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Hongqing Zhuang,1,* Xianzhi Zhao,1,* Lujun Zhao,1 Joe Y Chang,2 Ping Wang1 1Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, and Tianjin Lung Cancer Center, Tianjin, People's Republic of China; 2Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA *These authors contributed equally to this paper Abstract: The combination of radiotherapy and targeted therapy is an important approach in the application of targeted therapy in clinical practice, and represents an important opportunity for the development of radiotherapy itself. Numerous agents, including epidermal growth factor receptor, monoclonal antibodies, tyrosine kinase inhibitors, and antiangiogenic therapies, have been used for targeted therapy. A number of studies of radiotherapy combined with targeted therapy in non-small-cell lung carcinoma have been completed or are ongoing. This paper briefly summarizes the drugs involved and the important related clinical research, and indicates that considerable progress has been made with the joint efforts of the two disciplines. Many issues, including drug selection, identification of populations most likely to benefit, timing of administration of medication, and side effects of treatment require further investigation. However, further fundamental research and accumulation of clinical data will provide a more comprehensive understanding of these therapies. Targeted therapy in combination with radiotherapy has a bright future. Keywords: non-small-cell lung carcinoma, radiotherapy, epidermal growth factor receptor, monoclonal antibody, tyrosine kinase inhibitors, antiangiogenic therapies

Although intravenous bevacizumab (IVBEV) is the most promising treatment for cerebral radiation necrosis (CRN), there is no conclusion on the optimal dosage. Our retrospective study aimed to compare the efficacy and safety of high-dose with low-dose IVBEV in treating CRN associated with radiotherapy for brain metastases (BMs). This paper describes 75 patients who were diagnosed with CRN secondary to radiotherapy for BMs, treated with low-dose or high-dose IVBEV and followed up for a minimum of 6 months. The clinical data collected for this study include changes in brain MRI, clinical symptoms, and corticosteroid usage before, during, and after IVBEV treatment. At the 3-month mark following administration of IVBEV, a comparison of two groups revealed that the median percentage decreases in CRN volume on T2-weighted fluid-attenuated inversion recovery and T1-weighted gadolinium contrast-enhanced image (T1CE), as well as the signal ratio reduction on T1CE, were 65.8% versus 64.8% (p = 0.860), 41.2% versus 51.9% (p = 0.396), and 37.4% versus 35.1% (p = 0.271), respectively. Similarly, at 6 months post-IVBEV, the median percentage reductions of the aforementioned parameters were 59.5% versus 62.0% (p = 0.757), 39.1% versus 31.3% (p = 0.851), and 35.4% versus 28.2% (p = 0.083), respectively. Notably, the incidence of grade ≥3 adverse events was higher in the high-dose group (n = 4, 9.8%) than in the low-dose group (n = 0). Among patients with CRN secondary to radiotherapy for BMs, the administration of high-dose IVBEV did not demonstrate superiority over low-dose IVBEV. Moreover, the use of high-dose IVBEV was associated with a higher incidence of grade ≥3 adverse events compared with low-dose IVBEV., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background and Aims: The study aimed to create a new staging model for radiotherapy-based treatment for prognostic hepatocellular carcinoma (HCC) classification., Methods: The training cohort comprised 658 patients receiving stereotactic body radiotherapy and external validation cohort comprised 533 patients receiving three-dimensional conformal radiotherapy and intensity-modulated radiotherapy. We established a modified staging system as follows: stage I, solitary nodule without macrovascular invasion, or 2-3 nodules no more than 3.0 cm apart, and performance status (PS) 0-2 (Ia: ALBI-1 grade; Ib: ALBI-2 or 3 grade); stage II: 2-3 nodules with any one nodule more than 3.0-cm apart, or ≥4 nodules, and performance status 0-2 (IIa: ALBI-1 grade; IIb: ALBI-2 grade); stage III: macrovascular invasion, regional lymph node metastasis or distant metastasis, and performance status 0-2 (IIIa: ALBI-1 grade; IIIb: ALBI-2 grade); stage IV: performance status 3-4, or performance status 0-2 with ALBI-3 grade. We analyzed long-term overall survival based on different stages., Results: The staging model showed an excellent ability to discriminate patients according to four stages and seven substages with notably different curves in the training and validation cohort. The median survival decreased from stages I to IV with 63.0 months in stage I (not reached in Ia, and 53.0 months in Ib), 24.0 months in stage II (28.0 months in IIa, and 22.0 months in IIb), 11.0 months in stage III (18.0 months in IIIa, and 9.0 months in IIIb), and less than 9.0 months in stage IV in the training cohort., Conclusions: The modified staging model may provide an alternative for clinical radiation oncologists., Competing Interests: The authors have no conflicts of interest related to this publication., (© 2023 Authors.)

