RESUMEN
Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors and is characterized by a poor prognosis. Although G2- and S -phase expressed-1 (GTSE1) is known to be involved in the progression and metastasis of various cancers, its significance and mechanism in ccRCC remain unknown. In the present study, we found that GTSE1 was overexpressed in ccRCC tissues, especially in metastatic samples. Moreover, high GTSE1 expression was positively correlated with higher pT stage, tumor size, clinical stage, and WHO/ISUP grade and worse prognosis. And GTSE1 expression served as an independent prognostic factor for overall survival (OS). In addition, GTSE1 knockdown inhibited ccRCC cell proliferation, migration, and invasion, and enhanced cell apoptosis in vitro and in vivo. GTSE1 was crucial for epithelial-mesenchymal transition (EMT) in ccRCC. Mechanistically, GTSE1 depletion could upregulate the expression of Krüppel-like factor 4 (KLF4), which acts as a tumor suppressor in ccRCC. Downregulation of KLF4 effectively rescued the inhibitory effect induced by GTSE1 knockdown and reversed the EMT process. Overall, our results revealed that GTSE1 served as an oncogene regulating EMT through KLF4 in ccRCC, and that GTSE1 could also serve as a novel prognostic biomarker and may represent a promising therapeutic target for ccRCC.
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Carcinoma de Células Renales , Neoplasias Renales , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Factor 4 Similar a Kruppel , Proteínas Asociadas a Microtúbulos , Procesos Neoplásicos , PronósticoRESUMEN
BACKGROUND: At present, no effective clinical treatment is available for the late effects of radiation myelopathy. The aim of the present study was to assess the therapeutic effects of human umbilical cord-derived mesenchymal stromal cells (UC-MSCs) in a rat model of radiation myelopathy. METHODS: An irradiated cervical spinal cord rat model was generated. UC-MSCs were injected through the tail vein at 90, 97, 104 and 111 days post-irradiation. Behavioral tests were performed using the forelimb paralysis scoring system, and histological damage was examined using Nissl staining. The microcirculation in the spinal cord was assessed using von Willebrand factor (vWF) immunohistochemical analysis and laser-Doppler flowmetry. The microenvironment in the spinal cord was determined by measuring the pro-inflammatory cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in the serum and the anti-inflammatory cytokines brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) in the spinal cord. RESULTS: Multiple injections of UC-MSCs through the tail veil decreased the forelimb paralysis, decreased spinal cord histological damage, increased the number of neurons in the anterior horn of the spinal cord, increased the endothelial cell density and the microvessel density in the white matter and gray matter of the spinal cord, increased the relative magnitude of spinal cord blood flow, down-regulated pro-inflammatory cytokine expression in the serum, and increased anti-inflammatory cytokine expression in the spinal cord. CONCLUSION: Multiple injections of UC-MSCs via the tail vein in a rat model of radiation myelopathy significantly improved the microcirculation and microenvironment through therapeutic paracrine effects.
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Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Microcirculación , Traumatismos Experimentales por Radiación/terapia , Enfermedades de la Médula Espinal/terapia , Cola (estructura animal)/irrigación sanguínea , Cordón Umbilical/citología , Animales , Diferenciación Celular , Modelos Animales de Enfermedad , Ratas , Médula Espinal/fisiopatología , VenasRESUMEN
Objective: To report the initial results of an randomized clinical trail comparing the safety and efficacy between 7.5F and 9.2F flexible ureteroscope (FUS) in the management of renal calculi <2 cm. Materials and Methods: Eighty patients were enrolled and received retrograde intrarenal surgery (RIRS) with a different size FUS. The operation results and complications were compared. Results: Two cases in the 7.5F group and four cases in the 9.2F group failed to insert the 12/14F ureteral access sheath (UAS), respectively, and no significant difference (p = 0.396) was noted. However, 10/12F UAS was inserted in the 7.5F group, but not available in the 9.2F group, and thus, the 10/12F UAS inserting rate in the 7.5F group was higher than in the 9.2F group (100% vs 0%, p = 0.014), and the UAS insertion failure rate in 9.2F group was higher than in the 7.5F group (10% vs 0%, p = 0.040). The operation time in 7.5F group was shorter than the 9.2F group (35.60 ± 7.86 vs 41.05 ± 8.14, p = 0.003). Less irrigation was required in 7.5F group (813.93 ± 279.47 mL vs 1504.18 ± 385.31 mL, p = 0.000). The postoperative fever rate in 9.2F group was higher than 7.5F group (20% vs 5%, p = 0.043). There was no significant difference in sepsis (0% vs 2.5%, p = 0.314) between the two groups. No significant difference was noted in hospital stay (0.93 ± 0.49 days vs 1.14 ± 0.64 days, p = 0.099) between the two groups. The final stone-free rate (SFR) in 7.5F group was higher than 9.2F group (95% vs 80%, p = 0.043). Conclusion: The latest 7.5F mini FUS was a reliable instrument in RIRS to keep a good visualization with low requirement of irrigation, low postoperative infection complication, and also a high SFR when compared with the conventional 9.2F FUS. Clinical Trial Registration: NCT05231577.
