Association between programmed cell death ligand-1 expression in patients with cervical cancer and apparent diffusion coefficient values: a promising tool for patient´s immunotherapy selection.

OBJECTIVE: To investigate the associations between apparent diffusion coefficient (ADC) values extracted from three different region of interest (ROI) position approaches and programmed cell death ligand-1 (PD-L1) expression, and evaluate the performance of the nomogram established based on ADC values and clinicopathological parameters in predicting PD-L1 expression in cervical cancer (CC) patients. METHODS: Through retrospective recruitment, a training cohort of 683 CC patients was created, and a validation cohort of 332 CC patients was prospectively recruited. ROIs were delineated using three different methods to measure the mean ADC (ADCmean), single-section ADC (ADCss), and the minimum ADC of tumors (ADCmin). Logistic regression was employed to identify independent factors related to PD-L1 expression. A nomogram was drawn based on ADC values combined with clinicopathological features, its discrimination and calibration performances were estimated using the area under the curve (AUC) of receiver operating characteristic and calibration curve. The clinical benefits were evaluated by decision curve analysis. RESULTS: The ADCmin independently correlated with PD-L1 expression. The nomogram constructed with ADCmin and other independent clinicopathological-related factors: FIGO staging, pathological grade, parametrial invasion, and lymph node status demonstrated excellent diagnostic performance (AUC = 0.912 and 0.903, respectively), good calibration capacities, and greater net benefits compared to the clinicopathological model in both the training and validation cohorts. CONCLUSION: ADCmin independently correlated PD-L1 expression, and the nomogram established with ADCmin and clinicopathological independent prognostic factors had a strong predictive performance for PD-L1 expression, thereby serving as a promising tool for selecting cases eligible for immunotherapy. CLINICAL RELEVANCE STATEMENT: The minimum ADC can serve as a reliable imaging biomarker related to PD-L1 expression; the established nomogram combines the minimum ADC and clinicopathological factors that can assist clinical immunotherapy decisions.

Clinical characteristics and radiation therapy modality of younger patients with early-stage endometrial cancer, a multicenter study in China's real world.

BACKGROUND: Endometrial cancer is a prevalent gynecologic malignancy found in postmenopausal women. However, in the last two decades, the incidence of early-stage has doubled in women under 40 years old. This study aimed to investigate the clinical and pathological characteristics and adjuvant therapeutic modalities of both young and not -young patients with early-stage endometrial cancer in China's real world. METHODS: This retrospective study analyzed patients with early-stage endometrial cancer at 13 medical institutions in China from 1999 to 2015. The patients were divided into two groups: young (≤ 45 years old) and non-young (> 45 years old). Statistical comparisons were conducted between the two groups for clinical characteristics, pathological features, and survival. The study also identified factors that affect local recurrence-free survival (LRFS) using Cox proportional risk regression analysis. Propensity score matching (1:1) was used to compare the effects of local control between vaginal brachytherapy (VBT) alone and pelvic external beam radiotherapy (EBRT) ± VBT. RESULTS: The study involved 1,280 patients, 150 of whom were 45 years old or younger. The young group exhibited a significantly higher proportion of stage II, low-risk, lower uterine segment infiltration (LUSI), and cervical invasion compared to the non-young group. Additionally, the young patients had significantly larger maximum tumor diameters. The young group also had a significantly higher five-year overall survival (OS) and a five-year LRFS. Age is an independent risk factor for LRFS. There was no significant difference in LRFS between young patients with intermediate- to high-risk early-stage endometrial cancer who received EBRT ± VBT and those who received VBT alone. CONCLUSIONS: In the present study, young patients had better characteristics than the non-young group, while they exhibited higher levels of aggressiveness in certain aspects. The LRFS and OS outcomes were better in young patients. Age is an independent risk factor for LRFS. Additionally, VBT alone may be a suitable option for patients under 45 years of age with intermediate- to high-risk early-stage endometrial cancer, as it reduces the risk of toxic reactions and future second cancers while maintaining similar local control as EBRT.

