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1.
Biochim Biophys Acta Gen Subj ; 1867(1): 130251, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36244576

RESUMO

CdSe/ZnS Quantum dots (QDs) are possibly released to surface water due to their extensive application. Based on their high reactivity, even small amounts of toxicant QDs will disturb water microbes and pose a risk to aquatic ecology. Here, we evaluated CdSe/ZnS QDs toxicity to Tetrahymena thermophila (T. thermophila), a model organism of the aquatic environment, and performed metabolomics experiments. Before the omics experiment was conducted, QDs were found to induce inhibition of cell proliferation, and reactive oxygen species (ROS) production along with Propidium iodide labeled cell membrane damage indicated oxidative stress stimulation. In addition, mitochondrial ultrastructure alteration of T. thermophila was also confirmed by Transmission Electron Microscope results after 48 h of exposure to QDs. Further results of metabolomics detection showed that 0.1 µg/mL QDs could disturb cell physiological and metabolic metabolism characterized by 18 significant metabolite changes, of which twelve metabolites improved and three decreased significantly compared to the control. Kyoto Encyclopedia of Genes and Genomes analysis showed that these metabolites were involved in the ATP-binding cassette transporter and purine metabolism pathways, both of which respond to ROS-induced cell membrane damage. In addition, purine metabolism weakness might also reflect mitochondrial dysfunction associated with energy metabolism and transport abnormalities. This research provides deep insight into the potential risks of quantum dots in aquatic ecosystems.


Assuntos
Compostos de Cádmio , Pontos Quânticos , Compostos de Selênio , Tetrahymena thermophila , Pontos Quânticos/toxicidade , Compostos de Cádmio/toxicidade , Compostos de Cádmio/química , Compostos de Selênio/farmacologia , Tetrahymena thermophila/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ecossistema , Estresse Oxidativo , Água , Purinas , Lipídeos
2.
Int J Cancer ; 152(2): 151-161, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35913753

RESUMO

Adenocarcinoma (AC) and squamous cell carcinoma (SCC) are the main subtypes of esophageal cancer (EC), but nationwide survival of both EC subtypes has never been reported in China. Our study aimed to estimate the survival trends of EC by subtype in China and compare them with those in the United States for the same period. We used data from 64 Chinese cancer registries, which included EC patients diagnosed during 2008 and 2015 and followed up until 31st December 2017. The 5-year age-standardized relative survival by subtype, sex, age group and urban or rural area between 2008 and 2017 were analyzed. We stratified survival estimates by calendar period (2008-2009, 2010-2011, 2012-2014 and 2015-2017). Data from the SEER 18 program were calculated to estimate the survival of EC in the United States. A further comparison between the survivals in areas covered and not covered by population-based endoscopic screening programs in China was conducted. A total of 129 962 records were included in the survival analyses. Results revealed that age-standardized 5-year relative survivals for AC and SCC increased in both China and the United States from 2008 to 2017. In 2015 to 2017, 5-year survival from both subtypes in China was better than the United States (SCC: 36.9% vs 18.5%, AC: 34.8% vs 22.3%). The survival for both subtypes was significantly higher in screening areas than in nonscreening areas in China (SCC: 40.6% vs 32.8%; AC: 43.0% vs 31.3%). A survival gap in EC by subtype exists between China and the United States. Our results may support the beneficial effect of population-based endoscopic screening for survival, and may be poised to inform national policy-making in both countries.


