Publications by authors named "Hong Ma"

1,179 Publications

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AAV-mediated delivery of osteoblast/osteoclast-regulating miRNAs for osteoporosis therapy.

Mol Ther Nucleic Acids 2022 Sep 11;29:296-311. Epub 2022 Jul 11.

Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, USA.

Osteoporosis occurs due to a dysregulation in bone remodeling, a process requiring both bone-forming osteoblasts and bone-resorbing osteoclasts. Current leading osteoporosis therapies suppress osteoclast-mediated bone resorption but show limited therapeutic effects because osteoblast-mediated bone formation decreases concurrently. We developed a gene therapy strategy for osteoporosis that simultaneously promotes bone formation and suppresses bone resorption by targeting two microRNAs (miRNAs)-miR-214-3p and miR-34a-5p. We modulated the expression of these miRNAs using systemically delivered recombinant adeno-associated viral (rAAV) vectors targeting the bone. rAAV-mediated overexpression of miR-214-3p or inhibition of miR-34a-5p in the skeleton resulted in bone loss in adult mice, resembling osteoporotic bones. Conversely, rAAV-mediated inhibition of miR-214-3p or overexpression of miR-34a-5p reversed bone loss in mouse models for postmenopausal and senile osteoporosis by increasing osteoblast-mediated bone formation and decreasing osteoclast-mediated bone resorption. Notably, these mice did not show any apparent pathological phenotypes in non-skeletal tissues. Mechanistically, inhibiting miR-214-3p upregulated activating transcription factor 4 in osteoblasts and phatase and tensin homolog in osteoclasts, while overexpressing miR-34a-5p downregulated Notch1 in osteoblasts and TGF-β-induced factor homeobox 2 in osteoclasts. In summary, bone-targeting rAAV-mediated regulation of miR-214-3p or miR-34a-5p is a promising new approach to treat osteoporosis, while limiting adverse effects in non-skeletal tissues.
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http://dx.doi.org/10.1016/j.omtn.2022.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9352805PMC
September 2022

Effect of Etomidate vs Propofol for Total Intravenous Anesthesia on Major Postoperative Complications in Older Patients: A Randomized Clinical Trial.

JAMA Surg 2022 Aug 10. Epub 2022 Aug 10.

Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.

Importance: Older patients may benefit from the hemodynamic stability of etomidate for general anesthesia. However, it remains uncertain whether the potential for adrenocortical suppression with etomidate may increase morbidity.

Objective: To test the primary hypothesis that etomidate vs propofol for anesthesia does not increase in-hospital morbidity after abdominal surgery in older patients.

Design, Setting, And Participants: This multicenter, parallel-group, noninferiority randomized clinical trial (Etomidate vs Propofol for In-hospital Complications [EPIC]) was conducted between August 15, 2017, and November 20, 2020, at 22 tertiary hospitals in China. Participants were aged 65 to 80 years and were scheduled for elective abdominal surgery. Patients and outcome assessors were blinded to group allocation. Data analysis followed a modified intention-to-treat principle.

Interventions: Patients were randomized 1:1 to receive either etomidate or propofol for general anesthesia by target-controlled infusion.

Main Outcomes And Measures: Primary outcome was a composite of major in-hospital postoperative complications (with a noninferiority margin of 3%). Secondary outcomes included intraoperative hemodynamic measurements; postoperative adrenocortical hormone levels; self-reported postoperative pain, nausea, and vomiting; and mortality at postoperative months 6 and 12.

Results: A total of 1944 participants were randomized, of whom 1917 (98.6%) completed the trial. Patients were randomized to the etomidate group (n = 967; mean [SD] age, 70.3 [4.0] years; 578 men [59.8%]) or propofol group (n = 950; mean [SD] age, 70.6 [4.2] years; 533 men [56.1%]). The primary end point occurred in 90 of 967 patients (9.3%) in the etomidate group and 83 of 950 patients (8.7%) in the propofol group, which met the noninferiority criterion (risk difference [RD], 0.6%; 95% CI, -1.6% to 2.7%; P = .66). In the etomidate group, mean (SD) cortisol levels were lower at the end of surgery (4.8 [2.7] μg/dL vs 6.1 [3.4] μg/dL; P < .001), and mean (SD) aldosterone levels were lower at the end of surgery (0.13 [0.05] ng/dL vs 0.15 [0.07] ng/dL; P = .02) and on postoperative day 1 (0.14 [0.04] ng/dL vs 0.16 [0.06] ng/dL; P = .001) compared with the propofol group. No difference in mortality was observed between the etomidate and propofol groups at postoperative month 6 (2.2% vs 3.0%; RD, -0.8%; 95% CI, -2.2% to 0.7%) and 12 (3.3% vs 3.9%; RD, -0.6%; 95% CI, -2.3% to 1.0%). More patients had pneumonia in the etomidate group than in the propofol group (2.0% vs 0.3%; RD, 1.7%; 95% CI, 0.7% to 2.8%; P = .001). Results were consistent in the per-protocol population.

Conclusions And Relevance: Results of this trial showed that, compared with propofol, etomidate anesthesia did not increase overall major in-hospital morbidity after abdominal surgery in older patients, although it induced transient adrenocortical suppression.

Trial Registration: ClinicalTrials.gov Identifier: NCT02910206.
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http://dx.doi.org/10.1001/jamasurg.2022.3338DOI Listing
August 2022

Clinical characteristics and therapeutic response of immunoglobulin G4-related disease: a retrospective study of 127 Chinese patients.

Orphanet J Rare Dis 2022 08 4;17(1):307. Epub 2022 Aug 4.

Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Cirrhosis, National Clinical Research Center for Digestive Diseases, No.95 Yong-an Road, Xicheng District, Beijing, 100050, People's Republic of China.

Background And Aims: Immunoglobulin G4-related disease (IgG4-RD) is a multisystem fibroinflammatory condition. The aim of the present study was to characterize the clinical features and therapeutic response of patients with IgG4-RD and identify risk factors for disease relapse.

Methods: We collected baseline data of eligible patients with IgG4-RD and analyzed clinical features by interview and review of medical records. The patients who received glucocorticoids (GC) therapy with at least 3 months follow-up were used to characterize the therapeutic response and identify risk factors for relapse.

