The aim of the present study was to assess whether paediatric intensive care units (PICUs) in three central European countries comply with guidelines concerning infrastructure provided by the European Society ...
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Τρίτη 6 Νοεμβρίου 2018
A multinational survey on the infrastructural quality of paediatric intensive care units
Correction to: Practical approach to diastolic dysfunction in light of the new guidelines and clinical applications in the operating room and in the intensive care
In the original article [1], the authors noticed a typographical error in Figure 2. The top left box should have included "E/A
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Resveratrol reverses the negative effect of smoking on peri‐implant repair in the tibia of rats
Abstract
Objectives
Innovative approaches capable to improve peri‐implant bone repair are relevant in the presence of smoking, a risk factor for healing around implants. This study investigated the effect of resveratrol (RESV) on peri‐implant repair and its influence on bone‐related markers in rats submitted to cigarette smoking inhalation (CSI).
Materials and Methods
One titanium implant was inserted in each tibiae of rats assigned to: CSI+RESV(n:18); CSI+ placebo(n:18); Non‐CSI(n:18). One implant was removed for counter‐torque and the peri‐implant tissue was collected for mRNA quantification of BMP‐2, OPN, Runx2, Lrp‐5, Osx, β‐catenin, Dkk1, OPG, and RANKL. The other tibia was submitted to MicroCT to measure: bone volume, bone porosity, trabecular spacing, trabecular thickness and bone‐implant contact (BIC).
Results
No differences were detected between counter‐torque in CSI+RESV and Non‐CSI group (p>0.05), whereas CSI+placebo group presented lower values when compared to the others (p<0.05). RESV improved the BIC in CSI rats without differences when compared to non‐CSI group (p>0.05), whereas CSI+placebo showed reduced BIC when compared to the other groups (p<0.05). RESV reduced RANKL/OPG and Lrp‐5 levels and increased β‐catenin in CSI rats when compared to CSI+placebo (p<0.05).
Conclusion
Although further investigations should be considered using oral models of dental implants, within the limits of the present study, it was concluded that RESV reverses the negative effects of smoking in the peri‐implant repair, benefiting the modulation of bone‐related markers.
This article is protected by copyright. All rights reserved.
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The aqueous extract of Glycyrrhiza glabra effectively prevents induced gastroduodenal ulcers: experimental study on Wistar rats
Abstract
The recent studies have indicated the properties of ethnomedicinal plants in the prevention, control, and treatment of gastroduodenal ulcers. Glycyrrhiza glabra has been used in Iranian traditional medicine as a therapeutic supplement. The aim of our research was to survey the preventive property of aqueous extract of G. glabra leaf on ibuprofen-induced gastroduodenal ulcers by investigating the biochemical, hematological, immunological, and microscopic approaches in rats. In this study, 60 rats were used. The animals were randomly divided into six subgroups, including negative healthy control, untreated negative control, the positive control receiving omeprazole 60 mg/kg, and three groups receiving the G. glabra aqueous extract at 20 mg/kg, 60 mg/kg, and 180 mg/kg concentrations. After 14 days, gastroduodenal ulcers were caused by ibuprofen 400 mg/kg. Four hours after oral administration of ibuprofen, the rats were sacrificed and blood, stomach, and duodenum samples of them collected for analysis of biochemical, hematological, immunological, and microscopic parameters. The data were analyzed by SPSS 21 software. All doses of G. glabra could significantly (p ≤ 0.05) reduce the raised levels of ALP, AST, ALT, GGT, cholesterol, LDL, triglyceride, total and conjugated bilirubin, urea, creatinine, IL-1, IL-6, IL-12, IL-18, IFN-γ, and TNF-α and increase HDL, total protein, albumin, WBC, platelet, RBC, IL-4, IL-5, IL-10, IL-13, and IFN-α as compared to the untreated group. Also, aqueous extract of G. glabra prevented significantly (p ≤ 0.05) gastroduodenal ulcers as compared to the untreated group. In conclusion, the obtained results indicated the hepatoprotective, nephroprotective, hematoprotective, immunoprotective, and gastroduodenal protective properties of G. glabra aqueous extract.
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The Antineuroinflammatory Effect of Simvastatin on Lipopolysaccharide Activated Microglial Cells
Microglial cells, upon hyperactivation, produce proinflammatory cytokines and other oxidative stress mediators causing neuroinflammation, which is associated with the progress of many neurodegenerative diseases. Suppressing the microglial activation has hence been used as an approach for treating such diseases. In this study, the antineuroinflammatory effect of simvastatin was examined in lipopolysaccharide (LPS)-activated rat C6 glioma cells. The cell proliferation and cytotoxic effect of LPS and simvastatin on C6 glioma cells was evaluated by (MTT) assay. Neuroinflammation was induced in differentiated cell lines by treatment with 3.125 μg/mL of LPS for 12 h. Upon induction, the cell lines were treated with different concentrations (3.125, 6.25, 12.5, 25, 50, 100 μM) of simvastatin and incubated in a humidified CO2 incubator for 24 to 48 h. The optimum concentrations of LPS and simvastatin were found to be 3.125 μg/mL and 25 μM, respectively, with a cell viability of more than 90% at 24 h postincubation. Furthermore, proinflammatory marker expression was analyzed by flow cytometry and showed a decrease in interferon-γ, interleukin 6, nuclear factor-κB p65, and tumor necrosis factor-α in simvastatin-treated and LPS-induced neuroinflammatory cells, and the mean fluorescent values were found to be 21.75 ± 0.76, 20.9 ± 1.90, 19.72 ± 1.29, and 16.82 ± 0.97, respectively, as compared to the untreated cells. Thus, we show that simvastatin has the potential to regulate the anti-inflammatory response in microglial cells upon LPS challenge. Hence, simvastatin can be employed as a potent anti-inflammatory drug against neuroinflammatory diseases and neurodegenerative disorders.
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Electroacupuncture Mitigates Skeletal Muscular Lipid Metabolism Disorder Related to High-Fat-Diet Induced Insulin Resistance through the AMPK/ACC Signaling Pathway
The aim of this work is to investigate the effect of electroacupuncture (EA) on insulin sensitivity in high-fat diet (HFD) induced insulin resistance (IR) rats and to evaluate expression of AMPK/ACC signaling components. Thirty-two male Sprague-Dawley rats were randomized into control group, HFD group, HFD+Pi (oral gavage of pioglitazone) group, and HFD+EA group. Acupuncture was subcutaneously applied to Zusanli (ST40) and Sanyinjiao (SP6). For Zusanli (ST40) and Sanyinjiao (SP6), needles were connected to an electroacupuncture (EA) apparatus. Fasting plasma glucose was measured by glucose oxidase method. Plasma fasting insulin (FINS) and adiponectin (ADP) were determined by ELISA. Triglyceride (TG) and cholesterol (TC) were determined by Gpo-pap. Proteins of adiponectin receptor 1 (adipoR1), AMP-activated Protein Kinase (AMPK), and acetyl-CoA carboxylase (ACC) were determined by Western blot, respectively. Compared with the control group, HFD group exhibits increased levels of FPG, FINS, and homeostatic model assessment of insulin resistance (HOMA-IR) and decreased level of ADP and insulin sensitivity index (ISI). These changes were reversed by both EA and pioglitazone. Proteins of adipoR1 and AMPK were decreased, while ACC were increased in HFD group compared to control group. Proteins of these molecules were restored back to normal levels upon EA and pioglitazone. EA can improve the insulin sensitivity of insulin resistance rats; the positive regulation of the AMPK/ACC pathway in the skeletal muscle may be a possible mechanism of EA in the treatment of IR.
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Predictors of First‐Year Nonadherence and Discontinuation of Statins among Older Adults: A Retrospective Cohort Study
Abstract
Aims
To examine the level of and predictors of statin nonadherence and discontinuation among older adults.
Methods
Among 22,340 Australians aged ≥65 years who initiated statin therapy from January 2014 to December 2015, we estimated the first‐year nonadherence (proportion of days covered [PDC] <0.80) and discontinuation (≥90 days without statin coverage) rates. Predictors of nonadherence and discontinuation were examined via multivariable logistic regression. Analyses were performed separately for general beneficiaries (with a higher co‐payment; n=4,841) and concessional beneficiaries (with a lower co‐payment; n=17,499).
Results
During the one‐year follow‐up, 55.1% were nonadherent (concessional 52.6%; general beneficiaries 64.2%) and 44.7% discontinued statins (concessional 43.1%; general beneficiaries 50.4%). Among concessional beneficiaries, those aged 75‐84 years and ≥85 years were more likely to discontinue than people aged 65‐74 years, (odds ratio 1.11, 95% confidence interval 1.04‐1.19 and 1.38, 1.23‐1.54, respectively). Diabetes was associated with an increased likelihood of nonadherence and discontinuation, while hypertension, angina and congestive heart failure were associated with a lower likelihood of nonadherence and discontinuation. Anxiety was associated with an increased likelihood of discontinuation but polypharmacy (concurrent use of ≥5 drugs) was associated with a lower likelihood of nonadherence and discontinuation. Statin initiation by a general medical practitioner was associated with both increased likelihood of nonadherence and discontinuation. Similar predictors of nonadherence and discontinuation were identified for the general beneficiaries.
Conclusions
Among older adults prescribed statins, first‐year nonadherence and discontinuation is high. Specific population subgroups such as people aged ≥85 years, those with diabetes or anxiety may require additional attention to improve statin adherence.
https://ift.tt/2qxd2bS
Lumbar interbody fusion for adjacent segment disease: Illustrative cases
Publication date: Available online 6 November 2018
Source: Seminars in Spine Surgery
Author(s): Daniel G. Tobert, Heeren S. Makanji, Thomas D. Cha
Abstract
Adjacent segment disease (ASD) is a known complication of lumbar spine arthrodesis and refers to any type of deterioration at the adjacent cephalad or caudad motion segment to a prior fusion. The existing literature points to a multifactorial etiology including alterations of the physiologic biomechanics after fusion as well as the intrinsic spondylosis present at the time of the index operation. Revision posterior laminectomy and fusion can be technically challenging and has a higher complication rate than primary decompression and fusion procedures.
Lateral lumbar interbody fusion (LLIF) along with posterior extension of fusion in a hybrid technique provides a less invasive option for the surgical treatment of ASD. Adjacent level stenosis is addressed via indirect decompression of the central canal and foramina. In addition, an assortment of cages provides relative correction of coronal and sagittal plane deformity. This manuscript discusses the role of LLIF for the treatment of ASD and two illustrative cases are presented.
https://ift.tt/2RIz1sd
National Cancer Database report of nonmetastatic esophageal small cell carcinoma
Because the study of rare neoplasms, such as ESCC is highly limited by sample size and heterogeneity in existing reports, it is essential to perform large‐volume investigations of homogeneous patients. This study of a large, contemporary national database demonstrates that most ESCC is treated with CRT in the United States; adding local therapy to systemic therapy may be beneficial to these patients, although individualized multidisciplinary management is still recommended.
