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Two-dimensional (2D) zeolite, with a high aspect ratio, has more open skeletons and accessible active sites than its three-dimensional (3D) counterpart. However, traditional methods of obtaining 2D zeolites often cause structural damage and widespread skeleton defects, hindering efficient selectivity in molecular separation. In this study, we present, for the first time, a direct epitaxial synthesis of 2D zeolite (Epi-MWW) guided by hexagonal boron nitride (h-BN) with a coincidence matching of site lattices to MWW zeolite. The as-grown Epi-MWW zeolite possesses a high crystallinity and intact hexagonal 2D morphology, with an average thickness of 10 nm and an aspect ratio of over 50. Thanks to its excellent molecular accessibility, the diffusion time constants of o-xylene (OX) and p-xylene (PX) are as 12 and 133 times higher than those of conventional MCM-22, respectively; the PX/OX selectivity of Epi-MWW is 7.4 times better than MCM-22 as calculated by the ideal adsorbed solution theory.
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l-Cysteine, distinguished by its possession of reactive sulfhydryl groups within its molecular structure, plays a significant role in both biological systems and the pharmaceutical industry. It stands not only as a natural component integral to the constitution of glutathione but also as the principal precursor for the synthesis of l-cystine through an oxidation reaction. This study endeavors to introduce a novel approach to l-cysteine analysis, capitalizing on its optical activity, whereby an optical rotation detection system grounded in the principles of quantum weak measurement is proffered. The optical rotation angle corresponding to the concentration of chiral solutions can be accurately ascertained through spectral analysis. In practical implementation, a chiral sensing system, boasting a sensitivity of 372 nm/rad, was meticulously constructed, leveraging the concept of weak value amplification. Then, the real-time monitoring of chemical reactions involving l-cysteine and dimethyl sulfoxide was performed. Under the specific experimental conditions outlined in this investigation, it was observed that the oxidation process culminated within approximately 12 h. The application of weak measurement-based chiral sensors holds immense potential, providing robust technical support for real-time monitoring in fields such as chiral analysis and the synthesis of chiral pharmaceutical compounds.
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PURPOSE: This study aims to evaluate the risk factors of treatment-related pneumonitis (TRP) following thoracic radiotherapy/chemoradiotherapy combined with anti-PD1 monoclonal antibodies (mAbs) in patients with advanced esophageal squamous cell carcinoma (ESCC). METHODS: We retrospectively reviewed 97 patients with advanced ESCC who were treated with thoracic radiotherapy/chemoradiotherapy combined with anti-PD1 mAbs. Among them, 56 patients received concurrent radiotherapy with anti-PD1 mAbs and 41 patients received sequential radiotherapy with anti-PD1 mAbs. The median prescribed planning target volume (PTV) dose was 59.4â¯Gy (range from 50.4 to 66â¯Gy, 1.8-2.2â¯Gy/fraction). Clinical characteristics, the percentage of lung volume receiving more than 5-50â¯Gy in increments of 5â¯Gy (V5-V50, respectively) and the mean lung dose (MLD) were analyzed as potential risk factors for TRP. RESULTS: 46.4% (45/97), 20.6% (20/97), 20.6% (20/97), 4.1% (4/97), and 1.0% (1/97) of the patients developed any grade of TRP, grade 1 TRP, grade 2 TRP, grade 3 TRP, and fatal (grade 5) TRP, respectively. Anti-PD1 mAbs administered concurrently with radiotherapy, V5, V10, V15, V25, V30, V35, V40 and MLD were associated with the occurrence of grade 2 or higher TRP. Concurrent therapy (Pâ¯= 0.010, ORâ¯= 3.990) and V5 (Pâ¯= 0.001, ORâ¯= 1.126) were independent risk factors for grade 2 or higher TRP. According to the receiver operating characteristic (ROC) curve analysis, the optimal V5 threshold for predicting grade 2 or higher TRP was 55.7%. CONCLUSION: The combination of thoracic radiotherapy/chemoradiotherapy with anti-PD1 mAbs displayed a tolerable pulmonary safety profile. Although the incidence of TRP was high, grade 1-2 TRP accounted for the majority. Anti-PD1 mAbs administered concurrently with radiotherapy and the lung V5 were significantly associated with the occurrence of grade 2 or higher TRP. Therefore, it seems safer to control V5 below 55% in clinical, especially for the high-risk populations receiving concurrent therapy.
