Publications by authors named "Kai-Yuan Chen"

31 Publications

Contribution of Interleukin-10 Genotype to Triple Negative Breast Cancer Risk.

Anticancer Res 2021 May;41(5):2451-2457

Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan, R.O.C.;

Background/aim: Triple negative breast cancer (TNBC) is characterized by increased recurrence and poor survival. Mounting evidence suggests that interleukin-10 (IL-10) plays a role in carcinogenesis, however, little is known about the contribution of IL-10 to TNBC. The study evaluated the contribution of IL-10 promoter A-1082G (rs1800896), T-819C (rs3021097), A-592C (rs1800872) genotypes to the risk of TNBC.

Materials And Methods: IL-10 genotypes were examined among 1,232 breast cancer patients and 1,232 controls and evaluated.

Results: The percentages of AG and GG for IL-10 A-1082G genotypes were higher in the breast cancer patient group than in the control group. The GG genotype carriers were of higher risk for breast cancer [odds ratio (OR)=2.02, 95% confidence interval (CI)=1.28-3.21, p=0.0021]. Interestingly, G allele carriers were of higher risk of TNBC (OR=1.25, 95%CI=1.07-1.46, p=0.0050).

Conclusion: The G allele of IL-10 A-1082G genotype may serve as a predictor for TNBC risk. The finding should be validated in other populations.
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http://dx.doi.org/10.21873/anticanres.15020DOI Listing
May 2021

Notch-Regulated Dendritic Cells Restrain Inflammation-Associated Colorectal Carcinogenesis.

Cancer Immunol Res 2021 Mar 13;9(3):348-361. Epub 2021 Jan 13.

Department of Pathology, Case Western Reserve University, Cleveland, Ohio.

Conventional dendritic cells (cDC) play a central role in T-cell antitumor responses. We studied the significance of Notch-regulated DC immune responses in a mouse model of colitis-associated colorectal cancer in which there is epithelial downregulation of Notch/Hes1 signaling. This defect phenocopies that caused by (GDP-mannose 4,6-dehydratase) mutation in human colorectal cancers. We found that, although wild-type immune cells restrained dysplasia progression and decreased the incidence of adenocarcinoma in chimeric mice, the immune system with Notch2 deleted in all blood lineages or in only DCs promoted inflammation-associated transformation. Notch2 signaling deficiency not only impaired cDC terminal differentiation, but also downregulated CCR7 expression, reduced DC migration, and suppressed antigen cross-presentation to CD8 T cells. Transfer of Notch-primed DCs restrained inflammation-associated dysplasia progression. Consistent with the mouse data, we observed a correlation between infiltrating cDC1 and Notch2 signaling in human colorectal cancers and found that -mutant colorectal cancers showed decreased CCR7 expression and suppressed cDC1 signature gene expression. Suppressed cDC1 gene signature expression in human colorectal cancer was associated with a poor prognosis. In summary, our study supports an important role for Notch2 signaling in cDC1-mediated antitumor immunity and indicates that Notch2-controlled DCs restrain inflammation-associated colon cancer development in mice.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925430PMC
March 2021

Sarcopenia as a Prognostic Factor for 90-Day and Overall Mortality in Patients Undergoing Spine Surgery for Metastatic Tumors: A Multicenter Retrospective Cohort Study.

Neurosurgery 2020 10;87(5):1025-1036

Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan.

Background: Novel methods in predicting survival in patients with spinal metastases may help guide clinical decision-making and stratify treatments regarding surgery vs palliative care.

Objective: To evaluate whether the frailty/sarcopenia paradigm is predictive of survival and morbidity in patients undergoing surgery for spinal metastasis.

Methods: A total of 271 patients from 4 tertiary care centers who had undergone surgery for spinal metastasis were identified. Frailty/sarcopenia was defined by psoas muscle size. Survival hazard ratios were calculated using multivariate analysis, with variables from demographic, functional, oncological, and surgical factors. Secondary outcomes included improvement of neurological function and postoperative morbidity.

Results: Patients in the smallest psoas tertile had shorter overall survival compared to the middle and largest tertile. Psoas size (PS) predicted overall mortality more strongly than Tokuhashi score, Tomita score, and Karnofsky Performance Status (KPS). PS predicted 90-d mortality more strongly than Tokuhashi score, Tomita score, and KPS. Patients with a larger PS were more likely to have an improvement in deficit compared to the middle tertile. PS was not predictive of 30-d morbidity.

Conclusion: In patients undergoing surgery for spine metastases, PS as a surrogate for frailty/sarcopenia predicts 90-d and overall mortality, independent of demographic, functional, oncological, and surgical characteristics. The frailty/sarcopenia paradigm is a stronger predictor of survival at these time points than other standards. PS can be used in clinical decision-making to select which patients with metastatic spine tumors are appropriate surgical candidates.
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http://dx.doi.org/10.1093/neuros/nyaa245DOI Listing
October 2020

Development of a precision medicine pipeline to identify personalized treatments for colorectal cancer.

BMC Cancer 2020 Jun 24;20(1):592. Epub 2020 Jun 24.

