Publications by authors named "Wei Meng"

755 Publications

Identification of a Hydroxypyrimidinone Compound () as a Potent APJ Receptor Agonist for the Potential Treatment of Heart Failure.

J Med Chem 2021 Dec 2. Epub 2021 Dec 2.

Departments of Discovery Chemistry, Bristol Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.

This paper describes our continued efforts in the area of small-molecule apelin receptor agonists. Recently disclosed compound showed an acceptable metabolic stability but demonstrated monodemethylation of the dimethoxyphenyl group to generate atropisomer metabolites . In this article, we extended the structure-activity relationship at the C2 position that led to the identification of potent pyrazole analogues with excellent metabolic stability. Due to the increased polarity at C2, the permeability for these compounds decreased. Further adjustment of the polarity by replacing the N1 2,6-dimethoxyphenyl group with a 2,6-diethylphenyl group and reoptimization for the potency of the C5 pyrroloamides resulted in potent compounds with improved permeability. Compound displayed excellent pharmacokinetic profiles in rat, monkey, and dog models and robust pharmacodynamic efficacy in the rodent heart failure model. Compound also showed an acceptable safety profile in preclinical toxicology studies and was selected as a backup development candidate for the program.
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http://dx.doi.org/10.1021/acs.jmedchem.1c01504DOI Listing
December 2021

GP73 is a TBC-domain Rab GTPase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity.

Nat Commun 2021 Dec 1;12(1):7004. Epub 2021 Dec 1.

Department of Clinical Laboratory, the Third Medical Center, Chinese PLA General Hospital, Beijing, China.

The prevalence of non-obese nonalcoholic fatty liver disease (NAFLD) is increasing worldwide with unclear etiology and pathogenesis. Here, we show GP73, a Golgi protein upregulated in livers from patients with a variety of liver diseases, exhibits Rab GTPase-activating protein (GAP) activity regulating ApoB export. Upon regular-diet feeding, liver-GP73-high mice display non-obese NAFLD phenotype, characterized by reduced body weight, intrahepatic lipid accumulation, and gradual insulin resistance development, none of which can be recapitulated in liver-GAP inactive GP73-high mice. Common and specific gene expression signatures associated with GP73-induced non-obese NAFLD and high-fat diet (HFD)-induced obese NAFLD are revealed. Notably, metformin inactivates the GAP activity of GP73 and alleviates GP73-induced non-obese NAFLD. GP73 is pathologically elevated in NAFLD individuals without obesity, and GP73 blockade improves whole-body metabolism in non-obese NAFLD mouse model. These findings reveal a pathophysiological role of GP73 in triggering non-obese NAFLD and may offer an opportunity for clinical intervention.
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http://dx.doi.org/10.1038/s41467-021-27309-1DOI Listing
December 2021

Molecular characterization and expression patterns of glucocorticoid receptors in the viviparous black rockfish Sebastes schlegelii.

Gen Comp Endocrinol 2021 Nov 27:113947. Epub 2021 Nov 27.

Key Laboratory of Mariculture (Ocean University of China), Ministry of Education, Ocean University of China, Qingdao 266003, PR China. Electronic address:

Glucocorticoid receptors (GRs) are ligand-activated transcription factors associated with anti-inflammation, stress, metabolism and gonadal development. In this study, two gr genes (gr1 and gr2) were cloned and analyzed from a viviparous teleost, black rockfish (Sebastes schlegelii). The phylogenetic analysis of GRs showed that GR1 and GR2 clustered into teleost GR1 and GR2 separately and differed from the GRs of tetrapods or basal ray-finned fishes. Black rockfish GRs possess four modular domains of the nuclear receptor superfamily: an N-terminal domain (NTD), a DNA-binding domain (DBD), a hinge region (HR) and a ligand-binding domain (LBD). Nine conserved amino acid inserts were found in the GR1 DBD, and the ligand cavity-related amino acids of GR1 and GR2 LBD were slightly different. Tissue distribution analysis revealed that grs was widely expressed in various tissues, while cyp11b was mainly expressed in the testis and head kidney. The cyp11b transcripts were localized in the interrenal glands of the head kidney, the main source of cortisol; grs transcripts were detected in oocytes, the follicle layer and the ovarian wall. Histologically, significant blood vessel dilation was observed in the fetal membrane during or after parturition of black rockfish. The highest levels of serum cortisol and ovarian cyp11b mRNA were detected in parturition. In addition, the relative expression level of gr1 was upregulated significantly after delivery, while the levels of gr2 showed no significant change. In addition, in vitro GC treatment inhibited the expression of il1b but significantly upregulated the transcription of il1r1. These data provide evidence that GRs are likely to work as anti-inflammatory factors by inhibiting the functions of pro-inflammatory factors in the parturition of black rockfish.
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http://dx.doi.org/10.1016/j.ygcen.2021.113947DOI Listing
November 2021

Direct effect of RFRP-3 microinjection into the lateral ventricle on the hypothalamic kisspeptin neurons in ovariectomized estrogen-primed rats.

Exp Ther Med 2022 Jan 4;23(1):24. Epub 2021 Nov 4.

Graduate School, Chengde Medical University, Chengde, Hebei 067000, P.R. China.

