Evaluating artificial intelligence-enhanced digital urine cytology for bladder cancer diagnosis.

BACKGROUND: This study evaluated the diagnostic effectiveness of the AIxURO platform, an artificial intelligence-based tool, to support urine cytology for bladder cancer management, which typically requires experienced cytopathologists and substantial diagnosis time. METHODS: One cytopathologist and two cytotechnologists reviewed 116 urine cytology slides and corresponding whole-slide images (WSIs) from urology patients. They used three diagnostic modalities: microscopy, WSI review, and AIxURO, per The Paris System for Reporting Urinary Cytology (TPS) criteria. Performance metrics, including TPS-guided and binary diagnosis, inter- and intraobserver agreement, and screening time, were compared across all methods and reviewers. RESULTS: AIxURO improved diagnostic accuracy by increasing sensitivity (from 25.0%-30.6% to 63.9%), positive predictive value (PPV; from 21.6%-24.3% to 31.1%), and negative predictive value (NPV; from 91.3%-91.6% to 95.3%) for atypical urothelial cell (AUC) cases. For suspicious for high-grade urothelial carcinoma (SHGUC) cases, it improved sensitivity (from 15.2%-27.3% to 33.3%), PPV (from 31.3%-47.4% to 61.1%), and NPV (from 91.6%-92.7% to 93.3%). Binary diagnoses exhibited an improvement in sensitivity (from 77.8%-82.2% to 90.0%) and NPV (from 91.7%-93.4% to 95.8%). Interobserver agreement across all methods showed moderate consistency (κ = 0.57-0.61), with the cytopathologist demonstrating higher intraobserver agreement than the two cytotechnologists across the methods (κ = 0.75-0.88). AIxURO significantly reduced screening time by 52.3%-83.2% from microscopy and 43.6%-86.7% from WSI review across all reviewers. Screening-positive (AUC+) cases required more time than negative cases across all methods and reviewers. CONCLUSIONS: AIxURO demonstrates the potential to improve both sensitivity and efficiency in bladder cancer diagnostics via urine cytology. Its integration into the cytopathological screening workflow could markedly decrease screening times, which would improve overall diagnostic processes.

Global terrestrial drought and its projected socioeconomic implications under different warming targets.

Droughts are increasingly frequent as the Earth warms, presenting adaptation challenges for ecosystems and human communities worldwide. A strategic environmental assessment (SEA) and the integration of adaptation strategies into policies, plans, and programs (PPP) are two important approaches for enhancing climate resilience and fostering sustainable development. This study developed an innovative approach to strengthen the SEA of droughts by quantifying the impacts of future temperature increases. A novel method for projecting drought events was integrated into the SEA process by leveraging multiple data sources, including atmospheric reanalysis, reconstructions, satellite-based observations, and model simulations. We identified drought conditions using terrestrial water storage (TWS) anomalies and applied a random forest (RF) model for disentangling the drivers behind drought events. We then set two global warming targets (2.0 °C and 2.5 °C) and analyzed drought changes under three shared socioeconomic pathways (SSP126, SSP370, SSP585). In a 2.0 °C warming world, over 50 % of the global surface will face increased drought risk. With an additional 0.5 °C increase, >60 % of the land will be prone to further drought escalation. We utilized copulas to build the joint distribution for drought duration and severity, estimating the joint return periods (JRP) for bivariate drought hazard. In tropical and subtropical regions, JRP reductions exceeding half are projected for >33 % of the regional land surface under 2.0 °C warming and for >50 % under 2.5 °C warming. Finally, we projected the impacts of drought events on population and gross domestic product (GDP). Among the three SSPs, under SSP370, population exposure is highest and GDP exposure is minimal under 2.0 °C warming. Global GDP and population risks from drought are projected to increase by 37 % and 24 %, respectively, as warming continues. This study enhances the accuracy of SEA in addressing drought risks and vulnerabilities, supporting climate-resilient planning and adaptive strategies.

Two new saponins from the rhizomes of Paris yunnanensis Franch.

