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This study leverages the ancient craft of weaving to prepare membranes that can effectively treat oil/water mixtures, specifically challenging nanoemulsions. Drawing inspiration from the core-shell architecture of spider silk, we have engineered fibers, the fundamental building blocks for weaving membranes, that feature a mechanically robust core for tight weaving, coupled with a CO2-responsive shell that allows for on-demand wettability adjustments. Tightly weaving these fibers produces membranes with ideal pores, achieving over 99.6% separation efficiency for nanoemulsions with droplets as small as 20 nm. They offer high flux rates, on-demand self-cleaning, and can switch between sieving oil and water nanodroplets through simple CO2/N2 stimulation. Moreover, weaving can produce sufficiently large membranes (4800 cm2) to assemble a module that exhibits long-term stability and performance, surpassing state-of-the-art technologies for nanoemulsion separations, thus making industrial application a practical reality.
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Background: Malnutrition adversely affects prognosis in various medical conditions, but its implications in older adults with Chronic Obstructive Pulmonary Disease (COPD) in the ICU are underexplored. The geriatric nutritional risk index (GNRI) is a novel tool for assessing malnutrition risk. This study investigates the association between GNRI and 90-day mortality in this population. Methods: We selected older adults with COPD admitted to the ICU from Medical Information Mart for Intensive Care (MIMIC)-IV 2.2 database. A total of 666 patients were categorized into four groups based on their GNRI score: normal nutrition (>98), mild malnutrition (92-98), moderate malnutrition (82-91), and severe malnutrition (≤81) groups. We employed a restricted cubic spline (RCS) analysis to assess the presence of a curved relationship between them and to investigate any potential threshold saturation effect. Results: In multivariate Cox regression analyses, compared with individuals had normal nutrition (GNRI in Q4 >98), the adjusted HR values for GNRI in Q3 (92-98), Q2 (82-91), and Q1 (≤81) were 1.81 (95% CI: 1.27-2.58, p=0.001), 1.23 (95% CI: 0.84-1.79, p=0.296), 2.27 (95% CI: 1.57-3.29, p<0.001), respectively. The relationship between GNRI and 90-day mortality demonstrates an L-shaped curve (p=0.016), with an approximate inflection point at 101.5. Conclusion: These findings imply that GNRI is a useful prognostic tool in older adults with COPD in the ICU. An L-shaped relationship was observed between GNRI and 90-day mortality in these patients.
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Avaliação Geriátrica , Desnutrição , Avaliação Nutricional , Estado Nutricional , Valor Preditivo dos Testes , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/mortalidade , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Idoso , Masculino , Feminino , Estudos Retrospectivos , Fatores de Risco , Desnutrição/mortalidade , Desnutrição/diagnóstico , Medição de Risco , Avaliação Geriátrica/métodos , Fatores de Tempo , Idoso de 80 Anos ou mais , Prognóstico , Fatores Etários , Bases de Dados Factuais , Unidades de Terapia Intensiva/estatística & dados numéricosRESUMO
A prominent cause of cancer-related fatalities with a poor prognosis is lung adenocarcinoma (LUAD). KIF5A, a crucial member of the kinesin superfamily, is linked to drug resistance in malignancies. This work aims to investigate the mechanism of KIF5A in docetaxel (DTX) resistance in LUAD cells. The results of bioinformatics analysis, qRT-PCR and western blot analysis show that KIF5A, which is involved in the glycolysis pathway, is highly expressed in LUAD and is positively correlated with glycolysis-related genes. We further verify that silencing of KIF5A inhibits DTX resistance, glycolysis, and lactate production in LUAD cells via cell counting kit-8 (CCK-8), flow cytometry, Seahorse XFe 96, lactate, and glucose assays. Mechanistically, KIF5A promotes DTX resistance in LUAD, and this effect is attenuated upon the addition of an LDHA inhibitor. Chromatin immunoprecipitation and dual-luciferase reporter assays reveal that FOXP3 transcriptionally activates KIF5A. Knockdown of FOXP3 reduces lactate production and enhances DTX sensitivity in LUAD, which is restored upon simultaneous overexpression of KIF5A. Our findings reveal that FOXP3 increases DTX resistance in LUAD cells by enhancing lactate production through the upregulation of KIF5A level. In conclusion, our study provides a novel treatment target for improving chemosensitivity in LUAD.