RFamide-related peptide-3 (RFRP-3) may be involved in the inhibition of kisspeptin, but there is no direct evidence that RFRP-3 can directly act on kisspeptin neurons. The present study aimed to investigate the role and mechanism of RFRP-3 and kisspeptin in the hypothalamic-pituitary reproductive axis. In order to detect the expression and localization of RFRP-3 and kisspeptin in dorsomedial hypothalamic nucleus, double immunofluorescence method combined with confocal microscopy were performed. RFRP-3 was injected into the lateral ventricle of ovariectomized estrogen primed rats. Blood and brain tissues were collected at 60-, 120-, 240- and 360-min. Serum levels of gonadotropin-releasing hormone, luteinizing hormone and follicle-stimulating hormone were detected by ELISA. Kisspeptin expression in hypothalamus was detected by western blotting. Finally, surface plasmon resonance was used to verify whether RFRP-3 can directly interact with kisspeptin. Confocal images indicated that RFRP-3 and kisspeptin were co-expressed in the same neurons in the hypothalamus of ovariectomized estrogen-primed rats. Serum concentrations of gonadotropin-releasing hormone, luteinizing hormone and follicle-stimulating hormone were demonstrated to be significantly reduced following microinjection of RFRP-3 into the lateral ventricle for 60, 120, 240 and 360 min compared with the corresponding saline groups. The expression levels of kisspeptin in hypothalamus were gradually decreased following microinjection of RFRP-3 into the lateral ventricle. In addition, the affinity constant (K) of RFRP-3 binding to kisspeptin was 6.005x10 M, indicating that RFRP-3 bound directly to kisspeptin in the range of protein-protein binding strength (K, 10-10 M). In conclusion, RFRP-3 may regulate the hypothalamic-pituitary reproductive axis by inhibiting the expression of hypothalamic kisspeptin and direct binding.
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http://dx.doi.org/10.3892/etm.2021.10946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593914PMC
January 2022

Identification of 6-Hydroxypyrimidin-4(1)-one-3-carboxamides as Potent and Orally Active APJ Receptor Agonists.

ACS Med Chem Lett 2021 Nov 22;12(11):1766-1772. Epub 2021 Oct 22.

Research and Development, Bristol Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.

The apelin receptor (APJ) is a significant regulator of cardiovascular function and is involved in heart failure and other cardiovascular diseases. (Pyr)apelin-13 is one of the endogenous agonists of the APJ receptor. Administration of (Pyr)apelin-13 increases cardiac output in preclinical models and humans. Recently we disclosed clinical lead BMS-986224 (), a C3 oxadiazole pyridinone APJ receptor agonist with robust pharmacodynamic effects similar to (Pyr)apelin-13 in an acute rat pressure-volume loop model. Herein we describe the structure-activity relationship of the carboxamides as oxadiazole bioisosteres at C3 of the pyridinone core and C5 of the respective pyrimidinone core. This study led to the identification of structurally differentiated 6-hydroxypyrimidin-4(1)-one-3-carboxamide with pharmacodynamic effects comparable to those of compound .
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http://dx.doi.org/10.1021/acsmedchemlett.1c00385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8591725PMC
November 2021

Path Planning and Impedance Control of a Soft Modular Exoskeleton for Coordinated Upper Limb Rehabilitation.

Front Neurorobot 2021 1;15:745531. Epub 2021 Nov 1.

School of Electronic and Electrical Engineering, University of Leeds, Leeds, United Kingdom.

The coordinated rehabilitation of the upper limb is important for the recovery of the daily living abilities of stroke patients. However, the guidance of the joint coordination model is generally lacking in the current robot-assisted rehabilitation. Modular robots with soft joints can assist patients to perform coordinated training with safety and compliance. In this study, a novel coordinated path planning and impedance control method is proposed for the modular exoskeleton elbow-wrist rehabilitation robot driven by pneumatic artificial muscles (PAMs). A convolutional neural network-long short-term memory (CNN-LSTM) model is established to describe the coordination relationship of the upper limb joints, so as to generate adaptive trajectories conformed to the coordination laws. Guided by the planned trajectory, an impedance adjustment strategy is proposed to realize active training within a virtual coordinated tunnel to achieve the robot-assisted upper limb coordinated training. The experimental results showed that the CNN-LSTM hybrid neural network can effectively quantify the coordinated relationship between the upper limb joints, and the impedance control method ensures that the robotic assistance path is always in the virtual coordination tunnel, which can improve the movement coordination of the patient and enhance the rehabilitation effectiveness.
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http://dx.doi.org/10.3389/fnbot.2021.745531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8591133PMC
November 2021

Sacubitril Ameliorates Cardiac Fibrosis Through Inhibiting TRPM7 Channel.

Front Cell Dev Biol 2021 29;9:760035. Epub 2021 Oct 29.

State Key Laboratory of Natural Medicines, Department of Life Sciences and Technology, China Pharmaceutical University, Nanjing, China.

Heart failure caused by cardiac fibrosis has become a major challenge of public health worldwide. Cardiomyocyte programmed cell death (PCD) and activation of fibroblasts are crucial pathological features, both of which are associated with aberrant Ca influx. Transient receptor potential cation channel subfamily M member 7 (TRPM7), the major Ca permeable channel, plays a regulatory role in cardiac fibrosis. In this study, we sought to explore the mechanistic details for sacubitril, a component of sacubitril/valsartan, in treating cardiac fibrosis. We demonstrated that sacubitril/valsartan could effectively ameliorate cardiac dysfunction and reduce cardiac fibrosis induced by isoprotereno (ISO) . We further investigated the anti-fibrotic effect of sacubitril in fibroblasts. LBQ657, the metabolite of sacubitril, could significantly attenuate transforming growth factor-β 1 (TGF-β1) induced cardiac fibrosis by blocking TRPM7 channel, rather than suppressing its protein expression. In addition, LBQ657 reduced hypoxia-induced cardiomyocyte PCD suppression of Ca influx regulated by TRPM7. These findings suggested that sacubitril ameliorated cardiac fibrosis by acting on both fibroblasts and cardiomyocytes through inhibiting TRPM7 channel.
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http://dx.doi.org/10.3389/fcell.2021.760035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586221PMC
October 2021

Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells.

Cell Death Dis 2021 10 21;12(11):977. Epub 2021 Oct 21.

Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.

