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Endocrine-resistant ER+HER2- breast cancer (BC) is particularly aggressive and leads to poor clinical outcomes. Effective therapeutic strategies against endocrine-resistant BC remain elusive. Here, analysis of the RNA-sequencing data from ER+HER2- BC patients receiving neoadjuvant endocrine therapy and spatial transcriptomics analysis both show the downregulation of innate immune signaling sensing cytosolic DNA, which primarily occurs in endocrine-resistant BC cells, not immune cells. Indeed, compared with endocrine-sensitive BC cells, the activity of sensing cytosolic DNA through the cGAS-STING pathway is attenuated in endocrine-resistant BC cells. Screening of kinase inhibitor library show that this effect is mainly mediated by hyperactivation of AKT1 kinase, which binds to kinase domain of TBK1, preventing the formation of a trimeric complex TBK1/STING/IRF3. Notably, inactivation of cGAS-STING signaling forms a positive feedback loop with hyperactivated AKT1 to promote endocrine resistance, which is physiologically important and clinically relevant in patients with ER+HER2- BC. Blocking the positive feedback loop using the combination of an AKT1 inhibitor with a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of endocrine-resistant tumors in humanized mice models, providing a potential strategy for treating patients with endocrine-resistant BC.
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Resistance to HER2-targeted therapy is the major cause of treatment failure in patients with HER2+ breast cancer (BC). Given the key role of immune microenvironment in tumor development, there is a lack of an ideal prognostic model that fully accounts for immune infiltration. In this study, WGCNA analysis was performed to discover the relationship between immune-related signaling and prognosis of HER2+ BC. After Herceptin-resistant BC cell lines established, transcriptional profiles of resistant cell line and RNA-sequencing data from GSE76360 cohort were analyzed for candidate genes. 85 samples of HER2+ BC from TCGA database were analyzed by the Cox regression, XGBoost and Lasso algorithm to generalize a credible immune-related prognostic index (IRPI). Correlations between the IRPI signature and tumor microenvironment were further analyzed by multiple algorithms, including single-cell RNA sequencing data analysis. Patients with high IRPI had suppressive tumor immune microenvironment and worse prognosis. The suppression of type I interferon signaling indicated by the IRPI in Herceptin-resistant HER2+ BC was validated. And we elucidated that the suppression of cGAS-STING pathway is the key determinant underlying immune escape in Herceptin-resistant BC with high IRPI. A combination of STING agonist and DS-8201 could serve as a new strategy for Herceptin-resistant HER2+ BC.
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Neoplasias da Mama , Resistencia a Medicamentos Antineoplásicos , Proteínas de Membrana , Nucleotidiltransferases , Receptor ErbB-2 , Trastuzumab , Microambiente Tumoral , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/imunologia , Feminino , Trastuzumab/uso terapêutico , Trastuzumab/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Nucleotidiltransferases/metabolismo , Nucleotidiltransferases/genética , Transdução de Sinais , Linhagem Celular Tumoral , Prognóstico , Regulação Neoplásica da Expressão GênicaRESUMO
An intelligent colorimetric sensing platform integrated with in situ immunomagnetic separation function was developed for ultrasensitive detection of Escherichia coli O157: H7 (E. coli O157: H7) in food. Captured antibody modified magnetic nanoparticles (cMNPs) and detection antibody/horseradish peroxidase (HRP) co-functionalized AuNPs (dHAuNPs) were firstly synthesized for targeted enrichment and colorimetric assay of E. coli O157: H7, in which remarkable signal amplification was realized by loading large amounts of HRP on the surface of AuNPs. Coupling with the optical collimation attachments and embedded magnetic separation module, a highly integrated optical device was constructed, by which in situ magnetic separation and high-quality imaging of 96-well microplates containing E. coli O157: H7 was achieved with a smartphone. The concentration of E. coli O157: H7 could be achieved in one-step by performing digital image colorimetric analysis of the obtained image with a custom-designed app. This biosensor possesses high sensitivity (1.63 CFU/mL), short detecting time (3 h), and good anti-interference performance even in real-sample testing. Overall, the developed method is expected to be a novel field detection platform for foodborne pathogens in water and food as well as for the diagnosis of infections due to its portability, ease of operation, and high feasibility.
