Publications by authors named "Lan Huang"

659 Publications

Echocardiographic Right Ventricular Outflow Track Notch Formation and the Incidence of Acute Mountain Sickness.

High Alt Med Biol 2021 Jun 21. Epub 2021 Jun 21.

Institute of Cardiovascular Diseases of PLA, The Second Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, China.

Yuan, Fangzhengyuan, Zhexue Qin, Chuan Liu, Shiyong Yu, Jie Yang, Jun Jin, Shizhu Bian, Xubin Gao, Jihang Zhang, Chen Zhang, Mingdong Hu, Jingbin Ke, Yuanqi Yang, Jingdu Tian, Chunyan He, Wenzhu Gu, Chun Li, Rongsheng Rao, and Lan Huang. Echocardiographic right ventricular outflow track notch formation and the incidence of acute mountain sickness. 00:000-000, 2021. High-altitude exposure causes acute mountain sickness (AMS) and increases pulmonary arterial pressure (PAP). The notching of echocardiographic right ventricular outflow tract flow velocity envelope (right ventricular outflow tract [RVOT] notching), is related to increased PAP. We speculate that acute high-altitude exposure may trigger RVOT notching, which may be associated with AMS. All 130 subjects, ascended to 4,100 m from low altitude by bus within 7 days, underwent physiological and echocardiographic testing. The subjects with a total score of 3 or above and in the presence of a headache were diagnosed with AMS according to Lake Louise criteria. After high-altitude exposure, the incidence of RVOT notching and AMS was 20% and 28.5%, respectively. The subjects with AMS had a higher incidence (37.8%) of RVOT notching than those without AMS (12.9%). Multivariate logistic regression analysis showed that RVOT notching was associated with systolic pulmonary artery pressure (SPAP) (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.05-1.17;  < 0.001) and the occurrence of AMS (OR, 5.48; 95% CI, 1.96-15.35;  = 0.001). Although linear regression analysis showed a weak correlation between SPAP and Lake Louise AMS score in the overall population ( = 0.20,  = 0.020), this correlation was more pronounced in the subpopulation with RVOT notching ( = 0.44,  = 0.023) and SPAP was not related to Lake Louise AMS score in the subpopulation without RVOT notching ( = 0.03,  = 0.698). Among AMS symptoms, the incidence of headache and fatigue were higher in subjects with RVOT notching than those in subjects without RVOT notching. We first observe that high-altitude exposure triggers RVOT notching formation, which is associated with AMS occurrence. Clinical Trial Registration No: ChiCTR-RCS-12002232.
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http://dx.doi.org/10.1089/ham.2020.0196DOI Listing
June 2021

Structural basis for CSPG4 as a receptor for TcdB and a therapeutic target in Clostridioides difficile infection.

Nat Commun 2021 06 18;12(1):3748. Epub 2021 Jun 18.

Department of Physiology and Biophysics, University of California, Irvine, CA, USA.

C. difficile is a major cause of antibiotic-associated gastrointestinal infections. Two C. difficile exotoxins (TcdA and TcdB) are major virulence factors associated with these infections, and chondroitin sulfate proteoglycan 4 (CSPG4) is a potential receptor for TcdB, but its pathophysiological relevance and the molecular details that govern recognition remain unknown. Here, we determine the cryo-EM structure of a TcdB-CSPG4 complex, revealing a unique binding site spatially composed of multiple discontinuous regions across TcdB. Mutations that selectively disrupt CSPG4 binding reduce TcdB toxicity in mice, while CSPG4-knockout mice show reduced damage to colonic tissues during C. difficile infections. We further show that bezlotoxumab, the only FDA approved anti-TcdB antibody, blocks CSPG4 binding via an allosteric mechanism, but it displays low neutralizing potency on many TcdB variants from epidemic hypervirulent strains due to sequence variations in its epitopes. In contrast, a CSPG4-mimicking decoy neutralizes major TcdB variants, suggesting a strategy to develop broad-spectrum therapeutics against TcdB.
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http://dx.doi.org/10.1038/s41467-021-23878-3DOI Listing
June 2021

New frontiers against sorafenib resistance in renal cell carcinoma: From molecular mechanisms to predictive biomarkers.

Pharmacol Res 2021 Jun 15;170:105732. Epub 2021 Jun 15.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, PR China. Electronic address:

Renal cell carcinoma (RCC) is a highly vascularized tumor and prone to distant metastasis. Sorafenib is the first targeted multikinase inhibitor and first-line chemical drug approved for RCC therapy. In fact, only a small number of RCC patients benefit significantly from sorafenib treatment, while the growing prevalence of sorafenib resistance has become a major obstacle for drug therapy effectivity of sorafenib. The molecular mechanisms of sorafenib resistance in RCC are not completely understood by now. Herein, we comprehensively summarize the underlying mechanisms of sorafenib resistance and molecular biomarkers for predicting sorafenib responsiveness. Moreover, we outline strategies suitable for overcoming sorafenib resistance and prospect potential approaches for identifying biomarkers associated with sorafenib resistance in RCC, which contributes to guide individualized and precision drug therapy.
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http://dx.doi.org/10.1016/j.phrs.2021.105732DOI Listing
June 2021

Cancer-associated fibroblasts induce monocytic myeloid-derived suppressor cell generation via IL-6/exosomal miR-21-activated STAT3 signaling to promote cisplatin resistance in esophageal squamous cell carcinoma.

Cancer Lett 2021 Jun 15;518:35-48. Epub 2021 Jun 15.

Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou, 450052, Henan, China; School of Life Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China; Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, 450052, China. Electronic address:

Drug resistance remains the major obstacle limiting the effectiveness of chemotherapy for esophageal squamous cell carcinoma (ESCC)[1]. However, how stromal cells cooperate with immune cells to contribute to drug resistance is not yet fully understood. In this study, we observed that monocytic myeloid-derived suppressor cells (M-MDSCs) were correlated with cisplatin resistance in patients with ESCC. Furthermore, CAFs promoted differentiation of monocytes into M-MDSCs phenotypically and functionally in vitro. Mechanically, both interleukin (IL)-6 and exosome-packed microRNA-21 (miR-21) secreted by CAFs synergistically promoted the generation of M-MDSCs via activating the signal transducing activator of transcription 3 (STAT3) by IL-6 in an autocrine manner. Combined blocking of IL-6 receptor and inhibition of miR-21 significantly reversed CAF-mediated M-MDSC generation. Notably, the effects of CAFs on M-MDSC induction were abolished by inhibiting STAT3 signaling. Functionally, CAF-induced M-MDSCs promoted drug resistance of tumor cells upon cisplatin treatment. Clinically, ESCC patients with high infiltration of CAFs and CD11b myeloid cells had unfavorable predicted overall survival both in our cohort and in TCGA data. Taken together, our study reveals a paracrine and autocrine of IL-6 caused by CAFs co-activate STAT3 signaling, promoting the generation of M-MDSCs, and highlights the important role of CAFs in cooperation with M-MDSCs in promoting drug resistance, thus providing potential opportunities for reversing drug resistance through inhibition of STAT3 signaling.
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http://dx.doi.org/10.1016/j.canlet.2021.06.009DOI Listing
June 2021

m6AGE: A Predictor for N6-Methyladenosine Sites Identification Utilizing Sequence Characteristics and Graph Embedding-Based Geometrical Information.

Front Genet 2021 27;12:670852. Epub 2021 May 27.

Key Laboratory of Symbol Computation and Knowledge Engineering of Ministry of Education, and College of Computer Science and Technology, Jilin University, Changchun, China.

N-methyladenosine (mA) is one of the most prevalent RNA post-transcriptional modifications and is involved in various vital biological processes such as mRNA splicing, exporting, stability, and so on. Identifying mA sites contributes to understanding the functional mechanism and biological significance of mA. The existing biological experimental methods for identifying mA sites are time-consuming and costly. Thus, developing a high confidence computational method is significant to explore mA intrinsic characters. In this study, we propose a predictor called m6AGE which utilizes sequence-derived and graph embedding features. To the best of our knowledge, our predictor is the first to combine sequence-derived features and graph embeddings for mA site prediction. Comparison results show that our proposed predictor achieved the best performance compared with other predictors on four public datasets across three species. On the dataset, our predictor outperformed 1.34% (accuracy), 0.0227 (Matthew's correlation coefficient), 5.63% (specificity), and 0.0081 (AUC) than comparing predictors, which indicates that m6AGE is a useful tool for mA site prediction. The source code of m6AGE is available at https://github.com/bokunoBike/m6AGE.
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http://dx.doi.org/10.3389/fgene.2021.670852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191635PMC
May 2021

NK and NKT cells have distinct properties and functions in cancer.

Oncogene 2021 Jun 12. Epub 2021 Jun 12.

Division of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, USA.

Natural killer (NK) and natural killer T (NKT) cells are two important cell subsets of the innate immune system. NK and NKT cells share many phenotypes and functions for anti-tumor immunity; however, the dynamic changes in phenotypes and functional interactions within the tumor microenvironment during tumor development and progression are unknown. Here we report that NK and NKT cells have distinct properties, metabolic profiles, and functions during tumor development. Using the mouse E0771 breast cancer and B16 melanoma models, we found that both NK and NKT cells are dynamically involved in the immune responses to cancer but have distinct distributions and phenotypic profiles in tumor sites and other peripheral organs during the course of tumor development and progression. In the early stages of tumor development, both NK and NKT cells exhibit effector properties. In the later cancer stages, NK and NKT cells have impaired cytotoxic capacities and dysfunctional states. NK cells become senescent cells, while NKT cells, other than invariant NKT (iNKT) cells, are exhausted in the advanced cancers. In contrast, iNKT cells develop increases in activation and effector function within the breast tumor microenvironment. In addition, senescent NK cells have heightened glucose and lipid metabolism, but exhausted NKT cells display unbalanced metabolism in tumor microenvironments of both breast cancer and melanoma tumor models. These studies provide a better understanding of the dynamic and distinct functional roles of NK and NKT cells in anti-tumor immunity, which may facilitate the development of novel immunotherapies targeting NK and NKT cells for cancer treatment.
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http://dx.doi.org/10.1038/s41388-021-01880-9DOI Listing
June 2021

Bayesian approaches to benefit-risk assessment for diagnostic tests.

J Biopharm Stat 2021 Jun 6:1-18. Epub 2021 Jun 6.

Food and Drug Administration, Center for Device and Radiological Health, Silver Spring, Maryland, USA.

Benefit-risk assessment plays an important role in the evaluation of medical devices. Unlike the therapeutic devices, the diagnostic tests usually affect patient life indirectly since subsequent therapeutic treatment interventions (such as proper treatment in time, further examination or test, no action, etc.) will depend on correct diagnosis and monitoring of the disease status. A benefit-risk score using statistical models by integrating the information from benefit (true positive and true negative) and risk (false positive and false negative) for diagnostic tests with binary outcomes (i.e., positive and negative) will help evaluation of the utility and the uncertainty of a particular diagnostic device. In this paper, we develop two types of Bayesian models with conjugate priors for constructing the benefit-risk (BR) measures with corresponding credible intervals, one based on a Multinomial model with Dirichlet prior, and the other based on independent Binomial models with independent Beta priors. We then propose a Bayesian power prior model to incorporate the historical data or the real-world data (RWD). Both the fixed and random power prior parameters are considered for Bayesian borrowing. We evaluate the performance of the methods by simulations and illustrate their implementation using a real example.
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http://dx.doi.org/10.1080/10543406.2021.1931272DOI Listing
June 2021

Improved plant cytosine base editors with high editing activity, purity, and specificity.

Plant Biotechnol J 2021 May 27. Epub 2021 May 27.

Department of Biotechnology, School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, China.

