Publications by authors named "Yue Zhou"

1,036 Publications

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The Safety and Effectiveness of Bevacizumab in the Treatment of Nonsquamous Non-Small-Cell Lung Cancer: A Meta-Analysis of Randomized Controlled Trials.

Biomed Res Int 2021 7;2021:5537899. Epub 2021 Sep 7.

Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, China.

Objective: Bevacizumab was currently available for nonsquamous non-small-cell lung cancer (NSqNSCLC) patients and has been studied in several randomized controlled trials (RCTs) for treatment of these patients. This meta-analysis summarizes the most up-to-date evidences regarding the effects and adverse reactions of bevacizumab in the treatment of NSqNSCLC patients.

Methods: The authors searched for RCTs from electronic database including PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. Experimental arm was defined as the bevacizumab-containing group and the control arm as the bevacizumab-free group. Data of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse reactions were synthetically extracted. A protocol for this meta-analysis has been registered on PROSPERO (http://www.crd.york.ac.uk/prospero).

Results: Ten RCTs that involved a total of 3134 patients were included. The experimental group was associated with significant superior ORR (RR 1.63, 95% CI 1.24 to 2.14, < 0.001), OS (HR 0.90, 95% CI 0.82 to 0.99, < 0.001), and prolonged PFS (HR 0.68, 95% CI 0.62 to 0.74, < 0.001) compared to the control. No significant difference was observed regarding DCR (RR 1.13, 95% CI 0.99 to 1.30, = 0.08). The experimental group showed higher rate of hypertension (RR 6.91, 95% CI 4.62 to 10.35, < 0.00001) and hemorrhagic events (RR 3.07, 95% CI 1.78 to 5.30, < 0.0001) than the control group. The experimental group showed lower rate of anemia (RR 0.72, 95% CI 0.55 to 0.96, = 0.02) than the control group. No significant difference was observed regarding treatment-related adverse event grade 3-5 (TRAE3-5) (RR 1.23, 95% CI 0.99 to 1.53, = 0.06), thrombocytopenia (RR 1.11, 95% CI 0.92 to 1.33, = 0.29), and neutropenia (RR 1.11, 95% CI 0.88 to 1.40, = 0.36).

Conclusion: This meta-analysis showed that bevacizumab could increase ORR, OS, and prolonged PFS for treatment of NSqNSCLC patients. However, no significant improvement in DCR was observed and bevacizumab could increase the rate of hypertension and hemorrhagic events. Bevacizumab was an acceptable option for NSqNSCLC patients. This trial is registered with : CRD42021226790.
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http://dx.doi.org/10.1155/2021/5537899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440089PMC
September 2021

HSF1 is involved in suppressing A1 phenotype conversion of astrocytes following spinal cord injury in rats.

J Neuroinflammation 2021 Sep 16;18(1):205. Epub 2021 Sep 16.

Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, 226001, People's Republic of China.

Background: Two activation states of reactive astrocytes termed A1 and A2 subtypes emerge at the lesion sites following spinal cord injury (SCI). A1 astrocytes are known to be neurotoxic that participate in neuropathogenesis, whereas A2 astrocytes have been assigned the neuroprotective activity. Heat shock transcription factor 1 (HSF1) plays roles in protecting cells from stress-induced apoptosis and in controlling inflammatory activation. It is unknown whether HSF1 is involved in suppressing the conversion of A1 astrocytes following SCI.

Methods: A contusion model of the rat spinal cord was established, and the correlations between HSF1 expression and onset of A1 and A2 astrocytes were assayed by Western blot and immunohistochemistry. 17-AAG, the agonist of HSF1, was employed to treat the primary cultured astrocytes following a challenge by an A1-astrocyte-conditioned medium (ACM) containing 3 ng/ml of IL-1α, 30 ng/ml of TNF-α, and 400 ng/ml of C1q for induction of the A1 subtype. The effects of 17-AAG on the phenotype conversion of astrocytes, as well as underlying signal pathways, were examined by Western blot or immunohistochemistry.

Results: The protein levels of HSF1 were significantly increased at 4 days and 7 days following rat SCI, showing colocalization with astrocytes. Meanwhile, C3-positive A1 astrocytes were observed to accumulate at lesion sites with a peak at 1 day and 4 days. Distinctively, the S100A10-positive A2 subtype reached its peak at 4 days and 7 days. Incubation of the primary astrocytes with ACM markedly induced the conversion of the A1 phenotype, whereas an addition of 17-AAG significantly suppressed such inducible effects without conversion of the A2 subtype. Activation of HSF1 remarkably inhibited the activities of MAPKs and NFκB, which was responsible for the regulation of C3 expression. Administration of 17-AAG at the lesion sites of rats was able to reduce the accumulation of A1 astrocytes.

Conclusion: Collectively, these data reveal a novel mechanism of astrocyte phenotype conversion following SCI, and HSF1 plays key roles in suppressing excessive increase of neurotoxic A1 astrocytes.
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http://dx.doi.org/10.1186/s12974-021-02271-3DOI Listing
September 2021

Sintilimab, stereotactic body radiotherapy and granulocyte-macrophage colony stimulating factor as second-line therapy for advanced non-small cell lung cancer: safety run-in results of a multicenter, single-arm, phase II trial.

Radiat Oncol 2021 Sep 15;16(1):177. Epub 2021 Sep 15.

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

Objectives: The SWORD trial is the first multicenter, single arm, phase II study assessing the safety and efficacy of a PD-1 inhibitor (Sintilimab), stereotactic body radiotherapy (SBRT) and granulocyte-macrophage colony stimulating factor (GM-CSF) in advanced non-small cell lung cancer (NSCLC) without sensitizing driver mutations. A safety run-in phase was conducted to determine the tolerability of the experimental treatment.

Materials And Methods: Twenty metastatic NSCLC patients who failed first-line chemotherapy were enrolled, and they received SBRT (8 Gy × 3) to one lesion, followed by Sintilimab (200 mg d1, every 3 weeks, until disease progression, unacceptable toxicity, or up to 35 cycles) and GM-CSF (125 μg/m d1-d14, cycle 1) within 2 weeks after SBRT. In addition, blood and tissue samples were serially collected for translational research.

Results: Median age of the patients was 61 and all of them had more than 5 lesions at baseline. The sites of SBRT included lung (n = 11), mediastinal lymph node (n = 5), liver (n = 1), abdominal lymph node (n = 1), pleural nodule (n = 1) and vertebra (n = 1). No patients had dose-limiting toxicities (DLTs) and 18 patients experienced treatment-related adverse event (TRAE). The most common TRAEs were fatigue (50%), fever (30%), and ostealgia (20%), and they all were grade 1. Only 2 grade 3 TRAEs were observed, including elevation of liver enzymes in one and transient acute heart failure in another. No grade 4 or 5 AE was observed.

