Medicine by Alexandros G.Sfakianakis: 06/13/17

Τρίτη 13 Ιουνίου 2017

Blockade of GLUT1 by WZB117 resensitizes breast cancer cells to adriamycin.

The tolerance to adriamycin of cancer as a common and stubborn obstacle occurred during curing breast cancer patients needs to be overcome. In the present study, we explored whether inhibiting the glucose transporter 1 (GLUT1) could restore the activity of adriamycin in breast cancer cell line MCF-7 resistant to adriamycin and the possible underlying mechanisms. Adriamycin-resistant cell line MCF-7/ADR was selected stepwise from the parental MCF-7 cells and the level of GLUT1 was measured. Then, the MCF-7/ADR cells were incubated with adriamycin, WZB117 (a specific GLUT1 inhibitor), or both. The viability, proliferation and apoptosis of cells and the level of glucose and lactate were measured, respectively. Finally, the cytosolic and mitochondrial proteins were isolated and the activity of the adenosine monophosphate-activated protein kinase (AMPK)/phosphorylated AMPK, mammalian target of rapamycin (mTOR)/phosphorylated mTOR, and apoptotic-related protein BCL-2-associated X protein (BAX), Bcl-2 was assayed by western blot. We found that WZB117 resensitized MCF-7/ADR to adriamycin and increased BAX translocated to mitochondria, which through activation of AMPK and inhibition of mTOR in a high probability. Inhibition of the GLUT1 could partially restore the antineoplastic effects of adriamycin in the adriamycin-resistant MCF-7 cell line possibly through activating the AMPK, downregulating the mTOR pathway, and increasing the BAX translocation to mitochondria. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Spontaneous regression of malignant melanoma - is it based on the interplay between host immune system and melanoma antigens?.

Malignant melanoma (MM) is the most aggressive and uneasily treatable form of skin cancer. Up to 90% of deaths because of skin tumours are estimated to be caused by this malignancy. Spontaneous regression is described as a partial or complete disappearance of cancer. It can be defined if the clinical and histological diagnosis of malignancy is verified and any therapeutic intervention potentially inducing mechanisms leading to regression has not been applied. Regression occurs more frequently in melanoma than in other types of tumours; it is reported to be six times higher than in other malignancies. Up to 50% of primary MM is reported to undergo spontaneous regression. However, spontaneous regression of the metastatic form of tumour is a rare phenomenon observed in only 0.23% of cases. The most frequently mentioned factors leading to spontaneous regression of MM are operative trauma, infection, vaccination (BCG and rabies vaccines) and immunological factors. Other well-documented circumstances associated with regression of metastatic MM include blood transfusion and various endocrine factors. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Renal impairment and use of nephrotoxic agents in patients with multiple myeloma in the clinical practice setting in the United States

Abstract

Renal impairment is a common complication of multiple myeloma and deterioration in renal function or renal failure may complicate clinical management. This retrospective study in patients with multiple myeloma using an electronic medical records database was designed to estimate the prevalence of renal impairment (single occurrence of estimated glomerular filtration rate [eGFR] <60 mL/min per 1.73 m² on or after multiple myeloma diagnosis) and chronic kidney disease (at least two eGFR values <60 mL/min per 1.73 m² after multiple myeloma diagnosis that had been measured at least 90 days apart), and to describe the use of nephrotoxic agents. Eligible patients had a first diagnosis of multiple myeloma (ICD-9CM: 203.0x) between January 1, 2012 and March 31, 2015 with no prior diagnoses in the previous 6 months. Of 12,370 eligible patients, the prevalence of both renal impairment and chronic kidney disease during the follow-up period was high (61% and 50%, respectively), and developed rapidly following the diagnosis of multiple myeloma (6-month prevalence of 47% and 27%, respectively). Eighty percent of patients with renal impairment developed chronic kidney disease over the follow-up period, demonstrating a continuing course of declining kidney function after multiple myeloma diagnosis. Approximately 40% of patients with renal impairment or chronic kidney disease received nephrotoxic agents, the majority of which were bisphosphonates. As renal dysfunction may impact the clinical management of multiple myeloma and is associated with poor prognosis, the preservation of renal function is critical, warranting non-nephrotoxic alternatives where possible in managing this population.

In this observational study, the prevalence of both renal impairment and chronic kidney disease was high in patients with multiple myeloma, affecting 61% and 50%, respectively, of patients in the OSCER cancer database in the US for the period 2012 to 2015. The onset of renal impairment was rapid after the multiple myeloma diagnosis; however, 40% of these patients nevertheless received concomitant nephrotoxic agents, most of which were intravenous bisphosphonates. As renal impairment is associated with reduced survival and may affect clinical management, preservation of renal function is critical, and non-nephrotoxic alternatives are warranted where possible in managing the multiple myeloma population.

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Racial disparities in survival outcomes by breast tumor subtype among African American women in Memphis, Tennessee

Abstract

Racial disparities in survival among African American (AA) women in the United States have been well documented. Breast cancer mortality rates among AA women is higher in Memphis, Tennessee as compared to 49 of the largest US cities. In this study, we investigated the extent to which racial/ethnic disparities in survival outcomes among Memphis women are attributed to differences in breast tumor subtype and treatment outcomes. A total of 3527 patients diagnosed with stage I–IV breast cancer between January 2002 and April 2015 at Methodist Health hospitals and West Cancer Center in Memphis, TN were included in the analysis. Kaplan–Meier survival curves were generated and Cox proportional hazards regression were used to compare survival outcomes among 1342 (38.0%) AA and 2185 (62.0%) non-Hispanic White breast cancer patients by race and breast tumor subtype. Over a mean follow-up time of 29.9 months, AA women displayed increased mortality risk [adjusted hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.35–2.03] and were more likely to be diagnosed at advanced stages of disease. AA women with triple-negative breast cancer (TNBC) had the highest death rate at 26.7% compared to non-Hispanic White women at 16.5%. AA women with TNBC and luminal B/HER2- breast tumors had the highest risk of mortality. Regardless of race, patients who did not have surgery had over five times higher risk of dying compared to those who had surgery. These findings provide additional evidence of the breast cancer disparity gap between AA and non-Hispanic White women and highlight the need for targeted interventions and policies to eliminate breast cancer disparities in AA populations, particularly in Memphis, TN.

Breast cancer mortality is highest among African American (AA) women in Memphis, TN. When stratified by breast tumor subtype, AA women with triple-negative breast cancer and luminal B/HER2- breast tumors had the highest risk of mortality compared to European American women. These findings highlight the need for targeted interventions to reduce breast cancer disparities in AA populations, particularly those in Memphis, TN.

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Real-Time Polymerase Chain Reaction–Based Detection of Bordetella pertussis in Mexican Infants and Their Contacts: A 3-Year Multicenter Study

To evaluate the usefulness of real-time polymerase chain reaction (RT-PCR) as a diagnostic method for the detection of Bordetella pertussis in hospitalized patients aged <1 year with a clinical diagnosis of whooping cough, as well as to identify the role of household contacts as a source of infection.

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Obesity, Visceral Adipose Tissue, and Cognitive Function in Childhood

To evaluate the effects of a 9-month physical activity intervention on changes in adiposity and cognitive control based on pretrial weight status (ie, healthy weight vs obese) in children.

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FDA Approves First Generic Truvada for HIV Infection and Pre-Exposure Prophylaxis (PrEP)

June 8, 2017 - The U.S. Food and Drug Administration has approved the first generic version of Truvada for the treatment of HIV-1, in combination with other antiretroviral agents, and for pre-exposure prophylaxis (PrEP) in combination with safer sex...

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Tumor Associated with CD70 Expression is Involved in Promoting Tumor Migration and Macrophage Infiltration in GBM

Abstract

Tumor migration/metastasis and immunosuppression are major obstacles in effective cancer therapy. Incidentally, these 2 hurdles usually coexist inside tumors, therefore making therapy significantly more complicated, as both oncogenic mechanisms must be addressed for successful therapeutic intervention. Our recent report highlights that the tumor expression of a TNF family member, CD70, is correlated with poor survival for primary gliomas. In this study, we investigated how CD70 expression by GBM affects the characteristics of tumor cells and the tumor microenvironment. We found that the ablation of CD70 in primary GBM decreased CD44 and SOX2 gene expression, and inhibited tumor migration, growth, and the ability to attract monocyte-derived M2 macrophages in vitro. In the tumor microenvironment, CD70 was associated with immune cell infiltrates, such as T cells; myeloid-derived suppressor cells; and monocytes/macrophages based on the RNA-sequencing profile. The CD163+ macrophages were far more abundant than T cells were. This overwhelming level of macrophages was identified only in GBM and not in low-grade gliomas and normal brain specimens, implying their tumor association. CD70 was detected only on tumor cells, not on macrophages, and was highly correlated with CD163 gene expression in primary GBM. Additionally, the co-expression of the CD70 and CD163 genes was found to correlate with decreased survival for patients with primary GBM. Together, these data suggest that CD70 expression is involved in promoting tumor aggressiveness and immunosuppression via tumor-associated macrophage recruitment/activation. Our current efforts to target this molecule using chimeric antigen receptor T cells hold great potential for treating patients with GBM. This article is protected by copyright. All rights reserved.

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What do adolescents with asthma really think about adherence to inhalers? Insights from a qualitative analysis of a UK online forum

Objective

To explore the barriers and facilitators to inhaled asthma treatment in adolescents with asthma.

Design

Qualitative analysis of posts about inhaler treatment in adolescents from an online forum for people with asthma. Analysis informed by the Perceptions and Practicalities Approach.

