Publications by authors named "Yanbin Liu"

101 Publications

Inhalable nanocatchers for SARS-CoV-2 inhibition.

Proc Natl Acad Sci U S A 2021 Jul 2;118(29). Epub 2021 Jul 2.

Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China;

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2), presents an urgent health crisis. More recently, an increasing number of mutated strains of SARS-CoV-2 have been identified globally. Such mutations, especially those on the spike glycoprotein to render its higher binding affinity to human angiotensin-converting enzyme II (hACE2) receptors, not only resulted in higher transmission of SARS-CoV-2 but also raised serious concerns regarding the efficacies of vaccines against mutated viruses. Since ACE2 is the virus-binding protein on human cells regardless of viral mutations, we design hACE2-containing nanocatchers (NCs) as the competitor with host cells for virus binding to protect cells from SARS-CoV-2 infection. The hACE2-containing NCs, derived from the cellular membrane of genetically engineered cells stably expressing hACE2, exhibited excellent neutralization ability against pseudoviruses of both wild-type SARS-CoV-2 and the D614G variant. To prevent SARS-CoV-2 infections in the lung, the most vulnerable organ for COVID-19, we develop an inhalable formulation by mixing hACE2-containing NCs with mucoadhesive excipient hyaluronic acid, the latter of which could significantly prolong the retention of NCs in the lung after inhalation. Excitingly, inhalation of our formulation could lead to potent pseudovirus inhibition ability in hACE2-expressing mouse model, without imposing any appreciable side effects. Importantly, our inhalable hACE2-containing NCs in the lyophilized formulation would allow long-term storage, facilitating their future clinical use. Thus, this work may provide an alternative tactic to inhibit SARS-CoV-2 infections even with different mutations, exhibiting great potential for treatment of the ongoing COVID-19 epidemic.
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http://dx.doi.org/10.1073/pnas.2102957118DOI Listing
July 2021

The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression.

Cell Death Dis 2021 Jul 5;12(7):680. Epub 2021 Jul 5.

Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.

It has been recently reported that CD38 expressed on tumor cells of multiple murine and human origins could be upregulated in response to PD-L1 antibody therapy, which led to dysfunction of tumor-infiltrating CD8 T immune cells due to increasing the production of adenosine. However, the role of tumor expressed-CD38 on neoplastic formation and progression remains elusive. In the present study, we aimed to delineate the molecular and biochemical function of the tumor-associated CD38 in lung adenocarcinoma progression. Our clinical data showed that the upregulation of tumor-originated CD38 was correlated with poor survival of lung cancer patients. Using multiple in vitro assays we found that the enzymatic activity of tumor expressed-CD38 facilitated lung cancer cell migration, proliferation, colony formation, and tumor development. Consistently, our in vivo results showed that inhibition of the enzymatic activity or antagonizing the enzymatic product of CD38 resulted in the similar inhibition of tumor proliferation and metastasis as CD38 gene knock-out or mutation. At biochemical level, we further identified that cADPR, the mainly hydrolytic product of CD38, was responsible for inducing the opening of TRPM2 iron channel leading to the influx of intracellular Ca and then led to increasing levels of NRF2 while decreasing expression of KEAP1 in lung cancer cells. These findings suggested that malignant lung cancer cells were capable of using cADPR catalyzed by CD38 to facilitate tumor progression, and blocking the enzymatic activity of CD38 could be represented as an important strategy for preventing tumor progression.
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http://dx.doi.org/10.1038/s41419-021-03968-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256983PMC
July 2021

Distinct Infection Forms of SARS-CoV-2 Among People Living With HIV.

Res Sq 2021 Jun 9. Epub 2021 Jun 9.

Background: People living with HIV (PLWH) are immunodeficient, it is vague if they are more susceptible to SARS-CoV-2 infection than HIV negative individuals.

Methods: In this cross-sectional study, 857 PLWH and 1048 HIV negative individuals were enrolled from the Wuchang district in Wuhan, China. We compared the total rate of SARS-CoV-2 infection, the rate of COVID-19, asymptomatic carriers, and unapparent infectors in the two groups. The risk factors associated with SARS-CoV-2 infection among PLWH were explored.

Results: Fourteen out of 857 (1.63%) PLWH were infected with SARS-CoV-2, while 68 of 1048 (6.49%) HIV negative individuals were infected. In PLWH, there were 6 confirmed COVID-19 (0.70%), 4 asymptomatic carriers (0.47%) and 4 unapparent infectors (0.47%). In the HIV negative group, the cases of COVID-19, asymptomatic carrier, and unapparent infector were 5 (0.48%), 0 (0.00%), and 63 (6.01%), respectively. After adjusting for age, gender, and chronic comorbidities, the rate of SARS-CoV-2 infection in PLWH was lower than that in HIV negative group (1.96% vs 5.74%, P=0.001). The morbidity of COVID-19 was similar between the two groups (P=0.107), but the rate of unapparent infection in PLWH was lower than that in the HIV negative group (0.54% vs 5.46%, P=0.001). Older age (aOR=4.50, 95%CI: 1.34-15.13, P=0.015) and OIs (aOR=9.59, 95%CI: 1.54-59.92, P=0.016) were risk factors for SARS-CoV-2 infection among PLWH.

Conclusions: PLWH has different infection forms of SARS-CoV-2 compared with the general population. Older age and OIs were considered to driving causes of SARS-CoV-2 infection among PLWH.
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http://dx.doi.org/10.21203/rs.3.rs-569883/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202431PMC
June 2021

People Living with HIV Easily lose their Immune Response to SARS-CoV-2: Result From A Cohort of COVID-19 Cases in Wuhan, China.

Res Sq 2021 Jun 7. Epub 2021 Jun 7.

