Publications by authors named "Hui Lu"

722 Publications

Alterations of the Human Lung and Gut Microbiomes in Non-Small Cell Lung Carcinomas and Distant Metastasis.

Microbiol Spectr 2021 Nov 17:e0080221. Epub 2021 Nov 17.

Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. Although dysbiosis of the lung and gut microbiota have been associated with NSCLC, their relative contributions are unclear; in addition, their roles in distant metastasis (DM) are still illusive. We recruited in total 121 participants, including 87 newly diagnosed treatment-naive NSCLC patients of various stages and 34 healthy volunteers, and surveyed their fecal and sputum microbiota. We compared the microbial profiles between groups, identified microbial biomarkers, and generated machine learning models for distinguishing healthy individuals from patients with NSCLC and patients of various stages. We found significant perturbations of gut and sputum microbiota in patients with NSCLC and DM. A machine learning model combining both microbiota (combined model) performed better than an individual data set in patient stratification, with the highest area under the curve (AUC) value of 0.896. Sputum and gut microbiota both contributed to the combined model; in most cases, sputum-only models performed similar to the combined models. Several microbial biomarkers were shared by both microbiotas, indicating their similar roles at distinct body sites. Microbial biomarkers of distinct disease stages were mostly shared, suggesting biomarkers for DM could be acquired early. Furthermore, Pseudomonas aeruginosa, a species previously associated with wound infections, was significantly more abundant in brain metastasis, indicating that distinct types of DMs could have different microbes. Our results indicate that alterations of the sputum microbiota have stronger relationships with NSCLC and DM than the gut and strongly support the feasibility of metagenome-based noninvasive disease diagnosis and risk evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT03454685). Our survey on gut and sputum microbiota revealed that both were significantly disturbed in non-small cell lung cancer (NSCLC) and associated with distant metastasis (DM) while only the sputum microbiota was associated with non-DM NSCLC. The lung microbiota could therefore have a stronger association with (and thus may contribute more to) disease development than the gut microbiota. Mathematic models using both microbiotas performed better in patient stratification than using individual microbiota. Sputum models, however, performed similar to the combined models, suggesting a convenient, noninvasive diagnostic for NSCLC. Microbial biomarkers of distinct disease stages were mostly shared, suggesting that the same set of microbes were underlying disease progression, and the signals for distant metastasis could be acquired at early stages of the disease. Our results strongly support the feasibility of noninvasive diagnosis of NSCLC, including distant metastasis, are of clinical importance, and should warrant further research on the underlying molecular mechanisms.
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http://dx.doi.org/10.1128/Spectrum.00802-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8597645PMC
November 2021

Disease Prevalence and Fatality, Life History Strategies, and Behavioral Control of the COVID Pandemic.

Evol Psychol Sci 2021 Nov 9:1-10. Epub 2021 Nov 9.

Department of Psychology, Faculty of Social Sciences, University of Macau, Taipa, Macao, China.

The COVID-19 pandemic caught the world by surprise and raised many questions. One of the questions is whether infectious diseases indeed drive fast life history (LH) as the extent research suggests. This paper challenges this assumption and raises a different perspective. We argue that infectious diseases enact either slower or faster LH strategies and the related disease control behavior depending on disease severity. We tested and supported the theorization based on a sample of 662 adult residents drawn from all 32 provinces and administrative regions of mainland China. The findings help to broaden LH perspectives and to better understand unusual social phenomena arising from the COVID-19 pandemic.
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http://dx.doi.org/10.1007/s40806-021-00306-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576458PMC
November 2021

Prenylated xanthones with α-glucosidase and α-amylase inhibitory effects from the pericarp of .

J Asian Nat Prod Res 2021 Nov 11:1-10. Epub 2021 Nov 11.

General Hospital of North Theater, PLA, Shenyang 110015, China.

Two new prenylated xanthones, mangoxanthones A-B (-), together with four known compounds -, were isolated from the ethanol extract of the pericarp of . The structures of these compounds have been elucidated based on spectroscopic analysis. The analysis results of chiral HPLC revealed compounds and were scalemic mixtures respectively. All isolated compounds were biologically evaluated for their α-glucosidase and α-amylase inhibitory effects using assays. Compound showed moderate inhibitory activities against α-glucosidase and α-amylase with IC of 29.06 ± 1.86 and 22.74 ± 2.07 μM, respectively. Molecular docking predicted the binding sites of compound to α-glucosidase and α-amylase. A preliminary structure-activity relationship was discussed.
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http://dx.doi.org/10.1080/10286020.2021.1967328DOI Listing
November 2021

Spatio-temporal variations of the major meteorological disasters and its response to climate change in Henan Province during the past two millennia.

PeerJ 2021 2;9:e12365. Epub 2021 Nov 2.

School of Economics and Management, Sanming University, Sanming, Fujian, China.

In China, historical documents have recorded large quantities of information related to natural disasters, and these disasters have had long-lasting effects on economic and social activities. Understanding the occurrence of the natural disasters and their spatio-temporal variation characters is crucial for sustainable of our society. Therefore, based on the collection and collation of historical documents, and adopting mathematical statistics, Kriging interpolation, correlation analysis and other methods, we systematically explored the meteorological disasters in Henan Province during the past two millennia in analyzing their spatio-temporal distribution characters and driving forces. The results demonstrate that there were five major types of meteorological disasters in Henan Province, including drought, flood, hails, low temperature and frost and insect pests, which presented obvious spatio-temporal variations and have occurred frequently during the past two millennia. According to the historical documents, the major meteorological disasters occurred 1,929 times in Henan from 221 BCE to 2000 CE. On the whole, the disaster frequency show that the occurrence cycle of the meteorological disasters has obvious changes, which mainly occurred in the middle and late stages during the past two millennia, especially after 1300 CE. Furthermore, we also find that the variation of meteorological disaster events is consistent with the variation of temperature in eastern China and the frequency of meteorological disaster increases in the cold period, but decreases in the warm period. In addition, there are obvious differences in the spatial distribution of the major meteorological disaster, which were mainly distributed in the northwest and southern part region of the Henan Province before 1911 CE. While after 1911 CE, the northern and southeastern parts were the meteorological disaster-prone areas in this region during this period. Spatial correlation analysis of each meteorological disaster before and after 1911 CE points out the droughts disaster frequency-occurring district has transferred in different periods, while the hail and low temperature and frost disasters just have a smaller transferred during these two periods. Conversely, the frequency-occurring districts of floods and insect pest disasters have no obviously transferred in different periods. These results can provide an important scientific basis for governmental decision makers and local people to prevent and mitigate meteorological disaster in the future.
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http://dx.doi.org/10.7717/peerj.12365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8570160PMC
November 2021

Efficacy of Conbercept in the Treatment of Choroidal Neovascularization Secondary to Pathologic Myopia.

