Publications by authors named "Minghua Yang"

78 Publications

Pulse therapy with vincristine and dexamethasone for childhood acute lymphoblastic leukaemia (CCCG-ALL-2015): an open-label, multicentre, randomised, phase 3, non-inferiority trial.

Lancet Oncol 2021 09 27;22(9):1322-1332. Epub 2021 Jul 27.

Department of Hematology/Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai, China.

Background: Vincristine plus dexamethasone pulses are generally used throughout maintenance treatment for childhood acute lymphoblastic leukaemia. However, previous studies remain inconclusive about the benefit of this maintenance therapy and the absence of randomised, controlled trials in patients with low-risk or high-risk acute lymphoblastic leukaemia provides uncertainty. We therefore aimed to determine if this therapy could be safely omitted beyond 1 year of treatment without leading to an inferior outcome in any risk subgroup of childhood acute lymphoblastic leukaemia.

Methods: This open-label, multicentre, randomised, phase 3, non-inferiority trial involved 20 major medical centres across China. We enrolled patients who were aged 0-18 years with newly diagnosed acute lymphoblastic leukaemia that was subsequently in continuous remission for 1 year after initial treatment. Patients with secondary malignancy or primary immunodeficiency were excluded. Eligible patients were classified as having low-risk, intermediate-risk, or high-risk acute lymphoblastic leukaemia based on minimal residual disease and immunophenotypic and genetic features of leukaemic cells. Randomisation and analyses were done separately for the low-risk and intermediate-to-high-risk cohorts. Randomisation was generated by the study biostatistician with a block size of six. Stratification factors included participating centre, sex, and age at diagnosis; the low-risk cohort was additionally stratified for ETV6-RUNX1 status, and the intermediate-to-high-risk cohort for cell lineage. Patients in each risk cohort were randomly assigned (1:1) to either receive (ie, the control group) or not receive (ie, the experimental group) seven pulses of intravenous vincristine (1·5 mg/m) plus oral dexamethasone (6 mg/m per day for 7 days) during the second year of treatment. The primary endpoint was difference in 5-year event-free survival between the experimental group and the control group for both the low-risk and intermediate-to-high-risk cohorts, with a non-inferiority margin of 0·05 (5%). The analysis was by intention to treat. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-IPR-14005706.

Findings: Between Jan 1, 2015, and Feb 20, 2020, 6141 paediatric patients with newly diagnosed acute lymphoblastic leukaemia were registered to this study. Approximately 1 year after diagnosis and treatment, 5054 patients in continuous remission were randomly assigned, including 2923 (1442 in the control group and 1481 in the experimental group) with low-risk acute lymphoblastic leukaemia and 2131 (1071 control, 1060 experimental) with intermediate-to-high risk acute lymphoblastic leukaemia. Median follow-up for patients who were alive at the time of analysis was 3·7 years (IQR 2·8-4·7). Among patients with low-risk acute lymphoblastic leukaemia, no difference was observed in 5-year event-free survival between the control group and the experimental group (90·3% [95% CI 88·4-92·2] vs 90·2% [88·2-92·2]; p=0·90). The one-sided 95% upper confidence bound for the difference in 5-year event-free survival probability was 0·024, establishing non-inferiority. Among patients with intermediate-to-high-risk acute lymphoblastic leukaemia, no difference was observed in 5-year event-free survival between the control group and the experimental group (82·8% [95% CI 80·0-85·7] vs 80·8% [77·7-84·0]; p=0·90), but the one-sided 95% upper confidence bound for the difference in 5-year event-free survival probability was 0·055, giving a borderline inferior result for those in the experimental group. In the low-risk cohort, we found no differences in the rates of infections, symptomatic osteonecrosis, or other complications during the second year of maintenance treatment between patients in the control and experimental groups. Patients with intermediate-to-high-risk acute lymphoblastic leukaemia in the control group were more likely to develop grade 3-4 pneumonia (26 [2·4%] of 1071 vs ten [0·9%] of 1060) and vincristine-related peripheral neuropathy (17 [1·6%] vs six [0·6%]) compared with the experimental group. Incidence of grade 5 fatal infection was similar between the control group and the experimental group in both the low-risk cohort (two [0·1%] of 1442 vs five [0·3%] of 1481) and intermediate-to-high risk cohort (six [0·6%] of 1071 vs five [0·5%] of 1060).

Interpretation: Vincristine plus dexamethasone pulses might be omitted beyond 1 year of treatment for children with low-risk acute lymphoblastic leukaemia. Additional studies are needed for intermediate-to-high-risk acute lymphoblastic leukaemia.

Funding: VIVA China Children's Cancer Foundation, the National Natural Science Foundation of China, the China fourth round of Three-Year Public Health Action Plan (2015-2017), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, US National Cancer Institute, St Baldrick's Foundation, and the American Lebanese Syrian Associated Charities.

Translation: For the Chinese translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S1470-2045(21)00328-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416799PMC
September 2021

Targeting NF-κB-dependent alkaliptosis for the treatment of venetoclax-resistant acute myeloid leukemia cells.

Biochem Biophys Res Commun 2021 07 24;562:55-61. Epub 2021 May 24.

Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA. Electronic address:

Venetoclax is a highly selective BCL2 inhibitor widely used in the treatment of leukemia, especially chronic lymphocytic leukemia and acute myeloid leukemia (AML). However, long-term use of venetoclax may lead to secondary drug resistance, which constitutes an important obstacle to prolonging the duration of the therapeutic response. Here, we show that the acquired resistance to venetoclax in human AML cell lines depends on NF-κB activation rather than on the upregulation of anti-apoptotic BCL2L1 expression. Moreover, alkaliptosis induced by the small molecular compound JTC801, but not necroptosis and ferroptosis, inhibits the growth of venetoclax-resistant AML cells in vitro and in xenograft mouse models. Mechanistically, NF-κB-mediated CA9 downregulation is required for intracellular pH upregulation, thereby inducing alkaliptosis in venetoclax-resistant cells. These findings provide a new strategy to selectively remove venetoclax-resistant AML cells.
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http://dx.doi.org/10.1016/j.bbrc.2021.05.049DOI Listing
July 2021

Lipid Metabolism in Ferroptosis.

Adv Biol (Weinh) 2021 08 20;5(8):e2100396. Epub 2021 May 20.

Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA.