AMPK activation coupling SENP1-Sirt3 axis protects against acute kidney injury.

Acute kidney injury (AKI) is a critical clinical condition that causes kidney fibrosis, and it currently lacks specific treatment options. In this research, we investigate the role of the SENP1-Sirt3 signaling pathway and its correlation with mitochondrial dysfunction in proximal tubular epithelial cells (PTECs) using folic acid (FA) and ischemia-reperfusion-induced (IRI) AKI models. Our findings reveal that Sirt3 SUMOylation site mutation (Sirt3 KR) or pharmacological stimulation (metformin) protected mice against AKI and subsequent kidney inflammation and fibrosis by decreasing the acetylation level of mitochondrial SOD2, reducing mitochondrial reactive oxygen species (mtROS), and subsequently restoring mitochondrial ATP level, reversing mitochondrial morphology and alleviating cell apoptosis. In addition, AKI in mice was similarly alleviated by reducing mtROS levels using N-acetyl-L-cysteine (NAC) or MitoQ. Metabolomics analysis further demonstrated an increase in antioxidants and metabolic shifts in Sirt3 KR mice during AKI, compared with Sirt3 wild-type (WT) mice. Activation of the AMPK pathway using metformin promoted the SENP1-Sirt3 axis and protected PTECs from apoptosis. Hence, the augmented deSUMOylation of Sirt3 in mitochondria, activated through the metabolism-related AMPK pathway, protects against AKI and subsequently mitigated renal inflammation and fibrosis through Sirt3-SOD2-mtROS, which represents a potential therapeutic target for AKI.

Practice patterns of adjuvant radiotherapy in women with stage I to II endometrial carcinoma: a real-world multi-institutional analysis in China.

BACKGROUND: This study aimed to report clinical practice patterns of postoperative radiotherapy for stage I to II endometrial carcinoma (EC) patients treated in 13 Chinese medical centers. METHODS: We included early stage EC patients treated by hysterectomy and adjuvant RT between 2003 and 2017 from 13 institutions. Patients were classified into 4 risk groups based on ESMO-ESGO-ESTRO recommendations (2014). RESULTS: A total of 1,227 cases were analyzed. Along the 15 years of the study, an increasing tendency was found towards administration for vaginal brachytherapy (VBT) alone, while the proportion of external beam pelvic radiotherapy (EBRT) alone remained stable in the corresponding period. When radiation modalities were stratified by risk groups, proportion of VBT alone significantly increased in all risk groups. The higher the risk, the later VBT became the main adjuvant treatment modality. However, EBRT alone or with VBT remained the main adjuvant method for high-risk patients. There were 13 dose-fractionation schemes for VBT alone with the scheme of 30 Gy in 6 fractions prescribed at 0.5cm under the vaginal mucosa accounting for most. There were 17 schemes for VBT boost and the most common schedule was 10 Gy in 2 fractions. The upper 3-5cm part of vagina was the most frequent target. 89.6% of the practitioners performed two-dimensional VBT technique. The median dose for EBRT was 50 Gy. From 2003 to 2017, conventional radiotherapy was gradually replaced by three-dimensional conformal radiotherapy modality and intensity modulated radiotherapy. CONCLUSION: We report a significant shift from EBRT to VBT alone for high-intermediate-risk, intermediate-risk and low-risk EC patients from 2003 to 2017 while EBRT remained the main radiation modality for high-risk early stage patients. There has been remarkable heterogeneity among VBT dose fractionation schedules across China. TRIAL REGISTRATION: The clinical trial ID was ChiCTR-PRC-17010712. It was authorized by the Institutional Review Board of Peking Union Medical College Hospital (N0. S-K139).

The effects of continuous straw returning strategies on SOC balance upon fresh straw incorporation.

