bluuebunny/crossref_metadata_2025 huggingface dataset:
N-Terminomics TAILS Identifies Host Cell Substrates of Poliovirus and Coxsackievirus B3 3C Proteinases That Modulate Virus Infection
Authors: Jagdeo Julienne M. , Dufour Antoine , Klein Theo , Solis Nestor , Kleifeld Oded , Kizhakkedathu Jayachandran , Luo Honglin , Overall Christopher M. , Jan Eric
Published: February 2018

Enteroviruses encode proteinases that are essential for processing of the translated viral polyprotein. In addition, viral proteinases also target host proteins to manipulate cellular processes and evade innate antiviral responses to promote replication and infection. Although some host protein substrates of enterovirus proteinases have been identified, the full repertoire of targets remains unknown. We used a novel quantitative
in vitro
proteomics-based approach, termed
t
erminal
a
mine
i
sotopic
l
abeling of
s
ubstrates (TAILS), to identify with high confidence 72 and 34 new host protein targets of poliovirus and coxsackievirus B3 (CVB3) 3C proteinases (3C
pro
s) in HeLa cell and cardiomyocyte HL-1 cell lysates, respectively. We validated a subset of candidate substrates that are targets of poliovirus 3C
pro
in vitro
including three common protein targets, phosphoribosylformylglycinamidine synthetase (PFAS), hnRNP K, and hnRNP M, of both proteinases. 3C
pro
-targeted substrates were also cleaved in virus-infected cells but not noncleavable mutant proteins designed from the TAILS-identified cleavage sites. Knockdown of TAILS-identified target proteins modulated infection both negatively and positively, suggesting that cleavage by 3C
pro
promotes infection. Indeed, expression of a cleavage-resistant mutant form of the endoplasmic reticulum (ER)-Golgi vesicle-tethering protein p115 decreased viral replication and yield. As the first comprehensive study to identify and validate functional enterovirus 3C
pro
substrates
in vivo
, we conclude that N-terminomics by TAILS is an effective strategy to identify host targets of viral proteinases in a nonbiased manner.

IMPORTANCE
Enteroviruses are positive-strand RNA viruses that encode proteases that cleave the viral polyprotein into the individual mature viral proteins. In addition, viral proteases target host proteins in order to modulate cellular pathways and block antiviral responses in order to facilitate virus infection. Although several host protein targets have been identified, the entire list of proteins that are targeted is not known. In this study, we used a novel unbiased proteomics approach to identify ∼100 novel host targets of the enterovirus 3C protease, thus providing further insights into the network of cellular pathways that are modulated to promote virus infection.
Transcriptional Regulation of Carnitine Catabolism in Pseudomonas aeruginosa by CdhR
Authors: Meadows Jamie A. , Wargo Matthew J.
Published: February 2018

Pathogens must metabolize host-derived compounds during infection and properly regulate the responsible pathways. Carnitine is a common eukaryotic-associated quaternary amine compound that can be catabolized by
Pseudomonas aeruginosa
. Here we expand on our understanding of how this metabolic pathway is regulated and provide details on how carnitine catabolism is intertwined with glycine betaine catabolism at the level of transcriptional control.
Tick-Borne Encephalitis Virus Vaccine-Induced Human Antibodies Mediate Negligible Enhancement of Zika Virus Infection
In
Vitro
and in a Mouse Model
Authors: Duehr James , Lee Silviana , Singh Gursewak , Foster Gregory A. , Krysztof David , Stramer Susan L. , Bermúdez González Maria C. , Menichetti Eva , Geretschläger Robert , Gabriel Christian , Simon Viviana , Lim Jean K. , Krammer Florian
Published: February 2018

The relationship between serial infections of two different serotypes of dengue virus and more severe disease courses is well-documented in the literature, driven by so-called antibody-dependent enhancement (ADE). Recently, studies have shown the possibility of ADE in cells exposed to anti-DENV human plasma and then infected with ZIKV and also in mouse models of ZIKV pathogenesis after passive transfer of anti-DENV human plasma. In this study, we evaluated the extent to which this phenomenon occurs using sera from individuals immunized against tick-borne encephalitis virus (TBEV). This is highly relevant, since large proportions of the European population are vaccinated against TBEV or otherwise seropositive.
Gut microbiota modulate T cell trafficking into human colorectal cancer
Authors: Cremonesi Eleonora , Governa Valeria , Garzon Jesus Francisco Glaus , Mele Valentina , Amicarella Francesca , Muraro Manuele Giuseppe , Trella Emanuele , Galati-Fournier Virginie , Oertli Daniel , Däster Silvio Raffael , Droeser Raoul A , Weixler Benjamin , Bolli Martin , Rosso Raffaele , Nitsche Ulrich , Khanna Nina , Egli Adrian , Keck Simone , Slotta-Huspenina Julia , Terracciano Luigi M , Zajac Paul , Spagnoli Giulio Cesare , Eppenberger-Castori Serenella , Janssen Klaus-Peter , Borsig Lubor , Iezzi Giandomenica
Published: February 2018

Objective

Tumour-infiltrating lymphocytes (TILs) favour survival in human colorectal cancer (CRC). Chemotactic factors underlying their recruitment remain undefined. We investigated chemokines attracting T cells into human CRCs, their cellular sources and microenvironmental triggers.

Design

Expression of genes encoding immune cell markers, chemokines and bacterial 16S ribosomal RNA (16SrRNA) was assessed by quantitative reverse transcription-PCR in fresh CRC samples and corresponding tumour-free tissues. Chemokine receptor expression on TILs was evaluated by flow cytometry on cell suspensions from digested tissues. Chemokine production by CRC cells was evaluated in vitro and in vivo, on generation of intraperitoneal or intracecal tumour xenografts in immune-deficient mice. T cell trafficking was assessed on adoptive transfer of human TILs into tumour-bearing mice. Gut flora composition was analysed by 16SrRNA sequencing.

