Risk factors for radiation failure in early-stage glottic carcinoma: A systematic review and meta-analysis

Publication date: November 2016
Source:Oral Oncology, Volume 62
Author(s): Görkem Eskiizmir, Yasemin Baskın, Femin Yalçın, Hülya Ellidokuz, Robert L. Ferris
BackgroundRadiotherapy is one of the main treatment modalities for early-stage glottic carcinoma. Unfortunately, local failure may occur in a group of cases with T1-T2 glottic carcinoma. This meta-analysis sought to determine risk factors for radiation failure in patients with early-stage glottic carcinoma.MethodsA systematic and comprehensive search was performed for related studies published between 1995 and 2014. The primary end-point was 5-year local control. Data extraction and analysis were performed using the software STATA/SE 13.1 for Windows.ResultsTwenty-seven studies were eligible. A higher risk of radiation failure was demonstrated in male patients [relative risk (RR): 0.927, p<0.001] and those with low hemoglobin level (RR: 0.891, p<0.001) with a high agreement between studies (I-squared=0.0%). Moreover, T2 tumors (RR: 0.795, p<0.001), tumors with anterior commissure involvement (RR: 0.904, p<0.001), tobacco use during/after therapy (RR: 0.824, p<0.001), and "bulky" tumors (RR: 1.270, p<0.001] or tumors bigger in size (RR: 1.332, p<0.001]. Poorly differentiated tumors had a questionable risk of local failure, although a moderate to high interstudy heterogeneity was determined. A statistically significant contribution was not detected for age, presence of comorbidity, alcohol use or subglottic extension.ConclusionThis is the first meta-analysis which assessed the potential risk factors for radiation failure in patients with early-stage glottic carcinoma. Gender and pretreatment hemoglobin level are major influential factors associated with radiation failure in patients with early-stage glottic carcinoma. However, prospective, randomized clinical trials may permit better stratification of their relative contributions, and those who may benefit more from upfront surgery.



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Diagnosis of HPV driven oropharyngeal cancers: Comparing p16 based algorithms with the RNAscope HPV-test

Publication date: November 2016
Source:Oral Oncology, Volume 62
Author(s): Haïtham Mirghani, Odile Casiraghi, Joanne Guerlain, Furrat Amen, Ming-Xiao He, Xiao-Jun Ma, Yuling Luo, Céline Mourareau, Françoise Drusch, Aïcha Ben Lakdhar, Antoine Melkane, Lacau St Guily, Cécile Badoual, Jean Yves Scoazec, Isabelle Borget, Anne Aupérin, Veronique Dalstein, Philippe Vielh
BackgroundAccurate identification of HPV-driven oropharyngeal cancer (OPC) is a major issue and none of the current diagnostic approaches is ideal. An in situ hybridization (ISH) assay that detects high-risk HPV E6/E7 mRNA, called the RNAscope HPV-test, has been recently developed. Studies have suggested that this assay may become a standard to define HPV-status.MethodsTo further assess this test, we compared its performance against the strategies that are used in routine clinical practice: p16 immunohistochemistry (IHC) as a single test and algorithms combining p16-IHC with HPV-DNA identification by PCR (algorithm-1) or ISH (algorithm-2).Results105 OPC specimens were analyzed. The prevalence of HPV-positive samples varied considerably: 67% for p16-IHC, 54% for algorithm-1, 61% for algorithm-2 and 59% for the RNAscope HPV-test. Discrepancies between the RNAscope HPV-test and p16-IHC, algorithm-1 and 2 were noted in respectively 13.3%, 13.1%, and 8.6%.The 4 diagnostic strategies were able to identify 2 groups with different prognosis according to HPV-status, as expected. However, the greater survival differential was observed with the RNAscope HPV-test [HR: 0.19, 95% confidence interval (CI), 0.07–0.51, p=0.001] closely followed by algorithm-1 (HR: 0.23, 95% CI, 0.08–0.66, p=0.006) and algorithm-2 (HR: 0.26, 95% CI, 0.1–0.65, p=0.004). In contrast, a weaker association was found when p16-IHC was used as a single test (HR: 0.33, 95% CI, 0.13–0.81, p=0.02).ConclusionsOur findings suggest that the RNAscope HPV-test and p16-based algorithms perform better that p16 alone to identify OPC that are truly driven by HPV-infection. The RNAscope HPV-test has the advantage of being a single test.



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Lateral lymph node recurrence after total thyroidectomy and central neck dissection in patients with papillary thyroid cancer without clinical evidence of lateral neck metastasis

Publication date: November 2016
Source:Oral Oncology, Volume 62
Author(s): Young Chang Lim, Lihua Liu, Jae Won Chang, Bon Seok Koo
BackgroundThis study analyzed the incidence, pattern, and predictive factors for lateral lymph node (LN) recurrence in patients with papillary thyroid cancer (PTC) without clinical evidence of lateral LN metastasis.MethodsA retrospective analysis was performed on 246 patients with PTC who underwent total thyroidectomy and central neck dissection from 2004 to 2010. None of the patients had clinical evidence of lateral LN metastasis at the time of diagnosis. Predictive factors for lateral LN recurrence were evaluated using the chi-square test. Binary logistic regression was used for the multivariate analysis. Recurrence-free survival rates were estimated by the Kaplan–Meier and Cox regression methods.ResultsOf the 246 patients, 11 (4.5%) developed lateral LN recurrence with a median follow-up of 49months. In the multivariate analysis, tumor size >1cm (odds ratio [OR], 8.14; 95% confidence interval [CI], 1.01–65.68; p=0.049) and central LN metastasis (OR, 10.59; 95% CI, 1.32–85.17; p=0.026) were independent predictive factors of lateral LN recurrence. Especially, extranodal extension of a metastatic central LN (OR, 38.82; 95% CI, 5.71–264.10; p<0.001) was an independent predictor of lateral LN recurrence.ConclusionsTumor size and central LN metastasis were independent predictors of lateral LN recurrence in patients with PTC without initial clinical lateral neck metastasis who underwent total thyroidectomy and central neck dissection. Close surveillance may be necessary for early detection of lateral LN recurrence in PTC patients with tumor size ⩾1cm, and central LN metastasis with extranodal extension.



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Induction chemotherapy with docetaxel, cisplatin and fluorouracil followed by concurrent chemoradiotherapy or chemoradiotherapy alone in locally advanced non-endemic nasopharyngeal carcinoma

Publication date: November 2016
Source:Oral Oncology, Volume 62
Author(s): Dan Ou, Pierre Blanchard, Clément El Khoury, Francesca De Felice, Caroline Even, Antonin Levy, France Nguyen, François Janot, Philippe Gorphe, Eric Deutsch, Stephane Temam, Yungan Tao
ObjectivesTo evaluate the efficacy of induction chemotherapy with docetaxel, cisplatin and fluorouracil (TPF) followed by concurrent chemoradiotherapy (IC+CCRT) or CCRT alone in non-endemic locally advanced nasopharyngeal carcinoma (NPC) patients.Materials and methodsData of 106 patients with NPC treated from January 1999 to June 2012 with IC+CCRT (n=58) or CCRT alone (n=48) were retrospectively reviewed.ResultsMedian follow-up was 6.4years. Distribution of age, performance status, stage and concurrent chemotherapy regimen were imbalanced between the two groups. The 5-year overall survival (OS) and progression-free survival (PFS) were not significantly different between IC+CCRT and CCRT groups (OS: 78.3% vs. 82.7%, p=0.77; PFS: 72.5% vs. 68.2%, p=0.81, respectively). There were less total cumulative incidence of grade 3–4 late radiation morbidity in the IC+CCRT group (44.8% vs. 70.8%, p=0.01). Five-year OS for patients with post-IC complete response (CR), partial response (PR) and stable disease (SD) sub-groups were 100%, 79.4% and 60%, respectively.ConclusionCompared with CCRT alone, IC (TPF regimen)+CCRT did not improve OS or PFS in patients with NPC, but less grade 3–4 late toxicities were observed. Responsiveness of IC may provide additional prognostic information.



