Publications by authors named "Ling Zhong"

213 Publications

Effects of temperature on life-history traits of the newly invasive fall armyworm, in Southeast China.

Ecol Evol 2021 May 18;11(10):5255-5264. Epub 2021 Mar 18.

Institute of Entomology Jiangxi Agricultural University Nanchang China.

In mid-May, 2019, the fall armyworm (FAW) invaded Jiangxi Province, China, and caused extensive damage to corn crops. However, little attention has been given to the life-history traits of the FAW. In the present study, we systematically investigated the life-history traits of the newly invasive FAW on corn leaves at 19, 22, 25, 28, and 31°C under a photoperiod of LD 15:9 hr. The FAW thrived on the corn leaves with short developmental periods, high survival rates of larvae and pupae, very high mating success rates, and high fecundity. The pupal developmental stage was significantly longer in males than females at all temperatures, thus resulting in a protogyny phenomenon. The pupal weight was heaviest after a relatively shorter larval development stage at a higher temperature (25°C); thus, the FAW did not follow the temperature-size rule. Females were smaller than males, indicating sexual size dimorphism. A small proportion of females delayed their pre-oviposition period and began to lay eggs on the 7th to 9th day after adult emergence. There were positive relationships between pupal weight and larval developmental time and between adult weight and fecundity. There was a negative relationship between fecundity and longevity. These findings can help us to predict the population dynamics of the FAW on corn and to develop a suitable and practical management strategy.
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http://dx.doi.org/10.1002/ece3.7413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131782PMC
May 2021

The albumin-to-alkaline phosphatase ratio as an independent predictor of future non-alcoholic fatty liver disease in a 5-year longitudinal cohort study of a non-obese Chinese population.

Lipids Health Dis 2021 May 16;20(1):50. Epub 2021 May 16.

Cardiology Department, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, 330006, China.

Background: The albumin-to-alkaline phosphatase ratio (AAPR) is a newly developed index of liver function, but its association in patients with non-alcoholic fatty liver disease (NAFLD) has not been established. The aim of this study was to investigate the association between the AAPR and NAFLD in a non-obese Chinese population.

Methods: The study included 10,749 non-obese subjects without NAFLD at baseline and divided them into quintiles according to the AAPR. A Cox multiple regression model was used to examine the association between the AAPR and its quintiles and the incidence of NAFLD.

Results: The average age of the study population was 43.65 ± 15.15 years old. During the 5-year follow-up, 1860 non-obese subjects had NAFLD events. In the Cox multiple regression model, after adjusting the model according to important risk factors, the AAPR and NAFLD risk were independently correlated, and with a gradual increase in the AAPR, the NAFLD risk decreased gradually (HR: 0.61, 95% CI: 0.47, 0.81; P-trend< 0.0001). Additionally, there were significant interactions between the AAPR and BMI, blood pressure and lipids (P-interaction < 0.05). Stratified analysis showed that the risk of AAPR-related NAFLD decreased in people with normal blood pressure and lipid levels, while the risk of AAPR-related NAFLD increased abnormally in people who were underweight.

Conclusions: This longitudinal cohort study provides the first evidence that the AAPR is an independent predictor of future NAFLD events in non-obese people. For non-obese people with a low AAPR, especially those with BMI < 18.5 kg/m, more attention should be given to the management of risk factors for NAFLD to prevent future NAFLD.
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http://dx.doi.org/10.1186/s12944-021-01479-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126124PMC
May 2021

Comparative Phosphoproteomics of Classical Bordetellae Elucidates the Potential Role of Serine, Threonine and Tyrosine Phosphorylation in Biology and Virulence.

Front Cell Infect Microbiol 2021 13;11:660280. Epub 2021 Apr 13.

School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.

The genus is divided into two groups: classical and non-classical. , and are known as classical bordetellae, a group of important human pathogens causing whooping cough or whooping cough-like disease and hypothesized to have evolved from environmental non-classical bordetellae. infections have increased globally driving the need to better understand these pathogens for the development of new treatments and vaccines. One unexplored component in is the role of serine, threonine and tyrosine phosphorylation. Therefore, this study characterized the phosphoproteome of classical bordetellae and examined its potential role in biology and virulence. Applying strict identification of localization criteria, this study identified 70 unique phosphorylated proteins in the classical group with a high degree of conservation. Phosphorylation was a key regulator of metabolism with proteins involved in gluconeogenesis, TCA cycle, amino acid and nucleotide synthesis significantly enriched. Three key virulence pathways were also phosphorylated including type III secretion system, alcaligin synthesis and the BvgAS master transcriptional regulatory system for virulence genes in . Seven new phosphosites were identified in BvgA with 6 located in the DNA binding domain. Of the 7, 4 were not present in non-classical bordetellae. This suggests that serine/threonine phosphorylation may play an important role in stabilizing/destabilizing BvgA binding to DNA for fine-tuning of virulence gene expression and that BvgA phosphorylation may be an important factor separating classical from non-classical bordetellae. This study provides the first insight into the phosphoproteome of classical species and the role that Ser/Thr/Tyr phosphorylation may play in biology and virulence.
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http://dx.doi.org/10.3389/fcimb.2021.660280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076611PMC
April 2021

Combination efficacy of ruxolitinib with standard-of-care drugs in CRLF2-rearranged Ph-like acute lymphoblastic leukemia.

Leukemia 2021 Apr 24. Epub 2021 Apr 24.

Children's Cancer Institute, School of Women's and Children's Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk ALL subtype with high rates of relapse and poor patient outcome. Activating mutations affecting components of the JAK-STAT signaling pathway occur in the majority of Ph-like ALL cases. The use of JAK inhibitors represents a potential treatment option for Ph-like ALL, although we and others have shown that CRLF2-rearranged Ph-like ALL responds poorly to single-agent JAK inhibitors in the preclinical setting. Therefore, the aim of this study was to identify effective combination treatments against CRLF2-rearranged Ph-like ALL, and to elucidate the underlying mechanisms of synergy. We carried out a series of high-throughput combination drug screenings and found that ruxolitinib exerted synergy with standard-of-care drugs used in the treatment of ALL. In addition, we investigated the molecular effects of ruxolitinib on Ph-like ALL by combining mass spectrometry phosphoproteomics with gene expression analysis. Based on these findings, we conducted preclinical in vivo drug testing and demonstrated that ruxolitinib enhanced the in vivo efficacy of an induction-type regimen consisting of vincristine, dexamethasone, and L-asparaginase in 2/3 CRLF2-rearranged Ph-like ALL xenografts. Overall, our findings support evaluating the addition of ruxolitinib to conventional induction regimens for the treatment of CRLF2-rearranged Ph-like ALL.
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http://dx.doi.org/10.1038/s41375-021-01248-8DOI Listing
April 2021

Nuclear Leukocyte Immunoglobulin-like Receptor A3 Is Monomeric and Is Involved in Multiple Layers of Regulated Gene Expression and Translation.

J Proteome Res 2021 06 1;20(6):3078-3089. Epub 2021 Apr 1.

Mechanisms of Diseases and Translational Research, School of Medical Sciences, Department of Pathology, UNSW, Sydney 2052, Australia.