Abstract
Background
Esophageal small cell carcinoma (ESCC) is a rare malignancy for which there is no consensus management approach. This is the largest known analysis of nonmetastatic ESCC patients to date, evaluating national practice patterns and outcomes of surgical‐based therapy vs chemoradiotherapy (CRT) vs chemotherapy alone.
Methods
The National Cancer Data Base was queried for esophageal cancer patients with histologically confirmed nonmetastatic ESCC. Univariable and multivariable logistic regression ascertained factors associated with receipt of surgical‐based management. Kaplan‐Meier analysis evaluated overall survival (OS) and the log‐rank test is used to compare OS between groups; Cox univariate and multivariate analyses determined variables associated with OS.
Results
Altogether, 323 patients were analyzed; 64 (20%) patients underwent surgical‐based therapy, 211 (65%) CRT, and 48 (15%) chemotherapy alone. On multivariable analysis, no single factor significantly predicted for administration of surgery. Despite no OS differences between the surgery‐based (median OS 21 months) and CRT arms (18 months), both were superior to CT alone (10 months) (P < 0.001). Among other factors, receiving any local therapy independently predicted for higher OS over chemotherapy alone on Cox multivariate analysis (P < 0.001).
Conclusions
This study of a large, contemporary national database demonstrates that most ESCC is treated with CRT in the United States; adding local therapy to systemic therapy may be beneficial to these patients, although individualized multidisciplinary management is still recommended.
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A dose-escalation study of docetaxel, oxaliplatin, and S-1 (DOS) as a first-line therapy for patients with unresectable metastatic gastric cancer
Abstract
Purpose
The aim of this study was to determine the recommended dose (RD) for a docetaxel/oxaliplatin/S-1 (DOS) regimen in patients with unresectable gastric cancer and to preliminarily evaluate its efficacy.
Methods
Previously untreated patients with histologically proven unresectable metastatic gastric cancer were enrolled (n = 16). Docetaxel and oxaliplatin were administered intravenously on day 8 and S-1 was administered orally twice a day on days 1–14. Each cycle was repeated every 3 weeks. Dose-limiting toxicities (DLTs) were evaluated during the first treatment cycle. Three dose escalations of DOS were employed in this study: level 1 (50/100/80 mg/m2), level 2 (50/130/80 mg/m2), and level 3 (60/130/80 mg/m2).
Results
According to the 3 + 3 dose-escalating schedule, we determined that the RD and maximum tolerated dose for this regimen were level 1 and level 2, respectively. The DLTs were grade 3 diarrhea and febrile neutropenia. The overall response rate was 78% (7/9) for patients with measurable lesions and consisted of two complete responses and five partial responses. Five patients underwent conversion surgery. The median follow-up time was 19 months with median survival time and progression-free survival being 19.6 months and 7.6 months, respectively.
Conclusions
The results from this study demonstrated the safety and tolerability of DOS in unresectable metastatic gastric cancer patients and revealed promising preliminary efficacy with a high conversion rate. A phase II trial of DOS regimen using the identified RD is ongoing.
https://ift.tt/2JKS7Lb
Development of poly(ADP-ribose) polymerase inhibitors in the treatment of BRCA-mutated breast cancer.
| Related Articles |
Development of poly(ADP-ribose) polymerase inhibitors in the treatment of BRCA-mutated breast cancer.
Clin Adv Hematol Oncol. 2018 Jul;16(7):491-501
Authors: Sulai NH, Tan AR
Abstract
The poly(ADP-ribose) polymerases (PARPs) 1 and 2 are DNA-binding enzymes that play a critical role in the repair of DNA. The use of PARP inhibitors is a rational therapeutic approach to selectively killing a subset of cancer cells with deficiencies in DNA repair pathways. PARP inhibitors that have undergone clinical investigation in the treatment of breast cancer include olaparib, talazoparib, veliparib, niraparib, and rucaparib. The antitumor activity of PARP inhibitors as single agents has been demonstrated in BRCA-associated metastatic breast cancer. In 2018, olaparib became the first oral PARP inhibitor to receive approval in the United States for the treatment of advanced BRCA-mutated breast cancer, an approval that represents a major change in the treatment paradigm for this subtype of breast cancer. PARP inhibition plus chemotherapy and PARP inhibition plus immunotherapy are novel approaches undergoing extensive study in breast cancer. This review focuses on the clinical development of PARP inhibitors administered singly or in combination with other agents for early-stage and metastatic BRCA-mutated breast cancer.
PMID: 30067621 [PubMed - indexed for MEDLINE]
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In vivo gene correction with targeted sequence substitution through microhomology-mediated end joining.
 | Related Articles |
In vivo gene correction with targeted sequence substitution through microhomology-mediated end joining.
Biochem Biophys Res Commun. 2018 07 07;502(1):116-122
Authors: Shin JH, Jung S, Ramakrishna S, Kim HH, Lee J
Abstract
Genome editing technology using programmable nucleases has rapidly evolved in recent years. The primary mechanism to achieve precise integration of a transgene is mainly based on homology-directed repair (HDR). However, an HDR-based genome-editing approach is less efficient than non-homologous end-joining (NHEJ). Recently, a microhomology-mediated end-joining (MMEJ)-based transgene integration approach was developed, showing feasibility both in vitro and in vivo. We expanded this method to achieve targeted sequence substitution (TSS) of mutated sequences with normal sequences using double-guide RNAs (gRNAs), and a donor template flanking the microhomologies and target sequence of the gRNAs in vitro and in vivo. Our method could realize more efficient sequence substitution than the HDR-based method in vitro using a reporter cell line, and led to the survival of a hereditary tyrosinemia mouse model in vivo. The proposed MMEJ-based TSS approach could provide a novel therapeutic strategy, in addition to HDR, to achieve gene correction from a mutated sequence to a normal sequence.
PMID: 29787760 [PubMed - indexed for MEDLINE]
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Fingolimod can act as a facilitator to establish the primary T-cell response with reduced need of adjuvants.
| Related Articles |
Fingolimod can act as a facilitator to establish the primary T-cell response with reduced need of adjuvants.
Vaccine. 2018 Nov 02;:
Authors: Gao C, Zhuang X, Zhang L, Li M, Li JJ, Li JB, Zhu Q
Abstract
The CD8+ T-cell response is an essential part of the adaptive immunity. Adjuvants are routinely required for priming of T cells against antigens encountered in lymph nodes (LNs) to generate antigen-specific immunity but may concomitantly trigger unexpected inflammatory responses. Sphingosine-1-phosphate (S1P) induces transient desensitization of S1P receptors on LN T cells and temporarily blocks their egress, leading to prolonged intranodal retention that allows effective immunosurveillance and increases the chance of priming. In light of the regulatory role of S1P in T-cell migration, we here develop a strategic approach to the T-cell priming with protein vaccine containing low-dose TLR-based adjuvants (LDAV) to induce antigen-specific CD8+ T cell responses as efficiently as using regular dose adjuvants in vaccine (RDAV). We found that when combined with one low dose of the S1P analog fingolimod administered into the same vaccination site posteriorly at a specific time, LDAV can elicit a primary response that reaches the level of that induced by RDAV with respect to the response magnitude and functionality. Time-course studies indicate that LDAV and fingolimod in combination act to mimic the expansion kinetics of RDAV-primed antigen-specific CD8+ T cells. Further, intranodal accumulation of cDC1 is markedly enhanced in mice receiving the combination vaccination despite the decrease in adjuvant use. Of particular note is the marginal cutaneous inflammation at the injection site, indicating an added benefit of using fingolimod. Therefore, fingolimod as a nonadjuvant agent essentially facilitates antigen-specific T-cell priming with reduced need of adjuvants and minimized adverse reactions.
PMID: 30392766 [PubMed - as supplied by publisher]
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In vivo cancer vaccination: Which dendritic cells to target and how?
| Related Articles |
In vivo cancer vaccination: Which dendritic cells to target and how?
Cancer Treat Rev. 2018 Oct 25;71:88-101
Authors: Chiang CL, Kandalaft LE
Abstract
The field of cancer immunotherapy has been revolutionized with the use of immune checkpoint blockade antibodies such as anti-programmed cell death 1 protein (PD-1) and chimeric antigen receptor T cells. Significant clinical benefits are observed in different cancer types with these treatments. While considerable efforts are made in augmenting tumor-specific T cell responses with these therapies, other immunotherapies that actively stimulate endogenous anti-tumor T cells and generating long-term memory have received less attention. Given the high cost of cancer immunotherapies especially with chimeric antigen receptor T cells, not many patients will have access to such treatments. The next-generation of cancer immunotherapy could entail in vivo cancer vaccination to activate both the innate and adaptive anti-tumor responses. This could potentially be achieved via in vivo targeting of dendritic cells which are an indispensable link between the innate and adaptive immunities. Dendritic cells highly expressed toll-like receptors for recognizing and eliminating pathogens. Synthetic toll-like receptors agonists could be synthesized at a low cost and have shown promise in preclinical and clinical trials. As different subsets of human dendritic cells exist in the immune system, activation with different toll-like receptor agonists could exert profound effects on the quality and magnitude of anti-tumor T cell responses. Here, we reviewed the different subsets of human dendritic cells. Using published preclinical and clinical cancers studies available on PubMed, we discussed the use of clinically approved and emerging toll-like receptor agonists to activate dendritic cells in vivo for cancer immunotherapy. Finally, we searched www.clinicaltrials.gov and summarized the active cancer trials evaluating toll-like receptor agonists as an adjuvant.
PMID: 30390423 [PubMed - as supplied by publisher]
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Molecular and chemical characterization of mutant and nonmutant genotypes of saffron grown in Saudi Arabia
This study will provide a breakthrough in cultivating a mutant type of saffron, the most expensive spice worldwide in Saudi Arabia.
Abstract
Saffron (Crocus sativus L.) is an important spice and medicinal plant that is cultivated in Asia, Europe, North Africa, and North America. Its morphological and biochemical parameters, such as the changes in the floral parts (six tepals, three stamens, three stigmata), biomass, and chlorophyll content, are primarily affected by environmental conditions. A polymerase chain reaction–rapid amplified polymorphic DNA (PCR‐RAPD) approach was used to analyze the extent of the polymorphisms between C. sativus genotypes grown in the Saudi climate. In this research study, the DNA fingerprints of the stigmata of C. sativus genotypes [K1 & K2 = C. sativus var. cashmerianus, C1 = C. sativus (nonmutant), T1 = mutant (T0‐2B), T2 = mutant (T1‐2B), T3 = mutant (T4‐2A)] were determined according to the floral parts, and a total of 10 decamer primers were used for PCR‐RAPD analysis. Only three pairs of arbitrary primers showed polymorphisms (33.3%–88.2%) in the total genomic DNA extracted from these genotypes. Jaccard's similarity index (JSI) ranged from 0.88 to 1.0. An unweighted pair group method with arithmetic mean (UPGMA) similarity and dendrogram matrix showed that two genotypes (T1‐2B and T4‐2A) were closely related to each other and to the strain CM‐cashmerianus, while the T0 of C. sativus genotype showed divergence.
https://ift.tt/2D7TDWH
Pharmacogenetic relevance of endothelial nitric oxide synthase polymorphisms and gene interactions
Pharmacogenomics, Ahead of Print.
https://ift.tt/2SPSkkx
Pharmacogenetics to prevent heparin-induced thrombocytopenia: what do we know?
