bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regression for skewed biomarker outcomes subject to pooling
Authors: Mitchell Emily M. , Lyles Robert H. , Manatunga Amita K. , Danaher Michelle , Perkins Neil J. , Schisterman Enrique F. 
Published: February 2014

SummaryEpidemiological studies involving biomarkers are often hindered by prohibitively expensive laboratory tests. Strategically pooling specimens prior to performing these lab assays has been shown to effectively reduce cost with minimal information loss in a logistic regression setting. When the goal is to perform regression with a continuous biomarker as the outcome, regression analysis of pooled specimens may not be straightforward, particularly if the outcome is right‐skewed. In such cases, we demonstrate that a slight modification of a standard multiple linear regression model for poolwise data can provide valid and precise coefficient estimates when pools are formed by combining biospecimens from subjects with identical covariate values. When these‐homogeneous pools cannot be formed, we propose a Monte Carlo expectation maximization (MCEM) algorithm to compute maximum likelihood estimates (MLEs). Simulation studies demonstrate that these analytical methods provide essentially unbiased estimates of coefficient parameters as well as their standard errors when appropriate assumptions are met. Furthermore, we show how one can utilize the fully observed covariate data to inform the pooling strategy, yielding a high level of statistical efficiency at a fraction of the total lab cost.
Oncological predictive value of the 2004 World Health Organisation grading classification in primary T1 non‐muscle‐invasive bladder cancer. A step forward or back?
Authors: Pellucchi Federico , Freschi Massimo , Moschini Marco , Rocchini Lorenzo , Maccagnano Carmen , Nazareno Suardi , Bergamaschi Franco , Montorsi Francesco , Colombo Renzo 
Published: February 2014

ObjectiveTo compare the clinical reliability of the 1973 and 2004 World Health Organisation (WHO) classification systems in pT1 bladder cancer.Patients and MethodsWe retrospectively evaluated 291 consecutive patients who had pT1 high grade bladder cancer between 2004 and 2011. All tumours were simultaneously evaluated by a single uro‐pathologist as high grade and G2 or G3. All patients underwent a second transurethral resection (TUR) and those confirmed with non‐muscle‐invasive bladder cancer at second TUR received bacille Calmette‐Guérin. Follow‐up included urine cytology and cystoscopy 3 months after second TUR and then every 6 months for 5 years. Univariate and multivariate analysis to determine recurrence‐free survival (RFS) and progression‐free survival (PFS) rates were performed using the Kaplan–Meier method with the log‐rank test.ResultsG2 tumours were found in 124 (46.6%) and G3 in 142 (53.4%) patients. The mean (median; range) follow‐up period was 31.1 (19; 1–93) months. The 5‐year RFS rate was 39.1% for the overall high grade population, and 49.1 and 31.8% for G2 and G3 subgroups, respectively. The 5‐year PFS was 82% for the overall high grade population and 89 and 73% for G2 and G3 subgroups, respectively. RFS (P < 0.002) and PFS (P < 0.001) rates were significantly different between the G2 and G3 subgroups. In multivariate analysis, only the grade assessed according to the 1973 WHO significantly correlated with both RFS (P = 0.003) and PFS (P < 0.001).ConclusionThe results suggest that the 1973 WHO classification system has higher prognostic reliability for patients with T1 disease. If confirmed, these findings should be carefully taken into account when making treatment decisions for patients with T1 bladder cancer.
Long‐acting testosterone injections for treatment of testosterone deficiency after brachytherapy for prostate cancer
Authors: Balbontin Felipe G. , Moreno Sergio A. , Bley Enrique , Chacon Rodrigo , Silva Andres , Morgentaler Abraham 
Published: February 2014

