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1.
Curr Zool ; 68(4): 489-498, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36090147

RESUMO

Deciphering the role of climatic oscillations in species divergence helps us understand the mechanisms that shape global biodiversity. The cold-adapted species may have expanded their distribution with the development of glaciers during glacial period. With the retreat of glaciers, these species were discontinuously distributed in the high-altitude mountains and isolated by geographical barriers. However, the study that focuses on the speciation process of cold-adapted species is scant. To fill this gap, we combined population genetic data and ecological niche models (ENMs) to explore divergence process of snow partridge (Lerwa lerwa). Lerwa lerwa is a cold-adapted bird that is distributed from 4,000 to 5,500 m. We found 2 genetic populations within L. lerwa, and they diverged from each other at about 0.40-0.44 million years ago (inter-glacial period after Zhongliangan glaciation). The ENMs suggested that L. lerwa expanded to the low elevations of the Himalayas and Hengduan mountains during glacial period, whereas it contracted to the high elevations, southern of Himalayas, and Hengduan mountains during inter-glacial periods. Effective population size trajectory also suggested that L. lerwa expanded its population size during the glacial period. Consistent with our expectation, the results support that inter-glacial isolation contributed to the divergence of cold-adapted L. lerwa on Qinghai-Tibetan Plateau. This study deepens our understanding of how climatic oscillations have driven divergence process of cold-adapted Phasianidae species distributed on mountains.

2.
Front Pharmacol ; 13: 986962, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091840

RESUMO

Background: In this pooled analysis, the aim was to investigate the clinicopathological characteristics of patients with uncommon epidermal growth factor receptor (EGFR) (ucm-EGFRms) along with their treatment responses and survival following osimertinib treatment. Methods: Univariate chi-square analysis was conducted to analyze the correlation between clinical characteristics, EGFR mutation type, and treatment response, and the Kaplan-Meier method was applied for survival analysis. Univariate logistic regression model and Cox proportional hazards model were performed to compare the efficacy and prognosis in subgroup analysis. Results: Seventy-two NSCLC patients in total were included in this pooled analysis. The objective response rate (ORR) for osimertinib treatment was 57.0%, with a median PFS of 7.1 months. Twenty-eight patients received osimertinib as first-line therapy with an ORR of 67.9%, which was higher than that in patients who received osimertinib as second- or later-line therapy, and their response rate was 50%, nevertheless, no statistically significant differences were found (p = 0.139). However, patients who received first-line osimertinib showed a more significant PFS benefit than those who received second- or later-line therapy (mPFS: 16.8 months vs 6.0 months HR: 2.453, 95%CI: 1.285-4.682, p =0.004). Subgroup analysis showed that patients with a single, non-ex20ins, ucm-EGFRm displayed a superior efficacy advantage and favorable survival benefit following osimertinib treatment, with an ORR of 68.8% and an mPFS at 15.1 months. By contrast, patients with a multiple ucm-EGFRm that contain T790M exhibited the worst outcome of osimertinib treatment, with an ORR of 47.6% and an mPFS of only 3.6 months, respectively. Conclusion: Patients with um-EGFRms exhibit favorable but inconsistent responses and survival outcomes following osimertinib treatment, which is closely related to the mutation pattern and cooccurring partner mutant genes. Administering osimertinib for the treatment of patients with um-EGFRm might be considered an effective treatment option in some circumstances.