Cytosine base editors (CBEs) are great additions to the expanding genome editing toolbox. To improve C-to-T base editing in plants, we first compared seven cytidine deaminases in the BE3-like configuration in rice. We found A3A/Y130F-CBE_V01 resulted in the highest C-to-T base editing efficiency in both rice and Arabidopsis. Furthermore, we demonstrated this A3A/Y130F cytidine deaminase could be used to improve iSpyMacCas9-mediated C-to-T base editing at A-rich PAMs. To showcase its applications, we first applied A3A/Y130F-CBE_V01 for multiplexed editing to generate microRNA-resistant mRNA transcripts as well as pre-mature stop codons in multiple seed trait genes. In addition, we harnessed A3A/Y130F-CBE_V01 for efficient artificial evolution of novel ALS and EPSPS alleles which conferred herbicide resistance in rice. To further improve C-to-T base editing, multiple CBE_V02, CBE_V03 and CBE_V04 systems were developed and tested in rice protoplasts. The CBE_V04 systems were found to have improved editing activity and purity with focal recruitment of more uracil DNA glycosylase inhibitors (UGIs) by the engineered single guide RNA 2.0 scaffold. Finally, we used whole-genome sequencing (WGS) to compare six CBE_V01 systems and four CBE_V04 systems for genome-wide off-target effects in rice. Different levels of cytidine deaminase-dependent and sgRNA-independent off-target effects were indeed revealed by WGS among edited lines by these CBE systems. We also investigated genome-wide sgRNA-dependent off-target effects by different CBEs in rice. This comprehensive study compared 21 different CBE systems, and benchmarked PmCDA1-CBE_V04 and A3A/Y130F-CBE_V04 as next-generation plant CBEs with high editing efficiency, purity, and specificity.
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http://dx.doi.org/10.1111/pbi.13635DOI Listing
May 2021

Overloading stress-induced progressive degeneration and self-repair in condylar cartilage.

Ann N Y Acad Sci 2021 May 7. Epub 2021 May 7.

Department of Orthodontics, Stomatological Hospital of Chongqing Medical University, Chongqing, China.

Overloading stress-induced condylar cartilage degeneration acts as the main pathologic change in temporomandibular joint osteoarthritis (TMJ-OA). However, the progression of degeneration and the ability for self-repair remain poorly understood. Here, we explored the progression of cartilage degeneration by dividing pathological stages using a steady mouth-opening mouse model. Then, we observed changes of cartilage by removing the loading at different stages to test the potential self-repair after degeneration induced. Three-dimensional confocal microscopy combined with histology and micro-CT scanning was applied to examine TMJ at different stages of degeneration before and after self-repair. We found the cartilage underwent progressive and thorough degeneration as the overloading stress developed. During the initial adaptation stage, robust proliferation of posteromedial cartilage began at the area of direct loading. Subsequently, widespread chondrocyte apoptosis was found, followed by new chondrocyte proliferation in aggregates with matrix degradation and subchondral bone catabolism. Finally, with cartilage surface damage, the degeneration reached a point where the lesion could not be reversed by self-repair. While the cartilage nearly returned to normal when the interference was removed within 5 days. These results suggested overloading force induces a pathological process of successive degeneration in TMJ cartilage, which can be reversed by self-repair at early stages.
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http://dx.doi.org/10.1111/nyas.14606DOI Listing
May 2021

RIFS2D: A two-dimensional version of a randomly restarted incremental feature selection algorithm with an application for detecting low-ranked biomarkers.

Comput Biol Med 2021 Jun 17;133:104405. Epub 2021 Apr 17.

College of Computer Science and Technology, Jilin University, Changchun, Jilin, 130012, China; Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education, Jilin University, Changchun, Jilin, 130012, China. Electronic address:

The era of big data introduces both opportunities and challenges for biomedical researchers. One of the inherent difficulties in the biomedical research field is to recruit large cohorts of samples, while high-throughput biotechnologies may produce thousands or even millions of features for each sample. Researchers tend to evaluate the individual correlation of each feature with the class label and use the incremental feature selection (IFS) strategy to select the top-ranked features with the best prediction performance. Recent experimental data showed that a subset of continuously ranked features randomly restarted from a low-ranked feature (an RIFS block) may outperform the subset of top-ranked features. This study proposed a feature selection Algorithm RIFS2D by integrating multiple RIFS blocks. A comprehensive comparative experiment was conducted with the IFS, RIFS and existing feature selection algorithms and demonstrated that a subset of low-ranked features may also achieve promising prediction performance. This study suggested that a prediction model with promising performance may be trained by low-ranked features, even when top-ranked features did not achieve satisfying prediction performance. Further comparative experiments were conducted between RIFS2D and t-tests for the detection of early-stage breast cancer. The data showed that the RIFS2D-recommended features achieved better prediction accuracy and were targeted by more drugs than the t-test top-ranked features.
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http://dx.doi.org/10.1016/j.compbiomed.2021.104405DOI Listing
June 2021

Enabling Photoactivated Cross-Linking Mass Spectrometric Analysis of Protein Complexes by Novel MS-Cleavable Cross-Linkers.

Mol Cell Proteomics 2021 Apr 27;20:100084. Epub 2021 Apr 27.

Department of Physiology and Biophysics, University of California, Irvine, California, USA. Electronic address:

Cross-linking mass spectrometry (XL-MS) is a powerful tool for studying protein-protein interactions and elucidating architectures of protein complexes. While residue-specific XL-MS studies have been very successful, accessibility of interaction regions nontargetable by specific chemistries remain difficult. Photochemistry has shown great potential in capturing those regions because of nonspecific reactivity, but low yields and high complexities of photocross-linked products have hindered their identification, limiting current studies predominantly to single proteins. Here, we describe the development of three novel MS-cleavable heterobifunctional cross-linkers, namely SDASO (Succinimidyl diazirine sulfoxide), to enable fast and accurate identification of photocross-linked peptides by MS. The MS-based workflow allowed SDASO XL-MS analysis of the yeast 26S proteasome, demonstrating the feasibility of photocross-linking of large protein complexes for the first time. Comparative analyses have revealed that SDASO cross-linking is robust and captures interactions complementary to residue-specific reagents, providing the foundation for future applications of photocross-linking in complex XL-MS studies.
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http://dx.doi.org/10.1016/j.mcpro.2021.100084DOI Listing
April 2021

Plant electrical signals: A multidisciplinary challenge.

J Plant Physiol 2021 Jun 15;261:153418. Epub 2021 Apr 15.

College of Information and Electrical Engineering, China Agricultural University, Beijing, 100083, China; Key Laboratory of Agricultural Information Acquisition Technology, Ministry of Agriculture, Beijing, 100083, China. Electronic address:

Plant electrical signals, an early event in the plant-stimulus interaction, rapidly transmit information generated by the stimulus to other organs, and even the whole plant, to promote the corresponding response and trigger a regulatory cascade. In recent years, many promising state-of-the-art technologies applicable to study plant electrophysiology have emerged. Research focused on expression of genes associated with electrical signals has also proliferated. We propose that it is appropriate for plant electrical signals to be considered in the form of a "plant electrophysiological phenotype". This review synthesizes research on plant electrical signals from a novel, interdisciplinary perspective, which is needed to improve the efficient aggregation and use of plant electrical signal data and to expedite interpretation of plant electrical signals.
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http://dx.doi.org/10.1016/j.jplph.2021.153418DOI Listing
June 2021

Recurrent pheochromocytoma with catecholamine cardiomyopathy and left ventricular thrombus: a case report.

