1β,25-Dihydroxyvitamin D3: A new vitamin D metabolite in human serum

Publication date: Available online 11 February 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Steven Pauwels, Ivo Jans, Jaak Billen, Annemieke Heijboer, Annemieke Verstuyf, Geert Carmeliet, Chantal Mathieu, Miguel Maestro, Etienne Waelkens, Pieter Evenepoel, Roger Bouillon, Dirk Vanderschueren, Pieter Vermeersch
BackgroundThe measurement of 1α,25(OH)2D3 in human serum poses a true challenge as concentrations are very low and structurally similar metabolites can interfere.Materials and methodsDuring optimization of our in-house LC-MSMS method for serum 1α,25(OH)2D3 a previously co-eluting isobaric interference was separated. The isobar was identified as 1β,25(OH)2D3 by comparing retention time and fragmentation spectra to standards (other isobaric dihydroxylated vitamin D3 analogs). 1β,25(OH)2D3 showed specific cluster formation (water), not present in 1α,25(OH)2D3. 1β,25(OH)2D3 was measured in serum of apparently healthy human volunteers (n=20), patients with high serum 25-hydroxyvitamin D [25(OH)D] concentrations (>50ng/mL) (n=33 among which 4 with very high levels (>150ng/mL)) and patients with kidney failure (n=68; 39 stage 1–3, 29 stage 4–5). Pearson's r was calculated for correlations and Mann-Whitney statistic to compare group medians.ResultsMedian serum 1β,25(OH)2D3 was 11pg/mL in apparently healthy volunteers and increased to 20pg/mL for serum 25(OH)D concentrations above 80ng/mL (n=22) (p<0.0001). 1β,25(OH)2D3 concentrations were significantly correlated to serum 25(OH)D concentrations (r=0.85) for the combined results from healthy volunteers and patient sera (n=53) (p<0.0001). For patients with kidney failure, median serum 1β,25(OH)2D3 was 7pg/mL and not different from the median level in healthy volunteers (p=0.06). The median concentration did not vary with different stages.ConclusionsWe present evidence for the widespread presence of 1β,25(OH)2D3, a new vitamin D metabolite, in human serum. The level increases with rising serum 25(OH)D concentrations and is particularly high in patients with very high 25(OH)D levels. We previously demonstrated that 1β,25(OH)2D3 is a poor genomic agonist but a potent non-genomic antagonist of 1α,25(OH)2D3. The clinical implications of the presence of this analog therefore require further exploration.



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Pilot study to evaluate a plasma device for the treatment of onychomycosis

Summary

Onychomycosis is a fungal infection of the nail unit, and is the most common of the nail disorders. Current therapies for onychomycosis have less than ideal efficacy and have the potential for adverse effects. As previous studies have shown that nonthermal plasma inhibits the in vitro growth of Trichophyton rubrum, we conducted a pilot study on 19 participants with toenail onychomycosis. The primary endpoint was safety of the device, and secondary outcome measures were clinical efficacy and mycological cure. Patient satisfaction was measured using questionnaires at the completion of the study. All but one patient met the primary endpoint of safety and there were no long-term sequelae. The overall clinical cure was 53.8% and the mycological cure was 15.4%. The majority of patients were satisfied with the treatment. Our conclusions are that nonthermal plasma is a safe treatment and may have a beneficial effect on toenail onychomycosis.

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Fingolimod and melanoma risk: is there sufficient evidence?

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Screening for colorectal cancer

Publication date: Available online 10 February 2017
Source:Seminars in Oncology
Author(s): Youngjee Choi, Heather F. Sateia, Kimberly S. Peairs, Rosalyn W. Stewart
This review will comprise a general overview of the impact of colorectal cancer (CRC), as well as CRC risk factors, screening modalities, guideline recommendations for screening in average-risk and high-risk individuals, and our approach to CRC screening.



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Characterization of outcomes in patients with metastatic non-small cell lung cancer treated with programmed cell death protein 1 inhibitors past RECIST v1.1-defined disease progression in clinical trials

Publication date: Available online 10 February 2017
Source:Seminars in Oncology
Author(s): Dickran Kazandjian, Patricia Keegan, Daniel L Suzman, Richard Pazdur, Gideon M Blumenthal
ImportanceBased on anecdotal cases of clinically important decreases in tumor size following initial evidence of disease progression when treating patients with anti-PD-1 therapies, investigators have conducted clinical trials in patients with metastatic non-small lung cancer (mNSCLC) receiving anti-PD-1 therapy allowing for treatment past RECIST-defined disease progression (TPP). However, it remains unclear what the true benefit of TPP is.ObjectiveWe describe the findings of a pooled analysis of three clinical trials where treatment of patients with mNSCLC permitted TPP in terms of reduction in the sum of target lesions following initial RECIST-defined progression.DesignWe analyzed pooled data from three trials submitted to FDA evaluating anti-PD-1 therapy for the treatment of patients with mNSCLC in which patients were allowed to receive TPP. We identified patients who received TPP and the characteristics and post-TPP change in tumor burden. Results from this retrospective analysis are descriptively stated.ParticipantsAll patients had advanced or metastatic NSCLC and had previously received a platinum-based doublet regimen.ResultsIn total, 535 patients were treated with anti-PD-1 therapy in three clinical trials of which 121 patients (23%) received TPP. Among all 535 patients treated with anti-PD-1 therapy, the partial response (PR) rate (≥30% reduction in the size of target lesions compared to baseline) following TPP was 1.9% (10 of 535) or 8.3% (10 of 121) in the TPP subgroup. Patients who responded to TPP were more likely to have responded to the initial course of anti-PD-1 therapy, prior to progression.Conclusions and RelevanceOur evaluation indicated that 1.9% of anti-PD-1-treated patients with mNSCLC achieved a PR after receiving TPP. The subgroup of patients who received TPP appeared to have similar baseline characteristics and response to initial treatment compared to the overall population. This suggests that a treatment strategy that includes TPP may not benefit the overall population. The risks of TPP should be weighed against the low likelihood of a PR and the potential for changing to a different therapy with a higher likelihood of benefit.



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Prevention of 5-fluorouracil-induced early severe toxicity by pre-therapeutic dihydropyrimidine dehydrogenase deficiency screening: Assessment of a multiparametric approach

Publication date: Available online 11 February 2017
Source:Seminars in Oncology
Author(s): M. Boisdron-Celle, O. Capitain, R. Faroux, C. Borg, J.P. Metges, M.P. Galais, M. Kaassis, J. Bennouna, K. Bouhier-Leporrier, E. Francois, I. Baumgaertner, V. Guerin-Meyer, O. Cojocarasu, C. Roemer-Becuwe, C. Stampfli, L. Rosenfeld, T. Lecompte, V. Berger, A. Morel, E. Gamelin
Background5-FU-based treatments can lead to early-onset severe (4 to 5%) even fatal (0.3%) toxicities in patients with dihydropyrimidine dehydrogenase (DPD) deficiency. This multicenter prospective cohort study aimed to assess the clinical benefit of pre-therapeutic screening for DPD deficiency using a multiparametric approach.MethodsTwo parallel cohorts of patients treated with 5-FU-based chemotherapy for colorectal carcinoma were compared in a prospective non-randomized study. In Arm A, patients had DPD deficiency screening before treatment whereas in Arm B no pre-therapy screening was performed. Dosing was based on 5-FU administration guidelines of each institution. DPD deficiency screening was performed using a combined multiparametric approach (5-FU^{ODPM Tox}). The frequency of early grade 4-5 toxic events potentially induced by 5-FU was compared in the two groups.Results1142 patients (n=1116 evaluable) were enrolled. In Arm A, out of 718 evaluable patients, 9 grade 4 early toxicities potentially related to 5-FU were reported in 9 patients (1.2%) with no toxic death despite 1 complete DPD deficiency and 24 partial deficiencies. The 24 patients with partial deficiency had safe PK-monitored 5-FU. In Arm B, out of 398 evaluable patients, 17 grade 4-5 toxic early events potentially related to 5-FU were reported in 12 patients (4.2%). The incidence of early severe toxicity was significantly higher in Arm B, (p = 0.0019), confirming the positive impact of pre-therapeutic DPD assessment. The percent of patients with a toxicity grade 3 or higher observed in Arm A was 10.8% (n=78) compared to 17.55% (n=69) reported in Arm B (p=0.0497). The percentage of death was reduced from 2.5/1000 in Arm B to 0 in Arm A. The time to occurrence of all grade ≥3 toxicities was determined in both arms and the difference between the 2 arms was significant (P=0.047). Overall, one patient with complete DPD deficiency confirmed retrospectively died within 13 days from grade 5 multivisceral toxicity. Enrollment was prematurely closed after external experts' decision.ConclusionsMultiparametric pre-therapeutic DPD deficiency screening significantly lowered the risk of early severe toxicity and avoided an early toxic death. This approach should be used for safe administration of 5-FU-based treatments.



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Advances in understanding tumour evolution through single-cell sequencing

Publication date: Available online 11 February 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Jack Kuipers, Katharina Jahn, Niko Beerenwinkel
The mutational heterogeneity observed within tumours poses additional challenges to the development of effective cancer treatments. A thorough understanding of a tumour's subclonal composition and its mutational history is essential to open up the design of treatments tailored to individual patients. Comparative studies on a large number of tumours permit the identification of mutational patterns which may refine forecasts of cancer progression, response to treatment and metastatic potential.The composition of tumours is shaped by evolutionary processes. Recent advances in next-generation sequencing offer the possibility to analyse the evolutionary history and accompanying heterogeneity of tumours at an unprecedented resolution, by sequencing single cells. New computational challenges arise when moving from bulk to single-cell sequencing data, leading to the development of novel modelling frameworks.In this review, we present the state of the art methods for understanding the phylogeny encoded in bulk or single-cell sequencing data, and highlight future directions for developing more comprehensive and informative pictures of tumour evolution.



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Synthesis and pharmacological evaluation of pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as potential GABAA-R ligands

Publication date: Available online 11 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Guerrini Gabriella, Giovanna Ciciani, Simona Daniele, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Claudia Martini, Silvia Selleri
The synthesis of a new series of 6-phenyl- and 6-benzylpyrazolo[1,5-a]pyrimidin-7(4H)-ones 2a-g and 3a-g, strictly related to derivatives with pyrazolobenzotriazine (PBT) and pyrazoloquinazoline (PQ) scaffold, was realized. The in vitro GABAA-receptor subtype affinity was evaluated and from preliminary pharmacological studies, compound 3g shows anxiolytic-like effect at 10-30 mg/kg.

Graphical abstract

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Construction of a library of structurally diverse ribonucleopeptides with catalytic groups

Publication date: Available online 10 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Tomoki Tamura, Shun Nakano, Eiji Nakata, Takashi Morii
Functional screening of structurally diverse libraries consisting of proteins or nucleic acids is an effective method to obtain receptors or aptamers with unique molecular recognition characteristics. However, further modification of these selected receptors to exert a newly desired function is still a challenging task. We have constructed a library of structurally diverse ribonucleopeptides (RNPs) that are modified with a catalytic group, in which the catalytic group aligns with various orientations against the ATP binding pocket of RNA subunit. As a proof-of-principle, the screening of the constructed RNP library for the catalytic reaction of ester hydrolysis was successfully carried out. The size of both the substrate-binding RNA library and the catalytic group modified peptide library are independently expandable, and thus, the size of RNPs library could be enlarged by a combination of these two subunits. We anticipate that the library of functionalized and structurally diverse RNPs would be expanded for various other catalytic reactions.

