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The identification of readers, an important class of proteins that recognize modified residues at specific sites, is essential to uncover the biological roles of post-translational modifications. Photoreactive crosslinkers are powerful tools for investigating readers. However, existing methods usually employ synthetically challenging photoreactive warheads, and their high-energy intermediates generated upon irradiation, such as nitrene and carbene, may cause substantial non-specific crosslinking. Here we report dimethylsulfonium as a methyllysine mimic that binds to specific readers and subsequently crosslinks to a conserved tryptophan inside the binding pocket through single-electron transfer under ultraviolet irradiation. The crosslinking relies on a protein-templated σ-π electron donor-acceptor interaction between sulfonium and indole, ensuring excellent site selectivity for tryptophan in the active site and orthogonality to other methyllysine readers. This method could escalate the discovery of methyllysine readers from complex cell samples. Furthermore, this photo crosslinking strategy could be extended to develop other types of microenvironment-dependent conjugations to site-specific tryptophan.
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Lisina , Compuestos de Sulfonio , Triptófano , Triptófano/química , Triptófano/análogos & derivados , Compuestos de Sulfonio/química , Lisina/química , Lisina/análogos & derivados , Transporte de Electrón , Rayos Ultravioleta , Reactivos de Enlaces Cruzados/química , Procesos Fotoquímicos , Humanos , Proteínas/químicaRESUMEN
BACKGROUND & AIMS: Sarcopenia has been widely recognized as an important predictor of poor outcomes in patients with cancer after surgery, but the controversy remains, and its impact on surgical and oncologic outcomes in patients after abdominal surgery for digestive tract cancer is poorly described. The aim of this study was to evaluate the prognostic impact of sarcopenia on surgical and oncologic outcomes in patients after abdominal surgery for digestive tract cancer. METHODS: Six thousand four hundred and forty-seven consecutive patients who underwent abdominal surgery for digestive tract cancer in our institution were prospectively included. Sarcopenia was defined as skeletal muscle index below the lowest sex-specific quartile using computed tomography scan at L3 before surgery. The surgical and oncologic outcomes were recorded, and univariate and multivariate analyses were performed. RESULTS: Sarcopenia was present in 1638 of 6447 patients (25.4%) with digestive tract cancer before surgery based on the diagnostic cut-off values (43.13 cm2/m2 for men and 37.81 cm2/m2 for women). The incidence of postoperative total and pulmonary complications, and 30-day readmission were significantly higher in sarcopenic group than in nonsarcopenic group (37.4% vs 12.9%, P < 0.001; 3.1% vs 2.1%, P = 0.026; 1.1% vs 0.4%, P = 0.003, respectively). The postoperative hospital stay was significantly longer in sarcopenic patients (9.42 ± 3.40 vs 8.51 ± 3.17 days, P < 0.001). There were significantly more patients receiving postoperative chemotherapy or radiotherapy in sarcopenic group than in nonsarcopenic group (73.1% vs 69.2%, P = 0.003; 10.6% vs 8.8%, P = 0.038, respectively), and patients with sarcopenia had significantly more chemotherapy modifications including delay, dose reduction, or termination (48.5% vs 44.2%, P = 0.018). In addition, during the follow-up period, sarcopenic patients had significantly lower rate of overall survival and disease-free survival than nonsarcopenic patients (53.9% vs 69.3%, P = 0.002; 36.8% vs 59.7%, P = 0.000, respectively). In multivariate analysis, sarcopenia was found to be a risk factor for postoperative complications [odds ratio (OR) = 5.418, 95% confidence interval (CI) = 2.986-9.828, P < 0.001], and was an unfavorable prognostic factor for poor overall survival [hazard ratio (HR) = 0.649, 95% CI = 0.426-0.991, P = 0.045] and disease-free survival (HR = 0.514, 95% CI = 0.348-0.757, P = 0.001). CONCLUSIONS: Sarcopenia could be used as a strong and independent prognostic factor for poor surgical and oncologic outcomes in patients after abdominal surgery for digestive tract cancer. Identification of preoperative sarcopenia in digestive surgery for cancer and targeted approaches may improve its negative outcomes.
