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The immune resistance of tumor microenvironment (TME) causes immune checkpoint blockade therapy inefficient to hepatocellular carcinoma (HCC). Emerging strategies of using chemotherapy regimens to reverse the immune resistance provide the promise for promoting the efficiency of immune checkpoint inhibitors. The induction of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) in tumor cells evokes the adaptive immunity and remodels the immunosuppressive TME. In this study, we report that mitoxantrone (MIT, a chemotherapeutic drug) activates the cGAS-STING signaling pathway of HCC cells. We provide an approach to augment the efficacy of MIT using a signal transducer and activator of transcription 3 (STAT3) inhibitor called napabucasin (NAP). We prepare an aminoethyl anisamide (AEAA)-targeted polyethylene glycol (PEG)-modified poly (lactic-co-glycolic acid) (PLGA)-based nanocarrier for co-delivery of MIT and NAP. The resultant co-nanoformulation can elicit the cGAS-STING-based immune responses to reshape the immunoresistant TME in the mice orthotopically grafted with HCC. Consequently, the resultant co-nanoformulation can promote anti-PD-1 antibody for suppressing HCC development, generating long-term survival, and inhibiting tumor recurrence. This study reveals the potential of MIT to activate the cGAS-STING signaling pathway, and confirms the feasibility of nano co-delivery for MIT and NAP on achieving HCC chemo-immunotherapy.

Asunto(s)

Carcinoma Hepatocelular , Inmunoterapia , Neoplasias Hepáticas , Proteínas de la Membrana , Mitoxantrona , Nucleotidiltransferasas , Factor de Transcripción STAT3 , Mitoxantrona/farmacología , Mitoxantrona/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Animales , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Humanos , Nucleotidiltransferasas/metabolismo , Proteínas de la Membrana/metabolismo , Factor de Transcripción STAT3/metabolismo , Ratones , Inmunoterapia/métodos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Benzofuranos , Naftoquinonas

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AIM: IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. Pregnant IgAN patients are more susceptible to adverse pregnancy outcomes (APO). However, the risk factor for APO and its effects on the long-term renal outcome of pregnant IgAN patients remained unclear. METHODS: We performed a retrospective observational study covering 2003-2019 that included 44 female IgAN patients with pregnancy history to investigate the risk factor for APO and its impact on clinical outcome in IgAN. Renal function outcome and proteinuria remission were evaluated in pregnant IgAN women with and without APO. RESULTS: In this retrospective and observational study, we found that patients with APO exhibited higher levels of serum creatinine and IgM, and lower haemoglobin levels while other clinical characteristics, pathological characteristics and therapy protocol had no significant difference. We found that anaemia and a higher level of serum IgM were independent risk factors for APO. IgAN pregnant women without APO experienced a higher proportion of proteinuria remission than those with APO, but there is no difference in the renal function outcome. CONCLUSION: Pregnant IgAN patients with higher risks, including lower haemoglobin levels and higher IgM levels deserve intensive monitoring, and aggressive therapy to reduce proteinuria should be carried out in pregnant IgAN patients with APO.

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[This retracts the article DOI: 10.3892/ol.2018.9810.].

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Sugammadex (SUG) is a novel antagonist of neuromuscular blocking agents (NMBAs). The NMBA rocuronium is usually employed to obtain better surgical conditions in kidney transplant. Nevertheless, rocuronium has several disadvantages, such as an increased risk of pulmonary complications. Thus, SUG is vital to kidney-transplant surgery. However, because SUG is excreted by the kidneys in prototypes, the pharmacokinetics (PK) may be affected in patients with renal impairment. We developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to monitor SUG in plasma samples to investigate the PK of SUG in kidney-transplant patients. Due to the complexity and limitation of other methods of sample preparation, magnetic solid-phase extraction (MSPE) was adopted to purify samples. Chromatographic separation was obtained using a reversed-phase Polaris® C18 column and gradient elution with 0.1% formic acid (FA) in water as phase A and in methanol (MeOH) as phase B as mobile phases. The transitions 999.7 → 963.9 (m/z) and 1055.7 → 1012.2 (m/z) were used to quantify SUG and ORG26265, respectively, under negative electrospray ionization. A linear calibration curve was achieved in concentrations varying from 100 to 10 000 ng mL-1. The acceptable accuracy varied from 95.7% to 106.4%, and intra- and inter-precision did not exceed 15% (20% at the lower limit of quantitation (LLOQ)). The matrix effect, stability, dilution integrity, and carry-over were validated. This method was applied successfully for the PK study of 13 recipients and 12 donors of kidney transplant after intravenous injection of SUG (2 mL per kg bodyweight).