Result: Totally 127 IgG4-RD patients, including 92 males and 35 females, were enrolled in the present study. The median age of onset was 63.0 years, ranging from 23 to 86. The pancreas, bile duct and lymph nodes were the most frequently involved organs. The serum IgG4 level was elevated in 94.5% of the patients and was correlated with the number of organs involved. Patients classified as head and neck limited group were more likely to be female. Compared to Mikulicz syndrome and systemic involvement group, pancreato-hepatobiliary group had higher aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, bilirubin and lower IgG4 level. Mikulicz syndrome and systemic involvement group had the highest IgG4-RD RI score, IgG level. Among 92 patients who received medical therapy with at least 3 months follow-up, 76 received GC alone or in combination with immunomodulator (IM) and 16 patients did not take GC. 74 out of the 76 patients (97.3%) achieved remission, with 59 of them remained in remission and 15 of them relapsed. Whereas 16 patients did not take GC, among them, 6 patients achieved remission with one relapsed. On multivariate analysis, higher initial score of ACR/EULAR IgG4-RD Classification Criteria and GC withdrawal were independent predictors for relapse.

Conclusion: Four phenotypes of IgG4-RD showed different demographic and serological features. GC + IM therapy was safe and effective and might protect patients from relapse. The independent risk factors of relapse were GC withdrawal and higher score of ACR/EULAR IgG4-RD Classification Criteria.
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http://dx.doi.org/10.1186/s13023-022-02404-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9351161PMC
August 2022

Mutation or not, what directly establishes a neoplastic state, namely cellular immortality and autonomy, still remains unknown and should be prioritized in our research.

J Cancer 2022 4;13(9):2810-2843. Epub 2022 Jul 4.

Department of Pathology, The Affiliated Hospital, Guizhou Medical University, Guiyang 550004, Guizhou Province, P.R. China.

Although the concept that cancer is caused by mutations has been widely accepted, there still are ample data deprecating it. For example, embryonic cells displaced in non-embryonic environments may develop to cancer, whereas cancer cells placed in embryonic environments may be reverted to phenotypic normal. Although many intracellular or extracellular aberrations are known to be able to initiate a lengthy tumorigenesis, the molecular or cellular alterations that directly establish a neoplastic state, namely cellular immortality and autonomy, still remain unknown. Hereditary traits are encoded not only by gene sequences but also by karyotype and DNA or chromosomal structures that may be altered via non-mutational mechanisms, such as post-translational modifications of nuclear proteins, to initiate tumorigenesis. However, the immortal and autonomous nature of neoplasms makes them "new" organisms, meaning that neoplasms should have mutations to distinguish themselves from their host patients in the genome. Neoplasms are malignant if they bear epigenetic or genetic alterations in mutator genes, i.e. the genes whose alterations accelerate other genes to mutate, whereas neoplasms are benign if their epigenetic or genetic aberrations occur only in non-mutator genes. Future mechanistic research should be focused on identifying the alterations that directly establish cellular immortality and autonomy. Benign tumors may have many fewer alterations and thus be much better models than cancers for such research. Future translational research should be aimed at identifying the cellular factors that control cancer cells' phenotypes and at establishing approaches of directing cancer cells towards differentiation, which should be a promising therapeutic tactic.
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http://dx.doi.org/10.7150/jca.72628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9330459PMC
July 2022

Screening of small molecular biomarker candidates using untargeted metabolomics strategy in peripheral blood from rats with neuroinflammatory injury induced by whole-brain irradiation.

Biomed Chromatogr 2022 Jul 28:e5464. Epub 2022 Jul 28.

School of Life Science, Beijing Institute of Technology, Beijing, China.

Neuroinflammatory injury is one of the typical brain injuries after the body is exposed to radiation. It is mainly characterized by the release of inflammatory factors by activated microglia and peripherally invading lymphocytes. To provide early warning for nerve injury and early diagnosis of neurodegenerative diseases, it is of great significance to explore the biomarker candidates of neuroinflammatory injury. This study focused on the screening of small molecular biomarker candidates in peripheral blood from rats with neuroinflammatory injury induced by whole-brain irradiation. The rats were exposed to 0, 10, 10 × 3, and 30 Gy of cobalt-60 γ-rays. Serum was collected on the 30th day after exposure and analyzed using reversed-phase liquid chromatography and hydrophilic interaction liquid chromatography coupled with high-resolution mass spectrometry based on untargeted metabolomics. Biomarker candidates were investigated by comparing the 0-Gy group and three irradiation groups using univariate statistical analysis, principal component analysis, and orthogonal partial least squares discriminant analysis. Eleven biomarker candidates were putatively identified, and four major altered metabolic pathways were found. The screened small molecular biomarker candidates could be used as a useful supplement to traditional biomacromolecule markers and may be valuable for radiation protection, target therapy of inflammatory injury, and discovery of new target drugs for the prevention and cure of related neurodegenerative diseases.
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http://dx.doi.org/10.1002/bmc.5464DOI Listing
July 2022

Long-Term, Low-Level Microwave Radiation Impairs Learning and Memory Synbindin: Molecular Basis and Underlying Mechanism.

Biomed Environ Sci 2022 06;35(6):552-557

State Key Lab of Space Medicine Fundamentals and Application (SMFA), Astronaut Research and Training Center, Beijing 100094, China.

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http://dx.doi.org/10.3967/bes2022.074DOI Listing
June 2022

Colocalized targeting of TGF-β and PD-L1 by bintrafusp alfa elicits distinct antitumor responses.

J Immunother Cancer 2022 Jul;10(7)

Department of TIP OIO, EMD Serono Research and Development Institute, Billerica, Massachusetts, USA

Background: Bintrafusp alfa (BA) is a bifunctional fusion protein designed for colocalized, simultaneous inhibition of two immunosuppressive pathways, transforming growth factor-β (TGF-β) and programmed death-ligand 1 (PD-L1), within the tumor microenvironment (TME). We hypothesized that targeting PD-L1 to the tumor by BA colocalizes the TGF-β trap (TGF-βRII) to the TME, enabling it to sequester TGF-β in the tumor more effectively than systemic TGF-β blockade, thereby enhancing antitumor activity.