Inhibitors of the lipogenic enzyme fatty acid synthase (FASN) have attracted much attention in the last decade as potential targeted cancer therapies. However, little is known about the molecular determinants of cancer cell sensitivity to FASN inhibitors (FASNis), which is a major roadblock to their therapeutic application. Here, we find that pharmacological starvation of endogenously produced FAs is a previously unrecognized metabolic stress that heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors. Evaluation of the death decision circuits controlled by the BCL-2 family of proteins revealed that FASN inhibition is accompanied by the upregulation of the pro-death BH3-only proteins BIM, PUMA, and NOXA. Cell death triggered by FASN inhibition, which causally involves a palmitate/NADPH-related redox imbalance, is markedly diminished by concurrent loss of BIM or PUMA, suggesting that FASN activity controls cancer cell survival by fine-tuning the BH3 only proteins-dependent mitochondrial threshold for apoptosis. FASN inhibition results in a heightened mitochondrial apoptosis priming, shifting cells toward a primed-for-death state "addicted" to the anti-apoptotic protein BCL-2. Accordingly, co-administration of a FASNi synergistically augments the apoptosis-inducing activity of the dual BCL-X/BCL-2 inhibitor ABT-263 (navitoclax) and the BCL-2 specific BH3-mimetic ABT-199 (venetoclax). FASN inhibition, however, fails to sensitize breast cancer cells to MCL-1- and BCL-X-selective inhibitors such as S63845 and A1331852. A human breast cancer xenograft model evidenced that oral administration of the only clinically available FASNi drastically sensitizes FASN-addicted breast tumors to ineffective single-agents navitoclax and venetoclax in vivo. In summary, a novel FASN-driven facet of the mitochondrial priming mechanistically links the redox-buffering mechanism of FASN activity to the intrinsic apoptotic threshold in breast cancer cells. Combining next-generation FASNis with BCL-2-specific BH3 mimetics that directly activate the apoptotic machinery might generate more potent and longer-lasting antitumor responses in a clinical setting.
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http://dx.doi.org/10.1038/s41419-021-04262-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531299PMC
October 2021

Relay Catalysis by Achiral Borane and Chiral Phosphoric Acid in the Metal-Free Asymmetric Hydrogenation of Chromones.

Org Lett 2021 Nov 20;23(21):8565-8569. Epub 2021 Oct 20.

Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute for Chemistry, Chinese Academy of Sciences, Beijing 100190, China.

A strategy of relay catalysis by achiral borane and chiral phosphoric acid was successfully developed for the asymmetric hydrogenation of chromones, giving the desired products in high yields with up to 95% ee. Achiral borane and chiral phosphoric acid are highly compatible in this reaction. The achiral borane acts as a Lewis acid for the first-step hydrogenation, and the chiral phosphoric acid acts as an effective chiral proton shuttle to control the enantioselectivity.
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http://dx.doi.org/10.1021/acs.orglett.1c03286DOI Listing
November 2021

Preferential removal of benzene, toluene, ethylbenzene, and xylene (BTEX) by persulfate in ethanol-containing aquifer materials.

Environ Sci Pollut Res Int 2021 Oct 20. Epub 2021 Oct 20.

Collaborative Innovation Center for Water Pollution Control and Water Safety in Karst Area, Guilin University of Technology, Guilin, China.

The effective approaches to eliminate impacts of ethanol on the biodegradation of benzene, toluene, ethylbenzene, and xylene (BTEX) are concerned in the bioremediation of groundwater contaminated with ethanol-blended gasoline. In situ chemical oxidation (ISCO) is a common technique widely used for the remediation of contaminated groundwater. However, the selectivity of ISCO for BTEX and ethanol removal is poorly understood. Therefore, a batch experiment was performed with different aquifer materials, including calcareous soil, basalt soil, granite soil, dolomite, and sand. Gasoline was used to provide dissolved BTEX and ethanol reagent was used as additive to improve the quality of gasoline and to reduce the possibility of air pollution caused by gasoline. Persulfate (PS) was used as a chemical oxidant to oxidize organic contaminants. The target concentrations of BTEX and ethanol were 20 mg/L and 1000 mg/L, respectively. The results showed that ethanol could be preferentially degraded in the absence of PS and inhibit BTEX biodegradation. However, BTEX could be preferentially removed prior to ethanol in all aquifer materials used at ambient temperature, when PS was added at a PS/BTEX molar ratio of 150. Over 94% BTEX in sand, dolomite, and granite soil was preferentially removed with the first-order decay rate constants of 0.890-2.703 day within the first ~ 10 days, followed by calcareous and basalt soil at the constants of 0.123-0.371 day. Ethanol could compete with BTEX for sulfate radical at the first-order decay rate constants of 0.005-0.060 day for the first 25 days, which was slower than that of BTEX. The pH quickly decreased to < 2.5 in dolomite, sand, and granite soil, but maintained > 6.2 in calcareous soil. Rich organic matter in calcareous and basalt soil had an inhibition effect on BTEX oxidation by PS. The pH buffer in calcareous soil may imply the potential of PS oxidation combined with bioremediation in carbonate rock regions.
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http://dx.doi.org/10.1007/s11356-021-16926-4DOI Listing
October 2021

CBX7 is Dualistic in Cancer Progression Based on its Function and Molecular Interactions.

Front Genet 2021 1;12:740794. Epub 2021 Oct 1.

Department of Neurology, the First Affiliated Hospital of Nanchang University, Jiangxi Province, China.

Chromobox protein homolog 7 (CBX7) is a member of the Chromobox protein family and participates in the formation of the polycomb repressive complex 1(PRC1). In cells, CBX7 often acts as an epigenetic regulator to regulate gene expression. However, pathologically, abnormal expression of CBX7 can lead to an imbalance of gene expression, which is closely related to the occurrence and progression of cancers. In cancers, CBX7 plays a dual role; On the one hand, it contributes to cancer progression in some cancers by inhibiting oncosuppressor genes. On the other hand, it suppresses cancer progression by interacting with different molecules to regulate the synthesis of cell cycle-related proteins. In addition, CBX7 protein may interact with different RNAs (microRNAs, long noncoding RNAs, circular RNAs) in different cancer environments to participate in a variety of pathways, affecting the development of cancers. Furthermore, CBX7 is involved in cancer-related immune response and DNA repair. In conclusion, CBX7 expression is a key factor in the occurrence and progression of cancers.
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http://dx.doi.org/10.3389/fgene.2021.740794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517511PMC
October 2021

Screening Hit to Clinical Candidate: Discovery of BMS-963272, a Potent, Selective MGAT2 Inhibitor for the Treatment of Metabolic Disorders.