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Técnicas Biossensoriais , Colorimetria , Escherichia coli O157 , Microbiologia de Alimentos , Ouro , Peroxidase do Rábano Silvestre , Separação Imunomagnética , Nanopartículas Metálicas , Escherichia coli O157/isolamento & purificação , Colorimetria/métodos , Ouro/química , Peroxidase do Rábano Silvestre/química , Separação Imunomagnética/métodos , Técnicas Biossensoriais/métodos , Nanopartículas Metálicas/química , Contaminação de Alimentos/análise , Limite de Detecção , Smartphone , Anticorpos Imobilizados/imunologia , Anticorpos Imobilizados/química , Nanopartículas de Magnetita/químicaRESUMO
BACKGROUND: Mitochondrial outer membrane permeabilisation (MOMP) plays a pivotal role in cellular death and immune activation. A deeper understanding of the impact of tumour MOMP on immunity will aid in guiding more effective immunotherapeutic strategies. METHODS: A comprehensive pan-cancer dataset comprising 30 cancer-type transcriptomic cohorts, 20 immunotherapy transcriptomic cohorts and three immunotherapy scRNA-seq datasets was collected and analysed to determine the influence of tumour MOMP activity on clinical prognosis, immune infiltration and immunotherapy effectiveness. Leveraging 65 scRNA-Seq datasets, the MOMP signature (MOMP.Sig) was developed to accurately reflect tumour MOMP activity. The clinical predictive value of MOMP.Sig was explored through machine learning models. Integration of the MOMP.Sig model and a pan-cancer immunotherapy CRISPR screen further investigated potential targets to overcome immunotherapy resistance, which subsequently underwent clinical validation. RESULTS: Our research revealed that elevated MOMP activity reduces mortality risk in cancer patients, drives the formation of an anti-tumour immune environment and enhances the response to immunotherapy. This finding emphasises the potential clinical application value of MOMP activity in immunotherapy. MOMP.Sig, offering a more precise indicator of tumour cell MOMP activity, demonstrated outstanding predictive efficacy in machine-learning models. Moreover, with the assistance of the MOMP.Sig model, FOXO1 was identified as a core modulator that promotes immune resistance. Finally, these findings were successfully validated in clinical immunotherapy cohorts of skin cutaneous melanoma and triple-negative breast cancer patients. CONCLUSIONS: This study enhances our understanding of MOMP activity in immune modulation, providing valuable insights for more effective immunotherapeutic strategies across diverse tumours.
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Imunoterapia , Membranas Mitocondriais , Neoplasias , Humanos , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Membranas Mitocondriais/metabolismo , Imunomodulação/efeitos dos fármacosRESUMO
Chronic wounds are characterized with excessive biofluid and persistent infection. Therefore, there is an urgent desire to develop a multifunctional wound dressing that can meet the extreme requirements including effective antibacterial and powerful wound microenvironment regulation and protection function to promote wounds heal quickly. In this study, a multifunctional composite dressing (HA-AMP/SF/Alg/Rb-BG-AIEgens) was synthesized by combining a mesoporous bioactive glass framework loaded with AIEgens (Rb-BG-AIEgens) with cross-linked antimicrobial peptide grafted hyaluronic acid (HA-AMP), sodium alginate (Alg), and silk fibroin (SF). It is important to note that the Rb-BG-AIEgens can achieve real-time and sensitive bacterial detection. HA-AMP can achieve broad spectrum antibacterial and avoid the residue of drug-resistant bacteria. The HA-AMP/SF/Alg/Rb-BG-AIEgens dressing can up-regulate related proliferative proteins, thereby promoting regeneration of tissue and the rapid healing of chronic wounds. With good biocompatibility and antibacterial ability, HA-AMP/SF/Alg/Rb-BG-AIEgens dressing has great potential to become a next generation wound dressing for clinical biological fluid management and chronic bacterial infection treatment.
