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Effects of lentiviral vector-mediated RNA interference of hypoxia inducible factor-1α on the expression of related genes in human pancreatic cancer Patu8988 cells

Guanglei FAN ; Minbin DENG ; Yiwei WU ; Qixian YANG ; Bin ZHANG ; Longbao XU

Chinese Journal of Nuclear Medicine and Molecular Imaging.2013;33(5):377-380. doi:10.3760/cma.j.issn.2095-2848.2013.05.015

Objective To investigate the inhibitory effect of the lentiviral vector (LV)-mediated RNA interference (RNAi) targeting HIF-1α on the expression of HIF-1α and Glut-1 in human pancreatic cancer Patu8988 cells.Methods The RNAi targeting HIF-1α was combined to LV,and transfected into Patu8988 cells.The Patu8988 cells transfected with the empty vector and exposed to 0.5％ O2 for 4 h served as hypoxia negative control,the Patu8988 cells not transfected with vector and exposed to 0.5％ O2 for 4 h as hypoxia blank control,and the Patu8988 cells transfected with LV-RNAi-HIF-1α and exposed to 0.5％O2 for 4 h as experimental group.The expression of HIF-1α was measured by RT-PCR and Western blot respectively.The expression of Glut-1 was measured by RT-PCR.Each group was compared according to oneway analysis of variance and two-sample t test.Results After transfection with LV-RNAi-HIF-1α,HIF-1α mRNA expression decreased by 65.1％ (0.209/0.321) and 80.6％ (0.791/0.982) (t=10.52,15.24,both P＜0.05) under normoxia and hypoxia conditions,meanwhile with the empty vector,HIF-1α mRNA expression decreased by 0.6％ (0.002/0.321) and 7.2％ (0.071/0.982) (t =5.26,7.38,both P＜0.05).Under hypoxia conditions,the protein of HIF-1α in experimental group cells (0.159±0.010) was down-regulated obviously compared to the negative control group (0.745± 0.012) and the blank control group (0.711 ± 0.023)(F=35.52,t =6.72,10.56,all P＜0.05).The expression of Glut-1 mRNA in experimental group cells (0.040±0.003) decreased obviously compared to the negative control group (0.054±0.003) and blank control group (0.062±0.004) (F=35.28,t=5.94,8.55,all P＜0.01).Conclusion Gene silencing of HIF-1α using LV-mediated RNAi can inhibit the expression of HIF-1α and decrease the expression of Glut-1mRNA in Patu8988 cells.

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Enhancement of 131I therapeutic efficacy on differentiated thyroid cancer by nuclear factor-κB inhibitor in nude mice

Zhaowei MENG ; Qiang JIA ; Shen WANG ; Jian TAN

Chinese Journal of Nuclear Medicine and Molecular Imaging.2013;(2):129-133. doi:10.3760/cma.j.issn.2095-2848.2013.02.008

Objective To study whether Bay 11-7082,a nuclear factor-kappa B (NF-KB) inhibitor,could enhance the treatment efficacy of 131I on DTC in nude mice.Methods Total thyroid ablation nude mice models were prepared by intraperitoneal injection of 37 MBq 131I.The xenografted mice were divided into4 groups (18/group):131I group,Bay 11-7082 group,combination of 131I and Bay 11-7082 group and control group.Drug dosages were given as:intraperitoneal injection of 37 MBqT31I on day 1 in the 7th week in the 131I group; intraperitoneal injection of 10 mg/kg Bay 11-7082 on day 1,2 and 3 in the 7th week in the Bay 11-7082 group; intraperitoneal injection of both 131I and Bay 11-7082 as above-mentioned in the combined treatment group; injection of saline in the control group.The xenografted tumor volume curves were drawn every 7 days.Pertechnetate imaging was performed before thyroid ablation.Post-ablative and post-therapeutic 131I whole body imaging was conducted.On day 7 in the 7th week,6 mice in each group were sacrificed and apoptotic staining was performed on excised xenograft tumors.Apoptosis index was determined as positive cells over total ceils × 100％.One-way analysis of variance and q test were performed for statistical analysis.Results Thyroid and stomach could be visualized on pertechnetate imaging before thyroid ablation.Post-ablative 131I imaging showed increased uptake by the thyroid gland.Post-therapeutic 131I imaging showed increased uptake by the malignant tumor lesions in both the 131I and combined groups.Tumor volume curves showed significant differences in volume changes among different methods of therapy from the end of the 8th week (F =11.91-246.56,all P ＜ 0.01).Combined treatment was more effective than single-therapies (q =3.36-14.99,all P ＜ 0.01).Apoptosis indices for the control group,131I group,Bay 11-7082 group and combined group were (0.28 ±0.15)％,(5.49 ±0.69)％,(6.82 ±0.72)％ and (16.21 ± 1.57) ％,respectively (F =304.40,P ＜ 0.01).Apoptosis index in the combined group was significantly higher than those in each single therapy group (q =15.33 and 13.33,both P ＜ 0.01).Conclusion NF-κB inhibition by Bay 11-7082 could effectively enhance the treatment efficacy of 131I on DTC.