Lipid metabolism is a complex biochemical process that participates in the regulation of cell survival and death. Ferroptosis is a form of iron-dependent regulated cell death driven by abnormal lipid metabolism, leading to lipid peroxidation and subsequent plasma membrane rupture. A variety of antioxidant systems and membrane repair pathways can diminish oxidative damage, enabling survival and growth in response to ferroptotic signals. Such impairment of ferroptosis machinery is implicated in various pathological conditions and diseases, especially cancer and tissue damage. It is discussed here how lipid metabolism pathways, including lipid synthesis, degradation, storage, transformation, and utilization, modulate ferroptosis sensitivity or tolerance in different models, especially cancer.
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http://dx.doi.org/10.1002/adbi.202100396DOI Listing
August 2021

Clinical characteristics of tumor lysis syndrome in childhood acute lymphoblastic leukemia.

Sci Rep 2021 05 6;11(1):9656. Epub 2021 May 6.

Department of Hematology and Oncology, Children's Hospital of Nanjing Medical University, Nanjing, China.

Tumor lysis syndrome (TLS) is a common and fatal complication of childhood hematologic malignancies, especially acute lymphoblastic leukemia (ALL). The clinical features, therapeutic regimens, and outcomes of TLS have not been comprehensively analyzed in Chinese children with ALL. A total of 5537 children with ALL were recruited from the Chinese Children's Cancer Group, including 79 diagnosed with TLS. The clinical characteristics, treatment regimens, and survival of TLS patients were analyzed. Age distribution of children with TLS was remarkably different from those without TLS. White blood cells (WBC) count ≥ 50 × 10/L was associated with a higher risk of TLS [odds ratio (OR) = 2.6, 95% CI = 1.6-4.5]. The incidence of T-ALL in TLS children was significantly higher than that in non-TLS controls (OR = 4.7, 95% CI = 2.6-8.8). Hyperphosphatemia and hypocalcemia were more common in TLS children with hyperleukocytosis (OR = 2.6, 95% CI = 1.0-6.9 and OR = 5.4, 95% CI = 2.0-14.2, respectively). Significant differences in levels of potassium (P = 0.004), calcium (P < 0.001), phosphorus (P < 0.001) and uric acid (P < 0.001) were observed between groups of TLS patients with and without increased creatinine. Laboratory analysis showed that older age was associated with a higher level of creatinine. Calcium level was notably lower in males. WBC count, lactate dehydrogenase, and creatinine levels were significantly higher in T-ALL subgroup, whereas procalcitonin level was higher in B-ALL children. Older age, infant, a higher level of WBC and T-ALL were risk factors TLS occurrence. Hyperleukocytosis has an impact on the severity of TLS, while renal injury may be an important feature in the process of TLS.
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http://dx.doi.org/10.1038/s41598-021-88912-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102476PMC
May 2021

cDNA cloning, expression and bioinformatical analysis of Tssk genes in tree shrews.

Comput Biol Chem 2021 Jun 10;92:107474. Epub 2021 Mar 10.

Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming, 650201, China. Electronic address:

Tree shrews are more closely related to primate animals than rodents in many aspects. In addition, they also possess several advantageous characteristics including small body size, high brain-to-body mass ratio, low cost of feeding and maintenance, short reproductive cycle and life span, which make them promising novel laboratory animals to replace more precious larger primate animals. Testis-specific serine/threonine kinase (Tssk) plays important roles in spermatogenesis and/or the regulation of sperm function. However, studies on Tssk in tree shrews have not been reported yet. In the present study, the full-length sequences of five members of the Tssk family in tree shrews were cloned and their CDS region sequences were analyzed by basic bioinformatics. The phylogenetic tree and prokaryotic protein expression system of Tssk gene of tree shrews were constructed. The mRNA expressions of Tssk genes in 11 tissues/organs from tree shrews were studied. The results showed that: 1. the length of the CDS region of tree shrew Tssk gene for Tssk1B, Tssk2, Tssk3 (variant X1 / X2), Tssk4 (variant X1 / X2) and Tssk6 is 1080bp, 1077bp, 867 / 807bp, 1014 / 984bp, 822bp, respectively, encoding 359, 358, 288/268, 337/327 and 273 amino acids, respectively; the cloned sequences of Tssk genes have been submitted to GenBank with the following accession numbers: KX091161(Tssk1B), KX091162(Tssk2), KX091163(Tssk3 variant X1)/KX091164(Tssk3 variant X2), KX091165(Tssk4variant X1)/KX091166(Tssk4variant X2), KX091160(Tssk6). 2. All tree shrew Tssk proteins distribute in cytoplasm, indicating that they are hydrophilic and non-secretory proteins, with multiple phosphorylation sites of serine and/or threonine. In addition, they are all mixed proteins with similar tertiary structures sharing a highly conserved functional domain of S_TKc (Serine/Threonine protein kinases, catalytic domain). 3.The molecular phylogenetic tree of five Tssk genes in tree shrews indicates that they are neither rodent nor primate animal, but are closely related to primate animals. 4. Five members of the Tssk recombinant proteins in tree shrews were successfully obtained using the constructed prokaryotic protein expression system. 5. Five Tssk genes are specifically expressed in the testis and/or sperm of tree shrews. Additionally, small amount of Tssk1B was expressed in several tissues other than testis and sperm. Limited mRNA levels of Tssk2 and Tssk4 were expressed in the brain, while mRNA of Tssk3 or Tssk6 could only be detected in the testis and sperm. This study will provide fundamental data on reproductive biology of tree shrews, which paves a way for further studying Tssk's biological function in this novel model animal.
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http://dx.doi.org/10.1016/j.compbiolchem.2021.107474DOI Listing
June 2021

Biological mechanisms of growth performance and meat quality in porcine muscle tissue.

Anim Biotechnol 2021 Mar 11:1-9. Epub 2021 Mar 11.

Yunnan Key Laboratory of Animal Nutrition and Feed Science, Yunnan Agricultural University, Kunming, China.

