Optimum Parameters in Ultrasound Coherent Plane Wave Compounding for High LPWV Estimation: Validation on Phantom and Feasibility in 10 Subjects.

OBJECTIVES: The aim of this study is to determine the optimum and fine values of the number and transmission angles of tilted plane waves for coherent plane-wave compounding (CPWC)-based high local pulse wave velocity (LPWV) estimation. METHODS: A Verasonics system incorporating a linear array probe L14-5/38 with 128 elements and a pulsatile pump, CompuFlow1000, were used to acquire radio frequency data of 3, 5, 7, and 9 tilted plane wave sequences with angle intervals from 0° to 12° with a coarse interval increment step of 1°, and the angle intervals from 0° to 2° with a fine interval increment step of 0.25° from a carotid vessel phantom with the LPWV of 13.42 ± 0.90 m/s. The mean value, standard deviation, and coefficients of variation (CV) of the estimated LPWVs were calculated to quantitatively assess the performance of different configurations for CPWC-based LPWV estimation. Ten healthy human subjects of two age groups were recruited to assess the in vivo feasibility of the optimum parameter values. RESULTS: The CPWC technique with three plane waves (PRF of 12 kHz corresponding to a frame rate of 4000 Hz) with an interval of 0.75° had LPWVs of 13.52 ± 0.08 m/s with the lowest CV of 1.84% on the phantom, and 5.49 ± 1.46 m/s with the lowest CV of 12.35% on 10 subjects. CONCLUSIONS: The optimum parameters determined in this study show the best repeatability of the LPWV measurements with a vessel phantom and 10 healthy subjects, which support further studies on larger datasets for potential applications.

Surufatinib combined with photodynamic therapy induces ferroptosis to inhibit cholangiocarcinoma in vitro and in tumor models.

The curative effect of single therapy for advanced cholangiocarcinoma (CCA) is poor, thus investigating combined treatment strategies holds promise for improving prognosis. Surufatinib (SUR) is a novel multikinase inhibitor that has been confirmed to prolong survival of patients with advanced CCA. Photodynamic therapy (PDT) can also ablate advanced CCA and relieve biliary obstruction. In this study, we explored the anti-CCA effect of SUR combined with PDT, and explored the underlying mechanism. We found that SUR could effectively inhibit the abilities of proliferation, migration and metastasis in CCA cells (HUCCT-1, RBE). The ability of SUR to inhibit CCA was also confirmed by the HUCCT-1 cell xenograft model in Balb/c nude mice and CCA patient-derived organoids. SUR combined with PDT can significantly enhance the inhibitory effect on CCA, and can be alleviated by two ferroptosis inhibitors (Ferrostatin-1, Deferoxamine). By detecting the level of reactive oxygen species, lipid peroxides, malondialdehyde and glutathione, we further confirmed that SUR combined with PDT can inhibit CCA cells by inducing ferroptosis. Glutathione peroxidase 4 (GPX4) belongs to the glutathione peroxidase family and is mainly responsible for the metabolism of intracellular hydrogen peroxide. GPX4 inhibits ferroptosis by reducing cytotoxic lipid peroxides (L-OOH) to the corresponding alcohols (L-OH). Acyl-CoA synthetase long-chain family member 4 (ACSL4) is a member of the long-chain fatty acid coenzyme a synthetase family and is mainly involved in the biosynthesis and catabolism of fatty acids. ACSL4 induces ferroptosis by promoting the accumulation of lipid peroxides. Both SUR and PDT can induce ferroptosis by promoting ACSL4 and inhibiting GPX4. The regulation effect is found to be more significant in combined treatment group. In conclusion, SUR combined with PDT exerted an anti-CCA effect by inducing ferroptosis. Combination therapy provides a new idea for the clinical treatment of CCA.

Theta burst stimulation for enhancing upper extremity motor functions after stroke: a systematic review of clinical and mechanistic evidence.

