bluuebunny/crossref_metadata_2025_split huggingface dataset:
EGFR-TKI Resistance Due to BIM Polymorphism Can Be Circumvented in Combination with HDAC Inhibition
Authors: Nakagawa Takayuki , Takeuchi Shinji , Yamada Tadaaki , Ebi Hiromichi , Sano Takako , Nanjo Shigeki , Ishikawa Daisuke , Sato Mitsuo , Hasegawa Yoshinori , Sekido Yoshitaka , Yano Seiji 
Published: February 2013

Abstract
BIM (BCL2L11) is a BH3-only proapoptotic member of the Bcl-2 protein family. BIM upregulation is required for apoptosis induction by EGF receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) in EGFR-mutant forms of non–small cell lung cancer (NSCLC). Notably, a BIM deletion polymorphism occurs naturally in 12.9% of East Asian individuals, impairing the generation of the proapoptotic isoform required for the EGFR-TKIs gefitinib and erlotinib and therefore conferring an inherent drug-resistant phenotype. Indeed, patients with NSCLC, who harbored this host BIM polymorphism, exhibited significantly inferior responses to EGFR-TKI treatment than individuals lacking this polymorphism. In an attempt to correct this response defect in the resistant group, we investigated whether the histone deacetylase (HDAC) inhibitor vorinostat could circumvent EGFR-TKI resistance in EGFR-mutant NSCLC cell lines that also harbored the BIM polymorphism. Consistent with our clinical observations, we found that such cells were much less sensitive to gefitinib-induced apoptosis than EGFR-mutant cells, which did not harbor the polymorphism. Notably, vorinostat increased expression in a dose-dependent manner of the proapoptotic BH3 domain-containing isoform of BIM, which was sufficient to restore gefitinib death sensitivity in the EGFR mutant, EGFR-TKI–resistant cells. In xenograft models, while gefitinib induced marked regression via apoptosis of tumors without the BIM polymorphism, its combination with vorinostat was needed to induce marked regression of tumors with the BIM polymorphism in the same manner. Together, our results show how HDAC inhibition can epigenetically restore BIM function and death sensitivity of EGFR-TKI in cases of EGFR-mutant NSCLC where resistance to EGFR-TKI is associated with a common BIM polymorphism. Cancer Res; 73(8); 2428–34. ©2013 AACR.
Proteomic Analysis of Ubiquitin Ligase KEAP1 Reveals Associated Proteins That Inhibit NRF2 Ubiquitination
Authors: Hast Bridgid E. , Goldfarb Dennis , Mulvaney Kathleen M. , Hast Michael A. , Siesser Priscila F. , Yan Feng , Hayes D. Neil , Major Michael B. 
Published: February 2013

Abstract
Somatic mutations in the KEAP1 ubiquitin ligase or its substrate NRF2 (NFE2L2) commonly occur in human cancer, resulting in constitutive NRF2-mediated transcription of cytoprotective genes. However, many tumors display high NRF2 activity in the absence of mutation, supporting the hypothesis that alternative mechanisms of pathway activation exist. Previously, we and others discovered that via a competitive binding mechanism, the proteins WTX (AMER1), PALB2, and SQSTM1 bind KEAP1 to activate NRF2. Proteomic analysis of the KEAP1 protein interaction network revealed a significant enrichment of associated proteins containing an ETGE amino acid motif, which matches the KEAP1 interaction motif found in NRF2. Like WTX, PALB2, and SQSTM1, we found that the dipeptidyl peptidase 3 (DPP3) protein binds KEAP1 via an “ETGE” motif to displace NRF2, thus inhibiting NRF2 ubiquitination and driving NRF2-dependent transcription. Comparing the spectrum of KEAP1-interacting proteins with the genomic profile of 178 squamous cell lung carcinomas characterized by The Cancer Genome Atlas revealed amplification and mRNA overexpression of the DPP3 gene in tumors with high NRF2 activity but lacking NRF2 stabilizing mutations. We further show that tumor-derived mutations in KEAP1 are hypomorphic with respect to NRF2 inhibition and that DPP3 overexpression in the presence of these mutants further promotes NRF2 activation. Collectively, our findings further support the competition model of NRF2 activation and suggest that “ETGE”-containing proteins such as DPP3 contribute to NRF2 activity in cancer. Cancer Res; 73(7); 2199–210. ©2013 AACR.
Effect of halloysite nanotubes on curing behavior, mechanical, and microstructural properties of acrylonitrile–butadiene rubber nanocomposites
Authors: Ismail Hanafi , Ahmad Hazwani Syaza 
Published: February 2013