Growth performance and meat quality are important traits for pig production. The aim of the present study was to investigate the molecular mechanisms underlying growth performance and meat quality, and to identify novel target molecules for predicting the growth performance and meat quality. The differentially expressed genes (DEGs) in Diannan small ears pigs (DSP) and Landrace pigs (LP) were assessed by RNA-sequencing analyzing technology. A total of 339 DEGs were obtained between DSP and LP. 146 DEGs were upregulated in LP compared with DSP and 193 DEGs were upregulated in DSP compared with LP. The DEGs were significantly enriched in 26 GO and 3 KEGG pathways. The protein-protein interaction (PPI) network with 201 nodes and 382 edges was constructed and 5 modules were extracted from the entire network. The identified upregulated expression of genes involved in glycolysis and myogenesis as well as extracellular matrix may be associated with fast body and muscle deposition rates in LP. Increased expression of genes involved in PPAR signaling pathway and fatty acid metabolism as well as oxidative phosphate processes could be related to the intramuscular fat deposition and meat quality in DSP. The present study may provide an improved understanding of the growth performance and meat quality.
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http://dx.doi.org/10.1080/10495398.2021.1886939DOI Listing
March 2021

Prognostic factors for CNS control in children with acute lymphoblastic leukemia treated without cranial irradiation.

Blood 2021 Jul;138(4):331-343

Departments of Oncology, Global Pediatric Medicine, Biostatistics and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN.

To identify the prognostic factors that are useful to improve central nervous system (CNS) control in children with acute lymphoblastic leukemia (ALL), we analyzed the outcome of 7640 consecutive patients treated on Chinese Children's Cancer Group ALL-2015 protocol between 2015 and 2019. This protocol featured prephase dexamethasone treatment before conventional remission induction and subsequent risk-directed therapy, including 16 to 22 triple intrathecal treatments, without prophylactic cranial irradiation. The 5-year event-free survival was 80.3% (95% confidence interval [CI], 78.9-81.7), and overall survival 91.1% (95% CI, 90.1-92.1). The cumulative risk of isolated CNS relapse was 1.9% (95% CI, 1.5-2.3), and any CNS relapse 2.7% (95% CI, 2.2-3.2). The isolated CNS relapse rate was significantly lower in patients with B-cell ALL (B-ALL) than in those with T-cell ALL (T-ALL) (1.6%; 95% CI, 1.2-2.0 vs 4.6%; 95% CI, 2.9-6.3; P < .001). Independent risk factors for isolated CNS relapse included male sex (hazard ratio [HR], 1.8; 95% CI, 1.1-3.0; P = .03), the presence of BCR-ABL1 fusion (HR, 3.8; 95% CI, 2.0-7.3; P < .001) in B-ALL, and presenting leukocyte count ≥50×109/L (HR, 4.3; 95% CI, 1.5-12.2; P = .007) in T-ALL. Significantly lower isolated CNS relapse was associated with the use of total intravenous anesthesia during intrathecal therapy (HR, 0.2; 95% CI, 0.04-0.7; P = .02) and flow cytometry examination of diagnostic cerebrospinal fluid (CSF) (HR, 0.2; 95% CI, 0.06-0.6; P = .006) among patients with B-ALL. Prephase dexamethasone treatment, delayed intrathecal therapy, use of total intravenous anesthesia during intrathecal therapy, and flow cytometry examination of diagnostic CSF may improve CNS control in childhood ALL. This trial was registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-14005706).
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http://dx.doi.org/10.1182/blood.2020010438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323972PMC
July 2021

Cerium oxide nanoparticle-loaded polyvinyl alcohol nanogels delivery for wound healing care systems on surgery.

Drug Deliv 2021 Dec;28(1):390-399

Emergency Department, Dongying People's Hospital, Dongying, China.

This study was designed to establish the composition of wound bandages based on Cerium nanoparticle (CeNP)-loaded polyvinyl alcohol (PVA) nanogels. The CeNP nanogel (Ce-nGel) was fabricated by the fructose-mediated reduction of Cerium oxide solutions within the PVA matrix. The influences of different experimental limitations on PVA nanogel formations were examined. The nanogel particle sizes were evaluated by transmission electron microscopy and determined to range from ∼10 to 50 nm. Additionally, glycerol was added to the Ce-nGels, and the resulting compositions (Ce-nGel-Glu) were coated on cotton fabrics to generate the wound bandaging composite. The cumulative drug release profile of the Cerium from the bandage was found to be ∼38% of the total loading after two days. Additionally, antibacterial efficacy was developed for Gam positive and negative microorganisms. Moreover, we examined healing of skin wounds formed in mouse models over 24 days. In contrast to the untreated wounds, rapid healing was perceived in the Ce-nGel-Glu-treated wound with less damage. These findings indicate that Ce-nGel-Glu-based bandaging materials could be a potential candidate for wound healing applications in the future.
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http://dx.doi.org/10.1080/10717544.2020.1858998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894430PMC
December 2021

Characteristics of the Jejunal Microbiota in 35-Day-Old Saba and Landrace Piglets.

Pol J Microbiol 2020 Sep 8;69(3):367-378. Epub 2020 Sep 8.

Yunnan Provincial Key Laboratory of Animal Nutrition and Feed Science, Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming, China.

The balanced microbiological system is a significant hallmark of piglet health. One of the crucial factors affecting intestinal microbiota is the host's genetics. This study explored the difference in the diversity of jejunal microbiota between Saba (SB) and Landrace (LA) piglets. Nine Saba and nine Landrace piglets were fed with sow's milk until day 35. Jejunal contents were harvested for 16S rRNA sequencing. The birth weight, body weight, and average daily gain of Saba piglets were lower than those of Landrace piglets ( < 0.01). Firmicutes were the main phylum in Saba and Landrace piglets, and the Saba piglets had a higher ( < 0.05) abundance of Bacteroidetes compared with Landrace piglets. The two most abundant genera were and in the jejunum of Landrace and Saba piglets. Compared with Landrace piglets, the Saba piglets had significantly lower ( < 0.05) abundance of , and . The functional prediction showed that "d-glutamine and d-glutamate metabolism" and "one carbon pool by folate" pathways were enriched in Saba piglets, while "limonene and pinene degradation", "tryptophan metabolism", and "sulfur relay system" pathways were enriched in Landrace piglets. In summary, the growth performance was higher for Landrace piglets compared with Saba piglets due to their genetic characteristics. The rich diversity and fewer infection-associated taxa were observed in Saba piglets, partially accounting for their higher adaptability to environmental perturbations than Landrace piglets. Furthermore, different pig breeds may regulate their health through different metabolic pathways.
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http://dx.doi.org/10.33073/pjm-2020-041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810115PMC
September 2020

MgO Nanoparticles Protect against Titanium Particle-Induced Osteolysis in a Mouse Model Because of Their Positive Immunomodulatory Effect.

