bluuebunny/crossref_metadata_2025_split huggingface dataset:
Statistical issues in the validation of prognostic, predictive, and surrogate biomarkers
Authors: Sargent Daniel J , Mandrekar Sumithra J 
Published: August 2013

Background Biomarkers have many distinct purposes, and depending on their intended use, the validation process varies substantially. Purpose The goal of this article is to provide an introduction to the topic of biomarkers, and then to discuss three specific types of biomarkers, namely, prognostic, predictive, and surrogate. Results A principle challenge for biomarker validation from a statistical perspective is the issue of multiplicity. In general, the solution to this multiplicity challenge is well known to statisticians: pre-specification and replication. Critical requirements for prognostic marker validation include uniform treatment, complete follow-up, unbiased case selection, and complete ascertainment of the many possible confounders that exist in the context of an observational sample. In the case of predictive biomarker validation, observational data are clearly inadequate and randomized controlled trials are mandatory. Within the context of randomization, strategies for predictive marker validation can be grouped into two categories: retrospective versus prospective validation. The critical validation criteria for a surrogate endpoint is to ensure that if a trial uses a surrogate endpoint, the trial will result in the same inferences as if the trial had observed the true endpoint. The field of surrogate endpoint validation has now moved to the multi-trial or meta-analytic setting as the preferred method. Conclusions Biomarkers are a highly active research area. For all biomarker developmental and validation studies, the importance of fundamental statistical concepts remains the following: pre-specification of hypotheses, randomization, and replication. Further statistical methodology research in this area is clearly needed as we move forward.
A Retrospective Review of Anterior Cruciate Ligament Reconstruction Using Patellar Tendon
Authors: Chahal Jaskarndip , Lee Andrew , Heard Wendell , Bach Bernard R. 
Published: August 2013

Background: The comparative data in the literature regarding rates of reoperation, revision ligament surgery, and contralateral surgery following anterior cruciate ligament reconstruction (ACLR) are variable and are often derived from studies with multiple surgeons, multiple centers, different surgical techniques, and a wide variety of graft choices. Purpose: To describe and analyze a single surgeon’s experience with ACLR using bone–patellar tendon–bone (BPTB) as the primary graft choice over a 25-year period. Study Design: Retrospective case series. Methods: All patients who underwent ACLR from 1986 to 2012 were identified from a prospectively maintained database. Traditional follow-up was only for patients who sought subsequent surgery with the index surgeon or presented with contralateral ACL injury. Covariates of interest included age, sex, time, and graft selection. Outcomes of interest included reoperation rates after primary/revision ACLR, rate of revision ACLR, success of meniscal repair with concomitant ACLR, and the proportion of patients undergoing contralateral surgery. Results: A total of 1981 patients (mean age, 29 years; 49% male) were identified. Of patients undergoing primary ACLR (n = 1809), 74% had BPTB autograft and 26% had a central third BPTB allograft. The mean age of patients undergoing autograft and allograft ACLR was 26 and 36 years, respectively ( P < .05). Allograft tissue usage increased over time ( P < .05). The rate of personal ACLR revision surgery was 1.7% (n = 30) for primary cases and 3.5% (n = 6) for revision cases. There were no significant differences in revision rates between primary autograft (1.6%) and allograft (2.0%) ACLR. With allograft use, the method of sterilization did not affect revision rates. The overall reoperation rate following primary ACLR was 10%; the 5-year reoperation rate was 7.7%. The reoperation rate was lower for primary cases reconstructed with allograft versus autograft (5% vs 12%) ( P < .0001). Among primary ACLR cases, 332 patients (18%) underwent concomitant meniscal repair; 14% required revision meniscal surgery. The rate of contralateral ACLR was 6%. Conclusion: This information is useful for patients in the informed consent process, for perioperative decision making regarding graft choice, and for identifying patients who are at risk for injuring the uninvolved knee. The observed results in this series also emphasize that allograft ACLR can produce sustainable results with low complication rates in appropriately selected patients.
Genomic characterization of JG068, a novel virulent podovirus active against Burkholderia cenocepacia
Authors: Lynch Karlene H , Abdu Ashraf H , Schobert Max , Dennis Jonathan J 
Published: August 2013

Abstract

Background
As is true for many other antibiotic-resistant Gram-negative pathogens, members of the Burkholderia cepacia complex (BCC) are currently being assessed for their susceptibility to phage therapy as an antimicrobial treatment. The objective of this study was to perform genomic and limited functional characterization of the novel BCC phage JG068 (vB_BceP_JG068).

