Chemical screen identifies shikonin as a broad DNA damage response inhibitor that enhances chemotherapy through inhibiting ATM and ATR

DNA damage response (DDR) is a highly conserved genome surveillance mechanism that preserves cell viability in the presence of chemotherapeutic drugs. Hence, small molecules that inhibit DDR are expected to enhance the anti-cancer effect of chemotherapy. Through a recent chemical library screen, we identified shikonin as an inhibitor that strongly suppressed DDR activated by various chemotherapeutic drugs in cancer cell lines derived from different origins. Mechanistically, shikonin inhibited the activation of ataxia telangiectasia mutated (ATM), and to a lesser degree ATM and RAD3-related (ATR), two master upstream regulators of the DDR signal, through inducing degradation of ATM and ATR-interacting protein (ATRIP), an obligate associating protein of ATR, respectively. As a result of DDR inhibition, shikonin enhanced the anti-cancer effect of chemotherapeutic drugs in both cell cultures and in mouse models. While degradation of ATRIP is proteasome dependent, that of ATM depends on caspase- and lysosome-, but not proteasome. Overexpression of ATM significantly mitigated DDR inhibition and cell death induced by shikonin and chemotherapeutic drugs. These novel findings reveal shikonin as a pan DDR inhibitor and identify ATM as a primary factor in determining the chemo sensitizing effect of shikonin. Our data may facilitate the development of shikonin and its derivatives as potential chemotherapy sensitizers through inducing ATM degradation.

Effect of cognitive intervention based on conception of knowledge and belief on cognition level and negative moods / 现代临床护理

Objective To explore the effect of cognitive intervention based on conception of knowledge and belief on cognition level and negative moods in the lung cancer patients undergoing radiotherapy. Methods Toally 84 lung cancer patients hospitalized in our hospital from March 2014 to November 2015 were equally divided into the study group and the control group by a random digit table. The control group received the traditional model of nursing, while the study group was treated with cognition intervention based on conception of knowledge and belief as well as the same routine care as in the control group for 4 weeks. Before and after 4 weeks intervention, the two groups were compared in terms of their knowledge, belief, behaviors, self care ability, depression and anxiety. Results Before intervention, there were no significant differences between the two groups in terms of their knowledge, belief, behaviors, self care ability, depression and anxiety (all P>0.05). After the intervention, the scores on knowledge, belief, behavior and self care ability in the study group were all significantly higher than those of the control group and the scores on anxiety and depression were both statistically significantly lower than those of the control group (all P<0.05). Conclusion The cognition intervention based on conception of knowledge and belief on cognition level and negative moods to the lung cancer patients is effective in improvement of their knowledge, belief, behavior as well as in alleviation of their anxiety and depression.

Effect of focused nursing model on negative emotions and subjective well-being in patients with lung cancer / 现代临床护理

Objective To explore the effect of focused nursing model on negative emotions and subjective well-being of lung cancer patients. Methods Eighty-six lung cancer patients hospitalized from November 2014 to November 2016 in our hospital were divided into two groups according to the order of admission in equal number. The control group was treated with routine care, and the observation group was with focused nursing model. The two groups were compared in terms of anxiety by SAS, depression by SDS, subjective well-being. Results The scores by SAS and SDS in the observation group were lower than those in the control group (P<0.05). The levels of objective support, subjective support, self-evaluation and subjective well-being index of the observation group were higher than the control group (P <0.05). Conclusion Focused nursing model can effectively relieve negative emotions, improve subjective well-being of lung cancer patients, worthy of clinical promotion.

Value of SWI in intravenous thrombolytic therapy of acute cerebral infarction / 实用放射学杂志

Objective To investigate the decisional value of susceptibility weighted imaging(SWI) in intravenous thrombolytic therapy to acute cerebral infarction.Methods According to cerebral microbleeds(CMBs) by SWI, 35 cases of acute cerebral infarction in window-time random were divided into experimental group(14 cases) with CMBs and control group(21 cases) without CMBs.After intravenous thrombolysis, the number of hemorrhagic transformation(HT) was counted by SWI, and statistic difference was compared between the experimental group and the control group(P<0.05).Results After intravenous thrombolytic therapy of acute infarction,12 cases with HT among experimental group, and only 2 cases with HT among control group, there was significant statistically difference between two groups(P<0.05).Conclusion SWI sequence has greater sensitivity in detecting CMBs,and can also assess the state of blood brain barrier(BBB) and vascular wall indirectly.It plays a very important role in giving a decision in the treatment of intravenous thrombolytic with window-time.

