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1.
J Clin Invest ; 132(5)2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35085106

RESUMO

SMAD3 plays a central role in cancer metastasis, and its hyperactivation is linked to poor cancer outcomes. Thus, it is critical to understand the upstream signaling pathways that govern SMAD3 activation. Here, we report that SMAD3 underwent methylation at K53 and K333 (K53/K333) by EZH2, a process crucial for cell membrane recruitment, phosphorylation, and activation of SMAD3 upon TGFB1 stimulation. Mechanistically, EZH2-triggered SMAD3 methylation facilitated SMAD3 interaction with its cellular membrane localization molecule (SARA), which in turn sustained SMAD3 phosphorylation by the TGFB receptor. Pathologically, increased expression of EZH2 expression resulted in the accumulation of SMAD3 methylation to facilitate SMAD3 activation. EZH2-mediated SMAD3 K53/K333 methylation was upregulated and correlated with SMAD3 hyperactivation in breast cancer, promoted tumor metastasis, and was predictive of poor survival outcomes. We used 2 TAT peptides to abrogate SMAD3 methylation and therapeutically inhibit cancer metastasis. Collectively, these findings reveal the complicated layers involved in the regulation of SMAD3 activation coordinated by EZH2-mediated SMAD3 K53/K333 methylation to drive cancer metastasis.


Assuntos
Neoplasias da Mama , Proteína Smad3 , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metilação , Fosforilação , Transdução de Sinais , Proteína Smad3/genética , Proteína Smad3/metabolismo
2.
Dis Colon Rectum ; 65(4): 519-528, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-34759244

RESUMO

BACKGROUND: The safety and feasibility of laparoscopic surgery for the management of rectal gastrointestinal stromal tumors are unknown. OBJECTIVE: This study aimed to compare the surgical and oncologic results of laparoscopic versus open surgery for the treatment of rectal gastrointestinal stromal tumors. DESIGN: This was a retrospective multicenter propensity score-matched study to minimize heterogeneity between groups and focus on the difference between surgery strategies. SETTINGS: Eleven Chinese tertiary hospitals participated in this study. PATIENTS: A total of 364 patients with pathologically confirmed rectal gastrointestinal stromal tumors were retrospectively analyzed. MAIN OUTCOME MEASURES: Relapse-free survival, postoperative hospital stay length, and 30-day postoperative complication rate were the main outcome measures. RESULTS: We enrolled 214 patients who underwent surgical operation for primary localized rectal gastrointestinal stromal tumors. After propensity score matching, 134 cases involved in the comparison (67 laparoscopic vs 67 open surgery) were randomly matched (1:1) by sex, age, tumor size, tumor site, and neoadjuvant therapy. The laparoscopic surgery group had superior relapse-free survival (χ2 = 4.46, p = 0.04), and fewer complications (6.0% vs 25.4%, p = 0.002). No significant difference was found in the length of postoperative hospital stay between the laparoscopic surgery and open surgery groups (9.66 ± 5.42 vs. 10.64 ± 4.93, p = 0.28). Subgroup analysis showed that the laparoscopic surgery group had superior relapse-free survival (χ2 = 4.14, p = 0.04) and fewer complications after surgery (2.9% vs 24.4%, p = 0.01) in the rectal gastrointestinal stromal tumors ≤5 cm subgroup. LIMITATIONS: This study was limited by the nature of retrospective reviews and relatively short follow-up period. CONCLUSIONS: Laparoscopic surgery offers a safe and feasible option for the radical resection of primary localized rectal gastrointestinal stromal tumors, especially for patients with rectal gastrointestinal stromal tumors ≤5 cm. See Video Abstract at http://links.lww.com/DCR/B764. CIRUGA LAPAROSCPICA VERSUS CIRUGA ABIERTA PARA TUMORES DEL ESTROMA GASTROINTESTINAL DE RECTO UN ANLISIS MULTICNTRICO EMPAREJADO POR PUNTAJE DE PROPENSIN: ANTECEDENTES:Se desconoce la seguridad y factibilidad de la cirugía laparoscópica para el tratamiento de los tumores del estroma gastrointestinal de recto.OBJETIVO:Comparar los resultados quirúrgicos y oncológicos de la cirugía laparoscópica versus cirugía abierta para el tratamiento de los tumores del estroma gastrointestinal de recto.DISEÑO:Estudio retrospectivo multicéntrico emparejado por puntuación de propensión para minimizar la heterogeneidad entre los grupos y centrarse en las diferencias entre las estrategias quirúrgicas.AJUSTES:Once hospitales terciarios de la China participaron en este estudio.PACIENTES:Se analizaron retrospectivamente un total de 364 pacientes con tumores del estroma gastrointestinal de recto confirmados patológicamente.PRINCIPALES MEDIDAS DE VALORACION:Supervivencia sin recidiva, duración de la estancia hospitalaria postquirúrgica y tasa de complicaciones postquirúrgicas a los 30 días.RESULTADOS:Inscribimos a 214 pacientes que fueron sometidos a cirugía por tumores primariamente localizados del estroma gastrointestinal de recto. Después del emparejamiento por puntaje de propensión, 134 casos involucrados en la comparación (67 laparoscópicos versus 67 cirugía abierta) fueron emparejados aleatoriamente (1: 1) por sexo, edad, tamaño del tumor, sitio del tumor y terapia neoadyuvante. El grupo de cirugía laparoscópica tuvo una supervivencia sin recidiva superior (χ2 = 4,46, p = 0,04) y menos complicaciones (6,0% frente a 25,4%, p = 0,002). No se encontraron diferencias significativas en la duración de la estancia hospitalaria postquirúrgica entre los grupos de cirugía laparoscópica y cirugía abierta (9,66 ± 5,42 frente a 10,64 ± 4,93, p = 0,28). El análisis de subgrupos mostró que el grupo de cirugía laparoscópica tuvo una supervivencia sin recidiva superior (χ2 = 4,14, p = 0,04) y menos complicaciones después de la cirugía (2,9% frente a 24,4%, p = 0,01) en el subgrupo de tumores del estroma gastrointestinal de recto ≤ 5 cm.LIMITACIONES:La naturaleza de la revisión retrospectiva y el período de seguimiento relativamente corto son limitaciones de este estudio.CONCLUSIONES:La cirugía laparoscópica ofrece una opción segura y factible para la resección radical de tumores primariamente localizados del estroma gastrointestinal de recto, especialmente para pacientes con tumores ≤5 cm. Consulte Video Resumen en http://links.lww.com/DCR/B764.