Background To date, whether the immune response for SARS-CoV-2 infection among people living with HIV(PLWH) is different from HIV-naïve individuals is still not clear. Methods In this cohort study, COVID-19 patients admitted to hospital in Wuhan between January 15 and April 1, 2020, were enrolled. Patients were categorized into PLWH and HIV-naïve group. All patients were followed up regularly (every fifteen days) until November 30, 2020, and the immune response towards SARS-CoV-2 was observed. Results Totally, 18 PLWH and 185 HIV-naïve individuals with COVID-19 were enrolled. The positive conversion rates of IgG were 56% in PLWH and 88% in HIV-naïve patients respectively, and the peak was on the 45th day after COVID-19 onset. However, the positive rate of IgG dropped to 12% in PLWH and 33% among HIV-naïve individuals by the end of the study. The positive conversion rate of IgG among asymptomatic carriers is significantly lower than that among moderate patients (AOR = 0.18, 95% CI: 0.05-0.65) and PLWH had a lower IgG seroconversion rate compared to the HIV-naive group (AOR = 0.22, 95% CI: 0.05-0.90). Patients with lower lymphocyte counts at onset had a higher positive conversion rate (AOR = 0.29, 95% CI: 0.09-0.90) and longer duration for IgG (AHR = 4.01, 95% CI: 1.78-9.02). Conclusions The positive conversion rate of IgG for SARS-CoV-2 was relatively lower and quickly lost in PLWH, which meant PLWH was in a disadvantaged situation when affected with COVID-19.
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http://dx.doi.org/10.21203/rs.3.rs-543375/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202430PMC
June 2021

Novel irreversible covalent BTK inhibitors discovered using DNA-encoded chemistry.

Bioorg Med Chem 2021 Jul 19;42:116223. Epub 2021 May 19.

X-Chem Inc., 100 Beaver Street, Waltham, MA 02453, USA. Electronic address:

Libraries of DNA-Encoded small molecules created using combinatorial chemistry and synthetic oligonucleotides are being applied to drug discovery projects across the pharmaceutical industry. The majority of reported projects describe the discovery of reversible, i.e. non-covalent, target modulators. We synthesized multiple DNA-encoded chemical libraries terminated in electrophiles and then used them to discover covalent irreversible inhibitors and report the successful discovery of acrylamide- and epoxide-terminated Bruton's Tyrosine Kinase (BTK) inhibitors. We also demonstrate their selectivity, potency and covalent cysteine engagement using a range of techniques including X-ray crystallography, thermal transition shift assay, reporter displacement assay and intact protein complex mass spectrometry. The epoxide BTK inhibitors described here are the first ever reported to utilize this electrophile for this target.
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http://dx.doi.org/10.1016/j.bmc.2021.116223DOI Listing
July 2021

Discovery of Novel, Potent Inhibitors of Hydroxy Acid Oxidase 1 (HAO1) Using DNA-Encoded Chemical Library Screening.

J Med Chem 2021 05 6;64(10):6730-6744. Epub 2021 May 6.

X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States.

Inhibition of hydroxy acid oxidase 1 (HAO1) is a strategy to mitigate the accumulation of toxic oxalate that results from reduced activity of alanine-glyoxylate aminotransferase (AGXT) in primary hyperoxaluria 1 (PH1) patients. DNA-Encoded Chemical Library (DECL) screening provided two novel chemical series of potent HAO1 inhibitors, represented by compounds -. Compound was further optimized via various structure-activity relationship (SAR) exploration methods to , a compound with improved potency and absorption, distribution, metabolism, and excretion (ADME)/pharmacokinetic (PK) properties. Since carboxylic acid-containing compounds are often poorly permeable and have potential active glucuronide metabolites, we undertook a brief, initial exploration of acid replacements with the aim of identifying non-acid-containing HAO1 inhibitors. Structure-based drug design initiated with Compound led to the identification of a nonacid inhibitor of HAO1, , which has weaker potency and increased permeability.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02271DOI Listing
May 2021

Structure optimization of gasket based on orthogonal experiment and NSGA-II.

Sci Prog 2021 Apr-Jun;104(2):368504211011347

Vehicle Engineering Department, Army Academy of Armored Forces, Beijing, China.

With the aim of enhancing both reliability and fatigue life of gasket, this study combines finite element analysis, orthogonal experimental design, dynamically-guided multi-objective optimization, and the non-dominated sorting genetic algorithm with elitist strategy to optimize the geometric parameters of the cylinder gasket. The finite element method was used to analyze the temperature field, thermal-mechanical coupling stress field, and deformation of cylinder gasket. The calculation results were experimentally validated by measured temperature data, and comparison results show that the maximum error between calculated value and experiment value is 7.1%, which is acceptable in engineering problems. Based on above results and orthogonal experiment design method, the effects of five factors, including diameter of combustion chamber circle, diameter of coolant flow hole, length of the insulation zone between third and fourth cylinders, thickness of gasket, and bolt preload, on three indexes: temperature, stress, and deformation of gasket, were examined in depth. Through the variance analysis of the results, three important factors were identified to proceed later calculation. The dynamically guided multi-objective optimization strategy and the non-dominated sorting genetic algorithm were effectively used and combined to determine the optimal geometric parameters of cylinder gasket. Furthermore, calculation results suggest that temperature, stress, and deformation of the optimized cylinder gasket have been improved by 27.88 K, 16.84 MPa, and 0.0542 mm, respectively when compared with the origin object, which shows the excellent performance of gasket optimization and effectiveness of the proposed optimization strategy.
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http://dx.doi.org/10.1177/00368504211011347DOI Listing
April 2021

Bispecific Estrogen Receptor α Degraders Incorporating Novel Binders Identified Using DNA-Encoded Chemical Library Screening.

J Med Chem 2021 04 12;64(8):5049-5066. Epub 2021 Apr 12.

X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States.

