Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.770
Filtrar
1.
Front Neurol ; 13: 923310, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36090859

RESUMO

Objective: Neuroimaging meta-analysis identified abnormal neural activity alterations in patients with type 2 diabetes mellitus (T2DM), but there was no consistency or heterogeneity analysis between different brain imaging processing strategies. The aim of this meta-analysis was to determine consistent changes of regional brain functions in T2DM via the indicators obtained by using different post-processing methods. Methods: Since the indicators obtained using varied post-processing methods reflect different neurophysiological and pathological characteristics, we further conducted a coordinate-based meta-analysis (CBMA) of the two categories of neuroimaging literature, which were grouped according to similar data processing methods: one group included regional homogeneity (ReHo), independent component analysis (ICA), and degree centrality (DC) studies, while the other group summarized the literature on amplitude of low-frequency fluctuation (ALFF) and cerebral blood flow (CBF). Results: The final meta-analysis included 23 eligible trials with 27 data sets. Compared with the healthy control group, when neuroimaging studies were combined with ReHo, ICA, and DC measurements, the brain activity of the right Rolandic operculum, right supramarginal gyrus, and right superior temporal gyrus in T2DM patients decreased significantly. When neuroimaging studies were combined with ALFF and CBF measurements, there was no clear evidence of differences in the brain function between T2DM and HCs. Conclusion: T2DM patients have a series of spontaneous abnormal brain activities, mainly involving brain regions related to learning, memory, and emotion, which provide early biomarkers for clarifying the mechanism of cognitive impairment and neuropsychiatric disorders in diabetes. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=247071, PROSPERO [CRD42021247071].

2.
Eur J Med Chem ; 243: 114728, 2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-36084534

RESUMO

Currently, there is a significant unmet need for novel analgesics with fewer side effects. In this study, we carried out structural modification of a hit compound previously identified in an artificial-intelligence (AI) virtual screening and discovered the potent analgesic, benzo[b]thiophene-2-carboxamide analog (compound 25) with new structural scaffold. We investigated the signaling pathways of opioid receptors mediated by compound 25, and found this racemic compound activated mu-opioid receptor through the cyclic adenosine monophosphate (cAMP) and ß-arrestin-2-mediated pathways with strong potency and efficacy, and accompanying nociceptin-orphanin FQ opioid peptide and delta-opioid receptors through the cAMP pathway with weak potencies. Compound 25 elicited potent antinociception in thermal-stimulated pain (ED50 value of 127.1 ± 34.65 µg/kg) and inflammatory-induced allodynia models with less gastrointestinal transit inhibition and antinociceptive tolerance than morphine. Overall, this study revealed a novel analgesic with reduced risks of side effects.

3.
Artigo em Inglês | MEDLINE | ID: mdl-36129040

RESUMO

Ion signals in electrospray ionization (ESI) mass spectrometry (MS) are affected by addition of acid or base. Acids or bases are typically added to samples to enhance detection of analytes in positive- or negative-ion mode, respectively. To carry out simultaneous monitoring of analytes with different ionogenic moieties by ESI-MS, a rapid acid/base switching system was developed. The system was further coupled with flow injection analysis (FIA) and liquid chromatography (LC) MS. The two variants enable detection of separated analytes immediately after alternating addition of acid and base. The methods were tested using a set of phospholipids (PLs) as analytes. The rapid acid/base switching enhanced signals of some of the PL analytes in both ion modes of MS. Both FIA-MS and LC-MS with acid/base switching show signal enhancements (∼1.3-23.2 times) of some analyte signals when compared with analysis conducted without acid/base switching. The proposed methods are suitable for simultaneous analysis of cationic and anionic analytes. The FIA-MS and LC-MS methods with acid/base switching were also applied in analysis of lipid extract from real samples (sausage and porcine liver). However, the FIA-MS results were affected by ionization competition and isobaric interference due to the complexity of the sample matrix and diversity of PL species. In contrast, the LC-MS mode provides adequate selectivity to observe signal enhancement for specific analyte ions. Overall, alternating addition of acid and base immediately before the ESI source can improve analytical performance without the need to carry out separate analyses targeting different types of analytes.

