Background Gastric cancer frequently harbors TP53 mutations, posing a challenge for therapies directly targeting mutant p53. Fibroblast growth factor receptor 1 (FGFR1) is a potential therapeutic target, but its interaction with mutant p53 in gastric cancer remains poorly understood. Methods We evaluated our newly designed FGFR1 inhibitor, S29, across multiple gastric cancer cell lines. Synthetic lethal partners of mutant p53 were identified using the Synthetic Lethality Online Analysis Database and validated through molecular assays, including overexpression and knockdown of p53 and E2F3. Clinical tissue samples were analyzed to confirm the pathological relevance of the FGFR1-E2F3-p53 axis. Results S29 effectively suppressed gastric cancer cell growth while concurrently increasing mutant p53 expression and downregulating E2F3. We identified E2F3 as a synthetic lethal partner of mutant p53. While p53 knockdown abolished S29's inhibitory effects, the combination of mutant p53 accumulation and FGFR1-mediated E2F3 inhibition significantly triggered G2/M cell cycle arrest and programmed cell death. These findings were consistent with expression patterns observed in clinical samples. Conclusions Our study demonstrates that FGFR1 inhibition induces synthetic lethality in mutant p53 gastric cancer by targeting the E2F3 axis. These results suggest that S29 provides a strategic therapeutic approach for patients with TP53 mutations.

Inspired by reports that HDAC blockade can trigger compensatory activation of the LIFR-JAK1-STAT3 axis in solid tumors, we designed and synthesized a series of niclosamide-based STAT3/HDAC dual-target inhibitor candidates by incorporating a SAHA-derived hydroxamate zinc-binding group into the pleiotropic, STAT3-modulating niclosamide scaffold. Biological evaluation identified NS06 as the best-balanced analogue, with IC50 values of 1.49 and 1.41 μM against MDA-MB-231 and HCT116 cells, respectively. Mechanistic studies showed that NS06 bound STAT3 in vitro (SPR, KD = 5.82 μM), suppressed STAT3 phosphorylation, and inhibited HDAC1, HDAC3, and HDAC6 with IC50 values of 129.1, 451.2, and 230.4 nM, respectively, while showing limited inhibition of HDAC4 and HDAC11 in the primary screen. NS06 also increased histone H3 acetylation, induced apoptosis, and inhibited migration and colony formation. In addition, NS06 retained antiproliferative activity in a 3D tumor spheroid model and showed improved Caco-2 permeability together with moderate liver microsomal stability (t1/2 ≈ 48.6 min in rat liver microsomes). Docking and 100-ns molecular dynamics simulations further supported chemically plausible binding modes in the HDAC1 catalytic pocket and the STAT3 SH2 domain. Overall, these findings support niclosamide as a tractable scaffold for mechanism-driven STAT3/HDAC dual-target inhibitor design and identify NS06 as a promising lead for further optimization against solid tumors.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with limited therapeutic options and poor clinical outcomes. In this study, we report the rational design and synthesis of a novel series of pyrimidine-4,6-diamine derivatives targeting OLIG2, a critical transcription factor involved in GBM progression. Among the synthesized compounds, B01 emerged as a potent and selective OLIG2 inhibitor, exhibiting strong anti-proliferative activity in U87 and U251 cells with IC50 values of 7.0 μM and 6.4 μM, respectively. Mechanistic studies confirmed that B01 directly and dose-dependently downregulated nuclear OLIG2 levels, with an IC50 of 0.88 μM. Notably, B01 demonstrated synergistic anti-tumor activity in combination with temozolomide (TMZ). In vivo, B01 reduced tumor volume by 46 % compared to control in a U87 xenograft model, with enhanced efficacy observed in combination therapy. Pharmacokinetic analysis revealed a favorable half-life (t1/2 = 3.3 h) and systemic exposure. This study identifies a novel and selective OLIG2 inhibitor, B01, with potent anti-GBM activity and therapeutic synergy with TMZ, making it a compelling candidate for further preclinical development.

Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), which serves the critical pillar for the treatment of non-small cell lung cancer (NSCLC). However, the acquired resistance remains a challenge for its clinical application, for which, practical strategies to reverse gefitinib resistance in NSCLC are necessary. Ferroptosis, a programmed cell death driven by ferritin-dependent lipid peroxidation, involves in NSCLC progression and related chemoresistance. In our previous work, the self-synthesised EGFR inhibitor Yfq07 (N4, N6-disubstituted pyrimidine-4,6-diamine derivatives) displayed a considerable inhibitory effect on NSCLC both in vitro and in vivo. Herein, we observed that Yfq07 suppressed the proliferation of PC-9GR and HCC827GR cells, two gefitinib resistance NSCLC cell lines. Mechanically, Yfq07 inhibited the phosphorylation of the Discoidin Domain Receptor 1 (DDR1), a receptor tyrosine kinase (RTK) highly expressed in multiple cancers, accompanied by downregulated miR-3648 and upregulated SOCS2. Inhibition or knockdown of DDR1 suppressed the proliferation, migration, and invasion of gefitinib-resistant NSCLC cells, and on the other hand, also downregulated miR-3648 and promoted SOCS2 expression. More specifically, miR-3648 targeted the 3'UTR segment of SOCS2 mRNA and thus affecting the P-ERK signalling pathway to regulate the malignant behaviors of gefitinib-resistant NSCLC cells. Furthermore, Yfq07 also indirectly induced the ferroptosis of gefitinib-resistant NSCLC cells via SOCS2 triggered inhibition of xCT-GPX4 pathway. In conclusion, our study indicates that DDR1 inhibitor Yfq07 promotes ferroptosis and reverses gefitinib-resistance of NSCLC through DDR1-miR-3648-SOCS2 signalling pathway, which provides insights for targeted therapy of gefitinib-resistant NSCLC and drug developments targeting ferroptosis.

This study aimed to develop the first dual-target small molecule inhibitor concurrently targeting Discoidin domain receptor 1 (DDR1) and Epidermal growth factor receptor (EGFR), which play a crucial interdependent roles in non-small cell lung cancer (NSCLC), demonstrating a synergistic inhibitory effect. A series of innovative dual-target inhibitors for DDR1 and EGFR were discovered. These compounds were designed and synthesized using structural optimization strategies based on the lead compound BZF02, employing 4,6-pyrimidine diamine as the core scaffold, followed by an investigation of their biological activities. Among these compounds, D06 was selected and showed micromolar enzymatic potencies against DDR1 and EGFR. Subsequently, compound D06 was observed to inhibit NSCLC cell proliferation and invasion. Demonstrating acceptable pharmacokinetic performance, compound D06 exhibited its anti-tumor activity in NSCLC PC-9/GR xenograft models without apparent toxicity or significant weight loss. These collective results showcase the successful synthesis of a potent dual-targeted inhibitor, suggesting the potential therapeutic efficacy of co-targeting DDR1 and EGFR for DDR1/EGFR-positive NSCLC.

A series of novel chalcone analogs derived from syringaldehyde have been synthesized through acid or base-catalyzed aldol condensation. The anticancer activity of the newly synthesized compounds was assessed against a range of women-specific cancer cell lines, including A2780 (ovarian cancer), HeLa and C33a (cervical cancer), and MDA-MB-453, MDA-MB-231 and MCF-7 (breast cancer). The majority of these compounds demonstrated remarkable cytotoxicity against the tested cancer cells. Compound 2a displayed the most promising anti-proliferation activity against the selected female cancer cells, while also exhibiting the weakest cytotoxicity towards human normal cells. Therefore, it was chosen as the active compound based on both drug efficacy and safety considerations in this study. The findings indicated that compound 2a induced cell apoptosis and G2/M phase arrest by causing significant DNA damage and provoking a strong DNA damage response. Moreover, the results indicated that compound 2a affected the phosphorylation and distribution of FAK, thereby inhibiting cell adhesion and migration. Furthermore, compound 2a exhibited excellent potential in inhibiting A2780-derived xenograft tumor growth in mice, without any impact on their body weight. Tissue distribution experiments indicated that compound 2a tended to accumulate in the ovary in vivo. Overall, these results suggest that compound 2a may serve as a promising lead compound for developing anticancer agents against female cancer, especially in the case of ovarian cancer treatment.