Participants

Fifty-four forum participants (39 adolescents ≥16 years, 5 parents of adolescents, 10 adults with asthma) identified using search terms 'teenager inhaler' and 'adolescent inhaler'.

Setting

Posts from adolescents, parents and adults with asthma taking part in the Asthma UK online forum between 2006 and 2016, UK.

Results

Practical barriers reducing the ability to adhere included forgetfulness and poor routines, inadequate inhaler technique, organisational difficulties (such as repeat prescriptions), and families not understanding or accepting their child had asthma. Prompting and monitoring inhaler treatment by parents were described as helpful, with adolescents benefiting from self-monitoring, for example, by using charts logging adherence. Perceptions reducing the motivation to adhere included asthma representation as episodic rather than chronic condition with intermittent need of inhaler treatment. Adolescents and adults with asthma (but not parents) described concerns related to attributed side effects (eg, weight gain) and social stigma, resulting in 'embarrassment of taking inhalers'. Facilitators to adherence included actively seeking general practitioners'/consultants' adjustments if problems arose and learning to deal with the side effects and stigma. Parents were instrumental in creating a sense of responsibility for adherence.

Conclusions

This online forum reveals a rich and novel insight into adherence to asthma inhalers by adolescents. Interventions that prompt and monitor preventer inhaler use would be welcomed and hold potential. In clinical consultations, exploring parents' beliefs about asthma diagnosis and their role in dealing with barriers to treatment might be beneficial. The social stigma of asthma and its role in adherence were prominent and continue to be underestimated, warranting further research and action to improve public awareness of asthma.

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Gene Therapy of Adult Neuronal Ceroid Lipofuscinoses with CRISPR/Cas9 in Zebrafish

Human Gene Therapy , Vol. 0, No. 0.

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Gene Delivery of Activated Factor VII Using Alternative Adeno-Associated Virus Serotype Improves Hemostasis in Hemophiliac Mice with FVIII Inhibitors and Adeno-Associated Virus Neutralizing Antibodies

Human Gene Therapy , Vol. 0, No. 0.

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Intranasal Adeno-Associated Virus Mediated Gene Delivery and Expression of Human Iduronidase in the Central Nervous System: A Noninvasive and Effective Approach for Prevention of Neurologic Disease in Mucopolysaccharidosis Type I

Human Gene Therapy , Vol. 0, No. 0.

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Transgene Expression in Dogs After Liver-Directed Hydrodynamic Delivery of Sleeping Beauty Transposons Using Balloon Catheters

Human Gene Therapy , Vol. 0, No. 0.

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Author Index

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Editorial Board

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A Duplicated, Truncated amh Gene Is Involved in Male Sex Determination in an Old World Silverside

A master sex-determining gene, the Y chromosome-linked anti-Müllerian hormone (amhy), has been described in two New World atheriniform species but little is known on the distribution, evolution, and function(s) of this gene in other Atheriniformes. Interestingly, amhy has been found to coexist with temperature-dependent sex determination (TSD), providing a unique opportunity to explore the interplay between genotypic and environmental sex determination. In this study, the search for an amhy homologue was extended to an Old World atheriniform, the cobaltcap silverside Hypoatherina tsurugae (Atherinidae). The full sequences, including the coding and non-coding regions, of the autosomal amh (amha) and a putative amhy were obtained. The deduced Amha and Amhy proteins comprised 511 and 340 amino acids, respectively. PCR analysis with genomic DNA from wild adults and from laboratory-reared juveniles revealed a high, but not complete association of about 95% between amhy and maleness. The spatio-temporal expression of amhy and amha during gonadal sex differentiation was analyzed by qRT-PCR and in situ hybridization (ISH). amhy transcription (in amhy-positive larvae) started before and peaked during histological differentiation of the gonads whereas amha was negligible during the same period in both genotypes. These results demonstrate that the amhy, although with some structural differences in relation to the amhy of some New World atheriniforms, is strongly associated with maleness and probably important for testicular development in this Old World atheriniform. Thus, amhy is a candidate for sex determination gene in cobaltcap silverside and will be key to scrutinize the mechanism of sex determination in this species.

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Coronary angiogenic effect of long-term administration of Nigella sativa

Coronary angiogenesis is one of the preferable adaptive responses of aerobic training. Previous studies found inotropic and hypertrophic cardiac effects for long-term administration of Nigella sativa (NS), but no...

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The effect of Astragalus polysaccharides on attenuation of diabetic cardiomyopathy through inhibiting the extrinsic and intrinsic apoptotic pathways in high glucose -stimulated H9C2 cells

Apoptosis plays a critical role in the progression of diabetic cardiomyopathy (DC). Astragalus polysaccharides (APS), an extract of astragalus membranaceus (AM), is an effective cardioprotectant. Currently, littl...

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Resveratrol distinctively modulates the inflammatory profiles of immune and endothelial cells

The phenolic substance resveratrol (RES) is a plant metabolite known to modulate numerous physiological functions and to exert beneficial effects as a cancer-chemopreventing agent and on neurological, hepatic,...

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A Kinome RNAi Screen in Drosophila Identifies Novel Genes Interacting with Lgl, aPKC and Crb Cell Polarity Genes in Epithelial Tissues

In both Drosophila melanogaster and mammalian systems, epithelial structure and underlying cell polarity are essential for proper tissue morphogenesis and organ growth. Cell polarity interfaces with multiple cellular processes that are regulated by the phosphorylation status of large protein networks. To gain insight into the molecular mechanisms that coordinate cell polarity with tissue growth, we screened a boutique collection of RNAi stocks targeting the kinome for their capacity to modify Drosophila 'cell polarity' eye and wing phenotypes. Initially we identified kinase or phosphatase genes whose depletion modified adult eye phenotypes associated with the manipulation of cell polarity complexes (via overexpression of Crb or aPKC). We next conducted a secondary screen to test whether these cell polarity modifiers altered tissue overgrowth associated with depletion of Lgl in the wing. These screens identified Hippo, JNK, and Notch signalling pathways, previously linked to cell polarity regulation of tissue growth. Furthermore, novel pathways, not previously connected to cell polarity regulation of tissue growth were identified, including Wingless (Wg/Wnt), Ras and lipid/Phospho-inositol-3-kinase (PI3K) signalling pathways. Additionally, we demonstrated that the 'nutrient sensing' kinases, Salt Inducible Kinase 2 and 3 (SIK2 and 3) are potent modifiers of cell polarity phenotypes and regulators of tissue growth. Overall, our screen has revealed novel cell-polarity interacting kinases and phosphatases that affect tissue growth, providing a platform for investigating molecular mechanisms coordinating cell polarity and tissue growth during development.

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Patterns of Genetic Structure and Linkage Disequilibrium in a Large Collection of Pea Germplasm

Pea (Pisum sativum, L.) is a major pulse crop used both for animal and human alimentation. Owing to its association with nitrogen-fixing bacteria, it is also a valuable component for low-input cropping systems. To evaluate the genetic diversity and the scale of linkage disequilibrium (LD) decay in pea, we genotyped a collection of 917 accessions gathering elite cultivars, landraces and wild relatives using an array of ~13,000 single nucleotide polymorphisms (SNP). Genetic diversity is broadly distributed across three groups corresponding to wild/landraces peas, winter types and spring types. At a finer subdivision level, genetic groups relate to local breeding programs and type usage. Linkage disequilibrium is steeply decreasing as genetic distance increase. When considering subsets of the data, LD values can be higher, even if the steep decay remains. We looked for genomic regions exhibiting high level of differentiation between wild/landraces, winter and spring pea respectively. Two regions on linkage groups 5 and 6 containing 33 SNPs exhibit stronger differentiation between winter and spring peas than would be expected under neutrality. Interestingly QTLs for resistance to cold acclimation and frost resistance have been identified previously in the same regions.

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Pulmonary arterial hypertension due to an intratumoral shunt: an unexpected side effect of sunitinib

Future Oncology Ahead of Print.

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Real-world treatment outcomes in patients with metastatic Merkel cell carcinoma treated with chemotherapy in the USA

Future Oncology Ahead of Print.

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Clinical and Genome-Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer

Purpose: Our purpose was to characterize the clinical influences, genetic risk factors, and gene mechanisms contributing to persistent cisplatin-induced peripheral neuropathy (CisIPN) in testicular cancer survivors (TCS). Experimental Design: TCS given cisplatin-based therapy completed the validated EORTC QLQ-CIPN20 questionnaire. An ordinal CisIPN phenotype was derived and associations with age, smoking, excess drinking, hypertension, body mass index, diabetes, hypercholesterolemia, cumulative cisplatin dose, and self-reported health were examined for 680 TCS. Genotyping was performed on the Illumina HumanOmniExpressExome chip. Following quality control and imputation, 5.1 million SNPs in 680 genetically European TCS formed the input set. GWAS and PrediXcan were used to identify genetic variation and genetically-determined gene expression traits, respectively, contributing to CisIPN. We evaluated two independent datasets for replication: Vanderbilt's electronic health database, BioVU and CALGB 90401 trial. Results: Eight sensory items formed a subscale with good internal consistency (Cronbach a=0.88). Variables significantly associated with CisIPN included age at diagnosis (OR per year=1.06, p=2 x 10^-9), smoking (OR=1.54, p=0.004), excess drinking (OR=1.83, p=0.007), and hypertension (OR=1.61, p=0.03). CisIPN was correlated with lower self-reported health (OR=0.56; p=2.6 x 10^-9) and weight gain adjusted for years since treatment (OR per Dkg/m²=1.05, p=0.004). PrediXcan identified lower expressions of MIDN and RPRD1B, and higher THEM5 expression as associated with CisIPN (p-value for each < 5 x 10^-6) with replication of RPRD1B meeting significance criteria (Fisher's combined p=0.0089). Conclusions: CisIPN is associated with age, modifiable risk factors and genetically-determined expression level of RPRD1B. Further study of implicated genes could elucidate the pathophysiologic underpinnings of CisIPN.

