Substrate Stiffness Regulates Arterial-Venous Differentiation of Endothelial Progenitor Cells via the Ras/Mek Pathway

Publication date: Available online 18 July 2017
Source:Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Author(s): Changyue Xue, Tao Zhang, Xueping Xie, Qi Zhang, Shu Zhang, Bofeng Zhu, Yunfeng Lin, Xiaoxiao Cai
Cells sense and respond to the biophysical properties of their surrounding environment by interacting with the extracellular matrix (ECM). Therefore, the optimization of these cell–matrix interactions is critical in tissue engineering. The vascular system is adapted to specific functions in diverse tissues and organs. Appropriate arterial-venous differentiation is vital for the establishment of functional vasculature in angiogenesis. Here, we have developed a polydimethylsiloxane (PDMS)-based substrate capable of simulating the physiologically relevant stiffness of both venous (7 kPa) and arterial (128 kPa) tissues. This substrate was utilized to investigate the effects of changes in substrate stiffness on the differentiation of endothelial progenitor cells (EPCs). As EPCs derived from mouse bone marrow were cultured on substrates of increasing stiffness, the mRNA and protein levels of the specific arterial endothelial cell marker ephrinB2 were found to increase, while the expression of the venous marker EphB4 decreased. Further experiments were performed to identify the mechanotransduction pathway involved in this process. The results indicated that substrate stiffness regulates the arterial and venous differentiation of EPCs via the Ras/Mek pathway. This work shows that modification of substrate stiffness may represent a method for regulating arterial-venous differentiation for the fulfilment of diverse functions of the vasculature.

Graphical abstract

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Let’s not forget about the vagus and other updates on recent autonomic research

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Woman faked cancer, friends say - NRToday.com

NRToday.com

Woman faked cancer, friends say NRToday.com Gaskin told friends Hanns and Elsa Dobson, as well as others, that she had been diagnosed with medullary thyroid cancer. News went from bad to worse when she claimed doctors, who initially had described her cancer as treatable, later said it was Stage ...

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Dendritic Cell Lineage Potential in Human Early Hematopoietic Progenitors

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Julie Helft, Fernando Anjos-Afonso, Annemarthe G. van der Veen, Probir Chakravarty, Dominique Bonnet, Caetano Reis e Sousa
Conventional dendritic cells (cDCs) are thought to descend from a DC precursor downstream of the common myeloid progenitor (CMP). However, a mouse lymphoid-primed multipotent progenitor has been shown to generate cDCs following a DC-specific developmental pathway independent of monocyte and granulocyte poiesis. Similarly, here we show that, in humans, a large fraction of multipotent lymphoid early progenitors (MLPs) gives rise to cDCs, in particular the subset known as cDC1, identified by co-expression of DNGR-1 (CLEC9A) and CD141 (BDCA-3). Single-cell analysis indicates that over one-third of MLPs have the potential to efficiently generate cDCs. cDC1s generated from CMPs or MLPs do not exhibit differences in transcriptome or phenotype. These results demonstrate an early imprinting of the cDC lineage in human hematopoiesis and highlight the plasticity of developmental pathways giving rise to human DCs.

Graphical abstract

Teaser

Dendritic cells (DCs) are thought to descend from a DC precursor downstream of the common myeloid progenitor (CMP). Helft et al. show that multipotent lymphoid progenitors (MLPs) in humans are more efficient producers of CD141⁺DNGR-1⁺ cDC1s than CMPs. Therefore, DC lineage imprinting can occur in early hematopoietic progenitors in humans.


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KMT2A and KMT2B Mediate Memory Function by Affecting Distinct Genomic Regions

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Cemil Kerimoglu, M. Sadman Sakib, Gaurav Jain, Eva Benito, Susanne Burkhardt, Vincenzo Capece, Lalit Kaurani, Rashi Halder, Roberto Carlos Agís-Balboa, Roman Stilling, Hendrik Urbanke, Andrea Kranz, A. Francis Stewart, Andre Fischer
Kmt2a and Kmt2b are H3K4 methyltransferases of the Set1/Trithorax class. We have recently shown the importance of Kmt2b for learning and memory. Here, we report that Kmt2a is also important in memory formation. We compare the decrease in H3K4 methylation and de-regulation of gene expression in hippocampal neurons of mice with knockdown of either Kmt2a or Kmt2b. Kmt2a and Kmt2b control largely distinct genomic regions and different molecular pathways linked to neuronal plasticity. Finally, we show that the decrease in H3K4 methylation resulting from Kmt2a knockdown partially recapitulates the pattern previously reported in CK-p25 mice, a model for neurodegeneration and memory impairment. Our findings point to the distinct functions of even closely related histone-modifying enzymes and provide essential insight for the development of more efficient and specific epigenetic therapies against brain diseases.

Graphical abstract

Teaser

Kerimoglu et al. report that the related histone methyltransferases Kmt2a and Kmt2b are both required for memory function but control different neuronal gene-expression programs. Loss of Kmt2a partially recapitulates changes in H3K4me3 seen in Alzheimer's models.


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CRKL Mediates p110β-Dependent PI3K Signaling in PTEN-Deficient Cancer Cells

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Jing Zhang, Xueliang Gao, Fabienne Schmit, Guillaume Adelmant, Michael J. Eck, Jarrod A. Marto, Jean J. Zhao, Thomas M. Roberts
The p110β isoform of PI3K is preferentially activated in many tumors deficient in the phosphatase and tensin homolog (PTEN). However, the mechanism(s) linking PTEN loss to p110β activation remain(s) mysterious. Here, we identify CRKL as a member of the class of PI3Kβ-interacting proteins. Silencing CRKL expression in PTEN-null human cancer cells leads to a decrease in p110β-dependent PI3K signaling and cell proliferation. In contrast, CRKL depletion does not impair p110α-mediated signaling. Further study showed that CRKL binds to tyrosine-phosphorylated p130Cas in PTEN-null cancer cells. Since Src family kinases are known both to be regulated by PTEN and to phosphorylate and activate p130Cas, we tested and found that Src inhibition cooperated with p110β inhibition to suppress the growth of PTEN-null cells. These data suggest both a potential mechanism linking PTEN loss to p110β activation and the possible benefit of dual inhibition of Src and PI3K for PTEN-null tumors.

Graphical abstract

Teaser

Zhang et al. find a role for CRKL in regulating p110β-dependent PI3K activity in PTEN-null cancer cells through its association with p110β/p85. A PTEN/FAK/Src/p130Cas axis may activate CRKL/p110β in PTEN-null cancer cells. Src inhibition cooperates with PI3K or p110β inhibition to suppress the growth of PTEN-null tumor cells.


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Crosstalk between Regulatory T Cells and Tumor-Associated Dendritic Cells Negates Anti-tumor Immunity in Pancreatic Cancer

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Jung-Eun Jang, Cristina H. Hajdu, Caroline Liot, George Miller, Michael L. Dustin, Dafna Bar-Sagi
Regulatory T (Treg) cell infiltration constitutes a prominent feature of pancreatic ductal adenocarcinoma (PDA). However, the immunomodulatory function of Treg cells in PDA is poorly understood. Here, we demonstrate that Treg cell ablation is sufficient to evoke effective anti-tumor immune response in early and advanced pancreatic tumorigenesis in mice. This response is dependent on interferon-γ (IFN-γ)-producing cytotoxic CD8⁺ T cells. We show that Treg cells engage in extended interactions with tumor-associated CD11c⁺ dendritic cells (DCs) and restrain their immunogenic function by suppressing the expression of costimulatory ligands necessary for CD8⁺ T cell activation. Consequently, tumor-associated CD8⁺ T cells fail to display effector activities when Treg cell ablation is combined with DC depletion. We propose that tumor-infiltrating Treg cells can promote immune tolerance by suppressing tumor-associated DC immunogenicity. The therapeutic manipulation of this axis might provide an effective approach for the targeting of PDA.

Graphical abstract

Teaser

Pancreatic tumors recruit dendritic cells that can switch between preventing or promoting immune responses. Jang et al. show that regulatory T cells are responsible for instructing the dendritic cells to prevent anti-tumor immunity. Removing the regulatory T cell subset allows dendritic cells to induce a potent anti-tumor immune response.


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Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Ashwin Unnikrishnan, Elli Papaemmanuil, Dominik Beck, Nandan P. Deshpande, Arjun Verma, Ashu Kumari, Petter S. Woll, Laura A. Richards, Kathy Knezevic, Vashe Chandrakanthan, Julie A.I. Thoms, Melinda L. Tursky, Yizhou Huang, Zara Ali, Jake Olivier, Sally Galbraith, Austin G. Kulasekararaj, Magnus Tobiasson, Mohsen Karimi, Andrea Pellagatti, Susan R. Wilson, Robert Lindeman, Boris Young, Raj Ramakrishna, Christopher Arthur, Richard Stark, Philip Crispin, Jennifer Curnow, Pauline Warburton, Fernando Roncolato, Jacqueline Boultwood, Kevin Lynch, Sten Eirik W. Jacobsen, Ghulam J. Mufti, Eva Hellstrom-Lindberg, Marc R. Wilkins, Karen L. MacKenzie, Jason W.H. Wong, Peter J. Campbell, John E. Pimanda
Myelodysplastic syndromes and chronic myelomonocytic leukemia are blood disorders characterized by ineffective hematopoiesis and progressive marrow failure that can transform into acute leukemia. The DNA methyltransferase inhibitor 5-azacytidine (AZA) is the most effective pharmacological option, but only ∼50% of patients respond. A response only manifests after many months of treatment and is transient. The reasons underlying AZA resistance are unknown, and few alternatives exist for non-responders. Here, we show that AZA responders have more hematopoietic progenitor cells (HPCs) in the cell cycle. Non-responder HPC quiescence is mediated by integrin α5 (ITGA5) signaling and their hematopoietic potential improved by combining AZA with an ITGA5 inhibitor. AZA response is associated with the induction of an inflammatory response in HPCs in vivo. By molecular bar coding and tracking individual clones, we found that, although AZA alters the sub-clonal contribution to different lineages, founder clones are not eliminated and continue to drive hematopoiesis even in complete responders.

