Search

Objective: Bendamustine was approved for treating chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma. Despite its therapeutic benefits, the long-term safety of bendamustine in a large population remains inadequately understood. This study evaluates the adverse events (AEs) associated with bendamustine, using a real-world pharmacovigilance database to support its clinical application.Methods: We conducted a post-marketing risk analysis to assess the association between bendamustine and its AEs. Data were extracted from the US FDA’s Adverse Event Reporting System (FAERS), covering the period from January 2017 to September 2023. The characteristics of bendamustine-associated AEs and the onset time were further analyzed. Statistical analysis was performed using MYSQL 8.0, Navicat Premium 15, Microsoft EXCEL 2016, and Minitab 21.0.Results: 9,461,874 reports were collected from the FAERS database, 9,131 identified bendamustine as the “primary suspected” drug. We identified 331 significant disproportionality preferred terms (PTs). Common AEs included pyrexia, neutropenia, infusion site reaction, progressive multifocal leukoencephalopathy (PML), injection site vasculitis, and pneumonia—all documented on bendamustine’s label. Notably, 16 unexpected and significant AEs were discovered, including hypogammaglobulinemia, which is concerning due to its potential to increase infection susceptibility following bendamustine treatment. Other significant findings were anaphylactic reactions, PML, and cutaneous malignancies, suggesting updates to the drug’s label may be necessary. Physicians should monitor for neurological and skin changes in patients and discontinue treatment if PML is suspected. Moreover, the median onset time for bendamustine-associated AEs was 13 days, with an interquartile range [IQR] of 0–59 days, predominantly occurring on the first day post-initiation. The β of bendamustine-related AEs suggested risk reduction over time.Conclusion: Our study uncovered some potential pharmacovigilance signals for bendamustine, providing important insights for its safe and effective clinical use.

Abstract Tumor growth, metastasis and therapeutic response are believed to be regulated by the tumor and its microenvironment (TME) in advanced renal cell carcinoma (RCC). However, the mechanisms underlying genomic, transcriptomic and epigenetic alternations in RCC progression have not been completely defined. In this study, single-cell RNA-sequencing (scRNA-seq) data were obtained from eight tissue samples of RCC patients, including two matched pairs of primary and metastatic sites (lymph nodes), along with Hi-C, transposable accessible chromatin by high-throughput (ATAC-seq) and RNA-sequencing (RNA-seq) between RCC (Caki-1) and human renal tubular epithelial cell line (HK-2). The identified target was verified in clinical tissue samples (microarray of 407 RCC patients, TMA-30 and TMA-2020), whose function was further validated by in vitro and in vivo experiments through knockdown or overexpression. We profiled transcriptomes of 30514 malignant cells, and 14762 non-malignant cells. Comprehensive multi-omics analysis revealed that malignant cells and TME played a key role in RCC. The expression programs of stromal cells and immune cells were consistent among the samples, whereas malignant cells expressed distinct programs associated with hypoxia, cell cycle, epithelial differentiation, and two different metastasis patterns. Comparison of the hierarchical structure showed that SERPINE2 was related to these NNMF expression programs, and at the same time targeted the switched compartment. SERPINE2 was highly expressed in RCC tissues and lowly expressed in para-tumor tissues or HK-2 cell line. SERPINE2 knockdown markedly suppressed RCC cell growth and invasion, while SERPINE2 overexpression dramatically promoted RCC cell metastasis both in vitro and in vivo. In addition, SERPINE2 could activate the epithelial-mesenchymal transition pathway. The above findings demonstrated that the role of distinct expression patterns of malignant cells and TME played a distinct role in RCC progression. SERPINE2 was identified as a potential therapeutic target for inhibiting metastasis in advanced RCC.