Results

CRC infiltration by distinct T cell subsets was associated with defined chemokine gene signatures, including CCL5, CXCL9 and CXCL10 for cytotoxic T lymphocytes and T-helper (Th)1 cells; CCL17, CCL22 and CXCL12 for Th1 and regulatory T cells; CXCL13 for follicular Th cells; and CCL20 and CCL17 for interleukin (IL)-17-producing Th cells. These chemokines were expressed by tumour cells on exposure to gut bacteria in vitro and in vivo. Their expression was significantly higher in intracecal than in intraperitoneal xenografts and was dramatically reduced by antibiotic treatment of tumour-bearing mice. In clinical samples, abundance of defined bacteria correlated with high chemokine expression, enhanced T cell infiltration and improved survival.

Conclusions

Gut microbiota stimulate chemokine production by CRC cells, thus favouring recruitment of beneficial T cells into tumour tissues.
Downregulation of exosomal miR-204-5p and miR-632 as a biomarker for FTD: a GENFI study
Authors: Schneider Raphael , McKeever Paul , Kim TaeHyung , Graff Caroline , van Swieten John Cornelis , Karydas Anna , Boxer Adam , Rosen Howie , Miller Bruce L , Laforce Jr Robert , Galimberti Daniela , Masellis Mario , Borroni Barbara , Zhang Zhaolei , Zinman Lorne , Rohrer Jonathan Daniel , Tartaglia Maria Carmela , Robertson Janice
Published: February 2018

Objective

To determine whether exosomal microRNAs (miRNAs) in cerebrospinal fluid (CSF) of patients with frontotemporal dementia (FTD) can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort and in sporadic FTD.

Methods

GENFI participants were either carriers of a pathogenic mutation in progranulin, chromosome 9 open reading frame 72 or microtubule-associated protein tau or were at risk of carrying a mutation because a first-degree relative was a known symptomatic mutation carrier. Exosomes were isolated from CSF of 23 presymptomatic and 15 symptomatic mutation carriers and 11 healthy non-mutation carriers. Expression of 752 miRNAs was measured using quantitative PCR (qPCR) arrays and validated by qPCR using individual primers. MiRNAs found differentially expressed in symptomatic compared with presymptomatic mutation carriers were further evaluated in a cohort of 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer’s disease (AD) and 10 healthy controls (HCs) of similar age.

Results

In the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared with presymptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 (90% CI 0.79 to 0.98) and 0.81 (90% CI 0.68 to 0.93), respectively, and when combined an area of 0.93 (90% CI 0.87 to 0.99). In sporadic FTD, only miR-632 was significantly decreased compared with AD and HCs. Decrease of miR-632 revealed an area of 0.90 (90% CI 0.81 to 0.98).

Conclusions

Exosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD.
Triiodothyronine attenuates the progression of renal injury in a rat model of chronic kidney disease
Authors: El Agaty Sahar M.
Published: February 2018

This study was designed to investigate whether and how triiodothyronine (T3) affects renal function in an experimental model of chronic kidney disease. Twenty-four female rats were divided into the following groups: sham-operated control group (n = 8), 5/6 nephrectomized group (Nx, n = 8), and 5/6 nephrectomized group treated with T3 for 2 weeks (T3-Nx, n = 8). T3 administration significantly decreased serum levels of urea, creatinine, tumour necrosis factorα, and interleukin-6 compared with serum levels in the Nx group. The levels of malondialdehyde, transforming growth factor β, fibronectin, and collagen IV, as well as the expression of inducible nitric oxide synthase, nuclear factor κB, poly(ADP-ribose) polymerase, caspase-3, and Bax were all significantly decreased, though not normalized, in the remnant kidney of rats in the T3-Nx group compared with Nx rats. Glutathione, heme oxygenase-1 levels, as well as endothelial nitric oxide synthase expression were increased in the remnant kidney of the T3-Nx group. Histological studies revealed focal necrosis of renal tubules associated with inflammatory cell infiltration and fibrosis in the Nx group. These changes were alleviated in T3-Nx rats. This study showed that T3 administration attenuated the clinical and histological signs of renal injury in 5/6 nephrectomized rats by mitigating renal oxidative stress, inflammation, apoptosis, and fibrosis.
Fair Enough
Authors: Kurokawa David , Procaccia Ariel D. , Wang Junxing
Published: February 2018

We consider the problem of fairly allocating indivisible goods, focusing on a recently introduced notion of fairness called
maximin share guarantee
: each player’s value for his allocation should be at least as high as what he can guarantee by dividing the items into as many bundles as there are players and receiving his least desirable bundle. Assuming additive valuation functions, we show that such allocations may not exist, but allocations guaranteeing each player 2/3 of the above value always exist. These theoretical results have direct practical implications.
Compact Implementations of ARX-Based Block Ciphers on IoT Processors
Authors: Seo Hwajeong , Jeong Ilwoong , Lee Jungkeun , Kim Woo-Hwan
Published: February 2018

In this article, we present implementations for Addition, Rotation, and eXclusive-or (ARX)-based block ciphers, including LEA and HIGHT, on IoT devices, including 8-bit AVR, 16-bit MSP, 32-bit ARM, and 32-bit ARM-NEON processors. We optimized 32-/8-bitwise ARX operations for LEA and HIGHT block ciphers by considering variations in word size, the number of general purpose registers, and the instruction set of the target IoT devices. Finally, we achieved the most compact implementations of LEA and HIGHT block ciphers. The implementations were fairly evaluated through the Fair Evaluation of Lightweight Cryptographic Systems framework, and implementations won the competitions in the first and the second rounds.
Resistance training recovers attenuated APPL1 expression and improves insulin-induced Akt signal activation in skeletal muscle of type 2 diabetic rats
Authors: Kido Kohei , Ato Satoru , Yokokawa Takumi , Sato Koji , Fujita Satoshi
Published: February 2018

