bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultra‐short bowel is an independent risk factor for liver fibrosis in adults with home parenteral nutrition
Authors: Cazals‐Hatem Dominique , Billiauws Lore , Rautou Pierre‐Emmanuel , Bondjemah Vanessa , Poté Nicolas , Corcos Olivier , Paradis Valérie , Joly Francisca
Published: August 2017

Background & Aims

Intestinal failure‐associated liver disease is rare in adults and risk factors are unclear. The aim of this study was to determine risk factors of liver fibrosis in adults receiving home parenteral nutrition for intestinal failure and its impact on survival.

Methods

We retrospectively analysed patients with irreversible intestinal failure who underwent a liver biopsy between 2000 and 2013. Significant liver fibrosis was defined as ≥F2 according to NASH‐CRN score.

Results

Thirty‐two patients (46 years [29‐60]) underwent liver biopsy 55 months (9‐201) after beginning parenteral nutrition. Twenty‐six patients (81%) had a short bowel (gut < 200 cm), including 12 (37%) with an ultra‐short bowel (gut < 20 cm). Eighteen patients (56%) had liver fibrosis (4 F2, 10 F3, 4 F4), associated with steatohepatitis (72%) and/or cholestasis (17%). Factors associated with occurrence of liver fibrosis included ultra‐short bowel (83% vs 13% at 60 months; P < .001), alcohol consumption (73% vs 33% at 60 months; P < .001) and diabetes (80% vs 34% at 60 months; P = .01). Home parenteral nutrition composition, quantity, or duration, episodes of sepsis, abandoned bowel segment were not associated with fibrosis. Ultra‐short bowel [risk ratio 12.4, P < .001] and alcohol consumption [risk ratio 7.4, P = .009] independently predicted the development of liver fibrosis on multivariate analysis. After a median follow‐up of 118 months (72‐155), survival was poorer in patients who developed liver fibrosis than in those without (59% vs 92% at 120 months; P = .02).

Conclusion

An ultra‐short bowel and alcohol consumption are independent risk factors for liver fibrosis in adults requiring HPN.
Endothelial precursor cells stimulate pericyte‐like coverage of bone marrow‐derived mesenchymal stem cells through platelet‐derived growth factor‐BB induction, which is enhanced by substance P
Authors: Zhang Mingzi , Ahn Woosung , Kim Sumin , Hong Hyun Sook , Quan Chengshi , Son Youngsook
Published: August 2017

Objective

The aim of this study was to evaluate the angiogenicity of a combination of BM‐EPCs and BM‐MSCs in vitro in the presence of SP and its working mechanism.

Methods

BM‐MSCs and BM‐EPCs were cocultured with or without SP. ELISA and RT‐PCR were performed to detect angiogenic factors such as VEGF and PDGF‐BB. N‐cadherin was detected by Western blot analysis. The tubular network‐forming ability was evaluated by a Matrigel tube‐forming assay.

Results

BM‐EPCs coculture with BM‐MSCs strongly stimulated the recruitment of BM‐MSCs onto the BM‐EPC‐generated endothelial tubular network. Upon SP treatment, endothelial branching point, tubule length, and tubular recruitment of BM‐MSCs were further increased and stabilized. The coculture of BM‐EPCs and BM‐MSCs synergistically stimulated expression of VEGF, VEGF receptor, N‐cadherin, and PDGF‐BB, all of which were further enhanced by SP treatment. Blockade of PDGF‐BB by its functional blocking antibodies markedly reduced the BM‐MSC incorporation into the endothelial tubules. SP‐pretreated BM‐MSCs were preferentially incorporated into the preformed BM‐EPC tubular network.

Conclusions

BM‐EPCs along with SP promote the pericyte‐like coverage of BM‐MSCs on endothelial tubules possibly through the induction of PDGF‐BB.
Prevalence of transactive response DNA‐binding protein 43 (TDP‐43) proteinopathy in cognitively normal older adults: systematic review and meta‐analysis
Authors: Nascimento C. , Di Lorenzo Alho A. T. , Bazan Conceição Amaral C. , Leite R. E. P. , Nitrini R. , Jacob‐Filho W. , Pasqualucci C. A. , Hokkanen S. R. K. , Hunter S. , Keage H. , Kovacs G. G. , Grinberg L. T. , Suemoto C. K.
Published: August 2017

Objective

To perform a systematic review and meta‐analysis on the prevalence of transactive response DNA‐binding protein 43 (TDP‐43) proteinopathy in cognitively normal older adults.

Methods

We systematically reviewed and performed a meta‐analysis on the prevalence of TDP‐43 proteinopathy in older adults with normal cognition, evaluated by the Mini‐Mental State Examination or the Clinical Dementia Rating. We estimated the overall prevalence of TDP‐43 using random‐effect models, and stratified by age, sex, sample size, study quality, antibody used to assess TDP‐43 aggregates, analysed brain regions, Braak stage, Consortium to Establish a Registry for Alzheimer's Disease score, hippocampal sclerosis and geographic location.

Results

A total of 505 articles were identified in the systematic review, and 7 were included in the meta‐analysis with 1196 cognitively normal older adults. We found an overall prevalence of TDP‐43 proteinopathy of 24%. Prevalence of TDP‐43 proteinopathy varied widely across geographic location (North America: 37%, Asia: 29%, Europe: 14%, and Latin America: 11%). Estimated prevalence of TDP‐43 proteinopathy also varied according to study quality (quality score >7: 22% vs. quality score <7: 42%), antibody used to assess TDP‐43 proteinopathy (native: 18% vs. hyperphosphorylated: 24%) and presence of hippocampal sclerosis (without 24% vs. with hippocampal sclerosis: 48%). Other stratified analyses by age, sex, analysed brain regions, sample size and severity of AD neuropathology showed similar pooled TDP‐43 prevalence.

