Ligand-based pharmacophore modelling, structure optimisation, and biological evaluation for the identification of 2-heteroarylthio-N-arylacetamides as novel HSP90 C-terminal inhibitors.

Targeting Heat shock protein 90 (HSP90) C-terminus is an important strategy to develop HSP90 inhibitors without inducing heat shock response. The development of C-terminal inhibitors, however, is hampered by a lack of understanding regarding the interaction between the HSP90 C-terminus and the present inhibitors. We collected seven classical and structurally diverse HSP90 C-terminal inhibitors and constructed a ligand-based pharmacophore model. The subsequent virtual screening and structural optimisation led to the identification of 2-heteroarylthio-N-arylacetamides as novel HSP90 C-terminal inhibitors. 9 and 27 exhibited strong antitumour activity in vitro by inhibiting proliferation and inducing apoptosis in multiple cancer cell lines. These compounds disrupted the interaction between HSP90 C-terminus and peptidylprolyl isomerase D, exerting a stronger inhibitory effect than novobiocin. 27 significantly induced the degradation of HSP90 clients without triggering heat shock response. In an in vivo study using 4T1 mice breast cancer models, 9 showed a potent antitumour effect without obvious toxicity.

Effects of neoadjuvant stereotactic body radiotherapy plus adebrelimab and chemotherapy for triple-negative breast cancer: A pilot study.

Background: Emerging data have supported the immunostimulatory role of radiotherapy, which could exert a synergistic effect with immune checkpoint inhibitors (ICIs). With proven effective but suboptimal effect of ICI and chemotherapy in triple-negative breast cancer (TNBC), we designed a pilot study to explore the efficacy and safety of neoadjuvant stereotactic body radiotherapy (SBRT) plus adebrelimab and chemotherapy in TNBC patients. Methods: Treatment-naïve TNBC patients received two cycles of intravenous adebrelimab (20 mg/kg, every 3 weeks), and SBRT (24 Gy/3 f, every other day) started at the second cycle, then followed by six cycles of adebrelimab plus nab-paclitaxel (125 mg/m² on days 1 and 8) and carboplatin (area under the curve 6 mg/mL per min on day 1) every 3 weeks. The surgery was performed within 3-5 weeks after the end of neoadjuvant therapy. Primary endpoint was pathological complete response (pCR, ypT0/is ypN0). Secondary endpoints included objective response rate (ORR), residual cancer burden (RCB) 0-I, and safety. Results: 13 patients were enrolled and received at least one dose of therapy. 10 (76.9%) patients completed SBRT and were included in efficacy analysis. 90% (9/10) of patients achieved pCR, both RCB 0-I and ORR reached 100% with three patients achieved complete remission. Adverse events (AEs) of all-grade and grade 3-4 occurred in 92.3% and 53.8%, respectively. One (7.7%) patient had treatment-related serious AEs. No radiation-related dermatitis or death occurred. Conclusions: Adding SBRT to adebrelimab and neoadjuvant chemotherapy led to a substantial proportion of pCR with acceptable toxicities, supporting further exploration of this combination in TNBC patients. Funding: None. Clinical trial number: NCT05132790.

Application of Engineered Dendritic Cell Vaccines in Cancer Immunotherapy: Challenges and Opportunities.

OPINION STATEMENT: The primary objective of this study is to evaluate the effectiveness of cancer vaccines containing genetically modified dendritic cells (DCs) in inducing transformational immune responses. This paper sheds considerable light on DCs' function in advancing treatment techniques. This objective is achieved by thoroughly analyzing the many facets of DCs and their strategic integration into cancer treatment. Due to their role as immune response regulators, DCs can potentially enhance cancer treatment strategies. DCs have the potential to revolutionize immunotherapy, as shown by a comprehensive analysis of their numerous characteristics. The review deftly transitions from examining the fundamentals of preclinical research to delving into the complexities of clinical implementation while acknowledging the inherent challenges in translating DC vaccine concepts into tangible progress. The analysis also emphasizes the potential synergistic outcomes that can be achieved by combining DC vaccines with established pharmaceuticals, thereby emphasizing the importance of employing a holistic approach to enhance treatment efficacy. Despite the existence of transformative opportunities, advancement is hindered by several obstacles. The exhaustive analysis of technical complexities, regulatory dynamics, and upcoming challenges provides valuable insights for overcoming obstacles requiring strategic navigation to incorporate DC vaccines successfully. This document provides a comprehensive analysis of the developments in DC-based immunotherapy, concentrating on its potential to transform cancer therapy radically.