Adapter protein containing Pleckstrin homology (PH) domain, phosphotyrosine-binding (PTB) domain, and leucine zipper motif 1 (APPL1) has been reported as a positive regulator of insulin-stimulated Akt activation. The expression of APPL1 is reduced in skeletal muscles of type 2 diabetic (T2D) animals, implying that APPL1 may be an important factor affecting insulin sensitivity. However, the regulation of APPL1 expression and the physiological interventions modulating these effects are unclear. Accordingly, we first confirmed that APPL1 expression and insulin-induced Akt phosphorylation were significantly attenuated in skeletal muscles of T2D rats. Additionally, we found that APPL1 expression levels were significantly correlated with fasting blood glucose levels. Next, we identified important signals involved in the expression of APPL1. APPL1 mRNA expression increased upon AMP-activated protein kinase, calcium, p38 mitogen-activated protein kinase, and insulin-like growth factor-1 signal activation. Moreover, acute resistance exercise in vivo significantly activated these signaling pathways. Finally, through in vivo experiments, we found that chronic resistance training (RT) increased APPL1 expression and activated insulin-induced Akt signaling in skeletal muscles of rats with T2D. Furthermore, variations in APPL1 expression (i.e., the difference between control and RT muscles) significantly correlated with variations in insulin-stimulated Akt phosphorylation under the same conditions. Therefore, chronic RT recovered attenuated APPL1 expression and improved insulin-stimulated Akt phosphorylation in skeletal muscles of T2D rats. Accordingly, APPL1 may be a key regulator of insulin resistance in skeletal muscle, and RT may be an important physiological treatment increasing APPL1 expression, which is attenuated in T2D.
Assessment of Two Years’ Sputum Smear Results among Tuberculosis Suspected Patients in Gambella Regional Hospital, Western Ethiopia
Authors: Wolde Mistire , Fereja Alemayehu
Published: February 2018

Background. Determining burden of pulmonary tuberculosis (PTb) may be associated with success of directly observed theraphy (DOT) services in high PTb areas, such as Gambella, Ethiopia. Objective. To assess burden of sputum smear positive SSP-PTb reports in Gambella Regional Hospital, in two consecutive years: mid 2013 to 2015. Methods. From March 2013 to February 2015, PTb suspected patients’ sputum Acid Fast Bacilli test results were collected from laboratory registration book of Gambella Regional Hospital, western Ethiopia. Results. Of the total 3064 results, the proportions of males and individuals whose age is between 16 and 25 years were 1823 (59.5%) and 1046 (34.1%), respectively. Majority of samples were coming from newly PTb suspected patients (2587, or 84.4%); and of them, SSP-PTb cases were 9.9%. The overall SSP-PTb cases decreased by 2.1% in March 2014 to February 2015 as compared to March 2013 to Feburary 2014. Meanwhile, AFB smear negative cases were significantly associated with being male [1.384 (1.064–1.801)] and being of age group 16–25 years [1.517 (1.007–2.287)]. Conclusion. In Gambella region, although the distribution of AFB smear results had no significant yearly variations and the overall burden of SSP cases was decreased, still a lot of work needs to be undertaken on the PTb prevention and control program.
New Ni-Anthracene Complex for Selective and Sensitive Detection of 2,4,6-Trinitrophenol
Authors: Reddy Kumbam Lingeshwar , Kumar Anabathula Manoj , Dhir Abhimanew , Krishnan Venkata
Published: February 2018

Selective and sensitive detection of explosive materials through a simple approach is an attractive area of research having implications on public safety and homeland security. Considering this implication in mind, a new Ni-anthracene complex was designed and synthesized and has been demonstrated as an efficient fluorescence chemosensor for the selective and sensitive detection of 2,4,6-trinitrophenol. Firstly, a fluorescent anthracene ligand (A) was synthesized by treating anthracene-9-carboxaldehyde with 1,3-diaminopropane in presence of a weak acid. To achieve superior selectivity and great quenching efficiency for 2,4,6-trinitrophenol (TNP), a Ni complex, namely, [Ni(μ2-L)(NO3)] (B), was synthesized via the reaction of A with Ni(NO3)2·6H2O. Complex B showed strong emission peak (λmax) at 412 nm and exhibited high selectivity towards TNP among other nitroaromatics and anions. 100 equivalents of TNP made 95% fluorescence quenching of B and its detection limit for TNP was calculated as 2.8 μM.
Clinical Relapses of Atypical HUS on Eculizumab: Clinical Gap for Monitoring and Individualised Therapy
Authors: Teoh Chia Wei , Gorman Kathleen Mary , Lynch Bryan , Goodship Timothy H. J. , Dolan Niamh Marie , Waldron Mary , Riordan Michael , Awan Atif
Published: February 2018

Atypical hemolytic uremic syndrome (aHUS) is caused by dysregulation of the complement system. A humanised anti-C5 monoclonal antibody (eculizumab) is available for the treatment of aHUS. We present the first description of atypical HUS in a child with a coexistent diagnosis of a POL-III leukodystrophy. On standard eculizumab dosing regime, there was evidence of ongoing C5 cleavage and clinical relapses when immunologically challenged. Eculizumab is an effective therapy for aHUS, but the recommended doses may not be adequate for all patients, highlighting the need for ongoing efforts to develop a strategy for monitoring of treatment efficacy and potential individualisation of therapy.
Antidiarrheal Activity of 80% Methanolic Leaf Extract of Justicia schimperiana
Authors: Mekonnen Belay , Asrie Assefa Belay , Wubneh Zewdu Birhanu
Published: February 2018