Bispecific degraders (PROTACs) of ERα are expected to be advantageous over current inhibitors of ERα signaling (aromatase inhibitors/SERMs/SERDs) used to treat ER+ breast cancer. Information from DNA-encoded chemical library (DECL) screening provides a method to identify novel PROTAC binding features as the linker positioning, and binding elements are determined directly from the screen. After screening ∼120 billion DNA-encoded molecules with ERα WT and 3 gain-of-function (GOF) mutants, with and without estradiol to identify features that enrich ERα competitively, the off-DNA synthesized small molecule exemplar exhibited nanomolar ERα binding, antagonism, and degradation. Click chemistry synthesis on an alkyne E3 ligase engagers panel and an azide variant of rapidly generated bispecific nanomolar degraders of ERα, with PROTACs and inhibiting ER+ MCF7 tumor growth in a mouse xenograft model of breast cancer. This study validates this approach toward identifying novel bispecific degrader leads from DECL screening with minimal optimization.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00127DOI Listing
April 2021

Creep-Fatigue Experiment and Life Prediction Study of Piston 2A80 Aluminum Alloy.

Materials (Basel) 2021 Mar 13;14(6). Epub 2021 Mar 13.

Department of Weapon and Control, Army Academy of Armored Forces, Beijing 100072, China.

In order to improve the reliability and service life of vehicle and diesel engine, the fatigue life prediction of the piston in a heavy diesel engine was studied by finite element analysis of piston, experiment data of aluminum alloy, fatigue life model based on energy dissipation criteria, and machine learning algorithm. First, the finite element method was used to calculate and analyze the temperature field, thermal stress field, and thermal-mechanical coupling stress field of the piston, and determine the area of heavy thermal and mechanical load that will affect the fatigue life of the piston. Second, based on the results of finite element calculation, the creep-fatigue experiment of 2A80 aluminum alloy was carried out, and the cyclic response characteristics of the material under different loading conditions were obtained. Third, the fatigue life prediction models based on energy dissipation criterion and twin support vector regression are proposed. Then, the accuracy of the two models was verified using experiment data. The results show that the model based on the twin support vector regression is more accurate for predicting the material properties of aluminum alloy. Based on the established life prediction model, the fatigue life of pistons under actual service conditions is predicted. The calculation results show that the minimum fatigue life of the piston under plain condition is 2113.60 h, and the fatigue life under 5000 m altitude condition is 1425.70 h.
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http://dx.doi.org/10.3390/ma14061403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001697PMC
March 2021

Understanding and exploiting the fatty acid desaturation system in Rhodotorula toruloides.

Biotechnol Biofuels 2021 Mar 19;14(1):73. Epub 2021 Mar 19.

Temasek Life Sciences Laboratory, 1 Research Link, National University of Singapore, Singapore, 117604, Singapore.

Background: Rhodotorula toruloides is a robust producer of triacylglycerol owing to its fast growth rate and strong metabolic flux under conditions of high cell density fermentation. However, the molecular basis of fatty acid biosynthesis, desaturation and regulation remains elusive.

Results: We present the molecular characterization of four fatty acid desaturase (FAD) genes in R. toruloides. Biosynthesis of oleic acid (OA) and palmitoleic acid (POA) was conferred by a single-copy ∆9 Fad (Ole1) as targeted deletion of which abolished the biosynthesis of all unsaturated fatty acids. Conversion of OA to linoleic acid (LA) and α-linolenic acid (ALA) was predominantly catalyzed by the bifunctional ∆12/∆15 Fad2. FAD4 was found to encode a trifunctional ∆9/∆12/∆15 FAD, playing important roles in lipid and biomass production as well as stress resistance. Furthermore, an abundantly transcribed OLE1-related gene, OLE2 encoding a 149-aa protein, was shown to regulate Ole1 regioselectivity. Like other fungi, the transcription of FAD genes was controlled by nitrogen levels and fatty acids in the medium. A conserved DNA motif, (T/C)(G/A)TTGCAGA(T/C)CCCAG, was demonstrated to mediate the transcription of OLE1 by POA/OA. The applications of these FAD genes were illustrated by engineering high-level production of OA and γ-linolenic acid (GLA).

Conclusion: Our work has gained novel insights on the transcriptional regulation of FAD genes, evolution of FAD enzymes and their roles in UFA biosynthesis, membrane stress resistance and, cell mass and total fatty acid production. Our findings should illuminate fatty acid metabolic engineering in R. toruloides and beyond.
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http://dx.doi.org/10.1186/s13068-021-01924-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977280PMC
March 2021

Inhibition of TNFR1 Attenuates LPS Induced Apoptosis and Inflammation in Human Nucleus Pulposus Cells by Regulating the NF-KB and MAPK Signalling Pathway.

Neurochem Res 2021 Jun 13;46(6):1390-1399. Epub 2021 Mar 13.

Department of Orthopedic Surgery, Liaocheng People's Hospital, Shandong First Medical University, 67 Dong Chang Xi Road, Liaocheng, 252000, Shandong, People's Republic of China.

Intervertebral disc degeneration (IDD) is accompanied by nucleus pulposus (NP) cell apoptosis, inflammation, and extracellular matrix degradation. Tumour necrosis factor receptor 1 (TNFR1) is a receptor of TNF-α, and is deeply involved in the processes of IDD. However, the effect of TNFR1 inhibition on IDD is not clear. Herein, we report that TNFR1 was increased in LPS-treated HNPCs. The aim of this study was to investigate the potential therapeutic effect of TNFR1 siRNA and selective antagonists of TNFR1 (GSK1995057) on HNPC damage. The results showed that the blockade of TNFR1 by TNFR1 siRNA and GSK1995057 effectively suppressed the cell viability loss, apoptosis, and inflammation induced by LPS in HNPCs. Furthermore, we found that TNFR1 siRNA and GSK1995057 inhibited activation of the NF-KB and MAPK signalling pathways in LPS-stimulated HNPCs. In summary, the blockade of TNFR1 effectively suppressed LPS-induced apoptosis and inflammation in HNPCs through the NF-KB and MAPK signalling pathways. This revealed that the blockade of TNFR1 may provide a potential therapeutic treatment for IDD.
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http://dx.doi.org/10.1007/s11064-021-03278-1DOI Listing
June 2021

HuR up-regulates cell surface PD-L1 via stabilizing CMTM6 transcript in cancer.