4.
Front Digit Health ; 4: 945276, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36120710

RESUMO

Objective: Patients with diabetes have an increased risk of dementia. Improved prediction of dementia is an important goal in developing future prevention strategies. Diabetic retinopathy screening (DRS) photographs may be a convenient source of imaging biomarkers of brain health. We therefore investigated the association of retinal vascular measures (RVMs) from DRS photographs in patients with type 2 diabetes with dementia risk. Research Design and Methods: RVMs were obtained from 6,111 patients in the GoDARTS bioresource (635 incident cases) using VAMPIRE software. Their association, independent of Apo E4 genotype and clinical parameters, was determined for incident all cause dementia (ACD) and separately Alzheimer's disease (AD) and vascular dementia (VD). We used Cox's proportional hazards with competing risk of death without dementia. The potential value of RVMs to increase the accuracy of risk prediction was evaluated. Results: Increased retinal arteriolar fractal dimension associated with increased risk of ACD (csHR 1.17; 1.08-1.26) and AD (HR 1.33; 1.16-1.52), whereas increased venular fractal dimension (FDV) was associated with reduced risk of AD (csHR 0.85; 0.74-0.96). Conversely, FDV was associated with increased risk of VD (csHR 1.22; 1.07-1.40). Wider arteriolar calibre was associated with a reduced risk of ACD (csHR 0.9; 0.83-0.98) and wider venular calibre was associated with a reduced risk of AD (csHR 0.87; 0.78-0.97). Accounting for competing risk did not substantially alter these findings. RVMs significantly increased the accuracy of prediction. Conclusions: Conventional DRS photographs could enhance stratifying patients with diabetes at increased risk of dementia facilitating the development of future prevention strategies.

5.
Analyst ; 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36125110

RESUMO

The change in lysosomal pH is an important physiological indicator in the process of cell autophagy. Herein, a ratiometric fluorescent probe, 4-(2-(1H-benzo[d]imidazol-2-yl)vinyl)-N,N-dimethylaniline (BD), has been synthesized and applied for lysosomal pH detection and cell autophagy imaging. In this probe, the imidazole group and dimethylamino group possess excellent lysosomal targeting ability and the benzimidazole moiety acts as a proton reaction site. BD reveals an obvious ratiometric fluorescence emission with an ideal pKa value of 4.73 and a linear response in the range of 4.06-5.20, which is considered useful for the quantitative detection and imaging of lysosomal pH change. Meanwhile, BD exhibits a larger Stokes shift, good selectivity, strong photostability, good reversibility and good biocompatibility, which makes BD capable of being applied to complex biological environments. Ratiometric fluorescence imaging studies show that BD can selectively monitor the pH in the lysosomes of live cells, and even real-time dynamic monitoring of cell autophagy can be conducted. Moreover, BD also shows excellent application potential in the field of anticounterfeiting.

6.
Biology (Basel) ; 11(7)2022 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-36101343

RESUMO

The relationship between inflammatory bowel disease and sleep disturbances is complicated and of increasing interest. We investigated the inflammatory and immunological consequences of EA in sleep-deprived colitis and found that dextran sulfate sodium (DSS)-induced colitis in sleep-fragmented (SF) mice was more severe than that in mice with normal sleep. This increase in the severity of colitis was accompanied by reduced body weight, shortened colon length, and deteriorated disease activity index. DSS with SF mice presented obvious diminished intestinal tight junction proteins (claudin-1 and occludin), elevated proinflammatory cytokines (CRP, IFN-γ, IL-6), lowered melatonin and adiponectin levels, downregulated vasoactive intestinal peptide (VIP) type 1 and 2 receptor (VPAC1, VPAC2) expression, and decreased diversity of gut bacteria. EA ameliorated colitis severity and preserved the performance of the epithelial tight junction proteins and VIP receptors, especially VPAC2. Meanwhile, the innate lymphoid cells-derived cytokines in both group 2 (IL-4, IL5, IL-9, IL-13) and group 3 (IL-22, GM-CSF) were elevated in mice colon tissue. Furthermore, dysbiosis was confirmed in the DSS group with and without SF, and EA could maintain the species diversity. Firmicutes could be restored, such as Lachnospiraceae, and Proteobacteria become rebalanced, mainly Enterobacteriaceae, after EA intervention. On the other hand, SF plays different roles in physiological and pathological conditions. In normal mice, interrupted sleep did not affect the expression of claudin-1 and occludin. But VPAC1, VPAC2, and gut microbiota diversity, including Burkholderiaceae and Rhodococcus, were opposite to mice in an inflamed state.