Methods: Multiple technologies were used to characterize the TGF-β trap binding avidity. BA versus combinations of anti-PD-L1 and TGF-β trap or the pan-TGF-β antibody fresolimumab were compared in proliferation and two-way mixed lymphocyte reaction assays. Immunophenotyping of tumor-infiltrating lymphocytes (TILs) and RNA sequencing (RNAseq) analysis assessing stromal and immune landscape following BA or the combination therapy were performed in MC38 tumors. TGF-β and PD-L1 co-expression and their associated gene signatures in MC38 tumors and human lung carcinoma tissue were studied with single-cell RNAseq (scRNAseq) and immunostaining. BA-induced internalization, degradation, and depletion of TGF-β were investigated in vitro.

Results: BA and fresolimumab had comparable intrinsic binding to TGF-β1, but there was an ~80× avidity-based increase in binding affinity with BA. BA inhibited cell proliferation in TGF-β-dependent and PD-L1-expressing cells more potently than TGF-β trap or fresolimumab. Compared with the combination of anti-PD-L1 and TGF-β trap or fresolimumab, BA enhanced T cell activation in vitro and increased TILs in MC38 tumors, which correlated with efficacy. BA induced distinct gene expression in the TME compared with the combination therapy, including upregulation of immune-related gene signatures and reduced activities in TGF-β-regulated pathways, such as epithelial-mesenchymal transition, extracellular matrix deposition, and fibrosis. Regulatory T cells, macrophages, immune cells of myeloid lineage, and fibroblasts were key PD-L1/TGF-β1 co-expressing cells in the TME. scRNAseq analysis suggested BA modulation of the macrophage phenotype, which was confirmed by histological assessment. PD-L1/TGF-β1 co-expression was also seen in human tumors. Finally, BA induced TGF-β1 internalization and degradation in the lysosomes.

Conclusion: BA more effectively blocks TGF-β by targeting TGF-β trap to the tumor via PD-L1 binding. Such colocalized targeting elicits distinct and superior antitumor responses relative to single agent combination therapy.
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http://dx.doi.org/10.1136/jitc-2021-004122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9305820PMC
July 2022

A two-photon lysosome-targeted probe for endogenous formaldehyde in living cells.

Authors:
Ting Cao Hong Ma

RSC Adv 2022 Jun 20;12(28):18093-18101. Epub 2022 Jun 20.

Department of Chemistry, Taiyuan Normal University Jinzhong 030619 P. R. China.

Formaldehyde (FA) is a gaseous signaling molecule that plays a vital role in various biological processes as well as neurodegenerative diseases. Therefore, it is of great practical significance to develop effective and reliable chemical sensors for the monitoring of endogenous FA. Here, we designed and synthesized a two-photon (810 nm) turn-on chemosensor (aminomorpholine naphthalimide) that accurately localizes lysosomes in cells for imaging of cellular endogenous FA. The fluorescence emission peak of was at ∼540 nm, with a slight blue shift (∼528 nm) in response to FA, while the green fluorescence intensity increased. The probe exhibits excellent selectivity for FA among other biological interference species and a fast response time for FA. It is worth mentioning that the probe successfully imaged endogenous FA in cells in two-photon mode, making the probe an effective research tool in the biomedical field to study diseases related to abnormal FA expression.
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http://dx.doi.org/10.1039/d2ra02672dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9208363PMC
June 2022

Long non-coding RNA H19 contributes to spinal cord ischemia/reperfusion injury through increasing neuronal pyroptosis by miR-181a-5p/HMGB1 axis.

Aging (Albany NY) 2022 07 5;14(13):5449-5463. Epub 2022 Jul 5.

Department of Anesthesiology, First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China.

Pyroptosis, a programmed inflammatory necrotizing cell death, is likely involved in spinal cord ischemia-reperfusion (SCI/R) injury, but the mechanisms initiating driving neuronal pyroptosis must be further revealed. The aim of this study is to unravel the mechanism of long non-coding RNA (lncRNA) H19 during SCI/R. SCI/R model was induced in C57BL/6 mice by blocking the aortic arch , and oxygen-glucose deprivation/reperfusion (OGD/R) injury model of PC12 cells was established . Our results showed that H19 and HMGB1 expression was upregulated, while miR-181a-5p was downregulated in the SCI/R mice and OGD/R-treated PC12 cells. SCI/R induced pathological damage, pyroptosis and inflammation compared with the sham group. H19 acted as a molecular sponge to suppress miR-181a-5p, and HMGB1 was identified as a direct target of miR-181a-5p. MiR-181a-5p overexpression inhibited the increase of IL-1β, IL-18 and TNF-α production and NLRP3, ASC, and Cleaved-caspase-1 expression in OGD/R-treated PC12 cells; while miR-181a-5p silencing exerted opposite effects. HMGB1 overexpression reversed H19 knockdown-mediated the inhibition of pyroptosis and inflammation in OGD/R-treated PC12 cells. , H19 knockdown promoted the hind limb motor function recovery and alleviated the pathological damage, pyroptosis and inflammation induced by SCI/R. LncRNA H19/miR-181a-5p/HMGB1 pathway contributes to pyroptosis via activating caspase1 signaling during SCI/R, suggesting that this axis may be a potent therapeutic target in SCI/R.
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http://dx.doi.org/10.18632/aging.204160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9320554PMC
July 2022

Adverse childhood experiences in offspring living with parental mental illness: a controlled study from China.

J Ment Health 2022 Jul 1:1-10. Epub 2022 Jul 1.

Peking University Sixth Hospital, Peking University Institute of Mental Health, National Clinical Research Center for Mental Disorders, Beijing, PR China.

Background: Adverse childhood experiences (ACEs) affect children's development, and their harm to health is pervasive throughout the life course.

Aims: To identify ACEs and their risk factors in Chinese household with or without parental mental illness.

Methods: A controlled study was conducted among 181 young adults with parental mental illness (positive group) and 201 demographically matched individuals without parental mental illness (negative group). Univariate and multivariate analyses were performed to study the correlation between ACEs and their risk factors.

Results: The positive group suffered emotional abuse, domestic violence, bullying, and cumulative ACEs more frequently than the negative group. In the positive group, living in rural areas and having a low household economic status during childhood were identified as risk factors for cumulative ACEs, whereas a higher education level of the mother was a protective factor for cumulative ACEs in univariate analyses. Low household economic status remained an independent risk factor for cumulative ACEs in the positive group in multivariate analyses.