Oncogene 2021 Mar 1;40(12):2230-2242. Epub 2021 Mar 1.

Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.

Despite the well-established role of CMTM6 in the stabilization of cell surface PD-L1 in cancer cells, the mechanisms underlying CMTM6 expression and regulation are still largely unknown. Here we unexpectedly find a strikingly positive correlation between CMTM6 and Hu-Antigen R (HuR) expression in most types of cancer. Mechanistically, we elucidate HuR stabilizes CMTM6 mRNA via direct association with AU-rich elements (AREs) in its 3'UTR and predominantly up-regulates CMTM6, which is readily abolished by HuR-specific inhibitor, MS-444. Phenotypically, we notice abundant cell surface PD-L1 in HuR-high cancer cells, which significantly inhibits immune activation of co-cultured T cells as indicated by IL-2 production. Treatment with MS-444 completely relieves immune suppression imposed by HuR-overexpression and further stimulates immune responses. Ectopic HuR accelerates allograft tumor progression in vivo, which is greatly compromised by simultaneous administration with MS-444. Our study uncovers a novel mechanism in control of CMTM6 and therefore PD-L1 expression, and suggests the potential of combining HuR inhibitor with PD-1/PD-L1 antibodies for cancer immunotherapy.
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http://dx.doi.org/10.1038/s41388-021-01689-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994200PMC
March 2021

Effect of a genetically engineered interferon-alpha versus traditional interferon-alpha in the treatment of moderate-to-severe COVID-19: a randomised clinical trial.

Ann Med 2021 12;53(1):391-401

Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China.

Background: There are few effective therapies for coronavirus disease 2019 (COVID-19) upon the outbreak of the pandemic. To compare the effectiveness of a novel genetically engineered recombinant super-compound interferon (rSIFN-co) with traditional interferon-alpha added to baseline antiviral agents (lopinavir-ritonavir or umifenovir) for the treatment of moderate-to-severe COVID-19.

Method: In this multicenter randomized (1:1) trial, patients hospitalized with moderate-to-severe COVID-19 received either rSIFN-co nebulization or interferon-alpha nebulization added to baseline antiviral agents for no more than 28 days. The primary endpoint was the time to clinical improvement. Secondary endpoints included the overall rate of clinical improvement assessed on day 28, the time to radiological improvement and virus nucleic acid negative conversion.

Results: A total of 94 patients were included in the safety set (46 patients assigned to rSIFN-co group, 48 to interferon-alpha group). The time to clinical improvement was 11.5 days versus 14.0 days (95% CI 1.10 to 2.81,  = .019); the overall rate of clinical improvement on day 28 was 93.5% versus 77.1% (difference, 16.4%; 95% CI 3% to 30%); the time to radiological improvement was 8.0 days versus 10.0 days ( = .002), the time to virus nucleic acid negative conversion was 7.0 days versus 10.0 days ( = .018) in the rSIFN-co and interferon alpha arms, respectively. Adverse events were balanced with no deaths among groups.

Conclusions And Relevance: rSIFN-co was associated with a shorter time of clinical improvement than traditional interferon-alpha in the treatment of moderate-to-severe COVID-19 when combined with baseline antiviral agents. rSIFN-co therapy alone or combined with other antiviral therapy is worth to be further studied.Key messagesThere are few effective therapies for coronavirus disease 2019 (COVID-19) upon the outbreak of the pandemic. Interferon alphas, by inducing both innate and adaptive immune responses, have shown clinical efficacy in treating severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus.In this multicenter, head-to-head, randomized, clinical trial which included 94 participants with moderate-to-severe COVID-19, the rSIFN-co plus antiviral agents (lopinavir-ritonavir or umifenovir) was associated with a shorter time of clinical improvement than interferon-alpha plus antiviral agents.
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http://dx.doi.org/10.1080/07853890.2021.1890329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906612PMC
December 2021

An unhealing wound and subcutaneous nodules due to Sporothrix globosa after a cat bite.

PLoS Negl Trop Dis 2020 12 3;14(12):e0008859. Epub 2020 Dec 3.

Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.

A 51-year-old man with 3-month unhealing cat bite wound was diagnosed with sporotrichosis, a subacute-to-chronic infection caused by the worldwide endemic, dimorphic fungus Sporothrix globosa. The case would help clinicians to raise awareness of human sporotrichosis due to cat bites, which remains rare and is likely to be underrecognized and misdiagnosed.
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http://dx.doi.org/10.1371/journal.pntd.0008859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714111PMC
December 2020

Primary sialorrhea and its surgical treatment with denervation of the submandibular glands in combination with sublingual gland excision.

J Craniomaxillofac Surg 2021 Jan 21;49(1):47-51. Epub 2020 Nov 21.

Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China. Electronic address:

Objectives: The purpose of this study was to evaluate the effectiveness of ablating postganglionic parasympathetic fibers of the submandibular ganglion in combination with sublingual gland excision in the treatment of primary sialorrhea.

Materials And Methods: Healthy volunteers were initially chosen to determine a basic saliva flow rate value by saliva collection. Next, unstimulated and stimulated saliva flow rates, and a visual analog scale index for sialorrhea were recorded in all the patients pre- and postoperatively. In addition, the generalized anxiety disorder scale was used to assess preoperative anxiety symptoms. The follow-up durations ranged from 24 to 36 months after surgery.