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Targeting ferroptosis for cancer therapy has slowed because of an incomplete understanding of ferroptosis mechanisms under specific pathological contexts such as tumorigenesis and cancer treatment. Here, we identify TRPML1-mediated lysosomal exocytosis as a potential anti-ferroptotic process through genome-wide CRISPR-Cas9 activation and kinase inhibitor library screening. AKT directly phosphorylated TRPML1 at Ser343 and inhibited K552 ubiquitination and proteasome degradation of TRPML1, thereby promoting TRPML1 binding to ARL8B to trigger lysosomal exocytosis. This boosted ferroptosis defense of AKT-hyperactivated cancer cells by reducing intracellular ferrous iron and enhancing membrane repair. Correlation analysis and functional analysis revealed that TRPML1-mediated ferroptosis resistance is a previously unrecognized feature of AKT-hyperactivated cancers and is necessary for AKT-driven tumorigenesis and cancer therapeutic resistance. TRPML1 inactivation or blockade of the interaction between TRPML1 and ARL8B inhibited AKT-driven tumorigenesis and cancer therapeutic resistance in vitro and in vivo by promoting ferroptosis. A synthetic peptide targeting TRPML1 inhibited AKT-driven tumorigenesis and enhanced the sensitivity of AKT-hyperactivated tumors to ferroptosis inducers, radiotherapy, and immunotherapy by boosting ferroptosis in vivo. Together, our findings identified TRPML1 as a therapeutic target in AKT-hyperactivated cancer.
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Ferroptose , Neoplasias , Proteínas Proto-Oncogênicas c-akt , Animais , Humanos , Camundongos , Fatores de Ribosilação do ADP/metabolismo , Carcinogênese/patologia , Carcinogênese/genética , Linhagem Celular Tumoral , Ferroptose/efeitos dos fármacos , Lisossomos/metabolismo , Neoplasias/patologia , Neoplasias/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , UbiquitinaçãoRESUMO
Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. The approved step-up dose regimen of 1/2/60/30 mg IV is designed to mitigate cytokine release syndrome (CRS) and maximize efficacy in early cycles. A population pharmacokinetic (popPK) model was developed from 439 patients with relapsed/refractory B-Cell Non-Hodgkin lymphoma receiving Mosun IV monotherapy, including fixed dosing (0.05-2.8 mg IV every 3 weeks (q3w)) and Cycle 1 step-up dosing groups (0.4/1/2.8-1/2/60/30 mg IV q3w). Prior to Mosun treatment, ~50% of patients had residual levels of anti-CD20 drugs (e.g., rituximab or obinutuzumab) from prior treatment. CD20 receptor binding dynamics and rituximab/obinutuzumab PK were incorporated into the model to calculate the Mosun CD20 receptor occupancy percentage (RO%) over time. A two-compartment model with time-dependent clearance (CL) best described the data. The typical patient had an initial CL of 1.08 L/day, transitioning to a steady-state CL of 0.584 L/day. Statistically relevant covariates on PK parameters included body weight, albumin, sex, tumor burden, and baseline anti-CD20 drug concentration; no covariate was found to have a clinically relevant impact on exposure at the approved dose. Mosun CD20 RO% was highly variable, attributed to the large variability in residual baseline anti-CD20 drug concentration (median = 10 µg/mL). The 60 mg loading doses increased Mosun CD20 RO% in Cycle 1, providing efficacious exposures in the presence of the competing anti-CD20 drugs. PopPK model simulations, investigating Mosun dose delays, informed treatment resumption protocols to ensure CRS mitigation.