Front Med (Lausanne) 2021 21;8:720804. Epub 2021 Oct 21.

Department of Ophthalmology, Zibo Central Hospital, Zibo, China.

To observe the clinical efficacy of conbercept in the treatment of choroidal neovascularization (CNV) secondary to pathologic myopia. We used retrospective analysis of the clinical data of 20 patients (24 eyes) with pathologic myopia choroidal neovascularization (PM-CNV). All patients were treated with intravitreal injection of conbercept 0.5 mg (0.05 ml), a vascular endothelial growth factor (VEGF) receptor fusion protein, and all patients completed at least 6 months of follow-up. Fundus, best corrected visual acuity (BCVA), fundus fluorescein angiography (FFA), optical coherence tomography (OCT), multifocal electroretinogram (mfERG) were assessed before and after treatment. Primary outcome was the functional change in amplitude by mfERG and secondary outcome was the structural change in central macular thickness (CRT) by OCT. The CNV area, leakage of CNV lesions, ocular and systemic adverse events were observed before and after treatment. The BCVA were 64.33 ± 10.83 letters, 65.42 ± 11.24 letters, 67.67 ± 7.07 letters after treatment 1, 3, 6 month, respectively, which showed improvement compared with the baseline ( < 0.05). The CRT decreased significantly from 308.50 ± 45.48 μm to 219.63 ± 30.27 μm, 221.33 ± 40.65 μm, 220.96 ± 33.09 μm after treatment 1, 3, 6 month, respectively ( < 0.05). The P1 response of mfERG amplitude improved from 40.71 ± 9.69 nv/deg2 to 50.67 ± 9.48 nv/deg2, 54.92 ± 8.45 nv/deg2, 55.67 ± 6.74 nv/deg2 after treatment 1, 3, 6 month, respectively ( < 0.05). After 6 months of treatment, the leakage of CNV lesions disappeared in 20 (83.3%) eyes, and the leakage area of CNV lesions was significantly reduced in 4 (16.7%) eyes. The intravitreal injection of conbercept significantly reduced CRT and the CNV area, inhibited the leakage of CNV, improved the BCVA, increased the response of mfERG amplitude, and restored the retinal function. The intravitreal injection of conbercept can change the morphology and function of the macular in PM-CNV, which is safe and effective for the treatment of PM-CNV.
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http://dx.doi.org/10.3389/fmed.2021.720804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566718PMC
October 2021

Growth Factors and Their Roles in Multiple Sclerosis Risk.

Front Immunol 2021 21;12:768682. Epub 2021 Oct 21.

Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.

Background: Previous studies have suggested essential roles of growth factors on the risk of Multiple Sclerosis (MS), but it remains undefined whether the effects are causal.

Objective: We applied Mendelian randomization (MR) approaches to disentangle the causal relationship between genetically predicted circulating levels of growth factors and the risk of MS.

Methods: Genetic instrumental variables for fibroblast growth factor (FGF) 23, growth differentiation factor 15 (GDF15), insulin growth factor 1 (IGF1), insulin-like growth factor binding proteins 3 (IGFBP3) and vascular endothelial growth factor (VEGF) were obtained from up-to-date genome-wide association studies (GWAS). Summary-level statistics of MS were obtained from the International Multiple Sclerosis Genetics Consortium, incorporating 14,802 subjects with MS and 26,703 healthy controls of European ancestry. Inverse-variance weighted (IVW) MR was used as the primary method and multiple sensitivity analyses were employed in this study.

Results: Genetically predicted circulating levels of FGF23 were associated with risk of MS. The odds ratio (OR) of IVW was 0.63 (95% confidence interval [CI], 0.49-0.82; < 0.001) per one standard deviation increase in circulating FGF23 levels. Weighted median estimators also suggested FGF23 associated with lower MS risk (OR = 0.67; 95% CI, 0.51-0.87; = 0.003). While MR-Egger approach provided no evidence of horizontal pleiotropy (intercept = -0.003, = 0.95). Results of IVW methods provided no evidence for causal roles of GDF1, IGF1, IGFBP3 and VEGF on MS risks, and additional sensitivity analyses confirmed the robustness of these null findings.

Conclusion: Our results implied a causal relationship between FGF23 and the risk of MS. Further studies are warranted to confirm FGF23 as a genetically valid target for MS.
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http://dx.doi.org/10.3389/fimmu.2021.768682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566812PMC
October 2021

Lymphocyte activation gene-3 is associated with programmed death-ligand 1 and programmed cell death protein 1 in small cell lung cancer.

Ann Transl Med 2021 Sep;9(18):1468

Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.

Background: In recent years, immunotherapy has achieved notable success in cancer treatment. Indeed, the novel immune checkpoint lymphocyte activation gene-3 (LAG3) has shown promising therapeutic efficacy in non-small cell lung cancer. However, it is unclear about the role of LAG3 in immunotherapy and survival in small cell lung cancer (SCLC).

Methods: The expression of LAG3 in SCLC was evaluated in four public datasets. The association of LAG3 with programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), and overall survival (OS) was investigated. The LAG3-related biological processes and pathways were identified by functional analyses.

Results: LAG3 expression was detected in SCLC tumor tissues. In the cBioPortal dataset with 81 clinical SCLC samples, LAG3 expression was markedly associated with PD-1 and PD-L1 expression (both P<0.050). In addition, Patients with high LAG3 expression had a trend toward a better OS (P=0.073). A similar survival trend was also observed in the GSE60052 dataset. Significantly, LAG3 expression was related to immune-related biological processes, such as immune response, antigen processing and presentation, and T cell co-stimulation (all P<0.001).

