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Gut microbiota are linked to chronic inflammation and carcinogenesis. Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer patients. Here, we investigated the contribution of gut microbiota to chemoresistance in patients with colorectal cancer. We found that Fusobacterium (F.) nucleatum was abundant in colorectal cancer tissues in patients with recurrence post chemotherapy, and was associated with patient clinicopathological characterisitcs. Furthermore, our bioinformatic and functional studies demonstrated that F. nucleatum promoted colorectal cancer resistance to chemotherapy. Mechanistically, F. nucleatum targeted TLR4 and MYD88 innate immune signaling and specific microRNAs to activate the autophagy pathway and alter colorectal cancer chemotherapeutic response. Thus, F. nucleatum orchestrates a molecular network of the Toll-like receptor, microRNAs, and autophagy to clinically, biologically, and mechanistically control colorectal cancer chemoresistance. Measuring and targeting F. nucleatum and its associated pathway will yield valuable insight into clinical management and may ameliorate colorectal cancer patient outcomes.
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Autofagia , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Fusobacterium nucleatum/fisiología , Microbioma Gastrointestinal , Animales , Antineoplásicos/uso terapéutico , Capecitabina/uso terapéutico , Neoplasias Colorrectales/metabolismo , Resistencia a Antineoplásicos , Xenoinjertos , Ratones , MicroARNs/metabolismo , Trasplante de Neoplasias , Compuestos de Platino/uso terapéutico , Recurrencia , Receptores Toll-Like/metabolismo , Microambiente TumoralRESUMEN
BACKGROUND AND AIM: Cohort studies have linked metabolic syndrome (MetS) to gastrointestinal (GI) cancer risk. We aimed to evaluate the associations between MetS, its components, and combinations of MetS components with eight GI cancers risk. METHODS: We conducted a systematic search of prospective cohort studies and performed a meta-analysis. Subgroup analyses regarding diagnostic criteria, sex, cancer sites, histological subtypes, ethnic groups, and studies adjusted for alcohol consumption were carried out. Mendelian randomization (MR) was employed to evaluate the causality between 17 MetS-related traits and eight GI cancers among Europeans and Asians separately. RESULTS: Meta-analyses of 31 prospective studies indicated that MetS was significantly associated with an increased risk of colorectal cancer (CRC) (RR [95% CI] = 1.13 [1.12-1.15]), esophageal cancer (EC) (RR [95% CI] = 1.17 [1.03-1.32]), gallbladder cancer (GBC) (RR [95% CI] = 1.37[1.10-1.71]), liver cancer (LC) (RR [95% CI] = 1.46 [1.29-1.64]), and pancreatic cancer (PaC) (RR [95% CI] = 1.25 [1.20-1.30]), but not gastric cancer (GC) (RR [95% CI] = 1.11 [0.96-1.28]). Regarding the associations between MetS components and GI cancers risk, the following associations showed statistical significance: obesity-CRC/LC/EC/, hypertriglyceridemia-LC/PaC, reduced high-density lipoprotein (HDL)-CRC/LC/GC/PaC, hyperglycemia-CRC/LC/PaC, and hypertension-CRC/LC/EC/PaC. Sex-specific associations were observed between individual MetS components on GI cancers risk. Among the top three common combinations in both sexes, obesity + HTN + hyperglycemia had the strongest association with CRC risk (RR [95% CI] = 1.54 [1.49-1.61] for males and 1.27 [1.21-1.33] for females). MR analyses revealed causality in 16 exposure-outcome pairs: waist-to-hip ratio/BMI/HbA1c-CRC; BMI/childhood obesity/waist circumference/T2DM/glucose-EC; BMI/waist circumference/cholesterol-LC; cholesterol/childhood obesity/waist circumference/HbA1c-PaC; and HbA1c-GBC. These results were robust against sensitivity analyses. CONCLUSIONS: Since MetS is reversible, lifestyle changes or medical interventions targeting MetS patients might be potential prevention strategies for GI cancers.