Graphical abstract

Teaser

Unnikrishnan et al. discover that patients who fail to respond to frontline therapy with 5-azacitidine (AZA) have a higher baseline proportion of quiescent hematopoietic progenitor cells. Longitudinal sampling reveals that, although AZA response fails to eradicate clonal hematopoiesis, it restores functional hematopoiesis from progenitors with a lower mutational burden.


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Crystal Structure of the Human Ribosome in Complex with DENR-MCT-1

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Ivan B. Lomakin, Elena A. Stolboushkina, Anand T. Vaidya, Chenguang Zhao, Maria B. Garber, Sergey E. Dmitriev, Thomas A. Steitz
The repertoire of the density-regulated protein (DENR) and the malignant T cell-amplified sequence 1 (MCT-1/MCTS1) oncoprotein was recently expanded to include translational control of a specific set of cancer-related mRNAs. DENR and MCT-1 form the heterodimer, which binds to the ribosome and operates at both translation initiation and reinitiation steps, though by a mechanism that is yet unclear. Here, we determined the crystal structure of the human small ribosomal subunit in complex with DENR-MCT-1. The structure reveals the location of the DENR-MCT-1 dimer bound to the small ribosomal subunit. The binding site of the C-terminal domain of DENR on the ribosome has a striking similarity with those of canonical initiation factor 1 (eIF1), which controls the fidelity of translation initiation and scanning. Our findings elucidate how the DENR-MCT-1 dimer interacts with the ribosome and have functional implications for the mechanism of unconventional translation initiation and reinitiation.

Graphical abstract

Teaser

Some HCV-like viruses and specific cellular mRNAs use the DENR-MCT-1 heterodimer to initiate protein synthesis by an unknown mechanism. Lomakin et al. determined by X-ray crystallography the binding interface between the human small ribosomal subunit and the DENR-MCT-1 heterodimer, which is important for the DENR-MCT-1 function in non-canonical translation initiation and reinitiation.


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The Lysine Acetyltransferase GCN5 Is Required for iNKT Cell Development through EGR2 Acetylation

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Yajun Wang, Chawon Yun, Beixue Gao, Yuanming Xu, Yana Zhang, Yiming Wang, Qingfei Kong, Fang Zhao, Chyung-Ru Wang, Sharon Y.R. Dent, Jian Wang, Xiangping Xu, Hua-Bin Li, Deyu Fang
The development of CD1d-restricted invariant natural killer T (iNKT) cells, a population that is critical for both innate and adaptive immunity, is regulated by multiple transcription factors, but the molecular mechanisms underlying how the transcriptional activation of these factors are regulated during iNKT development remain largely unknown. We found that the histone acetyltransferase general control non-derepressible 5 (GCN5) is essential for iNKT cell development during the maturation stage. GCN5 deficiency blocked iNKT cell development in a cell-intrinsic manner. At the molecular level, GCN5 is a specific lysine acetyltransferase of early growth responsive gene 2 (EGR2), a transcription factor required for iNKT cell development. GCN5-mediated acetylation positively regulated EGR2 transcriptional activity, and both genetic and pharmacological GCN5 suppression specifically inhibited the transcription of EGR2 target genes in iNKT cells, including Runx1, promyelocytic leukemia zinc finger protein (PLZF), interleukin (IL)-2Rb, and T-bet. Therefore, our study revealed GCN5-mediated EGR2 acetylation as a molecular mechanism that regulates iNKT development.

Graphical abstract

Teaser

Wang et al. demonstrate that GCN5 is essential for programing iNKT cell development. Loss of GCN5 blocks iNKT cell development in a cell-intrinsic manner. GCN5 directly catalyzes the iNKT lineage-specific factor EGR2 to turn on its transcriptional activity for the expression of genes required for iNKT development.


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The Transcription Factor Tcf1 Contributes to Normal NK Cell Development and Function by Limiting the Expression of Granzymes

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Beena Jeevan-Raj, Jasmine Gehrig, Mélanie Charmoy, Vijaykumar Chennupati, Camille Grandclément, Paolo Angelino, Mauro Delorenzi, Werner Held
The transcription factor Tcf1 is essential for the development of natural killer (NK) cells. However, its precise role has not been clarified. Our combined analysis of Tcf1-deficient and transgenic mice indicated that Tcf1 guides NK cells through three stages of development. Tcf1 expression directed bone marrow progenitors toward the NK cell lineage and ensured the survival of NK-committed cells, and its downregulation was needed for terminal maturation. Impaired survival of NK-committed cells was due to excessive expression of granzyme B (GzmB) and other granzyme family members, which induced NK cell self-destruction during maturation and following activation with cytokines or target cells. Mechanistically, Tcf1 binding reduced the activity of a Gzmb-associated regulatory element, and this accounted for the reduced Gzmb expression in Tcf1-expressing NK cells. These data identify an unexpected requirement to limit the expression of cytotoxic effector molecules for the normal expansion and function of NK cells.

Graphical abstract

Teaser

The transcription factor Tcf1 is essential for NK cell development, but its role has not been clarified. Jeevan-Raj et al. identify a stage-specific role for Tcf1 in ensuring the survival of NK-committed cells. Tcf1 limited the expression of granzymes, thereby preventing granzyme-mediated NK cell self-destruction.


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Genome-wide RNAi Screen for Fat Regulatory Genes in C. elegans Identifies a Proteostasis-AMPK Axis Critical for Starvation Survival

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Christopher M. Webster, Elizabeth C. Pino, Christopher E. Carr, Lianfeng Wu, Ben Zhou, Lucydalila Cedillo, Michael C. Kacergis, Sean P. Curran, Alexander A. Soukas
Organisms must execute metabolic defenses to survive nutrient deprivation. We performed a genome-wide RNAi screen in Caenorhabditis elegans to identify fat regulatory genes indispensable for starvation resistance. Here, we show that opposing proteostasis pathways are principal determinants of starvation survival. Reduced function of cytoplasmic aminoacyl tRNA synthetases (ARS genes) increases fat mass and extends starvation survival, whereas reduced proteasomal function reduces fat and starvation survival. These opposing pathways converge on AMP-activated protein kinase (AMPK) as the critical effector of starvation defenses. Extended starvation survival in ARS deficiency is dependent upon increased proteasome-mediated activation of AMPK. When the proteasome is inhibited, neither starvation nor ARS deficiency can fully activate AMPK, leading to greatly diminished starvation survival. Thus, activity of the proteasome and AMPK are mechanistically linked and highly correlated with starvation resistance. Conversely, aberrant activation of the proteostasis-AMPK axis during nutritional excess may have implications for obesity and cardiometabolic diseases.

Graphical abstract

Teaser

Using a genome-wide screen for fat regulatory genes in C. elegans, Webster et al. define a proteostasis-AMPK signaling axis that is central to organismal starvation defenses. The results suggest that enhanced survival under elevated proteasome activity is due to AMPK activation and not to increased fuel availability.


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Loss of Hepatic Mitochondrial Long-Chain Fatty Acid Oxidation Confers Resistance to Diet-Induced Obesity and Glucose Intolerance

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Jieun Lee, Joseph Choi, Ebru S. Selen Alpergin, Liang Zhao, Thomas Hartung, Susanna Scafidi, Ryan C. Riddle, Michael J. Wolfgang
The liver has a large capacity for mitochondrial fatty acid β-oxidation, which is critical for systemic metabolic adaptations such as gluconeogenesis and ketogenesis. To understand the role of hepatic fatty acid oxidation in response to a chronic high-fat diet (HFD), we generated mice with a liver-specific deficiency of mitochondrial long-chain fatty acid β-oxidation (Cpt2^L−/− mice). Paradoxically, Cpt2^L−/− mice were resistant to HFD-induced obesity and glucose intolerance with an absence of liver damage, although they exhibited serum dyslipidemia, hepatic oxidative stress, and systemic carnitine deficiency. Feeding an HFD induced hepatokines in mice, with a loss of hepatic fatty acid oxidation that enhanced systemic energy expenditure and suppressed adiposity. Additionally, the suppression in hepatic gluconeogenesis was sufficient to improve HFD-induced glucose intolerance. These data show that inhibiting hepatic fatty acid oxidation results in a systemic hormetic response that protects mice from HFD-induced obesity and glucose intolerance.