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BACKGROUND: Tie2, a functional angiopoietin receptor, is expressed in vascular endothelial cells and plays an important role in angiogenesis and vascular stability. This study aimed to evaluate the effects of an agonistic Tie2 signal on renal interstitial fibrosis (RIF) and elucidate the underlying mechanisms. METHODS: We established an in vivo mouse model of folic acid-induced nephropathy (FAN) and an in vitro model of lipopolysaccharide-stimulated endothelial cell injury, then an agonistic Tie2 monoclonal antibody (Tie2 mAb) was used to intervent these processes. The degree of tubulointerstitial lesions and related molecular mechanisms were determined by histological assessment, immunohistochemistry, western blotting, and qPCR. RESULTS: Tie2 mAb attenuated RIF and reduced the level of fibroblast-specific protein 1 (FSP1). Further, it suppressed vascular cell adhesion molecule-1 (VCAM-1) and increased CD31 density in FAN. In the in vitro model, Tie2 mAb was found to decrease the expression of VCAM-1, Bax, and α-smooth muscle actin (α-SMA). CONCLUSIONS: The present findings indicate that the agonistic Tie2 mAb exerted vascular protective effects and ameliorated RIF via inhibition of vascular inflammation, apoptosis, and fibrosis. Therefore, Tie2 may be a potential target for the treatment of this disease. IMPACT: This is the first report to confirm that an agonistic Tie2 monoclonal antibody can reduce renal interstitial fibrosis in folic acid-induced nephropathy in mice. This mechanism possibly involves vascular protective effects brought about by inhibition of vascular inflammation, apoptosis and fibrosis. Our data show that Tie2 signal may be a novel, endothelium-specific target for the treatment of tubulointerstitial fibrosis.
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Células Endoteliales , Enfermedades Renales , Ratones , Animales , Células Endoteliales/metabolismo , Receptor TIE-2/metabolismo , Molécula 1 de Adhesión Celular Vascular , Fibrosis , Anticuerpos Monoclonales/farmacología , Enfermedades Renales/inducido químicamente , Ácido Fólico , Inflamación , Angiopoyetina 1 , Angiopoyetina 2RESUMEN
Viral diseases have caused great economic losses to the aquaculture industry. However, there are currently no specific drugs to treat these diseases. Herein, we utilized Siniperca chuatsi as an experimental model, and successfully extracted two tissue factor pathway inhibitors (TFPIs) that were highly distributed in different tissues. We then designed four novel peptides based on the TFPIs, named TS20, TS25, TS16, and TS30. Among them, TS25 and TS30 showed good biosafety and high antiviral activity. Further studies showed that TS25 and TS30 exerted their antiviral functions by preventing viruses from invading Chinese perch brain (CPB) cells and disrupting Siniperca chuatsi rhabdovirus (SCRV)/Siniperca chuatsi ranairidovirus (SCRIV) viral structures. Additionally, compared with the control group, TS25 and TS30 could significantly reduce the mortality of Siniperca chuatsi, the relative protection rates of TS25 against SCRV and SCRIV were 71.25 % and 53.85 % respectively, and the relative protection rate of TS30 against SCRIV was 69.23 %, indicating that they also had significant antiviral activity in vivo. This study provided an approach for designing peptides with biosafety and antiviral activity based on host proteins, which had potential applications in the prevention and treatment of viral diseases.