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Asymmetric enamine alkylation represents a powerful tool for stereoselective C-C bond formation; in contrast, the development of enantioselective enamine acylation remains elusive. Here, we report that a chiral phosphoric acid can render an in-situ-formed enamine to undergo a stereoselective intramolecular α-carbon acylation, providing an alternative approach for the synthesis of useful pyrrolinones and indolinones bearing tetrasubstituted stereocenters. Utilizing an effective integration of the desymmetrization strategy and bifunctional organocatalysis, the first example of enantioselective enamine acylation is achieved by employing readily available aminomalonic esters and cyclic ketones. Instead of reactive and moisture-sensitive acyl chlorides, common esters with low electrophilicity were successfully used as efficient acylating reagents via hydrogen bonding interactions. The utility is demonstrated in the concise and enantioselective synthesis of (+)-LipidGreen I and II. Experimental studies and DFT calculations establish the reaction pathway and the origin of stereocontrol.

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PURPOSE: The purpose of this study was to evaluate and compare the anatomic characteristics of eyes with Fuchs endothelial corneal dystrophy (FECD) with eyes without FECD. METHODS: This study was a retrospective chart review performed at an academic medical center. Patients with FECD were identified through a search of the electronic medical records. Eligible patients underwent Scheimpflug imaging and optical biometry and were compared with age and sex-matched control subjects who underwent similar testing in preparation for cataract surgery. Several measurements of the cornea, anterior chamber, and eyes were evaluated using multivariable linear regression models and multivariable logistic regression models. RESULTS: A total of 404 eyes (202 eyes with FECD and 202 control eyes) were included in this study. Compared with controls, eyes with FECD had shallower AC depths, lower AC volumes, and narrower angles. Conversely, the spherical equivalent before cataract surgery, corneal pachymetry, and corneal volume were higher in eyes with FECD. On Scheimpflug imaging analysis, these anatomical differences were present in FECD eyes with and without corneal edema. After adjusting for sex, these differences remained statistically significant. Shorter axial length was found to be statistically significant in male eyes but not in female eyes with FECD. CONCLUSIONS: This study reports new ocular characteristics in FECD eyes with and without edema. Optical biometry and Scheimpflug imaging established that the anatomic findings in eyes with FECD were not simply due to the larger volume of an edematous cornea but rather unique to eyes with FECD. These findings will provide reliable, normative data for future studies examining surgical, medical, and anatomical factors in FECD.

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Chemotherapy drug efflux, toxic side effects, and low efficacy against drug-resistant cells have plagued safe and efficient cancer theranostics. However, the materials or methods that resolve these defects all-in-one are scarce. Here, a new cancer theranostics strategy is proposed by utilizing changes in lysosomal acidity in cancer cells to activate the membranolytic model to overcome these obstacles together. Therefore, a simple fluorescent anthracene derivative Lyso-Mito is developed, which has a perfect pKa (4.62) value that falls between the pH of lysosomes in cancer and normal cells. Lyso-Mito itself can precisely target and convert the pH perturbation of lysosomes in cancer cells to fluorescent response and membranolytic module activity to accomplish the low drug efflux, weak toxic side effects, and low drug-resistant cancer diagnosis and treatment without linking other functional units or any additional assistance. Hereby, a new cancer theranostics strategy of integrating organelle microenvironment and the membranolytic model is realized.

