Sentinel lymph node biopsy for head and neck mucosal cancers - an update on the current evidence.

Sentinel lymph node biopsy for head and neck mucosal cancers - an update on the current evidence.

Oral Dis. 2016 Mar 7;

Authors: Green B, Blythe JN, Brennan PA

Abstract
Regional metastases are a prominent feature of mucosal-associated head and neck squamous cell carcinomas and are an important prognostic factor. Sentinel lymph node biopsy (SLNB) is one modality that has potential to add to the accuracy of neck staging, though it is currently not used as widely in the head and neck as it is in other areas such as breast cancer. We review the efficacy of SLNB in head and neck mucosal squamous cell carcinomas and provide an overview of current practice and include details of technical advances. This article is protected by copyright. All rights reserved.

PMID: 26948863 [PubMed - as supplied by publisher]

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An increased prevalence of self-reported allergic rhinitis in major Chinese cities from 2005 to 2011.

An increased prevalence of self-reported allergic rhinitis in major Chinese cities from 2005 to 2011.

Allergy. 2016 Mar 7;

Authors: Wang X, Zheng M, Lou H, Wang C, Zhang Y, Bo M, Ge S, Zhang N, Zhang L, Bachert C

Abstract
BACKGROUND: The prevalence of allergic rhinitis (AR) has increased worldwide in recent decades. The present study was conducted to investigate the prevalence of self-reported AR and profiles of AR-related comorbidities in the adult population of China over time.
METHODS: This study surveyed residents of 18 major cities in mainland China. Telephone interviews were conducted with study participants after sampling target telephone numbers by random digital dialing. The questions asked during telephone interviews were based on those included in validated questionnaires, and focused on topics regarding allergic rhinitis, non-allergic rhinitis, acute/chronic rhinosinusitis, asthma, and atopic dermatitis.
RESULTS: During 2011, a total of 47,216 telephone interviews were conducted, and the overall response rate was 77.5%. When compared with the AR prevalence in 11 cities surveyed in 2005, there was a significant increase in self-reported adult AR in eight of those cities (P < 0.01). In 2011, the standardized prevalence of self-reported adult AR in the 18 cities was 17.6%. The concentration of SO2 was positively correlated with the prevalence of AR (r = 0.504, P = 0.033). A multiple regression model showed that the absolute change in household yearly income was significantly associated with the change in prevalence of AR (R(2) = 0.68), after adjusting for PM10 , SO2 , NO2, temperature and humidity. The overall prevalences of NAR, ARS, CRS, asthma, and AD in the general population were 16.4%, 5.4%, 2.1%, 5.8%, and 14%, respectively.
CONCLUSION: During a 6-year period, there was a significant increase in the prevalence of self-reported AR in the general Chinese adult population. The incidence of AR being accompanied by rhinosinusitis, asthma or AD was significantly higher among individuals having self-reported AR compared with the general population. This article is protected by copyright. All rights reserved.

PMID: 26948849 [PubMed - as supplied by publisher]

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New technique for bloodless surgery to the scalp.

New technique for bloodless surgery to the scalp.

Br J Oral Maxillofac Surg. 2016 Mar 2;

Authors: Jolly K, Hammond D, Maher M, Evriviades D

PMID: 26948705 [PubMed - as supplied by publisher]

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Laryngeal dysplasia: a prospective cohort study of 70 patients.

Laryngeal dysplasia: a prospective cohort study of 70 patients.

Clin Otolaryngol. 2016 Mar 7;

Authors: Yeo JC, Connor KL, Adamson RM

Abstract
Laryngeal dysplasia is a poorly understood pre-malignant condition that requires diligent surveillance, to ensure timely diagnosis and optimal management. A dedicated laryngeal dysplasia clinic provides a platform for regular surveillance of these patients and for prospective data analysis. Our follow-up strategy is different to the recommendations from the ENT-UK consensus document on laryngeal dysplasia but appears to be a reasonable approach. The clinical appearance of the laryngeal lesion, histological grade of dysplasia and continual exposure to risk factors are factors in determining decision making for follow-up and re-biopsy. Multi-centre prospective collection of data and analysis of outcomes will provide evidence for best practice. This article is protected by copyright. All rights reserved.

PMID: 26948695 [PubMed - as supplied by publisher]

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A machine learning approach to the accurate prediction of multi-leaf collimator positional errors.

A machine learning approach to the accurate prediction of multi-leaf collimator positional errors.

Phys Med Biol. 2016 Mar 7;61(6):2514-2531

Authors: Carlson JN, Park JM, Park SY, Park JI, Choi Y, Ye SJ

Abstract
Discrepancies between planned and delivered movements of multi-leaf collimators (MLCs) are an important source of errors in dose distributions during radiotherapy. In this work we used machine learning techniques to train models to predict these discrepancies, assessed the accuracy of the model predictions, and examined the impact these errors have on quality assurance (QA) procedures and dosimetry. Predictive leaf motion parameters for the models were calculated from the plan files, such as leaf position and velocity, whether the leaf was moving towards or away from the isocenter of the MLC, and many others. Differences in positions between synchronized DICOM-RT planning files and DynaLog files reported during QA delivery were used as a target response for training of the models. The final model is capable of predicting MLC positions during delivery to a high degree of accuracy. For moving MLC leaves, predicted positions were shown to be significantly closer to delivered positions than were planned positions. By incorporating predicted positions into dose calculations in the TPS, increases were shown in gamma passing rates against measured dose distributions recorded during QA delivery. For instance, head and neck plans with 1%/2 mm gamma criteria had an average increase in passing rate of 4.17% (SD  =  1.54%). This indicates that the inclusion of predictions during dose calculation leads to a more realistic representation of plan delivery. To assess impact on the patient, dose volumetric histograms (DVH) using delivered positions were calculated for comparison with planned and predicted DVHs. In all cases, predicted dose volumetric parameters were in closer agreement to the delivered parameters than were the planned parameters, particularly for organs at risk on the periphery of the treatment area. By incorporating the predicted positions into the TPS, the treatment planner is given a more realistic view of the dose distribution as it will truly be delivered to the patient.

PMID: 26948678 [PubMed - as supplied by publisher]

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Proteomic profiling identifies the inorganic pyrophosphatase (PPA1) protein as a potential biomarker of metastasis in laryngeal squamous cell carcinoma.

Proteomic profiling identifies the inorganic pyrophosphatase (PPA1) protein as a potential biomarker of metastasis in laryngeal squamous cell carcinoma.

Amino Acids. 2016 Mar 7;

Authors: Bodnar M, Luczak M, Bednarek K, Szylberg L, Marszalek A, Grenman R, Szyfter K, Jarmuz-Szymczak M, Giefing M

Abstract
Relapse and metastasis are the main causes of unfavorable outcome in head and neck cancers. Whereas, understanding of the molecular background of these processes is far from being complete. Therefore, in this study we aimed to identify potential biomarker candidates of relapse and metastasis in laryngeal squamous cell carcinoma (LSCC) by combining the 2D electrophoresis based protein screen and immunohistochemical analysis of candidate proteins. We screened three groups of LSCC cell lines derived from primary tumors, recurrent tumors and metastases and identified seven proteins that differed significantly in relative abundance between the analyzed groups. Among the identified proteins were the heat shock proteins HSP60 and HSP70 that were significantly downregulated both in recurrences- and metastases-derived cell lines but not in primary tumor-derived cell lines. Moreover, we identified significant upregulation of the annexin V, calreticulin and the inorganic pyrophosphatase (PPA1) exclusively in the metastases-derived cell lines. As these upregulated proteins could potentially become novel biomarkers of metastasis, we have compared their abundance in primary tumor LSCC N(0) cases, primary tumor LSCC N(+) cases as well as in LSCC metastases N(+). Our results show an intense increase of cytoplasmic PPA1 abundance in the N(+) (p = 0.000042) compared to the N(0) group. In summary, we show a group of proteins deregulated in recurrences and metastases of LSCC. Moreover, we suggest the PPA1 protein as a potential new biomarker for metastasis in this cancer.

PMID: 26948660 [PubMed - as supplied by publisher]

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Maxillary expansion and maxillomandibular expansion for adult OSA: A systematic review and meta-analysis.

Maxillary expansion and maxillomandibular expansion for adult OSA: A systematic review and meta-analysis.

J Craniomaxillofac Surg. 2016 Feb 6;

Authors: Abdullatif J, Certal V, Zaghi S, Song SA, Chang ET, Gillespie MB, Camacho M

Abstract
OBJECTIVE: This study sought to systematically review the international literature for articles evaluating maxillary expansion and maxillomandibular expansion as treatments for obstructive sleep apnea (OSA) in adults and to perform a meta-analysis.
DATA SOURCES: Nine databases (including MEDLINE/PubMed).
REVIEW METHODS: Searches were performed through January 8, 2016. The PRISMA statement was followed.
RESULTS: Eight adult studies (39 patients) reported polysomnography and/or sleepiness outcomes. Six studies reported outcomes for maxillary expansion (36 patients), and the apnea-hypopnea index (AHI) decreased from a mean (M) ± standard deviation (SD) of 24.3 ± 27.5 [95% CI 15.3, 33.3] to 9.9 ± 13.7 [95% CI 5.4, 14.4] events/hr (relative reduction: 59.3%). Maxillary expansion improved lowest oxygen saturation (LSAT) from a M ± SD of 84.3 ± 8.1% [95% CI 81.7, 87.0] to 86.9 ± 5.6% [95% CI 85.1, 88.7]. Maxillomandibular expansion was reported in two studies (3 patients) and AHI decreased from a M ± SD of 47.53 ± 29.81 [95% CI -26.5 to 121.5] to 10.7 ± 3.2 [95% CI 2.8, 18.6] events/hr (relative reduction: 77.5%). Maxillomandibular expansion improved LSAT from a M ± SD of 76.7 ± 14.5% [95% CI 40.7, 112.7] to 89.3 ± 3.1 [95% CI 81.6, 97].
CONCLUSION: The current literature demonstrates that maxillary expansion can improve and maxillomandibular expansion can possibly improve AHI and LSAT in adults; however, given the paucity of studies, these remain open for additional research efforts.