Objective: To develop an inflammation-based risk stratification tool for operative mortality in patients with acute type A aortic dissection. Methods: Between January 1, 2016 and December 31, 2021, 3124 patients from Beijing Anzhen Hospital were included for derivation, 571 patients from the same hospital were included for internal validation, and 1319 patients from other 12 hospitals were included for external validation. The primary outcome was operative mortality according to the Society of Thoracic Surgeons criteria. Least absolute shrinkage and selection operator regression were used to identify clinical risk factors. A model was developed using different machine learning algorithms. The performance of the model was determined using the area under the receiver operating characteristic curve (AUC) for discrimination, calibration curves, and Brier score for calibration. The final model (5A score) was tested with respect to the existing clinical scores. Results: Extreme gradient boosting was selected for model training (5A score) using 12 variables for prediction—the ratio of platelet to leukocyte count, creatinine level, age, hemoglobin level, prior cardiac surgery, extent of dissection extension, cerebral perfusion, aortic regurgitation, sex, pericardial effusion, shock, and coronary perfusion—which yields the highest AUC (0.873 [95% confidence interval (CI) 0.845-0.901]). The AUC of 5A score was 0.875 (95% CI 0.814-0.936), 0.845 (95% CI 0.811-0.878), and 0.852 (95% CI 0.821-0.883) in the internal, external, and total cohort, respectively, which outperformed the best existing risk score (German Registry for Acute Type A Aortic Dissection score AUC 0.709 [95% CI 0.669-0.749]). Conclusion: The 5A score is a novel, internally and externally validated inflammation-based tool for risk stratification of patients before surgical repair, potentially advancing individualized treatment. Trial Registration: clinicaltrials.gov Identifier: NCT04918108

Abstract Metastasis is crucial for the prognosis of hepatocellular carcinoma (HCC). Distinguishing the potential risk factors for distant metastasis in small HCC (diameter ≤ 5 cm) is of great significance for improving the prognosis. HCC patients in the Surveillance, Epidemiology and End Results (SEER) registry with tumors ≤ 5 cm in diameter between January 2010 and December 2015 were retrieved. Demographic and clinicopathological metrics were extracted, including age, sex, race, marital status, tumor size, histological grade, T stage, N stage, M stage, alpha-fetoprotein (AFP), and liver fibrosis score. Univariate and multivariate logistic regression analyses were used to identify independent risk factors correlated with extrahepatic metastasis in small HCC. Propensity score matching (PSM) analysis was performed to balance the confounding factors in baseline characteristics. A total of 4176 eligible patients were divided into a non-metastasis group (n = 4033) and a metastasis group (n = 143) based on metastasis status. In multivariate analysis, larger tumor size, poor histological differentiation, regional lymph node metastasis, and elevated serum AFP levels were identified as independent risk factors for distant metastasis (P

Ample evidence indicates that the development and progression of renal cell carcinoma (RCC) are complex pathological processes involving interactions between tumor cells, immune cells and stromal components. Tumor infiltrated immune cells determine whether tumor advancement is promoted or inhibited. Among them, infiltrated B lymphocytes are present in all stages of RCC, playing a major role in determining tumor formation and advancement, as an essential part in the tumor microenvironment (TME). Although the advent of targeted and immune therapies has remarkably improved the survival of patients with advanced RCC, few cases can achieve complete response due to drug resistance. In this review article, we intend to summary the recent studies that outline the interaction networks of B cells with other cells, discuss the role of B cells in RCC development and progression, and assess their impact on RCC immunotherapy.

Ovarian aging is a complex process characterized by a decline in oocyte quantity and quality, directly impacting fertility and overall well-being. Recent researches have identified mitochondria as pivotal players in the aging of ovaries, influencing various hallmarks and pathways governing this intricate process. In this review, we discuss the multifaceted role of mitochondria in determining ovarian fate, and outline the pivotalmechanisms through whichmitochondria contribute to ovarian aging. Specifically, we emphasize the potential of targeting mitochondrial dysfunction through innovative therapeutic approaches, including antioxidants, metabolic improvement, biogenesis promotion, mitophagy enhancement, mitochondrial transfer, and traditional Chinese medicine. These strategies hold promise as effective means to mitigate age-related fertility decline and preserve ovarian health. Drawing insights from advanced researches in the field, this review provides a deeper understanding of the intricate interplay between mitochondrial function and ovarian aging, offering valuable perspectives for the development of novel therapeutic interventions aimed at preserving fertility and enhancing overall reproductive health. [ABSTRACT FROM AUTHOR]