Results: A total of 10 patients were included in this study. Preoperatively, the mean unstimulated saliva flow rate for the 10 patients was 11.26 ± 4.19 ml/10 min, the stimulated saliva flow rate was 16.76 ± 3.49 ml/6 min, and the visual analog scale index was 66.29 ± 14.86. Postoperatively, the mean unstimulated and stimulated saliva flow rates were significantly reduced to 5.99 ± 1.33 ml/10 min (p = 0.001) and 13.28 ± 1.86 ml/6 min (p = 0.013), respectively, and the visual analog scale index was 25.41 ± 5.6 (p < 0.001). No complications were found after operation.

Conclusion: This study demonstrates that ablation of postganglionic parasympathetic fibers of the submandibular ganglion in combination with sublingual gland excision by an intraoral approach is a simple, safe, and efficient approach for treating primary sialorrhea.
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http://dx.doi.org/10.1016/j.jcms.2020.11.006DOI Listing
January 2021

Characteristics of Pulmonary Auscultation in Patients with 2019 Novel Coronavirus in China.

Respiration 2020 4;99(9):755-763. Epub 2020 Nov 4.

Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, China,

Background: Effective auscultations are often hard to implement in isolation wards. To date, little is known about the characteristics of pulmonary auscultation in novel coronavirus (COVID-19) pneumonia.

Objectives: The aim of this study was to explore the features and clinical significance of pulmonary auscultation in COVID-19 pneumonia using an electronic stethoscope in isolation wards.

Methods: This cross-sectional, observational study was conducted among patients with laboratory-confirmed COVID-19 at Wuhan Red-Cross Hospital during the period from January 27, 2020, to February 12, 2020. Standard auscultation with an electronic stethoscope was performed and electronic recordings of breath sounds were analyzed.

Results: Fifty-seven patients with average age of 60.6 years were enrolled. The most common symptoms were cough (73.7%) during auscultation. Most cases had bilateral lesions (96.4%) such as multiple ground-glass opacities (69.1%) and fibrous stripes (21.8%). High-quality auscultation recordings (98.8%) were obtained, and coarse breath sounds, wheezes, coarse crackles, fine crackles, and Velcro crackles were identified. Most cases had normal breath sounds in upper lungs, but the proportions of abnormal breath sounds increased in the basal fields where Velcro crackles were more commonly identified at the posterior chest. The presence of fine and coarse crackles detected 33/39 patients with ground-glass opacities (sensitivity 84.6% and specificity 12.5%) and 8/9 patients with consolidation (sensitivity 88.9% and specificity 15.2%), while the presence of Velcro crackles identified 16/39 patients with ground-glass opacities (sensitivity 41% and specificity 81.3%).

Conclusions: The abnormal breath sounds in COVID-19 pneumonia had some consistent distributive characteristics and to some extent correlated with the radiologic features. Such evidence suggests that electronic auscultation is useful to aid diagnosis and timely management of the disease. Further studies are indicated to validate the accuracy and potential clinical benefit of auscultation in detecting pulmonary abnormalities in COVID-19 infection.
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http://dx.doi.org/10.1159/000509610DOI Listing
January 2021

In situ buccal carcinoma in a teenager after hematopoietic stem cell transplantation: A case report.

Medicine (Baltimore) 2020 Oct;99(43):e22781

Department of Oral and Maxillofacial-Head and Neck Oncology, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China.

Rationale: Hematopoietic stem cell transplantation (HSCT) is the most effective treatment for the majority of patients who have malignant haemolytic disease. Although the success rate of HSCT has increased, the increasing number of cases suffering from secondary solid malignancies after HSCT has attracted more interest recently.

Patient Concerns: A 16-year-old female patient from China presented with a crusty and painful lesion on the left buccal mucosa with a history of chronic graft-versus-host disease following allogeneic HSCT for acute myeloid leukaemia.

Diagnosis: An incisional biopsy of the lesion showed stratified squamous epithelium mucosa with severe dysplasia (carcinoma in situ). Subsequently, a wide local excision was performed and histological examination revealed early infiltrating squamous epithelial mucosa (carcinoma in situ).

Interventions: She was being treated in the oral and maxillofacial surgery clinic with an incisional biopsy of the left buccal mucosa. She also received a wide local excision.

Outcomes: Follow-up for 4 years showed no recurrence.

Lessons: This case helps raise awareness of the diagnosis of oral symptoms in young patients after HSCT. Due to the increasing application of HSCT, raising awareness in oral and dental physicians may be required to improve long-term clinical outcome of patients who underwent HSCT.
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http://dx.doi.org/10.1097/MD.0000000000022781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581110PMC
October 2020

Preventing mother to child transmission of HIV: lessons learned from China.

BMC Infect Dis 2020 Oct 26;20(1):792. Epub 2020 Oct 26.

Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430071, China.

Background: The program for the prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV) was launched in 2003 in China, but few studies have been conducted to describe the panorama of PMTCT. We investigated the rate and associated factors of mother-to-child transmission (MTCT) in China from 2004 to 2018.

Methods: HIV-infected pregnant women from two areas in China between 2004 and 2018 were enrolled. Antiretrovirals (ARVs) were provided to the mothers and their babies, and the children were followed and tested for HIV.

Results: In total, 857 mothers and their 899 children were enrolled, and the overall MTCT rate was 6.6% (95% CI 5.0-8.2). The MTCT rates of nonintervention, only formula feeding (FF), infant prophylaxis (IP) + FF, single dosage antiretrovirals (sdARVs) + IP + FF, zidovudine (AZT) alone+IP + FF and prenatal combination antiretroviral therapy (cART) + IP + FF were 36.4, 9.4, 10.0, 5.7, 3.8 and 0.3%, respectively. The MTCT rate declined over time. No ARVs, CD4 count < 200/μL, low birth weight, and breastfeeding were associated with MTCT of HIV. For different ARVs, a higher MTCT rate was observed for AZT alone, sdARVs, and no ARVs compared to cART for pregnant women.

