Is transketolase like 1 a target for the treatment of differentiated thyroid carcinoma? A study on thyroid cancer cell lines

Summary  Radioactive iodine-refractory [¹⁸F] fluorodeoxy-glucose-positron emission tomography-positive thyroid carcinomas represent especially aggressive tumors. Targeting glucose metabolism by the transketolase isoenzyme transketolase like 1 (TKTL-1) which is over-expressed in various neoplasms, may be effective. The correlation of TKTL-1 expression and the response to oxythiamine as the currently best-characterized inhibitor of transketolases was studied in differentiated thyroid cancer cell lines. We determined TKTL-1 expression, proliferation, glucose uptake and GLUT-1 expression in non-treated thyroid cells and recorded the effect of oxythiamine on iodide uptake and on thymidine uptake. TKTL 1 was highest expressed in cell lines derived from more invasive tumors but the expression level was not strongly correlated to proliferation rate, to GLUT-1 expression or to the response to oxythiamine. Oxythiamine showed only a weak effect in the TKTL-1 expressing cell lines. Over-expression of TKTL-1 is not an indicator for responsiveness to oxythiamine. More specific inhibitors should be tested.     

内科危重病患者血清甲状腺激素水平的监测及预后评估

目的探讨危重患者甲状腺功能的变化。方法186例内科危重住院患者作为观察组,同期健康体检者186例作为对照组,观察正常甲状腺病态综合征(euthyroid sick syndrome,ESS)发生情况,对比观察组与对照组、观察组中存活组与病死组治疗前后甲状腺激素检查结果,ESS者治疗前后甲状腺激素检查结果,ESS与死亡的关系。结果186例内科危重病患者中发生ESS78例,发生率41.93%(78/186);观察组入院时TT3、FT3低于对照组,TT4、FT4、TSH两组比较无显著性差异(P>0.05);观察组中存活组和病死组比较TSH无显著性差异外、病死组TT3、FT3、TT4、FT4均低于存活组(P<0.05);原发病治疗好转后,甲状腺激素可恢复或接近正常;发生ESS病死率30.77%高于未发生变化的病死率13.9%。结论血清甲状腺激素水平的变化反映了危重住院患者的全身状态和严重程度,动态检测血清中甲状腺激素水平可以观察肺心病的发展和转归。     

Hepatic and muscle expression of thyroid hormone receptors in association with body and muscle growth in large yellow croaker, Pseudosciaena crocea (Richardson)

The role of thyroid hormone (TH) and its receptors (TRs) in the regulation of body growth and muscle accretion is well established in mammals and birds, whereas the involvement of THs and TRs in fish growth, especially during the muscle accretion period of juvenile-adult transition, is unknown. This study describes the cloning of the partial cDNA sequences of TRalpha and TRbeta in large yellow croaker, Pseudosciaena crocea (Richardson) and the patterns of TRalpha and TRbeta mRNA expression in liver and muscle of 1- and 2-year-old large yellow croaker, associated with changes in body mass and muscle characteristics. Two TRalpha isoforms (TRalpha1, TRalpha2) and TRbeta were identified in large yellow croaker. The deduced amino acid sequences showed high homology to the TRs of human and other teleosts. Hepatic TRbeta mRNA expression was markedly lower in 2-year-old large yellow croaker compared with the 1-year-old, while no significant age difference was observed for hepatic TRalpha mRNA expression. Muscle expression of TRalpha mRNA was significantly higher in 2-year-old large yellow croaker, whereas TRbeta exhibited no significant age difference. Meanwhile, serum concentration of T(4) was significantly decreased in 2-year-old large yellow croaker, but no change was observed for T(3). The body mass, fork length and body height of 2-year-old large yellow croaker were 4.7, 1.6 and 1.7 times greater, respectively compared with that of 1-year-old. Average diameters of skeletal muscle in 2-year-old large yellow croaker were remarkably larger than that in 1-year-old with no significant difference in muscle crude fat content. The down-regulation of hepatic TRbeta expression was associated with the decrease in general growth rate and the increase in muscle expression of TRalpha was accompanied with muscle accretion and myofiber hypertrophy, implicating the different roles of TRs in the regulation of growth in large yellow croaker.     

