Dynamics of Plasma Cytokines in a Patient with Deficiency of Interleukin-36 Receptor Antagonist Successfully Treated with Anakinra

Generalized pustular psoriasis (GPP) is an autoinflammatory disease characterized by abrupt-onset episodes of erythematous skin plaques with countless pustules, fever, marked neutrophilia and increased acute phase reactants (APR).¹ Loss-of-function mutations in the IL36RN gene, encoding for interleukin (IL)-36 receptor antagonist (IL-36Ra), have been described in a significant proportion of GPP patients.^2,3 Previous studies have shown in vitro and ex vivo enhanced production of pro-inflammatory cytokines (IL-1, IL-6 and IL-8) and successful outcomes with anti-IL-1 drugs in patients carrying IL36RN mutations.^1,2 However, little is known about the correlation of plasma cytokines, inflammatory markers and clinical follow-up, before and after treatment with anti-IL-1 drugs.

This article is protected by copyright. All rights reserved.

http://ift.tt/2yJNrTx

Comment on: A Visual Literacy Course for Dermatology Trainees

We would like to congratulate Griffin and colleagues on their report of an innovative training programme in visual literacy for dermatology registrars (residents).¹ Our experience of visual literacy training for registrars in South London resonates with that of the Manchester group, and we would like to add to this by describing our observation of some additional qualitative benefits which may be derived from such training. Training similar to that described by the Griffin et al was delivered to 10 dermatology registrars at the Dulwich Picture Gallery in London, England from September 2016 – January 2017 in 5 one hour sessions. Baseline and post-course assessments, scored on the unique accurate observations method described by Huang et al,² were carried out and demonstrated an increase in the number of unique accurate observations per image following the course compared to pre-course assessment.

This article is protected by copyright. All rights reserved.

http://ift.tt/2hI0zgC

A quinidine non responsive novel KCNT1 mutation in an Indian infant with epilepsy of infancy with migrating focal seizures

Publication date: Available online 14 October 2017
Source:Brain and Development
Author(s): Priyanka Madaan, Prashant Jauhari, Aparajita Gupta, Biswaroop Chakrabarty, Sheffali Gulati
Epilepsy of infancy with migrating focal seizures {a.k.a malignant migrating partial seizures of infancy (MMPSI)} is an uncommon epileptic encephalopathy with a poor prognosis. Migrating focal seizures with autonomic features, developmental stagnation and refractoriness to treatment are its key features. It is caused by genetic defects in various ion channels, most common being sodium activated potassium channel (KCNT1), found in up to 50% of cases. With advent of genetic diagnosis and precision medicine, many targeted therapies have been identified. Antagonist of KCNT1 coded ion channel like Quinidine has shown promising results in MMPSI. Here we report first mutation proven case of MMPSI from India. This child had a novel heterozygous missense mutation in exon10 of the KCNT1 gene (chr9:138650308; c.808C > C/G (p.Q270E)) which was pathogenic. Neither quinidine nor ketogenic diet could control his seizures. Ultimately, the child succumbed to his illness at nine months of age.



http://ift.tt/2yjJ3r9

Dynamics of Plasma Cytokines in a Patient with Deficiency of Interleukin-36 Receptor Antagonist Successfully Treated with Anakinra

Generalized pustular psoriasis (GPP) is an autoinflammatory disease characterized by abrupt-onset episodes of erythematous skin plaques with countless pustules, fever, marked neutrophilia and increased acute phase reactants (APR).¹ Loss-of-function mutations in the IL36RN gene, encoding for interleukin (IL)-36 receptor antagonist (IL-36Ra), have been described in a significant proportion of GPP patients.^2,3 Previous studies have shown in vitro and ex vivo enhanced production of pro-inflammatory cytokines (IL-1, IL-6 and IL-8) and successful outcomes with anti-IL-1 drugs in patients carrying IL36RN mutations.^1,2 However, little is known about the correlation of plasma cytokines, inflammatory markers and clinical follow-up, before and after treatment with anti-IL-1 drugs.

This article is protected by copyright. All rights reserved.

http://ift.tt/2yJNrTx

Comment on: A Visual Literacy Course for Dermatology Trainees

We would like to congratulate Griffin and colleagues on their report of an innovative training programme in visual literacy for dermatology registrars (residents).¹ Our experience of visual literacy training for registrars in South London resonates with that of the Manchester group, and we would like to add to this by describing our observation of some additional qualitative benefits which may be derived from such training. Training similar to that described by the Griffin et al was delivered to 10 dermatology registrars at the Dulwich Picture Gallery in London, England from September 2016 – January 2017 in 5 one hour sessions. Baseline and post-course assessments, scored on the unique accurate observations method described by Huang et al,² were carried out and demonstrated an increase in the number of unique accurate observations per image following the course compared to pre-course assessment.

This article is protected by copyright. All rights reserved.

http://ift.tt/2hI0zgC

Safe Administration of An Anti-PD-1 Antibody to Kidney-transplant Patients: 2 Clinical Cases and Review of the Literature

Antiprogrammed cell-death protein 1 (PD-1) antibodies have revolutionized therapy of metastatic melanoma and other tumors, but some subgroups of patients such as immunosuppressed patients after solid-organ transplantation, have regularly been excluded from clinical studies. We report 2 cases of kidney-transplant patients who received an anti-PD-1 antibody to treat metastatic melanoma. Treatment was tolerated well with no relevant adverse events and stable kidney functions, but the melanoma progressed in both patients. Factors potentially affecting risk of allograft rejection and response to treatment, for example, immunosuppressive regimen and therapeutic sequence, are discussed on the basis of current literature. Further studies are necessary to determine the risk of allograft rejection and the therapeutic benefit of anti-PD-1 antibodies for organ-transplanted patients, in particular as these checkpoint inhibitors have become therapeutic standard in a variety of tumors other than melanoma.

http://ift.tt/2gDIWij

Relationship Between PD-L1 Expression and CD8+ T-cell Immune Responses in Hepatocellular Carcinoma

As PD-1/PD-L1 immune checkpoint inhibitors exhibited promising clinical outcomes in various types of solid tumors, PD-1/PD-L1 blockades have been explored for the treatment of hepatocellular carcinoma (HCC). However, the association of PD-L1 with antitumor immunoregulation is not clearly defined in HCC. Here, we evaluated the characteristics of PD-L1 expression, CD8+ T-cell infiltration and their relationship in HCC. A total of 411 resected tumor specimens from HCC patients were immunostained for PD-L1 and CD8. Only 78 (19%) cases showed ≥5% membranous PD-L1 expression on tumor cells, although a significantly positive correlation was found between PD-L1 expression and CD8+ T-cell densities. Moreover, patients with higher tumor PD-L1 expression also showed a higher hepatitis B virus load, which was also related to increased CD8 infiltration. Survival analysis suggested that both tumor and stroma PD-L1 status did not significantly affect overall survival or recurrence-free survival in patients. Although high CD8+ T-cell density was overall associated with better overall survival and recurrence-free survival, its favorable prognostic value was eliminated by high tumor PD-L1 expression. Further flow cytometric and enzyme-linked immunosorbent assay (ELISA) results from the coculture of HCC cell lines with specific CD8+ cytotoxic T lymphocytes (CTLs) demonstrated that CD8+ CTLs remarkably upregulated PD-L1 expression on tumor cell lines by HLA class-I specificity, and the overexpression of tumor PD-L1 impaired interferon-γ secretion by CD8+ CTLs in a negative feedback regulation mechanism. In conclusion, our findings reveal an interaction between PD-L1 expression and CD8+ T-cell immunity in HCC, although PD-L1 is not a prognostic factor for the patients.

http://ift.tt/2gDIMHJ

DCOne as an Allogeneic Cell-based Vaccine for Multiple Myeloma

Multiple myeloma (MM) is characterized by progressive immune dysregulation, loss of myeloma-specific immunity, and an immunosuppressive milieu that fosters disease growth and immune escape. Accordingly, cancer vaccines that reverse tumor-associated immune suppression represent a promising therapeutic avenue of investigation. We examined the potential of an allogeneic cellular vaccine to generate immune responses against MM tumor cells. The DCOne vaccine is comprised of a human myeloid leukemia cell line differentiated into a fully functional dendritic cell, expressing a range of tumor-associated antigens that are also known targets in MM. We found that the myeloma-specific antigens expressed by the DCOne vaccine can traffic via extracellular vesicles to surrounding antigen-presenting cells, thus stimulating autologous T-cell responses. Indeed, coculture of peripheral blood mononuclear cells from patients with MM with the DCOne vaccine resulted in the expansion of activated CD8+ T cells expressing interferon-γ and perforin, with no significant change in the percentage of CD4+ T cells producing interleukin-10. Further, coculture of patient's tumor cells with peripheral blood mononuclear cells and DCOne induced cytotoxic T-lymphocyte-mediated killing of autologous MM cells. These findings demonstrate that the allogeneic DCOne vaccine can induce T-cell activation and myeloma-specific immunity via cross presentation of antigens by native antigen-presenting cells.

http://ift.tt/2gECDLs

Efficacy and Safety of Pembrolizumab in Patients Enrolled in KEYNOTE-030 in the United States: An Expanded Access Program

KEYNOTE-030 (ClinicalTrials.gov ID, NCT02083484) was a global expanded access program that allowed access to pembrolizumab, an antiprogrammed death 1 antibody, for patients with advanced melanoma before its regulatory approval. Patients with unresectable stage III/IV melanoma that progressed after standard-of-care therapy, including ipilimumab and, if BRAFV600 mutant, a BRAF inhibitor, were eligible to receive pembrolizumab 2 mg/kg every 3 weeks. Response was assessed by immune-related response criteria by investigator review. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. In the United States, 979 patients enrolled between April and September 2014. Of the 947 evaluable patients, 621 (65.6%) remained on treatment and transitioned to receive commercial pembrolizumab following approval by the Food and Drug Administration, whereas 326 (34.4%) discontinued, most commonly for disease progression (39.6%) or death (26.4%). Objective response rate was 14.5% (95% confidence interval, 12.2%–16.8%) in the treated population (n=947) and 22.1% (95% confidence interval, 18.8%–25.5%) in patients who had ≥1 response assessment reported (n=619). Twelve patients achieved complete response. One hundred eighty-one (19.1%) patients experienced ≥1 treatment-related AE, most commonly general disorders (8.0%), skin/subcutaneous tissue disorders (7.3%), and gastrointestinal disorders (6.4%); 29 (3.1%) patients experienced ≥1 grade 3/4 treatment-related AE. Immune-mediated AEs were also reported. There were no treatment-related deaths. The safety and efficacy observed in this expanded access program were consistent with those previously reported for similar populations and support the use of pembrolizumab for patients with advanced melanoma.

http://ift.tt/2gDIGzR

Nivolumab-associated Nephrotic Syndrome in a Patient With Renal Cell Carcinoma: A Case Report

Introduction: Immune checkpoint inhibitors have taken an important place in the treatment of different types of malignancies. These drugs are known to have specific immune-mediated adverse events. We describe a case of severe nephrotic syndrome secondary to treatment with nivolumab in a patient with renal cell carcinoma. Case Presentation: A 62-year-old man was treated with nivolumab for papillary renal cell carcinoma type 2 for 8 weeks when he was admitted to the hospital with a severe nephrotic syndrome and acute kidney injury. Renal biopsy showed focal segmental glomerulosclerosis. Treatment with high-dose corticosteroids had insufficient effect, but the addition of mycophenolate mofetil resulted in remission of the nephrotic syndrome and recovery of renal function. Proteinuria subsequently relapsed during corticosteroid tapering. Conclusions: The time course in this patient strongly suggests that the nephrotic syndrome occurred as an adverse drug reaction to nivolumab treatment. If during nivolumab treatment renal insufficiency, hypoalbuminemia, or proteinuria develops, further analysis for a possible nephrotic syndrome is warranted for early detection and treatment of this life-threatening complication.

