Antiviral Therapy Reduces Hepatocellular Carcinoma Recurrence in Patients With Low HBV-DNA Levels: A Randomized Controlled Trial

Background: Despite antiviral treatment has been shown to reduce hepatocellular carcinoma (HCC) recurrence after curative treatment for hepatitis B virus (HBV)-related HCC in patients with high preoperative HBV-DNA levels, it is still unclear whether antiviral therapy is useful in reducing recurrence in patients with low preoperative HBV-DNA levels. Methods: In this randomized controlled trial, 200 patients who underwent curative resection for HCC with low baseline HBV-DNA levels were randomly assigned to receive preemptive antiviral therapy or not. The primary endpoints were recurrence-free survival. This study was censored on March 31, 2015 when all surviving patients had a minimum follow-up of 60 months. The analysis was done on an intention-to-treat basis. Results: The baseline clinical, laboratory, and tumor characteristics of the 2 groups were comparable. The 1-, 3-, and 5-year recurrence-free survival rates for the antiviral group and the control group were 85.9%, 55.2%, and 52.0% and 80.6%, 40.9%, and 32.3%, respectively. The corresponding overall survival rates for the 2 groups were 94.0%, 75.7%, and 64.1% and 90.0%, 62.4%, and 43.7%, respectively. The recurrence-free survival and overall survival for the antiviral group were significantly better than the control group (P = 0.016, P = 0.004, respectively). After adjusting for confounding prognostic factors in a Cox model, the relative risks of recurrence and death for antiviral treatment were 0.601 [95% confidence interval (CI), 0.409–0.884; P = 0.010] and 0.509 (95% CI, 0.333–0.778; P = 0.002), respectively. Antiviral therapy was an independent protective factor of late tumor recurrence (hazard ratio [HR] = 0.316, 95% CI 0.157–0.637; P = 0.001) but not of early tumor recurrence (HR = 0.782, 95% CI, 0.493–1.240; P = 0.296). Conclusions: In patients with low preoperative HBV-DNA levels, antiviral therapy significantly reduced HCC recurrence after R0 hepatic resection.

https://ift.tt/2qDByYZ

Functional Trajectories Before and After Major Surgery in Older Adults

Objectives: We hypothesized that distinct sets of functional trajectories can be identified in the year before and after major surgery, with unique transition probabilities from pre to postsurgical functional trajectories, and that outcomes would be better among participants undergoing elective versus nonelective surgery. Background: Major surgery is common and can be highly morbid in older persons. The relationship between the course of disability (ie, functional trajectory) before and after surgery in older adults has not been well-studied for most operations. Methods: Prospective cohort study of 754 community-living persons 70 years or older. The analytic sample included 250 participants who underwent their first major surgery during the study period. Results: Before surgery, 4 functional trajectories were identified: no disability (n = 60, 24.0%), and mild (n = 84, 33.6%), moderate (n = 73, 29.2%), and severe (n = 33, 13.2%) disability. After surgery, 4 functional trajectories were identified: rapid (n = 39, 15.6%), gradual (n = 76, 30.4%), partial (n = 70, 28.0%), and little (n = 57, 22.8%) improvement. Rapid improvement was seen for n = 31 (51.7%) participants with no disability before surgery, but was uncommon among those with mild disability (n = 8, 9.5%) and was not observed in the moderate and severe trajectory groups. For participants with mild to moderate disability before surgery, gradual improvement (n = 46, 54.8%) and partial improvement (n = 36, 49.3%) were most common. Most participants with severe disability (n = 27, 81.8%) before surgery exhibited little improvement. Outcomes were better for participants undergoing elective versus nonelective surgery. Conclusions: Functional prognosis in the year after major surgery is highly dependent on premorbid function.

https://ift.tt/2QyE3XO

Extraction of oil from high‐moisture tuna liver by subcritical dimethyl ether: a comparison with different extraction methods

Abstract

Tuna liver, which is currently discarded in fish industry, is a valuable source of marine oil rich in n‐3 polyunsaturated fatty acids (PUFAs), vitamin A and vitamin D. In this study, subcritical dimethyl ether extraction (SDEE) was applied in the extraction of oil from high‐moisture tuna liver. Besides, other different extraction methods including wet reduction (WR), enzymatic extraction (EE), and supercritical carbon dioxide fluid extraction (SFE‐CO₂) were used for comparisons, to assess the effect of different extraction methods on yield, oil quality, flavour (volatile compounds and sensory assessing), vitamin contents and fatty acids composition. Compared with traditional methods, the high‐quality liver oil could be obtained with excellent yields by SDEE and SFE‐CO₂, because they could prevent the oxidation of lipids, and, reduce the damage of PUFAs and vitamins effectively. Besides, only minor differences in volatile compounds and vitamins contents were observed between SDEE‐oil and SFE‐CO₂‐oil, which was attributed to the differences in solubility to the solvents used. The oil with higher contents of vitamin A and α‐vitamin E could be obtained by SDEE. The main limitations of SFE‐CO₂ were energy‐consuming due to high pressure used and the necessary pretreatment of freeze‐drying. However, these drawbacks could be overcome in SDEE because the pressure employed in SDEE was quite low (0.8 MPa) and the freeze‐drying was unnecessary. Therefore, SDEE would be a simple, effective and promising technique to obtain the high quality oil rich in n‐3 PUFAs and vitamins in fish oil industry.

Practical Applications: Subcritical dimethyl ether extraction (SDEE) was a rising technology in oil extraction. It could extract oil from the high‐moisture materials without freeze‐drying under relative low pressure. As we know, freeze‐drying is a necessary pre‐processing in ordinary sub‐ and super‐ critical fluid extraction. The high quality of oil could be obtained by SDEE, similar with the quality of the oil obtained by supercritical fluid extraction, with dramatically declined operational costs.

https://ift.tt/2ScCNu7

Evolution of safety and other quality parameters of the Greek PDO table olives ‘Prasines Elies Chalkidikis’ during industrial scale processing and storage

Abstract

The evolution of safety and other quality parameters of the Greek green table olives PDO 'Prasines Elies Chalkidikis' that are prepared according to the Spanish style processing was examined systematically at industrial scale and 12 month storage for two consecutive periods for the first time. Evolution of safety parameters (bacteria/yeasts, pH, acidity) during fermentation in brine and on olives upon storage, changes in olive color and texture during storage and the fate of characteristic hydrophilic and hydrophobic antioxidants (oleuropein, ligstroside and related compounds, ****tocopherol, squalene and sodium content were monitored using appropriate methods. Sensory scores were also provided in certain cases. Findings supported that the final product is microbiologically safe and except of trade quality parameters that were satisfied, attention should be paid to the reduction in phenolic compounds (hydroxytyrosol, tyrosol) content and the important increase in sodium content due to fermentation and storage in brine. This prototype model study indicates loopholes in the efforts to establish table olives as a functional food.

Practical applications: Industry has to compromise legal safety and nutritional aspects with traditional processing and storage conditions that are applied in PDO table olive production, considering also intrinsic cultivar characteristics of the drupes. Policy makers, regulatory bodies, IOC, and the industry may profit from the substantiation provided by the results of this two year study

https://ift.tt/2DSN3Vh

Rare case of low-grade extranodal NK/T-cell lymphoma, nasal type, arising in the setting of chronic rhinosinusitis and harboring a novel N-terminal KIT mutation

Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT), is a rare aggressive subtype of non-Hodgkin lymphoma characterized by angioinvasion, angiodestruction, necrosis and strong association with Epstein-Barr v...

https://ift.tt/2DDv8Rv

Prevalence and Associated Phenotypes of PLXNA1 Variants in Normosmic and Anosmic Idiopathic Hypogonadotropic Hypogonadism

Idiopathic Hypogonadotropic Hypogonadism (IHH) can be divided into two major forms, normosmic IHH and Kallmann syndrome (KS). Genetic mutations are responsible for the majority of IHH. PLXNA1 has recently been implicated in the GnRH neuron migration and the etiology of KS. We aimed to investigate the prevalence and associated phenotypes of PLXNA1 variants in a large cohort of IHH patients. We screened the whole exome data of 215 IHH patients in a single center for causative PLXNA1 variants. Our studies revealed eight novel (p.Arg836His, p.Lys1451Arg, p.Val287Met, p.Val536Ile, p.Ser1850Arg, p.Ile1701Val, p.Arg319Trp, and p.Pro485Leu) and two previously described (p.Arg528Trp and p.Gly720Glu) heterozygous PLXNA1 variants in 9 affected individuals from 7 unrelated families. Only three of nine patients were anosmic (KS) while the remaining patients showed normal olfactory function (nIHH). Seven of nine patients (77.7%) harbored additional one or two variants in other nIHH/KS‐associated genes, including PROKR2, IGSF10, HS6ST1, SEMA3E, CCDC141, FGFR1, NRP1, POLR3A, and SRA1. Our findings indicate that PLXNA1 variants cause not only anosmic but also normosmic IHH with a relatively high prevalence (3.9%). Heterozygous missense PLXNA1 variants appear to be involved together with other IHH gene variants in bringing about the IHH disease phenotype.

This article is protected by copyright. All rights reserved.

https://ift.tt/2TFmWFZ

Long noncoding RNAs as biotargets in cisplatin-based drug resistance

Future Oncology, Ahead of Print.


https://ift.tt/2S76Nrd

Use and costs of originator and biosimilar erythropoiesis-stimulating agents in the treatment of chemotherapy-induced anemia: real-world evidence from an Italian hospital

Future Oncology, Ahead of Print.


https://ift.tt/2DUnZ06

Microbial virulence, molecular epidemiology and pathogenic factors of fluoroquinolone-resistant Haemophilus influenzae infections in Guangzhou, China

Fluoroquinolone-resistant Haemophilus influenzae (FRHI) has been reported worldwide but remain unclear in China.

https://ift.tt/2QfYyvv

Decoding Gestural Iconicity

Abstract

Speakers frequently perform representational gestures to depict concepts in an iconic fashion. For example, a speaker may hold her index finger and thumb apart to indicate the size of a matchstick. However, the process by which a physical handshape is mentally transformed into abstract spatial information is not well understood. We present a series of experiments that investigate how people decode the physical form of an articulator to derive imaginary geometrical constructs, which we call "gesture form." We provide quantitative evidence for several key properties that play a role in this process. First, "profiling," the ability to focus on a structural subunit within the complex form of the physical hand. Second, "perspective," for which we show that one and the same handshape seen from different perspectives can lead to different spatial interpretations. Third, "selectivity," the fact that gestures focus on specific spatial features at the expense of others. Our results provide a first step toward mapping out the process of how representational gestures make the communication of spatial information possible.

https://ift.tt/2Kri178

Hedgehog signaling regulates cell motility and optic fissure and stalk formation during vertebrate eye morphogenesis [RESEARCH ARTICLE]

Hannah B. Gordon, Sarah Lusk, Keith R. Carney, Emily O. Wirick, Brooke Froelich Murray, and Kristen M. Kwan

Establishment of precise three-dimensional tissue structure is vital for organ function. In the visual system, optic fissure and stalk morphogenesis is a crucial yet poorly understood process, disruptions of which can lead to coloboma, a birth defect causing visual impairment. Here, we use four-dimensional imaging, cell tracking, and molecular genetics in zebrafish to define the cell movements underlying normal optic fissure and stalk formation. We determine how these events are disrupted in a coloboma model in which the Hedgehog (Hh) receptor ptch2 is lost, resulting in overactive Hh signaling. In the ptch2 mutant, cells exhibit defective motile behaviors and morphology. Cells that should contribute to the fissure do not arrive at their correct position, and instead contribute to an ectopically large optic stalk. Our results suggest that overactive Hh signaling, through overexpression of downstream transcriptional targets, impairs cell motility underlying optic fissure and stalk formation, via non-cell-autonomous and cell-autonomous mechanisms. More broadly, our cell motility and morphology analyses provide a new framework for studying other coloboma-causing mutations that disrupt optic fissure or stalk formation.