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Neoplasias Gastrointestinales/epidemiología , Neoplasias Gastrointestinales/cirugía , Complicaciones Posoperatorias/epidemiología , Sarcopenia/epidemiología , China/epidemiología , Estudios de Cohortes , Comorbilidad , Femenino , Tracto Gastrointestinal/cirugía , Humanos , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Readmisión del Paciente/estadística & datos numéricos , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Sarcopenia/diagnóstico por imagen , Análisis de Supervivencia , Tomografía Computarizada por Rayos X/métodosRESUMEN
BACKGROUND AND OBJECTIVES: Short bowel syndrome (SBS) is a complicated and challenging disease where home parenteral nutrition (HPN) is widely used. The complications of long-term HPN-dependent in adult patients with SBS are poorly documented. This study was mainly aimed to assess the prevalence and risk factors of HPNassociated complications in adult patients with SBS, especially the catheter-related sepsis and HPN-associated liver/biliary disorders. METHODS AND STUDY DESIGN: 47 non-malignant adult patients with SBS who received HPN for more than 2 years in our clinical nutrition center were included. Patients were divided into two groups according to whether HPN-associated complications were present or not. Student's t-test and χ2 test were applied to compare the differences between the two groups. RESULTS: The mean frequency of catheter-related sepsis was 0.31±0.05 per catheter year of HPN. An higher incidence of catheter-related infections (p<0.001) and shorter delay between HPN onset and first infection (p<0.001) were identified as risk factors for catheter-related sepsis. A total of 25 patients (53.2%) developed HPN-associated liver/biliary diseases. The identified risk factors for HPNassociated liver/biliary disorders were higher rate of catheter-related infections (p=0.009), shorter delay between HPN onset and first infection (p=0.017), higher energy content of HPN (p=0.014), higher glucose rate of HPN (p=0.009), and lower lipid rate of HPN (p=0.022). CONCLUSION: Our study revealed that adult patients with SBS receiving long-term HPN treatment developed a low prevalence of catheter-related sepsis but a rather high prevalence of HPN-associated liver/biliary disorders. We also identified several risk factors for HPN-associated complications which should be taken notice of in clinical practice.
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Nutrición Parenteral en el Domicilio/efectos adversos , Síndrome del Intestino Corto/dietoterapia , Adulto , Enfermedades de las Vías Biliares/inducido químicamente , Catéteres/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Cancer cachexia remains a leading cause of morbidity and mortality worldwide, despite extensive research and clinical trials. The prominent clinical feature of cancer cachexia is the continuous loss of skeletal muscle that cannot be fully reversed by conventional nutritional support, and that leads to progressive functional impairment. The mechanism underlying muscle loss in patients with cachexia is poorly understood. The present study analyzed 21 cancer patients with or without cachexia, and demonstrated that mitofusin-2 (Mfn2) was downregulated in the rectus abdominis of patients with cachexia, which was associated with body weight loss. In vitro cell experiments indicated that loss of Mfn2 was associated with atrophy of the C2C12 mouse myoblast cell line. Furthermore, in vivo animal experiments demonstrated that cachexia decreased gastrocnemius muscle mass and Mfn2 expression, and overexpression of Mfn2 in gastrocnemius muscle was able to partially attenuate cachexia-induced gastrocnemius muscle loss. The results of the present study suggested that Mfn2 is involved in cachexia-induced muscle loss and may serve as a potential target for therapy of cachexia.
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INTRODUCTION: The role of laparoscopic surgery in the repair for peptic ulcer disease is unclear. The present study aimed to compare the safety and efficacy of laparoscopic versus open repair for peptic ulcer disease. METHODS: Randomized controlled trials (RCTs) comparing laparoscopic versus open repair for peptic ulcer disease were identified from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and references of identified articles and relevant reviews. Primary outcomes were postoperative complications, mortality, and reoperation. Secondary outcomes were operative time, postoperative pain, postoperative hospital stay, nasogastric tube duration, and time to resume diet. Statistical analysis was carried out by Review Manage software. RESULTS: Five RCTs investigating a total of 549 patients, of whom, 279 received laparoscopic repair and 270 received open repair, were included in the final analysis. There were no significant differences between these two procedures in some primary outcomes including overal postoperative complication rate, mortality, and reoperation rate. Subcategory analysis of postoperative complications showed that laparoscopic repair had also similar rates of repair site leakage, intra-abdominal abscess, postoperative ileus, pneumonia, and urinary tract infection as open surgery, except of the lower surgical site infection rate (P < 0.05). In addition, there were also no significant differences between these two procedures in some second outcomes including operative time, postoperative hospital stay, and time to resume diet, but laparoscopic repair had shorter nasogastric tube duration (P < 0.05) and less postoperative pain (P < 0.05) than open surgery. CONCLUSIONS: Laparoscopic surgery is comparable with open surgery in the setting of repair for perforated peptic ulcer. The obvious advantages of laparoscopic surgery are the lower surgical site infection rate, shorter nasogastric tube duration and less postoperative pain. However, more higher quality studies should be undertaken to further assess the safety and efficacy of laparoscopic repair for peptic ulcer disease.