The leukocyte immunoglobulin-like receptor A3 (LILRA3) is a soluble protein primarily expressed by peripheral blood monocytes and is abundant in sera of healthy donors. Extracellular LILRA3 is anti-inflammatory and displays neuro-regenerative functions in vitro. However, its intracellular expression, distribution, and function(s) remain unknown. Using a combination of high-resolution confocal and super-resolution microscopy, we identified intracellular expression of native LILRA3 in the nucleus of peripheral blood monocytes and in vitro-derived macrophages. This unexpected nuclear localization of LILRA3 was confirmed in LILRA3-GFP-transfected HEK293T cells. Western blot of proteins fractionated from primary macrophages and the transfected HEK293T cells confirmed nuclear localization of the native and expressed LILRA3 proteins. Interestingly, most of the LILRA3 in the nucleus was in a monomeric form like the biologically active secreted protein, while that in the other cellular compartments was in mixed monomeric, dimeric, and oligomeric forms. The predominant presence of monomeric LILRA3 in the nucleus was independently corroborated in transfected live HEK293T cells using the number and molecular brightness (N&B) analysis method. Immunoprecipitation and mass spectrometric peptide sequencing studies revealed that nuclear LILRA3 co-immunoprecipitated with several nuclear proteins involved in host protein synthesis machinery via direct interactions to a key multifunctional RNA-binding protein, the Ewing sarcoma breakpoint region 1 protein (EWS) (data are available via ProteomeXchange with identifier PXD024602). The biological significance of the nuclear expression of LILRA3 and its interaction with these key proteins remain to be elucidated.
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http://dx.doi.org/10.1021/acs.jproteome.0c00946DOI Listing
June 2021

A dynamic pandemic model evaluating reopening strategies amid COVID-19.

Authors:
Ling Zhong

PLoS One 2021 26;16(3):e0248302. Epub 2021 Mar 26.

Department of Economics, Cheung Kong Graduate School of Business, Beijing, China.

Among over 200 COVID-19 affected countries, some are fighting to "flatten the curve", while some others are considering reopening after lockdown. It remains unclear how different reopening strategies obstruct the local virus containment and impact the economy. We develop a model with travelers across heterogeneous epicenters. A low-risk area attempts to safely reopen utilizing internal policies, such as social distancing and contact tracing, and external policies, including capacity quota, quarantine, and tests. Simulations based on the COVID-19 scenario show that external policies differ in efficacy. They can substitute each other and complement internal policies. Simultaneous relaxation of both channels may lead to a new wave of COVID-19 and large economic costs. This work highlights the importance of quantitative assessment prior to implementing reopening strategies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248302PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996987PMC
April 2021

LDL/HDL cholesterol ratio is associated with new-onset NAFLD in Chinese non-obese people with normal lipids: a 5-year longitudinal cohort study.

Lipids Health Dis 2021 Mar 25;20(1):28. Epub 2021 Mar 25.

Department of Cardiology, Jiangxi Provincial People's Hospital, Aiguo 152 Rd, Nanchang, 330006, China.

Background: Low-density lipoprotein to high density lipoprotein (LDL/HDL) cholesterol ratio has been reported to predict the risk of many metabolic diseases. However, the association between the LDL/HDL cholesterol ratio and nonalcoholic fatty liver disease (NAFLD) has not been established.

Methods: A longitudinal cohort design was adopted in this study; 9767 non-obese subjects without NAFLD were included and analyzed. The subjects were grouped according to the quintile of LDL/HDL cholesterol ratio. The cumulative incidence of NAFLD and the independent effect of the LDL/HDL cholesterol ratio on NAFLD during 5 years of follow-up were calculated using the Kaplan-Meier method and Cox proportional-hazards regression model.

Results: During the 5-year follow-up period, 841 subjects were diagnosed with new-onset NAFLD, and the 1-, 2-, 3-, 4-, and 5-year cumulative incidence rates of NAFLD were 1.16, 4.65, 8.33, 12.43, and 25.14%, respectively. In the multivariable-adjusted Cox proportional-hazards regression model, the LDL/HDL cholesterol ratio was significantly associated with the risk for NAFLD (HR: 1.66, 95% CI: 1.38-1.99, P trend< 0.001), especially among young people (HR: 3.96, 95% CI: 1.50-10.46, P interaction< 0.05). Additionally, receiver operating characteristic curve analysis showed that the LDL/HDL cholesterol ratio was better than HDL cholesterol and LDL cholesterol in predicting new-onset NAFLD.

Conclusions: LDL/HDL cholesterol ratio is an independent predictor of NAFLD in Chinese non-obese people with normal lipids, and its predictive value is higher than that of other lipoproteins. In clinical practice, the LDL/HDL cholesterol ratio can be used to identify people at high risk of NAFLD.
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http://dx.doi.org/10.1186/s12944-021-01457-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993485PMC
March 2021

Dynamic blood single-cell immune responses in patients with COVID-19.

Signal Transduct Target Ther 2021 03 6;6(1):110. Epub 2021 Mar 6.

The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.

The 2019 coronavirus disease (COVID-19) outbreak caused by the SARS-CoV-2 virus is an ongoing global health emergency. However, the virus' pathogenesis remains unclear, and there is no cure for the disease. We investigated the dynamic changes of blood immune response in patients with COVID-19 at different stages by using 5' gene expression, T cell receptor (TCR), and B cell receptors (BCR) V(D)J transcriptome analysis at a single-cell resolution. We obtained single-cell mRNA sequencing (scRNA-seq) data of 341,420 peripheral blood mononuclear cells (PBMCs) and 185,430 clonotypic T cells and 28,802 clonotypic B cells from 25 samples of 16 patients with COVID-19 for dynamic studies. In addition, we used three control samples. We found expansion of dendritic cells (DCs), CD14+ monocytes, and megakaryocytes progenitor cells (MP)/platelets and a reduction of naïve CD4+ T lymphocytes in patients with COVID-19, along with a significant decrease of CD8+ T lymphocytes, and natural killer cells (NKs) in patients in critical condition. The type I interferon (IFN-I), mitogen-activated protein kinase (MAPK), and ferroptosis pathways were activated while the disease was active, and recovered gradually after patient conditions improved. Consistent with this finding, the mRNA level of IFN-I signal-induced gene IFI27 was significantly increased in patients with COVID-19 compared with that of the controls in a validation cohort that included 38 patients and 35 controls. The concentration of interferon-α (IFN-α) in the serum of patients with COVID-19 increased significantly compared with that of the controls in an additional cohort of 215 patients with COVID-19 and 106 controls, further suggesting the important role of the IFN-I pathway in the immune response of COVID-19. TCR and BCR sequences analyses indicated that patients with COVID-19 developed specific immune responses against SARS-CoV-2 antigens. Our study reveals a dynamic landscape of human blood immune responses to SARS-CoV-2 infection, providing clues for therapeutic potentials in treating COVID-19.
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http://dx.doi.org/10.1038/s41392-021-00526-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936231PMC
March 2021

The Influence of Changes in Work Stressors and Coping Resources on Sleep Disturbances: Evidence from the OHSPIW Cohort Study.