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Neoplasias Gastrointestinales , Análisis de la Aleatorización Mendeliana , Síndrome Metabólico , Humanos , Síndrome Metabólico/genética , Síndrome Metabólico/epidemiología , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/etiología , Neoplasias Gastrointestinales/epidemiología , Estudios Prospectivos , Masculino , Factores de Riesgo , Femenino , Riesgo , Estudios de Cohortes , Obesidad/complicacionesRESUMEN
It remains challenging to translate the findings from genome-wide association studies (GWAS) of autoimmune diseases (AIDs) into interventional targets, presumably due to the lack of knowledge on how the GWAS risk variants contribute to AIDs. In addition, current immunomodulatory drugs for AIDs are broad in action rather than disease-specific. We performed a comprehensive protein-centric omics integration analysis to identify AIDs-associated plasma proteins through integrating protein quantitative trait loci datasets of plasma protein (1348 proteins and 7213 individuals) and totally ten large-scale GWAS summary statistics of AIDs under a cutting-edge systematic analytic framework. Specifically, we initially screened out the protein-AID associations using proteome-wide association study (PWAS), followed by enrichment analysis to reveal the underlying biological processes and pathways. Then, we performed both Mendelian randomization (MR) and colocalization analyses to further identify protein-AID pairs with putatively causal relationships. We finally prioritized the potential drug targets for AIDs. A total of 174 protein-AID associations were identified by PWAS. AIDs-associated plasma proteins were significantly enriched in immune-related biological process and pathways, such as inflammatory response (P = 3.96 × 10-10). MR analysis further identified 97 protein-AID pairs with potential causal relationships, among which 21 pairs were highly supported by colocalization analysis (PP.H4 > 0.75), 10 of 21 were the newly discovered pairs and not reported in previous GWAS analyses. Further explorations showed that four proteins (TLR3, FCGR2A, IL23R, TCN1) have corresponding drugs, and 17 proteins have druggability. These findings will help us to further understand the biological mechanism of AIDs and highlight the potential of these proteins to develop as therapeutic targets for AIDs.
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BACKGROUND & AIMS: Most patients with gastric cancer (GCa) are diagnosed at an advanced stage. We aimed to investigate novel fecal signatures for clinical application in early diagnosis of GCa. METHODS: This was an observational study that included 1043 patients from 10 hospitals in China. In the discovery cohort, 16S ribosomal RNA gene analysis was performed in paired samples (tissues and feces) from patients with GCa and chronic gastritis (ChG) to determine differential abundant microbes. Their relative abundances were detected using quantitative real-time polymerase chain reaction to test them as bacterial candidates in the training cohort. Their diagnostic efficacy was validated in the validation cohort. RESULTS: Significant enrichments of Streptococcus anginosus (Sa) and Streptococcus constellatus (Sc) in GCa tumor tissues (P < .05) and feces (P < .0001) were observed in patients with intraepithelial neoplasia, early and advanced GCa. Either the signature parallel test SaâªSc or single signature Sa/Sc demonstrated superior sensitivity (Sa: 75.6% vs 72.1%, P < .05; Sc: 84.4% vs 64.0%, P < .001; and SaâªSc: 91.1% vs 81.4%, P < .01) in detecting early GCa compared with advanced GCa (specificity: Sa: 84.0% vs 83.9%, Sc: 70.4% vs 82.3%, and SaâªSc: 64.0% vs 73.4%). Fecal signature SaâªSc outperformed SaâªCEA/ScâªCEA in the discrimination of advanced GCa (sensitivity: 81.4% vs 74.2% and 81.4% vs 72.3%, P < .01; specificity: 73.4% vs 81.0 % and 73.4% vs 81.0%). The performance of SaâªSc in the diagnosis of both early and advanced GCa was verified in the validation cohort. CONCLUSION: Fecal Sa and Sc are noninvasive, accurate, and sensitive signatures for early warning in GCa. (ClinicalTrials.gov, Number: NCT04638959).
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Neoplasias Gástricas , Streptococcus constellatus , Detección Precoz del Cáncer , Heces , Humanos , Neoplasias Gástricas/diagnóstico , Streptococcus anginosus/genética , Streptococcus constellatus/genéticaRESUMEN
BACKGROUND: Colorectal cancer (CRC) incidence has increased among patients aged <50 years. Exploring high-risk factors and screening high-risk populations may help lower early-onset CRC (EO-CRC) incidence. We developed noninvasive predictive models for EO-CRC and investigated its risk factors. METHODS: This retrospective multicenter study collected information on 1756 patients (811 patients with EO-CRC and 945 healthy controls) from two medical centers in China. Sociodemographic features, clinical symptoms, medical and family history, lifestyle, and dietary factors were measured. Patients from one cohort were randomly assigned (8:2) to two groups for model establishment and internal validation, and another independent cohort was used for external validation. Multivariable logistic regression, random forest, and eXtreme Gradient Boosting (XGBoost) were performed to establish noninvasive predictive models for EO-CRC. Some variables in the model influenced EO-CRC occurrence and were further analyzed. Multivariable logistic regression analysis yielded adjusted odd ratios (ORs) and 95% confidence intervals (CIs). RESULTS: All three models showed good performance, with areas under the receiver operator characteristic curves (AUCs) of 0.82, 0.84, and 0.82 in the internal and 0.78, 0.79, and 0.78 in the external validation cohorts, respectively. Consumption of sweet (OR 2.70, 95% CI 1.89-3.86, P < 0.001) and fried (OR 2.16, 95% CI 1.29-3.62, P < 0.001) foods ≥3 times per week was significantly associated with EO-CRC occurrence. CONCLUSION: We established noninvasive predictive models for EO-CRC and identified multiple nongenetic risk factors, especially sweet and fried foods. The model has good performance and can help predict the occurrence of EO-CRC in the Chinese population.
