Intraosseous and Intravenous Epinephrine Administration Routes in Out-of-Hospital Cardiac Arrest: Survival and Neurologic Outcomes.

BACKGROUND: The rate of survival after out-of-hospital cardiac arrest varies depending on the timeliness and effectiveness of prehospital interventions. This study was conducted to compare out-of-hospital cardiac arrest outcomes between intravenous and intraosseous routes and between upper and lower extremity routes for drug administration. METHODS AND RESULTS: We retrospectively analyzed data (collected using the Utstein template) from 1220 patients who had experienced out-of-hospital cardiac arrest in Taiwan's Taoyuan City between January 2021 and August 2023. The patients were stratified into intravenous and intraosseous groups by treatment approach and upper and lower extremity access groups by access site. The study outcomes were survival to discharge, favorable neurologic outcomes (Cerebral Performance Category score 1 or 2), and survival for >2 hours. The study groups were statistically compared before and after propensity score matching. Significant pre-propensity score matching differences were observed between intravenous and intraosseous groups, and the aforementioned study outcomes were better in the intravenous group than in the intraosseous group. However, the between-group differences became nonsignificant after propensity score matching. Furthermore, lower extremity access and delayed epinephrine administration were associated with worse outcomes. Survival rates fell below 12.6% when time to treatment exceeded 15 minutes, particularly in the cases of intraosseous access and lower extremity access. CONCLUSIONS: This study highlights the benefits of early intervention and upper extremity access for drug administration in patients with out-of-hospital cardiac arrest. Intraosseous access may serve as a viable alternative to intravenous access. Timely administration of essential drugs during resuscitation can improve clinical outcomes and thus has implications for emergency medical service training.

From Gatekeeper to Facilitator: Balancing Between Sexual Rights and Protection From Harm in Dementia Adults.

OBJECTIVE: The assessment of sexual consent capacity has been a challenge due to its dynamic nature, influenced by factors such as time, environment, individuals involved, and the nature of activities. Particularly in people living with dementia, the complexity is intensified with the interplay of the disease's impact, residential care setting, and legal constraints. This amplifies the dilemma faced by practitioners-whether to prioritize protection or encourage and support sexual expression. This article aims to provide a sensible approach to uphold the sexual autonomy of people living with dementia while mitigating the potential risks of them being involved as either perpetrators or victims. METHODS: In this narrative review, a literature search spanning from 1990 to 2023 was carried out on PubMed. Relevant articles on people living with dementia and topics related to sexuality were scrutinized. RESULTS: 41 relevant articles identified themes related to the impact of cognitive impairment on sexuality, challenges in residential care facilities, sexual consent capacity assessment models, and ethical frameworks regarding sexual rights and law. CONCLUSION: Discussions highlight the often neglected influence of prolonged suppression of sexual expression and the benefits of actualization of sexual autonomy, especially in people living with dementia, whose sense of identity is fading. It scrutinizes the limitations of existing sexual consent capacity evaluation models, emphasizing ethical concerns, practical challenges, and the need for a more balanced approach. Proposed strategies advocate for a shift from a gatekeeper to a facilitator role, offering principles for setting educational programs and policies to mitigate obstacles, supporting sexual rights, and safeguarding vulnerable groups.

Animal neuropathic pain aroused by conglutinating oxidative regenerative cellulose on dorsal root ganglion.

Neuropathic pain arises as a consequence of injury or disease in the peripheral or central nervous system. Clinical cases have shown that spine postoperative chronic neuropathic pain remains a troublesome issue in medical treatment due to the presence of various degrees of peridural fibrosis and different inflammatory factors after spinal surgery. To address this issue, we developed a new neuropathic mice model that successfully simulates the real clinical situation by applying oxidative regenerative cellulose to L5 DRG (dorsal root ganglion). Behavior tests were done by von Fray and thermal stimuli. ELISA and real-time PCR were employed to detect the expression of genes involved in neuropathic pain. This model not only successfully induces chronic pain but also causes membrane thickening, non-neuronal cell recruitment, and a local increase of TNFα and interleukin-6. Additionally, this model did not cause neuron loss in the affected DRG, which mimics the characteristics of sticky tissue-induced neuropathic pain after clinic surgery. Based on this model, we administrated a TNF inhibitor to mice and successfully reduced mechanical allodynia after DRG surgery. In this study, the developed animal model may be a novel platform for delivering neuropathic pain treatments, such as target-based drug discovery or personalized diagnostic approaches.