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Application of 13N-NH3 PET in the evaluation of hypometabolic brain lesions on 18F-FDG PET

Zhifeng CHEN ; Weian CHEN ; Dianchao YUE ; Xiaoyan WANG ; Xiangsong ZHANG ; Xinchong SHI

Chinese Journal of Nuclear Medicine and Molecular Imaging.2013;(2):146-149. doi:10.3760/cma.j.issn.2095-2848.2013.02.012

Objective To investigate the usefulness of 13N-NH3 PET in detecting brain lesions which show hypometabolism on 18F-FDG PET.Methods 13N-NH3 PET imaging was performed for a prospective study in 18 patients with brain lesions that showed hypometabolism compared with normal brain tissue on 18F-FDG PET scans.Fourteen patients underwent 18 F-FDG PET imaging for initial diagnosis and 4 patients for detection of astrocytoma recurrence (13 males,5 females,age 20-68 (42.4 ± 12.6) years).Ten gliomas,1 metastatic tumor,1 dysembryoplastic neuroepithelial tumor (DNT) and 6 non-neoplastic lesions (including 3 cases of radiation necrosis,2 cases of encephalitic foci,and 1 case of ischemic lesion)were verified by histopathological examination (n =13) or clinical follow-up (n =5).The tumor-to-contralateral brain tissue ratios (T/C) were calculated by the ROI method.The diagnostic efficacy of 13N-NH3 PET was evaluated.Paired t test and two-sample t test were performed to analyze the differences of T/C between different groups.Results Seven (5 astrocytomas and 2 glioblastomas) of 12 brain tumors (sensitivity:58％,7/12) showed increased 13N-NH3 uptake (higher uptake than the contralateral brain tissue),while 3 low-grade gliomas,1 metastatic tumor,and 1 DNT showed decreased 13N-NH3 uptake (no uptake or lower uptake than the contralateral brain tissue).The uptake ratio of 13N-NH3 was significantly higher than that of 18 F-FDG (1.24 ± 0.66 vs 0.67 ± 0.24,t =-3.740,P ＜ 0.05) in the tumors.All six non-neoplastic lesions showed decreased 13N-NH3 uptake (specificity:6/6).The T/C ratios of 18F-FDG and 13N-NH3 in the non-neoplastic lesions were 0.68 ±0.15 and 0.70 ±0.19,respectively,and there was no significant difference between them (t =-0.246,P ＞ 0.05).The T/C ratio of 13N-NH3 in the tumors was significantly higher than that in the non-neoplastic lesions (1.24 ± 0.53 vs 0.70 ± 0.19,t =2.624,P ＜ 0.05).Conclusion 13N-NH3 PET imaging may be helpful to detect and differentiate brain tumors with hypometabolism as detected by 18 F-FDG PET imaging from non-neoplastic lesions with high specificity,especially for cerebral astrocytomas,but the sensitivity is relatively limited.