https://ift.tt/2DKDjeX

Left-right asymmetry in heart development and disease: forming the right loop [REVIEW]

Audrey Desgrange, Jean-Francois Le Garrec, and Sigolene M. Meilhac

Extensive studies have shown how bilateral symmetry of the vertebrate embryo is broken during early development, resulting in a molecular left-right bias in the mesoderm. However, how this early asymmetry drives the asymmetric morphogenesis of visceral organs remains poorly understood. The heart provides a striking model of left-right asymmetric morphogenesis, undergoing rightward looping to shape an initially linear heart tube and align cardiac chambers. Importantly, abnormal left-right patterning is associated with severe congenital heart defects, as exemplified in heterotaxy syndrome. Here, we compare the mechanisms underlying the rightward looping of the heart tube in fish, chick and mouse embryos. We propose that heart looping is not only a question of direction, but also one of fine-tuning shape. This is discussed in the context of evolutionary and clinical perspectives.

https://ift.tt/2Qi1XKr

Distinct cis-acting elements mediate targeting and clustering of Drosophila polar granule mRNAs [RESEARCH ARTICLE]

Whitby V. I. Eagle, Daniel K. Yeboah-Kordieh, Matthew G. Niepielko, and Elizabeth R. Gavis

Specification and development of Drosophila germ cells depend on molecular determinants within the germ plasm, a specialized cytoplasmic domain at the posterior of the embryo. Localization of numerous mRNAs to the germ plasm occurs by their incorporation, as single-transcript ribonucleoprotein (RNP) particles, into complex RNP granules called polar granules. Incorporation of mRNAs into polar granules is followed by recruitment of additional like transcripts to form discrete homotypic clusters. The cis-acting localization signals that target mRNAs to polar granules and promote homotypic clustering remain largely uncharacterized. Here, we show that the polar granule component (pgc) and germ cell-less (gcl) 3' untranslated regions contain complex localization signals comprising multiple, independently weak and partially functionally redundant localization elements (LEs). We demonstrate that targeting of pgc to polar granules and self-assembly into homotypic clusters are functionally separable processes mediated by distinct classes of LEs. We identify a sequence motif shared by other polar granule mRNAs that contributes to homotypic clustering. Our results suggest that mRNA localization signal complexity may be a feature required by the targeting and self-recruitment mechanism that drives germ plasm mRNA localization.

https://ift.tt/2DH2izw

The Hippo pathway effector Taz is required for cell morphogenesis and fertilization in zebrafish [RESEARCH ARTICLE]

Chaitanya Dingare, Alina Niedzwetzki, Petra A. Klemmt, Svenja Godbersen, Ricardo Fuentes, Mary C. Mullins, and Virginie Lecaudey

Hippo signaling is a critical pathway that integrates extrinsic and intrinsic mechanical cues to regulate organ size. Despite its essential role in organogenesis, little is known about its role in cell fate specification and differentiation. Here, we unravel a novel and unexpected role of the Hippo pathway effector Taz (wwtr1) in controlling the size, shape and fate of a unique cell in the zebrafish ovary. We show that wwtr1 mutant females are infertile. In teleosts, fertilization occurs through the micropyle, a funnel-like opening in the chorion, formed by a unique enlarged follicle cell, the micropylar cell (MC). We describe here, for the first time, the mechanism that underlies the differentiation of the MC. Our genetic analyses show that Taz is essential for MC fate acquisition and subsequent micropyle formation in zebrafish. We identify Taz as the first bona fide MC marker and show that Taz is specifically and strongly enriched in the MC precursor. Altogether, we performed the first genetic and molecular characterization of the MC and propose that Taz is a key regulator of MC fate.

This article has an associated 'The people behind the papers' interview.

https://ift.tt/2Qf6pcQ

Hey2 regulates the size of the cardiac progenitor pool during vertebrate heart development [RESEARCH ARTICLE]

Natalie Gibb, Savo Lazic, Xuefei Yuan, Ashish R. Deshwar, Meaghan Leslie, Michael D. Wilson, and Ian C. Scott

A key event in heart development is the timely addition of cardiac progenitor cells, defects in which can lead to congenital heart defects. However, how the balance and proportion of progenitor proliferation versus addition to the heart is regulated remains poorly understood. Here, we demonstrate that Hey2 functions to regulate the dynamics of cardiac progenitor addition to the zebrafish heart. We found that the previously noted increase in myocardial cell number found in the absence of Hey2 function was due to a pronounced expansion in the size of the cardiac progenitor pool. Expression analysis and lineage tracing of hey2-expressing cells showed that hey2 is active in cardiac progenitors. Hey2 acted to limit proliferation of cardiac progenitors, prior to heart tube formation. Use of a transplantation approach demonstrated a likely cell-autonomous (in cardiac progenitors) function for Hey2. Taken together, our data suggest a previously unappreciated role for Hey2 in controlling the proliferative capacity of cardiac progenitors, affecting the subsequent contribution of late-differentiating cardiac progenitors to the developing vertebrate heart.

https://ift.tt/2DDMm0S

The Ric-8A/G{alpha}13/FAK signalling cascade controls focal adhesion formation during neural crest cell migration in Xenopus [RESEARCH ARTICLE]

Gabriela Toro-Tapia, Soraya Villaseca, Andrea Beyer, Alice Roycroft, Sylvain Marcellini, Roberto Mayor, and Marcela Torrejon

Ric-8A is a pleiotropic guanine nucleotide exchange factor involved in the activation of various heterotrimeric G-protein pathways during adulthood and early development. Here, we sought to determine the downstream effectors of Ric-8A during the migration of the vertebrate cranial neural crest (NC) cells. We show that the Gα13 knockdown phenocopies the Ric-8A morphant condition, causing actin cytoskeleton alteration, protrusion instability, and a strong reduction in the number and dynamics of focal adhesions. In addition, the overexpression of Gα13 is sufficient to rescue Ric-8A-depleted cells. Ric-8A and Gα13 physically interact and colocalize in protrusions of the cells leading edge. The focal adhesion kinase FAK colocalizes and interacts with the endogenous Gα13, and a constitutively active form of Src efficiently rescues the Gα13 morphant phenotype in NC cells. We propose that Ric-8A-mediated Gα13 signalling is required for proper cranial NC cell migration by regulating focal adhesion dynamics and protrusion formation.

https://ift.tt/2Qi1R5x

Exploring landscapes of brain morphogenesis with organoids [SPOTLIGHT]

Denis Jabaudon and Madeline Lancaster

The field of developmental neuroscience is benefitting from recent technological advances that allow access to organogenesis in vitro via organoid preparations. These methods have been applied to better understanding neural identity, and have opened up a window into the early events that occur during development of the human brain. However, current approaches are not without their limitations, and although brain organoids and other in vitro paradigms recapitulate many processes with remarkable fidelity, there are clear differences between brain organoid development in vitro and brain development in vivo. These topics were discussed extensively at a recent workshop organized by The Company of Biologists entitled 'Thinking beyond the dish: taking in vitro neural differentiation to the next level'. Here, we summarize the common themes that emerged from the workshop and highlight some of the limitations and the potential of this emerging technology. In particular, we discuss how organoids can help us understand not only healthy and diseased brain, but also explore new arrays of cellular behaviors.

https://ift.tt/2DH2ij0

N-linked glycosylation restricts the function of Short gastrulation to bind and shuttle BMPs [RESEARCH ARTICLE]

Erika Negreiros, Sophie Herszterg, Kyung-Hwa Kang, Amanda Camara, Wagner B. Dias, Katia Carneiro, Ethan Bier, Adriane Regina Todeschini, and Helena Araujo

Disorders of N-linked glycosylation are increasingly reported in the literature. However, the targets that are responsible for the associated developmental and physiological defects are largely unknown. Bone morphogenetic proteins (BMPs) act as highly dynamic complexes to regulate several functions during development. The range and strength of BMP activity depend on interactions with glycosylated protein complexes in the extracellular milieu. Here, we investigate the role of glycosylation for the function of the conserved extracellular BMP antagonist Short gastrulation (Sog). We identify conserved N-glycosylated sites and describe the effect of mutating these residues on BMP pathway activity in Drosophila. Functional analysis reveals that loss of individual Sog glycosylation sites enhances BMP antagonism and/or increases the spatial range of Sog effects in the tissue. Mechanistically, we provide evidence that N-terminal and stem glycosylation controls extracellular Sog levels and distribution. The identification of similar residues in vertebrate Chordin proteins suggests that N-glycosylation may be an evolutionarily conserved process that adds complexity to the regulation of BMP activity.

https://ift.tt/2Qh16JU

TWE-PRIL reverse signalling suppresses sympathetic axon growth and tissue innervation [RESEARCH ARTICLE]

Laura Howard, Erin Wosnitzka, Darian Okakpu, Matthew A. White, Sean Wyatt, and Alun M. Davies

TWE-PRIL is a naturally occurring fusion protein of components of two TNF superfamily members: the extracellular domain of APRIL; and the intracellular and transmembrane domains of TWEAK with no known function. Here, we show that April^–/– mice (which lack APRIL and TWE-PRIL) exhibited overgrowth of sympathetic fibres in vivo, and sympathetic neurons cultured from these mice had significantly longer axons than neurons cultured from wild-type littermates. Enhanced axon growth from sympathetic neurons cultured from April^–/– mice was prevented by expressing full-length TWE-PRIL in these neurons but not by treating them with soluble APRIL. Soluble APRIL, however, enhanced axon growth from the sympathetic neurons of wild-type mice. siRNA knockdown of TWE-PRIL but not siRNA knockdown of APRIL alone also enhanced axon growth from wild-type sympathetic neurons. Our work reveals the first and physiologically relevant role for TWE-PRIL and suggests that it mediates reverse signalling.

https://ift.tt/2Qi1NTl

Basal epithelial tissue folding is mediated by differential regulation of microtubules [RESEARCH ARTICLE]

Mike R. Visetsouk, Elizabeth J. Falat, Ryan J. Garde, Jennifer L. Wendlick, and Jennifer H. Gutzman

The folding of epithelial tissues is crucial for development of three-dimensional structure and function. Understanding this process can assist in determining the etiology of developmental disease and engineering of tissues for the future of regenerative medicine. Folding of epithelial tissues towards the apical surface has long been studied, but the molecular mechanisms that mediate epithelial folding towards the basal surface are just emerging. Here, we utilize zebrafish neuroepithelium to identify mechanisms that mediate basal tissue folding to form the highly conserved embryonic midbrain-hindbrain boundary. Live imaging revealed Wnt5b as a mediator of anisotropic epithelial cell shape, both apically and basally. In addition, we uncovered a Wnt5b-mediated mechanism for specific regulation of basal anisotropic cell shape that is microtubule dependent and likely to involve JNK signaling. We propose a model in which a single morphogen can differentially regulate apical versus basal cell shape during tissue morphogenesis.

https://ift.tt/2DJQFHY

Vangl2-dependent regulation of membrane protrusions and directed migration requires a fibronectin extracellular matrix [RESEARCH ARTICLE]

Anna M. Love, Dianna J. Prince, and Jason R. Jessen

During zebrafish gastrulation the planar cell polarity (PCP) protein Vang-like 2 (Vangl2) regulates the polarization of cells that are engaged in directed migration. However, it is unclear whether Vangl2 influences membrane-protrusive activities in migrating gastrula cells and whether these processes require the fibronectin extracellular matrix. Here, we report that Vangl2 modulates the formation and polarization of actin-rich filopodia-like and large lamellipodia-like protrusions in ectodermal cells. By contrast, disrupted Glypican4/PCP signaling affects protrusion polarity but not protrusion number or directed migration. Analysis of fluorescent fusion protein expression suggests that there is widespread Vangl2 symmetry in migrating cells, but there is enrichment at membrane domains that are developing large protrusions compared with non-protrusive domains. We show that the fibronectin extracellular matrix is essential for cell-surface Vangl2 expression, membrane-protrusive activity and directed migration. Manipulation of fibronectin protein levels rescues protrusion and directed migration phenotypes in vangl2 mutant embryos, but it is not sufficient to restore either PCP, or convergence and extension movements. Together, our findings identify distinct roles for Vangl2 and Glypican4/PCP signaling during membrane protrusion formation and demonstrate that cell-matrix interactions underlie Vangl2-dependent regulation of protrusive activities in migrating gastrula cells.