Assuntos
Tumores do Estroma Gastrointestinal , Laparoscopia , Neoplasias Retais , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Laparoscopia/métodos , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/cirurgia , Pontuação de Propensão , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia , Estudos Retrospectivos
3.
Cancer Commun (Lond) ; 41(12): 1373-1386, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34738326

RESUMO

BACKGROUND: To date, there is no approved blood-based biomarker for breast cancer detection. Herein, we aimed to assess semaphorin 4C (SEMA4C), a pivotal protein involved in breast cancer progression, as a serum diagnostic biomarker. METHODS: We included 6,213 consecutive inpatients from Tongji Hospital, Qilu Hospital, and Hubei Cancer Hospital. Training cohort and two validation cohorts were introduced for diagnostic exploration and validation. A pan-cancer cohort was used to independently explore the diagnostic potential of SEMA4C among solid tumors. Breast cancer patients who underwent mass excision prior to modified radical mastectomy were also analyzed. We hypothesized that increased pre-treatment serum SEMA4C levels, measured using optimized in-house enzyme-linked immunosorbent assay kits, could detect breast cancer. The endpoints were diagnostic performance, including area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. Post-surgery pathological diagnosis was the reference standard and breast cancer staging followed the TNM classification. There was no restriction on disease stage for eligibilities. RESULTS: We included 2667 inpatients with breast lesions, 2378 patients with other solid tumors, and 1168 healthy participants. Specifically, 118 patients with breast cancer were diagnosed with stage 0 (5.71%), 620 with stage I (30.00%), 966 with stage II (46.73%), 217 with stage III (10.50%), and 8 with stage IV (0.39%). Patients with breast cancer had significantly higher serum SEMA4C levels than benign breast tumor patients and normal controls (P < 0.001). Elevated serum SEMA4C levels had AUC of 0.920 (95% confidence interval [CI]: 0.900-0.941) and 0.932 (95%CI: 0.911-0.953) for breast cancer detection in the two validation cohorts. The AUCs for detecting early-stage breast cancer (n = 366) and ductal carcinoma in situ (n = 85) were 0.931 (95%CI: 0.916-0.946) and 0.879 (95%CI: 0.832-0.925), respectively. Serum SEMA4C levels significantly decreased after surgery, and the reduction was more striking after modified radical mastectomy, compared with mass excision (P < 0.001). The positive rate of enhanced serum SEMA4C levels was 84.77% for breast cancer and below 20.75% for the other 14 solid tumors. CONCLUSIONS: Serum SEMA4C demonstrated promising potential as a candidate biomarker for breast cancer diagnosis. However, validation in prospective settings and by other study groups is warranted.