Conclusions: This study demonstrated that LAG3 is an important immune checkpoint that is closely associated with PD-1/PD-L1. LAG3 may be a promising novel immunotherapy target for SCLC.
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http://dx.doi.org/10.21037/atm-21-4481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8506769PMC
September 2021

Correction to: Clinical features and treatment efficacy for IgG4-related thyroiditis.

Orphanet J Rare Dis 2021 Nov 1;16(1):459. Epub 2021 Nov 1.

Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, State Key Laboratory of Complex Severe and Rare Diseases, Ministry of Education and National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), No.1 Shuai Fu Yuan, Dong Cheng District, Beijing, 100730, People's Republic of China.

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http://dx.doi.org/10.1186/s13023-021-02071-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8561975PMC
November 2021

Gastrointestinal Bleeding, but Not Other Gastrointestinal Symptoms, Is Associated With Worse Outcomes in COVID-19 Patients.

Front Med (Lausanne) 2021 13;8:759152. Epub 2021 Oct 13.

COVID-19 Study Group, General Hospital of Northern Theater Command, Shenyang, China.

Patients with coronavirus disease 2019 (COVID-19) can present with gastrointestinal (GI) symptoms. However, the prevalence of GI symptoms and their association with outcomes remain controversial in COVID-19 patients. All COVID-19 patients consecutively admitted to the Wuhan Huoshenshan hospital from February 2020 to April 2020 were collected. Disease severity and outcomes were compared between COVID-19 patients with and without GI symptoms. Logistic regression analyses were performed to evaluate the association of GI symptoms with the composite endpoint and death in COVID-19 patients. A composite endpoint was defined as transfer to intensive care unit, requirement of mechanical ventilation, and death. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Overall, 2,552 COVID-19 patients were included. The prevalence of GI symptoms was 21.0% (537/2,552). Diarrhea (8.9%, 226/2,552) was the most common GI symptom. Patients with GI symptoms had significantly higher proportions of severe COVID-19 and worse outcomes than those without. Univariate logistic regression analyses demonstrated that GI symptoms were significantly associated with the composite endpoint (OR = 2.426, 95% CI = 1.608-3.661; < 0.001) and death (OR = 2.137, 95% CI = 1.209-3.778; = 0.009). After adjusting for age, sex, and severe/critical COVID-19, GI symptoms were still independently associated with the composite endpoint (OR = 2.029, 95% CI = 1.294-3.182; = 0.002), but not death (OR = 1.726, 95% CI = 0.946-3.150; = 0.075). According to the type of GI symptoms, GI bleeding was an independent predictor of the composite endpoint (OR = 8.416, 95% CI = 3.465-20.438, < 0.001) and death (OR = 6.640, 95% CI = 2.567-17.179, < 0.001), but not other GI symptoms (i.e., diarrhea, abdominal discomfort, nausea and/or vomiting, constipation, acid reflux and/or heartburn, or abdominal pain). GI symptoms are common in COVID-19 patients and may be associated with their worse outcomes. Notably, such a negative impact of GI symptoms on the outcomes should be attributed to GI bleeding.
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http://dx.doi.org/10.3389/fmed.2021.759152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548414PMC
October 2021

GEDpm-cg: Genome Editing Automated Design Platform for Point Mutation Construction in .

Front Bioeng Biotechnol 2021 15;9:768289. Epub 2021 Oct 15.

Biodesign Center, Key Laboratory of Systems Microbial Biotechnology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China.

Advances in robotic system-assisted genome editing techniques and computer-aided design tools have significantly facilitated the development of microbial cell factories. Although multiple separate software solutions are available for vector DNA assembly, genome editing, and verification, by far there is still a lack of complete tool which can provide a one-stop service for the entire genome modification process. This makes the design of numerous genetic modifications, especially the construction of mutations that require strictly precise genetic manipulation, a laborious, time-consuming and error-prone process. Here, we developed a free online tool called GEDpm-cg for the design of genomic point mutations in . The suicide plasmid-mediated counter-selection point mutation editing method and the overlap-based DNA assembly method were selected to ensure the editability of any single nucleotide at any locus in the chromosome. Primers required for both DNA assembly of the vector for genetic modification and sequencing verification were provided as design results to meet all the experimental needs. An design task of over 10,000 single point mutations can be completed in 5 min. Finally, three independent point mutations were successfully constructed in guided by GEDpm-cg, which confirms that the design results could accurately and seamlessly be bridged with or experiments. We believe this platform will provide a user-friendly, powerful and flexible tool for large-scale mutation analysis in the industrial workhorse via robotic/software-assisted systems.
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http://dx.doi.org/10.3389/fbioe.2021.768289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8554027PMC
October 2021

MLST/MVLST Analysis and Antibiotic Resistance of in Shandong Province of China.

Iran J Public Health 2021 Sep;50(9):1805-1815

Shandong Center for Diseases Control and Prevention, Shandong Provincial Key Laboratory of Infectious Diseases Control and Prevention, Jinan, China.

Background: is an important bacterium causing profuse watery diarrhea. Cholera had swept the whole Shandong province from 1975 to 2013.

Methods: From epidemiological data and pulsed-field gel electrophoresis data, we selected 86 isolates appearing in Shandong Province in China from 1975 to 2013 and characterized them by multilocus sequence typing (MLST)/multi-virulence locus sequence typing (MVLST), antibiogram and analysis of genes related to antibiotic resistance.

Results: Combined MLST/MVLST data revealed 33 sequence types and a major group. Within the group, 3 subgroups (ST1, ST24 and ST29) were revealed, prevalent in the strains isolated during the 1980s, 1990s and 21st century, respectively. All the O1 isolates after 1990 were found to be El Tor variants harboring the classical gene. The gene of O139 strains had a mutation at amino acid position 62 (N→D). Antibiotic resistance of increased over time. Most El Tor variants between 1998 and 1999 were resistant to trimethoprim/sulfamethoxazole. The O139 strain, since its appearance in 1997, had significantly broader spectrum of antibiotic resistance than O1 variants. The presence of the SXT element corresponds to the trend of growing drug resistance.