Continuous straw returning is widely encouraged for augmenting soil organic carbon (SOC) in arable lands. However, the magnitude of changes in net SOC related to native SOC mineralization and new SOC development upon fresh straw incorporation remains elusive, particularly in soils after continuous straw returning with different strategies. To address this, soil that had undergone nine years of straw returning with different strategies (NS, non-straw returning; DS, direct straw returning; IS, indirect straw returning) was incubated with fresh 13C-labeled straw for 45 days. Fresh straw incorporation stimulated native SOC-derived CO2 emission in DS soil, which in turn promoted straw-derived CO2 emission in IS soil. Overall, the amounts of newly developed SOC from straw (2.41-2.59 g C/kg soil) overcompensated for the native SOC losses (0.91-1.37 g C/kg soil) by mineralization, and led to net C sequestration in all treatments. No obvious difference was found in the amounts of SOC sequestrated from straw between the DS and NS soils, while the amount of native SOC mineralization increased by 40-50% in the DS soil relative to other treatments, thus resulting in lower net C sequestration in the DS soil (1.21 g C/kg soil) than IS and NS soil (1.43 and 1.65 g C/kg for IS and NS soil, respectively). Spearman's correlation analyses indicated a significant (p < 0.01) and positive correlation between SOC contents and native soil C mineralization, while the soil microbial index played a greater role in influencing fresh straw sequestration (p < 0.01). In conclusion, the DS soil showed a weaker effect on SOC sequestration than IS after 9 years of practices, upon fresh straw incorporation. This difference may be attributed to the magnitude of native SOC mineralization in the soil. Besides the straw-C input rate, results emphasize that native soil C protection should be also considered in long-term SOC sequestration practices.

Preoperative serum CA125 level and age at diagnosis: An effective prognosis prediction tool for patients with early-stage endometrial cancer.

OBJECTIVE: To investigate the combined predictive value of the preoperative serum cancer antigen 125 (CA125) level and age at diagnosis among patients with early-stage endometrial cancer (EC) after initial treatment. METHODS: We retrospectively analyzed data from patients with early-stage EC from 1999 to 2015 in multiple institutions in China. All 447 patients received postoperative adjuvant radiotherapy for FIGO 2009 stage I and II EC with complete data on preoperative serum CA125 levels. All patients were divided into four groups according to the ESMO-ESGO-ESTRO risk classification. The predictive probability of 5-year overall survival (OS) and the sensitivity and specificity of CA125 and age were calculated. RESULTS: The median follow-up time was 59 months (3-201 months). The 5-year OS and disease-free survival rates were 94.4% and 89.1%. Multivariate analysis showed that the preoperative CA125 level and age at diagnosis were independent prognostic factors for 5-year OS. The area under the curve for CA125 combined with age at diagnosis for 5-year OS was .692, and the corresponding sensitivity and specificity were 68.2% and 68.2% (p < .002), which were significantly better than the corresponding values for CA125 or age alone. After all 447 patients were divided into four groups according to CA125 combined with age, the 5-year OS of the elderly and higher CA125 group was only 73.7%. CONCLUSIONS: Although preoperative CA125 had limited sensitivity in predicting the prognosis for early-stage EC after initial treatment, it remains a useful serum marker for risk assessment of early-stage EC. Combining CA125 with age may increase its predictive sensitivity.

Large area MCP-PMT design with good time performance.

A new large area photomultiplier tube based on the microchannel plates (MCP-PMT) with high collection efficiency (CE) and good time performance is proposed in this paper. A novel focusing system with two cylindrical and a conical barrels is designed to generate the accelerating and focusing electric field. A three-dimensional model is developed by CST Studio Suite to validate its feasibility. Finite Integral Technique and Monte Carlo method are combined to simulate the process. Results predict that CE of the novel MCP-PMT is expected to be 100%. TTS of the photoelectrons from the whole photocathode achieves 1.2 ns. Differ from other large area PMTs, it performs well in the geomagnetic field.

Utilization Trend and Comparison of Different Radiotherapy Modes for Patients with Early-Stage High-Intermediate-Risk Endometrial Cancer: A Real-World, Multi-Institutional Study.