Sleep 2021 Feb 20. Epub 2021 Feb 20.

Department of Occupational and Environmental Health, School of Public Health, Xinjiang Medical University, Urumqi, China.

Study Objectives: We investigated whether changes in psychosocial work conditions affect the risk of sleep disturbances.

Methods: Data pertaining to 2738 males and 1431 females were obtained from the Occupational Health Study of Petroleum Industry Workers (OHSPIW), a prospective cohort study of Chinese petroleum industry workers. The subjects were assessed with regard to work-related stressors, coping resources and sleep disturbances at baseline (2012) and follow-up (2018). The variations in work stressors and coping resources, which were assessed using the Occupation Stress Inventory-Reviewed (OSI-R), were calculated. Sleep disturbances were evaluated with the self-reported Pittsburgh Sleep Quality Index (PSQI).

Results: Increased work stressors (OR=1.57, 95% CI=1.24-1.99) and decreased coping resources (OR=2.03, 95% CI=1.48-2.78) were correlated with the likelihood of sleep disturbances in male and female workers. The primary risk factors included high role overload, increased responsibility, enhanced physical environment stressors, reduced self-care, and reduced rational coping. A reduction in work stressors was a protective factor against sleep disturbances in females only (OR=0.63, 95% CI=0.45-0.88). Coping resources had a modifying effect on the relationship between increased work stressors and sleep disturbances, with increased coping resources being associated with a lower odds of increased works stressors on sleep disturbances (OR=1.29, 95%CI=1.01-1.66) than decreased coping resources (OR=3.60, 95%CI=1.10-11.81).

Conclusions: Changes in work stressors and coping resources have a significant influence on the risk of sleep disturbances. Our findings highlight important precautionary strategies to abate adverse psychosocial working environments and to strengthen coping resources to prevent work-related sleep disturbances.
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http://dx.doi.org/10.1093/sleep/zsab039DOI Listing
February 2021

Development and preliminary validation of a self-rating anxiety inventory for maintenance haemodialysis patients.

Psychol Health Med 2021 Feb 18:1-13. Epub 2021 Feb 18.

Department of Nephrology, Daping Hospital, Third Military Medical University, Chongqing, China.

This study aimed to develop a self-rating anxiety inventory for maintenance haemodialysis patients (AI-MHD) and perform preliminary validation to provide a simple, effective, and highly specific practical tool for effective anxiety disorder screening in haemodialysis patients. Based on existing general anxiety disorder screening scales and common symptoms of MHD patients as a reference and after expert discussions and preliminary validation at a single dialysis centre, a self-rating AI-MHD containing 12 items was developed. Subsequently, the AI-MHD was applied in 4 dialysis centres and compared with GAD-7 and HADS-A. Further multicentre validation showed that Cronbach's alpha for the scale was 0.918; the AI-MHD score not only significantly differed between the anxiety disorders group and the non-anxiety disorders group (p<0.001) but also correlated with GAD-7 and HADS-A scores (p<0.001). In addition, the Kaiser-Meyer-Olkin (KMO) score was 0.847, and Bartlett's test of sphericity was significant (x=849.45, p<0.001). The anxiety disorder detection rate was 93%, and the specificity was 90%, which were significantly better than the screening results using the GAD-7 and HADS-A scales in the same groups. Although there were limitations, such as the sample size and regionality, the AI-MHD showed good efficacy and reliability in rating anxiety in MHD patients.
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http://dx.doi.org/10.1080/13548506.2021.1890159DOI Listing
February 2021

Enhancement of myogenic potential of muscle progenitor cells and muscle healing during pregnancy.

FASEB J 2021 Mar;35(3):e21378

Department of Orthopaedic Surgery, The University of Texas Health Science Center at Houston, Houston, TX, USA.

The decline of muscle regenerative potential with age has been attributed to a diminished responsiveness of muscle progenitor cells (MPCs). Heterochronic parabiosis has been used as a model to study the effects of aging on stem cells and their niches. These studies have demonstrated that, by exposing old mice to a young systemic environment, aged progenitor cells can be rejuvenated. One interesting idea is that pregnancy represents a unique biological model of a naturally shared circulatory system between developing and mature organisms. To test this hypothesis, we evaluated the muscle regeneration potential of pregnant mice using a cardiotoxin (CTX) injury mouse model. Our results indicate that the pregnant mice demonstrate accelerated muscle healing compared to nonpregnant control mice following muscle injury based on improved muscle histology, superior muscle regeneration, and a reduction in inflammation and necrosis. Additionally, we found that MPCs isolated from pregnant mice display a significant improvement of myogenic differentiation capacity in vitro and muscle regeneration in vivo when compared to the MPCs from nonpregnant mice. Furthermore, MPCs from nonpregnant mice display enhanced myogenic capacity when cultured in the presence of serum obtained from pregnant mice. Our proteomics data from these studies provides potential therapeutic targets to enhance the myogenic potential of progenitor cells and muscle repair.
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http://dx.doi.org/10.1096/fj.202001914RDOI Listing
March 2021

Truncated YY1 interacts with BASP1 through a 339KLK341 motif in YY1 and suppresses vascular smooth muscle cell growth and intimal hyperplasia after vascular injury.

Cardiovasc Res 2021 Jan 28. Epub 2021 Jan 28.

Vascular Biology and Translational Research Laboratory, School of Medical Sciences, UNSW Medicine, University of New South Wales, Sydney NSW 2052, Australia.

Aims: In-stent restenosis and late stent thrombosis are complications associated with the use of metallic and drug-coated stents. Strategies that inhibit vascular smooth muscle cell (SMC) proliferation without affecting endothelial cell (EC) growth would be helpful in reducing complications arising from percutaneous interventions. Our group previously showed that the forced expression of the injury-inducible zinc finger (ZNF) transcription factor, yin yang-1 (YY1) comprising 414 residues inhibits neointima formation in carotid arteries of rabbits and rats. YY1 inhibits SMC proliferation without affecting EC growth. Identifying a shorter version of YY1 retaining cell-selective inhibition would make it more amenable for potential use as a gene therapeutic agent.

Methods And Results: We dissected YY1 into a range of shorter fragments (YY1A-D, YY1Δ) and found that the first two ZNFs in YY1 (construct YY1B, spanning 52 residues) repressed SMC proliferation. Receptor Binding Domain analysis predicts a three residue (339KLK341) interaction domain. Mutation of 339KLK341 to 339AAA341 in YY1B (called YY1Bm) abrogated YY1B's ability to inhibit SMC but not EC proliferation and migration. Incubation of recombinant GST-YY1B and GST-YY1Bm with SMC lysates followed by precipitation with glutathione-agarose beads and mass spectrometric analysis identified a novel interaction between YY1B and BASP1. Overexpression of BASP1, like YY1, inhibited SMC but not EC proliferation and migration. BASP1 siRNA partially rescued SMC from growth inhibition by YY1B. In the rat carotid balloon injury model, adenoviral overexpression of YY1B, like full-length YY1, reduced neointima formation, whereas YY1Bm had no such effect. CD31 immunostaining suggested YY1B could increase re-endothelialization in a 339KLK341-dependent manner.

