The Effects of a 6-Week Plyometric and Sprint Interval Training Intervention on Soccer Player's Physical Performance.

Despite the well-documented benefits of sprint interval training (SIT) and plyometric training (PT) in improving the physical fitness of soccer players, it remains unclear which of these training methods is superior for enhancing players' aerobic and anaerobic performance. Therefore, this study aimed to compare the effects of SIT and PT on physical performance measures of male soccer players. Thirty male soccer players were randomly assigned to PT (n = 10), SIT (n = 10), and an active control group (CON, n = 10). Before and after the training period, participants underwent a battery of tests consisting of vertical jump, Wingate, linear sprint with and without ball dribbling, change of direction, ball kick, and the Yo-Yo intermittent recovery level 1 (Yo-Yo IR1) tests. Both groups exhibited similar improvements in maximal kicking distance (PT, effect size [ES] = 0.68; SIT, ES = 0.92) and measures of aerobic fitness including maximum oxygen uptake (PT, ES = 1.24; SIT, ES = 1.26) and first (PT, ES = 0.85; SIT, ES = 1.08) and second (PT, ES = 0.86; SIT, ES = 0.98) ventilatory thresholds. However, PT intervention resulted in greater changes in vertical jump (ES = 1.72 vs. 0.82, p = 0.001), anaerobic power (peak power, ES = 1.62 vs. 0.97, p = 0.009; mean power, ES = 1.15 vs. 1.20, p = 0.05), linear speed (20-m, ES = -1.58 vs. -0.98, p = 0.038; 20-m with ball, ES = -0.93 vs. 0.71, p = 0.038), and change of direction ability (ES = -2.56 vs. -2.71, p = 0.046) than SIT. In conclusion, both PT and SIT demonstrated effectiveness in enhancing aerobic performance among male soccer players. However, PT yielded superior improvements in anaerobic power, vertical jump, linear speed, and change of direction performance compared to SIT. These findings suggest that PT may offer additional benefits beyond aerobic conditioning.

TRMT10C gene polymorphisms confer hepatoblastoma susceptibility: evidence from a seven-center case-control study.

N1-methyladenosine (m1A) is a reversible epigenetic modification of RNAs. Aberrant m1A modification levels due to dysregulation of m1A regulators have been observed in multiple cancers. tRNA methyltransferase 10C (TRMT10C) can install m1A in RNAs; however, its role in hepatoblastoma remains unknown. We conducted this study to identify causal polymorphisms in the TRMT10C gene for hepatoblastoma susceptibility in a cohort of Chinese children (313 cases vs. 1446 controls). The genotypes of four potential functional polymorphisms (rs7641261 C>T, rs2303476 T>C, rs4257518 A>G, and rs3762735 C>G) were determined in participants using TaqMan real-time PCR. The associations of these polymorphisms with hepatoblastoma susceptibility were estimated by logistic regression analysis adjusted for age and sex. All four polymorphisms were significantly associated with hepatoblastoma risk. In particular, under the recessive genetic model, these polymorphisms conferred an increased risk of hepatoblastoma: rs7641261 C>T [adjusted odds ratio (OR)=1.64, 95% confidence interval (CI)=1.04-2.58, P=0.033], rs2303476 T>C (adjusted OR=1.87, 95% CI=1.16-3.02, P=0.010), rs4257518 A>G (adjusted OR=1.45, 95% CI=1.09-1.94, P=0.012), and rs3762735 C>G (adjusted OR=3.83, 95% CI=2.15-6.82, P<0.0001). Combined analysis revealed that kids had an increased risk of developing hepatoblastoma if they harbored at least one risk genotype (adjusted OR=1.94, 95% CI=1.48-2.54, P<0.0001). In addition, the combined risk effects of the four SNPs persisted across all the subgroups. We identified four hepatoblastoma susceptibility loci in the TRMT10C gene. Identifying more disease-causing loci may facilitate the development of genetic marker panels to predict individuals' hepatoblastoma predisposition.

Exploring the transactive relationships of influence factors for online asynchronous learning transactive memory system.

