Publications by authors named "Han Liu"

876 Publications

Ultrasound (US)-activated redox dyshomeostasis therapy reinforced by immunogenic cell death (ICD) through a mitochondrial targeting liposomal nanosystem.

Theranostics 2021 13;11(19):9470-9491. Epub 2021 Sep 13.

State Key Laboratory of Silkworm Genome Biology, School of Materials and Energy, Southwest University, Chongqing 400715, China.

An imbalance in redox homeostasis consistently inhibits tumor cell proliferation and further causes tumor regression. Thus, synchronous glutaminolysis inhibition and intracellular reactive oxygen (ROS) accumulation cause severe redox dyshomeostasis, which may potentially become a new therapeutic strategy to effectively combat cancer. Mitochondrial-targeting liposomal nanoparticles (abbreviated MLipRIR NPs) are synthesized by the encapsulation of R162 (inhibitor of glutamate dehydrogenase 1 [GDH1]) and IR780 (a hydrophobic sonosensitizer) within the lipid bilayer, which are exploited for ultrasound (US)-activated tumor dyshomeostasis therapy reinforced by immunogenic cell death (ICD). R162 released from MLipRIR NPs disrupts the glutaminolysis pathway in mitochondria, resulting in downregulated enzymatic activity of glutathione peroxidase (GPx). In addition, loaded IR780 can generate high levels of ROS under US irradiation, which not only interrupts mitochondrial respiration to induce apoptosis but also consumes local glutathione (GSH). GSH depletion accompanied by GPx deactivation causes severe ferroptosis of tumor cells through the accumulation of lipid peroxides. Such intracellular redox dyshomeostasis effectively triggers immunogenic cell death (ICD), which can activate antitumor immunity for the suppression of both primary and distant tumors with the aid of immune checkpoint blockade. Taking advantage of multimodal imaging for therapy guidance, this nanoplatform may potentiate systemic tumor eradication with high certainty. Taken together, this state-of-the-art paradigm may provide useful insights for cancer management by disrupting redox homeostasis.
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http://dx.doi.org/10.7150/thno.62984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490505PMC
September 2021

Specific Deubiquitinating Enzymes Promote Host Restriction Factors Against HIV/SIV Viruses.

Front Immunol 2021 22;12:740713. Epub 2021 Sep 22.

Center for Pathogen Biology and Infectious Diseases, Institute of Virology and AIDS Research, The First Hospital of Jilin University, Changchun, China.

Hijacking host ubiquitin pathways is essential for the replication of diverse viruses. However, the role of deubiquitinating enzymes (DUBs) in the interplay between viruses and the host is poorly characterized. Here, we demonstrate that specific DUBs are potent inhibitors of viral proteins from HIVs/simian immunodeficiency viruses (SIVs) that are involved in viral evasion of host restriction factors and viral replication. In particular, we discovered that T cell-functioning ubiquitin-specific protease 8 (USP8) is a potent and specific inhibitor of HIV-1 virion infectivity factor (Vif)-mediated apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3)G (A3G) degradation. Ectopic expression of USP8 inhibited Vif-induced A3G degradation and suppressed wild-type HIV-1 infectivity even in the presence of Vif. In addition, specific DUBs repressed Vpr-, Vpu-, and Vpx-triggered host restriction factor degradation. Our study has revealed a previously unrecognized interplay between the host's DUBs and viral replication. Enhancing the antiviral activity of DUBs therefore represents an attractive strategy against HIVs/SIVs.
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http://dx.doi.org/10.3389/fimmu.2021.740713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492978PMC
September 2021

Enhanced recovery after surgery protocols in total knee arthroplasty via midvastus approach: a randomized controlled trial.

BMC Musculoskelet Disord 2021 Oct 8;22(1):856. Epub 2021 Oct 8.

Department of Orthopaedic Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, China.

Background: Enhanced recovery after surgery (ERAS) protocols were rapidly adopted in many surgeries such as fast-track arthroplasty. The study aimed to investigate the impact of ERAS protocols on the clinical effect of total knee arthroplasty (TKA) via the midvastus approach.

Methods: A total of 69 patients who underwent primary unilateral TKA via the midvastus approach from October 2018 to June 2019 were enrolled and randomly divided into two groups: ERAS group and Control group. The ERAS protocols were adopted for the ERAS group and consisted of pure juice drinking 2 h before the surgery, optimization of the preoperative anesthesia plan, phased use of tourniquets, and the use of tranexamic acid as well as a drug cocktail. The operative time, first postoperative walking time, first straight leg elevation time, postoperative hospitalization time, visual analogue scale score (VAS score), Hospital for Special Surgery score (HSS score), conventional Knee Society score (KSS), and knee range of motion (ROM) were used to assess the clinical effects in the two groups. All the included patients were followed up for 12 months.

Results: There were no significant differences in the basic demographic information and operation time between the ERAS and Control groups (P > 0.05). The first postoperative walking time (2.11 ± 0.11 h) and first postoperative straight leg elevation time (6.14 ± 1.73 h) in the ERAS group were significantly earlier than those in the Control group (P < 0.001) and the postoperative hospitalization time was significantly shorter (3.11 ± 0.32 days). The postoperative mean VAS scores in both groups were significantly reduced compared with those before surgery (P < 0.001). The VAS scores for the ERAS group were significantly lower than those for the Control group at 1, 2, and 7 days after surgery (P < 0.001). The mean HSS scores, KSS, and knee ROM were significantly increased in both the ERAS and Control groups at 1, 3, 6, and 12 months after surgery (P < 0.001). In addition, the HSS scores, KSS, and knee ROM in the ERAS group were significantly higher than those in the Control group at 1 month after surgery (P < 0.001).

Conclusions: ERAS protocols improved the clinical effects of TKA via the midvastus approach, facilitating early out-of-bed activity and comfortable postoperative rehabilitation exercise, and further increasing patient satisfaction.

Trial Registration: ClinicalTrials.gov Identifier: NCT04873544 .
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http://dx.doi.org/10.1186/s12891-021-04731-6DOI Listing
October 2021

RBMS1 regulates lung cancer ferroptosis through translational control of SLC7A11.