Department of Medicine, Division of Medical Oncology, Duke University Medical Center, 3008 Snyderman Building, 905 S. LaSalle St., Durham, NC, 27710, USA.

Background: Metastatic colorectal cancer (CRC) continues to be a major health problem, and current treatments are primarily for disease control and palliation of symptoms. In this study, we developed a precision medicine strategy to discover novel therapeutics for patients with CRC.

Methods: Six matched low-passage cell lines and patient-derived xenografts (PDX) were established from CRC patients undergoing resection of their cancer. High-throughput drug screens using a 119 FDA-approved oncology drug library were performed on these cell lines, which were then validated in vivo in matched PDXs. RNA-Seq analysis was then performed to identify predictors of response.

Results: Our study revealed marked differences in response to standard-of-care agents across patients and pinpointed druggable pathways to treat CRC. Among these pathways co-targeting of fibroblast growth factor receptor (FGFR), SRC, platelet derived growth factor receptor (PDGFR), or vascular endothelial growth factor receptor (VEGFR) signaling was found to be an effective strategy. Molecular analyses revealed potential predictors of response to these druggable pathways.

Conclusions: Our data suggests that the use of matched low-passage cell lines and PDXs is a promising strategy to identify new therapies and pathways to treat metastatic CRC.
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http://dx.doi.org/10.1186/s12885-020-07090-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313200PMC
June 2020

MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis.

Nat Metab 2020 03 9;2(3):270-277. Epub 2020 Mar 9.

Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA.

Critical to the bacterial stringent response is the rapid relocation of resources from proliferation toward stress survival through the respective accumulation and degradation of (p)ppGpp by RelA and SpoT homologues. While mammalian genomes encode MESH1, a homologue of the bacterial (p)ppGpp hydrolase SpoT, neither (p)ppGpp nor its synthetase has been identified in mammalian cells. Here, we show that human MESH1 is an efficient cytosolic NADPH phosphatase that facilitates ferroptosis. Visualization of the MESH1-NADPH crystal structure revealed a bona fide affinity for the NADPH substrate. Ferroptosis-inducing erastin or cystine deprivation elevates MESH1, whose overexpression depletes NADPH and sensitizes cells to ferroptosis, whereas MESH1 depletion promotes ferroptosis survival by sustaining the levels of NADPH and GSH and by reducing lipid peroxidation. The ferroptotic protection by MESH1 depletion is ablated by suppression of the cytosolic NAD(H) kinase, NADK, but not its mitochondrial counterpart NADK2. Collectively, these data shed light on the importance of cytosolic NADPH levels and their regulation under ferroptosis-inducing conditions in mammalian cells.
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http://dx.doi.org/10.1038/s42255-020-0181-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252213PMC
March 2020

Protective effects of valproic acid on 6-hydroxydopamine-induced neuroinjury.

Environ Toxicol 2020 Aug 13;35(8):840-848. Epub 2020 Mar 13.

Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.

Oxidative stress may play critically important roles in the etiology of Parkinson's disease (PD). 6-Hydroxydopamine (6-OHDA) is a physiological neurotoxin reported to induce oxidative-induced apoptosis of dopaminergic neurons in PD mice models. Valproic acid (VPA), a clinical mood stabilizer, is a HDAC inhibitor with neuroprotective capacities. In the study, we aim at examining the feasibility of VPA as a protector for dopaminergic neurons against damage from 6-OHDA, and the intracellular mechanisms. The 6-OHDA-induced neurotoxicity to the human dopaminergic cell line SH-SY5Y was applied for examining VPA protective effects. Pretreatment with VPA was able to improve cell viability and reduce 6-OHDA-induced reactive oxygen species. Furthermore, a significant suppression of apoptotic caspases including cleaved caspase-3, caspase-7, and caspase-9 was observed. The results also revealed VPA decreased the 6-OHDA-induced Bax/Bcl2 ratio, as measured at protein level. These novel findings indicate that VPA may be capable of protecting the SH-SY5Y dopaminergic neuronal cells from 6-OHDA-induced toxicity via the deceasing of apoptotic caspases (cleaved caspase-3, caspase-7, and caspase-9) and reducing of the Bax/Bcl2 ratio. Very possibly, VPA could serve as not only a mood stabilizer but also a potential antidote for PD prevention.
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http://dx.doi.org/10.1002/tox.22920DOI Listing
August 2020

Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance.

Genes Dis 2021 Mar 29;8(2):203-214. Epub 2019 Oct 29.

Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA.

