Application of positron emission tomography/computed tomography in radiation treatment planning for head and neck cancers

18-fluorodeoxygluocose positron emission tomography/computed tomography(18FDG-PET/CT) provides significant information in multiple settings in the management of head and neck cancers(HNC). This article seeks to define the additional benefit of PET/CT as related to radiation treatment planning for squamous cell carcinomas(SCCs) of the head and neck through a review of relevant literature. By helping further define both primary and nodal volumes, radiation treatment planning can be improved using PET/CT. Special attention is paid to the independent benefit of PET/CT in targeting mucosal primaries as well as in detecting nodal metastases. The utility of PET/CT is also explored for treatment planning in the setting of SCC of unknown primary as PET/CT may help define a mucosal target volume by guiding biopsies for examination under anesthesia thus changing the treatment paradigm and limiting the extent of therapy. Implications of the use of PET/CT for proper target delineation in patients with artifact from dental procedures are discussed and the impact of dental artifact on CT-based PET attenuation correction is assessed. Finally, comment is made upon the role of PET/CT in the high-risk post-operative setting, particularly in the context of radiation dose escalation. Real case examples are used in these settings to elucidate the practical benefits of PET/CT as related to radiation treatment planning in HNCs.

Surface-ligand effect on radiosensitization of ultrasmall luminescent gold nanoparticles

Gold nanoparticles(AuNPs)could serve as pot ential radiother apy sensitizers because of their exceptional biocompatibility and high.Z material nature;however,since in vitro and in vivo behaviors of AuNPs are determined not only by their particle size but also by their surface chemistries,whether surface ligands can affect their radiosensitization has seldom been investi-gated in the radiosensitization of AuNPs.By conducting head-to-head comparison on radio-sensitization of two kinds of ultrasmall(~2 nm)near-infrared(NIR)emitting AuNPs that are coated with zwitterionic glutathione and neutr al polyethylene glyol(PEG)ligands,respectively,we found that zwitterionic glut athione coated AuNPs(GS-AuNPs)can reduce survival rates of MCF-7 cells under irr adiation of clinically used megavoltage photon beam at low dosage of~2.25 Gy.On the other hand,PEG-AuNPs can serve as a radiation-protecting agent and enabled MCF-7 cells more resistant to the irradiation,clearly indicating the key role of surface cheistry in radiosensitization of AuNPs.More detailed studies suggested that such difference was inde-pendent of cellular uptake and its eficiency,but might be related to the ligand-induced difference in photoelectron generation and/or inter actions between AuNPs and X-ray triggered reactive oxygen species(ROS).

A Comparison between Three-Dimensional Conformal Radiotherapy, Intensity-Modulated Radiotherapy, and Volumetric-Modulated Arc Therapy Techniques for Stereotactic Body Radiotherapy of Lung Tumors

Introduction: The aim of this study is to dosimetrically compare 3D CRT, IMRT, and VMAT techniques that employ coplanar and non-coplanar beams for the SBRT of lung tumors. Methods and Materials: Nine (n = 9) consecutive SBRT lung patients with ten tumor sites who were previously treated at our institution were selected for this study. Six (n = 6) treatment plans were created for each PTV: 1 coplanar and 1 non-coplanar 3D CRT, IMRT, and VMAT such that 98% of PTV received 100% of prescription dose, Rx of 50 Gy in 5 fractions. The data collected from each plan included the conformity index, R50%, and homogeneity index of the target as well as the volume of normal tissue irradiated by 5 Gy, 25 Gy isodose lines, V5 and V20 of total lung, and maximum dose to organs at risk. Beam angles and arc lengths were chosen in order to achieve the lowest total lung V5, V20 and R50% values. Results: According to the observed data, the mean total lung V5 and V20 values were lowest for the non-coplanar VMAT plans, but were not statistically different from the other planning techniques. Conformity values were similar for the IMRT and VMAT plans, and significantly lower than the 3D CRT plans. R50% values were lowest for the VMAT plans and significantly lower than both IMRT and 3D CRT plans in both coplanar and non-coplanar beam arrangements. However, dose homogeneity in the PTV is significantly higher in the IMRT coplanar plans than the corresponding 3D CRT and SmartArc (SA) coplanar plans. Coplanar VMAT plans were able to produce a significant 35.5% reduction in the maximum cord dose than coplanar 3D CRT plans

Clinical,pathological,and adjuvant chemotherapy use differences among microsatellite unstable and microsatellite stable colon cancers