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Neoplasias Colorrectales , Estilo de Vida , Humanos , Pueblo Asiatico , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/etiología , Estudios Retrospectivos , Factores de Riesgo , Distribución AleatoriaRESUMEN
Poly(ethylene terephthalate) (PET) is a manufactured plastic broadly available, whereas improper disposal of PET waste has become a serious burden on the environment. Leaf-branch compost cutinase (LCC) is one of the most powerful and promising PET hydrolases, and its mutant LCCICCG shows high catalytic activity and excellent thermal stability. However, low binding affinity with PET has been found to dramatically limit its further industrial application. Herein, TrCBM and CfCBM were rationally selected from the CAZy database to construct fusion proteins with LCCICCG, and mechanistic studies revealed that these two domains could bind with PET favorably via polar amino acids. The optimal temperatures of LCCICCG-TrCBM and CfCBM-LCCICCG were measured to be 70 and 80 °C, respectively. Moreover, these two fusion proteins exhibited favorable thermal stability, maintaining 53.1% and 48.8% of initial activity after the incubation at 90 °C for 300 min. Compared with LCCICCG, the binding affinity of LCCICCG-TrCBM and CfCBM-LCCICCG for PET has been improved by 1.4- and 1.3-fold, respectively, and meanwhile their degradation efficiency on PET films was enhanced by 3.7% and 24.2%. Overall, this study demonstrated that the strategy of constructing fusion proteins is practical and prospective to facilitate the enzymatic PET degradation ability.
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Compostaje , Tereftalatos Polietilenos , Tereftalatos Polietilenos/química , Estudios Prospectivos , CarbohidratosRESUMEN
Entanglement swapping, which is a core component of quantum network and an important platform for testing the foundation of quantum mechanics, can enable the entangling of two independent particles without direct interaction both in discrete variable and continuous variable systems. Conventionally, the realization of entanglement swapping relies on the Bell-state measurement. In particular, for entanglement swapping in continuous variable regime, such Bell-state measurement involves the optic-electro and electro-optic conversion, which limits the applications of the entanglement swapping for constructing broadband quantum network. In this Letter, we propose and demonstrate a measurement-free all-optical entanglement swapping. In our scheme, a high-gain parametric amplifier based on the four-wave mixing process is exploited to realize the function of Bell-state measurement without detection, which avoids the introduction of the optic-electro and electro-optic conversion. Our results provide an all-optical paradigm for implementing entanglement swapping and pave the way to construct a measurement-free all-optical broadband quantum network.
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OBJECTIVE: Microbiota disorder promotes chronic inflammation and carcinogenesis. High glycolysis is associated with poor prognosis in patients with colorectal cancer (CRC). However, the potential correlation between the gut microbiota and glucose metabolism is unknown in CRC. DESIGN: 18F-FDG (18F-fluorodeoxyglucose) PET (positron emission tomography)/CT image scanning data and microbiota PCR analysis were performed to measure the correlation between metabolic alterations and microbiota disorder in 33 patients with CRC. Multiple colorectal cancer models, metabolic analysis and Seahorse assay were established to assess the role of long non-coding RNA (lncRNA) enolase1-intronic transcript 1 (ENO1-IT1) in Fusobacterium (F.) nucleatum-induced glucose metabolism and colorectal carcinogenesis. RNA immunoprecipitation and chromatin immunoprecipitation sequencing were conducted to identify potential targets of lncRNA ENO1-IT1. RESULTS: We have found F. nucleatum abundance correlated with high glucose metabolism in patients with CRC. Furthermore, F. nucleatum supported carcinogenesis via increasing CRC cell glucose metabolism. Mechanistically, F. nucleatum activated lncRNA ENO1-IT1 transcription via upregulating the binding efficiency of transcription factor SP1 to the promoter region of lncRNA ENO1-IT1. Elevated ENO1-IT behaved as a guider modular for KAT7 histone acetyltransferase, specifying the histone modification pattern on its target genes, including ENO1, and consequently altering CRC biological function. CONCLUSION: F. nucleatum and glucose metabolism are mechanistically, biologically and clinically connected to CRC. Targeting ENO1 pathway may be meaningful in treating patients with CRC with elevated F. nucleatum.