Conclusions: Children living with parental mental illness are more vulnerable to ACEs, and our findings highlight the importance of socioeconomic factors in increasing the risk of ACEs. To alleviate the deleterious impact of parental mental illness on offspring, multidimensional supports are needed.
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http://dx.doi.org/10.1080/09638237.2022.2091765DOI Listing
July 2022

The Key Network of mRNAs and miRNAs Regulated by HIF1A in Hypoxic Hepatocellular Carcinoma Cells.

Front Genet 2022 14;13:857507. Epub 2022 Jun 14.

Ningxia Key Laboratory of Prevention and Control of Common Infectious Diseases, The School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.

Hypoxia plays an essential role in the progression of hepatocellular carcinoma (HCC), whereas hypoxia inducible factor-1 (HIF-1) is the key transcription factor allowing HCC to survive hypoxia. The aim of this study was to define the essential mRNAs and miRNAs regulated by HIF1A and dissect their functions, interactions, and tumor-infiltrating immune cells in HCC. A human HCC cell line HepG2 was used as a cell model of HCC. The CRISPR/Cas9 system was used to knock out in HepG2 cells, and RNA sequencing was utilized to characterize differentially expressed mRNAs and miRNAs in the -knockout HepG2 cells; the identified candidates were then analyzed by GO annotation and KEGG pathway enrichment to study their function and establish a PPI network. Quantitative (q) PCR was used to verify if there were significant differences in the expression of mRNAs, and the association of the selected mRNAs expression with immune cell infiltration levels was further analyzed using The Cancer Genome Atlas (TCGA) pan-cancer data. Using RNA-sequencing, we discovered that there were 1535 mRNAs differentially expressed (adjusted < 0.05, |fold change|>1.5) in the -knockout HepG2 cells, among which there were 644 mRNAs upregulated and 891 mRNAs downregulated. GO annotation and KEGG pathway enrichment showed that these mRNAs were involved in glycolysis/gluconeogenesis, PI3K-Akt signaling pathways, and HIF-1 signaling pathways. In addition, we found that there were 309 miRNAs differentially expressed (adjusted < 0.05, |fold change|>1.5) in the HIF1A-knockout HepG2 cells, of which there were 213 miRNAs upregulated and 96 miRNAs downregulated. Our further analyses uncovered that these miRNA putative targets were involved in the hippo signaling pathway, axon guidance, and tight junction. Moreover, the construction and analysis of the PPI network showed that , , and were recognized as hub genes with the highest connectivity degrees. Importantly, in the -knockout HepG2 cells, our qRT-PCR data confirmed the selected mRNA changes revealed by RNA-sequencing, and with TCGA pan-cancer data, we revealed that the expressional levels of these three genes, , , and , were associated with immune cell infiltration levels. The identified potential key network of mRNAs and miRNAs regulated by in the HCC cells suggests a key role of in the tumorigenesis of HCC.
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http://dx.doi.org/10.3389/fgene.2022.857507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9237512PMC
June 2022

Intraventricular Bone Dust Migration After Endoscopic Third Ventriculostomy: Illustrative Report of 2 Cases.

Pediatr Neurosurg 2022 Jun 22. Epub 2022 Jun 22.

Introduction Autologous bone dust replacement is a commonly used technique to seal a defect created from a burrhole. However, post-operative migration of these bone fragments may occur as an uncommon complication of endoscopic third ventriculostomy (ETV). Case Presentation We report 2 cases of intraventricular bone dust migration resulting in acute hydrocephalus from physical obstruction of the stoma and infection. Discussion/Conclusion From our 2 cases as well as other reported cases, the bone dust may have acted as a foreign body and served as a nidus of infection, in addition to causing physical obstruction. Lumbar puncture performed after ETV may have resulted in a suction effect of the bone dust from the burrhole into the ventricular system. Both our cases necessitated urgent surgical intervention to extract the bone fragments and restore CSF flow. Because of its potential complications, we recommend against using autologous bone dust for closure of a burrhole defect after ETV.
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http://dx.doi.org/10.1159/000525665DOI Listing
June 2022

Phylotranscriptomic Analyses Reveal Multiple Whole-Genome Duplication Events, the History of Diversification and Adaptations in the Araceae.

Ann Bot 2022 Jun 7. Epub 2022 Jun 7.

Germplasm Bank of Wild Species, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan, China.

Background And Aims: The Araceae are one of the most diverse monocot families with numerous morphological and ecological novelties. Plastid and mitochondrial genes have been used to investigate the phylogeny, and interpret shifts in the pollination biology and biogeography of the Araceae. In contrast, the role of whole-genome duplication (WGD) in the evolution of eight subfamilies remains unclear.

Methods: New transcriptomes or low-depth whole-genome sequences of 65 species were generated through Illumina sequencing. We reconstructed the phylogenetic relationships of Araceae using concatenated and species tree methods, estimated then the age of major clades using TreePL. We inferred the WGD events by Ks and gene tree methods. We investigated the diversification patterns applying time-dependent and trait-dependent models. The expansions of gene families and functional enrichments were analyzed using CAFE and InterProScan.

Key Results: Gymnostachydoideae was the earliest diverging lineage followed successively by Orontioideae, Lemnoideae and Lasioideae. In turn, they were followed by the clade of 'bisexual climbers' comprised of Pothoideae and Monsteroideae, which was resolved as the sister to the unisexual-flowered clade of Zamioculcadoideae and Aroideae. A special WGD event ψ (Psi) shared by the True-Araceae clade occurred in the Early Cretaceous. Net diversification rates first declined, increased then through time in the Araceae. The best diversification rate shift along the stem lineage of the True-Araceae clade was detected, and net diversification rates enhanced following the ψ-WGD. Functional enrichment analyses revealed that some genes, such as heat shock protein, glycosyl hydrolase and cytochrome P450, expanded within the True-Araceae clade.

Conclusions: Our results improve our understanding of aroid phylogeny using the large number of single/low-copy nuclear genes. In contrast to the Proto-Araceae group and the lemnoid clade adaption to aquatic environments, our analyses of WGD, diversification and functional enrichment indicated that WGD may play a more important role in the evolution of adaptations to tropical, terrestrial environments in the True-Araceae clade. These insights provide us with new resources to interpret the evolution of the Araceae.
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http://dx.doi.org/10.1093/aob/mcac062DOI Listing
June 2022

HIF-1 Regulates the Progression of Cervical Cancer by Targeting YAP/TAZ.