J Med Chem 2021 Oct 6;64(19):14773-14792. Epub 2021 Oct 6.

MGAT2 inhibition is a potential therapeutic approach for the treatment of metabolic disorders. High-throughput screening of the BMS internal compound collection identified the aryl dihydropyridinone compound (hMGAT2 IC = 175 nM) as a hit. Compound had moderate potency against human MGAT2, was inactive vs mouse MGAT2 and had poor microsomal metabolic stability. A novel chemistry route was developed to synthesize aryl dihydropyridinone analogs to explore structure-activity relationship around this hit, leading to the discovery of potent and selective MGAT2 inhibitors , , and that are stable to liver microsomal metabolism. After triaging out due to its inferior potency, pharmacokinetics, and structure-based liabilities and tetrazole due to its inferior channel liability profile, (BMS-963272) was selected as the clinical candidate following demonstration of on-target weight loss efficacy in the diet-induced obese mouse model and an acceptable safety and tolerability profile in multiple preclinical species.
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http://dx.doi.org/10.1021/acs.jmedchem.1c01356DOI Listing
October 2021

Distribution characteristics and potential pollution assessment of heavy metals (Cd, Pb, Zn) in reservoir sediments from a historical artisanal zinc smelting area in Southwest China.

Environ Sci Pollut Res Int 2021 Oct 4. Epub 2021 Oct 4.

College of Agriculture, Guizhou University, Guiyang, 550025, China.

Reservoir sediment contamination with heavy metals produced by mining activities has aroused widespread global concern owing to its potential threat to human health. In this study, the total concentrations and speciation of heavy metals (Cd, Pb, Zn) in the Lexi (LX) and Maoshui (MS) reservoirs around the historical artisanal zinc smelting area in Southwest China were determined, and pollution indices were applied to assess the pollution levels and potential ecological risks of the two reservoirs. The results showed that all the detected samples in the two reservoirs presented significant metal accumulation, especially for Cd, as compared with the soil background values in Guizhou Province. Between the two reservoirs, the vertical distribution characteristics of each metal in sediment columns were similar. The heavy metal concentrations of the three columns in the LX reservoir reached their maxima at 35, 15, and 10 cm and showed a trend of first increasing and then decreasing overall. However, the heavy metal contents of the three columns in the MS reservoir all exhibited wave-like characteristics in the vertical direction, and all of them reached a relatively obvious high point at approximately 5 and 30 cm. The geoaccumulation index (I) and potential ecological risk index (RI) indicated that Cd was strongly enriched and represented the main risk factor, and the pollution level of the MS reservoir was significantly higher than that of the LX reservoir. Furthermore, the effect coefficients (ERMQ) confirmed that the two reservoirs are likely to have toxic impacts on aquatic organisms and need to be controlled and mitigated. The speciation analysis of heavy metals revealed that Cd was primarily in the acid-extractable fraction (69.57%, 68.28%), Pb was chiefly in the reducible fraction (55.24%, 42.18%) and oxidizable fraction (22.60%, 38.02%), and Zn was mainly in the oxidizable fraction (32.54%, 37.65%) in the LX and MS reservoirs, respectively. The ratios of the secondary phase and primary phase (RSP) and risk assessment code (RAC) evaluation demonstrated that Cd in the sediments of the two reservoirs presents a very high potential ecological risk, and Pb and Zn were at medium to high ecological risk levels. This study highlighted that the artisanal zinc smelting activities had caused serious heavy metal pollution in reservoir sediments, posing a threat to the local ecological environment.
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http://dx.doi.org/10.1007/s11356-021-16824-9DOI Listing
October 2021

Prognostic value of CD169-positive macrophages in various tumors: a meta-analysis.

Bioengineered 2021 12;12(1):8505-8514

Department of Emergency Surgery, Department of Emergency Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China.

The study aimed to evaluate the prognostic value of CD169 expression in tumor-infiltrating macrophages from regional lymph nodes (RLN) in various tumors. In order to identify eligible articles, PubMed, EMBASE, Web of Science, and Cochrane Library were used to conduct a systematic search. Pooled hazard ratios (HRs) or odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were adopted to assess the relationship between CD169 expression and overall survival (OS) and clinicopathological characteristics. Ten studies, including eleven cohorts with 1699 patients, were enrolled. We found that high CD169 expression in tumor-infiltrating macrophages from RLN was associated with a favorable OS (HR = 0.56, 95%CI: 0.39-0.79, P = 0.001). Subgroup analysis showed that high CD169+ expression had more predictive power in digestive system tumors (HR = 0.52, 95%CI: 0.42-0.67, <0.001). In addition, high CD169 expression was significantly linked with lymph node metastasis (OR = 0.66, 95%CI: 0.47-0.94, P = 0.020) and TNM stage (OR = 0.62, 95%CI: 0.48-0.80, P < 0.001). High CD169 expression in tumor-infiltrating macrophages from RLN was correlated with favorable survival outcome in patients with malignancies. CD169 may be a novel and effective prognostic marker, especially for digestive system tumors.
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http://dx.doi.org/10.1080/21655979.2021.1985857DOI Listing
December 2021

3,4-diaminopyridine treatment for Lambert-Eaton myasthenic syndrome in adults: a meta-analysis of randomized controlled trials.

BMC Neurol 2021 Sep 25;21(1):371. Epub 2021 Sep 25.

Department of Neurosurgery, the First Affiliated Hospital of Nanchang University, No.17, Yongwai Street, Jiangxi Province, 330006, Nanchang, China.

Background: Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of neuromuscular transmission. The objective was to examine the efficacy and safety of 3,4-diaminopyridine (3,4-DAP) in patients with LEMS.

