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BACKGROUND: Early dissemination to distant organs accounts for the dismal prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). Chronic, dysregulated, persistent and unresolved inflammation provides a preferred tumor microenvironment (TME) for tumorigenesis, development, and metastasis. A better understanding of the key regulators that maintain inflammatory TME and the development of predictive biomarkers to identify patients who are most likely to benefit from specific inflammatory-targeted therapies is crucial for advancing personalized cancer treatment. METHODS: This study identified cell-specific expression of CALB2 in human PDAC through single-cell RNA sequencing analysis and assessed its clinicopathological correlations in tissue microarray using multi-color immunofluorescence. Co-culture systems containing cancer-associated fibroblasts (CAFs) and patient-derived organoids (PDOs) in vitro and in vivo were employed to elucidate the effects of CALB2-activated CAFs on PDAC malignancy. Furthermore, CUT&RUN assays, luciferase reporter assays, RNA sequencing, and gain- or loss-of-function assays were used to unravel the molecular mechanisms of CALB2-mediated inflammatory reprogramming and metastasis. Additionally, immunocompetent KPC organoid allograft models were constructed to evaluate CALB2-induced immunosuppression and PDAC metastasis, as well as the efficacy of inflammation-targeted therapy. RESULTS: CALB2 was highly expressed both in CAFs and cancer cells and correlated with an unfavorable prognosis and immunosuppressive TME in PDAC patients. CALB2 collaborated with hypoxia to activate an inflammatory fibroblast phenotype, which promoted PDAC cell migration and PDO growth in vitro and in vivo. In turn, CALB2-activated CAFs upregulated CALB2 expression in cancer cells through IL6-STAT3 signaling-mediated direct transcription. In cancer cells, CALB2 further activated Ca2+-CXCL14 inflammatory axis to facilitate PDAC metastatic outgrowth and immunosuppression. Genetic or pharmaceutical inhibition of CXCL14 significantly suppressed CALB2-mediated metastatic colonization of PDAC cells in vivo and extended mouse survival. CONCLUSIONS: These findings identify CALB2 as a key regulator of inflammatory reprogramming to promote PDAC metastatic progression. Combination therapy with αCXCL14 monoclonal antibody and gemcitabine emerges as a promising strategy to suppress distant metastasis and improve survival outcomes in PDAC with CALB2 overexpression.
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Metástase Neoplásica , Neoplasias Pancreáticas , Microambiente Tumoral , Humanos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Camundongos , Animais , Inflamação/patologia , Inflamação/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Feminino , Masculino , PrognósticoRESUMO
Lower extremity peripheral artery disease (PAD) is a growing global health problem. New methods to diagnose PAD have been explored in recent years. At present, the majority of imaging methods for PAD focus on the macrovascular blood flow, and the exploration of microcirculation and tissue perfusion of PAD remains largely insufficient. In this report, we applied three new imaging technologies, i.e., second near-infrared region (NIR-II, 900-1,880â nm wavelengths) imaging, optical coherence tomography angiography (OCTA), and laser speckle flowgraphy (LSFG), in a PAD patient with a healthy human subject as control. Our results showed that the PAD patient had poorer tissue perfusion than the control without observed adverse effects. Moreover, compared with the first near-infrared region (NIR-I, 700-900â nm wavelengths) imaging results, NIR-II imaging had a higher signal-to-background ratio and resolution than NIR-I imaging and detected microvessels that were not detected by NIR-I imaging. These observations suggested that NIR-II imaging, OCTA, and LSFG are potentially safe and effective methods for diagnosing PAD.
