Publications by authors named "Lai Wei"

1,043 Publications

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Comparative analysis of mite genomes reveals positive selection for diet adaptation.

Commun Biol 2021 Jun 3;4(1):668. Epub 2021 Jun 3.

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.

Diet is a powerful evolutionary force for species adaptation and diversification. Acari is one of the most abundant clades of Arachnida, exhibiting diverse dietary types, while the underlying genetic adaptive mechanisms are not fully understood. Based on comparative analyses of 15 Acari genomes, we found genetic bases for three specialized diets. Herbivores experienced stronger selection pressure than other groups; the olfactory genes and gene families involving metabolizing toxins showed strong adaptive signals. Genes and gene families related to anticoagulation, detoxification, and haemoglobin digestion were found to be under strong selection pressure or significantly expanded in the blood-feeding species. Lipid metabolism genes have a faster evolutionary rate and been subjected to greater selection pressures in fat-feeding species; one positively selected site in the fatty-acid amide hydrolases 2 gene was identified. Our research provides a new perspective for the evolution of Acari and offers potential target loci for novel pesticide development.
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http://dx.doi.org/10.1038/s42003-021-02173-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175442PMC
June 2021

M2 tumor-associated macrophages play important role in predicting response to neoadjuvant chemotherapy in triple-negative breast carcinoma.

Breast Cancer Res Treat 2021 May 25. Epub 2021 May 25.

Department of Pathology, Wexner Medical Center, The Ohio State University, 410 W. 10th Ave, Columbus, OH, 43210, USA.

Purpose: Two types of macrophages are present in tumor microenvironment. M1 macrophages exhibit potent anti-tumor properties, while M2 macrophages play the pro-tumoral roles. The presence of M2 macrophages is associated with worsened overall survival in triple-negative breast carcinoma (TNBC) patients. However, the relationship between M2 macrophages and response to neoadjuvant chemotherapy (NAC) is unknown.

Methods: M2 macrophages were investigated on biopsy whole sections from 66 TNBCs treated with NAC by CD163 together with other immune checkpoint markers (PD1, PD-L1 and CD8) using a multi-color immunohistochemical multiplex assay.

Results: Incomplete response was significantly associated with older age, lower PD-L1 expression (tumor and stroma), lower levels of CD8-positive TILs in stroma, but higher level of CD163-positive macrophages, with the level of CD163-positive M2 macrophages in peritumoral area as the strongest factor.

Conclusions: Our data have demonstrated that the level of CD163-positive M2 macrophages was significantly higher in TNBC patients with incomplete response than patients with complete response, suggesting M2 macrophages' important role in predicting TNBC patients' response to NAC.
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http://dx.doi.org/10.1007/s10549-021-06260-1DOI Listing
May 2021

The Chinese Society of Hepatology position statement on the redefinition of fatty liver disease.

J Hepatol 2021 May 18. Epub 2021 May 18.

Department of Infectious Diseases, Guizhou Provincial People's Hospital, Guiyang 550002, China.

Fatty liver disease associated with metabolic dysfunction is of increasing concern in mainland China, the world's most populous country. The incidence of fatty liver disease is highest in China, surpassing the incidence in European countries and the USA. An international consensus panel recently published an influential report recommending a novel definition of fatty liver disease associated with metabolic dysfunction. This recommendation includes a switch in name from nonalcoholic fatty liver disease (NAFLD) to metabolic-associated fatty liver disease (MAFLD) and adoption of a set of positive criteria for disease diagnosis that are independent of alcohol intake or other liver diseases. Given the unique importance of this proposal, the Chinese Society of Hepatology (CSH) invited leading hepatologists and gastroenterologists representing their respective provinces and cities to reach consensus on alternative definitions for fatty liver disease from a national perspective. The CSH endorsed the proposal of changing the term NAFLD to MAFLD (supportedby 95.45% or participants). We expect that the new definition will result in substantial improvements in health care for patients and advance disease awareness, public health policy, and political, scientific and funding outcomes for MAFLD in China.
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http://dx.doi.org/10.1016/j.jhep.2021.05.003DOI Listing
May 2021

The diagnostic accuracy of intravoxel incoherent motion and diffusion kurtosis imaging in the differentiation of malignant and benign soft-tissue masses: which is better?

Acta Radiol 2021 May 17:2841851211017511. Epub 2021 May 17.

Department of Radiology, The Second Hospital, Dalian Medical University, Shahekou, Dalian, PR China.

Background: It is difficult for conventional magnetic resonance imaging (MRI) to distinguish benign soft-tissue masses (STMs) from malignant masses.

Purpose: To quantitatively compare the diagnostic value of intravoxel incoherent motion (IVIM) and diffusion kurtosis imaging (DKI) in STMs.

Material And Methods: The data from 58 patients with STMs were retrospectively analyzed. The GE Discovery 3.0-T MRI scanner was used to acquire conventional MRI sequences, IVIM, and DKI images. The chi-square test, independent sample t-test, and Mann-Whitney U tests were used to compare the differences between conventional MRI features, IVIM, and DKI parameters (D, D, f, mean kurtosis [MK], and mean diffusivity [MD]) between the benign and malignant groups. Receiver-operating characteristic (ROC) curve analysis was also performed.

