Professor Daqing Ma, MD, PhD

Li X, Ma X, Liu Y, Chang E, Cui J, Ma D, Zhang Jet al., 2022, Predictive value of Leukocyte ImmunoTest (LIT™) in cancer patients: a prospective cohort study., Front Oncol, Vol: 12, ISSN: 2234-943X

Early diagnosis of cancer is crucial to initiate prompt treatment for better patient outcomes. The host immune function and its associated modulators are considered to be potential biomarkers for early cancer diagnosis. Immune and immune-checkpoint biomarkers have been reported to contribute to cancer development, while a high neutrophil-to-lymphocyte ratio has been shown to be associated with poor survival outcomes in a variety of cancers. One hundred sixty-one cancer patients were recruited to take a cost-effective novel Leukocyte ImmuneTest (LIT). LIT was measured to objectively determine the pre-treatment immune status of patients. The correlation between LIT and other conventional diagnostic markers or tumor-related variables was then investigated. Significant correlations between LIT and white blood cell count, smoking status, and tumor stage 4 were found. In addition, the LIT score significantly differentiated between malignant and benign tumors in this study population. Our work raises the possibility to use LIT for general screening surveillance before further costly specialized equipment is applied for cancer diagnosis.

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Liao Z, Ou X, Zhou C, Ma D, Zhao H, Huang Het al., 2022, Xenon attenuated neonatal lipopolysaccharide exposure induced neuronal necroptosis and subsequently improved cognition in juvenile rats., Front Pharmacol, Vol: 13, ISSN: 1663-9812

Background: Neonatal sepsis is known to cause neurodevelopment impairment and has been reported to increase risks for neurological/psychiatric disorders. In this study, we investigated the effect of xenon, a well-known potent neuroprotective gas, on neonatal sepsis-induced neurodevelopment impairment in rats together with underlying mechanism by focusing on receptor-interacting protein kinase (RIP) mediated neuronal necroptosis. Methods: 3-day-old Sprague-Dawley rat pups were exposed to either 70% xenon or N2 balanced with O2 for 6 h, during which lipopolysaccharide (LPS) was injected intraperitoneally for 3 times (500 μg/kg for the 1st and 250 μg/kg for the second and third dose; n = 6-10/group). In another cohort of 3-day-old rat pups, intracerebroventricular injection of necrostatin-1 (4 µg in 4 µl saline, a RIP-1-targeted inhibitor of necroptosis) was performed 20 min after the third dose of LPS. The learning ability and memory were assessed 25 days after LPS injection. Then, their hippocampus was collected for neuronal necroptosis with RIP and MIKL assessments using western blot and in situ immunostaining. Systemic and neuro-inflammation was also assessed. Results: LPS insult resulted in elevation of pro-inflammatory cytokine TNF-𝝰 and IL-6, caused neuronal necroptosis and damaged synaptic integrity at the brain developing stage, which finally led to the long-term cognitive impairment. Xenon inhibited necroptosis associated mediator RIP-1, RIP-3, and MLKL activation, protected neurons and attenuated cognitive dysfunction induced by LPS. Like xenon, the similar pattern changes induced by a RIP-1 inhibitor Necrostatin-1 were also found. Conclusion: This study indicates that necroptosis is involved in neonatal sepsis-induced neurofunctional impairments and xenon may be a novel therapeutic strategy to prevent/treat cognitive impairment in neonatal septic patients.

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Chen Q, Qin Z, Sun Y, Liu X, Soo AP, Chang E, Sun Q, Yi B, Wang D-X, Zhao H, Ma D, Gu Jet al., 2022, Dexmedetomidine Activates Akt, STAT6 and IRF4 Modulating Cytoprotection and Macrophage Anti-Inflammatory Phenotype Against Acute Lung Injury in vivo and in vitro, JOURNAL OF INFLAMMATION RESEARCH, Vol: 15, Pages: 2707-2720

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• Citations: 1

Juan Z, Chen J, Ding B, Yongping L, Liu K, Wang L, Le Y, Liao Q, Shi J, Huang J, Wu Y, Ma D, Ouyang W, Tong Jet al., 2021, Probiotic supplement attenuates chemotherapy-related cognitive impairment in patients with breast cancer: a randomised, double-blind, and placebo-controlled trial., European Journal of Cancer, Vol: 161, Pages: 10-22, ISSN: 0959-8049

