Zika Virus: Obstetric and Pediatric Anesthesia Considerations

As of November 2016, the Florida Department of Health (FDH) and the Centers for Disease Control and Prevention have confirmed more than 4000 travel-related Zika virus (ZIKV) infections in the United States with >700 of those in Florida. There have been 139 cases of locally acquired infection, all occurring in Miami, Florida. Within the US territories (eg, Puerto Rico, US Virgin Islands), >30,000 cases of ZIKV infection have been reported. The projected number of individuals at risk for ZIKV infection in the Caribbean and Latin America approximates 5 million. Similar to Dengue and Chikungunya viruses, ZIKV is spread to humans by infected Aedes aegypti mosquitoes, through travel-associated local transmission, via sexual contact, and through blood transfusions. South Florida is an epicenter for ZIKV infection in the United States and the year-round warm climate along with an abundance of mosquito vectors that can harbor the flavivirus raise health care concerns. ZIKV infection is generally mild with clinical manifestations of fever, rash, conjunctivitis, and arthralgia. Of greatest concern, however, is growing evidence for the relationship between ZIKV infection of pregnant women and increased incidence of abnormal pregnancies and congenital abnormalities in the newborn, now medically termed ZIKA Congenital Syndrome. Federal health officials are observing 899 confirmed Zika-positive pregnancies and the FDH is currently monitoring 110 pregnant women with evidence of Zika infection. The University of Miami/Jackson Memorial Hospital is uniquely positioned just north of downtown Miami and within the vicinity of Liberty City, Little Haiti, and Miami Beach, which are currently "hot spots" for Zika virus exposure and transmissions. As the FDH works fervently to prevent a Zika epidemic in the region, health care providers at the University of Miami and Jackson Memorial Hospital prepare for the clinical spectrum of ZIKV effects as well as the safe perioperative care of the parturients and their affected newborns. In an effort to meet anesthetic preparedness for the care of potential Zika-positive patients and perinatal management of babies born with ZIKA Congenital Syndrome, this review highlights the interim guidelines from the Centers for Disease Control and Prevention and also suggest anesthetic implications and recommendations. In addition, this article reviews guidance for the evaluation and anesthetic management of infants with congenital ZIKV infection. To better manage the perioperative care of affected newborns, this article also reviews the comparative anesthetic implications of babies born with related congenital malformations.

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Coming to a Patient Near You: The Zika Virus and Anesthetic Implications

No abstract available

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Subcellular Hypoxia: A Survival Guide

No abstract available

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Subcellular Energetics and Metabolism: Potential Therapeutic Applications

Part I of this review discussed the similarities between embryogenesis, mammalian adaptions to hypoxia (primarily driven by hypoxia-inducible factor-1 [HIF-1]), ischemia-reperfusion injury (and its relationship with reactive oxygen species), hibernation, diving animals, cancer, and sepsis, and it focused on the common characteristics that allow cells and organisms to survive in these states. Part II of this review describes techniques by which researchers gain insight into subcellular energetics and identify potential future tools for clinicians. In particular, P31 nuclear magnetic resonance to measure high-energy phosphates, serum lactate measurements, the use of near-infrared spectroscopy to measure the oxidation state of cytochrome aa3, and the ability of the protoporphyrin IX-triplet state lifetime technique to measure mitochondrial oxygen tension are discussed. In addition, this review discusses novel treatment strategies such as hyperbaric oxygen, preconditioning, exercise training, therapeutic gases, as well as inhibitors of HIF-1, HIF prolyl hydroxylase, and peroxisome proliferator-activated receptors.

http://ift.tt/2rnvWnz

Subcellular Energetics and Metabolism: A Cross-Species Framework

Although it is generally believed that oxidative phosphorylation and adequate oxygenation are essential for life, human development occurs in a profoundly hypoxic environment and "normal" levels of oxygen during embryogenesis are even harmful. The ability of embryos not only to survive but also to thrive in such an environment is made possible by adaptations related to metabolic pathways. Similarly, cancerous cells are able not only to survive but also to grow and spread in environments that would typically be fatal for healthy adult cells. Many biological states, both normal and pathological, share underlying similarities related to metabolism, the electron transport chain, and reactive species. The purpose of Part I of this review is to review the similarities among embryogenesis, mammalian adaptions to hypoxia (primarily driven by hypoxia-inducible factor-1), ischemia-reperfusion injury (and its relationship with reactive oxygen species), hibernation, diving animals, cancer, and sepsis, with a particular focus on the common characteristics that allow cells and organisms to survive in these states.

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Characterization of pomegranate (Punica granatum L.) seed and oils

Abstract

The main objective of current study was to characterize of pomegranate (Punica granatum L.) seed and oils as a source of phytochemical and bioactive compounds. While total phenol contents of seed extracts vary between 23.6 mg gallic acid equivalent /g and 28.8 mg gallic acid equivalent /g, their antioxidant activities were changed between 17.6 % and 22.9 % (p<0.05). The seeds of pomegranate varieties contained 347 - 647 mg / kg Ca, 2076 - 3846 mg / kg K, 1572 - 2327 mg / kg P, and 1357 - 1781 mg / kg Mg. While the total phenol contents of seed oils change between 7.8 mg gallic acid equivalent / g and 19.2 mg GAE /g, antioxidant activity of oil samples varied between 6.8 % and 8.8 % (p<0.05). The predominant fatty acid of oils is punicic acid, and punicic acid contents of oil samples were found between 71.2 % and 77.6 %. Oleic acid contents of seed oils were determined between 7.6 % and 9.1 %. In addition, γ-tocopherol contents of pomegranate oil ranged from 236 mg /100 g to 389 mg /100g. Pomegranate seeds are sources of bioactive and phytochemical such as fatty acid, γ-tocopherol, total phenolic content and flavonoids with potentially high antioxidant activities.

Practical applications: In folk medicine for many centuries, pomegranate is an important source of bioactive and phytochemical compounds. Pomegranate fruit are known to posses strong antioxidant activity, and its oil consists of approximately 80% punicic acid. Pomegranate seed contains a range of nutraceutical components such as punicic acid, sterols and γ-tocopherol.

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Antimicrobial activity of puffball(Bovistella radicata) and separation of bioactive compounds

To test the antimicrobial activity of different extracts and fermentation broth from puffball(Bovistella radicata), the different extracts and fermentation broth of puffball were prepared, the active fraction was...

http://ift.tt/2rnPtnS

Mannan endo-1,4-β-mannosidase from Kitasatospora sp. isolated in Indonesia and its potential for production of mannooligosaccharides from mannan polymers

Mannan endo-1,4-β-mannosidase (commonly known as β-mannanase) catalyzes a random cleavage of the β-d-1,4-mannopyranosyl linkage in mannan polymers. The enzyme has been utilized in biofuel production from lignocel...

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Different abundance and correlational patterns exist between total and presumed pathogenic V. vulnificus and V. parahaemolyticus in shellfish and waters along the North Carolina coast

Abstract

Monitoring of Vibrio vulnificus and Vibrio parahaemolyticus abundance is pertinent due to the ability of these species to cause disease in humans through aquatic vectors. Previously, we performed a multiyear investigation tracking Vibrio spp. levels in five sites along the southeastern North Carolina coast. From February 2013 to October 2015 total V. vulnificus, and V. parahaemolyticus abundance was measured in water, oysters, and clams. In the current study, pathogenic subpopulations were identified in these isolates using molecular markers, revealing that 5.3% of V. vulnificus isolates possessed the virulence-correlated gene (vcgC), and 1.9% of V. parahaemolyticus isolates harbored one or both of the virulence associated hemolysin genes (tdh and trh). Total V. parahaemolyticus abundance was not sufficient to predict the abundance of pathogenic subpopulations. Specifically, pathogenic V. parahaemolyticus isolates were more often isolated in cooler waters and were sometimes isolated when no other V. parahaemolyticus strains were detectable. V. vulnificus clinical (C-) genotypes correlated with total V. vulnificus, however salinity, water depth and total suspended solids influenced C- and E-genotypes differently. Lastly, we documented individual oysters harboring significantly higher V. vulnificus levels for which there was no ecological explanation, a phenomenon that deserves closer attention due to the potentially elevated health hazard associated with these 'hot' shellfish.

http://ift.tt/2qHvw9b

Biogeography of cryoconite bacterial communities on glaciers of the Tibetan Plateau

Abstract

Cryoconite holes, water-filled pockets containing biological and mineralogical deposits that form on glacier surfaces, play important roles in glacier mass balance, glacial geochemistry, and carbon cycling. The presence of cryoconite material decreases surface albedo and accelerates glacier mass loss, a problem of particular importance in the rapidly melting Tibetan Plateau. No studies have addressed the microbial community composition of cryoconite holes and their associated ecosystem processes on Tibetan glaciers. To further enhance our understanding of these glacial ecosystems on the Tibetan Plateau and to examine their role in carbon cycling as the glaciers respond to climate change, we explored the bacterial communities within cryoconite holes associated with three climatically distinct Tibetan Plateau glaciers using Illumina sequencing of the V4 region of the 16S rRNA gene. Cryoconite bacterial communities were dominated by Cyanobacteria, Chloroflexi, Betaproteobacteria, Bacteroidetes and Actinobacteria. Cryoconite bacterial community composition varied according to their geographical locations, exhibiting significant differences among glaciers studied. Regional beta diversity was driven by the interaction between geographic distance and environmental variables; the latter contributed more than geographic distance to the variation in cryoconite microbial communities. Our study is the first to describe the regional-scale spatial variability and to identify the factors that drive regional variability of cryoconite bacterial communities on the Tibetan Plateau.

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Spinescope

Publication date: Available online 19 May 2017
Source:Seminars in Spine Surgery
Author(s): Scott D. Boden




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Thromboembolic and bleeding complications during oral anticoagulation therapy in cancer patients with atrial fibrillation: a Danish nationwide population-based cohort study

Abstract

Coexisting cancer in patients with atrial fibrillation (AF) has been associated with thromboembolism and bleeding. We used Danish population-based medical databases to conduct a population-based cohort study that included all AF patients who redeemed a prescription for vitamin K antagonists (VKA) or non-VKA oral anticoagulant (NOAC) between July 2004 and December 2013. We characterized these patients according to the presence (N = 11,855) or absence (N = 56,264) of a cancer diagnosis before redemption of their oral anticoagulant prescription, and then examined their 1-year risk of thromboembolic or bleeding complications or death. We next used Cox regression to compare the hazard ratios for complications among VKA- or NOAC-treated AF patients with versus without a cancer diagnosis, after adjusting for sex, age, and CHA₂DS₂ VASc score. One-year risks of thromboembolic complications in AF patients who redeemed a VKA prescription were similar in those with (6.5%) and without (5.8%) cancer [hazard ratio (HR) 1.0 (95% confidence interval (CI): 0.93, 1.1)]. This also was found for bleeding complications (5.4% vs. 4.3%, HR 1.1 [95% CI: 1.0, 1.2]). For AF patients with cancer who redeemed a NOAC prescription, risks were also similar for thromboembolic complications (4.9% of cancer patients vs. 5.1% of noncancer patients, HR 0.80 [95% CI: 0.61, 1.1]), and for bleeding complications (4.4% vs. 3.1%, HR 1.2 [95% CI: 0.92, 1.7]). The absolute risks of thromboembolic or bleeding complications were nearly the same in patients with and without cancer who redeemed prescription for VKAs or NOACs.