This systematic review aimed to evaluate the effects of different theta burst stimulation (TBS) protocols on improving upper extremity motor functions in patients with stroke, their associated modulators of efficacy, and the underlying neural mechanisms. We conducted a meta-analytic review of 29 controlled trials published from January 1, 2000, to August 29, 2023, which investigated the effects of TBS on upper extremity motor, neurophysiological, and neuroimaging outcomes in poststroke patients. TBS significantly improved upper extremity motor impairment (Hedge's g = 0.646, p = 0.003) and functional activity (Hedge's g = 0.500, p < 0.001) compared to controls. Meta-regression revealed a significant relationship between the percentage of patients with subcortical stroke and the effect sizes of motor impairment (p = 0.015) and functional activity (p = 0.018). Subgroup analysis revealed a significant difference in the improvement of upper extremity motor impairment between studies using 600-pulse and 1200-pulse TBS (p = 0.002). Neurophysiological studies have consistently found that intermittent TBS increases ipsilesional corticomotor excitability. However, evidence to support the regional effects of continuous TBS, as well as the remote and network effects of TBS, is still mixed and relatively insufficient. In conclusion, TBS is effective in enhancing poststroke upper extremity motor function. Patients with preserved cortices may respond better to TBS. Novel TBS protocols with a higher dose may lead to superior efficacy compared with the conventional 600-pulse protocol. The mechanisms of poststroke recovery facilitated by TBS can be primarily attributed to the modulation of corticomotor excitability and is possibly caused by the recruitment of corticomotor networks connected to the ipsilesional motor cortex.

Effectiveness and safety of Lacosamide in pediatric patients with epilepsy under four years: Results from a prospective cohort study in China.

BACKGROUND: Lacosamide (LCM) has shown promising efficacy and safety outcomes in clinical trials. However, the evidence is limited among pediatric patients especially under four years in real-world. The study investigated the treatment outcomes and safety of LCM in patients under four years based on the data of the epilepsy registry of Children in China. METHODS: A prospective cohort study was conducted among patients under 4 years who newly received LCM as monotherapy or adjunctive therapy. The treatment outcomes were measured by retention rate of LCM, 50 % response rates and seizure-free rates during follow-up. The retention rate of LCM was assessed using the Kaplan-Meier survival model. Adverse events were reported as a percentage of all participants. RESULTS: Of 109 participants (mean follow-up: 18.6 months), 59 received LCM as monotherapy and 50 as adjunctive therapy. Sixty patients had focal epilepsy, 44 had generalized epilepsy and 5 had combined generalized and focal epilepsy. 70 % of patients in the monotherapy group and 41 % in the adjunctive therapy group remained on LCM treatment without additional treatments for at least one year. In patients with monotherapy, 50 % response rate and seizure-free rate were 75 % and 56 % at 12 months, respectively. In adjunctive therapy group, these rates were 51 % and 36 %, respectively. Lower baseline seizure frequency in both treatment groups (monotherapy: p < 0.001; adjunctive therapy: p = 0.02) and younger age groups within the monotherapy group (P = 0.04) correlated with a higher LCM retention rate. Adverse events were reported by 15 patients (13.8 %), with somnolence being the most common (7 of 15 patients). CONCLUSION: With a comprehensive information and high-quality of data, the study demonstrates the effective treatment outcome and safety of LCM. The study adds reliable evidence to exiting real-word evidence of LCM in the specific age group of patients with epilepsy to fill the evidence gap.

Clinical manifestations, antimicrobial resistance and genomic feature analysis of multidrug-resistant Elizabethkingia strains.

