bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduced contribution of thermally labile sugar lesions to DNA double strand break formation after exposure to heavy ions
Authors: Singh Satyendra K , Bencsik-Theilen Alena , Mladenov Emil , Jakob Burkhard , Taucher-Scholz Gisela , Iliakis George 
Published: April 2013

Abstract
In cells exposed to low linear energy transfer (LET) ionizing-radiation (IR),double-strand-breaks (DSBs) form within clustered-damage-sites (CDSs) fromlesions disrupting the DNA sugar-phosphate backbone. It is commonly assumed thatall DSBs form promptly and are immediately detected by the cellularDNA-damage-response (DDR) apparatus. However, there is evidence that the pool ofDSBs detected by physical methods, such as pulsed-field gel electrophoresis(PFGE), comprises not only promptly forming DSBs (prDSBs) but also DSBsdeveloping during lysis at high temperatures from thermally-labile sugar-lesions(TLSLs). We recently demonstrated that conversion of TLSLs to DNA breaks andultimately to DSBs also occurs in cells during the first hour ofpost-irradiation incubation at physiological temperatures. Thus, TLSL-dependentDSBs (tlDSBs) are not an avoidable technique-related artifact, but a reality thecell always faces. The biological consequences of tlDSBs and the dependence oftheir formation on LET require in-depth investigation. Heavy-ions (HI) are apromising high-LET radiation modality used in cancer treatment. HI are alsoencountered in space and generate serious radiation protection problems toprolonged space missions. Here, we study, therefore, the effect of HI on theyields of tlDSBs and prDSBs. We report a reduction in the yield of tlDBSsstronger than that earlier reported for neutrons, and with pronounced cell linedependence. We conclude that with increasing LET the complexity of CDSsincreases resulting in a commensurate increase in the yield prDSBs and adecrease in tlDSBs. The consequences of these effects to the relative biologicaleffectiveness are discussed.
Structurally differentiated cis-elements that interact with PU.1 are functionally distinguishable in acute promyelocytic leukemia
Authors: Qian Maoxiang , Jin Wen , Zhu Xuehua , Jia Xiaohong , Yang Xianwen , Du Yanzhi , Wang Kankan , Zhang Ji 
Published: April 2013

AbstractBackgroundTranscription factor PU.1, a member of the ETS family, is a master regulator of myeloid differentiation whose functional disruption is often associated with acute myeloid leukemia (AML). Although much has been learned about PU.1 over the past decades, relatively little is known aboutcis-elements that interact with this factor under physiological or pathological conditions, especially in the whole-genome scale. We aimed to define the cistrome of PU.1 in acute promyelocytic leukemia (APL) cells and characterize thecis-elements bound by PU.1.MethodsChromatin immunoprecipitation with specific antibody coupled with deep sequencing (ChIP-seq) was used to investigate thein vivoPU.1 binding sites at the whole-genome scale in APL-derived NB4 cells. The ChIP-quantitative (q)-PCR and luciferase reporter assays were used to validate the binding events andtrans-activity, respectively. Various computational analyses, including motif mining, evolutionary conservation analysis and functional enrichment analysis, were performed to characterize thecis-elements that interacted with PU.1.ResultsA total of 26,907 significantly enriched binding regions of PU.1 were identified under the false discovery rate 0.1% in NB4 cells. PU.1 bound to various types of genomic regions and acted as a promoter-enhancer dual binding transcription factor. Based on the sequence length and composition, two types of representative motifs were identified in PU.1 binding sites: a long and a short motif. The long motif, characterized by high sequence specificity and binding affinity, predominantly resided in the promoter-distal regions. In contrast, the short one, with strong evolutionary constraint, represented the primary PU.1cis-elements in the promoter-proximal regions. Interestingly, the short one showed more preference to be correlated with the binding of other factors, especially PML/RARα. Moreover, genes targeted by both PU.1 and PML/RARα were significantly involved in categories associated with oncogenesis, hematopoiesis and the pathogenesis of acute myeloid leukemia.ConclusionsOur results demonstrate that structurally differentiatedcis-elements that interact with PU.1 are functionally distinguishable in APL, suggesting that the sequence diversity ofcis-elements might be a critical mechanism by which cells interpret the genome, and contribute to distinct physiological and/or pathological function.
Krüppel-like factor 6 (KLF6) promotes cell proliferation in skeletal myoblasts in response to TGFβ/Smad3 signaling
Authors: Dionyssiou Mathew G , Salma Jahan , Bevzyuk Mariya , Wales Stephanie , Zakharyan Lusine , McDermott John C 
Published: April 2013

Abstract

Background
Krüppel-like factor 6 (KLF6) has been recently identified as a MEF2D target gene involved in neuronal cell survival. In addition, KLF6 and TGFβ have been shown to regulate each other’s expression in non-myogenic cell types. Since MEF2D and TGFβ also fulfill crucial roles in skeletal myogenesis, we wanted to identify whether KLF6 functions in a myogenic context.

