Osteosarcoma (OS) is a primary bone malignancy characterized by early metastasis and generally poor prognosis. ESPN is highly expressed and plays an important role in regulating the aggressive phenotypes of several cancer cell types. However, little is known about the molecular mechanisms underlying ESPN-mediated migration and invasion in OS cells. In this study, we first analyzed the survival of osteosarcoma patients using Kaplan-Meier analysis to assess the prognostic relevance of ESPN. To further evaluate its clinical significance, we performed immunohistochemical analysis on osteosarcoma tissue samples and benign osteochondroma (OC) tissues. The biological function of ESPN in osteosarcoma was confirmed by a series of experiments conducted both in vitro and in vivo. Additionally, we explored the underlying molecular mechanisms through Western blotting, co-immunoprecipitation, immunofluorescence, and PCR, revealing key downstream signaling pathways. In this study, we demonstrate that ESPN, acting as an oncogene, is highly expressed in OS cell lines and tissues, promoting OS cell proliferation and metastasis. Mechanistically, ESPN promoted the phosphorylation of PI3K by direct interaction with it and active the AKT/mTOR pathway, which enhanced the expression of the transcription factor ZEB1 and initiating the epithelial-mesenchymal transition (EMT) cascade. Furthermore, we validated that mTOR-mediated activation of p70 ribosomal protein S6 kinase (p70S6K) promotes the translation of ZEB1, thereby enhancing the growth and motility of OS cells. Our findings reveal a previously unrecognized function of ESPN in OS, closely linked with EMT and cancer metastasis progression. Targeting ESPN may represent a potential therapeutic approach for patients with OS.
Many Gram-negative enterobacteria translocate virulence proteins (effectors) into intestinal epithelial cells using a type III secretion system (T3SS) to subvert the activity of various cell functions possess. Many T3SS effectors have been extensively characterized, but there are still some effector proteins whose functional information is completely unknown. In this study, two predicted effectors of unknown function, EspN and EspS (Escherichia coli secreted protein N and S), were selected for analysis of translocation, distribution and structure prediction. The TEM1 (β-lactamase) translocation assay was performed, which showed that EspN and EspS are translocated into host cells in a T3SS-dependent manner during bacterial infection. A phylogenetic tree analysis revealed that homologs of EspN and EspS are widely distributed in pathogenic bacteria. Multiple sequence alignment revealed that EspN and its homologs share a conserved C-terminal region (673-1133 a.a.). Furthermore, the structure of EspN (673-1133 a.a.) was also predicted and well-defined, which showed that it has three subdomains connected by a loop region. EspS and its homologs share a sequence-conserved C-terminal (146-291 a.a.). The predicted structure of EspS (146-291 a.a.) is composed of a β-sheet consisting of four β-strands and several short helices, which has a TM score of 0.5014 with the structure of the Vibrio cholerae RTX cysteine protease domain (PDBID: 3eeb). These results suggest that EspN and EspS may represent two important classes of T3SS effectors associated with pathogen virulence, and our findings provide important clues to understanding the potential functions of EspN and EspS.
Patients with metastasis have an extremely poor prognosis in head and neck squamous cell carcinoma (HNSCC). Emerging studies have illuminated the impact of intratumor microbiota on cancer metastasis, though the specific role of Fusobacterium nucleatum (F. nucleatum) in HNSCC metastasis remains unresolved. This research found that intratumoral F. nucleatum abundance was elevated and correlated to diminished disease-free survival in HNSCC patients exhibiting lymph node metastasis. F. nucleatum invasion into primary and metastatic tumor tissues was observed using fluorescence in situ hybridization. F. nucleatum induced adhesion to endothelial cells and facilitated transendothelial migration via upregulating ESPN expression in HNSCC cells, which is an actin-binding protein. Mechanistically, F. nucleatum activated TLR4 signaling, inducing elevated expression of the transcription factor MYB, which subsequently stimulated ESPN transcription. Furthermore, metronidazole treatment significantly reduced metastatic incidence in vivo. These results indicate the significant potential of targeting F. nucleatum as a therapeutic approach in metastatic HNSCC.