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Volatile solid additive is an effective and simple strategy for morphology control in organic solar cells (OSCs). The development of environmentally friendly new additives which can also be easily removed without high-temperature thermal annealing treatment is currently a trend, and the working mechanism needs to be further studied. Herein, a highly volatile and non-halogenated solid additive 1-benzothiophene (BBT) is reported to regulate molecular aggregation and stacking of active layer components. According to the film-forming kinetics process, a momentary intermediate phase is formed during spin-coating, which slows down the film-forming process and leads to more ordered molecular stacking in the solid film after introducing solid additive BBT. Subsequently, after solvent vapor annealing (SVA) further treatment, the resultant blend films exhibit a tighter and more ordered molecular stacking. Consequently, the synergistic effect of solid additive BBT and SVA treatment can effectively control morphology of active layer and improve carrier transport characteristics, thereby enhancing the performance of OSCs. Finally, in D18-Cl:N3 system, an impressive power conversion efficiency of 19.53% is achieved. The work demonstrates that the combination of highly volatile solid additives and SVA treatment is an effective morphology control strategy, guiding the development of efficient OSCs.
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Fokienia hodginsii (F. hodginsii), belonging to the genus Fokienia of the Cupressaceae. F. hodginsii has significant application value due to its wood properties and great research value in evolutionary studies as a gymnosperm. However, the genome of F. hodginsii remains unknown due to the large size of gymnosperms genome. Pacific Bioscience sequencing, Hi-C mapping, whole-genome Bisulfite Sequencing (BS-Seq), long-read isoform sequencing (Iso-Seq), direct RNA sequencing (DRS), quantitative proteomics, and metabonomics analysis are employed to facilitate genome assembly, gene annotation, and investigation into epigenetic mechanisms. In this study, the 10G F. hodginsii genome is assembled into 11 chromosomes. Furthermore, 50 521 protein-coding genes are annotated and determined that 65% of F. hodginsii genome comprises repetitive sequences. It is discovered that transposable element (TE)-including introns is associated with higher expression. The DNA methylome of F. hodginsii reveals that xylem has a higher DNA methylation level compared to callus. Moreover, DRS reveals the significant alterations in RNA full-length ratio, which potentially associated with poly(A) length (PAL) and alternative polyadenylation (APA). Finally, the morphology measurement and metabonomics analysis revealed the difference of 14 cultivars. In summary, the genomes and epigenetics datasets provide a molecular basis for callus formation in the gymnosperm family.
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Control tissue is essential for ensuring the precision of semiquantitative analysis in back-table fluorescence imaging. However, there remains a lack of agreement on the appropriate selection of control tissues. To evaluate the back-table fluorescence imaging performance of different normal tissues and identify the optimal normal tissue, a cohort of 39 patients with orbital tumors were enrolled in the study. Prior to surgery, these patients received indocyanine green (ICG) and following resection, 43 normal control tissues (34 adipose tissues, 3 skin tissues, 3 periosteal tissues, and 3 muscle tissues) were examined using back-table fluorescence imaging. The skin tissue demonstrated significantly elevated fluorescence intensity in comparison to the diseased tissue, whereas the muscle tissue exhibited a broad range and standard deviation of fluorescence signal intensity. Conversely, the adipose and periosteum displayed weak fluorescence signals with a relatively consistent distribution. Additionally, no significant correlations were found between the signal-to-background ratio (SBR) of adipose tissue and patients' ages, genders, weights, disease duration, tumor origins, dosing of administration of ICG infusion, and the time interval between ICG infusion and surgery. However, a positive correlation was observed between the SBR of adipose tissue and its size, with larger adipose tissues (>1 cm) showing an average SBR 27% higher than smaller adipose tissues (≤1 cm). In conclusion, the findings of this study demonstrated that adipose tissue consistently exhibited homogeneous hypofluorescence during back-table fluorescence imaging, regardless of patient clinical variables or imaging parameters. The size of the adipose tissue was identified as the primary factor influencing its fluorescence imaging characteristics, supporting its utility as an ideal control tissue for back-table fluorescence imaging.