ACS Biomater Sci Eng 2020 05 17;6(5):3005-3014. Epub 2020 Apr 17.

School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore 639798, Singapore.

Aseptic prosthetic loosening (APL) often leads to the failure of prostheses. It is inseparable from wear-particle-induced macrophage-mediated inflammatory responses and osteolysis. Mg is a metal ion with excellent anti-inflammatory properties. Herein, Mg was introduced into a nanomedicine (MgO nanoparticles (MNPs)) to protect against APL. MNPs could be phagocytized by macrophages and gradually degraded intracellularly. Following MNPs treatment, lipopolysaccharide (LPS)-activated macrophages polarized into deeper M1 phenotype at 6 h but then switched to the M2 phenotype at 48 h. Furthermore, the MNPs suppressed the titanium (Ti) particle-induced osteoclastogenesis and osteolysis in vivo. However, the MNPs exhibited no impact on the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis and even inhibited osteogenesis in vitro. The contrary results between the in vitro and in vivo experiments imply that macrophages are the key factor in the inhibited osteoclastogenesis in vivo because the pathogenic process of APL is mainly attributed to macrophages, osteoblasts, and osteoclasts. Accordingly, an indirect coculture system was designed that considers the immunomodulatory effect of macrophages. RANKL-induced osteoclastogenesis was significantly inhibited under the influence of MNPs in the indirect coculture system. Taken together, the MNPs inhibited the inflammatory responses of macrophages provoked by the Ti particles and thus regulated the expressions of RANKL and OPG in osteoblasts to suppress osteoclastogenesis. The target cell of MNPs was macrophages but not osteoclasts, indicating the importance of the immunomodulatory effect of macrophages. These results collectively demonstrated that MNPs can prevent APL and other osteolysis-related diseases.
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http://dx.doi.org/10.1021/acsbiomaterials.9b01852DOI Listing
May 2020

The role of circular RNAs in hematological malignancies.

Genomics 2020 11 4;112(6):4000-4008. Epub 2020 Jul 4.

Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China. Electronic address:

Circular RNAs (circRNAs) are a class of noncoding RNAs (ncRNAs) that lack a 5' end cap or a 3' end poly-(A) tail and form a circular structure through covalent bonds. Compared to linear RNAs, circRNAs are more conservative and stable, and their distribution is spatiotemporally regulated. circRNAs, as a new type of competitive endogenous RNA (ceRNA), are involved in many disease processes and are also related to the occurrence and development of tumors. Over the past three years, the role of circRNAs in hematological malignancies has received increasing attention. Related research has shown that circRNAs may regulate the occurrence and development of hematological malignancies and contribute to drug resistance through a variety of molecular mechanisms. Therefore, to lay the foundation and point out directions for further research on circRNAs, this article systematically reviews the research progress on circRNAs in leukemia, lymphoma, and myeloma.
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http://dx.doi.org/10.1016/j.ygeno.2020.06.051DOI Listing
November 2020

Serum ferritin as an independent risk factor for severity in COVID-19 patients.

J Infect 2020 10 24;81(4):647-679. Epub 2020 Jun 24.

Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China. Electronic address:

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http://dx.doi.org/10.1016/j.jinf.2020.06.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313486PMC
October 2020

Strategic plan for management of COVID-19 in paediatric haematology and oncology departments.

Lancet Haematol 2020 05 1;7(5):e359-e362. Epub 2020 Apr 1.

Department of Paediatric Haematology and Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Electronic address:

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http://dx.doi.org/10.1016/S2352-3026(20)30104-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270946PMC
May 2020

Effect of Dasatinib vs Imatinib in the Treatment of Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.

JAMA Oncol 2020 03;6(3):358-366

State Key Laboratory of Experimental Hematology and Division of Pediatric Blood Diseases Center, Institute of Hematology and Blood Diseases Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Tianjin, China.

Importance: A randomized clinical trial is needed to determine whether the second-generation Abl-tyrosine kinase inhibitor dasatinib is more effective than the first-generation inhibitor imatinib mesylate for childhood Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).

Objective: To determine whether dasatinib given at a daily dosage of 80 mg/m2 is more effective than imatinib mesylate at a daily dosage of 300 mg/m2 to improve event-free survival of children with Philadelphia chromosome-positive ALL in the context of intensive chemotherapy without prophylactic cranial irradiation.

Design, Setting, And Participants: This open-label, phase 3 randomized clinical trial was conducted at 20 hospitals in China. Enrollment occurred from January 1, 2015, through September 18, 2018, and randomization was stopped on October 4, 2018, when the early stopping criterion of the trial was met. Patients aged 0 to 18 years were recruited. Of the 225 patients with the diagnosis, 35 declined participation and 1 died before treatment, leaving 189 patients available for analysis. Data were analyzed from January 1 through August 4, 2019.

Interventions: Patients were randomized to receive daily dasatinib (n = 92) or imatinib (n = 97) continuously for the entire duration of ALL therapy from the time of diagnosis made during remission induction to the end of continuation therapy.

Main Outcomes And Measures: The primary outcome was event-free survival, analyzed based on intention to treat. The secondary outcomes were relapse, death due to toxic effects, and overall survival.

Results: Among the 189 participants (136 male [72.0%]; median age, 7.8 [interquartile range (IQR), 5.2-11.3] years) and a median follow-up of 26.4 (IQR, 16.3-34.1) months, the 4-year event-free survival and overall survival rates were 71.0% (95% CI, 56.2%-89.6%) and 88.4% (95% CI, 81.3%-96.1%), respectively, in the dasatinib group and 48.9% (95% CI, 32.0%-74.5%; P = .005, log-rank test) and 69.2% (95% CI, 55.6%-86.2%; P = .04, log-rank test), respectively, in the imatinib group. The 4-year cumulative risk of any relapse was 19.8% (95% CI, 4.2%-35.4%) in the dasatinib group and 34.4% (95% CI, 15.6%-53.2%) in the imatinib group (P = .01, Gray test), whereas the 4-year cumulative risk of an isolated central nervous system relapse was 2.7% (95% CI, 0.0%-8.1%) in the dasatinib group and 8.4% (95% CI, 1.2%-15.6%) in the imatinib group (P = .06, Gray test). There were no significant differences in the frequency of severe toxic effects between the 2 treatment groups.