Since both atrial fibrillation and cancer are common, any increased risk of complications among patients treated with vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs) may have major public health implications. This study found that the absolute risks of thromboembolic or bleeding complications were nearly the same in patients with and without cancer who redeemed prescriptions for VKAs or NOACs.

http://ift.tt/2qH7GKx

The PAZOREAL noninterventional study to assess effectiveness and safety of pazopanib and everolimus in the changing metastatic renal cell carcinoma treatment landscape

Future Oncology Ahead of Print.


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A Targeted Capture Linkage Map Anchors the Genome of the Schistosomiasis Vector Snail, Biomphalaria glabrata

The aquatic planorbid snail Biomphalaria glabrate is one of the most intensively-studied mollusks due to its role in the transmission of schistosomiasis. Its 916 Mb genome has recently been sequenced and annotated, but it remains poorly assembled. Here we used targeted capture markers to map over 10,000 B. glabrate scaffolds in a linkage cross of 94 F1 offspring, generating 24 linkage groups. We added additional scaffolds to these linkage groups based on linkage disequilibrium analysis of targeted capture and whole-genome sequences of 96 unrelated snails. Our final linkage map consists of 18,613 scaffolds comprising 515 Mb, representing 56% of the genome and 75% of genic and nonrepetitive regions. There are 18 large (>10 Mb) linkage groups, likely representing the expected 18 haploid chromosomes, and more than 50% of the genome has been assigned to linkage groups of at least 17 Mb. Comparisons with other gastropod genomes reveal patterns of synteny and chromosomal rearrangements. Linkage relationships of key immune-relevant genes may help clarify snail-schistosome interactions. By focusing on linkage among genic and nonrepetitive regions, we have generated a useful resource for associating snail phenotypes with causal genes, even in the absence of a complete genome assembly. A similar approach could potentially improve numerous poorly-assembled genomes in other taxa. This map will facilitate future work on this host of a serious human parasite.

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Phased Genotyping-by-Sequencing Enhances Analysis of Genetic Diversity and Reveals Divergent Copy Number Variants in Maize

High-throughput sequencing of reduced representation genomic libraries has ushered in an era of genotyping-by-sequencing (GBS), where genome-wide genotype data can be obtained for nearly any species. However, there remains a need for imputation-free GBS methods for genotyping large samples taken from heterogeneous populations of heterozygous individuals. This requires a number of issues encountered with GBS be considered, including the sequencing of non-overlapping sets of loci across multiple GBS libraries, a common missing data problem that results in low call rates for markers per individual, and a tendency for applicability only in inbred line samples with sufficient linkage disequilibrium for accurate imputation. We addressed these issues while developing and validating a new, comprehensive platform for GBS. This study supports the notion that GBS can be tailored to particular aims, and using Zea mays our results indicate that large samples of unknown pedigree can be genotyped to obtain complete and accurate GBS data. Optimizing size selection to sequence a high proportion of shared loci among individuals in different libraries and using simple in silico filters, a GBS procedure was established that produces high call rates per marker (>85%) with accuracy exceeding 99.4%. Furthermore, by capitalizing on the sequence-read structure of GBS data (stacks of reads), a new tool for resolving local haplotypes and scoring phased genotypes was developed, a feature that is not available in many GBS pipelines. Using local haplotypes reduces the marker dimensionality of the genotype matrix while increasing the informativeness of the data. Phased GBS in maize also revealed the existence of reproducibly inaccurate (apparent accuracy) genotypes that were due to divergent copy number variants unobservable in the underlying single nucleotide polymorphism data.

http://ift.tt/2r222Wa

Genetic Subtraction Profiling Identifies Candidate miRNAs Involved in Rice Female Gametophyte Abortion

Female gametophyte is an important participant in sexual reproduction of plants. The molecular mechanism of its development has received much attention in recent years. As important regulators of gene expression, miRNAs have been certified to play a significant role in many biological processes of plants including sexual reproduction. In this study, to investigate the potential regulatory effects of miRNAs on rice female gametophytes abortion, we used the high-throughput sequencing method to compare the miRNA transcriptome in ovules of a high frequency female-sterile line (fsv1) and a rice wild-type line (Gui 99) during ovule development. As a result, 522 known miRNAs and 295 novel miRNAs were identified to be expressed in the developing ovule of rice, while 100 known miRNAs were significantly differentially expressed during ovule development between these two rice lines. Combining with the gene expression information, a total of 627 coherent target genes of these differential expressed known miRNAs between fsv1 and Gui 99 were identified. The functional analyses of these coherent target genes revealed that the coherent target genes of differential expressed known miRNAs between two rice lines involved in many biological pathways, such as protein degradation, auxin signal transduction and transcription factor regulation. These results provide us important clues to investigate the regulatory roles of miRNAs in rice female gametophyte abortion.

http://ift.tt/2rBcrFG

Validated Bayesian Differentiation of Causative and Passenger Mutations

In many contexts, the problem arises of determining which of many candidate mutations is the most likely to be causative for some phenotype. It is desirable to have a way to evaluate this probability that relies as little as possible on previous knowledge, to avoid bias against discovering new genes or functions. We are isolating mutants with blocked cell cycle progression in Chlamydomonas, and determining mutant genome sequences. Due to the intensity of UV mutagenesis required for efficient mutant collection, the mutants contain multiple mutations altering coding sequence. To provide a quantitative estimate of probability that each individual mutation in a given mutant is the causative one, we develop a Bayesian approach. The approach employs four independent indicators: sequence conservation of the mutated coding sequence with Arabidopsis; severity of the mutation relative to Chlamydomonas wild type based on Blosum62 scores; meiotic mapping information for location of the causative mutation relative to known molecular markers; and, for a subset of mutants, transcriptional profile of the candidate wild type genes through the mitotic cell cycle. These indicators are statistically independent, and so can be combined quantitatively into a single probability calculation. We validate this calculation: recently isolated mutations that were not in the training set for developing the indicators, with high calculated probability of causality, are confirmed in every case by additional genetic data to indeed be causative. Analysis of best reciprocal blast relationships among Chlamydomonas and other eukaryotes indicate that the Ts-lethal mutants that our procedure recovers are highly enriched for fundamental cell-essential functions conserved broadly across plants and other eukaryotes, accounting for the high information content of sequence alignment to Arabidopsis.

http://ift.tt/2r2abdu

Discovery and Optimization of HKT288, a Cadherin-6 Targeting ADC for the Treatment of Ovarian and Renal Cancer. [Research Articles]

Despite an improving therapeutic landscape, significant challenges remain in treating the majority of advanced ovarian and renal cancer patients. We identified the cell-cell adhesion molecule cadherin-6 (CDH6) as a lineage gene having significant differential expression in ovarian and kidney cancer. HKT288 is an optimized CDH6-targeting DM4-based antibody drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal anti-tumor activity and highlights CDH6 as a novel antigen for biotherapeutic development. In order to more robustly predict patient benefit of targeting CDH6, we incorporate a population-based patient-derived xenograft (PDX) clinical trial (PCT) to capture the heterogeneity of response across an unselected cohort of 30 models - a novel preclinical approach in ADC development. HKT288 induces durable tumor regressions of ovarian and renal cancer models in vivo, including 40% of models on the PCT and features a pre-clinical safety profile supportive of progression towards clinical evaluation.

http://ift.tt/2r1PaPZ

Activated NOTCH-Induced Intratumoral Heterogeneity Drives Lung Cancer [Research Watch]

Activated NOTCH signaling is both tumor-suppressive and protumorigenic in SCLC.

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A WNT-Producing Niche Drives Lung Adenocarcinoma [Research Watch]

Lung adenocarcinomas contain cells that exhibit high WNT signaling and cells that provide WNT ligands.

http://ift.tt/2r23VT9

CHD4-Mediated DNA Hypermethylation Promotes Colorectal Cancer [Research Watch]

CHD4 maintains epigenetic silencing of tumor suppressor genes to promote tumorigenesis.

http://ift.tt/2rBp43h

Brigatinib Achieves Whole-Body and Intracranial Responses [Research Watch]

Brigatinib is tolerable and has antitumor activity in crizotinib-resistant ALK-positive NSCLC.

http://ift.tt/2r1TfUd

Midostaurin Gets FDA Nod for AML [News in Brief]

Drug is first that targets FLT3 mutations in patients with this leukemia.

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HPV Vaccine Slashes Rates of Oral Infection [News in Brief]

Yet vaccine uptake remains low despite likely protection from oropharyngeal cancer.

http://ift.tt/2r22CDC

AZD5363 Has Clinical Activity in Patients with AKT1-Mutant Solid Tumors [Research Watch]

Targeting mutant AKT1 has antitumor activity in a basket trial of patients with AKT1-mutant tumors.

http://ift.tt/2rARNW9

Association of fibrinogen level with early neurological deterioration among acute ischemic stroke patients with diabetes

Diabetes mellitus (DM) is a risk factor for early neurological deterioration (END) in acute ischemic stroke. The prothrombotic protein fibrinogen is frequently elevated in patients with diabetes, and may be as...

http://ift.tt/2qGNb0l

The intracerebral hemorrhage acutely decreasing arterial pressure trial II (ICH ADAPT II) protocol

Aggressively lowering blood pressure (BP) in acute intracerebral hemorrhage (ICH) may improve outcome. Although there is no evidence that BP reduction changes cerebral blood flow, retrospective magnetic resona...

http://ift.tt/2pUIjrr

The association between lunar phase and intracranial aneurysm rupture: Myth or reality? Own data and systematic review

It is a common belief in medical community that lunar phases have an impact on human health. A growing body of evidence indicates that lunar phases can predict the risk to develop acute neurological and vascul...

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Water Concentration Analysis of the Surgical Margin—Response

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Water Concentration Analysis of the Surgical Margin—Letter

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TAM Receptor Tyrosine Kinases in Cancer Drug Resistance

Receptor tyrosine kinases (RTK) are major regulators of key biological processes, including cell growth, survival, and differentiation, and were established early on as proto-oncogenes, with aberrant expression linked to tumor progression in many cancers. Therefore, RTKs have emerged as major targets for selective therapy with small-molecule inhibitors. However, despite improvements in survival rates, it is now apparent that the targeting of RTKs with selective inhibitors is only transiently effective, as the majority of patients eventually become resistant to therapy. As chemoresistance is the leading cause of cancer spread, progression, and mortality, there is an increasing need for understanding the mechanisms by which cancer cells can evade therapy-induced cell death. The TAM (Tyro3, Axl, Mer) subfamily of RTKs in particular feature in a variety of cancer types that have developed resistance to a broad range of therapeutic agents, including both targeted as well as conventional chemotherapeutics. This article reviews the roles of TAMs as tumor drivers and as mediators of chemoresistance, and the potential effectiveness of targeting them as part of therapeutic strategies to delay or combat resistance. Cancer Res; 77(11); 1–4. ©2017 AACR.