The phytochemical investigation on the rhizomes of Paris yunnanensis Franch. resulted in the discovery and characterisation of six compounds, including two new saponins named parisyunnanosides M-N (1-2), and four known ones (3-6). The structures of isolated compounds were determined by spectroscopic data analysis and chemical methods. Compound 2 is a pregnane-type saponin with a special α,ß-unsaturated carboxylic acid moiety at C-17, which is first discovered in genus Paris. The anti-inflammatory activity of the isolated compounds was assessed in vitro. The results demonstrated that compounds 3 and 4 could significantly inhibit the production of NO which was induced by LPS in RAW 264.7 cells with IC50 values of 0.67 ± 0.17 µM and 0.85 ± 0.12 µM, respectively.

Exploring the potential of Paris polyphylla var. yunnanensis pollen manipulation in modifying seed dormancy.

Paris polyphylla var. yunnanensis, a well-known Chinese medicinal herb, shows a unique physiological trait characterized by the cyclic opening and closing of its anthers after pollen maturation. The aim of this study was to explore the implications of this phenomenon on breeding. RNA sequencing coupled with methylation sequencing was used to scrutinize and compare gene expression profiles and methylation alterations in pollen and seeds during anther opening and closing, along with cold exposure. Genes enriched within Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were examined to identify gene clusters susceptible to temperature-related methylation changes in both pollen and seeds. Four pollen treatment models, namely, normal control, "pollen protected from low temperatures," "pollen from just-opened anther," and "pollen from close-blocked anther," were used to produce corresponding seeds via artificial pollination. Subsequently, qRT-PCR was used to validate modifications in the expression patterns of marker genes in pollinated seeds under diverse treatment scenarios. Genes exhibiting significant differences in expression between anthers and normal tissues, along with gene regions linked to methylation variations attributed to low-temperature-treated pollen and seeds, were identified through transcriptomic analysis. Convergence was observed in three signaling pathways: oxidative phosphorylation (ko00190), plant hormone signal transduction (Ko04075), and zeatin biosynthesis (ko00908). Notably, gene clusters prone to temperature-induced methylation changes, such as NADH-ubiquinone oxidoreductase chain 5, plasma membrane ATPase 4, cytochrome c oxidase subunit 2, cis-zeatin O-glucosyltransferase, ABSCISIC ACID-INSENSITIVE 5-like protein 4, and indole-3-acetic acid-amido synthetase (IAAS), were identified. Evaluation using various pollen pollination models revealed altered expression patterns of five dormancy-regulating marker genes: IAAS, sucrose synthase (SUS), gibberellin 2-oxidase (GA2ox), ABA INSENSITIVE 2 (ABI2), and auxin-repressed protein (ARP), in seeds pollinated with pollen from close-blocked anthers, cold-protected pollen, and pollen from freshly opened anthers. The close-blocked anther treatment led to significantly upregulated expression of IAAS, SUS, GA2ox, and ABI2, whereas ARP expression decreased markedly, indicating a propensity toward prolonged seed dormancy. Conversely, in the low-temperature-protected anther model, SUS, ARP, GA2ox, and IAAS exhibited reduced expression levels, whereas the expression of ABI2 was upregulated, overall facilitating seed germination.

[Emergencies and exceptional health situations: The Paris fire department at the heart of the action]. / Urgences et situations sanitaires exceptionnelles : la brigade des sapeurs-pompiers de Paris au cœur de l'action.

The Paris fire department is at the heart of the management of exceptional health situations and large-scale emergencies. Their operational strategies are benchmarks, both in France and internationally. Their expertise in the context of the Olympic Games makes them a major player.

Jean-Martin Charcot, member of thesis juries at the Paris medical school (1862-1893).