Graphical abstract

Teaser

Lee et al. show that, contrary to expectations, the loss of hepatic fatty acid oxidation (FAO) confers resistance to weight gain and adiposity in response to a high-fat diet. Additionally, they show that loss of hepatic FAO—and, consequently, hepatic gluconeogenesis—protects mice from high-fat-diet-induced glucose intolerance.


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Dynamic Control of Dendritic mRNA Expression by CNOT7 Regulates Synaptic Efficacy and Higher Cognitive Function

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Rhonda L. McFleder, Fernanda Mansur, Joel D. Richter
Translation of mRNAs in dendrites mediates synaptic plasticity, the probable cellular basis of learning and memory. Coordination of translational inhibitory and stimulatory mechanisms, as well as dendritic transport of mRNA, is necessary to ensure proper control of this local translation. Here, we find that the deadenylase CNOT7 dynamically regulates dendritic mRNA translation and transport, as well as synaptic plasticity and higher cognitive function. In cultured hippocampal neurons, synaptic stimulation induces a rapid decrease in CNOT7, which, in the short-term, results in poly(A) tail lengthening of target mRNAs. However, at later times following stimulation, decreased poly(A) and dendritic localization of mRNA take place, similar to what is observed when CNOT7 is depleted over several days. In mice, CNOT7 is essential for hippocampal-dependent learning and memory. This study identifies CNOT7 as an important regulator of RNA transport and translation in dendrites, as well as higher cognitive function.

Graphical abstract

Teaser

McFleder et al. find that CNOT7, the major deadenylase in eukaryotes, has a specialized role in neurons. CNOT7 regulates the dendritic localization and translation of specific mRNAs and mediates synaptic plasticity and learning and memory in mice.


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Emi2 Is Essential for Mouse Spermatogenesis

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Lakshmi Gopinathan, Radoslaw Szmyd, Diana Low, M. Kasim Diril, Heng-Yu Chang, Vincenzo Coppola, Kui Liu, Lino Tessarollo, Ernesto Guccione, Ans M.M. van Pelt, Philipp Kaldis
The meiotic functions of Emi2, an inhibitor of the APC/C complex, have been best characterized in oocytes where it mediates metaphase II arrest as a component of the cytostatic factor. We generated knockout mice to determine the in vivo functions of Emi2—in particular, its functions in the testis, where Emi2 is expressed at high levels. Male and female Emi2 knockout mice are viable but sterile, indicating that Emi2 is essential for meiosis but dispensable for embryonic development and mitotic cell divisions. We found that, besides regulating cell-cycle arrest in mouse eggs, Emi2 is essential for meiosis I progression in spermatocytes. In the absence of Emi2, spermatocytes arrest in early diplotene of prophase I. This arrest is associated with decreased Cdk1 activity and was partially rescued by a knockin mouse model of elevated Cdk1 activity. Additionally, we detected expression of Emi2 in spermatids and sperm, suggesting potential post-meiotic functions for Emi2.

Graphical abstract

Teaser

Gopinathan et al. use mouse genetics to characterize the in vivo functions of Emi2, a meiotic inhibitor of APC/C. Emi2 knockout mice are sterile, revealing that Emi2 is essential for oocytes and spermatocytes to complete meiotic divisions. Impaired Cdk1 activity upon loss of Emi2 contributes to spermatogenic defects.


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Robust Identification of Developmentally Active Endothelial Enhancers in Zebrafish Using FANS-Assisted ATAC-Seq

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Aurelie Quillien, Mary Abdalla, Jun Yu, Jianhong Ou, Lihua Julie Zhu, Nathan D. Lawson
Identification of tissue-specific and developmentally active enhancers provides insights into mechanisms that control gene expression during embryogenesis. However, robust detection of these regulatory elements remains challenging, especially in vertebrate genomes. Here, we apply fluorescent-activated nuclei sorting (FANS) followed by Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) to identify developmentally active endothelial enhancers in the zebrafish genome. ATAC-seq of nuclei from Tg(fli1a:egfp)^y1 transgenic embryos revealed expected patterns of nucleosomal positioning at transcriptional start sites throughout the genome and association with active histone modifications. Comparison of ATAC-seq from GFP-positive and -negative nuclei identified more than 5,000 open elements specific to endothelial cells. These elements flanked genes functionally important for vascular development and that displayed endothelial-specific gene expression. Importantly, a majority of tested elements drove endothelial gene expression in zebrafish embryos. Thus, FANS-assisted ATAC-seq using transgenic zebrafish embryos provides a robust approach for genome-wide identification of active tissue-specific enhancer elements.

Graphical abstract

Teaser

Quillien et al. apply ATAC-seq to nuclei isolated from transgenic zebrafish embryos to successfully identify a compendium of active endothelial-specific enhancer elements.


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CRISPR-Mediated Integration of Large Gene Cassettes Using AAV Donor Vectors

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Rasmus O. Bak, Matthew H. Porteus
The CRISPR/Cas9 system has recently been shown to facilitate high levels of precise genome editing using adeno-associated viral (AAV) vectors to serve as donor template DNA during homologous recombination (HR). However, the maximum AAV packaging capacity of ∼4.5 kb limits the donor size. Here, we overcome this constraint by showing that two co-transduced AAV vectors can serve as donors during consecutive HR events for the integration of large transgenes. Importantly, the method involves a single-step procedure applicable to primary cells with relevance to therapeutic genome editing. We use the methodology in primary human T cells and CD34⁺ hematopoietic stem and progenitor cells to site-specifically integrate an expression cassette that, as a single donor vector, would otherwise amount to a total of 6.5 kb. This approach now provides an efficient way to integrate large transgene cassettes into the genomes of primary human cells using HR-mediated genome editing with AAV vectors.

Graphical abstract

Teaser

Integration of transgenes into specific sites of the genome of primary cells using CRISPR/Cas9 and AAV donor vectors is currently hampered by the limited packaging capacity of AAV. Bak and Porteus now report a method for efficient integration of large transgenes that exceed the capacity of a single AAV.


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Angiogenesis Dysregulation in Psoriatic Arthritis: Molecular Mechanisms

Angiogenesis Dysregulation in Psoriatic Arthritis: Molecular Mechanisms: There is evidence that psoriatic arthritis is closely linked to angiogenesis. Morphological changes described in blood vessels of psoriatic arthritis joints suggest the presence of a dysregulated angiogenesis resulting in the formation of immature vessels. Even if the reason of this inefficient angiogenesis is still unclear, an imbalance between angiogenic and antiangiogenic factors is probably responsible for inducing a dysregulated angiogenesis in psoriatic arthritis, which seems to be involved in its pathogenesis and clinical features. Nevertheless, among chronic arthritides, while angiogenesis in rheumatoid arthritis has been largely studied with a great amount of literature data, limited data on angiogenesis role in psoriatic arthritis are available. This review article is focused on current knowledge on the mechanisms responsible for dysregulated angiogenesis in psoriatic arthritis.

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Hepatobiliary Oncologic Surgery in the Elderly

Abstract

Purpose of Review

This review aims to describe the treatment and outcomes in the perioperative management of elderly patients undergoing hepatic surgery for cancer.

Recent Findings

There is a broad perception that elderly patients are more frail and less able to tolerate major resection. They are therefore offered surgery less often than younger patients. Elderly patients can tolerate major hepatectomies with comparable length of surgery, rate of transfusion, and length of hospital stay as younger patients. However, they are more apt to develop significant cardiopulmonary complications and require discharge to an acute care facility. When matched for tumor stage, disease-specific survival is similar to younger patients.

Summary

Contrary to what is sometimes perceived, elderly patients can tolerate major hepatic resection. However, this requires careful patient selection and preoperative evaluation, as elderly patients are more prone to complications, concerns related to quality of life outcomes and perioperative mortality.

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Activity of panobinostat in combination with bortezomib and dexamethasone in advanced, proteasome inhibitor refractory multiple myeloma

Activity of panobinostat in combination with bortezomib and dexamethasone in advanced, proteasome inhibitor refractory multiple myeloma:

Summary

The patient described here presented with relapsed multiple myeloma progressing after therapy with immunomodulatory agents (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib and carfilzomib). Eventually, the patient achieved an excellent response to the combination of panobinostat, bortezomib and dexamethasone, overcoming resistance to proteasome inhibitors and achieving a sustained VGPR (very good partial remission), which was consolidated with high-dose melphalan and autologous stem-cell transplantation.

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Soft tissue profile changes after Functional Mandibular Advancer or Herbst appliance treatment in class II patients

Soft tissue profile changes after Functional Mandibular Advancer or Herbst appliance treatment in class II patients:

Abstract

Objective

The objective of the present study is to compare the effects on soft tissue profile in class II patients after treatment with either "Functional Mandibular Advancer" (FMA) or Herbst appliance.

Materials and methods

The study included n = 42 patients treated with either FMA (n = 21) or Herbst appliance (n = 21) by the same experienced orthodontist. The treatment followed a single-step advancement protocol. Lateral cephalograms were analyzed through a set of customized measurements. The actual therapeutic effect was calculated using data from a growth survey. After testing for normal distribution and homogeneity of variance, data were analyzed by one-sample Student's t tests and independent Student's t tests. Statistical significance was set at p < 0.05.