Background:Colon cancers are categorized into mismatch repair deficient/microsatellite unstable(MSI-H)and mismatch repair proficient/microsatellite stable(MSS)cancers.This study aims to compare the disease char-acteristics and trends in the utilization of cancer therapies across different age groups and stages in these two groups.Methods:MSI-H and MSS colon adenocarcinomas from 2010 to 2016 were identified using the National Can-cer Database.We compared patient and disease characteristics between the two groups and evaluated the use of adjuvant chemotherapy across age groups and cancer stages.Within MSI-H and MSS groups,we conducted a land-mark analysis after propensity score matching for adjuvant chemotherapy versus no chemotherapy to determine its effect on survival.Results:Of the 542,368 patients that met inclusion criteria,120,751(22%)had mismatch repair results avail-able-out of these 96,928(80%)had MSS colon cancers while 23,823(19.7%)had MSI-H cancers.MSI-H disease had a bimodal age distribution(<40 years=22%;≥75 years=26%)and was frequent among females(22%)and non-Hispanic Whites(20%).Among those<65 years,15%of low-risk stage 2 MSI-H patients and 40%of high-risk stage 2 MSI-H patients received adjuvant chemotherapy.More than two-thirds of stage 3 patients<65 years received adjuvant chemotherapy in both groups.After conducting propensity-score matching for age,gender,and co-morbidities,we found that adjuvant chemotherapy use had a trend towards lower overall survival(OS)in low-risk stage 2 MSI-H(HR=1.8[95%CI,0.8-4.02])and high-risk stage 2 MSI-H(HR=1.42[95%CI,0.96-2.12])groups.Adjuvant chemotherapy significantly improved OS in stage 3 colon cancer patients irrespective of microsatellite status or risk category of disease.Conclusions:MSI-H colon cancer had bimodal age distribution.Among stage 2 MSI-H patients<65 years,a notable proportion received adjuvant chemotherapy.Among MSI-H stage 2 patients,adjuvant chemotherapy use was associated with lower survival while it significantly improved survival for stage 3 patients,irrespective of MSI status.

Typical Cell Signaling Response to Ionizing Radiation: DNA Damage and Extranuclear Damage

To treat many types of cancer, ionizing radiation （IR） is primarily used as external-beam radiotherapy, brachytherapy, and targeted radionuclide therapy. Exposure of tumor cells to JR can induce DNA damage as well as generation of reactive oxygen species （ROS） and reactive nitrogen species （RNS） which can cause non-DNA lesions or extracellular damage like lipid perioxidation. The initial radiation-induced cell responses to DNA damage and ROS like the proteolytic processing, as well as synthesis and releasing ligands （such as growth factors, cytokines, and hormone） can cause the delayed secondary responses in irradiated and unirradiated bystander cells through paracrine and autocrine pathways.

A phase I study with Satraplatin and simultaneous chest radiation for non-small cell lung cancer

Introduction: Satraplatin has been given in combination therapy for lung cancer to utilize its radio-sensitizing properties. The optimal dose of satra-platin given concurrently with radiation therapy for locally advanced non-small cell lung cancer (NSC-LC) has not been defined. This phase I trial attempts to identify a maximally tolerated dose (MTD) and dose limiting toxicity (DLT) for Satraplatin given con-currently with radiation for locally advanced N-SCLC. Patients and Methods: 15 patients with histologically confirmed Stage IIIA/B NSCLC entered onto this study with four dose escalations (10 to 40 mg daily) of Satraplatin. Eligibility included patients with NSCLC and one of the following criteria: 1) previously untreated, inoperable disease and planned to receive radiation therapy to primary disease site;2) previously resected disease with mediastinal relapse;or 3) metastatic disease in no more than one distant site. Results: The most common toxicities reported were all grades of fatigue (n = 9), nausea (n = 9), constipation (n = 7), fever (n = 7), and vomiting (n = 6). No DLT at the 1st, 2nd, and 3rd dose levels was identified. At the 4th dose level, one patient developed grade III elevation of liver function tests (LFTs) and a second patient developed grade III diarrhea with fever requiring hospitalization. There were 8 partial responses out of 11 evaluable patients for response (RR 67%). Conclusion: Elevated LFTs and diarrhea appear to be the principal DLTs of concurrent daily oral Satraplatin and thoracic radiation in the outpatient setting. The MTD of concurrent Satraplatin with thoracic radiation therapy appears to be 40 mg daily.

二维电离室矩阵在放疗的质量保证体系中的应用

肿瘤的放射治疗中,为了检测治疗设备的性能以及确保放疗计划实施的可靠性和准确性,必须具备完善的质量保证体系(Quality Assurance,QA).本文研究将德国PTW公司研发的二维电离室矩阵Seven29应用到放疗的日常QA过程中,使用Seven29和与之配套的八角体模或平板体模来测量剂量分布图,并与治疗计划系统计算出来的剂量分布图进行比较.对治疗设备每月的QA,最重要的项目是检测射线性能的连续性,检测方法是对连续两个月机器性能的参数进行比较.采用PTW公司的软件Veri Soft和Multi Check进行数据分析,经大量的实验验证和比较,结果表明二维电离室矩阵是剂量测量和分析的有效工具,其精度高、可靠性强、使用方便,是实现无胶片化和无纸化放疗体系的重要组成部分.