Assuntos
Neoplasias da Mama , Semaforinas , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Feminino , Humanos , Mastectomia , Estudos Prospectivos , Estudos Retrospectivos
4.
Front Med (Lausanne) ; 8: 746307, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34805215

RESUMO

Stain normalization often refers to transferring the color distribution to the target image and has been widely used in biomedical image analysis. The conventional stain normalization usually achieves through a pixel-by-pixel color mapping model, which depends on one reference image, and it is hard to achieve accurately the style transformation between image datasets. In principle, this difficulty can be well-solved by deep learning-based methods, whereas, its complicated structure results in low computational efficiency and artifacts in the style transformation, which has restricted the practical application. Here, we use distillation learning to reduce the complexity of deep learning methods and a fast and robust network called StainNet to learn the color mapping between the source image and the target image. StainNet can learn the color mapping relationship from a whole dataset and adjust the color value in a pixel-to-pixel manner. The pixel-to-pixel manner restricts the network size and avoids artifacts in the style transformation. The results on the cytopathology and histopathology datasets show that StainNet can achieve comparable performance to the deep learning-based methods. Computation results demonstrate StainNet is more than 40 times faster than StainGAN and can normalize a 100,000 × 100,000 whole slide image in 40 s.

6.
Nat Commun ; 12(1): 5639, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34561435

RESUMO

Computer-assisted diagnosis is key for scaling up cervical cancer screening. However, current recognition algorithms perform poorly on whole slide image (WSI) analysis, fail to generalize for diverse staining and imaging, and show sub-optimal clinical-level verification. Here, we develop a progressive lesion cell recognition method combining low- and high-resolution WSIs to recommend lesion cells and a recurrent neural network-based WSI classification model to evaluate the lesion degree of WSIs. We train and validate our WSI analysis system on 3,545 patient-wise WSIs with 79,911 annotations from multiple hospitals and several imaging instruments. On multi-center independent test sets of 1,170 patient-wise WSIs, we achieve 93.5% Specificity and 95.1% Sensitivity for classifying slides, comparing favourably to the average performance of three independent cytopathologists, and obtain 88.5% true positive rate for highlighting the top 10 lesion cells on 447 positive slides. After deployment, our system recognizes a one giga-pixel WSI in about 1.5 min.


Assuntos
Citodiagnóstico/métodos , Aprendizado Profundo , Diagnóstico por Computador/métodos , Detecção Precoce de Câncer , Neoplasias do Colo do Útero/diagnóstico , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Redes Neurais de Computação , Curva ROC , Reprodutibilidade dos Testes
7.
J Surg Oncol ; 124(7): 1128-1135, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34324197

RESUMO

BACKGROUND AND OBJECTIVES: This study aimed to characterize the efficacy of neoadjuvant imatinib in rectal gastrointestinal stromal tumors (GISTs) and the prognostic characteristics of patients after surgery. METHODS: Patients with rectal GISTs who received neoadjuvant imatinib between 2000 and 2019 were selected from 11 large-scale tertiary hospitals in China. The best response to neoadjuvant imatinib was assessed. Propensity score matching (PSM) was conducted to reduce confounders. Recurrence free survival (RFS) and overall survival (OS) were estimated using Kaplan-Meier method. RESULTS: Of the 100 patients, 75, 18, and 7 had a partial response (PR), stable disease (SD), and progressive disease (PD), respectively. The median tumor size decreased from 5 cm before treatment to 4 cm after treatment (p < 0.001). A total of 31 patients underwent genetic testing after surgery; 23 of patients with exon 11 mutation had PR and 2 had SD. One of the patients with exon 9 mutation had PR, 2 had SD, and 1 had PD. Two patients with the wild type GIST had PD. A total of 86 patients underwent surgery of which 85 underwent complete resection; 72 underwent anal preservation and 40 underwent local excision (LE). After PSM, patients who received neoadjuvant therapy had higher rates of LE (p = 0.001) and anal preservation (p = 0.033) than those of patients without neoadjuvant therapy. The median follow-up time was 37 months. Nine patients experienced recurrence and one patient died. The 3-year RFS and OS rates were 95.0% and 100%, respectively. After PSM, we found that there was no significant difference in RFS between patients who received or did not receive neoadjuvant therapy (p = 0.623). Univariate analysis showed postneoadjuvant tumor size (p = 0.469) and mitotic count (p = 0.294) were not associated with the RFS in patients who received neoadjuvant imatinib. CONCLUSIONS: Neoadjuvant imatinib can shrink rectal GIST size, increasing the possibility of complete resection and anal preservation. Further studies are warranted to understand the long-term outcomes of rectal GISTs in patients receiving neoadjuvant imatinib.