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Therapeutic IgE Antibodies: Harnessing a Macrophage-Mediated Immune Surveillance Mechanism against Cancer

IgG monoclonal antibodies have made significant contributions to cancer therapy, but suffer from several limitations that restrict their effectiveness in unleashing host immune system components against tumors. The development of monoclonal antibodies of an alternative class, namely IgE, may offer enhanced immune surveillance and superior effector cell potency against cancer cells. In our recent article, we elaborate our proof-of-concept studies of a mouse/human chimeric IgE antibody (MOv18 IgE), which is specific for the cancer-associated antigen folate receptor alpha. We demonstrate superior antitumor efficacy for IgE compared with an otherwise identical IgG in a syngeneic immunocompetent animal, and we identify TNFα/MCP-1 signaling as an IgE-mediated mechanism of monocyte and macrophage activation and recruitment to tumors. These findings draw parallels with powerful macrophage-activating functions employed by IgE against parasites, rather than allergic IgE mechanisms. The potential clinical application of IgE-derived drugs in clinical oncology is clear if the antitumor activity of MOv18 IgE in these preclinical experiments can be replicated in patients. In particular, different IgE antibodies with specificity for many other antigens already validated as targets for IgG suggest a wide potential for development of a novel class of antibody therapy. Cancer Res; 77(11); 1–5. ©2017 AACR.

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Cancer Treatment Side Effects: A Meta-Analysis of the Relationship between Response Expectancies and Experience

Although previous research has, overall, suggested a moderate relationship between response expectancies (REs) and cancer treatment-related side-effects, empirical results have been mixed.

http://ift.tt/2r1MPVo

Differences in Symptom Clusters Identified Using Ratings of Symptom Occurrence Versus Severity in Lung Cancer Patients Receiving Chemotherapy

An important question in symptom clusters research is whether the number and types of symptom clusters vary based on the specific dimension of the symptom experience used to create the clusters.

http://ift.tt/2rATBOZ

Distinguishing between spiritual distress, general distress, spiritual well-being, and spiritual pain among cancer patients during oncology treatment

Spiritual distress is present in ∼25% of oncology patients. We examined the extent to which this measure is identical to a variety of other measures, such as spiritual well-being, spiritual injury, spiritual pain, and general distress.

http://ift.tt/2r1MKRh

Interpreting findings from Mendelian randomization using the MR-Egger method

Abstract

Mendelian randomization-Egger (MR-Egger) is an analysis method for Mendelian randomization using summarized genetic data. MR-Egger consists of three parts: (1) a test for directional pleiotropy, (2) a test for a causal effect, and (3) an estimate of the causal effect. While conventional analysis methods for Mendelian randomization assume that all genetic variants satisfy the instrumental variable assumptions, the MR-Egger method is able to assess whether genetic variants have pleiotropic effects on the outcome that differ on average from zero (directional pleiotropy), as well as to provide a consistent estimate of the causal effect, under a weaker assumption—the InSIDE (INstrument Strength Independent of Direct Effect) assumption. In this paper, we provide a critical assessment of the MR-Egger method with regard to its implementation and interpretation. While the MR-Egger method is a worthwhile sensitivity analysis for detecting violations of the instrumental variable assumptions, there are several reasons why causal estimates from the MR-Egger method may be biased and have inflated Type 1 error rates in practice, including violations of the InSIDE assumption and the influence of outlying variants. The issues raised in this paper have potentially serious consequences for causal inferences from the MR-Egger approach. We give examples of scenarios in which the estimates from conventional Mendelian randomization methods and MR-Egger differ, and discuss how to interpret findings in such cases.

http://ift.tt/2qDjm39

Focused high-resolution sonography of the suprascapular nerve: A simple surrogate marker for neuralgic amyotrophy?

http://ift.tt/2q2w0Wc

Usability of a home-based test for the measurement of fecal calprotectin in asymptomatic IBD patients

The aim of our work was to test the usability of fecal calprotectin (FC) home-based test in inflammatory bowel disease (IBD) patients.

http://ift.tt/2qGBnvf

(P008) Impact of Radiotherapy on Lymphotropic Invasive Micropapillary Carcinoma of the Breast: An Analysis From the National Cancer Data Base

Invasive micropapillary carcinoma (IMPC) is an uncommon variant of breast cancer, accounting for <2% of all cases. Previous studies of this subtype demonstrated a higher propensity for lymph node metastases compared with invasive ductal carcinoma. Due to this lymphotropic nature, patients with IMPC were once thought to experience worse survival outcomes compared to invasive ductal carcinoma. Our group previously performed analyses of IMPC patients using the Surveillance, Epidemiology, and End Results database and found survival outcomes comparable to invasive ductal carcinoma.

http://ift.tt/2rASONK

Parathyroid Hormone Levels Predict Long-Term Outcome After Operative Management of Parathyroid Cancer

Horm Metab Res
DOI: 10.1055/s-0043-109562

The role of parathyroid hormone (PTH) serum levels for prediction of outcome is ill defined for parathyroid cancer, which is a very rare disease. This investigation of 17 consecutive patients with parathyroid cancer, (re-)operated on at a tertiary referral center between 1994 and July 2016, with a mean follow-up of 179.6 months (15 years) aimed to clarify the suitability of PTH serum levels for prediction of clinical outcome after comprehensive operative management of parathyroid cancer. Cancer-specific mortality occurred significantly more often with the performance of sternotomy before or at first operation at this institution (80 vs. 0%; p=0.002); mean PTH serum levels before first operation (1 105 vs. 357 pg/ml; p=0.008; r=0.77) and at most recent follow-up (3 167 vs. 101 pg/ml; p=0.019; r=0.60); and normalization of PTH serum levels at most recent follow-up (0 vs. 64%; p=0.034). For cancer-specific survival, receiver-operating characteristics analysis identified as optimum cut-off point an initial PTH serum level of 700 pg/ml. For local recurrence, no significant associations were found. Kaplan-Meier analysis confirmed that the patients with initial PTH serum levels >700 pg/ml (plog-rank=0.011) and sternotomy (plog-rank<0.001), but not node or lung metastases, had worse cancer-specific survival. Parathyroid cancer is much more an endocrine disease with oncological features than an oncological disease with endocrine features. Operative intervention(s) should be comprehensive and directed at clearing all metabolically active parathyroid tumor deposits early. If surgical cure cannot be reached, it is pivotal to achieve metabolic control, obviating the need for, or facilitating, medical therapy of hypercalcemia, and preserve renal function.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

http://ift.tt/2qGGdsc

Dieulafoy of cecum; A rare cause of a refractory gastrointestinal bleeding in an uncommon location

http://ift.tt/2pUxMfK

(P014) Population-Based Analysis of Radiation Omission in Elderly Breast Cancer Patients

There is increasing evidence that radiation can be omitted in select older breast cancer patients who are compliant with hormonal blockade, but no recent population-based data exists to guide possible guideline recommendations.

http://ift.tt/2r1AdgM

(P006) Care Pathway Alternatives for Early Stage Breast Cancer Radiotherapy: A National Cancer Database Analysis

Adjuvant whole breast radiation (WBI) represents the standard of care following breast conserving surgery. Alternatives to standard WBI, which can shorten treatment duration and cost, include hypofractionated WBI (HFRT), accelerated partial breast irradiation (APBI) and endocrine therapy-alone (ET-alone). We sought to evaluate the proportion of patients that would be eligible for these alternatives using the National Cancer Database (NCDB).

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(S050) WITHDRAWN

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(P010) Concurrent Chemotherapy With Adjuvant Radiation for Breast Cancer After Incomplete Response to Neoadjuvant Chemotherapy: Safety and Outcomes

For locally advanced breast cancer (LABC), an incomplete clinical and pathological response to neoadjuvant chemotherapy is an adverse prognostic factor. The safety and utility of adding concurrent chemotherapy to adjuvant radiation therapy in high-risk patients has not yet been determined.

http://ift.tt/2rAF4CO

(P002) Differential Expression of Microrna Between Standard Conventional Dose Versus Ablative Dose Radiation in Colorectal Cancer

The biologic heterogeneity of cancer confers a spectrum of radiation responsiveness warranting radiation dose escalation for certain cancers. However, clinicopathologic propensity for extensive microscopic spread negate strategies to reduce treatment volumes thus inhibiting safe dose escalation. A major regulator of the ionizing radiation (IR) response is microRNA (miR) with a critical function in cancer biology through their ability to regulate hundreds of genes in a gene network through differential sequence complementarity.

http://ift.tt/2r1DOvd

(P012) Breast Cancer Patients With Collagen Vascular Disease May Be Undertreated With Radiation Despite Low Rates of Toxicity

National guidelines include collagen vascular disease (CVD) as a relative contraindication to breast conserving therapy (BCT) out of concern for greater radiation toxicity. We studied the use of radiation in patients with breast cancer and CVD and the incidence of acute and late toxicity. We hypothesized that patients with CVD may be undertreated with postlumpectomy radiation compared to our institutional rate of approximately 95%.

http://ift.tt/2r1Gvgl

(P001) DMAPT Inhibits NF-KAPPA B Activity and Increases Sensitivity of Prostate Cancer Cells to X-Rays In Vitro and in Tumor Xenografts In Vivo

Constitutive activation of the pro-survival transcription factor NF-κB has been associated with resistance to both chemotherapy and radiation therapy in many human cancers, including prostate cancer. Our lab and others have demonstrated that the natural product parthenolide is able to inhibit NF-κB activity and sensitize PC-3 prostate cancers cells to X-rays in vitro; however, parthenolide has poor bioavailability in vivo and therefore has little clinical utility in this regard. We show here that treatment of PC-3 and DU145 human prostate cancer cells with Dimethyl-amino-parthenolide (DMAPT), a parthenolide derivative with increased bioavailability, inhibits constitutive and radiation-induced NF-kB binding activity and slows prostate cancer cell growth.

http://ift.tt/2rB2lo8

(P003) Delivery of Ultra-Rapid Flash Radiation Therapy and Demonstration of Normal Tissue Sparing After Abdominal Irradiation of Mice

Normal tissue toxicity is the primary constraint on administering curative radiation doses for cancer. A number of groups have recently shown that ultra-fast FLASH radiation delivery spares normal tissues and increases the therapeutic index over conventional radiation delivery.

http://ift.tt/2r1IhOP

(P007) Treatment Changes Associated With Pre-Operative Axillary Ultrasound on Breast Cancer

To assess the impact of axillary ultrasound (AUS) on treatment of breast cancer. The pre-operative (AUS) with or without ultrasound guided biopsy is being increasingly used in the pre-operative workup of breast cancer. We sought to assess the impact of AUS on treatment of breast cancer.

http://ift.tt/2rAEOU9

(P009) Assessment of Lumpectomy Cavity Radiotherapy Boost Volume With Repeat CT Simulation

Lumpectomy cavity (LC) radiotherapy boost after breast conserving surgery and whole breast irradiation (WBRT) reduces local cancer recurrence. Radiotherapy boost correlates with increased rates of fibrosis and may have worse cosmetic outcomes. LC volumes and subsequent boost volumes may decrease with increasing time from surgery. This study evaluates the timing of CT simulation and radiotherapy technique for cavity directed radiotherapy boost. We seek to determine if repeat CT simulation results in smaller boost volumes which may minimize treatment related toxicity and maximize local tumor control.

http://ift.tt/2r1uBDg

(P011) Postmastectomy Radiotherapy for T3N0 Breast Cancers: A National Cancer Database Analysis

The role for postmastectomy radiation therapy (PMRT) for women pT3N0M0 breast cancer is controversial. We sought to determine the benefit of PMRT in this cohort using the National Cancer Database (NCDB).

http://ift.tt/2rAN86i

(P013) Outcomes After Salvage Mastectomy for an Ipsilateral Breast Tumor Recurrence After Breast Conservation Therapy

To identify predictors of outcomes in women undergoing salvage mastectomy for an ipsilateral breast tumor recurrence (IBTR) after lumpectomy followed by radiation (BCT).