Conclusions: These studies identify a truncated form of YY1 (YY1B) that can interact with BASP1 and inhibits SMC proliferation, migration and intimal hyperplasia after balloon injury of rat carotid arteries as effectively as full length YY1. We demonstrate the therapeutic potential of YY1B in vascular proliferative disease.
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http://dx.doi.org/10.1093/cvr/cvab021DOI Listing
January 2021

Extending the Depth of Human Plasma Proteome Coverage Using Simple Fractionation Techniques.

J Proteome Res 2021 02 20;20(2):1261-1279. Epub 2021 Jan 20.

Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW 2052, Australia.

Human plasma is one of the most widely used tissues in clinical analysis, and plasma-based biomarkers are used for monitoring patient health status and/or response to medical treatment to avoid unnecessary invasive biopsy. Data-driven plasma proteomics has suffered from a lack of throughput and detection sensitivity, largely due to the complexity of the plasma proteome and in particular the enormous quantitative dynamic range, estimated to be between 9 and 13 orders of magnitude between the lowest and the highest abundance protein. A major challenge is to identify workflows that can achieve depth of plasma proteome coverage while minimizing the complexity of the sample workup and maximizing the sample throughput. In this study, we have performed intensive depletion of high-abundant plasma proteins or enrichment of low-abundant proteins using the Agilent multiple affinity removal liquid chromatography (LC) column-Human 6 (Hu6), the Agilent multiple affinity removal LC column-Human 14 (Hu14), and ProteoMiner followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS PAGE) and C18 prefractionation techniques. We compared the performance of each of these fractionation approaches to identify the method that satisfies requirements for analysis of clinical samples and to include good plasma proteome coverage in combination with reasonable sample output. In this study, we report that one-dimensional (1D) gel-based prefractionation allows parallel sample processing and no loss of proteome coverage, compared with serial chromatographic separation, and significantly accelerates analysis time, particularly important for large clinical projects. Furthermore, we show that a variety of methodologies can achieve similarly high plasma proteome coverage, allowing flexibility in method selection based on project-specific needs. These considerations are important in the effort to accelerate plasma proteomics research so as to provide efficient, reliable, and accurate diagnoses, population-based health screening, clinical research studies, and other clinical work.
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http://dx.doi.org/10.1021/acs.jproteome.0c00670DOI Listing
February 2021

Visualized podocyte-targeting and focused ultrasound responsive glucocorticoid nano-delivery system against immune-associated nephropathy without glucocorticoid side effect.

Theranostics 2021 1;11(6):2670-2690. Epub 2021 Jan 1.

Department of Nephrology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.

Glucocorticoids are widely used in the treatment of nephritis, however, its dose-dependent side effects, such as the increased risk of infection and metabolic disturbances, hamper its clinical use. This study reports a visualized podocyte-targeting and focused ultrasound responsive glucocorticoid nano-delivery system (named as Dex/[email protected]α), which specific delivers dexamethasone (Dex) to podocyte targets and reduces systemic side effects. The glucocorticoid nano-delivery system was synthesized by a lipid thin film and a simple facile acoustic-emulsification method. This glucocorticoid nano-delivery system used BMS-470539 (BMS-α), a synthetic compound, as a "navigator" to specifically identify and target the melanocortin-1 receptor (MC-1R) on podocytes. The loaded perfluoropentane (PFP) realizes the directed "explosion effect" through ultrasound-targeted microbubble destruction (UTMD) technology under the coordination of low intensity focused ultrasound (LIFU) to completely release Dex. Both and experiments have demonstrated that Dex/[email protected]α accurately gathered to podocyte targets and improved podocyte morphology. Moreover, , proteinuria and serum creatinine levels were significantly reduced in the group treated with Dex/[email protected]α, and no severe side effects were detected. Furthermore, Dex/[email protected]α, with capabilities of ultrasound, photoacoustic and fluorescence imaging, provided individualized visual guidance and the monitoring of treatment. This study provides a promising strategy of Dex/[email protected]α as effective and safe against immune-associated nephropathy.
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http://dx.doi.org/10.7150/thno.53083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806481PMC
January 2021

A rare case of adult diffuse midline glioma with H3 K27M mutant in the prepontine cistern.

J Int Med Res 2021 Jan;49(1):300060520981266

Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China.

Diffuse midline glioma with the H3.3 histone A () or H3 clustered histone 2/3 () K27M mutation occurs primarily in children and less frequently in adults involving the midline structures of the central nervous system. This case report describes an adult patient with a diffuse midline glioma H3 K27M mutant in the prepontine cistern, which is an unusual site in clinical practice. The clinical, radiographic and histopathological data from the case are presented. Magnetic resonance imaging showed a progressively enlarged and enhanced nodule in the right prepontine cistern, with diffuse involvement of the meninges and communicating hydrocephalus. Analysis of the cerebrospinal fluid occasionally found suspiciously atypical cells with hyperchromatic nuclei and multiple nucleoli, as well as a severely elevated opening pressure and protein level, slightly elevated white cell count and decreased chloride level. Empirical antituberculosis treatment was administered but eventually proved to be ineffective. The definite diagnosis was made by histopathological analysis of the lesion based on the features of positive H3 K27M mutant protein and diffusely infiltrating growth. A diffuse midline glioma with the H3 K27M mutation may rarely present in an unusual site. A biopsy is recommended at an early stage for suspected cases to facilitate a definite diagnosis.
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http://dx.doi.org/10.1177/0300060520981266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809314PMC
January 2021

Significant functional differences in differentiated Conditionally Reprogrammed (CRC)- and Feeder-free Dual SMAD inhibited-expanded human nasal epithelial cells.

J Cyst Fibros 2021 Mar 5;20(2):364-371. Epub 2021 Jan 5.

School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), University of New South Wales and Sydney Children's Hospital, Sydney, NSW, Australia; Department of Respiratory Medicine, Sydney Children's Hospital, Sydney, NSW, Australia. Electronic address:

Background: Patient-derived airway cells differentiated at Air Liquid Interface (ALI) are valuable models for Cystic fibrosis (CF) precision therapy. Different culture expansion methods have been established to extend expansion capacity of airway basal cells, while retaining functional airway epithelium physiology. Considerable variation in response to CFTR modulators is observed in cultures even within the same CFTR genotype and despite the use of similar ALI culture techniques. We aimed to address culture expansion method impact on differentiation.

Methods: Nasal epithelial brushings from 14 individuals (CF=9; non-CF=5) were collected, then equally divided and expanded under conditional reprogramming culture (CRC) and feeder-serum-free "dual-SMAD inhibition" (SMADi) methods. Expanded cells from each culture were differentiated with proprietary PneumaCult™-ALI media. Morphology (Immunofluorescence), global proteomics (LC-MS/MS) and function (barrier integrity, cilia motility, and ion transport) were compared in CRC and SMADi under basal and CFTR corrector treated (VX-809) conditions.

