RESUMEN
Replicative senescence of mesenchymal stem cells (MSCs) caused by repeated cell culture undermines their potential as a cell therapy because of the reduction in their proliferation and therapeutic potential. Glutaminase-1 (GLS1) is reported to be involved in the survival of senescent cells, and inhibition of GLS1 alleviates age-related dysfunction via senescent cell removal. In the present study, we attempted to elucidate the association between MSC senescence and GLS1. We conducted in vitro and in vivo experiments to analyze the effect of GLS1 inhibition on senolysis and the therapeutic effects of MSCs. Inhibition of GLS1 in Wharton's jelly-derived MSCs (WJ-MSCs) reduced the expression of aging-related markers, such as p16, p21, and senescence-associated secretory phenotype genes, by senolysis. Replicative senescence-alleviated WJ-MSCs, which recovered after short-term treatment with bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES), showed increased proliferation and therapeutic effects compared to those observed with senescent WJ-MSCs. Moreover, compared to senescent WJ-MSCs, replicative senescence-alleviated WJ-MSCs inhibited apoptosis in serum-starved C2C12 cells, enhanced muscle formation, and hindered apoptosis and fibrosis in mdx mice. These results imply that GLS1 inhibition can ameliorate the therapeutic effects of senescent WJ-MSCs in patients with muscle diseases such as Duchenne muscular dystrophy. In conclusion, GLS1 is a key factor in modulating the senescence mechanism of MSCs, and regulation of GLS1 may enhance the therapeutic effects of senescent MSCs, thereby increasing the success rate of clinical trials involving MSCs.
RESUMEN
BACKGROUND: Gastric cancer (GC) is a prevalent malignancy with limited therapeutic options for advanced stages. This study aimed to identify novel therapeutic targets for GC by profiling HSP90 client kinases. METHODS: We used mass spectrometry-based activity-based protein profiling (ABPP) with a desthiobiotin-ATP probe, combined with sensitivity analysis of HSP90 inhibitors, to profile kinases in a panel of GC cell lines. We identified kinases regulated by HSP90 in inhibitor-sensitive cells and investigated the impact of MASTL knockdown on GC cell behavior. Global proteomic analysis following MASTL knockdown was performed, and bioinformatics tools were used to analyze the resulting data. RESULTS: Four kinases-MASTL, STK11, CHEK1, and MET-were identified as HSP90-regulated in HSP90 inhibitor-sensitive cells. Among these, microtubule-associated serine/threonine kinase-like (MASTL) was upregulated in GC and associated with poor prognosis. MASTL knockdown decreased migration, invasion, and proliferation of GC cells. Global proteomic profiling following MASTL knockdown revealed NEDD4-1 as a potential downstream mediator of MASTL in GC progression. NEDD4-1 was also upregulated in GC and associated with poor prognosis. Similar to MASTL inhibition, NEDD4-1 knockdown suppressed migration, invasion, and proliferation of GC cells. CONCLUSIONS: Our multi-proteomic analyses suggest that targeting MASTL could be a promising therapy for advanced gastric cancer, potentially through the reduction of tumor-promoting proteins including NEDD4-1. This study enhances our understanding of kinase signaling pathways in GC and provides new insights for potential treatment strategies.
