RESUMEN

Metabolic reprogramming toward glycolysis is a hallmark of cancer malignancy. The molecular mechanisms by which the tumor glycolysis pathway promotes immune evasion remain to be elucidated. Here, by performing genome-wide CRISPR screens in murine tumor cells co-cultured with cytotoxic T cells (CTLs), we identified that deficiency of two important glycolysis enzymes, Glut1 (glucose transporter 1) and Gpi1 (glucose-6-phosphate isomerase 1), resulted in enhanced killing of tumor cells by CTLs. Mechanistically, Glut1 inactivation causes metabolic rewiring toward oxidative phosphorylation, which generates an excessive amount of reactive oxygen species (ROS). Accumulated ROS potentiate tumor cell death mediated by tumor necrosis factor alpha (TNF-α) in a caspase-8- and Fadd-dependent manner. Genetic and pharmacological inactivation of Glut1 sensitizes tumors to anti-tumor immunity and synergizes with anti-PD-1 therapy through the TNF-α pathway. The mechanistic interplay between tumor-intrinsic glycolysis and TNF-α-induced killing provides new therapeutic strategies to enhance anti-tumor immunity.

Asunto(s)

Neoplasias , Factor de Necrosis Tumoral alfa , Ratones , Animales , Humanos , Factor de Necrosis Tumoral alfa/metabolismo , Transportador de Glucosa de Tipo 1 , Evasión Inmune , Especies Reactivas de Oxígeno/metabolismo , Glucólisis , Linfocitos T/metabolismo , Línea Celular Tumoral

RESUMEN

Mild cognitive impairment (MCI) is common in patients with hypertension. Prevalence estimates of MCI in hypertensive patients are needed to guide both public health and clinical decision making. A literature search was conducted in four databases, including PubMed, Embase, Cochrane Library, and Web of Science, from their inception to February 2021. The methodological quality assessment used the risk of bias tool. The pooled prevalence of MCI in hypertensive patients was determined by a random-effects model. Heterogeneity was explored using sensitivity analysis, subgroup analysis, and random effects meta-regression. Of 2314 references, 11 studies (47,179 participants) were included in the meta-analysis. The overall pooled prevalence of MCI in patients with hypertension was 30% (95% CI, 25-35), with significant heterogeneity present (I2 = 99.3%, p < 0.001). In subgroup analyses, Asian and European samples had a prevalence of 26% (95% CI, 20-31) and 40% (95% CI, 14-66), respectively; cross-sectional and cohort studies had a prevalence of 28% (95% CI, 24-32) and 38% (95% CI, -5-81); age older than 60 years had a prevalence of 28% (95% CI, 23-33); community-based and clinic-based samples had a prevalence of 17% (95% CI, 15-19) and 42% (95% CI, 23-62); and MCI diagnosis using the MoCA, NIA-AA, MMSE, and Peterson criteria had a prevalence of 64% (95% CI, 59-68), 18% (95% CI, 16-19), 19% (95% CI, 15-23), and 13% (95% CI, 9-17). Meta-regression analysis showed that different MCI diagnostic criteria could be the source of heterogeneity in the pooled results. MCI is common in patients with hypertension, with an overall prevalence of 30%. Earlier cognitive screening and management in hypertensive patients should be advocated.

Asunto(s)

Enfermedad de Alzheimer , Disfunción Cognitiva , Hipertensión , Disfunción Cognitiva/epidemiología , Estudios Transversales , Humanos , Hipertensión/complicaciones , Hipertensión/epidemiología , Persona de Mediana Edad , Prevalencia

RESUMEN

Epithelial-repair-dependent mucosal healing (MH) is associated with a more favorable prognosis for patients with inflammatory bowel disease (IBD). MH is accomplished via repair and regeneration of the intestinal epithelium. However, the mechanism underlying MH is ill defined. We found a striking upregulation of peroxisomes in the injured crypts of IBD patients. By increasing peroxisome levels in Drosophila midguts, we found that peroxisome elevation enhanced RAB7-dependent late endosome maturation, which then promoted stem and/or progenitor-cell differentiation via modulation of Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT)-SOX21A signaling. This in turn enhanced ISC-mediated regeneration. Importantly, RAB7 and SOX21 were upregulated in the crypts of IBD patients. Moreover, administration of drugs that increased peroxisome levels reversed the symptoms of dextran sulfate sodium (DSS)-induced colitis in mice. This study demonstrates a peroxisome-mediated epithelial repair mechanism, which opens a therapeutic avenue for the enhancement of MH in IBD patients.

