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Chemoresistance poses a significant challenge in the treatment of advanced head and neck squamous cell cancer (HNSCC). The role and mechanism of circular RNAs (circRNAs) in HNSCC chemoresistance remain understudied. We conducted circRNA microarray analysis to identify differentially expressed circRNAs in HNSCC. The expression of circRNAs from the tyrosylprotein sulfotransferase 2 (TPST2) gene and miRNAs was evaluated through qPCR, while the circular structure of circTPST2 was verified using Sanger sequencing and RNase R. Through Western blotting, biotin-labeled RNA pulldown, RNA immunoprecipitation, mass spectrometry, and rescue experiments, we discovered miR-770-5p and nucleolin as downstream targets of circTPST2. Functional tests, including CCK8 assays and flow cytometry, assessed the chemoresistance ability of circTPST2, miR-770-5p, and Nucleolin. Additionally, FISH assays determined the subcellular localization of circTPST2, miR-770-5p, and Nucleolin. IHC staining was employed to detect circTPST2 and Nucleolin expression in HNSCC patients. circTPST2 expression was inversely correlated with cisplatin sensitivity in HNSCC cell lines. Remarkably, high circTPST2 expression correlated with lower overall survival rates in chemotherapeutic HNSCC patients. Mechanistically, circTPST2 reduced chemosensitivity through sponge-like adsorption of miR-770-5p and upregulation of the downstream protein Nucleolin in HNSCC cells. The TCGA database revealed improved prognosis for patients with low circTPST2 expression after chemotherapy. Moreover, analysis of HNSCC cohorts demonstrated better prognosis for patients with low Nucleolin protein expression after chemotherapy. We unveil circTPST2 as a circRNA associated with chemoresistance in HNSCC, suggesting its potential as a marker for selecting chemotherapy regimens in HNSCC patients. Further exploration of the downstream targets of circTPST2 advanced our understanding and improved treatment strategies for HNSCC.
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Primary cilia are hairlike organelles that are present on the majority of mammalian cells. They are regarded as the regulatory 'hub' of cell functions due to their indispensable roles for several signaling pathways, such as Hh and Wnt pathways. Originally, cilia defects were found to cause a panoply of human diseases commonly referred to as 'ciliopathies'. Evidence is accumulating that cilia defects are involved in the onset and development of cancer. Some proteins that cause cilia defects have been identified as oncogenes in multiple cancer types. Hence, understanding the pathways that cause cilia defects in cancer is of utmost importance for the development of novel cancer therapeutic targets. The present review article provides a critical overview of the molecular targets of primary cilia defects in cancer, and highlights their vast potential as therapeutic targets and novel biomarkers.
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Cílios , Neoplasias , Animais , Humanos , Mamíferos , Neoplasias/genética , Neoplasias/metabolismo , Via de Sinalização WntRESUMO
Circular RNA (circRNA) is a type of endogenous, highstability, noncoding RNA. circRNAs exhibit various biological functions, and are involved in physiological and pathological processes occurring in various diseases, including cancers. They can not only act as microRNA and protein sponges, but also interact with proteins, translated peptides, and transcriptional and translational regulators, and compete with premRNA splicing. Chemotherapy is one of the most important types of cancer treatment. However, the resistance of cancer cells to chemotherapy is a leading reason for the failure of chemotherapy. It has been reported that circRNAs play important roles in cancer resistance via a number of mechanisms. The functions of the circRNAs provide insight into their roles in chemoresistance pathways. In addition, some circRNAs may serve as novel biomarkers for the diagnosis and prognosis of cancer resistance. Obtaining improved understanding of the molecular regulatory networks featuring circRNAs in tumors and searching for markers for the diagnosis and treatment of cancer resistance are leading issues in circRNA research. The present review introduced the functions of circRNAs, illustrated the mechanisms underlying drug resistance in cancer, described the contributions of circRNAs to this resistance and discussed the potential application of circRNAs in the treatment of drugresistant cancer. In particular, the review aimed to reveal the main mechanisms of circRNAs in cancer drug resistance, including mechanisms involving drug transport and metabolism, alterations of drug targets, DNA damage repair, downstream resistance mechanisms, adaptive responses and the tumor microenvironment. The findings may provide novel therapeutic targets for clinical treatment of cancer chemoresistance.