Asunto(s)
Proliferación Celular , Proteínas Serina-Treonina Quinasas , Proteoma , Proteómica , Neoplasias Gástricas , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/tratamiento farmacológico , Humanos , Línea Celular Tumoral , Proteómica/métodos , Proteoma/metabolismo , Proliferación Celular/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Movimiento Celular/efectos de los fármacos , Proteínas HSP90 de Choque Térmico/metabolismo , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/genética , Ubiquitina-Proteína Ligasas Nedd4/metabolismo , Ubiquitina-Proteína Ligasas Nedd4/genética , Regulación Neoplásica de la Expresión Génica , Terapia Molecular Dirigida , Proteínas Asociadas a MicrotúbulosRESUMEN
Type 2 diabetes mellitus (T2DM) increases the risk of non-alcoholic fatty liver disease (NAFLD) progression to advanced stages, especially upon high-fat diet (HFD). HFD-induced hepatic fibrosis can be marked by oxidative stress, inflammation, and activation of hepatic stellate cells. Sirtuin 1/2 (SIRT1/2), NAD-dependent class III histone deacetylases, are involved in attenuation of fibrosis. In our conducted research, TGF-ß1-activated LX-2 cells, free fatty acid (FFA)-treated simultaneous co-culture (SCC) cells, and HFD-induced hepatic fibrosis in Zucker diabetic fatty (ZDF) rats, a widely used animal model in the study of metabolic syndromes, were used to evaluate the protective effect of Tenovin-1, a SIRT1/2 inhibitor. ZDF rats were divided into chow diet, HFD, and HFD + Tenovin-1 groups. Tenovin-1 reduced hepatic damage, inhibited inflammatory cell infiltration, micro/ macro-vesicular steatosis and prevented collagen deposition HFD-fed rats. Tenovin-1 reduced serum biochemical parameters, triglyceride (TG) and malondialdehyde (MDA) levels but increased glutathione, catalase, and superoxide dismutase levels. Tenovin-1 mitigated proinflammatory cytokines IL-6, IL-1ß, TNFα and fibrosis biomarkers in HFD rats, TGF-ß1-activated LX-2 and FFA treated SCC cells. Additionally, Tenovin-1 suppressed SIRT1/2 expression and inhibited JNK-1 and STAT3 phosphorylation in HFD rats and FFA-treated SCC cells. In conclusion, Tenovin-1 attenuates hepatic fibrosis by stimulating antioxidants and inhibiting inflammatory cytokines under HFD conditions in diabetic rats.
Asunto(s)
Dieta Alta en Grasa , Cirrosis Hepática , Ratas Zucker , Sirtuina 1 , Sirtuina 2 , Animales , Dieta Alta en Grasa/efectos adversos , Ratas , Cirrosis Hepática/metabolismo , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/inducido químicamente , Sirtuina 1/metabolismo , Sirtuina 2/metabolismo , Sirtuina 2/antagonistas & inhibidores , Masculino , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Estrés Oxidativo/efectos de los fármacosRESUMEN
This study aimed to evaluate the physiological role of NAMPT associated with MDPC-23 odontoblast cell proliferation. Cell viability was measured using the (DAPI) staining, caspase activation analysis and immunoblotting were performed. Visfatin promoted MDPC-23 odontoblast cell growth in a dose-dependent manner. Furthermore, the up-regulation of Visfatin promoted odontogenic differentiation and accelerated mineralization through an increase in representative odontoblastic biomarkers in MDPC-23 cells. However, FK-866 cell growth in a dose-dependent manner induced nuclear condensation and fragmentation. FK-866-treated cells showed H&E staining and increased apoptosis compared to control cells. The expression of anti-apoptotic factors components of the mitochondria-dependent intrinsic apoptotic pathway significantly decreased following FK-866 treatment. The expression of pro-apoptotic increased upon FK-866 treatment. In addition, FK-866 activated caspase-3 and PARP to induce cell death. In addition, after treating FK-866 for 72 h, the 3/7 activity of MDPC-23 cells increased in a concentration-dependent manner, and the IHC results also confirmed that Caspase-3 increased in a concentration-dependent. Therefore, the presence or absence of NAMPT expression in dentin cells was closely related to cell proliferation and formation of extracellular substrates.