Background. Diarrhea is one of the leading causes of preventable death in developing countries and mainly affects children and infants. It has been reported that the leaf of Justicia schimperiana is used as an antidiarrheal agent in Libo Kemekem district, northwest Ethiopia. Method. The 80% methanolic leaf extract of J. schimperiana was evaluated for its activity against castor oil‐induced diarrhea, enteropooling, and gastrointestinal motility in mice. Results. Significant reduction (p < 0.001) in the total defecation and diarrheal drops was produced by all the test doses of the extract. Percentage inhibition of wet feces was 42.58, 65.07, and 74.96% at 100, 200, and 400 mg/kg doses of the extract, respectively. The extract also significantly inhibited castor oil‐induced enteropooling at all test doses. The percent reduction in mean weight of intestinal contents was 66.96, 67.83, and 76.52% at 100, 200, and 400 mg/kg doses of the extract, respectively. The extract significantly reduced gastrointestinal movement of charcoal meal as well at 200 (p < 0.01) and 400 mg/kg (p < 0.001) doses. Conclusion. In conclusion, the methanolic leaf extract of J. schimperiana has an antidiarrheal activity and this supports the use of this plant in the treatment of diarrhea in the traditional settings.
Effect of Hemifacial Spasm on Intraocular Pressure Measurement
Authors: Cicik Erdogan , Yildirim Rengin , Arici Ceyhun , Dikkaya Funda , Arslan Osman Sevki
Published: February 2018

Purpose. To evaluate the effect of hemifacial spasm (HFS) on intraocular pressure (IOP) measurement. Methods. Twenty-four consecutive patients with HFS and 25 age- and gender-matched randomly selected eyes of healthy volunteers underwent corneal pachymetry and IOP measurements using Goldmann applanation tonometer (GAT) and noncontact tonometer (NCT). IOP measurements were performed before (during HFS) and 2 weeks after Botox injections in HFS patients and in healthy volunteers without Botox injections. Results. There was no statistical difference between involved eye side and uninvolved eye side of HFS patients in measured central corneal thickness. Similarly, no difference was found between involved eye side of HFS patients and controls. There were no statistically significant differences comparing IOP values before treatment and levels measured at 2 weeks of Botox injections, either with GAT (p=0.33, 0.11) or NCT (p=0.80, 0.43) devices in the involved eyes and uninvolved eyes of patients with HFS, respectively. There were also no significant differences in these parameters (GAT (p=0.63) and NCT (p=0.54)) in controls. Conclusions. Contractions in facial muscles may not lead to significant increase in IOP in HFS patients. This result may help clinical decision making in the treatment of glaucoma patients with HFS. This trial is registered with NCT03390803.
Primary Peritonitis: An Index Case of Mycoplasma hominis Infection in a Healthy Female
Authors: Drexel Sabrina , Tseng Daniel
Published: February 2018

Introduction. Primary peritonitis in healthy immunocompetent individuals is rare. Several case reports of Streptococcus species causing peritonitis have been described. Here, we present the first case of Mycoplasma hominis as the cause of primary peritonitis in a healthy woman. Case Report. A 42-year-old female with history of uterine fibroids was admitted with abdominal pain and intraperitoneal fluid of unknown etiology. She was initially managed nonoperatively and empirically treated with broad spectrum antibiotics. Blood and urine cultures were unrevealing. Increasing abdominal pain and peritoneal fluid prompted diagnostic laparoscopy which revealed a dense fibrinous exudate covering the entire peritoneal cavity. Peritoneal fluid and biopsies were sent for cytology and culture. The peritoneal fluid was eventually sent for 16 s ribosomal analysis, which discovered Mycoplasma hominis RNA. Her antibiotics were narrowed, and she eventually made a full recovery. Discussion. M. hominis is a rare source of systemic infection but has been known to colonize the urogenital tract and cause localized infections. This is the first presentation of M. hominis causing primary peritonitis in a healthy immunocompetent female. Multidisciplinary management of these patients is critical to achieve a timely diagnosis. Surgical exploration is often unavoidable to rule out secondary peritonitis.
Poly(delta-gluconolactone) and Poly(delta-gluconolactone-ε-caprolactone) from delta-Gluconolactone and ε-Caprolactone by Ring-Opening Polymerization
Authors: Li Ruijiang , Wang Peng , Ren Haohao , Li Hong , Ding Zhengwen , Yan Yonggang
Published: February 2018

Poly(delta-gluconolactone) (PGL) and poly(delta-gluconolactone-ε-caprolactone) (P(GL-CL)) were synthesized through ring-opening polymerization (ROP) and characterized by FT-IR, NMR, XRD, intrinsic viscosity, GPC, DSC, and TGA. The crystallinity of P(GL-CL) with various d-GL/CL ratios (d-GL/CL = 5 : 5, 4 : 6, 3 : 7, 2 : 8, and 1 : 9) was 12.09 to 59.78% while PGL was amorphous. Melting temperature (Tm) of these polymers was 49.8 to 62.0°C and decomposition temperature was 282 to 489°C depending on the d-GL/CL ratios. In addition, all these polymers were degradable and the degradation rates could be controlled by adjusting d-GL/CL ratios. These results indicated that PGL and P(GL-CL) might be promising novel absorbable materials.
Efficient 3D Volume Reconstruction from a Point Cloud Using a Phase-Field Method
Authors: Jeong Darae , Li Yibao , Lee Heon Ju , Lee Sang Min , Yang Junxiang , Park Seungwoo , Kim Hyundong , Choi Yongho , Kim Junseok
Published: February 2018