Clinical research on systemic chemotherapy concurrent whole brain radiotherapy for brain metastases from non-small cell lung cancer / 国际肿瘤学杂志

Objective To explore the feasibility and safety of systemic chemotherapy concurrent whole brain radiotherapy (WBRT) for non-small cell lung cancer (NSCLC) with brain metastases.Methods Eighty cases of NSCLC patients with brain metastases were divided into observation group (40 cases) and the control group (40 cases) according to random number table.Patients were given systemic chemotherapy synchronous WBRT or sequential WBRT.Results The Ⅰ-Ⅳ degree leukocytopenia incidences of the two groups were 12.5％,25.0％,25.0％,0.0 and 30.0％,25.0％,12.5％,15.0％,and there was statistical significance (x2 =12.12,P ＜ 0.05).In the observation group,the total remission rate was 20％ (8/40),and it was 22.5％ (9/40) in the control group,with no significant difference (x2 =1.79,P ＞ 0.05).The median progression free survival of the observation group and of the control group were (3.5 ± 2.3) months and (3.6 ±1.1) months,respec-tively,with no significant difference (t =5.23,P ＞ 0.05).But the 1-years survival rate in the observation group was 37.5％ (15/40),significantly higher than that in the control group (17.5％,7/40),which had statistical significance (x2 =9.11,P ＜ 0.05).Conclusion The safety of systemic chemotherapy synchronous WBRT for NSCLC patients with brain metastases is higher,with good curative effect and strong application feasibility.

Genome-wide screening of CpG island methylation changes induced by low-dose X-ray radiation in mice / 南方医科大学学报

<p><b>OBJECTIVE</b>To study the methylation changes in promoter CpG islands induced by low-dose X-ray radiation (LDR).</p><p><b>METHODS</b>Twenty male BALB/c mice were randomly divided into control and fractionated radiation group exposed to 6 MV X-ray for 10 days (0.05 Gy/day). All the mice were sacrificed 2 h after the last radiation on day 10, and blood samples were collected for detecting DNA methylation changes using Roche-NimbleGen mouse DNA methylation 3×720K Promoter Plus CpG Island Array. MeDIP-qPCR was used to further validate the methylation status of specific genes.</p><p><b>RESULTS</b>A total of 811 genes were found to show specific hypermethylation in fractional radiation group as compared with the control group, involving almost all the main biological processes by GO analysis. Eight candidate genes (Rad23b, Tdg, Ccnd1, Ddit3, Llgl1, Rasl11a, Tbx2, and Slc6a15) were confirmed to be hypermethylated in LDR samples by MeDIP-qPCR, consistent with the results of the methylation chip study.</p><p><b>CONCLUSION</b>LDR induces promoter hypermethylation on specific genes, which may contribute to radiation-induced pathogenesis.</p>

Protective effects of EGCG against methylation changes induced by low dose radiation / 中华放射医学与防护杂志

Objective To investigate the role of epigallocatechin gallate ( EGCG) in reversing the CpG island methylation of Rad23b and Ddit3 gene promoter and its mRNA expression induced by 0?5 Gy X-rays. Methods Thirty BALB/c male mice were randomly divided into 6 groups: control group, irradiation group, low/high dose of EGCG group, low/high dose of EGCG with irradiation group. For the irradiation group, mice were fractionally exposed with 6 MV X-rays for 10 d (0?05 Gy/d × 10 d). 2 hours after the final irradiation, all mice were killed and such tissues as blood, kidney, liver, spleen, brain, and lung were collected. Methylation and expression levels of Rad23b and Ddit3 were measured by bisulfate sequencing primers ( BSP) and Real-time PCR, respectively. Results Compare to the control group, Rad23b was hypermethylated in PBMC, liver, spleen, brain and lung (t= -20?19, -14?80, -12?05,-28?42, -12?58, P<0?05) in the irradiation group. Meanwhile, its mRNA expression level was down-regulated in PBMC, liver, brain and lung (t=25?25, 17?43, 11?53, 22?85, P<0?05). Similarly, a significant hypermethylation change of Ddit3 was observed in PBMC, liver and lung after irradiation ( t=-52?89, -20?31, -3?85, P<0?05) so that the mRNA expression of Ddit3 decreased in PBMC and liver ( t = 11?89, 16?52, P < 0?05 ). Compared to the irradiation group, EGCG with different concentrations of 10, 20 mg/kg significantly reduced the methylation level of Rad23b and Ddit3 ( t =-13?39-7?99, P<0?05), and induced re-expression of mRNA (t= -34?02 - -2?89, P<0?05). This change was more notable in the irradiation group with the high dose of EGCG. Conclusions As a natural drug, EGCG may play an important role in affecting DNA methylation and hence protects DNA from radiation damage.

