A sensitive label-free immunosensor for detection α-Fetoprotein in whole blood based on anticoagulating magnetic nanoparticles

Publication date: 15 September 2017
Source:Biosensors and Bioelectronics, Volume 95
Author(s): Tingting Xu, Bo Chi, Fan Wu, Shangshang Ma, Shuyue Zhan, Meihui Yi, Hong Xu, Chun Mao
Accurate values of tumor markers in blood play an especially important role in the diagnosis of illness. Here, based on the combination of three techniques include anticoagulant technology, nanotechnology and biosensing technology, a sensitive label-free immunosensor with anti-biofouling electrode for detection α-Fetoprotein (AFP) in whole blood was developed by anticoagulating magnetic nanoparticles. The obtained products of Fe3O4-ɛ-PL-Hep nanoparticles were characterized by fourier transform infrared (FT-IR) spectra, transmission electron microscopy (TEM), ζ-potential and vibrating sample magnetometry (VSM). Moreover, the blood compatibility of anticoagulating magnetic nanoparticles was characterized by in vitro coagulation tests, hemolysis assay and whole blood adhesion tests. Combining the anticoagulant property of heparin (Hep) and the good magnetism of Fe3O4, the Fe3O4-ɛ-PL-Hep nanoparticles could improve not only the anti-biofouling property of the electrode surface when they contact with whole blood, but also the stability and reproducibility of the proposed immunosensor. Thus, the prepared anticoagulating magnetic nanoparticles modified immunosensor for the detection of AFP showed excellent electrochemical properties with a wide concentration range from 0.1 to 100ng/mL and a low detection limit of 0.072ng/mL. Furthermore, five blood samples were assayed using the developed immunosensor. The results showed satisfactory accuracy with low relative errors. It indicated that our developed immunoassay was competitive and could be potentially used for the detection of whole blood samples directly.



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Expression of long non-coding RNAs in autoimmunity and linkage to enhancer function and autoimmune disease risk genetic variants

Publication date: Available online 15 April 2017
Source:Journal of Autoimmunity
Author(s): T.M. Aune, P.S. Crooke, A.E. Patrick, J.T. Tossberg, N.J. Olsen, C.F. Spurlock
Genome-wide association studies have identified numerous genetic variants conferring autoimmune disease risk. Most of these genetic variants lie outside protein-coding genes hampering mechanistic explorations. Numerous mRNAs are also differentially expressed in autoimmune disease but their regulation is also unclear. The majority of the human genome is transcribed yet its biologic significance is incompletely understood. We performed whole genome RNA-sequencing [RNA-seq] to categorize expression of mRNAs, known and novel long non-coding RNAs [lncRNAs] in leukocytes from subjects with autoimmune disease and identified annotated and novel lncRNAs differentially expressed across multiple disorders. We found that loci transcribing novel lncRNAs were not randomly distributed across the genome but co-localized with leukocyte transcriptional enhancers, especially super-enhancers, and near genetic variants associated with autoimmune disease risk. We propose that alterations in enhancer function, including lncRNA expression, produced by genetics and environment, change cellular phenotypes contributing to disease risk and pathogenesis and represent attractive therapeutic targets.



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Editorial Board ((ofc))

Publication date: April 2017
Source:Acta Histochemica, Volume 119, Issue 3





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Hypothyroidism associated with parathyroid disorders

Publication date: Available online 15 April 2017
Source:Best Practice & Research Clinical Endocrinology & Metabolism
Author(s): Giovanna Mantovani, Marta Elli Francesca, Sabrina Corbetta
Hypothyroidism may occur in association with congenital parathyroid disorders determining parathyroid hormone insufficiency, which is characterized by hypocalcemia and concomitant inappropriately low secretion of parathormone (PTH). The association is often due to loss of function of genes common to thyroid and parathyroid glands embryonic development. Hypothyroidism associated with hypoparathyroidism is generally mild and not associated with goiter; moreover, it is usually part of a multisystemic involvement not restricted to endocrine function as occurs in patients with 22q11 microdeletion/DiGeorge syndrome, the most frequent disorders. Hypothyroidism and hypoparathyroidism may also follow endocrine glands' damages due to autoimmunity or chronic iron overload in thalassemic disorders, both genetically determined conditions. Finally, besides PTH deficiency, hypocalcemia can be due to PTH resistance in pseudohypoparathyroidism; when hormone resistance is generalized, patients can suffer from hypothyroidism due to TSH resistance. In evaluating patients with hypothyroidism and hypocalcemia, physical examination and clinical history are essential to drive the diagnostic process, while routine genetic screening is not recommended.



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Sex differences in autonomic response and situational appraisal of a competitive situation in young adults

Publication date: Available online 16 April 2017
Source:Biological Psychology
Author(s): Diana Abad-Tortosa, Adrián Alacreu-Crespo, Raquel Costa, Alicia Salvador, Miguel Ángel Serrano
Competition is a social stressor capable of eliciting physiological responses modulated by the outcome. The main objective of this study was to analyze the psychophysiological changes associated with competition and its outcome in men and women, taking into account the role of situational appraisal. To this end, 112 young people (46 men and 66 women) participated in a laboratory task in a competitive or non-competitive condition, while Blood Pressure (BP), Heart Rate Variability (HRV), and Skin Conductance (SC) responses were measured. Our results indicate that competition elicits higher systolic blood pressure (SBP) than a non-competitive task; in addition, winners presented a greater R-R decrease from baseline to task, greater R-R Recovery, and lower frustration and external attribution than losers. Regarding sex, men perceived their opponent's capacity to be lower and their own capacity to be greater than women did, and they also showed higher R-R decreases and lower SC increases. In conclusion, we found a complex pattern of different psychophysiological responses to competition associated with outcome and sex in a laboratory competition. This result could be related to the use of more passive or active coping strategies.



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Pneumoperitoneum without Intestinal Perforation in a Neonate: Case Report and Literature Review

Pneumoperitoneum in a preterm neonate usually indicates perforation of the intestine and is considered a surgical emergency. However, there are cases of pneumoperitoneum with no evidence of rupture of the intestine reported in the literature. We report a case of pneumoperitoneum with no intestinal perforation in a preterm neonate with respiratory distress syndrome who was on high frequency oscillatory ventilation (HFOV). He developed bilateral pulmonary interstitial emphysema with localized cystic lesion, likely localized pulmonary interstitial emphysema, and recurrent pneumothoraces. He was treated with dexamethasone to wean from the ventilator. Pneumoperitoneum developed in association with left sided pneumothorax following mechanical ventilation and cardiopulmonary resuscitation. Pneumoperitoneum resolved after the pneumothorax was resolved with chest tube drainage. He died from acute cardiorespiratory failure. At autopsy, there was no evidence of intestinal perforation. This case highlights the fact that pneumoperitoneum can develop secondary to pneumothorax and does not always indicate intestinal perforation or require exploratory laparotomy.

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Chinese medicine Bu-Fei decoction attenuates epithelial-mesenchymal transition of non-small cell lung cancer via inhibition of transforming growth factor β1 signaling pathway in vitro and in vivo

Publication date: 23 May 2017
Source:Journal of Ethnopharmacology, Volume 204
Author(s): Xi-Ran He, Shu-Yan Han, Xiao-Hong Li, Wen-Xian Zheng, Li-Na Pang, Shan-Tong Jiang, Ping-Ping Li
Ethnopharmacological relevanceTraditional Chinese medicine Bu-Fei decoction (BFD) has been utilized to treat patients with Qi deficiency for decades, with the advantages of invigorating vital energy, clearing heat-toxin and moistening lung, etc. According to previous clinical experience and trials, BFD has been found to indeed improve life quality of lung cancer patients and prolong survival time. Nevertheless, little is known on its potential mechanisms so far. Being regarded as a pivotal cytokine in the tumor microenvironment, transforming growth factor β (TGF-β) stands out as a robust regulator of epithelial-mesenchymal transition (EMT), which is closely linked to tumor progression.Aim of the studyThe present study was designed to explore whether BFD antagonized EMT via blocking TGF-β1-induced signaling pathway, and then help contribute to create a relatively steady microenvironment for confining lung cancer.Materials and methodsThis experiment was performed in lung adenocarcinoma A549 cells both in vitro and in vivo. In detail, the influences mediated by TGF-β1 alone or in combination with different concentrations of BFD on migration were detected by wound healing and transwell assays, and the effects of BFD on cell viability were determined by cell counting kit-8 (CCK-8) assay. TGF-β1, EMT relevant proteins and genes were evaluated by western blotting, confocal microscopy, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC) and enzyme-linked immuno sorbent assay (ELISA). Female BALB/C nude mice were subcutaneously implanted A549 cells and given BFD by gavage twice daily for 28 days. The tumor volume was monitored every 4 days to draw growth curve. The tumor weight, expression levels of EMT-related protein in tumor tissues and TGF-β1 serum level were evaluated, respectively.ResultsBFD only exerted minor effects on A549 cell proliferation and this was in accordance with the in vivo result, which showed that the tumor growth and weight were not be restrained by BFD administration. However, the data elucidated that BFD could dose-dependently suppress EMT induced by TGF-β1 in vitro via attenuating canonical Smad signaling pathway. In the A549 xenograft mouse model, BFD also inhibited protein markers that are associated with EMT and TGF-β1 secretion into serum.ConclusionsBased on these above data, the conclusion could be put forward that BFD probably attenuated TGF-β1 mediated EMT in A549 cells via decreasing canonical Smad signaling pathway both in vitro and in vivo, which may help restrain the malignant phenotype induced by TGF-β1 in A549 cells to some extent.

Graphical abstract

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Does exclusion of cancers registered only from death-certificate information diminish socio-demographic disparities in recorded survival?

Publication date: June 2017
Source:Cancer Epidemiology, Volume 48
Author(s): Hanna E. Tervonen, David Roder, Stephen Morrell, Hui You, David C. Currow
BackgroundDeath Certificate Only (DCO) cancer cases are commonly excluded from survival analyses due to unknown survival time. This study examines whether socio-demographic factors are associated with DCO diagnosis, and the potential effects of excluding DCO cases on socio-demographic cancer survival disparities in NSW, Australia.MethodsNSW Cancer Registry data for cases diagnosed in 2000–2008 were used in this study. Logistic regression was used to estimate the odds of DCO registration by socio-demographic sub-group (socio-economic disadvantage, residential remoteness, country of birth, age at diagnosis). Cox proportional hazard regression was used to estimate the probability of death from cancer by socio-demographic subgroup when DCO cases were included and excluded from analyses.ResultsDCO cases consisted of 1.5% (n=4336) of all cases (n=299,651). DCO diagnosis was associated with living in socio-economically disadvantaged areas (most disadvantaged compared with least disadvantaged quintile: odds ratio OR 1.25, 95%CI 1.12–1.40), living in inner regional (OR 1.16, 95%CI 1.08–1.25) or remote areas (OR 1.48, 95%CI 1.01–2.19), having an unknown country of birth (OR 1.63, 95%CI 1.47–1.81) and older age. Including or excluding DCO cases had no significant impact on hazard ratios for cancer death by socio-economic disadvantage quintile or remoteness category, and only a minor impact on hazard ratios by age.ConclusionSocio-demographic factors were associated with DCO diagnosis in NSW. However, socio-demographic cancer survival disparities remained unchanged or varied only slightly irrespective of including/excluding DCO cases. Further research could examine the upper limits of DCO proportions that significantly alter estimated cancer survival differentials if DCOs are excluded.