https://ift.tt/2DFTrOB

Inhibition of cell fate repressors secures the differentiation of the touch receptor neurons of Caenorhabditis elegans [RESEARCH ARTICLE]

Chaogu Zheng, Felix Qiaochu Jin, Brian Loeber Trippe, Ji Wu, and Martin Chalfie

Terminal differentiation generates the specialized features and functions that allow postmitotic cells to acquire their distinguishing characteristics. This process is thought to be controlled by transcription factors called 'terminal selectors' that directly activate a set of downstream effector genes. In Caenorhabditis elegans, the differentiation of both the mechanosensory touch receptor neurons (TRNs) and the multidendritic nociceptor FLP neurons uses the terminal selectors UNC-86 and MEC-3. The FLP neurons fail to activate TRN genes, however, because a complex of two transcriptional repressors (EGL-44/EGL-46) prevents their expression. Here, we show that the ZEB family transcriptional factor ZAG-1 promotes TRN differentiation not by activating TRN genes but by preventing the expression of EGL-44/EGL-46. As EGL-44/EGL-46 also inhibits the production of ZAG-1, these proteins form a bistable, negative-feedback loop that regulates the choice between the two neuronal fates.

https://ift.tt/2QfUAD7

Prp8 regulates oncogene-induced hyperplastic growth in Drosophila [RESEARCH ARTICLE]

Cecilia H. Fernandez-Espartero, Alberto Rizzo, Alexander D. Fulford, Julia Falo-Sanjuan, Damien Goutte-Gattat, and Paulo S. Ribeiro

Although developmental signalling pathways control tumourigenic growth, the cellular mechanisms that abnormally proliferating cells rely on are still largely unknown. Drosophila melanogaster is a genetically tractable model that is used to study how specific genetic changes confer advantageous tumourigenic traits. Despite recent efforts, the role of deubiquitylating enzymes in cancer is particularly understudied. We performed a Drosophila in vivo RNAi screen to identify deubiquitylating enzymes that modulate Ras^V12-induced hyperplastic growth. We identified the spliceosome core component Prp8 as a crucial regulator of Ras-, EGFR-, Notch- or RET-driven hyperplasia. Loss of prp8 function alone decreased cell proliferation, increased cell death, and affected cell differentiation and polarity. In hyperplasia, Prp8 supported tissue overgrowth independently of caspase-dependent cell death. The depletion of prp8 efficiently blocked Ras-, EGFR- and Notch-driven tumours but, in contrast, enhanced tumours that were driven by oncogenic RET, suggesting a context-specific role in hyperplasia. These data show, for the first time, that Prp8 regulates hyperplasia, and extend recent observations on the potential role of the spliceosome in cancer. Our findings suggest that targeting Prp8 could be beneficial in specific tumour types.

https://ift.tt/2Qja2yp

Left-right asymmetry in heart development and disease: forming the right loop [REVIEW]

Audrey Desgrange, Jean-Francois Le Garrec, and Sigolene M. Meilhac

Extensive studies have shown how bilateral symmetry of the vertebrate embryo is broken during early development, resulting in a molecular left-right bias in the mesoderm. However, how this early asymmetry drives the asymmetric morphogenesis of visceral organs remains poorly understood. The heart provides a striking model of left-right asymmetric morphogenesis, undergoing rightward looping to shape an initially linear heart tube and align cardiac chambers. Importantly, abnormal left-right patterning is associated with severe congenital heart defects, as exemplified in heterotaxy syndrome. Here, we compare the mechanisms underlying the rightward looping of the heart tube in fish, chick and mouse embryos. We propose that heart looping is not only a question of direction, but also one of fine-tuning shape. This is discussed in the context of evolutionary and clinical perspectives.

https://ift.tt/2Qi1XKr

Distinct cis-acting elements mediate targeting and clustering of Drosophila polar granule mRNAs [RESEARCH ARTICLE]

Whitby V. I. Eagle, Daniel K. Yeboah-Kordieh, Matthew G. Niepielko, and Elizabeth R. Gavis

Specification and development of Drosophila germ cells depend on molecular determinants within the germ plasm, a specialized cytoplasmic domain at the posterior of the embryo. Localization of numerous mRNAs to the germ plasm occurs by their incorporation, as single-transcript ribonucleoprotein (RNP) particles, into complex RNP granules called polar granules. Incorporation of mRNAs into polar granules is followed by recruitment of additional like transcripts to form discrete homotypic clusters. The cis-acting localization signals that target mRNAs to polar granules and promote homotypic clustering remain largely uncharacterized. Here, we show that the polar granule component (pgc) and germ cell-less (gcl) 3' untranslated regions contain complex localization signals comprising multiple, independently weak and partially functionally redundant localization elements (LEs). We demonstrate that targeting of pgc to polar granules and self-assembly into homotypic clusters are functionally separable processes mediated by distinct classes of LEs. We identify a sequence motif shared by other polar granule mRNAs that contributes to homotypic clustering. Our results suggest that mRNA localization signal complexity may be a feature required by the targeting and self-recruitment mechanism that drives germ plasm mRNA localization.

https://ift.tt/2DH2izw

The Hippo pathway effector Taz is required for cell morphogenesis and fertilization in zebrafish [RESEARCH ARTICLE]

Chaitanya Dingare, Alina Niedzwetzki, Petra A. Klemmt, Svenja Godbersen, Ricardo Fuentes, Mary C. Mullins, and Virginie Lecaudey

Hippo signaling is a critical pathway that integrates extrinsic and intrinsic mechanical cues to regulate organ size. Despite its essential role in organogenesis, little is known about its role in cell fate specification and differentiation. Here, we unravel a novel and unexpected role of the Hippo pathway effector Taz (wwtr1) in controlling the size, shape and fate of a unique cell in the zebrafish ovary. We show that wwtr1 mutant females are infertile. In teleosts, fertilization occurs through the micropyle, a funnel-like opening in the chorion, formed by a unique enlarged follicle cell, the micropylar cell (MC). We describe here, for the first time, the mechanism that underlies the differentiation of the MC. Our genetic analyses show that Taz is essential for MC fate acquisition and subsequent micropyle formation in zebrafish. We identify Taz as the first bona fide MC marker and show that Taz is specifically and strongly enriched in the MC precursor. Altogether, we performed the first genetic and molecular characterization of the MC and propose that Taz is a key regulator of MC fate.

This article has an associated 'The people behind the papers' interview.

https://ift.tt/2Qf6pcQ

Hey2 regulates the size of the cardiac progenitor pool during vertebrate heart development [RESEARCH ARTICLE]

Natalie Gibb, Savo Lazic, Xuefei Yuan, Ashish R. Deshwar, Meaghan Leslie, Michael D. Wilson, and Ian C. Scott

A key event in heart development is the timely addition of cardiac progenitor cells, defects in which can lead to congenital heart defects. However, how the balance and proportion of progenitor proliferation versus addition to the heart is regulated remains poorly understood. Here, we demonstrate that Hey2 functions to regulate the dynamics of cardiac progenitor addition to the zebrafish heart. We found that the previously noted increase in myocardial cell number found in the absence of Hey2 function was due to a pronounced expansion in the size of the cardiac progenitor pool. Expression analysis and lineage tracing of hey2-expressing cells showed that hey2 is active in cardiac progenitors. Hey2 acted to limit proliferation of cardiac progenitors, prior to heart tube formation. Use of a transplantation approach demonstrated a likely cell-autonomous (in cardiac progenitors) function for Hey2. Taken together, our data suggest a previously unappreciated role for Hey2 in controlling the proliferative capacity of cardiac progenitors, affecting the subsequent contribution of late-differentiating cardiac progenitors to the developing vertebrate heart.

https://ift.tt/2DDMm0S

The Ric-8A/G{alpha}13/FAK signalling cascade controls focal adhesion formation during neural crest cell migration in Xenopus [RESEARCH ARTICLE]

Gabriela Toro-Tapia, Soraya Villaseca, Andrea Beyer, Alice Roycroft, Sylvain Marcellini, Roberto Mayor, and Marcela Torrejon

Ric-8A is a pleiotropic guanine nucleotide exchange factor involved in the activation of various heterotrimeric G-protein pathways during adulthood and early development. Here, we sought to determine the downstream effectors of Ric-8A during the migration of the vertebrate cranial neural crest (NC) cells. We show that the Gα13 knockdown phenocopies the Ric-8A morphant condition, causing actin cytoskeleton alteration, protrusion instability, and a strong reduction in the number and dynamics of focal adhesions. In addition, the overexpression of Gα13 is sufficient to rescue Ric-8A-depleted cells. Ric-8A and Gα13 physically interact and colocalize in protrusions of the cells leading edge. The focal adhesion kinase FAK colocalizes and interacts with the endogenous Gα13, and a constitutively active form of Src efficiently rescues the Gα13 morphant phenotype in NC cells. We propose that Ric-8A-mediated Gα13 signalling is required for proper cranial NC cell migration by regulating focal adhesion dynamics and protrusion formation.

https://ift.tt/2Qi1R5x

Exploring landscapes of brain morphogenesis with organoids [SPOTLIGHT]

Denis Jabaudon and Madeline Lancaster

The field of developmental neuroscience is benefitting from recent technological advances that allow access to organogenesis in vitro via organoid preparations. These methods have been applied to better understanding neural identity, and have opened up a window into the early events that occur during development of the human brain. However, current approaches are not without their limitations, and although brain organoids and other in vitro paradigms recapitulate many processes with remarkable fidelity, there are clear differences between brain organoid development in vitro and brain development in vivo. These topics were discussed extensively at a recent workshop organized by The Company of Biologists entitled 'Thinking beyond the dish: taking in vitro neural differentiation to the next level'. Here, we summarize the common themes that emerged from the workshop and highlight some of the limitations and the potential of this emerging technology. In particular, we discuss how organoids can help us understand not only healthy and diseased brain, but also explore new arrays of cellular behaviors.