Jean-Martin Charcot is considered the founding father of modern neurology. There are many general and specialized biographies about him, the result being that a new text is unexpected or would likely amount to plagiarism. However, part of the duties for Charcot's medical professorship have not, to date, been studied at all. This article will focus on the role of Charcot as a member of doctorate juries and, in particular, as the president of these juries. I have reviewed around 12,500 theses one by one. These were defended at the Paris medical school from 1862, Charcot's first year as an agrégé (assistant professor), to his death in 1893. Among the theses, I have selected all of those that discuss neuropsychiatry in the broadest terms (3,663). I have paid particular attention to all of those for which Charcot was part of the jury. This involves 608 theses. All of the data were entered in a database (Filemaker) to facilitate identifying those theses corresponding to one or more of the criteria. Statistical comparisons were then carried out (Excel spreadsheet). In addition to these results, brief individualized surveys were conducted on theses selected for their representativeness, either for the subject matter (multiple sclerosis, aphasia, tabes, general paralysis, etc.) or for specific criteria (foreigners, women, etc.), but all of the theses were defended before a jury that included Charcot. This makes it possible to track how the areas of study in the medical world changed over time, and particularly those of Charcot. The juries Charcot was obliged to be a part of, without any particular ties to the candidate and/or any involvement in the selection and supervision of the work, must be differentiated from the thesis juries for his students. In the latter case, the thesis subjects were most often linked to Charcot's researches. Providing a thesis subject was motivated, in certain cases, by the desire to disseminate new data in the medical profession, not only by dint of the theses themselves but also through the reports that the medical press published regularly (e.g. the diagnosis of various types of shaking) and through the commercial publication of these data, in some cases with a preface by Charcot. In other cases, the thesis was a step in the long process of developing a theory (hysteria). Or it led to a flowering of new ideas, insufficiently proven, which Charcot would only cover in his Lessons once there was convincing confirmation (amyotrophy). This rich cornucopia gives rise to certain neglected nuggets, as well as works that have entered the classical corpus-for example, the theses of Léopold Ordenstein, Ivan Poumeau, Isaac Bruhl, Albert Gombault, and Pierre Janet.

Characterization of a glycosyltransferase from Paris polyphylla for application in biosynthesis of rare ophiopogonins and ginsenosides.

Saponins are bioactive components of many medicinal plants, possessing complicated chemical structures and extensive pharmacological activities, but the production of high-value saponins remains challenging. In this study, a 6'-O-glucosyltransferase PpUGT7 (PpUGT91AH7) was functionally characterized from Paris polyphylla Smith var. yunnanensis (Franch.) Hand. -Mazz., which can transfer a glucosyl group to the C-6' position of diosgenin-3-O-rhamnosyl-(1 â†’ 2)-glucoside (1), pennogenin-3-O-rhamnosyl-(1 â†’ 2)-glucoside (2), and diosgenin-3-O-glucoside (5). The KM and Kcat values of PpUGT7 towards the substrate 2 were 8.4 µM and 2 × 10-3 s-1, respectively. Through molecular docking and site-directed mutagenesis, eight residues were identified to interact with the sugar acceptor 2 and be crucial for enzyme activity. Moreover, four rare ophiopogonins and ginsenosides were obtained by combinatorial biosynthesis, including an undescribed compound ruscogenin-3-O-glucosyl-(1 â†’ 6)-glucoside (10). Firstly, two monoglycosides 9 and 11 were generated using a known sterol 3-O-ß-glucosyltransferase PpUGT80A40 with ruscogenin (7) and 20(S)-protopanaxadiol (8) as substrates, which were further glycosylated to the corresponding diglycosides 10 and 12 under the catalysis of PpUGT7. In addition, compounds 7-11 were found to show inhibitory effects on the secretion of TNF-α and IL-6 in macrophages RAW264.7. The findings provide valuable insights into the enzymatic glycosylation processes in the biosynthesis of bioactive saponins in P. polyphylla var. yunnanensis, and also serve as a reference for utilizing UDP-glycosyltransferases to construct high-value or rare saponins for development of new therapeutic agents.

Impact of implementing the first edition of the Paris system for reporting: A systematic review and meta-analysis.

