The role of kinesin family members in hepatobiliary carcinomas: from bench to bedside.

As a major component of the digestive system malignancies, tumors originating from the hepatic and biliary ducts seriously endanger public health. The kinesins (KIFs) are molecular motors that enable the microtubule-dependent intracellular trafficking necessary for mitosis and meiosis. Normally, the stability of KIFs is essential to maintain cell proliferation and genetic homeostasis. However, aberrant KIFs activity may destroy this dynamic stability, leading to uncontrolled cell division and tumor initiation. In this work, we have made an integral summarization of the specific roles of KIFs in hepatocellular and biliary duct carcinogenesis, referring to aberrant signal transduction and the potential for prognostic evaluation. Additionally, current clinical applications of KIFs-targeted inhibitors have also been discussed, including their efficacy advantages, relationship with drug sensitivity or resistance, the feasibility of combination chemotherapy or other targeted agents, as well as the corresponding clinical trials. In conclusion, the abnormally activated KIFs participate in the regulation of tumor progression via a diverse range of mechanisms and are closely associated with tumor prognosis. Meanwhile, KIFs-aimed inhibitors also carry out a promising tumor-targeted therapeutic strategy that deserves to be further investigated in hepatobiliary carcinoma (HBC).

Identifying a novel cuproptosis-related necroptosis gene subtype-related signature for predicting the prognosis, tumor microenvironment, and immunotherapy of hepatocellular carcinoma.

Background: Cuproptosis and necroptosis represent two distinct programmed cell death modalities implicated in neoplastic progression; however, the role of combining cuproptosis and necroptosis in hepatocellular carcinoma (HCC) remains to be elucidated. Methods: A total of 29 cuproptosis-related necroptosis genes (CRNGs) were identified, followed by an extensive analysis of their mutational characteristics, expression patterns, prognostic implications, and associations with the tumor microenvironment (TME). Subsequently, a CRNG subtype-related signature was developed, and its value of prognostic prediction, TME, and therapeutic responses in HCC were thoroughly investigated. Last, quantitative real-time PCR and Western blotting were employed for investigating the signature gene expression in 15 paired clinical tissue samples. Results: Two distinct CRNG subtypes were discerned, demonstrating associations between CRNG expression patterns, clinicopathological attributes, prognosis, and the TME. A CRNG subtype-related prognostic signature, subjected to external validation, was constructed, serving as an independent prognostic factor for HCC patients, indicating poor prognosis for high-risk individuals. Concurrently, the signature's correlations with an immune-suppressive TME, mutational features, stemness properties, immune checkpoint genes, chemoresistance-associated genes, and drug sensitivity were observed, signifying its utility in predicting treatment responses. Subsequently, highly accurate and clinically convenient nomograms were developed, and the signature genes were validated via quantitative real-time PCR and Western blotting, further substantiating the stability and dependability of the CRNG subtype-related prognostic signature. Conclusion: Overall, this investigation presented an extensive panorama of CRNGs and developed the CRNG subtype-related prognostic signature, which holds potential for implementation in personalized treatment strategies and prognostic forecasting for HCC patients.

Identifying the programmed cell death index of hepatocellular carcinoma for prognosis and therapy response improvement by machine learning: a bioinformatics analysis and experimental validation.

