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Patients with RET fusions represent 1-2% of all cases of non-small cell lung cancer (NSCLC), the majority of whom are younger, and are extremely rare in the elderly. As a selective RET inhibitor, pralsetinib has been shown to be efficacious and well-tolerated in patients with RET-fusion NSCLC. Nevertheless, there are currently insufficient data available for assessing the activity and safety of pralsetinib in elderly patients with NSCLC. Herein, we report an 81-year-old NSCLC patient with KIF5B-RET fusion, who achieved stable disease for more than 9 months at a low-dose of pralsetinib as second-line therapy. Of particular note, during pralsetinb therapy, his clinical course was complicated by cryptococcal pneumonia and staphylococcus aureus lung abscess. Our study demonstrates that pralsetinib is an effective therapeutic option that provides survival benefits for elderly NSCLC patients harboring RET fusion. However, during pralsetinb therapy, treating physicians should maintain particular vigilance for the increased risk of infection, especially in elderly patients.
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Hyperhomocysteinemia (HHcy) is an established and potent independent risk factor for degenerative diseases, including cardiovascular disease (CVD), Alzheimer disease, type II diabetes mellitus, and chronic kidney disease. HHcy has been shown to inhibit proliferation and promote inflammatory responses in endothelial cells (EC), and impair endothelial function, a hallmark for vascular injury. However, metabolic processes and molecular mechanisms mediating HHcy-induced endothelial injury remains to be elucidated. This study examined the effects of HHcy on the expression of microRNA (miRNA) and mRNA in human aortic EC treated with a pathophysiologically relevant concentration of homocysteine (Hcy 500 µM). We performed a set of extensive bioinformatics analyses to identify HHcy-altered metabolic and molecular processes. The global functional implications and molecular network were determined by Gene Set Enrichment Analysis (GSEA) followed by Cytoscape analysis. We identified 244 significantly differentially expressed (SDE) mRNA, their relevant functional pathways, and 45 SDE miRNA. HHcy-altered SDE inversely correlated miRNA-mRNA pairs (45 induced/14 reduced mRNA) were discovered and applied to network construction using an experimentally verified database. We established a hypothetical model to describe the biochemical and molecular network with these specified miRNA/mRNA axes, finding: 1) HHcy causes metabolic reprogramming by increasing glucose uptake and oxidation, by glycogen debranching and NAD+/CoA synthesis, and by stimulating mitochondrial reactive oxygen species production via NNT/IDH2 suppression-induced NAD+/NADP-NADPH/NADP+ metabolism disruption; 2) HHcy activates inflammatory responses by activating inflammasome-pyroptosis mainly through ↓miR193bâ↑CASP-9 signaling and by inducing IL-1ß and adhesion molecules through the ↓miR29câ↑NEDD9 and the ↓miR1256â↑ICAM-1 axes, as well as GPCR and interferon α/ß signaling; 3) HHcy promotes cell degradation by the activation of lysosome autophagy and ubiquitin proteasome systems; 4) HHcy causes cell cycle arrest at G1/S and S/G2 transitions, suppresses spindle checkpoint complex and cytokinetic abscission, and suppresses proliferation through ↓miRNA335/↑VASH1 and other axes. These findings are in accordance with our previous studies and add a wealth of heretofore-unexplored molecular and metabolic mechanisms underlying HHcy-induced endothelial injury. This is the first study to consider the effects of HHcy on both global mRNA and miRNA expression changes for mechanism identification. Molecular axes and biochemical processes identified in this study are useful not only for the understanding of mechanisms underlying HHcy-induced endothelial injury, but also for discovering therapeutic targets for CVD in general.