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The value of diagnosing kidney neoplasms with 18F-FDG PET/CT

Jianhua SONG ; Jinhua ZHAO ; Xiang CHEN ; Yan XING

Chinese Journal of Nuclear Medicine and Molecular Imaging.2013;(3):184-187. doi:10.3760/cma.j.issn.2095-2848.2013.03.007

Objective To explore the clinical diagnostic value of 18 F-FDG PET/CT in patients with kidney neoplasms.Methods Seventy-nine patients (52 males,27 females,average age (57.3 ± 14.1) years),who had definitive diagnosis of kidney neoplasms by 18F-FDG PET/CT and pathological or clinical comprehensive diagnosis in recent five years,were analyzed retrospectively.The diagnosis by PET/CT was made according to the changes of kidney shape,tumor density and FDG uptake (SUVmax).The diagnostic efficacy was calculated.Results Among the 79 patients,70 cases were finally diagnosed as malignant tumors (including 40 cases of renal cell carcinoma,5 cases of renal pelvis carcinoma,8 cases of lymphoma,16 cases of metastatic tumor,and 1 case of renal fascia capsule liposarcoma) and 9 cases of benign tumors (including 7 cases of angiomyolipomas,1 case of renal acidophilic cell adenoma,1 case of metanephric adenoma; the benign tumors did not contain small lipid sample hamartoma cases).The detective rate of kidney neoplasms with 18F-FDG PET/CT was 97.5％ (77/79).For the identification of benign and malignant lesions,the sensitivity of 18F-FDG PET/CT was 92.9％ (65/70),specificity was 7/9,accuracy was 91.1％ (72/79),positive predictive value was 97.0％ (65/67),and negative predictive value was 58.3 ％ (7/12).Conclusions 18 F-FDG PET/CT can detect and identify most of kidney tumors.Whole-body checking and comprehensive evaluation on kidney cancer patients are still the main advantages of PET/CT.

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Value of SPECT/CT imaging for follow-up of bone metastases

Ke DONG ; Hongcheng SHI ; Jiang LIU ; Yiqiu ZHANG ; Shuguang CHEN ; Liang CAI

Chinese Journal of Nuclear Medicine and Molecular Imaging.2013;(3):199-202. doi:10.3760/cma.j.issn.2095-2848.2013.03.011

Objective To retrospectively evaluate the value of SPECT/CT imaging for follow-up of bone metastases.Methods A total of 178 patients with bone metastases (387 lesions) underwent 2 or more events of whole-body bone scintigraphy (WBS) and SPECT/CT imaging.Sequential images were analyzed by 2 experienced,nuclear medicine physicians.Each lesion was interpreted as progressive,remissive or stable in WBS or SPECT/CT independently.Reasons for the discordance between WBS and SPECT/CT results were analyzed.The results of clinical follow-up,including clinical symptoms,tumor markers,serum ALP,radiograph,CT and MRI,were likewise classified as progressive,remissive or stable.The x2 test was used to compare the differences between the two imaging methods.Results The follow-up results of the two imaging methods were consistent in 313 (80.88％,313/387) lesions,including 208 in progression and 105 in remission or stable condition.Among the 74(19.12％,74/387) lesions showing discordance,48 showed remission or stable conditions on WBS but progression on SPECT/CT (64.86％,48/74) ; while 26 showed progression on WBS but remission or stable condition on SPECT/CT (35.14％,26/74).There was a statistically significant difference of the follow-up results between WBS and SPECT/CT (x2 =6.54,P ＜0.05).Conclusion SPECT/CT is more valuable than WBS for follow-up of bone metastases.

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Significance of CEA, CA15-3 and biochemical markers of bone turnover in the diagnosis of bone metastasis from breast cancer

Guanglei FAN ; Renming WAN ; Mingya PENG ; Yufen LUAN ; Jun ZHAO ; Jianwen LIU ; Longbao XU

Chinese Journal of Nuclear Medicine and Molecular Imaging.2013;(3):203-206. doi:10.3760/cma.j.issn.2095-2848.2013.03.012