J Clin Invest 2021 Oct 5. Epub 2021 Oct 5.

Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.

Ferroptosis, an iron-dependent non-apoptotic cell death, is a highly regulated tumor suppressing process. However, functions and mechanisms of RNA binding proteins in regulation of evasion of ferroptosis during lung cancer progression are still largely unknown. Here we reported that the RNA binding protein RBMS1 participated in lung cancer development through mediating ferroptosis evasion. Through an shRNA-mediated systematic screen, we discovered that RBMS1 was a key ferroptosis regulator. Clinically, RBMS1 was elevated in lung cancer and its high expression was associated with reduced patient survival. Conversely, depletion of RBMS1 inhibited lung cancer progression both in vivo and in vitro. Mechanistically, RBMS1 interacted with the translation initiation factor eIF3d directly to bridge the 3'- and 5'-UTRs of SLC7A11. RBMS1 ablation inhibited the translation of SLC7A11, reduced SLC7A11-mediated cystine uptake and promotes ferroptosis. In a drug screen that targeted RBMS1, we further uncovered that nortriptyline hydrochloride decreased the level of RBMS1, thereby promoting ferroptosis. Importantly, RBMS1 depletion or inhibition by nortriptyline hydrochloride sensitized radioresistant lung cancer cells to radiotherapy. Our findings established RBMS1 as a translational regulator of ferroptosis and a prognostic factor with therapeutic potentials and clinical values.
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http://dx.doi.org/10.1172/JCI152067DOI Listing
October 2021

LncRNA MEG3 restrained pulmonary fibrosis induced by NiO NPs via regulating hedgehog signaling pathway-mediated autophagy.

Environ Toxicol 2021 Oct 5. Epub 2021 Oct 5.

Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, China.

Long noncoding RNA maternally expressed gene 3 (lncRNA MEG3) was down-regulated in pulmonary fibrosis of rats induced by Nickel oxide nanoparticles (NiO NPs), while the downstream regulatory mechanisms of MEG3 remain unclear. This study aimed to investigate the relationship among MEG3, Hedgehog (Hh) signaling pathway and autophagy in pulmonary fibrosis caused by NiO NPs. The pulmonary fibrosis model in rats was constructed by intratracheal instillation of 0.015, 0.06, and 0.24 mg/kg NiO NPs twice a week for 9 weeks. Collagen deposition model was established by treating A549 cells with 25, 50, and 100 μg/mL NiO NPs for 24 h. Our results indicated that NiO NPs activated Hh pathway, down-regulated the expression of MEG3, and reduced autophagy activity in vivo and in vitro. Meanwhile, the autophagy process was promoted by Hh pathway inhibitor (CDG-0449), while the collagen formation in A549 cells was reduced by autophagy activator (Rapamycin). Furthermore, the overexpressed MEG3 inhibited the activation of Hh pathway, resulting in autophagy activity enhancement along with collagen formation reduction. In summary, lncRNA MEG3 can restrain pulmonary fibrosis induced by NiO NPs via regulating hedgehog signaling pathway-mediated autophagy, which may serve as a potential therapeutic strategy for pulmonary fibrosis.
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http://dx.doi.org/10.1002/tox.23379DOI Listing
October 2021

Tailoring effects of the chain length and terminal substituent on the photochromism of solid-state spiropyrans.

Org Biomol Chem 2021 Sep 30. Epub 2021 Sep 30.

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

Recently, by constructing a haloalkyl chain, a new class of solid-state spiropyrans showing advanced photochromic activity has been developed, but the tailoring effect of the haloalkyl chain on photochromism is unclear. Here, the photochromism of solid-state spiropyrans with different chain lengths and end substituents is investigated, which gives a clear correlation between the chain length/end substituent and the thermodynamic stability of zwitterionic merocyanine. This work provides a useful designing strategy for tailoring the photochromism of solid-state spiropyrans.
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http://dx.doi.org/10.1039/d1ob01797gDOI Listing
September 2021

Synthetic Pseudaminic-Acid-Based Antibacterial Vaccine Confers Effective Protection against Infection.

ACS Cent Sci 2021 Sep 8;7(9):1535-1542. Epub 2021 Sep 8.

Department of Chemistry, the State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, 999077 Pokfulam, Hong Kong SAR, P. R. China.

exhibits resistance to most first-line antibiotics; thus, development of new antibacterial agents is urgently required. Pseudaminic acid exists as the surface glycan of . In this study, we chemically synthesized pseudaminic acid, conjugated it to carrier protein CRM197 using the OPA (-phthalaldehyde) chemistry, and obtained three Pse-CRM197 conjugates with different Pse loadings. These Pse-CRM197 conjugates were found to stimulate high immune responses in mice, which protected the vaccinated mice from infections caused by Pse-producing . Our data indicate that chemically synthesized Pse-CRM197 conjugates can be developed into vaccines against Pse-bearing pathogens, thus offering a feasible alternative for the control of clinical infections caused by multidrug-resistant (MDR) , for which current treatment options are extremely limited.
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http://dx.doi.org/10.1021/acscentsci.1c00656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461771PMC
September 2021

Soft Elastomeric Capacitor for Strain and Stress Monitoring on Sutured Skin Tissues.

ACS Sens 2021 Sep 28. Epub 2021 Sep 28.

Department of Mechanical Engineering, University of St. Thomas, St. Paul, Minnesota 55105, United States.