Asunto(s)
Apoptosis , Proliferación Celular , Nicotinamida Fosforribosiltransferasa , Odontoblastos , Nicotinamida Fosforribosiltransferasa/metabolismo , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Odontoblastos/efectos de los fármacos , Odontoblastos/citología , Odontoblastos/metabolismo , Animales , Ratones , Línea Celular , Citocinas/metabolismo , Caspasa 3/metabolismo , Diferenciación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Acrilamidas/farmacología , Odontogénesis/efectos de los fármacosRESUMEN
Until now, thermally activated delayed fluorescence (TADF) materials based on bridged boron-based acceptors have been primarily developed as dopants. However, in this study, we synthesized and characterized multifunctional deep-blue TADF materialsât-OBO-DMAC and t-OBO-DPACâusing bridged boron-based acceptors in combination with dimethylacridine or diphenylacridine as donors. These materials serve as both dopants and hosts. Theoretical calculations and experimentally measured photophysical properties of t-OBO-DMAC reveal a smaller singlet-triplet energy difference, higher photoluminescence quantum yield, and more efficient reverse intersystem crossing compared to t-OBO-DPAC. When evaluated as TADF emitters, t-OBO-DMAC and t-OBO-DPAC exhibited maximum external quantum efficiency (EQE) of 14.4 and 7.3% with deep-blue color coordinates of (0.14, 0.11) and (0.15, 0.07), respectively. Both materials were further assessed as hosts in various configurations, including host-only, TADF, phosphorescent, and phosphor-sensitized fluorescence (PSF)-emitting systems. Notably, t-OBO-DMAC demonstrated a high maximum EQE of 13.9% with deep-blue color coordinates of (0.15, 0.07) in a nondoped host-only device. Remarkably, both materials achieved EQEs exceeding 20% in the PSF devices. Our study marks a critical advancement in the field that breaks the conventional boundaries of the dopant and host and demonstrates unprecedented multifunctionalities for advanced organic light-emitting diodes.
RESUMEN
The jawless vertebrates (agnathans/cyclostomes) are ancestral animals comprising lampreys and hagfishes as the only extant representatives. They possess an alternative adaptive immune system (AIS) that uses leucine-rich repeats (LRR)-based variable lymphocyte receptors (VLRs) instead of the immunoglobulin (Ig)-based antigen receptors of jawed vertebrates (gnathostomes). The different VLR types are expressed on agnathan lymphocytes and functionally resemble gnathostome antigen receptors. In particular, VLRB is functionally similar to the B cell receptor and is expressed and secreted by B-like lymphocytes as VLRB antibodies that bind antigens with high affinity and specificity. The potential repertoire scale of VLR-based antigen receptors is believed to be at least comparable to that of Ig-based systems. VLR proteins inherently possess characteristics that render them excellent candidates for biotechnological development, including tractability to recombinant approaches. In recent years, scientists have explored the biotechnological development and utility of VLRB proteins as alternatives to conventional mammalian antibodies. The VLRB antibody platform represents a non-traditional approach to generating a highly diverse repertoire of unique antibodies. In this review, we first describe some aspects of the biology of the AIS of the jawless vertebrates, which recognizes antigens by means of unique receptors. We then summarize reports on the development of VLRB-based antibodies and their applications, particularly those from the inshore hagfish (Eptatretus burgeri) and their potential uses to address microbial diseases in aquaculture. Hagfish VLRB antibodies (we call Ccombodies) are being developed and improved, while obstacles to the advancement of the VLRB platform are being addressed to utilize VLRBs effectively as tools in immunology. VLRB antibodies for novel antigen targets are expected to emerge to provide new opportunities to tackle various scientific questions. We anticipate a greater interest in the agnathan AIS in general and particularly in the hagfish AIS for greater elucidation of the evolution of adaptive immunity and its applications to address microbial pathogens in farmed aquatic animals and beyond.