Graphical abstract

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Design, synthesis and preliminary biological evaluation of indole-3-carboxylic acid-based skeleton of Bcl-2/Mcl-1 dual inhibitors

Publication date: Available online 11 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Tingting Liu, Yichao Wan, Renshuai Liu, Lin Ma, Minyong Li, Hao Fang
The B-cell lymphoma-2 (Bcl-2) family proteins are attractive targets for cancer therapy. In our previous work, the structure-activity relationship of WL-276 was studied. According to the results, rhodanine derivatives show potent binding affinity for Bcl-2 and Mcl-1 protein and show weaker activity against Bcl-XL protein. Based on the previous results, a new class of indole-3-carboxylic acid-based derivatives were designed and synthesized as Bcl-2/Mcl-1 dual inhibitors. Among them, compound 17 has a Ki value of 0.26 μM for Bcl-2 protein and is better than WL-276. Further more, it inhibits the myeloid cell leukemia sequence 1 (Mcl-1) protein with a Ki value of 72 nM. Especially, compound 31 can selectively acting on Bcl-2 and Mcl-1 protein but not Bcl-XL protein, which has great significance for developing dual inhibitors targeting Bcl-2 and Mcl-1 protein, as well as specific antitumor abilities in cells.

Graphical abstract

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3-Phenylalkyl-2H-chromenes and -chromans as novel rhinovirus infection inhibitors

Publication date: Available online 10 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Cinzia Conti, Luca Proietti Monaco, Nicoletta Desideri
Following our studies on structure-activity relationships of anti-rhinovirus chromene and chroman derivatives, we designed and synthesized new series of 3-phenylalkyl-2H-chromenes and –chromans bearing differently sized, aliphatic linker chains between the two cycles. The cytotoxicity and the antiviral activity of the new compounds on human rhinovirus (HRV) serotype 1B and 14 infection were evaluated in HeLa cell cultures. Most of the tested compounds interfered with HRV1B multiplication in the micromolar or submicromolar concentrations while HRV14 was less susceptible. 3-[3-(4-Chlorophenyl)propyl]chroman (9c) was selected for preliminary mechanism of action studies due to its potent activity against both serotypes (IC50 of 0.48 μM and 1.36 μM towards HRV1B and 14, respectively) coupled with high selectivity (SI = 206.18 and 73.26, respectively). Results of time of addition/removal studies suggest that 9c, similarly to related derivatives, behaves as a capsid binder interfering with some early events of the HRV1B infectious cycle.

Graphical abstract

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A retrospective analysis of catheter-based sources in intravascular brachytherapy

Publication date: Available online 10 February 2017
Source:Brachytherapy
Author(s): J. DeCunha, C. Janicki, S.A. Enger
PurposeCoronary artery disease involves the deposition of plaque along the walls of a coronary artery leading to narrowed or blocked vessels (stenosis) and is one of the main causes of death in developed countries. Percutaneous transluminal coronary angioplasty (PTCA) is used to reverse stenosis. Restenosis (renarrowing) of the treated vessel is a major complication of PTCA. A metal mesh tube (stent) can be placed inside the vessel to prevent restenosis. Tissue stress incurred during PTCA and stenting can provoke neointimal cell proliferation leading to in-stent restenosis (ISR). Intravascular brachytherapy (IVBT), a form of internal radiotherapy, is used to treat ISR. Renewed interest in IVBT is being expressed as a treatment for patients with ISR in drug-eluting stents. Current treatment planning (TP) of IVBT is extremely limited and assumes human tissue can be approximated by water. The interactions of arterial plaque, guidewires, and the stent have been shown to attenuate radiation significantly but are ignored in TP. Other models have determined the degree of attenuation by each factor in isolation. For the first time, we create a model with several inhomogenities present to determine whether attenuation by multiple inhomogenities combines linearly or if a larger dose reduction than anticipated is realized. We are also able to evaluate a spatial distribution of dose around the source and in arterial walls.Methods and MaterialsA dosimetric analysis of two commercially available IVBT systems was performed in a Monte Carlo–based particle simulation (Geant4). Absorbed dose was calculated using a model of a human coronary artery with a calcified plaque and stent. Dose delivered in water was also calculated to evaluate the accuracy of a water approximation.ResultsDose as a function of θ shows significant variation around IVBT sources. For the Guidant Galileo, dose is reduced by 20% behind stent struts and as much as 66% in a region occluded by the guidewire, plaque, and stent. For the Novoste Beta Cath device, delivered dose is reduced by 19% and 58%, respectively, in the same regions.ConclusionSOur findings show that the water approximation used in clinical practice to calculate dose is inaccurate when inhomogeneities are present. Methods proposed for calculating dose perturbations in IVBT may underestimate the magnitude of dose reduction. Increasing source dwell time seems unlikely to resolve dosimetric issues in IVBT. The effectiveness of currently existing β-emitting devices may be reduced in patients with complex lesions at the treatment site. Investigation of new radioisotopes and off-centering devices should be considered to improve dose outcomes.



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Intraoperative factors associated with stranded source placement accuracy in low–dose rate prostate brachytherapy

Publication date: Available online 10 February 2017
Source:Brachytherapy
Author(s): M.F. Jamaluddin, S. Ghosh, M.P. Waine, M. Tavakoli, J. Amanie, A.D. Murtha, D. Yee, N. Usmani
PurposeThe quality of a low–dose rate prostate brachytherapy implant depends on the accurate placement of sources in their planned locations. This study investigates intraoperative factors that potentially contribute to stranded source placement inaccuracy in prostate brachytherapy.Methods and MaterialsIntraoperative video images of the brachytherapist's hand motions and needle insertions during the implant procedure were acquired for analysis. Using video analysis software, maximum and average needle insertion velocities were determined. The number of needle insertion attempts and the use of the brachytherapist's other hand to manipulate the needle direction were also recorded. Sources misplacements were analyzed using an ultrasound-based method described elsewhere.ResultsFifteen patients agreed to undergo this study; 1619 ¹²⁵I seeds were inserted using 357 needles; 1197 seeds were confidently identified using ultrasound images and included in the analysis. The mean overall misplacement was 0.49 cm (0–2 cm, 95% CI = 0.47–0.51); 614 seeds were delivered with a single pass and 583 seeds with >1 passes (range 2–6). The mean maximum needle velocity was 12.34 cm s⁻¹ (range 4–28 cm s⁻¹) and mean average velocity was 4.76 cm s⁻¹ (range 0.4–17.4 cm s⁻¹); 747 seeds were delivered with manipulation of the needle. The generalized linear model test was used to analyze factors contributing to seed misplacement, and it was found that a maximum speed <12 cm s⁻¹ was associated with a decrease in seed misplacement by 0.049 cm vs. a maximum speed >12 cm s⁻¹, p = 0.0121). Other evaluated factors were found to have no statistically significant correlation with seed misplacement: average speed (p = 0.4947), manual manipulation of needle (p = 0.9264), and number of needle passes (p = 0.8907).ConclusionsThis study identified that needles inserted with lower maximum velocity were associated with less seed misplacement. Manual manipulation of the needle, number of passes, and average speed did not show statistically significant correlation with seed misplacement.



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GTL001 and bivalent CyaA-based therapeutic vaccine strategies against human papillomavirus and other tumor-associated antigens induce effector and memory T-cell responses that inhibit tumor growth

Publication date: Available online 10 February 2017
Source:Vaccine
Author(s): Michaël Esquerré, Marie Momot, Anne Goubier, Christophe Gonindard, Stéphane Leung-Theung-Long, Yolande Misseri, Marie-Christine Bissery
GTL001 is a bivalent therapeutic vaccine containing human papillomavirus (HPV) 16 and HPV18 E7 proteins inserted in the Bordetella pertussis adenylate cyclase (CyaA) vector intended to prevent cervical cancer in HPV-infected women with normal cervical cytology or mild abnormalities. To be effective, therapeutic cervical cancer vaccines should induce both a T cell-mediated effector response against HPV-infected cells and a robust CD8⁺ T-cell memory response to prevent potential later infection. We examined the ability of GTL001 and related bivalent CyaA-based vaccines to induce, in parallel, effector and memory CD8⁺ T-cell responses to both vaccine antigens. Intradermal vaccination of C57BL/6 mice with GTL001 adjuvanted with a TLR3 agonist (polyinosinic-polycytidylic acid) or a TLR7 agonist (topical 5% imiquimod cream) induced strong HPV16 E7-specific T-cell responses capable of eradicating HPV16 E7-expressing tumors. Tumor-free mice also had antigen-specific memory T-cell responses that protected them against a subsequent challenge with HPV18 E7-expressing tumor cells. In addition, vaccination with bivalent vaccines containing CyaA-HPV16 E7 and CyaA fused to a tumor-associated antigen (melanoma-specific antigen A3, MAGEA3) or to a non-viral, non-tumor antigen (ovalbumin) eradicated HPV16 E7-expressing tumors and protected against a later challenge with MAGEA3- and ovalbumin-expressing tumor cells, respectively. These results show that CyaA-based bivalent vaccines such as GTL001 can induce both therapeutic and prophylactic anti-tumor T-cell responses. The CyaA platform can be adapted to different antigens and adjuvants, and therefore may be useful for developing other therapeutic vaccines.



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Influenza vaccination in healthcare workers; comparison of side effects and preferred route of administration of intradermal versus intramuscular administration

Publication date: Available online 10 February 2017
Source:Vaccine
Author(s): W.J. Meijer, A.M.J. Wensing, A.A. Bos, J.C.F. Kuiphuis, E.M.M. Hagelen, J.C. Wilschut, M.J.T. de Vries, A. Riezebos-Brilman
ObjectiveTo explore the nature and severity of side effects and future preference of intradermal versus intramuscular influenza vaccination in healthcare workers.DesignProspective cohort study.SettingTwo University Medical Centers in The Netherlands.ParticipantsHealthcare workers receiving an influenza vaccination.MethodsHealthcare workers that were vaccinated during the influenza vaccination season of 2012–2013 were approached for participation in a questionnaire study. The questionnaire was divided into two parts. The first part had to be answered directly after vaccination and the second part two weeks after vaccination. The motivation for vaccine uptake, whether or not the HCWs had direct contact with patients and the prevalence and severity of local and systemic side effects of influenza vaccination were explored. In addition, it was assessed how participants experienced the vaccination and which type of administration they preferred for future vaccination.ResultsSide effects of vaccination were more prevalent in the intradermal group versus the intramuscular group (56% versus 26%, p<0.001). Local side effects were perceived as more severe in healthcare workers receiving the intradermal vaccine. Directly after vaccination, healthcare workers preferred the intradermal vaccination. Two weeks after vaccination both types of vaccine were equally appreciated.ConclusionsThis study shows that there are significant differences in the nature and severity of side effects upon intramuscular and intradermal influenza vaccination. This difference did not result in a preference among the vaccinated subjects for one type of vaccine.



