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Recycling endosomes regulate plasma membrane recycling. Recently, recycling endosome-associated proteins have been implicated in the positioning and orientation of the mitotic spindle and cytokinesis. Loss of MYO5B, encoding the recycling endosome-associated myosin Vb, is associated with tumor development and tissue architecture defects in the gastrointestinal tract. Whether loss of MYO5B expression affects mitosis is not known. Here, we demonstrate that loss of MYO5B expression delayed cytokinesis, perturbed mitotic spindle orientation, led to the misorientation of the plane of cell division during the course of mitosis, and resulted in the delamination of epithelial cells. Remarkably, the effects on spindle orientation, but not cytokinesis, were a direct consequence of physical hindrance by giant late endosomes, which were formed in a chloride channel-sensitive manner concomitant with a redistribution of chloride channels from the cell periphery to late endosomes upon loss of MYO5B. Rab7 availability was identified as a limiting factor for the development of giant late endosomes. In accordance, increasing rab7 availability corrected mitotic spindle misorientation and cell delamination in cells lacking MYO5B expression. In conclusion, we identified a novel role for MYO5B in the regulation of late endosome size control and identify the inability to control late endosome size as an unexpected novel mechanism underlying defects in cell division orientation and epithelial architecture.
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Endossomos/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Miosina Tipo V/metabolismo , Fuso Acromático/metabolismo , Animais , Células CACO-2 , Adesão Celular/fisiologia , Divisão Celular/fisiologia , Linhagem Celular , Membrana Celular/metabolismo , Citocinese/genética , Citocinese/fisiologia , Endossomos/genética , Células Epiteliais/metabolismo , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitose/fisiologia , Cadeias Pesadas de Miosina/genética , Miosina Tipo V/genética , Proteínas rab de Ligação ao GTP/metabolismo , proteínas de unión al GTP Rab7RESUMO
BACKGROUND AND AIMS: Progressive familial intrahepatic cholestasis (PFIC) 6 has been associated with missense but not biallelic nonsense or frameshift mutations in MYO5B, encoding the motor protein myosin Vb (myoVb). This genotype-phenotype correlation and the mechanism through which MYO5B mutations give rise to PFIC are not understood. The aim of this study was to determine whether the loss of myoVb or expression of patient-specific myoVb mutants can be causally related to defects in canalicular protein localization and, if so, through which mechanism. APPROACH AND RESULTS: We demonstrate that the cholestasis-associated substitution of the proline at amino acid position 600 in the myoVb protein to a leucine (P660L) caused the intracellular accumulation of bile canalicular proteins in vesicular compartments. Remarkably, the knockout of MYO5B in vitro and in vivo produced no canalicular localization defects. In contrast, the expression of myoVb mutants consisting of only the tail domain phenocopied the effects of the Myo5b-P660L mutation. Using additional myoVb and rab11a mutants, we demonstrate that motor domain-deficient myoVb inhibited the formation of specialized apical recycling endosomes and that its disrupting effect on the localization of canalicular proteins was dependent on its interaction with active rab11a and occurred at the trans-Golgi Network/recycling endosome interface. CONCLUSIONS: Our results reveal a mechanism through which MYO5B motor domain mutations can cause the mislocalization of canalicular proteins in hepatocytes which, unexpectedly, does not involve myoVb loss-of-function but, as we propose, a rab11a-mediated gain-of-toxic function. The results explain why biallelic MYO5B mutations that affect the motor domain but not those that eliminate myoVb expression are associated with PFIC6.
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Colestase Intra-Hepática/genética , Mutação , Cadeias Pesadas de Miosina/genética , Miosina Tipo V/genética , Genótipo , Humanos , Células Tumorais CultivadasRESUMO
BACKGROUND: After radical surgery, patients with esophageal cancer should undergo long-term surveillance of disease relapse. However, the optimal follow-up strategy remains to be explored. METHOD: A total of 4688 patients were recruited. Recursive partition analysis was applied to develop recurrence risk stratification for patients. The follow-up strategies of each stratification were developed based on monthly recurrence probability and validated by bootstrap validation and an external dataset. A Markov decision-analytic model was constructed to evaluate the cost-effectiveness of the follow-up strategies. RESULTS: Patients were stratified into four groups according to four pathological features. The authors applied a random survival forest to calculate the monthly recurrence probability of each group. Based on the temporal distribution of recurrences, the authors further established surveillance strategies for four groups. The strategies were validated as optimal protocols by bootstrap resampling and another dataset. Markov cost-effective analysis indicated that our recommended strategies outperformed the mainstream protocols from guidelines. Using less than 12 visits across the first 5 years on average, our follow-up strategies were more efficient than the NCCN recommended strategies (14 visits average). Our results also supported the computerized tomography from the neck to the upper abdomen as a routine examination and PETCT of distant metastasis for some groups with high risks. CONCLUSION: Our study provided data-driven evidence of personalized and economic follow-up strategies for esophageal cancer patients and shed light on follow-up optimization for other cancer types.
