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BackgroundBreast cancer (BC) is one of the most common cancers worldwide. The inevitability of drug resistance to initial anti-HER-2 therapy necessitates the emergence of second-line anti-HER-2 drugs which exhibit a promising outlook. Consequently, it is imperative to appraise their efficacy through network meta-analysis and ascertain their comparative cost-effectiveness.MethodsThe data used in our analysis were acquired from patients enrolled in the EMILIA, DESTINY-Breast03, and PHOEBE phase III randomized clinical trials. A partitioned survival model was used for patients diagnosed with HER-2-positive metastatic Breast cancer. The model was crafted with a time horizon of 10 years, operating on a 21-day cycle and incorporating a 5% discount rate for both costs and outcomes. The willingness-to-pay threshold was set at $36,058.06 per quality-adjusted life year (QALY). The impact of parameter uncertainty on the findings was assessed using a one-way deterministic sensitivity analysis and probability sensitivity analysis.FindingsWithin the model encompassing 1782 patients, the utilization of pyrotinib plus capecitabine (PC) treatment yielded an additional 0.70 QALY in comparison to T-DM1, resulting in an incremental cost-effectiveness ratio (ICER) of $31,121.53 per QALY gained. Similarly, the administration of T-DXd treatment led to an additional 0.80 QALY compared to T-DM1, resulting in an ICER of $153,950.19 per QALY gained. The PC strategies are considered more cost-effective than T-DXd when the WTP threshold is set at $36,058.06 per QALY. However, this method is not cost effective for T-DXd. The probability of the PC strategies being cost-effective was 62%, whereas the probability of T-DXd was 0% when compared to T-DM1.ConclusionPC is a cost-effective therapy for patients afflicted with HER-2-positive metastatic BC compared to T-DM1 from the perspective of China at a WTP threshold of $36,058.06 per QALY. Nevertheless, T-DXd is not as cost-effective as T-DM1, considering its current medication pricing. Therefore, reducing the cost of T-DXd could improve its overall cost-effectiveness.

Abstract Background The possibility of adverse effects of medical treatment (AEMT) is increasing worldwide, but little is known about AEMT in China. This study analyzed the health burden of AEMT in China in recent years through the Global Burden of Disease Study (GBD) 2019 and compared it with the worldwide average level and those in different sociodemographic index (SDI) regions. Methods We calculated the age-standardized rate (ASR) of deaths, disability-adjusted life years (DALYs), years of life lost (YLLs), years lived with disability (YLDs), incidence and prevalence attributed to AEMT in China, worldwide and countries with different sociodemographic indices during 1990–2019 using the latest data and methods from the GBD 2019. Results From 1990 to 2019, the global age-standardized death rate (ASDR), DALYs, and YLLs for AEMT showed a significant downward trend and were negatively associated with the SDI. By 2040, the ASDR is expected to reach approximately 1.58 (95% UI: 1.33–1.80). From 1990 to 2019, there was no significant change in the global incidence of AEMT. The occurrence of AEMT was related to sex, and the incidence of AEMT was greater among females. In addition, the incidence of AEMT-related injuries and burdens, such as ASR of DALYs, ASR of YLLs and ASR of YLDs, was greater among women than among men. Very old and very young people were more likely to be exposed to AEMT. Conclusions From 1990 to 2019, progress was made worldwide in reducing the harm caused by AEMT. However, the incidence and prevalence of AEMT did not change significantly overall during this period. Therefore, the health sector should pay more attention to AEMT and take effective measures to reduce AEMT.

Redox homeostasis refers to the dynamic equilibrium between oxidant and reducing agent in the body which plays a crucial role in maintaining normal physiological activities of the body. The imbalance of redox homeostasis can lead to the development of various human diseases. Lysosomes regulate the degradation of cellular proteins and play an important role in influencing cell function and fate, and lysosomal dysfunction is closely associated with the development of various diseases. In addition, several studies have shown that redox homeostasis plays a direct or indirect role in regulating lysosomes. Therefore, this paper systematically reviews the role and mechanisms of redox homeostasis in the regulation of lysosomal function. Therapeutic strategies based on the regulation of redox exerted to disrupt or restore lysosomal function are further discussed. Uncovering the role of redox in the regulation of lysosomes helps to point new directions for the treatment of many human diseases.

