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Background: Normal lung tissue tolerance constitutes a limiting factor in delivering the required dose of radiotherapy to cure thoracic and chest wall malignancies. Radiation-induced lung fibrosis (RILF) is considered a critical determinant for late normal tissue complications. While RILF mouse models are frequently approached e.g., as a single high dose thoracic irradiation to investigate lung fibrosis and candidate modulators, a systematic radiobiological characterization of RILF mouse model is urgently needed to compare relative biological effectiveness (RBE) of particle irradiation with protons, helium-, carbon and oxygen ions now available at HIT. We aimed to study the dose-response relationship and fractionation effect of photon irradiation in development of pulmonary fibrosis in C57BL/6 mouse.Methods: Lung fibrosis was evaluated 24 weeks after single and fractionated whole thoracic irradiation by quantitative assessment of lung alterations using CT. The fibrosis index (FI) was determined based on 3D-segmentation of the lungs considering the two key fibrosis parameters affected by ionizing radiation i.e., a dose/fractionation dependent reduction of the total lung volume and increase of the mean lung density.Results: The effective dose required to induce 50% of the maximal possible fibrosis (ED 50 ) was 14.55 ± 0.34Gy and 27.7 ± 1.22Gy, for single and five- fractions irradiation, respectively. Applying a deterministic model an α/β = 4.49 ± 0.38 Gy for the late lung radiosensitivity was determined. Intriguingly, we found that a linear-quadratic model could be applied to in-vivo log transformed fibrosis (FI) vs. irradiation doses. The LQ model revealed an α/β for lung radiosensitivity of 4.4879 Gy for single fraction and 3.9474 for 5-fractions. Our FI based data were in good agreement with a meta-analysis of previous lung radiosensitivity data derived from different clinical endpoints and various mouse strains. The effect of fractionation on RILF development was further estimated by the biologically effective dose (BED) model with threshold BED (BED Tr ) = 30.33 Gy and BED ED50  = 61.63 Gy, respectively.Conclusion: The systematic radiobiological characterization of RILF in the C57BL/6 mouse reported in this study marks an important step towards precise estimation of dose-response for development of lung fibrosis. These radiobiological parameters combined with a large repertoire of genetically engineered C57BL/6 mouse models, build a solid foundation for further biologically individualized risk assessment of RILF and functional RBE prediction on novel of particle qualities. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and tumor recurrence and metastasis are major factors that contribute to the poor outcome of patients with HCC. Long noncoding RNAs (lncRNAs) are known to regulate different tumorigenic processes, and a growing body of evidence indicates that Hippo kinase signaling is inactivated in many cancers. However, the upstream lncRNA regulators of Hippo kinase signaling in HCC are poorly understood. Methods: Using a lncRNA microarray, we identified a novel lncRNA, uc.134, whose expression was significantly decreased in the highly aggressive HCC cell line HCCLM3 compared with MHCC97L cells. Furthermore, we evaluated uc. 134 expression in clinical samples using in situ hybridization (ISH) and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. The full-length transcript of uc.134 was confirmed using rapid amplification of cDNA ends (RACE) analyses. To investigate the biological function of uc.134, we performed gain-of-function and loss-of-function studies both in vitro and in vivo. The underlying mechanisms of uc.134 in HCC were investigated using RNA pulldown, RNA immunoprecipitation, ubiquitination assays, Western blotting, mRNA microarray analyses, and qRT-PCR analyses. Results: The ISH assay revealed that uc.134 expression was significantly decreased in 170 paraffin-embedded samples from patients with HCC compared with adjacent tissues and uc.134 expression directly correlated with patient prognosis. Furthermore, we defined a 1867-bp full-length transcript of uc.134 using 5′- and 3′-RACE analysis. The overexpression of uc.134 inhibited HCC cell proliferation, invasion, and metastasis in vitro and in vivo, whereas the knockdown of