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Circulating tumor stem like cells in oral squamous cell carcinoma: An unresolved paradox

Publication date: November 2016
Source:Oral Oncology, Volume 62
Author(s): Shanaya Patel, Kavan Shah, Sheefa Mirza, Kanisha Shah, Rakesh Rawal
ObjectiveCirculating tumor cells (CTCs) are increasingly gaining importance due to their immense potential in enhancing diagnosis, prognosis and response to therapy in solid malignancies. Therefore, we aimed to comprehend the molecular diversity and critical role of this disseminated tumor population in OSCC.MethodologyCD44+ subpopulation was isolated using immuno-magnetic cell separation and their purity was validated using flow cytometry. Characterisation of self renewal potential and resistance to chemotherapy was assessed using tumor sphere forming and cytotoxicity assay. Gene expression profile of pertinent CSC (CD44s, CD44v3, CD44v6) and stemness markers (Bmi1 and Nanog) was carried out in CD44+ cells using Real Time PCR. Predominantly expressed markers and their association with clinico-pathological conditions were substantiated in 30 OSCC patients.ResultFlow cytometry analysis depicted a predominant population of CD44+CD24−CD45− cells suggesting that circulating tumor cells had a subpopulation of CSC like cells in the circulation. These cells demonstrated increased sphere forming capability and intrinsic chemo-resistance compared to non-CSC, thus indicating the CSC features of self-renewal and chemo-resistance. Additionally, CD44+ cells showed significantly increased expression levels of CD44v6 and Nanog compared to CD44− cells. Clinically, expression pattern of CD44v6 and Nanog correlated with different anatomical subsites, loco-regional aggressiveness of the disease and recurrence, thus opening newer avenues that can be explored for better prognostic and therapeutic implications.ConclusionThis study explored the inevitable role of CD44v6 and Nanog as circulating stem like cell markers in assessment of loco-regional aggressiveness, detection of relapse and therapeutic response and resistance.



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Effects of geographic area and socioeconomic status in Taiwan on survival rates of head and neck cancer patients after radiotherapy

Publication date: November 2016
Source:Oral Oncology, Volume 62
Author(s): Tsu-Jen Kuo, Chi-Hsiang Chu, Pei-Ling Tang, Yu-Cheng Lai




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Tumor necrosis factor-α did not enhance α-smooth muscle actin expression in fibroblastic cell cultures derived from healthy donors

Publication date: Available online 27 October 2016
Source:Oral Oncology
Author(s): Lucas Novaes Teixeira, Flávio de Melo Garcia, Victor Ângelo Martins Montalli, Marcelo Sperandio, Elizabeth Ferreira Martinez, Vera Cavalcanti de Araújo




http://ift.tt/2dZgfIv

Lung metastasectomy in adenoid cystic cancer: Is it worth it?

Publication date: Available online 26 October 2016
Source:Oral Oncology
Author(s): Lara Girelli, Laura Locati, Carlotta Galeone, Paolo Scanagatta, Leonardo Duranti, Lisa Licitra, Ugo Pastorino
Background and purposeAdenoid cystic carcinoma (ACC) of salivary glands is characterized by long-term distant metastasis, most commonly in lungs. No agreement has been reached about the role of surgical treatment of pulmonary lesions. We evaluated the long-term results of lung metastasectomy for ACC in order to identify factors that should be taken into account in selecting patients eligible for surgery and treatment planning.Patients and methodsA retrospective study was conducted on 109 patients selected from our institutional experience and from the International Registry of Lung Metastases. Survival was calculated by Kaplan-Meier estimate and prognostic factors endowed with a predictive power for most other metastatic cancers were investigated.ResultsThe cumulative survival was 66.8% at 5years and 40.5% at 10years. In patients with a disease-free interval (DFI) greater than 36months, the overall survival was 76.5% at 5years. Survival in case of complete surgical resection was 69.5% at 5years. Multivariate analysis confirmed DFI and completeness of resection resulted in the best prognostic variables.DiscussionLung metastasectomy should be considered as a therapeutic option to achieve local control of disease when 2 conditions are met: (1) complete surgical resection is feasible and (2) the time to pulmonary relapse after primary tumor treatment is greater than 36months. Symptomatic benefits of an incomplete lung resection in slow-growing tumors such as ACC remain uncertain. The turning point in the management of disseminated cancers will be clarified with biological profiling of ACC and the development of targeted therapies.



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Amidst the excitement: A cautionary tale of immunotherapy, pseudoprogression and head and neck squamous cell carcinoma

Publication date: Available online 21 October 2016
Source:Oral Oncology
Author(s): Shrujal S. Baxi, Lara A. Dunn, Barbara A. Burtness




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Host and clinical aspects in patients with benign migratory glossitis

Publication date: January 2017
Source:Archives of Oral Biology, Volume 73
Author(s): Rafaela Scariot, Thiago Beltrami Dias Batista, Marcia Olandoski, Cleber Machado Souza, Paulo Henrique Couto Souza, Antonio Adilson Soares Lima, Paula Cristina Trevilatto
ObjectiveInvestigate the association of clinical, cytological and genetic characteristics with benign migratory glossitis (BMG).Study designSample consisted of 175 patients, 44 with BMG and 131 control patients. Clinical examination and DMFT index were assessed. Cytological evaluation determined cell morphology and morphometry. Genetic evaluation was performed by analysing IL6 polymorphisms by real-time PCR. Univariate and multivariate analyses were performed (p<0.05).ResultsThere was a higher level of anxiety, DMFT score and a prevalence of fissured tongue in BMG group. A high mean nuclear/cytoplasmic area ratio was observed in patients with BMG. There was predominance of Papanicolaou class II I BMG group. IL6 allele G rs2069843 polymorphism was associated with BMG in the dominant model. In multivariate analysis, DMFT and anxiety scale remained associated with BMG.



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Editorial Board

Publication date: November 2016
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases, Volume 133, Issue 5





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An unusual case of focal segmental glomerulosclerosis presenting with retropharyngeal edema

Publication date: November 2016
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases, Volume 133, Issue 5
Author(s): C.-H. Hsu, M.-Y. Wu, Y.-C. Liu, C.-S. Wong
IntroductionAcute neck swelling with pharyngeal signs often triggers emergency consultation. Treatment and diagnosis are usually multidisciplinary. Failing to find a possible etiology may lead to misdiagnosis.Case presentationA young man presented to the emergency room with a 4-day history of cough, neck swelling and sore throat. Laboratory testing showed a leukocyte count of 9200 without left shift. Mild elevated CRP with 1.7 was noted and computed tomography (CT) showed fluid accumulation in the retropharyngeal space and neck edema down to thyroid region. Antibiotic was prescribed and admitted to infection ward under the impression of deep neck infection. During hospitalization, needle aspiration was performed where water fluid was collected without pus. Investigations showed massive proteinuria, hypoalbuminemia and hypercholesterolemia. The early focal segmental glomerulosclerosis was found by renal biopsy. After prednisolone 60mg daily and albumin supplement, the neck swelling, swallowing pain and general edema had completely resolved.DiscussionThe purpose of this case is to raise awareness of nephrotic syndrome as an unusual but possibly cause of retropharyngeal edema. We highlight the diagnostic features that will allow the physicians to make the correct diagnosis, avoid unnecessary incision and drainage, and commence effective treatment early in the disease course.



