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Background: Adjuvant therapy is used to reduce the risk of hepatocellular carcinoma (HCC) recurrence and improve patient prognosis. Exploration of treatment strategies that are both efficacious and safe has been extensively performed in the recent years. Although donafenib has demonstrated good efficacy in the treatment of advanced HCC, its use as adjuvant therapy in HCC has not been reported. Objectives: To investigate the efficacy and safety of postoperative adjuvant donafenib treatment in patients with HCC at high-risk of recurrence. Design: Retrospective study. Methods: A total of 196 patients with HCC at high-risk of recurrence were included in this study. Of these, 49 received adjuvant donafenib treatment, while 147 did not. Survival outcomes and incidence of adverse events (AEs) in the donafenib-treated group were compared. Inverse probability of treatment weighting (IPTW) method was used. Results: The median follow-up duration was 21.8 months [interquartile range (IQR) 17.2–27.1]. Before IPTW, the donafenib-treated group exhibited a significantly higher 1-year recurrence-free survival (RFS) rate (83.7% versus 66.7%, p = 0.023) than the control group. Contrarily, no significant difference was observed in the 1-year overall survival (OS) rates between the two groups (97.8% versus 91.8%, p = 0.120). After IPTW, the 1-year RFS and OS rates (86.6% versus 64.8%, p = 0.004; 97.9% versus 89.5%, p = 0.043, respectively) were higher than those in the control group. Multivariate analysis revealed that postoperative adjuvant donafenib treatment was an independent protective factor for RFS. The median duration of adjuvant donafenib treatment was 13.6 (IQR, 10.7–18.1) months, with 44 patients (89.8%) experienced AEs, primarily grade 1–2 AEs. Conclusion: Postoperative adjuvant donafenib treatment effectively reduced early recurrence among patients with HCC at high-risk of recurrence, while exhibiting favorable safety and tolerability profile. However, these findings warrant further investigation. Plain language summary: Comparison of the outcomes of patients with HCC with or without donafenib after radical resection to better understand the efficacy and safety of postoperative adjuvant donafenib Why was this study done? Donafenib is the only new-generation targeted drug developed in the past 14 years that has demonstrated superior efficacy and increased safety in the first-line treatment of HCC. We aimed to explore whether postoperative adjuvant donafenib can improve the prognosis of patients with HCC at high-risk of recurrence. What did the researchers do? Medical data of patients with HCC at high-risk of recurrence who underwent radical resection at two medical centers between April 2021 and October 2022 were collected to compare long-term outcomes of patients treated with and without donafenib and explore the safety of adjuvant donafenib treatment. What did the researchers find? A total of 196 patients with HCC at high-risk of recurrence, including 49 who received adjuvant donafenib treatment and 147 who did not, were analyzed. At a median follow-up of 21.8 months, it was observed that adjuvant donafenib treatment effectively reduced early recurrence among patients with HCC at high-risk of recurrence, while exhibiting favorable safety and compliance profiles. What do the findings mean? The study provides real-world clinical empirical data on adjuvant donafenib treatment for patients with HCC at high-risk of recurrence, and these results may provide new directions for adjuvant treatment of HCC. [ABSTRACT FROM AUTHOR]

Background & aims: Pyogenic liver abscesses (PLA) are space‐occupying lesions in the liver that produce high morbidity and mortality. The clinical characteristics and prognosis of abscesses is different depending on the bacterial culture results and require different strategies for management. The aim of this study was to investigate the clinical characteristics and prognostic factors of patients with PLA. Methods: Clinical features, laboratory tests and etiology of PLA between 2006 to 2011 and 2012 to 2017 in a single hospital were retrospectively reviewed. The incidence and mortality of PLA caused by Escherichia coli and Klebsiella pneumoniae were compared and the risk factors for multiple organ dysfunction (MODS) and endophthalmitis were evaluated. Results: Among the 1,572 PLA patients, the proportion with PLA increased from 333 (21.2%) in 2006‐2011 to 1,239 (78.8%) in 2012‐2017 without any investigation and treatment procedure differences. K pneumoniae was the main isolate in analysed pus cultures (85.6%). The mortality rate of patients with K pneumoniae infection was lower in the latter period (6.7% vs 0.7%, P =.035). Multivariate analyses revealed that age, fever, MODS and length of hospital stay were factors affecting poor prognosis (death + unhealed/uncured) in PLA patients after treatment and that cardiovascular disease, pleural effusion and pulmonary infection were risk factors for MODS, while diabetes mellitus was the only risk factor for endophthalmitis. Most patients (95.5%) with PLA recovered after abscess drainage/puncture and antibiotic therapy. Conclusions: Pleural effusion, fever, MODS and length of hospital stays were factors useful in predicting PLA outcomes. [ABSTRACT FROM AUTHOR]