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BACKGROUND: The Clinical Treatment Score post-5 years (CTS5) is a risk stratification tool used to determine the risk of late recurrence in hormone receptor-positive (HR+), HER2-negative breast cancer (BC). Limited data exist on its use in HR+, HER2-positive (HER2+) BC. PATIENTS AND METHODS: CTS5 was evaluated in HR+, HER2+ BC in the North Central Cancer Treatment Group (NCCTG) N9831 (Alliance) and NSABP B-31 (NRG) trials. RESULTS: A total of 1,862 patients with HR+, HER2+ BC without recurrence 5 years after enrollment were included. Overall, the CTS5 score was significantly associated with recurrence-free survival (RFS), with a hazard ratio (HR) of 1.35 (95% CI, 1.12-1.63; P=.002), but did not reach statistical significance in patients who received trastuzumab (n=829; HR, 1.29; 95% CI, 0.98-1.71; P=.07). CTS5 risk category was not significantly associated with RFS. In patients who received trastuzumab, other variables used in CTS5, including patient age and tumor size, were not significantly associated with RFS. N3 was significantly associated with worse outcomes (HR, 1.86; 95% CI, 1.09-3.17; P=.02) compared with N0-N1. Paradoxically, higher tumor grade was associated with better outcomes after 5 years in the multivariate analysis (HR, 0.71; 95% CI, 0.50-1.00; P=.05). The incidence of recurrences or deaths between years 5 to 10 was 10.6% in the CTS5 low-risk category, 5.6% in the intermediate-risk category, and 9.8% in the high-risk category. CONCLUSIONS: The CTS5 model does not accurately predict the risk of late recurrence in HR+, HER2+ BC treated with adjuvant trastuzumab in the N9831 and B-31 trials. This study underlines the need to develop a new prognostic model to better delineate the risk of late recurrence in patients with HR+, HER2+ BC receiving adjuvant trastuzumab. CLINICALTRIALS: gov identifiers: NCT00005970 (NCCTG N9831) and NCT00004067 (NRG/NSABP B-31).

Asunto(s)

Neoplasias de la Mama , Recurrencia Local de Neoplasia , Receptor ErbB-2 , Receptores de Progesterona , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/metabolismo , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/epidemiología , Pronóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Medición de Riesgo/métodos , Factores de Riesgo , Trastuzumab/uso terapéutico

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Hepatocellular carcinoma (HCC) is a prevalent primary liver cancer often associated with chronic hepatitis B virus infection (CHB) and liver cirrhosis (LC), underscoring the critical need for biomarker discovery to improve patient outcomes. Emerging as a promising avenue for biomarker development, proteomic technology leveraging liquid biopsy from small extracellular vesicles (sEV) offers new insights. Here, we evaluated various methods for sEV isolation and identified polysaccharide chitosan (CS) as an optimal approach. Subsequently, we employed optimized CS-based magnetic beads (Mag-CS) for sEV separation from serum samples of healthy controls, CHB, LC, and HBV-HCC patients. Leveraging data-independent acquisition mass spectrometry coupled with machine learning, we uncovered potential vesicular protein biomarker signatures (KNG1, F11, KLKB1, CAPNS1, CDH1, CPN2, NME2) capable of distinguishing HBV-HCC from CHB, LC, and non-HCC conditions. Collectively, our findings highlight the utility of Mag-CS-based sEV isolation for identifying early detection biomarkers in HBV-HCC.