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Treatment of pancreatic cancer patient-derived xenograft panel with metabolic inhibitors reveals efficacy of phenformin

Purpose: To identify effective metabolic inhibitors to suppress the aggressive growth of pancreatic ductal adenocarcinoma (PDAC), we explored the in vivo anti-tumor efficacy of metabolic inhibitors in a panel of patient-derived PDAC xenograft models (PDXs), and investigated whether genomic alterations of tumors correlate with the sensitivity to metabolic inhibitors. Experimental Design: Mice with PDAC tumors from six to thirteen individual PDXs were randomized and treated, once daily for 4 weeks, with either PBS (vehicle) or the glutaminase inhibitor BPTES, transaminase inhibitor aminooxyacetate (AOA), pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA), autophagy inhibitor chloroquine (CQ), mitochondrial complex I inhibitor phenformin/metformin. Results: Among the single agents tested, phenformin showed significant tumor growth inhibition (>30% compared to vehicle) in 5 out of 12 individual PDXs. Metformin displayed significant growth inhibition in 3 out of 12 PDXs similar to BPTES (2/8 PDXs) and DCA (2/6 PDXs). AOA and CQ had the lowest response rates. Intriguingly, tumor growth inhibition of PDXs by phenformin inversely correlates with the tumors showing a phenformin gene expression signature prior to therapy. The PDXs more sensitive to phenformin showed a baseline reduction in amino acids and elevation in oxidized glutathione. There was no correlation between phenformin response and genetic alterations in KRAS, TP53, SMAD4 or PTEN. Conclusions: Phenformin treatment showed relatively higher anti-tumor efficacy against established PDAC tumors, compared to the efficacy of other metabolic inhibitors and metformin. Phenformin treatment significantly diminished PDAC tumor progression and prolonged tumor doubling time, which provides rationale for further clinical evaluation of phenformin as a therapeutic agent in pancreatic cancer.

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U.S. Food and Drug Administration Approval Summary: Atezolizumab for Metastatic Non-Small Cell Lung Cancer

On October 18 2016, the U.S. Food and Drug Administration approved atezolizumab (TECENTRIQ®, Genentech Inc.) for treatment of patients with metastatic non-small cell lung cancer (mNSCLC) whose disease progressed during or following platinum-containing chemotherapy. Approval was based on demonstration of clinically meaningful improvements in overall survival (OS) and an acceptable safety profile in two randomized clinical trials (OAK and POPLAR). Median OS in OAK, a phase III trial, was 13.8 months (95% confidence interval [CI] 11.8,15.7) in the atezolizumab arm compared with 9.6 months (95% CI 8.6,11.2) in the docetaxel arm (HR=0.74 [95% CI 0.63,0.87]; p=0.0004). Median OS in POPLAR, a phase II trial, was 12.6 months (95% CI 9.7, 16.0) and 9.7 months (95% CI 8.6, 12.0) (HR=0.69 [95% CI 0.52, 0.92]) for the atezolizumab and docetaxel arms, respectively. In patients treated with atezolizumab, the most common (≥20%) adverse reactions were fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, and constipation; the most common (≥2%) grade 3-4 adverse events were dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, anemia, musculoskeletal pain, AST increase, ALT increase, dysphagia, and arthralgia. Clinically significant immune-related adverse events for patients receiving atezolizumab included 1.4% incidence each of Grade 3-4 pneumonitis, hepatitis, colitis, and thyroid disease.

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Detection of Head and Neck Cancer in Surgical Specimens Using Quantitative Hyperspectral Imaging

Purpose: This study intends to investigate the feasibility of using hyperspectral imaging (HSI) to detect and delineate cancers in fresh, surgical specimens of patients with head and neck cancers. Experimental Design: A clinical study was conducted in order to collect and image fresh, surgical specimens from patients (N = 36) with head and neck cancers undergoing surgical resection. A set of machine-learning tools were developed to quantify hyperspectral images of the resected tissue in order to detect and delineate cancerous regions which were validated by histopathological diagnosis. More than two million reflectance spectral signatures were obtained by HSI and analyzed using machine-learning methods. The detection results of HSI were compared with autofluorescence imaging and fluorescence imaging of two vital-dyes of the same specimens. Results: Quantitative HSI differentiated cancerous tissue from normal tissue in ex vivo surgical specimens with a sensitivity and specificity of 91% and 91%, respectively, and which was more accurate than autofluorescence imaging (p<0.05) or fluorescence imaging of 2-NBDG (p<0.05) and proflavine (p<0.05). The proposed quantification tools also generated cancer probability maps with the tumor border demarcated and which could provide real-time guidance for surgeons regarding optimal tumor resection. Conclusions: This study highlights the feasibility of using quantitative HSI as a diagnostic tool to delineate the cancer boundaries in surgical specimens, and which could be translated into the clinic application with the hope of improving clinical outcomes in the future.

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Relationship of the breast ductal carcinoma in situ immune microenvironment with clinico-pathological and genetic features

Purpose: The immune microenvironment of breast ductal carcinoma in situ (DCIS) has yet to be fully explored, and the relationship of immune cells to genetic features of DCIS is unknown. Experimental Design: We quantified tumour associated lymphocytes (TILs) and evaluated PD-L1 protein levels by immunohistochemistry in a cohort of pure DCIS (138 and 79 cases respectively), some of which had copy number (n=55) and mutation data (n=20). Results: TILs were identified in the stroma surrounding DCIS (119/138, 86%) and present at a median TIL score of 5% (range 0-90%). Most DCIS were negative for tumour cell PD-L1 staining (89%), but 25% of cases were positive for immune cell staining. We observed that, as in invasive breast cancer, TILs and PD-L1 positivity were significantly greater in high grade (p=0.002/0.035), ER-negative (p=0.02/0.02) and ERBB2 amplified tumours (p<0.001/0.048). Comedo necrosis was significantly positively associated with TILs (p<0.0001) but not PD-L1. The TILs score was significantly higher in cases with TP53 mutation (p=0.03) but not PIK3CA or GATA3 mutation. In the cases with copy number data, both the fraction of the genome altered and the number of telomeric imbalances were significantly positively correlated with TILs (both p<0.001). This result strongly contrasted with invasive breast cancer data, where aneuploidy was not correlated to TIL levels. Conclusions: Although a small cohort, our data suggest a preliminary model by which the progression of DCIS to invasive carcinoma may involve an altered relationship of tumour copy number with the immune microenvironment, possibly by the immunoediting of the tumour.

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Dendritic cell/cytokine induced killer cell immunotherapy combined with S-1 in patients with advanced pancreatic cancer: A prospective study

Purpose: Advanced pancreatic cancer has remained challenging to treat effectively. This study aimed to investigate the clinical effects and safety of immunotherapy with dendritic cells and cytokine induced killer cells (DC-CIK) administered with the chemotherapy (CT) S-1 in this malignancy. Experimental Design: Consecutive patients (n=47) with advanced pancreatic cancer were treated with either DC-CIK + S-1, DC-CIK alone, S-1 alone, or best supportive care. Results: DC-CIK plus S-1 produced significantly longer median OS and PFS (212 and 136 days) compared with DC-CIK (128 and 85 days), CT (141 and 92 days) or supportive care only (52 and 43 days) (P<0.001). After adjusting for competing risk factors, DC-CIK combined with S-1 and receipt of 2 or more cycles of DC-CIK treatment remained independent predictors of disease free and overall survival (P<0.05). Phenotypic analysis of peripheral blood mononuclear cells demonstrated that the CD3⁺, CD3⁺/CD4⁺ and CD8⁺/CD28⁺ T cell subsets were elevated (P <0.05), while the CD3⁺/CD8⁺, CD3⁺/CD16⁺/CD56⁺ and CD4⁺/CD25⁺ cell subsets were significantly decreased after DC-CIK cell therapy (P <0.05). There were no grade 3 or 4 toxicities. Additionally the mutational frequency in cell-free tumor DNA (cfDNA) declined in 4/14 patients who received DC-CIK, and was associated with a more favorable survival. Conclusion: Treatment of advanced pancreatic cancer with combined with DC-CIK infusions and S-1 was safe, resulted in favorable PFS and OS, and modulated the peripheral blood immune repertoire.

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Role of platelet-derived Tgf{beta}1 in the progression of ovarian cancer

Purpose: Transforming growth factor β1 (Tgfß1) plays an important role in cancer. Most of Tgfß1 in plasma is from platelets, thus we studied whether platelet Tgfß1 has any role in the progression of ovarian cancer, and whether this role is limited to metastasis or also involves the growth of primary tumors. Experimental Design: We compared the growth of murine ovarian cancer cell-induced tumors in platelet-specific Tgfß1 deficient mice and wild-type mice. Using resected tumor nodules, we studied the effect of platelet Tgfß1 on neoangiogenesis and on platelet extravasation into tumors. To investigate the effect of Tgfß1 at different stages of ovarian cancer, we reduced expression of Tgfb1 receptor (its TgfßR1 component) in tumors at different time points after injection of cancer cells, and compared the final tumor size. Results: Lack of platelet Tgfß1 in mice reduced tumor growth, neoangiogenesis, and platelet extravasation. Ovarian cancer tumors in platelet-specific Tgfß1 deficient mice reached less than half of their size in wild-type littermates. Knockdown of TgfßR1on cancer cells in the first 2 weeks after their injection reduced tumor growth, but was less effective if initiated after 3 weeks. Conclusions: We showed that platelet Tgfß1 increased the growth of primary tumors in murine models of ovarian cancer. We also showed that inhibition of TgfßR1 is more effective in reducing the growth of ovarian cancer if initiated earlier. Our results supported a therapeutic benefit in preventing platelet activation, degranulation, and release of Tgfß1 in ovarian cancer.