ObjectiveTo evaluate the clinical and biochemical effects of long‐acting testosterone undecanoate injections in men with prostate cancer treated with brachytherapy, as the use of testosterone therapy (TTh) in men with prostate cancer is highly controversial, with limited published safety data, particularly after brachytherapy treatment.Patients and MethodsIn all, 20 men treated with brachytherapy for prostate cancer received TTh for symptoms of testosterone deficiency from February 2005 to August 2013. Symptoms of testosterone deficiency included low libido, erectile dysfunction, and fatigue. The mode of TTh was long‐acting testosterone undecanoate injections in all cases. Sexual function was assessed by Sexual Health Inventory for Men (SHIM) questionnaire. Serum PSA and testosterone concentrations were recorded monthly for 3 months, then every 3 months for the first year, every 6 months for the second year, and annually then after.ResultsThe mean (range) age was 62 (49–74) years and the mean (range) serum PSA level at the time of prostate cancer diagnosis was 6.2 (2–11.5) ng/mL. The Gleason score was 2 + 3 in one patient, 3 + 3 in 15 patients, 3 + 4 in three patients and 4 + 4 in one patient. In all, 15 men were stage T1c and five were T2a. The mean (range) baseline total testosterone concentration was 343 (200–592) ng/dL, and 6.9 (2.1–9.7) ng/dL for free testosterone. The mean SHIM scores improved with treatment from 16.1 at baseline to 22.1 with TTh (P = 0.002). There was a decrease in mean PSA level from baseline of 0.7 ng/mL before initiation of TTh to 0.1 ng/mL at last follow‐up (P < 0.001), with a median (range) follow‐up of 31 (12–48) months. There were no cases of prostate cancer progression or recurrence.ConclusionsWith a median of 31‐months follow‐up, long‐acting testosterone injections in men with prostate cancer treated with brachytherapy produced significant clinical benefits. There were no cases of rising serum PSA, prostate cancer progression or recurrence.
Multiparametric magnetic resonance imaging (MRI) and subsequent MRI/ultrasonography fusion‐guided biopsy increase the detection of anteriorly located prostate cancers
Authors: Volkin Dmitry , Turkbey Baris , Hoang Anthony N. , Rais‐Bahrami Soroush , Yerram Nitin , Walton‐Diaz Annerleim , Nix Jeffrey W. , Wood Bradford J. , Choyke Peter L. , Pinto Peter A. 
Published: February 2014

ObjectiveTo describe the detection rate of anteriorly located prostate cancer (PCa) with the addition of magnetic resonance imaging (MRI)/ultrasonography (US) fusion‐guided biopsy (FGB) to the standard transrectal ultrasonography (TRUS)‐guided biopsy.Patients and MethodsAll patients, regardless of their biopsy history, who were referred for clinical suspicion of PCa (i.e elevated prostate‐specific antigen (PSA) level and abnormal digital rectal examination) underwent 3T multiparametric‐MRI (mpMRI) screening; and those with suspicious lesions in the anterior region of the prostate were identified. Patients then received a FGB of all suspicious lesions in addition to a systematic 12‐core extended sextant TRUS‐guided biopsy. We conducted a lesion‐based analysis comparing cancer detection rates of anterior targets using FGB vs systematic cores taken from the same anatomic sextant within the prostate. Lengths of cancer in the most involved core were also compared between the two biopsy techniques used. Patients with only anterior targets were analysed separately.ResultsOf 499 patients undergoing FGB, 162 had a total of 241 anterior lesions. The mean age, PSA level and prostate volume in this group were 62 years, 12.7 ng/dL, and 57 mL, respectively. In total, PCa was diagnosed in 121 anterior lesions (50.2%) identified on mpMRI. Sixty‐two (25.7%) of these anterior lesions were documented as positive for cancer on systematic 12‐core TRUS‐guided biopsy cores, while 97 (40.2%) were positive on the targeted FGB cores (P = 0.001). In lesions that were positive on both FGB and TRUS biopsy, the most involved core was 112% longer on FGB (3.7 vs 1.6 mm, P ≤ 0.01). Forty‐two patients had only anterior lesions on mpMRI; of these, 24 (57.1%) were found to have cancer on the FGB + TRUS biopsy platform. Six patients were positive on FGB only and 13 were positive on both biopsy techniques; however, 7/13 patients were upgraded to a higher Gleason score after FGB. All five patients positive on TRUS biopsy only were candidates for active surveillance.ConclusionThe results showed that FGB detects significantly more anteriorly located PCa than does TRUS‐guided biopsy alone and it may serve as an effective tool for the subset of patients with such tumours.
THE CONSIDERATION OF HUB‐AND‐SPOKE STATUS IN FTA FORMATION
Authors: Cao Jiyun 
Published: February 2014

ABSTRACTThis paper extends the literature on the determinants of free trade area (FTA) taking hub‐and‐spoke status and hub status‐seeking into account. The analysis is based on purely cross‐sectional data and the main findings are different from previous studies. First, the hub‐and‐spoke status and hub status‐seeking are two important determinants of FTA. Moreover, the hub‐and‐spoke status and hub status‐seeking have greater partial effects on the response probabilities than other determinants. Second, the probability of forming an FTA between a pair of economies is higher if they share a common language. Finally, the probability of forming an FTA between a pair of economies falls at first but eventually increases as the difference in their relative factor endowments increases.
A Reproducible and Translatable Model of Focal Ischemia in the Visual Cortex of Infant and Adult Marmoset Monkeys
Authors: Teo Leon , Bourne James A. 
Published: February 2014