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Cálculos Renales , Ureteroscopios , Humanos , Masculino , Femenino , Persona de Mediana Edad , Cálculos Renales/cirugía , Adulto , Riñón/cirugía , Resultado del Tratamiento , Complicaciones Posoperatorias/etiología , Docilidad , AncianoRESUMEN
BACKGROUND: The aim of this study was to investigate the effects and safety of 120 watt PVP surgery for the high risk prostate hyperplasia patients. METHODS: 120 watt PVP surgery was performed on 120 cases of high risk prostate hyperplasia patients. The assessment included the operation time, energy consumed, hemoglobin changes, and serum salt concentration, whether to keep urinary catheter, hospitalization time, and complications after the operation. International Prostate Symptom Scoring (IPSS), the maximum urine flow rate (Qmax) and residual urine volume (RUV) were conducted preoperatively and postoperatively for the patients. RESULTS: There were 30% of patients taking oral anti-coagulant drug (n = 36), 88 cases with abnormal ECGs. All the patient's internal diseases, include the cardiovascular disease (42/120), the hypertension (56/120), the respiratory system diseases (51/120), the cerebrovascular diseases (39/120), anemia (24/120), liver or kidney dysfunction (16/120), diabetes (18/120), hypoproteinemia (15/120) were under controlled. The average age, prostate volume and energy consumed was 82.8 ± 8.6 (70-96) years, 66.1 ± 25.3 (30-160) ml, and 224 ± 85 (31-596) kJ respectively. The average follow-up time was 20.8 ± 3.2 (18-24) months. The incidence of bladder neck contracture and urethral stricture were 1.7% and 0.8% respectively, no prostate cancer occurred during the subsequent follow-up period. CONCLUSIONS: 120 watt PVP surgery can safely and effectively alleviate the urination parameters of high risk prostate hyperplasia patients. The surgical process is safe and effective, and is not affected by the various internal diseases or the use of oral anti-coagulant drugs.
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Terapia por Láser/estadística & datos numéricos , Síntomas del Sistema Urinario Inferior/epidemiología , Síntomas del Sistema Urinario Inferior/prevención & control , Complicaciones Posoperatorias/epidemiología , Hiperplasia Prostática/epidemiología , Hiperplasia Prostática/cirugía , Enfermedades Urológicas/epidemiología , Anciano , Anciano de 80 o más Años , China , Comorbilidad , Humanos , Masculino , Prevalencia , Factores de Riesgo , Resultado del TratamientoRESUMEN
OBJECTIVE: To explore operative complications of photoselective vaporization of prostate (120 W) for treatment of benign prostatic hyperplasia (BPH). METHODS: The clinical data of 186 cases who underwent photoselective vaporization of prostate (120 W) for the treatment of BPH from May 2010 to April 2012, was statistically analyzed. RESULTS: The operative time ranged from 7 to 147 minutes, and the average time was (37.7 ± 21.5) minutes. No patient accepted intraoperative blood transfusion, and occurred transurethral resection syndrome or capsular perforation. The time of postoperative indwelling catheter ranged from 1 to 11 days, and average time was (4.3 ± 2.2) days. Surgical outcome was satisfactory. Early postoperative complications included bladder spasm (3 cases), transient dysuria (19 cases), urinary tractirritation (94 cases), secondary hemorrhage (26 cases), transient urge incontinence (19 cases), all cases were relieved after treatment. Long-term complications, including recurrence (1 case), bladder neck stenosis (2 cases) and urethral stricture (2 cases), who had required reoperation. Postoperative patients with international prostate symptom score (29.4 ± 3.4), maximum urinary flow rate ((6.0 ± 1.6) ml/s) and residual urine ((167 ± 150) ml) had improved (t = -76.0 - 61.4, P < 0.01). CONCLUSIONS: With less invasive, less bleeding and rapid postoperative recovery, photoselective vaporization of prostate (120 W) is a safe and effective minimally invasive treatment techniques for BPH. But there is still some complications after surgery and proper handling is required.