PMID: 26948172 [PubMed - as supplied by publisher]

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Tinnitus Self-Efficacy and Other Tinnitus Self-Report Variables in Patients With and Without Post-Traumatic Stress Disorder.

Tinnitus Self-Efficacy and Other Tinnitus Self-Report Variables in Patients With and Without Post-Traumatic Stress Disorder.

Ear Hear. 2016 Mar 4;

Authors: Fagelson MA, Smith SL

Abstract
OBJECTIVE: Individuals with tinnitus and co-occurring psychological conditions typically rate their tinnitus as more disturbing than individuals without such comorbidities. Little is known about how tinnitus self-efficacy, or the confidence that individuals have in their abilities to successfully manage the effects of tinnitus, is influenced by mental or psychological health (PH) status. The purpose of this study was to examine the influence of psychological state on tinnitus perceptions and tinnitus self-efficacy in individuals with chronic tinnitus.
DESIGN: Observational study. Three groups (N = 199) were examined and included: (1) those with tinnitus without a concurrent psychological condition (tinnitus-only; n = 103), (2) those with tinnitus and concurrent PH condition other than post-traumatic stress disorder (PTSD; tinnitus + PH; n = 34), and (3) those with tinnitus and PTSD (tinnitus + PTSD; n = 62). The Self-Efficacy for Tinnitus Management Questionnaire (SETMQ) was administered. Responses on the SETMQ were compared among the groups, as well as to other indicators of tinnitus perception such as (1) the percentage of time tinnitus was audible (tinnitus awareness), (2) the percentage of time tinnitus was distressing/bothersome, (3) tinnitus loudness, (4) tinnitus handicap inventory scores, (5) subjective ratings of degree of hearing loss, and (6) subjective ratings of sound tolerance problems.
RESULTS: The tinnitus + PTSD group reported significantly poorer tinnitus self-efficacy levels on average than the tinnitus-only group on all SETMQ subscales and poorer self-efficacy levels than the tinnitus + PH group for most subscales (except for routine management and devices). Tinnitus self-efficacy levels were similar between the tinnitus + PH and tinnitus-only groups except for the emotional response subscale in which the tinnitus-only patients reported higher self-efficacy on average than both the other groups. Group differences were not seen for tinnitus loudness ratings nor for the amount of time individuals were aware of their tinnitus. Group differences were observed for the percentage of time tinnitus was distressing/bothersome, self-reported degree of hearing loss, sound tolerance problems ratings, and responses on the tinnitus handicap inventory (THI). In general, the group differences revealed patient ratings for the tinnitus-only group were least severe, followed by the tinnitus + PH group, and the tinnitus + PTSD group rated tinnitus effects as most severe. With all patient responses, the tinnitus + PTSD group was found to be significantly more affected by tinnitus than the tinnitus-only group; in some cases, the responses were similar between the tinnitus + PTSD and tinnitus + PH group and in other cases, responses were similar between the tinnitus + PH group and the tinnitus-only group.
CONCLUSIONS: Tinnitus self-efficacy, along with other self-assessed tinnitus characteristics, varied across groups distinguished by PH diagnoses. In general, individuals with tinnitus and concurrent PTSD reported significantly poorer tinnitus self-efficacy and more handicapping tinnitus effects when compared to individuals with other psychological conditions or those with tinnitus alone. The group differences highlighted the need to consider tinnitus self-efficacy in intervention strategies, particularly for patients with tinnitus and concurrent PTSD as the results reiterated the unique ability of PTSD to interact in powerful and disturbing ways with the tinnitus experience and with patients' coping ability.

PMID: 26950001 [PubMed - as supplied by publisher]

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Fractionated Stereotactic Radiotherapy for Facial Nerve Schwannomas.

Fractionated Stereotactic Radiotherapy for Facial Nerve Schwannomas.

J Neurol Surg B Skull Base. 2016 Feb;77(1):75-80

Authors: Shi W, Jain V, Kim H, Champ C, Jain G, Farrell C, Andrews DW, Judy K, Liu H, Artz G, Werner-Wasik M, Evans JJ

Abstract
Purpose Data on the clinical course of irradiated facial nerve schwannomas (FNS) are lacking. We evaluated fractionated stereotactic radiotherapy (FSRT) for FNS. Methods Eight consecutive patients with FNS treated at our institution between 1998 and 2011 were included. Patients were treated with FSRT to a median dose of 50.4 Gy (range: 46.8-54 Gy) in 1.8 or 2.0 Gy fractions. We report the radiographic response, symptom control, and toxicity associated with FSRT for FNS. Results The median follow-up time was 43 months (range: 10-75 months). All patients presented with symptoms including pain, tinnitus, facial asymmetry, diplopia, and hearing loss. The median tumor volume was 1.57 cc. On the most recent follow-up imaging, five patients were noted to have stable tumor size; three patients had a net reduction in tumor volume. Additionally, six patients had improvement in clinical symptoms, one patient had stable clinical findings, and one patient had worsened House-Brackmann grade due to cystic degeneration. Conclusion FSRT treatment of FNS results in excellent control of growth and symptoms with a small rate of radiation toxicity. Given the importance of maintaining facial nerve function, FSRT could be considered as a primary management modality for enlarging or symptomatic FNS.

PMID: 26949592 [PubMed]

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Memorial - Dr. Joseph C. Fratantoni.

Memorial - Dr. Joseph C. Fratantoni.

Artif Cells Nanomed Biotechnol. 2016 Mar 7;:1

Authors: Alayash AI

PMID: 26950293 [PubMed - as supplied by publisher]

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Individual tumor volume responses to short-course oxaliplatin-containing induction chemotherapy in locally advanced rectal cancer – Targeting the tumor for radiation sensitivity?

Publication date: Available online 8 March 2016
Source:Radiotherapy and Oncology
Author(s): Kjersti Flatmark, Marie G. Saelen, Knut H. Hole, Torveig W. Abrahamsen, Karianne G. Fleten, Helga H. Hektoen, Kathrine R. Redalen, Therese Seierstad, Svein Dueland, Anne H. Ree
BackgroundNeoadjuvant treatment of locally advanced rectal cancer (LARC) involves chemoradiotherapy (CRT), which may cause significant toxicity, and the potential role and sequential placement of neoadjuvant chemotherapy (NACT) relative to CRT is under debate.Patients and methodsIn a non-randomized study of 72 LARC patients, short-course oxaliplatin-containing NACT was administered prior to CRT. Tumor volumes were calculated from magnetic resonance images before and after NACT, and four weeks after CRT, and associations between tumor volume responses and outcome were analyzed. Additionally, the impact of oxaliplatin exposure on radiosensitivity was examined in colorectal carcinoma cell lines.ResultsAll tumors except one responded to NACT, with better responses in T3 than T4 cases, and 69/72 patients obtained additional tumor volume reduction after subsequent CRT. However, no associations were found between tumor volume reduction and long-term outcome. Of note, oxaliplatin-resistant cells were significantly more radiosensitive than the oxaliplatin-sensitive counterparts.ConclusionsOxaliplatin-containing NACT led to substantial tumor volume reduction with particularly good responses in T3 cases. NACT did not impede subsequent CRT response, and experimental results rather suggested enhanced radiosensitivity in oxaliplatin-exposed cells, encouraging studies to explore the administration of NACT prior to CRT. Data are still lacking to support omitting radiation in LARC management.



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Thyroid Hormones, Oxidative Stress, and Inflammation

Inflammation and oxidative stress (OS) are closely related processes, as well exemplified in obesity and cardiovascular diseases. OS is also related to hormonal derangement in a reciprocal way. Among the various hormonal influences that operate on the antioxidant balance, thyroid hormones play particularly important roles, since both hyperthyroidism and hypothyroidism have been shown to be associated with OS in animals and humans. In this context, the nonthyroidal illness syndrome (NTIS) that typically manifests as reduced conversion of thyroxine (T4) to triiodothyronine (T3) in different acute and chronic systemic conditions is still a debated topic. The pathophysiological mechanisms of this syndrome are reviewed, together with the roles of deiodinases, the enzymes responsible for the conversion of T4 to T3, in both physiological and pathological situations. The presence of OS indexes in NTIS supports the hypothesis that it represents a condition of hypothyroidism at the tissue level and not only an adaptive mechanism to diseases.

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The Immunology of Neuromyelitis Optica-Current Knowledge, Clinical Implications, Controversies and Future Perspectives.

The Immunology of Neuromyelitis Optica-Current Knowledge, Clinical Implications, Controversies and Future Perspectives.

