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Microvesicles (MVs) containing proteins, nucleic acid or organelles are shed from the plasma membrane. Although the mechanisms of MV budding are well elucidated, the connection between endosomal trafficking and MV formation remains poorly understood. In this report, RAB22A is revealed to be crucial for EGFR-containing MVs formation by the RAB GTPase family screening. RAB22A recruits TBC1D2B, a GTPase-activating protein (GAP) of RAB7A, to inactivate RAB7A, thus preventing EGFR from being transported to late endosomes and lysosomes. RAB22A also engages SH3BP5L, a guanine-nucleotide exchange factor (GEF) of RAB11A, to activate RAB11A on early endosomes. Consequently, EGFR is recycled to the cell surface and packaged into MVs. Furthermore, EGFR can phosphorylate RAB22A at Tyr136, which in turn promotes EGFR-containing MVs formation. Our findings illustrate that RAB22A acts as a sorter on early endosomes to sort EGFR to recycling endosomes for MV shedding by both activating RAB11A and inactivating RAB7A.
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Endossomos , Receptores ErbB , Proteínas rab de Ligação ao GTP , Receptores ErbB/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Endossomos/metabolismo , Humanos , Transporte Proteico , Micropartículas Derivadas de Células/metabolismo , proteínas de unión al GTP Rab7/metabolismo , Células HeLa , Proteínas Ativadoras de GTPase/metabolismo , Lisossomos/metabolismoRESUMO
The phenomenon of glacial freezing and thawing involves microbial sequestration, release, and colonization, which has the potential to impact ecosystem functioning through changes in microbial diversity and interactions. In this study, we examined the structural features of microbial communities of the Dongkemadi glacier, including bacteria, fungi, and archaea, in four distinct glacial environments (snow, ice, meltwater, and frontier soil). The sequestration, release, and colonization of glacial microbes have been found to significantly impact the diversity and structure of glacial microbial communities, as well as the complexity of microbial networks. Specifically, the complexity of bacterial networks has been observed to increase in a sequential manner during these processes. Utilizing the Inter-Domain Ecological Network approach, researchers have further explored the cross-trophic interactions among bacteria, fungi, and archaea. The complexity of the bacteria-fungi-archaea network exhibited a sequential increase due to the processes of sequestration, release, and colonization of glacial microbes. The release and colonization of glacial microbes led to a shift in the role of archaea as key species within the network. Additionally, our findings suggest that the hierarchical interactions among various microorganisms contributed to the heightened complexity of the bacteria-fungi-archaea network. The primary constituents of the glacial microbial ecosystem are unclassified species associated with the Polaromonas. It is noteworthy that various key species in glacial ecosystems are influenced by the distinct environmental factors. Moreover, our findings suggest that key species are not significantly depleted in response to abrupt alterations in individual environmental factors, shedding light on the dynamics of microbial cross-trophic interactions within glacial ecosystems.
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Archaea , Bactérias , Ecossistema , Congelamento , Fungos , Camada de Gelo , Microbiota , Camada de Gelo/microbiologia , Archaea/genética , Bactérias/classificação , Bactérias/genética , Microbiologia do Solo , BiodiversidadeRESUMO
Lorcaserin is a 5-hydroxytryptamine 2C (serotonin) receptor agonist and a non-genotoxic rat carcinogen, which induced mammary tumors in male and female rats in a two-year bioassay. Female Sprague Dawley rats were treated by gavage daily with 0, 30, or 100 mg/kg lorcaserin, replicating bioassay dosing but for shorter duration, 12 or 24 weeks. To characterize exposure and eliminate possible confounding by a potentially genotoxic degradation product, lorcaserin and N-nitroso-lorcaserin were quantified in dosing solutions, terminal plasma, mammary and liver samples using ultra high-performance liquid chromatography-electrospray tandem mass spectrometry. N-nitroso-lorcaserin was not detected, supporting lorcaserin classification as non-genotoxic carcinogen. Mammary DNA samples (n = 6/dose/timepoint) were used to synthesize PCR products from gene segments encompassing hotspot cancer driver mutations (CDMs), namely regions of Apc, Braf, Egfr, Hras, Kras, Nfe2l2, Pik3ca, Setbp1, Stk11, and Tp53. Mutant fractions (MFs) in the amplicons were quantified by CarcSeq, an error corrected next-generation sequencing approach. Considering all recovered mutants, no significant differences between lorcaserin dose groups were observed. However, significant dose-responsive increases in Pik3ca H1047R mutation were observed at both timepoints (ANOVA, p < 0.05), with greater numbers of mutants and mutants with greater MFs observed at 24 weeks as compared to 12 weeks. These observations suggest lorcaserin promotes outgrowth of spontaneously occurring Pik3ca H1047R mutant clones leading to mammary carcinogenesis. Importantly, this work reports approaches to analyze clonal expansion and demonstrates CarcSeq detection of the carcinogenic impact (selective Pik3ca H0147R mutant expansion) of a non-genotoxic carcinogen using a treatment duration as short as 3 months.