Results: No significant difference in the structural morphology or baseline global proteomics profile were observed. Barrier integrity and cilia motility were significantly different, despite no difference in cell junction morphology or cilia abundance. Epithelial Sodium Channels and Calcium-activated Chloride Channel activity did not differ but CFTR mediated chloride currents were significantly reduced in SMADi compare to their CRC counterparts.

Conclusion: Alteration of cellular physiological function in vitro were more prominent than structural and differentiation potential in airway ALI. Since initial expansion culture conditions significantly influence CFTR activity, this could lead to false conclusions if data from different labs are compared against each other without specific reference ranges.
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http://dx.doi.org/10.1016/j.jcf.2020.12.019DOI Listing
March 2021

Aberrant RhoA activation in macrophages increases senescence-associated secretory phenotypes and ectopic calcification in muscular dystrophic mice.

Aging (Albany NY) 2020 12 23;12(24):24853-24871. Epub 2020 Dec 23.

Steadman Philippon Research Institute, Center for Regenerative Sports Medicine, Vail, CO 81657, USA.

Duchenne Muscular Dystrophy (DMD) patients often suffer from both muscle wasting and osteoporosis. Our previous studies have revealed reduced regeneration potential in skeletal muscle and bone, concomitant with ectopic calcification of soft tissues in double knockout (, ; utrophin-/-) mice, a severe murine model for DMD. We found significant involvement of RhoA/ROCK (Rho-Associated Protein Kinase) signaling in mediating ectopic calcification of muscles in mice. However, the cellular identity of these RhoA+ cells, and the role that RhoA plays in the chronic inflammation-associated pathologies has not been elucidated. Here, we report that CD68+ macrophages are highly prevalent at the sites of ectopic calcification of mice, and that these macrophages highly express RhoA. Macrophages from mice feature a shift towards a more pro-inflammatory M1 polarization and an increased expression of various senescence-associated secretory phenotype (SASP) factors that was reduced with the RhoA/ROCK inhibitor Y-27632. Further, systemic inhibition of RhoA activity in mice led to reduced number of RhoA+/CD68+ cells, as well as a reduction in fibrosis and ectopic calcification. Together, these data revealed that RhoA signaling may be a key regulator of imbalanced mineralization in the dystrophic musculoskeletal system and consequently a therapeutic target for the treatment of DMD or other related muscle dystrophies.
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http://dx.doi.org/10.18632/aging.202413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803538PMC
December 2020

Region-wide comprehensive implementation of roguing infected trees, tree replacement, and insecticide applications successfully controls citrus HLB.

Phytopathology 2020 Dec 23. Epub 2020 Dec 23.

University of Florida, Citrus Research and Education Center, 700 Experiment Station Road, Lake Alfred, Florida, United States, 33850;

Huanglongbing (HLB) is a devastating citrus disease worldwide. A three-pronged approach to controlling HLB has been suggested, namely, removal of HLB-symptomatic trees, psyllid control, and replacement with HLB-free trees. However, such a strategy did not lead to successful HLB control in many citrus producing regions. We hypothesize this is because of the small-scale or incomprehensive implementation of the program, conversely, a comprehensive implementation of such a strategy at regional level can successfully control HLB. Here we investigated the effects of region-wide comprehensive implementation of this scheme to control HLB in Gannan region, China, with a total planted citrus acreage of over 110,000 ha from 2013-2019. With the region-wide implementation of comprehensive HLB management, overall HLB incidence in Gannan decreased from 19.71% in 2014 to 3.86% in 2019. A partial implementation of such a program (without a comprehensive inoculum removal) at the regional level in Brazil resulted in HLB incidence increasing from 1.89% in 2010 to 19.02% in 2019. A dynamic regression model analyses predicated that in a region-wide comprehensive implementation of such a program, HLB incidence would be controlled to a level of less than 1%. Economic feasibility analyses showed that average net profits were positive for groves that implemented the comprehensive strategy, but negative for groves without such a program over a ten-year period. Overall, the key for the three-pronged program to successfully control HLB control is the large scale (region-wide) and comprehensiveness in implementation. This study provides valuable information to control HLB and other endemic diseases worldwide.
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http://dx.doi.org/10.1094/PHYTO-09-20-0436-RDOI Listing
December 2020

Novel Antioxidant Therapy with the Immediate Precursor to Glutathione, γ-Glutamylcysteine (GGC), Ameliorates LPS-Induced Cellular Stress in In Vitro 3D-Differentiated Airway Model from Primary Cystic Fibrosis Human Bronchial Cells.

Antioxidants (Basel) 2020 Nov 30;9(12). Epub 2020 Nov 30.

School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.

Systemic glutathione deficiency, inflammation, and oxidative stress are hallmarks of cystic fibrosis (CF), an inherited disease that causes persistent lung infections and severe damage to the respiratory system and many of the body organs. Improvements to current antioxidant therapeutic strategies are needed. The dietary supplement, γ-glutamylcysteine (GGC), which is the immediate precursor to glutathione, rapidly boosts cellular glutathione levels following a single dose in healthy individuals. Efficacy of GGC against oxidative stress induced by , which is a common and chronic pathogen infecting lungs of CF patients, remains unassessed. Primary mucocilliary differentiated airway (bronchial and/or nasal) epithelial cells were created from four individuals with CF. Airway oxidative stress and inflammation was induced by lipopolysaccharide (LPS). Parameters including global proteomics alterations, cell redox state (glutathione, oxidative stress), pro-inflammatory mediators (IL-8, IDO-1), and cellular health (membrane integrity, stress granule formation, cell metabolic viability) were assayed under six experimental conditions: (1) Mock, (2) LPS-challenged (3) therapeutic, (4) prophylactic (5) therapeutic and prophylactic and (6) GGC alone. Proteomic analysis identified perturbation of several pathways related to cellular respiration and stress responses upon LPS challenge. Most of these were resolved when cells were treated with GGC. While GGC did not resolve LPS-induced IL-8 and IDO-1 activity, it effectively attenuated LPS-induced oxidative stress and stress granule formation, while significantly increasing total intracellular glutathione levels, metabolic viability and improving epithelial cell barrier integrity. Both therapeutic and prophylactic treatments were successful. Together, these findings indicate that GGC has therapeutic potential for treatment and prevention of oxidative stress-related damage to airways in cystic fibrosis.
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http://dx.doi.org/10.3390/antiox9121204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760366PMC
November 2020

Association between the alanine aminotransferase/aspartate aminotransferase ratio and new-onset non-alcoholic fatty liver disease in a nonobese Chinese population: a population-based longitudinal study.

Lipids Health Dis 2020 Nov 25;19(1):245. Epub 2020 Nov 25.

Cardiology Department, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi Province, China.

Background: The alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ratio has been considered an alternative marker for hepatic steatosis. However, few studies have investigated the association of the ALT/AST ratio with non-alcoholic fatty liver disease (NAFLD) in nonobese people.

Methods: A total of 12,127 nonobese participants who were free of NAFLD participated in this study. The participants were divided into quintiles of the ALT/AST ratio. Multiple Cox regression models were used to explore the association of the ALT/AST ratio with new-onset NAFLD.