This study aimed to compare the outcomes of RT modalities among patients who met different HIR criteria based on multicentric real-world data over 15 years. The enrolled patients, who were diagnosed with FIGO I-II EC from 13 medical institutes and treated with hysterectomy and RT, were reclassified into HIR groups according to the criteria of GOG-249, PORTEC-2, and ESTRO-ESMO-ESGO, respectively. The trends in RT modes utilization were reviewed using the Man-Kendall test. The rate of VBT alone increased from zero in 2005 to 50% in 2015, which showed a significant upward trend (p < 0.05), while the rate of EBRT + VBT utilization declined from 87.5% to around 25% from 2005 to 2015 (p > 0.05). There were no significant differences in OS, DFS, LRFS, and DMFS between VBT alone and EBRT ± VBT in three HIR cohorts. Subgroup analyses in the GOG-249 HIR cohort showed that EBRT ± VBT had higher 5-year DFS, DMFS, and LRFS than VBT alone for patients without lymph node dissection (p < 0.05). Thus, VBT could be regarded as a standard adjuvant radiation modality for HIR patients. EBRT should be administrated to selected HIR patients who meet the GOG-249 criteria and did not undergo lymph node dissection.

Mitotic SENP3 activation couples with cGAS signaling in tumor cells to stimulate anti-tumor immunity.

Our previous studies show that the mitotic phosphorylation of SUMO-specific protease 3 (SENP3) can inhibit its de-SUMOylation activity in G2/M phase of the cell cycle. Inhibition of SENP3 plays a critical role in the correct separation of sister chromatids in mitosis. The mutation of mitotic SENP3 phosphorylation causes chromosome instability and promotes tumorigenesis. In this study, we find that the mutation of mitotic SENP3 phosphorylation in tumor cells can suppress tumor growth in immune-competent mouse model. We further detect an increase of CD8+ T cell infiltration in the tumors, which is essential for the anti-tumor effect in immune-competent mouse model. Moreover, we find that mitotic SENP3 activation increases micronuclei formation, which can activate cGAS signaling-dependent innate immune response. We confirmed that cGAS signaling mediates the mitotic SENP3 activation-induced anti-tumor immunity. We further show that p53 responding to DNA damage activates mitotic SENP3 by inhibiting phosphorylation, and further increases cellular senescence as well as the related innate immune response in tumor cells. Furthermore, TCGA database demonstrates that the SENP3 expression positively correlates with the induction of innate immune response as well as the survival of the p53 mutant pancreatic cancer patients. Together, these data reveal that mitotic SENP3 activation in tumor cells can promote host anti-tumor immune response by coupling with cGAS signaling.

Optimization design of the large area Dynode-MCP-PMT.

The optimization work of a newly proposed 20-in. photomultiplier tube based on dynode and microchannel plates (Dynode-MCP-PMT) are conducted in this paper. Three-dimensional models are developed in CST STUDIO SUITE to systematically investigate the effects of the size and bias voltage of the two focusing electrodes, dynode and the glass envelop handle based on the Finite Integral Technique and Monte Carlo method. Results predict that the collection efficiency and the transit time spread of the optimized design are substantially improved which are 100% and 3.7 ns.

SENP1-Sirt3 signaling promotes α-ketoglutarate production during M2 macrophage polarization.

The metabolic program is altered during macrophage activation and influences macrophage polarization. Glutaminolysis promotes accumulation of α-ketoglutarate (αKG), leading to Jumonji domain-containing protein D3 (Jmjd3)-dependent demethylation at H3K27me3 during M2 polarization of macrophages. However, it remains unclear how αKG accumulation is regulated during M2 polarization of macrophages. This study shows that SENP1-Sirt3 signaling controls glutaminolysis, leading to αKG accumulation during IL-4-stimulated M2 polarization. Activation of the SENP1-Sirt3 axis augments M2 macrophage polarization through the accumulation of αKG via glutaminolysis. We also identify glutamate dehydrogenase 1 (GLUD1) as an acetylated protein in mitochondria. The SENP1-Sirt3 axis deacetylates GLUD1 and increases its activity in glutaminolysis to promote αKG production, leading to M2 polarization of macrophages. Therefore, SENP1-Sirt3 signaling plays a critical role in αKG accumulation via glutaminolysis to promote M2 polarization.