Urine cytology is a noninvasive, widely used diagnostic tool for screening and surveillance of genitourinary tract neoplasms. However, the absence of unified terminology and clear objective morphological criteria limits the clinical benefit of urine cytology. The Paris System for Reporting Urine Cytology (TPS) was developed with the goal of standardizing reporting and improving urine cytology performance in detecting high-grade malignancy (HGM). We aimed to evaluate potential effects of TPS on improving urine cytology diagnostic performance and clinical utility by conducting a systematic review and meta-analysis. We searched six electronic databases to identify cross-sectional and cohort studies written in English assessing the accuracy of urine cytology in detecting genitourinary tract malignancies of patients under surveillance or with clinical suspicion of malignancy from January 2004 to December 2022. We extracted relevant data from eligible studies to calculate relative distribution of cytology diagnostic categories; ratio of atypical to HGM cytology diagnosis; and risk of HGM (ROHGM) and HGM likelihood ratio (HGM-LR) associated with cytology diagnostic categories. We used a generalized linear mixed model with logit transformation to combine proportions and multilevel mixed-effect logistic regression to pool diagnostic accuracy measurements. We performed meta-regression to evaluate any significant difference between TPS and non-TPS cohorts. We included 64 studies for 99,796 combined total cytology samples, across 31 TPS and 49 non-TPS cohorts. Pooled relative distribution [95% confidence interval (CI)] of negative for high-grade urothelial carcinoma (NHGUC)/negative for malignancy (NM); atypical urothelial cells (AUC); suspicious for high-grade urothelial carcinoma (SHGUC)/suspicious for malignancy (SM); low-grade urothelial neoplasm (LGUN); and HGM categories among satisfactory cytology cases were 83.8% (80.3%-86.9%), 8.0% (6.0%-10.6%), 2.2% (1.4%-3.3%), 0.01% (0.0%-0.1%), and 4.2% (3.2%-5.5%) in TPS versus 80.8% (76.8-2.7%), 11.3% (8.6%-14.7%), 1.8% (1.2%-2.7%), 0.01% (0.0%-0.1%), and 3.3% (2.5%-4.3%) in non-TPS cohorts. Adopting TPS classification resulted in a significant increase in the frequency of NHGUC and a reduction in AUC cytology diagnoses, respectively. The AUC/HGM ratio in TPS cohort was 2.0, which showed a statistically significant difference from the atypical/HGM ratio of 4.1 in non-TPS cohort (p-value: 0.01). Moreover, the summary rate (95% CI) of LGUN called AUC on cytology significantly decreased to 20.8% (14.9%-28.3%) in the TPS compared with 34.1% (26.4%-42.8%) in non-TPS cohorts. The pooled ROHGM (95% CI) was 20.4% (6.2%-50.0%) in nondiagnostic (NDX), 15.5% (9.6%-24.2%) in NHGUC, 40.2% (30.9%-50.2%) in AUC, 80.8% (72.9%-86.8%) in SHGUC, 15.1% (5.7%-34.3%) in LGUN, and 91.4% (87.3%-94.3%) in HGM categories in TPS studies. NHGUC, AUC, SHGUC, and HGM categories were associated with HGM-LR (95% CI) of 0.2 (0.1-0.3), 0.9 (0.6-1.3), 6.9 (2.4-19.9), and 16.8 (8.3-33.8). Our results suggest that TPS 1.0 has reduced the relative frequency of AUC diagnosis, AUC/HGM ratio, and the frequency of LGUNs diagnosed as AUC on cytology. Adopting this classification has improved the clinical utility of SHGUC and HGM cytology diagnoses in ruling in high-grade lesions. However, an NHGUC diagnosis does not reliably rule out the presence of a high-grade lesion.

[Urinary cytology for the detection of urothelial lesions]. / Rôle de la cytologie urinaire dans le dépistage des lésions urothéliales.

Urine cytology is a long-used technique for the detection of high grade neoplastic urothelial lesions. Since 2016, «The Paris System¼ classification has revolutionized this field by introducing a standardized terminology widely adopted by cytopathologists and urologists. In this article, we explain this classification and discuss its impact on the clinical management of patients with urothelial lesions, as well as its role in the secondary prevention of these lesions.

La cytologie urinaire est une technique utilisée depuis longtemps dans la détection des lésions urothéliales tumorales de haut grade. Depuis 2016, la classification «The Paris System¼ a révolutionné ce domaine en introduisant une terminologie standardisée largement adoptée par les cytopathologistes et les urologues. Dans cet article, nous expliquons cette classification et discutons de son impact sur la prise en charge clinique des lésions urothéliales, ainsi que son rôle dans la prévention secondaire de ces lésions.

Parkin R274W mutation affects muscle and mitochondrial physiology.

