3D in vitro cancer models for drug screening: A study of glucose metabolism and drug response in 2D and 3D culture models

Current drug screening protocols use in vitro cancer cell panels grown in 2D to evaluate drug response and select the most promising candidates for further in vivo testing. Most drug candidates fail at this stage, not showing the same efficacy in vivo as seen in vitro. An improved first screening that is more translatable to the in vivo tumor situation could aid in reducing both time and cost of cancer drug development. 3D cell cultures are an emerging standard for in vitro cancer cell models, being more representative of in vivo tumour conditions. To overcome the translational challenges with 2D cell cultures, 3D systems better model the more complex cell-to-cell contact and nutrient levels present in a tumour, improving our understanding of cancer complexity. Furthermore, cancer cells exhibit altered metabolism, a phenomenon described a century ago by Otto Warburg, and possibly related to changes in nutrient access. However, there are few reports on how 3D cultures differ metabolically from 2D cultures, especially when grown in physiological glucose conditions. Along with this, metabolic drug targeting is considered an underutilized and poorly understood area of cancer therapy. Therefore, the aim of this work was to investigate the effect of culture conditions on response to metabolic drugs and study the metabolism of 3D spheroid cultures in detail. To achieve this, multiple cancer cell lines were studied in high and low glucose concentrations and in 2D and 3D cultures. We found that glucose concentration is important at a basic level for growth properties of cell lines with different metabolic phenotypes and it affects sensitivity to metformin. Furthermore, metformin is able to shift metabolic phenotype away from OXPHOS dependency. There are significant differences in glucose metabolism of 3D cultures compared to 2D cultures, both related to glycolysis and oxidative phosphorylation. Spheroids have higher ATP-linked respiration in standard nutrient conditions and higher non-aerobic ATP production in the absence of supplemented glucose. Multi-round treatment of spheroids is able to show more robust response than standard 2D drug screening, including resistance to therapy. Results from 2D cultures both over and underestimate drug response at different concentrations of 5-fluorouracil (5-FU). A higher maximum effect of 5-FU is seen in models with lower OCR/ECAR ratios, an indication of a more glycolytic metabolic phenotype. In conclusion, both culture method and nutrient conditions are important consideration for in vitro cancer models. There is good reason to not maintain in vitro cultures in artificially high glucose conditions. It can have downstream affects on drug response and likely other important metrics. If possible, assays should also be implemented in 3D. If not in everyday assays, at least as a required increase in complexity to validate 2D results. Finally, metabolism even in the small scope presented here, is complex in terms of phenotypic variation. This shows the importance of metabolic screening in vitro to better understand the effects of these small changes and to model how a specific tumor may behave based on its complex metabolism

Evaluating the effectiveness of the core content of the incredible years with and without visual performance feedback for parents of children with autism

Title from PDF of title page (University of Missouri--Columbia, viewed on June 3, 2011).The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file.Dissertation advisor: Dr. Janine Stichter.Vita.Ph. D. University of Missouri--Columbia 2011."May 2011"Many children with autism display externalizing behavior due to challenges they face in the areas of communication, social skills and repetitive behavior or restricted interests. Parents have reported that it is difficult to know how to address these behaviors. Parent training programs have been found to increase parents' skills and decrease child externalizing behavior. The purpose of this study was to evaluate the effectiveness of the core content of The Incredible Years parent training program with and without Visual Performance Feedback in: a) increasing parent skills and b) decreasing child externalizing behavior. The secondary purpose was to assess the extent to which parents found the interventions socially valid. Using a multiple baseline design across parent-child dyads, data were collected on parent behaviors (use of clear commands, praise and descriptive play statements) and child behaviors (compliance, prompted compliance, on-task/appropriate behavior and externalizing behaviors). Phases included baseline, parent training and feedback. Results indicated that when the parent variables of clear commands, praise and descriptive play statements were combined, all parents made mild increases in their use of those skills during each phase. However, there was variability in specific variables across parents and phases. On the Eyberg Child Behavior Inventory, all parents reported decreases in child externalizing behavior from pre to post intervention. However, there was variability in specific variables across children and phases. Interpretation of these results is provided along with study limitations and future directions for research.Includes bibliographical reference

Intuitions and perceptual constraints on causal learning from dynamics

Many of the real world phenomena that cognizers must grapple with are continuous, not only in the values they can take, but also in how these values change over time. The mind must somehow abstract from these inputs to extract useful discrete concepts such as objects, events and causal relationships. We investigate several factors that affect basic inferences about causal relationships between continuous variables based on observations in continuous time. In a novel experiment, we explore the ways in which causal judgments are sensitive to factors that relate to causal inductive biases (e.g. causal lags, the direction of variation) and causal perception (e.g. the range and rapidity of variation). We argue standard statistical time-series models have limited utility in accounting for human sensitivity to these factors. We suggest further work is needed to fully understand the cognitive processes that underlie causal induction from time-series information

