Statistical Methods for Evaluating Biomarkers Subject to Detection Limit

As a cost effective diagnostic tool, numerous candidate biomarkers have been emerged for different diseases. The increasing effort of discovering informative biomarkers highlights the need for valid statistical modeling and evaluation. Our focus is on the biomarker data which are both measured repeatedly over time and censored by the sensitivity of given assay. Inappropriate handling of these types of data can cause biased results, resulting in erroneous medical decision.In the first topic, we extend the discriminant analysis to censored longitudinal biomarker data based on linear mixed models and modified likelihood function. The performance of biomarker is evaluated by area under the receiver operation characteristic (ROC) curve (AUC). The simulation study shows that the proposed method improves both parameter and AUC estimation over substitution methods when normality assumption is satisfied for biomarker data. Our method is applied to the biomarker study for acute kidney injury patients. In the second topic, we introduce a simple and practical evaluation method for censored longitudinal biomarker data. A modification of the linear combination approach by Su and Liu enables us to calculate the optimum AUC as well as relative importance of measurements from each time point. The simulation study demonstrates that the proposed method performs well in a practical situation. The application to real-world data is provided. In the third topic, we consider censored time-invariant biomarker data to discriminate time to event or cumulative events by a particular time point. C-index and time dependent ROC curve are often used to measure the discriminant potential of survival model. We extend these methods to censored biomarker data based on joint likelihood approach. Simulation study shows that the proposed methods result in accurate discrimination measures. The application to a biomarker study is provided. Both early detection and accurate prediction of disease are important to manage serious public health problems. Because many of diagnostic tests are based on biomarkers, discovery of informative biomarker is one of the active research areas in public health. Our methodology is important for public health researchers to identify promising biomarkers when the measurements are censored by detection limits

Une analyse efficace du procédé RTM à l aide de la méthode XFEM

Le procédé de fabrication par RTM (Resin Transfer Molding) a été étudié numériquement à l aide de la méthode XFEM (eXtended Finite Element Method) combinée avec la méthode Level set. La méthode XFEM permet d obtenir une bonne précision numérique de la pression près du front d écoulement, où son gradient est discontinu. Les fonctions de forme enrichies de la méthode XFEM sont proposées à l aide des valeurs de Level set en vue de décrire correctement l interpolation avec le front d écoulement. En plus, la méthode de Level set est utilisée pour transporter le front d écoulement à chaque pas de temps durant le remplissage du moule. Les valeurs de Level set sont calculées à l aide d une méthode de Galerkin implicite. Le solveur multi-frontal d IPSAP a été utilisé pour la résolution du système. Cette étude a été validée en comparaison avec les solutions analytiques.En outre, une méthode de localisation avec XFEM et la méthode Level set a été proposée afin d améliorer l efficacité de calcul. Elle permet de réduire le domaine de calcul près du front d écoulement. Par conséquent, le temps de calcul est fortement réduit grâce à cette méthode. Un test d efficacité a été fait avec des modèles simples en écoulement laminaire ou radial.Quelques exemples d application sont présentés pour illustrer la capacité de cette méthode. Une pale d éolienne a également traitée comme application industrielle. Enfin, une interface d utilisateur graphique a été développée en vue de fournir une facilité des pré- et post-processus.Numerical simulation for Resin Transfer Molding (RTM) manufacturing process is attempted by using the eXtended Finite Element Method (XFEM) combined with the level set method. XFEM allows to obtaining a good numerical precision of the pressure near the resin flow front, where its gradient is discontinuous. The enriched shape functions of XFEM are derived by using the level set values so as to correctly describe the interpolation with the resin flow front. In addition, the level set method is used to transport the resin flow front at each time step during the mold filling. The level set values are calculated by an implicit characteristic Galerkin FEM. The multi-frontal solver of IPSAP is adopted to solve the system. This work is validated by comparing the obtained results with analytic solutions.Moreover, a localization method of XFEM and level set method is proposed to increase the computing efficiency. The computation domain is reduced to the small region near the resin flow front. Therefore, the total computing time is strongly reduced by it. The efficiency test is made with simple channel or radial flow models. Several application examples are analyzed to demonstrate ability of this method. A wind turbine blade is also treated as industrial application. Finally, a Graphic User Interface (GUI) tool is developed so as to make easy the pre/post-processing of the simulation.ST ETIENNE-ENS des Mines (422182304) / SudocSudocFranceF