Hydrogen sulfide (H 2 S) is widely recognized as the third endogenous gas signaling molecule and may play a key role in cancer biological processes. ADT-OH (5-(4-hydroxyphenyl)-3H-1,2-dithiocyclopentene-3-thione) is one of the most widely used organic donors for the slow release of H 2 S and considered to be a potential anticancer compound. In this study, we investigated the antimetastatic effects of ADT-OH in highly metastatic melanoma cells. A tail-vein-metastasis model was established by injecting B16F10 and A375 cells into the tail veins of mice, whereas a mouse footpad-injection model was established by injecting B16F10 cells into mouse footpads. We showed that administration of ADT-OH significantly inhibited the migration and invasion of melanoma cells in the three different animal models. We further showed that ADT-OH dose-dependently inhibited the migration and invasion of B16F10, B16F1 and A375 melanoma cells as evaluated by wound healing and Transwell assays in vitro. LC-MS/MS and bioinformatics analyses revealed that ADT-OH treatment inhibited the EMT process in B16F10 and A375 cells by reducing the expression of FAK and the downstream response protein Paxillin. Overexpression of FAK reversed the inhibitory effects of ADT-OH on melanoma cell migration. Moreover, after ADT-OH treatment, melanoma cells showed abnormal expression of the H 2 S-producing enzymes CSE/CBS and the AKT signaling pathways. In addition, ADT-OH significantly suppressed the proliferation of melanoma cells. Collectively, these results demonstrate that ADT-OH inhibits the EMT process in melanoma cells by suppressing the CSE/CBS and FAK signaling pathways, thereby exerting its antimetastatic activity. ADT-OH may be used as an antimetastatic agent in the future., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Objective: To investigate the efficacy and safety of anti-vascular drug anlotinib in combination with stereotactic radiosurgery (SRS) for the treatment of brain metastases from non-small cell lung cancer (NSCLC). Methods: A total of 46 patients diagnosed with NSCLC brain metastases and treated with SRS in Peking University Third Hospital were included from October 2017 to June 2019. Of these, 21 patients (33 lesions) received anlotinib combined with SRS (combined treatment group), while 25 patients (35 lesions) only received SRS (SRS-alone group). The data of combined treatment group and SRS-alone group were compared, including remission rate of intracranial hypertension, response rate (RR) of local control of intracranial lesions, incidence of radiation-induced brain necrosis and intracranial progression-free survival (iPFS). The medication and adverse reactions of anlotinib in the combined treatment group were recorded. Results: The remission rate of intracranial hypertension in the combined treatment group was 71.4% (15/21), which was significantly higher than that in the SRS-alone group [12.0% (3/25), P< 0.001). However, the RR of combined treatment group and SRS-alone group was 80.9% (17/21) and 60.0% (15/25), respectively, with no statistically significant difference ( P =0.289). The incidence of radiation-induced brain necrosis in the combined treatment group was 3.0% (1/33), which was significantly lower than that in the SRS-alone group [20.0% (7/35), P =0.030]. The iPFS of the combination treatment group was (13.9±2.4) months, which was significantly longer than that in the SRS-alone group [(11.4±1.8) months, P <0.001]. The medication time of anlotinib in the combined treatment group was 6 (6, 18) weeks. One patient developed grade Ⅰ hypertension and one patient developed grade Ⅰ hand-foot syndrome. The incidence of drug-related adverse reactions was 9.5% (2/21). Conclusions: Anlotinib in combination with SRS may relieve brain edema, reduce the rate of radiation-induced brain necrosis, and the rate of drug-related adverse reactions were low.