http://ift.tt/2gECzeG

Circulating microRNA-339-5p and -21 in plasma as an early detection predictors of lung adenocarcinoma

Publication date: Available online 13 October 2017
Source:Pathology - Research and Practice
Author(s): Yongpan Sun, Hong Mei, Chuan Xu, Hongjun Tang, Wei Wei
BackgroundMany studies have shown that differentially expressed miRs in body fluids can serve as biomarkers in non-invasive detection of the cancers. However, the clinical significance of plasma miRs in the diagnosis of lung adenocarcinoma (LA) is still not clear. Therefore, we examined the LA-specific miRs in plasma, which could be utilized to diagnosis and monitor LA in routine clinical practice.MethodsTwenty-eight LA cases and twenty-eight healthy controls were recruited to our study. MiRs differential expression in plasma was measured by miRNA Microarray assay and revalidated by using qRT-PCR based absolute quantification methods The diagnostic power of circulating miRs in LA was evaluated using the receiver operating characteristics (ROC) curves and the area under the ROC curves (AUC).ResultsTumor tissues and plasma levels of miR-339-5p were significantly down-regulated in LA patients compared with those in the control group, whereas the levels of miR-21 in LA patients were significantly higher than control group. ROC analysis showed that miR-339-5p and miR-21 could distinguish LA patients from healthy controls with high AUC (0.900 and 0.880, respectively), sensitivity (0.821 and 0.821, respectively) and specificity (0.929 and 0.964, respectively). Importantly, the combination of miR-339-5p and miR-21 markedly improved AUC (0.963), sensitivity (0.929) and specificity (0.929).ConclusionPlasma miR-339-5p or miR-21 could serve as a potential biomarker for diagnosis of LA, however, the combination of miR-339-5p and miR-21 was more efficient for LA detection.



http://ift.tt/2yK2KeT

Applicability of an innovative steroid-profiling method to determine synthetic growth promoter abuse in cattle

Publication date: Available online 13 October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): M.H. Blokland, E.F. van Tricht, L.A. van Ginkel, S.S. Sterk
A robust LC-MS/MS method was developed to quantify a large number of phase I and phase II steroids in urine. The decision limit is for most compounds lower than 1ngml⁻¹ with a measurement uncertainty smaller than 30%. The method is fully validated and was applied to assess the influence of administered synthetic steroids and beta-agonists on the steroidogenesis. From three animal experiments, clenbuterol, diethylstilbestrol and stanozolol, the steroid profiles in urine of bovine animals were compared before and after treatment. It was demonstrated that the steroid profiles were altered due to these treatments. A predictive multivariate model was built to identify deviations from normal population steroid profiles. The abuse of synthetic steroids can be detected in urine samples from bovine animals using this model. The samples from the animal experiments were randomly analysed using this method and predictive model. It was shown that these samples were predicted correctly in the exogenous steroids group.

Graphical abstract

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Sources of 137Cs to an Arctic fjord (Hornsund, Svalbard)

Publication date: December 2017
Source:Journal of Environmental Radioactivity, Volume 180
Author(s): Agata Zaborska
Although primary sources of anthropogenic ¹³⁷Cs have decreased nowadays, the Arctic is exposed to a variety of secondary sources. These include riverine run-off, oceanic currents, drifting sea ice, melting glaciers and permafrost. Recent reports underline the role of glaciers, specifically cryoconite holes, in radionuclide accumulation. Therefore, this study investigates the hypothesis that melting glaciers are an important means of delivering ¹³⁷Cs for Arctic fjord (Hornsund, Svalbard). As marine sediments are the final sink for most contaminants, seven 30–40 cm long sediment cores collected in 2016 were investigated for ¹³⁷Cs activity concentration. Five were collected in a transect from the central to the outer part of the fjord while two were collected within one km of the different melting tidewater glaciers. Sediment layers were dated using ²¹⁰Pb to reveal the history of ¹³⁷Cs accumulation. The measured ¹³⁷Cs activity concentrations ranged from <0.1 to 7.7 Bq kg⁻¹. The activity concentrations ranging from 0.3 to 3.1 Bq kg⁻¹ were measured in surface (0–2 cm) sediments. The total ¹³⁷Cs inventories were calculated for five station and ranged from 322 to 908 Bq m⁻², of which 29–34 Bq m⁻² were deposited within the last decade. At two stations characterized by largest sediment accumulation rates only the last decade inventories were calculated and they ranged from 13 to 444 Bq·m⁻². The mean of ¹³⁷Cs fluxes calculated for last decade ranged from 2.7 to 44.1 Bq m⁻²yr⁻¹. The history of ¹³⁷Cs environmental inputs was well revealed in the sediments as the ¹³⁷Cs penetration depth agreed with the time of its introduction to the Arctic and the most pronounced ¹³⁷Cs activity concentration peak was found in sediments dated for circa 1963. Although ¹³⁷Cs fluxes and inventories were largest in the glacial bay (Brepollen), the ¹³⁷Cs was diluted in a large amount of sedimenting material. Based on the results in this study, the glaciers do not appear to act as important sources of ¹³⁷Cs to the marine environment in the Hornsund fjord.



http://ift.tt/2zmng20

Radionuclides in mushrooms and soil-to-mushroom transfer factors in certain areas of China

Publication date: December 2017
Source:Journal of Environmental Radioactivity, Volume 180
Author(s): Fei Tuo, Jing Zhang, Wenhong Li, Shuaimo Yao, Qiang Zhou, Zeshu Li
Activity concentrations of ²³⁸U, ²²⁶Ra, ²²⁸Ra, ¹³⁷Cs and ⁴⁰K in 64 mushroom samples collected in China from Yunnan, Fujian and Heilongjiang Provinces, were measured. Gamma-ray emissions were determined by using high-purity germanium (HPGe) γ spectrometry. The range of concentrations (Bq kg⁻¹ dry weight) for ²³⁸U, ²²⁶Ra, ²²⁸Ra, ¹³⁷Cs and ⁴⁰K in all investigated mushroom samples were from 0.12 to 12, 0.05 to 7.5, 0.14 to 14, MDC(<0.01) to 339, and 396 to 1880, respectively. Activity concentrations of ¹³⁷Cs in mushrooms showed some variation between species sampled at the same site. To calculate soil to mushroom transfer factors, levels of radionuclide in 15 paired soil samples and mushrooms were also investigated. The median transfer factors for ²³⁸U, ²²⁶Ra, ²²⁸Ra, ¹³⁷Cs and ⁴⁰K were 8.32 × 10⁻², 3.03 × 10⁻², 6.69 × 10⁻², 0.40 and 1.19, respectively. The results were compared with values of other areas.



http://ift.tt/2z8rNnT

Marine ecological risk assessment methods for radiation accidents

Publication date: December 2017
Source:Journal of Environmental Radioactivity, Volume 180
Author(s): Sufen Ye, Luoping Zhang, Huan Feng
Ecological risk assessment (ERA) is a powerful technical tool that can be used to analyze potential and extreme adverse environmental impacts. With the rapid development of nuclear power plants in coastal areas around the world, the establishment of approaches and methodologies for marine ERA with a focus on radiation accidents is an urgent requirement for marine environmental management. In this study, the approaches and methodologies for ERA pertaining to marine radiation accidents (MRA) are discussed and summarized with applications in case studies, such as the nuclear accident in Fukushima, Japan, and a hypothetical accident in Daya Bay, China. The concepts of ERA and Risk Degree of ERA on MRA are defined for the first time to optimize the ERA system. The results of case studies show that the ERA approach and methodology for MRA are scientifically sound and effective in both the early and late stage of MRAs along with classic ERA Approach and the ERICA Integrated Approach. The results can be useful in the decision-making processes and the risk management at the beginning of accident as well as the ecological restoration after the accident.



http://ift.tt/2zmyMKQ

The Effect of a Pediatric Intensive Care Severity-Tiered Pathway for Status Asthmaticus on Quality Measures and Outcomes

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


http://ift.tt/2xFvUM7

Corrigendum to “The influence of different abutment materials on tissue regeneration after surgical treatment of peri-implantitis – A randomized controlled preclinical study” [J Cranio-Maxillo-Facial Surg 45 (2017) 1190–1196]

The authors regret an incorrect approval number of "54-2532.1-45/12" by the Pest county government Department for Food Safety and Animal Health, Hungary. The correct number is "PEI/001/961-2/2013".

http://ift.tt/2gihKcf

Effects of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibition with Bococizumab on Lipoprotein Particles in Hypercholesterolemic Subjects

Publication date: Available online 14 October 2017
Source:Clinical Therapeutics
Author(s): Hong Wan, Barry Gumbiner, Tenshang Joh, Tom Riel, Chandrasekhar Udata, Philippe Forgues, Pamela D. Garzone
PurposeMonoclonal antibody inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) elicit significant reductions in serum LDL-C levels. However, little is known about their effects on lipoprotein particles. The purpose of this analysis was to evaluate the effect of PCSK9 inhibition with bococizumab (RN316/PF-04950615), a humanized monoclonal antibody to PCSK9, on LDL, VLDL, and HDL particle concentration and size in hypercholesterolemic subjects.MethodsData from 3 double-blind, placebo-controlled, randomized studies were analyzed. In study 1, a total of 67 hypercholesterolemic subjects received IV placebo or bococizumab 0.25, 0.5, 1, or 1.5 mg/kg weekly for 4 weeks. In studies 2 and 3, a total of 135 hypercholesterolemic subjects taking statins received IV placebo or bococizumab 0.25, 1, 3, or 6 mg/kg monthly for 12 weeks. Lipoprotein particle concentration and size were measured by using nuclear magnetic resonance spectroscopy.FindingsOverall, the majority of subjects were men (51.9%) aged >50 years of age and of white ethnic origin. In total, 189 subjects with both baseline and 2-week posttreatment data were included in the analysis. After PCSK9 inhibition with bococizumab 0.5, 1, 1.5, 3, and 6 mg/kg, concentrations of total LDL, total small LDL, and small VLDL particles decreased significantly versus baseline and placebo (P < 0.05), whereas concentrations of HDL particles increased (P < 0.05). The size of the LDL, VLDL, and HDL particles increased after PCSK9 inhibition. Reductions in LDL-C and total LDL particle concentrations were highly correlated.ImplicationsThe effect of inhibiting PCSK9 with bococizumab on lipoprotein particle concentration and size are consistent with the general mechanism of PCSK9 inhibitors in blocking PCSK9-mediated downregulation of LDL receptors. PCSK9 inhibition has the potential to provide a clinical benefit through the modulation of atherogenic lipoprotein particles in addition to LDL-C lowering, and this effect will likely be assessed in future analyses of data from cardiovascular outcomes trials of PCSK9 monoclonal antibodies that are currently being conducted. ClinicalTrials.gov identifiers: NCT01243151, NCT01342211, and NCT01350141.



http://ift.tt/2xFCJNG

The Effect of a Pediatric Intensive Care Severity-Tiered Pathway for Status Asthmaticus on Quality Measures and Outcomes

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


http://ift.tt/2xFvUM7

Implant-oriented navigation in orbital reconstruction. Part 1: technique and accuracy study

