The interaction between a ligand and a protein involves a multitude of conformational states. To achieve a particular deeply-bound pose the ligand must search across a rough free energy landscape, with many metastable minima. Creating maps of the ligand binding landscape is a great challenge, as binding and release events typically occur on timescales that are beyond the reach of molecular simulation. The WExplore enhanced sampling method is well-suited to build these maps, as it is designed to broadly explore free-energy landscapes, and is capable of simulating ligand release pathways that occur on timescales as long as minutes.
https://ift.tt/2zEqpMK
Παρασκευή 28 Σεπτεμβρίου 2018
Mapping the ligand binding landscape
Promising Scandium Radionuclides for Nuclear Medicine: A Review on the Production and Chemistry up to In Vivo Proofs of Concept
Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.
https://ift.tt/2Ncqdb8
Nanoscale topography and poroelastic properties of model tissue breast gland basement membranes
Basement membranes (BMs) are thin layers of condensed extracellular matrix proteins serving as permeability filters, cellular anchoring sites, and barriers against cancer cell invasion. It is believed that their biomechanical properties play a crucial role in determining cellular behavior and response, especially in mechanically active tissues like breast glands. In spite of this, so far relatively little attention has been dedicated to their analysis due to the difficulty of isolating and handling such thin layers of material.
https://ift.tt/2IqTi1U
The Dual Nature of Mimicry: Organismal Form and Beholder’s Eye
Abstract
Mimicry is often cited as a compelling demonstration of the power of natural selection. By adopting signs of a protected model, mimics usually gain a reproductive advantage by minimising the likelihood of being preyed upon. Yet while natural selection plays a role in the evolution of mimicry, it can be doubted whether it fully explains it. Mimicry is mediated by the emergence of formally analogous patterns (visual, olfactory, or acoustic) between unrelated organisms and by the fact that these patterns are meaningfully perceived as similar. The perception of similarity is always perceiver-dependent. Similarities between for instance colours are psychophysical phenomena, and their existence is conditioned by an intimate interdependence between perceivers and perceptible reality. In this sense, mimicry is by its very nature dualistic. The analogy in form needed to establish a mimicry does not emerge out of the blue. It depends on the ecological context and the morphogenetic potential of a species. In our proposal, we take into account both the developmental generators of formally analogous structures and the perceptual and cognitive processes that lead to the emergence of mimicry. We show that some of the rather controversial and nowadays largely neglected ideas found in non-Anglo-Saxon literature on mimicry (e.g. writings by Th. Eimer, F. Heikertinger, or N. Vavilov) deserve closer attention. We suggest that the diversity of mimicry types is due to differences in variational properties of form-generating and perceptual systems among diverse groups of organisms. We also anticipate that processes studied within social psychology and emotion research (such as the formation of a first impression or activation of the fear module) probably take place, at least in a simplified form, also in non-human animals. Finally, we argue that these meaning-attributive processes underlie the functionality of mimicry.
https://ift.tt/2QgyUmQ
Cancers, Vol. 10, Pages 365: Oncobox Bioinformatical Platform for Selecting Potentially Effective Combinations of Target Cancer Drugs Using High-Throughput Gene Expression Data
Cancers, Vol. 10, Pages 365: Oncobox Bioinformatical Platform for Selecting Potentially Effective Combinations of Target Cancer Drugs Using High-Throughput Gene Expression Data
Cancers doi: 10.3390/cancers10100365
Authors: Maxim Sorokin Roman Kholodenko Maria Suntsova Galina Malakhova Andrew Garazha Irina Kholodenko Elena Poddubskaya Dmitriy Lantsov Ivan Stilidi Petr Arhiri Andreyan Osipov Anton Buzdin
Sequential courses of anticancer target therapy lead to selection of drug-resistant cells, which results in continuous decrease of clinical response. Here we present a new approach for predicting effective combinations of target drugs, which act in a synergistic manner. Synergistic combinations of drugs may prevent or postpone acquired resistance, thus increasing treatment efficiency. We cultured human ovarian carcinoma SKOV-3 and neuroblastoma NGP-127 cancer cell lines in the presence of Tyrosine Kinase Inhibitors (Pazopanib, Sorafenib, and Sunitinib) and Rapalogues (Temsirolimus and Everolimus) for four months and obtained cell lines demonstrating increased drug resistance. We investigated gene expression profiles of intact and resistant cells by microarrays and analyzed alterations in 378 cancer-related signaling pathways using the bioinformatical platform Oncobox. This revealed numerous pathways linked with development of drug resistant phenotypes. Our approach is based on targeting proteins involved in as many as possible signaling pathways upregulated in resistant cells. We tested 13 combinations of drugs and/or selective inhibitors predicted by Oncobox and 10 random combinations. Synergy scores for Oncobox predictions were significantly higher than for randomly selected drug combinations. Thus, the proposed approach significantly outperforms random selection of drugs and can be adopted to enhance discovery of new synergistic combinations of anticancer target drugs.
https://ift.tt/2It8qMk
Rab14 overexpression regulates gemcitabine sensitivity through regulation of Bcl-2 and mitochondrial function in pancreatic cancer
Abstract
Rab family protein Rab14 has been implicated in the development of human cancers. To date, its expression pattern, biological function, and potential mechanism in pancreatic cancer have not been explored. In this study, we analyzed Rab14 expression in 103 cases of pancreatic cancer tissues using immunohistochemistry (IHC) and found that Rab14 was overexpressed in 41/103 cases (39.8%). Rab14 overexpression correlated with the advanced stage. Moreover, elevated Rab14 levels indicated poor prognosis of patients with pancreatic cancers. We used BxPC-3 and Capan-2 respectively for plasmid and siRNA transfection. MTT and colony formation assays showed that Rab14 transfection increased cell proliferation and colony formation in BxPC-3 cells. Rab14 siRNA knockdown inhibits proliferation and colony formation ability in Capan-2 cell line. Cell cycle analysis showed that Rab14 facilitated cell cycle progression. Matrigel invasion assay showed that Rab14 promoted BxPC-3 cell invasion while its depletion inhibited Capan-2 cell invasion. In addition, MTT and AnnexinV/PI analysis demonstrated that overexpression of Rab14 reduced gemcitabine sensitivity which conversely was increased by Rab14 knockdown. We also demonstrated that Rab14 upregulated mitochondrial membrane potential (MMP) while its depletion downregulated MMP during gemcitabine treatment. In addition, western blotting revealed that Rab14 overexpression upregulated cyclin D1, cyclin A, cyclin E, p-Rb, and Bcl-2 and downregulated p21. Rab14 also downregulated caspase3, PARP cleavage, and cytochrome c release. In conclusion, our data indicated that Rab14 was overexpressed in pancreatic cancer and promotes growth and gemcitabine resistance, possibly through regulation of mitochondrial function and Bcl-2.
https://ift.tt/2y08cY3
Development of pseudo-subarachnoid hemorrhage secondary to hypoxic-ischemic injury due to bleeding pulmonary arterio-venous malformation
The computed tomography (CT) finding of a pseudo-subarachnoid hemorrhage (SAH) may lead the treating physician into a diagnostic dilemma. We present a case of a pseudo-SAH in a patient with post-resuscitative ...
https://ift.tt/2OXwER2
Paclitaxel reversed trastuzumab resistance via regulating JUN in human gastric cancer cells identified by FAN analysis
Future Oncology, Ahead of Print.
https://ift.tt/2IqDJqO
Treatment preferences in human papillomavirus-associated oropharyngeal cancer
Future Oncology, Ahead of Print.
https://ift.tt/2NR8QBQ
Therapeutic Strategies in EGFR Mutant Non-Small Cell Lung Cancer
Opinion statement
Non-small cell lung cancer (NSCLC) harboring epidermal growth receptor (EGFR) mutation has distinct genomic characteristics. Introduction of systemic treatments that specifically targeted actionable EGFR mutations has changed the therapeutic paradigm in this group of patients. Moreover, newer generations of EGFR tyrosine-kinase inhibitors (EGFR-TKIs) with superior pharmacokinetics and pharmacodynamics properties such as dacomitinib and osimertinib, when used in the front-line setting, have shown more favorable treatment outcomes than first-generation EGFR-TKIs. In addition, evolving molecular technologies such as droplet digital polymerase chain reaction (ddPCR) and next-generation sequencing (NGS) has enhanced our understanding towards the genetics and epigenetics in pathogenesis, drug-resistant mechanisms as well as improved diagnostic accuracy and efficacy. On the other hand, the recent development in immunotherapies has pushed anti-cancer treatment to new frontiers in many cancers including lung cancer. While ongoing research are focusing on how benefits of immunotherapy can be potentiated, the combinational use of EGFR-TKIs and checkpoint inhibitors have been shown repeatedly in prior trials to cause significant toxicities. This approach cannot be recommended outside of a clinical trial at this time. Overall, remarkable progresses have opened new therapeutic strategies with which patient survival is further improved. In this review, we shall discuss the latest treatment strategies in EGFR mutation positive NSCLC with a focus on latest evidence, and how advances in molecular diagnostics can play an important role patient management.
https://ift.tt/2Io6Qv7
Coagulopathies and inflammatory diseases: ‘…glimpse of a Snark’
Silvina del Carmen | Sophie M Hapak | Sourav Ghosh | Carla V Rothlin
https://ift.tt/2zEluf6
Regulation of lymphocyte trafficking in central nervous system autoimmunity
Mohamed Oukka | Estelle Bettelli
https://ift.tt/2IoK869
Deletion 6q drives T-cell leukemia progression by ribosome modulation [Research Articles]
Deletion of chromosome 6q is a well-recognized abnormality found in poor-prognosis T-cell acute lymphoblastic leukemia (T-ALL). Using integrated genomic approaches, we identified two candidate haploinsufficient genes contiguous at 6q14, SYNCRIP (encoding hnRNP-Q) and SNHG5 (that hosts snoRNAs), both involved in regulating RNA maturation and translation. Combined silencing of both genes, but not of either gene alone, accelerated a Tal1/Lmo1/Notch1-driven mouse model of leukemogenesis, demonstrating the tumor suppressor nature of the two-gene region. Proteomic and translation profiling of cells in which we engineered a short 6q deletion by CRISPR/Cas9 genome editing indicated decreased ribosome and mitochondrial activities, suggesting that the resulting metabolic changes may regulate tumor progression. Indeed, xenograft experiments showed an increased leukemia initiating cell activity of primary human leukemic cells upon co-extinction of SYNCRIP and SNHG5. Our findings not only elucidate the nature of 6q deletion but also highlight the role of ribosome and mitochondria in T-ALL tumor progression.
https://ift.tt/2NR1bni
Genome-Informed Targeted Therapy for Osteosarcoma [Research Articles]
Osteosarcoma (OS) is a highly aggressive cancer for which treatment has remained essentially unchanged for over 30 years. OS is characterized by widespread and recurrent somatic copy-number alterations (SCNAs) and structural rearrangements. In contrast, few recurrent point mutations in protein-coding genes have been identified, suggesting that genes within SCNAs are key oncogenic drivers in this disease. SCNAs and structural rearrangements are highly heterogeneous across OS cases, suggesting the need for a genome-informed approach to targeted therapy. To identify patient-specific candidate drivers, we used a simple heuristic based on degree and rank order of copy number amplification (identified by Whole Genome Sequencing) and changes in gene expression as identified by RNAseq. Using patient-derived tumor xenografts, we demonstrate that targeting of patient-specific somatic copy number alterations leads to significant decrease in tumor burden, providing a roadmap for genome-informed treatment of OS.