Colorectal cancer is a leading cause of cancer deaths. Most colorectal cancer patients eventually develop chemoresistance to the current standard-of-care therapies. Here, we used patient-derived colorectal cancer organoids to demonstrate that resistant tumor cells undergo significant chromatin changes in response to oxaliplatin treatment. Integrated transcriptomic and chromatin accessibility analyses using ATAC-Seq and RNA-Seq identified a group of genes associated with significantly increased chromatin accessibility and upregulated gene expression. CRISPR/Cas9 silencing of fibroblast growth factor receptor 1 (FGFR1) and oxytocin receptor (OXTR) helped overcome oxaliplatin resistance. Similarly, treatment with oxaliplatin in combination with an FGFR1 inhibitor (PD166866) or an antagonist of OXTR (L-368,899) suppressed chemoresistant organoids. However, oxaliplatin treatment did not activate either FGFR1 or OXTR expression in another resistant organoid, suggesting that chromatin accessibility changes are patient-specific. The use of patient-derived cancer organoids in combination with transcriptomic and chromatin profiling may lead to precision treatments to overcome chemoresistance in colorectal cancer.
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http://dx.doi.org/10.1016/j.gendis.2019.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099686PMC
March 2021

Agent-Based Modelling to Delineate Spatiotemporal Control Mechanisms of the Stem Cell Niche.

Methods Mol Biol 2019 ;1975:3-35

Department of Biomedical Engineering, Duke University, Durham, NC, USA.

Agent-based modelling (ABM) offers a framework to realistically couple subcellular signaling pathways to cellular behavior and macroscopic tissue organization. However, these models have been previously inaccessible to many systems biologists due to the difficulties with formulating and simulating multi-scale behavior. In this chapter, a review of the Compucell3D framework is presented along with a general workflow for transitioning from a well-mixed ODE model to an ABM. These techniques are demonstrated through a case study on the simulation of a Notch-Delta Positive Feedback, Lateral Inhibition (PFLI) gene circuit in the intestinal crypts. Specifically, techniques for gene circuit-driven hypothesis formation, geometry construction, selection of simulation parameters, and simulation quantification are presented.
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http://dx.doi.org/10.1007/978-1-4939-9224-9_1DOI Listing
September 2019

is a microRNA safeguard for -induced inflammatory colon oncogenesis.

Elife 2018 12 13;7. Epub 2018 Dec 13.

Center for Genomics and Computational Biology, Duke University, Durham, United States.

Inflammation often induces regeneration to repair the tissue damage. However, chronic inflammation can transform temporary hyperplasia into a fertile ground for tumorigenesis. Here, we demonstrate that the microRNA acts as a central safeguard to protect the inflammatory stem cell niche and reparative regeneration. Although playing little role in regular homeostasis, deficiency leads to colon tumorigenesis after infection. targets both immune and epithelial cells to restrain inflammation-induced stem cell proliferation. targets Interleukin six receptor (IL-6R) and Interleukin 23 receptor (IL-23R) to suppress T helper 17 (Th17) cell differentiation and expansion, targets chemokine CCL22 to hinder Th17 cell recruitment to the colon epithelium, and targets an orphan receptor Interleukin 17 receptor D (IL-17RD) to inhibit IL-17-induced stem cell proliferation. Our study highlights the importance of microRNAs in protecting the stem cell niche during inflammation despite their lack of function in regular tissue homeostasis.
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http://dx.doi.org/10.7554/eLife.39479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314783PMC
December 2018

Outcomes of Posterior Thoracic Corpectomies for Metastatic Spine Tumors: An Analysis of 90 Patients.

World Neurosurg 2019 Mar 27;123:e371-e378. Epub 2018 Nov 27.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.

Objective: To retrospectively analyze the outcomes and complications of patients with metastatic thoracic spinal tumors (MTTs) who underwent posterior corpectomies.

Methods: Ninety patients with MTTs who underwent posterior corpectomies were retrospectively analyzed. Characteristics evaluated included number of MTTs per year, location, involved vertebrae numbers, sex, histology, pre- and postoperative American Spinal Injury Association (ASIA) grade, visual analog scale (VAS) pain scores, operative time, blood loss, and length of hospital stay.

Results: The average follow-up was 20.8 ± 27.9 months (range, 0.5-139.4 months). Of the patients, 76.67% had a single metastasis and 23.33% had multiple metastases. For histology, 16.67% were breast, 15.56% were lung, 12.22% were prostate, and 12.22% were renal cell carcinoma. Of the patients with paraplegia and paraparesis, 74% improved. One patient improved from ASIA grade A to D, 3 patients improved from grade B to C, 8 patients improved from grade C to D or E, and 25 patients improved from grade D to E. Three patients (6%) with ASIA grade A and 1 patient (2%) with ASIA grade B had no improvement. One patient with ASIA grade C and 8 patients (16%) with grade D had no improvement. After surgery, VAS pain scores decreased from 8.45 ± 1.57 to 1.211 ± 1.81. In terms of complications, 2 patients (2.22%) had deep vein thrombosis and 1 patient had pulmonary embolism (1.11%). Other complications included wound infection (4.44%), cerebrospinal fluid leak (4.44%), pleural effusion (3.33%), wound dehiscence (2.22%), cellulitis (1.11%), epidural hematoma (1.11%), and pneumothorax (1.11%). Of the patients, 2.22% had implant failure and pseudoarthrosis, with 1 patient needing revision surgery. One patient (1.11%) had tumor recurrence.