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Láseres de Estado Sólido , Complicaciones Posoperatorias/epidemiología , Próstata/cirugía , Hiperplasia Prostática/cirugía , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Limited response to programmed death ligand-1 (PD-L1)/programmed death 1 (PD-1) immunotherapy is a major hindrance of checkpoint immunotherapy in non-small cell lung cancer (NSCLC). The abundance of PD-L1 on the tumor cell surface is crucial for the responsiveness of PD-1/PD-L1 immunotherapy. However, the negative control of PD-L1 expression and the physiological significance of the PD-L1 inhibition in NSCLC immunotherapy remain obscure. METHODS: Bioinformatics analysis was performed to profile and investigate the long non-coding RNAs that negatively correlated with PD-L1 expression and positively correlated with CD8+T cell infiltration in NSCLC. Immunofluorescence, in vitro PD-1 binding assay, T cell-induced apoptosis assays and in vivo syngeneic mouse models were used to investigate the functional roles of LINC02418 and mmu-4930573I07Rik in regulating anti-PD-L1 therapeutic efficacy in NSCLC. The molecular mechanism of LINC02418-enhanced PD-L1 downregulation was explored by immunoprecipitation, RNA immunoprecipitation (RIP), and ubiquitination assays. RIP, luciferase reporter, and messenger RNA degradation assays were used to investigate the m6A modification of LINC02418 or mmu-4930573I07Rik expression. Bioinformatics analysis and immunohistochemistry (IHC) verification were performed to determine the significance of LINC02418, PD-L1 expression and CD8+T cell infiltration. RESULTS: LINC02418 is a negative regulator of PD-L1 expression that positively correlated with CD8+T cell infiltration, predicting favorable clinical outcomes for patients with NSCLC. LINC02418 downregulates PD-L1 expression by enhancing PD-L1 ubiquitination mediated by E3 ligase Trim21. Both hsa-LINC02418 and mmu-4930573I07Rik (its homologous RNA in mice) regulate PD-L1 therapeutic efficacy in NSCLC via Trim21, inducing T cell-induced apoptosis in vitro and in vivo. Furthermore, METTL3 inhibition via N6-methyladenosine (m6A) modification mediated by YTHDF2 reader upregulates hsa-LINC02418 and mmu-4930573I07Rik. In patients with NSCLC, LINC02418 expression is inversely correlated with PD-L1 expression and positively correlated with CD8+T infiltration. CONCLUSION: LINC02418 functions as a negative regulator of PD-L1 expression in NSCLC cells by promoting the degradation of PD-L1 through the ubiquitin-proteasome pathway. The expression of LINC02418 is regulated by METTL3/YTHDF2-mediated m6A modification. This study illuminates the underlying mechanisms of PD-L1 negative regulation and presents a promising target for improving the effectiveness of anti-PD-L1 therapy in NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Animales , Ratones , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Antígeno B7-H1/metabolismo , Receptor de Muerte Celular Programada 1 , Inmunoterapia , ARN/metabolismo , ARN/uso terapéutico , Ubiquitinación , Metiltransferasas/genética , Metiltransferasas/metabolismo , Metiltransferasas/uso terapéuticoRESUMEN
BACKGROUND: High prevalence and reoccurrence rate of nephrolithiasis bring about serious socioeconomic and healthcare burden, necessitating the need of effective therapeutic agents. Previous study revealed that gallic acid (GAL) alters the nucleation pathway of calcium oxalate (CaOx). On the other hand, it appears protective role against oxidative injury. Whether GAL could protect against crystal-induced lesion in vivo, and its underlying mechanism is yet unsolved. PURPOSE: This study aims to investigate the protective effects of GAL on the crystal-induced renal injury and its underlying mechanism in the mouse model of stone formation induced by glyoxylic acid. STUDY DESIGN AND METHODS: The mouse model of stone formation was established via successive intraperitoneal injection of glyoxylate. Proximal tubular epithelial cell line HK-2 treated with calcium oxalate monohydrate (COM) was used as in vitro model. The protective role of GAL on nephrolithiasis was tested by determination of tubular injury, crystal deposition and adhesion, levels of inflammatory cytokines, macrophage infiltration and the redox status of kidney. In vitro, effect of GAL on the ROS level and oxidative tubular injury induced by COM were detected, as well as major antioxidant pathway Nrf2/HO-1. RESULTS: Administration of GAL alleviates the renal deposition and adhesion of CaOx stone. Meanwhile, GAL ameliorates the inflammation and renal tubular injury. Level of intracellular ROS, osteopontin and CD44 are reduced, either in the mouse model of stone formation or in the COM-treated HK-2 cells after treatment of GAL. Mechanistically, GAL activates Nrf2/HO-1 pathway in HK-2 cells. Silencing Nrf2 abrogates the protective effect of GAL on the oxidative injury and adhesion of COM in HK-2 cells. CONCLUSION: Taken together, our study demonstrates the protective effect of GAL on the deposition of kidney stone and consequent tubular injury. Induction of the antioxidant pathway Nrf2/HO-1 was found to decrease the level of ROS and oxidative injury, thus implying that GAL could be a potential therapeutic agent for the treatment of nephrolithiasis.