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Liquid chromatography-high resolution mass spectrometric methods for the surveillance monitoring of cyanotoxins in freshwaters

Publication date: 1 August 2017
Source:Talanta, Volume 170
Author(s): Sara Bogialli, Claudio Bortolini, Iole Maria Di Gangi, Federica Nigro Di Gregorio, Luca Lucentini, Gabriella Favaro, Paolo Pastore
A comprehensive risk management on human exposure to cyanotoxins, whose production is actually unpredictable, is limited by reliable analytical tools for monitoring as many toxic algal metabolites as possible. Two analytical approaches based on a LC-QTOF system for target analysis and suspect screening of cyanotoxins in freshwater were presented. A database with 369 compounds belonging to cyanobacterial metabolites was developed and used for a retrospective data analysis based on high resolution mass spectrometry (HRMS). HRMS fragmentation of the suspect cyanotoxin precursor ions was subsequently performed for correctly identifying the specific variants. Alternatively, an automatic tandem HRMS analysis tailored for cyanotoxins was performed in a single chromatographic run, using the developed database as a preferred precursor ions list. Twenty-five extracts of surface and drinking waters contaminated by cyanobacteria were processed. The identification of seven uncommon microcystins (M(O)R, MC-FR, MSer⁷-YR, D-Asp³MSer⁷-LR, MSer⁷-LR, dmAdda-LR and dmAdda-YR) and 6 anabaenopeptins (A, B, F, MM850, MM864, oscyllamide Y) was reported. Several isobaric variants, fully separated by chromatography, were pointed out. The developed methods are proposed to be used by environmental and health agencies for strengthening the surveillance monitoring of cyanotoxins in water.

Graphical abstract

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Laryngeal function-preserving operation for T4a laryngeal cancer with vocal cord paralysis — A case report

Publication date: Available online 14 April 2017
Source:Auris Nasus Larynx
Author(s): Yukinori Asada, Koreyuki Kurosawa, Ko Matsumoto, Takahiro Goto, Kengo Katoh, Takayuki Imai, Shigeru Saijo, Kazuto Matsuura
For locally advanced laryngeal cancers, the standard treatment of choice is chemoradiotherapy if organ function needs to be conserved. Surgical treatment with larynx preservation is conducted only for limited cases. For locally advanced laryngeal cancers such as those with vocal cord fixation and/or cricoid cartilage destruction, there is no apparent standardized organ-preserving surgery keeping the essential laryngeal functions, viz. the airway, deglutition and articulation, uncompromized.Recently, our surgical team saw a patient with T4a advanced laryngeal cancer with vocal cord fixation who aspired to maintain his laryngeal function. Driven by his eagerness, we contrived novel techniques for laryngeal function preservation and performed a two-staged operation.In the first stage, extended vertical partial laryngectomy was conducted including resection of the affected thyroid, arytenoid, and cricoid cartilages, followed by local closure of the hypopharynx. Additionally, laryngeal suspension surgery and cricopharyngeal myotomy were performed in addition to suturing the epiglottis with the intact arytenoid cartilage to enhance swallowing function. In the second stage, airway reconstruction was performed using a local skin flap.As of 10 months after operation, there has been no tumor recurrence, and the reconstructed larynx has been working satisfactorily.In this report we describe an innovative operation that was especially contrived for laryngeal function preservation.



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Bilateral spontaneous symptomatic temporomandibular joint herniation into the external auditory canal: A case report and literature review

Publication date: Available online 14 April 2017
Source:Auris Nasus Larynx
Author(s): Yong Won Lee, Yong Ho Park
Spontaneous temporomandibular joint (TMJ) herniation is the entity of protrusion of the retrodiscal contents of the TMJ into the external auditory canal (EAC) through a persistent Huschke's foramen. There have been a number of reports of spontaneous TMJ herniation, but there are no reports of bilateral symptomatic TMJ herniation. We report a case of a 70-year-old man who complained of a crunching sound in both ears during mastication. Examination showed bulging from the anterosuperior wall of the EAC on each side when the patient opened his mouth, which pushed the tympanic membrane medially. Bony defects in the corresponding area were seen on computed tomography. We describe a very rare case of bilateral spontaneous TMJ herniation that caused symptoms by having a direct impact on the tympanic membrane.



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Involvement of the nuclear progestin receptor in LH-induced expression of membrane type 2-matrix metalloproteinase required for follicle rupture during ovulation in the medaka, Oryzias latipes

Publication date: Available online 14 April 2017
Source:Molecular and Cellular Endocrinology
Author(s): Katsueki Ogiwara, Takayuki Takahashi
Hormonal regulation of the expression of Mmp15, a proteolytic enzyme indispensable for ovulation in the teleost medaka, was investigated. In an in vitro culture system using preovulatory follicles, Mmp15 expression and ovulation were induced in the presence of recombinant luteinizing hormone (rLh). Both rLh-induced Mmp15 expression and ovulation were 17α, 20β-dihydroxy-4-pregnen-3-one-dependent, suggesting the involvement of a nuclear progestin receptor (Pgr). In vitro follicle ovulation and Mmp15 expression were reduced by treatment with the Pgr antagonist RU-486. Like Pgr, the transcription factor CCAAT/enhancer-binding protein β (Cebpb) was induced by rLh. ChIP analyses indicated that Pgr and Cebpb bound to the mmp15 promoter region. These results indicate that the rLh-induced expression of Mmp15 is mediated by Pgr and Cebpb. A differential timing of expression of Pgr and Cebpb in the preovulatory follicles appears to explain the considerably long time-lag from the pgr gene activation to mmp15 gene expression.



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Mandibular step osteotomy using CAD/CAM-derived surgical splint: case report

Mandibular step osteotomy is a useful technique for large mandibular setbacks. We report a case of a patient who had a mandibular step osteotomy using a CAD/CAM-derived wafer for mandibular setback with reduction of the arch.

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Restless leg syndrome and periodic limb movements in sleep: risk for cardiovascular disease

None declared.

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Subcutaneous dermatofibrosarcoma protuberans, a rare subtype with predilection for the head: A retrospective series of 18 cases

Dermatofibrosarcoma protuberans (DFSP) typically affects the dermis and subcutaneous tissue. The subcutaneous variant is rare.

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Evaluation of the chelating performance of biopolyelectrolyte green complexes (NIBPEGCs) for wastewater treatment from the metal finishing industry

Publication date: 5 August 2017
Source:Journal of Hazardous Materials, Volume 335
Author(s): Eduardo A. López-Maldonado, Oscar Gabriel Zavala García, Kevin Cruz Escobedo, Mercedes T. Oropeza-Guzman
In this paper nonstoichiometric interbiopolyelectrolyte green complexes (NIBPEGCs) were prepared using chitosan (Ch), alginate (AG) and poly(acrylic acid)(PAA). They are proposed as innovative formulations (polyelectrolytes and chelating agents) suitable for the elimination heavy metals contained in wastewater. This application may represent an integral solution for industries rejecting solid and aqueous metallic materials; however, it has not been previously reported. NIBPEGCs physicochemical performance was evaluated based on pH, particle size, surface charge, isoelectric point, dose, coagulation-flocculation kinetics and chemical affinity with seven metal ions. The experimental results showed that NIBPEGCs composed by AG/Ch and PAA/Chitosan have all the three complementary functions: chemical affinity, electrostatic interaction and particle entrapment anticipating more simple operation units to remove heavy metals. Complexes of AG/Ch (negative) were higher performance in removing heavy metals, with a dose window (150–180mg/L), lower dose of 410mg/L PAA/Ch (negative). Investigation of chelating performances of NIBPEGCs show that the efficiency of metal removal is: Ca˃Cr˃Cu˃Pb˃Ni˃Zn˃Cd. Transmittance vs time profiles, metals and zeta potential analysis showed that chelation capacity is the crucial factor to ensure metallic species removal, followed by physical entrapment of the metallic colloids. Integrating all presented results allow to sustain the development of excellent metals removal formulations.

Graphical abstract

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Synthesis, characterization and gas sensing properties of ZnO-decorated MWCNTs

Publication date: 15 August 2017
Source:Applied Surface Science, Volume 413
Author(s): Yong Jung Kwon, Ali Mirzaei, Sung Yong Kang, Myung Sik Choi, Jae Hoon Bang, Sang Sub Kim, Hyoun Woo Kim
In this work, ZnO-decorated multi-walled carbon nanotube (MWCNT) nanocomposites prepared using an in-situ method involving the thermal evaporation of Zn powders in the presence of MWCNTs. The gas sensing characteristics of the MWCNT/ZnO nanocomposites are studied, and results for the material characterizations for the synthesized nanocomposites confirm the formation of well-distributed ZnO nanoparticles onto MWCNTs, creating MWCNT/ZnO nanocomposites. The gas sensing properties of the MWCNT/ZnO nanocomposite gas sensor, such as response, cross-sensitivity, and response-recovery time, are investigated and compared with a bare MWCNT sensor. The decoration of ZnO nanoparticles greatly improves the gas sensing properties of bare MWCNTs. We discussed the possible mechanisms for the enhancement of sensing capabilities. The results suggest that decoration of n-type semiconducting oxide materials, such as ZnO in the form of nanoparticles, is a promising strategy for improvement of gas sensing properties of p-MWCNTs.



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Describing heterogeneity of unmet needs among adults with a developmental disability: An examination of the 2012 Canadian Survey on Disability

Publication date: June 2017
Source:Research in Developmental Disabilities, Volume 65
Author(s): Jennifer Zwicker, Arezou Zaresani, J.C. Herb Emery
BackgroundAs a signatory to the UN Convention on the Rights of Persons with Disabilities, Canada has committed to protect the rights and dignity of persons with developmental disabilities (DD), which means that labour markets, education, and training opportunities should be inclusive and accessible.PurposeDescribe the unmet employment, education and daily needs of adults with DD, with a sub analysis of persons with autism spectrum disorder (ASD) and cerebral palsy (CP) in Canada, to inform efficient and equitable policy development.Methods and proceduresSecondary analysis of 2012 Canadian Survey on Disability was used to study a sample including working age (15–64 years old) individuals with self-reported DD, CP and ASD. Persons with DD reported on their met and unmet needs in term of activities of daily living, education and employment.Outcomes and resultsLabour force participation is the lowest for those with DD compared to any other disability. Individuals with CP and ASD report a high level of unmet needs that differ in terms of educational, vocational and daily living supports.Conclusions and implicationsImproving labour force participation to be inclusive and accessible requires policy that considers the range of unmet needs that exist for persons with DD.