Assuntos
Adenocarcinoma , Carcinoma de Células Escamosas , Neoplasias Esofágicas , Humanos , Estados Unidos/epidemiologia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas/patologia , Programa de SEER , Adenocarcinoma/patologia , China/epidemiologia
3.
J Environ Manage ; 325(Pt A): 116497, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36270129

RESUMO

Investigating the release of organic pollutants from bricks made from solid waste is essential. Based on Fick's laws of diffusion, the diffusion model and diffusion-degradation model of polycyclic aromatic hydrocarbon (PAH) emission from the bricks were deduced. The degradation and 64-day emission of PAHs in solid bricks made of oil-based drill cuttings were observed experimentally. The emission and degradation characteristics of 14 PAHs were obtained and fitted with the diffusion and diffusion-degradation models. The emission of most of the PAHs from the bricks at the beginning was in good agreement with the diffusion model, except for benzo[a]anthracene, pyrene, benzo[b]fluoranthene, benzo[k]fluoranthene, and benzo[a]pyrene. However, the emission of PAHs after some time was significantly lower than the theoretical value of the diffusion model. Moreover, fitting with the diffusion-degradation model gave better results, indicating that a joint diffusion-degradation mechanism controlled the emission of PAHs. Therefore, the diffusion-degradation model can better predict the long-term emission of PAHs in bricks made of oil-based drill cuttings.


Assuntos
Poluentes Ambientais , Hidrocarbonetos Policíclicos Aromáticos , Fluorenos , Benzo(a)pireno/análise
4.
iScience ; 25(11): 105308, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36388952

RESUMO

Glaucoma is an optic neuropathy characterized by permanent visual field loss caused by the death of retinal ganglion cells (RGCs) and it is the leading cause of irreversible blindness worldwide. Consequently, there is an unmet need for the development of new strategies for its treatment. We investigated RGC replacement therapy as a treatment for ganglion cell loss. Human-induced pluripotent stem cells (hiPSCs) were differentiated into mature, functional RGCs in vitro, labeled with AAV2.7m8-SNCG-eGFP, and transplanted intravitreally in wild-type 4-month-old C57BL/6J mice. Survival of the transplanted hiPSC-RGCs was assessed by color fundus photography and histological studies confirmed the localization of the transplanted hiPSC-RGCs within the retina. Two-photon live imaging of retinal explants and electrophysiological studies confirmed that the morphology and function of the transplanted hiPSC-RGCs were similar to native RGCs. These experiments will provide key strategies to enhance the efficiency of stem cell replacement therapy for neurodegenerative diseases, including glaucoma.

5.
Artigo em Inglês | MEDLINE | ID: mdl-36403728

RESUMO

BACKGROUND AND AIMS: A one-size-fits-all approach to colorectal cancer (CRC) screening that does not account for CRC risk factors is not conducive to personalized screening. Based on the principle of "equal management of equal risks", we aimed to tailor and validate risk-adapted starting ages of CRC screening for individuals with different CRC risk factors. METHODS: A multi-center community-based population cohort (N=3,165,088) was used to evaluate the starting age of CRC screening with comprehensive consideration of risk factors. Age-specific 10-year cumulative risk curves were used to determine when individuals at greater risk for CRC reached the same risk level as the 50-year-old general population, which is currently the recommended starting age for CRC screening in China. RESULTS: During the study follow-up period (2013 to 2021), 4,840 incident CRCs were recorded. Family history of CRC, adverse lifestyle, and comorbidities demonstrated heterogeneous associations with CRC risk (hazard ratios [HRs]= 1.05 to 1.55, P<0.05). Men and women with CRC family history and at least two risk factors reached the standard benchmark risk (0.28%) for screening at the age of 40, 10 years earlier than their peers without risk factors in the general population. Proposed starting ages for CRC screening were validated in an independent community-based population cohort (N=1,023,367). CONCLUSION: We determined a risk-adapted CRC screening starting age for individuals with various CRC risk factors. Earlier, personalized screening based on these findings could allow for scarce health resources to be dedicated to individuals who benefit most.