Results: Tumor size and depth are statistically different in STTs. Ds, MK, and MD values in the malignant groups are significantly lower than the benign groups ( < 0.05). However, D and f values are not statistically different between the two groups. The area under the curve (AUC) of D value (0.859) is higher than MD (0.765) and MK (0.676) values for identifying benign and malignant STMs. The D value showed the best specificity (82.93%). The sensitivity and specificity of IVIM and DKI parameters are higher than that of conventional MRI sequences.

Conclusion: IVIM and DKI can be used to distinguish between benign and malignant STMs, with D as the most meaningful parameter.
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http://dx.doi.org/10.1177/02841851211017511DOI Listing
May 2021

Impact of Leaflet Tethering on Residual Regurgitation in Patients With Degenerative Mitral Disease After Interventional Edge-to-Edge Repair.

Front Cardiovasc Med 2021 29;8:647701. Epub 2021 Apr 29.

Shanghai Institute of Cardiovascular Disease, Fudan University, Shanghai, China.

Grade 2+ residual mitral regurgitation (MR 2+) is associated with the recurrence of MR and a lower survival rate in interventional mitral valve (MV) edge-to-edge (EE) repair. We sought to determine the MV anatomic factors affecting residual MR 2+ during interventional EE repair with the ValveClamp system in patients with degenerative MR (DMR). In this multicenter study, 62 patients with significant (grade 3+ to 4+) DMR underwent ValveClamp implantation across eight centers from July 2018 to December 2019. Patient clinical, anatomical, and procedural characteristics were prospectively collected and retrospectively analyzed. A single clamp was implanted in 59 patients, and two clamps were implanted in three patients. Residual MR 2+ was found in 14 patients (22.6%) immediately after the ValveClamp procedure. Patients with residual MR 2+ showed significantly larger preoperative tenting sizes and annular dimensions than the residual MR ≤1+ group. Multivariate analysis identified tenting volume as the major determinant of residual MR 2+ after ValveClamp procedures (odds ratio, 1.410 per 0.1-mL/m increase; 95% confidence interval, 1.167-1.705; < 0.001). Receiver operating characteristic curves identified a tenting volume index ≥0.82 mL/m as the optimal cutoff point to predict residual MR 2+ (area under curve, 0.84). Patients with a tenting volume index ≥0.82 mL/m were more likely to develop recurrent 3+ MR or undergo MV surgery during short-term follow-up ( < 0.001). Preoperative assessment of the tenting volume index will help to predict intraoperative residual MR 2+ in patients with DMR receiving EE-based interventional repair. Improvements in the interventional strategy are warranted for sustained MR reduction in patients with DMR with unfavorable anatomy.
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http://dx.doi.org/10.3389/fcvm.2021.647701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116490PMC
April 2021

Machine learning models to predict red blood cell transfusion in patients undergoing mitral valve surgery.

Ann Transl Med 2021 Apr;9(7):530

Department of Transfusion, Zhongshan Hospital, Fudan University, Shanghai, China.

Background: Red blood cell (RBC) transfusion therapy has been widely used in surgery, and has yielded excellent treatment outcomes. However, in some instances, the demand for RBC transfusion is assessed by doctors based on their experience. In this study, we use machine learning models to predict the need for RBC transfusion during mitral valve surgery to guide the surgeon's assessment of the patient's need for intraoperative blood transfusion.

Methods: We retrospectively reviewed 698 cases of isolated mitral valve surgery with and without combined tricuspid valve operation. Seventy percent of the database was used as the training set and the remainder as the testing set for 13 machine learning algorithms to build a model to predict the need for intraoperative RBC transfusion. According to the characteristic value of model mining, we analyzed the risk-related factors to determine the main effects of variables influencing the outcome.

Results: A total of 166 patients of the cases considered had undergone intraoperative RBC transfusion (24.52%). Of the 13 machine learning algorithms, CatBoost delivered the best performance, with an AUC of 0.888 (95% CI: 0.845-0.909) in testing set. Further analysis using the CatBoost model revealed that hematocrit (<37.81%), age (>64 y), body weight (<59.92 kg), body mass index (BMI) (<22.56 kg/m), hemoglobin (<122.6 g/L), type of surgery (median thoracotomy surgery), height (<160.61 cm), platelet (>194.12×10/L), RBC (<4.08×10/L), and gender (female) were the main risk-related factors for RBC transfusion. A total of 204 patients were tested, 177 of whom were predicted accurately (86.8%).

Conclusions: Machine learning models can be used to accurately predict the outcomes of RBC transfusion, and should be used to guide surgeons in clinical practice.
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http://dx.doi.org/10.21037/atm-20-7375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105834PMC
April 2021

Large-scale analysis of 2,152 Ig-seq datasets reveals key features of B cell biology and the antibody repertoire.

Cell Rep 2021 May;35(6):109110

Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China. Electronic address:

Antibody repertoire sequencing enables researchers to acquire millions of B cell receptors and investigate these molecules at the single-nucleotide level. This power and resolution in studying humoral responses have led to its wide applications. However, most of these studies were conducted with a limited number of samples. Given the extraordinary diversity, assessment of these key features with a large sample set is demanded. Thus, we collect and systematically analyze 2,152 high-quality heavy-chain antibody repertoires. Our study reveals that 52 core variable genes universally contribute to more than 99% of each individual's repertoire; a distal interspersed preferences characterize V gene recombination; the number of public clones between two repertoires follows a linear model, and the positive selection dominates at RGYW motif in somatic hypermutations. Thus, this population-level analysis resolves some critical features of the antibody repertoire and may have significant value to the large cadre of scientists.
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http://dx.doi.org/10.1016/j.celrep.2021.109110DOI Listing
May 2021

Real-Time Monitoring and Step-by-Step Guidance for Transapical Mitral Valve Edge-to-Edge Repair Using Transesophageal Echocardiography.