Sutures are ubiquitous medical devices for wound closures in human and veterinary medicine, and suture techniques are frequently evaluated by comparing tensile strengths in studies. Direct and nondestructive measurement of tensile force present in sutured biological skin tissue is a key challenge in biomechanical fields because of the unique and complex properties of each sutured skin specimen and the lack of compliant sensors capable of monitoring large levels of strain. The authors have recently proposed a soft elastomeric capacitor (SEC) sensor that consists of a highly compliant and scalable strain gauge capable of transducing geometric variations into a measurable change in capacitance. In this study, corrugated SECs are used to experimentally characterize the inherent biomechanical properties of canine skin specimens. In particular, an SEC corrugated with a re-entrant hexagonal honeycomb pattern is studied to monitor strain and stresses for three specific suture patterns: simple interrupted, cruciate, and intradermal patterns. Stress is estimated using constitutive models based on the Fractional Zener and the Kelvin-Voigt models, parametrized using a particle swarm algorithm from experimental data and results from a validated finite element model. Results are benchmarked against findings from the literature and show that SECs are valuable for clinical evaluation of tensile force in biological skins. It was found that both the ranking of suture pattern performance and the sutured skin's Young's modulus using the proposed approach agreed with data reported in the literature and that the estimated stress at the suture level closely matched that of an approximate finite element model.
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http://dx.doi.org/10.1021/acssensors.1c01477DOI Listing
September 2021

miR-6869-5p Transported by Plasma Extracellular Vesicles Mediates Renal Tubule Injury and Renin-Angiotensin System Activation in Obesity.

Front Med (Lausanne) 2021 8;8:725598. Epub 2021 Sep 8.

Central Laboratory, The Fifth Affiliated Hospital of Jinan University, Heyuan, China.

Obesity increases the risk of other diseases, including kidney disease. Local renal tubular renin-angiotensin system (RAS) activation may play a role in obesity-associated kidney disease. Extracellular vehicles (EVs) transmit necessary information in obesity and cause remote organ damage, but the mechanism is unclear. The aim of the study was to investigate whether the plasma EVs cargo miR-6869-5p causes RAS activation and renal tubular damage. We isolated plasma EVs from obese and lean subjects and analyzed differentially-expressed miRNAs using RNA-seq. Then, EVs were co-cultured with human proximal renal tubular epithelial cells (PTECs) . Immunohistochemical pathology was used to assess the degree of RAS activation and tubule injury . The tubule damage-associated protein and RAS activation components were detected by Western blot. Obesity led to renal tubule injury and RAS activation in humans and mice. Obese-EVs induce RAS activation and renal tubular injury in PTECs. Importantly, miR-6869-5p-treated PTECs caused RAS activation and renal tubular injury, similar to Obese-EVs. Inhibiting miR-6869-5p decreased RAS activation and renal tubular damage. Our findings indicate that plasma Obese-EVs induce renal tubule injury and RAS activation via miR-6869-5p transport. Thus, miR-6869-5p in plasma Obese-EVs could be a therapeutic target for local RAS activation in obesity-associated kidney disease.
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http://dx.doi.org/10.3389/fmed.2021.725598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455906PMC
September 2021

Overexpression Impairs the Development of Muscles, Tendons, and Aponeurosis in Soft Palates by Disrupting BMP-Smad and Shh-Gli1 Signaling.

Front Cell Dev Biol 2021 7;9:711334. Epub 2021 Sep 7.

Department of Oral Pathology, School of Stomatology, Dalian Medical University, Dalian, China.

The roles of bone morphogenetic protein (BMP) signaling in palatogenesis were well documented in the developing hard palate; however, little is known about how BMP signaling regulates the development of soft palate. In this study, we overexpressed transgene via allele to suppress BMP signaling in the developing soft palate. We found that BMP-Smad signaling was detected in the palatal muscles and surrounding mesenchyme. When BMP-Smad signaling was suppressed by the overexpressed , the soft palatal shelves were reduced in size with the hypoplastic muscles and the extroversive hypophosphatasia (HPP). The downregulated cell proliferation and survival in the soft palates were suggested to result from the repressed transcription and Gli1 activity, implicating that the BMP-Shh-Gli1 network played a similar role in soft palate development as in the hard palate. The downregulated Sox9, (), and expression in soft palate indicated the impaired differentiation of the aponeurosis and tendons, which was suggested to result in the hypoplasia of palatal muscles. Intriguingly, in the and the soft palates, the hypoplastic or abrogated muscles affected little the fusion of soft palate. Although the , , and transcription was significantly repressed in the tenogenic mesenchyme of the soft palate, the Sox9 expression, and the and transcription in aponeurosis mesenchyme were almost unaffected. It implicated that the fusion of soft palate was controlled by the mesenchymal clues at the tensor veli palatini (TVP) and levator veli palatini (LVP) levels, but by the myogenic components at the palatopharyngeus (PLP) level.
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http://dx.doi.org/10.3389/fcell.2021.711334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453081PMC
September 2021

GPR120 inhibits colitis through regulation of CD4T cell IL-10 production.

Gastroenterology 2021 Sep 15. Epub 2021 Sep 15.

Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, 77555, USA; Department of Pathology, The University of Texas Medical Branch, Galveston, TX, 77555, USA. Electronic address:

Background & Aims: G protein-coupled receptor (GPR) 120 has been implicated in regulating metabolic syndromes with anti-inflammatory function. However, the role of GPR120 in intestinal inflammation is unknown. Here, we investigated whether and how GPR120 regulates CD4T cell function to inhibit colitis development.

Methods: Dextran sodium sulfate (DSS)-induced colitis model, Citrobacter rodentium infection model, and CD4T cell adoptive transfer model were utilized to analyze the role of GPR120 in regulating colitis development. The effect of GPR120 on CD4T cell functions was analyzed by RNA sequencing, flow cytometry, and Seahorse metabolic assays. Mice were administered GPR120 agonist for investigating the potential of GPR120 agonist in preventing and treating colitis.

Results: Deficiency of GPR120 in CD4T cells resulted in more severe colitis in mice upon DSS insult and enteric infection. Transfer of GPR120-deficient CD4CD45RbT cells induced more severe colitis in Rag mice with lower intestinal IL-10CD4T cells. Treatment with GPR120 agonist, CpdA, promoted CD4T cell production of IL-10 by upregulating Blimp1 and enhancing glycolysis, which was regulated by mTOR. GPR120 agonist-treated wild-type but not IL-10-deficient and Blimp1-deficient Th1 cells induced less severe colitis. Furthermore, oral administration of GPR120 agonist protected mice from intestinal inflammation in both prevention and treatment schemes. Gpr120 expression was positively correlated with Il10 expression in the human colonic mucosa, including patients with inflammatory bowel diseases (IBD).

