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The joint H2/O2 can promote the transformation of TCE, tDCE and CF. A specific microbial community with higher diversity forms in the H2/O2 microcosm, and synchronously increases the anaerobic tceA and aerobic phe and soxB genes.

Purpose: To investigate the effect of volumetric-modulated arc therapy (VMAT) versus intensity-modulated radiotherapy (IMRT) for advanced non–small-cell lung cancer (NSCLC). Methods: Cases in which the primary tumors were treated with IMRT or VMAT as initial intervention in stages III and IV NSCLC patients from September 2008 to March 2020 were retrospectively analyzed. Propensity Score Matching (PSM) was used to assess the efficacy and toxicity of the two radiotherapy techniques. Results: A total of 637 patients were included, out of which 483 cases were treated with IMRT, while 154 received VMAT. A total of 308 patients were selected after PSM. Patients who were having acute radiation esophagitis and pneumonia treated with VMAT had a lower percentage than those treated with IMRT (p < 0.05) before PSM. However, there was no significant difference in grades 3 - 4 toxicity (χ2 = 2.77, p = 0.096). There were also no significant differences in the primary endpoints between the two groups after PSM (p > 0.05), while for secondary endpoints, all lung V5, and V20, mean lung dose and heart V30, heart V40, mean heart dose in all patients and stage N2 patients in VMAT after PSM were significantly lower than those of IMRT (p < 0.05). Conclusion: Radiation therapy of A-NSCLC primary tumors using VMAT and IMRT seem to produce similar efficacy. The volume parameters of normal tissues and organs is significantly lower in VMAT, especially in patients with stage N2. Therefore, VMAT may be more beneficial for reducing radiation damage in normal tissues and organs.

ObjectiveTo investigate the alteration of subclinical lesions of subcutaneous xenograft tumors in nude mice after EGFR-TKI treatment. MethodsHuman lung adenocarcinoma cell lines were subcutaneously transplanted on the right hind legs of the nude mice in control and treatment groups. Three-dimensional pathological section was taken to observe the subclinical lesion areas when the tumors’ long diameters in the control group grew to specified length. In the Gefitinib treatment group, the subclinical lesions were observed likewise after tumor shrinkage. The results were compared. ResultsThe long diameters of transplanted tumors in group C were 5, 10, 15, and 20mm, the smallest infiltration range of subclinical lesions was 0.23, 0.78, 1.24, and 2.98mm. The edge of transplanted tumor was extended 5.14mm, to include 95% of subclinical lesions. The long diameter of the transplanted tumor in the T group shrank to 15, 10, 5, and 0mm, the smallest infiltration range was 5.74, 2.13, 2.13, and 0.11mm, the edge of the transplanted tumor was extended 8.99mm to include 95% of subclinical lesions. The extended range in T group was significantly larger than group C (P=0.000). ConclusionThe subclinical lesion receded after gefitinib treatment, but was wider than that of tumor of subclinical lesion without treatment. Even if the complete imaging response was achieved, there were still small infiltrating lesions.

The resident standardized training is a basic national policy of cultivating the qualified residents in China and also a top managerial project. To guarantee the training quality, a supervision expert panel of resident standardized training was established in the First Affiliated Hospital of Chongqing Medical University in 2004. Through nearly twenty years of exploration and reform, a supervisory system suitable for the development of resident standardized training in our hospital has been established, and a batch of excellent supervision experts for resident standardized training have been thereby selected to take charge of the supervision of teaching, learning and management during training to enhance the training quality connotation construction.

Objective: To investigate the satisfaction and improvement demand of standardized residency training, and thus provide a basis for its strategy development and efficiency promotion. Methods: During 2017-2018, a survey was performed using a self-designed questionnaire and cluster sampling, involving 1050 standardized residency trainees from some tertiary comprehensive hospitals in Chongqing. The differential effects of various factors on the improvement demand were analyzed with χ2 test. Results: Totally 980 (93.3%) eligible questionnaires were collected. As shown by the analysis in four aspects of residency training management, security and satisfaction, as well as post-training employment plan, the majority of trainees (87.14%) felt satisfactory about the training; the trainees at different educational levels gave high satisfaction to residency training management and clinical skills training, but significantly differential satisfaction to non-clinical skills training, clinical work pressure and salary (P Conclusion: The standardized residency trainees in Chongqing have high overall satisfaction, and present an obvious demand for the improvement of standardized residency training. And the education level of trainees is one of the main influential factors.

Objective: To explore the effects of SOAP with scenario simulation on the clinical performance and professional identity of general residents after the standardized training. Methods: Eighty-six trainees were selected as study objects who received the general resident standardized training in Chongqing from November 2018 to October 2019, and they were divided into control group and study group using the random number table. The conventional general resident standardized training was performed in the control group, and it was conducted by combining SOAP teaching with scenario simulation in the study group. After training, the training environment acceptance and training satisfaction of trainees were evaluated using a self-designed questionnaire. And the changes in the clinical performance and professional identity of trainees were assessed by objective structured clinical examination (OSCE) and using a self-designed “general resident professional identity” questionnaire. Results: The training environment acceptance of trainees in the study group was significantly higher than that in the control group (P 0.05). After training, various item scores of OSCE in both groups were evidently increased (P 0.05), and they were markedly greater in the study group than in the control group (P 0.05); the improvement of professional identity and the training satisfaction in the study group were superior to those in the control group (P 0.05). Conclusion: In the general resident standardized training, SOAP teaching with scenario simulation can effectively improve the clinical performance, training satisfaction and professional identity of general residents, thus it has good feasibility.

