Lactate modulates RNA splicing to promote CTLA-4 expression in tumor-infiltrating regulatory T cells.

RNA splicing is involved in cancer initiation and progression, but how it influences host antitumor immunity in the metabolically abnormal tumor microenvironment (TME) remains unclear. Here, we demonstrate that lactate modulates Foxp3-dependent RNA splicing to maintain the phenotypic and functional status of tumor-infiltrating regulatory T (Treg) cells via CTLA-4. RNA splicing in Treg cells was correlated with the Treg cell signatures in the TME. Ubiquitin-specific peptidase 39 (USP39), a component of the RNA splicing machinery, maintained RNA-splicing-mediated CTLA-4 expression to control Treg cell function. Mechanistically, lactate promoted USP39-mediated RNA splicing to facilitate CTLA-4 expression in a Foxp3-dependent manner. Moreover, the efficiency of CTLA-4 RNA splicing was increased in tumor-infiltrating Treg cells from patients with colorectal cancer. These findings highlight the immunological relevance of RNA splicing in Treg cells and provide important insights into the environmental mechanism governing CTLA-4 expression in Treg cells.

Effects of Clip Anchoring on Preventing Migration of Fully Covered Self-Expandable Metal Stent in Patients Undergoing Endoscopic Retrograde Cholangiopancreatography: A Multicenter, Randomized Controlled Study.

INTRODUCTION: Fully covered self-expandable metal stents (FCSEMSs) are commonly placed in patients with biliary stricture during endoscopic retrograde cholangiopancreatography (ERCP). However, up to 40% of migration has been reported, resulting in treatment failure or the requirement for further intervention. Here, we aimed to investigate the effects of metal clip anchoring on preventing the migration of FCSEMS. METHODS: Consecutive patients requiring placement of FCSEMS were included in this multicenter randomized trial. The enrolled patients were randomly assigned in a 1:1 ratio to receive clip anchoring (clip group) or not (control group). The primary outcome was the migration rate at 6 months after stent insertion. The secondary outcomes were the rates of proximal and distal migration and stent-related adverse events. The analysis followed the intention-to-treat principle. RESULTS: From February 2020 to November 2022, 180 patients with biliary stricture were enrolled, with 90 in each group. The baseline characteristics were comparable between the 2 groups. The overall rate of stent migration at 6 months was significantly lower in the clip group compared with the control group (16.7% vs 30.0%, P = 0.030). The proximal and distal migration rates were similar in the 2 groups (2.2% vs 5.6%, P = 0.205; 14.4% vs 22.2%, P = 0.070). Notably, none of the patients (0/8) who received 2 or more clips experienced stent migration. There were no significant differences in stent-related adverse events between the 2 groups. DISCUSSION: Our data suggest that clip-assisted anchoring is an effective and safe method for preventing migration of FCSEMS without increasing the adverse events.

Nursing students'experience of flipped classroom combined with problem-based learning in a paediatric nursing course: a qualitative study.

BACKGROUND: Problem-based learning (PBL) is a student-centred approach that triggers learning by presenting problems cenarios early in the learning process.Flipped classrooms have been used in various disciplines using various models.Pre-class e- learning in aflipped classrooms can enrich knowledge acquisition in PBL teaching. This study was conducted to explore nursing students'experience of flipped classroom combined with problem-based learning in a paediatric nursing course. METHOD: This descriptive qualitative study was conducted between January and June 2022.Semi-structured interviews were conducted with nursing students who were participated in flipped classrooms combined with PBL teaching in a paediatric nursing course at Soochow university in China. Nursing students were selected using a purposive sampling method until no new data were generated (n = 16). RESULTS: We identified ten sub-themes and four higher-order themes based on these sub-themes: (1)stimulating interest in learning and enhancing autonomous learning,(2)improving independent thinking and problem-solving skills,(3)cultivating team work spirit, and (4) gaining knowledge and improving skills.The findings of our research contribute to show the effectiveness of the flipped classroom combined with PBL in a paediatric nursing course. CONCLUSION: The flipped classroom combined with PBL in a paediatric nursing course can enhances communication and cooperation abilities among nursing students, promoting common progress and the comprehensive development of nursing students.

Individualized Positive End-expiratory Pressure on Postoperative Atelectasis in Patients with Obesity: A Randomized Controlled Clinical Trial.