6.
Front Immunol ; 13: 1037739, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389847

RESUMO

Molting is one of the most important biological processes of crustacean species, and a number of molecular mechanisms facilitate this complex procedure. However, the understanding of the immune mechanisms underlying crustacean molting cycle remains very limited. This study performed transcriptome sequencing in hemolymph and hepatopancreas of the swimming crab (Portunus trituberculatus) during the four molting stages: post-molt (AB), inter-molt (C), pre-molt (D), and ecdysis (E). The results showed that there were 78,572 unigenes that were obtained in the hemolymph and hepatopancreas of P. trituberculatus. Further analysis showed that 98 DEGs were involved in immunity response of hemolymph and hepatopancreas, and most of the DEGs participated in the process of signal transduction, pattern recognition proteins/receptors, and antioxidative enzymes system. Specifically, the key genes and pathway involved in signal transduction including the GPCR126, beta-integrin, integrin, three genes in mitogen-activated protein kinase (MAPK) signaling cascade (MAPKKK10, MAPKK4, and p38 MAPK), and four genes in Toll pathway (Toll-like receptor, cactus, pelle-like kinase, and NFIL3). For the pattern recognition proteins/receptors, the lowest expression level of 11 genes was found in the E stage, including C-type lectin receptor, C-type lectin domain family 6 member A and SRB3/C in the hemolymph, and hepatopancreatic lectin 4, C-type lectin, SRB, Down syndrome cell adhesion molecule homolog, Down syndrome cell adhesion molecule isoform, and A2M. Moreover, the expression level of copper/zinc superoxide dismutase isoform 4, glutathione peroxidase, glutathione S-transferase, peroxiredoxin, peroxiredoxin 6, and dual oxidase 2 in stage C or stage D significantly higher than that of stage E or stage AB. These results fill in the gap of the continuous transcriptional changes that are evident during the molting cycle of crab and further provided valuable information for elucidating the molecular mechanisms of immune regulation during the molting cycle of crab.


Assuntos
Fenômenos Biológicos , Braquiúros , Síndrome de Down , Animais , Braquiúros/genética , Braquiúros/metabolismo , Transcriptoma , Muda/genética , Natação , Lectinas Tipo C/metabolismo , Integrinas/metabolismo , Moléculas de Adesão Celular/metabolismo
7.
Int J Pharm ; : 122420, 2022 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-36414187

RESUMO

PEGylated pterostilbene micelle (PTENPs) with higher bioavailability, biocompatibility, and water solubility were prepared. Then we detected the therapeutic effects in the treatment of inflammatory bowel disease (IBD), together with its potential mechanisms. The anti-oxidant effects and anti-inflammatory effects of PTENPs were determined under in vitro and in vivo conditions. Besides, the cellular toxicity of the PTENPs was determined in vitro, and biocompatibility testing was performed on a colitis mice model to determine its safety. The self-assembled PTENPs showed potency in treating IBD, which was featured by effectively anti-oxidant capacity, inhibition of cellular damages, and an anti-inflammatory role. In addition, PTENPs could inhibit the activation of TLR4, thereby inhibiting the NF-κB and MAPK signaling pathways. Meanwhile, it could protect colonic tissues from oxidative damage, which promoted the remission of colonic inflammation with low toxicity. Compared with free PTE, PTENPs could effectively ameliorate acute IBD with low toxicity, which may be related to the inactivation of TLR4, and inhibition of NF-κB and MAPK signaling pathways.

8.
Anal Methods ; 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36416138

RESUMO

An aptamer sensor based on manganese dioxide (MnO2) nanosheets was developed for the detection of zearalenone (ZEN). The ZEN aptamer was modified at the 5'-end by a 6-carboxyfluorescein (6-FAM) fluorophore with self-assembly on MnO2 nanosheets. Interaction of the 6-FAM fluorophore at the 5'-end of the ZEN aptamer with the MnO2 nanosheet lowered fluorescence (FL) intensity due to fluorescence resonance energy transfer (FRET). The introduction of ZEN into the sensing system resulted in hybridization with the ZEN aptamer, forming a stable G-quadruplex/ZEN, which exhibited a low affinity for the MnO2 nanosheet surface. The distance between the 6-FAM fluorophore and MnO2 nanosheet hampered FRET, with a consequent strong FL signal. Under the optimal experimental conditions, the FL intensity of the sensing system showed a good linear correlation with ZEN concentration in the range of 1.5-10.0 ng mL-1, and a detection limit (S/N = 3) of 0.68 ng mL-1. The sensing system delivered enhanced specificity for the detection of ZEN, and can find wide application in the detection of other toxins by replacing the sequence of the recognition aptamer.

