang
IntroductionClinically, we have observed that some oral cancer patients have a history of radiotherapy for head and neck cancer; we have named this condition radiotherapy-associated cancer (RAC). Gingival cancer, which is usually juxtaposed with other oral cancer subtypes, is seldom reported individually, and there are few reports on the association between the incidence of oral cancer and history of radiation therapy. Therefore, this study aimed to elucidate the clinicopathological features and prognosis of second primary gingival squamous cell carcinoma after head and neck radiotherapy.Materials and methodsThe data collected included 450 patients diagnosed with gingival squamous cell carcinoma from 1964 to 2012 at Sun Yat-sen University Cancer, among whom 52 patients had a history of radiotherapy for head and neck cancer. We retrospectively analysed the differences in the clinicopathological characteristics and prognosis between sporadic gingival squamous cell carcinoma and radiation-associated gingival carcinoma, with an emphasis on gingival carcinoma.ResultsSporadic gingival squamous cell carcinoma is less likely to have more advanced T stage, and the second primary tumour is more likely to be located in the molar area of the maxillary gingiva than in the mandibular gingiva (75.6% vs 24.4%, P < 0.05). The 5-year overall survival of patients with second primary gingival carcinoma was influenced by age distribution, T classification, N classification, clinical TNM stage, histological grade and radiation history in head and neck. Mandibular gingival carcinoma was more likely to have an increased neck lymph node metastasis than maxillary gingival carcinoma (P = 0.001), but there was no significant difference in 5-year overall survival between these two groups (P = 0.828). The main therapy for gingiva carcinoma is surgery or comprehensive treatment based on surgery.ConclusionsSecond primary gingival squamous cell carcinoma after radiotherapy demonstrated particular clinicopathologic features, such as prominent sites and TNM stage; and there was statistically significant difference in 5-year overall survival and prognosis between second primary gingival carcinoma after radiotherapy and sporadic gingival carcinoma.



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Case 20-2018: A 64-Year-Old Man with Fever, Arthralgias, and Testicular Pain

Presentation of Case. Dr. Jaime L. Schneider (Medicine): A 64-year-old man was admitted to this hospital with a 2-week history of fever, chills, arthralgias, abdominal and testicular pain, and leukocytosis. Twenty-five years before the current admission, while the patient was living in China, he…

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Case 19-2018: A 15-Year-Old Girl with Acute Kidney Injury

Presentation of Case. Dr. Helen I. Healy (Pediatrics): A 15-year-old girl was admitted to this hospital during the summer because of acute kidney injury. The patient had been well until 8 days before admission, when painful cramping in the lower abdomen and bloody diarrhea developed. Bowel…

https://ift.tt/2KznoUo

CTLA-4 regulates human Natural Killer cell effector functions

Publication date: Available online 30 June 2018
Source:Clinical Immunology
Author(s): Vassilios Lougaris, Giovanna Tabellini, Manuela Baronio, Ornella Patrizi, Luisa Gazzurelli, Noriko Mitsuiki, Maria Rosa Pozzi, Bodo Grimbacher, Silvia Parolini, Alessandro Plebani




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