Recessive mutations in the Parkin gene (PRKN) are the most common cause of young-onset inherited parkinsonism. Parkin is a multifunctional E3 ubiquitin ligase that plays a variety of roles in the cell including the degradation of proteins and the maintenance of mitochondrial homeostasis, integrity, and biogenesis. In 2001, the R275W mutation in the PRKN gene was identified in two unrelated families with a multigenerational history of postural tremor, dystonia and parkinsonism. Drosophila models of Parkin R275W showed selective and progressive degeneration of dopaminergic neuronal clusters, mitochondrial abnormalities, and prominent climbing defects. In the Prkn mouse orthologue, the amino acid R274 corresponds to human R275. Here we described an age-related motor impairment and a muscle phenotype in R274W +/+ mice. In vitro, Parkin R274W mutation correlates with abnormal myoblast differentiation, mitochondrial defects, and alteration in mitochondrial mRNA and protein levels. Our data suggest that the Parkin R274W mutation may impact mitochondrial physiology and eventually myoblast proliferation and differentiation.

Charcot's international visitors and pupils from Europe, the United States, and Russia.

The foundation by Jean-Martin Charcot (1825-1893) of the Salpêtrière School in Paris had an influential role in the development of neurology during the late-nineteenth century. The international aura of Charcot attracted neurologists from all parts of the world. We here present the most representative European, American, and Russian young physicians who learned from Charcot during their tutoring or visit in Paris or Charcot's travels outside France. These include neurologists from Great Britain and Ireland, the United States, Germany and Austria, Switzerland, Russia, Italy, Spain, Belgium and the Netherlands, Scandinavia and Finland, Poland, Bohemia, Hungary, and Romania. Particularly emblematic among the renowned foreign scientists who met and/or learned from Charcot were Charles-Edouard Brown-Séquard, who had interactions with Paris University and contributed to the early development of British and American neurological schools; John Hughlings Jackson, who was admired by Charcot and influenced French neurology similarly as Charcot did on British neurology; Silas Weir Mitchell, the pioneer in American neurology; Sigmund Freud, who was trained by Charcot to study patients with hysteria and then, back in Vienna, founded a new discipline called psychoanalysis; Aleksej Yakovlevich Kozhevnikov and almost all the founders of the Russian institutes of neurology who were instructed in Paris; and Georges Marinesco, who established the Romanian school of neurology and did major contributions thanks to his valuable relation with Charcot and French neurology.

Polyhydroxylated Spirostanol Saponins from the Rhizomes of Paris dulongensis.

Three new polyhydroxylated spirostanol steroidal saponins, dulongenosides B-D (2-4), along with 14 known compounds, dulongenoside A (1), padelaoside B (5), parisyunnanoside G (6), polyphyllin D (7), ophiopogonin C' (8), formosanin C (9), dioscin (10), paris saponin VII (11), paris H (12), parisyunnanoside I (13), protodioscin (14), proprotogracillin (15), crustecdysone (16), and stigmasterol-3-O-ß-d-glucopyranoside (17), were isolated from the rhizomes of Paris dulongensis (Melanthiaceae). Their chemical structures were elucidated based on extensive analyses of NMR and MS data and acidic hydrolyses. The isolates were evaluated for their cytotoxicity to five human cancer cell lines (HL-60, SW480, MDA-MB-231, A549, and A549/Taxol) and the normal human bronchial epithelial cell line BEAS-2B by the MTS test. Compounds 7-12 and 14 showed cytotoxic activity, with IC50 values ranging from 0.20 to 4.35 µM. Proprotogracillin selectively inhibited A549 (IC50=0.58 µM) and A549/Taxol (IC50=0.74 µM) cells, with no significant cytotoxic activity against HL-60, SW480, MDA-MB-231, or BEAS-2B cells, with IC50 values greater than 40 µM.

The cryptic metabolites and anti-phytopathogenic activities from Nigrospora lacticolonia and Penicillium rubens uncovered by the synergism with host Paris polyphylla, monoculture, and co-culture.

