RESUMEN
We studied the efficacy and safety of the combined treatment with programmed cell death 1 (PD-1) inhibitors and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy and subsequent PD-1 inhibitor maintenance treatment in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and high tumor burden. Forty-four R/R DLBCL patients with high tumor burden were enrolled in this study. The experimental group of 26 patients received combined therapy with PD-1 inhibitors and anti-CD19-CAR T cells, while the control group of 18 patients received anti-CD19-CAR T-cell therapy alone. The objective response rate (ORR) was 65.39% and 61.11% in the combination and control groups, respectively. The PD-1 inhibitor maintenance therapy was selected for patients who achieved complete response or partial response in the combination therapy group. Progression-free survival and overall survival rates in the combination group were higher than those in the control group 3 and 12 months after CAR T-cell infusion. There was no significant difference in the grade of cytokine release syndrome or immune effector cell associated neurotoxic syndrome between the two groups. In the maintenance therapy group, only eight patients experienced grade 1 Common Terminology Criteria for Adverse Events (CTCAE) and three grade 2 CTCAE. Overall, we found that the ORR was not affected by the combination therapy with PD-1 inhibitors and anti-CD19-CAR T cells. However, patients who had achieved the ORR might benefit from PD-1 inhibitor maintenance therapy after combination therapy without increased side effects.
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Linfoma de Células B Grandes Difuso , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Carga Tumoral , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Antígenos CD19 , Linfocitos T , ApoptosisRESUMEN
The persistence or recurrence of minimal residual disease (MRD) after chemotherapy predicts relapse of B-cell acute lymphoblastic leukemia (B-ALL). CD19-directed chimeric antigen receptor T (CD19 CAR-T) cells have shown promising responses in B-ALL. However, their role in chemotherapy-refractory MRD-positive B-ALL remains unclear. Here we aimed to assess the effectiveness and safety of CD19 CAR-T cells in MRD-positive B-ALL patients. From January 2018, a total of 14 MRD-positive B-ALL patients received one or more infusions of autogenous CD19 CAR-T cells. Among them, 12 patients achieved MRD-negative remission after one cycle of CAR-T infusion. At a median follow-up time of 647 days (range 172-945 days), the 2-year event-free survival rate in MRD-positive patients was 61.2% ± 14.0% and the 2-year overall survival was 78.6 ± 11.0%, which were significantly higher than patients with active disease (blasts ≥ 5% or with extramedullary disease). Moreover, patients with MRD had a lower grade of cytokine release syndrome (CRS) than patients with active disease. However, the peak expansion of CAR-T cells in MRD positive patients showed no statistical difference compared to patients with active disease. Five patients received two or more CAR-T cell infusions and these patients showed a decreased peak expansion of CAR-T cell in subsequent infusions. In conclusion, pre-emptive CD19 CAR-T cell treatment is an effective and safe approach and may confer sustained remission in B-ALL patients with chemotherapy-refractory MRD. The trials were registered at www.chictr.org.cn as ChiCTR-ONN-16009862 (November 14, 2016) and ChiCTR1800015164 (March 11, 2018).
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Antígenos CD19/inmunología , Linfoma de Células B/inmunología , Neoplasia Residual/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/inmunología , Adolescente , Adulto , Anciano , Femenino , Humanos , Inmunoterapia Adoptiva/métodos , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Recurrencia , Adulto JovenRESUMEN
Chimeric antigen receptor-T (CAR-T) cell therapy is a promising treatment for CD19+ B-cell malignancies. However, elimination of B cells by anti-CD19 CAR-T cells may lead to the reactivation of hepatitis B virus (HBV) and related hepatitis in patients with HBV infection. This study aims to evaluate the safety and efficacy of humanized anti-CD19 CAR-T (hCAR-T) therapy in B-cell malignancies with HBV infection. Twenty relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL) patients with HBV infection were treated with hCAR-T therapy. Among them, five hepatitis B antigen-positive patients who received antiviral prophylaxis did not develop HBV reactivation, including two patients who received both hCAR-T and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Among 15 patients with resolved HBV infection, two received antiviral prophylaxis, and the other 13 did not experience HBV reactivation without antiviral prophylaxis. One patient with resolved HBV infection experienced HBV reactivation 6 months after hCAR-T therapy and sequential allo-HSCT. Moreover, HBV infection did not affect in vivo expansion of hCAR-T cells or increase the risk of severe cytokine release syndrome. In conclusion, hCAR-T therapy is safe and effective in DLBCL and ALL patients with chronic and resolved HBV infection under proper antiviral prophylaxis.