Transactive memory system (TMS) makes learning and transferring knowledge easy and efficient. This study has constructed a conceptual model of TMS to reveal the crucial factors influencing the formation of a TMS in online asynchronous learning to foster knowledge sharing and collaboration and enhance knowledge transfer effectiveness. The conceptual model of TMS is built upon theoretical foundations concerning the creation of TMS and the variables influencing them. The study has put forth a set of hypotheses to predict the expected effects of group factors, individual factors, task interdependence, the degree of intellectual silence, and knowledge management on the formation of TMS. In this study, a total of 229 questionnaire data were collected from undergraduate, master's, and doctoral students in Northeast China who had experience with an online asynchronous learning TMS. Structural equation modeling has been employed to identify the key indicators involved and their influence on the formation of TMS. The empirical study was carried out using statistical analysis of SPSS data, with the results indicating that each factor has varying impacts on knowledge management, ultimately affecting the formation of TMS. These findings provide a more nuanced understanding of how these factors shape online asynchronous learning environments.

Modeling of Microplastics Migration in Soil and Groundwater: Insights into Dispersion and Particle Property Effects.

Migration of microplastics (MPs) in soil-groundwater systems plays a pivotal role in determining its concentration in aquifers and future threats to the terrestrial environment, including human health. However, existing models employing an advection-dispersion equation are insufficient to incorporate the holistic mechanism of MP migration. Therefore, to bridge the gap associated with MP migration in soil-groundwater systems, a dispersion-drag force coupled model incorporating a drag force on MPs along with dispersion is developed and validated through existing laboratory and field-scale experiments. The inclusion of the MP dispersion notably increased the global maximum particle velocity (vmaxp) of MPs, resulting in a higher concentration of MPs in the aquifer, which is also established by sensitivity analysis of MP dispersion. Additionally, increasing irrigation flux and irrigation areas significantly accelerates MP migration downward from soil to deep saturated aquifers. Intriguingly, vmaxp of MPs exhibited a nonlinear relationship with MPs' sizes smaller than 20 µm reaching the highest value (=1.64 × 10-5 m/s) at a particle size of 8 µm, while a decreasing trend was identified for particle sizes ranging from 20 to 100 µm because of the hindered effect by porous media and the weaker effect of the drag force. Moreover, distinct behaviors were observed among different plastic types, with poly(vinyl chloride), characterized by the highest density, displaying the lowest vmaxp and minimal flux entering groundwater. Furthermore, the presence of a heterogeneous structure with lower hydraulic conductivity facilitated MP dispersion and promoted their migration in saturated aquifers. The findings shed light on effective strategies to mitigate the impact of MPs in aquifers, contributing valuable insights to the broader scientific fraternity.

Phenotypic and genomic analysis of the hypervirulent methicillin-resistant Staphylococcus aureus ST630 clone in China.

Methicillin-resistant Staphylococcus aureus (MRSA) sequence type 630 (ST630) is a rarely reported lineage worldwide. This study aimed to trace the dissemination of the emerging MRSA ST630 clones in China and investigate their virulence potential. We collected 22 ST630-MRSA isolates from across China and performed whole-genome sequencing analysis and virulence characterization on these isolates. Epidemiological results showed that MRSA ST630 isolates were primarily isolated from pus/wound secretions, mainly originating from Jiangxi province, and carried diverse virulence and drug resistance genes. Staphylococcal cassette chromosome mec type V (SCCmec V) predominated (11/22, 50.0%) among the MRSA ST630 isolates. Interestingly, nearly half (45.5%) of the 22 ST630-MRSA isolates tested lacked intact SCCmec elements. Phylogenetic analysis demonstrated that ST630-MRSA could be divided into two distinct clades, with widespread dissemination mainly in Chinese regions. Five representative isolates were selected for phenotypic assays, including hemolysin activity, real-time fluorescence quantitative PCR, western blot analysis, hydrogen peroxide killing assay, blood killing assay, cell adhesion and invasion assay, and mouse skin abscess model. The results showed that, compared to the USA300-LAC strain, ST630 isolates exhibited particularly strong invasiveness and virulence in the aforementioned phenotypic assays. This study described the emergence of a highly virulent ST630-MRSA lineage and improved our insight into the molecular epidemiology of ST630 clones in China.IMPORTANCEMethicillin-resistant Staphylococcus aureus (MRSA) sequence type 630 (ST630) is an emerging clone with an increasing isolation rate in China. This study raises awareness of the hypervirulent MRSA ST630 clones in China and alerts people to their widespread dissemination. ST630-staphylococcal cassette chromosome mec V is a noteworthy clone in China, and we present the first comprehensive genetic and phenotypic analysis of this lineage. Our findings provide valuable insights for the prevention and control of infections caused by this emerging MRSA clone.