https://ift.tt/2Qcm214
CARD9 Deficiency Promotes Colitis-Associated Tumorigenesis [Research Watch]
Card9–/– mice had an increased fungal burden, and an antifungal reduced colitis-linked tumorigenesis.
https://ift.tt/2NMnEle
RAD52 Promotes Transcription-Associated Homologous Recombination Repair [Research Watch]
RAD52-mediated processing of R-loops initiates high-fidelity DNA repair in actively transcribed regions.
https://ift.tt/2Qcm0pY
Noncanonical Autophagy in Myeloid Cells Drives Tumor Immune Tolerance [Research Watch]
LC3-associated phagocytosis (LAP) in TAMs results in the immunosuppression of TILs.
https://ift.tt/2NLm8Qm
SPOP Mutations Disrupt Phase Separation to Impair Its Activity [Research Watch]
SPOP colocalizes with substrates in membraneless organelles, thereby enhancing ubiquitination.
https://ift.tt/2QjE4yC
METTL3 Promotes mRNA Translation to Drive Tumorigenesis [Research Watch]
METTL3 interacts with eIF3h to enhance the translation efficiency of target mRNAs including BRD4.
https://ift.tt/2NLxi7P
Planar cell polarity: the prickle gene acts independently on both the Ds/Ft and the Stan/Fz systems [RESEARCH ARTICLE]
Jose Casal, Beatriz Ibanez-Jimenez, and Peter A. Lawrence
https://ift.tt/2DEa4f3
Epithelial cells are polarised within the plane of the epithelium, forming oriented structures that have a coordinated and consistent polarity (planar cell polarity, PCP). In Drosophila, at least two separate molecular systems generate and interpret intercellular polarity signals: Dachsous/Fat, and the 'core' or Starry night/Frizzled system. Here, we study the prickle gene and its protein products Prickle and Spiny leg. Much research on PCP has focused on the asymmetric localisation of core proteins in the cell and as a result prickle was placed in the heart of the Starry night/Frizzled system. We investigate whether this view is correct and how the prickle gene relates to the two systems. We find that prickle can affect, separately, both systems; however, neither Prickle nor Spiny leg are essential components of the Dachsous/Fat or the Starry night/Frizzled system, nor do they act as a functional link between the two systems.
https://ift.tt/2DEa4f3
Role of SmcHD1 in establishment of epigenetic states required for the maintenance of the X-inactivated state in mice [RESEARCH ARTICLE]
Yuki Sakakibara, Koji Nagao, Marnie Blewitt, Hiroyuki Sasaki, Chikashi Obuse, and Takashi Sado
https://ift.tt/2zCVTmr
X inactivation in mammals is regulated by epigenetic modifications. Functional deficiency of SmcHD1 has been shown to cause de-repression of X-inactivated genes in post-implantation female mouse embryos, suggesting a role of SmcHD1 in the maintenance of X inactivation. Here, we show that de-repression of X-inactivated genes accompanied a local reduction in the enrichment of H3K27me3 in mouse embryonic fibroblasts deficient for SmcHD1. Furthermore, many of these genes overlapped with those having a significantly lower enrichment of H3K27me3 at the blastocyst stage in wild type. Intriguingly, however, depletion of SmcHD1 did not compromise the X-inactivated state in immortalized female mouse embryonic fibroblasts, in which X inactivation had been established and maintained. Taking all these findings together, we suggest that SmcHD1 facilitates the incorporation of H3K27me3 and perhaps other epigenetic modifications at gene loci that are silenced even with the lower enrichment of H3K27me3 at the early stage of X inactivation. The epigenetic state at these loci would, however, remain as it is at the blastocyst stage in the absence of SmcHD1 after implantation, which would eventually compromise the maintenance of the X-inactivated state at later stages.
https://ift.tt/2zCVTmr
ROCK-nmMyoII, Notch and Neurog3 gene-dosage link epithelial morphogenesis with cell fate in the pancreatic endocrine-progenitor niche [RESEARCH ARTICLE]
Eric D. Bankaitis, Matthew E. Bechard, Guoqiang Gu, Mark A. Magnuson, and Christopher V. E. Wright
https://ift.tt/2DEMxLe
During mouse pancreas organogenesis, endocrine cells are born from progenitors residing in an epithelial plexus niche. After a period in a lineage-primed Neurog3LO state, progenitors become endocrine committed via upregulation of Neurog3. We find that the Neurog3LO to Neurog3HI transition is associated with distinct stages of an epithelial egression process: narrowing the apical surface of the cell, basalward cell movement and eventual cell-rear detachment from the apical lumen surface to allow clustering as nascent islets under the basement membrane. Apical narrowing, basalward movement and Neurog3 transcriptional upregulation still occur without Neurog3 protein, suggesting that morphogenetic cues deployed within the plexus initiate endocrine commitment upstream or independently of Neurog3. Neurog3 is required for cell-rear detachment and complete endocrine-cell birth. The ROCK-nmMyoII pathway coordinates epithelial-cell morphogenesis and the progression through Neurog3-expressing states. NmMyoII is necessary for apical narrowing, basalward cell displacement and Neurog3 upregulation, but all three are limited by ROCK activity. We propose that ROCK-nmMyoII activity, Neurog3 gene-dose and Notch signaling integrate endocrine fate allocation with epithelial plexus growth and morphogenesis, representing a feedback control circuit that coordinates morphogenesis with lineage diversification in the endocrine-birth niche.
https://ift.tt/2DEMxLe
RPM-1 and DLK-1 regulate pioneer axon outgrowth by controlling Wnt signaling [RESEARCH ARTICLE]
Eun Chan Park and Christopher Rongo
https://ift.tt/2DEMsHq
Axons must correctly reach their targets for proper nervous system function, although we do not fully understand the underlying mechanism, particularly for the first 'pioneer' axons. In C. elegans, AVG is the first neuron to extend an axon along the ventral midline, and this pioneer axon facilitates the proper extension and guidance of follower axons that comprise the ventral nerve cord. Here, we show that the ubiquitin ligase RPM-1 prevents the overgrowth of the AVG axon by repressing the activity of the DLK-1/p38 MAPK pathway. Unlike in damaged neurons, where this pathway activates CEBP-1, we find that RPM-1 and the DLK-1 pathway instead regulate the response to extracellular Wnt cues in developing AVG axons. The Wnt LIN-44 promotes the posterior growth of the AVG axon. In the absence of RPM-1 activity, AVG becomes responsive to a different Wnt, EGL-20, through a mechanism that appears to be independent of canonical Fz-type receptors. Our results suggest that RPM-1 and the DLK-1 pathway regulate axon guidance and growth by preventing Wnt signaling crosstalk.
https://ift.tt/2DEMsHq
An interview with James Sharpe [SPOTLIGHT]
Seema Grewal
https://ift.tt/2zEEn1r
James Sharpe is a developmental biologist who studies the process of limb development using a multi-disciplinary approach, combining experimental systems, imaging and computer modelling. Formerly based at the Centre for Genomic Regulation in Barcelona, James was recently appointed Head of EMBL Barcelona. We caught up with James at the British Society for Developmental Biology Spring Meeting to ask him about his research, his thoughts on computational modelling, and his vision for the new EMBL Barcelona site.
https://ift.tt/2zEEn1r
ANGUSTIFOLIA contributes to the regulation of three-dimensional morphogenesis in the liverwort Marchantia polymorpha [RESEARCH ARTICLE]
Tomoyuki Furuya, Koro Hattori, Yoshitaka Kimori, Sakiko Ishida, Ryuichi Nishihama, Takayuki Kohchi, and Hirokazu Tsukaya
https://ift.tt/2DGcCtg
Arabidopsis thaliana mutants deficient in ANGUSTIFOLIA (AN) exhibit several phenotypes at the sporophyte stage, such as narrow and thicker leaves, trichomes with two branches, and twisted fruits. It is thought that these phenotypes are caused by abnormal arrangement of cortical microtubules (MTs). AN homologs are present in the genomes of diverse land plants, including the basal land plant Marchantia polymorpha, and their molecular functions have been shown to be evolutionarily conserved in terms of the ability to complement the A. thaliana an-1 mutation. However, the roles of ANs in bryophytes, the life cycle of which includes a dominant haploid gametophyte generation, remain unknown. Here, we have examined the roles of AN homologs in the model bryophyte M. polymorpha (MpAN). Mpan knockout mutants showed abnormal twisted thalli and suppressed thallus growth along the growth axis. Under weak blue light conditions, elongated thallus growth was observed in wild-type plants, whereas it was suppressed in the mutants. Moreover, disordered cortical MT orientations were observed. Our findings suggest that MpAN contributes to three-dimensional morphogenesis by regulating cortical MT arrangement in the gametophytes of bryophytes.
https://ift.tt/2DGcCtg
Enpp1 inhibits ectopic joint calcification and maintains articular chondrocytes by repressing hedgehog signaling [RESEARCH ARTICLE]
Yunyun Jin, Qian Cong, Jelena Gvozdenovic-Jeremic, Jiajie Hu, Yiqun Zhang, Robert Terkeltaub, and Yingzi Yang
https://ift.tt/2zEcfeV
The differentiated phenotype of articular chondrocytes of synovial joints needs to be maintained throughout life. Disruption of the articular cartilage, frequently associated with chondrocyte hypertrophy and calcification, is a central feature in osteoarthritis (OA). However, the molecular mechanisms whereby phenotypes of articular chondrocytes are maintained and pathological calcification is inhibited remain poorly understood. Recently, the ecto-enzyme Enpp1, a suppressor of pathological calcification, was reported to be decreased in joint cartilage with OA in both human and mouse, and Enpp1 deficiency causes joint calcification. Here, we found that hedgehog (Hh) signaling activation contributes to ectopic joint calcification in the Enpp1–/– mice. In the Enpp1–/– joints, Hh signaling was upregulated. Further activation of Hh signaling by removing the patched 1 gene in the Enpp1–/– mice enhanced ectopic joint calcification, whereas removing Gli2 partially rescued the ectopic calcification phenotype. In addition, reduction of Gαs in the Enpp1–/– mice enhanced joint calcification, suggesting that Enpp1 inhibits Hh signaling and chondrocyte hypertrophy by activating Gαs-PKA signaling. Our findings provide new insights into the mechanisms underlying Enpp1 regulation of joint integrity.
https://ift.tt/2zEcfeV
The regulation of cilium assembly and disassembly in development and disease [REVIEW]
Lei Wang and Brian D. Dynlacht
https://ift.tt/2DEMgIc
The primary cilium is an antenna-like organelle assembled on most types of quiescent and differentiated mammalian cells. This immotile structure is essential for interpreting extracellular signals that regulate growth, development and homeostasis. As such, ciliary defects produce a spectrum of human diseases, termed ciliopathies, and deregulation of this important organelle also plays key roles during tumor formation and progression. Recent studies have begun to clarify the key mechanisms that regulate ciliary assembly and disassembly in both normal and tumor cells, highlighting new possibilities for therapeutic intervention. Here, we review these exciting new findings, discussing the molecular factors involved in cilium formation and removal, the intrinsic and extrinsic control of cilium assembly and disassembly, and the relevance of these processes to mammalian cell growth and disease.