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Trasplante de Células Madre Hematopoyéticas , Virus de la Hepatitis B/fisiología , Hepatitis B Crónica/prevención & control , Inmunoterapia Adoptiva , Linfoma de Células B Grandes Difuso/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores Quiméricos de Antígenos , Activación Viral , Adulto , Aloinjertos , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Ibrutinib might improve the efficacy of anti-CD19 chimeric antigen receptor (CD19 CAR) T-cell therapy in chronic lymphocytic leukemia (CLL). We studied the possibility and mechanism of the synergistic effect of ibrutinib and CAR-T cells in other types of lymphoma. In this study, we selected the CD19 CAR-T cells of a patient with lymphoma who failed in his CD19 CAR-T-cell therapy and a dose of 8 mg/kg/d ibrutinib. Subcutaneous and tail vein tumorigenic mice were established with Raji cells. The differences in the synergistic effect between these 2 models were compared by bioluminescence imaging (BLI) monitoring and flow cytometry (FCM). The expression of the STAT-3 signaling pathway was assessed by western blot analysis. There was no synergistic effect of ibrutinib and CD19 CAR-T cells in vitro. Programmed cell death-ligand 1 (PD-L1) was expressed in 0.23 ± 0.06% of Raji cells. In the subcutaneous tumorigenic model, the luciferase signal was reduced significantly in the group receiving ibrutinib combined with CD19 CAR-T cells. Moreover, the proportion of CD19 CAR-T cells was higher in the polytherapy group than in the CAR-T-cell monotherapy group. However, we did not get an analogous synergistic effect in the tail vein tumorigenic model. STAT-3 signaling pathway expression in the residual tumor cells did not differ between those with and those without ibrutinib, suggesting that the IL-10/STAT-3/PD-L1 pathway was not involved in the synergistic effect. Therefore, some other mechanism might be a target for ibrutinib. Our results provide evidence for the use of ibrutinib in polytherapy for other types of B-cell lymphoma.
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Adenina/análogos & derivados , Antígenos CD19/inmunología , Inmunoterapia Adoptiva , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Adenina/farmacología , Adulto , Anciano , Animales , Biomarcadores de Tumor , Línea Celular Tumoral , Terapia Combinada , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunofenotipificación , Inmunoterapia Adoptiva/métodos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/terapia , Masculino , Ratones , Persona de Mediana Edad , Estadificación de Neoplasias , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Factor de Transcripción STAT3/metabolismo , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We studied the efficacy and safety of humanized CAR-T therapy following intensive chemotherapy for refractory/relapsed (R/R) acute lymphoblastic leukaemia (B-ALL). Twenty-three patients with R/R B-ALL were pretreated with intensive chemotherapy (fludarabine combined with medium-dose cytarabine) 12 days before CAR-T therapy. Adverse events (AEs), curative effects, infection indicators and cytokine release syndrome (CRS) were monitored. Each of the 23 patients received a dose of 1·0 × 106 cells/kg CAR-T cell infusion on day 0. After 14 days, 19 patients (82·61%) achieved complete response (CR) or CR with incomplete count recovery. No survival benefit was achieved with consolidative haematopoietic stem-cell transplantation (HSCT), with a median follow-up of 14·0 months (range, 1·5-21·0 months). The notable AEs were grade 1-2 CRS in 18 patients, while the other five patients were grade 3 CRS. No patients died of CRS. Only one patient died of respiratory failure due to cytomegalovirus infection 24 days after infusion. The proportion of leukaemic cells in bone marrow on infusion day and the peaks of IL-6, TNF-α and IL-8 levels were correlated with CRS levels. A lower disease burden was achieved by intensive lymphodepleting chemotherapy, and the subsequent CAR-T therapy had a high response and manageable toxicity. Trial registration: The patients were enrolled in a clinical trial of ChiCTR-ONN-16009862, and ChiCTR1800019622.