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Laparoscopía/efectos adversos , Úlcera Péptica Perforada/cirugía , Complicaciones Posoperatorias/epidemiología , Humanos , Tiempo de Internación , Tempo Operativo , Ensayos Clínicos Controlados Aleatorios como Asunto , Reoperación , Resultado del TratamientoRESUMEN
Chronic inflammation is a well-known etiological factor for colorectal cancer (CRC) and cancer cells are known to preferentially metabolize glucose through aerobic glycolysis. However, the connection between chronic inflammation and aerobic glycolysis in the development of CRC is largely unexplored. The present study investigated whether interleukin-6 (IL-6), a pro-inflammatory cytokine, promotes the development of CRC by regulating the aerobic glycolysis and the underlying molecular mechanisms. In colitis-associated CRC mouse, anti-IL-6 receptor antibody treatment reduced the incidence of CRC and decreased the expression of key genes in aerobic glycolysis, whereas the plasma concentrations of glucose and lactate were not affected. Consistently, IL-6 treatment stimulated aerobic glycolysis, upregulated key genes in aerobic glycolysis and promoted cell proliferation and migration in SW480 and SW1116 CRC cells. 6-phoshofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) was the most downregulated gene by anti-IL-6 receptor antibody in colorectal adenoma tissues. Further analysis in human samples revealed overexpression of PFKFB3 in colorectal adenoma and adenocarcinoma tissues, which was also associated with lymph node metastasis, intravascular cancer embolus and TNM stage. In addition, the effect of IL-6 on CRC cells can be abolished by knocking down PRKFB3 through siRNA transfection. Our data suggest that chronic inflammation promotes the development of CRC by stimulating aerobic glycolysis and IL-6 is functioning, at least partly, through regulating PFKFB3 at early stage of CRC.
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Proliferación Celular/genética , Neoplasias Colorrectales/genética , Interleucina-6/genética , Fosfofructoquinasa-2/biosíntesis , Animales , Línea Celular Tumoral , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica , Glucólisis , Humanos , Interleucina-6/metabolismo , Ratones , Estadificación de Neoplasias , Fosfofructoquinasa-2/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Interleukin-6 (IL-6) is a well-known etiological factor of colitis-associated colorectal cancer (CAC) and has a significant role in CAC progression. In addition, hypoxia-inducible factor 1α (HIF-1α) serves a primary role in the progression of CAC. However, the association between IL-6 and HIF-1α during the progression of CAC remains unclear. To investigate this association, the present study induced CAC in a mouse model using azoxymethane and dextran sulfate sodium. In addition, an anti-IL-6 receptor antibody was used to inhibit IL-6. In this model, anti-IL-6 receptor antibody treatment significantly inhibited the development of CAC and the expression of HIF-1α, in colorectal adenomas and adenocarcinomas. In patients with CAC, the HIF-1α gene was demonstrated to be overexpressed in tumor tissue compared with adjacent non-malignant tissue. Furthermore, HIF-1α mRNA expression was positively correlated with serum IL-6 concentration. The results of the present study suggest that IL-6 promotes CAC progression, in the early stage of the disease, through HIF-1α regulation.
RESUMEN
Hypoxia has been proved to be a typical character of solid tumors. Tumor cells prefer to use glucose through the glycolysis pathway instead of aerobic respiration. However, the precise molecular mechanism underlying this so-called Warburg effect remains elusive. In the current study, siRNA was synthesized and transfected into BxPC-3 cell line to silence the expression of HIF-1α gene. It was found that hypoxia induced hypoxia-inducible factor 1α (HIF-1α) overexpression in BxPC-3 cells, enhanced the expression of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase A, thus facilitating glycolysis and making tumor cells more tolerant to hypoxic stress. The silencing of HIF-1α gene significantly attenuated glycolysis under hypoxic conditions, inhibited the growth and invasion ability of BxPC-3 cells, and enhanced hypoxia-induced cell apoptosis.