Despite significant treatment advances, breast cancer remains the leading cause of cancer death in women. From the current treatment situation, in addition to developing chemoresistant tumours, distant organ metastasis, and recurrences, patients with breast cancer often have a poor prognosis. Aptamers as ''chemical antibodies'' may be a way to resolve this dilemma. Aptamers are single-stranded, non-coding oligonucleotides (DNA or RNA), resulting their many advantages, including stability for long-term storage, simplicity of synthesis and function, and low immunogenicity, a high degree of specificity and antidote. Aptamers have gained popularity as a method for diagnosing and treating specific tumors in recent years. This article introduces the application of ten different aptamer delivery systems in the treatment and diagnosis of breast cancer, and systematically reviews their latest research progress in breast cancer treatment and diagnosis. It provides a new direction for the clinical treatment of breast cancer.

Water inrush is the biggest threat for safe mining in the Ruifeng coalmine, located in North China. In the study mining area, the floor water inrush is mainly caused by mining activities and collapse column. In this article, the mechanical criteria of floor water inrush are obtained based on cusp catastrophe theory, which is used to assess floor water inrush risk in the Ruifeng coalmine. Theoretical analysis shows that floor water inrush is very likely to occur during coal mining without the influence of geological structures. Additionally, FLAC3D was used to simulate the damage of floor strata during the mining face advances. Numerical results show that the water inrush channel occurs in front of the mining face due to the influence of stress concentration. Therefore, a microseismic monitoring system was applied to monitor the formation of water inrush pathway. Field monitoring results show that two water inrush pathways were accurately predicted and positioned. Based on the microseismic monitoring results, target grouting was adopted to prevent water inrush. This study provides significant guidance for the prevention of floor water inrush.

Abnormal intracellular metabolism not only provides nutrition for tumor occurrence and development, but also sensitizes the function of various immune cells in the immune microenvironment to promote tumor immune escape. This review discusses the emerging role of immune cells in the progress of pancreatic cancer, acrossing metabolic reprogramming and key metabolic pathways present in different immune cell types. At present, the hotspots of metabolic reprogramming of immune cells in pancreatic cancer progression mainly focuses on glucose metabolism, lipid metabolism, tricarboxylic acid cycle and amino acid metabolism, which affect the function of anti-tumor immune cells and immunosuppressive cells in the microenvironment, such as macrophages, dendritic cells, T cells, myeloid-derived suppressor cells, neutrophils and B cells by a series of key metabolic signaling pathways, such as PI3K/AKT, mTOR, AMPK, HIF-1α, c-Myc and p53. Drugs that target the tumor metabolism pathways for clinical treatment of pancreatic cancer are also systematically elaborated, which may constitute food for others' projects involved in clinical anti-cancer research.

With the advancement of computer technology, machine learning-based artificial intelligence technology has been increasingly integrated and applied in the fields of medicine, biology, and pharmacy, thereby facilitating their development. Transporters have important roles in influencing drug resistance, drug–drug interactions, and tissue-specific drug targeting. The investigation of drug transporter substrates and inhibitors is a crucial aspect of pharmaceutical development. However, long duration and high expenses pose significant challenges in the investigation of drug transporters. In this review, we discuss the present situation and challenges encountered in applying machine learning techniques to investigate drug transporters. The transporters involved include ABC transporters (P-gp, BCRP, MRPs, and BSEP) and SLC transporters (OAT, OATP, OCT, MATE1,2-K, and NET). The aim is to offer a point of reference for and assistance with the progression of drug transporter research, as well as the advancement of more efficient computer technology. Machine learning methods are valuable and attractive for helping with the study of drug transporter substrates and inhibitors, but continuous efforts are still needed to develop more accurate and reliable predictive models and to apply them in the screening process of drug development to improve efficiency and success rates.