http://ift.tt/2r1zhZT

(P015) Radiotherapy After Skin-Sparing Mastectomy and Placement of a Tissue Expander: Effectiveness of a Coordinated, Multidisciplinary Approach

We previously showed that immediate reconstruction can result in compromised postmastectomy radiotherapy plans. To facilitate combining reconstruction and radiation, patients expected to require PMRT had had a tissue expander (TE) placed at the time of skin-sparing mastectomy. This was partly deflated prior to radiotherapy, refilled after its completion and patients underwent the final phase of reconstruction several months thereafter. The aim of this study was to assess the primary outcomes and the radiotherapy plans when this strategy was employed.

http://ift.tt/2rAER2h

(P080) Immune Parameters as Predictors of Pneumonitis and Survival in Locally Advanced Non-Small Cell Lung Cancer Treated With Chemoradiation

Immune parameters have been identified as predictors of overall survival (OS) and radiation pneumonitis (RP) following stereotactic radiotherapy for early stage non-small cell lung cancer (ES-NSCLC). This association is unclear for locally advanced non-small cell lung cancer (LA-NSCLC). We assess pre-treatment immune parameters and change in value from pre- to post treatment as predictors of RP and OS in patients treated with chemoradiation (CRT) for LA-NSCLC.

http://ift.tt/2r1DLQ3

Gastroduodenal Burkitt Lymphoma Presenting as Demyelinating Polyneuropathy

http://ift.tt/2qGY9mQ

Opened Proton Pump Inhibitor Capsules Reduce Time to Healing Compared with Intact Capsules for Marginal Ulceration Following Roux-en-Y Gastric Bypass

http://ift.tt/2pUEv9O

Psychiatric Disorders and Function in Adolescents with Tetralogy of Fallot

To assess psychiatric disorders and function in adolescents with repaired tetralogy of Fallot (TOF) without and with a genetic diagnosis and to evaluate associations of functioning with medical factors, IQ, and demographics.

http://ift.tt/2r1nRp7

Trajectories of Externalizing and Internalizing Behaviors in Preterm Children Admitted to a Neonatal Intensive Care Unit

To examine the trajectories of internalizing and externalizing behavior problems of preterm children between 16 months and 6 years of age and predictors of trajectories, including gestational age, child dysregulation, maternal depression, socioeconomic status, and parenting.

http://ift.tt/2rAr4ZM

Targeted Next Generation Sequencing Approach in Patients Referred for Silver-Russell Syndrome Testing Increases the Mutation Detection Rate and Provides Decisive Information for Clinical Management

To investigate the contribution of differential diagnoses to the mutation spectrum of patients referred for Silver-Russell syndrome (SRS) testing.

http://ift.tt/2rAlcj7

Hypertrophic Cardiomyopathy in Childhood: Risk Management Through Family Screening

The spectrum of hypertrophic cardiomyopathy (HCM) ranges from silent phenotypes, typically with mild hypertrophy in asymptomatic patients, to aggressive phenotypes with malignant arrhythmias or hemodynamic compromise in patients with severe hypertrophy and disabling symptoms. This is true for adult patients as well as for children with HCM. Reports depicting worst-case scenarios of severe progressive hypertrophy and clinical deterioration in childhood tend to dominate the literature on childhood HCM, and few population studies have been published.

http://ift.tt/2rAvtvA

Epidemiology of Live Born Infants with Nonimmune Hydrops Fetalis—Insights from a Population-Based Dataset

To evaluate the incidence, etiology, and 1-year mortality of nonimmune hydrops fetalis (NIHF) and to identify risk factors for mortality in a contemporary population-based dataset.

http://ift.tt/2r1nPxv

Kinase Inhibitor Screening in Myeloid Malignancies

Kinase pathways are primary effectors of many targeted therapy approaches for cancer. Kinase pathways can be dysregulated by mechanisms far more diverse than chromosomal rearrangements or point mutations, which drove the initial application of kinase inhibitors to cancer. Functional screening with kinase inhibitors is one tool by which we can understand the diversity of target kinases and candidate drugs for patients before fully understanding the mechanistic rationale for kinase pathway dysregulation. By combining functional screening with genomic data, it is also possible to accelerate understanding of these mechanistic underpinnings.

http://ift.tt/2qAir2O

Patient needs and preferences for herb-drug-disease interaction alerts: a structured interview study

While complementary and alternative medicine (CAM) is commonly used in the United States and elsewhere, and hazardous interactions with prescription drugs can occur, patients do not regularly communicate with ...

http://ift.tt/2q28BnH

Clinical characteristics of impulse control and related disorders in Chinese Parkinson’s disease patients

Impulse control and related disorders (ICRDs) are clinically complications in Parkinson's disease (PD). However, the clinical characteristics of ICRDs in Chinese PD patients were rarely reported. We aimed to e...

http://ift.tt/2qA46Ug

Epithelial Mesenchymal Transition (EMT) in Metastatic Breast Cancer in Omani Women

Abstract

Breast cancer (BC) in Oman affects younger women and has a more aggressive course. Clinical and biological variables like age, pregnancy, tumor size, type, grade, receptor expression and proliferation predict disease aggression but there is no direct predictor of metastasis except lymphovascular invasion. Epithelial-mesenchymal transition (EMT) is characterized by epithelial cells losing epithelial and acquiring mesenchymal morpho-immunophenotypic characteristics. In tumors, EMT-like transitions may signify a metastatic phenotype and have features in common with cancer stem cells (CSC) which show resistance to chemotherapy. This study aimed to identify EMT and CSC phenotypes in metastatic and non-metastatic breast cancer in Omani women and their association with conventional clinico-pathological predictors of BC. In a retrospective study of ninety-six Omani women with breast cancer, the association of age, pregnancy/lactation, tumor size, type, grade, ductal carcinoma insitu (DCIS), lymphovascular invasion, hormone/ HER2 receptor expression and Ki67 proliferation index (Ki67 PI) was tested with EMT/ CSC phenotype and metastasis. Young age ≤ 40 years, lymphovascular invasion and EMT had a strong association with metastasis; CSC approached significance. Vimentin expression in tumor cells, fibronectin and MMP-11 in stroma were reliable markers of EMT; dual EMT and CSC phenotype (Vim+/ CD44+/ CD 24−/low) had a strong association with apocrine variant, basal-like tumors and triple negative cancers. EMT had a strong association with Ki67 proliferation index (PI) and CSC with HER2-like tumors and distant metastasis. These select markers may be useful in metastasis-prediction in pre-treatment biopsies.

http://ift.tt/2qCMhnB

Table of contents

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Hepatology Highlights

http://ift.tt/2qGphCh

Notices

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Instructions to authors and Information for readers

http://ift.tt/2qG5pzq

Masthead

http://ift.tt/2pU9hzs

Statin use, candidate mevalonate pathway biomarkers, and colon cancer survival in a population-based cohort study

Statin use, candidate mevalonate pathway biomarkers, and colon cancer survival in a population-based cohort study

British Journal of Cancer advance online publication, May 18 2017. doi:10.1038/bjc.2017.139

Authors: Ronan T Gray, Maurice B Loughrey, Peter Bankhead, Chris R Cardwell, Stephen McQuaid, Roisin F O'Neill, Kenneth Arthur, Victoria Bingham, Claire McGready, Anna T Gavin, Jacqueline A James, Peter W Hamilton, Manuel Salto-Tellez, Liam J Murray & Helen G Coleman

http://ift.tt/2pZcmuc

Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases

Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases

British Journal of Cancer advance online publication, May 18 2017. doi:10.1038/bjc.2017.142

Authors: Sagun Parakh, John J Park, Shehara Mendis, Rajat Rai, Wen Xu, Serigne Lo, Martin Drummond, Catherine Rowe, Annie Wong, Grant McArthur, Andrew Haydon, Miles C Andrews, Jonathan Cebon, Alex Guminski, Richard F Kefford, Georgina V Long, Alexander M Menzies, Oliver Klein & Matteo S Carlino

http://ift.tt/2rknRQw

Hallmarks of response to immune checkpoint blockade

Hallmarks of response to immune checkpoint blockade

British Journal of Cancer advance online publication, May 18 2017. doi:10.1038/bjc.2017.136

Authors: Alexandria P Cogdill, Miles C Andrews & Jennifer A Wargo

http://ift.tt/2pZ4AjZ

Stroma-regulated HMGA2 is an independent prognostic marker in PDAC and AAC

Stroma-regulated HMGA2 is an independent prognostic marker in PDAC and AAC

British Journal of Cancer advance online publication, May 18 2017. doi:10.1038/bjc.2017.140

Authors: Carina Strell, Karin Jessica Norberg, Artur Mezheyeuski, Jonas Schnittert, Praneeth R Kuninty, Carlos Fernández Moro, Janna Paulsson, Nicolai Aagaard Schultz, Dan Calatayud, Johannes Matthias Löhr, Oliver Frings, Caroline Sophie Verbeke, Rainer Lothar Heuchel, Jai Prakash, Julia Sidenius Johansen & Arne Östman

http://ift.tt/2rklgGF

Frozen shoulder and risk of cancer: a population-based cohort study

Frozen shoulder and risk of cancer: a population-based cohort study

British Journal of Cancer advance online publication, May 18 2017. doi:10.1038/bjc.2017.146

Authors: Alma B Pedersen, Erzsébet Horváth-Puhó, Vera Ehrenstein, Mikael Rørth & Henrik T Sørensen

http://ift.tt/2pZ5zk7

GP participation in increasing uptake in a national bowel cancer screening programme: the PEARL project

GP participation in increasing uptake in a national bowel cancer screening programme: the PEARL project

British Journal of Cancer advance online publication, May 18 2017. doi:10.1038/bjc.2017.129

Authors: Sally C Benton, Piers Butler, Katy Allen, Michelle Chesters, Sally Rickard, Sally Stanley, Richard Roope, Daniel Vulkan & Stephen W Duffy

http://ift.tt/2rkf810

Sequencing of DICER1 in sarcomas identifies biallelic somatic DICER1 mutations in an adult-onset embryonal rhabdomyosarcoma

Sequencing of DICER1 in sarcomas identifies biallelic somatic DICER1 mutations in an adult-onset embryonal rhabdomyosarcoma

British Journal of Cancer advance online publication, May 18 2017. doi:10.1038/bjc.2017.147

Authors: Leanne de Kock, Barbara Rivera, Timothée Revil, Paul Thorner, Catherine Goudie, Dorothée Bouron-Dal Soglio, Catherine S Choong, John R Priest, Paul J van Diest, Jantima Tanboon, Anja Wagner, Jiannis Ragoussis, Peter FM Choong & William D Foulkes

http://ift.tt/2pZkL0u

Targeted sequencing-based analyses of candidate gene variants in ulcerative colitis-associated colorectal neoplasia

Targeted sequencing-based analyses of candidate gene variants in ulcerative colitis-associated colorectal neoplasia

British Journal of Cancer advance online publication, May 18 2017. doi:10.1038/bjc.2017.148

Authors: Sanjiban Chakrabarty, Vinay Koshy Varghese, Pranoy Sahu, Pradyumna Jayaram, Bhadravathi M Shivakumar, Cannanore Ganesh Pai & Kapaettu Satyamoorthy

http://ift.tt/2rkcQyO

Proof of concept non-invasive estimation of peripheral venous oxygen saturation

Pulse oximeters continuously monitor arterial oxygen saturation. Continuous monitoring of venous oxygen saturation (SvO2) would enable real-time assessment of tissue oxygen extraction (O2E) and perfusion changes ...