The synergism of host Paris polyphylla medium, the monoculture, and the coculture led to seventeen new metabolites, including eight sesquiterpenes, 1-7 having uncommon structural motifs compared to similar caryophyllene derivatives, 8 with an unprecedented bicyclic framework, and three xyloketals (13-15) with unprecedented frameworks from Nigrospora lacticolonia; one polyketide, 17 with novel bicyclo [2.2.2] undecane skeleton, and five polyketide-terpenoid hybrids, 20 (one novel sulfated), 21-24 from Penicillium rubens. The structures were determined mainly by the NMR, HRESIMS, ECD calculation, and single-crystal X-ray diffraction. Nine cryptic compounds (2-4, 5, 12-15, 17) were produced by the inductions of host medium and the coculture. The compounds 13 from N. lacticolonia, 24-26, 28, 29, and 31 from P. rubens indicated significant antiphytopathogenic activities against N. lacticolonia with MICs at 2-4 µg/mL. Moreover, compounds 22-26, 28, 29, and 31 from P. rubens showed antifungal activities against P. rubens with MICs at 2-4 µg/mL. The synergistic effects of host medium and the coculture can induce the structural diversity of metabolites.

Arbuscular mycorrhiza and plant growth promoting endophytes facilitates accumulation of saponin under moderate drought stress.

Objective: Paris polyphylla var. yunnanensis, one of the important medicinal plant resources in Yunnan, China, usually takes 6-8 years to be harvested. Therefore, it is urgent to find a method that can not only shorten its growth years, but also improve its quality. In this study, we examined the effects of a combination treatment of arbuscular mycorrhizal fungi (AMF) and plant growth-promoting endophytes (PGPE) and drought stress on the accumulation of saponins in it. Methods: P. polyphylla var. yunnanensis was infected with a mixture of AMF and PGPE under drought stress. The content of saponins, as well as morphological, physiological, and biochemical indicators, were all measured. The UGTs gene related to saponin synthesis was obtained from transcriptome data by homologous comparison, which were used for RT-PCR and phylogenetic analysis. Results: Regardless of water, AMF treatment could infect the roots of P. polyphylla var. yunnanensis, however double inoculation with AMF and PGPE (AMF + PGPE) would reduce the infection rate of AMF. Plant height, aboveground and underground fresh weight did not differ significantly between the single inoculation AMF and the double inoculation treatment under different water conditions, but the inoculation treatment significantly increased the plant height of P. polyphylla var. yunnanensis compared to the non-inoculation treatment. Single inoculation with AMF considerably increased the net photosynthetic rate, stomatal conductance, and transpiration rate of P. polyphylla var. yunnanensis leaves under various water conditions, but double inoculation with AMF + PGPE greatly increased the intercellular CO2 concentration and chlorophyll fluorescence parameter (Fv/Fm). Under diverse water treatments, single inoculation AMF had the highest proline content, whereas double inoculation AMF + PGPE may greatly improve the amount of abscisic acid (ABA) and indoleacetic acid (IAA) compared to normal water under moderate drought. Double inoculation AMF + PGPE treatment improved the proportion of N, P, and K in the rhizome of P. polyphylla var. yunnanensis under various water conditions. Under moderate drought stress, AMF + PGPE significantly enhanced the contents of P. polyphylla var. yunnanensis saponins I, II, VII, and total saponins as compared to normal water circumstances. Farnesyl diphosphate synthase (FPPS), Geranyl pyrophosphate synthase (GPPS), Cycloartenol synthase (CAS), and Squalene epoxidase (SE1) were the genes that were significantly up-regulated at the same time. The amount of saponins was favorably linked with the expression of CAS, GPPS, and SE1. Saponin VI content and glycosyl transferase (UGT) 010922 gene expression were found to be substantially associated, as was saponin II content and UGT010935 gene expression. Conclusion: Under moderate drought, AMF + PGPE was more conducive to the increase of hormone content, nutrient absorption, and total saponin content in P. polyphylla var. yunnanensis, and AMF + PGPE could up regulate the expression of key genes and UGTs genes in one or more steroidal saponin synthesis pathways to varying degrees, thereby stimulating the synthesis and accumulation of steroidal saponins in the rhizome of P. polyphylla var. yunnanensis. The combination of AMF and PGPE inoculation, as well as adequate soil drought, reduced the buildup of saponins in P. polyphylla var. yunnanensis and increased its quality.

Paris saponin VII inhibits triple-negative breast cancer by targeting the MEK/ERK/STMN1 signaling axis.