Results

For both FFAs, significant upper lip retrusion, increase in lower lip's thickness, and length of the lower face occurred. Additionally, significant lower lip retrusion and straightening of the profile were found in FMA and Herbst appliance patients. All remaining variables revealed no significant differences.

Conclusions

Treatment-related changes on the facial soft tissue profile could be regarded similar in class II patients treated with FMA or Herbst appliance. No treatment-related changes that were specific for FMA or Herbst appliance could be identified. Only moderate changes were noted comparing pre- and posttreatment soft tissue profiles.

Clinical relevance

Despite proven differences in skeletal and dental treatment effects, the facial profile has not to be taken into consideration when choosing between FMA and Herbst appliance for class II treatment.

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Macrophage type 2 differentiation in a patient with laryngeal squamous cell carcinoma and metastatic prostate adenocarcinoma to the cervical lymph nodes

Macrophage type 2 differentiation in a patient with laryngeal squamous cell carcinoma and metastatic prostate adenocarcinoma to the cervical lymph nodes:

Abstract

Background

The tumor microenvironment often polarizes infiltrating macrophages towards a type 2, or M2 phenotype, that is characterized by expression of various cysteine-rich, scavenger receptors, including CD163. The primary function of M2 macrophages is to facilitate wound healing. As such, they are capable of providing metabolic support to a growing tumor, neovascularization, as well as protection from cytotoxic T cells. The tumor microenvironment contains a milieu of secreted factors and vesicles, which in certain circumstances can gain access to lymphatic vessels that drain to local lymph nodes.

Case presentation

We report a 59-year-old male with recurrent T4 squamous cell carcinoma (SCC) of the larynx with synchronous prostate adenocarcinoma confined to the prostate and regional pelvic lymph nodes, without metastatic disease. The patient underwent salvage total laryngectomy and bilateral neck dissection with final pathology revealing a recurrent moderately differentiated SCC involving the larynx as well as prostate cancer in draining level 4 cervical lymph nodes bilaterally. CD163 staining was performed on the primary tumor, a negative draining lymph node, and a level four lymph node with a focus of metastatic prostate cancer and compared to benign controls. The negative draining lymph node demonstrated a large CD163 population of cells as did the interface of the focus of prostate cancer and surrounding lymph node. CD163 levels were markedly increased in this patient compared to benign lymph node controls. The macrophage differentiation at the primary tumor in the larynx was strongly CD163 positive supporting an immune permissive environment for tumor growth and metastasis.

Conclusion

We describe a unique case of solitary metastatic prostate cancer to cervical lymph nodes in the setting of a laryngeal cancer. These observations suggest that SCC-derived factors drive a tumor-supportive environment in draining lymph nodes dominated by an overwhelming number of CD163+, M2 macrophages. Lymph nodes that are 'primed' by SCC differentiation to M2 phenotype may be at higher risk of harboring metastases.

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Highlights of the 31st annual meeting of the Society for Immunotherapy of Cancer (SITC), 2016

Highlights of the 31st annual meeting of the Society for Immunotherapy of Cancer (SITC), 2016:

Abstract

Therapeutic efforts to engage the immune system against cancer have yielded exciting breakthroughs and a growing list of approved immune-based agents across a variety of disease states. Despite the early successes and durable responses associated with treatments such as immune checkpoint inhibition, there is still progress to be made in the field of cancer immunotherapy. The 31st annual meeting of the Society for Immunotherapy of Cancer (SITC 2016), which took place November 11–13, 2016 in National Harbor, Maryland, showcased the latest advancements in basic, translational, and clinical research focused on cancer immunology and immunotherapy. Novel therapeutic targets, insights into the dynamic tumor microenvironment, potential biomarkers, and novel combination approaches were some of the main themes covered at SITC 2016. This report summarizes key data and highlights from each session.

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Regression of multifocoal in transit melanoma metastases after palliative resection of dominant masses and 2 years after treatment with ipilimumab

Regression of multifocoal in transit melanoma metastases after palliative resection of dominant masses and 2 years after treatment with ipilimumab:

Abstract

Background

Spontaneous regression of metastatic melanoma and delayed responses more than one year after treatment with ipilimumab are rarely seen.

Case presentation

Here, we present the case of a patient with in transit metastases from cutaneous melanoma on his right lower extremity who achieved complete regression of all metastatic lesions 13 months after the first of two consecutive palliative resections of dominant masses and more than two years after treatment with ipilimumab.

Conclusion

The exact cause of our patient's sudden onset of tumor regression remains speculative. We hypothesize that the operative trauma followed by the postoperative infections augmented an innate immune response.

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Angiosarcoma treated successfully with anti-PD-1 therapy - a case report

Angiosarcoma treated successfully with anti-PD-1 therapy - a case report:

Abstract

Background

Angiosarcomas are tumors of malignant endothelial origin that have a poor prognosis with a five-year survival of less than 40%. These tumors can be found in all age groups, but are more common in older patients; with the cutaneous form most common in older white men. Combined modality therapy including surgery and radiation appears to have a better outcome than each modality alone. When metastatic, agents such as liposomal doxorubicin, paclitaxel and ifosfamide have activity but it is short-lived and not curative. Immunotherapy targeting either the PD-1 receptor or PD-L1 ligand has recently been shown to have activity in multiple cancers including melanoma, renal, and non-small lung cancer. Although these agents have been used in sarcoma therapy, their ability to treat angiosarcoma has not been reported.

Case presentation

Here we describe the case of a 63-year-old man who presented initially with angiosarcoma of the nose and received surgery for the primary. Over 4 years he had recurrent disease in the face and liver and was treated with nab-paclitaxel, surgery, and radioembolization, but continued to have progressive disease. His tumor was found to express PD-L1 and he received off-label pembrolizumab 2 mg/kg every 21 days for 13 cycles with marked shrinkage of his liver disease and no new facial lesions. Secondary to this therapy he developed hepatitis and has been treated with decreasing doses of prednisone. During the 8 months off therapy he has developed no new or progressive lesions.

Conclusions

Although occasional responses to immunotherapy have been reported for sarcomas, this case report demonstrates that angiosarcoma can express PD-L1 and have a sustained response to PD-1 directed therapy.

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Chemokine (CC motif) ligand 18 upregulates Slug expression to promote stem ‐cell like features by activating the mammalian target of rapamycin pathway in oral squamous cell carcinoma

Chemokine (CC motif) ligand 18 upregulates Slug expression to promote stem ‐cell like features by activating the mammalian target of rapamycin pathway in oral squamous cell carcinoma: In conclusion, our data suggested that CCL18 upregulated Slug expression to promote EMT and stem cell‐like features by activating the mTOR pathway in oral cancer. These findings provide new potential targets for the early diagnosis and treatment of OSCC.

The study provided evidence that elevated CCL18 induced migration, invasion, epithelial‐mesenchymal transition (EMT), and the obtain of cancer stem‐cell like characteristics in OSCC cells. Moreover, we found that these CCL18‐derived responses were initiated by Slug overexpression via stimulating the mTOR signaling pathway in OSCC. (Source: Cancer Science)

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Hypoxia as a target for drug combination therapy of liver cancer

Hypoxia as a target for drug combination therapy of liver cancer: Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer deaths worldwide. The standard of care for intermediate HCC is transarterial chemoembolization, which combines tumour embolization with locoregional delivery of the chemotherapeutic doxorubicin. Embolization therapies induce hypoxia, leading to the escape and proliferation of hypoxia-adapted cancer cells. The transcription factor that orchestrates responses to hypoxia is hypoxia-inducible factor 1 (HIF-1). The aim of this work is to show that targeting HIF-1 with combined drug therapy presents an opportunity for improving outcomes for HCC treatment. HepG2 cells were cultured under normoxic and hypoxic conditions exposed to doxorubicin, rapamycin and combinations thereof, and analyzed for viability and the expression ...

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Report of two cases of acute cardiac adverse events in patients with colorectal carcinoma receiving oral capecitabine

Report of two cases of acute cardiac adverse events in patients with colorectal carcinoma receiving oral capecitabine: Capecitabine is an oral fluoropyrimidine chemotherapeutic agent, which, after oral administration, is metabolized to its active cytotoxic compound: 5-fluorouracil (5-FU). Cardiotoxicity is a recognized side effect of 5-FU, a closely related fluorinated pyrimidine antagonist. In the present report, we report on two patients who were admitted to our department after being treated with oral capecitabine for colorectal carcinoma and developed symptoms and signs of acute myocardial infarction that resolved after appropriate treatment and monitoring. The above two cases are discussed in the context of fluoropyrimidine, 5-FU, and capecitabine-induced cardiotoxicity; in addition, a detailed literature review of relevant cases and patient series reports is presented. (Source: Anti-Cancer Drugs)

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3-Bromopyruvate enhances TRAIL-induced apoptosis in human nasopharyngeal carcinoma cells through CHOP-dependent upregulation of TRAIL-R2

3-Bromopyruvate enhances TRAIL-induced apoptosis in human nasopharyngeal carcinoma cells through CHOP-dependent upregulation of TRAIL-R2: Past reports have shown that the sensitivity of cancer cells to TRAIL-induced apoptosis is related to their expression of TRAIL-death receptors on the cell surface. However, the level of TRAIL-death receptors expression on cancer cells is always low. Our previous research showed that nasopharyngeal carcinoma (NPC) cells have a poor sensitivity to low doses of TRAIL. Here, we evaluated combined treatment with the energy inhibitor 3-bromopyruvate (3BP) and TRAIL as a method to produce an increased apoptotic response in NPC cells. The results showed that 3BP and TRAIL together produced higher cytotoxicity and increased TRAIL-R2 expression in NPC cells compared with the effects of either 3BP or TRAIL alone. These findings led us to hypothesize that 3BP may sensitize NPC cells to TRAIL. 3BP is ...

