RESUMEN
We analyzed the risk factors of mortality for patients with pulmonary tuberculosis under the Directly Observed Treatment Shortcourse (DOTS) and established a predictive nomogram for the risk of mortality. The retrospective cohort analysis was conducted on the treatment outcomes of 11207 tuberculosis patients in the tuberculosis management information system in Tianjin from 2014 to 2019. Based on the multivariable unconditional logistic regression, we analyzed the risk factors of mortality in patients with pulmonary TB and established the death risk prediction nomogram. We further applied cross-validation and the receiver operating characteristic (ROC) curve to explore the efficiency of the nomogram. There were 10,697 patients in the survival group and 510 in the mortality group who had successfully initiated DOTS, and the mortality rate was 4.55%. Multivariable logistic regression analysis showed that age, male, relapse cases, first sputum positivity, patient delay, and HIV-positive were independent risk factors for pulmonary TB death. The calibration curve shows that the average absolute error between the predicted mortality risk and the actual death risk is 0.003. The ROC curve shows that the area under the curve where the line-up model predicts the risk of death is 0.816 (95% CI: 0.799â¼0.832). The nomogram model based on independent risk factors of mortality in TB patients shows good discrimination and accuracy, with potentially high clinical value in screening patients with a high risk of death, which could be useful for setting the interventional strategies in patients with tuberculosis who had successfully initiated DOTS.
Asunto(s)
Nomogramas , Tuberculosis Pulmonar , Humanos , Masculino , Estudios Retrospectivos , Resultado del Tratamiento , Estudios de Cohortes , Curva ROC , Tuberculosis Pulmonar/tratamiento farmacológicoRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) damages lung epithelial stem/progenitor cells. Ideal anti-SARS-CoV-2 drug candidates should be screened to prevent secondary injury to the lungs. Here, we propose that in vitro three-dimensional organoid and lung injury repair mouse models are powerful models for the screening antiviral drugs. Lung epithelial progenitor cells, including airway club cells and alveolar type 2 (AT2) cells, were co-cultured with supportive fibroblast cells in transwell inserts. The organoid model was used to evaluate the possible effects of hydroxychloroquine, which is administered as a symptomatic therapy to the coronavirus disease 2019 (COVID-19) patients, on the function of mouse lung stem/progenitor cells. Hydroxychloroquine was observed to promote the self-renewal of club cells and differentiation of ciliated and goblet cells in vitro. Additionally, it inhibited the self-renewal ability of AT2 cells in vitro. Naphthalene- or bleomycin-induced lung injury repair mouse models were used to investigate the in vivo effects of hydroxychloroquine on the regeneration of club and AT2 cells, respectively. The naphthalene model indicated that the proliferative ability and differentiation potential of club cells were unaffected in the presence of hydroxychloroquine. The bleomycin model suggested that hydroxychloroquine had a limited effect on the proliferation and differentiation abilities of AT2 cells. These findings suggest that hydroxychloroquine has limited effects on the regenerative ability of epithelial stem/progenitor cells. Thus, stem/progenitor cell-derived organoid technology and lung epithelial injury repair mouse models provide a powerful platform for drug screening, which could possibly help end the pandemic.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Lesión Pulmonar , Animales , Bleomicina , Diferenciación Celular , Modelos Animales de Enfermedad , Hidroxicloroquina/farmacología , Pulmón , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/tratamiento farmacológico , Ratones , Naftalenos , Organoides , Regeneración , SARS-CoV-2 , TecnologíaRESUMEN
Colon cancer, also known as colorectal carcinoma (CRC), remains to be one of the most mainsprings of cancer-produced deaths entire world. We planned to grab the role and possible biological cause of a long noncoding RNA, namely, small nucleolar RNA host gene 15 (SNHG15), in CRC. The mRNA level of SNHG15 in CRC tissues and cells was detected, followed by investigating the impacts of the depression of SNHG15 on CRC cell proliferation (viability and colony-forming), apoptosis, migration, and invasion. Moreover, the association between SNHG15 and miR-141 and the correlation between miR-141 and SIRT1 were also explored. Besides, the influences of dysregulated SNHG15 on the Wnt/ß-catenin signal-related proteins were determined. SNHG15 was highly expressed in CRC tissues and cells. Depression of SNHG15 depressed proliferation, enhanced apoptosis, and repressed the migration and invasion of CRC cells. In addition, SNHG15 presented a downside tendency on regulating miR-141, and the miR-141 inhibitor dramatically changeover the impacts of SNHG15 depression on tumor growth and metastasis. Moreover, SIRT1 was verified as a functional target of miR-141 in CRC cells. Besides, the suppression of SNHG15 remarkably controlled activating the Wnt/ß-catenin signals, which was reversed after inhibiting miR-141 at the same time. The investigated results in this research revealed that the increased expression of SNHG15 may enhance the process of CRC by acting as a ceRNA in regulating SIRT1 expression by sponging miR-141. Thus we propose that Wnt/ß-catenin signals may be a downriver regulator in mediating the impacts of SNHG15 in CRC and SNHG15-miR-141-SIRT1 axis may pave a new sight in explaining the biological processes of CRC.
Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , MicroARNs/genética , ARN Largo no Codificante/genética , Sirtuina 1/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Basal progenitor cells are crucial for the establishment and maintenance of the tracheal epithelium. However, it remains unclear how these progenitor cells are specified during foregut development. Here, we found that ablation of the Wnt chaperone protein Gpr177 (also known as Wntless) in mouse tracheal epithelium causes a significant reduction in the number of basal progenitor cells accompanied by cartilage loss in Shh-Cre;Gpr177loxp/loxp mutants. Consistent with the association between cartilage and basal cell development, Nkx2.1+p63+ basal cells are co-present with cartilage nodules in Shh-Cre;Ctnnb1DM/loxp mutants, which maintain partial cell-cell adhesion but not the transcription regulation function of ß-catenin. More importantly, deletion of Ctnnb1 in the mesenchyme leads to the loss of basal cells and cartilage, concomitant with reduced transcript levels of Fgf10 in Dermo1-Cre;Ctnnb1loxp/loxp mutants. Furthermore, deletion of Fgf receptor 2 (Fgfr2) in the epithelium also leads to significantly reduced numbers of basal cells, supporting the importance of Wnt/Fgf crosstalk in early tracheal development.
Asunto(s)
Factor 10 de Crecimiento de Fibroblastos/metabolismo , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Mucosa Respiratoria/embriología , Tráquea/embriología , Vía de Señalización Wnt/fisiología , Animales , Factor 10 de Crecimiento de Fibroblastos/genética , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Ratones , Ratones Mutantes , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Mucosa Respiratoria/citología , Tráquea/citología , Proteína 1 Relacionada con Twist/genética , Proteína 1 Relacionada con Twist/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
BACKGROUND: Human infections with the H7N9 virus could lead to lung damage and even multiple organ failure, which is closely associated with a high mortality rate. However, the metabolic basis of such systemic alterations remains unknown. METHODS: This study included hospitalized patients (nâ¯=â¯4) with laboratory-confirmed H7N9 infection, healthy controls (nâ¯=â¯9), and two disease control groups comprising patients with pneumonia (nâ¯=â¯9) and patients with pneumonia who received steroid treatment (nâ¯=â¯10). One H7N9-infected patient underwent lung biopsy for histopathological analysis and expression analysis of genes associated with lung homeostasis. H7N9-induced systemic alterations were investigated using metabolomic analysis of sera collected from the four patients by using ultra-performance liquid chromatography-mass spectrometry. Chest digital radiography and laboratory tests were also conducted. FINDINGS: Two of the four patients did not survive the clinical treatments with antiviral medication, steroids, and oxygen therapy. Biopsy revealed disrupted expression of genes associated with lung epithelial integrity. Histopathological analysis demonstrated severe lung inflammation after H7N9 infection. Metabolomic analysis indicated that fatty acid metabolism may be inhibited during H7N9 infection. Serum levels of palmitic acid, erucic acid, and phytal may negatively correlate with the extent of lung inflammation after H7N9 infection. The changes in fatty acid levels may not be due to steroid treatment or pneumonia. INTERPRETATION: Altered structural and secretory properties of the lung epithelium may be associated with the severity of H7N9-infection-induced lung disease. Moreover, fatty acid metabolism level may predict a fatal outcome after H7N9 virus infection.
Asunto(s)
Ácidos Grasos/metabolismo , Subtipo H7N9 del Virus de la Influenza A/patogenicidad , Gripe Humana/virología , Pulmón/patología , Anciano , Cromatografía Líquida de Alta Presión , Femenino , Hospitalización , Humanos , Oxigenoterapia Hiperbárica , Gripe Humana/metabolismo , Gripe Humana/patología , Gripe Humana/terapia , Masculino , Metabolómica/métodos , Persona de Mediana Edad , Esteroides/uso terapéutico , Resultado del TratamientoRESUMEN
Chronic inflammation is associated with an increased number of leukocytes in the spleen, which are then redirected to the site of inflammation. However, it remains unknown how leukocyte recruitment is regulated. Herein, chronic inflammation was induced by intraperitoneal injection of pristane into mice. Leukocytes in the spleen or in the peritoneal cavity were quantified by flow cytometry. We found that the loss of IL-6 decreased macrophage recruitment to the spleen and the peritoneal cavity during pristane-induced inflammation. The loss of TNFα delayed the recruitment of neutrophils and macrophages to the spleen and inhibited the recruitment of neutrophils, macrophages, B cells, and T cells. The recruitment of neutrophils and macrophages into the spleen or peritoneal cavity was largely inhibited in the absence of LTα. The loss of TNFα receptor 1/2 resulted in reduced recruitment of neutrophils, macrophages, and dendritic cells into the spleen, but only neutrophil recruitment was inhibited in the peritoneal cavity. Similarly, a lack of B cells significantly impeded the recruitment of neutrophils, macrophages, and dendritic cells to the spleen. However, only macrophage recruitment was inhibited in the absence of T cells in the spleen. These data provide insight into the development of chronic inflammation induced by noninfectious substances.