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In dairy farming, the uncertainty of cow calving date often imposes waiting costs for days on farmers. Improving the accuracy of calving date prediction would mitigate these costs, specifically before a few days of the event. We monitored and analyzed the heart rate patterns of eight pregnant cows in the days leading up to calving using a dedicated monitoring device. We decomposed the heart rate data into three distinct components: trend, daily cycle, and the remainder, and discovered that the heart rate trend exhibited a sharp decline more than 40 h before the calving event via the trend turning point. To detect the turning point, we applied common financial technical indicators traditionally used to identify turning points of asset prices in trading markets for the extracted heart rate trend. This study remains a feasibility study because of the limited observations, but it indicates that these indicators can effectively capture the trend's turning point in real time, offering a promising approach for enhanced calving prediction. In addition to discussing the practical implications for cow management, we also contemplate the broader utility of these technical indicators in the context of various dynamic scientific data analyses.
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Industria Lechera , Estudios de Factibilidad , Frecuencia Cardíaca , Animales , Bovinos , Femenino , Embarazo , Frecuencia Cardíaca/fisiología , Industria Lechera/economía , Industria Lechera/métodos , Parto/fisiología , Factores de TiempoRESUMEN
OBJECTIVE: Immune thrombocytopenia (ITP) is a common bleeding disorder. Although global lipidomic analyses have identified a potential role for lipid species in platelet function, there is currently no evidence to support a causal relationship between plasma lipids and ITP. To investigate this further, we conducted a two-sample Mendelian randomization analysis to determine whether there is a genetically predicted causal relationship between 179 plasma lipid groups and ITP. METHODS: Genome-wide association data from 179 plasma lipid species from 7,174 Finnish subjects were used in a preliminary analysis of ITP GWAS data from the GWAS catalogue database (GCST90018865, case=675, control=488,749). Causal analyses were performed using random inverse variance weighting (IVW) with MR-Egger and weighted median as complementary analyses. Sensitivity analyses were conducted using the MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis. To assess the association of lipid metabolites with the risk of developing ITP, multivariate MR analysis was performed. Significant correlations were found. The final identification of lipid metabolites was further evaluated using the Steiger test for chain imbalance. RESULTS: The results of this study showed that six plasma lipid species, sterol esters (27:1/20:2) (SE) (odds ratio [OR]: 1.30, 95% confidence interval [CI]: 1.06-1.60, p=0.013), phosphatidylethanolamine (18:0_0:0) (PE) (OR: 1. 46, 95% CI: 1.10-1.95, p=0.009), phosphatidylcholine (16:0_18:3) (PC) (OR: 1.51, 95% CI: 1.12-2.02, p=0.006), phosphatidylcholine-ether (O-16:0_16:0) (PCO) (OR: 0.64, 95% CI: 0. 47-0.88, p = 0.005), phosphatidylethanolamine-ether (O-18:2_20:4) (PEO) (OR: 0.71, 95% CI: 0.55-0.93, p=0.013), triacylglycerol (49:1) (TAG) (OR: 1.65, 95% CI: 1.21-2.24, p=0.001), and ITP were all significantly correlated. MVMR analysis showed that genetically predicted phosphatidylcholine ethers may independently influence ITP without dependence on other metabolites. Triacylglycerol may be affected by other plasma liposomal metabolites and is a risk factor for the development of ITP. CONCLUSION: The current work provides evidence for a causal role of six plasma lipids in ITP and provides new perspectives for combining genomics and metabolomics to explore the biological mechanisms of ITP. These findings may contribute to the screening, prevention, and treatment of ITP.