Identification potential biomarkers for diagnosis, and progress of breast cancer by using high-pressure photon ionization time-of-flight mass spectrometry.

BACKGROUND: In this study, exhaled breath testing has been considered a promising method for the detection and monitoring of breast cancer (BC). METHODS: A high-pressure photon ionization time-of-flight mass spectrometry (HPPI-TOFMS) platform was used to detect volatile organic compounds (VOCs) in breath samples. Then, machine learning (ML) models were constructed on VOCs for the diagnosis of BC and its progression monitoring. Ultimately, 1981 women with useable breath samples were included in the study, of whom 937 (47.3 %) had been diagnosed with BC. VOC panels were used for ML model construction for BC detection and progression monitoring. RESULTS: On the blinded testing cohort, this VOC-based model successfully differentiated patients with and without BC with sensitivity, specificity, and area under receiver operator characteristic curve (AUC) values of 85.9 %, 90.4 %, and 0.946. The corresponding AUC values when differentiating between patients with and without lymph node metastasis (LNM) or between patients with tumor-node-metastasis (TNM) stage 0/I/II or III/IV disease were 0.840 and 0.708, respectively. While developed VOC-based models exhibited poor performance when attempting to differentiate between patients based on pathological patterns (Ductal carcinoma in situ (DCIS) vs Invasive BC (IBC)) or molecular subtypes (Luminal vs Human epidermal growth factor receptor 2 (HER2+) vs Triple-negative BC (TNBC)) of BC. CONCLUSION: Collectively, the HPPI-TOFMS-based breathomics approaches may offer value for the detection and progression monitoring of BC. Additional research is necessary to explore the fundamental mechanisms of the identified VOCs.

Genomic correlates of the response to first-line PD-1 blockade plus chemotherapy in patients with advanced non-small-cell lung cancer.

BACKGROUND: Programmed death 1 (PD-1) blockade plus chemotherapy has become the new first-line standard of care for patients with advanced non-small-cell lung cancer (NSCLC). Yet not all NSCLC patients benefit from this regimen. This study aimed to investigate the predictors of PD-1 blockade plus chemotherapy in untreated advanced NSCLC. METHODS: We integrated clinical, genomic, and survival data from 287 patients with untreated advanced NSCLC who were enrolled in one of five registered phase 3 trials and received PD-1 blockade plus chemotherapy or chemotherapy alone. We randomly assigned these patients into a discovery cohort (n = 125), a validation cohort (n = 82), and a control cohort (n = 80). The candidate genes that could predict the response to PD-1 blockade plus chemotherapy were identified using data from the discovery cohort and their predictive values were then evaluated in the three cohorts. Immune deconvolution was conducted using transcriptome data of 1014 NSCLC patients from The Cancer Genome Atlas dataset. RESULTS: A genomic variation signature, in which one or more of the 15 candidate genes were altered, was correlated with significantly inferior response rates and survival outcomes in patients treated with first-line PD-1 blockade plus chemotherapy in both discovery and validation cohorts. Its predictive value held in multivariate analyses when adjusted for baseline parameters, programmed cell death ligand 1 (PD-L1) expression level, and tumor mutation burden. Moreover, applying both the 15-gene panel and PD-L1 expression level produced better performance than either alone in predicting benefit from this treatment combination. Immune landscape analyses revealed that tumors with one or more variation in the 15-gene panel were associated with few immune infiltrates, indicating an immune-desert tumor microenvironment. CONCLUSION: These findings indicate that a 15-gene panel can serve as a negative prediction biomarker for first-line PD-1 blockade plus chemotherapy in patients with advanced NSCLC.

