Bmi1 facilitates the progression of cholangiocarcinoma by inhibiting Foxn2 expression dependent on a histone H2A ubiquitination manner.

Cholangiocarcinoma (CCA), an exceptionally aggressive malignancy originating from the epithelium of the bile duct, poses a formidable challenge in cancer research and clinical management. Currently, attention is focused on exploring the oncogenic role and prognostic implications associated with Bmi1 in the context of CCA. In our study, we assessed the correlation of Bmi1 and Foxn2 expression across all types of CCA and evaluated their prognostic significance. Our results demonstrated that Bmi1 exhibits significantly upregulated expression in CCA tissues, while Foxn2 expression shows an inverse pattern. Simultaneously, the high expression of Bmi1, coupled with the low expression of Foxn2, indicates an unfavorable prognosis. Through in vitro and in vivo experiments, we confirmed the crucial role of Foxn2 in the proliferation, metastasis, and epithelial-mesenchymal transition (EMT) of CCA. Mechanistically, Bmi1 promotes the ubiquitination of histone H2A (H2AUb), leading to chromatin opening attenuation and a decrease in Foxn2 expression, ultimately driving CCA progression. Additionally, we described the potential value of Bmi1 and H2AUb inhibitors in treating CCA through in vitro experiments and orthotopic models. This study is of significant importance in deepening our understanding of the interaction between Bmi1 and Foxn2 in CCA and has the potential to advance the development of precision therapies for CCA.

Collagen degradation assessment with an in vitro rotator cuff tendinopathy model using multiparametric ultrashort-TE magnetization transfer (UTE-MT) imaging.

PURPOSE: This study aims to assess ultrashort-TE magnetization transfer (UTE-MT) imaging of collagen degradation using an in vitro model of rotator cuff tendinopathy. METHODS: Thirty-six supraspinatus tendon specimens were divided into three groups and treated with 600 U collagenase (Group 1), 150 U collagenase (Group 2), and phosphate buffer saline (Group 3). UTE-MT imaging was performed to assess changes in macromolecular fraction (MMF), macromolecule transverse relaxation time (T2m), water longitudinal relaxation rate constant (R1m), the magnetization exchange rate from the macromolecular to water pool (Rm0 w) and from water to the macromolecular pool (Rm0 m), and magnetization transfer ratio (MTR) at baseline and following digestion and their differences between groups. Biochemical and histological studies were conducted to determine the extent of collagen degradation. Correlation analyses were performed with MMF, T2m, R1m, Rm0 w, Rm0 m, and MTR, respectively. Univariate and multivariate linear regression analyses were performed to evaluate combinations of UTE-MT parameters to predict collagen degradation. RESULTS: MMF, T2m, R1m, Rm0 m, and MTR decreased after digestion. MMF (r = -0.842, p < 0.001), MTR (r = -0.78, p < 0.001), and Rm0 m (r = -0.662, p < 0.001) were strongly negatively correlated with collagen degradation. The linear regression model of differences in MMF and Rm0 m before and after digestion explained 68.9% of collagen degradation variation in the tendon. The model of postdigestion in MMF and T2m and the model of MTR explained 54.2% and 52.3% of collagen degradation variation, respectively. CONCLUSION: This study highlighted the potential of UTE-MT parameters for evaluation of supraspinatus tendinopathy.

Cogeneration of Clean Water and Valuable Energy/Resources via Interfacial Solar Evaporation.

Water, covering over two-thirds of the Earth's surface, holds immense potential for generating clean water, sustainable energy, and metal resources, which are the cornerstones of modern society and future development. It is highly desired to produce these crucial elements through eco-friendly processes with minimal carbon footprints. Interfacial solar evaporation, which utilizes solar energy at the air-liquid interface to facilitate water vaporization and solute separation, offers a promising solution. In this review, we systematically report the recent progress of the cogeneration of clean water and energy/resources including electricity, hydrogen, and metal resources via interfacial solar evaporation. We first gain insight into the energy and mass transport for a typical interfacial solar evaporation system and reveal the residual energy and resources for achieving the cogeneration goal. Then, we summarize the recent advances in materials/device designs for efficient cogeneration. Finally, we discuss the existing challenges and potential opportunities for the further development of this field.