Media play an integral part in the presentation of information surrounding gambling, and thus, it is important to consider the sharing of such details to inform and educate about suggested participation in sports wagering. This study analyzes discourse during ESPN's dedicated sports betting program, ESPN Bet Live (formerly Daily Wager), to produce a typology of responsible mediated gambling language offered by on-air talent and through visual graphics to an active gambling audience. Analysis of 45 episodes aired during the men's and women's NCAA basketball tournaments between 2021 and 2024 revealed four broad categories- announcer transparency, bet certainty, bookmaking education, and investment terminology- and four distinct types of evidence- X's & O's, traditional statistics, betting statistics, and non-scientific. Announcers rarely communicated specific responsible gambling recommendations but offered justification primarily through analysis of game play and traditional statistics. As media coverage of sports betting hurdles beyond journalistic responsibility of reporting scandals to the integration of gambling information and recommendations, it is incumbent upon sports media to present wagering information in a responsible manner.
Hypertension (HTN) is a well-known complication among patients on pediatric kidney replacement therapy (KRT). We aimed to evaluate demographics, longitudinal changes and outcomes of high blood pressure (BP) among children and adolescents on KRT. Data on BP and antihypertensive (AH) medications reported to the ESPN/ERA Registry on 6071 patients from 28 European countries starting KRT < 20 years of age between 2007 and 2021, were included. Hypertension (HTN), AH medication use, and uncontrolled HTN were reported in 60.7%, 45.0%, and 32.0% of patients, respectively. Prevalence of uncontrolled HTN was 49.7% in HD, 42.3% in PD, and 27.3% in transplanted patients. Younger age, dialysis, and shorter KRT vintage were risk factors for uncontrolled HTN. AH medication use was lower among young patients, females and those on dialysis, and higher with a shorter KRT vintage and non-CAKUT kidney disease. Among AH medication users, 27.9% of transplantation, 48.1% of PD and 58.9% of HD patients showed a systolic BP > 95th percentile. Uncontrolled HTN significantly decreased over time in HD patients (52.3% at dialysis start vs. 42.5% after 5 years; annual percentage change [APC] - 3.5%; 95%CI: - 6.2; -0.7), despite similar AH medication use. After 5 years, transplanted patients showed a significant reduction in both prevalence of uncontrolled HTN (APC - 3.6%; 95%CI: - 5.7; - 1.5) and AH medication use (APC - 1.6%; 95%CI: - 2.6; - 0.6%). No trends were found for PD patients. Uncontrolled HTN was not associated with mortality (aHR 1.02; 95%CI: 0.79-1.33). HTN is highly prevalent in children and adolescents on KRT. Younger children and HD patients should be carefully evaluated for BP status after entering dialysis or shortly after transplantation.
暂无摘要（点击查看详情）
The choice of vascular access (VA) plays a key role in the success of hemodialysis (HD). Despite their widespread use, central venous catheters (CVCs) are associated with higher rates of dysfunction, thrombosis, and catheter-related bloodstream infections (CRBSI). We investigated current practices in pediatric HD across European pediatric nephrology centers, focusing on VA choices, infection control measures, and CRBSI management. An online questionnaire was e-mailed to 119 members of the European Society for Pediatric Nephrology (ESPN) Dialysis Working Group and European Pediatric Dialysis Working Group (EPDWG). Descriptive statistics were used to summarize practices across centers, comparative analyses between centers in countries with Human Development Index (HDI) > 0.90 and < 0.90. Thirty-one centers across Europe participated in the survey. CVCs were the primary VA in 73.1% of the centers. Twenty (66.7%) centers reported malfunction as the most common CVC complication, followed by catheter thrombosis (19.4%) and CRBSI (12.9%). The diagnostic approach for CRBSI varied widely, with 35.4% of centers relying on a single positive catheter culture, while 57.9% did not collect a second culture from the peripheral vein or HD circuit. The most common empirical treatment was glycopeptides combined with third-generation cephalosporins. Nearly all centers used intravenous antibiotics for less than 3 weeks, and over half modified lock solutions with antibiotics following CRBSI diagnosis. Catheter removal practices were inconsistent, even in cases of severe infection. Centers reported a total of 548 HD patients. Exit-site infections and CRBSI were observed in 98 (17.8%) and 155 (28.2%) patients, respectively. CRBSI rates and CRBSI-related catheter replacements were significantly higher in centers from countries with HDI < 0.90 and in centers without a dedicated pediatric HD unit. The suboptimal adherence to current VA recommendations and wide variability in catheter care practices including the prevention, diagnosis, and management of CRBSI highlight the need for standardized pediatric-specific protocols to enhance catheter longevity and improve patient outcomes. • Central venous catheters are widely used in pediatric hemodialysis but carry a high risk of complications, especially catheter-related bloodstream infections (CRBSI). • This multinational survey reveals significant variability in vascular access selection, CRBSI prevention, diagnosis, and treatment across European pediatric hemodialysis centers, with clear disparities by national HDI levels. • The findings highlight the need for standardization of vascular access care and CRBSI management and evidence-based pediatric-specific guidelines.