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Oxalato de Calcio , Nefrolitiasis , Animales , Ratones , Antioxidantes/metabolismo , Oxalato de Calcio/metabolismo , Modelos Animales de Enfermedad , Ácido Gálico/farmacología , Glioxilatos , Riñón , Nefrolitiasis/inducido químicamente , Nefrolitiasis/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/metabolismo , Osteopontina/metabolismo , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: Mixed hematopoietic chimerism via bone marrow transplantation has been shown to induce donor specific tolerance to solid organ allografts, but graft versus host disease (GVHD) remains to be a risk. Composite tissue allografts may need a higher percentage of donor chimerism compared with less immunogenic solid organ allografts. In this study, we investigated the potential of mesenchymal stem cells (MSCs) in the induction of stable and high level chimerism and subsequent donor-specific tolerance to composite tissue allograft without the incidence of graft versus host disease (GVHD). METHODS: Fully mismatched, 4- to 8-wk-old Brown Norway (RT1(n)) and Lewis (RT1(1)) rats were used as cell or hind-limb donors and recipients, respectively. Recipients received a conditioning regimen consisting of antilymphocyte serum, standard immunosuppressive therapy (rapamycin: 0.2 mg/kg/d; days 0 approximately 130) and 3 Gy total body irradiation, followed by an intraportal co-infusion of allogeneic MSCs and bone marrow cells (day 0); then performing hind-limb allotransplants (30 d after BMT); 100 d after hind-limb transplantations, immunosuppressive therapy was stopped and to observe the survival time of the hind-limb allografts. RESULTS: When co-infusion of allogeneic MSCs was administered, 14/15 recipients developed stable and high level chimerism. Subsequently, in the donor specific group, the survival time of hind-limb allografts without RAPA were remarkably prolonged compared with other groups. The results of the histopathological evaluation of skin biopsy and mixed lymphocyte cultures confirmed this operational donor specific tolerance. Without MSCs, only 2/7 of the recipients developed stable chimerism, but GVHD occurred in both of them, and the level of the chimerism was much lower. On the other hand, GVHD was not observed in any of the recipients infused with MSCs (0/15). CONCLUSION: This study indicates a potential use of MSCs for induction of stable and high level mixed hematopoietic chimerism and subsequent donor specific tolerance in clinical composite tissue allotransplantation.
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Trasplante de Médula Ósea/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Miembro Posterior/trasplante , Tolerancia Inmunológica/fisiología , Trasplante de Células Madre Mesenquimatosas/métodos , Quimera por Trasplante/inmunología , Animales , Células Cultivadas , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Enfermedad Injerto contra Huésped/inmunología , Prueba de Cultivo Mixto de Linfocitos , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/inmunología , Ratas , Ratas Endogámicas BN , Ratas Endogámicas Lew , Ratas Endogámicas WF , Acondicionamiento Pretrasplante/métodos , Trasplante HomólogoRESUMEN
BACKGROUND: OTUB1 (ovarian tumor domain protease domain-containing ubiquitin aldehyde-binding proteins)-mediated deubiquitination of FOXM1 (Forkhead box M1) participates in carcinogenesis of various tumors. We aim to investigate the effect and mechanism of OTUB1/FOXM1 on RCC (renal cell carcinoma) progression. Expression levels of OTUB1 in RCC tissues and cell lines were examined by qRT-PCR (quantitative real-time polymerase chain reaction) and immunohistochemistry. Cell proliferation was measured with CCK8 (Cell Counting Kit-8) and colony formation assays. Wound healing and transwell assays were used to determine cell migration and invasion, respectively. The effect of OTUB1 on FOXM1 ubiquitination was examined by Immunoprecipitation. Western blot was used to uncover the underlying mechanism. In vivo subcutaneous xenotransplanted tumor model combined with immunohistochemistry and western blot were used to examine the tumorigenic function of OTUB1. RESULTS: OTUB1 was up-regulated in RCC tissues and cell lines, and was associated with poor prognosis of RCC patients. Knockdown of OTUB1 inhibited cell viability and proliferation, as well as migration and invasion of RCC cells. Mechanistically, knockdown of OTUB1 down-regulated FOXM1 expression by promoting its ubiquitination. Down-regulation of FOXM1 inhibited ECT2 (epithelial cell transforming 2)-mediated Rho signaling. Moreover, the inhibition of RCC progression caused by OTUB1 knockdown was reversed by FOXM1 over-expression. In vivo subcutaneous xenotransplanted tumor model also revealed that knockdown of OTUB1 could suppress in vivo RCC growth via down-regulation of FOXM1-mediated ECT2 expression. CONCLUSIONS: OTUB1-mediated deubiquitination of FOXM1 up-regulates ECT-2 to promote tumor progression in RCC, providing a new potential therapeutic target for RCC treatment.