3.
J Gastrointest Oncol ; 13(4): 1761-1771, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36092352

RESUMO

Background: For patients with colon or stomach adenocarcinoma, 5-fluorouracil (5-FU) is an essential component of systemic chemotherapy in the palliative and adjuvant settings. The post-transcriptional regulatory factor cytoplasmic polyadenylation element-binding protein 1 (CPEB1) has been reported to be linked to tumor metastasis. This study aimed to investigate the relationship between CPEB1 expression and 5-FU treatment response in patients with colon and stomach adenocarcinomas. Methods: The expression of CPEB1 in stomach adenocarcinoma and colorectal cancer (CRC) tissues and in cell lines was determined by quantitative real-time PCR (qRT-PCR) and immunohistochemistry analyses. Transwell assays were employed to analyze the effects of CPEB1 on the migration and invasion abilities of gastric cancer (GC) and CRC cells. Results: The expression levels of CPEB1 were increased in colon and stomach adenocarcinoma and were negatively correlated with malignancy and poor patient survival. Data suggested that patients with CRC or GC who had strong CPEB1 expression responded poorly to 5-FU treatment. Furthermore, knockdown of CPEB1 inhibited the migration and invasion of CRC and GC cells via a mechanism involving decreased expression of matrix metalloprotein (MMP)2, 7, and 9. Finally, our methylated RNA immunoprecipitation PCR (meRIP qPCR) data suggested that the increased CPEB1 expression in colon and stomach adenocarcinomas might be mediated by FTO (FTO alpha-ketoglutarate dependent dioxygenase)-dependent m6A demethylation of CPEB1 mRNA. Conclusions: Our results indicate that the level of CPEB1 expression may be valuable for predicting the benefit of 5-FU treatment for patients with colon and stomach adenocarcinomas. We therefore propose that low CPEB1 expression may represent a novel biomarker for personalized 5-FU therapy.

4.
Nanoscale ; 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36098072

RESUMO

Polydopamine (PDA) is capable of wide drug delivery for biomedical applications by virtue of an adjustable polymerization process, including surface coating and conjugation. Inspired by the polymerization of dopamine, we introduce a layer-by-layer hybrid co-assembly strategy for the incorporation of doxorubicin (DOX) and dopamine to form PDA "carrier-drug" hybrid assembly. The "carrier-drug" hybrid assembly relies on the π-π stacking interaction between the drug (DOX) and carrier (PDA), and such the stacked-layer structure enables PDA nanoparticles with a superior drug loading of 58%, which is about 1.7-fold higher than that of the DOX surface coating (∼35%). To further improve blood circulation stability and enhance tumor penetration, we herein propose the conjugation of native apolipoprotein A-I (apoA-I) with tumor-homing cyclic peptide iRGD for PDA surface modification. The "carrier-drug" hybrid assembly can respond to triple stimuli of the acidic pH, concentrated reactive oxygen species (ROS), and near-infrared (NIR) light irradiation for realizing site-specific and on-demand drug release. In chemo-photothermal synergy therapy, the "carrier-drug" hybrid assembly performs efficient tumor penetration and accumulation, dramatically suppressing tumor growth and metastasis in a 4T1 orthotopic tumor-bearing mice model at a safe level. Collectively, our findings share new insights into the design of "carrier-drug" hybrid assembly for enhanced chemo-photothermal oncotherapy.

5.
Anal Chem ; 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36098546

RESUMO

Ru-based catalysis results in highly unsaturated fatty acid (HUFA) ethyl esters (EE) deuterated to various extents. The products carry 2H (D) mainly at their bis-allylic positions, where they are resistant to autoxidation compared to natural HUFA and are promising as neurological and retinal drugs. We characterized the extent of deuteration at each allylic position of docosa-4,7,10,13,16,19-hexaenoic acid deuterated to completion at bis-allylic and allylic positions (D-DHA) by two-dimensional (2D) and high-field (600 and 950 MHz) NMR. In separate experiments, the kinetics of docosahexaenoic acid (DHA) EE deuteration was evaluated using Paternò-Büchi (PB) reaction tandem mass spectrometry (MS/MS) analysis, enabling deuteration to be quantitatively characterized for isotopologues (D0-D14 DHA) at each internal allylic position. NMR analysis shows that the net deuteration of the isotopologue mixture is about 94% at the bis-allylic positions, and less than 1% remained as the protiated -CH2-. MS analysis shows that deuteration kinetics follow an increasing curve at bis-allylic positions with higher rate for internal bis-allylic positions. Percent D of bis-allylic positions increases linearly from D1 to D9 in which all internal bis-allylic positions (C9, C12, C15) deuterate uniformly and more rapidly than external bis-allylic positions (C6, C18). The mono-allylic positions near the methyl end (C21) show a steep increase of D only after the D10 isotopologue has been deuterated to >90%, while the mono-allylic position near the carboxyl position, C3, deuterates last and least. These data establish detailed methods for the characterization of Ru-catalyzed deuteration of HUFA as well as the phenomenological reaction kinetics as net product is formed.

