Adjuvant donafenib for hepatocellular carcinoma patients at high-risk of recurrence after radical resection: a real-world experience.

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.

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.

Research on the Law of Coal Pillar Spontaneous Combustion and Fire Prevention and Control Technology.

In coal pillar fires, the fire source is hard to be detected and the adjacent goaf is extremely likely to be affected. Such fires would give rise to thermal and dynamic disasters in mines, further causing casualties and environmental disruption. In this study, with the coal pillar spontaneous combustion (CPSC) accident in Chahasu Coal Mine taken as the research object, the oxygen uptake and limit of oxygen concentration of CPSC were explored. Based on the research results, a similar model was constructed, where a control group was used to simulate the hazardous area of CPSC in a bid to investigate the law of CPSC. Moreover, the polymer colloid perfusion system was constructed and the drilling parameters and perfusion process parameters were determined, and practices concerning spontaneous fire control were carried out. Here are the conclusions: First, air leakage in the coal pillar may lead to coal spontaneous combustion due to the impact of rib spalling, threatening 2-6 m above the middle of the coal pillar at a shallow position. Second, coal pillar grouting, injecting polymer colloids for cooling, and coal pillar cement reinforcement prove to be effective ways to prevent CPSC fires and combat recombustion.

Detection and management of coal seam outcrop fire in China: a case study.

The outcrop fire area in Rujigou Coal Mine in Ningxia, China has been burning continuously for over 100 years. This not only results in wastage of resources but also poses significant damage to the ecological environment. Previous research on open fire detection has mainly focused on coalfield fire areas, using single method such as infrared remote sensing or surface temperature measurement, magnetic method, electrical method, radon measurement and mercurimetry. However, the outcrop fire area has migrated to deeper parts over the years, conventional single fire zone detection methods are not capable of accurately detecting the extent of the fire zone, inversion interpretation is faced with the problem of many solutions. In fire management, current research focuses on the development of new materials, such as fly ash gel, sodium silicate gel, etc., However, it is often difficult to quickly extinguish outcrop fire areas with a single technique. Considering this status quo, unmanned aerial vehicle (UAV) infrared thermal imaging was employed to initially detect the scope of the outcrop fire area, and then both the spontaneous potential and directional drilling methods were adopted for further scope detection in pursuit of more accurate results. In addition, an applicable fire prevention and extinguishing system was constructed, in which three-phase foam was injected for the purpose of absorbing heat and cooling. Furthermore, the composite colloid was used to plug air leakage channels, and loess was backfilled to avoid re-combustion. The comprehensive detection and control technologies proposed in this study can be applied to eliminating the outcrop fire area and protecting the environment. This study can provide guidance and reference for the treatment of other outcrop fire areas.

Detection of Spontaneous Combustion Areas of Coal Gangue Dumps and Comprehensive Governance Technologies: A Case Study.

Spontaneous combustion of coal gangue dumps not only releases toxic and harmful gases, polluting the environment, but also leads to explosion accidents and casualties due to improper handling. This paper focuses on delineating the fire area, constructing a comprehensive fire prevention and extinguishing system, and restoring the ecological environment. Infrared thermal imaging was used to detect the shallow fire area, while intensive drilling was conducted to detect the deep fire area. The stability of the coal gangue dump was enhanced by perfusing three-phase foam for cooling and using a curing material to fill the cracks. Land reclamation was then performed to restore the ecological environment. The results indicate that spontaneous combustion of coal gangue dumps can trigger the spread of the fire area from the outside to the inside, gradually expanding due to the 'stack effect'. The sources of spontaneous combustion in gangue fire areas are mainly located 3-5 m below the flat surface, and the shallow and deep fire areas are interconnected, posing a significant danger. These research findings can serve as a reference for detecting fire areas in coal gangue dumps and controlling environmental pollution.

Application of a two-state kinetic model to the heterogeneous kinetics of reaction between cysteine and hydrogen peroxide in amorphous lyophiles.

The bimolecular reaction between cysteine (CSH) and hydrogen peroxide (H(2)O(2)) in amorphous PVP and trehalose lyophiles has been examined at different reactant and excipient concentrations and at varying pH and temperature. Initial rates of product formation and complete reactant and product concentration-time profiles were generated by HPLC analyses of reconstituted solutions of lyophiles stored for various periods of time. While only cystine (CSSC) forms in aqueous solutions, cysteine sulfinic (CSO(2)H) and sulfonic (CSO(3)H) acids are significant degradants in amorphous solids. The formation of alternative degradants was consistent with the solution reaction mechanism, which involves a reactive sulfenic acid (CSOH) intermediate, coupled with the restricted mobility in the amorphous solid-state, which favors reaction of CSOH with the smaller, mobility-advantaged H(2)O(2) over its reaction with cysteine. Complex rate laws (i.e., deviations from 1st order for each reactant) observed in initial rate studies and biphasic concentration-time profiles in PVP were successfully fitted by a two-state kinetic model assuming two reactant populations with different reactivities. The highly reactive population forms CSSC preferentially while the less reactive population generates primarily sulfinic and sulfonic acids. Reactions in trehalose could be described by a simple one-state model. In contrast to the reaction in aqueous solutions, the 'pH' effect was minimal in amorphous solids, suggesting a change in the rate-determining step to diffusion control for the model reaction occurring in amorphous lyophiles.