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The transboundary mercury (Hg) pollution has caused adverse effects on fragile ecosystems of the Tibetan Plateau (TP). Yet, knowledge of transport paths and source regions of atmospheric Hg on the inland TP remains poor. Continuous measurements of atmospheric total gaseous mercury (TGM) were conducted in the central TP (Tanggula station, 5100 m a.s.l., June-October). Atmospheric TGM level at Tanggula station (1.90 ± 0.30 ng m-3) was higher than the background level in the Northern Hemisphere. The identified high-potential source regions of atmospheric TGM were primarily located in the northern South Asia region. TGM concentrations were lower during the Indian summer monsoon (ISM)-dominant period (1.81 ± 0.25 ng m-3) than those of the westerly-receding period (2.18 ± 0.40 ng m-3) and westerly-intensifying period (1.91 ± 0.26 ng m-3), contrary to the seasonal pattern in southern TP. The distinct TGM minima during the ISM-dominant period indicated lesser importance of ISM-transported Hg to Tanggula station located in the northern boundary of ISM intrusion, compared to stations in proximity to South and Southeast Asia source regions. Instead, from the ISM-dominant period to the westerly-intensifying period, TGM concentrations showed an increasing trend as westerlies intensified, indicating the key role of westerlies in transboundary transport of atmospheric Hg to the inland TP.
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A class of chiral-bridged biphenyl phosphine-carboxylate bifunctional ligands CB-Phos has been developed and successfully applied to Pd(0)-catalyzed single enantioselective C-H arylation and a one pot cascade reaction involving Suzuki cross-coupling and C-H arylation. The catalytic system provides a new and convenient way for the synthesis of versatile chiral dihydrophenanthridines with rich structures and broad functional group tolerance. Good to excellent yields with high enantioselectivities were generally achieved. The reaction mechanism of the cascade reaction was also preliminarily discussed.
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Pericytes, a specific type of mesenchymal cell that surround the basement membrane of pulmonary venules and capillaries. They are crucial pathological features observed in individuals with the severe lung disease of pulmonary fibrosis (PF). The presence of pericytes leads to inflammation and fibrosis in the lung interstitium and alveolar space due to the release of various cytokines and chemokines. Pericytes also stimulate the proliferation and activation of fibroblasts, thereby promoting the progression of PF. Previous studies examining the mechanism of action of pericytes have primarily focused on cell signal transduction pathways, cell growth and death processes, and the synthesis and breakdown of extracellular matrix (ECM). Notably, the transforming growth factor-ß (TGF-ß) and Wnt signaling pathways have been associated with the action of pericytes in driving the progression of PF. It is therefore clear that pericytes play an essential role in the development of PF, while also offering possible avenues for targeted therapeutic intervention against this condition. The current article provides a comprehensive review on how pericytes contribute to inflammatory responses, as well as their importance for understanding the mechanism of PF. In addition, this review discusses the potential use of pericyte-targeted approaches for the treatment of patients affected by this debilitating lung disease.
