Promising therapeutics of gastrointestinal cancers in clinical trials

Many novel therapeutics are being developed for patients with cancers along the gastrointestinal (GI) tract. These emerging agents are frequently classified by their biological targets such as tumor growth pathways, tumor metabolism, microenvironment, etc. Some agents targeting cancer growth pathways are based on existing clinically validated therapeutic targets, such as regorafenib for hepatocellular carcinoma (HCC), while other agents focus on newly identified targets, such a

Bayesian meta-analysis models for heterogeneous genomics data

<p>The accumulation of high-throughput data from vast sources has drawn a lot attentions to develop methods for extracting meaningful information out of the massive data. More interesting questions arise from how to combine the disparate information, which goes beyond modeling sparsity and dimension reduction. This dissertation focuses on the innovations in the area of heterogeneous data integration.</p><p>Chapter 1 contextualizes this dissertation by introducing different aspects of meta-analysis and model frameworks for high-dimensional genomic data.</p><p>Chapter 2 introduces a novel technique, joint Bayesian sparse factor analysis model, to vertically integrate multi-dimensional genomic data from different platforms. </p><p>Chapter 3 extends the above model to a nonparametric Bayes formula. It directly infers number of factors from a model-based approach.</p><p>On the other hand, chapter 4 deals with horizontal integration of diverse gene expression data; the model infers pathway activities across various experimental conditions. </p><p>All the methods mentioned above are demonstrated in both simulation studies and real data applications in chapters 2-4.</p><p>Finally, chapter 5 summarizes the dissertation and discusses future directions.</p>Dissertatio

Analysis of Peptides and Proteins in Their Binding to GroEL

The GroEL-GroES is an essential molecular chaperon system that assists protein folding in cell. Binding of various substrate proteins to GroEL is one of the key aspects in GroEL-assisted protein folding. Small peptides may mimic segments of the substrate proteins in contact with GroEL, and allow detailed structural analysis of the interactions. A model peptide SBP has been shown to bind to a region in GroEL that is important for binding of substrate proteins. Here, we investigated whether the observed GroEL-SBP interaction represented those of GroEL-substrate proteins, and whether SBP was able to mimic various aspects of substrate proteins in GroE- assisted protein folding cycle. We found that SBP competed with substrate proteins, including α-lactalbumin, rhodanese, and malate dehydrogenase, in binding to GroEL. SBP stimulated GroEL ATP hydrolysis rate in a manner similar to that of α-lactalbumin. SBP did not prevent GroES from binding to GroEL, and GroES association reduced the ATPase rates of GroEL/SBP and GroEL/α-lactalbumin to a comparable extent. Binding of both SBP and α-lactalbumin to apo GroEL was dominated by hydrophobic interaction. Interestingly, association of α- lactalbumin to GroEL/GroES was thermodynamically distinct from that to GroEL with reduced affinity and decreased contribution from hydrophobic interaction. However, SBP did not display such differential binding behaviors to apo GroEL and GroEL/GroES, likely due to the lack of a contiguous polypeptide chain that links all of the bound peptide fragments. Nevertheless, studies using peptides provide valuable information on the nature of GroEL-substrate protein interaction, which is central to understand the mechanism of GroEL-assisted protein folding

Automatic 2-D/3-D Vessel Enhancement in Multiple Modality Images Using a Weighted Symmetry Filter

Automated detection of vascular structures is of great importance in understanding the mechanism, diagnosis and treatment of many vascular pathologies. However, automatic vascular detection continues to be an open issue because of difficulties posed by multiple factors such as poor contrast, inhomogeneous backgrounds, anatomical variations, and the presence of noise during image acquisition. In this paper, we propose a novel 2D/3D symmetry filter to tackle these challenging issues for enhancing vessels from different imaging modalities. The proposed filter not only considers local phase features by using a quadrature filter to distinguish between lines and edges, but also uses the weighted geometric mean of the blurred and shifted responses of the quadrature filter, which allows more tolerance of vessels with irregular appearance. As a result, this filter shows a strong response to the vascular features under typical imaging conditions. Results based on 8 publicly available datasets (six 2D datasets, one 3D dataset and one 3D synthetic dataset) demonstrate its superior performance to other state-ofthe- art methods