Conclusion: The analysis of genotypic polymorphism and enhanced resistance of indicated continuous variation and evolution of this pathogenic agent in Shandong Province.
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http://dx.doi.org/10.18502/ijph.v50i9.7053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542817PMC
September 2021

MZINBVA: variational approximation for multilevel zero-inflated negative-binomial models for association analysis in microbiome surveys.

Brief Bioinform 2021 Oct 26. Epub 2021 Oct 26.

SJTU-Yale Joint Center for Biostatistics and Data Science, Shanghai Jiao Tong University, 800 Dongchuan RD, 200240, Shanghai, China.

As our understanding of the microbiome has expanded, so has the recognition of its critical role in human health and disease, thereby emphasizing the importance of testing whether microbes are associated with environmental factors or clinical outcomes. However, many of the fundamental challenges that concern microbiome surveys arise from statistical and experimental design issues, such as the sparse and overdispersed nature of microbiome count data and the complex correlation structure among samples. For example, in the human microbiome project (HMP) dataset, the repeated observations across time points (level 1) are nested within body sites (level 2), which are further nested within subjects (level 3). Therefore, there is a great need for the development of specialized and sophisticated statistical tests. In this paper, we propose multilevel zero-inflated negative-binomial models for association analysis in microbiome surveys. We develop a variational approximation method for maximum likelihood estimation and inference. It uses optimization, rather than sampling, to approximate the log-likelihood and compute parameter estimates, provides a robust estimate of the covariance of parameter estimates and constructs a Wald-type test statistic for association testing. We evaluate and demonstrate the performance of our method using extensive simulation studies and an application to the HMP dataset. We have developed an R package MZINBVA to implement the proposed method, which is available from the GitHub repository https://github.com/liudoubletian/MZINBVA.
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http://dx.doi.org/10.1093/bib/bbab443DOI Listing
October 2021

Propranolol Suppresses Proliferation and Migration of HUVECs through Regulation of the miR-206/VEGFA Axis.

Biomed Res Int 2021 16;2021:7629176. Epub 2021 Oct 16.

Department of Dermatology, Children's Hospital of Soochow University, Suzhou, Jiangsu Province 215025, China.

Propranolol has been used in the first-line therapy of infantile hemangioma (IH) for a number of years; however, the mechanisms through which propranolol regulates IH are not yet fully understood. In the present study, microRNA (miRNA/miR) sequencing analysis was performed to identify differentially expressed miRNAs in human umbilical vascular endothelial cells (HUVECs) treated with propranolol. Cell viability and apoptosis were detected using CCK-8 assay and flow cytometry, respectively. Cell migration was assessed using wound healing, Transwell, and tube formation assays. Methylation-specific PCR was then used to investigate the promoter methylation status. The levels of oxidative stress indicators, including superoxide dismutase, glutathione, and malondialdehyde were also detected. Finally, cell cycle analysis was performed using flow cytometry and western blotting. It was observed that propranolol induced the upregulation of miR-206 in HUVECs, which was caused by demethylation of the miR-206 promoter. Moreover, propranolol significantly inhibited the proliferation of HUVECs by inducing apoptosis, while these phenomena were reversed by miR-206 antagomir. VEGFA was found to be a target gene of miR-206. In addition, propranolol notably inhibited the migration and induced G1 arrest of the HUVECs, whereas these results were eliminated by miR-206 antagomir. Collectively, the findings of the present study demonstrated that propranolol may inhibit the proliferation and migration in HUVECs via modulating the miR-206/VEGFA axis. These findings suggest a novel mechanism through which propranolol suppresses the progression of IH.
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http://dx.doi.org/10.1155/2021/7629176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541866PMC
October 2021

Analysis of Shared Genetic Regulatory Networks for Alzheimer's Disease and Epilepsy.

Biomed Res Int 2021 14;2021:6692974. Epub 2021 Oct 14.

Department of Neurology, Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Diseases, Tianjin Dementia Institute, Tianjin 300350, China.

Alzheimer's disease (AD) and epilepsy are neurological disorders that affect a large cohort of people worldwide. Although both of the two diseases could be influenced by genetic factors, the shared genetic mechanism underlying the pathogenesis of them is still unclear. In this study, we aimed to identify the shared genetic networks and corresponding hub genes for AD and epilepsy. Firstly, the gene coexpression modules (GCMs) were constructed by weighted gene coexpression network analysis (WGCNA), and 16 GCMs were identified. Through further integration of GCMs, genome-wide association studies (GWASs), and expression quantitative trait loci (eQTLs), 4 shared GCMs of AD and epilepsy were identified. Functional enrichment analysis was performed to analyze the shared biological processes of these GCMs and explore the functional overlaps between these two diseases. The results showed that the genes in shared GCMs were significantly enriched in nervous system-related pathways, such as Alzheimer's disease and neuroactive ligand-receptor interaction pathways. Furthermore, the hub genes of AD- and epilepsy-associated GCMs were captured by weighted key driver analysis (wKDA), including , , , , , , , , and . The shared GCMs and hub genes might provide novel therapeutic targets for AD and epilepsy.
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http://dx.doi.org/10.1155/2021/6692974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8538392PMC
October 2021

Motor training improves coordination and anxiety in symptomatic -null mice despite impaired functional connectivity within the motor circuit.

Sci Adv 2021 Oct 22;7(43):eabf7467. Epub 2021 Oct 22.

Department of Pharmacology and Physiology, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA.

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http://dx.doi.org/10.1126/sciadv.abf7467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8535852PMC
October 2021

Allometric scaling of biomass with nitrogen and phosphorus above- and below-ground in herbaceous plants varies along water-salinity gradients.

AoB Plants 2021 Aug 9;13(4):plab030. Epub 2021 Jun 9.

Institute of Arid Ecology and Environment, Xinjiang University, Urumqi 830046, China.

