Precision targeting in oncology: The future of conjugated drugs.

Coupled drugs, especially antibody-coupled drugs (ADCs), are a hot topic in oncology. As the development of ADCs has progressed, different coupling modes have emerged, inspired by their structural design have emerged. Technological advances have led to interweaving and collision of old and new concepts of coupled drugs, and have even challenged the concepts and techniques of coupled drugs at this stage. For example, antibody-oligonucleotide conjugates are a new class of chimeric biomolecules synthesized by coupling oligonucleotides with monoclonal antibodies through linkers, offering precise targeting and improved pharmacokinetic properties. This study aimed to elucidate the mechanism of action of coupled drugs and their current development status in antitumor therapy to provide better strategies for antitumor therapy.

DHPS-Mediated Hypusination Regulates METTL3 Self-m6A-Methylation Modification to Promote Melanoma Proliferation and the Development of Novel Inhibitors.

Discovering new treatments for melanoma will benefit human health. The mechanism by which deoxyhypusine synthase (DHPS) promotes melanoma development remains elucidated. Multi-omics studies have revealed that DHPS regulates m6A modification and maintains mRNA stability in melanoma cells. Mechanistically, DHPS activates the hypusination of eukaryotic translation initiation factor 5A (eIF5A) to assist METTL3 localizing on its mRNA for m6A modification, then promoting METTL3 expression. Structure-based design, synthesis, and activity screening yielded the hit compound GL-1 as a DHPS inhibitor. Notably, GL-1 directly inhibits DHPS binding to eIF5A, whereas GC-7 cannot. Based on the clarification of the mode of action of GL-1 on DHPS, it is found that GL-1 can promote the accumulation of intracellular Cu2+ to induce apoptosis, and antibody microarray analysis shows that GL-1 inhibits the expression of several cytokines. GL-1 shows promising antitumor activity with good bioavailability in a xenograft tumor model. These findings clarify the molecular mechanisms by which DHPS regulates melanoma proliferation and demonstrate the potential of GL-1 for clinical melanoma therapy.

[Stellera chamaejasme against multidrug resistance of triple-negative breast cancer MDA-MB-231 cell through Nrf2].

This study aims to investigate the effect and mechanism of Stellera chamaejasme extract(SCL) on multidrug resistance(MDR) in breast cancer. Human triple-negative breast cancer cell line MDA-MB-231 and its adriamycin-resistant cell line MDA-MB-231/ADR were used in the experiment. Cell viability was detected by methyl thiazolyl tetrazolium(MTT) assay, and cell apoptosis was detected by DAPI staining and Annexin-V/Pi double staining. Western blot(WB) was used to detect the expression levels of Keap1, Nrf2, HO-1, Bcl-2, Bax, caspase-9, and caspase-3. Immunofluorescence staining was used to observe the distribution of Nrf2 in the cell, and flow cytometry was used to detect the level of reactive oxygen species(ROS) in the cell. The results showed that the resis-tance factor of SCL was 0.69, and that of adriamycin and paclitaxel was 8.40 and 16.36, respectively. DAPI staining showed that SCL could cause nuclear shrinkage and fragmentation of breast cancer cells. Annexin-V/Pi double staining showed that the average apoptosis rate of the drug-resistant cells was 32.64% and 50.29%, respectively under medium and high doses of SCL. WB results showed that SCL could significantly reduce the expression levels of anti-apoptotic proteins Bcl-2, caspase-9, and caspase-3 and significantly increase the expression level of pro-apoptotic protein Bax. Further studies showed that SCL could significantly promote the expression of Keap1, significantly inhibit the expression of Nrf2 and HO-1, and significantly reduce the expression level of Nrf2 in the nucleus. Correspondingly, flow cytometry showed that the intracellular ROS level was significantly increased. In conclusion, SCL can significantly inhibit the proliferation of MDA-MB-231 multidrug-resistant cells of triple-negative breast cancer and cause cell apoptosis, and the mechanism is related to inhibiting Keap1/Nrf2 signaling pathway, leading to ROS accumulation in drug-resistant cells and increasing the expression of apoptosis-related proteins.

