bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drug repositioning for orphan genetic diseases through Conserved Anticoexpressed Gene Clusters (CAGCs)
Authors: Molineris Ivan , Ala Ugo , Provero Paolo , Di Cunto Ferdinando 
Published: October 2013

Abstract

Background
The development of new therapies for orphan genetic diseases represents an extremely important medical and social challenge. Drug repositioning, i.e. finding new indications for approved drugs, could be one of the most cost- and time-effective strategies to cope with this problem, at least in a subset of cases. Therefore, many computational approaches based on the analysis of high throughput gene expression data have so far been proposed to reposition available drugs. However, most of these methods require gene expression profiles directly relevant to the pathologic conditions under study, such as those obtained from patient cells and/or from suitable experimental models. In this work we have developed a new approach for drug repositioning, based on identifying known drug targets showing conserved anti-correlated expression profiles with human disease genes, which is completely independent from the availability of ‘ad hoc’ gene expression data-sets.

Results
By analyzing available data, we provide evidence that the genes displaying conserved anti-correlation with drug targets are antagonistically modulated in their expression by treatment with the relevant drugs. We then identified clusters of genes associated to similar phenotypes and showing conserved anticorrelation with drug targets. On this basis, we generated a list of potential candidate drug-disease associations. Importantly, we show that some of the proposed associations are already supported by independent experimental evidence.

Conclusions
Our results support the hypothesis that the identification of gene clusters showing conserved anticorrelation with drug targets can be an effective method for drug repositioning and provide a wide list of new potential drug-disease associations for experimental validation.
Aneuploidy in neuroblastoma tumors is not associated with inactivating point mutations in the STAG2 gene
Authors: Djos Anna , Fransson Susanne , Kogner Per , Martinsson Tommy 
Published: October 2013

Abstract

Background
Chromosomal instability is a hallmark of human cancer caused by errors in mitotic control and chromosome segregation. STAG2 encodes a subunit of the cohesion complex that participates in mitotic chromatid separation and was recently found to show low expression and inactivating mutations in Ewing’s sarcoma, melanoma and glioblastoma.
In the childhood tumor neuroblastoma (NB) segmental chromosomal alterations are associated with poor prognosis whereas tumors displaying whole chromosome gains and losses have a much better prognosis.

Method
As the genetic contribution to aneuploidy is unknown in NB, we investigated the presence of STAG2 mutations through sequence analysis of all 33 coding exons in 37 primary NB tumors.

Results and conclusion
As no STAG2 mutation was detected in this study, we conclude that inactivating mutation of STAG2 is not likely causative to neuroblastoma aneuploidy.
Lovastatin improves impaired synaptic plasticity and phasic alertness in patients with neurofibromatosis type 1
Authors: Mainberger Florian , Jung Nikolai H , Zenker Martin , Wahlländer Ute , Freudenberg Leonie , Langer Susanne , Berweck Steffen , Winkler Tobias , Straube Andreas , Heinen Florian , Granström Sofia , Mautner Victor-Felix , Lidzba Karen , Mall Volker 
Published: October 2013

Abstract

Background
Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders causing learning disabilities by mutations in the neurofibromin gene, an important inhibitor of the RAS pathway. In a mouse model of NF1, a loss of function mutation of the neurofibromin gene resulted in increased gamma aminobutyric acid (GABA)-mediated inhibition which led to decreased synaptic plasticity and deficits in attentional performance. Most importantly, these defictis were normalized by lovastatin. This placebo-controlled, double blind, randomized study aimed to investigate synaptic plasticity and cognition in humans with NF1 and tried to answer the question whether potential deficits may be rescued by lovastatin.

Methods
In NF1 patients (n = 11; 19–44 years) and healthy controls (HC; n = 11; 19–31 years) paired pulse transcranial magnetic stimulation (TMS) was used to study intracortical inhibition (paired pulse) and synaptic plasticity (paired associative stimulation). On behavioural level the Test of Attentional Performance (TAP) was used. To study the effect of 200 mg lovastatin for 4 days on all these parameters, a placebo-controlled, double blind, randomized trial was performed.

Results
In patients with NF1, lovastatin revealed significant decrease of intracortical inhibition, significant increase of synaptic plasticity as well as significant increase of phasic alertness. Compared to HC, patients with NF1 exposed increased intracortical inhibition, impaired synaptic plasticity and deficits in phasic alertness.