Conclusions: Our results suggest that posterior thoracic corpectomies for MTTs have a reasonable complication rate with favorable outcomes.
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http://dx.doi.org/10.1016/j.wneu.2018.11.172DOI Listing
March 2019

Single-Cell Transcriptomics Reveals Heterogeneity and Drug Response of Human Colorectal Cancer Organoids.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:2378-2381

Organoids are three-dimensional cell cultures that mimic organ functions and structures. The organoid model has been developed as a versatile in vitro platform for stem cell biology and diseases modeling. Tumor organoids are shown to share ~ 90% of genetic mutations with biopsies from same patients. However, it's not clear whether tumor organoids recapitulate the cellular heterogeneity observed in patient tumors. Here, we used single-cell RNA-Seq to investigate the transcriptomics of tumor organoids derived from human colorectal tumors, and applied machine learning methods to unbiasedly cluster subtypes in tumor organoids. Computational analysis reveals cancer heterogeneity sustained in tumor organoids, and the subtypes in organoids displayed high diversity. Furthermore, we treated the tumor organoids with a first-line cancer drug, Oxaliplatin, and investigated drug response in single-cell scale. Diversity of tumor cell populations in organoids were significantly perturbed by drug treatment. Single-cell analysis detected the depletion of chemosensitive subgroups and emergence of new drug tolerant subgroups after drug treatment. Our study suggests that the organoid model is capable of recapitulating clinical heterogeneity and its evolution in response to chemotherapy.
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http://dx.doi.org/10.1109/EMBC.2018.8512784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317967PMC
July 2018

Microbiota of Inflammatory Bowel Disease Models.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:2374-2377

Gut microbiome plays an important role in inflammatory bowel disease (IBD), a group of intestinal chronic inflammation conditions that affect a large population. The animal models of IBD have long been established on basis of pathological features, but their ability to recapitulate patient gut microbiota is unknown. We investigated and compared the composition and biodiversity of bacterial population in the fecal samples from rat models of the two IBD subtypes, and compared them with patient samples. Our analyses revealed that inflammation reduces overall microbiome diversity and increased variation between individuals. We identified specific microbial signatures associated with the two IBD subtypes that were consistent between the animal models and human IBD patients, suggesting that the animal models can partially recapitulate the microbiota in human diseases. Furthermore, metagenome prediction analysis suggested microbial functions that were likely altered by host-microbiota interactions in IBD models.
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http://dx.doi.org/10.1109/EMBC.2018.8512848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709594PMC
July 2018

Intramedullary and Extramedullary Thoracic Spinal Lipomas Without Spinal Dysraphism: Clinical Presentation and Surgical Management.

World Neurosurg 2019 Jan 11;121:156-159. Epub 2018 Oct 11.

Department of Neurological Surgery, University of California, San Francisco, California, USA.

Background: Intradural intramedullary lipomas without dysraphism are rare tumors. Although they appear extramedullary on imaging, they invade into the intramedullary substance of the spinal cord. We present 2 cases and discuss their clinical presentation, radiologic findings, and surgical management.

Case Description: Case 1 is a 21-year-old woman who presented with upper back pain from recurrent lipoma. She had undergone partial excision in 2008 at an outside hospital. Physical examination revealed full strength but hyperreflexia in the legs. Magnetic resonance imaging (MRI) revealed a recurrent thoracic spinal tumor with spinal cord compression. Surgery was performed, and it was found that the tumor was both extramedullary and intramedullary, with an obscure delineation between tumor and cord. Subtotal excision was performed, and the patient remained neurologically intact. Case 2 is a 47-year-old woman who presented with leg weakness, difficulty in walking, and foot drop. Physical examination revealed 4/5 in the lower extremities. MRI demonstrated a spinal lipoma with thoracic cord compression. Even though the tumor appeared to be an extramedullary lesion by MRI, intraoperatively, the tumor became intramedullary with loss of distinction between the spinal cord and tumor. Subtotal excision was performed, and the patient regained her strength to 5/5 postoperatively.

Conclusions: Intramedullary thoracic spinal lipomas without spinal dysraphism are rare. Although these tumors may appear completely extramedullary on imaging, extreme care should be taken during surgery because the lesions eventually become intramedullary, intercalating within the substance of the spinal cord, precluding gross total resection.
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http://dx.doi.org/10.1016/j.wneu.2018.09.156DOI Listing
January 2019

Prometheus revisited.

J Clin Invest 2018 06 30;128(6):2192-2193. Epub 2018 Apr 30.