9.
Zhongguo Dang Dai Er Ke Za Zhi ; 24(11): 1259-1265, 2022 Nov 15.
Artigo em Chinês | MEDLINE | ID: mdl-36398553

RESUMO

OBJECTIVES: To investigate the risk factors for acute kidney injury (AKI) in children with cardiac arrest (CA) and the influencing factors for prognosis. METHODS: A retrospective analysis was performed on the medical records of the children who developed CA in the pediatric intensive care unit (PICU) of Hunan Children's Hospital from June 2016 to June 2021. According to the presence or absence of AKI within 48 hours after return of spontaneous circulation (ROSC) for CA, the children were divided into two groups: AKI (n=50) and non-AKI (n=113). According to their prognosis on day 7 after ROSC, the AKI group was further divided into a survival group (n=21) and a death group (n=29). The multivariate logistic regression analysis was used to investigate the risk factors for early AKI in the children with CA and the influencing factors for prognosis. RESULTS: The incidence rate of AKI after CA was 30.7% (50/163). The AKI group had a 7-day mortality rate of 58.0% (29/50) and a 28-day mortality rate of 78.0% (39/50), and the non-AKI group had a 7-day mortality rate of 31.9% (36/113) and a 28-day mortality rate of 58.4% (66/113). The multivariate logistic regression analysis showed that long duration of cardiopulmonary resuscitation (OR=1.164, 95%CI: 1.088-1.246, P<0.001), low baseline albumin (OR=0.879, 95%CI: 0.806-0.958, P=0.003), and adrenaline administration before CA (OR=2.791, 95%CI: 1.119-6.961, P=0.028) were closely associated with the development of AKI after CA, and that low baseline pediatric critical illness score (OR=0.761, 95%CI: 0.612-0.945, P=0.014), adrenaline administration before CA (OR=7.018, 95%CI: 1.196-41.188, P=0.031), and mechanical ventilation before CA (OR=7.875, 95%CI: 1.358-45.672, P=0.021) were closely associated with the death of the children with AKI after CA. CONCLUSIONS: Albumin should be closely monitored for children with ROSC after CA, especially for those with long duration of cardiopulmonary resuscitation, low baseline pediatric critical illness score, adrenaline administration before CA, and mechanical ventilation before CA, and such children should be identified and intervened as early as possible to reduce the incidence of AKI and the mortality rate.


Assuntos
Injúria Renal Aguda , Parada Cardíaca , Criança , Humanos , Prognóstico , Estudos Retrospectivos , Estado Terminal , Parada Cardíaca/complicações , Injúria Renal Aguda/epidemiologia , Unidades de Terapia Intensiva Pediátrica , Fatores de Risco , Epinefrina , Albuminas
10.
Water Res ; 226: 119310, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36369683

RESUMO

Heavy metal(loid)s (HMs) have been consistently entering the food chain, imposing great harm on environment and public health. However, previous studies on the spatial dynamics and transport mechanism of HMs have been profoundly limited by the field sampling issues, such as the uneven observations of individual carriers and their spatial mismatch, especially over large-scale catchments with complex environment. In this study, a novel methodological framework for mapping HMs at catchment scale was proposed and applied, combining a species distribution model (SDM) with physical environment and human variables. Based on the field observations, we ecologicalized HMs in different carriers as different species. This enabled the proposed framework to model the 'enrichment area' of individual HMs in the geographic space (termed as the HM 'habitat') and identify their 'hotspots' (peak value points) within the catchment. Results showed the output maps of HM habitats from secondary carriers (soil, sediment, and wet deposition) well agreed with the influence of industry contaminants, hydraulic sorting, and precipitation washout process respectively, indicating the potential of SDM in modeling the spatial distributions of the HM. The derived maps of HMs from secondary carriers, along with the human and environmental variables were then input as explanatory variables in SDM to predict the spatial patterns of the final HM accumulation in river water, which was observed to have largely improved the prediction quality. These results confirmed the value of our framework to leverage SDMs from ecology perspective to study HM contamination transport at catchment scale, offering new insights not only to map the spatial HM habitats but also help locate the HM transport chains among different carriers.