J Int Med Res 2021 Apr;49(4):3000605211007723

Department of Cardiology, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China.

Pheochromocytoma is a rare and usually benign tumor of the adrenal glands. We report a case of a 40-year-old woman with recurrent pheochromocytoma and catecholamine cardiomyopathy. She had no history of other types of tumors or connective tissue disease. She had already undergone surgery twice to remove the pheochromocytoma, which had now recurred for the second time. A thrombus in the left ventricle was also noted upon imaging examination, which dissipated after anticoagulation therapy using dabigatran, allowing the patient to opt for an elective third surgery. This paper describes the clinical outcome of using the anticoagulant dabigatran to treat left ventricular thrombosis in this rare case of recurrent pheochromocytoma, and thus further contributing to the knowledge of the clinical management of this rare and complicated disease.
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http://dx.doi.org/10.1177/03000605211007723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074535PMC
April 2021

Diagnosis of Interventional Transvaginal Maternal Diseases Based on Color Doppler Ultrasound.

J Healthc Eng 2021 1;2021:5517785. Epub 2021 Apr 1.

Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.

In recent years, with the development of color Doppler ultrasound technology in obstetrics, this noninvasive, direct, convenient, and sensitive inspection method has become one of the best methods to observe the fetal circulation in the uterus. This paper discusses the clinical value of using transvaginal color Doppler ultrasound in the differential diagnosis of ovarian corpus luteum disease and ectopic pregnancy disease. This paper selects 100 cases of ectopic pregnancy and 100 cases of pregnant corpus luteum as the experimental research objects. Clinical analysis of transvaginal color Doppler ultrasonography was performed on all patients. In the process of measuring the patient's ectopic pregnancy, the size of the patient's adnexal mass is mainly measured, and the blood flow spectrum is measured. The clinical choice of transvaginal color Doppler ultrasound method to distinguish ectopic pregnancy disease and corpus luteum pregnancy disease can play a significant value. It can be effectively diagnosed according to the type of disease, then effective methods can be studied for clinical treatment, the quality of life of patients with the two diseases can be significantly improved, and the clinical application value of color Doppler ultrasound can be improved.
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http://dx.doi.org/10.1155/2021/5517785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032514PMC
April 2021

The Association Between Notching of the Right Ventricular Outflow Tract Flow Velocity Doppler Envelope and Impaired Right Ventricular Function After Acute High-Altitude Exposure.

Front Physiol 2021 1;12:639761. Epub 2021 Apr 1.

Institute of Cardiovascular Diseases of PLA, The Second Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, China.

Introduction: Pulmonary artery pressure (PAP) is increased and right ventricular (RV) function is well preserved in healthy subjects upon exposure to high altitude (HA). An increase in PAP may trigger notching of the right ventricular outflow tract Doppler flow velocity envelope (RVOT notch), which is associated with impaired RV function in patients with pulmonary hypertension. However, whether HA exposure can induce RVOT notch formation and the subsequent impact on cardiac function in healthy subjects remains unclear.

Methods: A total of 99 subjects (69 males and 30 females) with a median age of 25 years were enrolled in this study; they traveled from 500 to 4100 m by bus over a 2-day period. All subjects underwent a comprehensive physiological and echocardiographic examination 1 day before ascension at low altitude and 15 ± 3 h after arrival at HA. The RVOT notch was determined by the presence of a notched shape in the RVOT Doppler flow velocity envelope. The systolic PAP (SPAP) was calculated as Bernoulli equation SPAP = 4 × (maximum tricuspid regurgitation velocity)+5 and mean PAP (mPAP) = 0.61 × SPAP+2. Cardiac output was calculated as stroke volume × heart rate. Pulmonary capillary wedge pressure (PCWP) was calculated as 1.9+1.24 × mitral E/e'. Pulmonary vascular resistance (PVR) was calculated as (mPAP-PCWP)/CO.

Results: After HA exposure, 20 (20.2%) subjects had an RVOT notch [notch (+)], and 79 (79.8%) subjects did not have an RVOT notch [notch (-)]. In the multivariate logistic regression analysis, the SPAP, right ventricular global longitude strain (RV GLS), and tricuspid E/A were independently associated with the RVOT notch. The SPAP, mPAP, PVR, standard deviations of the times to peak systolic strain in the four mid-basal RV segments (RVSD4), peak velocity of the isovolumic contraction period (ICV), and the peak systolic velocity (s') at the mitral/tricuspid annulus were increased in all subjects. Conversely, the pulse oxygen saturation (SpO), RV GLS, and tricuspid annulus plane systolic excursion (TAPSE)/SPAP were decreased. However, the increases of SPAP, mPAP, PVR, and RVSD4 and the decreases of SpO, RV GLS, and TAPSE/SPAP were more pronounced in the notch (+) group than in the notch (-) group. Additionally, increased tricuspid ICV and mitral/tricuspid s' were found only in the notch (-) group.

Conclusion: HA exposure-induced RVOT notch formation is associated with impaired RV function, including no increase in the tricuspid ICV or s', reduction of RV deformation, deterioration in RV-pulmonary artery coupling, and RV intraventricular synchrony.
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http://dx.doi.org/10.3389/fphys.2021.639761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047424PMC
April 2021

Sex-Dependent Association Between Early Morning Ambulatory Blood Pressure Variations and Acute Mountain Sickness.

Front Physiol 2021 18;12:649211. Epub 2021 Mar 18.

Institute of Cardiovascular Diseases of PLA, The Second Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, China.

Background: Acute high altitude (HA) exposure elicits blood pressure (BP) responses in most subjects, and some of them suffer from acute mountain sickness (AMS). However, a 24-h ambulatory BP (ABP) change and the correlation with the occurrence of AMS in different sexes are still unclear.

Objectives: This prospective study aimed to investigate HA induced BP responses in males and females and the relationship between AMS and 24-h ABP.