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Pericitos , Fibrose Pulmonar , Pericitos/patologia , Pericitos/metabolismo , Humanos , Fibrose Pulmonar/patologia , Fibrose Pulmonar/metabolismo , Animais , Fator de Crescimento Transformador beta/metabolismo , Transdução de Sinais , Matriz Extracelular/metabolismo , Via de Sinalização WntRESUMO
The human lymphoblastoid cell line TK6 stands out as the most widely employed human cell line in genotoxicity testing, as recommended by various testing guidelines for in vitro assessments. Nevertheless, like many testing cell lines, TK6 lacks functional phase I drug-metabolizing enzymes crucial for chemical genotoxicity evaluations. This protocol introduces a lentivirus-based methodology for establishing a panel of TK6-derived cell lines, each expressing one of 14 cytochrome P450s (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, and CYP3A7). The utilization of a lentiviral expression system ensures stable transduction, offering notable advantages such as sustained transgene expression, high transduction efficiency, positive selection feasibility, and user-friendly application. Additionally, we present a detailed procedure for validating the enhanced expression of each CYP in the established cell lines through real-time PCR, western blotting, and mass spectrometry analysis. Lastly, we exemplify the application of these CYP-expressing TK6 cell lines in genotoxicity testing, employing a flow-cytometry-based in vitro micronucleus test. Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Basic Protocol 1: Lentivirus production and transduction for TK6 cells Support Protocol: Selecting a single clone of CYP-expressing TK6 cells Basic Protocol 2: Validation of CYP expression in TK6 cell lines Basic Protocol 3: Application of transduced cell lines in flow-cytometry-based micronucleus assay.
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Sistema Enzimático do Citocromo P-450 , Lentivirus , Humanos , Lentivirus/genética , Lentivirus/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP2E1/genética , Linhagem CelularRESUMO
BACKGROUND: Vesicular stomatitis virus (VSV) is a typical non-segmented negative-sense RNA virus of the genus Vesiculovirus in the family Rhabdoviridae. VSV can infect a wide range of animals, including humans, with oral blister epithelial lesions. VSV is an excellent model virus with a wide range of applications as a molecular tool, a vaccine vector, and an oncolytic vector. To further understand the interaction between VSV and host cells and to provide a theoretical basis for the application prospects of VSV, we analyzed the expression of host differentially expressed genes (DEGs) during VSV infection using RNA-Seq. RESULTS: Our analyses found a total of 1015 differentially expressed mRNAs and 161 differentially expressed LncRNAs in BHK-21 cells infected with VSV for 24 h compared with controls. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment showed that the differentially expressed lncRNAs and their target genes were mainly concentrated in pathways related to apoptosis, cancer, disease, and immune system activation, including the TNF, P53, MAPK, and NF-kappaB signaling pathways. The differentially expressed lncRNA can modulate immune processes by regulating genes involved in these signaling transmissions. Ten randomly selected DEGs, namely, Il12rb2, F2, Masp2, Mcl1, FGF18, Ripk1, Fas, BMF, POLK, and JAG1, were validated using RT-qPCR. As predicted through RNA-Seq analysis, these DEGs underwent either up- or downregulation, suggesting that they may play key regulatory roles in the pathways mentioned previously. CONCLUSIONS: Our study showed that VSV infection alters the host metabolic network and activates immune-related pathways, such as MAPK and TNF. The above findings provide unique insights for further study of the mechanism of VSV-host interactions and, more importantly, provide a theoretical basis for VSV as an excellent vaccine carrier.
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RNA Longo não Codificante , Vacinas , Animais , Humanos , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Perfilação da Expressão Gênica , RNA-Seq , TranscriptomaRESUMO
Transition metal dichalcogenide (TMD) nanotubes offer a unique platform to explore the properties of TMD materials at the one-dimensional limit. Despite considerable efforts thus far, the direct growth of TMD nanotubes with controllable chirality remains challenging. Here we demonstrate the direct and facile growth of high-quality WS2 and WSe2 nanotubes on Si substrates using catalytic chemical vapour deposition with Au nanoparticles. The Au nanoparticles provide unique accommodation sites for the nucleation of WS2 or WSe2 shells on their surfaces and seed the subsequent growth of nanotubes. We find that the growth mode of nanotubes is sensitive to the temperature. With careful temperature control, we realize ~79% WS2 nanotubes with single chiral angles, with a preference of 30° (~37%) and 0° (~12%). Moreover, we demonstrate how the geometric, electronic and optical properties of the synthesized WS2 nanotubes can be modulated by the chirality. We anticipate that this approach using Au nanoparticles as catalysts will facilitate the growth of TMD nanotubes with controllable chirality and promote the study of their interesting properties and applications.