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The effect of Fe3O4 nanoparticles (Fe3O4 NPs) on the electron transfer process in aerobic composting systems remains unexplored. In this study, we compared the electron transfer characteristics of DOM in sludge composting without additives (group CK) and with the addition of 50 mg/kg Fe3O4 NPs additive (group Fe). It was demonstrated that the electron transfer capacity (ETC) and electron donating capacity (EDC) of compost-derived DOM increased by 13%-29% and 40%-47%, respectively, with the addition of Fe3O4 NPs during sludge composting. Analyzing the composition and structure of DOM revealed that Fe3O4 NPs promoted the formation of humic acid-like substances and enhanced the aromatic condensation degree of DOM. Correlation analysis indicated that the increase in EDC of DOM was closely associated with the phenolic group in DOM and influenced by quinone groups and the degree of aromatization of DOM. The higher EDC and the structural evolution of DOM in group Fe reduced the bioaccessibility of Cu, Cr, Ni, Zn. This study contributes to a deeper understanding of the redox evolutionary mechanism of DOM in sludge composting and broadens the application of iron oxides additives.
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Compostagem , Esgotos , Esgotos/química , Substâncias Húmicas/análise , Elétrons , Compostos Férricos/químicaRESUMO
Nanozymes have been attracting widespread interest for the past decade, especially in the field of cancer therapy, due to their intrinsic catalytic activities, strong stability, and ease of synthesis. However, enhancing their catalytic activity in the tumor microenvironment (TME) remains a major challenge. Herein, we manipulate catalytic activities of Ru nanozymes via modulating lattice spacing in Ru nanocrystals supported on nitrogen-doped carbon support, to achieve improvement in multiple enzyme-like activities that can form cascade catalytic reactions to boost cancer cell killing. In addition, the lattice expansion in Ru nanocrystals improve the responsiveness of the nanozymes to self-powered electric field, achieving maximized cancer therapeutic outcome. Under the electrical stimulation provided by a human self-propelled triboelectric device, the Ru-based nanozyme (Ru1000) with a lattice expansion of 5.99% realizes optimal catalytic performance and cancer therapeutic outcome of breast cancer in female tumor-bearing mice. Through theoretical calculations, we uncover that the lattice expansion and electrical stimulation promote the catalytic reaction, simultaneously, by reducing the electron density and shifting the d-band center of Ru active sites. This work provides opportunities for improving the development of nanozymes.
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Rutênio , Microambiente Tumoral , Animais , Rutênio/química , Catálise , Feminino , Camundongos , Humanos , Linhagem Celular Tumoral , Microambiente Tumoral/efeitos dos fármacos , Neoplasias da Mama/terapia , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Nanopartículas/química , Camundongos Endogâmicos BALB C , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
Colorectal cancer (CRC) continues to be a major health issue even though screening methods have facilitated early detection. Despite the high sensitivity of white-light colonoscopy, it frequently overlooks invasive flat or depressed lesions, which can lead to the development of larger, advanced tumors. Fluorescence molecular imaging (FMI) offers a promising approach for early tumor detection by targeting specific molecular characteristics of lesions. CD24 is upregulated during the adenoma-to-CRC transition, providing a potential target for FMI. Here, we developed a second near-infrared window (NIR-II) fluorescent probe with a high affinity for CD24 and evaluated its efficacy and targeting ability in cellular models, murine models, and clinical samples of CRC. CD24 expression was elevated in 76% of adenomas and 80% of CRCs. In a colitis-associated cancer mouse model, NIR-II imaging with the CD24-targeted probe achieved a significantly higher tumor-to-background ratio compared to conventional NIR-I imaging. The probe demonstrated exceptional sensitivity (92%) and specificity (92%) for detecting CRC, including small lesions less than 1 mm in size. This led to the identification of precancerous lesions missed by white-light detection and lesions missed by NIR-I imaging. Moreover, ex vivo human tissue incubation with the probe supported the potential for intraprocedural lesion identification via topical probe application during colonoscopy. In conclusion, this study successfully demonstrates the potential of CD24-targeted NIR-II imaging for identifying colorectal neoplasia, highlighting its significance for early CRC detection in the gastrointestinal tract.