Methods
KLF6 protein expression levels and promoter activity were analyzed using standard cellular and molecular techniques in cell culture.

Results
We found that KLF6 and MEF2D are co-localized in the nuclei of mononucleated but not multinucleated myogenic cells and, that the MEF2 cis element is a key component of the KLF6 promoter region. In addition, TGFβ potently enhanced KLF6 protein levels and this effect was repressed by pharmacological inhibition of Smad3. Interestingly, pharmacological inhibition of MEK/ERK (1/2) signaling resulted in re-activation of the differentiation program in myoblasts treated with TGFβ, which is ordinarily repressed by TGFβ treatment. Conversely, MEK/ERK (1/2) inhibition had no effect on TGFβ-induced KLF6 expression whereas Smad3 inhibition negated this effect, together supporting the existence of two separable arms of TGFβ signaling in myogenic cells. Loss of function analysis using siRNA-mediated KLF6 depletion resulted in enhanced myogenic differentiation whereas TGFβ stimulation of myoblast proliferation was reduced in KLF6 depleted cells.

Conclusions
Collectively these data implicate KLF6 in myoblast proliferation and survival in response to TGFβ with consequences for our understanding of muscle development and a variety of muscle pathologies.
Timing of renal replacement therapy initiation by AKIN classification system
Authors: Leite Tacyano T , Macedo Etienne , Pereira Samuel M , Bandeira Sandro RC , Pontes Pedro HS , Garcia André S , Militão Fernanda R , Sobrinho Irineu MM , Assunção Livia M , Libório Alexandre B 
Published: April 2013

Abstract
Introduction
Previous studies using Acute Kidney Injury Network (AKIN)/RIFLE criteria to classify early initiation of renal replacement therapy (RRT) have defined it as the therapy started in less severe AKIN/RIFLE stages. Generally, these studies failed in demonstrating measurable benefits.

Methods
We compared RRT initiation in critically ill patients and defined early or late RRT in reference to timing after stage 3 AKIN was met: patients beginning RRT within 24 hours after acute kidney injury (AKI) stage 3 were considered early starters. AKIN criteria were evaluated by both urine output (UO) and serum creatinine (sCr) and patients with acute-on-chronic kidney disease were excluded. A propensity score methodology was used to control variables.

Results
A total of 358 critically ill patients were submitted to RRT. Only 150 patients with pure AKI at stage 3 were analyzed. Mortality was lower in the early RRT group (51.5 vs. 77.9%, P = 0.001). After achieving balance between the groups using a propensity score, there was a significant 30.5 (95% confidence interval [CI] 14.4 to 45.2%, P = 0.002) relative decrease of mortality in the early RRT group. Moreover, patients on the early RRT group had lower duration of mechanical ventilation, time on RRT and a trend to lower intensive care unit (ICU) length of stay.

Conclusions
For the first time, AKIN was used with UO criterion to evaluate early and late RRT. Using a time-based approach could be a better parameter to access the association between RRT initiation and outcomes in patients with AKI.
The western painted turtle genome, a model for the evolution of extreme physiological adaptations in a slowly evolving lineage
Authors: Bradley Shaffer H , Minx Patrick , Warren Daniel E , Shedlock Andrew M , Thomson Robert C , Valenzuela Nicole , Abramyan John , Amemiya Chris T , Badenhorst Daleen , Biggar Kyle K , Borchert Glen M , Botka Christopher W , Bowden Rachel M , Braun Edward L , Bronikowski Anne M , Bruneau Benoit G , Buck Leslie T , Capel Blanche , Castoe Todd A , Czerwinski Mike , Delehaunty Kim D , Edwards Scott V , Fronick Catrina C , Fujita Matthew K , Fulton Lucinda , Graves Tina A , Green Richard E , Haerty Wilfried , Hariharan Ramkumar , Hernandez Omar , Hillier LaDeana W , Holloway Alisha K , Janes Daniel , Janzen Fredric J , Kandoth Cyriac , Kong Lesheng , de Koning AP Jason , Li Yang , Literman Robert , McGaugh Suzanne E , Mork Lindsey , O'Laughlin Michelle , Paitz Ryan T , Pollock David D , Ponting Chris P , Radhakrishnan Srihari , Raney Brian J , Richman Joy M , St John John , Schwartz Tonia , Sethuraman Arun , Spinks Phillip Q , Storey Kenneth B , Thane Nay , Vinar Tomas , Zimmerman Laura M , Warren Wesley C , Mardis Elaine R , Wilson Richard K 
Published: April 2013