Genome-wide DNA methylation changes induced by low dose radiation in mouse / 中华放射医学与防护杂志

Objective To study the whole genome DNA methylation changes induced by low dose radiation (LDR) in mouse,and mRNA expression profiles of DNMT1 and MBD2 in peripheral blood mononuclear cell (PBMC) and tissues.Methods Thirty male BALB/c mice were randomly divided into 3 groups:control,single exposure (0.5 Gy),and fractionated exposure of 6 MV X-rays for 10 d (0.05 Gy/d × 10 d).Control mice were sham-treated.To determine the immediate (early) effect of irradiation,15 mice (5/group) were sacrificed 2 h after the last irradiation.The other 15 mice were sacrificed 1 month after the last irradiation (delayed effect).Before sacrifice,blood was sampled immediately.Kidney,liver,spleen,brain and lung tissues were collected.A global DNA methylation quantification Kit and highperformance liquid chromatography (HPLC) were used to investigate the methylation level in blood DNA.The expressions of DNMT1 and MBD2 were determined by RT-PCR.Results For the early effects of irradiation,as compared with controls,fractionated exposure to X-ray irradiation led to the significant depression of global DNA methylation level in blood (t =10.19 and 8.93,P ＜ 0.05).DNMT1 and MBD2 mRNA were down-regulated in PBMC,kidney and liver (t =5.06,3.01,3.97,12.25,3.50 and 3.73,P ＜0.05),and MBD2 was also down-regulated in spleen (t =3.03,P ＜ 0.05).However,no changes were observed in single exposed group.As for the delayed effects,the methylation levels of blood were not changed in the single or fractionated exposed groups,and only MBD2 mRNA was down-regulated in PBMC and brain of fractionated exposed group (t =3.52 and 2.85,P ＜ 0.05).Conclusions Fractionated LDR exposure can induce genome DNA hypomethylation,which is tissue-specific,and may be related with down-regulation of DNMT1 and MBD2.

Effects of Chinese herbal medicine Yiqi Huayu Recipe on apoptosis of dorsal root ganglion neurons and expression of caspase-3 in rats with lumbar nerve root compression / 中西医结合学报

To observe the effects of Yiqi Huayu Recipe, a Chinese compound herbal medicine, on apoptosis of dorsal root ganglion (DRG) neurons and expression of caspase-3 in rats after lumbar nerve root compression injury.

Renal Trauma :CT Diagnosis and Its Clinical Value / 实用放射学杂志

Objective To evaluate the clinic value of CT in diagnosis and classification of renal trauma.Methods 78 cases of renal trauma were analyzed retrospectively.Results Based on CT manifestations,the renal trauma could be divided into Ⅳ types;Ⅰ type,rupture of kidney in 36 cases;Ⅱ type,subcapsular hematoma in 28 cases ;Ⅲ type,broken kidney in 16 cases;Ⅳ type,single hematoma around the kidney in 2 cases.The conservative treatment was used for Ⅰ type and Ⅱ type.Ⅲ type underwent surgical operation.Conclusion The definitive diagnosis and classification of renal trauma can be made by CT,and that can provide significant value in planning surgical treatment

Methylation status of DLEC1 promoter in colorectal cancer patients and its clinical relevance / 第二军医大学学报

Objective To detect the methylation status of DLEC1 promoter in the tissue and serum of colorectal cancer(CRC) patients and to evaluate its clinical relevance.Methods Genomic DNA was extracted from the tissues(cancer tissue and corresponding adjacent normal tissue) and sera of 71 CRC patients;serum genomic DNA was also obtained from 20 patients with benign gastrointestinal diseases and 20 healthy donors.Promoter methylation status of DLEC1 gene was detected by methylation-specific polymerase chain reaction(MSP).Results The incidence of aberrant methylation of DLEC1 promoter was 45.1%(32/71) in CRC tissues,which was significantly higher than that in the adjacent normal tissues(7.1%,4/56)(P

Effect of ginsenosides from Panax ginseng on proliferation of human osteosarcoma cell U_2OS / 中草药

Object To find out which of the 27 ginsenosides isolated from Panax ginseng C A Mey that may inhibit the proliferation of human osteosarcoma cell line U 2OS Methods Effects of each individual ginsenoside on the proliferation of U 2OS cell were studied by determining the viability of cancer cells during culture with or without the presence of the test compound DNA assay was determined by flow cytometry Results Ginsonosides Ro, Rh 1, Rh 2, F 1 and L 8 at concentrations of 5 ?mol/L could obviously suppress the proliferation of U 2OS cells while ginsenosides Rg 1, F 3, Rf, PPT and PT significantly inhibited the cancer cells Flow cytometry revealed that ginsenosides Ro, Rg 1, Rf, F 1, Rh 2 ,PPT and PT induced cell cycle arrest at G 0/G 1 phase with obvious decrease of cell count at S and G 2+M phase Moreover, ginsenosides Rf 1, Rg 1, F 1 and PPT induced significantly high rates of cell death as compared with the control Conclusion These data suggested that ginsenosides inhibited U 2OS proliferation via cell cycle arrest or induction of cell death