https://ift.tt/2DEMgIc
RAR{gamma} is required for mesodermal gene expression prior to gastrulation in Xenopus [RESEARCH ARTICLE]
Amanda Janesick, Weiyi Tang, Toshi Shioda, and Bruce Blumberg
https://ift.tt/2zEgo2c
The developing vertebrate embryo is exquisitely sensitive to retinoic acid (RA) concentration, particularly during anteroposterior patterning. In contrast to Nodal and Wnt signaling, RA was not previously considered to be an instructive signal in mesoderm formation during gastrulation. Here, we show in Xenopus that RAR is indispensable for the expression of early mesoderm markers and is, therefore, an obligatory factor in mesodermal competence and/or maintenance. We identified several novel targets upregulated by RA receptor signaling in the early gastrula that are expressed in the circumblastoporal ring and linked to mesodermal development. Despite overlapping expression patterns of the genes encoding the RA-synthesizing enzyme Aldh1a2 and the RA-degrading enzyme Cyp26a1, RAR1 functions as a transcriptional activator in early mesoderm development, suggesting that RA ligand is available to the embryo earlier than previously appreciated. RAR1 is required for cellular adhesion, as revealed by spontaneous dissociation and depletion of ncam1 mRNA in animal caps harvested from RAR1 knockdown embryos. RAR1 knockdown obliterates somite boundaries, and causes loss of Myod protein in the presomitic mesoderm, but ectopic, persistent expression of Myod protein in the trunk. Thus, RAR1 is required for stabilizing the mesodermal fate, myogenic commitment, somite boundary formation, and terminal skeletal muscle differentiation.
https://ift.tt/2zEgo2c
Methylation-dependent Tissue Factor suppression contributes to the reduced malignancy of IDH1 mutant gliomas
Purpose: Gliomas with isocitrate dehydrogenase 1 mutations (IDH1mut) are less aggressive than IDH1 wild-type (IDH1wt) gliomas and have global genomic hypermethylation. Yet it is unclear how specific hypermethylation events contribute to the IDH1mut phenotype. Previously, we showed that the gene encoding the procoagulant Tissue Factor (TF), F3, is among the most hypermethylated and downregulated genes in IDH1mut gliomas, correlating with greatly reduced thrombosis in IDH1mut glioma patients. Because TF also increases the aggressiveness of many cancers, the current study explored the contribution of TF suppression to the reduced malignancy of IDH1mut gliomas. Experimental Design: TF expression was manipulated in patient-derived IDH1mut and IDH1wt glioma cells, followed by evaluation of in vitro and in vivo behavior and analyses of cell signaling pathways. Results: A demethylating agent, decitabine, increased F3 transcription and TF-dependent coagulative activity in IDH1mut cells, but not in IDH1wt cells. TF induction enhanced the proliferation, invasion, and colony formation of IDH1mut cells, and increased the intracranial engraftment of IDH1mut GBM164 from 0% to 100% (P=0.0001). Conversely, TF knockdown doubled the median survival of mice engrafted with IDH1wt/EGFRvIIIamp GBM6, and caused complete regression of IDH1wt/EGFRamp GBM12 (P=0.001). In vitro and in vivo effects were linked to activation of receptor tyrosine kinases (RTKs) by TF through a Src-dependent intracellular pathway, even when extracellular RTK stimulation was blocked. TF stimulated invasion predominately through upregulation of β-catenin. Conclusions:These data show that TF suppression is a component of IDH1mut glioma behavior, and that it may therefore be an attractive target against IDH1wt gliomas.
https://ift.tt/2IsNMvO
Host IDO2 gene status influences tumor progression and radiotherapy response in KRAS-driven sporadic pancreatic cancers
Purpose: Heritable genetic variations can affect the inflammatory tumor microenvironment, which can ultimately impact cancer susceptibility and clinical outcomes. Recent evidence indicates that IDO2, a positive modifier in inflammatory disease models, is frequently upregulated in pancreatic ductal adenocarcinoma (PDAC). A unique feature of IDO2in humans is the high prevalence of two inactivating single nucleotide polymorphisms (SNPs) which affords the opportunity to carry out loss-of-function studies directly in humans. In this study we sought to address whether genetic loss of IDO2 may influence PDAC development and responsiveness to treatment. Experimental Design: Transgenic Ido2+/+and Ido2-/-micein which oncogenic KRAS is activated in pancreatic epithelial cells were evaluated for PDAC. Two patient datasets (N=200) were evaluated for the two IDO2-inactivating SNPs together with histologic, RNA expression and clinical survival data. Results: PDAC development was notably decreased in the Ido2-/- mice (30% vs 10%, P<0.05), with a female predominance similar to the association observed for one of the human SNPs. In patients, the biallelic occurrence of either of the two IDO2-inactivating SNPs was significantly associated with markedly improved disease-free survival in response to adjuvant radiotherapy (P<0.01), a treatment modality that has been highly debated due to its variable efficacy. Conclusions: The results of this study provide genetic support for IDO2 as a contributing factor in PDAC development and argue that IDO2genotype analysis has the immediate potential to influence the PDAC care decision-making process through stratification of those patients who stand to benefit from adjuvant radiotherapy.
https://ift.tt/2R3KJ0O
Increased Cardiovascular Risk for Diclofenac Initiators
FRIDAY, Sept. 28, 2018 -- Diclofenac initiators have increased cardiovascular risk compared with non-initiators, according to a study published online Sept. 4 in The BMJ. Morten Schmidt, M.D., Ph.D., from Aarhus University Hospital in Denmark, and...
https://ift.tt/2OjC4Zz
Tenth-Graders Use Combustible, Edible, Vaporized Cannabis
FRIDAY, Sept. 28, 2018 -- Among 10th-grade students using cannabis, edible and vaporized products are used in addition to combustible products, with 61.7 percent reporting multiple administration methods, according to a study published online Sept....
https://ift.tt/2xZzUnN
Handheld Device Inspired by Star Trek May Allow Rapid Diagnosis
FRIDAY, Sept. 28, 2018 -- A device inspired by the Star Trek famous tricorder device pairs a handheld sensor with a smartphone app to measure the levels of various metabolites associated with multiple diseases in fluid samples from patients,...
https://ift.tt/2OkAerz
Pharmaceutical Executive Defends 400 Percent Price Hike
FRIDAY, Sept. 28, 2018 -- A pharmaceutical executive is defending his company's 400 percent price hike on an antibiotic, according to a report published in Formulary Watch. Nostrum Laboratories increased the price of a bottle of nitrofurantoin,...
https://ift.tt/2xXDX3T
Physicians Often Don't Address Their Burnout
FRIDAY, Sept. 28, 2018 -- More than half of physicians experience burnout, and many do not seek treatment for burnout, according to a report published in the American Medical Association's AMA Wire. Noting that the same traits that help physicians...
https://ift.tt/2OjC4c1
miRNA-448 inhibits cell growth by targeting BCL-2 in hepatocellular carcinoma
Increasing evidence indicates that aberrant micro (mi)RNA-448 expression plays a critical role in the progression of several human cancers. However, the function of miRNA-448 in hepatocellular carcinoma (HCC) has not been fully investigated.
https://ift.tt/2OlF8EH
Early Detection of Ovarian Cancer
Early detection of ovarian cancer could reduce mortality by 10% to 30%. Effective screening requires high sensitivity (>75%) and extremely high specificity (99.7%). Clinical trials suggest the best specificity is achieved with 2-stage strategies in which increasing serum CA125 level triggers transvaginal sonography to detect a malignant pelvic mass, although evidence for such approaches improving overall survival has been limited. Screening may be improved by combining CA125 with novel biomarkers, such as autoantibodies, circulating tumor DNA, or microRNAs. In order to detect premetastatic ovarian cancers originating in the distal fallopian tube, more sensitive approaches to diagnostic imaging are required.
https://ift.tt/2N88Rwb
Blue-light imaging compared with high-definition white light for real-time histology prediction of subcentimetric colorectal polyps: a prospective randomized study
Blue light imaging (BLI) is a new chromoendoscopy technology, potentially useful for differentiating neoplastic from non-neoplastic lesions. Present study was aimed at comparing BLI with high-definition white light (HDWL) in the real-time histology prediction of subcentimetric (<10 mm) colonic polyps.
https://ift.tt/2R96895
Clinical disease activity and endoscopic severity correlate poorly in children newly diagnosed with Crohn’s Disease
/Aims: Treatment goals in Crohn's disease (CD) have evolved to target mucosal healing. There is now a drive to determine if non-invasive measures can adequately identify the attainment and persistence of this goal. Currently, data describing the relationship between clinical indices and endoscopic appearance in pediatric Crohn's disease (CD) are sparse. Our aim was to compare endoscopic severity with the weighted Pediatric Crohn's Disease Activity Index (wPCDAI) in children with newly diagnosed CD.
https://ift.tt/2N6ASnX
Quality of life and fear of cancer recurrence in T1 colorectal cancer patients treated with endoscopic or surgical tumor resection
To optimize therapeutic decision-making in T1 colorectal cancer (T1 CRC) patients, it is important to elicit the patient's perspective next to considering medical outcome. Because empirical data on patient-reported impact of different treatment options are lacking, we evaluated patients' quality of life, perceived time to recovery and fear of cancer recurrence after endoscopic or surgical treatment for T1 CRC.
https://ift.tt/2R9nG4F
G-EYE colonoscopy is superior to standard colonoscopy for increasing adenoma detection rate: an international randomized controlled trial (with videos)
Colorectal cancer (CRC) is largely preventable with routine screening and surveillance colonoscopy; however, interval cancers arising from precancerous lesions missed by standard colonoscopy (SC) still occur. Increased adenoma detection rate (ADR) has been found to be inversely associated with interval cancers. The G-EYE device comprises a reusable balloon integrated at the distal tip of a standard colonoscope, which flattens haustral folds, centralizes the colonoscope's optics and reduces bowel slippage.
https://ift.tt/2N7ZGfi
236 Low Fidelity Model for Chest Tube Thoracostomy
Chest tube thoracostomy is a low frequency, high stress, life-saving procedure. Although non-cadaveric commercial trainers are available, their procurement and maintenance can be financially prohibitive. We designed and fabricated a trainer that contains enough structural detail to perform all of the steps of the procedure, is inexpensive, and easy to use and reuse.
https://ift.tt/2OSt9LM
Persistent Facial Swelling in an 8-Year-Old
An 8-year-old previously healthy girl presented with acute swelling and scaling of the right side of the face overlying the mandible. She had a 2-year history of intermittent bilateral facial swelling, with prior episodes resolving without treatment in 4-6 weeks. These episodes had not responded to topical corticosteroid or antifungal therapy. On examination, the patient was afebrile with age-appropriate vital signs. She had firm, nontender facial edema extending from the right oral commissure to the cheek, with overlying red-purple scaling plaques (Figure).
https://ift.tt/2Qi8Wzj
Daily Intake of Soft Drinks and Moderate-to-Severe Acne Vulgaris in Chinese Adolescents
To investigate the association of soft drink consumption and the intake of sugar from soft drinks with the prevalence of acne in adolescents.
https://ift.tt/2zDef6V
Racial and Ethnic Disparities in the Use of Mother's Milk Feeding for Very Low Birth Weight Infants in Massachusetts
To examine the extent to which maternal race/ethnicity is associated with mother's milk use among hospitalized very low birth weight (VLBW) infants and maternal receipt of hospital breastfeeding support practices (human milk prenatal education, first milk expression <6 hours after delivery, lactation consultation <24 hours, any skin-to-skin care <1 month).
https://ift.tt/2Qjm6w9
Intravenous Immunoglobulin Versus Anti-D Immunoglobulin: When Better Treatment May Not Be the Best Treatment
In this volume of The Journal, Lioger et al report on a systematic review comparing the efficacy and safety of anti-D immunoglobulin (anti-D) and intravenous immunoglobulin (IVIG) in the treatment of pediatric immune thrombocytopenia (ITP).1 The methodology of the authors is meticulous, and this work clearly highlights the significant gaps in evidence that persist in the management of ITP despite the fact that it is one of the most common diseases encountered in pediatric hematology. The authors performed a search for randomized controlled trials that enrolled children <18 years of age with primary ITP and that evaluated the effect of anti-D and IVIG.
https://ift.tt/2zDzVzN
Longitudinal Associations between Neurodevelopment and Psychosocial Health Status in Patients with Repaired D-Transposition of the Great Arteries
To examine associations between measurements of neurodevelopment and psychosocial health status at age 8 and 16 years in patients with repaired dextro-transposition of the great arteries.
https://ift.tt/2QheBpb
All Aboard Meal Train: Can Child-Friendly Menu Labeling Promote Healthier Choices in Hospitals?