Conclusions And Relevance: Intensive chemotherapy including dasatinib at a dosage of 80 mg/m2 per day yielded superior results in the treatment of Philadelphia chromosome-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m2 per day and provided excellent control of central nervous system leukemia without the use of prophylactic cranial irradiation.

Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IPR-14005706.
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http://dx.doi.org/10.1001/jamaoncol.2019.5868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990720PMC
March 2020

Long non-coding RNA SNHG5 regulates chemotherapy resistance through the miR-32/DNAJB9 axis in acute myeloid leukemia.

Biomed Pharmacother 2020 Mar 26;123:109802. Epub 2019 Dec 26.

Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, China. Electronic address:

Background: Acute myeloid leukemia (AML) is a common hematopoietic malignancy with invasive activity. Drug resistance greatly contributes to the poor efficacy of chemotherapy in AML treatment. Recent research indicates that long non-coding RNAs (LncRNAs) regulates chemotherapy resistance in malignancy.

Methods: Microarray analysis was used to screen out AML related genes, and interaction between small nucleolar RNA host gene 5(SNHG5) and miR-32, as well as that between miR-32 and DNAJB9. Quantitative real-time PCR (qRT-PCR) and In situ hybridization(ISH) were used to determine the expression levels of SNHG5, miR-32 and DNAJB9 mRNA in AML cell lines and clinic samples. Western blot was performed to detect protein expression levels. After being treated with varying concentrations of Adriamycin(ADM), cell viability was evaluated using a cell counting kit-8(CCK8).

Results: We carried out a genome-wide LncRNA expression study and found SNHG5 aberrantly overexpressed in AML comparing to the donors. Knock-down of SNHG5 promoted sensitivity of AML cells to chemotherapy. In addition, miR-32 was identified as the downstream target of SNHG5 and miR-32 inhibitor abrogated the inhibiting effects of downregulated SNHG5 on AML cell viability. Furthermore, inhibited SNHG5 decreased DNAJB9 expression levels by sponging miR-32. The SNHG5/miR-32/DNAJB9 axis targeted autophagy to regulate chemotherapy resistance.

Conclusion: SHNG5 regulates chemotherapy resistance by targeting the miR-32/DNAJB9 axis in acute myeloid leukemia, which provided a novel potential target for AML and revealed an important mechanism of chemotherapy resistance.
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http://dx.doi.org/10.1016/j.biopha.2019.109802DOI Listing
March 2020

Discrimination of the microbial subspecies using the ribosomal protein spectra coupled with the metabolite high resolution mass spectra.

Talanta 2020 Feb 20;208:120361. Epub 2019 Sep 20.

National Center for Organic Mass Spectrometry in Shanghai, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China. Electronic address:

Routine microbial identification by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) has been achieved based on the spectra of ribosomal proteins with molecular masses between 2000 and 20000Da. It is a rapid, cost-effective, and simple method to characterize different species of microorganisms. But for some subspecies of molds, there are high similarities between their spectra in 2000-20000Da, it makes them indistinguishable in this mass range. Based on the specialized metabolite production, there are obvious differences between the high resolution spectra of the same samples in 600-2000Da. It allows the rapid discrimination of these microbial subspecies. The ability of the method to discriminate microbial subspecies was demonstrated by characterizing three different Aspergillus niger strains. Furthermore, this approach has been applied to discriminate two different Acremonium alternatum strains which were collected from mildew plants. It demonstrated the applicability of the method to the actual samples. The high resolution MS in the range of 600-2000Da was presented as a complementary approach for the routine method in 2000-20000Da. The molds could be identified into species-level group by the spectra between 2000 and 20000Da and the strains within each group could be further discriminated based on differences in metabolites. The spectra between 2000 and 20000Da and the spectra between 600 and 2000Da were obtained from the same samples, which extracted with the same method. There is no need of additional pre-processing to obtain the high resolution spectra. It potentially provides a powerful tool for the fast and accurate identification of microbial subspecies.
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http://dx.doi.org/10.1016/j.talanta.2019.120361DOI Listing
February 2020

Autophagic degradation of the circadian clock regulator promotes ferroptosis.

Autophagy 2019 11 26;15(11):2033-2035. Epub 2019 Aug 26.

The Third Affiliated Hospital, Guangzhou Medical University , Guangzhou , Guangdong , China.

Macroautophagy (hereafter referred to as autophagy) involves a lysosomal degradation pathway and plays a context-dependent role in promoting either cell survival or cell death during stress; excessive or impaired autophagy is implicated in various types of cell death. In particular, lipid peroxidation-associated ferroptosis has recently been recognized as a type of autophagy-dependent cell death, but the mechanisms involved remain largely obscure. Our recent findings demonstrate that clockophagy, namely the selective autophagic degradation of the circadian clock regulator ARNTL/BMAL1, promotes ferroptotic cancer cell death and . Mechanically, the cargo receptor SQSTM1/p62 is responsible for the autophagic degradation of ARNTL in response to type 2 ferroptosis inducers (e.g., RSL3 and FIN56), but not type 1 ferroptosis inducers (e.g., erastin, sulfasalazine, and sorafenib). Consequently, clockophagy-mediated ARNTL degradation promotes lipid peroxidation and subsequent ferroptosis through blocking HIF1A-dependent fatty acid uptake and lipid storage. These findings highlight a novel type of selective autophagy in regulated cell death.
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http://dx.doi.org/10.1080/15548627.2019.1659623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844535PMC
November 2019

Metabolomics Coupled with Transcriptomics Approach Deciphering Age Relevance in Sepsis.

Aging Dis 2019 Aug 1;10(4):854-870. Epub 2019 Aug 1.

1Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.