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Carcinogénesis/genética , Neoplasias Colorrectales/genética , Infecciones por Fusobacterium/genética , Glucólisis/genética , ARN Largo no Codificante/genética , Animales , Biomarcadores de Tumor , Neoplasias Colorrectales/diagnóstico por imagen , Proteínas de Unión al ADN , Fluorodesoxiglucosa F18/farmacocinética , Fusobacterium nucleatum , Microbioma Gastrointestinal , Regulación Neoplásica de la Expresión Génica , Histona Acetiltransferasas , Humanos , Ratones , Fosfopiruvato Hidratasa , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pronóstico , Radiofármacos/farmacocinética , Transducción de Señal , Células Tumorales Cultivadas , Proteínas Supresoras de TumorRESUMEN
Previous studies have suggested that gut microbiota plays a critical role in colorectal cancer (CRC). Although preliminary comparisons of the oral and gut microbiota between CRC and healthy control (HC) patients have been made, the association between microbiome abundance and host clinical factors has not been fully illustrated, especially oral health conditions. Matching samples of unstimulated saliva, cancer tissues or biopsies and stools were collected from 30 CRC and 30 HC patients from Shanghai Jiao Tong University affiliated Renji Hospital for 16S rRNA sequencing analysis. The diversity in salivary and mucosal microbiome, but not stool microbiome of CRC group, was significantly different from that of HC, as demonstrated by the Principal Component Analysis. Logistic regression analysis revealed that older age and higher oral hygiene index (OHI) were independent risk factors for CRC, with odds ratios and 95% confidence intervals of 1.159 (1.045-1.284) and 4.398 (1.328-14.567), respectively. Salivary Firmicutes to Bacteroides ratio in CRC was significantly higher than that in the HC group (P < .001), while the mucosal ratio was slightly decreased in CRC (P < .05). Salivary Rothia and Streptococcus levels were positively correlated with OHI, while Alloprevotella, Fusobacterium, Peptostreptoccus and Prevotella genera levels were negatively associated with OHI. NetShift analysis revealed that salivary Peptococcus, Centipeda and mucosal Subdoligranulum genus might act as key drivers during the process of carcinogenesis. In conclusion, the current study provides insights into the potential influence of host clinical factors on oral and gut microbiome composition and can be a guide for future studies.
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To beat the channel capacity limit of conventional quantum dense coding (QDC) with fixed quantum resources, we experimentally implement the orbital angular momentum (OAM) multiplexed QDC (MQDC) in a continuous variable system based on a four-wave mixing process. First, we experimentally demonstrate that the Einstein-Podolsky-Rosen entanglement source coded on OAM modes can be used in a single channel to realize the QDC scheme. Then, we implement the OAM MQDC scheme by using the Einstein-Podolsky-Rosen entanglement source coded on OAM superposition modes. In the end, we make an explicit comparison of channel capacities for four different schemes and find that the channel capacity of the OAM MQDC scheme is substantially enhanced compared to the conventional QDC scheme without multiplexing. The channel capacity of our OAM MQDC scheme can be further improved by increasing the squeezing parameter and the number of multiplexed OAM modes in the channel. Our results open an avenue to construct high-capacity quantum communication networks.
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The laws of quantum mechanics forbid the perfect copying of an unknown quantum state, known as the no-cloning theorem. In spite of this, approximate cloning with imperfect fidelity is possible, which opens up the field of quantum cloning. In general, quantum cloning can be divided into discrete variable and continuous variable (CV) categories. In the CV regime, all-optical implementation of the optimal NâM quantum cloning has been proposed in two original parallel works, which involves a parametric amplifier and a set of beam splitters and thus avoids the optic-electro and electro-optic conversions in the current CV quantum cloning technologies. However, such original proposal of all-optical CV optimal NâM quantum cloning scheme has never been experimentally implemented. Here, we show that optimal NâM quantum cloning of coherent states can be realized by utilizing a parametric amplifier based on four-wave mixing process in a hot atomic vapor and a set of beam splitters. In particular, we realize 1âM, 2âM, and 4âM quantum cloning. We find that the fidelity of NâM quantum cloning increases with the decrease of clone number M and the increase of original replica number N. The best cloning fidelity achieved in our experiment is about 93.3% ±1.0% in the 4â5 case. Our results may find potential applications in realizing all-optical high-fidelity quantum state transfer and all-optical high-compatibility eavesdropping attack in quantum communication networks.
