Publications by authors named "Zhilin Hu"

28 Publications

  • Page 1 of 1

A predictive model based on liquid biopsy for non-small cell lung cancer to assess patient's prognosis: Development and application.

Tissue Cell 2022 Aug 14;77:101854. Epub 2022 Jun 14.

Department of Respiratory, Hwa Mei Hospital, University of Chinese Academy of Sciences, China; Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, China.

Background And Objective: Improving ability to predict the prognosis of patients with progressive lung cancer is an important task in the era of precision medicine. Here, a predictive model based on liquid biopsy for non-small cell lung cancer (NSCLC) was established to improve prognosis prediction in patients with progressive NSCLC.

Methods: Clinical data and blood samples of 500 eligible patients were collected and screened from the electronic case database and blood sample center of Hwa Mei Hospital, University of Chinese Academy of Sciences and Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences. Patients were randomly assigned to training set (300 cases) and validation set (200 cases) in a ratio of 3:2 by random number method. Baseline levels of the two datasets were compared. Progression-free survival (PFS) analysis was performed on the training set using Kaplan-Meier method. The independent prognostic factors affecting patients' PFS were determined by multivariate Cox regression analysis. The prognosis predictive model of patients was constructed by using the nomogram. Calibration curve and C-index were used to evaluate the accuracy of the prognosis predictive model in both internal and external validations.

Results: In training set, the age distribution of patients was 59.00 (46.00, 71.00) years, including 137 (45.7 %) females and 163 (54.3 %) males, 198 cases (66.0 %) with Eastern Cooperative Oncology Group (ECOG) score 0-1, and 102 cases (34.0 %) with ECOG score 2. In verification set, the age distribution of patients was 60.00 (48.25, 73.00) years, including 92 females (46.0 %) and 108 males (54.0 %), 130 cases (65.0%) with ECOG score 0-1, and 70 cases (35.0 %) with ECOG score 2. Patients in training set showed PFS differences stratified by gene mutation type (p < 0.0001), differentiation degree (p < 0.0001), circulating tumor cell (CTC) content (p = 0.00026), and brain metastasis (p < 0.0001). Besides, multivariate Cox regression analysis indicated that gene mutation type, differentiation degree, CTC content (p = 0.002), and brain metastasis (p = 0.005) are independent prognostic factors for PFS. These factors were included in the nomogram parameters, and both internally validated calibration curve (C-index = 0.672) and externally validated calibration curve (C-index = 0.657), showing good predictive performance of the model.

Conclusion: The predictive model has a good predictive ability for prognosis of patients with progressive NSCLC. Notably, the differentiation degree and CTC content are both impact factors for PFS of patients, and the performance of these indicators in predicting the survival of patients with progressive NSCLC needs to be clarified in the future.
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http://dx.doi.org/10.1016/j.tice.2022.101854DOI Listing
August 2022

SENP7 senses oxidative stress to sustain metabolic fitness and antitumor functions of CD8+ T cells.

J Clin Invest 2022 04;132(7)

Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Oncogenes and Related Genes, Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai, China.

The functional integrity of CD8+ T cells is tightly coupled to metabolic reprogramming, but how oxidative stress directs CD8+ T cell metabolic fitness in the tumor microenvironment (TME) remains elusive. Here, we report that SUMO-specific protease 7 (SENP7) senses oxidative stress to maintain the CD8+ T cell metabolic state and antitumor functions. SENP7-deficient CD8+ T cells exhibited decreased glycolysis and oxidative phosphorylation, resulting in attenuated proliferation in vitro and dampened antitumor functions in vivo. Mechanistically, CD8+ T cell-derived ROS triggered cytosolic SENP7-mediated PTEN deSUMOylation, thereby promoting PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, lowering T cell-intrinsic ROS restricted SENP7 cytosolic translocation and repressed CD8+ T cell metabolic and functional activity in human colorectal cancer samples. Our findings reveal that SENP7, as an oxidative stress sensor, sustains CD8+ T cell metabolic fitness and effector functions and unveil an oxidative stress-sensing machinery in tumor-infiltrating CD8+ T cells.
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http://dx.doi.org/10.1172/JCI155224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8970670PMC
April 2022

ZFP91 disturbs metabolic fitness and antitumor activity of tumor-infiltrating T cells.

