BRD4 is a member of the bromodomain and extra terminal domain (BET) family of proteins, containing two bromodomains and one extra terminal domain, and is overexpressed in several human malignancies. However, its expression in gastric cancer has not yet been well illustrated. This study aimed to elucidate the overexpression of BRD4 in gastric cancer and its clinical significance as a novel therapeutic target. Fresh gastric cancer tissues and paraffin-embedded specimens of gastric cancer patients were collected, and the BRD4 expression was examined by Western Blot Analysis (WB) and Immunohistochemistry Analysis (IHC), respectively. The possible relationship between BRD4 expression and the clinicopathological features as well as survival in gastric cancer patients was analyzed. The effect of BRD4 silencing on human gastric cancer cell lines was investigated by MTT assay, WB, wound healing assay, and Transwell invasion. The results showed that the expression level in tumor tissues and adjacent tissues was significantly higher than that in normal tissues, respectively (P < 0.01). BRD4 expression level in gastric cancer tissues was strongly correlated with the degree of tumor differentiated degree (P = 0.033), regional lymph nodes metastasis (P = 0.038), clinical staging (P = 0.002), and survival situation (P = 0.000), while the gender (P = 0.564), age (P = 0.926) and infiltrating depth (P = 0.619) of patients were not associated. Increased BRD4 expression resulted in poor overall survival (P = 0.003). In in vitro assays, BRD4 small interfering RNA resulted in significantly decreased BRD4 protein expression, therefore inhibiting proliferation, migration, and invasion of gastric cancer cells. BRD4 might be a novel biomarker for the early diagnosis, prognosis, and therapeutic target in gastric cancer.

Acetylshikonin (AS) is an active component of Lithospermum erythrorhizon Sieb. et Zucc that exhibits activity against various cancers; however, the underlying mechanisms of AS against oesophageal squamous carcinoma (ESCC) need to be elusive. The research explores the anti-cancer role and potential mechanism of AS on ESCC invitro and invivo, providing evidences for AS treatment against ESCC. In this study, we firstly demonstrated that AS treatment effectively inhibits cell viability and proliferation of ESCC cells. In addition, AS significantly induces G1/S phage arrest and promotes apoptosis in ESCC cell lines. Further studies reveal that AS induces ER stress, as observed by dose- and time-dependently increased expression of BIP, PDI, PERK, phosphorylation of eIF2α , CHOP and splicing of XBP1. CHOP knockdown or PERK inhibition markedly rescue cell apoptosis induced by AS. Moreover, AS treatment significantly inhibits ESCC xenograft growth in nude mice. Elevated expression of BIP and CHOP is also observed in xenograft tumours. Taken together, AS inhibits proliferation and induces apoptosis through ER stress-activated PERK/eIF2α /CHOP pathway in ESCC, which indicates AS represents a promising candidate for ESCC treatment.

1, 8-naphthimide is a novel tumor inhibitor targeting nuclear DNA, which makes it applicable to the design and development of anti-osteosarcoma drugs. The aim of this study is to establish a satisfactory model based on 1, 8-naphthimide derivatives that makes reliable prediction as DNA-targeted chemotherapy agents for osteosarcoma. All compounds are constructed using ChemDraw software and subsequently optimized using Sybyl software. COMSIA method is used to construct QSAR model with the optimized compound in Sybyl software package. A series of new 1, 8-naphthalimide derivatives are designed and their IC50 values are predicted using the QSAR model. Finally, the newly designed compounds are screened according to IC50 values, and molecular docking experiments are conducted on the top ten compounds of IC50. The COMSIA model shows that q2 is 0.529 and the optimum number of components is 6. The model has a high r2 value of 0.993 and a low SEE of 0.033, with the F value and the r2 predicted to be 495.841 and 0.996 respectively. The statistical results and verification results of the model are satisfactory. In addition, analyzing the contour maps is conducive to finding the structural requirements. The results of this study can provide guidance for medical chemists and other related workers to develop targeted chemotherapy drugs for osteosarcoma.

Benzene exposure inhibits the hematopoietic system and leads to the occurrence of various types of leukemia. However, the mechanism underlying the hematotoxicity of benzene is still largely unclear. Emerging evidence has shown that exosomes are involved in toxic mechanisms of benzene. To understand the effect of 1,4-benzoquinone (PBQ; an active metabolite of benzene in bone marrow) on the exosomal release characteristics and role of exosomal secretion in PBQ-induced cytotoxicity. Exosomes were isolated from PBQ-treated HL-60 cells, purified by ultracentrifugation, and verified by transmission electron microscopy, nanoparticle tracking analysis and the presence of specific biomarkers. Our results showed that PBQ increased exosomal secretion in a dose-dependent manner, reaching a peak in 3 h at 10 μM PBQ treatment and then slowly decreasing in HL-60 cells. The exosomes contained miRNAs, which have been reported to be associated with benzene exposure or benzene poisoning. In particular, mir-34a-3p and mir-34A-5p were enriched in exosomes derived from PBQ-treated cells. In addition, the inhibition of exosomal release by GW4869 (an inhibitor of exosomal release) exacerbated PBQ-induced cytotoxicity, including increased intracellular reactive oxygen species levels, decreased mitochondrial membrane potential, and increased the apoptosis rate. Our findings illustrated that exosomes secretion plays an important role in antagonizing PBQ-induced cytotoxicity and maintaining cell homeostasis.