3-aminopropyltriethoxysilane modified MXene on three-dimensional nonwoven fiber substrates for low-cost, stable, and efficient solar-driven interfacial evaporation desalination.

Recently, the solar-driven interfacial evaporation desalination has attracted more and more attentions due to the advantages of low cost, zero energy consumption, and high water purification rate, etc. One of the bottlenecks of this emerging technique lies in a lack of simple and low-cost ways to construct three-dimensional (3D) hierarchical microstructures for photothermal membranes. To this end, a two-step strategy is carried out by combining surface functionalization with substrate engineering. Firstly, a silane coupling agent 3-aminopropyltriethoxysilane (APTES) is grafted onto an ideal photothermal material of Ti3C2Tx MXene, to improve the nanochannel sizes and hydrophilicity, which are attributed to enlarged interspaces of MXene and introduced hydrophilic group e.g., -NH2 and -OH, respectively. Secondly, a low-cost and robust nonwoven fiber (NWF) substrate, which has a 3D micron-sized mesh structure with interlaced fiber stacks, is employed as the skeleton to load enough APTES-grafted MXene by a simple soaking method. Benefited from above design, the Ti3C2Tx-APTES/NWF composite membrane with a 3D hierarchical structure shows enhanced light scattering and utilization, water transport and vapor escape. A remarkable evaporation rate of 1.457 kg m-2 h-1 and an evaporation efficiency of 91.48 % are attained for a large-area (5 × 5 cm2) evaporator, and the evaporation rate is further increased to 1.672 kg m-2 h-1 for a small-area (2 × 2 cm2) device. The rejection rates of salt ions and heavy metal ions are higher than 99 % and 99.99 %, respectively, and the removal rates of organic dye molecules are nearly to 100 %. Besides, the composite photothermal membrane exhibits great stabilities in harsh conditions such as high salinities, long cycling, large light intensities, strong acid/alkali environments, and mechanical bending. Most importantly, the photothermal membrane shows a considerable cost-effectiveness of 89.4 g h-1/$. Hence, this study might promote the commercialization of solar-driven interfacial evaporation desalination by collaboratively considering surface modification and substrate engineering for MXene.

Gut microbiota plays a significant role in gout.

With the development of social economy, the incidence of gout is increasing, which is closely related to people's increasingly rich diet. Eating a diet high in purine, fat, sugar and low-fibre for a long time further aggravates gout by affecting uric acid metabolism. The renal metabolism mechanism of uric acid has been thoroughly studied. To find a new treatment method for gout, increasing studies have recently been conducted on the mechanism of intestinal excretion, metabolism and absorption of uric acid. The most important research is the relationship between intestinal microbiota and the risk of gout. Gut microbiota represent bacteria that reside in a host's gastrointestinal tract. The composition of the gut microbiota is associated with protection against pathogen colonization and disease occurrence. This review focuses on how gut microbiota affects gout through uric acid and discusses the types of bacteria that may be involved in the occurrence and progression of gout. We also describe potential therapy for gout by restoring gut microbiota homeostasis and reducing uric acid levels. We hold the perspective that changing intestinal microbiota may become a vital method for effectively preventing or treating gout.

Insulin resistance and osteocalcin associate with the incidence and severity of postoperative delirium in elderly patients undergoing joint replacement.