Biomass allocation affects the ability of plants to acquire resources and nutrients; a limited allocation of nutrients, such as nitrogen and phosphorus, affects ecological processes. However, little research has been conducted on how plant allocation patterns change and on the trade-offs involved in allocation strategies when microhabitat gradients exist. We selected a 3.6 km transect in the Ebinur Lake Wetland Natural Reserve of Xinjiang, China, to investigate the relationships between plant traits (biomass and N and P concentrations) of herbaceous plants and environmental factors (soil moisture, salinity and nutrient content), and to determine the allometric scaling of biomass and stoichiometric traits between the above- and below-ground plant parts. The results show that the biomass and stoichiometric traits of plants reflected both the change of micro-environment and the natural characteristics of plants. With a decrease of the soil water availability and salinity, above- and below-ground N and P concentrations decrease gradually; scaling relationships exist between above- and below-ground plant parts, for biomass and N and P concentrations. Biomass allocation is influenced by soil nutrient ratios, and the allocation strategy tended to be conserved for N and variable for P. Second, the scaling relationships also show interspecific differences; all scaling exponents of are larger than for other species and indicate a 'tolerance' strategy, while other species tend to increase the below-ground biomass and N and P concentrations, i.e. a 'capture' strategy.
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http://dx.doi.org/10.1093/aobpla/plab030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500215PMC
August 2021

Limits of a Second Language: Native and Second Languages in Management Team Communication.

Front Psychol 2021 21;12:580946. Epub 2021 Sep 21.

BI Norwegian Business School, Oslo, Norway.

Cultural differences in speech acts are common challenges in management involving Chinese and Western managers. Comparing four groups - Native-speaking Chinese, English-speaking Chinese, Chinese-speaking Westerners, and non-Chinese- speaking Westerners, we assessed the effects of language and ethnicity on the ability to predict communication obstacles in a management team scenario. Bilingual subjects were less likely to be influenced by ethnic biases. Still, bilinguals were not more likely to adjust their metacognitions about communication toward those of the native speakers. The study creates a link between management, cognition and linguistics, as well as having consequences for the study of metacognition in cross-cultural management.
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http://dx.doi.org/10.3389/fpsyg.2021.580946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490803PMC
September 2021

Aneuploidy Underlies Tolerance and Cross-Tolerance to Drugs in Candida parapsilosis.

Microbiol Spectr 2021 Oct 6;9(2):e0050821. Epub 2021 Oct 6.

Department of Pharmacy, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.

species are the most common human fungal pathogens worldwide. Although C. albicans remains the predominant cause of candidiasis, infections caused by non-albicans species, including C. parapsilosis, are increasing. In C. albicans, genome plasticity has been shown to be a prevalent strategy of adaptation to stresses. However, the role of aneuploidy in C. parapsilosis is largely unknown. In this study, we found that six different aneuploid karyotypes conferred adaptation to the endoplasmic reticulum stress inducer tunicamycin (TUN) in C. parapsilosis. Interestingly, a specific aneuploidy including trisomy of chromosome 6 (Chr6x3) also enabled cross-tolerance to aureobasidin A (AbA), a sphingolipid biosynthesis inhibitor. Consistent with this, selection on AbA identified adaptors with three different aneuploid karyotypes, including Chr6x3, which also enabled cross-tolerance to both AbA and TUN. Therefore, as in other species, recurrent aneuploid karyotypes enable the adaptation of C. parapsilosis to specific stresses, and specific aneuploidies enable cross-adaptation to different stresses. Candida parapsilosis is an emerging human fungal pathogen, especially prevalent in neonates. Aneuploidy, having uneven numbers of chromosomes, is a well-known mechanism for adapting to stress in Candida albicans, the most common human fungal pathogen. In this study, we exposed C. parapsilosis to two very different drugs and selected for rare cells that grew in one of the drugs. We found that the majority of isolates that grew in the drugs had acquired an extra copy of one of several aneuploid chromosomes and that specific aneuploid chromosomes appeared in several independent cell clones. Importantly, an extra copy of chromosome 6 was detected following selection in either one of the drugs, and this extra chromosome conferred the ability to grow in both drugs, a property called cross-adaptation, or cross-tolerance. Thus, this study highlights the genome plasticity of C. parapsilosis and the ability of an extra copy of a single chromosome to promote cell growth in the presence of more than one drug.
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http://dx.doi.org/10.1128/Spectrum.00508-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8510177PMC
October 2021

DNA Damage Response and Repair Gene Alterations Increase Tumor Mutational Burden and Promote Poor Prognosis of Advanced Lung Cancer.

Front Oncol 2021 15;11:708294. Epub 2021 Sep 15.

Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.

DNA damage response and repair (DDR) gene alterations increase tumor-infiltrating lymphocytes, genomic instability, and tumor mutational burden (TMB). Whether DDR-related alterations relate to therapeutic response and prognosis in lung cancer lacking oncogenic drivers remains unknown. Pretherapeutic cancer samples of 122 patients [86 non-small cell lung cancer and 36 small cell lung cancer (SCLC)] harboring no alterations were collected. Through whole-exome sequencing, we outlined DDR mutational landscape and determined relationships between DDR gene alterations and TMB or intratumoral heterogeneity. Then, we evaluated the impacts of DDR gene alterations on therapeutic response and prognosis and established a DDR-based model for prognosis prediction. In addition, we investigated somatic interactions of DDR genes and immunomodulatory genes, immune expression patterns, immune microenvironment, and immune infiltration characteristics between DDR-deficient and DDR-proficient samples. Samples from cBioportal datasets were utilized for verification. We found that deleterious DDR gene alterations were closely associated with higher TMB than proficient-types ( < 0.001). DDR mechanisms attach great importance to the determination of patients' prognosis after chemotherapy, and alterations of base excision repair pathway in adenocarcinoma, nucleotide excision repair in squamous carcinoma, and homologous recombination pathway in SCLC tend to associate with worse progression-free survival to first-line chemotherapy (all < 0.05). A predictive nomogram model was constructed incorporating DDR-related alterations, clinical stage, and smoking status, with the area under curve values of 0.692-0.789 for 1- and 2-year receiver operating characteristic curves in training and testing cohorts. Furthermore, DDR-altered tumors contained enhanced frequencies of alterations in various genes of human leukocyte antigen (HLA) class I pathway including and than DDR-proficient samples. DDR-deficient types had lower expressions of STING1 ( = 0.01), CD28 ( = 0.020), HLA-DRB6 ( = 0.014) in adenocarcinoma, lower TNFRSF4 ( = 0.017), and TGFB1 expressions ( = 0.033) in squamous carcinoma, and higher CD40 ( = 0.012) and TNFRSF14 expressions = 0.022) in SCLC. DDR alteration enhanced activated mast cells in adenocarcinoma ( = 0.044) and M2 macrophage in squamous carcinoma ( = 0.004) than DDR-proficient types. Collectively, DDR gene alterations in lung cancer without oncogenic drivers are positively associated with high TMB. Specific DDR gene alterations tend to associate with worse progression-free survival to initial chemotherapy.
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http://dx.doi.org/10.3389/fonc.2021.708294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479169PMC
September 2021