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Anticorpos Biespecíficos , Antígenos CD20 , Linfoma de Células B , Humanos , Antígenos CD20/imunologia , Antígenos CD20/metabolismo , Pessoa de Meia-Idade , Masculino , Idoso , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/imunologia , Feminino , Adulto , Anticorpos Biespecíficos/farmacocinética , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/imunologia , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/administração & dosagem , Idoso de 80 Anos ou mais , Modelos Biológicos , Antineoplásicos Imunológicos/farmacocinética , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/uso terapêutico , Adulto Jovem , Relação Dose-Resposta a Droga , Esquema de Medicação , Rituximab/farmacocinética , Rituximab/administração & dosagemRESUMO
Objectives: Providing satisfactory healthcare services for breast cancer survivors can effectively reduce their burden and the pressure on medical resources. The aim of this study was to explore health care service demands for community-dwelling breast cancer survivors using the Kano model. Methods: A cross-sectional survey was conducted from January to March 2023 among breast cancer survivors discharged from a tertiary cancer hospital. Participants were asked to fill out a self-designed questionnaire involving the Kano model, which helped to categorize and prioritize the attributes of healthcare services. The questionnaire included 30 health care services. Additionally, their social demographic characteristics were collected during the survey. Results: A total of 296 valid questionnaires were collected, and demand attributes of the 30 health care services were evaluated. The findings revealed that one of 30 services was classified as "must-be attributes" (body image management), 13 as "one-dimensional attributes" (focused on medical security support, health management, and health counseling), 3 as "attractive attributes" (focused on communication needs and telehealth services), and 11 as "indifferent attributes" (mainly in the area of psycho-social services). Conclusions: Breast cancer survivors in the community have different levels of need for various health care services. It's crucial for healthcare providers to identify these needs and devise effective strategies to deliver the appropriate services. Services with must-be and one-dimensional attributes should be given priority, and efforts should be made to provide services with attractive attributes, hence improving the quality of life of breast cancer survivors.
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Objective: The treatment of breast cancer still faces great challenges, and it is necessary to continuously explore effective drugs and targets to promote immune precision medicine. This study aims to investigate the immune-related regulatory mechanism of cordycepin in breast cancer. Methods: Network pharmacology was employed to discovery the action of cordyceps on breast cancer targets, molecular docking was employed to analyze the interaction pattern between core components and targets, and biological information analysis was used to explore the target-related immune mechanism and verified in vitro experiments. Results: The results of this study indicate that cordycepin can effectively inhibit breast cancer. The roles of cordycepin's active component and its target gene ALB were elucidated through the combined use of network pharmacology and molecular docking. Bioinformatics analysis revealed convincing associations between ALB and many immune pathway marker genes. ALB was inhibited in tumor expression, and cordycepin was found to enhance the expression of ALB in vitro to play an anti-tumor role. Conclusion: Cordycepin regulates immune suppression of tumor, which is expected to open a new chapter of breast cancer immunotherapy.
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PURPOSE: Venetoclax is a potent, orally bioavailable BCL-2 inhibitor used in the treatment of some hematological malignancies. Crushing tablets may be necessary to help with the administration of venetoclax to patients with swallowing difficulties or patients requiring nasogastric tube feeding. The study was conducted to assess the bioavailability of crushed and finely ground venetoclax tablets relative to whole tablets. METHODS: An open-label, randomized, 3-way, crossover study in 15 healthy adult females was conducted. Venetoclax tablets were administered orally in a crushed, ground or intact form on Day 1 of each period with water following a high-fat breakfast. Pharmacokinetic samples were collected up to 72 hours postdosing. FINDINGS: The crushed and ground tablets met the bioequivalence criteria (0.80-1.25) relative to the intact tablets with respect to area under the concentration-time curve to time of the last measurable concentration (AUCt) and to infinite time (AUCinf) but exhibited a slightly lower maximum plasma concentration (Cmax). This was not considered clinically significant as only venetoclax overall exposure (AUC) has been shown to correlate with clinical efficacy. There was no change in the physical appearance and the evaluated physicochemical properties of crushed and ground venetoclax tablets after 72 hours of storage at 25°C/60% relative humidity. IMPLICATIONS: Crushing or grinding venetoclax tablets before administration could be considered as a viable alternative method of administration for patients who have difficulty swallowing whole venetoclax tablets or patients requiring nasogastric tube feeding. GOV IDENTIFIERS: NCT05909553, registered June 12, 2023.