Pericholecystic Fat Stranding as a Predictive Factor of Length of Stays of Patients with Acute Cholecystitis: A Novel Scoring Model.

Background: The 2018 Tokyo Guidelines (TG18) are used to classify the severity of acute cholecystitis (AC) but insufficient to predict the length of hospital stay (LOS). Methods: For patients with AC, clinical factors and computed tomography features, including our proposed grading system of pericholecystic fat stranding were used for predicting an LOS of ≥7 days in the logistic regression models. Results: Our multivariable model showed age ≥ 65 years (OR: 2.56, p < 0.001), C-reactive protein (CRP) ≥ 2 mg/dL (OR: 1.97, p = 0.013), gamma-glutamyltransferase levels (OR: 2.460, p = 0.001), TG18 grade (OR: 2.89 per grade, p < 0.001), and moderate to severe pericholecystic fat stranding (OR: 2.14, p = 0.012) exhibited prolonged LOS ≥ 7 days. Conclusions: We developed a scoring model, including TG18 grades (score of 1-3 per grade), our grading system of fat stranding (score of 1), CRP (score of 1), and gamma-glutamyltransferase (score of 1), and a cutoff of >3 had highest diagnostic performance.

Uterine mesenchymal tumours harboring the KAT6B/A::KANSL1 gene fusion represent a distinct type of uterine sarcoma based on DNA methylation profiles.

Uterine mesenchymal tumours harboring KAT6B/A::KANSL1 gene fusions typically exhibit histological and immunophenotypic overlap with endometrial stromal and smooth muscle tumours. To date it remains uncertain whether such neoplasms should be regarded as variants of smooth muscle or endometrial stromal neoplasm, or if they constitute a distinct tumour type. In this study we investigated DNA methylation patterns and copy number variations (CNVs) in a series of uterine tumours harboring KAT6B/A::KANSL1 gene fusions in comparison to other mesenchymal neoplasms of the gynecological tract. Unsupervised hierarchical clustering and t-SNE analysis of DNA methylation data (Illumina EPIC array) identified a distinct cluster for 8/13 KAT6B/A::KANSL1 tumours (herein referred to as core cluster). The other 5 tumours (herein referred to as outliers) did not assign to the core cluster but clustered near various other tumour types. CNV analysis did not identify significant alterations in the core cluster. In contrast, various alterations, including deletions at the CDKN2A/B and NF1 loci were identified in the outlier group. Analysis of the DNA methylation clusters in relation to histological features revealed that while tumours in the core KAT6B/A::KANSL1 cluster were histologically bland, outlier tumours frequently exhibited "high-grade" histologic features in the form of significant nuclear atypia, increased mitotic activity and necrosis. Three of the five patients with outlier tumours died from their disease while clinical follow-up in the remaining two patients was limited (less than 12 months). In comparison, none of the 7 out of 8 patients with tumors in the core KAT6B/A::KANSL1 sarcoma cluster, where follow-up was available, died from disease. Furthermore, only 1 out of 7 patients recurred (mean follow-up of 30 months). In conclusion, KAT6B/A::KANSL1 uterine sarcoma is a molecularly unique type of uterine tumour that should be recognized as a distinct entity. These tumors typically exhibit low-grade histologic features but are occasionally morphologically high-grade; the latter have a DNA methylation profile different from the typical low-grade neoplasms and may be associated with aggressive behaviour.

Association between QT prolongation and cardiovascular mortality in cancer patients.