Objective: To assess the potential dosimetric effects of arms movement in patients with Cyberknife spine tumors., Methods: In the study, 12 patients with thoracic and lumbar tumors were retrospectively selected respectively. The contour of the patient's arms was sketched and the CT density was modified to be equivalent to air in order to simulate the extreme case when the arm was completely removed from the radiation fields. The dose of simulated plan was re-calculated with the original beam parameters and compared with the original plan. The changes of V 100 , D 95 , and D 90 , conformity index (CI) and heterogeneity index (HI) in planning target volume (PTV), as well as D max , D 1cc and D 2cc in the spinal cord, stomach, esophagus, and intestines were analyzed by comparing with the original plans., Results: Compared with the original treatment plan, V 100 , D 95 , D 90 and CI of PTV for the simulated plan was increased by 0.86%, 2.02%, 1.97% and 0.80% respectively, the difference was statistically significant ( P < 0.05). D max , D 1cc and D 2cc of spinal cord was increased by 2.35%, 0.59% and 1.49% on average, compared with the original plan, the difference was statistically significant ( P < 0.05). The difference was statistically significant only in average D 2cc of stomach, which was increased by 1.70%, compared with the original plan ( P < 0.05). There was no significant difference in dose change of eso-phagus and intestine between the original and simulated plans., Conclusion: This study analyzed the most extreme arm position in spinal tumor of radiation therapy based on Cyberknife. It was found that the change of arm position had little effect on dosimetry. In addition, with the change of arm position, the dose in PTV and organ at risk (OAR) increased, but the increase was relatively small. Therefore, in some special cases where the patient really can't keep the arm position consistent during treatment, reasonable adjustment can be accepted. However, in order to ensure accurate radiotherapy, patient position should be as stable and consistent as possible.

Background: We sought to compare local tumor control after conventionally fractionated image-guided intensity-modulated radiotherapy (IMRT) versus adjuvant CyberKnife stereotactic body radiotherapy (SBRT) in patients who underwent separation surgery for metastatic epidural spinal cord compression (MESCC)., Methods: We retrospectively reviewed patients with MESCC who were treated at our hospital. The Kaplan-Meier method was used to estimate local progression and overall survival., Results: Fifty-six patients with MESCC underwent separation surgery between 2013 and 2018, among whom 6 were lost to follow-up, 24 received conventionally fractionated image-guided IMRT, and 26 were treated with CyberKnife SBRT. The median follow-up was 16.5 months (range, 2.1-47.5 months). Eleven patients experienced local failure including 9 and 2 from the IMRT and SBRT groups, respectively. The local progression-free survival rates were significantly higher in the SBRT group than IMRT group at 6 months (95.5% vs. 82.0%), 1 year (90.9% vs. 71.8%), and 2 years (90.9% vs. 57.6%) (P = 0.035). Multivariate Cox proportional hazards regression analysis identified radiotherapy method (P = 0.034) and receipt of preoperative radiotherapy (P = 0.047) as significant predictors of local control, while visceral metastasis (P = 0.048) and high-malignancy primary tumor type (P = 0.002) were negative predictors of overall survival. Moreover, postoperative SBRT was noninferior to IMRT in terms of pain control, adverse effects, and performance in treating irradiated spinal metastases., Conclusions: Hybrid surgery-radiosurgery therapy is a safe and effective treatment option for patients with MESCC. SBRT provided higher local control rates compared with IMRT. Thus postoperative SBRT should be considered for patients expected to have relatively long survival., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Secreted effectors from Magnaporthe oryzae play critical roles in the interaction with rice to facilitate fungal infection and disease development. M. oryzae -secreted protein MoHrip1 can improve plant defense as an elicitor in vitro, however, its biological function in fungal infection is not clear. In this study, we found that the expression of mohrip1 was significantly induced in the stages of fungal penetration and colonization. Although dispensable for the growth and conidiation, MoHrip1 was necessary for the full virulence of M. oryzae . Deletion of mohrip1 remarkably compromised fungal virulence on rice seedlings and even on rice leaves with wounds. Rice sheath inoculation assay further demonstrated the defects of mohrip1 -deleted mutants on penetration and proliferation in rice cells. Additionally, compared with WT and complementation strain, the inoculation of mohrip1 -deleted mutants induced a higher expression of specific defense related genes and a higher production of specific defensive compounds in rice leaves. These data collectively indicated that MoHrip1 is necessary for fungal penetration and invasive expansion, and further full virulence of rice blast fungus.

