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Chen-Lin Yu,1,2,* Hsiang-Lin Lee,3,4,* Shun-Fa Yang,2,5 Shih-Wei Wang,1,6 Ching-Pin Lin,4,7 Yi-Hsien Hsieh,2,5 Hui-Ling Chiou8,9 1Institute of Biomedical Science, Mackay Medical College, New Taipei City, Taiwan; 2Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; 3Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan; 4School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 5Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan; 6Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; 7Division of Hepatology and Gastroenterology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan; 8School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan; 9Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan*These authors contributed equally to this workCorrespondence: Yi-Hsien Hsieh; Hui-Ling Chiou, Tel +886-4-2473-0022, Fax +886-4- 2472-3229, Email hyhsien@csmu.edu.tw; hlchiou@csmu.edu.twObjective: Protodioscin (PD), a steroidal saponin, has a diverse pharmacological activity including neuroprotection, male fertility improvement, and cytotoxicity against various cancers cell lines of different origins. However, the effect of PD on hepatocellular carcinoma (HCC) is still unclear.Methods: Cell viability, colony formation and flow cytometry analysis for apoptosis profile, mitochondrial membrane potential endoplasmic reticulum (ER) expansion were employed to determine the effect of PD against HCC cells. Transient transfection of siRNA, immunofluorescent imaging and immunoprecipitation were used to elucidate the anti-cancer mechanism of PD. The in vivo toxicity and efficacy of PD were assessed by a xenograft mouse model.Results: PD induced apoptosis, loss of mitochondrial membrane potential and ER expansion in HCC cells. Either downregulation of Mfn1 or Bak reversed PD-induced apoptosis and loss of mitochondrial membrane potential. Further analysis revealed that Mfn1 and Bak will form a complex with IP3R to facilitate the transfer of Ca2+ from ER to mitochondria and apoptosis. In addition, our tumour xenograft model further verifies the in vivo anti-tumour effect of PD.Conclusion: Our study sheds light on the understanding of the anti-HCC effects of PD and may open new aspects for the development of novel treatment for human hepatocellular carcinoma.Graphical Abstract: Keywords: hepatocellular carcinoma, protodioscin, mitochondrial, apoptosis, endoplasmic reticulum

Chuan Tian,1,2,* Haifeng Ying,3,* Rongyuan Zhuang,4 Xiaowei Zhang,5 Hongmin Lu,6 Hui Wang,7 Shuowen Wang,8 Qi Li,1 Chungang Wang,9 Xun Cai1 1Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, People’s Republic of China; 2Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, People’s Republic of China; 3Department of Traditional Chinese Medicine, Ruijin Hospital, Medical College, Shanghai Jiaotong University, Shanghai 200025, People’s Republic of China; 4Department of Oncology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China; 5Department of Medical Oncology, Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China; 6Department of Oncology, Renji Hospital, Medical College, Shanghai Jiaotong University, Shanghai 200127, People’s Republic of China; 7Department of Oncology, Shanghai Tenth People’s Hospital, Shanghai Tongji University, Shanghai 200072, People’s Republic of China; 8Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, People’s Republic of China; 9Department of Radiotherapy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, People’s Republic of China *These authors contributed equally to this work Purpose: The relationship between the pharmacokinetics of irinotecan and outcomes of advanced colorectal cancer is unclear, and few studies have examined individualized irinotecan-based chemotherapy depending on plasma 7-ethyl-10-hydroxy camptothecin (SN-38) levels and dihydropyrimidine dehydrogenase (DPD) activity, particularly for the UGT1A1*6 or UGT1A1*28 heterozygous type. Methods: This study retrospectively explored the relationship among plasma SN-38 level 1.5 hours after critical enzyme for irinotecan (CPT-11) administration (CSN-38 1.5h), plasma SN-38 level 49 hours after CPT-11 administration (CSN-38 49h), DPD activity, and clinical outcomes for the UGT1A1*6 and UGT1A1*28 heterozygous types. Results: CSN-38 1.5h and CSN-38 49h of the UGT1A1*6 or UGT1A1*28 heterozygous type were close to those of UGT1A1*6 and UGT1A1*28 wild-types; some of those with relatively high CSN-38 1.5h levels obtained better median progression-free survival (mPFS), whereas others with higher CSN-38 49h concentrations showed a relatively high incidence of adverse reactions possibly because of the decreased activity of DPD. Conclusion: Increasing the dosage of CPT-11 according to CSN-38 1.5h may improve the efficacy in patients with lower CSN-38 1.5h levels. For cases with comparably low DPD activity, advisable primary and subsequent dose adjustment of 5-fluorouracil based on plasma 5-fluorouracil levels may be a practical strategy for reducing the occurrence of adverse reactions for personalized treatment of the UGT1A1*6 or UGT1A1*28 heterozygous type. Keywords: irinotecan, pharmacokinetics, enzyme activity, uridine diphosphate glucuronosyltransferase 1A1, colorectal cancer