Overview of adjuvant radiotherapy on survival, failure pattern and toxicity in stage I to II endometrial carcinoma: a long-term multi-institutional analysis in China.

BACKGROUND: This research aimed to provide an overview of the impact of adjuvant vaginal brachytherapy (VBT) and external beam pelvic radiotherapy (EBRT) with or without VBT on survival in stage I to II EC patients in China from a long-term multi-institutional analysis. METHODS: We retrospectively analyzed stage I to II EC patients from 13 institutions treated between 2003 and 2015. All patients underwent surgical staging and received adjuvant RT. Patients were divided into groups of low-risk (LR), intermediate-risk (IR), high-intermediate-risk (HIR) and high-risk (HR). Survival statistics, failure pattern, and toxicity of different radiation modalities in different risk groups were analyzed. RESULTS: A total of 1048 patients were included. HR disease represented 27.6%, HIR 17.7%, IR 27.7% and LR 27.1%, respectively. Endometrioid adenocarcinoma (EAC) and non-endometrioid carcinoma (NEC) accounted for 92.8 and 7.2%. A total of 474 patients received VBT alone and 574 patients received EBRT with or without VBT. As for EAC patients, the 5-year overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) rate was: 94.6, 90.4, 93.0 and 91.6%, respectively. For LR patients, EBRT (with or without VBT) seemed to be a risk factor. With the higher risk category, the survival benefit of EBRT gradually became remarkable. EBRT (with or without VBT) significantly increased DFS, LRFS and DMFS compared to VBT alone in the HR group (p < 0.05). Distant metastasis was the main failure pattern for all risk groups. As for NEC patients, the 5-year OS, DFS, LRFS and DMFS rate was: 93.4, 87.2, 91.7 and 89.3%, respectively. As for toxicity, EBRT (with or without VBT) significantly increased the incidence of grade 1-2 gastrointestinal, urinary, and hematological toxicity. CONCLUSIONS: For stage I to II EC patients, EAC accounted for the majority and had better prognosis than NEC. For EAC patients, VBT alone resulted in comparable survival to EBRT in the LR, IR and HIR groups, while EBRT significantly increased survival in the HR group. EBRT had higher rate of toxicity than VBT.

NR4A1 promotes LEF1 expression in the pathogenesis of papillary thyroid cancer.

The morbidity of papillary thyroid cancer (PTC) is on the rise, but its pathogenesis is still poorly understood. NR4A1 is a transcription factor primarily involving a wide range of pathophysiological responses, but its relationship with PTC malignancy remains unclear. This study demonstrates that high NR4A1 expression is strongly associated with poor survival outcomes in PTC patients. The depletion of NR4A1 significantly inhibited the proliferation of PTC cells by negating the LEF1-mediated oncogenic alteration. Mechanistically, NR4A1 directly binds to the promoter region of LEF1 and leads to crosstalk with histone acetylation and DNA demethylation to transcriptionally upregulate LEF1 expression, subsequently promoting downstream growth-related genes expressions in PTC. In the light of our findings, NR4A1 may be an emerging driving factor in PTC pathogenesis and progression.

An extended π-backbone for highly efficient near-infrared thermally activated delayed fluorescence with enhanced horizontal molecular orientation.