Conclusion: Sintilimab, SBRT and GM-CSF for advanced NSCLC is safe with manageable TRAEs and the trial continues to recruit participants. Trial registration ClinicalTrials.gov, NCT04106180. Registered 26 September 2019, SBRT in Combination With Sintilimab and GM-CSF for the Treatment of Advanced NSCLC-Tabular View-ClinicalTrials.gov.
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http://dx.doi.org/10.1186/s13014-021-01905-3DOI Listing
September 2021

Effective tools for RNA-derived therapeutics: siRNA interference or miRNA mimicry.

Theranostics 2021 11;11(18):8771-8796. Epub 2021 Aug 11.

Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, 117599 Singapore.

The approval of the first small interfering RNA (siRNA) drug Patisiran by FDA in 2018 marks a new era of RNA interference (RNAi) therapeutics. MicroRNAs (miRNA), an important post-transcriptional gene regulator, are also the subject of both basic research and clinical trials. Both siRNA and miRNA mimics are ~21 nucleotides RNA duplexes inducing mRNA silencing. Given the well performance of siRNA, researchers ask whether miRNA mimics are unnecessary or developed siRNA technology can pave the way for the emergence of miRNA mimic drugs. Through comprehensive comparison of siRNA and miRNA, we focus on (1) the common features and lessons learnt from the success of siRNAs; (2) the unique characteristics of miRNA that potentially offer additional therapeutic advantages and opportunities; (3) key areas of ongoing research that will contribute to clinical application of miRNA mimics. In conclusion, miRNA mimics have unique properties and advantages which cannot be fully matched by siRNA in clinical applications. MiRNAs are endogenous molecules and the gene silencing effects of miRNA mimics can be regulated or buffered to ameliorate or eliminate off-target effects. An in-depth understanding of the differences between siRNA and miRNA mimics will facilitate the development of miRNA mimic drugs.
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http://dx.doi.org/10.7150/thno.62642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419061PMC
August 2021

Label-free visible colorimetric biosensor for detection of multiple pathogenic bacteria based on engineered polydiacetylene liposomes.

J Colloid Interface Sci 2021 Aug 13;606(Pt 2):1684-1694. Epub 2021 Aug 13.

Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China; Beijing Advanced Innovation Centre for Biomedical Engineering, Beihang University, Beijing, 102402, China. Electronic address:

Bacterial infections are considered as a critical healthcare concern worldwide. Timely infection detection is crucial to effective antibiotic administration which can reduce the severity of infection and the occurrence of antibiotic resistance. We have developed label-free polydiacetylene (PDA) liposome-based colorimetric biosensor to detect and identify bacterial cultures at the genus and species level with naked eyes by simple color change. We found that among the various liposomal systems, moderate concentration of PDA, phospholipids and cholesterol in liposome assemblies can greatly influence the sensitivity to different bacteria, exhibiting unique chromatic properties of each bacterial strain. The strikingly different chromatic color change was due to the various mechanisms of interactions between bacterial toxins and biomimetic lipid bilayers. Furthermore, increase of cholesterol in liposome assemblies greatly enhanced the sensitivity of bacterial strains related to membrane destruction mediated by pore-formation mechanism such as S. aureus and E.coli, whereas the detection of the two bacterial strains was believed to rely on the specific recognition elements coupled with PDA moiety. As a proof of concept, a colorimetric finger-print array for distinguishing 6 bacterial species was studied. Particularly, the proposed bacterial detection platform is achieved through the interaction between bacterially secreted toxins and liposome bilayers instead of specific recognition of receptors-ligands. The results of both response time and sensitivity of label-free-liposome-based system show superior to previous reports on chromatic bacterial detection assays. By combing these results, the label-free-liposome-based colorimetric sensing platform shows great importance as a bacterial-sensing and discrimination platform.
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http://dx.doi.org/10.1016/j.jcis.2021.07.155DOI Listing
August 2021

Local Treatment of Non-small Cell Lung Cancer with a Spray-Dried Bevacizumab Formulation.

AAPS PharmSciTech 2021 Aug 31;22(7):230. Epub 2021 Aug 31.

Global Business Development, Lonza, Portsmouth, New Hampshire, USA.

Local delivery of biotherapeutics to the lung holds great promise for treatment of lung diseases, but development of physically stable, biologically active dry powder formulations of large molecules for inhalation has remained a challenge. Here, spray drying was used to manufacture a dry powder pulmonary formulation of bevacizumab, a monoclonal antibody approved to treat non-small cell lung cancer (NSCLC) by intravenous infusion. By reformulating bevacizumab for local delivery, reduced side effects, lower doses, and improved patient compliance are possible. The formulation had aerosol properties suitable for delivery to the deep lung, as well as good physical stability at ambient temperature for at least 6 months. Bevacizumab's anti-VEGF bioactivity was not impacted by the manufacturing process. The formulation was efficacious in an in vivo rat model for NSCLC at a 10-fold decrease in dose relative to the intravenous control.
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http://dx.doi.org/10.1208/s12249-021-02095-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408070PMC
August 2021

Ginsenoside Rg1 attenuates premature ovarian failure of D-gal induced POF mice through downregulating p16INK4a and upregulating SIRT1 expression.

Endocr Metab Immune Disord Drug Targets 2021 Aug 30. Epub 2021 Aug 30.

Department of Histology and Embryology, Dali University, Dali 671000. China.

Background: Premature ovarian failure (POF) refers to pathological amenorrhea before 40 years.

Aim/objective: To explore regulatory effect of Rg1 on POF and clarify associated mechanisms.

Materials And Methods: POF mice were induced by injecting with D-galactose (D-gal, 200 mg/kg/day). Mice were divided into phosphate buffered saline (PBS), D-gal (POF mice), D-gal/Rg1 group (POF mice administrating D-gal/Rg1). Weight growth rate and ovarian weight coefficient were measured. Serum estradiol (E2), follicle stimulating hormone (FSH), luteinizing hormone (LH), superoxide dismutase (SOD), catalase (CAT) levels were examined using ELISA. Status of follicle and corpus luteum was determined using hematoxylin-eosin (HE) staining. P16 and silent-mating type information regulation-2 homolog-1 (SIRT1) was determined using western blotting and RT-PCR.

Findings: Weight growth rate and ovarian weight coefficient of mice in D-gal group were significantly decreased than PBS group (p<0.05). Serum E2, LH, SOD, CAT levels were significantly decreased, FSH levels were remarkably increased in D-gal group than PBS group (p<0.05). Rg1 (D-gal/Rg1 group) significantly increased weight growth rate and ovarian weight coefficient, enhanced E2, LH, SOD, CAT levels and decreased FSH levels than D-gal group (p<0.05). HE staining demonstrated normal follicle morphology/structure of mice in PBS group and decreased number of follicles, obvious vacuolation of corpus luteum and increased atretic follicles of mice in D-gal group. Compared with D-gal group, number of follicles was increased, luteal follicles was decreased of mice in D-gal/Rg1 group (p<0.05). Rg1 significantly (D-gal/Rg1) downregulated p16 and upregulated SIRT1 expression in ovarian tissues of mice compared to D-gal group (p<0.05).