Assuntos
Tumores do Estroma Gastrointestinal/mortalidade , Mesilato de Imatinib/uso terapêutico , Terapia Neoadjuvante , Neoplasias Retais/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Feminino , Seguimentos , Tumores do Estroma Gastrointestinal/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Neoplasias Retais/terapia , Estudos Retrospectivos
8.
Comput Struct Biotechnol J ; 19: 3852-3863, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34285783

RESUMO

Diverse styles of cytopathology images have a negative effect on the generalization ability of automated image analysis algorithms. This article proposes an unsupervised method to normalize cytopathology image styles. We design a two-stage style normalization framework with a style removal module to convert the colorful cytopathology image into a gray-scale image with a color-encoding mask and a domain adversarial style reconstruction module to map them back to a colorful image with user-selected style. Our method enforces both hue and structure consistency before and after normalization by using the color-encoding mask and per-pixel regression. Intra-domain and inter-domain adversarial learning are applied to ensure the style of normalized images consistent with the user-selected for input images of different domains. Our method shows superior results against current unsupervised color normalization methods on six cervical cell datasets from different hospitals and scanners. We further demonstrate that our normalization method greatly improves the recognition accuracy of lesion cells on unseen cytopathology images, which is meaningful for model generalization.

9.
BMC Gastroenterol ; 21(1): 246, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34074253

RESUMO

BACKGROUND: Small intestine duplication cysts (SIDCs) are rare congenital anatomical abnormalities of the digestive tract and a rare cause of hematochezia. CASE PRESENTATION: We describe an adult female presented with recurrent hematochezia. The routine gastric endoscope and colonic endoscope showed no positive findings. Abdominal CT scan indicated intussusception due to the "doughnut" sign, but the patient had no typical symptoms. Two subsequent capsule endoscopes revealed a protruding lesion with bleeding in the distal ileum. Surgical resection was performed and revealed a case of SIDC measuring 6 * 2 cm located inside the ileum cavity. The patient remained symptom-free throughout a 7-year follow-up period. CONCLUSION: SIDCs located inside the enteric cavity can easily be misdiagnosed as intussusception by routine radiologic examinations.


Assuntos
Cistos , Intussuscepção , Adulto , Cistos/complicações , Cistos/diagnóstico por imagem , Cistos/cirurgia , Feminino , Hemorragia Gastrointestinal/etiologia , Humanos , Íleo , Intussuscepção/diagnóstico por imagem , Intussuscepção/etiologia , Intussuscepção/cirurgia , Estômago
10.
Nat Commun ; 12(1): 3651, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34131122

RESUMO

Extracellular cytokines are enriched in the tumor microenvironment and regulate various important properties of cancers, including autophagy. However, the precise molecular mechanisms underlying the link between autophagy and extracellular cytokines remain to be elucidated. In the present study, we demonstrate that IL-6 activates autophagy through the IL-6/JAK2/BECN1 pathway and promotes chemotherapy resistance in colorectal cancer (CRC). Mechanistically, IL-6 triggers the interaction between JAK2 and BECN1, where JAK2 phosphorylates BECN1 at Y333. We demonstrate that BECN1 Y333 phosphorylation is crucial for BECN1 activation and IL-6-induced autophagy by regulating PI3KC3 complex formation. Furthermore, we investigate BECN1 Y333 phosphorylation as a predictive marker for poor CRC prognosis and chemotherapy resistance. Combination treatment with autophagy inhibitors or pharmacological agents targeting the IL-6/JAK2/BECN1 signaling pathway may represent a potential strategy for CRC cancer therapy.