Large skin defect in Type V aplasia cutis congenita treated with conservative treatment: a case report.

Aplasia cutis congenita (ACC) is a congenital disorder that can be classified into nine types, with Type I ACC being the most common. Type V ACC associated with fetus papyraceus is a rare subtype of ACC. We report the case of a Type V ACC in a male newborn with extensive abdominal skin defects. The patient received conservative treatment using hydrogel foam and silicone foam dressings. Approximately five weeks later, the patient was discharged when more than 60% of the skin had completed epithelialization. After discharge from West China Second University Hospital, Chengdu , the patient continued to be followed up regularly at the Burns and Plastic Surgery Clinic at local hospital in Gansu. We followed up the child by telephone. After 4 months of follow-up, scar tissue formation was observed in the trunk area. The infant is 2 years and 5 months old now, physical examination did not reveal any organ problems.

Integrating Photoelectrochemical Feature on a Hydrovoltaic Chip with High-Salinity Adaption as a Self-Powered Device for Formaldehyde Monitoring.

Alternative energy sources are required due to the decline in fossil fuel resources. Therefore, devices that utilize hydrovoltaic technology and light energy have drawn widespread attention because they are emission-free and solar energy is inexhaustible. However, previous investigations mainly focused on accelerating the water evaporation rate at the electrode interface. Here, a cooperative photoelectrochemical effect on a hydrovoltaic chip is achieved using NH2-MIL-125-modified TiO2 nanotube arrays (NTs). This device demonstrated significantly improved evaporation-triggered electricity generation. Under LED illumination, the open-circuit voltage (VOC) of the NH2-MIL-125/TiO2NTs active layer of the hydrovoltaic chip was enhanced by 90.3% (up to 400.2 mV). Furthermore, the prepared hydrovoltaic chip showed good high-salinity tolerance, maintaining 74.6% of its performance even in 5 M NaCl. By introducing a Schiff-based reaction between the active layer and formaldehyde, a fully integrated flexible sensor was successfully fabricated for formaldehyde monitoring, and a low limit of detection of 5.2 × 10-9 M was achieved. This novel strategy for improving the performance of hydrovoltaic devices offers a completely new general approach to construct self-powered devices for point-of-care sensing.

Exploration of the application potential of serum multi-biomarker model in colorectal cancer screening.

Analyzing blood lipid and bile acid profile changes in colorectal cancer (CRC) patients. Evaluating the integrated model's diagnostic significance for CRC. Ninety-one individuals with colorectal cancer (CRC group) and 120 healthy volunteers (HC group) were selected for comparison. Serum levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and apolipoproteins (Apo) A1, ApoA2, ApoB, ApoC2, and ApoC3 were measured using immunoturbidimetric and colorimetric methods. Additionally, LC-MS/MS was employed to detect fifteen bile acids in the serum, along with six tumor markers: carcinoembryonic antigen (CEA), carbohydrate antigens (CA) 125, CA19-9, CA242, CA50, and CA72-4. Group comparisons utilized independent sample t-tests and Mann-Whitney U tests. A binary logistic regression algorithm was applied to fit the indicators and establish a screening model; the diagnostic accuracy of individual Indicators and the model was analyzed using receiver operating characteristic (ROC) curves. The CRC group showed significantly lower levels in eight serum lipid indicators and eleven bile acids compared to the HC group (P < 0.05). Conversely, serum levels of TG, CA19-9, and CEA were elevated (P < 0.05). Among the measured parameters, ApoA2 stands out for its strong correlation with the presence of CRC, showcasing exceptional screening efficacy with an area under the curve (AUC) of 0.957, a sensitivity of 85.71%, and a specificity of 93.33%. The screening model, integrating ApoA1, ApoA2, lithocholic acid (LCA), and CEA, attained an impressive AUC of 0.995, surpassing the diagnostic accuracy of individual lipids, bile acids, and tumor markers. CRC patients manifest noteworthy alterations in both blood lipids and bile acid profiles. A screening model incorporating ApoA1, ApoA2, LCA, and CEA provides valuable insights for detecting CRC.