Int J Mol Sci. 2016;17(3)

Authors: Jasiak-Zatonska M, Kalinowska-Lyszczarz A, Michalak S, Kozubski W

Abstract
Neuromyelitis optica (NMO) is an autoimmune, demyelinating disorder of the central nervous system (CNS) with typical clinical manifestations of optic neuritis and acute transverse myelitis attacks. Previously believed to be a variant of multiple sclerosis (MS), it is now considered an independent disorder which needs to be differentiated from MS. The discovery of autoantibodies against aquaporin-4 (AQP4-IgGs) changed our understanding of NMO immunopathogenesis and revolutionized the diagnostic process. AQP4-IgG is currently regarded as a specific biomarker of NMO and NMO spectrum disorders (NMOsd) and a key factor in its pathogenesis. Nevertheless, AQP4-IgG seronegativity in 10%-25% of NMO patients suggests that there are several other factors involved in NMO immunopathogenesis, i.e., autoantibodies against aquaporin-1 (AQP1-Abs) and antibodies against myelin oligodendrocyte glycoprotein (MOG-IgGs). This manuscript reviews current knowledge about NMO immunopathogenesis, pointing out the controversial issues and showing potential directions for future research. Further efforts should be made to broaden our knowledge of NMO immunology which could have important implications for clinical practice, including the use of potential novel biomarkers to facilitate an early and accurate diagnosis, and modern treatment strategies improving long-term outcome of NMO patients.

PMID: 26950113 [PubMed - as supplied by publisher]

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Car-driven regeneration protects liver from failure following tissue loss and bears therapeutic potential.

Car-driven regeneration protects liver from failure following tissue loss and bears therapeutic potential.

J Hepatol. 2016 Mar 3;

Authors: Tschuor C, Kachaylo E, Perparim L, Raptis DA, Linecker M, Tian Y, Herrmann U, Grabliauskaite K, Weber A, Columbano A, Graf R, Humar B, Clavien PA

Abstract
BACKGROUND & AIMS: Liver can recover following resection. If tissue loss is too excessive, however, liver failure will develop as is known from the Small-for-Size-Syndrome (SFSS). The molecular processes underlying liver failure are ill-understood. Here, we explored the role and the clinical potential of Nr1i3 (constitutive androstane receptor, Car) in liver failure following hepatectomy.
METHODS: Activators of Car, various hepatectomies, Car(-/-) mice, humanized CAR mice, human tissue and ex vivo liver slice cultures were used to study Car in the SFSS. Pathways downstream of Car were investigated by in vivo siRNA knockdown.
RESULTS: Excessive tissue loss causing liver failure is associated with deficient induction of Car. Re-activation of Car by an agonist normalizes all features associated with experimental SFSS. The beneficial effects of Car activation are relayed through Foxm1, an essential promoter of the hepatocyte cell cycle. Deficiency in the CAR-FOXM1 axis likewise is evident in human SFSS. Activation of human CAR mitigates SFSS in humanized CAR mice and improves the culture of human liver slices.
CONCLUSIONS: Impaired hepatic Car-Foxm1 signaling provides a first molecular characterization of liver that fails to recover after tissue loss. Our findings place deficient regeneration as a principal cause behind the SFSS and suggest CAR agonists may bear clinical potential against liver failure.
LAY ABSTRACT: The unique regenerative capacity of liver has its natural limits. Following too excessive tissue loss, such as through extended resection in the clinic, liver failure may develop. This entity is known as Small-for-Size Syndrome (SFSS) and represents the most frequent cause of death due to liver surgery. Here we show that deficient induction of the protein Car, a central regulator of liver function and growth, is a cause of liver failure following extended resection; re-activation of Car through pharmacological means is sufficient to prevent or rescue from the SFSS.

PMID: 26948495 [PubMed - as supplied by publisher]

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Astrocytic gliomas WHO grades II and III.

Astrocytic gliomas WHO grades II and III.

Handb Clin Neurol. 2016;134:345-60

Authors: Berger MS, Hervey-Jumper S, Wick W

Abstract
World Health Organization grades II and III lower-grade astrocytomas are a challenging area in neuro-oncology. One the one hand, for proper diagnosis, the analysis of molecular factors, especially mutation status of isocitrate dehydrogenase and 1p/19q status in the tumor status needs to be done in addition to classical neuropathology. Further, the high clinical and prognostic value of a maximal safe resection requires a profound knowledge of presurgical diagnosis and surgical as well as imaging techniques to ensure optimal outcome for patients. Also medical treatment may be more intensive than previously believed, with randomized trials providing evidence for a benefit in overall survival by combined chemoradiation versus radiation alone. A critical problem concerns the considerable undesirable effects of therapeutic interventions on long-term health-related quality of life, cognitive and functional outcome as well as future developments in this still difficult disease that will need to be addressed in future trials.

PMID: 26948365 [PubMed - in process]

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Molecular classification of gliomas.

Molecular classification of gliomas.

Handb Clin Neurol. 2016;134:97-120

Authors: Masui K, Mischel PS, Reifenberger G

Abstract
The identification of distinct genetic and epigenetic profiles in different types of gliomas has revealed novel diagnostic, prognostic, and predictive molecular biomarkers for refinement of glioma classification and improved prediction of therapy response and outcome. Therefore, the new (2016) World Health Organization (WHO) classification of tumors of the central nervous system breaks with the traditional principle of diagnosis based on histologic criteria only and incorporates molecular markers. This will involve a multilayered approach combining histologic features and molecular information in an "integrated diagnosis". We review the current state of diagnostic molecular markers for gliomas, focusing on isocitrate dehydrogenase 1 or 2 (IDH1/IDH2) gene mutation, α-thalassemia/mental retardation syndrome X-linked (ATRX) gene mutation, 1p/19q co-deletion and telomerase reverse transcriptase (TERT) promoter mutation in adult tumors, as well as v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and H3 histone family 3A (H3F3A) aberrations in pediatric gliomas. We also outline prognostic and predictive molecular markers, including O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and discuss the potential clinical relevance of biologic glioblastoma subtypes defined by integration of multiomics data. Commonly used methods for individual marker detection as well as novel large-scale DNA methylation profiling and next-generation sequencing approaches are discussed. Finally, we illustrate how advances in molecular diagnostics affect novel strategies of targeted therapy, thereby raising new challenges and identifying new leads for personalized treatment of glioma patients.

PMID: 26948350 [PubMed - in process]

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Evaluation of glioblastomas and lymphomas with whole-brain CT perfusion: Comparison between a delay-invariant singular-value decomposition algorithm and a Patlak plot.

Evaluation of glioblastomas and lymphomas with whole-brain CT perfusion: Comparison between a delay-invariant singular-value decomposition algorithm and a Patlak plot.

J Neuroradiol. 2016 Mar 2;

Authors: Hiwatashi A, Togao O, Yamashita K, Kikuchi K, Yoshimoto K, Mizoguchi M, Suzuki SO, Yoshiura T, Honda H

Abstract
OBJECTIVE: Correction of contrast leakage is recommended when enhancing lesions during perfusion analysis. The purpose of this study was to assess the diagnostic performance of computed tomography perfusion (CTP) with a delay-invariant singular-value decomposition algorithm (SVD+) and a Patlak plot in differentiating glioblastomas from lymphomas.
MATERIALS AND METHODS: This prospective study included 17 adult patients (12 men and 5 women) with pathologically proven glioblastomas (n=10) and lymphomas (n=7). CTP data were analyzed using SVD+ and a Patlak plot. The relative tumor blood volume and flow compared to contralateral normal-appearing gray matter (rCBV and rCBF derived from SVD+, and rBV and rFlow derived from the Patlak plot) were used to differentiate between glioblastomas and lymphomas. The Mann-Whitney U test and receiver operating characteristic (ROC) analyses were used for statistical analysis.
RESULTS: Glioblastomas showed significantly higher rFlow (3.05±0.49, mean±standard deviation) than lymphomas (1.56±0.53; P<0.05). There were no statistically significant differences between glioblastomas and lymphomas in rBV (2.52±1.57 vs. 1.03±0.51; P>0.05), rCBF (1.38±0.41 vs. 1.29±0.47; P>0.05), or rCBV (1.78±0.47 vs. 1.87±0.66; P>0.05). ROC analysis showed the best diagnostic performance with rFlow (Az=0.871), followed by rBV (Az=0.771), rCBF (Az=0.614), and rCBV (Az=0.529).
CONCLUSION: CTP analysis with a Patlak plot was helpful in differentiating between glioblastomas and lymphomas, but CTP analysis with SVD+ was not.

PMID: 26947963 [PubMed - as supplied by publisher]

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Mutation in the caveolin-3 gene causes asymmetrical distal myopathy.

Mutation in the caveolin-3 gene causes asymmetrical distal myopathy.

Neuropathology. 2016 Mar 7;

Authors: Chen J, Zeng W, Han C, Wu J, Zhang H, Tong X

Abstract
Mutations in the gene encoding caveolin-3 (CAV3) can cause a broad spectrum of clinical phenotypes, including limb girdle muscular dystrophy, rippling muscle disease, distal myopathy (MD), idiopathic persistent elevation of serum creatine kinase and cardiomyopathy. MD is a relatively rare subtype of caveolinopathy. Here, we report a sporadic case of a middle-aged female Chinese patient with MD in which a CAV3 mutation was identical to that previously reported in cases of rippling muscle disease. T1-weighted enhanced skeletal muscle MRI of the lower limbs showed an abnormal signal in the distal and proximal muscles. A muscle biopsy revealed moderate dystrophic changes, and immunohistochemical staining showed reduced CAV-3 expression in the plasmalemma. Genetic analysis revealed a heterozygous c.136G > A (p.Ala46Thr) CAV3 mutation that appeared to be de novo because it was absent from the patient's parents. This study suggested that the CAV3 c.136G > A (p.Ala46Thr) mutation can cause MD as well as different phenotypes in different individuals, suggesting that additional unknown loci must affect the disease phenotypes.

PMID: 26947586 [PubMed - as supplied by publisher]

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In vivo imaging reveals rapid astrocyte depletion and axon damage in a model of neuromyelitis optica-related pathology.

Related Articles

In vivo imaging reveals rapid astrocyte depletion and axon damage in a model of neuromyelitis optica-related pathology.