Cancer patients are at high risk for suicide, particularly when they are informed about the cancer diagnosis or hospitalized for cancer treatment. Therefore, oncology healthcare settings such as large general hospitals in China, may represent an ideal setting to identify and treat suicidality in cancer patients. However, the clinical epidemiology of suicidality of Chinese cancer patients remains largely unknown. This study examined the prevalence and correlates of suicidal ideation among Chinese cancer inpatients of large general hospitals. A total of 517 cancer inpatients were consecutively recruited from two tertiary general hospitals of a metropolitan city in northern China, and administered with standardized questionnaires to collect data on sociodemographics, mental health, and cancer-related clinical characteristics. Suicidal ideation and mental health were measured with a single self-report question "In the past month, did you think about ending your life?" and Hospital Anxiety and Depression Scale, respectively. The one-month prevalence of suicidal ideation was 15.3% in Chinese cancer inpatients. In multivariable Logistic regression, depression, anxiety, moderate-to-severe pain, metastatic cancer, poor performance status, surgery, and palliative care were significantly associated with suicidal ideation. Cancer inpatients of large Chinese general hospitals have high prevalence of suicidal ideation and therefore potentially at high risk for suicide. Suicide prevention efforts for cancer inpatients should include periodic evaluation of suicidality, effective pain management, psychooncological supports, and, when necessary, psychiatric treatment and crisis intervention.

Background: Radiosensitivity by blocking the epidermal growth factor receptor and cyclooxygenase-2 pathways with erlotinib and celecoxib in A549 human lung cancer cell was investigated., Methods: MTT assays were used to detect the antitumor effects of erlotinib and celecoxib in A549 cells. Colony formation assays were used to evaluate the antitumor effects. Flow cytometry analysis was used to assess the cell cycle and cell apoptosis, and western blotting analysis was performed to evaluate the expression of AKT and phosphorylated AKT., Results: Either erlotinib or celecoxib inhibited the A549 cell proliferation in a dose-dependent manner. Combining Erlotinib or celecoxib with radiation can suppress the cell colony formation and the Dq, D0, SF2 of the combining erlotinib or celecoxib with radiation was lower than in the combinations either erlotinib or celecoxib with radiation (t= 6.62, P< 0.05). The SER of radiation with celecoxib or erlotinib and celecoxib and erlotinib were 1.299, 1.503 and 2.217, respectively. The Flow cytometry analysis results showed that either celecoxib or erlotinib could induce G0/G1 arrest, and reduction of S phase cell proportion, especially when combinations erlotinib-celecoxib with radiation. Either celecoxib or erlotinib could enhance radiation-induced apoptosis, especially significant when combinations erlotinib-celecoxib with radiation. Moreover, radiation can promote the expression of pAKT, and the pAKT was remarkably lowest in the combinations erlotinib-celecoxib with radiation group (t= 4.89, P< 0.05)., Conclusions: Blocking both EGFR- and COX-2-related pathways could enhance the antitumor effect of radiation. The underlying mechanisms including the enhancement of apoptosis and radiation-induced G0/G1 arrest, possibly via inhibiting the PI3K/AKT signaling pathway.

Aims: This study evaluated the safety and efficacy of stereotactic radiation therapy (SRT) for the treatment of patients with oligometastases or oligorecurrence within mediastinal lymph nodes (MLNs) originating from different tumors., Methods: Between October 2006 and May 2015, patients with MLN oligometastases or oligorecurrence were enrolled and treated with SRT at our hospital. The primary endpoint was MLN local control (LC). Secondary endpoints were time to symptom alleviation, overall survival (OS) after SRT, and toxicity using the Common Terminology Criteria for Adverse Events (CTCAE v4.0)., Results: Eighty-five patients with 98 MLN oligometastases or oligorecurrences were treated with SRT. For the entire cohort, the 1-year and 5-year actuarial LC rates were 97% and 77%, respectively. Of 53 symptomatic patients, symptom alleviation was observed in 47 (89%) after a median of 5 days (range, 3-30 days). The median OS was 27.2 months for all patients. For patients with non-small cell lung cancer, univariate and multivariate analyses revealed that a shorter interval between diagnosis of primary tumors and SRT and larger MLN SRT volume were associated with worse OS. CTCAE v4.0 ≥ Grade 3 toxicities occurred in six patients (7%), with Grade 5 in three patients (all with RT history to MLN station 7)., Conclusions: SRT is a safe and efficacious treatment modality for patients with oligometastases or oligorecurrence to MLNs originating from different tumors, except for patients who received radiotherapy to MLN station 7. Further investigation is warranted to identify the patients who benefit most from this treatment modality.