7.
Artigo em Inglês | MEDLINE | ID: mdl-36114790

RESUMO

BACKGROUND: Herpes zoster (HZ), which is caused by reactivation of the latent varicella zoster virus, was not listed as a side effect of any vaccines until the introduction of coronavirus disease 2019 (COVID-19) vaccine. This study used a nationwide population database to examine whether the HZ risk is increased after receiving the influenza vaccination. METHODS: This population-based retrospective self-controlled case series evaluated the association between influenza vaccine exposure and HZ risk. Data were collected from Taiwan's National Health Insurance Research Database between 2015 and 2017. Patients with HZ diagnosed within 6 months before and after receiving the influenza vaccination were included. After receiving the influenza vaccine, the first 15 and 30 days were defined as risk intervals, while the other periods were defined as control intervals. Poisson regression was used to compare the incidence rate ratio (IRR) for HZ during the risk interval vs. the control interval. RESULTS: In total, 13,728 patients were diagnosed with HZ before and after receiving the influenza vaccine. The IRR for days 1-15 was significantly higher (IRR = 1.11; 95% confidence interval [CI], 1.02-1.20), but insignificant for days 1-30 (IRR = 1.04; 95% CI, 0.98-1.10). In a subgroup analysis, the IRRs were significantly higher in participants, including 50-64 years old (1.16; 95% CI, 1.02-1.33), males (1.14; 95% CI, 1.01-1.28), and healthier individuals (i.e., no history of cancer or autoimmune diseases). CONCLUSIONS: There was a slight increase in risk of HZ in people receiving influenza vaccine in the first 1-15 days after vaccination.

8.
Zootaxa ; 5141(6): 592-600, 2022 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-36095771

RESUMO

Three new species of the genus Hexarhopalus Fairmaire, 1891, all of the nominate subgenus, are described and figured from China: Hexarhopalus (Hexarhopalus) ferreri sp. nov. from Yunnan, H. (H.) tianbaoyanensis sp. nov. from Fujian, and H. (H.) yeziyangi sp. nov. from Jiangxi.


Assuntos
Besouros , Distribuição Animal , Animais , China
9.
J Med Syst ; 46(10): 67, 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36097228

RESUMO

Resource coordination in surgical scheduling remains challenging in health care delivery systems. This is especially the case in highly-specialized settings such as coordinating Intraoperative Neurophysiologic Monitoring (IONM) resources. Inefficient coordination yields higher costs, limited access to care, and creates constraints to surgical quality and outcomes. To maximize utilization of IONM resources, optimization-based algorithms are proposed to effectively schedule IONM surgical cases and technologists and evaluate staffing needs. Data with 10 days of case volumes, their surgery durations, and technologist staffing was used to demonstrate method effectiveness. An iterative optimization-based model that determines both optimal surgery and technologist start time (operational scenario 4) was built in an Excel spreadsheet along with Excel's Solver settings. It was compared with current practice (operational scenario 1) and optimization solution on only surgery start time (operational scenario 2) or technologist start time (operational scenario 3). Comparisons are made with respect to technologist overtime and under-utilization time. The results conclude that scenario 4 significantly reduces overtime by 74% and under-utilization time by 86% as well as technologist needs by 10%. For practices that do not have flexibility to alter surgeon preference on surgery start time or IONM technologist staffing levels, both scenarios 2 and 3 also result in substantial reductions in technologist overtime and under-utilization. Moreover, IONM technologist staffing options are discussed to accommodate technologist preferences and set constraints for surgical case scheduling. All optimization-based approaches presented in this paper are able to improve utilization of IONM resources and ultimately improve the coordination and efficiency of highly-specialized resources.


Assuntos
Monitorização Neurofisiológica Intraoperatória , Cirurgiões , Custos e Análise de Custo , Humanos
10.
J Formos Med Assoc ; 2022 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-36100494

RESUMO

BACKGROUND: Data on self-harm (SH) repetition in non-Western adolescents are limited; this study is to survey the predictors. METHODS: A total of 5879 adolescents (mean age 16.02 years) in Northern Taiwan were recruited. The participants filled in online questionnaires about their sociodemographic data, suicidality, depressive symptoms, self-esteem, social support, family discord, impulsivity, and alcohol and tobacco use at baseline (T1) and at the 1 year follow-up (T2). We used logistic regression analysis to examine the predictors of SH continuation. Generalized structural equation modeling (GSEM) was then estimated to analyze the treatable variables for both years and to investigate their relationships and mediating effects. RESULTS: A total of 125 students were identified as being in the SH continuation group; while 470 students were identified as being in the SH stop group. The SH continuation rate was 21%; no significant gender difference was found. Logistic regression analysis showed that the predictors of SH continuation were low school ranking, poor quality of listening from relatives, use of the cutting method for SH, and a suicide plan in the past year at T1, and more depressed mood, use of the cutting method for SH, more suicide ideation and plans at T2. Similar predictors were found by GSEM; self-esteem at T1 and depressed mood at T2 were found to be mediators in the pathways. CONCLUSION: The continuation rate of SH was similar to that reported in Western countries. These predictors should be included in the treatment plan to prevent SH continuation.