Acupuncture for nausea and vomiting during pregnancy: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Pregnant women commonly experience challenging nausea and vomiting, which significantly affect their general well-being and daily life. Although medication is often used for relief, it may not alleviate symptoms completely, emphasizing the need for complementary therapies. Acupuncture is one of the complementary treatments for nausea and vomiting of pregnancy (NVP). Studying the outcomes of acupuncture for NVP can shed light on this issue and inform treatment guidelines. Therefore, we systematically evaluated the effectiveness and safety of acupuncture in managing NVP, considering the traditional meridian and acupoint theories. METHODS: PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Wanfang Database, Chinese Science and Technology Periodical Database, ClinicalTrials.gov, and the Chinese Clinical Trial Registry were searched on May 1, 2024. Randomized controlled trials (RCTs) that compared acupuncture for NVP with sham acupuncture, placebo, and Western medicine (WM) or acupuncture plus WM with WM alone were included. The risk of bias was assessed using the Cochrane risk-of-bias tool. A meta-analysis was conducted using RevMan 5.4.1, and the quality of evidence for each outcome was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: Twenty-four RCTs (with 26 publications) involving 2390 women were included. Acupuncture plus WM significantly led to a reduction in Pregnancy-Unique Quantification of Emesis (PUQE) scores and ineffective rates compared with WM alone (PUQE: mean difference [MD] -1.95, 95 % confidence interval [CI] -3.08 to -0.81, P = 0.0008, I2 = 90 %, six studies; ineffective rates: risk ratio [RR] 0.27, 95 % CI 0.19 to 0.39, P < 0.00001, I2 = 7 %, 16 studies). It also resulted in a greater improvement in ketonuria, shorter length of stay, and lower scores on the NVP Quality of Life and Chinese Medicine Syndrome Scale. Acupuncture was superior to WM in terms of reduction in ineffective rates (RR 0.50, 95 % CI 0.30 to 0.81, P = 0.006, I2 = 0 %, five studies). Acupuncture and WM had comparable results in improvement in PUQE scores (MD -0.80, 95 % CI -3.06 to 1.46, P = 0.49, I2 = 89 %, three studies) and ketonuria negative rates. The evidence is not clear regarding the impact of acupuncture on depression and anxiety compared with that of sham acupuncture. The incidence of severe adverse events was not significantly different between acupuncture and WM or sham acupuncture. Evidence certainty ranged from moderate to very low. Of the 24 RCTs, 19 used the Neiguan (PC6) acupoint, 16 used the Zusanli (ST36) acupoint, and 13 used the Zhongwan (CV12) acupoint. CONCLUSION: According to the current systematic review and meta-analysis, acupuncture combined with WM may be a more effective treatment for NVP than WM alone. Furthermore, acupuncture may be as effective as WM. PC6, ST36, and CV12 are the most commonly used acupoints. Although more robust and larger studies are required, the current evidence supports the use of acupuncture in NVP treatment, as it has been demonstrated to be safe.

Tislelizumab plus cetuximab and irinotecan in refractory microsatellite stable and RAS wild-type metastatic colorectal cancer: a single-arm phase 2 study.

Immunotherapy confers little to no benefit in the treatment of microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Mechanistic insights suggested that epidermal growth factor receptor (EGFR) antibody plus irinotecan might augment the tumor immune response in mCRC. Therefore, we conducted a proof-of-concept, single-arm, phase 2 study (ChiCTR identifier: ChiCTR2000035642) of a combination treatment regimen including tislelizumab (anti-PD-1), cetuximab (anti-EGFR) and irinotecan in 33 patients with MSS and RAS wild-type (WT) mCRC who were previously treated with ≥2 lines of therapy. The primary endpoint was met, with a confirmed objective response rate of 33%. As secondary endpoints, the disease control rate was 79%, and the median progression-free survival and overall survival were 7.3 and 17.4 months respectively. Among the 33 patients, 32 (97.0%) had treatment-related adverse events (AEs). Three (9.1%) reported grade ≥ 3 AEs, including rash (n = 1), neutropenia (n = 2). The post-hoc evaluation of dynamic circulating tumor DNA using next generation sequencing and the analysis of peripheral immune proteomics landscape using Olink revealed that lower variant allele frequency (VAF) at baseline, greater reduction in VAF on treatment, and a hot peripheral macroenvironment were associated with the treatment response independently. Our study showed the antitumor activity of tislelizumab, cetuximab, and irinotecan combination with a tolerable safety profile in previously treated MSS and RAS WT mCRC.

Colquhounia root tablet improves diabetic kidney disease by regulating epithelial-mesenchymal transition via the PTEN/PI3K/AKT pathway.