Conclusions: Our findings demonstrate the role of GPR120 in regulating intestinal CD4T cell production of IL-10 to inhibit colitis development, which identifies GPR120 as a potential therapeutic target for treating IBD.
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http://dx.doi.org/10.1053/j.gastro.2021.09.018DOI Listing
September 2021

Association between cesarean section and sensory integration dysfunction in preschool children: a prospective cohort study.

Zhongguo Dang Dai Er Ke Za Zhi 2021 Aug;23(8):773-778

Department of Child Health Care, Children's Hospital of Shanghai/Children's Hospital of Shanghai Jiao Tong University, Shanghai 200062, China.

Objectives: To study the association between cesarean section and sensory integration dysfunction (SID) in preschool children through a prospective cohort study.

Methods: Based on the multicenter mother-infant cohort established by the Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine and the International Peace Maternity and Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine in 2012, the sensory integration functions (three dimensions: vestibular balance, tactile defensiveness, and proprioception) of 392 preschool children were evaluated by the Chinese Children Sensory Integration Capacity Development Rating Scale in 2017. Births by cesarean section were the exposure factors, and the children born by vaginal delivery were enrolled as controls. A multivariable logistic regression analysis was used to evaluate the association of cesarean section with each dimension of SID.

Results: The prevalence rate of SID was 21.9% (86/392) among the preschool children, and the prevalence rates of vestibular balance disorder, tactile over-responsivity, and proprioceptive disorder were 5.9% (23/392), 5.4% (21/392), and 15.1% (59/392) respectively. After adjustment for the confounding factors including maternal age at delivery and maternal educational level and child birth situation, the cesarean section group had a significant increase in the risk of proprioceptive disorder (=4.16, 95%: 1.41-12.30, <0.05). The stratified analysis based on sex showed that the boys born by cesarean section had a significantly higher risk of proprioceptive disorder than those born by vaginal delivery (=5.75, 95%: 1.26-26.40, <0.05).

Conclusions: Cesarean section can significantly increase the risk of proprioceptive disorder in preschool children, especially in boys.
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http://dx.doi.org/10.7499/j.issn.1008-8830.2104115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428918PMC
August 2021

Echinatin mitigates H2O2-induced oxidative damage and apoptosis in lens epithelial cells via the Nrf2/HO-1 pathway.

Adv Clin Exp Med 2021 Sep 9. Epub 2021 Sep 9.

Chongqing Aier Eye Hospital, China.

Background: Oxidative stress has been reported to be an early factor in the development of cataracts. Echinatin (Ech) is an active ingredient of licorice that exhibits antioxidant effects.

Objectives: To investigate the effects of Ech on oxidative stress-induced lens epithelial cell (LEC) damage.

Material And Methods: Human lens epithelial B3 cells (HLECs) were exposed to hydrogen peroxide (H2O2) and were pretreated with or without Ech. For rescue experiments, ML385, an inhibitor of the Nrf2 pathway, was added into the medium.

Results: Echinatin reversed the H2O2-induced reduction of cell viability in B3 cells. Additionally, H2O2 induced oxidative stress, evidenced by an increase of reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and a decrease in superoxide dismutase (SOD) and catalase (CAT) levels, which could be abolished by Ech. Echinatin treatment also reduced HLEC apoptosis induced by H2O2. In addition, Ech pretreatment promoted Bcl-2 expression, and suppressed Bax and caspase-3 expression levels, in H2O2-treated B3 cells. Moreover, H2O2 significantly reduced Nrf2 nuclear localization, as well as HO-1 and NQO1 expression, which could be reversed by Ech. Inhibition of Nrf2 by ML385 aggravated H2O2-induced oxidative damage and apoptosis in HLECs, and the protective effects of Ech on H2O2-induced oxidative damage and apoptosis could be restored by ML385.

Conclusions: Echinatin mitigates H2O2-induced oxidative damage and apoptosis in HLECs via the Nrf2/HO-1 pathway, suggesting that Ech may be a potential drug for the treatment of cataracts.
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http://dx.doi.org/10.17219/acem/139130DOI Listing
September 2021

Tadalafil enhances the therapeutic efficacy of BET inhibitors in hepatocellular carcinoma through activating Hippo pathway.

Biochim Biophys Acta Mol Basis Dis 2021 Dec 9;1867(12):166267. Epub 2021 Sep 9.

Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou 310009, China; Cancer Center of Zhejiang University, Hangzhou 310058, China. Electronic address:

Bromodomain and extraterminal (BET) proteins are promising therapeutic targets for hematological and solid tumors. However, BET inhibitor monotherapy did not show a significant therapeutic benefit for hepatocellular carcinoma (HCC) in preclinical trials. Here, we identified YAP/TAZ genes, as determinants for sensitivity to BET inhibitors. YAP/TAZ expression, especially TAZ, promote resistance to BET inhibitor. In addition, we analyzed that the mRNA level of PDE5 was positively correlated with YAP/TAZ based on TCGA database and demonstrated tadalafil, a PDE5 inhibitor, could block YAP/TAZ protein expression by activating Hippo pathway. Cotreatment with tadalafil and JQ-1 synergistically reduced YAP/TAZ protein expression, suppressed proliferation and induced G0-G1 arrest of cultured HCC cells. JQ-1 alone does not show significant benefits in a mouse model of HCC induced by c-Myc/N-Ras plasmids. In contrast, the combination, tadalafil and JQ-1, successfully suppressed tumor progression, enhanced antitumor immunity by improving the ratio of activated CD8 and extended the survival time of mice. Our data define the key role of YAP/TAZ in mediating resistance to BET inhibitor, described the PDE5/PKG/Hippo/YAP/TAZ axis and identified a common clinical drug that can be developed as an effective combined strategy to overcome BET inhibitor resistance in MYC/Ras-driven HCC.
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http://dx.doi.org/10.1016/j.bbadis.2021.166267DOI Listing
December 2021

Genome-Wide Association Study of Vascular Bundle-Related Traits in Maize Stalk.

Front Plant Sci 2021 16;12:699486. Epub 2021 Jul 16.

State Key Laboratory of North China Crop Improvement and Regulation, Hebei Sub-center for National Maize Improvement Center, College of Agronomy, Hebei Agricultural University, Baoding, China.