Pharmacogenomics, Ahead of Print.
https://ift.tt/2zzOLGx
Analysis of outpatient HER2 testing in New York state using the statewide planning and research cooperative system
Pharmacogenomics, Ahead of Print.
https://ift.tt/2SPPr34
Rosuvastatin pharmacogenetics in African populations
Pharmacogenomics, Ahead of Print.
https://ift.tt/2SQixzv
Urogenital pathogens, associated with Trichomonas vaginalis, among pregnant women in Kilifi, Kenya: a nested case-control study
Screening of curable sexually transmitted infections is frequently oriented towards the diagnosis of chlamydia, gonorrhea, syphilis and trichomoniasis, whereas other pathogens, sometimes associated with simila...
https://ift.tt/2F9oAfQ
Study of Healthcare Personnel with Influenza and other Respiratory Viruses in Israel (SHIRI): study protocol
The Study of Healthcare Personnel with Influenza and other Respiratory Viruses in Israel (SHIRI) prospectively follows a cohort of healthcare personnel (HCP) in two hospitals in Israel. SHIRI will describe the fr...
https://ift.tt/2qxSQXn
Tox and Hound – Twisted Interactions
by Andrew Stolbach I. Depolarization Medicine should center on the patient, so I start this story with an anonymous person dropping dead.1 Perhaps this person first heard about the medication from a friend who raved about his new allergy pill. Then, the day of a routine doctor's appointment, our patient saw an advertisement for […]
EMCrit Project by Tox & Hound.
https://ift.tt/2QlcOjC
Association of symptoms and interval breast cancers in the mammography-screening programme: population-based matched cohort study
Association of symptoms and interval breast cancers in the mammography-screening programme: population-based matched cohort study
Association of symptoms and interval breast cancers in the mammography-screening programme: population-based matched cohort study, Published online: 07 November 2018; doi:10.1038/s41416-018-0308-2
Association of symptoms and interval breast cancers in the mammography-screening programme: population-based matched cohort study
https://ift.tt/2QonVYV
Metabolite and lipoprotein responses and prediction of weight gain during breast cancer treatment
Metabolite and lipoprotein responses and prediction of weight gain during breast cancer treatment
Metabolite and lipoprotein responses and prediction of weight gain during breast cancer treatment, Published online: 07 November 2018; doi:10.1038/s41416-018-0211-x
Metabolite and lipoprotein responses and prediction of weight gain during breast cancer treatment
https://ift.tt/2PgESIg
Statins attenuate outgrowth of breast cancer metastases
Statins attenuate outgrowth of breast cancer metastases
Statins attenuate outgrowth of breast cancer metastases, Published online: 07 November 2018; doi:10.1038/s41416-018-0267-7
Statins attenuate outgrowth of breast cancer metastases
https://ift.tt/2Qpzlfd
Type 2 diabetes and risk of colorectal cancer in two large U.S. prospective cohorts
Type 2 diabetes and risk of colorectal cancer in two large U.S. prospective cohorts
Type 2 diabetes and risk of colorectal cancer in two large U.S. prospective cohorts, Published online: 07 November 2018; doi:10.1038/s41416-018-0314-4
Type 2 diabetes and risk of colorectal cancer in two large U.S. prospective cohorts
https://ift.tt/2PgERnG
Dysregulated circular RNAs in medulloblastoma regulate proliferation and growth of tumor cells via host genes
The present study aims to investigate the expression profiles of circRNAs and related mechanisms in MB. We screened circRNAs expression profiles via HiseqTM Sequencer from four normal cerebellum and four MB samples. Subsequently, we validated expression levels of eight differential circRNAs by quantitative RT‐PCR. Moreover, we silenced Circ‐SKA3 and Circ‐DTL with small interfere RNAs and over expressed their host genes to investigate their role in pathogenesis of medulloblastoma. The present study exploited circRNAs profiling in MB firstly and demonstrated that Circ‐SKA3 and Circ‐DTL played an important role in the tumorigenesis and development of MB and might be considered as novel and potential biomarkers for the diagnosis and new targets for intervention of MB
Abstract
Circular RNAs (circRNAs) have been demonstrated to be involved in various biological processes. Nevertheless, the function of circRNAs in medulloblastoma (MB) is still unknown. The present study aimed to investigate the expression profiles of circRNAs and related mechanisms for regulating the proliferation and growth of tumor cells in MB. The expression profiles of circRNAs were screened from four normal cerebellum and four MB samples using a HiSeq Sequencer. Bioinformatic analysis was employed to predict the interaction between circRNAs and mRNAs in MB. Subsequently, the expression levels of eight differential circRNAs [circ‐SKA3 (hsa_circ_0029696), circ‐DTL (hsa_circ_0000179), circ‐CRTAM, circ‐MAP3K5 (hsa_circ_0006856), circ‐RIMS1‐1 (hsa_circ_0132250), circ‐RIMS1‐2 (hsa_circ_0076967), circ‐FLT3‐1 (hsa_circ_0100165), and circ‐FLT3‐2 (hsa_circ_0100168)] were validated using quantitative reverse transcription−polymerase chain reaction. Moreover, circ‐SKA3 and circ‐DTL were silenced using small interfering RNAs and their host genes were overexpressed to investigate their role in the pathogenesis of MB. A total of 33 circRNAs were found to be differentially expressed in MB tissues (fold change ≥ 2.0, FDR <0.05), of which three were upregulated and 30 were downregulated; six circRNAs were experimentally validated successfully. Upregulated circ‐SKA3 and circ‐DTL promoted the proliferation migration and invasion in vitro by regulating the expression of host genes. This novel study exploited the profiling of circRNAs in MB and demonstrated that circ‐SKA3 and circ‐DTL were crucial in the tumorigenesis and development of MB and might be considered as novel and potential biomarkers for the diagnosis and new targets for the intervention of MB.
https://ift.tt/2PgFXja
Purified vitexin compound 1, a new neolignan isolated compound, promotes PUMA‐dependent apoptosis in colorectal cancer
We demonstrated that VB1 promoted apoptosis via p53‐dependent induction of p53 upregulated modulator of apoptosis (PUMA) and further to induce Bax activation and mitochondrial dysfunction in colon cancer HCT‐116 and LoVo cells. And we provide a novel insight for the antitcancer mechanism of VB1 and scientific rationale for further development of VB1 as a novel anticancer drug used alone or in combination with other chemotherapeutic agents in the treatment of colorectal cancer clinically.
Abstract
Purified vitexin compound 1 (VB1, a neolignan isolated and extracted from the seed of Chinese herb Vitex negundo) is an effective antitumor agent and exhibits promising clinical activity against various cancers including colorectal cancer. However, it remains unknown about the precise underlying mechanism associated with the antitumor effect of VB1 and how it triggers apoptosis in cancer cells. Here, we demonstrated that VB1 promoted apoptosis via p53‐dependent induction of p53 upregulated modulator of apoptosis (PUMA) and further to induce Bax (Bcl‐2‐associated X protein) activation and mitochondrial dysfunction in colon cancer HCT‐116 and LoVo cells. Deficiency in p53, PUMA, or Bax abrogated VB1‐induced apoptosis and promoted cell survival in HCT‐116 cells. Furthermore, the combination of VB1 with chemotherapeutic drugs 5‐fluorouracil (5‐FU) or NVP‐BZE235 resulted in a synergistic antitumor effect via PUMA induction in HCT‐116 cells. VB1 significantly suppressed the cell proliferation of wild‐type (WT) HCT‐116 and LoVo cells in vitro and tumor growth in vivo. The results indicate that p53/PUMA/Bax axis plays a critical role in VB1‐induced apoptosis and VB1 may have valuable clinical applications in cancer therapy as a novel anticancer agent used alone or in combination with other chemotherapeutic drugs.
https://ift.tt/2zxs0CS
Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy
LDHA contributes to diverse bio‐characteristics of tumors via numerous mechanisms. LDHA has been used as a tumor biomarker for clinical diagnosis and treatment and is considered as a potential anticancer target.
Abstract
Elevated glycolysis remains a universal and primary character of cancer metabolism, which deeply depends on dysregulated metabolic enzymes. Lactate dehydrogenase A (LDHA) facilitates glycolytic process by converting pyruvate to lactate. Numerous researches demonstrate LDHA has an aberrantly high expression in multiple cancers, which is associated with malignant progression. In this review, we summarized LDHA function in cancer research. First, we gave an introduction of structure, location, and basic function of LDHA. Following, we discussed the transcription and activation mode of LDHA. Further, we focused on the function of LDHA in cancer bio‐characteristics. Later, we discussed the clinical practice of LDHA in cancer prevention and treatment. What we discussed gives a precise insight into LDHA especially in cancer research, which will contribute to exploring cancer pathogenesis and its handling measures.
https://ift.tt/2Pf8Mg3
Phase III Trial of Adjuvant Sunitinib in Patients With High-Risk Renal Cell Carcinoma: Exploratory Pharmacogenomic Analysis
Purpose: In the S-TRAC trial, adjuvant sunitinib prolonged disease-free survival (DFS) versus placebo in patients with loco-regional renal cell carcinoma at high risk of recurrence after nephrectomy. An exploratory analysis evaluated associations between single nucleotide polymorphisms (SNPs) in several angiogenesis- or hypoxia-related genes and clinical outcomes in S-TRAC. Experimental Design: Blood samples were genotyped for 10 SNPs and one insertion/deletion mutation using TaqMan assays. DFS was compared using log-rank tests for each genotype in sunitinib versus placebo groups and between genotypes within each of three (sunitinib, placebo, and combined sunitinib plus placebo) treatment groups. P-values were unadjusted. Results: In all, 286 patients (sunitinib, n=142; placebo, n=144) were genotyped. Longer DFS (HR [95% confidence interval]) was observed with sunitinib versus placebo for VEGFR1 rs9554320 C/C (0.44 [0.21-0.91]; P=0.023), VEGFR2 rs2071559 T/T (0.46 [0.23-0.90]; P=0.020), and eNOS rs2070744 T/T (0.53 [0.30-0.94]; P=0.028). Shorter DFS was observed for VEGFR1 rs9582036 C/A versus C/C with sunitinib, placebo, and combined therapies (P≤0.05), and A/A vs C/C with sunitinib (P=0.022). VEGFR1 rs9554320 A/C versus A/A was associated with shorter DFS in the placebo (P=0.038) and combined (P=0.006) groups. Conclusions: Correlations between VEGFR1 and VEGFR2 SNPs and longer DFS with sunitinib suggest germline SNPs are predictive of improved outcomes with adjuvant sunitinib in patients with renal cell carcinoma. Independent validation studies are needed to confirm these findings.
https://ift.tt/2yWCsEp
Preclinical development and first-in-human imaging of the integrin {alpha}v{beta}6 with [18F]{alpha}v{beta}6-Binding Peptide in metastatic carcinoma.