Trimethyltin chloride (TMT) is an organotin heat stabilizer that is widely used in the production of plastics, and has strong toxicity. Here, the effect of trimethyltin chloride on mouse kidneys and its related mechanism were studied by taking TMT mouse with drinking water as a model. Histological examination and TUNEL results showed that the trimethyltin chloride group had typical apoptosis and necroptosis characteristics. Therefore, the level of oxidative stress was detected,and the expression of related genes was verified by real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot methods. The results showed that oxidative stress was activated (MDA,SOD,CAT,T-AOC), released ROS, activated NF-κB pathway,activated inflammasome (NLRP3,Caspase-1,ASC), and inflammasome-secreted inflammatory factors (IL-1β). The expression of apoptosis (BCL-2, BAX, Caspase-3, Caspase-9) and necroptosis (RIPK1, RIPK33, MLKL, Caspase-8) increased.In addition, HEK293T human embryonic kidney cells were treated with trimethyltin chloride, and the results were similar to the tissue. In conclusion, TMT can induce oxidative stress, activate NF-κB pathway, and induce apoptosis and necroptosis through inflammasomes.

Abstract Background Extrahepatic metastasis is the independent risk factor of poor survival of primary hepatic carcinoma (PHC), and most occurs in the chest and abdomen. Currently, there is still no available method to predict thoracoabdominal extrahepatic metastasis in PHC. In this study, a novel nomogram model was developed and validated for prediction of thoracoabdominal extrahepatic metastasis in PHC, thereby conducted individualized risk management for pretreatment different risk population. Methods The nomogram model was developed in a primary study that consisted of 330 consecutive pretreatment patients with PHC. Large-scale datasets were extracted from clinical practice. The nomogram was based on the predictors optimized by data dimension reduction through Lasso regression. The prediction performance was measured by the area under the receiver operating characteristic (AUROC), and calibrated to decrease the overfit bias. Individualized risk management was conducted by weighing the net benefit of different risk population via decision curve analysis. The prediction performance was internally and independently validated, respectively. An independent-validation study using a separate set of 107 consecutive patients. Results Four predictors from 55 high-dimensional clinical datasets, including size, portal vein tumor thrombus, infection, and carbohydrate antigen 125, were incorporated to develop a nomogram model. The nomogram demonstrated valuable prediction performance with AUROC of 0.830 (0.803 in internal-validation, and 0.773 in independent-validation, respectively), and fine calibration. Individual risk probability was visually scored. Weighing the net benefit, threshold probability was classified for three-independent risk population, which was 71.8%, respectively. According to this classification, pretreatment risk management was based on a treatment-flowchart for individualized clinical decision-making. Conclusions The proposed nomogram is a useful tool for pretreatment risk management of thoracoabdominal extrahepatic metastasis in PHC for the first time, and may handily facilitate timely individualized clinical decision-making for different risk population.

The atomization process of a liquid jet in supersonic crossflow with a Mach number of 1.94 was investigated numerically under the Eulerian-Lagrangian scheme. The droplet stripping process was calculated by the KH (Kelvin-Helmholtz) breakup model, and the secondary breakup due to the acceleration of shed droplets was calculated by the combination of the KH breakup model and the RT (Rayleigh-Taylor) breakup model. In our research, the existing KH-RT model was modified by optimizing the empirical constants incorporated in this model. Moreover, it was also found that the modified KH-RT breakup model is applied better to turbulent inflow of a liquid jet than laminar inflow concluded from the comparisons with experimental results. To validate the modified breakup model, three-dimensional spatial distribution and downstream distribution profiles of droplet properties of the liquid spray in the Ma=1.94 airflow were successfully predicted in our simulations. Eventually, abundant numerical cases under different operational conditions were launched to investigate the correlations of SMD (Sauter Mean Diameter) with the nozzle diameter as well as the airflow Mach number, and at the same time, modified multivariate power functions were developed to describe the correlations.