BACKGROUND: Chemotherapy-related cognitive impairment (CRCI) is highly prevalent in patients with cancer and is associated with poor outcomes and quality of life. To date, the management of CRCI remains a clinical challenge. Herein, we aim to determine the preventive effects of probiotics on CRCI development and underlying mechanisms. METHODS: We conducted a randomised, double-blind and placebo-controlled trial (ChiCTR-INQ-17014181) of 159 patients with breast cancer and further investigated the underlying mechanism in a pre-clinical setting. From 2018 to 2019, patients with breast cancer (Stage I-III) who needed adjuvant chemotherapy were screened, enrolled and randomly assigned to receive either probiotics or placebo (three capsules, twice/day) during chemotherapy. Their cognition, anxiety and depression were assessed with well-established assays; their plasma biomarkers, metabolites and faecal microbiota compositions were measured. In addition, the systemic effects of the metabolites found in the clinical trial on long-term potentiation, synapse injury, oxidative stress and glial activation were assessed in rats. RESULTS: Probiotics supplement significantly decreased the incidence of CRCI, improved the allover cognitive functions, changed the gut microbial composition and modulated nine plasma metabolite changes. Among these metabolites, p-Mentha-1,8-dien-7-ol, Linoelaidyl carnitine and 1-aminocyclopropane-1-carboxylic acid were negatively correlated with the occurrence of CRCI. Furthermore, probiotics supplement increased plasma p-Mentha-1,8-dien-7-ol in rats. Administration of exogenous p-Mentha-1,8-dien-7-ol significantly alleviated chemotherapy-induced long-term potentiation impairment, synapse injury, oxidative stress and glial activation in the hippocampus of rats. CONCLUSION: Our data indicated that probiotics supplement prevents the occurrence of CRCI in patients with breast cancer via modulating plasma metabolites, including p-Mentha-

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Gao W, Li W, Yan Y, Yang R, Zhang Y, Jin M, Luo Z, Xie L, Ma Y, Xu X, Wang G, Kong Z, Gao Y, Li Y, Ruan Z, Zheng J, Ma D, Wang Qet al., 2021, Transcutaneous electrical acupoint stimulation applied in lower limbs decreases the incidence of paralytic ileus after colorectal surgery: A multicenter randomized controlled trial, SURGERY, Vol: 170, Pages: 1618-1626, ISSN: 0039-6060

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• Citations: 18

Ma D, 2021, The role of the vagus nerve on Dexmedetomidine promoting survival and lung protection in a sepsis model in rats, European Journal of Pharmacology, ISSN: 0376-6357

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Hu C, Huang Y, Wu L, Zhao H, Pac Soo C, Lian Q, Ma Det al., 2021, Apoptosis and necroptosis occur in the different brain regions of hippocampus in a rat model of hypoxia asphyxia, INTERNATIONAL JOURNAL OF NEUROSCIENCE, Vol: 131, Pages: 843-853, ISSN: 0020-7454

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• Citations: 3

Chen L, Alam A, Pac-Soo A, Chen Q, Shang Y, Zhao H, Yao S, Ma Det al., 2021, Pretreatment with valproic acid alleviates pulmonary fibrosis through epithelial-mesenchymal transition inhibition in vitro and in vivo, LABORATORY INVESTIGATION, Vol: 101, Pages: 1166-1175, ISSN: 0023-6837

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• Citations: 9

Chen L, Alam A, Pac-Soo A, Chen Q, Shang Y, Zhao H, Yao S, Ma Det al., 2021, Pretreatment with valproic acid alleviates pulmonary fibrosis through epithelial-mesenchymal transition inhibition in vitro and in vivo., Lab Invest, Vol: 101, Pages: 1166-1175

Epithelial-mesenchymal transition (EMT) plays a crucial role in the development of pulmonary fibrosis. This study aims to investigate the effects of valproic acid (VPA) on EMT in vitro and in vivo. In vitro, EMT was induced by the administration of transforming growth factor-β1 (TGF-β1) in a human alveolar epithelial cell line (A549). The dose effects of VPA (0.1-3 mM) on EMT were subsequently evaluated at different timepoints. VPA (1 mM) was applied prior to the administration of TGF-β1 and the expression of E-cadherin, vimentin, p-Smad2/3 and p-Akt was assessed. In addition, the effects of a TGF-β type I receptor inhibitor (A8301) and PI3K-Akt inhibitor (LY294002) on EMT were evaluated. In vivo, the effects of VPA on bleomycin-induced lung fibrosis were evaluated by assessing variables such as survival rate, body weight and histopathological changes, whilst the expression of E-cadherin and vimentin in lung tissue was also evaluated. A8301 and LY294002 were used to ascertain the cellular signaling pathways involved in this model. The administration of VPA prior to TGF-β1 in A549 cells prevented EMT in both a time- and concentration-dependent manner. Pretreatment with VPA downregulated the expression of both p-Smad2/3 and p-Akt. A8301 administration increased the expression of E-cadherin and reduced the expression of vimentin. LY294002 inhibited Akt phosphorylation induced by TGF-β1 but failed to prevent EMT. Pretreatment with VPA both increased the survival rate and prevented the loss of body weight in mice with pulmonary fibrosis. Interestingly, both VPA and A8301 prevented EMT and facilitated an improvement in lung structure. Overall, pretreatment with VPA attenuated the development of pulmonary fibrosis by inhibiting EMT in mice, which was associated with Smad2/3 deactivation but without Akt cellular signal involvement. This study investigated the effect of valproic acid (VPA) on epithelial-mesenchymal transition (EMT). In vitro, VP

