BPA induces testicular damage in male rodents via apoptosis, autophagy, and ferroptosis.

Bisphenol A (BPA), chemically known as 2,2-bis(4-hydroxyphenyl) propane, is one of the most common endocrine-disrupting chemicals in our environment. Long-term or high-dose exposure to BPA may lead to testicular damage and adversely affect male reproductive function. In vivo studies on rodents have demonstrated that BPA triggers apoptosis in testicular cells through both intrinsic and extrinsic pathways. Further in vitro studies on spermatogonia, Sertoli cells, and Leydig cells have all confirmed the pro-apoptotic effects of BPA. Given these findings, apoptosis is considered a primary mode of cell death induced by BPA in testicular tissue. In addition, BPA promotes autophagy by altering the activity of the Akt/mTOR pathway and upregulating the expression of autophagy-related genes and proteins. Recent studies have also identified ferroptosis as a significant contributing factor to BPA-induced testicular damage, further complicating the landscape of BPA's effects. This review summarizes natural substances that mitigate BPA-induced testicular damage by inhibiting these cell death pathways. These findings not only highlight potential therapeutic strategies but also underscore the need for further research into the underlying mechanisms of BPA-induced toxicity, particularly as it pertains to human health risk assessment and the development of more effective BPA management strategies.

Application of MR images in radiotherapy planning for brain tumor based on deep learning.

PURPOSE: Explore the function and dose calculation accuracy of MRI images in radiotherapy planning through deep learning methods. METHODS: 131 brain tumor patients undergoing radiotherapy with previous MR and CT images were recruited for this study. A new series of MRI from the aligned MR was firstly registered to CT images strictly using MIM software and then resampled. A deep learning method (U-NET) was used to establish a MRI-to-CT conversion model, for which 105 patient images were used as the training set and 26 patient images were used as the tuning set. Data from additional 8 patients were collected as the test set, and the accuracy of the model was evaluated from a dosimetric standpoint. RESULTS: Comparing the synthetic CT images with the original CT images, the difference in dosimetric parameters D98, D95, D2 and Dmean of PTV in 8 patients was less than 0.5%. The gamma passed rates of PTV and whole body volume were: 1%/1 mm: 93.96%±6.75%, 2%/2 mm: 99.87%±0.30%, 3%/3 mm: 100.00%±0.00%; and 1%/1 mm: 99.14%±0.80%, 2%/2 mm: 99.92%±0.08%, 3%/3 mm: 99.99%±0.01%. CONCLUSION: MR images can be used both in delineation and treatment efficacy evaluation and in dose calculation. Using the deep learning way to convert MR image to CT image is a viable method and can be further used in dose calculation.

Meta-analysis of PD-(L)1 inhibitor plus chemotherapy versus chemotherapy as first-line treatment in extensive-stage small-cell lung cancer.

BACKGROUND: Immunotherapy targeting programmed death 1(PD-1) and its ligand (PD-L1) has been successful in extensive-stage small cell lung cancer (ES-SCLC). However, first-line PD-(L)1 inhibitor combined with chemotherapy (immunochemotherapy) versus chemotherapy has not been well studied. METHODS: Randomized controlled trials had been searched from PubMed, Embase, and the Cochrane Library until December 29, 2022. Randomized effect consistency models were applied for estimating the pooled hazard ratios (HRs) and odds ratios (ORs). Study outcomes included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), 6-month and 1-year disease progression rate, 1-year and 2-year mortality rate, and Grade ≥3 adverse events (AEs). RESULTS: Six eligible trials with 2600 ES-SCLC patients were included. Compared with chemotherapy, immunochemotherapy significantly improved ORR (OR 1.32, 95% CI 1.07-1.63; p = 0.01), PFS (HR 0.68, 95% CI 0.58-0.78; p < 0.001), and OS (HR 0.72, 96% CI 0.66-0.78, p < 0.001) without increasing Grade ≥3 AEs (p = 0.07). Compared with patients with chemotherapy, the 6-month disease progression rate was reduced by 0.39 (p = 0.01) and the 1-year disease progression rate was reduced by 0.75 (p < 0.001), the 1-year mortality rate was reduced by 0.33 (p < 0.001) and the 2-year mortality rate was reduced by 0.50 (p < 0.001) respectively in patients with immunochemotherapy. However, patients with brain metastases failed to prolong PFS and OS from immunochemotherapy (p > 0.05). CONCLUSION: Compared with chemotherapy, PD-(L)1 inhibitor plus chemotherapy as first-line treatment could improve the efficacy and prognosis of ES-SCLC patients without more serious side effects. However, more research is needed to validate these results.