Background: Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes mellitus that can lead to end-stage renal disease. Colquhounia root tablet (CRT) has shown therapeutic potential in treating DKD, but its efficacy and underlying mechanisms remain to be elucidated. Methods: A randomized controlled clinical trial was conducted on 61 DKD patients. The treatment group received CRT in addition to standard therapy, while the control group received standard therapy alone. Treatment efficacy and adverse events were evaluated after 3 months. Additionally, in vitro experiments using human renal tubular epithelial cells (HK-2) were performed to investigate the effect of CRT on high glucose (HG)-induced epithelial-mesenchymal transition (EMT) and the involvement of the PTEN/PI3K/AKT signaling pathway. Results: CRT treatment significantly improved proteinuria and increased the effective treatment rate in DKD patients compared to the control group, with no significant difference in adverse events. Moreover, CRT reversed HG-induced EMT in HK-2 cells, as evidenced by the downregulation of α-SMA and upregulation of E-cadherin at both mRNA and protein levels. Mechanistically, CRT increased PTEN expression and inhibited the PI3K/AKT pathway, similar to the effects of the PI3K inhibitor LY29400. The combination of CRT and LY29400 further enhanced PTEN mRNA expression under HG conditions. Conclusion: CRT effectively improves proteinuria in DKD patients and ameliorates HG-induced EMT in HK-2 cells. The underlying mechanism may involve the upregulation of PTEN and subsequent inhibition of the PI3K/AKT signaling pathway. These findings provide new insights into the therapeutic potential of CRT for DKD treatment.

Association between oxidative balance score and diabetic kidney disease, low estimated glomerular filtration rate and albuminuria in type 2 diabetes mellitus patients: a cross-sectional study.

Objective: The oxidative balance score (OBS) is a comprehensive concept that includes 20 oxidative stressors and can be used to assess individual pro-oxidant versus antioxidant exposure, and the aim of the present study was to investigate the association between OBS and the risk of diabetic kidney disease (DKD), low estimated glomerular filtration rate (low-eGFR) and albuminuria in patients with diabetes mellitus (DM). Methods: This cross-sectional study included nationally representative consecutive National Health and Nutrition Examination Survey DM patients aged 18 years and older from 2003-2018. The continuous variable OBS was converted into categorical variables by quartiles, and weighted multiple logistic regression analyses and restricted triple spline models were used to explore the relationships. We also performed subgroup analyses and interaction tests to verify the stability of the results. Results: A total of 5389 participants were included, representing 23.6 million non-institutionalized US residents. The results from both multivariate logistic regression analysis and restricted cubic spline models indicated that OBS and dietary OBS levels were negatively associated with the risk of DKD, low-eGFR, and albuminuria, without finding a significant correlation between lifestyle OBS and these clinical outcomes. Compared to the lowest OBS quartile group, the prevalence risk of DKD (OR = 0.61, 95% CI: 0.46-0.80), low-eGFR (OR = 0.46, 95% CI: 0.33-0.64) and albuminuria (OR = 0.68, 95% CI: 0.51-0.92) decreased by 39%, 54% and 32%, respectively, in the highest OBS quartile group. The results remained stable in subgroup analyses and no interaction between subgroups was found. Conclusion: Higher levels of OBS and dietary OBS were associated with a lower risk of DKD, low-eGFR, and albuminuria. These findings provided preliminary evidence for the importance of adhering to an antioxidant-rich diet and lifestyle among individuals with diabetes.

Meta-analysis of efficacy and safety of pembrolizumab for the treatment of advanced or recurrent cervical cancer.