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Diabetes Mellitus Tipo 2 , Hiperhomocisteinemia , Células Endoteliales , Homocisteína , Humanos , Hiperhomocisteinemia/genética , Oxidación-Reducción , Transducción de SeñalRESUMEN
BACKGROUND: Considerable research has been devoted to examining the mental health conditions of patients with COVID-19 and medical staff attending to these patients during the COVID-19 pandemic. However, there are few insights concerning how the pandemic may take a toll on the mental health of the general population, and especially of nonpatients (ie, individuals who have not contracted COVID-19). OBJECTIVE: This study aimed to investigate the association between social media use and mental health conditions in the general population based on a national representative sample during the peak of the COVID-19 outbreak in China. METHODS: We formed a national representative sample (N=2185) comprising participants from 30 provinces across China, who were the first to experience the COVID-19 outbreak in the world. We administered a web-based survey to these participants to analyze social media use, health information support received via social media, and possible psychiatric disorders, including secondary traumatic stress (STS) and vicarious trauma (VT). RESULTS: Social media use did not cause mental health issues, but it mediated the levels of traumatic emotions among nonpatients. Participants received health information support via social media, but excessive social media use led to elevated levels of stress (ß=.175; P<.001), anxiety (ß=.224; P<.001), depression (ß=.201; P<.001), STS (ß=.307; P<.001), and VT (ß=.688; P<.001). Geographic location (or geolocation) and lockdown conditions also contributed to more instances of traumatic disorders. Participants living in big cities were more stressed than those living in rural areas (P=.02). Furthermore, participants from small cities or towns were more anxious (P=.01), stressed (P<.001), and depressed (P=.008) than those from rural areas. Obtaining more informational support (ß=.165; P<.001) and emotional support (ß=.144; P<.001) via social media increased their VT levels. Peer support received via social media increased both VT (ß=.332; P<.001) and STS (ß=.130; P<.001) levels. Moreover, geolocation moderated the relationships between emotional support on social media and VT (F2=3.549; P=.029) and the association between peer support and STS (F2=5.059; P=.006). Geolocation also interacted with health information support in predicting STS (F2=5.093; P=.006). CONCLUSIONS: COVID-19 has taken a severe toll on the mental health of the general population, including individuals who have no history of psychiatric disorders or coronavirus infection. This study contributes to the literature by establishing the association between social media use and psychiatric disorders among the general public during the COVID-19 outbreak. The study findings suggest that the causes of such psychiatric disorders are complex and multifactorial, and social media use is a potential factor. The findings also highlight the experiences of people in China and can help global citizens and health policymakers to mitigate the effects of psychiatric disorders during this and other public health crises, which should be regarded as a key component of a global pandemic response.
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Ansiedad/epidemiología , COVID-19/epidemiología , Salud Mental/estadística & datos numéricos , Medios de Comunicación Sociales/estadística & datos numéricos , Encuestas y Cuestionarios , Adulto , COVID-19/psicología , China/epidemiología , Depresión/epidemiología , Brotes de Enfermedades , Femenino , Humanos , Masculino , Pandemias , Estrés Psicológico/epidemiologíaRESUMEN
Pirfenidone has been widely used in the treatment of idiopathic pulmonary fibrosis (IPF). However, the role of pirfenidone in LPS-induced acute lung injury (ALI) remains unclear. This study aims to investigate the protective effects of pirfenidone in ALI and to explore its underlying mechanism. Pirfenidone clearly reduces LPS-triggered ALI as indicated by significant pathological alterations, reduced oxidative stress and inflammatory responses in vivo. Furthermore, pirfenidone also blocks apoptosis of LPS-induced alveolar epithelial type II (ATII) cells through inhibition of endoplasmic reticulum (ER) stress and mitochondrial injury in vivo and in vitro. A lower expression level of BAP31, an ER transmembrane protein, was found to be associated with ALI followed LPS challenge. The reintroduction of BAP31 blunted LPS induced ER stress and mitochondrial damage and therefore alleviated ATII cell apoptosis, which correlated with pirfenidone treatment. Knockdown of BAP31 expression in pirfenidone treated ATII cells re-activated ER stress, mitochondrial damage and followed cellular apoptosis. In summary, this study confirms the beneficial effect of pirfenidone on ER stress and mitochondrial dysfunction mediated apoptosis via upregulation of BAP31. Our results demonstrated that pirfenidone may be considered as a potential agent for the treatment of ALI in the future.