BACKGROUND: Cancer patients' vulnerability to QT prolongation contradicts certain anti-cancer drug usage. Until now, the QT prolongation's impact on CV mortality in cancer patients remains unclear, potentially biasing therapeutic decisions. METHODS: This retrospective observational cohort included adult cancer patients with an electrocardiogram (ECG) performed in a tertiary hospital in Taiwan. The first performed ECGs after cancer diagnosis (n = 59,568) were analyzed. The corrected QT intervals by Bazett (QTcB), Fridericia (QTcFri), and Framingham (QTcFra) formulae were used to predict the 90-day and one-year CV mortality according to the Taiwan death registry. RESULTS: The AUC of QTcB (90 days: 0.70, 1 year: 0.68) for predicting CV mortality was better than QTcFri and QTcFra (90 days: 0.63 and 0.50, 1 year: 0.65 and 0.56). Using the restricted cubic spline regression model adjusted by age and comorbidities, QTcB increased a significant but trivial risk of CV mortality at 90 days (hazard ratio, 1.007, P = 0.02) and one year (1.006, P < 0.01). Compared to those with QTcB < 500ms, the patients with QTcB ≥ 500ms were older and had more comorbidities and mortalities within one year. The incidence of sudden death and ventricular arrhythmias was only 0.2%. After adjusting for comorbidities, QTcB was neither associated with 90-day nor one-year CV mortality. In the patients already with QTcB ≥ 500ms, the patients receiving the unexpected uses of QT-prolonging drugs were not associated with higher one-year CV mortality than those without (P = 0.14). CONCLUSIONS: Rather than a prolonged QT interval per se, comorbidities contributed to CV mortality and irreversible outcomes in cancer patients.

Prevalence of Low FIB-4 in MASLD-Related Hepatocellular Carcinoma: A Multicentre Study.

BACKGROUND: Major society guidelines recommend the fibrosis-4 index (FIB-4) as the initial step to risk stratifying people with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to evaluate the proportion of people with MASLD-related hepatocellular carcinoma (HCC) and a low FIB-4. METHODS: This cohort study included 613 consecutive adults (33% female) diagnosed with MASLD-related HCC from January 2008 to August 2023 at seven international centres in Australia, India, Japan, South Korea, Singapore and the United States. The primary objective was to determine the proportion of participants with a low FIB-4, defined as FIB-4 < 1.3, or < 2 if age > 65 years, in people without cirrhosis. RESULTS: The mean (±SD) age and body mass index were 71 (±11) years and 27 (±7) kg/m2, respectively. Overall, 235 participants (38%) did not have known cirrhosis. The median FIB-4 was 3.90 (IQR 2.42-6.42). A total of 78 participants (13%) had a low FIB-4. Among participants without known cirrhosis (n = 235), 62 participants (26%) had a low FIB-4. Participants with a low FIB-4 had larger median total tumour diameter (p < 0.001) and lower median serum alpha-fetoprotein (p = 0.005), compared to participants without a low FIB-4. Cirrhosis was associated with lower odds of low FIB-4, but not other factors such as male sex, type 2 diabetes, or obesity. CONCLUSION: More than a quarter of those with MASLD-related HCC without cirrhosis have a low FIB-4. The proposed clinical care pathways may not identify these people for further evaluation.

Directional Coupling to a λ/5000 Nanowaveguide.