A novel technique for localization of small pulmonary nodules

BACKGROUND: To show the safety and accuracy of a new marking technique using an image-guided technique for preoperative localization of a small pulmonary nodule. METHODS: CT data of a patient with a peripheral pulmonary nodule < 20 mm were transmitted to a surgical navigation system (StealthStation Treon Treatment Guidance System; Medtronic; Louisville, KY). To match preoperative CT image data to the physical space occupied by the patient during surgery, five to six superficial skin fiducials were used for registration. A 16-gauge needle attached by a positioning sensor was advanced into or immediately adjacent to the nodule for injection of methylene blue under guidance of the StealthStation system. Then the lesion marked by the methylene was thoracoscopically resected. RESULTS: Seventeen patients (12 men and 5 women; mean age, 51.3 years) underwent this procedure, and all the nodules were identified due to the precise location of the probe. They were resected with sufficient margins. There were no surgical complications. The average time of registration was 4.8 +/- 0.9 min (+/- SD). Registration error was on average 2.7 +/- 0.2 mm. CONCLUSIONS: Image-guided navigation is useful, accurate, and safe in the localization of small peripheral lung lesions.     

Effects of larval-juvenile treatment with perchlorate and co-treatment with thyroxine on zebrafish sex ratios

The objective of this study was to determine the effect of larval-juvenile exposure to perchlorate, a thyroid hormone synthesis inhibitor, on the establishment of gonadal sex ratios in zebrafish. Zebrafish were exposed to untreated water or water containing perchlorate at 100 or 250 ppm for a period of 30 days starting at 3 days postfertilization (dpf). Recovery treatments consisted of a combination of perchlorate and exogenous thyroxine (T4; 10 nM). Thyroid histology was assessed at the end of the treatment period (33 dpf), and gonadal histology and sex ratios were determined in fish that were allowed an additional 10-day period of growth in untreated water. As expected, exposure to perchlorate caused changes in thyroid histology consistent with hypothyroidism and these effects were reversed by co-treatment with exogenous T4. Perchlorate did not affect fish survival but co-treatment with T4 induced higher mortality. However, relative to the corresponding perchlorate concentration, co-treatment with T4 caused increased mortality only at a perchlorate concentration of 100 ppm. Perchlorate alone or in the presence of T4 suppressed body length at 43 dpf relative to control values. Perchlorate exposure skewed the sex ratio toward female in a concentration-dependent manner, and co-treatment with T4 not only blocked the feminizing effect of perchlorate but also overcompensated by skewing the sex ratio towards male. Moreover, co-treatment with T4 advanced the onset of spermatogenesis in males. There was no clear association between sex ratios and larval survival or growth. We conclude that endogenous thyroid hormone plays a role in the establishment of gonadal sex phenotype during early development in zebrafish.     

Triiodothyronine suppresses humoral immunity but not T-cell-mediated immune response in incubating female eiders (Somateria mollissima)

Immunity is believed to share limited resources with other physiological functions and this may partly account for the fitness costs of reproduction. Previous studies have shown that the acquired immunity of female common eiders (Somateria mollissima) is suppressed during the incubation fast. To save energy, triiodothyronine (T(3)) is adaptively decreased during fasting in most bird species, despite T(3) levels are maintained throughout incubation in female eiders. However, the relationship between thyroid hormones and the immune system is not fully understood. The current study aimed to determine the endocrine mechanisms that underlie immunosuppression in incubating female eiders. To this end we assessed the effects of exogenous T(3) on both components of the acquired immune system in 42 free-ranging incubating birds. Half of the females were implanted with T(3) pellets, while the other half sham implanted served as control. We measured variations in the immunoglobulin index, the T-cell-mediated immune response, body mass, and plasma parameters in both groups before and after manipulation. T(3) levels in implanted females were four times higher and mass loss was 40% greater than in control females. Implanted females also showed an 18% decrease in the immunoglobulin index, while the T-cell-mediated immune response was not significantly affected by the treatment. Finally, the treatment did not induce any significant changes in corticosterone levels. Our study shows that exogenous T(3) decreased only one component of the acquired immune system. We suggest that the immunosuppressive effect of T(3) could be mediated by its effects on body fat reserves. Further experiments are required to determine: (1) the relationship between adiposity and immune function, (2) the adaptive significance of immunosuppression during incubation in eiders.     