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Neoplasias Esofágicas , Recidiva Local de Neoplasia , Humanos , Estudos de Coortes , Seguimentos , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/patologia , Probabilidade , Análise Custo-BenefícioRESUMO
BACKGROUND: Although electromagnetic navigation bronchoscopy (ENB) is highly sensitive in the diagnosis of peripheral pulmonary nodules (PPNs), its diagnostic yield for subgroups of smaller PPNs is under evaluation. OBJECTIVES: Diagnostic yield evaluation of biopsy using ENB for PPNs <2 cm. DESIGN: The diagnostic yield, sensitivity, specificity, positive predictive value, and negative predictive value of the ENB-mediated biopsy for PPNs were evaluated. METHODS: Patients who had PPNs with diameters <2 cm and underwent ENB-mediated biopsy between May 2015 and February 2020 were consecutively enrolled. The final diagnosis was made via pathological examination after surgery. RESULTS: A total of 82 lesions from 65 patients were analyzed. The median tumor size was 11 mm. All lesions were subjected to ENB-mediated biopsy, of which 29 and 53 were classified as malignant and benign, respectively. Subsequent segmentectomy, lobectomy, or wedge resection, following pathological examinations were performed on 64 nodules from 57 patients. The overall sensitivity, specificity, positive predictive value, and negative predictive value for nodules <2 cm were 53.3%, 91.7%, 92.3%, and 51.2%, respectively. The receiver operating curve showed an area under the curve of 0.721 (p < 0.001). Additionally, the sensitivity, specificity, positive predictive value, and negative predictive value were 62.5%, 100%, 100%, and 42.9%, respectively, for nodules with diameters equal to or larger than 1 cm; and 30.8%, 86.7%, 66.7%, and 59.1%, respectively, for nodules less than 1 cm. In the subgroup analysis, neither the lobar location nor the distance of the PPNs to the pleura affected the accuracy of the ENB diagnosis. However, the spiculated sign had a negative impact on the accuracy of the ENB biopsy (p = 0.010). CONCLUSION: ENB has good specificity and positive predictive value for diagnosing PPNs <2 cm; however, the spiculated sign may negatively affect ENB diagnostic accuracy. In addition, the diagnostic reliability may only be limited to PPNs equal to or larger than 1 cm.
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Broncoscopia , Fenômenos Eletromagnéticos , Neoplasias Pulmonares , Nódulos Pulmonares Múltiplos , Valor Preditivo dos Testes , Humanos , Broncoscopia/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/diagnóstico , Nódulos Pulmonares Múltiplos/patologia , Nódulos Pulmonares Múltiplos/diagnóstico , Nódulos Pulmonares Múltiplos/cirurgia , Estudos Retrospectivos , Carga Tumoral , Adulto , Nódulo Pulmonar Solitário/patologia , Nódulo Pulmonar Solitário/diagnóstico , Nódulo Pulmonar Solitário/cirurgia , Nódulo Pulmonar Solitário/diagnóstico por imagem , Reprodutibilidade dos Testes , Idoso de 80 Anos ou mais , Biópsia Guiada por Imagem/métodosRESUMO
Background: Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma which that highly aggressive and heterogeneous. Glycolysis has been implicated in the regulation of tumor microenvironment (TME) and development. In this study, we aimed to establish a glycolysis-related prognostic model for the risk stratification, prognosis prediction, and immune landscape evaluation in patients with DLBCL. Methods: Three independent datasets GSE181063, GSE10846, and GSE53786 containing gene expression profiles and clinical data were downloaded from the Gene Expression Omnibus (GEO) database. The glycolysis-related prognostic model was developed with Cox and Least Absolute Shrinkage and Selector Operation (LASSO) regression and validated. A nomogram integrating clinical factors and glycolytic risk scores was constructed. The composition of the TME was analyzed with the ESTIMATE algorithm and single-sample gene set enrichment analysis (ssGSEA). Results: A glycolytic risk model containing eight genes was developed. The area under the receiver operating characteristic (ROC) curve (AUC) for the 1-, 3-, and 5-year was 0.718, 0.695, and 0.688, respectively. Patients in the high-risk group had significantly lower immune scores, elevated tumor purity, and poorer survival compared with those in the low-risk group. The nomogram constructed based on glycolytic risk score, age, Eastern Cooperative Oncology Group performance status (ECOG-PS), use of rituximab, and cell of origin (COO) displayed better prediction performance compared with the International Prognostic Index (IPI) in DLBCL. The glycolytic risk score was negatively correlated with the infiltration level of activated CD8 T cells, activated dendritic cells, natural killer cells, and macrophages and immune checkpoint molecules including PD-L2, CTLA4, TIM-3, TIGIT, and B7-H3. Conclusion: These results suggested that the glycolytic risk model could accurately and stably predict the prognosis of patients with DLBCL and might unearth the possible explanation for the glycolysis-related poor prognosis.