Silicon-based microdevices are considered promising candidates for consolidating several terahertz technologies into a common and practical platform. The practicality stems from the relatively low loss, device compactness, ease of fabrication, and wide range of available passive and active functionalities. Nevertheless, typical device footprints are limited by diffraction to several hundreds of micrometers, which hinders emerging nanoscale applications at terahertz frequencies. While metallic gap modes provide nanoscale terahertz confinement, efficiently coupling to them is difficult. Here, we present and experimentally demonstrate a strategy for efficiently interfacing subterahertz radiation (λ = 1 mm) to a waveguide formed by a nanogap, etched in a gold film, that is 200 nm (λ/5000) wide and up to 4.5 mm long. The design principle relies on phase matching dielectric and nanogap waveguide modes, resulting in efficient directional coupling between them when they are placed side-by-side. Broadband far-field terahertz transmission experiments through the dielectric waveguide reveal a transmission dip near the designed wavelength due to resonant coupling. Near-field measurements on the surface of the gold layer confirm that such a dip is accompanied by a transfer of power to the nanogap, with an estimated coupling efficiency of ∼10%. Our approach efficiently interfaces millimeter waves with nanoscale waveguides in a tailored and controllable manner, with important implications for on-chip nanospectroscopy, telecommunications, and quantum technologies.

Pre-treatment pan-immune-inflammation value as a prognostic marker of pazopanib in soft tissue sarcoma.

Background: Increasingly, more evidence has shown that inflammation stress and the tumor microenvironment pose a negative effect on targeted therapy. The neutrophil-to-lymphocyte ratio is considered to be a surrogate biomarker of inflammation and can predict pazopanib treatment effect in non-adipocytic soft-tissue sarcoma (STS). The role of the pan-immune-inflammation value (PIV) in STS is still yet to be determined. Objectives: We sought whether the pre-treatment PIV could be applied to predict the response of pazopanib in STS. Design: We conducted a retrospective analysis of 75 patients who had been treated with pazopanib for recurrent or metastatic non-adipocytic STS. Methods: Our cohort was stratified into either a pre-treatment high PIV group with PIV ⩾310 (n = 45) or a low PIV group with PIV <310 (n = 30). We compared their clinical features and outcomes. Cox regression analysis was employed to determine the risk factors of disease progression and mortality. Kaplan-Meier survival curves were utilized to assess both the progression-free survival (PFS) and overall survival (OS). Results: The results revealed that a pre-treatment high PIV (⩾310) is a risk factor for progression under pazopanib (hazard ratio: 1.91; 95% confidence interval: 1.08-3.36; p = 0.025). The median PFS and OS of the pre-treatment high PIV group were found to be significantly lower than the low PIV group (0.33 vs 0.75 years; p = 0.023, 0.46 vs 1.63 years; p = 0.025). Conclusion: High pre-treatment PIV in STS patients may indicate an elevated risk of disease progression and mortality. Pre-treatment PIV reflects inflammation stress and acts as a practical biomarker for STS patients treated with pazopanib.

Liver Cancer in 2021: Global Burden of Disease Study.

BACKGROUND & AIMS: The epidemiology of adult primary liver cancer continues to evolve, related to the increasing prevalence of metabolic disease, rising alcohol consumption, advancements in vaccination for hepatitis B (HBV), and antiviral therapy for hepatitis C (HCV). Disparities in care and the burden of liver cancer between populations persist. We assess trends in the burden of liver cancer and contributions by various etiologies across 204 countries and territories from 2010 to 2021. METHODS: Utilizing the methodological framework of the Global Burden of Disease Study 2021, we analyzed global and regional temporal trends in incidence and mortality, and the contributions of various etiologies of liver disease. RESULTS: In 2021, there were an estimated 529202 incident cases and 483875 deaths related to liver cancer. From 2010 to 2021, global liver cancer incident cases and deaths increased by 26% and 25%, respectively. Global age-standardized incidence rates (ASIRs) and death rates (ASDRs) for liver cancer declined but rose in the Americas and Southeast Asia. HBV remained the dominant cause of global incident liver cancer cases and deaths. Metabolic dysfunction-associated steatotic liver disease (MASLD) was the only etiology of liver cancer with rising ASIRs and ASDRs. By contrast, ASIRs and ASDRs remained stable for alcohol-related liver cancer, and declined for HBV- and HCV-related liver cancer. CONCLUSIONS: While age-adjusted incidence and deaths from liver cancer have started to decline, the absolute number of incident cases and deaths continues to increase. Population growth and aging contribute to the observed disconnect in the temporal trends of absolute cases and rates. Disparities remain, and MASLD-related liver cancer continues to surge.