Prognostic value of esophageal cancer immune prognostic index in advanced esophageal squamous cell carcinoma patients with anti-programmed cell death-1 therapy.

BACKGROUND: This study aimed to determine whether the immune prognostic index (ECIPI), based on hemoglobin (Hb) and neutrophil-to-lymphocyte ratio (NLR), could predict the prognosis in patients with advanced esophageal squamous cell carcinoma (ESCC) receiving programmed cell death-1 (PD-1) inhibitor treatment. METHODS: Advanced ESCC patients who had been treated with PD-1 inhibitors from Jan 2016 to Oct 2021 were included. Kaplan-Meier method and Cox proportional hazards regression were used to analyze progression-free survival (PFS) and overall survival (OS). The overall response rate (ORR) was the percentage of complete and partial responses. Univariate and multivariate analyses were used for estimating hazard ratio (HR) and 95% confidence interval (CI). Patients were grouped by ECIPI (good: Hb > 105 g/L and NLR ≤ 4.3; intermediate: Hb ≤ 105 g/L and NLR ≤ 4.3, or Hb > 105 g/L and NLR < 4.3; poor: Hb ≤ 105 g/L and NLR > 4.3). Variables for the multivariate model were selected if the p-value was below 0.05 in the univariate analysis. All statistical comparisons were two-way, and a p-value below 0.05 was set as statistical significance. RESULTS: Totally, of 123 ESCC patients with stage III or IV were included in the study. Efficacy evaluation showed that patients with pretreatment ECIPI good had the best ORR compared with those with ECIPI intermediate and ECIPI poor (53% vs. 22% vs. 8%, p < 0.01). Multivariate analysis showed that ECIPI was an independent influential factor for PFS (p = 0.004) and OS (p < 0.001). Kaplan-Meier curves demonstrated that patients with ECIPI good had the longest PFS (median: 11.6 vs. 3.5 vs. 1.7 months, p < 0.0001) and OS (median: 23.6 vs. 16.7 vs. 4.0 months, p < 0.0001) compared with those with ECIPI intermediate and ECIPI poor. Subgroup analysis indicated that ECIPI good was associated with improved PFS and OS in patients with ECOG 0-1, PD-1 inhibitor plus chemotherapy, first-line treatment, and smoke (all p < 0.05). CONCLUSIONS: Pretreatment ECIPI was associated with the prognosis in advanced ESCC patients with anti-PD-1 therapy, suggesting that ECIPI may be a useful tool to identify patients likely sensitive to PD-1 inhibitors.

Monophosphoryl lipid A ameliorates radiation-induced lung injury by promoting the polarization of macrophages to the M1 phenotype.