Conclusions: Rg1 could delay premature ovarian failure in D-gal induced POF mouse model through downregulating p16 and upregulating SIRT1 expression.
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http://dx.doi.org/10.2174/1871523020666210830164152DOI Listing
August 2021

Polyoxometalate Interlayered Zinc-Metallophthalocyanine Molecular Layer Sandwich as Photocoupled Electrocatalytic CO Reduction Catalyst.

J Am Chem Soc 2021 Sep 24;143(34):13721-13730. Epub 2021 Aug 24.

Key Lab of Organic Optoelectronics and Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing, 100084, China.

Developing efficient and robust heterogeneous metallophthalocyanine electrocatalysts for CO reduction remains a challenge. Here, a general synthetic method of zinc-metallophthalocyanine (MPc) molecular layer/polyoxometalate (POM) sandwich lamellar material is developed, and thus improved performance of electrocatalytic and photocoupled electrocatalytic CO reduction is achieved. The incorporation of POM could prevent the packing of MPc molecular layers from aggregation, which would be favorable to the exposure of active sites. The molecular layer sandwich catalyst presents superior CO reduction activity, delivering the highest CO Faradaic efficiency (FE) of 96.1% at -0.7 V vs RHE in dark field. Under light irradiation, over 93% FE is achieved in a broad potential range from -0.6 to -0.9 V vs RHE with a maximum of 96.2%, and the carbon monoxide turnover frequency could exceed 2060 h. Photoelectrochemical tests and luminescence characterizations reveal the molecular layer is beneficial for carrier separation during light irradiation; density functional theory calculations and electron paramagnetic resonance indicated a 2-fold enhancement of the external light field on the catalytic performance.
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http://dx.doi.org/10.1021/jacs.1c05580DOI Listing
September 2021

[Distribution Characteristics and Ecological Risk Assessment of Soil Heavy Metals in Typical Watersheds of the Qinghai-Tibet Plateau].

Huan Jing Ke Xue 2021 Sep;42(9):4422-4431

Gansu Key Laboratory of Arid Climatic Change and Reducing Disaster, Key Laboratory of Arid Climatic Change and Disaster Reduction, Lanzhou Institute of Arid Meteorology of China Meteorology Administration, Lanzhou 730020, China.

The Qinghai-Tibet Plateau is an extremely vulnerable area that is sensitive to human activities. In recent years, more and more human disturbances have been detected in this area. This study analyzed the spatial distribution and ecological risks of 7 heavy metals (Cr, Ni, Cu, Zn, As, Cd, and Pb) in two regions, namely the Bailong River and Yellow River and their two tributaries (BY region) in Gannan and the Yarlung Zangbo River and its two tributaries (YZ region) in Tibet. In terms of spatial distribution, concentrations of the seven heavy metals were higher in the east and lower in the west of the BY region. The average concentrations all exceeded the background value of the Qinghai-Tibet Plateau, especially for Cd (4.50 times) and As (2.83 times). High Pb concentrations were mainly found in water, urban and rural residential land, and industrial and construction land. In the YZ region, heavy metal concentrations were lower along the river, while high-altitude areas exhibited higher heavy metal concentrations. The average concentrations of Ni, Zn, As, and Cd exceeded the background values of the Qinghai-Tibet Plateau, especially that of Cd (3.13 times), which mostly exhibited high values in water coverage areas. The geo-accumulation index method and the potential ecological risk index method show that the degree of As and Cd pollution was relatively high in the BY region in Gannan, with the greatest potential ecological risk occurring in the water coverage area. In the YZ region in Tibet, the degree of Cd pollution was high, with the highest potential ecological risk also occurring in the water coverage area. This study provides significant guidance for the environmental protection, sustainable development, and utilization of soil under different types of land use in the Qinghai-Tibet Plateau.
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http://dx.doi.org/10.13227/j.hjkx.202012123DOI Listing
September 2021

Inhibition of immunoproteasome subunit low molecular mass polypeptide 7 with ONX-0914 improves hypoxic-ischemic brain damage via PI3K/Akt signaling.

Neuroreport 2021 Oct;32(14):1206-1215

Department of Pediatrics, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China.

The immunoproteasome subunit low molecular mass polypeptide 7 (LMP7) leads to brain injuries, such as autoimmune neuritis and ischemic stroke, by activating inflammation. However, the roles and mechanisms of LMP7 in hypoxic-ischemic brain damage (HIBD) remain unclear. This study explored these issues in a rat model of HIBD. Pathology was evaluated using hematoxylin-eosin staining. LMP7 expression was detected using western blot analysis, reverse transcription-quantitative PCR (RT-qPCR), and immunohistochemical staining. The presence of proinflammatory cytokines, including tumor necrosis factor-a, interleukin-6, and interleukin-1β, was tested using ELISA and RT-qPCR. Behavioral performance was evaluated using a short-term neurological function score and the Morris water maze test. Compared to those in the Sham group, the HIBD group exhibited obvious upregulated LMP7 and pro-inflammatory cytokine levels. HIBD rats exhibited severe pathological and behavioral damage. LMP7 inhibition with ONX-0914 reduced proinflammatory cytokine expression, attenuated pathological damage, and enhanced behavioral performance of rats with HIBD. Inhibition of phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling with LY29400 increased LMP7 expression and abolished the protective effects of ONX-0914 in HIBD rats. Our findings indicate that LMP7 aggravates brain injury by triggering inflammatory responses in HIBD rats. LMP7 inhibition with ONX-0914 exerts protective effects on HIBD rats, possibly via PI3K/Akt signaling.
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http://dx.doi.org/10.1097/WNR.0000000000001715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389355PMC
October 2021

Antibiotic use and irrational antibiotic prescriptions in 66 primary healthcare institutions in Beijing City, China, 2015-2018.

BMC Health Serv Res 2021 Aug 18;21(1):832. Epub 2021 Aug 18.

Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.

Objectives: To identify the patterns of antibiotic use and irrational antibiotic prescriptions in primary healthcare institutions (PHIs) in Dongcheng District of Beijing, China.

Materials And Methods: All primary healthcare institutions (7 community healthcare centres and 59 community healthcare stations in total) in Dongcheng District were included in the study. Prescription data from January 2015 to December 2018 was derived from the Beijing Prescription Reviewing System of Primary healthcare institutions and analysed retrospectively. The antibiotic prescription rate was calculated and cases of irrational antibiotic prescriptions were identified.