Insights of the peroxychloroformyl radical ClC(O)OO via microwave spectrum.

The exploration of Venus has received much attention in the past and will keep growing due to the starting of the NASA DAVINCI project. To explain the extremely low O2 : CO ratio observed in Venus' atmosphere, a chlorine-initiated CO oxidation catalytic cycle has been proposed. However, relevant studies on the key intermediates, such as the peroxychloroformyl radical (ClC(O)OO), are rare. In this study, the ClC(O)OO radical was observed using Fourier-Transform Microwave (FTMW) spectroscopy under the supersonic expansion condition. Two conformers, trans-ClC(O)OO and cis-ClC(O)OO, and their chlorine isotopologues were detected. The molecular constants including the fine and hyperfine constants, were determined. Based on the experimental and the ab initio calculations, the unpaired electron is mostly located at the terminal oxygen atom, supported by the small magnetic hyperfine constants of chlorine. In addition, the angles between the Cl-C bond and the a-axis of the trans-35ClC(O)OO and trans-37ClC(O)OO are similar, but these angles are different for cis-ClC(O)OO, making the quadrupole coupling tensors in the inertial axes disagree with the ratio of the quadrupole moments of 35Cl and 37Cl. Finally, we concluded that the ClC(O)OO radicals should behave similarly to other peroxyl radicals, as assumed in the current photochemical model of Venus.

Comparative efficacy of THR-ß agonists, FGF-21 analogues, GLP-1R agonists, GLP-1-based polyagonists, and Pan-PPAR agonists for MASLD: A systematic review and network meta-analysis.

AIMS: To compare the efficacy of thyroid hormone receptor beta (THR-ß) agonists, fibroblast growth factor 21 (FGF-21) analogues, glucagon-like peptide-1 receptor agonists (GLP-1RAs), GLP-1-based polyagonists, and pan-peroxisome proliferator-activated receptor (Pan-PPAR) agonists in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: A database search for relevant randomized double-blind controlled trials published until July 11, 2024, was conducted. Primary outcomes were the relative change in hepatic fat fraction (HFF) and liver stiffness assessed non-invasively by magnetic resonance imaging proton density fat fraction and elastography. Secondary outcomes included histology, liver injury index, lipid profile, glucose metabolism, blood pressure, and body weight. RESULTS: Twenty-seven trials (5357 patients with MASLD) were identified. For HFF reduction, GLP-1-based polyagonists were most potentially effective (mean difference [MD] -51.47; 95 % confidence interval [CI]: -68.25 to -34.68; surface under the cumulative ranking curve [SUCRA] 84.9) vs. placebo, followed by FGF-21 analogues (MD -47.08; 95 % CI: -58.83 to -35.34; SUCRA 75.5), GLP-1R agonists (MD -37.36; 95 % CI: -69.52 to -5.21; SUCRA 52.3) and THR-ß agonists (MD -33.20; 95 % CI: -43.90 to -22.51; SUCRA 36.9). For liver stiffness, FGF-21 analogues were most potentially effective (MD -9.65; 95 % CI: -19.28 to -0.01; SUCRA 82.2) vs. placebo, followed by THR-ß agonists (MD -5.79; 95 % CI: -9.50 to -2.09; SUCRA 58.2), and GLP-1RAs (MD -5.58; 95 % CI: -15.02 to 3.86; SUCRA 54.7). For fibrosis improvement in histology, GLP-1-based polyagonists were most potentially effective, followed by FGF-21 analogues, THR-ß agonists, Pan-PPAR agonists, and GLP-1R agonists; For MASH resolution in histology, GLP-1-based polyagonists were most potentially effective, followed by THR-ß agonists, GLP-1R agonists, FGF-21 analogues, and Pan-PPAR agonists. THR-ß agonists are well-balanced in liver steatosis and fibrosis, and excel at improving lipid profiles; FGF-21 analogues are effective at improving steatosis and particularly exhibit strong antifibrotic abilities. GLP-1R agonists showed significant benefits in improving liver steatosis, glucose metabolism, and body weight. GLP-1-based polyagonists have demonstrated the most potential efficacy overall in terms of comprehensive curative effect. Pan-PPAR agonists showed distinct advantages in improving liver function and glucose metabolism. CONCLUSION: These results illustrate the relative superiority of the five classes of therapy in the treatment of MASLD and may serve as guidance for the development of combination therapies.