Homochiral light-sensitive metal-organic framework photoelectrochemical gated transistor for enantioselective discrimination of monosaccharides.

As pure antipodes may differ in biological interactions, pharmacology, and toxicity, discrimination of enantiomers is important in the pharmaceutical and agrochemical industries. Two major challenges in enantiomer determination are transducing and amplifying the distinct chiral-recognition signals. In this study, a light-sensitive organic photoelectrochemical transistor (OPECT) with homochiral character is developed for enantiomer discrimination. Demonstrated with the discrimination of glucose enantiomers, the photoelectrochemically active gate electrode is prepared by integrating Au nanoparticles (AuNPs) and a chiral Cu(II)-metal-organic framework (c-CuMOF) onto TiO2 nanotube arrays (TNT). The captured glucose enantiomers are oxidized to hydrogen peroxide (H2O2) by the oxidase-mimicking AuNPs-loaded c-CuMOF. Based on the confinement effect of the mesopocket structure of the c-CuMOF and the remarkable charge transfer ability of the 1D nanotubular architecture, variations in H2O2 yield are translated into significant changes in OPECT drain currents (ID) by inducing a catalytic precipitation reaction. Variations in ID confer a sensitive discrimination of glucose enantiomers with a limit of detection (LOD) of 0.07 µM for L-Glu and 0.05 µM for D-Glu. This enantiomer-driven gate electrode response strategy not only provides a new route for enantiomer identification, but also helps to understand the origin of the high stereoselectivity in living systems.

Auditory change detection and visual selective attention: association between MMN and N2pc.

While the auditory and visual systems each provide distinct information to our brain, they also work together to process and prioritize input to address ever-changing conditions. Previous studies highlighted the trade-off between auditory change detection and visual selective attention; however, the relationship between them is still unclear. Here, we recorded electroencephalography signals from 106 healthy adults in three experiments. Our findings revealed a positive correlation at the population level between the amplitudes of event-related potential indices associated with auditory change detection (mismatch negativity) and visual selective attention (posterior contralateral N2) when elicited in separate tasks. This correlation persisted even when participants performed a visual task while disregarding simultaneous auditory stimuli. Interestingly, as visual attention demand increased, participants whose posterior contralateral N2 amplitude increased the most exhibited the largest reduction in mismatch negativity, suggesting a within-subject trade-off between the two processes. Taken together, our results suggest an intimate relationship and potential shared mechanism between auditory change detection and visual selective attention. We liken this to a total capacity limit that varies between individuals, which could drive correlated individual differences in auditory change detection and visual selective attention, and also within-subject competition between the two, with task-based modulation of visual attention causing within-participant decrease in auditory change detection sensitivity.

[Research progress on chemical constituents and pharmacological activities of small molecule compounds in scorpions].

Scorpions, a group of oldest animals with wide distribution in the world, have a long history of medicinal use. Scorpio, the dried body of Buthus martensii, is a rare animal medicine mainly used for the treatment of liver diseases, spasm, and convulsions in children in China. The venom has been considered as the active substance of scorpions. However, little is known about the small molecules in the venom of scorpions. According to the articles published in recent years, scorpions contain amino acids, fatty acids, steroids, and alkaloids, which endow scorpions with antimicrobial, anticoagulant, metabolism-regulating, and antitumor activities. This paper summarizes the small molecule chemical components and pharmacological activities of scorpions, with a view to providing valuable information for the discovery of new active molecules and the clinical use of scorpions.

Metabolic syndrome's new therapy: Supplement the gut microbiome.

This letter to the editor discusses the publication on gut microbiome supplementation as therapy for metabolic syndrome. Gut microbiome dysbiosis disrupts intestinal bacterial homeostasis and is related to chronic inflammation, insulin resistance, cardiovascular diseases, type 2 diabetes mellitus, and obesity. Previous research has found that increasing the abundance of beneficial microbiota in the gut modulates metabolic syndrome by reducing chronic inflammation and insulin resistance. Prebiotics, probiotics, synbiotics, and postbiotics are often used as supplements to increase the number of beneficial microbes and thus the production of short-chain fatty acids, which have positive effects on the gut microbiome and metabolic syndrome. In this review article, the author summarizes the available supplements to increase the abundance of beneficial gut microbiota and reduce the abundance of harmful microbiota in patients with metabolic disorders. Our group is also researching the role of the gut microbiota in chronic liver disease. This article will be of great help to our research. At the end of the letter, the mechanism of the gut microbiota in chronic liver disease is discussed.