Yichao Geng,1– 3,* Shengfa Su,2,3,* Li Cao,2,* Ting Yang,4 Weiwei Ouyang,2,3 Lingfeng Liu,2,3 Bibo Wu,2,3 Qiuning Zhang,5 Bing Lu,2,3 Xiaohu Wang1,5 1The First School of Clinical Medicine, Lanzhou University, Lanzhou, People’s Republic of China; 2Department of Oncology, The Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China; 3Department of Oncology, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, People’s Republic of China; 4Department of Pathophysiology, Guizhou Medical University, Guiyang, People’s Republic of China; 5Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaohu WangThe First School of Clinical Medicine, Lanzhou University, Lanzhou, People’s Republic of China, Tel +8613909407551,Fax +86 931 5196196, Email xhwang@impcas.ac.cn; Bing Lu Department of Oncology, The Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China, Tel +8613809432527, Fax +86 851 6513076, Email lbgymaaaa@163.comPurpose: This study was designed to evaluate the effects of PD-1 inhibitor on lung tissue morphology and the immune system in a mouse model of radiation-induced lung injury (RILI) and to assess interactions between radiation therapy and PD-1 inhibition.Methods: Twenty C57BL/6 mice were divided randomly into four groups of five mice each. Mice were treated with an anti-mouse PD-1 monoclonal antibody, whole thorax irradiation, both or neither. Lung tissue morphology and pathological changes were assessed by hematoxylin-eosin staining; lung fibrosis was assessed by Masson staining and analysis of hydroxyproline; CD3+, CD4+, and CD8+ T lymphocytes in lung tissues were detected immunohistochemically; and the concentrations of transforming growth factor-β 1 (TGF-β 1) and interleukin-6 (IL-6) in lung tissue were evaluated by cytokine multiplex analysis.Results: Lung injury scores and indicators of pulmonary fibrosis were higher in mice administration whole thorax irradiation than in control mice. Inflammatory infiltrate scores, alveoli deformation scores, collagen volume fractions and hydroxyproline contents in lung tissues were all significantly higher in mice administered PD-1 inhibitor plus irradiation than in the other three groups. Similarly, the percentages of CD3+ and CD8+T cells and the concentrations of IL-6 and TGF-β 1 in lung tissue were significantly higher in mice treated with radiation and PD-1 inhibitor than in the other groups. However, PD-1 inhibitor and irradiation interacted significantly only in the elevation of TGF-β 1 level.Conclusion: Whole thorax X-ray irradiation in mice can cause pulmonary injury and fibrosis, which could be exacerbated by PD-1 inhibitors. Radiotherapy combined with PD-1 inhibitors may aggravate RILI by synergistically upregulating TGF-β 1 expression, thereby affecting the immune-inflammatory microenvironment in the lungs.Keywords: PD-1 inhibitors, radiotherapy, radiation fibrosis, lung injury, transforming growth factor-β 1

Objective:.To explore the feasibility of volumetric-modulated arc therapy (VMAT) instead of intensity-modulated radiotherapy (IMRT) for primary tumors of advanced non–small-cell lung cancer (A-NSCLC). Methods:.We used propensity score matching (PSM) and multicenter retrospective analysis to study the efficacy and toxicity of VMAT technology in radiotherapy for primary tumors of A-NSCLC.We used the chi-squared test to analyze the response rate(RR), local control (LC), acute radiation injury, and dose-volume parameters; the Kaplan–Meier and log-rank tests were used to determine local-regional progression-free survival (LRPFS) and overall survival (OS). Results: LRPFS was significantly prolonged in stage III patients treated with IMRT before PSM (P< .05) and cases of grade 1 or 2 acute radiation esophagitis (RE) or radiation pneumonia(RP) in the IMRT than the VMAT(P< .05), but cases of grade 3 or 4 RE and RP were not significantly different between the groups (P> .05). Before PSM, there was no significant difference in the LRPFS and OS rates of the whole study group and the RR, LC, and stage IV subgroups, respectively (P> .05). After PSM, there was no significant difference in the RR, LC, LRPFS, OS, RP, or RE of patients treated with VMAT and IMRT (P> .05), normal whole-lung (V5, V20, MLD), heart (V30, V40, MHD), and equal dose-volume parameters were significantly lower in the VMAT group (P< .05).Conclusion:.Radiation therapy of A-NSCLC primary tumors using VMAT can achieve a similar efficacy to that of IMRT but with significantly lower low-dose volume parameters of normal tissues and organs; this is true especially in stage N2 cases, where the reduction in radiation damage may be more favorable.

5550 Background: Platinum-refractory or platinum-resistant ovarian cancer remains unmet medical need with an unfavorable prognosis. Its treatment options are limited and sequentially with multiple single-agent regimens or bevacizumab plus single-agent regimens are recommended. Mitoxantrone hydrochloride liposome (PLM60) is the first approved mitoxantrone nano-drug, which has shown favorable pharmacokinetic characteristics with long circulation and high cumulation in tumor tissue, thus has a promising anti-tumor activity. This trial aimed to explore the efficacy and safety of PLM60 in patients with platinum-refractory or platinum-resistant ovarian cancer. Methods: In this multi-center, open-label, single arm study, patients with histologically confirmed, epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, either platinum-refractory or platinum-resistant, with at least one measurable lesion were recruited. PLM60 20 mg/m2 was administered on day 1 of each 21-day cycle for up to 8 cycles treatment or until disease progression or intolerable toxicities. The primary endpoint was safety, adverse events were graded according to CTCAE 5.0. Second endpoint included overall response rate (ORR), duration of response (DoR), disease control rate (DCR), progression free survival (PFS) and overall survival (OS) as per RECIST 1.1. Results: 47 eligible patients with a median age of 54 years (range, 35-67) were treated in 7 institutions in China, including 15 platinum-refractory patients and 32 platinum-resistant patients. 32 (68.1%) of 47 patients received at least 3 prior lines of therapy. Treatment related adverse events (TRAEs) of any grade occurred in 45 (95.7%) of 47 patients, in which 31 (66.0%) were ≥ grade 3. The most common ≥ grade 3 TRAEs (incidence ≥10%) were leucopenia (51.1%), neutropenia (40.4%), anemia (19.1%), lymphocytopenia (17.0%) and thrombocytopenia (17.0%). At the cut-off data of October 31 2021, 39 patients were evaluable for response. ORR was 17.9% (7/39, 95% CI:7.5-33.5%, 7 PRs) and DCR was 56.4% (22/39, 95% CI:39.6-72.2%, 15 SDs). Among 21 platinum-resistant patients with ≥3 prior lines, the median DoR was 4.6 month, 2 responders had a DoR of > 6 months. The ORR and DCR of this cohort were 28.6% (6/21, 95% CI: 11.3-52.2%, 6 PRs) and 61.9% (13/21, 95% CI: 38.4-81.9%, 7 SDs), respectively. Median PFS was 3.6 month (95% CI 1.4-4.6), OS data was not mature. Objective response was not observed in platinum-refractory patients. Conclusions: PLM60 had an encouraging efficacy especially in platinum-resistant patients who had received at least 3 prior lines with tolerable safety profiles. Clinical trial information: NCT04718376.