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BACKGROUND AND AIM: Fusobacterium nucleatum is increasingly being recognized as an important risk factor in colorectal cancer and colorectal adenoma. Endoscopic polypectomy is associated with a decreased incidence of colorectal cancer; however, patients still suffer from a risk of metachronous adenoma. Currently, there are few effective non-invasive factors that may predict metachronous colorectal adenoma. Here, we evaluated the performance of F. nucleatum in predicting metachronous adenoma. METHODS: Fecal samples and clinical information of patients before endoscopic polypectomy were collected from 367 patients in a retrospective cohort, and 238 patients in a prospective cohort. The abundance of fecal F. nucleatum was measured via quantitative polymerase chain reaction. Surveillance colonoscopies were conducted between 1 and 3 years after polypectomy (average follow-up 27.07 months for the retrospective cohort & 22.57 months for the prospective cohort) to identify metachronous adenoma. Candidate predictive factors and cut-off value of F. nucleatum abundance were identified from the retrospective cohort and then validated in the prospective cohort. RESULTS: A high abundance of fecal F. nucleatum was found to be an independent risk factor for metachronous adenomas (odds ratio, 6.38; P < 0.001) in the retrospective cohort and was validated in the prospective cohort with a specificity of 65.00%, and a sensitivity of 73.04%, and an overall performance with the area under the curve of 0.73. CONCLUSION: Fecal abundance of F. nucleatum may be a reliable predictor for metachronous adenoma after endoscopic polypectomy.
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Adenoma , Pólipos del Colon/cirugía , Neoplasias Colorrectales , Adenoma/cirugía , Neoplasias Colorrectales/cirugía , Fusobacterium nucleatum , Humanos , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
BACKGROUND AND AIM: We have previously shown that fecal microbial markers might be useful for non-invasive diagnosis of colorectal cancer (CRC) and adenoma. Here, we assessed the application of microbial DNA markers, as compared with and in combination with fecal immunochemical test (FIT), in detecting CRC and adenoma in symptomatic patients and asymptomatic subjects. METHODS: We recruited 676 subjects [210 CRC, 115 advanced adenoma (AA), 86 non-advanced adenoma, and 265 non-neoplastic controls], including 241 symptomatic and 435 asymptomatic subjects. Fecal abundances of Fusobacterium nucleatum, a Lachnoclostridium sp. m3, Bacteroides clarus, and Clostridium hathewayi were quantified by quantitative PCR. Combining score of the four microbial markers (4Bac) and diagnostic prediction were determined using our previously established scoring model and cutoff values and FIT with a cutoff of 100 ng Hb/mL. RESULTS: 4Bac detected similar percentages of CRC [85.3% (95%CI: 79.2-90.2%) vs 84.9% (68.1-94.9%)] and AA [35.7% (12.8-64.9%) vs 38.6% (29.1-48.8%)], while FIT detected more CRC [72.1% (63.7-79.4%) vs 66.7% (48.2-82.0%)] and AA [28.6% (8.4-58.1%) vs 16.8% (10.1-25.6%)], in symptomatic vs asymptomatic subjects, respectively. Focusing on the asymptomatic cohort, 4Bac was more sensitive for diagnosing CRC and AA than FIT (P < 0.001), with lower specificity [83.3% (77.6-88.0%) vs 98.6% (96.0-99.7%)]. FIT failed to detect any non-advanced adenoma [0% (0.0-4.2%)] compared with 4Bac [41.9% (31.3-53.0%), P < 0.0001]. Combining 4Bac with FIT improved sensitivities for CRC [90.9% (75.7-98.1%)] and AA [48.5% (38.4-58.7%)] detection. CONCLUSION: Quantitation of fecal microbial DNA markers may serve as a new test, stand alone, or in combination with FIT for screening colorectal neoplasm in asymptomatic subjects.