J Oncol 2022 25;2022:3814809. Epub 2022 May 25.

Department of Occupational and Environmental Health, School of Public Health, Xinjiang Medical University, Urumqi, 830017, China.

Cervical carcinoma is one of the serious pernicious cancers that influence women's health. Invasion and metastasis are the chief reason of poor prognosis of cervical carcinoma. Hypoxia-inducible factor-1 (HIF-1) is a significant regulatory factor of intracellular oxygen supersession, and its expression or increased activity is closely related to the arise and expansion of various human tumors. However, the relationship between HIF-1 (hypoxia-inducible factor 1) and Hippo pathway target gene Yes-related protein (YAP) and transcriptional coactivator (TAZ) in cervical carcinoma remains unclear. Here, we studied the clinical correlation of HIF-1 and YAP/TAZ expression in normal tissues, cervical intraepithelial neoplasia (CIN), and cervical squamous cell carcinoma (CSCC). In order to analyze the role of HIF-1 in CCSC in vitro, SiHa cells with high expression of HIF-1 and C33a cells with low expression of HIF-1 were screened by detection. After transfection with lentivirus, HIF-1 levels were downregulated in SiHa cells and upregulated in C33a Cells, respectively. Then, the expression of HIF-1 in transfected cervical cancer cells Siha and C33a was detected by qRT-PCR and Western blot, and the expression of YAP/TAZ was detected in cervical squamous cell carcinoma cells after HIF-1 expression was altered. To explore HIF-1 role in cell proliferation, invasion, and metastasis, we examined the changes of cell function in cervical cancer cells with HIF-1 overexpression and inhibition by MTT assay, wound healing assay, Transwell test, and other cell function tests. At the same time, HIF-1 overexpression and HIF-1 inhibition cervical cancer cells were transplanted into nude mice, and tumors were isolated from the nude mice, and tumor volume and weight were observed. In conclusion, HIF-1 significantly promotes the proliferation, invasion, and migration of cervical carcinoma cells by upregulating YAP/TAZ. In addition, YAP/TAZ, the target gene of Hippo pathway, plays an important role in CCSC cells, pointing out that HIF-1 is provided with treatment potential for the treatment of CCSC.
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http://dx.doi.org/10.1155/2022/3814809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9159877PMC
May 2022

Observation of Ultrafast Interfacial Exciton Formation and Relaxation in Graphene/MoS Heterostructure.

J Phys Chem Lett 2022 Jun 3:5123-5130. Epub 2022 Jun 3.

Department of Physics, Shanghai University, Shanghai 200444, China.

Heterostructures constructed from graphene and transition metal dichalcogenides (TMDs) have established a new platform for optoelectronic applications. After a large number of studies, one intriguing debate is the existence of the interfacial exciton in graphene/TMDs. Hereby, by combined optical pump-terahertz probe spectroscopy and transient absorption spectroscopy, we report the observation of the interfacial exciton in graphene/MoS heterostructure. With the photon energy well below the band gap of monolayer MoS, the hot electrons of graphene are transferred to MoS within 0.5 ps; subsequently, the relaxation of the holes in graphene and electrons in MoS shows an identical time scale of 15-18 ps, which manifests the formation and relaxation of the interfacial exciton in the heterostructure following photoexcitation. Moreover, a model of the carrier heating and photogating effect in graphene is proposed to estimate the amount of transferred charge, which agrees well with the experimental results. Our study provides insights into the dynamics of graphene-based heterostructure interfacial non-equilibrium carriers.
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http://dx.doi.org/10.1021/acs.jpclett.2c01197DOI Listing
June 2022

Postmastectomy Radiotherapy After Neoadjuvant Chemotherapy in cTN Breast Cancer Patients: A Single Center Experience and Review of Current Literature.

Front Oncol 2022 17;12:881047. Epub 2022 May 17.

Department of Breast Surgery and Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Purpose: Postmastectomy radiotherapy (PMRT) after neoadjuvant chemotherapy (NAC) in breast cancer patients with initial clinical stage cTN, especially for those who achieved ypTN, is still controversial. This study was to evaluate the survival prognosis of cTN patients after NAC with or without PMRT, and to discuss the selection of patients who may omit PMRT.

Patients And Methods: From January 2005 to December 2017, 3055 female breast cancer patients underwent mastectomy in our medical center, among whom 215 patients of cTN stage, receiving NAC with or without PMRT were finally analyzed. The median follow-up duration was 72.6 months. The primary endpoint was disease-free survival (DFS), and secondary endpoint was overall survival (OS). Comparison was conducted between PMRT and non-PMRT subgroups.

Results: Of the 215 eligible patients, 35.8% (77/215) cTN patients achieved ypTN after NAC while 64.2% (138/215) of the patients remained nodal positive (ypTN). The 5-year DFS of ypTN non-PMRT was 79.5% (95% confidence interval [CI] 63.4-95.6%). No statistically significant difference was observed between the ypTN PMRT and non-PMRT subgroups for the 5-year DFS (78.5% vs 79.5%, = 0.673) and OS (88.8% vs 90.8%, = 0.721). The 5-years DFS didn't obviously differ between the ypTN non-PMRT subgroup and cTN subgroup (79.5% vs 93.3%, = 0.070). By using Cox regression model in multivariate analyses of prognosis in ypTN PMRT subgroup, HER2 overexpression and triple-negative breast cancer were significantly poor predictors of DFS and OS, while ypN stage was significant independent predictors of OS.

Conclusion: An effective response to NAC (ypTN) indicates a sufficiently favorable prognosis, and PMRT might be omitted for cTN breast cancer patients with ypTN after NAC.
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http://dx.doi.org/10.3389/fonc.2022.881047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9152099PMC
May 2022

Photocurable Hydrogel Substrate-Better Potential Substitute on Bone-Marrow-Derived Dendritic Cells Culturing.

Materials (Basel) 2022 May 5;15(9). Epub 2022 May 5.

Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou 310009, China.