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N-linked glycosylation restricts the function of Short gastrulation to bind and shuttle BMPs [RESEARCH ARTICLE]

Erika Negreiros, Sophie Herszterg, Kyung-Hwa Kang, Amanda Camara, Wagner B. Dias, Katia Carneiro, Ethan Bier, Adriane Regina Todeschini, and Helena Araujo

Disorders of N-linked glycosylation are increasingly reported in the literature. However, the targets that are responsible for the associated developmental and physiological defects are largely unknown. Bone morphogenetic proteins (BMPs) act as highly dynamic complexes to regulate several functions during development. The range and strength of BMP activity depend on interactions with glycosylated protein complexes in the extracellular milieu. Here, we investigate the role of glycosylation for the function of the conserved extracellular BMP antagonist Short gastrulation (Sog). We identify conserved N-glycosylated sites and describe the effect of mutating these residues on BMP pathway activity in Drosophila. Functional analysis reveals that loss of individual Sog glycosylation sites enhances BMP antagonism and/or increases the spatial range of Sog effects in the tissue. Mechanistically, we provide evidence that N-terminal and stem glycosylation controls extracellular Sog levels and distribution. The identification of similar residues in vertebrate Chordin proteins suggests that N-glycosylation may be an evolutionarily conserved process that adds complexity to the regulation of BMP activity.

https://ift.tt/2Qh16JU

Hedgehog signaling regulates cell motility and optic fissure and stalk formation during vertebrate eye morphogenesis [RESEARCH ARTICLE]

Hannah B. Gordon, Sarah Lusk, Keith R. Carney, Emily O. Wirick, Brooke Froelich Murray, and Kristen M. Kwan

Establishment of precise three-dimensional tissue structure is vital for organ function. In the visual system, optic fissure and stalk morphogenesis is a crucial yet poorly understood process, disruptions of which can lead to coloboma, a birth defect causing visual impairment. Here, we use four-dimensional imaging, cell tracking, and molecular genetics in zebrafish to define the cell movements underlying normal optic fissure and stalk formation. We determine how these events are disrupted in a coloboma model in which the Hedgehog (Hh) receptor ptch2 is lost, resulting in overactive Hh signaling. In the ptch2 mutant, cells exhibit defective motile behaviors and morphology. Cells that should contribute to the fissure do not arrive at their correct position, and instead contribute to an ectopically large optic stalk. Our results suggest that overactive Hh signaling, through overexpression of downstream transcriptional targets, impairs cell motility underlying optic fissure and stalk formation, via non-cell-autonomous and cell-autonomous mechanisms. More broadly, our cell motility and morphology analyses provide a new framework for studying other coloboma-causing mutations that disrupt optic fissure or stalk formation.

https://ift.tt/2DKDjeX

TWE-PRIL reverse signalling suppresses sympathetic axon growth and tissue innervation [RESEARCH ARTICLE]

Laura Howard, Erin Wosnitzka, Darian Okakpu, Matthew A. White, Sean Wyatt, and Alun M. Davies

TWE-PRIL is a naturally occurring fusion protein of components of two TNF superfamily members: the extracellular domain of APRIL; and the intracellular and transmembrane domains of TWEAK with no known function. Here, we show that April^–/– mice (which lack APRIL and TWE-PRIL) exhibited overgrowth of sympathetic fibres in vivo, and sympathetic neurons cultured from these mice had significantly longer axons than neurons cultured from wild-type littermates. Enhanced axon growth from sympathetic neurons cultured from April^–/– mice was prevented by expressing full-length TWE-PRIL in these neurons but not by treating them with soluble APRIL. Soluble APRIL, however, enhanced axon growth from the sympathetic neurons of wild-type mice. siRNA knockdown of TWE-PRIL but not siRNA knockdown of APRIL alone also enhanced axon growth from wild-type sympathetic neurons. Our work reveals the first and physiologically relevant role for TWE-PRIL and suggests that it mediates reverse signalling.

https://ift.tt/2Qi1NTl

Basal epithelial tissue folding is mediated by differential regulation of microtubules [RESEARCH ARTICLE]

Mike R. Visetsouk, Elizabeth J. Falat, Ryan J. Garde, Jennifer L. Wendlick, and Jennifer H. Gutzman

The folding of epithelial tissues is crucial for development of three-dimensional structure and function. Understanding this process can assist in determining the etiology of developmental disease and engineering of tissues for the future of regenerative medicine. Folding of epithelial tissues towards the apical surface has long been studied, but the molecular mechanisms that mediate epithelial folding towards the basal surface are just emerging. Here, we utilize zebrafish neuroepithelium to identify mechanisms that mediate basal tissue folding to form the highly conserved embryonic midbrain-hindbrain boundary. Live imaging revealed Wnt5b as a mediator of anisotropic epithelial cell shape, both apically and basally. In addition, we uncovered a Wnt5b-mediated mechanism for specific regulation of basal anisotropic cell shape that is microtubule dependent and likely to involve JNK signaling. We propose a model in which a single morphogen can differentially regulate apical versus basal cell shape during tissue morphogenesis.

https://ift.tt/2DJQFHY

Inhibition of cell fate repressors secures the differentiation of the touch receptor neurons of Caenorhabditis elegans [RESEARCH ARTICLE]

Chaogu Zheng, Felix Qiaochu Jin, Brian Loeber Trippe, Ji Wu, and Martin Chalfie

Terminal differentiation generates the specialized features and functions that allow postmitotic cells to acquire their distinguishing characteristics. This process is thought to be controlled by transcription factors called 'terminal selectors' that directly activate a set of downstream effector genes. In Caenorhabditis elegans, the differentiation of both the mechanosensory touch receptor neurons (TRNs) and the multidendritic nociceptor FLP neurons uses the terminal selectors UNC-86 and MEC-3. The FLP neurons fail to activate TRN genes, however, because a complex of two transcriptional repressors (EGL-44/EGL-46) prevents their expression. Here, we show that the ZEB family transcriptional factor ZAG-1 promotes TRN differentiation not by activating TRN genes but by preventing the expression of EGL-44/EGL-46. As EGL-44/EGL-46 also inhibits the production of ZAG-1, these proteins form a bistable, negative-feedback loop that regulates the choice between the two neuronal fates.

https://ift.tt/2QfUAD7

Vangl2-dependent regulation of membrane protrusions and directed migration requires a fibronectin extracellular matrix [RESEARCH ARTICLE]

Anna M. Love, Dianna J. Prince, and Jason R. Jessen

During zebrafish gastrulation the planar cell polarity (PCP) protein Vang-like 2 (Vangl2) regulates the polarization of cells that are engaged in directed migration. However, it is unclear whether Vangl2 influences membrane-protrusive activities in migrating gastrula cells and whether these processes require the fibronectin extracellular matrix. Here, we report that Vangl2 modulates the formation and polarization of actin-rich filopodia-like and large lamellipodia-like protrusions in ectodermal cells. By contrast, disrupted Glypican4/PCP signaling affects protrusion polarity but not protrusion number or directed migration. Analysis of fluorescent fusion protein expression suggests that there is widespread Vangl2 symmetry in migrating cells, but there is enrichment at membrane domains that are developing large protrusions compared with non-protrusive domains. We show that the fibronectin extracellular matrix is essential for cell-surface Vangl2 expression, membrane-protrusive activity and directed migration. Manipulation of fibronectin protein levels rescues protrusion and directed migration phenotypes in vangl2 mutant embryos, but it is not sufficient to restore either PCP, or convergence and extension movements. Together, our findings identify distinct roles for Vangl2 and Glypican4/PCP signaling during membrane protrusion formation and demonstrate that cell-matrix interactions underlie Vangl2-dependent regulation of protrusive activities in migrating gastrula cells.

https://ift.tt/2DFTrOB

Prp8 regulates oncogene-induced hyperplastic growth in Drosophila [RESEARCH ARTICLE]

Cecilia H. Fernandez-Espartero, Alberto Rizzo, Alexander D. Fulford, Julia Falo-Sanjuan, Damien Goutte-Gattat, and Paulo S. Ribeiro

Although developmental signalling pathways control tumourigenic growth, the cellular mechanisms that abnormally proliferating cells rely on are still largely unknown. Drosophila melanogaster is a genetically tractable model that is used to study how specific genetic changes confer advantageous tumourigenic traits. Despite recent efforts, the role of deubiquitylating enzymes in cancer is particularly understudied. We performed a Drosophila in vivo RNAi screen to identify deubiquitylating enzymes that modulate Ras^V12-induced hyperplastic growth. We identified the spliceosome core component Prp8 as a crucial regulator of Ras-, EGFR-, Notch- or RET-driven hyperplasia. Loss of prp8 function alone decreased cell proliferation, increased cell death, and affected cell differentiation and polarity. In hyperplasia, Prp8 supported tissue overgrowth independently of caspase-dependent cell death. The depletion of prp8 efficiently blocked Ras-, EGFR- and Notch-driven tumours but, in contrast, enhanced tumours that were driven by oncogenic RET, suggesting a context-specific role in hyperplasia. These data show, for the first time, that Prp8 regulates hyperplasia, and extend recent observations on the potential role of the spliceosome in cancer. Our findings suggest that targeting Prp8 could be beneficial in specific tumour types.

https://ift.tt/2Qja2yp

Authors' response

We thank Dr Webb for his comments on our article (Abdelkarim A, Jerrold L. Clinical considerations and potential liability associated with the use of ionizing radiation in orthodontics. Am J Orthod Dentofacial Orthop 2018;154:15-25). Because his was a very detailed and well-supported opinion, we felt the need to respond in kind. As we mentioned in our original article, we must stress again that there are no legally binding statutes, rules, or regulations that provide explicit radiographic prescription protocols for orthodontic practice.

https://ift.tt/2FCYIcd

Patients' preferences regarding age, sex, and attire of orthodontists

We investigated whether patients in different age groups are influenced by the age, sex, and attire of an orthodontist.

https://ift.tt/2r3099N

Information for readers

https://ift.tt/2FE49b4

Computerized measurement of the location and value of the minimum sagittal linear dimension of the upper airway on reconstructed lateral cephalograms compared with 3-dimensional values

Identifying the location and value of the smallest airway dimension can be useful in screening and planning treatment for patients with obstructive sleep apnea. Our objectives in this study were to (1) objectively identify the vertical location and value of the minimum sagittal linear dimension (MSLD) on 2-dimensional reconstructed lateral cephalograms (RLCs), (2) compare the location and value of the MSLD on RLCs with the vertical location and sagittal dimension of the minimum cross-sectional area (MCSA), and (3) investigate the association between the MSLD on RLCs and both the MCSA and the airway volume.

https://ift.tt/2qYhL6S

Editorial Board

https://ift.tt/2FE46vU

New perspective for evaluation of tooth widths in patients with missing or peg-shaped maxillary lateral incisors: Quadrant analysis

Missing or peg-shaped maxillary lateral incisors can affect the mesiodistal dimensions of the dentition.

https://ift.tt/2r2vXfd

Table of Contents

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Directory: AAO Officers and Organizations

https://ift.tt/2r12fHj

Erratum

Correction to: Paquette DE. In defense of corporate sponsorships and a plea for civility. Am J Orthod Dentofacial Orthop 2018;154:459–460. The author information section should have included the following disclaimer: The author completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving personal fees from Henry Schein Orthodontics and being a Key Opinion Lead for various manufacturers for the past 30 years.

https://ift.tt/2FQpKNJ

Anterior open bite due to temporomandibular joint osteoarthrosis with muscle dysfunction treated with temporary anchorage devices

Skeletal Class II high-angle open bite is often accompanied by osteoarthrosis of the temporomandibular joint (TMJ-OA). This type of malocclusion is challenging to correct, and it has been reported that patients with TMJ-OA treated with orthognathic surgery often experience skeletal relapse and a poor prognosis. This case report describes the treatment of a 25-year-old woman with retrognathia and TMJ-OA, whose masseter and temporal muscle activities were weak. Temporary anchorage devices were placed in the maxilla and the mandible, and the first molars were intruded.

https://ift.tt/2r4iJ1w

When the patient is his own doctor …

Your housepainter, Fred, is almost a member of the family. He's known you for more than 2 decades, after painting and wallpapering your then brand new home. You've always wanted to take care of Fred's conspicuous malocclusion. Resolution of his crowding would not only enhance his appearance but would greatly simplify his home care. But Fred is a proud man, and has declined your treatment offers, regardless of your promise to make the fee very affordable. He says he never wants to be indebted to anyone.

https://ift.tt/2FCYK3P

Assessment of hypoxic lip training for lip incompetence by electromyographic analysis of the orbicularis oris muscle

The aims of this study were to determine the difference in electromyography (EMG) of the orbicularis oris muscles between subjects with lip incompetence and lip competence and to elucidate the effectiveness of hypoxic lip training with EMG.

https://ift.tt/2r1JiEl

Is the quality of manipulated images adequate?