Methods: Forty-six subjects were matched according to demographic parameters by propensity score matching with a ratio of 1:1. All the subjects were monitored by a 24-h ABP device; the measurement was one period of 24 h BP. 2018 Lake Louise questionnaire was used to evaluate AMS.

Results: Both the incidence of AMS (14 [60.9%] vs. 5 [21.7%], = 0.007) and headache (18 [78.3%] vs. 8 [34.8%], = 0.003) were higher in females than in males. All subjects showed an elevated BP in the early morning [morning systolic BP (SBP), 114.72 ± 13.57 vs. 120.67 ± 11.10, = 0.013]. The elevation of morning SBP variation was more significant in females than in males (11.95 ± 13.19 vs. -0.05 ± 14.49, = 0.005), and a higher morning BP surge increase (4.69 ± 18.09 vs. -9.66 ± 16.96, = 0.005) was observed after acute HA exposure in the female group. The increase of morning SBP was associated with AMS occurrence ( = 0.662, < 0.001) and AMS score ( = 0.664, = 0.001). Among the AMS symptoms, we further revealed that the incidence ( = 0.786, < 0.001) and the severity of headache ( = 0.864, < 0.001) are closely correlated to morning SBP.

Conclusions: Our study demonstrates that females are more likely to suffer from AMS than males. AMS is closely associated with elevated BP in the early morning period, which may be correlated to higher headache incidence in subjects with higher morning SBP.
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http://dx.doi.org/10.3389/fphys.2021.649211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012890PMC
March 2021

A Novel Position-Specific Encoding Algorithm (SeqPose) of Nucleotide Sequences and Its Application for Detecting Enhancers.

Int J Mol Sci 2021 Mar 17;22(6). Epub 2021 Mar 17.

Health Informatics Lab, College of Computer Science and Technology, Key Laboratory of Symbolic Computation and Knowledge Engineering of the Ministry of Education, Jilin University, Changchun 130012, China.

Enhancers are short genomic regions exerting tissue-specific regulatory roles, usually for remote coding regions. Enhancers are observed in both prokaryotic and eukaryotic genomes, and their detections facilitate a better understanding of the transcriptional regulation mechanism. The accurate detection and transcriptional regulation strength evaluation of the enhancers remain a major bioinformatics challenge. Most of the current studies utilized the statistical features of short fixed-length nucleotide sequences. This study introduces the location information of each k-mer (SeqPose) into the encoding strategy of a DNA sequence and employs the attention mechanism in the two-layer bi-directional long-short term memory (BD-LSTM) model (spEnhancer) for the enhancer detection problem. The first layer of the delivered classifier discriminates between enhancers and non-enhancers, and the second layer evaluates the transcriptional regulation strength of the detected enhancer. The SeqPose-encoded features are selected by the Chi-squared test, and 45 positions are removed from further analysis. The existing studies may focus on selecting the statistical DNA sequence descriptors with large contributions to the prediction models. This study does not utilize these statistical DNA sequence descriptors. Then the word vector of the SeqPose-encoded features is obtained by using the word embedding layer. This study hypothesizes that different word vector features may contribute differently to the enhancer detection model, and assigns different weights to these word vectors through the attention mechanism in the BD-LSTM model. The previous study generously provided the training and independent test datasets, and the proposed spEnhancer is compared with the three existing state-of-the-art studies using the same experimental procedure. The leave-one-out validation data on the training dataset shows that the proposed spEnhancer achieves similar detection performances as the three existing studies. While spEnhancer achieves the best overall performance metric MCC for both of the two binary classification problems on the independent test dataset. The experimental data shows that the strategy of removing redundant positions (SeqPose) may help improve the DNA sequence-based prediction models. spEnhancer may serve well as a complementary model to the existing studies, especially for the novel query enhancers that are not included in the training dataset.
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http://dx.doi.org/10.3390/ijms22063079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002641PMC
March 2021

Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy.

Sci Transl Med 2021 Mar;13(587)

Division of Infectious Diseases, Allergy and Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA.

The functional state of T cells is a key determinant for effective antitumor immunity and immunotherapy. Cellular metabolism, including lipid metabolism, controls T cell differentiation, survival, and effector functions. Here, we report that development of T cell senescence driven by both malignant tumor cells and regulatory T cells is a general feature in cancers. Senescent T cells have active glucose metabolism but exhibit unbalanced lipid metabolism. This unbalanced lipid metabolism results in changes of expression of lipid metabolic enzymes, which, in turn, alters lipid species and accumulation of lipid droplets in T cells. Tumor cells and T cells drove elevated expression of group IVA phospholipase A, which, in turn, was responsible for the altered lipid metabolism and senescence induction observed in T cells. Mitogen-activated protein kinase signaling and signal transducer and activator of transcription signaling coordinately control lipid metabolism and group IVA phospholipase A activity in responder T cells during T cell senescence. Inhibition of group IVA phospholipase A reprogrammed effector T cell lipid metabolism, prevented T cell senescence in vitro, and enhanced antitumor immunity and immunotherapy efficacy in mouse models of melanoma and breast cancer in vivo. Together, these findings identify mechanistic links between T cell senescence and regulation of lipid metabolism in the tumor microenvironment and provide a new target for tumor immunotherapy.
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http://dx.doi.org/10.1126/scitranslmed.aaz6314DOI Listing
March 2021

Expanding the scope of plant genome engineering with Cas12a orthologs and highly multiplexable editing systems.

Nat Commun 2021 03 29;12(1):1944. Epub 2021 Mar 29.

Department of Plant Science and Landscape Architecture, University of Maryland, College Park, MD, USA.

CRISPR-Cas12a is a promising genome editing system for targeting AT-rich genomic regions. Comprehensive genome engineering requires simultaneous targeting of multiple genes at defined locations. Here, to expand the targeting scope of Cas12a, we screen nine Cas12a orthologs that have not been demonstrated in plants, and identify six, ErCas12a, Lb5Cas12a, BsCas12a, Mb2Cas12a, TsCas12a and MbCas12a, that possess high editing activity in rice. Among them, Mb2Cas12a stands out with high editing efficiency and tolerance to low temperature. An engineered Mb2Cas12a-RVRR variant enables editing with more relaxed PAM requirements in rice, yielding two times higher genome coverage than the wild type SpCas9. To enable large-scale genome engineering, we compare 12 multiplexed Cas12a systems and identify a potent system that exhibits nearly 100% biallelic editing efficiency with the ability to target as many as 16 sites in rice. This is the highest level of multiplex edits in plants to date using Cas12a. Two compact single transcript unit CRISPR-Cas12a interference systems are also developed for multi-gene repression in rice and Arabidopsis. This study greatly expands the targeting scope of Cas12a for crop genome engineering.
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http://dx.doi.org/10.1038/s41467-021-22330-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007695PMC
March 2021

Referential Values of Testicular Volume Measured by Ultrasonography in Normal Children and Adolescents: Z-Score Establishment.