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Enfermedades de los Peces , Infecciones por Rhabdoviridae , Rhabdoviridae , Animales , Enfermedades de los Peces/virología , Infecciones por Rhabdoviridae/veterinaria , Infecciones por Rhabdoviridae/inmunología , Infecciones por Rhabdoviridae/prevención & control , Rhabdoviridae/fisiología , Antivirales/farmacología , Antivirales/química , Percas , Proteínas de Peces/química , Proteínas de Peces/genética , Proteínas de Peces/inmunología , Péptidos/farmacología , Péptidos/química , Infecciones por Virus ARN/veterinaria , Infecciones por Virus ARN/inmunología , Infecciones por Virus ARN/prevención & controlRESUMEN
Mitochondrial dysfunction contributes to cerebral ischemia-reperfusion (CI/R) injury, which can be ameliorated by Sirtuin-3 (SIRT3). Under stress conditions, the SIRT3-promoted mitochondrial functional recovery depends on both its activity and expression. However, the approach to enhance SIRT3 activity after CI/R injury remains unelucidated. In this study, Sprague-Dawley (SD) rats were intracranially injected with either adeno-associated viral Sirtuin-1 (AAV-SIRT1) or AAV-sh_SIRT1 before undergoing transient middle cerebral artery occlusion (tMCAO). Primary cortical neurons were cultured and transfected with lentiviral SIRT1 (LV-SIRT1) and LV-sh_SIRT1 respectively before oxygen-glucose deprivation/reoxygenation (OGD/R). Afterwards, rats and neurons were respectively treated with a selective SIRT3 inhibitor, 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP). The expression, function, and related mechanism of SIRT1 were investigated by Western Blot, flow cytometry, immunofluorescence staining, etc. After CI/R injury, SIRT1 expression decreased in vivo and in vitro. The simulation and immune-analyses reported strong interaction between SIRT1 and SIRT3 in the cerebral mitochondria before and after CI/R. SIRT1 overexpression enhanced SIRT3 activity by increasing the deacetylation of SIRT3, which ameliorated CI/R-induced cerebral infarction, neuronal apoptosis, oxidative stress, neurological and motor dysfunction, and mitochondrial respiratory chain dysfunction, promoted mitochondrial biogenesis, and retained mitochondrial integrity and mitochondrial morphology. Meanwhile, SIRT1 overexpression alleviated OGD/R-induced neuronal death and mitochondrial bioenergetic deficits. These effects were reversed by AAV-sh_SIRT1 and the neuroprotective effects of SIRT1 were partially offset by 3-TYP. These results suggest that SIRT1 restores the structure and function of mitochondria by activating SIRT3, offering neuroprotection against CI/R injury, which signifies a potential approach for the clinical management of cerebral ischemia.
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Isquemia Encefálica , Mitocondrias , Neuronas , Ratas Sprague-Dawley , Daño por Reperfusión , Sirtuina 1 , Sirtuina 3 , Animales , Sirtuina 1/metabolismo , Sirtuina 1/genética , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Mitocondrias/metabolismo , Masculino , Sirtuina 3/metabolismo , Sirtuina 3/genética , Neuronas/metabolismo , Neuronas/patología , Ratas , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Apoptosis , SirtuinasRESUMEN
OBJECTIVE: To analyze the clinical effect of urokinase on the prevention of thrombosis in children with primary nephrotic syndrome. METHODS: A total of 370 children diagnosed with primary nephrotic syndrome (PNS) in the Children's Hospital of Soochow University and Zibo Maternal and Child Health Hospital from January 2018 to December 2022 were selected as the research objects. The patients were divided into a urokinase adjuvant therapy group and non-urokinase adjuvant therapy group according to the application of drugs. The clinical data of the children were collected, including sex, age, drug application, bleeding during treatment, and telephone follow-up, to record whether thromboembolism occurred in the acute stage and remission stage. The clinical pattern of PNS, renal biopsy, histopathological type, and related laboratory indexes before and after treatment were recorded. RESULTS: A total of 313 patients were treated with urokinase and 57 patients were not. More thrombotic events was observed in non-urokinase group compared to the urokinase group(2 versus 0 episodes, p = 0.02). The thrombotic events observed included one patient had pulmonary embolism combined with right ventricular thrombosis, and another had intracranial venous thrombosis. More minor bleeding events occurred in urokinase group compared to the non-urokinase group(7 versus 1 episodes, p = 1.0). No major bleeding events occurred in either group. CONCLUSION: The rational prophylactic use of urokinase anticoagulation in children with PNS can prevent the formation of thromboembolism and has good safety.
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Síndrome Nefrótico , Tromboembolia , Trombosis , Niño , Humanos , Activador de Plasminógeno de Tipo Uroquinasa/uso terapéutico , Síndrome Nefrótico/complicaciones , Síndrome Nefrótico/tratamiento farmacológico , Síndrome Nefrótico/inducido químicamente , Estudios Retrospectivos , Hemorragia/inducido químicamente , Trombosis/etiología , Trombosis/prevención & control , Anticoagulantes/uso terapéuticoRESUMEN
Multistatic synthetic aperture radar (SAR) is a special mode of SAR system. The radar transmitter and receiver are located on different satellites, which brings many advantages, such as flexible baseline configuration, diverse receiving modes, and more detailed ground object classification information. The multistatic SAR has been widely used in interferometry, moving target detection, three-dimensional imaging, and other fields. The frequency offset between different oscillators will cause a modulation phase error in the signal. Therefore, phase synchronization is one of the most critical problems to be addressed in distributed SAR systems. This article reviews phase synchronization techniques, which are mainly divided into two methods: synchronization by direct microwave link and synchronization by a data-based estimation algorithm. Furthermore, the future development of synchronization technology is anticipated.