Kidney transplantation (KT) is the preferred treatment for paediatric patients with kidney failure, but information on trends in paediatric KT in Europe is lacking. We aimed to report on time trends in paediatric (0-17 years) KT rates and recipient characteristics in Europe between 2010 and 2021. Thirty-one countries contributing data from 2010 to 2021 on paediatric KT to the European Society for Paediatric Nephrology/European Renal Association Registry were included. We reported trends in KT rates [per million age-related population (pmarp)], overall and by patient subgroup for Europe, and at macro-economic and country-specific levels. We also reported clinical variables in the first year post-KT. The 2020-21 period was analysed separately to account for the COVID-19 pandemic. The paediatric KT rate was stable at ≈5 pmarp between 2010 and 2019, and about one-fourth were pre-emptive KTs. In 2020-21 the KT rate was 5.6 pmarp. In low-, middle- and high-gross domestic product (GDP) countries, KT rates (pmarp) were 2.1, 6.1 and 7.6, respectively, and increased in low-GDP countries by 4.1% per year from 2010 to 2019, mainly in the youngest recipients. The proportion of pre-emptive KT increased only in middle-GDP countries. Low-GDP countries showed a higher prevalence of short stature while high-GDP countries showed more overweight/obese, hypertensive and anaemic patients. The rate of paediatric KT in Europe has remained stable, with differences between GDP groups. Low-GDP countries had the lowest KT rates, but with an increasing trend over time. Opportunities to further increase access to paediatric KT should be explored.
Glomerular nephropathy resulting from the genetic defects in COL4A3/4/5 genes including the classical Alport syndrome is the second most common hereditary kidney disease characterized by persistent haematuria progressing to the need for kidney replacement therapy, frequently associated with sensorineural deafness, and occasionally with ocular anomalies. Diagnosis and management of COL4A3/4/5 glomerulopathy is a great challenge due to its phenotypic heterogeneity, multiple modes of inheritance, variable expressivity, and disease penetrance of individual variants as well as imperfect prognostic and progression factors and scarce and limited clinical trials, especially in children. As a joint initiative of the European Rare Kidney disease reference Network (ERKNet), European Renal Association (ERA Genes&Kidney), and European Society for Paediatric Nephrology (ESPN) Inherited renal disorders working group, a team of experts including adult and paediatric nephrologists, kidney geneticists, audiologists, ophthalmologists, and a kidney pathologist were selected to perform a systematic literature review on 21 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions. The experts formulated recommendations and formally graded them at a consensus meeting with input from patient representatives and a voting panel of nephrologists representing all regions of the world. Genetic diagnostics comprising joint analysis of COL4A3/4/5 genes is already the key diagnostic test during the initial evaluation of an individual presenting with persistent haematuria, proteinuria, kidney failure of unknown origin, focal segmental sclerosis of unknown origin, and possibly cystic kidney disease. Early renin-angiotensin system blockade is the standard of care therapy; sodium-glucose cotransporter-2 inhibitors may be added in adults with proteinuria and chronic kidney disease. Relatives with heterozygous COL4A3/4/5 variants should only be considered as the last possible resource for living kidney donation. This guideline provides guidance for the diagnosis and management of individuals with pathogenic variants in COL4A3/4/5 genes.