BACKGROUND: Elizabethkingia is emerging as an opportunistic pathogen in humans. The aim of this study was to investigate the clinical epidemiology, antimicrobial susceptibility, virulence factors, and genome features of Elizabethkingia spp. METHODS: Clinical data from 71 patients who were diagnosed with Elizabethkingia-induced pneumonia and bacteremia between August 2019 and September 2021 were analyzed. Whole-genome sequencing was performed on seven isolates, and the results were compared with a dataset of 83 available Elizabethkingia genomes. Genomic features, Kyoto Encyclopedia of Genes and Genomes (KEGG) results and clusters of orthologous groups (COGs) were analyzed. RESULTS: The mean age of the patients was 56.9 ± 20.7 years, and the in-hospital mortality rate was 29.6% (21/71). Elizabethkingia strains were obtained mainly from intensive care units (36.6%, 26/71) and emergency departments (32.4%, 23/71). The majority of the strains were isolated from respiratory tract specimens (85.9%, 61/71). All patients had a history of broad-spectrum antimicrobial exposure. Hospitalization for invasive mechanical ventilation or catheter insertion was found to be a risk factor for infection. The isolates displayed a high rate of resistance to cephalosporins and carbapenems, but all were susceptible to minocycline and colistin. Genomic analysis identified five ß-lactamase genes (blaGOB, blaBlaB, blaCME, blaOXA, and blaTEM) responsible for ß-lactam resistance and virulence genes involved in stress adaptation (ureB/G, katA/B, and clpP), adherence (groEL, tufA, and htpB) and immune modulation (gmd, tviB, cps4J, wbtIL, cap8E/D/G, and rfbC). Functional analysis of the COGs revealed that "metabolism" constituted the largest category within the core genome, while "information storage and processing" was predominant in both the accessory and unique genomes. The unique genes in our 7 strains were mostly enriched in KEGG pathways related to microRNAs in cancer, drug resistance (ß-lactam and vancomycin), ABC transporters, biological metabolism and biosynthesis, and nucleotide excision repair mechanisms. CONCLUSION: The Elizabethkingia genus exhibits multidrug resistance and carries carbapenemase genes. This study presents a comparative genomic analysis of Elizabethkingia, providing knowledge that facilitates a better understanding of this microorganism.

Rapamycin improves the survival of epilepsy model cells by blocking phosphorylation of mTOR base on computer simulations and cellular experiments.

PURPOSE: Epilepsy is a chronic brain dysfunction characterized by recurrent epileptic seizures. Rapamycin is a naturally occurring macrolide from Streptomyces hygroscopicus, and rapamycin may provide a protective effect on the nervous system by affecting mTOR. Therefore, we investigated the pharmacologic mechanism of rapamycin treating epilepsy through bioinformatics analysis, cellular experiments and supercomputer simulation. METHODS: Bioinformatics analysis was used to analyze targets of rapamycin treating epilepsy. We established epilepsy cell model by HT22 cells. RT-qPCR, WB and IF were used to verify the effects of rapamycin on mTOR at gene level and protein level. Computer simulations were used to model and evaluate the stability of rapamycin binding to mTOR protein. RESULTS: Bioinformatics indicated mTOR played an essential role in signaling pathways of cell growth and cell metabolism. Cellular experiments showed that rapamycin could promote cell survival, and rapamycin did not have an effect on mRNA expression of mTOR. However, rapamycin was able to significantly inhibit the phosphorylation of mTOR at protein level. Computer simulations indicated that rapamycin was involved in the treatment of epilepsy through regulating phosphorylation of mTOR at protein level. CONCLUSION: We found that rapamycin was capable of promoting the survival of epilepsy cells by inhibiting the phosphorylation of mTOR at protein level, and rapamycin did not have an effect on mRNA expression of mTOR. In addition to the traditional study that rapamycin affects mTORC1 complex by acting on FKBP12, this study found rapamycin could also directly block the phosphorylation of mTOR, therefore affecting the assembly of mTORC1 complex and mTOR signaling pathway.

Characteristics of pine wood nematode disease in Nankang District, Ganzhou, Jiangxi Province, China.

Pine wood nematode (PWN) disease is one of the major disasters in forests of southern China, causing substantial forest resources and ecological and economic losses. Based on field surveys and WFV image data from the GF-1 satellite, we constructed a spatial identification model of PWN disease with the random forest model to explore the relative influences of topography, human activities and stand factors on the occurrence of diseases and predict their spatial distribution. We then used the spatial autocorrelation analysis to assess the distribution characteristics of PWN disease at the regional scale. The results showed that the random forest model constructed in this study was effective in identifying pine nematode diseases (AUC value=0.99, overall accuracy=0.96). The norma-lized difference greenness index (NDGI), the distance to the highway, and normalized vegetation index (NDVI) were important factors in explaining the spatial variations of PWN disease occurrence. There was a positive spatial correlation in the occurrence of PWN disease (not randomly distributed but with obvious spatial aggregation characteristics). The high occurrence areas of pine wood nematode disease concentrated in Chitu Township, Zhufang Township and Shibatang Township, low occurrence areas concentrated in the vicinity of Rongjiang Street. The areas far away from the highway, low in elevation, and close to county roads were suffered to PWN disease. The results could serve the regional monitoring of pine nematode disease occurrence and provide practical guidance for PWN disease management.