6.
Plant Cell ; 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36099055

RESUMO

Peptide ligases are versatile enzymes that can be utilized for precise protein conjugation for bioengineering applications. Hyperactive peptide asparaginyl ligases (PALs), such as butelase-1, belong to a small class of enzymes from cyclotide-producing plants that can perform site-specific, rapid ligation reactions after a target peptide Asx (asparagine/aspartic acid) residue binds to the active site of the ligase. How PALs specifically recognize their polypeptide substrates has remained elusive, especially at the prime binding side of the enzyme. Here we report crystal structures that capture VyPAL2, a catalytically efficient PAL from Viola yedoensis, in an activated state, with and without a bound substrate. The bound structure shows one ligase with the N-terminal polypeptide tail from another ligase molecule trapped at its active site, revealing how Asx inserts in the enzyme's S1 pocket and why a hydrophobic residue is required at the P2' position. Beside illustrating the anchoring role played by P1 and P2' residues, these results uncover a role for the Gatekeeper residue at the surface of the S2 pocket in shifting the non-prime portion of the substrate and, as a result, the activity towards ligation or hydrolysis. These results suggest a picture for proenzyme maturation in the vacuole and will inform the rational design of peptide ligases with tailored specificities.

7.
Occup Ther Int ; 2022: 9693648, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36110198

RESUMO

This paper presents a research design for an integrated intervention using sensory integration training fused with social sports games for the treatment of children with autism. This study used a multiple baseline cross-subject design in a single-subject experiment, with structured play as the independent variable and expressive language skills of children with autism spectrum disorders as the dependent variable, with three phases of intervention: baseline, intervention period, and maintenance period. The expressive language ability was examined in terms of both oral expression and gestural expression, where the intervention effect of the oral expression was analyzed in terms of four components: the total number of words, the total number of sentences, average sentence length, and vocabulary complexity of oral expression, and the intervention effect of the gestural expression was analyzed in terms of changes in the frequency of children's gestural expression behaviors. For the categories classified by sensory integration ability, there are corresponding specific training programs that combine various physical exercises and play equipment to train the various abnormal functions of children with autism. Stereotyped behavior is a repetitive, self-imposed, and purposeless physical action, usually in the form of continuous and repetitive movements, sounds, and so on. 4 times a week, 25 minutes each time, the activity of recognizing pictures and familiar objects is carried out first, and then the children choose the structured game model and the initiative to build and take turns with the researchers to build. Stereotypic behaviors cause a great deal of distress in the lives of children with autism, and it is necessary to explore how to implement positive and effective interventions. Subjects' play abilities developed after receiving effective critical response training. The subjects' practice and symbolic play showed good immediate and maintenance intervention effectiveness; their associative and functional play showed no significant intervention effectiveness. The enhancement of the sensory integration skills of children with autism through sensory integration training resulted in a relative reduction of stereotypic behavior about the stimulus-seeking function, which had a positive effect on the intervention of stereotypic behavior.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Terapia Ocupacional , Transtorno do Espectro Autista/terapia , Transtorno Autístico/terapia , Criança , Humanos , Idioma , Terapia Ocupacional/métodos
8.
Eur J Med Chem ; 243: 114736, 2022 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-36115208