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Bactericidal activity of sera from adolescents vaccinated with bivalent rLP2086 against meningococcal serogroup B outbreak strains from France

Publication date: Available online 10 February 2017
Source:Vaccine
Author(s): Muhamed-Kheir Taha, Julio Cesar Hawkins, Paul Liberator, Ala-Eddine Deghmane, Lubomira Andrew, Li Hao, Thomas R. Jones, Lisa K. McNeil, Robert E. O'Neill, John L. Perez, Kathrin U. Jansen, Annaliesa S. Anderson
ObjectivesBivalent rLP2086 (Trumenba®; MenB-FHbp), composed of two factor H binding proteins (FHbps), is a vaccine approved in the United States for prevention of Neisseria meningitidis serogroup B (MnB) invasive meningococcal disease (IMD). Bactericidal activity of sera from subjects vaccinated with bivalent rLP2086 was assessed against MnB isolates from recent disease outbreaks in France.MethodsMnB isolates from IMD cases were characterized by whole genome sequencing and FHbp expression was assessed using a flow cytometry-based assay. Sera from subjects (11–<19years old) vaccinated with bivalent rLP2086 at 0, 2, and 6months were evaluated. Bactericidal activity was measured in serum bactericidal assays using human complement (hSBAs). The response rate (RR) represents the percentage of subjects with an hSBA titer ⩾1:4.ResultsThe six MnB outbreak isolates expressed diverse FHbp variants: A22, B03, B24 (two isolates), B44, and B228. FHbp expression levels ranged from 1309 to 8305 (mean fluorescence intensity units). The RR of preimmune sera from subjects was 7% to 27%. RRs increased for all isolates after each vaccine dose. After two doses, RRs ranged from 40% to 93%. After dose 3, RRs were ⩾73% for all isolates (range, 73%–100%).ConclusionsEach of the representative French outbreak isolates was killed by sera from subjects vaccinated with bivalent rLP2086. Vaccination elicited an immune response with bactericidal activity against these diverse isolates in a large proportion of subjects at risk. These results provide additional support for the licensure strategy of testing MnB strains expressing vaccine-heterologous FHbp variants in hSBAs and further illustrate the breadth of efficacy of this protein-based MnB vaccine.



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PCV13 serotype decrease in Italian adolescents and adults in the post-PCV13 era: Herd protection from children or secular trend?

Publication date: Available online 10 February 2017
Source:Vaccine
Author(s): Francesco Nieddu, Maria Moriondo, Elisa De Vitis, Silvia Ricci, Giuseppe Indolfi, Massimo Resti, Caterina Vocale, Maria Paola Landini, Assunta Sartor, Chiara Azzari
Background and aim of the workIn 2010 PCV13 replaced PCV7 in the pediatric vaccination schedule for Italian children. While a strong herd effect was demonstrated for PCV7, a possible herd effect due to PCV13 is still under debate. Our aim was to evaluate differences in the distribution of pneumococcal serotypes between the pre and post-PCV13 eras in unvaccinated Italian adolescents and adults with laboratory-confirmed pneumococcal infection from 3 Italian Regions with a high rate of PCV13 vaccination of children.Patients and methodsAdolescents and adults admitted with laboratory-confirmed pneumococcal infection in the hospitals of 3 Italian Regions (Friuli-Venezia Giulia, Emilia Romagna, and Tuscany) between April 2006 and June 2016 were included in the study. Diagnosis of pneumococcal infection and serotyping were performed with Real Time PCR directly on normally sterile fluids or on culture isolates.Results523 patients with laboratory-confirmed pneumococcal infection were enrolled (Male/Female ratio was 300/223, 1.3; median age 67.1, IQR 53.4–74.9). None of the patients had been vaccinated with any pneumococcal vaccine; 96.4% were serotyped. Overall, the most frequent serotypes were 3 (67/504, 13.3%), 8 (43/504, 8.5%), and 19A (38/504, 7.5%). Serotype distribution differed among age classes and clinical presentations.Overall, PCV13 serotypes accounted for 47.6% of cases: 62.3% in the pre-PCV13 era and 45.0% in the post-PCV13 era; (p=0.005 OR=2.03; CL 95%: 1.2–3.3). Serotype 7F accounted for 12/77 (15.6%) of all serotypes in the pre-PCV13 period and for 12/427 (2.8%) in the post-PCV13 period and was the only serotype significantly contributing to the difference in percentage between pre and post-PCV13 eras.ConclusionOur study demonstrated a difference in percentage in serotype distribution in adolescents and adults laboratory-confirmed pneumococcal infection between the pre and post-PCV13 eras. This difference is mainly due to the decrease of serotype 7F. Thus, in order to decrease disease burden, adults and in particular the elderly should be offered a specific vaccination program.



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Vacuum-assisted decellularization: an accelerated protocol to generate tissue-engineered human tracheal scaffolds

Publication date: April 2017
Source:Biomaterials, Volume 124
Author(s): Colin R. Butler, Robert E. Hynds, Claire Crowley, Kate H.C. Gowers, Leanne Partington, Nicholas J. Hamilton, Carla Carvalho, Manuela Platé, Edward R. Samuel, Alan J. Burns, Luca Urbani, Martin A. Birchall, Mark W. Lowdell, Paolo De Coppi, Sam M. Janes
Patients with large tracheal lesions unsuitable for conventional endoscopic or open operations may require a tracheal replacement but there is no present consensus of how this may be achieved. Tissue engineering using decellularized or synthetic tracheal scaffolds offers a new avenue for airway reconstruction. Decellularized human donor tracheal scaffolds have been applied in compassionate-use clinical cases but naturally derived extracellular matrix (ECM) scaffolds demand lengthy preparation times. Here, we compare a clinically applied detergent-enzymatic method (DEM) with an accelerated vacuum-assisted decellularization (VAD) protocol. We examined the histological appearance, DNA content and extracellular matrix composition of human donor tracheae decellularized using these techniques. Further, we performed scanning electron microscopy (SEM) and biomechanical testing to analyze decellularization performance. To assess the biocompatibility of scaffolds generated using VAD, we seeded scaffolds with primary human airway epithelial cells in vitro and performed in vivo chick chorioallantoic membrane (CAM) and subcutaneous implantation assays. Both DEM and VAD protocols produced well-decellularized tracheal scaffolds with no adverse mechanical effects and scaffolds retained the capacity for in vitro and in vivo cellular integration. We conclude that the substantial reduction in time required to produce scaffolds using VAD compared to DEM (approximately 9 days vs. 3–8 weeks) does not compromise the quality of human tracheal scaffold generated. These findings might inform clinical decellularization techniques as VAD offers accelerated scaffold production and reduces the associated costs.



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Direct 3D bioprinting of prevascularized tissue constructs with complex microarchitecture

Publication date: April 2017
Source:Biomaterials, Volume 124
Author(s): Wei Zhu, Xin Qu, Jie Zhu, Xuanyi Ma, Sherrina Patel, Justin Liu, Pengrui Wang, Cheuk Sun Edwin Lai, Maling Gou, Yang Xu, Kang Zhang, Shaochen Chen
Living tissues rely heavily on vascular networks to transport nutrients, oxygen and metabolic waste. However, there still remains a need for a simple and efficient approach to engineer vascularized tissues. Here, we created prevascularized tissues with complex three-dimensional (3D) microarchitectures using a rapid bioprinting method – microscale continuous optical bioprinting (μCOB). Multiple cell types mimicking the native vascular cell composition were encapsulated directly into hydrogels with precisely controlled distribution without the need of sacrificial materials or perfusion. With regionally controlled biomaterial properties the endothelial cells formed lumen-like structures spontaneously in vitro. In vivo implantation demonstrated the survival and progressive formation of the endothelial network in the prevascularized tissue. Anastomosis between the bioprinted endothelial network and host circulation was observed with functional blood vessels featuring red blood cells. With the superior bioprinting speed, flexibility and scalability, this new prevascularization approach can be broadly applicable to the engineering and translation of various functional tissues.



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A new approach to analyze data from EEG-based concealed face recognition system

Publication date: Available online 10 February 2017
Source:International Journal of Psychophysiology
Author(s): A.H. Mehrnam, A.M. Nasrabadi, M. Ghodoosi, A. Mohammadian, Sh. Torabi
The purpose of this study is to extend a feature set with non-linear features to improve classification rate of guilty and innocent subjects. Non-linear features can provide extra information about phase space. The Event-Related Potential (ERP) signals were recorded from 49 subjects who participated in concealed face recognition test. For feature extraction, at first, several morphological characteristics, frequency bands, and wavelet coefficients (we call them basic-features) are extracted from each single-trial ERP. Recurrence Quantification Analysis (RQA) measures are then computed as non-linear features from each single-trial. We apply Genetic Algorithm (GA) to select the best feature set and this feature set is used for classification of data using Linear Discriminant Analysis (LDA) classifier. Next, we use a new approach to improve classification results based on introducing an adaptive-threshold. Results indicate that our method is able to correctly detect 91.83% of subjects (45 correct detection of 49 subjects) using combination of basic and non-linear features, that is higher than 87.75% for basic and 79.59% for non-linear features. This shows that combination of non-linear and basic- features could improve classification rate.



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Maternal morbidity and mortality in ElShatby and Dar Ismail maternity hospitals in Alexandria: A comparative study

Publication date: Available online 10 February 2017
Source:Alexandria Journal of Medicine
Author(s): Sahar khashab, Nermeen S. El Beltagy, Dina Badie
ObjectiveTo compare ElShatby University Maternity Hospital and Dar Ismail Public Hospital in regard to antenatal, natal, and postnatal morbidity and the causes of maternal mortality.MethodsA cross-sectional survey was conducted to study females who gave birth in each of the hospitals. Then, a prospective survey of the women was conducted until the 42nd day after delivery. Data were gathered from women who delivered in addition to their caring obstetricians as well as reviewing their medical records. Additionally, records of maternal mortality were reviewed. All females who gave birth between January and April 2014 (3months) were included in the study.ResultsTwo hundred and eighty females participated in the study (130 from ElShatby University Maternity Hospital and 150 from Dar Ismail Public Hospital). Significantly more rural women (29.2%) gave birth at ElShatby University Hospital than at Dar Ismail Public Hospital (16.7%), p=0.012. More than half of all the study participants (51.8%) suffered from anemia during pregnancy. A minority (5%) of the women were diagnosed with preeclampsia, all of whom gave birth at ElShatby Hospital. Caesarean section rate was significantly higher among women delivered at ElShatby University Hospital compared to Dar Ismail Hospital (61.5% versus 41.3%, p<001). Only 8.2% of all women needed ICU admission at ElShatby Hospital. The most common cause of maternal mortality was eclampsia, which accounted for 75% of deceased women.ConclusionFuture studies are needed to identify and understand better the avoidable factors contributing to the relatively high rates of maternal morbidity and mortality in public hospitals. Such information will be of significant use in the processes related to providing quality services, ensuring accessibility of those services, and allocating corresponding resources aimed at reducing maternal morbidity and mortality.



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Are Portrait Artists Superior Face Recognizers? Limited Impact of Adult Experience on Face Recognition Ability.

Author: Tree, Jeremy J.; Horry, Ruth; Riley, Howard; Wilmer, Jeremy B.

DOI: 10.1037/xhp0000328

Publication Date: POST AUTHOR CORRECTIONS, 9 February 2017

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Evolving the Keys to Visual Crowding.

Author: Van der Burg, Erik; Olivers, Christian N. L.; Cass, John

DOI: 10.1037/xhp0000337

Publication Date: POST AUTHOR CORRECTIONS, 9 February 2017

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The First Letter Position Effect in Visual Word Recognition: The Role of Spatial Attention.

Author: Aschenbrenner, Andrew J.; Balota, David A.; Weigand, Alexandra J.; Scaltritti, Michele; Besner, Derek

DOI: 10.1037/xhp0000342

Publication Date: POST AUTHOR CORRECTIONS, 9 February 2017

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It Does Exist! A Left-to-Right Spatial-Numerical Association of Response Codes (SNARC) Effect Among Native Hebrew Speakers.