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Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , RNA Circular/fisiologia , HumanosRESUMO
OBJECTIVE: To compare the efficacy and safety of different doses of daunorubicin combined with a standard dose of cytarabine as induction chemotherapy in newly diagnosed primary acute myeloid leukemia (AML) patients. METHODS: The clinical data and outcome were retrospectively analyzed in 86 newly diagnosed primary AML patients who were under 65 years old and treated with daunorubicin combined with cytarabine (DA regimen) at West China Hospital of Sichuan University from January 2017 to June 2019. Patients were divided into 2 groups based on the dose of daunorubicin they received, 35 cases in the escalated-dose group ï¼»75 mg/(m2·d)ï¼½ and 51 cases in the standard-dose group ï¼»60 mg/(m2·d)ï¼½. And then the effects of different doses of daunorubicin on complete remission (CR) rate, minimal residual disease (MRD)-negative CR rate, relapse-free survival (RFS), overall survival (OS), and adverse events were analyzed. RESULTS: Median follow-up time of all the patients was 15 months. The CR rate and MRD- CR rate of the escalated-dose group was 88.5% and 71.4%, respectively, which were higher than 64.7% and 41.2% of the standard-dose group (P=0.029, P=0.008). The estimated 2-year RFS of the escalated-dose group was 68.4%, which was higher than 38.5% of the standard-dose group (P=0.015), but estimated 2-year OS showed no statistically significant difference (77.1% vs 66.7%, P=0.059), as well as grade 3ï¼4 adverse events. The escalated dose of daunorubicin had prolonged RFS (13 months vs not reached, P=0.022) and OS (23 months vs not reached, P=0.029) in the FLT3-ITDï¼ AML patients. CONCLUSION: The escalated dose of daunorubicin can induce higher complete remission rate, deeper remission and longer duration of remission without increasing adverse events in newly diagnosed primary AML patients.
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Daunorrubicina , Leucemia Mieloide Aguda , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Citarabina/uso terapêutico , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/tratamento farmacológico , Indução de Remissão , Estudos RetrospectivosRESUMO
BACKGROUND: The effect of a combination of a goal-directed fluid protocol and preoperative carbohydrate loading on postoperative complications in elderly patients still remains unknown. Therefore, we designed this trial to evaluate the relative impact of preoperative carbohydrate loading and intraoperative goal-directed fluid therapy versus conventional fluid therapy (CFT) on clinical outcomes in elderly patients following gastrointestinal surgery. METHODS: This prospective randomized controlled trial with 120 patients over 65 years undergoing gastrointestinal surgery were randomized into a CFT group (n = 60) with traditional methods of fasting and water-deprivation, and a GDFT group (n = 60) with carbohydrate (200 ml) loading 2 h before surgery. The CFT group underwent routine monitoring during surgery, however, the GDFT group was conducted by a Vigileo/FloTrac monitor with cardiac index (CI), stroke volume variation (SVV), and mean arterial pressure (MAP). For all patients, demographic data, intraoperative parameters and postoperative outcomes were recorded. RESULTS: Patients in the GDFT group received significantly less crystalloids fluid (1111 ± 442.9 ml vs 1411 ± 412.6 ml; p < 0.001) and produced significantly less urine output (200 ml [150-300] vs 400 ml [290-500]; p < 0.001) as compared to the CFT group. Moreover, GDFT was associated with a shorter average time to first flatus (56 ± 14.1 h vs 64 ± 22.3 h; p = 0.002) and oral intake (72 ± 16.9 h vs 85 ± 26.8 h; p = 0.011), as well as a reduction in the rate of postoperative complications (15 (25.0%) vs 29 (48.3%) patients; p = 0.013). However, postoperative hospitalization or hospitalization expenses were similar between groups (p > 0.05). CONCLUSIONS: Focused on elderly patients undergoing open gastrointestinal surgery, we found perioperative fluid optimisation may be associated with improvement of bowel function and a lower incidence of postoperative complications. TRIAL REGISTRATION: ChiCTR, ChiCTR1800018227 . Registered 6 September 2018 - Retrospectively registered.