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Nowadays, as a result of the frequent occurrence of accidental injuries and traumas such as bone damage, the number of people causing bone injuries or fractures is increasing around the world. The design and fabrication of ideal bone tissue engineering (BTE) materials have become a research hotspot in the scientific community, and thus provide a novel path for the treatment of bone diseases. Among the materials used to construct scaffolds in BTE, including metals, bioceramics, bioglasses, biomacromolecules, synthetic organic polymers, etc., natural biopolymers have more advantages against them because they can interact with cells well, causing natural polymers to be widely studied and applied in the field of BTE. In particular, alginate has the advantages of excellent biocompatibility, good biodegradability, non-immunogenicity, non-toxicity, wide sources, low price, and easy gelation, enabling itself to be widely used as a biomaterial. However, pure alginate hydrogel as a BTE scaffold material still has many shortcomings, such as insufficient mechanical properties, easy disintegration of materials in physiological environments, and lack of cell-specific recognition sites, which severely limits its clinical application in BTE. In order to overcome the defects of single alginate hydrogels, researchers prepared alginate composite hydrogels by adding one or more materials to the alginate matrix in a certain proportion to improve their bioapplicability. For this reason, this review will introduce in detail the methods for constructing alginate composite hydrogels, including alginate/polymer composite hydrogels, alginate/bioprotein or polypeptide composite hydrogels, alginate/bioceramic composite hydrogels, alginate/bioceramic composite hydrogels, and alginate/nanoclay composite hydrogels, as well as their biological application trends in BTE scaffold materials, and look forward to their future research direction. These alginate composite hydrogel scaffolds exhibit both unexceptionable mechanical and biochemical properties, which exhibit their high application value in bone tissue repair and regeneration, thus providing a theoretical basis for the development and sustainable application of alginate-based functional biomedical materials.
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Alginatos , Materiales Biocompatibles , Huesos , Hidrogeles , Ingeniería de Tejidos , Andamios del Tejido , Alginatos/química , Ingeniería de Tejidos/métodos , Hidrogeles/química , Humanos , Andamios del Tejido/química , Materiales Biocompatibles/química , Animales , Regeneración Ósea/efectos de los fármacosRESUMEN
To achieve the optimal alginate-based oral formulation for delivery of hydrophobic drugs, on the basis of previous research, we further optimized the synthesis process parameters of alginate-g-oleylamine derivatives (Ugi-FOlT) and explored the effects of different degrees of substitution (DSs) on the molecular self-assembly properties of Ugi-FOlT, as well as the in vitro cytotoxicity and drug release behavior of Ugi-FOlT. The resultant Ugi-FOlT exhibited good amphiphilic properties with the critical micelle concentration (CMC) ranging from 0.043 mg/mL to 0.091 mg/mL, which decreased with the increase in the DS of Ugi-FOlT. Furthermore, Ugi-FOlT was able to self-assemble into spherical micellar aggregates in aqueous solution, whose sizes and zeta potentials with various DSs measured by dynamic light scattering (DLS) were in the range of 653 ± 25~710 ± 40 nm and -58.2 ± 1.92~-48.9 ± 2.86 mV, respectively. In addition, RAW 264.7 macrophages were used for MTT assay to evaluate the in vitro cytotoxicity of Ugi-FOlT in the range of 100~500 µg/mL, and the results indicated good cytocompatibility for Ugi-FOlT. Ugi-FOlT micellar aggregates with favorable stability also showed a certain sustained and pH-responsive release behavior for the hydrophobic drug ibuprofen (IBU). Meanwhile, it is feasible to control the drug release rate by regulating the DS of Ugi-FOlT. The influence of different DSs on the properties of Ugi-FOlT is helpful to fully understand the relationship between the micromolecular structure of Ugi-FOlT and its macroscopic properties.