Asunto(s)

Carcinoma Hepatocelular , Quitosano , Virus de la Hepatitis B , Neoplasias Hepáticas , Proteómica , Humanos , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/virología , Proteómica/métodos , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/sangre , Vesículas Extracelulares/metabolismo , Hepatitis B Crónica/sangre , Biomarcadores de Tumor/sangre , Cirrosis Hepática/sangre , Cirrosis Hepática/virología , Masculino , Femenino

RESUMEN

BACKGROUND: Ureteral stricture (US) is a pathological stenosis in the urinary tract characterized by increased collagen synthesis and inflammation. Autophagy activation has been shown to ameliorate tissue fibrosis and protect against fibrotic diseases. Verapamil has beneficial therapeutic benefits on fibrotic disorders. The pharmacological effects of verapamil on fibroblast autophagy in US and the underlying mechanism need to be investigated further. METHODS: US patients were recruited to isolate scar tissues, hematoxylin-eosin (HE) and Masson trichrome staining were performed to analyze histopathological changes. The US animal model was established and administered with verapamil (0.05 mg/kg) in the drinking water. Transforming growth factor (TGF)-ß1 was adopted to facilitate collagen synthesis in fibroblasts. The mRNA and protein expressions were examined by qRT-PCR, western blot, immunofluorescence and immunohistochemistry. ELISA was adopted to measure interleukin (IL)-1ß and IL-6 levels. Molecular interaction experiments like dual luciferase reporter and chromatin immunoprecipitation (ChIP) assays were performed to analyze the interaction between signal transducers and activators of transcription 3 (STAT3) and RNA polymerase II associated factor 1 (PAF1). RESULTS: Herein, our results revealed that verapamil activated TGF-ß1-treated fibroblast autophagy and inhibited inflammation and fibrosis by repressing Ca2+/calmodulin-dependent protein kinase II (CaMK II) δ-mediated STAT3 activation. Our following tests revealed that STAT3 activated PAF1 transcription. PAF1 upregulation abrogated the regulatory effect of verapamil on fibroblast autophagy and fibrosis during US progression. Finally, verapamil mitigated US in vivo by activating fibroblast autophagy. CONCLUSION: Taken together, verapamil activated TGF-ß1-treated fibroblast autophagy and inhibited fibrosis by repressing the CaMK IIδ/STAT3/PAF1 axis.

Asunto(s)

Autofagia , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Fibroblastos , Fibrosis , Factor de Transcripción STAT3 , Factor de Crecimiento Transformador beta1 , Obstrucción Ureteral , Verapamilo , Verapamilo/farmacología , Verapamilo/uso terapéutico , Autofagia/efectos de los fármacos , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Obstrucción Ureteral/tratamiento farmacológico , Obstrucción Ureteral/complicaciones , Obstrucción Ureteral/metabolismo , Factor de Transcripción STAT3/metabolismo , Humanos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Masculino , Factor de Crecimiento Transformador beta1/metabolismo , Cicatriz/patología , Cicatriz/metabolismo , Cicatriz/tratamiento farmacológico , Cicatriz/etiología , Cicatriz/prevención & control , Modelos Animales de Enfermedad , Inflamación/metabolismo , Transducción de Señal/efectos de los fármacos , Femenino , Persona de Mediana Edad

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The visible light-induced decarboxylative cascade reaction of fluoroalkyl carboxylic acids has been achieved for the efficient synthesis of fluorinated compounds. However, most of the transformations rely on noble iridium metal complex. Herein, a visible light-induced metal-free decarboxylative cascade reaction of fluoroalkyl carboxylic acids has been realized. This protocol features simple operation, transition metal, and good functional group tolerance.