Intraoperative navigation is frequently used to assess the position of the implant in orbital reconstruction. Interpretation of the feedback from the navigation system to a three-dimensional position of the implant needs to be done by the surgeon, and feedback is only gathered after the implant has been positioned. An implant-oriented navigation approach is proposed, with real-time intuitive feedback during insertion. A technical framework was set up for implant-oriented navigation, with requirements for planning, implant tracking, and feedback.

http://ift.tt/2kOrSuL

Longitudinal melanonychia due to voriconazole therapy during treatment of chromoblastomycosis

http://ift.tt/2giIlpy

A feasibility study for a triple-blind randomized controlled trial investigating the effects of oral isotretinoin on mood and quality of life in patients with acne vulgaris

Summary

Isotretinoin is used in the treatment of severe acne vulgaris (AV), but has controversially been associated with depression and suicide. Large prospective studies have failed to translate this clinically. We undertook a feasibility study to investigate the parameters of a triple-blind, randomized controlled trial (RCT) assessing the effect of oral isotretinoin on quality of life (QoL) and mood in patients with AV. Patients meeting the inclusion criteria were randomized for 2 weeks to isotretinoin or doxycycline. Participants completed verified depression and QoL screening questionnaires at baseline and week 2. In total, 194 patients with AV were screened, with 48 meeting the inclusion criteria and 13 of these being willing to participate. The follow-up rate was 92% and questionnaire response rate was 96%. To our knowledge, this is the first study to demonstrate a successful design for a triple-blind RCT investigating the effects of isotretinoin on mood in patients with AV.

http://ift.tt/2ynKRkQ

Longitudinal melanonychia due to voriconazole therapy during treatment of chromoblastomycosis

http://ift.tt/2giIlpy

A feasibility study for a triple-blind randomized controlled trial investigating the effects of oral isotretinoin on mood and quality of life in patients with acne vulgaris

Summary

Isotretinoin is used in the treatment of severe acne vulgaris (AV), but has controversially been associated with depression and suicide. Large prospective studies have failed to translate this clinically. We undertook a feasibility study to investigate the parameters of a triple-blind, randomized controlled trial (RCT) assessing the effect of oral isotretinoin on quality of life (QoL) and mood in patients with AV. Patients meeting the inclusion criteria were randomized for 2 weeks to isotretinoin or doxycycline. Participants completed verified depression and QoL screening questionnaires at baseline and week 2. In total, 194 patients with AV were screened, with 48 meeting the inclusion criteria and 13 of these being willing to participate. The follow-up rate was 92% and questionnaire response rate was 96%. To our knowledge, this is the first study to demonstrate a successful design for a triple-blind RCT investigating the effects of isotretinoin on mood in patients with AV.

http://ift.tt/2ynKRkQ

Peri-operative blood transfusion for resected colon cancer: Practice patterns and outcomes in a population-based study

Publication date: December 2017
Source:Cancer Epidemiology, Volume 51
Author(s): Sunil V. Patel, Kelly E. Brennan, Sulaiman Nanji, Safiya Karim, Shaila Merchant, Christopher M. Booth
Background & objectivesLiterature suggests that peri-operative blood transfusion among patients with resected colon cancer may be associated with inferior long-term survival. The study objective was to characterize this association in our population.MethodsThis is a retrospective cohort study using the population-based Ontario Cancer Registry (2002–2008). Pathology reports were obtained for a 25% random sample of all cases and constituted the study population. Log binomial regression was used to identify factors associated with transfusion. Cox proportional hazards model explored the association between transfusion and cancer specific survival (CSS) and overall survival (OS).ResultsThe study population included 7198 patients: 18% stage I, 36% stage II, 40% stage III, and 6% stage IV. Twenty-eight percent of patients were transfused. Factors independently associated with transfusion included advanced age (p<0.001), female sex (p<0.001), greater comorbidity (p<0.001), more advanced disease (p<0.001) and open surgical resection (p<0.001). Transfusion was associated with inferior CSS (HR 1.51, 95% CI 1.38–1.65) and OS (HR 1.52, 95% CI 1.41–1.63), after adjusting for important confounders.ConclusionsPeri-operative transfusion rates among patients with colon cancer have decreased over time. Transfusion is associated with inferior long-term CSS and OS.



http://ift.tt/2ibOF2N

Acne in late adolescence is not associated with a raised risk of subsequent malignant melanoma among men

Publication date: December 2017
Source:Cancer Epidemiology, Volume 51
Author(s): Teresa Mota Garcia, Ayako Hiyoshi, Ruzan Udumyan, Hugo Sjöqvist, Katja Fall, Scott Montgomery
BackgroundTo evaluate the association of acne in late adolescence with the risk for subsequent malignant melanoma (MM) in men.MethodsSwedish register-based cohort study of 242,096 males born between 1952 and 1956, who took part in compulsory assessments for Swedish military conscription in late adolescence between 1969 and 1975, with subsequent diagnoses of MM (n=1,058) up to December 31, 2009. Covariates included measures of childhood circumstances and information from adolescence on presence of acne, physical fitness, cognitive function, body mass index (BMI), and a summary of diagnoses. Cox regression was used for the analysis.ResultsIn total 1,058 men were diagnosed with MM. Acne was not associated with subsequent MM, with an adjusted hazard ratio (and 95% confidence interval) of 0.95 (0.61 to 1.49). Men with parents who were agricultural workers, and men who lived in northern Sweden, had lower physical fitness, or lower cognitive function had a lower risk of MM. Overweight and obesity was associated with a raised risk, with an adjusted hazard ratio of 1.39 (1.14, 1.71).ConclusionsAcne in late adolescence is unlikely to represent a raised risk for subsequent MM in men. Overweight or obesity was identified as a raised risk for MM, possibly due to the associated increased skin surface area.



http://ift.tt/2gDGOXQ

Methodological issues of assessing the risk of a second cancer occurring in the same site as a first cancer using registry data

Publication date: December 2017
Source:Cancer Epidemiology, Volume 51
Author(s): Jérémie Jégu, Marie Moitry, Simona Bara, Brigitte Trétarre, Anne-Valérie Guizard, Anne-Sophie Woronoff, Laetitia Daubisse-Marliac, Véronique Bouvier, Xavier Troussard, Marc Colonna, Delphine Klein, Bénédicte Lapôtre-Ledoux, Michel Velten
ObjectiveTo present methodological issues that can arise with the assessment of the risk of a second primary cancer (SPC) occurring in the same site as a first cancer using registry data.Material and methodsData from ten French cancer registries were used, including data for patients with a first prostate cancer (in males), breast cancer (in females), and colon, lung and kidney cancer (in both sexes) diagnosed between 1989 and 2004. Standardized incidence ratios (SIRs) of SPC were computed by excluding, or not, the risk of an SPC at the same site.ResultsFor prostate cancer, the SIR dropped from 1.11 to 0.72 when the risk of SPC of the prostate was included. SIRs increased from 1.36 to 1.45, from 1.14 to 1.21, from 1.57 to 2.01, and from 1.37 to 1.51 for breast, colon, lung, and kidney respectively.ConclusionThe inclusion, or not, of an SPC at the same site can impact on SPC risk estimates.



http://ift.tt/2iaFwaz

A systematic review of instrumental variable analyses using geographic region as an instrument

Publication date: December 2017
Source:Cancer Epidemiology, Volume 51
Author(s): Emily A. Vertosick, Melissa Assel, Andrew J. Vickers
BackgroundInstrumental variables analysis is a methodology to mitigate the effects of measured and unmeasured confounding in observational studies of treatment effects. Geographic area is increasingly used as an instrument.MethodsWe conducted a literature review to determine the properties of geographic area in studies of cancer treatments. We identified cancer studies performed in the United States which incorporated instrumental variable analysis with area-wide treatment rate within a geographic region as the instrument. We assessed the degree of treatment variability between geographic regions, assessed balance of measured confounders afforded by geographic area and compared the results of instrumental variable analysis to those of multivariable methods.ResultsGeographic region as an instrument was relatively common, with 22 eligible studies identified, many of which were published in high-impact journals. Treatment rates did not vary greatly by geographic region. Covariates were not balanced by the instrument in the majority of studies. Eight out of eleven studies found statistically significant effects of treatment on multivariable analysis but not for instrumental variables, with the central estimates of the instrumental variables analysis generally being closer to the null.ConclusionsWe recommend caution and an investigation of IV assumptions when considering the use of geographic region as an instrument in observational studies of cancer treatments. The value of geographic region as an instrument should be critically evaluated in other areas of medicine.



http://ift.tt/2gDwnns

Colchicine is an active treatment for everolimus-induced oral ulcers

Publication date: Available online 13 October 2017
Source:European Journal of Cancer
Author(s): Stanislas Ropert, Romain Coriat, Benjamin Verret, Audrey Perret, Francesca Lucibello, Ali N. Chamseddine, Jean-Pierre Armand, Angelo Paci, Olivier Mir




http://ift.tt/2xFzCFu

Effectiveness of photodynamic therapy associated with irrigants over two biofilm models

Publication date: Available online 13 October 2017
Source:Photodiagnosis and Photodynamic Therapy
Author(s): Ricardo Abreu da Rosa, Manuela Favarin Santini, José Antônio Poli de Figueiredo, Fernanda Visioli, Jefferson Ricardo Pereira, Rodrigo Ricci Vivan, Francisco Montagner, Marcus Vinícius Reis Só
BackgroundThis study aimed to evaluate the antibacterial effect and the biofilm disruption promoted by antimicrobial photodynamic therapy (aPDT) associated with sodium hypochlorite (NaOCl) and chlorexidine (CHX) over monospecies and multispecies biofilms.MethodsIn monospecies model, forty-six premolars were inoculated with Enterococcus faecalis for 21days and divided into three groups: saline, CHX and NaOCl. After irrigation, aPDT was performed. Samples were collected at baseline (S1) and after irrigation (S2) and aPDT (S3). Colony-forming unit (CFU) counts were performed. In multispecies model, sixty bovine dentin blocks were infected intraorally for 72 hous and divided into six groups: saline, saline/aPDT, CHX, CHX/aPDT, NaOCl and NaOCl/aPDT. The percentage and the biovolume of live cells and the total biovolume were assessed using confocal laser scanning microscopy.ResultsCHX and NaOCl showed the lowest CFU counts (P<0.05). aPDT reduced the bacterial counts in saline (S2-S3; P<0.05). The lowest amount of live cells was observed in CHX, CHX/aPDT, NaOCl and NaOCl/aPDT. aPDT did not reduce the total biovolume (P>0.05).ConclusionaPDT associated with saline reduced the bacterial load in root canals infected with E. faecalis. aPDT did not reduce the total biovolume in situ; however, the irrigant was decisive to disrupt multispecies biofilms.