Pore-Forming Toxin-Driven Recovery of Peroxidase-Mimicking Activity in Biomass Channels for Label-Free Electrochemical Bacteria Sensing.

The development of sensitive, selective, and rapid methods to detect bacteria in complex media is essential to ensuring human health. Virulence factors, particularly pore-forming toxins (PFTs) secreted by pathogenic bacteria, play a crucial role in bacterial diseases and serve as indicators of disease severity. In this study, a nanochannel-based label-free electrochemical sensing platform was developed for the detection of specific pathogenic bacteria based on their secreted PFTs. In this design, wood substrate channels were functionalized with a Fe-based metal-organic framework (FeMOF) and then protected with a layer of phosphatidylcholine (PC)-based phospholipid membrane (PM) that serves as a peroxidase mimetic and a channel gatekeeper, respectively. Using Staphylococcus aureus (S. aureus) as the model bacteria, the PC-specific PFTs secreted by S. aureus perforate the PM layer. Now exposed to the FeMOF, uncharged 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) molecules in the electrolyte undergo oxidation to cationic products (ABTS•+). The measured transmembrane ionic current indicates the presence of S. aureus and methicillin-resistant S. aureus (MRSA) with a low detection limit of 3 cfu mL-1. Besides excellent specificity, this sensing approach exhibits satisfactory performance for the detection of target bacteria in the complex media of food.

Rspo2-LGR4 exacerbates hepatocellular carcinoma progression via activation of Wnt/b-catenin signaling pathway / Rspo2-LGR4 agrava la progresión del carcinoma hepatocelular al activar la vía de señalización Wnt/beta-catenina

Background: The leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4) plays an important role in stem cell differentiation, organ development and cancer. Whether LGR4 affects the progression of hepatocellular carcinoma (HCC) remains unknown. This study aimed to reveal the role of LGR4 in HCC. Methods: Clinical samples of HCC were collected to assess the expression of LGR4 and its correlation with patients’ clinical characteristics. The expression level of LGR4 in HCC cells was altered by pharmacological and genetic methods, and the role of LGR4 in HCC progression was analyzed by in vivo and in vitro assays. HCC was induced by diethylnitrosamine (DEN) and carbon tetrachloride (CCl4) in wild-type and LGR4 deficient mice, the effect of LGR4 on HCC was examined by histopathological evaluation and biochemical assays. Results: LGR4 expression was up-regulated in HCC samples, and its expression level was positively correlated with tumor size, microvascular invasion (MVI), TNM stage and pathological differentiation grade of HCC patients. In the mouse HCC model induced by DEN+CCl4, knockdown of LGR4 effectively inhibited the progression of HCC. Silencing of LGR4 inhibited the proliferation, migration, invasion, stem cell-like properties and Warburg effect of HCC cells. These phenotypes were promoted by R-spondin2 (Rspo2), an endogenous ligand for LGR4. Rspo2 markedly increased the nuclear translocation of β-catenin, whereas IWR-1, an inhibitor of Wnt/β-catenin signaling, reversed its effect. Deficiency of LGR4 significantly reduced the nuclear translocation of β-catenin and the expression of its downstream target genes cyclinD1 and c-Myc. Conclusions: LGR4 promotes HCC progression via Wnt/β-catenin signaling pathway. (AU)