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Understanding drug transport across the placental barrier is important for assessing the potential fetal drug toxicity and birth defect risks. Current in vivo and in vitro models have structural and functional limitations in evaluating placental drug transfer and toxicity. Microphysiological systems (MPSs) offer more accurate and relevant physiological models of human tissues and organs on a miniature scale for drug development and toxicology testing. MPSs for the placental barrier have been recently explored to study placental drug transfer. We utilized a multilayered hydrogel membrane-based microphysiological model composed of human placental epithelial and endothelial cells to replicate the key structure and function of the human placental barrier. A macroscale human placental barrier model was created using a transwell to compare the results with the microphysiological model. Placental barrier models were characterized by assessing monolayer formation, intercellular junctions, barrier permeability, and their structural integrity. Three small-molecule drugs (glyburide, rifaximin, and caffeine) that are prescribed or taken during pregnancy were studied for their placental transfer. The results showed that all three drugs crossed the placental barrier, with transfer rates in the following order: glyburide (molecular weight, MW = 494 Da) < rifaximin (MW = 785.9 Da) < caffeine (MW = 194.19 Da). Using non-compartmental analysis, we estimated human pharmacokinetic characteristics based on in vitro data from both MPS and transwell models. While further research is needed, our findings suggest that MPS holds potential as an in vitro tool for studying placental drug transfer and predicting fetal exposure, offering insights into pharmacokinetics.
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Glibureto , Placenta , Humanos , Gravidez , Feminino , Células Endoteliais , Cafeína , RifaximinaRESUMO
Osteosarcoma is a highly aggressive cancer and lacks effective therapeutic targets. We found that L3MBTL2 acts as a tumor suppressor by transcriptionally repressing IFIT2 in osteosarcoma. L3MBTL2 recruits the components of Polycomb repressive complex 1.6 to form condensates via both Pho-binding pockets and polybasic regions within carboxyl-terminal intrinsically disordered regions; the L3MBTL2-induced condensates are required for its tumor suppression. Multi-monoubiquitination of L3MBTL2 by UBE2O results in its proteasomal degradation, and the UBE2O/L3MBTL2 axis was crucial for osteosarcoma growth. There is a reverse correlation between L3MBTL2 and UBE2O in osteosarcoma tissues, and higher UBE2O and lower L3MBTL2 are associated with poorer prognosis in osteosarcoma. Pharmacological blockage of UBE2O by arsenic trioxide can enhance L3MBTL2-induced condensates and consequently suppress osteosarcoma growth. Our findings unveil a crucial biological function of L3MBTL2-induced condensates in mediating tumor suppression, proposing the UBE2O-L3MBTL2 axis as a potential cancer therapeutic target in osteosarcoma.