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Estudio de Asociación del Genoma Completo , Lípidos , Análisis de la Aleatorización Mendeliana , Púrpura Trombocitopénica Idiopática , Humanos , Púrpura Trombocitopénica Idiopática/sangre , Púrpura Trombocitopénica Idiopática/genética , Lípidos/sangre , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
BACKGROUND: This retrospective study analyzed tumor tissue profiling data to assess the potential of comprehensive genomic profiling (CGP) for patient care across diverse solid tumors. MATERIAL AND METHODS: Patients with newly diagnosed or recurrent stage IIIB or IV lung adenocarcinoma with a null immunophenotype and esophageal, gastric, pancreatic, or bile duct cancer between January 2020 and July 2023 at two medical centers in Taiwan were included. One cohort was a part of the National Biobank Consortium of Taiwan project, whereas the other consisted of patients undergoing routine clinical practice. Tumor samples were subjected to CGP using FoundationOne®CDx, with therapeutic implications determined using OncoKB classification. RESULTS: FoundationOne®CDx testing of 574 patients was successful in 456 (79.4%) patients. Clinically actionable genomic alterations were detected in 21.1% (96/456) of the patients, including 17.5%, 2.9%, and 0.7% of patients with evidence levels 1, 2, and 3, respectively. Lung adenocarcinoma accounted for the largest proportion of samples with at least one actionable gene alteration (63.2%), followed by bile duct (26.9%), gastric (17.6%), esophageal (4.0%), and pancreatic (3.1%) cancers. Based on CGP results, 43 patients (9.4%) received matched targeted therapy. The median overall survival of patients who received matched therapy or not was 26.1 months (95% confidence interval (CI), 16.7-35.5 months) and 10.6 months (95% CI, 8.1-13.1 months; hazard ratio, 0.28, 95% CI, 0.14-0.55, p < 0.001), respectively. CONCLUSIONS: This study provides comprehensive insights into the genomic profiles of diverse cancers in Taiwan, highlighting the crucial role of CGP in identifying actionable genomic alterations and guiding effective therapeutic strategies in real-world practice.
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BACKGROUND: Breast cancer (BC) is the most common malignant tumor in women worldwide, and further elucidation of the molecular mechanisms involved in BC pathogenesis is essential to improve the prognosis of BC patients. RNA Binding Motif Protein 8 A (RBM8A), with high affinity to a myriad of RNA transcripts, has been shown to play a crucial role in genesis and progression of multiple cancers. We attempted to explore its functional significance and molecular mechanisms in BC. METHODS: Bioinformatics analysis was performed on publicly available BC datasets. qRT-PCR was used to determine the expression of RBM8A in BC tissues. MTT assay, clone formation assay and flow cytometry were employed to examine BC cell proliferation and apoptosis in vitro. RNA immunoprecipitation (RIP) and RIP-seq were used to investigate the binding of RBM8A/EIF4A3 to the mRNA of IGF1R/IRS-2. RBM8A and EIF4A3 interactions were determined by co-immunoprecipitation (Co-IP) and immunofluorescence. Chromatin immunoprecipitation (Ch-IP) and dual-luciferase reporter assay were carried out to investigate the transcriptional regulation of RBM8A by TEAD4. Xenograft model was used to explore the effects of RBM8A and TEAD4 on BC cell growth in vivo. RESULTS: In this study, we showed that RBM8A is abnormally highly expressed in BC and knockdown of RBM8A inhibits BC cell proliferation and induces apoptosis in vitro. EIF4A3, which phenocopy RBM8A in BC, forms a complex with RBM8A in BC. Moreover, EIF4A3 and RBM8A complex regulate the expression of IGF1R and IRS-2 to activate the PI3K/AKT signaling pathway, thereby promoting BC progression. In addition, we identified TEAD4 as a transcriptional activator of RBM8A by Ch-IP, dual luciferase reporter gene and a series of functional rescue assays. Furthermore, we demonstrated the in vivo pro-carcinogenic effects of TEAD4 and RBM8A by xenograft tumor experiments in nude mice. CONCLUSION: Collectively, these findings suggest that TEAD4 novel transcriptional target RBM8A interacts with EIF4A3 to increase IGF1R and IRS-2 expression and activate PI3K/AKT signaling pathway, thereby further promoting the malignant phenotype of BC cells.