Author: Zohar-Shai, Bar; Tzelgov, Joseph; Karni, Avi; Rubinsten, Orly

DOI: 10.1037/xhp0000336

Publication Date: POST AUTHOR CORRECTIONS, 9 February 2017

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Multisensory Cue Combination After Sensory Loss: Audio-Visual Localization in Patients With Progressive Retinal Disease.

Author: Garcia, Sara E.; Jones, Pete R.; Reeve, Eleanor I.; Michaelides, Michel; Rubin, Gary S.; Nardini, Marko

DOI: 10.1037/xhp0000344

Publication Date: POST AUTHOR CORRECTIONS, 9 February 2017

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Haptic Search for Movable Parts.

Author: Plaisier, Myrthe A.; Overvliet, Krista E.

DOI: 10.1037/xhp0000345

Publication Date: POST AUTHOR CORRECTIONS, 9 February 2017

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Sex differences in the development of prolactinoma in mice overexpressing hCG{beta}: role of TGF{beta}1

Female transgenic mice that overexpress the human chorionic gonadotrophin β subunit (hCGβ+) develop prolactinomas, whereas hCGβ+ males do not. The high levels of circulating hCG induce massive luteinization in the ovary of hCGβ+ females, and progesterone becomes the primary steroid hormone produced, but estradiol remains at physiological level. The involvement of high levels of progesterone in lactotroph proliferation is not clearly understood; hence, the pathogenesis of prolactinomas in hCGβ+ females remains unclear. TGFβ1 is an inhibitor of lactotroph function, and the reduced TGFβ1 activity found in prolactinomas has been proposed to be involved in tumor development. The aim of the present work was to study the role of TGFβ1 in the gender-specific development of prolactinomas in hCGβ+ mice. We compared the expression of different components of the pituitary TGFβ1 system in males and females in this model. We found reduced TGFβ1 levels, reduced expression of TGFβ1 target genes, TGFβ1 receptors, Ltbp1, Smad4 and Smad7 in hCGβ+ female pituitaries. However, no differences were found between the transgenic and wild-type male pituitaries. We postulate that decreased pituitary TGFβ1 activity in hCGβ+ females is involved in the development of prolactinomas. In fact, we demonstrated that an in vivo treatment carried out for increasing pituitary TGFβ1 activity, was successful in reducing the prolactinoma development, and the hyperprolactinemia in hCGβ+ females. Moreover, the stronger TGFβ1 system found in males could protect them from excessive lactotroph proliferation. Sex differences in the regulation of the pituitary TGFβ1 system could explain gender differences in the incidence of prolactinoma.

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Angiotensin II induces differential insulin action in rat skeletal muscle

Angiotensin II (ANGII) is reportedly involved in the development of skeletal muscle insulin resistance. The present investigation evaluated the effects of two ANGII doses on the phenotypic characteristics of insulin resistance syndrome and insulin action and signaling in rat skeletal muscle. Male Sprague–Dawley rats were infused with either saline (SHAM) or ANGII at a commonly used pressor dose (100 ng/kg/min; ANGII-100) or a higher pressor dose (500 ng/kg/min; ANGII-500) via osmotic minipumps for 14 days. We demonstrated that ANGII-100-infused rats exhibited the phenotypic features of non-obese insulin resistance syndrome, including hypertension, impaired glucose tolerance and insulin resistance of glucose uptake in the soleus muscle, whereas ANGII-500-treated rats exhibited diabetes-like symptoms, such as post-prandial hyperglycemia, impaired insulin secretion and hypertriglyceridemia. At the cellular level, insulin-stimulated glucose uptake in the soleus muscle of the ANGII-100 group was 33% lower (P < 0.05) than that in the SHAM group and was associated with increased insulin-stimulated IRS-1 Ser³⁰⁷ and decreased Akt Ser⁴⁷³ and AS160 Thr⁶⁴² phosphorylation and GLUT-4 expression. However, ANGII-500 infusion did not induce skeletal muscle insulin resistance or impair insulin signaling elements as initially anticipated. Moreover, we found that insulin-stimulated glucose uptake in the ANGII-500 group was accompanied by the enhanced expression of ACE2 and MasR proteins, which are the key elements in the non-classical pathway of the renin–angiotensin system. Collectively, this study demonstrates for the first time that chronic infusion with these two pressor doses of ANGII induced differential metabolic responses at both the systemic and skeletal muscle levels.

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Editorial Advisory Board

Publication date: March 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 3





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Contents

Publication date: March 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 3





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Totally Implantable Wireless Ultrasonic Doppler Blood Flowmeters: Toward Accurate Miniaturized Chronic Monitors

Publication date: March 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 3
Author(s): Michael A. Rothfuss, Jignesh V. Unadkat, Michael L. Gimbel, Marlin H. Mickle, Ervin Sejdić
Totally implantable wireless ultrasonic blood flowmeters provide direct-access chronic vessel monitoring in hard-to-reach places without using wired bedside monitors or imaging equipment. Although wireless implantable Doppler devices are accurate for most applications, device size and implant lifetime remain vastly underdeveloped. We review past and current approaches to miniaturization and implant lifetime extension for wireless implantable Doppler devices and propose approaches to reduce device size and maximize implant lifetime for the next generation of devices. Additionally, we review current and past approaches to accurate blood flow measurements. This review points toward relying on increased levels of monolithic customization and integration to reduce size. Meanwhile, recommendations to maximize implant lifetime should include alternative sources of power, such as transcutaneous wireless power, that stand to extend lifetime indefinitely. Coupling together the results will pave the way for ultra-miniaturized totally implantable wireless blood flow monitors for truly chronic implantation.



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Masthead

Publication date: March 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 3





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Quantitative Analysis of Contrast-Enhanced Ultrasound Imaging in Invasive Breast Cancer: A Novel Technique to Obtain Histopathologic Information of Microvessel Density

Publication date: March 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 3
Author(s): Naoko Mori, Shunji Mugikura, Shoki Takahashi, Koichi Ito, Chiaki Takasawa, Li Li, Minoru Miyashita, Atsuko Kasajima, Yu Mori, Takanori Ishida, Tetsuya Kodama, Kei Takase
We examined whether enhancement area ratios obtained by the new bubble detection method correlate with histologic microvessel density in invasive breast cancer. Forty consecutive patients with invasive breast cancer lesions underwent contrast-enhanced ultrasound. The ratio of enhanced area to manually segmented tumor area (enhancement area ratio) was obtained with the new method at peak and delayed phases (50–54, 55–59, 60–64 and 65–69 s). We also analyzed time–intensity curves to obtain peak intensity and area under curve. Enhancement area ratios in both peak and delayed phases (50–54, 55–59, 60–64 and 65–69 s) were significantly correlated with microvessel density (r = 0.57, 0.62, 0.68, 0.61 and 0.58; p = 0.0001, <0.0001, <.0001, <.0001 and 0.0001, respectively). In time–intensity curve analysis, peak intensity was significantly correlated (r = 0.43, p = 0.0073), whereas area under the curve was not (r = 0.29, p = 0.0769). Enhancement area ratios obtained by the new method were correlated with microvessel density in invasive breast cancer.



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A Novel Approach to Detecting Postpartum Hemorrhage Using Contrast-Enhanced Ultrasound

Publication date: March 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 3
Author(s): Kenji Imai, Tomomi Kotani, Hiroyuki Tsuda, Tomoko Nakano, Akihiro Hirakawa, Fumitaka Kikkawa
The aim of this study was to estimate the efficacy of contrast-enhanced ultrasound (CEUS) in detecting postpartum hemorrhage (PPH) after cesarean section. This is the first study of CEUS in obstetric hemorrhage. A total of 37 patients, operated at Nagoya University Hospital, underwent CEUS. We evaluated the findings of CEUS, which were qualitatively defined as positive when pooling or leakage of contrast agent was observed in the uterine cavity, by measuring the amount of bleeding during the first 4 h after cesarean section. The time–intensity curve patterns of leaked contrast agents were also analyzed for quantitative prediction of the amount of blood loss. Significant differences between the excessive hemorrhage (N = 7) and non-excessive hemorrhage groups (N = 30) were noted in the occurrence of positive CEUS (p = 0.011). Additionally, mean postpartum blood loss markedly increased in patients with a positive CEUS (p = 0.002). From a quantitative perspective, the time until leakage of contrast agents was detected correlated with the amount of bleeding, but the other characteristics of the time–intensity curve pattern did not provide valuable information. In conclusion, CEUS, which enables bedside assessment and rapid diagnosis, is a promising strategy for the detection of PPH.



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Contrast-Enhanced Ultrasound Using Perfluorobutane-Containing Microbubbles in the Assessment of Liver Allograft Damage: An Exploratory Prospective Study

Publication date: March 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 3
Author(s): Ijin Joo, Jae Young Lee, Dong Ho Lee, Ju Hyeon Jeon, Hyeyoung Kim, Nam-Joon Yi, Kwang-Woong Lee, Kyung-Suk Suh
This prospective study investigated the usefulness of contrast (perfluorobutane-containing microbubbles)-enhanced ultrasound in the non-invasive assessment of liver allograft damage. Forty-one liver recipients underwent contrast-enhanced ultrasound followed by a liver biopsy. The hepatic filling rate (time between the arrival of contrast agent in the right hepatic artery and the maximum intensity of hepatic parenchyma) and parenchymal intensity difference before and after instantaneous high-power emission in the Kupffer phase were measured. Patients with allograft damage had higher hepatic filling rates and lower parenchymal intensity differences than those without damage (42.0 ± 16.9 vs. 30.5 ± 7.7 s, p = 0.005; 6.1 ± 7.4 vs. 16.6 ± 16.1 dB, p = 0.047, respectively). In the diagnosis of liver allograft damage, hepatic filling rate and parenchymal intensity difference had sensitivities of 61.5% and 90.9% and specificities of 92.6% and 63.6% using cutoffs of >38.5 s and ≤10.3 dB, respectively. In conclusion, contrast-enhanced ultrasound may be a promising tool in the detection of liver allograft damage.