We congratulate Batra et al for addressing a relevant topic: the impact of gingival alterations on smile esthetics (Batra P, Daing A, Azam I, Miglani R, Bhardwaj A. Impact of altered gingival characteristics on smile esthetics: Laypersons' perspectives by Q sort methodology. Am J Orthod Dentofacial Orthop 2018; 154:82-90). The authors used a reliable method (Q sort) and concluded that asymmetric gingival alterations and optical color changes have the greatest negative impacts on laypersons' perceptions.

https://ift.tt/2FEZ5Di

Class II correction: Extraction or nonextraction?

The patient with a Class II malocclusion, proclination, or moderate crowding of the mandibular anterior teeth, and a moderate-to-low mandibular plane angle is a treatment-planning challenge. The records of 3 patients are presented. For 2 of them, extraction treatment was used to resolve the Class II malocclusion problem. Each of these patients was treated with the removal of maxillary first premolars and mandibular second premolars. The third patient was treated with Class II elastics without extractions.

https://ift.tt/2raDQiN

Authors' response

Thanks for showing interest in our research. We wish to address your concerns and to state the following points. Regarding the control smile used as a starting point for the manipulation and creation of the discrepancies that the study objectives targeted, we referred to the article cited as your reference 1: Garber DA, Salama MA. The aesthetic smile: diagnosis and treatment. Periodontol 2000 1996;11:18-28. That article states: "Classically, the prosthodontist would like to set up a denture so that the level of the gingival margins of the maxillary teeth parallel the form of the upper lip.

https://ift.tt/2FQpDSj

CAD-CAM design and 3-dimensional printing of mini-implant retained orthodontic appliances

The objective of this article was to illustrate the digital process in the custom fabrication of metallic mini-implant supported appliances. An implant-supported appliance was produced for a patient using a CAD-CAM procedure without a physical impression or a printed model. The work flow consisted of mini-implant insertion into the palate, recording an intraoral digital scan, digital design with incorporation of a scanned expansion mechanism, direct 3-dimensional metal printing via laser melting, laser welding of the hyrax mechanism, insertion, and activation of the appliance.

https://ift.tt/2r28VF9

December 2018:154(6)

https://ift.tt/2FQpyOv

Micro-osteoperforations accelerate orthodontic tooth movement by stimulating periodontal ligament cell cycles

The aim of this study was to investigate the mechanism of how micro-osteoperforations (MOPs) accelerate tooth movement. We focused on inflammation, cell proliferation, and apoptosis of periodontal ligament cells and performed immunostaining of MOPs exposed to tumor necrosis factor-alpha (TNF-α), proliferating cell nuclear antigen (PCNA), and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) during experimental tooth movement.

https://ift.tt/2r1zxWV

Effects of vibrational devices on orthodontic tooth movement: A systematic review

The aim of this systematic review was to investigate the ability of vibrational devices to increase the rate of orthodontic tooth movement or reduce pain associated with orthodontic treatment.

https://ift.tt/2r3daQF

Orthodontic imaging: The future is now

The special article, "Clinical considerations and potential liability associated with the use of ionizing radiation in orthodontics" (Abdelkarim A, Jerrold L. Am J Orthod Dentofacial Orthop 2018;154:15-25), provides a considerable amount of information regarding the risks, benefits, imaging selection criteria, and timing (before, progress, final) of radiographic imaging in orthodontics. The advantages and limitations of various imaging techniques are discussed in detail. The references are numerous, and "the process of prescribing radiographs in orthodontics" is summed up succinctly as being "based on the practitioner's clinical judgment for a particular patient's presentation, and the ALARA directive—keeping radiation as low as reasonably achievable."

https://ift.tt/2FE3ZR0

Tensile testing of the mechanical behavior of the human periodontal ligament

The periodontal ligament (PDL) plays a key role in alveolar bone remodeling and resorption during tooth movements. The prediction of tooth mobility under functional dental loads requires a deep understanding o...

https://ift.tt/2RbI8l1

Liver Fat is Associated With Markers of Inflammation and Oxidative Stress in Analysis of Data From the Framingham Heart Study

Non-alcoholic fatty liver disease is an inflammatory condition that results in progressive liver disease. It is unknown if individuals with hepatic steatosis, but not known to have liver disease, have higher serum concentrations of markers of systemic inflammation and oxidative stress

https://ift.tt/2PRONnQ

Association Between Intake of Red and Processed Meat and Survival in Patients With Colorectal Cancer in a Pooled Analysis

Red and processed meat intake is associated with colorectal cancer (CRC) incidence, but it is not clear if intake is associated with patient survival after diagnosis

https://ift.tt/2R5CgKd

Safety of Tofacitinib for Treatment of Ulcerative Colitis, Based on 4.4 Years of Data From Global Clinical Trials

Tofacitinib is an oral, small-molecule inhibitor of JAK approved in several countries for the treatment of ulcerative colitis (UC). We report integrated safety analyses of tofacitinib-treated patients with moderate to severe UC.

https://ift.tt/2PTZsyJ

Association Between Cigarette Smoking and Alcohol Consumption and Sessile Serrated Polyps in Subjects 30 to 49 Years Old

We investigated the prevalence of sessile serrated polyps (SSPs) and the association between SSP risk and modifiable lifestyle factors in asymptomatic young adults.

https://ift.tt/2Ra3uiS

Effects of Alcohol Consumption and Metabolic Syndrome on Mortality in Patients with Non-alcoholic and Alcohol-Related Fatty Liver Disease

Non-alcoholic and alcohol-related fatty liver disease are overlapping diseases in which metabolic syndrome and alcohol consumption each contribute to progressive liver disease. We aimed to assess the effects of alcohol consumption and metabolic syndrome on mortality in individuals with fatty liver.

https://ift.tt/2POR0kf

Variation in Endoscopic Activity Assessment and Endoscopy Score Validation in Adults with Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) is assessed endoscopically (endoscopic activity), based on grades of edema, rings, exudates, furrows, and strictures (EREFS). We examined variations in endoscopic assessments of severity, developed and validated 3 EREFS-based scoring systems, and assessed responsiveness of these systems using data from a randomized placebo-controlled trial of patients with EoE.

https://ift.tt/2Ra6WtZ

Author Correction: WWOX controls hepatic HIF1α to suppress hepatocyte proliferation and neoplasia

Author Correction: WWOX controls hepatic HIF1α to suppress hepatocyte proliferation and neoplasia

Author Correction: WWOX controls hepatic HIF1α to suppress hepatocyte proliferation and neoplasia, Published online: 23 November 2018; doi:10.1038/s41419-018-1158-9

Author Correction: WWOX controls hepatic HIF1α to suppress hepatocyte proliferation and neoplasia

https://ift.tt/2KuighQ

Sustained low efficiency dialysis should not be interrupted for performing transpulmonary thermodilution measurements

Treatment of multiple organ failure frequently requires enhanced hemodynamic monitoring. When renal replacement is indicated, it remains unclear whether transpulmonary thermodilution (TPTD) measurements are in...

https://ift.tt/2BuCW6v

The long noncoding RNA LINC00312 induces lung adenocarcinoma migration and vasculogenic mimicry through directly binding YBX1

Abstract

Vasculogenic mimicry (VM) gives rise to tumor neovascularization that is critical for tumor growth and metastasis. Long non-coding RNAs (lncRNAs) have been implicated in diverse and fundamental biological processes. LINC00312 is associated with lung adenocarcinoma. In this study, we found that LINC00312 induced migration, invasion and VM of lung cancer cells by direct binding to the transcription factor Y-Box Binding Protein 1 (YBX1). Moreover, we demonstrated that YBX1 is associated with different fragments within 0–2410 nt 5'region of LINC00312. In addition, LINC00312 is associated with VM in 124 lung adenocarcinoma clinical specimens. The results suggest that LINC00312 is a promising therapeutic and diagnostic target for lung adenocarcinoma.

https://ift.tt/2BvmB1z

Nrf2 deficiency in aged mice exacerbates cellular senescence promoting cerebrovascular inflammation

Abstract

Aging-induced pro-inflammatory phenotypic alterations of the cerebral vasculature critically contribute to the pathogenesis of vascular cognitive impairment. Cellular senescence is a fundamental aging process that promotes inflammation; however, its role in cerebrovascular aging remains unexplored. The present study was undertaken to test the hypothesis that advanced aging promotes cellular senescence in the cerebral vasculature. We found that in cerebral arteries of 24-month-old mice, expression of molecular markers of senescence (p16^INK4a, p21) is upregulated as compared to that in young controls. Induction of senescence programs in cerebral arteries is associated by an upregulation of a wide range of inflammatory cytokines and chemokines, which are known to contribute to the senescence-associated secretory phenotype (SASP) in vascular cells. Age-related cerebrovascular senescence and inflammation are associated with neuroinflammation, as shown by the molecular footprint of microglia activation in the hippocampus. Genetic depletion of the pro-survival/anti-aging transcriptional regulator Nrf2 exacerbated age-related induction of senescence markers and inflammatory SASP factors and resulted in a heightened inflammatory status of the hippocampus. In conclusion, our studies provide evidence that aging and Nrf2 dysfunction promote cellular senescence in cerebral vessels, which may potentially cause or exacerbate age-related pathology.

https://ift.tt/2QfaYDP

Do wearable alcohol-based handrub dispensers increase hand hygiene compliance? - a mixed-methods study

Hand Hygiene (HH) compliance was shown to be poor in several studies. Improving the availability of alcohol-based hand rub (ABHR) is a cornerstone for increasing HH compliance.

https://ift.tt/2S89oRs

The acceptability of screening for Carbapenemase Producing Enterobacteriaceae (CPE): cross-sectional survey of nursing staff and the general publics’ perceptions

Carbapenemase Producing Enterobacteriaceae (CPE) has spread rapidly and presents a growing challenge in antimicrobial resistance (AMR) management internationally. Screening for CPE may involve a rectal swab, ther...

https://ift.tt/2S7Khyo

TSPYL5-mediated inhibition of p53 promotes human endothelial cell function

Abstract

Testis-specific protein, Y-encoded like (TSPYL) family proteins (TSPYL1-6), which are members of the nucleosome assembly protein superfamily, have been determined to be involved in the regulation of various cellular functions. However, the potential role of TSPYL family proteins in endothelial cells (ECs) has not been determined. Here, we demonstrated that the expression of TSPYL5 is highly enriched in human ECs such as human umbilical vein endothelial cells (HUVECs) and human pluripotent stem cell-differentiated ECs (hPSC-ECs). Importantly, TSPYL5 overexpression was shown to promote EC proliferation and functions, such as migration and tube formation, by downregulating p53 expression. Adriamycin-induced senescence was markedly blocked by TSPYL5 overexpression. In addition, the TSPYL5 depletion-mediated loss of EC functions was blocked by p53 inhibition. Significantly, TSPYL5 overexpression promoted angiogenesis in Matrigel plug and wound repair in a mouse skin wound healing model in vivo. Our results suggest that TSPYL5, a novel angiogenic regulator, plays a key role in maintaining endothelial integrity and function. These findings extend the understanding of TSPYL5-dependent mechanisms underlying the regulation of p53-related functions in ECs.

https://ift.tt/2BsVMeo

Glioblastoma with primitive neuronal component: Cytologic findings in intraoperative squash preparations

https://ift.tt/2RaTW7e

Spindle cell lipoma mimicking pleomorphic adenoma: A diagnostic challenge on cytology

Spindle cell lipoma (SCL) is a benign neoplasm of mature adipose tissue mostly located in the neck, back, and shoulder region. It is composed of a variable admixture of adipocytes, benign spindle cells, and collagen fibres. While the histopathologic features of SCL are quite characteristic and well described, a cytologic diagnosis of SCL might be challenging. We present a case of a 36‐year‐old female with a swelling in the left preauricular region since last 6 mo. On fine needle aspiration, a diagnosis of lipomatous pleomorphic adenoma (PA) was rendered because of the presence of benign spindle‐shaped cells, adipocytes, and abundant myxoid material. However, on histopathologic examination, the diagnosis was SCL which was confirmed by immunohistochemistry. Preauricular region is a rare site of occurrence of SCL. An acquaintance with its varied cytomorphologic features and a knowledge of its unusual sites of occurrence is essential to prevent its misdiagnosis as other myxoid benign and malignant spindle cell lesions.

https://ift.tt/2POSR8p

Role of fine needle aspiration cytology in the management of supraclavicular lymph node metastasis: Review of our experience

Introduction

In the 19th century Virchow described that metastasis to left supraclavicular lymph nodes (SLN) could originate in neoplasms located under the diaphragm. In the same way, right SLN metastasis are usually thought to arise from thoracic neoplasms. Our aims are to review our experience with metastatic SLN diagnosed by fine‐needle aspiration cytology (FNAC) and to discuss the location of the primary in these cases.