Assuntos
Autofagia/fisiologia , Proteína Beclina-1/metabolismo , Tratamento Farmacológico , Interleucina-6/metabolismo , Autofagia/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/metabolismo , Proteína Beclina-1/química , Proteína Beclina-1/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-6/farmacologia , Janus Quinase 2/química , Janus Quinase 2/metabolismo , Fosforilação , Domínios e Motivos de Interação entre Proteínas , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
11.
Int J Med Sci ; 18(11): 2366-2371, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33967613

RESUMO

Coronavirus Disease 2019 (COVID-19) emerges as a global pandemic and there is a lack of evidence about the clinical course and outcome of patients on maintenance hemodialysis (MHD). Here we conducted a retrospective longitudinal study aimed to analyze the clinical features and outcome of MHD patients hospitalized with COVID-19. Of 3126 inpatients with COVID-19 at 3 Branches of Wuhan Tongji Hospital from Jan 18th to Mar 9th, 2020, 19 patients were undergoing maintenance hemodialysis. Among the 19 MHD patients with COVID-19, 6 patients (31.6%) died, and 13 patients (68.4%) were able to be discharged. Baseline characteristics, clinical courses, laboratory findings, and dynamic trajectories of major laboratory markers were compared between survivors and nonsurvivors. According to our findings, MHD patients with COVID-19 who experienced non-surviving outcome had more elevated CRP, IL6 and procalcitonin as well as fibrinogen levels at various points compared to survivors. Thus the dysregulation of immune response as well as coagulation abnormalities might be highly involved in the pathological process of COVID-19, contributing to the poor prognosis in MHD patients.


Assuntos
COVID-19/etiologia , Falência Renal Crônica/complicações , Diálise Renal , SARS-CoV-2 , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/análise , COVID-19/tratamento farmacológico , COVID-19/imunologia , Feminino , Hospitalização , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
13.
Cell Rep Med ; 2(3): 100217, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33763656

RESUMO

Implementation of complete mesogastric excision in gastric cancer surgery, named D2 lymphadenectomy plus complete mesogastric excision (D2+CME), has recently been proposed as an optimal procedure. However, the safety and efficacy of D2+CME remain uncertain. In this randomized controlled trial, patients receiving D2+CME exhibit less intraoperative blood loss, more lymph node harvesting, and earlier postoperative flatus than patients receiving conventional D2 radical surgery. Univariate Cox regression analysis reveals that the risk ratio for postoperative flatus in D2+CME group is 1.247 (p = 0.044). Overall postoperative complications are comparable between the two groups, but complications are significantly less severe in the D2+CME group than the D2 group (Clavien-Dindo classification grade ≥ IIIa: 4 D2+CME patients [11.8%] versus 9 D2 patients [33.3%]; p = 0.041). In conclusion, our work shows that D2+CME is associated with better short-term outcomes and surgical safety than conventional D2 dissection for patients with advanced gastric cancer.


Assuntos
Gastrectomia/métodos , Excisão de Linfonodo/métodos , Linfonodos/cirurgia , Mesentério/cirurgia , Neoplasias Gástricas/cirurgia , Estômago/cirurgia , Adulto , Perda Sanguínea Cirúrgica/fisiopatologia , Perda Sanguínea Cirúrgica/prevenção & controle , Progressão da Doença , Feminino , Flatulência/diagnóstico , Flatulência/etiologia , Flatulência/fisiopatologia , Humanos , Linfonodos/patologia , Masculino , Mesentério/patologia , Pessoa de Meia-Idade , Razão de Chances , Segurança do Paciente , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/fisiopatologia , Estômago/patologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Resultado do Tratamento
14.
Oncogene ; 40(16): 2952-2967, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33742125

RESUMO

Tumor angiogenesis plays vital roles in tumorigenesis and development; regulatory mechanism of angiogenesis is still not been fully elucidated. NSD2, a histone methyltransferase catalyzing di-methylation of histone H3 at lysine 36, has been proved a critical molecule in proliferation, metastasis, and tumorigenesis. But its role in tumor angiogenesis remains unknown. Here we demonstrated that NSD2 promoted tumor angiogenesis in vitro and in vivo. Furthermore, we confirmed that the angiogenic function of NSD2 was mediated by STAT3. Momentously, we found that NSD2 promoted the methylation and activation of STAT3. In addition, mass spectrometry and site-directed mutagenesis assays revealed that NSD2 methylated STAT3 at lysine 163 (K163). Meanwhile, K to R mutant at K163 of STAT3 attenuated the activation and angiogenic function of STAT3. Taken together, we conclude that methylation of STAT3 catalyzed by NSD2 promotes the activation of STAT3 pathway and enhances the ability of tumor angiogenesis. Our findings investigate a NSD2-dependent methylation-phosphorylation regulation pattern of STAT3 and reveal that NSD2/STAT3/VEGFA axis might be a potential target for tumor therapy.