Halloysite nanotubes (HNTs) have been used as a new type of filler for acrylonitrile–butadiene rubber (NBR) matrix. The NBR/HNT nanocomposites were prepared using a two-roll mill by adding 0–7 parts per hundred rubber (phr) HNTs, and the effect of the loading of HNTs on the curing behavior, mechanical, and microstructural properties were also investigated in this study. The cure characteristics showed that the cure time ( t90) and scorch time ( ts2) decreased, whereas the maximum torque ( MH) exhibited an increasing trend from 0 to 7 phr. The tensile properties improved until optimum loading of HNTs (5 phr) and thermal stability increased with increasing HNT loading. The morphological study revealed the HNTs homogeneously dispersed inside the NBR matrix and good interaction occurred between HNTs and NBR.
Experimental activation of the sphenopalatine ganglion provokes cluster-like attacks in humans
Authors: Schytz Henrik W , Barløse Mads , Guo Song , Selb Juliette , Caparso Anthony , Jensen Rigmor , Ashina Messoud 
Published: February 2013

Background High frequency (HF) stimulation of the sphenopalatine ganglion (SPG) is an emerging abortive treatment for cluster headache (CH) attacks. HF SPG stimulation is thought to exert its effect by physiologically blocking parasympathetic outflow. We hypothesized that low frequency (LF) SPG stimulation may activate the SPG, causing increased parasympathetic outflow and thereby provoking cluster attacks in CH patients. Methods In a double-blind randomized cross-over study, seven CH patients implanted with an SPG neurostimulator were randomly allocated to receive HF or LF stimulation for 3 min on 2 separate days. We recorded headache characteristics and autonomic symptoms during and after stimulation. Results Six patients completed the study. Three out of six patients (50%) reported ipsilateral cluster-like attacks during or within 30 min of LF SPG stimulation. These cluster-like attacks were all successfully treated with the therapeutic HF SPG stimulation. One out of six reported a cluster-like attack with 3 min HF SPG stimulation, which was also successfully treated with continued HF therapeutic SPG stimulation. Discussion LF SPG stimulation may induce cluster-like attacks with autonomic features, which can subsequently be treated by HF SPG stimulation. Efferent parasympathetic outflow from the SPG may initiate autonomic symptoms and activate trigeminovascular sensory afferents, which may initiate the onset of pain associated with CH.
Prognostic Classification of Fifth Metatarsal Stress Fracture Using Plantar Gap
Authors: Lee Kyung Tai , Park Young Uk , Jegal Hyuk , Park Jong Won , Choi Jung Pil , Kim Jin Su 
Published: February 2013

Background: There have been diverse results even in same Torg type of fifth metatarsal stress fractures. Methods: Eighty-six cases with a fifth metatarsal stress fracture that were treated with modified tension band wiring from January 2003 to May 2009 were evaluated retrospectively. Each case was classified according to Torg’s classification and a new classification. Using the new proposed classification, cases were subdivided into complete fracture and incomplete fracture. The cases of incomplete fracture were subdivided based on presence or absence of plantar gap more than 1 mm. After surgery, bone union was determined by CT. Statistical analysis of the Torg classification and time for bone union as well as the proposed new classification and time for bone union was performed. Results: There was a significant difference in the time for bone union among the three Torg types ( P = 0.004). The mean time for bone union in group A (complete fracture, n = 32) was 67.5 ± 28.8, and it was 103.2 ± 47.7 for group B (incomplete fracture, n = 54). There was a significant difference in time for bone union between them ( P < 0.001). The mean time for bone union in group B1 (incomplete fracture, plantar gap less than 1 mm, n = 16) was 73.9 ± 26.7, and it was 115.5 ± 45.4 for group B2 (incomplete fracture, plantar gap 1 mm or more, n = 38). There was a significant difference in time for bone union between them ( P < 0.001). Conclusion: The results of this study suggest that the classification incorporating the plantar gap might be used for classification of fifth metatarsal stress fractures. Level of Evidence: Level III, retrospective comparative series.
c-Maf Transcription Factor Regulates ADAMTS-12 Expression in Human Chondrogenic Cells
Authors: Hong Eunmee , Yik Jasper , Amanatullah Derek F. , Di Cesare Paul E. , Haudenschild Dominik R. 
Published: February 2013