Methods: We searched several databases to identify relevant studies, including PubMed, EMBASE, Web of Science, MEDLINE, Cochrane Neuromuscular Disease Group Specialized Register and the Cochrane Central Register of Controlled Trials(CENTRAL). The primary outcome, quantitative myasthenia gravis (QMG) score and the secondary outcome, compound muscle action potentials (CMAP) amplitude were pooled by meta-analysis.

Results: Six randomised controlled trials (RCTs) involving 115 patients with LEMS were included. QMG score showed a significant decrease (improvement) of 2.76 points (95 % CI, -4.08 to -1.45, p < 0.001) after treatment with 3, 4-DAP. Moreover, the overall mean CMAP amplitude improved significantly in LEMS patients with 3, 4-DAP treatment, compared with placebo treatment (mean difference 1.34 mV, 95 % CI, 0.98 to 1.70, p < 0.001). The overall assessment of all included trials showed a low risk of bias and low heterogeneity.

Conclusions: The pooled results of RCTs demonsrated with moderate to high evidence that 3,4-DAP has a significant effect on LEMS treatment, with improvements in muscle strength score and CMAP amplitude.
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http://dx.doi.org/10.1186/s12883-021-02405-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464094PMC
September 2021

Randomized double-blind trial comparing low dose and conventional dose of a modified traditional herbal formula Guizhi Fuling Wan in women with symptomatic uterine fibroids.

J Ethnopharmacol 2022 Jan 22;283:114676. Epub 2021 Sep 22.

School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong; Department of Chinese Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China; Virginia University of Integrative Medicine, Fairfax, USA. Electronic address:

Ethnopharmacological Relevance: The herbal formula Guizhi Fuling Wan is one common remedy for treating uterine fibroids (UFs) and the relevant symptoms in Traditional Chinese Medicine (TCM). Previous systematic reviews showed that Guizhi Fuling Formula appeared to have additional benefit based on mifepristone treatment in reducing volume of fibroids.

Aim Of Study: To study the efficacy and safety of the conventional dose of a modified herbal formula Guizhi Fuling Wan in patients with symptomatic uterine fibroids in comparison with a sub-effective dose control.

Materials And Methods: This randomized double-blind, dosage-controlled trial was carried out in an outpatient clinic of traditional Chinese medicine in Hong Kong. Women with symptomatic uterine fibroids diagnosed according to the WHO International Classification of Diseases (ICD-10) were recruited and randomly assigned to one of two groups that received modified Guizhi Fuling Wan at either a low dose or the conventional dose on a daily basis for 16 weeks. This study was quality controlled by a data safety monitoring board. The primary outcome was the symptom severity as measured with the Uterine Fibroid Symptom-Quality of Life questionnaire. The secondary outcomes included quality of life, menstrual bleeding (measured on a pictorial blood loss assessment chart), pain severity (measured on the 6-point behavioral rating scale), change in Chinese medicine syndrome score, fibroid volume (measured by magnetic resonance imaging), hemoglobin level, and hormone levels.

Results: Seventy-eight women were recruited for this study. Between-groups comparison showed no significant difference at the endpoint for all outcomes except for the Chinese medicine syndrome score; however, at the endpoint, within-group comparison showed significant improvement in both groups relative to baseline in symptom severity, functional influence of pelvic pain, Chinese medicine syndrome score, and fibroid volume and uterus condition on magnetic resonance imaging (p < 0.05).The low-dose group yielded greater endpoint improvement in the Chinese medicine syndrome score than the conventional-dose group (p=0.024). No serious adverse events related to the intervention were noted.

Conclusion: Both low-dose and conventional-dose preparations significantly ameliorated uterine fibroid-related symptoms and fibroid volume, although no significant difference was found between the low-dose and conventional-dose groups. The herbal formula GuizhiFuling Wan is safe in women with uterine fibroids.
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http://dx.doi.org/10.1016/j.jep.2021.114676DOI Listing
January 2022

Efficacy and Safety of Chinese Herbal Medicine on Treatment of Breast Cancer: A Meta-analysis of Randomized Controlled Trials.

Am J Chin Med 2021 16;49(7):1557-1575. Epub 2021 Sep 16.

University of Hong Kong, School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P. R. China.

Breast cancer is currently the most common cancer in women, and it accounts for 11.6% of all cancer diagnoses in 2018. Breast cancer patients frequently resort to alternative medicine in addition to conventional Western therapy. This study is to evaluate clinical effectiveness of Chinese herbal medicine (CHM) on breast cancer by conducting meta-analyses on 81 randomized controlled trials (RCTs) with a total of 7215 subjects from eight databases. All RCTs compared patients using Western therapy alone and those using additional CHM therapy to evaluate the difference of primary (tumor response, mean time to progression (mTTP), overall survival (OS) and progression free survival (PFS)) and secondary outcome measures (tumor markers). Results showed that under the RECIST1.1 criteria, 52% patients with additional CHM therapy (67%, under WHO criteria) achieved either a complete response (CR) or a partial response (PR), compared to 38% patients with Western therapy alone (53%, under the WHO criteria). The risk ratio was 1.31 ([Formula: see text] < 0.00001, 95% CI = 1.15-1.50) for patients with CHM plus Western therapy and 1.25 ([Formula: see text] < 0.00001, 95% CI = 1.18-1.98) for those with Western therapy. Moreover, patients with complementary CHM therapy were associated with an mTTP of 2.79 months longer ([Formula: see text] < 0.00001) and an OS of 1.90 months longer ([Formula: see text] < 0.00001); they also had an increase in 3-year PFS ([Formula: see text]= 0.002), 2- ([Formula: see text]= 0.0002) and 5-year ([Formula: see text]= 0.006) OS rates. Therefore, complementary CHM therapy might demonstrate clinical benefits for breast cancer patients in terms of tumor response and survival. Clinical studies with further stratification of tumor stages and intervention types are highly warranted.
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http://dx.doi.org/10.1142/S0192415X21500737DOI Listing
September 2021

Visible light-driven self-powered aptasensors for ultrasensitive Microcystin-LR detection based on the carrier density effect of N-doped graphene hydrogel/hematite Schottky junctions.