Conclusions: Although the overall MTCT rate remains relatively high, the real-world effect of prenatal cART+IP + FF in China has exerted the same protective effects in high-income countries. With the extension of prenatal cART for pregnant women with HIV, the MTCT rate of HIV has gradually declined in China. However, the coverage of prenatal cART for pregnant women should be further improved. The effect of only post-exposure prophylaxis for infants was limited.
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http://dx.doi.org/10.1186/s12879-020-05516-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586644PMC
October 2020

Subcutaneous injection of IFN alpha-2b for COVID-19: an observational study.

BMC Infect Dis 2020 Oct 2;20(1):723. Epub 2020 Oct 2.

Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.

Background: The global pandemic of coronavirus disease 2019 (COVID-19) infection is ongoing and associated with high mortality. The aim of this study was to investigate the efficacy and safety of subcutaneous injection of interferon alpha-2b (IFN alpha-2b) combined with lopinavir/ritonavir (LPV/r) in the treatment of COVID-19 infection, compared with that of using LPV/r alone.

Methods: Patients diagnosed with laboratory-confirmed COVID-19 infection in Wuhan Red Cross hospital during the period from January 23, 2020 to March 19, 2020 were included. The length of stay, the time to viral clearance and adverse reactions during hospitalization were compared between patients using oral LPV/r and combined therapy of LPV/r and subcutaneous injection of IFN alpha-2b.

Results: A total of 22 patients were treated with LPV/r alone and 19 with combined therapy with subcutaneous injection of IFN alpha-2b. The average length of hospitalization in the combination group was shorter than that of LPV/r group (16 ± 9.7 vs 23 ± 10.5 days; P = 0.028). Moreover, the days of hospitalization in early intervention group decreased from 25 ± 8.5 days to 10 ± 2.9 days compared with delayed intervention group (P = 0.001). Combined therapy with IFN alpha-2b also significantly reduced the duration of detectable virus in the upper respiratory tract. No patient in each group was transferred to intensive care unit (ICU) or died during the treatment. There was no significant difference in the adverse effect composition between two groups.

Conclusions: Subcutaneous injection of IFN alpha-2b combined with LPV/r shortened the length of hospitalization and accelerated viral clearance in COVID-19 patients, which deserves further investigation in clinical practice.
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http://dx.doi.org/10.1186/s12879-020-05425-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530488PMC
October 2020

Risk factors for surgical site infection after major oral oncological surgery: the experience of a tertiary referral hospital in China.

J Int Med Res 2020 Aug;48(8):300060520944072

Department of Oral Medicine, Beijing Stomatological Hospital & School of Stomatology, Capital Medical University, Beijing, China.

Objective: To identify risk factors associated with surgical site infection (SSI) after major oral oncological surgery.

Methods: This retrospective study reviewed data from patients that underwent major surgery for oral cancer at a tertiary referral hospital in China between January 2005 and July 2016. SSI was diagnosed within 30 days. Demographic, cancer-related, preoperative, perioperative and postoperative data were analysed using descriptive statistics and univariate and multivariate analyses of the risk factors for SSI.

Results: A total of 786 patients were enrolled, of whom 125 had SSI (15.9%), which were all incisional. Independent risk factors for SSI, identified by multivariate analysis, were diabetes mellitus (odds ratio [OR] 2.147, 95% confidence interval [CI] 1.240, 3.642), prior radiotherapy (OR 4.595, 95% CI 1.293, 17.317) and oral-neck communication (OR 2.838, 95% CI 1.263, 7.604); and factors reflecting large extent resections were tracheostomy (OR 2.235, 95% CI 1.435, 3.525), anterolateral thigh flap (OR 1.971, 95% CI 1.103, 3.448) and latissimus dorsi flap (OR 4.178, 95% CI 1.325, 13.189).

Conclusions: Multiple risk factors were associated with SSI after major oral oncological surgery. To minimize SSI risk, surgeons managing oral cancer patients should have a better understanding of the risk factors, including diabetes mellitus, prior radiotherapy, tracheostomy, oral-neck communication and flap reconstruction.
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http://dx.doi.org/10.1177/0300060520944072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463046PMC
August 2020

Identification of anti-tumoral feedback loop between VHLα and hnRNPA2B1 in renal cancer.

Cell Death Dis 2020 08 11;11(8):688. Epub 2020 Aug 11.

Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.

Our previous study identified a novel VHLα isoform which negatively modulated hnRNPA2B1 expression and therefore influenced pyruvate kinase transcript splicing in renal cancer, while the regulation and initiation of alternative translation are largely unknown. Here we unraveled the CUG-mediated translation start of VHLα, which was subjected to the regulation by both eukaryotic initiator factor eIF2A and RNA helicase eIF4A. Unexpectedly, we found hnRNPA2B1 promoted VHLα alternative translation as well via direct interaction with its octadic pentamer region of VHL transcript. The N-terminal of VHLα was indispensable in mediating ubiquitination of hnRNPA2B1 at lysine residues 274 and 305. We further identified aberrant overexpression of c-myc as upstream oncogenic signaling to positively regulate hnRNPA2B1 transcription in renal cancer. Therefore, our data suggested an anti-tumoral feedback loop between VHLα and hnRNPA2B1.
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http://dx.doi.org/10.1038/s41419-020-02861-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443127PMC
August 2020

LINC00973 is involved in cancer immune suppression through positive regulation of Siglec-15 in clear-cell renal cell carcinoma.

Cancer Sci 2020 Oct 31;111(10):3693-3704. Epub 2020 Aug 31.

Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.