RESUMO

Berberine and jatrorrhizine are major bioactive components that are emerging as potential anti-cancer drugs. However, no zinc(II) - berberine/jatrorrhizine - curcumin compounds have been reported in the literature to date. Therefore, the molecular mechanisms associated with their cytotoxicity remain unexplored. To investigate the potential mitochondria-targeting ability, anti-neoplastic activity, and utility in cell imaging of berberine and jatrorrhizine derivates, four novel zinc(II) complexes, [Zn(Ber)(H2O)Cl2] (Zn(Ber)), [Zn(Ber)(Cur)Cl] (Zn(CurBer)), [Zn(Jat)(H2O)Cl2] (Zn(Jat)), and [Zn(Jat)(Cur)Cl] (Zn(CurJat)) bearing the berberine-derived ligand 2,2,2-trifluoroacetate 10-methoxy-9-((9-((2-(pyridin-2-yl)ethyl)amino)nonyl)oxy) -5,6-dihydro- [1,3]dioxolo[4,5-g]isoquinolino [(Torre et al., 2015; de Ruijter et al., 2020) 3,23,2-a]isoquinolin-7-ium (Ber), the jatrorrhizine-derived ligand 2,2,2-trifluoroacetate 2,9,10-trimethoxy-3-((9- ((2-(pyridin-2-yl)ethyl)amino)nonyl)oxy)-5,6-dihydroisoquinolino [(Torre et al., 2015; de Ruijter et al., 2020) 3,23,2-a]isoquinolin-7-ium (Jat), and/or curcumin (H-Cur) were first synthesised in this study. Zn(Ber), Zn(CurBer), Zn(Jat), and Zn(CurJat) showed higher cytotoxicity against human MCF-7 (breast adenocarcinoma) cells than did cisplatin, with IC50 values ranging from 0.21 to 4.45 µM. The anti-neoplastic activities of the zinc(II) - berberine/jatrorrhizine - curcumin complexes were in the following order: Zn(CurBer) > Zn(CurJat) > Zn(Ber) > Zn(Jat) > cisplatin > H-Cur > Ber > Jat > ZnCl2. Among these, Zn(CurBer) displayed the highest cytotoxicity (0.21 ± 0.06 µM). Furthermore, mechanistic investigations revealed that Zn(CurBer) and Zn(CurJat) could accumulate in the mitochondria, exhibit red fluorescence, and trigger mitophagy and apoptosis. In vivo anti-cancer evaluations also suggested that Zn(CurBer) inhibited MCF-7 xenograft tumour growth more effectively than cisplatin and Zn(CurJat). This is the first report describing the synthesis of zinc(II) - berberine/jatrorrhizine - curcumin complexes and their potential use as molecular probes and mitochondria-targeting anti-neoplastic drugs.

10.
Biofabrication ; 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36126647

RESUMO

Liver organoids represent emerging human-relevant in vitro liver models that have a wide range of biomedical applications in basic medical studies and preclinical drug discovery. However, the generation of liver organoids currently relies on the conventional Matrigel dome method, which lacks precise microenvironmental control over organoid growth and results in significant heterogeneity of the formed liver organoids. Here, we demonstrate a novel high-throughput culture method to generate uniform liver organoids from human pluripotent stem cell-derived foregut stem cells in micropatterned agarose scaffold. By using this approach, more than 8000 uniformly-sized liver organoids containing liver parenchyma cells, non-parenchymal cells, and a unique stem cell niche could be efficiently and reproducibly generated in a 48-well plate with a size coefficient of variation significance smaller than that in the Matrigel dome. Additionally, the liver organoids highly expressed liver-specific markers, including ALB, HNF4α, and AFP, and displayed liver functions, such as lipid accumulation, glycogen synthesis, albumin secretion, and urea synthesis. As a proof of concept, we evaluated the acute hepatotoxicity of acetaminophen (APAP) in these organoids and observed APAP-induced liver fibrosis. Overall, we expect that the liver organoids will facilitate wide biomedical applications in hepatotoxicity analysis and liver disease modeling.

