Indiana University-Purdue University Indianapolis (IUPUI) / Purpose: The purpose was to comprehensively assess the impact of PD-L1 expression on the efficacy of immune checkpoint inhibitors on Overall Survival (OS) and Progression-Free Survival (PFS). Methods: A systematic literature search and review was conducted through June 2019. I searched all eligible randomized controlled trials comparing PD-1/PD-L1 monotherapy to an active comparator in adult patients with advanced cancer across multiple tumor types. The Cochrane risk-of-bias tool was used to assess trial quality. A random-effects model was used for the meta-analysis. Heterogeneity was assessed using Cochran Q statistic and I2 test. Publication bias was assessed by visual inspection of a funnel plot and Begg’s test. Results: I identified and included 23 trials involving 14,434 participants. When stratifying PD-L1 positive (+) and negative (-) patients using varying thresholds of expression, a significant group difference was observed at PD-L1 >1% ( p=0.04; PD-L1(+): HR, 0.72; 95% CI, 0.65-0.79; PD-L1(-): HR,0.83; 95% CI, 0.75-0.91), at PD-L1 >10% (p=0.02; PD-L1(+): HR,0.50; 95% CI, 0.38-0.62; PD-L1 (-): HR, 0.74; 95% CI, 0.57-0.90) and at PD-L1>50% (p=0.01; PD-L1(+): HR,0.59; 95% CI, 0.51-0.68; PD-L1(-): HR, 0.93; 95% CI, 0.71-1.15). Across tumor types, both PD-L1(+) and PD-L1(-) patients treated with an immunotherapy had improved OS compared with patients receiving standard care therapies. A PFS benefit was observed and favored patients treated with a PD-1/PD-L1 inhibitor versus standard of care. However, there was significant heterogeneity and the benefit on PFS was not statistically significant between PD-L1(+) and PD-L1(-) groups using varying cut-off levels of PD-L1 expression. No differences between sub-groups of interest including median follow-up time, type of inhibitor, and line of therapy for either PD-L1(+) or PD-L1(-) patients at 1% cut-off were identified. Conclusion: This study supports the use of PD-L1 as a predictive biomarker of improved response to immunotherapies. As thresholds increase and specifically above the 10% PD-L1 expression threshold, patients who were positive for PD-L1 appeared to have better OS compared to those who were negative for PD-L1. Further investigation is needed to assess the clinical usefulness of PD-L1 at various expression levels with improved technologies that have the potential to enhance assay accuracy and precision.

Reconstructing sparse signals from undersampled measurements is a challenging problem that arises in many areas of data science, such as signal processing, circuit design, optical engineering and image processing. The most natural way to formulate such problems is by searching for sparse, or parsimonious, solutions in which the underlying phenomena can be represented using just a few parameters. Accordingly, a natural way to phrase such problems revolves around L0 minimization in which the sparsity of the desired solution is controlled by directly counting the number of non-zero parameters. However, due to the nonconvexity and discontinuity of the L0 norm such optimization problems can be quite difficult. One modern tactic to treat such problems is to leverage convex relaxations, such as exchanging the L0 norm for its convex analog, the L1 norm. However, to guarantee accurate reconstructions for L1 minimization, additional conditions must be imposed, such as the restricted isometry property. Accordingly, in this thesis, we propose a novel extension to current approaches revolving around truncated L1 minimization and demonstrate that such approach can, in important cases, provide a better approximation of L0 minimization. Considering that the nonconvexity of the truncated L1 norm makes truncated l1 minimization unreliable in practice, we further generalize our method to partial L1 minimization to combine the convexity of L1 minimization and the robustness of L0 minimization. In addition, we provide a tractable iterative scheme via the augmented Lagrangian method to solve both optimization problems. Our empirical study on synthetic data and image data shows encouraging results of the proposed partial L1 minimization in comparison to L1 minimization.