Background: Despite advancements in hepatocellular carcinoma (HCC) treatments, the prognosis for patients remains suboptimal. Cumulative evidence suggests that programmed cell death (PCD) exerts crucial functions in HCC. PCD-related genes are potential predictors for prognosis and therapeutic responses. Methods: A systematic analysis of 14 PCD modes was conducted to determine the correlation between PCD and HCC. A novel machine learning-based integrative framework was utilized to construct the PCD Index (PCDI) for prognosis and therapeutic response prediction. A comprehensive analysis of PCDI genes was performed, leveraging data including single-cell sequencing and proteomics. GBA was selected, and its functions were investigated in HCC cell lines by in vitro experiments. Results: Two PCD clusters with different clinical and biological characteristics were identified in HCC. With the computational framework, the PCDI was constructed, demonstrating superior prognostic predictive efficacy and surpassing previously published prognostic models. An efficient clinical nomogram based on PCDI and clinicopathological factors was then developed. PCDI was intimately associated with immunological attributes, and PCDI could efficaciously predict immunotherapy response. Additionally, the PCDI could predict the chemotherapy sensitivity of HCC patients. A multilevel panorama of PCDI genes confirmed its stability and credibility. Finally, the knockdown of GBA could suppress both the proliferative and invasive capacities of HCC cells. Conclusion: This study systematically elucidated the association between PCD and HCC. A robust PCDI was constructed for prognosis and therapy response prediction, which would facilitate clinical management and personalized therapy for HCC.

Portable and automated analyzer for rapid and high precision in vitro dissolution of drugs.

We developed a novel portable and automated dissolution test analyzer for rapid and high precision in vitro dissolution testing of drugs. The analyzer consists of a flow-through-cell drug dissolution system, an automated sequential sampling system, a high-speed capillary electrophoresis (HSCE) system, and a data acquisition system. Combining the high-temporal resolution flow-gating sampling approach with HSCE, which has outstanding advantages of efficient separation and resolution, the analyzer can achieve rapid analysis and exhibits the ability in miniaturization for on-site assessment of different active pharmaceutical ingredients. To integrate the flow-through-cell dissolution system with HSCE, a specially designed flow-gating-injection (FGI) interface was employed. The performance of the analyzer was investigated by analyzing the dissolution of immediate-release drugs including single dose (amoxicillin dispersible tablets) and fixed dose combination (amoxicillin and clavulanate potassium) drug tablets with the high-temporal resolutions of 12 s and 20 s, respectively. The dissolution profiles of different active pharmaceutical ingredients could be simultaneously and automatically monitored with high repeatability and accuracy. The analyzer was successfully utilized for the pharmaceutical quality control and bio-relevant dissolution testing, as well as in vivo-in vitro correlation analysis. Our portable analyzer is miniaturized, convenient and of low-cost, and will provide a valuable tool for dissolution testing in pharmaceutical research and development.

High-throughput monitoring of biomass conversion reaction with automatic time-resolved analysis.

Reactions of biomass conversions are of great importance in fine chemistry for substantial development. While numerous studies have been performed to search for functional materials to catalyze biomass conversions, a robust and high-throughput analytical method is rather limited, which may hamper further integration and automation of the reactions. Here we propose an automatic and sequential method for the investigation of glucose conversion. By combining sequential sample injection and high-speed capillary electrophoresis (HSCE) techniques, we can monitor the glucose conversion from the beginning toward the end with a good temporal resolution. The HSCE assays are performed using short capillaries (effective length of 10 cm, i.d./o.d. of 50 µm/365 µm), and the analytes are separated at an electric field of 467 V/cm and are detected by UV-absorption at 200 nm with mixed 0.2 mM CTAB, 10 mM borate, 20 mM sorbic acid (pH 12.2) as the background electrolyte. All compounds involved in the reaction, including all products (fructose, 5-hydroxymethylfurfural, formic acid and levulinic acid) and the remaining substrate glucose, are efficiently separated and simultaneously detected from just one analysis with a temporal resolution of one minute. The method exhibits high-resolution separation, a wide linear range with limit-of-detection down to µg/mL-level, as well as excellent repeatability in sequential analysis. It is indicated that the proposed method is of great value in the analysis of complicated biomass conversion and could be potentially applied in various catalytic chemical reactions.