Conclusions

Different methodology to access TDP‐43, and also differences in lifestyle and genetic factors across different populations could explain our results. Standardization of TDP‐43 measurement, and future studies about the impact of genetic and lifestyle characteristics on the development of neurodegenerative diseases are needed.
Evolutionarily diverse SYP1 Qa‐SNAREs jointly sustain pollen tube growth in Arabidopsis
Authors: Slane Daniel , Reichardt Ilka , El Kasmi Farid , Bayer Martin , Jürgens Gerd
Published: August 2017

Intracellular membrane fusion is effected by SNARE proteins that reside on adjacent membranes and form bridging trans‐SNARE complexes. Qa‐SNARE members of the Arabidopsis SYP1 family are involved in membrane fusion at the plasma membrane or during cell plate formation. Three SYP1 family members have been classified as pollen‐specific as inferred from gene expression profiling studies, and two of them, SYP124 and SYP125, are confined to angiosperms. The SYP124 gene appears genetically unstable, whereas its sister gene SYP125 shows essentially no variation among Arabidopsis accessions. The third pollen‐specific member SYP131 is sister to SYP132, which appears evolutionarily conserved in the plant lineage. Although evolutionarily diverse, the three SYP1 proteins are functionally overlapping in that only the triple mutant syp124 syp125 syp131 shows a specific and severe male gametophytic defect. While pollen development and germination appear normal, pollen tube growth is arrested during passage through the style. Our results suggest that angiosperm pollen tubes employ a combination of ancient and modern Qa‐SNARE proteins to sustain their growth‐promoting membrane dynamics during the reproductive process.
A new species and a new record of raphignathoid mites (Acari: Raphignathoidea: Camerobiidae, Stigmaeidae) occurring in the galleries of bark beetles (Coleoptera: Curculionidae: Scolytinae) from Russia
Authors: Khaustov Alexander , Abramov Vladimir
Published: August 2017

Female, larva and protonymph of a new species, Neophyllobius abiegnus sp. nov., collected in the galleries of Pityophthorus micrographus (Linnaeus) (Coleoptera: Curculionidae: Scolytinae) in European Russia are described. Protonymph of Neophyllobius sp. is recorded from Crimea in the galleries of Pityogenes bistridentatus (Eichhoff). Stigmaeus mitrofanovi Khaustov, 2014 is recorded from Western Siberia in the galleries of bark beetles Polygraphus proximus Blandford and Polygraphus subopacus Thomson for the first time from Asia.
Combating corruption in global health
Authors: Mackey Tim K. , Kohler Jillian , Lewis Maureen , Vian Taryn
Published: August 2017

Corruption is a critical challenge to global health efforts, and combating it requires international action, advocacy, and research.
Fluoride Depletes Acidogenic Taxa in Oral but Not Gut Microbial Communities in Mice
Authors: Yasuda Koji , Hsu Tiffany , Gallini Carey A. , Mclver Lauren J. , Schwager Emma , Shi Andy , DuLong Casey R. , Schwager Randall N. , Abu-Ali Galeb S. , Franzosa Eric A. , Garrett Wendy S. , Huttenhower Curtis , Morgan Xochitl C.
Published: August 2017

Fluoride has been added to drinking water and dental products since the 1950s. The beneficial effects of fluoride on oral health are due to its ability to inhibit the growth of bacteria that cause dental caries. Despite widespread human consumption of fluoride, there have been only two studies of humans that considered the effect of fluoride on human-associated microbial communities, which are increasingly understood to play important roles in health and disease. Notably, neither of these studies included a true cross-sectional control lacking fluoride exposure, as study subjects continued baseline fluoride treatment in their daily dental hygiene routines. To our knowledge, this work (in mice) is the first controlled study to assess the independent effects of fluoride exposure on the oral and gut microbial communities. Investigating how fluoride interacts with host-associated microbial communities in this controlled setting represents an effort toward understanding how common environmental exposures may potentially influence health.
Design of ballasted railway track foundations using numerical modelling. Part II: Applications
Authors: Sayeed Md. Abu , Shahin Mohamed A.
Published: August 2017

This paper is the second of two companion papers in relation to a new design method for ballasted railway track foundations. Development of the new design method has been explained in the first paper (i.e., Part I: Development), and the procedures for using the method and its practical application on some field case studies are presented in this paper. A special feature of the proposed design method is that it considers the true impact of train dynamic moving loads and number of repeated applications of the traffic tonnage. The proposed method is applied to four case studies of actual tracks and the results are compared with field measurements and found to be in good agreement. It should be noted that, although the proposed design method is able to overcome most shortcomings of the existing methods and found to provide excellent outcomes, further verification with more field case studies is highly desirable.
An Eco-Epidemiological Model with Different Competition Coefficients and Strong-Allee in the Prey
Authors: Saifuddin Md , Samanta Sudip , Biswas Santanu , Chattopadhyay Joydev
Published: August 2017

Strong-Allee effect and competition coefficients provide useful insight to the dynamics of eco-epidemiological systems. Basically, different competition coefficients in the prey population lead to the emergent carrying capacity. The study of population dynamics under the influence of strong-Allee parameter has attracted a lot attention from researchers. But the dynamics of such systems under the combined effect of disease, Allee and emergent carrying capacity is yet to receive attention from researchers. A simple eco-epidemiological model with strong-Allee effect in prey population is proposed and analyzed with the aim to observe the dynamics of such system under the combined influence of strong-Allee parameter and competition coefficients. The basic mathematical features of the model are analyzed with the help of equilibrium analysis, stability analysis, bistability and bifurcation theory. Our numerical simulations reveal that in the absence of strong-Allee effect, the three species eco-epidemiological system produces chaos by increasing the force of infection. However, we observe that chaotic dynamics thus obtained can be controlled by the Allee parameter as well as the competition coefficients.
Poincaré Map Construction for Some Classic Two Predators–One Prey Systems
Authors: Osipov Alexandr V. , Söderbacka Gunnar
Published: August 2017