Purpose:The study was undertaken to develop and evaluate the potential of an integrin αvβ6-binding peptide (αvβ6-BP) for noninvasive imaging of a diverse range of malignancies with positron emission tomography (PET). Experimental Design: The peptide αvβ6-BP was prepared on solid phase and radiolabeled with 4-[18F]fluorobenzoic acid. In vitro testing included ELISA, serum stability, and cell binding studies using a paired αvβ6-expressing and αvβ6-null cell lines. In vivo evaluation (PET/CT, biodistribution and autoradiography) was performed in a mouse model bearing the same paired αvβ6-expressing and αvβ6-null cell xenografts. A first-in-human PET/CT imaging study was performed in patients with metastatic lung, colon, breast or pancreatic cancer. Results: [18F]αvβ6-BP displayed excellent affinity and selectivity for the integrin in vitro (IC50(αvβ6) = 1.2 nM vsIC50(αβ3) >10 μM) in addition to rapid target-specific cell binding and internalization (72.5±0.9% binding and 52.5±1.8% respectively). Favorable tumor affinity and selectivity were retained in the mouse model and excretion of unbound [18F]αvβ6-BP was rapid, primarily via the kidneys. In patients, [18F]αvβ6-BP was well tolerated without noticeable adverse side effects. PET images showed significant uptake of [18F]αvβ6-BP in both the primary lesion and metastases, including metastasis to brain, bone, liver and lung. Conclusions:The clinical impact of [18F]αvβ6-BP PET imaging demonstrated in this first-in-human study is immediate for a broad spectrum of malignancies.
https://ift.tt/2RFvLgV
Data Offers New Insights into AML [News in Brief]
Large dataset integrating genomic sequencing and drug response information available online.
https://ift.tt/2PdJrDo
EGFR cooperates with EGFRvIII to recruit macrophages in glioblastoma
Amplification of the EGFR gene and its truncation mutant EGFRvIII are hallmarks of glioblastoma. Although co-expression of EGFR and EGFRvIII confers a growth advantage, how EGFR and EGFRvIII influence the tumor microenvironment remains incompletely understood. Here we show that EGFR and EGFRvIII cooperate to induce macrophage infiltration via upregulation of the chemokine CCL2. EGFRvIII was significantly enriched in glioblastoma patient samples with high CCL2, and knockout of CCL2 in tumors co-expressing EGFR and EGFRvIII led to decreased infiltration of macrophages. KRAS was a critical signaling intermediate for EGFR and EGFRvIII-induced expression of CCL2. Our results illustrate how EGFR and EGFRvIII direct the microenvironment in glioblastoma.
https://ift.tt/2OsJCVZ
Assessment of tumor redox status through (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid positron emission tomography imaging of system xc- activity
The cell's endogenous antioxidant system is vital to maintenance of redox homeostasis. Despite its central role in normal and pathophysiology, no non-invasive tools exist to measure this system in patients. The cystine/glutamate antiporter system xc- maintains the balance between intracellular reactive oxygen species and antioxidant production through the provision of cystine, a key precursor in glutathione biosynthesis. Here we show that tumor cell retention of a system xc--specific positron emission tomography radiotracer, (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG), decreases in proportion to levels of oxidative stress following treatment with a range of redox-active compounds. The decrease in [18F]FSPG retention correlated with a depletion of intracellular cystine resulting from increased de novo glutathione biosynthesis, shown through [U-13C6, U-15N2]cystine isotopic tracing. In vivo, treatment with the chemotherapeutic doxorubicin decreased [18F]FSPG tumor uptake in a mouse model of ovarian cancer, coinciding with markers of oxidative stress but preceding tumor shrinkage and decreased glucose utilization. Having already been used in pilot clinical trials, [18F]FSPG PET could be rapidly translated to the clinic as an early redox indicator of tumor response to treatment.
https://ift.tt/2Drli5U
Inhibition of thioredoxin/thioredoxin reductase induces synthetic lethality in lung cancers with compromised glutathione homeostasis
Glutathione (GSH)/GSH reductase (GSR) and thioredoxin/thioredoxin reductase (TXNRD) are two major compensating thiol-dependent antioxidant pathways that maintain protein dithiol/disulfide balance. We hypothesized that functional deficiency in one of these systems would render cells dependent on compensation by the other system for survival, providing a mechanism-based synthetic lethality approach for treatment of cancers. The human GSR gene is located on chromosome 8p12, a region frequently lost in human cancers. GSR deletion was detected in about 6% of lung adenocarcinomas in The Cancer Genome Atlas database. To test whether loss of GSR sensitizes cancer cells to TXNRD inhibition, we knocked out or knocked down the GSR gene in human lung cancer cells and evaluated their response to the TXNRD inhibitor auranofin. GSR deficiency sensitized lung cancer cells to this agent. Analysis of a panel of 129 NSCLC cell lines revealed that auranofin sensitivity correlated with the expression levels of the GSR, glutamate-cysteine ligase catalytic subunit (GCLC), and NAD(P)H quinone dehydrogenase 1 (NQO1) genes. In NSCLC patient-derived xenografts with reduced expression of GSR and/or GCLC, growth was significantly suppressed by treatment with auranofin. Together these results provide a proof of concept that cancers with compromised expression of enzymes required for GSH homeostasis or with chromosome 8p deletions that include the GSR gene may be targeted by a synthetic lethality strategy with inhibitors of TXNRD.
https://ift.tt/2OuX5wC
M2 macrophage-derived exosomes promote cell migration and invasion in colon cancer
Clinical and experimental evidence has shown that tumor-associated macrophages promote cancer initiation and progression. However, the macrophage-derived molecular determinants that regulate colorectal cancer (CRC) metastasis have not been fully characterized. Here we demonstrate that M2 macrophage-regulated CRC cells migration and invasion is dependent upon M2 macrophage-derived exosomes (MDE). MDE displayed a high expression level of miR-21-5p and miR-155-5p, and MDE-mediated CRC cells migration and invasion depended on these two miRNAs. Mechanistically, miR-21-5p and miR-155-5p were transferred to CRC cells by MDE and bound to the BRG1 coding sequence, downregulating expression of BRG1, which has been identified as a key factor promoting CRC metastasis, yet is downregulated in metastatic CRC cells. Collectively, these findings show that M2 macrophages induce CRC cells migration and invasion and provide significant plasticity of BRG1 expression in response to tumor microenvironments during malignant progression. This dynamic and reciprocal cross-talk between CRC cells and M2 macrophages provides a new opportunity for the treatment of metastatic CRC.
https://ift.tt/2DpqneR
Antifibrotic therapy disrupts stromal barriers and modulates the immune landscape in pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDA) remains one of the deadliest forms of cancer, in part, because it is largely refractory to current therapies. The failure of most standard therapies in PDA, as well as promising immune therapies, may be largely ascribed to highly unique and protective stromal microenvironments that present significant biophysical barriers to effective drug delivery, that are immunosuppressive, and that can limit the distribution and function of anti-tumor immune cells. Here, we utilized stromal re-engineering to disrupt these barriers and move the stroma toward normalization using a potent antifibrotic agent, halofuginone. In an autochthonous genetically engineered mouse model of PDA, halofuginone disrupted physical barriers to effective drug distribution by decreasing fibroblast activation and reducing key extracellular matrix elements that drive stromal resistance. Concomitantly, halofuginone treatment altered the immune landscape in PDA, with greater immune infiltrate into regions of low hylauronan, which resulted in increased number and distribution of both classically activated inflammatory macrophages and cytotoxic T cells. In concert with a direct effect on carcinoma cells, this led to widespread intratumoral necrosis and reduced tumor volume. These data point to the multifunctional and critical role of the stroma in tumor protection and survival and demonstrate how compromising tumor integrity to move toward a more normal physiologic state through stroma-targeting therapy will likely be an instrumental component in treating PDA.
https://ift.tt/2OvMBNh
Mammary precancerous stem and non-stem cells evolve into cancers of distinct subtypes
There are distinct cell subpopulations in normal epithelial tissue, including stem cells, progenitor cells, and more differentiated cells, all of which have been extensively studied for their susceptibility to tumorigenesis. However, normal cells usually have to progress through a precancerous lesion state before becoming a full-blown tumor. Precancerous early lesions are heterogeneous, and the cell subset that is the primary source of the eventual tumor remains largely unknown. By using mouse models that are tailored to address this question, we identified a keratin 6a-expressing precancerous stem cell (PcSC) subset and a more differentiated whey acidic protein-positive (WAP+) cell subset in mammary precancerous lesions initiated by the Wnt1 oncogene. Both cell subsets rapidly progressed to cancer upon introduction of constitutively active versions of either HRAS or BRAF. However, the resulting tumors were dramatically different in protein profiles and histopathology: keratin 6a+ precancerous cells gave rise to adenocarcinoma while WAP+ cells yielded metaplastic carcinoma with severe squamous differentiation and more robust activation of MEK/ERK signaling. Therefore, both stem and non-stem cells in mammary precancerous lesions can contribute to the eventual cancers, but their differentiation status determines the resulting cancer phenotype. This work identifies a previously unknown player in cancer heterogeneity and suggests that cancer prevention should target precancerous cells broadly and not be limited to PcSC.
https://ift.tt/2DpqlDL
CDC Director Says Congo Ebola Outbreak May Be Uncontainable
TUESDAY, Nov. 6, 2018 -- It may not be possible to bring the Ebola outbreak in Congo under control, and the deadly disease may become entrenched in the northeastern part of the country, U.S. Centers for Disease Control and Prevention Director Robert...
https://ift.tt/2Pfl6wZ
Over Two Million People Living With Hep C From 2013 to 2016
TUESDAY, Nov. 6, 2018 -- During 2013 to 2016, more than two million people in the United States had current hepatitis C virus (HCV) infection, according to a study published online Nov. 6 in Hepatology. Megan G. Hofmeister, M.D., M.P.H., from the...
https://ift.tt/2zvREbf
Medicaid Expansion Tied to Better Kidney Disease Survival
TUESDAY, Nov. 6, 2018 -- There were significant improvements in one-year survival among patients with end-stage renal disease (ESRD) initiating dialysis following Medicaid expansion with the Affordable Care Act, according to a study published online...
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CDC: Cases of Polio-Like Illness Still Increasing in the U.S.
