RITA selectively inhibits proliferation of BAP1-deficient cutaneous melanoma cells in vitro / 南方医科大学学报

OBJECTIVE@#To screen for small molecular compounds with selective inhibitory activity against cutaneous melanoma cells with BAP1 deletion.@*METHODS@#Cutaneous melanoma cells expressing wild-type BAP1 were selected to construct a BAP1 knockout cell model using CRISPR-Cas9 system, and small molecules with selective inhibitory activity against BAP1 knockout cells were screened from a compound library using MTT assay. Rescue experiment was carried out to determine whether the sensitivity of BAP1 knockout cells to the candidate compounds was directly related to BAP1 deletion. The effects of the candidate compounds on cell cycle and apoptosis were detected with flow cytometry, and the protein expressions in the cells were analyzed with Western blotting.@*RESULTS@#The p53 activator RITA from the compound library was shown to selectively inhibit the viability of BAP1 knockout cells. Overexpression of wild-type BAP1 reversed the sensitivity of BAP1 knockout cells to RITA, while overexpression of the mutant BAP1 (C91S) with inactivated ubiquitinase did not produce any rescue effect. Compared with the control cells expressing wild-type BAP1, BAP1 knockout cells were more sensitive to RITA-induced cell cycle arrest and apoptosis (P < 0.0001) and showed an increased expression of p53 protein, which was further increased by RITA treatment (P < 0.0001).@*CONCLUSION@#Loss of BAP1 results in the sensitivity of cutaneous melanoma cells to p53 activator RITA. In melanoma cells, the activity of ubiquitinase in BAP1 is directly related to their sensitivity to RITA. An increased expression of p53 protein induced by BAP1 knockout is probably a key reason for RITA sensitivity of melanoma cells, suggesting the potential of RITA as a targeted therapeutic agent for cutaneous melanoma carrying BAP1-inactivating mutations.

Thyroid abnormalities and influencing factors in medical radiology workers in Guangdong Province / 环境与职业医学

Background The thyroid gland is one of the organs sensitive to ionizing radiation, and there are few studies on the effects of long-term exposure to low doses of ionizing radiation on the thyroid gland of radiation workers. Objective To investigate thyroid abnormalities in workers in medical radiology departments in Guangdong Province and to identify potential influencing factors of thyroid abnormalities. Methods A total of 1657 radiation workers from 48 hospitals in Guangdong Province were selected as survey subjects using convenience sampling, and their personal dose monitoring results and health examination information were retrospectively analyzed to determine the factors affecting thyroid abnormalities. Results The M (P25, P75) of thyroid absorbed dose (DT) was 1.55 (0.65, 3.96) mGy in the 1657 investigated workers. The attribute-specific medians of DT were 1.29, 1.38, 1.99, and 3.51 mGy for departments of diagnostic radiology, interventional radiology, radiotherapy, and nuclear medicine, respectively; and 1.10, 1.55, and 1.80 mGy for job titles of nurse, technician, and physician, respectively. Differences in DT by gender, age, years of radiological work, age of radiation exposure onset, occupational category, and job title were statistically significant (Z=−6.35, H=708.52, 918.20, 31.19, 95.64, 39.28, P<0.05). The positive rate of thyroid abnormalities in investigated workers was 46.53% (771/1657). Among them, the positive rate of abnormal thyroid function was 22.87% (379/1657), that of abnormal thyroid morphology was 33.98% (563/1657), and that of thyroid nodule was 26.55% (440/1657). The differences in thyroid abnormality rates by gender, age, years of radiation work, age of radiation exposure onset, DT, and job title of radiation workers were statistically significant (χ2=51.89, 49.64, 20.54, 18.29, 12.07, 16.16, P<0.05). The differences in abnormal thyroid function positive rate by gender, age of radiation exposure onset, and job title were statistically significant (χ2=26.21, 6.21, 8.32, P<0.05). The differences in the positive rates of abnormal thyroid morphology and nodules were statistically significant by gender, age, years of radiological work, age of radiation exposure onset, DT, and job title (abnormal thyroid morphology, χ2=40.24, 64.17, 37.63, 15.17, 19.28, 15.05; nodules, χ2=31.41, 77.98, 42.11, 19.16, 21.70, 13.52, P<0.05). The positive rates of thyroid abnormality, thyroid morphology abnormality, and nodules all showed a linear increasing trend with increasing age, years of radiation work, and age of radiation exposure onset (P<0.05). The results of logistic regression analysis indicated that the factors influencing thyroid abnormalities were female (OR=2.17, 95%CI: 1.72-2.74), increased years of radiological work (OR=1.04, 95%CI: 1.03-1.06), onset of radiation exposure in age groups of 30-34 and ≥35 years (OR=1.63, 95%CI: 1.12-2.37; OR=2.58, 95%CI: 1.74-3.29), and working in department of diagnostic radiology (OR=1.40, 95%CI: 1.07-1.84). Conclusion Long-term exposure to low doses of ionizing radiation has an effect on thyroid abnormalities in medical radiation workers. Among them, being female, physicians, and working in department of diagnostic radiology are at a higher risk of abnormal thyroid function; being female, increased years of radiation work, and radiation exposure onset at age ≥30 years are associated with a higher risk of reporting abnormal thyroid morphology.