BACKGROUND: Individualized positive end-expiratory pressure (PEEP) guided by dynamic compliance improves oxygenation and reduces postoperative atelectasis in nonobese patients. The authors hypothesized that dynamic compliance-guided PEEP could also reduce postoperative atelectasis in patients undergoing bariatric surgery. METHODS: Patients scheduled to undergo laparoscopic bariatric surgery were eligible. Dynamic compliance-guided PEEP titration was conducted in all patients using a downward approach. A recruitment maneuver (PEEP from 10 to 25 cm H2O at 5-cm H2O step every 30 s, with 15-cm H2O driving pressure) was conducted both before and after the titration. Patients were then randomized (1:1) to undergo surgery under dynamic compliance-guided PEEP (PEEP with highest dynamic compliance plus 2 cm H2O) or PEEP of 8 cm H2O. The primary outcome was postoperative atelectasis, as assessed with computed tomography at 60 to 90 min after extubation, and expressed as percentage to total lung tissue volume. Secondary outcomes included Pao2/inspiratory oxygen fraction (Fio2) and postoperative pulmonary complications. RESULTS: Forty patients (mean ± SD; 28 ± 7 yr of age; 25 females; average body mass index, 41.0 ± 4.7 kg/m2) were enrolled. Median PEEP with highest dynamic compliance during titration was 15 cm H2O (interquartile range, 13 to 17; range, 8 to 19) in the entire sample of 40 patients. The primary outcome of postoperative atelectasis (available in 19 patients in each group) was 13.1 ± 5.3% and 9.5 ± 4.3% in the PEEP of 8 cm H2O and dynamic compliance-guided PEEP groups, respectively (intergroup difference, 3.7%; 95% CI, 0.5 to 6.8%; P = 0.025). Pao2/Fio2 at 1 h after pneumoperitoneum was higher in the dynamic compliance-guided PEEP group (397 vs. 337 mmHg; group difference, 60; 95% CI, 9 to 111; P = 0.017) but did not differ between the two groups 30 min after extubation (359 vs. 375 mmHg; group difference, -17; 95% CI, -53 to 21; P = 0.183). The incidence of postoperative pulmonary complications was 4 of 20 in both groups. CONCLUSIONS: Postoperative atelectasis was lower in patients undergoing laparoscopic bariatric surgery under dynamic compliance-guided PEEP versus PEEP of 8 cm H2O. Postoperative Pao2/Fio2 did not differ between the two groups.

Evolutionary research trend of Polygonatum species: a comprehensive account of their transformation from traditional medicines to functional foods.

With the advances in Polygonatum research, there is a huge interest in harnessing the valuable functional ingredients of this genus with the potential for functional foods. This review emphasizes the different aspects of Ploygonatum based research starting from its bioactive compounds, their structural characterization, various extraction methods, as well as biological activities. In view of its integral use as an essential medicinal plant, our review emphasizes on its promising food applications both as an ingredient and as a whole food, and its improved health benefits with potential for agricultural and environmental relevance are also discussed. As we collated the recent research information, we present the main challenges and limitations of the current research trend in this area which can upgrade the further expansion of Polygonatum-related research that will strengthen its economic and accessible nutritional value in the food and health industries. By highlighting the need for the unattended species, this review not only fills existing research gaps, but also encourages the researchers to find new avenues for the natural production of bio-based functional materials and the development of highly functional and health-promoting foods for disease prevention and treatment.

Lycium barbarum (Goji) as functional food: a review of its nutrition, phytochemical structure, biological features, and food industry prospects.

Lycium genus (Goji berry) is recognized as a good source of homology of medicine and food, with various nutrients and phytochemicals. Lately, numerous studies have focused on the chemical constituents and biological functions of the L. barbarum L., covering phytochemical and pharmacological aspects. We aim to provide exclusive data on the nutrients of L. barbarum L. fruits and phytochemicals, including their structural characterization, the evolution of extraction, and purification processes of different phytochemicals of L. barbarum L. fruit while placing greater emphasis on their wide-ranging health effects. This review also profitably offers innovative approaches for the food industry and industrial applications of L. barbarum L. and addresses some current situations and problems in the development of L. barbarum L. in deep processing products, which can provide clues for the sustainable development of L. barbarum L. industry.