Methods

We have reviewed all lymph node FNACs diagnosed in a single tertiary hospital between 2010 and 2017 and we have included all cases of metastatic SLN.

Results

We have found 57 cases of SLN FNAC with a diagnosis of malignancy, 39 of which had no previous diagnosis (17 left, 20 right and 2 bilateral SLN). The most frequent diagnosis were adenocarcinoma, squamous cell carcinoma and small cell carcinoma. Right and bilateral SLN showed mainly lung metastasis. Left lesions were more widely distributed, with 11 originating in the lung, followed by the breast, gastroesophageal junction and prostate gland. In two cases, the primary origin was not identified. In SLN with metastasis of a known origin, the main source of the tumor was again the lung and only one case originated in the stomach (left SLN metastasis).

Conclusions

The origin of SLN metastasis seems to be dependent on both the frequency of tumor types in each geographic area and tumor location. Left SLN are more frequently involved by infradiaphragmatic primary tumors, while right SLN are exclusively involved by supradiaphragmatic neoplasms.

https://ift.tt/2Ranyl2

Cytomorphological features of high‐grade intraepithelial neoplasia/carcinoma of the cervix following chemoradiotherapy

Background

Cervicovaginal cytology as a follow‐up study in women with a history of a cervical carcinoma treated with chemo‐radiotherapy (CRT) plays an important role; however, the cytomorphological characteristics for the diagnosis of high‐grade squamous intraepithelial lesions (H‐SIL) in post‐CRT patients have not been established. The aim of the study is to find the cytomorphological characteristics that support the diagnosis of H‐SIL by conventional cytology in these patients.

Materials and methods

This is a cross‐sectional study from 2009 to 2015, which includes patients with a diagnosis of squamous cell carcinoma treated with CRT, who all have cervix cytology for follow‐up and a later biopsy.

Results

We identified 82 cases, where the most frequent clinical stage was IIA1 to IIB with 26 cases (61.9%), the most common symptom was transvaginal bleeding (64.29%). The cytological characteristics that were statistically associated with the presence of a positive biopsy were the presence of a hemorrhagic background (45.2% vs. 12.5%, P = .007), high cellularity (45.2% vs. 15%, P < .001), disposition in groups/sheets (69% vs. 22.5%, P < .001), postradiotherapy changes at the background of the smear (73.8 vs. 50%, P < .001) and an increased nuclear/cytoplasmic ratio (100% vs. 22.5%, P < .001).

Conclusions

In patients with CRT, the presence of specific features can help the diagnosis of H‐SIL with excellent diagnostic performance.

https://ift.tt/2PR6Ev8

Mediastinal seminoma presenting as a neck mass falsely diagnosed as anaplastic thyroid carcinoma: A case report

Germ cell tumors can occur in the mediastinum. They account for about 20% of tumors at this location. The majority are located in the anterior mediastinum and usually occur in young adult males. Extension of mediastinal germ cell tumors into the neck with mass formation is a very rare and unusual event. Herein, we report a case of a 34 year old male who presented with a progressively enlarging neck mass. Fine Needle Aspiration (FNA) was performed as initial evaluation and showed cellular smears comprising atypical large cells with prominent irregular nucleoli and moderate amount of cytoplasm with lymphocytic infiltrate and some epithelioid granulomas in the background. The mass was misdiagnosed initially on the cytology smears as anaplastic thyroid carcinoma. The subsequent tissue core biopsy showed sheets and nests of atypical cells admixed with ill‐defined granulomatous inflammation. By immunohistochemistry, the tumor cells were immunoreactive with SALL4, PLAP and OCT3/4, compatible with malignant germ cell tumor, seminomatous type. It is very rare for patients with primary mediastinal seminoma to present initially with a neck mass. Fine Needle Aspiration (FNA) of this "neck mass" can lead to misinterpretation of findings due to similarities in cytological features between malignant germ cell tumors and other undifferentiated malignant neoplasms and the diagnosis, therefore, can be very challenging.

https://ift.tt/2R5omaU

Cell block cellularity: A comparison of two fixatives and their impact on cellularity

Background

Ancillary testing including immunohistochemistry and molecular diagnostics has become an increasingly important component for the evaluation of cytologic specimens. Ancillary testing is important not only for diagnosis but also for predictive and prognostic evaluation. While a number of substrates are appropriate for ancillary testing, cell block specimens are commonly utilized and the success of ancillary testing depends on cell‐block cellularity.

Methods

Forty‐six pairs of cases each fixed in both formalin and CytoLyt were each analyzed by two evaluators for overall cellularity. Linear regression was used to assess inter‐rater reliability of cell counts for each method. Cellularity scores for each case were obtained by averaging the scores for each rater and cellularity was compared between the methods.

Results

Inter‐rater agreement was very good for both methods. The coefficient of determination was 1.0 and 0.99 for the CytoLyt and formalin methods respectively. Cell blocks using the CytoLyt method have lower levels of cellularity than cell blocks performed by the formalin method.

Conclusions

Cell blocks prepared using a formalin fixative yield significantly greater cellularity than those produced by the CytoLyt method. Formalin fixation appears to optimize cellularity of cell blocks useful for ancillary testing.

https://ift.tt/2PN0Gvo

A 10 year retrospective review of fine needle aspiration cytology of cystic lesions of the breast with emphasis on papillary cystic lesions

Background

Fine needle aspiration cytology (FNA) is a simple, safe, cost effective, and accurate method for diagnosis of cystic lesions of the breast. Our study aims to correlate FNA cytology of cystic lesions of the breast with the histologic diagnosis.

Methods

During a period of 10 years (2007‐2017), 314 cases of breast cystic lesions were retrieved from a total 1073 cases of breast FNAs. Of these, 78 cases from 77 patients (mean age = 54.6, female: male = 76:1) with simultaneous FNA and core needle biopsy (CNB) and/or excision specimen were reviewed. The FNA cytology reports were correlated with the histology results of CNB (n = 72) and breast excision (n = 20).

Results

Overall, 73 of 78 (93.6%) FNA cases were concordant with CNB and/or excision results. Fifty‐five benign FNAs were all concordant with histology and reported as benign (negative predictive value = 100%). The positive predictive value of FNA with a malignant diagnosis was 100%, 71.4% for a suspicious diagnosis, and 33.3% for atypical cytologic diagnosis. Two of six papillary lesions were discordant with the concurrent CNB, but the FNA results were concordant with the final histology on excision.

Conclusions

FNA allows accurate diagnosis of benign cystic lesions. FNA also plays a prominent role in evaluating cystic papillary lesions of the breast and helps to prevent false negative results on the simultaneous CNB. It is essential that FNA and CNB diagnoses be used in combination to make the correct diagnosis and for clinical management.

https://ift.tt/2R9sS8i

Cervical cancer screening by molecular Pap‐transformation of gynecologic cytology

Background

Cervical cancer is one of the common cancers in women accounting for 7.9% of all cancers. In India it is the second commonest cancer in women. The immortality of the cancer cell and the relatively long time frame from acquisition of infection to development of cervical cancer was established. As major advancements like LBC, HPV testing were introduced in the recent years, screening has taken a new avatar, the Molecular pap!! The objectives of this study were: To compare gynecologic cytology and abnormal results with respect to conventional and LBC. To study the role of HPV cotesting and ancillary tests performed, that is, HPV CISH, and p16ink4a by IHC.

Methods

About 71 924 Conventional and LBC samples were included from August 2009 to December 2017. Cases for HPV testing along the conventional smears were 1539. HPV can be tested from the same LBC vial as the sample remains stable at room temperature for 6 weeks. HPV DNA PCR was carried out in our laboratory for High and Low risk genotypes. Cytology findings were also correlated with histology.

Results

Detection rate of SILs in LBC samples were higher (2.20%). The commonest abnormality was LSIL in LBC and ASCUS in conventional smears. Commonest HR HPV and LR HPV detected was 1 61 856 and 61 142.

Conclusion

LBC with HPV cotesting improves sensitivity and specificity and reduces ambiguous results; allows better compliance, as a negative result of both tests allows patients to get screening every 5 years, thereby increasing screening intervals, important in a resource limited situation.

https://ift.tt/2PMfWst

Cytomorphologic diagnosis of inguinal node metastasis of Sertoli cell tumour

https://ift.tt/2R3Yc8E

Lobular breast carcinoma metastasis to skeletal muscle, two case reports diagnosed by ultrasound guided FNA with evaluation of the roles of interventional cytopathology

Skeletal muscle metastasis from breast carcinoma is a relatively rare clinical entity. We report two cases of breast cancer metastatic to the skeletal muscle, diagnosed by ultrasound guided fine needle aspiration (US‐FNA) biopsy done by interventional cytopathologists at an outpatient cytopathology center. Our two patients presented with lower anterior neck firmness and chest wall mass, respectively. Ultrasound evaluation of our first case demonstrated hypo‐echoic thickened anterior strap muscles while in the second case there was significant distortion of the anatomy from previous surgeries. It was necessary to proceed with FNA biopsy even when their ultrasound findings were equivocal, to establish a definite rapid diagnosis. The immediate onsite evaluation findings were suggestive of malignancy in both cases with subsequent core biopsy confirming the diagnosis of metastatic breast carcinoma. In cytopathology, point‐of‐care (POC) ultrasound is used as an adjunct tool that offers visual guidance during FNA of nonpalpable masses and enables sampling of lesional "hot" spots to ensure specimen adequacy. Studies have demonstrated a reduction in FNA nondiagnostic rates with the use of ultrasound‐guidance consequently reducing health care costs associated with nondiagnostic FNAs. US‐FNA also provides adequate samples for cell block preparations. Metastatic lobular carcinoma of the breast has a wide range of clinical presentations and a high level of suspicion is advised. Cytopathologists‐performed US‐FNA is a proven, less‐invasive, cost‐effective tool that provides timely cytologic diagnosis.

https://ift.tt/2PP7wk4

Yeasts and pseudoyeasts in genitourinary cytopathology

https://ift.tt/2RayMpF

Touch imprint (TI) cytology of needle core biopsies (NCB) in pathology laboratories: A practice survey of participants in the College of American Pathologists (CAP) Non Gynecologic Cytopathology (NGC) Education Program

Background

Intra‐procedural assessment of touch imprint (TI) cytology from needle core biopsies (NCB) is used to ensure sample adequacy and to provide immediate diagnosis in various settings. We aimed to survey laboratories for current practices on the use of cytology with NCB.

Methods

A voluntary supplemental questionnaire including questions on demographics, personnel involved, sites, accessioning, and reporting was sent with the College of American Pathologists (CAP) 2015 Non gynecologic Cytopathology Education Program to survey practices of cytologic assessment of NCB.

Results

Among 844 respondents, 403 (48%) performed cytologic assessment of NCB. Common body sites included lung (94%; 368/392), liver (87%; 340/ 392), and lymph nodes/spleen (77%; 303/392). Most of the time, a pathologist was present on‐site 75% (295/393) for adequacy assessment which was usually verbally reported to the provider performing the procedure. Specimens were prepared by cytotechnologists (50%; 193 of 388) or pathologists (45%; 176 of 388) by touching the core to the slide (50%; 196 of 390) and rolling the core on the slide (45%; 177/390). Among the respondents, 19% said that cytotechnologists independently performed immediate assessment of TI of NCB. Most laboratories (69%; 264/384) evaluated air‐dried slides with a modified Giemsa stain and rendered one TI/NCB combined report (87%, 334/385).