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Traslado Adoptivo , Trasplante de Células Madre Hematopoyéticas , Depleción Linfocítica , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Adolescente , Adulto , Anciano , Aloinjertos , Antígenos CD19 , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidadRESUMEN
BACKGROUND: Protein neddylation plays a tumor-promoting role in esophageal cancer. Our previous study demonstrated that neddylation inhibition induced the accumulation of ATF4 to promote apoptosis in esophageal cancer cells. However, it is completely unknown whether neddylation inhibition could induce autophagy in esophageal cancer cells and affect the expression of other members of ATF/CREB subfamily, such as ATF3. METHODS: The expression of relevant proteins of NF-κB/Catalase/ATF3 pathway after neddylation inhibition was determined by immunoblotting analysis and downregulated by siRNA silencing for mechanistic studies. ROS generation upon MLN4924 treatment was determined by H2-DCFDA staining. The proliferation inhibition induced by MLN4924 was evaluated by ATPLite assay and apoptosis was evaluated by Annexin V /PI double staining. RESULTS: For the first time, we reported that MLN4924, a specific inhibitor of Nedd8-activating enzyme, promoted the expression of ATF3 to induce autophagy in esophageal cancer. Mechanistically, MLN4924 inhibited the activity of CRLs and induced the accumulation of its substrate IκBα to block NF-κB activation and Catalase expression. As a result, MLN4924 activated ATF3-induced protective autophagy, thereby inhibiting MLN4924-induced apoptosis, which could be alleviated by ATF3 silencing. CONCLUSIONS: In our study, we elucidates a novel mechanism of NF-κB/Catalase/ATF3 pathway in MLN4924-induced protective autophagy in esophageal cancer cells, which provides a sound rationale and molecular basis for combinational anti-ESCC therapy with knockdown ATF3 and neddylation inhibitor (e.g. MLN4924). Video abstract.
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Factor de Transcripción Activador 3/metabolismo , Ciclopentanos/farmacología , Inhibidores Enzimáticos/farmacología , Neoplasias Esofágicas/tratamiento farmacológico , FN-kappa B/metabolismo , Pirimidinas/farmacología , Enzimas Activadoras de Ubiquitina/antagonistas & inhibidores , Apoptosis , Autofagia , Catalasa/metabolismo , Línea Celular Tumoral , Humanos , Transducción de SeñalRESUMEN
Protein neddylation, a process of conjugating neural precursor cell expressed, developmentally downregulated 8 (NEDD8) to substrates, plays a tumor-promoting role in lung carcinogenesis. Our previous study showed MLN4924, an inhibitor of NEDD8 activating enzyme (E1), significantly inhibits the growth of multiple cancer cells. However, resistance can develop to MLN4924 by mutation. Therefore, it is important to further understand how NEDD8 acts in lung cancer. In the present study, we demonstrated NEDD8 is overactivated in lung cancers and confers a worse patient overall survival. Furthermore, we report that in lung adenocarcinoma cells, NEDD8 depletion significantly suppressed lung cancer cell growth and progression both in vitro and in vivo. Mechanistic studies revealed that NEDD8 depletion induced the accumulation of a panel of tumor-suppressive cullin-RING ubiquitin ligase substrates (e.g., p21, p27, and Wee1) via blocking their degradation, triggering cell cycle arrest at G2 phase, thus inducing apoptosis or senescence in a cell-line-dependent manner. The present study demonstrates the role of NEDD8 in regulating the malignant phenotypes of lung cancer cells and further validates NEDD8 as a potential therapeutic target in lung cancer.
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Adenocarcinoma del Pulmón/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Proteína NEDD8/metabolismo , Adenocarcinoma del Pulmón/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclopentanos/farmacología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Ubiquitina/metabolismoRESUMEN
Neddylation, a post-translational modification that adds an ubiquitin-like protein NEDD8 to substrate proteins, modulates many important biological processes, including tumorigenesis. The process of protein neddylation is overactivated in multiple human cancers, providing a sound rationale for its targeting as an attractive anticancer therapeutic strategy, as evidence by the development of NEDD8-activating enzyme (NAE) inhibitor MLN4924 (also known as pevonedistat). Neddylation inhibition by MLN4924 exerts significantly anticancer effects mainly by triggering cell apoptosis, senescence and autophagy. Recently, intensive evidences reveal that inhibition of neddylation pathway, in addition to acting on tumor cells, also influences the functions of multiple important components of the tumor microenvironment (TME), including immune cells, cancer-associated fibroblasts (CAFs), cancer-associated endothelial cells (CAEs) and some factors, all of which are crucial for tumorigenesis. Here, we briefly summarize the latest progresses in this field to clarify the roles of neddylation in the TME, thus highlighting the overall anticancer efficacy of neddylaton inhibition.