Results
JG068 is a podovirus that forms large, clear plaques on Burkholderia cenocepacia K56-2. Host range analysis indicates that this phage can infect environmental, clinical, and epidemic isolates of Burkholderia multivorans, B. cenocepacia, Burkholderia stabilis, and Burkholderia dolosa, likely through interaction with the host lipopolysaccharide as a receptor. The JG068 chromosome is 41,604 base pairs (bp) in length and is flanked by 216 bp short direct terminal repeats. Gene expression originates from both host and phage promoters and is in the forward direction for all 49 open reading frames. The genome sequence shows similarity to Ralstonia phage ϕRSB1, Caulobacter phage Cd1, and uncharacterized genetic loci of blood disease bacterium R229 and Burkholderia pseudomallei 1710b. CoreGenesUniqueGenes analysis indicates that JG068 belongs to the Autographivirinae subfamily and ϕKMV-like phages genus. Modules within the genome encode proteins involved in DNA-binding, morphogenesis, and lysis, but none associated with pathogenicity or lysogeny. Similar to the signal-arrest-release (SAR) endolysin of ϕKMV, inducible expression of the JG068 SAR endolysin causes lysis of Escherichia coli that is dependent on the presence of an N-terminal signal sequence. In an in vivo assay using the Galleria mellonella infection model, treatment of B. cenocepacia K56-2-infected larvae with JG068 results in a significant increase in larval survival.

Conclusions
As JG068 has a broad host range, does not encode virulence factors, is obligately lytic, and has activity against an epidemic B. cenocepacia strain in vivo, this phage is a highly promising candidate for BCC phage therapy development.
Genome-wide gene expression profiling of stress response in a spinal cord clip compression injury model
Authors: Chamankhah Mahmood , Eftekharpour Eftekhar , Karimi-Abdolrezaee Soheila , Boutros Paul C , San-Marina Serban , Fehlings Michael G 
Published: August 2013

Abstract

Background
The aneurysm clip impact-compression model of spinal cord injury (SCI) is a standard injury model in animals that closely mimics the primary mechanism of most human injuries: acute impact and persisting compression. Its histo-pathological and behavioural outcomes are extensively similar to human SCI. To understand the distinct molecular events underlying this injury model we analyzed global mRNA abundance changes during the acute, subacute and chronic stages of a moderate to severe injury to the rat spinal cord.

Results
Time-series expression analyses resulted in clustering of the majority of deregulated transcripts into eight statistically significant expression profiles. Systematic application of Gene Ontology (GO) enrichment pathway analysis allowed inference of biological processes participating in SCI pathology. Temporal analysis identified events specific to and common between acute, subacute and chronic time-points. Processes common to all phases of injury include blood coagulation, cellular extravasation, leukocyte cell-cell adhesion, the integrin-mediated signaling pathway, cytokine production and secretion, neutrophil chemotaxis, phagocytosis, response to hypoxia and reactive oxygen species, angiogenesis, apoptosis, inflammatory processes and ossification. Importantly, various elements of adaptive and induced innate immune responses span, not only the acute and subacute phases, but also persist throughout the chronic phase of SCI. Induced innate responses, such as Toll-like receptor signaling, are more active during the acute phase but persist throughout the chronic phase. However, adaptive immune response processes such as B and T cell activation, proliferation, and migration, T cell differentiation, B and T cell receptor-mediated signaling, and B cell- and immunoglobulin-mediated immune response become more significant during the chronic phase.

Conclusions
This analysis showed that, surprisingly, the diverse series of molecular events that occur in the acute and subacute stages persist into the chronic stage of SCI. The strong agreement between our results and previous findings suggest that our analytical approach will be useful in revealing other biological processes and genes contributing to SCI pathology.
Interaction between two rice mitogen activated protein kinases and its possible role in plant defense
Authors: Sheikh Arsheed H , Raghuram Badmi , Jalmi Siddhi K , Wankhede Dhammaprakash P , Singh Pallavi , Sinha Alok K 
Published: August 2013

Abstract

Background
The canonical mitogen activated protein kinase (MAPK) signaling pathway plays a vital role in carrying out the normal growth and development of the plant. The pathway, connecting the upstreams signal with the downstream target is considered to be linear, mostly starting with a MAPKKK and ending in a MAPK.