Results: We extracted 11,166,905 prescriptions from the database. Only 189,962 prescriptions were included in the study, among which 9167 (4.8%) contained antibiotics. The antibiotic prescription rate fell from 5.2% in 2015 to 4.1% in 2018 while irrational antibiotic prescription rate increased from 10.4 to 11.8%. Acute Bronchitis was the most prevalent diagnosis (17.6%) for antibiotic prescriptions, followed by Unspecified Acute Respiratory Tract Infection (14.4%), Acute Tonsillitis (9.9%), and Urinary Tract Infection (6.4%). Around 10% of the prescriptions for the top 7 diagnoses identified were rated as irrational. Cephalosporins, fluoroquinolones, and macrolides were the most prescribed antibiotics, which accounted for 89.3% of all antibiotic prescriptions. Of all the antibiotic prescriptions, 7531 were reviewed, among which 939 (12.5%) were rated as irrational because of antibiotic use. Among all the irrational prescriptions, prescriptions with inappropriate antibiotic use and dosage accounted for the majority (54.4%).

Conclusion: Although a relatively low level of antibiotic utilization was found in PHIs in Dongcheng District of Beijing, the utilization patterns differed considerably from developed countries and irrational prescriptions remained. Considering the imbalanced allocation of medical resources between primary healthcare setting and secondary and tertiary hospitals, there need to be more efforts invested in regions with different levels of economic development.
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http://dx.doi.org/10.1186/s12913-021-06856-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371863PMC
August 2021

Reproductive cells and peripheral parietal cells collaboratively participate in meiotic fate acquisition in rice anthers.

Plant J 2021 Aug 15. Epub 2021 Aug 15.

State Key Lab of Plant Genomics, Institute of Genetics and Developmental Biology, Innovation Academy for Seed Design, Chinese Academy of Sciences, Beijing, 100101, China.

In flowering plants, the transition from mitosis to meiosis is the precondition for gametogenesis, which is the most crucial event during sexual reproduction. Here, we report an intriguing mechanism whereby germ cells and surrounding somatic cells cooperatively involve in the meiotic switch during anther development in rice (Oryza sativa). In double mutants with loss function of both leptotene chromosome establishment- and somatic cell layer differentiation-associated genes, chromosome morphology in the reproductive cells remains the same as that in somatic cells, and sporogenous cells fail to differentiate into pollen mother cells. OsSPOROCYTELESS and MICROSPORELESS1, two pivotal genes involved in meiosis entry, are prominently downregulated in anthers of plants with mutations in both MULTIPLE SPOROCYTE1 and LEPTOTENE 1. In addition, the transcription of redox-related genes is also affected. Therefore, germ cells and the surrounding somatic cells collaboratively participate in meiosis initiation in rice.
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http://dx.doi.org/10.1111/tpj.15461DOI Listing
August 2021

Mechanisms and Implications of CDK4/6 Inhibitors for the Treatment of NSCLC.

Front Oncol 2021 30;11:676041. Epub 2021 Jul 30.

Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.

Cyclin-dependent kinases (CDKs) are key regulators of cell cycle progression in malignant tumor cells and play an important role through complex molecular interactions. Dysregulation of CDK dependent pathways is often found in non-small cell lung cancer, which indicates its vulnerability and can be used in clinical benefit. CDK4/6 inhibitors can prevent tumor cells from entering the G approved 1 and S phases, which have been studied in a series of explorations and brought great clinical effect to patients and encouragement to both physicians and researchers, thereby showing potential as a new therapeutic agent. A series of preclinical and clinical studies have been carried out on CDK4/6 inhibitors in NSCLC, and have been achieved some results, which may become a new potential treatment in the future. This review focuses on the research progress on CDK4/6 inhibitors in NSCLC, particularly the mechanisms of action, drugs, clinical research progress, and future application.
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http://dx.doi.org/10.3389/fonc.2021.676041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361448PMC
July 2021

Psychological Interventions for Healthcare Providers With PTSD in Life-Threatening Pandemic: Systematic Review and Meta-Analysis.

Front Psychiatry 2021 29;12:697783. Epub 2021 Jul 29.

West China School of Public Health, Sichuan University, Chengdu, China.

This study aims to evaluate the effect of psychological interventions on healthcare providers (HCP) with post-traumatic stress disorder (PTSD) due to their necessary exposure in life-threatening pandemic. We performed a systematic research on Medline, Embase, Cochrane Central, PsycInfo, Cochrane Central Register of Controlled Trials, Clinicaltrials.gov, ProQuest PTSD Pubs ProQuest Dissertations & Theses Global, and other gray databases by January 2021. Randomized controlled trials involving therapeutic interventions for HCP with PTSD were included. The primary outcome was PTSD symptom severity. Summary standardized mean differences (SMDs) and 95% confidence intervals were estimated using inverse variance meta-analysis with fixed effects. Risks of bias were assessed using Cochrane methods. Among 773 citations, this review includes six studies, randomizing 810 participants. A meta-analysis of the effect of interventions compared to placebo showed a significant reduction of PTSD symptom severity: Cognitive Behavioral Therapy-Brief (CBT-B) ( = 27.80, 95% CI: 17.12, 38.48), Cognitive Behavioral Therapy-Long (CBT-L) ( = 26.50, 95% CI: 15.75, 37.25), and Mindfulness-Based Stretching and Deep Breathing Exercise (MBX) ( = 17.2, 95% CI: 6.57, 27.83). CBT-L and CBT-B also showed a significant effect on depression severity. The most effective and feasible treatment option for HCP with PTSD is still unclear, but CBT and MBX have displayed the most significant effects based on current limited evidence. Future research in this area-preferably large robust randomized controlled trials-is much needed.
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http://dx.doi.org/10.3389/fpsyt.2021.697783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358144PMC
July 2021

Mutual-reinforcing sonodynamic therapy against Rheumatoid Arthritis based on sparfloxacin sonosensitizer doped concave-cubic rhodium nanozyme.

Biomaterials 2021 09 9;276:121063. Epub 2021 Aug 9.

Tianjin Key Laboratory of Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 300072, Tianjin, PR China. Electronic address:

Rheumatoid arthritis (RA) is an autoimmune disease associated with synovitis and cartilage destruction. Ultrasound (US)-driven sonodynamic therapy (SDT) possess a good application prospect in RA therapy because of its non-invasiveness and strong tissue penetration capabilities, which can kill activated synovial inflammatory cells. Nevertheless, the tiny accumulation of sonosensitizers in the joints and the hypoxic synovial microenvironment severely limit the therapeutic effect of SDT. Hence, we developed a sonosensitizer spafloxacin (SPX) doped and human serum albumin (HSA) loaded concave-cubic rhodium (Rh) nanozyme (Rh/SPX-HSA) to realize mutual-reinforcing SDT during ultrasonic activation. On the one hand, SPX would cause mitochondrial dysfunction by inducing excessive reactive oxygen species (ROS) production, thus suppressing fibroblast-like synoviocyte (FLS) under US conditions. On the other hand, concave-cubic rhodium was utilized as a nanozyme with endogenous peroxidase (POD) and catalase (CAT)-like enzyme activities, which not only relieved the hypoxia of the joint to resist angiogenesis, but also enormously ascended the SDT efficacy by rising O levels. Interestingly, the activity of nanozymes was also improved by the ultrasonic cavitation effect, thereby realizing mutual-reinforcing SDT. Overall, our strategy provided Rh-based to achieve effective SDT under hypoxic microenvironment, which offered a promising prospect for highly efficient treatment of RA.
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http://dx.doi.org/10.1016/j.biomaterials.2021.121063DOI Listing
September 2021

Comparative Genotoxicity and Mutagenicity of Cigarette, Cigarillo, and Shisha Tobacco Products in Epithelial and Cardiac Cells.

