Concordance Study in Hepatectomy Recommendations Between Watson for Oncology and Clinical Practice for Patients with Hepatocellular Carcinoma in China.

BACKGROUND: With the improvement in diagnostic imaging, perioperative care and surgical technique, the indications and complexity of liver resections have developed. However, the surgical indications remain controversial especially for some complex or advanced hepatocellular carcinomas. This study was designed to evaluate the concordance between hepatectomy recommendations proposed by Watson for Oncology, a cognitive technology providing decision support, and those determined by surgeons in our center for patients with hepatocellular carcinoma. METHODS: We retrospectively reviewed 243 patients with hepatocellular carcinoma who were recommended for surgical treatment and received hepatectomy between 2008 and 2016 at the Zhujiang Hospital of Southern Medical University. Watson for Oncology classified the treatment options into three categories: recommended, for consideration and not recommended. Treatment recommendations were considered concordant if the hepatectomy recommendations were designated "recommended" or "for consideration" by Watson for Oncology. The factors potentially affecting concordance rate were also analyzed in our study. RESULTS: The hepatectomy recommendations of 174 patients were concordant. There were significant differences in the coincidence rate between concordant group and discordant group considering tumor numbers (P = 0.006), extension of hepatectomy (P = 0.009) and BCLC staging system (P < 0.001). Lower degrees of concordance were observed in patients with multiple tumors, major hepatectomy and portal hypertension by using logistic regression analysis (OR = 0.309, P = 0.004; OR = 0.384, P = 0.004; and OR = 0.376, P = 0.022, respectively). CONCLUSION: The concordance between Watson for Oncology and surgeons' hepatectomy recommendation for hepatocellular carcinoma was only 72%. Differences in practice patterns for HCC between the USA (where Watson for Oncology was calibrated) and China may be the major cause of discordance. Watson for Oncology still requires further improvement and localization to be widely applied in China.

Plectin-1-targeted recognition for enhancing comprehensive therapy in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) poses a formidable challenge due to its aggressive nature and poor prognosis. Gemcitabine (Gem), a primary therapeutic option, functions by inhibiting DNA synthesis and promoting apoptosis, thereby impeding the progression of PDAC. However, Gem is hindered by suboptimal pharmacokinetics and efficacy. In response to these challenges, we have developed a nanoparticle (NP) designed for specific recognition of plectin-1 in PDAC cell membranes. The NPs encapsulate Gem while demonstrating pH-responsive drug release characteristics in the acidic tumor microenvironment. This targeted approach enhances local drug delivery while alleviating concerns about systemic toxicity. Furthermore, the NPs are enriched with indocyanine green (ICG), renowned for its strong photothermal effects, thereby further enhancing therapeutic outcomes. This study presents an innovative therapeutic strategy for PDAC based on a plectin-1-targeted recognition delivery approach. The approach is applied to enhance chemotherapy, combined with photothermal therapy (PTT), inducing apoptosis in PDAC cell lines and improving the pharmacokinetics of Gem. In conclusion, the delivery strategy based on plectin-1-targeted recognition shows promising preclinical prospects for enhancing therapeutic efficacy in PDAC, offering valuable insights for future clinical applications.

The Detection of Divalent Iron and Reactive Oxygen Species During Ferroptosis with the Use of a Dual-Reaction Turn-On Fluorescent Probe.

PURPOSE: Ferroptosis, a programmed cell death modality, is an iron-dependent, non-apoptosis pathway that is characterized by the upregulation of divalent iron and reactive oxygen species (ROS) levels. However, the sensitive and rapid detection to track changes in ferroptosis is challenging, partially due to the lack of methods for monitoring the Fe(II) accumulation and ROS generation. PROCEDURES: Herein, we reported a dual-reaction fluorescent probe DR-1 with turn-on response, which realized the simultaneous visualizing of Fe(II) and ROS with a single probe. The structure of fluorescence quenching group and turn-on fluorophore constitute a double switch for DR-1, which increases its specificity and stability. RESULTS: During ferroptotic cell death, the upregulation of ROS levels led to the cleavage of quenching group of DR-1, and the aggregation of Fe(II) resulting in fluorescence recovery. CONCLUSIONS: Overall, this study provides a new dual-reaction probe that shows the great potential to explore the mechanism of ferroptosis in vitro and in vivo by fluorescence imaging.