Results
Here we report a novel interaction between two rice MAPKs, OsMPK20-4 and OsMPK3 suggesting the complex nature of the pathway rather than a linear one at individual steps. The interaction between OsMPK20-4 and OsMPK3 found by yeast two-hybrid analysis was confirmed in planta by co-immunoprecipitation and fluorescence resonance energy transfer (FRET) assays. The interaction is specific and is phosphorylation independent. The results suggest a role of the interaction between OsMPK20-4 and OsMPK3 in basic plant defense.

Conclusions
The current novel work showing the physical interaction between two plant MAPKs, OsMPK20-4 and OsMPK3 is the diversion from the dogma of a typical MAPK cascade thereby opening a new dimension to the MAPK signal transduction.
Histone acetyltransferase PCAF Up-regulated cell apoptosis in hepatocellular carcinoma via acetylating histone H4 and inactivating AKT signaling
Authors: Zheng Xin , Gai Xiaohong , Ding Feihu , Lu Zhongtang , Tu Kangsheng , Yao Yingmin , Liu Qingguang 
Published: August 2013

Abstract
Background
PCAF is an important intrinsic histone acetyltransferases. This study tried to establish the effect of PCAF on HCC cell apoptosis.

Method
Both in vitro and in vivo experiments including IHC, DAPI staining, caspase 3/7 activity assay, BrdU assay, MTT assay, western immunoblotting and co-immunoprecipitation were used here.

Results
PCAF was found to be expressed at the low level in most of HCC cell lines. PCAF overexpression induced cell apoptosis and growth arrest with increased Histone H4 acetylation and inactivation of AKT signaling in Huh7 and HepG2 cells. The opposite results were obtained by silencing PCAF in Hep3B cells. The co-immunoprecipitation assay confirmed that PCAF protein was bound with histone H4 protein in the nucleus of Hep3B cells. Finally, the in vivo experiment confirmed the findings mentioned-above.

Conclusion
These data identified PCAF promotes cell apoptosis and functions as a HCC repressor through acetylating histone H4 and inactivating AKT signaling.
Lack of association between lipoprotein(a) genetic variants and subsequent cardiovascular events in Chinese Han patients with coronary artery disease after percutaneous coronary intervention
Authors: Li Zhi-Gen , Li Guang , Zhou Ying-Ling , Chen Zhu-Jun , Yang Jun-Qing , Zhang Ying , Sun Shuo , Zhong Shi-Long 
Published: August 2013

Abstract

Background
Elevated lipoprotein(a) [Lp(a)] levels predict cardiovascular events incidence in patients with coronary artery disease (CAD). Genetic variants in the rs3798220, rs10455872 and rs6415084 single-nucleotide polymorphisms (SNPs) in the Lp(a) gene (LPA) correlate with elevated Lp(a) levels, but whether these SNPs have prognostic value for CAD patients is unknown. The present study evaluated the association of LPA SNPs with incidence of subsequent cardiovascular events in CAD patients after percutaneous coronary intervention (PCI).

Methods
TaqMan SNP genotyping assays were performed to detect the rs6415084, rs3798220 and rs10455872 genotypes in 517 Chinese Han patients with CAD after PCI. We later assessed whether there was an association of these SNPs with incidence of major adverse cardiovascular events (MACE: cardiac death, nonfatal myocardial infarction, ischemic stroke and coronary revascularization). Serum lipid profiles were also determined using biochemical methods.

Results
Only the rs6415084 variant allele was associated with higher Lp(a) levels [41.3 (20.8, 74.6) vs. 18.6 (10.3, 40.9) mg/dl, p < 0.001]. During a 2-year follow-up period, 102 patients suffered MACE, and Cox regression analysis demonstrated that elevated Lp(a) (≥30 mg/dl) levels correlated with increased MACE (adjusted HR, 1.69; 95% CI 1.13-2.53), but there was no association between LPA genetic variants (rs6415084 and rs3798220) and MACE incidence (p > 0.05).

Conclusions
Our data did not support a relationship between genetic LPA variants (rs6415084 and rs3798220) and subsequent cardiovascular events after PCI in Chinese Han CAD patients.
Correlation analysis of preoperative serum alpha-fetoprotein (AFP) level and prognosis of hepatocellular carcinoma (HCC) after hepatectomy
Authors: Ma Wen-jun , Wang Hai-yong , Teng Li-song 
Published: August 2013

Abstract

Background
To investigate the prediction value of preoperative serum alpha-fetoprotein (AFP) level for the prognosis of hepatocellular carcinoma (HCC), by comparing pathological characteristics, recurrence rate and survival rate after hepatectomy.