Results: During the five-year follow-up period, 2147 individuals (17.7%) developed new-onset NAFLD. After adjusting for all non-collinear covariates, the multiple Cox regression analysis results showed that a higher ALT/AST ratio was independently associated with new-onset NAFLD in nonobese Chinese (adjusted hazard ratios [aHRs]: 2.10, 95% confidence intervals: 1.88, 2.36). The aHRs for NAFLD across increasing quintiles of the ALT/AST ratio were 1, 1.63 (1.30, 2.04), 2.07 (1.65, 2.60), 2.84 (2.33, 3.48) and 3.49 (2.78, 4.39) (P for trend< 0.001). The positive association was more significant among people with high blood pressure, high blood lipids and hyperglycaemia, as well as in men. Additionally, the regression spline showed that the saturation effect of the ALT/AST ratio on NAFLD risk was at 0.93 in this study population, which was 1.22 in males and 0.89 in females.

Conclusions: In nonobese Chinese individuals without NAFLD at baseline, the increase in the ALT/AST ratio is closely associated with the risk of new-onset NAFLD.
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http://dx.doi.org/10.1186/s12944-020-01419-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690093PMC
November 2020

Nontargeted Identification of Plasma Proteins O-, N-, and S-Transmethylated by O-Methyl Organophosphates.

Anal Chem 2020 12 17;92(23):15420-15428. Epub 2020 Nov 17.

School of Chemistry, University of New South Wales, Sydney, New South Wales 2052, Australia.

Organophosphates (OPs) are used worldwide as pesticides. However, acute and chronic exposure to OPs can cause serious adverse health effects. The mechanism of delayed OP toxicity is thought to involve off-target inhibition of serine proteases, although the precise molecular details remain unclear owing to the lack of an analytical method for global detection of protein targets of OPs. Here, we report the development of a mass spectrometry method to identify OP-adducted proteins from complex mixtures in a nontargeted manner. Human plasma was incubated with the OP dichlorvos that was 50% isotopically labeled and 50% unlabeled. Proteins and protein adducts were extracted, digested, and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to detect "twin ions" of peptides that were covalently modified by a chemical reaction with dichlorvos. The LC-MS/MS data were processed by a blended data analytics software (Xenophile) to detect the amino acid residue sites of proteins that were covalently modified by exposure to OPs. We discovered that OPs can transmethylate the N, S, and O side chains of His, Cys, Glu, Asp, and Lys residues. For model systems, such transmethylation reactions were confirmed by LC-MS, nuclear magnetic resonance (NMR), and rationalized using electronic structure calculations. Methylation of the ubiquitous antioxidant glutathione by dichlorvos can decrease the reducing/oxidizing equilibrium of glutathione in liver extracts, which has been implicated in diseases and pathological conditions associated with delayed OP toxicity.
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http://dx.doi.org/10.1021/acs.analchem.0c03077DOI Listing
December 2020

Massive gastrointestinal bleeding caused by a Dieulafoy's lesion in a duodenal diverticulum: A case report.

World J Clin Cases 2020 Oct;8(20):5013-5018

Department of Gastroenterology and Hepatology, Chengdu Second People's Hospital, Chengdu 610017, Sichuan Province, China.

Background: Dieulafoy's lesion is a rare vascular abnormality characterized by a small abnormally dilated artery that runs a tortuous course in the submucosa. There is usually no ulcer present in Dieulafoy's lesions and the overlying mucosa is most often normal. Bleeding caused by a Dieulafoy's lesion is usually urgent, massive, life-threatening and prone to recurrence. Dieulafoy's lesions have been reported throughout the digestive tract although the majority of them have been found in the upper digestive tract especially the stomach and duodenum. However, a Dieulafoy's lesion occurring inside a duodenal diverticulum is very rare.

Case Summary: A 74-year-old Asian male with epigastric pain, hematemesis and melena was admitted to our clinic. Before admission, the patient had vomited 500 mL of dark red blood, and passed 200 g of black tarry stool. Conservative management was first undertaken as the patient had not been fasting. However, hemorrhage recurred and the patient went into shock. Urgent endoscopy was performed and a diverticulum of 1.8 cm × 1.2 cm × 0.8 cm was found on the anterior wall of the descending duodenum. The diverticulum was covered with a blood clot. After the clot was removed, an artery stump was observed in the diverticulum with a diameter of 2-3 mm. Two titanium hemostatic clips were inserted to clamp the vessel stump. The patient was discharged 7 d post-endoscopy and followed for 6 mo with no recurrence.

Conclusion: This case was diagnosed with a Dieulafoy's lesion inside a duodenal diverticulum which has rarely been reported. Hematemesis was stopped by clamping the vessel stump with titanium clips. No complications occurred.
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http://dx.doi.org/10.12998/wjcc.v8.i20.5013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642557PMC
October 2020

Expressions and relationship of Krüppel-like factor 15 and endothelial nitric oxide synthase in experimental deep venous thrombosis.

Ann Transl Med 2020 Sep;8(17):1090

Department of Sports Medicine, the First Affiliated Hospital of Kunming Medical University, Kunming, China.

Background: Deep vein thrombosis (DVT) is an early postoperative complication. Thrombosis formation, which is potentially life-threatening, seriously affects the rehabilitation of patients after surgery. We aimed to establish a C57 mouse model of DVT and to examine the changes in the expression of Krüppel-like factor 15 (KLF15) and endothelial nitric oxide synthase (eNOS) in venous wall tissues, and we also investigated the regulatory relationship of KLF15 and eNOS in the thrombin-induced human umbilical vein endothelial cell (HUVEC) injury cell model.

Methods: The DVT model was established using the inferior vena cava (IVC) stenosis method. The expression levels of KLF15 and eNOS were analyzed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). In cell experiments, the expression of KLF15 and eNOS was analyzed in the model of thrombin-induced HUVEC injury with KLF15 siRNA.

Results: Compared to the control and sham-operated groups, KLF15 in the DVT group was upregulated, while eNOS was downregulated. The results of cell experiments revealed that KLF15 was downregulated in the thrombin+KLF15 siRNA group compared with the thrombin group. Meanwhile, eNOS was upregulated in the thrombin+KLF15 siRNA group compared with the thrombin group. These findings suggested that KLF15 regulated the expression of eNOS in the DVT model.

Conclusions: We successfully constructed a DVT mouse model. In the early stage of DVT formation, KLF15 regulated the expression and inhibited the antithrombotic effect of eNOS, resulting in thrombi formation.
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http://dx.doi.org/10.21037/atm-20-5828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575959PMC
September 2020

miR-451a suppression of IL-6R can inhibit proliferation and increase apoptosis through the JAK2/STAT3 pathway in multiple myeloma.

Oncol Lett 2020 Dec 8;20(6):339. Epub 2020 Oct 8.

Department of Hematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China.