Analysis of influence factors for lens abnormality for medical radiation workers in Guangdong province / 中华放射医学与防护杂志

Objective:To investigate the exposure level of ionizing radiation in medical radiation workers in Guangdong province, as well as their abnormality in the lens of the eye, and to analyze associated influence factors.Methods:In this study, 1 501 radiation workers from 60 hospitals were selected by using convenient sampling method for retrospecotive analysis of absorbed doses ( DL) to the lens of the eye, health examination information and the relevant influence factors. Results:The median value M and the 25 th and 75 th percentile values ( P25, P75)of the distribution of absorbed doses were 4.86, 2.99 and 7.90 mGy, respectively. The median values for male and female were 5.14 and 3.94 mGy, respectively. The median values for the Levels I, Ⅱ and Ⅲ medical institutions were 2.95, 3.51 and 5.06 mGy, respectively. The median values were radiotherapy 4.05 mGy, radiodiagnosis 4.84 mGy, interventional radiology 5.39 mGy and nuclear medicine 6.71 mGy, as well as nurses 3.48 mGy, physicians 5.03 mGy and technologists 5.03 mGy, respectively. There were statistically significant differences in dose distribution for different gender, age, length of radiation service, age at the beginning of radiation exposure, level of medical institution, occupational category and post ( Z=-6.72, H=389.64, 511.17, 70.29, 53.29, 49.06, 39.89, P<0.05). The detectable rate for increased cortical density of lens was 22.45% (337/1 501) and for lens turbidity was 8.19% (123/1 501). The detectable rate of increased cortical density showed a linear increasing trend with the increase in age, age of radiation service, age at the beginning of exposure to radiation, level of medical institution and dose ( χ2=366.36, 313.77, 15.18, 21.61, 92.13, P<0.05). The detectable rate of lens opacity increased linearly with the increase in age, length of radiation service, level of medical institution and dose( χ2=69.64, 67.65, 67.65, 37.37, P<0.05), and decreased linearly with the increase in age at the beginning of radiation exposure ( χ2=4.25, P<0.05). Logistic regression analysis showed that age was the influencing factor of increased cortical density ( χ2=165.98, P<0.05), and the risk of cortical densification increased with age ( OR=1.33, 95% CI: 1.27-1.39). Age, length of radiation service and occupation were the influencing factors of lens opacity ( χ2=25.78, 4.99, 6.88, P<0.05). The risk of lens opacity increased with age ( OR=1.17, 95% CI: 1.10-1.24). The risk of lens opacity increased with age of radiation service ( OR=1.06, 95% CI: 1.01-1.12). The risk of ocular opacity was higher in interventional radiology than that in diagnostic radiology, radiotherapy and nuclear medicine ( OR=2.59, 95% CI: 1.27-5.25). Conclusions:Long-term exposure to low dose ionizing radiation has a certain correlation with the abnormal lens detectable rate of medical radiation workers. Age, length of radiation service and occupation are the influencing factors of lens opacity.