Post-traumatic growth in caregivers of children hospitalized in the PICU due to traffic accident: a qualitative study.

BACKGROUND: Globally, tens of millions of children are hospitalized every year for non-fatal traffic accident injuries, being confronted with an injured child can be extremely stressful for parents. Understandably, a significant level of psychological distress may ensue. Traumatic losses may lead parents to find new insights in life and develop a greater sense of spirituality and strength. METHOD: Semi-structured interviews were conducted with caregivers of children who were hospitalized in the pediatric intensive care unit (PICU) with traffic accident injuries at children's hospitals in China between January and June 2022. Caregivers were selected using a purposive sampling method until no new data were generated (n = 24). RESULTS: We identified eleven sub-themes and four higher-order themes based on these sub-themes: (1) changes in their life philosophy, (2) personal strength enhancement, (3) relationship improvements, and (4) effective responses. The findings of our research contribute to a better understanding of the psychological status of the caregivers of children injured by traffic accidents. CONCLUSION: Professionals should guide caregivers from a positive perspective, stimulate their strengths and potential, increase personnel support and communication, promote positive coping, formulate targeted management countermeasures to improve the PTG level of caregivers, and develop strategies to maintain stable mental health and well-being.

E2F family play important roles in tumorigenesis.

Tumors are serious threats to human health. The transcription factors are regarded as the potential targets for tumor treatment. As an important family of transcription factors, E2F family transcription factors (E2Fs) play vital roles in cell proliferation and regulation. However, the expression feature, gene functions, and molecular interactions of E2Fs in tumorigenesis are not clear. In this study, the transcriptome data, mutation data, and protein-protein interaction data of 10 high-incidence tumors in China from the TCGA database were integrated and analyzed to explore the expression, structure, function, mutation, and phylogenetic characteristics of E2Fs. The results showed that E2F1 and E2F7 were regularly upregulated in the tumor samples. Moreover, E2Fs participated in the regulation of the cell cycle, cell aging, and other signaling pathways. As an important regulator, E2F1 interacted with more proteins than other E2Fs. At the same time, the genetic mutation types of E2Fs varied in tumor type and patient sex, of which gene amplification accounts for the largest proportion. Phylogenetic analysis showed that E2Fs were conserved in 41 species, including fruit flies, nematodes, and humans. Meanwhile, E2Fs had a tendency for gene expansion during evolution. In conclusion, this study clarified the expression pattern, mutation characteristics, and evolutionary trend of E2Fs in high-incidence tumors in China, and suggested that E2F family transcription factors could be novel diagnostic markers for tumor diseases. Furthermore, this work can provide a theoretical basis for the development of anti-tumor-targeted drugs.

Mode selection in InGaAs/InGaAsP quantum well photonic crystal lasers based on coupled double-heterostructure cavities.

Photonic crystal lasers with a high-Q factor and small mode volume are ideal light sources for on-chip nano-photonic integration. Due to the submicron size of their active region, it is usually difficult to achieve high output power and single-mode lasing at the same time. In this work, we demonstrate well-selected single-mode lasing in a line-defect photonic crystal cavity by coupling it to the high-Q modes of a short double-heterostructure photonic crystal cavity. One of the FP-like modes of the line-defect cavity can be selected to lase by thermo-optically tuning the high-Q mode of the short cavity into resonance. Six FP-like modes are successively tuned into lasing with side mode suppression ratios all exceeding 15 dB. Furthermore, we show a continuous wavelength tunability of about 10 nm from all the selected modes. The coupled cavity system provides a remarkable platform to explore the rich laser physics through the spatial modulation of vacuum electromagnetic field at submicron scale.

Exploration of walnut components and their association with health effects.

Traditionally, walnuts have occupied an imperative position in the functional food market with consistently recognized nutritious and functional properties. In the past years, the lipid profile of walnuts has brought much scientific attention via linking a cascade of biological attributes and health-promoting effects. Over time, researchers have focused on diversified composition (polyphenols and vitamins) of different parts of walnut (flower, pellicle, and kernel) and emphasized their physiological significance. Consequently, a plethora of reports has emerged on the potential role of walnut consumption against a series of diseases including cancer, gut dysbiosis, cardiovascular, and neurodegenerative diseases. Therefore, we accumulated the updated data on composition and classification, extraction methods, and utilization of different parts of walnuts as well as associated beneficial effects under in vivo and clinical studies. Altogether, this review summarized the ameliorative effects of a walnut-enriched diet in chronic diseases which can be designated to the synergistic or individual effects of walnut components mainly through anti-oxidative and anti-inflammatory role.