Conclusions

This is the first survey performed specifically to determine the practice of adequacy assessment of TI of NCB. Cytotechnologists are generally not performing adequacy assessment of TI without pathologist oversight. A single report is usually issued which includes the adequacy assessment as a part of the final report.

https://ift.tt/2PRasww

Radiochemotherapy in esophageal cancer

Summary

Esophageal cancer is one of the ten most frequent tumors worldwide. There are two major histologies: squamous cell carcinomas, which appear more frequently in the upper part of the esophagus, and adenocarcinomas, which are predominantly found in the distal part and at the gastroesophageal junction. Most patients suffer from locally advanced tumors, for which the prognosis is still poor with a 5-year survival rate of 15–25%. Treatment is based on histology, tumor stage, location of the tumor, performance status, age, and comorbidities and it consists of surgery, chemotherapy, or radiotherapy or a combination of these. Over the past decades, neoadjuvant radiochemotherapy followed by surgery became standard of care in patients with locally advanced squamous cell carcinomas suitable for surgery. The treatment of locally advanced adenocarcinomas and junctional tumors is still under debate and consists of either perioperative chemotherapy or neoadjuvant chemoradiotherapy followed by surgery. In patients not suitable for surgery, definitive radiochemotherapy is considered the treatment of choice. Modern radiotherapy in esophageal cancer is increasingly conformal and the dose at organs-at-risk could be reduced over the years to lower the rate of treatment-related side effects. Individualization of treatment and new combinations of systemic agents are under investigation to improve treatment outcome.

https://ift.tt/2r42uS1

Selective BTK inhibition improves bendamustine therapy response and normalizes immune effector functions in chronic lymphocytic leukemia

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been shown to be highly effective in patients with chronic lymphocytic leukemia (CLL) and is approved for CLL treatment. Unfortunately, resistance and intolerance to ibrutinib has been observed in several studies, opening the door for more specific BTK inhibitors. CC‐292 (spebrutinib) is a BTK inhibitor with increased specificity for BTK and less inhibition of other kinases. Our in vitro studies showed that CC‐292 potently inhibited B‐cell receptor signaling, activation, proliferation and chemotaxis of CLL cells. In in vivo studies using the adoptive transfer TCL1 mouse model of CLL, CC‐292 reduced tumor load and normalized tumor‐associated expansion of T cells and monocytes, while not affecting T cell function. Importantly, the combination of CC‐292 and bendamustine impaired CLL cell proliferation in vivo and enhanced the control of CLL progression. Our results demonstrate that CC‐292 is a specific BTK inhibitor with promising performance in combination with bendamustine in CLL. Further clinical trials are warranted to investigate the therapeutic efficacy of this combination regimen.

This article is protected by copyright. All rights reserved.

https://ift.tt/2QiBJay

CLPTM1L/CRR9 Ectodomain Interaction with GRP78 at the Cell Surface Signals for Survival and Chemoresistance upon ER Stress in Pancreatic Adenocarcinoma Cells

Altered regulation of endoplasmic reticulum (ER) homeostasis has been implicated in many cancers and has recently become a therapeutic and chemosensitization target of interest. We have identified Cleft Lip and Palate Transmembrane 1‐Like (CLPTM1L)/Cisplatin Resistance Related Protein 9 (CRR9) as an ER stress related mediator of cytoprotection in pancreatic cancer. We recently demonstrated that CLPTM1L is highly expressed in pancreatic ductal adenocarcinoma and associated with poor outcome. Furthermore, we have discovered that CLPTM1L interacts with phosphoinositol‐3‐kinase‐alpha at the tumor cell surface and causes up‐regulation of Bcl‐xL and pAkt mediated survival signaling. Here, we demonstrate surface relocalization and survival signaling by CLPTM1L triggered by endoplasmic reticular (ER) stress. We demonstrate the interaction of with CLPTM1L with the central ER stress survival mediator, Glucose Regulated Protein 78 (GRP78)/Binding Immunoglobulin Protein (BiP) and PI3K‐alpha /p110α. This interaction and surface relocalization of CLPTM1L and GRP78 is induced by ER stress, including that caused by treatment with gemcitabine. We demonstrate that the extracellular loop of CLPTM1L is required for gemcitabine resistance and interaction with GRP78. This interaction and the chemoresistance effect conferred by this pathway is targetable with our recently developed inhibitory CLPTM1L antibodies, which may represent novel modalities of chemosensitization and treatment of pancreatic adenocarcinoma. Anchorage independent growth, GRP78‐mediated chemoresistance, and Akt phosphorylation were abrogated by inhibition of CLPTM1L. These findings demonstrate a novel and potentially targetable mechanism of cytoprotection and chemoresistance in pancreatic tumors.

This article is protected by copyright. All rights reserved.

https://ift.tt/2DESO7W

A controlled trial of HNSCC patient‐derived xenografts reveals broad efficacy of PI3Kα inhibition in controlling tumor growth

Head and neck squamous cell carcinomas (HNSCCs) frequently harbor alterations in the PI3K/AKT/mTOR signalling axis, particularly in the PIK3CA gene. PI3K‐targeted agents have therefore gained considerable preclinical and clinical interest as emerging therapies for HNSCC. Identification of predictive biomarkers of response would advance the clinical application of PI3K‐targeted drugs for patients in order to achieve maximal benefit. To date, studies of drug biomarkers have largely focused on screening cell lines, with much more limited in vivo testing, usually only as validation. This approach has rarely enabled accurate predictions of clinical efficacy. Recently, clinical trials of PDX models (PDX clinical trials) have been introduced as a preclinical approach to interrogate interpatient response heterogeneity. Already, PDX clinical trial responses have been demonstrated to correlate closely with patient outcomes. Here, using both an HNSCC specific, 28‐cell line panel and a PDX clinical trial of 80 xenografts derived from 20 unique HNSCC tumors, we systematically examine patterns of response to PI3K inhibition in HNSCC. We find EGFR, AKT1 and CSMD1 copy number aberrations, but not PIK3CA mutations, to be associated with responsiveness to PI3K‐targeted drugs. Further, we reveal PI3Kα inhibition to be almost globally tumoristatic in HNSCC xenografts regardless of PIK3CA mutational status, emphasizing its potential as a stabilizing neoadjuvant therapy for HNSCC patients.

https://ift.tt/2DDp7US

Strong associations of a healthy lifestyle with all stages of colorectal carcinogenesis: results from a large cohort of participants of screening colonoscopy

The risk of developing colorectal cancer (CRC) is associated with a wide range of dietary and lifestyle factors. The individual contribution of single modifiable factors, such as alcohol consumption, physical activity, smoking, body mass index (BMI) or dietary components, to the development of CRC has been investigated extensively, but evidence on their combined effect at various stages of colorectal carcinogenesis is sparse. The aim of this study was to analyze the association of a healthy lifestyle pattern with prevalence of early and advanced colorectal neoplasms. A total of 13,600 participants of screening colonoscopy in Saarland/Germany (mean age 62.9 years) who were enrolled in the KolosSal study (Effektivität der Früherkennungs‐Koloskopie: eine Saarland‐weite Studie) from 2005 until 2013 were included in this cross‐sectional analysis. Dietary and lifestyle data were collected and colonoscopy results were extracted from physicians' reports. The association of an a priori defined healthy lifestyle score ‐ including dietary intake, alcohol consumption, physical activity, smoking and BMI ‐ with early and advanced colorectal neoplasms was assessed by multiple logistic regression analyses with comprehensive adjustment for potential confounders. Strong inverse dose‐response relationships were observed between an overall healthier lifestyle pattern and presence of advanced colorectal neoplasms, non‐advanced adenomas and hyperplastic polyps (p value <0.0001 in all cases), with adjusted odds ratios (95% CI) for the highest compared to the lowest category of the healthy lifestyle score of 0.41 (0.30‐0.56), 0.42 (0.33‐0.54) and 0.39 (0.29‐0.54) respectively. A healthy lifestyle is strongly associated with lower risk of all stages of colorectal neoplasms.

This article is protected by copyright. All rights reserved.

https://ift.tt/2QiUkmU

EIF4A3-induced circular RNA MMP9 (circMMP9) acts as a sponge of miR-124 and promotes glioblastoma multiforme cell tumorigenesis

Abstract

Background

Circular RNAs (circRNAs) have been found to play critical roles in the development and progression of various cancers. However, little is known about the effects of the circular RNA network on glioblastoma multiforme (GBM).

Methods

A microarray was used to screen circRNA expression in GBM. Quantitative real-time PCR was used to detect the expression of circMMP9. GBM cells were transfected with a circMMP9 overexpression vector or siRNA, and cell proliferation, migration and invasion, as well as tumorigenesis in nude mice, were assessed to examine the effect of circMMP9 in GBM. Biotin-coupled miRNA capture, fluorescence in situ hybridization and luciferase reporter assays were conducted to confirm the relationship between circMMP9 and miR-124.

Results

In this study, we screened differentially expressed circRNAs and identified circMMP9 in GBM. We found that circMMP9 acted as an oncogene, was upregulated in GBM and promoted the proliferation, migration and invasion abilities of GBM cells. Next, we verified that circMMP9 served as a sponge that directly targeted miR-124; circMMP9 accelerated GBM cell proliferation, migration and invasion by targeting miR-124. Furthermore, we found that cyclin-dependent kinase 4 (CDK4) and aurora kinase A (AURKA) were involved in circMMP9/miR-124 axis-induced GBM tumorigenesis. Finally, we found that eukaryotic initiation factor 4A3 (eIF4A3), which binds to the MMP9 mRNA transcript, induced circMMP9 cyclization and increased circMMP9 expression in GBM.

Conclusions

Our findings indicate that eIF4A3-induced circMMP9 is an important underlying mechanism in GBM cell proliferation, invasion and metastasis through modulation of the miR-124 signaling pathway, which could provide pivotal potential therapeutic targets for the treatment of GBM.

Graphical abstract

https://ift.tt/2TBVyZj

CircSLC3A2 functions as an oncogenic factor in hepatocellular carcinoma by sponging miR-490-3p and regulating PPM1F expression

Abstract

Background

Non-coding RNAs (ncRNAs) have been reported to participate in tumor progression by regulating gene expression. Previous studies showed that protein phosphatase Mg2⁺/Mn2⁺ dependent 1F (PPM1F) acts a dual role in cancer growth and metastasis. But, the underlying mechanisms by which ncRNAs regulate PPM1F expression in hepatocellular carcinoma (HCC) are poorly understood.

Methods

The association between PPM1F or miR-490-3p expression and clinicopathological features and prognosis in patients with HCC was analyzed by TCGA RNA-sequencing data. CircSLC3A2 was identified to bind with miR-490-3p by bioinformatic analysis, and the binding sites between miR-490-3p and PPM1F or circSLC3A2 were confirmed by dual luciferase report and RNA immunoprecipitation (RIP) assays. The localization and clinical significance of miR-490-3p and circSLC3A2 in patients with HCC were investigated by fluorescence in situ hybridization (FISH). MTT, Agar, and Transwell assays were conducted to evaluate the effects of miR-490-3p or circSLC3A2 on cell proliferation and invasive potential.

Results

The expression of PPM1F or miR-490-3p was associated with poor survival and tumor recurrence, and acted as an independent prognostic factor in patients with HCC. Re-expression of miR-490-3p inhibited HCC cell proliferation and invasion by targeting PPM1F, but its inhibitor reversed these effects. Moreover, circSLC3A2, predominantly localized in the cytoplasm, exhibited an oncogenic role by sponging miR-490-3p and regulating PPM1F expression, and harbored a positive correlation with poor survival in patients with HCC.