Sepsis is a severe disease frequently occurred in the Intenisive Care Unit (ICU), which has a very high morbidity and mortality, especially in patients aged over 65 years. Owing to the aging effect and the ensuing deterioration of body function, the elder patients may have atypical responses to sepsis. Diagnosis and pathogenesis of sepsis in this population are thus difficult, which hindered effective treatment and management in clinic. To investigated age effects on sepsis, 158 elderly septic patients and 71 non-septic elderly participants were enrolled, and their plasma samples were collected for transcriptomics (RNA-seq) and metabolomics (NMR and GC-MS) analyses, which are both increasingly being utilized to discover key molecular changes and potential biomarkers for various diseases. Protein-protein interaction (PPI) analysis was subsequently performed to assist cross-platform integration. Real time polymerase chain reaction (RT-PCR) was used for validation of RNA-seq results. For further understanding of the mechanisms, cecal ligation and puncture (CLP) experiment was performed both in young and middle-aged rats, which were subjected to NMR-based metabolomics study and validated for several key inflammation pathways by western blot. Comprehensive analysis of data from the two omics approaches provides a systematic perspective on dysregulated pathways that could facilitate the development of therapy and biomarkers for elderly sepsis. Additionally, the metabolites of lactate, arginine, histamine, tyrosine, glutamate and glucose were shown to be highly specific and sensitive in distinguishing septic patients from healthy controls. Significant increases of arginine, trimethylamine N-oxide and allantoin characterized elderly patient incurred sepsis. Further analytical and biological validations in different subpopulations of septic patients should be carried out, allowing accurate diagnostics and precise treatment of sepsis in clinic.
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http://dx.doi.org/10.14336/AD.2018.1027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675524PMC
August 2019

Clockophagy is a novel selective autophagy process favoring ferroptosis.

Sci Adv 2019 07 24;5(7):eaaw2238. Epub 2019 Jul 24.

The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510510, China.

Ferroptosis is a form of nonapoptotic regulated cell death driven by iron-dependent lipid peroxidation. Autophagy involves a lysosomal degradation pathway that can either promote or impede cell death. A high level of autophagy has been associated with ferroptosis, but the mechanisms underpinning this relationship are largely elusive. We characterize the contribution of autophagy to ferroptosis in human cancer cell lines and mouse tumor models. We show that "clockophagy," the selective degradation of the core circadian clock protein ARNTL by autophagy, is critical for ferroptosis. We identify SQSTM1 as a cargo receptor responsible for autophagic ARNTL degradation. ARNTL inhibits ferroptosis by repressing the transcription of , thus activating the prosurvival transcription factor HIF1A. Genetic or pharmacological interventions blocking ARNTL degradation or inhibiting EGLN2 activation diminished, whereas destabilizing HIF1A facilitated, ferroptotic tumor cell death. Thus, our findings reveal a new pathway, initiated by the autophagic removal of ARNTL, that facilitates ferroptosis induction.
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http://dx.doi.org/10.1126/sciadv.aaw2238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656546PMC
July 2019

Eucalyptal D Enhances the Antifungal Effect of Fluconazole on Fluconazole-Resistant by Competitively Inhibiting Efflux Pump.

Front Cell Infect Microbiol 2019 20;9:211. Epub 2019 Jun 20.

State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China.

The frequent emergence of azole-resistant strains has increasingly led azoles to fail in treating candidiasis. Combination with other drugs is a good option to effectively reduce or retard its incidence of resistance. Natural products are a promising synergist source to assist azoles in treating resistant candidiasis. Eucalyptal D (ED), a formyl-phloroglucinol meroterpenoid, is one of the natural synergists, which could significantly enhance the anticandidal activity of fluconazole (FLC) in treating FLC resistant . The checkerboard microdilution assay showed their synergistic effect. The agar disk diffusion test illustrated the key role of ED in synergy. The rhodamine 6G (R6G) efflux assay reflected ED could reduce drug efflux, but quantitative reverse transcription PCR analysis revealed the upregulation of and genes in ED treating group. Efflux pump-deficient strains were hyper-susceptible to ED, thus ED was speculated to be the substrate of efflux pump Cdr1p and Cdr2p to competitively inhibit the excretion of FLC or R6G, which mainly contributed to its synergistic effect.
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http://dx.doi.org/10.3389/fcimb.2019.00211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595430PMC
February 2020

Bioactive A-ring rearranged limonoids from the root barks of .

Acta Pharm Sin B 2019 May 1;9(3):545-556. Epub 2019 Mar 1.

Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.

Screening active natural products, rapid identification, and accurate isolation are of great important for modern natural lead compounds discovery. We hereby reported the isolation of seven new neotecleanin-type limonoids (-), seven new limonoids with 5-oxatricyclo[5.4.0.11., 4.]hendecane ring system (-), and two new precursors (-) together with four known limonoids (-) from the root barks of . Their structures, including their absolute configurations, were elucidated based on analyses of HR-ESI-MS, 1D/2D NMR, ECD spectrum calculations and single-crystal X-ray diffraction techniques. Compounds , , , , , , showed significant anti-inflammatory activities in LPS-induced RAW 264.7 cell line, BV2 microglial cells, and -stimulated THP-1 human monocytic cells. Walrobsin M () exhibited anti-inflammatory activity with IC value of 7.96±0.36 μmol/L, and down-regulated phosphorylation levels of ERK and p38 in a dose-dependent manner.
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http://dx.doi.org/10.1016/j.apsb.2019.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543057PMC
May 2019

HMGB1 regulates erastin-induced ferroptosis via RAS-JNK/p38 signaling in HL-60/NRAS cells.

Am J Cancer Res 2019 1;9(4):730-739. Epub 2019 Apr 1.

Department of Pediatrics, Xiangya Hospital, Central South University Changsha 410008, Hunan, People's Republic of China.

Ferroptosis is emerging as a new form of regulated cell death driven by oxidative injury promoting lipid peroxidation in an iron-dependent manner. High mobility group box 1 (HMGB1) plays an important role in leukemia pathogenesis and chemotherapy resistance. The mechanisms of ferroptosis in tumor pathogenesis and treatment have been a recent research focus but the role of HMGB1 in regulating ferroptosis especially in leukemia still remains largely unknown. Here, we shown that HMGB1 is a critical regulator of eratin-induced ferroptosis in HL-60 cell line expressing NRAS (HL-60/NRAS). Erastin enhanced ROS levels, thereby promoting cytosolic translocation of HMGB1 and enhancing cell death. Knockdown of HMGB1 decreased erastin-induced ROS generation and cell death in an iron-mediated lysosomal pathway in HL-60/NRAS cells. Knockdown of HMGB1 or rat sarcoma (RAS), or pharmacological inhibition of JNK and p38 decreased TfR1 levels in HL-60/NRAS cells. Importantly, these data were further supported by our in vivo experiment, in which xenografts formed by HMGB1 knockdown HL-60/NRAS cells had lower PTGS2 and TfR1 expression than that in control mice. Taken together, these results suggest that HMGB1 is a novel regulator of ferroptosis via the RAS-JNK/p38 pathway and a potential drug target for therapeutic interventions in leukemia.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511643PMC
April 2019

H NMR-Based Metabolomics Reveals Refined-Huang-Lian-Jie-Du-Decoction (BBG) as a Potential Ischemic Stroke Treatment Drug With Efficacy and a Favorable Therapeutic Window.

