Publications by authors named "Lai Wang"

263 Publications

Peptidylarginine Deiminase and Alzheimer's Disease.

J Alzheimers Dis 2021 Nov 23. Epub 2021 Nov 23.

Epigenetics & Translational Medicine Laboratory, School of Life Sciences, Henan University, Kaifeng, Henan Province, P.R. China.

Peptidylarginine deiminases (PADs) are indispensable enzymes for post-translational modification of proteins, which can convert Arg residues on the surface of proteins to citrulline residues. The PAD family has five isozymes, PAD1, 2, 3, 4, and 6, which have been found in multiple tissues and organs. PAD2 and PAD4 were detected in cerebral cortex and hippocampus from human and rodent brain. In the central nervous system, abnormal expression and activation of PADs are involved in the pathological changes and pathogenesis of Alzheimer's disease (AD). This article reviews the classification, distribution, and function of PADs, with an emphasis on the relationship between the abnormal activation of PADs and AD pathogenesis, diagnosis, and the therapeutic potential of PADs as drug targets for AD.
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http://dx.doi.org/10.3233/JAD-215302DOI Listing
November 2021

miR122-controlled all-in-one nanoplatform for theranostic of drug-induced liver injury by visualization imaging guided on-demand drug release.

Mater Today Bio 2021 Sep 12;12:100157. Epub 2021 Nov 12.

State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing, 210009, China.

Drug-induced liver injury (DILI) is a challenging clinical problem with respect to both diagnosis and management. As a newly emerging biomarker of liver injury, miR122 shows great potential in early and sensitive detection of DILI. Glycyrrhetinic acid (GA) possesses desirable therapeutic effect on DILI, but its certain dose-dependent side effects after long-term and/or high-dose administration limit its clinical application. In this study, in order to improve the precise diagnosis and effective treatment of DILI, GA loaded all-in-one theranostic nanoplatform was designed by assembling of upconversion nanoparticles and gold nanocages. As a proof of concept, we demonstrated the applicability of this single-wavelength laser-triggered theranostic nanoplatform for the spatiotemporally controllable imaging of DILI and miR122-controlled on-demand drug release and . This novel nanoplatform opens a promising avenue for the clinical diagnosis and treatment of DILI.
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http://dx.doi.org/10.1016/j.mtbio.2021.100157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8604687PMC
September 2021

Encapsulation-Enabled Perovskite-PMMA Films Combining a Micro-LED for High-Speed White-Light Communication.

ACS Appl Mater Interfaces 2021 Nov 8;13(45):54143-54151. Epub 2021 Nov 8.

Tsinghua Shenzhen International Graduate School and Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen 518055, China.

Cesium lead halide perovskite nanocrystals have recently become emerging materials for color conversion in visible light communication (VLC) and solid-state lighting (SSL), due to their fast response and desirable optical properties. Herein, perovskite nanocrystal-polymethyl methacrylate (PNC-PMMA) films with red and yellow emission are prepared. The PNC-PMMA films, with optical properties such as a short lifetime and air stability, are used to make broadband color converters based on a high-bandwidth 75 μm blue micro-LED (μLED) for VLC. The yellow-emitting CsPb(Br/I) PNC-PMMA has a high bandwidth of 347 MHz, while the red-emitting CsPbI PNC-PMMA exhibits a higher modulation bandwidth of 822 MHz, which is ∼65 times larger than that of conventional phosphors. After fixing the two PNC-PMMA films in front of the μLED, a qualified warm white light is generated with a correlated color temperature of 5670 K, a color rendering index of 75.7, and a de L'Eclairage (CIE) coordinate at (0.33, 0.35). Although the color conversion of the blue light sacrifices some received power and slightly reduces the overall bandwidth from 1.130 to 1.005 GHz, a maximum real-time data rate of 1.7 Gbps is still achievable using the non-return-to-zero on-off keying modulation scheme, which is ∼6 times higher than that of the previous record. This study provides a practical approach to develop a considerably high-bandwidth white-light system for both high-speed VLC and high-quality SSL.
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http://dx.doi.org/10.1021/acsami.1c15873DOI Listing
November 2021

In vitro investigations into the roles of CYP450 enzymes and drug transporters in the drug interactions of zanubrutinib, a covalent Bruton's tyrosine kinase inhibitor.

Pharmacol Res Perspect 2021 12;9(6):e00870

BeiGene USA, Inc., San Mateo, CA, USA.

Zanubrutinib is a highly selective, potent, orally available, targeted covalent inhibitor (TCI) of Bruton's tyrosine kinase (BTK). This work investigated the in vitro drug metabolism and transport of zanubrutinib, and its potential for clinical drug-drug interactions (DDIs). Phenotyping studies indicated cytochrome P450 (CYP) 3A are the major CYP isoform responsible for zanubrutinib metabolism, which was confirmed by a clinical DDI study with itraconazole and rifampin. Zanubrutinib showed mild reversible inhibition with half maximal inhibitory concentration (IC ) of 4.03, 5.69, and 7.80 μM for CYP2C8, CYP2C9, and CYP2C19, respectively. Data in human hepatocytes disclosed induction potential for CYP3A4, CYP2B6, and CYP2C enzymes. Transport assays demonstrated that zanubrutinib is not a substrate of human breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP)1B1/1B3, organic cation transporter (OCT)2, or organic anion transporter (OAT)1/3 but is a potential substrate of the efflux transporter P-glycoprotein (P-gp). Additionally, zanubrutinib is neither an inhibitor of P-gp at concentrations up to 10.0 μM nor an inhibitor of BCRP, OATP1B1, OATP1B3, OAT1, and OAT3 at concentrations up to 5.0 μM. The in vitro results with CYPs and transporters were correlated with the available clinical DDIs using basic models and mechanistic static models. Zanubrutinib is not likely to be involved in transporter-mediated DDIs. CYP3A inhibitors and inducers may impact systemic exposure of zanubrutinib. Dose adjustments may be warranted depending on the potency of CYP3A modulators.
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http://dx.doi.org/10.1002/prp2.870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524670PMC
December 2021

14,15-EET Reduced Brain Injury from Cerebral Ischemia and Reperfusion via Suppressing Neuronal Parthanatos.