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Lesión Pulmonar Aguda/tratamiento farmacológico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Proteínas de la Membrana/agonistas , Piridonas/farmacología , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Lesión Pulmonar Aguda/inmunología , Lesión Pulmonar Aguda/patología , Células Epiteliales Alveolares , Animales , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Células Cultivadas , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico/inmunología , Técnicas de Silenciamiento del Gen , Humanos , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/inmunología , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/inmunología , Mitocondrias/patología , Cultivo Primario de Células , Alveolos Pulmonares/inmunología , Alveolos Pulmonares/patología , Piridonas/uso terapéutico , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/patologíaRESUMEN
We used 335 Mycobacterium tuberculosis strains from 2010 National Epidemiologic Survey for TB in China and performed comparative sequence analysis of 38â¯kDa gene after amplification. From the results, we found that there were 5.07% M.tuberculosis strains that demonstrated genetic diversity of 38â¯kDa in China, and 2.99% strains showed polymorphism of the 38â¯kDa antigen, and this may be the reason for changes in the antigen produced, which may in turn cause alterations of related functions, thereby allowing immune evasion.
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Antígenos Bacterianos/genética , Variación Genética , Mycobacterium tuberculosis/genética , Secuencia de Aminoácidos , China , Epítopos de Linfocito B/genética , Epítopos de Linfocito T/genética , Humanos , Evasión Inmune/genética , Datos de Secuencia Molecular , Mutación , Mycobacterium tuberculosis/inmunología , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: The study aimed to identify the potential biomarkers in pulmonary tuberculosis (TB) and TB latent infection based on bioinformatics analysis. METHODS: The microarray data of GSE57736 were downloaded from Gene Expression Omnibus database. A total of 7 pulmonary TB and 8 latent infection samples were used to identify the differentially expressed genes (DEGs). The protein-protein interaction (PPI) network was constructed by Cytoscape software. Then network-based neighborhood scoring analysis was performed to identify the important genes. Furthermore, the functional enrichment analysis, correlation analysis and logistic regression analysis for the identified important genes were performed. RESULTS: A total of 1084 DEGs were identified, including 565 down- and 519 up-regulated genes. The PPI network was constructed with 446 nodes and 768 edges. Down-regulated genes RIC8 guanine nucleotide exchange factor A (RIC8A), basic leucine zipper transcription factor, ATF-like (BATF) and microtubule associated monooxygenase, calponin LIM domain containing 1 (MICAL1) and up-regulated genes ATPase, Na+/K+ transporting, alpha 4 polypeptide (ATP1A4), histone cluster 1, H3c (HIST1H3C), histone cluster 2, H3d (HIST2H3D), histone cluster 1, H3e (HIST1H3E) and tyrosine kinase 2 (TYK2) were selected as important genes in network-based neighborhood scoring analysis. The functional enrichment analysis results showed that these important DEGs were mainly enriched in regulation of osteoblast differentiation and nucleoside triphosphate biosynthetic process. The gene pairs RIC8A-ATP1A4, HIST1H3C-HIST2H3D, HIST1H3E-BATF and MICAL1-TYK2 were identified with high positive correlations. Besides, these genes were selected as significant feature genes in logistic regression analysis. CONCLUSIONS: The genes such as RIC8A, ATP1A4, HIST1H3C, HIST2H3D, HIST1H3E, BATF, MICAL1 and TYK2 may be potential biomarkers in pulmonary TB or TB latent infection.
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Many studies have reported the association between the matrix metalloproteinase (MMP) polymorphisms and lung cancer susceptibility, but the results were inconclusive. We conducted a meta-analysis, using a comprehensive strategy based on the logistic regression and a model-free approach, to derive a more precise estimation of the relationship between MMP1, MMP2, MMP9 and MMP13 polymorphisms with lung cancer risk. A total of 22 case-control studies including 8202 cases and 7578 controls were included in this meta-analysis. For MMP1-1607 1G/2G, increased lung cancer risk was found among Asians in additive model(OR = 1.34, 95%CI:1.18-1.53) and with model-free approach(ORG = 1.41, 95%CI:1.21-1.65). For MMP2-1306 C/T and -735 C/T, based on the model-free approach, a significantly reduced risk was found in Asians(MMP2-1306 C/T:ORG = 0.49,95%CI:0.42-0.57; MMP2-735 C/T: ORG = 0.71, 95%CI:0.61-0.84). For MMP9-1562 C/T, a significantly increased risk was found among Asians(OR = 2.73, 95%CI:1.74-4.27) with model-free approach. For MMP13-77A/G, there was no association between this polymorphism and lung cancer risk in the recessive model(OR = 1.02, 95%CI:0.83-1.26) and with the model-free approach(ORG = 0.95, 95%CI:0.76-1.17). Therefore, this meta-analysis suggests that the MMP1-1607 1G/2G, MMP2-1306 C/T, MMP2-735 C/T, MMP9 -1562 C/T polymorphisms were risk factors for lung cancer among Asians, while MMP13 -77A/G polymorphism was not associated with lung cancer risk.