The development of novel targeted therapies is opening new perspectives in the treatment of pediatric brain tumors. Their precise role in therapeutic protocols still needs still to be defined. Thus, these novel pharmacological approaches in pediatric neurosurgery were the topic of the European Society for Pediatric Neurosurgery (ESPN) Consensus Conference held in Lyon (France) in January 25-27, 2024. The paper reviews the current knowledge about targeted therapy as well as the current literature published on the topic. The conference aimed for an interdisciplinary consensus debate among pediatric oncologists and pediatric neurosurgeons on the following questions. Question 1: What is the current role for targeted therapies as neoadjuvant treatments before pediatric brain tumor removal? Question 2: What are the benefits, cost/efficiency, and long-term side effects of targeted therapies in the treatment of pediatric brain tumors? Question 3: Based on contemporary data, at which stage and in which pathologies do targeted therapies play a significant role? Ninety-two participants answered consensus polls on the state of the art of targeted therapies, the ethical issues related to their use, and the evolving change in the role of pediatric neurosurgeons. The neoadjuvant role of targeted therapies is difficult to define as there are many different entities to consider. Despite the recently reported potential benefits, questions regarding the use of targeted therapies are manifold, in particular regarding sustainable benefits and long-term side effects. Additionally, challenging cost issues is a limiting factor for the broader availability of these drugs. Studies have demonstrated superiority of targeted therapy compared to chemotherapy both in randomized trials and compared to historical cohorts in the management of a subset of low-grade gliomas. The same drug combinations, BRAFi and MEKi, may be effective in HGG that have relapsed, progressed, or failed to respond to first-line therapy. Similar conclusions on efficacy may be drawn for mTORi in TSC and selumetinib in plexiform neurofibromas. For other tumors, the picture is still obscure due to the lack of data or even the lack of suitable targets. In conclusion, targeted treatment may not always be the best option even when a target has been identified. Safe surgery remains to be a favorable option in the majority of cases. The constantly evolving drug technology and the absence of long-term safety and efficacy studies made it difficult to reach a consensus on the predefined questions. However, a report of the conference is summarizing the present debate and it might serve as a guideline for future perspectives and ongoing research.
Cancer and its treatment may lead to kidney injury and the need for kidney replacement therapy (KRT). We identified 287 pediatric KRT patients with a history of malignancy from the European Society for Paediatric Nephrology/European Renal Association Registry. Of these, 197 had cancer as a primary cause of KRT (group 1) and 90 had a malignancy diagnosis before KRT (group 2). Two matched controls without malignancy were randomly selected for each patient. Data were complemented with a questionnaire. Median time to kidney transplantation (KT) from KRT initiation was 2.4 (IQR: 1.5-4.7), 1.5 (IQR: 0.4-3.3), 3.6 (IQR: 1.3 to Q3 not reached), and 1.1 (IQR: 0.3-3.6) years for group 1, their controls, group 2, and their controls, respectively. Overall 10-year mortality for those on KRT was higher among cancer patients vs controls in group 1: 16% vs 9% (adjusted hazard ratio 2.02, 95% CI: 1.21-3.37) and in group 2: 23% vs 14% (adjusted hazard ratio 2.32, 95% CI: 1.11-4.85). In contrast, 10-year patient survival after the first KT was comparable to controls (93% vs 96%; 100% vs 94%, in groups 1 and 2, respectively). In summary, childhood cancer survivors' KT was delayed, and their overall mortality when on KRT was increased, but once transplanted, their long-term outcome was similar to other KT recipients.
