Liraglutide restores angiogenesis in palmitate-impaired human endothelial cells through PI3K/Akt-Foxo1-GTPCH1 pathway

Publication date: December 2016
Source:Peptides, Volume 86
Author(s): Jing Ke, Rui Wei, Fei Yu, Jingjing Zhang, Tianpei Hong
Glucagon-like peptide-1 (GLP-1) and its analogues have a beneficial role in cardiovascular system. Here, we aimed to investigate whether liraglutide, a GLP-1 analogue, modulated angiogenesis impaired by palmitic acid (PA) in cultured human umbilical vein endothelial cells (HUVECs). Cells were incubated with liraglutide (3–100 nmol/L) in the presence of PA (0.5mmol/L), and endothelial tube formation was observed and quantified. The protein levels of signaling molecules were analyzed and the specific inhibitors were used to identify the signaling pathways through which liraglutide affected angiogenesis. Results showed that liraglutide ameliorated endothelial tube formation impaired by PA in HUVECs in a dose-dependent manner. Meanwhile, liraglutide increased the phosphorylation of Akt and forkhead box O1 (Foxo1), and upregulated the levels of guanosine 5′-triphosphate cyclohydrolase 1 (GTPCH1) and endothelial nitric oxide synthase (eNOS) in PA-impaired HUVECs. Notably, addition of the PI3K inhibitor LY294002, Foxo1 nuclear export inhibitor trifluoperazine dihydrochloride (TFP), GTPCH1 inhibitor 2,4-diamino-6-hydroxypyrimidine (DAHP) or NOS inhibitor N-nitro-l-arginine-methyl ester (L-NAME) eliminated the angiogenic effect of liraglutide. Moreover, either LY294002 or TFP abolished the liraglutide-induced upregulation of GTPCH1 and eNOS protein levels. In conclusion, liraglutide restores angiogenesis in PA-impaired HUVECs. The effect is mediated via upregulation of GTPCH1 and eNOS levels in a PI3K/Akt-Foxo1-dependent mechanism.



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Carnosine ameliorates cognitive deficits in streptozotocin-induced diabetic rats: Possible involved mechanisms

Publication date: December 2016
Source:Peptides, Volume 86
Author(s): Siamak Ahshin-Majd, Samira Zamani, Taktom Kiamari, Zahra Kiasalari, Tourandokht Baluchnejadmojarad, Mehrdad Roghani
Diabetic patients are at increased risk to develop cognitive deficit and senile dementia. This study was planned to assess the benefits of chronic carnosine administration on prevention of learning and memory deterioration in streptozotocin (STZ)-diabetic rats and to explore some of the involved mechanisms. Rats were divided into 5 groups: i.e., control, carnosine100-treated control, diabetic, and carnosine-treated diabetics (50 and 100mg/kg). Carnosine was injected i.p. at doses of 50 or 100mg/kg for 7 weeks, started 1 week after induction of diabetes using streptozotocin. Treatment of diabetic rats with carnosine at a dose of 100mg/kg at the end of the study lowered serum glucose, improved spatial recognition memory in Y maze, improved retention and recall in elevated plus maze, and prevented reduction of step-through latency in passive avoidance task. Furthermore, carnosine at a dose of 100mg/kg reduced hippocampal acetylcholinesterase (AChE) activity, lowered lipid peroxidation, and improved superoxide dismutase (SOD) activity and non-enzymatic antioxidant defense element glutathione (GSH), but not activity of catalase. Meanwhile, hippocampal level of nuclear factor-kappaB (NF-κB), tumor necrosis factor α (TNF-α), and glial fibrillary acidic protein (GFAP) decreased and level of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase 1 (HO-1) increased upon treatment of diabetic group with carnosine at a dose of 100mg/kg. Taken together, chronic carnosine treatment could ameliorate learning and memory disturbances in STZ-diabetic rats through intonation of NF-κB/Nrf2/HO-1 signaling cascade, attenuation of astrogliosis, possible improvement of cholinergic function, and amelioration of oxidative stress and neuroinflammation.



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The predictive value of plasma catestatin for all-cause and cardiac deaths in chronic heart failure patients

Publication date: December 2016
Source:Peptides, Volume 86
Author(s): Fen Peng, Songyun Chu, Wenhui Ding, Lin Liu, Jing Zhao, Xiaojing Cui, Renxu Li, Jie Wang
Catestatin (CST) is a proteolytic fragment of Chromogranin A with a broad spectrum of activities in the cardiovascular system. The level of plasma CST increases in chronic heart failure patients, but its potential relationship to patient prognosis is unknown. In this study, we measured plasma CST levels in 202 chronic heart failure patients and followed them for a median of 52.5 months. The plasma CST level was higher in patients with all-cause death and cardiac death than in survivors. According to univariate COX regression, higher plasma CST levels predicted increased risk of all-cause and cardiac death. After adjustment for other confounding factors, plasma CST was an independent risk factor for both outcomes, and the hazard ratios (HRs) were 1.84 (95% CI: 1.02–3.32, p=0.042) and 2.41 (95% CI: 1.26–4.62, p=0.008) for all-cause death and cardiac death, respectively. The new risk-predictive model considering CST was superior to the previous model for both outcomes by ANOVA and likelihood ratio tests (p=0.040 and p=0.008, respectively). Concurrent increases in plasma BNP (B-type natriuretic peptide) and CST levels predicted the highest risk for both all-cause and cardiac deaths [HR=5.18 (95% CI: 1.94–13.87, p=0.001) and HR=9.19 (95% CI: 2.75–30.78, p<0.001), respectively]. Large-scale studies are needed to further assess the value of plasma CST in predicting heart failure prognosis.



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Add-on therapy with anagliptin in Japanese patients with type-2 diabetes mellitus treated with metformin and miglitol can maintain higher concentrations of biologically active GLP-1/total GIP and a lower concentration of leptin

Publication date: December 2016
Source:Peptides, Volume 86
Author(s): Takeshi Osonoi, Miyoko Saito, Natsuyo Hariya, Moritaka Goto, Kazuki Mochizuki
Metformin, α-glucosidase inhibitors (α-GIs), and dipeptidyl peptidase 4 inhibitors (DPP-4Is) reduce hyperglycemia without excessive insulin secretion, and enhance postprandial plasma concentration of glucagon-like peptide-1 (GLP-1) in type-2 diabetes mellitus (T2DM) patients. We assessed add-on therapeutic effects of DPP-4I anagliptin in Japanese T2DM patients treated with metformin, an α-GI miglitol, or both drugs on postprandial responses of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), and on plasma concentration of the appetite-suppressing hormone leptin. Forty-two Japanese T2DM patients with inadequately controlled disease (HbA1c: 6.5%–8.0%) treated with metformin (n=14), miglitol (n=14) or a combination of the two drugs (n=14) received additional treatment with anagliptin (100mg, p.o., b.i.d.) for 52 weeks. We assessed glycemic control, postprandial responses of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), and on plasma concentration of leptin in those patients. Add-on therapy with anagliptin for 52 weeks improved glycemic control and increased the area under the curve of biologically active GLP-1 concentration without altering obesity indicators. Total GIP concentration at 52 weeks was reduced by add-on therapy in groups treated with miglitol compared with those treated with metformin. Add-on therapy reduced leptin concentrations. Add-on therapy with anagliptin in Japanese T2DM patients treated with metformin and miglitol for 52 weeks improved glycemic control and enhanced postprandial concentrations of active GLP-1/total GIP, and reduce the leptin concentration.



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Gayle & Richard Olson prize pages

Publication date: November 2016
Source:Peptides, Volume 85





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Regional specificity of the gut-incretin response to small intestinal glucose infusion in healthy older subjects

Publication date: December 2016
Source:Peptides, Volume 86
Author(s): Rachael S. Rigda, Laurence G. Trahair, Tanya J. Little, Tongzhi Wu, Scott Standfield, Christine Feinle-Bisset, Christopher K. Rayner, Michael Horowitz, Karen L. Jones
The importance of the region, as opposed to the length, of small intestine exposed to glucose in determining the secretion of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) remains unclear. We sought to compare the glycemic, insulinemic and incretin responses to glucose administered to the proximal (12–60cm beyond the pylorus), or more distal (>70cm beyond the pylorus) small intestine, or both. 10 healthy subjects (9M,1F; aged 70.3±1.4years) underwent infusion of glucose via a catheter into the proximal (glucose proximally; GP), or distal (glucose distally; GD) small intestine, or both (GPD), on three separate days in a randomised fashion. Blood glucose, serum insulin and plasma GLP-1, GIP and CCK responses were assessed. The iAUC for blood glucose was greater in response to GPD than GP (P<0.05), with no difference between GD and GP. GP was associated with minimal GLP-1 response (P=0.05), but substantial increases in GIP, CCK and insulin (P<0.001 for all). GPD and GD both stimulated GLP-1, GIP, CCK and insulin (P<0.001 for all). Compared to GP, GPD induced greater GLP-1, GIP and CCK responses (P<0.05 for all). Compared with GPD, GD was associated with greater GLP-1 (P<0.05), but reduced GIP and CCK (P<0.05 for both), responses. We conclude that exposure of glucose to the distal small intestine appears necessary for substantial GLP-1 secretion, while exposure of both the proximal and distal small intestine result in substantial secretion of GIP.