Effects of individualized positive end-expiratory pressure combined with recruitment maneuver on intraoperative ventilation during abdominal surgery: a systematic review and network meta-analysis of randomized controlled trials.

Low tidal volume ventilation strategy may lead to atelectasis without proper positive end-expiratory pressure (PEEP) and recruitment maneuver (RM) settings. RM followed by individualized PEEP was a new method to optimize the intraoperative pulmonary function. We conducted a systematic review and network meta-analysis of randomized clinical trials to compare the effects of individualized PEEP + RM on intraoperative pulmonary function and hemodynamic with other PEEP and RM settings. The primary outcomes were intraoperative oxygenation index and dynamic compliance, while the secondary outcomes were intraoperative heart rate and mean arterial pressure. In total, we identified 15 clinical trials containing 36 randomized groups with 3634 participants. Ventilation strategies were divided into eight groups by four PEEP (L: low, M: moderate, H: high, and I: individualized) and two RM (yes or no) settings. The main results showed that IPEEP + RM group was superior to all other groups regarding to both oxygenation index and dynamic compliance. LPEEP group was inferior to LPEEP + RM, MPEEP, MPEEP + RM, and IPEEP + RM in terms of oxygenation index and LPEEP + RM, MPEEP, MPEEP + RM, HPEEP + RM, IPEEP, and IPEEP + RM in terms of dynamic compliance. All comparisons were similar for secondary outcomes. Our analysis suggested that individualized PEEP and RM may be the optimal low tidal volume ventilation strategy at present, while low PEEP without RM is not suggested.

Paediatric oncology ward nurses' experiences of patients' deaths in China: A qualitative study.

BACKGROUND: Considering cancer death is second only to accidental death in the number of lives claimed each year,nurses in paediatric oncology wards often experience helplessness, sadness, frustration and such other adverse emotions when they witness children's death due to cancer.However,there is a lack of qualitative studies on nurses who witness the death of children in paediatric oncology wards in China. METHOD: A qualitative study was conducted using a semi-structured interview guide with 22 paediatric oncology ward nurses. Interviews were recorded and simultaneously translated and transcribed. Thematic analysis was used to analyse the data. RESULTS: The analysis resulted in the identification of three main thematic categories: Different emotional expression, Different copingstrategies, A weak support system. Nursing managers should pay attention to problems faced by nurses in paediatric oncology wards, and take targeted measures in terms of continuing training courses, improving the psychological adaptability of oncology professional nurses, and providing them substantive support. CONCLUSION: Nurses in paediatric oncology wards have strong stress responses to facing the death of children. They reported experiencing complex psychological feelings and have different coping attitudes. Healthcare authorities should recognise and understand the needs of paediatric oncology ward nurses, who often witness the death of children. Appropriate and effective support measures should be planned and implemented for these nurses to maintain their mental health, thus enabling them to better serve patients.

Imidazo[1,2-a]pyridin-6-yl-benzamide analogs as potent RAF inhibitors.

A series of imidazo[1,2-a]pyridin-6-yl-benzamide analogs was designed as inhibitors of B-RAFV600E. Medicinal chemistry techniques were employed to explore the SAR for this series and improve selectivity versus P38 and VEGFR2.

Xylomexicanins I and J: Limonoids with Unusual B/C Rings from Xylocarpus granatum.

Two tetranortriterpenoids with new skeletons, xylomexicanins I and J (1 and 2), were isolated during the investigation of chemical constituents from seeds of the Chinese mangrove, Xylocarpus granatum. Xylomexicanin I (1) is an unprecedented limonoid with bridged B- and C-rings. A biosynthesis pathway for 1 from xylomexicanin F is proposed.

Discovery of imidazo[1,2-a]-pyridine inhibitors of pan-PI3 kinases that are efficacious in a mouse xenograft model.

