Immune effector dysfunction signatures predict outcomes in patients with colorectal cancer.

BACKGROUND: Immune effector dysfunction (IED) is mainly manifested as immune exhaustion and senescence, which are the primary obstacles to the success of cancer immunotherapy. In the current study, we characterized the prognostic relevance of IED signatures in patients with colorectal cancer (CRC). METHODS: Immunohistochemistry (IHC) data of CRC tissue samples from 41 newly diagnosed patients in our clinical center (HDPH cohort) were used to investigate the prognostic importance of IED signatures. The results were validated by the RNA sequencing data of 372 CRC patients from the Cancer Genome Atlas (TCGA) database. RESULTS: In the HDPH cohorts, high Natural Killer (NK) and CD8+ tumor-infiltrating lymphocytes (TILs) were associated with poor overall survival (OS) and relapse-free survival (RFS) in CRC patients. Optimal IED signatures, including high expression of CCR9, ISG20, and low expression of ICOS, and CACNA2D2, predicted poor OS and RFS. Moreover, high-risk scores estimated by a weighted combination of these four IED genes were associated with poor OS and RFS. Notably, risk stratification was constructed by combining risk score and tumor node metastasis (TNM) stage better than TNM stage alone in predicting OS and RFS for CRC patients. The above results were confirmed in the TCGA cohort. CONCLUSION: CCR9, ISG20, ICOS, and CACNA2D2 were optimal IED signatures for predicting the outcomes of CRC patients, which might be a potential biomarker for prognostic stratification and designing novel CRC therapy.

Fludarabine Enhances Radiosensitivity by Promoting Ferroptosis in B-Cell Lymphoma.

The objective of this study is to investigate the impact of fludarabine, a signal transducer and activator of transcription-1 (STAT1) inhibitor, on the radiosensitivity of B-cell lymphoma (BCL) and to explore the underlying mechanisms. Radiotherapy is one of the primary treatments for BCL, and STAT1 plays a critical role in the transcription of cell proliferation-related genes, which are associated with radiotherapy and ferroptosis. This study aims to determine whether fludarabine can enhance the radiosensitivity of BCL and to elucidate the molecular pathways involved. Various in vitro methodologies, including CCK-8 assays, clonogenic formation assays, immunohistochemistry, immunofluorescence, flow cytometry, qRT-PCR, and Western blot analyses, were employed in B-cell lymphoma cell models to thoroughly investigate the effects of fludarabine on radiosensitivity. Subsequently, the obtained results were further validated through in vivo animal models and by examining human diffuse large B-cell lymphoma (DLBCL) cancer samples. Our findings demonstrate that the combination of fludarabine and irradiation synergistically inhibits cell viability and colony formation, while inducing apoptosis and ferroptosis in B-cell lymphoma cell lines Raji and Su-DHL-10. Moreover, fludarabine was found to enhance the ferroptosis induced by radiation, thereby synergistically impeding the growth of BCL. In vivo experiments confirmed these findings, revealing that the intraperitoneal injection of fludarabine significantly enhanced the inhibitory effects of radiation on Raji cell xenograft models, leading to an increased percentage of ferroptosis compared to models without fludarabine. Additionally, the administration of liproxstatin-1, a ferroptosis inhibitor, attenuated the inhibition of xenograft growth caused by the combination of fludarabine and irradiation. Furthermore, our analysis of clinical data revealed that increased co-expression of STAT1 and GPX4 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. These results highlight the potential of fludarabine to enhance radiosensitivity and ferroptosis induction as a promising therapeutic strategy for BCL. Our results demonstrated that fludarabine promoted radiation-induced BCL death through the ferroptosis pathway. We have identified a previously unrecognized mechanism in the fludarabine and radiation combination, indicating that it is necessary to conduct prospective clinical trials to verify this new treatment regimen in BCL.

LncRNA SATB2-AS1 promotes tumor growth and metastasis and affects the tumor immune microenvironment in osteosarcoma by regulating SATB2.

Our previous report has identified a lncRNA SATB2-AS1, which was significantly up-regulated in osteosarcoma tissue and promotes the proliferation of osteosarcoma cells in vitro. However, the mechanisms of SATB2-AS1 regulating the growth and metastasis of osteosarcoma cells in vivo and its role in the prognosis of osteosarcoma patients are still unclear. In this study, the transcriptome sequencing data of 87 patients with osteosarcoma from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database and 7 patients from our clinical center (GZFPH) was used to evaluate the importance of SATB2-AS1 and SATB2 on the prognosis. The effect of SATB2-AS1 on the growth and metastasis of osteosarcoma cells in vivo was verified by a mouse tumor model. The potential mechanisms of SATB2-AS1 regulating SATB2 were further explored by dual-luciferase reporter gene assay, RNA pull-down assay, and bioinformatics analysis. The results suggested that increased co-expression of SATB2-AS1 and SATB2 was significantly associated with poor overall survival (OS) and relapse-free survival (RFS), and was a biomarker for risk stratification in patients with osteosarcoma. Mechanistically, SATB2-AS1 promotes tumor growth and lung metastasis by regulating SATB2 in vivo. SATB2-AS1 directly binds to POU3F1 for mediating SATB2 expression in MNNG/HOS cells. In addition, SATB2-AS1 and SATB2 might be potential immunomodulators for negatively affecting immune cell infiltration by the IL-17 signaling pathway. In summary, SATB2-AS1 promoted tumor cell growth and lung metastasis by activating SATB2, thereby associated with poor prognosis in patients with osteosarcoma, which indicated that SATB2-AS1 and SATB2 might be novel biomarkers for risk stratification and promising therapeutic targets for osteosarcoma.