Int J Mol Sci 2021 Sep 7;22(18). Epub 2021 Sep 7.

School of Life Sciences, Henan University, Kaifeng 475000, China.

To investigate the effect of 14,15-EET on the parthanatos in neurons induced by cerebral ischemia and reperfusion, middle cerebral artery occlusion and reperfusion (MCAO/R) and oxygen glucose deprivation/reoxygenation (OGD/R) were used to simulate cerebral ischemia reperfusion in vivo and in vitro, respectively. TTC staining and the Tunel method were used to detect cerebral infarct volume and neuronal apoptosis. Western blot and immunofluorescence were used to detect poly (ADP-ribose) polymerase-1 (PARP-1) activation and AIF nuclear translocation. The production of reactive oxygen species (ROS) and the expression of antioxidant genes were detected by Mito SOX, DCFH-DA and qPCR methods. MCAO/R increased cerebral infarct volume and neuronal apoptosis in mice, while 14,15-EET pretreatment increased cerebral infarct volume and neuronal apoptosis. OGD/R induced reactive oxygen species generation, PARP-1 cleavage, and AIF nuclear translocation in cortical neurons. 14,15-EET pretreatment could enhance the antioxidant gene expression of glutathione peroxidase (GSH-Px), heme oxygenase-1 (HO-1) and superoxide dismutase (SOD) in cortical neurons after ischemia and reperfusion. 14,15-EET inhibits the neuronal parthanatos induced by MCAO/R through upregulation of the expression of antioxidant genes and by reducing the generation of reactive oxygen species. This study advances the EET neuroprotection theory and provides a scientific basis for targeted clinical drugs that reduce neuronal parthanatos following cerebral ischemia and reperfusion.
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http://dx.doi.org/10.3390/ijms22189660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471287PMC
September 2021

8.75  Gbps visible light communication link using an artificial neural network equalizer and a single-pixel blue micro-LED.

Opt Lett 2021 Sep;46(18):4670-4673

Visible light communication (VLC) beyond 10 Gbps is an important characteristic that can support the future 6 G high-capacity requirements. On the one hand, in order to break the electro-optics (E-O) bandwidth limitation of the light-emitting diodes (LEDs), we fabricated two high-bandwidth (>) single wetting layer micro-LEDs with 50 and 75 µm active regions. On the other hand, for mitigating the nonlinear effects of the VLC system, an artificial neural network equalizer is designed and implemented in offline digital signal processing. Both efforts lead to a breakthrough of data rates at a single VLC link. Using quadrature phase shift keying orthogonal frequency division multiplexing, the data rate of a 1.025 GHz VLC link based on a 75 µm micro-LED can reach 8.75 Gbps with a bit-error-ratio (BER) of 2.73×10. In addition, the E-O characteristics and communication performances of micro-LED with two diameters are compared and discussed. To the best of our knowledge, the data rate of 8.75 Gbps is the highest record of the VLC link based on a single-pixel blue micro-LED with a BER within the forward error correction citation of 3.8×10.
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http://dx.doi.org/10.1364/OL.437632DOI Listing
September 2021

Insulin/IGF-1 signaling and heat stress differentially regulate HSF1 activities in germline development.

Cell Rep 2021 Aug;36(9):109623

Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA. Electronic address:

Germline development is sensitive to nutrient availability and environmental perturbation. Heat shock transcription factor 1 (HSF1), a key transcription factor driving the cellular heat shock response (HSR), is also involved in gametogenesis. The precise function of HSF1 (HSF-1 in C. elegans) and its regulation in germline development are poorly understood. Using the auxin-inducible degron system in C. elegans, we uncovered a role of HSF-1 in progenitor cell proliferation and early meiosis and identified a compact but important transcriptional program of HSF-1 in germline development. Interestingly, heat stress only induces the canonical HSR in a subset of germ cells but impairs HSF-1 binding at its developmental targets. Conversely, insulin/insulin growth factor 1 (IGF-1) signaling dictates the requirement for HSF-1 in germline development and functions through repressing FOXO/DAF-16 in the soma to activate HSF-1 in germ cells. We propose that this non-cell-autonomous mechanism couples nutrient-sensing insulin/IGF-1 signaling to HSF-1 activation to support homeostasis in rapid germline growth.
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http://dx.doi.org/10.1016/j.celrep.2021.109623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442575PMC
August 2021

A Phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of CXD101 in patients with advanced solid-organ cancer expressing HR23B or lymphoma.

BMC Cancer 2021 Jul 23;21(1):851. Epub 2021 Jul 23.

Department of Haematology, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals, Oxford, UK.

Background: This Phase 2a dose expansion study was performed to assess the safety, tolerability and preliminary efficacy of the maximum tolerated dose of the oral histone de-acetylase (HDAC) inhibitor CXD101 in patients with relapsed / refractory lymphoma or advanced solid organ cancers and to assess HR23B protein expression by immunohistochemistry as a biomarker of HDAC inhibitor sensitivity.

Methods: Patients with advanced solid-organ cancers with high HR23B expression or lymphomas received CXD101 at the recommended phase 2 dose (RP2D). Key exclusions: corrected QT > 450 ms, neutrophils < 1.5 × 10/L, platelets < 75 × 10/L, ECOG > 1. Baseline HR23B expression was assessed by immunohistochemistry.