Alterations in PI3K/AKT signaling are known to be implicated with tumorigenesis. The PI3 kinases family of lipid kinases has been an attractive therapeutic target for cancer treatment. Imidazopyridine compound 1, a potent, selective, and orally available pan-PI3K inhibitor, identified by scaffold morphing of a benzothiazole hit, was further optimized in order to achieve efficacy in a PTEN-deleted A2780 ovarian cancer mouse xenograft model. With a hypothesis that a planar conformation between the core and the 6-heteroaryl ring will allow for the accommodation of larger 5'-substituents in a hydrophobic area under P-loop, SAR efforts focused on 5'-alkoxy heteroaryl rings at the 6-position of imidazopyridine and imidazopyridazine cores that have the same dihedral angle of zero degrees. 6'-Alkoxy 5'-aminopyrazines in the imidazopyridine series were identified as the most potent compounds in the A2780 cell line. Compound 14 with 1,1,1-trifluoroisopropoxy group at 6'-position demonstrated excellent potency and selectivity, good oral exposure in rats and in vivo efficacy in A2780 tumor-bearing mouse. Also, we disclose the X-ray co-crystal structure of one enantiomer of compound 14 in PI3Kα, confirming that the trifluoromethyl group fits nicely in the hydrophobic hot spot under P-loop.

[Research on Temporal and Spatial Evolution of Reheating Double-Pulse Laser-Induced Plasma].

In order to investigate the emission enhancement mechanisms of reheating Double Pulse Laser-Induced Breakdown Spectroscopy (DP-LIBS), single pulse LIBS (SP-LIBS) and reheating DP-LIBS were carried out on an alloy steel sample respectively. The plasma emission was collected by an Echelle spectrometer with high resolution, while the plasma structure was monitored via fast-photography. The temporal and spatial evolutio ns of the plasma generated by SP-LIBS and reheating DP-LIBS were being studied. It is found that the plasma temperature in reheating DP-LIBS was higher than that of SP-LIBS, and there was a turning point for the decay rate of plasma temperature in reheating DP-LIBS when the delay time was equal to the interpulse time of DP-LIBS. Moreover, the inte nsity of the plasma image was increased by reheating DP-LIBS, and the height and width of the central region of the plasma were increased about 23.5% and 15.1% respectively. The results of spatial distribution showed that the intensity of Fe II and N I lines in the plasma were obviously enhanced by reheating DP-LIBS when the distance from the sample surface was larger than 0.6 mm. While the intensity enhancement for Fe I lines were little, even in some positio ns the intensity of Fe I lines decreased. The plasma temperature of double-pulse configuration was about 2 000 K higher than that of SP-LIBS, and a larger hot region in the plasma was generated. It is evidenced that the emission enhancement mechanisms in reheating DP-LIBS is that the second laser pulse re-excited the plasma induced by the first laser pulse, and the higher plasma temperature resulted from the re-exciting process.

[The Detection of Raman Spectra on Dissolved Gas in Transformer Oil and Its Spectral Linear Model Analysis].

Raman spectroscopy gas detection technology which uses a single wavelength laser detection of gas samples without contact and loss is suitable for dissolved gas detection in oil-immersed transformers. Combined with the features of Raman spectral lines, the analysis of the detection mechanism in Raman spectroscopy technology has been made. Raman spectral lines have been presented in the expression of the convolution of Lorentz function and Gaussian function, which shows preferable Raman spectrum peak linear outline basic characteristics. In this paper, the basic features of the peak height, the peak position and the half peak width, are the main targets of peak searching, and the fundamental purpose of this paper is to obtain qualitative and quantitative analysis of the sample. Therefore, the experimental data of Raman spectroscopy is designed based on the comparison method to realize the automatic peak seeking model to achieve the detection target. Therefore, according to the automatic peak searching model based on the comparison method is designed to achieve the detection target. The simulation results of using peak searching model in the Voigt linear model show that spectrum peak height and peak position are in conformity with the theory in the test experiment. Based on the establishment of Raman spectroscopy detection platform aiming at the dissolved gas in transformer oil, the analysis of the experimental data show that the actual values of the half peak height and width are (8.7，11.5)(cm-1)in the Voigt linear model with deviations. Setting the value as 10.257 cm-1 to modify the parameter, then compared with the research results, it shows that the modified Voigt linear model and the peak searching model have better adaptability and practicability. Combined with the gas detection in the experimental platform in the experimental platform of Raman spectroscopy,detection of seven kinds of transformer fault characteristic gas and analysis of peak searching have been completed effectively. In terms of methane gas, the linear relationship among the unit gas content, Raman characteristic peak intensity and the area has been obtained, which has laid a foundation for the quantitative analysis of the dissolved gas in transformer oil.