The liver's extraordinary ability to regenerate has been known since the myth of Prometheus, but the mechanisms involved are still being discovered. Various small animal models have been used in this quest. Two of the most popular include partial hepatectomy (PHx), in which two-thirds of the liver mass is surgically removed to evoke a massive, immediate stimulus for regeneration, and prolonged exposure to toxins that kill liver cells more gradually, provoking chronic regenerative activity. In either case, multiple types of cells must interact effectively to repopulate the organ with functional mature hepatocytes and thus assure ultimate restoration of healthy liver structure and function. This complexity has confounded efforts to distinguish specific changes that occur in cells that repopulate the hepatocyte compartment from changes in other cell populations, including subpopulations of hepatocytes or hepatocyte precursors that do not become regenerative. In the current issue of the JCI, Wang et al. used translating ribosome affinity purification followed by high-throughput RNA sequencing (TRAP-seq) to isolate mRNAs from repopulating hepatocytes in order to profile gene expression specifically in the hepatocytes that regenerate the liver following toxic injury imposed by inherent byproducts of tyrosine metabolism. This innovative methodology can potentially be used to design therapeutic strategies for liver regeneration.
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http://dx.doi.org/10.1172/JCI120933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983318PMC
June 2018

Aldolase B-Mediated Fructose Metabolism Drives Metabolic Reprogramming of Colon Cancer Liver Metastasis.

Cell Metab 2018 Jun 26;27(6):1249-1262.e4. Epub 2018 Apr 26.

Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA. Electronic address:

Cancer metastasis accounts for the majority of cancer-related deaths and remains a clinical challenge. Metastatic cancer cells generally resemble cells of the primary cancer, but they may be influenced by the milieu of the organs they colonize. Here, we show that colorectal cancer cells undergo metabolic reprogramming after they metastasize and colonize the liver, a key metabolic organ. In particular, via GATA6, metastatic cells in the liver upregulate the enzyme aldolase B (ALDOB), which enhances fructose metabolism and provides fuel for major pathways of central carbon metabolism during tumor cell proliferation. Targeting ALDOB or reducing dietary fructose significantly reduces liver metastatic growth but has little effect on the primary tumor. Our findings suggest that metastatic cells can take advantage of reprogrammed metabolism in their new microenvironment, especially in a metabolically active organ such as the liver. Manipulation of involved pathways may affect the course of metastatic growth.
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http://dx.doi.org/10.1016/j.cmet.2018.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5990465PMC
June 2018

Matrix metalloproteinase inhibitors enhance the efficacy of frontline drugs against Mycobacterium tuberculosis.

PLoS Pathog 2018 04 26;14(4):e1006974. Epub 2018 Apr 26.

Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, United States of America.

Mycobacterium tuberculosis (Mtb) remains a grave threat to world health with emerging drug resistant strains. One prominent feature of Mtb infection is the extensive reprogramming of host tissue at the site of infection. Here we report that inhibition of matrix metalloproteinase (MMP) activity by a panel of small molecule inhibitors enhances the in vivo potency of the frontline TB drugs isoniazid (INH) and rifampicin (RIF). Inhibition of MMP activity leads to an increase in pericyte-covered blood vessel numbers and appears to stabilize the integrity of the infected lung tissue. In treated mice, we observe an increased delivery and/or retention of frontline TB drugs in the infected lungs, resulting in enhanced drug efficacy. These findings indicate that targeting Mtb-induced host tissue remodeling can increase therapeutic efficacy and could enhance the effectiveness of current drug regimens.
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http://dx.doi.org/10.1371/journal.ppat.1006974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919409PMC
April 2018

A Notch positive feedback in the intestinal stem cell niche is essential for stem cell self-renewal.

Mol Syst Biol 2017 04 28;13(4):927. Epub 2017 Apr 28.

School of Electrical and Computer Engineering, Cornell University, Ithaca, NY, USA

The intestinal epithelium is the fastest regenerative tissue in the body, fueled by fast-cycling stem cells. The number and identity of these dividing and migrating stem cells are maintained by a mosaic pattern at the base of the crypt. How the underlying regulatory scheme manages this dynamic stem cell niche is not entirely clear. We stimulated intestinal organoids with Notch ligands and inhibitors and discovered that intestinal stem cells employ a positive feedback mechanism via direct Notch binding to the second intron of the Notch1 gene. Inactivation of the positive feedback by CRISPR/Cas9 mutation of the binding sequence alters the mosaic stem cell niche pattern and hinders regeneration in organoids. Dynamical system analysis and agent-based multiscale stochastic modeling suggest that the positive feedback enhances the robustness of Notch-mediated niche patterning. This study highlights the importance of feedback mechanisms in spatiotemporal control of the stem cell niche.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408779PMC
http://dx.doi.org/10.15252/msb.20167324DOI Listing
April 2017

Fucosylation Deficiency in Mice Leads to Colitis and Adenocarcinoma.

Gastroenterology 2017 01 14;152(1):193-205.e10. Epub 2016 Sep 14.

Department of Pathology, Case Western Reserve University, Cleveland, Ohio; Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio. Electronic address:

Background & Aims: De novo synthesis of guanosine diphosphate (GDP)-fucose, a substrate for fucosylglycans, requires sequential reactions mediated by GDP-mannose 4,6-dehydratase (GMDS) and GDP-4-keto-6-deoxymannose 3,5-epimerase-4-reductase (FX or tissue specific transplantation antigen P35B [TSTA3]). GMDS deletions and mutations are found in 6%-13% of colorectal cancers; these mostly affect the ascending and transverse colon. We investigated whether a lack of fucosylation consequent to loss of GDP-fucose synthesis contributes to colon carcinogenesis.