Results: Fifty-one patients enrolled between March 2014 and September 2019, 47 received CXD101 (19 solid-organ cancer, 28 lymphoma). Thirty-four patients received ≥80% RP2D. Baseline characteristics: median age 57.4 years, median prior lines 3, male sex 57%. The most common grade 3-4 adverse events were neutropenia (32%), thrombocytopenia (17%), anaemia (13%), and fatigue (9%) with no deaths on CXD101. No responses were seen in solid-organ cancers, with disease stabilisation in 36% or patients; the overall response rate in lymphoma was 17% with disease stabilisation in 52% of patients. Median progression-free survival was 1.2 months (95% confidence interval (CI) 1.2-5.4) in solid-organ cancers and 2.6 months (95%CI 1.2-5.6) in lymphomas. HR23B status did not predict response.

Conclusions: CXD101 showed acceptable tolerability with efficacy seen in Hodgkin lymphoma, T-cell lymphoma and follicular lymphoma. Further studies assessing combination approaches are warranted.

Trial Registration: ClinicalTrials.gov identifier NCT01977638 . Registered 07 November 2013.
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http://dx.doi.org/10.1186/s12885-021-08595-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306282PMC
July 2021

Autoimmune hepatitis following COVID-19 vaccination: True causality or mere association?

J Hepatol 2021 11 18;75(5):1250-1252. Epub 2021 Jun 18.

Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore; Medicine Academic Clinical Programme, SingHealth Duke-NUS Academic Medical Centre, Singapore. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2021.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404983PMC
November 2021

A Traditional Chinese Medicine Traceability System Based on Lightweight Blockchain.

J Med Internet Res 2021 06 21;23(6):e25946. Epub 2021 Jun 21.

School of Medical Information Engineering, Guangzhou University of Chinese Medicine, Guangzhou, China.

Background: Recently, the problem of traditional Chinese medicine (TCM) safety has attracted attention worldwide. To prevent the spread of counterfeit drugs, it is necessary to establish a drug traceability system. A traditional drug traceability system can record the whole circulation process of drugs, from planting, production, processing, and warehousing to use by hospitals and patients. Once counterfeit drugs are found, they can be traced back to the source. However, traditional drug traceability systems have some drawbacks, such as failure to prevent tampering and facilitation of sensitive disclosure. Blockchain (including Bitcoin and Ethernet Square) is an effective technology to address the problems of traditional drug traceability systems. However, some risks impact the reliability of blockchain, such as information explosion, sensitive information leakage, and poor scalability.

Objective: To avoid the risks associated with the application of blockchain, we propose a lightweight block chain framework.

Methods: In this framework, both horizontal and vertical segmentations are performed when designing the blocks, and effective strategies are provided for both segmentations. For horizontal segmentation operations, the header and body of the blockchain are separated and stored in the blockchain, and the body is stored in the InterPlanetary File System. For vertical segmentation operations, the blockchain is cut off according to time or size. For the addition of new blocks, miners only need to copy the latest part of the blockchain and append the tail and vertical segmentation of the block through the consensus mechanism.

Results: Our framework could greatly reduce the size of the blockchain and improve the verification efficiency.

Conclusions: Experimental results have shown that the efficiency improves compared with ethernet when a new block is added to the blockchain and a search is conducted.
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http://dx.doi.org/10.2196/25946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277409PMC
June 2021

Experimental investigation of 16.6 Gbps SDM-WDM visible light communication based on a neural network receiver and tricolor mini-LEDs.

Opt Lett 2021 Jun;46(12):2888-2891

Visible light communication (VLC) based on a light-emitting diode (LED) suffers from a limited bandwidth of commercial LED, device nonlinearity, channel distortion, and transmitted power caused by a complex free-space channel, power amplifier, and illuminant devices resulting in a limited data rate. In this Letter, to provide an alternative high-speed solution, we first designed and fabricated three 175 µm tricolor mini-LEDs with various wavelengths. They are used to set up a spatial division multiplexing-wavelength division multiplexing VLC system over a 2 m link. Then we utilize a neural network receiver to replace the traditional channel estimation, equalization, and demodulation at the offline digital signal processing of the receiver. The experiment showed that the data rates of 2.65, 7, and 7 Gbps were achieved in three respective links using quadrature phase shift keying-optical orthogonal frequency division multiplexing. The three data rates have bit-error rates below the forward error correction limit, whose data rate sum of 16.6 Gbps is the highest mini/micro-LED-based VLC, to the best of our knowledge.
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http://dx.doi.org/10.1364/OL.428013DOI Listing
June 2021

Evaluation of the Absorption, Metabolism, and Excretion of a Single Oral 1-mg Dose of Tropifexor in Healthy Male Subjects and the Concentration Dependence of Tropifexor Metabolism.

Drug Metab Dispos 2021 07 5;49(7):548-562. Epub 2021 May 5.

Novartis Institute for BioMedical Research, East Hanover, New Jersey (L.W.-L., Z.M., L.W., H.G., M.K., H.J.E., J.C.); Novartis Institute for BioMedical Research, Cambridge, Massachusetts (J.G., E.M.); and Novartis Institute for BioMedical Research, Basel, Switzerland (M.W., R.W., G.C.).