Conclusions
This study demonstrates, for the first time, a link between a pathological RAS pathway activity, intracortical inhibition and impaired synaptic plasticity and its rescue by lovastatin in humans. Our findings revealed mechanisms of attention disorders in humans with NF1 and support the idea of a potential clinical benefit of lovastatin as a therapeutic option.
HOXB7 mRNA is overexpressed in pancreatic ductal adenocarcinomas and its knockdown induces cell cycle arrest and apoptosis
Authors: Chile Thais , Fortes Maria Angela Henriques Zanella , Corrêa-Giannella Maria Lúcia Cardillo , Brentani Helena Paula , Maria Durvanei Augusto , Puga Renato David , de Paula Vanessa de Jesus R , Kubrusly Marcia Saldanha , Novak Estela Maria , Bacchella Telésforo , Giorgi Ricardo Rodrigues 
Published: October 2013

AbstractBackgroundHuman homeobox genes encode nuclear proteins that act as transcription factors involved in the control of differentiation and proliferation. Currently, the role of these genes in development and tumor progression has been extensively studied. Recently, increased expression ofHOXB7homeobox gene (HOXB7) in pancreatic ductal adenocarcinomas (PDAC) was shown to correlate with an invasive phenotype, lymph node metastasis and worse survival outcomes, but no influence on cell proliferation or viability was detected. In the present study, the effects arising from the knockdown ofHOXB7in PDAC cell lines was investigated.MethodsReal time quantitative PCR (qRT-PCR) (Taqman) was employed to assessHOXB7mRNA expression in 29 PDAC, 6 metastatic tissues, 24 peritumoral tissues and two PDAC cell lines. siRNA was used to knockdownHOXB7mRNA in the cell lines and its consequences on apoptosis rate and cell proliferation were measured by flow cytometry and MTT assay respectively.ResultsOverexpression ofHOXB7mRNA was observed in the tumoral tissues and in the cell lines MIA PaCa-2 and Capan-1.HOXB7knockdown elicited (1) an increase in the expression of the pro-apoptotic proteins BAX and BAD in both cell lines; (2) a decrease in the expression of the anti-apoptotic protein BCL-2 and in cyclin D1 and an increase in the number of apoptotic cells in the MIA PaCa-2 cell line; (3) accumulation of cell in sub-G1 phase in both cell lines; (4) the modulation of several biological processes, especially in MIA PaCa-2, such as proteasomal ubiquitin-dependent catabolic process and cell cycle.ConclusionThe present study confirms the overexpression ofHOXB7mRNA expression in PDAC and demonstrates that decreasing its protein level by siRNA could significantly increase apoptosis and modulate several biological processes.HOXB7might be a promising target for future therapies.
Associations between risk perception, spontaneous adaptation behavior to heat waves and heatstroke in Guangdong province, China
Authors: Liu Tao , Xu Yan Jun , Zhang Yong Hui , Yan Qing Hua , Song Xiu Ling , Xie Hui Yan , Luo Yuan , Rutherford Shannon , Chu Cordia , Lin Hua Liang , Ma Wen Jun 
Published: October 2013

Abstract

Background
In many parts of the world, including in China, extreme heat events or heat waves are likely to increase in intensity, frequency, and duration in light of climate change in the next decades. Risk perception and adaptation behaviors are two important components in reducing the health impacts of heat waves, but little is known about their relationships in China. This study aimed to examine the associations between risk perception to heat waves, adaptation behaviors, and heatstroke among the public in Guangdong province, China.

Methods
A total of 2,183 adult participants were selected using a four-stage sampling method in Guangdong province. From September to November of 2010 each subject was interviewed at home by a well-trained investigator using a structured questionnaire. The information collected included socio-demographic characteristics, risk perception and spontaneous adaptation behaviors during heat wave periods, and heatstroke experience in the last year. Chi-square tests and unconditional logistic regression models were employed to analyze the data.