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Dieta da Carga de Carboidratos/métodos , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Hidratação/métodos , Cuidados Intraoperatórios/métodos , Complicações Pós-Operatórias/prevenção & controle , Cuidados Pré-Operatórios/métodos , Idoso , Feminino , Avaliação Geriátrica/métodos , Objetivos , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Estudos Prospectivos , Resultado do TratamentoRESUMO
In this work, microwave (MW) irradiation was employed to enhance the zero-valent iron (ZVI)-dominated de-contamination of chromite ore processing residue (COPR). A coupling system and the traditional two-step procedure were both conducted to evaluate the effects of MW irradiation on the reduction and the incorporation of COPR into the composite materials-based geopolymers. The factors including the ratios of liquid to solid, the mass ratios of ZVI to COPR, and the acid dosage had some obvious influence on the reduction of COPR in the MW system. The compressive strengths of 31.54 and 41.56 MPa were determined from the two-step procedure and the coupling system at the COPR dosage of 10% (mass ratio), respectively. The employment of MW irradiation not only strengthened the formation of the geopolymer matrices but also improved the chemical stabilization of Cr species in the solidified blocks. The coupled process was more conducive to incorporating the treated COPR into the geopolymer-based crystalline microstructures compared with the subsequent usage of ZVI reduction and MW irradiation.
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Cromo , Ferro , Cromo/análise , Resíduos Industriais/análise , Micro-OndasRESUMO
AIM: To investigate the significance of ultrasound elastography for evaluating stiffness of the human lens nucleus in volunteers with different ages. METHODS: A total of 90 volunteers (lens transparency, uncorrected visual acuity ≥0.5, intraocular pressure: 14-19 mm Hg) were divided into 3 groups according to age: Group A (30 people, median age: 82±3.5y, mean axial lengths 23.7±0.5 mm); Group B (30 people, median age: 46±2.1y, mean axial lengths 23.9±0.4 mm); and Group C (30 people, median age: 22±3.5y, mean axial lengths 24.0±0.4 mm). Lens nuclear stiffness was measured by Free-hand qualitative elastography by independent operators. Strain gray scale and color-coded elastography maps were recorded. In each case, three consecutive detections were performed and strain ratio was used for statistical analysis. RESULTS: Elastography analysis showed excellent diagnostic performance for lens sclerosis. Lens strain ratio was lowest (0.03±0.01)% in Group A and highest (2.03±0.43)% in Group C. Lens strain ratio was moderate (0.64±0.10)% in Group B. There were significant differences between these three groups (P<0.05). The lens nucleus strain rate changes with age. With aging, the lens nucleus strain rate and resilience decrease, demonstrating harder texture. CONCLUSION: The relationship between human lens stiffness and age is demonstrated by ultrasound elastography. Older age is associated with lower strain ratio and less resilience of the lens.
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OBJECTIVE@#To compare the efficacy and safety of different doses of daunorubicin combined with a standard dose of cytarabine as induction chemotherapy in newly diagnosed primary acute myeloid leukemia (AML) patients.@*METHODS@#The clinical data and outcome were retrospectively analyzed in 86 newly diagnosed primary AML patients who were under 65 years old and treated with daunorubicin combined with cytarabine (DA regimen) at West China Hospital of Sichuan University from January 2017 to June 2019. Patients were divided into 2 groups based on the dose of daunorubicin they received, 35 cases in the escalated-dose group [75 mg/(m@*RESULTS@#Median follow-up time of all the patients was 15 months. The CR rate and MRD@*CONCLUSION@#The escalated dose of daunorubicin can induce higher complete remission rate, deeper remission and longer duration of remission without increasing adverse events in newly diagnosed primary AML patients.