Considering the vital role teachers play in language teaching, the frequency of, and motivation behind L1 usage in L2 teaching is a very interesting and current area of research. Despite this, there does not seem to be a lot of research done in this area in the context of the Swedish EFL classroom for young learners. The aim of the current study was therefore to contribute to this area of research first, by investigating teachers’ use of Swedish when talking during their English teaching and their rationale for using Swedish instead of English, and second, by determining if there is a difference in the teachers’ use of Swedish depending on the learning objective of the lesson. This was done by using a mixed-method approach, where four English teachers in Sweden, all teaching grades 4-6, were observed in two lessons each, followed by semi-structured interviews. The results showed that Instructions, Asking questions, Praise and Translation were the most used L1 functions, while Evaluation, Classroom equipment and Humor were not employed by any of the teachers. Furthermore, the study demonstrated that the factors for L1 usage were the students’ age, support for the students’ understanding, efficiency and making the students feel comfortable in the learning environment, corresponding with previous research to a great extent. Additionally, it was also found that there was indeed a difference depending on the learning objective. Based on the findings in the study, it is suggested that teachers should be encouraged to assume a mindful approach to their L1 usage.

Regression with L1-regularization, Lasso, is a popular algorithm for recovering the sparsity pattern (also known as model selection) in linear models from observations contaminated by noise. We examine a scenario where a fraction of the zero co-variates are highly correlated with non-zero co-variates making sparsity recovery difficult. We propose two methods that adaptively increment the regularization parameter to prune the Lasso solution set. We prove that the algorithms achieve consistent model selection with high probability while using fewer samples than traditional Lasso. The algorithm can be extended to a broad set of L1-regularized M-estimators for linear statistical models.

No description available.

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirement for the degree of Doctor of Philosophy. Johannesburg, 2004 / Alkaline phosphatase (ALP) is a ubiquitously expressed enzyme, that has been shown to play a role in cell differentiation and organogenesis. One study has also demonstrated ALP activity in rat adipocytes. The purpose of the present study was therefore to determine whether ALP is expressed in preadipocytes and what role it may have in adipogenesis. ALP activity was detected in the murine preadipocyte cell line, 3T3-L1, and in human preadipocytes isolated from mammary tissue, and from subcutaneous abdominal fat depots. In all the cell types studied ALP activity increased in parallel with adipogenesis. In the 3T3 -L1 cell line the tissue- non -specific ALP inhibitors, levamisole and histidine inhibited ALP activity, and adipogenesis, whereas the tissue specific ALP inhibitor Phe- Gly-Gly did not inhibit ALP or adipogenesis. In human preadipocytes, histidine inhibited adipogenesis and ALP activity, whereas levamisole inhibited adipogenesis, but did not block ALP activity in intact cells. However, levamisole did inhibit ALP activity by 50% in cell extracts. Levamisole was able to inhibit adipogenesis in human preadipocytes. The tissue specific ALP inhibitor, Phe Gly Gly, did not inhibit ALP activity or adipogenesis in human preadipocytes. ALP activity and adipogenesis, were compared in preadipocytes isolated from mammary tissue taken from black (13) and white (15) female subjects. Both ALP activity and adipogenesis, were lower in white compared to black female subjects. iii Immunocytochemical, analysis of the 3T3-L1 cell line and human preadipocytes demonstrated that ALP activity was restricted to the lipid droplets of these cells. ALP activity was also measured in serum samples obtained from 100 African subjects (74 females and 26 males) of varying BMI. ALP activity was found to be higher in obese than lean subjects, whereas, the other liver enzymes or products measured in serum were not. In fact these variables correlated to varying degrees with waist-hip ratio, whereas ALP levels did not. This suggest that liver function is predominantly influenced by abdominal obesity whereas serum ALP levels are more influenced by overall body adiposity. In conclusion, ALP, may be involved in the control of adipogenesis, in the 3T3- L1 preadipocyte cell line and in human preadipocytes isolated from mammary adipose tissue and subcutaneous abdominal adipose tisssue. The presence of ALP activity in lipid droplets in 3T3-L1 cells and human preadipocytes, and the ability of ALP inhibitors to block adipogenesis strongly suggest that ALP plays a role in the control of adipogenesis. / IT2017

