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5-Hydroxytryptophan (5-HTP), a precursor of the neurotransmitter serotonin in mammals, has demonstrated efficacy in treating various diseases such as depression, fibromyalgia and obesity. However, conventional biosynthesis methods of 5-HTP are limited by low yield and high reagent and process costs. In this study, the strain C1T7-S337A/F318Y with optimized promoter distribution was obtained, and the 5-HTP yield was 60.30â¯% higher than that of the initial strain. An efficient fermentation process for 5-HTP synthesis was developed using strain C1T7-S337A/F318Y with whey powder as a substrate for cell growth and inducer production. Shake flask fermentation experiments yielded 1.302â¯g/L 5-HTP from 2.0â¯g/L L-tryptophan (L-Trp), surpassing the whole-cell biocatalysis by 42.86â¯%. Scale-up to a 5â¯L fermenter further increased the yield to 1.649â¯g/L. This fermentation strategy substantially slashed reagent cost by 95.39â¯%, providing a more economically viable and environmentally sustainable route for industrial biosynthesis of 5-HTP. Moreover, it contributes to the broader utilization of whey powder in various industries.
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Epithelial ovarian cancer (EOC) is an often-fatal malignancy marked by the development of resistance to platinum-based chemotherapy. Thus, accurate prediction of platinum drug efficacy is crucial for strategically selecting postoperative interventions to mitigate the risks associated with suboptimal therapeutic outcomes and adverse effects. Tissue-derived extracellular vesicles (tsEVs), in contrast to their plasma counterparts, have emerged as a powerful tool for examining distinctive attributes of EOC tissues. In this study, 4D data-independent acquisition (DIA) proteomic sequencing was performed on tsEVs obtained from 58 platinum-sensitive and 30 platinum-resistant patients with EOC. The analysis revealed a notable enrichment of differentially expressed proteins that were predominantly associated with immune-related pathways. Moreover, pivotal immune-related proteins (IRPs) were identified by LASSO regression. These factors, combined with clinical parameters selected through univariate logistic regression, were used for the construction of a model employing multivariate logistic regression. This model integrated three tsEV IRPs, CCR1, IGHV_35 and CD72, with one clinical parameter, the presence of postoperative residual lesions. Thus, this model could predict the efficacy of initial platinum-based chemotherapy in patients with EOC post-surgery, providing prognostic insights even before the initiation of chemotherapy.
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Carcinoma Epitelial de Ovario , Vesículas Extracelulares , Neoplasias Ováricas , Humanos , Femenino , Vesículas Extracelulares/metabolismo , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Anciano , Resistencia a Antineoplásicos , Platino (Metal)/uso terapéutico , Platino (Metal)/farmacología , Adulto , Proteómica/métodos , Pronóstico , Biomarcadores de Tumor/metabolismoRESUMEN
CD28 and 4-1BB costimulatory endodomains included in chimeric antigen receptor (CAR) molecules play a critical role in promoting sustained antitumor activity of CAR-T cells. However, the molecular events associated with the ectopic and constitutive display of either CD28 or 4-1BB in CAR-T cells have been only partially explored. In the current study, we demonstrated that 4-1BB incorporated within the CAR leads to cell cluster formation and cell death in the forms of both apoptosis and necroptosis in the absence of CAR tonic signaling. Mechanistic studies illustrate that 4-1BB sequesters A20 to the cell membrane in a TRAF-dependent manner causing A20 functional deficiency that in turn leads to NF-κB hyperactivity, cell aggregation via ICAM-1 overexpression, and cell death including necroptosis via RIPK1/RIPK3/MLKL pathway. Genetic modulations obtained by either overexpressing A20 or releasing A20 from 4-1BB by deleting the TRAF-binding motifs of 4-1BB rescue cell cluster formation and cell death and enhance the antitumor ability of 4-1BB-costimulated CAR-T cells.