J Clin Invest 2021 10;131(19)

Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Oncogenes and Related Genes, Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Proper metabolic activities facilitate T cell expansion and antitumor function; however, the mechanisms underlying disruption of the T cell metabolic program and function in the tumor microenvironment (TME) remain elusive. Here, we show a zinc finger protein 91-governed (ZFP91-governed) mechanism that disrupts the metabolic pathway and antitumor activity of tumor-infiltrating T cells. Single-cell RNA-Seq revealed that impairments in T cell proliferation and activation correlated with ZFP91 in tissue samples from patients with colorectal cancer. T cell-specific deletion of Zfp91 in mice led to enhanced T cell proliferation and potentiated T cell antitumor function. Loss of ZFP91 increased mammalian target of rapamycin complex 1 (mTORC1) activity to drive T cell glycolysis. Mechanistically, T cell antigen receptor-dependent (TCR-dependent) ZFP91 cytosolic translocation promoted protein phosphatase 2A (PP2A) complex assembly, thereby restricting mTORC1-mediated metabolic reprogramming. Our results demonstrate that ZFP91 perturbs T cell metabolic and functional states in the TME and suggest that targeting ZFP91 may improve the efficacy of cancer immunotherapy.
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http://dx.doi.org/10.1172/JCI144318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483753PMC
October 2021

Efficient separation of aluminum foil from mixed-type spent lithium-ion power batteries.

J Environ Manage 2021 Nov 10;298:113500. Epub 2021 Aug 10.

School of Environment and Energy, South China University of Technology, Guangzhou, 510006, PR China.

The disposal of spent lithium-ion power batteries (LIBs) has become an important research topic owing to the booming market for electric vehicles. However, the recovery efficiency of the alkaline solution and organic solvent methods currently used to separate Al foil from cathode materials still has room for improvement. The insufficient separation of Al foil and complexity of the battery types present obstacles to the extraction of valuable metals using simple processes. In this study, an efficient approach is developed to separate the Al foil in mixed-type spent LIBs (M-LIBs), namely, LiNiCoMnO (NCM), LiFePO (LFP), and LiMnO (LMO) LIBs, by controlled pyrolysis. Hundred percent of the Al foil was recovered at the temperature of 450 °C, holding time of 60 min, and heating rate of 10 °C/min. The purity of Al in the recovered foil was 99.41 %, 99.83 % and 99.92 %, and the recovery efficiency of the active cathode materials was 96.01 %, 99.80 % and 99.15 % for NCM, LFP and LMO, respectively, without the loss of active cathode materials. The obtained active cathode materials exhibited a favorable crystalline structure, and the average particle diameter was reduced from 300.497 to 24.316 μm with a smaller and looser morphology. The process could be well fitted with the Friedman differential equation, and the correlation coefficients were higher than 0.99. The efficient separation could be attributed to the complete rupture of long chain -(CHCF)- bonds in the poly (vinylidene difluoride) (PVDF) binder, which resulted in the formation of HF, trifluorobenzene, alkanes, and gaseous single molecule CHCF. Therefore, this work potentially provides an alternative approach for the efficient separation of Al foil in M-LIBs, thereby simplifying the process and achieving lower cost, reduced loss of valuable metals, and higher recovery efficiency.
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http://dx.doi.org/10.1016/j.jenvman.2021.113500DOI Listing
November 2021

Using Endoscopic Optical Coherence Tomography to Detect and Treat Early-Stage Pancreatic Cancers.

Front Oncol 2021 15;11:591484. Epub 2021 Mar 15.

Department of Surgical Oncology, The James Cancer Hospital and Solove Research Institute, Wexner Medical Center and College of Medicine at the Ohio State University, Columbus, OH, United States.

We developed a novel technology capable of detecting early-stage pancreatic cancers using high-resolution three-dimensional endoscopic optical coherence tomography (Endo-OCT), and treating them using high dose rate brachytherapy (HDR) under the Endo-OCT image guidance. This technology integrates our custom-built ultra-high resolution endoscopic three-dimensional OCT diagnostic imaging device with a commercial high dose rate brachytherapy system (HDR), resulting in a compact, portable, easy-to-operate, and low-cost Endo-OCT image-guided high dose rate brachytherapy (OCT-IGHDR) system. The system has the dual functions of diagnosis and treatment that can precisely detect and measure the location and size of the early-stage pancreatic cancer or premalignant lesions and then treat them from the inside of the pancreatic duct with an accurate and focused dose while greatly reducing the radiation toxicity to the neighboring tissues and organs. This minimally-invasive treatment technology could avoid the potential complications from surgery and reduces the high operation cost. This technology could also be applied to treat diseases of the esophagus, rectum, bronchus, and other aerodigestive organs that are suitable for use with an endoscopic device. In this article, we describe the concept of this technology and the preliminary experiments that could demonstrate the concept by using this homemade Endo-OCT machine to image the pancreatic duct for diagnosis of early-stage pancreatic cancer or premalignant lesions and to perform Endo-OCT image-guided brachytherapy.
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http://dx.doi.org/10.3389/fonc.2021.591484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005647PMC
March 2021

SENP3 senses oxidative stress to facilitate STING-dependent dendritic cell antitumor function.