We propose an explicit hybrid numerical method for the efficient 3D volume reconstruction from unorganized point clouds using a phase-field method. The proposed three-dimensional volume reconstruction algorithm is based on the 3D binary image segmentation method. First, we define a narrow band domain embedding the unorganized point cloud and an edge indicating function. Second, we define a good initial phase-field function which speeds up the computation significantly. Third, we use a recently developed explicit hybrid numerical method for solving the three-dimensional image segmentation model to obtain efficient volume reconstruction from point cloud data. In order to demonstrate the practical applicability of the proposed method, we perform various numerical experiments.
Fabrication, Characterization, and Functionalization of Single-Walled Carbon Nanotube Conjugated with Tamoxifen and Its Anticancer Potential against Human Breast Cancer Cells
Authors: Oskoueian Arshin , Amin Matori Khamirul , Bayat Saadi , Oskoueian Ehsan , Ostovan Farhad , Toozandehjani Meysam
Published: February 2018

In this experiment, we aimed to fabricate SWCNT conjugated with tamoxifen and evaluated its anticancer potential against human breast cancer cells (MCF-7). The results showed that SWCNT was synthetized successfully using chemical vapor deposition (CVD) method. The results of Raman spectroscopy, SEM, and TEM analyses confirmed the synthesis of highly pure SWCNT. The functionalization of SWCNT was performed by oxidizing of SWCNT, attachment of polyethylene glycol (PEG) to oxidized SWCNT, and attachment of azelaic acid to the polyethylene glycol group. As a result, the SWCNT with free functional carboxylic acid and hydroxyl groups (SWCNT-PEG) was developed. The SWCNT-PEG was then conjugated with tamoxifen (SWCNT-PEG-TAM). The FT-IR together with NMR results confirmed the conjugation of tamoxifen to functionalized SWCNT (SWCNT-PEG-TAM). The cytotoxic concentrations (CC50) of SWCNT-PEG, tamoxifen, and SWCNT-PEG-TAM were >100, 12.67±2.69, and 5.49±1.34μg/ml, respectively. Linking tamoxifen to functionalized SWCNT enhanced the cytotoxic action of tamoxifen against breast cancer cells up to 2.3 times. The results of the morphological examination and caspase-3 activity confirmed the higher cytotoxic action of SWCNT-PEG-TAM as compared to free tamoxifen. The results obtained in this study indicated that this delivery system enhanced the therapeutic effects and anticancer potential of tamoxifen against human breast cancer cells.
A Phase I Study of CPI-613 in Combination with High-Dose Cytarabine and Mitoxantrone for Relapsed or Refractory Acute Myeloid Leukemia
Authors: Pardee Timothy S. , Anderson Rebecca G. , Pladna Kristin M. , Isom Scott , Ghiraldeli Lais P. , Miller Lance D. , Chou Jeff W. , Jin Guangxu , Zhang Wei , Ellis Leslie R. , Berenzon Dmitriy , Howard Dianna S. , Hurd David D. , Manuel Megan , Dralle Sarah , Lyerly Susan , Powell Bayard L.
Published: February 2018

Purpose: CPI-613, a lipoate analogue that inhibits pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase (KGDH), has activity in patients with myeloid malignancies. This study explored the role of mitochondrial metabolism in chemotherapy response and determined the MTD, efficacy, and safety of CPI-613 combined with high-dose cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia.

Experimental Design: The role of mitochondrial response to chemotherapy was assessed in cell lines and animal models. A phase I study of CPI-613 plus cytarabine and mitoxantrone was conducted in patients with relapsed or refractory AML.

Results: Exposure to chemotherapy induced mitochondrial oxygen consumption that depended on PDH. CPI-613 sensitized AML cells to chemotherapy indicating that mitochondrial metabolism is a source of resistance. Loss of p53 did not alter response to CPI-613. The phase I study enrolled 67 patients and 62 were evaluable for response. The overall response rate was 50% (26CR+5CRi/62). Median survival was 6.7 months. In patients over 60 years old, the CR/CRi rate was 47% (15/32) with a median survival of 6.9 months. The response rate for patients with poor-risk cytogenetics also was encouraging with 46% (11/24 patients) achieving a CR or CRi. RNA sequencing analysis of a subset of baseline bone marrow samples revealed a gene expression signature consistent with the presence of B cells in the pretreatment marrow of responders.

Conclusions: The addition of CPI-613 to chemotherapy is a promising approach in older patients and those with poor-risk cytogenetics. Clin Cancer Res; 24(9); 2060–73. ©2018 AACR.
REGγ Controls Hippo Signaling and Reciprocal NF-κB–YAP Regulation to Promote Colon Cancer
Authors: Wang Qingwei , Gao Xiao , Yu Tong , Yuan Lei , Dai Jie , Wang Weicang , Chen Geng , Jiao Chan , Zhou Wang , Huang Quan , Cui Long , Zhang Pei , Moses Robb E. , Yang Jianhua , Chen Fengyuan , Fu Junjiang , Xiao Jianru , Li Lei , Dang Yongyan , Li Xiaotao
Published: February 2018

Purpose: Colorectal cancer is one of the most commonly diagnosed cancers closely associated with inflammation and hyperactive growth. We previously demonstrated a regulatory circuit between the proteasome activator REGγ and NF-kappaB (NF-κB) during colon inflammation, known to be important in the development of colitis-associated cancer as well as sporadic colorectal cancer. How the inflammatory microenvironment affects the Hippo pathway during colorectal cancer development is largely unknown.

Experimental Design: Here, we used REGγ-deficient colon cancer cell lines, REGγ knockout mice, and human colorectal cancer samples to identify the novel molecular mechanism by which REGγ functions as an oncoprotein in the development of colorectal cancer.