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Adenocarcinoma de Pulmão , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Fatores de Transcrição Forkhead , Cinesinas , Ácido Láctico , Neoplasias Pulmonares , Cinesinas/genética , Cinesinas/metabolismo , Humanos , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Docetaxel/farmacologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Ácido Láctico/metabolismo , Linhagem Celular Tumoral , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antineoplásicos/farmacologia , Glicólise/efeitos dos fármacos , Glicólise/genéticaRESUMO
The role of prophylactic cranial irradiation (PCI) in limited-stage small cell lung cancer (LS-SCLC) has been questioned in the era of magnetic resonance imaging (MRI). The purpose of this study was to re-evaluate the efficacy of PCI in patients with LS-SCLC. Three electronic databases were searched, including PubMed, Embase, and the Cochrane Library from January 2012 to April 2022. All relevant publications were included based on the inclusion criteria, and survival data and brain metastasis (BM) rates were extracted and pooled. Ten studies were selected which involved 532 patients who received PCI and 613 patients who did not receive PCI. In pooled estimates, PCI significantly improved overall survival (OS) and progression-free survival (PFS) [hazard ratio (HR) = 0.71, 95% confidence interval (CI): 0.61-0.82, p <0.001; HR = 0.68, 95% CI: 0.48-0.97, p = 0.03, respectively]. Additionally, the use of PCI was associated with a significant reduction in the risk of brain metastasis (BM, risk ratio = 0.64, 95% CI: 0.46-0.90, p = 0.009). In subgroup analyses. The authors found that the PCI effects on OS were independent of region and the use of brain imaging after initial treatment. These findings demonstrate that PCI improves OS and PFS while decreasing the risk of BM in patients with LS-SCLC, implying that PCI remains necessary even in the MRI era. Key Words: Prophylactic cranial irradiation, Small cell lung cancer, Magnetic resonance imaging, Brain metastasis.
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Irradiação Craniana , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Neoplasias Encefálicas/prevenção & controle , Neoplasias Encefálicas/secundário , Irradiação Craniana/métodos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/radioterapiaRESUMO
Membranes are important in the pharmaceutical industry for the separation of antibiotics and salts. However, its widespread adoption has been hindered by limited control of the membrane microstructure (pore architecture and free-volume elements), separation threshold, scalability, and operational stability. In this study, 4,4',4'',4'''-methanetetrayltetrakis(benzene-1,2-diamine) (MTLB) as prepared as a molecular building block for fabricating thin-film composite membranes (TFCMs) via interfacial polymerization. The relatively large molecular size and rigid molecular structure of MTLB, along with its non-coplanar and distorted conformation, produced thin and defect-free selective layers (~27â nm) with ideal microporosities for antibiotic desalination. These structural advantages yielded an unprecedented high performance with a water permeance of 45.2â L m-2 h-1 bar-1 and efficient antibiotic desalination (NaCl/adriamycin selectivity of 422). We demonstrated the feasibility of the industrial scaling of the membrane into a spiral-wound module (with an effective area of 2.0â m2). This module exhibited long-term stability and performance that surpassed those of state-of-the-art membranes used for antibiotic desalination. This study provides a scientific reference for the development of high-performance TFCMs for water purification and desalination in the pharmaceutical industry.
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Antibacterianos , Membranas Artificiais , Nylons , Antibacterianos/química , Antibacterianos/isolamento & purificação , Nylons/química , Purificação da Água/métodos , Filtração/métodos , PermeabilidadeRESUMO
Current literatures suggest a growing body of evidence highlighting the pivotal role of Immunogenic Cell Death (ICD) in multiple tumor types. Nevertheless, the potential and mechanisms of ICD in diffuse large B-cell lymphoma (DLBCL) remain inadequately studied. To address this gap, our current study aims to examine the impact of ICD on DLBCL and identify a corresponding gene signature in DLBC. Using the expression profiles of ICD-associated genes, the gene expression omnibus (GEO) samples were segregated into ICD-high and ICD-low subtypes utilizing non-negative matrix factorization clustering. Next, univariate and LASSO Cox regression analyses were employed to establish the ICD-related gene signature. Subsequently, the CIBERSORT tool, ssGSEA, and ESTIMATE algorithm were utilized to examine the association between the signature and tumor immune microenvironment of DLBC. Finally, the oncoPredict algorithm was implemented to evaluate the drug sensitivity prediction of DLBCL patients. These findings suggest that the immune microenvironment of the ICD-high group with a poor prognosis was significantly suppressed. An 8-gene ICD-related signature was identified and validated to prognosticate and evaluate the tumor immune microenvironment in DLBCL. Similarly, the high-risk group exhibited a worse prognosis compared to the low-risk group, and the immune function was considerably suppressed. Moreover, the results of oncoPredict algorithm indicated that patients in the high-risk group exhibited higher sensitivity to Cisplatin, Cytarabine, Epirubicin, Oxaliplatin, and Vincristine with low IC50. In conclusion, the present study provides novel insights into the role of ICD in DLBCL by identifying a new biomarker for the disease and may have implications for the development of immune-targeted therapies for the tumor.