Peripheral B-Cell Immunophenotyping Identifies Heterogeneity in IgG4-Related Disease.

Front Immunol 2021 17;12:747076. Epub 2021 Sep 17.

Department of Rheumatology, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.

Objectives: To elucidate heterogeneity of IgG4-related disease (IgG4-RD) based on B cell immunophenotyping.

Methods: Immunophenotyping of 4 B-cell subsets in peripheral blood from patients with active IgG4-RD (aIgG4-RD, n=105) was performed using flow cytometry to get preliminary B-cell heterogeneity spectrum. Then 10 B-cell subsets were characterized in aIgG4-RD (n = 49), remissive IgG4-RD (rIgG4-RD, n = 49), and healthy controls (HCs, n = 47), followed by principal components analysis (PCA) and cluster analysis to distinguish B-cell immunophenotypes and classify IgG4-RD patients into subgroups.

Results: Cluster analysis identified two endotypes in 105 aIgG4-RD patients based on 4 B-cell subsets: Group1 with higher Breg and naive B cells (n = 48), and Group2 with higher plasmablasts and memory B cells (MBCs) (n = 57). PCA indicated that aIgG4-RD consisted of plasmablast-naive B cell and MBCs-Breg axes abnormalities. There was a negative relationship between naive B cells and disease activity. Both plasmablasts and MBCs were positively associated with serological biomarkers. Cluster analysis stratified aIgG4-RD patients into 3 subgroups based on 10 B-cell subsets: subgroup1 with low MBCs and normal Breg, subgroup2 with high MBCs and low Breg, and subgroup3 with high plasmablasts and low naive B cells. Patients in subroup2 and subgroup3 were more likely to be resistant to treatment.

Conclusion: Patients with aIgG4-RD can be divided into 3 subgroups based on B cell heterogeneity. The B cell immunophenotyping could help elucidate the pathogenesis of IgG4-RD, identify patients with potential refractory IgG4-RD, and provide important information for the development of new therapies.
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http://dx.doi.org/10.3389/fimmu.2021.747076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484311PMC
September 2021

Metformin sensitises hepatocarcinoma cells to methotrexate by targeting dihydrofolate reductase.

Cell Death Dis 2021 10 2;12(10):902. Epub 2021 Oct 2.

Hefei National Laboratory for Physical Sciences at Microscale, The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China.

Metformin, the first-line drug for type II diabetes, has recently been considered an anticancer agent. However, the molecular target and underlying mechanism of metformin's anti-cancer effects remain largely unclear. Herein, we report that metformin treatment increases the sensitivity of hepatocarcinoma cells to methotrexate (MTX) by suppressing the expression of the one-carbon metabolism enzyme DHFR. We show that the combination of metformin and MTX blocks nucleotide metabolism and thus effectively inhibits cell cycle progression and tumorigenesis. Mechanistically, metformin not only transcriptionally represses DHFR via E2F4 but also promotes lysosomal degradation of the DHFR protein. Notably, metformin dramatically increases the response of patient-derived hepatocarcinoma organoids to MTX without obvious toxicity to organoids derived from normal liver tissue. Taken together, our findings identify an important role for DHFR in the suppressive effects of metformin on therapeutic resistance, thus revealing a therapeutically targetable potential vulnerability in hepatocarcinoma.
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http://dx.doi.org/10.1038/s41419-021-04199-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487431PMC
October 2021

Multimodal MR Images-Based Diagnosis of Early Adolescent Attention-Deficit/Hyperactivity Disorder Using Multiple Kernel Learning.

Front Neurosci 2021 14;15:710133. Epub 2021 Sep 14.

Shanghai Jiao Tong University-Yale Joint Center for Biostatistics and Data Science, Shanghai Jiao Tong University, Shanghai, China.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common brain diseases among children. The current criteria of ADHD diagnosis mainly depend on behavior analysis, which is subjective and inconsistent, especially for children. The development of neuroimaging technologies, such as magnetic resonance imaging (MRI), drives the discovery of brain abnormalities in structure and function by analyzing multimodal neuroimages for computer-aided diagnosis of brain diseases. This paper proposes a multimodal machine learning framework that combines the Boruta based feature selection and Multiple Kernel Learning (MKL) to integrate the multimodal features of structural and functional MRIs and Diffusion Tensor Images (DTI) for the diagnosis of early adolescent ADHD. The rich and complementary information of the macrostructural features, microstructural properties, and functional connectivities are integrated at the kernel level, followed by a support vector machine classifier for discriminating ADHD from healthy children. Our experiments were conducted on the comorbidity-free ADHD subjects and covariable-matched healthy children aged 9-10 chosen from the Adolescent Brain and Cognitive Development (ABCD) study. This paper is the first work to combine structural and functional MRIs with DTI for early adolescents of the ABCD study. The results indicate that the kernel-level fusion of multimodal features achieves 0.698 of AUC (area under the receiver operating characteristic curves) and 64.3% of classification accuracy for ADHD diagnosis, showing a significant improvement over the early feature fusion and unimodal features. The abnormal functional connectivity predictors, involving default mode network, attention network, auditory network, and sensorimotor mouth network, thalamus, and cerebellum, as well as the anatomical regions in basal ganglia, are found to encode the most discriminative information, which collaborates with macrostructure and diffusion alterations to boost the performances of disorder diagnosis.
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http://dx.doi.org/10.3389/fnins.2021.710133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477011PMC
September 2021

Adaptation to Fluconazole via Aneuploidy Enables Cross-Adaptation to Amphotericin B and Flucytosine in Cryptococcus neoformans.