In this paper, we consider a family of systems with two predators feeding on one prey. We show how to construct a positively invariant set in which it is possible to define a Poincaré map for examining the behavior of the system, mainly in the case when both predators survive. We relate it to examples from earlier works.
Constructing a Chaotic System with Any Number of Attractors
Authors: Zhang Xu
Published: August 2017

Applying some transformation to an autonomous system, we obtain a new system, which might keep the dynamical behavior of the original system or generate different dynamics. But this is often accompanied by the appearance of discontinuous points, where the vector field for the new system is not continuous at these points. We discuss the effects of the discontinuous points, and provide two methods to construct systems with any preassigned number of chaotic attractors via some transformation. The first one does not change the geometric structure of the attractors, since the discontinuous points are out of the basin of attraction. The second one might make the new systems have different dynamics, like multiscroll chaotic attractors, or infinitely many chaotic attractors. These results illustrate that both the equilibria and the discontinuous points affect the global dynamics.
Assessment of sulphate and iron reduction rates during reactor start-up for passive anaerobic co-treatment of acid mine drainage and sewage
Authors: Smyntek Peter M. , Chastel Jeffrey , Peer Rebecca A. M. , Anthony Evan , McCloskey Jacob , Bach Emily , Wagner Rachel C. , Bandstra Joel Z. , Strosnider William H. J.
Published: August 2017

Passive co-treatment of municipal wastewater (MWW) and acid mine drainage (AMD) has shown promise over the past decade for simultaneous remediation of these widespread waste streams. To investigate the efficiency and rates of iron and sulphate reduction during the start-up of anaerobic co-treatment using a novel, process-based kinetic modeling approach, twenty-four replicate 1L-cubitainers containing a 5:2 MWW:AMD mixture and Kaldnes plastic media were sealed, incubated and sacrificially sampled for key water quality parameters over 30 days. Alkalinity generation, pH increase and efficient removal of iron, aluminum and phosphate were observed. The observed sulphate and iron reduction rates were relatively slow, and the removal of sulphate, organic carbon and nitrogen was modest and incomplete. Overall, the results confirm the efficacy of AMD-MWW co-treatment for removal of key pollutants, but also highlight factors that may limit this emerging technology.

Supplementary material:
The fitted model parameters used to describe the behaviour of Fe, H
2
S and SO
4
2−
are available at
https://doi.org/10.6084/m9.figshare.c.3841279
MMI partial extraction geochemistry for the resolution of anthropogenic activities across the archaeological Roman town of Calleva Atrebatum
Authors: Sylvester Graham C. , Mann Alan W. , Cook Samantha R. , Wilson Clare A.
Published: August 2017

Sixty three soils samples, fourteen samples of previously excavated archaeological material, and five background soil samples taken at the Silchester Roman Town of Calleva Atrebatum in the County of Hampshire, United Kingdom were analysed by the Mobile Metal Ion (MMI) method for a total of fifty three elements. Samples from within the town walls showed considerably higher concentrations than samples outside for many elements; Au, Ag, Cu and Sn were in extremely anomalous concentrations, Bi, Cd, Hg, Mo, P and Pb were anomalous and Sb and Zn in elevated concentrations. The overall pattern of element distribution is one of an annulus of higher elemental concentrations surrounding a centre of generally lower values centred on the previously excavated Forum basilica. The elements Zr, Ti, Th, Ti, Tl, Nb, Sn, Sc, Cr, Co, Sb, Bi, Ce, Nd (and all other REEs), show similar distributions to one another, and their distribution and that of the noble and base metals, as highlighted by various additive indices, is considered to be the result of metallurgical processing on site. The low values for most elements around the Forum basilica are the result of disturbance of the soil geochemical profile in this area by previous archaeological excavation.
Analysis and Design of Associative Memories for Memristive Neural Networks with Deviating Argument
Authors: Zhang Jin-E
Published: August 2017

We investigate associative memories for memristive neural networks with deviating argument. Firstly, the existence and uniqueness of the solution for memristive neural networks with deviating argument are discussed. Next, some sufficient conditions for this class of neural networks to possess invariant manifolds are obtained. In addition, a global exponential stability criterion is presented. Then, analysis and design of autoassociative memories and heteroassociative memories for memristive neural networks with deviating argument are formulated, respectively. Finally, several numerical examples are given to demonstrate the effectiveness of the obtained results.
Antioxidant Effects of a Hydroxytyrosol‐Based Pharmaceutical Formulation on Body Composition, Metabolic State, and Gene Expression: A Randomized Double‐Blinded, Placebo‐Controlled Crossover Trial
Authors: Colica Carmela , Di Renzo Laura , Trombetta Domenico , Smeriglio Antonella , Bernardini Sergio , Cioccoloni Giorgia , Costa de Miranda Renata , Gualtieri Paola , Sinibaldi Salimei Paola , De Lorenzo Antonino
Published: August 2017