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Acute lung injury (ALI) is an acute inflammatory lung disease associated with both innate and adaptive immune responses. Hexokinase 2 (HK2) is specifically highly expressed in numerous types of inflammationrelated diseases and models. In the present study in vitro and in vivo effects of targeted degradation of HK2 on ALI were explored. The degradation of HK2 by the targeting peptide TAT (transactivator of transcription protein of HIV1)ataxin 1 (ATXN1)chaperonemediated autophagytargeting motif (CTM) was demonstrated by ELISA and western blotting in vitro and in vivo. The inhibitory effects of TATATXN1CTM on lipopolysaccharide (LPS)induced inflammatory responses were examined using ELISAs. The therapeutic effects of TATATXN1CTM on LPSinduced ALI were examined via histological examination and ELISAs in mice. 10 µM TATATXN1CTM administration decreased HK2 protein expression and the secretion of proinflammatory cytokines (TNFα and IL1ß) without altering HK2 mRNA expression in LPStreated both in vitro and in vivo, while pathological lung tissue damage and the accumulation of leukocytes, neutrophils, macrophages and lymphocytes in ALI were also significantly suppressed by 10 µM TATATXN1CTM treatment. TATATXN1CTM exhibited antiinflammatory activity in vitro and decreased the severity of ALI in vivo. HK2 degradation may represent a novel therapeutic approach for ALI.
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Lesão Pulmonar Aguda , Hexoquinase , Animais , Camundongos , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Hexoquinase/antagonistas & inibidores , Hexoquinase/metabolismo , Lipopolissacarídeos/efeitos adversos , Pulmão/patologiaRESUMO
OBJECTIVE: Transbronchial biopsy is a safe manner with fewer complications than percutaneous transthoracic needle biopsy; however, the current diagnostic yield is still necessitating further improvement. We aimed to evaluate the diagnostic yield of using virtual bronchoscopic navigation (VBN) and cone-beam CT (CBCT) for transbronchial biopsy and to investigate the factors that affected the diagnostic sensitivity. METHODS: We retrospectively investigated 255 patients who underwent VBN-CBCT-guided transbronchial biopsy at our two centers from May 2021 to April 2022. A total of 228 patients with final diagnoses were studied. Patient characteristics including lesion size, lesion location, presence of bronchus sign, lesion type and imaging tool used were collected and analyzed. Diagnostic yield was reported overall and in groups using different imaging tools. RESULTS: The median size of lesion was 21 mm (range of 15.5-29 mm) with 46.1% less than 2 cm in diameter. Bronchus sign was present in 87.7% of the patients. The overall diagnostic yield was 82.1%, and sensitivity for malignancy was 66.3%. Patients with lesion > 2 cm or with bronchus sign were shown to have a significantly higher diagnostic yield. Four patients had bleeding and no pneumothorax occurred. CONCLUSION: Guided bronchoscopy with VBN and CBCT was an effective diagnostic method and was associated with a high diagnostic yield in a safe manner. In addition, the multivariant analysis suggested that lesion size and presence of bronchus sign could be a predictive factor for successful bronchoscopic diagnosis.