Mol Cell 2021 03;81(5):940-952.e5

Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China. Electronic address:

STING-dependent cytosolic DNA sensing in dendritic cells (DCs) initiates antitumor immune responses, but how STING signaling is metabolically regulated in the tumor microenvironment remains unknown. Here, we show that oxidative stress is required for STING-induced DC antitumor function through a process that directs SUMO-specific protease 3 (SENP3) activity. DC-specific deletion of Senp3 drives tumor progression by blunting STING-dependent type-I interferon (IFN) signaling in DCs and dampening antitumor immune responses. DC-derived reactive oxygen species (ROS) trigger SENP3 accumulation and the SENP3-IFI204 interaction, thereby catalyzing IFI204 deSUMOylation and boosting STING signaling activation in mice. Consistently, SENP3 senses ROS to facilitate STING-dependent DC activity in tissue samples from colorectal cancer patients. Our results reveal that oxidative stress as a metabolic regulator promotes STING-mediated DC antitumor immune responses and highlights SENP3 as an overflow valve for STING signaling induction in the metabolically abnormal tumor microenvironment.
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http://dx.doi.org/10.1016/j.molcel.2020.12.024DOI Listing
March 2021

ZFP91 is required for the maintenance of regulatory T cell homeostasis and function.

J Exp Med 2021 02;218(2)

Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Oncogenes and Related Genes, Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Autophagy programs the metabolic and functional fitness of regulatory T (T reg) cells to establish immune tolerance, yet the mechanisms governing autophagy initiation in T reg cells remain unclear. Here, we show that the E3 ubiquitin ligase ZFP91 facilitates autophagy activation to sustain T reg cell metabolic programming and functional integrity. T reg cell-specific deletion of Zfp91 caused T reg cell dysfunction and exacerbated colonic inflammation and inflammation-driven colon carcinogenesis. TCR-triggered autophagy induction largely relied on T reg cell-derived ZFP91 to restrict hyperglycolysis, which is required for the maintenance of T reg cell homeostasis. Mechanistically, ZFP91 rapidly translocated from the nucleus to the cytoplasm in response to TCR stimulation and then mediated BECN1 ubiquitination to promote BECN1-PIK3C3 complex formation. Therefore, our results highlight a ZFP91-dependent mechanism promoting TCR-initiated autophagosome maturation to maintain T reg cell homeostasis and function.
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http://dx.doi.org/10.1084/jem.20201217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769166PMC
February 2021

Induced fluorescent enhancement of protein-directed synthesized gold nanoclusters for selective and sensitive detection of flame retardants.

Sci Total Environ 2020 Apr 10;713:136488. Epub 2020 Jan 10.

School of Environment and Energy, South China University of Technology, Guangzhou 510006, Guangdong, PR China.

Organophosphate flame retardants (OPFRs), typical toxic and hazardous pollutants, are called for new detection approaches to avoid laborious synthetic procedures and large and expensive instruments. Hence, a novel fluorescent probe was constructed for quantitative detection of OPFRs via heightening the fluorescence of acetylcholinesterase synthesized gold nanoclusters (AChE-AuNCs). The as-prepared AChE-AuNCs exhibited high fluorescence emission at about 398 nm with the average particle size of about 1.60 nm. When the AChE-AuNCs was applied to the proposed fluorescent detection, excellent sensitivity with wide linear range (50-1000 ng L) and low detection limit (30 ng L) for TClPP with the response time less than 1 h were achieved. The fluorescent probe could be extended to detect other three types of OPFRs (TEP, TPHP, and TBOEP) and the target pollutants could be detectable in the presence of halogenated flame retardants. The mechanism might be mainly contributed by the interaction between OPFRs and AChE-AuNCs restricting internal vibration consumption of their capping ligands. The proposed detection approach could be easily operated and was not involved with other intermediate products. Therefore, AChE-AuNCs could be a promising fluorescent probe for rapid, selective and sensitive detection of OPFRs and even in the practical application.
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http://dx.doi.org/10.1016/j.scitotenv.2019.136488DOI Listing
April 2020

Acylglycerol Kinase Maintains Metabolic State and Immune Responses of CD8 T Cells.

Cell Metab 2019 08 13;30(2):290-302.e5. Epub 2019 Jun 13.

Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China. Electronic address:

CD8 T cell expansions and functions rely on glycolysis, but the mechanisms underlying CD8 T cell glycolytic metabolism remain elusive. Here, we show that acylglycerol kinase (AGK) is required for the establishment and maintenance of CD8 T cell metabolic and functional fitness. AGK deficiency dampens CD8 T cell antitumor functions in vivo and perturbs CD8 T cell proliferation in vitro. Activation of phosphatidylinositol-3-OH kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling, which mediates elevated CD8 T cell glycolysis, is tightly dependent on AGK kinase activity. Mechanistically, T cell antigen receptor (TCR)- and CD28-stimulated recruitment of PTEN to the plasma membrane facilitates AGK-PTEN interaction and AGK-triggered PTEN phosphorylation, thereby restricting PTEN phosphatase activity in CD8 T cells. Collectively, these results demonstrate that AGK maintains CD8 T cell metabolic and functional state by restraining PTEN activity and highlight a critical role for AGK in CD8 T cell metabolic programming and effector function.
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http://dx.doi.org/10.1016/j.cmet.2019.05.016DOI Listing
August 2019

Metabolic control of regulatory T cell stability and function by TRAF3IP3 at the lysosome.