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Idoso , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica , Citarabina/uso terapêutico , Daunorrubicina , Quimioterapia de Indução , Leucemia Mieloide Aguda/tratamento farmacológico , Indução de Remissão , Estudos RetrospectivosRESUMO
Heart surgery in patients from high-altitude areas is more challenging than usual. Few studies have been published on this issue, and none of them have discussed the effect of an altitude change (from high to low altitude) on a patient's physiology or its effects on a patient's perioperative management. Here, we present the case of a 46-year-old man who was a long-time resident of Tibetan area in Sichuan (altitude >3000 m) who underwent Stanford type A aortic dissection emergency surgery on the plain. Anesthetic management occurred through monitoring of the bispectral index (BIS) and transesophageal echocardiography (TEE), and we used a relatively loose fluid hydration strategy. The surgery was performed using cardiopulmonary bypass (CPB), deep hypothermia (DH), and selective antegrade cerebral perfusion. The most prominent anesthesia challenges for these patients are physiological changes due to habitation in an high-altitude environment (chronic hypoxemia), which can cause hyperhemoglobinemia, polycythemia, hypercoagulable blood, and even pulmonary hypertension, cor pulmonale, or congestive heart failure. Optimized perioperative management and close cooperation among the entire cardiac medical team were the key factors in the successful management of this rare case.
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Anestesia , Dissecção Aórtica , Altitude , Dissecção Aórtica/diagnóstico por imagem , Dissecção Aórtica/cirurgia , Ponte Cardiopulmonar , Ecocardiografia Transesofagiana , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
PA28γ is a nuclear activator of the 20S proteasome, which is involved in the regulation of several essential cellular processes and angiogenesis. Over the past 20 years, many amino acid sites and motifs have been proven to play important roles in the characteristic functions of PA28γ. The number of binding partners and validated cellular functions of PA28γ have increased, which has facilitated the clarification of its involvement in different biological events. PA28γ is involved in the progression of various diseases, and its aberrant overexpression in cancer is remarkable. Patients with low levels of PA28γ expression have a higher survival rate than those with high levels of PA28γ expression, as has been shown for a wide variety of tumors. The functions of PA28γ in cancer can be divided into five main categories: cell proliferation, cell apoptosis, metastasis and invasion, cell nuclear dynamics that have relevance to angiogenesis, and viral infection. In this review, we focus on the role of PA28γ in cancer, summarizing its aberrant expression, prooncogenic effects and underlying mechanisms in various cancers, and we highlight the possible cancer-related applications of PA28γ, such as its potential use in the diagnosis, targeted treatment and prognostic assessment of cancer.
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BACKGROUND: Oral squamous cell carcinoma (OSCC) has the highest mortality rate among all head and neck cancers and a relatively low five-year survival rate. Generally, the development of an oral mucosal malignancy represents a multistep process beginning with normal oral mucosa epithelium and culminating in OSCC after transitioning through intermediary oral premalignant disorders (OPMDs), during which dysplasia is often observed. Noncoding RNAs (ncRNAs) are RNAs that are not translated into proteins, but still can participate in regulating neoplastic cell behavior. Recently, data have emerged on the role of ncRNAs in the progression of oral mucosal malignant diseases, but the exact mechanisms through which ncRNAs are involved remain to be elucidated. CONCLUSIONS: Knowledge on ncRNAs has added an extra layer of complexity to our understanding of the malignant progression of oral mucosal diseases. The identification of ncRNAs in multiple body fluids as biomarkers may provide new diagnostic options that can be used for the diagnosis and prognosis of OPMDs and OSCC, respectively. Despite overall advances that have been made in cancer treatment, the treatment options for OPMDs and OSCC are still limited. Several studies have shown that ncRNA-based treatment regimens may hold promise as alternative methods for treating OPMDs and OSCC. The use of ncRNAs as therapeutic agents, including miR-155, miR-34 and lncRNA HOTAIR, appear promising.
