Publications by authors named "Yan Gong"

510 Publications

Pitavastatin stimulates retinal angiogenesis via HMG-CoA reductase-independent activation of RhoA-mediated pathways and focal adhesion.

Graefes Arch Clin Exp Ophthalmol 2021 Jul 30. Epub 2021 Jul 30.

Department of Biological Repositories, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430071, Hubei, China.

Background: Excessive angiogenesis of the retina is a key component of irreversible causes of blindness in many ocular diseases. Pitavastatin is a cholesterol-lowering drug used to reduce the risk of cardiovascular diseases. Various studies have shown the effects of pitavastatin on angiogenesis but the conclusions are contradictory. The effects of pitavastatin on retinal angiogenesis have not been revealed. This study investigated the effects of pitavastatin at clinically relevant concentrations on retinal angiogenesis and its underlying mechanisms using retinal microvascular endothelial cells (RMECs).

Methods: The effects of pitavastatin on retinal angiogenesis were determined using in vitro model of retinal angiogenesis, endothelial cell migration, adhesion, proliferation, and apoptosis assays. The mechanism studies were conducted using immunoblotting and stress fiber staining.

Results: Pitavastatin stimulated capillary network formation of RMECs in a similar manner as vascular endothelial growth factor (VEGF) and lipopolysaccharide (LPS). Pitavastatin also increased RMEC migration, adhesion to Matrigel, growth, and survival. The combination of pitavastatin with VEGF or LPS was more effective than VEGF or LPS alone in stimulating biological activities of RMECs, suggesting that pitavastatin can enhance the stimulatory effects of VEGF and LPS on retinal angiogenesis. Pitavastatin acted on RMECs in a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase-independent manner. In contrast, pitavastatin activated pro-angiogenic microenvironment via promoting the secretion of VEGF and stimulated retinal angiogenesis via multiple mechanisms including activation of RhoA-mediated pathways, induction of focal adhesion complex formation, and activation of ERK pathway.

Conclusion: Our work provides a preclinical evidence on the pro-angiogenic effect of pitavastatin in retina via multiple mechanisms that are irrelevant to mevalonate pathway.
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http://dx.doi.org/10.1007/s00417-021-05328-4DOI Listing
July 2021

MUC3A promotes non-small cell lung cancer progression via activating the NFκB pathway and attenuates radiosensitivity.

Int J Biol Sci 2021 16;17(10):2523-2536. Epub 2021 Jun 16.

Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China.

Mucin 3A (MUC3A) is highly expressed in non-small cell lung cancer (NSCLC), but its functions and effects on clinical outcomes are not well understood. Tissue microarray of 92 NSCLC samples indicated that high levels of MUC3A were associated with poor prognosis, advanced staging, and low differentiation. MUC3A knockdown significantly suppressed NSCLC cell proliferation and induced G1/S accumulation via downregulating cell cycle checkpoints. MUC3A knockdown also inhibited tumor growth and had synergistic effects with radiation. MUC3A knockdown increased radiation-induced DNA double strain breaks and γ-H2AX phosphorylation in NSCLC cells. MUC3A downregulation inhibited the BRCA-1/RAD51 pathway and nucleus translocation of P53 and XCRR6, suggesting that MUC3A promoted DNA damage repair and attenuated radiation sensitivity. MUC3A knockdown also resulted in less nucleus translocation of RELA and P53 . Immunoprecipitation revealed that MUC3A interacted with RELA and activated the NFκB pathway via promoting RELA phosphorylation and interfering the binding of RELA to IκB. Our studies indicated that MUC3A was a potential oncogene and associated with unfavorable clinical outcomes. NSCLC patients with a high MUC3A level, who should be more frequent follow-up and might benefit less from radiotherapy.
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http://dx.doi.org/10.7150/ijbs.59430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315024PMC
June 2021

Fluorescent detection of microRNA-21 in MCF-7 cells based on multifunctional gold nanorods and the integration of chemotherapy and phototherapy.

Mikrochim Acta 2021 Jul 14;188(8):253. Epub 2021 Jul 14.

Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science, MOE, Shandong Key Laboratory of Biochemical Analysis, Key Laboratory of Analytical Chemistry for Life Science in Universities of Shandong, College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China.

MicroRNA-21 is an important biomarker of tumor early prediction and metastasis, and its accurate detection is of great significance for tumor diagnosis and treatment. It will be a meaningful work to combine the detection of RNA with chemotherapy and photothermal therapy on the same composite material. Herein, we designed a multifunctional nanocomposite based on gold nanorods (AuNRs), making use of microRNA-triggered drug release and near-infrared photothermal effect, which has been developed for cancer therapy and microRNA-21detection. Firstly, the AuNRs with photothermal effect were synthesized as carriers for drug delivery. Then the surface of gold nanorods was modified by functional DNA chains to provide an efficient site for doxorubicin (DOX) loading. Finally, folic acid was introduced to achieve the targeted treatment of MCF-7 cells. The microRNA competed with the double-stranded DNA, resulting in the release of DOX and the recovery of fluorescence signal located at 595 nm with an excitation of 488 nm effectively. The nano-biosensor could not only achieve dual-function of diagnosis and treatment of cancer cells, but also accomplish the detection of microRNA in tumor cells. It showed a high selectivity for microRNA-21 determination with a limit of detection (LOD) of 2.1 nM from the linear relationship from 1.0 × 10 M to 5.0 × 10 M. This scheme provides an outstanding strategy for cell imaging, treatment, and detection, which serves as a promising candidate in the field of biomedical research.
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http://dx.doi.org/10.1007/s00604-021-04917-8DOI Listing
July 2021

Identification of a new azoreductase driven prodrug from bardoxolone methyl and 5-aminosalicylate for the treatment of colitis in mice.

Chin J Nat Med 2021 Jul;19(7):545-550

State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

For local treatment of ulcerative colitis, a new azoreductase driven prodrug CDDO-AZO from bardoxolone methyl (CDDO-Me) and 5-aminosalicylate (5-ASA) was designed, synthesized and biologically evaluated. It is proposed that orally administrated CDDO-AZO is stable before reaching the colon, while it can also be triggered by the presence of azoreductase in the colon to fragment into CDDO-Me and 5-ASA, generating potent anti-colitis effects. Superior to olsalazine (OLS, a clinically used drug for ulcerative colitis) and CDDO-Me plus 5-ASA, CDDO-AZO significantly attenuated inflammatory colitis symptoms in DSS-induced chronic colitis mice, which suggested that CDDO-AZO may be a promising anti-ulcerative colitis agent.
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http://dx.doi.org/10.1016/S1875-5364(21)60055-9DOI Listing
July 2021

Adverse Cardiovascular Outcomes and Antihypertensive treatment: A Genome-Wide Interaction Meta-Analysis in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS).