Tropifexor (NVP-LJN452) is a highly potent, selective, nonsteroidal, non-bile acid farnesoid X receptor agonist for the treatment of nonalcoholic steatohepatitis. Its absorption, metabolism, and excretion were studied after a 1-mg oral dose of [C]tropifexor was given to four healthy male subjects. Mass balance was achieved with ∼94% of the administered dose recovered in excreta through a 312-hour collection period. Fecal excretion of tropifexor-related radioactivity played a major role (∼65% of the total dose). Tropifexor reached a maximum blood concentration (C) of 33.5 ng/ml with a median time to reach C of 4 hours and was eliminated with a plasma elimination half-life of 13.5 hours. Unchanged tropifexor was the principal drug-related component found in plasma (∼92% of total radioactivity). Two minor oxidative metabolites, M11.6 and M22.4, were observed in circulation. Tropifexor was eliminated predominantly via metabolism with >68% of the dose recovered as metabolites in excreta. Oxidative metabolism appeared to be the major clearance pathway of tropifexor. Metabolites containing multiple oxidative modifications and combined oxidation and glucuronidation were also observed in human excreta. The involvement of direct glucuronidation could not be ruled out based on previous in vitro and nonclinical in vivo studies indicating its contribution to tropifexor clearance. The relative contribution of the oxidation and glucuronidation pathways appeared to be dose-dependent upon further in vitro investigation. Because of these complexities and the instability of glucuronide metabolites in the gastrointestinal tract, the contribution of glucuronidation remained undefined in this study. SIGNIFICANCE STATEMENT: Tropifexor was found to be primarily cleared from the human body via oxidative metabolism. In vitro metabolism experiments revealed that the relative contribution of oxidation and glucuronidation was concentration-dependent, with glucuronidation as the predominant pathway at higher concentrations and the oxidative process becoming more important at lower concentrations near clinical exposure range. The body of work demonstrated the importance of carefully designed in vivo and in vitro experiments for better understanding of disposition processes during drug development.
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http://dx.doi.org/10.1124/dmd.120.000349DOI Listing
July 2021

Clinical Features and Predictors of Dysplasia in Proximal Sessile Serrated Lesions.

Clin Endosc 2021 Jul 29;54(4):578-588. Epub 2021 Apr 29.

Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore, Singapore.

Background/aims: Proximal colorectal cancers (CRCs) account for up to half of CRCs. Sessile serrated lesions (SSLs) are precursors to CRC. Proximal location and presence of dysplasia in SSLs predict higher risks of progression to cancer. The prevalence of dysplasia in proximal SSLs (pSSLs) and clinical characteristics of dysplastic pSSLs are not well studied.

Methods: Endoscopically resected colonic polyps at our center between January 2016 and December 2017 were screened for pSSLs. Data of patients with at least one pSSL were retrieved and clinicopathological features of pSSLs were analysed. pSSLs with and without dysplasia were compared for associations.

Results: Ninety pSSLs were identified, 45 of which had dysplasia giving a prevalence of 50.0%. Older age (65.9 years vs. 60.1 years, p=0.034) was associated with the presence of dysplasia. Twelve pSSLs were 10 mm or larger. After adjusting for age, pSSLs ≥10 mm had an adjusted odds ratio of 5.98 (95% confidence interval, 1.21-29.6) of having dysplasia compared with smaller pSSLs.

Conclusion: In our cohort of pSSLs, the prevalence of dysplasia is high at 50.0% and is associated with lesion size ≥10 mm. Endoscopic resection for all proximal serrated lesions should be en-bloc to facilitate accurate histopathological examination for dysplasia as its presence warrants shorter surveillance intervals.
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http://dx.doi.org/10.5946/ce.2020.198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357591PMC
July 2021

Transfer-printed, tandem microscale light-emitting diodes for full-color displays.

Proc Natl Acad Sci U S A 2021 May;118(18)

Department of Electronic Engineering, Beijing National Research Center for Information Science and Technology, Center for Flexible Electronics Technology, Tsinghua University, 100084 Beijing, China;

Inorganic semiconductor-based microscale light-emitting diodes (micro-LEDs) have been widely considered the key solution to next-generation, ubiquitous lighting and display systems, with their efficiency, brightness, contrast, stability, and dynamic response superior to liquid crystal or organic-based counterparts. However, the reduction of micro-LED sizes leads to the deteriorated device performance and increased difficulties in manufacturing. Here, we report a tandem device scheme based on stacked red, green, and blue (RGB) micro-LEDs, for the realization of full-color lighting and displays. Thin-film micro-LEDs (size ∼100 μm, thickness ∼5 μm) based on III-V compound semiconductors are vertically assembled via epitaxial liftoff and transfer printing. A thin-film dielectric-based optical filter serves as a wavelength-selective interface for performance enhancement. Furthermore, we prototype arrays of tandem RGB micro-LEDs and demonstrate display capabilities. These materials and device strategies provide a viable path to advanced lighting and display systems.
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http://dx.doi.org/10.1073/pnas.2023436118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106345PMC
May 2021

Kaempferol induces ROS-dependent apoptosis in pancreatic cancer cells via TGM2-mediated Akt/mTOR signaling.

BMC Cancer 2021 Apr 12;21(1):396. Epub 2021 Apr 12.

Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China.

Background: Kaempferol, a natural flavonoid, exhibits anticancer properties by scavenging reactive oxygen species (ROS). However, increasing evidence has demonstrated that, under certain conditions, kaempferol can inhibit tumor growth by upregulating ROS levels. In this study, we aimed to investigate whether kaempferol effectively suppresses pancreatic cancer through upregulation of ROS, and to explore the underlying molecular mechanism.

Methods: PANC-1 and Mia PaCa-2 cells were exposed to different concentrations of kaempferol. Cell proliferation and colony formation were evaluated by CCK-8 and colony formation assays. Flow cytometry was performed to assess the ROS levels and cell apoptosis. The mRNA sequencing and KEGG enrichment analysis were performed to identify differentially expressed genes and to reveal significantly enriched signaling pathways in response to kaempferol treatment. Based on biological analysis, we hypothesized that tissue transglutaminase (TGM2) gene was an essential target for kaempferol to induce ROS-related apoptosis in pancreatic cancer. TGM2 was overexpressed by lentivirus vector to verify the effect of TGM2 on the ROS-associated apoptotic signaling pathway. Western blot and qRT-PCR were used to determine the protein and mRNA levels, respectively. The prognostic value of TGM2 was analyzed by Gene Expression Profiling Interactive Analysis (GEPIA) tools based on public data from the TCGA database.