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Liu Y, Yang H, Fu Y, Pan Z, Qiu F, Xu Y, Yang X, Chen Q, Ma D, Liu Zet al., 2021, TRPV1 Antagonist Prevents Neonatal Sevoflurane-Induced Synaptic Abnormality and Cognitive Impairment in Mice Through Regulating the Src/Cofilin Signaling Pathway, FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, Vol: 9, ISSN: 2296-634X

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• Citations: 3

Hu C, Iwasaki M, Liu Z, Wang B, Li X, Lin H, Li J, Li JV, Lian Q, Ma Det al., 2021, Lung but not brain cancer cell malignancy inhibited by commonly used anesthetic propofol during surgery: Implication of reducing cancer recurrence risk, Journal of Advanced Research, Vol: 31, Pages: 1-12, ISSN: 2090-1232

IntroductionIntravenous anesthesia with propofol was reported to improve cancer surgical outcomes when compared with inhalational anesthesia. However, the underlying molecular mechanisms largely remain unknown.ObjectivesThe anti-tumor effects of propofol and the possible underlying mechanism including altered metabolic and signaling pathways were studied in the current study.MethodsThe cell viability, proliferation, migration, and invasion of cancer cells were analyzed with CCK-8, Ki-67 staining, wound healing, and Transwell assay, respectively. The protein changes were analyzed with Western blot and immunofluorescent staining. The metabolomics alteration was studied with 1H-NMR spectroscopy. The gene expression regulations were analyzed with PCR gene array and qRT-PCR experiments.ResultsIn this study, we found that propofol reduced cell viability and inhibited cell proliferation, migration and invasion of lung cancer cells, but not neuroglioma cells. In lung cancer cells, propofol downregulated glucose transporter 1 (GLUT1), mitochondrial pyruvate carrier 1 (MPC1), p-Akt, p-Erk1/2, and hypoxia- inducible factor 1 alpha (HIF-1 α ) expressions and upregulated pigment epithelium-derived factor (PEDF) expression. Propofol increased intracellular glutamate and glycine but decreased acetate and formate whilst increased glucose, lactate, glutamine, succinate, pyruvate, arginine, valine, isoleucine, and leucine and glycerol, and decreased acetate, ethanol, isopropanol in the culture media of lung cancer cells. Furthermore, VEGFA, CTBP1, CST7, CTSK, CXCL12, and CXCR4 gene expressions were downregulated, while NR4A3, RB1, NME1, MTSS1, NME4, SYK, APC, and FAT1 were upregulated following the propofol treatment. Consistent with the phenotypical changes, these molecular and metabolic changes were not found in the neuroglioma cells.ConclusionOur findings indicated anti-tumor effects of propofol on the lung cancer but not brain cancer, through the regulation of tumor metasta

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Iwasaki M, Ma D, 2021, General Anesthesia Type and Cancer Prognosis: Comment, ANESTHESIOLOGY, Vol: 135, Pages: 191-191, ISSN: 0003-3022

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Alam A, Rampes S, Patel S, Hana Z, Ma Det al., 2021, Anesthetics or anesthetic techniques and cancer surgical outcomes: a possible link, KOREAN JOURNAL OF ANESTHESIOLOGY, Vol: 74, Pages: 191-203, ISSN: 2005-6419

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• Citations: 7

Li Y, Wu B, Hu C, Hu J, Lian Q, Li J, Ma Det al., 2021, The Role of Vagus Nerve on Dexmedetomidine Induced Survival and Lung Protection in a Sepsis Model in Rats.

