The innate immune response is vital for the success of prophylactic vaccines and immunotherapies. Control of signaling in innate immune pathways can improve prophylactic vaccines by inhibiting ...unfavorable systemic inflammation and immunotherapies by enhancing immune stimulation. In this work, we developed a machine learning-enabled active learning pipeline to guide
in vitro
experimental screening and discovery of small molecule immunomodulators that improve immune responses by altering the signaling activity of innate immune responses stimulated by traditional pattern recognition receptor agonists. Molecules were tested by
in vitro
high throughput screening (HTS) where we measured modulation of the nuclear factor κ-light-chain-enhancer of activated B-cells (NF-κB) and the interferon regulatory factors (IRF) pathways. These data were used to train data-driven predictive models linking molecular structure to modulation of the NF-κB and IRF responses using deep representational learning, Gaussian process regression, and Bayesian optimization. By interleaving successive rounds of model training and
in vitro
HTS, we performed an active learning-guided traversal of a 139 998 molecule library. After sampling only ∼2% of the library, we discovered viable molecules with unprecedented immunomodulatory capacity, including those capable of suppressing NF-κB activity by up to 15-fold, elevating NF-κB activity by up to 5-fold, and elevating IRF activity by up to 6-fold. We extracted chemical design rules identifying particular chemical fragments as principal drivers of specific immunomodulation behaviors. We validated the immunomodulatory effect of a subset of our top candidates by measuring cytokine release profiles. Of these, one molecule induced a 3-fold enhancement in IFN-β production when delivered with a cyclic di-nucleotide stimulator of interferon genes (STING) agonist. In sum, our machine learning-enabled screening approach presents an efficient immunomodulator discovery pipeline that has furnished a library of novel small molecules with a strong capacity to enhance or suppress innate immune signaling pathways to shape and improve prophylactic vaccination and immunotherapies.
We combine high-throughput wet lab experimentation and data-driven computation in a closely coupled active learning loop in order to identify novel molecules with exceptional properties.
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IJS, KILJ, NUK, UL, UM, UPUK
Abstract
Ovarian cancer is leading cause of deaths among all gynecological malignancies. The presence of intrinsic and acquired drug resistance are major challenges in the treatment and clinical ...management of ovarian cancer. Ovarian cancer cells typically cluster into tumor spheroids and float in the ascitic fluid, which are characteristic of the aggressiveness of these tumor cells. We have recently developed a three-dimensional microfluidic platform with tumor spheroids and continuous fluidic flow to closely emulate the physiological condition in the ascites of ovarian cancer patients. Using this model, we showed for the first time that clinically relevant levels of ascitic shear stress induced drug resistance in ovarian tumor spheroids. Such chemoresistance was mediated through the increased expression of ABC-binding cassette transporter G2 and P-glycoprotein. By profiling the microRNAs (miRNAs) expression patterns under flow conditions, we identified miR-199a-3p as a critical mechanosensitive miRNA that was downregulated under shear stress through regulating the miRNA biogenesis machinery. miR-199a-3p expression was found to be inversely correlated with enhanced drug resistance properties and chemoresistant ovarian cancer sublines. Ectopic expression of miRNA-199a-3p could reverse the shear stress-induced expression of ABC-binding cassette transporter G2 and P-glycoprotein in ovarian tumor spheroids, confirming that the effect was miR-199a-3p specific. Taken together, these findings highlight the importance of shear stress-mediated decrease of miR-199a-3p in the regulation of drug response in ovarian cancer, which provide new insights in the understanding of cancer biology and potential effective treatment.
Citation Format: Shan-Shan Li, Carman K. M. Ip, Ho-Cheung Shum, Alice S. T. Wong. SHEAR STRESS DOWNREGULATION OF MIR-199A-3P DRIVES CHEMORESISTANCE IN OVARIAN CANCER CELLS abstract. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-059.
Abstract
Metastasis is one of the major challenges for the treatment of ovarian cancer. Unlike other solid tumors, ovarian cancer primarily disseminates within the peritoneal cavity. A crucial step ...in metastasis formation is the adhesion of ovarian cancer cells onto the peritoneal mesothelium under ascitic shear flow. However, the adhesion mechanisms engaged in this tumor-mesothelium interaction remain elusive due to a lack of physiologically relevant model to manipulate and investigate this dynamic process. In this study, using a 3D microfluidic platform, we found that the metastatic population of cancer stem cells (M-CSCs) exhibited slower rolling velocity and higher binding ability to the peritoneal mesothelium than non-metastatic (NM)-CSCs under flow condition. This adhesion cascade was mediated by P-selectin which expressed on the peritoneal mesothelium. The key carbohydrate determinant on M-CSCs was a glycoprotein, but not a glycolipid, with its recognition as sialyl-Lewis X (sLeX) in a sialic acid- and fucose-dependent manner. Moreover, several glycosyltransferase genes including B4GALT4, ST3GAL3, ST3GAL4 and FUT-5 involved the synthesis of sLeX were upregulated in M-CSCs. Knocking down FUT-5 significantly inhibited ovarian tumor cell adhesion on the mesothelium in vitro and reduced the metastatic potential in vivo. Taken together, our findings revealed that a distinct sLeX-P-selectin axis of ovarian tumor-mesothelium interaction in early metastasis and may offer the possibility of new therapeutic targets. (This work is supported by RGC grant 17122014)
Citation Format: Shan-Shan Li, Carman K. M. Ip, Ayon A. Hassan, Matthew Y. H. Tang, Susan Yung, Tak-Mao Chan, Ho Cheung Shum, Alice S. T. Wong. Sialyl Lewis X-P-selectin connection between ovarian tumor-mesothelium in early stage metastasis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5885. doi:10.1158/1538-7445.AM2017-5885
Post-translation modifications of proteins alter their functional activity and thus are key contributors of tumor initiation and progression. Glycosylation, one of the most common post-translational ...modifications of proteins, has been associated with tumorigenesis for decades. However, due to complexity in analysis of the functional effects of glycosylation, definitive information on the role of altered glycosylation in cancer is lacking. Importantly, imputing changes in glycosylation in proteins from analysis of DNA mutations has not been attempted globally. It is thus critical to elucidate the role of glycosylation in tumor pathophysiology as well as potential roles of altered glycosylation as cancer biomarkers and therapeutic targets. In this review, we summarize the evidence that glycosylation regulates functions of a set of frequently mutated oncogenes and tumor suppressors. Moreover, we explore the potential that protein sequence changes engendered by genomic mutations broadly alter glycosylation and thus promote tumor initiation and progression.