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Neck tumour

Publication date: November 2016
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases, Volume 133, Issue 5
Author(s): C.A. Righini, A. Bally, L. Giraud




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Primary epidermoid carcinoma of the lacrimal sac

Publication date: November 2016
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases, Volume 133, Issue 5
Author(s): A. El Bousaadani, R. Abada, M. Belhadji, M. Mahtar




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Erratum to “Head and neck adenoid cystic carcinoma: A prospective multicenter REFCOR study of 95 cases” [Eur. Ann. Otorhinolaryngol. Head Neck Dis. 133 (1) (2016) 13–7]

Publication date: Available online 26 October 2016
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): M. Meyers, B. Granger, P. Herman, F. Janot, R. Garrel, N. Fakhry, G. Poissonnet, A.-C. Baglin, M. Lefèvre, B. Baujat




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Ameloblastoma of the jaws: Management and recurrence rate

Publication date: Available online 25 October 2016
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): A. Laborde, R. Nicot, T. Wojcik, J. Ferri, G. Raoul
IntroductionAmeloblastoma is a rare, benign odontogenic tumour associated with a high recurrence rate. It accounts for 1% of all tumours of the jaws. The purpose of this study was to compare the ameloblastoma recurrence rate according to the type of treatment: radical or conservative.Patients and methodsAll patients with a diagnosis of ameloblastoma between 1991 and 2013 were retrospectively identified in order to extract topographic, radiological, and histological data and the type of treatment: conservative (marsupialization, enucleation, curettage) or radical (segmental resection) and to compare the recurrence rate according to the type of treatment.ResultsTwenty-seven patients were included, managed by conservative treatment (CT) in 22 cases and radical treatment (RT) in 14 cases. The recurrence rate was 90.9% in the CT group and 9.1% in the RT group (P=0.025) with a mean follow-up of 56.2 months.DiscussionThe recurrence rate after conservative treatment was higher than that after radical treatment. These results are similar to those reported in the literature. The choice of treatment must be adapted to the macroscopic and histological characteristics of each tumour and to the patient.



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Guidelines of the French Society of Otorhinolaryngology (SFORL). First-line treatment of epistaxis in adults

Publication date: Available online 24 October 2016
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): E. Bequignon, B. Vérillaud, L. Robard, J. Michel, V. Prulière Escabasse, L. Crampette, O. Malard
ObjectivesThe authors present the guidelines of the French Otorhinolaryngology-Head and Neck Surgery Society (SFORL) on first-line treatment of epistaxis in adults.MethodsA multidisciplinary work-group was entrusted with a review of the scientific literature on the above topic. Guidelines were drawn up, based on the articles retrieved and the group members' individual experience. They were then read over by an editorial group independent of the work-group. The guidelines were graded as A, B, C or expert opinion, by decreasing level of evidence.ResultsIn first-line, clearing out blood-clots and bidigital compression are recommended. In case of persistent bleeding, local anesthesia with a vasoconstrictor is essential before nasal diagnostic and therapeutic procedures. When the origin of bleeding is not anterior, nasal endoscopy is an essential procedure, identifying the bleeding site in most cases. In case of active bleeding, cauterization is recommended but is only feasible if the bleeding site is clearly visible. When the bleeding site is not identifiable or the first measures failed, anterior packing may be performed by a non-specialist physician. Epistaxis requires subsequent nasal endoscopy performed by an ENT specialist. Patients should be informed of the measures to be taken in case of epistaxis at home, and the risks associated with the various treatments.



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Nasal NK/T-cell lymphoma: A tragic case

Publication date: Available online 24 October 2016
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): L. Taali, M. Abou-Elfadl, M. Fassih, M. Mahtar
IntroductionNasal NK/T-cell lymphoma is a rare clinicopathological entity, formerly called midline lethal granuloma. Following progress in histology and the routine use of immunohistochemistry, nasal NK/T-cell lymphoma was recognized as a distinct entity by WHO in 2001.Case reportThe authors report the case of a 22-year-old, insulin-dependent diabetic woman, who presented with mid-facial inflammatory swelling following facial trauma, initially diagnosed and treated as cellulitis of the face. The subsequent course was rapidly progressive and fatal, with the development of midline destructive disease. Histological examinations concluded on NK/T-cell lymphoma.DiscussionThe various differential diagnoses of NK/T-cell lymphoma include gangrenous cellulitis, invasive mycotic rhinosinusitis, Wegener's granulomatosis, actinomycosis, and facial T-cell lymphoma. The clinical presentation of this case was atypical, resulting in delayed diagnosis and treatment. Treatment is based on radiotherapy and chemotherapy, but the prognosis remains very poor even when treatment is rapidly initiated.



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Guidelines of the French Society of Otorhinolaryngology (SFORL). Second-line treatment of epistaxis in adults

Publication date: Available online 17 October 2016
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): B. Verillaud, L. Robard, J. Michel, V. Pruliere Escabasse, E. Béquignon, L. Crampette, O. Malard
ObjectivesThe authors present the guidelines of the French Oto-Rhino-Laryngology – Head and Neck Surgery Society (Société Française d'Oto-Rhino-Laryngologie et de Chirurgie de la Face et du Cou: SFORL) on second-line treatment of epistaxis in adults, after failure of anterior and/or anterior–posterior nasal packing.MethodsA multidisciplinary work group was entrusted with a review of the scientific literature on the above topic. Guidelines were drawn up, based on the articles retrieved and the group members' individual experience. They were then read over by an editorial group independent of the work group. The final version was established in a coordination meeting. The guidelines were graded as A, B, C or expert opinion, by decreasing level of evidence.ResultsArterial embolization should be performed by an experienced interventional neuroradiologist with adequate technical facilities, to reduce the risk of complications. Cerebral and supra-aortic vessel CT angiography should be performed in case of post-traumatic epistaxis with suspected internal carotid injury. In case of persistent bleeding despite endoscopic hemostasis of the sphenopalatine artery, anterior ethmoidal artery hemostasis should be performed via a medial canthal incision, with endoscopic assistance as needed. In case of persistent epistaxis despite the usual surgical and neuroradiological procedures, surgical exploration of the sinonasal cavities should be performed, with elective coagulation in case of bleeding from secondary branches, and/or ethmoidectomy in case of diffuse bleeding. A decision-tree was drawn up for the management of second-line treatment of epistaxis.



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Management of chronic spontaneous urticaria in routine clinical practice: A Delphi-method questionnaire among specialists to test agreement with current European guidelines statements

Publication date: Available online 28 October 2016
Source:Allergologia et Immunopathologia
Author(s): A. Giménez-Arnau, M. Ferrer, J. Bartra, I. Jáuregui, M. Labrador-Horrillo, J. Ortiz de Frutos, J.F. Silvestre, J. Sastre, M. Velasco, A. Valero
BackgroundChronic spontaneous urticaria (CSU) is a frequent clinical entity that often presents a diagnostic and therapeutic challenge.ObjectiveTo explore the degree of agreement that exists among the experts caring for patients with CSU diagnosis, evaluation, and management.MethodsAn online survey was conducted to explore the opinions of experts in CSU, address controversial issues, and provide recommendations regarding its definition, natural history, diagnosis, and treatment. A modified Delphi method was used for the consensus.ResultsThe questionnaire was answered by 68 experts (dermatologists, allergologists, and primary care physicians). A consensus was reached on 54 of the 65 items posed (96.4%). The experts concluded that CSU is a difficult-to-control disease of unpredictable evolution. Diagnostic tests should be limited and based on clinical history and should not be indiscriminate. Autoinflammatory syndromes and urticarial vasculitis must be ruled out in the differential diagnosis. A cutaneous biopsy is only recommended when wheals last more than 24h, to rule out urticarial vasculitis. The use of specific scales to assess the severity of the disease and the quality of life is recommended. In patients with severe and resistant CSU, second-generation H1-antihistamines could be used at doses up to four times the standard dose before giving second-line treatments. Omalizumab is a safe and effective treatment for CSU that is refractory to H1-antihistamines treatment. In general, diagnosis and treatment recommendations given for adults could be extrapolated to children.ConclusionsThis work offers consensus recommendations that may be useful in the management of CSU.