AbstractModels of ischemic brain injury in the nonhuman primate (NHP) are advantageous for investigating mechanisms of central nervous system (CNS) injuries and testing of new therapeutic strategies. However, issues of reproducibility and survivability persist in NHP models of CNS injuries. Furthermore, there are currently no pediatric NHP models of ischemic brain injury. Therefore, we have developed a NHP model of cortical focal ischemia that is highly reproducible throughout life to enable better understanding of downstream consequences of injury. Posterior cerebral arterial occlusion was induced through intracortical injections of endothelin‐1 in adult (n = 5) and neonatal (n = 3) marmosets, followed by magnetic resonance imaging (MRI), histology and immunohistochemistry. MRI revealed tissue hyperintensity at the lesion site at 1–7 days followed by isointensity at 14–21 days. Peripheral macrophage and serum albumin infiltration was detected at 1 day, persisting at 21 days. The proportional loss of total V1 as a result of infarction was consistent in adults and neonates. Minor hemorrhagic transformation was detected at 21 days at the lesion core, while neovascularization was detected in neonates, but not in adults. We have developed a highly reproducible and survivable model of focal ischemia in the adult and neonatal marmoset primary visual cortex, demonstrating similar downstream anatomical and cellular pathology to those observed in post‐ischemic humans.
Inhibition of PKC‐θ preserves cardiac function and reduces fibrosis in streptozotocin‐induced diabetic cardiomyopathy
Authors: Li Zhao , Abdullah Chowdhury S , Jin Zhu‐Qiu 
Published: February 2014

Background and PurposeT‐cell infiltration, interstitial fibrosis and cardiac dysfunction have been observed in diabetic patients with cardiovascular diseases. PKC‐θ is crucial for the activation of mature T‐cells. We hypothesized that inhibition of PKC‐θ might protect diabetic hearts through inhibition of T‐cell stimulation and maintenance of tight junction integrity.Experimental ApproachA model of type 1 diabetes was induced by streptozotocin (STZ) (50 mg kg–1 for 5 days) in male C57BL/6J wild‐type (WT) mice and Rag1 knockout (KO) mice which lack mature lymphocytes. A cell‐permeable selective PKC‐θ peptide inhibitor (PI) was administered i.p. (0.2 mg kg–1·day–1) for 4 weeks (first phase) and 2 weeks (second phase). At the end of the 11th week, cardiac contractile force was measured in isolated perfused hearts. Cardiac morphology and fibrosis were determined. Phosphorylation of PKC‐θ at Tyr358, infiltrated T‐cells and tight junction protein ZO‐1 within the hearts were detected, using immunohistochemcial techniques.Key ResultsPI did not affect high blood glucose level in both WT and Rag1 KO diabetic mice. Diabetes induced cardiac fibrosis in WT mice but not in Rag1 KO mice. PI attenuated cardiac fibrosis and improved cardiac contractility of WT diabetic hearts. PI decreased expression of phosphorylated PKC‐θ, reduced the infiltration of T‐cells and increased ZO‐1 expression within WT diabetic hearts.Conclusion and ImplicationsInhibition of PKC‐θ improves cardiac function and reduces cardiac fibrosis in WT mice with streptozotocin‐induced diabetes. Mature T‐cells play a key role in pathophysiology of diabetic cardiomyopathy.
The novel benzimidazole derivative BRP‐7 inhibits leukotriene biosynthesis in vitro and in vivo by targeting 5‐lipoxygenase‐activating protein (FLAP)
Authors: Pergola C , Gerstmeier J , Mönch B , Çalışkan B , Luderer S , Weinigel C , Barz D , Maczewsky J , Pace S , Rossi A , Sautebin L , Banoglu E , Werz O 
Published: February 2014