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OBJECTIVE: To investigate a non-toxic AdCTLA4-Ig-based protocol for non-myeloablative allogeneic hematopoietic cell transplantation to induce donor-specific tolerance to hind limb allografts in rats. METHODS: Fully mismatched, 4 to 8 week old Brown Norway (RT1(n)) and Lewis (RT1(1)) rats were used as cell/organ donors and recipients, respectively. Recipients were treated with AdCTLA4-Ig (5 x 10(9) PFU, day -30, 0, 30), standard immunosuppressive therapy (MP: 10 mg x kg(-1) x d(-1), MMF: 20 mg x kg(-1) x d(-1), RAPA: 0.2 mg x kg(-1) x d(-1);day -33 - 100), soon after total body irradiation (3 Gy, day -30) and donor bone marrow (100 x 10(6), day -30) transplantation (BMT). Thirty days after BMT, chimeric animals received hind limb transplantations. And 100 days after hind limb transplantations, immunosuppressive therapy was changed for low-dosed CsA (8 mg x kg(-1) x d(-1), day 100-), until the allografts were rejected. RESULTS: In Group C, hematopoietic chimerism was (38.8 +/- 10.6)% at day 0, and was stable (29.3 +/- 11.9)% at 330 days post-BMT. There was no graft versus host disease in both Group C and Group D. When the standard immunosuppressive therapy was stopped and changed for low-dosed CsA, chimeric recipients (Lewis, RT1(1)) permanently accepted (> 200 days) donor specific (Brown Norway, RT1(n)) hind limb allografts in Group C, yet rapidly rejected in Group A (8 +/- 2) d, Group B (18 +/- 3) d and in Group C (20 +/- 2) d. Lymphocytes of graft tolerant animals' demonstrated hyporesponsiveness in mixed lymphocyte cultures in a donor-specific manner in Group C. Tolerant graft histology showed no obliterative arteriopathy or chronic rejection. CONCLUSION: The AdCTLA4-Ig based conditioning regimen with donor BMT produce stable mixed chimerism and induce donor-specific tolerance to hind limb allografts.
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Miembro Posterior/trasplante , Tolerancia Inmunológica , Inmunoconjugados/farmacología , Acondicionamiento Pretrasplante/métodos , Abatacept , Adenoviridae , Animales , Supervivencia de Injerto , Prueba de Cultivo Mixto de Linfocitos , Masculino , Distribución Aleatoria , Ratas , Ratas Endogámicas BN , Ratas Endogámicas Lew , Quimera por Trasplante/inmunología , Trasplante HomólogoRESUMEN
OBJECTIVE: Sunitinib/sorafenib (SU/SO), dendritic cells (DCs), or DC-cytokine-induced killer (CIK) could significantly prolong progression-free survival (PFS), 3-year overall survival (OS), or 5-year OS for patients with metastatic renal cell carcinoma (mRCC). We retrospectively analyzed the clinical efficacy between SU/SO combined with DC-CIK and SU/SO monotherapy in treating renal cell carcinoma (RCC) patients with metastasis after radical nephrectomy. MATERIALS AND METHODS: All patients (n = 34) with postoperative mRCC in our hospital from January 2009 to January 2014 were received either SU/SO monotherapy (Group 1, n = 15) or in combination with DC-CIK (Group 2, n = 19). A retrospective study was based on the primary endpoint (PFS) and secondary endpoint (OS). RESULTS: At a median follow-up of 19.5 months, in Group 2, as compared with in Group 1, the median PFS was significantly longer (28.0 vs. 11.0 months, P = 0.03). Moreover, the 3-year OS was higher (57.1% vs. 28.6%). The cases of progressive diseases (PDs) and deaths were less in Group 2 than that in Group 1 (PD: 8 vs. 9, deaths: 3 vs. 5); however, the cases of stable diseases were more (11 vs. 6). In addition, the 3-year OS was higher in SU + DC-CIK group than that in SO + DC-CIK group (63.36% vs. 50%). There was no significant difference for PFS between SO + DC-CIK group and SU single agent group. CONCLUSIONS: SU/SO with DC-CIK could significantly prolong the median PFS, improve the 3-year OS rate, prolong the 3-year OS. It is likely to be a new approach for mRCC after radical nephrectomy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Vacunas contra el Cáncer , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/terapia , Células Asesinas Inducidas por Citocinas/inmunología , Células Dendríticas/inmunología , Inmunoterapia Adoptiva , Neoplasias Renales/inmunología , Neoplasias Renales/terapia , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Terapia Combinada , Células Asesinas Inducidas por Citocinas/metabolismo , Células Dendríticas/metabolismo , Femenino , Humanos , Inmunoterapia Adoptiva/métodos , Indoles/administración & dosificación , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Niacinamida/administración & dosificación , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Cuidados Posoperatorios , Pirroles/administración & dosificación , Estudios Retrospectivos , Sorafenib , Sunitinib , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Sunitinib is a tyrosine kinase inhibitor with effective therapeutic outcomes in patients with renal-cell carcinoma. The study were to analyze the association of single-nucleotide polymorphisms present in cell-free DNA and pharmacokinetics with sunitinib treatment-emergent adverse events in Chinese patients with renal-cell carcinoma. MATERIALS AND METHODS: We genotyped 8 keys SNPs in 6 candidate genes. The plasma concentrations of sunitinib and N-desethyl sunitinib were measured using a high performance liquid chromatography-tandam mass spectrometry method. Correlations between the single-nucleotide polymorphisms and adverse events were investigated by univariate and multivariate logistic regression and we quantitatively evaluated the effect of single-nucleotide polymorphisms on the pharmacokinetics of sunitinib by using a population PK model. RESULTS: Necessary dose reductions of sunitinib were significantly correlated with SNP rs1933437 in FLT3. A higher severity of AEs were collected with SNP rs2032582 in ABCB1 and rs1800812 in PDGFRα. Thrombocytopenia was collected with rs1800812 in PDGFRα. Our study provides a population PK model of sunitinib with the ABCB1 genotype as a predictive covariate for apparent oral clearance. CONCLUSIONS: Our study preliminarily confirmed the hypothesis that the pharmacokinetics of sunitinib is affected by the SNPs of enzyme in Chinese renal-cell carcinoma patients, and this affects the different distribution and severity of adverse events of sunitinib.