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Corrigendum to “Caring for children with intellectual disabilities part 1: Experience with the population, pain-related beliefs, and care decisions” [Res. Dev. Disabil. 62 (2017) 197–208]

Publication date: Available online 14 April 2017
Source:Research in Developmental Disabilities
Author(s): Lara M. Genik, C. Meghan McMurtry, Lynn M. Breau




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Expression of coproporphyrinogen oxidase is associated with detection of upper gastrointestinal carcinomas by 5-aminolevulinic acid-mediated photodynamic diagnosis

Publication date: Available online 14 April 2017
Source:Photodiagnosis and Photodynamic Therapy
Author(s): Kumi Ogihara, Hajime Isomoto, Hiroki Kurumi, Tsutomu Kanda, Mikiko Hashisako, Kazuhiro Tabata, Hiroyuki Ishii, Ken Ohnita, Naoyuki Yamaguchi, Yuko Akazawa, Kayoko Matsushima, Fuminao Takeshima, Masaki Kunizaki, Shigekazu Hidaka, Atsushi Nanashima, Junya Fukuoka, Takeshi Nagayasu, Kazuhiko Nakao
Background5-Aminolevulinic acid is a precursor of photosensitizing protoporphyrin IX and has been applied for photodynamic diagnosis of brain and bladder tumors with few side effects. Although most upper gastrointestinal tumors can be detected during photodynamic diagnosis, some tumors containing signet-ring cells cannot be visualized. Here, we aimed to assess whether proteins involved in the absorbance, activation, and turnover of protoporphyrin IX altered the fluorescence signal in gastric cancer.MethodsAminolevulinic acid-mediated photodynamic diagnosis was performed in 23 lesions from 20 patients using an endoscope equipped with a blue laser light that caused red fluorescence emission of photosensitizing protoporphyrin IX. Red fluorescence signal and intensity was assessed during photodynamic diagnosis procedures. Lesions were resected by endoscopic and/or laparoscopic surgery, and specimens were immunostained and assessed for the expression of ATP-binding cassette sub-family G member 2, oligopeptide transporter-1, and coproporphyrinogen oxidase.ResultsPhotodynamic diagnosis was negative in four cases (17.4%). Three cases of photodynamic diagnosis-negative lesions were signet-ring cell carcinomas, and only one case was differentiated adenocarcinoma (intestinal type). Twenty intestinal type, photodynamic diagnosis-positive lesions showed high expression of coproporphyrinogen oxidase, whereas signet-ring cell carcinomas were all negative. Oligopeptide transporter-1 immunoreactivity was significantly higher in tumors of intestinal type. ATP-binding cassette sub-family G member 2 expression tended to be higher in luminal surface tumors than in intestinal type tumors.ConclusionAminolevulinic acid-mediated photodynamic diagnosis provided good detection of upper gastrointestinal tumors of intestinal type but not diffuse type tumors, such as signet-ring cell carcinomas, possibly owing to coproporphyrinogen oxidase expression.



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Comparing Originator Biologics and Biosimilars: A Review of the Relevant Issues

Publication date: Available online 15 April 2017
Source:Clinical Therapeutics
Author(s): Corrado Blandizzi, Pier Luigi Meroni, Giovanni Lapadula
PurposeWe provide a review of current knowledge on comparability between biosimilars and originator biologics in view of the continuous evolution occurring in this highly dynamic area.MethodsEnglish-language literature indexed in MEDLINE was explored, without time limits, to July 31, 2016, using the terms biosimilar, biotechnologic drug, biologic drug, monoclonal antibody, fusion protein, and anti–tumor necrosis factor. The reference lists of identified articles were examined carefully for additional pertinent publications.FindingsBiological medicines are much more structurally complex and extremely sensitive to manufacturing conditions and therefore more difficult to characterize and produce than small molecule drugs. Even minor changes in manufacturing may lead to significant variations of the cellular systems used for biological production, as well as to differences in the structure, stability, or other quality aspects of the end product, all of which have the potential to affect tolerability and/or efficacy and increase the risk of immune responses. Owing to these issues, specific regulatory guidance on biosimilars is continuously evolving, and there is some disagreement on which studies need to be implemented to approve a biosimilar. According to current literature, the following points on biosimilars deserve consideration: biosimilar development is characterized by global harmonization, although several not fully answered questions remain regarding extrapolation of indications, switching or interchangeability, and tolerability; in patients with rheumatic diseases, the tolerability and efficacy of biosimilars in clinical practice remain to be established; several medical and patient associations have published position papers on biosimilars requesting that safety, efficacy, and traceability be carefully considered; long-term postmarketing studies should be implemented to allow physicians to gain confidence in biosimilars.ImplicationsOn the basis of current knowledge, and taking into consideration both regulatory rules and medical society positions, it can be concluded that, although cost savings are highly desirable, the approval process for biosimilars needs to place tolerability and efficacy, supported by scientifically sound evidence, as the highest priority. Moreover, physicians must retain full authority regarding the decision about which biopharmaceutical to use for treating patients.



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The effect of focal cortical frontal and posterior lesions on recollection and familiarity in recognition memory

Publication date: Available online 15 April 2017
Source:Cortex
Author(s): Vess Stamenova, Fuqiang Gao, Sandra E. Black, Michael L. Schwartz, Natasha Kovacevic, Michael P. Alexander, Brian Levine
Recognition memory can be subdivided into two processes: recollection (a contextually rich memory) and familiarity (a sense that an item is old). The brain network supporting recognition encompasses frontal, parietal and medial temporal regions. Which specific regions within the frontal lobe are critical for recollection vs. familiarity, however, are unknown; past studies of focal lesion patients have yielded conflicting results. We examined patients with focal lesions confined to medial polar (MP), right dorsal frontal (RDF), right frontotemporal (RFT), left dorsal frontal (LDF), temporal, and parietal regions and matched controls. A series of words and their humorous definitions were presented either auditorily or visually to all participants. Recall, recognition, and source memory were tested at 30 min and 24 hr delay, along with "remember/know" judgements for recognized items. The MP, RDF, temporal and parietal groups were impaired on subjectively reported recollection; their intact recognition performance was supported by familiarity. None of the groups were impaired on cued recall, recognition familiarity or source memory. These findings suggest that the MP and RDF regions, along with parietal and temporal regions, are necessary for subjectively-reported recollection, while the LDF and right frontal ventral regions, as those affected in the RTF group, are not.



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Longitudinal changes in the fronto-striatal network are associated with executive dysfunction and behavioral dysregulation in Huntington’s disease: 30 months IMAGE-HD data

Publication date: Available online 15 April 2017
Source:Cortex
Author(s): Juan F. Domínguez D, Govinda Poudel, Julie C. Stout, Marcus Gray, Phyllis Chua, Beth Borowsky, Gary F. Egan, Nellie Georgiou-Karistianis
Neuropsychiatric disturbance−particularly executive dysfunction and behavioral dysregulation−is a common feature of Huntington's disease (HD), with implications for functional capacity and quality of life. No study to date has ascertained whether longitudinal change in brain activity is associated with neuropsychiatric deficits in HD. We used a set-response-shifting task together with functional magnetic resonance imaging to investigate 30-month longitudinal blood-oxygen level dependent (BOLD) signal changes in the fronto-striatal attentional control network in premanifest and symptomatic HD (pre-HD and symp-HD, respectively), relative to healthy control participants. We also assessed the extent to which changes in the BOLD signal over time were related to neuropsychiatric measures in the domains of executive dysfunction and behavioral dysregulation. Associations were also evaluated with clinical and disease severity. We found no longitudinal BOLD differences between pre-HD and controls over 30 months. In contrast, reduction in BOLD response over time was greater in symp-HD, relative to controls, in task-related areas (e.g., anterior cingulate cortex and striatum) and in regions from the default mode network (e.g., medial prefrontal cortex and posterior cingulate/precuneus). Moreover, when considered across both premanifest and symptomatic stages, longitudinal BOLD signal decline in the right dorsolateral prefrontal cortex and putamen was associated with executive dysfunction and behavioral dysregulation measures. In addition, longitudinal reduction in BOLD signal, in fronto-striatal and default mode networks, correlated with disease severity. These results suggest that longitudinal change in fronto-striatal and default mode networks may be useful in understanding the biological underpinnings of functional decline in HD. Such findings offer new avenues for targeted treatments in terms of minimizing psychiatric impairment and potentially maximizing cognitive function.



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Influence of response bias and internal/external source on lateral posterior parietal successful retrieval activity

Publication date: Available online 15 April 2017
Source:Cortex
Author(s): Danielle R. King, Michael B. Miller
In studies of recognition memory, regions of the lateral posterior parietal cortex exhibit greater activity (as indexed by the fMRI BOLD signal) during correct recognition of "old" (studied) items than correct rejection of "new" (unstudied) items. This effect appears to be source-sensitive, with greater activity associated with recognition of perceived than imagined events. Parietal successful retrieval activity also varies with response bias, or the tendency to be conservative about making "old" judgments. Here, we examined whether differences in response bias associated with recognition judgments of perceived and imagined events could account for source-based differences in LPPC activity. Participants perceived and imagined items in response to cue words and then at test, made recognition judgments in blocks that knowingly contained either a high or low proportion of old to new trials. While participants were indeed more conservative when making judgments about perceived than imagined events, the neuroimaging results demonstrated that response bias and source effects occurred in non-overlapping parietal regions. These findings suggest that source-based differences in LPPC activity cannot be explained by differences in response bias associated with recognizing perceived and imagined events.