Esophageal cancer:diagnosis and management

Esophageal cancer is the 7th leading cause of cancer deaths worldwide.While squamous cell carcinoma is the most prevalent histology internationally,adenocarcinoma of the distal esophagus accounts for nearly 50% of cases in developed countries due to the differences in the etiologic factors such as gastroesophageal reflux disease(GERD) and obesity that predominate.While surgery is the mainstay of treatment of this disease,the utilization of chemoradiation,eitherused postoperatively or neoadjuvantly,has become a standard practice in the United States.What is the optimal management approach is still an area of contention,however,and may be different in different regions around the world.This article reviews some of these controversies,including the role for surgery in patients treated with definitive chemoradiation.At the end,we will also outline recommendations regarding radiotherapy procedures and techniques.

E2FBP1 antagonizes the p16^(INK4A)-Rb tumor suppressor machinery for growth suppression and cellular senescence by regulating promyelocytic leukemia protein stability

Cellular senescence is an irreversible cell cycle arrest triggered by the activation of oncogenes or mitogenic signaling as well as the enforced expression of tumor suppressors such as p53, p16INK4A and promyelocytic leukemia protein （PML） in normal cells. E2F-binding protein 1 （E2FBP1）, a transcription regulator for E2F, induces PML reduction and suppresses the formation of PML-nuclear bodies, whereas the down-regulation of E2FBP1 provokes the PML-dependent premature senescence in human normal fibroblasts. Here we report that the depletion of E2FBP1 induces the accumulation of PML through the Ras-dependent activation of MAP kinase signaling. The cellular levels of p16INK4A and p53 are elevated during premature senescence induced by depletion of E2FBP1, and the depletion of p16INK4A, but not p53 rescued senescent cells from growth arrest. Therefore, the premature senescence induced by E2FBP1 depletion is achieved through the pl6INK4A-Rb pathway. Similar to human normal fibroblasts, the growth inhibition induced by E2FBP1 depletion is also observed in human tumor cells with intact p16INK4A and Rb. These results suggest that E2FBP1 functions as a critical antagonist to the pI6INK4A-Rb tumor suppressor machinery by regulating PML stability.

Cell polarity protein Par3 complexes with DNA-PK via Ku70 and regulates DNA double-strand break repair

The partitioning-defective 3 （Par3）, a key component in the conserved Par3/Par6/aPKC complex, plays fundamental roles in cell polarity. Herein we report the identification of Ku70 and Ku80 as novel Par3-interacting proteins through an in vitro binding assay followed by liquid chromatography-tandem mass spectrometry. Ku70/Ku80 proteins are two key regulatory subunits of the DNA-dependent protein kinase （DNA-PK）, which plays an essential role in repairing double-strand DNA breaks （DSBs）. We determined that the nuclear association of Par3 with Ku70/Ku80 was enhanced by γ-irradiation （IR）, a potent DSB inducer. Furthermore, DNA-PKcs, the catalytic subunit of DNA-PK, interacted with the Par3/Ku70/Ku80 complex in response to IR. Par3 over-expression or knockdown was capable of up- or downregulating DNA-PK activity, respectively. Moreover, the Par3 knockdown cells were found to be defective in random plasmid integration, defective in DSB repair following IR, and radiosensitive, phenotypes similar to that of Ku70 knockdown cells. These findings identify Par3 as a novel component of the DNA-PK complex and implicate an unexpected link of cell polarity to DSB repair.

Centrosome Functions as a Molecular Dynamo in the Living Cell

Recent development in the field of quantum biology highlights that the intracellular electromagnetic field (EMF) of microtubules plays an important role in many fundamental cellular processes such as mitosis. Here I propose an intriguing hypothesis that centrosome functions as molecular dynamo to generate electric flow over the microtubules, leading to the electric excitation of microtubule EMF that is required for spindle body microtubule self-assembly. With the help of motors proteins within the centrosome, centrosome transforms the energy from ATP into intracellular EMF in the living cell that shapes the functions of microtubules. There will be a general impact for the cell biology field to understand the mechanistic function of centrosome for the first time in correlation with its structural features. This hypothesis can be tested with technics such as super resolution live cell microscope.