Hydroxytyrosol (HT) plays a significant role in cardiovascular disease (CVD) protection, and its metabolites are able to protect from the endothelial dysfunction commonly present in atherosclerosis. This randomized double‐blinded, placebo‐controlled crossover trial determined the effect in healthy volunteers of two gastroresistant capsules containing 15 mg/day of HT, for a 3‐week period (HTT). Evaluation of nutritional status, serum metabolites, oxidative stress biomarkers, and gene expression of 9 genes related to oxidative stress, inflammation, and CVDs was performed. Oxidation biomarkers like thiol group (p = 0.001), total antioxidant status (TAS) (p = 0.001), superoxide dismutase 1 (SOD1) (2−ΔΔCt = 3.7), and plasma concentration of HT (2.83 μg·mL−1) were significantly increased, while nitrite (p = 0.001), nitrate (p = 0.001), and malondialdehyde (MDA) (p = 0.02) were drastically reduced after HTT. A significant reduction of body fat mass percentage (p = 0.01), suprailiac skinfold (p = 0.01), and weight (p = 0.04; Δ% = −0.46%) was observed after HTT. This study shows that regular intake of 15 mg/day of HT changed body composition parameters and modulated the antioxidant profile and the expression of inflammation and oxidative stress‐related genes. However, it is advisable to personalize HT doses in order to exert its health benefits in CVD prevention and protection of LDL‐C particles from oxidative damage. This trial is registered with ClinicalTrials.gov NCT01890070.
Calciphylaxis of the Postmenopausal Female Breast: An Uncommonly Encountered Mimic of Carcinoma
Authors: Novotny Aaron G. , Simpson Ashley B. , Kral Melinda A. , Calhoun Benjamin C. , Cocco Amy E. , Billings Steven D. , Miller Susan K. , Lebda Paulette L. , Sturgis Charles D.
Published: August 2017

Calciphylaxis is a serious medical condition that is typically associated with end-stage renal disease and presents as the sequelae of calcifications in arterioles with subsequent ischemia of affected tissues. Classically, calciphylaxis produces ulcerated and necrotic skin lesions. These may be biopsied to aid in confirmation of the diagnosis. Herein we report a case of a large necrotic breast lesion in the clinical setting of calciphylaxis, and we emphasize that a multidisciplinary approach to diagnosis and management is important to avoid unnecessary oncological resection.
Predictors of Functional and Quality of Life Outcomes following Deep Brain Stimulation Surgery in Parkinson’s Disease Patients: Disease, Patient, and Surgical Factors
Authors: Abboud Hesham , Genc Gencer , Thompson Nicolas R. , Oravivattanakul Srivadee , Alsallom Faisal , Reyes Dennys , Wilson Kathy , Cerejo Russell , Yu Xin Xin , Floden Darlene , Ahmed Anwar , Gostkowski Michal , Ezzeldin Ayman , Marouf Hazem , Mansour Ossama Y. , Machado Andre , Fernandez Hubert H.
Published: August 2017

Objective. The primary objective was to evaluate predictors of quality of life (QOL) and functional outcomes following deep brain stimulation (DBS) in Parkinson’s disease (PD) patients. The secondary objective was to identify predictors of global improvement. Methods. PD patients who underwent DBS at our Center from 2006 to 2011 were evaluated by chart review and email/phone survey. Postoperative UPDRS II and EQ-5D were analyzed using simple linear regression adjusting for preoperative score. For global outcomes, we utilized the Patient Global Impression of Change Scale (PGIS) and the Clinician Global Impression of Change Scale (CGIS). Results. There were 130 patients in the dataset. Preoperative and postoperative UPDRS II and EQ-5D were available for 45 patients, PGIS for 67 patients, and CGIS for 116 patients. Patients with falls/postural instability had 6-month functional scores and 1-year QOL scores that were significantly worse than patients without falls/postural instability. For every 1-point increase in preoperative UPDRS III and for every 1-unit increase in body mass index (BMI), the 6-month functional scores significantly worsened. Patients with tremors, without dyskinesia, and without gait-freezing were more likely to have “much” or “very much” improved CGIS. Conclusions. Presence of postural instability, high BMI, and worse baseline motor scores were the greatest predictors of poorer functional and QOL outcomes after DBS.
The Role of Three-Dimensional Scaffolds in Treating Long Bone Defects: Evidence from Preclinical and Clinical Literature—A Systematic Review
Authors: Roffi Alice , Krishnakumar Gopal Shankar , Gostynska Natalia , Kon Elizaveta , Candrian Christian , Filardo Giuseppe
Published: August 2017

Long bone defects represent a clinical challenge. Bone tissue engineering (BTE) has been developed to overcome problems associated with conventional methods. The aim of this study was to assess the BTE strategies available in preclinical and clinical settings and the current evidence supporting this approach. A systematic literature screening was performed on PubMed database, searching for both preclinical (only on large animals) and clinical studies. The following string was used: “(Scaffold OR Implant) AND (Long bone defect OR segmental bone defect OR large bone defect OR bone loss defect).” The search retrieved a total of 1573 articles: 51 preclinical and 4 clinical studies were included. The great amount of preclinical papers published over the past few years showed promising findings in terms of radiological and histological evidence. Unfortunately, this in vivo situation is not reflected by a corresponding clinical impact, with few published papers, highly heterogeneous and with small patient populations. Several aspects should be further investigated to translate positive preclinical findings into clinical protocols: the identification of the best biomaterial, with both biological and biomechanical suitable properties, and the selection of the best choice between cells, GFs, or their combination through standardized models to be validated by randomized trials.
Replication Stress Leading to Apoptosis within the S-phase Contributes to Synergism between Vorinostat and AZD1775 in HNSCC Harboring High-Risk TP53 Mutation
Authors: Tanaka Noriaki , Patel Ameeta A. , Tang Lin , Silver Natalie L. , Lindemann Antje , Takahashi Hideaki , Jaksik Roman , Rao Xiayu , Kalu Nene N. , Chen Tseng-Cheng , Wang Jiping , Frederick Mitchell J. , Johnson Faye , Gleber-Netto Frederico O. , Fu Siqing , Kimmel Marek , Wang Jing , Hittelman Walter N. , Pickering Curtis R. , Myers Jeffrey N. , Osman Abdullah A.
Published: August 2017

Purpose: The cure rate for patients with advanced head and neck squamous cell carcinoma (HNSCC) remains poor due to resistance to standard therapy primarily consisting of chemoradiation. As mutation of TP53 in HNSCC occurs in 60% to 80% of non–HPV-associated cases and is in turn associated with resistance to these treatments, more effective therapies are needed. In this study, we evaluated the efficacy of a regimen combining vorinostat and AZD1775 in HNSCC cells with a variety of p53 mutations.

