The blood-retinal barrier (BRB) consists of tightly interconnected capillary endothelial cells covered with pericytes and glia, but the role of the pericytes in BRB regulation is not fully ...understood. Here, we show that platelet-derived growth factor (PDGF)-B/PDGF receptor beta (PDGFRβ) signalling is critical in formation and maturation of BRB through active recruitment of pericytes onto growing retinal vessels. Impaired pericyte recruitment to the vessels shows multiple vascular hallmarks of diabetic retinopathy (DR) due to BRB disruption. However, PDGF-B/PDGFRβ signalling is expendable for maintaining BRB integrity in adult mice. Although selective pericyte loss in stable adult retinal vessels surprisingly does not cause BRB disintegration, it sensitizes retinal vascular endothelial cells (ECs) to VEGF-A, leading to upregulation of angiopoietin-2 (Ang2) in ECs through FOXO1 activation and triggering a positive feedback that resembles the pathogenesis of DR. Accordingly, either blocking Ang2 or activating Tie2 greatly attenuates BRB breakdown, suggesting potential therapeutic approaches to reduce retinal damages upon DR progression.
The image texture features obtained from 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) images of non-small cell lung cancer (NSCLC) have revealed tumor ...heterogeneity. A combination of genomic data and radiomics may improve the prediction of tumor prognosis. This study aimed to predict NSCLC metastasis using a graph neural network (GNN) obtained by combining a protein–protein interaction (PPI) network based on gene expression data and image texture features. 18F-FDG PET/CT images and RNA sequencing data of 93 patients with NSCLC were acquired from The Cancer Imaging Archive. Image texture features were extracted from 18F-FDG PET/CT images and area under the curve receiver operating characteristic curve (AUC) of each image feature was calculated. Weighted gene co-expression network analysis (WGCNA) was used to construct gene modules, followed by functional enrichment analysis and identification of differentially expressed genes. The PPI of each gene module and genes belonging to metastasis-related processes were converted via a graph attention network. Images and genomic features were concatenated. The GNN model using PPI modules from WGCNA and metastasis-related functions combined with image texture features was evaluated quantitatively. Fifty-five image texture features were extracted from 18F-FDG PET/CT, and radiomic features were selected based on AUC (n = 10). Eighty-six gene modules were clustered by WGCNA. Genes (n = 19) enriched in the metastasis-related pathways were filtered using DEG analysis. The accuracy of the PPI network, derived from WGCNA modules and metastasis-related genes, improved from 0.4795 to 0.5830 (p < 2.75 × 10−12). Integrating PPI of four metastasis-related genes with 18F-FDG PET/CT image features in a GNN model elevated its accuracy over a without image feature model to 0.8545 (95% CI = 0.8401–0.8689, p-value < 0.02). This model demonstrated significant enhancement compared to the model using PPI and 18F-FDG PET/CT derived from WGCNA (p-value < 0.02), underscoring the critical role of metastasis-related genes in prediction model. The enhanced predictive capability of the lymph node metastasis prediction GNN model for NSCLC, achieved through the integration of comprehensive image features with genomic data, demonstrates promise for clinical implementation.
Abstract
Metastasis is the principal cause of cancer related deaths. Tumor invasion is essential for metastatic spread. However, determinants of invasion are poorly understood. We addressed this ...knowledge gap by leveraging a unique attribute of kidney cancer. Renal tumors invade into large vessels forming tumor thrombi (TT) that migrate extending sometimes into the heart. Over a decade, we prospectively enrolled 83 ethnically-diverse patients undergoing surgical resection for grossly invasive tumors at UT Southwestern Kidney Cancer Program. In this study, we perform comprehensive histological analyses, integrate multi-region genomic studies, generate in vivo models, and execute functional studies to define tumor invasion and metastatic competence. We find that invasion is not always associated with the most aggressive clone. Driven by immediate early genes, invasion appears to be an opportunistic trait attained by subclones with diverse oncogenomic status in geospatial proximity to vasculature. We show that not all invasive tumors metastasize and identify determinants of metastatic competency. TT associated with metastases are characterized by higher grade, mTOR activation and a particular immune contexture. Moreover, TT grade is a better predictor of metastasis than overall tumor grade, which may have implications for clinical practice.