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Hydroceles—Not Just For Men

Publication date: Available online 14 April 2017
Source:The Journal of Emergency Medicine
Author(s): Danielle Biggs, Amy Patwa, Steve Gohsler
BackgroundHydroceles develop in females through the canal of Nuck. This canal is formed when the processes vaginalis fails to obliterate during development. The canal of Nuck can lead to the formation of not only hydroceles, but hernias as well. Although physicians typically think of hydroceles occurring in males, on rare occasions, they do occur in females because of this defect. They are often mistaken for incarcerated hernias, making ultrasound an excellent tool to distinguish between them and guide further treatment.Case ReportWe report a rare case of a 46-year-old female with the chief complaint of a painful groin mass. A diagnosis of a hydrocele was made by point of care ultrasonography in the emergency department after being misdiagnosed by computed tomography scan on two previous occasions.Why Should an Emergency Physician Be Aware of This?Point of care ultrasound (POCUS) is a valuable tool for emergency physicians and can lead to quick diagnoses and appropriate management of the patient. Using ultrasound in conjunction with other imaging modalities can improve diagnostic accuracy. POCUS is portable and a powerful tool for immediate answers, and continues to prove its utility for clinical decision making.



http://ift.tt/2nPa2ZO

Initial Asthma Severity Assessment Tools as Predictors of Hospitalization

Publication date: Available online 14 April 2017
Source:The Journal of Emergency Medicine
Author(s): Natalia Paniagua, Amaia Elosegi, Isabel Duo, Ana Fernandez, Elisa Mojica, Lorea Martinez-Indart, Santiago Mintegi, Javier Benito
BackgroundAssessment tools to classify and prioritize patients, such as systems of triage, and indicators of severity, such as clinical respiratory scores, are helpful in guiding the flow of asthmatic patients in the emergency department.ObjectiveOur aim was to assess the performance of the Pediatric Assessment Triangle (PAT), triage level (TL), Pulmonary Score (PS), and initial O2 saturation (O2 sat), in predicting hospitalization in pediatric acute asthma exacerbations.Study DesignRetrospective study evaluating PAT, TL, and PS at presentation, and initial O2 sat of asthmatic children in the pediatric emergency department (PED). The primary outcome measure was the rate of hospitalization. Secondary outcomes were length of stay (LOS) in the PED and admission to the pediatric intensive care unit (PICU).ResultsPAT, TL, PS, and initial O2 sat were recorded in 14,953 asthmatic children. Multivariate analysis yielded the following results: Abnormal PAT and more severe TLs (I–II) were independent risk factors for hospitalization (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.4–1.8; OR 3.4, 95% CI 2.6–4.3, respectively) and longer LOS (OR 1.5, 95% CI 1.3–1.7; OR 2.6, 95% CI 2–3.3, respectively). PS > 3 showed a strong association with hospitalization (OR 8.1, 95% CI 7–9.4), PICU admission (OR 9.6, 95% CI 3–30.9) and longer LOS (OR 6.2, 95% CI 5.6–6.9). O2 sat < 94% was an independent predictor of admission (OR 5.2, 95% CI 4.6–5.9), PICU admission (OR 4.6, 95% CI 4.5–4.6), and longer LOS (OR 4.6, 95% CI 4.1–5.2).ConclusionsPAT, TL, PS, and initial O2 sat are good predictors of hospitalization in pediatric acute asthma exacerbations.



http://ift.tt/2pmWuBI

Editorial Board

Publication date: May 2017
Source:Dental Materials, Volume 33, Issue 5





http://ift.tt/2pjc8Rr

Dentin on the nanoscale: Hierarchical organization, mechanical behavior and bioinspired engineering

Publication date: Available online 14 April 2017
Source:Dental Materials
Author(s): Luiz E. Bertassoni
ObjectiveKnowledge of the structural organization and mechanical properties of dentin has expanded considerably during the past two decades, especially on a nanometer scale. In this paper, we review the recent literature on the nanostructural and nanomechanical properties of dentin, with special emphasis in its hierarchical organization.MethodsWe give particular attention to the recent literature concerning the structural and mechanical influence of collagen intrafibrillar and extrafibrillar mineral in healthy and remineralized tissues. The multilevel hierarchical structure of collagen, and the participation of non-collagenous proteins and proteoglycans in healthy and diseased dentin are also discussed. Furthermore, we provide a forward-looking perspective of emerging topics in biomaterials sciences, such as bioinspired materials design and fabrication, 3D bioprinting and microfabrication, and briefly discuss recent developments on the emerging field of organs-on-a-chip.ResultsThe existing literature suggests that both the inorganic and organic nanostructural components of the dentin matrix play a critical role in various mechanisms that influence tissue properties.SignificanceAn in-depth understanding of such nanostructural and nanomechanical mechanisms can have a direct impact in our ability to evaluate and predict the efficacy of dental materials. This knowledge will pave the way for the development of improved dental materials and treatment strategies.ConclusionsDevelopment of future dental materials should take into consideration the intricate hierarchical organization of dentin, and pay particular attention to their complex interaction with the dentin matrix on a nanometer scale.



http://ift.tt/2pj8k2J

Inequalities in Abdominal Aortic Aneurysm Screening in England: Effects of Social Deprivation and Ethnicity

Publication date: Available online 14 April 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): J. Jacomelli, L. Summers, A. Stevenson, T. Lees, J.J. Earnshaw
ObjectivePopulation screening for abdominal aortic aneurysm (AAA) in men is currently ongoing in several countries. The aim was to examine the effects of deprivation and ethnicity on uptake of screening for abdominal aortic aneurysm (AAA) and prevalence of AAA.MethodsThis was a review of outcomes from a population screening programme using data collected contemporaneously on a bespoke national database. Men aged 65 in two annual cohorts (2013/14 and 2014/15) were invited for AAA screening. Attendance and prevalence of AAA (aortic diameter >2.9 cm) were recorded. Results were compared according to measures of social deprivation and recorded ethnicity.ResultsSome 593,032 men were invited and 461,898 attended for ultrasound screening; uptake 77.9%. Uptake was related to social deprivation: 65.1% in the most deprived decile, 84.1% in the least deprived: OR for least deprived 2.84, 95% CI 2.76-2.92, p<.0001. Men in deprived areas were more likely to actively decline screening: 6% versus 3.8% in the least deprived decile. AAA were twice as common in the most deprived compared with the least deprived decile: OR 2.1, 95% CI 1.77-2.27, p<.0001. AAA were more common in white British men than in black (OR 0.46, 95% CI 0.31-0.71) or Asian (OR 0.18, 95% CI 0.13-0.26) men. There was considerable local variation in all findings.ConclusionsSocial deprivation affects uptake of AAA screening in 65 year old men. Local factors are the most important determinants of uptake, so solutions to improve uptake must be designed at local, not national level.



http://ift.tt/2oefvW5

Cry toxin specificities of insect ABCC transporters closely related to lepidopteran ABCC2 transporters

Publication date: Available online 14 April 2017
Source:Peptides
Author(s): Haruka Endo, Shiho Tanaka, Kazuhiro Imamura, Satomi Adegawa, Shingo Kikuta, Ryoichi Sato
In this study, we examined insect and human ABCC transporters closely related to the lepidopteran ABC transporter C2 (ABCC2), a powerful receptor for the Bacillus thuringiensis Cry toxin, for their responses to various Cry toxins. ABCC2 and the lepidopteran ABC transporter C3 (ABCC3) conferred cultured cells with susceptibility to a lepidopteran-specific Cry1Aa toxin but not to lepidopteran-specific Cry1Ca and Cry1Da. One coleopteran ABCC transporter specifically responded to a coleopteran-specific Cry8Ca toxin. ABCC transporters from a dipteran insect and humans did not respond to any of the tested Cry toxins that are active to lepidopteran and coleopteran insects. These results yield important information for our understanding of insect specificity of Cry toxins and provide the first demonstration of a coleopteran ABCC transporter that serves as a Cry toxin receptor.



http://ift.tt/2oC6qZB

Combined loss of three DNA damage response pathways renders C. elegans intolerant to light

Publication date: Available online 14 April 2017
Source:DNA Repair
Author(s): Ivo van Bostelen, Marcel Tijsterman
Infliction of DNA damage initiates a complex cellular reaction − the DNA damage response − that involves both signaling and DNA repair networks with many redundancies and parallel pathways. Here, we reveal a surprisingly simple, straightforward, linear order of events for how a simple multicellular eukaryote, C. elegans, deals with DNA damage induced by light. Separately inactivating repair or replicative bypass of photo-lesions results in cellular hypersensitivity towards UV-light, but impeding repair of replication associated DNA breaks does not. Yet, we observe an unprecedented synergistic relationship when these pathways are inactivated in combination. C. elegans mutants that lack nucleotide excision repair (NER), translesion synthesis (TLS) and alternative end joining (altEJ) grow undisturbed in the dark, but become sterile when grown in light. Even exposure to very low levels of normal daylight impedes animal growth. We show that NER and TLS operate to suppress the formation of lethal DNA breaks that require polymerase theta-mediated end joining (TMEJ) for their repair. Our data testifies to the enormous genotoxicity of light and to the demand of multiple layers of protection against an environmental threat that is so common.



http://ift.tt/2nP0Ep0

Unraveling the Regulation of Hepatic Metabolism by Insulin

Publication date: Available online 14 April 2017
Source:Trends in Endocrinology & Metabolism
Author(s): Paul M. Titchenell, Mitchell A. Lazar, Morris J. Birnbaum
During insulin-resistant states such as type 2 diabetes mellitus (T2DM), insulin fails to suppress hepatic glucose production but promotes lipid synthesis leading to hyperglycemia and hypertriglyceridemia. Defining the downstream signaling pathways underlying the control of hepatic metabolism by insulin is necessary for understanding both normal physiology and the pathogenesis of metabolic disease. We summarize recent literature highlighting the importance of both hepatic and extrahepatic mechanisms in insulin regulation of liver glucose and lipid metabolism. We posit that a failure of insulin to inappropriately regulate liver metabolism during T2DM is not exclusively from an inherent defect in canonical liver insulin signaling but is instead due to a combination of hyperinsulinemia, altered substrate supply, and the input of several extrahepatic signals.



http://ift.tt/2oBR47y

Radiology Education

Publication date: Available online 14 April 2017
Source:Academic Radiology
Author(s): Aine Marie Kelly, Priscilla J. Slanetz




http://ift.tt/2ohAbeT

Magnetic Resonance Imaging Evaluation of Urothelial Cell Carcinoma: Histopathological Correlation, Staging, and Treatment Planning

Publication date: Available online 14 April 2017
Source:Current Problems in Diagnostic Radiology
Author(s): Peter A. Harri, Lauren Alexander, Juan C. Camacho, Courtney C. Moreno, Pardeep Mittal




http://ift.tt/2pCuTMi

Granulomatous-lymphocytic Interstitial Lung Disease in a Patient with Common Variable Immunodeficiency

Publication date: Available online 14 April 2017
Source:Current Problems in Diagnostic Radiology
Author(s): Jehan L. Shah, Sagar Amin, Nupur Verma, Tan-Lucien Mohammed
Common variable immunodeficiency (CVID) is the most common primary immunodeficiency and consists of impaired immunoglobulin production causing recurrent sinopulmonary infections. The most common cause of mortality for this disorder, however, is from the development of malignancy and autoimmune disorders. One common entity that develops is a systemic granulomatous and lymphoproliferative disorder that can cause an interstitial lung disease more formally referred to as granulomatous-lymphocytic interstitial lung disease (GL-ILD). We discuss a case of a 25-year-old female with CVID and GL-ILD and review the literature to summarize the most common radiological findings in order to raise the suspicion for GL-ILD on HRCT and delineate this from infection and other mimickers. We will also review key histopathological characteristics for diagnosis and the clinical approach and treatment options for this rare disease.IntroductionCommon variable immunodeficiency (CVID) is a primary immunodeficiency characterized by impaired immunoglobulin (Ig) production with low IgG and IgA levels resulting in the inability to make antibodies against infections.¹ While historically patients with CVID suffered most commonly from recurrent sinopulmonary infections, the use of IVIG and antibiotics have improved survival and shifted our focus to the increased risk for malignancy, mainly lymphoproliferative disorders, and autoimmune disorders, which are the main cause of mortality. Patients with CVID are often screened with HRCT to evaluate for active infections and the destructive changes associated with recurrent infections such as bronchiectasis in association with pulmonary function tests to gauge a patient′s respiratory function and tailor treatment options. One common and important distinction from pneumonia and bronchiectasis is granulomatous-lymphocytic interstitial lung disease (GL-ILD), which can be seen in 5–15% of patients with CVID and reduce the life span from an average of 29 years to 14 years. ² We present the case of a 25-year-old female diagnosed with CVID and biopsy proven GL-ILD. We will discuss the key pulmonary and extrapulmonary findings on HRCT, review the pathology, and differentiate GL-ILD from other common entities.