TUESDAY, Nov. 6, 2018 -- Cases of a polio-like condition that mainly affects children continue to rise this year in the United States, health officials say. There have been 219 possible cases of acute flaccid myelitis (AFM) reported in 25 states,...
https://ift.tt/2zvIb3G.
Inhaled Nitrite Does Not Improve Exercise Capacity in HFpEF
TUESDAY, Nov. 6, 2018 -- Administration of inhaled nitrite is not associated with improvement in exercise capacity compared with placebo among patients with heart failure with preserved ejection fraction (HFpEF), according to a study published in...
https://ift.tt/2Pi3Y9R
Temporal and geographic patterns of stab injuries in young people: a retrospective cohort study from a UK major trauma centre
Objectives
To describe the epidemiology of assaults resulting in stab injuries among young people. We hypothesised that there are specific patterns and risk factors for injury in different age groups.
DesignEleven-year retrospective cohort study.
SettingUrban major trauma centre in the UK.
Participants1824 patients under the age of 25 years presenting to hospital after a stab injury resulting from assault.
OutcomesIncident timings and locations were obtained from ambulance service records and triangulated with prospectively collected demographic and injury characteristics recorded in our hospital trauma registry. We used geospatial mapping of individual incidents to investigate the relationships between demographic characteristics and incident timing and location.
ResultsThe majority of stabbings occurred in males from deprived communities, with a sharp increase in incidence between the ages of 14 and 18 years. With increasing age, injuries occurred progressively later in the day (r2=0.66, p<0.01) and were less frequent within 5 km of home (r2=0.59, p<0.01). Among children (age <16), a significant peak in injuries occurred between 16:00 and 18:00 hours, accounting for 22% (38/172) of injuries in this group compared with 11% (182/1652) of injuries in young adults. In children, stabbings occurred earlier on school days (hours from 08:00: 11.1 vs non-school day 13.7, p<0.01) and a greater proportion were within 5 km of home (90% vs non-school day 74%, p=0.02). Mapping individual incidents demonstrated that the spike in frequency in the late afternoon and early evening was attributable to incidents occurring on school days and close to home.
ConclusionsAge, gender and deprivation status are potent influences on the risk of violent injury in young people. Stab injuries occur in characteristic temporal and geographical patterns according to age group, with the immediate after-school period associated with a spike in incident frequency in children. This represents an opportunity for targeted prevention strategies in this population.
https://ift.tt/2PdoqbL
C-Reactive Protein Levels at the Midpregnancy Can Predict Gestational Complications
Although essential for a successful pregnancy, a growing body of evidence suggests that maternal inflammation, when dysregulated, may represent a risk factor for both maternal and neonatal outcomes. Here, we assessed the accuracy of maternal C-reactive protein (CRP) concentrations at the middle phase of pregnancy in the identification of maternal adverse outcomes (MAO) until delivery. A correlation between CRP and a complicated pregnancy including both maternal and neonatal adverse outcomes has been investigated, too. In this retrospective study, conducted at the Diabetology Unit of IRCCS Ospedale Policlinico San Martino, Genoa (Italy), 380 outpatient pregnant women have been enrolled at the prenatal visit before performing a 75 g oral glucose tolerance test at 24th-26th gestational week for gestational diabetes mellitus (GDM) screening. Demographic, medical, and reproductive history has been obtained by verbal interview. Data about pregnancy and delivery have been retrieved from medical records. The median value of maternal baseline serum CRP was 3.25 μg/mL. Women experiencing MAO were older, more frequently suffering from hypertension, and showed higher CRP concentrations, with a cutoff value >1.86 μg/mL found by a ROC curve analysis to be accurately predictive for MAO. By a logistic regression analysis, serum CRP levels >1.86 μg/mL have been found to predict MAO also considering maternal age, hypertension, and GDM. Maternal CRP levels have been positively associated with overall pregnancy adverse outcomes (maternal and neonatal), too. In conclusion, in pregnant women serum levels of CRP can early recognize subjects at higher risk for maternal and neonatal complications needing a more stringent follow-up.
https://ift.tt/2Qquc6C
Biochemical Activity and Hypoglycemic Effects of Rumex obtusifolius L. Seeds Used in Armenian Traditional Medicine
Diabetes mellitus (DM) is a serious chronic metabolic disorder. Various diseases are being treated with medicinal plants and that is because of the less side effects of the current therapy. The diversity of plants in Armenia is due to the singularity of natural environment. However, biochemical activity of these plants has not been studied well. Thus, the goal was to investigate biochemical activity and antihyperglycemic properties of Rumex obtusifolius L. in rabbits with hyperglycemia. The high content of total phenolic compounds, flavonoids, and tannins has been determined in this plant extract. Oral administration of ethanol extract showed significant effect on hyperglycemia, reducing fasting glucose levels (57.3%, p
https://ift.tt/2Dset45
Contrast-Enhanced Ultrasound to Monitor Early Recurrence of Primary Hepatocellular Carcinoma after Curative Treatment
Objective. To evaluate contrast-enhanced ultrasound (CEUS) for monitoring early intrahepatic recurrence of primary hepatocellular carcinoma (HCC) after curative treatment. Methods. We prospectively analyzed 97 patients (124 nodules) with primary HCC who underwent hepatic resection or radiofrequency ablation and subsequently experienced intrahepatic recurrence. Patients were assessed with conventional ultrasound and CEUS. They were also assessed with contrast-enhanced computed tomography (CECT) and/or magnetic resonance imaging (MRI). The image characteristics of CEUS of recurrent hepatocellular carcinoma and high-grade dysplastic nodules (HGDNs) were analyzed. In addition, the ability of CEUS and CECT/MRI to assess internal artery vascularization in recurrent disease was compared. Results. CEUS of recurrent hepatocellular carcinoma showed hyperenhancement in the arterial phase in 96 of 99 nodules, and it showed hypo- or isoenhancement for portal venous and delayed phases. The most common enhancement patterns were "fast-in and slow-out" and "fast-in and fast-out". Based on the arterial hyperenhancement of lesions and with clinical data such as patient history of HCC and increased level of serum alpha-fetoprotein, the diagnostic accuracy of CEUS for recurrent HCC was significantly higher than that based on the enhancement pattern of "fast-in and fast-out". CEUS of HGDNs showed local or global hyperenhancement during the arterial phase, isoenhancement during the portal venous phase, and isoenhancement or slight hypoenhancement during the delayed phase. The enhancement pattern was "fast-in and slow-out". In some cases, it was difficult to differentiate HGDNs from recurrent disease using CEUS. Vascularization in recurrent disease was significantly higher when assessed by CEUS than when assessed with CECT/MRI (P
https://ift.tt/2Qqu6Mi
Front cover story: Eur. J. Immunol. 11'18
Our front cover features a Masson staining of lung sections from ovalbumin (OVA)‐induced asthmatic wild type mouse. Allergic airway inflammation is apparent with collagen fibrils deposition around the airways where immune cells, mainly eosinophils, accumulate and where airway epithelial cells had an abnormal morphology showing little or single thick epithelial microvilli. The image was a part of research article by Jiajia et al. (pp. 1838–1850), where the authors discovered an asthmatic pathogenesis in a murine model that is mediated by the TLR2‐TSLP signaling axis.
https://ift.tt/2QqtZAm
Back cover story: Eur. J. Immunol. 11'18
Our back cover features H&E staining of a section from a mouse eye with experimental autoimmune uveitis (EAU), induced by immunization with IRBP, a retinal‐specific antigen. The image shows a portion of the retina, adjacent to the optic nerve head, with changes typical for EAU, namely, retinal folding, loss of photoreceptor cells and intense infiltration of inflammatory cells. The image is taken from Lyu et al. (pp. 1810–1816), where the authors show that treatment with the compound TMP778 inhibited the development of EAU. TMP778 is a specific inhibitor of RORγt, the transcription factor for IL‐17, but unexpectedly, the treatment inhibited the production of both IL‐17 and IFN‐γ.
https://ift.tt/2DtXuye
Safranal protects against beta-amyloid peptide-induced cell toxicity in PC12 cells via MAPK and PI3 K pathways
Abstract
Alzheimer's disease is a type of cerebrovascular problem with progressive mental disabilities for the patient. This study aimed to investigate the protective effect of safranal on toxicity and oxidative damage induced by beta-amyloid (Aβ) and hydrogen peroxide (H2O2) in PC12 cells as an appropriate model of Alzheimer's cell damage. PC12 cells pretreated with saffron extract (2.5–40 μg/ml), essential oil (2.5–40 μg/ml), safranal (2.5–5-40 μM) and donepezil (5, 10 and 20 μM) for 120 min. Then exposed to either Aβ (25 μM) for 48 h or H2O2 (150 μM) for 24 h. In the end, the cell survival and intracellular reactive oxygen species (ROS) production analyzed. The anti-apoptotic effects of safranal in PC12 cells were studied using flow cytometry after PI staining. Also, western blot analysis of Cyt c, survivin, p44/42 MAPK (ERK1/2), Phospho-p44/42 MAPK (ERK1/2), PI3 Kinase P85, Phospho-PI3 Kinase P85, phospho SAPK/JNK, SAPK/JNK and caspase 3 performed for detection of apoptosis. Safranal (2.5 and 5 μM) and donepezil (10 and 20 μM) significantly decreased the Aβ toxicity. The ROS significantly attenuated when cells pretreated with essential oil, saffron extract, safranal, and donepezil. Cell apoptosis significantly increased after treatment with Aβ (25–35) (25 μM) compared to control. However, after pretreatment with safranal (2.5 μM) apoptosis was significantly reduced. Western blot analysis of PC12 cells showed that 25 μM Aβ (25–35) could increase proteins involved in apoptosis signaling and pretreatment with safranal (2.5 μM) could decrease the apoptosis. According to the results, safranal showed anti-apoptotic and antioxidant effects and may exert promising potential for the prevention of Alzheimer's disease.
https://ift.tt/2PfGMJ5
Estimating Prevalence of Hepatitis C Virus Infection in the United States, 2013‐2016
Hepatitis C virus (HCV) infection is the most commonly reported bloodborne infection in the United States, causing substantial morbidity and mortality and costing billions of dollars annually. To update the estimated HCV prevalence among all adults aged ≥18 years in the United States, we analyzed 2013‐2016 data from the National Health and Nutrition Examination Survey (NHANES) to estimate the prevalence of HCV in the noninstitutionalized civilian population and used a combination of literature reviews and population size estimation approaches to estimate the HCV prevalence and population sizes for four additional populations: incarcerated people, unsheltered homeless people, active‐duty military personnel, and nursing home residents. We estimated that during 2013‐2016 1.7% (95% confidence interval [CI], 1.4‐2.0%) of all adults in the United States, approximately 4.1 (3.4‐4.9) million persons, were HCV antibody‐positive (indicating past or current infection) and that 1.0% (95% CI, 0.8‐1.1%) of all adults, approximately 2.4 (2.0‐2.8) million persons, were HCV RNA–positive (indicating current infection). This includes 3.7 million noninstitutionalized civilian adults in the United States with HCV antibodies and 2.1 million with HCV RNA and an estimated 0.38 million HCV antibody‐positive persons and 0.25 million HCV RNA–positive persons not part of the 2013‐2016 NHANES sampling frame. Conclusion: Over 2 million people in the United States had current HCV infection during 2013‐2016; compared to past estimates based on similar methodology, HCV antibody prevalence may have increased, while RNA prevalence may have decreased, likely reflecting the combination of the opioid crisis, curative treatment for HCV infection, and mortality among the HCV‐infected population; efforts on multiple fronts are needed to combat the evolving HCV epidemic, including increasing capacity for and access to HCV testing, linkage to care, and cure.
https://ift.tt/2zx5HgQ
Dual Polymerizations: Untapped Potential for Biomaterials
Application of block copolymers in medicine often relies on controlling polymer behavior by varying polymer side chains to add functionality and tune hydrophobicity. Changing the polymer backbone is an emerging powerful strategy to modulate polymer self‐assembly, rigidity, reactivity, and biodegradability. Herein, dual polymerization strategies for the synthesis of backbone‐segmented block copolymers for biomedical applications are highlighted.