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Neoplasias Ósseas , Osteossarcoma , Humanos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Osteossarcoma/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo , UbiquitinaçãoRESUMO
OBJECTIVE: Pregnant women experience enormous psychological pressure, particularly during the late trimester. Symptoms of depression in late pregnancy may persist postpartum, increasing the incidence of postpartum depression. This study is aimed to investigate the factors influencing depressive symptoms among pregnant women in their third trimester at a Chinese tertiary hospital and provide information for effective intervention. METHODS: Pregnant women in their third trimester who visited the Ningbo Women and Children's Hospital between January 1, 2020 and June 30, 2022 participated in this study. A score of ≥ 13 on the Edinburgh Postnatal Depression Scale (EPDS) was considered as positive for depressive symptom. Potential influencing factors were examined by using an online questionnaire and analyzed using multivariate logistic regression. RESULTS: A total of 1196 participants were recruited. The mean EPDS score was 7.12 ± 4.22. The positive screening rate for depressive symptom was 9.9%. Univariate analysis showed that living with partner, annual family income, planned pregnancy, sleep quality, and partner's drinking habits were related to positive screening for depression(P < 0.05). Furthermore, multivariate logistic regression analysis showed that living away from the partner (odds ratio [OR]: 2.054, 95% confidence interval [CI]: 1.094-3.696, P = 0.02), annual family income < 150,000 Chinese Yuan (CNY; OR: 1.762, 95% CI: 1.170-2.678, P = 0.007), poor sleep quality (OR: 4.123, 95% CI: 2.764-6.163, P < 0.001), and partner's frequent drinking habit (OR: 2.227, 95% CI: 1.129-4.323, P = 0.019) were independent influencing factors for positive depression screening (P < 0.05). CONCLUSION: Family's economic condition, sleep quality, living with partner, and partner's drinking habits were related to positive depression screening in late pregnancy. Pregnant women with these risk factors should be given more attention and supported to avoid developing depression.
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Depressão Pós-Parto , Depressão , Feminino , Humanos , Gravidez , Estudos Transversais , Depressão/diagnóstico , Depressão/epidemiologia , Depressão/psicologia , Depressão Pós-Parto/diagnóstico , Depressão Pós-Parto/epidemiologia , Depressão Pós-Parto/psicologia , População do Leste Asiático , Terceiro Trimestre da Gravidez , Fatores de Risco , Centros de Atenção TerciáriaRESUMO
Lapatinib, an oral tyrosine kinase inhibitor used as a first-line treatment for HER2-positive breast cancer, has been reported to be associated with hepatotoxicity; however, the underlying mechanisms remain unclear. In this study, we report that lapatinib causes cytotoxicity in multiple types of hepatic cells, including primary human hepatocytes, HepaRG cells, and HepG2 cells. A 24-h treatment with lapatinib induced cell cycle disturbances, apoptosis, and DNA damage, and decreased the protein levels of topoisomerase in HepG2 cells. We investigated the role of cytochrome P450 (CYP)-mediated metabolism in lapatinib-induced cytotoxicity using our previously established HepG2 cell lines, which express each of 14 CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7). We demonstrate that lapatinib is metabolized by CYP1A1, 3A4, 3A5, and 3A7. Among these, lapatinib-induced cytotoxicity and DNA damage were attenuated in cells overexpressing CYP3A5 or 3A7. Additionally, we measured the production of three primary metabolites of lapatinib (O-dealkylated lapatinib, N-dealkylated lapatinib, and N-hydroxy lapatinib) in CYP1A1-, 3A4-, 3A5-, and 3A7-overexpressing HepG2 cells. We compared the cytotoxicity of lapatinib and its 3 metabolites in primary human hepatocytes, HepaRG cells, and HepG2 cells and demonstrated that N-dealkylated lapatinib is more toxic than the parent drug and the other metabolites. Taken together, our results indicate that lapatinib-induced cytotoxicity involves multiple mechanisms, such as apoptosis and DNA damage; that N-dealkylated lapatinib is a toxic metabolite contributing to the toxic effect of lapatinib; and that CYP3A5- and 3A7-mediated metabolism plays a role in attenuating the cytotoxicity of lapatinib.