Assuntos
Neoplasias do Colo/irrigação sanguínea , Histona-Lisina N-Metiltransferase/metabolismo , Proteínas Repressoras/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Carcinogênese , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Xenoenxertos , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Metilação , Camundongos , Camundongos Nus , Neovascularização Patológica/metabolismo
15.
Eur J Surg Oncol ; 47(7): 1668-1674, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33581967

RESUMO

BACKGROUND: The surgical approaches and resection extent for rectal gastrointestinal stromal tumors (GISTs) are controversial due to the low incidence of this disease. A multicenter retrospective cohort study was conducted to compare the postoperative and oncologic outcomes of local excision (LE) and radical resection (RR) in patients with low rectal GIST. PATIENTS AND METHODS: The medical records of rectal GIST patients from 11 large-scale medical centers in China (January 2000-December 2019) were reviewed. All patients were divided into either the LE group or the RR group. Propensity score matching (PSM) was conducted to reduce confounders. RESULTS: A total of 280 patients with low rectal GIST were enrolled. After PSM, 144 patients were included (72 in each group). The LE group showed a higher anal preservation rate (100.0% vs. 76.4%, P < 0.001), shorter operation time (77.1 ± 68.4 min vs. 159.1 ± 83.6 min, P < 0.001), fewer complications (8.3% vs. 22.2%, P = 0.021) and shorter postoperative hospital stay (4.9 ± 4.1 d vs. 10.7 ± 8.1 d, P < 0.001) than the RR group. There was no significant difference in recurrence-free survival (RFS) between the RR and LE groups among patients with tumors ≤2 cm (P = 0.220), and the RR group had a superior RFS than the LE group in patients with tumors >2 cm (P = 0.046). CONCLUSIONS: LE resulted in improved postoperative outcomes and comparable oncological safety with a low rectal GIST of ≤2 cm. However, for patients with a low rectal GIST of >2 cm, RR might be a more appropriate option with better RFS.


Assuntos
Procedimentos Cirúrgicos do Sistema Digestório/métodos , Tumores do Estroma Gastrointestinal/cirurgia , Neoplasias Retais/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Feminino , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Pontuação de Propensão , Neoplasias Retais/mortalidade , Taxa de Sobrevida
16.
Bioorg Med Chem ; 32: 115997, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33440319

RESUMO

This study describes the synthesis of novel 1,3,5-triazine derivatives as potent inhibitors of cervical cancer. The compounds were initially tested for inhibition of PI3K/mTOR, where they showed significant inhibitory activity. The top-ranking molecule (compound 6 h) was further tested against class I PI3K isoforms, such as PI3Kα, PI3Kß, PI3Kγ and PI3Kδ, where it showed the most significant activity against PI3Kα. Compound 6 h was then tested for anti-cancer activity against triple-negative breast cancer cells (MDA-MB321), human breast cancer cells (MCF-7), human cervical cancer cells (HeLa) and human liver cancer cells (HepG2), and it showed the greatest potency against HeLa cells. The effects of compound 6 h were further evaluated against the HeLa cells, where it showed significant attenuation of cell viability by inducing cell cycle arrest in the G1 phase. Compound 6 h induced apoptosis and reduced migration and invasion of HeLa cells. Western blotting analysis showed that 6 h inhibited PI3K and mTOR with positive modulation of Bcl-2 and Bax levels in HeLa cells. The effects of compound 6 h were also investigated in a tumour xenograft mouse model, where it showed reduction of tumour volume and weight. It also inhibited the PI3K/Akt/mTOR signalling cascade in xenograft tumour tissues, as evidenced by western blotting analysis. The results of the present study suggest the possible utility of the designed 1,3,5-triazine derivative as a potent inhibitor of cervical cancer.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Triazinas/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismo , Triazinas/síntese química , Triazinas/química , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
17.
Biomed Pharmacother ; 133: 110960, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33197763