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Silenciador del Gen , Glucólisis/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/fisiología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Animales , Apoptosis , Hipoxia de la Célula , Línea Celular Tumoral , Proliferación Celular , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Isoenzimas/genética , L-Lactato Deshidrogenasa/genética , Lactato Deshidrogenasa 5 , Ácido Láctico/biosíntesis , Ratones , Ratones Desnudos , Invasividad Neoplásica , Trasplante de Neoplasias , Proteínas Serina-Treonina Quinasas/genética , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , ARN Interferente Pequeño/genética , TransfecciónRESUMEN
BACKGROUND AND OBJECTIVES: Consumption of dietary fat has been reported to be associated with gastric cancer risk, but the results of epidemiologic studies remain inconsistent. We conducted a meta-analysis to summarize the evidence regarding the association between dietary fat intake and gastric cancer risk. METHODS: A comprehensive search of PubMed and EMBASE was performed to identify observational studies providing quantitative estimates between dietary fat and gastric cancer risk. Random effects model was used to calculate the summary relative risk(SRR) in the highest versus lowest analysis. Categorical dose-response analysis was conducted to quantify the association between dietary fat intake and gastric cancer risk. Heterogeneity among studies was evaluated using I2 and tau2(between study variance)statistics. Subgroup analysis and publication bias analysis were also performed. RESULTS: Twenty-two articles were included in the meta-analysis. The SRR for gastric cancer was 1.18 for individuals with highest intake versus lowest intake of total fat (95% confidence interval [CI]: 0.999-1.39; n = 28; P< 0.001; tau2 = 0.12; I2 = 69.5%, 95% CI: 55%-79%) and 1.08 with a daily increase in total fat intake (20 g/d) (95%CI: 1.02-1.14; n = 6; P = 0.09; tau2 = 0.002; I2 = 46.8%, 95% CI: 0%-79%). Positive association between saturated fat intake (SRR = 1.31; 95%CI: 1.09-1.58;n = 18;P<0.001; tau2 = 0.08; I2 = 60.6%, 95% CI: 34%-76%), inverse association between polyunsaturated fat intake (SRR = 0.77; 95%CI: 0.65-0.92; n = 16; P = 0.003; tau2 = 0.06; I2 = 56.2%, 95% CI: 23%-75%) and vegetable fat intake (SRR = 0.55; 95%CI: 0.41-0.74; n = 4;P = 0.12; tau2 = 0.04; I2 = 48.6%, 95% CI: 0%-83%), and no association between monounsaturated fat intake (SRR = 1.00; 95%CI: 0.79-1.25; n = 14; P< 0.001; tau2 = 0.10; I2 = 63.0%, 95% CI: 34%-79%) and animal fat intake (SRR = 1.10; 95%CI: 0.90-1.33; n = 6; P = 0.13;tau2 = 0.02; I2 = 42.0%, 95% CI: 0%-70%) and gastric cancer risk were observed. CONCLUSIONS: Our results suggest that intake of total fat is potentially positively associated with gastric cancer risk, and specific subtypes of fats account for different effects. However, these findings should be confirmed by further well-designed cohort studies with detailed dietary assessments and strict control of confounders.
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Grasas de la Dieta , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/etiología , Humanos , Oportunidad Relativa , RiesgoRESUMEN
Muscle atrophy F-Box (MAFbx)/atrogin-1 and muscle ring-finger-1 (MuRF-1) have been identified as two muscle-specific E3 ubiquitin ligases that are highly expressed in skeletal muscle during muscle atrophy. However, the role of muscle-specific E3 ubiquitin ligases during the process of muscle atrophy of cancer cachexia remains largely unknown. In the present study, we analyzed the expression of atrogin-1 and MuRF-1 in the skeletal muscle of patients with malignant and benign disease. The possible mechanisms were studied both in a colon 26-induced cancer cachexia mouse model and in tumor necrosis factor-α (TNF-α) induced atrophy C2C12 cells. Our results demonstrated that atrogin-1 and MuRF-1 tended to be increased in the skeletal muscle of patients with malignant disease even before weight loss. Non-tumor body weights and gastrocnemius weights were significantly decreased while expression levels of ubiquitin proteasome pathway associated genes (atrogin-1, MuRF-1, ubiquitin and E2-14K) were upregulated in cancer cachexia mice. Significant myotube atrophy with atrogin-1 overexpression was observed in the C2C12 cells treated with TNF-α. Meanwhile, knockdown of atrogin-1 by small interfering RNA (siRNA) protected C2C12 cells from the adverse effect of TNF-α. In conclusion, muscle-specific E3 ubiquitin ligases were upregulated during cancer cachexia, and atrogin-1 may be a potential molecular target for treating muscle atrophy induced by cancer cachexia.