BACKGROUND: This meta-analysis seeks to assess the efficacy and safety of pembrolizumab in individuals with advanced or recurrent cervical cancer. METHODS: Databases from PubMed, Embase, and the Cochrane Library were all thoroughly searched for pertinent research. Outcomes include complete response (CR), partial response (PR), stable disease (SD), disease progression (PD), overall response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), and adverse events (AEs) were retrieved for further analysis. RESULTS: Ten trials with 721 patients were included in this meta-analysis. The pooled results for patients with cervical cancer receiving pembrolizumab were as follows: CR (0.06, 95%CI: 0.02-0.10), PR (0.15, 95%CI: 0.08-0.22), SD (0.16, 95%CI: 0.13-0.20), PD (0.50, 95%CI: 0.25-0.75), ORR (0.26, 95%CI: 0.11-0.41) and DCR (0.42, 95%CI: 0.13-0.71), respectively. Regarding survival analysis, the pooled mPFS and mOS were 3.81 and 10.15 months. Subgroup analysis showed that pembrolizumab in combination was more beneficial in CR (0.16 vs. 0.03, p = 0.012), PR (0.24 vs. 0.08, p = 0.032), SD (0.11 vs. 0.19, p = 0.043), ORR (0.42 vs. 0.11, p = 0.014), and mPFS (5.54 months vs. 2.27 months, p < 0.001) than as single agent. The three most common AEs were diarrhoea (0.25), anaemia (0.25), and nausea (0.21), and the incidence of grade 3-5 AEs was significantly lower, rarely surpassing 0.10. CONCLUSIONS: For patients with advanced or recurrent cervical cancer, this systematic review and meta-analysis demonstrated that pembrolizumab had a favourable efficacy and tolerability. Future research will primarily focus on optimising customised regiments that optimally integrate pembrolizumab into new therapies and combination strategies. Designed to maximise patient benefit and efficiently control adverse effects while maintaining a high standard of living.

This study demonstrated the efficacy and safety of pembrolizumab in individuals with advanced or recurrent cervical cancer. The study found that an upfront combination of chemotherapy and pembrolizumab immunotherapy appears to be a compelling strategy for these patients. More large-scale and multicentre randomised controlled trials will be required in the future to validate the precise benefits of pembrolizumab in new therapies and combination strategies for the treatment of cervical cancer.

Clinical Effect of Personalized Adjustable Mandibular Advancement Device on Obstructive Sleep Apnea.

Aims/Background: Mandibular advancement devices are effective in treating mild or moderate obstructive sleep apnea (OSA), but such devices that are commonly used in clinical settings require further improvement. In this study, we evaluated the clinical effects of personalized adjustable mandibular advancement devices on mild or moderate OSA. Methods: Forty patients with mild or moderate OSA were randomly divided into experimental (personalized adjustable device) and control (traditional device) groups. Side effects, including increased salivation, dry mouth, muscle aches, and temporomandibular joint discomfort, were assessed. Respiratory markers during sleep, including the apnea-hypopnea index, mean blood oxygen saturation, lowest blood oxygen saturation and maximum apnea time, were evaluated using polysomnography. The upper airway cross-sectional area and temporomandibular joint morphology and motion trajectory were evaluated using cone beam computed tomography. Results: Side effects were significantly lower in the experimental group than in the control group. Respiratory marker levels were significantly restored post-treatment. Soft palate- and tongue-pharyngeal cross-sectional areas were significantly increased in both groups, but temporomandibular joint morphology or motion trajectory remained unchanged. Conclusion: The personalized adjustable mandibular advancement devices may reduce side effects and are effective in treating patients with OSA. Clinical Trial Registration: The study was registered and approved by the Chinese Clinical Trial Registry (ChiCTR2400080306). https://www.chictr.org.cn/showproj.html?proj=206538.

Driver mutation subtypes involve with differentiated immunophenotypes influencing pancreatic cancer outcomes.

Despite many studies focusing on the prognostic biomarkers in pancreatic adenocarcinomas (PAADs), there is ill-informed about the relationships between their genomic features and immune characteristics. Herein, we deeply investigated the involvement of major driver mutation subtypes with immunophenotypes impacting PAAD outcomes. Based on public data analyses of RNA expression-based immune subtypes in PAAD, in contrast to KRAS G12D & TP53 co-mutant patients with poor outcomes, the best immune subtype C3 (inflammatory) characterized by high Th1/Th2 ratio was relatively enriched in KRASnon-G12DTP53wt patients with better survival, whereas the inferior subtype C2 (IFN-γ dominant) with low Th1/Th2 ratio was more common in the former than in the latter. Moreover, contrary to the highly immunosuppressive microenvironment (high Treg, high ratio of Treg to tumor-specific CD4+ T cell) in KRASG12DTP53mut patients, KRASG12VTP53wt individuals exhibited an inflamed context profiled by multiplex immunohistochemistry. It could be responsible for their outstanding survival advantage over others in postsurgical PAAD patients receiving adjuvant chemotherapy as shown by our cohort. Together, KRASG12VTP53wt may be a promising biomarker for prognostic evaluation and screening certain candidates with PAAD to get desirable survival benefit from adjuvant chemotherapy.

Dimensionless analysis-based permeability model of reinforced concrete under tension.