Aims: To evaluate the safety and efficacy of stereotactic radiotherapy (SRT, both stereotactic body RT [SBRT] and fractionated stereotactic RT [FSRT]) in the treatment of patients with recurrent or second primary mediastinal lymph node metastases (R/SP-MLNMs) originating from non-small cell lung cancer (NSCLC)., Methods: Between 10/2006 and 7/2013, patients with R/SP-MLNMs originating from NSCLC were enrolled and treated with SRT at our hospital; their data was stored in prospectively-collected database. The enrolled patients were divided into Group A (without prior RT) and Group B (with prior RT). The primary end-point was overall survival (OS). The secondary end-points were the MLNM local control (LC), the time to symptom alleviation, and toxicity using the Common Terminology Criteria for Adverse Events (CTCAE v4.0)., Results: Thirty-three patients were treated (16 in Group A with 19 R/SP-MLNMs and 17 in Group B with 17 R/SP-MLNMs). For the entire cohort, the median OS was 25.5 months with a median follow-up of 20.9 months (range, 3.2-82). The 1-year and 3-year actuarial LC rates were 100% and 86%, respectively. Symptom alleviation was observed in 52% of patients, after a median of 6 days (range, 3-18). CTCAE v4.0 ≥ Grade 3 toxicities occurred in 5 patients (15%; all in Group B); among them, Grade 5 in 2 patients., Conclusions: We recommend exercising extreme caution in using SRT for R/SP-MLNMs in patients who received prior RT (particularly to LN station 7). For patients without previous RT, SRT appears to be safe and efficacious treatment modality; prospective studies are warranted.

Purpose: Erlotinib is a novel therapeutic agent for cancer treatment. This study was performed to investigate the role of c-MET-PI3K-AKT pathway in the regulation of erlotinib-induced radiosensitization., Methods: A973 lung adenocarcinoma cells treated with 6 Gy of radiation were incubated in the presence of erlotinib. The apoptotic rate after 24 hours, the colony-formating rate after 14 days, and changes in the c-MET expression levels after 14 days of irradiation were examined. Surviving fractions in different treatment groups (blank control, radiation alone, erlotinib alone, anti-c-MET monoclonal antibody alone, combined erlotinib and radiation, and combined erlotinib and radiation with anti-c-MET monoclonal antibody groups) were determined, the survival curves were plotted, and the sensitizer enhancement ratio was calculated using colony formation assays. Expressions of c-MET, p-c-MET, PI3K, AKT, and p-AKT in cells in different treatment groups were examined by Western blot analysis., Results: The apoptotic rate in the combined erlotinib and radiation group was higher than those in single treatment groups; however, the colony-forming rate remained approximately 2.04 ± 1.02%. The expression of c-MET in colony-forming cells in the combined group significantly increased, and the blockade of c-MET activity significantly enhanced the radiosensitizing effect of erlotinib. The expression of c-Met, p-c-MET, PI3K, AKT, and p-AKT among colony-forming cells significantly decreased upon the inhibition of c-MET., Conclusions: Upregulated activity of the c-MET-PI3K-AKT pathway was found to be important for cell survival under combined the treatment with erlotinib and radiation. The blockade of the c-MET-PI3K-AKT signaling pathway enhanced the radiosensitizing effect of erlotinib.

Bevacizumab, one of the best-known patents of VEGF inhibitor, has demonstrated significant radiosensitive effects on various preclinical tumor models and clinical trials recently. The radiosensitive effects of this novel patent have achieved satisfactory efficacy through the following mechanisms: normalization of the tumor vasculature, overcoming resistance to radiation, inhibition of repopulation after radiation, and blockade of radiation-induced increased VEGF expression. The combination of bevacizumab with radiotherapy in the treatment of malignant tumors was an inevitable path for the further clinical development of bevacizumab and a very good opportunity for improving the curative effect of radiotherapy. However, many questions such as those regarding the bevacizumab administration dosage and schedule, radio sensitivity efficacy evaluation and multi-target radiosensitive therapy need further research. The advent of bevacizumab combined with radiation has left physicians to encounter multiple challenges as well as opportunities for improving anti-cancer drug treatments.