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Complete response to anti-PD-1 nivolumab in massive skin metastasis from melanoma: efficacy and tolerability in an elderly patient

Complete response to anti-PD-1 nivolumab in massive skin metastasis from melanoma: efficacy and tolerability in an elderly patient: The advent of immune checkpoint inhibitors anti-PD-1/PD-L1 has delivered new and effective treatment options with proven clinical benefits for patients affected by metastatic melanoma. The 30–40% of treated patients experience an objective tumour regression, with a significantly prolonged survival and an improved quality of life. Here, we report a case of a 75-year-old Caucasian woman affected by a massive cutaneous metastasis from a BRAF wild-type melanoma who experienced multiple relapses after surgery and repeated electrochemotherapy treatments. A poor response was observed after systemic therapy with ipilimumab, whereas a marked reduction in the lesion size was obtained during the treatment with nivolumab, with an objectively complete response after 6 months. Therapy was well tolerat...

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Quantitation of DNA methylation in Epstein-Barr virus–associated nasopharyngeal carcinoma by bisulfite amplicon sequencing

Quantitation of DNA methylation in Epstein-Barr virus–associated nasopharyngeal carcinoma by bisulfite amplicon sequencing: Epigenetic changes, including DNA methylation, disrupt normal cell function, thus contributing to multiple steps of carcinogenesis. Nasopharyngeal carcinoma (NPC) is endemic in southern China and is highly ass...

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MAPK pathway and TERT promoter gene mutation pattern and its prognostic value in melanoma patients： a retrospective study of 2793 cases

MAPK pathway and TERT promoter gene mutation pattern and its prognostic value in melanoma patients： a retrospective study of 2793 cases:

Purpose: Ethnic differences are conspicuous in melanoma. This study is to obtain a comprehensive view of a genomic landscape and a better understanding of the correlations of gene mutation status with clinicopathological characteristics and disease prognosis in Asian population.<br /><br />Experimental Design: 2793 melanoma patient samples were retrospectively collected and analyzed for mutations in C-KIT, BRAF, NRAS, and PDGFRA coding regions and TERT promoter region by Sanger sequencing. Mutations were correlated to clinicopathological features and overall survival.<br /><br />Results: The incidences of somatic mutations within the BRAF, NRAS, C-KIT, TERT-228, TERT-250, and PDGFRA genes were 23.7%, 10.4% 8.0%, 5.9%, 5.5%, and 1.4%, respectively. Hotspot mutations accounted for 95.8% and 87.2% of BRAF and NRAS mutations, respectively; meanwhile, C-KIT and PDGFRA mutations showed more heterogeneity. BRAF, C-KIT, and NRAS mutations were mutually exclusive. BRAF, C-KIT, NRAS, and numbers of gene mutations of MAPK pathway were all independent negative prognostic factors (P=0.007, other P<0.001, respectively). In acral melanoma, BRAF, C-KIT, and NRAS mutations were all independent prognostic factors of worse OS (all P<0.001); while in mucosal melanoma only C-KIT was (P=0.006). Although correlated with BRAF mutations (P=0.001 and P<0.001 for C228T and C250T, respectively), TERT promoter gene mutations were not correlated with OS (P=0.406 and 0.256, respectively).<br /><br />Conclusions: MAPK pathway and TERT promoter gene mutations are differentially represented in Asian population. Mutations in BRAF, C-KIT, and NRAS have prognostic values that vary by melanoma subtypes. Clinical treatment targeting these critical pathways should be directly at these poor prognosis subpopulations for maximum potential impact.

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Atypical responses in patients with advanced melanoma, lung cancer, renal-cell carcinoma and other solid tumors treated with anti-PD-1 drugs: A Systematic Review

Atypical responses in patients with advanced melanoma, lung cancer, renal-cell carcinoma and other solid tumors treated with anti-PD-1 drugs: A Systematic Review: Anti-programmed death receptor 1 (PD-1) drugs nivolumab and pembrolizumab were recently approved for the treatment of advanced melanoma and other solid tumors. Atypical patterns of response (i.e. tumor shrinkage or stabilization after initial progression) were observed in about 10% of metastatic melanoma patients treated with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) drug ipilimumab and were associated with improved survival; however, the rate of atypical response patterns to anti-PD-1 therapy is not clear.

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Treatment of late sequelae after radiotherapy for head and neck cancer

 Treatment of late sequelae after radiotherapy for head and neck cancer

via ScienceDirect Publication: Cancer Treatment Reviews

Publication date: Available online 18 July 2017
Source:Cancer Treatment Reviews
Author(s): Primož Strojan, Katherine A. Hutcheson, Avraham Eisbruch, Jonathan J. Beitler, Johannes A. Langendijk, Anne W.M. Lee, June Corry, William M. Mendenhall, Robert Smee, Alessandra Rinaldo, Alfio Ferlito
Radiotherapy (RT) is used to treat approximately 80% of patients with cancer of the head and neck. Despite enormous advances in RT planning and delivery, a significant number of patients will experience radiation-associated toxicities, especially those treated with concurrent systemic agents. Many effective management options are available for acute RT-associated toxicities, but treatment options are much more limited and of variable benefit among patients who develop late sequelae after RT. The adverse impact of developing late tissue damage in irradiated patients may range from bothersome symptoms that negatively affect their quality of life to severe life-threatening complications. In the region of the head and neck, among the most problematic late effects are impaired function of the salivary glands and swallowing apparatus. Other tissues and structures in the region may be at risk, depending mainly on the location of the irradiated tumor relative to the mandible and hearing apparatus. Here, we review the available evidence on the use of different therapeutic strategies to alleviate common late sequelae of RT in head and neck cancer patients, with a focus on the critical assessment of the treatment options for xerostomia, dysphagia, mandibular osteoradionecrosis, trismus, and hearing loss.

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Is Cancer Information Exchanged on Social Media Scientifically Accurate?

Is Cancer Information Exchanged on Social Media Scientifically Accurate?:

Abstract

Cancer patients and their caregivers are increasingly using social media as a platform to share cancer experiences, connect with support, and exchange cancer-related information. Yet, little is known about the nature and scientific accuracy of cancer-related information exchanged on social media. We conducted a content analysis of 12 months of data from 18 publically available Facebook Pages hosted by parents of children with acute lymphoblastic leukemia (N = 15,852 posts) and extracted all exchanges of medically-oriented cancer information. We systematically coded for themes in the nature of cancer-related information exchanged on personal Facebook Pages and two oncology experts independently evaluated the scientific accuracy of each post. Of the 15,852 total posts, 171 posts contained medically-oriented cancer information. The most frequent type of cancer information exchanged was information related to treatment protocols and health services use (35%) followed by information related to side effects and late effects (26%), medication (16%), medical caregiving strategies (13%), alternative and complementary therapies (8%), and other (2%). Overall, 67% of all cancer information exchanged was deemed medically/scientifically accurate, 19% was not medically/scientifically accurate, and 14% described unproven treatment modalities. These findings highlight the potential utility of social media as a cancer-related resource, but also indicate that providers should focus on recommending reliable, evidence-based sources to patients and caregivers.

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Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors

 : From laboratory to patients

via ScienceDirect Publication: Cancer Treatment Reviews

Publication date: Available online 18 July 2017
Source:Cancer Treatment Reviews
Author(s): Filip Janku
The phosphoinositide 3-kinase (PI3K) pathway is an intracellular signaling pathway that has regulatory roles in cell survival, proliferation, and differentiation, and a critical role in tumorigenesis. In cancer, multiple studies have investigated the therapeutic targeting of the PI3K pathway, and multiple inhibitors targeting PI3K and its isoforms, protein kinase B/AKT, mammalian target of rapamycin (mTOR), and other pathway proteins have been developed. For the treatment of solid tumors, only allosteric mTOR inhibitors, such as everolimus and temsirolimus, are currently approved for clinical use. This review describes the PI3K inhibitors that have progressed from the laboratory to late-stage clinical trials, and discusses the challenges that have prevented other compounds from doing the same. Challenges to the therapeutic effectiveness of some PI3K inhibitors include the absence of reliable and effective biomarkers, their limited efficacy as single agents, insufficient development of rational therapeutic combinations, the use of schedules with a variety of off-target effects, and suboptimal therapeutic exposures. Therefore, with regard to PI3K inhibitors currently in late-stage clinical trials, the identification of appropriate biomarkers of efficacy and the development of optimal combination regimens and dosing schedules are likely to be important for graduation into clinical practice.