Kinetics and mechanism for the reaction of cysteine with hydrogen peroxide in amorphous polyvinylpyrrolidone lyophiles.

PURPOSE: Peroxide impurities play a critical role in drug oxidation. In metal-free aqueous solutions, hydrogen peroxide (H(2)O(2)) induced thiol oxidation involves a bimolecular nucleophilic reaction to form a reactive sulfenic acid intermediate (RSOH), which reacts with a second thiol to form a disulfide (RSSR). This study examines the reaction of cysteine (CSH) and H(2)O(2) in amorphous polyvinylpyrrolidone (PVP) lyophiles to explore the possible relevance of the solution mechanism to reactivity in an amorphous glass. MATERIALS AND METHODS: Amorphous PVP lyophiles containing CSH and H(2)O(2) at varying initial 'pH' and reactant concentrations were prepared by methods designed to minimize reaction during lyophilization. Kinetic studies were conducted anaerobically at 25 degrees C and reactants and products were monitored by HPLC. Products were characterized and the kinetic data were fit to models adapted from the solution mechanism. RESULTS: Key differences in the reactions in aqueous solution and amorphous PVP are: (1) while only cystine (CSSC) forms in solution, three degradants-cysteine sulfinic acid (CSO(2)H), cysteine sulfonic acid (CSO(3)H) and cystine (CSSC)--form in amorphous PVP; (2) simple bimolecular kinetics govern the solution reaction while initial rates in amorphous PVP suggested more complex kinetics (i.e., non-unity values for reaction order); and (3) heterogeneous (i.e., biphasic) reaction dynamics are evident in amorphous PVP. The differences in product formation and apparent reaction orders in the solid-state could be rationalized by partitioning of the same reactive intermediate to multiple products in the solid-state due to the restricted mobility of CSH. Beyond the initial rate region, the kinetics in amorphous PVP could be described by the Kohlrausch-Williams-Watts (KWW) stretched-exponential equation or by assuming two populations of reactant molecules having different reactivities. CONCLUSIONS: When reactive intermediates are involved, differences in degradant profiles and other characteristics (e.g., rate constants, apparent reaction order) in the amorphous-state may simply reflect altered rates for individual reaction steps due to glass-induced changes in relative reactant mobilities rather than a change in overall mechanism.

Kinetics and mechanism of the reaction of cysteine and hydrogen peroxide in aqueous solution.

The oxidation of thiol-containing small molecules, peptides, and proteins in the presence of peroxides is of increasing biological and pharmaceutical interest. Although such reactions have been widely studied there does not appear to be a consensus in the literature as to the reaction products formed under various conditions, the reaction stoichiometry, and the reaction mechanisms that may be involved. This study examines the reaction kinetics of cysteine (CSH) with hydrogen peroxide (H(2)O(2)) in aqueous buffers (in the absence of metal ions) over a wide range of pH (pH 4-13) and at varying ratios of initial reactant concentrations to explore the range of conditions in which a two-step nucleophilic model describes the kinetics. The disappearance of CSH and H(2)O(2) and appearance of cystine (CSSC) versus time were monitored by reverse-phase high-performance liquid chromatography (HPLC). The effects of oxygen, metal ions (Cu(2+)), pH (4-13), ionic strength, buffer concentration, and temperature were evaluated. Data obtained at [H(2)O(2)](0)/[CSH](0) ratios from 0.01-2.3 demonstrate that the reaction of CSH with H(2)O(2) in the absence of metal ions is quantitatively consistent with a two-step nucleophilic reaction mechanism involving rate-determining nucleophilic attack of thiolate anion on the unionized H(2)O(2) to generate cysteine sulfenic acid (CSOH) as an intermediate. Second-order rate constants for both reaction steps were generated through model fitting. At [H(2)O(2)](0)/[CSH](0) > 10, the % CSSC formed as a product of the reaction declines due to the increased importance of alternative competing pathways for consumption of CSOH. A thorough understanding of the mechanism in aqueous solution will provide valuable background information for current studies aimed at elucidating the influence of such factors on thiol oxidation in solid-state formulations.