Toxicol Sci 2021 Aug 13. Epub 2021 Aug 13.

Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM.

Epidemiology studies link cigarillos and shisha tobacco (delivered through a hookah waterpipe) to increased risk for cardiopulmonary diseases. Here we performed a comparative chemical constituent analysis between three cigarette, three cigarillo, and eight shisha tobacco products. The potency for genotoxicity and oxidative stress of each product's generated total particulate matter (TPM) was also assessed using immortalized oral, lung, and cardiac cell lines to represent target tissues. Levels of the carcinogenic carbonyl formaldehyde were 32-95-fold greater, while acrolein was similar across the shisha aerosols generated by charcoal heating compared to cigarettes and cigarillos. Electric-mediated aerosol generation dramatically increased acrolein to levels exceeding those in cigarettes and cigarillos by up to 43-fold. Equivalent cytotoxic-mediated cell death and dose response for genotoxicity through induction of mutagenicity and DNA strand breaks was seen between cigarettes and cigarillos, while minimal to no effect was observed with shisha tobacco products. In contrast, increased potency of TPM from cigarillos compared to cigarettes for inducing oxidative stress via reactive oxygen radicals and lipid peroxidation across cell lines was evident, while positivity was seen for shisha tobacco products albeit at much lower levels. Together, these studies provide new insight into the potential harmful effects of cigarillos for causing tobacco-associated diseases. The high level of carbonyls in shisha products, that in turn are impacted by the heating mechanism, reside largely in the gas phase which will distribute throughout the respiratory tract and systemic circulation to likely increase genotoxic stress.
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http://dx.doi.org/10.1093/toxsci/kfab101DOI Listing
August 2021

LPS-Induced Inflammation Affects Midazolam Clearance in Juvenile Mice in an Age-Dependent Manner.

J Inflamm Res 2021 3;14:3697-3706. Epub 2021 Aug 3.

Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People's Republic of China.

Purpose: Inflammation has a significant impact on CYP3A activity. We hypothesized that this effect might be age dependent. Our objective was to conduct a population pharmacokinetic study of midazolam in mice at different developmental stages with varying degrees of inflammation to verify our hypothesis.

Methods: Different doses (2 and 5 mg/kg) of lipopolysaccharide (LPS) were used to induce different degrees of systemic inflammation in Swiss mice (postnatal age 9-42 days, n = 220). The CYP3A substrate midazolam was selected as the pharmacological probe to study CYP3A activity. Postnatal age, current body weight, serum amyloid A protein 1 (SAA1) levels and LPS doses were collected as covariates to perform a population pharmacokinetic analysis using NONMEM 7.2.

Results: A population pharmacokinetic model of midazolam in juvenile and adult mice was established. Postnatal age and current body weight were the most significant and positive covariates for clearance and volume of distribution. LPS dosage was the most significant and negative covariate for clearance. LPS dosage can significantly reduce the clearance of midazolam by 21.8% and 38.7% with 2 mg/kg and 5 mg/kg, respectively. Moreover, the magnitude of the reduction was higher in mice with advancing postnatal age.

Conclusion: Both inflammation and ontogeny have an essential role in CYP3A activity in mice. The effect of LPS-induced systemic inflammation on midazolam clearance in mice is dependent on postnatal age.
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http://dx.doi.org/10.2147/JIR.S321492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349217PMC
August 2021

Adipose-derived stem cells alleviate radiation-induced dermatitis by suppressing apoptosis and downregulating cathepsin F expression.

Stem Cell Res Ther 2021 08 9;12(1):447. Epub 2021 Aug 9.

Department of Head and Neck Surgery, Central Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Tongzipo Road 283, Changsha, 410013, Hunan Province, China.

Background: Radiation-induced dermatitis is a serious side effect of radiotherapy, and very few effective treatments are currently available for this condition. We previously demonstrated that apoptosis is an important feature of radiation-induced dermatitis and adipose-derived stem cells (ADSCs) are one of the most promising types of stem cells that have a protective effect on acute radiation-induced dermatitis. Cathepsin F (CTSF) is a recently discovered protein that plays an important role in apoptosis. In this study, we investigated whether ADSCs affect chronic radiation-induced dermatitis, and the underlying mechanisms involved.

Methods: ADSCs were isolated from male Sprague-Dawley (SD) rats and characterized. For in vivo studies, rats were randomly divided into control and ADSC-treated groups, and cultured ADSCs were transplanted into radiation-induced dermatitis model rats. The effects of ADSC transplantation were determined by skin damage scoring, histopathological analysis, electron microscopy, immunohistochemical staining, and western blotting analysis of apoptosis-related proteins. To evaluate the effects of ADSCs in vitro, radiation-induced apoptotic cells were treated with ADSC culture supernatant, and apoptosis-related protein expression was investigated by TUNEL staining, flow cytometry, and western blotting.

Results: In the in vivo studies, skin damage, inflammation, fibrosis, and apoptosis were reduced and hair follicle and sebaceous gland regeneration were enhanced in the ADSC group compared with the control group. Further, CTSF and downstream pro-apoptotic proteins (Bid, BAX, and caspase 9) were downregulated, while anti-apoptotic proteins (Bcl-2 and Bcl-XL) were upregulated. In vitro, ADSCs markedly attenuated radiation-induced apoptosis, downregulated CTSF and downstream pro-apoptotic proteins, and upregulated anti-apoptotic proteins.

Conclusion: ADSCs protect against radiation-induced dermatitis by exerting an anti-apoptotic effect through inhibition of CTSF expression. ADSCs may be a good therapeutic candidate to prevent the development of radiation-induced dermatitis.
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http://dx.doi.org/10.1186/s13287-021-02516-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351374PMC
August 2021

Association of CASC18/miR-20a-3p/TGFB2 ceRNA axis with occult lymph node metastasis in tongue squamous cell carcinoma.

Mol Med 2021 08 6;27(1):85. Epub 2021 Aug 6.

Translational Medicine Centre, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, People's Republic of China.

Background: Tongue squamous cell carcinoma (TSCC) ranks as the most prevalent malignancy in the oral cavity. TSCC patients with occult lymph node metastasis (OLNM) are thought to be at risk of worse outcome. However, regulatory mechanisms underlying OLNM remain less investigated.