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Aerobic glycolysis (the Warburg effect) facilitates tumor growth, and drugs targeting aerobic glycolysis are being developed. However, how the Warburg effect is directly regulated is largely unknown. Here we show that transcription factor SIX1 directly increases the expression of many glycolytic genes, promoting the Warburg effect and tumor growth in vitro and in vivo. SIX1 regulates glycolysis through HBO1 and AIB1 histone acetyltransferases. Cancer-related SIX1 mutation increases its ability to promote aerobic glycolysis and tumor growth. SIX1 glycolytic function is directly repressed by microRNA-548a-3p, which is downregulated, inversely correlates with SIX1, and is a good predictor of prognosis in breast cancer patients. Thus, the microRNA-548a-3p/SIX1 axis strongly links aerobic glycolysis to carcinogenesis and may become a promising cancer therapeutic target.
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Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Glucólisis/genética , Proteínas de Homeodominio/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Regulación hacia Abajo , Humanos , MicroARNs/genéticaRESUMEN
Lactate dehydrogenase A (LDHA), a key enzyme regulating aerobic glycolysis, is overexpressed in many human cancers, and correlates with poor clinical outcomes. Aerobic glycolysis is a hallmark of cancer, and drugs targeting its regulators, including LDHA, are being developed. However, the mechanisms of LDHA inhibition and the physiological significance of the LDHA inhibitors in cancer cells are unclear. Here, we show that microRNA-30a-5p (miR-30a-5p) suppresses LDHA expression by directly targeting its 3'-UTR. Through inhibition of LDHA, miR-30a-5p dampens glycolysis by decreasing glucose uptake, lactate production, ATP generation, and extracellular acidification rate (ECAR), and increasing oxygen consumption rate (OCR) in breast cancer cells. Importantly, glycolysis regulated by miR-30a-5p is critical for its regulating breast tumor growth and metastasis both in vitro and in vivo. In breast cancer patients, miR-30a-5p expression is negatively correlated with LDHA expression. Moreover, patients who had increased glucose uptake in tumors assessed by PET scans showed decreased miR-30a-5p expression and increased expression of LDHA. Our findings provide clues regarding the role of miR-30a-5p as a tumor suppressor in breast cancer through the inhibition of LDHA. Targeting LDHA through miR-30a-5p could be a potential therapeutic strategy in breast cancer.
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Neoplasias de la Mama/enzimología , Movimiento Celular , Proliferación Celular , Glucólisis , L-Lactato Deshidrogenasa/metabolismo , MicroARNs/metabolismo , Regiones no Traducidas 3' , Animales , Sitios de Unión , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Glucosa/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Isoenzimas/genética , Isoenzimas/metabolismo , L-Lactato Deshidrogenasa/genética , Lactato Deshidrogenasa 5 , Ácido Láctico/metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , Metástasis de la Neoplasia , Consumo de Oxígeno , Interferencia de ARN , Transducción de Señal , Factores de Tiempo , Transfección , Carga TumoralRESUMEN
This single-center, observational study analyzed the association between plasma concentration of sorafenib and its safety and efficacy in Chinese patients with metastatic renal cell carcinoma (mRCC). Adult patients with RCC (n = 94), treated with sorafenib were enrolled between January 2014 and January 2015. Sorafenib plasma concentrations were measured by liquid chromatography-tandem mass spectrometry. Safety and efficacy variables were evaluated using National Cancer Institute-Common Toxicity Criteria for Adverse Events and Response Evaluation Criteria in Solid Tumors criteria. Association of plasma concentration with safety and efficacy was analyzed. The steady state plasma concentration of sorafenib after 2 weeks of treatment ranged from 881 to 12,526 ng/mL. Major adverse reactions (ADRs) included diarrhea (76.5%), hand-foot syndrome (HFS; 68.99%) and fatigue (55.32%). Significant association was reported between plasma concentration and all the ADRs except rash. At 6 weeks, complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) was reported in 3.1%, 13.82%, 52.2% and 13.82% patients, respectively. Objective response and disease control rates were 17.02% and 69.14%. Plasma concentration of sorafenib was >10,000 ng/mL in patients with severe ADRs, which decreased with reduction in dose or discontinuation of treatment. After 21.2 weeks follow-up, median progression free survival was 12.3 months. CR, PR, SD and PD were reported in 1%, 46%, 33% and 19% patients. In conclusion, plasma concentration of sorafenib was associated with its safety and efficacy in Chinese patients with mRCC.