BACKGROUND: Radiation-induced lung injury (RILI) often occurs during clinical chest radiotherapy and acute irradiation from accidental nuclear leakage. This study explored the role of monophosphoryl lipid A (MPLA) in RILI. MATERIALS AND METHODS: The entire thoracic cavity of C57BL/6N mice was irradiated at 20 Gy with or without pre-intragastric administration of MPLA. HE staining, Masson trichrome staining, and TUNEL assay were used to assess lung tissue injury after treatment. The effect of irradiation on the proliferation of MLE-12 cells was analyzed using the Clonogenic assay. The effect of MPLA on the apoptosis of MLE-12 cells was analyzed using flow cytometry. Expression of γ-H2AX and epithelial-mesenchymal transition (EMT) markers in MLE-12 cells was detected by immunofluorescence and Western blot, respectively. RESULTS: MPLA attenuated early pneumonitis and late pulmonary fibrosis after thoracic irradiation and reversed radiation-induced EMT in C57 mice. MPLA further promoted proliferation and inhibited apoptosis of irradiated MLE-12 cells in vitro. Mechanistically, the radioprotective effect of MPLA was mediated by exosomes secreted by stimulated macrophages. Macrophage-derived exosomes modulated DNA damage in MLE-12 cells after irradiation. MPLA promoted the polarization of RAW 264.7 cells to the M1 phenotype. The exosomes secreted by M1 macrophages suppressed EMT in MLE-12 cells after irradiation. CONCLUSION: MPLA is a novel treatment strategy for RILI. Exosomes derived from macrophages are key to the radioprotective role of MPLA in RILI.

Correlation Between Adjuvant Chemotherapy Regimen, Recurrence Pattern and Prognosis of Cholangiocarcinoma After Radical Surgery.

BACKGROUND AND PURPOSE: About 70% of patients with radical surgery Cholangiocarcinoma (CCA) have recurrence and metastasis. There are few studies on the relationship between CCA adjuvant chemotherapy (mono or combined therapy), recurrence pattern (local, regional, distant recurrence) and prognosis [(Disease free survival, DFS), (Overall survival, OS)] after radical surgery. This study focuses on the correlation between CCA adjuvant chemotherapy, recurrence pattern and prognosis. METHODS: The study involved retrospective analysis of data: preoperative hematology, clinical pathology, adjuvant chemotherapy regimens, recurrence pattern, DFS and OS, of 207 patients with CCA. Chi-square test was used to analyze the correlation between related factors and postoperative recurrence. Survival curves were plotted by Kaplan-Meier method, P-values were calculated by Log-rank for univariate analysis, multivariate COX regression method for multivariate analysis. RESULTS: Using chi-square test, there were correlations between high carbohydrate antigen 19-9 level(CA19-9≥35), vascular invasion, single-agent adjuvant chemotherapy and postoperative recurrences (p=0.04, p=0.04, p=0.02), COX multivariate regression analysis showed that adjuvant chemotherapy (single vs. doublet drug regimen) was an independent prognostic factor for DFS (11.0 vs. 24.6 months, HR=2.88, P=0.01), whereas recurrence pattern (local vs. distant; regional vs. distant) was an independent prognostic factor for OS (31.2 months vs. 20.4 months, HR=0.58, p=0.01; 32.0 months vs. 20.4 months, HR=0.51, p=0.01). CONCLUSION: Adjuvant chemotherapy regimen was an independent prognostic factor of DFS, whereas recurrence patterns were independent prognostic factors for OS. adjuvant chemotherapy with doublet drug regimen was correlated with longer DFS, and different recurrence modes affect OS.

GSTP1 as a novel target in radiation induced lung injury.

The glutathione S-transferase P1(GSTP1) is an isoenzyme in the glutathione-S transferases (GSTs) enzyme system, which is the most abundant GSTs expressed in adult lungs. Recent research shows that GSTP1 is closely related to the regulation of cell oxidative stress, inhibition of cell apoptosis and promotion of cytotoxic metabolism. Interestingly, there is evidence that GSTP1 single nucleotide polymorphisms (SNP) 105Ile/Val related to the risk of radiation induced lung injury (RILI) development, which strongly suggests that GSTP1 is closely associated with the occurrence and development of RILI. In this review, we discuss our understanding of the role of GSTP1 in RILI and its possible mechanism.

Changes in the nutritional status of nine vitamins in patients with esophageal cancer during chemotherapy.