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Caquexia/genética , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Neoplasias/genética , ARN Mensajero/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina/metabolismo , Adulto , Anciano , Animales , Caquexia/etiología , Caquexia/metabolismo , Estudios de Casos y Controles , Línea Celular , Modelos Animales de Enfermedad , Femenino , Humanos , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Atrofia Muscular/etiología , Atrofia Muscular/metabolismo , Neoplasias/complicaciones , Neoplasias/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Ligasas SKP Cullina F-box/genética , Proteínas Ligasas SKP Cullina F-box/metabolismo , Proteínas de Motivos Tripartitos , Factor de Necrosis Tumoral alfa/farmacología , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
OBJECTIVE: To investigate cachexia in hospitalized patients with digestive system cancer and evaluate its impact on clinical outcomes. METHODS: By analyzing the clinical data of 5118 hospitalized patients with digestive system cancer in Zhongshan Hospital of Fudan University from January 2012 to December 2013, cachexia was investigated and clinical outcomes between cachexia patients and non-cachexia patients was compared. RESULTS: The total cachexia rate of hospitalized patients with digestive system cancer was 15.7%(803/5118). The highest rate of cachexia was 34.0%(89/262) in patients with pancreatic cancer followed by gastric cancer 22.4%(261/1164), colon cancer 21.7%(146/672), and rectal cancer 20.1%(117/581). In cachexia group and non-cachexia group, the overall completion rate of radical resection was 67.1%(539/803) and 74.5%(3214/4315) respectively(P<0.05). Compared to the non-cachexia group, the cachexia group was associated with longer postoperative hospital stay [(11.5±6.2) d vs. (9.4±4.9) d, P<0.05], slower postoperative recovery of bowel function [(3.4±0.9) d vs. (3.2±0.8) d, P<0.05], longer postoperative time to intake of semifluid [(4.4±1.5) d vs. (3.9±1.1) d, P<0.05], and more postoperative complications within 28 days after radical surgery [8.9%(48/539) vs. 5.8%(186/3214), P<0.05]. After radical surgery, the ICU admission rate of the cachexia group [24.3%(131/539)] was higher than that of the non-cachexia group [20.1%(646/3214)] with significant difference(P<0.05). Compared to non-cachexia group, the reoperation rate [3.2%(17/539) vs. 1.5%(48/3214), P<0.05], ventilator support rate [8.0%(43/539)vs. 5.7%(184/3214), P<0.05] and mortality [2.4%(13/539) vs. 1.1%(35/3214), P<0.05] in the cachexia group were all significantly higher(all P<0.05). CONCLUSIONS: Cachexia is commen in patients with digestive system cancer. Cachexia has significant adverse effects on clinical outcomes in hospitalized patients with digestive system cancer.
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Caquexia/etiología , Neoplasias del Colon/complicaciones , Neoplasias del Recto/complicaciones , Neoplasias Gástricas/complicaciones , Defecación , Humanos , Complicaciones Posoperatorias , ReoperaciónRESUMEN
OBJECTIVE: To evaluate the safety and short-term outcomes of laparoscopic-assisted surgery for rectal cancer by comparing the efficacy of laparoscopy and open surgery. METHODS: Clinical data of patients with rectal cancer treated by laparoscopy or open surgery in Zhongshan Hospital from April 2011 to June 2012 were analyzed retrospectively, and the clinical outcomes between the two groups were compared. RESULTS: Ninety-six rectal cancer patients undergoing laparoscopic surgery(LS) were enrolled. A total of 216 rectal cancer patients underwent open surgery(OS). There was no operative death in both groups. In LS and OS group, the overall completion rates of TME were 86.4%(83/96) vs. 89.3%(193/216)(P>0.05) respectively, and the overall anal reservation rates were 78.1%(75/96) vs. 75.0%(162/216)(P>0.05) respectively. The mean distance to proximal resection margin and distal resection margin respectively were (10.3±4.1) cm vs.(10.0±4.3) cm(P>0.05) and (3.4±0.9) cm vs. (3.6±1.4) cm(P>0.05) respectively. The mean number of harvested lymph nodes respectively were (12.8±5.2) vs.(13.7±6.4)(P>0.05). Compared to OS, LS presented less blood loss [(98.0±28.7) ml vs. (175.0±41.0) ml, P<0.05], shorter postoperative hospital stay [(9.4±4.9) d vs.(11.6±6.2) d, P<0.05], quicker postoperative recovery of bowel function[(2.7±0.9) d vs. (3.4±0.9) d, P<0.05], shorter postoperative time to intake semi-solid[(3.7±1.2) d vs. (4.4±1.5) d, P<0.05], less postoperative complications(15.6% vs. 25.9%, P<0.05), but longer operative time[(155.7±48.4) min vs. (120.0±26.7) min, P<0.05]. Postoperative follow-up was 6 to 24 months, and the local recurrence of LS and OS was 2.1% and 2.3%(P>0.05). CONCLUSION: Laparoscopic surgery can obtain the same radical efficacy for rectal cancer as compared to open surgery.