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BACKGROUND: The overall prognosis of primary mediastinal germ cell tumors (PMGCTs) is poor and the associated prognostic factors are not fully understood. Our goal was to investigate the prognostic factors of PMGCTs and to develop a validated prognostic prediction model. MATERIALS AND METHODS: A total of 114 PMGCTs with specific pathological types were included in this study. Clinicopathological characteristics of nonseminomatous PMGCTs and mediastinal seminomas were compared using the χ2 or Fisher's exact test. Independent prognostic factors of nonseminomatous PMGCTs screened using the univariate and multivariate Cox regression analysis were then used to generate a nomogram. The predictive performance of the nomogram was evaluated using the concordance index, decision curve, and the area under the receiver operating characteristic curve (AUC) and validated by bootstrap resampling. The Kaplan-Meier curves of independent prognostic factors were analyzed. RESULTS: This study included 71 cases of nonseminomatous PMGCTs and 43 cases of mediastinal seminomas. The 3-year overall survival rates for nonseminomatous PMGCTs and mediastinal seminomas patients were 54.5 and 97.4%, respectively. The overall survival prognostic nomogram for nonseminomatous PMGCTs was established by integrating independent prognostic factors, including the Moran-Suster stage, white blood cell, hemoglobin, and platelet-lymphocyte ratio. The nomogram demonstrated good performance with a concordance index of 0.760 and the 1-year and 3-year AUC values of 0.821 and 0.833, respectively. These values were better than those of the Moran-Suster stage system. The bootstrap validation had an AUC of 0.820 (0.724-0.915) and showed a well-fitting calibration curve. Besides, patients with mediastinal seminomas showed favorable clinical outcomes and all the nine patients received neoadjuvant therapy and postoperative surgery achieved pathological complete response. CONCLUSION: A nomogram based on staging and blood routine examination results was established to accurately and consistently predict the prognosis of patients with nonseminomatous PMGCTs.
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Neoplasias do Mediastino , Neoplasias Embrionárias de Células Germinativas , Seminoma , Neoplasias Testiculares , Humanos , Masculino , Prognóstico , Neoplasias do Mediastino/terapia , Nomogramas , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/terapiaRESUMO
Microvillus inclusion disease (MVID) is a rare, inherited, congenital, diarrheal disorder that is invariably fatal if left untreated. Within days after birth, MVID presents as a life-threatening emergency characterized by severe dehydration, metabolic acidosis, and weight loss. Diagnosis is cumbersome and can take a long time. Whether MVID could be diagnosed before birth is not known. Anecdotal reports of MVID-associated fetal bowel abnormalities suspected by ultrasonography (that is, dilated bowel loops and polyhydramnios) have been published. These are believed to be rare, but their prevalence in MVID has not been investigated. Here, we have performed a comprehensive retrospective study of 117 published MVID cases spanning three decades. We find that fetal bowel abnormalities in MVID occurred in up to 60% of cases of MVID for which prenatal ultrasonography or pregnancy details were reported. Suspected fetal bowel abnormalities appeared in the third trimester of pregnancy and correlated with postnatal, early-onset diarrhea and case-fatality risk during infancy. Fetal bowel dilation correlated with MYO5B loss-of-function variants. In conclusion, MVID has already started during fetal life in a significant number of cases. Genetic testing for MVID-causing gene variants in cases where fetal bowel abnormalities are suspected by ultrasonography may allow for the prenatal diagnosis of MVID in a significant percentage of cases, enabling optimal preparation for neonatal intensive care.