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Background: Ferroptosis plays a crucial role in the occurrence and development of cerebral ischemia-reperfusion (I/R) injury and is regulated by mitogen-activated protein kinase 1/2 (ERK1/2). In China, Naodesheng Pills (NDSP) are prescribed to prevent and treat cerebrosclerosis and stroke. However, the protective effects and mechanism of action of NDSP against cerebral I/R-induced ferroptosis remain unclear. We investigated whether NDSP exerts its protective effects against I/R injury by regulating ferroptosis and aimed to elucidate the underlying mechanisms. Methods: The efficacy of NDSP was evaluated using a Sprague-Dawley rat model of middle cerebral artery occlusion and an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model. Brain injury was assessed using 2,3,5-triphenyltetrazolium chloride (TTC), hematoxylin and eosin staining, Nissl staining, and neurological scoring. Western blotting was performed to determine the expression levels of glutathione peroxidase 4 (GPX4), divalent metal-ion transporter-1 (DMT1), solute carrier family 7 member 11 (SLC7A11), and transferrin receptor 1 (TFR1). Iron levels, oxidative stress, and mitochondrial morphology were also evaluated. Network pharmacology was used to assess the associated mechanisms. Results: NDSP (1.08 g/kg) significantly improved cerebral infarct area, cerebral water content, neurological scores, and cerebral tissue damage. Furthermore, NDSP inhibited I/R- and OGD/R-induced ferroptosis, as evidenced by the increased protein expression of GPX4 and SLC7A11, suppression of TFR1 and DMT1, and an overall reduction in oxidative stress and Fe2+ levels. The protective effects of NDSP in vitro were abolished by the GPX4 inhibitor RSL3. Network pharmacology analysis revealed that ERK1/2 was the core target gene and that NDSP reduced the amount of phosphorylated ERK1/2. Conclusion: NDSP exerts its protective effects against I/R by inhibiting cerebral I/R-induced ferroptosis, and this mechanism is associated with the regulation of ferroptosis via the ERK1/2 signaling pathway.
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Medicamentos de Ervas Chinesas , Ferroptose , Sistema de Sinalização das MAP Quinases , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Ferroptose/efeitos dos fármacos , Animais , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Masculino , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Modelos Animais de Doenças , Fármacos Neuroprotetores/farmacologiaRESUMO
Comprehending the phylogeography of invasive organisms enhances our insight into their distribution dynamics, which is instrumental for the development of effective prevention and management strategies. In China, Pomacea canaliculata and Pomacea maculata are the two most widespread and damaging species of the non-native Pomacea spp.. Given this species' rapid spread throughout country, it is urgent to investigate the genetic diversity and structure of its different geographic populations, a task undertaken in the current study using the COI and ITS1 mitochondrial and ribosomal DNA genes, respectively. The result of this study, based on a nationwide systematic survey, a collection of Pomacea spp., and the identification of cryptic species, showed that there is a degree of genetic diversity and differentiation in P. canaliculata, and that all of its variations are mainly due to differences between individuals within different geographical populations. Indeed, this species contains multiple haplotypes, but none of them form a systematic geographical population structure. Furthermore, the COI gene exhibits higher genetic diversity than the ITS1 gene. Our study further clarifies the invasive pathways and dispersal patterns of P. canaliculata in China to provide a theoretical basis.
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Complexo IV da Cadeia de Transporte de Elétrons , Variação Genética , Genética Populacional , Haplótipos , China , Animais , Complexo IV da Cadeia de Transporte de Elétrons/genética , Filogeografia , Filogenia , Espécies Introduzidas , DNA Espaçador Ribossômico/genética , Gastrópodes/genéticaRESUMO
Polatuzumab vedotin is a CD79b-directed antibody-drug conjugate that targets B cells and delivers the cytotoxic payload monomethyl auristatin E (MMAE). The phase III POLARIX study (NCT03274492) evaluated polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) as first-line treatment of diffuse large B-cell lymphoma (DLBCL). To examine dosing decisions for this regimen, population pharmacokinetic (popPK) analysis, using a previously developed popPK model, and exposure-response (ER) analysis, were performed. The popPK analysis showed no clinically meaningful relationship between cycle 6 (C6) antibody-conjugated (acMMAE)/unconjugated MMAE area under the concentration-time curve (AUC) or maximum concentration, and weight, sex, ethnicity, region, mild or moderate renal impairment, mild hepatic impairment, or other patient and disease characteristics. In the ER analysis, C6 acMMAE AUC was significantly associated with longer progression-free and event-free survival (both p = 0.01). An increase of <50% in acMMAE/unconjugated MMAE exposure did not lead to a clinically meaningful increase in adverse events of special interest. ER data and the benefit-risk profile support the use of polatuzumab vedotin 1.8 mg/kg once every 3 weeks with R-CHP for six cycles in patients with previously untreated DLBCL.