To evaluate patient meal orders and consumption with a revised menu design that includes child-friendly labeling.
https://ift.tt/2zDKh2H
Opioid Prescribing Practices for Pediatric Headache
To characterize the frequency of opioid prescribing for pediatric headache in both ambulatory and emergency department (ED) settings, including prescribing rates by provider type.
https://ift.tt/2zDmsIe
Mycoplasma pneumoniae-Induced Red Fingers
An 11-year-old girl presented with a 4-day history of erythema of her distal fingers. The lesions appeared on all fingers simultaneously after 1 week of fever and a nonproductive cough. She had received only acetaminophen, and her medical history was unremarkable. At presentation, she had intense, well-delineated erythematous macules in the periungual and pulp areas of all fingers (Figure), but not her toes, and without associated pain, tenderness, swelling, numbness, or Raynaud's phenomenon. The nail plates were normal, and there was no periungual telangiectasia.
https://ift.tt/2QlKld9
Composite Health Outcomes in Pediatric and Young Adult Kidney Transplant Recipients
To assess composite health outcomes in pediatric and young adult kidney transplant recipients following kidney transplantation.
https://ift.tt/2Qi8WiN
Screening for Latent Tuberculosis Infection in Migrants With CKD: A Cost-effectiveness Analysis
In countries with a low tuberculosis (TB) incidence, TB disproportionately affects populations born abroad. TB persists in these populations through reactivation of latent TB infection (LTBI) acquired before immigration. Those with chronic kidney disease (CKD) are at increased risk for reactivation and may benefit from LTBI screening and treatment.
https://ift.tt/2OnhEPt
Co-immunoprecipitation Assay for Studying Functional Interactions Between Receptors and Enzymes
https://ift.tt/2R90p36
Isolation of Physiologically Active Thylakoids and Their Use in Energy-Dependent Protein Transport Assays
We present protocols herein for high-yield isolation of physiologically active thylakoids and protein transport assays for the chloroplast twin arginine translocation (cpTat), secretory (cpSec1), and signal recognition particle (cpSRP) pathways.
https://ift.tt/2zE0yVv
Analysis of Thylakoid Membrane Protein Complexes by Blue Native Gel Electrophoresis
A protocol for the elucidation of plant thylakoid protein complex organization and composition with blue native polyacrylamide gel electrophoresis (BN-PAGE) and 2D-SDS-PAGE is described. The protocol is optimized for Arabidopsis thaliana, but can be used for other plant species with minor modifications.
https://ift.tt/2QiZFal
Rat Model of Adhesive Capsulitis of the Shoulder
This protocol presents an in vivo rat model of adhesive capsulitis. The model includes an internal fixation of the glenohumeral joint with extra-articular suture fixation for an extended time, resulting in a decreased rotational range of motion (ROM) and increased joint stiffness.
https://ift.tt/2zCFD52
Many Proxies Unaware of Centenarians' Thoughts on Death
FRIDAY, Sept. 28, 2018 -- Many proxies of centenarians are not well-informed about the centenarians' thoughts and plans regarding the end of life (EOL), according to a study published in the July issue of the Journal of the American Geriatrics...
https://ift.tt/2NNxrHS
No Benefit to Negative Pressure Wound Therapy After C-Section
FRIDAY, Sept. 28, 2018 -- For obese women, use of prophylactic negative pressure wound therapy versus standard dressings does not reduce superficial surgical site infections after cesarean section, according to a study published in the August issue...
https://ift.tt/2NR6Qd5
Strategies to Cut Cardiovascular Risk Factors Show Mixed Results
FRIDAY, Sept. 28, 2018 -- Cardiovascular disease (CVD) risk factors remain prevalent despite known, proven strategies to reduce risk, according to research published in the Sept. 7 issue of the U.S. Centers for Disease Control and Prevention's...
https://ift.tt/2QhF6L9
CDC: Congenital Syphilis More Than Doubled Since 2013
FRIDAY, Sept. 28, 2018 -- The number of cases of sexually transmitted diseases (STDs) is continuing to increase, with an associated increase in the number of cases of congenital syphilis, according to a report published by the U.S. Centers for...
https://ift.tt/2QgNNFz
Cardioverter-Defibrillator Vests Do Not Cut Sudden Death Post MI
FRIDAY, Sept. 28, 2018 -- Wearing a cardioverter-defibrillator does not reduce arrhythmic death in patients with acute myocardial infarction and an ejection fraction of 35 percent or less, according to a study published in the Sept. 27 issue of the...
https://ift.tt/2NMGDwj
Implementing EMRs Affects Time Spent With Patients in Clinic
FRIDAY, Sept. 28, 2018 -- Following a six-month learning period to implement an electronic medical record (EMR) system, outpatient orthopedic clinics return to pre-implementation efficiency, but there may be other lasting effects on productivity,...
https://ift.tt/2QhI96d
Surgical Mesh Itself Not Tied to Increased Complications
FRIDAY, Sept. 28, 2018 -- Use of mesh is not independently associated with an increase in the rate of complications of pelvic organ prolapse repair, according to a study published in the August issue of The Journal of Urology. Kai B. Dallas, M.D.,...
https://ift.tt/2NOa2Gf
Prevalence of TBI 2.5 Percent Among U.S. Children
FRIDAY, Sept. 28, 2018 -- The prevalence of traumatic brain injury (TBI) is 2.5 percent among U.S. children, and TBI is associated with several health conditions, according to a study published online Sept. 24 in JAMA Pediatrics. Juliet...
https://ift.tt/2Qlo1An
Nintedanib Plus Sildenafil No Better Than Nintedanib in IPF
FRIDAY, Sept. 28, 2018 -- Nintedanib plus sildenafil does not provide benefit over nintedanib alone for patients with idiopathic pulmonary fibrosis (IPF) and diffusion capacity of the lungs for carbon monoxide (DLCO) of 35 percent or less of the...
https://ift.tt/2NOa159
Proton Pump Inhibitor Use Tied to Hip Fracture in Dialysis Patients
FRIDAY, Sept. 28, 2018 -- Proton pump inhibitor (PPI) use is associated with increased risk of hip fracture among dialysis patients, according to a study published online Sept. 27 in the Clinical Journal of the American Society of...
https://ift.tt/2QlnYVd
Mechanisms of monocyte cell death triggered by dengue virus infection
Abstract
Arthropod-borne viral diseases caused by dengue virus (DENV) are major re-emerging public health problem worldwide. In spite of intense research, DENV pathogenesis is not fully understood and remains enigmatic; however, current evidence suggests that dengue progression is associated with an inflammatory response, mainly in patients suffering from a second DENV infection. Monocytes are one of the main target cells of DENV infection and play an important role in pathogenesis since they are known to produce several inflammatory cytokines that can lead to endothelial dysfunction and therefore vascular leak. In addition, monocytes play an important role in antibody dependent enhancement, infection with consequences in viral load and immune response. Despite the physiological functions of monocytes in immune response, their life span in the bloodstream is very short, and activation of monocytes by DENV infection can trigger different types of cell death. For example, DENV can induce apoptosis in monocytes related with the production of Tumor necrosis factor alpha (TNF-α). Additionally, recent studies have shown that DENV-infected monocytes also exhibit a cell death process mediated by caspase-1 activation together with IL-1 production, referred to as pyroptosis. Taken together, the aforementioned studies strongly depict that multiple cell death pathways may be occurring in monocytes upon DENV-2 infection. This review provides insight into mechanisms of DENV-induced death of both monocytes and other cell types for a better understanding of this process. Further knowledge in cell death induced by DENV will help in the developing novel strategies to prevent disease progression.
https://ift.tt/2NPmaqk
Quantifying Intermembrane Distances with Serial Image Dilations
https://ift.tt/2NKAdxD
Use of High-Throughput Automated Microbioreactor System for Production of Model IgG1 in CHO Cells
A detailed protocol for the concurrent operation of 48 parallel cell cultures under varied conditions in a microbioreactor system is presented. Cell culture process, harvest and subsequent antibody titer analysis are described.
https://ift.tt/2QfXF2m
Continuous Theta Burst Stimulation of the Posterior Medial Frontal Cortex to Experimentally Reduce Ideological Threat Responses
Threats reliably evoke shifts in high-level ideological investment, but little work to date has explored the neural mechanisms underlying these dynamics. This paper describes how continuous theta burst transcranial magnetic stimulation may be employed to test the contribution of the posterior medial frontal cortex (and/or other regions) to threat-related ideological shifts.
https://ift.tt/2N55Mgd
MedixSafe to exhibit at EMS World Expo Booth #547
Visit us at EMS World Expo Booth #547 to see the latest in narcotics and key security!
https://ift.tt/2zD26id
Neonatal abstinence syndrome: Infants falling victim to the opioid crisis
Learn how infants who were exposed to opioids present while suffering from withdrawal
https://ift.tt/2Qfhh6N
Rare loss of function variants in candidate genes and risk of colorectal cancer
Abstract
Although ~ 25% of colorectal cancer or polyp (CRC/P) cases show familial aggregation, current germline genetic testing identifies a causal genotype in the 16 major genes associated with high penetrance CRC/P in only 20% of these cases. As there are likely other genes underlying heritable CRC/P, we evaluated the association of variation at novel loci with CRC/P. We evaluated 158 a priori selected candidate genes by comparing the number of rare potentially disruptive variants (PDVs) found in 84 CRC/P cases without an identified CRC/P risk-associated variant and 2440 controls. We repeated this analysis using an additional 73 CRC/P cases. We also compared the frequency of PDVs in select genes among CRC/P cases with two publicly available data sets. We found a significant enrichment of PDVs in cases vs. controls: 20% of cases vs. 11.5% of controls with ≥ 1 PDV (OR = 1.9, p = 0.01) in the original set of cases. Among the second cohort of CRC/P cases, 18% had a PDV, significantly different from 11.5% (p = 0.02). Logistic regression, adjusting for ancestry and multiple testing, indicated association between CRC/P and PDVs in NTHL1 (p = 0.0001), BRCA2 (p = 0.01) and BRIP1 (p = 0.04). However, there was no significant difference in the frequency of PDVs at each of these genes between all 157 CRC/P cases and two publicly available data sets. These results suggest an increased presence of PDVs in CRC/P cases and support further investigation of the association of NTHL1, BRCA2 and BRIP1 variation with CRC/P.
https://ift.tt/2xXWg9m
New Research From Psychological Science
Read about the latest research published in Psychological Science:
The Emotional-Ambiguity Hypothesis: A Large-Scale Test
C. J. Brainerd
Valence (positive vs. negative) and arousal (calming vs. exciting) are core dimensions of emotion, but their relationship is not well understood. Brainerd tested the emotional-ambiguity hypothesis, in which valence ambiguity (the degree of uncertainty in people's valence evaluation of an item or event) controls the relationship between valence and arousal. Using three databases of emotional words and three databases of emotional pictures, he calculated how the correlation between valence and arousal changed for different levels of valence ambiguity, measured by the standard deviations of valence ratings for each item (i.e., items with larger standard deviations are considered more ambiguous because they elicit a wider range of valence ratings). Analysis showed that words and pictures that elicited more defined valence perceptions had high arousal ratings, and those that drew ambiguous valence evaluations had lower arousal ratings, independent of positive or negative valence. These results indicate that valence ambiguity determines the strength of the valence-arousal link, supporting the emotional-ambiguity hypothesis. Thus, valence standard deviations might be used to control arousal confounds in experiments that manipulate valence.