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Neoplasias de la Mama , Proteínas de Unión al ADN , Regulación Neoplásica de la Expresión Génica , Proteínas Musculares , Proteínas de Unión al ARN , Receptor IGF Tipo 1 , Factores de Transcripción de Dominio TEA , Animales , Femenino , Humanos , Ratones , Apoptosis/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Ratones Desnudos , Proteínas Musculares/metabolismo , Proteínas Musculares/genética , Unión Proteica , Receptor IGF Tipo 1/metabolismo , Receptor IGF Tipo 1/genética , Receptores de Somatomedina/metabolismo , Receptores de Somatomedina/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Transducción de Señal , Factores de Transcripción de Dominio TEA/metabolismoRESUMEN
Epstein-Barr virus (EBV), a common gamma herpesvirus, establishes a life-long latent infection in the host to defend against innate immune recognition, which is closely related to a variety of malignant tumors, but its specific mechanism is unclear. BFRF3, an EBV-encoded small capsid protein, is mainly involved in the assembly of the viral capsid structure and the maintenance of its stability. Here, we showed that BFRF3 can inhibit TNF-α-mediated NF-кB promoter activation. Moreover, BFRF3 downregulates NF-кB-mediated promoter activation and transcription of inflammatory cytokines, including IL-6 and IL-8. Dual-luciferase reporter assay demonstrated that BFRF3 restrains NF-кB promoter activity at or below the p65 level, and coimmunoprecipitation analysis revealed that BFRF3 not only interacts with p65 but also binds to its critical truncated Rel homology domain (RHD) and transcriptional activation domain (TAD). However, BFRF3 does not affect the dimerization of p65-p50, but overexpression of BFRF3 reduces the nuclear accumulation of p65, and the phosphorylation of p65 (Ser536) is repressed during BFRF3 transfection and EBV lytic infection, which promotes the proliferation of EBV. Overall, our study suggested that BFRF3 may play a crucial role in antiviral immunity to defend against EBV infection by inhibiting NF-κB activity.
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Proteínas de la Cápside , Herpesvirus Humano 4 , FN-kappa B , Transducción de Señal , Factor de Transcripción ReIA , Humanos , Herpesvirus Humano 4/metabolismo , Herpesvirus Humano 4/inmunología , Herpesvirus Humano 4/fisiología , Proteínas de la Cápside/metabolismo , Proteínas de la Cápside/genética , Factor de Transcripción ReIA/metabolismo , FN-kappa B/metabolismo , Células HEK293 , Infecciones por Virus de Epstein-Barr/metabolismo , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/inmunología , Regiones Promotoras Genéticas , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
PURPOSE: To develop a novel adaptation of the Whitaker test for assessing the surgical effects of ileal ureter replacement (IUR), and to evaluate its feasibility and effect in the postoperative evaluation. PATIENTS AND METHODS: From November 2021 to September 2023, patients undergoing the modified Whitaker test following IUR were prospectively enrolled. The relative pressure was defined as the pelvis pressure minus the bladder pressure. Successful nephrostomy removal was defined as absence of symptoms and improved or stable hydronephrosis. RESULTS: The 51 ureters from 39 patients underwent the modified Whitaker test after IUR. The modified Whitaker test was performed successfully on all patients without any reported discomfort. The relative pressure of 47 ureters kept steady (< 15 cmH2O) throughout the examination with well ileal ureter peristalsis and was classified into type I. The relative pressure of 2 ureters increased with perfusion reaching a range of 15-22 cmH2O, with well ileal ureteral peristalsis observed (type II). The relative pressure of 2 ureters increased along with perfusion, with weakening of ileal ureter peristalsis or a leakage of contrast medium, and the relative pressure surpassed 22 cmH2O (type III). Nephrostomy tubes were promptly removed for type I and type II ureters, while removal for type III ureters occurred after a 2-month period. None of the 39 patients required additional interventions for recurrent obstruction. CONCLUSION: The modified Whitaker test was a safe and effective approach for the evaluation of surgical effects of IUR, offering additional evidence to assess the safety of nephrostomy tube removal.