Comparison of photosynthetic responses between haptophyte Phaeocystis globosa and diatom Skeletonema costatum under phosphorus limitation

The diatom Skeletonema costatum and the haptophyte Phaeocystis globosa often form blooms in the coastal waters of the South China Sea. Skeletonemacostatum commonly dominates in nutrient enrichment coastal waters, whereas P. globosa starts flourishing after the diatom blooms when phosphorus (P) is limited. Therefore, P limitation was proposed to be a critical factor affecting diatom–haptophyte transition. To elucidate the tolerance to P limitation in P. globosa compared with S. costatum, the effect of P limitation on their photosystem II (PSII) performance was investigated and their photosynthesis acclimation strategies in response to P limitation were evaluated. P limitation did not affect the growth of P. globosa over 7 days but decreased it for S. costatum. Correspondingly, the PSII activity of S. costatum was significantly inhibited by P limitation. The decline in PSII activity in S. costatum under P limitation was associated with the impairment of the oxygen-evolving complex (the donor side of PSII), the hindrance of electron transport from QA− to QB (the acceptor side of PSII), and the inhibition of electron transport to photosystem I (PSI). The 100% decrease in D1 protein level of S. costatum after P limitation for 6 days and PsbO protein level after 2 days of P limitation were attributed to its enhanced photoinhibition. In contrast, P. globosa maintained its photosynthetic activity with minor impairment of the function of PSII. With accelerated PSII repair and highly increased non-photochemical quenching (NPQ), P. globosa can avoid serious PSII damage under P limitation. On the contrary, S. costatum decreased its D1 restoration under P limitation, and the maximum NPQ value in S. costatum was only one-sixth of that in P. globosa. The present work provides extensive evidence that a close interaction exists between the tolerance to P limitation and photosynthetic responses of S. costatum and P. globosa

Ventral Visual Pathway-Cerebellar Circuit Deficits in Alcohol Dependence: Long- and Short-Range Functional Connectivity Density Study

Objective: To identify the underlying intrinsic functional connectome changes in patients with alcohol dependence.Methods: A functional connectivity density (FCD) analysis was used to report on the functional connectivity changes in 24 male patients with alcohol dependence (age, 47.83 ± 6.93 years) and 24 healthy male subjects (age, 47.67 ± 6.99 years). We defined the voxels with a correlated threshold of r &gt; 0.25 inside their neighborhood (radius sphere ≤ 6 mm) as shortFCD, and radius sphere &gt; 6 mm as longFCD. We repeated the network analysis using a range of correlation r thresholds (r = 0.30, 0.35, 0.40, 0.45, 0.50, 0.6, and 0.75) to determine whether between-group differences were substantially affected by the selection of the different R-value thresholds used. A ROC curve was used to test the ability of the FCD in discriminating between the two groups. Pearson's correlation was used to evaluate the relationships between the FCD differences in brain areas and demographic characteristics.Results: The covered differences in brain areas in binarized shortFCD were larger than binarized longFCD in both groups. The intra-group FCD differences did not depend on the selection of different thresholds used. Patients with alcohol dependence were associated with the longFCD deficit in the cerebellum posterior lobe, and shortFCD deficit in the ventral system of the visual pathway and increased shortFCD in the left precentral gyrus, right salience network and right cingulate gyrus. A ROC curve demonstrated that these specific brain areas alone discriminated between the two groups with a high degree of sensitivity and specificity. In the alcohol dependence group, the cerebellum posterior lobe, visual association cortex and the salience network displayed significant correlations with demographic characteristics.Conclusions: The shortFCD analysis was more sensitive than the longFCD analysis in finding differences in the brain areas. The ventral visual pathway-cerebellar circuit deficit appeared to be altered in patients with alcohol dependence