Front Pharmacol 2019 12;10:337. Epub 2019 Apr 12.

Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.

Huang-Lian-Jie-Du-Decoction (HLJDD) is a traditional Chinese medicine (TCM) used to treat ischemic stroke. However, the complexity of its chemical composition makes quality control difficult. Berberine, baicalin, and geniposide are the three main ingredients in HLJDD. Here, a formula of BBG comprised of berberine, baicalin, and geniposide, known as Refined-Huang-Lian-Jie-Du-Decoction, was investigated for its efficacy, therapeutic window, and mechanisms of action. BBG was assessed on two major types of ischemic stroke, cerebral ischemia-reperfusion (I/R) injury, and continuous ischemia injury, respectively. BBG showed efficacy comparable to HLJDD in the treatment of cerebral I/R injury within 5 h after injury initiation but did poorly in treating continuous ischemia injury. BBG exhibited neuroprotective effects on cerebral I/R injury by regaining the balance in energy metabolism, oxidative stress, amino acid metabolism, inflammation, and nucleic acid metabolism. These results suggested that BBG could be a good alternative to HLJDD, with high efficacy and a long therapeutic window, which shows great potential for drug development to treat stroke.
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http://dx.doi.org/10.3389/fphar.2019.00337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474285PMC
April 2019

Extracellular HMGB1 prevents necroptosis in acute myeloid leukemia cells.

Biomed Pharmacother 2019 Apr 2;112:108714. Epub 2019 Mar 2.

Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, 410008, China. Electronic address:

Changes in the expression and subcellular localization of high mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) molecule, have been implicated in tumorigenesis and tumor cell death in response to cancer therapy. Specifically, HMGB1 release has been shown to occur with a specific form of induced cell death known as necroptosis. In the present study, we examined the role of HMGB1 in the necroptosis of acute myeloid leukemia (AML) cells. In two AML cell lines and primary AML cells from two patients, etoposide induced necroptosis via cIAP1/2 degradation when caspase activity was inhibited by Z-VAD-fmk, but treatment with extracellular HMGB1 prevented this necroptosis. Interestingly, HMGB1 did not prevent the degradation of cIAP1/2, but rather activated the nuclear factor kappa B pathway. The results of the present study provide evidence that extracellular HMGB1 is not only an important DAMP molecule released by cells upon necrosis, but also a regulatory factor that prevents necroptosis in AML cells.
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http://dx.doi.org/10.1016/j.biopha.2019.108714DOI Listing
April 2019

Treatment abandonment in childhood acute lymphoblastic leukaemia in China: a retrospective cohort study of the Chinese Children's Cancer Group.

Arch Dis Child 2019 06 31;104(6):522-529. Epub 2019 Jan 31.

Department of Hematology/Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Key Lab of Pediatric Hematology and Oncology of China Ministry of Health, and National Children's Medical Center, Shanghai, China.

Objectives: Before 2003, most children with acute lymphoblastic leukaemia (ALL) abandoned treatment, with only approximately 30% treated in China. With the development of national insurance for underprivileged patients, we assessed the current frequency and causes of treatment abandonment among patients with ALL who were enrolled in the Chinese Children's Cancer Group ALL protocol between 2015 and 2016.

Methods: Demographic, clinical and laboratory data on patients who abandoned treatment, as well as economic and sociocultural data of their families were collected and analysed. General health-related statistics were retrieved from publicly accessible databanks maintained by the Chinese government.

Results: At a median follow-up of 119 weeks, 83 (3.1%, 95% CI 2.5% to 3.8%) of the 2641 patients abandoned treatment. Factors independently associated with abandonment included standard/high-risk ALL (OR 2.62, 95% CI 1.43 to 4.77), presence of minimal residual disease at the end of remission induction (OR 3.57, 95% CI 1.90 to 6.74) and low-income economic region (OR 3.7, 95% CI 1.89 to 7.05). According to the family members, economic constraints (50.6%, p=0.0001) were the main reason for treatment abandonment, followed by the belief of incurability, severe side effects and concern over late complications.

Conclusions: The rate of ALL treatment abandonment has been greatly reduced in China. Standard/high-risk ALL, residence in a low-income region and economic difficulties were associated with treatment abandonment.

Clinical Trial Registration Number: ChiCTR-IPR-14005706, pre-results.
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http://dx.doi.org/10.1136/archdischild-2018-316181DOI Listing
June 2019

Ataxia-telangiectasia with a novel ATM gene mutation and Burkitt leukemia: A case report.

Mol Clin Oncol 2018 Nov 17;9(5):493-498. Epub 2018 Sep 17.

Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.

Ataxia-telangiectasia (A-T) is an infrequent autosomal recessive disorder that involves multiple systems and is characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, radiosensitivity, immune deficiency with recurrent respiratory infections, and a tendency to develop lymphoid malignancies. A-T is caused by mutations in the ATM gene, with >1,000 mutations reported to date and gradually increasing in number. Patients with A-T have an increased incidence of cancers. The aim of the present study was to retrospectively review the case of a patient who presented at the age of 5 years with cerebellar ataxia without telangiectasia, and was diagnosed with Burkitt leukemia by bone marrow biopsy and molecular testing at the age of 7 years at the Xiangya Hospital of Central South University (Changsha, China). The patient received chemotherapy with the pediatric CCCG-BNHL-2015 regimen (R4 group) and achieved a complete remission after 2 courses. However, recurrent respiratory infections and thrombosis occurred during chemotherapy. The diagnosis of A-T was confirmed by uncovering two variants of the ATM gene, including c.742C>T (p.R248X; rs730881336) in exon 7 and c.6067-c.6068 ins GAGGGAAGAT in exon 41 by whole-exome sequencing. Unfortunately, the patient's parents refused follow-up treatment and he succumbed to recurrent severe infections 4 months after the diagnosis of Burkitt leukemia. The diagnosis of A-T may be challenging, as its phenotype can be incomplete early in the course of the disease. Detailed medical history, characteristic clinical manifestations and increasingly developed exome sequencing techniques may be helpful in diagnosing this rare disease. Management should be based on multidisciplinary guidance and other treatment options must be investigated in the future.
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http://dx.doi.org/10.3892/mco.2018.1721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200993PMC
November 2018

Total Saponins of Aralia Elata (Miq) Seem Alleviate Calcium Homeostasis Imbalance and Endoplasmic Reticulum Stress-Related Apoptosis Induced by Myocardial Ischemia/Reperfusion Injury.