Studies of chemosensory genes are key to a better understanding of intra- and interspecific communications between insects and their environment and provide opportunities for developing environmentally friendly pesticides to target pest species. The bamboo locust Ceracris kiangsu Tsai (Orthoptera: Acrididae) is one of the most important bamboo leaf-eating insects in southern China. However, the genes underlying olfactory sensation are lacking in the bamboo locust. In this study, the transcriptomes of male and female C. kiangsu antennae were sequenced and analyzed. A total of 125 chemosensory genes, including 91 odorant receptors (ORs), 13 ionotropic receptors (IRs), 13 odorant-binding proteins (OBPs), six chemosensory proteins (CSPs), and two sensory neuron membrane proteins, were identified based on sequence alignment and phylogenetic analyses. The expression patterns of all candidate genes on the antennae of males and females, maxillary palps, tarsi, wings, and thoraxes-abdomens were confirmed by real-time quantitative PCR. The analyses demonstrated that most genes are highly expressed in the antennae, and 35 ORs, 7 IRs, 10 OBPs, and 1 CSP exhibit significantly male-biased expression patterns, indicating their potential functions in mating behavior and the recognition of female sex pheromones. In addition to the antennal-predominant genes, some were abundant in the maxillary palps and some in the non-olfactory tissues, suggesting their different functions in the olfactory system of C. kiangsu. Our research offers an extensive resource for investigating the chemoreception mechanism of C. kiangsu. Further studies of olfactory function will provide comprehensive methods and original strategies for integrated pest management.

Background: Hepatocellular carcinoma (HCC) frequently occurs in cirrhosis and closely relates to poor prognosis of cirrhotic patients. Alpha-fetoprotein (AFP) is the most widely used biomarker in HCC diagnosis but not sensitive and specific to detect HCC at low AFP levels. In order to enhance the ability of AFP to detect HCC developed on cirrhosis, we attempted to combine AFP with conventional clinical metrics to develop a simple and effective method for identifying cirrhotic patients with complicating HCC at various AFP levels.Methods: Cirrhotic patients with or without HCC hospitalized to receive therapy for the first time were recruited and their clinical data were retrospectively collected. A model for diagnosing HCC was developed with routine clinical metrics and AFP by binary logistic regression analysis and internally validated. The goodness of fit, diagnostic accuracy and clinical usefulness of the model were evaluated using a calibration curve, the area under the receiver operating characteristic curve (AUROC) and a decision curve analysis, respectively.Results: A total of 574 patients with cirrhosis mainly caused by hepatitis B were recruited in this study, including 286 cases of simple cirrhosis (LC) and 288 cases of cirrhosis with HCC (LCC) (124 AFP-negative), with an average age of 53.2 ± 12.1 years and 81.4% males. Twelve of the 19 clinical metrics (age, gender, AFP, liver function tests, serum electrolytes, and coagulation tests) significantly differed between the LC and LCC groups. A model was successfully developed with age, AFP, Na+, Cl−, alkaline phosphatase, and activated partial thromboplastin time, which exhibited good performance in diagnosing LCC, with an AUROC of 0.918 (95%CI 0.895–0.940), 82.3% sensitivity, 89.5% specificity, and 85.9% accuracy for all patients, which were much higher values than those for AFP [0.846 (95%CI 0.815–0.878), 72.9, 81.5, and 77.2%, respectively]. For cirrhotic patients complicated with AFP-negative HCC, the model showed an AUROC of 0.854 (95%CI 0.812–0.896), 68.5% sensitivity, 86.6% specificity, and 80.0% accuracy. A high net benefit could be obtained in clinical decision making according to the model.Conclusion: A diagnostic model combining simple clinical metrics with AFP is valuable for the identification of cirrhotic patients complicating HCC with various AFP levels.