11.
Front Immunol ; 13: 972746, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091011

RESUMO

Background: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder of the immune regulatory system caused by forkhead box P3 (FOXP3) mutations. Abnormal numbers or functions of regulatory T (Treg) cells account for the various autoimmune symptoms. We aimed to explore the molecular genetics and phenotypic spectra of patients with atypical IPEX syndrome in China. Methods: We analyzed the molecular, clinical and immune phenotype characteristics of five Chinese patients with FOXP3 mutations. Results: We summarized the molecular and phenotypic features of five patients with FOXP3 mutations, including two novel mutations. Four of the five patients displayed atypical phenotypes, and one developed immune-related peripheral neuropathy. Three of the five patients showed normal frequencies of Treg cells, but the proportions of subsets of Treg cells, CD4+ T cells and B cells were out of balance. Conclusions: Our report broadens the understanding of the clinical features of atypical IPEX syndrome. Our detailed analyses of the immunological characteristics of these patients enhance the understanding of the possible mechanisms underlying the clinical manifestations.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X , Enteropatias , Poliendocrinopatias Autoimunes , Diabetes Mellitus Tipo 1/congênito , Diarreia , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Doenças do Sistema Imunitário/congênito , Fenótipo , Síndrome
12.
Opt Lett ; 47(18): 4632-4635, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36107050

RESUMO

Extreme events are observed in the spatiotemporal chaos dynamics of a three-element laterally coupled laser array. With the help of statistical and dynamical analyses, we confirm that spatiotemporal chaos induces extreme pulses that are high enough to be identified as extreme events and cannot be found in synchronization chaos. Interestingly, our results show that extreme events always preferentially appear in the middle laser as the laser separation ratio is decreased (i.e., upon increasing the coupling strength), and then in the two outer lasers. This thus reveals the importance of the middle laser in the transition between synchronization chaos and spatiotemporal chaos states. Additionally, we show the evolution of extreme events in the plane of the pump level and laser separation ratio by calculating the corresponding proportion. Our results build a relation between extreme events and the spatiotemporal dynamics, which makes it easy to understand the formation mechanism of extreme events.

13.
J Dtsch Dermatol Ges ; 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36108333

RESUMO

BACKGROUND AND OBJECTIVES: Despite the well-established association between bullous pemphigoid (BP) and neurological diseases, the association between BP and psychiatric disorders remains unclear. In this study, we aimed to investigate the association between BP and various psychiatric disorders. PATIENTS AND METHODS: PubMed, Embase, and Cochrane Library databases were searched for the identification of eligible cohort and case-control studies until May 30, 2021. Meta-analyses of crude estimates and adjusted estimates of odds ratio (OR) for case-control studies and hazard ratio (HR) cohort studies were then conducted. RESULTS: Sixteen studies involving 637,285 patients were included for the qualitative synthesis. In the meta-analysis of adjusted estimates for case-control studies, patients with BP exhibited a significantly higher prevalence of psychiatric disorders (OR 1.77, 95 % confidence interval (CI) 1.07-2.92) and schizophrenia (OR 2.63, 95 % CI 2.03-3.39). Regarding the analysis of adjusted estimates of cohort studies, BP presented no significantly higher risk of depression (HR 1.09, 95 % CI 0.94-1.26) and schizophrenia (HR 1.35, 95 % CI 0.76-2.39). CONCLUSIONS: Psychiatric disorders, especially schizophrenia, have a significantly higher risk of preceding BP.