Self-Affirmation Effects Are Produced by School Context, Student Engagement With the Intervention, and Time: Lessons From a District-Wide Implementation
Geoffrey D. Borman, Jeffrey Grigg, Christopher S. Rozek, Paul Hanselman, and Nathaniel A. Dewey
Borman and colleagues used data from a randomized controlled trial in an urban school area to investigate the effects of self-affirmation on the academic performance of students in stigmatized groups. During the school year, seventh graders completed up to four writing exercises about two or three important personal values (self-affirmation condition) or about unimportant values (control condition). The researchers designated Black and Hispanic students as potentially more vulnerable to stereotype threat (performing below expectations because of stereotypes about the abilities of one's racial, ethnic, gender, or cultural group), and tracked their academic performance for 3 years. Results showed that the self-affirmation exercises bolstered the students' academic performance, even after 3 years. These benefits were more pronounced in schools in which Black and Hispanic students were a small minority and had lower academic standing but also when students were more engaged with the exercise, discussing a value in terms of its importance to them. These results suggest that self-affirmation effectively reduced the growth of the racial achievement gap usually seen across the high school transition but that these effects depend both on context, such as school environment, and on individual factors, such as engagement with self-affirmation.
Calculation Efficiencies for Mean Numerosity
Joshua A. Solomon and Michael J. Morgan
How efficiently can people compare the textures of visual displays on the basis of the number of elements and their distributions? Solomon and Morgan presented pairs of visual stimuli, each one divided into 16 sectors. Each sector contained between zero and four elements (dots). Participants were asked to indicate which of the two stimuli had the greater average number of dots per occupied sector. The two stimuli either had the same number of sectors with dots (four or eight sectors) or unequal numbers of sectors with dots (i.e., one had four and the other had eight). Results showed that observers identified the stimulus with the greater average number of dots just as accurately when the stimuli had the same number of sectors occupied by dots as when they did not. However, observers were not efficient in this task, especially when there were eight occupied sectors in at least one of the stimuli. In sum, observers can discriminate local density, independently of the number of sectors in a visual display, and Solomon and Morgan argue that traditional numerosity discriminations are also based on small numbers of element clusters.
https://ift.tt/2QfUfwx
Advantages and disadvantages of the prone position in the surgical treatment of supracondylar humerus fractures in children
Publication date: Available online 27 September 2018
Source: Injury
Author(s): Maurizio De Pellegrin, Dario Fracassetti, Désirée Moharamzadeh, Carlo Origo, Nunzio Catena
Abstract
Introduction
Supracondylar humerus fractures are the most common elbow injuries in children. The widely adopted approach for Gartland III extension type consists of closed reduction and percutaneous pinning; the pin configuration can be lateral or crossed in relationship with the habit of the surgeons. Iatrogenic injury of the ulnar nerve is the most common risk during the insertion of the medial pin. The aim of this study was to analyze advantages and disadvantages of percutaneous pinning with the patient in prone position.
Materials and Methods
A literature review of the period 2005 – 2017 was carried out; four medical search engine (Pubmed, Cochrane Library, ISI Web of Science and Scopus) were consulted using the review's filter and the key words "Ulnar nerve AND supracondylar humerus fractures". The total number of patients were analyzed for: ulnar nerve injuries, anesthesiologic management, time of surgery.
Results
Twenty-nine papers were read, 23 regarding cross pinning in supine position and 6 in prone position. On one hand, 1529 children were treated with closed reduction and cross pinning in supine position; 69 of these patients (4.5%) suffered from iatrogenic ulnar nerve injury. On the other hand, 579 patients underwent the same treatment in prone position; no ulnar nerve lesions were reported in this group. Only one article compared both groups of children in supine and prone position regarding time of anesthesia which is slightly higher in the prone group. There were no differences between supine and prone positions regarding x-ray exposition, time of surgery, closed reduction manoeuvers, pin positioning, x-ray results, clinical and functional results.
Discussion and Conclusions
The ulnar nerve in children is hypermobile in the cubital tunnel and tends to dislocate anteriorly over the medial epicondyle, especially when the elbow is in hyperflexion. This may be the reason of the increased risk of nerve injury during the insertion of the medial pin in supine position and, instead, an advantage of the prone position. The insertion of both pins from the lateral side could reduce this complication. Larger studies need to be carried out regarding the reported higher duration of anesthesia in prone position.
https://ift.tt/2R7C2T5
The long noncoding RNA SNHG1 regulates colorectal cancer cell growth through interactions with EZH2 and miR-154-5p
Abstract
Background
Mounting evidence demonstrates that long noncoding RNAs (lncRNAs) have critical roles during the initiation and progression of cancers. In this study, we report that the small nucleolar RNA host gene 1 (SNHG1) is involved in colorectal cancer progression.
Methods
We analyzed RNA sequencing data to explore abnormally expressed lncRNAs in colorectal cancer. The effects of SNHG1 on colorectal cancer were investigated through in vitro and in vivo assays (i.e., CCK-8 assay, colony formation assay, flow cytometry assay, EdU assay, xenograft model, immunohistochemistry, and western blot). The mechanism of SNHG1 action was explored through bioinformatics, RNA fluorescence in situ hybridization, luciferase reporter assay, RNA pull-down assay, chromatin immunoprecipitation assay and RNA immunoprecipitation assay.
Results
Our analysis revealed that SNHG1 was upregulated in human colorectal cancer tissues, and high SNHG1 expression was associated with reduced patient survival. We also found that high SNHG1 expression was partly induced by SP1. Moreover, SNHG1 knockdown significantly repressed colorectal cancer cells growth both in vitro and in vivo. Mechanistic investigations demonstrated that SNHG1 could directly interact with Polycomb Repressive Complex 2 (PRC2) and modulate the histone methylation of promoter of Kruppel like factor 2 (KLF2) and Cyclin dependent kinase inhibitor 2B (CDKN2B) in the nucleus. In the cytoplasm, SNHG1 acted as a sponge for miR-154-5p, reducing its ability to repress Cyclin D2 (CCND2) expression.
Conclusions
Taken together, the results of our studies illuminate how SNHG1 formed a regulatory network to confer an oncogenic function in colorectal cancer and suggest that SNHG1 may serve as a potential target for colorectal cancer diagnosis and treatment.
https://ift.tt/2Qirj7r
Immunological Correlates of Response to Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma
Abstract
Background
The identification of prognostic and/or predictive biomarkers for response to immune checkpoint inhibitors (ICI) could help guide treatment decisions.
Objective
We assessed changes in programmed cell death-1 (PD1)/PD1 ligand (PDL1) expression in key immunomodulatory cell subsets (myeloid-derived suppressor cells [MDSC]; cytotoxic T lymphocytes [CTL]) following ICI therapy and investigated whether these changes correlated with outcomes in patients with metastatic urothelial carcinoma (mUC).
Patients and Methods
Serial peripheral blood samples were collected from ICI-treated mUC patients. Flow cytometry was used to quantify PD1/PDL1 expression on MDSC (CD33+HLADR−) and CTL (CD8+CD4−) from peripheral blood mononuclear cells. MDSC were grouped into monocytic (M)-MDSC (CD14+CD15−), polymorphonuclear (PMN)-MDSC (CD14−CD15+), and immature (I)-MDSC (CD14−CD15−). Mixed-model regression and Wilcoxon signed-rank or rank-sum tests were performed to assess post-ICI changes in immune biomarker expression and identify correlations between PD1/PDL1 expression and objective response to ICI.
Results
Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy. Based on available data, 27.5% had prior intravesical Bacillus Calmette–Guérin therapy, 42% had prior neoadjuvant chemotherapy, and 70% had prior cystectomy or nephroureterectomy. Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) M-MDSC, while doses of anti-PD1 correlated with decreased %PD1+ M- and I-MDSC. Although pre-treatment %PD1+ CTL did not predict response, a greater %PD1+ CTL within 9 weeks after ICI initiation correlated with objective response.
Conclusions
Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.
https://ift.tt/2xIU8TC
Reconstruction of a subtotal upper lip defect with a facial artery musculomucosal flap, kite flap, and radial forearm free flap: a case report
Abstract
Background
For reconstructive surgeons, massive midface defects, including large, full-thickness wounds on the upper lip, can be very challenging. Although there are many methods for reconstruction of upper lip defects, it is difficult to obtain satisfactory restoration of oral functions and good cosmetic results.
Case presentation
This case report presents a man with massive midface defects, including upper lip, left nose, and cheek defects. Over the previous 2 years, the patient had three reconstructions with sequential free flaps for the resection of recurrent tumors, the first of which was in March of 2016; this resulted in the patient having massive midface defects, including an upper lip defect, a defect on the left side of the nose, and one on the left cheek. The defects were reconstructed using a radial forearm free flap (RFFF), a facial artery musculomucosal (FAMM) flap, and a kite flap. In June 2016, he underwent a second reconstruction, this time of the left nose defect, using a left anterolateral thigh (ALT) flap. In March of 2017, the patient underwent a third reconstruction with the use of a free ALT on the left intraoral cheek and the defects on the neck. All flaps survived. No complications were encountered postoperatively. The patient regained good oral sphincter function with no reports of drooling. Although the patient underwent three surgeries, the reconstruction results were acceptable.