uc.134 produced the opposite results. Furthermore, we confirmed that uc.134 (1408-1867 nt) binds to CUL4A (592-759 aa region) and inhibits its nuclear export. Moreover, we demonstrated that uc.134 inhibits the CUL4Amediated ubiquitination of LATS1 and increases YAPS127 phosphorylation to silence the target genes of YAP. Finally, a positive correlation between uc.134, LATS1, and pYAPS127 was confirmed in 90 paraffin-embedded samples by ISH and immunohistochemical staining. Conclusions: Our study identifies that a novel lncRNA, uc.134, represses hepatocellular carcinoma progression by inhibiting the CUL4A-mediated ubiquitination of LATS1 and increasing YAPS127 phosphorylation. The use of this lncRNA may offer a promising treatment approach by inhibiting YAP and activating Hippo kinase signaling. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to evaluate the application of three-dimensional conformal radiotherapy (3D-CRT) for elderly patients with non-small cell lung cancer (NSCLC) based on computed tomography (CT) simulations in different respiratory phases. Methods: A total of 64 patients aged >70 years old with NSCLC were treated by 3D-CRT using CT images in different respiratory phases. The gross tumor volumes (GTVs) at the end of inspiration and end of expiration were combined to obtain the total GTV, which was close to the motional range of tumors during respiration, and no additional expansion of the clinical target volume (CTAV) to planning target volume (PTV) (CTAV:PTV) was included during the recording of respiratory movements. Patients were also planned according to the classic 3D-CRT approach. Efficacy, prognostic factors, and side effects were evaluated. Results: Compared with the classic approach, the average PTV was 18.9% lower (median: 17.3%), and the average lung volume receiving a prescribed dose for a tumor was 22.4% lower (median: 20.9%). The 1-, 2-, and 3-year survival rates were 70.6%, 54.9%, and 29.4%, respectively, with an overall tumor response rate of 79.7%. The Karnofsky performance status and N stage were independent prognostic factors, whereas age was not. Conclusion: Without affecting therapeutic effects, CT simulations in different respiratory phases were well-tolerated in elderly patients with NSCLC, could effectively reduce PTV, and could improve the quality of life. [ABSTRACT FROM AUTHOR]

Upregulation of matrix metalloproteinase MMP-14 (MT1-MMP) is associated with poor prognosis in cancer patients, but it is unclear how MMP-14 becomes elevated in tumors. Here, we show that miR-181a-5p is downregulated in aggressive human breast and colon cancers where its levels correlate inversely with MMP-14 expression. In clinical specimens, enhanced expression of MMP-14 was observed in cancer cells located at the invasive front of tumors where miR-181a-5p was downregulated relative to adjacent normal cells. Bioinformatics analyses defined a potential miR-181a-5p response element within the 30-untranslated region of MMP-14 that was validated in reporter gene experiments. Ectopic miR-181a-5p reduced MMP-14 expression, whereas miR-181a-5p attenuation elevated MMP-14 expression. In support of a critical relationship between these two genes, miR-181a-5p-mediated reduction of MMP-14 levels was sufficient to decrease cancer cell migration, invasion, and activation of pro-MMP-2. Furthermore, this reduction in MMP-14 levels was sufficient to reduce in vivo invasion and angiogenesis in chick chorioallantoic membrane assays. Taken together, our results establish the regulation of MMP-14 in cancers by miR-181a-5p through a posttranscriptional mechanism, and they further suggest strategies to elevate miR-181a-5p to prevent cancer metastasis. [ABSTRACT FROM AUTHOR]