[Effects of Land Use Structure and Spatial Pattern at Different Temporal and Spatial Scales on Water Quality in Suzhou Creek].

Relationships between land use and water quality of rivers and lakes vary spatially and temporally. These variations were analyzed using spatial analysis and mathematical statistical methods for the Suzhou Creek in Shanghai. Based on the data of water quality and land use in 2001， 2005， 2010， 2015， and 2020， five spatial scales （200， 500， 1 000， 2 000， and 5 000 m reach buffer） of the landscape pattern were extracted using correlation and redundancy analysis to explore the impact of land use composition and spatial pattern on water quality at different spatial and temporal scales. The results showed that： ① the water quality of Suzhou Creek has gradually improved in the past 20 years； other indicators were between Class II to Class IV in 2020 except TN， and TN was the main pollutant. ② The main land use type of the buffer zone was construction land， and the proportion of greenland and woodland showed a small growth trend. ③ The water quality was closely related to landscape pattern， showing temporal and spatial scale effects. On the time scale， indicators such as construction land， agricultural land， landscape dominance， aggregation， and diversity had significant correlations with various water quality parameters， and there was an inverse correlation in 2010 compared with that in other years for NH4+-N， TP， and TN. The landscape pattern in 2001 had the greatest explanation for water quality， with an explanation rate of 93.65%. The impact of greenland and woodland on water quality has begun to emerge in the past 10 years. ④ On the spatial scale， there were significant correlations between greenland and woodland， patch number， landscape shape index， diversity index， and water quality. There was a strong positive regulatory effect of greenland and woodland on NH4+-N， TP， and TN at the scale of 2 000 m. The patch number and landscape shape index had relatively strong regulatory effects on water quality on a larger spatial scale， whereas the Shannon diversity index had a better positive regulatory effect on water quality on a small scale. The landscape pattern within a buffer of 2 000 m had the highest interpretation degree for all factors， with an explanation rate of 68.47%. The study showed that rationally planning the proportion of greenland and woodland within the 2 000 m buffer zone and optimizing its landscape configuration is an important measure to purify the surface water quality of Suzhou Creek.

LncRNA AL645608.3 mediates malignant progression of acute myeloid leukemia.

OBJECTIVE: To investigate the role of lncRNA AL645608.3 in the malignant progression of acute myeloid leukemia (AML) cells and explore relevant molecular mechanisms. METHODS: The expression level of AL645608.3 was measured in AML cell lines (THP-1, HL-60, KG-1, and AML-193) via real-time quantitative polymerase chain reaction (RT-qPCR). Small hairpin RNA (shRNA) and open reading frame of AL645608.3 were cloned into lentiviral vectors and were infected into THP-1 and AML-193 cells. The expression of casitas B-lineage lymphoma (CBL), interferon regulatory factor 6 (IRF6), and interferon beta 1 (IFNB1) was detected through RT-qPCR, and western blot. Co-immunoprecipitation (Co-IP) on IRF6 was conducted. Matrix metalloprotease-9 (MMP-9) activity was evaluated via gelatin zymography assay. RESULTS: LncRNA AL645608.3 was expressed in the four AML cell lines (THP-1, HL-60, KG-1, and AML-193). Silencing AL645608.3 mitigated the expression of IRF6 and IFNB1 but elevated the expression of CBL in THP-1 cells. Oppositely, AL645608.3 overexpression up-regulated the expression of IRF6 and IFNB1 but decreased the expression of CBL in AML-193 cells. Co-IP results proved that AL645608.3 could directly mediate IRF6 activity in THP-1 and AML-193 cells. MMP-9 activity was decreased by AL645608.3 knockdown and was improved by AL645608.3 overexpression in AML-193 cells. CONCLUSION: AL645608.3 is expressed in different AML cell lines, and mediates the expression of CBL, IRF6, IFNB1, and MMP-9. These findings might deepen our comprehension of the molecular mechanisms underlying AML.