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Prenatal and postnatal exposure to polycyclic aromatic hydrocarbons and allergy symptoms in city children

Publication date: Available online 25 October 2016
Source:Allergologia et Immunopathologia
Author(s): J. Jerzynska, D. Podlecka, K. Polanska, W. Hanke, I. Stelmach, W. Stelmach
BackgroundStudies indicate that exposure to polycyclic aromatic hydrocarbons (PAH) is associated with adverse respiratory and allergy outcomes. Exposure to PAH may impair the immune function of the foetus and, subsequently, be responsible for an increased susceptibility of children to allergic diseases.ObjectivesThe aim of the present study was to assess the association between mother's exposure to PAH during pregnancy and allergy diseases in their infants. We also assessed the above associations using measured PAH exposure in children's urine during the first two years of life.MethodsThe current analysis was restricted to 455 mothers and their children from Lodz district. The women were interviewed three times during the pregnancy in order to collect demographic, socio-economic and medical history data. Children's health status was assessed at the age of 10–18 months and repeated at two years of age. The associations between dependent dichotomous variables and urine concentrations of 1-hydroxypyrene (1-HP) were analysed using logistic regression.ResultsWe showed that higher urine concentrations of 1-HP in mothers at 20–24 weeks of pregnancy increased the risk of more frequent respiratory infections (p=0.02) in children during their first year of life. Higher 1-HP concentrations in children's urine increased the risk of food allergy (p=0.002) in children during their first two years of life.ConclusionsThis study suggests awareness of environmental factors, which may affect children's health since PAH showed to be a risk factor for airway infections and food allergy in children after adjustment for other risk factors.



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Allergenicity of vertebrate tropomyosins: Challenging an immunological dogma

Publication date: Available online 24 October 2016
Source:Allergologia et Immunopathologia
Author(s): J. González-Fernández, A. Daschner, C. Cuéllar
With the exception of tilapia tropomyosin, other anecdotic reports of tropomyosin recognition of vertebrate origin are generally not accompanied by clinical significance and a dogmatic idea is generally accepted about the inexistence of allergenicity of vertebrate tropomyosins, based mainly on sequence similarity evaluations with human tropomyosins. Recently, a specific work-up of a tropomyosin sensitised patient with seafood allergy, demonstrated that the IgE-recognition of tropomyosin from different fish species can be clinically relevant. We hypothesise that some vertebrate tropomyosins could be relevant allergens. The hypothesis is based on the molecular evolution of the proteins and it was tested by in silico methods. Fish, which are primitive vertebrates, could have tropomyosins similar to those of invertebrates. If the hypothesis is confirmed, tropomyosin should be included in different allergy diagnosis tools to improve the medical protocols and management of patients with digestive or cutaneous symptoms after fish intake.



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Knowledge and attitudes among patients with asthma and parents and physicians towards influenza vaccination

Publication date: Available online 24 October 2016
Source:Allergologia et Immunopathologia
Author(s): A. Kaya, N. Altınel, G. Karakaya, F. Çetinkaya
BackgroundInfluenza is an infectious disease, dangerous for all people, especially for some risk groups such as patients with chronic diseases and health care workers. But most of the people under the risk of influenza, including health care workers are not immunised because of misinformation. In this study, we aimed to determine the knowledge, beliefs and attitudes of patients with allergic rhinitis and asthma and parents of such children related to influenza vaccination. Attitudes and beliefs of physicians treating these patients about influenza vaccination were also investigated.MethodsTwo different questionnaires consisting of various items related to influenza vaccine were distributed to physicians and patients and parents of children with asthma and allergic disease.ResultsThe physicians group consisted of 189 physicians from various branches. About one third of physicians from various branches reported that they did not believe the vaccine's effectiveness. Most of the participating physicians did not immunise themselves with influenza vaccination despite the fact that any patient of theirs had died due to influenza infection.Although nearly half of the 183 patients had been vaccinated with influenza vaccine, only 27% of adults and 11.7% of children had been vaccinated annually.ConclusionsAsthmatic patients are not immunised regularly with influenza vaccine due to misperceptions about vaccine effectiveness and fear of adverse effects. Another important reason of this is that most the physicians caring for these patients neither immunise themselves nor recommend the vaccine to their patients.



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Novel AICDA mutation in a case of autosomal recessive hyper-IgM syndrome, growth hormone deficiency and autoimmunity

Publication date: Available online 24 October 2016
Source:Allergologia et Immunopathologia
Author(s): A. Fazel, S. Kashef, S. Aleyasin, S. Harsini, Z. Karamizadeh, S. Zoghi, S.K. Flores, K. Boztug, N. Rezaei
BackgroundThe Hyper-immunoglobulin M syndromes (HIGM) are a heterogeneous group of genetic disorders, which have been rarely reported to be associated with growth hormone deficiency (GHD).Methods and resultsA nine-year-old girl with recurrent urinary tract infections, diarrhoea, sinopulmonary infections, and failure to thrive since the age of six months had normal CD3+, CD4+, CD8+T lymphocytes, and CD19+B lymphocytes and natural killer (NK) cells, but extremely elevated IgM and significantly decreased IgG and IgA. In view of the patient's short stature, growth hormone evaluation was carried out and growth hormone deficiency established. The patient underwent Ig replacement therapy and received growth hormone therapy in addition to antibiotics and responded well. Furthermore, the patient developed benign cervical lymphadenopathy, as well as elevated erythrocyte sedimentation rate, positive autoantibodies to SSA-Ro, and severely dry eyes, which partially responded to both the punctate occlusion and systemic corticosteroids, at the age of seven years. Sequencing analysis of the exons from activation-induced cytidine deaminase (AICDA) gene revealed that the patient was homozygous for a single T to C transversion at position 455 in exon 4, which replaces a Valine with an Alanine.ConclusionsTo our knowledge, this is a new AICDA mutation, which has not been reported previously in HIGM. The mutation analysis could improve diagnosis of HIGM patients and also elaborating on the spectrum of AICDA mutations.



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Gut microbiota and allergy/asthma: From pathogenesis to new therapeutic strategies

Publication date: Available online 28 October 2016
Source:Allergologia et Immunopathologia
Author(s): Y.B. Kang, Y. Cai, H. Zhang
Asthma and atopy, classically associated with hyper-activation of the T helper 2 (Th2) arm of adaptive immunity, are among the most common chronic illnesses worldwide. Emerging evidence relates atopy and asthma to the composition and function of gut microbiota composition. Moreover, certain gut microbial strains have been shown to inhibit or attenuate immune responses associated with chronic inflammation in experimental models. Although still a relatively nascent field of research, evidence to date suggests that the gut microbiome may represent fertile targets for prevention or management of allergic asthma and other diseases in which adaptive immune dysfunction is a prominent feature. The oral probiotics/prebiotic represents a possible therapeutic for improving asthma and allergic disease. Especially, recent technological developments that permit identification of microbes and their products using culture-independent molecular detection techniques. In this review, we literaturely summarise the aggravation or improvement of metabolic diseases by role of gut microbiota, probiotics/prebiotic treatment.