Analyst 2021 Oct 11;146(20):6220-6227. Epub 2021 Oct 11.

Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, School of Petrochemical Engineering, Changzhou University, Changzhou 213164, China.

In this work, a novel visible light-driven self-powered photoelectrochemical (PEC) platform was designed based on 3D N-doped graphene hydrogel/hematite nanocomposites (NGH/FeO) a facile one-pot hydrothermal route. The coupling NGH with FeO could generate a Schottky junction, which promoted the separation of charges. Moreover, Mott-Schottky measurements validated that the carrier concentration achieved by NGH/FeO was about 3.4 × 10 times in comparison to that of pure FeO, which was beneficial for efficient charge transfer. Owing to the carrier density effect and Schottky junction, the photocurrent of the as-fabricated NGH/FeO nanocomposites was 6.9-fold higher than that of pure FeO. On the basis of such excellent Schottky junctions, an ultrasensitive visible light-induced self-powered PEC aptasensor was developed using a Microcystin-LR (MC-LR) aptamer. The as-fabricated PEC aptasensor displayed good analytical performance toward MC-LR detection in terms of wide linear range (1 pM-5 nM), low detection limit (0.23 pM, S/N = 3), excellent selectivity and high stability. This new strategy can provide a way for regulating nanostructures for more sensitive PEC sensors by increasing the carrier density.
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http://dx.doi.org/10.1039/d1an01462eDOI Listing
October 2021

Phylogeny and subcellular localization analyses reveal distinctions in monocot and eudicot class IV acyl-CoA-binding proteins.

Planta 2021 Sep 10;254(4):71. Epub 2021 Sep 10.

College of Life Science, Northeast Forestry University, Harbin, 150040, China.

Main Conclusion: Plant class IV ACBPs diverged with the split of monocots and eudicots. Difference in the subcellular localization supported the functional variation of plant class IV ACBP. Acyl-CoA-binding proteins (ACBPs) are divided into class I-IV in plants. Class IV ACBPs are kelch motif containing proteins that are specific to plants. The currently known subcellular localizations of plant class IV ACBPs are either in the cytosol (Arabidopsis) or in the peroxisomes (rice). However, it is not clear whether peroxisomal localization of class IV ACBP is a shared character that distinguishes eudicots and monocots. Here, the phylogeny of class IV ACBPs from 73 plant species and subcellular localization of class IV ACBPs from six monocots and eudicots were conducted. Phylogenetic analysis of 112 orthologues revealed that monocot class IV ACBPs were basal to the monophyletic clade formed by eudicots and basal angiosperm. Transient expression of GFP fusions in onion epidermal cells demonstrated that monocot maize (Zea mays), wheat (Triticum aestivum), and sorghum (Sorghum bicolor) and eudicot poplar (Populus trichocarpa) all contained at least one peroxisomal localized class IV ACBP, while orthologues from cucumber (Cucumis sativus L.) and soybean (Glycine max) were all cytosolic. Combining the location of Arabidopsis and rice class IV ACBPs, it indicates that maintaining at least one peroxisomal class IV ACBP could be a shared feature within the tested monocots, while cytosolic class IV ACBPs would be preferred in the tested eudicots. Furthermore, the interaction between OsACBP6 and peroxisomal ATP-binding cassette (ABC) transporter provided clues for the functional mechanism of OsACBP6.
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http://dx.doi.org/10.1007/s00425-021-03721-1DOI Listing
September 2021

Percutaneous Intracoronary Delivery of Plasma Extracellular Vesicles Protects the Myocardium Against Ischemia-Reperfusion Injury in Canis.

Hypertension 2021 Nov 7;78(5):1541-1554. Epub 2021 Sep 7.

Cardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University, The Sixth People's Hospital of Nantong (H.W., Y.X., C.S., M.W., J.Z., J.X., J.X.), Shanghai University, China.

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.17574DOI Listing
November 2021

Postoperative Coronary Artery Spasm After Mitral Valve Replacement and Cox-Maze IV Procedure: A Case Report.

Heart Surg Forum 2021 Aug 25;24(4):E731-E733. Epub 2021 Aug 25.

Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, P.R. China.

Background: Few cases have been reported about coronary artery spasm after a mitral valve replacement and concomitant Cox-Maze IV procedure. We report the case of an adult male who developed right coronary artery (RCA) spasm after a mitral valve replacement with tricuspid valve repair and Cox-Maze IV procedure.

Case Report: A 66-year-old male, complaining of progressive exertional shortness of breath, was diagnosed with severe mitral stenosis, moderate tricuspid regurgitation, complete right bundle branch block, and persistent atrial fibrillation (AF) in our clinic. The patient underwent elective mitral valve replacement, tricuspid valve repair, and Cox-Maze IV procedure. Four hours after surgery, a 12-lead electrocardiogram (ECG) showed progressive elevation of ST-segment in the avF and III leads and Troponin-T was over 7000 pg/mL. After one hour, Troponin-T increased to over 10000 pg/mL, and ECG still showed persisted ST-segment elevation in inferior leads. Emergent angiography was performed, and intra-coronary administration of nitroglycerin completely relieved the spasm.

Conclusion: Potential risks of coronary injury after valvular surgery and Cox-Maze IV procedure need further aggressive investigation and postoperative ischemia should prompt an emergent coronary angiography to identify the cause and apply immediate therapy.
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http://dx.doi.org/10.1532/hsf.4005DOI Listing
August 2021

Predicting Range of Initial Warfarin Dose Based on Pharmacometabolomic and Genetic Inputs.

Clin Pharmacol Ther 2021 12 13;110(6):1585-1594. Epub 2021 Sep 13.

Department of Clinical Pharmacy, Jinling Hospital, State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China.