Objectives To develop and prospectively validate a novel model incorporating claims and community-level socioeconomic data to predict preterm birth at scale among pregnant Medicaid women with no history of preterm birth (PTB). Study design A longitudinal Texas Medicaid cohort study, with 2-year retrospective model building (October 2015-October 2017) and a 1-year prospective model validation phase (January 2018-December 2018). Methods Inclusion criteria were females aged 11 to 55 years with at least 1 live singleton birth and no history of PTB. The primary outcome was live singleton birth earlier than 35 weeks. Covariates were medical/mental/behavioral comorbidities, obstetric history, sociodemographic characteristics, and health services utilization. Of multiple models built, the most parsimonious was selected to classify pregnancies as very high, high, medium, and low risk. Model performance was evaluated using positive predictive value (PPV), sensitivity, case identification ratio (1 / PPV), and timing of prediction. Results The model was built on 6689 pregnancies and validated on 7855 pregnancies. PTB rate earlier than 35 weeks was approximately 3.3%. Significant risk predictors included prenatal visit attendance, insurance gap days, and medical/obstetrical comorbidities. Model PPV was approximately 4-fold higher for very high-risk women (14.7%) vs cohort (3.3%) and so was the case identification ratio (1:7 vs 1:30, respectively). Sensitivity was good, with 57% of PTBs classified as medium risk or higher. Timing of prediction was clinically relevant, with more than 80% of PTBs risk stratified before 24 weeks. Conclusions We report a novel PTB prediction model among pregnant Medicaid women without PTB history, which is timely, accurate, practical, and scalable. We leverage Medicaid and community data readily accessible by Medicaid plans to support population-level interventions to prevent PTBs.

Background Cetuximab has been approved for use for first-line treatment of patients with wild-type KRAS metastatic colorectal cancer (CRC). However, treatment with cetuximab has shown limited efficacy as a CRC monotherapy. In addition, natural killer (NK) cell function is known to be severely attenuated in cancer patients. The goal of this study was to develop a new strategy to enhance antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by NK cells, in combination with cetuximab against CRC cells. Methods Ex vivo expanded NK cells were stimulated with reovirus, and reovirus-activated NK cells mediated ADCC assay were performed on CRC cells in combination with cetuximab. The synergistic antitumor effects of reovirus-activated NK cells and cetuximab were tested on DLD-1 tumor-bearing mice. Finally, Toll-like receptor 3 (TLR3) knockdown in NK cells, along with chemical blockade of TLR3/dsRNA complex, and inhibition of the TLR3 downstream signaling pathway, were performed to explore the mechanisms by which reovirus enhances NK cell cytotoxicity. Results We first confirmed that exposure of NK cells to reovirus enhanced their cytotoxicity in a dose-dependent manner.We then investigated whether reovirus-activated NK cells exposed to cetuximab-bound CRC cells exhibited greater anti-tumor efficacy than either monotherapy. Co-culture of CRC cell lines with reovirus-activated NK cells indicated that NK cytotoxicity was significantly higher in combination with cetuximab, regardless of KRAS mutation status or EGFR expression level. We also found that reovirus activation of NK cells, in conjunction with cetuximab, resulted in significantly stronger anti-tumor efficacy.Finally, TLR3 knockdown, inhibition of TLR3/dsRNA complex or TBK1/IKKε demonstrated that activation of NK cells by reovirus was dependent on TLR3 and its downstream signaling pathway. Conclusions This study demonstrated that combination treatment of reovirus-activated NK cells with cetuximab synergistically enhances their anti-tumor cytotoxicity, suggesting a strong candidate strategy for clinical treatment of CRC.

Purpose The aim of the present study was to investigate the efficacy of recombinant human endostatin (ES) (rh-ES) combined with radiation on rat cardiomyocyte apoptosis and the regulatory mechanism of transforming growth factor beta1 (TGF-β1)/Sma and Mad-related protein 3 (Smad3)/connective tissue growth factor (CTGF) signaling. Method The primary cardiomyocytes were isolated from neonatal Sprague–Dawley rats for culture in vitro and divided into blank control group (without treatment), 10 Gy radiation + siTGF-β1 siRNA (gene silencing) group, ES + siTGF-β1 siRNA group, and 10 Gy radiation + ES + siTGF-β1 siRNA group. Methyl thiazolyl tetrazolium assay was used to calculate the half-maximal inhibitory concentration (IC50) of rh-ES on cardiomyocytes. Adenoviral vector was constructed for virus packaging to silence TGF-β1 expression in cardiomyocytes. Quantitative real-time polymerase chain reaction and Western blot were carried out to analyze TGF-β1, Smad2, Smad3 and CTGF expression at both gene and protein levels. Flow cytometry and electron microscope were used to examine cell apoptosis. Results ES had a dose-dependent inhibitory effect on the proliferation of primary rat cardiomyocytes. ES combined with radiotherapy significantly inhibited cardiomyocyte proliferation and promoted cell apoptosis (P P Conclusion The combination therapy with rh-ES and radiation can promote cardiomyocyte apoptosis and aggravate myocardial cell damage via TGF-β1/Smad3/CTGF signaling pathway.