AIM: While insulin sensitivity plays an important role in maintaining glucose metabolic homeostasis and cognitive function, its impact on postoperative delirium (POD) remains unclear. This study aimed to investigate the association between POD and indicators of insulin sensitivity, including insulin resistance and osteocalcin. METHODS: A total of 120 elderly patients undergoing joint replacement were recruited and divided into delirium and non-delirium groups. Plasma and cerebrospinal fluid (CSF) samples were collected for the analysis of biomarkers, including insulin, uncarboxylated osteocalcin (ucOC), total osteocalcin (tOC), and glucose. Insulin resistance was assessed through the homeostatic model assessment of insulin resistance (HOMA-IR). MAIN RESULTS: Out of the total, 28 patients (23.3%) experienced POD within 5 days after surgery. Patients with delirium exhibited higher levels of preoperative HOMA-IR and ucOC in CSF and plasma, and of tOC in CSF (P = 0.028, P < 0.001, P = 0.005, P = 0.019). After adjusting for variables, including age, Mini-Mental State Examination score, surgical site and preoperative fracture, only preoperative ucOC in CSF and HOMA-IR were significantly linked to the incidence of delirium (OR = 5.940, P = 0.008; OR = 1.208, P = 0.046, respectively), both of which also correlated with the severity of delirium (P = 0.007, P < 0.001). Receiver operating curve analysis indicated that preoperative HOMA-IR and ucOC in CSF might partly predict POD (area under the curve [AUC] = 0.697, 95% confidence interval [CI] = 0.501-0.775, AUC = 0.745, 95% CI = 0.659-0.860). CONCLUSIONS: We observed that preoperative elevated HOMA-IR and ucOC in CSF were associated with the incidence and severity of POD. While these preliminary results need confirmation, they suggest a potential involvement of insulin resistance and osteocalcin in the pathological mechanism of POD. Geriatr Gerontol Int 2024; 24: 421-429.

Recent Progress of Wide Bandgap Perovskites towards Two-Terminal Perovskite/Silicon Tandem Solar Cells.

Perovskite/silicon tandem solar cells have garnered considerable interest due to their potential to surpass the Shockley-Queisser limit of single-junction Si solar cells. The rapidly advanced efficiencies of perovskite/silicon tandem solar cells benefit from the significant improvements in perovskite technology. Beginning with the evolution of wide bandgap perovskite cells towards two-terminal (2T) perovskite/silicon tandem solar cells, this work concentrates on component engineering, additives, and interface modification of wide bandgap perovskite cells. Furthermore, the advancements in 2T perovskite/silicon tandem solar cells are presented, and the influence of the central interconnect layer and the Si cell on the progression of the tandem solar cells is emphasized. Finally, we discuss the challenges and obstacles associated with 2T perovskite/silicon tandem solar cells, conducting a thorough analysis and providing a prospect for their future.

RAS-selective lethal small molecule 3 inhibits the fibrosis of pathological scar fibroblasts / 中国组织工程研究

BACKGROUND:Abnormal extracellular matrix accumulation and excessive proliferation of fibroblasts are the main manifestations of pathological scars.Excessive proliferation of fibroblasts leads to the production of large amounts of collagen-based extracellular matrix.Therefore,to investigate the role of fibroblast fibrosis in the formation of pathological scar will provide a new idea for revealing the mechanism of pathological scar and biological therapy. OBJECTIVE:To investigate the effect of RAS-selective lethal small molecule 3(RSL3)on the fibrosis of human pathological scar fibroblasts. METHODS:Then cases of pathological scar tissue and normal skin tissue samples from the same individuals,provided by the Department of Burn Plastic Surgery,General Hospital of Ningxia Medical University,were collected.Fibroblasts of human pathological scar and human normal skin were extracted and used in the following experiments.The general condition of the pathological scar tissue and the normal skin tissue was detected by hematoxylin-eosin staining.The appearance of fibroblasts from pathological scar and normal skin were observed by inverted microscope.The fibroblasts were verified by immunofluorescence assay.The cells were treated with different concentrations of RSL3(1,3,5,7,9,11,13 μmol/L).The inhibitory concentration of RSL3 on fibroblasts was detected by cell counting kit-8.Control group(without treatment)and RSL3 intervention group(treated with 7 μmol/L RSL3 for 24 hours)were set up.The mRNA and protein expressions of glutathione peroxidase 4,type Ⅰ collagen,type Ⅲ collagen and α-smooth muscle actin were detected by Qrt-PCR and western blot,respectively.Level of malondialdehyde in cells was detected.The residual scratch area was measured by cell scratch test after 24 hours to calculate the percentage of residual scratch area. RESULTS AND CONCLUSION:The expression of glutathione peroxidase 4 in the pathological scar group was higher than that in the normal skin group(Mrna:t=3.252,P<0.01;protein:t=5.075,P<0.01).The expression of glutathione peroxidase 4 in the pathological scar fibroblast group was higher than that in the normal skin fibroblast group(Mrna:t=10.32,P<0.01;protein:t=26.22,P<0.01).Compared with the control group,the expression of glutathione peroxidase 4 was decreased(Mrna:t=2.798,P<0.05;protein:t=4.643,P<0.01),the content of malondialdehyde was increased(t=2.917,P<0.05),the expression of type Ⅰ collagen(Mrna:t=15.84,P<0.01;protein:t=4.610,P<0.01),type Ⅲ collagen(Mrna:t=28.86,P<0.01;protein:t=7.713,P<0.01)and α-smooth muscle actin(Mrna:t=2.671,P<0.05;protein:t=7.417,P<0.01)were decreased in the RSL3 intervention group.Compared with the control group,the migration ability was weakened in the RSL3 intervention group(t=14.06,P<0.01).To conclude,RSL3 can inhibit the expression of glutathione peroxidase 4 and then inhibit the ability of fibrosis and migration of pathological scar fibroblasts.