Assuntos
Metais Pesados , Poluentes do Solo , Humanos , Poluentes do Solo/análise , Monitoramento Ambiental/métodos , Medição de Risco , Metais Pesados/análise , Solo , China
11.
J Invertebr Pathol ; : 107852, 2022 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-36384189

RESUMO

Decapod iridescent virus 1 (DIV1) is an emerging viral pathogen that infects diverse freshwater and marine crustacean species and causes considerable economic losses that seriously threaten crustacean farming and has caused enormous financial losses in recent years. In this study, we detected DIV1 from diseased crabs, with clinical symptoms such as loss of vitality and white gill filaments with edema, in a Marsupenaeus japonicus and Portunus trituberculatus polyculture pond. Four DIV1 isolates from crab samples (two isolates) and shrimp samples (two isolates) were sequenced and assembled successfully. Molecular characterization and phylogenetic analysis of the four DIV1 isolates were conducted. The DIV1 isolates from crab samples have a close genetic relationship with shrimp DIV1s, indicating the viruses share the same ancestor with those from shrimps. Our study provides valuable insights into disease prevention and control of the shrimp-crab polyculture system.

12.
Chem Biol Drug Des ; 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36394145

RESUMO

The treatment of advanced non-small cell lung cancer (NSCLC) has made substantial progress due to the rapid development of small molecule targeted therapy, with dramatically prolonged survival. As an effective drug for the treatment of NSCLC, epidermal growth factor receptor (EGFR) inhibitors are currently experiencing issues like severe adverse events and drug resistance. It is urgent to develop novel types of EGFR inhibitors to overcome the abovementioned limitations. Pyrrole always works well as a probe for the creation of novel medication candidates for hard-to-treat conditions like lung cancer. Although the design, synthesis, and biological assays of pyrrole derivatives have been reported, their inhibitory actions against the receptor tyrosine kinase (RTK) EGFR have not been in-depthly studied. This review highlights the small molecule EGFR inhibitors containing pyrrole heterocyclic pharmacophores in recent years, and the research on their mechanism, biological activity, and structure-activity relationship (SAR).

13.
Arch Pharm (Weinheim) ; : e2200191, 2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36344425

RESUMO

The blockade of the overexpression of pro-inflammatory cytokines by anti-inflammatory natural products has been proven therapeutically beneficial in the treatment of acute lung injury (ALI). Given the fact that cinnamic acid has been proven to have significant anti-inflammatory activity, we selected it as a promising lead compound to develop more effective analogs in treating ALI. Learning from the symmetric structure of curcumin, 32 new symmetric cinnamic derivatives were designed, synthesized, and evaluated for their anti-inflammatory activity. Among them, 6h not only displayed a remarkable inhibitory activity in vitro (85.9% and 65.7% for  IL-6 and TNF-α, respectively) without cytotoxicity but also possessed chemical structure stability. Furthermore, an in vivo study in mice revealed that the administration of 6h significantly attenuated lipopolysaccharide-induced ALI, providing new lead structures for the development of anti-inflammatory drugs for the treatment of ALI.