Antecedentes: El receptor de acoplamiento de proteínas G de secuencia repetida 4 (LGR4), rico en leucina, juega un papel importante en la diferenciación de células madre, el desarrollo de órganos y el cáncer. Se desconoce si LGR4 afecta la progresión del carcinoma hepatocelular (HCC). El objetivo de este estudio es revelar el papel de LGR4 en el HCC. Métodos: Se recolectaron muestras clínicas de HCC para evaluar la expresión de LGR4 y su correlación con los resultados clínicos de HCC. Alterar los niveles de expresión de LGR4 en las células de HCC mediante métodos farmacológicos y genéticos y analizar el papel de LGR4 en la progresión del cáncer de hígado mediante mediciones in vivo e in vitro. El HCC fue inducido en ratones de tipo salvaje y con defectos de LGR4 con Nitrosamina de dietilo (DEN) y cloruro de carbono (CCl4), y los efectos de LGR4 sobre el HCC fueron detectados por evaluación histopatológica y determinación bioquímica. Resultados: La expresión de LGR4 está regulada en HCC, y su nivel de expresión está positivamente relacionado con el tamaño tumoral, la infiltración microvascular (MVI), la etapa de TNM y el grado de diferenciación patológica en pacientes con HCC. En el modelo de HCC de ratón inducido por DEN+CCl4, golpear bajo LGR4 inhibió efectivamente la progresión del HCC. El silencio de LGR4 inhibe la proliferación, migración, invasión, propiedades similares a las células madre y el efecto Warburg de las células HCC. Estos fenotipos son promovidos por el ligando endógeno roof slab-specific sponge 2 (Rspo2)de LGR4. El Rspo2 aumentó significativamente la translocación nuclear de la proteína beta-catenina, mientras que el inhibidor de la señalización Wnt/beta-cateninaIWR-1 revirtió su acción... (AU)

Clinical pathological characteristics of "crawling-type" gastric adenocarcinoma cancer: A case report.

BACKGROUND: Gastric cancer (GC) is a significant health problem worldwide, and early detection and accurate diagnosis are crucial for improving patient outcomes. Crawling-type gastric adenocarcinoma is a rare subtype of GC that has unique histopathological and clinical characteristics, and its diagnosis and management can be challenging. This pathological type of GC is also rare. CASE SUMMARY: Here, we report the case of a patient who underwent ordinary endoscopy, narrow-band imaging, and endoscopic ultrasonography intending to determine the extent of tumor invasion and upper abdominal enhanced computed tomography and whether there was tumor metastasis. Then, endoscopic submucosal dissection was performed. After pathological and immunohistochemical examination, the pathological diagnosis was crawling-type gastric adenocarcinoma. This is a very rare and special pathological type of tumor. This case highlights the importance of using advanced endoscopic techniques and pathological examination in diagnosing and managing gastric crawling-type adenocarcinoma. Moreover, the findings underscore the need for continued research and clinical experience in this rare subtype of GC to improve patient outcomes. CONCLUSION: The "crawling-type" GC is a rare and specific tumor pathology. It is difficult to identify and diagnose gliomas via endoscopy. The tumor is ill-defined, with a flat appearance and indistinct borders due to the lack of contrast against the background mucosa. Pathology revealed that the tumor cells were hand-like, so the patient has diagnosed with "crawling-type" gastric adenocarcinoma.

TTN Mutation in Endometrial Endometrioid Carcinoma Is Associated with Poor Clinical Outcomes and High Tumor Mutation Burden.

Endometrioid endometrial carcinoma (EEC) stands as a prevalent gynecologic malignancy in developed regions. However, predicting relapse cases remains challenging, necessitating the identification of a novel biomarker for EEC relapse. The assessment of tumor mutational burden (TMB) is pivotal for immunotherapy in EEC patients. However, both whole-exome sequencing (WES) and targeted sequencing encountered application-related difficulties. In light of this, standardized and simplified techniques for TMB measurement are imperative. In this study, we employed WES on 25 EEC patients (12 relapsed cases and 13 non-relapsed cases) who accepted hysterectomy surgery (CHCAMS cohort). We additionally obtained a total of 391 tumor samples with clinicopathological features from TCGA website to broaden the study cohort. In the CHCAMS cohort, the TTN mutant group showed shorter progression-free survival (p < 0.001) and overall survival (p < 0.001) than TTN wild-type group. Additionally, we discovered that the number of TTN mutations per sample was significantly linked with TMB-WES in CHCAMS cohort and TCGA cohort (p < 0.05). And the number of TTN mutations per sample in POLE mutant group was greater than in the POLE wild-type group (p < 0.0001). In conclusion, TTN mutation may serve as a biomarker for EEC prognosis. TTN mutation is also associated with WES-TMB, and could be a simplified TMB measurement technique.