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Strain-Initialized Robust Bone Surface Detection in 3-D Ultrasound

Publication date: March 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 3
Author(s): Mohammad Arafat Hussain, Antony J. Hodgson, Rafeef Abugharbieh
Three-dimensional ultrasound has been increasingly considered as a safe radiation-free alternative to radiation-based fluoroscopic imaging for surgical guidance during computer-assisted orthopedic interventions, but because ultrasound images contain significant artifacts, it is challenging to automatically extract bone surfaces from these images. We propose an effective way to extract 3-D bone surfaces using a surface growing approach that is seeded from 2-D bone contours. The initial 2-D bone contours are estimated from a combination of ultrasound strain images and envelope power images. Novel features of the proposed method include: (i) improvement of a previously reported 2-D strain imaging-based bone segmentation method by incorporation of a depth-dependent cumulative power of the envelope into the elastographic data; (ii) incorporation of an echo decorrelation measure-based weight to fuse the strain and envelope maps; (iii) use of local statistics of the bone surface candidate points to detect the presence of any bone discontinuity; and (iv) an extension of our 2-D bone contour into a 3-D bone surface by use of an effective surface growing approach. Our new method produced average improvements in the mean absolute error of 18% and 23%, respectively, on 2-D and 3-D experimental phantom data, compared with those of two state-of-the-art bone segmentation methods. Validation on 2-D and 3-D clinical in vivo data also reveals, respectively, an average improvement in the mean absolute fitting error of 55% and an 18-fold improvement in the computation time.



http://ift.tt/2lyLGO3

Diagnosis of Complex Pulley Ruptures Using Ultrasound in Cadaver Models

Publication date: March 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 3
Author(s): Isabelle Schöffl, Arnica Hugel, Volker Schöffl, Wolfgang Rascher, Jörg Jüngert
Pulley ruptures are common in climbing athletes. The purposes of this study were to determine the specific positioning of each pulley with regards to the joint, and to evaluate the ultrasound diagnostics of various pulley rupture combinations. For this, 34 cadaver fingers were analyzed via ultrasound, the results of which were compared to anatomic measurements. Different pulley ruptures were then simulated and evaluated using ultrasound in standardized dynamic forced flexion. Visualization of the A2 and A4 pulleys was achieved 100% of the time, while the A3 pulley was visible in 74% of cases. Similarly, injuries to the A2 and A4 pulleys were readily observable, while A3 pulley injuries were more challenging to identify (sensitivity of 0.2 for singular A3 pulley, 0.5 for A2/A4 pulley and 0.33 for A3/A4 pulley ruptures). Receiver operating characteristic analysis was used to evaluate the optimal tendon-bone distance for pulley rupture diagnosis, a threshold which was determined to be 1.9 mm for A2 pulley ruptures and 1.85 for A4 pulley ruptures. This study was the first to carry out a cadaver ultrasound examination of a wide variety of pulley ruptures. Ultrasound is a highly accurate tool for visualizing the A2 and A4 pulleys in a cadaver model. This method of pathology diagnosis was determined to be suitable for injuries to the A2 and A4 pulleys, but inadequate for A3 pulley injuries.



http://ift.tt/2l3oUkB

High-Resolution Elastography for Thin-Layer Mechanical Characterization: Toward Skin Investigation

Publication date: March 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 3
Author(s): Caroline Chartier, Yassine Mofid, Cécile Bastard, Véronique Miette, Annabel Maruani, Laurent Machet, Frédéric Ossant
Interest in elasticity estimation for thin layers is increasing because of the various potential applications, including dermatology and cosmetology. In this context, we propose a dedicated elastographic system using 1-D high-frequency transient elastography (HF-TE) to estimate the 1-D Young's modulus through the dermis and hypodermis, which are the two human skin layers of interest in this study. An experimental validation of the HF-TE method was first carried out on two homogeneous tissue-mimicking hard and soft phantoms. The Young's modulus values obtained in these phantoms were compared with those obtained by two complementary shear wave propagation techniques: shear wave-induced resonance elastography (SWIRE) and supersonic shear imaging (SSI). A third two-layer thin phantom, with mechanical properties similar to those of skin, was used to validate the ability of HF-TE to distinguish layers and measure elasticity. Finally, preliminary in vivo experiments conducted on forearm and cheek skin revealed the promising performance of HF-TE in measuring elasticity in the dermis and hypodermis.



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Acoustic Impedance Analysis with High-Frequency Ultrasound for Identification of Fatty Acid Species in the Liver

Publication date: March 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 3
Author(s): Kazuyo Ito, Kenji Yoshida, Hitoshi Maruyama, Jonathan Mamou, Tadashi Yamaguchi
Acoustic properties of free fatty acids present in the liver were studied as a possible basis for non-invasive ultrasonic diagnosis of non-alcoholic steatohepatitis. Acoustic impedance was measured for the following types of tissue samples: Four pathologic types of mouse liver, five kinds of FFAs in solvent and five kinds of FFAs in cultured Huh-7 cells. A transducer with an 80-MHz center frequency was incorporated into a scanning acoustic microscopy system. Acoustic impedance was calculated from the amplitude of the signal reflected from the specimen surface. The Kruskal–Wallis test revealed statistically significant differences (p < 0.01) in acoustic impedance not only among pathologic types, but also among the FFAs in solvent and in cultured Huh-7 cells. These results suggest that each of the FFAs, especially palmitate, oleate and palmitoleate acid, can be distinguished from each other, regardless of whether they were in solution or absorbed by cells.



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Comparison of Two Inexpensive Rapid Prototyping Methods for Manufacturing Filament Target Ultrasound Phantoms

Publication date: March 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 3
Author(s): Krisztián Füzesi, Miklós Gyöngy
Current use of 3-D printers to manufacture ultrasound phantoms is limited to relatively expensive photopolymer jetting printers. The present work investigates the feasibility of using two common and inexpensive 3-D printer technologies, fused deposition modeling (FDM) and digital light processing (DLP), to print custom filament target phantoms. Acoustic characteristics obtained from printed solid blocks indicated that the printing materials—acrylonitrile butadiene styrene and polylactic acid for FDM and a photopolymer for DLP printing—were appropriate for use as scatterers. A regular grid of filaments was printed to study printing accuracy. As a proof of concept of the phantom manufacturing process, a complex pattern of filament targets was placed in de-ionized water to create a phantom, which was then imaged using an ultrasound imager. The pattern was clearly identifiable, although multiple reflections were observed, which underscores the importance of future work to enhance printing resolution. This goal is deemed possible using improvement of the DLP printing setup.



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Calendar

Publication date: March 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 3





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Effect of Low-Intensity Cavitation on the Isolated Human Thoracic Artery in Vitro

Publication date: Available online 10 February 2017
Source:Ultrasound in Medicine & Biology
Author(s): Algimantas Bubulis, Vida Garalienė, Vytautas Jurėnas, Jonas Navickas, Saulius Giedraitis
Reported here are the results of an experimental study on the response to low-intensity cavitation induced by low-frequency (4–6 W/cm², 20 kHz and 32.6 kHz) ultrasound of isolated human arterial samples taken during conventional myocardial revascularization operations. Studies have found that low-frequency ultrasound results in a significant (48%–54%) increase in isometric contraction force and does not depend on the number of exposures (10 or 20) or the time passed since the start of ultrasound (0, 10 and 20 min), but does depend on the frequency and location (internal or external) of the blood vessels for the application of ultrasound. Diltiazem (an inhibitor of slow calcium channels) and carbachol (an agonist of muscarinic receptors) used in a concentration-dependent manner did not modify the relaxation dynamics of smooth muscle affected by ultrasound. Thus, ultrasound conditioned to the augmentation of the isometric contraction force the smooth muscle of blood vessels and did not improve endothelial- and calcium channel blocker-dependent relaxation.



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Fluorinated oligo(ethylene glycol) methacrylate-based copolymers: Tuning of self assembly properties and relationship with rheological behavior

Publication date: 10 March 2017
Source:Polymer, Volume 112
Author(s): Federica Zuppardi, Francesco Raffaele Chiacchio, Roberta Sammarco, Mario Malinconico, Giovanna Gomez d'Ayala, Pierfrancesco Cerruti
A series of thermo-responsive oligo(ethylene glycol) methacrylate (OEGMA, Mn = 300 g/mol)-pentafluorostyrene (PFS) copolymers was prepared, and the effect of composition on polymer conformation changes and size of the self-assembled particles in solution was studied. Furthermore, the relationship between self-aggregation mechanistic steps in water and rheological properties is reported. Water-soluble OEGMA-PFS copolymers were synthesized at different molar ratios via free radical polymerization, and their phase transition behavior was investigated in detail by dynamic light scattering (DLS), ¹H NMR, simultaneous rheometry-FTIR spectroscopy, and transmission electronic microscopy (TEM). All copolymers exhibited sharp and reversible LCST in water. LCST and particle size of the self-assemblying copolymers can be precisely tuned by varying monomer molar ratio. Simultaneous rheometry-FTIR spectroscopy showed that above the LCST, copolymers with higher OEGMA content form micron-sized and hydrated particles, resulting in a pseudo-hydrogel structure. When the hydrophobic character increases, a more significant dehydration of OEGMA side chains leads to a strengthening of polymer chain interactions, resulting in the formation of nanosized and phase-segregated particles. These results are also relevant with a view of using these structures as a template for the preparation of chemically or physically stabilized nanoparticles to be employed for a variety of applications, such as immobilization, controlled release and flocculation in water treatment.

Graphical abstract

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Isoindigo dye incorporated copolymers with diselenophenylethene: Synthesis, characterization, and enhanced mobilities in field-effect transistors with electrodes modified by thiol-based self-assembled monolayers

Publication date: 10 March 2017
Source:Polymer, Volume 112
Author(s): Keli Shi, Weifeng Zhang, Xiaotong Liu, Ye Zou, Gui Yu
In this study, we report the design and synthesis of two donor−acceptor isoindigo dye-based copolymers, namely PIIVS1 and PIIVS2, in which π−extended diselenophenylethene building block acts as electron-donating units. The charge transport properties of both copolymers were studied by fabricating field-effect transistors (FETs). The two copolymers-based FETs with electrodes modified by thiol self-assembled monolayers (SAMs) showed enhanced mobilities of up to 1.58 cm² V⁻¹ s⁻¹ (average: 1.28 cm² V⁻¹ s⁻¹), almost two times higher than those achieved in unmodified counterparts. Thereby, a systematical investigation on PIIVS2-based PFETs was performed, indicating contact resistances, contact angles and Au work function all changed in different extents, and more uniform thin film morphologies obtained in thiol-treated PFET devices. The results demonstrate the potential and feasibility of electrodes modification by thiol-based SAMs on improving the device performance of FETs.

Graphical abstract

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Carbon dot – Unique reinforcing filler for polymer with special reference to physico-mechanical properties

Publication date: 10 March 2017
Source:Polymer, Volume 112
Author(s): P.R. Sreenath, Seema Singh, M.S. Satyanarayana, Prolay Das, K. Dinesh Kumar
This work reports the reinforcing efficiency of carbon dots (CDs) in carboxylated acrylonitrile butadiene (XNBR) latex at very low concentration. Amine and carboxyl functionalized CDs have been synthesized from citric acid and glycine. The CDs are covalently conjugated to XNBR latex using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) and N-hydroxysuccinimide (NHS) as coupling agents. The covalent conjugation of CDs with XNBR latex has been confirmed by Fourier transform infrared spectroscopy (FTIR), dynamic light scattering (DLS) and X-ray photoelectron spectroscopy (XPS). The optical properties of CDs and XNBR-CDs conjugate have been characterized by ultraviolet (UV) - visible, fluorescence spectroscopy, time-resolved fluorescence spectrophotometer and haze meter. The tensile stress-strain properties of XNBR latex dramatically increases by the addition of CDs to XNBR latex. The maximum tensile stress of 2 phr of CDs loaded XNBR latex is nearly 215% higher than the maximum tensile stress of neat XNBR latex. There is a concomitant decrease in the tan δ peak height and increase in the tan δ peak temperature of XNBR latex with the incorporation of CDs to XNBR latex. In addition, the storage modulus (G′) value of sample containing 2 phr of CDs is 161% higher than the storage modulus value (G′) of neat XNBR latex. The onset of degradation temperature (Ti) value of sample containing 4 phr of CDs is 40 °C higher than the Ti value of neat XNBR latex. On the other hand, the maximum degradation temperature (Tmax) of XNBR latex containing 1 phr of CDs is 11 °C higher than the Tmax value of neat XNBR latex. Morphology of pristine CDs and XNBR-CDs conjugate has been analyzed using transmission electron microscopy (TEM). To the best of our knowledge, this is the first report which analyzes the effect of CDs on the physico-mechanical properties of elastomer contrary to the other novel fillers of carbon family.