14.
J Nanobiotechnology ; 20(1): 469, 2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36329497

RESUMO

BACKGROUND: Osteoarthritis (OA) is a common joint disorder worldwide which causes great health and economic burden. However, there remains an unmet goal to develop an effective therapeutic method to prevent or delay OA. Chondrocytes, as the major cells involved in OA progression, may serve as a promising therapeutic target. RESULTS: A kind of carbon dots (CDs) with excellent biocompatibility was fabricated from folic acid via hydrothermal method and could effectively attenuate osteoarthritis. It was demonstrated that CDs treatment could rescue IL1ß-induced proinflammatory responses, oxidative stress, cartilage degeneration and extracellular matrix degradation. Moreover, CDs reprogrammed lipopolysaccharide (LPS)-induced macrophage inflammation and polarization. Conditioned medium (CM) from CDs-treated macrophages could attenuate IL1ß-induced chondrocyte injury. Also, CM from CDs-treated chondrocytes had immunoregulatory functions on macrophages. Mechanistically, CDs inhibited the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPK) signaling pathways in IL1ß-stimulated chondrocytes. In vivo, anterior cruciate ligament transection (ACLT) mice model was adopted and it was indicated that intra-articular injection of CDs effectively delays OA pathogenesis. CONCLUSIONS: Taken together, these findings indicated CDs could mediate OA via promoting cartilage repair and immunomodulating macrophages within local microenvironment, which may provide evidences for utilizing CDs as a novel nanomaterial for OA treatment.


Assuntos
Condrócitos , Osteoartrite , Camundongos , Animais , Condrócitos/metabolismo , NF-kappa B/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/farmacologia , Ácido Fólico/metabolismo , Carbono/farmacologia , Carbono/uso terapêutico , Osteoartrite/metabolismo , Macrófagos/metabolismo
15.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 38(11): 1030-1035, 2022 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-36328433

RESUMO

Objective To screen nanobodies against prostate specific membrane antigen (PSMA). Methods Based on the naive phage display library, three rounds of screening were performed targeting the PSMA antigen, and positive clones were identified by ELISA and sequencing was performed. The positive cloned gene sequence was inserted into the pET28a prokaryotic expression vector and transformed into E.coli BL21. The expression of the recombinant protein was induced by IPTG and purified using Ni column, with the purified product verified by SDS-PAGE. Results Four PSMA nanobodies VHH1, VHH2, VHH3 and VHH4 were obtained by screening. The VHH1 failed to obtain protein expression, while the VHH2, VHH3 and VHH4 proteins were expressed. The purity of anti-PSMA nanobodies showed high and relative molecular mass (Mr) of about 17 000. Conclusion The sequence of anti-PSMA nanobody was successfully obtained by screening the naive phage nanobody library and were subjected to prokaryotic expression and purified.


Assuntos
Bacteriófagos , Anticorpos de Domínio Único , Masculino , Humanos , Anticorpos de Domínio Único/genética , Bacteriófagos/genética , Próstata , Glutamato Carboxipeptidase II/genética , Glutamato Carboxipeptidase II/metabolismo , Escherichia coli/genética
16.
Lancet Oncol ; 23(11): e515-e520, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36328025

RESUMO

The aim of this Policy Review was to compare China's overall and synchronous participation in clinical trials for innovative anticancer drugs with that of the USA, the EU, Japan, and South Korea, and to assess changes in the participation rate trends in these five regions. Relevant data from the top 20 international pharmaceutical companies from 2011 to 2021 were systematically collected from the Trialtrove and Pharmaprojects databases. Among the 8260 trials for 954 new anticancer drugs identified, China was involved in 8·8% of the trials and with 20·4% of the drugs being trialled. These participation rates are significantly lower than those for South Korea (14·5% of trials and 36·3% of drugs), Japan (16·1% of trials and 38·7% of drugs), the EU (40·6% of trials and 67·7% of drugs), and the USA (65·7% of trials and 91·2% of drugs; p<0·0001 for all). Similar results were found for the synchronous participation rate, defined as the proportion of drugs or trials at the highest development stage internationally, for the 803 tested drugs, which ranged from 9·0% in China to 87·7% in the USA. China's participation rate in early phase trials (4·4%) and in synchronous trials (5·4%) was even lower, in stark contrast to that of the USA (66·1% for early phase trials and 89·1% for synchronous trials). The fastest growing annual rate of participation in trials was observed in China (15·7%), followed by South Korea (8·2%) and Japan (6·8%); no change was detected in the USA or the EU. This Policy Review shows that Chinese participation in the clinical development of innovative cancer drugs by international pharmaceutical companies has increased over the past decade, but an obvious gap persists in comparison with the USA, the EU, Japan, and South Korea, especially in its synchronous participation and early participation rates.