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Muerte Celular , Receptores Quiméricos de Antígenos , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa , Humanos , Receptores Quiméricos de Antígenos/metabolismo , Receptores Quiméricos de Antígenos/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismo , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Animales , Necroptosis , Apoptosis , Transducción de Señal , Ratones , FN-kappa B/metabolismo , Línea Celular Tumoral , Ubiquitina/metabolismoRESUMEN
This study investigated the effects of exclusive donor milk or formula in the first 7 days after birth, on the time to full enteral feeding, growth, and morbidity of adverse events related to premature infants. This was a retrospective study carried out from July 2014 to December 2019 at the Department of Neonatology of Shanghai Children's Hospital. All infants with a birth weight < 1,500 g and a gestational age ≤ 32 who received exclusive donor milk or formula in the first 7 days after birth were included in this study. The time to full enteral feeding (defined as 150 mL/kg) in the donor milk group was significantly shorter than in the formula group (18 vs. 22 days, p = 0.01). Donated breast milk was also associated with a lower incidence of NEC (4.4 vs. 7%, p < 0.01), ROP (3.8 vs. 13.2%, p < 0.01), and culture-confirmed sepsis (11 vs. 22.6%, p < 0.01). Using donated breast milk instead of current formula milk for early enteral nutrition can shorten the time to full enteral feeding and reduce the incidence of NEC, ROP, and sepsis.
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Chimeric Antigen Receptor (CAR) T cell therapy has produced revolutionary success in hematological cancers such as leukemia and lymphoma. Nonetheless, its translation to solid tumors faces challenges due to manufacturing complexities, short-lived in vivo persistence, and transient therapeutic impact. We introduce 'Drydux' - an innovative macroporous biomaterial scaffold designed for rapid, efficient in-situ generation of tumor-specific CAR T cells. Drydux expedites CAR T cell preparation with a mere three-day turnaround from patient blood collection, presenting a cost-effective, streamlined alternative to conventional methodologies. Notably, Drydux-enabled CAR T cells provide prolonged in vivo release, functionality, and enhanced persistence exceeding 150 days, with cells transitioning to memory phenotypes. Unlike conventional CAR T cell therapy, which offered only temporary tumor control, equivalent Drydux cell doses induced lasting tumor remission in various animal tumor models, including systemic lymphoma, peritoneal ovarian cancer, metastatic lung cancer, and orthotopic pancreatic cancer. Drydux's approach holds promise in revolutionizing solid tumor CAR T cell therapy by delivering durable, rapid, and cost-effective treatments and broadening patient accessibility to this groundbreaking therapy.
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Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos , Animales , Humanos , Receptores Quiméricos de Antígenos/inmunología , Inmunoterapia Adoptiva/métodos , Ratones , Linfocitos T/inmunología , Neoplasias/terapia , Neoplasias/inmunología , Femenino , Línea Celular TumoralRESUMEN
Small extracellular vesicles (sEVs), a form of extracellular vesicles, are lipid bilayered structures released by all cells. Large-scale studies on sEVs from clinical samples are necessary, but a major obstacle is the lack of rapid, reproducible, efficient, and low-cost methods to enrich sEVs. Acoustic microfluidics have the advantage of being label-free and biocompatible, which have been reported to successfully enrich sEVs. In this paper, we present a highly efficient acoustic microfluidic trap that can offer low and large volume compatible ways of enriching sEVs from biological fluids by flexible structure design. It uses the idea of pre-loading larger seed particles in the acoustic trap to enable sub-micron particle capturing. The microfluidic chip is actuated using a piezoelectric plate transducer attached to a silicon-glass bonding plate with circular cavities. Each cavity works as a resonant unit, excited at the frequency of both the half wave resonance in the main plane and inverted quarter wave resonance in the depth direction, which has the ability to strongly trap seed particles at the center, thereby improving the subsequent nanoparticle capture efficiency. Mean trapping efficiencies of 35.62% and 64.27% were obtained using 60 nm and 100 nm nanobeads, respectively. By the use of this technology, we have successfully enriched sEVs from cell culture conditioned media and blood plasma at a flow rate of 10 µL min-1. The isolated sEV subpopulations are characterized by NTA and TEM, and their protein cargo is determined by WB. This acoustic trapping chip provides a rapid and robust method to enrich sEVs from biofluids with high reproducibility and sufficient quantities. Therefore, it can serve as a new tool for biological and clinical research such as cancer diagnosis and drug delivery.