Objective: ADAMTS ( a disintegrin and metalloproteinase with thrombo spondin type-1 motif) zinc metalloproteinases are important during the synthesis and breakdown of cartilage extracellular matrix. ADAMTS-12 is up-regulated during in vitro chondrogenesis and embryonic limb development; however, the regulation of ADAMTS-12 expression in cartilage remains unknown. The transcription factor c-Maf is a member of Maf family of basic ZIP (bZIP) transcription factors. Expression of c-Maf is highest in hypertrophic chondrocytes during embryonic development and postnatal growth. We hypothesize that c-Maf and ADAMTS-12 are co-expressed during chondrocyte differentiation and that c-Maf regulates ADAMTS-12 expression during chondrogenesis. Design: Promoter analysis and species alignments identified potential c-Maf binding sites in the ADAMTS-12 promoter. c-Maf and ADAMTS-12 co-expression was monitored during chondrogenesis of stem cell pellet cultures. Luciferase expression driven by ADAMTS-12 promoter segments was measured in the presence and absence of c-Maf, and synthetic oligonucleotides were used to confirm specific binding of c-Maf to ADAMTS-12 promoter sequences. Results: In vitro chondrogenesis from human mesenchymal stem cells revealed co-expression of ADAMTS-12 and c-Maf during differentiation. Truncation and point mutations of the ADAMTS-12 promoter evaluated in reporter assays localized the response to the proximal 315 bp of the ADAMTS-12 promoter, which contained a predicted c-Maf recognition element (MARE) at position -61. Electorphoretic mobility shift assay confirmed that c-Maf directly interacted with the MARE at position -61. Conclusions: These data suggest that c-Maf is involved in chondrocyte differentiation and hypertrophy, at least in part, through the regulation of ADAMTS-12 expression at a newly identified MARE in its proximal promoter.
Medication adherence in schizophrenia: factors influencing adherence and consequences of nonadherence, a systematic literature review
Authors: Higashi Kyoko , Medic Goran , Littlewood Kavi J. , Diez Teresa , Granström Ola , De Hert Marc 
Published: February 2013

Background: Nonadherence to medication is a recognized problem and may be the most challenging aspect of treatment. Methods: We performed a systematic review of factors that influence adherence and the consequences of nonadherence to the patient, healthcare system and society, in patients with schizophrenia. Particular attention was given to the effect of nonadherence on hospitalization rates, as a key driver of increased costs of care. A qualitative systematic literature review was conducted using a broad search strategy using disease and adherence terms. Due to the large number of abstracts identified, article selection was based on studies with larger sample sizes published after 2001. Thirty-seven full papers were included: 15 studies on drivers and 22 on consequences, of which 12 assessed the link between nonadherence and hospitalization. Results: Key drivers of nonadherence included lack of insight, medication beliefs and substance abuse. Key consequences of nonadherence included greater risk of relapse, hospitalization and suicide. Factors positively related to adherence were a good therapeutic relationship with physician and perception of benefits of medication. The most frequently reported driver and consequence were lack of insight and greater risk of hospitalization respectively. Conclusions: Improving adherence in schizophrenia may have a considerable positive impact on patients and society. This can be achieved by focusing on the identified multitude of factors driving nonadherence.
Notch controls generation and function of human effector CD8+ T cells
Authors: Kuijk Loes M. , Verstege Marleen I. , Rekers Niels V. , Bruijns Sven C. , Hooijberg Erik , Roep Bart O. , de Gruijl Tanja D. , van Kooyk Yvette , Unger Wendy W. J. 
Published: February 2013

Key PointsActivation-induced Notch signaling is crucial for both generation and effector functions of primary naive CD8 T cells. Notch signaling is needed for expansion and IFNγ release but not for cytolytic activity of established effector CD8 T cells.
Multidrug-resistant gram-negative bacteria colonization of healthy US military personnel in the US and Afghanistan
Authors: Vento Todd J , Cole David W , Mende Katrin , Calvano Tatjana P , Rini Elizabeth A , Tully Charla C , Zera Wendy C , Guymon Charles H , Yu Xin , Cheatle Kristelle A , Akers Kevin S , Beckius Miriam L , Landrum Michael L , Murray Clinton K 
Published: February 2013

Abstract

Background
The US military has seen steady increases in multidrug-resistant (MDR) gram-negative bacteria (GNB) infections in casualties from Iraq and Afghanistan. This study evaluates the prevalence of MDR GNB colonization in US military personnel.

Methods
GNB colonization surveillance of healthy, asymptomatic military personnel (101 in the US and 100 in Afghanistan) was performed by swabbing 7 anatomical sites. US-based personnel had received no antibiotics within 30 days of specimen collection, and Afghanistan-based personnel were receiving doxycycline for malaria chemoprophylaxis at time of specimen collection. Isolates underwent genotypic and phenotypic characterization.