BACKGROUND: Many studies have investigated the relationships between vitamins and esophageal cancer (EC). Most of these studies focused on the roles of vitamins in the prevention and treatment of EC, and few studies have examined the changes in vitamin nutritional status and their influencing factors before and after chemotherapy for EC. Chemotherapy may have a considerable effect on EC patients' vitamin levels and hematological indicators. AIM: To research the nutritional status of multiple vitamins in EC patients during chemotherapy and to assess its clinical significance. METHODS: EC patients admitted to our center from July 2017 to September 2020 were enrolled in this study. Serum concentrations of nine vitamins (A, D, E, B9, B12, B1, C, B2 and B6), hemoglobin, total protein, albumin, blood calcium, blood phosphorus concentrations and body mass index (BMI) were measured in all EC patients. The changes in nine vitamins, hematological indicators and BMI were compared before and after two cycles of chemotherapy. The possible influential factors were analyzed. RESULTS: In total, 203 EC patients receiving chemotherapy were enrolled in this study. Varying degrees of vitamin A, D, C and B2 deficiency and weight loss were found in these patients, and the proportions of vitamin B2 and vitamin C deficiencies increased significantly after chemotherapy (both P < 0.05). Serum concentrations of vitamins A, C, B2 and B6 and BMI before and after chemotherapy were statistically significant (all P < 0.05). Multivariate analysis showed that vitamin A levels significantly differed between male and female EC patients, whereas vitamin D concentration significantly differed in EC patients in different stages (all P < 0.05). Correlations were observed between the changes in serum concentrations of vitamin A and C before and after two cycles chemotherapy and the change in BMI (P < 0.05). Hemoglobin, total protein, serum albumin and blood calcium concentrations significantly decreased in EC patients after chemotherapy (all P < 0.05), while the blood phosphorus level significantly increased after chemotherapy (P < 0.05). Using the difference in vitamin concentrations as the independent variables and the difference in BMI as the dependent variable, logistic regression analysis revealed statistically significant differences for vitamin A, vitamin D and vitamin C (F = 5.082, P = 0.002). CONCLUSION: Vitamin A, D, C and B2 were mainly deficient in patients with EC during chemotherapy. Multivitamin supplementation may help to improve the nutritional status, chemotherapy tolerance and efficacy.

PP2A and tumor radiotherapy.

Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that serves as a key regulator of cellular physiology in the context of apoptosis, mitosis, and DNA damage responses. Canonically, PP2A functions as a tumor suppressor gene. However, recent evidence suggests that inhibiting PP2A activity in tumor cells may represent a viable approach to enhancing tumor sensitivity to chemoradiotherapy as such inhibition can cause cells to enter a disordered mitotic state that renders them more susceptible to cell death. Indeed, there is evidence that inhibiting PP2A can slow tumor growth following radiotherapy in a range of cancer types including ovarian cancer, liver cancer, malignant glioma, pancreatic cancer, and nasopharyngeal carcinoma. In the present review, we discuss current understanding of the role of PP2A in tumor radiotherapy and the potential mechanisms whereby it may influence this process.

Glucosamine protects against radiation-induced lung injury via inhibition of epithelial-mesenchymal transition.

Radiotherapy is one of the most important treatments for chest tumours. Although there are plenty of strategies to prevent damage to normal lung tissues, it cannot be avoided with the emergence of radiation-induced lung injury. The purpose of this study was to investigate the potential radioprotective effects of glucosamine, which exerted anti-inflammatory activity in joint inflammation. In this study, we found glucosamine relieved inflammatory response and structural damages in lung tissues after radiation via HE staining. Then, we detected the level of epithelial-mesenchymal transition marker in vitro and in vivo, which we could clearly observe that glucosamine treatment inhibited epithelial-mesenchymal transition. Besides, we found glucosamine could inhibit apoptosis and promote proliferation of normal lung epithelial cells in vitro caused by radiation. In conclusion, our data showed that glucosamine alleviated radiation-induced lung injury via inhibiting epithelial-mesenchymal transition, which indicated glucosamine could be a novel potential radioprotector for radiation-induced lung injury.

Knockdown GTSE1 enhances radiosensitivity in non-small-cell lung cancer through DNA damage repair pathway.