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Ciclopentanos/uso terapéutico , Proteína NEDD8/metabolismo , Neoplasias/tratamiento farmacológico , Pirimidinas/uso terapéutico , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Fibroblastos Asociados al Cáncer/metabolismo , Supervivencia Celular/efectos de los fármacos , Senescencia Celular , Ensayos Clínicos como Asunto , Ciclopentanos/farmacología , Humanos , Proteína NEDD8/antagonistas & inhibidores , Neoplasias/metabolismo , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacosRESUMEN
Metastasis is the leading cause of tumor-related death from lung cancer. However, limited success has been achieved in the treatment of lung cancer metastasis due to the lack of understanding of the mechanisms that underlie the metastatic process. In this study, Lewis lung carcinoma (LLC) cells which expressed green fluorescent protein in the nucleus and red fluorescent protein in the cytoplasm were used to record metastatic process in real-time via a whole-mouse imaging system. Using this system, we show the neddylation inhibitor MLN4924 inhibits multiple steps of the metastatic process, including intravascular survival, extravasation, and formation of metastatic colonies, thus finally suppressing tumor metastasis. Mechanistically, MLN4924 efficiently inhibits the expression of MMP2, MMP9, and vimentin and disrupts the actin cytoskeleton at an early stage to impair invasive potential and subsequently causes a DNA damage response, cell cycle arrest, and apoptosis upon long exposure to MLN4924. Furthermore, MMP2 and MMP9 are overexpressed in patient lung adenocarcinoma, which conferred a worse overall survival. Together, targeting the neddylation pathway via MLN4924 suppresses multiple steps of the metastatic process, highlighting the potential therapeutic value of MLN4924 for the treatment of metastatic lung cancer.
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Neoplasias Pulmonares/metabolismo , Proteína NEDD8/metabolismo , Metástasis de la Neoplasia/prevención & control , Animales , Apoptosis/fisiología , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Ciclopentanos/farmacología , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Pulmonares/fisiopatología , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteína NEDD8/fisiología , Invasividad Neoplásica/fisiopatología , Metástasis de la Neoplasia/fisiopatología , Procesamiento Proteico-Postraduccional/fisiología , Pirimidinas/farmacología , Transducción de Señal , Enzimas Activadoras de Ubiquitina/metabolismo , Vimentina/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The adverse effects of iron overload have raised more concerns as a growing number of studies reported its association with immune disorders. This study aimed to investigate alterations in the immune system by iron overload in patients with myelodysplastic syndrome (MDS) and an iron-overloaded mouse model. The peripheral blood from patients was harvested to test the effect of iron overload on the subsets of T lymphocytes, and the level of reactive oxygen species (ROS) was also evaluated. The data showed that iron-overloaded patients had a lower percentage of CD3+ T cells and disrupted T cell subsets, concomitant with higher ROS level in lymphocytes. In order to explore the mechanism, male C57Bl/6 mice were intraperitoneally injected with iron dextran at a dose of 250 mg/kg every 3 days for 4 weeks to establish an iron-overloaded mouse model and the blood of each mouse was collected for the analysis of the T lymphocyte subsets and T cell apoptosis. The results showed that iron overload could reduce the percentage of CD3+ T cells and the ratio of Th1/Th2 and Tc1/Tc2 but increase the percentage of regulatory T (Treg) cells and the ratio of CD4/CD8. We also found that iron overload induced the apoptosis of T lymphocytes and increased its ROS level. Furthermore, these effects could be partially recovered after treating with antioxidant N-acetyl-L-cysteine (NAC) or iron chelator deferasirox (DFX). Taken together, these observations indicated that iron overload could selectively affect peripheral T lymphocytes and induce an impaired cellular immunity by increasing ROS level.
