Exosome proteomics study of the effects of traditional cigarettes and electronic cigarettes on human bronchial epithelial cells.

Electronic cigarette (e-Cig) has been promoted as a safer alternative to traditional cigarette (t-Cig) recently. However, there are limited scientific data on the potential health effects of e-Cig use. In this study, we evaluated the cytotoxicities of e-Cig and t-Cig condensate solutions (e-CigCS and t-CigCS) on human bronchial epithelial cells (16HBE cells) in vitro, and employed the exosome proteomic technique to systematically assess the effects of e-CigCS and t-CigCS on 16HBE cells. Cytotoxicity assay showed 16HBE cells were more sensitive to t-CigCS than e-CigCS. Proteomic analysis demonstrated that there are 431 differential expressed exosomal proteins (DEEPs) in test groups compared to the control air group (P-value<0.05) and t-CigCS has a greater influence than e-CigCS on exosomal protein expression. Bioinformatic analysis showed the DEEPs from the t-Cig group were significantly enriched in pathways in cancer while tobacco-flavored e-Cig (e-Cigt) and menthol-flavored e-Cig (e-Cigm) groups were not. Further validations of some DEEPs, such as NF-κB p65, Sulfiredoxin-1(SRXN1) and Thioredoxin-interacting protein (TXNIP), were carried out using immunoblot and Real-time PCR analysis, showing that t-Cig may have a greater influence than e-Cig on tumor development and metastasis. Taken together, the finding reported here strongly support our hypothesis that electronic cigarettes are significantly less toxic compared with traditional cigarette.

Radiation Oncology: Future Vision for Quality Assurance and Data Management in Clinical Trials and Translational Science.

The future of radiation oncology is exceptionally strong as we are increasingly involved in nearly all oncology disease sites due to extraordinary advances in radiation oncology treatment management platforms and improvements in treatment execution. Due to our technology and consistent accuracy, compressed radiation oncology treatment strategies are becoming more commonplace secondary to our ability to successfully treat tumor targets with increased normal tissue avoidance. In many disease sites including the central nervous system, pulmonary parenchyma, liver, and other areas, our service is redefining the standards of care. Targeting of disease has improved due to advances in tumor imaging and application of integrated imaging datasets into sophisticated planning systems which can optimize volume driven plans created by talented personnel. Treatment times have significantly decreased due to volume driven arc therapy and positioning is secured by real time imaging and optical tracking. Normal tissue exclusion has permitted compressed treatment schedules making treatment more convenient for the patient. These changes require additional study to further optimize care. Because data exchange worldwide have evolved through digital platforms and prisms, images and radiation datasets worldwide can be shared/reviewed on a same day basis using established de-identification and anonymization methods. Data storage post-trial completion can co-exist with digital pathomic and radiomic information in a single database coupled with patient specific outcome information and serve to move our translational science forward with nimble query elements and artificial intelligence to ask better questions of the data we collect and collate. This will be important moving forward to validate our process improvements at an enterprise level and support our science. We have to be thorough and complete in our data acquisition processes, however if we remain disciplined in our data management plan, our field can grow further and become more successful generating new standards of care from validated datasets.

A study of skin marker alignment using different diamond-shaped light fields for prone breast external-beam radiation therapy.

For breast cancer patients treated in the prone position with tangential fields, a diamond-shaped light field (DSLF) can be used to align with corresponding skin markers for image-guided radiation therapy (IGRT). This study evaluates and compares the benefits of different DSLF setups. Seventy-one patients who underwent daily tangential kilovoltage (kV) IGRT were categorized retrospectively into four groups: (1) DSLF field size (FS) = 10 × 10 cm2 , gantry angle = 90° (right breast)/270° (left breast), with the same isocenter as treatment tangential beams; (2) same as group 1, except DSLF FS = 4 × 4 cm2 ; (3) DSLF FS = 4 × 4-6 × 8 cm2 , gantry angle = tangential treatment beam, off-isocenter so that the DSLF was at the approximate breast center; and (4) No-DSLF. We compared their total setup time (including any DSLF/marker-based alignment and IGRT) and relative kV-based couch shift corrections. For groups 1-3, DSLF-only dose distributions (excluding kV-based correction) were simulated by reversely shifting the couch positions from the computed tomography plans, which were assumed equivalent to the delivered dose when both DSLF and IGRT were used. For patient groups 1-4, the average daily setup time was 2.6, 2.5, 5.0, and 8.3 min, respectively. Their mean and standard deviations of daily kV-based couch shifts were 0.64 ± 0.4, 0.68 ± 0.3, 0.8 ± 0.6, and 1.0 ± 0.6 cm. The average target dose changes after excluding kV-IGRT for groups 1-3 were-0.2%, -0.1%, and +0.4%, respectively, whereas DSLF-1 was most efficient in sparing heart and chest wall, DSLF-2 had lowest lung Dmax ; and DSLF-3 maintained the highest target coverage at the cost of highest OAR dose. In general, the use of DSLF greatly reduces patient setup time and may result in smaller IGRT corrections. If IGRT is limited, different DSLF setups yield different target coverage and OAR dose sparing. Our findings will help DSLF setup optimization in the prone breast treatment setting.