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Acústica , Vesículas Extracelulares , Vesículas Extracelulares/química , Humanos , Técnicas Analíticas Microfluídicas/instrumentación , Técnicas Analíticas Microfluídicas/métodos , Nanopartículas/química , Dispositivos Laboratorio en un Chip , Medios de Cultivo Condicionados/químicaRESUMEN
Dendrobium is a rich source of high-value natural components. Endophytic fungi are well studied, yet bacteria research is limited. In this study, endophytic bacteria from Dendrobium nobile were isolated using an improved method, showing inhibition of pathogens and growth promotion. JC-3jx, identified as Paenibacillus peoriae, exhibited significant inhibitory activity against tested fungi and bacteria, including Escherichia coli. JC-3jx also promoted corn seed rooting and Dendrobium growth, highlighting its excellent biocontrol and growth-promoting potential.
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Dendrobium , Endófitos , Paenibacillus , Dendrobium/microbiología , Dendrobium/crecimiento & desarrollo , Paenibacillus/genética , Paenibacillus/aislamiento & purificación , Endófitos/aislamiento & purificación , Endófitos/genética , Raíces de Plantas/microbiología , Zea mays/microbiologíaRESUMEN
Disrupted gastrointestinal (GI) motility is highly prevalent in patients with inflammatory bowel disease (IBD), but its potential causative role remains unknown. Herein, the role and the mechanism of impaired GI motility in colitis pathogenesis are investigated. Increased colonic mucosal inflammation is found in patients with chronic constipation (CC). Mice with GI dysmotility induced by genetic mutation or chemical insult exhibit increased susceptibility to colitis, dependent on the gut microbiota. GI dysmotility markedly decreases the abundance of Lactobacillus animlalis and increases the abundance of Akkermansia muciniphila. The reduction in L. animlalis, leads to the accumulation of linoleic acid due to compromised conversion to conjugated linoleic acid. The accumulation of linoleic acid inhibits Treg cell differentiation and increases colitis susceptibility via inducing macrophage infiltration and proinflammatory cytokine expression in macrophage. Lactobacillus and A. muciniphila abnormalities are also observed in CC and IBD patients, and mice receiving fecal microbiota from CC patients displayed an increased susceptibility to colitis. These findings suggest that GI dysmotility predisposes host to colitis development by modulating the composition of microbiota and facilitating linoleic acid accumulation. Targeted modulation of microbiota and linoleic acid metabolism may be promising to protect patients with motility disorder from intestinal inflammation.
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Colitis , Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Motilidad Gastrointestinal , Ácido Linoleico , Animales , Microbioma Gastrointestinal/fisiología , Ratones , Ácido Linoleico/metabolismo , Colitis/metabolismo , Colitis/microbiología , Colitis/inducido químicamente , Humanos , Ratones Endogámicos C57BL , Masculino , Estreñimiento/metabolismo , Estreñimiento/microbiología , Femenino , Akkermansia , Lactobacillus/metabolismoRESUMEN
Fusobacterium nucleatum (F. nucleatum) promotes intestinal tumor growth and its relative abundance varies greatly among patients with CRC, suggesting the presence of unknown, individual-specific effectors in F. nucleatum-dependent carcinogenesis. Here, we identify that F. nucleatum is enriched preferentially in KRAS p.G12D mutant CRC tumor tissues and contributes to colorectal tumorigenesis in Villin-Cre/KrasG12D+/- mice. Additionally, Parabacteroides distasonis (P. distasonis) competes with F. nucleatum in the G12D mouse model and human CRC tissues with the KRAS mutation. Orally gavaged P. distasonis in mice alleviates the F. nucleatum-dependent CRC progression. F. nucleatum invades intestinal epithelial cells and binds to DHX15, a protein of RNA helicase family expressed on CRC tumor cells, mechanistically involving ERK/STAT3 signaling. Knock out of Dhx15 in Villin-Cre/KrasG12D+/- mice attenuates the CRC phenotype. These findings reveal that the oncogenic effect of F. nucleatum depends on somatic genetics and gut microbial ecology and indicate that personalized modulation of the gut microbiota may provide a more targeted strategy for CRC treatment.