Results: REGγ can directly interact with Lats1 and promote its degradation, which facilitates Yes-associated protein (YAP) activation in colon cancer cells. REGγ deficiency significantly attenuated colon cancer growth, associated with decreased YAP activity. Suppression of tumor growth due to REGγ depletion was overcome by constitutively active YAP. Surprisingly, reciprocal activation of the YAP and NF-κB pathways was observed in human colon cancer cells. REGγ overexpression was found in over 60% of 172 colorectal cancer specimens, highly correlating with the elevation of YAP and p65. Postoperative follow-up revealed a significantly lower survival rate in patients with concomitantly high expression of REGγ, YAP, and p-p65.

Conclusions: REGγ could be a master regulator during colorectal cancer development to promote YAP signaling and reinforce cross-talks between inflammation and growth pathways, and REGγ might be a new marker for prognosis of colorectal cancer patients. Clin Cancer Res; 24(8); 2015–25. ©2018 AACR.
The Effect of Chemically Modified Tetracycline-3 on the Progression of Dental Caries in Rats
Authors: Xu Jun , Miao Congcong , Tian Zhenchuan , Li Jinlu , Zhang Chunmei , Yang Dongmei
Published: February 2018

Objective: Matrix metalloproteinases (MMPs) exist in human saliva and dentin and play an important role in the degradation of organic matrix in teeth. Chemically modified tetracycline-3 (CMT-3) is an inhibitor of MMPs. CMT-3 has been used experimentally to treat caries since 1999, but no distinction between dental caries prevalence and dentin caries prevalence has been described. Methods: A total of 65 Sprague-Dawley rats were randomly divided into three groups. The positive control group (25 rats) was inoculated with Streptococcus mutans (ATCC700610) and fed the cariogenic feed of improved Keyes Diet 2000. The CMT-3 group (25 rats) was also inoculated with S. mutans and fed the cariogenic feed of improved Keyes Diet 2000; the surfaces of rats’ molars were daily treated with 0.02% CMT-3. The negative control group (15 rats) was only fed the standard rodent chow. At the end of the 10th week, the dental caries prevalence and dentin caries prevalence of each group were calculated, and the regions of caries were assessed. Results: No caries was found in the negative control group. The dental caries prevalence of the CMT-3 and the positive control group was 75.0 and 83.3%, respectively (p > 0.05, Table 2). The dentin caries prevalence of the CMT-3 and the positive control group was 33.3 and 70.8%, respectively (p < 0.05, Table 2). The Keyes scoring of dentin caries in the CMT-3 group was significantly lower than that in the positive control group (p < 0.05, Table 3). Conclusions: CMT-3 had no effect on the prevalence of dental caries, but could lower the prevalence and slow down the progression of dentin caries.
Magnesium as a Neuroprotective Agent: A Review of Its Use in the Fetus, Term Infant with Neonatal Encephalopathy, and the Adult Stroke Patient
Authors: Lingam Ingran , Robertson Nicola J.
Published: February 2018

Magnesium is an intracellular cation essential for many en-zymatic processes and cellular functions. Magnesium sulfate acts as an endogenous calcium channel antagonist at neuronal synapses, thought to prevent excessive activation of N-methyl-D-aspartate receptors by excitatory amino acids, such as glutamate, and by downregulation of proinflammatory pathways. Early intervention is essential in the prevention of the secondary phase of neuronal injury. The immature brain is particularly prone to excitotoxicity, and inflammation has been strongly implicated in the pathogenesis of cerebral palsy. This article explores the current status of magnesium being used as an adjunct to hypothermia in term neonatal encephalopathy (NE) against a background of its use in other populations. There is some evidence for magnesium sulfate as a neuroprotective agent, however animal studies of NE at term equivalent age have been confounded by concomitant hypothermia induced by magnesium itself. Nevertheless, the combination of magnesium and cooling has been shown to be more effective than either treatment alone in adult rodents. In the preterm baby, magnesium sulfate given antenatally in threatened preterm labor has demonstrated a significant reduction in the risk of cerebral palsy at 2 years of age, though the benefit is not clear at school age. In adult clinical studies of ischemic and hemorrhagic stroke, there have been disappointing results for magnesium sulfate as a neuroprotective strategy. Importantly, clinical neurological scores may be affected by the increased hypotonia observed. We suggest that magnesium sulfate should be carefully re-evaluated as a neuroprotective agent given its favorable safety profile, relative low cost, and widespread availability.
Surrogat-Endpunkt als Hinweis auf das Gesamtüberleben: PPS birgt keinen Vorteil
Authors: Reinmuth Niels
Published: February 2018

Background: In patients with non-small-cell lung cancer (NSCLC), the effects of second-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies. Therefore, using individual-level data, we aimed to determine the relationships between progression-free survival (PFS) and post-progression survival (PPS) with OS in patients with advanced NSCLC treated with docetaxel monotherapy as second-line chemotherapy. Methods: Between April 2002 and December 2014, data from 86 patients with advanced NSCLC who underwent second-line docetaxel monotherapy following first-line treatment with platinum combination chemotherapy were analyzed. The relationships of PFS and PPS with OS were analyzed at the individual level. Results: Spearman rank correlation and linear regression analyses showed that PPS was strongly associated with OS (r = 0.86, p < 0.05, R 2 = 0.93), whereas PFS was moderately correlated with OS (r = 0.50, p < 0.05, R 2 = 0.21). Performance status at the end of second-line treatment and the number of regimens after progression beyond second-line chemotherapy were significantly associated with PPS (p < 0.05). Conclusions: In patients with advanced NSCLC with unknown oncogenic driver mutations undergoing docetaxel monotherapy as second-line chemotherapy, when compared with PFS, PPS had a stronger association with OS. This finding suggests that subsequent treatment after disease progression following second-line docetaxel monotherapy has a significant influence on OS.
Eine ungewöhnliche Nebennieren-Raumforderung: Ein Fallbericht
Authors: Seidel Ann-Katrin , Pless Miklos , Michel Christian , Soll Christopher , Hochuli Caroline , Gubler Jacques
Published: February 2018