Clin Pharmacol Ther 2021 Jul 7. Epub 2021 Jul 7.

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, FL, USA.

We sought to identify genome-wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome-wide antihypertensive drug-SNP interaction tests for four drug classes (β-blockers, n=9,195; calcium channel blockers [CCB], n=10,511; thiazide/thiazide-like diuretics, n=3,516; ACE-inhibitors/ARBs, n=2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among hypertensive patients of European ancestry. Top SNPs from the meta-analyses were tested for replication of cardiovascular outcomes in an independent CHARGE study (n=21,267), blood pressure (BP) response in independent ICAPS studies (n=1,552), and ethnic validation in African Americans from GenHAT (n=5,115). One signal reached genome-wide significance in the β-blocker-SNP interaction analysis (rs139945292, Interaction P=1.56 x 10 ). rs139945292 was validated through BP response to β-blockers, with the T-allele associated with less BP reduction (systolic BP response P=6 x 10 , Beta=3.09, diastolic BP response P=5 x 10 , Beta=1.53). The T-allele was also associated with increased adverse cardiovascular risk within the β-blocker treated patients subgroup (P=2.35 x 10 , OR [95% CI] = 1.57 [1.23-1.99]). The locus showed nominal replication in CHARGE, and consistent directional trends in β-blocker treated African Americans. rs139945292 is an eQTL for the 50kb upstream gene NTM (neurotrimin). No SNPs attained genome-wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE-inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in β-blocker treated patients. Further investigation into this region is warranted.
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http://dx.doi.org/10.1002/cpt.2355DOI Listing
July 2021

Vangl2 limits chaperone-mediated autophagy to balance osteogenic differentiation in mesenchymal stem cells.

Dev Cell 2021 Jul 1;56(14):2103-2120.e9. Epub 2021 Jul 1.

Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address:

Lysosomes are the recycling center and nutrient signaling hub of the cell. Here, we show that lysosomes also control mesenchymal stem cell (MSC) differentiation by proteomic reprogramming. The chaperone-mediated autophagy (CMA) lysosome subgroup promotes osteogenesis, while suppressing adipogenesis, by selectively removing osteogenesis-deterring factors, especially master transcriptional factors, such as adipogenic TLE3, ZNF423, and chondrogenic SOX9. The activity of the CMA-committed lysosomes in MSCs are controlled by Van-Gogh-like 2 (Vangl2) at lysosomes. Vangl2 directly binds to lysosome-associated membrane protein 2A (LAMP-2A) and targets it for degradation. MSC-specific Vangl2 ablation in mice increases LAMP-2A expression and CMA-lysosome numbers, promoting bone formation while reducing marrow fat. The Vangl2:LAMP-2A ratio in MSCs correlates inversely with the capacity of the cells for osteoblastic differentiation in humans and mice. These findings demonstrate a critical role for lysosomes in MSC lineage acquisition and establish Vangl2-LAMP-2A signaling as a critical control mechanism.
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http://dx.doi.org/10.1016/j.devcel.2021.06.011DOI Listing
July 2021

A Lightweight Localization Strategy for LiDAR-Guided Autonomous Robots with Artificial Landmarks.

Sensors (Basel) 2021 Jun 30;21(13). Epub 2021 Jun 30.

Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China.

This paper proposes and implements a lightweight, "real-time" localization system (SORLA) with artificial landmarks (reflectors), which only uses LiDAR data for the laser odometer compensation in the case of high-speed or sharp-turning. Theoretically, due to the feature-matching mechanism of the LiDAR, locations of multiple reflectors and the reflector layout are not limited by geometrical relation. A series of algorithms is implemented to find and track the features of the environment, such as the reflector localization method, the motion compensation technique, and the reflector matching optimization algorithm. The reflector extraction algorithm is used to identify the reflector candidates and estimates the precise center locations of the reflectors from 2D LiDAR data. The motion compensation algorithm predicts the potential velocity, location, and angle of the robot without odometer errors. Finally, the matching optimization algorithm searches the reflector combinations for the best matching score, which ensures that the correct reflector combination could be found during the high-speed movement and fast turning. All those mechanisms guarantee the algorithm's precision and robustness in the high speed and noisy background. Our experimental results show that the SORLA algorithm has an average localization error of 6.45 mm at a speed of 0.4 m/s, and 9.87 mm at 4.2 m/s, and still works well with the angular velocity of 1.4 rad/s at a sharp turn. The recovery mechanism in the algorithm could handle the failure cases of reflector occlusion, and the long-term stability test of 72 h firmly proves the algorithm's robustness. This work shows that the strategy used in the SORLA algorithm is feasible for industry-level navigation with high precision and a promising alternative solution for SLAM.
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http://dx.doi.org/10.3390/s21134479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271365PMC
June 2021

Pollution characteristics, sources and health risk of metals in urban dust from different functional areas in Nanjing, China.

Environ Res 2021 Jun 29;201:111607. Epub 2021 Jun 29.

Wuxi Center for Disease Control and Prevention (The Affiliated Wuxi Center for Disease Control and Prevention of Nanjing Medical University), No. 499 Jincheng Road, Wuxi, 214000, China. Electronic address:

Urban dust is an important medium of potential toxic metal (PTM) pollution that affects human health and the urban ecosystems. A total of 374 fugitive dust samples were collected in Nanjing, a fast-developing city in southern China, including six sub-types of dust (residential district, commercial district, industrial district, traffic district, cultural and educational district, green land). Chemical analysis of eighteen metal elements by inductively coupled plasma mass spectrometry was carried out to establish the sub-type sources profiles of fine particles for fugitive dust. The results show that these metals (Cu, Zn, Se, Sr, Mo, Cd, Sb, and Pb) are mainly from anthropogenic sources and present a high degree of pollution; Mn, As, and Ba are moderately affected by human activities and present a significant degree of pollution; Ni, Co, Cr, Tl, V, Be, and Ti mainly originate from natural sources and present significant, moderate and minimal degrees of pollution. For the dust types from different functional areas, the differences of enrichment factor (EF) values were relatively small. Metals were highly concentrated in dust from residential, cultural and educational district, which had high density population and would pose higher health risk. In all types of dust, the metals rich in crust (Ti, Mn, Ba, Sr) and the metals (Cu, Zn, Pb) closely connected with city activities were the main components. Factor analysis revealed that there were six main sources of metals in dust collected from Nanjing: industrial activity, building decoration, soil dust, metal smelting, traffic emissions, and brake abrasion. Generally, noncarcinogenic and carcinogenic health risks of metals found in dust are rarely found for children and adults based on health risk assessments. However, the noncarcinogenic risk of Pb in commercial districts for children should be noted because its hazard quotient was higher than the safety threshold level. For the accumulative health risk of eighteen metals, the noncarcinogenic risk values of dust from six functional areas for children were all over the threshold (1.0), whereas below 1.0 for adults. The difference between children and adults was relatively obvious. All accumulative risk values of carcinogenic metals did not exceed the carcinogenic risk threshold of 1 × 10, which suggested that no risk prevention measures were needed.
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http://dx.doi.org/10.1016/j.envres.2021.111607DOI Listing
June 2021

Extracellular Matrix Stiffness Regulates DNA Methylatioan by PKCα-Dependent Nuclear Transport of DNMT3L.