Sleep patterns correlates with the efficacy of tDCS on post-stroke patients with prolonged disorders of consciousness.

BACKGROUND: The subclassification of prolonged disorders of consciousness (DoC) based on sleep patterns is important for the evaluation and treatment of the disease. This study evaluates the correlation between polysomnographic patterns and the efficacy of transcranial direct current stimulation (tDCS) in patients with prolonged DoC due to stroke. METHODS: In total, 33 patients in the vegetative state (VS) with sleep cycles or without sleep cycles were randomly assigned to either active or sham tDCS groups. Polysomnography was used to monitor sleep changes before and after intervention. Additionally, clinical scale scores and electroencephalogram (EEG) analysis were performed before and after intervention to evaluate the efficacy of tDCS on the patients subclassified according to their sleep patterns. RESULTS: The results suggest that tDCS improved the sleep structure, significantly prolonged total sleep time (TST) (95%CI: 14.387-283.527, P = 0.013) and NREM sleep stage 2 (95%CI: 3.157-246.165, P = 0.040) of the VS patients with sleep cycles. It also significantly enhanced brain function of patients with sleep cycles, which were reflected by the increased clinical scores (95%CI: 0.340-3.440, P < 0.001), the EEG powers and functional connectivity in the brain and the 6-month prognosis. Moreover, the changes in NREM sleep stage 2 had a significant positive correlation with each index of the ß band. CONCLUSION: This study reveals the importance of sleep patterns in the prognosis and treatment of prolonged DoC and provides new evidence for the efficacy of tDCS in post-stroke patients with VS patients subclassified by sleep pattern. Trial registration URL: https://www. CLINICALTRIALS: gov . Unique identifier: NCT03809936. Registered 18 January 2019.

[Relationship between sleep architecture and severity of obstructive sleep apnea].

OBJECTIVE: To investigate the effect of obstructive sleep apnea (OSA) on different sleep stages, and the relationship between N3 stage of non-rapid eye movement sleep and respiratory abnormal events. METHODS: A total of 188 adult patients who underwent overnight polysomnography(PSG)monitoring in Sir Run Run shaw Hospital of Zhejiang University from June 24th to December 26th 2019 were enrolled in the study. OSA patients were classified into 3 groups (mild, moderate and severe) according to the apnea-hypopnea index (AHI). PSG data, AHI and the lowest SPO2 in each stage of sleep were compared among three groups. RESULTS: There was no significant difference in total sleep time and sleep efficiency among patients with different severity of OSA (all P>0.05). The proportion of N3 stage in moderate and severe OSA groups were significantly smaller than that in mild OSA group (all P<0.05). The proportion of N3 stage in severe OSA group was also smaller than that in moderate OSA group (P<0.05). In addition, severe OSA group had a longer latency of N3 stage than mild and moderate OSA groups (all P<0.05). The latency of N3 stage in moderate OSA group was longer than that in mild OSA group (P<0.05). The AHI in N3 stage was markedly lower than that in other sleep stages (all P<0.01), regardless of the severity of OSA. Supine AHI in N3 stage in mild and moderate groups was significantly lower than that in N1, N2 and rapid eye movement (REM) stages (all P<0.01). Supine AHI in N3 stage in severe group was also lower than that in N2 and REM stages (P<0.05 or P<0.01). The lowest SPO2 in N3 stage was significantly higher than that in N1, N2 and REM stages (P<0.05 or P<0.01), regardless of the severity of OSA. CONCLUSIONS: s The proportion of N3 stage is lower in OSA patients, and N3 stage has less sleep respiratory events than non-N3 stages. The results suggest that the increased N3 stage proportion may indicate less severity of OSA.

Meteorological conditions conducive to PM2.5 pollution in 2016/2017 in the Western Yangtze River Delta, China.