Results
This study found that 14.8%, 65.3% and 19.9% of participants perceived heat waves as a low, moderate or high health risk, respectively. About 99.1% participants employed at least one spontaneous adaptation behavior, and 26.2%, 51.2% and 22.6% respondents employed <4, 4–7, and >7 adaptation behaviors during heat waves, respectively. Individuals with moderate (OR=2.93, 95% CI: 1.38-6.22) or high (OR=10.58, 95% CI: 4.74-23.63) risk perception experienced more heatstroke in the past year than others. Drinking more water and wearing light clothes in urban areas, while decreasing activity as well as wearing light clothes in rural areas were negatively associated with heatstroke. Individuals with high risk perception and employing <4 adaptation behaviors during heat waves had the highest risks of heatstroke (OR=47.46, 95% CI: 12.82-175.73).

Conclusions
There is a large room for improving health risk perception and adaptation capacity to heat waves among the public of Guangdong province. People with higher risk perception and fewer adaptation behaviors during heat waves may be more vulnerable to heat waves.
Biomechanical comparison of three stand-alone lumbar cages — a three-dimensional finite element analysis
Authors: Chen Shih-Hao , Chiang Ming-Chieh , Lin Jin-Fu , Lin Shang-Chih , Hung Ching-Hua 
Published: October 2013

Abstract

Background
For anterior lumbar interbody fusion (ALIF), stand-alone cages can be supplemented with vertebral plate, locking screws, or threaded cylinder to avoid the use of posterior fixation. Intuitively, the plate, screw, and cylinder aim to be embedded into the vertebral bodies to effectively immobilize the cage itself. The kinematic and mechanical effects of these integrated components on the lumbar construct have not been extensively studied. A nonlinearly lumbar finite-element model was developed and validated to investigate the biomechanical differences between three stand-alone (Latero, SynFix, and Stabilis) and SynCage-Open plus transpedicular fixation. All four cages were instrumented at the L3-4 level.

Methods
The lumbar models were subjected to the follower load along the lumbar column and the moment at the lumbar top to produce flexion (FL), extension (EX), left/right lateral bending (LLB, RLB), and left/right axial rotation (LAR, RAR). A 10 Nm moment was applied to obtain the six physiological motions in all models. The comparison indices included disc range of motion (ROM), facet contact force, and stresses of the annulus and implants.

Results
At the surgical level, the SynCage-open model supplemented with transpedicular fixation decreased ROM (>76%) greatly; while the SynFix model decreased ROM 56-72%, the Latero model decreased ROM 36-91%, in all motions as compared with the INT model. However, the Stabilis model decreased ROM slightly in extension (11%), lateral bending (21%), and axial rotation (34%). At the adjacent levels, there were no obvious differences in ROM and annulus stress among all instrumented models.

Conclusions
ALIF instrumentation with the Latero or SynFix cage provides an acceptable stability for clinical use without the requirement of additional posterior fixation. However, the Stabilis cage is not favored in extension and lateral bending because of insufficient stabilization.
Balance ability and postural stability among patients with painful shoulder disorders and healthy controls
Authors: Baierle Tobias , Kromer Thilo , Petermann Carmen , Magosch Petra , Luomajoki Hannu 
Published: October 2013

Abstract

Background
In therapeutic settings, patients with shoulder pain often exhibit deficient coordinative abilities in their trunk and lower extremities. The aim of the study was to investigate 1) if there is a connection between shoulder pain and deficits in balance ability and postural stability, 2) if pain intensity is related to balance ability and postural stability, and 3) if there is a connection between body mass index (BMI) and balance ability and postural stability.

Methods
In this case–control study, patients (n = 40) with pathological shoulder pain (> 4 months) were matched with a healthy controls (n = 40) and were compared with regard to their balance ability and postural stability. Outcome parameters were postural stability, balance ability and symmetry index which were measured using the S3-Check system. In addition, the influence of shoulder pain intensity and BMI on the outcome parameters was analysed.

Results
Patients with shoulder pain showed significantly worse results in measurements of postural stability right/left (p < 0.01) and front/back (p < 0.01) as well as balance ability right/left (p = 0.01) and front/back (p < 0.01) compared to healthy controls. There were no significant group differences with regard to symmetry index. However, there was a significant (p < 0.01) symmetry shift towards the affected side within the shoulder pain group. There was no correlation between pain intensity and measurements of balance ability or postural stability. Likewise, no correlation between BMI and deficiencies in balance ability and postural stability was established.