11.
Eur J Intern Med ; 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36127218

RESUMO

BACKGROUND: A growing number of studies have demonstrated a causal association between lipoprotein(a) [Lp(a)] and atherosclerotic cardiovascular diseases (ASCVDs), but its association with all-cause and cause-specific mortality remains unclear. Therefore, this study aimed to explore the association of Lp(a) with all-cause and cause-specific mortality. METHODS: This prospective cohort study included 8,525 participants from the third National Health and Nutrition Examination Survey. Lp(a) was considered an exposure variable, all-cause and cause-specific mortality were used as outcome variables, and all participants were followed from the interview date until death or December 31, 2015. COX proportional hazards regression models, stratified analysis, sensitivity analysis, restricted cubic spline plots and Kaplan-Meier survival curves were used to analyze the association of Lp(a) with all-cause and cause-specific mortality. RESULTS: After adjusting for traditional cardiovascular risk factors, Lp(a) remained strongly associated with all-cause and CVDs-related mortality (P for trend = 0.007 and < 0.001). Subgroup analyses showed that higher Lp(a) remained associated with higher risk of all-cause mortality in those > 60 years of age, with a BMI < 30 kg/m2, and without diabetes, whereas the association between Lp(a) and CVDs-related mortality remained stable in participants ≤ 60 years of age, male, with a BMI < 30 kg/m2, with hypertension, without diabetes, or without CVDs (P < 0.05). In sensitivity analyses, we found that the association of Lp(a) with all-cause and CVDs-related mortality remained robust after excluding individuals who died within one year of follow-up (P for trend = 0.041 and 0.002). CONCLUSIONS: Lp(a) was associated with the risk of all-cause and CVDs-related mortality.

12.
Chem Sci ; 13(34): 10159-10160, 2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-36128235

RESUMO

[This corrects the article DOI: 10.1039/C8SC04892D.].

13.
Front Surg ; 9: 919225, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36117839

RESUMO

Objective: Fracture classification evolves dynamically with new and enhanced imaging modalities. This paper aims to introduce a novel hypothesis of a sophisticated fracture classification system for the proximal femur trochanteric region (AO/OTA-31A) based on 3D-CT images and accommodate the clinical requirement of the worldwide outbreak of geriatric hip fractures with large amounts of surgical operations. Methods: In the current practice of widely preoperative 3D-CT application and cephalomedullary nailing, we attempt to propose a new comprehensive classification system to describe the fracture characteristics in a more detailed and sophisticated architecture, and pay the most important concern to the parameters that contribute to fracture stability reconstruction in osteosynthesis. Results: The new four-by-four comprehensive classification system, followed the structure of the AO/OTA system, incorporates many fracture characteristics as dividing indexes into multiple grade levels, such as fracture line direction, the number of fragments, the lesser trochanter fragment and its distal extension (>2 cm), the posterior coronal fragment and its anterior expansion (to the entry portal of head-neck implant at the lateral cortex), the lateral wall and anterior cortex fracture, and the anteromedial inferior corner comminution. From a panoramic perspective, there are four types and each type has four subtypes. A1 is simple two-part fractures (20%), A2 is characterized by lesser trochanter fragment and posterior coronal fractures (62.5%), A3 is reverse obliquity and transverse fractures with complete lateral wall broken (15.5%), and A4 is medial wall comminution which further lacks anteromedial cortex transmission of compression force (2%). For subtypes, A2.2 is with a banana-like posterior coronal fragment, A2.4 is with distal cortex extension >2 cm of the lesser trochanter and anterior expansion of the posterior coronal fragment(s) to the entry portal of head-neck implants, A3.4 is a primary pantrochanteric fracture, and A4.4 is a concomitant ipsilateral segmental fracture of the neck and trochanter region. Conclusion: Classification represents diversity under consistency. The four-by-four sophisticated classification system delineates fracture characteristics in more detail. It is applicable in the time of rapid outbreak of trochanteric fractures in the older population, the large amounts of surgical operations, and incorporates various rare and/or more complicated subtypes which is unclassifiable before.