Primary hyperoxaluria (PH) is a rare disorder with significant morbidity and mortality if left untreated. Given the rarity, global inequities in diagnostics and treatment are expected. Recently introduced RNA interference therapeutics (RNAi) have dramatically changed the outcome for PH patients, potentially disproportionately affecting low-resource regions. Understanding these disparities is crucial for implementing measures to ensure equitable healthcare access for PH patients worldwide. This study aims to evaluate the current global health situation for PH patients upon the introduction of targeted therapeutics. An international cross-sectional questionnaire study was conducted among healthcare providers involved in PH care. Responses were gathered between March 2023 and April 2024 and distributed by e-mail via various international nephrology networks. Meta-analysis (mixed random effects model with inverse-variance weighting) was used to analyze data and adjust for subgroup differences. We gathered 136 responses from 57 countries, representing all World Bank regions. Overall access to genetic analysis diagnostics was 82% (confidence interval 77%-91%) and to urinary oxalate measurement 97% (93%-100%). Significant differences (P < .05) between low- and high-income countries were found for most diagnostics including genetic testing, plasma oxalate, plasma and urinary glycolate. Conservative therapies (e.g. pyridoxine and alkalinizing agents) were highly available globally (98% and 95%), but significant differences in access to peritoneal dialysis, and kidney and liver transplantation were reported (P < .05). Access to the RNAi therapeutic lumasiran was limited to high- and middle-income countries, with 53% (40%-66%) of all countries having access (78% high-income versus 56% middle-income). Even in high-income countries, RNAi was not always accessible. We found global disparities in access to optimal management of PH patients, disproportionately affecting low-income countries, but even existing between high-income countries. These results may provide support for initiatives to improve the outcome of PH patients worldwide in an era of new targeted therapeutic treatments.
暂无摘要（点击查看详情）
Stereocilia are giant, specialized microvilli on auditory sensory cells in the inner ear. Their precise size and tiered organization is essential for function and strictly controlled by actin-regulating proteins during postnatal development. Among these proteins, Espins (ESPNs) and Espin-like (ESPNL) proteins contribute to normal stereocilia development; however, potential overlapping function between these families has not been explored. We found that ESPNL exists as both a long isoform and a novel short isoform. The short isoform localized differently from the long isoform and was lost from stereocilia when mechanotransduction was blocked. To understand how long isoforms contribute to stereocilia architecture, we generated mutations causing their loss while sparing short isoforms. While mutating ESPN-1 had little effect on stereocilia morphology or auditory function, loss of the long ESPNL isoform caused degeneration of shorter, mechanotransducing stereocilia rows, resulting in progressive hearing loss. Double mutant mice lacking both ESPN and ESPNL long isoforms showed more rapid onset of the same phenotype, demonstrating that these proteins both contribute to mechanotransducing stereocilia development and maintenance.
This study aims to investigate the correlation between esophageal second primary neoplasm (ESPN) in head and neck cancers. Panendoscopy findings of ESPN can guide clinicians in timely interventions and improve patients' outcomes. We performed a retrospective cohort study in Linkou Chang Gung Memorial Hospital, and 365 patients who met the criteria from 2015 to 2021 were enrolled. We collected the lifestyle habits and panendoscopy report after the HNC was diagnosed. Of 365 HNC patients, 37 (10.1%) had ESPNs, which included low dysplasia, high dysplasia, squamous cell carcinoma in situ and squamous cell carcinoma. We found that alcohol (P = .004) and areca-quids (AQs) consumption (P = .003) had significant differences in different HNC subsites. Oral cavity cancers had the highest association with alcohol and AQs consumption. Hypopharyngeal cancer has the highest ESPN incidence with highest odds ratio (OR = 13.3, P < .001), followed by oropharynx, larynx, and oral cavity. In addition, we found that alcohol (P = .002) and cigarette consumption (P = .040) were associated with the ESPN development. Other panendoscopy findings such as gastroesophageal reflux disease, esophageal mucosa break, gastritis ulceration, and gastritis showed insignificant correlations with the occurrence of ESPN. Half of the ESPN were found within 24 months after the diagnosis of HNC, especially for hypopharyngeal cancer, in which ESPN even occurs within 12 months of the diagnosis of primary tumor. Routine panendoscopy for patients with HNC is highly advised, and our study suggests having intensive surveys in the first 24 months after the diagnosis of primary HNC; especially for hypopharyngeal cancer. This study was reported in strict compliance with the strengthening the reporting of observational studies in epidemiology (STROBE) guideline.