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Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Estudos Retrospectivos , Biópsia/métodos , Tomografia Computadorizada de Feixe Cônico , Brônquios/patologia , Broncoscopia/métodosRESUMO
BACKGROUND: Rituximab resistance is one of the great challenges in the treatment of diffuse large B-cell lymphoma (DLBCL), but relevant biomarkers and signalling pathways remain to be identified. Coptis chinensis and its active ingredients have antitumour effects; thus, the potential bioactive compounds and mechanisms through which Coptis chinensis acts against rituximab-resistant DLBCL are worth exploring. OBJECTIVE: To elucidate the core genes involved in rituximab-resistant DLBCL and the potential therapeutic targets of candidate monomers of Coptis chinensis. METHODS: Using the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP), the Similarity Ensemble Approach and Swiss Target Prediction, the main ingredients and pharmacological targets of Coptis chinensis were identified through database searches. Through the overlap between the pharmacological targets of Coptis chinensis and the core targets of rituximab-resistant DLBCL, we identified the targets of Coptis chinensis against rituximab-resistant DLBCL and constructed an active compound-target interaction network. The targets and their corresponding active ingredients of Coptis chinensis against rituximab-resistant DLBCL were molecularly docked. RESULTS: Berberine, quercetin, epiberberine and palmatine, the active components of Coptis chinensis, have great potential for improving rituximab-resistant DLBCL via PIK3CG. CONCLUSION: This study revealed biomarkers and Coptis chinensis-associated molecular functions for rituximab-resistant DLBCL.
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Biologia Computacional , Coptis , Resistencia a Medicamentos Antineoplásicos , Linfoma Difuso de Grandes Células B , Simulação de Acoplamento Molecular , Farmacologia em Rede , Rituximab , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Humanos , Rituximab/farmacologia , Rituximab/uso terapêutico , Farmacologia em Rede/métodos , Coptis/química , Biologia Computacional/métodos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/química , Medicina Tradicional Chinesa/métodosRESUMO
Background: Breast cancer represents a leading cause of malignancy among Chinese women, posing a significant health burden. The diagnosis of metastatic breast cancer, particularly to uncommon sites like the skin and stomach, presents distinct challenges. Case introduction: This case report describes a 71-year-old Chinese women with a persistent back rash lasting more than 6 months. Physical examination revealed red papules on her back. Immunohistochemistry confirmed positive for cytokeratin 7(CK7), GATA-3 and GCDFP15, as well as negative staining of cytokeratin 20 (CK20), suggesting breast cancer metastasis. Further evaluation revealed a breast nodule and axillary lymph node enlargement, with biopsies confirming invasive lobular carcinoma (ILC). Abdominal computed tomography (CT) revealed thickening of the gastric and ascending colon walls. Gastroscopy revealed chronic superficial atrophic gastritis. However, gastric metastasis was further confirmed by pathology. The patient initiated endocrine therapy with fulvestrant and exemestane, resulting in rash resolution and stable breast and stomach lesions after 3 months. Overall, the patient is experiencing an improvement in her condition and remains stable while continuing treatment. Conclusion: This case highlights the importance of considering atypical metastatic patterns in breast cancer and the potential efficacy of endocrine therapies in managing such cases. Moreover, it emphasizes the need for vigilance in breast cancer patients, especially those with ILC, as gastrointestinal symptoms may indicate gastric metastasis (GMs). Ultimately, early detection and appropriate treatment strategies, such as endocrine therapy, can contribute to improved outcomes in these challenging cases.
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Stimulus-responsive membranes demonstrate promising applications in switchable oil/water emulsion separations. However, they are unsuitable for the treatment of double emulsions like oil-in-water-in-oil (O/W/O) and water-in-oil-in-water (W/O/W) emulsions. For efficient separation of these complicated emulsions, fine control over the wettability, response time, and aperture structure of the membrane is required. Herein, dual-coated fibers consisting of primary photothermal-responsive and secondary CO2-responsive coatings are prepared by two steps. Automated weaving of these fibers produces membranes with photothermal- and CO2-responsive characteristics and narrow pore size distributions. These membranes exhibit fast switching wettability between superhydrophilicity (under CO2 stimulation) and high hydrophobicity (under near-infrared stimulation), achieving on-demand separation of various O/W/O and W/O/W emulsions with separation efficiencies exceeding 99.6%. Two-dimensional low-field nuclear magnetic resonance and correlated spectra technique are used to clarify the underlying mechanism of switchable double emulsion separation. The approach can effectively address the challenges associated with the use of stimulus-responsive membranes for double emulsion separation and facilitate the industrial application of these membranes.