Explainable cancer factors discovery: Shapley additive explanation for machine learning models demonstrates the best practices in the case of pancreatic cancer.

Pancreatic cancer is one of digestive tract cancers with high mortality rate. Despite the wide range of available treatments and improvements in surgery, chemotherapy, and radiation therapy, the five-year prognosis for individuals diagnosed pancreatic cancer remains poor. There is still research to be done to see if immunotherapy may be used to treat pancreatic cancer. The goals of our research were to comprehend the tumor microenvironment of pancreatic cancer, found a useful biomarker to assess the prognosis of patients, and investigated its biological relevance. In this paper, machine learning methods such as random forest were fused with weighted gene co-expression networks for screening hub immune-related genes (hub-IRGs). LASSO regression model was used to further work. Thus, we got eight hub-IRGs. Based on hub-IRGs, we created a prognosis risk prediction model for PAAD that can stratify accurately and produce a prognostic risk score (IRG_Score) for each patient. In the raw data set and the validation data set, the five-year area under the curve (AUC) for this model was 0.9 and 0.7, respectively. And shapley additive explanation (SHAP) portrayed the importance of prognostic risk prediction influencing factors from a machine learning perspective to obtain the most influential certain gene (or clinical factor). The five most important factors were TRIM67, CORT, PSPN, SCAMP5, RFXAP, all of which are genes. In summary, the eight hub-IRGs had accurate risk prediction performance and biological significance, which was validated in other cancers. The result of SHAP helped to understand the molecular mechanism of pancreatic cancer.

Reconstructive interpolation for pulse wave estimation to improve local PWV measurement of carotid artery.

Ultrasonic transit time (TT)-based local pulse wave velocity (PWV) measurement is defined as the distance between two beam positions on a segment of common carotid artery (CCA) divided by the TT in the pulse wave propagation. However, the arterial wall motions (AWMs) estimated from ultrasonic radio frequency (RF) signals with a limited number of frames using the motion tracking are typically discrete. In this work, we develop a method involving motion tracking combined with reconstructive interpolation (MTRI) to reduce the quantification errors in the estimated PWs, and thereby improve the accuracy of the TT-based local PWV measurement for CCA. For each beam position, normalized cross-correlation functions (NCCFs) between the reference (the first frame) and comparison (the remaining frames) RF signals are calculated. Thereafter, the reconstructive interpolation is performed in the neighborhood of the NCCFs' peak to identify the interpolation-deduced peak locations, which are more exact than the original ones. According to which, the improved AWMs are obtained to calculate their TT along a segment of the CCA. Finally, the local PWV is measured by applying a linear regression fit to the time-distance result. In ultrasound simulations based on the pulse wave propagation models of young, middle-aged, and elderly groups, the MTRI method with different numbers of interpolated samples was used to estimate AWMs and local PWVs. Normalized root mean squared errors (NRMSEs) between the estimated and preset values of the AWMs and local PWVs were calculated and compared with ones without interpolation. The means of the NRMSEs for the AWMs and local PWVs based on the MTRI method with one interpolated sample decrease from 1.14% to 0.60% and 7.48% to 4.61%, respectively. Moreover, Bland-Altman analysis and coefficient of variation were used to validate the performance of the MTRI method based on the measured local PWVs of 30 healthy subjects. In conclusion, the reconstructive interpolation for the pulse wave estimation improves the accuracy and repeatability of the carotid local PWV measurement.

Mitochondrial DNA copy number plays opposing roles in T-lymphocyte infiltration of colorectal cancer based on mismatch repair status: new directions for immunotherapy?