Exploring the investigation level for individual monitoring for medical radiation workers in Guangdong province / 中华放射医学与防护杂志

Objective:To explore the investigation level of individual monitoring for medical radiation workers.Methods:Monitoring and analysis of individual doses to the medical radiation workers in Guangdong province were performed, from 2016 to 2019, by the Individual Dose Monitoring Department of Guangdong Provincial Hospital for Occupational Disease Prevention and Control.Results:The numbers of monitored workers were diagnostic radiology 53 674, dental radiology 2 563, nuclear medicine 5 001, radiotherapy 16 687, interventional radiology 22 272 and others 2 087 from 2016 to 2019, of which the number of individuals with doses in excess of investigation level 1.25 mSv, were 76, 6, 18, 28, 133 and 2 respectively. The non-real doses made up 67.1 %, 100 %, 55.6 %, 82.1 %, 76.7 % and 100 % of their respective totals. Their 99th percentile doses P99 were 0.37, 0.39, 0.67, 0.35, 0.54 and 0.30 mSv, and the average periodic dose equivalent were 0.07, 0.06, 0.11, 0.06, 0.07 and 0.05 mSv respectively, indicating a statistically significant difference existing in the average annual effective dose between groups ( Z=-26.139--2.681, P<0.001). Conclusions:Due to non-reality of doses in excess of investigation levels and high labor cost, it is suggested to currently use 0.40 mSv per 3 months as investigation level for diagnostic radiology, dental radiology, radiotherapy and others, and 0.70 mSv per 3 months as for nuclear medicine and interventional radiology.

Bortezomib and obatoclax for dual blockade of protein degradation pathways show synergistic anti-tumor effect in human acute T lymphoblastic leukemia cells / 南方医科大学学报

OBJECTIVE@#To explore whether bortezomib and a Bcl-2 inhibitor exhibit synergistic anti-tumor effect in human acute T lymphoblastic leukemia cells.@*METHODS@#MTT assay was used to determine the cytotoxicity of bortezomib in the absence or presence of Bcl-2 inhibitors (obatoclax, AT-101 and ABT-199) in Jurkat cells. The effects of drug treatment on the expression of Bcl-2 family proteins, LC3B, p62, ubiquitin, BiP/Grp78, p-JNK, p-p38 and CHOP proteins were examined by Western blotting. Flow cytometry was used to determine the effects of bortezomib and Bcl-2 inhibitors (obatoclax, AT-101 and ABT-199) on cell apoptosis. Quantitative real-time PCR was used to measure the mRNA expression levels of the key regulatory factors of unfolded protein reaction (UPR). A zebrafish xenograft model was used to study the anti-tumor effect of bortezomib, obatoclax and their combination in vivo.@*RESULTS@#Bortezomib or Bcl-2 inhibitors alone inhibited the cell viability of Jurkat cells, but only obatoclax and bortezomib showed synergistic cytotoxicity and pro-apoptotic effect. Obatoclax, rather than AT-101 and ABT- 199, blocked autophagic flux in the cells evidenced by concomitant accumulation of LC3B-Ⅱ and p62. Both bortezomib and obatoclax alone caused accumulation of polyubiquinated proteins, and their combination showed a synergistic effect, which was consistent with their synergistic cytotoxicity. The dual blockade of proteasome and autophagy by the combination of bortezomib and obatoclax triggered unfolded protein response followed by cell apoptosis. Preventing UPS dysfunction by tauroursodeoxycholic acid (TUDCA) significantly attenuated the cytotoxicity and pro-apoptotic effect of bortezomib in combination with obatoclax. In zebrafish xenograft models, bortezomib combined with obatoclax significantly decreased tumor foci formation.@*CONCLUSIONS@#Bortezomib and obatoclax for dual blockade of protein degradation pathways show synergistic anti-tumor effect in human acute T lymphoblastic leukemia cells.

Survey of nuclear medicine practice in Guangdong in 2016 / 中华放射医学与防护杂志

Objective To survey the basic situation of diagnosis and treatment in clinical nuclear medicine across Guangdong province,evaluate the risks of exposure to the radiation workers and public and explore the countermeasures to control radiation exposre.Methods A survey team was set up to survey,by filling questionnaires,the basic information on nuclear medicine practices for workers,equipment,radionuclide,frequency and dose to workers and radiation protection measures.Results A total of 71 nuclear medicine institutions was involved in the survey with 733 radiation workers in 2016 in Guangdong.The average annual effective dose to nuclear medicine workers was (0.55±0.66) mSv per year.The total pieces of nuclear medical equipment was up to 189 in 2016 including 59 SPECT/CT scanners (5 SPECT),28 PET/CT scanners and 54 thyroid scanners.Total activity of 1.15× 10s MBq in radiopharmaceuticals was used in 325 903 examinations and treatments with the number of frequency of 2.97 examinations per 1 000 population.Concluions There have been a rapid progress in practice of nuclear medicine over the past 20 years in Guangdong province with departments of nuclear medicine set up in 18 of 21 cities.Compared with 1998,the activity in radiopharmaceuticals used has increased by 414％ in 2016 and the number of frequency of examination and treatment has increased by 111％.The rapid expansion of nuclear medicine practice has also caused potential risks of radiation to the public and environment.