Organ-specific colonization suggests that specific cell-cell recognition is essential. Yet, very little is known about this particular interaction. Moreover, tumor cell lodgement requires binding ...under shear stress, but not static, conditions. Here, we successfully isolate the metastatic populations of cancer stem/tumor-initiating cells (M-CSCs). We show that the M-CSCs tether more and roll slower than the non-metastatic (NM)-CSCs, thus resulting in the preferential binding to the peritoneal mesothelium under ascitic fluid shear stress. Mechanistically, this interaction is mediated by P-selectin expressed by the peritoneal mesothelium. Insulin-like growth factor receptor-1 carrying an uncommon non-sulfated sialyl-Lewis
(sLe
) epitope serves as a distinct P-selectin binding determinant. Several glycosyltransferases, particularly α1,3-fucosyltransferase with rate-limiting activity for sLe
synthesis, are highly expressed in M-CSCs. Tumor xenografts and clinical samples corroborate the relevance of these findings. These data advance our understanding on the molecular regulation of peritoneal metastasis and support the therapeutic potential of targeting the sLe
-P-selectin cascade.
p70 S6 kinase and actin dynamics Ip, Carman K.M.; Wong, Alice S.T.
Spermatogenesis,
20/1/1/, Volume:
2, Issue:
1
Journal Article
Peer reviewed
Open access
p70 S6 kinase (p70
S6K
), a member of the AGC serine/threonine kinase family, was initially identified as a key player, together with its downstream effector S6, in the regulation of cellular growth ...and survival. The p70
S6K
protein has emerged in recent years as a multifunctional protein which also regulates the actin cytoskeleton and thus plays a role in cell migration. This new function is through two important activities of p70
S6K
, namely actin cross-linking and Rac1 and Cdc42 activation. The testis is critically dependent on an intricate balance of fundamental cellular processes such as adhesion, migration, and differentiation. It is increasingly evident that Rho GTPases and actin binding proteins play fundamental roles in regulating spermatogenesis within the testis. In this review, we will discuss current findings of p70
S6K
in the control of actin cytoskeleton dynamics. In addition, the potential role of p70
S6K
in spermatogenesis and testicular function will be highlighted.
Purpose - This paper proposes an infrastructure of a responsive supply chain network, focusing on the deployment of the m-commerce technology which transforms a traditional supply chain network to be ...more effective in coping with market changes.Design methodology approach - The proposed supply chain infrastructure embraces the concepts of distributed object technology, wireless markup language (WML), and extensible markup language (XML) schema to enable efficient data exchange among various data objects which reside in distributed platforms over geographically-isolated regions, thereby leveraging the responsiveness of the entire supply chain network. A case study is conducted to evaluate the feasibility of the proposed model.Findings - Recent studies have found that wireless technology, mobile computing and internet programming techniques drive the development of mobile solution in various industries. Apart from location tracking of goods as well as relevant services, m-commerce is able to play an important role to enhance the performance of a supply chain network, which is concerned with the proper monitoring of suppliers and production circles, encompassing a wide spectrum of value chain activities ranging from product design to after-sales services.Originality value - The significance of this research is the demonstration of the synergy of using a combination of emerging technologies to form an integrated system that helps achieve flexibility and agility in supply chain network.
The multiple resource-constrained project scheduling problem is a very important issue in construction engineering. Its solution can improve the productivity of construction industry greatly. We ...present a genetic algorithm for solution of multi-types resource usage problems in multiple resource constrained project scheduling. The objective is to determine the starting time of all activities in a project to meet precedence and resource constraints with lower resource usage. A nonlinear integer programming model has been established. The Monte Carlo method (MCM) is compared with genetic algorithms (GAs) in solutions. The numerical examples show that genetic algorithms can achieve better performance for resource-constrained project scheduling problem (RCPSP) than MCM.
Ovarian cancer is a highly metastatic disease and has the highest mortality rate of all gynecological tumors. In contrast to many other types of cancer that metastasize through lymphatics and/or ...hematogenous routes, ovarian cancer metastasizes by peritoneal dissemination, which relies on the ability of cancer cells to detach from the primary tumor, adhere to, and eventually invade through the peritoneum. This involves dynamic changes in cell-cell adhesion, which is primarily mediated by cell surface receptors known as cadherins. In this review, we will describe the unique profiles of cadherins with their associated signal molecules, catenins, in ovarian cancer and the roles of these adhesion molecules in disease development, tumor cell progression, and the formation of ascites. We will discuss how cadherins perform these functions and their link to a variety of signaling pathways. Finally, we will review the recent findings regarding the potential of cadherins as new therapeutic targets in the treatment of ovarian cancer.
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FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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