Front Pediatr 2021 11;9:648711. Epub 2021 Mar 11.

Department of Ultrasonography, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.

To establish Z-score regression equation derived from age for testicular volume measured by ultrasonography in normal boys aged 0 to 18 years old. The length (L), width (W), and height (H) of 3,328 testicles from 1,664 Chinese boys were measured by ultrasonography. Lambert's formula: L × W × H × 0.71 was used to calculate testicular volume. Z-score regression equation derived from age was established by regression analysis of predicted values of testicular volume and standard deviations. There was no significant difference between left and right testicular volumes. Testicular volume was positively correlated with age, and logarithmic transformation of testicular volume can show a fine curve fit with age. To establish Z-score regression equation derived from age, the predicted values of testicular volume used cubic regression equations, and the standard deviation used square regression equations. The Z-score regression equation derived from age was calculated by the formula: z = [lg (L × W × H × 0.71) - (-0.3524-0.01759 × x+0.009417 × x2-0.0001840 × x3)]/(0.1059+0.01434 × x-0.0005324 × x2). The current study provided a reference value for testicular volume of boys aged 0 to 18 years old. Z-score regression equation derived from age for testicular volume can be established. Z-score will be of great value for the testicular development assessment and disease diagnosis and follow-up.
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http://dx.doi.org/10.3389/fped.2021.648711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991569PMC
March 2021

BBB-crossing adeno-associated virus vector: An excellent gene delivery tool for CNS disease treatment.

J Control Release 2021 May 26;333:129-138. Epub 2021 Mar 26.

School of Medicine, Yangzhou University, Yangzhou 225600, China; Department of Oncology, Yangzhou Traditional Chinese Medical Hospital, Yangzhou 225600, China. Electronic address:

The presence of the blood-brain barrier (BBB) remains a challenge in the treatment of central nervous system (CNS) diseases, as it hinders the infiltration of many therapeutic drugs into the brain parenchyma. Therefore, developing efficacious pharmacological agents that can traverse the BBB is crucial for optimal treatment of diseases of the CNS such as neurodegenerative conditions and brain tumors. Adeno-associated virus (AAV), one of the most promising gene therapy vectors, has been shown to cross the BBB safely and is non-pathogenic in nature and therefore has been utilized for numerous diseases of the CNS. Along with the development of protein engineering techniques such as directed evolution including DNA shuffling, a great number of BBB-crossing AAVs have been developed, that could be systemically injected for therapeutic benefit. In this review, we discuss several feasible approaches to improve transportation of therapeutic agents to the CNS. We also discuss the advantages of using BBB-crossing AAVs, their role as a gene delivery agent and highlight the different types of BBB-AAV vectors that have been developed in order to provide a greater insight into how they can be used in diseases of the CNS.
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http://dx.doi.org/10.1016/j.jconrel.2021.03.029DOI Listing
May 2021

Plinabulin, a Distinct Microtubule-Targeting Chemotherapy, Promotes M1-Like Macrophage Polarization and Anti-tumor Immunity.

Front Oncol 2021 3;11:644608. Epub 2021 Mar 3.

Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.

Reprogramming tumor infiltrating myeloid cells to elicit pro-inflammatory responses is an exciting therapeutic maneouver to improve anti-tumor responses. We recently demonstrated that a distinct microtubule-targeting drug, plinabulin-a clinical-stage novel agent-modulates dendritic cell maturation and enhances anti-tumor immunity. Here, we investigated the effects of plinabulin on macrophage polarization and . Plinabulin monotherapy induced significant tumor growth inhibition in mice bearing subcutaneous MC38 colon cancer. Importantly, the regressing tumors were characterized by an increase in M1-like/M2-like tumor-associated macrophages (TAM) ratio. The efficacy of plinabulin remained unaltered in T cell-deficient Rag2 mice, suggesting an important role of macrophages in driving the drug's anti-tumor effect. Exposure of murine and healthy human macrophages to plinabulin induced polarization toward the M1 phenotype, including increased expression of co-stimulatory molecules CD80, CD86 and pro-inflammatory cytokines IL-1β, IL-6, and IL-12. M2-associated immunosuppressive cytokines IL-10 and IL-4 were reduced. This pro-inflammatory M1-like skewing of TAMs in response to plinabulin was dependent on the JNK pathway. Functionally, plinabulin-polarized human M1 macrophages directly killed HuT 78 tumor cells . Importantly, plinabulin induced a functional M1-like polarization of tumor infiltrating macrophages in murine tumors as well as in tumor samples from ovarian cancer patients, by preferentially triggering M1 proliferation. Our study uncovers a novel immunomodulatory effect of plinabulin in directly triggering M1 polarization and proliferation as well as promoting TAM anti-tumoral effector functions.
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http://dx.doi.org/10.3389/fonc.2021.644608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966525PMC
March 2021

Extracting Biomedical Entity Relations using Biological Interaction Knowledge.

Interdiscip Sci 2021 Jun 17;13(2):312-320. Epub 2021 Mar 17.

College of Computer Science and Technology, Jilin University, Changchun, 130012, China.

Discovering relations of cross-type biomedical entities is crucial for biology research. A large amount of potential or indirect connected biological relations is hidden in millions of biomedical literatures and biological databases. The previous rules-based and deep learning approaches rely on plenty of manual annotations, which is laborious, time-consuming and unsatisfactory. It is necessary to be able to combine available annotated gene databases, chemical, genomic, clinical and other types of data repositories as domain knowledge to assist the extraction of biological entity relations from numerous literatures. Under this scenario, this paper proposes BioGraphSAGE model, a Siamese graph neural network with structured databases as domain knowledge to extract biological entity relations from literatures. Our model combines both biological semantic features and positional features to improve the recognition of relations between distant entities in the same literature. The experiment results show that BioGraphSAGE achieves the best F1 score among other relation extraction models on smaller annotated samples. Moreover, the proposed model can still maintain a F1 score of 0.526 without using annotated training samples.
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http://dx.doi.org/10.1007/s12539-021-00425-8DOI Listing
June 2021

L1CAM overexpression promotes tumor progression through recruitment of regulatory T cells in esophageal carcinoma.