Results: Kaempferol effectively suppressed pancreatic cancer in vitro and in vivo. Kaempferol promoted apoptosis in vitro by increasing ROS generation, which was involved in Akt/mTOR signaling. TGM2 levels were significantly increased in PDAC tissues compared with normal tissues, and high TGM2 expression was positively correlated with poor prognosis in pancreatic cancer patients. Decreased TGM2 mRNA and protein levels were observed in the cells after treatment with kaempferol. Additionally, TGM2 overexpression downregulated ROS production and inhibited the abovementioned apoptotic signaling pathway.

Conclusions: Kaempferol induces ROS-dependent apoptosis in pancreatic cancer cells via TGM2-mediated Akt/mTOR signaling, and TGM2 may represent a promising prognostic biomarker for pancreatic cancer.
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http://dx.doi.org/10.1186/s12885-021-08158-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042867PMC
April 2021

Bone Morphogenetic Protein Pathway Antagonism by Grem1 Regulates Epithelial Cell Fate in Intestinal Regeneration.

Gastroenterology 2021 07 2;161(1):239-254.e9. Epub 2021 Apr 2.

Intestinal Stem Cell Biology Lab, Wellcome Centre Human Genetics, University of Oxford, Oxford, United Kingdom; Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, and Oxford National Institute for Health Research Biomedical Research Centre, Oxford, United Kingdom. Electronic address:

Background & Aims: In homeostasis, intestinal cell fate is controlled by balanced gradients of morphogen signaling. The bone morphogenetic protein (BMP) pathway has a physiological, prodifferentiation role, predominantly inferred through previous experimental pathway inactivation. Intestinal regeneration is underpinned by dedifferentiation and cell plasticity, but the signaling pathways that regulate this adaptive reprogramming are not well understood. We assessed the BMP signaling landscape and investigated the impact and therapeutic potential of pathway manipulation in homeostasis and regeneration.

Methods: A novel mouse model was generated to assess the effect of the autocrine Bmp4 ligand on individual secretory cell fate. We spatiotemporally mapped BMP signaling in mouse and human regenerating intestine. Transgenic models were used to explore the functional impact of pathway manipulation on stem cell fate and intestinal regeneration.

Results: In homeostasis, ligand exposure reduced proliferation, expedited terminal differentiation, abrogated secretory cell survival, and prevented dedifferentiation. After ulceration, physiological attenuation of BMP signaling arose through upregulation of the secreted antagonist Grem1 from topographically distinct populations of fibroblasts. Concomitant expression supported functional compensation after Grem1 deletion from tissue-resident cells. BMP pathway manipulation showed that antagonist-mediated BMP attenuation was obligatory but functionally submaximal, because regeneration was impaired or enhanced by epithelial overexpression of Bmp4 or Grem1, respectively. Mechanistically, Bmp4 abrogated regenerative stem cell reprogramming despite a convergent impact of YAP/TAZ on cell fate in remodeled wounds.

Conclusions: BMP signaling prevents epithelial dedifferentiation, and pathway attenuation through stromal Grem1 upregulation was required for adaptive reprogramming in intestinal regeneration. This intercompartmental antagonism was functionally submaximal, raising the possibility of therapeutic pathway manipulation in inflammatory bowel disease.
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http://dx.doi.org/10.1053/j.gastro.2021.03.052DOI Listing
July 2021

A prospective randomized tandem gastroscopy pilot study of linked color imaging versus white light imaging for detection of upper gastrointestinal lesions.

J Gastroenterol Hepatol 2021 Sep 12;36(9):2562-2567. Epub 2021 Apr 12.

Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore.

Background And Aim: Gastrointestinal (GI) lesions may have subtle morphological changes. Linked color imaging (LCI) combines narrow-band wavelength light and white light imaging (WLI) in appropriate balance to enhance lesion detection. We compared the detection rates of upper GI lesions using LCI and WLI.

Method: Patients were randomized in a 1:1 ratio to receive tandem gastroscopy with WLI inspection followed by LCI, or vice versa. Endoscopic examination was performed using the EG-L590ZW gastroscope and the LASEREO endoscope system (Fujifilm Co., Tokyo, Japan). Histology was reported by a specialist GI pathologist blinded to the technique of lesion detection and was used as the gold standard for diagnosis.

Results: Ninety patients (mean age 66.8 years, 51.5% male patients) were randomized to either LCI examination first followed by WLI (LCI-WLI), or vice versa (WLI-LCI). An 18.9% of gastroscopies in the study were for surveillance of previously known gastric cancer precursors. Ten patients (11.1%) had a history of Helicobacter pylori infection. There was no significant difference in the time taken for examination under LCI (311 ± 96 s) and WLI (342 ± 86 s) (P = 0.700). LCI detection rates were higher than WLI detection rates for gastric cancer precursors such as atrophic gastritis (2.19% vs 0.55%) (P < 0.01) and intestinal metaplasia (19.73% vs 7.67%) (P < 0.01). Both sensitivity (82.74% vs 50.96%) and specificity (98.71% vs 96.10%) of LCI were higher than WLI for detection of upper GI lesions.

Conclusions: Linked color imaging had better detection rates, sensitivity, and specificity for detection of upper GI lesions compared with WLI.
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http://dx.doi.org/10.1111/jgh.15515DOI Listing
September 2021

Full-duplex high-speed indoor optical wireless communication system based on a micro-LED and VCSEL array.