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Covalent organic framework (COF) membranes featuring uniform topological structures and devisable functions, show huge potential in water purification and molecular separation. Nevertheless, the inability of uniform COF membranes to be produced on an industrial scale and their nonenvironmentally friendly fabrication method are the bottleneck preventing their industrial applications. Herein, we report a new green and industrially adaptable scraping-assisted interfacial polymerization (SAIP) technique to fabricate scalable and uniform TpPa COF membranes. The process used non-toxic and low-volatility ionic liquids (ILs) as organic phase instead of conventional organic solvents for interfacial synthesis of TpPa COF layer on a support membrane, which can simultaneously achieve the purposes of (i) improving the greenness of membrane-forming process and (ii) fabricating a robust membrane that can function beyond the conventional membranes. This approach yields a large-area, continuous COF membrane (19×25â cm2 ) with a thickness of 78â nm within a brief period of 2â minutes. The resulting membrane exhibited an unprecedented combination of high permeance (48.09â L m-2 h-1 bar-1 ) and antibiotic desalination efficiency (e.g., NaCl/adriamycin separation factor of 41.8), which is superior to the commercial benchmarking membranes.
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Although visual feature estimations are accurate and precise, overall estimation errors (i.e., the difference between estimates and actual values) tend to show systematic patterns. For example, estimates of orientations are systematically biased away from horizontal and vertical orientations, showing an oblique illusion. Additionally, many recent studies have demonstrated that estimations of current visual features are systematically biased toward previously seen features, showing a serial dependence. However, no study examined whether the overall estimation errors were correlated with the serial dependence bias. To address this question, we enrolled three groups of participants to estimate orientation, motion speed, and point-light-walker direction. The results showed that the serial dependence bias explained over 20% of overall estimation errors in the three tasks, indicating that we could use the serial dependence bias to predict the overall estimation errors. The current study first demonstrated that the serial dependence bias was not independent from the overall estimation errors. This finding could inspire researchers to investigate the neural bases underlying the visual feature estimation and serial dependence.
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Ilusões , Percepção Visual , Humanos , Viés , Movimento (Física)RESUMO
Heat-stable antifungal factor (HSAF) produced by the biocontrol bacterium Lysobacter enzymogenes shows considerable antifungal activity and has broad application potential in the agricultural and medical fields. There is a great demand for pure HSAF compounds in academic or industrial studies. However, an efficient preparation method that produces a high yield and high purity of HSAF is lacking, limiting the development of HSAF as a new drug. In the present study, high-speed counter-current chromatography (HSCCC) combined with column chromatography was successfully developed for the separation and preparation of HSAF from the crude extract of L. enzymogenes OH11. The crude extract was obtained by macroporous resin adsorption and desorption, and the main impurities were partly removed by ultraviolet light (254 nm) and gel filtration (Sephadex LH-20). In the HSCCC procedure, the selected suitable two-phase solvent system (n-hexane/ethyl acetate/methanol/water = 3:5:4:5, v/v, the lower phase added with 0.1% TFA) with a flow rate of 2.0 mL/min and a sample loading size of 100 mg was optimized for the separation. As a result, a total of 42 mg HSAF with a purity of 97.6% and recovery of 91.7% was yielded in one separation. The structure elucidation based on HR-TOF-MS, 1H and 13C NMR, and antifungal activities revealed that the isolated compound was unambiguously identified as HSAF. These results are helpful for separating and producing HSAF at an industrial scale, and they further demonstrate that HSCCC is a useful tool for isolating bioactive constituents from beneficial microorganisms.
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Liquid-liquid phase separation (LLPS) plays a key role in the regulation of life activities. Here, we reported a protein from Synechocystis sp. PCC 6803 and annotated as Slr0280. To obtain a water-soluble protein, we deleted the N-terminus transmembrane domain and named it Slr0280Δ. Slr0280Δ with high concentration can undergo LLPS at a low temperature in vitro. It belongs to the phosphodiester glycosidase family of proteins and has a segment of a low-complexity sequence region (LCR), which is thought to regulate the LLPS. Our results show that electrostatic interactions impact the LLPS of Slr0280Δ. We also acquired the structure of Slr0280Δ, which has many grooves on the surface with a large distribution of positive and negative charges. This may be advantageous for the LLPS of Slr0280Δ through electrostatic interactions. Furthermore, the conserved amino acid (arginine at position 531) located on the LCR is important for maintaining the stability of Slr0280Δ as well as LLPS. Our research indicated that the LLPS of proteins can be transformed into aggregation by changing the surface charge distribution.