Radiotherapy is an important strategy for NSCLC. However, although a variety of comprehensive radiotherapy-based treatments have dominated the treatment of NSCLC, it cannot be avoided to overcome the growing radioresistance during radiotherapy. The purpose of this study was to elucidate the radiosensitizing effects of NSCLC via knockdown GTSE1 expression and its mechanism. Experiments were performed by using multiple NSCLC cells such as A549, H460 and H1299. Firstly, we found GTSE1 conferred to radioresistance via clonogenic assay and apoptosis assay. Then, we detected the level of DNA damage through comet assay and γH2AX foci, which we could clearly observe knockdown GTSE1 enhance DNA damage after IR. Furthermore, through using laser assay and detecting DNA damage repair early protein expression, we found radiation could induce GTSE1 recruited to DSB site and initiate DNA damage response. Our finding demonstrated that knockdown GTSE1 enhances radiosensitivity in NSCLC through DNA damage repair pathway. This novel observation may have therapeutic implications to improve therapeutic efficacy of radiation.

Precise prediction of the radiation pneumonitis in lung cancer: an explorative preliminary mathematical model using genotype information.

Purpose: Radiation pneumonitis (RP) is the most significant dose-limiting toxicity and is one major obstacle for lung cancer radiotherapy. Grade ≥2 RP usually needs clinical interventions and serve RP could be life threatening. Clinically, tissue response could be strikingly different even two similar patients after identical radiotherapy. Previous methods for the RP prediction can hardly distinguish substantial variations among individuals. Reliable predictive factors or methods emphasizing the individual differences are strongly desired by clinical radiation oncologists. The purpose of this study is to develop an approach for the personalized RP risk prediction. Experimental Design: One hundred eighteen lung cancer patients who received radiotherapy were enrolled. Seven hundred thousand single-nucleotide polymorphism (SNP) sites were assessed via Generalized Linear Models via Lasso and Elastic-Net Regularization (GLMNET) to determine their synergistic effects on the RP risk prediction. Non-genetic factors including patient's phenotypes and clinical interventional parameters were separately assessed by statistic test. Based on the results of the aforementioned analysis, a multiple linear regression model named Radiation Pneumonitis Index (RPI) was built, for the assessment of Grade ≥2RP risk. Results: Only previous surgery and fractional dose were discovered statistical significantly associated with grade ≥2RP. Thirty-nine effective SNPs for predicting the Grade ≥2RP risk were discovered and their coefficients of the synergistic effect were determined. The RPI score can successfully distinguish the RP≥2 population with 92.0% sensitivity and 100% specificity. Conclusions: Individual radiation sensitivity can be determined with genotype information and personalized radiotherapy could be achieved based on mathematical model result.

[Automatic segmentation of head and neck organs at risk based on three-dimensional U-NET deep convolutional neural network].

The segmentation of organs at risk is an important part of radiotherapy. The current method of manual segmentation depends on the knowledge and experience of physicians, which is very time-consuming and difficult to ensure the accuracy, consistency and repeatability. Therefore, a deep convolutional neural network (DCNN) is proposed for the automatic and accurate segmentation of head and neck organs at risk. The data of 496 patients with nasopharyngeal carcinoma were reviewed. Among them, 376 cases were randomly selected for training set, 60 cases for validation set and 60 cases for test set. Using the three-dimensional (3D) U-NET DCNN, combined with two loss functions of Dice Loss and Generalized Dice Loss, the automatic segmentation neural network model for the head and neck organs at risk was trained. The evaluation parameters are Dice similarity coefficient and Jaccard distance. The average Dice Similarity coefficient of the 19 organs at risk was 0.91, and the Jaccard distance was 0.15. The results demonstrate that 3D U-NET DCNN combined with Dice Loss function can be better applied to automatic segmentation of head and neck organs at risk.

GSTP1 Ile105Val polymorphism might be associated with the risk of radiation pneumonitis among lung cancer patients in Chinese population: A prospective study.