Recent Advances on the Molecular Mechanism and Clinical Trials of Venous Thromboembolism.

Venous thromboembolism is a condition that includes deep vein thrombosis and pulmonary embolism. It is the third most common cardiovascular disease behind acute coronary heart disease and stroke. Over the past few years, growing research suggests that venous thrombosis is also related to the immune system and inflammatory factors have been confirmed to be involved in venous thrombosis. The role of inflammation and inflammation-related biomarkers in cerebrovascular thrombotic disease is the subject of ongoing debate. P-selectin leads to platelet-monocyte aggregation and stimulates vascular inflammation and thrombosis. The dysregulation of miRNAs has also been reported in venous thrombosis, suggesting the involvement of miRNAs in the progression of venous thrombosis. Plasminogen activator inhibitor-1 (PAI-1) is a crucial component of the plasminogen-plasmin system, and elevated levels of PAI-1 in conjunction with advanced age are significant risk factors for thrombosis. In addition, it has been showed that one of the ways that neutrophils promote venous thrombosis is the formation of neutrophil extracellular traps (NETs). In recent years, the role of extracellular vesicles (EVs) in the occurrence and development of VTE has been continuously revealed. With the advancement of research technology, the complex regulatory role of EVs on the coagulation process has been gradually discovered. However, our understanding of the causes and consequences of these changes in venous thrombosis is still limited. Therefore, we review our current understanding the molecular mechanisms of venous thrombosis and the related clinical trials, which is crucial for the future treatment of venous thrombosis.

The role and application of vesicles in triple-negative breast cancer: Opportunities and challenges.

Extracellular vesicles (EVs) carry DNA, RNA, protein, and other substances involved in intercellular crosstalk and can be used for the targeted delivery of drugs. Triple-negative breast cancer (TNBC) is rich in recurrent and metastatic disease and lacks therapeutic targets. Studies have proved the role of EVs in the different stages of the genesis and development of TNBC. Cancer cells actively secrete various biomolecules, which play a significant part establishing the tumor microenvironment via EVs. In this article, we describe the roles of EVs in the tumor immune microenvironment, metabolic microenvironment, and vascular remodeling, and summarize the application of EVs for objective delivery of chemotherapeutic drugs, immune antigens, and cancer vaccine adjuvants. EVs-based therapy may represent the next-generation tool for targeted drug delivery for the cure of a variety of diseases lacking effective drug treatment.

Protective effect of intranasal insulin on postoperative cognitive dysfunction in elderly patients with metabolic syndrome undergoing noncardiac surgery: a randomized clinical trial.