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Neoplasias Colorrectales , Fusobacterium nucleatum , Animales , Humanos , Ratones , Carcinogénesis/genética , Neoplasias Colorrectales/patología , Fusobacterium nucleatum/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , ARN HelicasasRESUMEN
The F-box and WD repeat domain containing 7 (FBXW7) tumour suppressor gene encodes a substrate-recognition subunit of Skp, cullin, F-box (SCF)-containing complexes. The tumour-suppressive role of FBXW7 is ascribed to its ability to drive ubiquitination and degradation of oncoproteins. Despite this molecular understanding, therapeutic approaches that target defective FBXW7 have not been identified. Using genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screens, focussed RNA-interference screens and whole and phospho-proteome mass spectrometry profiling in multiple FBXW7 wild-type and defective isogenic cell lines, we identified a number of FBXW7 synthetic lethal targets, including proteins involved in the response to replication fork stress and proteins involved in replication origin firing, such as cell division cycle 7-related protein kinase (CDC7) and its substrate, DNA replication complex GINS protein SLD5 (GINS4). The CDC7 synthetic lethal effect was confirmed using small-molecule inhibitors. Mechanistically, FBXW7/CDC7 synthetic lethality is dependent upon the replication factor telomere-associated protein RIF1 (RIF1), with RIF1 silencing reversing the FBXW7-selective effects of CDC7 inhibition. The delineation of FBXW7 synthetic lethal effects we describe here could serve as the starting point for subsequent drug discovery and/or development in this area.
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Proteínas de Ciclo Celular , Neoplasias , Humanos , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Línea Celular Tumoral , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Ubiquitinación , Interferencia de ARN , Dominios Proteicos , Ubiquitina-Proteína Ligasas/metabolismo , Neoplasias/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Cromosómicas no Histona/genéticaRESUMEN
Electro-conductive hydrogels emerge as a stretchable conductive materials with diverse applications in the synthesis of flexible strain sensors. However, the high-water content and low cross-links density cause them to be mechanically destroyed and freeze at subzero temperatures, limiting their practical applications. Herein, we report a one-pot strategy by co-incorporating cellulose nanofiber (CNF), Poly pyrrole (PPy) and glycerol with polyvinyl alcohol (PVA) to prepare hydrogel. The addition of PPy endowed the hydrogel with good conductivity (â¼0.034 S/m) compared to the no PPy@CNF group (â¼0.0095 S/m), the conductivity was increased by 257.9 %. The hydrogel exhibits comparable ionic conductivity at -18 °C as it does at room temperature. It's attributed to the glycerol as a cryoprotectant and the formation of hydrated [Zn(H2O)n]2+ ions via strong interaction between Zn2+ and water molecules. Moreover, the cellulose nanofiber intrinsically assembled into unique hierarchical structures allow for strong hydrogen bonds between adjacent cellulose and PPy polymer chains, greatly improve the mechanical strength (stressâ¼0.65 MPa, strainâ¼301 %) and excellent viscoelasticity (G'max â¼ 82.7 KPa). This novel PPy@CNF-PVA hydrogel exhibits extremely high Gauge factor (GF) of 2.84 and shows excellent sensitivity, repeatability and stability. Therefore, the hydrogel can serve as reliable and stable strain sensor which shows excellent responsiveness in human activities monitoration.
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Nanofibras , Polímeros , Humanos , Alcohol Polivinílico , Celulosa , Pirroles , Glicerol , Conductividad Eléctrica , Hidrogeles , Poli A , AguaRESUMEN
Head and neck squamous cell carcinomas (HNSCC) remain a poorly understood disease clinically and immunologically. HPV is a known risk factor of HNSCC associated with better outcome, whereas HPV-negative HNSCC are more heterogeneous in outcome. Gene expression signatures have been developed to classify HNSCC into four molecular subtypes (classical, basal, mesenchymal, and atypical). However, the molecular underpinnings of treatment response and the immune landscape for these molecular subtypes are largely unknown. Herein, we described a comprehensive immune landscape analysis in three independent HNSCC cohorts (>700 patients) using transcriptomics data. We assigned the HPV- HNSCC patients into these four molecular subtypes and characterized the tumor microenvironment using deconvolution method. We determined that atypical and mesenchymal subtypes have greater immune enrichment and exhibit a T-cell exhaustion phenotype, compared to classical and basal subtypes. Further analyses revealed different B cell maturation and antibody isotypes enrichment patterns, and distinct immune microenvironment crosstalk in the atypical and mesenchymal subtypes. Taken together, our study suggests that treatments that enhances B cell activity may benefit patients with HNSCC of the atypical subtypes. The rationale can be utilized in the design of future precision immunotherapy trials based on the molecular subtypes of HPV- HNSCC.