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Neoplasias Pulmonares/enzimología , Metaloproteasas/genética , Polimorfismo de Nucleótido Simple , Humanos , Neoplasias Pulmonares/genética , Análisis de RegresiónRESUMEN
OBJECTIVE: To analyze the clinical features and differential diagnosis of pulmonary infection with Mycobacterium massiliense (M. massiliense). METHODS: The clinical manifestations and laboratory test results of our patient were analyzed and the strain isolated from the patient was tested by bacteriological and molecular methods. The partial gene fragments of rpoB and hsp65 were amplified by PCR, sequenced and compared with GeneBank database in NCBI for identification of Mycobacterium species. RESULTS: The patient was a 72 year old female, who had been admitted to hospital several times because of recurrent respiratory symptoms which had failed to improve upon treatment. This time, pulmonary infection with M. massiliense was confirmed by clinical manifestation and laboratory results. M. massilence isolated from the sputum of our patient was confirmed by bacteriological and molecular methods. The results of specific segments of rpoB and hsp65 tested by PCR and sequence analysis, and compared with that of mycobacterium in NCBI, showed that the DNA homology was 100% and 99% respectively. The results of drug sensitivity test showed that this strain was resistant to multiple drugs. According to the results of drug susceptibility tests and the condition of the patient, therapy with cefoxitin sodium and amikacin was used and the drugs were effective. CONCLUSIONS: The clinical manifestations and the chest imaging of pulmonary infection with M. massiliens were similar to those of Mycobacterium tuberculosis, which can be differentiated by laboratory tests.
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Enfermedades Pulmonares/microbiología , Infecciones por Mycobacterium/microbiología , Mycobacterium , Anciano , ADN Bacteriano/genética , Femenino , Humanos , Pruebas de Sensibilidad Microbiana , Mycobacterium/genética , Mycobacterium/aislamiento & purificaciónRESUMEN
Mechanical ventilation is an indispensable life-support modality for critically ill patients with acute lung injury or acute respiratory distress syndrome. Unfortunately, mechanical ventilation even the protective ventilation strategies may evoke ventilator-induced lung injury. Heme oxygenase-1 (HO-1) has recently exhibited anti-inflammatory and anti-oxidative properties in vitro and in vivo. The effect of HO-1 in ventilator-induced lung injury has not been fully characterized. In this study, rabbits were subjected to high tidal volume ventilation to induce ventilator-induced lung injury, which was confirmed by histopathological alterations, increased bronchoalveolar lavage fluid protein content and lung wet-to-dry ratio. In contrast to the level of HO-1 expression in high tidal volume group, pretreatment with hemin, an inducer of HO-1, further up-regulated HO-1 expression. At the same time, these lung injury indexes were attenuated markedly. This pulmonary protection was accompanied by a decrease in bronchoalveolar lavage fluid neutrophil count and in lung myeloperoxidase activity. Besides, pretreatment with hemin prohibited the production of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-8, and up-regulated the level of anti-inflammatory cytokine interleukin (IL)-10 in bronchoalveolar lavage fluid. Furthermore, a decreased malondialdehyde activity, a marker of oxidative stress and a robust increase in total antioxidant capacity were observed in hemin-treated animals. Our findings suggest that HO-1 up-regulation by hemin plays a protective role in ventilator-induced lung injury by suppression inflammatory process and oxidative stress.