Introduction: Cancer, a significant global health concern, necessitates innovative treatments. The pivotal role of chronic inflammation in cancer development underscores the urgency for novel therapeutic strategies. Benzothiazole derivatives exhibit promise due to their distinctive structures and broad spectrum of biological effects. This study aims to explore new anti-tumor small molecule drugs that simultaneously anti-inflammatory and anticancer based on the advantages of benzothiazole frameworks.Methods: The compounds were characterized by nuclear magnetic resonance (NMR), liquid chromatograph-mass spectrometer (LC-MS) and high performance liquid chromatography (HPLC) for structure as well as purity and other related physicochemical properties. The effects of the compounds on the proliferation of human epidermoid carcinoma cell line (A431) and human non-small cell lung cancer cell lines (A549, H1299) were evaluated by MTT method. The effect of compounds on the expression levels of inflammatory factors IL-6 and TNF-α in mouse monocyte macrophages (RAW264.7) was assessed using enzyme-linked immunosorbent assay (ELISA). The effect of compounds on apoptosis and cell cycle of A431 and A549 cells was evaluated by flow cytometry. The effect of compounds on A431 and A549 cell migration was evaluated by scratch wound healing assay. The effect of compounds on protein expression levels in A431 and A549 cells was assessed by Western Blot assay. The physicochemical parameters, pharmacokinetic properties, toxicity and drug similarity of the active compound were predicted using Swiss ADME and admetSAR web servers.Results: Twenty-five novel benzothiazole compounds were designed and synthesized, with their structures confirmed through spectrogram verification. The active compound 6-chloro-N-(4-nitrobenzyl) benzo[d] thiazol-2-amine (compound B7) was screened through a series of bioactivity assessments, which significantly inhibited the proliferation of A431, A549 and H1299 cancer cells, decreased the activity of IL-6 and TNF-α, and hindered cell migration. In addition, at concentrations of 1, 2, and 4 μM, B7 exhibited apoptosis-promoting and cell cycle-arresting effects similar to those of the lead compound 7-chloro-N-(2, 6-dichlorophenyl) benzo[d] thiazole-2-amine (compound 4i). Western blot analysis confirmed that B7 inhibited both AKT and ERK signaling pathways in A431 and A549 cells. The prediction results of ADMET indicated that B7 had good drug properties.Discussion: This study has innovatively developed a series of benzothiazole derivatives, with a focus on compound B7 due to its notable dual anticancer and anti-inflammatory activities. B7 stands out for its ability to significantly reduce cancer cell proliferation in A431, A549, and H1299 cell lines and lower the levels of inflammatory cytokines IL-6 and TNF-α. These results position B7B7 as a promising candidate for dual-action cancer therapy. The study’s mechanistic exploration, highlighting B7’s simultaneous inhibition of the AKT and ERK pathways, offers a novel strategy for addressing both the survival mechanisms of tumor cells and the inflammatory milieu facilitating cancer progression.