BACKGROUND: Researchers have previously reported that mitochondrial DNA copy number (mtDNA-CN) can play different roles in microsatellite instable/mismatch repair-deficient (MSI/dMMR) and microsatellite stable/mismatch repair-proficient (MSS/pMMR) colorectal cancer (CRC). To support malignancy, dMMR CRC relies on glycolysis, while pMMR CRC favors oxidative phosphorylation. However, it is unclear whether mtDNA-CN changes are related to T cell infiltration in CRC. METHODS: The mtDNA-CN was detected by qRT-PCR in 532 patients, and the expression of CD3 and CD8 in 485 patients was detected by immunohistochemistry. The correlation between mtDNA-CN and the prognosis of CRC patients was further analyzed, and the correlation between mtDNA-CN and T lymphocyte infiltration was also analyzed. Biopsy specimens from the immune checkpoint inhibitors (ICIs) treatment cohort were obtained to verify the correlation between mtDNA-CN and the efficacy of ICIs. The effects of mtDNA-CN and MMR status on gene expression were analyzed by RNA-seq. RESULTS: Our results show that mtDNA-CN has inverse relationships to CRC prognosis in cases with different MMR statuses, potentially inducing the U-shaped association in CRC. The opposing correlations between mtDNA-CN and T lymphocyte infiltration in cases of dMMR CRC and pMMR CRC further suggest that mtDNA-CN might play an important role in CRC development. More importantly, cases of pMMR CRC with lower mtDNA-CN and of dMMR CRC with higher mtDNA-CN can benefit more dramatically from ICIs. Furthermore, RNA-seq revealed a link between the level of mtDNA-CN and T lymphocyte infiltration in CRC cases with different MMR statuses. CONCLUSION: Our study found a potential relationship between mtDNA-CN and CRC development that differs by MMR status, potentially providing a rationale for the use of mtDNA-CN as both a predictive biomarker and a therapeutic target for ICIs.

MRI-defined T3, clear mesorectal fascia mid-low rectal cancer: is neoadjuvant treatment necessary?

AIM: Neoadjuvant treatments (nCRT) are becoming the standard treatment for patients with stage II or III mid-low rectal cancer. Recently, some studies have shown that surgery alone may be sufficient for patients with T3 rectal cancer. This raises the question of whether nCRT is necessary for all patients with T3 rectal cancer. Therefore, this study compared the clinical outcomes of patients with MRI-defined T3, clear MRF mid-low rectal cancer treated with surgery alone (TME group) or nCRT followed by surgery (nCRT + TME group). METHODS: A total of 1509 patients were enrolled in this study. After a 1:1 propensity score matching analysis, 480 patients were included in each group. The primary endpoint was 3-year disease-free survival (DFS). The secondary endpoints included the perioperative outcomes, histopathologic outcomes, and other follow-up outcomes. RESULTS: nCRT had advantages in rates of sphincter-preserving surgery and tumor downstaging, but it was accompanied by a higher rate of enterostomies. At 3 years after surgery, local recurrence occurred in 3.3% of patients in the TME group and in 3.5% of patients in the nCRT + TME group (P = 0.914), the DFS rates were 78.3% in the TME group and 75.3% in the nCRT + TME group (P = 0.188), and the overall survival rates were 90.3% in the TME group and 89.9% in the nCRT + TME group (P = 0.776). CONCLUSIONS: Surgery alone versus nCRT followed by surgery may provide similar long-term oncological outcomes for patients with MRI-defined T3, clear MRF, and mid-low rectal cancer. nCRT may cause overtreatment in some patients.

Effects of tumour budding on adjuvant chemotherapy in colorectal cancer.