http://ift.tt/2nOsiSR

Spending an Evening in the Dark: The Radiology Medical Student Call Experience

Publication date: Available online 14 April 2017
Source:Current Problems in Diagnostic Radiology
Author(s): Dennis Monks, Brian Pagano, Matthew Hartman
IntroductionThe level of independent decision making required of a radiology resident, as well as the acuity of studies populating the worklist, differ between the normal work day and a call shift. However, unlike clerkships where call is standard, medical students in radiology typically only have half of the true resident experience. In order to expose our rotating medical students to what a future career in radiology might actually look like, we implemented a required call shift as part of our medical student curriculumMaterials and MethodsAll rotating third and fourth year medical students were assigned a single three-hour short call shift alongside a radiology resident during the final week of their rotation. Following this shift, students answered questions via anonymous online survey regarding their perceptions of radiology (primary endpoint) as well as workload and role of radiology in the clinical care of patients (secondary endpoints).ResultsFollowing medical student call, 63% of students reported a more positive view of radiology as a career. Additionally, 57% felt that radiology residents work as much or more than other specialties while one call, and several students identified communication issues with regards to indications or appropriateness of studies.ConclusionsWhile we hope that this overwhelmingly positive experience will draw more students into radiology as a career, we also believe that many participating medical students will benefit from a greater understanding of what a radiologist′s job entails, as well as how this may be affected by communication issues or increased utilization of imaging.



http://ift.tt/2nOyryz

upper respiratory tract infection; +22 new citations

22 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

upper respiratory tract infection

These pubmed results were generated on 2017/04/15

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

http://ift.tt/2piaAXU

Tyrosine kinase inhibitors reprogramming immunity in renal cell carcinoma: rethinking cancer immunotherapy.

Related Articles

Tyrosine kinase inhibitors reprogramming immunity in renal cell carcinoma: rethinking cancer immunotherapy.

Clin Transl Oncol. 2017 Apr 13;:

Authors: Aparicio LM, Fernandez IP, Cassinello J

Abstract
The immune system regulates angiogenesis in cancer by way of both pro- and antiangiogenic activities. A bidirectional link between angiogenesis and the immune system has been clearly demonstrated. Most antiangiogenic molecules do not inhibit only VEGF signaling pathways but also other pathways which may affect immune system. Understanding of the role of these pathways in the regulation of immunosuppressive mechanisms by way of specific inhibitors is growing. Renal cell carcinoma (RCC) is an immunogenic tumor in which angiogenesis and immunosuppression work hand in hand, and its growth is associated with impaired antitumor immunity. Given the antitumor activity of selected TKIs in metastatic RCC (mRCC), it seems relevant to assess their effect on the immune system. The confirmation that TKIs improve cell cytokine response in mRCC provides a basis for the rational combination and sequential treatment of TKIs and immunotherapy.

PMID: 28409322 [PubMed - as supplied by publisher]

http://ift.tt/2pm5180

Molecular characterization and function of tenomodulin, a marker of tendons and ligaments that integrate musculoskeletal components.

Related Articles

Molecular characterization and function of tenomodulin, a marker of tendons and ligaments that integrate musculoskeletal components.

Jpn Dent Sci Rev. 2016 Nov;52(4):84-92

Authors: Shukunami C, Yoshimoto Y, Takimoto A, Yamashita H, Hiraki Y

Abstract
Tendons and ligaments are dense fibrous bands of connective tissue that integrate musculoskeletal components in vertebrates. Tendons connect skeletal muscles to the bone and function as mechanical force transmitters, whereas ligaments bind adjacent bones together to stabilize joints and restrict unwanted joint movement. Fibroblasts residing in tendons and ligaments are called tenocytes and ligamentocytes, respectively. Tenomodulin (Tnmd) is a type II transmembrane glycoprotein that is expressed at high levels in tenocytes and ligamentocytes, and is also present in periodontal ligament cells and tendon stem/progenitor cells. Tnmd is related to chondromodulin-1 (Chm1), a cartilage-derived angiogenesis inhibitor, and both Tnmd and Chm1 are expressed in the CD31(-) avascular mesenchyme. The conserved C-terminal hydrophobic domain of these proteins, which is characterized by the eight Cys residues to form four disulfide bonds, may have an anti-angiogenic function. This review highlights the molecular characterization and function of Tnmd, a specific marker of tendons and ligaments.

PMID: 28408960 [PubMed - in process]

http://ift.tt/2plKNv0

Nogo-A in the visual system development and in ocular diseases.

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Nogo-A in the visual system development and in ocular diseases.

Biochim Biophys Acta. 2017 Apr 10;:

Authors: Pernet V

Abstract
Nogo-A is a potent myelin-associated inhibitor for neuronal growth and plasticity in the central nervous system (CNS). Its effects are mediated by the activation of specific receptors that intracellularly control cytoskeleton rearrangements, protein synthesis and gene expression. Moreover, Nogo-A has been involved in the development of the visual system and in a variety of neurodegenerative diseases and injury processes that can alter its function. For example, Nogo-A was shown to influence optic nerve myelinogenesis, the formation and maturation of retinal axon projections, and retinal angiogenesis. In adult animals, the inactivation of Nogo-A exerted remarkable effects on visual plasticity. Relieving Nogo-A-induced inhibition increased axonal sprouting after optic nerve lesion and axonal rewiring in the visual cortex of intact adult mice. This review aims at presenting our current knowledge on the role of Nogo-A in the visual system and to discuss how its therapeutic targeting may promote visual improvement in ophthalmic diseases.

PMID: 28408340 [PubMed - as supplied by publisher]

http://ift.tt/2plXSoa

Nasal powders of thalidomide for local treatment of nose bleeding in persons affected by hereditary hemorrhagic telangiectasia.

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Nasal powders of thalidomide for local treatment of nose bleeding in persons affected by hereditary hemorrhagic telangiectasia.

Int J Pharm. 2016 Nov 30;514(1):229-237

Authors: Colombo G, Bortolotti F, Chiapponi V, Buttini F, Sonvico F, Invernizzi R, Quaglia F, Danesino C, Pagella F, Russo P, Bettini R, Colombo P, Rossi A

Abstract
In this work nasal powder formulations of thalidomide were designed and studied to be used by persons affected by hereditary hemorrhagic telangiectasia as a complementary anti-epistaxis therapy, with the goal of sustaining the effect obtained with thalidomide oral treatment after its discontinuation for adverse effects. Three nasal powders were prepared using as carriers β-CD or its more hydrophilic derivatives such as hydropropyl-β-CD and sulphobutylether-β-CD and tested with respect to technological and biopharmaceutical features after emission with active and passive nasal powder devices. For all formulated powders, improved dissolution rate was found compared to that of the raw material, making thalidomide promptly available in the nasal environment at a concentration favouring an accumulation in the mucosa. The very limited transmucosal transport measured in vitro suggests a low likelihood of significant systemic absorption. The topical action on bleeding could benefit from the poor absorption and from the fact that about 2-3% of the thalidomide applied on the nasal mucosa was accumulated within the tissue, particularly with the β-CD nasal powder.

PMID: 27863666 [PubMed - indexed for MEDLINE]

http://ift.tt/2nOx4zG

Physicochemical Characterization of a Polysaccharide Fraction from Platycladus orientalis (L.) Franco and Its Macrophage Immunomodulatory and Anti-Hepatitis B Virus Activities.

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Physicochemical Characterization of a Polysaccharide Fraction from Platycladus orientalis (L.) Franco and Its Macrophage Immunomodulatory and Anti-Hepatitis B Virus Activities.

J Agric Food Chem. 2016 Jul 27;64(29):5813-23

Authors: Lin Z, Liao W, Ren J

Abstract
A polysaccharide fraction, here called POP1, was purified from the leaves of Platycladus orientalis (L.) Franco by water extraction and alcohol precipitation. Physicochemical characterization indicated that POP1 had a relative molecular weight of 8.10 × 10(3) Da and consisted of rhamnose (5.74%), arabinose (12.58%), mannose (10.97%), glucose (64.96%), and galactose (6.55%). The main linkage types of POP1 consisted of (1→5)-linked α-l-Ara, (1→3)-linked α-l-Man, (1→6)-linked β-l-Rha, (1→4)-linked α-d-Glc, (1→6)-linked α-d-Glc, (1→6)-linked β-d-Gal, (1→3,6)-linked β-d-Gal, and termination with α-l-Man and α-d-Glc residues based on periodate oxidation, Smith degradation, methylation, and NMR analysis. POP1 exhibited excellent immunostimulating activity by enhancing macrophage NO, TNF-α, IL-6, and IL-12 secretion and activating related mRNA expression. Besides, POP1 showed significant anti-HBV activity through inhibiting the expression of HBsAg (IC50 = 1.33 ± 0.12 mg/mL) and HBeAg (IC50 = 1.67 ± 0.13 mg/mL) and interfering with the HBV DNA replication (IC50 = 0.80 ± 0.03 mg/mL). The present study suggested that POP1 could be used as immunoregulatory agent in functional foods for the prevention of HBV infection.

PMID: 27345527 [PubMed - indexed for MEDLINE]

http://ift.tt/2pm4naG

MiR-150 Regulates Poststroke Cerebral Angiogenesis via Vascular Endothelial Growth Factor in Rats.

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MiR-150 Regulates Poststroke Cerebral Angiogenesis via Vascular Endothelial Growth Factor in Rats.

CNS Neurosci Ther. 2016 06;22(6):507-17

Authors: He QW, Li Q, Jin HJ, Zhi F, Suraj B, Zhu YY, Xia YP, Mao L, Chen XL, Hu B

Abstract
AIMS: Angiogenesis is a harmonized target for poststroke recovery. Therefore, exploring the mechanisms involved in angiogenesis after stroke is vitally significant. In this study, we are reporting a miR-150-based mechanism underlying cerebral poststroke angiogenesis.
METHODS: Rat models of middle cerebral artery occlusion (MCAO) and cell models of oxygen-glucose deprivation were conducted. Capillary density, tube formation, cell proliferation, and cell migration were measured by FITC-dextran assay, matrigel assay, Ki-67 staining, and wound healing assay, respectively. The expression of miR-150 and vascular endothelial growth factor (VEGF) was, respectively, measured by RT-PCR and Western blotting. Dual-luciferase assay was conducted to confirm the binding sites between miR-150 and VEGF.
RESULTS: We found that miR-150 expression in the brain and serum of rats subjected to cerebral ischemia, and in oxygen-glucose-deprived brain microvascular endothelial cells (BMVECs) and astrocytes. Upregulation of miR-150 expression could decrease vascular density of infarct border zone in rat after MCAO and decrease tube formation, proliferation, and migration of BMVECs. We also found that miR-150 could negatively regulate the expression of VEGF, and VEGF was confirmed to be a direct target of miR-150. Moreover, VEGF mediated the function of miR-150 on tube formation, proliferation, and migration of BMVECs.
CONCLUSIONS: Our data suggested that miR-150 could regulate cerebral poststroke angiogenesis in rats through VEGF.