Methods
108 cases of HCC patients who received liver resection in our hospital from 2005 to 2011 were enrolled in this study. According to preoperative serum AFP level, the patients were divided into AFP ≤ 20 ng/mL group, AFP 20 to 400 ng/mL group and AFP > 400 ng/mL group, and the clinicopathological and cytopathological features were compared. All the patients were followed up for 24 months, the postoperative recurrence rates and survival rates were compared and analyzed, and the risk factors for HCC postoperative survival rate were studied by multifactor regression analysis.

Results
Of the 108 cases of HCC patients, there were 42 cases in AFP ≤20 ng/mL group, 28 cases in AFP 20–400 ng/mL group and 39 cases in AFP > 400 ng/mL group. It was shown that cell differentiation degrees (χ
2 = 20.198, P = 0.000) and microvascular invasion rates (χ
2 = 20.358, P = 0.000) were significantly different among the three groups. The AFP ≤ 20 ng/mL group showed higher cell differentiation degrees and significantly lower microvascular invasion rates compared to the other groups (P < 0.05). The follow-up data showed that postoperative 2-year recurrence rate (χ
2 = 6.164, P = 0.046), 18-month survival rate (χ
2 = 7.647, P = 0.022) and 24-month survival rate (χ
2 = 6.725, P = 0.035) of the three groups were significantly different, and we found that the AFP ≤ 20 ng/mL group had lower postoperative 2-year recurrence rate, and higher 18-month survival rate and 24-month survival rate than the other two groups (P <0.05). Multiple logistic regression analysis indicated that tumor diameter (≥ 5 cm) and preoperative serum AFP level (> 400 ng/mL) were closely correlated with HCC postoperative survival rate (P <0.05).

Conclusions
It is shown that preoperative serum AFP level has considerable predictive value for the malignant feature and prognosis of HCC. It is suggested that HCC patients with no contraindication of operation and serum AFP ≤ 20 ng/mL can benefit most from primary treatment of hepatectomy. While HCC patients with serum AFP higher than 20 ng/mL need comprehensive therapy besides surgical resection and close follow up.
Simultaneous laparoscopic splenectomy and right hemihepatectomy for littoral cell angiosarcoma accompanied with liver metastases
Authors: Wang Liang , Xiu Dianrong , Jiang Bin , Ma Zhaolai , Yuan Chunhui , Li Lei 
Published: August 2013

Abstract
Despite the wide acceptance of laparoscopic resection for treatment of abdominal tumors, only few cases of simultaneous laparoscopic removal of the spleen and the right liver have been reported to date. Littoral cell angiosarcoma (LCAS), which arises from the littoral cells lining the sinus channels of the splenic red pulp, is a rare condition, and there is limited literature on littoral cell angiosarcoma with liver metastases. We present the case of a 28-year-old woman with postoperative pathologically-proven LCAS with right liver metastases. The patient’s surgery was safely performed, and her postoperative course was uneventful until now. This case suggests that concomitant laparoscopic splenectomy (LS) and right hemihepatectomy is a suitable surgical option for selected patients.
Forecasting the absolute and relative shortage of physicians in Japan using a system dynamics model approach
Authors: Ishikawa Tomoki , Ohba Hisateru , Yokooka Yuki , Nakamura Kozo , Ogasawara Katsuhiko 
Published: August 2013

Abstract

Background
In Japan, a shortage of physicians, who serve a key role in healthcare provision, has been pointed out as a major medical issue. The healthcare workforce policy planner should consider future dynamic changes in physician numbers. The purpose of this study was to propose a physician supply forecasting methodology by applying system dynamics modeling to estimate future absolute and relative numbers of physicians.

Method
We constructed a forecasting model using a system dynamics approach. Forecasting the number of physician was performed for all clinical physician and OB/GYN specialists. Moreover, we conducted evaluation of sufficiency for the number of physicians and sensitivity analysis.