BACKGROUND: Insulin plays a crucial and multifactorial role in cognitive activity, with insulin resistance appearing in neurodegenerative and metabolic diseases. Insulin resistance contributes to the pathobiology of postoperative cognitive dysfunction (POCD) in experimental models, which can be rescued by intranasal insulin administration. AIMS: To test the effect of intranasal insulin on the incidence of POCD in elderly patients with metabolic syndrome. METHODS: The study was designed as a randomized, double-blind, placebo-controlled clinical trial. 116 elderly participants were randomly assigned to receive either 40 IU insulin (n = 58) or placebo (n = 58) for 7 days. The primary outcome was the incidence of POCD at 7 days and 3 months after surgery. Secondary outcomes included the degree of peripheral insulin resistance postoperatively, changes in peripheral inflammation levels and the safety of interventions. RESULTS: The results showed that POCD occurred in the insulin group on the 7th postoperative day in 11 (20.8%) patients, which was fewer than the 23 (45.1%) patients in the placebo group (P = 0.008). The insulin group indicated better cognitive functional performance on language and memory test than the placebo group (P < 0.05). Mean peripheral plasma concentration of TNF-α (P < 0.05) and CRP (P < 0.001) in the insulin group was significantly declined compared with the placebo group on D3 and D7. CONCLUSIONS: Intranasal insulin administration reduced the incidence of POCD and alleviated peripheral inflammatory levels in elderly patients with metabolic syndrome. TRIAL REGISTRY: Chinese Clinical Trial Registry (ChiCTR1800015502).

Breaking the mold: Overcoming resistance to immune checkpoint inhibitors.

Immune checkpoint blockade-based therapies are effective against a sorts of cancers. However, drug resistance is a problem that cannot be ignored. This review intends to elucidate the mechanisms underlying drug tolerance induced by PD-1/PD-L1 inhibitors, as well as to outline proposed mechanism-based combination therapies and small molecule drugs that target intrinsic immunity and immune checkpoints. According to the differences of patients and types of cancer, the optimization of individualized combination therapy will help to enhance PD-1/PD-L1-mediated immunoregulation, reduce chemotherapy resistance, and provide new ideas for chemotherapy-resistant cancer.

Graded Heterojunction Improves Wide-Bandgap Perovskite for Highly Efficient 4-Terminal Perovskite/Silicon Tandem Solar Cells.

Wide-bandgap (WBG) perovskite solar cells (PSCs) are essential for highly efficient and stable silicon/perovskite tandem solar cells. In this study, we adopted a synthetic strategy with lead thiocyanate (Pb(SCN)2) additive and methylammonium chloride (MACl) posttreatment to enhance the crystallinity and improve the interface of WBG perovskite films with a bandgap of 1.68 eV. The excessive PbI2 was formed at grain boundaries and converted into MAPbI3-xClx perovskites, which are utilized to form the graded heterojunction (GHJ) and compressive strain. This is beneficial for passivating nonradiative recombination defects, suppressing halide phase segregation, and facilitating carrier extraction. Subsequently, the device with GHJ delivered a champion efficiency of 20.30% and superior stability in ambient air and under 85 °C. Finally, we achieved a recorded efficiency of 30.91% for 4-terminal WBG perovskite/TOPCon tandem silicon solar cells. Our findings demonstrate a promising approach for fabricating efficient and stable WBG PSCs through the formation of GHJ.

[Stellera chamaejasme extract against multidrug resistance of breast cancer cell line MCF-7].