Objective To evaluate the significance of tumor markers CEA and CA15-3,and biochemical markers of bone turnover (total procol]agen type Ⅰ amino-terminal propeptide (TP I NP),β-isomerized carboxyterminal propeptide (β-CTx),ALP and PTH) in the diagnosis of bone metastasis from breast cancer.Methods A total of 78 patients (all females) with mean age (56.72 ± 10.76) years,who were diagnosed with breast cancer,were included in this study.The patients were divided into two groups based on radionuclide bone imaging:with bone metastasis (n =32) and without bone metastasis (n =46).The serum concentrations of CEA,CA15-3,TP I NP,[β-CTx,PTH,ALP were measured.Gleason scores were evaluated.The diagnostic value was evaluated by ROC curve.The two groups were compared using two-sample t test.The correlations between bone metastasis and tumor markers,bone metastasis and biochemical markers of bone turnover were analyzed with Pearson correlation and logistic analysis.Results The serum levels of CEA,CA15-3,TPINP,β-CTx,PTH and ALP were significantly higher in the group with bone metastasis than those in the group without bone metastasis (t:4.16-7.56,all P ＜ 0.05).For the diagnosis of bone metastasis from breast cancer,the AUC of CEA,CA15-3,TPINP,[β-CTx,PTH and ALP was 0.815,0.887,0.869,0.852,0.844,0.731,respectively.Using the cut-off values of 4.18 μg/L for CEA,0.04 U/L for CA15-3,49.70 μg/L for TP I NP,0.47 pg/L for β-CTx,54.90 ng/L for PTH and 49.90 U/L for ALP,the sensitivities were 56.3％ (18/32),75.0％ (24/32),78.1％ (25/32),81.3％ (26/32),78.1％ (25/32),68.8％ (22/32) and the specificities were 80.4％ (37/46),84.8％ (39/46),76.1％ (35/46),78.3％ (36/46),69.6％ (32/46),58.7％ (27/46),respectively.CEA,CA15-3,TPINP,β-CTx,PTH,ALP and Gleason score were positively correlated with the presence of bone metastasis (r:0.267-0.636,all P ＜ 0.05).CEA,CA15-3,TP I NP,β-CTx,PTH and Gleason score were independent predictors for bone metastasis of breast cancer (odds ratios:2.45,3.44,1.24,1.54,1.11,2.22,all P ＜0.05).The total coincidence rate of regression model was 81.3％ (26/32) in patients with bone metastasis.Conclusions The diagnostic values of CEA,CA15-3,TP I NP,β-CTx and PTH are comparable.Combined use of these parameters may be helpful for the early diagnosis of bone metastasis from breast cancer.

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Synergistic effects of nuclear factor-kappa B inhibition by small interferece RNA on 131I therapy in differentiated thyroid cancer cells

Yajing HE ; Zhaowei MENG ; Jian TAN

Chinese Journal of Nuclear Medicine and Molecular Imaging.2013;(3):207-212. doi:10.3760/cma.j.issn.2095-2848.2013.03.013