Mechanical Stimulation of the HT7 Acupuncture Point to Reduce Ethanol Self-Administration in Rats

Background. Alcoholism, which is a disabling addiction disorder, is a major public health problem worldwide. The present study was designed to determine whether the application of acupuncture at the Shenmen (HT7) point suppresses voluntary alcohol consumption in addicted rats and whether this suppressive effect is potentiated by the administration of naltrexone. Methods. Rats were initially trained to self-administer a sucrose solution by operating a lever. A mechanical acupuncture instrument (MAI) for objective mechanical stimulation was used on rats whose baseline response had been determined. In addition, the effect of HT7 acupuncture on beta-endorphin concentration and ethanol intake via naltrexone were investigated in different groups. Results. We found that ethanol intake and beta-endorphin level in rats being treated with the MAI at the HT7 point reduced significantly. The treatment of naltrexone at high doses reduced the ethanol intake and low-dose injection of naltrexone in conjunction with the MAI also suppressed ethanol intake. Conclusions. The results of the current study indicate that using the MAI at the HT7 point effectively reduces ethanol consumption in rats. Furthermore, the coadministration of the MAI and a low dose of naltrexone can produce some more potent reducing effect of ethanol intake than can acupuncture alone

Combinations of idelalisib with rituximab and/or bendamustine in patients with recurrent indolent non-Hodgkin lymphoma

Key Points Combining phosphatidylinositol-3-kinase δ inhibition with rituximab, bendamustine, or both is feasible and active in relapsed iNHL. The safety of novel combinations should be proven in phase 3 trials before adoption in clinical practice.</jats:p

Neuropeptides SP and CGRP Underlie the Electrical Properties of Acupoints

Electrical skin measurements at acupuncture points (acupoints) have been utilized as a diagnostic and therapeutic aid for more than 50 years. Although acupoints are described as having distinct electrical properties, such as high conductance and low impedance, the underlying mechanisms are currently unknown. The present study investigated in a rat model of hypertension whether the high conductance at acupoints is a result of the release of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) during neurogenic inflammation in the referred pain area. When plasma extravasation from neurogenic inflammation was examined by exploring the leakage of intravenously injected Evans blue dye (EBD) to the skin, extravasated EBD was found most frequently in acupoints on the wrist. The increased conductance and temperature at these acupoints occurred during the development of hypertension. The increase in conductance and plasma extravasation at acupoints in hypertensive rats was ablated by cutting median and ulnar nerves, blocking small diameter afferent fibers with resiniferatoxin (RTX) injection into median and ulnar nerves, or antagonizing SP or CGRP receptors in acupoints. In turn, intradermal injection of SP or CGRP resulted in increased conductance and plasma extravasation in naïve rats. Elevated levels of SP and CGRP were found in the acupoints of hypertensive rats. These findings suggest that the high conductance at acupoints is due to vascular leakage following local release of SP and CGRP during neurogenic inflammation

The anti-angiogenic herbal composition Ob-X inhibits adipose tissue growth in obese mice