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Antineoplásicos/farmacocinética , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Niacinamida/análogos & derivados , Compuestos de Fenilurea/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Adulto , Anciano , Antineoplásicos/efectos adversos , Biomarcadores , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/mortalidad , Cromatografía Líquida de Alta Presión , Monitoreo de Drogas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Niacinamida/efectos adversos , Niacinamida/farmacocinética , Variantes Farmacogenómicas , Compuestos de Fenilurea/efectos adversos , Polimorfismo Genético , Inhibidores de Proteínas Quinasas/efectos adversos , Sorafenib , Espectrometría de Masas en Tándem , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: To investigate the effect of sunitinib on the expressions of co-stimulatory molecule ligands, programmed death ligand 1 (PD-L1), PD-L2, CD80, CD86, B7-H4 and herpes virus entry mediator (HVEM) on peripheral blood monocyte-derived dendritic cells (DCs) from patients with renal cell carcinoma (RCC). METHODS: Monocyte-derived DCs from patients with RCC were cultured in vitro and randomly divided into three groups: sunitinib combined with lipopolysaccharide (LPS), LPS only and dimethyl sulfoxide (DMSO) treatment. Sunitinib plus LPS group was pretreated with 200 ng/mL sunitinib for 12 hours followed by stimulated with 1 µg/mL LPS for 24 hours; LPS group was pretreated with 1 µL/mL DMSO for 12 hours and then stimulated with 1 µg/mL LPS for 24 hours; DMSO group was treated with 1 µL/mL DMSO for 36 hours. Morphological changes were observed by an inverted microscope. Flow cytometry was used to detect the expressions of PD-L1, PD-L2, CD80, CD86, B7-H4 and HVEM. RESULTS: Sunitinib-LPS co-treated and LPS-treated cells had typical dendrites, while DMSO-treated cells had no obvious dendrites. Compared with the LPS-treated group, the expressions of CD80, PD-L1 and B7-H4 on DCs significantly decreased in the sunitinib-LPS group; the expressions of PD-L1, PD-L2, CD80, CD86, B7-H4 and HVEM were lower in the DMSO group. CONCLUSION: Sunitinib inhibits the expressions of CD80, PD-L1 and B7-H4 on DCs induced by LPS.
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Carcinoma de Células Renales/genética , Células Dendríticas/efectos de los fármacos , Indoles/farmacología , Pirroles/farmacología , Antígeno B7-1/genética , Antígeno B7-1/inmunología , Antígeno B7-2/genética , Antígeno B7-2/inmunología , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/inmunología , Células Cultivadas , Células Dendríticas/inmunología , Regulación hacia Abajo/efectos de los fármacos , Femenino , Humanos , Indoles/efectos adversos , Ligandos , Masculino , Monocitos/efectos de los fármacos , Monocitos/inmunología , Proteína 2 Ligando de Muerte Celular Programada 1/genética , Proteína 2 Ligando de Muerte Celular Programada 1/inmunología , Pirroles/efectos adversos , SunitinibRESUMEN
OBJECTIVE: To observe the changes of programmed death-1 ligand 1 (PD-L1) and PD-L2 expressions on mouse bone marrow-derived dendritic cells (DCs) stimulated by sunitinib. METHODS: DCs were randomly divided into four groups which were treated with sunitinib (100, 200, 300 ng/mL) and dimethylsulfoxide (DMSO), respectively. After 48 hours, PD-L1 and PD-L2 expression levels were analyzed by flow cytometry. RESULTS: Compared with the control group, the expression of PD-L1 on mature DCs (mDCs) and all DCs [including mature DCs and immature DCs (imDCs)] was significantly down-regulated in sunitinib treatment groups. The PD-L1 expression percentages of imDCs, mDCs and DCs were significantly reduced in sunitinib treatment groups; the percentage of mDCs expressing PD-L2 also dropped in all treatment groups, and the percentage of DCs expressing PD-L2 decreased in 100 and 300 ng/mL sunitinib treatment groups. CONCLUSION: Sunitinib can significantly reduce the expressions of PD-L1 and PD-L2 on mouse DCs.