Objective: This study aimed to develop and validate a simple-to-use nomogram for early hepatocellular carcinoma (HCC) patients undergoing a preoperative consultation and doctors conducting a postoperative evaluation.Methods: A total of 2,225 HCC patients confirmed with stage I or II were selected from the Surveillance, Epidemiology, and End Results database between January 2010 and December 2015. The patients were randomly divided into two groups: a training group (n = 1,557) and a validation group (n = 668). Univariate and multivariate hazards regression analyses were used to identify independent prognostic factors. The Akaike information criterion (AIC) was used to select variables for the nomogram. The performance of the nomogram was validated concerning its ability of discrimination and calibration and its clinical utility.Results: Age, alpha-fetoprotein (AFP), race, the degree of differentiation, and therapy method were significantly associated with the prognosis of early HCC patients. Based on the AIC results, five variables (age, race, AFP, degree of differentiation, and therapy method) were incorporated into the nomogram. The concordance indexes of the simple nomogram in the training and validation groups were 0.707 (95% CI: 0.683–0.731) and 0.733 (95% CI: 0.699–0.767), respectively. The areas under the receiver operating characteristic (ROC) curve of the nomogram in the training and validation groups were 0.744 and 0.764, respectively, for predicting 3-year survival, and 0.786 and 0.794, respectively, for predicting 5-year survival. Calibration plots showed good consistency between the predictions of the nomogram and the actual observations in both the training and validation groups. Decision curve analysis (DCA) showed that the simple nomogram was clinically useful, and the overall survival significantly differed between low- and high-risk groups divided by the median score of the nomogram in the training group (P < 0.001).Conclusion: A simple-to-use nomogram based on a large population-based study is developed and validated, which is a conventional tool for doctors to facilitate the individual consultation of preoperative patients and the postoperative personalized evaluation.

The Qianlishan complex, located in Hunan Province of South China, is closely associated with intense W-dominated polymetallic mineralization. The Qianlishan complex is composed of three phases: the main-phase porphyritic and equigranular granites, granite porphyry, and mafic dykes. Geochronologically, the zircon U-Pb dating results show that the porphyritic and equigranular granites have ages of approximately 159 and 158 Ma, respectively, similar to those of mafic dykes (approximately 158 Ma), while the granite porphyry was formed later at approximately 145 Ma. Geochemically, the mafic dykes are characterized by calc-alkaline high-Mg andesite (HMA) with high MgO, TiO2, Mg#, and CA/TH index. They exhibit significantly depleted εNd(t) and εHf(t) with high Ba/La, La/Nb, and (La/Yb)N, indicating that they formed from mixing melts of depleted asthenospheric mantle and metasomatized subcontinental lithospheric mantle (SCLM). The main-phase granites are peraluminous and are characterized by high SiO2, low (La/Yb)N ratios, and relative depletion in Ba, Sr, Ti, and Eu. They also display negative correlations between La, Ce, Y, and Rb contents, suggesting that they are highly fractionated S-type granites. Furthermore, they show high εNd(t) and εHf(t), CaO/Na2O ratios, HREE, and Y contents, indicating that they were produced by parental melting of ancient basement mixed with mantle-derived components. In contrast, the granite porphyry shows A-type signature granites, with higher εNd(t) and εHf(t) and CaO/Na2O ratios than the main-phase granites but similar Zr/Nb and Zr/Hf ratios to the mafic dykes, suggesting that they are the products of partial melting of a hybrid source with ancient basement and the mafic dykes. We thus infer that the slab roll-back led to generation of Qianlishan back-arc basalt and HMA and further triggered the formation of the Qianlishan granite.

The aim of this study was to create an experimental model of aortic dissection (AD) with a long-term patent false lumen to develop new treatments for Stanford type B aortic dissection. Sixteen adult beagle dogs (weight 14–18 kg) were used. After exposure and partially clamping, the descending aorta was cut through the adventitia to one-third of the depth of the tunica media. The aortic wall was divided into two layers by raspatory. Then half the circumference of the inner layer was cut transversely. All of the proximal layers and the distal outer layers were anastomosed together. Epinephrine was immediately used to expand the false lumen, and the effect was terminated using nitroglycerin when necessary. All dogs underwent both digital subtraction angiography (DSA) and computed tomography angiography (CTA) immediately after and 1 week and 1 month after surgery. The dogs were followed up at 1 day, 3 months, 1 year, and 2 years. The surgery was successful in 12 dogs. Dissection formation was observed immediately after epinephrine administration and confirmed by DSA and CTA. Our results showed typical characteristics of AD, such as a tear, septum, and true and false lumens. This is an easy and feasible way of developing a Stanford type B AD model by intravenous injection of epinephrine. In this canine model of AD, the false lumen has excellent long-term patency and the dissection plane is histologically similar to that in human AD. This model may contribute to the development of new treatments for Stanford type B AD.