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Iatrogenic mandibular fracture after open reduction and internal fixation in a patient with osteogenesis imperfecta

To the best of our knowledge, this is the first report to discuss the possible mechanisms of an iatrogenic fracture during operation on an original mandibular fracture in a patient with osteogenesis imperfecta.

http://ift.tt/2kNzXzX

Unraveling the mechanistic effects of electric field stimulation towards directing stem cell fate and function: A tissue engineering perspective

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): Greeshma Thrivikraman, Sunil Kumar Boda, Bikramjit Basu
Electric field (EF) stimulation can play a vital role in eliciting appropriate stem cell response. Such an approach is recently being established to guide stem cell differentiation through osteogenesis/neurogenesis/cardiomyogenesis. Despite significant recent efforts, the biophysical mechanisms by which stem cells sense, interpret and transform electrical cues into biochemical and biological signals still remain unclear. The present review critically analyses the variety of EF stimulation approaches that can be employed to evoke appropriate stem cell response and also makes an attempt to summarize the underlying concepts of this notion, placing special emphasis on stem cell based tissue engineering and regenerative medicine. This review also discusses the major signaling pathways and cellular responses that are elicited by electric stimulation, including the participation of reactive oxygen species and heat shock proteins, modulation of intracellular calcium ion concentration, ATP production and numerous other events involving the clustering or reassembling of cell surface receptors, cytoskeletal remodeling and so on. The specific advantages of using external electric stimulation in different modalities to regulate stem cell fate processes are highlighted with explicit examples, in vitro and in vivo.

Graphical abstract

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Mechanotransduction of human pluripotent stem cells cultivated on tunable cell-derived extracellular matrix

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): In Gul Kim, Chang-Hyun Gil, Joseph Seo, Soon-Jung Park, Ramesh Subbiah, Taek-Hee Jung, Jong Soo Kim, Young-Hoon Jeong, Hyung-Min Chung, Jong Ho Lee, Man Ryul Lee, Sung-Hwan Moon, Kwideok Park
Cell-derived matrices (CDM) are becoming an attractive alternative to conventional biological scaffolding platforms due to its unique ability to closely recapitulate a native extracellular matrix (ECM) de novo. Although cell-substrate interactions are recognized to be principal in regulating stem cell behavior, very few studies have documented the acclimation of human pluripotent stem cells (hPSCs) on pristine and altered cell-derived matrices. Here, we investigate crosslink-induced mechanotransduction of hPSCs cultivated on decellularized fibroblast-derived matrices (FDM) to explore cell adhesion, growth, migration, and pluripotency in various biological landscapes. The results showed either substrate-mediated induction or inhibition of the Epithelial-Mesenchymal-Transition (EMT) program, strongly suggesting that FDM stiffness can be a dominant factor in mediating hPSC plasticity. We further propose an optimal FDM substratum intended for long-term hPSC cultivation in a feeder-free niche-like microenvironment. This study carries significant implications for hPSC cultivation and encourages more in-depth studies towards the fundamentals of hPSC-CDM interactions.



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Biofabricating atherosclerotic plaques: In vitro engineering of a three-dimensional human fibroatheroma model

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): Anna Mallone, Chantal Stenger, Arnold Von Eckardstein, Simon P. Hoerstrup, Benedikt Weber
Atherosclerotic plaques are cholesterol-induced inflammatory niches accumulating in the vascular sub-endothelial space. Cellular and extracellular composition of human plaques is maneuvered by local inflammation that leads to alterations in the original vascular microenvironment and to the recruitment of an invading fibrous layer (fibroatharoma). In the present study we introduce a bioengineered three-dimensional model of human fibroatheroma (ps-plaque) assembled with a tailored hanging-drop protocol. Using vi-SNE based multidimensional flow cytometry data analysis we compared the myeloid cell-populations in ps-plaques to those in plaques isolated from human carotid arteries. We observed that plasmacytoid and activated dendritic cells are the main myeloid components of human carotid plaques and that both cell types are present in the biofabricated model. We found that low-density lipoproteins affect cell viability and contribute to population polarization in ps-plaques. The current work describes the first human bioengineered in vitro model of late atherosclerotic lesion for the investigation of atherosclerosis aetiopathogenesis.

Graphical abstract

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Rethinking liquid biopsy: Microfluidic assays for mobile tumor cells in human body fluids

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): Kuang Hong Neoh, Ayon Ahmed Hassan, Anqi Chen, Yukun Sun, Peng Liu, Kai-Feng Xu, Alice S.T. Wong, Ray P.S. Han
Traditionally, liquid biopsy is a blood test involving the harvesting of tumor materials from peripheral blood. Tumor cells from non-blood body fluids have always been clinically available in cytological examinations but limited for use in differential diagnosis due to the low sensitivity of conventional cytopathology. With the recent significant progress in microfluidic and downstream molecular technologies, liquid biopsies have now evolved to include harvesting tumor cells and DNA fragments in all kinds of non-blood body fluids. This expansion into general body fluids presages the notion that liquid biopsy could soon be used in competition, as well as, in complementarity with tissue biopsy. Preliminary research of fluid-harvested tumor materials to spot early-stage tumors, monitor disease progression for metastasis and recurrence, and detect chemoresistance have been reported. To reflect the propagation of tumor cells in non-blood body fluids, we introduced the term Mobile Tumor Cells (MTCs), in lieu of the widely accepted term of circulating tumor cells (CTCs) resident in the bloodstream. Our review starts with a discussion on the clinical significance of MTCs, followed by a presentation of microfluidic techniques for MTC capture and various strategies for their identification. Hopefully, the phenotypic and genomic data acquired from harvested MTCs can be used to guide and improve cancer treatment decisions.



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ZIF-67 derived porous Co3O4 hollow nanopolyhedron functionalized solution-gated graphene transistors for simultaneous detection of glucose and uric acid in tears

Publication date: 15 March 2018
Source:Biosensors and Bioelectronics, Volume 101
Author(s): Can Xiong, Tengfei Zhang, Weiyu Kong, Zhixiang Zhang, Hao Qu, Wei Chen, Yanbo Wang, Linbao Luo, Lei Zheng
Biomarkers in tears have attracted much attention in daily healthcare sensing and monitoring. Here, highly sensitive sensors for simultaneous detection of glucose and uric acid are successfully constructed based on solution-gated graphene transistors (SGGTs) with two separate Au gate electrodes, modified with GOx-CHIT and BSA-CHIT respectively. The sensitivity of the SGGT is dramatically improved by co-modifying the Au gate with ZIF-67 derived porous Co3O4 hollow nanopolyhedrons. The sensing mechanism for glucose sensor is attributed to the reaction of H2O2 generated by the oxidation of glucose near the gate, while the sensing mechanism for uric acid is due to the direct electro-oxidation of uric acid molecules on the gate. The optimized glucose and uric acid sensors show the detection limits both down to 100nM, far beyond the sensitivity required for non-invasive detection of glucose and uric acid in tears. The glucose and uric acid in real tear samples was quantitatively detected at 323.2 ± 16.1μM and 98.5 ± 16.3μM by using the functionalized SGGT device. Due to the low-cost, high-biocompatibility and easy-fabrication features of the ZIF-67 derived porous Co3O4 hollow nanopolyhedron, they provide excellent electrocatalytic nanomaterials for enhancing sensitivity of SGGTs for a broad range of disease-related biomarkers.



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Direct colorimetric detection of unamplified pathogen DNA by dextrin-capped gold nanoparticles

Publication date: 15 March 2018
Source:Biosensors and Bioelectronics, Volume 101
Author(s): Amy M. Baetsen-Young, Matthew Vasher, Leann L. Matta, Phil Colgan, Evangelyn C. Alocilja, Brad Day
The interaction between gold nanoparticles (AuNPs) and nucleic acids has facilitated a variety of diagnostic applications, with further diversification of synthesis match bio-applications while reducing biotoxicity. However, DNA interactions with unique surface capping agents have not been fully defined. Using dextrin-capped AuNPs (d-AuNPs), we have developed a novel unamplified genomic DNA (gDNA) nanosensor, exploiting dispersion and aggregation characteristics of d-AuNPs, in the presence of gDNA, for sequence-specific detection. We demonstrate that d-AuNPs are stable in a five-fold greater salt concentration than citrate-capped AuNPs and the d-AuNPs were stabilized by single stranded DNA probe (ssDNAp). However, in the elevated salt concentrations of the DNA detection assay, the target reactions were surprisingly further stabilized by the formation of a ssDNAp-target gDNA complex. The results presented herein lead us to propose a mechanism whereby genomic ssDNA secondary structure formation during ssDNAp-to-target gDNA binding enables d-AuNP stabilization in elevated ionic environments. Using the assay described herein, we were successful in detecting as little as 2.94 fM of pathogen DNA, and using crude extractions of a pathogen matrix, as few as 18 spores/µL.



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Unstable Thyroid Function in Older Adults Is Caused by Alterations in Both Thyroid and Pituitary Physiology and Is Associated with Increased Mortality

Thyroid , Vol. 0, No. 0.


http://ift.tt/2ylui7i

87th Annual Meeting of the American Thyroid Association

Thyroid Oct 2017, Vol. 27, No. S1: P-1-A-156.


http://ift.tt/2z6tB0B

Short Call Abstracts

Thyroid Oct 2017, Vol. 27, No. S1: A-166-A-188.


http://ift.tt/2yjUXRP

Short Call Author Abstract Index

Thyroid Oct 2017, Vol. 27, No. S1: A-189-A-191.


http://ift.tt/2z6tzWx

Abstract Author Index

Thyroid Oct 2017, Vol. 27, No. S1: A-157-A-165.


http://ift.tt/2yn38P1

Unstable Thyroid Function in Older Adults Is Caused by Alterations in Both Thyroid and Pituitary Physiology and Is Associated with Increased Mortality

Thyroid , Vol. 0, No. 0.


http://ift.tt/2ylui7i

87th Annual Meeting of the American Thyroid Association

Thyroid Oct 2017, Vol. 27, No. S1: P-1-A-156.


http://ift.tt/2z6tB0B

Short Call Abstracts

Thyroid Oct 2017, Vol. 27, No. S1: A-166-A-188.


http://ift.tt/2yjUXRP

Short Call Author Abstract Index

Thyroid Oct 2017, Vol. 27, No. S1: A-189-A-191.


http://ift.tt/2z6tzWx

Abstract Author Index

Thyroid Oct 2017, Vol. 27, No. S1: A-157-A-165.


http://ift.tt/2yn38P1

Laser Sintering Technology and Balling Phenomenon

Photomedicine and Laser Surgery , Vol. 0, No. 0.