RESUMO

The root of Codonopis bulleynana Forest ex Diels (cbFeD), a tonic food widely used in Yunnan Province of China, was found to have a wide range of pharmacological effects. The present study was designed to investigate the anti-fibrotic effect of water extracts of cbFeD in chronic liver injury mice model induced by carbon tetrachloride (CCl4) and to explore its underlying mechanisms. Phytochemical analysis revealed multiple components were present in the water extract of cbFeD and the compounds were mostly enriched in organic acid and its derivatives, flavone, amino acid derivatives, nucleotide and its derivatives, carbohydrates etc. Treatment with cbFeD significantly attenuated liver injury and fibrosis in CCl4-administered mice evidenced by improved liver histology, ameliorated apoptosis of hepatocytes, and decreased transaminase levels in the serum. Decreased activities of superoxide dismutase (SOD) and catalase (CAT) were markedly reversed upon treatment with cbFeD while levels of malondialdehyde (MDA) and glutathione (GSH) were significantly restored towards normal values. cbFeD also suppressed intrahepatic inflammatory cell infiltration and Kupffer cell activation. Furthermore, our study revealed an inhibitory effect of cbFeD on hepatic stellate cells (HSCs) activation both in vitro and in vivo. In conclusion, cbFeD could exert a protective role against liver fibrosis in mice model induced by CCl4 that is comparable to the positive control silymarin and might be developed into a promising anti-fibrotic drug.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Codonopsis , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática Experimental/prevenção & controle , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Apoptose/efeitos dos fármacos , Tetracloreto de Carbono , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Codonopsis/química , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Mediadores da Inflamação/metabolismo , Macrófagos do Fígado/efeitos dos fármacos , Macrófagos do Fígado/metabolismo , Macrófagos do Fígado/patologia , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Raízes de Plantas
18.
J Hepatol ; 74(6): 1295-1302, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33347952

RESUMO

BACKGROUND & AIMS: The evolution and clinical significance of abnormal liver chemistries and the impact of hepatitis B infection on outcome in patients with COVID-19 is not well characterized. This study aimed to explore these issues. METHODS: This large retrospective cohort study included 2,073 patients with coronavirus disease 2019 (COVID-19) and definite outcomes in Wuhan, China. Longitudinal liver function tests were conducted, with associated factors and risk of death determined by multivariate regression analyses. A prognostic nomogram was formulated to predict the survival of patients with COVID-19. The characteristics of liver abnormalities and outcomes of patients with COVID-19, with and without hepatitis B, were compared after 1:3 propensity score matching. RESULTS: Of the 2,073 patients, 1,282 (61.8%) had abnormal liver chemistries during hospitalization, and 297 (14.3%) had a liver injury. The mean levels of aspartate aminotransferase (AST) and direct bilirubin (D-Bil) increased early after symptom onset in deceased patients and showed disparity compared to levels in discharged patients throughout the clinical course of the disease. Abnormal AST (adjusted hazard ratio [HR] 1.39; 95% CI 1.04-1.86, p = 0.027) and D-Bil (adjusted HR 1.66; 95% CI 1.22-2.26; p = 0.001) levels at admission were independent risk factors for mortality due to COVID-19. A nomogram was established based on the results of multivariate analysis and showed sufficient discriminatory power and good consistency between the prediction and the observation. HBV infection in patients did not increase the risk of poor COVID-19-associated outcomes. CONCLUSIONS: Abnormal AST and D-Bil levels at admission were independent predictors of COVID-19-related mortality. Therefore, monitoring liver chemistries, especially AST and D-Bil levels, is necessary in hospitalized patients with COVID-19. LAY SUMMARY: Liver test abnormalities (in particular elevations in the levels of aspartate aminotransferase [AST] and direct bilirubin [D-Bil]) were observed after symptom onset in patients who went on to die of coronavirus disease 2019 (COVID-19). Abnormal levels of AST and D-Bil at admission were independent predictors of COVID-19-related mortality. HBV infection in patients did not increase the risk of poor COVID-19-associated outcomes.