The IL-6R/JAK2/STAT3 pathway mediated by interleukin-6 (IL-6) plays an important role in the occurrence and development of multiple myeloma (MM), which is associated with decreased microRNA-451a. However, the biological function of microRNA-451a in MM remains unclear. The bone marrow (BM) of patients with MM was sampled, and the plasma cells were enriched. BM miR-451a, IL-6 and IL-6R levels and Ki-67 expression intensity were evaluated using reverse transcription-quantitative PCR, ELISA and flow cytometry, respectively. U266 cell proliferation, viability and apoptosis were measured using BrdU, CCK-8 and Annexin V/propidium iodide assays, respectively. Total and phospo-(p-)JAK2 and p-STAT3 levels were measured by western blotting. Dual-luciferase reporter assays were performed to validate the predicted target binding sites. miR-451a expression was low in patients with MM and was associated with the Revised International Staging System (R-ISS) stage. IL-6 concentrations were significantly higher in patients with MM than in normal controls and were inversely associated with miR-451a levels (r=-0.96, P<0.0001). IL-6R levels were positively correlated with the R-ISS stage. miR-451a was downregulated, and IL-6R was upregulated in myeloma cell lines. Treatment with an miR-451a mimic inhibited viability and induced apoptosis in U266 cells. p-JAK2 and p-STAT3 levels were significantly lower in mimic-treated U266 cells than in control cells. Thus, miR-451a was shown to regulate myeloma cell proliferation and apoptosis via the IL-6R/JAK2/STAT3 pathway and may be used to predict patient prognosis.
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http://dx.doi.org/10.3892/ol.2020.12202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583731PMC
December 2020

Characterization of the binding ability of the odorant binding protein BminOBP9 of Bactrocera minax to citrus volatiles.

Pest Manag Sci 2021 Mar 21;77(3):1214-1225. Epub 2020 Oct 21.

National Center for Citrus Improvement (Changsha), Hunan Agricultural University, Changsha, People's Republic of China.

Background: Bactrocera minax, one of the most important citrus pests, oviposits exclusively on citrus fruit. In the insect olfactory system, odorant-binding proteins (OBPs) facilitate the initial recognition role of host odor molecules. The aim of this study was to characterize the functional OBPs of B. minax and identify specific volatile organic compounds in the Citrus genus as OBP targets.

Results: BminOBP9 (BminGOBP99a), a closely related homolog of BdorGOBP99a, which reduces the egg-laying behavior of Bactrocera dorsalis through silencing technology, was cloned, expressed, and purified. The binding ability of BminOBP9 to 11 citrus volatiles was then examined using fluorescence competition binding assays (FCBA). The results demonstrated that BminOBP9 could bind to all tested citrus volatiles, as could BdorGOBP99a, ZcucGOBP99a, and ZtauGOBP99a. Interestingly, the binding ability of BminOBP9 was the strongest among the four, suggesting that BminOBP9 may have a function in the specific recognition of citrus volatiles. Furthermore, we aligned the above four proteins and found nine distinctive amino acid sites in BminOBP9. To identify the unique binding sites of BminOBP9, we produced the nine mutants using site-directed mutagenesis. Further FCBA showed that the binding ability of the nine mutants to citrus volatiles significantly reduced, and six of them (substitutes S24P, L36F, E53K, N68D, D112A, and S118R) had the weakest binding ability.

Conclusion: The results demonstrated that BminOBP9 was the specific protein involved in the perception of citrus host volatiles by B. minax. Moreover, BminOBP9 could prove efficient in screening the candidate odors for pest management. © 2020 Society of Chemical Industry.
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http://dx.doi.org/10.1002/ps.6132DOI Listing
March 2021

Neoadjuvant Pyrotinib plus Trastuzumab and Chemotherapy for Stage I-III HER2-Positive Breast Cancer: A Phase II Clinical Trial.

Oncologist 2020 12 20;25(12):e1909-e1920. Epub 2020 Oct 20.

Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing, People's Republic of China.

Lessons Learned: This is the first trial to explore the neoadjuvant therapy of pyrotinib in HER2-positive operable and locally advanced breast cancer, in combination with epirubicin plus cyclophosphamide followed by docetaxel plus trastuzumab. Results primarily showed that pyrotinib in combination with epirubicin plus cyclophosphamide followed by docetaxel plus trastuzumab was effective and safe in HER2-positive operable and locally advanced breast cancer. A subsequent randomized controlled trial is still warranted to confirm these results.

Background: The efficacy and safety of neoadjuvant therapy of pyrotinib, a new irreversible tyrosine kinase inhibitor (TKI), was first estimated in patients with HER2-positive breast cancer in this phase II study, in combination with trastuzumab and chemotherapy.

Methods: Between February 19, 2019, and November 20, 2019, 20 female Chinese patients with stage I-III HER2-positive breast cancer were assigned to receive eight cycles of neoadjuvant pyrotinib (P) in combination with four cycles of epirubicin (E) and cyclophosphamide (C) followed by four cycles of docetaxel (T) and trastuzumab (H), once every 3 weeks, referred to as P + EC-TH.

Results: A total of 19 patients completed the therapy and final surgery. The total pathological complete response (tpCR) rate was 73.7% (95% confidence interval [CI], 48.8-90.9), and no recurrence or metastasis occurred during the short-term follow-up period. The objective response rate (ORR) was 100% (95% CI, 82.4-100). The most common adverse events (AEs) were diarrhea and leukopenia in 18 of 20 patients (90%), but no grade 5 AEs were reported.

Conclusion: This study showed that in HER2-positive operable or locally advanced breast cancer, the tpCR rate of P + EC-TH neoadjuvant therapy was about twice as high as that of EC-TH neoadjuvant therapy reported in other trials, with tolerable side effects.
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http://dx.doi.org/10.1002/onco.13546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108050PMC
December 2020

Circulating miR-451a levels as a potential biomarker to predict the prognosis of patients with multiple myeloma.

Oncol Lett 2020 Nov 21;20(5):263. Epub 2020 Sep 21.

Department of Hematology, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, P.R. China.

The natural course of multiple myeloma (MM) varies greatly between patients. The Revised MM International Staging System (R-ISS) identifies high-risk patients, but it is unsuitable for assessing minimal residual disease (MRD). Furthermore, the focal location of myeloma cells and clonal evolution often produce false negative results in flow cytometry. Extracellular microRNA (miRNA/miR) expression levels are stable in bodily fluids, and are retrievable and measurable from fresh or archived serum or plasma samples. Therefore, the present study aimed to investigate the clinical utility of circulating miRNA levels in patients with MM, particularly miR-451a, which is commonly downregulated in MM, and whether it could predict the prognosis and relapse of patients with MM. In total, 66 patients with MM, stratified using the R-ISS criteria, were recruited, while 10 healthy subjects (transplantation donors) were enrolled as controls. Reverse transcription-quantitative PCR was used to evaluate miR-451a expression in bone marrow (BM) and in the circulation. IL-6 levels were measured using ELISA, while western blotting was conducted to analyze the protein expression levels of the IL-6 receptor (IL-6R). During follow-up, MRD was assessed via multiparameter flow cytometry (MFC). miR-451a was identified to target IL-6R using a dual-luciferase reporter assay. Circulating miR-451a levels were low in patients with MM, and was found to be 0.39 times that of the control group (U=4.00; P<0.001). Among the 66 patients with MM, the median level of miR-451a was 0.73 and 0.41 times that of the control group in R-ISS stage I MM (15 patients) and R-ISS stage II stage (17 patients), respectively; patients with R-ISS stage III MM (34 patients) had the lowest level, at 0.24 times the value of the control group. Circulating miR-451a levels had a strong positive correlation with miR-451a levels in BM, but negatively correlated with IL-6 and IL-6R levels. After two courses of consolidation chemotherapy, 19 patients achieved complete remission, 10 of whom presented steady circulating miR-451a levels during follow-up; the other nine patients had an abrupt decrease in circulating miR-451a levels. The turning points in the trend appeared 4-8 weeks before positive results were obtained via MFC, and 4-16 weeks before clinical relapse. Moreover, miR-451a overexpression notably downregulated the expression of the IL-6R mRNA and protein. Collectively, circulating miR-451a levels potentially represent a novel biomarker to monitor MRD and predict relapse.
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http://dx.doi.org/10.3892/ol.2020.12126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517596PMC
November 2020