Conclusions
For massive midface defects, including large, full-thickness wounds on the upper lip, the combination of a FAMM flap, kite flap, and RFFF promotes the reconstruction of the complex midface structure and improves the resulting functionality.
https://ift.tt/2zCYTQ5
Structure and evolution of double minutes in diagnosis and relapse brain tumors
Abstract
Double minute chromosomes are extrachromosomal circular DNA fragments frequently found in brain tumors. To understand their evolution, we characterized the double minutes in paired diagnosis and relapse tumors from a pediatric high-grade glioma and four adult glioblastoma patients. We determined the full structures of the major double minutes using a novel approach combining multiple types of supporting genomic evidence. Among the double minutes identified in the pediatric patient, only one carrying EGFR was maintained at high abundance in both samples, whereas two others were present in only trace amounts at diagnosis but abundant at relapse, and the rest were found either in the relapse sample only or in the diagnosis sample only. For the EGFR-carrying double minutes, we found a secondary somatic deletion in all copies at relapse, after erlotinib treatment. However, the somatic mutation was present at very low frequency at diagnosis, suggesting potential resistance to the EGFR inhibitor. This mutation caused an in-frame RNA transcript to skip exon 16, a novel transcript isoform absent in EST database, as well as about 700 RNA-seq of normal brains that we reviewed. We observed similar patterns involving longitudinal copy number shift of double minutes in another four pairs (diagnosis/relapse) of adult glioblastoma. Overall, in three of five paired tumor samples, we found that although the same oncogenes were amplified at diagnosis and relapse, they were amplified on different double minutes. Our results suggest that double minutes readily evolve, increasing tumor heterogeneity rapidly. Understanding patterns of double minute evolution can shed light on future therapeutic solutions to brain tumors carrying such variants.
https://ift.tt/2R7cx4j
A salamander's top down effect on fungal communities in a detritivore ecosystem
ABSTRACT
The soil decomposer community is a primary driver of carbon cycling in forest ecosystems. Understanding the processes that structure this community is critical to our understanding of the global carbon cycle. In North American forests, soil fungal communities are regulated by grazing soil invertebrates, which are in turn controlled by the predatory red-backed salamander (Plethodon cinereus). The presence of these soil invertebrate taxa is known to exert direct top-down control via selective grazing on saprotrophic fungi, with direct consequences for biogeochemical cycling in soil. We investigated whether the removal of P. cinereus would relieve top-down control on decomposer fungal communities in a tri-trophic mesocosm study. Fungal communities were characterized using metabarcoding and high-throughput DNA sequencing. The β-diversity of fungal communities differed between salamander presence and absence treatments with a strong effect on saprotrophic fungal communities. We concluded that P. cinereus, a mesopredator in the detritivore food chain, exerts a prominent control on the composition and functional diversity of fungal communities in soil through a multi-trophic top-down process. Given their capacity to govern the compositions of soil invertebrates, the activity of these amphibians may be important for regulating ecosystem function and nutrient cycling in temperate forest systems.https://ift.tt/2zDfa7z
Mucin degradation niche as a driver of microbiome composition and Akkermansia muciniphila abundance in a dynamic gut model is donor independent
ABSTRACT
Akkermansia muciniphila, an abundant mucin degrading intestinal bacterium, has been correlated with human health in various studies. The in vitro SHIME model was used to reach a mechanistic understanding of A. muciniphila's colonization preferences and its response to environmental parameters such as colon pH and mucins. These insight can help to identify the optimal conditions for successful in vivo application. After a period of mucin deprivation, we found that mucin supplementation resulted in significantly different microbial communities, with more Akkermansia, Bacteroides and Ruminococcus. Mucin treatment accounted for 26% of the observed variation in the microbial community at OTU level (P = 0.001), whereas the donor effect was limited (8%) (P = 0.035), indicating mucins to constitute an important ecological niche shaping the microbiota composition. The effect of colonic pH had a less profound impact on the microbiome with both pH and donor origin explaining around 10% of the variability in the dataset. Yet, higher simulated colonic pH had a positive impact on Akkermansia abundance while short chain fatty acid analysis displayed a preference for propionate production with higher colonic pH. Our results show that mucins as nutritional resource are a more important modulator of the gut microbiome than colon pH as environmental factor.https://ift.tt/2xVmMjK
Spatial structuring of bacterial communities in epilithic biofilms in the Acquarossa river (Italy)
ABSTRACT
Epilithic river biofilms characterize the rock surfaces along the Acquarossa river (Viterbo, Italy); they are in part red and in part black colored, maintaining a well-defined borderline. This peculiarity has raised questions about the biotic and abiotic phenomena that might avoid the mixing of the two biofilms. In this study, the structuring of bacterial communities in black and red epilithic biofilm in the Acquarossa river has been investigated with both culture dependent and independent approaches. Data obtained highlighted a (very) different taxonomic composition of black and red epilithons bacterial communities, dominated by Acinetobacter sp. and iron-oxidizing bacteria, respectively. The chemical characterization of both river water and biofilms revealed a substantial heavy metals pollution of the environment; heavy metals were also differentially accumulated in red and black epilithons. Overall, our data revealed that the structuring of red and black epilithons might be affected mainly by the antagonistic interactions exhibited by bacterial genera dominating the two biofilms. These findings suggest that biotic factors might be responsible for the structuring of natural bacterial communities, suggesting that there is a selection of populations at very small scale, and that different populations might compete for different niches.https://ift.tt/2zCOSCo
Metagenomic sequencing provides insights into microbial detoxification in the guts of small mammalian herbivores (Neotoma spp.)
ABSTRACT
Microbial detoxification of plant toxins influences the use of plants as food sources by herbivores. Stephen's woodrats (Neotoma stephensi) specialize on juniper, which is defended by oxalate, phenolics and monoterpenes, while closely related N. albigula specialize on cactus, which only contains oxalate. Woodrats maintain two gut chambers harboring dense microbial communities: a foregut chamber proximal to the major site of toxin absorption, and a cecal chamber in their hindgut. We performed several experiments to investigate the location and nature of microbial detoxification in the woodrat gut. First, we measured toxin concentrations across gut chambers of N. stephensi. Compared to food material, oxalate concentrations were immediately lower in the foregut, while concentrations of terpenes remained high in the foregut, and were lowest in the cecal chamber. We conducted metagenomic sequencing of the foregut chambers of both woodrat species and cecal chambers of N. stephensi to compare microbial functions. We found that most genes associated with detoxification were more abundant in the cecal chambers of N. stephensi. However, some genes associated with degradation of oxalate and phenolic compounds were more abundant in the foregut chambers. Thus, microbial detoxification may take place in various chambers depending on the class of chemical compound.https://ift.tt/2xX9OBZ
The genome of a novel isolate of Prochlorococcus from the Red Sea contains transcribed genes for compatible solute biosynthesis
ABSTRACT
Marine microbes possess genomic and physiological adaptations to cope with varying environmental conditions. So far, the effects of high salinity on the most abundant marine photoautotrophic organism, Prochlorococcus, in marine oligotrophic environments, are mostly unknown. Here, we report the isolation of a new Prochlorococcus strain (RSP50) belonging to high-light (HL) clade II from the Red Sea, one of the warmest and most saline bodies of water in the global oceans. A comparative genomic analysis identified a set of 59 genes that were exclusive to RSP50 relative to currently available Prochlorococcus genomes, the majority of which (70%) encode for hypothetical proteins of unknown function. However, three of the unique genes encode for a complete pathway for the biosynthesis of the compatible solute glucosylglycerol, and are homologous to enzymes found in the sister lineage Synechococcus. Metatranscriptomic analyses of this metabolic pathway in the water column of the Red Sea revealed that the corresponding genes were constitutively transcribed, independent of depth and light, suggesting that osmoregulation using glucosylglycerol is a general feature of HL II Prochlorococcus in the Red Sea.https://ift.tt/2zBDBC5
Spatial and temporal characterization of epiphytic microbial communities associated with Eurasian watermilfoil: a highly invasive macrophyte in North America
ABSTRACT
Bacterial communities that inhabit the surface of aquatic plants are thought to play a critical role in relation to host fitness and function. However, little is known about their structure and dynamics in comparison with those of bacterioplankton. In this study, we performed a comprehensive spatial and temporal characterization of epibacterial communities associated with Eurasian watermilfoil (EWM; Myriophyllum spicatum), an invasive macrophyte, which has established itself in thousands of lakes across North America. EWM samples were collected from 10 lakes in Minnesota, once a month, for six consecutive months, along with surrounding water and sediment. High-throughput DNA sequencing analyses, performed on all samples (n = 522) using the Illumina platform, indicated that EWM-associated epibacterial communities were distinct from those found in water and sediment. EWM-specific microbiota was comprised of operational taxonomic units classified to the families Rhodobacteraceae, Comamonadaceae, Cyanobacteria Subsection I Family I, Aeromonadaceae, Planctomycetaceae, Sphingomonadaceae and Verrucomicrobiaceae. In addition, several identified taxa were overrepresented in EWM samples when compared to water and sediment. Amongst all the environmental factors examined, water temperature had the greatest influence on epibacterial community structure. Our findings suggest that EWM harbor specific, but temporally adapted, epibacterial communities that are potentially involved in host–microbe interactions.https://ift.tt/2xX9MKn
Oleandrin synergizes with cisplatin in human osteosarcoma cells by enhancing cell apoptosis through activation of the p38 MAPK signaling pathway
Abstract
Purpose
Our previous studies have reported the antitumor effect of oleandrin on osteosarcoma; however, its chemosensitizing effect in osteosarcoma treatment is still unknown. Therefore, we explored the sensitizing effects of oleandrin to cisplatin in osteosarcoma and investigated the potential mechanisms.
Methods
After exposure to oleandrin and/or cisplatin, CCK-8 and colony formation assays, DAPI staining and flow cytometry were performed to detect cell proliferation and apoptosis in 143B, U-2OS and MG-63 osteosarcoma cells. The median-effect analysis was applied to evaluate the combined effect. Western blot was used to determine the expression of related proteins. Osteosarcoma xenografts and histological observations were applied to confirm the combined effect in vivo.
Results
Compared with cisplatin or oleandrin alone, the combined treatment significantly inhibited cell proliferation and induced cell apoptosis. The median-effect analysis indicated a synergistic cytotoxic effect. The combined treatment downregulated Bcl-2 and upregulated Bax and cleaved caspase-3, -8 and -9. And the suppression of caspases reduced cell death. Furthermore, oleandrin alone or with cisplatin, activated the p38 MAPK/Elk-1 pathway. The inhibition of the p38 MAPK pathway increased cell viability and reduced apoptosis. In vivo, the combined treatment was also verified to significantly inhibit tumor growth, induce apoptosis and activate the p38 MAPK pathway.
Conclusions
The combination of oleandrin with cisplatin exerts a synergistic antitumor effect in osteosarcoma, which relates to the activation of the p38 MAPK pathway.
https://ift.tt/2OVR7pm
The significance of SUMOylation of angiogenic factors in cancer progression
.
https://ift.tt/2R77AbN
Concomitant 1p36 deletion and TNFRSF14 mutations in primary cutaneous follicle center lymphoma frequently expressing high levels of EZH2 protein
Abstract
Primary cutaneous follicle center lymphoma (PCFCL) is an indolent variant of follicular lymphoma (FL) with limited information available on the genetic background of the disease. The genetic hallmark of nodal FL, the t(14;18) translocation, affecting the BCL2 gene, is rare in PCFCL. Loss of 1p36, the most common secondary chromosomal abnormality in nodal FL, has been recently reported in 16.7% of PCFCL cases. In order to further characterize PCFCL, 21 cases were analyzed using interphase fluorescence in situ hybridization with BCL2 break apart and 1p36/1q25 dual color probes. Sanger sequencing was used to investigate TNFRSF14 and EZH2 mutations and immunohistochemistry to assess BCL2, EZH2 protein expressions.
1p36 deletion occurred in 22% (5/21), BCL2 gene break in 10% (2/20) of the PCFCL cases. Mutations of the candidate tumor suppressor gene of the 1p36 region, TNFRSF14 mutations were detected in 4/17 (23.5%) cases with 2 cases presenting with concurrent 1p36 deletion. EZH2 hotspot mutations at Y641, A682, and A692 were not found. High EZH2 protein expression associated with a BCL2 negative phenotype was observed in 43% (9/21) of the cases. BCL2 gene break or 1p36 deletion did not impact the prognosis; however, they showed association with advanced stages at diagnosis (p = 0.016) and a tendency with shorter event free survival (p = 0.052).