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Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Doxorrubicina , Linfoma Difuso de Grandes Células B , Prednisona , Rituximab , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Doxorrubicina/farmacocinética , Doxorrubicina/análogos & derivados , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Ciclofosfamida/farmacocinética , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prednisona/administração & dosagem , Prednisona/farmacocinética , Prednisona/uso terapêutico , Rituximab/farmacocinética , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Adulto , Área Sob a Curva , Modelos Biológicos , Imunoconjugados/farmacocinética , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Relação Dose-Resposta a Droga , Intervalo Livre de ProgressãoRESUMO
Electrocatalytic nitrate reduction reaction (NitRR) in neutral condition offers a promising strategy for green ammonia synthesis and wastewater treatment, the rational design of electrocatalysts is the cornerstone. Inspired by modern factory design where both machines and logistics matter for manufacturing, it is reported that cobalt phosphide (CoP) nanoparticles embedded in zinc-based zeolite imidazole frameworks (Zn-ZIF) function as a nanofactory with high performance. By selective phosphorization of ZnCo bimetallic zeolite imidazole framework (ZnCo-ZIF), the generated CoP nanoparticles act as "machines" (active sites) for molecular manufacturing (NO3 - to NH4 + conversion). The purposely retained framework (Zn-ZIFs) with positive charge promotes logistics automation, i.e., the automatic delivery of NO3 - reactants and timely discharge of NH4 + products in-and-out the nanofactory due to electrostatic interaction. Moreover, the interaction between Zn-ZIF and CoP modulates the Co sites into electron insufficient state with upshifted d-band center, facilitating the reduction/hydrogenation of NO3 - to ammonia and restricting the competitive hydrogen evolution. Consequently, the assembled CoP/Zn-ZIF nanofactory exhibits superior NitRR performances with a high Faraday efficiency of ≈97% and a high ammonia yield of 0.89 mmol cm-1 h-1 in neutral condition, among the best of reported electrocatalysts. The work provides new insights into the design principles of efficient NitRR electrocatalysts.
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BACKGROUND: Bone metastases are rare in oral squamous cell carcinoma (OSCC). It has not been defined on the risk and prognosis of OSCC patients with bone metastases. The purpose of this study was to assess the factors associated with the development and prognosis of bone metastases among OSCC patients. METHODS: Demographic and clinicopathological characteristics of OSCC patients diagnosed between 2010 and 2019 was retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. To explore risk factors for developing bone metastases and prognosis, the univariate and multivariate logistic and Cox regression analysis were performed, further the predictive nomogram models were constructed. RESULTS: The incidence rate of bone metastases in newly diagnosed OSCC patients was 0.91 % (95 %CI 0.81% -1.02 %). Ultimately, 137 OSCC patients with bone metastases and 19,469 OSCC patients without bone metastases were included in the present study. Pathological grade, primary site, T/N stage and distant organ metastases (liver/lung/brain) were independently associated with the risk of developing bone metastases among OSCC patients. The C-index of a constructed risk-predicting nomogram was 0.86 (95 %CI 0.83-0.89). Multivariate Cox regression analysis indicated that lung metastases, the use of surgery as well as chemotherapy were three independent prognostic factors. The C-indexes of constructed risk-predicting nomograms were 0.70 (95 %CI 0.65-0.75), 0.68 (95 %CI 0.63-0.73) for OS and CSS, respectively. Calibration plots demonstrated an agreementbetween the established nomogram's predicted survival and actual survival. In addition, decision curve analysis (DCA) indicated these established nomograms had considerable net benefits and clinical utilities. CONCLUSION: This study defined the risk and prognostic factors for bone metastases among OSCC patients and the established nomograms were well calibrated for discrimination to predict bone metastasis development and prognosis.