http://ift.tt/2qGfGvg

NAFLD as a Sexual Dimorphic Disease: Role of Gender and Reproductive Status in the Development and Progression of Nonalcoholic Fatty Liver Disease and Inherent Cardiovascular Risk

Abstract

Nonalcoholic fatty liver disease (NAFLD) spans steatosis through nonalcoholic steatohepatis, cirrhosis, and hepatocellular carcinoma (HCC) associated with striking systemic features and excess cardiovascular and liver-related mortality. The pathogenesis of NAFLD is complex and multifactorial. Endocrine derangements are closely linked with dysmetabolic traits. For example, in animal and human studies, female sex is protected from dysmetabolism thanks to young individuals' ability to partition fatty acids towards ketone body production rather than very low density lipoprotein (VLDL)-triacylglycerol, and to sex-specific browning of white adipose tissue. Ovarian senescence facilitates both the development of massive hepatic steatosis and the fibrotic progression of liver disease in an experimental overfed zebrafish model. Consistently, estrogen deficiency, by potentiating hepatic inflammatory changes, hastens the progression of disease in a dietary model of nonalcoholic steatohepatitis (NASH) developing in ovariectomized mice fed a high-fat diet. In humans, NAFLD more often affects men; and premenopausal women are equally protected from developing NAFLD as they are from cardiovascular disease. It would be expected that early menarche, definitely associated with estrogen activation, would produce protection against the risk of NAFLD. Nevertheless, it has been suggested that early menarche may confer an increased risk of NAFLD in adulthood, excess adiposity being the primary culprit of this association. Fertile age may be associated with more severe hepatocyte injury and inflammation, but also with a decreased risk of liver fibrosis compared to men and postmenopausal status. Later in life, ovarian senescence is strongly associated with severe steatosis and fibrosing NASH, which may occur in postmenopausal women. Estrogen deficiency is deemed to be responsible for these findings via the development of postmenopausal metabolic syndrome. Estrogen supplementation may at least theoretically protect from NAFLD development and progression, as suggested by some studies exploring the effect of hormonal replacement therapy on postmenopausal women, but the variable impact of different sex hormones in NAFLD (i.e., the pro-inflammatory effect of progesterone) should be carefully considered.

http://ift.tt/2qEMxRc

Notch ligand Delta-like 1 as a novel molecular target in childhood neuroblastoma

Abstract

Background

Neuroblastoma is the most common extracranial solid malignancy in childhood, responsible for 15% of all pediatric cancer deaths. It is an heterogeneous disease that does not always respond to classical therapy; so the identification of new and specific molecular targets to improve existing therapy is needed. We have previously demonstrated the involvement of the Notch pathway in the onset and progression of neuroblastoma. In this study we further investigated the role of Notch signaling and identified Delta-like 1 (DLL1) as a novel molecular target in neuroblastoma cells with a high degree of MYCN amplification, which is a major oncogenic driver in neuroblastoma. The possibility to act on DLL1 expression levels by using microRNAs (miRNAs) was assessed.

Methods

DLL1 mRNA and protein expression levels were measured in three different neuroblastoma cell lines using quantitative real-time PCR and Western Blot analysis, respectively. Activation of the Notch pathway as a result of increased levels of DLL1 was analyzed by Immunofluorescence and Western Blot methods. In silico tools revealed the possibility to act on DLL1 expression levels with miRNAs, in particular with the miRNA-34 family. Neuroblastoma cells were transfected with miRNA-34 family members, and the effect of miRNAs transfection on DLL1 mRNA expression levels, on cell differentiation, proliferation and apoptosis was measured.

Results

In this study, the DLL1 ligand was identified as the Notch pathway component highly expressed in neuroblastoma cells with MYCN amplification. In silico analysis demonstrated that DLL1 is one of the targets of miRNA-34 family members that maps on chromosome regions that are frequently deregulated or deleted in neuroblastoma. We studied the possibility to use miRNAs to target DLL1. Among all miRNA-34 family members, miRNA-34b is able to significantly downregulate DLL1 mRNA expression levels, to arrest cell proliferation and to induce neuronal differentiation in malignant neuroblastoma cells.

Conclusions

Targeted therapies have emerged as new strategies for cancer treatment. This study identified the Notch ligand DLL1 as a novel and attractive molecular target in childhood neuroblastoma and its results could help to devise a targeted therapy using miRNAs.

http://ift.tt/2qCrtNo

An innovative strategy to clone positive modifier genes of defects caused by mtDNA mutations: MRPS18C as suppressor gene of m.3946G>A mutation in MT - ND1 gene

Abstract

We have developed a new functional complementation approach to clone modifier genes which overexpression is able to suppress the biochemical defects caused by mtDNA mutations (suppressor genes). This strategy consists in transferring human genes into respiratory chain-deficient fibroblasts, followed by a metabolic selection in a highly selective medium. We used a normalized expression cDNA library in an episomal vector (pREP4) to transfect the fibroblasts, and a medium with glutamine and devoid of any carbohydrate source to select metabolically. Growing the patient's fibroblasts in this selective medium, the deficient cells rapidly disappear unless they are rescued by the cDNA of a suppressor gene. The use of an episomal vector allows us to carry out several rounds of transfection/selection (cyclical phenotypic rescue) to enrich the rescue with true clones of suppressor genes. Using fibroblasts from a patient with epileptic encephalopathy with the m.3946G>A (p.E214K) mutation in the MT-ND1 gene, several candidate genes were identified and one of them was characterized functionally. Thus, overexpression of MRPS18C gene (that encode for bS18m protein) suppressed the molecular defects produced by this mtDNA mutation, recovering the complex I activity and reducing the ROS produced by this complex to normal levels. We suggest that modulation of bS18m expression may be an effective therapeutic strategy for the patients with this mutation.

http://ift.tt/2qBLsvE

Patients with community-acquired bacteremia of unknown origin: clinical characteristics and usefulness of microbiological results for therapeutic issues: a single-center cohort study

Bacteremia of unknown origin (BUO) are associated with increased mortality compared to those with identified sources. Microbiological data of those patients could help to characterize an appropriate empirical ...

http://ift.tt/2qFXzp7

A pre-therapeutic coating for medical devices that prevents the attachment of Candida albicans

Hospital acquired fungal infections are defined as "never events"—medical errors that should never have happened. Systemic Candida albicans infections results in 30–50% mortality rates. Typically, adhesion to abi...

http://ift.tt/2qFW0rz

Mentor Spotlight: Monica L. Baskin, PhD

Dr. Tiffany Carson, a K01 awardee, recognizes her mentor Dr. Monica Baskin for the guidance and encouragement that she has provided throughout her career.

http://ift.tt/2r11Si7

A prospective study of XELIRI plus bevacizumab as a first-line therapy in Japanese patients with unresectable or recurrent colorectal cancer (KSCC1101)

Abstract

Background

This study was designed to evaluate the efficacy and toxicity of XELIRI plus bevacizumab for the treatment of Japanese patients with unresectable or recurrent colorectal cancer (CRC).

Methods

This was a multicenter, single-arm, open-label prospective study. The major inclusion criteria were previously untreated unresectable or recurrent CRC, presence of measurable lesions, ≥20 years of age, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients received bevacizumab (7.5 mg/kg on day 1) and XELIRI (irinotecan 200 mg/m² on day 1 plus capecitabine 800 mg/m² b.i.d. on days 1–14) every 3 weeks. The primary endpoint was the objective tumor response rate.

Results

A total of 36 patients were enrolled in this study from July 2011 to September 2012. One patient did not fulfill the eligibility criteria and one patient withdrew their consent before the start of the treatment protocol. The confirmed objective response rate was 58.8% (95% CI 35.1–70.2%). The median progression-free survival was 9.6 months (95% CI 5.1–11.1 months) and the median overall survival was 23.1 months (95% CI 11.3–36.7 months). The grade ≥3 adverse events that were frequently encountered in this study were neutropenia (31.4%), leukopenia (22.9%), diarrhea (22.9%), anemia (20.0%), anorexia (20.0%) and febrile neutropenia (17.2%). The frequency of grade 3/4 adverse events, such as neutropenia and leukopenia, was much higher in patients with a UGT1A1 polymorphism.

Conclusions

A first-line therapy comprising XELIRI plus bevacizumab yielded a promising response rate. However, careful attention should be given to adverse clinical events in Japanese patients receiving treatment with unresectable or recurrent CRC.

http://ift.tt/2r17ysd

Monitoring ER/SR Calcium Release with the Targeted Ca2+ Sensor CatchER+

We present protocols for the application of our targeted genetically-encoded calcium indicator (GECI) CatchER+ for monitoring rapid calcium transients in the endoplasmic/sarcoplasmic reticulum (ER/SR) of HEK293 and skeletal muscle C2C12 cells using real-time fluorescence microscopy. A protocol for the in situ Kd measurement and calibration is also discussed.

http://ift.tt/2rmAniw

Neuromolecular Regulation of Aggression Differs by Social Role during Joint Territory Defense

In response to a territory intrusion, neighboring males of the African cichlid fish Astatotilapia burtoni engage in aggressive joint territory defense in a manner that depends on their social role. Here, we examine the possible function of several neuroendocrine and neuromodulator pathways previously implicated in the regulation of complex social behavior. We find that the neuromolecular regulation of aggression during joint territory defense is very much dependent on an individual's role in this context. In neighbors but not in residents, aggression is correlated to gene expression in the medial part of the dorsal telencephalon (area Dm), the putative homolog to the mammalian basolateral amygdala. This correlation is strikingly high for expression of the serotonin receptor 5-HT_2c, suggesting the serotonin system is important in regulating context-dependent behavior. Furthermore, by examining candidate gene expression co-variance patterns in area Dm and in the lateral part of the dorsal telencephalon (area Dl), the putative homolog to the mammalian hippocampus, we identify two main patterns: gene expression is co-regulated within, but not across, brain regions, and co-regulation is synergistic rather than antagonistic. Our results highlight the critical effect of social context on both behavior and its neuromolecular basis.

http://ift.tt/2q4HlEg

FDA Grants Brigatinib Accelerated Approval for Metastatic Non-Small Cell Lung Cancer

On April 28, the FDA granted accelerated approval to the targeted therapy brigatinib (Alunbrig™) for patients with metastatic non-small cell lung cancer (NSCLC) and alterations in the ALK gene whose cancer has progressed during their initial therapy.

http://ift.tt/2qzLSly

Simultaneous Isolation of High Quality Cardiomyocytes, Endothelial Cells, and Fibroblasts from an Adult Rat Heart

Several protocols have been developed and described for the isolation of different cardiac cell types from a rat heart. Here, an optimized protocol is described that allows the isolation of high-quality major cardiac cell types (cardiomyocytes, endothelial cells, and fibroblasts) from a single preparation, reducing the experimental costs.

http://ift.tt/2qFJ6tB

Amyotrophic lateral sclerosis-like superoxide dismutase 1 proteinopathy is associated with neuronal loss in Parkinson’s disease brain