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Sobrecarga de Hierro/metabolismo , Síndromes Mielodisplásicos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Subgrupos de Linfocitos T/metabolismo , Anciano , Anciano de 80 o más Años , Animales , Complejo CD3/sangre , Relación CD4-CD8 , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Humanos , Sobrecarga de Hierro/sangre , Recuento de Linfocitos , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Síndromes Mielodisplásicos/sangre , Linfocitos T/metabolismo , Linfocitos T Reguladores/metabolismo , Células TH1/metabolismo , Células Th2/metabolismoRESUMEN
Chronic pain is still a basic science and clinical challenge. Unraveling of the neurobiological mechanisms involved in chronic pain will offer novel targets for the development of therapeutic strategies. It is well known that central sensitization in the anterior cingulate cortex (ACC) plays a critical role in initiation, development, and maintenance of chronic pain. However, the underlying mechanisms still remain elusive. Here, we reported that caveolin-1 (Cav-1), a scaffolding protein in membrane rafts, was persistently upregulated and activated in the ACC neurons after chronic constriction injury (CCI) in mice. Knockdown or blocking of Cav-1 in the contralateral ACC to the injury side reversed CCI-induced pain behavioral and neuronal sensitization and overexpression of Cav-1 in the ipsilateral ACC-induced pain behavior in the unaffected hindpaw. Furthermore, we found that Cav-1 directly binding with NMDA receptor 2B subunit (NR2B) and promotion of NR2B surface levels in the ACC contributed to modulation of chronic neuropathic pain. Disrupting the interaction of Cav-1 and NR2B through microinjection of a short peptide derived from the C-terminal of NR2B into the ACC exhibited a significant anti-nociception effect associated with decrease of surface NR2B expression. Moreover, Cav-1 increased intracellular Ca(2+) concentration and activated the ERK/CREB signaling pathway in an NR2B-dependent manner in the ACC. Our findings implicate that Cav-1 in the ACC neurons modulates chronic neuropathic pain via regulation of NR2B and subsequent activation of ERK/CREB signaling, suggesting a possible caveolin-mediated process would participate in neuronal transmission pathways implicated in pain modulation.
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Caveolina 1/fisiología , Dolor Crónico/metabolismo , Giro del Cíngulo/metabolismo , Neuralgia/metabolismo , Receptores de N-Metil-D-Aspartato/fisiología , Animales , Dolor Crónico/patología , Técnicas de Silenciamiento del Gen , Giro del Cíngulo/patología , Células HEK293 , Humanos , Masculino , Ratones , Neuralgia/patologíaRESUMEN
Ginsenosides, the primary bioactive ingredients derived from the root of Panax ginseng, are eagerly in demand for tumor patients as a complementary and alternative drug. Ginsenosides have increasingly become a "hot topic" in recent years due to their multifunctional role in treating colorectal cancer (CRC) and regulating tumor microenvironment (TME). Emerging experimental research on ginsenosides in the treatment and immune regulation of CRC has been published, while no review sums up its specific role in the CRC microenvironment. Therefore, this paper systematically introduces how ginsenosides affect the TME, specifically by enhancing immune response, inhibiting the activation of stromal cells, and altering the hallmarks of CRC cells. In addition, we discuss their impact on the physicochemical properties of the tumor microenvironment. Furthermore, we discuss the application of ginsenosides in clinical treatment as their efficacy in enhancing tumor patient immunity and prolonging survival. The future perspectives of ginsenoside as a complementary and alternative drug of CRC are also provided. This review hopes to open up a new horizon for the cancer treatment of Traditional Chinese Medicine monomers.
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Fasting, without inducing malnutrition, has been shown to have various beneficial effects, including the inhibition of tumor initiation and progression. However, prolonged fasting poses challenges for many cancer patients, particularly those in intermediate and terminal stages. Thus, there is an urgent need for the development of fasting mimetics which harness the protective effects of fasting but more suitable for patients. In this study, we first highlighted the pivotal role of silibinin in AMP-activated protein kinase (AMPK) pathway and may serve, as a potential fasting mimetic via screening hepatoprotective drugs. Further metabolic analysis showed that silibinin inhibited the adenosine triphosphate (ATP) levels, glucose uptake and diminished glycolysis process, which further confirmed that silibinin served as a fasting mimetic. In addition, fasting synergized with silibinin, or used independently, to suppress the growth of hepatocellular carcinoma (HCC) in vivo. Mechanistically, silibinin upregulated death receptor 5 (DR5) through AMPK activation, and thus promoting extrinsic apoptosis and inhibiting HCC growth both in vitro and in vivo. Inhibition of AMPK using small interfering RNA (siRNA) or compound C, an AMPK inhibitor, significantly attenuated the upregulation of DR5 and the apoptotic response induced by silibinin. These findings suggest that silibinin holds promise as a fasting mimetic and may serve as an adjuvant drug for HCC treatment.