PURPOSE/OBJECTIVE(S) Radiation induced heart damage (RIHD) is an important late toxicity of thoracic radiotherapy, which is closely relating with the fractional dose of radiotherapy. With the wide application of stereotactic body radiotherapy and hyperfractionated radiotherapy, the single dose and biological equivalent dose (BED) of the heart of exposure have increased when comparing with conventionally fractionated radiotherapy. However, the mean cardiac dose (MHD), which is frequently used clinically to ensure the control of cardiac damage, is continuously decreased to 26 Gy, 20 Gy, etc. There is still controversy about how much dose could control heart radiation damage better. In this study, 15 Gy/3f low-dose irradiation of the whole heart of rats, which BED is similar with 24 Gy/12f irradiation, is selected to explore the possibility and characteristics of RIHD occurrence, and explore the effect of combined recombinant human endostatin on myocardial damage. MATERIALS/METHODS 75 SD adult male rats were randomly divided into control (C group, E group, MHD25 group) and experimental group (MHD15 group, MHD15+E group). The irradiation method was single dose 5 Gy/f, once per day, continuous irradiation 3d or 5d. After the irradiation, the E group and MHD15+E group were given recombinant human endostatin 6mg/kg intraperitoneal injection, once per day, for 14 consecutive days. At 1, 3, and 6 months after intervention, 5 rats in each group were randomly selected for HE, Masson, and immunohistochemical CD34 microvessel staining, and Western Blot detected mitochondrial Complex II protein expression. Two-way ANOVA statistics. RESULTS Compared with C group, edema and disorder of myocardial cells, infiltration of inflammatory cells and decrease of microvessel density was observed at 1 month after intervention in HE staining in MHD15 and MHD15+E group. The expression of complex II protein decreased at 6 months, and the degree of decrease was less than that in MHD25 group (positive control group) (P < 0.05). The microvessel density was further decreased compared with 1 month. Myocardial fibrosis induced by 15 Gy/3f low-dose irradiation of SD rat heart mainly occurred at 6 months, which observed myocardial cord or reticular fibrosis and collagen deposition. Semi-quantitative analysis of myocardial collagen volume fraction CVF significantly increased (P < 0.001) in HE and Masson staining. Details is shown in the table below. Compared with C group, E group observed myocardial edema and decreased microvessel density. There was no significant difference between MHD15 and MHD15+E group. CONCLUSION Low dose irradiation of 15 Gy/3f (BED = 40 Gy) still cause myocardial fibrosis and damage of cardiac function in SD rats. RIHD were observed after 6 months, which was equal to about 1/5 of the rat's life span, and the time was delayed when compared with the time of RIHD caused by high dose irradiation. Cardiotoxicity was not increased significantly combining recombinant human endostatin on the basis of low-dose cardiac.

Background GLS-010, a novel engineered fully human immunoglobin G4 monoclonal antibody, can specially block the PD-1/PD-L1/2 axis and reactivate the antitumor immunity. Aim This phase Ia/Ib study was carried out to evaluate the safety, recommended phase II dose (R2PD), and primary antitumor effects of GLS-010 in patients with advanced, refractory lymphoma and solid tumors. Methods In phase Ia study, patients with refractory solid tumors and lymphoma enrolled and received GLS-010 at a dose of 1, 4, or 10 mg/kg Q2W; 240 mg Q3W or Q2W. The primary objective was to assess the dose-limiting toxicity (DLT). In phase Ib study, doses were expanded in 9 specific tumors to ensure the R2PD and explore the efficacy. Tumor mutation burden level and PD-L1 expression were also assessed with whole-exome sequencing and immunohistochemistry (SP263), respectively. Results Up to April 18, 2020, a total of 289 patients (n = 24, phase Ia; n = 265, phase Ib) were enrolled. DLT was not observed in phase Ia part. The T1/2, CLss, and Vd were similar among all dose groups and different tumors. The most common treatment-emergent adverse events (TEAEs) were anemia, leukopenia, elevated alanine aminotransaminase/asparate aminotransferase (ALT/AST), and elevated bilirubin. And hypothyroidism was the most common immune-related adverse event (irAE). The incidence of grade ≥3 TEAE was 39.8%, while grade ≥3 irAE was only 4.5%. Based on safety studies, pharmacokinetics/pharmacodynamics, and preclinical data, 240-mg Q2W was recommended as the expansion dose. The overall objective response rate was 23.6%, with 10 patients achieving complete response. Patients with a high PD-L1 expression level (31.3% Versus. 13.7%, p = 0.012) or t-issue tumor mutation burden level (31.3% Versus. 5.6%, p = 0.009) showed a significantly better response. Conclusion GLS-010 showed acceptable safety profile and favorable clinical response. The dose of 240 mg Q2W was an optimal recommended dose as monotherapy.