J Interv Cardiol 2021 21;2021:6659261. Epub 2021 Apr 21.

Department of Cardiology, Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai, China.

MitraClip edge-to-edge (E2E) repair system is the only transcatheter device recommended in the current guidelines for treating mitral regurgitation (MR). The percutaneous femoral venous transseptal access of MitraClip requires a complex steerable delivery system and may thus be technically complex to optimally position and deploy the clip onto the mitral valve. A transapical approach for E2E repair has been devised to treat MR for the ease of operation (ValveClamp system, Hanyu Medical Technology, Shanghai). The first-in-human study of ValveClamp has demonstrated its early feasibility and effectiveness for the treatment of patients with degenerative MR. Transesophageal echocardiography (TEE) is the only imaging modality required for intraoperative guidance of ValveClamp implantation. Successful implantation depends on accurate localization and orientation of the clamp and efficient intraoperative communication between the echocardiographer and the intervention team. Thus, the focus of this review is on elaborating how two-dimensional (2D) and three-dimensional (3D) TEE are used in clinical practice to guide ValveClamp implantation and it may facilitate the understanding of simplicity and safety of this novel procedure. We also describe the implementation of several novel advancements in 3D TEE imaging, which improve the confidence of image interpretation for intraoperative guidance and expedite implantation times.
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http://dx.doi.org/10.1155/2021/6659261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084671PMC
April 2021

Health-related quality of life in Chinese population with non-alcoholic fatty liver disease: a national multicenter survey.

Health Qual Life Outcomes 2021 May 7;19(1):140. Epub 2021 May 7.

Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, No.168, Litang Road, Changping District, Beijing, 102218, China.

Background: Health Related Quality of Life (HRQL) is a multi-dimensional construct that can comprehensively evaluate the patient's health status, including physical, emotional, mental and social well-being. In this study, we aimed to evaluate the impact of non-alcoholic fatty liver disease (NAFLD) on HRQL in a Chinese population.

Methods: In this national multicenter cross-sectional survey, patients with NAFLD were enrolled. Chronic Liver Disease Questionnaire (CLDQ)-NAFLD was used to qualify HRQL. Univariate and multivariate analysis were used to identify independent risk factors of HRQL.

Results: A total of 5181 patients with NAFLD from 90 centers were enrolled in this study (mean age, 43.8 ± 13.3 years; male, 65.8%). The overall CLDQ score was 5.66 ± 0.89. Multivariate logistic regression analysis showed that body mass index (BMI: HR, 1.642; 95% CI, 1.330-2.026), alanine transaminase (ALT: HR, 1.006; 95% CI, 1.001-1.011), triglyceride (HR, 1.184; 95% CI, 1.074-1.305), disease severity (HR, 3.203; 95% CI, 1.418-7.232) and cardiovascular disease (HR, 4.305; 95% CI, 2.074-8.939) were independent risk factors for overall CLDQ score. In the logistic analyses of individual domain, BMI and triglyceride were independent risk factors of all domains. ALT, disease severity, diabetes, depression and cardiovascular disease were influencing factors for the CLDQ score of several domains.

Conclusions: This national multicenter cross-sectional survey in China indicated that the HRQL in patients with NAFLD was impaired. HRQL was found to be significantly associated with sociodemographic and clinical factors. Attention should be paid to the optimally managing care of patients with NAFLD to improve their HRQL.
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http://dx.doi.org/10.1186/s12955-021-01778-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106221PMC
May 2021

Corrigendum to 'Engineering human ventricular heart tissue based on macroporous iron oxide scaffolds' [Acta Biomaterialia 88 (2019) 540-553].

Acta Biomater 2021 Jun 2;127:353. Epub 2021 May 2.

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai 200032, China; Shanghai Key Laboratory of Birth Defect, Children's Hospital of Fudan University, Shanghai 201102, China. Electronic address:

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http://dx.doi.org/10.1016/j.actbio.2021.04.031DOI Listing
June 2021

Context-dependent and -independent selection on synonymous mutations revealed by 1,135 genomes of Arabidopsis thaliana.

Authors:
Duan Chu Lai Wei

BMC Ecol Evol 2021 04 28;21(1):68. Epub 2021 Apr 28.

College of Life Sciences, Beijing Normal University, No. 19 Xinjiekouwai Street, Haidian, Beijing, China.

Background: Synonymous mutations do not alter the amino acids and therefore are regarded as neutral for a long time. However, they do change the tRNA adaptation index (tAI) of a particular codon (independent of its context), affecting the tRNA availability during translation. They could also change the isoaccepting relationship with its neighboring synonymous codons in particular context, which again affects the local translation process. Evidence of selection pressure on synonymous mutations has emerged.