Asunto(s)
Enfermedades de los Peces , Anguila Babosa , Animales , Anguila Babosa/inmunología , Anguila Babosa/genética , Enfermedades de los Peces/inmunología , Inmunidad Adaptativa , Receptores de Antígenos/genética , Receptores de Antígenos/inmunología , Proteínas de Peces/inmunología , Proteínas de Peces/genéticaRESUMEN
Metformin is an anti-diabetic drug that exerts protective effects against neurodegenerative diseases. In this study, we investigated the protective effects of metformin against manganese (Mn)-induced cytotoxicity associated with Parkinson's disease-like symptoms in N27-A dopaminergic (DA) cells. Metformin (0.1-1 mM) suppressed Mn (0.4 mM)-induced cell death in a concentration-dependent manner. Metformin pretreatment effectively suppressed the Mn-mediated increase in the levels of oxidative stress markers, such as reactive oxygen species (ROS) and thiobarbituric acid reactive substances. Moreover, metformin restored the levels of the antioxidants, superoxide dismutase, intracellular glutathione, and glutathione peroxidase, which were reduced by Mn. Metformin (0.5 mM) significantly attenuated the decrease in sirtuin-1 (SIRT1) and peroxisome proliferator activated receptor gamma coactivator-1 alpha levels, which were increased by Mn (0.4 mM). In addition, metformin inhibited the expression of microRNA-34a, which directly targeted SIRT1. Metformin also inhibited the loss of Mn-induced mitochondrial membrane potential (ΔΨm) and activation of the apoptosis marker, caspase-3. Furthermore, metformin-mediated inhibition of ROS generation and caspase-3 activation, recovery of ΔΨm, and restoration of cell viability were partially reversed by the SIRT1 inhibitor, Ex527. These results suggest that metformin may protects against Mn-induced DA neuronal cell death mediated by oxidative stress and mitochondrial dysfunction possibly via the regulation of SIRT1 pathway.
Asunto(s)
Manganeso , Metformina , Manganeso/toxicidad , Manganeso/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Caspasa 3/metabolismo , Metformina/farmacología , Sirtuina 1/metabolismo , Apoptosis , Estrés Oxidativo , Neuronas DopaminérgicasRESUMEN
The man-made sea dike has disrupted the natural link between riverine and marine ecosystems and caused eutrophication within the aquatic ecosystem. The eutrophic water discharge has also raised concerns. As a representative tidal flat with the longest dike in the world, Saemangeum has experienced the problem of eutrophication. To elucidate the discharge water effects on the benthic food web dynamics, a four-year round sampling was conducted in/outside of the Saemangeum sea dike. Stable isotope analysis was applied to benthos (a total of 54 species) and their potential diets. Water discharge tripled in period II (2021-2022) compared to the period I (2019-2020). However, there were no significant impact changes in food web structure between the two periods due to improved lake water quality in period II. A positive correlation of nutrient concentration between the inner and outer areas of the dike revealed a direct effect of the water discharge on the outer tidal flat. The water discharge altered the spatial environmental conditions and the food web structure of the outer tidal flat. High TN concentrations stimulated the biomass of microphytobenthos (MPB) near the water gates, which in turn increased MPB consumption by benthos, demonstrating the in/direct impacts of water discharge on the food web. Furthermore, filter feeders exhibited a more sensitive response to spatial organic matter distribution compared to deposit feeders in diet utilization. Overall, our novel findings on food web dynamics in a representative tidal flat with artificial structures emphasize the necessity of continuous monitoring to ensure the sustainability of coastal ecosystems.
Asunto(s)
Ecosistema , Cadena Alimentaria , Humanos , Biomasa , Calidad del Agua , Agua DulceRESUMEN
The attention to materials with hot exciton channel and triplet-triplet fusion (TTF) mediated high-lying reverse intersystem crossing (hRISC) has been raised for their ability to convert non-emissive 'dark' triplets into radiative singlet excitons. This spin conversion process results in high exciton utilization efficiency (EUE) that exceeds the theoretical limits. Notably, it is known that such spin conversion processes from the high-lying excited triplet to the singlet state are facilitated by the orthogonal orbital transition effect governed by the El-Sayed's rule. In this study, an anthracene derivative with indenoquinoline substituent 7,7-dimethyl-9-(10-(4-(naphthalen-1-yl)phenyl)anthracen-9-yl)-7H-indeno[1,2-f]quinoline (2MIQ-NPA) was synthesized and analyzed to investigate whether the hRISC process occurs in these molecules, even when the El-Sayed's rule is not followed. The hRISC channels of the emitter were fully unraveled through DFT calculations and experiments, which were quantitatively subdivided using transient electroluminescence measurements. The results showed that 2MIQ-NPA, which does not follow the El-Sayed's rule and has a relatively strong spin-orbit coupling matrix element of 0.116 cm-1 between the high-lying triplet state of T4 and the lowest singlet state of S1, effectively converted triplet excitons into singlet excitons with an EUE of 64.3%, contributed by a direct hot exciton channel of 19.2% and a TTF-mediated hot exciton channel of 15.1%. Despite the low outcoupling efficiency, the non-doped device with 2MIQ-NPA achieved an excellent device performance with an external quantum efficiency of 7.0%.