Opt Express 2021 Feb;29(3):3891-3903

We built a full-duplex high-speed optical wireless communication (OWC) system based on high-bandwidth micro-size devices, for which micro-LED and VCSEL arrays are implemented to establish downlink and uplink, respectively. The high-capacity downlink based on a single-pixel quantum dot (QD) micro-LED can reach a data rate of 2.74 Gbps with adaptive orthogonal frequency division multiplexing (OFDM). VCSEL-based line-of-sight (LOS) and non-line-of-sight (NLOS) uplinks are designed with lens-free receiving functions for a 2.2-m communication distance. Experimental results have been demonstrated and confirmed that both downlink and uplinks are capable of providing sufficient bandwidth for a multi-gigabit OWC. Besides, the lens-free uplink receiver can alleviate requirements for aligning and improve the mobility of the transmitter. The VCSELs implemented for both systems work with low driving currents of 140-mA and 190-mA under consideration of the human eye safety. For non-return-to-zero on-off keying (NRZ-OOK), both uplinks can achieve 2.125 Gbps with bit-error-rate (BER) lower than the forward error correction (FEC) threshold of 3.8×10 for Ethernet access.
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http://dx.doi.org/10.1364/OE.412348DOI Listing
February 2021

A single-chip multi-beam steering optical phased array: design rules and simulations.

Opt Express 2021 Mar;29(5):7049-7059

A waveguide-based multi-beam steering device is proposed for light detection and ranging (LIDAR). The device integrates binary gratings with an optical phased array (OPA), thus enabling a single-chip LIDAR system. The device can provide an N×M beam array that covers a wide angular range while phase shifters help realize steering over a narrow angle range between the beams. The antenna structure for 1D beam splitting is realized by combining the design of a grating coupler and a beam splitter grating, and a uniform beam splitting is achieved along the other dimension using non-uniformly distributed antennas. To illustrate the design, an OPA with an 11×11 beam array is designed at a wavelength of 905 nm. The OPA achieves a wide total field of view (FOV) of 68.8° × 77° with a narrow beam-array-steering angle of 6.5°, enabling a wide-FOV 3D sensing with a high frame rate.
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http://dx.doi.org/10.1364/OE.417821DOI Listing
March 2021

The Histone Modifications of Neuronal Plasticity.

Neural Plast 2021 11;2021:6690523. Epub 2021 Feb 11.

Institute of Chronic Disease Risks Assessment, School of Nursing and Health Sciences, Henan University, Kaifeng, 475004 Henan Province, China.

Nucleosomes composed of histone octamer and DNA are the basic structural unit in the eukaryote chromosome. Under the stimulation of various factors, histones will undergo posttranslational modifications such as methylation, phosphorylation, acetylation, and ubiquitination, which change the three-dimensional structure of chromosomes and affect gene expression. Therefore, the combination of different states of histone modifications modulates gene expression is called histone code. The formation of learning and memory is one of the most important mechanisms for animals to adapt to environmental changes. A large number of studies have shown that histone codes are involved in the formation and consolidation of learning and memory. Here, we review the most recent literature of histone modification in regulating neurogenesis, dendritic spine dynamic, synapse formation, and synaptic plasticity.
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http://dx.doi.org/10.1155/2021/6690523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892255PMC
November 2021

The evolving role of EUS-guided tissue acquisition.

J Dig Dis 2021 Apr 11;22(4):204-213. Epub 2021 Mar 11.

Department of Laboratory Medicine, Section of Pathology, Changi General Hospital; Pathology Academic Clinical Programme, SingHealth Duke-NUS Academic Medical Centre, Singapore.

The introduction of endoscopic ultrasound-guided fine-needle aspiration into clinical practice was a pivotal moment for diagnostic gastrointestinal endoscopy. It facilitates the ease of tissue acquisition from previously inaccessible sites. The performance characteristics of cytological diagnosis are excellent. However, there remain areas of inadequacies. These include procedural inefficiencies such as the need for rapid on-site cytological evaluation or macroscopic on-site evaluation, the crucial role of histology for diagnosis in specific conditions, the issue of sampling errors and the need for repeat procedures, and the shift towards personalized medicine, which requires histology, immunohistochemical studies, and molecular analysis. The original Trucut biopsy needle had been cumbersome to use, but the recent introduction of newer-generation biopsy needles has transformed the landscape, such that there is now a greater focus on tissue acquisition for histological assessment. Concomitant technological advances of endoscopic ultrasound processors enabled higher-resolution imaging, and facilitated image enhancement using contrast harmonic endoscopic ultrasound and endoscopic ultrasound elastography. These techniques can be used as an adjunct to guide tissue acquisition in challenging situations. There is ongoing research on the use of artificial intelligence to complement diagnostic endoscopic ultrasound and the early data are promising. Artificial intelligence may be especially important to guide clinical decision-making if biopsy results are nondiagnostic.
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http://dx.doi.org/10.1111/1751-2980.12976DOI Listing
April 2021

Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development.

J Med Chem 2020 12 2;63(24):15541-15563. Epub 2020 Dec 2.

Poly (ADP-ribose) polymerase (PARP) plays a significant role in DNA repair responses; therefore, this enzyme is targeted by PARP inhibitors in cancer therapy. Here we have developed a number of fused tetra- or pentacyclic dihydrodiazepinoindolone derivatives with excellent PARP enzymatic and cellular PARylation inhibition activities. These efforts led to the identification of pamiparib (BGB-290, ), which displays excellent PARP-1 and PARP-2 inhibition with IC of 1.3 and 0.9 nM, respectively. In a cellular PARylation assay, this compound inhibits PARP activity with IC = 0.2 nM. Cocrystal of pamiparib shows similar binding sites with PARP with other PARP inhibitors, but pamiparib is not a P-gp substrate and shows excellent drug metabolism and pharmacokinetics (DMPK) properties with significant brain penetration (17-19%, mice). The compound is currently being investigated in phase III clinical trials as a maintenance therapy in platinum-sensitive ovarian cancer and gastric cancer.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01346DOI Listing
December 2020

Studies on Carrier Recombination in GaN/AlN Quantum Dots in Nanowires with a Core-Shell Structure.