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Alginatos , Liberación de Fármacos , Interacciones Hidrofóbicas e Hidrofílicas , Micelas , Alginatos/química , Ratones , Animales , Células RAW 264.7 , Aminas/química , Sistemas de Liberación de Medicamentos , Portadores de Fármacos/química , Ibuprofeno/química , Ibuprofeno/farmacología , Supervivencia Celular/efectos de los fármacosRESUMEN
The performance of nano-zero-valent iron for heavy metal remediation can be enhanced via incorporation into bimetallic carbon composites. However, few economical and green approaches are available for preparing bimetallic composite materials. In this study, novel Co/Fe bimetallic biochar composites (BC@Co/Fe-X, where X = 5 or 10 represents the CoCl2 concentration of 0.05 or 0.1 mol L-1) were prepared for the adsorption of Pb2+. The effect of the concentration of cross-linked metal ions on Pb2+ adsorption was investigated, with the composite prepared using 0.05 mol L-1 Co2+ (BC@Co/Fe-5) exhibiting the highest adsorption performance. Various factors, including the adsorption period, Pb2+ concentration, and pH, affected the adsorption of Pb2+ by BC@Co/Fe-5. Further characterisation of BC@Co/Fe-5 before and after Pb2+ adsorption using methods such as X-ray diffraction and X-ray photoelectron spectroscopy suggested that the Pb2+ adsorption mechanism involved (i) Pb2+ reduction to Pb0 by Co/Fe, (ii) Co/Fe corrosion to generate Fe2+ and fix Pb2+ in the form of PbO, and (iii) Pb2+ adsorption by Co/Fe biochar. Notably, BC@Co/Fe-5 exhibited excellent remediation performance in simulated Pb2+-contaminated water and soil with good recyclability.
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We present an innovative process for directly transforming poly(ethylene terephthalate) (PET), a polymer extensively used in food and beverage packaging, into trans-isomer-enriched 1,4-cyclohexanedimethanol (CHDM), a key ingredient in advanced specialty polymers. Our approach leverages a dual-catalyst system featuring palladium on reduced graphene oxide (Pd/r-GO) and oxalate-gel-derived copper-zinc oxide (og-CuZn), utilizing hydrogenation/hydrogenolysis relay catalysis. This method efficiently transforms PET into polyethylene-1,4-cyclohexanedicarboxylate (PECHD), which is then converted into CHDM with an impressive overall yield of 95 % in a two-stage process. Our process effectively handles various post-consumer PET plastics, converting them into CHDM with yields between 78 % and 89 % across different substrates. Additionally, we demonstrate the applicability and scalability of this approach through a temperature-programmed three-stage relay process on a 10-gram scale, which results in purified CHDM with an isolated yield of 87 % and a notably higher trans/cis ratio of up to 4.09/1, far exceeding that of commercially available CHDM. This research not only provides a viable route for repurposing PET waste but also enhances the control of selectivity patterns in multistage relay catalysis.
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Circular RNA (CircRNA) is a type of non-coding RNAs in which both ends are covalently linked. Researchers have demonstrated that many circRNAs can act as biomarkers of diseases. However, traditional experimental methods for circRNA-disease associations identification are labor-intensive. In this work, we propose a novel method based on the heterogeneous graph neural network and metapaths for circRNA-disease associations prediction termed as HMCDA. First, a heterogeneous graph consisting of circRNA-disease associations, circRNA-miRNA associations, miRNA-disease associations and disease-disease associations are constructed. Then, six metapaths are defined and generated according to the biomedical pathways. Afterwards, the entity content transformation, intra-metapath and inter-metapath aggregation are implemented to learn the embeddings of circRNA and disease entities. Finally, the learned embeddings are used to predict novel circRNA-disase associations. In particular, the result of extensive experiments demonstrates that HMCDA outperforms four state-of-the-art models in fivefold cross validation. In addition, our case study indicates that HMCDA has the ability to identify novel circRNA-disease associations.