Abstract

Neuronal loss in numerous neurodegenerative disorders has been linked to protein aggregation and oxidative stress. Emerging data regarding overlapping proteinopathy in traditionally distinct neurodegenerative diseases suggest that disease-modifying treatments targeting these pathological features may exhibit efficacy across multiple disorders. Here, we describe proteinopathy distinct from classic synucleinopathy, predominantly comprised of the anti-oxidant enzyme superoxide dismutase-1 (SOD1), in the Parkinson's disease brain. Significant expression of this pathology closely reflected the regional pattern of neuronal loss. The protein composition and non-amyloid macrostructure of these novel aggregates closely resembles that of neurotoxic SOD1 deposits in SOD1-associated familial amyotrophic lateral sclerosis (fALS). Consistent with the hypothesis that deposition of protein aggregates in neurodegenerative disorders reflects upstream dysfunction, we demonstrated that SOD1 in the Parkinson's disease brain exhibits evidence of misfolding and metal deficiency, similar to that seen in mutant SOD1 in fALS. Our data suggest common mechanisms of toxic SOD1 aggregation in both disorders and a potential role for SOD1 dysfunction in neuronal loss in the Parkinson's disease brain. This shared restricted proteinopathy highlights the potential translation of therapeutic approaches targeting SOD1 toxicity, already in clinical trials for ALS, into disease-modifying treatments for Parkinson's disease.

http://ift.tt/2rmfAMf

Endocytic vesicle rupture is a conserved mechanism of cellular invasion by amyloid proteins

Abstract

Numerous pathological amyloid proteins spread from cell to cell during neurodegenerative disease, facilitating the propagation of cellular pathology and disease progression. Understanding the mechanism by which disease-associated amyloid protein assemblies enter target cells and induce cellular dysfunction is, therefore, key to understanding the progressive nature of such neurodegenerative diseases. In this study, we utilized an imaging-based assay to monitor the ability of disease-associated amyloid assemblies to rupture intracellular vesicles following endocytosis. We observe that the ability to induce vesicle rupture is a common feature of α-synuclein (α-syn) assemblies, as assemblies derived from WT or familial disease-associated mutant α-syn all exhibited the ability to induce vesicle rupture. Similarly, different conformational strains of WT α-syn assemblies, but not monomeric or oligomeric forms, efficiently induced vesicle rupture following endocytosis. The ability to induce vesicle rupture was not specific to α-syn, as amyloid assemblies of tau and huntingtin Exon1 with pathologic polyglutamine repeats also exhibited the ability to induce vesicle rupture. We also observe that vesicles ruptured by α-syn are positive for the autophagic marker LC3 and can accumulate and fuse into large, intracellular structures resembling Lewy bodies in vitro. Finally, we show that the same markers of vesicle rupture surround Lewy bodies in brain sections from PD patients. These data underscore the importance of this conserved endocytic vesicle rupture event as a damaging mechanism of cellular invasion by amyloid assemblies of multiple neurodegenerative disease-associated proteins, and suggest that proteinaceous inclusions such as Lewy bodies form as a consequence of continued fusion of autophagic vesicles in cells unable to degrade ruptured vesicles and their amyloid contents.

http://ift.tt/2q1mH8F

Reality Training: Shots fired during forced entry for patient welfare check

Discuss your guidelines and protocols for checking on the well-being of a patient

http://ift.tt/2qFB2ZB

En Face Preparation of Mouse Blood Vessels

A procedure for making en face preparations of the mouse carotid artery and aorta is described. Such preparations, when immunofluorescently stained with specific antibodies, enable us to study localization of proteins and identification of cell types within the entire vascular wall by confocal microscopy.

http://ift.tt/2rAi6Lm

Understanding the interrelationship between the synthesis of urea and gluconeogenesis by formulating an overall balanced equation

It is well known that a strong metabolic interrelationship exists between ureagenesis and gluconeogenesis. In this paper, we present a detailed, overall equation, describing a possible metabolic link between ureagenesis and gluconeogenesis. We adopted a guided approach in which we strongly suggest that students, when faced with the problem of obtaining the overall equation of a metabolic pathway, carefully account for all atoms and charges of the single reactions, as well as the cellular localizations of the substrates, and the related transport systems. If this suggestion is always taken into account, a balanced, overall equation of a metabolic pathway will be obtained, which strongly facilitates the discussion of its physiological role. Unfortunately, textbooks often report unbalanced overall equations of metabolic pathways, including ureagenesis and gluconeogenesis. Most likely the reason is that metabolism and enzymology have been neglected for about three decades, owing to the remarkable advances of molecular biology and molecular genetics. In this paper, we strongly suggest that students, when faced with the problem of obtaining the overall reaction of a metabolic pathway, carefully control if the single reactions are properly balanced for atoms and charges. Following this suggestion, we were able to obtain an overall equation describing the metabolic interrelationship between ureagenesis and gluconeogenesis, in which urea and glucose are the final products. The aim is to better rationalize this topic and to convince students and teachers that metabolism is an important and rewarding chapter of human physiology.

http://ift.tt/2pTHiQA

Measuring osmosis and hemolysis of red blood cells

Since the discovery of the composition and structure of the mammalian cell membrane, biologists have had a clearer understanding of how substances enter and exit the cell's interior. The selectively permeable nature of the cell membrane allows the movement of some solutes and prevents the movement of others. This has important consequences for cell volume and the integrity of the cell and, as a result, is of utmost clinical importance, for example in the administration of isotonic intravenous infusions. The concepts of osmolarity and tonicity are often confused by students as impermeant isosmotic solutes such as NaCl are also isotonic; however, isosmotic solutes such as urea are actually hypotonic due to the permeant nature of the membrane. By placing red blood cells in solutions of differing osmolarities and tonicities, this experiment demonstrates the effects of osmosis and the resultant changes in cell volume. Using hemoglobin standard solutions, where known concentrations of hemoglobin are produced, the proportion of hemolysis and the effect of this on resultant hematocrit can be estimated. No change in cell volume occurs in isotonic NaCl, and, by placing blood cells in hypotonic NaCl, incomplete hemolysis occurs. By changing the bathing solution to either distilled water or isosmotic urea, complete hemolysis occurs due to their hypotonic effects. With the use of animal blood in this practical, students gain useful experience in handling tissue fluids and calculating dilutions and can appreciate the science behind clinical scenarios.

http://ift.tt/2pTDbDQ

Seeing is believing: a demonstration of critical fusion frequency and its multidimensional nature

http://ift.tt/2pTErao

"Thinking ethics": a novel, pilot, proof-of-concept program of integrating ethics into the Physiology curriculum in South India

Integrating medical ethics into the physiology teaching-learning program has been largely unexplored in India. The objective of this exercise was to introduce an interactive and integrated ethics program into the Physiology course of first-year medical students and to evaluate their perceptions. Sixty medical students (30 men, 30 women) underwent 11 sessions over a 7-mo period. Two of the Physiology faculty conducted these sessions (20–30 min each) during the routine physiology (theory/practicals) classes that were of shorter duration and could, therefore, accommodate the discussion of related ethical issues. This exercise was in addition to the separate ethics classes conducted by the Medical Ethics department. The sessions were open ended, student centered, and designed to stimulate critical thinking. The students' perceptions were obtained through a semistructured questionnaire and focused group discussions. The students found the program unique, thought provoking, fully integrated, and relevant. It seldom interfered with the physiology teaching. They felt that the program sensitized them about ethical issues and prepared them for their clinical years, to be "ethical doctors." Neutral observers who evaluated each session felt that the integrated program was relevant to the preclinical year and that the program was appropriate in its content, delivery, and student involvement. An ethics course taught in integration with Physiology curriculum was found to be beneficial, feasible, and compatible with Physiology by students as well as neutral observers.

http://ift.tt/2pTSjkL

Visualizing fundamental neuronal computation for life science students

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A simple laboratory exercise with rat isolated esophagus and stomach fundus to reveal functional differences between striated and smooth muscle cells

This study describes an undergraduate student laboratory activity using isolated preparations from rat gastrointestinal tissues that possess contractile profiles typically exhibited by striated and smooth muscle cells. While students are introduced to an ex vivo methodology, they can compare differences in trace experiments, twitch aspects, phasic and tonic properties, force-frequency relationships, and pharmacological responsiveness of esophageal (striated) and fundic (smooth muscle) segments. Muscle strips were subjected to electrical field stimulation (EFS) applied by platinum electrodes immersed in the physiological solution. The contractile profile of EFS responses varied between these two types of gut preparations. Atropine and tubocurarine revealed differential inhibitory influences in esophagus or fundus tissues; caffeine and procaine produced similar effects, i.e., potentiation and blockade of the EFS-induced contractile response in these tissues, respectively. Experimental results obtained during the activity helped the improvement of student learning about basic concepts previously discussed in theoretical lectures. To measure student learning with this laboratory exercise, a questionnaire was applied before and after the activity, and the number of expected correct answers, concerning the mechanisms of contraction in striated and smooth muscle, could be clearly evidenced.

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A Homozygous Potentially Pathogenic Variant in the PAXBP1 Gene in a Large Family with Global Developmental Delay and Myopathic Hypotonia

ABSTRACT

PAX binding protein 1 (PAXBP1) is an adaptor protein linking the transcription factor PAX3 and PAX7 to the histone methylation machinery. PAXBP1 is a nuclear protein and its high expression is known in brain cerebellar hemisphere and cerebellum. Moreover, it is also found in abundance in muscle precursor cells that are involved in myogenesis and skeletal muscles formation. Whole genome SNP genotyping and exome sequencing in a family with distinct syndrome of global developmental delay and hypotonia mapped the disease locus to the chromosome 21q22.11 and identified a homozygous missense variant (c.1612C>T) in the PAXBP1 gene, respectively. This variant is predicted to change the highly conserved strongly basic arginine at position 538 in the PAX7 binding domain of PAXBP1 to a neutral cysteine (p.Arg538Cys) residue.

Arg538 is highly conserved and the variant is predicted to be deleterious by variety of in silico tools. Furthermore, protein modeling studies showed that in the mutant protein (Cys538), the shorter cysteine is incapable of forming hydrogen bond with the side chain of nearby Asp517 due to its reduced size and lower polarizability. As a consequence, a slight local perturbation of the loop conformation in the PAX7 binding domain of the PAXBP1 protein was observed. Our findings suggest that the pathogenic variant in PAX binding protein underlies distinct syndrome of global developmental delay and myopathic hypotonia. This clinical report should prompt a search for mutations in PAXBP1 in patients presenting with developmental delay and hypotonia. Moreover, these results imply that establishment of PAXBP1 targets and its spatiotemporal interaction will help in understanding of development of cerebellar and will provide basis for developing therapeutic approaches.

Graphical Abstract

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DNA damage marker γH2AX is a potential predictive marker for progression of epithelial dysplasia of the oral cavity

Abstract

Aims

To evaluate the relationships between immunohistochemical markers related to cellular senescence, cell proliferation and histological grade of epithelial dysplasia of the oral cavity (OD). In addition, the predictive value of these markers for progression of OD was assessed.

Methods

Retrospective immunohistochemical analyses were performed on 86 formalin fixed and paraffin embedded specimens of OD and oral squamous cell carcinoma (OSCC) for Ki67, γH2AX, p53, p16, H3K9me3 and CycD1. Three separate areas representing the highest severity of OD on each slide were digitally annotated by two independent pathologists. Mean automated histoscores of the selected markers were generated and compared to that of age-matched healthy controls (n=24). Follow-up data of OD was retrieved and anonymised by a clinical team member and linked using unique participant identifiers. The median follow-up was 10.9 years (interquartile range: 10.1-11.5).