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Organic-inorganic lead halide perovskites (OLHPs) have demonstrated exceptional properties in high-performance photoelectric devices. However, the impact of A-site cations, specifically formamidinium and methylammonium (MA), on the optoelectronic properties of OLHPs, particularly in the context of hot carrier utilization, remains a topic of debate. In this study, we propose a method for characterizing hot carrier transportation by measuring the hot carrier mobility and momentum-dependent transient photocurrent influenced by A-site cations in OLHPs. Our findings reveal that the direction of photon drag current is reversed upon substitution of the MA cation, suggesting the strong localization of hot carriers by the MA cation dipole. Furthermore, the correlation between the hot carrier photoconductivity and the electronic structure in different A-site cation samples indicates that hot carrier mobility in OLHPs can be reduced by >50% due to the influence of A-site cations.
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The pyroptosis of cardiomyocytes has become an essential topic in heart failure research. The abnormal accumulation of these biological factors, including angiotensin II, advanced glycation end products, and various growth factors (such as connective tissue growth factor, vascular endothelial growth factor, transforming growth factor beta, among others), activates the nuclear factor-κB (NF-κB) signaling pathway in cardiovascular diseases, ultimately leading to pyroptosis of cardiomyocytes. Therefore, exploring the underlying molecular biological mechanisms is essential for developing novel drugs and therapeutic strategies. However, our current understanding of the precise regulatory mechanism of this complex signaling pathway in cardiomyocyte pyroptosis is still limited. Given this, this study reviews the milestone discoveries in the field of pyroptosis research since 1986, analyzes in detail the similarities, differences, and interactions between pyroptosis and other cell death modes (such as apoptosis, necroptosis, autophagy, and ferroptosis), and explores the deep connection between pyroptosis and heart failure. At the same time, it depicts in detail the complete pathway of the activation, transmission, and eventual cardiomyocyte pyroptosis of the NF-κB signaling pathway in the process of heart failure. In addition, the study also systematically summarizes various therapeutic approaches that can inhibit NF-κB to reduce cardiomyocyte pyroptosis, including drugs, natural compounds, small molecule inhibitors, gene editing, and other cutting-edge technologies, aiming to provide solid scientific support and new research perspectives for the prevention and treatment of heart failure.
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Insuficiência Cardíaca , Miócitos Cardíacos , NF-kappa B , Piroptose , Transdução de Sinais , Piroptose/fisiologia , Humanos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , NF-kappa B/metabolismo , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , AnimaisRESUMO
Plant glutathione peroxidases (GPXs) are important enzymes for removing reactive oxygen species in plant cells and are closely related to the stress resistance of plants. This study identified the GPX gene family members of pepper (Capsicum annuum L.), "CM333", at the whole-genome level to clarify their expression patterns and enzyme activity changes under abiotic stress and ABA treatment. The results showed that eight CaGPX genes were unevenly distributed across four chromosomes and one scaffold of the pepper genome, and their protein sequences had Cys residues typical of the plant GPX domains. The analysis of collinearity, phylogenetic tree, gene structure, and conserved motifs indicated that the CaGPX gene sequence is conserved, structurally similar, and more closely related to the sequence structure of Arabidopsis. Meanwhile, many cis elements involved in stress, hormones, development, and light response were found in the promoter region of the CaGPX gene. In addition, CaGPX1/4 and CaGPX6 were basically expressed in all tissues, and their expression levels were significantly upregulated under abiotic stress and ABA treatment. Subcellular localization showed that CaGPX1 and CaGPX4 are localized in chloroplasts. Additionally, the variations in glutathione peroxidase activity (GSH-Px) mostly agreed with the variations in gene expression. In summary, the CaGPXs gene may play an important role in the development of peppers and their response to abiotic stress and hormones.