Ann Neurol. 2016 Mar 6;

Authors: Herwerth M, Kalluri SR, Srivastava R, Kleele T, Kenet S, Illes Z, Merkler D, Bennett JL, Misgeld T, Hemmer B

Abstract
OBJECTIVE: Neuromyelitis optica (NMO) is an autoimmune disease of the CNS, which resembles multiple sclerosis (MS). NMO differs from MS, however, in the distribution and histology of neuroinflammatory lesions and shows a more aggressive clinical course. Moreover, the majority of NMO patients carry IgG autoantibodies against aquaporin-4 (AQP4), an astrocytic water channel. Antibodies against AQP4 can damage astrocytes via complement, but NMO histopathology also shows demyelination, and - importantly - axon injury, which may determine permanent deficits following NMO relapses. The dynamics of astrocyte injury in NMO and the mechanisms by which toxicity spreads to axons are not understood.
METHODS: Here, we establish in vivo imaging of the spinal cord, one of the main sites of NMO pathology, as a powerful tool to study the formation of experimental NMO-related lesions caused by human AQP4 antibodies in mice.
RESULTS: We found that human AQP4 antibodies caused acute astrocyte depletion with initial oligodendrocyte survival. Within two hours of antibody application, we observed secondary axon injury in the form of progressive swellings. Astrocyte toxicity and axon damage were dependent on AQP4 antibody concentration and complement, specifically C1q.
INTERPRETATION: In vivo imaging of the spinal cord reveals the swift development of NMO-related acute axon injury following AQP4 antibody-mediated astrocyte depletion. This approach will be useful in studying the mechanisms underlying the spread of NMO pathology beyond astrocytes, as well as in evaluating potential neuroprotective interventions. This article is protected by copyright. All rights reserved.

PMID: 26946517 [PubMed - as supplied by publisher]

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A Preclinical Model for ERα-Positive Breast Cancer Points to the Epithelial Microenvironment as Determinant of Luminal Phenotype and Hormone Response.

A Preclinical Model for ERα-Positive Breast Cancer Points to the Epithelial Microenvironment as Determinant of Luminal Phenotype and Hormone Response.

Cancer Cell. 2016 Mar 1;

Authors: Sflomos G, Dormoy V, Metsalu T, Jeitziner R, Battista L, Scabia V, Raffoul W, Delaloye JF, Treboux A, Fiche M, Vilo J, Ayyanan A, Brisken C

Abstract
Seventy-five percent of breast cancers are estrogen receptor α positive (ER(+)). Research on these tumors is hampered by lack of adequate in vivo models; cell line xenografts require non-physiological hormone supplements, and patient-derived xenografts (PDXs) are hard to establish. We show that the traditional grafting of ER(+) tumor cells into mammary fat pads induces TGFβ/SLUG signaling and basal differentiation when they require low SLUG levels to grow in vivo. Grafting into the milk ducts suppresses SLUG; ER(+) tumor cells develop, like their clinical counterparts, in the presence of physiological hormone levels. Intraductal ER(+) PDXs are retransplantable, predictive, and appear genomically stable. The model provides opportunities for translational research and the study of physiologically relevant hormone action in breast carcinogenesis.

PMID: 26947176 [PubMed - as supplied by publisher]

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Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies.

Related Articles

Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies.

Nutr Metab Cardiovasc Dis. 2015 Jul;25(7):623-34

Authors: Asemi Z, Saneei P, Sabihi SS, Feizi A, Esmaillzadeh A

Abstract
AIMS: This systematic review and meta-analysis of observational studies was conducted to summarize the evidence on the association between calcium intake and mortality.
METHODS AND RESULTS: PubMed, Institute for Scientific Information (ISI) (Web of Science), SCOPUS, SciRUS, Google Scholar, and Excerpta Medica dataBASE (EMBASE) were searched to identify related articles published through May 2014. We found 22 articles that assessed the association between total, dietary, and supplementary intake with mortality from all-causes, cardiovascular disease (CVD), and cancer. Findings from this meta-analysis revealed no significant association between total and dietary calcium intake and mortality from all-causes, CVD, and cancer. Subgroup analysis by the duration of follow-up revealed a significant positive association between total calcium intake and CVD mortality for cohort studies with a mean follow-up duration of >10 years (relative risk (RR): 1.35; 95% confidence interval (CI): 1.09-1.68). A significant inverse association was seen between dietary calcium intake and all-cause (RR: 0.84; 95% CI: 0.70-1.00) and CVD mortality (RR: 0.88; 95% CI: 0.78-0.99) for studies with a mean follow-up duration of ≤10 years. Although supplemental calcium intake was not associated with CVD (RR: 0.95; 95% CI: 0.82-1.10) and cancer mortality (RR: 1.22; 95% CI: 0.81-1.84), it was inversely associated with the risk of all-cause mortality (RR: 0.91; 95% CI: 0.88-0.94).
CONCLUSIONS: We found a significant relationship between the total calcium intake and an increased risk of CVD mortality for studies with a long follow-up time and a significant protective association between dietary calcium intake and all-cause and CVD mortality for studies with a mean follow-up of ≤10 years. Supplemental calcium intake was associated with a decreased risk of all-cause mortality.

PMID: 25912278 [PubMed - indexed for MEDLINE]

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Proteomic insights into the functional basis for the response regulator DrRRA of Deinococcus radiodurans

10.3109/09553002.2016.1150618<br/>Liangyan Wang

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Escitalopram attenuates β-amyloid-induced tau hyperphosphorylation in primary hippocampal neurons through the 5-HT1A receptor mediated Akt/GSK-3β pathway.

Escitalopram attenuates β-amyloid-induced tau hyperphosphorylation in primary hippocampal neurons through the 5-HT1A receptor mediated Akt/GSK-3β pathway.

Oncotarget. 2016 Feb 29;

Authors: Wang YJ, Ren QG, Gong WG, Wu D, Tang X, Li XL, Wu FF, Bai F, Xu L, Zhang ZJ

Abstract
Tau hyperphosphorylation is an important pathological feature of Alzheimer's disease (AD). To investigate whether escitalopram could inhibit amyloid-β (Aβ)-induced tau hyperphosphorylation and the underlying mechanisms, we treated the rat primary hippocampal neurons with Aβ1-42 and examined the effect of escitalopram on tau hyperphosphorylation. Results showed that escitalopram decreased Aβ1-42-induced tau hyperphosphorylation. In addition, escitalopram activated the Akt/GSK-3β pathway, and the PI3K inhibitor LY294002 blocked the attenuation of tau hyperphosphorylation induced by escitalopram. Moreover, the 5-HT1A receptor agonist 8-OH-DPAT also activated the Akt/GSK-3β pathway and decreased Aβ1-42-induced tau hyperphosphorylation. Furthermore, the 5-HT1A receptor antagonist WAY-100635 blocked the activation of Akt/GSK-3β pathway and the attenuation of tau hyperphosphorylation induced by escitalopram. Finally, escitalopram improved Aβ1-42 induced impairment of neurite outgrowth and spine density, and reversed Aβ1-42 induced reduction of synaptic proteins. Our results demonstrated that escitalopram attenuated Aβ1-42-induced tau hyperphosphorylation in primary hippocampal neurons through the 5-HT1A receptor mediated Akt/GSK-3β pathway.

PMID: 26950279 [PubMed - as supplied by publisher]

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Effect of HMGCR genetic variation on neuroimaging biomarkers in healthy, mild cognitive impairment and Alzheimer's disease cohorts.

Effect of HMGCR genetic variation on neuroimaging biomarkers in healthy, mild cognitive impairment and Alzheimer's disease cohorts.

Oncotarget. 2016 Feb 29;

Authors: Cao L, Wang HF, Tan L, Sun FR, Tan MS, Tan CC, Jiang T, Yu JT, Tan L, Alzheimer's Disease Neuroimaging Initiative

Abstract
Alzheimer's disease (AD) has become a considerable public health issue. The mechanisms underlying AD onset and progression remain largely unclear. 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is a strong functional AD candidate gene because it encodes part of the statin-binding domain of the enzyme, which serves as the rate-limiting step in cholesterol synthesis in all mammalian cells. Here, we evaluated the potential role of HMGCR (rs3846662) in AD-related pathology by assessing neuroimaging biomarkers. We enrolled in 812 subjects from the Alzheimer's disease Neuroimaging Initiative dataset. In general, it is possible that HMGCR (rs3846662) could be involved in preventing the atrophy of right entorhinal (P=0.03385) and left hippocampus (P=0.01839) in the follow-up research of two years. What's more, it lowered the drop rate of glucose metabolism in right temporal. We then further validated them in the AD, mild cognitive impairment (MCI), normal control (NC) sub-groups. All the results in the MCI groups confirmed the association. The results of our study indicated that HMGCR (rs3846662) plays a vital role in AD pathology mainly by influencing brain structure and glucose metabolism during AD progression.

PMID: 26950278 [PubMed - as supplied by publisher]

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High circulating activin A level is associated with tumor progression and predicts poor prognosis in lung adenocarcinoma.

High circulating activin A level is associated with tumor progression and predicts poor prognosis in lung adenocarcinoma.