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Variations of B cell subpopulations in peripheral blood of healthy Mexican population according to age: Relevance for diagnosis of primary immunodeficiencies

Publication date: Available online 22 October 2016
Source:Allergologia et Immunopathologia
Author(s): L. Berrón-Ruíz, G. López-Herrera, C.E. Ávalos-Martínez, C. Valenzuela-Ponce, E. Ramírez-SanJuan, G. Santoyo-Sánchez, F. Mújica Guzmán, F.J. Espinosa-Rosales, L. Santos-Argumedo
BackgroundPeripheral blood B cells include lymphocytes at various stages of differentiation, each with a specific function in the immune response. All these stages show variations in percentage and absolute number throughout human life. The numbers and proportions of B subpopulation are influenced by factors such as gender, age, ethnicity, and lifestyle. This study establishes reference values according to age of peripheral blood B cell subtypes in healthy Mexican population.MethodsPeripheral blood from healthy new-borns and adults were analysed for total B cell subpopulations, using surface markers such as CD19, IgM, IgD, CD21, CD24, CD27, and CD38, to identify naïve, memory with and without isotype switch, double-negative, transitional, and plasmablast cells.ResultsWe observed a significant variation in terms of frequency and absolute counts between all groups analysed. Values from each B cell subpopulation show variations according to age.ConclusionsIn order to attempt to elucidate reference values for B cell subpopulation, the present study evaluated a population sample of healthy blood donors from this region. Values reported here can also be used as a tool for diagnosis of diseases in which B cell maturation is affected.



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Evidence in immunotherapy for paediatric respiratory allergy: Advances and recommendations

Publication date: Available online 21 October 2016
Source:Allergologia et Immunopathologia
Author(s): M. Tortajada-Girbés, M. Mesa del Castillo, H. Larramona, J.M. Lucas, M. Álvaro, A.I. Tabar, M.J. Jerez, A. Martínez-Cañavate
Allergic respiratory diseases are major health problems in paediatric population due their high level of prevalence and chronicity, and to their relevance in the costs and quality of life. One of the most important risk factors for the development of airway diseases in children and adolescents is atopy. The mainstays for the treatment of these diseases are avoiding allergens, controlling symptoms, and preventing them through sustained desensitization by allergen immunotherapy (AIT). AIT is a treatment option that consists in the administration of increasing amounts of allergens to modify the biological response to them, inducing long-term tolerance even after treatment has ended. This treatment approach has shown to decrease symptoms and improve quality of life, becoming cost effective for a large number of patients. In addition, it is considered the only treatment that can influence the natural course of the disease by targeting the cause of the allergic inflammatory response. The aim of this publication is to reflect the advances of AIT in the diagnosis and treatment of allergic respiratory diseases in children and adolescents reviewing articles published since 2000, establishing evidence categories to support the strength of the recommendations based on evidence. The first part of the article covers the prerequisite issues to understand how AIT is effective, such as the correct etiologic and clinical diagnosis of allergic respiratory diseases. Following this, the article outlines the advancements in understanding the mechanisms by which AIT achieve immune tolerance to allergens. Administration routes, treatment regimens, dose and duration, efficacy, safety, and factors associated with adherence are also reviewed. Finally, the article reviews future advances in the research of AIT.



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Chondrosarcoma of the hyoid bone – Report of a case and a literature review of the suitable treatment strategy

Publication date: Available online 18 October 2016
Source:Auris Nasus Larynx
Author(s): Daisuke Maki, Taisuke Mori, Masanori Teshima, Kenya Kobayashi, Fumihiko Matsumoto, Akihiro Sakai, Kenji Okami, Seiichi Yoshimoto
Chondrosarcoma is a rare malignant tumor occurring in the trunk and long bones. We present an extremely rare case of chondrosarcoma of the hyoid bone with clinical and pathological correlation and a literature review. We searched all cases of the hyoid chondrosarcoma in PubMed (MEDLINE) between 1990 and 2015. Eighteen cases were analyzed, including the present case. Most of them were low grade type. In 12 cases where intraoperative findings were recorded, no adhesion to the surrounding tissue was observed. Chondrosarcoma of the hyoid bone is usually low grade type, and there may be no invasion to the adjacent structures even if invasion is suspected by imaging findings. In order to preserve swallowing and laryngeal function, total hyoidectomy without laryngectomy should be indicated according to the intraoperative findings. Needle biopsy is an effective diagnostic technique, but open biopsy should be avoided to prevent the dissemination. To the best of our knowledge, this is the first presentation of hyoid bone chondrosarcoma with the investigation of intraoperative findings and pre-operative diagnostic modality.



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Congenital nasal cavity stenosis in children with craniosyntosis: A report of 4 rare cases

Publication date: Available online 25 October 2016
Source:Auris Nasus Larynx
Author(s): Yew Toong Liew, Siew Shuin Soo, Anna Marie Nathan, Anura Michelle Manuel
Congenital bony nasal stenosis (CBNS) is a very rare but life-threatening cause of airway obstruction in neonates and infants. This review aims to assess the presentation and early airway management of 4 new cases of craniosynostosis with bilateral nasal cavity stenosis. Patients were treated with endoscopic endonasal widening of the nasal cavity and stenting. All patients were extubated well post-operatively with resolution of symptoms. They remained asymptomatic with stents in situ for at least 6 months with no complications reported.Minimally invasive endoscopic endonasal widening of the nasal cavity with stenting is an effective and safe way of addressing nasal cavity stenosis.



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Comparing performance of Bonfils fiberscope and GlideScope videolaryngoscope for awake intubation

The recent article by Nassar et al [1] comparing performance of Bonfils fiberscope and GlideScope videolaryngoscope for awake intubation in the morbidly obese patients with expected difficult airways was of great interest to us. They showed that Bonfils fiberscope was more tolerated by patients with statistical difference, whereas GlideScope videolaryngoscope provided shorter intubation time and less intubation attempts but without statistical significance. Given that the airway management of morbidly obese patients often presents a unique challenge to the anesthesiologists, their findings have potential implications.

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Sudden cardiorespiratory collapse associated with Takotsubo cardiomyopathy upon transferring a patient to the operation bed

Here, we report a case of cardiopulmonary collapse associated with Takotsubo cardiomyopathy after moving a patient to the operation bed.

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Rapid-sequence intubation of a patient with difficult airway using a double-lumen endotracheal tube with the Pentax-AWS Airwayscope and a soft-tipped tube exchanger

Rapid-sequence intubation of a double-lumen tube is difficult, especially in patients with difficult airway [1]. Here we report successful rapid-sequence intubation of a patient with difficult airway using a double-lumen endotracheal tube (DLT) with the Pentax-AWS Airwayscope (AWS) (HOYA, Tokyo, Japan) videolaryngoscope equipped with a newly developed Intlock for DLT (ITL-LL) (HOYA), combined with a soft-tipped tube exchange catheter (TE-Soft) (Cook Medical, IN, USA).

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A distinct microbiota composition is associated with protection from food allergy in an oral mouse immunization model

Publication date: December 2016
Source:Clinical Immunology, Volume 173
Author(s): Susanne C. Diesner, Cornelia Bergmayr, Barbara Pfitzner, Vera Assmann, Durga Krishnamurthy, Philipp Starkl, David Endesfelder, Michael Rothballer, Gerhard Welzl, Thomas Rattei, Thomas Eiwegger, Zsolt Szépfalusi, Heinz Fehrenbach, Erika Jensen-Jarolim, Anton Hartmann, Isabella Pali-Schöll, Eva Untersmayr
In our mouse model, gastric acid-suppression is associated with antigen-specific IgE and anaphylaxis development. We repeatedly observed non-responder animals protected from food allergy. Here, we aimed to analyse reasons for this protection. Ten out of 64 mice, subjected to oral ovalbumin (OVA) immunizations under gastric acid-suppression, were non-responders without OVA-specific IgE or IgG1 elevation, indicating protection from allergy. In these non-responders, allergen challenges confirmed reduced antigen uptake and lack of anaphylactic symptoms, while in allergic mice high levels of mouse mast-cell protease-1 and a body temperature reduction, indicative for anaphylaxis, were determined. Upon OVA stimulation, significantly lower IL-4, IL-5, IL-10 and IL-13 levels were detected in non-responders, while IL-22 was significantly higher. Comparison of fecal microbiota revealed differences of bacterial communities on single bacterial Operational-Taxonomic-Unit level between the groups, indicating protection from food allergy being associated with a distinct microbiota composition in a non-responding phenotype in this mouse model.