Background: Growing data suggest that DNA damage repair and detoxification pathways play crucial roles in radiation-induced toxicities. To determine whether common functional single-nucleotide polymorphisms (SNPs) in candidate genes from these pathways can be used as predictors of radiation pneumonitis (RP), we conducted a prospective study to evaluate the associations between functional SNPs and risk of RP. Methods: We recruited a total of 149 lung cancer patients who had received intensity modulated radiation therapy (IMRT). GSTP1 and XRCC1 were genotyped using the SurPlexTM-xTAG method in all patients. RP events were prospectively scored using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Kaplan-Meier analysis was used to determine the cumulative probability of RP of grade ≥ 2. Cox proportional hazard regression was performed to identify clinical variables and SNPs associated with risk of RP grade ≥ 2, using univariate and multivariate analysis, respectively. Results: With a median follow-up of 9 months, the incidence of RP of grade ≥ 2 was 38.3%. A predicting role in RP was observed for the GSTP1 SNP (adjusted hazard ratio 3.543; 95% CI 1.770-7.092; adjusted P< 0.001 for the Ile/Val and Val/Val genotypes versus Ile/Ile genotype). Whereas, we found that patients with XRCC1 399Arg/Gln and Gln/Gln genotypes had a lower risk of RP compares with those carrying Arg/Arg genotype (adjusted HR 0.653; 95% CI 0.342-1.245), but with no statistical significance observed (adjusted P = 0.195). Conclusions: Our results suggested a novel association between GSTP1 SNP 105Ile/Val and risk of RP development, which suggests the potential use of this genetic polymorphism as a predictor of RP. In addition, genetic polymorphisms of XRCC1 399Arg/Gln may also be associated with RP.

Association of DNA repair gene polymorphisms with the risk of radiation pneumonitis in lung cancer patients.

A total of 149 lung cancer patients were recruited to receive intensity modulated radiation therapy (IMRT). The association of developing radiation pneumonitis (RP) with genetic polymorphism was evaluated. The risks of four polymorphic sites in three DNA repair related genes (ERCC1, rs116615:T354C and rs3212986:C1516A; ERCC2, rs13181:A2251C; XRCC1, rs25487:A1196G) for developing grade ≥ 2 RP were assessed respectively. It was observed that ERCC1 T354C SNP had a significant effect on the development of grade ≥ 2 RP (CT/TT vs. CC, adjusted HR = 0.517, 95% CI, 0.285-0.939; adjusted P = 0.030). It is the first time demonstrating that CT/TT genotype of ERCC1 354 was significantly associated with lower RP risk after radio therapy.

A propensity-matched analysis of surgery and stereotactic body radiotherapy for early stage non-small cell lung cancer in the elderly.

Elderly patients with early stage non-small cell lung cancer (NSCLC) who undergo surgical resection are at a high risk of treatment-related complications. Stereotactic body radiation therapy (SBRT) is considered an alternative treatment option with a favorable safety profile. Given that prospective comparative data on SBRT and surgical treatments are limited, we compared the 2 treatments for early stage NSCLC in the elderly.We retrospectively collected information from the database at our geriatric institution on patients with clinical stage IA/B NSCLC who were treated with surgery or SBRT. The patients were matched using a propensity score based on gender, age, T stage, tumor location, pulmonary function (forced expiratory volume in 1 second [FEV1]% and FEV1), Charlson comorbidity score, and World Health Organization performance score. We compared locoregional control rate, recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS) between the 2 treatment cohorts before and after propensity score matching.A total of 106 patients underwent surgery, and 74 received SBRT. Surgical patients were significantly younger (72.6 ±â€Š7.9 vs 82.6 ±â€Š4.1 years, P = 0.000), with a significantly higher rate of adenocarcinoma (P = 0.000), better Eastern Cooperative Oncology Group performance scores (P = 0.039), and better pulmonary function test results (P = 0.034 for predicted FEV1 and P = 0.032 for FEV1). In an unmatched comparison, there were significant differences in locoregional control (P = 0.0012) and RFS (P < 0.001). The 5-year OS was 69% in patients who underwent surgery and 44.6% in patients who underwent SBRT (P = 0.0007). The 5-year CSS was 73.9% in the surgery group and 57.5% in the SBRT group (P = 0.0029). Thirty-five inoperable or marginally operable surgical patients and 35 patients who underwent SBRT were matched to their outcomes in a blinded manner (1:1 ratio, caliper distance = 0.25). In this matched comparison, the follow-up period of this subgroup ranged from 4.2 to 138.1 months, with a median of 58.7 months. Surgery was associated with significantly better locoregional control (P = 0.0191) and RFS (P = 0.0178), whereas no significant differences were found in OS (5-year OS, 67.8% for surgery vs 47.4% for SBRT, P = 0.07) or CSS (67.8% for surgery vs 58.2% for SBRT, P = 0.1816).This retrospective analysis found superior locoregional control rates and RFS after surgery compared with SBRT, but there were no differences in OS or CSS. SBRT is an alternative treatment option to surgery in elderly NSCLC patients who cannot tolerate surgical resection because of medical comorbidities. Our findings support the need to compare the 2 treatments in randomized controlled trials.