Methods: In the present study, CASC18/miR-20a-3p/TGFB2 axis was identified and evaluated by bioinformatic and qRT-PCR analyses. Effects of CASC18 knockdown on cell migration and invasion were determined by wound healing and transwell assays. Western blot, ELISA, RNA pulldown and luciferase reporter assays were performed for mechanism verification.

Results: CASC18 was identified up-regulating in TSCC tumours, and especially in those from patients with OLNM. Importantly, we found higher CASC18 expression was positively correlated with the presence of OLNM and worse outcome of TSCC patients. Furthermore, we demonstrated that CASC18 knockdown repressed cell migration and invasion through inhibiting epithelial-mesenchymal transition, which could be partly rescued by miR-20a-3p inhibitor. Regarding the molecular mechanism, we further confirmed that CASC18 functioned as a ceRNA to sponge miR-20a-3p to enhanceTGFB2 expression and secretion.

Conclusion: In conclusion, we have reported a novel CASC18/miR-20a-3p/TGFB2 ceRNA axis in OLNM of TSCC. Our findings will contribute to a deeper understanding of the molecular mechanism of OLNM in TSCC, and facilitate the development of diagnostic methods for assisting treatment decision-making.
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http://dx.doi.org/10.1186/s10020-021-00345-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349069PMC
August 2021

Acute kidney injury in patients with acute coronary syndrome after percutaneous coronary intervention: pathophysiologies, risk factors and preventive measures.

Cardiology 2021 06 24. Epub 2021 Jun 24.

Percutaneous coronary intervention (PCI) has been an effective treatment for acute coronary syndrome (ACS) patients. Acute kidney injury (AKI) is one of the common complications after PCI, which seriously affects the living quality and survival time of patients. The approach followed for the patient with AKI after PCI depends on the clinical context and may vary by resource availability. This review focuses on the pathophysiologies, influencing factors, and preventive measures of AKI in patients with ACS after PCI. The knowledge may better serve the patients and improve their outcomes. Many studies have been carried out for the definition and standard of AKI in the past few years. Etiologies of AKI after PCI included renal damage of contrast medium and atherosclerotic embolism, cardiac insufficiency and surgical factors on renal function. Basic conditions, treatment modalities, and perioperative changes are major risk factors of AKI. Studies have reported that the prevention of contrast-induced nephropathy, modulating the volume overload, some pharmaceuticals and blood purification treatment are helpful to prevent the occurrence of AKI.
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http://dx.doi.org/10.1159/000517991DOI Listing
June 2021

Fasting Glucose of 6.1 mmol/L as a Possible Optimal Target for Type 2 Diabetic Patients with Insulin Glargine: A Randomized Clinical Trial.

J Diabetes Res 2021 14;2021:5524313. Epub 2021 Jul 14.

Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.

To observe whether different insulin glargine titration algorithms based on fasting blood glucose (FBG) levels lead to different glycaemic variations (GVs) in type 2 diabetes (T2D) patients, a prospective, randomized, single-centre, comparative, three-arm parallel-group, open-label, treat-to-target, 24-week study was performed. A total of 71 uncontrolled T2D patients were recruited and randomized 1 : 3 : 3 into Groups 1, 2, and 3 (insulin titration goals of FBG ≤ 5.6, ≤6.1, and ≤7.0) for this study. The initiated insulin glargine dose was recommended at 0.2 U/kg/day and was then titrated following the FBG target. Patients were subjected to two 3-day continuous glucose monitoring (CGM) at baseline and the endpoint, wherein the CGM data were analysed, and the study's primary endpoint was the difference in 24 hrs mean amplitude of glycaemic excursion (MAGE) among the three groups. We observed that patients in the three groups had similar MAGE levels at the endpoint; however, Group 2 achieved a significant decrease in the MAGE level from baseline to the endpoint as compared to Groups 1 and 3 (all < 0.05). We also observed that these patients had significant glycated haemoglobin A1c (HbA1c) value improvements as compared to the other two groups (all < 0.05). Therefore, choosing an FBG level of 6.1 mmol/L as an insulin titration target provided significant GVs and HbA1c value improvements in T2D patients. Moreover, our data indicated that an FBG of 6.1 mmol/L could possibly be an insulin glargine titration target in T2D patients.
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http://dx.doi.org/10.1155/2021/5524313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294995PMC
July 2021

Discovery of novel inhibitors of human phosphoglycerate dehydrogenase by activity-directed combinatorial chemical synthesis strategy.

Bioorg Chem 2021 Jul 8;115:105159. Epub 2021 Jul 8.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China; West China School of Pharmacy, Sichuan University, Chengdu 610041, China. Electronic address:

Serine, the source of the one-carbon units essential for de novo purine and deoxythymidine synthesis plays a crucial role in the growth of cancer cells. Phosphoglycerate dehydrogenase (PHGDH) which catalyzes the first, rate-limiting step in de novo serine biosynthesis has become a promising target for the cancer treatment. Here we identified H-G6 as a potential PHGDH inhibitor from the screening of an in-house small molecule library based on the enzymatic assay. We adopted activity-directed combinatorial chemical synthesis strategy to optimize this hit compound. Compound b36 was found to be the noncompetitive and the most promising one with IC values of 5.96 ± 0.61 μM against PHGDH. Compound b36 inhibited the proliferation of human breast cancer and ovarian cancer cells, reduced intracellular serine synthesis, damaged DNA synthesis, and induced cell cycle arrest. Collectively, our results suggest that b36 is a novel PHGDH inhibitor, which could be a promising modulator to reprogram the serine synthesis pathway and might be a potential anticancer lead worth further exploration.
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http://dx.doi.org/10.1016/j.bioorg.2021.105159DOI Listing
July 2021

Artificial intelligence-based analysis for immunohistochemistry staining of immune checkpoints to predict resected non-small cell lung cancer survival and relapse.

Transl Lung Cancer Res 2021 Jun;10(6):2452-2474

Center for Thoracic Oncology, Mount Sinai Cancer, New York, NY, USA.

Background: Conventional analysis of single-plex chromogenic immunohistochemistry (IHC) focused on quantitative but spatial analysis. How immune checkpoints localization related to non-small cell lung cancer (NSCLC) prognosis remained unclear.

Methods: Here, we analyzed ten immune checkpoints on 1,859 tumor microarrays (TMAs) from 121 NSCLC patients and recruited an external cohort of 30 NSCLC patients with 214 whole-slide IHC. EfficientUnet was applied to segment tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs), while ResNet was performed to extract prognostic features from IHC images.

Results: The features of galectin-9, OX40, OX40L, KIR2D, and KIR3D played an un-negatable contribution to overall survival (OS) and relapse-free survival (RFS) in the internal cohort, validated in public databases (GEPIA, HPA, and STRING). The IC-Score and Res-Score were two predictive models established by EfficientUnet and ResNet. Based on the IC-Score, Res-Score, and clinical features, the integrated score presented the highest AUC for OS and RFS, which could achieve 0.9 and 0.85 in the internal testing cohort. The robustness of Res-Score was validated in the external cohort (AUC: 0.80-0.87 for OS, and 0.83-0.94 for RFS). Additionally, the neutrophil-to-lymphocyte ratio (NLR) combined with the PD-1/PD-L1 signature established by EfficientUnet can be a predictor for RFS in the external cohort.