Cancer Biol Med 2021 Mar 12. Epub 2021 Mar 12.

Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.

Objective: L1 cell adhesion molecule (L1CAM) exhibits oncogenic activity in tumors. However, the link between L1CAM and the tumor microenvironment remains poorly understood in patients with esophageal squamous cell carcinoma (ESCC). In this study, we investigated how L1CAM expression in ESCC affects the oncogenic characteristics of tumor cells and the tumor microenvironment.

Methods: Human ESCC samples were collected, and the mRNA and protein levels of L1CAM were examined by real-time PCR and immunohistochemistry. Overexpression and knockdown gene expression assays were used for mechanistic studies. The cell proliferation and cell cycle were measured with CCK-8 assays and flow cytometry. Cell migration and invasion ability were measured with Transwell assays. Multiplex bead-based assays were performed to identity the factors downstream of L1CAM. Xenograft studies were performed in nude mice to evaluate the effects of L1CAM on tumor growth and regulatory T cell (Treg) recruitment.

Results: L1CAM expression was significantly elevated in ESCC tissues ( < 0.001) and correlated with poorer prognosis ( < 0.05). Ablation of L1CAM in ESCC cells inhibited tumor growth and migration, and increased tumor cell apoptosis ( < 0.05). In the tumor microenvironment, L1CAM expression correlated with Treg infiltration in ESCC by affecting CCL22 secretion. Mechanistically, L1CAM facilitated CCL22 expression by activating the PI3K/Akt/NF-κB signaling pathway. Furthermore, CCL22 promoted Treg recruitment to the tumor site; the Tregs then secreted TGF-β, which in turn promoted L1CAM expression Smad2/3 in a positive feedback loop.

Conclusions: Our findings provide new insight into the mechanism of immune evasion mediated by L1CAM, suggesting that targeting L1CAM-CCL22-TGF-β crosstalk between tumor cells and Tregs may offer a unique means to improve treatment of patients with ESCC.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0182DOI Listing
March 2021

Blood pressure and left ventricular function changes in different ambulatory blood pressure patterns at high altitude.

J Clin Hypertens (Greenwich) 2021 Jun 6;23(6):1133-1143. Epub 2021 Mar 6.

Institute of Cardiovascular Diseases of PLA, the Second Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, China.

Acute high-altitude (HA) exposure induces physiological responses of the heart and blood pressure (BP). However, few studies have investigated the responses associated with dipper and non-dipper BP patterns. In this prospective study, 72 patients underwent echocardiography and 24-h ambulatory BP testing at sea level and HA. Patients were divided into dipper and non-dipper groups according to BP at sea level. Acute HA exposure elevated 24-h systolic and diastolic BP and increased BP variability, particularly in the morning. Moreover, acute exposure increased left ventricular torsion, end-systolic elastance, effective arterial elastance, and untwisting rate, but reduced peak early diastolic velocity/late diastolic velocity and peak early diastolic velocity/early diastolic velocity, implying enhanced left ventricular systolic function but impaired filling. Dippers showed pronounced increases in night-time BP, while non-dippers showed significant elevation in day-time BP, which blunted differences in nocturnal BP fall, and lowest night-time and evening BP. Dippers had higher global longitudinal strain, torsion, and untwisting rates after acute HA exposure. Variations in night-time systolic BP correlated with variations in torsion and global longitudinal strain. Our study firstly demonstrates BP and cardiac function variations during acute HA exposure in different BP patterns and BP increases in dippers at night, while non-dippers showed day-time increases. Furthermore, enhanced left ventricular torsion and global longitudinal strain are associated with BP changes. Non-dippers showed poor cardiac compensatory and maladaptive to acute HA exposure. However, the exact mechanisms involved need further illumination.
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http://dx.doi.org/10.1111/jch.14235DOI Listing
June 2021

Security Analysis of a Color Image Encryption Algorithm Using a Fractional-Order Chaos.

Entropy (Basel) 2021 Feb 23;23(2). Epub 2021 Feb 23.

Guangdong Mechanical and Electronical College of Technology, Guangzhou 510515, China.

Fractional-order chaos has complex dynamic behavior characteristics, so its application in secure communication has attracted much attention. Compared with the design of fractional-order chaos-based cipher, there are fewer researches on security analysis. This paper conducts a comprehensive security analysis of a color image encryption algorithm using a fractional-order hyperchaotic system (CIEA-FOHS). Experimental simulation based on excellent numerical statistical results supported that CIEA-FOHS is cryptographically secure. Yet, from the perspective of cryptanalysis, this paper found that CIEA-FOHS can be broken by a chosen-plaintext attack method owing to its some inherent security defects. Firstly, the diffusion part can be eliminated by choosing some special images with all the same pixel values. Secondly, the permutation-only part can be deciphered by some chosen plain images and the corresponding cipher images. Finally, using the equivalent diffusion and permutation keys obtained in the previous two steps, the original plain image can be recovered from a target cipher image. Theoretical analysis and experimental simulations show that the attack method is both effective and efficient. To enhance the security, some suggestions for improvement are given. The reported results would help the designers of chaotic cryptography pay more attention to the gap of complex chaotic system and secure cryptosystem.
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http://dx.doi.org/10.3390/e23020258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927140PMC
February 2021

Females and Males Show Differences in Early-Stage Transcriptomic Biomarkers of Lung Adenocarcinoma and Lung Squamous Cell Carcinoma.

Diagnostics (Basel) 2021 Feb 19;11(2). Epub 2021 Feb 19.

College of Computer Science and Technology, Jilin University, Changchun 130012, China.