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Background: Esophageal squamous cell carcinoma (ESCC) is characterized clinically by frequent recurrence, leading to a poor prognosis after radical surgery. The aim of this study was to identify a prognostic nomogram to predict the post-progression survival (PPS) of ESCC patients based on the features of primary tumor and recurrence. Methods: A total of 234 ESCC patients who underwent recurrence after radical surgery were enrolled in this study. The independent prognostic factors screened by the univariate and multivariate Cox regression analysis were subsequently used to construct a nomogram. The predictive performance of the nomogram was evaluated with the concordance index (C-index), decision curve, and the area under the receiver operating characteristic curve (AUC) and validated in two validation cohorts. The Kaplan-Meier curves of different recurrence patterns were analyzed. Results: The prognostic nomogram of PPS was established by integrating independent prognostic factors, including age, body mass index, number of lymph node dissection, recurrence pattern, and recurrence treatment. The nomogram demonstrated good performance, with C-index values of 0.756, 0.817, and 0.730 for the training and two validation cohorts. The 1-year AUC values were 0.773, 0.798, and 0.735 and 3-year AUC values were 0.832, 0.871, and 0.791, respectively. Furthermore, we found that patients with bone metastasis displayed the worst PPS compared to other isolated recurrence patterns. Conclusion: We constructed a nomogram to reliably predict PPS, which would be valuable to provide individual managements for ESCC patients after radical surgery.
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BACKGROUND: The impact of early oral feeding after esophagectomy on brain-gut peptide secretion and gut function recovery has not been well investigated. This study aimed to fill this research gap. METHODS: This study was based on a randomized clinical trial (ClinicalTrials.gov: NCT01998230). The patients in the early oral feeding group started oral food intake on postoperative day 1. In the late oral feeding group, nasogastric/nasoenteral feeding was applied from postoperative day 1 to 7, after which the patients began oral food intake. Serum brain-gut peptides were selected as the primary end points and tested before surgery and on postoperative days 1, 3, and 5. The time to first flatus and first defecation after surgery were evaluated. RESULTS: A total of 110 participants undergoing minimally invasive McKeown esophagectomy were prospectively included, with 63 patients in the early oral feeding group and 47 patients in the late oral feeding group. The distribution of clinicopathological characteristics was balanced between the 2 groups. Perioperative dynamic surveillance demonstrated higher serum concentrations of excitatory brain-gut peptides (gastrin P = .021, motilin P = .027, and substance-P P = .023) and lower serum concentrations of inhibitory brain-gut peptides (cholecystokinin P = .004 and somatostatin P = .019) in the early oral feeding group. Perioperative serum levels of brain-gut peptides correlated with postoperative early flatus and defecation. The multivariate analysis showed early oral feeding (versus late oral feeding) to be an independent predictive factor for early flatus and defecation (hazard ratio 2.40, P < .001; hazard ratio 2.73, P < .001, respectively). CONCLUSION: The early oral feeding program may accelerate the recovery of gut function by regulating brain-gut peptide secretion. Brain-gut peptides are possible treatment targets to improve early oral feeding benefits and promote personalized early oral feeding programs.
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Esofagectomia , Flatulência , Encéfalo , Esofagectomia/efeitos adversos , Humanos , Intubação Gastrointestinal , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Recuperação de Função FisiológicaRESUMO
Microvillus inclusion disease (MVID) is a rare enteropathy caused by mutations in the MYO5B or STX3 gene. MVID is a disease that is difficult to manage with clinical heterogeneity. Therefore, knowledge about factors influencing MVID morbidity and mortality is urgently needed. Triggered by a recent study that reported a high percentage of preterm births in twelve cases of MVID, we have conducted a comprehensive retrospective study involving 88 cases of MVID with reported gestational ages. We found that moderate to late preterm birth occurred in more than half of all cases, and this was particularly prominent in MYO5B-associated MVID. Preterm birth in MVID counterintuitively correlated with higher birth weight percentiles, and correlated with higher stool outputs and a significantly shorter average survival time. Data from this study thus demonstrate an increased risk of preterm birth in MYO5B-associated MVID, with a clinical impact on morbidity and mortality. Adverse effects associated with preterm birth should be taken into account in the care of children diagnosed with MVID. Documentation of gestational age may contribute to a better prognostic risk assessment in MVID.