Adv Healthc Mater 2021 Jun 26:e2100821. Epub 2021 Jun 26.

Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China.

Extracellular matrix (ECM) stiffness has profound effects on the regulation of cell functions. DNA methylation is an important epigenetic modification governing gene expression. However, the effects of ECM stiffness on DNA methylation remain elusive. Here, it is reported that DNA methylation is sensitive to ECM stiffness, with a global hypermethylation under stiff ECM condition in mouse embryonic stem cells (mESCs) and embryonic fibroblasts compared with soft ECM. Stiff ECM enhances DNA methylation of both promoters and gene bodies, especially the 5' promoter regions of pluripotent genes. The enhanced DNA methylation is functionally required for the loss of pluripotent gene expression in mESCs grown on stiff ECM. Further experiments reveal that the nuclear transport of DNA methyltransferase 3-like (DNMT3L) is promoted by stiff ECM in a protein kinase C α (PKCα)-dependent manner and DNMT3L can be binding to Nanog promoter regions during cell-ECM interactions. These findings unveil DNA methylation as a novel target for the mechanical sensing mechanism of ECM stiffness, which provides a conserved mechanism for gene expression regulation during cell-ECM interactions.
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http://dx.doi.org/10.1002/adhm.202100821DOI Listing
June 2021

Three-dimensional Transcranial Microbubble Cavitation Localization by Four Sensors.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 Jun 24;PP. Epub 2021 Jun 24.

Cavitation is the fundamental physical mechanism of various focused ultrasound (FUS)-mediated therapies in the brain. Accurately knowing the 3D location of cavitation in real-time can improve the targeting accuracy and avoid off-target tissue damage. Existing techniques for 3D passive transcranial cavitation detection require the use of expensive and complicated hemispherical phased arrays with 128 or 256 elements. The objective of this study was to investigate the feasibility of using four sensors for transcranial 3D localization of cavitation. Differential microbubble cavitation detection combined with the time difference of arrival algorithm was developed for the localization using the four sensors. Numerical simulation using k-Wave toolbox was performed to validate the proposed method for transcranial cavitation source localization. The sensors with a center frequency of 2.25 MHz and a 6-dB bandwidth of 1.39 MHz were used to locate cavitation generated by FUS (500 kHz) sonication of microbubbles that were injected into a tube positioned inside an ex vivo human skullcap. Cavitation emissions from the microbubbles were detected transcranially using the four sensors. Both simulation and experimental studies found that the proposed method achieved accurate 3D cavitation localization. The accuracy of the localization method with the skull was measured to be 1.9 ± 1.0 mm when the cavitation source was located within 30 mm from the geometric center of the sensor network, which was not significantly different from that without the skull (1.7 ± 0.5 mm). The accuracy decreased as the cavitation source was away from the geometric center of the sensor network. It also decreased as the pulse length increased. Its accuracy was not significantly affected by the sensor position relative to the skull. In summary, four sensors combined with the proposed localization algorithm offer a simple approach for 3D transcranial cavitation localization.
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http://dx.doi.org/10.1109/TUFFC.2021.3091950DOI Listing
June 2021

HHLA2 deficiency inhibits non-small cell lung cancer progression and THP-1 macrophage M2 polarization.

Cancer Med 2021 Jun 21. Epub 2021 Jun 21.

Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China.

Background: Human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) is a member of B7 family, which is upregulated in multiple tumors. However, its exact functions in non-small cell lung cancer (NSCLC) have not been fully understood. This study aimed to investigate the biological roles of HHLA2 in human NSCLC and the relevant mechanisms. In addition, the effects of tumor cell-derived HHLA2 on tumor-associated macrophage (TAM) polarization were explored.

Methods: NSCLC cell growth, migration, and invasion were assessed by colony formation and modified Boyden chamber assays. Cell cycle and the CD163+ TAMs were examined by flow cytometry. A co-culture model of THP-1 macrophages and NSCLC cells was conducted to investigate the impacts of tumor cell-derived HHLA2 on THP-1 macrophage polarization. Moreover, a xenograft nude mouse model was established to explore the effects of HHLA2 on tumorigenesis in vivo.

Results: HHLA2 was upregulated in A549 and H1299 cells compared with the normal lung epithelial BEAS-2B cells. HHLA2 deficiency inhibited NSCLC cell proliferation, migration, invasion, and induced G0/G1 phase arrest partially via inhibiting EGFR/MAPK/ERK signaling pathway. Furthermore, HHLA2 knockdown inhibited M2 polarization of TAMs via downregulating IL-10. In addition, knockdown of HHLA2 inhibited tumor growth in vivo.

Conclusion: HHLA2 downregulation inhibited NSCLC growth and TAM M2 polarization. HHLA2 may serve as a therapeutic target and promising prognostic biomarker in NSCLC.
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http://dx.doi.org/10.1002/cam4.4081DOI Listing
June 2021

NEK2 plays an active role in Tumorigenesis and Tumor Microenvironment in Non-Small Cell Lung Cancer.

Int J Biol Sci 2021 11;17(8):1995-2008. Epub 2021 May 11.

Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan, University, Wuhan, Hubei 430071, China.

Abnormal expression and dysfunction of Never-in-mitosis-A-related kinase 2 (NEK2) result in tumorigenesis. High levels of NEK2 are related to malignant progression, drug resistance, and poor prognosis. However, the relationship between NEK2 levels and the occurrence of non-small cell lung cancer (NSCLC) remains unknown. This study aimed to explore the impacts of NEK2 on the oncogenesis of NSCLC and the tumor microenvironment. Downregulation of NEK2 inhibited A549 and H1299 cell proliferation, migration, and invasion, blocking cell cycle at the G0/G1 phase. Loss of NEK2 inhibited the release of IL-10 from tumor cells, M2-like polarization of macrophages, angiogenesis, and vascular endothelial cell migration. Furthermore, NEK2 deficiency inhibited tumor growth . Taken together, NEK2 knockdown inhibited the occurrence and development of NSCLC, M2 polarization of macrophages, and angiogenesis. The abnormal expression of NEK2 might not only indicate tumor progression and patient prognosis but also serve as a potential molecular therapeutic target with great development prospects.
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http://dx.doi.org/10.7150/ijbs.59019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193268PMC
May 2021

Immunological modulation of the Th1/Th2 shift by ionizing radiation in tumors (Review).