Oncotarget. 2016 Feb 29;

Authors: Hoda MA, Rozsas A, Lang E, Klikovits T, Lohinai Z, Torok S, Berta J, Bendek M, Berger W, Hegedus B, Klepetko W, Renyi-Vamos F, Grusch M, Dome B, Laszlo V

Abstract
Activin A (ActA)/follistatin (FST) signaling has been shown to be deregulated in different tumor types including lung adenocarcinoma (LADC). Here, we report that serum ActA protein levels are significantly elevated in LADC patients (n=64) as compared to controls (n=46, p=0.015). ActA levels also correlated with more advanced disease stage (p<0.0001) and T (p=0.0035) and N (p=0.0002) factors. M1 patients had significantly higher ActA levels than M0 patients (p<0.001). High serum ActA level was associated with poor overall survival (p<0.0001) and was confirmed as an independent prognostic factor (p=0.004). Serum FST levels were increased only in female LADC patients (vs. female controls, p=0.031). Two out of five LADC cell lines secreted biologically active ActA, while FST was produced in all of them. Transcripts of both type I and II ActA receptors were detected in all five LADC cell lines. In conclusion, our study does not only suggest that measuring blood ActA levels in LADC patients might improve the prediction of prognosis, but also indicates that this parameter might be a novel non-invasive biomarker for identifying LADC patients with organ metastases.

PMID: 26950277 [PubMed - as supplied by publisher]

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High LEF1 expression predicts adverse prognosis in chronic lymphocytic leukemia and may be targeted by ethacrynic acid.

High LEF1 expression predicts adverse prognosis in chronic lymphocytic leukemia and may be targeted by ethacrynic acid.

Oncotarget. 2016 Feb 29;

Authors: Wu W, Zhu H, Fu Y, Shen W, Miao K, Hong M, Xu W, Fan L, Young KH, Liu P, Li J

Abstract
Aberrant activation of lymphoid enhancer-binding factor-1 (LEF1) has been identified in several cancers, including chronic lymphocytic leukemia (CLL). As a key transcription factor of the Wnt/β-catenin pathway, LEF1 helps to regulate important genes involved in tumor cell death mechanisms. In this study, we determined LEF1 gene expression levels in CLL (n = 197) and monoclonal B-cell lymphocytosis (MBL) (n = 6) patients through real-time RT-PCR. LEF1 was significantly up-regulated in both MBL and CLL patients compared with normal B cells. Treatment-free survival (TFS) time and overall survival (OS) time were much longer in CLL patients with low LEF1 expression than in those with high LEF1 levels. Furthermore, Wnt inhibitor ethacrynic acid (EA) induced both apoptosis and necroptosis in primary CLL cells. EA also enhanced the cytotoxicity of both fludarabine and cyclophosphamide against CLL cells in vitro. Finally, we demonstrated that EA functions by inhibiting the recruitment of LEF1 to DNA promoters and restoring cylindromatosis (CYLD) expression in CLL cells. Our results showed, for the first time, that high LEF1 expression is associated with poor survival for CLL patients. Combined with other chemotherapeutic drugs, EA may be a promising therapeutic agent for CLL.

PMID: 26950276 [PubMed - as supplied by publisher]

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Angiogenesis in NSCLC: is vessel co-option the trunk that sustains the branches?

Angiogenesis in NSCLC: is vessel co-option the trunk that sustains the branches?

Oncotarget. 2016 Feb 29;

Authors: Coelho AL, Gomes MP, Catarino RJ, Rolfo C, Lopes AM, Medeiros RM, Araújo AM

Abstract
The critical role of angiogenesis in tumor development makes its inhibition a valuable new approach in therapy, rapidly making anti-angiogenesis a major focus in research. While the VEGF/VEGFR pathway is the main target of the approved anti-angiogenic molecules in NSCLC treatment, the results obtained are still modest, especially due to resistance mechanisms. Accumulating scientific data show that vessel co-option is an alternative mechanism to angiogenesis during tumor development in well-vascularized organs such as the lungs, where tumor cells highjack the existing vasculature to obtain its blood supply in a non-angiogenic fashion. This can explain the low/lack of response to current anti-angiogenic strategies. The same principle applies to lung metastases of other primary tumors. The exact mechanisms of vessel co-option need to be further elucidated, but it is known that the co-opted vessels regress by the action of Angiopoietin-2 (Ang-2), a vessel destabilizing cytokine expressed by the endothelial cells of the pre-existing mature vessels. In the absence of VEGF, vessel regression leads to tumor cell loss and hypoxia, with a subsequent switch to a neoangiogenic phenotype by the remaining tumor cells. Unravelling the vessel co-option mechanisms and involved players may be fruitful for numerous reasons, and the particularities of this form of vascularization should be carefully considered when planning anti-angiogenic interventions or designing clinical trials for this purpose. In view of the current knowledge, rationale for therapeutic approaches of dual inhibition of Ang-2 and VEGF are swiftly gaining strength and may serve as a launchpad to more successful NSCLC anti-vascular treatments.

PMID: 26950275 [PubMed - as supplied by publisher]

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Covered Stents versus Uncovered Stents for Unresectable Malignant Biliary Strictures: A Meta-Analysis

Aim. To summarize the covered or uncovered SEMS for treatment of unresectable malignant distal biliary obstruction, comparing the stent patency, patient survival, and incidence of adverse events between the two SEMSs. Methods. The meta-analysis search was performed independently by two of the authors, using MEDLINE, EMBASE, OVID, and Cochrane databases on all studies between 2010 and 2015. Pooled effect was calculated using either the fixed or the random effects model. Results. Statistics shows that there is no difference between SEMSs in the hazard ratio for patient survival (HR 1.04; 95% CI, 0.92–1.17; ) and stent patency (HR 0.87, 95% CI: 0.58 to 1.30, ). However, incidence of adverse events (OR: 0.74, 95% CI: 0.57 to 0.97, ) showed significant different results in the covered SEMS, with dysfunctions events (OR: 0.75, 95% CI: 0.56 to 1.00, ) playing a more important role than complications (OR: 0.87, 95% CI: 0.58 to 1.30, ). Conclusions. Covered SEMS group had lower incidence of adverse events. There is no significant difference in dysfunctions, but covered SEMS trends to be better, with no difference in stent patency, patient survival, and complications.

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Associations between Milk and Egg Allergens and the HLA-DRB1/DQ Polymorphism: A Bioinformatics Approach

Background: Little is known about the associations between human leukocyte antigens (HLAs) and food allergies. Our aim was to analyze the associations between the HLA class II polymorphism and food allergy using bioinformatics. Methods: A two-step algorithm was developed which mimics the food allergen processing in the human body. In the first step, the allergen is digested by pepsin, trypsin and chymotrypsin. In the second step, the digested fragments bind to the most frequent 12 HLA-DRB1 and 5 HLA-DQ alleles, and the binding affinities are predicted. Results: The algorithm was applied to 13 well-known milk and egg allergens. The predicted HLA binders were compared to known T-cell and IgE epitopes originating from the same allergens, and 77% of them were found to overlap. We found that the peptides generated from milk allergens bind to DRB1*01:01, DQ7 and DQ8 but not to DRB1*03:01, DRB1*04:04, DRB1*12:01 and DRB1*15:01. The peptides generated from egg allergens bind to DRB1*01:01, DQ4, DQ7 and DQ8 but not to DRB1*03:01, DRB1*04:04 and DRB1*12:01. They bind to all the DQs studied. The alleles that bind to allergen peptides could be considered as susceptible to the particular allergy and the nonbinding alleles as protective. Conclusions: The alleles DRB1*01:01, DQ7 and DQ8 are considered as susceptible to cow's milk allergy and DRB1*03:01, DRB1*04:04, DRB1*12:01 and DRB1*15:01 as protective. The alleles DRB1*01:01, DQ4, DQ7 and DQ8 are considered as susceptible to egg allergy and DRB1*03:01, DRB1*04:04 and DRB1*12:01 as protective. Protective DQs against egg allergy were not revealed in this study.
Int Arch Allergy Immunol 2016;169:33-39

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Fractionation of Source Materials Leads to a High Reproducibility of the SQ House Dust Mite SLIT-Tablets

Background: The production of house dust mite (HDM) allergen products for allergy immunotherapy has traditionally been based on purified mite bodies or whole-mite culture, which are quite different source materials with a limited possibility for adjusting the chemical composition. The SQ HDM SLIT-tablet is a fast-dissolving pharmaceutical formulation that has been developed for sublingual immunotherapy (SLIT) of HDM respiratory allergic disease. Objective: The objective of the present study was to establish a process for the production of drug substances for the SQ HDM SLIT-tablet offering a high reproducibility and independent control of the major allergens. Methods: Process controls were documented in a comprehensive process parameter qualification. The analyses comprised composition by crossed immunoelectrophoresis, protein content by BCA, total IgE binding potency by Centaur assay, quantitative major allergen determination by radial immunodiffusion and ELISA, and the ranking of emPAI scores generated by mass spectrometry. Results: Analysis of 20 batches of final product yielded a normalized mean and standard deviation for IgE binding potency of 100 ± 4.5. The standard deviation in the contents of Der f 1 and Der p 1 were correspondingly 11.9 and 6.1, whereas the variation in the group 2 major allergen content was 6.4. All measured 95% confidence limits between batches were less than 12%. Conclusions: The production process for the SQ HDM SLIT-tablet based on the separation of source material into four fractions each enriched in one major allergen enables precise adjustment of the relative major allergen content and high reproducibility of the final product.
Int Arch Allergy Immunol 2016;169:23-32

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Increased Levels of Interleukin-33 and Thymic Stromal Lymphopoietin in Exhaled Breath Condensate in Chronic Bronchial Asthma