Nanomaterials (Basel) 2020 Nov 20;10(11). Epub 2020 Nov 20.

Department of Electronic Engineering, Beijing National Research Center for Information Science and Technology, Tsinghua University, Beijing 100084, China.

GaN quantum dots embedded in nanowires have attracted much attention due to their superior optical properties. However, due to the large surface-to-volume ratio of the nanowire, the impacts of surface states are the primary issue responsible for the degradation of internal quantum efficiency (IQE) in heterostructured dot-in-nanowires. In this paper, we investigate the carrier recombination mechanism of GaN/AlN dot-in-nanowires with an in situ grown AlN shell structure. Ultraviolet photoelectron spectroscopy (UPS) measurements were performed to describe the band bending effect on samples with different shell thicknesses. Temperature-dependent photoluminescence (TDPL) data support that increasing the AlN shell thickness is an efficient way to improve internal quantum efficiency. Detailed carrier dynamics was analyzed and combined with time-resolved photoluminescence (TRPL). The experimental data are consistent with our physical model that the AlN shell can effectively flatten the band bending near the surface and isolate the surface non-radiative recombination center. Our systematic research on GaN/AlN quantum dots in nanowires with a core-shell structure may significantly advance the development of a broad range of nanowire-based optoelectronic devices.
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http://dx.doi.org/10.3390/nano10112299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699813PMC
November 2020

Long-term cardiovascular disease mortality among 160 834 5-year survivors of adolescent and young adult cancer: an American population-based cohort study.

Eur Heart J 2021 01;42(1):101-109

Departments of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai 200032, China.

Aims: Our aim was to assess the risk of cardiovascular disease (CVD) mortality in US 5-year survivors of adolescent and young adult (AYA) cancer compared with those of the general population and contemporaneous 5-year survivors of childhood cancer.

Methods And Results: A total of 160 834 5-year AYA cancer survivors (aged 15-39 years at diagnosis) were included, representing 2 239 390 person-years of follow-up. Overall, 2910 CVD deaths occurred, which was 1.4-fold [95% confidence interval (CI) 1.3-1.4] that expected in the general population, corresponding to 3.6 (95% CI 3.2-3.9) excess CVD deaths per 10 000 person-years. The highest risk of cardiac mortality was experienced after Hodgkin's lymphoma (HL), and the highest risk of cerebrovascular mortality was observed with central nervous system (CNS) tumours. Even survivors in their 6th and 7th decades of life, the risk of CVD mortality remained markedly higher than that of the matched general population. Competing risk analysis showed that the cumulative mortality of CVD was elevated among AYA cancer survivors compared with childhood cancer survivors during the whole study period.

Conclusion: Long-term AYA cancer survivors have a greater risk of CVD mortality than the US general population and childhood cancer survivors. Vulnerable subgroups, especially survivors of HL and CNS tumours, require continued close follow-up care for cardiovascular conditions throughout survivorship.
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http://dx.doi.org/10.1093/eurheartj/ehaa779DOI Listing
January 2021

Statins induce skeletal muscle atrophy via GGPP depletion-dependent myostatin overexpression in skeletal muscle and brown adipose tissue.

Cell Biol Toxicol 2021 06 9;37(3):441-460. Epub 2020 Oct 9.

State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.

Myopathy is the major adverse effect of statins. However, the underlying mechanism of statin-induced skeletal muscle atrophy, one of statin-induced myopathy, remains to be elucidated. Myostatin is a negative regulator of skeletal muscle mass and functions. Whether myostatin is involved in statin-induced skeletal muscle atrophy remains unknown. In this study, we uncovered that simvastatin administration increased serum myostatin levels in mice. Inhibition of myostatin with follistatin, an antagonist of myostatin, improved simvastatin-induced skeletal muscle atrophy. Simvastatin induced myostatin expression not only in skeletal muscle but also in brown adipose tissue (BAT). Mechanistically, simvastatin inhibited the phosphorylation of forkhead box protein O1 (FOXO1) in C2C12 myotubes, promoting the nuclear translocation of FOXO1 and thereby stimulating the transcription of myostatin. In differentiated brown adipocytes, simvastatin promoted myostatin expression mainly by inhibiting the expression of interferon regulatory factor 4 (IRF4). Moreover, the stimulative effect of simvastatin on myostatin expression was blunted by geranylgeranyl diphosphate (GGPP) supplementation in both myotubes and brown adipocytes, suggesting that GGPP depletion was attributed to simvastatin-induced myostatin expression. Besides, the capacities of statins on stimulating myostatin expression were positively correlated with the lipophilicity of statins. Our findings provide new insights into statin-induced skeletal muscle atrophy. Graphical headlights 1. Simvastatin induces skeletal muscle atrophy via increasing serum myostatin levels in mice; 2. Simvastatin promotes myostatin expression in both skeletal muscle and brown adipose tissue through inhibiting GGPP production; 3. The stimulating effect of statins on myostatin expression is positively correlated with the lipophilicity of statins.
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http://dx.doi.org/10.1007/s10565-020-09558-wDOI Listing
June 2021

Spatial and seasonal variation of water parameters, sediment properties, and submerged macrophytes after ecological restoration in a long-term (6 year) study in Hangzhou west lake in China: Submerged macrophyte distribution influenced by environmental variables.

Water Res 2020 Nov 2;186:116379. Epub 2020 Sep 2.