The vascular bundle plays an important role in nutrient transportation in plants and exerts great influence on crop yield. Maize is widely used for food, feed, and fuel, producing the largest yield in the world. However, genes and molecular mechanism controlling vascular bundle-related traits in maize have largely remained undiscovered. In this study, a natural population containing 248 diverse maize inbred lines genotyped with high-throughput SNP markers was used for genome-wide association study. The results showed that broad variations existed for the vascular bundle-related traits which are subject to genetic structure and it was suitable for association analysis. In this study, we identified 15, 13, 2, 1, and 5 SNPs significantly associated with number of small vascular bundle, number of large vascular bundle, average area of single small vascular bundle, average area of single large vascular bundle, and cross-sectional area, respectively. The 210 candidate genes in the confidence interval can be classified into ten biological processes, three cellular components, and eight molecular functions. As for the Kyoto Encyclopedia of Genes and Genomes analysis of the candidate genes, a total of six pathways were identified. Finally, we found five genes related to vascular development, three genes related to cell wall, and two genes related to the mechanical strength of the stalk. Our results provide the further understanding of the genetic foundation of vascular bundle-related traits in maize stalk.
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http://dx.doi.org/10.3389/fpls.2021.699486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423097PMC
July 2021

The effectiveness and feasibility of fluid resuscitation directed by microcirculation monitoring in patients with septic shock: a randomized controlled trial.

Ann Palliat Med 2021 Aug;10(8):9069-9077

Department of Emergency and Critical Care, Shanghai Changzheng Hospital, Naval Military Medical University, Shanghai, China.

Background: This study sought to examine fluid resuscitation in septic shock patients by monitoring their sublabial point of care microcirculation score (POEM) scores (a 3.5 cut-off value was used as the end point of recovery). It also sought to explore the effectiveness and safety of using the POEM score in the fluid resuscitation of septic shock.

Methods: Patients were randomly allocated to the experimental group or the control group. In the experimental group, a POEM score >3 was used as the end point of fluid resuscitation. In the control group, the doctor just monitor, don't know the data. Patients' heart rates, mean arterial pressure (MAP), Acute Physiology and Chronic Health Disease Classification System II (APACHE II) scores, Sequential Organ Failure Assessment (SOFA) scores, and oxygenation index scores were recorded at 2, 24, 48, 72 h, and on the 7th day after admission to the study. Statistically significant differences between the 2 groups were examined.

Results: Thirty-one septic shock patients (comprising 14 patients in the experimental group and 17 patients in the control group) participated in our study. Patients' parameters upon admission to the study, including MAP, blood lactate and APACHE score, SOFA score, POEM score, cardiac output (CO), and central venous pressure (CVP), were recorded at 2 h; There was no significant difference in the APACHE II scores, SOFA scores, and oxygenation index scores at 48 h between the 2 groups; however, at 72 h, the scores of the experimental group were significantly better than those of the control group (P<0.05).

Conclusions: Under the guidance of POEM scores, limited fluid resuscitation reduced the intake of fluid any unnecessary amounts of fluids. POEM scores also offered certain protective effects to organ function at the early stage of septic shock, and did not affect patients' circulation.

Trial Registration: Chinese Clinical Trial Registry (ChiCTR2100049510).
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http://dx.doi.org/10.21037/apm-21-1971DOI Listing
August 2021

Real-world efficacy of osimertinib in previously EGFR-TKI treated NSCLC patients without identification of T790M mutation.

J Cancer Res Clin Oncol 2021 Aug 26. Epub 2021 Aug 26.

Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ, USA.

Background: The efficacy of osimertinib in previously EGFR-TKI-treated NSCLC without identification of T790M mutational status remains unclear in real-world practice.

Patients And Methods: 417 patients had stage III-IV NSCLC harboring EGFR mutation and 154 out of 417 patients receiving osimertinib as ≥ second-line EGFR-TKI were identified. The time to treatment failure and risk of death were analyzed.

Results: Higher risk of death was found in EGFR-mutant patients with age ≥ 65 years, non-adenocarcinoma, no surgery or radiation, non-exon 19 deletion/exon 21 L858R, higher ECOG PS (2-4), PD-L1 expression ≥ 50%, and bone/liver/adrenal metastasis (all p < 0.05). Osimertinib as ≥ second-line TKI in patients with/without identification of T790M revealed lower risk of death compared to first-line first/second generation TKI without subsequent osimertinib (p = 0.0002; 0.0232, respectively). However, osimertinib-treated patients with T790M did not have superior survival than those without (p = 0.2803). A higher risk of treatment failure for osimertinib was found in males, patients with first-line TKI duration ≤ 12 months, BMI drop > 10%, and PD-L1 expression ≥ 50% (All p < 0.05). Nonetheless, osimertinib as ≥ second-line TKI in patients without identification of 790 M did not have higher risk of treatment failure than those with T790M (p = 0.1236).

Conclusions: This study demonstrates that osimertinib as second line or subsequent TKI in EGFR-TKI-treated patients without identification of T790M revealed lower risk of death compared to first-line first/second generation TKI without subsequent osimertinib, in real-world practice. Additionally, EGFR-mutant patients with PD-L1 expression ≥ 50% had a higher risk of treatment failure for osimertinib and worse overall survival than those with PD-L1 expression < 50%. These results suggest that osimertinib as second line or subsequent TKI may be a potential alternative option for the treatment of patients without identification of T790M and PD-L1 expression ≥ 50% is associated with a significantly poor outcome in patients receiving osimertinib.
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http://dx.doi.org/10.1007/s00432-021-03766-5DOI Listing
August 2021

Case Report: Life-Threatening Post-operative Hemorrhage in Klippel-Trenaunay Syndrome Associated With Hypofibrinogenemia.

Front Med (Lausanne) 2021 9;8:669793. Epub 2021 Aug 9.

Department of Critical-Care Medicine, Qilu Hospital of Shandong University, Shandong University, Jinan, China.