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Intestinal fibrosis is a common complication of inflammatory bowel disease. So far, there is no safe and effective drug for intestinal fibrosis. Pirfenidone is an anti-fibrotic compound available for the treatment of idiopathic pulmonary fibrosis. Here, we explored the anti-proliferative and anti-fibrotic properties of pirfenidone on primary human intestinal fibroblasts (p-hIFs). p-hIFs were cultured in the absence and presence of pirfenidone. Cell proliferation was measured by a real-time cell analyzer (xCELLigence) and BrdU incorporation. Cell motility was monitored by live cell imaging. Cytotoxicity and cell viability were analyzed by Sytox green, Caspase-3 and Water Soluble Tetrazolium Salt-1 (WST-1) assays. Gene expression of fibrosis markers was determined by quantitative reverse transcription PCR (RT-qPCR). The mammalian target of rapamycin (mTOR) signaling was analyzed by Western blotting and type I collagen protein expression additionally by immunofluorescence microscopy. Pirfenidone dose-dependently inhibited p-hIF proliferation and motility, without inducing cell death. Pirfenidone suppressed mRNA levels of genes that contribute to extracellular matrix production, as well as basal and TGF-ß1-induced collagen I protein production, which was associated with inhibition of the rapamycin-sensitive mTOR/p70S6K pathway in p-hIFs. Thus, pirfenidone inhibits the proliferation of intestinal fibroblasts and suppresses collagen I production through the TGF-ß1/mTOR/p70S6K signaling pathway, which might be a novel and safe anti-fibrotic strategy to treat intestinal fibrosis.
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Colágeno Tipo I/biossíntese , Fibroblastos/citologia , Fibroblastos/metabolismo , Intestinos/citologia , Piridonas/farmacologia , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Proteínas da Matriz Extracelular/metabolismo , Fibroblastos/efeitos dos fármacos , Humanos , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fator de Crescimento Transformador beta1/farmacologiaRESUMO
Microvillus inclusion disease (MVID) is a rare inherited and invariably fatal enteropathy, characterized by severe intractable secretory diarrhea and nutrient malabsorption. No cure exists, and patients typically die during infancy because of treatment-related complications. The need for alternative treatment strategies is evident. Several pharmacological interventions with variable successes have been tried and reported for individual patients as part of their clinical care. Unfortunately, these interventions and their outcomes have remained hidden in case reports and have not been reviewed. Further, recent advances regarding MVID pathogenesis have shed new light on the outcomes of these pharmacological interventions and offer suggestions for future clinical research and trials. Hence, an inventory of reported pharmacological interventions in MVID, their rationales and outcomes, and a discussion of these in the light of current knowledge is opportune. Together with a discussion on MVID-specific pharmacokinetic, -dynamic, and -genetic concerns that pose unique challenges regarding pharmacological strategies, we envision that this paper will aid researchers and clinicians in their efforts to develop pharmacological interventions to combat this devastating disease.
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HEADING AIMS: MicroRNA-27b (miR-27b) has been shown to play a role in the progression of many different forms of cancer, but its specific relevance in the context of non-small cell lung cancer (NSCLC) remains uncertain. As such, this study sought to explore the role of miR-27b in NSCLC and the mechanisms whereby it functions. MATERIALS AND METHODS: We quantified miR-27b and target gene expression via quantitative real-time PCR (RT-qPCR).We then used functional including proliferation assays, migration assay, flow cytometry, and western blotting to explore the mechanisms whereby miR-27b functions in vitro and in vivo. We additionally confirmed miR-27b target genes via luciferase reporter assay. KEY FINDINGS: We observed a marked decrease in miR-27b expression in NSCLC patient samples relative to paracancerous control tissues. We further found that altering miR-27b expression levels in vitro affected NSCLC tumor cell migration, proliferation, and ability to undergo epithelial-mesenchymal transition. Through the use of target prediction algorithms we identified Snail to be a miR-27b target protein that was suppressed when this miRNA was highlight expressed. Lastly, we found miR-27b expression to increase NSCLC cell sensitivity to cisplatin through its ability to target Snail. SIGNIFICANCE: Our results clearly demonstrate that miR-27b can suppress NSCLC tumor development and progression, highlighting this miR-27b/Snail1 axis as putative target for the therapeutic treatment of NSCLC.