The aim of the paper is to evaluate the efficacy of CyberKnife® for the treatment of primary or metastatic retroperitoneal tumours. Twenty-eight patients were treated. The prescription isodose line (median, 78%; range, 70-84%) covered the planning target volume at a total dose of 2000-6000 cGy (median, 4500 cGy) and a biologically effective dose of 3750-10,080 cGy (median, 7680 cGy) in 2-10 fractions (median, five fractions). The results showed that the complete response, partial response, stable disease, and progressive disease rates were 43% (12/28), 36% (10/28), 18% (5/28), and 4% (1/28) respectively. The overall response rate was 96%. The 1-, 2- and 3-year local control rates were 92%, 86%, and 86% respectively. The 1-, 2- and 3-year overall survival rates were 60%, 49%, and 49% respectively. No significant difference was found between local progression-free survival and overall survival. Moreover, if a patient only had metastases in the retroperitoneum and local control was effective, there was no significant difference between local progression-free survival and overall progression-free survival. In conclusion, CyberKnife treatment for retroperitoneal tumours resulted in high response rates with minimal side effects. All radiation-induced side effects were well tolerated., (© 2013 John Wiley & Sons Ltd.)

Purpose: To evaluate the efficacy of cyberknife (CK) and neurosurgery (NS) in patients newly diagnosed as solitary brain metastasis (SBM) from non-small cell lung cancer (NSCLC)., Methods and Materials: We retrospectively analyzed 76 patients between 1990 and 2012 from our institution, including 38 patients performing CK and the other half performing NS. The observation end point was overall survival time (OS), local control of treated metastasis (LC) and intracranial control (IC). Kaplan-Meier OS curves were compared with the log-rank test. Cox regression analysis was used to determine prognosticators for OS, LC and IC., Results: The baseline characteristic between the two groups was not significantly different. The 1-year OS rates were 53.5% and 30.5% in the CK group and NS group, respectively, (p=0.121). The 1-year LC rates were 50.8% and 31.3%, respectively, (p=0.078). The 1-year IC rates were 50.8% and 27.7%, respectively, (p=0.066). In multivariate analysis, improved OS was significantly associated with younger age (p=0.016), better ECOG performance status (p=0.000) and graded prognostic assessment (GPA, 3.5-4.0, p=0.006). The LC was also associated with better ECOG performance status (p=0.000). The IC was associated with both better ECOG performance status (p=0.000) and GPA (3.5-4.0, p=0.005)., Conclusions: There was no statistical difference between CK and NS for SBM from NSCLC in OS, LC and IC. However, CK is less invasive and may be more acceptable for patients. The result needs randomized trials to confirm and further study., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Late course accelerated hyperfractionation radiotherapy (LCAHR) is used as a standard treatment option for locally advanced esophageal squamous cell carcinoma (LAESCC) in China, but concerns remain regarding its efficacy and safety. The purpose of this paper was to evaluate the efficacy and safety of LCAHR. The comparisons examined were as follows: LCAHR versus conventional fractionation radiotherapy (CFR) and LCAHR plus chemotherapy (CT) versus LCAHR alone., Methods: We searched the Cochrane Library, MEDLINE, EMBASE, CENTRAL, CBMdisc, and CNKI, as well as employing manual searches. The primary end points were survival and local control. The second end point was toxicities., Results: Based on search criteria, we found 29 trials involving 3187 patients. Our results showed that LCAHR, compared with CFR, improved the survival and local control, and was, thus, more therapeutically beneficial. Further analysis revealed that LCAHR plus CT proved to be better for patients' survival and local control compared to LCAHR alone. Acute toxicities were increased rather than late toxicities., Conclusions: There was a significant survival and local control benefit of LCAHR over CFR, as well as LCAHR plus CT over LCAHR alone. Considering the strength of the evidence, the results of this study indicate that this regimen would be a new promising modality worth further investigation., (© 2012 Tianjin Lung Cancer Institute and Wiley Publishing Asia Pty Ltd.)

Endostatin has been demonstrated to represent a promising novel medicine to treat malignant tumors, and it may be more effective when combined with conventional treatment. Meanwhile, a promising area of research in radiation oncology is the integration of molecular targeting agents to improve the effectiveness of radiotherapy (RT) in the control of primary tumor. Antiangiogenic agents are one such class of targeted therapies and have shown promise in both laboratory and clinical experiments. Endostatin in combination with RT has feasibility; but it also has lots of problems. Further understanding of the mechanisms is needed.