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Enterovirus G (EV-G) belongs to the Picornaviridae family and infects porcine populations worldwide. A total of 20 EV-G genotypes (EV-G1 to EV-G20) have been identified. In this study, we isolated and characterized an EV-G strain, named EV-G/YN29/2022, from the feces of diarrheic pigs. This was the first EV-G6 strain isolated in China. Comparison of the whole genome nucleotide and corresponding amino acid sequences showed that the isolate was more closely related to those of the EV-G6 genotype than other genotypes, with the complete genome sequence similarity ranging from 83.7% (Iba46442) to 84.4% (PEV-B-KOR), and corresponding amino acid homology ranged from 96% (Iba46442) to 96.8% (PEV-B-KOR). Similarly, the VP1 gene and corresponding amino acid sequences of EV-G/YN29/2022 were highly similar to those of the EV-G6 genotype (>82.9% and >94.3%, respectively). Thus, the isolated strain was classified as EV-G6 genotype. This was the first EV-G6 strain isolated in China. Pathogenicity analyses revealed that EV-G/YN29/2022 infection caused mild diarrhea, typical skin lesions, and weight reduction. The strain was mainly distributed to the intestinal tissue but was also found in the brain, mesenteric lymph nodes, spleen, and liver. Our results can be used as a reference to further elucidate the epidemiology, evolution, and pathogenicity of EV-G.

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Porcine pleuropneumonia is one of the respiratory diseases that pigs are susceptible to Actinobacillus pleuropneumoniae (A. pleuropneumoniae), poses a great threat to the global pig industry. Glutathione (GSH) is an important sulfur source, cellular antioxidant and virulence determinant of many pathogenic bacteria. In this study, roles of two HbpA-like proteins HbpA1 and HbpA2 of A. pleuropneumoniae were analyzed. A. pleuropneumoniae mutants without HbpA2 were basically unable to grow in chemically defined medium (CDM) with GSH as the sole sulfur source and had significantly reduced oxidative tolerance; whereas mutation in hbpA1 led to reduced survival under low-temperature environments. Neither HbpA1 nor HbpA2 affects utilization of heme. These two HbpA-like proteins are not associated with the virulence of A. pleuropneumoniae. Our results reveal the correlation of A. pleuropneumoniae HbpA1 and HbpA2 in GSH utilization, highlight the roles of HbpA1 in the cold stress resistance and HbpA2 in the anti-oxidative response. GSH limitation is not a way to attenuate colonization and pathogenicity of A. pleuropneumoniae.

Asunto(s)

Actinobacillus pleuropneumoniae , Proteínas Bacterianas , Glutatión , Estrés Oxidativo , Actinobacillus pleuropneumoniae/patogenicidad , Actinobacillus pleuropneumoniae/genética , Actinobacillus pleuropneumoniae/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Animales , Virulencia , Glutatión/metabolismo , Azufre/metabolismo , Porcinos , Frío , Infecciones por Actinobacillus/microbiología , Infecciones por Actinobacillus/veterinaria , Enfermedades de los Porcinos/microbiología

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Pyruvate kinase M2 (PKM2) is a key metabolic enzyme. Yet, its role in cerebral ischemia injury remains unclear. In this study we demonstrated that PKM2 expression was increased in the microglia after mouse cerebral ischemia-reperfusion (I/R) injury. We found that microglial polarization-mediated pro-inflammatory effect was mediated by PKM2 after cerebral I/R. Mechanistically, our results revealed that nuclear PKM2 mediated ischemia-induced microglial polarization through association with acetyl-H3K9. Hif-1α mediated the effect of nuclear PKM2/histone H3 on microglial polarization. PKM2-dependent Histone H3/Hif-1α modifications contributed the expression of CCL2 and induced up-regulation of microglial polarization in peri-infarct, resulting in neuroinflammation. Inhibiting nuclear translocation of microglial PKM2 reduced ischemia-induced pro-inflammation and promoted neuronal survival. Together, this study identifies nucleus PKM2 as a crucial mediator for regulating ischemia-induced neuroinflammation, suggesting PKM2 as a potential therapeutic target in ischemic stroke.