Results: The proposed selection patterns on synonymous mutations are never formally and systematically tested in plant species. We fully take advantage of the SNP data from 1,135 A. thaliana lines, and found that the synonymous mutations that increase tAI or the isoaccepting mutations in isoaccepting codon context tend to have higher derived allele frequencies (DAF) compared to other synonymous mutations of the opposite effects.

Conclusions: Synonymous mutations are not strictly neutral. The synonymous mutations that increase tAI or the isoaccepting mutations in isoaccepting codon context are likely to be positively selected. We propose the concept of context-dependent and -independent selection on synonymous mutations. These concepts broaden our knowledge of the functional consequences of synonymous mutations, and should be appealing to phytologists and evolutionary biologists.
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http://dx.doi.org/10.1186/s12862-021-01792-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079846PMC
April 2021

Colonic Motility Is Improved by the Activation of 5-HT Receptors on Interstitial Cells of Cajal in Diabetic Mice.

Gastroenterology 2021 Apr 23. Epub 2021 Apr 23.

Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada. Electronic address:

Background & Aims: Constipation is commonly associated with diabetes. Serotonin (5-HT), produced predominantly by enterochromaffin (EC) cells via tryptophan hydroxylase 1 (TPH1), is a key modulator of gastrointestinal (GI) motility. However, the role of serotonergic signaling in constipation associated with diabetes is unknown.

Methods: We generated EC cell reporter Tph1-tdTom, EC cell-depleted Tph1-DTA, combined Tph1-tdTom-DTA, and interstitial cell of Cajal (ICC)-specific Kit-GCaMP6 mice. Male mice and surgically ovariectomized female mice were fed a high-fat high-sucrose diet to induce diabetes. The effect of serotonergic signaling on GI motility was studied by examining 5-HT receptor expression in the colon and in vivo GI transit, colonic migrating motor complexes (CMMCs), and calcium imaging in mice treated with either a 5-HT receptor (HTR2B) antagonist or agonist.

Results: Colonic transit was delayed in males with diabetes, although colonic Tph1 cell density and 5-HT levels were increased. Colonic transit was not further reduced in diabetic mice by EC cell depletion. The HTR2B protein, predominantly expressed by colonic ICCs, was markedly decreased in the colonic muscles of males and ovariectomized females with diabetes. Ca activity in colonic ICCs was decreased in diabetic males. Treatment with an HTR2B antagonist impaired CMMCs and colonic motility in healthy males, whereas treatment with an HTR2B agonist improved CMMCs and colonic motility in males with diabetes. Colonic transit in ovariectomized females with diabetes was also improved significantly by the HTR2B agonist.

Conclusion: Impaired colonic motility in mice with diabetes was improved by enhancing HTR2B signaling. The HTR2B agonist may provide therapeutic benefits for constipation associated with diabetes.
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http://dx.doi.org/10.1053/j.gastro.2021.04.040DOI Listing
April 2021

Multi-Mode Reconfigurable DNA-Based Chemical Reaction Circuits for Soft Matter Computing and Control.

Angew Chem Int Ed Engl 2021 Apr 23. Epub 2021 Apr 23.

Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China.

Developing smart material systems for performing different tasks in diverse environments remains challenging. Here, we show that by integrating stimuli-responsive soft materials with multi-mode reconfigurable DNA-based chemical reaction circuits (D-CRCs), it can control size change of microgels with multiple reaction pathways and adapt expansion behaviors to meet diverse environments. We first use pH-responsive intramolecular conformational switches for regulating DNA strand displacement reactions (SDRs). The ability to regulate SDRs with tunable pH-dependence allows to build dynamic chemical reaction networks with diverse reaction pathways. We confirm that the designed DNA switching circuits are reconfigurable at different pH and perform different logic operations, and the swelling of DNA switching circuit-integrated microgel systems can be programmably directed by D-CRCs. Our approach provides insight into building smart responsive materials and fabricating autonomous soft robots.
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http://dx.doi.org/10.1002/anie.202102169DOI Listing
April 2021

Conjunctival Microbiota in Patients With Type 2 Diabetes Mellitus and Influences of Perioperative Use of Topical Levofloxacin in Ocular Surgery.

Front Med (Lausanne) 2021 6;8:605639. Epub 2021 Apr 6.

Department of Ophthalmology and Eye Institute, Ear, Nose and Throat (ENT) Hospital of Fudan University, Shanghai, China.

Patients with type 2 diabetes mellitus (T2DM) are prone to ocular surface infections. We therefore characterized the conjunctival microbiome of T2DM patients and the influence of topical levofloxacin to investigate whether a dysbiosis is associated with this phenomenon. Conjunctival microbiome of 79 T2DM patients and 113 non-diabetic controls was profiled using the 16S rDNA sequencing approach. Furthermore, 21 T2DM and 14 non-diabetic patients who underwent cataract surgeries were followed up perioperatively and the influence of pre- and post-operative levofloxacin on the conjunctival microbiome was further investigated prospectively and compared longitudinally. The α-diversity of the conjunctival microbiota was significantly higher in T2DM patients than in controls ( < 0.05). Significant differences in both composition and function of the conjunctival microbiome were identified on the ocular surface of T2DM patients as compared to non-diabetic controls. Particularly, phylum and , genus , and were enriched, while genus was reduced on the T2DM ocular surface. Microbial genes functioning of bacterial chemotaxis was elevated in the conjunctival microbiome of T2DM patients. Furthermore, compared to the initial status, several genera including were more abundant in the conjunctival microbiome of T2DM patients after 3-days use of preoperative levofloxacin topically, while no genus was more abundant in the non-diabetic follow-up group. No difference was observed between initial status and 7 days after ceasing all postoperative medications in both diabetic and non-diabetic follow-up groups. The conjunctival microbiome of T2DM patients was more complex and may respond differently to topical antibiotics.
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http://dx.doi.org/10.3389/fmed.2021.605639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055849PMC
April 2021

Bone Metastases, Skeletal-Related Events, and Survival in Patients With Metastatic Non-Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitors.