14.
Clin Oral Investig ; 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36109374

RESUMO

OBJECTIVE: The objective of this study was to determine if hemodialysis patients who have undergone an invasive dental treatment are at risk of developing infective endocarditis. MATERIALS AND METHODS: This study was a cohort case-control design and used secondary data collected from the National Health Insurance Research Database of Taiwan. The case group and the control group were each comprised of 19,602 hemodialysis patients. The control group was matched for four variables: age, gender, a medical history of diabetes mellitus, and a cerebrovascular event. After matching, the case group and the control group were each comprised of 19,602 hemodialysis patients. Cox regression analysis determined hazard ratios and 95% confidence intervals. RESULTS: Patients were followed up at 1 month and 3 months after receiving invasive dental treatment. The results showed the cohort case-control hazard ratio was 0.88 (95% CI, 0.49, 1.57) 1 month after receiving invasive dental treatment. Three months after receiving IDT, the cohort case-control hazard ratio was 1.04 (95% CI, 0.71, 1.52). Hazard ratios did not differ significantly between groups. CONCLUSIONS: Hemodialysis patients who received invasive dental treatment had no greater risk of developing infective endocarditis than matched control patients. The results of this study should alleviate concerns for hemodialysis patients and dentists about invasive dental treatment procedures. We recommend hemodialysis patients undergo invasive dental treatment when needed. CLINICAL RELEVANCE: The results of this study showed that invasive dental treatment did not increase their risk of developing infective endocarditis. Hemodialysis patients in need of an invasive dental procedure should be encouraged to undergo treatment if the dentist deems it necessary.

15.
Artigo em Inglês | MEDLINE | ID: mdl-36111786

RESUMO

Collision-induced dissociation (CID) tandem mass spectrometry is commonly used for carbohydrate structural determinations. In the CID tandem mass spectrometry approach, carbohydrates are dissociated into fragments, and this is followed by the structural identification of fragments through subsequent CID. The success of the structural analysis depends on the structural correlation of fragments before and after dissociation, that is, structural memory of fragments. Fragments that completely lose the memory of their original structures cannot be used for structural analysis. By contrast, fragments with extremely strong correlations between the structures before and after fragmentation retain the information on their original structures as well as have memories of their precursors' entire structures. The CID spectra of these fragments depend on their own structures and on the remaining parts of the precursor structures, making structural analysis impractical. For effective structural analysis, the fragments produced from a precursor must have good structural memory, meaning that the structures of these fragments retain their original structure, and they must not be strongly affected by the remaining parts of the precursors. In this study, we found that most of the carbohydrate fragments produced by low-energy CID have good memory in terms of linkage position and anomericity. Fragments with ugly memory, where fragment structures change with the remaining parts of the precursors, can be attributed to C ion formation in a linear form. Fragments with ugly memory can be changed to have good memory by preventing linear C ion generation by using an alternative CID sequence, or the fragments of ugly memory can become useful in structural analysis when the contribution of linear C ions in fragmentation patterns is understood.

16.
In Vivo ; 36(5): 2083-2091, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36099092

RESUMO

BACKGROUND/AIM: The T cell's flexibility of the immune system to be regulated affects the onset of type 1 diabetes (T1D). However, the mechanisms of endoplasmic reticulum (ER) stress and inflammasome activation in the circulating CD3+CD56+ T cells of patients with T1D remain unclear. This study evaluated the role of CD3+CD56+ T cells in T1D and their correlations with ER stress, inflammasome activation and disease characteristics. MATERIALS AND METHODS: The frequency of circulating CD3+CD56+ T cells was determined using flow cytometry in healthy individuals and patients with T1D. Calnexin, NLR family pyrin domain containing 3 (NLRP3), ASC, caspase-1 (Casp1), cleaved caspase-3 (C-Casp3), and annexin V (AnnV) expression and propidium iodide staining in CD3+/CD56+ T cells were analyzed using flow cytometry. RESULTS: The frequency of CD3+CD56+ T cells was reduced in patients with T1D relative to that in healthy individuals. In addition, high calnexin, NLRP3, ASC and Casp1 expression in CD3+CD56+ T cells was negatively correlated with the percentage of CD3+CD56+ T cells in patients with T1D. CONCLUSION: ER stress, inflammasome activation, and a lower peripheral frequency of circulating CD3+CD56+ T cells might indicate disease progression and necessitate clinical T1D immunological self-tolerance monitoring.


Assuntos
Diabetes Mellitus Tipo 1 , Inflamassomos , Calnexina/metabolismo , Humanos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Linfócitos T/metabolismo
17.
Front Immunol ; 13: 1003761, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36105812

RESUMO

[This corrects the article DOI: 10.3389/fimmu.2022.935700.].