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Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal/fisiologia , Neoplasias Pulmonares/tratamento farmacológico , MicroRNAs/fisiologia , Fatores de Transcrição da Família Snail/fisiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Regulação para Baixo , Células HEK293 , Humanos , Neoplasias Pulmonares/patologiaRESUMO
Cyclooxygenase-2 (COX-2) and interleukin-32 (IL-32) expression has been examined in various carcinomas and inflammations, and has been suggested to be significant in tumor progression and prognosis. The present study was conducted to investigate the expression of COX-2 and IL-32 in primary gastric B-cell lymphoma in order to define their clinical significance and their association with Helicobacter pylori (Hp) infection. COX-2 and IL-32 protein expression was detected in 31 primary gastric B-cell lymphoma patients and 19 chronic gastritis patients with immunohistochemistry. COX-2 and IL-32 expression was significantly higher in primary gastric lymphoma (PGL) tissues compared with gastritis tissues (51.6 vs. 21.1% for COX-2, P=0.032; and 58.1 vs. 26.3% for IL-32, P=0.029) and was significantly higher in Hp+ lymphoma tissues compared with Hp- lymphoma tissues (66.7 vs. 20% for COX-2, P=0.015; and 71.4 vs. 30% for IL-32, P=0.029). In the PGL tissues, the expression level of COX-2 was positively correlated with the expression level of IL-32, and the two were each positively correlated with Hp infection (P=0.004 for COX-2 and IL-32; P=0.01 for COX-2 and Hp infection; and P=0.003 for IL-32 and Hp infection). COX-2 expression was found to be significantly associated (P<0.05) with an aggressive tumor type, higher expression of Ki-67, frequent lymph node metastasis and advanced stage. IL-32 expression was found to be significantly correlated (P<0.05) with frequent lymph node metastasis and an advanced stage. The survival time was longer in the COX-2- and IL-32- lymphoma patients compared with the COX-2+ and IL-32+ lymphoma patients, but these differences were not statistically significant. These results suggested that Hp infection and the expression of COX-2 and IL-32 were closely linked with each other, and that the overexpression of COX-2 and IL-32 was correlated with tumor progression in primary gastric B-cell lymphoma, thus indicating potential novel therapeutic target.
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The programmed death-1 (PD-1)/programmed death-ligands (PD-Ls) signal pathway has been implicated as a potential immune escape mechanism in several human cancers. However, the studies of PD1/PDLs pathway in esophageal squamous cell carcinoma (ECSS) are not yet sufficient. The current study investigated the expression of PDL1, PDL2 and PD1 in ESCC tissues. The correlations between the expression of these proteins and clinical histopathological parameters were analyzed. Then the stable transfected Ec109 cell lines overexpressing PDL1/PDL2 were established by plasmid transfection successfully. Ec109 and CD8+ T cells were cocultured to analyze the effects of PD1/PDLs signal pathway on the function of CD8+ T cells including proliferation, apoptosis and interferonγ production. We found that PDL1-positive patients had significantly poorer prognosis than the negative patients, while their prognosis was not related to PDL2 expression. The count of PD1+ TILs (tumorinfiltrating lymphocytes) was negatively correlated with both PDL1 and PDL2 expression. In functional studies, we found that PD1/PDLs signal pathway was able to downregulate the function of CD8+ T lymphocyte and its function could be restored by blocking the signal pathway. This indicates that PD1/PDLs may prevent effective antitumor immunity, which provides important evidence to delineate the cellular immune deficiency mechanism in ESCC. Therefore, PD-1/PD-Ls are predicted to become novel targets for ESCC immunotherapy.