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IFC (editorial board)

Publication date: November 2016
Source:Peptides, Volume 85





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Pathological downstaging and survival after induction chemotherapy and radical cystectomy for clinically node-positive bladder cancer—Results of a nationwide population-based study

Publication date: December 2016
Source:European Journal of Cancer, Volume 69
Author(s): Tom J.N. Hermans, Elisabeth E. Fransen van de Putte, Simon Horenblas, Richard P. Meijer, Joost L. Boormans, Katja K.H. Aben, Michiel S. van der Heijden, Ronald de Wit, Laurens V. Beerepoot, Rob H.A. Verhoeven, Bas W.G. van Rhijn
BackgroundInduction chemotherapy (IC) for clinically node-positive bladder cancer is applied without clinical evidence of improved outcome. Our objective was to compare complete pathological downstaging (pCD) and overall survival (OS) for IC versus upfront radical cystectomy (RC) in cT1-4aN1-3M0 urothelial carcinoma (UC).MethodsThis population-based study included 659 cN+ patients treated with RC between 1995 and 2013. IC was applied in 212 (32%) patients. We defined pCD as ≤(y)pT1N0 at RC. Multivariable analyses were preformed to identify independent predictors of pCD and OS.ResultsIn cN1 and cN2–3 patients, 31% and 19% of patients proved to be pN0 at upfront RC. In cN1, pCD was achieved in 39% following IC versus 5% for upfront RC (P < 0.001). In cN2–3 UC, rates were 27% versus 3% (P < 0.001). Three-year OS for pCD and ypCD were 81% and 84%, respectively. Three-year OS rates were 66% versus 37% (cN1) and 43% versus 22% (cN2-3), again in favour of IC (P < 0.001). In multivariable analyses, IC was associated with pCD (Odds ratio, 14; 95% confidence interval [CI], 7.4–25) and a 53% decreased risk of death (Hazard ratio [HR], 0.47; 95% CI, 0.36–0.61). Indication bias and unequal distributions of factors associated with OS (e.g. patients proceeding to RC) limit interpretation of our results.ConclusionsPatients with clinical nodal involvement should not be neglected. Up to 1/4 of patients with cN+ disease had pN0 at upfront RC. Moreover, IC followed by RC for clinically node-positive UC was associated with improved pathological downstaging compared with RC alone. A potential OS benefit for IC needs to be validated in a randomised trial.Take home messageIC followed by RC for clinically node-positive UC is associated with improved pathological downstaging compared with RC alone. A potential OS benefit for IC needs to be validated in a randomised trial.



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The 21-gene recurrence score assay in node-negative early breast cancer: Prognostic, predictive or presumptuous?

Publication date: November 2016
Source:European Journal of Cancer, Volume 68
Author(s): Katarzyna J. Jerzak, Kathleen I. Pritchard




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Do aromatase inhibitors increase cardiovascular risk? Piecing together the evidence

Publication date: November 2016
Source:European Journal of Cancer, Volume 68
Author(s): Danielle N. Desautels, Phillip S. Blanchette, Kathleen I. Pritchard




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Phase III randomised chemoprevention study with selenium on the recurrence of non-invasive urothelial carcinoma. The SELEnium and BLAdder cancer Trial

Publication date: December 2016
Source:European Journal of Cancer, Volume 69
Author(s): Maria E. Goossens, Maurice P. Zeegers, Hendrik van Poppel, Steven Joniau, Koen Ackaert, Filip Ameye, Ignace Billiet, Johan Braeckman, Alex Breugelmans, Jochen Darras, Kurt Dilen, Lieven Goeman, Bertrand Tombal, Siska Van Bruwaene, Ben Van Cleyenbreugel, Frank Van der Aa, Kris Vekemans, Frank Buntinx
BackgroundIn Belgium, bladder cancer (BC) is the fifth most common cancer in men. The per-patient lifetime cost is high. Previous epidemiological studies have consistently reported that selenium concentrations were inversely associated with the risk of BC. We therefore hypothesised that selenium may be suitable for chemoprevention of recurrence of BC.MethodThe Selenium and Bladder Cancer Trial (SELEBLAT) was an academic phase III placebo-controlled, double-blind, randomised clinical trial designed to determine the effect of selenium on recurrence of non-invasive urothelial carcinoma conducted in 14 Belgian hospitals. Patients were randomly assigned by a computer program to oral selenium yeast 200 μg once a day or placebo for three years, in addition to standard care. All study personnel and participants were blinded to treatment assignment for the duration of the study. All randomised patients were included in the intention to treat (ITT) and safety analyses. Per protocol analyses (PPAs) included all patients in the study three months after start date.ResultsBetween September 18, 2009 and April 18, 2013, 151 and 141 patients were randomised in the selenium and placebo group. Patients were followed until December 31, 2015. The ITT analysis resulted in 43 (28%; 95% CI, 0.21–0.35) and 45 (32%; 95% CI, 0.24–0.40) recurrences in the selenium and placebo group. The hazard ratio (HR) was 0.85 (95% CI, 0.56–1.29; p = 0.44) while the HR for the PPA resulted in 42 and 39 (28%; 95% CI, 0.20–0.35) recurrences in the selenium and placebo group (HR = 0.96 [95% CI, 0.62–1.48]; p = 0.93).ConclusionSelenium supplementation does not lower the probability of recurrence in BC patients.



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Early tumour response as a survival predictor in previously- treated patients receiving triplet hepatic artery infusion and intravenous cetuximab for unresectable liver metastases from wild-type KRAS colorectal cancer

Publication date: November 2016
Source:European Journal of Cancer, Volume 68
Author(s): Mohamed Bouchahda, Valérie Boige, Denis Smith, Abdoulaye Karaboué, Michel Ducreux, Mohamed Hebbar, Céline Lepère, Christian Focan, Rosine Guimbaud, Pasquale Innominato, Sameh Awad, Carlos Carvalho, Salvatore Tumolo, Stephanie Truant, Thierry De Baere, Denis Castaing, Philippe Rougier, Jean-François Morère, Julien Taieb, René Adam, Francis Lévi
BackgroundEarly tumour shrinkage has been associated with improved survival in patients receiving cetuximab-based systemic chemotherapy for liver metastases from colorectal cancer (LM-CRC). We tested this hypothesis for previously treated LM-CRC patients receiving cetuximab (500 mg/m²) and triplet hepatic artery infusion (HAI) within European trial OPTILIV.MethodsIrinotecan (180 mg/m²), 5-fluorouracil (2800 mg/m²) and oxaliplatin (85 mg/m²) were given as chronomodulated or conventional delivery. Patients were retrospectively categorised as early responders (complete or partial RECIST response after three courses) or non-early responders (late or no response). Prognostic factors were determined using multivariate logistic or Cox regression models.ResultsResponse was assessed in 57 of 64 registered patients (89%), who had previously received one to three prior systemic chemotherapy protocols. An early response occurred at 6 weeks in 16 patients (28%; 9 men, 7 women), aged 33–76 years, with a median of 12 liver metastases (LMs) (2–50), involving five segments (1–8). Ten patients had a late response, and 31 patients had no response. Grade 3–4 fatigue selectively occurred in the non-early responders (0% versus 26%; p = 0.024). Early tumour response was jointly predicted by chronomodulation—odds ratio (OR): 6.0 (1.2–29.8; p = 0.029)—and LM diameter ≤57 mm—OR: 5.3 (1.1–25.0; p = 0.033). Early tumour response predicted for both R0-R1 liver resection—OR: 11.8 (1.4–100.2; p = 0.024) and overall survival—hazard ratio: 0.39 (0.17–0.88; p = 0.023) in multivariate analyses.ConclusionsEarly tumour response on triplet HAI and systemic cetuximab predicted for complete macroscopic liver resection and prolonged survival for LM-CRC patients within a multicenter conversion-to-resection medicosurgical strategy. Confirmation is warranted for early response on HAI to guide decision making.Protocol numbers: EUDRACT 2007-004632-24NCT00852228.



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Methadone is superior to fentanyl in treating neuropathic pain in patients with head-and-neck cancer

Publication date: Available online 19 October 2016
Source:European Journal of Cancer
Author(s): J. Haumann, J.W. Geurts, S.M.J. van Kuijk, B. Kremer, E.A. Joosten, M.H.J. van den Beuken-van Everdingen




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Biology and treatment of renal tumours in childhood

Publication date: November 2016
Source:European Journal of Cancer, Volume 68
Author(s): Jesper Brok, Taryn D. Treger, Saskia L. Gooskens, Marry M. van den Heuvel-Eibrink, Kathy Pritchard-Jones
In Europe, almost 1000 children are diagnosed with a malignant renal tumour each year. The vast majority of cases are nephroblastoma, also known as Wilms' tumour (WT). Most children are treated according to Société Internationale d'Oncologie Pédiatrique Renal Tumour Study Group (SIOP-RTSG) protocols with pre-operative chemotherapy, surgery, and post-operative treatment dependent on stage and histology. Overall survival approaches 90%, but a subgroup of WT, with high-risk histology and/or relapsed disease, still have a much poorer prognosis. Outcome is similarly poor for the rare non-WT, particularly for malignant rhabdoid tumour of the kidney, metastatic clear cell sarcoma of the kidney (CCSK), and metastatic renal cell carcinoma (RCC).Improving outcome and long-term quality of life requires more accurate risk stratification through biological insights. Biomarkers are also needed to signpost potential targeted therapies for high-risk subgroups. Our understanding of Wilms' tumourigenesis is evolving and several signalling pathways, microRNA processing and epigenetics are now known to play pivotal roles. Most rhabdoid tumours display somatic and/or germline mutations in the SMARCB1 gene, whereas CCSK and paediatric RCC reveal a more varied genetic basis, including characteristic translocations. Conducting early-phase trials of targeted therapies is challenging due to the scarcity of patients with refractory or relapsed disease, the rapid progression of relapse and the genetic heterogeneity of the tumours with a low prevalence of individual somatic mutations. A further consideration in improving population survival rates is the geographical variation in outcomes across Europe.This review provides a comprehensive overview of the current biological knowledge of childhood renal tumours alongside the progress achieved through international collaboration. Ongoing collaboration is needed to ensure consistency of outcomes through standardised diagnostics and treatment and incorporation of biomarker research. Together, these objectives constitute the rationale for the forthcoming SIOP-RTSG 'UMBRELLA' study.