Neck pain due to cervical facet joint pain has a prevalence of 36-60% in chronic neck pain. Pulsed radiofrequency for such pain has been verified. After proper patient selection, pulsed radiofrequency of the cervical facet joints provide long-term pain relief in a routine clinical setting. In the patient selection, clinical and sagittal alignment parameters are rarely discussed for the outcome. In the present study, we analyzed the factors from the clinical data and sagittal alignment parameters and investigated the associated predictors of pulsed radiofrequency for cervical facet joint pain. There were 204 patients with cervical facet joint pain who received a medial branch block and pulsed radiofrequency between 2015 and 2020 after excluding patients with neurological symptoms and other confounding factors. The patients were classified into good and poor outcome groups based on the improvement of the pain score(visual analog scale). Clinical and radiological data were analyzed. Multivariable logistic model showed that the predictors were cervical lordosis including two methods (odds ratio [OR] 0.92, 95% confidence interval [CI]: 0.89-0.96 for C2-C7 Cobb angle; OR 0.91, 95% CI: 0.88-0.95 for the angle measured by the Jackson method), ossification of the nuchal ligament, number of diseased facet joints, anterior cervical discectomy with fusion, and adjacent facet joint after anterior cervical discectomy with fusion. With the results, we demonstrated that the outcome were related to cervical lordosis including two methods, formation of ossification of nuchal ligament, the number of diseased facet joints, post anterior cervical discectomy with fusion, and adjacent facet joint post anterior cervical discectomy with fusion. The corresponding optimal cutoff for discriminating a poor outcome was 7° for the C2-C7 Cobb angle and - 2° for the angle measured using the Jackson method., Competing Interests: Declarations Ethics approval The study was approved by the Institutional Review Board of E-Da hospital (EMRP-111-065). Competing interests The authors declare no competing interests. Medical writing, editorial, and other assistance No., (© 2024. The Author(s).)

Background: The implementation of sterile insect technique (SIT) has proven effective in the area-wide suppression of several significant agricultural and sanitary pests by using traditional cobalt-60 ( 60 Co-γ) as a radiation source. Recently, X-ray has been validated as a feasible alternative to 60 Co-γ radiation sources. Nonetheless, higher doses of X-ray irradiation led to insect sterility but diminish mating competitiveness, thereby impacting the effectiveness of SIT applications., Results: In this study, we assessed the impact of various X-ray irradiation doses (ranging from 0 to 366 Gy) on the fecundity, fertility, and mating competitiveness of Cydia pomonella, a globally invasive fruit pest. Results demonstrated that the sterility rate of irradiated males increased with dose up to 200 Gy, then stabilized. Exposure to 200 Gy reduced male mating competitiveness, with competitiveness index (CI) values of 0.17 in the laboratory and 0.096 in the orchard. This decline is likely linked to the decreased expression of genes associated with sex pheromones recognition, such as CpomOR3a, CpomOR3b, and CpomOR5, post-irradiation. Fumigation of linalool at varying concentrations (70, 83, and 96 μL/m 3 ) enhanced mating competitiveness of males, particularly at moderate levels, possibly by restoring pheromones recognition. Implementation of repeated releases of sterilized males on a pilot scale led to a notable reduction in the population of C. pomonella in the field., Conclusion: These findings indicate that fumigation with plant volatiles has the potential to mitigate male sterility induced by X-ray irradiation, offering a promising approach to enhance the efficacy of SIT applications for the control of C. pomonella. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Background: Sepsis-induced myocardial dysfunction (SIMD) may contribute to the poor prognosis of septic patients. Carvacrol (2-methyl-5-isopropyl phenol), a phenolic monoterpene compound extracted from various aromatic plants and fragrance essential oils, has multiple beneficial effects such as antibacterial, anti-inflammatory, and antioxidant properties. These attributes make it potentially useful for treating many diseases. This study aims to investigate the effects of CAR on LPS-induced myocardial dysfunction and explore the underlying mechanism., Results: H9c2 cells were stimulated with 10 µg/ml LPS for 12 h, and c57BL/6 mice were intraperitoneally injected with 10 mg/kg LPS to establish a septic-myocardial injury model. Our results showed that CAR could improve cardiac function, significantly reduce serum levels of inflammatory cytokines (including TNF-α, IL-1β, and IL-6), decrease oxidative stress, and inhibit cardiomyocyte apoptosis in LPS-injured mice. Additionally, CAR significantly downregulated the expression of TLR4, MyD88, and NF-κB in LPS-injured mice and H9c2 cells. It also inhibited the upregulation of inflammasome components (such as NLRP3, GSDMD, and IL-1β) in H9c2 cells triggered by LPS., Conclusion: Taken together, CAR exhibited potential cardioprotective effects against sepsis, which may be mainly attributed to the TLR4/MyD88/NF-κB pathway and the NLRP3 inflammasome., Competing Interests: Declarations Ethics approval and consent to participate All the animal experiments procedures were performed with the approval of the Air Force Military Medical University (No. 20191206). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Validation of the specificity of ICP-MS methods by ICH Q2 (R2) through spiking experiments cannot characterize the multi-atomic interference of complex high matrix samples, possibly affecting the accuracy of the method and reliability of results. In this study, we highlight this issue by investigating the elemental impurities in lanthanum carbonate raw materials and use isotope ratio analysis to overcome this limitation and establishing an accurate ICP-MS method for 24 elemental impurities (listed in ICH Q3D). An Agilent 7900 ICP-MS was used with an automatic sampler for sample determination in the He mode. The isotope ratio of elemental impurities in the spiked samples was analyzed to characterize polyatomic interference and select the exclusive mass number of elemental impurities. While the recovery rate of most elemental impurities met the requirements, that of selenium (default measurement mass number 78 Se) exceeded the standard in the matric sample. The isotope ratio of Se ( 78 Se/ 82 Se) was much higher than the theoretical value, indicating that the response intensity of m / z 78 was formed by the combination of 78 Se and other mass-to-charge ratios, such as LaOH 2+ formed by the large amount of La in the matrix. Therefore, 82 was chosen as the mass number for Se. The validation results indicate that the method has strong specificity, high accuracy, and is simple and facile. This study provides technical support for the control of elemental impurities in lanthanum carbonates and isotope ratios can be used as a supplementary means of spiked recovery rates.

Purpose: To investigate the surgical outcomes and intraoperative parameters of 3D visualization system for macular diseases in highly myopic eyes., Methods: In this single-center, prospective, randomized, comparative interventional study, 40 highly myopic eyes (axial length > 26 mm) were randomly assigned to either a 3D visualization system or a conventional microscope group. Surgical outcomes and intraoperative parameters, including the number of indocyanine green injections, surgical time, and epiretinal membrane/internal limiting membrane peeling time, were compared., Results: The 3D group required significantly fewer indocyanine green injections (1.3 ± 0.5 vs. 2.3 ± 0.7, P < 0.001), had shorter epiretinal membrane/internal limiting membrane peeling times (522.8 ± 258.0 vs. 751.8 ± 320.2 seconds, P < 0.05), and experienced fewer intraoperative retinal hemorrhages (0 vs. 7 cases, P < 0.05) compared with the conventional microscope group. Anatomical and functional outcomes were comparable between the two groups., Conclusion: The 3D system exhibited a lower number of indocyanine green injections, shorter epiretinal membrane/internal limiting membrane peeling times, and a reduced incidence of intraoperative retinal hemorrhages, suggesting the 3D visualization system may offer advantages for macular surgery in highly myopic eyes., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Background: Instead of completely suppressing blood vessels inside tumors, vascular normalization therapy is proposed to normalize and prune the abnormal vasculature in tumor microenvironment (TME) to acquire a normal and stable blood flow and perfusion. The theoretical basis for the use of "blood-activating and stasis-resolving" formulas in Traditional Chinese Medicine to treat cancer is highly consistent with the principle of vascular normalization therapy, suggesting the potential application of these traditional formulas in vascular normalization therapy., Purpose: To study the underlying mechanisms of a classical "blood-activating and stasis-resolving" formula, Taohong Siwu decoction (TSD), in enhancing the efficacy of chemotherapy for breast cancer treatment., Study Design: HUVECs and transgenic zebrafish embryos were used as the major model in vitro. A 4T1 mouse breast cancer model was applied to study tumor vasculature normalization of TSD and the combination effects with DOX., Results: Our data showed that TSD exhibited anti-angiogenic potential in HUVECs and transgenic zebrafish embryos. After 20 days treatment, TSD significantly normalized the tumor vasculature by remodeling vessel structure, reducing intratumoral hypoxia and vessel leakage, and promoting vessel maturation and blood perfusion in 4T1 breast tumor-bearing mice. Moreover, the anti-tumor efficacy of doxorubicin liposome in 4T1 breast tumors was significantly improved by TSD, including the suppression of tumor cell proliferation, angiogenesis, hypoxia, and the increase of cell apoptosis, which is likely through the vascular normalization induced by TSD. TSD also shifted the macrophage polarization from M2 to M1 phenotype in TME during the combination therapy, as evidenced by the reduced number of CD206 + macrophages and increased number of CD86 + macrophages. Additionally, TSD treatment protected against doxorubicin-induced cardiotoxicity in animals, as evidenced by the reduced cardiomyocytes apoptosis and improved heart function., Conclusion: This study demonstrated for the first time that TSD as a classical Chinese formula can enhance the drug efficacy and reduce the side effects of doxorubicin. These findings can support that TSD could be used as an adjuvant therapy in combination with conventional chemotherapy for the future breast cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