A key pathological feature of neurodegenerative diseases (NDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) is the accumulation of aggregated and misfolded protein aggregates with limited effective therapeutic agents. TFEB (transcription factor EB), a key regulator of lysosomal biogenesis and autophagy, plays a pivotal role in the degradation of protein aggregates and has thus been regarded as a promising therapeutic target for these NDs. Here, we systematically summarize the molecular mechanisms and function of TFEB regulation. We then discuss the roles of TFEB and autophagy-lysosome pathways in major neurodegenerative diseases including AD and PD. Finally, we illustrate small molecule TFEB activators with protective roles in NDs animal models, which show great potential for being further developed into novel anti-neurodegenerative agents. Overall, targeting TFEB for enhancing lysosomal biogenesis and autophagy may represent a promising opportunity for the discovery of disease-modifying therapeutics for neurodegenerative disorders though more in-depth basic and clinical studies are required in the future.

A majority of breast cancer patients die of widespread aggressive multidrug-resistant tumors. Aspartate β-hydroxylase (ASPH) is an α-ketoglutarate-dependent dioxygenase and oncofetal antigen involved in embryogenesis. To illustrate if ASPH could be targeted for metastatic breast cancer, embedded and on-top three-dimensional (3-D) cultures, 3-D invasion, mammosphere formation, immunofluorescence, immunohistochemistry, Western blot, co-IP and microarray were conducted. In vitro metastasis was developed to imitate how cancer cells invade basement membrane at the primary site, transendothelially migrate, consequently colonize and outgrow at distant sites. Orthotopic and experimental pulmonary metastatic (tail vein injection) murine models were established using stable breast cancer cell lines. Cox proportional hazards regression models and Kaplan-Meier plots were applied to assess clinical outcome of breast cancer patients. In adult non-cancerous breast tissue, ASPH is undetectable. Pathologically, ASPH expression re-emerged at ductal carcinoma in situ (DCIS), and enhanced with disease progression, from early-stage invasive ductal carcinoma (IDC) to late-stage carcinoma. ASPH at moderate to high levels contribute to aggressive molecular subtypes, early relapse or more frequent progression and metastases, whereas substantially shortened overall survival and disease-free survival of breast cancer patients. Through direct physical interactions with A disintegrin and metalloproteinase domain-containing protein (ADAM)-12/ADAM-15, ASPH could activate SRC cascade, thus upregulating downstream components attributed to multifaceted metastasis. ASPH-SRC axis initiated pro-invasive invadopodium formation causing breakdown/disorganization of extracellular matrix (ECM), simultaneously potentiated epithelial-mesenchymal transition (EMT), induced cancer stem cell markers (CD44 and EpCAM), enhanced mammosphere formation and intensified 3-dimentional invasion. Oncogenic SRC upregulated matrix metallopeptidases (MMPs) were assembled by invadopodia, acting as executive effectors for multi-step metastasis. ASPH-SRC signal guided multi-organ metastases (to lungs, liver, bone, spleen, lymph nodes, mesentery or colon) in immunocompromised mice. Malignant phenotypes induced by ASPH-SRC axis were reversed by the third-generation small molecule inhibitor (SMI) specifically against β-hydroxylase activity of ASPH in pre-clinical models of metastatic breast cancer. Collectively, ASPH could activate ADAMs-SRC-MMPs cascades to promote breast cancer tumor progression and metastasis. ASPH could direct invadopodium construction as a biomechanical sensor and pro-metastatic outlet. ASPH-mediated cancer progression could be specifically/efficiently subverted by SMIs of β-hydroxylase activity. Therefore, ASPH emerges as a therapeutic target for breast cancer., Competing Interests: None., (AJCR Copyright © 2021.)