Int J Oncol 2021 Jul 10;59(1). Epub 2021 Jun 10.

Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.

Extensive evidence has documented that the balance between cytokines from T helper type 1 (Th1) and type 2 (Th2) cells is disrupted in the tumorigenic microenvironment compared with immunocompetent individuals. Ionizing radiation (IR) has been reported to markedly modulate the Th1/Th2 polarization in a concentration‑dependent manner. In the present review article, the immune modulation of Th1/Th2 and the IR‑induced crosstalk of the Th1/Th2 shift with immunocytes and tumor cells are summarized. The involvement of the Th1/Th2 shift in post‑radiotherapy complications is highlighted. Specifically, high‑dose IR has been shown to promote the Th2 shift, leading to an immunosuppressive cytokine network, while the impact of low‑dose IR remains controversial. The IR‑induced modulation of the Th1/Th2 shift is mediated by tumor cells and multiple immunocytes, including dendritic cells, tumor‑associated macrophages, cytotoxic T lymphocytes and natural killer cells. However, the excessive production of pro‑inflammatory factors, such as IFN‑γ and IL‑2, by Th1 cells, aggravates the clinical side‑effects of radiotherapy, including radiation‑induced lung and intestinal injury, radiation encephalopathy, as well as other complications. Therefore, further research into the underlying mechanism is required to confirm the potential applicability of the Th1/Th2 shift combined with IR in the treatment of malignant tumors.
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http://dx.doi.org/10.3892/ijo.2021.5230DOI Listing
July 2021

Autophagy Induced by a Novel Triazol Derivative Promotes Angiogenesis Through Decreasing Interferon-Inducible Protein 10 Level in Vascular Endothelial Cells.

J Cardiovasc Pharmacol 2021 07;78(1):e136-e146

Department of Vascuar Surgery, School of Biological Science and Technology, University of Jinan, Jinan, China; and.

Abstract: Autophagy plays an important role in angiogenesis, whereas the mechanisms of vascular endothelial cell (VEC) autophagy associated with angiogenesis remain unclear. In this study, we identified a novel triazol derivative (JL025) that significantly promoted angiogenesis both in vitro and in vivo. Moreover, JL025 had no effects on cell proliferation but dramatically increased the autophagy level of VEC. The suppression of autophagy inhibited JL025-induced angiogenesis in vitro and in vivo, suggesting that JL025-induced angiogenesis was dependent on the enhanced autophagy. Mechanistic studies indicated that JL025-induced VEC autophagy was related to the Protein Kinase B/mTOR signaling pathway. Meanwhile, JL025 decreased the antiangiogenic chemokine interferon-inducible protein 10 (IP10) protein level in human VECs. Importantly, the suppression of autophagy inhibited JL025-induced decrease of IP10 protein level, indicating that autophagy mediated the degradation of IP10. Taken together, our findings provide new insights into the relationship of VEC autophagy with angiogenesis, and JL025 may have a therapeutic potential in related diseases.
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http://dx.doi.org/10.1097/FJC.0000000000001034DOI Listing
July 2021

Hollow PtCo alloy nanospheres as a high- and oxygen generating nanozyme for radiotherapy enhancement in non-small cell lung cancer.

J Mater Chem B 2021 Jun;9(23):4643-4653

Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China. and Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China and Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China.

Radiotherapy, as well as chemotherapy and surgery, occupies an essential position in tumor treatment. Nonetheless, insufficient radiation deposition and hypoxia-related radioresistance of cancer cells still are serious challenges in radiotherapy. Herein, we proposed a hollow PtCo nanosphere (PtCo NS)-based novel radiosensitizer with three advantages to sensitize tumor radiotherapy: (i) the high-Z element Pt ensured higher radiation absorption to cause more DNA damage, (ii) the platinum (Pt) and cobalt (Co) elements exhibited a dual catalase-like enzymatic activity to convert endogenic H2O2 to O2 efficiently, and (iii) the unique hollow nature of the PtCo NS provided a large specific surface area, which could amplify the catalytic reaction of H2O2 to induce reactive oxygen species and cancer cell apoptosis upon combination with radiation. Both in vivo and in vitro studies showed that the hollow PtCo NS could significantly inhibit tumor growth, simultaneously relieving tumor hypoxia with good biocompatibility and biosafety. This work presents a simple but multifunctional radiosensitizer with a unique hollow structure for radiotherapy enhancement.
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http://dx.doi.org/10.1039/d1tb00486gDOI Listing
June 2021

Lactate Dehydrogenase B and Pyruvate Oxidation Pathway Associated With Carfilzomib-Related Cardiotoxicity in Multiple Myeloma Patients: Result of a Multi-Omics Integrative Analysis.

Front Cardiovasc Med 2021 29;8:645122. Epub 2021 Apr 29.

Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, United States.

Multiple myeloma (MM) is the second most frequent hematologic cancer in the United States. Carfilzomib (CFZ), an irreversible proteasome inhibitor being used to treat relapsed and refractory MM, has been associated with cardiotoxicity, including heart failure. We hypothesized that a multi-omics approach integrating data from different omics would provide insights into the mechanisms of CFZ-related cardiovascular adverse events (CVAEs). Plasma samples were collected from 13 MM patients treated with CFZ (including 7 with CVAEs and 6 with no CVAEs) at the University of Florida Health Cancer Center. These samples were evaluated in global metabolomic profiling, global proteomic profiling, and microRNA (miRNA) profiling. Integrative pathway analysis was performed to identify genes and pathways differentially expressed between patients with and without CVAEs. The proteomics analysis identified the up-regulation of lactate dehydrogenase B (LDHB) [fold change (FC) = 8.2, = 0.01] in patients who experienced CVAEs. The metabolomics analysis identified lower plasma abundance of pyruvate (FC = 0.16, = 0.0004) and higher abundance of lactate (FC = 2.4, = 0.0001) in patients with CVAEs. Differential expression analysis of miRNAs profiling identified mir-146b to be up-regulatein (FC = 14, = 0.046) in patients with CVAE. Pathway analysis suggested that the pyruvate fermentation to lactate pathway is associated with CFZ-CVAEs. In this pilot multi-omics integrative analysis, we observed the down-regulation of pyruvate and up-regulation of LDHB among patients who experienced CVAEs, suggesting the importance of the pyruvate oxidation pathway associated with mitochondrial dysfunction. Validation and further investigation in a larger independent cohort are warranted to better understand the mechanisms of CFZ-CVAEs.
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http://dx.doi.org/10.3389/fcvm.2021.645122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116486PMC
April 2021

MUC3A induces PD-L1 and reduces tyrosine kinase inhibitors effects in EGFR-mutant non-small cell lung cancer.