This study aimed to investigate the effect of hetrombopag combined with conventional treatment on immune function in patients with severe aplastic anemia (SAA). Patients were categorized into the control group (n = 50, receiving conventional treatment only) and experimental group (n = 50, receiving hetrombopag combined with conventional treatment). Before treatment and at weeks 18, 24, and 52 after treatment, the two groups were compared in routine blood test indicators, natural killer (NK) cell activity, and peripheral blood inflammatory factor levels. The overall remission rate and incidence of adverse events were also compared between the two groups. Outpatient or telephone follow-up was performed before treatment and at weeks 18, 24, and 52 after treatment to observe patients' immune function, treatment outcome, quality of life, and adverse events. Hemoglobin (Hb), and platelet count (PLT) (P < 0.05), and a rise in NK cell activity (P < 0.05). Interleukin (IL-10) levels were significantly higher, while IL-6 levels were significantly lower in the experimental group compared to the control group (P < 0.05). After receiving the treatment, all scores of SF-36 domains in both groups were higher than before treatment, particularly with higher scores in the experimental group (P < 0.05). Hetrombopag combined with conventional treatment improved the immune function and hematopoiesis of patients with SAA., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Osteosarcoma, a highly aggressive bone cancer, often develops resistance to conventional chemotherapeutics, leading to poor prognosis and survival rates. The malignancy and chemoresistance of osteosarcoma pose significant challenges in its treatment, highlighting the critical need for novel therapeutic approaches. Bruton's tyrosine kinase (BTK) plays a pivotal role in B-cell development and has been linked to various cancers, including breast, lung, and oral cancers, where it contributes to tumor growth and chemoresistance. Despite its established importance in these malignancies, the impact of BTK on osteosarcoma remains unexplored. Our study delves into the expression levels of BTK in osteosarcoma tissues by data from the GEO and TCGA database, revealing a marked increase in BTK expression compared with primary osteoblasts and a potential correlation with primary site progression. Through our investigations, we identified a subset of osteosarcoma cells, named cis-HOS, which exhibited resistance to cisplatin. These cells displayed characteristics of cancer stem cells (CSCs), demonstrated a higher angiogenesis effect, and had an increased migration ability. Notably, an upregulation of BTK was observed in these cisplatin-resistant cells. The application of ibrutinib, a BTK inhibitor, significantly mitigated these aggressive traits. Our study demonstrates that BTK plays a crucial role in conferring chemoresistance in osteosarcoma. The upregulation of BTK in cisplatin-resistant cells was effectively countered by ibrutinib. These findings underscore the potential of targeting BTK as an effective strategy to overcome chemoresistance in osteosarcoma treatment., (© 2024 Wiley Periodicals LLC.)

A huge majority of new chemical entities (NCEs) advancing through the drug discovery pipeline often have poor aqueous solubility. This requires formulation scientists to search for solubility enhancement strategies, within the constraints of time and material. To address these challenges, a strategic platform formulation is often required for a rapid compound screening to enable early exploratory PK and toxicology studies. Through this work, we present an option of a material-sparing, high yielding and solubility-enabling amorphous API and HPMCAS-L co-loaded mesoporous silica-based formulation. The usability of this platform formation strategy was assessed for a physico-chemically diverse set of eleven compounds. The formulation approach was successful in stabilizing the model compounds mesoporous silica. Additionally, through the presence of HPMCAS-L, the precipitation risk in supersaturable aqueous environment was significantly reduced. Finally, this manuscript provides fundamental, computational and experimental molecular-properties based formulation guidance tree to a priori gauge the (1) possibility of generating solid-state stable amorphous formulations and (2) sustaining in vitro supersaturation in extreme non-sink dissolution conditions. This unique and conceptual formulation guidance tree is believed to be extremely beneficial to drug discovery formulators to triage NCEs and streamline solubility-enabling formulation efforts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)