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MicroARNs , ARN Circular , Proyectos de Investigación , Aprendizaje , MicroARNs/genética , Redes Neurales de la ComputaciónRESUMEN
Lung adenocarcinoma is the most common type of lung cancer. We recently reported that inflammation-driven lung adenocarcinoma (IDLA) originates from alveolar type (AT)-II cells, which depend on major histocompatibility complex (MHC) class II to promote the expansion of regulatory T cells. The MHC class II-associated invariant chain (CD74) binds to the macrophage migration inhibitory factor (MIF), which is associated with promoting tumor growth and invasion. However, the role of MIF-CD74 in the progression of lung adenocarcinoma and the underlying mechanisms remain unclear. We aimed to explore the role of MIF-CD74 in the progression of lung adenocarcinoma and elucidate the mechanisms by which tumor necrosis (TNF)-α-mediated inflammation regulates CD74 and MIF expression in IDLA. In human lung adenocarcinoma, CD74 was upregulated on the surface of tumor cells originating from AT-II cells, which correlated positively with lymph node metastasis, tumor origin/nodal involvement/metastasis stage, and TNF-α expression. MIF interaction with CD74 promoted the proliferation and migration of A549 and H1299 cells in vitro. Using a urethane-induced IDLA mouse model, we observed that CD74 was upregulated in tumor cells and macrophages. MIF expression was upregulated in macrophages in IDLA. Blocking TNF-α-dependent inflammation downregulated CD74 expression in tumor cells and CD74 and MIF expression in macrophages in IDLA. Conditioned medium from A549 cells or activated mouse AT-II cells upregulated MIF in macrophages by secreting TNF-α. TNF-α-dependent lung inflammation contributes to the progression of lung adenocarcinoma by upregulating CD74 and MIF expression, and AT-II cells upregulate MIF expression in macrophages by secreting TNF-α. This study provides novel insights into the function of CD74 in the progression of IDLA.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Factores Inhibidores de la Migración de Macrófagos , Neumonía , Animales , Humanos , Ratones , Antígenos de Histocompatibilidad Clase II/metabolismo , Inflamación/metabolismo , Oxidorreductasas Intramoleculares , Neoplasias Pulmonares/metabolismo , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Neumonía/inducido químicamente , Neumonía/metabolismo , Factor de Necrosis Tumoral alfaRESUMEN
Mulberry (Morus alba L.) is an economically important plant for the silk industry and has the possibility of contributing immensely to Chinese pharmacopeia because of its health benefits. Domesticated silkworms feed only on mulberry leaves, meaning that the worms' survival depends on the mulberry tree. Mulberry production is threatened by climate change and global warming. However, the regulatory mechanisms of mulberry responses to heat are poorly understood. We performed transcriptome analysis of high-temperature-stressed (42 °C) M. alba seedlings using RNA-Seq technologies. A total of 703 differentially expressed genes (DEGs) were discovered from 18,989 unigenes. Among these, 356 were up-regulated, and 347 were down-regulated. KEGG analysis revealed that most DEGs were enriched in valine, leucine and isoleucine degradation, and in starch and sucrose metabolism, alpha-linolenic acid metabolism, carotenoid biosynthesis and galactose metabolism, among others. In addition, TFs such as the NAC, HSF, IAA1, MYB, AP2, GATA, WRKY, HLH and TCP families were actively involved in response to high temperatures. Moreover, we used RT-qPCR to confirm the expression changes of eight genes under heat stress observed in the RNA-Seq analysis. This study provides M. alba transcriptome profiles under heat stress and provides theoretical bases to researchers for better understanding mulberry heat response mechanisms and breeding heat-tolerant mulberry plants.