Background: Epithelium-derived cytokines such as thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33 are important contributors to inflammation in asthma. Exhaled breath condensate (EBC) is a noninvasive method used to assess the inflammation of airways. Our aim was to assess the levels of TSLP, IL-25, IL-33, and its receptor ST2l/IL-1 R4 in EBC in patients with asthma and to correlate these with serum levels and asthma control. Methods: EBC and serum levels of TSLP, IL-25, IL-33, and ST2l/IL-1 R4 were measured in 44 patients with chronic bronchial asthma (14 in the uncontrolled phase) and 19 healthy control participants. Results: EBC levels of IL-33 and TSLP and serum levels of IL-33 were statistically higher in patients with asthma than in controls. IL-25 and ST2l/IL-1 R4 were present in EBC at barely detectable levels and were not analyzed. The EBC and serum levels of all studied mediators did not differ between controlled and uncontrolled asthma patients, except for the serum level of ST2l/IL-1 R4, which was higher in uncontrolled asthma. There were no correlations between serum and EBC levels of TSLP and IL-33 or between either serum and EBC levels and the forced expiratory volume in 1 s or the total IgE level. Conclusions: Higher levels of IL-33 and TSLP in EBC provide evidence supporting a role for these mediators in asthma. Their levels do not discriminate between controlled and uncontrolled asthma. The local reaction within the epithelium is independent of the systemic reaction.
Int Arch Allergy Immunol 2016;169:51-56

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Food Sensitization in Medically Resistant Chronic Rhinosinusitis with or without Nasal Polyposis

Background: Nasal polyposis is a common nasal mass with unknown etiology. It has been assumed that allergy predisposes to polyp formation. Our objective was to compare the prevalence of food sensitization in medically resistant chronic rhinosinusitis patients with or without nasal polyposis. Methods: One hundred and fifty-five patients who fulfilled the inclusion and exclusion criteria were incorporated into this study. The results of their total serum IgE and food-specific IgE levels were examined. Results: The average age was 33 years (± 13) with 96 males and 59 females. The percentage of patients in each group that had a positive result for at least one tested allergen was 84% (88 patients in the sinusitis without polyposis group and 42 patients in nasal polyposis group). Patients without nasal polyposis reacted to an average of 4.6 foodstuffs, whereas patients with nasal polyposis reacted to 4.1. Egg white, sheefish and cherry were the most common type of sensitized food. There were no significant differences in the prevalence, type, number of positive food allergens and class level between the two groups. Conclusions: Food sensitization is common in medically resistant chronic rhinosinusitis. Since food sensitization prevalence, type and severity do not significantly differ between the two groups studied, food atopy is unlikely to be a major factor in nasal polyposis pathogenesis.
Int Arch Allergy Immunol 2016;169:40-44

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Immunological Characterization of Dutch Sesame Seed-Allergic Patients

Background: Sesame seed is an allergen of growing importance worldwide. However, knowledge of the clinically relevant sesame allergen and its cross-reactivity with homologous allergens is limited. The aim of this study was the immunological characterization of Dutch sesame seed-allergic patients and evaluation of cross-reactivity between sesame seed, tree nut and pollen allergens using different sources of allergen extracts. Methods: Six patients with a medical history of sesame seed allergy were included, i.e. 5 with an anaphylactic reaction and 1 with an oral allergy syndrome (OAS). The immunological background of the sesame seed and tree nut IgE sensitization was characterized with Western blotting and a basophil activation test (BAT). The major sesame allergen was identified by nanoLC-MS/MS. Cross-reactivity was measured using an immuno-inhibition assay with the Phadia ImmunoCAP system. Results: Oleosin was identified as the major allergen for the 5 patients with an anaphylactic reaction to sesame seed, but no cross-reactivity between sesame and tree nut proteins was observed. For the patient with OAS, IgE specific to oleosin was not detected but cross-reactivity between sesame seed and tree nut proteins was observed. The BAT and ImmunoCAP inhibition test added value to the clinical and immunological characterization of sesame seed-sensitized patients, distinguishing relevant and non-relevant sensitizations. Conclusions: Our immunological approach enabled us to fully characterize the sensitization pattern of 6 sesame seed-allergic patients. The different protein composition of commercially available allergen extracts influences the outcomes of the immunological assays and thus also the diagnosis to a large extent.
Int Arch Allergy Immunol 2016;169:13-22

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The ADAPAR Birth Cohort Study: Food Allergy Results at Five Years and New Insights

Background: Although food allergy (FA) is often a transient condition during childhood, when and in whom FA will resolve can be affected by many factors. In this study, we analyzed the data at 5 years on 33 children diagnosed with FA in the ADAPAR (Adana Pediatric Allergy Research) birth cohort study in southern Turkey. Methods: Thirty-three infants detected as having FA at the end of their first year in the ADAPAR study were assessed every 6 months until the age of 5 years. Each follow-up included a clinical examination, questionnaire, blood sampling and a skin-prick test. Results: Culprit allergens were cow's milk (n = 20), eggs (n = 17), chicken meat (n = 1) and bananas (n = 1). Of the 17 patients with egg allergy, 14 developed complete tolerance and 1 developed partial tolerance (i.e. tolerance to baked food). Of the 20 patients with milk allergy, complete tolerance was observed in 16 and partial tolerance in 1. The mean age of tolerance to egg was 22.4 ± 7.5 months and to cow's milk, it was 20.9 ± 1.1 months. Complete tolerance developed in 1 case allergic to chicken meat and in 1 case allergic to banana. Other allergic conditions were also determined: allergic rhinitis in 27.2%, atopic dermatitis in 21.2%, asthma in 9%, urticaria in 9% and drugs in 9%. Conclusions: Our results confirm early and high tolerance rates before school age in children with food allergies that started in infancy. This will help pediatricians to give more informed advice to parents of infants with cow's milk or hen's egg allergy.
Int Arch Allergy Immunol 2016;169:57-61

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Proven Non-β-Lactam Antibiotic Allergy in Children

Background: Parallel to the increasing use of non-β-lactam (NBL) antibiotics, allergic reactions to this drug group seem to increase. Data about NBL antibiotic hypersensitivity in children are limited. The aim of this study is to evaluate characteristic reactions to NBL antibiotics in children. Method: Patients with suspected NBL allergy were assessed between 2011 and 2015. Characteristics of the reactions and results of skin and drug provocation tests (DPTs) were recorded. Results: In total, 96 patients aged 75.15 ± 56.77 months (range: 3-208) were assessed. Clarithromycin (63.6%) was the most common cause of reactions reported. After ingestion of NBL antibiotics, maculopapular rash, urticaria/angioedema and anaphylaxis presented in 48.9, 40.7 and 10.4% of the patients, respectively. Tests were performed in 85 patients. Intradermal tests were positive in 3 patients (clarithromycin, ciprofloxacin and cotrimoxazole) and DPT was positive in 1 patient (clarithromycin). Eleven patients could not be tested. Seven patients had severe anaphylaxis, and 4 patients with urticaria/angioedema had to take their medications at the time of the reaction so desensitization was performed. When only patients confirmed by tests were evaluated, NBL allergy was 4.7% (4/85) in our study group. However, when patients who could not be tested, but were regarded as suffering from drug hypersensitivity according to clinical findings, were included, the frequency of NBL allergy was 15.6% (15/96). Conclusion: Most of the children with suspected NBL do not have true hypersensitivity. The frequency of confirmed hypersensitivity is low, and thus a detailed history should be taken from patients with suspected NBL hypersensitivity and DPTs should be performed in patients without contraindications.
Int Arch Allergy Immunol 2016;169:45-50

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No such thing as 'parametrized deficiency' in the left periphery

Some embedded finite domains in English resist main clause phenomena (MCP). The incompatibility of MCP with these domains applies to argument fronting, among others. In contrast, clitic left dislocation (CLLD) in Romance has a wider distribution. A number of authors have argued that the restricted distribution of English MCP follows from a structural deficiency of the English left periphery (LP). To account for the wider availability of CLLD in the Romance LP, it is proposed that the structural deficiency of the LP varies parametrically. This article challenges the appeal to parametric variation to account for the distribution of MCP. We show that PP preposing and infinitival TP preposing in French share the syntactic properties and distribution of English movements falling under MCP.

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L'opposition massif-comptable au niveau lexical et supra-lexical

A ce jour, la question de la localisation de l'opposition massif/comptable, soit au niveau du lexique (e.g. Nicolas 2002, Cheng et al. 2008), soit exclusivement au niveau de la syntaxique (Borer 2005, Bale & Barner 2009), continue de susciter de vifs débats. Sur le sujet, la flexibilité de l'opposition (la possibilité d'utiliser bon nombre de mots, moyennant le contexte adéquat, dans une syntaxe tantôt massive, tantôt comptable) est d'une importance cruciale (cf. Pelletier 2012). Dans la présente contribution, nous revisitons cette ancienne question, en y jetant un regard neuf, original à plus d'un titre. Sur la base de trois études de corpus, ainsi que d'une enquête d'acceptabilité, nous examinons le caractère flexible de 92 items lexicaux en français, afin d'identifier les facteurs (lexicaux, sémantiques, pragmatiques) influençant la réalisation massive ou comptable en discours. Outre certaines propriétés proprement lexicales (reflétées par les données distributionnelles), nous postulons un niveau supra-lexical sémantico-pragmatique, dont les lexèmes peuvent hériter certains traits morphosyntaxiques en contexte. D'après nous, ce niveau intermédiaire (à mi-chemin entre le lexique et la réalisation syntaxique) est nécessaire pour expliquer la teneur et la subtilité de nos données.

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Robustifying the viterbi algorithm

We present an efficient algorithm for estimating hidden state sequences in imprecise hidden Markov models (iHMMs), based on observed output sequences. The main difference with classical HMMs is that the local models of an iHMM are not represented by a single mass function, but rather by a set of mass functions. We consider as estimates for the hidden state sequence those sequences that are maximal. In this way, we generalise the problem of finding a state sequence with highest posterior probability, as is commonly considered in HMMs, and solved efficiently by the Viterbi algorithm. An important feature of our approach is that there may be multiple maximal state sequences, typically for iHMMs that are highly imprecise. We show experimentally that the time complexity of our algorithm tends to be linear in this number of maximal sequences, and investigate how this number depends on the local models.