Background: Despite of the recent success of EGFR inhibitory agents, the primary drug-resistant becomes a major challenge for EGFR inhibitor therapies. PTEN gene is an important positive regulatory factor for response to EGFR inhibitor therapy. Low-expression of PTEN is clearly one of the important reasons why tumor cells resisted to tyrosine kinase inhibitors., Methods: To investigate the drug-resistance reversal to gefitinb and the mechanism in PTEN low expression cells which radiated with X-rays in vitro, We demonstrated that H-157 lung cancer cells (low-expression of PTEN but phospho-EGFR overexpressed tumor cells) exposed to X-rays. The PTEN expressions and radiosensitizing effects of tyrosine kinase inhibitor before and after irradiation were observed. The cell-survival rates were evaluated by colony-forming assays. The cell apoptosis was investigated using FCM. The expressions of phospho-EGFR and PTEN were determined by Western blot analysis., Results: The results showed that the PTEN expressions were significantly enhanced by X-rays. Moreover, the cell growth curve and survival curve were down-regulated in the gefitinib-treated groups after irradiation. Meanwhile, the radiation-induced apoptosis of tumor cells was increased by inhibition of the EGFR through up-regulation of PTEN., Conclusion: These results suggested that PTEN gene is an important regulator on TKI inhibition, and the resistance to tyrosine kinase inhibitors might be reversed by irradiation in PTEN low expression cancer cells.

The optimal administration time for applying epidermal growth factor receptor inhibitors combined with radiotherapy has been unclear. We investigated the efficacy of combining gefitinib with radiation in different treatment schedules. We demonstrated that gefitinib was administered to A549 lung cancer cells in three ways (administration before irradiation, administration upon irradiation, administration after irradiation) to establish the radiosensitizing effect. Cell-survival rates were evaluated by colony-forming assays. Cell apoptosis and cell-cycle distribution were investigated using flow cytometry; meanwhile, the expression of P21, Cdc25c, Bcl-2, Bax, Rad51 and phosphorylated DNA-PKcs (phospho-DNA-PK) after 6 Gy irradiation and/or gefitinib were determined by Western blot analysis. The sensitizer enhancement ratios of the gefitinib administration before irradiation, administration upon irradiation, and administration after irradiation groups were 2.23, 1.51 and 1.30, respectively. A higher apoptosis rate and G(2)/M phase arrest were observed in cells at 48 h after exposure to 6 Gy irradiation when gefitinib was administrated before irradiation. Increased cell apoptosis and cell cycle arrest were further supported by the expression changes of Bcl-2, Bax, P21, Cdc25c, Rad51 and phospho-DNA-PK at the same time. The best radiosensitizing effect was obtained when gefitinib was delivered before irradiation. Apoptosis might be an important way of cell killing and G(2)/M phase arrest might be an important mechanism of apoptosis. The expression proportion changes of P21/Cdc25c proteins may play an important role in G(2)/M cell cycle arrest. Moreover, the pro-apoptotic/antiapoptotic and DNA repair factors may be important modulators taking part in the molecular events of the radiosensitizing effect of gefitinib combined with irradiation.

Purpose: CC chemokine receptor 1 (CCR1) plays a critical role in the recruitment of leukocytes to the site of inflammation. Tumor invasion and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. In this study, we aimed to assess the role of CCR1 in non-small cell lung cancer (NSCLC)., Methods: CCR1 expression was determined by Western blotting in two human NSCLC clones (95C and 95D) with different metastatic potential. We silenced CCR1 expression through microRNA-mediated RNA interference, and examined the invasiveness and proliferation of CCR1-silenced NSCLC cell through Matrigel assay and MTT assay. Matrix metalloproteinases (MMPs) activity was determined by gelatin zymography., Results: We found that expression of CCR1 was correlated with the aggressive phenotype of the NSCLC cells. CCR1 knockdown significantly suppressed the invasiveness of NSCLC cells, but had only a minor effect on cell proliferation. Moreover, we demonstrated that CCR1 knockdown significantly reduced the expression level of matrix metalloproteinase-9., Conclusions: These findings suggest that CCR1 contributes to NSCLC cell migration by stimulating cell invasion, independent of cell proliferation. CCR1 might be a new target for NSCLC therapy.