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Análisis de supervivencia libre de recaída audiométrica en pacientes con hipoacusia inmunomediada tratados exclusivamente con corticoides

Publication date: Available online 13 October 2017
Source:Acta Otorrinolaringológica Española
Author(s): Nieves Mata-Castro, Raimon García-Chilleron, Javier Gavilanes-Plasencia, Rafael Ramírez-Camacho, Alfredo García-Fernández, José Ramón García-Berrocal
ObjetivoDescribir los resultados en términos de supervivencia libre de recaída audiométrica y el ritmo de recaída en pacientes con hipoacusia inmunomediada tratados exclusivamente con corticoides.MétodoEstudio retrospectivo de pacientes, con recaídas audiométricas, en seguimiento desde 1995 hasta 2014, en 2 centros de la Comunidad de Madrid.ResultadosSe evaluaron 31 pacientes con una media de edad de 48,52 años (14,67 DE) de los cuales el 61,3% fueron mujeres. La mayoría de las hipoacusias fueron fluctuantes (48,4%). Solo el 16,1% de los pacientes presentaban enfermedad autoinmune sistémica. Existe una correlación positiva moderada entre ser mujer y presentar afectación sistémica (coeficiente de correlación de Spearman=0,356). La tasa relativa de incidencia de recaída en el primer año en nuestra serie fue de 2,01 recaídas/año con un IC95% (1,32-2,92). El tiempo de supervivencia medio del evento (recaída audiométrica) fue de 5,25 meses (DE 0,756). Con el análisis multivariante, la única variable que consiguió significación estadística fue la edad, con una hazard ratio de 1,032 (IC95%; 1,001-1,063, p=0,043)ConclusionesLa enfermedad inmunomediada del oído interno es una enfermedad crónica con recaídas. La mitad de los pacientes tratados exclusivamente con corticoides recaen antes de los 6 meses de seguimiento. Además, si un paciente no ha presentado recaída, tiene más riesgo de recaer cada año que pasa. El análisis de la supervivencia libre de recaída audiométrica permitirá comparar el efecto de tratamientos futuros y su capacidad para reducir el ritmo de recaídas.ObjectiveTo describe the results in terms of audiometric relapse-free survival and relapse rate in immunomediated hearing loss patients treated exclusively with corticosteroids.MethodRetrospective study of patients with audiometric relapses, monitored from 1995 to 2014, in two centres of the Community of Madrid.ResultsWe evaluated 31 patients with a mean age of 48.52 years (14.67 SD), of which 61.3% were women. Most hearing loss was fluctuating (48.4%). Only 16.1% of patients had systemic autoimmune disease. There is a moderate positive correlation between the sex variable and the systemic involvement variable (Spearman's correlation coefficient=0.356): specifically, between being female and systemic disease. The relative incidence rate of relapse in the first year was 2.01 relapses/year with a 95% CI (1.32 to 2.92). The mean survival time of the event (audiometric relapse) was 5.25 months (SD 0.756). With multivariate analysis, the only variable that achieved statistical significance was age, with a hazard ratio of 1.032 (95% CI; 1.001-1.063, P=.043).ConclusionsImmune-mediated disease of the inner ear is a chronic disease with relapses. Half of the patients with immunomediated hearing loss treated exclusively with corticosteroids relapse before 6 months of follow-up. In addition, if a patient has not relapsed, they are more likely to relapse as each year passes. Analysis of the of audiometric relapse- free survival will enable the effect of future treatments to be compared and their capacity to reduce the rhythm of relapses.



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Carcinoma análogo del secretor mamario de glándulas salivales: a propósito de un caso clínico

Publication date: Available online 13 October 2017
Source:Acta Otorrinolaringológica Española
Author(s): Carlota Rovira, Xavier León, Celina P. Vásquez, Montserrat López




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Vértigo y mareo en el hospital: frecuentación, flujo y características de los pacientes

Publication date: Available online 13 October 2017
Source:Acta Otorrinolaringológica Española
Author(s): Carmen Bécares Martínez, Marta M. Arroyo Domingo, Aurora López Llames, Jaime Marco Algarra, María M. Morales Suárez-Varela
Introducción y objetivosLos síntomas de vértigo y mareo son frecuentes en la población, se presentan como manifestación de un amplio abanico de enfermedades y habitualmente es difícil realizar un diagnóstico de certeza. El objetivo general de este estudio es obtener la información para evaluar estos síntomas en el entorno hospitalario. Los objetivos específicos son: estimar el peso global que representan estos síntomas en las derivaciones al hospital; conocer las características de los pacientes derivados y detallar el flujo de las consultas.MétodosEstudio descriptivo observacional. Se buscaron las propuestas de consulta realizadas en 2011 y 2012 al hospital por el síntoma de vértigo. Se analizaron características demográficas y clínicas de los pacientes, y administrativas de las derivaciones.ResultadosSe analizaron un total de 558 propuestas correspondientes a 494 pacientes. El vértigo supuso el 0,5% del total de las derivaciones realizadas desde Atención Primaria al hospital. El 63% de la muestra han sido mujeres, con una edad media de 58 años. El 88% de los pacientes fue valorado por Otorrinolaringología y el 24% por Neurología. Un 30,8% consultó en 3 o más ocasiones por el síntoma. El 16% fue valorado por enfermedad psiquiátrica en el hospital.ConclusionesEl vértigo como síntoma supone una carga significativa en el ámbito hospitalario. Los pacientes que lo presentan consultan en múltiples ocasiones y son valorados en distintas especialidades. En ciertos casos, el flujo de pacientes puede resultar excesivamente dinámico e ineficaz. En nuestro entorno, Otorrinolaringología es el principal receptor de pacientes con síntomas de vértigo y mareo.Introduction and objectivesVertigo and dizziness as symptoms are frequent in the population. They are present in a wide range of pathologies and it is usually difficult to make an accurate diagnosis. The general objective of this study is to obtain the information to evaluate vertigo and dizziness in the hospital setting. The specific objectives are: to estimate the burden of these symptoms at the hospital; to study patients' conditions and to detail the flow of these patients inside the hospital.MethodsObservational descriptive study. We made a search of the referral proposals made in 2011 and 2012 to the hospital because of vertigo symptoms. The patients' demographic and clinical characteristics, and the administrative details of the referrals were analysed.ResultsA total of 558 proposals were analysed corresponding to 494 patients. Vertigo accounted for 0.5% of all referrals made from Primary Care to the hospital. Sixty-three percent of the sample were women; the average age was 58 years. Eighty-eight percent of the patients were evaluated by Otorhinolaryngology, 24% by Neurology. Thirty point eight percent consulted on 3 or more occasions for the symptom. Sixteen percent were assessed for psychiatric conditions in the hospital.ConclusionsVertigo as a symptom is a significant burden in the hospital setting. The patients who suffer it consult on several occasions and are assessed by different specialties. This implies in some cases an excessive and ineffective flow of patients. In our setting, otorhinolaryngology is the main department to treat vertigo and dizziness patients.



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Significado pronóstico de la extensión extranodal en pacientes con carcinomas escamosos de cabeza y cuello cN0 con metástasis ganglionares ocultas

Publication date: Available online 13 October 2017
Source:Acta Otorrinolaringológica Española
Author(s): Joan Lop, Antoni Rigó, Alberto Codina, Julia de Juan, Miquel Quer, Xavier León
Introducción y objetivosLa presencia de extensión extranodal en adenopatías metastásicas de pacientes con carcinoma escamoso de cabeza y cuello es un reconocido factor de mal pronóstico. Sin embargo, pocos estudios analizan específicamente su significado en pacientes sin evidencia clínica de extensión ganglionar en el momento del diagnóstico inicial.Material y métodosEstudio retrospectivo de 348 pacientes con carcinoma escamoso de cabeza y cuello cN0 tratados con un vaciamiento cervical electivo. Se evaluó la presencia de metástasis ganglionares ocultas con extensión extranodal y se analizó su impacto sobre la supervivencia.ResultadosEl porcentaje de pacientes con metástasis ganglionares ocultas fue del 33%. De estos, un 23,5% presentaron al menos una adenopatía metastásica con extensión extranodal. Existieron diferencias significativas en la supervivencia específica en función del estatus ganglionar. La supervivencia a los 5 años para los pacientes sin afectación ganglionar patológica fue del 90%, para aquellos con metástasis ganglionares ocultas sin extensión extranodal, del 71,2%, y para los pacientes con metástasis ganglionares ocultas con extensión extranodal, del 25,9% (p=0,0001). En un estudio multivariante la presencia de metástasis ganglionares ocultas con extensión extranodal fue el factor relacionado de forma más importante con la supervivencia. La incorporación de la extensión extranodal como criterio de clasificación histopatológico en la octava edición del TNM mejoró la capacidad pronóstica en relación con las ediciones anteriores.ConclusionesLa presencia de adenopatías metastásicas con extensión extranodal es un factor de mal pronóstico en pacientes con carcinoma escamoso de cabeza y cuello sin evidencia clínica de afectación regional en el momento del diagnóstico de la enfermedad.Introduction and objectivesExtranodal extension in nodal metastases is an independent adverse prognostic factor in head and neck squamous cell carcinoma patients. However, few studies specifically address the subgroup of patients with no clinical evidence of nodal disease.Material and methodsWe retrospectively analysed data from 348 head and neck squamous cell carcinoma patients without any previous treatment and lacking clinical or radiological evidence of neck node metastases during the initial workup, treated with an elective neck dissection between 1992-2014. The incidence of occult metastatic neck nodes with extranodal extension and the impact of extranodal extension in survival were evaluated.ResultsThe proportion of patients with occult neck node metastases was 33%. Of these, 23.5% had at least one metastatic neck node with extranodal extension. There were significant differences in the disease-specific survival rate according to neck node status. Five-year disease-specific survival for patients without histopathological metastases was 90%, for patients with occult neck node metastases without extranodal extension it was 71.2%, and for patients with occult neck node metastases with extranodal extension it was 25.9% (P=.0001). The multivariate analysis revealed that the presence of occult node metastases with extranodal extension was the factor with strongest impact on survival. The inclusion of the extranodal extension as a criterion of histopathological evaluation in the 8th TNM classification edition improves the prognostic capacity compared to previous TNM editions.ConclusionsAppearance of metastatic neck nodes with extranodal extension is an adverse prognostic factor in head and neck squamous cell carcinoma patients without clinical evidence of regional disease during the initial workup of the tumour.



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Prone sleeping position in infancy: implications for cardiovascular and cerebrovascular function

Advances in neonatal care have improved the survival rates of preterm infants, however, the likelihood of brain injury and neurodevelopmental disability remains a significant problem. Whilst the etiology of preterm brain injury is complex, impairments in the cardio- and cerebro-vascular function have been implicated. During infancy, sleep is vital for brain development. However, instabilities in cardio- and cerebro-vascular function are most marked during sleep. Sleeping position is an important part of a safe sleeping environment.

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Postoperative care after tonsillectomy: what's the evidence?.

Purpose of review: The purpose of this review is to evaluate the current literature regarding postoperative management after tonsillectomy in children. Recent findings: Controversy remains regarding the ideal medication regimen to manage pain after tonsillectomy. Acetaminophen and ibuprofen are routinely used, although concerns of more severe postoperative hemorrhage with ibuprofen remain. Narcotics are prescribed commonly, but with extreme caution in children with severe obstructive sleep apnea. Although not always utilized by the authors, additional adjunctive medications such as perioperative dexamethasone, ketamine, and local infiltration of lidocaine into tonsillar pillars may decrease postoperative pain. Systematic reviews have shown that dexamethasone does not increase risk of posttonsillectomy bleeding. Summary: Adenotonsillectomy is one of the most common procedures performed on children and may have significant morbidity from postoperative pain and bleeding. Managing pain remains challenging and the optimal treatment regimen has not been definitively identified. Many medications and alternative therapies have been studied and suggest possible benefit. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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A hydrogel matrix prolongs persistence and promotes specific localization of an oncolytic adenovirus in a tumor by restricting nonspecific shedding and an antiviral immune response

Publication date: December 2017
Source:Biomaterials, Volume 147
Author(s): Bo-Kyeong Jung, Eonju Oh, JinWoo Hong, Yunki Lee, Ki Dong Park, Chae-Ok Yun
Currently, intratumoral injection of an oncolytic adenovirus (Ad) is the conventional administration route in clinical trials. Nonetheless, the locally administered Ad disseminates to the surrounding nontarget tissues and has short biological activity due to immunogenicity of Ad, thus necessitating multiple injections to achieve a sufficient therapeutic index. In the present study, a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-expressing oncolytic Ad (oAd-TRAIL) was encapsulated in a gelatin hydrogel (oAd-TRAIL/gel) to enhance and prolong antitumor efficacy of the virus after a single intratumoral injection. oAd-TRAIL/gel showed greater antitumor efficacy than naked oAd-TRAIL did due to enhanced and prolonged intratumoral accumulation of Ad up to a 20-day period, showing potent induction of apoptosis and inhibition of tumor cell proliferation. Furthermore, the gel system effectively prevented shedding of oncolytic Ad from the injection site to hepatic and other healthy tissues. oAd-TRAIL/gel treatment resulted in a markedly weaker antiviral immune response against Ad relative to naked oAd-TRAIL, further contributing to prolonged persistence of the oncolytic Ad in tumor tissue. Moreover, the hydrogel matrix preserved oAd-TRAIL's ability to induce an antitumor immune response, resulting in higher intratumoral infiltration by CD4⁺/CD8⁺ T cells. Taken together, these findings show that single intratumoral administration of the Ad/hydrogel modality may prolong and potentiate the therapeutic efficacy of Ad, modulate the immune reaction in favor of the virotherapy, and enhance intratumoral localization of the virus, ultimately overcoming limitations of oncolytic virotherapy revealed in recent clinical trials.