Asunto(s)

Diferenciación Celular , Neoplasias Colorrectales/patología , Regulación de la Expresión Génica , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/citología , Peroxisomas/fisiología , Células Madre/citología , Adolescente , Adulto , Animales , Neoplasias Colorrectales/metabolismo , Drosophila melanogaster , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/metabolismo , Mucosa Intestinal/lesiones , Mucosa Intestinal/metabolismo , Quinasas Janus/genética , Quinasas Janus/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Factores de Transcripción SOXB2/genética , Factores de Transcripción SOXB2/metabolismo , Factores de Transcripción STAT/genética , Factores de Transcripción STAT/metabolismo , Adulto Joven , Proteínas de Unión al GTP rab/genética , Proteínas de Unión al GTP rab/metabolismo , Proteínas de Unión a GTP rab7

RESUMEN

BACKGROUND: This systematic review is the first one to assess the effectiveness and safety of extracorporeal shock-wave therapy (ESWT) for patients with chronic musculoskeletal pain conditions (CMPC). METHODS: Seven electronic databases were searched for all relevant literature from inception to December 2019, including PubMed, the Web of Science, EMBASE, Cochrane library, China National Knowledge Infrastructure Database (CNKI), Chinese Scientific Journal Database (VIP), and Wanfang database. Only randomized controlled trials (RCTs) of ESWT for chronic musculoskeletal pain will be included. Two reviewers will independently select eligible studies and collected the detailed information, assessed the methodological quality. A third reviewer will join in discussion to solve disagreements. The mean difference (MD) or standard mean difference (SMD) with 95% confidence intervals (CIs) will be presented to demonstrate the effectiveness of ESWT for patients with chronic MSK pain conditions. RevMan 5.4 software will be used for statistical analysis. RESULTS: This systematic review will explore the effectiveness and safety of ESWT for patients with CMPC. The primary outcome includes pain level, and secondary outcome includes function limitation and adverse events. CONCLUSION: It can provide the updated evidence which is of great importance for patients, clinical practice and health related policy maker in ESWT treating CMPC.

Asunto(s)

Dolor Crónico/terapia , Tratamiento con Ondas de Choque Extracorpóreas , Metaanálisis como Asunto , Dolor Musculoesquelético/terapia , Revisiones Sistemáticas como Asunto , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto

RESUMEN

BACKGROUND: This is the first systematic review evaluating and statistically synthesis the current studies regarding the effects of Tai Chi on pain and disability in patients with low back pain (LBP). METHODS: Seven electronic databases including PubMed, EMBASE, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang and VIP information from inception to early March 2019 were searched. The Physiotherapy Evidence Database (PEDro) Scale was used to assess quality of all included randomized controlled trials (RCTs). The pooled effect size (weight mean difference, WMD) and 95% confidence interval (CI) were calculated to determine the effect of Tai Chi on pain and disability among LBP patients based on random effects model. RESULTS: The aggregated results of the meta-analysis suggested that Tai Chi significantly decreased pain (WMD = -1.27, 95%CI -1.50 to -1.04, P < .00001, I = 74%) and improve function disability, Oswestry disability index (ODI) subitems: pain intensity (WMD = -1.70, 95% CI -2.63 to -0.76, P = .0004, I = 89%); personal care (WMD = -1.93, 95% CI -2.86 to -1.00, P < .0001, I = 90%); lifting (WMD = -1.69, 95% CI -2.22 to -1.15, P < .0001, I = 66%); walking (WMD = -2.05, 95% CI -3.05 to -1.06, P < .0001, I = 88%); standing (WMD = -1.70, 95% CI -2.51 to -0.89, P < .0001, I = 84%); sleeping (WMD = -2.98, 95% CI -3.73 to -2.22, P < .00001, I = 80%); social life (WMD = -2.06, 95% CI -2.77 to -1.35, P < 0.00001, I = 80%) and traveling (WMD = -2.20, 95% CI -3.21 to -1.19, P < .0001, I = 90%), Japanese Orthopedic Association (JOA) score (WMD = 7.22, 95% CI 5.59-8.86, P < .00001, I = 0%), Medical Outcomes Study Questionnaire Short Form 36 Health Survey (SF-36) physical functioning (WMD = 3.30, 95% CI 1.92-4.68, P < .00001), and Roland-Morris Disability Questionnaire (RMDQ) (WMD = -2.19, 95% CI -2.56 to -1.82, P < .00001). CONCLUSION: We drew a cautious conclusion that Tai Chi alone or as additional therapy with routine physical therapy may decrease pain and improve function disability for patients with LBP. Further trials are needed to be conducted with our suggestions mentioned in the systematic review.

Asunto(s)

Dolor de la Región Lumbar/terapia , Manejo del Dolor/normas , Taichi Chuan/normas , Humanos , Manejo del Dolor/métodos , Modalidades de Fisioterapia/normas , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Taichi Chuan/métodos