J Exp Med 2018 09 16;215(9):2463-2476. Epub 2018 Aug 16.

Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Metabolic programs are crucial for regulatory T (T reg) cell stability and function, but the underlying mechanisms that regulate T reg cell metabolism are elusive. Here, we report that lysosomal TRAF3IP3 acts as a pivotal regulator in the maintenance of T reg cell metabolic fitness. T reg-specific deletion of impairs T reg cell function, causing the development of inflammatory disorders and stronger antitumor T cell responses in mice. Excessive mechanistic target of rapamycin complex 1 (mTORC1)-mediated hyper-glycolytic metabolism is responsible for the instability of TRAF3IP3-deficient T reg cells. Mechanistically, TRAF3IP3 restricts mTORC1 signaling by recruiting the serine-threonine phosphatase catalytic subunit (PP2Ac) to the lysosome, thereby facilitating the interaction of PP2Ac with the mTORC1 component Raptor. Our results define TRAF3IP3 as a metabolic regulator in T reg cell stability and function and suggest a lysosome-specific mTORC1 signaling mechanism that regulates T reg cell metabolism.
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http://dx.doi.org/10.1084/jem.20180397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122976PMC
September 2018

Regulation of T cell immunity by cellular metabolism.

Front Med 2018 Aug 16;12(4):463-472. Epub 2018 Aug 16.

Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

T cells are an important adaptive immune response arm that mediates cell-mediated immunity. T cell metabolism plays a central role in T cell activation, proliferation, differentiation, and effector function. Specific metabolic programs are tightly controlled to mediate T cell immune responses, and alterations in T cell metabolism may result in many immunological disorders. In this review, we will summarize the main T cell metabolic pathways and the important factors participating in T cell metabolic programming during T cell homeostasis, differentiation, and function.
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http://dx.doi.org/10.1007/s11684-018-0668-2DOI Listing
August 2018

In vitro cellular behaviors and toxicity assays of small-sized fluorescent silicon nanoparticles.

Nanoscale 2017 Jun;9(22):7602-7611

Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu 215123, China.

Extensive investigations have been carried out for evaluating the toxicology of various nanomaterials (e.g., carbon- and metal-based nanomaterials), which offer invaluable information for assessing the feasibility of nanomaterial-based wide-ranging applications. In recent years, sufficient efforts have been made to develop fluorescent small-sized silicon nanoparticles (SiNPs) as a novel optical material simultaneously featuring strong fluorescence and ultrahigh photostability, providing high promise for a myriad of biological, biomedical and electronic applications. It is worth pointing out that, despite the non- or low-toxicity of silicon, sufficient and objective toxicology evaluation of SiNPs is urgently required at both the in vitro and in vivo levels. However, there currently exists scanty information about the intracellular behaviors of the SiNPs, particularly the underlying mechanism of entry into cells and intracellular fate. Herein, we present a report aimed at determining the uptake and intracellular transport of SiNPs of ca. 4 nm diameter. Taking advantage of the strong and stable fluorescent signals of SiNPs, we reveal that these small-sized SiNPs accumulate in the plasma membrane prior to internalization, and are further internalized predominantly by clathrin-mediated and caveolae-dependent endocytosis. After endocytosis, the SiNPs are localized in early endosomes within a short time (∼1 h), while in up to 24 h of incubation the SiNPs are mainly transported to lysosomes in a microtubule-dependent way; and interestingly, to a smaller extent are sorted to the Golgi apparatus. Moreover, we demonstrate that there are no toxic effects of SiNPs on the cell metabolic activity and integrity of the plasma membrane.
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http://dx.doi.org/10.1039/c7nr00530jDOI Listing
June 2017

USP19 suppresses cellular type I interferon signaling by targeting TRAF3 for deubiquitination.

Future Microbiol 2017 07 10;12:767-779. Epub 2017 Apr 10.

Department of Laboratory Medicine, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, PR China.

Aim: To investigate host factors that mediate the immune escape of enterovirus 71 (EV71) in the context of deubiquitinating enzymes.

Materials & Methods: Utilize PCR array to screen candidate genes that may be involved in EV71-induced cellular antiviral immune responses, and utilize protein mass spectrometry analysis to identify the functional targets of the candidate regulator.

Results: EV71 infection induces the upregulation of ubiquitin-specific protease 19 (USP19) gene expression, which negatively regulates cellular antiviral type I interferon signaling. Additionally, we identify that USP19 suppresses cellular type I interferon signaling by targeting tumor necrosis factor receptor-associated factor 3 (TRAF3) molecule and decreasing TRAF3 ubiquitination of K63-linkage.