Abstract
Background
We describe the genome of the western painted turtle, Chrysemys picta bellii, one of the most widespread, abundant, and well-studied turtles. We place the genome into a comparative evolutionary context, and focus on genomic features associated with tooth loss, immune function, longevity, sex differentiation and determination, and the species' physiological capacities to withstand extreme anoxia and tissue freezing.

Results
Our phylogenetic analyses confirm that turtles are the sister group to living archosaurs, and demonstrate an extraordinarily slow rate of sequence evolution in the painted turtle. The ability of the painted turtle to withstand complete anoxia and partial freezing appears to be associated with common vertebrate gene networks, and we identify candidate genes for future functional analyses. Tooth loss shares a common pattern of pseudogenization and degradation of tooth-specific genes with birds, although the rate of accumulation of mutations is much slower in the painted turtle. Genes associated with sex differentiation generally reflect phylogeny rather than convergence in sex determination functionality. Among gene families that demonstrate exceptional expansions or show signatures of strong natural selection, immune function and musculoskeletal patterning genes are consistently over-represented.

Conclusions
Our comparative genomic analyses indicate that common vertebrate regulatory networks, some of which have analogs in human diseases, are often involved in the western painted turtle's extraordinary physiological capacities. As these regulatory pathways are analyzed at the functional level, the painted turtle may offer important insights into the management of a number of human health disorders.
Oral administration of carbonic anhydrase I ameliorates murine experimental colitis induced by Foxp3−CD4+CD25− T cells
Authors: Mori Kenichirou , Yamanishi Hirofumi , Ikeda Yoshiou , Kumagi Teru , Hiasa Yoichi , Matsuura Bunzo , Abe Masanori , Onji Morikazu 
Published: April 2013

Abstract
Oral tolerization with carbonic anhydrase I induces antigen-specific protection from murine experimental colitis, by inducing CD103+ dendritic cells and generating Foxp3+CD4+CD25+ regulatory T cells.
IBDs are thought to involve uncontrolled innate and adaptive immunity against intestinal self-antigens and bacterial antigens. Mouse CA I is a major cecal bacterial antigen in fecal extracts and is implicated in the pathogenesis of IBD. We show here that oral tolerization to CA I induced antigen-specific protection from intestinal inflammation in a murine model. Oral administration of CA I but not irrelevant antigen (KLH) ameliorated CD4+CD25− T cell transfer murine colitis and DSS-induced murine colitis. Next, we investigated the mechanisms involved in the therapeutic effects of oral administration, such as induction of ALDH1a2, transcription factors, cytokines, CD103+CD11c+ DCs, and generation of Tregs. Oral administration of CA I induced ALDH1a2 mRNA expression in the MLN and colon. When compared with PBS-treated mice, CA I-treated mice had higher Foxp3+CD4+CD25+ Treg and CD103+CD11c+ DC numbers in the MLN and colon; had higher TGF-β production in the MLN and colon; had lower RORγt mRNA expression in the MLN and colon; and had lower IL-17 mRNA expression and production in the MLN. These results demonstrate that oral administration of CA I induced antigen-specific immune tolerance by generating Foxp3+CD4+CD25+ Tregs and inhibiting Th17 cells in a murine colitis model, thus suggesting that oral tolerization with CA I is an effective therapeutic strategy for IBD regulation.
Commissioning services for people with dementia: how to get it right
Authors: Iliffe Steve 
Published: April 2013

SummaryThe current emphasis on improving the quality of dementia services is welcome, but it treats dementia as if it were separable from complex comorbidities, disability and frailty. As a consequence, dementia can overshadow other problems, from heart failure to multisystem failure at the end of life, which may be poorly managed. Three ways in which old age psychiatrists can reconnect dementia with the diseases and disorders of later life are described in this editorial. The first is to improve skills in general practice so that general practitioners (GPs) can take on the bulk of the clinical work of both diagnosis and management of dementia and its comorbidities, while specialists retain complex decision-making and management tasks. The second is for old age psychiatrists to function as consultants to social enterprises run by GPs for the purpose of managing almost all patients with dementia in general practice. The third is for community geriatricians and old age psychiatrists to work together in integrated organisations that take full clinical responsibility for older people with dementia.
Use of specialist services for obsessive–compulsive and body dysmorphic disorders across England
Authors: Drummond Lynne M. , Fineberg Naomi A. , Heyman Isobel , Veale David , Jessop Edmond 
Published: April 2013