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BACKGROUND: Neoadjuvant immunotherapy (nIT) is a rapidly emerging paradigm for advanced resectable non-small cell lung cancer (NSCLC). The objectives of this PRISMA/MOOSE/PICOD-guided systematic review and meta-analysis were (1) to assess the safety and efficacy of nIT, (2) to compare the safety and efficacy of neoadjuvant chemoimmunotherapy (nCIT) versus chemotherapy alone (nCT), and (3) to explore predictors of pathologic response with nIT and their association with outcomes. METHODS: Eligibility was resectable stage I-III NSCLC and the receipt of programmed death-1/programmed cell death ligand-1 (PD-L1)/cytotoxic T-lymphocyte-associated antigen-4 inhibitors before resection; other forms and modalities of neoadjuvant and/or adjuvant therapies were allowed. For statistical analysis, the Mantel-Haenszel fixed-effect or random-effect model was used, depending on the heterogeneity (I2 ). RESULTS: Sixty-six articles met the criteria (eight randomized studies, 39 prospective nonrandomized studies, and 19 retrospective studies). The pooled pathologic complete response (pCR) rate was 28.1%. The estimated grade ≥3 toxicity rate was 18.0%. Compared with nCT, nCIT achieved higher rates of pCR (odds ratio [OR], 7.63; 95% confidence interval [CI], 4.49-12.97; p < .001), progression-free survival (PFS) (hazard ratio [HR] 0.51; 95% CI, 0.38-0.67; p < .001), and overall survival (OS) (HR, 0.51; 95% CI, 0.36-0.74; p = .0003) but yielded similar toxicity rates (OR, 1.01; 95% CI, 0.67-1.52; p = .97). The results remained robust on sensitivity analysis when all retrospective publications were removed. pCR was associated with improved PFS (HR, 0.25; 0.15-0.43; p < .001) and OS (HR, 0.26; 95% CI, 0.10-0.67; p = .005). PD-L1 expressors (≥1%) were more likely to achieve a pCR (OR, 2.93; 95% CI, 1.22-7.03; p = .02). CONCLUSIONS: In patients with advanced resectable NSCLC, neoadjuvant immunotherapy was safe and efficacious. nCIT improved pathologic response rates and PFS/OS over nCT, particularly in patients who had tumors that expressed PD-L1, without increasing toxicities. PLAIN LANGUAGE SUMMARY: This meta-analysis of 66 studies showed that neoadjuvant immunotherapy for advanced resectable non-small cell lung cancer is safe and efficacious. Compared with chemotherapy alone, chemoimmunotherapy improved pathologic response rates and survival, particularly for patients who had tumors that expressed programmed cell death ligand-1, without increasing toxicities.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Terapia Neoadyuvante , Antígeno B7-H1 , Ligandos , Estudios Prospectivos , Estudios Retrospectivos , Inmunoterapia/efectos adversos , Inmunoterapia/métodosRESUMEN
Infectious spleen and kidney necrosis virus disease (ISKNVD) caused significant economic losses to the fishery industry. Epidermal growth factor receptor (EGFR), phosphatidylinositide 3-kinase (PI3K) played an important role in ISKNV invasion. However, the molecular regulatory mechanisms among EGFR, PI3K-Akt, and ISKNV invasion are not clear. In this study, ISKNV infection rapidly induced EGFR activation. While, EGFR activation promoted virus entry, but EGFR inhibitors and specific RNA (siRNA) decreased virus invasion. The PI3K-Akt as downstream signalling of EGFR was activated upon ISKNV infection. Consistent with the trends of EGFR, Akt activation increased ISKNV entry into cells, Akt inhibition by specific inhibitor or siRNA decreased ISKNV invasion. Akt silencing combination with EGFR activation showed that EGFR activation regulation ISKNV invasion is required for activation of the Akt signalling pathway. Those data demonstrated that ISKNV-induced EGFR activation positively regulated virus invasion by PI3K-Akt pathway and provided a better understanding of the mechanism of EGFR-PI3K-Akt involved in ISKNV invasion.
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Enfermedades de los Peces , Iridoviridae , Animales , Iridoviridae/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal , Receptores ErbB/genética , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismoRESUMEN
Recombination is one of the most important molecular mechanisms of prokaryotic genome evolution, but its exact roles are still in debate. Here we try to infer genome-wide recombination within a species, utilizing a dataset of 149 complete genomes of Escherichia coli from diverse animal hosts and geographic origins, including 45 in-house sequenced with the single-molecular real-time platform. Two major clades identified based on physiological, clinical and ecological characteristics form distinct genetic lineages based on scarcity of interclade gene exchanges. By defining gene-based syntenies for genomic segments within and between the two clades, we build a fine-scale recombination map for this representative global E. coli population. The map suggests extensive within-clade recombination that often breaks physical linkages among individual genes but seldom interrupts the structure of genome organizational frameworks as well as primary metabolic portfolios supported by the framework integrity, possibly due to strong natural selection for both physiological compatibility and ecological fitness. In contrast, the between-clade recombination declines drastically when phylogenetic distance increases to the extent where a 10-fold reduction can be observed, establishing a firm genetic barrier between clades. Our empirical data suggest a critical role for such recombination events in the early stage of speciation where recombination rate is associated with phylogenetic distance in addition to sequence and gene variations. The extensive intraclade recombination binds sister strains into a quasisexual group and optimizes genes or alleles to streamline physiological activities, whereas the sharply declined interclade recombination split the population into clades adaptive to divergent ecological niches.