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Cuprous oxide nanoparticles trigger ER stress-induced apoptosis by regulating copper trafficking and overcoming resistance to sunitinib therapy in renal cancer

Publication date: November 2017
Source:Biomaterials, Volume 146
Author(s): Qiwei Yang, Ye Wang, Qing Yang, Yi Gao, Xiaopeng Duan, Qingcheng Fu, Chuanmin Chu, Xiuwu Pan, Xingang Cui, Yinghao Sun
While the current standard first-line treatment for advanced renal cell carcinoma (RCC) is sunitinib, patients inevitably develop resistance to this drug. However, the rapid development of nanotechnology has provided emerging techniques for the treatment of advanced tumours, including RCC. In our previous research, cuprous oxide nanoparticles (CONPs) showed ideal anti-tumour effects and low systemic toxicity. While many inorganic nanomedicines, including CONPs, have similar pharmacological effects, their detailed mechanisms remain unknown. Copper chaperone proteins, which regulate the endocellular dosage and transport of copper, also play crucial roles in the progression of cancer. In this research, we discovered that CONPs can disrupt copper transportation by regulating the copper chaperone proteins ATOX1 and CCS in RCC cells and induce endoplasmic reticulum (ER) stress in vitro and in vivo by promoting the accumulation of intracellular calcium and reactive oxygen species (ROS). Furthermore, CONPs can initiate ER- and mitochondrial-dependent apoptosis by activating caspase-3, caspase-9 and caspase-12. In addition, CONPs downregulate the expression of AXL, MET, AKT, and ERK to recover sunitinib responsiveness in RCC cells with sunitinib resistance (SR) and may therefore facilitate the development of promising new pathways to treat patients with acquired SRRCC.

Graphical abstract

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Heart valve scaffold fabrication: Bioinspired control of macro-scale morphology, mechanics and micro-structure

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): Antonio D'Amore, Samuel K. Luketich, Giuseppe M. Raffa, Salim Olia, Giorgio Menallo, Antonino Mazzola, Flavio D'Accardi, Tamir Grunberg, Xinzhu Gu, Michele Pilato, Marina V. Kameneva, Vinay Badhwar, William R. Wagner
Valvular heart disease is currently treated with mechanical valves, which benefit from longevity, but are burdened by chronic anticoagulation therapy, or with bioprosthetic valves, which have reduced thromboembolic risk, but limited durability. Tissue engineered heart valves have been proposed to resolve these issues by implanting a scaffold that is replaced by endogenous growth, leaving autologous, functional leaflets that would putatively eliminate the need for anticoagulation and avoid calcification. Despite the diversity in fabrication strategies and encouraging results in large animal models, control over engineered valve structure-function remains at best partial. This study aimed to overcome these limitations by introducing double component deposition (DCD), an electrodeposition technique that employs multi-phase electrodes to dictate valve macro and microstructure and resultant function. Results in this report demonstrate the capacity of the DCD method to simultaneously control scaffold macro-scale morphology, mechanics and microstructure while producing fully assembled stent-less multi-leaflet valves composed of microscopic fibers. DCD engineered valve characterization included: leaflet thickness, biaxial properties, bending properties, and quantitative structural analysis of multi-photon and scanning electron micrographs. Quasi-static ex-vivo valve coaptation testing and dynamic organ level functional assessment in a pressure pulse duplicating device demonstrated appropriate acute valve functionality.



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Bile acid transporter mediated endocytosis of oral bile acid conjugated nanocomplex

Publication date: December 2017
Source:Biomaterials, Volume 147
Author(s): Jooho Park, Jeong Uk Choi, Kwangmeyung Kim, Youngro Byun
The development of highly funtional and orally available nanoparticles is the ultimate goal in nanoparticle delivery. Various functional nanoparticles have been studied to that end but there has yet to be an oral nanoparticle that can be successfully applied. Here, we describe for the first time a novel bile acid conjugated nanoparticle that can be selectively absorbed by bile acid transporters in the small intestine. The bile acid conjugate nanoparticles that were first treated with enterocytes were successfully attached to the cell surface and then internalized inside the cells. We show that bile acid based interaction between a nanoparticle and its transporter induces its endocytosis and cellular uptake. This feature of cellular activity, described here for the first time, could be well utilized in the uptake of nanoparticles or macromolecules inside epithelial cells for oral delivery. In animal studies, bile acid conjugated self-assembling nanocomplexes successfully interacted with bile acid transporters in the ileum and were subsequently taken up into the epithelial cells. Considering the importance of orally deliverable nanoparticles, this nanotechnology using bile acid conjugation and transporter mediated endocytosis could be a crucial method for the successful application of various nanoparticles.

Graphical abstract

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MTA promotes chemotaxis and chemokinesis of immune cells through distinct calcium-sensing receptor signaling pathways

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): Fengjiao Chang, Jin Man Kim, Youngnim Choi, Kyungpyo Park
Mineral trioxide aggregate (MTA) has been introduced as a choice material for regenerative dentistry. To date, the diverse biological activities of MTA, including its anti-inflammatory effects, have been extensively discussed. However, there is limited insight into the link between MTA and immune cell migration. In this study, we report the role of MTA in enhancing both chemotactic and chemokinetic immune cell migration through distinct signaling pathways. By using versatile live imaging techniques, we demonstrated that MTA-mediated CaSR activation induced diverse downstream pathways to govern cell migratory capacity. In this context, Cdc42 generates cytoskeleton-driven cellular protrusions to steer directional cell migration (chemotaxis) whereas Ca²⁺-calmodulin dependent myosin light chain kinase induces cell contractility that plays an important role in speeding up the average migration speed (chemokinesis). Our findings illuminate an unrecognized role for MTA and the related CaSR signaling network in immune cell migration, providing evidence that can drive development of novel approaches to immunological therapy.



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Editorial board

Publication date: December 2017
Source:Biomaterials, Volume 147





http://ift.tt/2xOxPMF

Unraveling the mechanistic effects of electric field stimulation towards directing stem cell fate and function: A tissue engineering perspective

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): Greeshma Thrivikraman, Sunil Kumar Boda, Bikramjit Basu
Electric field (EF) stimulation can play a vital role in eliciting appropriate stem cell response. Such an approach is recently being established to guide stem cell differentiation through osteogenesis/neurogenesis/cardiomyogenesis. Despite significant recent efforts, the biophysical mechanisms by which stem cells sense, interpret and transform electrical cues into biochemical and biological signals still remain unclear. The present review critically analyses the variety of EF stimulation approaches that can be employed to evoke appropriate stem cell response and also makes an attempt to summarize the underlying concepts of this notion, placing special emphasis on stem cell based tissue engineering and regenerative medicine. This review also discusses the major signaling pathways and cellular responses that are elicited by electric stimulation, including the participation of reactive oxygen species and heat shock proteins, modulation of intracellular calcium ion concentration, ATP production and numerous other events involving the clustering or reassembling of cell surface receptors, cytoskeletal remodeling and so on. The specific advantages of using external electric stimulation in different modalities to regulate stem cell fate processes are highlighted with explicit examples, in vitro and in vivo.

Graphical abstract

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Molecular insights for the biological interactions between polyethylene glycol and cells

Publication date: December 2017
Source:Biomaterials, Volume 147
Author(s): Li Xu, Jiapei Yang, Bai Xue, Chuan Zhang, Leilei Shi, Chenwei Wu, Yue Su, Xin Jin, Yumin Liu, Xinyuan Zhu
As the gold standard polymer for drug delivery system, polyethylene glycol (PEG) has excellent biocompatibility. It's reported that the low nonspecific interactions between PEG and body contribute to its biocompatibility. However, here we discover dynamic biological interactions exist between PEG and cells on the molecular level. PEG (2 kD) can induce metabolism modulations and survival autophagy by creating an intracellular hypoxic environment, which act as cellular survival strategies in response to the hypoxia. In the cellular adaption process during hypoxia, PEG-treated cells decrease energy consumption by reducing cell growth rate, increase energy supply by amino acid catabolism in a short period, and survival autophagy over a relatively long period, to keep energy homeostasis and survival. Our research provides molecular insights for understanding the mechanism underlying the excellent biocompatibility of PEG, which will be of fundamental importance for further related studies on other polymers and development of polymeric materials with improved characteristics.

Graphical abstract

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Mechanotransduction of human pluripotent stem cells cultivated on tunable cell-derived extracellular matrix

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): In Gul Kim, Chang-Hyun Gil, Joseph Seo, Soon-Jung Park, Ramesh Subbiah, Taek-Hee Jung, Jong Soo Kim, Young-Hoon Jeong, Hyung-Min Chung, Jong Ho Lee, Man Ryul Lee, Sung-Hwan Moon, Kwideok Park
Cell-derived matrices (CDM) are becoming an attractive alternative to conventional biological scaffolding platforms due to its unique ability to closely recapitulate a native extracellular matrix (ECM) de novo. Although cell-substrate interactions are recognized to be principal in regulating stem cell behavior, very few studies have documented the acclimation of human pluripotent stem cells (hPSCs) on pristine and altered cell-derived matrices. Here, we investigate crosslink-induced mechanotransduction of hPSCs cultivated on decellularized fibroblast-derived matrices (FDM) to explore cell adhesion, growth, migration, and pluripotency in various biological landscapes. The results showed either substrate-mediated induction or inhibition of the Epithelial-Mesenchymal-Transition (EMT) program, strongly suggesting that FDM stiffness can be a dominant factor in mediating hPSC plasticity. We further propose an optimal FDM substratum intended for long-term hPSC cultivation in a feeder-free niche-like microenvironment. This study carries significant implications for hPSC cultivation and encourages more in-depth studies towards the fundamentals of hPSC-CDM interactions.