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Ácido Abscísico , Capsicum , Regulação da Expressão Gênica de Plantas , Glutationa Peroxidase , Família Multigênica , Filogenia , Proteínas de Plantas , Estresse Fisiológico , Capsicum/genética , Capsicum/enzimologia , Capsicum/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Estresse Fisiológico/genética , Ácido Abscísico/farmacologia , Ácido Abscísico/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regiões Promotoras Genéticas , Sequência de AminoácidosRESUMO
BACKGROUND: HPV-16 infection and viral-host integration are the most important risk factors for cervical cancer (CC). The aim of this study is to develop a new molecular strategy integrated both the viral and host genome variations identifying and monitoring CC. METHOD: A total of 312 methylation and 538 RNA-seq datasets were collected from public databases to identify differentially methylated and expressed genes. HPV associated virus integration sites (VISs) were analysed using the ViMIC database. From September 2020 to August 2021, the 70 HPV-16 positive cases retrospectively collected from multi-centre cohorts were subjected to HPV-16 E6 deep sequencing and PCR-based host gene (ASTN1, DLX1, ITGA4, RXFP3, SOX17, ZNF671) methylation detection. RNAseq and expression validation (NNF671) were performed in C-33A cell line harbouring HPV D32E. Lasso and logistic regression algorithm were used to construct the CC diagnostic model. RESULTS: A positive correlation was observed between the average methylation level of CC patients and their pathological features including tumour stage (p = 0.0077) and HPV subtype (p < 0.001). ZNF671 was identified as a CC-specific methylation marker, with an impressive 93% sensitivity. Both HPV-16 D32E mutation and integration of HPV-16 down-regulated the ZNF671 expression. Finally, a CC diagnostic nomogram was developed by integrating ZNF671 methylation level and HPV E6 mutation feature, yielding an exceptional AUC of 0.997 (95% CI: 0.934-1.000). CONCLUSIONS: Our study demonstrated HPV viral mutations are closely related to host gene epigenetic alterations in CC. Integration of the viral and host genetic information might be a new promising strategy for CC screening.
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BACKGROUND: Early detection and treatment are effective methods for the management of oral squamous cell carcinoma (OSCC), which can be facilitated by the detection of tumor-specific OSCC biomarkers. The epidermal growth factor receptor (EGFR) and programmed death-ligand 1 (PD-L1) are important therapeutic targets for OSCC. Multispectral fluorescence molecular imaging (FMI) can facilitate the detection of tumor multitarget expression with high sensitivity and safety. Hence, we developed Nimotuzumab-ICG and Atezolizumab-Cy5.5 imaging probes, in combination with multispectral FMI, to sensitively and noninvasively identify EGFR and PD-L1 expression for the detection and comprehensive treatment of OSCC. METHODS: The expression of EGFR and PD-L1 was analyzed using bioinformatics data sources and specimens. Nimotuzumab-ICG and Atezolizumab-Cy5.5 imaging probes were developed and tested on preclinical OSCC cell line and orthotopic OSCC mouse model, fresh OSCC patients' biopsied samples, and further clinical mouthwash trials were conducted in OSCC patients. RESULTS: EGFR and PD-L1 were specifically expressed in human OSCC cell lines and tumor xenografts. Nimotuzumab-ICG and Atezolizumab-Cy5.5 imaging probes can specifically target to the tumor sites in an in situ human OSCC mouse model with good safety. The detection sensitivity and specificity of Nimotuzumab-ICG in patients were 96.4% and 100%, and 95.2% and 88.9% for Atezolizumab-Cy5.5. CONCLUSIONS: EGFR and PD-L1 are highly expressed in OSCC, the combination of which is important for a precise prognosis of OSCC. EGFR and PD-L1 expression can be sensitively detected using the newly synthesized multispectral fluorescence imaging probes Nimotuzumab-ICG and Atezolizumab-Cy5.5, which can facilitate the sensitive and specific detection of OSCC and improve treatment outcomes. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2100045738. Registered 23 April 2021, https://www.chictr.org.cn/bin/project/edit?pid=125220.