Methods: FX deficiency and GMDS deletion produce the same biochemical phenotype of GDP-fucose deficiency. We studied a mouse model of fucosylation deficiency (Fx-/- mice) and mice with the full-length Fx gene (controls). Mice were placed on standard chow or fucose-containing diet (equivalent to a control fucosylglycan phenotype). Colon tissues were collected and analyzed histologically or by enzyme-linked immunosorbent assays to measure cytokine levels; T cells also were collected and analyzed. Fecal samples were analyzed by 16s ribosomal RNA sequencing. Mucosal barrier function was measured by uptake of fluorescent dextran. We transplanted bone marrow cells from Fx-/- or control mice (Ly5.2) into irradiated 8-week-old Fx-/- or control mice (Ly5.1). We performed immunohistochemical analyses for expression of Notch and the hes family bHLH transcription factor (HES1) in colon tissues from mice and a panel of 60 human colorectal cancer specimens (27 left-sided, 33 right-sided).

Results: Fx-/- mice developed colitis and serrated-like lesions. The intestinal pathology of Fx-/- mice was reversed by addition of fucose to the diet, which restored fucosylation via a salvage pathway. In the absence of fucosylation, dysplasia appeared and progressed to adenocarcinoma in up to 40% of mice, affecting mainly the right colon and cecum. Notch was not activated in Fx-/- mice fed standard chow, leading to decreased expression of its target Hes1. Fucosylation deficiency altered the composition of the fecal microbiota, reduced mucosal barrier function, and altered epithelial proliferation marked by Ki67. Fx-/- mice receiving control bone marrow cells had intestinal inflammation and dysplasia, and reduced expression of cytokines produced by cytotoxic T cells. Human sessile serrated adenomas and right-sided colorectal tumors with epigenetic loss of MutL homolog 1 (MLH1) had lost or had lower levels of HES1 than other colorectal tumor types or nontumor tissues.

Conclusions: In mice, fucosylation deficiency leads to colitis and adenocarcinoma, loss of Notch activation, and down-regulation of Hes1. HES1 loss correlates with the development of human right-sided colorectal tumors with epigenetic loss of MLH1. These findings indicate that carcinogenesis in a subset of colon cancer is consequent to a molecular mechanism driven by fucosylation deficiency and/or HES1-loss.
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http://dx.doi.org/10.1053/j.gastro.2016.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5164974PMC
January 2017

NOTCH Signaling Regulates Asymmetric Cell Fate of Fast- and Slow-Cycling Colon Cancer-Initiating Cells.

Cancer Res 2016 06 11;76(11):3411-21. Epub 2016 Apr 11.

Department of Biomedical Engineering, Cornell University, Ithaca, New York. School of Electrical and Computer Engineering, Cornell University, Ithaca, New York. Department of Biomedical Engineering, Duke University, Durham, North Carolina.

Colorectal cancer cells with stem-like properties, referred to as colon cancer-initiating cells (CCIC), have high tumorigenic potential. While CCIC can differentiate to promote cellular heterogeneity, it remains unclear whether CCIC within a tumor contain distinct subpopulations. Here, we describe the co-existence of fast- and slow-cycling CCIC, which can undergo asymmetric division to generate each other, highlighting CCIC plasticity and interconvertibility. Fast-cycling CCIC express markers, such as LGR5 and CD133, rely on MYC for their proliferation, whereas slow-cycling CCIC express markers, such as BMI1 and hTERT, are independent of MYC. NOTCH signaling promotes asymmetric cell fate, regulating the balance between these two populations. Overall, our results illuminate the basis for CCIC heterogeneity and plasticity by defining a direct interconversion mechanism between slow- and fast-cycling CCIC. Cancer Res; 76(11); 3411-21. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-3198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891252PMC
June 2016

Notch signalling regulates asymmetric division and inter-conversion between lgr5 and bmi1 expressing intestinal stem cells.

Sci Rep 2016 05 16;6:26069. Epub 2016 May 16.

Department of Biomedical Engineering, Cornell University, Ithaca, New York, 14853, USA.

Rapidly cycling LGR5+ intestinal stem cells (ISCs) located at the base of crypts are the primary driver of regeneration. Additionally, BMI1 expression is correlated with a slow cycling pool of ISCs located at +4 position. While previous reports have shown interconversion between these two populations following tissue injury, we provide evidence that NOTCH signaling regulates the balance between these two populations and promotes asymmetric division as a mechanism for interconversion in the mouse intestine. In both in vitro and in vivo models, NOTCH suppression reduces the ratio of BMI1+/LGR5+ ISCs while NOTCH stimulation increases this ratio. Furthermore, NOTCH signaling can activate asymmetric division after intestinal inflammation. Overall, these data provide insights into ISC plasticity, demonstrating a direct interconversion mechanism between slow- and fast-cycling ISCs.
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http://dx.doi.org/10.1038/srep26069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867651PMC
May 2016

A miR-34a-Numb Feedforward Loop Triggered by Inflammation Regulates Asymmetric Stem Cell Division in Intestine and Colon Cancer.