Local tumor failure remains a major problem after radiation‐based nonsurgical treatment for unresectable locally advanced nonsmall cell lung cancer (NSCLC）and inoperable stage II NSCLC. The aim of this study was to evaluate the feasibility of simultaneous integrated boost of intensity‐modulated radiation therapy (SIB‐IMRT) to stage II‐III NSCLC with metastatic lymph nodes (ChiCTR 2000029304). Patients were diagnosed by pathology or PET‐CT. PTV was divided into two parts as follows, the PTV of primary tumor (PTVp) and the PTV of metastatic lymph nodes (PTVn). The radiotherapy doses were simultaneously prescripted 78 Gy (BED = 101.48 Gy) for PTVp and 60‐65 Gy (BED = 73.6‐81.25 Gy) for PTVn, 26f/5.2 weeks. Response was scored according to WHO criteria. Radiotherapy toxicity was scored according to RTOG criteria. Hematology and gastrointestinal toxicity were scored according to CTCAE1.0 criteria. A total of 20 patients were enrolled. Seventeen patients were diagnosed by pathology and three patients were diagnosed by PET‐CT. All patients were treated with SIB‐IMRT. The objective response rate (ORR) was 90%, with CR 25%, PR 65%, NC 10%, and PD 0%. Although radiotherapy toxicity was common, there were no grade ≥3, with radiation pneumonitis (10 cases), esophagitis (17 cases), and dermatitis (12 cases). The local control rates at 1, 3, and 5 years were 85%, 75%, and 70%, respectively. The overall survival（OS）and local progression‐free survival (LPFS) rates at 1, 3, and 5 years were 90%, 42.6%, and 35.5% and 84.4%, 35.5%, and 28.4%, respectively. SIB‐IMRT can significantly improve ORR and survival for stage II‐III NSCLC with metastatic lymph nodes, with high safety, and satisfactory efficacy. However, due to the limitation of small sample, these findings are needed to confirm by future trials with a larger sample size., The different radiation doses were simultaneously prescripted 78 Gy (PTVp）and 60‐65 Gy (PTVn). SIB‐IMRT can significantly improve ORR and survival for stage II‐III NSCLC with metastatic lymph nodes, with high safety and satisfactory efficacy.

Mapping expression quantitative trait loci (eQTLs) is an important avenue to identify putative genetic variants in regulatory regions. Famed eQTL mapping methods exploit the mean effects of locus-wise genetic variants on expression quantitative traits. Despite their successes, such methods are suboptimal because they neglect high-order heterogeneity inherent in genetic variants and covariates. High-order effects of observed loci are common due to their connections to various latent factors, i.e., latent interactions among genes and environmental factors. In this chapter, we introduce a new scheme to harmoniously integrate mean and high-order effects of genetic variants on expression quantitative trait. We rigorously evaluate its validity and utility of signal augmentation.

Purpose/Objective(s) To evaluate the efficiency and safety of Nab-paclitaxel plus cisplatin and concomitant thoracic radiotherapy in locally advanced non-small-cell lung cancer. Materials/Methods A total of 68 cases locally advanced NSCLC patients were enrolled in this study, and 38 cases were enrolled so far (1:1 in the experimental group and the control group, 19 cases in each group, 1 case in each group did not complete the treatment, a total of 36 cases were available for statistical analysis). The control group received paclitaxel combined with cisplatin regimen chemotherapy (paclitaxel 175mg/m2 on day 1, cisplatin 75mg/m2 on day 2; every 3-4 weeks for 2 consecutive cycles. Experimental group: nab-paclitaxel weekly at a dose of 40mg/m2, Cisplatin 75mg/m2 and repeated every 3-4 weeks for 2 consecutive cycles. Both groups received concomitant aggressive radical three-dimensional thoracic radiotherapy with continuously accelerated hyperfractionation. The primary endpoint was ORR and safety (including treatment-induced bone marrow suppression, the toxicity of liver and kidney function, cardiotoxicity, radiation pneumonia, and other toxic side effects). Secondary endpoints were local progression-free survival rate, the local recurrence rate of the primary tumor, and the local control rate of the primary tumor. Results 38 patients completed concomitant chemoradiotherapy. The effective rates ORR of experimental group and control group were 89.6% and 68.5%, respectively. The short-term efficacy was CR (0 cases 0%, 1 case 5.2%), PR (17 cases 89.6%, 12 cases 63.3%), SD (1 case 5.2%, 5 cases 26.3%), PD (1 case 5.2%, 1 case 5.2%) P = 0.001. Grade 3/4 leukopenia 2 (10.5%), 14 (73.7%), P = 0.001; grade 3/4 neutropenia 2 (10.5%), 14 (73.7%), P = 0.001; grade 3/4 anemia 1 (5.3%) and 2 (10.5%), P = 0.547; grade 3/4 thrombocytopenia 0(0%) and 2 (10.5%) of, P = 0.146. There were 11 (57.9%) and 6 (31.6%) of grade I radiation esophagitis, and 8 (42.1%) and 13 (68.4%) of grade II esophagitis respectively. No grade III-IV esophagitis was found. Conclusion The ORR and short-term efficiency of nab-paclitaxel plus cisplatin concomitant radiotherapy are better than the control group, and the hematological toxicity is lower than the control group.

Purpose/objective(s) The role of radiotherapy, in addition to chemotherapy, has not been thoroughly determined in metastatic non-small cell lung cancer (mNSCLC). The purpose of the study was to investigate clinical characterization and treatment-related parameter of long-term survival in mNSCLC patients treated with concurrent chemotherapy with thoracic radiation therapy. In our previous study, the count of CD4-positive and CD8-positive T cells was associated with overall survival (OS). We speculated that baseline lung immune prognostic index (LIPI) based on pretreatment neutrophils/(leukocytes minus neutrophils) ratio (dNLR) and lactate dehydrogenase (LDH) level may be associated with OS. Thus, the prognostic value of LIPI level was also evaluated in this study. Materials/methods We retrospectively analyzed 243 eligible patients with mNSCLC who were treated with chemotherapy and concurrent radiation to the primary tumor in two prospective studies. These patients had received at least two chemotherapy cycles and a thoracic radiation dose of at least 40 Gy in 2-Gy fractions, and did not receive targeted therapy or immunotherapy during lifetime. According to previous publications, dNLR greater than 3 and LDH greater than upper limit of normal was developed, characterizing 3 groups (good, 0 factors; intermediate, 1 factor; poor, 2 factors). Prognostic factors for OS were identified by using univariate and multivariate analysis. Propensity-score matching (PSM) were performed to further adjust for confounding. OS≥ 18 months was defined as long-term survival (LTS). Results According to LIPI, 141 patients were classified into good group, 83 patients in intermediate, and 19 patients in poor group. The number of patients was small in poor group. Thus, intermediate group and poor group were merged into the same risk group (intermediate-poor group). A total of 78 patients with long-term survival, 57 (40.4%) patients in good group, and 21 (20.6%) patients in intermediate-poor group. Univariate analysis showed that KPS score, T status, number of metastatic organs, brain metastasis, bone metastasis, radiation dose, and number of chemotherapy cycles, and LIPI were significant difference between LTS and non-LTS. Multivariate analysis showed that good LIPI and radiation dose (≥60 Gy) independently predicted long-term survival (P = 0.006, P = 0.012). After PSM, good LIPI remained to be correlated with long-term survival; the median survival time for good and intermediate-poor group were 13.7 months (95% CI, 11.37 - 16.02) and 11.0 months (95% CI, 9.52 - 12.48); the 1-, 2-, and 3-year OS rates were 59.8%, 21.2%, and 15.5% versus 41.5%, 10.2%, and 7.0% (χ2 = 5.603, P = 0.018). Conclusion For mNSCLC patients treated with chemotherapy in combination with thoracic radiation, LTS patients had good LIPI and receiving higher radiation dose to primary tumor. LIPI might be useful for identifying a subgroup that may benefit from thoracic radiotherapy with concurrent chemotherapy.