Flavonoids, and more specifically, red wine procyanidins, have many beneficial effectsagainst pathologies such as cardiovascular heart disease and related illnesses. Althoughadipose tissue has a central role in some of these pathologies, including obesity and diabetes,there is a lack of information about the effects of procyanidins on this tissue. This thesisaddresses this question. The effects of a grape seed procyanidin extract (GSPE) on the lipidand glucose metabolism of adipocytes were evaluated by taking the 3T3-L1 cell line as amodel of study. Results show that the GSPE has insulinomimetic effects, stimulating glucoseuptake, glycogen synthesis and trigliceride synthesis. To achieve this, the GSPE shares someof the mechanisms and intracellular mediators of the insulin-signalling pathways (such asGLUT-4 translocation, PI3K and p38 MAPK) but it must also use other, complementary,mechanisms. These results suggest that procyanidins have beneficial effects on diabetesand/or insulin resistance. This is partially proven by in vivo studies that show that GSPE hasantihyperglycemic properties on streptozotozin-induced diabetic rats. Also analyzed in thisthesis are the molecular mechanisms used by GSPE to explain the already described lipolyticeffects. Protein kinase A and PPARã are shown to be involved in these effects. Some ofthese results opened up another line of study into the effects of GSPE on the differentiationprocess of the 3T3-L1. These studies showed that procyanidins alter the differentiation ofpreadipocytes when added at the induction of differentiation. Since an increase in thenumber of adipocytes has a negative effect on obesity, this is a promising characteristic ofGSPE that should be taken into account when its possible antiobesity properties are studied. / Als flavonoides, i més concretament a les procianidines del vi negre, se'ls han atribuït moltespropietats beneficioses contra diverses patologies, com les malalties cardiovasculars i altrespatologies relacionades. Tot i que el teixit adipós juga un paper important en algunesd'aquestes patologies, com la obesitat i la diabetis, la informació referent l'acció de lesprocianidines en aquest teixit és escassa. Aquesta tesis estudia els efectes de les procianidinesderivades de pinyol de raïm (GSPE) en l'adipòcit, i per a dur-ho a terme es pren com amodel d'estudi la línia cel.lular 3T3-L1. Per una banda es descriuen els efectes del GSPE enel metabolisme de lípids i glúcids de la cèl.lula adiposa. El GSPE fa un paperinsulinomimètic: estimula la captació de glucosa, la síntesi de glicògen i la síntesi de triacilglicerols. L'anàlisi dels mecanismes moleculars per exercir aquests efectes mostra que GSPEen part comparteix mecanismes i vies de senyalització propis de la insulina (translocació deGLUT-4, PI3K, p38 MAPK); tanmateix, s'observa que GSPE ha d'usar també altresmecanismes complementaris. Aquests resultats suggereixen que GSPE pot tenir efectespositius en situacions de diabetis i/o resistència a insulina, donat que a més a més, els estudisin vivo mostren que GSPE és antihiperglicèmic en condicions de diabetis induïda perestreptozotocina. En aquesta tesis també s'analitzen els mecanismes moleculars queexplicarien els efectes lipolítics de les procianidines descrits en estudis previs, i s'ha trobatque la proteina kinasa A i PPARã hi estan involucrats. Part d'aquests resultats han obert unaaltra via d'estudi sobre els efectes de la GSPE en el procés de diferenciació de la cèl.lulaadiposa on s'ha observat que el tractament amb procianidines a l'inici de la diferenciaciódificulta aquesta transformació. Donat que l'augment del nombre d'adipòcits afectanegativament la obesitat, aquest efecte de les procianidines és una característicaprometedora que caldrà tenir en compte en l'estudi del seu possible paper antiobesitat.

Based on the premise that novice EAL learners have limited working memory resources to comprehend academic text, L1 explanatory notes were seen as a possible instrument to use in decreasing the cognitive demands of reading and increase the available working memory resources available for discussions. The hypotheses of this study were largely unsupported but from the data emerged a new hypothesis for second language acquisition; The Formality Hypothesis. This hypothesis posits that the presence or absence of the L1 signals various levels of formality in the learning task. Isolation of the L2 may therefore signal high levels of formality leading to the development of learners’ CALP (Cummins, 1979) whereas incorporation of the L1 into L2 input signals lower levels of formality leading to the development of learners’ BICS (Cummins, 1979).

Based on the premise that novice EAL learners have limited working memory resources to comprehend academic text, L1 explanatory notes were seen as a possible instrument to use in decreasing the cognitive demands of reading and increase the available working memory resources available for discussions. The hypotheses of this study were largely unsupported but from the data emerged a new hypothesis for second language acquisition; The Formality Hypothesis. This hypothesis posits that the presence or absence of the L1 signals various levels of formality in the learning task. Isolation of the L2 may therefore signal high levels of formality leading to the development of learners’ CALP (Cummins, 1979) whereas incorporation of the L1 into L2 input signals lower levels of formality leading to the development of learners’ BICS (Cummins, 1979).

Universiẗat, Diss., 2001--Duisburg.