Conclusion: This work suggests that USP19 is a previously unrecognized regulator employed by EV71 to evade host antiviral defenses.
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http://dx.doi.org/10.2217/fmb-2017-0006DOI Listing
July 2017

Design, synthesis, and evaluation of novel porcupine inhibitors featuring a fused 3-ring system based on the 'reversed' amide scaffold.

Bioorg Med Chem 2016 11 17;24(22):5861-5872. Epub 2016 Sep 17.

Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psychiatric-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, PR China. Electronic address:

The Wnt signaling pathway is an essential signal transduction pathway which leads to the regulation of cellular processes such as proliferation, differentiation and migration. Aberrant Wnt signaling is known to have an association with multiple cancers. Porcupine is an enzyme that catalyses the addition of palmitoleate to a serine residue in Wnt proteins, a process which is required for the secretion of Wnt proteins. Here we report the synthesis and structure-activity-relationship of the novel porcupine inhibitors based on a 'reversed' amide scaffold. The leading compound 53 was as potent as the clinical compound LGK974 in a cell based STF reporter gene assay. Compound 53 potently inhibited the secretion of Wnt3A, therefore was confirmed to be a porcupine inhibitor. Furthermore, compound 53 showed excellent chemical and plasma stabilities. However, the clearance of compound 53 in liver microsomal tests was moderate to high, and the solubility of compound 53 was suboptimal. Collective efforts toward further optimization of this novel tricyclic template to develop better porcupine inhibitors will be subsequently undertaken and reported in due course.
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http://dx.doi.org/10.1016/j.bmc.2016.09.041DOI Listing
November 2016

Aqueous synthesized quantum dots interfere with the NF-κB pathway and confer anti-tumor, anti-viral and anti-inflammatory effects.

Biomaterials 2016 11 31;108:187-96. Epub 2016 Aug 31.

Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou 215123, China. Electronic address:

The NF-κB pathway plays crucial roles in inflammatory responses and cell survival. Aberrant constitutive NF-κB activation is associated with various human diseases including cancer and inflammatory and auto-immune diseases. Consequently, it is highly desirable to develop new kinds of inhibitors, which are highly efficacious for blocking the NF-κB pathway. In this study, by using a typical kind of aqueous synthesized quantum dots (QDs), i.e., CdTe QDs, as a model, we for the first time demonstrated that the QDs could selectively affect the cellular nuclear factor-κB (NF-κB) signaling pathway, but do not affect the AKT or ERK pathways. Typically, the QDs efficiently inhibited the activation of IKKα and IKKβ, resulting in the suppression of both the canonical and the non-canonical NF-κB signaling pathways. Inhibition of NF-κB by QDs downregulates anti-apoptotic genes and promotes apoptosis in cancer cells. The QDs induced NF-κB inhibition and cytotoxicity could be blocked by N-acetylcysteine due to the reduced cellular uptake of QDs. Importantly, inhibition of NF-κB by QDs displayed promising effects against the viral replication and in vivo bacterial endotoxin-induced inflammatory responses. These data suggest the QDs as potent inhibitors of the NF-κB signaling pathway, both in vitro and in vivo. Our findings highlight the potential of using QDs in the development of anti-cancer, anti-viral, and anti-inflammatory approaches, and also facilitate better understanding of QDs-related cellular behavior under the molecular level.
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http://dx.doi.org/10.1016/j.biomaterials.2016.08.047DOI Listing
November 2016

Design, synthesis, and evaluation of potent Wnt signaling inhibitors featuring a fused 3-ring system.

Eur J Med Chem 2016 Jan 22;108:154-165. Epub 2015 Nov 22.

Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, PR China. Electronic address:

The Wnt signaling pathway is a critical developmental pathway which operates through control of cellular functions such as proliferation and differentiation. Aberrant Wnt signaling has been linked to the formation and metastasis of tumors. Porcupine, a member of the membrane-bound O-acyltransferase family of proteins, is an important component of the Wnt pathway. Porcupine catalyzes the palmitoylation of Wnt proteins, a process needed for their secretion and activity. Here we report a novel series of compounds obtained by a scaffold hybridization strategy from a known porcupine inhibitor class. The leading compound 59 demonstrated subnanomolar inhibition of Wnt signaling in a paracrine cellular assay. Compound 59 also showed excellent chemical, plasma and liver microsomal stabilities. Furthermore, compound 59 exhibited good pharmacokinetic profiles with 30% oral bioavailability in rat. Collectively, these results strongly support further optimization of this novel scaffold to develop better Wnt pathway inhibitors.
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http://dx.doi.org/10.1016/j.ejmech.2015.11.026DOI Listing
January 2016

Herpes Simplex Virus 1 (HSV-1) and HSV-2 Mediate Species-Specific Modulations of Programmed Necrosis through the Viral Ribonucleotide Reductase Large Subunit R1.