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Extracellular matrix-derived extracellular vesicles promote cardiomyocyte growth and electrical activity in engineered cardiac atria

Publication date: November 2017
Source:Biomaterials, Volume 146
Author(s): Minae An, Kihwan Kwon, Junbeom Park, Dong-Ryeol Ryu, Jung-A. Shin, Jihee Lee Kang, Ji Ha Choi, Eun-Mi Park, Kyung Eun Lee, Minna Woo, Minsuk Kim
Extracellular matrix (ECM) plays a critical role in the provision of the necessary microenvironment for the proper regeneration of the cardiac tissue. However, specific mechanisms that lead to ECM-mediated cardiac regeneration are not well understood. To elucidate the potential mechanisms, we investigated ultra-structures of the cardiac ECM using electron microscopy. Intriguingly, we observed large quantities of micro-vesicles from decellularized right atria. RNA and protein analyses revealed that these contained exosomal proteins and microRNAs (miRNAs), which we referred to herein as ECM-derived extracellular vesicles (ECM-EVs). One particular miRNA from ECM-EVs, miR-199a-3p, promoted cell growth of isolated neonatal cardiomyocytes and sinus nodal cells by repressing homeodomain-only protein (HOPX) expression and increasing GATA-binding 4 (Gata4) acetylation. To determine the mechanisms, we knocked down Gata4 and showed that miR-199a-3p actions required Gata4 for cell proliferation in isolated neonatal cardiomyocytes and sinus nodal cells. To further explore the role of this miRNA, we isolated neonatal cardiac cells and recellularized into atrial ECM, referred here has engineered atria. Remarkably, miR-199a-3p mediated the enrichment of cardiomyocyte and sinus nodal cell population, and enhanced electrocardiographic signal activity of sinus nodal cells in the engineered atria. Importantly, antisense of miRNA (antagomir) against miR-199a-3p was capable of abolishing these actions of miR-199a-3p in the engineered atria. We further showed in Ang II-infused animal model of sinus nodal dysfunction that miR-199-3p-treated cardiac cells remarkably ameliorated and restored the electrical activity as shown by normalization of the ECG, in contrast to untreated cells, which did not show electrical recovery. In conclusion, these results provide clear evidence of the critical role of ECM, in not only providing a scaffold for cardiac tissue growth, but also in promoting atrial electrical function through ECM-derived miR-199a-3p.



http://ift.tt/2wQLQZT

Successful transdermal allergen delivery and allergen-specific immunotherapy using biodegradable microneedle patches

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): Ji Hye Kim, Jung U. Shin, Seo Hyeong Kim, Ji Yeon Noh, Hye Ran Kim, Jungsoo Lee, Howard Chu, Kyoung Yong Jeong, Kyung Hee Park, Jung Dong Kim, Hong Kee Kim, Do Hyeon Jeong, Tai-Soon Yong, Jung-Won Park, Kwang Hoon Lee
Allergen-specific immunotherapy (SIT) is an effective treatment modality for allergic diseases such as atopic dermatitis (AD). However, frequent visits over a 3-year period as well as looming adverse events tend to discourage patient compliance. Therefore, a more convenient, effective, and safe method of SIT is needed.For several decades, use of microneedles has been promoted as an efficient and precise transdermal drug delivery method. In this study, we developed Dermatophagoides farinae (D. farinae) extract (DfE)-loaded microneedle patches, and evaluated their safety and efficacy as a novel SIT method. After 4 weeks of patch application, efficient allergen delivery and successful induction of immune response to DfE were demonstrated in mice, with no apparent adverse events. AD-induced NC/Nga mice received microneedle immunotherapy (MNIT) (10 μg), subcutaneous immunotherapy (SCIT) (10 μg), SCIT (100 μg), or placebo. Both MNIT (10 μg) and SCIT (100 μg) treatments improved clinical and histologic manifestations of AD skin lesions, altered immunoglobulin production, dampened Th2 cellular response, and boosted Treg infiltrates, without significant side effects; whereas SCIT (10 μg) or placebo subsets failed to show any effects. Based on the favorable safety and efficacy profiles demonstrated in mice by MNIT in the current study, we believe that MNIT may serve as a new SIT modality.



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Enhanced antitumor efficacy of arginine modified amphiphilic nanoparticles co-delivering doxorubicin and iSur-pDNA via the multiple synergistic effect

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): Yudong Song, Cui Tang, Chunhua Yin
Arginine and α-tocopherol succinate (α-TOS) double grafted N-trimethyl chitosan chloride (TMC) nanoparticles (TAS NPs) were designed and developed for effective co-delivery of doxorubicin (DOX) and Survivin shRNA-expressing pDNA (iSur-pDNA). With DOX loading into the hydrophobic core and iSur-pDNA combining to the hydrophilic shell, TAS/DOX/pDNA NPs demonstrated favorable structural stability and sustained release properties in vitro. With the special non-clathrin-dependent endocytosis, TAS/DOX/pDNA NPs presented higher cellular uptake and mainly distributed in ER and Golgi rather than lysosomes following internalization. The in vitro nuclear localization, gene silencing efficiency, cell apoptosis, and growth inhibition of tumor cells were significantly promoted by arginine modification. In the tumor-bearing mice model, TAS/DOX/pDNA NPs possessed the maximum antitumor efficiency as compared with single delivery of DOX or iSur-pDNA. Particularly, blank TAS NPs were selectively be toxic to tumor cells as evidenced by their capabilities to inhibit proliferation and induce apoptosis of tumor cells. The promising tumor treatment of TAS/DOX/pDNA NPs via a multiple synergistic manner arising from DOX and pDNA as well as the vectors would provide a potential strategy for a dual-delivery system to improve their therapeutic efficacies.



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Biofabricating atherosclerotic plaques: In vitro engineering of a three-dimensional human fibroatheroma model

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): Anna Mallone, Chantal Stenger, Arnold Von Eckardstein, Simon P. Hoerstrup, Benedikt Weber
Atherosclerotic plaques are cholesterol-induced inflammatory niches accumulating in the vascular sub-endothelial space. Cellular and extracellular composition of human plaques is maneuvered by local inflammation that leads to alterations in the original vascular microenvironment and to the recruitment of an invading fibrous layer (fibroatharoma). In the present study we introduce a bioengineered three-dimensional model of human fibroatheroma (ps-plaque) assembled with a tailored hanging-drop protocol. Using vi-SNE based multidimensional flow cytometry data analysis we compared the myeloid cell-populations in ps-plaques to those in plaques isolated from human carotid arteries. We observed that plasmacytoid and activated dendritic cells are the main myeloid components of human carotid plaques and that both cell types are present in the biofabricated model. We found that low-density lipoproteins affect cell viability and contribute to population polarization in ps-plaques. The current work describes the first human bioengineered in vitro model of late atherosclerotic lesion for the investigation of atherosclerosis aetiopathogenesis.

Graphical abstract

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Vascular smooth muscle cells derived from inbred swine induced pluripotent stem cells for vascular tissue engineering

Publication date: December 2017
Source:Biomaterials, Volume 147
Author(s): Jiesi Luo, Lingfeng Qin, Mehmet H. Kural, Jonas Schwan, Xia Li, Oscar Bartulos, Xiao-qiang Cong, Yongming Ren, Liqiong Gui, Guangxin Li, Matthew W. Ellis, Peining Li, Darrell N. Kotton, Alan Dardik, Jordan S. Pober, George Tellides, Marsha Rolle, Stuart Campbell, Robert J. Hawley, David H. Sachs, Laura E. Niklason, Yibing Qyang
Development of autologous tissue-engineered vascular constructs using vascular smooth muscle cells (VSMCs) derived from human induced pluripotent stem cells (iPSCs) holds great potential in treating patients with vascular disease. However, preclinical, large animal iPSC-based cellular and tissue models are required to evaluate safety and efficacy prior to clinical application. Herein, swine iPSC (siPSC) lines were established by introducing doxycycline-inducible reprogramming factors into fetal fibroblasts from a line of inbred Massachusetts General Hospital miniature swine that accept tissue and organ transplants without immunosuppression within the line. Highly enriched, functional VSMCs were derived from siPSCs based on addition of ascorbic acid and inactivation of reprogramming factor via doxycycline withdrawal. Moreover, siPSC-VSMCs seeded onto biodegradable polyglycolic acid (PGA) scaffolds readily formed vascular tissues, which were implanted subcutaneously into immunodeficient mice and showed further maturation revealed by expression of the mature VSMC marker, smooth muscle myosin heavy chain. Finally, using a robust cellular self-assembly approach, we developed 3D scaffold-free tissue rings from siPSC-VSMCs that showed comparable mechanical properties and contractile function to those developed from swine primary VSMCs. These engineered vascular constructs, prepared from doxycycline-inducible inbred siPSCs, offer new opportunities for preclinical investigation of autologous human iPSC-based vascular tissues for patient treatment.



http://ift.tt/2hoe5WH

Rethinking liquid biopsy: Microfluidic assays for mobile tumor cells in human body fluids

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): Kuang Hong Neoh, Ayon Ahmed Hassan, Anqi Chen, Yukun Sun, Peng Liu, Kai-Feng Xu, Alice S.T. Wong, Ray P.S. Han
Traditionally, liquid biopsy is a blood test involving the harvesting of tumor materials from peripheral blood. Tumor cells from non-blood body fluids have always been clinically available in cytological examinations but limited for use in differential diagnosis due to the low sensitivity of conventional cytopathology. With the recent significant progress in microfluidic and downstream molecular technologies, liquid biopsies have now evolved to include harvesting tumor cells and DNA fragments in all kinds of non-blood body fluids. This expansion into general body fluids presages the notion that liquid biopsy could soon be used in competition, as well as, in complementarity with tissue biopsy. Preliminary research of fluid-harvested tumor materials to spot early-stage tumors, monitor disease progression for metastasis and recurrence, and detect chemoresistance have been reported. To reflect the propagation of tumor cells in non-blood body fluids, we introduced the term Mobile Tumor Cells (MTCs), in lieu of the widely accepted term of circulating tumor cells (CTCs) resident in the bloodstream. Our review starts with a discussion on the clinical significance of MTCs, followed by a presentation of microfluidic techniques for MTC capture and various strategies for their identification. Hopefully, the phenotypic and genomic data acquired from harvested MTCs can be used to guide and improve cancer treatment decisions.



http://ift.tt/2ghwEiM

Multifunctional superparamagnetic nanoparticles conjugated with fluorescein-labeled designed ankyrin repeat protein as an efficient HER2-targeted probe in breast cancer

Publication date: December 2017
Source:Biomaterials, Volume 147
Author(s): Dong-Li Li, Jian-Er Tan, Ying Tian, Shun Huang, Peng-Hui Sun, Meng Wang, Yan-Jiang Han, Hong-Sheng Li, Hu-Bing Wu, Xing-Mei Zhang, Yi-Kai Xu, Quan-Shi Wang
Based on the discordance of human epidermal growth factor receptor-2 (HER2) expression between primary and metastatic/recurrent breast cancer, HER2 molecular imaging, which had potential to systemically assess and dynamically monitor HER2 expression, might improve the selection of patients for anti-HER2 therapy. In this study, designed ankyrin repeat protein (DARPin) G3, a novel binding protein with picomolar affinity for HER2, was used and multifunctional superparamagnetic nanoparticles modified with fluorescein-5-maleimide-labeled DARPin G3 (SPIO-G3-5MF) were developed for HER2 imaging. Our results showed that SPIO-G3-5MF nanoparticles, which possessed uniform size of about 100 nm, favorable dispersity and low cytotoxicity, could selectively bind to HER2-positive breast cancer cells even in the presence of trastuzumab. Biodistribution assay demonstrated that abundant accumulation and long retention of SPIO-G3-5MF were observed in HER2-positive transplantation breast tumors although a portion of SPIO-G3-5MF nanoparticles were unavoidably captured by liver and spleen. Further MR imaging revealed that SPIO-G3-5MF could selectively image HER2-positive transplantation breast tumors, yielding remarkable T2 signal reduction (50.33 ± 2.90% at 6 h and 47.29 ± 9.36% at 24 h). Our study suggested that SPIO-G3-5MF might be a promising MR molecular probe for diagnosing and monitoring HER2 expression state of breast cancer in the future.



http://ift.tt/2xOxQA8

Active immunotherapy for TNF-mediated inflammation using self-assembled peptide nanofibers

Publication date: December 2017
Source:Biomaterials, Volume 149
Author(s): Carolina Mora-Solano, Yi Wen, Huifang Han, Jianjun Chen, Anita S. Chong, Michelle L. Miller, Rebecca R. Pompano, Joel H. Collier
Active immunotherapies raising antibody responses against autologous targets are receiving increasing interest as alternatives to the administration of manufactured antibodies. The challenge in such an approach is generating protective and adjustable levels of therapeutic antibodies while at the same time avoiding strong T cell responses that could lead to autoimmune reactions. Here we demonstrate the design of an active immunotherapy against TNF-mediated inflammation using short synthetic peptides that assemble into supramolecular peptide nanofibers. Immunization with these materials, without additional adjuvants, was able to break B cell tolerance and raise protective antibody responses against autologous TNF in mice. The strength of the anti-TNF antibody response could be tuned by adjusting the epitope content in the nanofibers, and the T-cell response was focused on exogenous and non-autoreactive T-cell epitopes. Immunization with unadjuvanted peptide nanofibers was therapeutic in a lethal model of acute inflammation induced by intraperitoneally delivered lipopolysaccharide, whereas formulations adjuvanted with CpG showed comparatively poorer protection that correlated with a more Th1-polarized response. Additionally, immunization with peptide nanofibers did not diminish the ability of mice to clear infections of Listeria monocytogenes. Collectively this work suggests that synthetic self-assembled peptides can be attractive platforms for active immunotherapies against autologous targets.