6-OH-BDE-47 promotes human lung cancer cells epithelial mesenchymal transition via the AKT/Snail signal pathway.

Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have been detected in the various human tissues. The OH-PBDEs are suggested to be stronger endocrine-disrupting compounds than PBDEs, therefore the toxicological effects of OH-PBDEs had received lots of attention. However, there is no study about the carcinogenic effect of OH-PBDEs and their estrogen potencies on the tumorigenesis and development of cancer. In the present study, we found that 6-hydroxy-2,2',4',4'-tetrabromodiphenyl ether (6-OH-BDE-47), the most abundant OH-PBDE congeners in human serum, promoted the in vitro migration of lung cancer A549 and H358 cells by induction of epithelial to mesenchymal transition (EMT). This was confirmed by that 6-OH-BDE-47 significantly down regulated the expression of epithelial markers E-cadherin (E-Cad) and zona occludin-1 (ZO-1) while up regulated the mesenchymal markers vimentin (Vim) and N-cadherin (N-Cad). 6-OH-BDE-47 up regulated the protein while not mRNA levels of Snail, which was the key transcription factor of EMT. Silencing of Snail by use of siRNA attenuated the 6-OH-BDE-47 induced EMT. This suggested that the stabilization of Snail was essential for 6-OH-BDE-47 induced EMT. Further, the treatment of 6-OH-BDE-47 increased the phosphorylation of AKT and ERK in A549 cells. Only PI3K/AKT inhibitor (LY294002), but not ERK inhibitor (PD98059), completely blocked the 6-OH-BDE-47 induced up regulation of Snail and down regulation of E-Cad, suggesting that PI3K/AKT pathway is important for 6-OH-BDE-47-mediated Snail stabilization and EMT in A549 cells. Generally, our results revealed for the first time that 6-OH-BDE-47 promoted the EMT of lung cancer cells via AKT/Snail signals. This suggested that more attention should be paid to the effects of OH-PBDEs on tumorigenesis and development of lung cancer.

Hyperthermia inhibits the proliferation and invasive ability of mouse malignant melanoma through TGF-ß(1).

The degradation of basement membranes by tumor cells involves secretion and activation of proteinases, such as the matrix metalloproteinases (MMPs), and results from an imbalance between their inhibitors and activators that are controlled by various growth factors or cytokines, among which TGF-ß(1) may be the most intriguing. In order to study the therapeutic effect and molecular mechanism of hyperthermia on aggressive malignant melanoma, the expression levels of TGF-ß(1) and Smad4 in B16F10 cells were dynamically analyzed by RT-PCR and western blotting for 24 h after heat treatment, from which time-dependent changes were determined. As expected, the proliferation and invasive ability of B16F10 cells were suppressed strongly by heat treatment. Furthermore, we compared the expression of TGF-ß(1) in melanoma mouse models before and after magnetic fluid hyperthermia (MFH) in vivo. After hyperthermia, the tumor growth rate was reduced with a decline in TGF-ß(1) protein expression. We conclude that changes in the TGF-ß(1) pathway induced by hyperthermia may be an important part of the molecular mechanism involved.