Graphical abstract

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Hydrozirconated styrene copolymer as a macroinitiator to in situ synthesize polyethylene/polystyrene-g-polyethylene alloy via coordination polymerization

Publication date: 10 March 2017
Source:Polymer, Volume 112
Author(s): Yanhui Wang, Yichao Lin, Jun Zheng, Lin Ye, Zi'an Chen, Tao Tang
A new method to in situ synthesize polyethylene/polystyrene-g-polyethylene (PE/PS-g-PE) alloy based on hydrozirconation reaction with Cp2ZrHCl and coordination polymerization was reported. Hydrozirconation of vinyl-containing polystyrene (copolymer of styrene and 4-(vinylphenyl)-1-butene (PSVS)) was found to be an efficient way for immobilization of zirconocene pre-initiator onto polymer backbone by carbon-zirconium (C-Zr) sigma (σ) bond. By activation with MAO, the resultant hydrozirconated PSVS could act as a macroinitiator with multiple-initiating sites (Zr^δ+-C^δ-) for ethylene insertion and propagation in "graft from" fashion. The hydrozirconation and the following ethylene polymerization were monitored by NMR and GPC, revealing the successful synthesis of PS-g-PE and the following formation of free PE chains due to chain transfer characteristic of metallocene catalyst. Thus we could prepare PE/PS-g-PE alloy through in situ ethylene polymerization by this method. The presence of PS-g-PE in the resultant alloy endowed some special functionalization, for example, acting as compatibilizer in PE/PS blends.

Graphical abstract

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Characterization of hard-segment crystalline phase of thermoplastic polyurethane in the presence of butane and glycerol monosterate and its impact on mechanical property and microcellular morphology

Publication date: 10 March 2017
Source:Polymer, Volume 112
Author(s): N. Hossieny, V. Shaayegan, A. Ameli, M. Saniei, C.B. Park
The effects of glycerol monosterate (GMS) and high-pressure butane on the phase-separation and crystallization of the hard segment (HS) of thermoplastic polyurethane (TPU) were investigated. Small and wide angle x-ray diffraction, polarized optical microscopy and atomic force microscopy were used to characterize the crystalline morphology of TPU under various conditions. Overall, 60% higher HS crystallinity was observed in TPU-GMS samples annealed with butane compared to the neat-TPU samples. The toughness and Young Modulus in the TPU-GMS samples were increased due to the higher HS crystallinity compared to the neat-TPU samples. The HS crystallites were effectively utilized as heterogeneous bubble nucleation sites to induce microcellular morphologies in the TPU microstructure. Compared to neat-TPU, the TPU-GMS microcellular morphology showed higher cell density over the wide saturation temperature of 150–170 °C due to the increased HS phase separation and crystallization mechanism in the presence of GMS and dissolved butane.

Graphical abstract

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Smart polyolefins feeling the force: Color changeable poly(ethylene-vinyl acetate) and poly(ethylene-octene) in response to mechanical force

Publication date: 10 March 2017
Source:Polymer, Volume 112
Author(s): Meng Li, Weifeng Liu, Shiping Zhu
Spiropyran (SP) mechanophore cross-linker was covalently incorporated into two widely used polyolefins, poly(ethylene-vinyl acetate) (EVA) and poly(ethylene-octene) (EOC), through facile cross-linking by peroxide under hot press. It was found that (1'-(2-(methacryloyloxy)ethyl)-3′,3′ dimethylspiro[chromene-2,2'-indolin]-6-yl)methyl methacrylate (SP3) could not be thermally driven to merocyanine (MC) in polyolefins during high temperature cross-linking, which is superior to other types of SP mechanophores used for polymer processing. The force-induced ring-opening reaction of SP-to-MC was demonstrated on SP3-cross-linked EVA. It was found that increasing the SP content resulted in earlier activation and that more MC was driven from SP at a slower strain rate. When held at constant strain, MC gradually reverted to SP. The mechanoactivation of SP was also investigated for SP3-cross-linked EOC. This work represents the first example of color-changeable polyolefins in response to mechanical force and demonstrates the feasibility of applying mechanophores to widely-used commercial polyolefins for stress sensing.

Graphical abstract

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Predatory Invitations from Journals: More Than Just a Nuisance?

Physicians and academic researchers are frequently targeted with spam invitations to submit manuscripts to predatory journals. This study was conducted to understand the nature and characteristics of these invitations. All spam e-mails received by an academic medical oncologist over a 3-month period were collected and categorized. Presumed predatory journal invitations were analyzed and cross-checked against Beall's list of "potential, probable, or possible predatory" journals and publishers. Invitations to submit to predatory journals were the most common single type of spam received. The Oncologist 2017;22:00–00

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Validation of Progression-Free Survival as a Surrogate Endpoint for Overall Survival in Malignant Mesothelioma: Analysis of Cancer and Leukemia Group B and North Central Cancer Treatment Group (Alliance) Trials

Purpose.

The aim of this study was to investigate whether progression-free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in malignant mesothelioma.

Materials and Methods

Individual data were collected from 15 Cancer and Leukemia Group B (615 patients) and 2 North Central Cancer Treatment Group (101 patients) phase II trials. The effects of 5 risk factors for OS and PFS, including age, histology, performance status (PS), white blood cell count, and European Organisation for Research and Treatment of Cancer (EORTC) risk score, were used in the analysis. Individual-level surrogacy was assessed by Kendall's tau through a Clayton bivariate Copula survival (CBCS) model. Summary-level surrogacy was evaluated via the association between logarithms of the hazard ratio (log HR)—log HR_OS and log HR_PFS—measured in R² from a weighted least-square (WLS) regression model and the CBCS model.

Results.

The median PFS for all patients was 3.0 months (95% confidence interval [CI], 2.8–3.5 months) and the median OS was 7.2 months (95% CI, 6.5–8.0 months). Moderate correlations between PFS and OS were observed across all risk factors at the individual level, with Kendall's tau ranging from 0.46 to 0.47. The summary-level surrogacy varied among risk factors. The Copula R² ranged from 0.51 for PS to 0.78 for histology. The WLS R² ranged from 0.26 for EORTC and PS to 0.67 for age.

Conclusions.

The analyses demonstrated low to moderate individual-level surrogacy between PFS and OS. At the summary level, the surrogacy between PFS and OS varied significantly across different risk factors. With a short postprogression survival and a moderate correlation between PFS and OS, there is no evidence that PFS is a valid surrogate endpoint for OS in malignant mesothelioma. The Oncologist 2017;22:000–000

Implications for Practice

For better disease management and for more efficient clinical trial designs, it is important to know if progression-free survival (PFS) is a good surrogate endpoint for overall survival in malignant mesothelioma. With a relatively large database of 17 phase II trials and 716 patients from Cancer and Leukemia Group B and North Central Cancer Treatment Group, we conducted statistical analyses and found that there is no evidence to suggest that PFS is a valid surrogate endpoint for OS for malignant mesothelioma. Future research work is needed to find alternative surrogate endpoints for OS.

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Too Many Journals

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Immune checkpoint receptors in cancer: redundant by design?

Publication date: April 2017
Source:Current Opinion in Immunology, Volume 45
Author(s): Jing Li, Ling Ni, Chen Dong
Co-inhibitory receptors expressed on activated immune cells function to regulate T cell tolerance to self-antigens, also serving by tumor cells to escape from eradication by the host immune system. Therefore, blockade of immune checkpoint receptors (ICR) has become a promising immunotherapeutic strategy for treatment of a wide variety of cancers. However, blockade of one of the immune checkpoint receptors alone is often not sufficiently effective; co-blockade shows synergic effects in reversing immunosuppression. In this article, we summarize the expression patterns, mechanisms of action of different ICRs as well as the stages and sites they function in, and discuss how they execute non-redundant suppressive effects in anti-tumor immunity.



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Dendritic cells in cancer: the role revisited

Publication date: April 2017
Source:Current Opinion in Immunology, Volume 45
Author(s): Filippo Veglia, Dmitry I Gabrilovich
Dendritic cells (DCs) with their potent antigen presenting ability are long considered as critical factor in antitumor immunity. Despite high potential in promoting antitumor responses, tumor-associated DCs are largely defective in their functional activity and can contribute to immune suppression in cancer. In recent years existence of immune suppressive regulatory DCs in tumor microenvironment was described. Monocytic myeloid derived suppressor cells (M-MDSCs) can contribute to the pool of tumor associated DCs by differentiating to inflammatory DCs (inf-DCs), which appear to have specific phenotype and is critical component of antitumor response. Here we examine the role of inf-DCs along with other DC subsets in the regulation of immune responses in cancer. These novel data expand our view on the role of DCs in cancer and may provide new targets for immunotherapy.



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Potential role for growth hormone-releasing hormone in triple-negative breast cancer

Publication date: Available online 10 February 2017
Source:Peptides
Author(s): Alice Lee




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ANGIOTENSIN-(1-7)-DEPENDENT VASORELAXATION OF THE RENAL ARTERY EXHIBITS UNIQUE ANGIOTENSIN AND BRADYKININ RECEPTOR SELECTIVITY

Publication date: Available online 10 February 2017
Source:Peptides
Author(s): Mariam H.M. Yousif, Ibrahim F. Benter, Debra I. Diz, Mark C. Chappell
Angiotensin-(1-7) [Ang-(1-7)] exhibits blood pressure lowering actions, inhibits cell growth, and reduces tissue inflammation and fibrosis which may functionally antagonize an activated Ang II-AT1 receptor axis. Since the vascular actions of Ang-(1-7) and the associated receptor/signaling pathways varies in different vascular beds, the current study established the vasorelaxant properties of the heptapeptide in the renal artery of male Wistar male rats. Ang-(1-7) produced an endothelium-dependent vasodilator relaxation of isolated renal artery segments pre-contracted by a sub-maximal concentration of phenylephrine (PE) (10⁻⁷M). Ang-(1-7) induced vasodilation of the rat renal artery with an ED50 of 3±1nM and a maximal response of 42±6% (N=10). The two antagonists (10⁻⁵M each) for the AT7/Mas receptor (MasR) [D-Pro⁷]-Ang-(1-7) and [D-Ala⁷]-Ang-(1-7) significantly reduced the maximal response to 12±1% and 18±3%, respectively. Surprisingly, the AT2R receptor antagonist PD123319, the AT1R antagonist losartan and B2R antagonist HOE140 (10⁻⁶M each) also significantly reduced Ang-(1-7)-induced relaxation to 12±2%, 22±3% and 14±7%, respectively. Removal of the endothelium or addition of the soluble guanylate cyclase (sGC) inhibitor ODQ (10⁻⁵M) essentially abolished the vasorelaxant response to Ang-(1-7) (10±4% and 10±2%, P <0.05). Finally, the NOS inhibitor LNAME (10⁻⁴M) reduced the response to 13±2% (p<0.05), but the cyclooxygenase inhibitor indomethacin failed to block the Ang-(1-7) response. We conclude that Ang-(1-7) exhibits potent vasorelaxant actions in the isolated renal artery that are dependent on an intact endothelium and the apparent stimulation of a NO-sGC pathway. Moreover, Ang-(1-7)-dependent vasorelaxation was sensitive to antagonists against the AT7/Mas, AT1, AT2 and B2 receptor subtypes.