Cell Stem Cell 2016 Feb;18(2):189-202

School of Electrical and Computer Engineering, Cornell University, Ithaca, NY 14853, USA; Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA; Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA. Electronic address:

Emerging evidence suggests that microRNAs can initiate asymmetric division, but whether microRNA and protein cell fate determinants coordinate with each other remains unclear. Here, we show that miR-34a directly suppresses Numb in early-stage colon cancer stem cells (CCSCs), forming an incoherent feedforward loop (IFFL) targeting Notch to separate stem and non-stem cell fates robustly. Perturbation of the IFFL leads to a new intermediate cell population with plastic and ambiguous identity. Lgr5+ mouse intestinal/colon stem cells (ISCs) predominantly undergo symmetric division but turn on asymmetric division to curb the number of ISCs when proinflammatory response causes excessive proliferation. Deletion of miR-34a inhibits asymmetric division and exacerbates Lgr5+ ISC proliferation under such stress. Collectively, our data indicate that microRNA and protein cell fate determinants coordinate to enhance robustness of cell fate decision, and they provide a safeguard mechanism against stem cell proliferation induced by inflammation or oncogenic mutation.
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http://dx.doi.org/10.1016/j.stem.2016.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751059PMC
February 2016

Comprehensive models of human primary and metastatic colorectal tumors in immunodeficient and immunocompetent mice by chemokine targeting.

Nat Biotechnol 2015 Jun 25;33(6):656-60. Epub 2015 May 25.

Department of Medicine, Weill Cornell Medical College, New York, New York, USA.

Current orthotopic xenograft models of human colorectal cancer (CRC) require surgery and do not robustly form metastases in the liver, the most common site clinically. CCR9 traffics lymphocytes to intestine and colorectum. We engineered use of the chemokine receptor CCR9 in CRC cell lines and patient-derived cells to create primary gastrointestinal (GI) tumors in immunodeficient mice by tail-vein injection rather than surgery. The tumors metastasize inducibly and robustly to the liver. Metastases have higher DKK4 and NOTCH signaling levels and are more chemoresistant than paired subcutaneous xenografts. Using this approach, we generated 17 chemokine-targeted mouse models (CTMMs) that recapitulate the majority of common human somatic CRC mutations. We also show that primary tumors can be modeled in immunocompetent mice by microinjecting CCR9-expressing cancer cell lines into early-stage mouse blastocysts, which induces central immune tolerance. We expect that CTMMs will facilitate investigation of the biology of CRC metastasis and drug screening.
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http://dx.doi.org/10.1038/nbt.3239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532544PMC
June 2015

miR-1269 promotes metastasis and forms a positive feedback loop with TGF-β.

Nat Commun 2015 Apr 15;6:6879. Epub 2015 Apr 15.

1] School of Electrical and Computer Engineering, Cornell University, Ithaca, New York 14853, USA [2] Department of Biomedical Engineering, Cornell University, Ithaca, New York 14853, USA [3] Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, USA.

As patient survival drops precipitously from early-stage cancers to late-stage and metastatic cancers, microRNAs that promote relapse and metastasis can serve as prognostic and predictive markers as well as therapeutic targets for chemoprevention. Here we show that miR-1269a promotes colorectal cancer (CRC) metastasis and forms a positive feedback loop with TGF-β signalling. miR-1269a is upregulated in late-stage CRCs, and long-term monitoring of 100 stage II CRC patients revealed that miR-1269a expression in their surgically removed primary tumours is strongly associated with risk of CRC relapse and metastasis. Consistent with clinical observations, miR-1269a significantly increases the ability of CRC cells to invade and metastasize in vivo. TGF-β activates miR-1269 via Sox4, while miR-1269a enhances TGF-β signalling by targeting Smad7 and HOXD10, hence forming a positive feedback loop. Our findings suggest that miR-1269a is a potential marker to inform adjuvant chemotherapy decisions for CRC patients and a potential therapeutic target to deter metastasis.
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http://dx.doi.org/10.1038/ncomms7879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4399006PMC
April 2015

A metabolic signature of colon cancer initiating cells.

Annu Int Conf IEEE Eng Med Biol Soc 2014 ;2014:4759-62

Colon cancer initiating cells (CCICs) are more tumorigenic and metastatic than the majority of colorectal cancer (CRC) cells. CCICs have also been associated with stem cell-like properties. However, there is a lack of system-level understanding of what mechanisms distinguish CCICs from common CRC cells. We compared the transcriptomes of CD133+ CCICs and CD133- CRC cells from multiple sources, which identified a distinct metabolic signature for CD133(high) CCICs. High-resolution unbiased metabolomics was then performed to validate this CCIC metabolic signature. Specifically, levels of enzymes and metabolites involved in glycolysis, the citric acid (TCA) cycle, and cysteine and methionine metabolism are altered in CCICs. Analyses of the alterations further suggest an epigenetic link. This metabolic signature provides mechanistic insights into CCIC phenotypes and may serve as potential biomarkers and therapeutic targets for future CRC treatment.
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http://dx.doi.org/10.1109/EMBC.2014.6944688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302416PMC
September 2015

A bio-inspired spatial patterning circuit.