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Anticorpos Monoclonais Humanizados , Antígeno B7-H1 , Carcinoma de Células Escamosas , Receptores ErbB , Neoplasias Bucais , Imagem Óptica , Humanos , Antígeno B7-H1/metabolismo , Animais , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/diagnóstico , Imagem Óptica/métodos , Anticorpos Monoclonais Humanizados/uso terapêutico , Camundongos , Feminino , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/diagnóstico , Masculino , Linhagem Celular Tumoral , Pessoa de Meia-Idade , Imagem Molecular/métodos , Biomarcadores Tumorais/metabolismoRESUMO
Solid-state polymer electrolytes (SPEs) are promising for high-performance zinc metal batteries (ZMBs), but they encounter critical challenges of low ionic conductivity, limited Zn2+ transference number (tZn2+), and an unstable electrolyte-electrode interface. Here, we present an effective approach involving a missing-linker metallic organic framework (MOF)-catalyzed poly(ethylene glycol) diacrylate (PEGDA)/polyacrylamide (PAM) copolymer SPE for single Zn2+ conduction and seamless electrolyte-electrode contact. The single-Zn2+ conduction is facilitated by the anchoring of the OTF- anions onto the unsaturated metal sites of missing-linker MOF, while the PEGDA and PAM chains in competitive coordination with Zn2+ ions promote rapid Zn ion transport. Our all-solid-state electrolyte simultaneously achieves a superior ionic conductivity of 1.52 mS cm-1 and a high tZn2+ of 0.83 at room temperature, alongside uniform Zn metal deposition (1000 cycles in symmetric cells) and high Zn plating/striping efficiencies (>99% after 600 cycles in asymmetric cells). Applications of our SPE in Zn//VO2 full cells are further demonstrated with a long lifespan of 2000 cycles and an extremely low-capacity degradation rate of 0.012% per cycle. This work provides an effective strategy for using a missing-linker MOF to catalyze competitively coordinating copolymers for accelerating Zn2+ ion conduction, assisting the future design of all-solid-state ZMBs.
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Despite significant progress achieved in artificial self-sorting in solution, operating self-sorting in the body remains a considerable challenge. Here, we report an in vivo self-sorting peptide system via an in situ assembly evolution for combined cancer therapy. The peptide E3C16-SS-EIY consists of two disulfide-connected segments, E3C16SH and SHEIY, capable of independent assembly into twisted or flat nanoribbons. While E3C16-SS-EIY assembles into nanorods, exposure to glutathione (GSH) leads to the conversion of the peptide into E3C16SH and SHEIY, thus promoting in situ evolution from the nanorods into self-sorted nanoribbons. Furthermore, incorporation of two ligand moieties targeting antiapoptotic protein XIAP and organellar endoplasmic reticulum (ER) into the self-sorted nanoribbons allows for simultaneous inhibition of XIAP and accumulation surrounding ER. This leads to the cytotoxicity toward the cancer cells with elevated GSH levels, through activating caspase-dependent apoptosis and inducing ER dysfunction. In vivo self-sorting of E3C16-SS-EIY decorated with ligand moieties is thoroughly validated by tissue studies. Tumor-bearing mouse experiments confirm the therapeutic efficacy of the self-sorted assemblies for inhibiting tumor growth, with excellent biosafety. Our findings demonstrate an efficient approach to develop in vivo self-sorting systems and thereby facilitating in situ formulation of biomedical agents.
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Peptídeos , Humanos , Animais , Peptídeos/química , Peptídeos/farmacologia , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Glutationa/química , Glutationa/metabolismo , Linhagem Celular Tumoral , Nanotubos/químicaRESUMO
OBJECTIVE: Coagulation assessment in traumatic brain injury (TBI) typically relies upon laboratory-based standard coagulation tests (SCTs), including the activated partial thromboplastin time (aPTT), INR and platelet count. Rotational thromboelastometry (ROTEM) sigma is an alternative point-of-care assay; however, its role in isolated TBI is under-evaluated. The present study aims to assess the prognostic utility of ROTEM sigma in isolated TBI. METHODS: ROTEM sigma analysis was performed during the initial evaluation of patients presenting to the Royal Adelaide Hospital between February 2022 and 2023 with radiographically demonstrated traumatic intracranial haemorrhage and GCS ≤14. Patients with concomitant severe extracranial injury, or who received blood products or antifibrinolytic therapy prior to sample collection were excluded. RESULTS: Thirty-six patients had blood samples analysed with ROTEM, 25 of these patients were also evaluated with paired SCTs. Twenty-two per cent (8/36) of patients with isolated TBI had a hypocoaguable ROTEM profile, and this was associated with an increased incidence of head injury-related death (50% [4/8] vs 11% [3/28], P = 0.03). Median diagnostic turn-around-times were shorter for ROTEM parameters compared to SCT counterparts: EXTEM clotting time (CT) versus INR (20 vs 63 min, P < 0.01), and INTEM CT versus aPTT (21 vs 63 min, P < 0.01). EXTEM CT, FIBTEM CT and INR values had similar performance in predicting head injury-related death, area under the receiver operator curves were 0.8, 0.8 and 0.7, respectively. CONCLUSIONS: ROTEM sigma expedites the detection of clinically significant coagulopathy in isolated TBI. EXTEM and FIBTEM CT values are more rapidly attainable than INR and comparable in predicting head injury-related death.