PURPOSE/OBJECTIVE(S) Radiation induced heart damage (RIHD) is the leading cause of non-cancer-related deaths in patients receiving thoracic radiotherapy. The mean cardiac dose (MHD) of normal tissue tolerance in NCCN guidelines for radiotherapy has been continuously decreased from 35 Gy in 2017 to 2020 20 Gy, indicating there is controversy of MHD that how much dose could control cardiac radiation damage better. In this study, 15 Gy/3f (BED = 40 Gy) low-dose irradiation of SD rat heart was used to explore the mechanism and functional parameter changes of RIDH caused by low-dose irradiation, and to explore the effect of combining recombinant human endostatin (E). MATERIALS/METHODS 75 SD adult male rats were randomly divided into control group (C, E, MHD25) and experimental group (MHD15, MHD15+E). A single dose 5 Gy/f, once per day, continuous irradiation 3d or 5d. After the irradiation, the E group and MHD15+E group were given recombinant human endostatin 6mg/kg intraperitoneal injection, once per day, for 14 consecutive days. At 24h, 48h and 15d after the intervention, the blood of the rats was taken to measure CK, CK-MB, LDH and CRP. At 1, 3 and 6 months, 5 rats after cardiac echocardiography was performed in each group were randomly killed and myocardial tissues were collected for Masson staining, Western Blot and qPCR. Two-way ANOVA statistics. RESULTS There was no difference in LDH, CK, CK-MB, and CRP in the same time period among the groups at 24h, 48h, and 14d after intervention (P > 0. 05). Compared with group C, the EF and FS of the MHD25, MHD15 and MHD15+E group all decreased at 3 months (P 0.05). The EF and FS of the MHD25, MHD15 and MHD15+E group also decreased at 6 months (P 0.05). Comparing 6 months with 1 month, EF and FS of each group decreased (P 0.05). CONCLUSION SD rat heart 15 Gy/3f (BED = 40 Gy) low-dose irradiation cause cardiac function damage in the early stage and myocardial fibrosis in the late stage, the appearance delayed and degree is lower than that of high-dose irradiation. On the basis of low-dose irradiation, combined with recombinant human endostatin increase the expression of related factors of TGF-β/Smad signaling pathway. Echocardiography may be able to predict the occurrence of RIDH early, but serological predictive indicators have yet to be found.

Background: GLS-010 is a novel fully human anti-PD-1 mAb developed by the OMT transgenic rat platform. In Phase 1a study, GLS-010 exhibited good tolerance and 240mg (Q2W) was selected. Phase 1b study was conducted to evaluate the safety,anti-tumor activity and explore biomarkers of GLS-010 in pts with advanced solid tumors or lymphomas. Methods: All pts enrolled received GLS-010 240 mg every 2 weeks. Tumor response was assessed by RECIST 1.1 every 8 weeks. Adverse events (AEs) were graded by NCI CTCAE v4.03. Several biomarkers were explored, including PD-L1 by SP263 assay, tissue tumor mutation burden (tTMB) by whole exome sequencing (WES) from FFPE tissue, blood TMB (bTMB) by multi-gene panel based next-generation sequencing (NGS) from blood ctDNA. Results: As of 19 JUL 2019, 213 pts, median age of 55 (range: 21-75) years, were enrolled and 109 of 213 pts were still in treatment. The median dosing number was 7.5 (range: 1~41). Treatment-related AEs (TRAEs) occurred in 185 patients (70%), of which mostly were CTCAE grade 1-2. The most frequent TRAEs were related to hepatotoxicity, included “ALT increased” (32/213), “AST increased” (32/213), “blood bilirubin increased” (25/213). 53 of 163 pts, who received ≥1 response evaluation, achieved response (PR+CR, unconfirmed response included), including GC (4/21), EC (5/25), BTC (3/10), NSCLC (8/32), nasopharynx cancer (10/26),UC (2/8), HCC (0/12), cHL (18/21) and peripheral T/NK cell lymphoma (3/8). In all solid tumor types, pts with PD-L1-positive tumors experienced clinical benefit with significantly higher ORR (39.6% vs 14.5%, p=0.0025) and longer PFS (p=0.0241). ORR was higher for PD-L1 positive (TC≥25%) pts with lung cancer (66.7% vs 20.0%, p=0.051). For pan-caner analysis, ORR benefits of GLS-010 were also enhanced (51.9% versus 26.4%, p=0.0298) in pts with tTMB-high (>75th percentile, of each tumor type) versus tTMB-low. Pairing tTMB and survival data were analyzed in 129 pts, and tTMB-high pts benefit more with a significantly improved PFS (p=0.011). Also, improved PFS was observed in tTMB-high pts with EC (p=0.0059). For bTMB-high group, pts with EC achieved higher ORR (42.9% vs 6.3%, p=0.0672), which translated into PFS benefits (p=0.03). Conclusion: In conclusion, it is suggested that GLS-010 was well tolerated and had durable antitumor activity in Chinese tumor pts. PD-L1 has showed to be predictive of GLS-010 activity in solid tumors, especially in lung cancer. For pan-cancer analysis, it is preliminarily demonstrated that tTMB may be valuable biomarkers to predict the treatment response and benefit of GLS-010. For Chinese EC pts, tTMB and bTMB may be of value in predicting the response to PD-1 inhibitor. Citation Format: Lin Shen, Jifang Gong, Yuqin Song, Dingwei Ye, Zhihao Lu, Siyang Wang, Peijian Peng, Jianhua Chen, Ou Jiang, Guojun Zhang, Yuxian Bai, Jianji Pan, Chunguang Ma, Li Chen, Yi Ba, Qi Li, Ping Lu, Lingli Zhang, Xianli Yin, Shanzhi Gu, Huilai Zhang, Hang Su, Yongsheng Jiang, Bangwei Cao, Weiqing Han, Yan Sun, Feng Zhang, Weiwei Ouyang, Haiying Dong, Jianming Guo, Yabing Guo, Chongyuan Xu, Junyuan Qi, Li Wang, Jun Lv, Xiang Wang, Chris Chen, Jing Li, Yong Zheng, Ge Jin, Yining Yang, Guodong Zhao, Fan Yang, Kehui Xu, Xiangying Liang, Zhaoyang Pan, Haijin Meng. GLS-010, a novel fully human anti-PD-1 mAb in patients with advanced tumor: Preliminary results of a Phase Ib clinical trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3275.