18.
Clin Otolaryngol ; 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36106575

RESUMO

OBJECTIVES: Fungal rhinosinusitis is an inflammatory disease of the nose that may lead to life-threatening complications. This study compared the bacterial and fungal microbiomes between patients with invasive fungal rhinosinusitis (IFRS) and non-invasive fungal rhinosinusitis (NIFRS). DESIGN: This was a prospective study including 18 IFRS and NIFRS patients. Fugal and bacterial microbiomes from surgical specimens were sequenced from amplicons of the internal transcribed spacer 1 (ITS1) region and the V3-V4 region of the 16S locus, respectively. Microbiomes were generated using the Illumina MiSeq System 2 x 301 base pair chemistry with a paired-end protocol. SETTING: Tertiary medical center. RESULTS: Targeted metagenomics identified Aspergillus spp. as the predominant fungus in both IFRS and NIFRS patients. Based on phylum and genera level diversity, and abundance differences, significant differences of operational taxonomic units (OTUs) (Fusobacterium, Prevotella, Pseudomonas, Neisseria, and Streptococcus) were more abundant in NIFRS compared with IFRS patients. CONCLUSIONS: This is the first study to analyze bacterial and fungal microbiomes in patients with IFRS and NIFRS via ITS1 and 16S genomics sequencing. Bacterial microbiomes from patients with IFRS demonstrated dysbiosis (alterations in diversity and abundance) compared to those from patients with NIFRS.

19.
Front Immunol ; 13: 807915, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36059490

RESUMO

"On-target off-tumor" toxicity is a major challenge to the use of chimeric antigen receptor (CAR)-engineered T cells in the treatment of solid malignancies, because of the expression of target antigens in normal tissues. Mesothelin overexpression is associated with poor prognosis of multiple solid tumors, and would therefore appear to be a suitable antigen target. To understand the risk of toxicity to different organs on anti-mesothelin CAR T cell therapy, single-cell RNA sequencing (scRNA-seq) datasets derived from major human physiological systems were analyzed in this study, including the respiratory, cardiovascular, digestive, and urinary systems. According to scRNA-seq datasets, the organs were stratified into high or low risk based on the level of mesothelin expression. We report that the proportion of mesothelin-positive cells was 7.71%, 2.40% and 2.20% of myocardial cells, pulmonary cells and stomach cells, respectively, indicating that these organs could be at high risk of "on-target off-tumor" toxicity on anti-mesothelin CAR T cell therapy. By contrast, esophagus, ileum, liver, kidney and bladder exhibited low mesothelin expression (<1%). Therefore, these organs could be regarded as at low risk. Thus, the risk of toxicity to different organs and tissues in anti-mesothelin CAR T cell therapy may be predicted by these scRNA-seq data.


Assuntos
Imunoterapia Adotiva , Neoplasias , Proteínas Ligadas por GPI/metabolismo , Humanos , Imunoterapia Adotiva/efeitos adversos , Mesotelina , Neoplasias/genética , Neoplasias/terapia , RNA-Seq , Receptores de Antígenos de Linfócitos T
20.
Artigo em Inglês | MEDLINE | ID: mdl-36115198

RESUMO

High molecular weight (HMW) species are product-related variants that may impact therapeutic product safety and efficacy. Therefore, HMW species and aggregates are considered critical quality attributes and their levels should be closely monitored and controlled during drug development, commercial manufacturing, and shelf-life storage period for therapeutic monoclonal antibody drug products. Various biophysical and analytical methods have been developed to characterize the HMW species to understand their mechanisms of formation and assess potential product risk. However, host cell protein (HCP) analysis has seldom been conducted to characterize the impurities in aggregates. In this work, HCP analysis of enriched HMW species and drug substance (DS) from five different monoclonal antibodies (mAbs) was performed. More HCPs are identified in the enriched HMW than in the DS, thus demonstrating a potential interaction between HCPs and HMW. Certain HCPs, including commonly detected HCPs and problematic HCPs, were enriched in HMW fractions. Especially, the most abundant HCP from mAb1, CC motif chemokine, was 46 times more abundant in enriched HMW than DS. The enriched HMW was further fractionated into enriched dimers and enriched very HMW (vHMW) fractions. The CC motif chemokine was found to interact mainly with mAb1 dimer species rather than vHMW fraction. Removing the HMW species from mAb1 significantly decreased the CC motif chemokine level in the final mAb1 DS. Our findings demonstrate that some HCPs are more preferentially bound to HMW species and this finding may provide a new opportunity for removing HCPs in downstream purification steps.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...