Portable and automated analyzer for rapid and high precision in vitro dissolution of drugs / 药物分析学报

We developed a novel portable and automated dissolution test analyzer for rapid and high precision in vitro dissolution testing of drugs.The analyzer consists of a flow-through-cell drug dissolution system,an automated sequential sampling system,a high-speed capillary electrophoresis (HSCE) system,and a data acquisition system.Combining the high-temporal resolution flow-gating sampling approach with HSCE,which has outstanding advantages of efficient separation and resolution,the analyzer can achieve rapid analysis and exhibits the ability in miniaturization for on-site assessment of different active pharmaceutical ingredients.To integrate the flow-through-cell dissolution system with HSCE,a specially designed flow-gating-injection (FGI) interface was employed.The performance of the analyzer was investigated by analyzing the dissolution of immediate-release drugs including single dose (amoxicillin dispersible tablets) and fixed dose combination (amoxicillin and clavulanate potassium) drug tablets with the high-temporal resolutions of 12 s and 20 s,respectively.The dissolution profiles of different active pharmaceutical ingredients could be simultaneously and automatically monitored with high repeatability and accuracy.The analyzer was successfully utilized for the pharmaceutical quality control and bio-relevant dissolution testing,as well as in vivo-in vitro correlation analysis.Our portable analyzer is miniaturized,convenient and of low-cost,and will provide a valuable tool for dissolution testing in pharmaceutical research and development.

On-line dissolution analysis of multiple drugs encapsulated in electrospun nanofibers.

Electrospun nanofiber is a very attractive material which can be used as the support to form multiple-drug dosage. Understanding the dissolution process of different active drug ingredients released from electrospun fibers is of great importance to control and evaluate the quality of medicated nanofibers. Here we present the first study of on-line automatic analysis of dissolution of multiple drugs in electrospun fiber mats. Single-needle electrospinning technology is utilized to combine polymers, hydrophilic polyvinylpyrrolidone (PVP) and hydrophobic polycaprolactone (PCL) as carrier to load three poorly water-soluble non-steroidal anti-inflammatory drugs (paracetamol, nimesulide, and ibuprofen). The loading of the drugs in PVP/PCL electrospun fibers are characterized by various techniques, including scanning electron microscopy, X-ray diffraction, Fourier infrared spectroscopy and differential scanning calorimetry. The in vitro dissolution is investigated by our home-made portable analyzer, which can simultaneously on-line determine multiple drugs released from the nanofibers by a single step. The analysis shows a wide linear detection range of the drugs with limit-of-detection (LOD) down to µg/mL-level. The dissolution profiles of three ingredients in nanofibers can be monitored every thirty seconds from the beginning to the end in the entire dissolution process from only one HSCE run. The kinetic information of the dissolution, including the dissolution curve, characteristic dissolution time and dissolution efficiency, is obtained and evaluated for different dissolution media, drug loading content and the ratio of PVP/PCL. Our study provides a promising method for rapid and accurate dissolution testing of nanofiber-based drugs, and would extend the applications of separation techniques in pharmaceutical analysis.

Automatic Dissolution Testing with High-Temporal Resolution for Both Immediate-Release and Fixed-Combination Drug Tablets.

Dissolution testing plays many important roles throughout the pharmaceutical industry, from the research and development of drug products to the control and evaluation of drug quality. However, it is a challenging task to perform both high-efficient separation and high-temporal detection to achieve accurate dissolution profile of each active ingredient dissolved from a drug tablet. In our study, we report a novel non-manual-operation method for performing the automatic dissolution testing of drug tablets, by combining a program-controlled sequential analysis and high-speed capillary electrophoresis for efficient separation of active ingredients. The feasibility of the method for dissolution testing of real drug tablets as well as the performance of the proposed system has been demonstrated. The accuracy of drug dissolution testing is ensured by the excellent repeatability of the sequential analysis, as well as the similarity of the evaluation of dissolution testing. Our study show that the proposed method is capable to achieve simultaneous dissolution testing of multiple ingredients, and the matrix interferences can be avoided. Therefore it is of potential valuable applications in various fields of pharmaceutical research and drug regulation.