Conclusion

CircSLC3A2 acts as an oncogenic factor in HCC by sponging miR-490-3p and regulating PPM1F expression.

https://ift.tt/2AeXGgN

Enhancing 5-fluorouracil efficacy through suppression of PKM2 in colorectal cancer cells

Abstract

Purpose

Cancer cells alter regular metabolic pathways in order to sustain rapid proliferation. One example of metabolic remodeling in cancerous tissue is the upregulation of pyruvate kinase isoenzyme M2 (PKM2), which is involved in aerobic glycolysis. Indeed, PKM2 has previously been identified as a tumor biomarker and as a potential target for cancer therapy. Here, the role of PKM2 in the anticancer efficacy of 5-fluorouracil (5-FU) was evaluated in colorectal cancer (CRC).

Methods

HCT116, SW480 and HT-29 cells were used by transfection with lentiviral vectors expressing short hairpin RNA (shRNA) against PKM2. In response to 5-FU treatment, cellular proliferation was examined, the levels of ATP/ADP ratio were monitored, the intracellular accumulation of 5-FU was measured, and intracellular levels of phosphoenolpyruvate (PEP), pyruvate and lactate were evaluated by using liquid chromatography–mass spectrometry (LC–MS). A CRC subcutaneous tumor model was performed to investigate the effect of PKM2 inhibition on 5-FU efficacy in vivo.

Results

Suppression of PKM2 resulted in changes in glucose metabolism, leading to decreased synthesis of adenosine triphosphate (ATP). Reduced levels of ATP/ADP ratio resulted in the intracellular accumulation of 5-FU, consequently enhancing the therapeutic efficacy of this drug in several CRC cell lines. Furthermore, the enhanced efficacy of 5-FU by simultaneous inhibition of PKM2 was demonstrated in an in vivo HCT116 CRC model.

Conclusion

We show that the combination treatment showed superior anticancer efficacy as compared to 5-FU alone. These findings suggest that targeting PKM2 can increase the efficacy of chemotherapy, potentially providing a new approach for improving the outcome of chemotherapy in patients with CRC.

https://ift.tt/2BslvU2

Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex

Abstract

Hereditary spastic paraplegias (HSPs) are rare neurological disorders caused by progressive distal degeneration of the corticospinal tracts. Among the 79 loci and 65 spastic paraplegia genes (SPGs) involved in HSPs, mutations in SPAST, which encodes spastin, responsible for SPG4, are the most frequent cause of both familial and sporadic HSP. SPG4 is characterized by a clinically pure phenotype associated with restricted involvement of the corticospinal tracts and posterior columns of the spinal cord. It is rarely associated with additional neurological signs. However, both age of onset and severity of the disorder are extremely variable. Such variability is both intra- and inter-familial and may suggest incomplete penetrance, with some patients carrying mutations remaining asymptomatic for their entire life. We analysed a cohort of 842 patients with SPG4-HSP to assess genotype–phenotype correlations. Most patients were French (89%) and had a family history of SPG4-HSP (75%). Age at onset was characterized by a bimodal distribution, with high inter-familial and intra-familial variability, especially concerning first-degree relatives. Penetrance of the disorder was 0.9, complete after 70 years of age. Penetrance was lower in females (0.88 versus 0.94 in males, P = 0.01), despite a more diffuse phenotype with more frequent upper limb involvement. Seventy-seven per cent of pathogenic mutations (missense, frameshift, splice site, nonsense, and deletions) were located in the AAA cassette of spastin, impairing its microtubule-severing activity. A comparison of the missense and truncating mutations revealed a significantly lower age at onset for patients carrying missense mutations than those carrying truncating mutations, explaining the bimodal distribution of the age at onset. The age at onset for patients carrying missense mutations was often before 10 years, sometimes associated with intellectual deficiency. Neuropathological examination of a single case showed degeneration of the spinocerebellar and spinocortical tracts, as well as the posterior columns. However, there were numerous small-diameter processes among unusually large myelinated fibres in the corticospinal tract, suggesting marked regeneration. In conclusion, this large cohort of 842 individuals allowed us to identify a significantly younger age at onset in missense mutation carriers and lower penetrance in females, despite a more severe disorder. Neuropathology in one case showed numerous small fibres suggesting regeneration.

https://ift.tt/2FD7cAi

Long-term results and PSA kinetics after robotic SBRT for prostate cancer: multicenter retrospective study in Korea (Korean radiation oncology group study 15–01)

Abstract

Background

To evaluate the treatment outcome and prostate-specific antigen (PSA) change after stereotactic body radiotherapy (SBRT) for localized prostate cancer.

Methods

Patients with localized prostate cancer treated with SBRT at three academic hospitals were enrolled. Treatment was delivered using Cyberknife with dose range from 35 to 37.5 Gy in 5 fractions. Biochemical failure (BCF) was assessed with Phoenix definition and toxicities were scored with Radiation Therapy Oncology Group (RTOG) toxicity criteria. The PSA kinetics were analyzed in patients who received no androgen deprivation therapy (ADT) and showed no recurrence.

Results

Of the total 88 patients, 14 patients (15.9%) received ADT. After median follow-up of 63.8 months, the 5-year BCF free survival (BCFFS) was 94.7%. Two patients experienced late grade ≥ 3 GI toxicities (2.2%). The median nadir PSA was 0.12 ng/mL (range, 0.00–2.62 ng/mL) and the median time to nadir was 44.8 months (range, 0.40–85.7 months). Patients who reached nadir before 24 months showed poorer BCFFS than the others. The rate of PSA decline was maximum in the first year after treatment and gradually decreased with time. The pattern of PSA change was significantly different according to the risk groups (p = 0.011) with the slope of − 0.139, − 0.161 and − 0.253 ng/mL/month in low-, intermediate- and high-risk groups, respectively.

Conclusion

SBRT for localized prostate cancer showed favorable efficacy with minimal toxicities. The time to PSA nadir was significantly associated with treatment outcome. PSA revealed rapid initial decline and slower decrease with longer follow-up and the patterns of PSA changes were different according to the risk groups.

https://ift.tt/2QcW69k

Effectiveness of Multi-Criteria Optimization-based Trade-Off exploration in combination with RapidPlan for head & neck radiotherapy planning

Abstract

Background

A new strategy is introduced combining the use of Multi-Criteria Optimization-based Trade-Off Exploration (TO) and RapidPlan™ (RP) for the selection of optimisation parameters that improve the trade-off between sparing of organs at risk (OAR) and target coverage for head and neck radiotherapy planning. Using both approaches simultaneously; three different workflows were proposed for the optimisation process of volumetric-modulated arc therapy (VMAT) plans. The generated plans were compared to the clinical plans and the plans that resulted using RP and TO individually.

Methods

Twenty clinical VMAT plans previously administered were selected. Five additional plans were created for each patient: a clinical plan further optimised with TO (Clin+TO); two plans generated by in-house built RP models, RP_1 with the model built with VMAT clinical plans and RP_TO with the model built with VMAT plans optimised by TO. Finally, these last two plans were additionally optimised with TO for the creation of the plans RP_1 + TO and RP_TO⁺ respectively. The TO management was standardised to maximise the sparing of the parotid glands without compromising a clinically acceptable PTV coverage. Resulting plans were inter-compared based on dose-volume parameters for OAR and PTVs, target homogeneity, conformity, and plans complexity and deliverability.

Results

The plans optimised using TO in combination with RP showed significantly improved OAR sparing while maintaining comparable target dose coverage to the clinical plans. The largest OAR sparing compared to the clinical plans was achieved by the RP_TO⁺ plans, which reported a mean parotid dose average of 15.0 ± 4.6 Gy vs 22.9 ± 5.5 Gy (left) and 17.1 ± 5.0 Gy vs 24.8 ± 5.8 Gy (right). However, at the same time, RP_TO⁺ showed a slight dose reduction for the 99% volume of the nodal PTV and an increase for the 95% (when comparing to the clinical plans 76.0 ± 1.2 vs 77.4 ± 0.6 and 80.9 ± 0.9 vs 79.7 ± 0.4) but remained within clinical acceptance. Plans optimised with RP and TO combined, showed an increase in complexity but were proven to be deliverable.

Conclusion

The use of TO combined with RP during the optimisation of VMAT plans enhanced plan quality the most. For the RP_TO⁺ plans, acceptance of a slight deterioration in nodal PTV allowed the largest reduction in OAR dose to be achieved.

https://ift.tt/2DEHt7U

Safety and fertility outcomes after the conservative treatment of endometrioid borderline ovarian tumours

Abstract

Background

Because of the rarity of endometrioid borderline ovarian tumours (EBOTs), there is a paucity of data concerning the natural history and prognosis of this condition. Thus, the objective of our study was to establish the feasibility of fertility preservation in young women with EBOTs, as well as their oncological and reproductive outcomes.

Methods

Consecutive patients with EBOTs, treated at a tertiary referral centre during a span of 22 years, were retrospectively analysed. Recurrence-free interval, as well as its association with the type of surgery and with other clinical and pathological features, was assessed using the Kaplan-Meier and Cox proportional hazards methods.

Results

Of the 59 patients studied, the median follow-up time was 30 months (range, 6–177 months). Nine (15.3%) patients developed 13 recurrences 6–137 months after the initial surgeries, including three patients (5.1%; n = 3/59) who developed six invasive recurrences 8, 18 and 68 months after their initial surgeries. Conservative surgery showed a tendency towards a high recurrence rate (17.2% versus 13.3%); however, this difference was not significant (p = 0.45). The 5-year recurrence-free survival rate was significantly higher in the oophorectomy group than in the cystectomy group (p = 0.001). Cox regression analysis showed that none of the variables assessed were associated with an increased hazard ratio for recurrence, except for a younger age at diagnosis (p = 0.021). Of 20 patients who attempted to conceive, three pregnancies among two patients (10.0%) resulted in two live births.

Conclusions

Conservative surgery with unilateral adnexectomy can be proposed for young women with EBOTs with fertility desire; however, the reproductive result is not satisfactory. In addition, careful evaluations of the endometria should be offered during the initial surgery and follow-up period.

Trial registration

Retrospectively registered.

https://ift.tt/2R8YlYj

Factors associated with high-risk HPV infection and cervical cancer screening methods among rural Uyghur women aged > 30 years in Xinjiang

Abstract

Background

Cervical cancer is the most common genital malignant tumor in women worldwide. However, the reliability of different detection methods may vary according to populations and epidemics. This study analyzed factors relevant to high-risk human papillomavirus (hrHPV) infection among rural Uyghur women aged > 30 years and evaluated the value of different screening methods for cervical precancerous lesions.

Methods

From July 2015 to May 2016, 225 rural Uyghur women aged > 30 years were recruited from local health clinics throughout Pishan, Xinjiang, China. HrHPV DNA testing, colposcopy, biopsy of cervical precancerous lesions, and surveys were conducted. The results of different screening methods were compared, and factors associated with hrHPV infection were analyzed.

Results

The rates of hrHPV infection and cervical epithelial lesions were 9.3 and 1.8%, respectively. The area under the ROC curve was 0.538 (95% CI: 0.292, 0.784; P = 0.753) for the HPV test and 0.995 (95% CI: 0.988, 1.003; P < 0.001) for colposcopy. Factors associated with HPV infection included widowhood (OR = 13.601 (2.170, 85.263), P = 0.005) and ≥ 3 sexual partners in the past 5 years (OR = 16.808 (4.148, 68.101), P < 0.001). .

Conclusions

Among rural Uyghur women aged > 30 years, the main factors for HPV infection include marriage and frequent sexual intercourse. Colposcopy has a higher screening value for cervical epithelial lesions than hrHPV testing.

https://ift.tt/2PSYYIT