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Concurrent irradiation with the anti-programmed cell death ligand-1 immune checkpoint blocker durvalumab: Single centre subset analysis from a phase 1/2 trial

Publication date: November 2016
Source:European Journal of Cancer, Volume 68
Author(s): Antonin Levy, Christophe Massard, Jean-Charles Soria, Eric Deutsch
PurposeTo assess preliminary safety and efficacy results of the anti-programmed cell death ligand-1 (anti-PD-L1) durvalumab in combination with radiotherapy (RT) in an expansion cohort of patients included in a phase 1/2 trial at our institution.Patients and methodsData from patients who received concurrent palliative RT with durvalumab (10 mg/kg every 2 weeks via intravenous infusion) were analysed in terms of safety (CTCAE v4.0) and efficacy (RECIST v1.1 and tumour growth rate [TGR]).ResultsBetween 02/2014 and 04/2016, 10 patients received palliative local irradiation of 15 isolated lesions. Most patients (90%) had received one or more prior lines of systemic therapy for advanced disease. The median duration of exposure to durvalumab was 5.2 months with a median delivery of 11 cycles (range, 4–38 cycles). RT (conformal 3D RT, 79% and intracranial stereotactic RT, 21%) was delivered at a median biologically-effective dose of 28 Gy (range, 6–92), in a median number of five fractions (range, 1–10) and over a median duration of 6 d (range, 1–14). Five patients (50%) reported an irradiation-related adverse event (AE) grade (G) 1 or 2 and one patient had two G2 AEs. The most frequently reported AE (3/6) was G2 mucositis. There was no G3 or more RT-related AEs. All AEs were transient, lasted less than one week, and were manageable by standard guidelines. There was no unexpected AE. On 10/15 in-field (IF) evaluable lesions, the objective response (OR) rate was 60% (complete response, 2/10 and partial response, 4/10) and 4/10 stable disease (SD). All evaluated IF lesions had a TGR decrease resulting in a significant decrease in the TGR between the two periods (before versus after RT; p < 0.01). Outfields disease evaluation retrieved 10/14 SD and 4/14 progressive disease (PD). There was no out-field OR, no abscopal effect and no out-field difference between the two periods according to TGR (p = 0.09).ConclusionIn this small data set of patients, concurrent palliative RT with the anti-PD-L1 durvalumab was well tolerated.ClinicalTrials.gov number: NCT01693562; EudraCT number: 2012-002206-52.



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Methadone is superior to fentanyl in treating neuropathic pain in patients with head-and-neck cancer

Publication date: Available online 20 October 2016
Source:European Journal of Cancer
Author(s): Xiulu Ruan, Jin Jun Luo, Alan David Kaye




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A novel PLP1 mutation associated with optic nerve enlargement in two siblings with Pelizaeus–Merzbacher disease: A new MRI finding

Publication date: Available online 25 October 2016
Source:Brain and Development
Author(s): Efterpi Pavlidou, Vijaya Ramachandran, Veronica Govender, Clare Wilson, Rini Das, Victoria Vlachou, Evangelos Pavlou, Anand Saggar, Kshitij Mankad, Maria Kinali
Pelizaeus–Merzbacher disease (PMD) is a rare, X-linked disorder characterized by hypomyelination of the Central Nervous System due to mutations in the PLP1 gene. Certain mutations of the PLP1 gene correlate with specific clinical phenotypes and neuroimaging findings. We herein report a novel mutation of the PLP1 gene in two siblings with PMD associated with a rare and protean neuroimaging finding of optic nerve enlargement. To the best of our knowledge this is the first time that this novel mutation H133P of PLP1 gene is identified and clinically associated with optic nerve enlargement in PMD patients.



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“Symptomatic” infection-associated acute encephalopathy in children with underlying neurological disorders

Publication date: Available online 22 October 2016
Source:Brain and Development
Author(s): Yoshimichi Hirayama, Yoshiaki Saito, Yoshihiro Maegaki
BackgroundDevelopment of infection-associated acute encephalopathy (AE) is precipitated by several factors, including viral agents, age, and genetic polymorphisms. In addition, children with prior underlying neurological disorders can also present with AE.MethodWe reviewed 55 children with AE who were referred to hospitals participating in the Status Epilepticus Study Group from 1988 to 2013. AE was classified into eight subtypes: acute encephalopathy with biphasic seizures and late reduced diffusion (AESD); hemiconvulsion–hemiplegia syndrome (HH); acute necrotizing encephalopathy; hemorrhagic shock and encephalopathy syndrome (HSES); clinically mild encephalitis/encephalopathy with a reversible splenial lesion; acute encephalitis with refractory, repetitive partial seizures; Reye-like syndrome; and unclassified.ResultOf the 55 AE cases, 14 (25.4%) had underlying neurological disorders, including perinatal insults (n=6) and genetic syndrome and/or brain malformations (n=8). These preceding morbidities were relatively common in AESD (6/18, 33.3%), HH (3/9, 33.3%), and HSES (3/6, 50.0%). History of epilepsy or febrile seizures were frequent in HH cases (4/9, 44.4%), whereas they were rare in other AE subtypes.ConclusionAmong the AE subgroups, HH, HSES, and AESD frequently emerged in preceding etiologies with augmented neuronal excitability. These subgroups may have distinct pathomechanism from the "cytokine storm" mediated AEs during childhood.



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Reply

Publication date: Available online 26 October 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Linda Krause, Nikola S. Mueller, Stefanie Eyerich




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Multiplex platform technology and bioinformatics are essential for development of biomarkers in atopic dermatitis

Publication date: Available online 26 October 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Judith L. Thijs, Athula Herath, Marjolein S. de Bruin-Weller, DirkJan Hijnen




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Therapeutic reversal of food allergen sensitivity by mature retinoic acid–differentiated dendritic cell induction of LAG3+CD49b−Foxp3− regulatory T cells

Publication date: Available online 26 October 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Wojciech Dawicki, Chunyan Li, Jennifer Town, Xiaobei Zhang, John R. Gordon
BackgroundAnaphylaxis is a life-threatening condition for which we have limited therapeutic options. Although specific immunotherapy for food allergies is becoming more effective, it is still laborious and carries substantial risk of adverse events. On the other hand, regulatory dendritic cell (DC) therapy is effective in mouse models of allergic disease and has been shown to work with TH2 cells from atopic asthmatic patients.ObjectiveWe assessed whether DC immunotherapy could reverse food allergen sensitivity in mouse models to provide proof of concept relating to their use in the clinic.MethodsWe generated and characterized mature retinoic acid–skewed dendritic cells (DC-RAs) and assessed their abilities to reverse ovalbumin or peanut allergies in mouse models, as well as their operative mechanisms.ResultsDC-RAs displayed a mature yet tolerogenic phenotype, expressing IL-10, TGF-β, IL-27, and aldehyde dehydrogenase 1A2 but not IL-12 or IL-35; IL-10 and TGF-β together drove their suppression of TH2 cell proliferation. Delivery of specific allergen-presenting DC-RAs to half-maximally sensitized mice with ovalbumin or peanut allergy reduced anaphylactic responses to oral allergen challenge by 84% to 90%, as well as diarrhea, mast cell activation, and TH2 cytokine responses and serum allergen-specific IgE/IgG1 levels. DC-RA expression of IL-27 was important to their induction of CD25⁺ lymphocyte activation gene 3 (LAG3)⁺, CD49b⁻, forkhead box P3 (Foxp3)⁻ regulatory T cells in vitro, such that β subunit of IL-27 (Ebi)^−/− (ie, IL-27–incompetent) DC-RAs were ineffective in inducing food allergen tolerance.ConclusionOur data indicate that regulatory DC immunotherapy can be effective for food allergies and suggest that induction of Foxp3⁻ regulatory T cells might be a useful strategy for tolerance induction in this context.

Graphical abstract

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Evolution and predictive value of IgE responses toward a comprehensive panel of house dust mite allergens during the first 2 decades of life

Publication date: Available online 25 October 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Daniela Posa, Serena Perna, Yvonne Resch, Christian Lupinek, Valentina Panetta, Stephanie Hofmaier, Alexander Rohrbach, Laura Hatzler, Linus Grabenhenrich, Olympia Tsilochristou, Kuan-Wei Chen, Carl-Peter Bauer, Ute Hoffman, Johannes Forster, Fred Zepp, Antje Schuster, Ulrich Wahn, Thomas Keil, Susanne Lau, Susanne Vrtala, Rudolf Valenta, Paolo Maria Matricardi
BackgroundThe evolution of the IgE response to the numerous allergen molecules of Dermatophagoides pteronyssinus is still unknown.ObjectivesWe sought to characterize the evolutionary patterns of the IgE response to 12 molecules of D pteronyssinus from birth to adulthood and to investigate their determinants and clinical relevance.MethodsWe investigated the clinical data and sera of 722 participants in the German Multicenter Allergy Study, a birth cohort started in 1990. Diagnoses of current allergic rhinitis (AR) related to mite allergy and asthma were based on yearly interviews at the ages of 1 to 13 years and 20 years. IgE to the extract and 12 molecules of D pteronyssinus were tested by means of ImmunoCAP and microarray technology, respectively, in sera collected at ages 1, 2, 3, 5, 6, 7, 10, 13, and 20 years. Exposure to mites at age 6 and 18 months was assessed by measuring Der p 1 weight/weight concentration in house dust.ResultsOne hundred ninety-one (26.5%) of 722 participants ever had IgE to D pteronyssinus extract (≥0.35 kUA/L). At age 20 years, their IgE recognized most frequently Der p 2, Der p 1, and Der p 23 (group A molecules; prevalence, >40%), followed by Der p 5, Der p 7, Der p 4, and Der p 21 (group B molecules; prevalence, 15% to 30%) and Der p 11, Der p 18, clone 16, Der p 14, and Der p 15 (group C molecules; prevalence, <10%). IgE sensitization started almost invariably with group A molecules and expanded sequentially first to group B and finally to group C molecules. Early IgE sensitization onset, parental hay fever, and higher exposure to mites were associated with a broader polymolecular IgE sensitization pattern. Participants reaching the broadest IgE sensitization stage (ie, ABC) had significantly higher risk of mite-related AR and asthma than unsensitized participants. IgE to Der p 1 or Der p 23 at age 5 years or less predicted asthma at school age.ConclusionsParental hay fever and early exposure to D pteronyssinus allergens promote IgE polysensitization to several D pteronyssinus molecules, which in turn predicts current mite-related AR and current/future asthma. These results might inspire predictive algorithms and prevention strategies against the progression of IgE sensitization to mites toward AR and asthma.



