Cocktail hepatocarcinoma therapy by a super-assembled nano-pill targeting XPO1 and ATR synergistically / 药物分析学报

Intensive cancer treatment with drug combination is widely exploited in the clinic but suffers from inconsistent pharmacokinetics among different therapeutic agents.To overcome it,the emerging nanomedicine offers an unparalleled opportunity for encapsulating multiple drugs in a nano-carrier.Herein,a two-step super-assembled strategy was performed to unify the pharmacokinetics of a pep-tide and a small molecular compound.In this proof-of-concept study,the bioinformatics analysis firstly revealed the potential synergies towards hepatoma therapy for the associative inhibition of exportin 1(XPO1)and ataxia telangiectasia mutated-Rad3-related(ATR),and then a super-assembled nano-pill(gold nano drug carrier loaded AZD6738 and 97-110 amino acids of apoptin(AP)(AA@G))was con-structed through camouflaging AZD6738(ATR small-molecule inhibitor)-binding human serum albumin onto the AP-Au supramolecular nanoparticle.As expected,both in vitro and in vivo experiment results verified that the AA@G possessed extraordinary biocompatibility and enhanced therapeutic effect through inducing cell cycle arrest,promoting DNA damage and inhibiting DNA repair of hepatoma cell.This work not only provides a co-delivery strategy for intensive liver cancer treatment with the clinical translational potential,but develops a common approach to unify the pharmacokinetics of peptide and small-molecular compounds,thereby extending the scope of drugs for developing the advanced com-bination therapy.

Repurposing econazole as a pharmacological autophagy inhibitor to treat pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is characterized by the highest mortality among carcinomas. The pathogenesis of PDAC requires elevated autophagy, inhibition of which using hydroxychloroquine has shown promise. However, current realization is impeded by its suboptimal use and unpredictable toxicity. Attempts to identify novel autophagy-modulating agents from already approved drugs offer a rapid and accessible approach. Here, using a patient-derived organoid model, we performed a comparative analysis of therapeutic responses among various antimalarial/fungal/parasitic/viral agents, through which econazole (ECON), an antifungal compound, emerged as the top candidate. Further testing in cell-line and xenograft models of PDAC validated this activity, which occurred as a direct consequence of dysfunctional autophagy. More specifically, ECON boosted autophagy initiation but blocked lysosome biogenesis. RNA sequencing analysis revealed that this autophagic induction was largely attributed to the altered expression of activation transcription factor 3 (ATF3). Increased nuclear import of ATF3 and its transcriptional repression of inhibitor of differentiation-1 (ID-1) led to inactivation of the AKT/mammalian target of rapamycin (mTOR) pathway, thus giving rise to autophagosome accumulation in PDAC cells. The magnitude of the increase in autophagosomes was sufficient to elicit ER stress-mediated apoptosis. Furthermore, ECON, as an autophagy inhibitor, exhibited synergistic effects with trametinib on PDAC. This study provides direct preclinical and experimental evidence for the therapeutic efficacy of ECON in PDAC treatment and reveals a mechanism whereby ECON inhibits PDAC growth.

Research progress in DNA damage checkpoint mechanism / 中华放射肿瘤学杂志

A damage is a general event in the life of cells and may lead to mutation,cancer,and cell/organ death. DNA damage occurring in different phases of cell cycle can activate different damage checkpoint pathways to halt the progress of cell cycle in order to provide time for DNA damage repair. If DNA damage cannot be repaired,cellular apoptosis may be induced. Therefore,DNA damage checkpoint is of great significance for cell survival after DNA damage. This article summarizes recent research on DNA damage responses, including DNA damage checkpoint, DNA damage repair, transcriptional response, and cell apoptosis. We focus on how the DNA damage checkpoint pathway is activated after DNA damage,as well as the functional mechanism of the DNA damage checkpoint pathway. The review aims to help readers understand the great significance of DNA damage checkpoint pathway, providing a theoretical basis for its application in radiotherapy and chemotherapy for cancer.

Recent advances in DNA damage repair mechanism / 中华放射肿瘤学杂志

The stability of cell genetic material is influenced by a variety of factors, both internal and external, which can cause various types of DNA damage, such as DNA alkylation, oxidation, mismatching, loop structure, atypical DNA structure, single-strand break, and double-strand break.These DNA damages disrupt cellular homeostasis and dynamic equilibrium, which cause gene mutations, chromosomal abnormalities, and even degradation, aging, and death at different biological levels.By searching and identifying DNA damage sites, the cell activates a series of biochemical pathways, coordinates the progress of DNA replication and transcription, and then repairs the DNA damage.In this way, the cell maintains its independence and stability.While radiotherapy plays a role in eliminating tumors by DNA damages, it also initiates DNA damage responses.Among the responses, base excision repair, nucleotide excision repair, mismatch repair, double-strand break repair, and post-translesion synthesis repair play a key role in repairing the damages.The dysfunction of these repair pathways will cause differences in tumor radiation sensitivity.This paper summarizes recent research results in DNA damage repair, and focuses on the types of DNA damage and their repair mechanisms, so as to promote the understanding of the great significance of this field and to provide a theoretical basis for exploring the application of DNA damage repair pathways in tumor therapy.

Research progress in DNA damage checkpoint mechanism / 中华放射肿瘤学杂志

A damage is a general event in the life of cells and may lead to mutation,cancer,and cell/organ death. DNA damage occurring in different phases of cell cycle can activate different damage checkpoint pathways to halt the progress of cell cycle in order to provide time for DNA damage repair. If DNA damage cannot be repaired,cellular apoptosis may be induced. Therefore,DNA damage checkpoint is of great significance for cell survival after DNA damage. This article summarizes recent research on DNA damage responses, including DNA damage checkpoint, DNA damage repair, transcriptional response, and cell apoptosis. We focus on how the DNA damage checkpoint pathway is activated after DNA damage,as well as the functional mechanism of the DNA damage checkpoint pathway. The review aims to help readers understand the great significance of DNA damage checkpoint pathway, providing a theoretical basis for its application in radiotherapy and chemotherapy for cancer.