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Neoplasias Ósseas , Carcinoma de Células Escamosas , Neoplasias Bucais , Nomogramas , Programa de SEER , Humanos , Masculino , Neoplasias Ósseas/secundário , Neoplasias Ósseas/epidemiologia , Neoplasias Ósseas/diagnóstico , Feminino , Estudos Retrospectivos , Programa de SEER/estatística & dados numéricos , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Neoplasias Bucais/epidemiologia , Neoplasias Bucais/diagnóstico , Fatores de Risco , Prognóstico , Idoso , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/secundário , Carcinoma de Células Escamosas/diagnóstico , Adulto , Incidência , Estadiamento de NeoplasiasRESUMO
The favorable benefit-risk profile of polatuzumab vedotin, as demonstrated in a pivotal Phase Ib/II randomized study (GO29365; NCT02257567), coupled with the need for effective therapies in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), prompted the need to accelerate polatuzumab vedotin development. An integrated, fit-for-purpose clinical pharmacology package was designed to support regulatory approval. To address key clinical pharmacology questions without dedicated clinical pharmacology studies, we leveraged non-clinical and clinical data for polatuzumab vedotin, published clinical data for brentuximab vedotin, a similar antibody-drug conjugate, and physiologically based pharmacokinetic and population pharmacokinetic modeling approaches. We review strategies and model-informed outcomes that contributed to regulatory approval of polatuzumab vedotin plus bendamustine and rituximab in R/R DLBCL. These strategies made polatuzumab vedotin available to patients earlier than previously possible; depending on the strength of available data and the regulatory/competitive environment, they may also prove useful in accelerating the development of other agents.
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Imunoconjugados , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Farmacologia Clínica , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológicoRESUMO
OBJECTIVE: To investigate the prognostic impact of initial lung cancer (LC) on second primary breast cancer after LC (LC-BC) and further develop a nomogram for predicting the survival of patients. METHODS: All patients diagnosed with LC-BC and first primary BC (BC-1) during 2000-2017 were collected from Surveillance, Epidemiology, and End Results database. Pathological features, treatment strategies and survival outcomes were compared between LC-BC and BC-1 before and after propensity score matching (PSM). Cox regression analysis was performed to identify the prognostic factors associated with LC in patients with LC-BC. Additionally, least absolute shrinkage and selection operator regression analysis was used to select clinical characteristics for nomogram construction, which were subsequently evaluated using the concordance index (C-index), calibration curve and decision curve analysis (DCA). RESULTS: 827 429 patients with BC-1 and 1445 patients with LC-BC were included in the analysis. Before and after PSM, patients with BC-1 had a better prognosis than individuals with LC-BC in terms of both overall survival (OS) and breast cancer-specific survival (BCSS). Furthermore, characteristics such as more regional lymph node dissection, earlier stage and the lack of chemotherapy and radiation for LC were found to have a stronger predictive influence on LC-BC. The C-index values (OS, 0.748; BCSS, 0.818), calibration curves and DCA consistently demonstrated excellent predictive accuracy of the nomogram. CONCLUSION: In conclusion, patients with LC-BC have a poorer prognosis than those with BC-1, and LC traits can assist clinicians estimate survival of patients with LC-BC more accurately.
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Neoplasias da Mama , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias Pulmonares , Segunda Neoplasia Primária , Humanos , Feminino , Prognóstico , Neoplasias da Mama/terapia , Neoplasias Pulmonares/terapia , Pontuação de Propensão , NomogramasRESUMO
Objectives: Early identification of sarcopenia in patients with chronic liver disease is crucial for patient management and prevention of severe complications. We aimed to assess the effectiveness of Ishii score, Strength, Assistance with Walking, Rise from a Chair, Climb Stairs and Falls (SARC-F), SARC-F and Calf Circumference (SARC-CalF), and Mini Sarcopenia Risk Assessment-7 (MSRA-7) to screen sarcopenia in patients with chronic liver disease. Methods: This prospective study included patients with chronic liver disease in the infectious department of a tertiary hospital in Sichuan, China. Ishii score, SARC-F, SARC-CalF, and MSRA-7 were used to screen for sarcopenia risk. Sarcopenia was diagnosed according to the Asian Myometriosis Working Group (AWGS) 2019, which was used as the gold standard to compare the performance of the four screening tools. We completed clinical registration on the Chinese Clinical Trial Registration website (ChiCTR2100043910). Results: A total of 366 patients with chronic liver disease (22.4% women, mean age 48.96 ± 11.88 years) were evaluated. Based on the AWGS 2019 standard, the prevalence of sarcopenia in patients with chronic liver disease was 17.5%. Among all participants, receiver operating characteristic (ROC) produced an area under the curve (AUC) of 0.82 for Ishii score (sensitivity 85.94%, specificity 78.15%), 0.53 for SARC-F (sensitivity 6.25%, specificity 99.34%), 0.64 for SARC-CalF (sensitivity 45.31%, specificity 83.11%), and 0.55 for MSRA-7 (sensitivity 87.50%, specificity 22.85%). Based on AUC, decision curve analysis, and calibration curves, we concluded that Ishii score was the most accurate screening tool and was superior to the other tools. Conclusions: Ishii score is more suitable for screening sarcopenia in patients with chronic liver disease than the SARC-F, SARC-CalF, and MSRA-7, based on the AWGS 2019 criteria. Nursing professionals can use Ishii score as a clinical tool to screen for sarcopenia in patients with chronic liver disease, providing an indication cue for the final diagnosis of sarcopenia, improving diagnostic efficiency, and enabling early identification and prevention of complications resulting from sarcopenia.