Moderate Salinity Stress Increases the Seedling Biomass in Oilseed Rape (Brassica napus L.).

Oilseed rape (Brassica napus L.), an important oil crop of the world, suffers various abiotic stresses including salinity stress during the growth stage. While most of the previous studies paid attention to the adverse effects of high salinity stress on plant growth and development, as well as their underlying physiological and molecular mechanisms, less attention was paid to the effects of moderate or low salinity stress. In this study, we first tested the effects of different concentrations of NaCl solution on the seedling growth performance of two oilseed rape varieties (CH336, a semi-winter type, and Bruttor, a spring type) in pot cultures. We found that moderate salt concentrations (25 and 50 mmol L-1 NaCl) can stimulate seedling growth by a significant increase (10~20%, compared to controls) in both above- and underground biomasses, as estimated at the early flowering stage. We then performed RNA-seq analyses of shoot apical meristems (SAMs) from six-leaf-aged seedlings under control (CK), low (LS, 25 mmol L-1), and high (HS, 180 mmol L-1) salinity treatments in the two varieties. The GO and KEGG enrichment analyses of differentially expressed genes (DEGs) demonstrated that such a stimulating effect on seedling growth by low salinity stress may be caused by a more efficient capacity for photosynthesis as compensation, accompanied by a reduced energy loss for the biosynthesis of secondary metabolites and redirecting of energy to biomass formation. Our study provides a new perspective on the cultivation of oilseed rape in saline regions and new insights into the molecular mechanisms of salt tolerance in Brassica crops. The candidate genes identified in this study can serve as targets for molecular breeding selection and genetic engineering toward enhancing salt tolerance in B. napus.

High internal phase emulsions stabilized solely by sonicated quinoa protein isolate at various pH values and concentrations.

In this study, stable high internal phase emulsions (HIPEs) constructed solely by sonicated quinoa protein isolate (QPI) at various pH values and protein concentrations (c) were constructed, and differences of HIPE microstructures at these conditions were discussed. HIPEs stabilized by QPI at pH 7.0, 9.0 possessed smaller droplet size (14-24 µm), smoother appearance, and higher physical stability which were caused by polyhedral framework microstructure. However, at acidic conditions, QPI aggregates filled in the gaps between droplets (30-52 µm) instead of adsorbing to oil-water interface, which decreased the stability. The solid-like viscoelasticity of HIPEs were enhanced when the c increased while the increment of pH value had the significant opposite effect (decreased from about G' 1000 Pa, G″ 280 Pa to G' 350 Pa, G″ 50 Pa) due to the microstructure difference. This study broadens the commercial applications of quinoa protein in novel food products like fat substitutes.

Clinical and imaging characteristics of breast ductal carcinoma in situ with microinvasion.

BACKGROUND: We analyzed the clinical and imaging characteristics of patients with breast ductal carcinoma in situ with microinvasion (DCISM) and breast ductal carcinoma in situ (DCIS). METHODS: We analyzed the records of 40 patients diagnosed with DCISM and 61 patients with DCIS who were hospitalized at Shengjing Hospital (Shenyang, China) from January 2009 to June 2016. The size, hardness, and degree of calcification of tumors were determined by mammography and ultrasonography. RESULTS: In all, 37 DCISM patients and 45 DCIS patients showed clinical palpable masses (92.5% vs 73.77%, P = 0.018). Mammography showed that the mean size of tumor was larger in DCISM patients than that of DCIS patients (3.13 ± 1.51 vs 2.68 ± 1.77, P = 0.030). Ultrasound examination revealed calcification shadows in the solid tumor mass in 17 DCISM cases and 11 DCIS patients (42.5 vs 18.03%, P = 0.007). Furthermore, estrogen receptor positivity and progesterone receptor positivity were more common in DCIS patients (32.5% vs 54.10%, P = 0.033; 22.5% vs 45.90%, P = 0.017), and the percentage of menopausal patients were higher in DCISM patients than that of DCIS patients (70.00% vs 47.54%, P = 0.026). CONCLUSION: Clinically palpable and calcified tumor masses on sonography are more commonly encountered in DCISM lesions.

RASSF6 Is Downregulated In Human Bladder Cancers And Regulates Doxorubicin Sensitivity And Mitochondrial Membrane Potential Via The Hippo Signaling Pathway.