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Ratones Endogámicos C57BL , Microglía , Enfermedades Neuroinflamatorias , Piruvato Quinasa , Daño por Reperfusión , Animales , Microglía/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Masculino , Piruvato Quinasa/metabolismo , Ratones , Enfermedades Neuroinflamatorias/patología , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/metabolismo , Isquemia Encefálica/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Regulación hacia Abajo , Núcleo Celular/metabolismo , Histonas/metabolismo , Neuroprotección , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Células Cultivadas , Modelos Animales de Enfermedad , Neuronas/metabolismo , Neuronas/patología , Hormonas Tiroideas/metabolismo

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Sludge pretreatment plays a crucial role in solubilizing particulate matters to release organic matter for subsequent anaerobic fermentation (AF). This study innovatively combines radio frequency (RF) heating and alkaline treatment, and finds that the combined pretreatment achieved a sludge disintegration rate of 35.11 %, which is 15.19 % and 8.48 % higher than single RF or alkaline pretreatment. The dissociated ions from the alkali are conducive to RF action on sludge. Furthermore, the combined pretreatment significantly benefits the subsequent AF experiments, resulting in a 9-fold increase in volatile fatty acids production. Considering cost-effectiveness, the optimal operating condition is a 10-minute RF treatment at pH 10 with a total cost of 4.35 × 10-3 dollars per kg soluble chemical oxygen demand (SCOD) increased. These findings provide a foundational basis for the development of a novel technology for sludge pretreatment.

Asunto(s)

Ácidos Grasos Volátiles , Fermentación , Aguas del Alcantarillado , Anaerobiosis , Ondas de Radio , Concentración de Iones de Hidrógeno , Álcalis/farmacología , Análisis de la Demanda Biológica de Oxígeno , Calefacción , Calor

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BACKGROUND: The mpox pandemic has caused widespread public concern around the world. The spread of misinformation through the internet and social media could lead to an infodemic that poses challenges to mpox control. OBJECTIVE: This review aims to summarize mpox-related infodemiology studies to determine the characteristics, influence, prevention, and control measures of the mpox infodemic and propose prospects for future research. METHODS: The scoping review was conducted based on a structured 5-step methodological framework. A comprehensive search for mpox-related infodemiology studies was performed using PubMed, Web of Science, Embase, and Scopus, with searches completed by April 30, 2024. After study selection and data extraction, the main topics of the mpox infodemic were categorized and summarized in 4 aspects, including a trend analysis of online information search volume, content topics of mpox-related online posts and comments, emotional and sentiment characteristics of online content, and prevention and control measures for the mpox infodemic. RESULTS: A total of 1607 articles were retrieved from the databases according to the keywords, and 61 studies were included in the final analysis. After the World Health Organization's declaration of an mpox public health emergency of international concern in July 2022, the number of related studies began growing rapidly. Google was the most widely used search engine platform (9/61, 15%), and Twitter was the most used social media app (32/61, 52%) for researchers. Researchers from 33 countries were concerned about mpox infodemic-related topics. Among them, the top 3 countries for article publication were the United States (27 studies), India (9 studies), and the United Kingdom (7 studies). Studies of online information search trends showed that mpox-related online search volume skyrocketed at the beginning of the mpox outbreak, especially when the World Health Organization provided important declarations. There was a large amount of misinformation with negative sentiment and discriminatory and hostile content against gay, bisexual, and other men who have sex with men. Given the characteristics of the mpox infodemic, the studies provided several positive prevention and control measures, including the timely and active publishing of professional, high-quality, and easy-to-understand information online; strengthening surveillance and early warning for the infodemic based on internet data; and taking measures to protect key populations from the harm of the mpox infodemic. CONCLUSIONS: This comprehensive summary of evidence from previous mpox infodemiology studies is valuable for understanding the characteristics of the mpox infodemic and for formulating prevention and control measures. It is essential for researchers and policy makers to establish prediction and early warning approaches and targeted intervention methods for dealing with the mpox infodemic in the future.