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Exploiting road traffic data for very short term load forecasting in smart grids

If accurate short term prediction of electricity consumption is available, the Smart Grid infrastructure can rapidly and reliably react to changing conditions. The economic importance of accurate predictions justifies research for more complex forecasting algorithms. This paper proposes road traffic data as a new input dimension that can help improve very short term load forecasting. We explore the dependencies between power demand and road traffic data and evaluate the predictive power of the added dimension compared with other common features, such as historical load and temperature profiles.

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L'acquisition de la temporalité en FRL2: étude descriptive de narrations au passé par des apprenants néerlandophones et hispanophones

L'objectif de notre contribution est d'analyser comment des apprenants néerlandophones et hispanophones du français langue étrangère (FR L2) acquièrent la temporalité – plus spécifiquement la référence au passé – et de vérifier dans quelle mesure leurs interlangues se rapprochent de la langue cible ou, au contraire, reflètent de manière plus ou moins fidèle des mécanismes propres à la langue maternelle (L1). Afin de dresser une image aussi complète que possible, nous présenterons d'abord brièvement les notions essentielles à notre étude ainsi que nos hypothèses de recherche et nos données. Nous adopterons, dans notre description, une approche multifactorielle qui intègre l'analyse de différents moyens linguistiques – morphologiques, lexicaux, sémantiques – et qui essaiera de déterminer la raison du choix pour tel ou tel temps verbal du passé. Pour expliquer ces choix possibles, nous vérifierons les hypothèses de la primauté de l'aspect lexical et du transfert de la L1.

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Stamp duties forecasting models based on intra-annual data

This paper addresses the issue of providing timely forecasts for disaggregated fiscal data. In the aftermath of the 2008-2009 crisis governments have become increasingly aware of the importance to generate trustworthy, time-consistent budget forecasts. Recently, several papers (Onorante et. al., 2008; Pedragal & Perez, 2010; Hallet et. al., 2012. Ghysels & Ozkan, 2012) showed that using intra-annual data can increase forecasting performance. In addition, these models can provide governments with "early warning signals". A second strand of literature (Lutkepo, 2010; Asimakopoulos et. al., 2013) recognizes that aggregating the forecasts for different expenditure and revenue components reduces the forecast error of the resulting budget deficit. Unfortunately, little evidence is available concerning the best models for specific revenue categories like stamp duties or inheritance taxes. In this paper we contribute to the literature by modeling the regional revenues of stamp duties using quarterly and monthly data covering the time period 1994-2013. More than 60 models were tested, including a-theoretical AR and (E(G)) ARCH models, and more theory driven DL, ADL, VAR, VEC models. In addition, combination forecasts were produced. Forecast horizons vary from one month ahead to 2 years ahead; model selection is based on the Aikake Information Criteria and on theoretical arguments, stemming from housing models. Performance evaluation is based on MPE, MAPE and RMSPE of both insample as well as out-of-sample forecasts.. In general, multivariate models show lower in-sample forecasting errors than univariate models. Based on the out-of-sample performance, theory driven models outperform the least complex models for shorter forecasting horizons. However, with forecasts heading for 2 years the outperformance of the more advanced models is less convincing. In addition, the results reveal that combination forecasts strongly enhance the accuracy of stamp duties revenues forecasting models. In general, the results are in line with the findings of Favero & Marcellino (2005) : simple forecasting models and combined forecasts outperform more complicated specifications.

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Speech recognition web services for Dutch

In this paper we present 3 applications in the domain of Automatic Speech Recognition for Dutch, all of which are developed using our in-house speech recognition toolkit SPRAAK. The speech-to-text transcriber is a large vocabulary continuous speech recognizer, optimized for Southern Dutch. It is capable to select components and adjust parameters on the fly, based on the observed conditions in the audio and was recently extended with the capability of adding new words to the lexicon. The grapheme-to-phoneme converter generates possible pronunciations for Dutch words, based on lexicon lookup and linguistic rules. The speech-text alignment system takes audio and text as input and constructs a time aligned output where every word receives exact begin and end times. All three of the applications (and others) are freely available, after registration, as a web application on http://ift.tt/1YqPT4e and in addition, can be accessed as a web service in automated tools.

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Data on comparison between FLEC and CLIMPAQ Methods used for fast sorption measurements of VOCs on building materials

Publication date: Available online 7 March 2016
Source:Data in Brief
Author(s): Malak RIZK, Marie VERRIELE, Maxence MENDEZ, Nadège BLOND, Sébastien DUSANTER, Coralie SCHOEMAECKER, Patrice BLONDEAU, Stéphane LE CALVÉ, Nadine LOCOGE
A test emission chamber called CLIMPAQ has been coupled to a chromatography analyzer GC to measure volatile organic compounds (VOC) concentration during a sorption experiments (Fast sorption measurements of VOCs on building materials: Part 2 – Comparison between FLEC and CLIMPAQ methods, [1]). The equations used to calculate the mass transfer coefficient and the thickness of the boundary layer developed on the surface of a material are presented. In addition, the experimental profiles obtained using the CLIMPAQ chamber is also presented in the presence and the absence of a building material. Finally, the impact of chamber size on the obtained concentration profile using different chambers is shown using 3 types of chambers having different volumes, 1m3, 30m3 and a micro chamber of 40mL.



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Characterization of various cell lines from different ampullary cancer subtypes and cancer associated fibroblast-mediated responses

Abstract

Background

Ampullary cancer is a relatively rare form of cancer and usually treated by pancreatoduodenectomy, followed by adjuvant therapy. The intestinal subtype is associated with markedly improved prognosis after resection. At present, only few cell lines are available for in vitro studies of ampullary cancer and they have not been collectively characterized.

Methods

We characterize five ampullary cancer cell lines by subtype maker expression, epithelial-mesenchymal transition (EMT) features, growth and invasion, drug sensitivity and response to cancer-associated fibroblast conditioned medium (CAF-CM).

Results

On the basis of EMT features, subtype marker expression, growth, invasion and drug sensitivity three types of cell lines could be distinguished: mesenchymal-like, pancreatobiliary-like and intestinal-like. Heterogeneous effects from the cell lines in response to CAF-CM, such as different growth rates, induction of EMT markers as well as suppression of intestinal differentiation markers were observed. In addition, proteomic analysis showed a clear difference in intestinal-like cell line from other cell lines.

Conclusion

Most of the available AMPAC cell lines seem to reflect a poorly differentiated pancreatobiliary or mesenchymal-like phenotype, which is consistent to their origin. We suggest that the most appropriate cell line model for intestinal-like AMPAC is the SNU869, while others seem to reflect aggressive AMPAC subtypes.

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Snail heterogeneity in clear cell renal cell carcinoma

Abstract

Background

Intratumor heterogeneity may be responsible of the unpredictable aggressive clinical behavior that some clear cell renal cell carcinomas display. This clinical uncertainty may be caused by insufficient sampling, leaving out of histological analysis foci of high grade tumor areas. Although molecular approaches are providing important information on renal intratumor heterogeneity, a focus on this topic from the practicing pathologist' perspective is still pending.

Methods

Four distant tumor areas of 40 organ-confined clear cell renal cell carcinomas were selected for histopathological and immunohistochemical evaluation. Tumor size, cell type (clear/granular), Fuhrman's grade, Staging, as well as immunostaining with Snail, ZEB1, Twist, Vimentin, E-cadherin, β-catenin, PTEN, p-Akt, p110α, and SETD2, were analyzed for intratumor heterogeneity using a classification and regression tree algorithm.

Results

Cell type and Fuhrman's grade were heterogeneous in 12.5 and 60 % of the tumors, respectively. If cell type was homogeneous (clear cell) then the tumors were low-grade in 88.57 % of cases. Immunostaining heterogeneity was significant in the series and oscillated between 15 % for p110α and 80 % for Snail. When Snail immunostaining was homogeneous the tumor was histologically homogeneous in 100 % of cases. If Snail was heterogeneous, the tumor was heterogeneous in 75 % of the cases. Average tumor diameter was 4.3 cm. Tumors larger than 3.7 cm were heterogeneous for Vimentin immunostaining in 72.5 % of cases. Tumors displaying negative immunostaining for both ZEB1 and Twist were low grade in 100 % of the cases.

Conclusions

Intratumor heterogeneity is a common event in clear cell renal cell carcinoma, which can be monitored by immunohistochemistry in routine practice. Snail seems to be particularly useful in the identification of intratumor heterogeneity. The suitability of current sampling protocols in renal cancer is discussed.

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Chronic ethanol feeding promotes azoxymethane and dextran sulfate sodium-induced colonic tumorigenesis potentially by enhancing mucosal inflammation

Abstract

Background

Alcohol consumption is one of the major risk factors for colorectal cancer. However, the mechanism involved in this effect of alcohol is unknown.

Methods

We evaluated the effect of chronic ethanol feeding on azoxymethane and dextran sulfate sodium (AOM/DSS)-induced carcinogenesis in mouse colon. Inflammation in colonic mucosa was assessed at a precancerous stage by evaluating mucosal infiltration of neutrophils and macrophages, and analysis of cytokine and chemokine gene expression.