BACKGROUND: The present study aimed to investigate the clinicopathological significance and biological roles of RASSF6 in human bladder cancers. MATERIALS AND METHODS: Immunohistochemistry and Western blots were used to examine the protein expression of RASSF6 in bladder cancer tissues. Biological roles of RASSF6 were examined using MTT, colony formation assay, Matrigel invasion assay, cell cycle analysis, AnnexinV/PI staining and JC-1 staining. Western blot analysis was used to examine the potential mechanism. RESULTS: We found that RASSF6 was downregulated in 73 of 138 bladder cancer specimens, which correlated with advanced stages. RASSF6 overexpression decreased the cell growth rate and inhibited invasion ability in T24 cell line. Downregulation of RASSF6 using siRNA increased the cell proliferation rate and promoted invasion in 5637 cell line. Cell cycle studies showed that RASSF6 overexpression suppressed the process of cell cycle progression. RASSF6 overexpression also increased the cellular response to doxorubicin (DOX) treatment. AnnexinV/PI staining showed that RASSF6 overexpression promoted DOX-induced apoptosis with increased cytochrome c and cleavage of caspase-3 and caspase-9. We also showed that RASSF6 overexpression downregulated the mitochondrial membrane potential, while RASSF6 depletion showed the opposite effect. Western blot analysis demonstrated that RASSF6 overexpression repressed p-Rb and Bcl-xL while upregulating p21 expression. In addition, we found that RASSF6 overexpression affected the Hippo signaling pathway by downregulating YAP. Depletion of YAP downregulated Bcl-xL expression and abolished the effect of RASSF6 on Bcl-xL. Depletion of YAP also upregulated the level of apoptosis and downregulated mitochondrial membrane potential. YAP siRNA abolished the effects of RASSF6 on DOX-induced apoptosis and loss of mitochondrial membrane potential. CONCLUSION: Taken together, our results showed that RASSF6 was downregulated in bladder cancers. RASSF6 inhibited cell proliferation and invasion, as well as the progression of cancer, by regulating DOX sensitivity and mitochondrial membrane potential, possibly via the Hippo signaling pathway.

Ureteral stent placement and percutaneous nephrostomy in the management of hydronephrosis secondary to cervical cancer.

OBJECTIVE: This study aimed to evaluate the efficacy of ureteral stent placement for the treatment of hydronephrosis secondary to cervical cancer and analyze factors that may predict failure of ureteral stent placement and the differences between ureteral stent placement and percutaneous nephrostomy. STUDY DESIGN: Clinical data of patients with cervical cancer complicated with hydronephrosis admitted to our hospital from July 2008 to August 2018 were retrospectively analyzed. To evaluate the efficacy of ureteral stent placement and percutaneous nephrostomy in the management of hydronephrosis secondary to cervical cancer. RESULTS: A total of 89 patients were analyzed. A ureteral stent was successfully placed in 60 patients. Indwelling stent failed in 29 patients, and then percutaneous nephrostomy was performed. Both surgical procedures were safe and effective. There was a significant correlation between the success rate of ureteral stent placement and the degree of hydronephrosis and the length of the ureteral obstruction. There was no significant difference in the incidence of complications following ureteral stent placement and percutaneous nephrostomy, while there were significant differences between the two treatment modalities in terms of surgical time, hospitalization time, and surgical cost. CONCLUSION: Ureteral stent placement is the preferred method for the treatment of hydronephrosis secondary to cervical cancer. However, in patients with more severe hydronephrosis and ureteral obstruction >3 cm in length, percutaneous nephrostomy may be more appropriate.

Uric Acid Provides Protective Role in Red Blood Cells by Antioxidant Defense: A Hypothetical Analysis.

Uric acid (UA) is a major antioxidant molecule in the human blood, and it has been linked with cell longevity. However, it is unclear whether serum UA levels are associated with red blood cell (RBC) indexes. This cross-sectional study included 10,759 Chinese subjects, recruited from the Shanghai Xuhui Central Hospital from January 2014 to December 2017. The participants were categorized into gender groups and then further divided into three different subgroups according to their UA reference range as follows: low (male (UA < 0.202 mmol/l), female (UA < 0.143 mmol/l)), normal (male (0.417 mmol/l > UA ≥ 0.202 mmol/l), female (0.339 mmol/l > UA ≥ 0.143 mmol/l)), and high (male (UA ≥ 0.417 mmol/l), female (UA ≥ 0.339 mmol/l)). The associations of UA levels with RBC parameters were analyzed using 1-way ANOVA, Pearson correlations, and multivariate linear regression. The levels of mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, RBCs, and hemoglobin were lowest in the low UA group, followed by the normal UA group and high UA group (p < 0.001). Pearson analysis showed that there was a statistically significant correlation between UA levels with mean corpuscular hemoglobin, mean corpuscular hemoglobin concentrations, mean corpuscular volumes, RBC counts, and hemoglobin (p < 0.05). Multiple linear regression analysis suggested that there were statistically significant positive correlations between UA levels and RBC counts (B = 0.245, p < 0.001, 95% CI = 0.003 to 0.092), as well as UA levels and hemoglobin concentrations (B = 0.138, p < 0.001, 95% CI = 0.002 to 0.082). Furthermore, similar results were observed in both the male and female subgroups. The serum UA levels may be independently associated with RBC parameters, regardless of sex, and UA may protect RBCs owing to its antioxidant effect.