BACKGROUND: Triple-negative breast cancer (TNBC) is a category of breast cancer characterized with high molecular heterogeneity. Owing to the lack of effective therapeutic strategies, patients with TNBC have a poor prognosis. Paris saponin VII (PSⅦ), a steroidal saponin extracted from the rhizome of Trichillium tschonoskii Maxim, exhibits excellent anti-cancer activity in a variety of solid tumors. However, the role and potential mechanism of PSⅦ against TNBC remain unexplored. PURPOSE: This study aimed to elucidate the therapeutic effects of PSⅦ against TNBC and explore the potential mechanism of action. METHODS: We combined the analysis of public single-cell sequencing data with weighted gene co-expression network analysis (WGCNA) to identity differentially expressed genes (DEGs) that distinguished malignant and normal epithelial cells in TNBC. Subsequently, the biological features of DEGs in TNBC were evaluated. Gene set enrichment analysis (GSEA) was used to define potential pathways associated with the DEGs. The pharmacological activity of PSⅦ for TNBC was evidenced via in vitro and in vivo experiments, and molecular docking, molecular dynamics (MD), surface plasmon resonance (SPR) assay and western blotting were employed to confirm the relative mechanisms. RESULTS: Single-cell sequencing and WGCNA revealed STMN1 as a pivotal biomarker of TNBC. STMN1 overexpression in TNBC was associated with poor patient prognosis. GSEA revealed a significant accumulation of STMN1 within the MAPK signaling pathway. Furthermore, In vitro experiments showed that PSⅦ showed significantly suppressive actions on the proliferation, migration and invasion abilities for TNBC cells, while inducing apoptosis. Molecular docking, MD analysis and SPR assay indicated a robust interaction between PSⅦ and the MEK protein. Western blotting revealed that PSⅦ may inhibit tumor progression by suppressing the phosphorylation of MEK1/2 and the downstream phosphorylation of ERK1/2 and STMN1. Intraperitoneal injection of PSⅦ (10 mg/kg) notably reduced tumor growth by 71.26 % in a 4T1 xenograft model. CONCLUSION: In our study, the systems biology method was used to identify potential therapeutic targets for TNBC. In vitro and in vivo experiments demonstrated PSⅦ suppresses cancer progression by targeting the MEK/ERK/STMN1 signaling axis. For the first time, the inhibition of STMN1 phosphorylation has been indicated as a possible mechanism for the anticancer effects of PSⅦ. These results emphasize the potential value of PSⅦ as a promising anti-cancer drug candidate for further development in the field of TNBC therapeutics.

A Comprehensive Pathophysiologic, Histologic, and Biochemical Analysis of Buthus paris (C. L. Koch, 1839) Venom.

INTRODUCTION: Buthus species, including B paris, are classified as one of the most dangerous scorpion genera in Morocco, implicated in several cases of human death. Our objective is to characterize, for the first time, the toxicity and histopathologic and biochemical impacts of B paris venom. METHODS: We investigated the experimental pathophysiology of B paris venom by examining histologic changes in vital organs (heart, kidneys, liver, and lungs) and assessing biochemical enzymatic markers (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatine phosphokinase, urea, and creatinine) in mice injected subcutaneously with 2 doses of 400 and 450 mg·kg-1. RESULTS: Our results showed that the subcutaneous median lethal dose of B paris venom was around 0.52 mg·kg-1. Histologic findings revealed significant tissue damage in the previously mentioned vital organs, confirmed through biochemical analysis indicating impaired heart and liver functions. Additionally, an increase in urea, creatinine, and glucose levels occurred following B paris venom injection. CONCLUSION: Our findings show that B paris venom exhibits a high level of experimental toxicity. These results highlight the potentially lethal nature of this venom and emphasize the potential medical importance of this species.

Paris saponin VII reverses resistance to PARP inhibitors by regulating ovarian cancer tumor angiogenesis and glycolysis through the RORα/ECM1/VEGFR2 signaling axis.