Near-infrared thermally activated delayed fluorescence (NIR-TADF) materials with emission over 700 nm have been insufficiently investigated mainly due to the limited choice of strong donor/acceptor units for molecular construction and the limited electronic coupling between the donors and acceptors. Herein, a novel D-A1-A2-A3 configuration was developed for the design of a NIR-TADF material (TPA-CN-N4-2PY), in which three types of sub-acceptor units (CN: cyano; N4: dipyrido[3,2-a:2',3'-c]phenazine; PY: pyridine) were incorporated into a molecular skeleton to reinforce the electron-accepting strength. The attachment of two pyridine units on TPA-CN-N4 produced TPA-CN-N4-2PY with an extended π-backbone, which shifted the electroluminescence (EL) emission into the NIR region and enhanced the horizontal ratio of emitting dipole orientation (Θ//) simultaneously. TPA-CN-N4-2PY-based OLEDs demonstrated a record-high external quantum efficiency (EQE) of 21.9% with an emission peak at 712 nm and Θ// = 85% at the doping ratio of 9.0 wt%. On the contrary, the parent compound TPA-CN-N4-based OLEDs at the same doping ratio achieved an EQE of 23.4% at 678 nm with Θ// = 75%. This multiple sub-acceptors approach could enrich the design strategy of the NIR-TADF materials, and the large conjugated system could improve the Θ// for achieving efficient emitters.

Wernicke's encephalopathy in a rectal cancer patient with atypical radiological features: A case report.

BACKGROUND: Wernicke's encephalopathy is a disease caused by thiamine deficiency. The lesions usually involve the periphery of the aqueduct, midbrain, tectum, third ventricle, papillary body, and thalamus. It is very rare to affect the vermis and cerebellar hemispheres. CASE SUMMARY: We report a 77-year-old female patient admitted to the emergency department of our hospital for 2 d of unconsciousness. Brain magnetic resonance imaging showed increased diffusion weighted imaging signals in the bilateral thalamus, periventricular regions of the third ventricle, corpora quadrigemina, vermis, and cerebellar hemispheres. Wernicke's encephalopathy was considered. She was given thiamine therapy and became conscious after the treatment. CONCLUSION: Wernicke's encephalopathy may have various imaging manifestations. Clinicians should keep in mind that Wernicke's encephalopathy may occur in patients who experience prolonged periods of malnutrition.

Identification of GPC3 mutation and upregulation in a multidrug resistant osteosarcoma and its spheroids as therapeutic target.

BACKGROUND: Drug resistance and the lack of molecular therapeutic target are the main challenges in the management of osteosarcomas (OSs). Identification of novel genetic alteration(s) related with OS recurrence and chemotherapeutic resistance would be of scientific and clinical significance. METHODS: To identify potential genetic alterations related with OS recurrence and chemotherapeutic resistance, the biopsies of a 20-year-old male osteosarcoma patient were collected at primary site (p-OS) and from its metastatic tumor (m-OS) formed after 5 months of adjuvant chemotherapy. Both OS specimens were subjected to cancer-targeted next generation sequencing (NGS) and their cell suspensions were cultured under three-dimensional condition to establish spheroid therapeutic model. Transcript-oriented Sanger sequencing for GPC3, the detected mutated gene, was performed on RNA samples of p-OS and m-OS tissues and spheroids. The effects of anti-GPC3 antibody and its combination with cisplatin on m-OS spheroids were elucidated. RESULTS: NGS revealed 4 mutations (GPC3, SOX10, MDM4 and MAPK8) and 6 amplifications (MDM2, CDK4, CCND3, RUNX2, GLI1 and FRS2) in p-OS, and 3 mutations (GPC3, SOX10 and EGF) and 10 amplifications (CDK4, CCND3, MDM2, RUNX2, GLI1, FRS2, CARD11, RAC1, SLC16A7 and PMS2) in m-OS. Among those alterations, the mutation abundance of GPC3 was the highest (56.49%) in p-OS and showed 1.54 times increase in m-OS. GPC3 transcript-oriented Sanger sequencing confirmed the mutation at 1046 in Exon 4, and immunohistochemical staining showed increased GPC3 production in m-OS tissues and its spheroids. EdU cell proliferation and Calcein/PI cell viability assays revealed that of the anti-OS first line drugs (doxorubicin, cisplatin, methotrexate, ifosfamide and carboplatin), 10 µM carboplatin exerted the best inhibitory effects on the p-OS but not the m-OS spheroids. 2 µg/mL anti-GPC3 antibody effectively committed m-OS spheroids to death by itself (76.43%) or in combination with cisplatin (92.93%). CONCLUSION: This study demonstrates increased abundance and up-regulated expression of mutant GPC3 in metastatic osteosarcoma and its spheroids with multidrug resistance. As GPC3-targeting therapy has been used to treat hepatocellular carcinomas and it is also effective to OS PDSs, GPC3 would be a novel prognostic parameter and therapeutic target of osteosarcomas.