Int J Biol Sci 2021 12;17(7):1671-1681. Epub 2021 Apr 12.

Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China.

The immune checkpoint ligand programmed death-ligand 1 (PD-L1) and the transmembrane mucin (MUC) 3A are upregulated in non-small cell lung cancer (NSCLC), contributing to the aggressive pathogenesis and poor prognosis. Here, we report that knocking down the oncogenic MUC3A suppresses the PD-L1 expression in NSCLC cells. MUC3A is a potent regulator of epidermal growth factor receptor (EGFR) stability, and MUC3A deficiency downregulates the activation of the PI3K/Akt and MAPK pathways, which subsequently reduces the expression of PD-L1. Furthermore, knockdown of MUC3A and tyrosine kinase inhibitors (TKIs) in EGFR-mutant NSCLC cells play a synergistic effect on inhibited proliferation and promoted apoptosis . In the BALB/c nude mice xenograft model, MUC3A deficiency enhances EGFR-mutated NSCLC sensitivity to TKIs. Our study shows that transmembrane mucin MUC3A induces PD-L1, thereby promoting immune escape in NSCLC, while downregulation of MUC3A enhances TKIs effects in EGFR-mutant NSCLC. These findings offer insights into the design of novel combination treatment for NSCLC.
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http://dx.doi.org/10.7150/ijbs.57964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120466PMC
April 2021

Isoquercitrin protects HUVECs against high glucose‑induced apoptosis through regulating p53 proteasomal degradation.

Int J Mol Med 2021 07 13;48(1). Epub 2021 May 13.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.

High glucose (HG)‑induced endothelial apoptosis serves an important role in the vascular dysfunction associated with diabetes mellitus (DM). It has been reported that isoquercitrin (IQC), a flavonoid glucoside, possesses an anti‑DM effect, but the mechanism requires further investigation. The present study investigated the effect of IQC against HG‑induced apoptosis in human umbilical vein endothelial cells (HUVECs) and explored its molecular mechanism. HUVECs were treated with 5 or 30 mM glucose for 48 h. Endothelial cell viability was monitored using the Cell Counting Kit‑8 assay. Mitochondrial membrane potential was detected by JC‑1 staining. Apoptosis was observed by TUNEL staining and flow cytometry. Western blotting was used for the analysis of apoptosis‑associated proteins Bax, Bcl‑2, cleaved (C)‑caspase3, total‑caspase3, p53 and phosphorylated p53. Reverse transcription‑quantitative PCR was used to analyze the mRNA expression levels of Bax, Bcl‑2 and p53. Immunofluorescence staining was utilized to detect the expression levels and distribution of p53 and ubiquitin specific peptidase 10 (USP10) in HUVECs. The results revealed that IQC significantly attenuated HG‑induced endothelial apoptosis, as shown by decreased apoptotic cells observed by TUNEL, JC‑1 staining and flow cytometry. Moreover, under HG stress, IQC treatment markedly inhibited the increased expression levels of the pro‑apoptotic proteins p53, Bax and C‑caspase3, and increased the expression levels of the anti‑apoptotic protein Bcl‑2 in HUVECs. However, the anti‑apoptotic effect of IQC against HG was partially blunted by increasing p53 protein levels . IQC influenced the mRNA expression levels of Bax and Bcl‑2 in response to HG, but it did not affect the transcription of p53. Notably, IQC inhibited the HG‑induced phosphorylation of p53 at Ser15 and the nuclear transport of USP10, destabilizing p53 and increasing the proteasomal degradation of the p53 protein. The current findings revealed that IQC exerted a protective effect against the HG‑induced apoptosis of endothelial cells by regulating the proteasomal degradation of the p53 protein, suggesting that IQC may be used as a novel therapeutic compound to ameliorate DM‑induced vascular complications.
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http://dx.doi.org/10.3892/ijmm.2021.4955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121554PMC
July 2021

Scleral Buckling with Viscoelastics or Gas Injection for Bulging Retinal Detachments: A Retrospective Cohort Study.

J Ophthalmol 2021 8;2021:6694199. Epub 2021 Apr 8.

Ningbo Eye Hospital, Ningbo, China.

Objective: To examine the use of a viscoelastic agent instead of air in the vitreous cavity during surgery for scleral buckling.

Methods: This was a retrospective cohort study of patients who underwent scleral buckling surgery for bulging rhegmatogenous retinal detachment (RRD) at Ningbo Eye Hospital from 07/2016 to 12/2019. The patients were grouped into drainage, air injection, cryotherapy and explant (DACE) and drainage, viscoelastic injection, cryotherapy, and explant (DVCE) groups, which were comparatively assessed.

Results: There were 25 and 22 patients in the DVCE and DACE groups, respectively. The surgery was significantly shorter with DVCE than DACE ( < 0.05), with less intraoperative external pressure adjustment ( < 0.05). BCVA was lower in the DVCE group at 1 week compared with the DACE group ( < 0.05). Successful retinal reattachment was observed in 92.0% and 81.8% of the DVCE and DACE groups, respectively ( < 0.05). Cases requiring laser replenishing after the operation were less in the DVCE group compared with the DACE group ( < 0.05). There were no differences in complications and intraocular pressure between the two groups (all < 0.05).

Conclusion: DVCE has better operative characteristics and faster vision recovery than DACE, with similar outcomes.
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http://dx.doi.org/10.1155/2021/6694199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049804PMC
April 2021

Insight into Liver lncRNA and mRNA Profiling at Four Developmental Stages in Ningxiang Pig.

Biology (Basel) 2021 Apr 8;10(4). Epub 2021 Apr 8.

College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China.

Ningxiang pigs, a fat-type pig, are native to Ningxiang County in Hunan Province, with thousands of years of breeding history. This study aims to explore the expression profiles and functional networks on messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs) in the liver. Liver tissue of Ningxiang piglets was collected at 30, 90, 150, and 210 days after birth (four development stages), and the mRNA and lncRNA expression was profiled. Compared to mRNA and lncRNA expression profiles, most differentially expressed mRNAs (DEmRNAs) were upregulated at 30 days; however, most DElncRNAs were downregulated at 210 days. Via Short Time-series Expression Miner (STEM) analysis and weighted gene co-expression network analysis (WGCNA), a complex interaction between mRNAs and lncRNAs was identified, indicating that lncRNAs may be a critical regulatory element for mRNAs. One module of genes in particular (module profile 4) was related to fibril organization, vasculogenesis, GTPase activator activity, and regulation of kinase activity. The mRNAs and lncRNAs in module profile 4 had a similar pattern of expression, indicating that they have functional and regulatory relationships. Only , , and in the particular mRNA profile 4 were the target genes of lncRNAs in that profile, which shows the possible regulatory relationship between lncRNAs and mRNAs. The expression of these genes and lncRNAs in profile 4 was the highest at 30 days, and it is believed that these RNAs may play a critical role during the suckling period in order to meet the dietary requirements of piglets. In the lncRNA-mRNA co-expression network, the identified gene hubs and associated lncRNAs were shown to be involved in saccharide, lipid, and glucose metabolism, which may play an important role in the development and health of the liver. This result will lead to further investigation of liver lncRNA functions at various stages of development in Ningxiang pigs.
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http://dx.doi.org/10.3390/biology10040310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068270PMC
April 2021

Association of 1-Year Blood Pressure Variability With Long-term Mortality Among Adults With Coronary Artery Disease: A Post Hoc Analysis of a Randomized Clinical Trial.