Klippel-Trenaunay Syndrome (KTS) is a rare congenital disorder, characterized by venous and lymphatic malformations of the skin, soft tissue, and bone, causing limb hypertrophy. Although, a ruptured hemorrhagic corpus luteum is a rare condition in women of reproductive age, it can result in lethal outcomes. Here, we have described a patient with KTS and hypofibrinogenemia who went through recurrent lethal postoperative bleeding due to a ruptured hemorrhagic corpus luteum. This case suggested that conservative therapy might be the first choice and effective therapy for the patients with KTS, who suffered from bleeding complications of surgical therapy.
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http://dx.doi.org/10.3389/fmed.2021.669793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380826PMC
August 2021

Comparative transcriptome analysis of and -mediated defense responses in transgenic tomato.

PeerJ 2021 9;9:e11965. Epub 2021 Aug 9.

College of Horticulture, Henan Agricultural University, Zhengzhou, Henan, China.

Late blight caused by is one of the most devastating diseases in potatoes and tomatoes. At present, several late blight resistance genes have been mapped and cloned. To better understand the transcriptome changes during the incompatible interaction process between and , in this study, after spraying DEX, the leaves of MM-- and MM- transgenic plants at different time points were used for comparative transcriptome analysis. A total of 7,324 repeated DEGs were detected in MM-- plants at 2-h and 6-h, and 729 genes were differentially expressed at 6-h compared with 2-h. Only 1,319 repeated DEGs were found in MM- at 2-h and 6-h, of which 330 genes have the same expression pattern. Based on GO, KEGG and WCGNA analysis of DEGs, the phenylpropanoid biosynthesis, plant-pathogen interaction, and plant hormone signal transduction pathways were significantly up-regulated. Parts of the down-regulated DEGs were enriched in carbon metabolism and the photosynthesis process. Among these DEGs, most of the transcription factors, such as , , and , related to disease resistance or endogenous hormones SA and ET pathways, as well as , , gene were also significantly induced. Our results provide transcriptome-wide insights into and -mediated incompatibility interaction.
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http://dx.doi.org/10.7717/peerj.11965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359799PMC
August 2021

Towards an open and synergistic framework for mapping global land cover.

PeerJ 2021 4;9:e11877. Epub 2021 Aug 4.

Ministry of Education Key Laboratory for Earth System Modeling, Department of Earth System Science, Tsinghua University, Beijing, China.

Global land-cover datasets are key sources of information for understanding the complex inter-actions between human activities and global change. They are also among the most critical variables for climate change studies. Over time, the spatial resolution of land cover maps has increased from the kilometer scale to 10-m scale. Single-type historical land cover datasets, including for forests, water, and impervious surfaces, have also been developed in recent years. In this study, we present an open and synergy framework to produce a global land cover dataset that combines supervised land cover classification and aggregation of existing multiple thematic land cover maps with the Google Earth Engine (GEE) cloud computing platform. On the basis of this method of classification and mosaicking, we derived a global land cover dataset for 6 years over a time span of 25 years. The overall accuracies of the six maps were around 75% and the accuracy for change area detection was over 70%. Our product also showed good similarity with the FAO and existing land cover maps.
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http://dx.doi.org/10.7717/peerj.11877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349160PMC
August 2021

Amino acids metabolism by rumen microorganisms: Nutrition and ecology strategies to reduce nitrogen emissions from the inside to the outside.

Sci Total Environ 2021 Aug 11;800:149596. Epub 2021 Aug 11.

State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China; College of Animal Science and Technology, Shihezi University, Shihezi, Xinjiang 832000, China. Electronic address:

For the ruminant animal industry, the emission of nitrogenous substances, such as nitrous oxide (NO) and ammonia (NH), not only challenges environmental sustainability but also restricts its development. The metabolism of proteins and amino acids by rumen microorganisms is a key factor affecting nitrogen (N) excretion in ruminant animals. Rumen microorganisms that affect N excretion mainly include three types: proteolytic and peptidolytic bacteria (PPB), ureolytic bacteria (UB), and hyper-ammonia-producing bacteria (HAB). Microbes residing in the rumen, however, are influenced by several complex factors, such as diet, which results in fluctuations in the rumen metabolism of proteins and amino acids and ultimately affects N emission. Combining feed nutrition strategies (including ingredient adjustment and feed additives) and ecological mitigation strategies of NO and NH in industrial practice can reduce the emission of nitrogenous pollutants from the ruminant breeding industry. In this review, the characteristics of the rumen microbial community related to N metabolism in ruminants were used as the metabolic basis. Furthermore, an effective strategy to increase N utilisation efficiency in combination with nutrition and ecology was reviewed to provide an inside-out approach to reduce N emissions from ruminants.
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http://dx.doi.org/10.1016/j.scitotenv.2021.149596DOI Listing
August 2021

DAF-16 acts as the "hub" of astaxanthin's anti-aging mechanism to improve aging-related physiological functions in .

Food Funct 2021 Oct 4;12(19):9098-9110. Epub 2021 Oct 4.

Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou, 510642, Guangdong, China.

Astaxanthin (AX) is a xanthophyll carotenoid that can effectively inhibit the production of peroxides and thereby protect the body from oxidative damage. In recent years, AX had been shown to have anti-aging properties, both and . However, the underlying mechanisms by which AX regulates senescence related proteins and signaling pathways remain unclear. Therefore, we used () model binding proteomics to reveal AX anti-aging activity and its molecular mechanism. Our results suggest that AX promotes the health and lifespan of by improving mobility, reducing the accumulation of age pigments, and increasing resistance to heat stress. In terms of the underlying mechanism, AX helps prolong the life of worms by regulating AGE-1 in the insulin signaling pathway, promoting the transport of DAF-16 into the nucleus and then up-regulating the expression level of DAF-16's downstream proteins (such as superoxide dismutase [Mn] 2 (SOD-3), heat shock proteins (HSPs), glutathione -transferase (GST-4), ). Furthermore, AX may be a relevant response target for activation of dietary restriction pathways as a dietary restriction mimic. Meanwhile, proteomics data confirmed that there were 15 proteins enriched in the longevity regulation pathway. AX mainly regulates oxidative stress and the aging process by modulating the insulin signaling pathway around DAF-16 as the "hub". In addition to the insulin signaling pathway, other pathways including dietary restriction, AMP-activated protein kinase (AMPK), and mammal target of rapamycin (mTOR) are also dependent on DAF-16. These findings expand and deepen our knowledge of the underlying mechanism by which AX extends the lifespan of .
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http://dx.doi.org/10.1039/d1fo01069gDOI Listing
October 2021

Oseltamivir Improved Thrombocytopenia During Veno-Arterial Extracorporeal Membrane Oxygenation in Adults With Refractory Cardiac Failure: A Single-Center Retrospective Real-World Study.