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Carcinoma de Células Escamosas/genética , Neoplasias Bucais/genética , Lesões Pré-Cancerosas/genética , RNA Longo não Codificante/metabolismo , Animais , Humanos , RNA Longo não Codificante/genética , Pesquisa Translacional Biomédica , Microambiente Tumoral/genéticaAssuntos
Anestesiologia/métodos , Infecções por Coronavirus/prevenção & controle , Controle de Infecções/métodos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Serviço Hospitalar de Anestesia/métodos , COVID-19 , China , Infecções por Coronavirus/epidemiologia , Humanos , Pneumonia Viral/epidemiologiaRESUMO
AIM: To investigate the significance of ultrasound elastography for evaluating stiffness of the human lens nucleus in patients with anisometropia. METHODS: A total of 14 patients (28 eyes) with anisometropia were enrolled. The difference in refractive status between two eyes ≥-4.0 diopters (D) and the difference in axial length (AL) of the eyes was ≥3 mm. There were 5 males and 9 females with an average age of 62±3.3y. The test data of the long AL eye of each patient was included in group A (14 eyes), and test data of the eye with relative short AL was included in group B. Lens nuclear stiffness was measured with free-hand qualitative elastography by independent operators. Strain gray scale and color-coded elastography maps were recorded. In each case, three consecutive measurements were performed and strain ratio was used for statistical analysis. Photograph and sectional view of the lens were analyzed and archived by anterior segment image. RESULTS: In the long AL group, the strain rate in the nucleus of the lens was 0.16%±0.08%; in the short AL group, the strain rate in the nucleus of the lens was 0.54%±0.16%. Independent sample t-test analyses showed that the long AL group lens had a significantly smaller nuclear strain rate than the relatively short AL group, P<0.05. CONCLUSION: The relationship between human lens stiffness and different AL is demonstrated by ultrasound elastography. The long AL is associated with lower strain ratio and less resilience of the lens.
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OBJECTIVE: To construct a PA28γ overexpression cell line and determine its effects after infecting an oral squa-mous cell carcinoma (OSCC) cell line. METHODS: The PA28γ gene was cloned into the pLOV.CMV.cherry.2A.EF1a.PuroR lentiviral vector by polymerase chain reaction (PCR), and PCR and DNA sequencing alignment analysis were used for identification. Then, 293T cells were used to package viral diseases. Infected OSCC cells were used to construct a cell line with stable PA28γ overexpression. Finally, the level of PA28γ expression in the OSCC cell line was detected through Western blot. RESULTS: The successful construction of PA28γ recombinant lentiviral vectors was confirmed by DNA sequencing. The results of immunofluorescence showed that the PA28γ overexpression lentivirus successfully infected the OSCC cells and showed cherry red fluorescence. The results of Western blot demonstrated that the constructed cells with stable PA28γ overexpression significantly increased the expression of PA28γ. CONCLUSIONS: The PA28γ overexpression lentiviral vector can significantly increase its protein expression in OSCC cells. We provide a stable OSCC cell line for further study on the effect of PA28γ in OSCC.
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Carcinoma de Células Escamosas , Neoplasias Bucais , Autoantígenos , Linhagem Celular Tumoral , Vetores Genéticos , Humanos , Lentivirus , Complexo de Endopeptidases do Proteassoma , TransfecçãoRESUMO
OBJECTIVE: Proteasome activator 28γ (PA28γ) upregulation plays a critical role in the carcinogenesis of many malignancies, including oral cancer. We aim to screen the related genes of PA28γ and investigate their function in oral mucosa carcinogenesis. MATERIALS AND METHODS: Bioinformatics analysis was performed to screen the related genes of PA28γ. Immunohistochemical analysis was carried out to validate their correlation in oral squamous cell carcinoma (OSCC) and detect their expression levels in the whole process of oral mucosa carcinogenesis. The Kaplan-Meier method was used for estimating the overall survival, and the Cox models were constructed to predict the prognosis. RESULTS: U2 small nuclear RNA auxiliary factor 1 (U2AF1) was screened out, and the correlation between U2AF1 and PA28γ was further validated in OSCC. The expression levels of PA28γ and U2AF1 were gradually increased from normal to oral potentially malignant disorders (OPMD) to OSCC tissues. Overall survival was significantly shorter in patients with high U2AF1 expression and the combined application of U2AF1 and PA28γ notably improved the accuracy of prognosis prediction. CONCLUSION: U2AF1 and PA28γ might play pivotal roles in the progression of OPMD, which may provide insights into the development of new therapeutic strategies to prevent OPMD from becoming malignant.