J Natl Compr Canc Netw 2021 Apr 20:1-7. Epub 2021 Apr 20.

3Division of Medical Oncology, and.

Background: Bone metastases and skeletal-related events (SREs) are a frequent cause of morbidity in patients with metastatic non-small cell lung cancer (mNSCLC). Data are limited on bone metastases and SREs in patients with mNSCLC treated using immune checkpoint inhibitors (ICIs), and on the efficacy of bone-modifying agents (BMAs) in this setting. Here we report the incidence, impact on survival, risk factors for bone metastases and SREs, and impact of BMAs in patients with mNSCLC treated with ICIs in a multi-institutional cohort.

Patients And Methods: We conducted a retrospective study of patients with mNSCLC treated with ICIs at 2 tertiary care centers from 2014 through 2017. Overall survival (OS) was compared between patients with and without baseline bone metastases using a log-rank test. A Cox regression model was used to evaluate the association between OS and the presence of bone metastases at ICI initiation, controlling for other confounding factors.

Results: We identified a cohort of 330 patients who had received ICIs for metastatic disease. Median patient age was 63 years, most patients were treated in the second line or beyond (n=259; 78%), and nivolumab was the most common ICI (n=211; 64%). Median OS was 10 months (95% CI, 8.4-12.0). In our cohort, 124 patients (38%) had baseline bone metastases, and 43 (13%) developed SREs during or after ICI treatment. Patients with bone metastases had a higher hazard of death after controlling for performance status, histology, line of therapy, and disease burden (hazard ratio, 1.57; 95% CI, 1.19-2.08; P=.001). Use of BMAs was not associated with OS or a decreased risk of SREs.

Conclusions: Presence of bone metastases at baseline was associated with a worse prognosis for patients with mNSCLC treated with ICI after controlling for multiple clinical characteristics. Use of BMAs was not associated with reduced SREs or a difference in survival.
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http://dx.doi.org/10.6004/jnccn.2020.7668DOI Listing
April 2021

DNA-Scaffolded Disulfide Redox Network for Programming Drug-Delivery Kinetics.

Chemistry 2021 Jun 7;27(34):8745-8752. Epub 2021 May 7.

Department Shanghai Key Laboratory of Green Chemistry and Chemical Processes School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, P. R. China.

In response to specific stimuli, dynamic covalent materials enable the generation of new structures by reversibly forming/breaking chemical bonds, thus showing great potential for application in controlled drug release. However, using dynamic covalent chemistry to program drug-delivery kinetics remains challenging. Herein, an in situ polymerization-generated DNA-scaffolded disulfide redox network (DdiSRN) is reported in which nucleic acids are used as a scaffold for dynamic disulfide bonds. The constructed DdiSRN allows selective release of loading cargos inside cancer cells in response to redox stimuli. Moreover, the density of disulfide bonds in network can be tuned by precise control over their position and number on DNA scaffolds. As a result, drug-delivery kinetics can be programmed with a half-life, t , decreasing from 8.3 to 4.4 h, thus facilitating keeping an adequate drug concentration within the therapeutic window. Both in vitro and in vivo studies confirm that co-delivery of DOX and siRNA in combination with fast drug release inside cells using this DdiSRN enhances the therapeutic effect on multidrug-resistant cancer. This nontrivial therapeutic platform enabling kinetic control provides a good paradigm for precision cancer medicine.
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http://dx.doi.org/10.1002/chem.202100149DOI Listing
June 2021

Phase 2 Study of Ibrutinib in Classic and Variant Hairy Cell Leukemia.

Blood 2021 Mar 22. Epub 2021 Mar 22.

Ohio State University, Colmubus, Ohio, United States.

Hairy cell leukemia is a rare B-cell malignancy where there is a need for novel treatments for patients who do not benefit from purine analogues. Ibrutinib, an oral agent targeting Bruton tyrosine kinase in the B-cell receptor signaling pathway, is highly effective in several malignancies. Its activity in HCL was unknown. Therefore, we conducted a multisite phase 2 study (NCT01841723) of oral ibrutinib in patients with either relapsed classic or variant hairy cell leukemia. The primary outcome measure was the overall response rate at 32 weeks with response at 48 weeks and best response during treatment also assessed. Key secondary objectives were characterization of toxicity and determination of progression-free and overall survival. Thirty-seven patients were enrolled (24 at 420mg, 13 at 840mg). The median duration of follow-up was 3.5 years (range 0-5.9). The overall response rate at 32 weeks was 24% which increased to 36% at 48 weeks. The best overall response rate was 54%. The estimated 36-month progression-free and overall survivals were 73% and 85%, respectively. The most frequent adverse events were diarrhea (59%), fatigue (54%), myalgia (54%), and nausea (51%). Hematologic adverse events were common with anemia (43%), thrombocytopenia (41%), and neutropenia (35%). Ibrutinib can be safely administered to hairy cell leukemia patients with objective responses and results in prolonged disease control. While the initial primary outcome objective of the study was not met, the observation of objective responses in heavily pretreated patients coupled with a favorable progression-free survival suggest that ibrutinib may be beneficial in these patients.
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http://dx.doi.org/10.1182/blood.2020009688DOI Listing
March 2021

Identification of an intraocular microbiota.