The kidney is critical in the human body’s excretion of drugs and their metabolites. Renal transporters participate in actively secreting substances from the proximal tubular cells and reabsorbing them in the distal renal tubules. They can affect the clearance rates (CLr) of drugs and their metabolites, eventually influence the clinical efficiency and side effects of drugs, and may produce drug–drug interactions (DDIs) of clinical significance. Renal transporters and renal transporter-mediated DDIs have also been studied by many researchers. In this article, the main types of in vitro research models used for the study of renal transporter-mediated DDIs are membrane-based assays, cell-based assays, and the renal slice uptake model. In vivo research models include animal experiments, gene knockout animal models, positron emission tomography (PET) technology, and studies on human beings. In addition, in vitro–in vivo extrapolation (IVIVE), ex vivo kidney perfusion (EVKP) models, and, more recently, biomarker methods and in silico models are included. This article reviews the traditional research methods of renal transporter-mediated DDIs, updates the recent progress in the development of the methods, and then classifies and summarizes the advantages and disadvantages of each method. Through the sorting work conducted in this paper, it will be convenient for researchers at different learning stages to choose the best method for their own research based on their own subject’s situation when they are going to study DDIs mediated by renal transporters.

Abstract As the life expectancy of the population increases worldwide, cancer is becoming a substantial public health problem. Considering its recurrence and mortality rates, most cancer cases are difficult to cure. In recent decades, a large number of studies have been carried out on different cancer types; unfortunately, tumor incidence and mortality have not been effectively improved. At present, early diagnostic biomarkers and accurate therapeutic strategies for cancer are lacking. High temperature requirement A1 (HtrA1) is a trypsin-fold serine protease that is also a chymotrypsin-like protease family member originally discovered in bacteria and later discovered in mammalian systems. HtrA1 gene expression is decreased in diverse cancers, and it may play a role as a tumor suppressor for promoting the death of tumor cells. This work aimed to examine the role of HtrA1 as a cell type-specific diagnostic biomarker or as an internal and external regulatory factor of diverse cancers. The findings of this study will facilitate the development of HtrA1 as a therapeutic target.

Breast cancer is the leading cause of cancer death in women. At present, chemotherapy is the main method to treat breast cancer in addition to surgery and radiotherapy, but the process of chemotherapy is often accompanied by the development of drug resistance, which leads to a reduction in drug efficacy. Furthermore, mounting evidence indicates that drug resistance is caused by dysregulated cellular metabolism, and metabolic reprogramming, including enhanced glucose metabolism, fatty acid synthesis and glutamine metabolic rates, is one of the hallmarks of cancer. Changes in metabolism have been considered one of the most important causes of resistance to treatment, and knowledge of the mechanisms involved will help in identifying potential treatment deficiencies. To improve women’s survival outcomes, it is vital to elucidate the relationship between metabolic reprogramming and drug resistance in breast cancer. This review analyzes and investigates the reprogramming of metabolism and resistance to breast cancer therapy, and the results offer promise for novel targeted and cell-based therapies.

Background: Sintilimab + a bevacizumab biosimilar (IBI305) (SB) and atezolizumab + bevacizumab (AB) have been approved for the treatment of unresectable hepatocellular carcinoma (HCC). At present, oncologists and their patients remain indecisive on their preferred treatment regime. Therefore, assessing their efficacy via a network meta-analysis and determining their comparative cost-effectiveness is necessary.Objective: To evaluate the cost-effectiveness of SB and AB compared with sorafenib alone for the treatment of unresectable HCC.Materials and Methods: The data used in our analysis were obtained from patients in ORIENT-32 and IMbrave150 phase III randomized clinical trials. A Bayesian network meta-analysis and cost-effectiveness analysis that included 1,072 patients were performed in this study. A partitioned survival model was applied to the patients with unresectable HCC. The model was designed with a 15-year time horizon, 1-month cycle, and 5% discount rate for costs and outcomes. In China, an incremental cost-effectiveness ratio (ICER) value of less than $33,500 (three times the GDP per capita in 2020) per quality-adjusted life-year (QALY) is considered cost-effective. The influence of parameter uncertainty on the results was verified by one-way deterministic sensitivity analysis and probability sensitivity analysis. Furthermore, scenario analyses of the patient assistance program (PAP) were conducted to explore the cost-effectiveness of SB and AB.Results: For the model of 1,072 patients, treatment with SB produced an additional 0.617 QALYs compared with sorafenib, resulting in an ICER of $39,766.86/QALY. Similarly, treatment with AB produced an additional 0.596 QALYs compared with sorafenib, resulting in an ICER of $103,037.66/QALY. The probability sensitivity analysis showed that when the willingness-to-pay (WTP) threshold was $33,500/QALY, the cost-effectiveness of SB and AB was 15.4 and 0.4%, respectively. However, in the scenario analyses, the probability of SB and AB regimens being cost-effective was 65.4 and 15.8%, respectively, at a WTP of $33,500/QALY.Conclusion: The findings from our study showed that sintilimab + a bevacizumab biosimilar is a cost-effective regimen compared with sorafenib as the first-line therapy for unresectable HCC in China at a $33,500 WTP threshold if sintilimab PAP is considered. However, the atezolizumab + bevacizumab regimen is not cost-effective whether atezolizumab PAP is considered or not.