Experimental Design: Clonogenic survival assays and an orthotopic mouse model of oral cancer were used to examine the in vitro and in vivo sensitivity of high-risk mutant p53 HNSCC cell lines to vorinostat in combination with AZD1775. Cell cycle, replication stress, homologous recombination (HR), live cell imaging, RNA sequencing, and apoptosis analyses were performed to dissect molecular mechanisms.

Results: We found that vorinostat synergizes with AZD1775 in vitro to inhibit growth of HNSCC cells harboring high-risk mutp53. These drugs interact synergistically to induce DNA damage, replication stress associated with impaired Rad51-mediated HR through activation of CDK1, and inhibition of Chk1 phosphorylation, culminating in an early apoptotic cell death during the S-phase of the cell cycle. The combination of vorinostat and AZD1775 inhibits tumor growth and angiogenesis in vivo in an orthotopic mouse model of oral cancer and prolongs animal survival.

Conclusions: Vorinostat synergizes with AZD1775 in HNSCC cells with mutant p53 in vitro and in vivo. A strategy combining HDAC and WEE1 inhibition deserves further clinical investigation in patients with advanced HNSCC. Clin Cancer Res; 23(21); 6541–54. ©2017 AACR.
Burden and Profile of Somatic Mutation in Duodenal Adenomas from Patients with Familial Adenomatous- and MUTYH-associated Polyposis
Authors: Thomas Laura E. , Hurley Joanna J. , Meuser Elena , Jose Sian , Ashelford Kevin E. , Mort Matthew , Idziaszczyk Shelley , Maynard Julie , Brito Helena Leon , Harry Manon , Walters Angharad , Raja Meera , Walton Sarah-Jane , Dolwani Sunil , Williams Geraint T. , Morgan Meleri , Moorghen Morgan , Clark Susan K. , Sampson Julian R.
Published: August 2017

Purpose: Duodenal polyposis and cancer are important causes of morbidity and mortality in familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). This study aimed to comprehensively characterize somatic genetic changes in FAP and MAP duodenal adenomas to better understand duodenal tumorigenesis in these disorders.

Experimental Design: Sixty-nine adenomas were biopsied during endoscopy in 16 FAP and 10 MAP patients with duodenal polyposis. Ten FAP and 10 MAP adenomas and matched blood DNA samples were exome sequenced, 42 further adenomas underwent targeted sequencing, and 47 were studied by array comparative genomic hybridization. Findings in FAP and MAP duodenal adenomas were compared with each other and to the reported mutational landscape in FAP and MAP colorectal adenomas.

Results: MAP duodenal adenomas had significantly more protein-changing somatic mutations (P = 0.018), truncating mutations (P = 0.006), and copy number variants (P = 0.005) than FAP duodenal adenomas, even though MAP patients had lower Spigelman stage duodenal polyposis. Fifteen genes were significantly recurrently mutated. Targeted sequencing of APC, KRAS, PTCHD2, and PLCL1 identified further mutations in each of these genes in additional duodenal adenomas. In contrast to MAP and FAP colorectal adenomas, neither exome nor targeted sequencing identified WTX mutations (P = 0.0017).

Conclusions: The mutational landscapes in FAP and MAP duodenal adenomas overlapped with, but had significant differences to those reported in colorectal adenomas. The significantly higher burden of somatic mutations in MAP than FAP duodenal adenomas despite lower Spigelman stage disease could increase cancer risk in the context of apparently less severe benign disease. Clin Cancer Res; 23(21); 6721–32. ©2017 AACR.
Long-Term Progression of Sensorineural Hearing Loss and Tinnitus after Combined Intensity-Modulated Radiation Therapy and Cisplatin-Based Chemotherapy for Nasopharyngeal Carcinoma: A Case Report
Authors: Lee Ming S. , Penumala Sudha , Sweet Steven , De Luca Russell R. , Stearnes Ariel E. , Akgun Yamac
Published: August 2017

Sensorineural hearing loss (SNHL) is a common adverse effect for nasopharyngeal carcinoma (NPC) patients treated with chemoradiotherapy. We report a case of 12-year follow-up from a patient with stage IIB NPC, treated in 2004 with intensity-modulated radiotherapy and cisplatin-based chemotherapy. Pure-tone audiograms were conducted before treatment and at two other points in the 12-year period after treatment. Analysis of the patient’s audiograms reveals that the development of high-frequency SNHL started after treatment and reached a plateau accompanied by tinnitus approximately 32 months after treatment conclusion. After the plateau, high-frequency SNHL continued to develop slowly in the next 10 years, possibly a long-term effect from radiation-induced microvascular change of the hearing apparatus. The continuous high-frequency hearing decline is associated with increased tinnitus pitch in the patient. With experience learned from this case, we recommend hearing tests at regular intervals for at least 3–5 years for NPC patients treated with chemoradiotherapy. Patients need to be educated about tinnitus and counseling can be offered when they begin to feel inconvenienced by tinnitus. These patients also need to be advised against exposure to noise that can aggravate the already compromised hearing apparatus, leading to further hearing loss and worsening tinnitus. Limiting the peak dose and total cumulative dose of cisplatin should be considered based on the patients’ risk factors to achieve a balance between treatment efficacy and long-term adverse effects.
Perforated Gastric Ulcer Associated with Anti-Angiogenic Therapy
Authors: Libânio Diogo , Brandão Catarina , Pimentel-Nunes Pedro , Dinis-Ribeiro Mário
Published: August 2017