<jats:title>Abstract</jats:title> <jats:p>BackgroundSepsis often results in acute lung injury (ALI). Sedative dexmedetomidine (Dex) was reported to protect cells and organs due to its direct cellular effects. This study aims to investigate the role of vagus nerves on Dex induced lung protection in a model of lipopolysaccharide (LPS)-induced ALI in rats. MethodsThe bilateral cervical vagus nerve of male Sprague-Dawley rats was sectioned or just exposed without section as sham surgery. The ALI was induced by intraperitoneal injection of LPS (1 or 10 mg/kg). After LPS administration, Dex antagonist yohimbine (YOH) (1 mg/kg) and/or Dex (25 μg/kg) was injected intraperitoneally at 0, 4, 8 and 12 hours to rats with or without vagotomy. The severity of ALI was determined with survival curve analysis and lung pathological scores of haematoxylin and eosin (H-E) staining sections. The plasma concentrations of interleukin 1beta (IL-1β), tumour necrosis factor-alpha (TNF-α), catecholamine (CA) and acetylcholine (Ach) were measured with enzyme-linked immunosorbent assay (ELISA). ResultsThe median survival time of LPS-induced ALI rats was significantly prolonged by Dex (22 hours, 50% CI, [31.25, 90.63]) compared that in the LPS group (14 hours, 50% CI, [18.75, 81.25], P &lt; 0.05), and the acute lung injury score was significantly reduced by Dex (6.5, 50% CI, [5.75, 7.5] vs 11.5, 50% CI, [10.75, 12.50] in the LPS group, P &lt; 0.01). However, these protective effects of Dex were significantly reduced by either YOH administration or vagotomy. Dex significantly decreased LPS-induced plasma IL-1β (pg/ml) (20.75 ± 0.78 vs. 30.22 ± 2.62, P &lt; 0.01), TNF-α (pg/ml) (205.30 ± 9.39 vs. 273.40 ± 14.50, P &lt; 0.01), and CA (pg/ml) (825.70 ± 43.46 vs. 1188.00 ± 64.40, P &lt; 0.01) but increased the secretion of Ach (pg/ml) (507.20 ± 49.52 vs. 296.50 ± 62.44, P &

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Ishikawa M, Iwasaki M, Zhao H, Saito J, Hu C, Sun Q, Sakamoto A, Ma Det al., 2021, Inhalational Anesthetics Inhibit Neuroglioma Cell Proliferation and Migration via miR-138,-210 and-335, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 22

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• Citations: 7

Gao X, Xiong Y, Huang J, Zhang N, Li J, Zheng S, Lu K, Ma D, Yang B, Ning Jet al., 2021, The Effect of Mechanical Ventilation With Low Tidal Volume on Blood Loss During Laparoscopic Liver Resection: A Randomized Controlled Trial, ANESTHESIA AND ANALGESIA, Vol: 132, Pages: 1033-1041, ISSN: 0003-2999

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• Citations: 7

Wen J-L, Sun Q-Z, Cheng Z, Liao X-Z, Wang L-Q, Yuan Y, Li J-W, Hou L-S, Gao W-J, Wang W-J, Soh W-Y, Li B-F, Ma D-Qet al., 2021, Extracorporeal membrane oxygenation for coronavirus disease 2019-associated acute respiratory distress syndrome: Report of two cases and review of the literature, WORLD JOURNAL OF CLINICAL CASES, Vol: 9, Pages: 1953-1967, ISSN: 2307-8960

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Ishikawa M, Iwasaki M, Sakamoto A, Ma Det al., 2021, Anesthetics may modulate cancer surgical outcome: a possible role of miRNAs regulation., BMC Anesthesiol, Vol: 21

BACKGROUND: microRNAs (miRNAs) are single-stranded and noncoding RNA molecules that control post-transcriptional gene regulation. miRNAs can be tumor suppressors or oncogenes through various mechanism including cancer cell biology, cell-to-cell communication, and anti-cancer immunity. MAIN BODY: Anesthetics can affect cell biology through miRNA-mediated regulation of messenger RNA (mRNA). Indeed, sevoflurane was reported to upregulate miR-203 and suppresses breast cancer cell proliferation. Propofol reduces matrix metalloproteinase expression through its impact on miRNAs, leading to anti-cancer microenvironmental changes. Propofol also modifies miRNA expression profile in circulating extracellular vesicles with their subsequent anti-cancer effects via modulating cell-to-cell communication. CONCLUSION: Inhalational and intravenous anesthetics can alter cancer cell biology through various cellular signaling pathways induced by miRNAs' modification. However, this area of research is insufficient and further study is needed to figure out optimal anesthesia regimens for cancer patients.