PMID: 26922365 [PubMed - indexed for MEDLINE]

http://ift.tt/2pimn8E

Morphological Changes of Cortical and Hippocampal Neurons after Treatment with VEGF and Bevacizumab.

Related Articles

Morphological Changes of Cortical and Hippocampal Neurons after Treatment with VEGF and Bevacizumab.

CNS Neurosci Ther. 2016 Jun;22(6):440-50

Authors: Latzer P, Schlegel U, Theiss C

Abstract
AIMS: Vascular endothelial growth factor (VEGF) is a hallmark of glioblastoma multiforme (GBM) and plays an important role in brain development and function. Recently, it has been reported that treatment of GBM patients with bevacizumab, an anti-VEGF antibody, may cause a decline in neurocognitive function and compromise quality of life. Therefore, we investigated the effects of VEGF and bevacizumab on the morphology and on survival of neurons and glial cells.
METHODS: Dissociated cortical and hippocampal cell cultures of juvenile rats were treated with VEGF, bevacizumab, and VEGF + bevacizumab. Neuronal and glial cell viability was analyzed, and the morphology of neurons was objectified by morphometric analysis.
RESULTS: In cortical cultures, bevacizumab significantly decreased the number of neurons after 20 days and the number of glial cells subsequent 30 days. Additionally, an increase in the dendritic length of cortical neurons was obvious after 10 days of incubation with bevacizumab, but returned to control level after 30 days. In hippocampal cultures, cell viability was not affected by bevacizumab; however, dendritic length increased at day 10, but decreased after long-term treatment.
CONCLUSION: Therefore, bevacizumab obviously has a cytotoxic effect in cortical cultures and decreases the dendritic length in hippocampal neurons after long-term treatment.

PMID: 26861512 [PubMed - indexed for MEDLINE]

http://ift.tt/2plKMaq

Rapid Long-Range Disynaptic Inhibition Explains the Formation of Cortical Orientation Maps.

Related Articles

Rapid Long-Range Disynaptic Inhibition Explains the Formation of Cortical Orientation Maps.

Front Neural Circuits. 2017;11:21

Authors: Antolík J

Abstract
Competitive interactions are believed to underlie many types of cortical processing, ranging from memory formation, attention and development of cortical functional organization (e.g., development of orientation maps in primary visual cortex). In the latter case, the competitive interactions happen along the cortical surface, with local populations of neurons reinforcing each other, while competing with those displaced more distally. This specific configuration of lateral interactions is however in stark contrast with the known properties of the anatomical substrate, i.e., excitatory connections (mediating reinforcement) having longer reach than inhibitory ones (mediating competition). No satisfactory biologically plausible resolution of this conflict between anatomical measures, and assumed cortical function has been proposed. Recently a specific pattern of delays between different types of neurons in cat cortex has been discovered, where direct mono-synaptic excitation has approximately the same delay, as the combined delays of the disynaptic inhibitory interactions between excitatory neurons (i.e., the sum of delays from excitatory to inhibitory and from inhibitory to excitatory neurons). Here we show that this specific pattern of delays represents a biologically plausible explanation for how short-range inhibition can support competitive interactions that underlie the development of orientation maps in primary visual cortex. We demonstrate this statement analytically under simplifying conditions, and subsequently show using network simulations that development of orientation maps is preserved when long-range excitation, direct inhibitory to inhibitory interactions, and moderate inequality in the delays between excitatory and inhibitory pathways is added.

PMID: 28408869 [PubMed - in process]

http://ift.tt/2oxJmtD

Anticancer Agents; +104 new citations

104 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

Anticancer Agents

These pubmed results were generated on 2017/04/15

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

http://ift.tt/2oxGFrX

Gender differences in the bacteriology of rhinosinusitis.

Related Articles

Gender differences in the bacteriology of rhinosinusitis.

Eur Arch Otorhinolaryngol. 2017 Apr 13;:

Authors: Golan Y, Gavriel H, Lazarovich T, Eviatar E

Abstract
Evaluating gender differences in pathogens involving sinonasal tract disease in patients undergoing nasal surgery for chronic and recurrent rhinosinusitis (C/R RS). Retrospective analysis of 164 positive sinonasal swab cultures taken during endoscopic sinonasal surgery between the years 2006 and 2013. Study population included 79 (48.8%) female patients and 84 (51/2%) males with a mean age of 47.3 (13-88) years. Positive Staphylococcal growth was found in 38 (23.2%) patients, positive anaerobic growth in 25 (15.2%) patients and 67 (40.9%) patients had polymicrobial growth. Staphylococcal growth in the male population was significantly higher compared to the female population (p = 0.04). Odds ratio for a polymicrobial infection in males over 60 years old compared to females was 2.17 (CI 0.63-8.08, 95%). Anaerobes were found to be more frequent in males (17.9%) than in females (12.5%). Species of Streptococci showed no difference between gender and age groups. The results obtained suggest a difference between the causing pathogens in C/R RS between females and males. In the male population, staphylococcal species were found to be significantly more common with a greater tendency to polymicrobial pathogens and higher rates of anaerobes. These results might suggest different management protocols perioperatively in males and females.

PMID: 28409263 [PubMed - as supplied by publisher]

http://ift.tt/2pCp81c

Radioguided occult lesion localization for locally recurrent thyroid carcinoma.

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Radioguided occult lesion localization for locally recurrent thyroid carcinoma.

Eur Arch Otorhinolaryngol. 2017 Apr 13;:

Authors: Gulcelik MA, Karaman N, Dogan L, Sahiner I, Akgul GG, Kahraman YS, Vural GU

Abstract
The aim of this study was to present our experiences with patients operated on for the recurrence of papillary thyroid cancer with the combined use of preoperative ultrasonographic mapping and radioguided occult lesion localization (ROLL). Twenty patients who had already undergone total thyroidectomy and central/lateral neck dissection for papillary thyroid carcinoma were reoperated on due to locoregional metastasis. The patients with proven recurrences and high Tg wash-out levels in cytopathologic aspirates were operated on. For each patient, numbers of marked and non-marked lesions, and the metastatic and total numbers of marked/non-marked and non-mentioned lesions in the maps were recorded. Thirty-four of 40 (85%) lesions removed with ROLL were found to be malignant. In addition to the marked lesions during mapping, 60 additional lesions had been defined as suspicious. Fifty-six of these lesions were found at exact anatomic sites and localizations described and removed. Of 56 lesions, 36 (64%) were found to be metastatic. During postoperative follow-up, chylous leak with spontaneous regression in 7 days and seroma occurred in one patient. Radioguided occult lesion localization and preoperative mapping contribute to the safety and comfort of patients in planned reoperations on lateral and central neck regions.

PMID: 28409262 [PubMed - as supplied by publisher]

http://ift.tt/2nOut8U

Modeling sleep and neuropsychiatric disorders in zebrafish

Publication date: June 2017
Source:Current Opinion in Neurobiology, Volume 44
Author(s): Talia Levitas-Djerbi, Lior Appelbaum
What are the molecular and cellular mechanisms that link neurological disorders and sleep disturbances? The transparent zebrafish model could bridge this gap in knowledge due to its unique genetic and imaging toolbox, and amenability to high-throughput screening. Sleep is well-characterized in zebrafish and key regulators of the sleep/wake cycle are conserved, including melatonin and hypocretin/orexin (Hcrt), whereas novel sleep regulating proteins are continually being identified, such as Kcnh4a, Neuromedin U, and QRFP. Sleep deficiencies have been observed in various zebrafish models for genetic neuropsychiatric disorders, ranging from psychomotor retardation and autism to anxiety disorders. Understanding the link between neuropsychiatric disorders and sleep phenotypes in zebrafish may ultimately provide a platform for identifying therapeutic targets for clinical trials in humans.

Graphical abstract

http://ift.tt/2p4LRGH

Role of prophylactic central neck dissection in clinically node-negative differentiated thyroid cancer: assessment of the risk of regional recurrence.

Related Articles

Role of prophylactic central neck dissection in clinically node-negative differentiated thyroid cancer: assessment of the risk of regional recurrence.

Updates Surg. 2017 Apr 13;:

Authors: Calò PG, Lombardi CP, Podda F, Sessa L, Santini L, Conzo G

Abstract
Prophylactic central neck dissection in clinically node-negative patients remains controversial. The aim of this multicenter retrospective study was to determine the rate of metastases in the central neck in clinically node-negative differentiated thyroid cancer patients, to examine the morbidity, and to assess the risk of regional recurrence in patients treated with total thyroidectomy with concomitant bilateral or ipsilateral central neck dissection compared with those undergoing total thyroidectomy alone. 258 consecutive clinically node-negative patients were divided into three groups according to the procedures performed: total thyroidectomy only (group A), total thyroidectomy with concomitant ipsilateral central neck dissection (group B), and total thyroidectomy combined with bilateral central neck dissection (group C). Mean operative time and postoperative stay were shorter in Group A (p < 0.01). The incidence of postoperative transient hypoparathyroidism was lower in Group A (p = 0.03), whereas no differences in the incidence of permanent hypoparathyroidism and nerve palsy were present. Postoperative radioactive iodine administration was higher in group B and particularly C (p = 0.03) compared with group A. There were no statistically significant differences in terms of regional recurrence. Differentiated thyroid cancer has a high rate of central lymph node metastasis even in clinically node-negative patients; in the present study there was no statistically significant difference in the rates of locoregional recurrence between the three modalities of treatment. Total thyroidectomy appears to be an adequate treatment for clinically node-negative differentiated thyroid cancer. Prophylactic central neck dissection might be considered for differentiated thyroid cancer patients with large tumor size or extrathyroidal extension.

PMID: 28409443 [PubMed - as supplied by publisher]

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Alternative Means of Estimating (131)I Maximum Permissible Activity to Treat Thyroid Cancer.

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Alternative Means of Estimating (131)I Maximum Permissible Activity to Treat Thyroid Cancer.