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Enrolling African-American and Latino Patients with Asthma in Comparative Effectiveness Research: Lessons Learned From Eight Patient-Centered Studies

Publication date: Available online 24 October 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): C. Bradley Kramer, Lisa LeRoy, Sara Donahue, Andrea J. Apter, Tyra Bryant-Stephens, John Elder, Winifred Hamilton, Jerry A. Krishnan, Deborah Q. Shelef, James W. Stout, Kaharu Sumino, Stephen Teach, Alex D. Federman
BackgroundAfrican-American and Latino patients are often difficult to recruit for asthma studies. This challenge is a barrier to improving asthma care and outcomes for these populations.ObjectiveTo examine the recruitment experiences of 8 asthma comparative effectiveness studies that specifically targeted African-American and Latino patients, and identify the solutions they developed to improve recruitment.MethodsCase report methodology was used to gather and evaluate information on study design, recruitment procedures and outcomes from study protocols and annual reports, and in-depth interviews with each research team. Data were analyzed for themes, commonalities and differences.ResultsThere were 4 domains of recruitment challenges: individual participant, institutional, research team and study intervention. Participants had competing demands for time and some did not believe they had asthma. Institutional challenges included organizational policies governing monetary incentives and staff hiring. Research team challenges included ongoing training needs of recruitment staff, and intervention designs often were unappealing to participants because of inconveniences. Teams identified a host of strategies to address these challenges, most importantly engagement of patient and other stakeholders in study design and trouble-shooting, and flexibility in data collection and intervention application to meet the varied needs of patients.ConclusionAsthma researchers may have greater success with recruitment by addressing uncertainty among patients about asthma diagnosis, engaging stakeholders in all aspects of study design and implementation, and maximizing flexibility of study and intervention protocols. However, even with such efforts, engagement of African-American and Latino patients in asthma research may remain low. Greater investment in research on engaging these populations in asthma research may ultimately be needed to improve their asthma care and outcomes.

Teaser

Recruitment of low income, minority asthma patients into eight PCORI funded studies required time, extensive effort and resources. Researchers carefully addressed each barrier and engaged stakeholders in recruitment efforts beginning in the early stages of the studies.


http://ift.tt/2f2aqLs

Epicutaneous immunotherapy for the treatment of peanut allergy in children and young adults

Publication date: Available online 26 October 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Stacie M. Jones, Scott H. Sicherer, A. Wesley Burks, Donald Y.M. Leung, Robert W. Lindblad, Peter Dawson, Alice K. Henning, M. Cecilia Berin, David Chiang, Brian P. Vickery, Robbie D. Pesek, Christine B. Cho, Wendy F. Davidson, Marshall Plaut, Hugh A. Sampson, Robert A. Wood
BackgroundPeanut allergy is common, life-threatening, and without therapeutic options. We evaluated peanut epicutaneous immunotherapy (EPIT) by using Viaskin Peanut for peanut allergy treatment.ObjectiveWe sought to evaluate the clinical, safety, and immunologic effects of EPIT for the treatment of peanut allergy.MethodsIn this multicenter, double-blind, randomized, placebo-controlled study, 74 participants with peanut allergy (ages 4-25 years) were treated with placebo (n = 25), Viaskin Peanut 100 μg (VP100; n = 24) or Viaskin Peanut 250 μg (VP250; n = 25; DBV Technologies, Montrouge, France). The primary outcome was treatment success after 52 weeks, which was defined as passing a 5044-mg protein oral food challenge or achieving a 10-fold or greater increase in successfully consumed dose from baseline to week 52. Adverse reactions and mechanistic changes were assessed.ResultsAt week 52, treatment success was achieved in 3 (12%) placebo-treated participants, 11 (46%) VP100 participants, and 12 (48%) VP250 participants (P = .005 and P = .003, respectively, compared with placebo; VP100 vs VP250, P = .48). Median change in successfully consumed doses were 0, 43, and 130 mg of protein in the placebo, VP100, and VP250 groups, respectively (placebo vs VP100, P = .014; placebo vs VP250, P = .003). Treatment success was higher among younger children (P = 0.03; age, 4-11 vs >11 years). Overall, 14.4% of placebo doses and 79.8% of VP100 and VP250 doses resulted in reactions, predominantly local patch-site and mild reactions (P = .003). Increases in peanut-specific IgG4 levels and IgG4/IgE ratios were observed in peanut EPIT-treated participants, along with trends toward reduced basophil activation and peanut-specific TH2 cytokines.ConclusionsPeanut EPIT administration was safe and associated with a modest treatment response after 52 weeks, with the highest responses among younger children. This, when coupled with a high adherence and retention rate and significant changes in immune pathways, supports further investigation of this novel therapy.



http://ift.tt/2e7JRa2

Tertiary Lymphoid Organs in recalcitrant Chronic Rhinosinusitis

Publication date: Available online 22 October 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Aden H. Lau, Susan Lester, Sophia Moraitis, Judy Ou, Alkis J. Psaltis, Shaun McColl, Maureen Rischmueller, Peter-John Wormald, Sarah Vreugde

Teaser

Capsule Summary: We have found lymph node-like structures termed tertiary lymphoid organs (TLOs) within the mucosa of CRS patients in association with disease recalcitrance and tissue eosinophilia. This finding has potentially important diagnostic, prognostic and therapeutic implications.


http://ift.tt/2f28JOd

Association of a TNFSF13B (BAFF) regulatory region single nucleotide polymorphism with response to rituximab in ANCA-associated vasculitis

Publication date: Available online 22 October 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Federico Alberici, Rona M. Smith, Mariana Fonseca, Lisa C. Willcocks, Rachel B. Jones, Julia U. Holle, Stefan Wieczorek, Thomas Neumann, Davide Martorana, Gina Gregorini, Renato A. Sinico, Annette Bruchfeld, Iva Gunnarsson, Sophie Ohlsson, Bo Baslund, Vladimir Tesar, Zdenka Hruskova, Maria C. Cid, Augusto Vaglio, Paul A. Lyons, Kenneth G.C. Smith, David R.W. Jayne

Teaser

In ANCA-associated vasculitis (AAVs) response to rituximab is highly variable and predictors of response are needed. Our study identifies a single nucleotide polymorphism of the regulatory region of TNFSF13B (BAFF) associated with response to rituximab in AAV.


http://ift.tt/2e7C0tc

Autoimmune chronic spontaneous urticaria: what we know and what we don’t know

Publication date: Available online 21 October 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Pavel Kolkhir, Martin K. Church, Karsten Weller, Martin Metz, Oliver Schmetzer, Marcus Maurer
Chronic spontaneous urticaria (CSU) is a mast-cell driven skin disease, characterized by the recurrence of transient wheals, angioedema, or both for more than 6 weeks. Autoimmunity is thought to be one of the most frequent causes of CSU. Type I and type II autoimmunity, i.e. IgE to autoallergens and IgG autoantibodies to IgE or its receptor, respectively, have been implicated in the etiology and pathogenesis of CSU. We analyzed the relevant literature and assessed the existing evidence in support of a role for type I and II autoimmunity in CSU with the help of Hill's criteria of causality. For each of these criteria, i.e. strength of association, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment and analogy, we categorized the strength of evidence as "insufficient", "low", "moderate" or "high" and then assigned levels of causality for type I and II autoimmunity in CSU, from level 1 (causal relationship) to level 5 (causality not likely). Based on the evidence in support of Hill's criteria, type I autoimmunity in CSU has level 3 causality (causal relationship suggested) and type II autoimmunity has level 2 causality (causal relationship likely). There are still many aspects of the pathologic mechanisms of CSU that need to be resolved, but it is becoming clear that there are at least two distinct pathways, type I and type II autoimmunity, that contribute to the pathogenesis of this complex disease.



http://ift.tt/2f2e4oL

Home Visits are Needed to Address Asthma Health Disparities in Adults

Publication date: Available online 21 October 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Tyra Bryant-Stephens, Shakira Reed-Wells, Maryori Canales, Luzmercy Perez, A. Russell Localio, Andrea J. Apter
Research on asthma frequently recruits patients from clinics because the ready pool of patients leads to easy access to patients in office waiting areas, emergency departments, or hospital wards. Patients with other chronic conditions, and with mobility problems, face exposures at home that are not easily identified at the clinic. In this paper we describe the perspective of the community health workers and challenges they encountered when making home visits while implementing a research intervention in a cohort of low-income, minority patients. From their observations, poor housing, often the result of poverty and lack of social resources, is the real elephant in the chronic asthma room. To achieve a goal of reduced asthma morbidity and mortality will require a first-hand understanding of the real-world social and economic barriers to optimal asthma management and the solutions to those barriers.