This study explored the effect and underlying mechanism of Stellera chamaejasme extract(SCE) on multidrug resistance of breast cancer. The chemotherapy-sensitive breast cancer cell line MCF-7 and adriamycin(ADR)-resistant cell line MCF-7/ADR were used as experimental subjects. MTT assay was used to detect cell proliferation activity. Pi staining was used to detect the cell cycle. 4',6-Diamidino-2-phenylindole, dihydrochloride(DAPI) staining and flow cytometry were used to detect apoptosis. Dansylcadaverine(MDC) staining and GFP-LC3B-Mcherry adenovirus transfection were used to detect autophagy. The protein expression of Bcl-2, Bax, caspase-9, caspase-3, LC3B, p62, and Beclin-1 was detected by Western blot. The results showed that SCE could significantly inhibit the proliferation of both sensitive and resistant breast cancer cell lines. The drug resistance factor was 0.53, which was significantly lower than 59 of ADR. Meanwhile, the proportion of sensitive/resistant cells in the G_0/G_1 phase increased significantly after SCE treatment. In addition, DAPI staining showed that a series of apoptosis phenomena such as nuclear pyknosis, staining deepening, and nuclear fragmentation appeared in sensitive/resistant cell lines after SCE administration. Moreover, the results of flow cytometry double staining showed that the proportion of apoptotic cells in sensitive/resistant cell lines increased significantly after SCE administration. Besides, Western blot showed that the protein expression levels of caspase-3, caspase-9, and Bcl-2 significantly decreased and the expression level of Bax protein significantly increased in both breast cancer cell lines after SCE administration. Furthermore, SCE could also increase the positive fluorescent spots after MDC staining and yellow fluorescent spots after GFP-LC3B-mcherry transfection, and up-regulate the expression levels of autophagy-related proteins LC3B-Ⅱ, p62, and Beclin-1 in breast cancer cells. In summary, SCE may play the role of anti-multidrug resistance by blocking the cell cycle of breast cancer multidrug-resistant cells, blocking autophagy flow, and ultimately interfering with the apoptosis resistance of drug-resistant cells.

Conserved allosteric inhibitory site on the respiratory syncytial virus and human metapneumovirus RNA-dependent RNA polymerases.

Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are related RNA viruses responsible for severe respiratory infections and resulting disease in infants, elderly, and immunocompromised adults1-3. Therapeutic small molecule inhibitors that bind to the RSV polymerase and inhibit viral replication are being developed, but their binding sites and molecular mechanisms of action remain largely unknown4. Here we report a conserved allosteric inhibitory site identified on the L polymerase proteins of RSV and HMPV that can be targeted by a dual-specificity, non-nucleoside inhibitor, termed MRK-1. Cryo-EM structures of the inhibitor in complexes with truncated RSV and full-length HMPV polymerase proteins provide a structural understanding of how MRK-1 is active against both viruses. Functional analyses indicate that MRK-1 inhibits conformational changes necessary for the polymerase to engage in RNA synthesis initiation and to transition into an elongation mode. Competition studies reveal that the MRK-1 binding pocket is distinct from that of a capping inhibitor with an overlapping resistance profile, suggesting that the polymerase conformation bound by MRK-1 may be distinct from that involved in mRNA capping. These findings should facilitate optimization of dual RSV and HMPV replication inhibitors and provide insights into the molecular mechanisms underlying their polymerase activities.

Complete genome analysis of pathogenic Metschnikowia bicuspidata strain MQ2101 isolated from diseased ridgetail white prawn, Exopalaemon carinicauda.