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Geothermal resources are one of the most valuable resources in renewable energy because of their advantages of green environmental protection, stability, and reliability. Carbonate rock type geothermal reservoirs have great research significance. Carbonate rock type geothermal resources are abundant in the Shandong area. In this paper, we take the carbonate-type geothermal reservoir in the Diaozhen area of Jinan City as the research object, analyze the regional geothermal geological conditions, and identify the geological structure. Through physical logging exploration, hydrochemical analysis, isotope testing, and drilling exploration, we reveal the geothermal genesis mechanism and construct the genetic model of the carbonate geothermal system. The results show that Diaozhen area belongs to a low-temperature geothermal field and weak open karst thermal reservoir and that the reservoir is mainly Ordovician Majiagou group limestone. The thermal insulation caprock is the overlying Quaternary and Neogene strata with a cumulative thickness of 1376 m. The results of geophysical exploration wells and drilling data verify that the Mingshui fracture is seen around 1630-1645m, and the diorite intrusion is seen at 1610m. The Mingshui fracture connects the deep and shallow aquifers and is a geothermal fluid migration channel. The geothermal water in the Diaozhen area is mainly from the recharge of atmospheric precipitation, with a rich ion content and easy enrichment of trace elements. The regional thermal reservoir is mainly recharged by the deep circulation lateral runoff of Ordovician karst water. After long-distance deep circulation migration, groundwater continuously absorbs heat from the surrounding rock and is heated to geothermal raw water in the deep part. Deep geothermal water rises along the water-conducting fracture and mixes with shallow cold water to form shallow, low-temperature geothermal water.
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Targeting senescence has emerged as a promising strategy for liver cancer treatment. However, the lack of a safe agent capable of inducing complete senescence and being combined with senolytics poses a limitation. Here, we screened a natural product library and identified tryptanthrin (TRYP) as a potent inducer of cellular senescence in liver cancer cells both in vitro and in vivo. Mechanistically, Glutathione S-transferase P1 (GSTP1), a key regulator for redox homeostasis, was identified as a target protein for TRYP-induced senescence. TRYP directly bound to GSTP1 and inhibited its enzymatic activity, mediating reactive oxygen species (ROS) accumulation, followed by DNA damage response (DDR), consequently contributing to initiating primary senescence. Furthermore, TRYP triggered DNA damage-dependent activation of NF-κB pathway, which evoked senescence-associated secretory phenotype (SASP), thereby leading to senescence reinforcement. Importantly, TRYP exposed the vulnerability of tumor cells and sensitized senescent cells to apoptosis induced by senolytic agent ABT263, a Bcl2 inhibitor. Taken together, our findings reveal that TRYP induces cellular senescence via GSTP1/ROS/DDR/NF-κB/SASP axis, providing a novel potential application in synergizing with senolytic therapy in liver cancer.
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AQP3 (aquaporin 3 (Gill blood group)), a member of the AQP family, is an aquaglyceroporin which transports water, glycerol and small solutes across the plasma membrane. Beyond its role in fluid transport, AQP3 plays a significant role in regulating various aspects of tumor cell behavior, including cell proliferation, migration, and invasion. Nevertheless, the underlying regulatory mechanism of AQP3 in tumors remains unclear. Here, for the first time, we report that AQP3 is a direct target for ubiquitination by the SCFFBXW5 complex. In addition, we revealed that downregulation of FBXW5 significantly induced AQP3 expression to prompt macroautophagic/autophagic cell death in hepatocellular carcinoma (HCC) cells. Mechanistically, AQP3 accumulation induced by FBXW5 knockdown led to the degradation of PDPK1/PDK1 in a lysosomal-dependent manner, thus inactivating the AKT-MTOR pathway and inducing autophagic death in HCC. Taken together, our findings revealed a previously undiscovered regulatory mechanism through which FBXW5 degraded AQP3 to suppress autophagic cell death via the PDPK1-AKT-MTOR axis in HCC cells.Abbreviation: BafA1: bafilomycin A1; CQ: chloroquine; CRL: CUL-Ring E3 ubiquitin ligases; FBXW5: F-box and WD repeat domain containing 5; HCC: hepatocellular carcinoma; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; 3-MA: 3-methyladenine; PDPK1/PDK1: 3-phosphoinositide dependent protein kinase 1; RBX1/ROC1: ring-box 1; SKP1: S-phase kinase associated protein 1; SCF: SKP1-CUL1-F-box protein.