J Virol 2016 01 11;90(2):1088-95. Epub 2015 Nov 11.

Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, and Collaborative Innovation Center of Hematology and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China

Unlabelled: Receptor-interacting protein kinase 3 (RIP3) and its substrate mixed-lineage kinase domain-like protein (MLKL) are core regulators of programmed necrosis. The elimination of pathogen-infected cells by programmed necrosis acts as an important host defense mechanism. Here, we report that human herpes simplex virus 1 (HSV-1) and HSV-2 had opposite impacts on programmed necrosis in human cells versus their impacts in mouse cells. Similar to HSV-1, HSV-2 infection triggered programmed necrosis in mouse cells. However, neither HSV-1 nor HSV-2 infection was able to induce programmed necrosis in human cells. Moreover, HSV-1 or HSV-2 infection in human cells blocked tumor necrosis factor (TNF)-induced necrosis by preventing the induction of an RIP1/RIP3 necrosome. The HSV ribonucleotide reductase large subunit R1 was sufficient to suppress TNF-induced necrosis, and its RIP homotypic interaction motif (RHIM) domain was required to disrupt the RIP1/RIP3 complex in human cells. Therefore, this study provides evidence that HSV has likely evolved strategies to evade the host defense mechanism of programmed necrosis in human cells.

Importance: This study demonstrated that infection with HSV-1 and HSV-2 blocked TNF-induced necrosis in human cells while these viruses directly activated programmed necrosis in mouse cells. Expression of HSV R1 suppressed TNF-induced necrosis of human cells. The RHIM domain of R1 was essential for its association with human RIP3 and RIP1, leading to disruption of the RIP1/RIP3 complex. This study provides new insights into the species-specific modulation of programmed necrosis by HSV.
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http://dx.doi.org/10.1128/JVI.02446-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702709PMC
January 2016

Exploration of the linkage elements of porcupine antagonists led to potent Wnt signaling pathway inhibitors.

Bioorg Med Chem 2015 Nov 1;23(21):6855-68. Epub 2015 Oct 1.

Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, PR China. Electronic address:

The Wnt signaling pathway is a pivotal developmental pathway. It operates through control of cellular functions such as proliferation, differentiation, migration and polarity. Aberrant Wnt signaling has been implicated in the formation and metastasis of tumors. Porcupine is a component of the Wnt signaling pathway. It is a member of the membrane-bound O-acyltransferase family of proteins. Porcupine catalyzes the palmitoylation of Wnt proteins, a process which is essential to their secretion and activity. Here we report a novel series of compounds obtained by a scaffold hybridization strategy from two known porcupine inhibitor classes. The leading compound 62 demonstrated subnanomolar (IC50 0.11 nM) inhibition of Wnt signaling in a paracrine cellular reporter gene assay. Compound 62 also potently inhibited Wnt secretion into culture medium, an indication of direct inhibition of the porcupine protein. Furthermore, compound 62 showed excellent chemical, plasma and liver microsomal stabilities. Collectively, these results strongly support further optimization of this novel scaffold to develop better Wnt pathway inhibitors.
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http://dx.doi.org/10.1016/j.bmc.2015.09.048DOI Listing
November 2015

Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense.

Proc Natl Acad Sci U S A 2014 Oct 14;111(43):15438-43. Epub 2014 Oct 14.

Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China;

The receptor-interacting kinase-3 (RIP3) and its downstream substrate mixed lineage kinase domain-like protein (MLKL) have emerged as the key cellular components in programmed necrotic cell death. Receptors for the cytokines of tumor necrosis factor (TNF) family and Toll-like receptors (TLR) 3 and 4 are able to activate RIP3 through receptor-interacting kinase-1 and Toll/IL-1 receptor domain-containing adapter inducing IFN-β, respectively. This form of cell death has been implicated in the host-defense system. However, the molecular mechanisms that drive the activation of RIP3 by a variety of pathogens, other than the above-mentioned receptors, are largely unknown. Here, we report that human herpes simplex virus 1 (HSV-1) infection triggers RIP3-dependent necrosis. This process requires MLKL but is independent of TNF receptor, TLR3, cylindromatosis, and host RIP homotypic interaction motif-containing protein DNA-dependent activator of IFN regulatory factor. After HSV-1 infection, the viral ribonucleotide reductase large subunit (ICP6) interacts with RIP3. The formation of the ICP6-RIP3 complex requires the RHIM domains of both proteins. An HSV-1 ICP6 deletion mutant failed to cause effective necrosis of HSV-1-infected cells. Furthermore, ectopic expression of ICP6, but not RHIM mutant ICP6, directly activated RIP3/MLKL-mediated necrosis. Mice lacking RIP3 exhibited severely impaired control of HSV-1 replication and pathogenesis. Therefore, this study reveals a previously uncharacterized host antipathogen mechanism.
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http://dx.doi.org/10.1073/pnas.1412767111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4217423PMC
October 2014

A 2.5-mm diameter probe for photoacoustic and ultrasonic endoscopy.