Cell Discov 2021 Mar 9;7(1):13. Epub 2021 Mar 9.

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, China.

The current dogma in ophthalmology and vision research presumes the intraocular environment to be sterile. However, recent evidence of intestinal bacterial translocation into the bloodstream and many other internal organs including the eyes, found in healthy and diseased animal models, suggests that the intraocular cavity may also be inhabited by a microbial community. Here, we tested intraocular samples from over 1000 human eyes. Using quantitative PCR, negative staining transmission electron microscopy, direct culture, and high-throughput sequencing technologies, we demonstrated the presence of intraocular bacteria. The possibility that the microbiome from these low-biomass communities could be a contamination from other tissues and reagents was carefully evaluated and excluded. We also provide preliminary evidence that a disease-specific microbial signature characterized the intraocular environment of patients with age-related macular degeneration and glaucoma, suggesting that either spontaneous or pathogenic bacterial translocation may be associated with these common sight-threatening conditions. Furthermore, we revealed the presence of an intraocular microbiome in normal eyes from non-human mammals and demonstrated that this varied across species (rat, rabbit, pig, and macaque) and was established after birth. These findings represent the first-ever evidence of intraocular microbiota in humans.
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http://dx.doi.org/10.1038/s41421-021-00245-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943566PMC
March 2021

Micro-organic basis of functional gastrointestinal (GI) disorders: Role of microRNAs in GI pacemaking cells.

Indian J Gastroenterol 2021 Apr;40(2):102-110

Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226 014, India.

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http://dx.doi.org/10.1007/s12664-021-01159-7DOI Listing
April 2021

New progress in the study of germline susceptibility genes of myeloid neoplasms.

Oncol Lett 2021 Apr 23;21(4):317. Epub 2021 Feb 23.

Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.

In 2016, the World Health Organization incorporated 'myeloid neoplasms with germline predisposition' into its classification of tumors of hematopoietic and lymphoid tissues, revealing the important role of germline mutations in certain myeloid neoplasms, particularly myelodysplastic syndrome and acute myeloid leukemia. The awareness of germline susceptibility has increased, and some patients with myeloid neoplasms present with a preexisting disorder or organ dysfunction. In such cases, mutations in genes including CCAAT enhancer binding protein α (CEBPA), DEAD (Asp-Glu-Ala-Asp) box polypeptide 41 (DDX41), RUNX family transcription factor 1 (RUNX1), GATA binding protein 2 (GATA2), Janus kinase 2 (JAK2) and ETS variant transcription factor 6 (ETV6) have been recognized. Moreover, with the application of advanced technologies and reports of more cases, additional germline mutations associated with myeloid neoplasms have been identified and provide insights into the formation, prognosis and therapy of myeloid neoplasms. The present review discusses the well-known CEBPA, DDX41, RUNX1, GATA2, JAK2 and ETV6 germline mutations, and other mutations including those of lymphocyte adapter protein/SH2B adapter protein 3 and duplications of autophagy related 2B, GSK3B interacting protein αnd RB binding protein 6, ubiquitin ligase, that remain to be confirmed or explored. Recommendations for the management of diseases associated with germline mutations are also provided.
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http://dx.doi.org/10.3892/ol.2021.12578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933751PMC
April 2021

Subspace Clustering via Structured Sparse Relation Representation.

IEEE Trans Neural Netw Learn Syst 2021 Mar 5;PP. Epub 2021 Mar 5.

Due to the corruptions or noises that existed in real-world data sets, the affinity graphs constructed by the classical spectral clustering-based subspace clustering algorithms may not be able to reveal the intrinsic subspace structures of data sets faithfully. In this article, we reconsidered the data reconstruction problem in spectral clustering-based algorithms and proposed the idea of ``relation reconstruction.'' We pointed out that a data sample could be represented by the neighborhood relation computed between its neighbors and itself. The neighborhood relation could indicate the true membership of its corresponding original data sample to the subspaces of a data set. We also claimed that a data sample's neighborhood relation could be reconstructed by the neighborhood relations of other data samples; then, we suggested a much different way to define affinity graphs consequently. Based on these propositions, a sparse relation representation (SRR) method was proposed for solving subspace clustering problems. Moreover, by introducing the local structure information of original data sets into SRR, an extension of SRR, namely structured sparse relation representation (SSRR) was presented. We gave an optimization algorithm for solving SRR and SSRR problems and analyzed its computation burden and convergence. Finally, plentiful experiments conducted on different types of databases showed the superiorities of SRR and SSRR.
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http://dx.doi.org/10.1109/TNNLS.2021.3059511DOI Listing
March 2021

Serotonin Deficiency Is Associated With Delayed Gastric Emptying.

Gastroenterology 2021 Jun 2;160(7):2451-2466.e19. Epub 2021 Mar 2.

Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, Nevada. Electronic address:

Background & Aims: Gastrointestinal (GI) motility is regulated by serotonin (5-hydroxytryptamine [5-HT]), which is primarily produced by enterochromaffin (EC) cells in the GI tract. However, the precise roles of EC cell-derived 5-HT in regulating gastric motility remain a major point of conjecture. Using a novel transgenic mouse line, we investigated the distribution of EC cells and the pathophysiologic roles of 5-HT deficiency in gastric motility in mice and humans.

Methods: We developed an inducible, EC cell-specific Tph1 mouse, which was used to generate a reporter mouse line, Tph1-tdTom, and an EC cell-depleted line, Tph1-DTA. We examined EC cell distribution, morphology, and subpopulations in reporter mice. GI motility was measured in vivo and ex vivo in EC cell-depleted mice. Additionally, we evaluated 5-HT content in biopsy and plasma specimens from patients with idiopathic gastroparesis (IG).

Results: Tph1-tdTom mice showed EC cells that were heterogeneously distributed throughout the GI tract with the greatest abundance in the antrum and proximal colon. Two subpopulations of EC cells were identified in the gut: self-renewal cells located at the base of the crypt and mature cells observed in the villi. Tph1-DTA mice displayed delayed gastric emptying, total GI transit, and colonic transit. These gut motility alterations were reversed by exogenous provision of 5-HT. Patients with IG had a significant reduction of antral EC cell numbers and 5-HT content, which negatively correlated with gastric emptying rate.

Conclusions: The Tph1 mouse provides a powerful tool to study the functional roles of EC cells in the GI tract. Our findings suggest a new pathophysiologic mechanism of 5-HT deficiency in IG.
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http://dx.doi.org/10.1053/j.gastro.2021.02.060DOI Listing
June 2021

COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas.

Cell 2021 04 3;184(7):1895-1913.e19. Epub 2021 Feb 3.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China.

A dysfunctional immune response in coronavirus disease 2019 (COVID-19) patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 196 COVID-19 patients and controls and created a comprehensive immune landscape with 1.46 million cells. The large dataset enabled us to identify that different peripheral immune subtype changes are associated with distinct clinical features, including age, sex, severity, and disease stages of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in diverse epithelial and immune cell types, accompanied by dramatic transcriptomic changes within virus-positive cells. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis of and developing effective therapeutic strategies for COVID-19.
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http://dx.doi.org/10.1016/j.cell.2021.01.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857060PMC
April 2021

Strain Distribution and Drug Susceptibility of Invasive Fungal Infection in Clinical Patients With Systemic Internal Diseases.

Front Bioeng Biotechnol 2020 11;8:625024. Epub 2021 Feb 11.

Department of Dermatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Background: Patients with systemic internal diseases present high risks for invasive fungal infections, which results in increased morbidity and mortality. Identification of high-risk departments and susceptibility systems could help to reduce the infective rate clinically. Correct selection of sensitive anti-fungal drugs not only could improve the cure rate but also could reduce the adverse reactions and complications caused by long-term antifungal drug treatment, which can be especially important in patients with serious systemic diseases. Therefore, the distribution changes of invasive fungal strains in patients with systemic internal diseases and the choice of antifungal drugs in clinical practice should be updated.

Objective: This work aimed to investigate the incidence, strain distributions, and drug susceptibility of invasive fungal strains isolated from patients with systemic internal diseases.

Methods: Samples were collected from 9,430 patients who were diagnosed with internal diseases in our hospital from January to December 2018. We then cultured and identified the fungal strains using API 20C AUX. We performed drug sensitivity analysis the ATB Fungus-3 fungal susceptibility strip. Resistance was defined using the revised Clinical Laboratory Standardization Committee of United States breakpoints/epidemiological cutoff values to assign susceptibility or wild-type status to systemic antifungal agents.

Results: A total of 179 patients (49 female, 130 male) with fungal infection were included. The high-incidence departments were determined to be the respiratory department (34.64%), intensive care unit (ICU; 21.79%), and hepatology department (9.50%). The susceptible systems for infection were the respiratory tract (sputum, 68.72%, 123/179; secretion retained in the tracheal catheter, 3.35%, 6/179), urinary tract (urine, 9.50%, 17/179), and gastrointestinal tract (feces, 9.50%, 17/179). The major pathogens were (90.50%), (8.93%), and (0.56%). The infective candida subgroups were (70.95%), (6.15%), (5.59%), (3.91%), and (3.91%). The susceptibility of non- fungi for amphotericin B was 100.0%. The susceptibility rates of 5-fluorocytocine (5-FC) and voriconazole were 72.73 and 81.82%, respectively, for , 98.43 and 100% for , and 100% for both drugs for , , and . The susceptibility rates of fluconazole and itraconazole were 0 and 54.55%, respectively, for , 20 and 20% for , and 57.14 and 57.14% for . The resistance rate of for both fluconazole and itraconazole was 41.43%.