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Medios de Comunicación Sociales , Humanos , Medios de Comunicación Sociales/estadística & datos numéricos , Pandemias/prevención & control , Internet

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High-quality development of water resources supports high-quality socio-economic development. High-quality development connects high-quality life, and clarifying the key management contents of small watersheds plays an important role in building ecologically clean small watersheds and promoting regional production and life. Previous research on pollution loads has focused on examining the impact of various external drivers on pollution loads but still lacks research on the impact of changes in pollution sources themselves on pollution loads. In this study, sensitivity analysis was used to determine the impact of changes from different sources on the total pollution loads, which can recognize the critical pollution sources. We first employed the pollutant discharge coefficient method to quantify non-point source pollution loads in the small watershed in the upstream Tuojiang River basin from 2010 to 2021. Then, combination sensitivity analysis with Getis-Ord Gi* was used to identify the critical sources and their crucial areas at the global, districts (counties), and towns (streets) scales, respectively. The results indicate: (1) The pollution loads of COD, NH3-N, TN, and TP all show a decreasing trend, reducing by 18.3%, 16.2%, 18.6%, and 28.1% from 2010 to 2021, respectively; (2) Livestock and poultry breeding pollution source is the most critical source for majority areas across watershed; (3) High-risk areas are mainly concentrated in Jingyang district and its subordinate towns (streets). There is a trend of low-pollution risk areas transitioning to high-pollution risk areas, with high-risk areas predominantly concentrated in the southeast and exhibiting a noticeable phenomenon of pollution load spilling around. This study can promote other similar small watersheds, holding significant importance for non-point source pollution control in small watersheds.

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Monitoreo del Ambiente , Ríos , Contaminantes Químicos del Agua , China , Ríos/química , Monitoreo del Ambiente/métodos , Contaminantes Químicos del Agua/análisis , Medición de Riesgo , Contaminación Química del Agua/estadística & datos numéricos , Nitrógeno/análisis , Fósforo/análisis , Análisis Espacio-Temporal

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BACKGROUND: Anticoagulation and antiplatelet therapy effectively inhibit neointimal hyperplasia (NIH) in both arterial and venous systems but not in arteriovenous fistulae (AVF). The main site of AVF failure is the juxta-anastomotic area that is characterized by disturbed flow compared with laminar flow in the arterial inflow and the venous outflow. OBJECTIVES: We hypothesized that early thrombus formation is required for eccentric and heterogeneous NIH in the presence of disturbed flow. METHODS: Needle puncture and sutured AVF were created in C57BL/6 mice, in PF4-Cre × mT/mG reporter mice, and in Wistar rats. Human AVF samples were second-stage basilic vein transpositions. The tissues were examined by histology, immunofluorescence, immunohistochemistry, and en face staining. RESULTS: In the presence of disturbed flow, both mouse and human AVF showed eccentric and heterogeneous NIH. Maladapted vein wall was characterized by eccentric and heterogeneous neointima that was composed of a different abundance of thrombus and smooth muscle cells. PF4-cre × mT/mG reporter mice AVF showed that green fluorescent protein-labeled platelets deposit on the wall directly facing the fistula exit with endothelial cell loss and continue to accumulate in the presence of disturbed flow. Neither disturbed flow with limited endothelial cell loss nor nondisturbed flow induced heterogeneous neointima in different animal models. CONCLUSION: Early thrombus contributes to late heterogeneous NIH in the presence of disturbed flow. Disturbed flow, large area of endothelial cell loss, and thrombus formation are critical to form eccentric and heterogeneous NIH. Categorization of adapted or maladapted walls may be helpful for therapy targeting heterogeneous NIH.