Prevalence of Chronic liver disease in Cholangiocarcinoma: a Meta-Analysis.

INTRODUCTION: Chronic liver disease is a known risk factor for cholangiocarcinoma (CCA), but the proportion of people with CCA who have concurrent chronic liver disease is unclear. We aimed to evaluate the prevalence of chronic liver diseases in people with cholangiocarcinoma. METHODS: In this single-arm meta-analysis, we searched MEDLINE and EMBASE from inception to 10 August 2024 for articles in English containing data for cholangiocarcinoma with and without chronic liver diseases. Data were pooled to obtain the prevalence of different chronic liver diseases, with further stratification by geographical location and tumor location. RESULTS: In total, 118068 individuals diagnosed with cholangiocarcinoma were included, of whom 16771 had chronic liver diseases. A pooled analysis of 109 studies determined that the prevalence of chronic liver disease was 25.23% (95% CI: 20.82% - 30.23%; I2=99.0%), and 10.21% (7.75% - 13.35%; I2=98.6%) of CCA patients had cirrhosis. Chronic liver diseases were associated more with intrahepatic CCAs, compared to extrahepatic CCAs (RR: 2.46, CI: 2.37 - 2.55, p < 0.0001). This was observed across all etiologies of liver disease, except for primary sclerosing cholangitis which was associated with extrahepatic CCAs (RR: 0.49; CI: 0.43 - 0.57, p < 0.0001). CONCLUSION: Around one in four people with cholangiocarcinoma have chronic liver diseases, and one in ten have cirrhosis.

AB092. Imaging the histopathology subtypes of the growth hormone-secreting pituitary neuroendocrine tumor.

BACKGROUND: Sparsely granulated (SG) growth hormone-secreting pituitary neuroendocrine tumors (GH-PitNETs) often present with a more aggressive clinical course compared to densely granulated (DG) tumors. These subtypes exhibit distinct biological and imaging characteristics. Thus, this study aims to differentiate between the histopathological subtypes of GH-PitNETs using pre-operative magnetic resonance imaging (MRI). METHODS: A retrospective analysis was conducted on 83 acromegalic patients treated at our institution between 2000 and 2010. Tumor volumes were segmented from preoperative MRIs, including T1-weighted, T2-weighted, T1 with contrast, and T2 fluid attenuated inversion recovery (FLAIR) sequences. Reference regions of interest (ROIs) were delineated using gray and white matter from the same sequences. Two pathologists reviewed pathology specimens for anti-cytokeratin (CAM 5.2) and Pit-1 expression. Clinical and radiological biomarkers were compared between SG and DG patients. RESULTS: A total of 83 patients with complete histopathology and 51 patients with complete MRIs were included in the analysis. SG PitNETs exhibited higher rates of supra-sellar invasion (61.5%, P<0.001), larger tumor sizes, lower pre-operative GH levels, and increased post-operative residual tumor (65.4%, P<0.001) compared to DG PitNETs. Additionally, SG PitNETs showed greater hyperintensity on T2-weighted images and enhanced contrast, whereas DG PitNETs exhibited less contrast enhancement. Utilization of these imaging biomarkers demonstrated an 94.1% accuracy in T2 FLAIR and overall of 78.7% predicting the histopathological subtypes of GH-PitNETs. CONCLUSIONS: Distinct histopathological subtypes of GH-PitNETs represent crucial prognostic factors. Utilizing multimodal pre-operative MRIs, clinicians can accurately identify sparsely granulated GH-PitNETs, facilitating improved treatment planning strategies.