In conclusion, 1p36 deletion co-occurs with acquired TNFRSF14 mutations, suggesting a role of this tumor suppressor gene in the development of a subgroup of PCFCL. High EZH2 protein expression associated with BCL2 negative phenotype is common and might represent an ideal therapeutic target.
https://ift.tt/2xIslTi
HLA-G expression in gastric carcinoma: clinicopathological correlations and prognostic impact
Abstract
To analyze expression of human leukocyte antigen-G (HLA-G) in gastric adenocarcinoma and correlate its expression with histological and clinical variables. A continuous series of 94 unselected patients with gastric adenocarcinoma (stage I to III) were selected. All histological and clinical variables were collected including the intensity of intra- and peri-tumor lymphocytic infiltration. HLA-G expression was investigated using immunohistochemistry. All histological samples analyzed for HLA-G expression were taken from the primary gastric lesion and included non-neoplastic mucosa. Evaluation of HLA-G expression was performed on the transition zone between tumor and non-neoplastic mucosa, and the invasive front of the tumor and assessment was performed as follows: percentage of positive (strong expression vs weak) cells. A variable amount of HLA-G-positive tumor cells was found in 24 out of 94 cases (25.5%). No significant correlation was found between HLA-G expression and other clinicopathological variables (sex, age, stage, grade, histotype). The overall median survival was worse in patients with HLA-G-positive adenocarcinoma (24.3 months, CI95% 7.7–41.0) compared to those with HLA-G-negative tumors (66.3 months, CI95% 53.0–79.7; p < 0.0001). Two- and 5-year survival rates of HLA-G-negative patients were 88 and 44%, respectively, while were 42 and 11% in those HLA-G-positive. This trend was observed in all stages but was more marked in stage III. HLA-G expression is associated with poor survival in stage III gastric cancer patients and represents a possible immunoescape mechanism of cancer cells.
https://ift.tt/2Isbngd
Single tooth implants in the esthetic zone following a two‐stage all flapless approach: A retrospective analysis
Clinical Implant Dentistry and Related Research, EarlyView.
https://ift.tt/2xEFeh9
Short‐term and midterm outcomes of single‐incision laparoscopic surgery for right‐sided colon cancer
Asian Journal of Endoscopic Surgery, EarlyView.
https://ift.tt/2zCwVnw
Simultaneous laparoscopic left hemicolectomy and spleen‐preserving distal pancreatectomy for descending colon cancer with pancreatic invasion
Asian Journal of Endoscopic Surgery, EarlyView.
https://ift.tt/2InKytp
Robotic surgery in pediatric urology: Current status
Asian Journal of Endoscopic Surgery, EarlyView.
https://ift.tt/2zCxa1A
Midwives’ attitudes towards pregnant women using substances: Informing a care pathway
Publication date: Available online 27 September 2018
Source: Women and Birth
Author(s): Sadie Geraghty, Gemma Doleman, Annemarie De Leo
Abstract
Objective
The purpose of this study was to identify midwives' attitudes towards women using substances during pregnancy, which informed the development of an integrated care pathway for the provision of optimal care.
Methods
A mixed methods research design was used, that included an online survey via the online survey tool Qualtrics™ which collected quantitative data, and interviews and focus groups were used to collect qualitative data.
Findings
Participants held a positive or neutral view towards women who used substances during pregnancy, and the participants had an empathetic perception of the issue of substance use within pregnancy, believing that women were using substances due to the environment and circumstances that they lived in, and that they had been raised and socialised in.
Conclusion
Caring for women during pregnancy with substance misuse issues is complex and requires coordination and multidisciplinary care. Midwives have the capacity to provide sensitive midwifery care but require the framework to ensure women needing additional resources during pregnancy receive the services available and specific to their needs. The midwives in this study were supportive of developing an integrated care pathway to allow for collaborative care, and to enable a specialised midwifery approach.
https://ift.tt/2InGJV5
Attitudes toward prenatal screening for chromosomal abnormalities: A focus group study
Publication date: Available online 27 September 2018
Source: Women and Birth
Author(s): Sarah Munro, Julie Sou, Wei Zhang, Tima Mohammadi, Logan Trenaman, Sylvie Langlois, Aslam H. Anis
Abstract
Background
While discrete choice experiments (DCEs) are well established methods to ascertain patient preferences, there is limited literature describing use of qualitative methods in DCE design.
Aim
This article provides a case study of the qualitative research process for developing the conceptual attributes for a DCE for prenatal screening and diagnosis.
Methods
Participants were recruited through posters and social media. Four in-depth, semi-structured focus groups with pregnant women and their partners/support people were conducted in Metro Vancouver.
Findings
Our analysis indicates that choosing prenatal screening and diagnosis involves four intertwined decisions: whether to undergo screening and testing, which screening test to take, which diagnostic test to take, and what to do with a positive diagnosis. The factors that are important to women and their partners vary depending on the decision and include: time of diagnosis, information on conditions tested, false positives, cost, the invasiveness of the test, and potential harm to woman and baby.
Discussion
Findings suggest that certain attributes were more salient for screening versus diagnostic tests. Preferences were often shaped by a woman's perceived ability to care for a child with a genetic anomaly, personal risk factors, parity, views on termination, and perceptions on public or private coverage. Participants valued mental well-being and demonstrated a willingness to trade-off on certain attributes in order to minimize stress or anxiety during pregnancy.
Conclusion
Study findings will be used to inform DCE attributes, levels, and choice questions. Findings will be important for policy decisions surrounding prenatal testing.
https://ift.tt/2zBZjpA
Multimodal computational neocortical anatomy in pediatric hippocampal sclerosis
Annals of Clinical and Translational Neurology, EarlyView.
https://ift.tt/2R919oy
Altered tryptophan metabolism is associated with pediatric multiple sclerosis risk and course
Annals of Clinical and Translational Neurology, EarlyView.
https://ift.tt/2QhDscI
Urban air quality and associations with pediatric multiple sclerosis
Annals of Clinical and Translational Neurology, EarlyView.
https://ift.tt/2R0L84h
Clinical application of advanced MR methods in children: points to consider
Annals of Clinical and Translational Neurology, EarlyView.
https://ift.tt/2QhDcug
Cancers, Vol. 10, Pages 364: Sensitization of Cancer Cells to Radiation and Topoisomerase I Inhibitor Camptothecin Using Inhibitors of PARP and Other Signaling Molecules
Cancers, Vol. 10, Pages 364: Sensitization of Cancer Cells to Radiation and Topoisomerase I Inhibitor Camptothecin Using Inhibitors of PARP and Other Signaling Molecules
Cancers doi: 10.3390/cancers10100364
Authors: Yusuke Matsuno Mai Hyodo Haruka Fujimori Atsuhiro Shimizu Ken-ichi Yoshioka
Radiation and certain anticancer drugs damage DNA, resulting in apoptosis induction in cancer cells. Currently, the major limitations on the efficacy of such therapies are development of resistance and adverse side effects. Sensitization is an important strategy for increasing therapeutic efficacy while minimizing adverse effects. In this manuscript, we review possible sensitization strategies for radiation and anticancer drugs that cause DNA damage, focusing especially on modulation of damage repair pathways and the associated reactions.
https://ift.tt/2zBqIYQ
Cancers, Vol. 10, Pages 363: Fenofibrate Interferes with the Diapedesis of Lung Adenocarcinoma Cells through the Interference with Cx43/EGF-Dependent Intercellular Signaling
Cancers, Vol. 10, Pages 363: Fenofibrate Interferes with the Diapedesis of Lung Adenocarcinoma Cells through the Interference with Cx43/EGF-Dependent Intercellular Signaling
Cancers doi: 10.3390/cancers10100363
Authors: Katarzyna Piwowarczyk Edyta Kwiecień Justyna Sośniak Eliza Zimoląg Emiliana Guzik Jolanta Sroka Zbigniew Madeja Jarosław Czyż
Extravasation of circulating cancer cells is regulated by the intercellular/intracellular signaling pathways that locally impair the endothelial barrier function. Co-cultures of human umbilical vein endothelial cells (HUVECs) with lung adenocarcinoma A549 cells enabled us to identify these pathways and to quantify the effect of fenofibrate (FF) on their activity. A549 cells induced the disruption and local activation of endothelial continuum. These events were accompanied by epidermal growth factor (EGF) up-regulation in endothelial cells. Impaired A549 diapedesis and HUVEC activation were seen upon the chemical inhibition of connexin(Cx)43 functions, EGF/ERK1/2-dependent signaling, and RhoA/Rac1 activity. A total of 25 μM FF exerted corresponding effects on Cx43-mediated gap junctional coupling, EGF production, and ERK1/2 activation in HUVEC/A549 co-cultures. It also directly augmented endothelial barrier function via the interference with focal adhesion kinase (FAK)/RhoA/Rac1-regulated endothelial cell adhesion/contractility/motility and prompted the selective transmigration of epithelioid A549 cells. N-acetyl-L-cysteine abrogated FF effects on HUVEC activation, suggesting the involvement of PPARα-independent mechanism(s) in its action. Our data identify a novel Cx43/EGF/ERK1/2/FAK/RhoA/Rac1-dependent signaling axis, which determines the efficiency of lung cancer cell diapedesis. FF interferes with its activity and reduces the susceptibility of endothelial cells to A549 stimuli. These findings provide the rationale for the implementation of FF in the therapy of malignant lung cancers.
https://ift.tt/2Im6163
Errata a “Estudo Monocêntrico da Apresentação Clínica e Prognóstico a Longo Prazo de Doentes Portugueses com Esclerose Sistémica: Uma Iniciativa do Registo EUSTAR”
Article published with errors: https://ift.tt/2xExfAH
On page 312, where the authors' line reads as:
Carolina VIDAL1, Carina RUANO2, Vera BERNARDINO3, Pedro LAVADO CARREIRA3, Ana LLADÓ3, Maria Céu SANTOS4, Heidi GRUNER3, António PANARRA3, Nuno RISO3, Maria Francisca MORAES-FONTESAC,1
It should read:
Carolina VIDAL1,2, Carina RUANO3, Vera BERNARDINO1, Pedro LAVADO CARREIRA1, Ana LLADÓ1, Maria Céu SANTOS4, Heidi GRUNER1, António PANARRA1, Nuno RISO1, Maria Francisca MORAES-FONTESAC,1
On the same page, where the authors' affiliation on the footer reads as:
- Serviço de Medicina Interna. Hospital do Divino Espírito Santo de Ponta Delgada. São Miguel. Portugal.
- Serviço de Radiologia. Hospital de Santa Marta. Centro Hospitalar de Lisboa Central. Lisboa. Portugal.
- Unidade de Doenças Auto-Imunes/Serviço Medicina 7.2. Hospital de Curry Cabral. Centro Hospitalar de Lisboa Central. Lisboa. Portugal.
- Laboratório de Imunologia. Centro Hospitalar de Lisboa Central. Lisboa. Portugal.
It should read:
- Unidade de Doenças Auto-Imunes/Serviço Medicina 7.2. Hospital de Curry Cabral. Centro Hospitalar de Lisboa Central. Lisboa. Portugal.
- Serviço de Medicina Interna. Hospital do Divino Espírito Santo de Ponta Delgada. São Miguel. Portugal.
- Serviço de Radiologia. Hospital de Santa Marta. Centro Hospitalar de Lisboa Central. Lisboa. Portugal.