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BACKGROUND: Perioperative heparin-free anticoagulation extracorporeal membrane oxygenation (ECMO) for lung transplantation is rarely reported. OBJECTIVE: To evaluate the impact of a heparin-free strategy on bleeding and thrombotic events, blood transfusion, and coagulation function during the early perioperative period and on prognosis, and to observe its effect on different ECMO types. DESIGN: A retrospective cohort study. METHODS: Data were collected from 324 lung transplantation patients undergoing early perioperative heparin-free ECMO between August 2017 and July 2022. Clinical data including perioperative bleeding and thrombotic events, blood product transfusion, coagulation indicators and 1-year survival were analysed. RESULTS: Patients were divided in venovenous (VV; n = 251), venoarterial (VA; n = 40) and venovenous-arterial (VV-A; n = 33) groups. The VV group had the lowest intraoperative bleeding and thoracic drainage within 24 h postoperatively. Vein thrombosis occurred in 30.2% of patients within 10 days postoperatively or 1 week after ECMO withdrawal, and no significant difference was found among the three groups. Double lung transplantation, increased intraoperative bleeding, and increased postoperative drainage were associated with vein thrombosis. Except for acute myocardial infarction in one patient, no other serious thrombotic events occurred. The VV-ECMO group had the lowest demand for blood transfusion. The highest prothrombin time and the lowest fibrinogen levels were observed in the VA group during ECMO run, while the highest platelet counts were found in the VV group. Both intraoperative bleeding and thoracic drainage within 24 h postoperatively were independent predictors for 1-year survival, and no thrombosis-related deaths occurred. CONCLUSION: Short-term heparin-free anticoagulation, particularly VV-ECMO, did not result in serious thrombotic events or thrombosis-related deaths, indicating that it is a safe and feasible strategy for perioperative ECMO in lung transplantation.
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Anticoagulantes , Coagulação Sanguínea , Oxigenação por Membrana Extracorpórea , Transplante de Pulmão , Trombose , Humanos , Oxigenação por Membrana Extracorpórea/efeitos adversos , Oxigenação por Membrana Extracorpórea/mortalidade , Estudos Retrospectivos , Transplante de Pulmão/efeitos adversos , Transplante de Pulmão/mortalidade , Feminino , Masculino , Pessoa de Meia-Idade , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Adulto , Trombose/prevenção & controle , Trombose/etiologia , Fatores de Tempo , Coagulação Sanguínea/efeitos dos fármacos , Resultado do Tratamento , Fatores de Risco , Transfusão de Sangue , Heparina/administração & dosagem , Heparina/efeitos adversos , Hemorragia Pós-Operatória/prevenção & controle , Hemorragia Pós-Operatória/etiologia , Hemorragia Pós-Operatória/mortalidade , Perda Sanguínea Cirúrgica/prevenção & controleRESUMO
Metastatic clear cell renal cell carcinoma has heterogenous tumor microenvironment (TME). Among the metastatic lesions, pancreas metastasis is rare and controversy in treatment approaches. Here, extensive primary and metastatic lesion samples were included by single-cell RNA-seq to decipher the distinct metastasis TME. The hypoxic and inflammatory TME of pancreas metastasis was decoded in this study, and the activation of PAX8-myc signaling, and metabolic reprogramming were observed. The active components including endothelial cells, fibroblasts and T cells were profiled. Meanwhile, we also evaluated the effect of anti-angiogenesis treatment in the pancreas metastasis patient. The potential mechanisms of pancreatic tropism, instability of genome, and the response of immunotherapy were also discussed in this work. Taken together, our findings suggest a clue to the heterogeneity in metastasis TME and provide evidence for the treatment of pancreas metastasis in renal cell carcinoma patients.