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Antígeno B7-H1/biossíntese , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/imunologia , Neoplasias Esofágicas/imunologia , Proteína 2 Ligante de Morte Celular Programada 1/biossíntese , Evasão Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/imunologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Separação Celular , Técnicas de Cocultura , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteína 2 Ligante de Morte Celular Programada 1/imunologia , Reação em Cadeia da Polimerase em Tempo Real , TransfecçãoRESUMO
OBJECTIVES: Nil-by-mouth with enteral tube feeding is widely practised for several days after resection and reconstruction of oesophageal cancer. This study investigates early changes in postoperative gastric emptying and the feasibility of early oral feeding after thoracolaparoscopic oesophagectomy for patients with oesophageal cancer. METHODS: Between January 2013 and August 2013, gastric emptying of liquid food and the feasibility of early oral feeding after thoracolaparoscopic oesophagectomy was investigated in 68 patients. Sixty-five patients previously managed in the same unit who routinely took liquid food 7 days after thoracolaparoscopic oesophagectomy served as controls. RESULTS: The mean preoperative half gastric emptying time (GET1/2) was 66.4 ± 38.4 min for all 68 patients, and the mean GET1/2 at postoperative day (POD) 1 and POD 7 was statistically significantly shorter than preoperative GET1/2 (23.9 ± 15.7 min and 24.1 ± 7.9 min, respectively, both P-values <0.001). Of the 68 patients who were enrolled to analyse the feasibility of early oral feeding, 2 (3.0%) patients could not take food as early as planned. The rate of total complication was 20.6% (14/68) and 29.2% (19/65) in the early oral feeding group and the late oral feeding group, respectively (P = 0.249). Compared with the late oral feeding group, time to first flatus and bowel movement was significantly shorter in the early oral feeding group. CONCLUSIONS: Compared with preoperative gastric emptying, early postoperative gastric emptying for liquid food after oesophagectomy is significantly faster. Postoperative early oral feeding in patients with thoracolaparoscopic oesophagectomy is feasible and safe.
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Nutrição Enteral/estatística & dados numéricos , Neoplasias Esofágicas/cirurgia , Esofagectomia/métodos , Cuidados Pós-Operatórios/estatística & dados numéricos , Idoso , Nutrição Enteral/métodos , Esofagectomia/efeitos adversos , Feminino , Esvaziamento Gástrico , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Pós-Operatórios/métodos , Complicações Pós-Operatórias , Estudos Prospectivos , Fatores de RiscoRESUMO
Potentially fatal chemotherapy (CT)-related gastrorrhagia and gastric perforation in patients with gastric lymphoma present difficult problems to doctors. We retrospectively analyzed 54 patients with ulcerative gastric diffuse large B-cell lymphoma (G-DLBCL) to compare the safety and efficacy of low-dose pre-phase CT before 4-6 cycles of conventional-dose CT (n = 28) with 4-6 cycles of conventional-dose CT (n = 26) between October 2005 and August 2014. Patients who received low-dose pre-phase before conventional-dose CT showed a lower gastrorrhagia or gastric perforation rate (0% vs. 15.4%, p = 0.047) and higher complete response (CR) rate (78.6% vs. 46.2%, p = 0.023) and 5-year progression-free survival (PFS) rate (63% vs. 31%, p = 0.021) than patients who received conventional-dose CT alone. Our study suggests that low-dose pre-phase therapy before conventional-dose CT provides a safe and effective method for ulcerative G-DLBCL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Úlcera Gástrica/tratamento farmacológico , Adolescente , Adulto , Idoso , Ciclofosfamida/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento , Vincristina/administração & dosagem , Adulto JovemRESUMO
OBJECTIVE: To investigate the feasibility of no nasogastric intubation and early oral feeding at will after thoracolaparoscopic esophagectomy for patients with esophageal cancer. METHODS: Between January 2013 and January 2014, the feasibility of no nasogastric intubation and early oral feeding at postoperative day(POD) 1 after thoracolaparoscopic esophagectomy was prospectively investigated in 156 patients (trial group) with esophageal cancer in the Henan Cancer Hospital. One hundred and sixty patients previously managed in the same unit who were treated routinely after thoracolaparoscopic esophagectomy were served as control group. RESULTS: Of 156 patients of trial group, 6(3.8%) patients could not take food early as planned because of postoperative complications. The overall complication rate in trial group was 19.2%(30/156), which was 25.0%(30/160) in control group (P=0.217). The anastomotic leakage in trial group and control group was 2.6%(4/156) and 4.3%(7/160) respectively (P=0.380). Compared with control group, time to first flatus [(2.1±0.9) d vs. (3.3±1.1) d, P<0.001], bowel movement [(4.4±1.3) d vs. (6.6±1.0) d, P<0.001] and postoperative hospital stay [(8.3±3.2) d vs. (10.4±3.6) d, P<0.001] were significantly shorter in trial group. CONCLUSIONS: No nasogastric intubation and early oral feeding postoperatively in patients with thoracolaparoscopic esophagectomy is feasible and safe. This management can shorten postoperative hospital stay and fasten postoperative bowel function recovery.