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Mouse PDX Trial Suggests Synergy of concurrent Inhibition of RAF and EGFR in Colorectal Cancer with BRAF or KRAS mutations

Purpose: It is to evaluate the anti-tumor efficacy of cetuximab in combination with LSN3074753, an analogue of LY3009120 and pan-RAF inhibitor in 79 colorectal cancer (CRC) patient derived xenograft (PDX) models. Experimental Design: 79 well characterized CRC PDX models were employed to conduct a single mouse per treatment group (n=1) trial. Results: Consistent with clinical results, cetuximab was efficacious in wild type KRAS and BRAF PDX models, with an overall response rate (ORR) of 6.3% and disease control rate (DCR) of 20.3%. LSN3074753 was active in a small subset of PDX models that harbored KRAS or BRAF mutations. However, the combination treatment displayed the enhanced antitumor activity with DCR of 35.4%. Statistical analysis revealed that BRAF and KRAS mutations were the best predictors of the combinatorial activity, and were significantly associated with synergistic effect with a p value of 0.01 compared with cetuximab alone. In 12 models with BRAF mutations, the combination therapy resulted in a DCR of 41.7%, whereas either monotherapy had a DCR of 8.3%. Among 44 KRAS mutation models, cetuximab or LSN3074753 monotherapy resulted in a DCR of 13.6% or 11.4%, respectively, and the combination therapy increased DCR to 34.1%. Molecular analysis suggests that EGFR activation is a potential feedback and resistant mechanism of pan-RAF inhibition. Conclusions: MAPK and EGFR pathway activations are two major molecular hallmarks of CRC. This mouse PDX trial recapitulated clinical results of cetuximab. Concurrent EGFR and RAF inhibition demonstrated synergistic anti-tumor activity for CRC PDX models with a KRAS or BRAF mutation.

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ATF3 repression of BCL-XL determines apoptotic sensitivity to HDAC inhibitors across tumour types

Purpose: Histone deacetylase inhibitors (HDACi) are epigenome-targeting small molecules approved for the treatment of cutaneous T cell lymphoma and multiple myeloma. They have also demonstrated clinical activity in AML, non-small cell lung cancer and estrogen receptor-positive breast cancer, and trials are underway assessing their activity in combination regimens including immunotherpy. However, there is currently no clear strategy to reliably predict HDACi sensitivity. In colon cancer cells, apoptotic sensitivity to HDACi is associated with transcriptional induction of multiple immediate-early (IE) genes. Here, we examined whether this transcriptional response predicts HDACi sensitivity across tumour type, and investigated the mechanism by which it triggers apoptosis. Experimental design: Fifty cancer cell lines from diverse tumour types were screened to establish the correlation between apoptotic sensitivity, induction of IE genes, and components of the intrinsic apoptotic pathway. Results: We show that sensitivity to HDACi across tumour types is predicted by induction of the IE genes FOS, JUN and ATF3, but that only ATF3 is required for HDACi-induced apoptosis. We further demonstrate that the pro-apoptotic function of ATF3 is mediated through direct transcriptional repression of the pro-survival factor BCL-X_L (BCL2L1). These findings provided the rationale for dual inhibition of HDAC and BCL-X_L which we show strongly cooperate to overcome inherent resistance to HDACi across diverse tumour cell types. Conclusions: These findings explain the heterogenous responses of tumour cells to HDACi-induced apoptosis and suggest a framework for predicting response and expanding their therapeutic use in multiple cancer types.

http://ift.tt/2t017n3

Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic BRAF-Mutant Melanoma

Purpose: Encorafenib, a selective BRAF-inhibitor (BRAFi), has a pharmacological profile that is distinct from that of other clinically active BRAFis. We evaluated encorafenib in a phase I study in patients with BRAFi treatment-naive and pretreated BRAF-mutant melanoma. Experimental Design: The pharmacological activity of encorafenib was first characterized preclinically. Encorafenib monotherapy was then tested across a range of once-daily (QD; 50-700mg) or twice-daily (75-150mg) regimens in a phase I, open-label, dose-escalation and -expansion study in adult patients with histologically confirmed advanced/metastatic BRAF-mutant melanoma. Study objectives were to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D), characterize the safety and tolerability and pharmacokinetic profile, and assess the preliminary antitumor activity of encorafenib. Results: Preclinical data demonstrated that encorafenib inhibited BRAF-V600E kinase activity with a prolonged off-rate and suppressed proliferation and tumor growth of BRAF-V600E-mutant melanoma models. In the dose-escalation phase, 54 patients (29 BRAFi-pretreated and 25 BRAFi-naïve) were enrolled. Seven patients in the dose-determining set experienced dose-limiting toxicities. Encorafenib at a dose of 300mg QD was declared the RP2D. In the expansion phase, the most common all-cause adverse events were nausea (66%), myalgia (63%), and palmar-plantar erythrodysesthesia (54%). In BRAFi-naive patients, the overall response rate (ORR) and median progression-free survival (mPFS) were 60% and 12.4 months (95% CI, 7.4-NR). In BRAFi-pretreated patients, the ORR and mPFS were 22% and 1.9 months (95% CI, 0.9-3.7). Conclusions: Once-daily dosing of single-agent encorafenib had a distinct tolerability profile and showed varying antitumor activity across BRAFi-pretreated and BRAFi-naive patients with advanced/metastatic melanoma.

http://ift.tt/2t04nPp

Characterization of MK-4166, a clinical agonistic antibody that targets human GITR and inhibits the generation and suppressive effects of T regulatory cells

GITR is a T cell co-stimulatory receptor that enhances cellular and humoral immunity. The agonist anti-mouse GITR antibody DTA-1 has demonstrated efficacy in murine models of cancer primarily by attenuation of Treg-mediated immune suppression, but the translatability to human GITR biology has not been fully explored. Here we report the potential utility of MK-4166, a humanized GITR monoclonal antibody selected to bind to an epitope analogous to the DTA-1 epitope, which enhances the proliferation of both naïve and tumor-infiltrating T lymphocytes (TILs). We also investigated the role of GITR agonism in human anti-tumor immune responses and report here the preclinical characterization and toxicity assessment of MK-4166, which is currently being evaluated in a Phase I clinical study. Expression of human GITR was comparable to that of mouse GITR in tumor-infiltrating Tregs despite being drastically lower in other human TILs and in many human peripheral blood populations. MK-4166 decreased induction and suppressive effects of Tregs in vitro. In human TIL cultures, MK-4166 induced phosphorylation of NFκB and increased expression of dual specificity phosphatase 6 (DUSP6), indicating that MK-4166 activated downstream NFκB and Erk signaling pathways. Furthermore, MK-4166 downregulated FOXP3 mRNA in human tumor infiltrating Tregs, suggesting that, in addition to enhancing the activation of TILs, MK-4166 may attenuate the Treg-mediated suppressive tumor microenvironment.

http://ift.tt/2tk3ssm

Arl13b promotes gastric tumorigenesis by regulating Smo trafficking and activation of the Hedgehog signaling pathway

Inhibitors of the Hedgehog (Hh) pathway transducer Smoothened (Smo) have been approved for cancer treatment, but Smo mutations often lead to tumor resistance and it remains unclear how Smo is regulated. In this study, we identified the small GTPase Arl13b as a novel partner and regulator of Smo. Arl13b regulated Smo stability, trafficking and localization which are each crucial for Hh signaling. In gastric cancer cells, Arl13b stimulated proliferation, migration and invasion in vitro and in vivo. In clinical specimens of gastric cancer, Arl13b expression correlated strongly with tumor size and depth of invasion; patients with high levels of Arl13b had a poor prognosis. Our results show how Arl13b participates in Hh pathway activation in gastric cancer.

http://ift.tt/2smoc5s

Competition between DNA methylation, nucleotide synthesis and anti-oxidation in cancer versus normal tissues

Global DNA hypomethylation occurs in many cancer types but there is no explanation for its differential occurance or possible impact on cancer cell physiology. Here we address these issues with a computational study of genome-scale DNA methylation in 16 cancer types. Specifically, we identified (1) a possible determinant for global DNA methylation in cancer cells, and (2) a relationship between levels of DNA methylation, nucleotide synthesis and intracellular oxidative stress in cells. We developed a system of kinetic equations to capture the metabolic relations among DNA methylation, nucleotide synthesis, and anti-oxidative stress response, including their competitions for methyl and sulfur groups, based on known information about one-carbon metabolism and trans-sulfuration pathways. We observed a kinetic-based regulatory mechanism that controls reaction rates of the three competing processes when their shared resources are limited, particularly when the nucleotide synthesis rates or oxidative states are high. The combination of this regulatory mechanism and the need for rapid nucleotide synthesis, as well as high production of glutathione dictated by cancer-driving forces, led to the nearly universal observations of reduced global DNA methylation in cancer. Our model provides a natural explanation for differential global DNA methylation levels across cancer types and support the observation that more malignant cancers tend to exhibit reduced DNA methylation levels. Insights obtained from this work provide useful information about the complexities of cancer due to interplays among competing, dynamic biological processes.