Quantitative assessment of choroidal parameters and retinal thickness in central serous chorioretinopathy using ultra-widefield swept-source optical coherence tomography: a cross-sectional study.

OBJECTIVE: In this study, we used ultra-wide field swept-source optical coherence tomography angiography (UWF SS-OCTA) to assess changes in retinal thickness (RT) and choroidal parameters in individuals who had received a diagnosis of central serous chorioretinopathy (CSC). METHODS: The study encompassed the evaluation of 59 eyes from 47 patients with a diagnosis of CSC, alongside 33 fellow eyes and 31 eyes from healthy individuals (controls). The parameters assessed included RT, choroidal thickness (CT), choriocapillaris density, vascular density of the large choroidal vessel layer, three-dimensional choroidal vascularity index (3D-CVI), choroidal vessel volume per unit area (mCVV/a), and choroidal stroma volume per unit area (mCSV/a). RESULTS: Metrics including mCVV/a, mCSV/a, 3D-CVI, CT, and RT exhibited significantly elevated values in the eyes affected by CSC compared to those of the control group across nine subfields. Moreover, a substantial number of the subfields in both CSC-affected and fellow eyes exhibited increased values for mCVV/a, mCSV/a, 3D-CVI, CT, and RT when compared with the control group. Additionally, acute and chronic CSC subfields demonstrated significantly elevated values for mCVV/a, mCSV/a, 3D-CVI, CT, and RT in comparison to healthy control eyes. Notably, specific subfields associated with complex and atypical forms of CSC revealed higher metrics compared to those of the control group. CONCLUSION: In conclusion, the UWF SS-OCTA proved to be a valuable tool for exploring the anatomical etiology and clinical classification and diagnosis of CSC.

Old people's preference for nursing homes in East China: a discrete choice experiment.

BACKGROUND: The aged people who live in nursing home are predicted to keep growing in the following decades. There are both quantitative imbalance and structural imbalance in the utilization of nursing homes in China. This study aimed to analyze old people's preference for nursing homes and help the government optimize resource allocation. METHODS: A discrete choice experiment (DCE) was conducted and six attributes of nursing homes including monthly fee, distance from home, geographical location, medical facilities, environment of nursing homes and nursing staff were determined. Respondents were recruited from Nantong and Yangzhou city, China. In each city, two communities or villages were randomly selected. In each community/village, about 65 old people were randomly selected. Analysis was conducted using mixed logit regression models to determine preferences for potential attributes. RESULTS: A total of 233 old people were included in the analysis. The findings indicated that all six attributes were statistically significant factors for participants. "Professional nursing staff" was the most important characteristic to participants, followed by "Medical facilities". Compared with female, the males preferred professional nursing staff (ß = 2.939 vs. ß = 2.643, P < 0.001), medical facilities (ß = 1.890 vs. ß = 1.498, P < 0.001), and the environment (ß = 0.752, P < 0.01). For different age groups, participants aged 60-69 didn't pay attention to distance and location, while those aged 80 and above only paid attention to professional nursing staff and medical facilities. CONCLUSIONS: The present study provides important insights into the characteristics of nursing home that are most preferred by old people. Authorities should take into account old people's preference in the planning, design and evaluation of nursing homes.

Constraints of Sedimentary Environment on Shale Organic Matter Enrichment: Insights from Elemental Geochemistry and Multiple Factor Analysis.

The organic-rich shale of the Wufeng-Longmaxi formation is an important section for shale gas exploration. The traditional univariate or bivariate analysis causes researchers to have great controversy about its enrichment mechanism. This study explores the combination of multiple factor analysis (MFA) and element geochemistry to calculate the contribution rate of a paleoenvironment to organic matter enrichment and clarify the main controlling factors of organic matter enrichment. Research has shown that there is generally high productivity from the Wufeng (O3w)-Longmaxi formation (S1l) deposition. The degree of terrigenous clastic input and weathering during the period of the O3w is relatively low, and sedimentary water restriction is strong, mainly developing an anoxic-dysoxic sedimentary environment. During the deposition of S1l1, the input intensity and weathering of terrigenous debris were slightly enhanced, and the increase of the water column led to the development of an anoxic environment at the bottom of the water layer. During the S1l2+3 period, the degree of terrigenous debris and weathering is the largest, and the high oxygen content of the water column is mainly a normal oxic environment. An MFA calculation shows that the paleoproductivity and paleoredox environment of the organic-rich shale section have the highest contribution rate of about 59.57% to the enrichment of organic matter, which is higher than that of paleoclimate conditions and terrigenous clastic input, indicating that the enrichment of organic matter is mainly controlled by paleoproductivity and the preservation environment. This study provides a basis for the application of MFA in element geochemistry and can serve as a model for other studies.