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Citocromo P-450 CYP1A1 , Citocromo P-450 CYP3A , Humanos , Citocromo P-450 CYP3A/metabolismo , Citocromo P-450 CYP1A1/metabolismo , Lapatinib/toxicidade , Lapatinib/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Fígado/metabolismo , Microssomos Hepáticos/metabolismoRESUMO
A low F-number and 100% cold stop efficiency are beneficial for improving the performance of optical systems and have a wide range of applications in various thermal imaging scenarios. The cooled infrared coaxial four-mirror system can meet these two requirements, improve system integration, and reduce adjustment costs and difficulties. However, the secondary obstruction caused by the central hole of the third mirror will generate potential stray light. A structure model is proposed in which the primary mirror and the quaternary mirror are processed on the same mirror blank. In this model, a method is given to calculate system parameters using the obstruction ratio and magnification of each mirror. To evaluate the performance of the method, two design examples with different F-numbers (1.4, 1.0) were constructed. The influence of initial structural constraints on the exit pupil position and secondary obstruction was analyzed based on the design objectives of the examples. The aberrations were optimized by targeting the spot. In the optimization process, the incident coordinates and directions of the restricted edge field rays in the tertiary mirror and the quaternary mirror were limited to achieve control of the obstruction caused by the holes in the center of the mirrors. In the results, the RMS spot radius of the two design examples is smaller than the Airy disk radius, and the axial beam wavefront deviation RMS values are 0.026λ and 0.024λ, respectively. Moreover, the obstruction caused by the central holes of the mirrors is controlled within the given field of view. The results show that the proposed model and method can be used to design a low F-number cooled infrared coaxial four-mirror system and have good application prospects.
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Real-time and accurate estimation of surgical hemoglobin (Hb) loss is essential for fluid resuscitation management and evaluation of surgical techniques. In this study, we aimed to explore a novel surgical Hb loss estimation method using deep learning-based medical sponges image analysis. Whole blood samples of pre-measured Hb concentration were collected, and normal saline was added to simulate varying levels of Hb concentration. These blood samples were distributed across blank medical sponges to generate blood-soaked sponges. Eight hundred fifty-one blood-soaked sponges representing a wide range of blood dilutions were randomly divided 7:3 into a training group (n = 595) and a testing group (n = 256). A deep learning model based on the YOLOv5 network was used as the target region extraction and detection, and the three models (Feature extraction technology, ResNet-50, and SE-ResNet50) were trained to predict surgical Hb loss. Mean absolute error (MAE), mean absolute percentage error (MAPE), coefficient (R2) value, and the Bland-Altman analysis were calculated to evaluate the predictive performance in the testing group. The deep learning model based on SE-ResNet50 could predict surgical Hb loss with the best performance (R2 = 0.99, MAE = 11.09 mg, MAPE = 8.6%) compared with other predictive models, and Bland-Altman analysis also showed a bias of 1.343 mg with narrow limits of agreement (- 29.81 to 32.5 mg) between predictive and actual Hb loss. The interactive interface was also designed to display the real-time prediction of surgical Hb loss more intuitively. Thus, it is feasible for real-time estimation of surgical Hb loss using deep learning-based medical sponges image analysis, which was helpful for clinical decisions and technical evaluation.
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Aprendizado Profundo , Hidratação , Hemoglobinas , Técnicas de Diluição do Indicador , RessuscitaçãoRESUMO
Guanylate binding protein 5 (GBP5) is a member of the interferon (IFN)-inducible large guanosine triphosphate hydrolases (GTPase) family that regulates cell-autonomous immunity and malignant tumor transformation. However, its specific roles and underlying mechanisms GBP5 in gastric cancer (GC) remain unknown. In this study, we aimed to determine the role GBP5 and underlying mechanism of GBP5 in GC cell progression. Potential oncogenic roles of GBP5 in GC as well as its relationship with the tumor immune microenvironment (TIME) were comprehensively evaluated using bioinformatics analysis. Protein expression levels of GBP5 and their correlation with clinicopathological features of patients were assessed using immunohistochemistry. In addition, diverse in vitro functional experiments were performed to identify the functions of GBP5 in GC. Downstream targets of GBP5 were identified using RNA-sequencing analysis and verified using western blotting or quantitative polymerase chain reaction analysis in different cell lines. GBP5 expression is commonly upregulated and promotes the proliferation and migration of GC cells. Mechanistically, GBP5 was regulated by the IFNγ-Janus kinase (JAK1)-signal transducer and activator of transcription 1 (STAT1) axis and induced CXCL8 expression. Interestingly, GBP5-induced CXCL8 regulated the JAK1-STAT1 signaling pathway to form a positive feedback loop. Moreover, GBP5 is closely related to the TIME and may be used as a biomarker for predicting the efficacy of immunotherapy. Our findings revealed a new JAK1-STAT1/GBP5/CXCL8 pathway and highlighted the value of GBP5 as a predictive biomarker and novel target for GC intervention.