Targeted chemotherapy via HER2-based chimeric antigen receptor(CAR)engineered T-cell membrane coated polymeric nanoparticles

Cell membrane-derived nanoparticles(NPs)have recently gained popularity due to their desirable features in drug delivery such as mimicking properties of native cells,impeding systemic clearance,and altering foreign body responses.Besides NP technology,adoptive immunotherapy has emerged due to its promise in cancer specificity and therapeutic efficacy.In this research,we developed a biomimetic drug carrier based on chimeric antigen receptor(CAR)transduced T-cell membranes.For that purpose,anti-HER2 CAR-T cells were engineered via lentiviral transduction of anti-HER2 CAR coding lentiviral plasmids.Anti-HER2 CAR-T cells were characterized by their specific activities against the HER2 antigen and used for cell membrane extraction.Anti-cancer drug Cisplatin-loaded poly(D,L-lactide-co-glycolic acid)(PLGA)NPs were coated with anti-human epidermal growth factor receptor 2(HER2)-specific CAR engineered T-cell membranes.Anti-HER2 CAR-T-cell membrane-coated PLGA NPs(CAR-T-MNPs)were characterized and confirmed via fluorescent microscopy and flow cytometry.Membrane-coated NPs showed a sustained drug release over the course of 21 days in physiological conditions.Cisplatin-loaded CAR-T-MNPs also inhibited the growth of multiple HER2+cancer cells in vitro.In addition,in vitro uptake studies revealed that CAR-T-MNPs showed an increased uptake by A549 cells.These results were also confirmed via in vivo biodistribution and therapeutic studies using a subcutaneous lung cancer model in nude mice.CAR-T-MNPs localized preferentially at tumor areas compared to those of other studied groups and consisted of a significant reduction in tumor growth in tumor-bearing mice.In Conclusion,the new CAR modified cell membrane-coated NP drug-delivery platform has demonstrated its efficacy both in vitro and in vivo.Therefore,CAR engineered membrane-coated NP system could be a promising cell-mimicking drug carrier that could improve therapeutic outcomes of lung cancer treatments.

PDLIM1 sustains DNA damage response by promoting chromatin relaxation and activating DNA-PK complex

PDZ and LIM domain protein 1(PDLIM1)is a cytoplasmic LIM protein that regulates cytoskeleton organization and functions as a platform to coordinate various cellular processes.1 Accumulated evidence suggests that PDLIM1 plays important roles in tumorigenesis,tumor progression,and response to cancer therapy.Consistently,our results demonstrated that silencing PDLIM1 significantly inhibited the migration and the invasion of HeLa cells compared with control cells(Fig.S1).However,the feasibility of targeting PDLIM1 as an effective strategy for radiotherapy remains to be determined.

Mixed secondary chromatin structure revealed by modeling radiation-induced DNA fragment length distribution

Spatial chromatin structure plays fundamental roles in many vital biological processes including DNA replication, transcription,damage and repair. However, the current understanding of the secondary structure of chromatin formed by local nucleosomenucleosome interactions remains controversial, especially for the existence and conformation of 30 nm structure. Since chromatin structure influences the fragment length distribution(FLD) of ionizing radiation-induced DNA strand breaks, a 3D chromatin model fitting FLD patterns can help to distinguish different models of chromatin structure. Here, we developed a novel "30-C" model combining 30 nm chromatin structure models with Hi-C data, which measured the spatial contact frequency between different loci in the genome. We first reconstructed the 3D coordinates of the 25 kb bins from Hi-C heatmaps. Within the25 kb bins, lower level chromatin structures supported by recent studies were filled. Simulated FLD patterns based on the 30-C model were compared to published FLD patterns induced by heavy ion radiation to validate the models. Importantly, the 30-C model predicted that the most probable chromatin fiber structure for human interphase fibroblasts in vivo was 45% zig-zag 30 nm fibers and 55% 10 nm fibers.

口咽癌与人类乳头状瘤病毒有关：发病率快速上升，影响预后及相关政策

头颈部癌症是第六大常见的恶性肿瘤，世界范围内每年约有640000例新发病例。虽然近年来头颈部癌症发病率略有下降，但口咽部鳞状细胞癌发病率却大幅上升，发达国家尤为明显。

DNA mismatch repair in trinucleotide repeat instability

Trinucleotide repeat expansions cause over 30 severe neuromuscular and neurodegenerative disorders, including Huntington's disease, myotonic dystrophy type 1, and fragile X syndrome. Although previous studies have substantially advanced the understanding of the disease biology, many key features remain unknown. DNA mismatch repair(MMR) plays a critical role in genome maintenance by removing DNA mismatches generated during DNA replication. However, MMR components,particularly mismatch recognition protein MutSβ and its interacting factors MutLα and MutLγ, have been implicated in trinucleotide repeat instability. In this review, we will discuss the roles of these key MMR proteins in promoting trinucleotide repeat instability.