Cell Physiol Biochem 2018 2;50(1):28-40. Epub 2018 Oct 2.

Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Background/aims: Total saponins of Aralia elata (Miq) Seem (AS) from the Chinese traditional herb Long ya Aralia chinensis L. reportedly provide cardioprotective effects, but the exact mechanisms require further study. Previous studies have showed that myocardial ischemia/ reperfusion injury (MIRI) was related to calcium homeostasis imbalance and endoplasmic reticulum stress (ERS). Thus, this study aimed to demonstrate protective effects of AS on MIRI.

Methods: After administrating AS for 5 days, the left anterior descending artery coronary artery of Sprague-Dawley (SD) rats was ligated for 30 min. After 48 h of reperfusion, haemodynamics, Evans blue/ 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (HE) staining, masson staining and the levels of lactate dehydrogenase (LDH) and creatine kinase (CK), superoxide dismutase (SOD), malondialdehyde (MDA) were detected to assess MIRI. ATPase activity and Western Blot were used to study the mechanisms.

Results: Compared with IR group, AS treatment groups could significantly reduce myocardial infarct size; improve myocardial pathologic progress; decrease content of LDH, CK, and MDA; increase content of SOD; and restore the activities of Ca2+-Mg2+-ATPase, Na+-K+-ATPase, sarcoplasmic reticulum Ca2+-ATPases (SERCA), and calcineurin (CaN). AS treatment groups also significantly up-regulated the expression of GRP78, C/EBP homologous protein (CHOP), and Bax, and down-regulated the expression of Bcl-2, all similar to the effects of ERS.

Conclusion: These findings illustrated that AS could prevent myocardial ischemia/reperfusion injury and reduce calcium homeostasis imbalance and ERS-related apoptosis.
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http://dx.doi.org/10.1159/000493954DOI Listing
November 2018

Fanconi anemia in twins with neutropenia: A case report.

Oncol Lett 2018 Oct 14;16(4):5325-5330. Epub 2018 Aug 14.

Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.

Fanconi anemia (FA) is a rare inherited disease caused by mutations in genes that are primarily involved in DNA damage response or repair. The disease is often characterized by congenital malformations, progressive bone marrow failure, abnormal skin pigmentation patterns and susceptibility to cancer. The present study describes a pair of 4-year-old male twins, both of whom had been suffering from upper respiratory tract infections for >2 years. There was no indication of discomfort including fever, coughing, bleeding or fatigue from either child when the upper respiratory tract infection disappeared. Physical examination of the twins did not reveal anything significant, and no external anomalies were observed. In order to obtain additional diagnostic evidence, next-generation gene sequencing, chromosome breakage analysis and comet assays were performed. The results revealed double heterozygous mutations in the Fanconi Anemia Complementation Group D2 gene of the twins, therefore providing a conclusive diagnosis of FA. The case highlights how difficulties in clinical diagnosis may be overcome by including genetic screening tests into the range of diagnostic tests, which may also reveal unexpected results.
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http://dx.doi.org/10.3892/ol.2018.9304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144108PMC
October 2018

The Circadian Clock Controls Immune Checkpoint Pathway in Sepsis.

Cell Rep 2018 07;24(2):366-378

The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address:

Sepsis and septic shock are associated with life-threatening organ dysfunction caused by an impaired host response to infections. Although circadian clock disturbance impairs the early inflammatory response, its impact on post-septic immunosuppression remains poorly elucidated. Here, we show that Bmal1, a core circadian clock gene, plays a role in the regulation of host immune responses in experimental sepsis. Mechanistically, Bmal1 deficiency in macrophages increases PKM2 expression and lactate production, which is required for expression of the immune checkpoint protein PD-L1 in a STAT1-dependent manner. Consequently, targeted ablation of Pkm2 in myeloid cells or administration of anti-PD-L1-neutralizing antibody or supplementation with recombinant interleukin-7 (IL-7) facilitates microbial clearance, inhibits T cell apoptosis, reduces multiple organ dysfunction, and reduces septic death in Bmal1-deficient mice. Collectively, these findings suggest that the circadian clock controls the immune checkpoint pathway in macrophages and therefore represents a potential therapeutic target for lethal infection.
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http://dx.doi.org/10.1016/j.celrep.2018.06.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094382PMC
July 2018

TFAM is a novel mediator of immunogenic cancer cell death.

Oncoimmunology 2018;7(6):e1431086. Epub 2018 Feb 15.

The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.

Immunogenic cell death (ICD) is a type of cell death that is accompanied by the release of damage-associated molecular patterns (DAMPs) and results in a dead-cell antigen-specific immune response. Here, we report that spautin-1, an inhibitor of ubiquitin-specific peptidases, triggers immunogenic cancer cell death and . The anticancer activity of spautin-1 occurs independent of autophagy inhibition, but depends on the intrinsic mitochondrial apoptosis pathway. Spautin-1 causes mitochondrial oxidative injury, which results in JUN transcription factor activation in a JNK-dependent manner. Mechanistically, activation of JUN by spautin-1 leads to apoptosis by upregulation of pro-apoptotic BAD expression. Importantly, the release of TFAM, a mitochondrial DAMP, by apoptotic cells may contribute to spautin-1-induced ICD via its action on the receptor AGER. Indeed, cancer cells treated with spautin-1 were able to elicit an anticancer immune response when inoculated , in the absence of any adjuvant. This immunogenic effect of spautin-1-treated cancer cells was lost when TFAM or AGER were neutralized by specific antibodies. Altogether, our results suggest that spautin-1 may stimulate an apoptotic pathway that results in ICD, in TFAM- and AGER-dependent fashion.
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http://dx.doi.org/10.1080/2162402X.2018.1431086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980348PMC
February 2018
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