14.
Artigo em Inglês | MEDLINE | ID: mdl-36118092

RESUMO

Objective: The study aimed to explore the active ingredients, targets, and mechanism of action of Yiqi Jianpi recipe (YQJPR) in the treatment of COPD based on the network pharmacology and COPD rat models. Methods: The active ingredients and targets of YQJPR were collected by TCMSP. Disease-related protein targets were obtained from GeneCards. The Venn diagram was used to show the key therapeutic targets of COPD in YQJPR. The PPI network was established by STRING, and cytoHubba plug-in was used to screen the core targets within the network. GO functional enrichment and KEGG pathway enrichment analysis were performed to describe the functions and pathways of the core targets. Cytoscape software was used to construct the ingredient-target network and the core target-enrichment pathway network. The chemical constituents of YQJPR were analyzed by HPLC-MS/MS. Results: The network pharmacology showed 152 active ingredients and 225 targets in YQJPR for the treatment of COPD. The key active ingredients were quercetin, luteolin, kaempferol, tanshinone IIA, and baicalein. The contents of quercetin and luteolin in YQJPR were quantitatively measured by HPLC-MS/MS. 22 core genes were screened, including AKT1, IL-6, JUN, VEGFA, and CASP3, which were mainly involved in BPs such as cell proliferation and differentiation, oxidative/chemical stress, and regulation of DNA-binding transcription factor activity and regulated viral infection, tumor, HIF-1, MAPK, TNF, and IL-17 pathways. Animal experiments showed that YQJPR could significantly reduce the expression of p-ERK1/2, p-Akt, c-Myc, cleaved caspase-3, and p-Stat3 in lung tissue (p < 0.05). HE staining showed that, compared with the model group, YQJPR significantly improved lung tissue morphology and reduced lung inflammation in rats. Conclusion: The effects of YQJPR on COPD may involve multiple components, pathways, and targets. This study provides new ideas for further and more comprehensive exploration of the therapeutic effect of YQJPR on COPD in the future.

15.
Am J Transl Res ; 14(8): 5280-5294, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36105064

RESUMO

The main purpose of this research was to explore the molecular mechanisms of Jumonji Domain-Containing Protein 3 (JMJD3) in Alzheimer's disease (AD) and to analyze its role in the anti-AD mechanism of curcumin (CUR). In the in vitro study of AD, JMJD3 overexpression promoted the trimethylation of histone H3 lysine 27 (H3K27me3), downregulated brain-derived neurotrophic factor (BDNF ), improved the abnormality of mitochondrial stress response (MSR) markers, Aß accumulation, increased cell proliferation and inhibited apoptosis. Upregulating BDNF also achieved above similar results. Knockout of JMJD3 could downregulate BDNF, upregulate the level of H3K27me3 methylation and inhibit MSR markers, while transfection of JMJD3 RNAi could counteract the upregulated effect of BDNF. Then, MSR activator could also improve AD. In addition, JMJD3 in AD in vitro models was obviously upregulated under CUR stimulation, and it triggered a series of reactions as mentioned above. In the in vivo study, the levels of JMJD3, the mRNA and protein levels of BDNF in the right brain tissues of AD mice were downregulated, the methylation of H3K27me3 increased, and the MSR markers (ClpP, HSP6, HSP-60, ATFS-1, etc.) were downregulated; the above indexes were improved in varying degrees with the intervention of CUR. Thus, we conclude that CUR can induce the upregulation of JMJD3 and improve BDNF expression by promoting the demethylation of H3K27me3, thereby maintaining the balance of MSR and thus, preventing AD development.