Conclusions
Patients with pathological shoulder pain (> 4 months) have deficiencies in balance ability and postural stability; however the underlying mechanisms for this remain unclear. Neither pain intensity nor BMI influenced the outcome parameters. Patients with shoulder pain shift their weight to the affected side. Further research is needed to determine if balance training can improve rehabilitation results in patients with shoulder pathologies.
Agro-ecosystems impact malaria prevalence: large-scale irrigation drives vector population in western Ethiopia
Authors: Jaleta Kassahun T , Hill Sharon R , Seyoum Emiru , Balkew Meshesha , Gebre-Michael Teshome , Ignell Rickard , Tekie Habte 
Published: October 2013

Abstract

Background
Development strategies in Ethiopia have largely focused on the expansion of irrigated agriculture in the last decade to reduce poverty and promote economic growth. However, such irrigation schemes can worsen the socio-economic state by aggravating the problem of mosquito-borne diseases. In this study, the effect of agro-ecosystem practices on malaria prevalence and the risk of malaria transmission by the primary vector mosquito, Anopheles arabiensis, in Ethiopia were investigated.

Methods
In three villages in western Ethiopia practising large-scale sugarcane irrigation, traditional smallholder irrigation and non-irrigated farming, cross-sectional parasitological surveys were conducted during the short rains, after the long rains and during the dry season. Entomological surveys were undertaken monthly (February 2010-January 2011) in each village using light traps, pyrethrum spray collections and artificial pit shelters.

Results
Malaria prevalence and the risk of transmission by An. arabiensis assessed by the average human biting rate, mean sporozoite rate and estimated annual entomological inoculation rate were significantly higher in the irrigated sugarcane agro-ecosystem compared to the traditionally irrigated and non-irrigated agro-ecosystems. The average human biting rate was significantly elevated by two-fold, while the mean sporozoite rate was 2.5-fold higher, and the annual entomological inoculation rate was 4.6 to 5.7-fold higher in the irrigated sugarcane compared to the traditional and non-irrigated agro-ecosystems. Active irrigation clearly affected malaria prevalence by increasing the abundance of host seeking Anopheles mosquitoes year-round and thus increasing the risk of infective bites. The year-round presence of sporozoite-infected vectors due to irrigation practices was found to strengthen the coupling between rainfall and risk of malaria transmission, both on- and off-season.

Conclusion
This study demonstrates the negative impact of large-scale irrigation expansion on malaria transmission by increasing the abundance of mosquito vectors and indicates the need for effective vector monitoring and control strategies in the implementation of irrigation projects.
Measures of health-related quality of life and socio-cultural aspects in young patients who after mandible primary reconstruction with free fibula flap
Authors: Zhu Juanfang , Xiao Yan , Liu Fei , Wang Jing , Yang Wenli , Xie Weihong 
Published: October 2013

Abstract

Background
The reconstruction of mandibular defects after trauma or tumor resection is one of the most challenging problems facing reconstructive surgeons. Although the primary intended outcome of surgery to treat head-and-neck malignancies is still the disease-free survival of the patient, health-related quality of life (HRQOL) is now seen as an essential secondary outcome. This study aims to evaluate HRQOL outcomes in young patients undergoing primary mandible reconstruction with free fibula flap and to collect information about their socio-cultural situation.

Methods
The HRQOL outcomes of 25 young patients after primary mandible reconstruction with free fibula flap for mandible malignancies were assessed using the Medical Outcomes Study-Short Form-36 (MOS SF-36) and University of Washington Quality of Life (UW-QOL) questionnaires 12 months postoperatively.

Results
Using the UW-QOL questionnaire, the best-scoring domain was ‘pain’, whereas ‘chewing’ and ‘anxiety’ were given the lowest scores. Using the MOS SF-36 questionnaire, the best-scoring domain was ‘physical functioning’, while ‘bodily pain’ and ‘general health’ also scored well.

Conclusions
Mandible reconstruction with fibula flap will significantly influence a young patient’s HRQOL. Young patients pay more attention to postoperative facial appearance; this should be considered in surgical planning. The socio-cultural data show a fairly low level of education for the majority of patients.
Zinc inhibits osteoclast differentiation by suppression of Ca2+-Calcineurin-NFATc1 signaling pathway
Authors: Park Kwang Hwan , Park Boryung , Yoon Dong Suk , Kwon Seung-Hyun , Shin Dong Min , Lee Jin Woo , Lee Hyun Gyu , Shim Jae-Hyuck , Park Jeon Han , Lee Jae Myun 
Published: October 2013

Abstract

Background
Zinc, an essential trace element, inhibits osteoclast differentiation in vitro and in vivo. The molecular mechanism for the inhibitory effect of zinc, however, is poorly understood. The purpose of this study was to investigate the effect of zinc and determine its molecular mechanism on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis in mouse bone marrow-derived monocyte cells (BMMs) and RAW264.7 cells.