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BACKGROUND: Current management guidelines for the treatment of carotid stenosis are controversial. We performed this meta-analysis to evaluate the perioperative safety of carotid artery stenting (CAS) and endarterectomy. METHODS: We systematically searched EMBASE, PubMed, Web of Science, and the Cochrane Library from inception to November 10, 2022, for randomized controlled trials that compared CAS with carotid endarterectomy (CEA) among patients with carotid stenosis. The analyzed outcomes mainly included stroke, death, myocardial infarction (MI), cranial nerve palsy, the cumulative incidence of mortality, stroke, or MI and the cumulative incidence of death or stroke in the perioperative periods. The risk ratio (RR) and 95% confidence interval (95% CI) were calculated and pooled. Subgroup analyses were based on whether patients were symptomatic or asymptomatic. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. RESULTS: Seventeen randomized controlled trials with 12,277 participants (6514 and 5763 in the CAS and CEA groups, respectively) were included. Pooled analysis demonstrated that compared with CEA, CAS was associated with decreased risks of perioperative MI (RR = 0.47, 95% CI = 0.29â¼0.77) and perioperative cranial nerve palsy (RR = 0.02, 95% CI = 0.01â¼0.06) but higher risks of perioperative stroke (RR = 1.48, 95% CI = 1.18â¼1.87) and cumulative incidence of death or stroke (RR = 1.52, 95% CI = 1.20â¼1.93). CONCLUSIONS: The perioperative safety was equivalent between CAS and CEA. However, CEA may be preferred when considering both procedural safety and long-term efficacy in preventing recurrent stroke.
Assuntos
Estenose das Carótidas , Doenças dos Nervos Cranianos , Endarterectomia das Carótidas , Infarto do Miocárdio , Acidente Vascular Cerebral , Humanos , Estenose das Carótidas/complicações , Resultado do Tratamento , Stents/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Endarterectomia das Carótidas/efeitos adversos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Infarto do Miocárdio/epidemiologia , Artérias Carótidas/cirurgia , Doenças dos Nervos Cranianos/etiologia , Medição de Risco , Fatores de RiscoRESUMO
The scientific literature contains valuable information that can be used for future applications, but manual analysis presents challenges due to its size and disciplinary boundaries. The prevailing solution involves natural language processing (NLP) techniques such as information retrieval. Nonetheless, existing automated systems primarily provide either statistically based shallow information or deep information without traceability, thereby falling short of delivering high-quality and reliable insights. To address this, we propose an innovative approach of leveraging sentiment information embedded within the literature to track the opinions toward materials. In this study, we integrated material knowledge into text representation and constructed opinion data sets to hierarchically train deep learning models, named as Scientific Sentiment Network (SSNet). SSNet can effectively extract knowledge from the energy material literature and accurately categorize expert opinions into challenges and opportunities (94% and 92% accuracy, respectively). By incorporating sentiment features determined by SSNet, we can predict the ranking of emerging thermoelectric materials with a 70% correlation to experimental outcomes. Furthermore, our model achieves a commendable 68% accuracy in predicting suitable nanomaterials for atomic layer deposition (ALD) over time. These promising results offer a practical framework to extract and synthesize knowledge from the scientific literature, thereby accelerating research in the field of nanomaterials.