Abstract
Block copolymers with unique architectures and those that can self‐assemble into supramolecular structures are used in medicine as biomaterial scaffolds and delivery vehicles for cells, therapeutics, and imaging agents. To date, much of the work relies on controlling polymer behavior by varying the monomer side chains to add functionality and tune hydrophobicity. Although varying the side chains is an efficient strategy to control polymer behavior, changing the polymer backbone can also be a powerful approach to modulate polymer self‐assembly, rigidity, reactivity, and biodegradability for biomedical applications. There are many developments in the syntheses of polymers with segmented backbones, but these developments are not widely adopted as strategies to address the unique constraints and requirements of polymers for biomedical applications. This review highlights dual polymerization strategies for the synthesis of backbone‐segmented block copolymers to facilitate their adoption for biomedical applications.
https://ift.tt/2EDoVa8
Surfactant Free Delivery of Docetaxel by Poly[(R)‐3‐hydroxybutyrate‐(R)‐3‐hydroxyhexanoate]‐Based Polymeric Micelles for Effective Melanoma Treatments
![Advanced Healthcare Materials Surfactant Free Delivery of Docetaxel by Poly[(R)‐3‐hydroxybutyrate‐(R)‐3‐hydroxyhexanoate]‐Based Polymeric Micelles for Effective Melanoma Treatments](https://onlinelibrary.wiley.com/cms/attachment/1dd511d5-b1d9-4bd3-af45-3f030d97b825/adhm201801221-gra-0001-m.png)
Poly(PHBHx/PEG/PPG polyurethane) containing flexible and biodegradable PHBHx segments are designed to encapsulate docetaxel (DTX) in a nanosized micelle formulation, instead of with surfactants with undesired hemolysis or hypersensitivity effects. This drug‐loaded polymeric micelle formulation exhibits high drug‐loading efficiency, significantly reduced hemolysis, and effective drug intake in solid tumors, indicating the possibility of chemotherapeutic systematic delivery for better patient compliance.
Abstract
Docetaxel (DTX) is a new semisynthetic chemical in the taxoid family and serves a wide spectrum of chemotherapeutics. Current commercial formulation of DTX is based on the addition of the nonionic surfactants (i.e., ethanol and Tween 80), which are reported to cause severe hemolysis, hypersensitivity reactions, or neurotoxic toxicity and greatly hinders patient tolerance or compliance. In this report, a novel low‐toxic, biodegradable, and amphiphilic poly[(R)‐3‐hydroxybutyrate‐(R)‐3‐hydroxyhexanoate] (PHBHx)‐based polyurethane (a copolymer made of hydrophobic PHBHx with biocompatible D‐3‐hydroxybutyric acid as degradation product, thermosensitive polypropylene glycol (PPG), and hydrophilic polyethylene glycol (PEG) segments) with nanosized micelle formation ability to encapsulate DTX, as a surfactant free formulation, is reported. Interestingly, this DTX‐loaded poly(PHBHx/PEG/PPG urethane) micelle formulation with >90% drug loading efficiency shows significantly improved DTX solubility in aqueous medium, reduced hemolysis for better blood compatibility, and increased drug uptake in A375 melanoma cells, which provides the possibility of systematic delivery of DTX. As a proof‐of‐concept, an A375 melanoma xenograft mouse model is established to verify the therapeutic effect of this DTX‐loaded poly(PHBHx/PEG/PPG urethane) micelle formulation, indicating the promising application of PHBHx‐based polymeric nanosized micelle as a surfactant free formulation of chemotherapeutics which might greatly be beneficial for controllable delivery of pharmaceutics and cancer therapy.
https://ift.tt/2qvwBkU
Highly Efficient In Vivo Targeting of the Pulmonary Endothelium Using Novel Modifications of Polyethylenimine: An Importance of Charge
Polymer nanoparticles possess potent flexibility and customizability for tailored gene delivery. Size and charge tailoring of nanoparticles allows for specific targeting of the microvasculature within the lung with exceptionally high efficiency by fluorescent‐activated cell sorting quantification. Charge switching from a positive to a negative surface potential eliminates targeting. These principles allow for efficient delivery of stabilized messenger ribonucleic acid (mRNA) for potential therapeutic application.
Abstract
Pulmonary vascular disease encompasses a wide range of serious afflictions with important clinical implications. There is critical need for the development of efficient, nonviral gene therapy delivery systems. Here, a promising avenue to overcome critical issues in efficient cell targeting within the lung via a uniquely designed nanosystem is reported. Polyplexes are created by functionalizing hyperbranched polyethylenimine (PEI) with biological fatty acids and carboxylate‐terminated poly(ethylene glycol) (PEG) through a one‐pot 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide hydrochloride/N‐hydroxysuccinimide reaction. Following intravenous injection, polyplexes show an exceptionally high specificity to the pulmonary microvascular endothelium, allowing for the successful delivery of stabilized enhanced green fluorescent protein (eGFP) expressing messenger ribonucleic acid (mRNA). It is further shown, quantitatively, that positive surface charge is the main mechanism behind such high targeting efficiency for these polyplexes. Live in vivo imaging, flow cytometry of single cell suspensions, and confocal microscopy are used to demonstrate that positive polyplexes are enriched in the lung tissue and disseminated in 85–90% of the alveolar capillary endothelium, whilst being sparse in large vessels. Charge modification, achieved through poly(acrylic acid) or heparin coating, drives a highly significant reduction in both targeting percentage and targeting strength, highlighting the importance of specific surface charge, derived from chemical formulation, for efficient targeting of the pulmonary microvascular endothelium.
https://ift.tt/2QoNrgC
Silk Fibroin Microparticles with Hollow Mesoporous Silica Nanocarriers Encapsulation for Abdominal Wall Repair
Silk fibroin microparticles with hollow mesoporous silica nanocarrier encapsulation are generated by drying microfluidic emulsions. The composite microparticles have a distinctive micro‐nanostructure, and provide two barriers for controlling the drug release. After being sprayed onto a scaffold and implanted into a rat, the particles exhibit their potential value in abdominal wall repairing.
Abstract
Therapeutic vascularization appears to be an effective way of repairing abdominal wall defects. Attempts to implement this treatment tend to focus on the generation of featured drug carriers with the ability effectively to encapsulate the angiogenesis‐stimulating agents and control their release to maintain an appropriate concentration at the injured area. Here, a new type of composite microparticle (CM) composed of silk fibroin (SF) and hollow mesoporous silica nanocarriers (HMSNs) is presented for therapeutic agent delivery. The CMs are generated by drying microfluidic emulsion templates of HMSN‐dispersed SF solution. The resultant CMs have a distinctive micro‐nanostructure, in which two barriers control the drug release. The encapsulated HMSNs increase the drug‐carrying capacity of the CMs, and also form the first barrier via physical absorption. The microfluidic SF microparticles not only provide a shell with excellent monodispersity and biocompatibility but also form the second barrier via efficient encapsulation. Because of these superior properties of the CMs, the loaded drugs can be delivered with a satisfactory activity at the required rate, making them ideal for implementing therapeutic vascularization and repairing abdominal wall defects.
https://ift.tt/2CzarXb
Materials Science and Design Principles of Growth Factor Delivery Systems in Tissue Engineering and Regenerative Medicine
Growth factor delivery is emerging as a potential alternative for healing severely injured complex tissues. Engineering delivery system with increased payloads and tunable release kinetics remains challenging in the realm of translational research. This review discusses the complexities behind growth factors and biomaterials to advance the development of modern delivery systems to meet the current challenges for effective tissue repair.
Abstract
Growth factors (GFs) are signaling molecules that direct cell development by providing biochemical cues for stem cell proliferation, migration, and differentiation. GFs play a key role in tissue regeneration, but one major limitation of GF‐based therapies is dosage‐related adverse effects. Additionally, the clinical applications and efficacy of GFs are significantly affected by the efficiency of delivery systems and other pharmacokinetic factors. Hence, it is crucial to design delivery systems that provide optimal activity, stability, and tunable delivery for GFs. Understanding the physicochemical properties of the GFs and the biomaterials utilized for the development of biomimetic GF delivery systems is critical for GF‐based regeneration. Many different delivery systems have been developed to achieve tunable delivery kinetics for single or multiple GFs. The identification of ideal biomaterials with tunable properties for spatiotemporal delivery of GFs is still challenging. This review characterizes the types, properties, and functions of GFs, the materials science of widely used biomaterials, and various GF loading strategies to comprehensively summarize the current delivery systems for tunable spatiotemporal delivery of GFs aimed for tissue regeneration applications. This review concludes by discussing fundamental design principles for GF delivery vehicles based on the interactive physicochemical properties of the proteins and biomaterials.
https://ift.tt/2QtpmFL
Near‐Infrared‐Triggered Release of Ca2+ Ions for Potential Application in Combination Cancer Therapy
A nanosystem based upon gold nanocages and phase‐change materials is developed for controlling the intracellular release of Ca2+ ions through NIR laser irradiation. This new system can serve as an alternative to the traditional chemotherapeutics for cancer therapy with potentially reduced adverse impacts and side effects.