Excessive intraoperative blood loss independently predicts recurrence of hepatocellular carcinoma after liver transplantation.

BACKGROUND: Several studies have investigated the effect of intraoperative blood loss (IBL) on recurrence of tumors. However, the independent effect of IBL on oncological outcome after liver transplantation (LT) for hepatocellular carcinoma (HCC) is unclear. METHODS: A total of 479 patients who underwent LT for HCC from January 2001 to December 2012 at our institution were enrolled in this retrospective study. Kaplan-Meier and Cox regression methods were used to assess the recurrence rate, as well as its risk factors. Stratified analysis was performed to further examine the effect of IBL on HCC recurrence according to different characteristics of tumors. We also investigated the independent risk factors for excessive IBL using logistic regression analysis. RESULTS: The median follow-up was 28 months (range, 1-131 months). Kaplan-Meier analysis with the log-rank test according to IBL at per liter intervals showed that IBL > 4 L was significantly associated with a higher recurrence rate (P < 0.001). Multivariate analysis identified that IBL > 4 L (P < 0.001; hazard ratio [HR] = 2.32, 95 % confidence interval [CI] = 1.60-3.36) was an independent risk factor for post-LT HCC recurrence, as well as age < 60 years, exceeding Milan criteria, α-fetoprotein levels > 400 ng/mL, and micro- and macrovascular invasion. IBL > 4 L (P < 0.001; HR = 2.45, 95 % CI = 1.64-3.66) was also independently associated with early (within 1 year) recurrence after LT. Furthermore, a significant correlation between IBL > 4 L and vascular invasion (P = 0.019) was found. IBL > 4 L was independently associated with HCC recurrence for patients with vascular invasion, but not for patients without vascular invasion. Finally, we found that the presence of ascites, model for end-stage liver disease score, and operation time were independent risk factors for IBL > 4 L. CONCLUSIONS: Excessive IBL is an independent predictor of HCC recurrence after LT, especially in patients with vascular invasion.

Disruption of thalamic connectivity in Alzheimer's disease: a diffusion tensor imaging study.

The aim of this study was to evaluate the structural integrity of the thalamic connectivity of specific fiber tracts in different stages of Alzheimer's disease (AD) using diffusion tensor imaging (DTI). Thirty-five patients with AD and 22 normal control (NC) subjects were recruited. Based on Mini Mental State Examination score, the AD patients were divided into three subgroups for comparison with the NC group: mild (mi-AD, n = 14), moderate (mo-AD, n = 12), and severe (se-AD, n = 9) AD. The fornix (FX), anterior thalamic radiation (ATR), and posterior thalamic radiation (PTR) were selected to represent the thalamic connectivity with other brain regions. The fornix was divided into the column and body of the fornix (FX-1) and the bilateral fornix (crus)/stria terminalis (FX-2/ST) based on the atlas. Through the atlas-based analysis and fiber tracking method, we measured fractional anisotropy (FA), mean diffusivity (MD), and tract volume to reflect the microstructural and macrostructural changes of these fibers during AD progression. There were significant differences in the FA and MD of all fibers, except the right PTR, between the AD and NC subjects. Further subgroup analyses revealed that the mi-AD subgroup had decreased FA only in the FX-1 and increased MD in the FX-1 and bilateral ATR, the mo-AD subgroup showed declined FA and increased MD in the FX-1, bilateral FX-2/ST and ATR; the se-AD subgroup exhibited lower FA and higher MD values in all fibers except the right PTR. We also found reduced tract volume values in the FX and left ATR in the AD patients. Further subgroup analyses revealed that these differences only existed in the se-AD patients. Our DTI analyses indicate that the integrity of thalamic connectivity is progressively disrupted following cognitive decline in AD and that DTI parameters in the column and body of the fornix show promise as potential markers for the early diagnosis of AD and for monitoring disease progression.