Microbiol Spectr 2021 Oct 29;9(2):e0072321. Epub 2021 Sep 29.

Department of Pharmacy, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.

The high morbidity and mortality of cryptococcal meningitis is due to the limited range of therapeutic options: only three classes of antifungal drugs are available (polyenes [amphotericin B], azoles [fluconazole], and pyrimidine analogues [flucytosine]). Fluconazole is the most widely used antifungal drug in sub-Saharan Africa, where cryptococcal meningitis is a major cause of death in patients infected with HIV. In this study, we found that exposure to fluconazole, even for short times (48 h) at subinhibitory concentrations, drove rapid adaptation of Cryptococcus neoformans serotype A strain H99 via the acquisition of different aneuploid chromosomes. These aneuploidies conferred heteroresistance to fluconazole. Importantly, most of the adaptors were cross-tolerant to flucytosine. Some of the aneuploid adaptors were not heteroresistant to fluconazole but were tolerant to amphotericin B. Thus, exposure to one antifungal drug class can promote adaptation to two antifungal drug classes, highlighting the plasticity of the C. neoformans genome and raising concerns about the rapid reduction in the range of treatment options for cryptococcal infections. Cryptococcosis is a globally distributed invasive fungal infection caused by infections with Cryptococcus neoformans or Cryptococcus gattii. Only three classes of therapeutic drugs are clinically available for treating cryptococcosis: polyenes (amphotericin B), azoles (fluconazole), and pyrimidine analogues (flucytosine). Fluconazole is the primary drug available in resource-limited countries. Aneuploidy is a genomic state due to the gain or loss of chromosomes. We found that C. neoformans rapidly adapted to fluconazole by acquiring diverse aneuploidies and that specific aneuploidies enabled improved growth of isolates susceptible (tolerance) to amphotericin B and/or cross-tolerance to both fluconazole and flucytosine. Therefore, aneuploidy is an underlying mechanism of drug tolerance that not only arises rapidly during growth in fluconazole but can also confer tolerance to other antifungal drugs without prior exposure to those drugs. Resistant isolates have high MICs, and all cells grow similarly in medium with the drug, while tolerant isolates test as susceptible and grow slowly at drug concentrations above the MIC.
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http://dx.doi.org/10.1128/Spectrum.00723-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557924PMC
October 2021

Phenotype, function and clinical significance of innate lymphoid cells in immunoglobulin G4-related disease.

Rheumatology (Oxford) 2021 Sep 23. Epub 2021 Sep 23.

Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Beijing, China.

Objective: Innate immune system participates in immunoglobulin G4 related disease (IgG4-RD). While the role of innate lymphoid cells (ILCs) in IgG4-RD remains to be elucidated, we aimed to evaluate the phenotype, function and clinical significance of ILCs in IgG4-RD patients.

Methods: Sixty-seven untreated IgG4-RD patients, age and sex matched healthy controls (HCs) were enrolled. Circulating and tissue infiltration of ILCs were detected by flow cytometry. Serum suppression of tumorigenicity 2 (sST2) was detected by ELISA and membrane-bound ST2 (ST2L) was detected by flow cytometry. Tissue infiltration of IL-33 was measured by immunohistochemistry staining. RT-qPCR was performed to analyze the expression pattern of ILC2 associated genes between HCs and IgG4-RD patients. In addition, correlation analysis was performed in order to evaluate clinical significance of ILCs in IgG4-RD.

Results: The frequency of circulating pan ILCs in IgG4-RD patients was lower than in HCs. ILC2s was higher in IgG4-RD compared with HCs, whereas ILC1s was lower in IgG4-RD. sST2 and ST2L were increased in IgG4-RD than HC. Infiltration of ILC1s in submandibular glands of IgG4-RD was more prominent than ILC2s. Intracellular secretion of IL-9 was increased in ILC2s of IgG4-RD than in HCs. Circulating ILC2s correlated positively with Treg cells, the surface expression of CD154, PD-1 and CXCR5 in ILC2s correlated positively with CD19+B cells, serum IgG4 level and serum IgE, respectively.

Conclusion: ILCs and their subsets were significantly altered in IgG4-RD. We demonstrated the dysfunction of ILC2s in IgG4-RD by phenotype, correlation analysis, and function investigation, revealing ILC2s participated in the pathogenesis of IgG4-RD.
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http://dx.doi.org/10.1093/rheumatology/keab610DOI Listing
September 2021

Comparison of pathological findings between patients with relapsed and non-relapsed immunoglobin G4-related disease.

Chin Med J (Engl) 2021 Sep 9. Epub 2021 Sep 9.

Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing 100730, China Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China Department of Stomatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.

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http://dx.doi.org/10.1097/CM9.0000000000001713DOI Listing
September 2021

Genetical engineering for NK and T cell immunotherapy with CRISPR/Cas9 technology: Implications and challenges.

Cell Immunol 2021 Nov 1;369:104436. Epub 2021 Sep 1.

Department of Physiology and Neurobiology, Xinxiang Medical University, Xinxiang, Henan, PR China. Electronic address:

Immunotherapy has become one of the most promising strategies in cancer therapies. Among the therapeutic alternatives, genetically engineered NK/T cell therapies have emerged as powerful and innovative therapeutic modalities for cancer patients with precise targeting and impressive efficacy. Nonetheless, this approach still faces multiple challenges, such as immunosuppressive tumor microenvironment, exhaustion of immune effector cells in tumors, off-target effects manufacturing complexity, and poor infiltration of effector cells, all of which need to be overcome for further utilization to cancers. Recently, CRISPR/Cas9 genome editing technology, with the goal of enhancing the efficacy and increasing the availability of engineered effector cell therapies, has shown considerable potential in the novel strategies and options to overcome these limitations. Here we review the current progress of the applications of CRISPR in cancer immunotherapy. Furthermore, we discuss issues related to the NK/T cell applications, gene delivery methods, efficiency, challenges, and implications of CRISPR/Cas9.
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http://dx.doi.org/10.1016/j.cellimm.2021.104436DOI Listing
November 2021

Identification of subtypes correlated with tumor immunity and immunotherapy in cutaneous melanoma.