Annu Int Conf IEEE Eng Med Biol Soc 2014 ;2014:86-9

Lateral Inhibition (LI) is a widely conserved patterning mechanism in biological systems across species. Distinct from better-known Turing patterns, LI depend on cell-cell contact rather than diffusion. We built an in silico genetic circuit model to analyze the dynamic properties of LI. The model revealed that LI amplifies differences between neighboring cells to push them into opposite states, hence forming stable 2-D patterns. Inspired by this insight, we designed and implemented an electronic circuit that recapitulates LI patterning dynamics. This biomimetic system serve as a physical model to elucidate the design principle of generating robust patterning through spatial feedback, regardless of the underlying devices being biological or electrical.
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http://dx.doi.org/10.1109/EMBC.2014.6943535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304701PMC
October 2015

Coexistence of neurofibroma and meningioma at exactly the same level of the cervical spine.

J Chin Med Assoc 2014 Nov 12;77(11):594-7. Epub 2014 Aug 12.

Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, ROC; National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC.

We report a case of the coexistence of different spinal tumors at the same level of the cervical spine, without neurofibromatosis (NF), which was successfully treated with surgery. A 72-year-old female presented with right upper-limb clumsiness and weakness. Magnetic resonance imaging revealed an intradural, extramedullary tumor mass at the right C3-4 level with extradural extension into the intervertebral foramen. The extradural tumor was removed, and the pathology showed neurofibroma. After incision of the dura, the intradural tumor was removed, and was identified as meningioma in the pathological report. The patient did not meet the criteria of NF. Coexistence of neurofibroma and meningioma at exactly the same level of the spine without NF is extremely rare. Exploration of the intradural space may be necessary after resection of an extradural tumor if the surgical finding does not correlate well with the preoperative images.
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http://dx.doi.org/10.1016/j.jcma.2014.06.007DOI Listing
November 2014

Multiple myeloma with cavernous sinus involvement.

Kaohsiung J Med Sci 2013 Sep 6;29(9):517-8. Epub 2013 Apr 6.

Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan.

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http://dx.doi.org/10.1016/j.kjms.2013.01.008DOI Listing
September 2013

Post-translational regulation enables robust p53 regulation.

BMC Syst Biol 2013 Aug 30;7:83. Epub 2013 Aug 30.

School of Electrical and Computer Engineering, 402 Phillips Hall, Cornell University, Ithaca, NY 14853, USA.

Background: The tumor suppressor protein p53 plays important roles in DNA damage repair, cell cycle arrest and apoptosis. Due to its critical functions, the level of p53 is tightly regulated by a negative feedback mechanism to increase its tolerance towards fluctuations and disturbances. Interestingly, the p53 level is controlled by post-translational regulation rather than transcriptional regulation in this feedback mechanism.

Results: We analyzed the dynamics of this feedback to understand whether post-translational regulation provides any advantages over transcriptional regulation in regard to disturbance rejection. When a disturbance happens, even though negative feedback reduces the steady-state error, it can cause a system to become less stable and transiently overshoots, which may erroneously trigger downstream reactions. Therefore, the system needs to balance the trade-off between steady-state and transient errors. Feedback control and adaptive estimation theories revealed that post-translational regulation achieves a better trade-off than transcriptional regulation, contributing to a more steady level of p53 under the influence of noise and disturbances. Furthermore, post-translational regulation enables cells to respond more promptly to stress conditions with consistent amplitude. However, for better disturbance rejection, the p53- Mdm2 negative feedback has to pay a price of higher stochastic noise.

Conclusions: Our analyses suggest that the p53-Mdm2 feedback favors regulatory mechanisms that provide the optimal trade-offs for dynamic control.
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http://dx.doi.org/10.1186/1752-0509-7-83DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844394PMC
August 2013

A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells.

Cell Stem Cell 2013 May;12(5):602-15

School of Electrical and Computer Engineering, Cornell University, Ithaca, NY 14853, USA.

microRNAs regulate developmental cell-fate decisions, tissue homeostasis, and oncogenesis in distinct ways relative to proteins. Here, we show that the tumor suppressor microRNA miR-34a is a cell-fate determinant in early-stage dividing colon cancer stem cells (CCSCs). In pair-cell assays, miR-34a distributes at high levels in differentiating progeny, whereas low levels of miR-34a demarcate self-renewing CCSCs. Moreover, miR-34a loss of function and gain of function alter the balance between self-renewal versus differentiation both in vitro and in vivo. Mechanistically, miR-34a sequesters Notch1 mRNA to generate a sharp threshold response where a bimodal Notch signal specifies the choice between self-renewal and differentiation. In contrast, the canonical cell-fate determinant Numb regulates Notch levels in a continuously graded manner. Altogether, our findings highlight a unique microRNA-regulated mechanism that converts noisy input into a toggle switch for robust cell-fate decisions in CCSCs.
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http://dx.doi.org/10.1016/j.stem.2013.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646336PMC
May 2013