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Adenoma/diagnóstico , Enfermedades Asintomáticas , Neoplasias Colorrectales/diagnóstico , ADN Bacteriano/análisis , Heces/microbiología , Microbioma Gastrointestinal/genética , Anciano , Biomarcadores/análisis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: The topical antispasmodic agent l-menthol is commonly used for gastric peristalsis suppression during diagnostic upper gastrointestinal (GI) endoscopy. We evaluated the efficacy and safety of a single dose l-menthol solution in suppressing gastric peristalsis during upper GI endoscopy in Chinese patients. METHODS: In this phase III, multicenter, randomized, double-blind, placebo-controlled study (ClinicalTrials.gov: NCT03263910), 220 patients scheduled to undergo upper GI endoscopy at five Chinese referral centers received a single dose of either 160 mg of l-menthol (n = 109) or placebo (n = 111). Both treatments were sprayed endoscopically on the gastric mucosa. An independent committee evaluated the degree of gastric peristalsis (peristaltic score: grade 1-5). RESULTS: At baseline, the proportion of patients with grade 1 peristalsis (no peristalsis) did not differ between the groups. The proportion of patients with grade 1 peristalsis post-treatment was significantly higher in the l-menthol group (40.37%, 44/109) versus the placebo group (16.22%, 18/111; P < 0.001); the difference between the groups was 24.15% (95% confidence interval: 12.67%-35.63%; P < 0.001). In the l-menthol group, 61.47% of patients had grade 1 peristalsis after endoscopy versus 24.55% in the placebo group (P < 0.001). The ease of intragastric examination correlated significantly with the grade of peristalsis. The incidence of adverse events was comparable between the groups (P = 0.340). CONCLUSIONS: During upper GI endoscopy, a single dose of l-menthol solution (160 mg) sprayed on the gastric mucosa significantly attenuated gastric peristalsis versus placebo, thereby improving the visual stability without any safety concerns.
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Antidiarreicos , Mentol , China , Método Doble Ciego , Endoscopía Gastrointestinal , Mucosa Gástrica , HumanosRESUMEN
MiR-34a, an important tumor suppressor, has been demonstrated to possess great potential in tumor gene therapy. To achieve the upregulation of miR-34a expression level, an oligoethyleneimine (OEI) derivative was constructed and employed as the carrier through the modification with lipoic acid (LA), namely LA-OEI. In contrast to OEI, the derivative LA-OEI exhibited superior transfection efficiency measured by confocal laser scanning microscopy and flow cytometry, owing to rapid cargo release in the disulfide bond-based reduction sensitive pattern. The anti-proliferation and anti-migration effects were tested after the miR-34a transfection to evaluate the anti-tumor response, using human cervical carcinoma cell line HeLa as a model. The delivery of LA-OEI/miR-34a nanoparticles could achieve obvious anti-proliferative effect caused by the induction of cell apoptosis and cell cycle arrest at G1 phase. In addition, it could inhibit the migration of tumor cells via the downregulation of MMP-9 and Notch-1 level. Overall, the LA-OEI-mediated miR-34a delivery was potential to be used as an effective way in the tumor gene therapy.
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Antineoplásicos/farmacología , MicroARNs/metabolismo , Polietileneimina/química , Ácido Tióctico/química , Transfección , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células HeLa , Humanos , MicroARNs/genética , Nanopartículas/ultraestructura , Polietileneimina/síntesis química , Ácido Tióctico/síntesis química , Cicatrización de Heridas/efectos de los fármacosRESUMEN
OBJECTIVE: There is a need for early detection of colorectal cancer (CRC) at precancerous-stage adenoma. Here, we identified novel faecal bacterial markers for diagnosing adenoma. DESIGN: This study included 1012 subjects (274 CRC, 353 adenoma and 385 controls) from two independent Asian groups. Candidate markers were identified by metagenomics and validated by targeted quantitative PCR. RESULTS: Metagenomic analysis identified 'm3' from a Lachnoclostridium sp., Fusobacterium nucleatum (Fn) and Clostridium hathewayi (Ch) to be significantly enriched in adenoma. Faecal m3 and Fn were significantly increased from normal to adenoma to CRC (p<0.0001, linear trend by one-way ANOVA) in group I (n=698), which was further confirmed in group II (n=313; p<0.0001). Faecal m3 may perform better than Fn in distinguishing adenoma from controls (areas under the receiver operating characteristic curve (AUROCs) m3=0.675 vs Fn=0.620, p=0.09), while Fn performed better in diagnosing CRC (AUROCs Fn=0.862 vs m3=0.741, p<0.0001). At 78.5% specificity, m3 and Fn showed sensitivities of 48.3% and 33.8% for adenoma, and 62.1% and 77.8% for CRC, respectively. In a subgroup tested with faecal immunochemical test (FIT; n=642), m3 performed better than FIT in detecting adenoma (sensitivities for non-advanced and advanced adenomas of 44.2% and 50.8% by m3 (specificity=79.6%) vs 0% and 16.1% by FIT (specificity=98.5%)). Combining with FIT improved sensitivity of m3 for advanced adenoma to 56.8%. The combination of m3 with Fn, Ch, Bacteroides clarus and FIT performed best for diagnosing CRC (specificity=81.2% and sensitivity=93.8%). CONCLUSION: This study identifies a novel bacterial marker m3 for the non-invasive diagnosis of colorectal adenoma.