15个多发性内分泌腺瘤2A型家系的临床和RET基因突变研究

目的 研究15例多发性内分泌腺瘤2A型（MEN2A）先证者及其家系成员的临床表型和RET原癌基因突变情况。方法 收集15例MEN2A先证者家系的共119名家系成员,提取其外周血基因组DNA,分别对RET原癌基因第8、10、11、13、14、15、16外显子进行PCR产物直接测序。结果 在15个MEN2A家系中,共有49例检出RET原癌基因突变。其中37例有MEN2A临床表型,另12例为基因携带者,前者诊断MEN2A的年龄显著晚于后者[（43．0±13．9）岁比（9．8±7．4）岁,P〈0．01];37例MEN2A患者中甲状腺髓样癌（MTC）、嗜铬细胞瘤（PCC）和甲状旁腺增生或腺瘤（HPT）的发生率分别为91．9％,56．8％和10．8％;在15个MEN2A家系中,共检出5种基因突变类型,均位于RET原癌基因第11外显子634位点,分别为：C634W（13．3％）,C634Y（46．7％）,C634R（26．7％）,C634F（6．7％）,C634S（6．7％）。结论 15个MEN2A家系中,37例有临床表型的MEN2A患者平均确诊年龄高于国外相关报道;MEN2A患者MTC和PCC的发病率和国外文献报道的基本一致,而HPT则较低;所有MEN2A患者的RET原癌基因突变均位于634位点,较国外文献报道的单一。     

Optimal breathing protocol for dynamic contrast-enhanced MRI of solitary pulmonary nodules at 3T

The purpose of this study was to evaluate optimal breathing maneuvers that minimize lung parenchymal movement for dynamic contrast-enhanced MRI (DCE-MRI), which requires longer scan times, beyond the limit of a single breath hold. A healthy volunteer was scanned on a 3T MR scanner using two different breathing maneuvers. In the first, the healthy volunteer was instructed to hold his breath as much as possible and breathe in between breath holds while an image was obtained. In the second, the volunteer was instructed to breathe shallowly and freely throughout the scan. On the obtained images, the excursion of the highest point of the right diaphragm and the pulmonary vessel branches located in the four different anatomic regions of the lung were measured in two orthogonal planes. A patient with a solitary pulmonary nodule (SPN) underwent DCE-MRI utilizing a 2D spoiled gradient-echo (SPGR) sequence while the patient breathed shallowly and freely during the scan. The standard deviations of the excursion of the highest point and selected pulmonary vessels were much smaller during shallow, free breathing maneuver scans than those during breath hold maneuver scans. A dynamic perfusion-fitting curve of the SPN was obtained during the DCE-MRI using shallow free breathing. Shallow, free breathing allows smaller diaphragmatic cranial caudal and lung parenchymal displacements. Therefore, it can be useful during exams where targeting of the lesion is necessary, in studies with long scan times, such as dynamic MRI. This breathing maneuver makes it possible to analyze SPN with DCE-MRI while making use of the advantages of a higher magnetic field in conjunction.     

Detectability of lung nodules using flat panel detector with dual energy subtraction by two shot method: evaluation by ROC method

The aim of this study was to evaluate the effectiveness of dual-exposure dual energy subtraction technique in flat-panel chest radiography for lung nodules detection. Chest radiographs were acquired in 100 patients (57 men and 43 women; mean age, 60.2 years; range, 18-89 years) using a flat-panel digital chest system. These images were evaluated by seven radiologists. A continuous rating scale of 0-100 was used to represent each observer's confidence level regarding the presence or absence of lung nodules. Observer performance for detection of lung nodules with subtraction images was tested by using receiver operating characteristic (ROC) analysis of individual and averaged reader data. The average area under the ROC curve (Az value) significantly increased with subtraction images (Az=0.79 in standard radiographs versus Az=0.84 with subtraction images, p<0.05). In conclusion, the two-exposure dual-energy subtraction chest radiography significantly would improve detection of lung nodules.