Metastatic Latency, a Veiled Threat Kim, Kangsan; Marquez-Palencia, Mauricio; Malladi, Srinivas
Frontiers in immunology,
08/2019, Volume:
10
Journal Article
Peer reviewed
Open access
Metastatic relapse is observed in cancer patients with no clinical evidence of disease for months to decades after initial diagnosis and treatment. Disseminated cancer cells that are capable of ...entering reversible cell cycle arrest are believed to be responsible for these late metastatic relapses. Dynamic interactions between the latent disseminated tumor cells and their surrounding microenvironment aid cancer cell survival and facilitate escape from immune surveillance. Here, we highlight findings from preclinical models that provide a conceptual framework to define and target the latent metastatic phase of tumor progression. The hope is by identifying patients harboring latent metastatic cells and providing therapeutic options to eliminate metastatic seeds prior to their emergence will result in long lasting cures.
Facility location
is a prominent optimization problem that has inspired a large quantity of both theoretical and practical studies in combinatorial optimization. Although the problem has been ...investigated under various settings reflecting typical structures within the optimization problems of practical interest, little is known on how the problem behaves in conjunction with parity constraints. This shortfall of understanding was rather discouraging when we consider the central role of
parity
in the field of combinatorics. In this paper, we present the first constant-factor approximation algorithm for the facility location problem with parity constraints. We are given as the input a metric on a set of
facilities
and
clients
, the opening cost of each facility, and the
parity requirement
–
odd
,
even
, or
unconstrained
–of every facility in this problem. The objective is to open a subset of facilities and assign every client to an open facility so as to minimize the sum of the total opening costs and the assignment distances, but subject to the condition that the number of clients assigned to each open facility must have the same parity as its requirement. Although the unconstrained facility location problem as a relaxation for this parity-constrained generalization has unbounded gap, we demonstrate that it yields a structured solution whose parity violation can be corrected at small cost. This correction is prescribed by a
T
-join on an auxiliary graph constructed by the algorithm. This auxiliary graph does not satisfy the triangle inequality, but we show that a carefully chosen set of shortcutting operations leads to a cheap and
sparse
T
-join. Finally, we bound the correction cost by exhibiting a combinatorial multi-step construction of an upper bound. We also consider the parity-constrained
k
-center problem, the bottleneck optimization variant of parity-constrained facility location. We present the first constant-factor approximation algorithm also for this problem.
Since the intimate relationship between microbes and human health has been uncovered, microbes have been in the spotlight as therapeutic targets for several diseases. Microbes contribute to a wide ...range of diseases, such as gastrointestinal disorders, diabetes and cancer. However, as host-microbiome interactions have not been fully elucidated, treatments such as probiotic administration and fecal transplantations that are used to modulate the microbial community often cause nonspecific results with serious safety concerns. As an alternative, synthetic biology can be used to rewire microbial networks such that the microbes can function as therapeutic agents. Genetic sensors can be transformed to detect biomarkers associated with disease occurrence and progression. Moreover, microbes can be reprogrammed to produce various therapeutic molecules from the host and bacterial proteins, such as cytokines, enzymes and signaling molecules, in response to a disturbed physiological state of the host. These therapeutic treatment systems are composed of several genetic parts, either identified in bacterial endogenous regulation systems or developed through synthetic design. Such genetic components are connected to form complex genetic logic circuits for sophisticated therapy. In this review, we discussed the synthetic biology strategies that can be used to construct engineered therapeutic microbes for improved microbiome-based treatment.
Vascular endothelial growth factor (VEGF) signaling is a key pathway for angiogenesis and requires highly coordinated regulation. Although the Notch pathway-mediated suppression of excessive VEGF ...activity via negative feedback is well known, the positive feedback control for augmenting VEGF signaling remains poorly understood. Transcription factor Sox17 is indispensable for angiogenesis, but its association with VEGF signaling is largely unknown. The contribution of other Sox members to angiogenesis also remains to be determined.
To reveal the genetic interaction of Sox7, another Sox member, with Sox17 in developmental angiogenesis and their functional relationship with VEGF signaling.