BACKGROUND: High tumour budding has been indicated as a risk factor of poor survival in colorectal cancer. This study aimed to investigate the impact of tumour budding grades and the use of adjuvant chemotherapy on prognosis in patients with colorectal cancer. METHODS: This study included consecutive colorectal cancer patients who underwent radical surgery for primary colorectal adenocarcinoma at The Sixth Hospital of Sun Yat-sen University between 2009 and 2019. Tumour budding was assessed based on the recommendations of the International Tumor Budding Consensus Conference using haematoxylin and eosin (H&E)-stained slides with tumour samples. The primary outcome of interest was to correlate tumour budding with disease-free survival and overall survival; the secondary outcome was investigation of the impact of adjuvant therapy on different tumour budding grades. In addition, a subgroup analysis was performed for the effects of lymphocytic infiltration on adjuvant chemotherapy in patients with Bd3. RESULTS: Of 709 eligible patients, 412 with colorectal cancer were included. According to the International Tumor Budding Consensus Conference, 210 (50.9 per cent), 127 (30.8 per cent) and 75 (18.2 per cent) were classified as low budding (Bd1), intermediate budding (Bd2) and high budding (Bd3) respectively. Patients with Bd1, Bd2 and Bd3 had 5-year disease-free survival rates of 82.9 per cent, 70.1 per cent and 49.3 per cent respectively, and 5-year overall survival rates of 90 per cent, 79.5 per cent and 62.7 per cent respectively (P <0.001). Adjuvant chemotherapy yielded a significant survival benefit in patients with Bd3 (5-year disease-free survival, 65 per cent versus 31.4 per cent, P <0.001; 5-year overall survival, 84.4 per cent versus 63.1 per cent, P <0.001), but not in those with Bd1 or Bd2. In patients with Bd3, the benefit of adjuvant chemotherapy was maintained in those with low, but not high lymphocytic infiltration. CONCLUSION: High grade of tumour budding was strongly correlated with poorer survival outcomes in colorectal cancer. Patients with Bd3 benefited from adjuvant chemotherapy, with the exclusion of patients with high lymphocytic infiltration.

Mutant KRAS-activated circATXN7 fosters tumor immunoescape by sensitizing tumor-specific T cells to activation-induced cell death.

Mutant KRAS (KRASMUT) is often exploited by cancers to shape tumor immunity, but the underlying mechanisms are not fully understood. Here we report that tumor-specific cytotoxic T lymphocytes (CTLs) from KRASMUT cancers are sensitive to activation-induced cell death (AICD). circATXN7, an NF-κB-interacting circular RNA, governs T cell sensitivity to AICD by inactivating NF-κB. Mechanistically, histone lactylation derived from KRASMUT tumor cell-produced lactic acid directly activates transcription of circATXN7, which binds to NF-κB p65 subunit and masks the p65 nuclear localization signal motif, thereby sequestering it in the cytoplasm. Clinically, circATXN7 upregulation in tumor-specific CTLs correlates with adverse clinical outcomes and immunotherapeutic resistance. Genetic ablation of circAtxn7 in CD8+ T cells leads to mutant-selective tumor inhibition, while also increases anti-PD1 efficacy in multiple tumor models in female mice. Furthermore, targeting circATXN7 in adoptively transferred tumor-reactive CTLs improves their antitumor activities. These findings provide insight into how lymphocyte-expressed circRNAs contribute to T-cell fate decisions and anticancer immunotherapies.

Dreaming during gastrointestinal endoscopy under propofol, ciprofol, or remimazolam anesthesia: study protocol for a parallel-design double-blind, single-center trial.

BACKGROUND: Dreaming sometimes occurs during sedation. It has been reported that factors such as different anesthetics, depth of anesthesia, age, sex, and preoperative psychological state may affect dreams. Ciprofol and remimazolam are novel choices for painless endoscopy. Herein, we aimed to investigate dreaming during gastrointestinal endoscopy under propofol, ciprofol, and remimazolam anesthesia respectively. METHODS: This is a prospective, parallel-design double-blind, single-center clinical trial. Three hundred and sixty subjects undergoing elective painless gastroscopy, colonoscopy, or gastroenteroscopy will be enrolled. Eligible subjects will undergo propofol-, ciprofol-, or remimazolam-induced anesthesia to finish the examination. Interviews about the modified Brice questionnaire will be conducted in the recovery room. Incidence of dreaming is set as the primary outcome. Secondary outcomes include type of dreams, improvement of sleep quality, evaluation of patients, incidence of insufficient anesthesia, and intraoperative awareness. Safety outcomes are the incidences of hypotension and hypoxia during examination and adverse events during recovery. DISCUSSION: This study may observe different incidences of dreaming and diverse types of dreams, which might lead to different evaluations to the anesthesia procedure. Based on the coming results, anesthesiologists can make a better medication plan for patients who are going to undergo painless diagnosis and treatment. TRIAL REGISTRATION: This trial was registered at the Chinese Clinical Trial Registry on May 18, 2023 (registration number ChiCTR2300071565).

circGlis3 promotes ß-cell dysfunction by binding to heterogeneous nuclear ribonucleoprotein F and encoding Glis3-348aa protein.