J Nucl Med. 2017 Apr 13;:

Authors: Nichols KJ, Robeson W, Yoshida-Hay M, Zanzonico PB, Leveque FC, Bhargava KK, Tronco GG, Palestro CJ

Abstract
To protect bone marrow from over-irradiation, maximum permissible activity (MPA) of iodine-131 ((131)I) to treat thyroid cancer is that which limits absorbed dose to blood (as a surrogate of marrow) to < 200 cGy. The conventional approach (Method-1) requires repeated gamma-camera whole-body measurements along with blood samples. We sought to determine whether reliable MPA values can be obtained by simplified procedures. Methods: Data acquired over multiple time points were examined retrospectively for 65 thyroid cancer patients, referred to determine (131)I uptake and MPA for initial treatment following thyroidectomy (N = 39), including 17 patients with compromised renal function and 22 patients with known (N = 16) or suspected (N = 6) metastases. Total absorbed dose to blood (DTotal) was the sum of mean whole-body γ ray dose component (Dγ) from un-collimated gamma-camera measurements, and dose due to β emissions (Dβ) from blood samples. Method-2 estimated DTotal from Dβ alone, Method-3 estimated DTotal from Dγ alone, and Method-4 estimated DTotal from a single 48-hour gamma-camera measurement. MPA was computed as 200 cGy/DTotal for each DTotal estimate. Results: Method-2 had strongest correlation with conventional Method-1 (r = 0.98) and values similar to Method-1 (21.0±13.7 cGy/GBq versus 21.0±14.1 cGy/GBq, P = 0.11), while Method-3 had a weaker (P = 0.001) correlation (r = 0.94), and Method-4 had weakest (P < 0.0001) correlation ( r = 0.69) and lower dose (16.3±14.8 cGy/GBq, P < 0.0001). Consequently, correlation with Method-1 MPA was strongest for Method-2 MPA (r = 0.99) and weakest for Method-4 (r = 0. 75). Method-2 and Method-1 values agreed equally well regardless of whether patients had been treated with (131)I previously or had abnormal renal function. Conclusion: Because MPA based on blood measurements alone is comparable to MPA obtained with combined body counting and blood sampling, blood measurements alone are sufficient for determining MPA.

PMID: 28408530 [PubMed - as supplied by publisher]

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Clival chordomas: considerations after 16 years of endoscopic endonasal surgery.

Clival chordomas: considerations after 16 years of endoscopic endonasal surgery.

J Neurosurg. 2017 Apr 14;:1-10

Authors: Zoli M, Milanese L, Bonfatti R, Faustini-Fustini M, Marucci G, Tallini G, Zenesini C, Sturiale C, Frank G, Pasquini E, Mazzatenta D

Abstract
OBJECTIVE In the past decade, the role of the endoscopic endonasal approach (EEA) has relevantly evolved for skull base tumors. In this study, the authors review their surgical experience with using an EEA in the treatment of clival chordomas, which are deep and infiltrative skull base lesions, and they highlight the advantages and limitations of this ventral approach. METHODS All consecutive cases of chordoma treated with an EEA between 1998 and 2015 at a single institution are included in this study. Preoperative assessment consisted of neuroimaging (MRI and CT with angiography sequences) and endocrinological, neurological, and ophthalmological evaluations, which were repeated 3 months after surgery and annually thereafter. Postoperative adjuvant therapies were considered. RESULTS Sixty-five patients (male/female ratio 1:0.9) were included in this study. The median age was 48 years (range 9-80 years). Gross-total resection (GTR) was achieved in 47 cases (58.7%). On univariate analysis, primary procedures (p = 0.001), location in the superior or middle third of the clivus (p = 0.043), extradural location (p = 0.035), and histology of conventional chordomas (p = 0.013) were associated with a higher rate of GTR. The complication rate was 15.1%, and there were no perioperative deaths. Most complications did not result in permanent sequelae and included 2 CSF leaks (2.5%), 5 transient cranial nerve VI palsies (6.2%), and 2 internal carotid artery injuries (2.5%), which were treated with coil occlusion of the internal carotid artery without neurological deficits. Three patients (3.8%) presented with complications resulting in permanent neurological deficits due to a postoperative hematoma (1.2%) causing a hemiparesis, and 2 permanent ophthalmoplegias (2.5%). Seventeen patients (26.2%) have died of tumor progression over the course of follow-up (median 52 months, range 7-159 months). Based on Kaplan-Meier analysis, the survival rate was 77% at 5 years and 57% at 10 years. On multivariate analysis, the extent of tumor removal (p = 0.001) and the absence of previous treatments (p = 0.001) proved to be correlated with a longer survival rate. CONCLUSIONS The EEA was associated with a high rate of tumor removal and symptom control, with low morbidity and preservation of a good quality of life. These results allow for a satisfactory overall survival rate, particularly after GTR and for primary surgery. Considering these results, the authors believe that an EEA can be a helpful tool in chordoma surgery, achieving a good balance between as much tumor removal as possible and the preservation of an acceptable patient quality of life.

PMID: 28409727 [PubMed - as supplied by publisher]

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Post-operative diffusion weighted imaging as a predictor of posterior fossa syndrome permanence in paediatric medulloblastoma.

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Post-operative diffusion weighted imaging as a predictor of posterior fossa syndrome permanence in paediatric medulloblastoma.

Childs Nerv Syst. 2017 Mar;33(3):457-465

Authors: Chua FH, Thien A, Ng LP, Seow WT, Low DC, Chang KT, Lian DW, Loh E, Low SY

Abstract
PURPOSE: Posterior fossa syndrome (PFS) is a serious complication faced by neurosurgeons and their patients, especially in paediatric medulloblastoma patients. The uncertain aetiology of PFS, myriad of cited risk factors and therapeutic challenges make this phenomenon an elusive entity. The primary objective of this study was to identify associative factors related to the development of PFS in medulloblastoma patient post-tumour resection.
METHODS: This is a retrospective study based at a single institution. Patient data and all related information were collected from the hospital records, in accordance to a list of possible risk factors associated with PFS. These included pre-operative tumour volume, hydrocephalus, age, gender, extent of resection, metastasis, ventriculoperitoneal shunt insertion, post-operative meningitis and radiological changes in MRI. Additional variables included molecular and histological subtypes of each patient's medulloblastoma tumour. Statistical analysis was employed to determine evidence of each variable's significance in PFS permanence.
RESULTS: A total of 19 patients with appropriately complete data was identified. Initial univariate analysis did not show any statistical significance. However, multivariate analysis for MRI-specific changes reported bilateral DWI restricted diffusion changes involving both right and left sides of the surgical cavity was of statistical significance for PFS permanence.
CONCLUSION: The authors performed a clinical study that evaluated possible risk factors for permanent PFS in paediatric medulloblastoma patients. Analysis of collated results found that post-operative DWI restriction in bilateral regions within the surgical cavity demonstrated statistical significance as a predictor of PFS permanence-a novel finding in the current literature.

PMID: 28190209 [PubMed - indexed for MEDLINE]

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Posterior fossa syndrome with delayed MR evidence of unilateral superior cerebellar peduncle (SCP) damage.

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Posterior fossa syndrome with delayed MR evidence of unilateral superior cerebellar peduncle (SCP) damage.

Childs Nerv Syst. 2017 Mar;33(3):503-507

Authors: Carr K, Ghamasaee P, Singh A, Tarasiewicz I

Abstract
Posterior fossa syndrome (PFS) is a well-known sequela of midline posterior fossa tumor resection. Patients typically exhibit transient behavioral, motor, and oculomotor disturbances that resolve within a few weeks to several months after surgery. The underlying pathophysiology of PFS is not completely understood, but contemporary literature has implicated injury to the dentate nucleus and/or exiting dentatothalamocortical fiber bundles as a causative factor. The authors present a case of a young male who developed a delayed variant of PFS typified by motor deficits and demonstrated diffusion restriction in the ipsilateral superior cerebellar peduncle. Because the correlation between PFS and the superior cerebellar peduncle injury is poorly described in the literature, particularly with regard to relevant radiographic imaging, the authors of this report hope their findings will contribute to that insufficient body of evidence.

PMID: 27830331 [PubMed - indexed for MEDLINE]

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The keys to conservative treatment of early-stage squamous cell carcinoma of the tonsillar region

Publication date: Available online 14 April 2017
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): O. Laccourreye, P. Castelnau-Marchand, F. Rubin, C. Badoual, P. Halimi, P. Giraud
To analyze the medical literature devoted to work-up, epidemiology, local control, survival, complications and sequelae after conservative treatment for early-stage squamous cell carcinoma of the tonsillar region. An analysis of the PubMed (1975–2016) database was performed using the following keywords and associations: "tonsil/tonsillar region/oropharynx" AND "squamous cell carcinoma" AND "early-stage (I–II; T1–2N0M0)" AND "radiation therapy/radiotherapy" OR "conservative surgery/oropharyngectomy/transoral surgery/radical tonsillectomy". The search retrieved 10 retrospective series documenting local control and/or survival in series with more than 50 cases and a minimum 2 years' follow-up after conservative treatment; no prospective studies, meta-analyses and/or Cochrane analyses were found. Magnetic resonance imaging is the key radiological exam for local extension assessment. Human papilloma virus infection (HPV) is a risk factor that must be screened for systematically, since it induces tumoral radio-sensitivity and increases the risk of specific synchronous and metachronous second primaries. Whatever conservative treatment used, local control and survival rates higher than 85% were achieved. Implementing intensity-modulated radiation therapy reduced the incidence and severity of radiation-related complications and sequelae. Transoral surgery yielded very low morbidity/mortality rates, enabled association to ipsilateral neck dissection, and allowed radiation therapy to be reserved for the management of metachronous second primaries. Transoral surgery appeared to be the first-line option in the majority of cases. Lifetime follow-up adapted to HPV status is mandatory. The development of HPV vaccination does not mean that campaigns against smoking and alcohol abuse are of diminished importance.



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DNA–Protein Crosslink Proteolysis Repair

Publication date: Available online 14 April 2017
Source:Trends in Biochemical Sciences
Author(s): Bruno Vaz, Marta Popovic, Kristijan Ramadan
Proteins that are covalently bound to DNA constitute a specific type of DNA lesion known as DNA–protein crosslinks (DPCs). DPCs represent physical obstacles to the progression of DNA replication. If not repaired, DPCs cause stalling of DNA replication forks that consequently leads to DNA double-strand breaks, the most cytotoxic DNA lesion. Although DPCs are common DNA lesions, the mechanism of DPC repair was unclear until now. Recent work unveiled that DPC repair is orchestrated by proteolysis performed by two distinct metalloproteases, SPARTAN in metazoans and Wss1 in yeast. This review summarizes recent discoveries on two proteases in DNA replication-coupled DPC repair and establishes DPC proteolysis repair as a separate DNA repair pathway for genome stability and protection from accelerated aging and cancer.



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Intent to treat leukemia remission by CD19CAR T cells of defined formulation and dose in children and young adults.

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Intent to treat leukemia remission by CD19CAR T cells of defined formulation and dose in children and young adults.