Cities in Anhui province in the western Yangtze River Delta (YRD), China experienced more PM2.5 pollution days in the winter of 2016/2017 (Dec 2016 to Feb 2017) than in the previous two winters under conditions of emission deductions. By employing back-trajectory-clustering analysis together with daily air quality index (AQI) data from 2015 to 2017, routine and reanalysis meteorological data, and some climate indices, we investigated the transport paths, large-scale vertical motion and related climate background conducive to PM2.5 pollution in Anhui province. We obtained 5 air-mass paths affecting Anhui province in winter; among them, the slow-moving air-masses from the northeast and northwest often led to PM2.5 pollution. Thus, they belong to adverse transport paths, which accounted for approximately 52% in northern Anhui and 62% in central Anhui. Compared with winter 2015/2016, the proportions of adverse transport paths in winter 2016/2017 increased 13% in Hefei (central site), 3% in Suzhou (northern site), and 9% in Chizhou (southern site); correspondingly, east winds increased, and north winds weakened in the boundary layer, which favoured the accumulation of pollutants in Anhui. The processes of pollution and cleaning in Anhui were also closely related to vertical motion of the middle troposphere (500 hPa), and the sinking (ascending) corresponding to the aggravation (mitigation) of pollution. Compared with the winter of 2015/2016, the percentage of downward vertical velocity at 500 hPa exceeding 0.2 Pa/s increased evidently in the winter of 2016/2017. Thus, the vertical velocity at 500 hPa can be used as an important factor for air quality prediction in winter. The interannual changes in transport conditions are related to changes in the Asia zonal and meridional circulations and may further be ascribed to the thermal and dynamic conditions in the Tropical Ocean.

Characteristics of the water-soluble components of aerosol particles in Hefei, China.

Size-classified daily aerosol mass concentrations and concentrations of water-soluble inorganic ions were measured in Hefei, China, in four representative months between September 2012 and August 2013. An annual average mass concentration of 169.09 µg/m(3) for total suspended particulate (TSP) was measured using an Andersen Mark-II cascade impactor. The seasonal average mass concentration was highest in winter (234.73 µg/m(3)) and lowest in summer (91.71 µg/m(3)). Water-soluble ions accounted for 59.49%, 32.90%, 48.62% and 37.08% of the aerosol mass concentration in winter, spring, summer, and fall, respectively, which indicated that ionic species were the primary constituents of the atmospheric aerosols. The four most abundant ions were NO3(-), SO4(2-), Ca(2+) and NH4(+). With the exception of Ca(2+), the mass concentrations of water-soluble ions were in an intermediate range compared with the levels for other Chinese cities. Sulfate, nitrate, and ammonium were the dominant fine-particle species, which were bimodally distributed in spring, summer and fall; however, the size distribution became unimodal in winter, with a peak at 1.1-2.1 µm. The Ca(2+) peak occurred at approximately 4.7-5.8 µm in all seasons. The cation to anion ratio was close to 1.4, which suggested that the aerosol particles were alkalescent in Hefei. The average NO3(-)/SO4(2-) mass ratio was 1.10 in Hefei, which indicated that mobile source emissions were predominant. Significant positive correlation coefficients between the concentrations of NH4(+) and SO4(2-), NH4(+) and NO3(-), SO4(2-) and NO3(-), and Mg(2+) and Ca(2+) were also indicated, suggesting that aerosol particles may be present as (NH4)2SO4, NH4HSO4, and NH4NO3.

[Characteristics of precipitation pH and conductivity at Mt. Huang].

To understand the general characteristics of pH distribution and pollution in precipitation at Mt. Huang, statistical analyses were conducted for the routine measurements of pH and conductivity (K) at Mt. Huang during 2006-2011. The results showed that: (1) Over the period of study, the annual volume weighted mean (VWM) precipitation pH varied from 4.81 to 5.57, with precipitation acidity strengthening before 2009 and weakening thereafter. The precipitation acidity showed evident seasonal variations, with the VWM pH lowest in winter (4.78), and highest in summer (5.33). The occurrence frequency of acid rain was 46% , accounting for 45% of total rainfalls and with the most frequent pH falling into weak acid to neutral rain. (2) The annual VWM K varied from 16.91 to 27.84 microS x cm(-1), with no evident trend. As for ions pollution, the precipitation was relatively clean at Mt. Huang, with the most frequent K range being below 15 microS x cm(-1), followed by 15-25 microS x cm(-1). From February 2010 to December 2011, precipitation samples were collected on daily basis for ions analysis, as well as pH and K measurement in lab. Detailed comparisons were conducted between the two sets of pH and K, one set from field measurement and the other from lab measurement. The results indicated: (1) The lab measured pH (K) was highly correlated with the field pH (K); however, the lab pH tended to move towards neutral comparing with the corresponding field pH, and the shift range was closely correlated with the field pH and rainfall. The shift range of K from field to lab was highly correlated with the total ion concentration of precipitation. The field K showed evident negative correlation with the field pH with a correlation coefficient of -0.51. (2) When sampling with nylon-polyethylene bags, the statistics showed smaller bias between two sets of pH, with higher correlation coefficient between two sets of K. Furthermore, the lab K also showed evident negative correlation with the lab pH. Comparing with the observations at other alpine sites in central to eastern China, the natural precipitation at Mt. Huang was weaker in acidity and contains lower ion concentration.