Primary pancreatic neuroendocrine neoplasms:a clinicopathological analysis of 60 cases / 临床与实验病理学杂志

Purpose To study the clinicopathological characteristics of primary pancreatic neuroendocrine neoplasms. Method 60 cases of resected pancreatic neuroendocrine neoplasms according to the WHO (2010) classification of the digestive system of neuroen-docrine tumor to evaluate morphological standard, and combining with the literature to discuss the clinicopathological characteristics. Results Among the 60 cases, 23 cases were male patients, the rest were females, with male and female ratio of 1 ∶ 1. 61. The age of the patients were ranged from 19 to 69 years, with mean age of 49. 38 ± 11. 60 years. Tumor maximum diameter ranged from 0. 5 to 16 cm, and the mean diameter was 3. 29 ± 3. 53 cm. 30 cases located in the pancreatic head, 27 cases in the body and end of the pancre-as and 3 cases in the neck. Pathological examination showed the G1 (24 cases), G2 (25 cases), G3 (9 cases), and mixed adenon-euroendocrine carcinoma ( MANEC) in 2 cases. Immunohistochemical staining showed that NSE, CgA, Syn, and CD56 were diffusely positive expression. 45 patients were followed up for 4~80 months, 7 cases died, of which 1 case was G2, 4 cases were G3, and 2 ca-ses were MANEC. Conclusion Primary pancreatic neuroendocrine neoplasms is a relatively rare pancreatic malignant tumor, and the diagnosis is based primarily on histologic features and immunohistochemical examination. Accurate pathological assessment has impor-tant value to guide clinical treatment and prognosis.

Effect of Losartan on Myocardial Remodeling in Myocardial Infarction Rats’Model / 中国循环杂志

Objective: To investigate the effect of losartan on angiotensin II (Ang II) expression and myocardial remodeling in myocardial infarction (MI) rats’ model. Methods: A total of 32 SD male rats were divided into 4 groups, Sham operation group, MI group, MI with losartan 10mg/(kg·d) group and MI with losartan 20mg/(kg·d). n=8 in each group. MI model was established and the electrocardiogram changes before and after MI were recorded, hemodynamic indexes were detected at 4 weeks after MI, pathological changes of myocardial tissue were examined by HE staining. The myocardial mRNA and protein expressions of ACE2 and Ang II were detected by RT-PCR and Western Blot analysis. Results: Compared with Sham operation group, MI group showed increased LVMI and decreased LVEF P Conclusion: Losartan could increase ACE2 expression and therefore, inhibit Ang II expression and improve the ventricular remodeling in MI rats’ model.

Relationship among blood lipid,blood glucose,peripheral blood white cell levels and slow coronary flow / 心血管康复医学杂志

Objective:To explore the relationship among blood glucose,blood lipid levels,peripheral blood white cells and slow coronary flow (SCF).Methods:Clinical data of 183 patients receiving angiography in our hospital from Apr 2010 to Apr 2013 were retrospectively analyzed.Patients with TIMI grade 2 or lower coronary blood flow were defined as SCF;patients were divided into SCF group (n=93)and normal control group (n=90).Levels of blood lipid,glycosylated haemoglobin (HbA1c),hematocrit,and peripheral blood white cell levels were measured and compared between two groups.Results:Compared with normal control group,there was significant reduction in high density lipoprotein cholesterol (HDL-C) level [(1.21 ± 0.26)mmol/L vs.(1.12 ± 0.28)mmol/L,P =0.043],and significant rise in HbA1c level [(5.41±0.50)% vs.(5.83±0.45)%,P =0.01],hematocrit [(0.41 ±0.04)vs.(0.43±0.07),P =0.01]and white blood cell count [(6.1±1.6)109/L vs.(6.7±1.7)109/L,P <0.05]in SCF group.Logistic analysis indicated that white cell count was the risk factor of SCF (OR 1.920,95% CI 1.234~2.987,P =0.004).Conclusion:Levels of high density lipoprotein cholesterol,glycosylated haemoglobin, hematocrit and white blood cell count are related to slow coronary flow,and elevated white blood cell count may be a risk factor aggravating slow coronary slow.

Discussion of Effect that Management of Scientific Projects in Hospital Act on Supporting from National Natural Science Foundation of China / 中华医学科研管理杂志

The amount of the funds supported by National Natural Science Foundation of China (NSFC) played as an important role in judging the capabilities and tendency of scientific research.It is believed that the supporting rate of NSFC is promoted via scientific management policies.To explore the tendency and potential of scientific management plan in the first affiliated hospital of Xi'an Jiaotong University,we analyze the projects supported by NSFC of our hospital from 2002 to 2011.Accordingly,our outcomes show the supporting rates of variable programs from NSFC were similar to the average for whole nation.The inspiring policies encourage our staff to put their passion on the scientific research and funding application.The quality of bidding documents for NSFC is partially improved by the suggestions and lecture of invited experts who took the charge of evaluation of funds from NSFC for actively guide,so as to increase goal average.Of note,a cohort of the researchers at the age below 45 did the main contribution to scientific research developing and programs application from NS-FC.Furthermore,we will pay more attention to reach 3 point following:1.the policy of matching fund to strengthen the competition of the researchers all over the nation.2.the policy of Integrated research resources for the major programs.3.further improvement of projects supervision.