Anti-angiogenic therapy with bevacizumab, an inhibitor of vascular endothelial growth factor, is commonly used in metastatic colorectal cancer and is rarely associated with gastrointestinal perforation, perforation being more frequent in the primary tumor site or at the anastomotic level. We present the case of a 64-year-old male with stage IV rectal adenocarcinoma who was on palliative chemotherapy with FOLFOX and bevacizumab. After the 4th chemotherapy cycle, our patient started fever and epigastric pain. He was hemodynamically stable, and signs of peritoneal irritation were absent. There were no alterations in the abdominal X-ray, and C-reactive protein was markedly elevated. A CT scan revealed a de novo thickness in the gastric antrum. Upper digestive endoscopy showed an ulcerated 40-mm lesion in the angulus, with a 20-mm orifice communicating with an exsudative cavity revested by the omentum. A conservative approach was decided including fasting, broad-spectrum intravenous antibiotics, and proton-pump inhibitors. Subsequent gastroduodenal series showed no contrast extravasation, allowing the resumption of oral nutrition. Esophagogastroduodenoscopy after 8 weeks showed perforation closure. Biopsies did not show neoplastic cells or Heliobacter pylori infection. Although the success in the conservative management of perforation allowing the maintenance of palliative chemotherapy (without bevacizumab), the patient died after 4 months due to liver failure. The reported case shows an uncommon endoscopic finding due to a rare complication of anti-angiogenic therapy. Additionally, it reminds clinicians that a history of gastroduodenal ulcers should be actively sought before starting anti-angiogenic treatment and that suspicion for perforation should be high in these cases.
Identifying Relapses in Multiple Sclerosis Patients through Administrative Data: A Validation Study in the Lazio Region, Italy
Authors: Colais Paola , Agabiti Nera , Davoli Marina , Buttari Fabio , Centonze Diego , De Fino Chiara , Di Folco Marta , Filippini Graziella , Francia Ada , Galgani Simonetta , Gasperini Claudio , Giuliani Manuela , Mirabella Massimiliano , Nociti Viviana , Pozzilli Carlo , Bargagli AnnaMaria ,   on behalf of the Multiple Sclerosis Study Group, Lazio Region
Published: August 2017

Background: Relapse is frequently considered an outcome measure of disease activity in relapsing-remitting multiple sclerosis (MS). The objectives of this study were to identify relapse episodes in patients with MS in the Lazio region using health administrative databases and to evaluate the validity of the algorithm using patients enrolled at MS treatment centers. Methods: MS cases were identified in the period between January 1, 2006 and December 31, 2009 using data from regional Health Information Systems (HIS). An algorithm based on HIS was used to identify relapse episodes, and patients recruited at MS centers were used to validate the algorithm. Positive and negative predictive values (PPV, NPV) and the Cohen's kappa coefficient were calculated. Results: The overall MS population identified through HIS consisted of 6,094 patients, of whom 67.1% were female and the mean age was 41.5. Among the MS patients identified by the algorithm, 2,242 attended the centers and 3,852 did not. The PPV was 58.9%, the NPV was 76.3%, and the kappa was 0.36. Conclusions: The proposed algorithm based on health administrative databases does not seem to be able to reliably detect relapses; however, it may be a helpful tool to detect healthcare utilization, and therefore to identify the worsening condition of a patient's health.
Trifluoperazine-Induced Suicidal Erythrocyte Death and S-Nitrosylation Inhibition, Reversed by the Nitric Oxide Donor Sodium Nitroprusside
Authors: Ghashghaeinia Mehrdad , Wesseling Mauro Carlos , Ramos Elena , Petkova-Kirova Polina , Waibel Sabrina , Lang Elisabeth , Bissinger Rosi , Alzoubi Kossai , Edelmann Baerbel , Hosseinzadeh Zohreh , Dreischer Peter , Shahvaroughi-Farahani Azam , Mrowietz Ulrich , Köberle Martin , Kaestner Lars , Bernhardt Ingolf , Martínez-Ruiz Antonio , Wieder Thomas , Lang Florian
Published: August 2017

Background and Purpose: The high potency antipsychotic drug trifluoperazine (10-[3-(4-methyl-1-piperazinyl)-propyl]-2-(trifluoromethyl)-(10)H-phenothiazine dihydrochloride; TFP) may either counteract or promote suicidal cell death or apoptosis. Similar to apoptosis, erythrocytes may enter eryptosis, characterized by phosphatidylserine exposure at the cell surface and cell shrinkage. Eryptosis can be stimulated by an increase in cytoplasmic Ca2+ concentration ([Ca2+]i) and inhibited by nitric oxide (NO). We explored whether TFP treatment of erythrocytes induces phosphatidylserine exposure, cell shrinkage, and calcium influx, whether it impairs S-nitrosylation and whether these effects are inhibited by NO. Methods: Phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, and protein nitrosylation from fluorescence switch of the Bodipy-TMR/Sypro Ruby signal. Results: Exposure of human erythrocytes to TFP significantly enhanced the percentage of annexin-V-binding cells, raised [Ca2+]i, and decreased S-nitrosylation. The effect of TFP on annexin-V-binding was not affected by removal of extracellular Ca2+ alone, but was significantly inhibited by pre-treatment with sodium nitroprusside (SNP), an effect significantly augmented by additional removal of extracellular Ca2+. A 3 hours treatment with 0.1 µM Ca2+ ionophore ionomycin triggered annexin-V-binding and cell shrinkage, effects fully reversed by removal of extracellular Ca2+. Conclusions: TFP induces eryptosis and decreases protein S-nitrosylation, effects blunted by nitroprusside. The effect of nitroprusside is attenuated in the presence of extracellular Ca2+.
Effectiveness and Tolerability of Anticoagulants for Thromboprophylaxis after Major Joint Surgery: a Network Meta-Analysis
Authors: Wang Zhen , Zheng Jia , Zhao Yongqiang , Xiang Yungai , Chen Xiao , Jin Yi
Published: August 2017