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Adenoma/diagnóstico , Clostridiales/metabolismo , Neoplasias Colorrectales/diagnóstico , Heces/microbiología , Biomarcadores de Tumor/análisis , Estudios de Casos y Controles , Heces/química , Femenino , Humanos , Masculino , Metagenómica , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: To determine the safety and efficacy of different doses of tolvaptan for treating Chinese cirrhotic patients with or without hyponatraemia who still had ascites after routine therapy with diuretics. METHODS: In the present placebo-controlled, randomized, double-blinded, multicentre clinical trial, patients with cirrhotic ascites who failed to adequately respond to a combination of an aldosterone antagonist plus an orally administered loop diuretic were randomly placed at a 4:2:1 ratio into 3 groups [the 15 mg/day tolvaptan group (N = 301), 7.5 mg/day tolvaptan group (N = 153) and placebo group (N = 76)] for 7 days of treatment. The effects and safety were evaluated on days 4 and 7. A change in body weight from baseline on day 7 of treatment was the primary endpoint. RESULTS: The administration of 7.5 or 15 mg/day tolvaptan significantly decreased body weight from baseline on day 7 of treatment compared to that with placebo treatment (P = 0.026; P = 0.001). For the secondary endpoints, changes in abdominal circumference from baseline and improvements in ascites were markedly different in the treatment groups and the placebo group on day 7 (P7.5 = 0.05, P15.0 = 0.002 and P7.5 = 0.037, P15.0 = 0.003), but there was no difference between the 7.5 mg/day and 15 mg/day dosage groups. The 24-h cumulative urine volume was higher in the 7.5 mg/day and 15 mg/day tolvaptan groups than the placebo group (P = 0.002, P < 0.001) and was greater in the 15 mg/day tolvaptan group than the 7.5 mg/day tolvaptan group (P = 0.004). Sodium serum concentrations were higher in patients with hyponatraemia after tolvaptan treatment, with no significant difference between the two dosage groups. The incidence of serious adverse drug reactions was not different between the groups (P = 0.543). CONCLUSIONS: Tolvaptan treatment at 7.5 mg per day might be a good therapeutic choice for Chinese cirrhotic patients with ascites who did not achieve satisfactory clinical responses to previous treatment regimens with combination therapy with an aldosterone antagonist and an orally administered loop diuretic. TRIAL REGISTRATION: NCT01349348. Retrospectively registered May 2011.
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Ascitis , Diuréticos , Antagonistas de los Receptores de Hormonas Antidiuréticas , Ascitis/tratamiento farmacológico , Ascitis/etiología , Benzazepinas , China , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/tratamiento farmacológico , TolvaptánRESUMEN
CLINICAL PRESENTATION: A 28-year-old woman presented with a 3-year history of chronic watery diarrhoea along with abdominal pain and bloating, which could mostly be alleviated after defecation. Her symptom of diarrhoea, at least three times a day, could be relieved by neither probiotics nor antidiarrhoeal agents. She had also lost 5 kg in the last month. She denied family history, poor vaccine responses or significant infections in early childhood except for an allergy history to intravenous immunoglobulin (Ig) with immediate dyspnoea, palpitations and hypotension. Laboratory investigations suggested that the stool specimens were negative for viruses, parasites or bacteria. Laboratory evaluation revealed a low serum globulin level, 14.5 (reference range, 20-30 g/L); serum Ig levels were significantly abnormal: IgA <0.27 (0.7-4 g/L), IgM 0.24 (0.4-2.3 g/L), IgG 1.3 (7-16 g/L); white cell count 15.4×109/L (3.69-9.16×109/L); C-reactive protein (CRP) 20.5 (normal <10 mg/L); CD4+ lymphocyte/CD8+ lymphocyte 1.09% (1.5%-2%). Other laboratory findings were unremarkable, for example, tumour markers, autoantibodies and HIV, and so on. CT showed mesenteric nodule-like images and thickening of the wall and mucosa in small intestine. Peroral and transanal enteroscopy respectively demonstrated swelling mucosa and continuous granular lesions from duodenum to middle jejunum, and from middle ileum to terminal ileum (figure 1A-D).gutjnl;68/3/452/F1F1F1Figure 1Endoscopic images show swelling mucosa, dense nodular lesions in duodenum (A), upper jejunum (B), upper ileum (C) and terminal ileum (D). QUESTION: What is the most likely diagnosis?