Enhanced glypican-3-targeted identification of hepatocellular carcinoma with liver fibrosis by pre-degrading excess fibrotic collagen.

Most hepatocellular carcinomas (HCCs) occur in cirrhotic livers, but unequivocal diagnosis of early HCC from the fibrotic microenvironment remains a formidable challenge with conventional imaging strategies, mainly because of the massive fibrotic collagen deposition leading to hepatic nodules formation and dysfunction of contrast agent metabolism. Here, we developed a "sweep-and-illuminate" imaging strategy, pre-degrade hepatic fibrotic collagen with collagenase I conjugated human serum albumin (HSA-C) and then targeting visualize HCC lesion with GPC3 targeting nanoparticles (TSI NPs, TJ2 peptide-superparamagnetic iron oxide-indocyanine green) via fluorescence imaging (FLI) and magnetic particle imaging (MPI). TSI NPs delineated a clear boundary of HCC and normal liver, and the tumor-to-background ratios (TBRs) detected by FLI and MPI were 5.43- and 1.34-fold higher than the non-targeted group, respectively. HSA-C could degrade 24.7% fibrotic collagen, followed by 27.2% reduction of nonspecific NPs retention in mice with liver fibrosis. In a pathological state in which HCC occurs in the fibrotic microenvironment, HSA-C-mediated pre-degradation of fibrotic collagen reduced background signal interference in fibrotic tissues and enhanced the intratumoral uptake of TSI NPs, resulting in the clear demarcation between HCC and liver fibrosis, and the TBR was increased 2.61-fold compared to the group without HSA-C pretreatment. We demonstrated the feasibility of combined pre-degradation of fibrotic collagen and application of a GPC3-targeted FLI/MPI contrast agent for early HCC identification, as well as its clinical value in the management of patients with advanced liver fibrosis. STATEMENT OF SIGNIFICANCE: Given that liver fibrosis hinders early detection and treatment options of hepatocellular carcinomas (HCCs), we report a "sweep-and-illuminate" imaging strategy to enhance the efficiency of HCC identification by modulating the irreversible liver fibrosis. We first "sweep" nonspecific interference of contrast agent by pre-degrading fibrotic collagen with human serum albumin-carried collagenase I (HSA-C); and then specifically "illuminate" HCC lesions with GPC3-targeted-SPIO-ICG nanoparticles (TSI NPs). HSA-C can degrade 24.7% fibrotic collagen, followed by 27.2% reduction of nonspecific NPs retention in mice with liver fibrosis. Furthermore, in HCC models coexisting with liver fibrosis, the combined application of HSA-C and TSI NPs can clarify the demarcation between HCC and liver fibrosis with a 2.61-fold increase in the tumor-to-background ratio. This study may expand the potential of combinatorial biomaterials for early HCC diagnosis.

SUMO fosters assembly and functionality of the MutSγ complex to facilitate meiotic crossing over.

Crossing over is essential for chromosome segregation during meiosis. Protein modification by SUMO is implicated in crossover control, but pertinent targets have remained elusive. Here we identify Msh4 as a target of SUMO-mediated crossover regulation. Msh4 and Msh5 constitute the MutSγ complex, which stabilizes joint-molecule (JM) recombination intermediates and facilitates their resolution into crossovers. Msh4 SUMOylation enhances these processes to ensure that each chromosome pair acquires at least one crossover. Msh4 is directly targeted by E2 conjugase Ubc9, initially becoming mono-SUMOylated in response to DNA double-strand breaks, then multi/poly-SUMOylated forms arise as homologs fully engage. Mechanistically, SUMOylation fosters interaction between Msh4 and Msh5. We infer that initial SUMOylation of Msh4 enhances assembly of MutSγ in anticipation of JM formation, while secondary SUMOylation may promote downstream functions. Regulation of Msh4 by SUMO is distinct and independent of its previously described stabilization by phosphorylation, defining MutSγ as a hub for crossover control.