The emergence of Poly (ADP-ribose) polymerase inhibitors (PARPi) has marked the beginning of a precise targeted therapy era for ovarian cancer. However, an increasing number of patients are experiencing primary or acquired resistance to PARPi, severely limiting its clinical application. Deciphering the underlying mechanisms of PARPi resistance and discovering new therapeutic targets is an urgent and critical issue to address. In this study, we observed a close correlation between glycolysis, tumor angiogenesis, and PARPi resistance in ovarian cancer. Furthermore, we discovered that the natural compound Paris saponin VII (PS VII) partially reversed PARPi resistance in ovarian cancer and demonstrated synergistic therapeutic effects when combined with PARPi. Additionally, we found that PS VII potentially hindered glycolysis and angiogenesis in PARPi-resistant ovarian cancer cells by binding and stabilizing the expression of RORα, thus further inhibiting ECM1 and interfering with the VEGFR2/FAK/AKT/GSK3ß signaling pathway. Our research provides new targeted treatment for clinical ovarian cancer therapy and brings new hope to patients with PARPi-resistant ovarian cancer, effectively expanding the application of PARPi in clinical treatment.

International cross-cultural development and field testing of the primary care practice questionnaire for the PaRIS survey (PaRIS-PCPQ).

BACKGROUND: The PaRIS survey, an initiative of the Organisation for Economic Co-operation and Development (OECD), aims to assess health systems performance in delivering primary care by measuring the care experiences and outcomes of people over 45 who used primary care services in the past six months. In addition, linked data from primary care practices are collected to analyse how the organisation of primary care practices and their care processes impact care experiences and outcomes. This article describes the development and validation of the primary care practice questionnaire for the PaRIS survey, the PaRIS-PCPQ. METHOD: The PaRIS-PCPQ was developed based on domains of primary care practice and professional characteristics included in the PaRIS conceptual framework. Questionnaire development was conducted in four phases: (1) a multi-step consensus-based development of the source questionnaire, (2) translation of the English source questionnaire into 17 languages, (3) cross-national cognitive testing with primary care professionals in participating countries, and (4) cross-national field-testing. RESULTS: 70 items were selected from 7 existing questionnaires on primary care characteristics, of which 49 were included in a first draft. Feedback from stakeholders resulted in a modified 34-item version (practice profile, care coordination, chronic care management, patient follow-up, and respondent characteristics) designed to be completed online by medical or non-medical staff working in a primary care practice. Cognitive testing led to changes in the source questionnaire as well as to country specific localisations. The resulting 32-item questionnaire was piloted in an online survey and field test. Data from 540 primary care practices from 17 countries were collected and analysed. Final revision resulted in a 34-item questionnaire. CONCLUSIONS: The cross-national development of a primary care practice questionnaire is challenging due to the differences in care delivery systems. Rigorous translation and cognitive testing as well as stakeholder engagement helped to overcome most challenges. The PaRIS-PCPQ will be used to assess how key characteristics of primary care practices relate to the care experiences and outcomes of people living with chronic conditions. As such, policymakers and care providers will be informed about the performance of primary care from the patient's perspective.

Nuclear long diameter as a new criterion to distinguish high-grade urothelial carcinoma cells from benign reactive cells.

OBJECTIVE: Recently, the nuclear area has attracted attention as a morphological parameter to differentiate high-grade urothelial carcinoma (HGUC) cells from benign reactive cells. The nuclear long diameter (NLD) strongly correlates with the nuclear area and is easy to subjectively estimate. Therefore, this study examined the usefulness of the NLD-to-neutrophil diameter ratio for detecting HGUC cells in urine cytology. METHODS: This study included 29, 26 and 18 patients with HGUC, glomerular disease and urolithiasis respectively. An image analysis system was used to measure the NLD of HGUC and benign reactive cells (reactive renal tubular cells and reactive urothelial cells) and the neutrophil diameter that appeared in the voided urine in these cases. The NLD index was calculated using the NLD-to-neutrophil diameter ratio. We subsequently compared HGUC and benign reactive cells with respect to NLD and NLD indices. In addition, the HGUC cell group and benign reactive cell group were compared by selecting the five cells with the largest NLD and NLD index on each slide. RESULTS: The NLD and NLD indices of HGUC cells were significantly higher than those of benign reactive cells in all cells and in the five cells with the largest NLD and NLD indices. The cut-off value of the NLD index for detecting HGUC cells was 1.25 in all cells and 1.80 in the five cells with the largest NLD index. CONCLUSIONS: The NLD index is a useful parameter that can be introduced into routine microscopic examinations to differentiate HGUC cells from benign reactive cells.