Background/Aims: Venous thromboembolism (VTE) is the most common complication after major joint surgery. VTE can easily develop into pulmonary embolism (PE), leading to cardiopulmonary dysfunction or sudden death. We aimed to comprehensively analyse the thromboprophylactic drugs that are used to prevent thrombosis and reduce bleeding risk. Methods: We searched the PubMed, EMBASE, and Cochrane databases for randomized controlled trials that evaluated the use of thromboprophylaxis after major joint surgery. The major outcomes were the numbers of all-cause VTE and bleeding events, and the secondary outcomes were major VTE and major bleeding/clinically relevant non-major bleeding events. A random-effects network meta-analysis was used to assess the effectiveness and tolerability of each anticoagulant after major joint surgery. Results: We included 104 trials that assessed 110,643 patients in our meta-analysis. The cluster ranking of major outcomes indicated that FXI-ASO, ardeparin, aspirin, and apixaban were ideal for preventing all-cause VTE and avoiding all bleeding events. Nadroparin, recombinant hirudin, and rivaroxaban effectively inhibited VTE but were associated with a high risk of bleeding. For secondary outcomes, we found that betrixaban, dalteparin, warfarin, and eribaxaban were ideal for preventing major VTE and reducing major bleeding, while rivaroxaban effectively inhibited major VTE but was associated with a high risk of major/clinically relevant non-major bleeding. A sensitivity analysis showed that the effect of apixaban was more robust for major outcomes, while aspirin was more robust for preventing all-cause bleeding events. In secondary outcomes, the effect of warfarin was more robust, while apixaban was still considered an ideal treatment to inhibit major VTE and bleeding events. Conclusion: Our study indicates that FXI-ASO, ardeparin, aspirin, and apixaban are ideal for preventing all-cause VTE and reducing all bleeding events, among which apixaban is the most reliable. Betrixaban, dalteparin, warfarin, and eribaxaban are ideal for preventing major VTE and reducing major/clinically relevant non-major bleeding events, among which warfarin is the most reliable.
Progenitor Cells and Clinical Outcomes in Patients With Heart Failure
Authors: Samman Tahhan Ayman , Hammadah Muhammad , Sandesara Pratik B. , Hayek Salim S. , Kalogeropoulos Andreas P. , Alkhoder Ayman , Mohamed Kelli Heval , Topel Matthew , Ghasemzadeh Nima , Chivukula Kaavya , Ko Yi-An , Aida Hiroshi , Hesaroieh Iraj , Mahar Ernestine , Kim Jonathan H. , Wilson Peter , Shaw Leslee , Vaccarino Viola , Waller Edmund K. , Quyyumi Arshed A.
Published: August 2017

Background

Endogenous regenerative capacity, assessed as circulating progenitor cell (PC) numbers, is an independent predictor of adverse outcomes in patients with cardiovascular disease. However, their predictive role in heart failure (HF) remains controversial. We assessed the relationship between the number of circulating PCs and the pathogenesis and severity of HF and their impact on incident HF events.

Methods and Results

We recruited 2049 adults of which 651 had HF diagnosis. PCs were enumerated by flow cytometry as CD45med
+
blood mononuclear cells expressing CD34, CD133, vascular endothelial growth factor receptor-2, and chemokine (C-X-C motif) receptor 4 epitopes. PC subsets were lower in number in HF and after adjustment for clinical characteristics in multivariable analyses, a low CD34
+
and CD34
+
/CXCR
+
cell count remained independently associated with a diagnosis of HF (
P
<0.01). PC levels were not significantly different in reduced versus preserved ejection fraction patients. In 514 subjects with HF, there were 98 (19.1%) all-cause deaths during a 2.2±1.5-year follow-up. In a Cox regression model adjusting for clinical variables, hematopoietic-enriched PCs (CD34
+
, CD34
+
/CD133
+
, and CD34
+
/CXCR4
+
) were independent predictors of all-cause death (hazard ratio 2.0, 1.6, 1.6-fold higher mortality, respectively;
P
<0.03) among HF patients. Endothelial-enriched PCs (CD34
+
/VEGF
+
) were independent predictors of mortality in patients with HF with preserved ejection fraction only (hazard ratio, 5.0;
P
=0.001).

Conclusions

PC levels are lower in patients with HF, and lower PC counts are strongly and independently predictive of mortality. Strategies to increase PCs and exogenous stem cell therapies designed to improve regenerative capacity in HF, especially, in HF with preserved ejection fraction, need to be further explored.
Neutrophil Activation of Endothelial Cell-Expressed TRPM2 Mediates Transendothelial Neutrophil Migration and Vascular Injury
Authors: Mittal Manish , Nepal Saroj , Tsukasaki Yoshikazu , Hecquet Claudie M. , Soni Dheeraj , Rehman Jalees , Tiruppathi Chinnaswamy , Malik Asrar B.
Published: August 2017

Rationale:

TRPM2 (transient receptor potential melastatin-2) expressed in endothelial cells (ECs) is a cation channel mediating Ca
2+
entry in response to intracellular generation of adenosine diphosphoribose—the TRPM2 ligand.