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Thyroid Surgery: To Drain or Not to Drain

A Randomized Clinical Trial.:

ORL J Otorhinolaryngol Relat Spec. 2017 Jul 15;79(4):202-211

Authors: Schietroma M, Pessia B, Bianchi Z, De Vita F, Carlei F, Guadagni S, Amicucci G, Clementi M

Abstract

PURPOSE: We conducted a prospective, randomized study to evaluate the necessity of drainage after thyroid surgery.

METHODS: The patients (n = 215) were randomly assigned to be treated with suction drains (group 1; n = 108) or not (group 2; n = 107).

RESULTS: The postoperative pain scores were significantly lower in the non-drained group than in the drained group of patients at postoperative days 0 and at 1. Hematomas, seromas, wound infections, transient biochemical hypoparathyroidism, and transient damage of the recurrent laryngeal nerve occurred more frequently in the drained group than in the non-drained group. The mean hospital stay was significantly shorter in the non-drained group than in the drained group.

CONCLUSIONS: Routine drain emplacement after thyroidectomy is unnecessary.

PMID: 28715809 [PubMed - as supplied by publisher]

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The most common pathogen identified through pus culturing was S. viridans, followed by K. pneumoniae. Bacteriology of peritonsillar abscess

 : the changing trend and predisposing factors

via ScienceDirect Publication: Brazilian Journal of Otorhinolaryngology

Publication date: Available online 17 July 2017
Source:Brazilian Journal of Otorhinolaryngology
Author(s): Yi-Wen Tsai, Yu-Hsi Liu, Hsing-Hao Su
IntroductionPeritonsillar abscess (PTA) is the most common deep neck infection. The infectious microorganism may be different according to clinical factors.ObjectiveTo identify the major causative pathogen of peritonsillar abscess and investigate the relationship between the causative pathogen, host clinical factors, and hospitalization duration.MethodsThis retrospective study included 415 hospitalized patients diagnosed with peritonsillar abscess who were admitted to a tertiary medical center from June 1990 to June 2013. We collected data by chart review and analyzed variables such as demographic characteristics, underlying systemic disease, smoking, alcoholism, betel nut chewing, bacteriology, and hospitalization duration.ResultsA total of 168 patients had positive results for pathogen isolation. Streptococcus viridans (28.57%) and Klebsiella pneumoniae (23.21%) were the most common microorganisms identified through pus culturing. The isolation rate of anaerobes increased to 49.35% in the recent 6 years (p=0.048). Common anaerobes were Prevotella and Fusobacterium spp. The identification of K. pneumoniae increased among elderly patients (age>65 years) with an odds ratio (OR) of 2.76 (p=0.03), and decreased in the hot season (mean temperature>26°C) (OR=0.49, p=0.04). No specific microorganism was associated with prolonged hospital stay.ConclusionThe most common pathogen identified through pus culturing was S. viridans, followed by K. pneumoniae. The identification of anaerobes was shown to increase in recent years. The antibiotics initially selected should be effective against both aerobes and anaerobes. Bacterial identification may be associated with host clinical factors and environmental factors.

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Water protection after tympanostomy (Shepard) tubes does not decrease otorrhea incidence

  – retrospective cohort study

via ScienceDirect Publication: Brazilian Journal of Otorhinolaryngology

Publication date: Available online 17 July 2017
Source:Brazilian Journal of Otorhinolaryngology
Author(s): João Subtil, Ana Jardim, Andre Peralta Santos, João Araújo, José Saraiva, João Paço
IntroductionMyringotomy for tube insertion is the most common otologic surgery. Otorrhea is a frequent complication of this procedure and, to prevent it, most surgeons strongly recommend avoiding contact with water as this is thought to adversely impact on post-operative quality of life.ObjectiveTo understand the benefit of this recommendation.MethodsObservational study – retrospective cohort study comparing the incidence of post-operative otorrhea and its impact on patients' quality of life, in two groups of patients comprising children under 10 years of age who underwent bilateral myringotomy and tube placement for chronic otitis media with effusion between May 2011 and May 2012. One group received water protection care after surgery, the other did not. Data was collected through telephonic interview, after one year of follow up (one year after the procedure). Water exposure without protection was considered the exposure event. Incidence of otorrhea and perceived impact on quality of life were the outcome measures. Results were compared after logistic regression.ResultsWe included 143 children: 116 were not exposed to water without protection and 27 were exposed. In the not exposed group 36.2% had at least one episode of otorrhea, compared to 40.0% of the exposed group. Odds ratio for otorrhea on exposed was 1.21 (95% CI 0.51–2.85, p=0.6). Negative impact on quality of life was reported by parents of 48.2% on the not exposed children, compared to 40.7% on the exposed group. This difference was not significant (p=0.5).ConclusionWe found that recommending water protection did not have beneficial effect on the incidence of otorrhea after myringotomy with tubes on chronic otitis media with effusion. However, such measures did not appear to have a negative impact on quality of life.

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Structural and Ultrastructural Changes to Type I Spiral Ganglion Neurons and Schwann Cells in the Deafened Guinea Pig Cochlea

Structural and Ultrastructural Changes to Type I Spiral Ganglion Neurons and Schwann Cells in the Deafened Guinea Pig Cochlea: We examined the time course of these degenerative changes in type I SGNs and their satellite Schwann cells at the ultrastructural level in guinea pigs at 2, 6, and 12  weeks following aminoglycoside-induced hearing loss. Degeneration of the peripheral fibres occurred prior to the degeneration of the type I SGN soma and was characterised by shrinkage of the fibre followed by retraction of the axoplasm, often leaving a normal myelin lumen devoid of axoplasmic cont ent. A statistically significant reduction in the cross-sectional area of peripheral fibres was evident as early as 2 weeks following deafening (p <  0.001, ANOVA). This was followed by a decrease in type I SGN density within Rosenthal's canal that was statistically significant 6 weeks following deafening (p <  0.001...

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The Sophono bone-conduction system: Surgical, audiologic, and quality-of-life outcomes

The Sophono bone-conduction system: Surgical, audiologic, and quality-of-life outcomes:

Timothy Mclean, MBBS; Irumee Pai, FRCS; Andrew Philipatos, BSc; Michael Gordon, FRACS

Abstract

We prospectively evaluated the surgical, audiologic, and quality-of-life outcomes in 5 patients-2 men and 3 women, aged 22 to 64 years (mean: 41.8)-who were implanted with the Sophono Alpha 2 MPO Processor. The indications for implantation of this bone-conduction device included recurrent ear canal infections with hearing aids (n = 3), single-sided deafness (n = 1), and patient preference in view of difficulty using a conventional hearing aid (n = 1). In addition to the patient with single-sided deafness, 3 patients had a bilateral mixed hearing loss and 1 had a bilateral conductive hearing loss. Outcomes measures included surgical complications, functional gain (FG), speech discrimination in quiet and noise, and patient satisfaction as determined by the Glasgow Benefit Inventory (GBI) and the Entific Medical Systems bone-anchored hearing aid questionnaire (BAQ). The only postsurgical complication noted was a minor skin reaction and pain in 1 patient that resolved with conservative management. In the 3 patients with the mixed hearing loss, the mean FG was 13.3, 20.0, 11.7, and 11.7 dB at 0.5, 1, 2, and 4 kHz, respectively; in the patient with the bilateral conductive hearing loss, the FG was 10, 25, 10, and 15 dB at the same frequencies. Speech discrimination scores with the Sophono device were comparable to those seen with conventional hearing aids. After implantation, all 5 patients experienced a positive quality-of-life outcome according to the GBI, although 1 of them had only a marginal improvement. On follow-up, all patients reported that they remained satisfied with their implant and that they used their device all day long. We conclude that the Sophono bone-conduction system is a safe and effective option that should be considered for patients with a mixed or conductive hearing loss who are unable to use a conventional hearing aid, as well as for those with single-sided deafness.

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Cochlear implant electrode array exposure: A delayed complication

Cochlear implant electrode array exposure: A delayed complication:

Christina Mishu, AuD; David A. Klodd, PhD; Miriam Redleaf, MD, FACS

Abstract

Exposure of the cochlear implant electrode array as a late complication has been reported rarely in the literature. A retrospective analysis revealed 4 patients presenting with exposure of their cochlear implant electrode arrays from 2 to 17 years after implantation. Data collected from these 4 patients were surgical implantation approach, type of implant, age at implant, interval between implant and complication, surgical correction of the problem, pathology at the time of correction, and length of follow-up after intervention. All 4 patients presented with otitis or mastoiditis. Each had undergone a transmastoid approach with facial recess and cochleostomy and full implant insertion. In 3 cases, the tympanic membrane had retracted to expose the electrode array. In 1 patient, the electrode array had eroded through the external canal, lateral to the facial recess. The exposed arrays were addressed surgically, including explantation/reimplantation for 1 patient. Cochlear implant electrode arrays can become exposed by relative migration of the array and the tympanic membrane. Implant surgeons and audiologists need to be aware of the possibility of this complication. Closure of the ear canal appears to be the most effective surgical intervention.

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Endoscopic Transcanal Myringoplasty for Anterior Perforations of the Tympanic Membrane.