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pH multistage responsive micellar system with charge-switch and PEG layer detachment for co-delivery of paclitaxel and curcumin to synergistically eliminate breast cancer stem cells

Publication date: December 2017
Source:Biomaterials, Volume 147
Author(s): Zhe Yang, Na Sun, Rui Cheng, Chenyang Zhao, Zerong Liu, Xian Li, Jie Liu, Zhongmin Tian
Several studies have demonstrated that cancer stem cells (CSCs) are responsible for replenishing bulk tumor cells, generating new tumors and causing metastasis and relapse. Although combination therapy with multiple chemotherapeutics is considered to be a promising approach for simultaneously eliminating non-CSCs and CSCs, it is difficult to deliver drugs into the inner region of a solid tumor where the CSCs are located due to a lack of capillaries. Here, we synthesized a pH-sensitive polymer, poly(ethylene glycol)-benzoic imine-poly(γ-benzyl-l-aspartate)-b-poly(1-vinylimidazole) block copolymer (PPBV), to develop a pH multistage responsive micellar system for co-delivering paclitaxel and curcumin and synergistically eliminating breast cancer stem cells (bCSCs) and non-bCSCs. This pH multistage responsive micellar system could intelligently switch its surface charge from neutral to positive, de-shield its PEG layer and reduce its size after long-circulation and extravasation from leaky blood vessels at tumor sites, thus facilitating their cellular uptake and deep tumor penetration. These advantages were also beneficial for the combinational therapy efficacy of PTX and CUR to reach the maximum level and achieve superior tumor inhibition activity and effective bCSCs-killing capacity in vivo. Consequently, this pH multistage responsive micellar system is a powerful platform for collaborative therapy with PTX and CUR to simultaneously eliminate bCSCs and non-CSCs.

Graphical abstract

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Single-walled carbon nanotube: One specific inhibitor of cancer stem cells in osteosarcoma upon downregulation of the TGFβ1 signaling

Publication date: December 2017
Source:Biomaterials, Volume 149
Author(s): Yanyan Miao, Haixia Zhang, Yubin Pan, Jian Ren, Miaoman Ye, Fangfang Xia, Rui Huang, Zhuoheng Lin, Shuai Jiang, Ya Zhang, Zhou Songyang, Yan Zhang
Cancer stem cells (CSCs) are believed to have a critical role in tumorigenesis, metastasis, therapeutic resistance or recurrence. Therefore, strategies designed to specifically target and eliminate CSCs have become one of the most promising and desirable ways for tumor treatment. Osteosarcoma stem cells (OSCs), the CSCs in osteosarcoma (OS), are critically associated with OS progression. Here, we show that single-walled carbon nanotubes (SWCNTs), including unmodified SWCNT (SWCNT-Raw) and SWCNT-COOH, have the ability to specifically inhibit the process of TGFβ1-induced OS cells dedifferentiation, prevent the stem cell phenotypes acquisition in OS cells and reduce the OSC viability under conditions which mimic the OS microenvironment. Concurrently, SWCNT treatment significantly down-regulates the expression of OSC markers in OS, and markedly reduces the tumor microvessel density and tumor growth. Furthermore, we found that SWCNT could suppress the TGFβ1-induced activation of TGFβ type I receptor and downstream signaling, which are key for the OSC formation and maintenance. Our results reveal an unexpected function of SWCNT in negative modulation of OSCs, and provide significant implications for the potential CSCs-targeted therapeutic applications of SWCNT.



http://ift.tt/2wCwLZd

Modular flow chamber for engineering bone marrow architecture and function

Publication date: November 2017
Source:Biomaterials, Volume 146
Author(s): Christian A. Di Buduo, Paolo M. Soprano, Lorenzo Tozzi, Stefania Marconi, Ferdinando Auricchio, David L. Kaplan, Alessandra Balduini
The bone marrow is a soft, spongy, gelatinous tissue found in the hollow cavities of flat and long bones that support hematopoiesis in order to maintain the physiologic turnover of all blood cells. Silk fibroin, derived from Bombyx mori silkworm cocoons, is a promising biomaterial for bone marrow engineering, because of its tunable architecture and mechanical properties, the capacity of incorporating labile compounds without loss of bioactivity and demonstrated ability to support blood cell formation. In this study, we developed a bone marrow scaffold consisting of a modular flow chamber made of polydimethylsiloxane, holding a silk sponge, prepared with salt leaching methods and functionalized with extracellular matrix components. The silk sponge was able to support efficient platelet formation when megakaryocytes were seeded in the system. Perfusion of the chamber allowed the recovery of functional platelets based on multiple activation tests. Further, inhibition of AKT signaling molecule, which has been shown to be crucial in regulating physiologic platelet formation, significantly reduced the number of collected platelets, suggesting the applicability of this tissue model for evaluation of the effects of bone marrow exposure to compounds that may affect platelet formation. In conclusion, we have bioengineered a novel modular system that, along with multi-porous silk sponges, can provide a useful technology for reproducing a simplified bone marrow scaffold for blood cell production ex vivo.



http://ift.tt/2wTxgBo

The Sunshine ACT And Oncology: Lessons Learned From Urology

Publication date: Available online 13 October 2017
Source:Seminars in Oncology
Author(s): Mahir Maruf, Piyush K. Agarwal, Abhinav Sidana




http://ift.tt/2wUNN50

Innate sensing of cancer's non-immunologic hallmarks

Ruth Seelige | Stephen Searles | Jack D Bui

http://ift.tt/2yfChVF

Emerging roles for long noncoding RNAs in B-cell development and malignancy

Publication date: Available online 13 October 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): M. Winkle, J.L. Kluiver, Diepstra Arjan, A. van den Berg
Long noncoding (lnc)RNAs have emerged as essential mediators of cellular biology, differentiation and malignant transformation. LncRNAs have a broad range of possible functions at the transcriptional, posttranscriptional and protein level and their aberrant expression significantly contributes to the hallmarks of cancer cell biology. In addition, their high tissue- and cell-type specificity makes lncRNAs especially interesting as biomarkers, prognostic factors or specific therapeutic targets. Here, we review current knowledge on lncRNA expression changes during normal B-cell development, indicating essential functions in the differentiation process. In addition we address lncRNA deregulation in B-cell malignancies, the putative prognostic value of this as well as the molecular functions of multiple deregulated lncRNAs. Altogether, the discussed work indicates major roles for lncRNAs in normal and malignant B cells affecting oncogenic pathways as well as the response to common therapeutics.



http://ift.tt/2yg9kZT

Advances in mechanisms of allergic disease in 2016

This review highlights advances in mechanisms of allergic disease, particularly type 2 innate lymphoid cells; TH2 lymphocytes; eicosanoid regulation of inflammation; extracellular vesicles in allergic responses; IL-33; microbiome properties, especially as they relate to mucosal barrier function; and a series of findings concerning the allergic inflammatory cells eosinophils, basophils, and mast cells. During the last year, mechanistic advances occurred in understanding type 2 innate lymphoid cells, particularly related to their response to ozone, involvement with experimental food allergy responses, and regulation by IL-33.

http://ift.tt/2xE4sJK

Fibrinogen-cleavage products and TLR4 promote the generation of programmed cell death 1 ligand 2(PD-L2)+ dendritic cells in allergic asthma

Inhaled protease allergens preferentially trigger Th2-mediated inflammation in allergic asthma. The role of dendritic cells (DCs) on the induction of Th2 cell responses in allergic asthma has been well documented; however, the mechanism by which protease allergens induce Th2-favorable DCs in the airway remains unclear.

http://ift.tt/2ymsGvs

Ethical Challenges with Treating Non-Adherent Patients in a Group Practice Setting

http://ift.tt/2xEpc8Y

Omalizumab Response in Patients with Chronic Idiopathic Urticaria: Insights from the XTEND-CIU Study

http://ift.tt/2kNXgcK

Adams-Oliver Syndrome With Moyamoya Disease for Cerebral Revascularisation Surgery.

No abstract available

http://ift.tt/2yKKcuZ

SonicCloud Builds Functionality of Hearing Aids Into iPhones

​The startup SonicCloud (https://soniccloud.com/) has launched an iOS app that allows those with moderate to severe hearing loss hear phone calls clearly by calibrating every mobile phone call for their unique hearing needs. The SonicCloud App users will be able to determine custom levels for their right and left ears by taking a quick hearing assessment on the app. Each user gets his or her own personal Hearing Fingerprint, which is driven by an algorithm in the cloud that adjusts to an individual's hearing needs. Incoming and outgoing calls are then processed through SonicCloud's "mixing board in the cloud," which optimizes voices and noisy environments. The SonicCloud App is the company's first step towards making hearing technology truly accessible to hearing-impaired individuals. SonicCloud was featured in Apple's 2017 Worldwide Developers Conference. 

               

Published: 10/13/2017 12:04:00 PM

http://ift.tt/2iahXyI

Prognostic Outcomes in Advanced Breast Cancer: The Metastasis-free Interval is Important

Publication date: Available online 13 October 2017
Source:Human Pathology
Author(s): Tiansheng Shen, Cheng Gao, Kui Zhang, Gene P. Siegal, Shi Wei
Metastatic breast cancer is a heterogeneous disease with a diverse clinical course. There have been limited studies regarding prognostic outcomes in patients with de novo metastatic breast cancer versus those with metastatic recurrence, with controversial observations. In this study, we sought to examine the difference in survival outcomes among patients with advanced breast cancer stratified based on metastasis-free interval (MFI), and to further explore the role of systemic therapy in these patient groups. Of 569 consecutive patients with stage IV breast cancer between 1998 and 2013, 201 had de novo metastatic disease (metastasis at diagnosis) and 368 developed metastatic recurrence, including 168 with a MFI≤24months and 200 with a MFI>24months. In the 492 patients who received systemic therapy, de novo metastasis was an independent favorable prognostic factor for overall survival after metastasis when compared to metastatic recurrence irrespective of MFI. Compared to the patients with metastatic recurrence with a MFI≤24months, those with a MFI>24months had a significantly superior survival outcome, although it did not reach statistical significance by multivariate analysis. In contrast, de novo metastatic breast cancer was associated with a worse prognosis when compared to recurring metastasis in the patients who did not receive systemic treatment. These findings provide more insight into the natural history of advanced breast cancer thus necessitating further investigation into the molecular mechanism of drug resistance.



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