Results

Ki67 (p<0.0001), γH2AX (p=0.03) and p53 (p=0.04) were significantly increased with higher histological grade of OD. γH2AX (p=0.03), but not histological grade of OD (p=0.73), was prospectively associated with disease progression. Using the median histoscore for γH2AX (median histoscore = 17) as a cut-off, histoscore≥17 was associated with an increased risk of disease progression (HR=3.15, 95%CI 1.41-7.39, p=0.0064).

Conclusions

Although proliferation marker Ki67, DNA damage/checkpoint markers γH2AX and p53 were increased in higher grade of OD, only γH2AX was predictive of disease progression. These observations may reflect the role of DNA replicative stress in the transformation from OD to OSCC. Larger studies should evaluate whether γH2AX can be used as a predictive marker of OD

This article is protected by copyright. All rights reserved.

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The mutational frequency of BRAF and KRAS in low grade serous testicular neoplasms – a case series

Abstract

Aims

Low grade serous neoplasms of the testis are rare neoplasms that demonstrate striking morphological similarities with the better-understood ovarian neoplasms. The cell of origin, relation to serous ovarian tumour and the pathogenesis of these neoplasms are not fully established.

Methods and results

As low grade serous ovarian neoplasms are known to harbour mutations in the MAP-kinase pathway, we investigated the involvement of BRAF and KRAS mutations in low grade testicular serous tumour by way of mutational analysis of 7 cases. Mutational analysis was performed by melting curve analysis followed by bidirectional sequencing. Our findings showed BRAF and/or KRAS mutation in 3 of the 7 cases, similar to the proportions reported in low grade ovarian serous neoplasms. Out of these three cases, one showed co-mutation of BRAF and KRAS.

Conclusion

This supports the role of aberrant signalling of the MAP-kinase pathway in the pathogenesis of low grade serous testicular neoplasms and provides a genetic link between low grade testicular and ovarian serous tumours.

This article is protected by copyright. All rights reserved.

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Comprehensive Registry of Esophageal Cancer in Japan, 2010

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Tarlov Cyst Hemorrhage Causing Acute Radiculopathy: A Case Report

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A Farewell From the Board of Editors of the Blue Journal

In June 2017, our board of editors (BOE) will hand over the reins of Clinical Gastroenterology and Hepatology (CGH) to Dr Fasiha Kanwal, the incoming editor-in-chief of CGH, and her BOE. This will mark the end of 5 "quick" years, during which we have been privileged to serve our readers, authors, and the American Gastroenterological Association (AGA) and its members. At the risk of sounding like a cliché, this endeavor has been one of the most enjoyable and fulfilling that I have embarked on in the past several years (and yes I do have somewhat of a life otherwise!).

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AGA White Paper: Training and Implementation of Endoscopic Image Enhancement Technologies

Endoscopic image-enhancement technologies provide opportunities to visualize normal and abnormal tissues within the gastrointestinal (GI) tract in a manner that complements conventional white light endoscopic imaging. The additional information that is obtained enables the endoscopist to better identify, delineate, and characterize lesions and can facilitate targeted biopsies or, in some cases, eliminate the need to send samples for histologic analysis. Some of these technologies have been available for more than a decade, but despite this fact, there is limited use of these technologies by endoscopists.

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Contents

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Information for Authors and Readers

Clinical Gastroenterology and Hepatology is the go-to resource on a broad spectrum of themes in clinical gastroenterology and hepatology. The official clinical practice journal of the AGA Institute brings you the best original research in the field with a unique combination of reviews, editorials, podcasts, video abstracts, and outcomes research—all supporting clinical practice. Articles on education, policy, and practice management highlight issues pertinent to clinicians.

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Editorial Board

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Cover

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Anxiety and depression in working-age cancer survivors: a register-based study

Abstract

Background

Anxiety and depression can be a long-term strain in cancer survivors. Little is known about the emotional situation of cancer survivors who have to deal with work- and family-related issues. The purpose of this study was to investigate anxiety and depression in working-age cancer survivors and associated factors.

Methods

A register-based sample of 3370 cancer survivors (25 to 55 years at time of diagnosis) diagnosed up to six years prior to the survey was recruited from two German cancer registries. Demographic and medical characteristics as well as self-reported measures were used.

Results

Overall, approximately 40% of the survivors reported moderate to high anxiety scores and approximately 20% reported moderate to high depression scores. Compared to the general population, working-age cancer survivors were more anxious but less depressed (p < .001). Subgroups with regard to time since diagnosis did not differ in anxiety or depression. Anxiety and depression in cancer survivors were associated with various variables. Better social support, family functioning and physical health were associated with lower anxiety and depression.

Conclusions

Overall, we found higher anxiety levels in cancer survivors of working-age than in the general population. A considerable portion of cancer survivors reported moderate to high levels of anxiety and depression. The results indicate the need for psychosocial screening and psycho-oncological support e.g. in survivorship programs for working-age cancer survivors. Assessing the physical health, social support and family background might help to identify survivors at risk for higher emotional distress.

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Hybrid peripheral nerve sheath tumors: report of five cases and detailed review of literature

Abstract

Background

Hybrid peripheral nerve sheath tumors (PNSTs) have been recognized recently and were first included in the 4th edition of World Health Organization (WHO) Classification of Tumors of Soft tissue and Bone, published in 2013. These tumors show combined features of more than one type of conventional benign peripheral nerve sheath tumors. The most common combinations are those of schwannoma/perineurioma followed by combinations of neurofibroma/schwannoma and neurofibroma/perineurioma. A detailed literature review of published cases is presented.

We have discussed the types and etiology, epidemiology and sites of localization, gross and microscopic appearances and immunohistochemical features of hybrid PNSTs and association of these tumors with tumor syndromes.

Case presentation

We have included five cases which were diagnosed in our department as we believe that publication of these new cases is relevant for the improved understanding of these specific tumors. Four of our five patients were males, mean age was 24 years. There was wide variation in the location of these tumors. Mean size of excised tumors was 5.5 cms in the greatest dimensions. Three out of five cases represented hybrid schwannoma/perineurioma histologically. No significant nuclear atypia, mitotic activity or necrosis seen. All five cases were completely excised. All five patients are alive and well at the time of writing with no recurrence.

Conclusion

Hybrid PNSTs are distinct tumors and are usually benign. However, rare case reports have described local recurrence and at least two recent case reports have described malignant transformation in these tumors. Further studies on large number of cases are required to determine the exact pathogenetic basis of these tumors.

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Venous thromboembolism in hospitalized patients receiving chemotherapy for malignancies at Japanese community hospital: prospective observational study

Abstract

Background

Although Asian population was recognized to have a lower risk of venous thromboembolism (VTE), its increasing prevalence and incidence remain unclear in patients with malignancies. We attempted to predict VTE development using activation markers of coagulation and fibrinolysis.

Methods

We enrolled patients with malignancy admitted to Tonan Hospital between April and December 2014 to receive a new-for-them chemotherapy regimen. All patients were examined for VTE by computed tomography and whole-leg compression ultrasonography before chemotherapy and three months later. We also examined plasma levels of thrombin-antithrombin complex (TAT) and plasmin α2-plasmin inhibitor complex (PIC) before chemotherapy. The cut off values of TAT and PIC were set at 2.1 ng/mL and 1.8 μg/mL, respectively.

Results

Of 97 patients, the majority (67%) had distant metastases. The most common malignancies were colorectal (26%), breast (23%), and stomach (19%) cancer. VTE was detected in 29 patients (31%); all were asymptomatic. VTE was newly developed in 12 patients in the three-month observation period, which means the incidence was 49 per 1000 person-years. Non-increased PIC with increased TAT was the only significant risk factor for both VTE prevalence and incidence in multivariate analysis, and the odds ratios were 3.0 (95% confidence interval, 1.1–8.2; P = 0.034) and 9.4 (95% confidence interval, 1.7–51.9; P = 0.011), respectively.

Conclusions

The prevalence and incidence of VTE were high in hospitalized Japanese patients receiving chemotherapy for malignancies. Non-increased PIC with increased levels of TAT may be an independent risk factor for VTE development.

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Cleavage of the urokinase receptor (uPAR) on oral cancer cells: regulation by transforming growth factor – β1 (TGF-β1) and potential effects on migration and invasion

Abstract

Background

Urokinase plasminogen activator (uPA) receptor (uPAR) is up-regulated at the invasive tumour front of human oral squamous cell carcinoma (OSCC), indicating a role for uPAR in tumour progression. We previously observed elevated expression of uPAR at the tumour-stroma interface in a mouse model for OSCC, which was associated with increased proteolytic activity. The tumour microenvironment regulated uPAR expression, as well as its glycosylation and cleavage. Both full-length- and cleaved uPAR (uPAR (II-III)) are involved in highly regulated processes such as cell signalling, proliferation, migration, stem cell mobilization and invasion. The aim of the current study was to analyse tumour associated factors and their effect on uPAR cleavage, and the potential implications for cell proliferation, migration and invasion.

Methods

Mouse uPAR was stably overexpressed in the mouse OSCC cell line AT84. The ratio of full-length versus cleaved uPAR as analysed by Western blotting and its regulation was assessed by addition of different protease inhibitors and transforming growth factor - β1 (TGF-β1). The role of uPAR cleavage in cell proliferation and migration was analysed using real-time cell analysis and invasion was assessed using the myoma invasion model.

Results

We found that when uPAR was overexpressed a proportion of the receptor was cleaved, thus the cells presented both full-length uPAR and uPAR (II-III). Cleavage was mainly performed by serine proteases and urokinase plasminogen activator (uPA) in particular. When the OSCC cells were stimulated with TGF-β1, the production of the uPA inhibitor PAI-1 was increased, resulting in a reduction of uPAR cleavage. By inhibiting cleavage of uPAR, cell migration was reduced, and by inhibiting uPA activity, invasion was reduced. We could also show that medium containing soluble uPAR (suPAR), and cleaved soluble uPAR (suPAR (II-III)), induced migration in OSCC cells with low endogenous levels of uPAR.

Conclusions

These results show that soluble factors in the tumour microenvironment, such as TGF-β1, PAI-1 and uPA, can influence the ratio of full length and uPAR (II-III) and thereby potentially effect cell migration and invasion. Resolving how uPAR cleavage is controlled is therefore vital for understanding how OSCC progresses and potentially provides new targets for therapy.

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Barriers and facilitators to smoking cessation in a cancer context: A qualitative study of patient, family and professional views

Abstract

Background

Continued smoking after cancer adversely affects quality of life and survival, but one fifth of cancer survivors still smoke. Despite its demands, cancer presents an opportunity for positive behaviour change. Smoking often occurs in social groups, therefore interventions which target families and individuals may be more successful. This qualitative study explored patients, family members and health professionals' views and experiences of smoking and smoking cessation after cancer, in order to inform future interventions.

Methods

In-depth qualitative interviews (n = 67) with 29 patients, 14 family members and 24 health professionals. Data were analysed using the 'Framework' method.

Results

Few patients and family members had used National Health Service (NHS) smoking cessation services and more than half still smoked. Most recalled little 'smoking-related' discussion with clinicians but were receptive to talking openly. Clinicians revealed several barriers to discussion. Participants' continued smoking was explained by the stress of diagnosis; desire to maintain personal control; and lack of connection between smoking, cancer and health.