BACKGROUND Trehalose is a naturally occurring disaccharide, which has been identified as an autophagy inducer and exhibits protective effect in cardiovascular diseases such as myocardial infraction and atherosclerosis. However, the functional role of trehalose in abdominal aortic aneurysm (AAA) remains undefined. METHODS To study the effect of trehalose in AAA, trehalose (1 g/kg per day) were given for 14 continuous days in a mouse model of elastase-induced abdominal aortic aneurysm. On day 14, ultrasound was performed to measure aortic diameter before the abdominal aortas were harvested and processed for further analysis. Verhoeff-Van Gieson staining and TUNEL staining were performed on paraffin sections to evaluate vascular histology and apoptosis, immunofluorescence staining and Western-blot were performed to evaluate expression of autophagy markers. RESULTS Echocardiography and in situ pictures demonstrated that trehalose attenuated infrarenal aorta dilation. Verhoeff- Van Gieson staining showed elastin degradation was improved in trehalose-treated group. Compared with vehicle-treated mice, trehalose treatment restored smooth muscle cell contractile phenotype with increased α-SMA, Calponin and Myh11 expression. Furthermore, trehalose also attenuated cell apoptosis and leukocytes infiltration. Importantly, trehalose induced autophagy with decrease SQSTM1/p62 accumulation, increased lamp2 expression and LC3B conversion. CONCLUSION Trehalose attenuated AAA progression with decreased inflammation and restored SMC contractile phenotype by inducing autophagy. These results demonstrated the therapeutic potential of trehalose in AAA. [ABSTRACT FROM AUTHOR]

The loss of microRNA-122 (miR-122) expression correlates to many characteristic properties of hepatocellular carcinoma (HCC) cells, including clonogenic survival, anchorage-independent growth, migration, invasion, epithelial-mesenchymal transition, and tumorigenesis. However, all of these findings do not sufficiently explain the oncogenic potential of miR-122. In the current study, we used two-dimensional differential in-gel electrophoresis to measure changes in the expression of thousands of proteins in response to the inhibition of miR-122 in human hepatoma cells. Several proteins that were upregulated on miR-122 inhibition were involved in the unfolded protein response (UPR) pathway. The overexpression of miR-122 resulted in the repression of UPR pathway activation. Therefore, miR-122 may act as an inhibitor of the chaperone gene expression and negatively regulate the UPR pathway in HCC. We further showed that the miR-122 inhibitor enhanced the stability of the 26S proteasome non-ATPase regulatory subunit 10 (PSMD10) through the up-regulation of its target gene cyclin-dependent kinase 4 (CDK4). This process may activate the UPR pathway to prevent chemotherapy-mediated tumor cell apoptosis. The current study suggests that miR-122 negatively regulates the UPR through the CDK4-PSMD10 pathway. The down-regulation of miR-122 activated the CDK4-PSMD10-UPR pathway to decrease tumor cell anticancer drug-mediated apoptosis. We identified a new HCC therapeutic target and proclaimed the potential risk of the therapeutic use of miR-122 silencing.

To share our experience of 102 cases of endovascular therapy for Stanford type B aortic dissection. Methods: Multiple imaging diagnostic modalities were used preoperatively to obtain the anatomical parameters of the aortic dissection. Stent grafts were implanted using digital subtraction angiography and intravascular ultrasound guidance. Follow-up computed tomography angiography 1 week and 1 year postoperatively was used to evaluate treatment efficacy and reveal complications such as endoleak, migration and fracture of the stent graft. Results: Clinical success was achieved in 101 cases (99.0%); one patient (1.0%) died within the perioperative period. Neither postoperative paraplegia nor conversion occurred. Endoleak occurred in 18 cases (17.6%). Conclusion: Endovascular therapy for Stanford type B aortic dissection is less invasive and leads to less severe complications and shorter hospital stay compared with traditional surgery. The short- and mid-term efficacy are persuasive, but further follow-up is required to determine long-term efficacy.