Conclusions: Overall, we established a reliable model to risk-stratify relapse and death in NSCLC with a generalization ability, which provided a convenient approach to spatial analysis of single-plex chromogenic IHC.
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http://dx.doi.org/10.21037/tlcr-21-96DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264317PMC
June 2021

Developmental Pharmacogenetics of CYP2D6 in Chinese Children: Loratadine as a Substrate Drug.

Front Pharmacol 2021 6;12:657287. Epub 2021 Jul 6.

Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, China.

The elucidation of CYP2D6 developmental pharmacogenetics in children has improved, however, these findings have been largely limited to studies of Caucasian children. Given the clear differences in CYP2D6 pharmacogenetic profiles in people of different ancestries, there remains an unmet need to better understand the developmental pharmacogenetics in populations of different ancestries. We sought to use loratadine as a substrate drug to evaluate the effects of ontogeny and pharmacogenetics on the developmental pattern of CYP2D6 in Chinese pediatric patients. Chinese children receiving loratadine treatment were enrolled in the present study. The metabolite-to-parent ratio (M/P ratio), defined as the molar ratio of desloratadine to loratadine of trough concentrations samples at steady-state condition, was used as a surrogate of CYP2D6 activity. Loratadine and desloratadine were determined by LC/MS/MS method. Variants of CYP2D6 were genotyped by polymerase chain reaction for CYP2D6 *4, *10, *41 and long polymerase chain reaction for CYP2D6 *5. A total of 40 patients were available for final analysis. The mean age was 4.50 (range 0.50-9.00) years and the mean weight was 19.64 (range 7.00-42.00) kg. The M/P ratio was significantly lower in intermediate metabolizers (IMs) compared to normal metabolizers (NMs) (10.18 ± 7.97 vs. 18.80 ± 15.83, = 0.03). Weight was also found to be significantly associated with M/P ratio ( = 0.03). The developmental pharmacogenetics of CYP2D6 in Chinese children was evaluated using loratadine as a substrate drug. This study emphasizes the importance of evaluating the developmental pharmacogenetics in populations of different ancestries.
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http://dx.doi.org/10.3389/fphar.2021.657287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292113PMC
July 2021

Formononetin relieves the facilitating effect of lncRNA AFAP1-AS1-miR-195/miR-545 axis on progression and chemo-resistance of triple-negative breast cancer.

Aging (Albany NY) 2021 07 21;13(14):18191-18222. Epub 2021 Jul 21.

Department of Breast, Longhua Hospital Affiliated to Shanghai University of TCM, Shanghai, China.

This investigation attempted to discern whether formononetin restrained progression of triple-negative breast cancer (TNBC) by blocking lncRNA AFAP1-AS1-miR-195/miR-545 axis. We prepared TNBC cell lines (i.e. MDA-MB-231 and BT-549) and normal human mammary epithelial cell line (i.e. MCF-10A) in advance, and the TNBC cell lines were, respectively, transfected by pcDNA3.1-lncRNA AFAP1-AS1, si-lncRNA AFAP1-AS1, pcDNA6.2/GW/EmGFP-miR-545 or pcDNA6.2/GW/EmGFP-miR-195. Resistance of TNBC cells in response to 5-Fu, adriamycin, paclitaxel and cisplatin was evaluated through MTT assay, while potentials of TNBC cells in proliferation, migration and invasion were assessed via CCK8 assay and Transwell assay. Consequently, silencing of lncRNA AFAP1-AS1 impaired chemo-resistance, proliferation, migration and invasion of TNBC cells (<0.05), and over-expression of miR-195 and miR-545, which were sponged and down-regulated by lncRNA AFAP1-AS1 (<0.05), significantly reversed the promoting effect of pcDNA3.1-lncRNA AFAP1-AS1 on proliferation, migration, invasion and chemo-resistance of TNBC cells (<0.05). Furthermore, CDK4 and Raf-1, essential biomarkers of TNBC progression, were, respectively, subjected to target and down-regulation of miR-545 and miR-195 (<0.05), and they were promoted by pcDNA3.1-lncRNA AFAP1-AS1 at protein and mRNA levels (<0.05). Additionally, formononetin significantly decreased expressions of lncRNA AFAP1-AS1, CDK4 and Raf-1, while raised miR-195 and miR-545 expressions in TNBC cells (<0.05), and exposure to it dramatically contained malignant behaviors of TNBC cells (<0.05). In conclusion, formononetin alleviated TNBC malignancy by suppressing lncRNA AFAP1-AS1-miR-195/miR-545 axis, suggesting that molecular targets combined with traditional Chinese medicine could yield significant clinical benefits in TNBC.
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http://dx.doi.org/10.18632/aging.203156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351708PMC
July 2021

Down-regulated IL36RN expression based on peripheral blood mononuclear cells and plasma of periodontitis patients and its clinical significance.

Authors:
Yue Zhou Yufu Liang

J Clin Lab Anal 2021 Sep 17;35(9):e23899. Epub 2021 Jul 17.

Department of Stomatology, Affiliated Hospital of Beihua University, Jilin, China.

Background: The role of IL-36 receptor antagonist (IL36RN), a mutated gene expression of IL-36 in periodontitis patients with peripheral blood mononuclear cells (PBMC) and plasma remains to be undetermined.

Materials And Methods: Our study discovered the IL36RN expression through GEO public databases and further validated by PBMC and plasma of periodontitis patients and healthy participants. A total of 194 participants of public datasets, consisting of 97 cases of periodontitis and 97 cases of healthy control were retrospectively evaluated and explored the gene enrichment pathways and clinical significance of IL36RN expression accompanied by three different cytokines. Furthermore, the clinical significance of IL36RN was evaluated in mild-to-severe patients of periodontitis by the receiver operating curve (ROC) using the area under the curve (AUC).

Results: IL36RN expressions were notably down-regulated in PBMC and plasma of periodontitis patients. Further, a positive correlation of IL36RN expression was significantly observed between PBMC and plasma of periodontitis patients while IL36RN expression was negatively correlated to serum-based three different cytokines of periodontitis patients. Meanwhile, the ROC-AUCs achieved a significantly higher range from 0.80 to 0.87 with PBMC of mild-to-severe and moderate-to-severe periodontitis patients whereas similar patients with plasma obtained a significant AUC range from 0.73 to 0.83.

Conclusion: IL36RN can distinctively be detectable in periodontitis patients with PBMC and plasma, which can act as a down-regulated mutated gene that might play an effective role in causing periodontitis. IL36RN may involve by other inflammatory cytokines in the pathogenesis of periodontitis.
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http://dx.doi.org/10.1002/jcla.23899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418502PMC
September 2021

Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke.