Doxorubicin (DOX) leads to myocardial cell damage and irreversible heart failure, which limits the clinical application of DOX. Naringin has biological functions of inhibiting inflammation, oxidative stress and apoptosis. Our aim was to investigate whether Naringin could prevent DOX-related cardiotoxicity in mice. Naringin was administered by gavage and mice were intraperitoneally injected with doxorubicin (1 mg/kg/day) for 15 days. H&E, Masson, TUNEL and others experiments were examined. NRVMs and H9C2 cells were treated with Naringin and DOX in vitro. Using IF, ELISA and Western Blot to detect the effect of Naringin and ECHS1 on cells. The results showed that Naringin could prevent DOX related cardiac injury, inhibit cardiac oxidative stress, inflammation and apoptosis in vivo and in vitro. Inhibition of ECHS1 could interfere the effect of Naringin on DOX-induced myocardial injury. Naringin may provide a new cardiac protective tool for preventing the cardiotoxicity of anthracycline drugs.

To assess the mechanism of the pharmacokinetic interaction between piperacillin and tazobactam, renal excretion and pharmacokinetic studies of piperacillin/tazobactam were investigated in normal and bacteremia rats. A bacteremia model was established to investigate the pharmacokinetic properties of piperacillin and tazobactam under different conditions. Renal slices were taken to examine the uptake of piperacillin and tazobactam. Pharmacokinetic studies of β-lactamase in rats were performed to study the contribution of rOat1/3 to the inhibition of tazobactam on β-lactamase. The AUC (from 2.93 ± 0.58 to 6.52 ± 1.44 mg·min/ml) and the plasma clearance (CLP) (from 2.41 ± 1.20 to 0.961 ± 0.212 ml/min/kg) of tazobactam were both altered after the intravenous coadministration of piperacillin and tazobactam in the bacteremia rats. The renal clearance (CLR) of tazobactam decreased from 1.30 ± 0.50 to 0.361 ± 0.043 ml/min/kg. In summary, there was a beneficial interaction between piperacillin and tazobactam mediated by rOat1 and rOat3. Piperacillin enhances the inhibitory effect of tazobactam on β-lactamase through the inhibition of rOat1 and rOat3 in rats. The contribution rate of rOat1/3 for the synergistic effect was 20% when the two drugs were coadministered. Keywords: Organic anion transporter, Piperacillin, Tazobactam, Drug-drug interaction

Currently, both acute kidney injury (AKI) and chronic kidney disease (CKD) are considered to be the leading public health problems with gradually increasing incidence rates around the world. Rhein is a monomeric component of anthraquinone isolated from rhubarb, a traditional Chinese medicine. It has anti-inflammation, anti-oxidation, anti-apoptosis, anti-bacterial and other pharmacological activities, as well as a renal protective effects. Rhein exerts its nephroprotective effects mainly through decreasing hypoglycemic and hypolipidemic, playing anti-inflammatory, antioxidant and anti-fibrotic effects and regulating drug-transporters. However, the latest studies show that rhein also has potential kidney toxicity in case of large dosages and long use times. The present review highlights rhein’s molecular targets and its different effects on the kidney based on the available literature and clarifies that rhein regulates the function of the kidney in a positive and negative way. It will be helpful to conduct further studies on how to make full use of rhein in the kidney and to avoid kidney damage so as to make it an effective kidney protection drug.