Long non-coding RNA SNHG1 relieves microglia activation by downregulating miR-329-3p expression in an in vitro model of cerebral infarction.

Following cerebral infarction, activated microglia cells can release a large amount of inflammatory cytokines, thereby exacerbating neuronal damage. It has been demonstrated that the long non-coding RNA small nucleolar RNA host gene 1 (SNHG1) exerts a protective effect against cerebral infarction. However, its specific role in cerebral infarction and underlying mechanism have yet to be fully elucidated. The present study aimed to investigate the effects of the SNHG1 and microRNA (miR)-329-3p in cerebral infarction and to determine the underlying molecular mechanisms. An in vitro oxygen-glucose deprivation (OGD) model was established using the BV-2 microglial cell line. The mRNA expression levels of SNHG1 and miR-329-3p were analyzed using reverse transcription-quantitative PCR and the protein expression levels of cleaved caspase-3 and caspase-3 were detected using western blotting. The binding relationship between SNHG1 and miR-329-3p was predicted using starBase and verified using a dual luciferase reporter assay. The release of TNF-α and nitric oxide, as well as caspase-3 activity, were detected using appropriate commercial kits. Flow cytometry analysis was performed to measure cell apoptosis. The results of the present study revealed that the expression levels of SNHG1 were upregulated in the OGD-induced BV-2 cell model. miR-329-3p was discovered to directly target SNHG1, and its mRNA expression levels were downregulated in the OGD-induced BV-2 cell model. The SNHG1-plasmid downregulated miR-329-3p expression levels, while this effect was reversed by transfection with the miR-329-3p mimic. The overexpression of SNHG1 or knockdown of miR-329-3p inhibited OGD-induced BV-2 cell activation. In conclusion, the results of the present study suggested that SNHG1 may reduce microglial cell activity by regulating the expression of miR-329-3p, indicating its potential protective role in cerebral infarction.

Effect of age as a continuous variable in early-stage endometrial carcinoma: a multi-institutional analysis in China.

OBJECTIVE: To explore the effect of age at diagnosis as a continuous variable on survival and treatment choice of patients with early-stage endometrial carcinoma (EC). MATERIALS AND METHODS: We retrospectively analyzed data from patients with early-stage EC from January 1999 to December 2015 in multiple institutions in China. All patients received primary hysterectomy/bilateral salpingo-oophorectomy and adjuvant radiotherapy for EC confirmed pathology of stage I and II disease (FIGO 2009 staging). All patients were divided into low-risk, intermediate-risk, high-intermediate-risk and high-risk groups according to ESMO-ESGO-ESTRO risk classification. RESULTS: The median follow-up time was 57months, and the 5-year cancer-specific survival (CSS) was 95.7%. Age as a continuous variable was an independent prognostic factor for CSS. With an increase in age, the hazard ratio (HR) for CSS increases gradually. Other independent prognostic factors included myometrial invasion (MI), grade, and chemotherapy. In the stratified analysis of age, the HRs of age on CSS in patients >70y were 5.516, 5.015, 4.469, 4.618, 5.334, and 5.821 after adjusting for cancer characteristics, local treatment, chemotherapy and treatment-related late toxicity. In patients 66-70-year-old, the HRs were 2.509, 2.074, 2.101, 2.091, 2.157 and 1.621 after adjusting for the above covariates. In patients ≤65y, there was no significant difference in the HR of age on CSS after adjustment. CONCLUSION: Age as a continuous variable is an independent prognostic factor and 65 year-old may be the best cut-off point for CSS in patients with early-stage EC in the Asian population. Quality of life should be given greater weight in the choice of therapeutic schedule for those patients >70 y.