http://ift.tt/2tkjK4p

An immunosuppressive dendritic cell subset accumulates at secondary sites and promotes metastasis in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) after complete surgical resection is often followed by distant metastatic relapse for reasons that remain unclear. In this study, we investigated how the immune response at secondary sites affects tumor spread in murine models of metastatic PDAC. Early metastases were associated with dense networks of CD11b+CD11c+MHC-II+CD24+CD64lowF4/80low dendritic cells (DC), which developed from monocytes in response to tumor-released GM-CSF. These cells uniquely expressed MGL2 and PD-L2 in the metastatic microenvironment and preferentially induced the expansion of T regulatory cells (Treg) in vitro and in vivo. Targeted depletion of this DC population in Mgl2DTR hosts activated cytotoxic lymphocytes, reduced Treg, and inhibited metastasis development. Moreover, blocking PD-L2 selectively activated CD8 T cells at secondary sites and suppressed metastasis, suggesting that the DC use this particular pathway to inhibit CD8 T cell-mediated tumor immunity. Phenotypically similar DC accumulated at primary and secondary sites in other models and in human PDAC. These studies suggest that a discrete DC subset both expands Treg and suppresses CD8 T cells to establish an immunosuppressive microenvironment conducive to metastasis formation. Therapeutic strategies to block the accumulation and immunosuppressive activity of such cells may help prevent PDAC progression and metastatic relapse after surgical resection.

http://ift.tt/2smrd5E

{beta}-Catenin is a candidate therapeutic target for myeloid neoplasms with del(5q)

Deletion of the chromosome 5q [del(5q)] is one of the most common cytogenetic abnormalities observed in patients with de novo myelodysplastic syndromes (MDS) and therapy-related MDS or acute myeloid leukemia (t-MDS/tAML). Emerging evidence indicates that activation of the Wnt/β-catenin pathway contributes to the development of myeloid neoplasms with del(5q). Whether β-catenin is a potential therapeutic target for myeloid neoplasms with del(5q) has yet to be evaluated. Here we report that genetic deletion of a single allele of β-catenin rescues ineffective hematopoiesis in an Apc haploinsufficient mouse model, which recapitulates several characteristic features of the pre-leukemic stage of myeloid neoplasms with a -5/del(5q). In addition, loss of a single allele of β-catenin reversed the defective self-renewal capacity of Apc-haploinsufficient hematopoietic stem cells (HSC) and reduced the frequency of apoptosis induced by Apc haploinsufficiency. Suppression of β-catenin by indomethacin or β-catenin shRNA reduced proliferation and survival of human leukemia cell lines with del(5q) but not of control leukemia cell lines in vitro; β-catenin inactivation also inhibited leukemia progression in vivo in xenograft mice reconstituted with del(5q) leukemia cell lines. Inhibition of β-catenin also stunted growth and colony-forming abilities of primary bone marrow cells from del(5q) AML patients in vitro. Overall, our data support the idea that β-catenin could serve as a therapeutic target for the treatment of myeloid neoplasms with del(5q).

http://ift.tt/2tjTrLK

Comprehensive evaluation of protein coding mononucleotide microsatellites in microsatellite-unstable colorectal cancer

Approximately 15% of colorectal cancers (CRC) exhibit microsatellite instability (MSI), which leads to accumulation of a large numbers of small insertions and deletions (indels). Genes that provide growth advantage to cells via loss-of-function mutations in microsatellites are called MSI target genes. Several criteria to define these genes have been suggested, one of them being simple mutation frequency. Microsatellite mutation rate, however, depends on the length and nucleotide context of the microsatellite. Therefore, assessing the general impact of mismatch repair deficiency on the likelihood of mutation events is paramount when following this approach. In order to identify MSI target genes, we developed a statistical model for the somatic background indel mutation rate of microsatellites to assess mutation significance. Exome sequencing data of 24 MSI CRC revealed indels at 54 million mononucleotide microsatellites of three or more nucleotides in length. The top 105 microsatellites from 71 genes were further analyzed in 93 additional MSI CRC. Mutation significance and estimated clonality of mutations determined the most likely MSI target genes to be the aminoadipate-semialdehyde dehydrogenase AASDH and the solute transporter SLC9A8. Our findings offer a systematic profiling of the somatic background mutation rate in protein-coding mononucleotide microsatellites, allowing a full cataloging of the true targets of MSI in CRC.

http://ift.tt/2smnTHJ

Targeting SRC coactivators blocks the tumor-initiating capacity of cancer stem-like cells

Tumor initiating cells (TICs) represent cancer stem-like cell (CSC) subpopulations within tumors that are thought to give rise to recurrent cancer after therapy. Identifying key regulators of TIC/CSC maintenance is essential for the development of therapeutics designed to limit recurrence. The steroid receptor coactivator 3 (SRC-3) is overexpressed in a wide range of cancers, driving tumor initiation, cell proliferation and, metastasis. Here, we report that SRC-3 supports the TIC/CSC state and induces an epithelial to mesenchymal transition (EMT) by driving expression of the master EMT regulators and stem cell markers. We also show that inhibition of SRC-3 and SRC-1 with SI-2, a second-generation SRC-3/SRC-1 small molecule inhibitor, targets the CSC/TIC population both in vitro and in vivo. Collectively, these results identify SRC coactivators as regulators of stem-like capacity in cancer cells and that these coactivators can serve as potential therapeutic targets to prevent the recurrence of cancer.

http://ift.tt/2tjTpDC

Smurf2-mediated stabilization of DNA topoisomerase II{alpha} controls genomic integrity

DNA topoisomerase IIα (Topo IIα) ensures genomic integrity and unaltered chromosome inheritance and serves as a major target of several anticancer drugs. Topo IIα function is well understood, but how its expression is regulated remains unclear. Here we identify the E3 ubiquitin ligase Smurf2 as a physiological regulator of Topo IIα levels. Smurf2 physically interacted with Topo IIα and modified its ubiquitination status to protect Topo IIα from the proteasomal degradation in dose- and catalytically-dependent manners. Smurf2-depleted cells exhibited a reduced ability to resolve DNA catenanes and pathological chromatin bridges formed during mitosis, a trait of Topo IIα-deficient cells and a hallmark of chromosome instability. Introducing Topo IIα into Smurf2-depleted cells rescued this phenomenon. Smurf2 was a determinant of Topo IIα protein levels in normal and cancer cells and tissues, and its levels affected cell sensitivity to the Topo II-targeting drug etoposide. Our results identified Smurf2 as an essential regulator of Topo IIα, providing novel insights into its control and into the suggested tumor suppressor functions of Smurf2.

http://ift.tt/2smsfiq

Autocrine BMP-4 signaling is a therapeutic target in colorectal cancer

Poor prognoses for colorectal cancer (CRC) patients with metastatic lesions have driven demand for the development of novel targeted therapies. Here we demonstrate that expression of bone morphogenetic protein 4 (BMP-4) is universally upregulated in human CRC cells and tissues, resulting in activated BMP signaling. Inhibition of endogenous BMP signaling by the BMP type I receptor inhibitor LDN-193189 elevated expression of the phosphatase DUSP5 in CRC cells, inducing apoptosis via dephosphorylation of Erk MAPK. Administering LDN-193189 to mice diminished tumor formation of CRC cells. Our findings suggest inhibition of autocrine BMP-4 as a candidate treatment strategy for CRC.

http://ift.tt/2tkf5Q4

RGS12 is a novel tumor suppressor gene in African American prostate cancer that represses AKT and MNX1 expression

MATERIALS AND METHODS Studies published between January 1965 and December 2015 were searched through five databases. Titles and abstracts of the retrieved records were screened using eligibility criteria to determine their appropriateness for study inclusion. Only numerical data were extracted for analysis. A summary effect size was estimated to determine the effects of laboratory pedagogies on learner performance and perceptions data were compiled to provide additional context.

RESULTS Of the 3,035 records screened, 327 underwent full-text review. Twenty-seven studies, comprising a total of 7,731 participants, were included in the analysis. The meta-analysis detected no effect (standardized mean difference = -0.03; 95% CI=-0.16-0.10; p=0.62) on learner performance. Additionally, a moderator analysis detected no effects (p≥0.16) for study design, learner population, intervention length, or specimen type.

CONCLUSIONS Across studies, student performance on knowledge examinations was equivalent regardless of being exposed to either dissection or another laboratory instructional strategy. This was true of every comparison investigated (i.e., dissection vs. prosection, dissection vs. digital media, dissection vs. models/modeling, and dissection vs. hybrid). In the context of short-term knowledge gains alone, dissection is no better, and no worse, than alternative instructional modalities. This article is protected by copyright. All rights reserved.

http://ift.tt/2tjQX01

Abstract

Although the Chiari malformations are well-studied and described developmental anomalies, there remains some incongruity in regards to their underlying etiologies. A number of theories have been proposed with the purpose of accounting for the embryology and pathogenesis of the Chiari I and II malformations and their associated complications and clinical syndromes. The present review aims to review the pertinent literature for all of the main theories that have been proposed, and outline their validity and relevance to our contemporary understanding of these anomalies. This article is protected by copyright. All rights reserved.

http://ift.tt/2tjDiWv

Emerging antimicrobial resistance in early and late-onset neonatal sepsis

Compared to developed countries, the use of antimicrobials in Egypt is less regulated and is available over the counter without the need for prescriptions. The impact of such policy on antimicrobial resistance...

http://ift.tt/2slV0f8

Prevalence of antimicrobial resistant pathogens from blood cultures: results from a laboratory based nationwide surveillance in Ghana

Blood stream infections (BSI) are critical medical conditions with high morbidity and mortality. There is paucity of information on BSI from surveillance studies in Ghana.

http://ift.tt/2sm8ZBm

Effectiveness of surface coatings containing silver ions in bacterial decontamination in a recovery unit

HAIs remain a frequent complication for hospitalised patients and pose a challenge that must be tackled by our health systems.