- Laboratório de Imunologia. Centro Hospitalar de Lisboa Central. Lisboa. Portugal.
https://ift.tt/2OTqiSL
Severe Postpartum Coagulopathy Without Haemorrhage: A Case Report
Postpartum haemorrhage is an important health issue worldwide, and it can be caused by uterine atony, retained placental tissue, trauma or coagulation disorders. Although coagulopathy represents a rare cause, it is a significant contributor to postpartum haemorrhage with poor outcomes. Associated with high morbidity and mortality rates, postpartum haemorrhage demands prevention, prompt diagnosis and effective management. We describe a unique case of severe coagulopathy caused by underestimated blood loss during caesarean section without postpartum bleeding, in which transfusion requirements were thromboelastometry-guided. This case report depicts how an early multidisciplinary approach and patient-centred care in an obstetric emergency contributes to a positive outcome from a challenging situation, enabling the prevention of an imminent, catastrophic haemorrhage.
https://ift.tt/2xEx1cP
Taste Receptor T1R1/T1R3 Promotes the Tumoricidal Activity of Hepatic CD49a+CD49b‐ Natural Killer Cells
European Journal of Immunology, Volume 0, Issue ja, -Not available-.
https://ift.tt/2OVL0l8
Biosimilar Agents for Psoriasis Treatment: The Perspective of Portuguese Patients
Introduction: Biosimilars are highly similar copies of previously approved original biologic medicines. Their introduction on the market may yield cost reduction. The aim of this study was to evaluate the perspectives of psoriasis patients on biosimilar medications.
Materials and Methods: We conducted a 14 questions survey of psoriasis patients receiving biological therapy and followed-up in a dermatology department of a Portuguese tertiary care hospital.
Results: From a total of 108 patients included, 70.4% of patients did not know the definition of biosimilar agent and 76.6% of patients showed partial or total interest in using a biosimilar drug. Nearly 80% of patients partially or totally agreed in using a biosimilar drug in order to reduce healthcare costs with psoriasis treatment. However, the lack of studies in the European population and in psoriatic patients led most of the patients (72.2% and 75.0%, respectively) to somewhat or completely oppose to the use of biosimilars. Demographic variables, household income and type of current biologic therapy did not affect patient preferences.
Discussion: Despite of the unfamiliarity of the respondents with biosimilars, most patients seem receptive to their use. Nevertheless, there are two issues of concern: i) the use of biosimilars that are not tested in a European population, and ii) its approval for psoriasis without trials in this disease. Thus, an immediate need exists for patient education about biosimilars.
Conclusion: Biosimilars may increase patient access to biologic therapies. Improved communication and the involvement of patients in decision-making regarding biosimilars may increase their acceptance in future.
https://ift.tt/2xEwXtB
Late Neuroborreliosis in an Erasmus Programme Student
Lyme disease is an endemic zoonosis, the most prevalent tick-transmitted infection in temperate areas of Europe, North America and Asia. It is a multisystemic disease with cutaneous, musculoskeletal, neurologic and cardiac manifestations, according to the stage of the disease. We describe a case of late neuroborreliosis in an Erasmus programme student living in Porto. We discuss the importance of the epidemiological suspicion, the clinical approach, the diagnostic criteria and the most adequate treatment.
https://ift.tt/2OWaajw
Venous Thromboembolism in Pediatric Age: A 15 Year Retrospective Review
Introduction: Pulmonary thromboembolism and deep venous thrombosis occur in pediatric age, with unknown incidence, morbidity and mortality. Our aim is to review the epidemiology, clinical presentation, complementary diagnostic tests and prognosis of patients with pulmonary thromboembolism and deep venous thrombosis.
Material and Methods: Retrospective, descriptive and analytical study of pediatric patients admitted to a Level II hospital for pulmonary thromboembolism and deep venous thrombosis, between 2000 and 2014. Demographic characteristics, clinical history, comorbidities and risk factors were studied.
Results: Eleven patients (n = 7 pulmonary thromboembolism, n = 5 deep venous thrombosis, n = 1 both), 64% females and with 16 years old average, were admitted. All patients with pulmonary thromboembolism presented symptoms of chest pain and/or dyspnea, 25% syncope/palpitations and 25% fever. All patients with deep venous thrombosis reported localized pain at the site of obstruction, 83% edema/cyanosis of the affected limb and 17% fever. The study of positive thrombophilia was the most frequent risk factor in both entities. The mean value of D-dimers was 3252 ug/dL and 2660 ug/dL in pulmonary thromboembolism and deep venous thrombosis, respectively. All patients started anticoagulation, three required intensive care, two had sequelae and one died.
Discussion: All patients had at least one risk factor, and hereditary hypercoagulability was most commonly established.
Conclusions: The increased incidence in the pediatric population described in some studies can be attributed to an increased awareness of this pathology, medical advances and increasing survival of chronic diseases. There is a lack of evidence-based recommendations identifying patients at risk of thrombosis so that decisions can be made carefully, balancing the risk and benefit in each case.
https://ift.tt/2xIDIdX
The Medical Carreer and the Key Factors Driving the Exodus of Doctors from the National Health Service in Portugal
Introduction: This article addresses the organization and management of medical careers in Portugal within the framework of the National Health Service. It focuses, in particular, on some indicators of motivation and professional satisfaction.
Material and Methods: This article is part of a broader research project on the organization of medical careers in Portugal. It draws on the results of a survey carried out to active medical doctors, residents and those that have already abandoned the National Health Service. The sample was drawn from the database of physicians enrolled in the Northern Section of the Medical Association.
Results: A total of 3253 physicians were surveyed. Physician satisfaction levels vary according to age, type of connection to the National Health Service and are associated with expectations regarding the professional future.
Discussion: Despite the close connection with the National Health Service, younger doctors showed higher levels of professional dissatisfaction and uncertainty regarding their professional future. Although with varying degrees of discontent depending on the groups considered, the dissatisfaction of the professionals interviewed is with the physical conditions of the workplace and with the opportunities for career advancement. At the level of interpersonal relations and training, satisfaction is high. The anticipation of retirement and the transfer to the private sector are options that professionals consider as a strategy to respond to professional dissatisfaction.
Conclusion: The study shows that the current functioning of the National Health Service does not diminish the interest in the practice of medicine, but rather motivates the search for more attractive and rewarding working conditions.
https://ift.tt/2OVuEch
Iron Deficiency and Obesity – Are we Diagnosing with Appropriate Indicators?
Introduction: We aim to define the iron deficiency prevalence and eventual differences between obese patients with and without metabolic syndrome.
Material and Methods: Analysis of patients evaluated at multidisciplinary consultation of obesity in our institution between 2013 and 2015 (n = 260). Iron deficiency: ferritin levels < 15 ng/mL. Exclusion criteria: prior bariatric surgery; lack of ferritin or hemoglobin determinations.
Results: We analyzed data from 215 patients (84.2% female) with a mean age of 42.0 ± 10.3 years. The median body mass index was 42.5 (40.0 - 46.8) kg/m2 and 52.1% had metabolic syndrome. Iron deficiency was present in 7.0%, with no differences between genders or between patients with or without metabolic syndrome. Hypertension was associated with lower prevalence of iron deficiency. Type 2 diabetes and hypertension patients had higher levels of ferritin. The multivariate analysis showed that metabolic syndrome and increasing body mass index were predictive of higher risk of iron deficiency while hypertension predicted lower odds of iron deficiency.
Discussion: The prevalence of iron deficiency was similar in other published studies. Iron deficiency may be underdiagnosed if based only on ferritin concentrations. In our study, diabetes and hypertension appear to contribute to the increase in ferritin levels described in obesity.
Conclusion: Ferritin may not be a reliable index for evaluating iron stores in obese patients, particularly when associated with comorbidities such as type 2 diabetes and hypertension. Further studies are needed to guide the diagnosis and iron supplementation in these patients.
https://ift.tt/2xHWQZC
Liver Multiacinar Regenerative Nodules: Imaging Findings and Clinical Implications
Introduction: Multiacinar regenerative nodules are benign hepatocellular nodules related to vascular disturbances of the liver. They strongly resemble conventional focal nodular hyperplasia but are connected to different clinical settings, typically chronic liver disease. The purpose of the present study was to describe the key imaging features of these lesions and compare them with a control arm of focal nodular hyperplasia.
Material and Methods: A blinded consensus review of liver magnetic resonance consisting of 26 cases of multiacinar regenerative nodules and 25 cases of focal nodular hyperplasia was performed. Lesion size, shape, margins, structure, T1 and T2 signal intensity, diffusion and contrast-enhanced features (including hepatobiliary phase), presence of a central scar and of a peripheral hypointense rim were compared between the two groups.
Results: Significant differences between multiacinar regenerative nodules and focal nodular hyperplasia included size (median 2.35 cm, IQR: 2.13, vs 6.00 cm, IQR: 5.20, respectively, p < 0.001), presence of a peripheral hypointense rim after contrast (n = 9 vs n = 2 cases, p = 0.038) and of a central scar (n = 9 vs n = 20, p = 0.002). There were no other significant differences.
Discussion: Overall multiacinar regenerative nodules and focal nodular hyperplasia have very similar imaging features but lack of a central scar and presence of a hypointense rim should suggest a diagnosis of multiacinar regenerative nodules.
Conclusions: Recognition of the imaging findings of multiacinar regenerative nodules can explain some atypical cases of focal nodular hyperplasia, avoiding unnecessary biopsies. They may also be the trigger to investigate an unsuspected underlying liver vascular abnormality.
https://ift.tt/2OXq2SQ
Validation of the Skindex-29 Questionnaire: Portuguese Version (Portugal)
Introduction: There is an increasing interest regarding the impact of skin diseases on quality of life. Skindex-29 is a questionnaire developed to evaluate this impact. This study aimed to validate Skindex-29 for the Portuguese population.
Material and Methods: From the 81 approached patients from two clinics, only 75 finished the study: 35 with skin disease and 40 without. A translation and back-translation were performed. Concerning accuracy and discrimination power, the scores were submitted to ROC curve analysis after being compared between both groups through Mann-Whitney test. Internal consistency was measured using Cronbach's α coefficient. Test/retest of each scale was assessed by the intra-class correlation coefficient, and by Kappa coefficient of agreement. Convergent validity was evaluated through Spearman correlations between Skindex-29 scores and SF-12 subscales. SPSS statistics and values of p < 0.05 with 95% confidence intervals were considered statistically significant.
Results: The Skindex-29 demonstrated to be an accurate instrument and statistically significant differences were found when comparing the disease and without-disease groups (p < 0.001). The reliability was high (Cronbach's α > 0.80) for each dimension ('Symptoms', 'Emotions' and 'Functioning') and for test-retest (ICC > 0.90, K > 0.494). About convergent validity, Skindex-29 Total score and the questions about 'Symptoms' and 'Functioning' were statistically correlated with the questions regarding the physical state of the SF-12 (-0.478; -0.459; -0.405, respectively).
Discussion: Results suggest that Skindex-29 can be used as an instrument to evaluate skin diseases' effect on quality of life in Portugal, being accurate and reliable. Despite having similar general health profiles as other individuals, dermatological patients showed a lower quality of life due to their disease. Results showed that Skindex-29 was better at assessing physical components rather than mental or
emotional components.
Conclusion: Skindex-29 appears to have evidence of validity including accuracy and reliability to be used as an instrument to evaluate the impact of skin diseases on quality of life in Portugal.
https://ift.tt/2xHWJNG
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