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OBJECTIVE: Carpal Tunnel Syndrome (CTS) is a prevalent neuropathy where accurate diagnosis is crucial for effective treatment planning. This study introduces a novel approach for CTS grading using ultrasound, specifically through the analysis of the cross-sectional area (CSA) and shear wave elastography (SWE) of the median nerve in various wrist positions. METHODS: Our research involved subjects from outpatient clinics, diagnosed with CTS through Nerve Conduction Studies (NCS), and a control group of healthy individuals. High-frequency ultrasound and SWE measurements were conducted in three wrist positions: straight, 45° extension, and 45° flexion. RESULTS: The key findings revealed significant differences in median nerve CSA and SWE values between the CTS and control groups across all wrist positions, with notable variances in SWE values correlating with wrist positioning. SWE demonstrated enhanced sensitivity and specificity in distinguishing between mild, moderate, and severe CTS, especially at 45° wrist flexion. In contrast, CSA measurements were limited in differentiating between the varying severity stages of CTS. CONCLUSIONS: The study concludes that SWE, particularly at 45° wrist flexion, provides a more precise diagnostic benchmark for CTS severity grading than CSA. This advancement in non-invasive diagnostic methodology not only aids in accurate CTS grading but also has significant implications in formulating tailored treatment strategies, potentially reducing the reliance on more invasive diagnostic methods like NCS. ADVANCEMENT IN KNOWLEDGE: This study marks a significant advancement in the ultrasound diagnosis of CTS. It particularly highlights the importance of applying SWE technology across various wrist joint angles, offering a new diagnostic benchmark. This discovery provides data support and additional insights for achieving an early consensus on ultrasound-based grading diagnosis of CTS.
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Lignin is endowed with antioxidant activity due to its diverse chemical structure. It is necessary to explore the relationship between antioxidant activity and the chemical structure of the lignin to develop its high-value utilization. Herein, we employed maleic acid (MA) as a hydrotropic agent to preferably isolate the lignin from distinct herbaceous sources (wheat straw and switchgrass) under atmospheric pressure conditions. The resultant acid hydrotropic lignin (AHL) isolated from wheat straw exhibited high radical scavenging rates, up to 98% toward DPPH and 94% toward ABTS. Further investigations indicated that during the MA hydrotropic fractionation (MAHF) process, lignin was carboxylated by MA at γ-OH of the side-chain, providing additional antioxidant activity from the carboxy group. It was also found that the radical scavenging rate of AHL has a positive correlation with carboxyl, phenolic hydroxyl contents, and the S-G (syringyl-guaiacyl) ratio, which could be realized by increasing the MAHF severity. Overall, this work underlies the enhancement origin of the antioxidant property of lignin, which will facilitate its application in biological fields as an efficient, cheap, and renewable antioxidant additive.
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Antioxidantes , Biomasa , Fraccionamiento Químico , Lignina , Maleatos , Triticum , Lignina/química , Lignina/aislamiento & purificación , Antioxidantes/química , Antioxidantes/farmacología , Antioxidantes/aislamiento & purificación , Triticum/química , Fraccionamiento Químico/métodos , Maleatos/química , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Depuradores de Radicales Libres/aislamiento & purificación , Panicum/químicaRESUMEN
Liver cancer represents a grave hepatic condition and constitutes a significant global health concern. Surgical resection remains the principal therapeutic modality for liver cancer. Nevertheless, perioperative malnutrition exerts a notable impact on patients with liver cancer, emerging as an independent risk factor for disease mortality and adverse outcomes. Hence, precise nutritional diagnosis and timely nutritional support hold the potential to enhance therapeutic efficacy and quality of life for liver cancer patients. This study represents a meticulous foray into the literature, extracting data from PubMed, Web of Science, and EMBASE databases, with a focus on the past 5 years. It scrutinizes the impact of malnutrition on patients undergoing liver cancer surgery, the etiological underpinnings of malnutrition within this patient cohort, the critical assessment of perioperative nutritional status, and the strategic approaches to nutritional support. Utilizing rigorous inclusion and exclusion criteria, the amassed scholarly works are meticulously synthesized, methodically organized, and categorically elaborated upon. Ultimately, the authors propose the incorporation of a multidisciplinary nutrition management team during the perioperative period, comprising nutritionists, pharmacists, physicians, nurses, psychologists, and rehabilitation therapists, among other specialized professionals. Together, they collaborate to devise and implement personalized nutritional support plans, monitor patients' nutritional status, and make necessary adjustments as required. Through comprehensive management and intervention, improvements in the nutritional status of liver cancer patients can be achieved, thereby enhancing surgical success rates and facilitating postoperative recovery. It is believed that this manuscript will offer valuable insights to advance the nutritional management during the perioperative phase of liver cancer, aiding in ameliorating patients' nutritional status and treatment outcomes.