IntroductionGastric cancer (GC) diagnosed in the elderly population has become a serious public health problem worldwide. Given the combined effects of frailty and the consequences of cancer treatment, older individuals with GC are more likely than young patients to suffer from postoperative complications and poor clinical outcomes. Nutrition, functional capacity and psychological state-based multimodal prehabilitation, which is dominated by Enhanced Recovery After Surgery (ERAS) pathway management, has been shown to reduce postoperative complications, promote functional recovery and decrease hospitalisation time in certain malignancies. However, no previous studies have investigated the clinical application of multimodal prehabilitation in frail older patients with GC.Methods and analysisThe study is a prospective, multicentre randomised controlled trial in which a total of 368 participants who meet the inclusion criteria will be randomised into either a prehabilitation group or an ERAS group. The prehabilitation group will receive multimodal prehabilitation combined with ERAS at least 2 weeks before the gastrectomy is performed, including physical and respiratory training, nutritional support, and therapy and psychosocial treatment. The ERAS group patients will be treated according to the ERAS pathway. All interventions will be supervised by family members. The primary outcome measures are the incidence and severity of postoperative complications. Secondary outcomes include survival, functional capacity and other short-term postoperative outcomes. Overall, the multimodal prehabilitation protocol may improve functional capacity, reduce the surgical stress response and concomitant systemic inflammation, and potentially modulate the tumour microenvironment to improve short-term and long-term clinical outcomes and patients’ quality of life.Ethics and disseminationAll procedures and participating centres of this study were approved by their respective ethics committees (QYFYKYLL 916111920). The final study results will be published separately in peer-reviewed journals.Trial registration numberNCT05352802.

To observe the efficacy and safety of different induction regimens of same total dosage of azacitidine (Aza), including standard dose (standard dose group) and low-dose long-term (adjusted dose group), in the treatment of elderly acute myeloid leukemia (AML). A total of 103 elderly patients with AML (non-acute promyelocytic leukemia) from January 2020 to June 2021 were enrolled. Aza was administered at the standard dose of 75 mg/(m2·d) for 7 days in the standard dose group (50 cases), while at 100 mg/d for 7-12 days in the adjusted dose group (53 cases). The administration days in adjusted dose group was calculated based on the total standard dose of the patient's single course of treatment. The efficacy and safety between standard dose group and adjusted dose group were compared. Subgroup analysis were performed in the two groups for Aza alone, Aza combined with BCL-2 inhibitor, and Aza combined with low-dose chemotherapy for efficacy and safety. There were no significant differences in overall response rate (ORR), incidence of adverse reaction, and 1-year overall survival (OS) rate between standard dose group and adjusted dose group (P >0.05). The ORR of combination was higher than that of Aza alone (P < 0.05), while there was no significant difference in ORR between Aza combined with BCL-2 inhibitor and Aza combined with low-dose chemotherapy (P >0.05). The combination of BCL-2 inhibitor did not increase the incidence of adverse reactions compared wtih Aza alone. There was a higher risk of myelosuppression and pulmonary infection with a combination of low-dose chemotherapy than with a combination of BCL-2 inhibitor and Aza alone (P <0.05). No significant difference was observed in 1-year OS between Aza alone, Aza combined with BCL-2 inhibitor, and Aza combined with low-dose chemotherapy (P >0.05). Both two induction regimens can be used in elderly AML patients who cannot tolerate intensive chemotherapy with similar overall effectiveness and safety. Aza combined with low-dose chemotherapy may result in increased ORR and an increased incidence of serious adverse reactions, and may not result in longer survival compared with Aza alone. Aza combined with BCL-2 inhibitor not only has similar effect in complete remission, objective response rate, and OS compared with Aza combined with low-dose chemotherapy, but also has higher safety.

Chronic obstructive pulmonary disease (COPD) is a serious chronic lung disease. Schisandrin A (SchA) is one of the most important active ingredients in Schisandra chinensis and has been used to treat various lung diseases in several countries. Here, we studied the pharmacological effect of SchA on airway inflammation induced by cigarette smoke (CS) and explored the therapeutic mechanism of SchA in COPD model mice. Our results showed that SchA treatment significantly improved the lung function of CS-induced COPD model mice and reduced the recruitment of leukocytes and hypersecretion of interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) in bronchoalveolar lavage fluid (BALF). H&E staining showed that SchA treatment could effectively reduce emphysema, immune cell infiltration and airway wall destruction. In addition, we found that SchA treatment can stimulate the expression of heme oxygenase-1 (HO-1) through the nuclear factor-erythroid 2-related factor (Nrf2) pathway, significantly reduce oxidative stress, increase catalase (CAT) and superoxide dismutase (SOD) levels, and suppress the level of malondialdehyde (MDA) in COPD model mice. Moreover, SchA treatment suppressed the generation of the NLRP3/ASC/Caspase1 inflammasome complex to inhibit the inflammatory response caused by IL-1β and IL-18 and pyroptosis caused by GSDMD. In conclusion, our study shows that SchA treatment can inhibit the production of ROS and the activation of the NLRP3 inflammasome by upregulating Nrf-2, thereby producing anti-inflammatory effects and reducing lung injury in COPD model mice. More importantly, SchA exhibited similar anti-inflammatory effects to dexamethasone in COPD model mice, and we did not observe substantial side effects of SchA treatment. The high safety of SchA makes it a potential candidate drug for the treatment of COPD.

We investigate the spin density matrix of in the Cartesian coordinate system of baryon-antibaryon pairs produced in annihilation. Using the helicity formalism of Jacob and Wick, we derive the expression for the spin-3/2 density matrices. Our analysis is based on the angular distribution of the process in the BESIII experiment. By decomposing the polarization state of particles along different coordinate axes, we examine the polarization dependence of the cross-section. Our results demonstrate that particles exhibit varying degrees of tensor polarization along the x-, y-, and z-axes, as well as weak vector polarization and rank-3 tensor polarization along the y-axis. To the best of our knowledge, this is the first study to calculate the polarization dependence of the cross-section distributions for the annihilation process . Our theoretical predictions are in good agreement with the experimental measurements.