Comput Struct Biotechnol J 2021 6;19:4472-4485. Epub 2021 Aug 6.

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China.

Because immune checkpoint inhibitors (ICIs) are effective for a subset of melanoma patients, identification of melanoma subtypes responsive to ICIs is crucial. We performed clustering analyses to identify immune subtypes of melanoma based on the enrichment levels of 28 immune cells using transcriptome datasets for six melanoma cohorts, including four cohorts not treated with ICIs and two cohorts treated with ICIs. We identified three immune subtypes (Im-H, Im-M, and Im-L), reproducible in these cohorts. Im-H displayed strong immune signatures, low stemness and proliferation potential, genomic stability, high immunotherapy response rate, and favorable prognosis. Im-L showed weak immune signatures, high stemness and proliferation potential, genomic instability, low immunotherapy response rate, and unfavorable prognosis. The pathways highly enriched in Im-H included immune, MAPK, apoptosis, calcium, VEGF, cell adhesion molecules, focal adhesion, gap junction, and PPAR. The pathways highly enriched in Im-L included Hippo, cell cycle, and ErbB. Copy number alterations correlated inversely with immune signatures in melanoma, while tumor mutation burden showed no significant correlation. The molecular features correlated with favorable immunotherapy response included immune-promoting signatures and pathways of PPAR, MAPK, VEGF, calcium, and glycolysis/gluconeogenesis. Our data recapture the immunological heterogeneity in melanoma and provide clinical implications for the immunotherapy of melanoma.
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http://dx.doi.org/10.1016/j.csbj.2021.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379294PMC
August 2021

Valuing informal carers' quality of life using best-worst scaling-Finnish preference weights for the Adult Social Care Outcomes Toolkit for carers (ASCOT-Carer).

Eur J Health Econ 2021 Sep 1. Epub 2021 Sep 1.

Personal Social Services Research Unit (PSSRU), University of Kent, Kent, UK.

This study developed Finnish preference weights for the seven-attribute Adult Social Care Outcomes Toolkit for carers (ASCOT-Carer) and investigated survey fatigue and learning in best-worst scaling (BWS) experiments. An online survey that included a BWS experiment using the ASCOT-Carer was completed by a sample from the general population in Finland. A block of eight BWS profiles describing different states from the ASCOT-Carer were randomly assigned to each respondent, who consecutively made four choices (best, worst, second best and second worst) per profile. The analysis panel data had 32,160 choices made by 1005 respondents. A scale multinomial logit (S-MNL) model was used to estimate preference weights for 28 ASCOT-Carer attribute levels. Fatigue and learning effects were examined as scale heterogeneity. Several specifications of the generalised MNL model were employed to ensure the stability of the preference estimates. The most and least-valued states were the top and bottom levels of the control over daily life attribute. The preference weights were not on a cardinal scale. We observed the position effect of the attributes on preferences associated with the best or second-best choices. A learning effect was found. The established preference weights can be used in evaluations of the effects of long-term care services and interventions on the quality of life of service users and caregivers. The learning effect implies a need to develop study designs that ensure equal consideration to all profiles (choice tasks) in a sequential choice experiment.
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http://dx.doi.org/10.1007/s10198-021-01356-3DOI Listing
September 2021

Tunicamycin Potentiates Antifungal Drug Tolerance via Aneuploidy in Candida albicans.

mBio 2021 08 31;12(4):e0227221. Epub 2021 Aug 31.

Shmunis School of Biomedical and Cancer Research, The George S. Wise Faculty of Life Sciences, Tel Aviv Universitygrid.12136.37, Tel Aviv, Israel.

How cells exposed to one stress are later able to better survive other types of stress is not well understood. In eukaryotic organisms, physiological and pathological stresses can disturb endoplasmic reticulum (ER) function, resulting in "ER stress." Here, we found that exposure to tunicamycin, an inducer of ER stress, resulted in the acquisition of a specific aneuploidy, chromosome 2 trisomy (Chr2x3), in Candida albicans. Importantly, the resulting aneuploidy also conferred cross-tolerance to caspofungin, a first-line echinocandin antifungal, as well as to hydroxyurea, a common chemotherapeutic agent. Exposure to a range of tunicamycin concentrations induced similar ER stress responses. Extra copies of one Chr2 gene, , affected both tunicamycin and caspofungin tolerance, while at least 3 genes on chromosome 2 (, , and ) affected only tunicamycin and not caspofungin responses. Other Chr2 genes ( and ) affected hydroxyurea tolerance but neither tunicamycin nor caspofungin tolerance. Deletion of components of the protein kinase C (PKC) or calcineurin pathways affected tolerance to both tunicamycin and caspofungin, supporting the idea that the ER stress response and echinocandin tolerance are regulated by overlapping stress response pathways. Thus, antifungal drug tolerance can arise rapidly via ER stress-induced aneuploidy. Candida albicans is a prevalent human fungal commensal and also a pathogen that causes life-threatening systemic infections. Treatment failures are frequent because few therapeutic antifungal drug classes are available and because drug resistance and tolerance limit drug efficacy. We found that C. albicans rapidly overcomes the cellular stress induced by the drug tunicamycin by duplicating chromosome 2. Also, chromosome 2 duplication confers tolerance not only to tunicamycin but also to the following two unrelated drugs: caspofungin, an antifungal drug, and hydroxyurea, a chemotherapeutic. Cross tolerance to the three drugs involves different sets of genes, although some genetic pathways affect the tolerance to two of these three drugs. This work highlights a serious concern, namely, that changes in whole chromosome copy number can occur in response to one type of stress, and yet, they may facilitate the emergence of tolerance to multiple drugs, including the few antifungal drug classes available to treat infections.
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http://dx.doi.org/10.1128/mBio.02272-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406271PMC
August 2021
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