http://ift.tt/2e7BZp8

Individualized Therapy for Persistent Asthma in Young Children

Publication date: Available online 21 October 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Anne M. Fitzpatrick, Daniel J. Jackson, David T. Mauger, Susan J. Boehmer, Wanda Phipatanakul, William J. Sheehan, James N. Moy, Ian M. Paul, Leonard B. Bacharier, Michael D. Cabana, Ronina Covar, Fernando Holguin, Robert F. Lemanske, Fernando D. Martinez, Jacqueline A. Pongracic, Avraham Beigelman, Sachin N. Baxi, Mindy Benson, Kathryn Blake, James F. Chmiel, Cori L. Daines, Michael O. Daines, Jonathan M. Gaffin, Deborah Ann Gentile, W. Adam Gower, Elliot Israel, Harsha Vardhan Kumar, Jason E. Lang, Stephen C. Lazarus, John J. Lima, Ngoc Ly, Jyothi Marbin, Wayne Morgan, Ross E. Myers, J. Tod Olin, Stephen P. Peters, Hengameh H. Raissy, Rachel G. Robison, Kristie Ross, Christine A. Sorkness, Shannon M. Thyne, Stanley J. Szefler
BackgroundPhenotypic presentations in young children with asthma are varied and may contribute to differential responses to asthma controller medications.MethodsThe Individualized Therapy for Asthma in Toddlers (INFANT) study was a multicenter, randomized, double-blind, double-dummy, clinical trial in children age 12-59 months (n=300) with asthma necessitating treatment with daily controller (Step 2) therapy. Participants completed a 2-8 week run-in period followed by three crossover periods with daily inhaled corticosteroid (ICS), daily leukotriene receptor antagonist (LTRA), and as-needed ICS treatment co-administered with albuterol. The primary outcome was differential response to asthma medication based on a composite measure of asthma control. The primary analysis involved two stages: determination of differential response, and assessment of whether three pre-specified features (aeroallergen sensitization, previous exacerbations, sex) predicted differential response.Results74% (170 of 230) of children with analyzable data had a differential response to the three treatment strategies. Within differential responders, the probability of best response was highest for daily ICS and was predicted by aeroallergen sensitization, but not exacerbation history or sex. The probability of best response to daily ICS was further increased in children with both aeroallergen sensitization and blood eosinophils ≥300/μL. In these children, daily ICS was associated with more asthma control days and fewer exacerbations compared to the other treatments.ConclusionsIn young children with asthma necessitating Step 2 treatment, phenotyping with aeroallergen sensitization and blood eosinophils is useful for guiding treatment selection and identifies children with a high exacerbation probability for whom treatment with daily ICS is beneficial despite possible risks of growth suppression.

Teaser

Phenotyping with aeroallergen sensitization and blood eosinophils is useful for guiding treatment selection in young children requiring Step 2 asthma treatment and can identify children for whom treatment with daily ICS is best.


http://ift.tt/2f2bpva

U-BIOPRED clinical adult asthma clusters linked to a subset of sputum -omics

Publication date: Available online 20 October 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Diane Lefaudeux, Bertrand De Meulder, Matthew J. Loza, Nancy Peffer, Anthony Rowe, Frédéric Baribaud, Aruna T. Bansal, Rene Lutter, Ana R. Sousa, Julie Corfield, Ioannis Pandis, Per S. Bakke, Massimo Caruso, Pascal Chanez, Sven-Erik Dahlén, Louise J. Fleming, Stephen J. Fowler, Ildiko Horvath, Norbert Krug, Paolo Montuschi, Marek Sanak, Thomas Sandstrom, Dominic E. Shaw, Florian Singer, Peter J. Sterk, Graham Roberts, Ian M. Adcock, Ratko Djukanovic, Charles Auffray, Kian. F. Chung
BackgroundAsthma is a heterogeneous disease in which there is a differential response to asthma treatments. This heterogeneity needs to be evaluated so that a personalised management approach can be provided.ObjectivesWe stratified patients with moderate-to-severe asthma based on clinico-physiological parameters and performed an -omics analysis of sputum.MethodsPartition-around-medoid clustering was applied to a training set of 266 asthma participants from the European U-BIOPRED adult cohort using 8 pre-specified clinic-physiological variables. This was repeated in a separate validation set of 152 asthmatics. The clusters were compared based on sputum proteomic and transcriptomic data.ResultsFour reproducible and stable clusters of asthmatics were identified. The training set cluster T1 consists of well-controlled moderate-to-severe asthmatics, while cluster T2 is a group of late-onset severe asthmatics with history of smoking and chronic airflow obstruction. Cluster T3 is similar to cluster T2 in terms of chronic airflow obstruction but is composed of non-smokers. Cluster T4 is predominantly composed of obese female uncontrolled severe asthmatics with increased exacerbations, but with normal lung function. The validation set exhibited similar clusters, demonstrating reproducibility of the classification. There were significant differences in sputum proteomics and transcriptomics between the clusters. The severe asthma clusters, T2, T3 and T4, had higher sputum eosinophilia than T1 with no differences in sputum neutrophil counts, exhaled nitric oxide and serum IgE levels.ConclusionClustering based on clinico-physiological parameters yielded 4 stable and reproducible clusters that associate with different pathobiological pathways.Clinical ImplicationsThe definition of four distinct clusters of asthma linked to different pathobiological pathways provides a better template for the phenotyping and personalised treatment of severe asthma, where high unmet needs remain.Capsule SummaryUnsupervised clustering of asthma on clinical features alone has led to the definition of four phenotypes. Sputum 'omics' analysis has revealed different biological pathways pointing towards potential new treatments.

Graphical abstract

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Intradermal Grass Pollen Allergen Immunotherapy for Seasonal Allergy: A Randomized Controlled Trial

Publication date: Available online 20 October 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Anna Slovick, Abdel Douiri, Rachel Muir, Andrea Guerra, Konstantinos Tsioulos, Evie Hay, Emily P.S. Lam, Joanna Kelly, Janet L. Peacock, Sun Ying, Mohamed H. Shamji, David J. Cousins, Stephen R. Durham, Stephen J. Till
BackgroundRepeated low dose grass pollen intradermal allergen injection suppresses allergen-induced cutaneous late phase responses, comparable with conventional subcutaneous and sublingual immunotherapy.ObjectiveTo evaluate the efficacy and safety of grass pollen intradermal immunotherapy in the treatment of allergic rhinitis.MethodsWe randomly assigned 93 adults with grass pollen allergic rhinitis to receive 7 pre-seasonal intradermal allergen injections (containing 7 nanograms of Phl p 5 major allergen) or histamine control. The primary endpoint was daily combined symptom-medication scores during the 2013 pollen season (area under curve). Analysis was by intention-to-treat. Skin biopsies were collected following intradermal allergen challenges and late phase responses measured four and seven, ten or thirteen months post-treatment.ResultsThere was no significant difference in primary endpoint between treatment arms (active n=46, control n=47, median difference, 14; 95% CI -172.5-215.1; P=.80). Among secondary endpoints, nasal symptoms were worse in the intradermal treatment group, measured by daily scores (median difference, 35; 95% CI 4.0-67.5; P=.03) and visual-analog scales (median difference, 53; 95% CI -11.6-125·2; P=.05). In a per protocol analysis, intradermal immunotherapy was further associated with worse asthma symptoms and fewer symptom free days. Intradermal immunotherapy increased serum Phl p-specific IgE (P=.001) compared to the control arm. T cells cultured from biopsies of intradermal immunotherapy subjects showed higher expression of Th2 surface marker CRTH2 (P=.04) and lower Th1 marker CXCR (P=.01), respectively. Late phase responses remained inhibited seven months after treatment (P=.03).ConclusionIntradermal allergen immunotherapy suppressed skin late responses but was not clinically effective and resulted in worsening of respiratory allergic symptoms.

Teaser

Grass pollen intradermal allergen immunotherapy was not clinically effective, but worsened seasonal allergic rhinitis symptoms with implications for novel immunotherapy that targets allergen delivery to the skin.


http://ift.tt/2e7FBHz

Are dust mite allergens more abundant and/or more stable than other Dermatophagoides pteronyssinus proteins?

Publication date: Available online 19 October 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Ryenne N. Ogburn, Thomas A. Randall, Yingrong Xu, Julia H. Roberts, Betelihem Mebrahtu, Jaret M. Karnuta, S. Dean Rider, Grace E. Kissling, Robert E. London, Anna Pomés, Larry Arlian, Michael C. Fitzgerald, Geoffrey A. Mueller




http://ift.tt/2e7IRmb

Aspirin-exacerbated respiratory disease: Mediators and mechanisms of a clinical disease

Publication date: Available online 19 October 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Katherine N. Cahill, Joshua A. Boyce




http://ift.tt/2f2bqiO

Adult atopic dermatitis and the risk of type 2 diabetes

Publication date: Available online 19 October 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Yuki M.F. Andersen, Alexander Egeberg, Gunnar H. Gislason, Lone Skov, Filip K. Knop, Jacob P. Thyssen

Teaser

While AD is not an independent risk factor for T2D in adjusted analysis, age, smoking, alcohol abuse and use of systemic and topical corticosteroids may increase the risk of T2D in adults with AD.


http://ift.tt/2e7DWle

Latent class analysis reveals clinically relevant atopy phenotypes in two birth cohorts

Publication date: Available online 19 October 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Alexander J. Hose, Martin Depner, Sabina Illi, Susanne Lau, Thomas Keil, Ulrich Wahn, Oliver Fuchs, Petra Ina Pfefferle, Elisabeth Schmaußer-Hechfellner, Jon Genuneit, Roger Lauener, Anne M. Karvonen, Caroline Roduit, Jean-Charles Dalphin, Josef Riedler, Juha Pekkanen, Erika von Mutius, Markus J. Ege, Carl Peter Bauer, Johannes Forster, Fred Zepp, Volker Wahn, Antje Schuster, Renate L. Bergmann, Karl E. Bergmann, Andreas Reich, Linus Grabenhenrich, Bianca Schaub, Georg J. Loss, Harald Renz, Michael Kabesch, Marjut Roponen, Anne Hyvärinen, Pekka Tiittanen, Sami Remes, Charlotte Braun-Fahrländer, Remo Frei, Vincent Kaulek, Marie-Laure Dalphin, Gert Doekes, Nicole Blümer, Urs Frey
BackgroundPhenotypes of childhood-onset asthma are characterized by distinct trajectories and functional features. For atopy, definition of phenotypes during childhood is less clear.ObjectiveTo define phenotypes of atopic sensitization over the first 6 years of life by a latent class analysis (LCA) integrating three dimensions of atopy: allergen specificity, time course, and levels of specific IgE.MethodsPhenotypes were defined by LCA in 680 children of the MAS and 766 of the PASTURE birth cohorts and compared to classical non-disjunctive definitions of seasonal, perennial, and food sensitization with respect to atopic diseases and lung function. Cytokine levels were measured in PASTURE.ResultsThe LCA classified predominantly by type and multiplicity of sensitization (food versus inhalant), allergen combinations, and sIgE levels. Latent classes were related to atopic disease manifestations with higher sensitivity and specificity than the classical definitions. LCA detected in both cohorts consistently a distinct group of children with severe atopy characterized by high seasonal sIgE and a strong propensity for asthma, hay fever, eczema and impaired lung function even in children without an established asthma diagnosis. Severe atopy was associated with an elevated interleukin-5/interferon-gamma ratio. A path analysis among sensitized children revealed that among all features of severe atopy only excessive sIgE production early in life impacted on asthma risk.ConclusionsLCA revealed a set of benign, symptomatic, and severe atopy phenotypes. The severe phenotype emerged as a latent condition with signs of a dysbalanced immune response. It determined high asthma risk via excessive sIgE production and directly impacted on impaired lung function.