Anticoagulation response to warfarin during the initial stage of therapy varies among individuals. In this study, we aimed to combine pharmacometabolomic and pharmacogenetic data to predict interindividual variation in warfarin response, and, on this basis, suggest an initial daily dose range. The baseline metabolic profiles, genotypes, and clinical information of 160 patients with heart valve disease served as the variables of the function of the last international normalized ratio measured before a patient's discharge (INR ) to screen for potential biomarkers. The partial least-squares model showed that two baseline metabolites (uridine and guanosine), one single-nucleotide variation (VKORC1), and four clinical parameters (weight, creatinine level, amiodarone usage, and initial daily dose) had good predictive power for INR (R  = 0.753 for the training set, 0.643 for the test set). With these biomarkers, a machine learning algorithm (two-dimensional linear discriminant analysis-multinomial logit model) was used to predict the subgroups with extremely warfarin-sensitive or less warfarin-sensitive patients with a prediction accuracy of 91% for the training set and 90% for the test set, indicating that individual responses to warfarin could be effectively predicted. Based on this model, we have successfully designed an algorithm,"IniWarD," for predicting an effective dose range in the initial 7-day warfarin therapy. The results indicate that the daily dose range suggested by the IniWarD system is more appropriate than that of the conventional genotype-based method, and the risk of bleeding or thrombus due to warfarin could thus be avoided.
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http://dx.doi.org/10.1002/cpt.2407DOI Listing
December 2021

The Detrimental and Beneficial Functions of Macrophages After Cochlear Injury.

Front Cell Dev Biol 2021 11;9:631904. Epub 2021 Aug 11.

MOE Key Laboratory for Developmental Genes and Human Disease, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, School of Life Sciences and Technology, Southeast University, Nanjing, China.

Macrophages are the main intrinsic immune cells in the cochlea; they can be activated and play a complicated role after cochlear injury. Many studies have shown that the number of macrophages and their morphological characteristics within the major cochlear partitions undergo significant changes under various pathological conditions including acoustic trauma, ototoxic drug treatment, age-related cochlear degeneration, selective hair cell (HC) and spiral ganglion neuron (SGN) elimination, and surgery. However, the exact role of these macrophages after cochlear injury is still unclear. Regulating the migration and activity of macrophages may be a therapeutic approach to reduce the risk or magnitude of trauma-induced hearing loss, and this review highlights the role of macrophages on the peripheral auditory structures of the cochlea and elucidate the mechanisms of macrophage injury and the strategies to reduce the injury by regulating macrophage.
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http://dx.doi.org/10.3389/fcell.2021.631904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385413PMC
August 2021

The Influences of Community-Enriched Environment on the Cognitive Trajectories of Elderly People.

Authors:
Shuyang Yu Meng Wei

Int J Environ Res Public Health 2021 08 23;18(16). Epub 2021 Aug 23.

National Institute of Social Development, Chinese Academy of Social Sciences, Beijing 100732, China.

To examine the influences of community-enriched environment on the cognitive trajectories of the elderly in China, using panel data of 10,057, 3994, 2387, and 1749 older persons aged 65-104 years of the 2005, 2008, 2011, and 2014 waves from the Chinese Longitudinal Health Longevity Survey (CLHLS) and a growth curve model, the authors analyzed the changing trend of elderly people's cognitive abilities with age. The influences of community-enriched environments on cognitive abilities were also investigated. Results show that when all the factors are out of consideration except age, for an older person aged 82.5 years, as he/she grows one year older, his/her cognitive abilities will be reduced by 0.139 points, while for one aged 92.5 years, they will be reduced by 0.199 points, which means cognitive abilities decline rapidly as the individuals grow older. The elderly people from communities with enriched environments have higher cognitive levels and slower declining speeds of cognitive abilities than the other elderly people, proving the long-term ability of such environments to facilitate cognitive abilities. An increase in the stimulation of the enriched environment is needed to prevent or slow down the degeneration of cognitive abilities.
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http://dx.doi.org/10.3390/ijerph18168866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394943PMC
August 2021

Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis.

Mol Cell 2021 Oct 25;81(19):4059-4075.e11. Epub 2021 Aug 25.

Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York YO10 5DD, UK.

DDX3X is a ubiquitously expressed RNA helicase involved in multiple stages of RNA biogenesis. DDX3X is frequently mutated in Burkitt lymphoma, but the functional basis for this is unknown. Here, we show that loss-of-function DDX3X mutations are also enriched in MYC-translocated diffuse large B cell lymphoma and reveal functional cooperation between mutant DDX3X and MYC. DDX3X promotes the translation of mRNA encoding components of the core translational machinery, thereby driving global protein synthesis. Loss-of-function DDX3X mutations moderate MYC-driven global protein synthesis, thereby buffering MYC-induced proteotoxic stress during early lymphomagenesis. Established lymphoma cells restore full protein synthetic capacity by aberrant expression of DDX3Y, a Y chromosome homolog, the expression of which is normally restricted to the testis. These findings show that DDX3X loss of function can buffer MYC-driven proteotoxic stress and highlight the capacity of male B cell lymphomas to then compensate for this loss by ectopic DDX3Y expression.
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http://dx.doi.org/10.1016/j.molcel.2021.07.041DOI Listing
October 2021

Incidence, Risk Factors, and Prognosis of Tricuspid Regurgitation After Cardiac Implantable Electronic Device Implantation: A Systematic Review and Meta-analysis.

J Cardiothorac Vasc Anesth 2021 Jun 25. Epub 2021 Jun 25.

Department of Cardiac Pacing and Electrophysiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, P.R., China; Xinjiang Key Laboratory of Cardiac Electrophysiology and Remodeling, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, P.R., China.