BACKGROUND: Metschnikowia bicuspidata is a pathogenic yesst that can cause disease in many different economic aquatic animal species. In recent years, there was a new disease outbreak in ridgetail white prawn (Exopalaemon carinicauda) in coastal areas of Jiangsu Province China that was referred to as zombie disease by local farmers. The pathogen was first isolated and identified as M. bicuspidata. Although the pathogenicity and pathogenesis of this pathogen in other animals have been reported in some previous studies, research on its molecular mechanisms is still very limited. Therefore, a genome-wide study is necessary to better understand the physiological and pathogenic mechanisms of M. bicuspidata. RESULT: In this study, we obtained a pathogenic strain, MQ2101, of M. bicuspidata from diseased E. carinicauda and sequenced its whole genome. The size of the whole genome was 15.98 Mb, and it was assembled into 5 scaffolds. The genome contained 3934 coding genes, among which 3899 genes with biological functions were annotated in multiple underlying databases. In KOG database, 2627 genes were annotated, which were categorized into 25 classes including general function prediction only, posttranslational modification, protein turnover, chaperones, and signal transduction mechanisms. In KEGG database, 2493 genes were annotated, which were categorized into five classes, including cellular processes, environmental information processing, genetic information processing, metabolism and organismal systems. In GO database, 2893 genes were annotated, which were mainly classified in cell, cell part, cellular processes and metabolic processes. There were 1055 genes annotated in the PHI database, accounting for 26.81% of the total genome, among which 5 genes were directly related to pathogenicity (identity ≥ 50%), including hsp90, PacC, and PHO84. There were also some genes related to the activity of the yeast itself that could be targeted by antiyeast drugs. Analysis based on the DFVF database showed that strain MQ2101 contained 235 potential virulence genes. BLAST searches in the CAZy database showed that strain MQ2101 may have a more complex carbohydrate metabolism system than other yeasts of the same family. In addition, two gene clusters and 168 putative secretory proteins were predicted in strain MQ2101, and functional analysis showed that some of the secretory proteins may be directly involved in the pathogenesis of the strain. Gene family analysis with five other yeasts revealed that strain MQ2101 has 245 unique gene families, including 274 genes involved in pathogenicity that could serve as potential targets. CONCLUSION: Genome-wide analysis elucidated the pathogenicity-associated genes of M. bicuspidate while also revealing a complex metabolic mechanism and providing putative targets of action for the development of antiyeast drugs for this pathogen. The obtained whole-genome sequencing data provide an important theoretical basis for transcriptomic, proteomic and metabolic studies of M. bicuspidata and lay a foundation for defining its specific mechanism of host infestation.

Mechanisms of drug resistance in breast cancer liver metastases: Dilemmas and opportunities.

Breast cancer is the leading cause of cancer-related deaths in females worldwide, and the liver is one of the most common sites of distant metastases in breast cancer patients. Patients with breast cancer liver metastases face limited treatment options, and drug resistance is highly prevalent, leading to a poor prognosis and a short survival. Liver metastases respond extremely poorly to immunotherapy and have shown resistance to treatments such as chemotherapy and targeted therapies. Therefore, to develop and to optimize treatment strategies as well as to explore potential therapeutic approaches, it is crucial to understand the mechanisms of drug resistance in breast cancer liver metastases patients. In this review, we summarize recent advances in the research of drug resistance mechanisms in breast cancer liver metastases and discuss their therapeutic potential for improving patient prognoses and outcomes.

Dynamic regulation using a quorum-sensing circuit enhances the production of tyrosol by Escherichia coli / 生物工程学报

Tyrosol is a natural polyphenolic product that is widely used in chemical, pharmaceutical and food industries. Currently, the de novo synthesis of tyrosol by Escherichia coli suffers from issues such as low cell density and poor yield. Therefore, the phenylpyruvate decarboxylase mutant ARO10F138L/D218G obtained in our previous study was fused with an alcohol dehydrogenase from different microorganisms for fusion expression, and the optimal ARO10F138L/D218G-L-YahK produced 1.09 g/L tyrosol in shake flasks. In order to further improve tyrosol production, feaB, a key gene in the competing pathway of 4-hydroxyphenylacetic acid, was knocked out, and the resulted strain produced 1.26 g/L tyrosol with an increase of 21.15% compared to that of the control. To overcome the low cell density in tyrosol fermentation, the quorum-sensing circuit was used to dynamically regulate the tyrosol synthesis pathway, so as to alleviate the toxic effect of tyrosol on chassis cells and relieve the growth inhibition. Using this strategy, the yield of tyrosol was increased to 1.74 g/L, a 33.82% increase. In a 2 L fermenter, the production of tyrosol in the engineered strain TRFQ5 dynamically regulated by quorum-sensing reached 4.22 g/L with an OD600 of 42.88. Compared with those in the engineered strain TRF5 statically regulated by induced expression, the yield was increased by 38.58% and the OD600 was enhanced by 43.62%. The combination of blocking the competing pathway using gene knockout technology, and reducing the inhibitory effect of tyrosol toxicity on chassis cells through quorum-sensing dynamic regulation increased the production of tyrosol. This study may facilitate the biosynthesis of other chemicals with high toxicity.