Graphical abstract

Teaser

Atopic sensitization was classified with respect to disease relevance in three phenotypes of benign, symptomatic, and severe atopy, which impacted on asthma risk via excessive production of specific IgE early in life and on poor lung function.


http://ift.tt/2f2cSBv

Cross-Talk between Human Mast Cells and Epithelial Cells by IgE-mediated Periostin Production in Eosinophilic Nasal Polyps

Publication date: Available online 19 October 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Dae Woo Kim, Marianna Kulka, Ara Jo, Kyoung Mi Eun, Narcy Arizmendi, Brian P. Tancowny, Seung-No Hong, Jung Pyo Lee, Hong Ryul Jin, Richard F. Lockey, Dong-Kyu Kim, Seong H. Cho

Teaser

Periostin is up-regulated in E-NP and is associated with disease severity and Th2 inflammatory markers. Periostin was produced by IgE-stimulated mast cells. Secreted periostin binds to integrin αV on the epithelial cell surface and induces TSLP release from epithelial cells in E-NP.


http://ift.tt/2f2cSS1

IL-17 Receptor Signaling in the Lung Epithelium Is Required for Mucosal Chemokine Gradients and Pulmonary Host Defense against K. pneumoniae

Publication date: Available online 27 October 2016
Source:Cell Host & Microbe
Author(s): Kong Chen, Taylor Eddens, Giraldina Trevejo-Nunez, Emily E. Way, Waleed Elsegeiny, David M. Ricks, Abhishek V. Garg, Carla J. Erb, Meihua Bo, Ting Wang, Wei Chen, Janet S. Lee, Sarah L. Gaffen, Jay K. Kolls
The cytokine IL-17, and signaling via its heterodimeric IL-17RA/IL-17RC receptor, is critical for host defense against extracellular bacterial and fungal pathogens. Polarized lung epithelial cells express IL-17RA and IL-17RC basolaterally. However, their contribution to IL-17-dependent pulmonary defenses in vivo remains to be determined. To address this, we generated mice with conditional deletion of Il17ra or Il17rc in Scgb1a1-expressing club cells, a major component of the murine bronchiolar epithelium. These mice displayed an impaired ability to recruit neutrophils into the airway lumen in response to IL-17, a defect in bacterial clearance upon mucosal challenge with the pulmonary pathogen Klebsiella pneumoniae, and substantially reduced epithelial expression of the chemokine Cxcl5. Neutrophil recruitment and bacterial clearance were restored by intranasal administration of recombinant CXCL5. Our data show that IL-17R signaling in the lung epithelium plays a critical role in establishing chemokine gradients that are essential for mucosal immunity against pulmonary bacterial pathogens.

Graphical abstract

Teaser

IL-17 plays key roles in host defense, but the target cells in the lung are unclear. Chen et al. show that pulmonary epithelial IL-17R signaling is essential for regulating chemokine gradients, neutrophil recruitment, and bacterial clearance in the lungs. Epithelial administration of an IL-17R agonist may benefit patients with pneumonia.


http://ift.tt/2e7HpQN

IL-17 Receptor Signaling in Oral Epithelial Cells Is Critical for Protection against Oropharyngeal Candidiasis

Publication date: Available online 27 October 2016
Source:Cell Host & Microbe
Author(s): Heather R. Conti, Vincent M. Bruno, Erin E. Childs, Sean Daugherty, Joseph P. Hunter, Bemnet G. Mengesha, Danielle L. Saevig, Matthew R. Hendricks, Bianca M. Coleman, Lucas Brane, Norma Solis, J. Agustin Cruz, Akash H. Verma, Abhishek V. Garg, Amy G. Hise, Jonathan P. Richardson, Julian R. Naglik, Scott G. Filler, Jay K. Kolls, Satrajit Sinha, Sarah L. Gaffen
Signaling through the IL-17 receptor (IL-17R) is required to prevent oropharyngeal candidiasis (OPC) in mice and humans. However, the IL-17-responsive cell type(s) that mediate protection are unknown. Using radiation chimeras, we were able to rule out a requirement for IL-17RA in the hematopoietic compartment. We saw remarkable concordance of IL-17-controlled gene expression in C. albicans-infected human oral epithelial cells (OECs) and in tongue tissue from mice with OPC. To interrogate the role of the IL-17R in OECs, we generated mice with conditional deletion of IL-17RA in superficial oral and esophageal epithelial cells (Il17ra^ΔK13). Following oral Candida infection, Il17ra^ΔK13 mice exhibited fungal loads and weight loss indistinguishable from Il17ra^−/− mice. Susceptibility in Il17ra^ΔK13 mice correlated with expression of the antimicrobial peptide β-defensin 3 (BD3, Defb3). Consistently, Defb3^−/− mice were susceptible to OPC. Thus, OECs dominantly control IL-17R-dependent responses to OPC through regulation of BD3 expression.

Graphical abstract

Teaser

IL-17 receptor signaling is required to prevent oropharyngeal candidiasis ("oral thrush") in both mice and humans. Conti et al. demonstrate in mice that IL-17R-dependent antifungal responses in superficial oral epithelial cells (OECs) are critical for protection. Moreover, OECs dominantly control IL-17R-dependent responses through production of the antimicrobial peptide β-defensin 3.


http://ift.tt/2e7IPea

Dynamics of Human and Viral RNA Methylation during Zika Virus Infection

Publication date: Available online 20 October 2016
Source:Cell Host & Microbe
Author(s): Gianluigi Lichinchi, Boxuan Simen Zhao, Yinga Wu, Zhike Lu, Yue Qin, Chuan He, Tariq M. Rana
Infection with the flavivirus Zika (ZIKV) causes neurological, immunological, and developmental defects through incompletely understood mechanisms. We report that ZIKV infection affects viral and human RNAs by altering the topology and function of N⁶-adenosine methylation (m⁶A), a modification affecting RNA structure and function. m⁶A nucleosides are abundant in ZIKV RNA, with twelve m⁶A peaks identified across full-length ZIKV RNA. m⁶A in ZIKV RNA is controlled by host methyltransferases METTL3 and METTL14 and demethylases ALKBH5 and FTO, and knockdown of methyltransferases increases, while silencing demethylases decreases, ZIKV production. YTHDF family proteins, which regulate the stability of m⁶A-modified RNA, bind to ZIKV RNA, and their silencing increases ZIKV replication. Profiling of the m⁶A methylome of host mRNAs reveals that ZIKV infection alters m⁶A location in mRNAs, methylation motifs, and target genes modified by methyltransferases. Our results identify a mechanism by which ZIKV interacts with and alters host cell functions.

Graphical abstract

Teaser

Lichinchi et al. show that Zika virus (ZIKV) RNA is modified at N⁶ methylation of adenosine (m⁶A). m⁶A modifications in ZIKV RNA control viral replication and are regulated by host methyltransferases and demethylases. ZIKV infection alters the location of m⁶A in host mRNAs, methylation motifs, and target genes modified by methyltransferases.


http://ift.tt/2e7Chwb

N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection

Publication date: Available online 20 October 2016
Source:Cell Host & Microbe
Author(s): Nandan S. Gokhale, Alexa B.R. McIntyre, Michael J. McFadden, Allison E. Roder, Edward M. Kennedy, Jorge A. Gandara, Sharon E. Hopcraft, Kendra M. Quicke, Christine Vazquez, Jason Willer, Olga R. Ilkayeva, Brittany A. Law, Christopher L. Holley, Mariano A. Garcia-Blanco, Matthew J. Evans, Mehul S. Suthar, Shelton S. Bradrick, Christopher E. Mason, Stacy M. Horner
The RNA modification N6-methyladenosine (m⁶A) post-transcriptionally regulates RNA function. The cellular machinery that controls m⁶A includes methyltransferases and demethylases that add or remove this modification, as well as m⁶A-binding YTHDF proteins that promote the translation or degradation of m⁶A-modified mRNA. We demonstrate that m⁶A modulates infection by hepatitis C virus (HCV). Depletion of m⁶A methyltransferases or an m⁶A demethylase, respectively, increases or decreases infectious HCV particle production. During HCV infection, YTHDF proteins relocalize to lipid droplets, sites of viral assembly, and their depletion increases infectious viral particles. We further mapped m⁶A sites across the HCV genome and determined that inactivating m⁶A in one viral genomic region increases viral titer without affecting RNA replication. Additional mapping of m⁶A on the RNA genomes of other Flaviviridae, including dengue, Zika, yellow fever, and West Nile virus, identifies conserved regions modified by m⁶A. Altogether, this work identifies m⁶A as a conserved regulatory mark across Flaviviridae genomes.