A phase IV study to evaluate the safety of fruquintinib in Chinese patients in real-world clinical practice.

INTRODUCTION: Fruquintinib is approved in China for patients with metastatic colorectal cancer (CRC) who progressed after 2 lines of chemotherapy. This postmarketing study was conducted to evaluate the safety of fruquintinib in the Chinese population, including previously treated patients with advanced CRC and other solid tumors. METHODS: Patients in the first cycle of fruquintinib or expected to start fruquintinib within a week were enrolled. Fruquintinib was administrated according to the label or per physicians' discretion. Patient characteristics and safety information were collected at baseline, 1 month, and 6 months after consent (or 30 days after the last dose). RESULTS: Overall, 3005 patients enrolled between April 24, 2019 and September 27, 2022. All enrolled patients received at least one dose of fruquintinib. Most patients had metastases at baseline. The median age was 60 years. More than half (64.0%) of the patients started fruquintinib at 5 mg, and the median treatment exposure was 2.7 months. Nearly one-third (32.5%) of patients with CRC received fruquintinib with concomitant antineoplastic agents. Treatment-emergent adverse events (TEAEs) leading to dose modification were reported in 626 (20.8%) patients, and 469 (15.6%) patients experienced TEAEs leading to treatment discontinuation. The most common grade ≥ 3 TEAEs were hypertension (6.6%), palmar-plantar erythrodysesthesia syndrome (2.2%), and platelet count decreased (1.0%). Combination therapy did not lead to excessive toxicities. CONCLUSIONS: The safety profile of fruquintinib in the real world was generally consistent with that in clinical studies, and the incidence of TEAEs was numerically lower than known VEGF/VEGFR inhibitor-related AEs. Fruquintinib exhibited manageable safety and tolerability in Chinese patients in the real-world setting.

Treatment patterns of patients with worsening heart failure with reduced ejection fraction.

AIMS: Patients with HFrEF and worsening HF events (WHFE) are at particularly high risk and urgently need disease-modifying therapy. CHART-HF assessed treatment patterns and reasons for medication decisions among HFrEF patients with and without WHFE. METHODS AND RESULTS: CHART-HF collected retrospective electronic medical records of outpatients with HF and EF < 45% between 2017-2019 from a nationwide panel of 238 cardiologists (458 patients) and the Geisinger Health System (GHS) medical record (1000 patients). The index visit in the WHFE cohort was the first outpatient cardiologist visit ≤6 months following the WHFE, and in the reference cohort was the last visit in a calendar year without WHFE. Demographic characteristics were similar between patients with and without WHFE in both the nationwide panel and GHS. In the nationwide panel, the proportion of patients with versus without WHFE receiving ≥50% of guideline-recommended dose on index visit was 35% versus 40% for beta blocker, 74% versus 83% for ACEI/ARB/ARNI, and 48% versus 49% for MRA. The proportion of patients receiving ≥50% of guideline-recommended dose was lower in the GHS: 29% versus 34% for beta-blocker, 16% versus 31% for ACEI/ARB/ARNI, and 18% versus 22% for MRA. For patients with and without WHFE, triple therapy on index date was 42% and 44% of patients from the nationwide panel, and 14% and 17% in the GHS. Comparing end of index clinic visit with 12-month follow-up in the GHS, the proportion of patients on no GDMT increased from 14% to 28% in the WHFE cohort and from 14 to 21% in the non-WHFE group. CONCLUSIONS: Major gaps in use of GDMT, particularly combination therapy, remain among US HFrEF patients. These gaps persist during longitudinal follow-up and are particularly large among patients with recent WHFE.