16.
Glob Chang Biol ; 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36070189

RESUMO

Multiple linear regression (MLR) is widely used to attribute causes of the interannual variability (IAV) of land carbon uptake, yet, parameter estimation in MLR can be problematic if the predictors are strongly inter-correlated. Recently, Humphrey et al., (2021) used MLR method to conclude that the indirect effect of soil moisture (SM) via land-atmosphere coupling, rather than direct effect of SM on photosynthesis and respiration, controls the IAV of NBP. Here we assess the validity of MLR and find that the direct effect of SM on NBP-IAV is greatly underestimated by MLR, which may undermine their main conclusion.

17.
Front Immunol ; 13: 972298, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36052088

RESUMO

Pancreatic adenosquamous carcinoma (ASPC) is a rare subtype of pancreatic cancer with lethal malignancy, and few studies have focused on the heterogeneity of ASPC. Here, we performed a single-cell sequencing procedure on pancreatic tumor tissue from an ASPC patient and a patient with high-grade intraductal papillary mucinous neoplasm (IPMN). Through the combined analysis of single-cell sequencing data from five pancreatic ductal adenocarcinoma (PDAC) patients, one IPMN patient, and one ASPC patient in a public database, we identified 11 main types of cells, including macrophages, B cells, cancer stem cells, ductal cells, fibroblasts, endo/stellate cells, neutrophils, acinar cells, T cells, natural killer (NK) cells, dendritic cells, and mast cells. Then, the different characteristics and differentiation paths of the immune microenvironment among IPMN, ASPC, and PDAC in macrophages, T cells, and cancer-associated fibroblasts (CAFs) were identified through multiple bioinformatics analyses. Two novel special cancer-associated fibroblasts were identified as nCAFs and imCAFs. Then, cancer cells in duct cells were identified using the infercnv software. Two ASPC-specific subgroups of cancer cells with squamous cell features were identified. Finally, the identified specific CAFs and cancer cells were mapped to TCGA-PAAD cohort through the cibersoftx software. All of these identified subgroups were calculated to have a significant prognostic value in pancreatic cancer patients. These findings will promote the clinical application of single-cell sequencing data of pancreatic cancer and deepen our understanding of ASPC.


Assuntos
Adenocarcinoma Mucinoso , Carcinoma Adenoescamoso , Carcinoma Ductal Pancreático , Neoplasias Intraductais Pancreáticas , Neoplasias Pancreáticas , Adenocarcinoma Mucinoso/patologia , Carcinoma Adenoescamoso/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Humanos , Neoplasias Intraductais Pancreáticas/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Prognóstico , Microambiente Tumoral/genética
18.
Front Immunol ; 13: 963031, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36059488

RESUMO

The clinical efficacy of current therapies for Hepatocellular carcinoma (HCC) are unsatisfactory. In recent years, chimeric antigen receptor (CAR) T-cell therapies have been developed for solid tumors including advanced HCC (aHCC), but limited progress has been made. Glypican-3 is a promising immunotherapeutic target for HCC since it is specifically highly expressed in HCC. A previous study indicated that GPC3-targeted CAR T-(CAR-GPC3) cells were well-tolerated and had prolonged survival for HCC patients and that Sorafenib could increase the antitumor activities of CAR-GPC3 T-cells against HCC in mouse models. Here, we report a patient with aHCC who achieved a complete response (CR) and a long survival period after the combination therapy of CAR-GPC3 T-cell plus sorafenib. A 60-year-old Asian male diagnosed with hepatitis B virus (HBV) related HCC developed liver recurrence and lung metastasis after liver tumor resection and trans-arterial chemoembolization therapy. The patient also previously received microwave ablation therapy for lung metastasis. After the enrollment, the patient underwent leukapheresis for CAR-GPC3 T-cells manufacturing. Seven days after leukapheresis, the patient started to receive 400 mg of Sorafenib twice daily. The patient received 4 cycles of CAR-GPC3 T cells (CT011) treatment and each cycle was divided into two infusions. Prior to each cycle of CT011 treatment, lymphodepletion was performed. The lymphodepletion regimen was cyclophosphamide 500 mg/m2/day for 2 to 3 days, and fludarabine 20-25 mg/m2/day for 3 to 4 days. A total of 4×109 CAR-GPC3 T cells were infused. The CT011 plus Sorafenib combination therapy was well tolerated. All the ≥ grade 3 AEs were hematological toxicities which were deemed an expected event caused by the preconditioning regimen. This patient obtained partial responses from the 3rd month and achieved CR in the 12th month after the first cycle of CT011 infusion according to the RECIST1.1 assessment. The tumor had no progression for more than 36 months and maintained the CR status for more than 24 months after the first infusion.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias Pulmonares , Receptores de Antígenos Quiméricos , Animais , Glipicanas , Masculino , Camundongos , Sorafenibe/uso terapêutico , Linfócitos T , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Artigo em Inglês | MEDLINE | ID: mdl-36112285