RESUMEN
Real-time stress distribution data for implants and cortical bones can aid in determining appropriate implant placement plans and improving the post-placement success rate. This study aims to achieve these goals via a parametric reduced-order model (ROM) method based on stress distribution data obtained using finite element analysis. For the first time, the finite element analysis cases for six design variables related to implant placement were determined simultaneously via the design of experiments and a sensitivity analysis. The differences between the minimum and maximum stresses obtained for the six design variables confirm that the order of their influence is: Young's modulus of the cancellous bone > implant thickness > front-rear angle > left-right angle > implant length. Subsequently, a one-dimensional (1-D) CAE solver was created using the ROM with the highest coefficient of determination and prognosis accuracy. The proposed 1-D CAE solver was loaded into the Ondemand3D program and used to implement a digital twin that can aid with dentists' decision making by combining various tooth image data to evaluate and visualize the adequacy of the placement plan in real time. Because the proposed ROM method does not rely entirely on the doctor's judgment, it ensures objectivity.
RESUMEN
Radiotherapy for cancer has been known to affect the responses of immune cells, especially those of CD8+ T cells that play a pivotal role in anti-tumor immunity. Clinical success of immune checkpoint inhibitors led to an increasing interest in the ability of radiation to modulate CD8+ T cell responses. Recent studies that carefully analyzed CD8+ T cell responses following radiotherapy suggest the beneficial roles of radiotherapy on anti-tumor immunity. In addition, numerous clinical trials to evaluate the efficacy of combining radiotherapy with immune checkpoint inhibitors are currently undergoing. In this review, we summarize the current status of knowledge regarding the changes in CD8+ T cells following radiotherapy from various preclinical and clinical studies. Furthermore, key biological mechanisms that underlie such modulation, including both direct and indirect effects, are described. Lastly, we discuss the current evidence and essential considerations for harnessing radiotherapy as a combination partner for immune checkpoint inhibitors.
Asunto(s)
Neoplasias , Oncología por Radiación , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Linfocitos T CD8-positivos , Terapia Combinada , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Microambiente TumoralRESUMEN
BACKGROUND: The maintenance of spindle pole integrity is essential for spindle assembly and chromosome segregation during mitosis. However, the underlying mechanisms governing spindle pole integrity remain unclear. METHODS: ENSA was inhibited by siRNA or MKI-2 treatment and its effect on cell cycle progression, chromosome alignment and microtubule alignment was observed by immunohistochemical staining and western blotting. PP2A-B55α knockdown by siRNA was performed to rescue the phenotype caused by ENSA inhibition. The interaction between ENSA and Aurora A was detected by in situ PLA. Furthermore, orthotopic implantation of 4Tl-luc cancer cells was conducted to confirm the consistency between the in vitro and in vivo relationship of the ENSA-Aurora A interaction. RESULTS: During mitosis, p-ENSA is localized at the spindle poles, and the inhibition of ENSA results in mitotic defects, such as misaligned chromosomes, multipolar spindles, asymmetric bipolar spindles, and centrosome defects, with a delay in mitotic progression. Although the mitotic delay caused by ENSA inhibition was rescued by PP2A-B55α depletion, spindle pole defects persisted. Notably, we observed a interaction between ENSA and Aurora A during mitosis, and inhibition of ENSA reduced Aurora A expression at the mitotic spindle poles. Injecting MKI-2-sensitized tumors led to increased chromosomal instability and downregulation of the MASTL-ENSA-Aurora A pathway in an orthotopic breast cancer mouse model. CONCLUSIONS: These findings provide novel insights into the regulation of spindle pole integrity by the MASTL-ENSA-Aurora A pathway during mitosis, highlighting the significance of ENSA in recruiting Aurora A to the spindle pole, independent of PP2A-B55α.