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Domínios ProteicosRESUMO
The successful implementation of thin-film composite membranes (TFCM) for challenging solute-solute separations in the pharmaceutical industry requires a fine control over the microstructure (size, distribution, and connectivity of the free-volume elements) and thickness of the selective layer. For example, desalinating antibiotic streams requires highly interconnected free-volume elements of the right size to block antibiotics but allow the passage of salt ions and water. Here, we introduce stevioside, a plant-derived contorted glycoside, as a promising aqueous phase monomer for optimizing the microstructure of TFCM made via interfacial polymerization. The low diffusion rate and moderate reactivity of stevioside, together with its nonplanar and distorted conformation, produced thin selective layers with an ideal microporosity for antibiotic desalination. For example, an optimized 18-nm membrane exhibited an unprecedented combination of high water permeance (81.2 liter m-2 hour-1 bar-1), antibiotic desalination efficiency (NaCl/tetracycline separation factor of 11.4), antifouling performance, and chlorine resistance.
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Antibacterianos , Tetraciclina , Cloretos , Extratos Vegetais , PoliésteresRESUMO
Anti-PD-1 immunotherapy has been widely applied in patients with some types of lymphoma. Classical Hodgkin's lymphoma (cHL) is highly sensitive to immunotherapy, but non-Hodgkin's lymphoma (NHL) does not show a good response. Studies have indicated that haematopoietic progenitor kinase 1 (HPK1) suppresses T cells and reduces antitumour immunity. Therefore, HPK1 inhibitors may restore and elicit antitumour immune responses and are promising candidate drug targets for cancer immunotherapy. We first explored the Gene Expression Profile Interactive Analysis (GEPIA) database and predicted that HPK1 expression was increased in diffuse large B-cell lymphoma (DLBCL) and associated with Nod-like receptor protein 3 (NLRP3) expression. We investigated whether an HPK1 inhibitor could enhance the tumour response to anti-PD-1 immunotherapy in NHL and the association between HPK1 and NLRP3 expression. Employing shHPK1 and an inhibitor, we demonstrated that the HPK1 inhibitor increased anti-PD-1-mediated T-cell cytotoxicity in BJAB and WSU-DLCL2 cells cocultured with peripheral blood mononuclear cells (PBMCs). HPK1 inhibitor treatment increased PD-1, PD-L1, Bax, p53 and NK-kB expression but decreased NLRP3 expression, indicating that the HPK1 inhibitor promoted apoptosis and blocked the NLRP3 inflammasome pathway to affect anti-PD-1-mediated T-cell cytotoxicity. Moreover, the HPK1 inhibitor enhanced the efficiency of anti-PD-1 immunotherapy in vivo in a zebrafish xenograft model of NHL. In summary, this study provides evidence that an HPK1 inhibitor enhanced the tumour response to anti-PD-1 immunotherapy in NHL by promoting apoptosis and blocking the NLRP3 pathway. These findings provide a potential therapeutic option for NHL combining HPK1 inhibitor treatment and anti-PD-1 immunotherapy.
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Doença de Hodgkin , Inibidores de Checkpoint Imunológico , Linfoma não Hodgkin , Animais , Humanos , Imunoterapia , Leucócitos Mononucleares/metabolismo , Linfoma não Hodgkin/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR , Peixe-Zebra , Inibidores de Checkpoint Imunológico/uso terapêuticoRESUMO
It is a novel therapeutic strategy to suppress tumour growth and metastasis by regulating the interaction between bioactivity ions and the biological process of tumour cells. This study synthesised a mesoporous hydroxyapatite (MHAP)-based nanocarrier for targeted delivery of the anti-cancer drug doxorubicin (DOX). To further strengthen the targeting of DOX-loaded nanocarrier to tumour, HA that could specifically identify receptor on the surface of tumours was functionally modified. The drug release properties curve showed that the MHAP-HA@DOX complex showed pH-sensitive and sustained release properties. Also, the MHAP-HA@DOX complex represented high toxicity against lung cancer A549 cells. Besides, it displayed a significant inhibitory effect on tumour growth rate in tumour-bearing mice, while no evident toxicity for mice was observed. This nano-material is hoped to be an effective and novel nano-drug for lung cancer.