Objective To study the effect of nuclear factor-kappa B (NF-κB) inhibition by small interference RNA (siRNA) on the apoptosis of DTC cells treated by 131 I.Methods DNA binding assay was performed at 24 h after 131I treatment (2 × 104 MBq/L) on KTC-1 cells.The cell survival assay was conducted at 48 h after 131 I treatment.Western blot was used to detect the changes of NF-κB p65 at 6 h after 131I treatment,and the changes of anti-apoptotic factors and apoptotic key factors at 24 h after 131 I treatment.The anti-apoptotic factors included in this study were X chromosome-linked inhibitor of apoptosis (XIAP),cellular inhibitor of apoptosis 1 (cIAP1) and B-cell lymphoma extra large (Bcl-xL),and the apoptotic key factors were caspase 3 and poly-ADP-ribose polymerase (PARP).A total of 4 groups were studied for the detection of p65 and anti-apoptotic factors by Western blot:no oligonucleotide transfection control group (A),no oligonucleotide transfection + 131I group (B),scrambled oligonucleotides transfection + 131I group (C) and p65 siRNA transfection + 131I group (D).Another 6 groups of studies were:oligonucleotide transfection control group (1),scrambled oligonucleotides transfection group (2),p65 siRNA transfection group (3),no oligonueleotide transfection + 131I group (4),scrambled oligonucleotides transfection +131I group (5) and p65 siRNA transfection + 131I group (6).One-way analysis of variance and q test were performed for statistical analysis.Results The results of DNA binding assays for the 6 groups (1,2,3,4,5,6) were (100.00 ± 11.65)％,(96.00 ± 17.98)％,(9.28 ±5.01)％,(322.72 ±50.81)％,(311.36 ±44.81)％ and (36.96 ± 15.66)％,respectively (F =137.74,P ＜0.01).NF-κB functions were strengthened with 131 I treatment (qgrouo 4∶1 =10.90,qroup 5∶2 =11.38,both P ＜ 0.01).However,NF-κB p65 siRNA transfection could inhibit NF-κB functions (qgroup1∶3 =18.25,qgroup4∶6 =13.71,both P ＜0.01).Cell survival rates of the 6 groups were (100.00 ± 11.65)％,(96.32 ± 9.44)％,(70.88 ±7.41)％,(64.16 ±9.50)％,(62.24 ±9.37)％ and (28.64 ±6.74)％ (F=52.76,P＜0.01).There were significant differences between groups 3 and 6,groups 4 and 6 (q =10.76 and 7.79,both P ＜ 0.01).Western blot results showed that the expression of NF-κB p65 in the 4 groups (A,B,C,D) were (56.60 ±7.37)％,(111.07 ± 13.31)％,(113.16± 15.04)％ and (12.46 ±2.74)％,respectively (F=60.17,P ＜ 0.01).The t65 levels increased with 131 I treatment (qgroup B∶A =6.20,qroup c∶ A =5.85,both P ＜0.01); while decreased significantly using NF-κB p65 siRNA transfection (qgroup B:D =-12.57; qgroupC∶D =11.41,both P ＜ 0.01).Western blot results showed that XIAP,cIAP1 and Bcl-xL in the 4 groups were (17.59±1.96)％,(16.45± 1.85)％ and (19.92 ±2.22)％; (98.37± 17.92)％,(109.81 ±19.16)％ and (95.59 ±22.20)％ ; (98.43 ±18.71)％,(98.86± 15.88)％ and (100.99 ±21.70)％ ;(7.00 ± 0.95) ％,(5.86 ± 0.35) ％ and (9.52 ± 0.90) ％,respectively (F =44.22,56.51 and 29.11,all P ＜ 0.01).131 I treatment induced higher expression of all the 3 genes (qgroup B∶ A =7.76,8.40 and 5.88,all P ＜0.01),while NF-κB p65 siRNA transfection,on the contrary,reduced the expression of all the 3 genes (qgroupB:D =8.82,9.40 and 6.71,all P ＜0.01).There were significant differences of p19,p17,p116 and p89 in the 6 groups(F =39.03,48.45,32.56,52.20,all P ＜ 0.01),especially among group 3,4 and 6 (q =3.18-9.98,all P ＜ 0.05).Conclusions 131I could activate NF-κB function and enhance the expressions of anti-apoptotic factors.NF-κB p65 siRNA transfection could effectively suppress this effect and therefore magnify 131I induced apoptosis in DTC cells.

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An investigation of a coincidence detection system for an all-digital small animal PET scanner

Wei LIU ; Yuanbao CHEN ; Anwen LONG ; Xin CHEN ; Zhongyi WU ; Yongxue ZHANG ; Qingguo XIE

Chinese Journal of Nuclear Medicine and Molecular Imaging.2013;(3):223-225. doi:10.3760/cma.j.issn.2095-2848.2013.03.016

Objective To investigate and design a coincidence detection system for an all-digital small animal PET scanner and evaluate its preliminary performance properties.Methods This coincidence module adopted a coincidence identification mode based on singles data in list-mode.Using digital signal processing technology,energy calibration,crystal identification,timing alignment and coincidence events extraction were performed on singles data in list-mode.The obtained data could be used for image reconstruction.Results The 13 × 13 crystal array was well recognized by the position histogram of one lutetium yttrium orthosilicate (LYSO) crystal block.In the coincidence timing histogram of the micro-Derenzo phantom,1.36 ns full width at half maximum was obtained.The rods with a diameter of 1.2 mm were clearly displayed in the reconstructed image of the micro-Derenzo phantom.Conclusion The coincidence module can provide satisfactory performance to meet the design needs of an all-digital small animal PET scanner.