Conclusions

A range of barriers to smoking cessation exist for patients and family members. These are insufficiently assessed and considered by clinicians. Interventions must be more effectively integrated into routine practice.

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Adoptive T cell therapy: An overview of obstacles and opportunities

The therapeutic potential of adoptive cell therapy (ACT) in cancer patients was first acknowledged 3 decades ago, but it was an esoteric approach at the time. In recent years, technological advancements have transformed ACT into a viable therapeutic option that can be curative in some patients. In fact, current ACT response rates are 80% to 90% for hematological malignancies and 30% for metastatic melanoma refractory to multiple lines of therapy. Although these results are encouraging, there is still much to be done to fulfill ACT's potential, specifically with regard to improving clinical efficacy, expanding clinical indications, reducing toxicity, and increasing production and cost-effectiveness. This review addresses the current major obstacles to ACT and presents potential solutions. Cancer 2017;123:2154-62. © 2017 American Cancer Society.

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Issue Information

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Somatic driver mutations in melanoma

Melanoma has one of the highest somatic mutational burdens among solid malignancies. Although the rapid progress in genomic research has contributed immensely to our understanding of the pathogenesis of melanoma, the clinical significance of the vast array of genomic alterations discovered by next-generation sequencing is far from being fully characterized. Most mutations prevalent in melanoma are simply neutral "passengers," which accompany functionally significant "drivers" under transforming conditions. The delineation of driver mutations from passenger mutations is critical to the development of targeted therapies. Novel advances in genomic data analysis have aided in distinguishing true driver mutations involved in tumor progression. Here, the authors review the current literature on important somatic driver mutations in melanoma, along with the implications for treatment. Cancer 2017;123:2104-17. © 2017 American Cancer Society.

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Molecular insights into melanoma brain metastases

Substantial proportions of patients with metastatic melanoma develop brain metastases during the course of their disease, often resulting in significant morbidity and death. Despite recent advances with BRAF/MEK and immune-checkpoint inhibitors in the treatment of patients who have melanoma with extracerebral metastases, patients who have melanoma brain metastases still have poor overall survival, highlighting the need for further therapy options. A deeper understanding of the molecular pathways involved in the development of melanoma brain metastases is required to develop more brain-specific therapies. Here, the authors summarize the currently known preclinical data and describe steps involved in the development of melanoma brain metastases. Only by knowing the molecular background is it possible to design new therapeutic agents that can be used to improve the outcome of patients with melanoma brain metastases. Cancer 2017;123:2163-75. © 2017 American Cancer Society.

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After a treatment breakthrough—progress, plateaus, and raising the bar

Although coverage of the new science of melanoma and its therapy has been extensive in the medical and scientific literature, this special issue of Cancer assembles several important contributions from leaders in the field of melanoma biology and therapy to educate and update readers concerning recent advances and expert thinking, which should be both informative and thought-provoking.

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Issue information - TOC-Masthead

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Genetically engineered mouse models of melanoma

Melanoma is a complex disease that exhibits highly heterogeneous etiological, histopathological, and genetic features, as well as therapeutic responses. Genetically engineered mouse (GEM) models provide powerful tools to unravel the molecular mechanisms critical for melanoma development and drug resistance. Here, we expound briefly the basis of the mouse modeling design, the available technology for genetic engineering, and the aspects influencing the use of GEMs to model melanoma. Furthermore, we describe in detail the currently available GEM models of melanoma. Cancer 2017;123:2089-103. © 2017 American Cancer Society.

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Issue Information

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Mechanisms and strategies to overcome resistance to molecularly targeted therapy for melanoma

The identification of driver mutations in melanoma has changed the field of cancer treatment. BRAF and NRAS mutations are predominant in melanoma and lead to overactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways. Selective inhibitors targeting key effectors of the MAPK pathway have revolutionized the treatment of patients with advanced metastatic BRAF-mutant melanoma. However, resistance to therapy is almost universal and remains a major challenge in clinical care, with the majority of patients progressing within 1 year. Dissecting the mechanisms of resistance to targeted therapies may offer new insights into strategies for overcoming resistance. This review describes the efficacy of therapies targeting the MAPK and PI3K/AKT signaling pathways in melanoma, details the mechanisms contributing to drug resistance, and discusses current approaches to improving outcomes further. Cancer 2017;123:2118-29. © 2017 American Cancer Society.

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Interaction of molecular alterations with immune response in melanoma

Major advances have been made in melanoma treatment with the use of molecularly targeted therapies and immunotherapies, and numerous regimens are now approved by the US Food and Drug Administration for patients with stage IV disease. However, therapeutic resistance remains an issue to both classes of agents, and reliable biomarkers of therapeutic response and resistance are lacking. Mechanistic insights are being gained through preclinical studies and translational research, offering potential strategies to enhance responses and survival in treated patients. A comprehensive understanding of the immune effects of common mutations at play in melanoma is critical, as is an appreciation of the molecular mechanisms contributing to therapeutic resistance to immunotherapy. These mechanisms and the interplay between them are discussed herein. Cancer 2017;123:2130-42. © 2017 American Cancer Society.

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Immune and molecular correlates in melanoma treated with immune checkpoint blockade

Immunotherapy for metastatic melanoma has a decades-long history, and the relatively recent use of checkpoint inhibitors has revolutionized treatment. Durable and sometimes complete remission of metastatic melanoma is now achievable in some patients who receive checkpoint-blocking therapy. However, it is unclear why some patients fare better than others. This review highlights several molecular indicators of response to checkpoint inhibition in metastatic melanoma, focusing on tumor programmed death ligand 1 expression, major histocompatibility complex class I expression, mutational load in the tumor, and T-cell infiltration into the tumor. In addition, clinical correlates of response, notably vitiligo and other immune-related adverse events, can potentially shed light on the mechanisms by which checkpoint blockade may achieve such great success, particularly in melanoma. The authors propose that microphthalmia-associated transcription factor—a key regulator of melanocyte survival, melanin production, and melanoma transformation—produces a molecular landscape in melanocytes and melanoma cells that can make melanomas particularly susceptible to checkpoint blockade and also can result in immune attack on normal melanocytes. Cancer 2017;123:2143-53. © 2017 American Cancer Society.

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The burden of rare cancers in the United States

Abstract

There are limited published data on the burden of rare cancers in the United States. By using data from the North American Association of Central Cancer Registries and the Surveillance, Epidemiology, and End Results program, the authors provide information on incidence rates, stage at diagnosis, and survival for more than 100 rare cancers (defined as an incidence of fewer than 6 cases per 100,000 individuals per year) in the United States. Overall, approximately 20% of patients with cancer in the United States are diagnosed with a rare cancer. Rare cancers make up a larger proportion of cancers diagnosed in Hispanic (24%) and Asian/Pacific Islander (22%) patients compared with non-Hispanic blacks (20%) and non-Hispanic whites (19%). More than two-thirds (71%) of cancers occurring in children and adolescents are rare cancers compared with less than 20% of cancers diagnosed in patients aged 65 years and older. Among solid tumors, 59% of rare cancers are diagnosed at regional or distant stages compared with 45% of common cancers. In part because of this stage distribution, 5-year relative survival is poorer for patients with a rare cancer compared with those diagnosed with a common cancer among both males (55% vs 75%) and females (60% vs 74%). However, 5-year relative survival is substantially higher for children and adolescents diagnosed with a rare cancer (82%) than for adults (46% for ages 65-79 years). Continued efforts are needed to develop interventions for prevention, early detection, and treatment to reduce the burden of rare cancers. Such discoveries can often advance knowledge for all cancers. CA Cancer J Clin 2017. © 2017 American Cancer Society.

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Paramedics using virtual reality to train for real-life emergencies

Trainees are able to treat the patient the same way they'd treat a real patient and hone decision-making skills in life-and-death situations

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Emergency Reporting users protected against “WannaCry” ransomware attack

In the wake of the destructive "WannaCry" Internet worm that struck hundreds of thousands of Internet users and has been called the biggest cyberattack in history, Emergency Reporting reminds Fire & EMS agencies that data security is critical.

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Introducing the New Toughbook 33, a 12" Fully Rugged 2-in-1 Detachable Tablet

WALLINGFORD, Conn. — Telrepco is pleased to announce that today Panasonic has officially announced the release of the Toughbook 33, the first fully rugged 2-in-1 detachable tablet. Featuring a 12" 3:2 aspect ratio display, detachable backlit keyboard, and more! Toughbook 33 Features: Intel Core i5 Processor 3:2 Aspect Ratio 12" Display Anti-reflective high brightness outdoor viewable ...

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Undetectable concentrations of an FDA-approved high-sensitivity cardiac Troponin T assay to rule out acute myocardial infarction at emergency department arrival

Abstract

Background

The objective of this study was to quantify the sensitivity of very low concentrations of high-sensitivity cardiac troponin T (hsTnT) at ED arrival for acute myocardial infarction (AMI) in a large cohort of chest pain patients evaluated in real-world clinical practice.

Methods

This retrospective study included consecutive ED patients with suspected cardiac chest pain evaluated in four urban EDs were, excluding those with ST-elevation AMI, cardiac arrest or abnormal kidney function. The primary outcomes were AMI at 7-, 30- and 90 days. Secondary outcomes included major adverse cardiac events (MACE: all-cause mortality, AMI and revascularization) and the individual MACE components. Test characteristics were calculated for hsTnT values from 3-200ng/L.

Results

7130 patients met inclusion criteria. AMI incidence at 7-, 30- and 90 days was 5.8%, 6.0% and 6.2%. When the hsTnT assay was performed at ED arrival, the limit of blank of the assay (3ng/L) ruled out 7-day AMI in 15.5% of patients with 100% sensitivity and negative predictive value. The limit of detection of the assay (5ng/L) ruled out AMI in 33.6% of patients with 99.8% sensitivity and 99.95% negative predictive value for 7-day AMI. The limit of quantification (the FDA-approved cutoff for lower the reportable limit) of 6ng/L ruled out AMI in 42.2% of patients with 99.8% sensitivity and 99.95% negative predictive value. The sensitivity of the cutoffs of <3, <5 and <6 ng/L for 7-day MACE was 99.6%, 97.4% and 96.6%, respectively. The NPV of the cutoffs of <3, <5 and <6 ng/L for 7-day MACE was 99.8%, 99.5% and 99.4%, respectively.A secondary analysis was performed in a subgroup of 3549 higher-risk patients who underwent serial troponin testing. In this subgroup, a cutoff of 3ng/L ruled out 7-day AMI in 9.6% of patients with 100% sensitivity and NPV; a cutoff of 5ng/L ruled out 7-day AMI in 23.3% of patients with 99.7% sensitivity and 99.9% NPV; a cutoff of 6ng/L ruled out 7-day AMI in 29.8% of patients with 99.7 and 99.9% NPV. In the higher-risk subgroup, the sensitivity of cutoffs of <3, <5 and <6 ng/L for 7-day MACE was 99.8%, 97.4% and 96.6%, respectively. In this higher-risk subgroup, the NPV of cutoffs of <3, <5 and <6 ng/L for 7-day MACE was 99.7%, 98.5% and 98.4%, respectively.

Conclusions

When used in real-world clinical practice conditions, hsTnT concentrations < 6 ng/L (below the lower reportable limit for an FDA-approved assay) at the time of ED arrival can rule out AMI with very high sensitivity and negative predictive value. The sensitivity for MACE is unacceptably low, thus a single-troponin rule-out strategy should only be used in the context of a structured risk evaluation.

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