Opt Express 2012 Oct;20(21):23944-53

Optical Imaging Laboratory, Department of Biomedical Engineering, Washington University in St. Louis, Campus Box 1097, One Brookings Drive, St. Louis, Missouri 63130, USA.

We have created a 2.5-mm outer diameter integrated photo-acoustic and ultrasonic mini-probe which can be inserted into a standard video endoscope's instrument channel. A small-diameter focused ultrasonic transducer made of PMN-PT provides adequate signal sensitivity, and enables miniaturization of the probe. Additionally, this new endoscopic probe utilizes the same scanning mirror and micromotor-based built-in actuator described in our previous reports; however, the length of the rigid distal section of the new probe has been further reduced to ~35 mm. This paper describes the technical details of the mini-probe and presents experimental results that both quantify the imaging performance and demonstrate its in vivo imaging capability, which suggests that it could work as a mini-probe for certain clinical applications.
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http://dx.doi.org/10.1364/OE.20.023944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601641PMC
October 2012

ADAM33 gene polymorphisms associate with asthma susceptibility and severity in East China han population.

J Asthma 2011 Dec 31;48(10):979-85. Epub 2011 Oct 31.

Department of Respiratory Medicine, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, PR China.

Objective: Multiple genetic and environmental factors impact the pathogenesis of asthma. ADAM33 (a disintegrin and metalloproteinase domain 33) represents a novel susceptibility gene for asthma in several diverse populations. The aim of this study was to determine whether single nucleotide polymorphisms (SNPs) of the ADAM33 gene associate with asthma susceptibility and severity in the Chinese Han population.

Methods: A total of 224 subjects were enrolled, including 74 normal controls and 150 asthmatic patients. The asthmatic enrollees were further categorized into high- or low-severity groups according to the percentage of forced expiratory volume in 1 second of predicted value, symptoms, nighttime awakening, requirement for short-acting β2-agonist, and interference with normal activities. Six SNPs (F + 1, ST + 4, S1, S2, T1, and T2) in ADAM33 were genotyped using the polymerase chain restriction fragment length polymorphism method.

Results: Three SNPs (F + 1, T1, and T2) of ADAM33 were found to have significant associations with asthma in the study population (p = .0058-.0067). The allele frequencies of two SNPs (F + 1, T1) in both the low- and high-severity groups were significantly different from the allele frequency in the control group. The allelic frequency of the T2 SNP was significantly different from that of the control group only in the high-severity group (p = .0081). Haplotype analysis demonstrated that the frequency of 7575G, 12433T, and 12462C (GTC haplotype) is higher in healthy controls than amongst asthma patients (78.4% vs. 61.8%, p = .0004).

Conclusions: Polymorphisms of the ADAM33 gene associate with asthma susceptibility in the east China Han population, and the genetic association is stronger in high-severity asthmatics.
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http://dx.doi.org/10.3109/02770903.2011.624233DOI Listing
December 2011

Method for optical coherence elastography of the cornea.

J Biomed Opt 2011 Jan-Feb;16(1):016005

Case Western Reserve University, Department of Biomedical Engineering, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.

The material properties of the cornea are important determinants of corneal shape and refractive power. Corneal ectatic diseases, such as keratoconus, are characterized by material property abnormalities, are associated with progressive thinning and distortion of the cornea, and represent a leading indication for corneal transplantation. We describe a corneal elastography technique based on optical coherence tomography (OCT) imaging, in which displacement of intracorneal optical features is tracked with a 2-D cross-correlation algorithm as a step toward nondestructive estimation of local and directional corneal material properties. Phantom experiments are performed to measure the effects of image noise and out-of-plane displacement on effectiveness of displacement tracking and demonstrated accuracy within the tolerance of a micromechanical translation stage. Tissue experiments demonstrate the ability to produce 2-D maps of heterogeneous intracorneal displacement with OCT. The ability of a nondestructive optical method to assess tissue under in situ mechanical conditions with physiologic-range stress levels provides a framework for in vivo quantification of 3-D corneal elastic and viscoelastic resistance, including analogs of shear deformation and Poisson's ratio that may be relevant in the early diagnosis of corneal ectatic disease.
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http://dx.doi.org/10.1117/1.3526701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3041813PMC
May 2011

Endoscopically guided spectral-domain OCT with double-balloon catheters.

Opt Express 2010 Aug;18(16):17364-72

Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.

Fourier-domain optical coherence tomography (OCT) and balloon-based catheters have furthered the potential of OCT as a real-time surveillance tool for Barrett's esophagus (BE). However, a balloon catheter, which expands the esophagus and centers the catheter, applies direct pressure on the esophagus. This may affect the tissue appearance and the ability to detect dysplasia in BE. To study this effect, we propose a double-balloon catheter to allow imaging with and without balloon-tissue contact. A system design based on a spectral-domain OCT platform is reported and validated by acquisition of high quality, volumetric images of swine esophagus in vivo.
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http://dx.doi.org/10.1364/OE.18.017364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408909PMC
August 2010

Automated quantification of colonic crypt morphology using integrated microscopy and optical coherence tomography.