Silicon (Si) plays an important role in improving soil nutrient availability and plant carbon (C) accumulation and may therefore impact the biogeochemical cycles of C, nitrogen (N), and phosphorus (P) in terrestrial ecosystems profoundly. However, research on this process in grassland ecosystems is scarce, despite the fact that these ecosystems are one of the most significant accumulators of biogenic Si (BSi). In this study, we collected the aboveground parts of four widespread grasses and soil profile samples in northern China and assessed the correlations between Si concentrations and stoichiometry and accumulation of C, N, and P in grasses at the landscape scale. Our results showed that Si concentrations in plants were significantly negatively correlated (p < 0.01) with associated C concentrations. There was no significant correlation between Si and N concentrations. It is worth noting that since the Si concentration increased, the P concentration increased from less than 0.10% to more than 0.20% and therefore C:P and N:P ratios decreased concomitantly. Besides, the soil noncrystalline Si played more important role in C, N, and P accumulation than other environmental factors (e.g., MAT, MAP, and altitude). These findings indicate that Si may facilitate grasses in adjusting the utilization of nutrients (C, N, and P) and may particularly alleviate P deficiency in grasslands. We conclude that Si positively alters the concentrations and accumulation of C, N, and P likely resulting in the variation of ecological stoichiometry in both vegetation and litter decomposition in soils. This study further suggests that the physiological function of Si is an important but overlooked factor in influencing biogeochemical cycles of C and P in grassland ecosystems.

Retailers offer BOPS (Buy Online, Pick Up in Store) service to improve consumers shopping experience. However, this greatly increases the decision complexity for retailers and consumers. For consumers, whether to purchase online or from a store with the BOPS service is a complex decision. This is especially true when the product has fit uncertainty. That is, consumers are uncertain about product fitness before using it. Also, their store visit cost can be heterogeneous and follows some distribution function. For a retailer, it needs to jointly optimize multiple decisions including the convenience degree of BOPS. To help the retailer develop the jointly optimal decisions, we first build a mathematical model where the retailer sells the product through online and store channel and analyzes the possible effects of BOPS. We find that the retailer should offer BOPS when the channel cost ratio (ratio of shipment fee divided by average store visit cost) is large enough. Through numerical studies, we show that the ratio of profit offering BOPS divided by the benchmark increases with the probability of product fit, shipment fee, and the convenience degree of BOPS. We then consider the case where the convenience degree of BOPS is also a decision itself. We find the optimal convenience degree of BOPS increases along with the average store visit cost and the probability of product fit. When the cost factor of offering the convenience for BOPS is larger than a threshold, the retailer should never offer BOPS.

To understand the past carbon accumulation of forest–steppe ecotone and to identify the main drivers of the long-term carbon dynamics, we selected Huangqihai Lake and analyzed the sediment records. We measured the organic carbon content (TOC; %) of sedimentary samples and quantified the carbon accumulation rate (CAR; g C m−2 yr−1). Furthermore, the climate, soil erosion, and vegetation development of the past 6800 years were reconstructed using physicochemical parameters and pollen records. Human activities were also obtained from a 2200-year history record. Our results showed that the CAR was high during 5800~4100 cal yr BP (40~60 g C m−2 yr−1), which is mainly attributed to the high sediment accumulation rate (SAR) during this period. Pearson’s correlation, redundancy analysis and hierarchical variation partitioning analyses suggested that the CAR was influenced by the SAR and TOC, while vegetation dynamics (broadleaved tree percentage and vegetation coverage) and local soil erosion were the main drivers of the TOC and SAR. Especially when the vegetation was dominated by broadleaved forests, the CAR was significantly high due to the high gross primary productivity and carbon density of forest compared with steppe. Our study highlights the direct influence of local vegetation and soil erosion on the CAR, whereas climate might influence indirectly by changing local vegetation and soil conditions. Moreover, our results showed that human activities had positive influences on the carbon accumulation dynamics in this region since 2200 cal yr BP by influencing the SAR.