Assuntos
Aspartato Aminotransferases/sangue , Bilirrubina/sangue , COVID-19/mortalidade , Mortalidade Hospitalar , Hepatopatias/complicações , SARS-CoV-2 , Idoso , Feminino , Hepatite B/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Estudos Retrospectivos
19.
Br J Anaesth ; 125(6): 895-911, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33121750

RESUMO

BACKGROUND: Current guidelines for perioperative management of coronavirus disease 19 (COVID-19) are mainly based on extrapolated evidence or expert opinion. We aimed to systematically investigate how COVID-19 affects perioperative management and clinical outcomes, to develop evidence-based guidelines. METHODS: First, we conducted a rapid literature review in EMBASE, MEDLINE, PubMed, Scopus, and Web of Science (January 1 to July 1, 2020), using a predefined protocol. Second, we performed a retrospective cohort analysis of 166 women undergoing Caesarean section at Tongji Hospital, Wuhan during the COVID-19 pandemic. Demographic, imaging, laboratory, and clinical data were obtained from electronic medical records. RESULTS: The review identified 26 studies, mainly case reports/series. One large cohort reported greater mortality in elective surgery patients diagnosed after, rather than before surgery. Higher 30 day mortality was associated with emergency surgery, major surgery, poorer preoperative condition and surgery for malignancy. Regional anaesthesia was favoured in most studies and personal protective equipment (PPE) was generally used by healthcare workers (HCWs), but its use was poorly described for patients. In the retrospective cohort study, duration of surgery, oxygen therapy and hospital stay were longer in suspected or confirmed patients than negative patients, but there were no differences in neonatal outcomes. None of the 262 participating HCWs was infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) when using level 3 PPE perioperatively. CONCLUSIONS: When COVID-19 is suspected, testing should be considered before non-urgent surgery. Until further evidence is available, HCWs should use level 3 PPE perioperatively for suspected or confirmed patients, but research is needed on its timing and specifications. Further research must examine longer-term outcomes. CLINICAL TRIAL REGISTRATION: CRD42020182891 (PROSPERO).


Assuntos
Infecções por Coronavirus/terapia , Assistência Perioperatória/métodos , Pneumonia Viral/terapia , Adulto , Anestesia por Condução , COVID-19 , Cesárea/métodos , Cesárea/mortalidade , Estudos de Coortes , Infecções por Coronavirus/complicações , Infecções por Coronavirus/prevenção & controle , Procedimentos Cirúrgicos Eletivos/mortalidade , Feminino , Humanos , Recém-Nascido , Tempo de Internação , Oxigenoterapia , Pandemias/prevenção & controle , Equipamento de Proteção Individual , Pneumonia Viral/complicações , Pneumonia Viral/prevenção & controle , Gravidez , Complicações Infecciosas na Gravidez , Resultado da Gravidez , Estudos Retrospectivos , Resultado do Tratamento
20.
Cell Rep ; 32(12): 108173, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32966783

RESUMO

To explore the mechanism of Rab5/RAB-5 activation during endocytic recycling, we perform a genome-wide RNAi screen and identify a recycling regulator, LET-502/ROCK. LET-502 preferentially interacts with RAB-5(GDP) and activates RABX-5 GEF activity toward RAB-5, presumably by disrupting the self-inhibiting conformation of RABX-5. Furthermore, we find that the concomitant loss of LET-502 and another CED-10 effector, TBC-2/RAB-5-GAP, results in an endosomal buildup of RAB-5, indicating that CED-10 directs TBC-2-mediated RAB-5 inactivation and re-activates RAB-5 via LET-502 afterward. Then, we compare the functional position of LET-502 with that of RME-6/RAB-5-GEF. Loss of LET-502-RABX-5 module or RME-6 leads to diminished RAB-5 presence in spatially distinct endosome groups. We conclude that in the intestine of C. elegans, RAB-5 resides in discrete endosome subpopulations. Under the oversight of CED-10, LET-502 synergizes with RABX-5 to revitalize RAB-5 on a subset of endosomes in the deep cytosol, ensuring the progress of basolateral recycling.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/citologia , Caenorhabditis elegans/metabolismo , Endocitose , Endossomos/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Quinases Associadas a rho/metabolismo , Animais , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/genética , Citosol/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Guanosina Difosfato/metabolismo , Intestinos/citologia , Mutação/genética , Ligação Proteica , Domínios Proteicos , Transporte Proteico , Quinases Associadas a rho/química , Quinases Associadas a rho/genética
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