http://ift.tt/2slNHnC

Fecal carriage of extended-spectrum β-lactamase- and carbapenemase-producing Enterobacteriaceae in Egyptian patients with community-onset gastrointestinal complaints: a hospital -based cross-sectional study

The aim of this study was to determine the prevalence of extended-spectrum β-lactamase (ESBL) and carbapenemase production among Enterobacteriaceae isolated from ambulatory patients with gastrointestinal compl...

http://ift.tt/2tjK8LS

Common periodontal pathogen may interfere with conception in women

According to a recent study, a common periodontal pathogen may delay conception in young women.

http://ift.tt/2sywFms

Prevalence and molecular characteristics of Staphylococcus aureus, including methicillin resistant strains, isolated from bulk can milk and raw milk products in pastoral communities of South-West Uganda

Staphylococcus aureus strains are now regarded as zoonotic agents. In pastoral settings where human-animal interaction is intimate, multi-drug resistant microorganisms have become an e...

http://ift.tt/2ro9ETE

Using genotyping to delineate tuberculosis transmission in long-term care facilities: single facility 4-year experience

Residents in long-term care facilities (LTCFs) are vulnerable to tuberculosis (TB) transmission; however, to delineate possible routes of TB transmission in LTCFs is difficult. This study aimed to address the ...

http://ift.tt/2s85zQL

Case report: microcephaly associated with Zika virus infection, Colombia

Recently there has been a large outbreak of Zika virus infections in Colombia, South America. The epidemic began in September 2015 and continued to April 2017, for the total number of Zika cases reported of 10...

http://ift.tt/2rox1MW

Adherence to response-guided pegylated interferon and ribavirin for people who inject drugs with hepatitis C virus genotype 2/3 infection: the ACTIVATE study

The aims of this analysis were to investigate treatment completion and adherence among people with ongoing injecting drug use or receiving opioid substitution therapy (OST) in a study of response-guided therap...

http://ift.tt/2s8qQd6

End-stage renal disease: a risk factor of deep neck infection – a nationwide follow-up study in Taiwan

Uremia is likely a risk factor for deep neck infection (DNI). However, only a few relevant cases have been reported, and evidence sufficient to support this hypothesis is lacking. The aim of the study is to in...

http://ift.tt/2rooae5

The Effects of Time Lag and Cure Rate on the Global Dynamics of HIV-1 Model

In this research article, a new mathematical model of delayed differential equations is developed which discusses the interaction among CD T cells, human immunodeficiency virus (HIV), and recombinant virus with cure rate. The model has two distributed intracellular delays. These delays denote the time needed for the infection of a cell. The dynamics of the model are completely described by the basic reproduction numbers represented by , , and . It is shown that if , then the infection-free equilibrium is locally as well as globally stable. Similarly, it is proved that the recombinant absent equilibrium is locally as well as globally asymptotically stable if . Finally, numerical simulations are presented to illustrate our theoretical results. Our obtained results show that intracellular delay and cure rate have a positive role in the reduction of infected cells and the increasing of uninfected cells due to which the infection is reduced.

http://ift.tt/2tjftyj

The biology of JC polyomavirus

Journal Name: Biological Chemistry
Issue: Ahead of print

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Frontmatter

Journal Name: Biological Chemistry
Volume: 398
Issue: 7
Pages: i-iii

http://ift.tt/2rti3QY

Proteases and cytokines as mediators of interactions between cancer and stromal cells in tumours

Journal Name: Biological Chemistry
Volume: 398
Issue: 7
Pages: 709-719

http://ift.tt/2rY2VyB

The cancer cell adhesion resistome: mechanisms, targeting and translational approaches

Journal Name: Biological Chemistry
Volume: 398
Issue: 7
Pages: 721-735

http://ift.tt/2rsR7kr

Mitochondrial cytochrome c oxidase is inhibited by ATP only at very high ATP/ADP ratios

Journal Name: Biological Chemistry
Volume: 398
Issue: 7
Pages: 737-750

http://ift.tt/2rY8VHs

Novel domain architectures and functional determinants in atypical annexins revealed by phylogenomic analysis

Journal Name: Biological Chemistry
Volume: 398
Issue: 7
Pages: 751-763

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Plasmin(ogen) serves as a favorable biomarker for prediction of survival in advanced high-grade serous ovarian cancer

Journal Name: Biological Chemistry
Volume: 398
Issue: 7
Pages: 765-773

http://ift.tt/2rY7atR

Is N,N-dimethylglycine N-oxide a choline and betaine metabolite?

Journal Name: Biological Chemistry
Volume: 398
Issue: 7
Pages: 775-784

http://ift.tt/2rsHVMI

Valproic acid (VPA) enhances cisplatin sensitivity of non-small cell lung cancer cells via HDAC2 mediated down regulation of ABCA1

Journal Name: Biological Chemistry
Volume: 398
Issue: 7
Pages: 785-792

http://ift.tt/2rY3HeE

Intra- or extra-exosomal secretion of HDGF isoforms: the extraordinary function of the HDGF-A N-terminal peptide

Journal Name: Biological Chemistry
Volume: 398
Issue: 7
Pages: 793-811

http://ift.tt/2rsImXy

Erratum to: Tropane alkaloids as substrates and inhibitors of human organic cation transporters of the SLC22 (OCT) and the SLC47 (MATE) families

Journal Name: Biological Chemistry
Volume: 398
Issue: 7
Pages: 813-813

http://ift.tt/2rY0hZz

Eliquis (apixaban) 5 mg tablets: Recall One Lot- Bottle labeled as Eliquis 5 mg was found to contain Eliquis 2.5 mg tablets

[Posted 06/13/2017] AUDIENCE: Cardiology, Pharmacy ISSUE: Bristol-Myers Squibb Company is voluntarily recalling one lot (#HN0063) of Eliquis 5 mg tablets to the consumer level. This lot was distributed nationwide in the U.S. to wholesalers and...

http://ift.tt/2ro9awS

Eliquis (apixaban) 5 mg tablets: Recall One Lot- Bottle labeled as Eliquis 5 mg was found to contain Eliquis 2.5 mg tablets

Changes in the Diagnosis and Management of Patent Ductus Arteriosus from 2006 to 2015 in United States Neonatal Intensive Care Units

To identify changes in the diagnosis, pharmacotherapy, and surgical ligation of patent ductus arteriosus (PDAs) in infants born premature and report on temporal changes in mortality and morbidity from a large volume of neonatal intensive care units (NICUs) in the US.

http://ift.tt/2rnJT5L

Improvement in Renal Cystic Disease of Tuberous Sclerosis Complex After Treatment with Mammalian Target of Rapamycin Inhibitor

Renal cysts occur in approximately 50% of patients with tuberous sclerosis complex, but their clinical significance and response to treatment are unknown. Abdominal imaging of 15 patients with tuberous sclerosis complex-associated renal cystic disease who had received mammalian target of rapamycin inhibitor therapy for other tuberous sclerosis complex-related indications was evaluated. Reductions in cyst number, sum diameter, and volume were observed.

http://ift.tt/2rofnsH

Resting Heart Rate Percentiles and Associated Factors in Children and Adolescents

To present population-based resting heart rate (RHR) percentiles and associated factors in children and adolescents.

http://ift.tt/2s7G9CA

Markers of Successful Extubation in Extremely Preterm Infants, and Morbidity After Failed Extubation

To identify variables associated with successful elective extubation, and to determine neonatal morbidities associated with extubation failure in extremely preterm neonates.

http://ift.tt/2s7mVxe

Predicting Infectious ComplicatioNs in Children with Cancer: an external validation study

http://ift.tt/2sZ0dr2

Prioritising action on occupational carcinogens in Europe: a socioeconomic and health impact assessment

http://ift.tt/2spuEtk

Pharmacologically directed strategies in academic anticancer drug discovery based on the European NCI compounds initiative

http://ift.tt/2sZ1gax

Comparing Corticosteroid Preparation and Dose in the Improvement of Shoulder Function and Pain: A Randomized, Single-Blind Pilot Study.

Introduction: Shoulder pain may arise from inflammation of the bursa separating the supraspinatus tendon from the coracoacromial ligament and acromion. The optimal treatment dose and preparation of intrabursal corticosteroid injection are unknown. Methods: This single-blinded equivalence study recruited 62 subjects randomizing them to one of following four arms: methylprednisolone 20 mg, methylprednisolone 40 mg, triamcinolone acetonide 20 mg, or triamcinolone acetonide 40 mg. QuickDASH, subject-reported pain, and adverse events were recorded in time of injection, 3 days later, 3 wks later, and 6 wks later. Primary outcome was QuickDASH improvements 6 wks after injection. Results: All four groups were equally matched regarding age, sex, ethnicity, and site injected. Six weeks after injection, no statistically significant changes were noted in QuickDASH improvement (as compared with time of injection) among the four arms. There were no statistically significant differences at 6 wks regarding improvement in pain. There were no statistically significant differences noted in adverse events among the four arms. Conclusions: Neither dose nor preparation of injectable corticosteroid influences magnitude of improvement in function or pain experienced. Although this study provides clinically relevant insight regarding corticosteroid dose and type when managing shoulder pain, the modest sample size may limit the conclusions that can be made about efficacy and adverse effects. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2s7yTH2

Lsp family proteins regulate antibiotic biosynthesis in Lysobacter enzymogenes OH11

Ax21 family proteins have been shown to play regulatory roles in plant- and animal-pathogenic species in the bacterial family Xanthomonadaceae, but the protein have not been investigated previously in the non-...

http://ift.tt/2tiDEwA

ESRD After Heart Failure, Myocardial Infarction, or Stroke in Type 2 Diabetic Patients With CKD