Assuntos
Antineoplásicos , Humanos , Antineoplásicos/uso terapêutico , China , Japão , República da Coreia/epidemiologia , Indústria Farmacêutica
17.
JAMA Netw Open ; 5(11): e2241441, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36355372

RESUMO

Importance: Although current guidelines highlight the need for earlier screening in women at increased risk of breast cancer in China, data on risk-adapted starting ages of screening are limited. Objective: To explore the risk-adapted starting age of breast cancer screening in China, with comprehensive consideration of breast cancer risk factors. Design, Setting, and Participants: A multicenter community-based cohort study was conducted under the framework of the Cancer Screening Program in Urban China. Data were collected from January 1, 2013, to December 31, 2018, for unscreened community-dwelling women aged 40 to 74 years without a history of cancer, kidney dysfunction, or severe heart, brain, or lung disease. Data analysis was performed from October 1, 2021, to August 16, 2022. Exposures: Baseline characteristics associated with breast cancer, including first-degree family history of breast cancer, benign breast disease, breastfeeding, age at menarche, and body mass index. Main Outcomes and Measures: Outcomes included breast cancer diagnosis and age at diagnosis. Risk-adapted starting age of screening was defined as the age at which women with different levels of breast cancer risk attained a 10-year cumulative risk level similar to women aged 50 years in the general population. Results: Of the 1 549 988 women enrolled in this study, 3895 had breast cancer (median follow-up, 4.47 [IQR, 3.16-6.35] years). Participants were divided into different risk groups according to breast cancer risk scores (driven by risk factors including first-degree family history of breast cancer, benign breast disease, breastfeeding, age at menarche, and body mass index). Using the 10-year cumulative risk of breast cancer at age 50 years in the general population as a benchmark (2.65% [95% CI, 2.50%-2.76%]), the optimal starting age of screening for women with high, medium, or low risk of breast cancer was identified as 43, 48, or after 55 years, respectively. An online calculator was developed to calculate an individual's optimal starting age of screening. Conclusions and Relevance: This study identifies the risk-adapted starting age of breast cancer screening based on the principle of equal management of equal risks, which may inform updates of current screening guidelines.


Assuntos
Neoplasias da Mama , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Detecção Precoce de Câncer , Estudos de Coortes , China/epidemiologia , Fatores de Risco
18.
Nat Cancer ; 3(10): 1192-1210, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36271172

RESUMO

The complement system is a critical immune component, yet its role in tumor immune evasion and CD8+ T cell activation is not clearly defined. Here, we demonstrate that epidermal growth factor receptor (EGFR)/Wnt signaling induces ß-catenin-mediated long noncoding RNA (lncRNA) LINC00973 expression to sponge CD55-targeting miR-216b and CD59-targeting miR-150. The consequently upregulated CD55/CD59 expression suppresses the complement system and cytokine secretion required for CD8+ T cell activation. CD55/CD59-neutralizing antibody treatment or mutation of the LINC00973 promoter activates the complement and CD8+ T cells, inhibiting tumor growth. Importantly, combined anti-CD55/CD59 and anti-programmed death 1 (anti-PD-1) antibody treatments elicit a synergistic tumor-inhibiting effect. In addition, CD55/CD59 levels are inversely correlated with infiltration of M1 macrophages and CD8+ T cells in human lung cancer specimens and predict patient outcome. These findings underscore the critical role of EGFR/Wnt/ß-catenin-upregulated CD55/CD59 expression in inhibiting the complement and CD8+ T cell activation for tumor immune evasion and immune checkpoint blockade resistance and identify a potential combination therapy to overcome these effects.