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BACKGROUND: Cerebral ischemia is characterized by its rapid onset and high rates of recurrence, morbidity, and mortality, with blood-brain barrier (BBB) permeability playing a vital role in brain injury. Therefore, it is important to understand the molecular mechanism which regulates the BBB during cerebral ischemia. MATERIALS AND METHODS: An in vitro model of oxygen-glucose deprivation (OGD) and an in vivo model of cerebral ischemia/reperfusion (I/R) were constructed. PD-1 overexpression vectors and vectors containing si-RNA were transfected and injected into in vitro and in vivo models. Western blotting, real-time quantitative PCR (qPCR), immunofluorescence (IF) analysis, and immunohistochemical staining were employed to evaluate the expression levels of programmed cell death-1 (PD-1), microglia M1 and M2 biomarkers, and tight junction proteins. Flow cytometry and ELISA were used to measure the levels of pro-inflammatory cytokines. The BBB permeability of brain tissues was evaluated by Evans blue dye (EBD) extravasation and transendothelial electrical resistance (TEER). Brain water content was measured to assess the extent of inflammatory exudation. The infarct volume and neurological severity score (NSS) were used to assess the severity of brain injury. Brain cell apoptosis was assessed by the TUNEL assay and hematoxylin-eosin (H&E) staining. RESULTS: PD-1 helped to convert the microglia M1 phenotype to the M2 phenotype and to reduce BBB permeability both in vitro and in vivo. Overexpression of PD-1 promoted a shift of the M1 phenotype to the M2 phenotype and reduced BBB permeability via the ERK and p38 MAPK signaling pathways. PD-1 reduced inflammatory exudation, BBB permeability, cell apoptosis, and brain injury in vivo. CONCLUSION: Our present study verified that PD-1 exerts an anti-inflammatory effect by converting the microglia M1 phenotype to the M2 phenotype, reducing BBB permeability, and thereby relieves brain injury caused by cerebral ischemia. PD-1 is potential therapeutic target for brain injury caused by cerebral ischemia.

Asunto(s)

Barrera Hematoencefálica , Isquemia Encefálica , Sistema de Señalización de MAP Quinasas , Microglía , Receptor de Muerte Celular Programada 1 , Daño por Reperfusión , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Animales , Microglía/metabolismo , Daño por Reperfusión/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Isquemia Encefálica/metabolismo , Masculino , Ratones , Sistema de Señalización de MAP Quinasas/fisiología , Apoptosis/fisiología , Ratones Endogámicos C57BL , Polaridad Celular/fisiología

RESUMEN

Gynecological cancer significantly affect the health of women. This review aimed to describe the global patterns and trends in the survival of patients with gynecological cancers. We searched PubMed, Embase, Web of Science, SinoMed, and SEER for survival analyses of cancer registration data of cervical, endometrial, and ovarian cancers published between 1980 and 2022. Globally, the highest 5-year observed survival rate for cervical cancer was 76.5% in Anshan, Liaoning, China (2008-2017). The 5-year observed survival rates of endometrial and ovarian cancers were higher in Finland (1995-1999, 82.5%) and Singapore (1988-1992, 62.0%). The 5-year relative survival rate of cervical cancer patients was higher in Haining, Zhejiang, China (2011-2014, 85.8%). Korea ranked first at 89.0% and 64.5% for endometrial and ovarian cancers, respectively. Survival rates have improved for cervical, endometrial, and ovarian cancers. Patients aged ≥ 75 years and those with advanced-stage disease had the worst 5-year survival rates. Survival rates were better for squamous cell carcinoma in cervical cancer, for endometrial carcinoma and mucinous adenocarcinoma in endometrial cancer, and for germ cell and sex-cord stromal tumors in ovarian cancer. Over the past four decades, the survival rates of gynecological cancers have increased globally, with notable increases in cervical and endometrial cancers. Survival rates are higher in developed countries, with a slow-growing trend. Future studies should focus on improving survival, especially in ovarian cancer patients.

Asunto(s)

Neoplasias de los Genitales Femeninos , Humanos , Femenino , Neoplasias de los Genitales Femeninos/mortalidad , Neoplasias de los Genitales Femeninos/epidemiología , Sistema de Registros , Tasa de Supervivencia , Neoplasias del Cuello Uterino/mortalidad , Neoplasias del Cuello Uterino/epidemiología