How cardiovascular (CV) events affect progression to end-stage renal disease (ESRD), particularly in the setting of type 2 diabetes, remains uncertain.

http://ift.tt/2slduML

Metabolic Acidosis or Respiratory Alkalosis? Evaluation of a Low Plasma Bicarbonate Using the Urine Anion Gap

Hypobicarbonatemia, or a reduced bicarbonate concentration in plasma, is a finding seen in 3 acid-base disorders: metabolic acidosis, chronic respiratory alkalosis and mixed metabolic acidosis and chronic respiratory alkalosis. Hypobicarbonatemia due to chronic respiratory alkalosis is often misdiagnosed as a metabolic acidosis and mistreated with the administration of alkali therapy. Proper diagnosis of the cause of hypobicarbonatemia requires integration of the laboratory values, arterial blood gas, and clinical history.

http://ift.tt/2tiLZjW

Pulsara's Prehospital Alerting Package selected as a JEMS Hot Product from EMS Today 2017

Pulsara's Prehospital Alerting Package among 30 innovative new products for emergency medical services and prehospital care. BOZEMAN, Mont. — Pulsara and JEMS (Journal of Emergency Medical Services) are proud to announce the selection of Pulsara's Prehospital Alerting Package as a Hot Product from the JEMS EMS Today Conference & Exposition, which was held February 23–25 in ...

http://ift.tt/2spnWnk

Subcutaneous Neurotrophin 4 Infusion Using Osmotic Pumps or Direct Muscular Injection Enhances Aging Rat Laryngeal Muscles

Here, we present a protocol to describe the use of neurotrophin 4 (NTF4) systemically and directly to remodel rat aging laryngeal muscles.

http://ift.tt/2sZ5w9Q

Immunoexpression of p16 in uterine leiomyomas with infarct-type necrosis: an analysis of 35 cases

Abstract

Aims

Uterine leiomyosarcomas frequently show p16 immunoexpression. However, p16 may also be expressed in some benign leiomyoma variants such as leiomyomas with bizarre nuclei and cellular leiomyomas, limiting its utility as a biomarker to distinguish between benign and malignant neoplasms. We investigated p16 expression in leiomyomas with infarct-type necrosis, tumours which may sometimes be misinterpreted as smooth muscle tumors of uncertain malignant potential or even leiomyosarcoma on conventional light microscopy.

Methods

p16 immunostaining was performed on 35 leiomyomas with infarct-type necrosis and the staining pattern was analyzed. Staining was classified as absent, scattered/isolated, <33%, 33-66% or >66% positive cells, and was assessed in the areas immediately surrounding and far from the infarct.

Results

The median age of patients was 44 years. Seventeen had hormonal/non-hormonal drugs and 3 were pregnant. The median tumour size was 7.25 cm. The mean mitotic count was 0.9/10 high-power-fields. Only one tumour had multifocal mild nuclear atypia. Positive p16 was noted in 34 of 35 (97.2%) tumours. It was typically patchy and was concentrated in areas immediately surrounding the necrosis. Far from the necrosis, p16 positivity was predominantly seen in scattered/isolated cells. One tumour without any worrisome microscopic features showed diffuse p16 positivity throughout. Median follow-up was 55 months and none of the patients experienced any recurrence.

Conclusion

p16 expression in benign uterine smooth muscle tumours with infarct-type necrosis is common. The staining is particularly concentrated adjacent to areas of necrosis. It is important to be aware of this potential pitfall when interpreting p16 expression.

http://ift.tt/2s7qzHi

Rewiring Neuronal Circuits: A New Method for Fast Neurite Extension and Functional Neuronal Connection

This procedure describes how to rapidly initiate, extend and connect neurites organized in microfluidic chambers using poly-D-lysine-coated beads fixed to micropipettes that guide neurite elongation.

http://ift.tt/2tir6FI

Preliminary Experience with Stent-Assisted Coiling of Aneurysms Arising from Small (

BACKGROUND AND PURPOSE:

The Low-Profile Visualized Intraluminal Support (LVIS) stent is a new device recently introduced for the treatment of wide-neck intracranial aneurysms. This single-center study presents the authors' preliminary experience using the LVIS stent to treat saccular aneurysms with parent arteries smaller than 2.5 mm.

MATERIALS AND METHODS:

Aneurysms with a LVIS stent used in a small parent vessel (<2.5 mm in diameter) between October 2014 and April 2016 were included. Procedure-related complications, angiographic results, clinical outcomes, and midterm follow-up data were analyzed retrospectively.

RESULTS:

A total of 22 patients was studied, including 5 ruptured and 17 unruptured aneurysms. Most of the aneurysms were located in the anterior circulation (90.9%). Stent placement in the parent arteries measuring 1.7–2.4 mm in diameter (mean, 2.1 mm) was successful in 100% of cases. Procedure-related complication developed in 1 patient (4.5%) who presented with aneurysm rupture. No permanent morbidity and mortality occurred. Immediate angiographic outcome showed complete occlusion in 8 aneurysms (36.4%), neck residual in 8 (36.4%), and residual aneurysm in 6 (27.3%). All patients underwent angiographic follow-up at a mean of 8.3 months, which revealed complete occlusion in 18 (81.8%) patients, neck remnant in 3 (13.6%), and residual sac in 1 (4.5%). No recanalization of the target aneurysm was observed. There was 1 case with asymptomatic in-stent stenosis.

CONCLUSIONS:

Our preliminary results show that the deployment of LVIS stents in small vessels is feasible, safe, and effective in the midterm. Larger studies with long-term follow-up are needed to validate our promising results.

http://ift.tt/2sYirZD

The Role of MRI in Diagnosing Neurovascular Compression of the Cochlear Nerve Resulting in Typewriter Tinnitus [HEAD & NECK]

BACKGROUND AND PURPOSE:

Typewriter tinnitus, a symptom characterized by paroxysmal attacks of staccato sounds, has been thought to be caused by neurovascular compression of the cochlear nerve, but the correlation between radiologic evidence of neurovascular compression of the cochlear nerve and symptom presentation has not been thoroughly investigated. The purpose of this study was to examine whether radiologic evidence of neurovascular compression of the cochlear nerve is pathognomonic in typewriter tinnitus.

MATERIALS AND METHODS:

Fifteen carbamazepine-responding patients with typewriter tinnitus and 8 control subjects were evaluated with a 3D T2-weighted volume isotropic turbo spin-echo acquisition sequence. Groups 1 (16 symptomatic sides), 2 (14 asymptomatic sides), and 3 (16 control sides) were compared with regard to the anatomic relation between the vascular loop and the internal auditory canal and the presence of neurovascular compression of the cochlear nerve with/without angulation/indentation.

RESULTS:

The anatomic location of the vascular loop was not significantly different among the 3 groups (all, P > .05). Meanwhile, neurovascular compression of the cochlear nerve on MR imaging was significantly higher in group 1 than in group 3 (P = .032). However, considerable false-positive (no symptoms with neurovascular compression of the cochlear nerve on MR imaging) and false-negative (typewriter tinnitus without demonstrable neurovascular compression of the cochlear nerve) findings were also observed.

CONCLUSIONS:

Neurovascular compression of the cochlear nerve was more frequently detected on the symptomatic side of patients with typewriter tinnitus compared with the asymptomatic side of these patients or on both sides of control subjects on MR imaging. However, considering false-positive and false-negative findings, meticulous history-taking and the response to the initial carbamazepine trial should be regarded as more reliable diagnostic clues than radiologic evidence of neurovascular compression of the cochlear nerve.

http://ift.tt/2sovu9H

Measurable Supratentorial White Matter Volume Changes in Patients with Diffuse Intrinsic Pontine Glioma Treated with an Anti-Vascular Endothelial Growth Factor Agent, Steroids, and Radiation [PEDIATRICS]

BACKGROUND AND PURPOSE:

Assessing the response to treatment in infiltrative brain tumors by using lesion volume–based response criteria is challenging. We hypothesized that in such tumors, volume measurements alone may not accurately capture changes in actual tumor burden during treatment. We longitudinally evaluated volume changes in both normal-appearing supratentorial white matter and the brain stem lesions in patients treated for diffuse intrinsic pontine glioma to determine to what extent adjuvant systemic therapies may skew the accuracy of tumor response assessments based on volumetric analysis.

MATERIALS AND METHODS:

The anatomic MR imaging and diffusion tensor imaging data of 26 patients with diffuse intrinsic pontine glioma were retrospectively analyzed. Treatment included conformal radiation therapy in conjunction with vandetanib and dexamethasone. Volumetric and diffusion data were analyzed with time, and differences between time points were evaluated statistically.

RESULTS:

Normalized brain stem lesion volume decreased during combined treatment (slope = –0.222, P < .001) and increased shortly after completion of radiation therapy (slope = 0.422, P < .001). Supratentorial white matter volume steadily and significantly decreased with time (slope = –0.057, P < .001).

CONCLUSIONS:

Longitudinal changes in brain stem lesion volume are robust; less pronounced but measurable changes occur in the supratentorial white matter. Volume changes in nonirradiated supratentorial white matter during the disease course reflect the effects of systemic medication on the water homeostasis of normal parenchyma. Our data suggest that adjuvant nontumor–targeted therapies may have a more substantial effect on lesion volume changes than previously thought; hence, an apparent volume decrease in infiltrative tumors receiving combined therapies may lead to overestimation of the actual response and tumor control.

http://ift.tt/2sYkblK

Involvement of cytochrome P450 in cisplatin treatment: implications for toxicity

Abstract

Purpose

The aim of this study is to evaluate the relationship between the CYP450 enzyme family and cisplatin toxicity.