Conclusion: Patients in the respiratory department, ICU, and hepatology department presented high rates of invasive fungal infections and should include special attention during clinical treatment. The respiratory tract, urinary tract, and gastrointestinal tract were the susceptible systems. , especially , was the main pathogen. From the perspective of drug sensitivity, amphotericin B should be given priority in treating the non- fungi infection in patients with systemic internal diseases, while the susceptibility of invasive fungal strains to azoles was variant. These data might provide clinical evidence for the prevention and treatment of invasive fungal infection in patients with systemic internal diseases.
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http://dx.doi.org/10.3389/fbioe.2020.625024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906281PMC
February 2021

TEMPORARY REMOVAL: Growth hormone improves insulin-like growth factor 1 and steroid hormone levels in follicle fluid, expression of hormone receptors in granulosa cells, and in vitro fertilization outcomes of poor ovarian responders.

Fertil Steril 2021 Feb 26. Epub 2021 Feb 26.

Reproductive Medicine Center, Sichuan Provincial Women's and Children's Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, Sichuan, People's Republic of China.

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http://dx.doi.org/10.1016/j.fertnstert.2021.01.006DOI Listing
February 2021

Assembly Pathway Selection with DNA Reaction Circuits for Programming Multiple Cell-Cell Interactions.

J Am Chem Soc 2021 Mar 25;143(9):3448-3454. Epub 2021 Feb 25.

Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai 200241, P. R. China.

The manipulation of cell-cell interactions promotes the study of multicellular behavior, but it remains a great challenge for programming multicellular assembly in complex reaction pathways with multiple cell types. Here we report a DNA reaction circuit-based approach to cell-surface engineering for the programmable regulation of multiple cell-cell interactions. The DNA circuits are designed on the basis of a stem-loop-integrated DNA hairpin motif, which has the capability of programming diverse molecular self-assembly and disassembly pathways by sequential allosteric activation. Modifying the cell surface with such DNA reaction circuits allows for performing programmable chemical functions on cell membranes and the control of multicellular self-assembly with selectivity. We demonstrate the selective control of targeting the capability of natural killer (NK) cells to two types of tumor cells, which show selectively enhanced cell-specific adaptive immunotherapy efficacy. We hope that our method provides new ideas for the programmable control of multiple cell-cell interactions in complex reaction pathways and potentially promotes the development of cell immunotherapy.
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http://dx.doi.org/10.1021/jacs.0c12358DOI Listing
March 2021

Structure-Activity Relationship Studies of Coumarin-like Diacid Derivatives as Human G Protein-Coupled Receptor-35 (hGPR35) Agonists and a Consequent New Design Principle.

J Med Chem 2021 03 25;64(5):2634-2647. Epub 2021 Feb 25.

Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116034, China.

A series of coumarin-like diacid derivatives were designed and synthesized as novel agonists of human G-protein-coupled receptor 35 (hGPR35). Active compounds were characterized to possess one acidic group on both sides of a fused tricyclic aromatic scaffold. Most of them functioned as full agonists selective to hGPR35 and exhibited excellent potency at low nanomolar concentrations. Substitution on the middle ring of the scaffold could effectively regulate compound potency. Structure-activity relationship studies and docking simulation indicated that compounds that carried two acidic groups with a proper special distance and attached to a rigid aromatic scaffold would most likely show a potent agonistic activity on hGPR35. Following this principle, we screened a list of known compounds and some were found to be potent GPR35 agonists, and compound even had an EC of 8 nM. Particularly, a dietary supplement pyrroloquinoline quinone (PQQ) was identified as a potent agonist (EC = 71.4 nM). To some extent, this principle provides a general strategy to design and recognize GPR35 agonists.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01624DOI Listing
March 2021

Checkpoint inhibitor immunotherapy toxicity and overall survival among older adults with advanced cancer.

J Geriatr Oncol 2021 Jun 21;12(5):813-819. Epub 2021 Feb 21.

Div. of Medical Oncology, Dept. of Internal Medicine, The Ohio State University Wexner Medical Center, USA. Electronic address:

Objectives: Despite growing evidence that checkpoint inhibitor immunotherapy (IO) toxicity is associated with improved treatment response, the relationship between immune-related adverse events (irAEs) and overall survival (OS) among older adults [age ≥ 70 years (y)] remains unknown. The study goal was to determine differences in OS based on age and ≥ grade 3 (G3) irAEs.

Materials And Methods: This was a retrospective cohort study of 673 patients with advanced cancer. Patients who received ≥1 dose of IO at our institution from 2011 to 2018 were eligible. The primary outcome was OS from the start of first line of IO treatment, compared between four patient groups stratified by age and ≥ G3 irAEs with adjustment for patient characteristics using a Cox proportional hazards model.

Results And Conclusion: Among all 673 patients, 35.4% were ≥ 70y, 39.8% had melanoma, and 45.6% received single-agent nivolumab. Incidence and types of ≥G3 irAEs did not differ by age. Median OS was significantly longer for all patients with ≥G3 irAEs (unadjusted 21.7 vs. 11.9 months, P = 0.007). There was no difference in OS among patients ≥70y with ≥G3 irAEs (HR 0.94, 95% CI 0.61-1.47, P = 0.79) in the multivariable analysis. Patients <70y with ≥G3 irAEs had significantly increased OS (HR 0.33, 95% CI 0.21-0.52, P < 0.001). Younger patients, but not older adults, with high-grade irAEs experience strong survival benefit. This difference may be due to the toll of irAEs themselves or the effects of treatments for irAEs, such as corticosteroids. Factors impacting OS of older adults after irAEs must be determined and optimized.
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http://dx.doi.org/10.1016/j.jgo.2021.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184608PMC
June 2021