The pioneering work from Lieping Chen's laboratory identified Siglec-15 as a novel tumor immune suppressor, while the regulatory mechanisms underlying the broad upregulation of Siglec-15 in human cancers remain obscure. Here we found that long non-coding RNA (lncRNA) LINC00973 was higher in Siglec-15-positive clear-cell renal cell carcinoma (ccRCC), and LINC00973 positively regulated Siglec-15 expression at transcriptional level. This effect was evidently dependent on miR-7109-3p (designated as miR-7109 hereafter), and we provided evidence that Siglec-15 is a direct target of miR-7109. Through sponging miR-7109, LINC00973 functioned as competing endogenous RNA (ceRNA) to control cell surface abundance of Siglec-15, and, consequently, was involved in cancer immune suppression. We further demonstrated that LINC00973 and miR-7109 expression in ccRCC antagonistically influenced immune activation of co-cultured Jurkat cells. Our study highlighted the importance of LINC00973-miR-7109-Siglec-15 in immune evasion in ccRCC, which offers significant opportunity for both therapeutic intervention and diagnostic/prognostic exploitations.
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http://dx.doi.org/10.1111/cas.14611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541001PMC
October 2020

A novel taxane, difluorovinyl-ortataxel, effectively overcomes paclitaxel-resistance in breast cancer cells.

Cancer Lett 2020 10 27;491:36-49. Epub 2020 Jul 27.

Department of Biochemistry, Zhongshan School of Medicine, SUN Yat-sen University, 74 Second Zhongshan Road, Guangzhou, 510080, China. Electronic address:

Paclitaxel (PTX) is widely used to treat breast and ovarian cancers, but innate and acquired resistance often compromises its applications. The objective of this study was to screen new-generation taxanes for their efficiency against both PTX-sensitive and PTX-resistant breast cancer cells. From twelve compounds, difluorovinyl-ortataxel (DFV-OTX) displayed potent cytotoxic activities against both PTX-sensitive and PTX-resistant breast cancer cells. Moreover, DFV-OTX effectively induced tubulin/microtubule polymerization and G2/M phase arrest, leading to apoptosis in both PTX-sensitive and PTX-resistant cancer cells. Molecular docking analysis showed that DFV-OTX possesses unique hydrogen-bonding and van der Waals interactions with β-tubulin. LC-MS/MS analysis also demonstrated that the intracellular drug amount of DFV-OTX was lower than that of PTX, which would be critical to overcome PTX-resistance. Furthermore, DFV-OTX exhibited clear efficacy in the MCF-7R and MDA-MB-231R tumor xenografts in mouse models. Taken together, our results demonstrate that the novel taxane, DFV-OTX, can effectively overcome PTX-resistance in MDA-MB-231R cells, wherein the drug resistance was attributed to ABCB1/ABCG2 upregulation and a distinct mode of action in MCF-7R cells. Our results strongly indicate that DFV-OTX is a promising chemotherapeutic agent for the treatment of PTX-resistant cancers.
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http://dx.doi.org/10.1016/j.canlet.2020.06.025DOI Listing
October 2020

Therapeutic Effect and Mechanisms of the Novel Monosulfactam 0073.

Antimicrob Agents Chemother 2020 09 21;64(10). Epub 2020 Sep 21.

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China

This study aimed to evaluate the antimicrobial activity of the novel monosulfactam 0073 against multidrug-resistant Gram-negative bacteria and and to characterize the mechanisms underlying 0073 activity. The activities of 0073, aztreonam, and the combination with avibactam were assessed by MIC and time-kill assays. The safety of 0073 was evaluated using 3-(4,5-dimethylthizol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and acute toxicity assays. Murine thigh infection and pneumonia models were employed to define efficacy. A penicillin-binding protein (PBP) competition assay and confocal microscopy were conducted. The inhibitory action of 0073 against β-lactamases was evaluated by the half-maximal inhibitory concentration (IC), and resistance development was evaluated via serial passage. The monosulfactam 0073 showed promising antimicrobial activity against , , and isolates producing metallo-β-lactamases (MBLs) and serine β-lactamases. In preliminary experiments, compound 0073 exhibited safety both and In the murine thigh infection model and the pneumonia models in which infection was induced by and , 0073 significantly reduced the bacterial burden. Compound 0073 targeted several PBPs and exerted inhibitory effects against some serine β-lactamases. Finally, 0073 showed a reduced propensity for resistance selection compared with that of aztreonam. The novel monosulfactam 0073 exhibited increased activity against β-lactamase-producing Gram-negative organisms compared with the activity of aztreonam and showed good safety profiles both and The underlying mechanisms may be attributed to the affinity of 0073 for several PBPs and its inhibitory activity against some serine β-lactamases. These data indicate that 0073 represents a potential treatment for infections caused by β-lactamase-producing multidrug-resistant bacteria.
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http://dx.doi.org/10.1128/AAC.00529-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508604PMC
September 2020

Identification of STXBP6-IRF1 positive feedback loop in regulation of PD-L1 in cancer.

Cancer Immunol Immunother 2021 Feb 22;70(2):275-287. Epub 2020 Jul 22.

Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou, 510080, China.

The clinical success of immune checkpoint blockade against diverse human cancers highlights the critical importance of insightful understanding into mechanisms underlying PD-L1 regulation. IFN-γ released by intratumoral lymphocytes regulates PD-L1 expression in tumor cells through JAK-STAT-IRF1 pathway, while the molecular events prime IRF1 to translocate into nucleus are still obscure. Here we identified STXBP6, previously recognized involving in SNARE complex assembly, negatively regulates PD-L1 transcription via retention of IRF1 in cytoplasm. IFN-γ exposure stimulates accumulation of cytosolic IRF1, which eventually saturates STXBP6 and triggers nuclear translocation of IRF1. Nuclear IRF1 in turn inhibits STXBP6 expression and thereby liberates more IRF1 to migrate to nucleus. Therefore, we identified a novel positive feedback loop between STXBP6 and IRF1 in regulation of PD-L1 expression in cancer. Furthermore, we demonstrate STXBP6 overexpression significantly inhibits T cell activation both in vitro and in vivo. These findings offer new insight into the complexity of PD-L1 expression in cancer and suggest a valuable measure to predict the response to PD-1/PD-L1-based immunotherapy.
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http://dx.doi.org/10.1007/s00262-020-02678-6DOI Listing
February 2021

Prolonged intermittent fever and massive splenomegaly in a miner working in the tropical jungle, China.