Background and PurposeLeukotrienes (LTs) are inflammatory mediators produced via the 5‐lipoxygenase (5‐LOX) pathway and are linked to diverse disorders, including asthma, allergic rhinitis and cardiovascular diseases. We recently identified the benzimidazole derivative BRP‐7 as chemotype for anti‐LT agents by virtual screening targeting 5‐LOX‐activating protein (FLAP). Here, we aimed to reveal the in vitro and in vivo pharmacology of BRP‐7 as an inhibitor of LT biosynthesis.Experimental ApproachWe analysed LT formation and performed mechanistic studies in human neutrophils and monocytes, in human whole blood (HWB) and in cell‐free assays. The effectiveness of BRP‐7 in vivo was evaluated in rat carrageenan‐induced pleurisy and mouse zymosan‐induced peritonitis.Key ResultsBRP‐7 potently suppressed LT formation in neutrophils and monocytes and this was accompanied by impaired 5‐LOX co‐localization with FLAP. Neither the cellular viability nor the activity of 5‐LOX in cell‐free assays was affected by BRP‐7, indicating that a functional FLAP is needed for BRP‐7 to inhibit LTs, and FLAP bound to BRP‐7 linked to a solid matrix. Compared with the FLAP inhibitor MK‐886, BRP‐7 did not significantly inhibit COX‐1 or microsomal prostaglandin E2 synthase‐1, implying the selectivity of BRP‐7 for FLAP. Finally, BRP‐7 was effective in HWB and impaired inflammation in vivo, in rat pleurisy and mouse peritonitis, along with reducing LT levels.Conclusions and ImplicationsBRP‐7 potently suppresses LT biosynthesis by interacting with FLAP and exhibits anti‐inflammatory effectiveness in vivo, with promising potential for further development.
Glabridin inhibits migration and invasion by transcriptional inhibition of matrix metalloproteinase 9 through modulation of NF‐κB and AP‐1 activity in human liver cancer cells
Authors: Hsieh Ming‐Ju , Lin Chiao‐Wen , Yang Shun‐Fa , Chen Mu‐Kuan , Chiou Hui‐Ling 
Published: February 2014

Background and PurposeHigh mortality and morbidity rates for hepatocellular carcinoma in Taiwan primarily result from uncontrolled tumour metastasis. Glabridin, a prenylated isoflavonoid of licorice (Glycyrrhiza glabra) roots, is associated with a wide range of biological properties, such as regulation of energy metabolism, oestrogenic, neuroprotective, anti‐osteoporotic and skin whitening. However, the effect of glabridin on the metastasis of tumour cells has not been clarified.Experimental ApproachA wound healing model and Boyden chamber assays in vitro were used to determine the effects of glabridin on the migration and invasion of human hepatocellular carcinoma (HHC) cells. Western blot analysis, gelatin zymography, real‐time PCR and promoter assays were used to evaluate the inhibitory effects of glabridin on matrix metalloproteinase 9 (MMP9) expression in these cells.Key ResultsGlabridin significantly inhibited migration/invasion capacities of HCC cells, Huh7 and Sk‐Hep‐1, cell lines that have low cytotoxicity in vitro, even at high concentrations. Western blot analysis and gelatin zymography showed that glabridin inhibited the expression, activities and protein levels of MMP9 and the phosphorylation of ERK1/2 and JNK1/2. These inhibitory effects were associated with an up‐regulation of tissue inhibitor of metalloproteinase‐1 and a down‐regulation of the transcription factors NF‐κB and activator protein 1 signalling pathways. Finally, the administration of glabridin effectively suppressed the tumour formation in the hepatoma xenograft model in vivo.Conclusion and ImplicationsGlabridin inhibited the invasion of human HCC cells and may have potential as a chemopreventive agent against liver cancer metastasis.
Sedimentary and structural record of the Albian growth of the Bakio salt diapir (the Basque Country, northern Spain)
Authors: Poprawski Y. , Basile C. , Agirrezabala L. M. , Jaillard E. , Gaudin M. , Jacquin T. 
Published: February 2014

AbstractHowever salt has a viscous rheology, overburden rocks adjacent to salt diapirs have a brittle rheology. Evidence of deformation within the overburden has been described from diapirs worldwide. Gravity‐driven deposits are also present along the flanks of several diapirs. The well‐known example from the La Popa Basin in northern Mexico shows that such deposits may be organized into halokinetic sequences. This leads to several questions: (i) How does diapir growth contribute to overburden deformation? (ii) Are halokinetic sequence models valid for other areas beyond the La Popa Basin. The Bakio diapir and its well‐exposed overburden in Basque Country, Spain provides key elements to address these questions. The Bakio diapir consists of Triassic red clays and gypsum and is flanked by synkinematic middle to upper Albian units that thin towards the diapir. The elongate diapir parallels the Gaztelugatxe normal fault to the NE: both strike NE–SW and probably formed together during the middle Albian, as synkinematic units onlap the fault scarp. The diapir is interpreted as a reactive diapir in response to middle Albian motion on the Gaztelugatxe fault. The rate of salt rise is estimated to be about 500 m Myr−1 during this passive stage. During Late Albian, the diapir evolved passively as the Gaztelugatxe fault became inactive. Synkinematic units thinning towards the diapir, major unconformities, slumps and other gravity‐driven deposits demonstrate that most deformation related to diapir growth occurred at the sea floor. Halokinetic sequences composed of alternating breccias and fine‐grained turbidites recorded cyclic episodes of diapir flank destabilization. This work provides insights into drape fold and halokinetic sequence models and offers a new simple method for estimating rates of diapir growth. This method may be useful for outcrop studies where biostratigraphical data are available and for other passive diapirs worldwide.
Sedimentary and tectonic evolution of Lake Ohrid (Macedonia/Albania)
Authors: Lindhorst K. , Krastel S. , Reicherter K. , Stipp M. , Wagner B. , Schwenk T. 
Published: February 2014