Targeting TSLP-Induced Tyrosine Kinase Signaling Pathways in -Rearranged Ph-like ALL.

Mol Cancer Res 2020 12 14;18(12):1767-1776. Epub 2020 Aug 14.

Children's Cancer Institute, School of Women's and Children's Health, UNSW Sydney, Sydney, Australia.

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is characterized by aberrant activation of signaling pathways and high risk of relapse. Approximately 50% of Ph-like ALL cases overexpress cytokine receptor-like factor 2 (CRLF2) associated with gene rearrangement. Activated by its ligand thymic stromal lymphopoietin (TSLP), CRLF2 signaling is critical for the development, proliferation, and survival of normal lymphocytes. To examine activation of tyrosine kinases regulated by TSLP/CRLF2, phosphotyrosine (P-Tyr) profiling coupled with stable isotope labeling of amino acids in cell culture (SILAC) was conducted using two CRLF2-rearranged (CRLF2r) Ph-like ALL cell lines stimulated with TSLP. As a result, increased P-Tyr was detected in previously reported TSLP-activated tyrosine kinases and substrates, including JAK1, JAK2, STAT5, and ERK1/2. Interestingly, TSLP also increased P-Tyr of insulin growth factor 1 receptor (IGF1R) and fibroblast growth factor receptor 1 (FGFR1), both of which can be targeted with small-molecule inhibitors. Fixed-ratio combination cytotoxicity assays using the tyrosine kinase inhibitors BMS-754807 and ponatinib that target IGF1R and FGFR1, respectively, revealed strong synergy against both cell line and patient-derived xenograft (PDX) models of CRLF2r Ph-like ALL. Further analyses also indicated off-target effects of ponatinib in the synergy, and novel association of the Ras-associated protein-1 (Rap1) signaling pathway with TSLP signaling in CRLF2r Ph-like ALL. When tested , the BMS-754807/ponatinib combination exerted minimal efficacy against 2 Ph-like ALL PDXs, associated with low achievable plasma drug concentrations. Although this study identified potential new targets in CRLF2r Ph-like ALL, it also highlights that validation of synergistic drug interactions is essential. IMPLICATION: Quantitative phosphotyrosine profiling identified potential therapeutic targets for high-risk CRLF2-rearranged Ph-like ALL.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-1098DOI Listing
December 2020

Cytoskeleton stiffness regulates cellular senescence and innate immune response in Hutchinson-Gilford Progeria Syndrome.

Aging Cell 2020 08 25;19(8):e13152. Epub 2020 Jul 25.

Department of Orthopaedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas.

Hutchinson-Gilford progeria syndrome (HGPS) is caused by the accumulation of mutant prelamin A (progerin) in the nuclear lamina, resulting in increased nuclear stiffness and abnormal nuclear architecture. Nuclear mechanics are tightly coupled to cytoskeletal mechanics via lamin A/C. However, the role of cytoskeletal/nuclear mechanical properties in mediating cellular senescence and the relationship between cytoskeletal stiffness, nuclear abnormalities, and senescent phenotypes remain largely unknown. Here, using muscle-derived mesenchymal stromal/stem cells (MSCs) from the Zmpste24 (Z24 ) mouse (a model for HGPS) and human HGPS fibroblasts, we investigated the mechanical mechanism of progerin-induced cellular senescence, involving the role and interaction of mechanical sensors RhoA and Sun1/2 in regulating F-actin cytoskeleton stiffness, nuclear blebbing, micronuclei formation, and the innate immune response. We observed that increased cytoskeletal stiffness and RhoA activation in progeria cells were directly coupled with increased nuclear blebbing, Sun2 expression, and micronuclei-induced cGAS-Sting activation, part of the innate immune response. Expression of constitutively active RhoA promoted, while the inhibition of RhoA/ROCK reduced cytoskeletal stiffness, Sun2 expression, the innate immune response, and cellular senescence. Silencing of Sun2 expression by siRNA also repressed RhoA activation, cytoskeletal stiffness and cellular senescence. Treatment of Zmpste24 mice with a RhoA inhibitor repressed cellular senescence and improved muscle regeneration. These results reveal novel mechanical roles and correlation of cytoskeletal/nuclear stiffness, RhoA, Sun2, and the innate immune response in promoting aging and cellular senescence in HGPS progeria.
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http://dx.doi.org/10.1111/acel.13152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431831PMC
August 2020

Neutrophil elastase triggers the development of autoimmune diabetes by exacerbating innate immune responses in pancreatic islets of non-obese diabetic mice.

Clin Sci (Lond) 2020 07;134(13):1679-1696

State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, China.

Type 1 diabetes is an autoimmune disease resulted from self-destruction of insulin-producing pancreatic β cells. However, the pathological pathways that trigger the autoimmune destruction remain poorly understood. Clinical studies have demonstrated close associations of neutrophils and neutrophil elastase (NE) with β-cell autoimmunity in patients with Type 1 diabetes. The present study aims to investigate the impact of NE inhibition on development of autoimmune diabetes in NOD mice. NE pharmacological inhibitor (sivelestat) or biological inhibitor (elafin) was supplemented into NOD mice to evaluate their effects on islet inflammation and diabetogenesis. The impact of NE inhibition on innate and adaptive immune cells was measured with flow cytometry and immunohistochemistry. A significant but transient increase in neutrophil infiltration accompanied with elevated NE activity was observed in the neonatal period of NOD mice. Treatment of NOD mice with sivelestat or elafin at the early age led to a marked reduction in spontaneous development of insulitis and autoimmune diabetes. Mechanistically, inhibition of NE significantly attenuated infiltration of macrophages and islet inflammation, thus ameliorating cytotoxic T cell-mediated autoimmune attack of pancreatic β cells. In vitro studies showed that NE directly induced inflammatory responses in both min6 β cells and RAW264.7 macrophages, and promoted macrophage migration. These findings support an important role of NE in triggering the onset and progression of β-cell autoimmunity, and suggest that pharmacological inhibition of NE may represent a promising therapeutic strategy for treatment of autoimmune diabetes.
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http://dx.doi.org/10.1042/CS20200021DOI Listing
July 2020