Aims and methodIn April 2007, the National Specialist Commissioning Team of the Department of Health commissioned a group of services to provide treatment to patients with the most severe and profound obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD). We decided to examine the usage of these services across England 4–5 years after the start of the new funding arrangements. This survey used data about patients treated in the financial year 2011–2012.ResultsDespite the services offering intensive home-based as well as residential and in-patient services, there was a greater proportion of referrals from London, the South East of England and counties closer to London.Clinical implicationsIt is important that all patients, regardless of where they live, have access to highly specialist services for OCD and BDD. We discuss potential ways of improving this access but we hope this paper will act as a discussion forum whereby we can receive feedback from others.
Sequential Phase I and II Trials of Stereotactic Body Radiotherapy for Locally Advanced Hepatocellular Carcinoma
Authors: Bujold Alexis , Massey Christine A. , Kim John J. , Brierley James , Cho Charles , Wong Rebecca K.S. , Dinniwell Rob E. , Kassam Zahra , Ringash Jolie , Cummings Bernard , Sykes Jenna , Sherman Morris , Knox Jennifer J. , Dawson Laura A. 
Published: April 2013

Purpose To describe outcomes of prospective trials of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC). Patients and Methods Two trials of SBRT for patients with active HCC unsuitable for standard locoregional therapies were conducted from 2004 to 2010. All patients had Child-Turcotte-Pugh class A disease, with at least 700 mL of non-HCC liver. The SBRT dose range was 24 to 54 Gy in six fractions. Primary end points were toxicity and local control at 1 year (LC1y), defined as no progressive disease (PD) of irradiated HCC by RECIST (Response Evaluation Criteria in Solid Tumors). Results A total of 102 patients were evaluable (Trial 1, 2004 to 2007: n = 50; Trial 2, 2007 to 2010: n = 52). Underlying liver disease was hepatitis B in 38% of patients, hepatitis C in 38%, alcohol related in 25%, other in 14%, and none in 7%. Fifty-two percent received prior therapies (no prior sorafenib). TNM stage was III in 66%, and 61% had multiple lesions. Median gross tumor volume was 117.0 mL (range, 1.3 to 1,913.4 mL). Tumor vascular thrombosis (TVT) was present in 55%, and extrahepatic disease was present in 12%. LC1y was 87% (95% CI, 78% to 93%). SBRT dose (hazard ratio [HR] = 0.96; P = .02) and being in Trial 2 (HR = 0.38; P = .03) were associated with LC1y on univariate analysis. Toxicity ≥ grade 3 was seen in 30% of patients. In seven patients (two with TVT PD), death was possibly related to treatment (1.1 to 7.7 months after SBRT). Median overall survival was 17.0 months (95% CI, 10.4 to 21.3 months), for which only TVT (HR = 2.47; P = .01) and being in Trial 2 (HR = 0.49; P = .01) were significant on multivariate analysis. Conclusion These results provide strong rationale for studying SBRT for HCC in a randomized trial.
90Yttrium-Ibritumomab Tiuxetan Consolidation of First Remission in Advanced-Stage Follicular Non-Hodgkin Lymphoma: Updated Results After a Median Follow-Up of 7.3 Years From the International, Randomized, Phase III First-Line Indolent Trial
Authors: Morschhauser Franck , Radford John , Van Hoof Achiel , Botto Barbara , Rohatiner Ama Z.S. , Salles Gilles , Soubeyran Pierre , Tilly Herve , Bischof-Delaloye Angelika , van Putten Wim L.J. , Kylstra Jelle W. , Hagenbeek Anton 
Published: April 2013