JAMA Netw Open 2021 Apr 1;4(4):e218418. Epub 2021 Apr 1.

Center for Integrative Cardiovascular and Metabolic Diseases, University of Florida, Gainesville.

Importance: Accumulating evidence indicates that higher blood pressure (BP) variability from one physician office visit to the next (hereafter referred to as visit-to-visit BP variability) is associated with poor outcomes. Short-term measurement (throughout 1 year) of visit-to-visit BP variability in high-risk older patients may help identify patients at increased risk of death.

Objective: To evaluate whether short-term visit-to-visit BP variability is associated with increased long-term mortality risk.

Design, Setting, And Participants: The US cohort of the International Verapamil SR-Trandolapril Study (INVEST), a randomized clinical trial of 16 688 patients aged 50 years or older with hypertension and coronary artery disease, was conducted between September 2, 1997, and December 15, 2000, with in-trial follow-up through February 14, 2003. The study evaluated a calcium antagonist (sustained-release verapamil plus trandolapril) vs β-blocker (atenolol plus hydrochlorothiazide) treatment strategy. Blood pressure measurement visits were scheduled every 6 weeks for the first 6 months and biannually thereafter. Statistical analysis was performed from September 2, 1997, to May 1, 2014.

Exposures: Visit-to-visit systolic BP (SBP) and diastolic BP variability during the first year of enrollment using 4 different BP variability measures: standard deviation, coefficient of variation, average real variability, and variability independent of the mean.

Main Outcomes And Measures: All-cause death, assessed via the US National Death Index, beginning after the exposure assessment period through May 1, 2014.

Results: For the present post hoc analysis, long-term mortality data were available on 16 688 patients (9001 women [54%]; mean [SD] age, 66.5 [9.9] years; 45% White patients, 16% Black patients, and 37% Hispanic patients). During a mean (SD) follow-up of 10.9 (4.2) years, 5058 patients (30%) died. All 4 variability measures for SBP were significantly associated with long-term mortality after adjustment for baseline demographic characteristics and comorbidities. After comparison of lowest vs highest variability measure quintiles, the magnitude of the association with death remained statistically significant even after adjustment for baseline demographic characteristics and comorbidities (average real variability: adjusted hazard ratio [aHR], 1.18; 95% CI, 1.08-1.30; standard deviation: aHR, 1.14; 95% CI, 1.04-1.24; coefficient of variation: aHR, 1.15; 95% CI, 1.06-1.26; variability independent of the mean: aHR, 1.15; 95% CI, 1.05-1.25). The signal was stronger in women compared with men. Associations of diastolic BP variability measures with death were weaker than for SBP and were not significant after adjustment.

Conclusions And Relevance: This study suggests that, in a large population of older patients with hypertension and coronary artery disease, short-term visit-to-visit SBP variability was associated with excess long-term mortality, especially for women. Efforts to identify and minimize visit-to-visit SBP variability may be important in reducing excess mortality later in life.

Trial Registration: ClinicalTrials.gov Identifier: NCT00133692.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.8418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085725PMC
April 2021

RRM2 silencing suppresses malignant phenotype and enhances radiosensitivity via activating cGAS/STING signaling pathway in lung adenocarcinoma.

Cell Biosci 2021 Apr 15;11(1):74. Epub 2021 Apr 15.

Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China.

Background: As one of the most common malignancy, lung adenocarcinoma (LUAD) is characterized by low 5-year survival rate. This research aimed to investigate the effects of ribonucleotide reductase regulatory subunit M2 (RRM2) on malignant biological behaviors and activation of cGAS/STING pathway. We also explored the synergistic sensitization mechanisms of RRM2 and radiotherapy.

Methods: Bioinformatic tools were used to evaluate the clinical significance of RRM2 in LUAD patients. The roles of RRM2 in malignant phenotype and DNA damage in LUAD cells were investigated with cell proliferation, colony formation, immunofluorescence, modified Boyden chamber and comet assays. The mouse models were used to evaluate the biological significance of RRM2 in vivo. Cytotoxic T cell infiltration was evaluated via flow cytometric analysis and immunohistochemistry staining in C57BL/6 mice. We also explored the synergistic effects of RRM2 silencing and radiation on LUAD cells with apoptosis assay and immunoblotting in vitro.

Results: Bioinformatic analysis revealed that RRM2 had diagnostic values for LUAD patients. Higher levels of RRM2 predicted worse prognosis. RRM2 silencing inhibited LUAD cell proliferation, invasion and migration. RRM2 knockdown induced S phase arrest and DNA damage. RRM2 silencing induced cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, and the downstream targets were regulated in a STING-dependent manner. Knockdown of RRM2 suppressed tumor growth in the xenograft tumor models. RRM2 deficiency increased CD8 + T cells in the tumor tissues and spleens. Furthermore, RRM2 silencing had synergistic effects with radiation on inhibiting cell proliferation and promoting apoptosis. Meanwhile, this combination promoted the activation of cGAS/STING signaling pathway synergistically, and simultaneously increased expression of IFNβ, CCL5 and CXCL10.

Conclusion: Our results demonstrated that RRM2 silencing had anti-tumor values and activated the cGAS/STING signaling pathway. RRM2 silencing increased CD8 + T cells infiltration. RRM2 silencing cooperated with radiation to inhibit LUAD cell proliferation, promote apoptosis and enhance the activation of cGAS/STING signaling pathway. RRM2 could be a promising target for tumor regression through cancer immunotherapy in LUAD.
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http://dx.doi.org/10.1186/s13578-021-00586-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051110PMC
April 2021

Pharmacogenetic predictors of nevirapine pharmacokinetics in Ghanaian children living with HIV with or without TB coinfection.

Infect Genet Evol 2021 Aug 8;92:104856. Epub 2021 Apr 8.

Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, United States. Electronic address:

Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor that is used in the treatment of human immunodeficiency virus (HIV) infection in children younger than 3 years old. Identifying genetic predictors of NVP pharmacokinetics (PK) in young children is important because inter-individual variability in NVP concentrations contributes to variable treatment response and the information may be used to individualize dosing decisions. We examined the relationship between genetic variations in relevant drug disposition genes and NVP PK parameters in Ghanaian children living with HIV eligible to initiate NVP-based antiretroviral therapy. Participants received NVP plus zidovudine and lamivudine or abacavir and lamivudine twice daily, and those with tuberculosis (TB) coinfection received concurrent anti-TB therapy with NVP. Pharmacokinetic sampling was performed after at least 4 weeks of antiretroviral therapy. Nevirapine minimum concentration (C), area under the concentration-time curve from time 0 to 12 h (AUC), and apparent clearance (CL/F) were calculated using non-compartmental analysis using Phoenix v8.0 software. Genotyping for CYP2B6, CYP2A6, CYP3A5, ABCB1, NR1I2, and NR1I3 single nucleotide polymorphism (SNPs) was performed by TaqMan® allelic discrimination method. The median (range) NVP dose received was 10 (7-14) mg/kg. Of the 53 participants, the median (range) C was 3.3 (0.0-14.0) mg/L and AUC was 56.0 (16.7-202.6) mg.hr/L. Using step-wise regression, CYP2B6 rs3745274 and NR1I2 rs6785049 SNPs were independent as well as joint predictors of NVP AUC, C, and CL/F. We concluded that genotyping for CYP2B6 rs3745274, and the NR1I2 rs6785049 G > A SNP (which encodes the transcriptional factor, pregnane X receptor), could improve prediction of NVP PK for individualized therapy.
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http://dx.doi.org/10.1016/j.meegid.2021.104856DOI Listing
August 2021

Single-cell resolution of lineage trajectories in the Arabidopsis stomatal lineage and developing leaf.

Dev Cell 2021 Apr;56(7):1043-1055.e4

Department of Biology, Stanford University, Stanford, CA 94305-5020, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305-5020, USA. Electronic address:

Dynamic cell identities underlie flexible developmental programs. The stomatal lineage in the Arabidopsis leaf epidermis features asynchronous and indeterminate divisions that can be modulated by environmental cues. The products of the lineage, stomatal guard cells and pavement cells, regulate plant-atmosphere exchanges, and the epidermis as a whole influences overall leaf growth. How flexibility is encoded in development of the stomatal lineage and how cell fates are coordinated in the leaf are open questions. Here, by leveraging single-cell transcriptomics and molecular genetics, we uncovered models of cell differentiation within Arabidopsis leaf tissue. Profiles across leaf tissues identified points of regulatory congruence. In the stomatal lineage, single-cell resolution resolved underlying cell heterogeneity within early stages and provided a fine-grained profile of guard cell differentiation. Through integration of genome-scale datasets and spatiotemporally precise functional manipulations, we also identified an extended role for the transcriptional regulator SPEECHLESS in reinforcing cell fate commitment.
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http://dx.doi.org/10.1016/j.devcel.2021.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054824PMC
April 2021

Optimal systolic blood pressure and reduced long-term mortality in older hypertensive women with prior coronary events - An analysis from INVEST☆.

Int J Cardiol Hypertens 2020 Dec 16;7:100052. Epub 2020 Sep 16.

Division of Cardiovascular Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.

Background: Hypertension and coronary artery disease (CAD) are a prevalent combination in older women, however limited data are available to guide blood pressure (BP) management. We hypothesized that older women with hypertension and CAD may not derive long-term benefit by achieving systolic BP (SBP) < 130 mmHg.

Methods: We analyzed long-term all-cause mortality data from the International Verapamil SR/Trandolapril Study (INVEST), stratified by risk attributable to clinical severity of CAD (women with prior coronary events of myocardial infarction or revascularization considered high risk, all others at low risk) and by age group (50-64 or ≥65 years). The prognostic impact of achieving mean in-trial SBP <130 (referent group) was compared with 130-139 and ≥ 140 mmHg using Cox proportional hazards, adjusting for demographic and clinical characteristics.

Results: SBPs <130, 130-139, and ≥140 were achieved in 2960, 3024, and 3232 women, respectively. Among high-risk women aged ≥65 years, those achieving SBP 130-139 mmHg had lower mortality up to 16.7 years later than those with SBP <130 (hazard ratio [HR] 0.81, 95% CI 0.69-0.96). High-risk women aged 50-64 achieving SBP 130-139 had a similar mortality risk as those with SBP <130 (HR 1.21, 95% CI 0.87-1.68), while those achieving SBP ≥140 mmHg had a higher mortality risk than SBP < 130 (HR 1.92, 95% CI 1.37-2.68). A similar pattern was observed among low-risk women ≥65 and <65 years old.

Conclusion: Among women ≥65 years old with hypertension and prior coronary events, in-trial SBP between 130 and 139 mmHg was associated with lower mortality over the long term versus SBP <130 mmHg.
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http://dx.doi.org/10.1016/j.ijchy.2020.100052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009246PMC
December 2020

Dual-energy computed tomography could reliably differentiate metastatic from non-metastatic lymph nodes of less than 0.5 cm in patients with papillary thyroid carcinoma.

Quant Imaging Med Surg 2021 Apr;11(4):1354-1367

Department of Radiology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China.

Background: Dual-energy computed tomography (DECT) has been widely applied to detect lymph node (LN) and lymph node metastasis (LNM) in various cancers, including papillary thyroid carcinoma (PTC). This study aimed to quantitatively evaluate metastatic cervical lymph nodes (LNs) <0.5 cm in patients with PTC using DECT, which has not been done in previous studies.

Methods: Preoperative DECT data of patients with pathologically confirmed PTC were retrospectively collected and analyzed between May 2016 and June 2018. A total of 359 LNs from 52 patients were included. Diameter, iodine concentration (IC), normalized iodine concentration (NIC), and the slope of the energy spectrum curve (λ) of LNs in the arterial and the venous phases were compared between metastatic and non-metastatic LNs. The optimal parameters were obtained from the receiver operating characteristic (ROC) curves. The generalized estimation equation (GEE) model was used to evaluate independent diagnostic factors for LNM.

Results: A total of 139 metastatic and 220 non-metastatic LNs were analyzed. There were statistical differences of quantitative parameters between the two groups (P value 0.000-0.007). The optimal parameter for diagnosing LNM was IC in the arterial phase, and its area under the curve (AUC), sensitivity, and specificity were 0.775, 71.9%, and 73.6%, respectively. When the three parameters of diameter, IC in the arterial phase, and NIC in the venous phase were combined, the prediction efficiency was better, and the AUC was 0.819. The GEE results showed that LNs located in level VIa [odds ratio (OR) 2.030, 95% confidence interval (CI): 1.134-3.634, P=0.017], VIb (OR 2.836, 95% CI: 1.597-5.038, P=0.000), diameter (OR 2.023, 95% CI: 1.158-3.532, P=0.013), IC in the arterial phase (OR 4.444, 95% CI: 2.808-7.035, P=0.000), and IC in the venous phase (OR 5.387, 95% CI: 3.449-8.413, P=0.000) were independent risk factors for LNM in patients with PTC.