Results
In BMMs, zinc treatment during osteoclast differentiation decreased RANKL-induced osteoclast formation in a dose-dependent manner. We show that zinc suppressed the mRNA levels of nuclear factor of activated T-cells, cytoplasmic 1 (Nfatc1). Zinc also accumulated phospho-Nfatc1 (p-Nfatc1) in the cytosol in a dose-dependent manner and inhibited the translocation of Nfatc1 to the nucleus in RAW264.7 cells. Zinc suppressed the activities of Nfatc1 in the nucleus without changing the activities of NF-κB in RAW264.7 cells. In contrast, calcineurin activity decreased in response to zinc but its protein level was unchanged. RANKL-induced Ca2+ oscillations were inhibited by zinc treatment, but phospho-phospholipase Cγ1 (p-PLCγ1), the upstream signaling molecule of Ca2+ oscillations, was unaffected. Moreover, a constitutively active form of Nfatc1 obviously rescued suppression of osteoclastogenesis by zinc.

Conclusions
Taken together, these results demonstrate for the first time that the inhibitory effect of zinc during osteoclastogesis is caused by suppressing the Ca2+-Calcineurin-NFATc1 signaling pathway. Thus, zinc may be a useful therapeutic candidate for the prevention of bone loss caused by NFATc1 activation in osteoclasts.
Spatial organization of dendritic cells within tumor draining lymph nodes impacts clinical outcome in breast cancer patients
Authors: Chang Andrew Y , Bhattacharya Nupur , Mu Jian , Setiadi A Francesca , Carcamo-Cavazos Valeria , Lee Gerald H , Simons Diana L , Yadegarynia Sina , Hemati Kaveh , Kapelner Adam , Ming Zheng , Krag David N , Schwartz Erich J , Chen Danny Z , Lee Peter P 
Published: October 2013

AbstractBackgroundDendritic cells (DCs) are important mediators of anti-tumor immune responses. We hypothesized that an in-depth analysis of dendritic cells and their spatial relationships to each other as well as to other immune cells within tumor draining lymph nodes (TDLNs) could provide a better understanding of immune function and dysregulation in cancer.MethodsWe analyzed immune cells within TDLNs from 59 breast cancer patients with at least 5 years of clinical follow-up using immunohistochemical staining with a novel quantitative image analysis system. We developed algorithms to analyze spatial distribution patterns of immune cells in cancer versus healthy intra-mammary lymph nodes (HLNs) to derive information about possible mechanisms underlying immune-dysregulation in breast cancer. We used the non-parametric Mann–Whitney test for inter-group comparisons, Wilcoxon Matched-Pairs Signed Ranks test for intra-group comparisons and log-rank (Mantel-Cox) test for Kaplan Maier analyses.ResultsDegree of clustering of DCs (in terms of spatial proximity of the cells to each other) was reduced in TDLNs compared to HLNs. While there were more numerous DC clusters in TDLNs compared to HLNs,DC clusters within TDLNs tended to have fewer member DCs and also consisted of fewer cells displaying the DC maturity marker CD83. The average number of T cells within a standardized radius of a clustered DC was increased compared to that of an unclustered DC, suggesting that DC clustering was associated with T cell interaction. Furthermore, the number of T cells within the radius of a clustered DC was reduced in tumor-positive TDLNs compared to HLNs. Importantly, clinical outcome analysis revealed that DC clustering in tumor-positive TDLNs correlated with the duration of disease-free survival in breast cancer patients.ConclusionsThese findings are the first to describe the spatial organization of DCs within TDLNs and their association with survival outcome. In addition, we characterized specific changes in number, size, maturity, and T cell co-localization of such clusters. Strategies to enhance DC function in-vivo, including maturation and clustering, may provide additional tools for developing more efficacious DC cancer vaccines.