Objective:

Because polymorphonuclear neutrophils (PMN) interaction with ECs generates reactive oxygen species, we addressed the possible role of TRPM2 expressed in ECs in the mechanism of transendothelial migration of PMNs.

Methods and Results:

We observed defective PMN transmigration in response to lipopolysaccharide challenge in adult mice in which the EC expressed TRPM2 is conditionally deleted (
Trpm2

iΔEC

). PMN interaction with ECs induced the entry of Ca
2+
in ECs via the EC-expressed TRPM2. Prevention of generation of adenosine diphosphoribose in ECs significantly reduced Ca
2+
entry in response to PMN activation of TRPM2 in ECs. PMNs isolated from
gp91phox
−/−
mice significantly reduced Ca
2+
entry in ECs via TRPM2 as compared with wild-type PMNs and failed to induce PMN transmigration. Overexpression of the adenosine diphosphoribose insensitive TRPM2 mutant channel (C1008→A) in ECs suppressed the Ca
2+
entry response. Further, the forced expression of TRPM2 mutant channel (C1008→A) or silencing of poly ADP-ribose polymerase in ECs of mice prevented PMN transmigration.

Conclusions:

Thus, endotoxin-induced transmigration of PMNs was secondary to TRPM2-activated Ca
2+
signaling and VE-cadherin phosphorylation resulting in the disassembly of adherens junctions and opening of the paracellular pathways. These results suggest blocking TRPM2 activation in ECs is a potentially important means of therapeutically modifying PMN-mediated vascular inflammation.
Cooperative Coevolution with Formula-Based Variable Grouping for Large-Scale Global Optimization
Authors: Wang Yuping , Liu Haiyan , Wei Fei , Zong Tingting , Li Xiaodong
Published: August 2017

For a large-scale global optimization (LSGO) problem, divide-and-conquer is usually considered an effective strategy to decompose the problem into smaller subproblems, each of which can then be solved individually. Among these decomposition methods, variable grouping is shown to be promising in recent years. Existing variable grouping methods usually assume the problem to be black-box (i.e., assuming that an analytical model of the objective function is unknown), and they attempt to learn appropriate variable grouping that would allow for a better decomposition of the problem. In such cases, these variable grouping methods do not make a direct use of the formula of the objective function. However, it can be argued that many real-world problems are white-box problems, that is, the formulas of objective functions are often known a priori. These formulas of the objective functions provide rich information which can then be used to design an effective variable group method. In this article, a formula-based grouping strategy (FBG) for white-box problems is first proposed. It groups variables directly via the formula of an objective function which usually consists of a finite number of operations (i.e., four arithmetic operations “[Formula: see text]”, “[Formula: see text]”, “[Formula: see text]”, “[Formula: see text]” and composite operations of basic elementary functions). In FBG, the operations are classified into two classes: one resulting in nonseparable variables, and the other resulting in separable variables. In FBG, variables can be automatically grouped into a suitable number of non-interacting subcomponents, with variables in each subcomponent being interdependent. FBG can easily be applied to any white-box problem and can be integrated into a cooperative coevolution framework. Based on FBG, a novel cooperative coevolution algorithm with formula-based variable grouping (so-called CCF) is proposed in this article for decomposing a large-scale white-box problem into several smaller subproblems and optimizing them respectively. To further enhance the efficiency of CCF, a new local search scheme is designed to improve the solution quality. To verify the efficiency of CCF, experiments are conducted on the standard LSGO benchmark suites of CEC'2008, CEC'2010, CEC'2013, and a real-world problem. Our results suggest that the performance of CCF is very competitive when compared with those of the state-of-the-art LSGO algorithms.
Early Rabbinic Judaism and the Danger in Ezekiel 1
Authors: Van De Water Rick
Published: August 2017

Rabbinic tradition indicates a revision of the text of the Book of Ezekiel in the first century ce and suggests the rationale behind it. Hanania ben Hezeqiah is said to have “harmonized” Ezekiel with the Torah shortly before the first Jewish revolt, to save the book from suppression by the rabbis. Hasty redaction, followed by immediate standardization, offers the best explanation for the atrocious grammar, orthography, and syntax of the received Hebrew text, along with the plethora of words and expressions common to post-biblical Hebrew. The goal of Hanania’s project was to discourage the conflation of the enthroned figure in Ezek. 1 with the “one like a son of man” in Dan. 7:13 and thus combat the “two Powers heresy.” His project is related to the outburst of speculation on the throne of yhwh and the merkabah in the mid-first century ce
Regional Human Rights Institutions and R2P: The Role of State Monitoring in Atrocity Prevention
Authors: Coe Brooke
Published: August 2017

This paper considers the potential of regional human rights institutions in the global South – including the Inter-American Commission on Human Rights, the African Commission on Human and Peoples’ Rights, and the asean Intergovernmental Commission on Human Rights – to exercise atrocity prevention functions. Specifically, it considers the possibilities and limits of their institutions and activities in contributing to early warning, direct prevention, and ‘root cause’ prevention, finding that much potential exists for the Inter-American and African Commission to make tangible contributions to prevention, broadly conceived, but that there remain important gaps between mandate and actual practices. The asean Commission lags significantly behind the others because of the Southeast Asian grouping’s continued commitment to non-interference. Despite this fact, asean norms and institutions are ever-evolving – even if slowly – and so opportunities may arise for the creation of prevention-relevant mandates and mechanisms that mirror those already embedded in the Inter-American and African systems.