Background: To investigate the effectiveness and mechanism of 125I seed continuous low-dose-rate irradiation on colonic cell line CL187 in vitro., Methods: The CL187 cell line was exposed to radiation of 60Cogamma ray at high dose rate of 2 Gy/min and 125I seed at low dose rate of 2.77 cGy/h. Radiation responses to different doses and dose rates were evaluated by colony-forming assay. Under 125I seed low dose rate irradiation, a total of 12 culture dishes were randomly divided into 4 groups: Control group, and 2, 5, and 10 Gy irradiation groups. At 48 h after irradiation, apoptosis was detected by Annexin and Propidium iodide (PI) staining. Cell cycle arrests were detected by PI staining. In order to investigate the influence of low dose rate irradiation on the MAPK signal transduction, the expression changes of epidermal growth factor receptor (EGFR) and Raf under continuous low dose rate irradiation (CLDR) and/or EGFR monoclonal antibodies were determined by indirect immunofluorescence., Results: The relative biological effect (RBE) for 125I seeds compared with 60Co gamma ray was 1.41. Apoptosis rates of CL187 cancer cells were 13.74% +/- 1.63%, 32.58% +/- 3.61%, and 46.27% +/- 3.82% after 2 Gy, 5 Gy, and 10 Gy irradiation, respectively; however, the control group apoptosis rate was 1.67% +/- 0.19%. G2/M cell cycle arrests of CL187 cancer cells were 42.59% +/- 3.21%, 59.84% +/- 4.96%, and 34.61% +/- 2.79% after 2 Gy, 5 Gy, and 10 Gy irradiation, respectively; however, the control group apoptosis rate was 26.44% +/- 2.53%. P < 0.05 vs. control groups by Student's t-test were found in every treated group both in apoptosis and in G2/M cell cycle arrest. After low dose rate irradiation, EGFR and Raf expression increased, but when EGFR was blocked by a monoclonal antibody, EGFR and Raf expression did not change., Conclusion: 125I seeds resulted in more effective inhibition than 60Co gamma ray high dose rate irradiation in CL187 cells. Apoptosis following G2/M cell cycle arrest was the main mechanism of cell-killing effects under low dose rate irradiation. CLDR could influence the proliferation of cells via MAPK signal transduction.

Human metallothionein III (MT III) gene was synthesized with Escherichia coli preference codon usage and expressed in E. coli in glutathione-S-transferase (GST) fusion form. The recombinant MT III was released by proteinase Factor Xa digestion and purified with the yield of 2 mg/L culture, and its specific Cd2+ binding capability was confirmed. E. coli strain BL21(DE3), expressing MT III, showed metal tolerance between 0.1 and 0.5 mM Cd2+ and bacterial growth was inhibited at 1 mM Cd2+. MT III expressing E. coli strain showed binding discrimination between different metal ions in combination use, with the preference order of Cd2+ > Cu2+ > Zn2+. It absorbed different metal ions with relatively constant ratio and showed a cumulative absorption capability for mixed heavy metals.

The purpose of this paper was to establish a method for the determination of modified bases, 5-methylcytosine and 8-hydroxyguanine, in DNA by GC/FID. The experimental conditions were explored systematically for the quantitative analysis of these two modified bases, and the components were identified by GC/MS. The results showed that the variant components in DNA treated with Fenton's reaction can be derivatized and separated successfully. The relative molar reactive factors of 5-methylcytosine and 8-hydroxyguanine were 3.0 and 1.3, respectively. The sensitivity for them were 5.50 x 10(9) mV.s/g and 7.59 x 10(10) mV.s/g, respectively, while their detectable limits were 36.4 pg/s and 15.8 pg/s, respectively. The coefficients of variation for gas chromatograph were less than 5%, for derivatization, less than 6%, and for the whole analysis process, less than 20%.

Aim: To compare the total coumarins from dried fruits of Cnidium monnieri (TCCM) and nilestriol (Nil) against osteoporosis., Methods: SD rats (40, female, 3-month-old) were randomly divided into basal control, age control, ovariectomized (Ova), Ova + TCCM 67 mg.kg-1, Ova + TCCM 200 mg.kg-1, 6 times a week, and Ova + Nil 1 mg.kg-1, i.g. once a week. After 12 wk, sections (20 microns) of proximal tibiae were examined histologically., Results: Ova reduced markedly the trabecular bone mass due to bone resorption excessed bone formation (% Tb. Ar -59%). Treatment with TCCM 67 mg.kg-1 partly suppressed bone turnover, but did not inhibit bone loss in Ova rats (% Tb.Ar -43%). Treatment with TCCM 200 mg.kg-1 and Nil 1 mg.kg-1 increased the trabecular area (% Tb. Ar +100% and +274%)., Conclusion: Nil was more potent than TCCM in protecting against osteoporosis in Ova rats via supression of bone turnover.