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Deng C-M, Ding T, Li S, Lei B, Xu M-J, Wang L, Xu S-C, Yang H-X, Sun X-Y, Li X-Y, Ma D, Wang D-Xet al., 2021, Neuraxial labor analgesia is associated with a reduced risk of postpartum depression: A multicenter prospective cohort study with propensity score matching, JOURNAL OF AFFECTIVE DISORDERS, Vol: 281, Pages: 342-350, ISSN: 0165-0327

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• Citations: 9

Iwasaki M, Saito J, Zhao H, Sakamoto A, Hirota K, Ma Det al., 2021, Inflammation Triggered by SARS-CoV-2 and ACE2 Augment Drives Multiple Organ Failure of Severe COVID-19: Molecular Mechanisms and Implications, INFLAMMATION, Vol: 44, Pages: 13-34, ISSN: 0360-3997

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• Citations: 120

Ishikawa M, Iwasaki M, Zhao H, Saito J, Hu C, Sun Q, Sakamoto A, Ma Det al., 2021, Sevoflurane and Desflurane Exposure Enhanced Cell Proliferation and Migration in Ovarian Cancer Cells via miR-210 and miR-138 Downregulation, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 22, ISSN: 1661-6596

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• Citations: 9

Liu C, Yu M, Li Y, Wang H, Xu C, Zhang X, Li M, Guo H, Ma D, Guo Xet al., 2021, Lidocaine inhibits the metastatic potential of ovarian cancer by blocking Na_V1.5-mediated EMT and FAK/Paxillin signaling pathway, CANCER MEDICINE, Vol: 10, Pages: 337-349, ISSN: 2045-7634

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• Citations: 22

Zhao H, Davies R, Ma D, 2021, Potential therapeutic value of dexmedetomidine in COVID-19 patients admitted to ICU., Br J Anaesth, Vol: 126, Pages: e33-e35

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Chang E, Wu L, Ruan X, Lu J, Lin B, Soo CP, Li T, Zhang J, Ma Det al., 2020, Laryngeal mask position evaluated by ultrasonography and fiberoptic bronchoscopy along with 3D-CTR constructive images: A prospective observational study, JOURNAL OF CLINICAL ANESTHESIA, Vol: 67, ISSN: 0952-8180

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• Citations: 1

Zhao T, Chen Y, Sun Z, Shi Z, Qin J, Lu J, Li C, Ma D, Zhou L, Song Xet al., 2020, Prenatal sevoflurane exposure causes neuronal excitatory/inhibitory imbalance in the prefrontal cortex and neurofunctional abnormality in rats, NEUROBIOLOGY OF DISEASE, Vol: 146, ISSN: 0969-9961

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• Citations: 17

Zhen C, Zhao H, Wu L, Alam A, Eguchi S, Weng H, Ma Det al., 2020, The Role of Neutrophil NETosis in Organ Injury: Novel Inflammatory Cell Death Mechanisms, INFLAMMATION, Vol: 43, Pages: 2021-2032, ISSN: 0360-3997

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• Citations: 41

Chen R, Yu Y-L, Li W, Liu Y, Lu J-X, Chen F, Zhou Q, Xia Z-Y, Gao L, Meng Q-T, Ma Det al., 2020, Gastrointestinal Symptoms Associated With Unfavorable Prognosis of COVID-19 Patients: A Retrospective Study, FRONTIERS IN MEDICINE, Vol: 7

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• Citations: 30

Wang D, Huang Y, Wang X, Chen X, Li J, Zhang S, Wu J, Liu D, Ma D, Mei Wet al., 2020, Circadian differences in emergence from volatile anaesthesia in mice: involvement of the locus coeruleus noradrenergic system, BRITISH JOURNAL OF ANAESTHESIA, Vol: 125, Pages: 548-559, ISSN: 0007-0912

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• Citations: 6

Jin Z, Hu J, Ma D, 2020, Postoperative delirium: perioperative assessment, risk reduction, and management, BRITISH JOURNAL OF ANAESTHESIA, Vol: 125, Pages: 492-504, ISSN: 0007-0912

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• Citations: 170

Jin Z, Suen KC, Wang Z, Ma Det al., 2020, Review 2: Primary graft dysfunction after lung transplant-pathophysiology, clinical considerations and therapeutic targets, JOURNAL OF ANESTHESIA, Vol: 34, Pages: 729-740, ISSN: 0913-8668

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• Citations: 10