The aim of this study was to compare the clinical efficacy of pemetrexed+cisplatin (PP) versus docetaxel+cisplatin (DP) for the treatment of stage IV lung adenocarcinoma. We retrospectively analyzed the clinical data of 147 patients with stage IV lung adenocarcinoma treated between January 2011 and December 2015, 100 of which were in the DP group whereas 47 were in the DP group. Main inclusion criteria were treatment-naive patients, first-line treatment with PP or DP with no molecular targeted therapy during treatment, 2-6 cycles of first-line chemotherapy with unknown status of epidermal growth factor receptor (EGFR) mutation, 18-75 years of age, and Karnofsky performance status score of at least 70. Prognostic factors for survival were identified by using univariate and multivariate analyses. Propensity score matching was performed to further adjust for confounding. A total of 47 pairs were successfully matched between the two groups. The median overall survival was 9.0 months in the DP group and 17.0 months in the PP group; the 1-year survival rate was 29.8 and 59.6%, respectively; the 2-year survival rate was 12.8 and 21.1%, respectively (χ=4.128, P=0.042); and median progression-free survival was 6.0 and 8.0 months, respectively (χ=4.839, P=0.028). Cox multivariate analysis showed that chemotherapy regimen and number of metastatic organs were independent factors for OS. The effect of the radiotherapy dose on the primary tumor on OS was close to statistically significant. The incidence of grade 3-4 neutropenia was more significantly reduced in the DP group than in the PP group after matching (61.7 vs. 27.7%, P=0.002), with no between-group difference for adverse effects on platelets or hemoglobin. For patients with stage IV lung adenocarcinoma and unknown EGFR mutation status, PP was more effective than DP in prolonging survival and had a less adverse effect on neutrophils.

[This corrects the article DOI: 10.1371/journal.pone.0184816.].

Purpose The aim of this prospective multi-institutional phase 2 study was to investigate disease control, survival outcomes, and toxicity after thoracic three-dimensional radiation therapy (3D-RT) with concurrent chemotherapy for newly diagnosed stage IV non-small cell lung cancer (NSCLC). Methods and Materials Eligible patients were 18 to 80 years of age, had a Karnofsky performance status (KPS) score ≥70%, and newly diagnosed stage IV NSCLC with limited metastatic disease (defined as involving ≤3 organs). Patients received platinum-doublet chemotherapy with concurrent irradiation to the primary tumor. Primary endpoints were overall survival (OS) and acute toxicity. Results From May 2008 to May 2012, 198 eligible patients were enrolled from 7 cancer centers. Most patients died with distant metastasis; only 10% died with isolated primary recurrence. Median OS time was 13.0 months (95% confidence interval [CI]: 11.7-14.3); OS rates were 53.5% at 1 year, 15.8% at 2 years, and 9.2% at 3 years. Median progression-free survival (PFS) time was 9.0 months (95% CI: 7.7-10.3); corresponding PFS rates were 30.8%, 8.2%, and 6.1%. The 1-year, 2-year, and 3-year local (primary tumor) control rates were 78.8%, 57.7%, and 55.4%. Multivariate analysis showed that delivery of ≥63 Gy to the primary tumor ( P =.014), having a primary tumor volume 3 ( P =.008), and having a stable or higher KPS score after treatment ( P =.01) were independent predictors of better OS. The most common severe (grades 3-4) acute toxicities were hematologic: leukopenia (37.9%), thrombocytopenia (10.1%), and anemia (6.9%). No patients experienced grade 4 or 5 radiation-related toxicity; 2.5% had acute grade 3 pneumonitis, and 6.6% had acute grade 3 radiation esophagitis. Conclusions Thoracic 3D-RT to the primary tumor with concurrent chemotherapy led to satisfactory survival outcomes with acceptable toxicity. Radiation dose, primary tumor volume, and PFS after treatment all predicted survival in these patients with limited-metastasis NSCLC.

In this article, we obtain generic stochastic representations and asymptotic distributions of gene–gene correlations with respect to differential magnitudes, residual correlations, and sample size of experiment. Our results establish theoretical foundation for tight clustering of co-expressed genes.