Graphical abstract

Teaser

N6-methyladenosine (m⁶A) post-transcriptionally regulates RNA function. Gokhale et al. demonstrate that the RNA genomes of HCV, ZIKV, DENV, YFV, and WNV are modified by m⁶A. Depletion of cellular machinery that regulates m⁶A or introduction of m⁶A-abrogating mutations within HCV RNA increase viral particle production, suggesting that m⁶A negatively regulates HCV.


http://ift.tt/2e7HRid

ICAM-5/Telencephalin Is a Functional Entry Receptor for Enterovirus D68

Publication date: Available online 27 October 2016
Source:Cell Host & Microbe
Author(s): Wei Wei, Haoran Guo, Junliang Chang, Yingzi Yu, Guanchen Liu, Nannan Zhang, Stephen H. Willard, Shu Zheng, Xiao-Fang Yu
Enterovirus D68 (EV-D68) is a member of the Picornaviridae family. Although EV-D68-associated infection was once considered rare, it has been increasing in recent years. EV-D68 infection is most frequently associated with respiratory illness. However, it has also been implicated in a polio-like neurological disorder, acute flaccid myelitis. Although sialic acid has been implicated in EV-D68 entry, the existence of a protein receptor has yet to be clarified. Here we identify neuron-specific intercellular adhesion molecule 5 (ICAM-5/telencephalin) as a cellular receptor for sialic acid-dependent and -independent EV-D68 viruses. EV-D68 bound specifically and efficiently to ICAM-5, and replication of EV-D68 in diverse cell types was inhibited by soluble ICAM-5 fragments. ICAM-5 silencing attenuated EV-D68 replication in permissive cells, and ICAM-5 expression in non-permissive cells allowed EV-D68 replication. The discovery of a neuron-specific adhesion molecule as an EV-D68 receptor has important implications for EV-D68 pathogenesis and may facilitate the development of novel intervention strategies.

Graphical abstract

Teaser

Enterovirus D68 (EV-D68) infection is on a worldwide upswing in recent years and has been linked to neurological symptoms in patients. Wei et al. show that the neuron-expressed intercellular adhesion molecule 5 (ICAM-5 or telencephalin) can serve as a cellular receptor for sialic acid-dependent and -independent EV-D68 viruses.


http://ift.tt/2e7GnEl

Estimation of Round-Trip Outer-Middle Ear Gain Using DPOAEs

Abstract

The reported research introduces a noninvasive approach to estimate round-trip outer-middle ear pressure gain using distortion product otoacoustic emissions (DPOAEs). Our ability to hear depends primarily on sound waves traveling through the outer and middle ear toward the inner ear. The role of the outer and middle ear in sound transmission is particularly important for otoacoustic emissions (OAEs), which are sound signals generated in a healthy cochlea and recorded by a sensitive microphone placed in the ear canal. OAEs are used to evaluate the health and function of the cochlea; however, they are also affected by outer and middle ear characteristics. To better assess cochlear health using OAEs, it is critical to quantify the effect of the outer and middle ear on sound transmission. DPOAEs were obtained in two conditions: (i) two-tone and (ii) three-tone. In the two-tone condition, DPOAEs were generated by presenting two primary tones in the ear canal. In the three-tone condition, DPOAEs at the same frequencies (as in the two-tone condition) were generated by the interaction of the lower frequency primary tone in the two-tone condition with a distortion product generated by the interaction of two other external tones. Considering how the primary tones and DPOAEs of the aforementioned conditions were affected by the forward and reverse outer-middle ear transmission, an estimate of the round-trip outer-middle ear pressure gain was obtained. The round-trip outer-middle ear gain estimates ranged from −39 to −17 dB between 1 and 3.3 kHz.

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Population-based analysis of breast cancer treatment by intrinsic sub-type in Manitoba, Canada

Publication date: December 2016
Source:Cancer Epidemiology, Volume 45
Author(s): Elizabeth Hammond, Emma Shu, Karagin Sawchuk, Yvonne Myal, Afshin Raouf, Thomas Klonisch, Sabine Hombach-Klonisch, Etienne Leygue, Sam Kung, Janice Safneck, Michael Mowat, Wayne Xu, Leigh Murphy, Marshall Pitz
BackgroundFew descriptive epidemiological studies on the incidence, treatment and survival can accurately reflect a whole population. Manitoba, Canada has an accurate cancer registry, a drug information program network and a breast screening program since 1995. This combined with a stable population provides true population data that can accurately describe the region.MethodsUsing a retrospective cohort design all Breast Cancer cases were obtained from 2004–2010 (N=5399) and grouped by Intrinsic sub-type. Identifiable co-morbidities, prescribed endocrine therapy, staging, surgery, treatment and overall and disease-free survival by intrinsic sub-type were evaluated.ResultsPrevalence of Luminal A (41.7%), Luminal B HER2- (15.6%), Luminal B HER2+ (8.9%), Basal-like(10.8%), and HER2+ non-luminal (5.1%) were consistent with other descriptive studies in Canada and Spain. Over this time period the number of lumpectomies increased 1.7% per year (P=0.007). There was a steady increase of 3.4% per year in the use of aromatase inhibitors (P=0.005). Pre-menopausal patients had an increased proportion of HER2+ and Basal-like sub-types. The 7year overall/disease-free survival percentages for Luminal A, Luminal B HER2-, Luminal B HER2+, Basal-like, and HER2+ non-luminal were 88.7%/83.6, 78.2%/73.0, 81.5%/73.3%, 67.7%/63.2%, 70.4%/65.6% respectively.ConclusionsReasons for variability in the prevalence of intrinsic sub-type by region is not fully understood. Manitoba is unique due the stability of the population, completeness of the registry and length of breast cancer screening program. Few true population-based studies grouped by intrinsic sub-type are available.ImpactDescriptive epidemiological studies guide future research by identifying factors that can affect treatment, recurrence, and survival.



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The burden of HPV associated cancers in two regions in Nigeria 2012–2014

Publication date: December 2016
Source:Cancer Epidemiology, Volume 45
Author(s): E.E. Jedy-Agba, E.O. Dareng, S.N. Adebamowo, M. Odutola, E.A. Oga, F. Igbinoba, T. Otu, E. Ezeome, F. Bray, R. Hassan, C.A. Adebamowo
IntroductionHPV attributable cancers are the second most common infection-related cancers worldwide, with much higher burden in less developed regions. There are currently no country-specific estimates of the burden of these cancers in Nigeria just like many other low and middle income countries.MethodsIn this study, we quantified the proportion of the cancer burden in Nigeria that is attributable to HPV infection from 2012 to 2014 using HPV prevalence estimated from previous studies and data from two population based cancer registries (PBCR) in Nigeria. We considered cancer sites for which there is strong evidence of an association with HPV infection based on the International Agency for Research on Cancer (IARC) classification. We obtained age and sex-specific estimates of incident cancers and using the World Standard Population, we derived age standardized incidence (ASR) rates for each cancer type by categories of sex, and estimated the population attributable fractions (PAF).ResultsThe two PBCR reported 4336 new cancer cases from 2012 to 2014. Of these, 1627 (37.5%) were in males and 2709 (62.5%) in females. Some 11% (488/4336) of these cancers were HPV associated; 2% (38/1627) in men and 17% (450/2709) in women. Of the HPV associated cancers, 7.8% occurred in men and 92.2% in women. The ASRs for HPV associated cancers was 33.5 per 100,000; 2.3 and 31.2 per 100,000 in men and women respectively. The proportion of all cancers attributable to HPV infection ranged from 10.2 to 10.4% (442–453 of 4336) while the proportion of HPV associated cancers attributable to HPV infection ranged from 90.6% to 92.8% (442–453 of the 488 cases). In men, 55.3% to 68.4% of HPV associated cancers were attributable to HPV infection compared to 93.6% to 94.8% in women. The combined ASR for HPV attributable cancers ranged from 31.0 to 31.7 per 100,000. This was 1.4 to 1.7 per 100,000 in men and 29.6 to 30.0 per 100,000 in women. In women, cervical cancer (n=392, ASR 28.3 per 100,000) was the commonest HPV attributable cancer, while anal cancer (n=21, ASR 1.2 per 100,000) was the commonest in men.ConclusionsHPV attributable cancers constitute a substantial cancer burden in Nigerian women, much less so in men. A significant proportion of cancers in Nigerian women would be prevented if strategies such as HPV DNA based screening and HPV vaccination are implemented.



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Racial/ethnicity disparities in invasive breast cancer among younger and older women: An analysis using multiple measures of population health

Publication date: December 2016
Source:Cancer Epidemiology, Volume 45
Author(s): Mei-Chuan Hung, Donatus U. Ekwueme, Sun Hee Rim, Arica White
IntroductionFew studies have examined age and racial/ethnic disparities in invasive breast cancer among younger (age 15–44 years) vs. older (age 45–64 years) women. This study estimates disparities in breast cancer among younger compared with older women by race/ethnicity using five measures of population health: life expectancy (LE), expected years of life lost (EYLL), cumulative incidence rate (CIR), and incidence and mortality rate ratios (IRR and MRR).MethodsUsing Surveillance, Epidemiology, and End Results data, LE and EYLL were estimated from a cohort of 15–44 and 45–64 years, non-Hispanic black (NHB), non-Hispanic white (NHW), and Hispanic women diagnosed with breast cancer, 2000–2013. Survival function was obtained from the study years and then extrapolated to lifetime using the Monte Carlo method. The CIR, IRR and MRR were calculated using 2009–2013 breast cancer incidence and mortality rates from the Centers for Disease Control and Prevention's National Program of Cancer Registries.ResultsThe estimated LE ranged from 32.12 to 7.42 years for localized to distant stages among younger NHB women compared to 33.05 to 9.95 years for younger NHW women. The estimated EYLL was 12.78 years for younger women, and 4.99 for older women. By race/ethnicity, it was 15.53 years for NHB, 14.23 years for Hispanic and 11.87 years for NHW (P<0.00025). The CIR for age-group 15–44 years (CIR15-44) indicated a 1 in 86 probability for NHB compared to a 1 in 87 probability for NHW being diagnosed with breast cancer by age 45. The estimated age-adjusted incidence rate for NHB-to-NHW women was IRR=1.10 (95%, CI=1.08–1.11) and the corresponding mortality rate was MRR=2.02 (95%, CI=1.94–2.11).ConclusionsThe breast cancer disparities between younger NHB compared to NHW women highlight the need for expanded efforts to address these disparities through primary prevention and to improve access to quality healthcare to minority women with breast cancer.