Signal transducer and activator of transcription 3 (STAT3) has been confirmed as an attractive therapeutic target for cancer therapy. Herein, we designed and synthesized a series of N-substituted Sulfamoylbenzamide STAT3 inhibitors based on small-molecule STAT3 inhibitor Niclosamide. Compound B12, the best active compound of this series, was identified as an inhibitor of IL-6/STAT3 signaling with an IC50 of 0.61-1.11 mu M in MDA-MB-231, HCT-116 and SW480 tumor cell lines with STAT3 overexpression, by inhibiting the phosphorylation of STAT3 of Tyr705 residue and the expression of STAT3 downstream genes, inducing apoptosis and inhibiting the migration of cancer cells. Furthermore, in vivo study revealed that compound B12 suppressed the MDA-MB-231 xenograft tumor growth in nude mice at the dose of 30 mg/kg (i.g.), which has better antitumor activity than the positive control Niclosamide. More importantly, B12 is an orally bioavailable anticancer agent as a promising candidate for further development. (c) 2021 Elsevier Masson SAS. All rights reserved.

A novel series of novel N-substituted (indole or indazole) benzamides were synthesized, and their anti-tumor properties were evaluated. The majority of tested compounds possessed moderate cytotoxicity, but inspiringly, we verified that active compound 5d presents an astonishing advantage by inhibiting the adhesion, migration, and invasion of osteosarcoma (OS) cells in vitro. Mechanistically, we confirmed 5d inhibited the migration ability of OS cells via the expression of genes related to adhesion, migration, and invasion. This effects of 5d suggest that it can be used as a potential chemotherapeutic drug to some aggressive and/or metastatic cancers, as well as in combination with other clinical anti-cancer drugs. In turn, this could enhance the therapeutic effect or reduce the risk of cell migration.

目的 探讨Ⅰ类切口手术后医院感染的危险因素及应对策略.方法 回顾性分析2019年8月至2020年8月在浙江省温州市中心医院住院治疗的Ⅰ类切口手术后136例发生医院感染患者(感染组)及136例未发生医院感染患者(非感染组)的临床资料.采用Logistic回归方法分析患者医院感染的危险因素,统计患者医院感染部位、感染病原体及抗菌药物使用等情况.结果 该研究时段Ⅰ类切口手术患者医院感染发生率为3.4％(136/3945).医院感染患者中,以呼吸道感染最常见,占75.7％(103/136).136例感染患者送检标本68例,送检率为50.0％,检出病原菌共53株,以革兰阴性菌为主(共33株,占62.3％).年龄>60岁、住院时间>7 d、有基础疾病、术中出血量>100 ml、术后有引流是Ⅰ类切口手术患者术后医院感染的独立危险因素(均P<0.05).136例医院感染患者中有122例使用了抗菌药物治疗,抗菌药物使用率达89.7％.结论 对于Ⅰ类切口手术患者,应缩短平均住院日、减少术中出血量、加强术后引流管理、提高病原菌送检率、规范临床合理用药以减少医院感染的发生.

当前,我国对高等药学教育质量进行重新定位和全面提升,各高校坚持"以本为本",推进"四个回归",争创"双一流"高校,落实"金专建设"计划,实验教学改革无疑是重中之重.通过分析国内外药学实验教学的不同特点,不难发现,我国药学类实验教学与国外存在着很大的差距.要提高药学类专业实验教学质量,培养高质量的药学专业人才,必须建立一套适合学生发展的、能够培养学生创新意识的实验教学体系.遵循这个思路,温州医科大学药学院从实验教学体系及实验教学平台建设等方面进行改革,形成了"一纵二横、以本为本,以学生为主体"的实验教学体系和"基础实验平台—专业综合实验平台—专业创新实验平台"的三级实验教学平台化建设模式,经多年运行效果明显.

Five new dithienopyrrolobenzothiadiazole (DTPBT)-based organic sensitizers were prepared for dye-sensitized solar cells (DSSCs). In this work, DTPBT unit was used as a donor to construct monoand di-anchored metal free organic sensitizers for the first time. The DTPBT unit applied as a donor or a n-spacer in mono-anchored dyes (W1 and W2) greatly influences the absorption range, HOMO-LUMO energy level and the solar cell performance of the dyes. The results show that the DTPBT unit is more suitable for acting as a n-spacer in D-n-A dyes. Di anchored dyes exhibit broader photo-spectra response and higher molar extinction coefficients than those of the mono-anchored dyes. Di-anchored dyes W4 and W5 with DTPBT as the donor, thiophene as the n-bridge achieve high power conversion efficiencies of 7.93%, 7.98% with 1 mM CDCA as the co-adsorbent, respectively. The results suggest that the DTPBT moiety is a promising donor candidate to develop efficient double anchored organic dyes for DSSCs.