Asunto(s)
Huso Acromático , Polos del Huso , Animales , Ratones , Huso Acromático/metabolismo , Polos del Huso/metabolismo , Centrosoma/metabolismo , Mitosis , ARN Interferente Pequeño/metabolismoRESUMEN
Glucocorticoids suppress the vascular inflammation that occurs under hypercholesterolemia, as demonstrated in an animal model fed a high-cholesterol diet. However, the molecular mechanisms underlying these beneficial effects remain poorly understood. Because cholesterol is oxidized to form cholesterol oxides (oxysterols) that are capable of inducing inflammation, we investigated whether glucocorticoids affect the immune responses evoked by 7α-hydroxycholesterol (7αOHChol). The treatment of human THP-1 monocytic cells with dexamethasone (Dex) and prednisolone (Pdn) downregulated the expression of pattern recognition receptors (PRRs), such as TLR6 and CD14, and diminished 7αOHChol-enhanced response to FSL-1, a TLR2/6 ligand, and lipopolysaccharide, which interacts with CD14 to initiate immune responses, as determined by the reduced secretion of IL-23 and CCL2, respectively. Glucocorticoids weakened the 7αOHChol-induced production of CCL2 and CCR5 ligands, which was accompanied by decreased migration of monocytic cells and CCR5-expressing Jurkat T cells. Treatment with Dex or Pdn also reduced the phosphorylation of the Akt-1 Src, ERK1/2, and p65 subunits. These results indicate that both Dex and Pdn impair the expression of PRRs and their downstream products, chemokine production, and phosphorylation of signaling molecules. Collectively, glucocorticoids suppress the innate immune response and activation of monocytic cells to an inflammatory phenotype enhanced or induced by 7αOHChol, which may contribute to the anti-inflammatory effects in hypercholesterolemic conditions.
RESUMEN
BACKGROUND: The prognostic nutritional index (PNI) is known to be correlated with clinical outcomes in non-small cell lung cancer (NSCLC) patients. However, its role has not been studied in patients who have undergone postoperative radiotherapy (PORT). This study aimed to investigate the relationship between PNI and survival and recurrence in NSCLC patients with PORT. METHODS: We reviewed 97 stage I-III NSCLC patients who received PORT between January 2006 and December 2016 at our institution. We obtained PNI values for both pre-RT (within 1 month before PORT) and post-RT (within 2 months after PORT) by using serum albumin and lymphocyte count. A cutoff value for PNI was determined by the receiver operating characteristic curve (ROC). The median follow-up period was 52.8 months. RESULTS: The ROC curve of post-RT PNI exhibited a higher area under the curve (AUC 0.68, cut-off: 47.1) than that of pre-RT PNI (AUC 0.55, cutoff: 50.3), so the group was divided into high post-RT PNI (> 47.1) and low post-RT PNI ( ≤ 47.1). The five-year overall survival rate (OS) was 66.2% in the high post-RT group, compared with 41.8% in the low post-RT PNI group (p = 0.018). Those with both low pre-RT and low post-RT PNI had the worst five-year OS of 31.1%. Post-RT PNI (HR 0.92, p = 0.003) was an independent risk factor for mortality. CONCLUSIONS: PNI after PORT was significantly associated with survival. This finding suggests that PNI can be used as a prognostic marker.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/tratamiento farmacológico , Evaluación Nutricional , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND/AIM: Studies have suggested that benefits of definitive radiotherapy might be limited to specific patients in clinically lymph node positive (cN1) prostate cancer (PC). However, the beneficial subgroup remains to be elucidated. This study aimed to analyze survival outcomes and prognostic factors after definitive radiotherapy and androgen deprivation therapy (definitive RT+ADT) in these patients and to define subgroups of patients who would benefit from definitive RT+ADT the most. PATIENTS AND METHODS: A total of 60 patients with cN1 PC treated with definitive RT+ADT in a single tertiary hospital were accrued. Their clinicopathological variables were analyzed and a new subgroup was identified based on statistically significant variables. RESULTS: At a median follow-up of 31 months, ADT duration ≥24 months (p=0.043, HR=0.26) and positive biopsy core ≥75% (p=0.044, HR=5.29) showed significant relationships with distant metastasis-free survival. Overall survival showed significant relationships with ADT duration ≥24 months (p=0.002, HR=0.06) and number of lymph node (LN) metastases ≥4 (p=0.019, HR=7.17). For prognostic subgroup analysis, patients were divided into three risk groups: low-risk group (LN metastases <4 and ADT ≥24 months), high-risk group (LN metastases ≥4 and ADT <24 months), and intermediate-risk group (all remaining cases). Three-year actuarial overall survival rates for the low-, intermediate-, and high-risk groups were 100%, 93.3%, and 45.7%. CONCLUSION: ADT duration and number of LN metastases were important prognostic factors in patients with cN1 PC receiving definitive RT+ADT, with low-risk cN1 PC patients showing better outcomes than others.