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Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Virus del Papiloma Humano , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/genética , Neoplasias de Cabeza y Cuello/genética , Inmunoterapia , Microambiente TumoralRESUMEN
BACKGROUND: One reason patients with cancer cannot benefit from immunotherapy is the lack of immune cell infiltration in tumor tissues. Cancer-associated fibroblasts (CAFs) are emerging as central players in immune regulation that shapes tumor microenvironment (TME). Earlier we reported that integrin α5 was enriched in CAFs in colorectal cancer (CRC), however, its role in TME and cancer immunotherapy remains unclear. Here, we aimed to investigate the role for integrin α5 in fibroblasts in modulating antitumor immunity and therapeutic efficacy combined with checkpoint blockade in CRC. METHODS: We analyzed the CRC single-cell RNA sequencing (scRNA-seq) database to define the expression of ITGA5 in CRC tumor stroma. Experimentally, we carried out in vivo mouse tumor xenograft models to confirm the targeting efficacy of combined α5ß1 inhibition and anti-Programmed death ligand 1 (PD-L1) blockade and in vitro cell-co-culture assay to investigate the role of α5 in fibroblasts in affecting T-cell activity. Clinically, we analyzed the association between α5 expression and infiltrating T cells and evaluated their correlation with patient survival and immunotherapy prognosis in CRC. RESULTS: We revealed that ITGA5 was enriched in FAP-CAFs. Both ITGA5 knockout fibroblasts and therapeutic targeting of α5 improved response to anti-PD-L1 treatment in mouse subcutaneous tumor models. Mechanistically, these treatments led to increased tumor-infiltrating CD8+ T cells. Furthermore, we found that α5 in fibroblasts correlated with extracellular matrix (ECM)-related genes and affected ECM deposition in CRC tumor stroma. Both in vivo analysis and in vitro culture and cell killing experiment showed that ECM proteins and α5 expression in fibroblasts influence T-cell infiltration and activity. Clinically, we confirmed that high α5 expression was associated with fewer CD3+ T and CD8+ T cells, and tissues with low α5 and high CD3+ T levels correlated with better patient survival and immunotherapy response in a CRC cohort with 29 patients. CONCLUSIONS: Our study identified a role for integrin α5 in fibroblasts in modulating antitumor immunity by affecting ECM deposition and showed therapeutic efficacy for combined α5ß1 inhibition and PD-L1 blockade in CRC.
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Antígeno B7-H1 , Neoplasias Colorrectales , Humanos , Animales , Ratones , Linfocitos T CD8-positivos , Integrina alfa5 , Fibroblastos , Neoplasias Colorrectales/genética , Matriz Extracelular/metabolismo , Microambiente TumoralRESUMEN
Skin wounds, especially large-area skin trauma, would bring great pain and even fatal risk to patients. In recent years, local autologous cell transplantation has shown great potential for wound healing and re-epithelialization. However, when the cell suspension prepared with normal saline is delivered to the wound, due to its low viscosity, it is easy to form big drops in the deposition and lose them from the wound bed, resulting in cell loss and uneven coverage. Here, we developed a novel air-assisted atomization device (AAAD). Under proper atomization parameters, 1% (w/v) sodium alginate (SA) solution carrier could be sprayed uniformly. Compared with normal saline, the run-off of the SA on the surface of porcine skin was greatly reduced. In theory, the spray height of AAAD could be set to achieve the adjustment of a large spray area of 1-12 cm2. In the measurement of droplet velocity and HaCaT cell viability, the spray height of AAAD would affect the droplet settling velocity and then the cell delivery survival rate (CSR). Compared with the spray height of 50 mm, the CSR of 100 mm was significantly higher and could reach 91.09% ± 1.82% (92.82% ± 2.15% in control). For bio-ink prepared with 1% (w/v) SA, the viability remained the same during the 72-h incubation. Overall, the novel AAAD uniformly atomized bio-ink with high viscosity and maintained the viability and proliferation rate during the delivery of living cells. Therefore, AAAD has great potential in cell transplantation therapy, especially for large-area or irregular skin wounds.