This study aimed to determine the pooled incidence, risk factors, and clinical prognosis of tricuspid regurgitation (TR) deterioration after implantation of a cardiac implantable electronic device (CIED). The study was designed as a meta-analysis of randomized controlled trials and observational studies. Patients with indications for CIEDs were selected as participants and CIED implantation was the intervention. PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure, Wanfang Data, and China Science and Technology Journal Database were searched systematically to identify studies. Thirty-seven studies with 8,144 patients were included. The pooled incidence of TR deterioration of at least one grade was 25.1% (95% confidence interval [CI], 20.9-29.3; Z = 11.60; p < 0.01; I = 94.8%, p < 0.01). Compared with TR incidence after permanent pacemaker implantation, that after implantable cardioverter-defibrillator implantation did not significantly increase (22.68% v 29.18%; odds ratio [OR], 0.615; 95% CI, 0.271-1.339; Z =1.16; p = 0.246). The pooled incidence of TR deterioration of at least two grades was 9.4% (95% CI, 6.6-12.1; Z = 6.72; p < 0.01; I = 86.0%, p < 0.01). Lead interference (OR, 8.704; 95% CI,4.450-17.028; Z= 6.32; p < 0.001) and pacemaker implantation time (OR, 1.153; 95% CI, 1.082-1.229; Z = 4.37; p < 0.001) were risk factors for worsening TR. Baseline atrial fibrillation, age, baseline mild TR, and left ventricular ejection fraction were not associated with TR. All-cause mortality (>one year after pacemaker implantation) was higher in patients with TR deterioration (hazard ratio, 1.598; 95% CI, 1.275-2.002; Z = 4.07; p < 0.01; I = 0%). TR is a common complication after CIED implantation. Lead interference and pacemaker implantation time were risk factors for TR worsening. Compared with patients without TR deterioration after pacemaker implantation, patients with TR deterioration had a poorer prognosis.
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http://dx.doi.org/10.1053/j.jvca.2021.06.025DOI Listing
June 2021

m6A Modification: A Double-Edged Sword in Tumor Development.

Front Oncol 2021 26;11:679367. Epub 2021 Jul 26.

Department of Pediatric Surgery, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.

Modification of m6A, as the most abundant mRNA modification, plays diverse roles in various biological processes in eukaryotes. Emerging evidence has revealed that m6A modification is closely associated with the activation and inhibition of tumor pathways, and it is significantly linked to the prognosis of cancer patients. Aberrant reduction or elevated expression of m6A regulators and of m6A itself have been identified in numerous tumors. In this review, we give a description of the dynamic properties of m6A modification regulators, such as methyltransferases, demethylases, and m6A binding proteins, and indicate the value of the balance between these proteins in regulating the expression of diverse genes and the underlying effects on cancer development. Furthermore, we summarize the "dual-edged weapon" role of RNA methylation in tumor progression and discuss that RNA methylation can not only result in tumorigenesis but also lead to suppression of tumor formation. In addition, we summarize the latest research progress on small-molecule targeting of m6A regulators to inhibit or activate m6A. These studies indicate that restoring the balance of m6A modification targeting specific imbalanced regulators may be a novel anti-cancer strategy.
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http://dx.doi.org/10.3389/fonc.2021.679367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350482PMC
July 2021

Correlation Between Prognostic Biomarker and Immune Infiltrates in Various Types of Cancers Including Hepatocellular Carcinoma.

Front Oncol 2021 22;11:608641. Epub 2021 Jul 22.

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Background: Solute carrier family 1 member 5 () is a major glutamine transporter and plays a key role in tumor growth. The main objectives of this study were to visualize the prognostic landscape of in multiple cancers and determine the relations between expression and tumor immunity.

Methods: expression and its effect on tumor prognosis were analyzed using multiple online tools Oncomine, Gene Expression Profiling Interactive Analysis, PrognoScan, and Kaplan-Meier plotter with their own datasets as well as the data from The Cancer Genome Atlas. The correlations between and tumor immune infiltrates were determined TIMER.

Results: expression was significantly higher in several types of cancers, including hepatocellular carcinoma (HCC), compared with corresponding normal tissues. High expression correlated with poor overall survival and with disease-free survival related to alcohol consumption. Moreover, expression correlated positively with the numbers of tumor-infiltrating B cells, CD4 T and CD8 T cells, macrophages, neutrophils, and dendritic cells in HCC and in lower-grade glioma (LGG). Also, expression showed strong correlations with diverse immune marker sets in HCC and LGG, indicating its role in regulating tumor immunity.

Conclusions: represents a useful prognostic biomarker in multiple cancers, and its expression correlates highly with tumor immune-cell infiltration, especially in HCC and LGG.
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http://dx.doi.org/10.3389/fonc.2021.608641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339971PMC
July 2021

Characterization of a -silenced high-grade serous ovarian cancer model during development of PARP inhibitor resistance.

NAR Cancer 2021 Sep 9;3(3):zcab028. Epub 2021 Jul 9.

Department of Obstetrics & Gynecology, University of Washington, Seattle, WA 98195, USA.

Acquired PARP inhibitor (PARPi) resistance in - or -mutant ovarian cancer often results from secondary mutations that restore expression of functional protein. is a less commonly studied ovarian cancer susceptibility gene whose promoter is sometimes methylated, leading to homologous recombination (HR) deficiency and PARPi sensitivity. For this study, the PARPi-sensitive patient-derived ovarian cancer xenograft PH039, which lacks HR gene mutations but harbors promoter methylation, was selected for PARPi resistance by cyclical niraparib treatment . PH039 acquired PARPi resistance by the third treatment cycle and grew through subsequent treatment with either niraparib or rucaparib. Transcriptional profiling throughout the course of resistance development showed widespread pathway level changes along with a marked increase in mRNA, which reflected loss of promoter methylation. Analysis of ovarian cancer samples from the ARIEL2 Part 1 clinical trial of rucaparib monotherapy likewise indicated an association between loss of methylation prior to on-study biopsy and limited response. Interestingly, the PARPi resistant PH039 model remained platinum sensitive. Collectively, these results not only indicate that PARPi treatment pressure can reverse methylation and restore RAD51C expression, but also provide a model for studying the clinical observation that PARPi and platinum sensitivity are sometimes dissociated.
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http://dx.doi.org/10.1093/narcan/zcab028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271218PMC
September 2021
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