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Autoantígenos/genética , Carcinogênese , Carcinoma de Células Escamosas/genética , Neoplasias Bucais/genética , Complexo de Endopeptidases do Proteassoma/genética , Fator de Processamento U2AF/genética , Animais , Linhagem Celular Tumoral , Feminino , Técnicas de Silenciamento de Genes , Humanos , Camundongos Endogâmicos C57BL , Mucosa BucalRESUMO
BACKGROUND: The placement of a temporary epicardial pacing wire is a challenge during a minimally invasive redo cardiac operation. The aim of this study is to assess the application of temporary endocardial pacing in patients who underwent minimally invasive redo tricuspid surgery. METHODS: Perioperative data of consecutive patients who underwent thoracoscopic redo tricuspid surgery were collected. All the tricuspid surgeries and combined procedures were performed under peripheral cardiopulmonary bypass without aortic cross-clamping. A sheath was introduced into the right jugular vein beside the percutaneous superior vena cava cannula and a temporary endocardial pacing catheter was guided into the right ventricle via the sheath prior to the right atrial closure. The pacemaker was connected and run as needed during or after operation. RESULTS: A total of 33 patients who underwent thoracoscopic redo tricuspid surgery were enrolled. Symptomatic tricuspid valve regurgitation (93.9%) and tricuspid valvular prosthesis obstruction (6.1%) after previous cardiac operations were noted as indications for a redo surgery. The mean time from previous cardiac operation to this time redo surgery was 13.3±6.4years. Isolated tricuspid valve replacement was performed in 18 patients (54.5%) and tricuspid valve plasty combined with or without mitral valve replacement was performed in 15 patients (45.5%). A temporary endocardial pacing catheter was successfully placed in the right ventricle for all patients with good sensing and pacing. No temporary pacing related complications occurred from insertion to removal of pacing catheter in the patients. CONCLUSIONS: This application of temporary endocardial pacing provided a safe and effective substitute for epicardial pacing in patients who underwent minimally invasive redo tricuspid surgery.
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Procedimentos Cirúrgicos Cardíacos , Ponte Cardiopulmonar , Marca-Passo Artificial , Toracoscopia , Insuficiência da Valva Tricúspide , Valva Tricúspide , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valva Tricúspide/patologia , Valva Tricúspide/fisiopatologia , Valva Tricúspide/cirurgia , Insuficiência da Valva Tricúspide/patologia , Insuficiência da Valva Tricúspide/fisiopatologia , Insuficiência da Valva Tricúspide/cirurgiaRESUMO
BACKGROUND: Breast lesions classified as BI-RADS-US 3 are probably benign and observation was recommended, while a considerable number of BI-RADS-US 4 lesions were benign, resulting in excessive biopsies. We focus exclusively on BI-RADS-US 3 and 4 lesions and hypothesize that improved diagnostic performance can be achieved by integrating real-time elastography (strain ratio) into the BI-RADS-US classification system. METHOD: From April 2010 to September 2015, 1071 lesions were included in the final analysis. After the conventional ultrasound examination, the BI-RADS-US (2013) classification was used to evaluate the lesions. Then the strain ratios were calculated, and the final diagnosis was made on the basis of histological results. The sensitivity, specificity, accuracy, PPV and NPV were calculated and the AUCs were compared. Additionally, an analysis of the diagnostic performance expressed by the pretest and posttest probability of disease (POD) was performed in BI-RADS-US 3 and 4A lesions. RESULTS: With the cutoff point of 2.98, the sensitivity, specificity and accuracy of the strain ratio method were 86.9â%, 86.6â% and 82.6â%, respectively. In BI-RADS-US 3 lesions, a suspicious strain ratio significantly modified the POD from 1.3â% to a posttest POD of 29.8â%. In BI-RADS-US 4A lesions, a suspicious strain ratio significantly modified the POD from 8.5â% to a posttest POD of 48.7â%. CONCLUSION: Ultrasonographic elastography (strain ratio) yields additional diagnostic information in the evaluation of BI-RADS-US 3 and 4 breast lesions. The strain ratios should be integrated into the BI-RADS-US classification system and into daily practice.