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Horseshoe bats (genus Rhinolophus, family Rhinolophidae) represent an important group within chiropteran phylogeny due to their distinctive traits, including constant high-frequency echolocation, rapid karyotype evolution, and unique immune system. Advances in evolutionary biology, supported by high-quality reference genomes and comprehensive whole-genome data, have significantly enhanced our understanding of species origins, speciation mechanisms, adaptive evolutionary processes, and phenotypic diversity. However, genomic research and understanding of the evolutionary patterns of Rhinolophus are severely constrained by limited data, with only a single published genome of R. ferrumequinum currently available. In this study, we constructed a high-quality chromosome-level reference genome for the intermediate horseshoe bat ( R. affinis). Comparative genomic analyses revealed potential genetic characteristics associated with virus tolerance in Rhinolophidae. Notably, we observed expansions in several immune-related gene families and identified various genes functionally associated with the SARS-CoV-2 signaling pathway, DNA repair, and apoptosis, which displayed signs of rapid evolution. In addition, we observed an expansion of the major histocompatibility complex class II (MHC-II) region and a higher copy number of the HLA- DQB2 gene in horseshoe bats compared to other chiropteran species. Based on whole-genome resequencing and population genomic analyses, we identified multiple candidate loci (e.g., GLI3) associated with variations in echolocation call frequency across R. affinis subspecies. This research not only expands our understanding of the genetic characteristics of the Rhinolophus genus but also establishes a valuable foundation for future research.
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Quirópteros , Ecolocación , Genoma , Animales , Quirópteros/genética , Quirópteros/virología , Quirópteros/fisiología , SARS-CoV-2/fisiología , SARS-CoV-2/genética , Cromosomas/genéticaRESUMEN
Introduction: Due to its unique structural features and bioactivities, the lignin-carbohydrate complex (LCC) displays great potential in vast industrial applications. However, the elucidation of how various pretreatment methods affect the structure and bioactivities remains unaddressed. Method: The three pretreatment methods were systematically studied on the variations of structures and bioactivities, and the Gramineae plant, i.e., wheat straw, was adopted in this study. The structures and bioactivities variation caused by different pretreatments were studied in detail. Result and Discussion: The results showed that compared to physical or chemical pretreatments, biological pretreatment was the most effective approach in improving the bioactivities of LCC. The LCC from biological pretreatment (enzymatic hydrolysis, ELCC4) had more functional groups while the lower weight-average molecular weight (Mw) and polydispersity index (PDI) were well-endowed. The highest antioxidant abilities against ABTS and DPPH of ELCC4 were high up to 95% and 84%, respectively. Furthermore, ELCC4 also showed the best ultraviolet (UV)-blocking rate of 96%, which was increased by 6% and 2% compared to LCC8 (physical pretreatment) and LLCC4 (chemical pretreatment). This work prospectively boosts the understanding of pretreatment strategies on the structures and bioactivities variation of LCC and facilitates its utilization as sustainable and biologically active materials in various fields.