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Escherichia coli/genética , Evolución Molecular , Variación Genética , Genoma Bacteriano , Recombinación Genética , Selección Genética , Animales , Estudio de Asociación del Genoma Completo , HumanosRESUMEN
Klebsiella pneumoniae is a ubiquitous human pathogen, and its clinical treatment faces two major challenges: multidrug resistance and the pathogenesis of hypervirulent K. pneumoniae. The discovery and study of conditionally essential (CE) genes that can function as potential antimicrobial targets has always been a research concern due to their restriction in the development of novel antibiotics. However, the lack of essential functional genomic data has hampered the study of the mechanisms of essential genes related to antimicrobial susceptibility. In this study, we developed a pooled CE genes mobile clustered regularly interspaced short palindromic repeat (CRISPR) interference screening method (Mobile-CRISPRi-seq) for K. pneumoniae to identify genes that play critical roles in antimicrobial fitness in vitro and host immunity in vivo. Targeting 870 predicted CE genes in K. pneumoniae, Mobile-CRISPRi-seq uncovered the depletion of tetrahydrofolate synthesis pathway genes folB and folP under trimethoprim pressure. Our screening also identified genes waaE and fldA related to polymyxin and ß-lactam susceptibility by applying a screening strategy based on Mobile-CRISPRi-seq and comparative genomics. Furthermore, using a mouse infection model and Mobile-CRISPRi-seq, multiple virulence genes were identified, and among these genes, pal, yciS, and ribB were demonstrated to contribute to the pathogenesis of K. pneumoniae. This study provides a simple, rapid, and effective platform for screening potential antimicrobial targets and virulence genes in K. pneumoniae, and this broadly applicable system can be expanded for high-throughput functional gene study in multiple pathogenic bacteria, especially in gram-negative bacteria. IMPORTANCE The discovery and investigation of conditionally essential (CE) genes that can function as potential antimicrobial targets has always been a research concern because of the restriction of antimicrobial targets in the development of novel antibiotics. In this study, we developed a pooled CE gene-wide mobile clustered regularly interspaced short palindromic repeat (CRISPR) interference sequencing (Mobile-CRISPRi-seq) strategy in Klebsiella pneumoniae to identify genes that play critical roles in the fitness of antimicrobials in vitro and host immunity in vivo. The data suggest a robust tool to screen for loss-of-function phenotypes in a pooled gene knockdown library in K. pneumoniae, and Mobile-CRISPRi-seq may be expanded to multiple bacteria for screening and identification of genes with crucial roles in the fitness of antimicrobials and hosts.
Asunto(s)
Genes Esenciales , Klebsiella pneumoniae , Humanos , Klebsiella pneumoniae/genética , Virulencia/genética , Técnicas de Silenciamiento del Gen , Bacterias/genética , Antibacterianos/farmacologíaRESUMEN
The Siberian roe deer (Capreolus pygargus) is a widely distributed ungulate in northeast China. Due to a series of human disturbance activities such as large-scale forest cutting, deforestation and reclamation, road construction in the past, the appearance and internal structure of forest vegetation in the habitat of Siberian roe have changed significantly. At the same time, Siberian roe population had a series of ecological adaptation responses in the face of such habitat changes. Therefore, two typical vegetation types with differences were selected in the Muling Forest, China. We used nutritional ecology and microbial metagenomic analysis techniques to compare the nutritional selection strategy and the structure and functional characteristics of faecal microbiota of Siberian roe groups in two vegetation types. The results showed that the α diversity of dietary and gut microbes of deer in Natural Forest was higher than that in Plantation Forest. However, the gut microbes of the Plantation Forest group contained more unique enzymes in the functional pathways of carbon metabolism and biosynthesis of amino acids. This study suggests that habitat type is associated with plant community composition, and contributes to changes in the intake proportions of major macronutrients by altering the availability, quality, and composition of certain edible plants. Feeding behaviour may be an important regulatory factor of gut microbiota structure and function of deer. The metabolic function of gut microbiota to different nutrients may affect the microbial community structure. Therefore, our results suggest that the gut microbes of Siberian roe may have coevolved with their diets, and reflect the adaptability of deer populations to environmental changes (e.g., vegetation type). Our study provides new insights into how spatial heterogeneity affects nutrition and microecosystems by describing the interactions among the environment, diet, and symbiotic gut microbes in wild ungulates.