Endoscopic Transcanal Myringoplasty for Anterior Perforations of the Tympanic Membrane.:

Related Articles

Endoscopic Transcanal Myringoplasty for Anterior Perforations of the Tympanic Membrane.

JAMA Otolaryngol Head Neck Surg. 2016 Nov 01;142(11):1088-1093

Authors: Tseng CC, Lai MT, Wu CC, Yuan SP, Ding YF

Abstract

Importance: Repairing anterior perforations of the tympanic membrane has been challenging for otolaryngologists. Therefore, devising a simple and effective technique for performing the repair is crucial.

Objective: To assess the results of endoscopic transcanal myringoplasty for repairing anterior perforations of the tympanic membrane.

Design, Setting, and Participants: This medical record review included 59 patients who underwent endoscopic transcanal myringoplasty from January 1, 2013, to June 1, 2015, at PoJen General Hospital, Taipei, Taiwan. Patients with ossicular chain disease and cholesteatoma or inadequate follow-up were excluded. Patients were followed up for 6 months, and final follow-up was completed on January 1, 2016.

Main Outcomes and Measures: The main outcome was the rate of overall graft success after endoscopic transcanal myringoplasty. Secondary outcomes included hearing results and prognostic factors.

Results: The study sample included the medical records of 59 patients (30 men [51%]; 29 women [49%]; mean [SD] age, 49.5 [13.1] years) who underwent endoscopic transcanal myringoplasty. Overall, 55 patients (93%) had a successful graft at 6 postoperative months. The mean (SD) preoperative and postoperative air-bone gaps were 15.9 (9.4) and 5.4 (7.0) dB, respectively, revealing a significant mean (SD) improvement of 10.3 (7.6) dB (Cohen d, 1.27; 95% CI, 0.90-1.63; P < .001, paired t test) in the gap. The postoperative air-bone gap in 46 patients (78%) was less than 10 dB; in 12 patients (20%), 10 to 20 dB; and in 1 patient (2%), more than 20 dB. Postoperative otorrhea significantly affected the graft success rate (odds ratio, 52.00; 95% CI, 4.08-662.55; P < .01, χ2 test). The visualization of the perforation margin (complete or partial) was not significantly associated with the graft success rate. However, partial visualization of the perforation margin significantly prolonged the mean (SD) operative time (complete vs partial, 59.2 [13.7] vs 68.1 [14.1] minutes; Cohen d, 0.64; 95% CI, 0.12-1.18; P = .02, t test).

Conclusions and Relevance: The rate of graft success and hearing outcomes for endoscopic transcanal myringoplasty are comparable with those of microscopic myringoplasty for repairing anterior perforations of the tympanic membrane. However, the present technique is simpler because postauricular incision, canalplasty, and general anesthesia are not required. Thus, endoscopic transcanal myringoplasty should be considered for repairing anterior perforations of the tympanic membrane.

PMID: 27540858 [PubMed - indexed for MEDLINE]

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A comparison of speech intonation production and perception abilities of Farsi speaking cochlear implanted and normal hearing children

A comparison of speech intonation production and perception abilities of Farsi speaking cochlear implanted and normal hearing children: Cochlear implant prosthesis facilitates spoken language development and speech comprehension in children with severe-profound hearing loss. However, this prosthesis is limited in encoding information about fundamental frequency and pitch that are essentially for recognition of speech prosody. The purpose of the present study is to investigate the perception and production of intonation in cochlear implant children and comparison with normal hearing children.

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“On-command” dissolvable tympanostomy tube in the chinchilla model: A proof of concept

"On-command" dissolvable tympanostomy tube in the chinchilla model: A proof of concept: To prove the concept that a dissolvable "on-command" tympanostomy tube placed into the tympanic membrane of a chinchilla can dissolve when a benign solution is applied and result in a well healed tympanic membrane without histologic evidence of injury.

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Fluid-Structure Finite-Element Modelling and Clinical Measurement of the Wideband Acoustic Input Admittance of the Newborn Ear Canal and Middle Ear

Fluid-Structure Finite-Element Modelling and Clinical Measurement of the Wideband Acoustic Input Admittance of the Newborn Ear Canal and Middle Ear: AbstractThe anatomical differences between the newborn ear and the adult one result in different input admittance responses in newborns than those in adults. Taking into account fluid-structure interactions, we have developed a finite-element model to investigate the wideband admittance responses of the ear canal and middle ear in newborns for frequencies up to 10  kHz. We have also performed admittance measurements on a group of 23 infants with ages between 14 and 28 days, for frequencies from 250 to 8000 Hz with 1/12-octave resolution. Sensitivity analyses of the model were performed to investigate the contributions of the ear canal and middle ear to the overall admittance responses, as well as the effects of the material parameters, measurement location and geometrical variability. T...

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Passive Transcutaneous Bone Conduction Hearing Implants: A Systematic Review.

Passive Transcutaneous Bone Conduction Hearing Implants: A Systematic Review.: Objective: To systematically review the literature on currently available passive transcutaneous bone conduction hearing implants (pTCBI) with regard to complications, audiological outcomes, and quality-of-life scores.

Data Sources: MEDLINE, EMBASE, Scopus, and Cochrane Library.

Study Selection: All identified English-language articles reporting on the implantation of currently available pTCBI's and their complications. Both pediatric and adult patients were included. No limitation was placed on study design or level of evidence.

Data Extraction: Complications, audiological outcomes including mean pure-tone average gain and mean speech reception threshold gain, and quality-of-life outcomes.

Data Synthesis: Twenty-six articles were included in the review. Four hundred eighty-two pTCBIs have been reported in the literature. Major complications including skin breakdown, wound dehiscence, hematoma, seroma, and inability to use the device occurred in 5.2% of patients. Minor complications including pain and self-resolving erythema at the implant site occurred in 13.1% of the patients. The weighted mean pure-tone average gain of the two included devices was 28.4 +/- 2.1 dB and the mean speech reception threshold gain was 32.9 +/- 3.9 dB. Favorable quality-of-life scores have been demonstrated with pTCBIs.

Conclusion: pTCBIs are a viable alternative to percutaneous devices in a carefully selected group of patients. These devices have demonstrated good audiological outcomes, low morbidity, and high patient satisfaction.

Copyright (C) 2017 by Otology & Neurotology, Inc. Image copyright (C) 2010 Wolters Kluwer Health/Anatomical Chart Company

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Response to therapy of papillary thyroid cancer of known BRAF status

Response to therapy of papillary thyroid cancer of known BRAF status:

Abstract

Context

A dynamic risk stratification with modified initial estimated risk based on response to therapy and disease course is one of the crucial changes adopted recently by the American Thyroid Association (ATA). This approach focuses on an individualized risk-adapted approach to the management of differentiated thyroid cancer. The BRAF V600E mutation is the most common genetic alteration in papillary thyroid cancer (PTC). However, the prognostic value of this mutation remains unclear.

Objective

The aim of this study was to examine the relation between the BRAF V600E status in PTC and all ATA response to therapy categories, as well as the recurrence and persistence of both biochemical and structural disease.

Participants

Unselected PTC cases with known BRAF status diagnosed from 2000–2013 and actively monitored at one institution (n=723) were reviewed retrospectively.

Main Outcome Measures

The association between the BRAF V600E mutation and clinicopathological characteristics, ATA 2015 response-to-therapy category, recurrence after a period of no evidence of disease (NED), and persistent biochemical or structural disease were analyzed.

Results

BRAF V600E was found in 65.7% (475/723) of PTC cases. Although BRAF mutation status correlated significantly with certain clinicopathological prognostic factors, there was no correlation with any of the response to therapy categories. Recurrences and persistent biochemical or structural disease were not associated with BRAF status.

Conclusions

Our data are consistent with those of other studies reporting a positive relation between BRAF V600E mutation and poor prognostic factors in PTC, however, the BRAF status did not significantly correlate with a response to therapy.

This article is protected by copyright. All rights reserved.

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The Effect of Routine Radiological Reporting of Thyroid Incidentalomas on Rates of Thyroid Needle Biopsy, Thyroid Surgery and Detection of Thyroid Malignancy

The Effect of Routine Radiological Reporting of Thyroid Incidentalomas on Rates of Thyroid Needle Biopsy, Thyroid Surgery and Detection of Thyroid Malignancy:

Abstract

Objective

This study looked at the effect of a changing radiology reporting policy to routinely review the thyroid gland where visible and report on any thyroid lesion, recommending further investigation as appropriate.

Context

Incidentaloma is a term used to describe a lesion found on imaging unrelated to the clinical issue under investigation. There is variability in the radiological reporting of thyroid incidentalomas and conflicting recommendations as to how these lesions should be managed.

Design

Data were collected retrospectively during a two year period, including 12 months before and 12 months after the change in reporting policy and categorised according to whether the lesion under investigation was a thyroid incidentaloma or a symptomatic thyroid lesion.

Patients

All patients undergoing ultrasound guided fine-needle aspiration cytology (FNAC) or core biopsy were included.

Measurements

The effects of the change in policy were analysed including rates of needle biopsy, rates of malignancy and subsequent surgical intervention.