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OBJECTIVE: Infliximab is a first-line biologic agent for the treatment of Crohn's disease (CD), in which loss of response (LOR) remains a challenge in the treatment of patients with CD. The study aimed to explore the association between body composition parameters and LOR to infliximab in CD patients. METHODS: 118 patients with CD admitted to the First Affiliated Hospital of Wenzhou Medical University and treated with infliximab from June 2015 to December 2021 were retrospectively enrolled. The body composition of patients was analyzed by computed tomography (CT). The primary outcome measure was the one-year LOR. Patients were divided into the Remission group and the LOR group to analyze the association between body composition parameters and the LOR to infliximab. RESULTS: The rate of sarcopenia in the LOR group was higher than in the Remission group (83.7% vs. 60.0%, P=0.008). Multivariate analysis showed that females had a lower risk of sarcopenia than males (OR=0.30, 95%CI 0.11-0.81, P =0.017); BMI was significantly associated with sarcopenia (OR=0.68, 95%CI 0.56-0.83, P <0.001); L1 CD and L2 CD had a lower risk of sarcopenia than L3 CD (OR=0.29, 95%CI 0.10-0.83, P =0.021; OR=0.25, 95%CI 0.07-0.87, P=0.028). CONCLUSIONS: Sarcopenia was identified as a risk factor for developing LOR in infliximab-treated patients.
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Background and objective: Few studies on endoscopic management of primary obstructive megaureter (POM) in adult patients have been reported. Our objective was to describe our technique and long-term outcomes for endoscopic management of adult POM. Methods: We included 76 adult POM patients undergoing endoscopic management between September 2015 and January 2024. Under endoscopic control, the stricture was dilated to 24-30 Fr while maintaining a balloon pressure of 25-35 atm for 3 min. An additional incision of the stenotic ring using either an electrode or holmium laser was performed in 39 patients. Data for patient characteristics, intraoperative variables, surgical complications, and follow-up results were analyzed. A descriptive statistical analysis was performed. Surgical success was defined as no tubes or stents in the body, stable or improved symptoms and renal function, and the absence of reflux or obstruction during the follow-up period. Key findings and limitations: All procedures were completed without conversion to open or laparoscopic surgery. The median operative time was 45 min (range 16-165) with median estimated blood loss of 2 ml (range 0-150). The median postoperative hospital stay was 3 d (range 1-15). No intraoperative complication occurred. At median postoperative follow-up of 42 mo (range 3-100) the overall success rate was 92.1%. Restenosis of the vesicoureteral junction (Clavien-Dindo grade III) occurred in five patients (6.6%), and high-grade vesicoureteral reflux occurred in one patient (1.3%), all of whom required secondary reconstruction surgery. Conclusions and clinical implications: The results indicate that our endoscopic management for adult POM is safe and effective, with favorable long-term outcomes. This approach could potentially serve as a first-line treatment option for adult POM. Patient summary: Primary obstructive megaureter (POM) occurs when the flow of urine is blocked because of a narrow segment in the tube between the kidney and bladder (ureter), which causes widening of the ureter further up. For our minimally invasive technique, a telescope is inserted through the urethra and bladder to reach the ureter for surgical treatment. Our results show that this is a safe procedure for POM in adults.
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Observational and genetic studies have reported the relationship between dyslexia and Alzheimer's disease (AD). Until now, the causal effect of dyslexia on AD risk has remained unclear. We conducted a two-sample univariable Mendelian randomization (MR) analysis to determine the causal association between dyslexia and the risk of AD, vascular dementia (VD), Lewy body dementia (LBD), and frontotemporal dementia (FTD) and its four subtypes. First, we selected 42 dyslexia genetic variants from a large-scale genome-wide association studies (GWAS) dataset and extracted their corresponding GWAS summary statistics from AD, VD, LBD, and FTD. Second, we selected four MR methods, including inverse-variance weighted (IVW), weighted median, MR-Egger, and MR-PRESSO. Heterogeneity, horizontal pleiotropy, and leave-one-out sensitivity analysis were then used to evaluate the reliability of all causal estimates. We also conducted multivariable MR (MVMR) and mediation analysis to assess the potential mediating role of cognitive performance (CP) or educational achievement (EA) on the causal association between dyslexia and AD. Two MVMR methods, including MV IVW and MV-Egger, and two-step MR were used to perform the analysis. Using IVW, we found a significant causal association between increased dyslexia and increased risk of AD (OR = 1.15, 95% CI: 1.04-1.28, P = 0.006), but not VD, LBD, FTD, or its four subtypes. MR-PRESSO further supported the statistically significant association between dyslexia and AD (OR = 1.15, 95% CI: 1.05-1.27, P = 0.006). All sensitivity analyses confirmed the reliability of causal estimates. Using MV IVW and mediation analysis, we found no causal relationship between dyslexia and AD after adjusting for CP but not EA, CP mediated the total effect of dyslexia on AD with a proportion of 46.32%. We provide genetic evidence to support a causal effect of increased dyslexia on increased risk of AD, which was largely mediated by CP. Reading activity may be a potential intervention strategy for AD by improving cognitive function.