Front Cardiovasc Med 2021 26;8:645867. Epub 2021 Jul 26.

Qilu Hospital, Shandong University, Jinan, China.

Severe thrombocytopenia is a common complication of extracorporeal membrane oxygenation (ECMO). Oseltamivir can be used to treat infection-associated thrombocytopenia. To evaluate the effect of oseltamivir on attenuating severe thrombocytopenia during ECMO. This was a single-center real-world study in critically ill patients supported with venous-arterial extracorporeal membrane oxygenation (VA-ECMO). Patients suspected or confirmed with influenza received oseltamivir according to the Chinese guidelines. Thrombocytopenia and survival were compared between the oseltamivir-treated and untreated group. The factors associated with survival were analyzed by multivariable Cox analysis. A total of 82 patients were included. All patients developed thrombocytopenia after initiating VA-ECMO. Twenty-three patients received oseltamivir (O group), and 59 did not use oseltamivir (O group). During the first 8 days after VA-ECMO initiation, the platelet count in the O group was higher than that in the O group (all < 0.05). The patients in the O group had a higher median nadir platelet count (77,000/μl, 6,000-169,000/μl) compared with the O group (49,000/μl, 2,000-168,000/μl; = 0.04). A nadir platelet count of <50,000/μl was seen in 26% of the patients in the O group, compared with 53% in the O group ( = 0.031). No significant difference in survival from cardiac failure was seen between the O and O group (48 vs. 56%, = 0.508). The Sequential Organ Failure Assessment (SOFA) score on initiation of VA-ECMO were independently associated with survival (OR = 1.12, 95% confidence interval (95% CI): 1.02-1.22, = 0.015). Oseltamivir could ameliorate VA-ECMO-related thrombocytopenia. These findings suggested the prophylactic potential of oseltamivir on severe thrombocytopenia associated with the initiation of VA-ECMO.
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http://dx.doi.org/10.3389/fcvm.2021.645867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349981PMC
July 2021

Total Synthesis of Mannopeptimycin β via β-Hydroxyenduracididine Ligation.

J Am Chem Soc 2021 Aug 5;143(32):12784-12790. Epub 2021 Aug 5.

Department of Chemistry, State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. China.

Nonribosomal peptide synthesis in bacteria has endowed cyclic peptides with fascinating structural complexity via incorporating nonproteinogenic amino acids. These bioactive cyclic peptides provide interesting structural motifs for exploring total synthesis and medicinal chemistry studies. Cyclic glycopeptide mannopeptimycins exhibit antibacterial activity against antibiotic-resistant Gram-positive pathogens and act as the lipid II binder to stop bacterial cell wall biosynthesis. Here, we report a strategy streamlining solution phase-solid phase synthesis and chemical ligation-mediated peptide cyclization for the total synthesis of mannopeptimycin β.
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http://dx.doi.org/10.1021/jacs.1c05922DOI Listing
August 2021

Critical roles of cytokine storm and secondary bacterial infection in acute kidney injury development in COVID-19: A multi-center retrospective cohort study.

J Med Virol 2021 12 14;93(12):6641-6652. Epub 2021 Aug 14.

Department of General Practice, Guizhou Provincial People's Hospital, Guiyang, China.

Acute kidney injury (AKI) may develop in patients with coronavirus disease 2019 (COVID-19) and is associated with in-hospital death. We investigated the incidence of AKI in 223 hospitalized COVID-19 patients and analyzed the influence factors of AKI. The incidence of cytokine storm syndrome and its correlation with other clinicopathologic variables were also investigated. We retrospectively enrolled adult patients with virologically confirmed COVID-19 who were hospitalized at three hospitals in Wuhan and Guizhou, China between February 13, 2020, and April 8, 2020. We included 124 patients with moderate COVID-19 and 99 with severe COVID-19. AKI was present in 35 (15.7%) patients. The incidence of AKI was 30.3% for severe COVID-19 and 4.0% for moderate COVID-19 (p < 0.001). Furthermore, cytokine storm was found in 30 (13.5%) patients and only found in the severe group. Kidney injury at admission (odds ratio [OR]: 3.132, 95% confidence interval [CI]: 1.150-8.527; p = 0.025), cytokine storm (OR: 4.234, 95% CI: 1.361-13.171; p = 0.013), and acute respiratory distress syndrome (ARDS) (OR: 7.684, 95% CI: 2.622-22.523; p < 0.001) were influence factors of AKI. Seventeen (48.6%) patients who received invasive mechanical ventilation developed AKI, of whom 64.7% (11/17) died. Up to 86.7% of AKI patients with cytokine storms may develop a secondary bacterial infection. The leukocyte counts were significantly higher in AKI patients with cytokine storm than in those without (13.0 × 10⁹/L, interquartile range [IQR] 11.3 vs. 8.3 × 10⁹/L, IQR 7.5, p = 0.005). Approximately 1/6 patients with COVID-19 eventually develop AKI. Kidney injury at admission, cytokine storm and ARDS are influence factors of AKI. Cytokine storm and secondary bacterial infections may be responsible for AKI development in COVID-19 patients.
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http://dx.doi.org/10.1002/jmv.27234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426723PMC
December 2021

Effect of gene mutation of plants on their mechano-sensibility: the mutant of EXO70H4 influences the buckling of Arabidopsis trichomes.

Analyst 2021 Aug 22;146(16):5169-5176. Epub 2021 Jul 22.

Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases co-constructed by Henan province & Education Ministry of P.R. China, Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450016, China.