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BACKGROUND: The greater omentum is derived from the foregut, and the right hemicolon is derived from the midgut based on developmental anatomy. This study aimed to investigate whether the greater omentum should be resected in laparoscopic complete mesocolic excision based on developmental anatomy for right-sided colon cancer. METHODS: A total of 183 consecutive patients with right-sided colon cancer were recruited in this study between February 2020 and July 2022. Ninety-eight patients underwent standard laparoscopic complete mesocolic excision surgery (CME group). The presence of isolated tumor cells and micrometastases was detected in resected greater omentum by the HE staining and immunohistochemistry analysis. Based on developmental anatomy, laparoscopic CME surgery with greater omentum preservation (DACME group) was proposed and performed on 85 right-sided colon cancer patients. To overcome selection bias, we performed a 1:1 match between two groups using four variables: age, sex, BMI, and ASA scores. RESULTS: No isolated tumor cells and micrometastases were found in the resected greater omentum specimen in the CME group. After the propensity score, 81 pairs were balanced and analyzed. Patients in the DACME group showed shorter operative time (194.9 ± 16.4 min vs.201.5 ± 11.5 min, p = 0.002), less blood loss (23.5 ± 24.7 ml vs.33.6 ± 26.3 ml, p = 0.013), and the shorter hospital stays (9.6 ± 1.7 days vs.10.3 ± 2.0 days, p = 0.010) compared with patients in the CME group. In addition, patients in the DACME group had a lower incidence of postoperative complications (4.9% vs.14.8%, p = 0.035) than patients in the CME group. CONCLUSION: The greater omentum should be preserved during right-sided colon cancer surgery, laparoscopic CME surgery based on developmental anatomy is technically safe and feasible for right-sided colon cancer.
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Neoplasias do Colo , Laparoscopia , Mesocolo , Humanos , Neoplasias do Colo/cirurgia , Neoplasias do Colo/patologia , Resultado do Tratamento , Omento/cirurgia , Omento/patologia , Micrometástase de Neoplasia , Colectomia , Excisão de Linfonodo , Mesocolo/cirurgiaRESUMO
BACKGROUND: The survival benefit of partial nephrectomy (PN) in pT3a RCC patients is controversial. Here we aimed to explore the potential benefit of PN for pT3aN0M0 renal cell carcinoma (RCC). MATERIAL AND METHODS: Data of patients with pT3aN0M0 RCC who were diagnosed between 2010 and 2012 in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database were retrospectively collected. Overall survival (OS) and cancer specific survival (CSS) were compared using a Cox proportional hazards model between PN and radical nephrectomy (RN) in pT3aN0M0 RCC. Propensity score (-adjusted, -stratified, -weighted, and -matched) analyses were performed to control for imbalances in individual risk factors. RESULTS: A total of 1277 patients with pT3aN0M0 RCC were identified, of whom 200 patients were treated with PN and 1077 patients were RN. PN showed favorable OS and CSS in 0-4 cm pT3aN0M0 RCC (P < 0.05), and similar OS and CSS in 4-7 cm pT3aN0M0 RCC, compared with RN using un-adjusted analyses. The Propensity score analyses further demonstrated the survival benefit of PN compared with the RN in 0-4 cm pT3aN0M0 RCC (P < 0.05). CONCLUSIONS: In this retrospective study, PN was associated with improved survival compared with RN in 0-4 cm pT3aN0M0 RCC. Moreover, survival was comparable between PN and RN in 4-7 cm pT3aN0M0 RCC. These data provided evidence that PN could be an alternative choice for T3aN0M0 RCC less than 7 cm. Particularly, patients with 0-4 cm pT3aN0M0 RCC might benefit from PN.