Graphical abstract

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Intraperitoneal injection of IDO-expressing dermal fibroblasts improves the allograft survival

Publication date: Available online 29 October 2016
Source:Clinical Immunology
Author(s): Mohsen Khosravi-Maharlooei, MohammadReza Pakyari, Reza B. Jalili, Ruhangiz T. Kilani, Aziz Ghahary
Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme with tolerogenic effects on different immune cells. Our group has previously shown that co-transplantation of IDO-expressing fibroblasts with donor tissues can delay immune rejection by inducing local immunosuppression. In this study, we have employed a systemic approach to improve allograft survival without using any immunosuppressive medication. To achieve this, 10 million lentiviral transduced IDO-expressing donor derived fibroblasts were injected into the peritoneal cavity of allograft recipients. We showed that IDO-fibroblast therapy increases the survival of both islets and skin allografts and decreases the infiltration of immune cells in subcutaneous transplanted skins. Indirect pathway of allo-reactive T cell activation was suppressed more than the direct pathway. Injected IDO-fibroblasts were found in peritoneal cavity and mesenteric lymph nodes of the recipient mice. In conclusion, IDO-expressing fibroblast therapy proved to be a novel approach in improving the allogeneic graft survival.



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Phenotypic changes of peripheral blood mononuclear cells upon corticosteroid treatment in idiopathic intermediate uveitis

Publication date: Available online 29 October 2016
Source:Clinical Immunology
Author(s): Karoline Walscheid, Toni Weinhage, Dirk Foell, Carsten Heinz, Maren Kasper, Arnd Heiligenhaus
We analyzed phenotype and function of peripheral blood mononuclear cells in 9 patients with active idiopathic intermediate uveitis (IIU) before and after 6 and 12weeks of systemic corticosteroid (CS) treatment and compared to 28 healthy individuals. Monocytes from IIU patients showed increased MHCII expression compared with controls (p=0.09). Treatment reduced expression of MHCII, CD86, CD39 and CD124 (all p<0.05), whereas the percentage of CD121b-expressing monocytes was increased by week 6 (p=0.039). Patients showed alterations in T cell polarization (Th1/Th2 ratio: patients 5.2 versus controls 3.1, p=0.054; Th17/Treg ratio: 3.0 versus 1.7, p=0.027). S100A12 serum levels were higher in active IIU (p=0.057). Phagocytosis, oxidative burst and serum cytokine levels did not differ between patients and controls, and were not altered by treatment. In conclusion, monocytes from patients with active IIU show increased co-stimulatory capacities, which are modulated by systemic CS treatment, whereas innate immune cell functions are not altered.



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Estrogen receptor alpha promotes lupus in (NZB×NZW)F1 mice in a B cell intrinsic manner

Publication date: Available online 29 October 2016
Source:Clinical Immunology
Author(s): Dana E. Tabor, Karen A. Gould
Lupus is a systemic autoimmune disease characterized by the production of autoreactive antibodies against nuclear antigens. Women are disproportionately affected by lupus, and this sex bias is thought to be due, in large part, to the ability of estrogens to promote lupus pathogenesis. Previously, we have shown that global deletion of estrogen receptor alpha (ERα) significantly attenuated loss of tolerance, immune cell activation, autoantibody production, and the development of lupus nephritis. Here we show that targeted deletion of ERα specifically in B cells retards production of pathogenic autoantibodies and the development of nephritis in lupus-prone (NZB×NZW)F1 mice. Furthermore, we observed that ERα deletion in B cells was associated with decreased B cell activation in young, pre-autoimmune (NZB×NZW)F1 females. Altogether, these data suggest that ERα acts in a B cell-intrinsic manner to control B cell activation, autoantibody production, and lupus nephritis.



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Inflammation elevated IL-33 originating from the lung mediates inflammation in acute lung injury

Publication date: Available online 29 October 2016
Source:Clinical Immunology
Author(s): Shi-hui Lin, Juan Fu, Chuan-jiang Wang, Feng Gao, Xuan-yun Feng, Qiong Liu, Ju Cao, Fang Xu
Excessive inflammatory reactions occur with acute respiratory distress syndrome (ARDS), however, the underlying mechanisms of ARDS remain incompletely understood. Here we investigated whether interleukin (IL)-33 was elevated in ARDS patients. Serum samples were obtained from 14 ARDS patients and 24 control healthy volunteers. ELISA was used to measure the concentrations of IL-33. Besides, we established pulmonary ARDS and extrapulmonary ARDS models in mice, and serum and lung tissue samples were collected for analyses. The results showed that serum IL-33 concentrations were significantly higher in pulmonary ARDS patients compared to controls. Also, the levels of IFN-γ and IL-2 were positively correlated with IL-33 levels. We also showed that there were increased IL-33 levels in both the serum and lungs in the pulmonary ARDS model. This was not the case, however, in the extrapulmonary ARDS model. Pulmonary inflammation and injury in the pulmonary ARDS model was reduced with IL-33 neutralizing antibody treatment.



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An overview of the necessary thymic contributions to tolerance in transplantation

Publication date: December 2016
Source:Clinical Immunology, Volume 173
Author(s): Joseph R. Scalea, John B. Hickman, Daniel J. Moore, Kenneth L. Brayman
The thymus is important for the development of the immune system. However, aging leads to predictable involution of the thymus and immunodeficiency. These immunodeficiencies may be rectified with thymic rejuvenation. Atrophy of the thymus is governed by a complex interplay of molecular, cytokine and hormonal factors. Herein we review the interaction of these factors across age and how they may be targeted for thymic rejuvenation. We further discuss the growing pre-clinical evidence defining the necessary and sufficient contributions of the thymus to successful tolerance induction in transplantation.



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Ebola virus vaccines: Where do we stand?

Publication date: Available online 28 October 2016
Source:Clinical Immunology
Author(s): Vincent Pavot
The recent outbreak of Ebola virus disease in West Africa has led to more than 11,000 deaths, with a peak in mortality from August through December of 2014. A meeting convened by the World Health Organization (WHO) in September 2014, concluded that an urgent unmet need exists for efficacy and safety testing of the Ebola virus vaccine candidates and that clinical trials should be expedited. These vaccines could be used both in an outbreak setting and to provide long-term protection in populations at risk of sporadic outbreaks.A number of vaccines have been evaluated in phase 1 trials, but the two most advanced first-generation Ebola vaccine candidates are the live replicating vesicular stomatitis virus (rVSV) and the replication-defective chimpanzee adenovirus 3 (ChAd3).This review focuses on these two vaccines in clinical development and discusses the future opportunities and challenges faced in the licensure and deployment of Ebola virus vaccines.



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The contribution of the programmed cell death machinery in innate immune cells to lupus nephritis

Publication date: Available online 22 October 2016
Source:Clinical Immunology
Author(s): FuNien Tsai, Harris Perlman, Carla M. Cuda
Systemic lupus erythematosus (SLE) is a chronic multi-factorial autoimmune disease initiated by genetic and environmental factors, which in combination trigger disease onset in susceptible individuals. Damage to the kidney as a consequence of lupus nephritis (LN) is one of the most prevalent and severe outcomes, as LN affects up to 60% of SLE patients and accounts for much of SLE-associated morbidity and mortality. As remarkable strides have been made in unlocking new inflammatory mechanisms associated with signaling molecules of programmed cell death pathways, this review explores the available evidence implicating the action of these pathways specifically within dendritic cells and macrophages in the control of kidney disease. Although advancements into the underlying mechanisms responsible for inducing cell death inflammatory pathways have been made, there still exist areas of unmet need. By understanding the molecular mechanisms by which dendritic cells and macrophages contribute to LN pathogenesis, we can improve their viability as potential therapeutic targets to promote remission.