Asunto(s)
Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/patología , Antagonistas de Andrógenos/uso terapéutico , Pronóstico , Factores de Riesgo , Metástasis Linfática/patología , Ganglios Linfáticos/patología , Estudios RetrospectivosRESUMEN
In the original publication [...].
RESUMEN
Background: The optimal condition for the clinical application of 18F-fluorocholine positron emission tomography-computed tomography (FCH-PET/CT) to detect recurrence sites in prostate-specific antigen (PSA) failure remains unclear due to the heterogeneity of prostate cancer failure. We aimed to evaluate the detection rate of FCH-PET/CT in prostate cancer patients with PSA failure and to determine the optimal PSA level for performing FCH-PET/CT. Methods: FCH-PET/CT was conducted in 89 patients diagnosed with PSA failure after radical treatment (radical prostatectomy in 75 and definitive radiotherapy in 14) between November 2018 and May 2021. Detection rates were examined via receiver operating characteristic (ROC) analysis, and multivariable logistic regression was performed to identify factors affecting positive FCH-PET/CT findings. We also conducted subgroup analyses according to the PSA failure patterns after the radical treatment (persistently high PSA [N = 48] and biochemical recurrence [BCR] [N = 41]). Results: FCH-PET/CT demonstrated a 59.6% overall detection rate, and the optimal PSA threshold for detecting positive findings was ≥ 1.00 ng/mL at the time of imaging. On multivariable analysis, PSA > 1.00 ng/mL (P < 0.001) was a significant predictor of positive FCH-PET/CT findings, especially regarding distant bone metastases (P < 0.001) and recurrence outside the pelvis (P < 0.001). In a subgroup analysis of patients with BCR after initial radical treatment, the area under the ROC curve (AUC) was 0.82, and PSA ≥ 1.75 ng/mL was the optimal value for identifying positive FCH-PET/CT findings. This PSA value was also associated with significantly higher detection rates of distant bone metastases and outside-pelvis metastasis (P < 0.001, both). Conclusion: FCH-PET/CT is a clinically useful tool for detecting tumor recurrence sites in prostate cancer patients with PSA failure if PSA has exceeded a certain value at the time of imaging. Particularly, higher AUC values were observed when FCH-PET/CT was performed in patients with BCR after initial treatment.
RESUMEN
This study aimed to exploring the pathophysiological mechanism of 7α,25-dihydroxycholesterol (7α,25-DHC) in osteoarthritis (OA) pathogenesis. 7α,25-DHC accelerated the proteoglycan loss in ex vivo organ-cultured articular cartilage explant. It was mediated by the decreasing extracellular matrix major components, including aggrecan and type II collagen, and the increasing expression and activation of degenerative enzymes, including matrix metalloproteinase (MMP)-3 and -13, in chondrocytes cultured with 7α,25-DHC. Furthermore, 7α,25-DHC promoted caspase dependent chondrocytes death via extrinsic and intrinsic pathways of apoptosis. Moreover, 7α,25-DHC upregulated the expression of inflammatory factors, including inducible nitric oxide synthase, cyclooxygenase-2, nitric oxide, and prostaglandin E2, via the production of reactive oxygen species via increase of oxidative stress in chondrocytes. In addition, 7α,25-DHC upregulated the expression of autophagy biomarker, including beclin-1 and microtubule-associated protein 1A/1B-light chain 3 via the modulation of p53-Akt-mTOR axis in chondrocytes. The expression of CYP7B1, caspase-3, and beclin-1 was elevated in the degenerative articular cartilage of mouse knee joint with OA. Taken together, our findings suggest that 7α,25-DHC is a pathophysiological risk factor of OA pathogenesis that is mediated a chondrocytes death via oxiapoptophagy, which is a mixed mode of apoptosis, oxidative stress, and autophagy.