Abstract
Calcium ion (Ca2+), an abundant species in the body, is a potential therapeutic ion with manageable side effects. However, the delivery of such a highly charged species represents a great challenge. Here, a nanosystem based on Au nanocages (AuNCs) and a phase‐change material (PCM) for delivering calcium chloride (CaCl2) into cancer cells and thereby triggering cell death upon near‐infrared (NIR) irradiation is demonstrated. In the absence of NIR irradiation, the nanosystem, denoted CaCl2‐PCM‐AuNC, shows negligible cytotoxicity because the Ca2+ ions are fully encapsulated in a solid matrix. Upon NIR irradiation, the Ca2+ ions are swiftly released due to the melting of PCM matrix in response to photothermal heating. The sudden increase in intracellular Ca2+ causes disruption to the mitochondrial Ca2+ homeostasis and thus the loss of mitochondrial membrane potential, subsequently resulting in cell apoptosis. This nanosystem provides a new method for cancer treatment by tightly managing the intracellular concentration of a physiologically essential element.
https://ift.tt/2AMMfhP
Decoy Oligodeoxynucleotides, Polysaccharides, and Targeted Peptide‐Functionalized Gold Nanorods for the Combined Treatment of Rheumatoid Arthritis
Herein, gold nanorods (GNRs) serve as nanocarriers for anti‐inflammatory dODN, antirheumatic drugs, as well as agents for thermotherapy. Targeted peptides and hydrophilic polysialic acid are modified to GNRs to increase targeting to inflammatory tissues and prolong in vivo circulation. GNRs‐dODN‐PSA‐PVCAM‐1 simultaneously inhibits NF‐κB pathway, absorbs inflammatory proteins, and conducts thermotherapy, which achieves a higher reduction of inflammation.
Abstract
Autoimmune diseases like rheumatoid arthritis (RA) possess complicated pathogenesis. Therefore, RA is hard to treat by monotherapies in clinical setting. All‐in‐one treatments that target inflamed joints and act efficiently are highly needed. Gold compounds are old anti‐RA therapies and are fabricated into gold nanorods (GNRs) that serve as anti‐RA therapeutics as well as nanocarriers for anti‐inflammatory nucleic acid drug‐NF‐κB‐decoy oligodeoxynucleotides (dODNs). A targeted peptide to vascular cell adhesion molecule‐1 (VCAM‐1) (PVCAM‐1) is modified onto the GNRs to facilitate enhanced accumulation of GNRs in inflamed tissues and enhanced cellular uptake of GNRs by inflamed cells. dODNs loaded and PVCAM‐1 modified GNRs (GNRs‐dODN‐PVCAM‐1) are covered by polysialic acid (PSA) to protect GNRs‐dODN‐PVCAM‐1 in vivo. Simultaneous GNRs, dODN, and thermotherapy show synergic effect on the reduction of TNF‐α and IL‐6 in inflamed macrophages and blood vessel cells. The simultaneous triple therapy (GNRs‐dODN‐PSA‐PVCAM‐1+laser) demonstrates excellent anti‐inflammatory efficacy in vitro and in vivo.
https://ift.tt/2F4ZOxn
A Bioprinted Cardiac Patch Composed of Cardiac‐Specific Extracellular Matrix and Progenitor Cells for Heart Repair
Therapies such as injectable human cardiac progenitor cells (hCPCs) and cardiac extracellular matrix (cECM) have shown improvements in treating damaged myocardium, but are limited by poor retention and functionality. Herein, cardiac patches composed of both hCPCs and cECM are created through 3D bioprinting and allow for the release of proregenerative paracrine factors toward the damaged myocardium for pediatric patients.
Abstract
Congenital heart defects are present in 8 of 1000 newborns and palliative surgical therapy has increased survival. Despite improved outcomes, many children develop reduced cardiac function and heart failure requiring transplantation. Human cardiac progenitor cell (hCPC) therapy has potential to repair the pediatric myocardium through release of reparative factors, but therapy suffers from limited hCPC retention and functionality. Decellularized cardiac extracellular matrix hydrogel (cECM) improves heart function in animals, and human trials are ongoing. In the present study, a 3D‐bioprinted patch containing cECM for delivery of pediatric hCPCs is developed. Cardiac patches are printed with bioinks composed of cECM, hCPCs, and gelatin methacrylate (GelMA). GelMA‐cECM bioinks print uniformly with a homogeneous distribution of cECM and hCPCs. hCPCs maintain >75% viability and incorporation of cECM within patches results in a 30‐fold increase in cardiogenic gene expression of hCPCs compared to hCPCs grown in pure GelMA patches. Conditioned media from GelMA‐cECM patches show increased angiogenic potential (>2‐fold) over GelMA alone, as seen by improved endothelial cell tube formation. Finally, patches are retained on rat hearts and show vascularization over 14 d in vivo. This work shows the successful bioprinting and implementation of cECM‐hCPC patches for potential use in repairing damaged myocardium.
https://ift.tt/2PAQxko
Reconstructing the Human Renal Vascular–Tubular Unit In Vitro
Reliable preclinical models of kidney function are needed for pharmaceutical screening and disease modeling. Herein, a vascular network and tubular pattern are created in perivascular cell containing collagen, opposed across a thin collagen membrane, and lined with kidney endothelial and epithelial cells. This human renal vascular–tubular unit recapitulates basic renal structure and function, showing promise as a next‐generation kidney‐on‐a‐chip platform.
Abstract
Engineered human kidney‐on‐a‐chip platforms show tremendous promise for disease modeling and drug screening. Outstanding challenges exist, however, in reconstructing the complex architecture, cellular make‐up, and matrix composition necessary for the proper modeling of kidney function. Herein, the first fully tunable human kidney‐on‐a‐chip platform is reported that allows the reconstruction of the native architecture of the renal endothelial–epithelial exchange interface using entirely cell‐remodelable matrix and patient‐derived kidney cells. This platform consists of a double‐layer human renal vascular–tubular unit (hRVTU) enabled by a thin collagen membrane that replicates the kidney exchange interface. It is shown that endothelial and epithelial cells lining their respective lumens remodel the membrane in culture into a ≈1 µm thick exchange interface composed of native basement membrane proteins. This interface displays sufficient mechanical integrity for media flow and blood perfusion. As a proof of principle, it is demonstrated that the hRVTU performs kidney‐specific functions including reabsorption of albumin and glucose from the epithelial channel. By incorporating multiple cell populations from single donors, it is demonstrated that the hRVTU may have utility for future precision medicine applications. The success of the system provides new opportunities for the next generation of organ‐on‐a‐chip models.
https://ift.tt/2RsZrxF
In Situ Forming Injectable Silk Fibroin Hydrogel Promotes Skin Regeneration in Full Thickness Burn Wounds
In situ forming hydrogels are developed using a natural silk fibroin biomaterial to aid wound repair and regeneration. The inherent self‐assembly property of two silk varieties allows tunable gelation and matrix formation at the wound site. The hydrogels provide a functional niche aiding skin regeneration, show transition from inflammation to proliferation stage, promote angiogenesis and accelerate healing of burn wounds.
Abstract
Full‐thickness skin wounds, associated with deep burns or chronic wounds pose a major clinical problem. Herein, the development of in situ forming hydrogel using a natural silk fibroin (SF) biomaterial for treating burn wounds is reported. Blends of SF solutions isolated from Bombyx mori and Antheraea assama show inherent self‐assembly between silk proteins and lead to irreversible gelation at body temperature. Investigation of the gelation mechanism reveals crosslinking due to formation of β‐sheet structures as examined by X‐ray diffraction and Fourier transform infrared spectroscopy. The SF hydrogel supports proliferation of primary human dermal fibroblasts and migration of keratinocytes comparable to collagen gel (Col) as examined under in vitro conditions. The SF hydrogel also provides an instructive and supportive matrix to the full‐thickness third‐degree burn wounds in vivo. A 3‐week comparative study with Col indicates that SF hydrogel not only promotes wound healing but also shows transitions from inflammation to proliferation stage as observed through the expression of TNF‐α and CD163 genes. Further, deposition and remodeling of collagen type I and III fibers suggests an enhanced overall tissue regeneration. Comparable results with Col demonstrate the SF hydrogel as an effective and inexpensive formulation toward a potential therapeutic approach for burn wound treatment.
https://ift.tt/2PAQtkE
Promoting Role of MXene Nanosheets in Biomedical Sciences: Therapeutic and Biosensing Innovations
MXene nanosheets are currently under investigation as a platform for various biomedical applications. Herein, an overview of requirements for the successful synthesis of MXenes is provided. Also the biological impacts of MXenes as well as their promoting role in drug delivery, cancer therapy, theranostics, and biosensing are highlighted.
Abstract
MXene nanosheets have emerged as biocompatible transition metal structures, which illustrate desirable performance for various applications due to their unique structural, physicochemical, and compositional features. MXenes are currently expanding their usage territory from mechanical, optical, chemical, and electronic fields toward biomedical areas. This is mainly originated from their large surface area and strong absorbance in near‐infrared region, which in combination with their facile surface functionalization with various polymers or nanoparticles, make them promising nanoplatforms for drug delivery, cancer therapy, precise biosensing and bioimaging. The facile surface modification of the MXenes can mediate the better in vivo performance of them through reduced toxicity, enhanced colloidal stability, and extended circulation within the body. Herein, the synthesis and state‐of‐the‐art progresses of MXene nanosheets designed for biomedical applications, including structural‐ and dose‐dependent antimicrobial activity, photothermal therapy, drug delivery, and implants are emphasized. Furthermore, biosensing applications are highlighted and a comprehensive discussion on photoacoustic imaging, magnetic resonance imaging, computed tomography imaging, and optical imaging of MXenes is presented. The challenges and future opportunities of applying MXene nanomaterials in the area of biomedicine are also discussed.
https://ift.tt/2z1ITFC
3D Cell Printing of Perfusable Vascularized Human Skin Equivalent Composed of Epidermis, Dermis, and Hypodermis for Better Structural Recapitulation of Native Skin
A key purpose for printing skin is to improve structural complexity of native skin over conventional construction, enabling the precise localization of multiple cell types and biomaterials. This article presents a novel printing platform for engineering a matured perfusable vascularized 3D human skin equivalent composed of epidermis, dermis, and hypodermis.
Abstract
Although skin cell‐printing has exhibited promises for fabrication of functional skin equivalents, existing skin models through 3D cell printing are still composed of dermal and epidermal layers. However, a key hope for printing skin is to improve structural complexity of human skin over conventional construction, enabling the precise localization of multiple cell types and biomaterials. Here, the complexity of skin anatomy is increased using 3D cell printing. A novel printing platform is suggested for engineering a matured perfusable vascularized 3D human skin equivalent composed of epidermis, dermis, and hypodermis. The skin model is evaluated using functional markers representing each region of epidermis, dermis, and hypodermis to confirm tissue maturation. It is hypothesized that the vascularized dermal and hypodermal compartments that provide a more realistic microenvironment can promote cross‐talks with the epidermal compartment, producing better recapitulation of epidermal morphogenesis. Skin stemness in epithelial tissue is investigated. These findings reveal that the full‐thickness skin has more similarities to the native human skin compared with the dermal and epidermal skin model, indicating that it better reflects the actual complexity of native human skin. It is envisioned that it offers better predictive and reliable in vitro platform for investigation of mechanisms of pathological research and skin disease modeling.
https://ift.tt/2OQkSMo
PEGylation Regulates Self‐Assembled Small‐Molecule Dye–Based Probes from Single Molecule to Nanoparticle Size for Multifunctional NIR‐II Bioimaging
Organic dye–based probes are highlighted in second near‐infrared (NIR‐II) imaging and how to precisely control the synthesized size of these NIR‐II probes is still challenging. This issue is addressed by regulating self‐assembled CH1055‐based probes from molecular to nanoparticle size by a PEGylation Strategy. The relationship between size and the chemical/physical properties is investigated, and their merits for multifunctional NIR‐II bioimaging are demonstrated.