Result & conclusion
As a result, it was forecast that the number of physicians would increase during 2008–2030 and the shortage would resolve at 2026 for all clinical physicians. However, the shortage would not resolve for the period covered. This suggests a need for measures for reconsidering the allocation system of new entry physicians to resolve maldistribution between medical departments, in addition, for increasing the overall number of clinical physicians.
Cold shock Y-box protein-1 proteolysis autoregulates its transcriptional activities
Authors: van Roeyen Claudia RC , Scurt Florian G , Brandt Sabine , Kuhl Vanessa A , Martinkus Sandra , Djudjaj Sonja , Raffetseder Ute , Royer Hans-Dieter , Stefanidis Ioannis , Dunn Sandra E , Dooley Steven , Weng Honglei , Fischer Thomas , Lindquist Jonathan A , Mertens Peter R 
Published: August 2013

AbstractBackgroundThe Y-box protein-1 (YB-1) fulfills pleiotropic functions relating to gene transcription, mRNA processing, and translation. It remains elusive how YB-1 shuttling into the nuclear and cytoplasmic compartments is regulated and whether limited proteolysis by the 20S proteasome releases fragments with distinct function(s) and subcellular distribution(s).ResultsTo address these questions, mapping of domains responsible for subcellular targeting was performed. Three nuclear localization signals (NLS) were identified. NLS-1 (aa 149-156) and NLS-2 (aa 185-194) correspond to residues with unknown function(s), whereas NLS-3 (aa 276-292) matches with a designated multimerization domain. Nuclear export signal(s) were not identified. Endoproteolytic processing by the 20S proteasome before glycine 220 releases a carboxy-terminal fragment (CTF), which localized to the nucleus, indicating that NLS-3 is operative. Genotoxic stress induced proteolytic cleavage and nuclear translocation of the CTF. Co-expression of the CTF and full-length YB-1 resulted in an abrogated transcriptional activation of the MMP-2 promoter, indicating an autoregulatory inhibitory loop, whereas it fulfilled similar trans-repressive effects on the collagen type I promoter.ConclusionCompartmentalization of YB-1 protein derivatives is controlled by distinct NLS, one of which targets a proteolytic cleavage product to the nucleus. We propose a model for an autoregulatory negative feedback loop that halts unlimited transcriptional activation.
Anti-tumour activity of longikaurin A (LK-A), a novel natural diterpenoid, in nasopharyngeal carcinoma
Authors: Zou Qing-Feng , Du Ji-Ke , Zhang Hua , Wang Hong-Bo , Hu Ze-Dong , Chen Shu-Peng , Du Yong , Li Man-Zhi , Xie Dan , Zou Juan , Sun Han-Dong , Pu Jian-Xin , Zeng Mu-Sheng 
Published: August 2013

Abstract

Background
Longikaurin A is a natural ent-kaurene diterpenoid isolated from Isodon genus. The ent-kaurene diterpenoids isolated from medicinal plants have been shown to have anti-disease effects. The present study was designed to examine the anti-tumour effects of longikaurin A (LK-A) in nasopharyngeal carcinoma in vitro and in vivo.

Methods
Apoptosis and cell cycle arrest were determined by flow cytometry analysis of the cells treated with Longikaurin A. The proteins of apoptosis signaling pathway were detected by western blotting analysis. Finally, we examined whether LK-A exhibits anti-tumour activity in xenograft models.

Results
Longikaurin A inhibited the cell growth by inducing apoptosis and cell cycle arrest. At low concentrations, longikaurin A induced S phase arrest and at higher concentrations, longikaurin A induced caspase-dependent apoptosis by regulating apoptotic molecules. Finally, longikaurin A significantly inhibited the tumour growth of CNE2 xenografts in vivo and showed no obvious effect on the body weights of the mice.

Conclusion
Our results suggest that Longikaurin A exhibited anti-tumour activity in nasopharyngeal carcinoma in vitro and in vivo.
Electronic structures and optical properties for Ag-N-codoped ZnO nanotubes
Authors: Feng Xian-Yang , Zhang Chang-Wen , Xu Xi-Jin , Wang Pei-Ji 
Published: August 2013

Abstract
The structural and electronic/optical properties of pure and Ag-N-codoped (8,0) ZnO nanotubes have been studied using first-principles calculations in the framework of the local spin density approximation. The configurations for Zn atoms replaced by Ag atoms are p-type semiconductor materials, and the bandgap increases when N atoms are doped into ZnO nanotube configurations. The optical studies based on dielectric function and reflectivity indicate that new transition peaks in the visible light range are observed, which can be ascribed to the Ag and N doping. Furthermore, there is a red shift observed with the increase of N concentration.