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Procedimientos Quirúrgicos del Sistema Digestivo , Laparoscopía , Neoplasias del Recto/cirugía , Canal Anal , Humanos , Ganglios Linfáticos , Recurrencia Local de Neoplasia , Tempo Operativo , Complicaciones Posoperatorias , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: The association between polymorphisms on 5p12 and breast cancer (BC) has been widely evaluated since it was first identified through genome-wide association approach; however, the studies have yielded contradictory results. We sought to investigate this inconsistency by performing a comprehensive meta-analysis on two wildly studied polymorphisms (rs10941679 and rs4415084) on 5p12. METHODS: Databases including Pubmed, EMBASE, Web of Science, EBSCO, and Cochrane Library databases were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. The random-effects model was applied, addressing heterogeneity and publication bias. RESULTS: A total of 19 articles involving 100,083 cases and 163,894 controls were included. An overall random-effects per-allele OR of 1.09 (95% CI: 1.06-1.12; P = 4.5 × 10(-8)) and 1.09 (95% CI: 1.05-1.12; P = 4.2 × 10(-7)) was found for the rs10941679 and rs4415084 polymorphism respectively. Significant results were found in Asians and Caucasians when stratified by ethnicity; whereas no significant associations were found among Africans/African-Americans. Similar results were also observed using dominant or recessive genetic models. In addition, we find both rs4415084 and rs10941679 conferred significantly greater risks of ER-positive breast cancer than of ER-negative tumors. CONCLUSIONS: Our findings demonstrated that rs10941679-G allele and rs4415084-T allele might be risk-conferring factors for the development of breast cancer, especially in Caucasians and East-Asians.
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Neoplasias de la Mama/genética , Cromosomas Humanos Par 5/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple , Pueblo Asiatico/genética , Neoplasias de la Mama/etnología , Neoplasias de la Mama/metabolismo , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/etnología , Genotipo , Humanos , Oportunidad Relativa , Receptores de Estrógenos/metabolismo , Factores de Riesgo , Población Blanca/genéticaRESUMEN
Cytochrome P450 1A2 (CYP1A2) encodes a member of the cytochrome P450 superfamily of enzymes, which play a central role in activating and detoxifying many carcinogens and endogenous compounds thought to be involved in the development of colorectal cancer (CRC). The CYP1A2*C (rs2069514) and CYP1A2*F (rs762551) polymorphism are two of the most commonly studied polymorphisms of the gene for their association with risk of CRC, but the results are conflicting. To derive a more precise estimation of the relationship between CYP1A2 and genetic risk of CRC, we performed a comprehensive meta-analysis which included 7088 cases and 7568 controls from 12 published case-control studies. In a combined analysis, the summary per-allele odds ratio for CRC was 0.91 (95% CI: 0.83-1.00, Pâ=â0.04), and 0.91 (95% CI: 0.68-1.22, Pâ=â0.53), for CYP1A2 *F and *C allele, respectively. In the subgroup analysis by ethnicity, significant associations were found in Asians for CYP1A2*F and CYP1A2*C, while no significant associations were detected among Caucasian populations. Similar results were also observed using dominant genetic model. Potential sources of heterogeneity were explored by subgroup analysis and meta-regression. No significant heterogeneity was detected in most of comparisons. This meta-analysis suggests that the CYP1A2 *F and *C polymorphism is a protective factor against CRC among Asians.