Abstract
To date, small‐molecule dye–based probes have been at the forefront of research in biomedical imaging, especially in the second near‐infrared (NIR‐II) window (1.0–1.7 µm). However, how to precisely regulate the synthesized size of NIR‐II organic dye–based probes remains challenging. Moreover, systematic studies on whether the size of NIR‐II probes affects optical/pharmacokinetic properties are still rare. Here, an ingenious PEGylation strategy is developed to regulate the self‐assembly size of organic dye–based (CH1055 scaffold) NIR‐II probes (SCH1–SCH4) from nanoparticles to the single molecule, and the relationship between their size and chemical/physical properties is thoroughly investigated. Based on their own merits, nanoprobe SCH1 (≈170 nm), with outstanding fluorescent brightness (quantum yield ≈0.14%), performs accurate tracing of the lymphatic system as well as identification of vessel networks in mice brains with excellent signal‐to‐background ratio images. Meanwhile, rapidly excreted SCH4, showing fast and high passive liver tumor uptake and promising tumor/normal tissue ratios (>7), is capable of facilitating precise image‐guided tumor surgery, and also demonstrates the first example of the assessment of liver fibrosis in the NIR‐II window.
https://ift.tt/2D7Cb5o
Facile Engineering of Long‐Term Culturable Ex Vivo Vascularized Tissues Using Biologically Derived Matrices
Vascularized tissue constructs are produced from a variety of biological matrix substitutes via 3D printing of evacuable poly(vinyl alcohol) scaffolds. This technique generates perfusable constructs with complex vascular geometries. Experimental studies reveal that the constructs are capable of long‐term sustenance of tumor tissue ex‐vivo, and allow for production of hybrid gut‐like organoid systems containing both epithelial and endothelial cells.
Abstract
Recent advances in tissue engineering and 3D bioprinting have enabled construction of cell‐laden scaffolds containing perfusable vascular networks. Although these methods partially address the nutrient‐diffusion limitations present in engineered tissues, they are still restricted in both their viable vascular geometries and matrix material compatibility. To address this, tissue constructs are engineered via encapsulation of 3D printed, evacuable, free standing scaffolds of poly(vinyl alcohol) (PVA) in biologically derived matrices. The ease of printability and water‐soluble nature of PVA grant compatibility with biologically relevant matrix materials and allow for easily repeatable generation of complex vascular patterns. This study confirms the ability of this approach to produce perfusable vascularized matrices capable of sustaining both cocultures of multiple cell types and excised tumor fragments ex vivo over multiple weeks. The study further demonstrates the ability of the approach to produce hybrid patterns allowing for coculture of vasculature and epithelial cell‐lined lumens in close proximity, thereby enabling ex vivo recapitulation of gut‐like systems. Taken together, the methodology is versatile, broadly applicable, and importantly, simple to use, enabling ready applicability in many research settings. It is believed that this technique has the potential to significantly accelerate progress in engineering and study of ex vivo organotypic tissue constructs.
https://ift.tt/2Se8kg4
Monolithic and Scalable Au Nanorod Substrates Improve PEDOT–Metal Adhesion and Stability in Neural Electrodes
A monolithic and scalable method is demonstrated for the fabrication of poly(3,4‐ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) on Au nanorod (Au‐nr) substrates, with superior mechanical and electrochemical stabilities. The reported technique to improve PEDOT:PSS electrode stability, using an Au‐nr adhesion layer, can benefit conductive polymer (CP)–based neural interfaces for chronic implants or neural stimulation applications where the long‐term stability of the CP film is critical.
Abstract
Poly(3,4‐ethylenenedioxythiophene) or PEDOT is a promising candidate for next‐generation neuronal electrode materials but its weak adhesion to underlying metallic conductors impedes its potential. An effective method of mechanically anchoring the PEDOT within an Au nanorod (Au‐nr) structure is reported and it is demonstrated that it provides enhanced adhesion and overall PEDOT layer stability. Cyclic voltammetry (CV) stress is used to investigate adhesion and stability of spin‐cast and electrodeposited PEDOT. The Au‐nr adhesion layer permits 10 000 CV cycles of coated PEDOT film in phosphate buffered saline solution without delamination nor significant change of the electrochemical impedance, whereas PEDOT coating film on planar Au electrodes delaminates at or below 1000 cycles. Under CV stress, spin‐cast PEDOT on planar Au delaminates, whereas electroplated PEDOT on planar Au encounters surface leaching/decomposition. After 5 weeks of accelerated aging tests at 60 °C, the electrodeposited PEDOT/Au‐nr microelectrodes demonstrate a 92% channel survival compared to only 25% survival for spin‐cast PEDOT on planar films. Furthermore, after a 10 week chronic implantation onto mouse barrel cortex, PEDOT/Au‐nr microelectrodes do not exhibit delamination nor morphological changes, whereas the conventional PEDOT microelectrodes either partially or fully delaminate. Immunohistochemical evaluation demonstrates no or minimal response to the PEDOT implant.
https://ift.tt/2ApzM3f
Bioimaging of Intact Polycaprolactone Nanoparticles Using Aggregation‐Caused Quenching Probes: Size‐Dependent Translocation via Oral Delivery
A platform technique for the bioimaging of intact polymeric nanoparticles is presented. Solid evidence is provided to support the size‐dependent translocation of polymeric nanoparticles. Intact nanoparticles of 50 and 200 nm can be absorbed across the intestinal epithelia and accumulated in the liver. Enterocytes and M cells mediated transcytosis are involved in the process.
Abstract
The limited information on biological fate impedes the development of more efficient polymeric nanoparticles for oral delivery of bio‐macromolecules. In this study, the in vivo fate as well as the trans‐epithelia transport of polycaprolactone (PCL) nanoparticles is explored by labeling with aggregation‐caused quenching probes, which is capable of identifying intact nanoparticles. Live imaging and confocal laser scan microscopy confirm size‐dependent absorption of PCL nanoparticles. In general, reducing particle size favors a faster and more oral absorption. Nanoparticles larger than 200 nm, such as 600 and 2000 nm, cannot be efficiently transported across the intestinal membrane. The absorbed nanoparticles (50 and 200 nm) mainly accumulate in the liver. Lymph may be the main absorption route for PCL nanoparticles, transporting 2.39 ± 1.81% and 0.98 ± 0.58% of administered 50 and 200 nm nanoparticles, respectively. Cellular uptake and transportation of PCL nanoparticles are also size dependent. Both enterocytes and M cells mediated transcytosis are involved in the transport of 50 nm PCL nanoparticles, while the M cell pathway is dominative for other nanoparticles. In conclusion, the study provides a valuable tool for bioimaging of intact polymeric nanoparticles as well as solid evidence supporting size‐dependent translocation of the nanoparticles via oral delivery.
https://ift.tt/2Pc9hXl
Dynamic PEG–Peptide Hydrogels via Visible Light and FMN‐Induced Tyrosine Dimerization
A dynamic hydrogel system is prepared using orthogonal photochemistry. The primary network is crosslinked by a modular thiol–norbornene photoclick reaction, whereas the secondary stiffening is achieved via visible light‐induced di‐tyrosine crosslinking. All components used in hydrogel crosslinking and stiffening are commercially available, making the system highly adaptable for studying the effect of spatial‐temporally regulated matrix mechanics on cell fate processes.
Abstract
Photoresponsive hydrogels have become invaluable 3D culture matrices for mimicking aspects of the extracellular matrix. Recent efforts have focused on using ultraviolet (UV) light exposure and multifunctional macromers to induce secondary hydrogel crosslinking and dynamic matrix stiffening in the presence of cells. This contribution reports the design of a novel yet simple dynamic poly(ethylene glycol)–peptide hydrogel system through flavin mononucleotide (FMN) induced di‐tyrosine crosslinking. These di‐tyrosine linkages effectively increase hydrogel crosslinking density and elastic modulus. In addition, the degree of stiffening in hydrogels at a fixed PEG macromer content can be readily tuned by controlling FMN concentration or the number of tyrosine residues built‐in to the peptide linker. Furthermore, tyrosine‐bearing pendant biochemical motifs can be spatial‐temporally patterned in the hydrogel network via controlling light exposure through a photomask. The visible light and FMN‐induced tyrosine dimerization process produces a cytocompatible and physiologically relevant degree of stiffening, as shown by changes of cell morphology and gene expression in pancreatic cancer and stromal cells. This new dynamic hydrogel scheme should be highly desirable for researchers seeking a photoresponsive hydrogel system without complicated chemical synthesis and secondary UV light irradiation.
https://ift.tt/2ECrWHZ
Polymer Self‐Assembled BMSCs with Cancer Tropism and Programmed Homing
After self‐assembly, living bone marrow mesenchymal stem cells (BMSCs) with amphiphilic hyperbranched polymers (AHP) conjugated with oleic acid (OA) and tumor‐targeted ligand folic acid (FA) show a significant increased ability in homing to gastric cancer cells and cause no damage to major organs. Membrane surface engineering by AHP‐OA‐FA makes living BMSCs present a promising vehicle for targeted delivery to cancer cells.
Abstract
Targeted therapy can improve the accuracy of diagnosis and treatment in the field of cancer management. Cellular surface engineering can enhance cell functions via mounting functional molecules onto cellular membranes. A novel amphiphilic hyperbranched polymer (AHP) conjugated with oleic acid (OA) and tumor‐targeted ligand folic acid (FA) is employed. The lipophilic chain can self‐assemble and infuse with the cytomembrane of bone marrow mesenchymal stem cells (BMSCs) with the end of FA left on the outside for targeting. The polymer tailored BMSCs can enhance tumor tropism in gastric cancer. BMSCs are characterized by the low immunogenicity and tumor tropism, which makes them promising targeting carriers. Regarding the integrated advantages of these two vectors, it is demonstrated that the functional amphiphilic AHP‐OA‐FA enhances the tumor tropism of BMSCs. Flow cytometry, standard MTT assay, and wound‐healing assay show that AHP‐OA‐FA has no influence on CD expression, proliferative capacity, and cell motility of BMSCs, respectively. Furthermore, in vitro transwell assay and ex vivo fluorescence image verify that AHP‐OA‐FA enhances tumor tropism of BMSCs compared to BMSCs and AHP‐OA‐Rhodamine B‐BMSCs. Finally, histological analysis demonstrates that AHP‐OA‐FA causes no damage to major organs. The results of this study suggest that living BMSCs self‐assembled with a polymer might be a promising vehicle for targeted delivery to cancer cells.
https://ift.tt/2Pc9fyH
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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