The incidence and mortality rates of lung cancers are different between females and males. Therefore, sex information should be an important part of how to train and optimize a diagnostic model. However, most of the existing studies do not fully utilize this information. This study carried out a comparative investigation between sex-specific models and sex-independent models. Three feature selection algorithms and five classifiers were utilized to evaluate the contribution of the sex information to the detection of early-stage lung cancers. Both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) showed that the sex-specific models outperformed the sex-independent detection of early-stage lung cancers. The Venn plots suggested that females and males shared only a few transcriptomic biomarkers of early-stage lung cancers. Our experimental data suggested that sex information should be included in optimizing disease diagnosis models.
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http://dx.doi.org/10.3390/diagnostics11020347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922551PMC
February 2021

Sex Differences in the Incidence and Risk Factors of Myocardial Injury in COVID-19 Patients: A Retrospective Cohort Study.

Front Physiol 2021 16;12:632123. Epub 2021 Feb 16.

The Second Affiliated Hospital, Institute of Cardiovascular Diseases of People's Liberation Army of China (PLA), Army Medical University, Chongqing, China.

Male novel coronavirus disease (COVID-19) patients tend to have poorer clinical outcomes than female patients, while the myocardial injury is strongly associated with COVID-19-related adverse events. Owing to a lack of corresponding data, we aimed to investigate the sex differences in the incidence of myocardial injury in COVID-19 patients and to identify the potential underlying mechanisms, which may partly account for the sex bias in the incidence of adverse events. This retrospective study included 1,157 COVID-19 patients who were hospitalized in Huoshenshan Hospital from 12 March 2020 to 11 April 2020. Data on the patients' demographic characteristics, initial symptoms, comorbidities and laboratory tests were collected. Totally, 571 (49.4%) female and 586 (50.6%) male COVID-19 patients were enrolled. The incidence of myocardial injury was higher among men than women (9.2 vs. 4.9%, = 0.004). In the logistic regression analysis, age, and chronic kidney disease were associated with myocardial injury in both sexes. However, hypertension [odds ratio (OR) = 2.25, 95% confidence interval (CI) 1.20-4.22], coronary artery disease ( = 2.46, 95% CI 1.14-5.34), leucocyte counts ( = 3.13, 95% CI 1.24-7.86), hs-CRP ( = 4.45, 95% CI 1.33-14.83), and D-dimer [ = 3.93 (1.27-12.19), 95% CI 1.27-12.19] were independent risk factors only in the men. The correlations of hs-CRP and D-dimer with hs-cTnI and BNP were stronger in the men. The incidence of myocardial injury in COVID-19 patients is sex-dependent, predominantly in association with a greater degree of inflammation and coagulation disorders in men. Our findings can be used to improve the quality of clinical management in such settings.
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http://dx.doi.org/10.3389/fphys.2021.632123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920972PMC
February 2021

Tumor-derived ILT4 induces T cell senescence and suppresses tumor immunity.

J Immunother Cancer 2021 Mar;9(3)

Division of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, USA

Background: Current immunotherapies including checkpoint blockade therapy have limited success rates in certain types of cancers. Identification of alternative checkpoint molecules for the development of effective strategies for tumor immunotherapy is urgently needed. Immunoglobulin-like transcript 4 (ILT4) is an immunosuppressive molecule expressed in both myeloid innate cells and malignant tumor cells. However, the role of tumor-derived ILT4 in regulating cancer biology and tumor immunity remains unclear.

Methods: ILT4 expression in tumor cells and patient samples was determined by real-time PCR, flow cytometry, and immunohistochemistry. T cell senescence induced by tumor was evaluated using multiple markers and assays. Moreover, metabolic enzyme and signaling molecule expression and lipid droplets in tumor cells were determined using real-time PCR, western blot and oil red O staining, respectively. Loss-of-function and gain-of-function strategies were used to identify the causative role of ILT4 in tumor-induced T cell senescence. In addition, breast cancer and melanoma mouse tumor models were performed to demonstrate the role of ILT4 as a checkpoint molecule for tumor immunotherapy.

Results: We reported that ILT4 is highly expressed in human tumor cells and tissues, which is negatively associated with clinical outcomes. Furthermore, tumor-derived ILT4/PIR-B (ILT4 ortholog in mouse) is directly involved in induction of cell senescence in naïve/effector T cells mediated by tumor cells in vitro and in vivo. Mechanistically, ILT4/PIR-B increases fatty acid synthesis and lipid accumulation in tumor cells activation of MAPK ERK1/2 signaling, resulting in promotion of tumor growth and progression, and induction of effector T cell senescence. In addition, blocking tumor-derived PIR-B can reprogram tumor metabolism, prevent senescence development in tumor-specific T cells, and enhance antitumor immunity in both breast cancer and melanoma mouse models.

Conclusions: These studies identify a novel mechanism responsible for ILT4-mediated immune suppression in the tumor microenvironment, and prove a novel concept of ILT4 as a critical checkpoint molecule for tumor immunotherapy.
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http://dx.doi.org/10.1136/jitc-2020-001536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929805PMC
March 2021

Proteasome regulation by reversible tyrosine phosphorylation at the membrane.

Oncogene 2021 Mar 18;40(11):1942-1956. Epub 2021 Feb 18.

Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.

Reversible phosphorylation has emerged as an important mechanism for regulating 26S proteasome function in health and disease. Over 100 phospho-tyrosine sites of the human proteasome have been detected, and yet their function and regulation remain poorly understood. Here we show that the 19S subunit Rpt2 is phosphorylated at Tyr439, a strictly conserved residue within the C-terminal HbYX motif of Rpt2 that is essential for 26S proteasome assembly. Unexpectedly, we found that Y439 phosphorylation depends on Rpt2 membrane localization mediated by its N-myristoylation. Multiple receptors tyrosine kinases can trigger Rpt2-Y439 phosphorylation by activating Src, a N-myristoylated tyrosine kinase. Src directly phosphorylates Rpt2-Y439 in vitro and negatively regulates 26S proteasome activity at cellular membranes, which can be reversed by the membrane-associated isoform of protein tyrosine phosphatase nonreceptor type 2 (PTPN2). In H1975 lung cancer cells with activated Src, blocking Rpt2-Y439 phosphorylation by the Y439F mutation conferred partial resistance to the Src inhibitor saracatinib both in vitro and in a mouse xenograft tumor model, and caused significant changes of cellular responses to saracatinib at the proteome level. Our study has defined a novel mechanism involved in the spatial regulation of proteasome function and provided new insights into tyrosine kinase inhibitor-based anticancer therapies.
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http://dx.doi.org/10.1038/s41388-021-01674-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990385PMC
March 2021