Asunto(s)
Inmunodeficiencia Variable Común/complicaciones , Diarrea/etiología , Enteritis/complicaciones , Intestino Delgado/patología , Adulto , Biopsia , Enfermedad Crónica , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/patología , Enteritis/diagnóstico , Enteritis/patología , Femenino , Humanos , Mucosa Intestinal/patologíaRESUMEN
The molecular mechanisms that control the development of colorectal cancer (CRC) remain poorly defined. Here we show Synbindin promoted CRC oncogenesis by activating Wnt signaling and altering gut microbiome. Synbindin upregulation in human CRCs was associated with poor patient prognosis. Intestine-specific disruption of Synbindin balanced the disturbed gut microbiota and protected mice against tumor formation in the colitis-associated cancer (CAC) model. The protective role was compromised after gut microbiota depletion. In host, increased goblet cells and mucin2 expression, together with increased intestinal epithelial cells (IECs) apoptosis and decreased epithelial proliferation were observed. Further transcriptomic sequencing identified Wnt signaling a major regulatory node downstream of Synbindin. Combined molecular and cellular characterizations revealed that Synbindin confers Disheveled-3 (DVL3)-based signalosome assembly and acts as a modular scaffold for DVL3 and Axin2 complex, orchestrating the intensity of Wnt signaling. These findings identify a critical role of Synbindin in gut microbiome composition and Wnt signaling activation in colorectal carcinogenesis, and highlight Synbindin as an adaptor protein with multifaceted roles.
Asunto(s)
Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/microbiología , Microbioma Gastrointestinal/fisiología , Proteínas del Tejido Nervioso/deficiencia , Proteínas de Transporte Vesicular/deficiencia , Vía de Señalización Wnt , Animales , Proteína Axina/metabolismo , Carcinogénesis , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/microbiología , Colitis/patología , Neoplasias Colorrectales/patología , Sulfato de Dextran , Proteínas Dishevelled/metabolismo , Células HCT116 , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microbiota/fisiología , Mucina 2/metabolismo , Proteínas del Tejido Nervioso/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Transporte Vesicular/metabolismoRESUMEN
BACKGROUND: Drug-induced liver injury (DILI) is the most common reason for a drug to be withdrawn from the market. Apart from stopping the offending drug, no regimens are available for treating idiosyncratic DILI in clinical practice. METHODS: We carried out a randomized, double-blind, multidoses, active drug controlled, multicentre phase II trial to assess the safety and efficacy of the study drug, magnesium isoglycyrrhizinate (MgIG), as compared to tiopronin, a standard therapy for DILI in China. The primary outcome was the proportion of alanine aminotransferase (ALT) normalization at week 4 after study drug administration. Logistic regression was used to examine the odds of ALT normalization between low dose (Group A) and high dose (Group B) vs active control (Group C). RESULTS: One hundred and seventy-four eligible subjects were randomized and enrolled into three groups: 59 in group A, 56 in group B and 59 in group C. It was shown that group A and group B lowered ALT level even at early stage of study drug administration; when compared with Group C (61.02%), the proportions of ALT normalization at week 4 were significantly greater in Group A (84.75%, P = .0029) and Group B (85.71%, P = .0037) respectively. The results from the univariate logistic model showed that the odds of ALT normalized among subjects in Group A were about 3.6 times greater (OR = 3.55, 95% CI: 1.47-8.57, P = .0049) than subjects in Group C. Similar effect was observed among subjects in Group B (OR = 3.83, 95% CI: 1.54-9.55, P = .0039). CONCLUSIONS: This trial provided preliminary evidence that MgIG is an effective and safe treatment for patients with acute DILI.