Water permeability of reinforced concrete is essential for transportation of ingress ions inside concrete structures. The coupling effect of permeability and loading presents a challenge for the experimental simulation of water-permeate reinforced concrete subjected to tension. This renders the development of the model based on dimensionless analysis, using a series of experimental tests from an innovative experimental system that allows simultaneous measurement of permeability and crack width. The experiments focused on both ordinary concrete and high strength concrete under tension. The relationship between permeability and variables such as deformation, diameter of rebars, tensile load, and crack width under tension was formulated through multiple regression analysis using the testing data. The load to deformation characteristics determines the permeability of the concrete under tension. The proposed model accounts for the influence of continuous loading on permeability, as demonstrated by the robust analysis and proposed yield effective point. The robust analysis demonstrates that the diameter of the rebar, load, and crack width exert minimal influence on the permeability of concrete at lower significance levels. However, permeability variations become pronounced from 0.5 threshold, with significant changes observed between 0.5 and 0.9 thresholds. The findings indicate a differential impact of the variables on the permeability of concrete under tension. The yield-effective points delineate the relationship between the rebar diameter, load, and crack-width on the permeability of concrete with a threshold of 0.5, 0.5, and 0.58, respectively. At a threshold of 0.78, higher permeability will occur in the concrete, attributed to the prevalence of deformation. This deformation highlights the parameters with the most significant influence on the permeability of concrete under tension. The robust analysis and yield effective point derivative are useful parameters to measure concrete permeability and evaluate the behavior of the permeability model under tension.

Emerging perspectives on precision therapy for Parkinson's disease: multidimensional evidence leading to a new breakthrough in personalized medicine.

PD is a prevalent and progressive neurodegenerative disorder characterized by both motor and non-motor symptoms. Genes play a significant role in the onset and progression of the disease. While the complexity and pleiotropy of gene expression networks have posed challenges for gene-targeted therapies, numerous pathways of gene variant expression show promise as therapeutic targets in preclinical studies, with some already in clinical trials. With the recognition of the numerous genes and complex pathways that can influence PD, it may be possible to take a novel approach to choose a treatment for the condition. This approach would be based on the symptoms, genomics, and underlying mechanisms of the disease. We discuss the utilization of emerging genetic and pathological knowledge of PD patients to categorize the disease into subgroups. Our long-term objective is to generate new insights for the therapeutic approach to the disease, aiming to delay and treat it more effectively, and ultimately reduce the burden on individuals and society.

Early rhombic lip Protogenin+ve stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma.

We identify a population of Protogenin-positive (PRTG+ve) MYChigh NESTINlow stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RLVZ). Oncogenic transformation of early Prtg+ve rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG+ve stem cells grow adjacent to a human-specific interposed vascular plexus in the RLVZ, a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTGhigh compartment of Gr3-MB in vivo using either the diphtheria toxin system or chimeric antigen receptor T cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RLVZ PRTG+ve stem cells inhabiting a specific perivascular niche. Targeting the PRTGhigh compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB.

A laponite-based immunologically active gel delivery system for long-acting tumor vaccine.

Traditional bolus vaccines typically require multiple doses, which complicates the vaccination process and may cause missed shots, leading to sub-optimal immunity and reduced vaccine effectiveness. Herein, a gel-based long-acting vaccine system with self-adjuvant properties based on laponite was constructed to simplify vaccination procedures and improve vaccine effectiveness. Firstly, the gel system could recruit multiple types of immune cells to form immune niches. Secondly, it could achieve sustained delivery of antigens to lymph nodes by active transport and passive drainage. Then, the gel system triggered the formation of a large number of germinal centers, which elicited enhanced and durable humoral immune responses, as well as strong cellular immune responses. As a result, it eventually showed good prophylactic and therapeutic effects in a variety of tumor models including melanoma, colorectal cancer and peritoneal metastasis models. By further combining the immunoadjuvant CpG ODN and cytokine IL-12, the effect of the gel-vaccine could be further enhanced. In a murine peritoneal metastasis model of colorectal carcinoma, a single administration of the gel-vaccine resulted in complete tumor eradication in 8/9 mice. In summary, this study developed an immunologically active gel-vaccine system. And as a robust and versatile vaccine platform, by loading different antigens and adjuvants, this gel-vaccine system is expected to realize its better therapeutic potential.