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Tinta , Solución Salina , Humanos , Viscosidad , Cicatrización de HeridasRESUMEN
BACKGROUND: Bipedicular/unipedicular percutaneous kyphoplasty are common treatments for OVCF, and there are no studies to show which is more beneficial for AVCF. The purpose of this study was to investigate the clinical efficacy of BPKP or UPKP in the treatment of AVCF. METHODS: The clinical data of AVCF patients treated by PKP were retrospectively analyzed. They were divided into two groups according to the surgical approach. General demographic data, perioperative complications, and general information related to surgery were recorded for both groups. The preoperative and postoperative vertebral height difference, vertebral local Cobb angle, lumbar pain VAS score and lumbar JOA score were counted for both groups. The above data were compared preoperatively, postoperatively and between the two groups. RESULTS: 25 patients with AVCF were successfully included and all were followed up for at least 12 months, with no complications during the follow-up period. 10 patients in the BPKP group and 15 patients in the UPKP group, with no statistically significant differences in general information between the two groups. The VAS scores of patients in the BPKP group were lower than those in the UPKP group at 12 months after surgery, and the differences were statistically significant, and there were no statistically significant differences between the two groups at other follow-up time points. In the BPKP group, 80% of patients had symmetrical and more homogeneous bone cement dispersion. 50% of patients in the UPKP group had a lateral distribution of bone cement and uneven bone cement distribution, and the difference in bone cement distribution between the two groups was statistically significant. CONCLUSION: For the treatment of AVCF, the clinical efficacy of both surgical approaches is basically the same. The distribution of cement is more symmetrical and uniformly diffused in the BPKP group, and the clinical efficacy VAS score is lower in the long-term follow-up. Bipedicular percutaneous kyphoplasty is recommended for the treatment of AVCF. THE ETHICAL REVIEW BATCH NUMBER: XZXY-LJ-20161208-047.
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Fracturas por Compresión , Cifoplastia , Fracturas de la Columna Vertebral , Humanos , Fracturas por Compresión/cirugía , Estudios de Casos y Controles , Cementos para Huesos/uso terapéutico , Estudios Retrospectivos , Fracturas de la Columna Vertebral/cirugíaRESUMEN
Head and neck squamous cell carcinoma (HNSCC) has one of the most hypoxic and immunosuppressive tumor microenvironments (TME) among solid tumors. However, there is no proven therapeutic strategy to remodel the TME to be less hypoxic and proinflammatory. In this study, we classified tumors according to a Hypoxia-Immune signature, characterized the immune cells in each subgroup, and analyzed the signaling pathways to identify a potential therapeutic target that can remodel the TME. We confirmed that hypoxic tumors had significantly higher numbers of immunosuppressive cells, as evidenced by a lower ratio of CD8+ T cells to FOXP3+ regulatory T cells, compared with nonhypoxic tumors. Patients with hypoxic tumors had worse outcomes after treatment with pembrolizumab or nivolumab, anti-programmed cell death-1 inhibitors. Our expression analysis also indicated that hypoxic tumors predominantly increased the expression of the EGFR and TGFß pathway genes. Cetuximab, an anti-EGFR inhibitor, decreased the expression of hypoxia signature genes, suggesting that it may alleviate the effects of hypoxia and remodel the TME to become more proinflammatory. Our study provides a rationale for treatment strategies combining EGFR-targeted agents and immunotherapy in the management of hypoxic HNSCC. Significance: While the hypoxic and immunosuppressive TME of HNSCC has been well described, comprehensive evaluation of the immune cell components and signaling pathways contributing to immunotherapy resistance has been poorly characterized. We further identified additional molecular determinants and potential therapeutic targets of the hypoxic TME to fully leverage currently available targeted therapies that can be administered with immunotherapy.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Cetuximab/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Receptores ErbB/genética , Linfocitos T CD8-positivos/metabolismo , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Hipoxia/genética , Microambiente Tumoral/genéticaRESUMEN
Paroxetine (PRX) is a common antidepressant drug which widely existence in natural environment. Numerous studies in the past few decades have focused on the beneficial effects of PRX on depression, however, the toxic properties and the potential mechanisms remain unclear. In this study, zebrafish embryos were exposed to 1.0, 5.0, 10 and 20 mg/L of PRX from 4 to 120-hour-post-fertilization (hpf), and it showed that PRX exposure caused adverse effects in zebrafish embryos, including decreased body length, blood flow velocity, cardiac frequency, cardiac output and increased burst activity and atria area. Meanwhile, the Tg (myl7: EGFP) and Tg (lyz: DsRed) transgenic zebrafish were used to detect the cardiotoxicity and inflammation response of PRX. Moreover, the heart development associated genes (vmhc, amhc, hand2, nkx2.5, ta, tbx6, tbx16 and tbx20) and inflammatory genes (IL-10, IL-1ß, IL-8 and TNF-α) were up-regulated after PRX challenge. In addition, Aspirin was used to alleviate the PRX-induced heart development disorder. In conclusion, our study verified the PRX induced inflammatory related cardiotoxicity in larva zebrafish. Meanwhile, the current study shown the toxic effects of PRX in aquatic organism, and provide for the environmental safety of PRX.