Evidence from the future

The outcome of any scientific experiment or intervention will naturally unfold over time. How then should individuals make causal inferences from measurements over time? Across three experiments, we had participants observe experimental and control groups over several days post-treatment in a fictional biological research setting. We identify competing perspectives in the literature: Contingency-driven accounts predict no effect of outcome timing while the contiguity principle suggests people will view a treatment as more harmful to the extent that bad treatment outcomes occur earlier rather than later. In contrast, inference to the functional form of a treatment effect can license extrapolation beyond the measurements and lead to different causal inferences. We find participants’ causal strength and direction judgments in temporal settings vary with minimal manipulations of instruction framing. When it is implied that the observations are made over a pre-planned number of days, causal judgments depend strongly on contiguity. When it is implied that the observation may be ongoing, participants extrapolate current trends into the future and adapt their causal judgments accordingly. When data are revealed sequentially, participants rely on extrapolation regardless of instruction framing. Our results demonstrate human flexibility in interpreting temporal evidence for causal reasoning and emphasize human tendency to generalize from evidence in ways that are acutely sensitive to task framing

Analisis Pengaruh Back Water (Air Balik) Terhadap Banjir Sungai Rangkui Kota Pangkalpinang

Beberapa permasalahan pokokyang menyebabkan terjadinya banjir di Sub DAS Rangkuisebagian besar disebabkan oleh penyempitan penampang sungai akibat sedimentasi, curahhujan yang cukup tinggi, serta pengaruh back water (air Balik) yang terjadi pada saatpasang laut tinggi. Back water tersebut menyebabkan terbendungnya aliran dari hulu,sehingga elevasi muka air pada penampang sungai meningkat. Tujuan dari penelitian iniadalah menganalisis pengaruh back water (air Balik) terhadap banjir Sungai RangkuiKota Pangkalpinang. Metode yang digunakan dalam penelitian ini adalah metodepenelusuran aliran melalui pemodelan aliran tak seragam (unsteasy flow) menggunakanperangkat lunak HEC-RAS.Beberapa data yang digunakan sebagai input ditetapkanberdasarkan analisis dan perhitungan. Boundary condition sebelah hulu digunakan debitrencana kala ulang 2, 5, 10 dan 25 tahun, sedangkan boundary condition sebelah hiliradalah tinggi muka air pasang tertinggi. Hasil penelitian menunjukkan bahwa besarnyadebit rencana pada periode ulang 2 tahun (Q2)=46.08 m³/d, periode 5 tahun (Q5)=57.68m³/d, periode 10 tahun (Q10)=64.88 m³/d dan periode 25 tahun (Q25)=72.79 m³/d. Tinggimuka air tertinggi dengan kenaikan muka air banjir (luapan) berkisar antara 0.15-1.4 muntuk kondisi tanpa pasang surut dan 0.60-1.90 m untuk kondisi dengan pengaruh pasangsurut. Semakin tingginya pasang surut yang terjadi, maka backwater sangat berpengaruhterhadap kenaikan elevasi di muka air hulu maupun hilir yang menyebabkan kenaikanelevasi muka air pada periode waktu tertentu, hingga melebihi elevasi tanggul yang adasaat ini.Kata kunci : banjir, penelusuran aliran, back wate

Pengaruh Program CSR PT Jasa Raharja (Persero) Cabang Riau terhadap Keberhasilan UMKM di Kota Pekanbaru

Corporate Social Responsibility (CSR) is a social responsibility for a business organization against its stakeholder group. PKBL is a form of BUMN social responsibility. According to Law No.19 of 2003 on BUMN, where one of the purposes and objectives of BUMN establishment is to actively provide guidance and assistance to weak economic entrepreneurs, cooperatives and communities, as well as policies that state that BUMN can set aside a portion of their net profit for the purpose of business development small, cooperative as well as community development around BUMN, then PT Jasa Raharja (Persero) is committed in the implementation of Partnership Program. Partnership Program is a program to increase the ability of small business to be tough and independent. The purpose of this study, namely to determine how much influence CSR program PT Jasa Raharja (Persero) branch of Riau to the success of UMKM in the city of Pekanbaru.The theory used in this research is Stimulus-Organism-Response (S-O-R) theory. The method used in this research is explanative quantitative method. Technique of collecting data in this research using direct questionnaires distributing to UMKM which have become Partners of PT Jasa Raharja (Persero) Branch of Riau with sample 68 determined by random sampling technique. To know the influence of both variables, the researcher use simple linear regression analysis.Based on the results of research on the influence of CSR program PT Jasa Raharja (Persero) Riau branch on the success of UMKM in the city of Pekanbaru, obtained regression coefficient value in this study is Y = 8.282 + 0.577 X with a significance level of 0.000. Of course smaller than α = 0.05. This means that there is influence CSR program PT Jasa Raharja (Persero) branch of Riau to the success of SMEs in the city of Pekanbaru by 75.7% and enter the category strongly influenced. The percentage indicates that the PT Jasa Raharja (Persero) branch of CSR program is very influential towards the happening of UMKM in Pekanbaru city. Thus H0 is rejected and Ha accepted

Toward a Computer-Scored Assessment of Marketing Expertise

In this paper, case-based measures of marketing expertise, a construct perhaps similar to critical thinking, are developed. The measures only achieved modest reliability. In a pre-post design, there was some evidence that students improved in marketing expertise during the quarter, but the effect is probably small, indicated that repeated training would likely be necessary to achieve more substantial learning gains