Dendritic cells (DCs) are recognized as the most effective antigen-presenting cells at present. DCs have corresponding therapeutic effects in tumor immunity, transplantation immunity, infection inflammation and cardiovascular diseases, and the activation of T cells is dependent on DCs. However, normal bone-marrow-derived Dendritic cells (BMDCs) cultured on conventional culture plates are easy to be activated during culturing, and it is difficult to imitate the internal immune function. Here, we reported a novel BMDCs culturing with hydrogel substrate (CCHS), where we synthesized low substituted Gelatin Methacrylate-30 (GelMA-30) hydrogels and used them as a substitute for conventional culture plates in the culture and induction of BMDCs in vitro. The results showed that 5% GelMA-30 substrate was the best culture condition for BMDCs culturing. The low level of costimulatory molecules and the level of development-related transcription factors of BMDCs by CCHS were closer to that of spleen DCs and were capable of better promoting T cell activation and exerting an immune effect. CCHS was helpful to study the transformation of DCs from initial state to activated state, which contributes to the development of DC-T cell immunotherapy.
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http://dx.doi.org/10.3390/ma15093322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9104740PMC
May 2022

Basic Characteristics of Flower Transcriptome Data and Derived Novel EST-SSR Markers of , an Endangered Species Endemic to Yunnan, Southwestern China.

Plants (Basel) 2022 Apr 29;11(9). Epub 2022 Apr 29.

Institute of Highland Forest Science, Chinese Academy of Forestry, Kunming 650224, China.

(Rubiaceae), an evergreen shrub or small tree, is endemic to China and confined to Nujiang Prefecture, Yunnan Province. This plant is of high ornamental value owing to its attractive pink flowers, sweet fragrance, and long flowering period. Due to the influence of climate change and human factors, the distribution range of has exhibited a significant shrinking trend, and it has become a vulnerable species that is in urgent need of conservation and rational utilization research. In this study, the flower transcriptome sequencing of was conducted using an Illumina HiSeq platform. We designed and developed a series of EST-SSR primers based on the flower transcriptome data of . The results showed that 98,389 unigenes were obtained from the flower transcriptome, all of which were aligned with sequences in public databases. Nr, Nt, Pfam, KOG/COG, Swiss-Prot, KEGG, and GO annotated 31,859, 13,853, 22,684, 10,947, 21,416, 9722, and 23,390 unigenes, respectively. The MISA (Microsatellite) tool was used to identify SSR loci from all unigenes, and a total of 15,384 SSRs were identified. Repeat motifs were given priority with mononucleotides, dinucleotides, and trinucleotides. The 81 primer pairs were synthesized randomly, of which 44 pairs showed effective amplification. A total of 17 primers showed stable amplification, and rich polymorphism was observed in 6 populations. We concluded via genetic diversity analysis that the average effective number of alleles (Ne), Shannon's information index (I), and polymorphism information content (PIC) were 1.925, 0.837, and 0.403, respectively. In conclusion, 17 EST-SSR primers can be used for subsequent population genetic diversity analysis and molecular-marker-assisted breeding, which is of great significance for formulating resource conservation and utilization strategies for .
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http://dx.doi.org/10.3390/plants11091204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9104135PMC
April 2022

Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results.

Nat Med 2022 06 9;28(6):1189-1198. Epub 2022 May 9.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.

Despite success in hematologic malignancies, the treatment landscape of chimeric antigen receptor (CAR) T cell therapy for solid tumors remains limited. Claudin18.2 (CLDN18.2)-redirected CAR T cells showed promising efficacy against gastric cancer (GC) in a preclinical study. Here we report the interim analysis results of an ongoing, open-label, single-arm, phase 1 clinical trial of CLDN18.2-targeted CAR T cells (CT041) in patients with previously treated, CLDN18.2-positive digestive system cancers ( NCT03874897 ). The primary objective was safety after CT041 infusion; secondary objectives included CT041 efficacy, pharmacokinetics and immunogenicity. We treated 37 patients with one of three CT041 doses: 2.5 × 10, 3.75 × 10 or 5.0 × 10 cells. All patients experienced a grade 3 or higher hematologic toxicity. Grade 1 or 2 cytokine release syndrome (CRS) occurred in 94.6% of patients. No grade 3 or higher CRS or neurotoxicities, treatment-related deaths or dose-limiting toxicities were reported. The overall response rate (ORR) and disease control rate (DCR) reached 48.6% and 73.0%, respectively. The 6-month duration of response rate was 44.8%. In patients with GC, the ORR and DCR reached 57.1% and 75.0%, respectively, and the 6-month overall survival rate was 81.2%. These initial results suggest that CT041 has promising efficacy with an acceptable safety profile in patients with heavily pretreated, CLDN18.2-positive digestive system cancers, particularly in those with GC.
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http://dx.doi.org/10.1038/s41591-022-01800-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9205778PMC
June 2022

Progress in Radiotherapy for Cholangiocarcinoma.

Front Oncol 2022 14;12:868034. Epub 2022 Apr 14.

Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Cholangiocarcinoma (CCA) originates from the epithelium of the bile duct and is highly malignant with a poor prognosis. Radical resection is the only treatment option to completely cure primary CCA. Due to the insidious onset of CCA, most patients are already in an advanced stage at the time of the initial diagnosis and may lose the chance of radical surgery. Radiotherapy is an important method of local treatment, which plays a crucial role in preoperative neoadjuvant therapy, postoperative adjuvant therapy, and palliative treatment of locally advanced lesions. However, there is still no unified and clear recommendation on the timing, delineating the range of target area, and the radiotherapy dose for CCA. This article reviews recent clinical studies on CCA, including the timing of radiotherapy, delineation of the target area, and dose of radiotherapy. Further, we summarize large fraction radiotherapy (stereotactic body radiotherapy [SBRT]; proton therapy) in CCA and the development of immunotherapy and the use of targeted drugs combined with radiotherapy.
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http://dx.doi.org/10.3389/fonc.2022.868034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9063097PMC
April 2022

Increased Serum Soluble Transferrin Receptor Levels Were Associated With High Prevalence of Cardiovascular Diseases: Insights From the National Health and Nutrition Examination Survey 2017-2018.

Front Cell Dev Biol 2022 12;10:874846. Epub 2022 Apr 12.

Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Iron deficiency is common in cardiovascular diseases (CVD), e.g., heart failure and coronary heart disease. Soluble transferrin receptor (sTfR) is a promising marker representing unmet cellular iron demands. However, whether higher serum sTfR is associated with increased risk of CVDs needs further investigation. In the present cross-sectional study, we analyzed data of 4,867 adult participants of the National Health and Nutrition Examination Survey (NHANES) 2017-2018. Linear regression models were employed to identify possible correlations between sTfR and other characteristics. The association between sTfR and CVDs was assessed with univariable and multivariable logistics regression models. The prevalence of CVDs was 9.5% among participants, and higher sTfR levels were found in participants with CVDs ( < 0.001). Linear regression models revealed positive associations between sTfR and age, body mass index, systolic blood pressure, glycated hemoglobulin A1c, and insulin resistance (all < 0.001). In the multivariable logistics regression model, the adjusted odds ratio of sTfR for CVDs was 2.05 (per 1 log mg/L, 95% confidence interval: 1.03∼4.05, = 0.046). Further subgroup analysis identified the associations of sTfR and CVDs were only significant in participants ≥60 years old, or with hypertension (all < 0.05). Our study demonstrated that increased serum sTfR levels were associated with a high prevalence of cardiovascular diseases.
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http://dx.doi.org/10.3389/fcell.2022.874846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9039157PMC
April 2022

Comparing Machine Learning Models and Statistical Models for Predicting Heart Failure Events: A Systematic Review and Meta-Analysis.

Front Cardiovasc Med 2022 6;9:812276. Epub 2022 Apr 6.

Zhejiang University, Hangzhou, China.

Objective: To compare the performance, clinical feasibility, and reliability of statistical and machine learning (ML) models in predicting heart failure (HF) events.

Background: Although ML models have been proposed to revolutionize medicine, their promise in predicting HF events has not been investigated in detail.

Methods: A systematic search was performed on Medline, Web of Science, and IEEE Xplore for studies published between January 1, 2011 to July 14, 2021 that developed or validated at least one statistical or ML model that could predict all-cause mortality or all-cause readmission of HF patients. Prediction Model Risk of Bias Assessment Tool was used to assess the risk of bias, and random effect model was used to evaluate the pooled c-statistics of included models.

Result: Two-hundred and two statistical model studies and 78 ML model studies were included from the retrieved papers. The pooled c-index of statistical models in predicting all-cause mortality, ML models in predicting all-cause mortality, statistical models in predicting all-cause readmission, ML models in predicting all-cause readmission were 0.733 (95% confidence interval 0.724-0.742), 0.777 (0.752-0.803), 0.678 (0.651-0.706), and 0.660 (0.633-0.686), respectively, indicating that ML models did not show consistent superiority compared to statistical models. The head-to-head comparison revealed similar results. Meanwhile, the immoderate use of predictors limited the feasibility of ML models. The risk of bias analysis indicated that ML models' technical pitfalls were more serious than statistical models'. Furthermore, the efficacy of ML models among different HF subgroups is still unclear.

Conclusions: ML models did not achieve a significant advantage in predicting events, and their clinical feasibility and reliability were worse.
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http://dx.doi.org/10.3389/fcvm.2022.812276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9020815PMC
April 2022

Effect of a contact-based education intervention on reducing stigma among community health and care staff in Beijing, China: Pilot randomized controlled study.

Asian J Psychiatr 2022 Jul 6;73:103096. Epub 2022 Apr 6.

Centre for Global Mental Health and Centre for Implementation Science, Health Service and Population Research Department, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom.

The aim was to assess the feasibility of an intervention to reduce stigma among primary care and community healthcare staff in Beijing, China through a contact-based education intervention. Participants were randomly assigned to: (i) "education only" group, a lecture-based education; or (ii) "education and contact" group, lectures plus contact with people with lived experience of mental illness. Each participant completed an assessment of mental health stigma related: knowledge (mental health knowledge schedule, MAKS); attitudes (mental illness: clinicians' attitudes scale, MICA-4); and behavior (reported and intended behavior scale, RIBS) before and after the intervention, with follow up at 1 month and 3 months after the intervention. A total of 121 healthcare staff were recruited. Both "education only" group and "education and contact" group showed improved knowledge after the intervention, MAKS scores increased by 1.77 ± 3.15 VS 2.46 ± 2.49 (both p < 0.001), respectively. There was no between-group difference in MAKS score. The "education and contact" group showed a significantly greater improvement for MICA and RIBS score than the "education only" group: the MICA score decreased by 4.43 ± 9.42 VS 8.41 ± 7.48 (p = 0.027), and the RIBS score increased by 2.28 ± 3.89 VS 4.57 ± 3.53 (p = 0.003), in the "education only" and the "education and contact" groups respectively, but the between group differences disappeared at 1 month and 3 months follow-up points. The positive effects on stigma levels (knowledge, attitudes and behaviours) in both groups were sustained at 3 months. The intervention to reduce stigma among the primary and community healthcare staff through a contact-based education intervention was feasible in Beijing.
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http://dx.doi.org/10.1016/j.ajp.2022.103096DOI Listing
July 2022

Control in Local Coordination Environment Boosting Activating Molecular Oxygen with an Atomically Dispersed Binary Mn-Co Catalyst.

ACS Appl Mater Interfaces 2022 Apr 14;14(16):18539-18549. Epub 2022 Apr 14.

State Key Laboratory of Catalysis, Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, People's Republic of China.

Activation of molecular oxygen plays a crucial role in natural organisms and the modern chemical industry. Herein, we report a Mn-Co dual-single-atom catalyst that exerts a specific synergy in boosting O activation by collaboration between two distinct types of activation sites. Taking the oxidative esterification of the biomass platform 5-hydroxymethylfurfural (HMF) as the model reaction, the activation of O is demonstrated through transforming O into a reactive superoxide anion radical (O) on Co-N sites and, meanwhile, by reversible consumption and supplement of coordinated surface oxygen as a new type of reactive oxygen species (ROS) on N,O-coordinated single-atom Mn sites (Mn-NO). EXAFS analysis results show a longer average Mn-O bond distance at near 2.19 Å, which makes the breaking and formation of surface Mn-O bonds easier to cycle. Control experiments support that such Mn-O bonding conditions could facilitate H-elimination of C-H in HMF. The co-existence of two types of ROS effectively matches the oxidation of hydroxyl and aldehyde groups, and thus, the overall reaction is boosted in excellent yield of diester (95.8%) with an extremely high carbon balance. This study represents a rare example of taking advantage of the synergy of the diatomic catalyst for activating O by two types of activation pathways.
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http://dx.doi.org/10.1021/acsami.2c01858DOI Listing
April 2022

Constitutively Active STAT5b Feminizes Mouse Liver Gene Expression.