Asunto(s)
Osteoartritis , Proteínas Proto-Oncogénicas c-akt , Ratones , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Condrocitos/metabolismo , Beclina-1/metabolismo , Osteoartritis/metabolismo , Osteoartritis/patología , Serina-Treonina Quinasas TOR/metabolismo , Células CultivadasRESUMEN
Because DNA double-strand breaks (DSBs) greatly threaten genomic integrity, effective DNA damage sensing and repair are essential for cellular survival in all organisms. However, DSB repair mainly occurs during interphase and is repressed during mitosis. Here, we show that, unlike mitotic cells, oocytes can repair DSBs during meiosis I through microtubule-dependent chromosomal recruitment of the CIP2A-MDC1-TOPBP1 complex from spindle poles. After DSB induction, we observed spindle shrinkage and stabilization, as well as BRCA1 and 53BP1 recruitment to chromosomes and subsequent DSB repair during meiosis I. Moreover, p-MDC1 and p-TOPBP1 were recruited from spindle poles to chromosomes in a CIP2A-dependent manner. This pole-to-chromosome relocation of the CIP2A-MDC1-TOPBP1 complex was impaired not only by depolymerizing microtubules but also by depleting CENP-A or HEC1, indicating that the kinetochore/centromere serves as a structural hub for microtubule-dependent transport of the CIP2A-MDC1-TOPBP1 complex. Mechanistically, DSB-induced CIP2A-MDC1-TOPBP1 relocation is regulated by PLK1 but not by ATM activity. Our data provide new insights into the critical crosstalk between chromosomes and spindle microtubules in response to DNA damage to maintain genomic stability during oocyte meiosis.
Asunto(s)
Cromosomas , Reparación del ADN , Microtúbulos , Oocitos , Centrómero , Daño del ADN , Meiosis , Huso Acromático/genética , Polos del Huso , Animales , Ratones , Complejos Multiproteicos , Cromosomas/metabolismoRESUMEN
Introduction: Glucose transporter-1 (GLUT-1) has been studied as a possible predictor for survival outcomes in locally advanced rectal cancer (LARC). Methods: We aimed to investigate the prognostic role of GLUT-1 in LARC using the data of 208 patients with clinical T3-4 stage and/or node-positive rectal adenocarcinoma, all of whom underwent neoadjuvant chemoradiotherapy (CRT) and subsequent total mesorectal excision (TME). Both pre-CRT and post-CRT specimens were immunohistologically stained for GLUT-1. Patients were classified into GLUT-1-positive and GLUT-1-negative groups and distant metastasis-free survival (DMFS) and overall survival (OS) was analyzed and compared. Results: At a median follow-up of 74 months, post-CRT GLUT-1 status showed a significant correlation with worse DMFS (p=0.027, HR 2.26) and OS (p=0.030, HR 2.30). When patients were classified into 4 groups according to yp stage II/III status and post-CRT GLUT-1 positivity [yp stage II & GLUT-1 (-), yp stage II & GLUT-1 (+), yp stage III & GLUT-1 (-), yp stage III & GLUT-1 (+)], the 5-year DMFS rates were 92.3%, 63.9%, 65.4%, and 46.5%, respectively (p=0.013). GLUT-1 (-) groups showed markedly better outcomes for both yp stage II and III patients compared to GLUT-1 (+) groups. A similar tendency was observed for OS. Discussion: In conclusion, post-CRT GLUT-1 may serve as a prognostic marker in LARC.