Purpose Updated results are presented after a median follow-up of 7.3 years from the phase III First-Line Indolent Trial of yttrium-90 (90Y) –ibritumomab tiuxetan in advanced-stage follicular lymphoma (FL) in first remission. Patients and Methods Patients with CD20+ stage III or IV FL with complete response (CR), unconfirmed CR (CRu), or partial response (PR) after first-line induction treatment were randomly assigned to 90Y-ibritumomab consolidation therapy (rituximab 250 mg/m2 days −7 and 0, then 90Y-ibritumomab 14.8 MBq/kg day 0; maximum 1,184 MBq) or no further treatment (control). Primary end point was progression-free survival (PFS) from date of random assignment. Results For 409 patients available for analysis (90Y-ibritumomab, n = 207; control, n = 202), estimated 8-year overall PFS was 41% with 90Y-ibritumomab versus 22% for control (hazard ratio [HR], 0.47; P < .001). For patients in CR/CRu after induction, 8-year PFS with 90Y-ibritumomab was 48% versus 32% for control (HR, 0.61; P = .008), and for PR patients, it was 33% versus 10% (HR, 0.38; P < .001). For 90Y-ibritumomab consolidation, median PFS was 4.1 years (v 1.1 years for control; P < .001). Median time to next treatment (TTNT) was 8.1 years for 90Y-ibritumomab versus 3.0 years for control (P < .001) with approximately 80% response rates to second-line therapy in either arm, including autologous stem-cell transplantation. No unexpected toxicities emerged during long-term follow-up. Estimated between-group 8-year overall survival rates were similar. Annualized incidence rate of myelodysplastic syndrome/acute myeloblastic leukemia was 0.50% versus 0.07% in 90Y-ibritumomab and control groups, respectively (P = .042). Conclusion 90Y-ibritumomab consolidation after achieving PR or CR/CRu to induction confers 3-year benefit in median PFS with durable 19% PFS advantage at 8 years and improves TTNT by 5.1 years for patients with advanced FL.
17β-Estradiol Activates Glucose Uptake via GLUT4 Translocation and PI3K/Akt Signaling Pathway in MCF-7 Cells
Authors: Garrido Pablo , Morán Javier , Alonso Ana , González Segundo , González Celestino 
Published: April 2013

AbstractThe relationship between estrogen and some types of breast cancer has been clearly established. However, although several studies have demonstrated the relationship between estrogen and glucose uptake via phosphatidylinositol 3-kinase (PI3K)/Akt in other tissues, not too much is known about the possible cross talk between them for development and maintenance of breast cancer. This study was designed to test the rapid effects of 17β-estradiol (E2) or its membrane-impermeable form conjugated with BSA (E2BSA) on glucose uptake in a positive estrogen receptor (ER) breast cancer cell line, through the possible relationship between key components of the PI3K/Akt signaling pathway and acute steroid treatment. MCF-7 human breast cancer cells were cultured in standard conditions. Then 10 nM E2 or E2BSA conjugated were administered before obtaining the cell lysates. To study the glucose uptake, the glucose fluorescent analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose was used. We report an ER-dependent activation of some of the key steps of the PI3K/Akt signaling pathway cascade that leads cells to improve some mechanisms that finally increase glucose uptake capacity. Our data suggest that both E2 and E2BSA enhance the entrance of the fluorescent glucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose, and also activates PI3K/Akt signaling pathway, leading to translocation of glucose transporter 4 to the plasma membrane in an ERα-dependent manner. E2 enhances ER-dependent rapid signaling triggered, partially in the plasma membrane, allowing ERα-positive MCF-7 breast cancer cells to increase glucose uptake, which could be essential to meet the energy demands of the high rate of proliferation.
Importance of Cysteine Residues in the Thyroid Hormone Transporter MCT8
Authors: Lima de Souza Elaine C. , Groeneweg Stefan , Visser W. Edward , Peeters Robin P. , Visser Theo J. 
Published: April 2013

Abstract
The thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8) is crucial for brain development as demonstrated by the severe psychomotor retardation in patients with MCT8 mutations. MCT8 contains 10 residues of the reactive amino acid cysteine (Cys) whose functional roles were studied using the Cys-specific reagent p-chloromercurybenzenesulfonate (pCMBS) and by site-directed mutagenesis. Pretreatment of JEG3 cells with pCMBS resulted in a dose- and time-dependent decrease of subsequent T3 uptake. Pretreatment with dithiothreitol did not affect TH transport or its inhibition by pCMBS. However, pCMBS inhibition of MCT8 was reversed by dithiothreitol. Inhibition of MCT8 by pCMBS was prevented in the presence of T3. The single and double mutation of C481A and C497A did not affect T3 transport, but the single mutants were less sensitive and the double mutant was completely insensitive to pCMBS. Similar effects on MCT8 were obtained using HgCl2 instead of pCMBS. In conclusion, we have identified Cys481 and Cys497 in MCT8 as the residues modified by pCMBS or HgCl2. These residues are probably located at or near the substrate-recognition site in MCT8. It remains to be investigated whether MCT8 function is regulated by modification of these Cys residues under pathophysiological conditions.