Results

There was a 122% increase in thyroid incidentalomas undergoing needle biopsy, the majority of these were detected on computed tomography. The number of malignancies increased from 1 to 4 from year 1 to year 2. All patients were >35 years old. One patient had a positron emission tomography (PET) detected cancer, 2/4 of the non-PET detected malignancies were <1.5cm.

Conclusion

This study posits that routine radiological reporting of thyroid incidentalomas, with further investigation when clinically appropriate, is warranted. The results suggest that lesion size and CT characteristics are not reliable criteria to triage patients for investigation/biopsy.

This article is protected by copyright. All rights reserved.

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Cutaneous Indeterminate Cell Histiocytosis of Donor Origin After Allogeneic Hematopoietic Stem-Cell Transplantation.

Cutaneous Indeterminate Cell Histiocytosis of Donor Origin After Allogeneic Hematopoietic Stem-Cell Transplantation.: Allogeneic hematopoietic stem-cell transplantation and solid-organ transplantation are associated with an increased risk of secondary neoplasms. Indeterminate cell histiocytosis (ICH) is a rare disease composed of so-called indeterminate cells, an alleged cutaneous dendritic cell subset displaying histological and some ultrastructural and immunophenotypic features of Langerhans cells but lacking Birbeck granules. We report a case of cutaneous ICH occurring after allogeneic hematopoietic stem-cell transplantation for a myelodysplastic syndrome in a 56-year-old man. Microsatellite analysis demonstrated that the neoplastic cells were derived from the donor's hematopoietic system. This case broadens the spectrum of complications after stem-cell transplantation and demonstrates that cutaneous ICH in the setting of myelodysplastic syndromes may have a nonrelated origin to dysplastic myeloid cells.

Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Predictors, Prognosis, and Management of New Clinically Important Atrial Fibrillation After Noncardiac Surgery: A Prospective Cohort Study

Predictors, Prognosis, and Management of New Clinically Important Atrial Fibrillation After Noncardiac Surgery: A Prospective Cohort Study: BACKGROUND: Despite the frequency of new clinically important atrial fibrillation (AF) after noncardiac surgery and its increased association with the risk of stroke at 30 days, there are limited data informing their prediction, association with outcomes, and management.

METHODS: We used the data from the PeriOperative ISchemic Evaluation trial to determine, in patients undergoing noncardiac surgery, the association of new clinically important AF with 30-day outcomes, and to assess management of these patients. We also aimed to derive a clinical prediction rule for new clinically important AF in this population. We defined new clinically important AF as new AF that resulted in symptoms or required treatment. We recorded an electrocardiogram 6 to 12 hours postoperatively and on the 1st, 2nd, and 30th days after surgery.

RESULTS: A total of 211 (2.5% [8351 patients]; 95% confidence interval, 2.2%–2.9%) patients developed new clinically important AF within 30 days of randomization (8140 did not develop new AF). AF was independently associated with an increased length of hospital stay by 6.0 days (95% confidence interval, 3.5–8.5 days) and vascular complications (eg, stroke or congestive heart failure). The usage of an oral anticoagulant at the time of hospital discharge among patients with new AF and a CHADS2 score of 0, 1, 2, 3, and ≥4 was 6.9%, 10.2%, 23.0%, 9.4%, and 33.3%, respectively. Two independent predictors of patients developing new clinically important AF were identified (ie, age and surgery). The prediction rule included the following factors and assigned weights: age ≥85 years (4 points), age 75 to 84 years (3 points), age 65 to 74 years (2 points), intrathoracic surgery (3 points), major vascular surgery (2 points), and intra-abdominal surgery (1 point). The incidence of new AF based on scores of 0 to 1, 2, 3 to 4, and 5 to 6 was 0.5%, 1.0%, 3.1%, and 5.3%, respectively.

CONCLUSIONS: Age and surgery are independent predictors of new clinically important AF in the perioperative setting. A minority of patients developing new clinically important AF with high CHADS2 scores are discharged on an oral anticoagulant. There is a need to develop effective and safe interventions to prevent this outcome and to optimize the management of this event when it occurs.

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Role of glutathione in the regulation of epigenetic mechanisms in disease

Publication date: November 2017
Source:Free Radical Biology and Medicine, Volume 112
Author(s): José Luis García-Giménez, Carlos Romá-Mateo, Gisselle Pérez-Machado, Lorena Peiró-Chova, Federico V. Pallardó
Epigenetics is a rapidly growing field that studies gene expression modifications not involving changes in the DNA sequence. Histone H3, one of the basic proteins in the nucleosomes that make up chromatin, is S-glutathionylated in mammalian cells and tissues, making Gamma-L-glutamyl-L-cysteinylglycine, glutathione (GSH), a physiological antioxidant and second messenger in cells, a new post-translational modifier of the histone code that alters the structure of the nucleosome. However, the role of GSH in the epigenetic mechanisms likely goes beyond a mere structural function. Evidence supports the hypothesis that there is a link between GSH metabolism and the control of epigenetic mechanisms at different levels (i.e., substrate availability, enzymatic activity for DNA methylation, changes in the expression of microRNAs, and participation in the histone code). However, little is known about the molecular pathways by which GSH can control epigenetic events. Studying mutations in enzymes involved in GSH metabolism and the alterations of the levels of cofactors affecting epigenetic mechanisms appears challenging. However, the number of diseases induced by aberrant epigenetic regulation is growing, so elucidating the intricate network between GSH metabolism, oxidative stress and epigenetics could shed light on how their deregulation contributes to the development of neurodegeneration, cancer, metabolic pathologies and many other types of diseases.

Graphical abstract

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Little Black Boxes: Noncardiac Implantable Electronic Medical Devices and Their Anesthetic and Surgical Implications

Little Black Boxes: Noncardiac Implantable Electronic Medical Devices and Their Anesthetic and Surgical Implications: Implanted electronic medical devices. or stimulators such as pacemakers and nerve stimulators have grown enormously in diversity and complexity over recent decades. The function and potential interaction of these devices with the perioperative environment is of increasing concern for anesthesiologists and surgeons. Because of the innate electromagnetic environment of the hospital (operating room, gastrointestinal procedure suite, and imaging suite), implanted device malfunction, reprogramming, or destruction may occur and cause physical harm (including nerve injury, blindness, deafness, burn, stroke, paralysis, or coma) to the patient. It is critical for the anesthesiologist and surgeon to be aware of the function and interaction of implanted devices, both with other implanted devices and procedures (such as magnetic resonance imaging and cardioversion) in the hospital environment. Because of these interactions, it is imperative that proper device function is assessed when the surgical procedure is complete. This review article will discuss these important issues for 12 different types of "little black boxes," or noncardiac implantable electronic medical devices.

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Giant Thebesian Valve Appearing As a Right Atrial Mass

Giant Thebesian Valve Appearing As a Right Atrial Mass: INTRACARDIAC MASSES are usually non-neoplastic and include infections, thrombi, and structural abnormalities. Neoplastic masses of the heart are rare and often are benign like myxomas, fibromas, lipomas, angiomas, and papillary fibroelastomas. They are seen more commonly in the right atrium.1 Malignant tumors of the heart can be primary or metastatic from the lungs, breast, or other tissues. The presenting symptoms from the cardiac masses are quite variable and depend on the size and location of the mass.

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Acute Type-B Aortic Dissection in Pregnancy: Therapeutic Challenges in a Multidisciplinary Setting

Acute Type-B Aortic Dissection in Pregnancy: Therapeutic Challenges in a Multidisciplinary Setting: ALTHOUGH ACUTE AORTIC dissection during pregnancy is a rare occurrence, it remains important because it is frequently a cardiovascular emergency that can be lethal for both the mother and the fetus. Clinical data from the International Registry of Acute Aortic Dissection have suggested that the risk of acute aortic dissection during pregnancy is about 0.2%.1 Despite this low prevalence, it should be noted that 50% of aortic dissections in women younger than 40 years occur in the setting of pregnancy.

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Hemoptysis in a Patient With Persistent Left Upper Lobe Consolidation

Hemoptysis in a Patient With Persistent Left Upper Lobe Consolidation: A 35-YEAR-OLD man (weight 67 kg, height 169.9 cm), with a history of cough, dyspnea on exertion, and hemoptysis of 90 days' duration, presented to the authors' institution for further evaluation. Eight months before his presentation, he underwent radiofrequency catheter ablation for paroxysmal atrial fibrillation. About 5 months after the procedure, he was admitted to the hospital in respiratory distress with dyspnea and hemoptysis. Thoracic computed tomography showed left upper lobe consolidation (Fig 1).

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Preoperative fasting in children

Preoperative fasting in children: 1A012A033J03


Key points

Prolonged preoperative fasting times for healthy elective cases have been extrapolated from the aspiration risk of 'full-stomach' emergency cases.

Gastric emptying is regulated by hormonal, neuronal, and metabolic feedback.

Residual gastric volume is a poor surrogate for the risk of aspiration, and there appears to be no causal link or critical volume threshold.

Perioperative pulmonary aspiration in children is rare. The incidence is 0.07–0.1% and the consequences of clear fluid aspiration are not catastrophic.



Newer liberal paediatric fasting regimens for elective cases seem to confer no increase in aspiration risk compared with more conservative regimens.

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