Radioresistance remains a major problem in the treatment of patients suffering from nasopharyngeal carcinoma (NPC). A better understanding of the mechanisms involved in the induction of radioresistance may provide strategies to improve NPC patients' response to therapy. The present study aimed to investigate the effect of microRNA (miR)-101 on the radioresistance of NPC cells. Analysis of miR-101 expression levels indicated that miR-101 was downregulated in NPC cell lines. Furthermore, ectopic expression of miR-101 suppressed cell proliferation and enhanced radiosensitivity of NPC cells. Stathmin 1 (STMN1) was additionally verified as a direct functional target of miR-101, which was found to be involved in cell viability, radioresistance and radiation-induced autophagy of NPC cells. In conclusions, the results of the present study suggested that the identified miR-101/STMN1 pathway contributed to the elucidation of the mechanisms of radioresistance in human NPC and that it may represent a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Several randomized controlled clinical trials have compared therapy with or without thalidomide in the treatment of advanced non-small cell lung cancer (NSCLC). However, these studies did not produce consistent results. We carried out a meta-analysis to determine the efficacy and safety of thalidomide-based therapy in patients with advanced NSCLC. For this meta-analysis, we selected randomized clinical trials that compared thalidomide in combination with other therapy or other therapy alone in patients with advanced NSCLC. The outcomes included median overall survival (OS), one- and two-year survival, tumor response, and toxicities. Hazard ratios (HRs) or risk ratios (RRs) were reported with 95% confidence intervals (CIs). A total of 5 eligible trials were included for the meta-analysis, with 729 patients in the thalidomide group and 711 patients in the control group. Compared with non-thalidomide-based therapy, patients receiving thalidomide plus other therapy did not differ significantly in terms of one- and two-year survival or tumor response (RR = 1.32, 95% CI: 0.66-2.63, p = 0.43; RR = 1.22, 95% CI: 0.48-3.11, p = 0.68; RR = 1.05, 95% CI: 0.92-1.19, p = 0.51, respectively). However, thalidomide-based therapy induced more grade 3-4 dizziness and constipation (RR = 2.05, 95% CI: 1.10-3.81, p = 0.02; RR = 4.78, 95% CI: 1.84-12.38, p = 0.001, respectively). The addition of thalidomide to other therapy did not improve survival and tumor response in patients with advanced NSCLC, and thalidomide-based therapy was associated with more grade 3/4 dizziness and constipation. [ABSTRACT FROM AUTHOR]

Background:Radiation-induced thyroid disorders have been reported in radiotherapy of head and neck cancers. This study evaluated the radiation-induced damages to thyroid gland in patients with nasopharyngeal carcinoma (NPC).Methods:Forty-five patients with NPC treated by radiotherapy underwent baseline thyroid hormones (free triiodothyronine, free thyroxine [fT4], and thyrotropin [TSH]) examination and CT scan before radiotherapy. The volume of the thyroid gland was calculated by delineating the structure in the corresponding CT slices using the radiotherapy treatment planning system. The thyroid doses were estimated using the treatment planning system. Subsequent CT scans were conducted at 6, 12, and 18 months after radiotherapy, whereas the hormone levels were assessed at 3, 6, 12, and 18 months after radiotherapy. Trend lines of the volume and hormone level changes against time were plotted. The relationship between the dose and the change of thyroid volume and hormone levels were evaluated using the Pearson correlation test.Results:An average of 20% thyroid volume reduction in the first 6 months and a further 8% shrinkage at 12 months after radiotherapy were observed. The volume reduction was dependent on the mean thyroid doses at 6, 12, and 18 months after radiotherapy (r= −0.399, −0.472, and −0.417, respectively). Serum free triiodothyronine and fT4 levels showed mild changes of <2.5% at 6 months, started to drop by 8.8% and 11.3%, respectively, at 12 months, and became stable at 18 months. The mean serum TSH level increased mildly at 6 months after radiotherapy and more steeply after 18 months. At 18 months after radiotherapy, 12 patients had primary hypothyroidism with an elevated serum TSH, in which 4 of them also presented with low serum fT4. There was a significant difference (p= 0.014) in the mean thyroid doses between patients with hypothyroidism and normal thyroid function.Conclusions:Radiotherapy for patients with NPC caused radiation-induced changes of the thyroid gland. The shrinkage of the gland was greatest in the first 6 months after radiotherapy, whereas the serum fT4 and TSH levels changed at 12 months. Radiation-induced changes were dependent on the mean dose to the gland. Therefore, measures to reduce the thyroid dose in radiotherapy should be considered. [ABSTRACT FROM AUTHOR]