PLoS Negl Trop Dis 2020 07 9;14(7):e0008278. Epub 2020 Jul 9.

Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.

Prolonged fever is a particular challenge. A 47-year-old man with 5-year intermittent fever and remarkable splenomegaly was diagnosed as chronic melioidosis after splenectomy. The case would help clinicians to raise awareness and include chronic melioidosis in the differential diagnosis for patients with the travel history in melioidosis endemic regions.
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http://dx.doi.org/10.1371/journal.pntd.0008278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347091PMC
July 2020

Retrospective analysis of 1,641 cases of classic fever of unknown origin.

Ann Transl Med 2020 Jun;8(11):690

Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.

Background: Fever of unknown origin (FUO) is commonly defined as fever higher than 38.3 °C on several occasions during at least 3 weeks with uncertain diagnosis after a number of obligatory investigations. It is a special type of fever and a common disease in internal medicine. However, due to its complex etiology, lack of characteristic clinical manifestations, and insufficient laboratory examination indicators, it often baffles clinicians in diagnosis. We herein present a study of the etiological factors and clinical features of classic fever of unknown origin (FUO) to provide help for related clinical diagnosis and treatment.

Methods: A total of 1,641 cases of patients with classic FUO hospitalized in West China Hospital of Sichuan University between January 1, 2011 and December 31, 2017, were collected, and the etiological factors of classic FUO were analyzed. A special effort was made to explore and screen the laboratory indicators related to infectious diseases, and the above data were compared with the clinical features of tuberculosis and lymphoma, which are difficult to diagnose.

Results: Among the 1,641 patients, 1,504 were finally diagnosed through various types of examination or diagnostic methods, and the diagnosis rate was 91.65%. Among all the causes of the 1,641 cases of FUO, 48.69% [799] were infectious diseases, of which tuberculosis was the most common, accounting for 19.50% [320]. Connective tissue diseases were responsible for 19.26% [316] of cases, of which adult-onset Still's disease (AOSD) was the most common, comprising 89 (5.42%) of the cases; 16.94% [278] were neoplastic diseases, and lymphoma (143, 8.71%) cases, was the most common malignant tumor; 6.76% [111] were other diseases; and in 8.35% [137] of cases, the cause was unclear. Through comparative analysis of tuberculosis and lymphoma, no significant differences were found between the symptoms, signs, and non-specific routine examination results of the two diseases. The diagnosis of these diseases was more dependent on tuberculosis-related examinations and pathological examinations.

Conclusions: Infectious diseases are the principal cause of classic FUO, in which tuberculosis accounts for a large proportion. Non-infectious diseases that cause FUO are mainly connective tissue diseases and malignant tumors. Of the various causes of classic FUO, tuberculosis and lymphoma are relatively difficult to diagnose. In most cases, the causes of classic FUO can be ascertained.
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http://dx.doi.org/10.21037/atm-20-3875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327343PMC
June 2020

MIAT inhibits proliferation of cervical cancer cells through regulating miR-150-5p.

Cancer Cell Int 2020 15;20:242. Epub 2020 Jun 15.

Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.

Background: To characterize the MIAT expression in cervical cancer and elucidate its mechanistic involvement in the tumor biology of this disease.

Methods: The relative expression of MIAT and miR-150 was determined by real-time PCR. Cell proliferation was measured by the CCK-8 and clonogenic assay. The anchorage-independent growth was evaluated by soft agar assay. The in vivo tumor progression was assayed with xenograft mice model. The regulatory effect of miR-150 on MIAT was interrogated by luciferase reporter assay. The endogenous CNKD1B protein was detected by western blotting.

Results: The low expression of MIAT was characterized in cervical cancer, which associated with relatively poor prognosis. Ectopic expression of MIAT inhibited malignant growth of cervical cancer both in vitro and in vivo. Mechanistically, MIAT regulated CDKN1B expression via competition with miR-150, and miR-150-inhibition directly suppressed cervical cancer cell growth.

Conclusions: Our study characterized the anti-tumor property of MIAT in cervical cancer and elucidated its competitively regulation of CDKN1B with miR-150. Our data highlighted the critical role of MIAT-miR-150-CDKN1B signaling axis in cervical cancer.
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http://dx.doi.org/10.1186/s12935-020-01338-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296772PMC
June 2020

Allele-aware chromosome-level genome assembly and efficient transgene-free genome editing for the autotetraploid cultivated alfalfa.

Nat Commun 2020 05 19;11(1):2494. Epub 2020 May 19.

School of Ecology and Environment, Northwestern Polytechnical University, 710072, Xi'an, China.

Artificially improving traits of cultivated alfalfa (Medicago sativa L.), one of the most important forage crops, is challenging due to the lack of a reference genome and an efficient genome editing protocol, which mainly result from its autotetraploidy and self-incompatibility. Here, we generate an allele-aware chromosome-level genome assembly for the cultivated alfalfa consisting of 32 allelic chromosomes by integrating high-fidelity single-molecule sequencing and Hi-C data. We further establish an efficient CRISPR/Cas9-based genome editing protocol on the basis of this genome assembly and precisely introduce tetra-allelic mutations into null mutants that display obvious phenotype changes. The mutated alleles and phenotypes of null mutants can be stably inherited in generations in a transgene-free manner by cross pollination, which may help in bypassing the debate about transgenic plants. The presented genome and CRISPR/Cas9-based transgene-free genome editing protocol provide key foundations for accelerating research and molecular breeding of this important forage crop.
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http://dx.doi.org/10.1038/s41467-020-16338-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237683PMC
May 2020