State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; School of Environmental Studies, China University of Geosciences, Wuhan 430074, China. Electronic address:

Submerged macrophyte restoration is the key stage in the reestablishment of an aquatic ecosystem. Previous studies have paid considerable attention to the effect of multiple environmental factors on submerged macrophytes. Meanwhile, few studies have been conducted regarding the spatial and seasonal characteristics of water and sediment properties and their long-term relationship with submerged macrophytes after the implementation of the submerged macrophytes restoration project. On a monthly basis, we monitored the spatial and seasonal variation in water parameters, sediment properties, and the submerged macrophyte characteristics of West Lake in Hangzhou from August 2013 to July 2019. From these measurements, we characterized the relationship between environmental factors and submerged macrophytes. Water nutrient concentrations continuously decreased with time, and the accumulation of sediment nutrients was accelerated as the submerged macrophyte communities developed on a long-term scale. The results indicated that the difference in water parameters was due to seasonal changes and land-use types in the watershed. The differences in the sediment properties were mainly attributed to seasonal changes and changes in the flow field. Redundancy analysis showed that the influence of water nutrients on the submerged macrophyte distribution was greater than that of sediment nutrients. The result also suggested that the developed root system, high stoichiometric homeostasis coefficients of P, and compensation ability of substantial leaf tissue may lead to a large distribution of Vallisneria natans in West Lake in Hangzhou. The correlation of water parameters and sediment properties with submerged macrophytes for a long time was very important as the restoration was achieved. To ensure the stability of the aquatic ecosystem after performing the submerged macrophyte restoration, a greater emphasis must be placed on reestablishing the entire ecosystem, including the restoration of aquatic animals and fish stocks. We expect these findings to serve as a reference for researchers and government agencies in the field of aquatic ecosystem restoration.
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http://dx.doi.org/10.1016/j.watres.2020.116379DOI Listing
November 2020

Beware the inflammatory cell-rich colonic polyp: a rare case of EBV-positive inflammatory pseudotumour-like follicular dendritic cell sarcoma with increased IgG4-positive plasma cells.

Pathology 2020 Oct 16;52(6):713-717. Epub 2020 Aug 16.

Pathology Section, Department of Laboratory Medicine, Changi General Hospital, Singhealth, Singapore.

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http://dx.doi.org/10.1016/j.pathol.2020.05.011DOI Listing
October 2020

Multi-user high-speed QAM-OFDMA visible light communication system using a 75-µm single layer quantum dot micro-LED.

Opt Express 2020 Jun;28(12):18332-18342

Next-generation visible light communication (VLC) is envisioned to evolve into a high-speed and multi-user system. In this work, a 75-µm single layer quantum dot (QD) micro-LED was fabricated, packaged and used to experimentally demonstrate a 3-meter QAM-OFDMA VLC system affording multiple users with a 1.06-GHz modulation bandwidth. The OFDMA system realized data rates of 1.2 Gbps and 750 Mbps with a BER of 0 and 3.6×10 for two independent users with a 1:1 bandwidth ratio, respectively. Additional sub-carrier allocation strategies and scenarios of 2∼6 users have been further evaluated, and all proposed strategies reach the sum-rate of beyond 1.41 Gbps while satisfying the forward error correction (FEC) criteria.
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http://dx.doi.org/10.1364/OE.395419DOI Listing
June 2020

Clinical guidance on endoscopic management of colonic polyps in Singapore.

Singapore Med J 2020 Jul 16. Epub 2020 Jul 16.

Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore.

Colonoscopy with endoscopic resection of detected colonic adenomas interrupts the adenoma-carcinoma sequence and reduces the incidence of colorectal cancer and cancer-related mortality. In the past decade, there have been significant developments in instruments and techniques for endoscopic polypectomy. Guidelines have been formulated by various professional bodies in Europe, Japan and the United States of America, but some of the recommendations differ between the various bodies. An expert professional workgroup under the auspices of the Academy of Medicine, Singapore, was set up to provide guidance on the endoscopic management of colonic polyps in Singapore. A total of 23 recommendations addressed the following issues: accurate description and diagnostic evaluation of detected polyps; techniques to reduce the risk of post-polypectomy bleeding and delayed perforation; the role of specific endoscopic resection techniques; the histopathological criteria for defining endoscopic cure; and the role of surveillance colonoscopy following curative resection.
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http://dx.doi.org/10.11622/smedj.2020108DOI Listing
July 2020

Pamiparib is a potent and selective PARP inhibitor with unique potential for the treatment of brain tumor.

Neoplasia 2020 09 8;22(9):431-440. Epub 2020 Jul 8.

Department of In Vivo Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing, PR China. Electronic address:

Pamiparib, an investigational Poly (ADP-ribose) polymerase (PARP) inhibitor in clinical development, demonstrates excellent selectivity for both PARP1 and PARP2, and superb anti-proliferation activities in tumor cell lines with BRCA1/2 mutations or HR pathway deficiency (HRD). Pamiparib has good bioavailability and is 16-fold more potent than olaparib in an efficacy study using BRCA1 mutated MDA-MB-436 breast cancer xenograft model. Pamiparib also shows strong anti-tumor synergy with temozolomide (TMZ), a DNA alkylating agent used to treat brain tumors. Compared to other PARP inhibitors, pamiparib demonstrated improved penetration across the blood brain barrier (BBB) in mice. Oral administration of pamiparib at a dose as low as 3 mg/kg is sufficient to abrogate PARylation in brain tumor tissues. In SCLC-derived, TMZ-resistant H209 intracranial xenograft model, combination of pamiparib with TMZ overcomes its resistance and shows significant tumor inhibitory effects and prolonged life span. Our data suggests that combination of pamiparib with TMZ has unique potential for treatment of brain tumors. Currently, the combination therapy of pamiparib with TMZ is evaluated in clinical trial [NCT03150862].
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http://dx.doi.org/10.1016/j.neo.2020.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350150PMC
September 2020
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