Methods

This article examined a collection of studies suggesting that CYP450 enzymes may influence cisplatin toxicity. We performed a narrative mini-review.

Results

The studies review showed that CYP450 enzymes have an important role in drug-induced hepatotoxicity and nephrotoxicity, mainly CYP2E1 and CYP4A11. The studies also suggested that the cisplatin and CYP2E1 interaction leads to the generation of reactive oxygen species (ROS) and other oxidants resulting in renal injury; and that ROS generated by both the use of cisplatin and by the CYP2E1 increases tissue damage, induces apoptosis, and causes liver failure.

Conclusions

We observed that there is an important relationship between CYP450 and cisplatin, involving increased toxicity. However, the possible mechanisms described for the involvement of CYP450 enzymes in nephrotoxicity and hepatotoxicity induced by cisplatin need to be confirmed by further studies. Therefore, there is a need for a deeper investigation focusing on cisplatin toxicity mediated by CYP450 enzymes, which would undoubtedly contribute to a better understanding of the mechanisms that have been implicated so far.

http://ift.tt/2skt0IE

Resting-State Seed-Based Analysis: An Alternative to Task-Based Language fMRI and Its Laterality Index [FUNCTIONAL]

BACKGROUND AND PURPOSE:

Language is a cardinal function that makes human unique. Preservation of language function poses a great challenge for surgeons during resection. The aim of the study was to assess the efficacy of resting-state fMRI in the lateralization of language function in healthy subjects to permit its further testing in patients who are unable to perform task-based fMRI.

MATERIALS AND METHODS:

Eighteen healthy right-handed volunteers were prospectively evaluated with resting-state fMRI and task-based fMRI to assess language networks. The laterality indices of Broca and Wernicke areas were calculated by using task-based fMRI via a voxel-value approach. We adopted seed-based resting-state fMRI connectivity analysis together with parameters such as amplitude of low-frequency fluctuation and fractional amplitude of low-frequency fluctuation (fALFF). Resting-state fMRI connectivity maps for language networks were obtained from Broca and Wernicke areas in both hemispheres. We performed correlation analysis between the laterality index and the z scores of functional connectivity, amplitude of low-frequency fluctuation, and fALFF.

RESULTS:

Pearson correlation analysis between signals obtained from the z score of fALFF and the laterality index yielded a correlation coefficient of 0.849 (P < .05). Regression analysis of the fALFF with the laterality index yielded an R² value of 0.721, indicating that 72.1% of the variance in the laterality index of task-based fMRI could be predicted from the fALFF of resting-state fMRI.

CONCLUSIONS:

The present study demonstrates that fALFF can be used as an alternative to task-based fMRI for assessing language laterality. There was a strong positive correlation between the fALFF of the Broca area of resting-state fMRI with the laterality index of task-based fMRI. Furthermore, we demonstrated the efficacy of fALFF for predicting the laterality of task-based fMRI.

http://ift.tt/2soTIAx

Striving for the Best: How Far Should We Go? Regarding "Impact of Modified TICI 3 versus Modified TICI 2b Reperfusion Score to Predict Good Outcome following Endovascular Therapy" [letter]

http://ift.tt/2soPGZ4

Caution; Confusion Ahead... [letter]

http://ift.tt/2sYqXI9

Reply: [reply]

http://ift.tt/2soPDN4

Clinically Feasible Microstructural MRI to Quantify Cervical Spinal Cord Tissue Injury Using DTI, MT, and T2*-Weighted Imaging: Assessment of Normative Data and Reliability [SPINE]

BACKGROUND AND PURPOSE:

DTI, magnetization transfer, T2*-weighted imaging, and cross-sectional area can quantify aspects of spinal cord microstructure. However, clinical adoption remains elusive due to complex acquisitions, cumbersome analysis, limited reliability, and wide ranges of normal values. We propose a simple multiparametric protocol with automated analysis and report normative data, analysis of confounding variables, and reliability.

MATERIALS AND METHODS:

Forty healthy subjects underwent T2WI, DTI, magnetization transfer, and T2*WI at 3T in <35 minutes using standard hardware and pulse sequences. Cross-sectional area, fractional anisotropy, magnetization transfer ratio, and T2*WI WM/GM signal intensity ratio were calculated. Relationships between MR imaging metrics and age, sex, height, weight, cervical cord length, and rostrocaudal level were analyzed. Test-retest coefficient of variation measured reliability in 24 DTI, 17 magnetization transfer, and 16 T2*WI datasets. DTI with and without cardiac triggering was compared in 10 subjects.

RESULTS:

T2*WI WM/GM showed lower intersubject coefficient of variation (3.5%) compared with magnetization transfer ratio (5.8%), fractional anisotropy (6.0%), and cross-sectional area (12.2%). Linear correction of cross-sectional area with cervical cord length, fractional anisotropy with age, and magnetization transfer ratio with age and height led to decreased coefficients of variation (4.8%, 5.4%, and 10.2%, respectively). Acceptable reliability was achieved for all metrics/levels (test-retest coefficient of variation < 5%), with T2*WI WM/GM comparing favorably with fractional anisotropy and magnetization transfer ratio. DTI with and without cardiac triggering showed no significant differences for fractional anisotropy and test-retest coefficient of variation.

CONCLUSIONS:

Reliable multiparametric assessment of spinal cord microstructure is possible by using clinically suitable methods. These results establish normalization procedures and pave the way for clinical studies, with the potential for improving diagnostics, objectively monitoring disease progression, and predicting outcomes in spinal pathologies.

http://ift.tt/2sYFCmv

[other]

http://ift.tt/2sYqTYV

Minor Stroke Syndromes in Large-Vessel Occlusions: Mechanical Thrombectomy or Thrombolysis Only? [INTERVENTIONAL]

http://ift.tt/2sYo0am

Myelin Detection Using Rapid Quantitative MR Imaging Correlated to Macroscopically Registered Luxol Fast Blue-Stained Brain Specimens [ADULT BRAIN]

BACKGROUND AND PURPOSE:

Myelin detection is of great value in monitoring diseases such as multiple sclerosis and dementia. However, most MR imaging methods to measure myelin are challenging for routine clinical use. Recently, a novel method was published, in which the presence of myelin is inferred by using its effect on the intra- and extracellular water relaxation rates and proton density, observable by rapid quantitative MR imaging. The purpose of this work was to validate this method further on the brains of 12 fresh, intact cadavers.

MATERIALS AND METHODS:

The 12 brains were scanned with a quantification sequence to determine the longitudinal and transverse relaxation rates and proton density as input for the myelin estimations. Subsequently, the brains were excised at postmortem examination, and brain slices were stained with Luxol fast blue to verify the presence of myelin. The optical density values of photographs of the stained brain slices were registered with the MR images and correlated with the myelin estimation performed by quantitative MR imaging.

RESULTS:

A correlation was found between the 2 methods with a mean Spearman for all subjects of 0.74 ± 0.11. Linear regression showed a mean intercept of 1.50% ± 2.84% and a mean slope of 4.37% ± 1.73%/%. A lower correlation was found for the separate longitudinal relaxation rates and proton density ( = 0.63 ± 0.12 and –0.73 ± 0.09, respectively). For transverse relaxation rates, the was very low (0.11 ± 0.28).

CONCLUSIONS:

The observed correlation supports the validity of myelin measurement by using the MR imaging quantification method.

http://ift.tt/2spb40v

Regarding "Embolization of Intracranial Dural Arteriovenous Fistulas Using PHIL Liquid Embolic Agent in 26 Patients: A Multicenter Study" [letter]

http://ift.tt/2sYpy4j

Synthetic MRI for Clinical Neuroimaging: Results of the Magnetic Resonance Image Compilation (MAGiC) Prospective, Multicenter, Multireader Trial [ADULT BRAIN]

BACKGROUND AND PURPOSE:

Synthetic MR imaging enables reconstruction of various image contrasts from 1 scan, reducing scan times and potentially providing novel information. This study is the first large, prospective comparison of synthetic-versus-conventional MR imaging for routine neuroimaging.

MATERIALS AND METHODS:

A prospective multireader, multicase noninferiority trial of 1526 images read by 7 blinded neuroradiologists was performed with prospectively acquired synthetic and conventional brain MR imaging case-control pairs from 109 subjects (mean, 53.0 ± 18.5 years of age; range, 19–89 years of age) with neuroimaging indications. Each case included conventional T1- and T2-weighted, T1 and T2 FLAIR, and STIR and/or proton density and synthetic reconstructions from multiple-dynamic multiple-echo imaging. Images were randomized and independently assessed for diagnostic quality, morphologic legibility, radiologic findings indicative of diagnosis, and artifacts.

RESULTS:

Clinical MR imaging studies revealed 46 healthy and 63 pathologic cases. Overall diagnostic quality of synthetic MR images was noninferior to conventional imaging on a 5-level Likert scale (P < .001; mean synthetic-conventional, –0.335 ± 0.352; = 0.5; lower limit of the 95% CI, –0.402). Legibility of synthetic and conventional morphology agreed in >95%, except in the posterior limb of the internal capsule for T1, T1 FLAIR, and proton-density views (all, >80%). Synthetic T2 FLAIR had more pronounced artifacts, including +24.1% of cases with flow artifacts and +17.6% cases with white noise artifacts.

CONCLUSIONS:

Overall synthetic MR imaging quality was similar to that of conventional proton-density, STIR, and T1- and T2-weighted contrast views across neurologic conditions. While artifacts were more common in synthetic T2 FLAIR, these were readily recognizable and did not mimic pathology but could necessitate additional conventional T2 FLAIR to confirm the diagnosis.

http://ift.tt/2sYxTFg

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Τρίτη 13 Ιουνίου 2017

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