Results
The only colonizing MDR GNB recovered in both populations was Escherichia coli (p=0.01), which was seen in 2% of US-based personnel (all perirectal) and 11% of Afghanistan-based personnel (10 perirectal, 1 foot+groin). Individuals with higher off-base exposures in Afghanistan did not show a difference in overall GNB colonization or MDR E. coli colonization, compared with those with limited off-base exposures.

Conclusion
Healthy US- and Afghanistan-based military personnel have community onset-MDR E. coli colonization, with Afghanistan-based personnel showing a 5.5-fold higher prevalence. The association of doxycycline prophylaxis or other exposures with antimicrobial resistance and increased rates of MDR E. coli colonization needs further evaluation.
Metabolic syndrome biomarkers and early breast cancer in Saudi women: evidence for the presence of a systemic stress response and/or a pre-existing metabolic syndrome-related neoplasia risk?
Authors: Alokail Majed S , Al-Daghri Nasser , Abdulkareem Amal , Draz Hossam M , Yakout Sobhy M , Alnaami Abdullah M , Sabico Shaun , Alenad Amal M , Chrousos George P 
Published: February 2013

AbstractBackgroundObesity has been linked to many adverse health consequences, including breast cancer. This study aims to determine adipocytokine and other biological changes in recently diagnosed breast cancer patients before therapy is started.MethodsA total of 109 female Saudi subjects [56 newly diagnosed, treatment-naïve, histologically-confirmed breast cancer cases and 53 age- and BMI-matched controls] were enrolled in this study. Anthropometric data were collected. Serum insulin, adipocytokines and plasminogen activator inhibitor-1 (PAI-1) concentrations were measured using a customized multiplex Luminex assay. Hypersensitive C-Reactive Protein (CRP), tumor necrosis factor-alpha (TNF-α), and angiotensin II (ANG II) were measured using ELISA.ResultsA few days in the diagnosis, breast cancer subjects had significantly higher systolic blood pressure (p = 0.03), glucose (p = 0.01), triglycerides (p = 0.001), leptin (p = 0.044), resistin (p = 0.04), ANG II (p = 0.02), TNF-α (p = 0.045), and CRP (p = 0.04) than the controls. On the other hand, HDL (p = 0.01) and adiponectin (p = 0.02) were significantly lower in cancer subjects than controls. A significant association was found between elevated triglycerides (TG) and breast cancer [OR (95% CI), 6.1(1.8, 15.6),p = 0.004], as well as elevated ANG II [OR (95% CI), 5.2(1.2, 14.3),p = 0.03]. On the other hand, aPAI and HDL correlated negatively with breast cancer [OR (95% CI), 0.076(0.01, 0.34),p = 0.001; 0.30(0.09, 0.95),p0.04, respectively].ConclusionCirculating ANGII and triglycerides were positively associated with early breast cancer. In contrast, HDL-cholesterol correlated negatively with ANG II and aPAI in these patients. This suggests that patients with recently diagnosed breast cancer have biochemical changes consistent with an activated stress response and/or that patients with metabolic syndrome manifestations have a higher risk of developing this disease.
SPARC expression in CML is associated to imatinib treatment and to inhibition of leukemia cell proliferation
Authors: Giallongo Cesarina , La Cava Piera , Tibullo Daniele , Barbagallo Ignazio , Parrinello Nunziatina , Cupri Alessandra , Stagno Fabio , Consoli Carla , Chiarenza Annalisa , Palumbo Giuseppe A , Di Raimondo Francesco 
Published: February 2013

Abstract

Background
SPARC is a matricellular glycoprotein with growth-inhibitory and antiangiogenic activity in some cell types. The study of this protein in hematopoietic malignancies led to conflicting reports about its role as a tumor suppressor or promoter, depending on its different functions in the tumor microenvironment. In this study we investigated the variations in SPARC production by peripheral blood cells from chronic myeloid leukemia (CML) patients at diagnosis and after treatment and we identified the subpopulation of cells that are the prevalent source of SPARC.

Methods
We evaluated SPARC expression using real-time PCR and western blotting. SPARC serum levels were detected by ELISA assay. Finally we analyzed the interaction between exogenous SPARC and imatinib (IM), in vitro, using ATP-lite and cell cycle analysis.