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Enfermedad de Alzheimer , Dislexia , Demencia Frontotemporal , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Humanos , Dislexia/genética , Demencia Frontotemporal/genética , Enfermedad de Alzheimer/genética , Enfermedad por Cuerpos de Lewy/genética , Demencia Vascular/genética , Demencia/genética , Demencia/etiología , Demencia/epidemiología , Factores de Riesgo , CausalidadRESUMEN
Paraneoplastic leukocytosis (PNL) in genitourinary cancer, though rare, can indicate aggressive behavior and poor outcomes. It has been potentially linked to cancer expressing G-CSF and GM-CSF, along with their respective receptors, exerting an autocrine/paracrine effect. In our study, we successfully established four patient-derived xenograft (PDX) lines and related cell lines from urothelial cancer (UC), conducting next-generation sequencing (NGS) for genetic studies. UC-PDX-LN1, originating from bladder cancer, exhibited two druggable targets - HRAS and ERCC2 - responding well to chemotherapy and targeted therapy, though not to tipifarnib, an HRAS inhibitor. Transcriptome analysis post-treatment illuminated potential mechanisms, with index protein analysis confirming their anticancer pathways. Mice implanted with UC-PDX-LN1 mirrored PNL observed in the patient's original tumor. Cytokine array and RT-PCR analyses revealed high levels of G-CSF and GM-CSF in our PDX and cell lines, along with their presence in culture media and tumor cysts.Leukocytosis within small vessels in and around the tumor, associated with NETosis and thrombus formation, suggested a mechanism wherein secreted growth factors were retained, further fueling tumor growth via autocrine/paracrine signaling. Disrupting this cancer cell-NETosis-thrombosis cycle, we demonstrated that anti-neutrophil or anticoagulant interventions enhanced chemotherapy's antitumor effects or prolonged survival in mice, even though these drugs lacked direct antitumor efficacy when used independently. Clinical observations in bladder cancer patients revealed PNL in 1.61% of cases (35/2162) with associated poor prognosis. These findings propose a novel approach, advocating for the combination of anticancer/NETosis/thrombosis strategies for managing UC patients presenting with PNL in clinical settings.
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Reproductive aging in female mammals is characterized by ovarian senescence, leading to a significant fertility decline. Lycium barbarum berry, or goji berry, is a food and medicine that appears in various formulas for treating infertility in traditional Chinese medicine. We investigated the function of an aqueous extract of Lycium barbarum berry (LB extract) to improve health status, fertility, and offspring development during female aging. Aged female mice were supplemented with LB extract, and its effects on fertility, locomotor activity, and offspring development were assessed. The results demonstrated that LB extract significantly increased pregnancy and live birth rates in naturally aged female mice. It also effectively improved aged animals' locomotor activity. Moreover, LB extract promoted the growth and development of offspring delivered from the aged animals and reduced the offspring's anxiety. During aging, fertility-related hormones gradually decline. However, the decline of anti-Müllerian hormone (AMH) and estradiol (E2) in the serum of aged mice was restored by LB extract supplementation. Immunohistochemical analysis revealed that the levels of oxidation and the inflammatory IL-6 in intra-ovarian cells were reduced by LB extract, while the antioxidant-associated proteins peroxiredoxin 4 (PRDX4) and nuclear factor erythroid 2-related factor 2 (NRF2) were increased. Bioinformatics analysis revealed a decline in egg PRDX4 expression with age across various species. This suggests that the antioxidant function protected by LB extract through PRDX4 may consistently promote fertility enhancement by improving ovarian function across different species. Importantly, LB extract did not induce significant adverse effects on aged female mice and their offspring. These findings highlight the potential of LB as a protective agent against ovarian oxidative stress, which preserves ovarian function and improves fertility rates in naturally senescent females.