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Inibidores da Angiogênese , Carcinoma de Células Renais , Neoplasias Renais , Neoplasias Pancreáticas , RNA-Seq , Análise de Célula Única , Microambiente Tumoral , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/secundário , Carcinoma de Células Renais/patologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/farmacologia , Análise de Célula Única/métodos , Fator de Transcrição PAX8/genética , Fator de Transcrição PAX8/metabolismo , Regulação Neoplásica da Expressão Gênica , Masculino , Feminino , Análise da Expressão Gênica de Célula ÚnicaRESUMO
BACKGROUND: Breast cancer mortality varies in urban and rural areas in China. Studies have reported urban-rural difference across time period, however, the evaluation on urban-rural differences in age and birth cohort effects is limited. Our aim was to quantitatively assess urban-rural disparities in age, period and cohort effects in breast cancer mortality in China. METHODS: We collected age-specific breast cancer mortality rates for urban and rural females aged 20-84 years from 1987 to 2021. Hierarchical age-period-cohort (HAPC) models were used to evaluate the effect of area (urban, rural) on breast cancer mortality and investigate urban-rural differences in age, time period and birth cohort effects. RESULTS: We found a significant area (urban, rural) effect on breast cancer mortality in that rural females had a lower mortality risk than urban females [-0.25 (95â¯% confidence interval (CI): -0.32, -0.17)]. Age trajectories of mortality based on the HAPC model showed nonlinear trends with adjustment for area variable. The urban-rural difference in age effect appeared to be divergent with age, and urban women had higher mortality risk in the senior age group. The urban-rural difference in birth cohort effect indicated a reversal around the birth cohort group of 1962-1966, after which rural females had a higher mortality risk than urban females. CONCLUSION: The area (urban, rural) could affect breast cancer mortality among women, and the effect of urban-rural difference varies with age and birth cohort. To promote the health of urban and rural females, the gap between urban and rural areas should be shorten.
Assuntos
Neoplasias da Mama , População Rural , População Urbana , Humanos , Feminino , Neoplasias da Mama/mortalidade , Neoplasias da Mama/epidemiologia , Pessoa de Meia-Idade , Adulto , Idoso , China/epidemiologia , População Rural/estatística & dados numéricos , População Urbana/estatística & dados numéricos , Idoso de 80 Anos ou mais , Adulto Jovem , Estudos de Coortes , Fatores Etários , População do Leste AsiáticoRESUMO
Effector proteins secreted by bacteria that infect mammalian and plant cells often subdue eukaryotic host cell defenses by simultaneously affecting multiple targets. However, instances when a bacterial effector injected in the competing bacteria sabotage more than a single target have not been reported. Here, we demonstrate that the effector protein, LtaE, translocated by the type IV secretion system from the soil bacterium Lysobacter enzymogenes into the competing bacterium, Pseudomonas protegens, affects several targets, thus disabling the antibacterial defenses of the competitor. One LtaE target is the transcription factor, LuxR1, that regulates biosynthesis of the antimicrobial compound, orfamide A. Another target is the sigma factor, PvdS, required for biosynthesis of another antimicrobial compound, pyoverdine. Deletion of the genes involved in orfamide A and pyoverdine biosynthesis disabled the antibacterial activity of P. protegens, whereas expression of LtaE in P. protegens resulted in the near-complete loss of the antibacterial activity against L. enzymogenes. Mechanistically, LtaE inhibits the assembly of the RNA polymerase complexes with each of these proteins. The ability of LtaE to bind to LuxR1 and PvdS homologs from several Pseudomonas species suggests that it can sabotage defenses of various competitors present in the soil or on plant matter. Our study thus reveals that the multi-target effectors have evolved to subdue cell defenses not only in eukaryotic hosts but also in bacterial competitors.