As social media continues to rapidly evolve, understanding public participation in discourse and ensuring accurate interpretation has become increasingly vital. The widespread incidence of anterior cruciate ligament (ACL) injuries in female soccer players, including many high-profile athletes, has prompted calls for research into potential risk factors and preventative strategies. In response to this growing concern, on April 29, 2025, a research collaboration between the Fédération Internationale de Football Association (FIFA) and Kingston University was announced, aiming to examine the relationship between ACL injuries and the menstrual cycle in female soccer players. This study utilizes framing theory to provide critical insight into the presentation and debate of public discourse regarding FIFA's ACL-menstrual cycle study announcement and examine how those reactions were framed. Comments were exported from the collaborative post by ESPN, ESPNW, and ESPNFC on Instagram, X (formerly Twitter), and Facebook. Human coding was used to identify prominent frames by which each comment was then coded to fall under. The following frames were identified from the comments: Denial, Encouragement, Timeliness, and Male Centricity, with Denial encompassing the largest number of comments across all three datasets. This study highlights the public discourse around sex-specific health topics and highlights the importance of intentional communication strategies when disseminating health information on social networking sites.
Clinical practice variation in the management of recurrent idiopathic focal segmental glomerulosclerosis (rFSGS) is poorly defined and likely hinders successful clinical trial design. We conducted an online survey between June 2024 and September 2024 of Pediatric Nephrology Research Consortium (PNRC) and European Society for Pediatric Nephrology (ESPN) members to evaluate global clinical practice patterns in the management of pediatric rFSGS and physician perceptions of barriers to rFSGS clinical trial participation. Of 120 responses (50 PNRC members from the US and Canada and 70 ESPN members from Europe, Asia, and South America), all respondents were physicians and 50% were transplant program medical directors. Pretransplant mutation analysis was routine in 104 (87%) centers, and native nephrectomy was routine for patients with and without hypoalbuminemia in 77 (66%) and 23 (19%) centers, respectively. Forty-two (35%) centers reported routine therapeutic interventions to prevent rFSGS prior to kidney transplantation; this increased to 79 centers (66%) in patients with previous recurrence. Plasmapheresis was the first therapeutic intervention in most centers, although it was used significantly more often in North America (96%) than Europe (77%; p = 0.005). Rituximab was administered in 102 (85%) centers as treatment for rFSGS. Common barriers to recruitment and inclusion of patients in clinical trials of rFSGS were limited site resources (36%), recipient/family reluctance (10%), and operational and logistical issues (26%). Heterogeneity of practice patterns in the management of pediatric rFSGS and barriers to clinical trials requires collaborative efforts to study and reach consensus on prevention and management of rFSGS.
Bone turnover abnormalities are common in chronic kidney disease (CKD) and contribute to bone fragility. Recently, the Kidney-Disease: Improving Global Outcomes (KDIGO) introduced the term CKD-associated osteoporosis to describe bone fragility in CKD and highlighted the role of bone turnover markers (BTM) in clinical evaluation and management of bone fragility. However, current clinical practice guidelines lack specific treatment targets for bone turnover. The aim of this consensus was to present recommendations for the use of BTM in the management of CKD-associated osteoporosis. The consensus was conducted by members of relevant working groups of the European Renal Association (ERA), International Osteoporosis Foundation (IOF), European Foundation for Clinical Chemistry and Laboratory Medicine (EFLM), and European Society of Pediatric Nephrology (ESPN). Bone-specific alkaline phosphatase and tartrate resistant acid phosphatase isoform 5b are not renally cleared and considered reliable diagnostic tools for bone evaluation in CKD-associated osteoporosis. Both have been proposed as reference BTM in CKD by a recent international consortium. Intact N-terminal telopeptide of type I collagen can also be used in CKD. The current consensus describes methodological considerations and the clinical usefulness of BTM in risk prediction, choice of therapeutic strategy, and treatment evaluation in CKD-associated osteoporosis. Specific diagnostic ranges for bone turnover abnormalities are provided. Future research should focus on the integration of these reference BTM with other diagnostic tools, establishment of concrete treatment targets, and development of treatment strategies to reach these targets.