Glucose limitation activates AMPK coupled SENP1-Sirt3 signalling in mitochondria for T cell memory development.

Metabolic programming and mitochondrial dynamics along with T cell differentiation affect T cell fate and memory development; however, how to control metabolic reprogramming and mitochondrial dynamics in T cell memory development is unclear. Here, we provide evidence that the SUMO protease SENP1 promotes T cell memory development via Sirt3 deSUMOylation. SENP1-Sirt3 signalling augments the deacetylase activity of Sirt3, promoting both OXPHOS and mitochondrial fusion. Mechanistically, SENP1 activates Sirt3 deacetylase activity in T cell mitochondria, leading to reduction of the acetylation of mitochondrial metalloprotease YME1L1. Consequently, deacetylation of YME1L1 suppresses its activity on OPA1 cleavage to facilitate mitochondrial fusion, which results in T cell survival and promotes T cell memory development. We also show that the glycolytic intermediate fructose-1,6-bisphosphate (FBP) as a negative regulator suppresses AMPK-mediated activation of the SENP1-Sirt3 axis and reduces memory development. Moreover, glucose limitation reduces FBP production and activates AMPK during T cell memory development. These data show that glucose limitation activates AMPK and the subsequent SENP1-Sirt3 signalling for T cell memory development.

Treatment optimization of pelvic external beam radiation and/or vaginal brachytherapy for patients with stage I to II high-risk Endometrioid adenocarcinoma: a retrospective multi-institutional analysis.

BACKGROUND: For stage I to II high-risk endometrioid adenocarcinoma patients, the optimal adjuvant radiotherapy modality remains controversial. The present study sought to optimize the treatment of pelvic external beam radiation (EBRT) with/or vaginal brachytherapy (VBT) for high-risk endometrioid adenocarcinoma patients in multiple radiation oncology centers across China. METHODS: This article retrospectively reviewed stage I to II patients with resected endometrioid adenocarcinoma treated at 13 radiation centers from 1999 to 2015. Patients were eligible if they had high-risk features (stage IB Grade 3 disease or stage II Grade 1-3 disease) on the basis of ESMO-ESGO-ESTRO risk group consensus. RESULTS: A total of 218 patients were included. Fifty-one patients received EBRT, 25 patients received VBT, and 142 patients were administered EBRT combined with VBT. The three groups were comparable in baseline characteristics, except the proportion of stage IB and Grade 3 disease in the VBT group was significantly higher and their age was older. Survival analysis showed that OS, DFS, LRFS and DMFS were significantly different among the three groups. Two out of three groups were compared with each other, and results demonstrated that DFS, LRFS and DMFS were worse in the VBT group than in the EBRT or EBRT + VBT group. The 3-year OS rates were 95.2, 85.2 and 95.1% in the EBRT, VBT and EBRT + VBT groups, respectively (p = 0.043). There was no significant difference in survival outcomes between EBRT group and EBRT + VBT group. A propensity matching analysis was performed to eliminate group differences. The results demonstrated that DFS and LRFS were significantly improved in the pelvic radiation group compared to the VBT group. Distant failure accounted for most of the failure patterns. Patients in the VBT group had significantly increased local and regional recurrence rates than patients in the EBRT or EBRT + VBT group. Acute and chronic radiation-induced toxicities were well tolerated for all patients. CONCLUSION: For patients with postoperative stage I to II high-risk endometrioid adenocarcinoma, compared with VBT alone, radiotherapy modalities including EBRT significantly improved DFS, LRFS and DMFS with tolerable adverse effects. Overall survival was not significantly different between EBRT and EBRT + VBT modalities.