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Proteínas Quinasas Dependientes de 3-Fosfoinosítido , Acuaporina 3 , Autofagia , Carcinoma Hepatocelular , Proteínas F-Box , Neoplasias Hepáticas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Humanos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Autofagia/fisiología , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Quinasas Dependientes de 3-Fosfoinosítido/metabolismo , Acuaporina 3/metabolismo , Acuaporina 3/genética , Proteínas F-Box/metabolismo , Línea Celular Tumoral , Ubiquitinación , Proteolisis , Lisosomas/metabolismo , AnimalesRESUMEN
A specific mechanism of mode coupling in a waveguide propagation is studied when two range-dependent eigenvalues approach each other. This phenomenon is analogous to the so-called quasi-crossing of states in atomic physics (Landau-Zener theory). It is considered for the sound wave propagation in a coastal wedge in the presence of a sound-speed profile. The change in mode composition and the corresponding spatial variability of the sound field are analyzed by using modes coupling equations and the parabolic equation with a field decomposition over adiabatic modes, respectively.
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Ubiquitin (Ub) and ubiquitin-like (Ubl) pathways are critical post-translational modifications that determine whether functional proteins are degraded or activated/inactivated. To date, >600 associated enzymes have been reported that comprise a hierarchical task network (e.g., E1-E2-E3 cascade enzymatic reaction and deubiquitination) to modulate substrates, including enormous oncoproteins and tumor-suppressive proteins. Several strategies, such as classical biochemical approaches, multiomics, and clinical sample analysis, were combined to elucidate the functional relations between these enzymes and tumors. In this regard, the fundamental advances and follow-on drug discoveries have been crucial in providing vital information concerning contemporary translational efforts to tailor individualized treatment by targeting Ub and Ubl pathways. Correspondingly, emphasizing the current progress of Ub-related pathways as therapeutic targets in cancer is deemed essential. In the present review, we summarize and discuss the functions, clinical significance, and regulatory mechanisms of Ub and Ubl pathways in tumorigenesis as well as the current progress of small-molecular drug discovery. In particular, multiomics analyses were integrated to delineate the complexity of Ub and Ubl modifications for cancer therapy. The present review will provide a focused and up-to-date overview for the researchers to pursue further studies regarding the Ub and Ubl pathways targeted anticancer strategies.
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Fertility counseling should be offered to all individuals of young reproductive age early in the patient's trajectory following a cancer diagnosis. Systemic cancer treatment and radiotherapy often have an inherent gonadotoxic effect with the potential to induce permanent infertility and premature ovarian failure. For the best chances to preserve a patient's fertility potential and to improve future quality of life, fertility preservation methods should be applied before cancer treatment initiation, thus multidisciplinary team-work and timely referral to reproductive medicine centers specialized in fertility preservation is recommended. We aim to review the current clinical possibilities for fertility preservation and summarize how infertility, as a late effect of gonadotoxic treatment, affects the growing population of young female cancer survivors.
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BACKGROUND: In adults undergoing noncardiac surgery, the correlation between intraoperative tidal volume and postoperative acute kidney injury (AKI) is unclear. This study aimed to investigate the effects of low tidal volume ventilation on the incidence of postoperative AKI compared with conventional tidal volume in adults undergoing noncardiac surgery. METHODS: This was a two-center prospective randomized controlled trial on adult patients who underwent noncardiac surgery and had a mechanical ventilation of >60 min. Patients were randomized to receive either a tidal volume of 6 mL/kg pre-predicted body weight (PBW, low tidal volume) or a tidal volume of 10 mL/kg pre-predicted body weight (conventional tidal volume). The primary outcome was the incidence of AKI after non-cardiac surgery. Appropriate statistical methods were used for this study. RESULTS: Among the 1982 randomized patients, 943 with low tidal volume and 958 with conventional tidal volume were evaluable for the primary outcome. Postoperative AKI occurred in 12 patients (1.3%) in the low tidal volume group and 11 patients (1.1%) in the conventional tidal volume group, with an odds ratio of 0.889 (95%CI, 0.391-2.03) and a relative risk of 0.999 ([95%CI, 0.989-1.01]; P=0.804). Postoperative serum creatinine levels increased in 284 (30.0%) patients with low tidal volume compared to 316 (32.0%) patients with conventional tidal volume (P=0.251). No difference in postoperative serum creatinine levels was found between the two groups (57.5 [49.0-68.2] µmol/L vs. 58.8[50.4-69.5] µmol/L, P=0.056). CONCLUSIONS: Among adults undergoing noncardiac surgery, low tidal volume mechanical ventilation did not significantly reduce the incidence of postoperative AKI compared with conventional tidal volume.