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Association of cigarette smoking and microRNA expression in rectal cancer: Insight into tumor phenotype

Publication date: December 2016
Source:Cancer Epidemiology, Volume 45
Author(s): Lila E. Mullany, Jennifer S. Herrick, Roger K. Wolff, John R. Stevens, Martha L. Slattery
Smoking is known to influence messenger RNA (mRNA) expression in colorectal cancer (CRC) cases. As microRNAs (miRNAs) are known repressors of mRNAs, we hypothesize that smoking may influence miRNA expression, thus altering mRNA expression. Our sample consisted of 1447 CRC cases that had normal colorectal mucosa and carcinoma miRNA data and lifestyle data. We examined current smoking, current versus never and former versus never (C/F/N) smoking¹1 C/F/N smoking: Differential miRNA expression in subjects who were current smokers at time of diagnosis compared to subjects who never smoked, and differential miRNA expression in former smokers compared to those who had never smoked., and pack-years smoked with miRNA expression in normal mucosa as well as differential miRNA expression between paired normal and carcinoma tissue for colon and rectal tissue to determine associations between smoking and miRNA expression. We adjusted for multiple comparisons using the Benjamini Hochberg false discovery rate (FDR).Significant associations were seen for rectal differential miRNA expression only. We analyzed miRNAs significantly associated with smoking with CIMP and MSI status, using a polytomous logistic regression. Two hundred and thirty-one miRNAs were differentially expressed with current smoking, 172 with C/F/N, and 206 with pack-years smoked; 111 were associated with all three. Forty-three miRNAs were unique to current smoking, 14 were unique to C/F/N and 57 were unique to pack years smoked. Of the 306 unique miRNAs associated with cigarette smoking, 41 were inversely associated and 200 were directly associated with CIMP high or MSI tumor molecular phenotype for either colon or rectal cancer. Our results suggest that cigarette smoking can alter miRNA expression and, given associations with CIMP high and MSI tumor molecular phenotype, it is possible that smoking influences tumor phenotype through altered miRNA expression.



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Association between the TCF7L2 polymorphism and colorectal cancer does not differ by diabetes and obesity statuses

Publication date: December 2016
Source:Cancer Epidemiology, Volume 45
Author(s): Hyun-Jeong Shim, Ran Lee, Min-Ho Shin, Hee-Nam Kim, Sun-Seog Kweon
This study evaluated the association between polymorphism in a newly identified locus, rs11196172, located in transcription factors 7-like 2 (TCF7L2) and colorectal cancer (CRC) risk according to diabetes and obesity statuses. A study enrolled 6138 CRC patients and 4367 community controls. The adjusted odds ratios (aORs) with age, sex, smoking, and body mass index of the A allele, compared with the G allele, was 1.08 (95% CI 1.01–1.16). The significantly higher risk of CRC with the A allele remained after adjusting for diabetic status (aOR 1.07, 95% CI 1.01–1.15). When stratified by diabetic or obesity status, significant associations between TCF7L2 polymorphism and CRC risk were limited to non-diabetic or normal-weight subjects. No significant interactions between the A/G allele and diabetes status or the A/G allele and overweight status were found.The results indicated that the TCF7L2 rs11196172 polymorphism increases the risk of CRC independently, with no evidence of an interaction with diabetes or obesity.



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Tea, coffee, and caffeinated beverage consumption and risk of epithelial ovarian cancers

Publication date: December 2016
Source:Cancer Epidemiology, Volume 45
Author(s): Andy C.Y. Leung, Linda S. Cook, Kenneth Swenerton, Blake Gilks, Richard P. Gallagher, Anthony Magliocco, Helen Steed, Martin Köbel, Jill Nation, Angela Brooks-Wilson, Nhu D. Le
BackgroundThe risk for epithelial ovarian cancer associated with the consumption of caffeinated beverages (tea, coffee, and soft drinks) and green tea is inconclusive. However, few studies have investigated the type of caffeinated beverage or the type of tea.ObjectiveWe assessed consumption of tea (black/caffeinated tea and green tea separately), coffee, and caffeinated soft drinks, as well as level of consumption, and the risk for epithelial ovarian cancer and its histotypes.Study designThis study was conducted within a population-based case-control study in Alberta and British Columbia, Canada from 2001 to 2012. After restricting to cases of epithelial invasive cancers and controls aged 40–79 years who completed an interview that included coffee, soft drink, and tea consumption (ascertained starting in 2005 in British Columbia and 2008 in Alberta), there were a total of 524 cases and 1587 controls. Those that did not meet the threshold for beverage consumption (at least once per month for 6 months or more) were classified as non-drinkers. Adult lifetime cumulative consumption (cup-years=cups/day*years) was calculated. Unconditional logistic regression was used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) to describe the association between the relevant drink consumption and risk.ResultsNo excess risk was seen for coffee or caffeinated soft drinks. Similarly, any tea consumption was not associated with risk, but when stratified by the type of tea, there was an increase in risk in black tea only drinkers (aOR=1.56; 95% CI:1.07–2.28 for >40 cup-years), but no excess risk for the exclusive green tea drinkers. Similar findings were observed for post-menopausal women. The association for black tea only consumption was mainly seen in the endometrioid histotype (aOR=3.19; 95% CI: 1.32–7.69).ConclusionBlack tea consumption may be associated with an increased risk epithelial ovarian carcinoma. The excess risk is seen only in the endometrioid histotype but not in serous or clear cell. Further studies are required to confirm these findings and identify the constituents in black tea that may increase the risk.



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Resource requirements for cancer registration in areas with limited resources: Analysis of cost data from four low- and middle-income countries

Publication date: Available online 25 October 2016
Source:Cancer Epidemiology
Author(s): Florence K.L. Tangka, Sujha Subramanian, Patrick Edwards, Maggie Cole-Beebe, D. Maxwell Parkin, Freddie Bray, Rachael Joseph, Les Mery, Mona Saraiya
BackgroundThe key aims of this study were to identify sources of support for cancer registry activities, to quantify resource use and estimate costs to operate registries in low- and middle-income countries (LMIC) at different stages of development across three continents.MethodsUsing the Centers for Disease Control and Prevention's (CDC's) International Registry Costing Tool (IntRegCosting Tool), cost and resource use data were collected from eight population-based cancer registries, including one in a low-income country (Uganda [Kampala)]), two in lower to middle-income countries (Kenya [Nairobi] and India [Mumbai]), and five in an upper to middle-income country (Colombia [Pasto, Barranquilla, Bucaramanga, Manizales and Cali cancer registries]).ResultsHost institution contributions accounted for 30%–70% of total investment in cancer registry activities. Cancer registration involves substantial fixed cost and labor. Labor accounts for more than 50% of all expenditures across all registries. The cost per cancer case registered in low-income and lower-middle-income countries ranged from US $3.77 to US $15.62 (United States dollars). In Colombia, an upper to middle-income country, the cost per case registered ranged from US $41.28 to US $113.39. Registries serving large populations (over 15 million inhabitants) had a lower cost per inhabitant (less than US $0.01 in Mumbai, India) than registries serving small populations (under 500,000 inhabitants) [US $0.22] in Pasto, Colombia.ConclusionThis study estimates the total cost and resources used for cancer registration across several countries in the limited-resource setting, and provides cancer registration stakeholders and registries with opportunities to identify cost savings and efficiency improvements. Our results suggest that cancer registration involve substantial fixed costs and labor, and that partnership with other institutions is critical for the operation and sustainability of cancer registries in limited resource settings. Although we included registries from a variety of limited-resource areas, information from eight registries in four countries may not be large enough to capture all the potential differences among the registries in limited-resource settings.



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Estimating the cost of operating cancer registries: Experience in Colombia

Publication date: Available online 17 October 2016
Source:Cancer Epidemiology
Author(s): Esther de Vries, Constanza Pardo, Nelson Arias, Luis Eduardo Bravo, Edgar Navarro, Claudia Uribe, María Clara Yepez, Daniel Jurado, Luz Stella Garci, Marion Piñeros, Patrick Edwards, Maggie Cole Beebe, Florence Tangka, Sujha Subramanian
BackgroundMaintaining population-based registries requires adequate and sustained resources; however, to date there has been no systematic evaluation to identify the resource needs for cancer registration in most countries, including Colombia. A systematic assessment of the costs can quantify the funding required and identify processes to improve efficiency of cancer registries.MethodsThe Centers for Disease Control and Prevention's (CDC's) International Registry Costing Tool (IntRegCosting Tool) was tailored specifically for the Colombian registries and was used to collect resource use data from five regional population-based cancer registries: Barranquilla, Bucaramanga, Cali, Manizales, and Pasto. The registries provided cost data for the year 2013 and cancer cases corresponding to the year 2010.ResultsWe identified an almost threefold variation in the average cost per case (77,932 to 214,082 Colombian pesos or US $41 to US $113 in 2013) across the registries, but there were also substantial differences in data collection approaches, types of data collected, and activities performed. Cost per inhabitant varied between 95 and 415 Colombian pesos (US $0.05 to US $0.22). Between 20% and 45% of the total cost was due to fixed cost activities.ConclusionsThe detailed economic information presented in this study constitutes a valuable source of activity-based cost data that registries can use to compare operations, assess key factors that lead to differences in cost per case, and identify potential approaches to improve efficiencies. Furthermore, the knowledge gained from studying the Colombian registries can help inform the planning and operations of other registries in the region.



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