RESUMEN

Long noncoding RNA small nucleolar RNA host gene 4 (SNHG4) is usually up-regulated in cancer and regulates the malignant behavior of cancer cells. However, its role in lung cancer remains elusive. In this study, we silenced the expression of SNHG4 in NCI-H1437 and SK-MES-1, two representative non-small-cell lung cancer cell lines, by transfecting them with siRNA (small interfering RNA) that specifically targets SNHG4. We observed significantly inhibited cell proliferation in vitro and reduced tumor growth in vivo after SNHG4 silencing. SNHG4 knockdown also led to cell cycle arrest at the G1 phase, accompanied with down-regulation of cyclin-dependent kinases CDK4 and CDK6. The migration and invasiveness of these two cell lines were remarkably inhibited after SNHG4 silencing. Moreover, our study revealed that the epithelial-mesenchymal transition (EMT) of lung cancer cells was suppressed by SNHG4 silencing, as evidenced by up-regulated E-cadherin and down-regulated SALL4, Twist, and vimentin. In addition, we found that SNHG4 silencing induced up-regulation of miR-98-5p. MiR-98-5p inhibition abrogated the effect of SNHG4 silencing on proliferation and invasion of lung cancer cells. In conclusion, our findings demonstrate that SNHG4 is required by lung cancer cells to maintain malignant phenotype. SNHG4 probably exerts its pro-survival and pro-metastatic effects by sponging anti-tumor miR-98-5p.

Asunto(s)

Movimiento Celular/genética , Transición Epitelial-Mesenquimal/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , MicroARNs/genética , ARN Largo no Codificante/genética , Proliferación Celular/genética , Humanos , Neoplasias Pulmonares/metabolismo , MicroARNs/metabolismo , Células Tumorales Cultivadas

RESUMEN

Long-term exposure to greenhouse environments exposes greenhouse workers to inhalation of antigens that can cause respiratory diseases. This study was conducted to investigate the prevalence and potential risk factors for bronchial asthma among the Chinese greenhouse workers based on questionnaire and spirometry data. This was an observational cross-sectional study, performed via stratified-cluster-random sampling. It was conducted in Liaoning Province from the northeast of People's Republic of China, using a population-based sample of 5,880 workers at 835 plastic film greenhouses. All subjects were interviewed using a standardized questionnaire and underwent pulmonary function tests. Multiple logistic regression analysis was conducted to assess associations between self-reported factors of greenhouse worker exposure and bronchial asthma and to identify potential risk factors for this disease. A total of 5,420 questionnaires were completed. The overall prevalence of asthma in greenhouse workers was 19.2% (1040/5420). Multiple logistic regression analysis revealed that the use of multiple pesticides (odds ratio [OR] 1.24, 95% confidence interval [CI] 1.03-1.49), bad odors in the greenhouse (OR = 1.26, 95% CI = 1.07-1.49), and report of the onset of cough when entering the greenhouse (OR = 1.25, 95% CI = 1.09-1.44) were associated with the development of asthma. In contrast, a higher body mass index (BMI >18.5 kg/m2, OR = 0.93, 95% CI = 0.90-0.95), planting flowers (OR = 0.92, 95% CI = 0.87-0.98), open sidewall to outside (natural ventilation) for at least 30 min per event (OR = 0.82, 95% CI = 0.69-0.96), living in greenhouse (OR = 0.85, 95% CI = 0.73-0.99), and experiencing cough before 14 years old (OR = 0.61, 95% CI = 0.43-0.84) were protective factors to the presentation of asthma among greenhouse workers. Our results suggest that asthma is a major public health problem among Chinese greenhouse workers and more attention should be devoted to preventive measures and management of this disease.

Asunto(s)

Asma/diagnóstico , Asma/epidemiología , Agricultores , Adulto , Anciano , Asma/etiología , China/epidemiología , Tos , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Exposición Profesional/análisis , Plaguicidas , Proyectos Piloto , Pruebas de Función Respiratoria , Factores de Riesgo , Encuestas y Cuestionarios , Lugar de Trabajo

RESUMEN

AIM: To investigate the role of translationally controlled tumor protein (TCTP) in lung cancer development. MAIN METHODS: A549 and HCC827 cells were transfected with shRNA specifically targeting TCTP mRNA. Cell growth was assessed by colony formation assay and cell counting kit-8. Cell cycle and apoptosis were analyzed by flow cytometry. Cell migration and invasion was measured by scratch and transwell assays. In vivo tumorigenicity was evaluated by tumor xenografts in nude mice. KEY FINDINGS: TCTP-silenced cells displayed a reduced ability of colony formation and a lower rate of proliferation in vitro. Knockdown of TCTP arrested cell cycle at G1 phase and led to downregulated expression of cyclins B1, D1 and E. Moreover, silencing of TCTP induced apoptosis and altered the levels of apoptosis-regulatory proteins such as cleaved caspase-3, Bcl-2, Bax and p53. Silencing of TCTP also inhibited migration and invasion of lung cancer cells. In addition, TCTP-silenced A549 cells, when subcutaneously inoculated in nude mice, formed tumors at a significantly slower rate. SIGNIFICANCE: Our in vitro and in vivo data indicate that silencing of TCTP inhibits growth, migration and invasion of lung cancer cells. Thus, TCTP may be a potential target for lung cancer therapy.

Asunto(s)

Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Pulmonares/metabolismo , Células A549 , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Ciclo Celular/efectos de los fármacos , Aumento de la Célula , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Xenoinjertos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/fisiopatología , Ratones , Ratones Desnudos , ARN Interferente Pequeño/genética , Proteína Tumoral Controlada Traslacionalmente 1