Blood. 2017 Apr 13;:

Authors: Gardner RA, Finney O, Annesley C, Brakke H, Summers C, Leger K, Bleakley M, Brown C, Mgebroff S, Spratt K, Hoglund V, Lindgren C, Oron AP, Li D, Riddell SR, Park JR, Jensen MC

Abstract
Transitioning CD19-directed CAR-T cells from early phase trials in relapsed patients to a viable therapeutic approach with predictable efficacy and low toxicity for broad application in patients with high unmet need is currently complicated by product heterogeneity resulting from transduction of undefined T cell mixtures, variability of transgene expression, and terminal differentiation of cells at the end of culture. A phase 1 trial of 45 children and young adults with relapsed or refractory B-lineage ALL was conducted using a CD19 CAR product of defined CD4/CD8 composition, uniform CAR expression, and limited effector differentiation. Products meeting all defined specifications occurred in 93% of enrolled subjects. The maximal tolerated dose (MTD) was 10(6) CAR-T cells/kg, and there were no deaths or instances of cerebral edema attributable to product toxicity. The overall intent-to-treat (ITT) minimal residual disease (MRD)-negative remission rate for this Phase I study was 89%. An MRD-negative remission rate measured among subjects who received a CAR T cell product was 93%, and 100% in the subset of patients that received flu/cy lymphodepletion. Twenty-three percent of patients developed reversible severe cytokine release syndrome (sCRS) and/or reversible severe neurotoxicity (sNT). These data demonstrate that manufacturing a defined composition CD19 CAR-T cell identifies an optimal cell dose with highly potent antitumor activity and a tolerable side effect profile in a cohort of patients with an otherwise dismal prognosis.

PMID: 28408462 [PubMed - as supplied by publisher]

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Effect of combined administration of aripiprazole and fluoxetine on cognitive functions in female rats exposed to ethyl alcohol.

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Effect of combined administration of aripiprazole and fluoxetine on cognitive functions in female rats exposed to ethyl alcohol.

Acta Neurobiol Exp (Wars). 2017;77(1):86-93

Authors: Kus K, Ratajczak P, Czaja N, Zaprutko T, Nowakowska E

Abstract
Alcoholism is a chronic and recurrent disease. The studies on ethyl alcohol show a progressive deterioration of cognitive functions (motor hyperactivity, operating memory). The aim of the study was to establish whether combined single and chronic administration of aripiprazole (ARI) and fluoxetine (FLU) affects animal locomotor activity or modifies spatial memory functions in female rats exposed to ethyl alcohol. Female Wistar rats were studied in the Morris Water Maze (MWM) and locomotor activity test. Rats undergoing the MWM and locomotor activity test were injected with saline on day 1, 7, 14 and 21 of testing. Results showed a statistically significant mobility increase in the group of ethanol‑exposed females (CEt) (21 days) compared to the non-ethanol-exposed group (CNEt). Upon ARI administration to CEt, no statistically significant differences in animal mobility were found, either upon single or chronic administration. Chronic administration of FLU (21 days) as well as combined administration of ARI+FLU (14 and 21 days) caused a statistically significant reduction of the females' mobility compared to the control CEt group. Single and chronic administration of ARI (7x) both show a spatial memory improvement in CEt. No memory improvement was observed, however, after 14 and 21 days of ARI administration. FLU, likewise, improved spatial memory both upon single and chronic administration. Combined administration of ARI+FLU improved memory in CEt only upon single administration. Lack of effect upon chronic administration may be due to tolerance to memory improvement developing upon combined administration of ARI+FLU. It can be concluded that ARI (1.5 mg/kg), FLU (5 mg/kg), and combined administration of these drugs improves spatial memory in CEt.

PMID: 28379219 [PubMed - indexed for MEDLINE]

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Temozolomide does not influence the transcription or activity of matrix metalloproteinases 9 and 2 in glioma cell lines.

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Temozolomide does not influence the transcription or activity of matrix metalloproteinases 9 and 2 in glioma cell lines.

J Clin Neurosci. 2017 Apr 10;:

Authors: Suzuki Y, Fujioka K, Ikeda K, Murayama Y, Manome Y

Abstract
Glioblastoma multiforme (GBM) is a treatment-resistant malignancy with poor prognosis. Temozolomide (TMZ) is widely used as a first-line drug for GBM. Although this improves patient prognosis, it does not completely eradicate the tumour. Even after total surgical resection, GBM can exhibit uncontrollable invasiveness at the tumour margins owing to activation of matrix metalloproteinases (MMPs) such as MMP-2 and -9; these degrade collagen IV in the basement membrane, which normally prevents cancer invasion. TMZ induces DNA damage and activates transcription factors including c-jun, c-fos, nuclear factor-κβ, and early growth response protein-1, which have putative binding sites on the MMP-9 promoter. TMZ may therefore enhance tumour invasion by stimulating MMP-9 transcription and enzymatic activity. To test this hypothesis, we investigated MMP-2 and -9 mRNA transcription and activity in GBM cell lines treated with TMZ. Human A172 GBM cells were exposed to TMZ (25% and 50% inhibitory concentrations) for 24 or 48h; cell cycle distribution and mRNA levels of MMP-2 and -9 were evaluated using flow cytometry and semi-quantitative reverse transcription PCR, respectively. MMP-2 and -9 enzymatic activities were assessed using gelatin zymography in human A172 and U373 MG GBM cells exposed to TMZ under the same conditions. TMZ altered A172 cell cycle distribution, but not MMP-2 or -9 mRNA levels. TMZ did not affect MMP-2 or -9 enzymatic activities in A172 or U373 MG cells. These findings indicated that TMZ is therefore unlikely to promote GBM invasiveness.

PMID: 28408249 [PubMed - as supplied by publisher]

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Extraforaminal compression of the L5 nerve: An anatomical study with application to failed posterior decompressive procedures.

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Extraforaminal compression of the L5 nerve: An anatomical study with application to failed posterior decompressive procedures.

J Clin Neurosci. 2017 Apr 10;:

Authors: Tubbs RS, Iwanaga J, Aly I, Moisi MD, Hanscom DR, Chapman JR, Loukas M, Oskouian RJ

Abstract
This anatomical study was performed to elucidate the pertinent foraminal and lateral L5 nerve anatomy to enhance our understanding of possible neurologic causes of failed decompression surgery. Persistent extraforaminal L5 nerve compression is a possible cause of persistent symptoms following lumbosacral surgery. The amount of extraforaminal space for the L5 ventral ramus was examined in fifty adult human skeletons (100 sides). Based on morphology, the specimens were then categorized (types I-IV) on the basis of the bony space available for the nerve at this location. Next, 25 embalmed adult cadavers (50 sides) underwent bilateral dissection of the lower lateral lumbar region. The type of bony extraforaminal outlet was documented for each cadaver on the basis of our skeletal analysis. Lastly, segments (intra- and extra-foraminal) of the L5 ventral ramus were excised and examined histologically. Types I-IV outlets were found in 43, 31, 20 and 6 skeletal sides, respectively. For cadavers, 22,15, 10 and 3 sides were found to have types I-IV bony outlets, respectively. In cadavers, all type IV outlets and 70% of the type III bony configurations adjacent to the L5 ventral ramus had signs of neural irritation/injury including vascular hyalinization and increased fibrosis distal to the intervertebral foramen. No distal segments of type I and type II outlets showed histological signs of neural compromise. Patients with symptoms referable to L5 nerve compression for whom no proximal pathology is identified could warrant investigation of the more distal extraforaminal segment of this nerve.

PMID: 28408248 [PubMed - as supplied by publisher]

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Molecular profiling of gene copy number abnormalities in key regulatory genes in high-risk B-lineage acute lymphoblastic leukemia: frequency and their association with clinicopathological findings in Indian patients.

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Molecular profiling of gene copy number abnormalities in key regulatory genes in high-risk B-lineage acute lymphoblastic leukemia: frequency and their association with clinicopathological findings in Indian patients.

Med Oncol. 2017 May;34(5):92

Authors: Bhandari P, Ahmad F, Das BR

Abstract
Genes related to key cellular pathways are frequently altered in B cell ALL and are associated with poor survival especially in high-risk (HR) subgroups. We examined gene copy number abnormalities (CNA) in 101 Indian HR B cell ALL patients and their correlation with clinicopathological features by multiplex ligation-dependent probe amplification. Overall, CNA were detected in 59 (59%) cases, with 26, 10 and 23% of cases harboring 1, 2 or +3 CNA. CNA were more prevalent in BCR-ABL1 (60%), pediatric (64%) and high WCC (WBC count) (63%) patients. Frequent genes deletions included CDNK2A/B (26%), IKZF1 (25%), PAX5 (14%), JAK2 (7%), BTG1 (6%), RB1 (5%), EBF1 (4%), ETV6 (4%), while PAR1 region genes were predominantly duplicated (20%). EBF1 deletions selectively associated with adults, IKZF1 deletions occurred frequently in high WCC and BCR-ABL1 cases, while PAR1 region gains significantly associated with MLL-AF4 cases. IKZF1 haploinsufficiency group was predominant, especially in adults (65%), high WCC (60%) patients and BCR-ABL1-negative (78%) patients. Most cases harbored multiple concurrent CNA, with IKZF1 concomitantly occurring with CDNK2A/B, PAX5 and BTG1, while JAK2 occurred with CDNK2A/B and PAX5. Mutually exclusive CNA included ETV6 and IKZF1/RB1, and EBF1 and JAK2. Our results corroborate with global reports, aggregating molecular markers in Indian HR B-ALL cases. Integration of CNA data from rapid methods like MLPA, onto background of existing gold-standard methods detecting significant chromosomal abnormalities, provides a comprehensive genetic profile in B-ALL.

PMID: 28401483 [PubMed - indexed for MEDLINE]

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B-Cell and Classical Hodgkin Lymphomas Associated With Immunodeficiency: 2015 SH/EAHP Workshop Report-Part 2.

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B-Cell and Classical Hodgkin Lymphomas Associated With Immunodeficiency: 2015 SH/EAHP Workshop Report-Part 2.

Am J Clin Pathol. 2017 Feb 01;147(2):153-170

Authors: de Jong D, Roemer MG, Chan JK, Goodlad J, Gratzinger D, Chadburn A, Jaffe ES, Said J, Natkunam Y

Abstract
Objectives: The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology submitted small and large B-cell lymphomas (BCLs), including classical Hodgkin lymphoma (CHL), in the context of immunodeficiency.
Methods: Clinicopathologic and molecular features were studied to explore unifying concepts in malignant B-cell proliferations across immunodeficiency settings.
Results: Cases submitted to the workshop spanned small BCLs presenting as nodal or extranodal marginal zone lymphoma and lymphoplasmacytic lymphoma, Epstein-Barr virus (EBV) positive in 75% of cases. Submitted large BCLs formed a spectrum from diffuse large B-cell lymphoma (DLBCL) to CHL across immunodeficiency settings. Additional studies demonstrated overexpression of PD-L1 and molecular 9p24 alterations in the large BCL spectrum and across different immunodeficiency settings.
Conclusions: Small BCLs occur in all immunodeficiency settings, and EBV positivity is essential for their recognition as immunodeficiency related. Large BCLs include a spectrum from DLBCL to CHL across all immunodeficiency settings; immunohistochemical and molecular features are suggestive of shared pathogenetic mechanisms involving PD-L1 immune checkpoints.

PMID: 28395108 [PubMed - indexed for MEDLINE]

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