Conclusions: DECT had good diagnostic performance in the differentiation of cervical metastatic LNs <0.5 cm in patients with PTC.
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http://dx.doi.org/10.21037/qims-20-846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930679PMC
April 2021

Mitochondrial aldehyde dehydrogenase (ALDH2) rescues cardiac contractile dysfunction in an APP/PS1 murine model of Alzheimer's disease via inhibition of ACSL4-dependent ferroptosis.

Acta Pharmacol Sin 2021 Mar 25. Epub 2021 Mar 25.

University of Wyoming College of Health Sciences, Laramie, WY, USA.

Alzheimer's disease (AD) is associated with high incidence of cardiovascular events but the mechanism remains elusive. Our previous study reveals a tight correlation between cardiac dysfunction and low mitochondrial aldehyde dehydrogenase (ALDH2) activity in elderly AD patients. In the present study we investigated the effect of ALDH2 overexpression on cardiac function in APP/PS1 mouse model of AD. Global ALDH2 transgenic mice were crossed with APP/PS1 mutant mice to generate the ALDH2-APP/PS1 mutant mice. Cognitive function, cardiac contractile, and morphological properties were assessed. We showed that APP/PS1 mice displayed significant cognitive deficit in Morris water maze test, myocardial ultrastructural, geometric (cardiac atrophy, interstitial fibrosis) and functional (reduced fractional shortening and cardiomyocyte contraction) anomalies along with oxidative stress, apoptosis, and inflammation in myocardium. ALDH2 transgene significantly attenuated or mitigated these anomalies. We also noted the markedly elevated levels of lipid peroxidation, the essential lipid peroxidation enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4), the transcriptional regulator for ACLS4 special protein 1 (SP1) and ferroptosis, evidenced by elevated NCOA4, decreased GPx4, and SLC7A11 in myocardium of APP/PS1 mutant mice; these effects were nullified by ALDH2 transgene. In cardiomyocytes isolated from WT mice and in H9C2 myoblasts in vitro, application of Aβ (20 μM) decreased cell survival, compromised cardiomyocyte contractile function, and induced lipid peroxidation; ALDH2 transgene or activator Alda-1 rescued Aβ-induced deteriorating effects. ALDH2-induced protection against Aβ-induced lipid peroxidation was mimicked by the SP1 inhibitor tolfenamic acid (TA) or the ACSL4 inhibitor triacsin C (TC), and mitigated by the lipid peroxidation inducer 5-hydroxyeicosatetraenoic acid (5-HETE) or the ferroptosis inducer erastin. These results demonstrate an essential role for ALDH2 in AD-induced cardiac anomalies through regulation of lipid peroxidation and ferroptosis.
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http://dx.doi.org/10.1038/s41401-021-00635-2DOI Listing
March 2021

Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality.

Eur Heart J 2021 05;42(18):1742-1756

Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, 1462 Clifton Road NE, Atlanta, GA 30322, USA.

Aims: Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown.

Methods And Results: We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality.

Conclusion: The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.
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http://dx.doi.org/10.1093/eurheartj/ehab107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244638PMC
May 2021

Tuning self-renewal in the Arabidopsis stomatal lineage by hormone and nutrient regulation of asymmetric cell division.

Elife 2021 03 19;10. Epub 2021 Mar 19.

Department of Biology, Stanford University, Stanford, United States.

Asymmetric and self-renewing divisions build and pattern tissues. In the Arabidopsis stomatal lineage, asymmetric cell divisions, guided by polarly localized cortical proteins, generate most cells on the leaf surface. Systemic and environmental signals modify tissue development, but the mechanisms by which plants incorporate such cues to regulate asymmetric divisions are elusive. In a screen for modulators of cell polarity, we identified , a negative regulator of ethylene signaling. We subsequently revealed antagonistic impacts of ethylene and glucose signaling on the self-renewing capacity of stomatal lineage stem cells. Quantitative analysis of cell polarity and fate dynamics showed that developmental information may be encoded in both the spatial and temporal asymmetries of polarity proteins. These results provide a framework for a mechanistic understanding of how nutritional status and environmental factors tune stem-cell behavior in the stomatal lineage, ultimately enabling flexibility in leaf size and cell-type composition.
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http://dx.doi.org/10.7554/eLife.63335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009662PMC
March 2021

Newly diagnosed cardiovascular disease in patients treated with immune checkpoint inhibitors: a retrospective analysis of patients at an academic tertiary care center.

Cardiooncology 2021 Mar 18;7(1):10. Epub 2021 Mar 18.

Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, PO Box 100486, 1345 Center Drive, Gainesville, FL, 32610-0486, USA.

Background: Immune checkpoint inhibitors (ICIs) are a novel class of anticancer agents that have demonstrated clinical response for both solid and hematological malignancies. ICIs are associated with development of immune-related adverse events including cardiotoxicity. We estimated the incidence of newly diagnosed cardiovascular disease in patients treated with ICIs at a large, tertiary care center.

Methods: All patients with a cancer diagnosis who received any ICI treatment in the University of Florida's Integrated Data Repository from 2011 to 2017 were included. Cardiovascular disease was defined as a new ICD diagnosis code for cardiomyopathy, heart failure, arrhythmia, heart block, pericardial disease, or myocarditis after initiation of ICI treatment.

Results: Of 102,701 patients with a diagnosis of malignancy, 424 patients received at least one ICI. Sixty-two (14.6%) patients were diagnosed with at least one new cardiovascular disease after initiation of ICI therapy. Of the 374 patients receiving one ICI, 21 (5.6%) developed heart failure. Of the 49 patients who received two ICIs sequentially, three (6.1%) developed heart failure and/or cardiomyopathy. Incident cardiovascular disease was diagnosed at a median of 63 days after initial ICI exposure. One patient developed myocarditis 28 days after receiving nivolumab. Mortality in ICI treated patients with a concomitant diagnosis of incident cardiovascular disease was higher compared to those who did not (66.1% vs. 41.4%, odds ratio = 2.77, 1.55-4.95, p = 0.0006).

Conclusions: This study suggests a high incidence of newly diagnosed cardiovascular disease after the initiation of ICI therapy in a real-world clinical setting.
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http://dx.doi.org/10.1186/s40959-021-00097-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977591PMC
March 2021
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