Objective: The growth and development of adipose tissue are thought to be associated with angiogenesis and extracellular matrix remodeling. Since the composition of the herbal extract called Ob-X has been shown to have both anti-angiogenic and matrix metalloproteinase (MMP)-inhibiting activities, we hypothesized that growth of adipose tissue can be regulated by Ob-X. Materials and Methods: The effects of Ob-X on angiogenesis and extracellular matrix remodeling were measured using in vitro and ex vivo assays. The effects of Ob-X on adipose tissue growth were investigated with nutritionally obese mice. Results: Ob-X inhibited angiogenesis in a dose-dependent manner in the human umbilical vein endothelial cell (HUVEC) tube formation assay in vitro and the rat aortic ring assay ex vivo. Ob-X also suppressed MMP activity in vitro. Administration of Ob-X to high fat diet-induced obese mice produced significant reductions in body weight gain and adipose tissue mass, compared to controls. The mass of both subcutaneous (SC) and visceral (VSC) fat was reduced in Ob-X-treated mice. The size of adipocytes in SC and VSC adipose tissues was also significantly reduced in Ob-X-treated mice. Ob-X treatment decreased the blood vessel density and MMP activity in VSC adipose tissues of nutritionally obese mice. Ob-X reduced mRNA levels of angiogenic factors (VEGF-A and FGF-2) and MMPs (MMP-2 and MMP-9), whereas it increased mRNA levels of angiogenesis inhibitors (TSP-1 and TIMP-2) in SC and VSC adipose tissues of nutritionally obese mice. Conclusion: Ob-X, which has anti-angiogenic and MMP-inhibitory activities, reduces adipose tissue mass in nutritionally induced obese mice, providing evidence that adipose tissue growth and development may be prevented by inhibiting angiogenesis. In addition, these data suggest that regulation of adipose tissue growth by inhibiting angiogenesis may alter the expression of genes involved in angiogenesis and the MMP system

Attenuation of immobilization stress-induced hypertension by temperature-controllable warm needle acupuncture in rats and the peripheral neural mechanisms

IntroductionWe and others have shown that electrical stimulation of the PC-6 acupoint over the wrist relieves hypertension by stimulating afferent sensory nerve fibers and activating the central endogenous opioid system. Warm needle acupuncture has long been utilized to treat various diseases in clinics.MethodsHere, we developed a temperature-controllable warm needle acupuncture instrument (WAI) and investigated the peripheral mechanism underlying the effect of warm needle acupuncture at PC-6 on hypertension in a rat model of immobilization stress-induced hypertension.ResultsStimulation with our newly developed WAI and traditional warm needle acupuncture attenuated hypertension development. Such effects were reproduced by capsaicin (a TRPV1 agonist) injection into PC-6 or WAI stimulation at 48°C. In contrast, PC-6 pretreatment with the TRPV1 antagonist capsazepine blocked the antihypertensive effect of WAI stimulation at PC-6. WAI stimulation at PC-6 increased the number of dorsal root ganglia double-stained with TRPV1 and CGRP. QX-314 and capsaicin perineural injection into the median nerve for chemical ablation of small afferent nerve fibers (C-fibers) prevented the antihypertensive effect of WAI stimulation at PC-6. Additionally, PC-6 pretreatment with RTX ablated the antihypertensive effect of WAI stimulation.ConclusionThese findings suggest that warm needle acupuncture at PC-6 activates C-fiber of median nerve and the peripheral TRPV1 receptors to attenuate the development of immobilization stress-induced hypertension in rats

Supercooling as a Viable Non-Freezing Cell Preservation Method of Rat Hepatocytes

Supercooling preservation holds the potential to drastically extend the preservation time of organs, tissues and engineered tissue products, and fragile cell types that do not lend themselves well to cryopreservation or vitrification. Here, we investigate the effects of supercooling preservation (SCP at -4oC) on primary rat hepatocytes stored in cryovials and compare its success (high viability and good functional characteristics) to that of static cold storage (CS at +4oC) and cryopreservation. We consider two prominent preservation solutions a) Hypothermosol (HTS-FRS) and b) University of Wisconsin solution (UW) and a range of preservation temperatures (-4 to -10 oC). We find that there exists an optimum temperature (-4oC) for SCP of rat hepatocytes which yields the highest viability; at this temperature HTS-FRS significantly outperforms UW solution in terms of viability and functional characteristics (secretions and enzymatic activity in suspension and plate culture). With the HTS-FRS solution we show that the cells can be stored for up to a week with high viability (~56%); moreover we also show that the preservation can be performed in large batches (50 million cells) with equal or better viability and no loss of functionality as compared to smaller batches (1.5 million cells) performed in cryovials