Genetic diversity and stability in starch physicochemical property traits of potato breeding lines.

Cross breeding may create wider genetic variation than two parents used in hybridization, but breeding efforts towards starch quality improvement are less reported in potato. A cross was made between Zhongshu-3 and Favorita to select desired starch properties in progenies. Among 206 F1 clones with potential high yield, starch qualities such as apparent amylose content (AAC), pasting viscosity, and thermal properties were further evaluated. A wide variation was observed in different starch physicochemical indices for 206 potato accessions. Twenty clones with high/low AAC, peak viscosity and peak gelatinization temperature were selected and then grown at another location to evaluate the stability of the traits. Similar wide range of variation in the starch properties was observed. Cluster analysis based on starch properties of the 20 selected clones indicating relative stability of the starch property traits across different locations. New breeding lines identified have potential for application in food and other industries.

Azoxystrobin Induces Apoptosis of Human Esophageal Squamous Cell Carcinoma KYSE-150 Cells through Triggering of the Mitochondrial Pathway.

Recent studies indicate that mitochondrial pathways of apoptosis are potential chemotherapeutic target for the treatment of esophageal cancer. Azoxystrobin (AZOX), a methoxyacrylate derived from the naturally occurring strobilurins, is a known fungicide acting as a ubiquinol oxidation (Qo) inhibitor of mitochondrial respiratory complex III. In this study, the effects of AZOX on human esophageal squamous cell carcinoma KYSE-150 cells were examined and the underlying mechanisms were investigated. AZOX exhibited inhibitory effects on the proliferation of KYSE-150 cells with inhibitory concentration 50% (IC50) of 2.42 µg/ml by 48 h treatment. Flow cytometry assessment revealed that the inhibitory effect of AZOX on KYSE-150 cell proliferation occurred with cell cycle arrest at S phase and increased cell apoptosis in time-dependent and dose-dependent manners. Cleaved poly ADP ribose polymerase (PARP), caspase-3 and caspase-9 were increased significantly by AZOX. It is worth noted that the Bcl-2/Bax ratios were decreased because of the down-regulated Bcl-2 and up-regulated Bax expression level. Meanwhile, the cytochrome c release was increased by AZOX in KYSE-150 cells. AZOX-induced cytochrome c expression and caspase-3 activation was significantly blocked by Bax Channel Blocker. Intragastric administration of AZOX effectively decreased the tumor size generated by subcutaneous inoculation of KYSE-150 cells in nude mice. Consistently, decreased Bcl-2 expression, increased cytochrome c and PARP level, and activated caspase-3 and caspase-9 were observed in the tumor samples. These results indicate that AZOX can effectively induce esophageal cancer cell apoptosis through the mitochondrial pathways of apoptosis, suggesting AZOX or its derivatives may be developed as potential chemotherapeutic agents for the treatment of esophageal cancer.

Changes in the cellular proteins of A549 infected with hepatitis E virus by proteomics analysis.

BACKGROUND: Our understanding of Hepatitis E virus (HEV) has changed enormously over the past 30 years, from a waterborne infection causing outbreaks of acute hepatitis in developing countries to an infection of global distribution causing a range of hepatic and extra-hepatic illness. However, the key proteins playing important parts in the virus infection were still unknown. Understanding the changes of cellular proteins in these cells exposed to HEV is helpful for elucidating molecular mechanisms associated with function alterations of HEV-infected susceptible cells. In the present study, a comparative gel-based proteomic analysis was employed to study the changes in cellular proteins of A549 exposed to HEV in vitro to provide novel information for understanding the functional alterations of A549 induced by HEV infection. RESULT: Of 2 585-3 152 protein spots visualized on each gel using silver staining, a total of 31 protein spots were found to be differentially expressed in HEV-infected A549 cells compared with mock-infected A549, including 10 significantly up-regulated protein spots and 21 significantly down-regulated protein spots. CONCLUSION: Our work is the first time regarding the proteomic analysis on the cellular responses to HEV infection. This work is helpful for investigating the molecular basis associated with the interaction between HEV and the host cells although more efforts should be required to discover the mechanisms.