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Immature myeloid cells in the tumor microenvironment: Implications for immunotherapy

Publication date: Available online 21 October 2016
Source:Clinical Immunology
Author(s): Neha Kamran, Mayuri Chandran, Pedro R Lowenstein, Maria G Castro
Various preclinical studies have demonstrated that the success of immunotherapeutic strategies in inhibiting tumor progression in animal models of Glioblastoma multiforme (GBM). It is also evident that tumor-induced immune suppression drastically impacts the efficacy of immune based therapies. Among the mechanisms employed by GBM to induce immunosuppression is the accumulation of regulatory T cells (Tregs) and Myeloid derived suppressor cells (MDSCs). Advancing our understanding about the pathways regulating the expansion, accumulation and activity of MDSCs will allow for the development of therapies aimed at abolishing the inhibitory effect of these cells on immunotherapeutic approaches. In this review, we have focused on the origin, expansion and immunosuppressive mechanisms of MDSCs in animal models and human cancer, in particular GBM.



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Crosstalk between the gut and the liver via susceptibility loci: Novel advances in inflammatory bowel disease and autoimmune liver disease

Publication date: Available online 21 October 2016
Source:Clinical Immunology
Author(s): Xinyang Li, Jun Shen, Zhihua Ran
Inflammatory bowel disease (IBD) is an autoimmune disorder characterized by chronic, relapsing intestinal inflammation. Autoimmune liver disease (AILD) may be involved in IBD as an extra-intestinal manifestation (EIM). Epidemiologic and anatomic evidence have demonstrated an intimate crosstalk between the gut and the liver. In this review, we briefly introduced nine groups of susceptibility loci shared by inflammatory bowel and autoimmune liver disease for the first time. The genome-wide association studies (GWAS) evidence of pathways involving crosstalk between the gut and the liver is clarified and explained. It has been found that HNF4-α, GPR35, MST1R, CARD9, IL2/IL21/IL2R, BACH2, TNFRSF14, MAdCAM-1, and FUT2 are the genes involved in tight junction formation, macrophage function, T helper cell or Treg cell cycle and function, TNF secretion, lymphocyte homing or intestinal dysbiosis, respectively. The intimate crosstalk between the gut and liver in immunity is also highlighted and discussed in this review.



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Downregulated expression of miR-142-3p in macrophages contributes to increased IL-6 levels in aged mice

Publication date: December 2016
Source:Molecular Immunology, Volume 80
Author(s): Yin Liu, Xiaoqi Song, Shu Meng, Minghong Jiang
Macrophages are innate immune cells that are important contributors to age-related functional impairment of the immune system. During the cell aging process, microRNAs are differentially expressed and participate in the regulation of aging-related immune responses. However, the role of aging-associated changes in miRNA expression in macrophages remains unclear. Here, we found that miR-142-3p expression is downregulated 50% in peritoneal macrophages from aged mice compared with young mice and is not upregulated by cell treatment with lipopolysaccharide (LPS), CpG, or polyinosinic-polycytidylic acid. Serum levels of miR-142-3p are also lower in aged mice than in young mice by q-PCR. Luciferase reporter analysis showed that IL-6 is a target of miR-142-3p in macrophages. In addition, the histone deacetylase inhibitor trichostatin A increased miR-142-3p expression by more than 3-fold in LPS-treated macrophages from aged mice compared with young mice, which in turn suppressed LPS-stimulated IL-6 production, suggesting that inhibition of miR-142-3p by histone deacetylation may be involved in the lack of response to LPS stimulation in macrophages of aged mice. These findings suggest that downregulation of miR-142-3p in macrophages of aged mice might contribute to IL-6-associated aging disorders and that epigenetic modification might be involved in age-related inflammatory diseases.



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Retinoid acid receptor-related orphan receptor alpha (RORα) regulates macrophage M2 polarization via activation of AMPKα

Publication date: December 2016
Source:Molecular Immunology, Volume 80
Author(s): Lei Xiao, Zihui Zhang, Xiaoqin Luo, Haixia Yang, Fan Li, Nanping Wang
Macrophages are able to polarize to pro-inflammatory M1 or anti-inflammatory M2 states with distinct phenotypes and physiological functions. RORα is a member of the nuclear receptor super family and plays important roles in lipid, glucose metabolism, as well as the inflammatory response. In this study, we examined the potential function of RORα in the regulation of macrophage polarization. Treatment of RAW264.7 macrophages with RORα agonist cholesterol sulfate (CH-S) and overexpression of RORα increased M2 macrophage markers expressions (Arg1, Ym1 and Fizz1) both on mRNA and protein levels. Conversely, selective antagonism (SR1001) abrogated the induction of M2 macrophage markers which induced by CH-S. In addition, CH-S induced phosphorylation of Adenosine monophosphate (AMP)-activated protein kinase α (AMPKα), which was accompanied by the activation of acetyl-CoA carboxylase 1 (ACC). However, SR1001 abolished the activation of AMPKα and ACC induced by CH-S. Meanwhile, inactivation of AMPKα by its inhibitor Compound C (CompC) abrogated the mRNA and protein levels of CH-S-induced M2 macrophage markers expressions. Together these findings reveal that RORα regulates macrophage M2 polarization via activation of AMPKα, which may provide a novel beneficial effect of RORα against inflammation.



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Immunogenic peptides: B & T Cell Epitopes of Per a 10 Allergen of Periplaneta americana

Publication date: December 2016
Source:Molecular Immunology, Volume 80
Author(s): Dhanapal Govindaraj, Swati Sharma, S.N. Gaur, Shakuntala Lavasa, Nagendra Prasad, Naveen Arora
Mapping of B and T cell epitopes of an allergen can be utilised in the development of alternative therapeutic modalities and diagnostics. The present study was aimed to identify B and T cell epitopes of Per a 10, a major cockroach allergen, by computational tools and subsequent validation by in vitro experiments. Per a 10 three-dimensional structure was homology modelled using structure of anionic trypsin from pacific chum salmon as a template. Seven B cell epitopes (B-P1 to B-P7) were predicted by sequence and structure based methods. Three T cell epitopes (T-P8 to T-P10) were predicted by binding score and inhibitory concentration dependent prediction tools. Predicted epitopes were synthesized and biological activity was assessed by ELISA, ELISA inhibition and PBMC proliferation assays. B cell peptides B-P5, B-P6 and B-P7 showed significantly high IgE binding with pooled and individual cockroach hypersensitive patients' sera while the T cell peptides did not show IgE binding. ELISA inhibition was performed to determine the potency of the predicted peptides. Fifty nanogram of peptide B-P7 was required for 50% IgE binding inhibition of surface bound Per a 10 whereas seventy five nanogram and ninety nanogram of B-P5 and B-P6 were required for the same respectively. Upon stimulation with T-P8 and T-P10 peptides, PBMCs from cockroach allergic patients' (n = 15) showed significant lymphocyte proliferation and induced IL-4 and IL-5 cytokine release in the culture supernatant demonstrating Th2 dominant cell mediated response of predicted T cell peptides. In conclusion, Per a 10 3-D structure obtained by homology modelling was used to identify B and T cell epitopes, followed by in vitro validation. The identified peptides can be potentially used in designing diagnostics and therapies for cockroach allergy.