RESUMO

As a forceful nematicide, fosthiazate has been largely applied in the management of root-knot nematodes and other herbivorous nematodes. However, the toxicity of fosthiazate to nontarget nematodes is unclear. To explore the toxicity and the mechanisms of fosthiazate in nontarget nematodes, Caenorhabditis elegans was exposed to 0.01-10 mg/L fosthiazate. The results implied that treatment with fosthiazate at doses above 0.01 mg/L could cause injury to the growth, locomotion behavior, and reproduction of the nematodes. Moreover, L1 larvae were more vulnerable to fosthiazate exposure than L4 larvae. Reactive oxygen species (ROS) production and lipofuscin accumulation were fairly increased in 1 mg/L fosthiazate-exposed nematodes. Treatment with 0.1 mg/L fosthiazate significantly inhibited the activity of acetylcholinesterase (p < 0.01). Furthermore, subacute exposure to 10 mg/L fosthiazate strongly influenced the expression of genes related to oxidative stress, reproduction, and nerve function (e.g., gst-1, sod-1, puf-8, wee-1.3, and ace-1 genes). These findings suggested that oxidative stress, reproduction and nerve disorders could serve as key endpoints of toxicity induced by fosthiazate. The cyp-35a family gene was the main metabolic fosthiazate in C. elegans, and the cyp-35a5 subtype was the most sensitive, with a change in expression level of 2.11-fold compared with the control. These results indicate that oxidative stress and neurological and reproductive disorders played fundamental roles in the toxicity of fosthiazate in C. elegans and may affect the abundance and function of soil nematodes.

20.
Sci Rep ; 12(1): 15356, 2022 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-36097050

RESUMO

To investigate if deep-sedated colonoscopy affects adenoma detection in certain colorectal segment. Review of colonoscopy reports, electronic images and medical records of individuals underwent screening colonoscopy with or without propofol sedation between October 2020 and March 2021 from seven hospitals in China. A total of 4500 individuals were analyzed. There was no significant difference in ADR between deep-sedated colonoscopy and unsedated colonoscopy [45.4% vs. 46.3%, P > 0.05]. The APP of deep-sedated colonoscopy was lower than unsedated colonoscopy (1.76 ± 0.81 vs. 2.00 ± 1.30, P < 0.05). Both average number of adenomas and luminal distention score of splenic flexure and descending colon were lower in deep-sedated colonoscopy (P < 0.05), and average number of adenomas was positively correlated with an improved distension score in splenic flexure and descending colon (splenic flexure r = 0.031, P < 0.05; descending colon r = 0.312, P < 0.05). Linear regression model showed deep-sedated colonoscopy significantly affected luminal distention of splenic flexure and descending colon as well as average number of adenomas detected in splenic flexure (P < 0.05). Deep-sedated colonoscopy decreased adenoma detection in splenic flexure and the luminal distention of splenic flexure and descending colon compared with unsedated colonoscopy.


Assuntos
Adenoma , Neoplasias Colorretais , Propofol , Adenoma/diagnóstico por imagem , Colonoscopia/métodos , Neoplasias Colorretais/diagnóstico por imagem , Humanos , Programas de Rastreamento/métodos
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