Zehn Jahre nach der zweiten Rezidiv-Behandlung eines diffusen großzelligen B-Zell-Lymphoms stellte sich ein 64-jähriger, beschwerdefreier Mann zur Jahreskontrolle in der onkologischen Sprechstunde vor. Im Abdomen-Ultraschall imponierte dabei eine neue eindrückliche Nebennieren-Raumforderung. Demzufolge stellte sich der dringende Verdacht auf ein Zweitmalignom auch in Hinblick auf die ausgedehnte onkologische Vorbehandlung. Überraschenderweise ergab die Histologie eine ganz andere, sehr seltene Ursache für diese pseudotumoröse Läsion. Übersetzung aus Case Rep Oncol 2017;10:981-986 (DOI: 10.1159/000481501)
Microcomputed Tomography Evaluation of Dentine Mineral Concentration in Primary Molars Managed by Three Treatment Protocols
Authors: Mijan Maitê Cevallos , Frencken Jo E. , Schwass Donald R. , Chaves Sacha B. , Leal Soraya Coelho
Published: February 2018

The objectives of the study were to quantify the dentine mineral concentration (DMC) in teeth restored conventionally, according to the atraumatic restorative treatment (ART) and ultraconservative (UCT) protocols (open cavities and small ART restorations), and the DMC underneath the open cavities of teeth managed by UCT versus nontreated, open cavities. We studied 50 teeth with restorations/open cavities, 39 restored teeth (9 by conventional restorative treatment [CRT], 17 by ART, and 13 by UCT) and 16 teeth with open cavities. Each restoration/open cavity was scanned using microcomputed tomography, with 3 hydroxyapatite disks with respective densities of 1.24, 1.33, and 1.57 g/cm3 as a reference. Images were reconstructed and the greyscale images were converted into DMC values. For each restoration/open cavity, 15 measurements of dentine immediately underneath and from the corresponding area in sound dentine were taken. DMC was expressed as a percentage of the DMC of sound dentine. ANOVA and the Student t test were used for statistical analysis. The mean DMC underneath restorations of the ART protocol group (98.93%) was statistically significantly higher than that of the UCT protocol group (91.98%), but not of the CRT protocol group (91.33%). On multiple surfaces, mean DMC in the axial area (94.32%) was statistically significantly higher than in the gingival area (92.80%). The mean DMC of open cavities managed by UCT protocol (89.05%) was statistically significantly higher than in nontreated open cavities (83.90%). In conclusion, a dentine-hypermineralized area underneath ART restorations was observed. Managing open cavities with a toothbrush and fluoride toothpaste (the UCT protocol) resulted in higher mineralized dentine underneath the cavity than in nontreated open cavities.
Craniofacial Distraction in the Management of Anterior Plagiocephaly: A Novel Idea and a Systematic Review of the Literature
Authors: Elbanoby Tarek
Published: February 2018

Background: The objective of this work is to present a review of all reports involving the management of unicoronal synostosis with distraction osteogenesis (DO). Also, we have innovated a new method in the treatment of cases of anterior plagiocephaly at a young age using DO. Methods: We present a case in which anterior plagiocephaly was treated by DO of both metopic and hemicoronal sutures in a 4-month-old female patient. A comprehensive systematic literature review was completed using the search terms “distraction osteogenesis,” “unicoronal synostosis,” “anterior plagiocephaly,” and “craniosynostosis.” We excluded all experimental articles and reviewed clinical reports detailing the use of DO in the management of unicoronal synostosis. Results: The study sample of this review consisted of 16 reports published over a period of 17 years that were analyzed in detail. The total number of patients treated by DO was 120, and the mean age at operation was 12 months. In the case presented, successful correction of the unicoronal synostosis was achieved. Conclusion: Hemicoronal and metopic suture distraction in anterior plagiocephaly achieves considerable improvement in the midline shift of the anterior cranial base and naso-orbital complex.
Heterogeneity of Thyroid Cancer
Authors: Chmielik Ewa , Rusinek Dagmara , Oczko-Wojciechowska Malgorzata , Jarzab Michal , Krajewska Jolanta , Czarniecka Agnieszka , Jarzab Barbara
Published: February 2018

There are 5 main histological types of thyroid cancers (TCs): papillary, follicular (also known as differentiated), poorly differentiated, anaplastic (the most aggressive form), and medullary TC, and only the latter arises from thyroid C cells. These different forms of TCs show significant variability, both among and within tumours. This great variation is particularly notable among the first 4 types, which all originate from thyroid follicular cells. Importantly, this heterogeneity is not limited to histopathological diversity only but is also manifested as variation in several genetic and/or epigenetic alterations, the numbers of interactions between the tumour and surrounding microenvironment, and interpatient differences, for example. All these factors contribute to the great complexity in the development of a tumour from cancer cells. In the present review, we summarise the knowledge accumulated about the heterogeneity of TCs. Further research in this direction should help to gain a better understanding of the underlying mechanisms contributing to the development and diversity of TCs, paving the way toward more effective treatment strategies.
Association of Blood Glucose and Clinical Outcome after Mechanical Thrombectomy for Acute Ischemic Stroke
Authors: Gordon Weston R. , Salamo Russell M. , Behera Anit , Chibnall John , Alshekhlee Amer , Callison Richard C. , Edgell Randall C.
Published: February 2018