Evaluating the value of CEA and CA153 during follow-up in HER-2 overexpressing breast cancer u-sing ROC curves / 实用肿瘤学杂志

Objective To explore the value of carcinoembryonic antigen ( CEA) and cancer antigen 153 ( CA153 ) in detecting tumor recurrences and to establish the optimal operating point of diagnosis of recurrences in HER-2 overexpressing breast cancer using ROC curves .Methods A total of 127 HER -2 overexpressing breast cancer patients was enrolled into this study and subdivided into two groups ,the recurrence group and the non-recurrence group .We created a ROC curve and found out the optimal operating point .Then we compared the advantage of detecting recurrences between optimal operating point in the ROC curve and the diagnostic point that we usually used .Results The recurrence groups showed significantly higher CEA and CA 153 levels than the non-recurrence groups(P<0.0001).The area under the curve(AUC)of the CEA and CA153 were 0.752 and 0.820 respectively and the optimal operating point were 3.5 ng/mL and 17.89 U/mL,respectively.The sensitivi-ties of the optimal operating point of CEA and CA 153 were 46.15%and 65.38%respectively,and the specifici-ties were 97.33%and 89.33%, respectively.Conclusion CEA and CA153 process medium value for detecting recurrences in HER-2 overexpressing breast cancer .

The influence of combined treatment of interleukin-2 and chemotherapy on T lymphocyte subgroup in acute myeloid leukemia / 中国医师进修杂志

Objective To investigate the influence and the clinical significance of interleukin-2 (IL-2) on T lymphocyte subgroup after chemotherapy in acute myeloid leukemia patients. Methods Fiftyfour acute myeloid leukemia patients were divided into treatment group (chemotherapy combined with IL-2,28 cases) and control group (pure chemotherapy,26 cases) by radom digits table. In treatment group, IL-2400 000 U was dripped after chemotherapy for 14 days. Then the T lymphocyte subgroup change before and after treatment was examined. Results After 14 days' treatment, the levels of CD3 (0.6026±0.2275 ),CD4(0.4972±0.1224),CD56(0.3016±0.1053 ) in treatment group were significantly higher than those before treatment(0.3926±0.2010,0.2264±0.1190,0.1729±0.1226) and in control group (0.4352±0.1930,0.2738±0.1362,0.1937±0.1268)(P< 0.05). Conclusion IL-2 treatment can obviously raise the levels of T lymphocyte subgroup and can raise the immunologic function.

Plasma adenomedullin, calcitonin gene-related peptide and c-type natriuretic peptide in rats with hypoxic pulmonary hypertension / 第三军医大学学报

Objective　To explore the effects of hypoxia on the syntheses and secretion of adrenomedullin (AM), calcitonin gene related peptide (CGRP) and c-type natriuretic peptide (CNP) and the relationship between these peptides. Methods　Rat models were established with hypoxia for 10, 20 and 30 d respectively and rats under normal altitude were served as control. Pulmonary artery pressure and the maximum increasing speed of right ventricle (RVdp/dtmax) were measured in every group. The dynamic changes of AM, CGRP and CNP concentrations in plasma were studied with radioimmunoassay. Results　During hypoxia, pulmonary artery pressure and RVdp/dtmax were enhanced. Plasma AM and CNP concentrations were increased while CGRP was decreased significantly. The plasma level of AM had positive correlation with that of CNP, but negatively correlated with that of CGRP. Conclusion　Results indicate that hypoxia may cause pulmonary artery pressure change and right ventricle has compensatory reaction to hypoxic pulmonary hypertension. Dynamic changes of plasma AM, CGRP and CNP concentrations can be regarded as indexes for condition of illness.