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Neoplasias Colorrectales/genética , Citocromo P-450 CYP1A2/genética , Polimorfismo Genético , Alelos , Estudios de Casos y Controles , Neoplasias Colorrectales/etnología , Predisposición Genética a la Enfermedad , Humanos , Oportunidad Relativa , RiesgoRESUMEN
CYP2C9 enzyme activity is involved in the metabolism of substances related to colorectal cancer (CRC), and it is functionally linked to a genetic polymorphism. Two allelic variants of the CYP2C9 gene, namely CYP2C9*2 and CYP2C9*3, differ from wild-type CYP2C9*1 by single amino acid substitutions. These mutated alleles encode enzymes with altered properties that are associated with impaired metabolism. In the past decade, a number of case-control studies have been carried out to investigate the relationship between the CYP2C9 polymorphism and CRC susceptibility, but the results were conflicting. To investigate this inconsistency, we performed a meta-analysis of 13 studies involving a total of 20,879 subjects for CYP2C9*2 and *3 polymorphisms to evaluate the effect of CYP2C9 on genetic susceptibility for CRC. Overall, the summary odds ratio of CRC was 0.94 (95%CI: 0.87-1.03, Pâ=â0.18) and 1.00 (95%CI: 0.86-1.16, Pâ=â0.99) for CYP2C9 *2 and *3 carriers, respectively. No significant results were observed in heterozygous and homozygous when compared with wild genotype for these polymorphisms. In the stratified analyses according to ethnicity, sample size, diagnostic criterion, HWE status and sex, no evidence of any gene-disease association was obtained. Our result suggest that the *2, *3 polymorphisms of CYP2C9 gene are not associated with CRC susceptibility.
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Hidrocarburo de Aril Hidroxilasas/genética , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/genética , Polimorfismo de Nucleótido Simple , Citocromo P-450 CYP2C9 , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , MasculinoRESUMEN
OBJECTIVE: To demonstrate the expression of proteolysis induce factor(PIF) in the gastrointestinal(GI) cancer cachexia patients and evaluate its role in cancer cachexia. METHODS: Examination of PIF was performed in urine samples from 28 GI cancer cachexia patients, 13 GI cancer patients without cachexia, and 12 weight loss patients with benign disease. PIF was added to the mice cultured C2C12 muscle cells, then the protein kinase B(Akt) phosphorylation and morphological change were measured. RESULTS: The positive rate of PIF in urine of 28 cancer cachexia patients was 53.6%(15/28). In the other two groups, no positive result was detected. PIF could successfully induce Akt phosphorylation, cell atrophy, metamorphosis, and death. The peak of this phosphorylation could be detected after half an hour of the initiation of PIF at a concentration of 4 nmol/L. CONCLUSIONS: PIF is specifically and highly expressed in GI cancer cachexia patients' urine. PIF can induce cancer cachexia possibly by activating Akt phosphorylation and inducing downstream proteolysis.
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Caquexia/etiología , Caquexia/metabolismo , Neoplasias Gastrointestinales/complicaciones , Animales , Línea Celular , Humanos , Ratones , Proteoglicanos , ProteolisisRESUMEN
To gain insight into the role of gene expression alterations in breast cancer progression, we conducted a comprehensive gene expression analysis of a series of cell lines derived from MCF10A, which include benign MCF10A cells, premalignant AT, and malignant CA1a tumor cells. We analyzed gene expression variation using the Agilent Human Genome Oligo Microarray with the goal of identifying gene-specific expression change events. In addition to a previously noted overexpression in oncogene MDM2, HRAS, and PCNA, our studies identified overexpression of Wnt signaling pathway in malignant breast cell lines. The Kaplan-Meier plot showed that high c-Myc expression in breast cancer was associated with tumor progression and the patient's poor survival. This study showed that the Wnt pathway has further provided a basis for the development of potential biomarker for breast cancer prognosis.
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Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Mama/metabolismo , Perfilación de la Expresión Génica , Lesiones Precancerosas/genética , Vía de Señalización Wnt , Biomarcadores de Tumor/metabolismo , Western Blotting , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Células Cultivadas , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/mortalidad , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de SupervivenciaRESUMEN
Pyruvate kinase type M2 (PKM2) has been reported to be involved in aerobic glycolysis and cell growth in various tumors. However, the expression pattern of PKM2 in colorectal cancer (CRC) and the correlation between PKM2 expression and CRC remains unclear. The aim of this study is to investigate PKM2 expression and its possible role in CRC. We found that expression of PKM2 was increased in CRC and the increased PKM2 expression was associated with later stage and lymph metastasis of the tumors. Knockdown of PKM2 suppressed the aerobic glycolysis and decreased lactate production of colon cancer RKO cells. Knockdown of PKM2 repressed proliferation and migration of the cells. Inhibition of PKM2 suppressed xenograft tumor growth of RKO cells in vivo. These results suggest that the expression of PKM2 plays a critical role in development of CRC, and it may provide a growth advantage for colon cancer cells. Thus, PKM2 might be a potential therapeutic target for CRC.