With the development of molecular biology, more and more mutants of plants have been constructed, where gene mutants have been found to influence not only the biological processes but also biophysical behaviors of plant cells. Trichomes are an important appendage, which has been found to act as an active mechanosensory switch transducing mechanical signals into physiology changes, where the mechanical property of trichomes is vital for such functions. Up to now, over 40 different genes have been found with the function of regulating trichome cell morphogenesis; however, the effect of gene mutants on trichome mechanosensory function remains elusive. In this study, we found that EXO70H4, one of the most up-regulated genes in the mature trichome, not only affects the thickness of the trichome cell wall but also the mechanical property (i.e., the Young's modulus) of trichomes. Finite element method simulation results show that the buckling instability and stress concentration (e.g., exerted by insects) cannot occur on the base of the mutant exo70H4 trichome, which might further interrupt the mechanical signal transduction from branches to the base of trichomes. These results indicated that the mutant exo70H4 trichome might lack the ability to act as an active mechanosensory switch against chewing insect herbivores. Our findings provide new information about the effect of gene mutation (like crop mutants) on the mechano-sensibility and capability to resist the agricultural pests or lodging, which could be of great significance to the development of agriculture.
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http://dx.doi.org/10.1039/d1an00682gDOI Listing
August 2021

Fabrication and Biomedical Applications of Heart-on-a-chip.

Int J Bioprint 2021 26;7(3):370. Epub 2021 Jun 26.

Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases Co-constructed by Henan Province and Education Ministry of P.R. China, Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450016, P.R. China.

Heart diseases have become the main killer threatening human health, and various methods have been developed to study heart disease. Among them, heart-on-a-chip has emerged in recent years as a method for constructing disease (or normal) models and is considered as a promising tool to study heart diseases. Compared with other methods, the advantages of heart-on-a-chip include the high portability, high throughput, and the capability to mimic microenvironments . It has shown a great potential in disease mechanism study and drug screening. In this paper, we review the recent advances in heart-on-a-chip, including the fabrication methods (., 3D bioprinting) and biomedical applications. By analyzing the structure of the existing heart-on-a-chip, we proposed that a highly integrated heart-on-a-chip includes four elements: Microfluidic chips, cells/microtissues, microactuators to construct the microenvironment, and microsensors for results readout. Finally, the current challenges and future directions of heart-on-a-chip are discussed.
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http://dx.doi.org/10.18063/ijb.v7i3.370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287510PMC
June 2021

An immune-related lncRNA signature for the prognosis of pancreatic adenocarcinoma.

Aging (Albany NY) 2021 07 20;13(14):18806-18826. Epub 2021 Jul 20.

Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning, China.

Recent evidence suggests that aberrant expression of long non-coding RNA (lncRNA) can drive the initiation and progression of malignancies. However, little is known about the prognostic potential of lncRNA. We aimed at constructing a lncRNA-based signature to improve the prognosis prediction of pancreatic adenocarcinoma (PAAD). The PAAD samples with clinical information were obtained from The Cancer Genome Atlas and International Cancer Genome Consortium. We established an eight-IRlncRNA signature in a training cohort. The prognostic value of eight-IRlncRNA signature was validated in two distinct cohorts when compared to other four prognostic models. We continued to analyze its independence in subgroups by univariate and multivariate Cox regression. We constructed a nomogram for clinicopathologic features and 1-, 3-, and 5-year overall survival performance. Moreover, Gene set enrichment analysis and Gene Set Variation Analysis distinguished the typical functions between high- and low-risk groups. In addition, we further observed the different correlations of immune cell between eight IRlncRNAs. Eight-IRlncRNA signature appears to be a good performer to predict the survival capability of PAAD patients, and the nomogram will enable PAAD patients to be more accurately managed in clinical practice.
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http://dx.doi.org/10.18632/aging.203323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351726PMC
July 2021

Low-temperature architecture of a cubic-phase CsPbBr single crystal for ultrasensitive weak-light photodetectors.

Chem Commun (Camb) 2021 Aug;57(63):7798-7801

Future Energy Laboratory, School of Materials Science and Engineering, Hefei University of Technology, Hefei, 230009, China. and Key Laboratory of Advanced Functional Materials and Devices of Anhui Province, Engineering Research Center of High Performance Copper Alloy Materials and Processing, Ministry of Education, Hefei, 230009, China.

We present the first report of a water-regulated method for obtaining a cubic-phase CsPbBr3 single crystal that could be frozen at low temperature with a CsBr/PbBr2 ratio of 1 : 1. The cubic CsPbBr3 single-crystal photodetector exhibits a superior responsivity of 278 A W-1, an EQE of 6.63 × 104%, and an ultrahigh detectivity of 4.36 × 1013 Jones under low-power 520 nm irradiation at 3 V.
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http://dx.doi.org/10.1039/d1cc03460jDOI Listing
August 2021

KDM4 Orchestrates Epigenomic Remodeling of Senescent Cells and Potentiates the Senescence-Associated Secretory Phenotype.

Nat Aging 2021 May 13;1(5):454-472. Epub 2021 May 13.

CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

Cellular senescence restrains the expansion of neoplastic cells through several layers of regulation. We report that the histone H3-specific demethylase KDM4 is expressed as human stromal cells undergo senescence. In clinical oncology, upregulated KDM4 and diminished H3K9/H3K36 methylation correlate with poorer survival of prostate cancer patients post-chemotherapy. Global chromatin accessibility mapping via ATAC-seq, and expression profiling through RNA-seq, reveal global changes of chromatin openness and spatiotemporal reprogramming of the transcriptomic landscape, which underlie the senescence-associated secretory phenotype (SASP). Selective targeting of KDM4 dampens the SASP of senescent stromal cells, promotes cancer cell apoptosis in the treatment-damaged tumor microenvironment (TME), and prolongs survival of experimental animals. Our study supports dynamic changes of H3K9/H3K36 methylation during senescence, identifies an unusually permissive chromatin state, and unmasks KDM4 as a key SASP modulator. KDM4 targeting presents a novel therapeutic avenue to manipulate cellular senescence and limit its contribution to age-related pathologies including cancer.
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http://dx.doi.org/10.1038/s43587-021-00063-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277122PMC
May 2021
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