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Antineoplásicos/farmacología , Antígeno B7-H1/genética , Médula Ósea/efectos de los fármacos , Células Dendríticas/efectos de los fármacos , Indoles/farmacología , Proteína 2 Ligando de Muerte Celular Programada 1/genética , Pirroles/farmacología , Animales , Antígeno B7-H1/metabolismo , Médula Ósea/metabolismo , Células Cultivadas , Células Dendríticas/metabolismo , Femenino , Expresión Génica/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , SunitinibRESUMEN
This study aims to investigate the surgical method and long-term efficacy of transpostceliac single-port 3-channel laparoscope in the treatment of complex renal cyst. A retrospective analysis was performed towards the 37 patients who underwent renal cyst unroofing decompression with single-port laparoscope from Jun. 2012 to Jul. 2013. The surgery was performed through the postceliac approach, a 2.5 cm incision was made 4-5 cm away from the iliac spine of midaxillary line, the Olympus single-port TriPort was then implanted, with the laparoscopic channel and the other two operation channels all as 5 mm. The operation was completed with the forceps and scissors which had flexible fronts. The cysts of the 37 patients were performed the appropriate surgical treatments according to their subtype grouping, on case was transferred to the open surgery, and there was no blood transfusion case. The operation time was 11-42 min, with the mean time as 23 min; the bleeding volume was 10-50 ml, with the mean volume as 26 ml; the postoperative follow-up was 1-6 months, and the ultrasound review did not find the recurrence of cyst; the postoperative lumbar scar was approximately 2.5 cm, and the patients could leave the bed and perform some acts on the exact day of the surgery; the hospitalization time was 1-2 d, with the average time as 1.2 d. The efficacy of the transpostceliac single-port 3-channel laparoscope in the treatment of complex renal cyst was positive, with low recurrence rate, and worthy of further promotion.
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This study aimed to assess the short-term efficacy of sequential therapy for T2/T3a bladder cancer with intravesical single-port laparoscopic partial cystectomy or open partial cystectomy combined with cisplatin plus gemcitabine (GC) chemotherapy in a prospective randomized controlled study. Thirty patients with bladder cancer who underwent open partial cystectomy (group A) or single-port laparoscopic partial cystectomy (group B) and received standard GC chemotherapy were analyzed. Perioperative functional indicators and tumor recurrence during a 1-year postoperative follow-up were compared between the two groups. The baseline characteristics were comparable between the two groups. The mean operative time, amount of blood loss and duration of hospital stay were 90.3 min, 182.0 ml and 7.3 days, respectively, for group A, and 105.3 min, 49.3 ml and 5.8 days, respectively, for group B. No secondary postoperative bleeding, urine leakage, wound infection or other complications were observed in the two groups. Postoperative scarring was not evident in group B. The overall incidence of surgical complications, tumor recurrence rate and complications during chemotherapy in the postoperative follow-up period of 12 months were similar between the two groups. Single-port laparoscopic partial cystectomy surgery is an idea surgical method for the treatment of invasive bladder cancer, with good surgical effect, minimal invasiveness, rapid recovery and short hospital stay. The data from 1-year postoperative follow-up showed that laparoscopic surgery was superior with regard to perioperative bleeding, postoperative recovery and duration of indwelling urinary catheter use. However, regarding the tumor recurrence rate, long-term comparative details are required to determine the effect of laparoscopic surgery.
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Previous studies have shown that the stroke volume variation (SVV), the pulse pressure variation (PPV) and the pleth variability index (PVI) could be successfully used for predicting fluid responsiveness (FR) in surgical patients. The aim of this study was to validate the ability of SVV, PPV and PVI to predict intraoperative FR in mechanically ventilated patients with obstructive jaundice (OJ). Thirty-two patients with OJ (mean serum total bilirubin 190.5 ± 95.3 µmol L(-1)) received intraoperative volume expansion (VE) with 250 ml colloids immediately after an exploratory laparotomy had been completed and after a 5 min period of hemodynamic stability. Hemodynamic variables were recorded before and after VE. FR was defined as an increase in stroke volume index > 10% after VE. The ability of SVV, PPV and PVI to predict FR was assessed by calculation of the area under the receiver operating characteristic curve. Eleven (34%) patients were responders and 21 patients were nonresponders to VE. The PPV was the unique dynamic index that had the moderate ability to predict FR during surgical procedures, the area under the curve was 0.71 (95% CI, 0.523 to 0.856; P = 0.039) and the threshold (sensitivity and specificity) discriminated responders was 7.5% (63.6%/71.4%). The present study concluded that SVV and PVI were not reliable predictors of FR, but PPV has some value predicting FR in patients with OJ intraoperatively.