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/cirurgia , Neoplasias Renais/patologia , Estudos Retrospectivos , Pontuação de Propensão , Nefrectomia/métodos , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a condition that may cause persistent pulmonary damage. The transformation of pericytes into myofibroblasts has been recognized as a key player during IPF progression. This study aimed to investigate the functions of lncRNA growth arrest-specific transcript 5 (GAS5) in myofibroblast transformation during IPF progression. METHODS: We created a mouse model of pulmonary fibrosis (PF) via intratracheal administration of bleomycin. Pericytes were challenged with exogenous transforming growth factor-ß1 (TGF-ß1). To determine the expression of target molecules, we employed quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemical and immunofluorescence staining. The pathological changes in the lungs were evaluated via H&E and Masson staining. Furthermore, the subcellular distribution of GAS5 was examined using FISH. Dual-luciferase reporter assay, ChIP, RNA pull-down, and RIP experiments were conducted to determine the molecular interaction. RESULTS: GAS5 expression decreased whereas PDGFRα/ß expression increased in the lungs of IPF patients and mice with bleomycin-induced PF. The in vitro overexpression of GAS5 or silencing of PDGFRα/ß inhibited the TGF-ß1-induced differentiation of pericytes to myofibroblasts, as evidenced by the upregulation of pericyte markers NG2 and desmin as well as downregulation of myofibroblast markers α-SMA and collagen I. Further mechanistic analysis revealed that GAS5 recruited KDM5B to promote H3K4me2/3 demethylation, thereby suppressing PDGFRα/ß expression. In addition, KDM5B overexpression inhibited pericyte-myofibroblast transformation and counteracted the promotional effect of GAS5 knockdown on pericyte-myofibroblast transformation. Lung fibrosis in mice was attenuated by GAS5 overexpression but promoted by GAS5 deficiency. CONCLUSION: GAS5 represses pericyte-myofibroblast transformation by inhibiting PDGFRα/ß expression via KDM5B-mediated H3K4me2/3 demethylation in IPF, identifying GAS5 as an intervention target for IPF.
Assuntos
Fibrose Pulmonar Idiopática , RNA Longo não Codificante , Animais , Camundongos , Bleomicina/efeitos adversos , Desmetilação , Proteínas de Ligação a DNA/metabolismo , Fibroblastos/metabolismo , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Pulmão , Camundongos Endogâmicos C57BL , Miofibroblastos/metabolismo , Pericitos/metabolismo , Pericitos/patologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
OBJECTIVE: To evaluate the efficacy of Chinese plaster containing rhubarb and mirabilite on surgical site infection (SSI) in patients with cesarean delivery (CD) by performing a randomized controlled trial. METHODS: This randomized controlled trial included 560 patients with CD due to fetal head descent enrolled at a tertiary teaching center between December 31, 2018 and October 31, 2021. Eligible patients were randomly assigned to a Chinese medicine (CM) group (280 cases) or a placebo group (280 cases) by a random number table, and were treated with CM plaster (made by rhubarb and mirabilite) or a placebo plaster, respectively. Both courses of treatment lasted from the day 1 of CD, followed day 2 until discharge. The primary outcome was the total number of patients with superficial, deep and organ/space SSI. The secondary outcome was duration of postoperative hospital stay, antibiotic intake, and unplanned readmission or reoperation due to SSI. All reported efficacy and safety outcomes were confirmed by a central adjudication committee that was unaware of the study-group assignments. RESULTS: During the recovery process after CD, the rates of localized swelling, redness and heat were significantly lower in the CM group than in the placebo group [7.55% (20/265) vs. 17.21% (47/274), P<0.01]. The durution of postoperative antibiotic intake was shorter in the CM group than in the placebo group (P<0.01). The duration of postoperative hospital stay was significantly shorter in the CM group than in the placebo group (5.49 ± 2.68 days vs. 8.96 ± 2.35 days, P<0.01). The rate of postoperative C-reactive protein elevation (â½100 mg/L) was lower in the CM group than in the placebo group [27.6% (73/265) vs. 43.8% (120/274), P<0.01]. However, there was no difference in purulent drainage rate from incision and superficial opening of incision between the two groups. No intestinal reactions and skin allergies were found in the CM group. CONCLUSIONS: CM plaster containing rhubarb and mirabilite had an effect on SSI. It is safe for mothers and imposes lower economic and mental burdens on patients undergoing CD. (Registration No. ChiCTR2100054626).