Oxid Med Cell Longev 2021 25;2021:9991001. Epub 2021 Jun 25.

College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China.

Ferroptosis is a nonapoptotic form of cell death characterized by iron-dependent accumulation of lipid hydroperoxides to lethal levels. Necroptosis, an alternative form of programmed necrosis, is regulated by receptor-interacting protein (RIP) 1 activation and by RIP3 and mixed-lineage kinase domain-like (MLKL) phosphorylation. Ferroptosis and necroptosis both play important roles in the pathological progress in ischemic stroke, which is a complex brain disease regulated by several cell death pathways. In the past few years, increasing evidence has suggested that the crosstalk occurs between necroptosis and ferroptosis in ischemic stroke. However, the potential links between ferroptosis and necroptosis in ischemic stroke have not been elucidated yet. Hence, in this review, we overview and analyze the mechanism underlying the crosstalk between necroptosis and ferroptosis in ischemic stroke. And we find that iron overload, one mechanism of ferroptosis, leads to mitochondrial permeability transition pore (MPTP) opening, which aggravates RIP1 phosphorylation and contributes to necroptosis. In addition, heat shock protein 90 (HSP90) induces necroptosis and ferroptosis by promoting RIP1 phosphorylation and suppressing glutathione peroxidase 4 (GPX4) activation. In this work, we try to deliver a new perspective in the exploration of novel therapeutic targets for the treatment of ischemic stroke.
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http://dx.doi.org/10.1155/2021/9991001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257382PMC
June 2021

Real-Time Voluntary Motion Prediction and Parkinson's Tremor Reduction Using Deep Neural Networks.

IEEE Trans Neural Syst Rehabil Eng 2021 26;29:1413-1423. Epub 2021 Jul 26.

Wearable tremor suppression devices (WTSD) have been considered as a viable solution to manage parkinsonian tremor. WTSDs showed their ability to improve the quality of life of individuals suffering from parkinsonian tremor, by helping them to perform activities of daily living (ADL). Since parkinsonian tremor has been shown to be nonstationary, nonlinear, and stochastic in nature, the performance of the tremor models used by WTSDs is affected by their inability to adapt to the nonlinear behaviour of tremor. Another drawback that the models have is their limitation to estimate or predict one step ahead, which introduces delay when used in real time with WTSDs, which compromises performance. To address these issues, this work proposes a deep neural network model that learns the correlations and nonlinearities of tremor and voluntary motion, and is capable of multi-step prediction with minimal delay. A generalized model that is task and user-independent is presented. The model achieved an average estimation percentage accuracy of 99.2%. The average future voluntary motion prediction percentage accuracy with 10, 20, 50, and 100 steps ahead was 97.0%, 94.0%, 91.6%, and 89.9%, respectively, with prediction time as low as 1.5 ms for 100 steps ahead. The proposed model also achieved an average of 93.8% ± 1.5% in tremor reduction when it was tested in an experimental setup in real time. The tremor reduction showed an improvement of 25% over the Weighted Fourier Linear Combiner (WFLC), an estimator commonly used with WTSDs.
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http://dx.doi.org/10.1109/TNSRE.2021.3097007DOI Listing
August 2021

Population Pharmacokinetics and Safety of Dasatinib in Chinese Children with Core-Binding Factor Acute Myeloid Leukemia.

Clin Pharmacokinet 2021 Jul 9. Epub 2021 Jul 9.

Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.

Background: Dasatinib, an orally administered Src-family kinase inhibitor, is combined with the standard chemotherapeutic regimen to enhance antineoplastic activity against core-binding factor acute myeloid leukemia (CBF-AML) in adults; however, limited data are available for use in children. In the present study, we studied the pharmacokinetics and safety of dasatinib in children.

Methods: Dasatinib (60 or 80 mg/m once daily) was administered to 20 children with CBF-AML. Blood samples were collected and drug concentrations were quantified by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Population pharmacokinetic analysis and Monte-Carlo simulations were performed using NONMEM software, and safety analyses were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (NCT03844360).

Results: Twenty pediatric patients (3.3-14.4 years of age) were included, and a total of 40 dasatinib concentrations were available for population pharmacokinetic analysis. The mean (standard deviation) of the estimated area under the concentration-time curve extrapolated to steady state (AUC) of dasatinib 60 and 80 mg/m was 366.1 (146.6) ng·h/mL and 425.3 (150.7) ng·h/mL, respectively. The majority of adverse events were grade 1/2 in severity, including thrombocytopenia, rash, and pain in the extremities. The estimated cumulative incidence of complete remission and complete molecular response were 95.0% and 75.5%, respectively.

Conclusions: The population pharmacokinetics of orally administered dasatinib were evaluated in pediatric CBF-AML patients. The AUC of dasatinib (80 mg/m) in CBF-AML pediatric patients was similar to those of dasatinib (100 mg) in adult patients. Dasatinib is well-tolerated in pediatric patients with CBF-AML.
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http://dx.doi.org/10.1007/s40262-021-01054-6DOI Listing
July 2021

How Much Benefit Can Patients Acquire from Enhanced Recovery After Surgery Protocols with Percutaneous Endoscopic Lumbar Interbody Fusion?

Int J Gen Med 2021 2;14:3125-3132. Epub 2021 Jul 2.

Department of Orthopedics, The Second Affiliated Xinqiao Hospital of Army Military Medical University, Chongqing, People's Republic of China.

Purpose: We aimed to explore the role of enhanced recovery after surgery (ERAS) in patients who underwent percutaneous endoscopic lumbar interbody fusion (PELIF).

Patients And Methods: We performed a retrospective, observational, cohort study on 91 patients who underwent PELIF for degenerative disc disease. The primary outcomes were postoperative opioid consumption, hospital length of stay (LOS), and hospital cost.

Results: Forty-six patients comprised the ERAS group, and 45 patients comprised the pre-ERAS group (control group). The groups had comparable demographic characteristics. Good compliance with the ERAS pathway was observed in the ERAS group. Patients in the ERAS group used significantly fewer morphine equivalents compared with the pre-ERAS group (25.0 vs 33.3, respectively; p = 0.017). Hospital LOS did not decrease significantly in the ERAS group compared with the pre-ERAS group (3.1days vs 3.4 days, respectively; p = 0.096). Likewise, there was no significant difference in hospital cost between the pre-ERAS group and the ERAS group ($10,598.60 vs $10,384.50, respectively; p = 0.468).

Conclusion: In the present study, the benefit of ERAS in the context of PELIF was limited. Although a multidisciplinary ERAS protocol can improve analgesia and decrease opioid consumption, no significant reduction in hospital LOS and cost was observed.
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http://dx.doi.org/10.2147/IJGM.S318876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260044PMC
July 2021
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