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Neem leaf glycoprotein regulates function of tumor associated M2 macrophages in hypoxic tumor core: Critical role of IL-10/STAT3 signaling

Publication date: December 2016
Source:Molecular Immunology, Volume 80
Author(s): Kuntal Kanti Goswami, Madhurima Sarkar, Sarbari Ghosh, Akata Saha, Tithi Ghosh, Ipsita Guha, Subhasis Barik, Saptak Banerjee, Soumyabrata Roy, Anamika Bose, Parthasarathi Dasgupta, Rathindranath Baral
Heterogeneous tumor microenvironment (TME), broadly divided into tumor core and peripheral sub-microenvironments, differentially polarize normal macrophages into a different form known as tumor associated M2 macrophages (M2TAMs) to promote tumor growth. In view of the extensive immune-editing role of NLGP, here, we have observed that NLGP is effective to convert M2TAMs (CD11b⁺F4/80^high) to M1 (CD11b⁺F4/80^low) more prominently in tumor core, along with downregulation of other M2 associated markers, like, ManR, Ym1, Fizz1. High IL-10:IL-12 ratio at tumor core was downregulated in NLGP treated melanoma bearing mice. Decrease in IL-10 by NLGP is again associated with the decrease in hypoxia, as indicated by prominent downregulation of HIF1α and VEGF, particularly at tumor core. Macrophages exposed to hypoxic tumor core lysates in vitro exhibited high IL-10, HIF1α and VEGF expression that was significantly downregulated by NLGP. Further evidences suggest M2TAM to M1 conversion by NLGP is associated with STAT3-regulated IL-10 dependent pathway without affecting the IL-4 dependent one. Such TAM modulatory functions of NLGP might help in the restriction of melanoma growth by increasing the proportion of M1 TAMs in tumor core that helps in prevention of tumor relapse and dissemination of the tumor mass.



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Prolonged survival effects induced by immature dendritic cells and regulatory T cells in a rat liver transplantation model

Publication date: November 2016
Source:Molecular Immunology, Volume 79
Author(s): Wubing He, Lihong Chen, Lin Zheng, Liuping Luo, Lingyun Gao
BackgroundDendritic cells (DCs) and regulatory T (Treg) cells are crucial for inducing immune tolerance. However, the suppressive function of infused Treg cells and immature DCs (imDCs) following solid organ transplantation remains unclear.MethodsImDCs derived from DA-donor rats and Treg cells isolated from spleens of Lewis rats were prepared. A heterotopic liver transplantation model was established to examine the immune tolerance effects of infusion of Treg-imDCs, imDCs and Treg cells individually. Th1/Th2 cytokines and TRAL were detected by ELISA. The overall rejection grade was assessed and the rejection activity index (RAI) was calculated. TUNEL-positive lymphocytes were detected in the portal area in liver sections.ResultsThe infusion of Treg-imDCs was more effective than imDCs or Treg cells individually. Moreover, the expression of IL-10 and TGF-β1 was significantly up-regulated, and IL-12 expression was significantly down-regulated, especially in the Treg-imDCs group. The percentage of TUNEL-positive cells was significantly higher in the Treg cells and imDCs groups. The RAI values in Treg-imDCs group on days 3 and 7 were lower than control, imDCs and Treg cells groups individually (p<0.05). Both TBIL and ALT levels in the Treg-imDCs and imDCs groups were significantly lower than those of the control and Treg cells groups, and serum TRAL levels increased significantly 10days after transplantation in the imDC and Treg-imDC groups compared with the control and Treg cells groups (P<0.001).ConclusionThese data demonstrated that infusion of Treg cells and/or imDCs induces alloantigen tolerance and prolongs liver allograft survival. The infusion of Treg-imDCs was more effective than imDCs or Treg cells individually. ImDCs synergize with Treg cells in inducing and maintaining the feedback loop between imDCs and Treg cells in vivo.



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Comparative assessment of lipid based nano-carrier systems for dendritic cell based targeting of tumor re-initiating cells in gynecological cancers

Publication date: November 2016
Source:Molecular Immunology, Volume 79
Author(s): Arpit Bhargava, Dinesh K. Mishra, Subodh K. Jain, Rupesh K. Srivastava, Nirmal K. Lohiya, Pradyumna K. Mishra
We aimed to identify an optimum nano-carrier system to deliver tumor antigen to dendritic cells (DCs) for efficient targeting of tumor reinitiating cells (TRICs) in gynecological malignancies. Different lipid based nano-carrier systems i.e. liposomes, ethosomes and solid lipid nanoparticles (SLNPs) were examined for their ability to activate DCs in allogeneic settings. Out of these three, the most optimized formulation was subjected for cationic and mannosylated surface modification and pulsed with DCs for specific targeting of tumor cells. In both allogeneic and autologous trials, SLNPs showed a strong ability to activate DCs and orchestrate specific immune responses for targeting TRICs in gynecological malignancies. Our findings suggest that the mannosylated form of SLNPs is a suitable molecular vector for DC based therapeutics. DCs pulsed with mannosylated SLNPs may be utilized as adjuvant therapy for specific removal of TRICs to benefit patients from tumor recurrence.



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A novel p38 MAPK indentified from Crassostrea hongkongensis and its involvement in host response to immune challenges

Publication date: November 2016
Source:Molecular Immunology, Volume 79
Author(s): Fufa Qu, Zhiming Xiang, Yang Zhang, Jun Li, Shu Xiao, Yuehuan Zhang, Fan Mao, Haitao Ma, Ziniu Yu
p38 mitogen-activated protein kinases (MAPKs) are conserved serine/threonine-specific kinases that are activated by various extracellular stimuli and play crucial regulatory roles in immunity, development and homeostasis. However, the function of p38s in mollusks, the second most diverse group of animals, is still poorly understood. In this study, a novel molluscan p38 (designated Chp38) was cloned and characterized from the Hong Kong oyster Crassostrea hongkongensis. Its full-length cDNA encoded a putative protein of 353 amino acids with a calculated molecular weight of approximately 40.3kDa. Similar to other reported p38 family proteins, the deduced Chp38 sequence contained a conserved dual phosphorylation TGY motif and a substrate binding site of ATRW. Phylogenetic analysis revealed that Chp38 was closest to its homolog from the Pacific oyster and belonged to the mollusk cluster. Quantitative real-time PCR analysis showed that Chp38 was constitutively expressed in all examined oyster tissues and developmental stages and that its expression in hemocytes was significantly up-regulated after pathogen (Vibrio alginolyticus and Staphylococcus haemolyticus) and PAMP (lipopolysaccharide and peptidoglycan) infections. Moreover, overexpression analysis revealed that Chp38 was localized in both the cytoplasm and nucleus of HEK293T cells and that it could significantly enhance AP-1 reporter gene activation in a dose-dependent manner. Altogether, these results provide the first experimental evidence of a functional p38 in oysters and suggest its involvement in the innate immunity of C. hongkongensis.



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Intercellular communication for innate immunity

Publication date: Available online 18 October 2016
Source:Molecular Immunology
Author(s): Tan A. Nguyen, Ken C. Pang, Seth L. Masters
An effective innate immune response relies on the detection of pathogen associated molecular patterns (PAMPs) by various host pattern recognition receptors (PRRs) that result in the production of pro-inflammatory cytokines and chemokines. Viruses and bacteria have co-evolved with the immune system and developed multiple strategies to usurp or circumvent host machinery and blunt the innate immune response in infected cells. Recently, it has become apparent that infected or dying cells can transmit PAMPs and host PRR signalling proteins to uninfected bystander cells to thereby bypass pathogen evasion strategies, and potentiate innate immune signalling. This bystander activation of innate immunity represents an alternative method by which the host can control infections via cell-to-cell communication. In this review, we discuss what is currently known about the intercellular transfer of pathogen- or host-derived RNA, DNA and proteins from infected cells to neighbouring cells and how this impacts on host innate immunity.



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