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Molecular networks related to the immune system and mitochondria are targets for the pesticide dieldrin in the zebrafish (Danio rerio) central nervous system

Publication date: Available online 10 February 2017
Source:Journal of Proteomics
Author(s): Andrew M. Cowie, Kathleena I. Sarty, Angella Mercer, Jin Koh, Karen A. Kidd, Christopher J. Martyniuk
The objectives of this study were to determine the behavioral and molecular responses in the adult zebrafish (Danio rerio) central nervous system (CNS) following a dietary exposure to the pesticide dieldrin. Zebrafish were fed pellets spiked with 0.03, 0.15, or 1.8μg/g dieldrin for 21days. Behavioral analysis revealed no difference in exploratory behaviors or those related to anxiety. Transcriptional networks for T-cell aggregation and selection were decreased in expression suggesting an immunosuppressive effect of dieldrin, consistent with other studies investigating organochlorine pesticides. Processes related to oxidative phosphorylation were also differentially affected by dieldrin. Quantitative proteomics (iTRAQ) using a hybrid quadrupole-Orbitrap identified 226 proteins that were different in abundance in one or more doses. These included ATP synthase subunits (mitochondrial) and hypoxia up-regulated protein 1 which were decreased and NADH dehydrogenases (mitochondrial) and signal recognition particle 9 which were up-regulated. Thus, proteins affected were functionally associated with the mitochondria and a network implicated PD and Huntington's disease as those associated with proteins. Molecular networks related to mitochondrial dysfunction and T-cell regulation are hypothesized to underlie the association between dieldrin and PD. These data contribute to a comprehensive transcriptomic and proteomic biomarker framework for pesticide exposures and neurodegenerative diseases.Biological significanceDieldrin is a persistent organochlorine pesticide that has been associated with human neurodegenerative disease such as Parkinson's disease. Dieldrin is ranked 18th on the 2015 U.S. Agency for Toxic Substances and Disease Registry and continues to be a pesticide of concern for human health. Transcriptomics and quantitative proteomics (ITRAQ) were employed to characterize the molecular networks in the central nervous system that are altered with dietary exposure to dieldrin. We found that transcriptional and protein networks related to the immune system, mitochondria, and Parkinson's disease were preferentially affected by dieldrin. The study provides new insight into the mechanisms of dieldrin neurotoxicity that may explain, in part, the association between this pesticide and increased risks to neurodegeneration. These data contribute in a significant way to developing a molecular framework for pesticide induced neurotoxicity.

Graphical abstract

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Super-SILAC mix coupled with SIM/AIMS assays for targeted verification of phosphopeptides discovered in a large-scale phosphoproteome analysis of hepatocellular carcinoma

Publication date: Available online 10 February 2017
Source:Journal of Proteomics
Author(s): Yu-Tsun Lin, Kun-Yi Chien, Chia-Chun Wu, Wen-Yu Chang, Lichieh Julie Chu, Min-Chi Chen, Chau-Ting Yeh, Jau-Song Yu
Plentiful studies have established a close association between aberrant phosphorylation and hepatocellular carcinoma (HCC). Here, we applied a quantitative phosphoproteomics platform combining dimethylation labeling and online 3D strong cation exchange chromatography (SCX)-titanium oxide (TiO2)/RP-LTQ-Orbitrap to compare phosphoproteomes between three pairs of HCC tissues and non-tumor counterparts. This analysis yielded 7868 quantifiable phosphopeptides and numerous up- or down-regulated candidates. Increased phosphorylation of LMNA and NIPA was confirmed using specific antibodies. To expand our verification capability, we evaluated the use of LTQ-Orbitrap run in SIM/Accurate inclusion mass screening (AIMS) mode with a super-SILAC mixture as an internal standard to quantify a subset of phosphopeptide candidates in HCC tissue samples. In sample I used for discovery experiment, we successfully quantified 32 (in SIM mode) and 30 (in AIMS mode) phosphopeptides with median coefficients of variation (CVs) of 7.5% and 8.3%, respectively. When the assay was applied to other three pairs of HCC specimens for verification experiment, 40 target phosphopeptides were quantified reliably (~7.5% CV), and more than half of them were differentially expressed between tumor and adjacent non-tumor tissues. Collectively, these results indicate the feasibility of using super-SILAC mix-SIM/AIMS assays for targeted verification of phosphopeptides discovered by large-scale phosphoproteome analyses of HCC specimens.SignificanceIn this study, we developed a strategy for conducting both discovery and targeted verification of deregulated phosphoproteins in HCC tissue specimens on LTQ-Orbitrap. This strategy allowed us to generate a quantitative HCC tissue phosphoproteome dataset containing significantly deregulated phosphoproteins that represents a valuable resource for the identification of potential HCC biomarkers and/or therapeutic targets. Furthermore, our proof-of-concept experiments demonstrated the feasibility of applying LTQ-Orbitrap, operated in SIM/AIMS mode, to multiplex and targeted verification of phosphopeptides in individual tissue specimens using a super-SILAC mix as an internal phosphopeptide standard. This method could be readily applied to verify dozens of phosphopeptide candidates in a larger HCC sample set.



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Calculating the incalculable. Optimal radioiodine dose in Graves’ hyperthyroidism

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Short-term UVB irradiation significantly increases vitamin D serum concentration in obese patients: a clinical pilot study

Abstract

Purpose

Deficiency of vitamin D is very common in obese people and treatment by oral supplementation is not effective in all patients. This exploratory pilot study investigated the influence of different doses of short-term ultraviolet B irradiation on serum 25-hydroxyvitamin-D₃ (25D) and 1,25-dihydroxyvitamin-D₃ (1,25D) levels in obese compared to normal weight subjects and obese controls.

Methods

Participants with skin types II and III (Fitzpatrick skin classification) were assigned to six groups including four intervention groups receiving irradiation (three groups of obese and one group of normal weight subjects) and two control groups without treatment (obese and normal weight). Intervention groups received three sessions of whole body UVB irradiation of three different doses (cumulative doses over three sessions: 0.28, 0.70, 1.75 minimal erythema dose) within 1 week of intervention. Serum 25D and 1,25D were measured at baseline and after irradiation. Outcome differences between groups were analyzed using a linear model.

Results

Serum 25D levels increased significantly in obese (+23.6 and +26.7%, respectively, p = 0.01) and normal weight (+15.6%, p = 0.02) intervention groups who received medium and high doses of ultraviolet B irradiation compared to control groups (+3.5 and −4.0%, respectively, p = 1.0). The increase in obese patients was 51.4% greater compared to normal weight controls irradiated with equal ultraviolet B doses. Low-level ultraviolet irradiation did not result in a significant change in serum 25D (+7.0%, p = 0.61). We did not detect any significant differences of 1,25D between groups (p = 0.25).

Conclusions

The current study indicates that short-term ultraviolet B irradiation increases 25D levels in obese patients.

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Bidirectional relationship between time preference and adolescent smoking and alcohol use: Evidence from longitudinal data

Publication date: July 2017
Source:Addictive Behaviors, Volume 70
Author(s): Young Kyung Do, Eunhae Shin
IntroductionScholarly interest in time preference as a potential predictor of risky health behaviors in adolescents has increased in recent years. However, most of the existing literature is limited due to the exclusive reliance on cross-sectional data, precluding the possibility of establishing the direction of causality. Using longitudinal data from the Korea Youth Panel Survey (2003–7), which followed up a nationally representative sample of 3449 adolescents aged 14years for five years, this study examines a bidirectional relationship between time preference and smoking and drinking behaviors among adolescents.MethodsWe used discrete time hazard models of smoking and drinking initiation as a function of time preference measured at the baseline and fixed-effects ordered logit model of time preference, respectively. Our measure of time preference was derived from the survey question on a hypothetical choice between immediate enjoyment today and likely higher scores on an exam tomorrow.ResultsThe overall results provide evidence on the bidirectional relationship; that is, higher time discounting (i.e., greater relative preference for present utility over future utility) results in an increased risk of engaging in smoking and drinking, and conversely, adopting such behaviors leads to a higher discount rate.ConclusionsThe bidirectional relationship may function as a mechanism for adolescents to engage in increased smoking and drinking or additional negative health behaviors via gateway effects, strengthening the case for preventing the initiation of risky health behaviors among adolescents.



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Assessing the role of impulsivity in smoking & non-smoking disordered gamblers

Publication date: July 2017
Source:Addictive Behaviors, Volume 70
Author(s): Célina A. Boothby, Hyoun S. Kim, Nicole K. Romanow, David C. Hodgins, Daniel S. McGrath
BackgroundCo-morbidity with other addictive behaviors is common in disordered gambling (DG). In particular, tobacco dependence has been found to be among the most prevalent disorders co-morbid with DG. While the extant literature has firmly established the co-occurrence of DG and smoking, there is a paucity of research examining factors that differentiate DGs who smoke from those who do not.ObjectivesTo address this empirical gap, the current study tested whether dimensions of trait impulsivity as measured by the UPPS-P Impulsive Behavior Scale (positive urgency, negative urgency, lack of premeditation, lack of perseverance, and sensation seeking), discriminated between non-DGs and DGs based on their present smoking status: non-smoker, occasional smoker, and daily smoker.MethodsTo this end, 564 community gamblers were recruited through a crowdsourcing platform (Amazon's Mechanical Turk) and completed an online survey, assessing problem gambling severity, tobacco use, and trait impulsivity.ResultsMANOVA analyses revealed significant main effects for both gambling severity and smoking status groups. Importantly, a significant gambling by smoking interaction was also found. Pairwise comparisons revealed that DGs who were daily smokers scored higher on negative urgency than those who smoked occasionally or not all. Furthermore, among non-DGs, smoking status failed to discriminate between mean scores on negative urgency. No other significant interaction effects were found for the remaining UPPS-P impulsivity facets.ConclusionsResults suggest that individual components of trait impulsivity, and more specifically negative urgency, successfully differentiate DGs who do not smoke, or just smoke occasionally, from DGs who smoke daily. These findings suggest that the degree of trait impulsivity may potentially distinguish between DGs and DGs who are dually addicted to other substances such as tobacco.



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A double-mediator based whole cell electrochemical biosensor for acute biotoxicity assessment of wastewater

Publication date: 15 May 2017
Source:Talanta, Volume 167
Author(s): Guanyue Gao, Deyu Fang, Yuan Yu, Liangzhuan Wu, Yu Wang, Jinfang Zhi
This work investigates the feasibility and sensitivity of a double-mediator based whole cell electrochemical biosensor to detect the acute biotoxicity of wastewater. The lipophilic mediator menadione was used to mediate the intracellular metabolic activities whereas hydrophilic potassium ferricyanide was employed as extracellular electron acceptor to transport the electron from the menadiol to anode. A chitosan hydrogel polymer film with boron-doped nanocrystalline diamond (BND) particles was electrodeposited onto a glassy carbon (GC) electrode to immobilize Saccharomyces cerevisiae cells and the mediators. The feasibility of the as-prepared biosensor was verified by determine the acute biotoxicity of four heavy metal ions(Cu²⁺, Cd²⁺, Ni²⁺, Pb²⁺), three phenol pollutants (3,5-dichlorophenol, 4-chlorophenol, phenol) and three real wastewater samples. The IC50 values for Cu²⁺, Cd²⁺, Ni²⁺, Pb²⁺ are 10.12mg/L,13.88mg/L, 17.06mg/L and 34.56mg/L. And the IC50 value is 16.48mg/L, 34.40mg/L and 44.55mg/L for 3,5-dichlorophenol, 4-chlorophenol and phenol, respectively. The results of this work indicate that the double-mediator based whole cell electrochemical biosensor could be applied into the acute toxicity assessment of real wastewater samples with excellent performance and highlight their merit as portable and sensitive, which may providing a reasonable and reliable way for wastewater toxicity online detection.