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Movimiento Celular , Proliferación Celular , Neoplasias Colorrectales/enzimología , Piruvato Quinasa/genética , Regulación hacia Arriba , Animales , Línea Celular Tumoral , Neoplasias Colorrectales/patología , Femenino , Expresión Génica , Glucólisis , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Trasplante de Neoplasias , Piruvato Quinasa/metabolismo , Carga TumoralRESUMEN
Increased production of hormone-sensitive lipase (HSL) protein has been demonstrated to be the major cause behind enhanced lipolysis in cancer cachexia. The mechanism governing this alteration is unknown and was presently investigated. This study was conducted to detect the expression of relevant receptors in the adipocytes of cancer cachexia patients, and to elucidate their implication in the increased lipolysis. Gene expressions of beta1-adrenoceptor (ADRB1), beta2-adrenoceptor (ADRB2), beta3-adrenoceptor (ADRB3), alpha2C-adrenoceptor (ADRA2C), natriuretic peptide receptor A (NPRA), insulin receptor (INSR), and HSL were determined in adipose tissues of 34 patients by real-time PCR. Protein levels of ADRB1 and HSL were determined by western blot analysis. beta1-Adrenoceptor (ADRB1) was also detected by immunofluorescence staining. mRNA expressions of both ADRB1 and HSL were approximately 50% elevated selectively in the cachexia group, whereas mRNA levels of the other receptors were unchanged. beta1-Adrenoceptor (ADRB1) protein expression was 1.5-fold increased in cachexia as compared with the cancer controls, and 3-fold increased as compared with nonmalignant controls, and was confirmed as a membrane protein in adipocytes by immunofluorescence. Hormone-sensitive lipase (HSL) protein expression was 2-2.5-fold increased selectively in cachectic patients. There was a positive correlation between the protein expressions of ADRB1 and HSL. As much as approximately 50% of the variations in HSL protein expression could be explained by variations in ADRB1 protein expression. There was a link between ADRB1 protein level and lipolytic rate. Increased ADRB1 expression may account for some of the functional changes of HSL in patients with cancer cachexia.
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Caquexia/fisiopatología , Lipólisis/genética , Neoplasias/genética , Receptores Adrenérgicos beta 1/fisiología , Tejido Adiposo/anatomía & histología , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Adulto , Anciano , Ácidos Grasos no Esterificados/metabolismo , Femenino , Quinasa 3 del Receptor Acoplado a Proteína-G/genética , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/cirugía , Humanos , Lipólisis/fisiología , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Neoplasias/fisiopatología , Selección de Paciente , Reacción en Cadena de la Polimerasa , ARN Neoplásico/genética , ARN Neoplásico/aislamiento & purificación , Receptor de Insulina/genética , Receptores Adrenérgicos beta 1/genética , Receptores del Factor Natriurético Atrial/genéticaRESUMEN
OBJECTIVE: To describe the imaging features of gastrointestinal stromal tumors (GISTs) at initial presentation with clinical, surgical, and pathologic correlation, and to evaluate values of various techniques in GISTs. METHODS: This retrospective study recruited 70 patients with histologically proved GISTs between December 2004, and May 2009 in the Department of General Surgery, Zhongshan Hospital, Fudan Univeristy, Shanghai, China. Each patient underwent CT scanning, 39 patients underwent simultaneous endoscopy, 12 patients underwent endoscopic ultrasound (EUS), and 36 patients underwent transabdominal ultrasonography (TAUS) simultaneously. Features of GISTs were assessed. RESULTS: Computerized tomography findings showed an eccentric mass in 44 patients, an intraluminal component in 24, and a transmural distribution in 2. Forty-two tumors were dumbbell-shaped, 2 were round, while 26 were irregular. Forty-three tumors presented with well-defined masses, while 27 with unclear borders. The arterial phase attenuation showed the continuous enhancement. The portal-venous phase attenuation was heterogeneous in 26 and homogeneous in the other 44. There was a significant correlation between certain CT features and tumor risk stratification. Gastrointestinal stromal tumors were characterized by a smooth shape and normal overlying mucosa in endoscopy, hypoechoic, and solid in TAUS. CONCLUSION: Imaging examinations are pivotal in the management of GISTs. The CT scan is valuable in the diagnosis, staging, and treatment planning of GISTs. Endoscopy and EUS contribute to the detection of mucosal lesions. Other methods including TAUS, fluorodeoxyglucose positron emission tomography, CT gastrography, and MRI help in specific cases.