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Neoplasias da Mama , Técnicas de Imagem por Elasticidade , Neoplasias da Mama/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Humanos , Sensibilidade e Especificidade , Ultrassonografia MamáriaRESUMO
The serum and glucocorticoid-regulated kinase (SGK) family has been implicated in the regulation of many cellular processes downstream of the PI3K pathway. It plays a crucial role in PI3K-mediated tumorigenesis, making it a potential therapeutic target for cancer. SGK family consists of three isoforms (SGK1, SGK2, and SGK3), which have high sequence homology in the kinase domain and similar substrate specificity with the AKT family. In order to identify novel compounds capable of inhibiting SGK3 activity, a high-throughput screening campaign against 50,400 small molecules was conducted using a fluorescence-based kinase assay that has a Z' factor above 0.5. It identified 15 hits (including nitrogen-containing aromatic, flavone, hydrazone, and naphthalene derivatives) with IC50 values in the low micromolar to sub-micromolar range. Four compounds with a similar scaffold (i.e., a hydrazone core) were selected for structural modification and 18 derivatives were synthesized. Molecular modeling was then used to investigate the structure-activity relationship (SAR) and potential protein-ligand interactions. As a result, a series of SGK inhibitors that are active against both SGK1 and SGK3 were developed and important functional groups that control their inhibitory activity identified.
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Proteínas Imediatamente Precoces/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Ensaios Enzimáticos , Humanos , Proteínas Imediatamente Precoces/química , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
Recent studies have demonstrated that some chemotherapeutic drugs can enhance antitumor immunity by eliminating and inactivating immunosuppressive cells. Oxaliplatin (OXP) induces immunogenic cell death by increasing the immunogenicity of cancer cells. However, the effects of OXP on the tumor immunosuppressive microenvironment remain unclear. The aim of the present study was to evaluate the antitumor activity of OXP by intraperitoneal (i.p.) administration in an abdominal implantation model of colon cancer and tested the tumor immune microenvironment to observe whether OXP affects the local immune inhibitory cell populations. Abdominal metastasis models were established by inoculation of CT26 cells. The antitumor efficacy of OXP and the tumor immune microenvironment were evaluated. The tumors and spleens of mice were harvested for flow cytometric analysis. Cluster of differentiation (CD)8+CD69+ T cells, regulatory T cells (Tregs), CD11b+F4/80high macrophages and myeloidderived suppressor cells (MDSCs) were evaluated by flow cytometric analysis. In vivo i.p. administration of OXP inhibited tumor growth in the abdominal metastasis model. Furthermore, OXP was observed to increase tumorinfiltrating activated CD8+ T cells in tumors, decrease CD11b+F4/80high macrophages in tumors and decrease MDSCs in the spleen. These results suggested that i.p. administration of OXP alone may inhibit tumor cell growth and induce the antitumor immunostimulatory microenvironment by eliminating immunosuppressive cells.
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Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Compostos Organoplatínicos/administração & dosagem , Abdome/patologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Humanos , Terapia de Imunossupressão/métodos , Injeções Intraperitoneais , Camundongos , Oxaliplatina , Baço/imunologia , Baço/patologia , Baço/transplante , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
OBJECTIVE: To analyze the clinical features,response to therapy and prognosis of intravascular large B-cell lymphoma (IVLBCL). METHODS: The clinical data of 17 cases with IVLBCL were retrospectively reviewed,and survival analysis was conducted. RESULTS: The study involved 10 males and 7 females of IVLBCL with a mean age of 53 years old. The most common symptom of the disease was recurrent fever (76.5%). The lymphoma was mainly observed in bone marrow (64.7%) and was clinically determined as stage â £B (70.6%). Many of the patients were also diagnosed with the hemophagocytic syndrome (29.4%). R-CHOP (rituximab,cyclophosphamide,epirubicin,vindesine,prednisone) or CHOP regimen chemotherapy significantly improved the survival of the patients (P=0.000 2). Unfortunately,those patients with bone marrow involvement were prone to relapse after treatment. CONCLUSION: IVLBCL is highly invasive and associated with poor prognosis. R-CHOP chemotherapy can significantly improve the prognosis.