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The variables in normalizing glomerular filtration rate

Fei LI ; Hongwei SI ; Jianhua GENG ; Shengzu CHEN

Chinese Journal of Nuclear Medicine and Molecular Imaging.2013;(3):238-240. doi:10.3760/cma.j.issn.2095-2848.2013.03.023

Normalizing GFR with variables is important for non-cancer patients,especially for kidney donors.The most frequently evaluated variables are body surface area (BSA),extracellular fluid volume (ECV) and lean body mass (LBM).It is difficult to accurately quantify BSA and the power of BSA normalization decreases in children and obesity population.The ECV normalization is suitable for healthy children,but its clinical value decreases in patients with damaged renal function.The LBM can be accurately measured and has a larger serviceable range in the normalization.Although the influence factors of LBM should be extensively evaluated,the available data indicate that LBM is more suitable in the normalization of GFR than BSA and ECV.

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The influence of position deviation on RAIU and the corresponding therapeutic dose calculations in patients with Graves hyperthyroidism

Congxin LI ; Juanjuan SONG ; Jiantao BA ; Yansong LIN

Chinese Journal of Nuclear Medicine and Molecular Imaging.2013;(2):116-119. doi:10.3760/cma.j.issn.2095-2848.2013.02.004

Objective To evaluate the influence of inappropriate position deviation on radioactive iodine uptake (RAIU),effective half-life (Teff) and the corresponding dose variances in patients suffering from Graves hyperthyroidism.Methods RAIU was examined in 20 patients with Graves hyperthyroidism (7 males,13 females,average age (46.60 ±9.55) years) 2,4,6,and 24 h after intake of the radioiodine capsule.A scintillation probe was positioned at the center of the inferior edge of the thyroid cartilage 25 cm away for 2 min,which was defined as the standard manipulation (test 1).Then,the probe was moved either 5 cm backward (test 2) or 5 cm higher (test 3) compared with test 1.Variants of RAIU,Teff as well as dose calculations were acquired by different combinations (CⅠ-Ⅸ) of 4 h and 24 h-RAIU,according to the above 3 manipulations (C Ⅰ-Ⅲ:test 1 for RAIU4 h,test 1,2,3 for RAIU24 h respectively ; C Ⅳ-Ⅵ:test 2 for RAIU4h,test 1,2,3 for RAIU24h respectively; CⅦ-Ⅸ:test 3 for RAIU4h,test 1,2,3 for RAIU24h respectively).Paired t test was used to compare the statistical differences between C H-Ⅸ to C Ⅰ.Results RAIU24 h of test 2 (68.08％ ± 7.88％) and test 3 (62.18％ ± 7.45％) were significantly lower than that of test 1 (78.05％ ± 8.31％ ;t =12.15,14.37,respectively,both P ＜ 0.01).Teffs of C Ⅱ (4.42 ± 0.73) d,CⅢ(3.76 ±0.53) d,CⅤ(5.59 ±0.46) d,CⅥ(4.47 ±0.44) d,CⅧ(5.94 ±0.54) d and CⅨ (5.45 ±0.66) d were significantly different from that of C Ⅰ (5.04 ±0.56) d which was defined as standard (t:3.86-13.64,all P ＜0.01).Among the 180 131I dose values calculated by different Teff and RAIU values induced from C Ⅰ-Ⅸ combinations,74.4％ (119/160) were over-calculated while 9.4％ (15/160) were under-calculated.Taking one patient as an example,the changes of RAIU24 h (decreased up to 26.0％) and the percentage of Teff deviation(66.9％,ranged from-47.5％ to 19.4％)led to an over-calculated 131 I dosage by as high as 129.8％ compared with CⅠ.Conclusions Incorrect positioning in RAIU detection could result in various false RAIU,Teff and 131I dose calculations.Such deviations could possibly exert an impact on the patients' therapeutic outcomes,thus influencing the efficacy of the iodine therapy.Optimization of RAIU positioning is essential for clinical practice to guarantee radioiodine dose management.

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