AbstractLake Ohrid, located on the Balkan Peninsula within the Dinaride–Albanide–Hellenide mountain belt, is a tectonically active graben within the South Balkan Extensional Regime (SBER). Interpretation of multichannel seismic cross sections and bathymetric data reveals that Lake Ohrid formed during two main phases of deformation: (1) a transtensional phase which opened a pull‐apart basin, and (2) an extensional phase which led to the present geometry of Lake Ohrid. After the initial opening, a symmetrical graben formed during the Late Miocene, bounded by major normal faults on each side in a pull‐apart type basin. The early‐stage geometry of the basin has a typical rhomboidal shape restricted by two sets of major normal faults. Thick undisturbed sediments are present today at the site where the acoustic basement is deepest, illustrating that Lake Ohrid is a potential target for drilling a long and continuous sediment core for studying environmental changes within the Mediterranean region. Neotectonic activity since the Pliocene takes place along the roughly N–S‐striking Eastern and Western Major Boundary Normal Faults that are partly exposed at the present lake floor. The tectono‐sedimentary structure of the basin is divided into three main seismic units overlying the acoustic basement associated with fluvial deposits and lacustrine sediments. A seismic facies analysis reveals a prominent cyclic pattern of high‐ and low‐amplitude reflectors. We correlate this facies cyclicity with vegetation changes within the surrounding area that are associated with glacial/interglacial cycles. A clear correlation is possible back to ca. 450 kyrs. Extrapolation of average sedimentation rates for the above mentioned period results in age estimate of ca. 2 Myrs for the oldest sediments in Lake Ohrid.
Dysmorphic choroid plexuses and hydrocephalus associated with increased nuchal translucency: Early ultrasound markers ofde novothanatophoric dysplasia typeIIwith cloverleaf skull (Kleeblattschaedel)
Authors: Tonni Gabriele , Palmisano Marcella , Ginocchi Vladimiro , Ventura Alessandro , Baldi Maurizia , Baffico Ave Maria 
Published: February 2014

AbstractPrenatal diagnosis of thanatophoric dysplasia (TD) typeIIpresenting in the first trimester with increased nuchal translucency (NT) and cloverleaf skull (Kleeblattschaedel) have been scantly reported in the medical record. Abnormal choroid plexus has been seen in association with fetal anomalies. Here we described a case of increasedNTassociated with indented choroid plexuses, early onset hydrocephalus and cloverleaf skull in a fetus subsequently diagnosed at early second trimester to carry ade novomutation encoding forTDtypeII. The findings of dysmorphic choroid plexus, early onset hydrocephalus and cloverleaf skull at first trimester scan may be early, useful ultrasound markers ofTDtypeII. Molecular analysis to control for possible overlapping syndromes were performed and resulted negative. PostmortemX‐ray and3D‐CTscan confirmed the cloverleaf skull, narrow thorax, straight femur with rhizomelic shortening of the limbs and the presence of a communicating hydrocephalus.
Allee Effect and the Uncertainty of Population Recovery
Authors: KUPARINEN ANNA , KEITH DAVID M. , HUTCHINGS JEFFREY A. 
Published: February 2014

AbstractRecovery of depleted populations is fundamentally important for conservation biology and sustainable resource harvesting. At low abundance, population growth rate, a primary determinant of population recovery, is generally assumed to be relatively fast because competition is low (i.e., negative density dependence). But population growth can be limited in small populations by an Allee effect. This is particularly relevant for collapsed populations or species that have not recovered despite large reductions in, or elimination of, threats. We investigated how an Allee effect can influence the dynamics of recovery. We used Atlantic cod (Gadus morhua) as the study organism and an empirically quantified Allee effect for the species to parameterize our simulations. We simulated recovery through an individual‐based mechanistic simulation model and then compared recovery among scenarios incorporating an Allee effect, negative density dependence, and an intermediate scenario. Although an Allee effect significantly slowed recovery, such that population increase could be negligible even after 100 years or more, it also made the time required for biomass rebuilding much less predictable. Our finding that an Allee effect greatly increased the uncertainty in recovery time frames provides an empirically based explanation for why the removal of threat does not always result in the recovery of depleted populations or species.El Efecto Allee y la Incertidumbre de la Recuperación de Poblaciones