Assuntos
Neoplasias Pulmonares , MicroRNAs , RNA Longo não Codificante , Humanos , beta Catenina , Linfócitos T CD8-Positivos/metabolismo , Inibidores de Checkpoint Imunológico , Proteína Cofatora de Membrana/genética , Antígenos CD55/genética , Proteínas do Sistema Complemento , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Anticorpos Neutralizantes , Citocinas , Antígenos CD59/genética
19.
J Control Release ; 352: 87-97, 2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36243236

RESUMO

Bacteria have the ability to invade and survive in host cells to form intracellular bacteria (ICBs), and challenges remain in the intracellular delivery of sufficient antibiotics to remove ICBs. Herein, antimicrobial peptide of epsilon-poly-l-lysine (ePL) and nitric oxide (NO) donors are integrated into nanoparticles (NPs) for ICB treatment without using any antibiotics. ePL was grafted with dodecyl alcohol through ethyl dichlorophosphate to prepare ePL-C12, followed by conjugation of nitrate-functionalized NO donors to obtain ePL-C12NO. PNO/C NPs were prepared from mixtures of ePL-C12NO and ePL-C12 and the optimal ePL-C12NO ratio was 7% in terms of bactericidal effect and macrophage toxicity. Once being engulfed by bacteria-infected macrophages (BIMs), NPs are disintegrated when encountering with ICB-secreted phosphatase, and the NP degradation accelerates intracellular NO release in response to the elevated glutathione levels in BIMs. The selective and abrupt release of NO and ePL with different antimicrobial mechanisms exhibits synergistic eradication of ICBs and no apparent toxicity to macrophages. ICB-infected mice show persistent weight loss and 100% of mortality rate after treatment with ePL-C12 NPs for 7 days, while PNO/C treatment causes entire survival of infected mice and full recovery of body weights to normal values. ICB-infected mice are also accompanied with apparent hepatomegaly and splenomegaly, which are only eliminated by PNO/C treatment without associated any pathological abnormality. PNO/C treatment reduces bacterial burdens in livers (2.45 log), spleens (2.16 log) and kidneys (3.46 log) and restores hepatic and renal function to normal levels. Thus, this study provides a feasible strategy to selectively release NO and cationic peptides in response to intracellular infection-derived signals, achieving synergistic eradication of ICBs and function restoration of the main tissues.

20.
Signal Transduct Target Ther ; 7(1): 346, 2022 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-36195615

RESUMO

Small-cell lung cancer (SCLC) is the most aggressive and lethal subtype of lung cancer, for which, better understandings of its biology are urgently needed. Single-cell sequencing technologies provide an opportunity to profile individual cells within the tumor microenvironment (TME) and investigate their roles in tumorigenic processes. Here, we performed high-precision single-cell transcriptomic analysis of ~5000 individual cells from primary tumors (PTs) and matched normal adjacent tissues (NATs) from 11 SCLC patients, including one patient with both PT and relapsed tumor (RT). The comparison revealed an immunosuppressive landscape of human SCLC. Malignant cells in SCLC tumors exhibited diverse states mainly related to the cell cycle, immune, and hypoxic properties. Our data also revealed the intratumor heterogeneity (ITH) of key transcription factors (TFs) in SCLC and related gene expression patterns and functions. The non-neuroendocrine (non-NE) tumors were correlated with increased inflammatory gene signatures and immune cell infiltrates in SCLC, which contributed to better responses to immune checkpoint inhibitors. These findings indicate a significant heterogeneity of human SCLC, and intensive crosstalk between cancer cells and the TME at single-cell resolution, and thus, set the stage for a better understanding of the biology of SCLC as well as for developing new therapeutics for SCLC.


Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Fatores de Transcrição/genética , Transcriptoma/genética , Microambiente Tumoral/genética
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