Circular RNAs (circRNAs) are crucial regulators of ß-cell function and are involved in lipotoxicity-induced ß-cell damage in type 2 diabetes mellitus (T2DM). We previously identified that circGlis3, a circRNA derived from exon 4 of the diabetes susceptibility gene Glis3, was upregulated in lipotoxic ß cells. However, the functional role and molecular mechanism of circGlis3 in ß cells remain largely unknown. Here, we revealed that the splicing factor CUGBP Elav-Like Family Member 1 (CELF1) facilitated the biogenesis of circGlis3. Moreover, we established a transgenic mouse model and confirmed that the overexpression of circGlis3 impaired ß-cell function. Mechanistically, circGlis3 bound to heterogeneous nuclear ribonucleoprotein F (hnRNPF) and blocked its nuclear translocation, thereby reducing Sirt1 levels. Additionally, circGlis3 encoded a 348aa protein that interacted with GLIS3 and inhibited its transcriptional activity. Our data uncover a critical role of circGlis3 in ß-cell dysfunction, suggesting that circGlis3 may be a potential therapeutic target for T2DM.

Sacrificial-Hydroxamate-Enabled Sizable Crystallization of Scandium Carboxylate Metal-Organic Frameworks.

Starting from labile hydroxamic acid ligands that are strong chelators, here, we implemented a sacrificial modulating strategy to prepare a series of scandium carboxylate metal-organic frameworks. Overcoming conventional syntheses that use excessive carboxylate modulators, the present strategy greatly reduces the organics required and produces large single crystals of several Sc-MOFs for X-ray crystallography.

TBK1 upregulates the interferon response against virus by the TBK1-IRF3/7 axis in yellow catfish (Pelteobagrus fulvidraco).

Yellow catfish (Pelteobagrus fulvidraco) is an important economic species of freshwater fish, widely distributed in China. Recently, viral diseases of yellow catfish have been identified in Chian (Hubei province), arising more attention to the viral immunity in P. fulvidraco. Tumor necrosis factor (TNF) receptor-associated factor NF-κB activator (TANK)-binding kinase 1 (TBK1) plays an essential role in IFN production and innate antiviral immunity. In the present study, we characterized the P. fulvidraco TBK1 (PfTBK1) and reported its function in interferon response. The full-length open reading frame (ORF) is 2184 bp encoding a protein with 727 amino acids, which is composed of four conserved domains, including KD, ULD, CCD1, and CCD2, similar to TBK1 in other species. Pftbk1 was widely expressed in all detected tissues by qPCR and was not inducible by the spring viremia of carp virus (SVCV), a single-strand RNA virus. In addition, the cellular distribution indicated that PfTBK1 was only located in the cytoplasm. Moreover, PfTBK1 induced strong IFN promoter activities through the Jak-stat pathway, and PfTBK1 interacted with and significantly phosphorylated IFN regulatory factor 3/7 (IRF3/7) in P. fulvidraco, promoting the nuclear translocation of pfIRF3 and PfIRF7, and PfTBK1 upregulated IFN response by PfTBK1-PfIRF3/7 axis. Above all, PfTBK1 triggered IFN response and strongly inhibited the replication of SVCV in EPC cells through induction of IFN downstream IFN-stimulated genes (ISGs). Summarily, this work reveals that PfTBK1 plays a positive regulatory role in IFN induction through the TBK1-IRF3/7 axis, laying a foundation for further exploring the molecular mechanism of the antiviral process in P. fulvidraco.