Radiation therapy is one of the most important methods for the treatment of malignant tumors. However, in radiotherapy for thoracic tumors such as breast cancer, lung cancer, esophageal cancer, and mediastinal lymphoma, the heart, located in the mediastinum, is inevitably affected by the irradiation, leading to pericardial disease, myocardial fibrosis, coronary artery disease, valvular lesions, and cardiac conduction system injury, which are considered radiation-induced heart diseases. Delayed cardiac injury especially myocardial fibrosis is more prominent, and its incidence is as high as 20–80%. Myocardial fibrosis is the final stage of radiation-induced heart diseases, and it increases the stiffness of the myocardium and decreases myocardial systolic and diastolic function, resulting in myocardial electrical physiological disorder, arrhythmia, incomplete heart function, or even sudden death. This article reviews the pathogenesis and prevention of radiation-induced myocardial fibrosis for providing references for the prevention and treatment of radiation-induced myocardial fibrosis.

Oncolytic viruses (OV) have recently emerged as a promising therapeutic modality in cancer treatment. OV selectively infect and kill tumor cells, while sparing untransformed cells. The direct cytotoxic effects combined with the capacity to trigger an immune response make OV an appealing combination partner in the burgeoning field of cancer immunotherapy. One of the leading OV therapeutic candidates is the double-stranded RNA virus reovirus. In order to improve the oncolytic activity of reovirus and allow for systemic administration despite the prevalence of neutralizing antibodies, cytokine-induced killer (CIK) cells were explored as cell carriers for reovirus delivery. In this study, CIK cells were successfully loaded with reovirus ex vivo, and viral replication was limited in CIK cells. Confocal microscopy and flow cytometry demonstrated that CIK cells retained reovirus on the surface. Moreover, CIK cells could promote reovirus infection of tumor cells in the presence of neutralizing antibodies; meanwhile, cytotoxicity of CIK cells was increased after loading with reovirus. These findings support further investigation of reovirus and CIK combination for antitumor therapy.

The abscopal effect has previously been described in various tumors and is associated with radiation therapy and hyperthermia, with possible underlying mechanisms explaining each observed case. In the present study, we aimed to investigate the antitumor effects of magnet-mediated hyperthermia on Walker-256 carcinosarcomas in rats at two different temperature ranges (42–46°C and 50–55°C). We also aimed to identify whether a higher therapeutic temperature of magnetic-mediated hyperthermia improves the abscopal antitumor effects, where localised irradiation of the tumor causes not only the irradiated tumor to shrink, but also tumors located far from the area of irradiation. Following induction of carcinosarcoma in both sides of the body, magnet-mediated hyperthermia was applied to one side only, leaving the other side as a control. The changes in tumor growth were observed. Our results demonstrated that magnet-mediated hyperthermia at a higher temperature inhibited the growth of carcinosarcoma at the site of treatment. Furthermore, the growth of the carcinosarcoma on the untreated side was also inhibited. The expression levels of proliferating cell nuclear antigen were decreased in the hyperthermia group, which was more significant in the higher temperature test group. Flow cytometric analysis showed an increased number of CD4- and CD8-positive T cells, and enzyme-linked immunosorbent assay showed increased levels of interferon-γ and interleukin-2 in the higher temperature group. These results suggested that magnet-mediated hyperthermia at a higher temperature (50–55°C) can improve the abscopal antitumor effects and stimulate a greater endogenous immune response in carcinosarcoma-bearing rats.

Background In functional genomics studies, tests on mean heterogeneity have been widely employed to identify differentially expressed genes with distinct mean expression levels under different experimental conditions. Variance heterogeneity (aka, the difference between condition-specific variances) of gene expression levels is simply neglected or calibrated for as an impediment. The mean heterogeneity in the expression level of a gene reflects one aspect of its distribution alteration; and variance heterogeneity induced by condition change may reflect another aspect. Change in condition may alter both mean and some higher-order characteristics of the distributions of expression levels of susceptible genes. Results In this report, we put forth a conception of mean-variance differentially expressed (MVDE) genes, whose expression means and variances are sensitive to the change in experimental condition. We mathematically proved the null independence of existent mean heterogeneity tests and variance heterogeneity tests. Based on the independence, we proposed an integrative mean-variance test (IMVT) to combine gene-wise mean heterogeneity and variance heterogeneity induced by condition change. The IMVT outperformed its competitors under comprehensive simulations of normality and Laplace settings. For moderate samples, the IMVT well controlled type I error rates, and so did existent mean heterogeneity test (i.e., the Welch t test (WT), the moderated Welch t test (MWT)) and the procedure of separate tests on mean and variance heterogeneities (SMVT), but the likelihood ratio test (LRT) severely inflated type I error rates. In presence of variance heterogeneity, the IMVT appeared noticeably more powerful than all the valid mean heterogeneity tests. Application to the gene profiles of peripheral circulating B raised solid evidence of informative variance heterogeneity. After adjusting for background data structure, the IMVT replicated previous discoveries and identified novel experiment-wide significant MVDE genes. Conclusions Our results indicate tremendous potential gain of integrating informative variance heterogeneity after adjusting for global confounders and background data structure. The proposed informative integration test better summarizes the impacts of condition change on expression distributions of susceptible genes than do the existent competitors. Therefore, particular attention should be paid to explicitly exploit the variance heterogeneity induced by condition change in functional genomics analysis. Electronic supplementary material The online version of this article (doi:10.1186/s12859-016-1393-y) contains supplementary material, which is available to authorized users.

Based on analyzing the characteristics of the environment of low concentration uranium, the traditional processing method of low concentration uranium waste-water, such as adsorption method, chemical precipitation, evaporation-enrichment method were summarized. Then the principle, characteristics and scope of the latest processing technology such as Bentonite method, Zero-valent iron, biological adsorption method were summarized, and finally points out that the comprehensive utilization of various methods is an effective way to deal with low concentration uranium waste-water.

Additional tables of real data analyses. This file displays more results derived by re-analyzing the gene expression profiles of peripheral circulating B Lymphocytes. (DOCX 30Â kb)