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BACKGROUND: The KCNQ1+KCNE1 (IKs) potassium channel plays a crucial role in cardiac adaptation to stress, in which ß-adrenergic stimulation phosphorylates the IKs channel through the cyclic adenosine monophosphate (cAMP)/PKA (protein kinase A) pathway. Phosphorylation increases the channel current and accelerates repolarization to adapt to an increased heart rate. Variants in KCNQ1 can cause long-QT syndrome type 1 (LQT1), and those with defective cAMP effects predispose patients to the highest risk of cardiac arrest and sudden death. However, the molecular connection between IKs channel phosphorylation and channel function, as well as why high-risk LQT1 mutations lose cAMP sensitivity, remain unclear. METHODS: Regular patch clamp and voltage clamp fluorometry techniques were utilized to record pore opening and voltage sensor movement of wild-type and mutant KCNQ1/IKs channels. The clinical phenotypic penetrance of each LQT1 mutation was analyzed as a metric for assessing their clinical risk. The patient-specific-induced pluripotent stem-cell model was used to test mechanistic findings in physiological conditions. RESULTS: By systematically elucidating mechanisms of a series of LQT1 variants that lack cAMP sensitivity, we identified molecular determinants of IKs channel regulation by phosphorylation. These key residues are distributed across the N-terminus of KCNQ1 extending to the central pore region of IKs. We refer to this pattern as the IKs channel PKA phosphorylation axis. Next, by examining LQT1 variants from clinical databases containing 10 579 LQT1 carriers, we found that the distribution of the most high-penetrance LQT1 variants extends across the IKs channel PKA phosphorylation axis, demonstrating its clinical relevance. Furthermore, we found that a small molecule, ML277, which binds at the center of the phosphorylation axis, rescues the defective cAMP effects of multiple high-risk LQT1 variants. This finding was then tested in high-risk patient-specific induced pluripotent stem cell-derived cardiomyocytes, where ML277 remarkably alleviates the beating abnormalities. CONCLUSIONS: Our findings not only elucidate the molecular mechanism of PKA-dependent IKs channel phosphorylation but also provide an effective antiarrhythmic strategy for patients with high-risk LQT1 variants.
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Proteínas Quinasas Dependientes de AMP Cíclico , Células Madre Pluripotentes Inducidas , Canal de Potasio KCNQ1 , Humanos , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Fosforilación , Canal de Potasio KCNQ1/genética , Canal de Potasio KCNQ1/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Síndrome de Romano-Ward/genética , Síndrome de Romano-Ward/metabolismo , AMP Cíclico/metabolismo , Miocitos Cardíacos/metabolismo , Mutación , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/metabolismo , Células HEK293 , Canales de Potasio con Entrada de VoltajeRESUMEN
Increased fatty acid synthesis benefits glioblastoma malignancy. However, the coordinated regulation of cytosolic acetyl-CoA production, the exclusive substrate for fatty acid synthesis, remains unclear. Here, we show that proto-oncogene tyrosine kinase c-SRC is activated in glioblastoma and remodels cytosolic acetyl-CoA production for fatty acid synthesis. Firstly, acetate is an important substrate for fatty acid synthesis in glioblastoma. c-SRC phosphorylates acetyl-CoA synthetase ACSS2 at Tyr530 and Tyr562 to stimulate the conversion of acetate to acetyl-CoA in cytosol. Secondly, c-SRC inhibits citrate-derived acetyl-CoA synthesis by phosphorylating ATP-citrate lyase ACLY at Tyr682. ACLY phosphorylation shunts citrate to IDH1-catalyzed NADPH production to provide reducing equivalent for fatty acid synthesis. The c-SRC-unresponsive double-mutation of ACSS2 and ACLY significantly reduces fatty acid synthesis and hampers glioblastoma progression. In conclusion, this remodeling fulfills the dual needs of glioblastoma cells for both acetyl-CoA and NADPH in fatty acid synthesis and provides evidence for glioma treatment by c-SRC inhibition.