Dose-volume parameters and clinical outcome of CT-guided free-hand high-dose-rate interstitial brachytherapy for cervical cancer.

Currently, image-based 3-dimentional (3D) planning brachytherapy allows for a better assessment of gross tumor volume (GTV) and the definition and delineation of target volume in cervix cancer. In this study, we investigated the feasibility of our novel computed tomography (CT)-guided free-hand high-dose-rate interstitial brachytherapy (HDRISBT) technique for cervical cancer by evaluating the dosimetry and preliminary clinical outcome of this approach. Dose-volume histogram (DVH) parameters were analyzed according to the Gynecological GEC-ESTRO Working Group recommendations for image-based 3D treatment in cervical cancer. Twenty cervical cancer patients who underwent CT-guided free-hand HDRISBT between March 2009 and June 2010 were studied. With a median of 5 (range, 4-7) implanted needles for each patient, the median dose of brachytherapy alone delivered to 90% of the target volume (D90) was 45 (range, 33-54) Gyα/ß10 for high-risk clinical target volume (HR-CTV) and 30 (range, 20-36) Gyα/ß10 for intermediate-risk clinical target volume (IR-CTV). The percentage of the CTV covered by the prescribed dose (V100) of HR-CTV with brachytherapy alone was 81.9%-99.2% (median, 96.7%). With an additional dose of external beam radiotherapy (EBRT), the median D90 was 94 (range, 83-104) Gyα/ß10 for HR-CTV and 77 (range, 70-87) Gyα/ß10 for IR-CTV; the median dose delivered to 100% of the target volume (D100) was 75 (range, 66-84) Gyα/ß10 for HR-CTV and 65 (range, 57-73) Gyα/ß10 for IR-CTV. The minimum dose to the most irradiated 2 cc volume (D2cc) was 73-96 (median, 83) Gyα/ß3 for the bladder, 64-98 (median, 73) Gyα/ß3 for the rectum, and 52-69 (median, 61) Gyα/ß3 for the sigmoid colon. After a median follow-up of 15 months (range, 3-24 months), two patients experienced local failure, and 1 showed internal iliac nodal metastasis. Despite the relatively small number of needles used, CT-guided HDRISBT for cervical cancer showed favorable DVH parameters and clinical outcome.

[Clinical analysis of 6 cases of primary small cell carcinoma of the larynx].

OBJECTIVE: To study the clinical characteristics, pathological features, diagnosis, therapy and prognosis of primary small cell carcinoma of the larynx (PSCCL). METHODS: Six cases of PSCCL collected from 1990 to 2009 was retrospectively analyzed. The diagnosis was confirmed by pathological examination. Among six patients, one case belonged to stage III, and the others were in stage IVA. One case abandoned treatment; one case received chemotherapy; one case underwent supraglottic hemilaryngectomy and adjuvant chemoradiotherapy; one case underwent induction chemotherapy, radiotherapy and consolidation chemotherapy. Two cases received induction chemotherapy, concurrent chemoradiation and consolidation chemotherapy. The drug regimens included bleomycin, fluorouracil, cisplatin, etoposide and taxel for 3-6 cycles. The radiotherapy technique included conventional radiotherapy, CT-Sim and three dimensional conformal radiation therapy with (60)Co or 4 MV X-ray for 60 - 66 Gy during 6 - 7 weeks. RESULTS: The time of follow-up was 3 - 24 months and the median was 13 months. Two patients applied with concurrent chemoradiation were alive without tumor. The patient abandoning therapy died of respiratory failure, and the others died of lung or liver metastasis after 8 - 12 months. CONCLUSIONS: PSCCL is a disseminated disease, so the pretreatment evaluation is necessary. Concurrent chemoradiation is an ideal treatment model for this disease.