J Biomed Opt 2008 Sep-Oct;13(5):054055

Case Western Reserve University, Department of Biomedical Engineering, Cleveland, Ohio 44106, USA.

Colonic crypt morphological patterns have shown a close correlation with histopathological diagnosis. Imaging technologies such as high-magnification chromoendoscopy and endoscopic optical coherence tomography (OCT) are capable of visualizing crypt morphology in vivo. We have imaged colonic tissue in vitro to simulate high-magnification chromoendoscopy and endoscopic OCT and demonstrate quantification of morphological features of colonic crypts using automated image analysis. 2-D microscopic images with methylene blue staining and correlated 3-D OCT volumes were segmented using marker-based watershed segmentation. 2-D and 3-D crypt morphological features were quantified. The accuracy of segmentation was validated, and measured features are in agreement with known crypt morphology. This work can enable studies to determine the clinical utility of high-magnification chromoendoscopy and endoscopic OCT, as well as studies to evaluate crypt morphology as a biomarker for colonic disease progression.
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http://dx.doi.org/10.1117/1.2993323DOI Listing
February 2009

Fourier domain optical coherence tomography with a linear-in-wavenumber spectrometer.

Opt Lett 2007 Dec;32(24):3525-7

1Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenve, Cleveland, Ohio 44106-7207, USA.

We describe Fourier domain optical coherence tomography equipped with a novel linear-in-wavenumber spectrometer. The presented device linearizes the spectral dispersion of the spectrometer in wavenumber using a specifically designed prism. The spectral linearity in wavenumber makes numerical interpolation into wavenumber unnecessary, reduces computing time, and furthermore results in improvement of the falloff of signal with image range inherent to frequency-domain optical coherence tomography imaging. Experiments demonstrate the improvement of the falloff and agree with the expected results from simulation.
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http://dx.doi.org/10.1364/ol.32.003525DOI Listing
December 2007

Analytical model of spectrometer-based two-beam spectral interferometry.

Appl Opt 2007 Dec;46(35):8499-505

Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland,OH 44106, USA.

We report an analytical model of signal formation in spectrometer-based two-beam spectral interferometry. Considering the pixel size, the optical resolution and the spectral resolution of the spectrometer, and dispersion, the model represents the signal recorded by a spectrometer based on a diffraction grating and linear detector array. The model is general, but degenerates to more familiar forms with simplifying assumptions. The model is validated by comparison with experimental measurements, where it is shown that the model can accurately predict both signal fall-off and axial resolution for Fourier-domain optical coherence tomography imaging. The model may be useful for determining design specifications and expected performance parameters for spectrometers for spectral interferometry.
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http://dx.doi.org/10.1364/ao.46.008499DOI Listing
December 2007

Theory of two beam interference with arbitrary spectra.

Opt Express 2006 Dec;14(26):12751-9

A new formulation describing the interference term of a two beam interferometer with unequal Gaussian spectra propagating in different dispersive media is provided by defining a composite standard deviation and a composite center frequency of the interfering spectra. This formulation is generalized to arbitrary spectra by decomposing each spectrum into a linear composition of Gaussian distributions. The effective phase and group delays indicate the effect of the unequal spectral distributions and the dispersive media. An effective coherence length is derived, different than the coherence lengths of the interfering fields. The accuracy of the new formulation is proven experimentally by using optical coherence tomography systems.
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http://dx.doi.org/10.1364/oe.14.012751DOI Listing
December 2006

Quasi-telecentric optical design of a microscope-compatible OCT scanner.

Opt Express 2005 Aug;13(17):6407-15

We report an optical coherence tomography (OCT) scanner design with optimized quasi-telecentric optics. This scanner achieves a uniform, Gaussian spot size of 15microm (1/e(2) diameter) over a range of 4.4mm in two orthogonal transverse scan dimensions. Model simulation using optical design software agrees with measurements by beam analyzer. We provide a reasonable design criterion of 0.05 (the ratio of the half separation of two orthogonal scanning mirrors to the front focal length of the optics that follow) for the quasi-telecentric scanner which corresponds to a spotsize and spot ellipticity variation of only 4% over the transverse scan range. Furthermore, this OCT scanner accommodates a microscope to precisely guide and document OCT imaging of small samples. OCT images of in-vivo human skin, human nail fold, and embryonic hearts (avian stage 22 and stage 28) demonstrate the image quality achieved with the scanner. The results indicate that optimizing the sample scanner optical design is important for optimizing OCT image quality.
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http://dx.doi.org/10.1364/opex.13.006407DOI Listing
August 2005
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