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Contaminantes Químicos del Agua , Pez Cebra , Animales , Cardiotoxicidad , Paroxetina/farmacología , Larva , Embrión no Mamífero , Inflamación , Contaminantes Químicos del Agua/toxicidad , Proteínas de Dominio T Box , Proteínas de Pez CebraRESUMEN
The PSMC3IP-MND1 heterodimer promotes meiotic D loop formation before DNA strand exchange. In genome-scale CRISPR-Cas9 mutagenesis and interference screens in mitotic cells, depletion of PSMC3IP or MND1 causes sensitivity to poly (ADP-Ribose) polymerase inhibitors (PARPi) used in cancer treatment. PSMC3IP or MND1 depletion also causes ionizing radiation sensitivity. These effects are independent of PSMC3IP/MND1's role in mitotic alternative lengthening of telomeres. PSMC3IP- or MND1-depleted cells accumulate toxic RAD51 foci in response to DNA damage, show impaired homology-directed DNA repair, and become PARPi sensitive, even in cells lacking both BRCA1 and TP53BP1. Epistasis between PSMC3IP-MND1 and BRCA1/BRCA2 defects suggest that abrogated D loop formation is the cause of PARPi sensitivity. Wild-type PSMC3IP reverses PARPi sensitivity, whereas a PSMC3IP p.Glu201del mutant associated with D loop defects and ovarian dysgenesis does not. These observations suggest that meiotic proteins such as MND1 and PSMC3IP have a greater role in mitotic DNA repair.
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Antineoplásicos , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Reparación del ADN , Daño del ADN , Proteína BRCA1/genética , Reparación del ADN por Recombinación , Línea Celular TumoralRESUMEN
Photothermal immunotherapy, the combination of photothermal hyperthermia and immunotherapy, is a noninvasive and desirable therapeutic strategy to address the deficiency of traditional photothermal ablation for tumor treatment. However, insufficient T-cell activation following photothermal treatment is a bottleneck to achieve satisfactory therapeutic effectiveness. In this work, a multifunctional nanoplatform is rationally designed and engineered on the basis of polypyrrole-based magnetic nanomedicine modified by T-cell activators of anti-CD3 and anti-CD28 monoclonal antibodies, which have achieved robust near infrared laser-triggered photothermal ablation and long-lasting T-cell activation, realizing diagnostic imaging-guided immunosuppressive tumor microenvironment regulation following photothermal hyperthermia by reinvigorating tumor-infiltrating lymphocytes. By virtue of high-efficient immunogenic cell death and dendritic cell maturation combined with T-cell activation, this nanosystem markedly restrains primary and abscopal tumors as well as metastatic tumors with negligible side effects in vivo, exerting the specific function for suppressing tumor recurrence and metastasis by establishing a long-term memory immune response.
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Hipertermia Inducida , Neoplasias , Humanos , Polímeros , Fototerapia , Pirroles , Neoplasias/terapia , Hipertermia/terapia , Inmunoterapia , Microambiente TumoralRESUMEN
Wood-based panels provide efficient alternatives to materials such as plastics derived from traditional petroleum sources and thereby help to mitigate greenhouse gas emissions. Unfortunately, using indoor manufactured panel products also results in significant emissions of volatile organic compounds including olefins, aromatic and ester compounds, which negatively affect human health. This paper highlights recent developments and notable achievements in the field of indoor hazardous air treatment technologies to guide future research toward environmentally friendly and economically feasible directions that may have a significant impact on the improvement of human settlements. Summarizing and synthesizing the principles, advantages, and limitations of different technologies can assist policymakers and engineers in identifying the most appropriate technology for a particular air pollution control program based on criteria such as cost-effectiveness, efficiency, and environmental impact. In addition, insights into the development of indoor air pollution control technologies are provided and potential areas for innovation, improvement of existing technologies, and development of new technologies are identified. Finally, the authors also hope that this sub-paper will raise public awareness of indoor air pollution issues and promote a better understanding of the importance of indoor air pollution control technologies for public health, environmental protection, and sustainable development.