Endocrinology 2022 05;163(5)

Department of Biology and Bioinformatics Program, Boston University, Boston, MA 02215, USA.

STAT5 is an essential transcriptional regulator of the sex-biased actions of GH in the liver. Delivery of constitutively active STAT5 (STAT5CA) to male mouse liver using an engineered adeno-associated virus with high tropism for the liver is shown to induce widespread feminization of the liver, with extensive induction of female-biased genes and repression of male-biased genes, largely mimicking results obtained when male mice are given GH as a continuous infusion. Many of the STAT5CA-responding genes were associated with nearby (< 50 kb) sites of STAT5 binding to liver chromatin, supporting the proposed direct role of persistently active STAT5 in continuous GH-induced liver feminization. The feminizing effects of STAT5CA were dose-dependent; moreover, at higher levels, STAT5CA overexpression resulted in some histopathology, including hepatocyte hyperplasia, and increased karyomegaly and multinuclear hepatocytes. These findings establish that the persistent activation of STAT5 by GH that characterizes female liver is by itself sufficient to account for the sex-dependent expression of a majority of hepatic sex-biased genes. Moreover, histological changes seen when STAT5CA is overexpressed highlight the importance of carefully evaluating such effects before considering STAT5 derivatives for therapeutic use in treating liver disease.
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http://dx.doi.org/10.1210/endocr/bqac046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9070516PMC
May 2022

Checkpoint Inhibitor Immune-Related Adverse Events: A Multimodality Pictorial Review.

Acad Radiol 2022 Apr 2. Epub 2022 Apr 2.

Department of Radiology, Columbia University Irving Medical Center, 622 W 168(th) Street, New York, New York, 10032.

Cancer immunotherapies are drugs that modulate the body's own immune system as an anticancer strategy. Checkpoint inhibitor immunotherapies interfere with cell surface binding proteins that function to promote self-recognition and tolerance, ultimately leading to upregulation of the immune response. Given the striking success of these agents in early trials in melanoma and lung cancer, they have now been studied in many types of cancer and have become a pillar of anticancer therapy for many tumor types. However, abundant upregulation results in a new class of side effects, known as immune-related adverse events (IRAEs). It is critical for the practicing radiologist to be able to recognize these events to best contribute to care for patients on checkpoint inhibitor immunotherapy. Here, we provide a comprehensive system-based review of immune-related adverse events and associated imaging findings. Further, we detail the best imaging modalities for each as well as describe problem solving modalities. Given that IRAEs can be subclinical before becoming clinically apparent, radiologists may be the first provider to recognize them, providing an opportunity for early treatment. Awareness of IRAEs and how to best image them will prepare radiologists to make a meaningful contribution to patient care as part of the clinical team.
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http://dx.doi.org/10.1016/j.acra.2022.03.007DOI Listing
April 2022

GITR/GITRL reverse signalling modulates the proliferation of hepatic progenitor cells by recruiting ANXA2 to phosphorylate ERK1/2 and Akt.

Cell Death Dis 2022 Apr 4;13(4):297. Epub 2022 Apr 4.

Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.

Hepatic stem/progenitor cells are the major cell compartment for tissue repair when hepatocyte proliferation is compromised in chronic liver diseases, but the expansion of these cells increases the risk of carcinogenesis. Therefore, it is essential to explore the pathways restricting their expansion and abnormal transformation. The ligand of glucocorticoid-induced tumour necrosis factor receptor (GITRL) showed the most highly increased expression in hepatic progenitor cells treated with transforming growth factor (TGF)-β1. If overexpressed by hepatic progenitor cells, GITRL stimulated cell proliferation by activating the epithelial-mesenchymal transition pathway and enhancing ERK1/2 and Akt phosphorylation via GITRL binding to ANXA2. However, GITR, the specific GITRL receptor, suppressed the epithelial-mesenchymal transition pathway of GITRL-expressing cells and decreased their growth by dissociating ANXA2 from GITRL and reducing downstream ERK1/2 and Akt phosphorylation. This study identifies GITR/GITRL reverse signalling as a cross-interaction pathway between immune cells and hepatic stem/progenitor cells that restricts the expansion of hepatic stem/progenitor cells and reduces the possibility of carcinogenesis.
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http://dx.doi.org/10.1038/s41419-022-04759-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8979965PMC
April 2022

CYP3A1 metabolism-based neurotoxicity of strychnine in rat.

Toxicology 2022 Mar 29;471:153156. Epub 2022 Mar 29.

Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563000, China. Electronic address:

Strychnine is one of the main bioactive and toxic constituents of Semen Strychni. In the present study, the neurotoxic effects of strychnine, and the role of individual differences in metabolism on susceptibility to neurotoxicity of strychnine were investigated. The acute toxicity was observed by a single dose of strychnine (2.92 mg/kg, i.g.) in rats, the epileptic stages of rats were scored according to Racine's scale. The neurotoxicity of strychnine was evaluated by the levels of ROS, MDA, SOD and GSH in hippocampus, striatum, and cortex tissues measurements and histopathological analysis. The concentrations of strychnine in the plasma, hippocampus, striatum, and cortex tissues were determined using high performance liquid chromatography tandem mass spectrometry (LC-MS/MS). The expressions of the cytochrome P450, which is the most critical protein family involved in drugs metabolism, were detected by proteomics. The mechanism of susceptibility to neurotoxicity of strychnine was elucidated by correlation analysis among above indicators. The results indicated that striatum and cortex were the main toxic targets of strychnine, and the CYP3A1 might be a susceptible biomarker to neurotoxicity of strychnine. These results provide valuable insights into the neurotoxic susceptibility of strychnine that will aid in the rational clinical use of strychnine (possibly including Semen Strychni).
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http://dx.doi.org/10.1016/j.tox.2022.153156DOI Listing
March 2022
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