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OBJECTIVE: Rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone, once every 3 weeks (R-CHOP21) is commonly used in non-Hodgkin's lymphoma (NHL), but accompanied by Pneumocystis carinii pneumonia (PCP) as a fatal treatment complication. This study aims to estimate the specific effectiveness and cost-effectiveness of PCP prophylaxis in NHL undergoing R-CHOP21. DESIGN: A two-part decision analytical model was developed. Prevention effects were determined by systemic review of PubMed, Embase, Cochrane Library and Web of Science from inception to December 2022. Studies reporting results of PCP prophylaxis were included. Enrolled studies were quality assessed with Newcastle-Ottawa Scale. Costs were derived from the Chinese official websites, and clinical outcomes and utilities were obtained from published literature. Uncertainty was evaluated through deterministic and probabilistic sensitivity analyses (DSA and PSA). Willingness-to-pay (WTP) threshold was set as US$31 315.23/quality-adjusted life year (QALY) (threefold the 2021 per capita Chinese gross domestic product). SETTING: Chinese healthcare system perspective. PARTICIPANTS: NHL receiving R-CHOP21. INTERVENTIONS: PCP prophylaxis versus no prophylaxis. MAIN OUTCOME MEASURES: Prevention effects were pooled as relative risk (RR) with 95% CI. QALYs and incremental cost-effectiveness ratio (ICER) were calculated. RESULTS: A total of four retrospective cohort studies with 1796 participants were included. PCP risk was inversely associated with prophylaxis in NHL receiving R-CHOP21 (RR 0.17; 95% CI 0.04 to 0.67; p=0.01). Compared with no prophylaxis, PCP prophylaxis would incur an additional cost of US$527.61, and 0.57 QALYs gained, which yielded an ICER of US$929.25/QALY. DSA indicated that model results were most sensitive to the risk of PCP and preventive effectiveness. In PSA, the probability that prophylaxis was cost-effective at the WTP threshold was 100%. CONCLUSION: Prophylaxis for PCP in NHL receiving R-CHOP21 is highly effective from retrospective studies, and routine chemoprophylaxis against PCP is overwhelmingly cost-effective from Chinese healthcare system perspective. Large sample size and prospective controlled studies are warranted.
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Linfoma não Hodgkin , Pneumonia por Pneumocystis , Masculino , Humanos , Análise de Custo-Efetividade , Estudos Retrospectivos , Pneumonia por Pneumocystis/prevenção & controle , Estudos Prospectivos , Antígeno Prostático Específico , Análise Custo-Benefício , Linfoma não Hodgkin/tratamento farmacológico , Anos de Vida Ajustados por Qualidade de VidaRESUMO
Background: Life expectancy for patients with malignant tumors has been significantly improved since the presence of the programmed cell death protein-1/programmed cell death protein ligand-1 (PD-1/PD-L1) inhibitors in 2014, but they impose heavy financial burdens for patients, the healthcare system and the nations. The objective of this study was to determine the survival benefits, toxicities, and monetary of programmed cell death protein-1/programmed cell death protein ligand-1 inhibitors and quantify their values. Methods: Randomized controlled trials (RCTs) of PD-1/PD-L1 inhibitors for malignant tumors were identified and clinical benefits were quantified by American Society of Clinical Oncology Value Framework (ASCO-VF) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). The drug price in Micromedex REDBOOK was used to estimate monthly incremental drug costs (IDCs) and the correlation between clinical benefits and incremental drug costs of experimental and control groups in each randomized controlled trial, and the agreement between two frameworks were calculated. Results: Up to December 2022, 52 randomized controlled trials were included in the quantitative synthesis. All the randomized controlled trials were evaluated by American society of clinical oncology value framework, and 26 (50%) met the American society of clinical oncology value framework "clinical meaningful value." 49 of 52 randomized controlled trials were graded by European society for medical oncology magnitude of clinical benefit scale, and 30 (61.2%) randomized controlled trials achieved European Society for Medical Oncology criteria of meaningful value. p-values of Spearman correlation analyses between monthly incremental drug costs and American society of clinical oncology value framework/European society for medical oncology magnitude of clinical benefit scale scores were 0.9695 and 0.3013, respectively. In addition, agreement between two framework thresholds was fair (κ = 0.417, p = 0.00354). Conclusion: This study suggests that there might be no correlation between the cost and clinical benefit of programmed cell death protein-1/programmed cell death protein ligand-1 inhibitors in malignancy, and the same results were observed in subgroups stratified by drug or indication. The results should be a wake-up call for oncologists, pharmaceutical enterprises and policymakers, and meanwhile advocate the refining of American Society of Clinical Oncology and European Society for Medical Oncology frameworks.