Background: Elevated blood glucose levels following acute ischemic stroke have been associated with adverse clinical outcomes in thrombolytic and nonthrombolytic treated patients. The current study examined multiple blood glucose parameters and their association with modified Rankin Scale (mRS) score at 3 months following mechanical thrombectomy and hospital discharge. Methods: Acute ischemic stroke patients undergoing mechanical thrombectomy with a retrievable stent at two stroke centers were studied. Admission blood glucose level, maximum blood glucose during the hospital stay, and serial blood glucose measurements within the first 24 h of hospital admission were recorded. Variability in blood glucose level was represented by the standard deviation of the serial measurements within the first 24 h. The following demographic and clinical data was also collected: age, sex, baseline NIHSS score, onset-to-reperfusion times, hemoglobin A1c, and stroke mechanism. Results: 79 patients were identified; at 3 months, 35 patients had an mRS score of 0–2 and 44 had had an mRS of 3–6. Among the blood glucose variables, standard deviation of blood glucose in the first 24 h following admission and maximum blood glucose during hospital stay were significantly higher in the mRS 3–6 group. In multivariate logistic regression analysis, only the standard deviation of blood glucose remained significant (OR = 1.07, 95% CI = 1.02–1.11, p = 0.003) in a model that adjusted for admission NIHSS score (p = 0.016) and number of stent retriever passes (p = 0.042). Conclusions: Greater blood glucose variability following acute ischemic stroke is associated with worse clinical outcome in patients undergoing mechanical thrombectomy.
Second-Generation Hydrogel Coils for the Endovascular Treatment of Intracranial Aneurysms
Authors: Taschner Christian A. , Chapot René , Costalat Vincent , Machi Paolo , Courthéoux Patrick , Barreau Xavier , Berge Jérôme , Pierot Laurent , Kadziolka Krzysztof , Jean Betty , Blanc Raphaël , Biondi Alessandra , Brunel Hervé , Gallas Sophie , Berlis Ansgar , Herbreteau Denis , Berkefeld Joachim , Urbach Horst , Elsheikh Samer , Fiehler Jens , Desal Hubert , Graf Erika , Bonafé Alain
Published: February 2018

Background and Purpose—

Endovascular embolization of intracranial aneurysms with hydrogel-coated coils lowers the risk of major recurrence, but technical limitations (coil stiffness and time restriction for placement) have prevented their wider clinical use. We aimed to assess the efficacy of softer, second-generation hydrogel coils.

Methods—

A randomized controlled trial was conducted at 22 centers in France and Germany. Patients aged 18 to 75 years with untreated ruptured or unruptured intracranial aneurysms measuring 4 to 12 mm in diameter were eligible and randomized (1:1 using a web-based system, stratified by rupture status) to coiling with either second-generation hydrogel coils or bare platinum coils. Assist devices were allowed as clinically required. Independent imaging core laboratory was masked to allocation. Primary end point was a composite outcome measure including major aneurysm recurrence, aneurysm retreatment, morbidity that prevented angiographic controls, and any death during treatment and follow-up. Data were analyzed as randomized.

Results—

Randomization began on October 15, 2009, and stopped on January 31, 2014, after 513 patients (hydrogel, n=256; bare platinum, n=257); 20 patients were excluded for missing informed consent and 9 for treatment-related criteria. Four hundred eighty-four patients (hydrogel, n=243; bare platinum, n=241) were included in the analysis; 208 (43%) were treated for ruptured aneurysms. Final end point data were available for 456 patients. Forty-five out of 226 (19.9%) patients in the hydrogel group and 66/230 (28.7%) in the control group had an unfavorable composite primary outcome, giving a statistically significant reduction in the proportion of an unfavorable composite primary outcome with hydrogel coils—adjusted for rupture status—of 8.4% (95% confidence interval, 0.5–16.2;
P
=0.036). Adverse and serious adverse events were evenly distributed between groups.

Conclusions—

Our results suggest that endovascular coil embolization with second-generation hydrogel coils may reduce the rate of unfavorable outcome events in patients with small- and medium-sized intracranial aneurysms.

Clinical Trial Registration—

URL:
https://www.drks.de/drks_web/
. Unique identifier: DRKS00003132.
The Pictorial Portrayal of Women and Didactic Messages in the Han and Six Dynasties
Authors: Cheng Wen-chien
Published: February 2018

This study examines the visual forms into which Liu Xiang’s (ca. 79-8 BCE) compilation Lienü zhuan (Categorized biographies of women) were translated during the Han (221 BCE-220 CE) and Six Dynasties (220-589) periods. After Liu Xiang’s work appeared, the images of lienü were established as a distinctive visual category, developed within a broader context of a didactic pictorial genre that engaged the use of images for both the living and the dead. They not only provided admonitory functions, but also were considered auspicious and visually pleasant. In addition to a body of excavated lienü images from these periods, I examine two later scrolls originally rooted in this pictorial genre of lienü, the Lienü renzhi tu (Sympathetic and wise women scroll) in the Palace Museum, Beijing, and the Nüshi zhen tu (Admonitions of the court instructress) in the British Museum. I argue that the two paintings epitomize an ideal female exemplar who is virtuous, graceful, and physically attractive – all these qualities and their textual associations served as markers of the owner/viewer’s elite status.
Chinese Women Go Global: Discursive and Visual Representations of the Foreign ‘Other’ in the Early Chinese Women’s Press and Media
Authors: Bailey Paul J.
Published: February 2018

This article explores the multiple and complex ways in which the gendered foreign ‘Other’ was discursively represented in primarily women’s magazines during the late Qing and early Republic, a period that begins with an unravelling of the confidence in the ‘traditional’ Chinese Woman as the symbol of China’s superior civilisation (and, in a larger context, when Chinese elites were increasingly compelled to interrogate the raison d’être of their own social and cultural values amidst growing Anglo-American global hegemony). The article suggests that the ‘othering’ of the foreign woman in the early twentieth century anticipates contemporary Han Chinese representations of the Western Woman as an ‘ambiguous fetish’ and of ethnic minority women as exotic figures on the lower rungs of a civilisational ladder.