The protective effect of orcinol glucoside on dexamethasone induced osteoblast cell damage through inhibition of glucocorticoid receptor nucleus translocation / 中国药理学通报

Aim To investigate the protective effect of orcinol glucoside on dexamethasone(DEX)-induced osteoblast injury and its mechanism. Methods Primary osteoblasts were extracted from calvaria of neonatal mice and cultured in medium with DEX(1 μmol•L

Association of peripheral axial length, retinal curvature with refraction in school-aged children / 中华实验眼科杂志

Objective:To investigate the association of peripheral axial lengths and retinal curvatures with refractive status.Methods:A cross-sectional study was conducted out.Two hundred and eighty-seven eyes of 287 consecutive children aged 6-15 years old who recieved eye examinations at Beijing Tongren Hospital from July to October 2021 were enrolled, including 154 males and 133 females.Uncorrected and best corrected visual acuity were tested with a standard logarithmic visual acuity chart.Spherical equivalent (SE) was measured via an auto refractometer after cycloplegia with tropicamide.The hyperopic, emmetropic and myopic groups were defined with a SE >+ 0.5 D, SE >-0.5 D to ≤+ 0.5 D and SE≤-0.5 D, respectively.Central and 30° peripheral eye lengths (nasal, temporal, superior, inferior) were obtained using the Lenstar LS900.Retinal coordinates were derived from partial coherence interferometry modeling and converted to retinal curvatures.According to the median horizontal peripheral eye length differences (absolute difference between nasal and temporal), participants were assigned to H1 group (absolute difference <0.35 mm) or H2 group (absolute difference ≥0.35 mm). According to the median vertical peripheral eye length differences (absolute difference between superior and inferior), participants were assigned to V1 group (absolute difference <0.32 mm) or V2 group (absolute difference ≥0.32 mm). Four groups of V1H1, V1H2, V2H1 and V2H2 were constructed according to the grouping methods in both directions above.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Beijing Tongren Hospital, Capital Medical University (No.TRECKY2021-162). Written informed consent was obtained from guardians of each subject prior to any medical examination.Results:The central axial length was 23.53(22.93, 24.10)mm.Peripheral eye lengths of temporal, nasal, superior and inferior were 22.75(22.11, 23.22)mm, 22.99(22.32, 23.45)mm, 23.24(22.58, 23.75)mm and 23.12(22.52, 23.56)mm, respectively.Temporal eye length was shorter than nasal, showing a statistically significant difference ( Z=-3.58, P<0.01). Compared with H2 group, H1 group had shorter central, nasal, superior and inferior eye lengths, showing statistically significant differences (all at P<0.05). Compared with V2 group, V1 group had shorter central, nasal and superior eye lengths, showing statistically significant differences (all at P<0.05). SE of H1 group was + 0.06 (-1.06, + 0.75) D, which was significantly greater than -0.32 (-1.64, + 0.56) D of H2 group ( Z=-2.10, P=0.04). SE of V1 group was + 0.13 (-0.81, + 0.80) D, which was significantly greater than -0.56 (-1.83, + 0.48) D of H2 group ( Z=-3.39, P<0.01). The myopia ratio of V1 group was 33.5% (58/173), which was significantly lower than 50.5% (53/105) of V2 group ( χ2=7.83, P<0.01). There was a significant overall difference in SE among VIH1, V1H2, V2H1 and V2H2 groups ( H=24.79, P<0.01). SE was greater in V1H1 group than V1H2, V2H1 and V2H2 groups (all at P<0.01). There was a significant difference in both horizontal and vertical retinal curvatures among different refractive groups ( H=22.34, 19.30; both at P<0.01). The retical curvature in both directions of hyperopic and emmetropic groups were significantly larger than those of myopic group (both at P<0.01). Conclusions:Peripheral eye lengths are asymmetric in school-aged children.Higher asymmetry is associated with myopic shifts.Myopic children have a steeper retina than the hyperopic and emmetropic children.