Sox7 is expressed specifically in endothelial cells and its global and endothelial-specific deletion resulted in embryonic lethality with severely impaired angiogenesis in mice, substantially overlapping with Sox17 in both expression and function. Interestingly, compound heterozygosity for Sox7 and Sox17 phenocopied vascular defects of Sox7 or Sox17 homozygous knockout, indicating that the genetic cooperation of Sox7 and Sox17 is sensitive to their combined gene dosage. VEGF signaling upregulated both Sox7 and Sox17 expression in angiogenesis via mTOR pathway. Furthermore, Sox7 and Sox17 promoted VEGFR2 (VEGF receptor 2) expression in angiogenic vessels, suggesting a positive feedback loop between VEGF signaling and SoxF.
Our findings demonstrate that SoxF transcription factors are indispensable players in developmental angiogenesis by acting as positive feedback regulators of VEGF signaling.
A large proportion of the recombinant proteins manufactured today rely on microbe-based expression systems owing to their relatively simple and cost-effective production schemes. However, several ...issues in microbial protein expression, including formation of insoluble aggregates, low protein yield, and cell death are still highly recursive and tricky to optimize. These obstacles are usually rooted in the metabolic capacity of the expression host, limitation of cellular translational machineries, or genetic instability. To this end, several microbial strains having precisely designed genomes have been suggested as a way around the recurrent problems in recombinant protein expression. Already, a growing number of prokaryotic chassis strains have been genome-streamlined to attain superior cellular fitness, recombinant protein yield, and stability of the exogenous expression pathways. In this review, we outline challenges associated with heterologous protein expression, some examples of microbial chassis engineered for the production of recombinant proteins, and emerging tools to optimize the expression of heterologous proteins. In particular, we discuss the synthetic biology approaches to design and build and test genome-reduced microbial chassis that carry desirable characteristics for heterologous protein expression.
Recent advances in battery technologies have reduced the financial burden of using the energy storage system (ESS) for customers. Peak cut, one of the benefits of using ESS, can be achieved through ...proper charging/discharging scheduling of ESS. However, peak cut is sensitive to load-forecasting error, and even a small forecasting error may result in the failure of peak cut. In this paper, we propose a two-phase approach of day-ahead optimization and real-time control for minimizing the total cost that comes from time-of-use (TOU), peak load, and battery degradation. In day-ahead optimization, we propose to use an internalized pricing to manage peak load in addition to the cost from TOU. The proposed method can be implemented by using dynamic programming, which also has an advantage of accommodating the state-dependent battery degradation cost. Then in real-time control, we propose a concept of marginal power to alleviate the performance loss incurred from load-forecasting error and mimic the offline optimal battery scheduling by learning from load-forecasting error. By exploiting the marginal power, real-time ESS charging/discharging power gets close to the offline optimal battery scheduling. Case studies show that under load-forecasting uncertainty, the peak power using the proposed method is only 22.4% higher than the offline optimal peak power, while the day-ahead optimization has 76.8% higher peak power than the offline optimal power. In terms of profit, the proposed method achieves 77.0% of the offline optimal profit while the day-ahead method only earns 19.6% of the offline optimal profit, which shows the substantial improvement of the proposed method.
The Notch pathway stabilizes sprouting angiogenesis by favoring stalk cells over tip cells at the vascular front. Because tip and stalk cells have different properties in morphology and function, ...their transcriptional regulation remains to be distinguished. Transcription factor Sox17 is specifically expressed in endothelial cells, but its expression and role at the vascular front remain largely unknown.
To specify the role of Sox17 and its relationship with the Notch pathway in sprouting angiogenesis.
Endothelial-specific Sox17 deletion reduces sprouting angiogenesis in mouse embryonic and postnatal vascular development, whereas Sox17 overexpression increases it. Sox17 promotes endothelial migration by destabilizing endothelial junctions and rearranging cytoskeletal structure and upregulates expression of several genes preferentially expressed in tip cells. Interestingly, Sox17 expression is suppressed in stalk cells in which Notch signaling is relatively high. Notch activation by overexpressing Notch intracellular domain reduces Sox17 expression both in primary endothelial cells and in retinal angiogenesis, whereas Notch inhibition by delta-like ligand 4 (Dll4) blockade increases it. The Notch pathway regulates Sox17 expression mainly at the post-transcriptional level. Furthermore, endothelial Sox17 ablation rescues vascular network from excessive tip cell formation and hyperbranching under Notch inhibition in developmental and tumor angiogenesis.
Our findings demonstrate that the Notch pathway restricts sprouting angiogenesis by reducing the expression of proangiogenic regulator Sox17.
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