Results
Our study shows that the CML cells of patients at diagnosis have a low mRNA and protein expression of SPARC. Low serum levels of this protein are also recorded in CML patients at diagnosis. However, after IM treatment we observed an increase of SPARC mRNA, protein, and serum level in the peripheral blood of these patients that had already started at 3 months and was maintained for at least the 18 months of observation. This SPARC increase was predominantly due to monocyte production. In addition, exogenous SPARC protein reduced the growth of K562 cell line and synergized in vitro with IM by inhibiting cell cycle progression from G1 to S phase.

Conclusion
Our results suggest that low endogenous SPARC expression is a constant feature of BCR/ABL positive cells and that IM treatment induces SPARC overproduction by normal cells. This exogenous SPARC may inhibit CML cell proliferation and may synergize with IM activity against CML.
Is insufficient knowledge of epilepsy the reason for low levels of healthcare in the Lao PDR?
Authors: Harimanana Aina , Chivorakul Phetvongsinh , Souvong Vimalay , Preux Pierre-Marie , Barennes Hubert 
Published: February 2013

Abstract

Background
The treatment gap for epilepsy is considerable in low and middle-income countries. In the Lao PDR it is estimated at over 90%. Health workers play a significant role in bridging the gap between people with epilepsy (PWE) and access to epilepsy care. In a national survey we assessed: 1) the knowledge and practices of health workers in the Lao PDR towards the disease, and, 2) patient attendance at health facilities.

Methods
We conducted a random three-stage sampling of health workers at the provincial, district and health center levels in 2009.

Results
Overall, 284 health workers were enrolled in 50 health facilities of 11 provinces: health centers 24.7%; district hospitals 23.2%; and province hospitals 52.1%. Only a minority of these (2.5%) recalled ever having received training or seeking information on epilepsy. Our survey showed a lack of knowledge in diagnosing and prescribing drugs for epilepsy, including phenobarbital, the first-line of treatment. The majority of respondents (59.9%) was unaware of the availability of antiepileptic drugs in health facilities. Only 10 (20%) health facilities, and no health centres, received people with epilepsy. It was estimated that one PWE per month receives medical attention. Traditional beliefs about PWE were common; such as the idea that epilepsy could be transmitted through saliva (63.2%). A higher attendance of PWE was observed in province hospitals where the knowledge of epilepsy care was higher. Global acceptance of people with epilepsy was low.

Conclusions
The low level of knowledge of epilepsy on the part of health workers may be contributing to the wide treatment gap in the Lao PDR. Improving knowledge of this disease and increasing the availability of antiepileptic drugs will reduce misconceptions about epilepsy, thus encouraging more PWE to seek treatment. Community-based educational programs and extensive advocacy for people with epilepsy only began in 2009.
Diverse captive non-human primates with phytanic acid-deficient diets rich in plant products have substantial phytanic acid levels in their red blood cells
Authors: Moser Ann B , Hey Jody , Dranchak Patricia K , Karaman Mazen W , Zhao Junsong , Cox Laura A , Ryder Oliver A , Hacia Joseph G 
Published: February 2013

Abstract

Background
Humans and rodents with impaired phytanic acid (PA) metabolism can accumulate toxic stores of PA that have deleterious effects on multiple organ systems. Ruminants and certain fish obtain PA from the microbial degradation of dietary chlorophyll and/or through chlorophyll-derived precursors. In contrast, humans cannot derive PA from chlorophyll and instead normally obtain it only from meat, dairy, and fish products.

Results
Captive apes and Old world monkeys had significantly higher red blood cell (RBC) PA levels relative to humans when all subjects were fed PA-deficient diets. Given the adverse health effects resulting from PA over accumulation, we investigated the molecular evolution of thirteen PA metabolism genes in apes, Old world monkeys, and New world monkeys. All non-human primate (NHP) orthologs are predicted to encode full-length proteins with the marmoset Phyh gene containing a rare, but functional, GA splice donor dinucleotide. Acox2, Scp2, and Pecr sequences had amino acid positions with accelerated substitution rates while Amacr had significant variation in evolutionary rates in apes relative to other primates.

Conclusions
Unlike humans, diverse captive NHPs with PA-deficient diets rich in plant products have substantial RBC PA levels. The favored hypothesis is that NHPs can derive significant amounts of PA from the degradation of ingested chlorophyll through gut fermentation. If correct, this raises the possibility that RBC PA levels could serve as a biomarker for evaluating the digestive health of captive NHPs. Furthermore, the evolutionary rates of the several genes relevant to PA metabolism provide candidate genetic adaptations to NHP diets.