Unveiling the innovative green synthesis mechanism of selenium nanoparticles by exploiting intracellular protein elongation factor Tu from Bacillus paramycoides. / 利用Bacillus paramycoidesç»†èƒžå† è›‹ç™½å»¶ä¼¸å› å­Tu揭示硒纳米颗粒的创新绿色合成机制.

Selenium nanoparticles (SeNPs) have garnered extensive research interest and shown promising applications across diverse fields owing to their distinctive properties, including antioxidant, anticancer, and antibacterial activity (Ojeda et al., 2020; Qu et al., 2023; Zambonino et al., 2021, 2023). Among the various approaches employed for SeNP synthesis, green synthesis has emerged as a noteworthy and eco-friendly methodology. Keshtmand et al. (2023) underscored the significance of green-synthesized SeNPs, presenting a compelling avenue in this domain. This innovative strategy harnesses the potential of natural resources, such as plant extracts or microorganisms, to facilitate the production of SeNPs.

Spatial Cancer-Immune Phenotypes Predict Shorter Recurrence-Free Survival in the No Specific Molecular Profile Molecular Subtype of Endometrial Carcinoma.

Compartmentation of the immune response into 3 main spatial cancer-immune phenotypes (SCIs) - inflamed, excluded, and desert - has been proposed as the main predictor of response to immune checkpoint inhibitors in solid tumors. The objective of the study was to define and characterize the SCI in a consecutive series of 213 endometrial carcinomas (ECs) by correlating it with molecular subtypes, clinicopathologic features, and prognosis. Immunohistochemistry (IHC) and next-generation sequencing were used to assign surrogate molecular EC subtypes: POLE mutant (POLE), mismatch repair deficient (MMRd), TP53 mutant (p53abn), and no specific molecular profile (NSMP). Immune cell markers (CD20, CD3, CD8, CD68, PD-L1) were assessed by IHC on whole sections and quantified by digital image analysis to define the 3 SCIs. ECs were stratified into 4 molecular subtypes: 17 (8.0%) POLE, 68 (31.9%) MMRd, 42 (19.7%) p53abn, and 86 (40.4%) NSMP. SCI determination showed 105 (49.3%) inflamed, 62 (29.1%) desert, and 46 (25.6%) excluded tumors. The inflamed phenotype was more prevalent in MMRd (64.7%) and POLE (76.5%) subtypes compared with NSMP (45.3%) and p53abn (21.4%). SCI revealed a strong correlation with disease-free survival in NSMP tumors: inflamed 96.2%, desert 83.2%, and excluded 40.5%. The SCI prognostic impact was also maintained in NSMP cases treated with adjuvant therapy resulting in a significant difference in recurrence between the inflamed and excluded phenotypes. To simplify SCI determination, a subset of immune cell markers was selected as appropriate to define the 3 SCI patterns: high intraepithelial CD8 for the inflamed phenotype; CD68, CD20, and PD-L1 to discriminate between desert and excluded tumors. The integration of SCI into molecular classification could be a promising opportunity to improve the prognostic risk stratification of patients and may guide the therapeutic approach, particularly in the NSMP subtype. Thus, the different patterns of immune response are a new prognostic parameter in the NSMP subtype.

SON is an essential RNA splicing factor promoting ErbB2 and ErbB3 expression in breast cancer.