目的 探讨耐碳青霉烯类肠杆菌科细菌(CRE)的临床分布及耐药性.方法 回顾性分析台州市第一人民医院2015年1月至2018年12月分离的186株CRE,对病原菌、标本来源、病区分布和临床常用抗菌药物的耐药性进行统计分析.结果 186株CRE菌株的病原菌主要是肺炎克雷伯菌(115株,占61.83％),其次是大肠埃希菌(26株,占13.98％)和阴沟肠杆菌(18株,占9.68％);标本来源主要是痰液(107株,占57.53％)、尿液(36株,占19.35％)和血液(18株,占9.68％);病区来源主要是重症监护病房(95株,占51.08％),其次为血液肿瘤科(24株,占12.90％)和中医康复科(19株,占10.22％).主要CRE菌株对阿米卡星的耐药率较低,为16.67％ ～24.35％,对妥布霉素的耐药率为33.33％ ～45.22％,对其余抗菌药物的耐药率均>50％.结论 CRE菌株分布广泛,对常用抗菌药物耐药率普遍较高.

Sustained activation of STAT3 is closely related to the cancer development, but the inhibitors for STAT3 overexpression are still in the clinical research stage. In this study, a series of 2,6-disubstituted purine derivatives were designed and synthesized, and their biological activities, as small molecule inhibitors of STAT3, were assessed. Compound PD26-TL07 exhibited remarkable antiproliferative activity against three cancer cell lines (IC50 values for HCT-116, SW480 and MDA-MB-231 were 1.77 ± 0.35, 1.51 ± 0.19, and 1.25 ± 0.38 μM, respectively). Moreover, detailed biological assays revealed that PD26-TL07 could effectively inhibited STAT3 phosphorylation, and had little inhibition to others’. The newly discovered PD26-TL07 displayed an expecting anticancer effect both in vitro and in vivo. The molecular docking models revealed that PD26-TL07 could bind to the SH2 domain of STAT3. Three additional compounds (PD26-BZ01, PD26-TL03 and PD26-AS06) were also able to inhibit this phosphorylation. This study described novel 2,6-disubstituted purine derivatives as potent anticancer agents targeting STAT3.

FGF2-FGFR1 autocrine pathway activation reduces the sensitivity of non-small cell lung cancer (NSCLC) cells to EGFR inhibitors like Gefitinib. Therefore, dual-specific drugs targeting EGFR and FGFR with high selectivity and activity are required. Through structure analysis of excellent EGFR inhibitors and FGFR inhibitors, we designed and synthesized 33 4,6-pyrimidinediamine derivatives as dual EGFR and FGFR inhibitors and selected BZF 2 as a potential EGFR and FGFR inhibitor after initial cell screening. Then, through kinase testing and western blot analysis, BZF 2 was defined as a dual EGFR and FGFR inhibitor with high selectivity 1and activity. Biological evaluation of NSCLC cell lines with the FGF2-FGFR1 autocrine loop indicated that BZF 2 significantly inhibited cell proliferation (IC50 values for H226 and HCC827 GR were 2.11 μM, and 0.93 μM, respectively), cell migration, and induced cell apoptosis and cell cycle arrest. Anti-tumor activity test in vivo showed that BZF 2 obviously shrank tumor size. Therefore, BZF 2 is a highly selective and potent dual EGFR/FGFR compound with promising therapeutic effects against EGFR/FGFR1-positive NSCLC.