Results

Chronic ethanol feeding significantly increased the number and size of polyps in colon of AOM/DSS treated mice. Confocal microscopic and immunoblot analyses showed a significant elevation of phospho-Smad, VEGF and HIF1α in the colonic mucosa. RT-PCR analysis at a precancerous stage indicated that ethanol significantly increases the expression of cytokines IL-1α, IL-6 and TNFα, and the chemokines CCL5/RANTES, CXCL9/MIG and CXCL10/IP-10 in the colonic mucosa of AOM/DSS treated mice. Confocal microscopy showed that ethanol feeding induces a dramatic elevation of myeloperoxidase, Gr1 and CD68-positive cells in the colonic mucosa of AOM/DSS-treated mice. Ethanol feeding enhanced AOM/DSS-induced suppression of tight junction protein expression and elevated cell proliferation marker, Ki-67 in the colonic epithelium.

Conclusion

This study demonstrates that chronic ethanol feeding promotes colonic tumorigenesis potentially by enhancing inflammation and elevation of proinflammatory cytokines and chemokines.

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Patterns of recurrence after selective postoperative radiation therapy for patients with head and neck squamous cell carcinoma

Abstract

Background

The radiation field for patients with postoperative head and neck squamous cell carcinoma is narrower in our institution than in Western countries to reduce late radiation related toxicities. This strategy is at a risk of loco-regional or distant metastasis. However, because patients are more closely checked than in Western countries by every 1 to 2 months intervals and it is supposed that regional recurrences are identified and salvage surgeries are performed more quickly. Therefore, it is considered that patient survival would not be compromised with this strategy. The aim of this study was to investigate the feasibility of this strategy retrospectively.

Methods

Patients who underwent neck dissection with close or positive margin, extra-capsular spread (ECS), multiple regional lymph node metastasis, pT4, with or without primary tumor resection were treated with postoperative radiation therapy. The volume of radiation field, especially the coverage of prophylactic regional lymph node area, was discussed among head and neck surgeons and radiation oncologists taking into account the clinical factors including patient's age, performance status, number of positive lymph nodes, size of metastatic lymph nodes, extension of primary tumor beyond the midline, and existence of ECS.

Results

Seventy-two patients were identified who were treated with postoperative radiation therapy for head and neck squamous cell carcinoma between November 2005 and December 2014. There were 20 patients with oropharynx, 19 with hypopharynx, 7 with larynx, 23 with oral cavity, and 3 with other sites. Thirty eight patients had their neck irradiated bilaterally and 34 unilaterally. Median follow-up period for patients without relapse was 20.7 months (5.1–100.7). Thirty two patients had disease relapse after treatment including 22 loco-regional recurrence and 14 distant metastases. Among 22 loco-regional recurrence, seven patients underwent salvage surgery and one of them was no relapse at the time of the analysis. Among patients without bilateral neck lymph node metastasis who were treated with unilateral neck irradiation, patients with oral cavity or recurrent disease had significantly lower DFS compared with those without (2-y DFS 41.7 % vs 88.2 %, p = 0.017).

Conclusions

In patients without bilateral neck lymph node involvement, the postoperative unilateral neck irradiation is a reasonable treatment strategy for patients with the exception of oral cavity or recurrent disease.

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The efficacy of iodine-125 permanent brachytherapy versus intensity-modulated radiation for inoperable salivary gland malignancies: study protocol of a randomised controlled trial

Abstract

Background

Radiation therapy is the method of choice for subjects with inoperable salivary gland malignancies. I-125 brachytherapy, delivering a high radiation dose to a tumor but sparing surrounding normal tissues, is supposed to be ideal modality for the treatment of salivary gland malignancies. We designed a randomised controlled clinical trial to compare the efficacy of I-125 permanent brachytherapy (PBT) versus intensity-modulated radiation therapy (IMRT) for inoperable salivary gland malignancies.

Methods/Design

In this study, inclusion criteria are subjects with inoperable salivary gland malignancies, aged 18–80 years, have provided informed consent, with at least one measurable tumor focus, be able to survive ≥3 months, Karnofsky performance status ≥60, have adequate hematopoietic function of bone marrow, have normal liver and kidney function, and are willing to prevent pregnancy.

Exclusion criteria include a history of radiation or chemotherapy, a history of other malignant tumors in the past 5 years, receiving other effective treatments, participating in other clinical trials, with circulatory metastasis, cognitive impairment, severe cardiovascular and cerebrovascular diseases, acute infection, uncontrolled systemic disease, history of interstitial lungdisease, and being pregnant or breast feeding.

The study will be conducted as a clinical, prospective, randomised controlled trial with balanced randomisation (1:1). The planned sample size is 90 subjects. Subjects with inoperable salivary gland malignancies are randomised to receive either I-125 PBT or IMRT, with stratification by tumor size and neck lymph node metastasis. Participants in both groups will be followed up at 2, 4, 6, 9, 12, 15, 18, 21 and 24 months after randomization. The primary outcome is local control rate of the primary site (based on imaging findings and clinical examination, RECIST criteria) in 1 year. Secondary outcomes are progression-free survival, overall survival, quality of life (QOL) measured with the European Organization for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30 and QLQ-H&N35) of Chinese version, and safety of treatment. Chi-squared test is used to compare the local control rates in both groups. The survival curves are estimated by the Kaplan-Meier method, and log-rank test is used to test the significant difference.

Discussion

Only few observational studies have investigated the effect of I-125 PBT on inoperable salivary gland malignancies. To our knowledge, this is the first randomised controlled trial to investigate the efficacy of I-125 PBT for subjects with inoperable salivary gland malignancies, and will add to the knowledge base for the treatment of these subjects.

Trial registration

The study is registered to Clinical Trials.gov (NCT02048254) on Jan 29, 2014.

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Anti-vascular effects of the cytosolic phospholipase A2 inhibitor AVX235 in a patient-derived basal-like breast cancer model

Abstract

Background

Group IVA cytosolic phospholipase A2 (cPLA2α) plays an important role in tumorigenesis and angiogenesis. It is overexpressed in basal-like breast cancer (BLBC), which is aggressive and usually triple-negative, making it unresponsive to current targeted therapies. Here, we evaluated the anti-angiogenic effects of a specific cPLA2α inhibitor, AVX235, in a patient-derived triple-negative BLBC model.

Methods

Mice bearing orthotopic xenografts received i.p. injections of AVX235 or DMSO vehicle daily for 1 week and then every other day for up to 19 days. Six treated and six control mice were terminated after 2 days of treatment, and the tumors excised for high resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS) and prostaglandin E2 (PGE2) enzyme immunoassay (EIA) analysis. A 1-week imaging study was performed on a separate cohort of mice. Longitudinal dynamic contrast enhanced (DCE)-MRI was performed before, after 4 days, and after 1 week of treatment. The mice were then perfused with a radiopaque vascular casting agent, and the tumors excised for micro-CT angiography. Subsequently, tumors were sectioned and stained with lectin and for Ki67 or α-smooth muscle actin to quantify endothelial cell proliferation and vessel maturity, respectively. Partial least squares discriminant analysis was performed on the multivariate HR MAS MRS data, and non-parametric univariate analyses using Mann–Whitney U tests (α = 0.05) were performed on all other data.

Results

Glycerophosphocholine and PGE2 levels, measured by HR MAS MRS and EIA, respectively, were lower in treated tumors after 2 days of treatment. These molecular changes are expected downstream effects of cPLA2α inhibition and were followed by significant tumor growth inhibition after 8 days of treatment. DCE-MRI revealed that AVX235 treatment caused a decrease in tumor perfusion. Concordantly, micro-CT angiography showed that vessel volume fraction, density, and caliber were reduced in treated tumors. Moreover, histology showed decreased endothelial cell proliferation and fewer immature vessels in treated tumors.

Conclusions

These results demonstrate that cPLA2α inhibition with AVX235 resulted in decreased vascularization and perfusion and subsequent inhibition of tumor growth. Thus, cPLA2α inhibition may be a potential new therapeutic option for triple-negative basal-like breast cancer.

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Targeting Rad50 sensitizes human nasopharyngeal carcinoma cells to radiotherapy

Abstract

Background

The Mre11-Rad50-Nbs1 (MRN) complex is well known for its crucial role in initiating DNA double strand breaks (DSBs) repair pathways to resistant irradiation (IR) injury and thus facilitating radioresistance which severely reduces radiocurability of nasopharyngeal cancer (NPC). Targeting native cellular MRN function would sensitize NPC cells to IR.

Methods

A recombinant adenovirus containing a mutant Rad50 gene (Ad-RAD50) expressing Rad50 zinc hook domain but lacking the ATPase domain and the Mre11 interaction domain was constructed to disrupt native cellular MRN functions. The effects of Ad-RAD50 on the MRN functions were assessed in NPC cells lines using western blot, co-immunoprecipitation and confocal microscopy analyses. The increased radiosensitivity of transient Ad-RAD50 to IR was examined in NPC cells, including MTT assay, colony formation. The molecular mechanisms of radiosensitization were confirmed by neutral comet assay and western bolts. Nude mice subcutaneous injection, tumor growth curve and TUNEL assay were used to evaluate tumor regression and apoptosis in vivo.

Results

Rad50 is remarkably upregulated in NPC cells after IR, implying the critical role of Rad50 in MRN functions. The transient expression of this mutant Rad50 decreased the levels of native cellular Rad50, Mre11 and Nbs1, weakened the interactions among these proteins, abrogated the G2/M arrest induced by DSBs and reduced the DNA repair ability in NPC cells. A combination of IR and mutant RAD50 therapy produced significant tumor cytotoxicity in vitro, with a corresponding increase in DNA damage, prevented proliferation and cell viability. Furthermore, Ad-RAD50 sensitized NPC cells to IR by causing dramatic tumor regression and inducing apoptosis in vivo.

Conclusion

Our findings define a novel therapeutic approach to NPC radiosensitization via targeted native cellular Rad50 disruption.

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