BACKGROUND: In breast cancer, ErbB receptors play a critical role, and overcoming drug resistance remains a major challenge in the clinic. However, intricate regulatory mechanisms of ErbB family genes are poorly understood. Here, we demonstrate SON as an ErbB-regulatory splicing factor and a novel therapeutic target for ErbB-positive breast cancer. METHODS: SON and ErbB expression analyses using public database, patient tissue microarray, and cell lines were performed. SON knockdown assessed its impact on cell proliferation, apoptosis, kinase phosphorylation, RNA splicing, and in vivo tumour growth. RNA immunoprecipitation was performed to measure SON binding. RESULTS: SON is highly expressed in ErbB2-positive breast cancer patient samples, inversely correlating with patient survival. SON knockdown induced intron retention in selective splice sites within ErbB2 and ErbB3 transcripts, impairing effective RNA splicing and reducing protein expression. SON disruption suppressed downstream kinase signalling of ErbB2/3, including the Akt, p38, and JNK pathways, with increased vulnerability in ErbB2-positive breast cancer cells compared to ErbB2-negative cells. SON silencing in ErbB2-positive breast cancer xenografts led to tumour regression in vivo. CONCLUSION: We identified SON as a novel RNA splicing factor that plays a critical role in regulating ErbB2/3 expression, suggesting SON is an ideal therapeutic target in ErbB2-positive breast cancers.

High-Resolution Intact Protein Analysis via Phase-Modulated, Stepwise Frequency Scan Ion Trap Mass Spectrometry.

Mass spectrometry (MS) using an electron multiplier for intact protein analysis remains limited. Because of the massive size and complex structure of proteins, the slow flight speed of their ions results in few secondary electrons and thus low detection sensitivity and poor spectral resolution. Thus, we present a compact ion trap-mass spectrometry approach to directly detect ion packets and obtain the high-resolution molecular signature of proteins. The disturbances causing deviations of ion motion and mass conversion have been clarified in advance. The radio frequency waveform used to manipulate ions is proposed to be a sequence of constant-frequency steps, interconnected by short time-outs, resulting in least dispersive distortion. Furthermore, more such constant-phase conjunctions are arranged in each step to compensate for fluctuations resulting from defects in the system and operation. In addition, two auxiliary pulses are generated in the right phase of each step to select ions of a specific secular state to detect one clean and sharp spectral line.This study demonstrates a top-down approach for the MS measurement of cytochrome C molecules, resulting in a spectral profile of the protein in its natural state at a resolution of 20 Da. Additionally, quick MS scans of other proteins were performed.

AFM-YOLOv8s: An Accurate, Fast, and Highly Robust Model for Detection of Sporangia of Plasmopara viticola with Various Morphological Variants.

Monitoring spores is crucial for predicting and preventing fungal- or oomycete-induced diseases like grapevine downy mildew. However, manual spore or sporangium detection using microscopes is time-consuming and labor-intensive, often resulting in low accuracy and slow processing speed. Emerging deep learning models like YOLOv8 aim to rapidly detect objects accurately but struggle with efficiency and accuracy when identifying various sporangia formations amidst complex backgrounds. To address these challenges, we developed an enhanced YOLOv8s, namely, AFM-YOLOv8s, by introducing an Adaptive Cross Fusion module, a lightweight feature extraction module FasterCSP (Faster Cross-Stage Partial Module), and a novel loss function MPDIoU (Minimum Point Distance Intersection over Union). AFM-YOLOv8s replaces the C2f module with FasterCSP, a more efficient feature extraction module, to reduce model parameter size and overall depth. In addition, we developed and integrated an Adaptive Cross Fusion Feature Pyramid Network to enhance the fusion of multiscale features within the YOLOv8 architecture. Last, we utilized the MPDIoU loss function to improve AFM-YOLOv8s' ability to locate bounding boxes and learn object spatial localization. Experimental results demonstrated AFM-YOLOv8s' effectiveness, achieving 91.3% accuracy (mean average precision at 50% IoU) on our custom grapevine downy mildew sporangium dataset-a notable improvement of 2.7% over the original YOLOv8 algorithm. FasterCSP reduced model complexity and size, enhanced deployment versatility, and improved real-time detection, chosen over C2f for easier integration despite minor accuracy trade-off. Currently, the AFM-YOLOv8s model is running as a backend algorithm in an open web application, providing valuable technical support for downy mildew prevention and control efforts and fungicide resistance studies.