目的:以嘌呤类STAT3小分子抑制剂S3I-V4-01为先导,设计并合成一系列新型目标化合物,通过初步的体外细胞实验检测其生物活性,以筛选出活性更优的化合物.方法:通过亲核取代反应合成了一系列目标化合物,运用荧光素酶报告基因法检测目标化合物对STAT3信号转导通路的影响,利用MTT实验检测目标化合物对人表皮鳞癌细胞A431和非小细胞肺癌细胞A549增殖的抑制作用.结果:本研究共合成8个终产物(Z2～Z5及H2～H5),其中,优势化合物H3能有效抑制STAT3磷酸化,阻断STAT3信号转导通路,抑制A431和A549的细胞增殖.结论:化合物H3比S3I-V4-01具有更强的p-STAT3抑制能力和抗肿瘤细胞增殖能力,并且可以在H3结构上进行优化,以进一步提高生物活性.

推进临床医学"5+3"一体化人才培养模式改革,是在医教协同背景下,构建我国新型临床医学人才培养体系的重要内容之一.温州医科大学从明确培养目标、创新培养方案、实施课程整合、优化教学方法、规范技能培训、完善保障机制等多方面入手,积极探索构建基于多创融合的临床医学"5+3"一体化人才培养创新模式,通过教学改革实践,对该培养模式进行初步思考、展望并不断优化,以期提高医学人才培养质量.

A series of 4-bromo-N-(3,5-dimethoxyphenyl)benzamide derivatives were designed and synthesised as novel fibroblast growth factor receptor-1 (FGFR1) inhibitors. We found that one of the most promising compounds, C9, inhibited five non-small cell lung cancer (NSCLC) cell lines with FGFR1 amplification, including NCI-H520, NCI-H1581, NCI-H226, NCI-H460 and NCI-H1703. Moreover, the IC50 values for the compound C9 were 1.36 ± 0.27 µM, 1.25 ± 0. 23 µM, 2.31 ± 0.41 µM, 2.14 ± 0.36 µM and 1.85 ± 0.32 µM, respectively. The compound C9 arrested the cell cycle at the G2 phase in NSCLC cell lines. The compound C9 also induced cellular apoptosis and inhibited the phosphorylation of FGFR1, PLCγ1 and ERK in a dose-dependent manner. In addition, molecular docking experiments showed that compound C9 binds to FGFR1 to form six hydrogen bonds. Taken together, our data suggested that the compound C9 represented a promising lead compound-targeting FGFR1.

Objective To analyze pathogen features and risk factors of post-chemotherapy bloodstream infection in patients with acute leukemia(AL).Methods Clinical data of 260 AL patients who had chemotherapy from January 2012 to December 2016 in Department of Hematology and Oncology,Taizhou First People's Hospital were reviewed.Occurrence of bloodstream infection and features of pathogen distribution were recorded.Risk factors of bloodstream infection were analyzed by logistic regression.Results Bloodstream infection occurred in 33 patients(12.7％).Thirty-six pathogens were isolated,including 9 strains(25.0％) of gram-positive bacteria,26 strains (72.2％) of gram-negative bacteria and 1 strain (2.8％) of fungi;staphylococcus epidermidis was 11.1％ (4/36) in gram-positive bacteria;escherichia coli was 30.6％ (11/36) in gram-negative bacteria.Univariate analysis showed that length of hospital stay,stage of chemotherapy,diabetes and duration of neutropenia were related to occurrence of bloodstream infection (P ＜ 0.05).Multivariate logistic regression analysis showed that diabetes(β =1.388,odds ratio =4.005,P =0.038) and duration of neutropenia ＞ 7 d(β =1.752,odds ratio =5.769,P ＜ 0.001) were independent risk factors of bloodstream infection.Conclusions Gram-negative bacteria are dominant among pathogens causing bloodstream infection in AL patients after chemotherapy.Incidence of bloodstream infection is closely associated with diabetes and duration of neutropenia.