Graphical abstract

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Selective colorimetric analysis of spermine based on the cross-linking aggregation of gold nanoparticles chain assembly

Publication date: 15 May 2017
Source:Talanta, Volume 167
Author(s): Jian Wang, Zhu Lian Wu, Hong Zhi Zhang, Yuan Fang Li, Cheng Zhi Huang
A selective colorimetric assay for spermine was proposed in this work. In a weak alkaline medium, the conformational structure of double-stranded calf thymus DNA (ctDNA) was loosened to install gold nanoparticles (AuNPs) into chains. While, the chain assembly of AuNPs could form cross-linking aggregates when spermine was present, which was attributed to the electrostatic interaction between the positive change of spermine and negative change both of AuNPs and ctDNA, as well as the groove binding between ctDNA and spermine. Under the optimum conditions, the aggregation degree of AuNPs was proportional to the concentration of spermine in the range of 0.1–2.0μM with a limit of detection of 11.6nM. More interestingly, AuNPs changed from red to purple and even to blue depending on the concentration of spermine, which could be developed as the colorimetric analysis of spermine. ctDNA-AuNPs assembly was demonstrated as a novel visual probe for the specific sensing of spermine with high specificity and sensitivity.

Graphical abstract

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Non-enzymatic sensors based on in situ laser-induced synthesis of copper-gold and gold nano-sized microstructures

Publication date: 15 May 2017
Source:Talanta, Volume 167
Author(s): Maxim S. Panov, Olga A. Vereshchagina, Sergey S. Ermakov, Ilya I. Tumkin, Evgeniia M. Khairullina, Mikhail Yu. Skripkin, Andrey S. Mereshchenko, Mikhail N. Ryazantsev, Vladimir A. Kochemirovsky
The synthesis of conductive gold and copper-gold microstructures with high developed surface based on the method of laser-induced metal deposition from solution was developed. The topology and crystallization phase of these structures were observed by means of scanning electron microscopy and X-ray diffraction, respectively. The electrochemical properties of the synthesized materials were investigated using cyclic voltamperometry and amperometry. According to the obtained results, it was found out that copper-gold microstructures demonstrate a linear dependence of Faraday current vs. concentration from 0.025 to 5µM for D-glucose and from 0.025 to 10µM for hydrogen peroxide. In turn, gold deposit exhibits a linear dependence of Faraday current vs. concentration from 0.025 to 50µM for D-glucose and from 0.025 to 1µM for hydrogen peroxide. Moreover, the synthesized materials reveal low detection limits (0.025µM) with respect to the aforementioned analytes, which is quite promising for their potential application in design and fabrication of new non-enzymatic biosensors.

Graphical abstract

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Trastuzumab in combination with weekly paclitaxel and carboplatin as neo-adjuvant treatment for HER2-positive breast cancer: The TRAIN-study

Publication date: March 2017
Source:European Journal of Cancer, Volume 74
Author(s): Mette S. van Ramshorst, Erik van Werkhoven, Ingrid A.M. Mandjes, Margaret Schot, Jelle Wesseling, Marie-Jeanne T.F.D. Vrancken Peeters, Jetske M. Meerum Terwogt, Monique E.M. Bos, Hendrika M. Oosterkamp, Sjoerd Rodenhuis, Sabine C. Linn, Gabe S. Sonke
AimTo determine the efficacy and safety of an anthracycline-free neo-adjuvant regimen consisting of weekly paclitaxel, carboplatin and trastuzumab in HER2-positive breast cancer.Patients and methodsPatients with stage II or III HER2-positive breast cancer received weekly paclitaxel ([P], 70 mg/m²), trastuzumab ([T], 2 mg/kg, loading dose 4 mg/kg) and carboplatin ([C], AUC = 3 mg ml⁻¹ min) for 24 weeks. In weeks 7, 8, 15, 16, 23 and 24, trastuzumab was administered without chemotherapy. The primary end-point was pathologic complete response in the surgical resection specimen, defined as the absence of invasive tumour cells in breast and axilla.ResultsOne hundred and eleven patients were included in the study, and 108 were evaluable for the primary end-point. The pathologic complete response rate was 43% (95% confidence interval [CI]: 33–52). Median follow-up was 52 months, and the 3-year event-free survival was 88% (95% CI: 82–94), and the 3-year overall survival was 92% (95% CI: 88–98). The most common grade 3–4 adverse events were neutropenia (67%) and thrombocytopenia (43%). Less than five percent of patients experienced febrile neutropenia. No symptomatic left ventricular systolic dysfunction was observed during neo-adjuvant treatment.ConclusionAn anthracycline-free neo-adjuvant regimen of weekly paclitaxel, trastuzumab and carboplatin is highly effective in HER2-positive breast cancer with manageable toxicity.



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Human papillomavirus as prognostic marker with rising prevalence in neck squamous cell carcinoma of unknown primary: A retrospective multicentre study

Publication date: March 2017
Source:European Journal of Cancer, Volume 74
Author(s): Lea Schroeder, Paolo Boscolo-Rizzo, Elisa Dal Cin, Salvatore Romeo, Lorena Baboci, Gerhard Dyckhoff, Jochen Hess, Carlota Lucena-Porcel, Anne Byl, Nikolaus Becker, Laia Alemany, Xavier Castellsagué, Miquel Quer, Xavier León, Manuel Wiesenfarth, Michael Pawlita, Dana Holzinger
Patients with neck squamous cell carcinomas of unknown primary tumour (NSCCUP) present with lymph node metastasis without evidence for a primary tumour. Most patients undergo an aggressive multimodal treatment, which induces severe, potentially unnecessary toxicity. Primary tumours of NSCCUP can be hidden in the oropharynx. Human papillomavirus (HPV) is causally involved in a subgroup of oropharyngeal squamous cell carcinomas (OPSCC) associated with early lymph node metastasis and good prognosis. Detection of markers for HPV transformation in NSCCUP could allow focussing on the oropharynx in primary tumour search and could be of value for choice and extent of treatment.In a retrospective multicentre study (Germany, Italy and Spain), we analysed metastatic lymph nodes from 180 NSCCUP patients for the presence of HPV DNA, HPV E6*I mRNA and cellular p16^INK4a overexpression, a surrogate marker for HPV-induced transformation. HPV status, defined as positivity for viral mRNA with at least one additional marker, was correlated with clinical parameters and survival outcome.A substantial proportion (16%) of NSCCUP were HPV-driven, mainly by HPV16 (89%). HPV prevalence increased with year of diagnosis from 9% during 1998–2004 to 23% during 2005–2014 (p = 0.007). HPV-driven NSCCUP had significantly better overall and progression-free survival rates (p ≤ 0.008).Based on this survival benefit, it is contended that HPV RNA status should be included in NSCCUP diagnosis and in therapeutic decision-making. Deintensification of radiation in patients with HPV-driven NSCCUP, while concurrently concentrating on the oropharynx appears to be a promising therapeutic strategy, the efficacy of which should be assessed in prospective trials. To our knowledge, this is the largest study on HPV in NSCCUP.



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Second- and third-generation drugs for immuno-oncology treatment—The more the better?

Publication date: March 2017
Source:European Journal of Cancer, Volume 74
Author(s): Wolfram C.M. Dempke, Klaus Fenchel, Peter Uciechowski, Stephen P. Dale
Recent success in cancer immunotherapy (anti-CTLA-4, anti-PD1/PD-L1) has confirmed the hypothesis that the immune system can control many cancers across various histologies, in some cases producing durable responses in a way not seen with many small-molecule drugs. However, only less than 25% of all patients do respond to immuno-oncology drugs and several resistance mechanisms have been identified (e.g. T-cell exhaustion, overexpression of caspase-8 and β-catenin, PD-1/PD-L1 gene amplification, MHC-I/II mutations). To improve response rates and to overcome resistance, novel second- and third-generation immuno-oncology drugs are currently evaluated in ongoing phase I/II trials (either alone or in combination) including novel inhibitory compounds (e.g. TIM-3, VISTA, LAG-3, IDO, KIR) and newly developed co-stimulatory antibodies (e.g. CD40, GITR, OX40, CD137, ICOS). It is important to note that co-stimulatory agents strikingly differ in their proposed mechanism of action compared with monoclonal antibodies that accomplish immune activation by blocking negative checkpoint molecules such as CTLA-4 or PD-1/PD-1 or others. Indeed, the prospect of combining agonistic with antagonistic agents is enticing and represents a real immunologic opportunity to 'step on the gas' while 'cutting the brakes', although this strategy as a novel cancer therapy has not been universally endorsed so far. Concerns include the prospect of triggering cytokine-release syndromes, autoimmune reactions and hyper immune stimulation leading to activation-induced cell death or tolerance, however, toxicity has not been a major issue in the clinical trials reported so far. Although initial phase I/II clinical trials of agonistic and novel antagonistic drugs have shown highly promising results in the absence of disabling toxicity, both in single-agent studies and in combination with chemotherapy or other immune system targeting drugs; however, numerous questions remain about dose, schedule, route of administration and formulation as well as identifying the appropriate patient populations. In our view, with such a wealth of potential mechanisms of action and with the ability to fine-tune monoclonal antibody structure and function to suit particular requirements, the second and third wave of immuno-oncology drugs are likely to provide rapid advances with new combinations of novel immunotherapy (especially co-stimulatory antibodies). Here, we will review the mechanisms of action and the clinical data of these new antibodies and discuss the major issues facing this rapidly evolving field.



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Melanoma and pregnancy

Abstract

Melanoma is the most common cancer in women during their reproductive years and kills more young Australians than any other single cancer. Care of women whose pregnancy is complicated by a diagnosis of malignancy is complex. The risk of delaying treatment to the mother, the short-term and long-term risks of premature delivery to the child, and the immediate risks to the foetus and long-term risks to the child of maternal treatment with surgery, radiotherapy or medical therapies must be considered.

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Disinfection by-product formation during chlor(am)ination of algal organic matters (AOM) extracted from Microcystis aeruginosa : effect of growth phases, AOM and bromide concentration

Abstract

Algae organic matter (AOM), including extracellular organic matter (EOM) and intracellular organic matter (IOM), has caused a series of problems to the water quality, among which formation of disinfection by-products (DBPs) during subsequent chlor(am)ination process was especially serious and concerned. This study characterized physicochemical properties of the EOM and IOM solution extracted from different growth phases of Microcystis aeruginosa and investigated the corresponding formation potential of DBPs during chlor(am)ination process. Besides, the effects of initial concentration of xEOM, IOM, and Br⁻ on the yields of disinfection by-product formation potential were studied. The results indicated that the specific UV absorbance (SUVA₂₅₄) values of IOM and EOM (1.09 and 2.66 L/mg m) were considerably lower than that of natural organic matter (NOM) (4.79 L/mg m). Fluorescence dates showed the soluble microbial by-product was dominant in both EOM and IOM, and the tryptophan was the main component of AOM. From the excitation–emission matrix figure of EOM and IOM, we found that the content of the high molecular weight protein substance in IOM was higher than EOM. During chlorination of EOM and IOM, the yields of four kinds of DBPs followed the order trichloroethene (TCM) > 1,1-DCP > dichloride acetonitrile (DCAN) > trichloronitromethane (TCNM), while the order was TCM > DCAN > TCNM > 1,1-DCP during chloramination process. The bromine substitution factor (BSF) value increased with the increasing of the concentration of Br⁻. When the concentration of Br⁻ was 500 μg/L, the BSF values of chlorination EOM and IOM were 51.1 and 68.4%, respectively. As the concentration of Br⁻ increased, the formation of Cl–DBPs was inhibited and the formation of Br–DBPs was promoted.

Graphical abstract

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