Hairpin-inserted cross-shaped DNA nanoprobe for ultrasensitive microRNA detection based on built-in target analogue cycle amplification.

It remains technically challenging to develop a sensitive assay system to isothermally amplify the signal for miRNA detection because of its low abundance in tested sample, sequence similarities and existence in complex biological environments. In this study, using miRNA-21 as target model, a hairpin-inserted cross-shaped DNA nanoprobe (CP) with four functional arms is constructed for the ultrasensitive detection of miRNA via one-step built-in target analogue (BTA) cycle-mediated signal amplification. BTA is pre-locked in one arm of CP probe and inactive. In the presence of target miRNA, BTA can be unlocked and initiate an isothermal amplification process. Utilizing as-designed CP probe, miRNA-21 can be detected to down to 500 fM, and the linear response range spans over five orders of magnitude. The nonspecific signal is less than 1% upon nontarget miRNAs. CP probe exhibits âˆ¼six times enhancement in resistance to nuclease degradation and no obvious degradation-induced fluorescence change is detected during the assay period. The recovery yield ranges from 98.2～105.5% in FBS solution. Because of the high sensitivity, desirable specificity, strong anti-interference ability and substantial increase in nuclease resistance, CP probe is a promising tool for the detection of miRNAs in a complex biological milieu.

Knowledge-based planning in robotic intracranial stereotactic radiosurgery treatments.

PURPOSE: To develop a knowledge-based planning (KBP) model that predicts dosimetric indices and facilitates planning in CyberKnife intracranial stereotactic radiosurgery/radiotherapy (SRS/SRT). METHODS: Forty CyberKnife SRS/SRT plans were retrospectively used to build a linear KBP model which correlated the equivalent radius of the PTV (req_PTV ) and the equivalent radius of volume that receives a set of prescription dose (req_Vi , where Vi  = V10% , V20% … V120% ). To evaluate the model's predictability, a fourfold cross-validation was performed for dosimetric indices such as gradient measure (GM) and brain V50% . The accuracy of the prediction was quantified by the mean and the standard deviation of the difference between planned and predicted values, (i.e., ΔGM = GMpred - GMclin and fractional ΔV50%  = (V50%pred - V50%clin )/V50%clin ) and a coefficient of determination, R2 . Then, the KBP model was incorporated into the planning for another 22 clinical cases. The training plans and the KBP test plans were compared in terms of the new conformity index (nCI) as well as the planning efficiency. RESULTS: Our KBP model showed desirable predictability. For the 40 training plans, the average prediction error from cross-validation was only 0.36 ± 0.06 mm for ΔGM, and 0.12 ± 0.08 for ΔV50% . The R2 for the linear fit between req_PTV and req_vi was 0.985 ± 0.019 for isodose volumes ranging from V10% to V120% ; particularly, R2  = 0.995 for V50% and R2  = 0.997 for V100% . Compared to the training plans, our KBP test plan nCI was improved from 1.31 ± 0.15 to 1.15 ± 0.08 (P < 0.0001). The efficient automatic generation of the optimization constraints by using our model requested no or little planner's intervention. CONCLUSION: We demonstrated a linear KBP based on PTV volumes that accurately predicts CyberKnife SRS/SRT planning dosimetric indices and greatly helps achieve superior plan quality and planning efficiency.

Paradoxical Mitophagy Regulation by PINK1 and TUFm.

Aberrant mitophagy has been implicated in a broad spectrum of disorders. PINK1, Parkin, and ubiquitin have pivotal roles in priming mitophagy. However, the entire regulatory landscape and the precise control mechanisms of mitophagy remain to be elucidated. Here, we uncover fundamental mitophagy regulation involving PINK1 and a non-canonical role of the mitochondrial Tu translation elongation factor (TUFm). The mitochondrion-cytosol dual-localized TUFm interacts with PINK1 biochemically and genetically, which is an evolutionarily conserved Parkin-independent route toward mitophagy. A PINK1-dependent TUFm phosphoswitch at Ser222 determines conversion from activating to suppressing mitophagy. PINK1 modulates differential translocation of TUFm because p-S222-TUFm is restricted predominantly to the cytosol, where it inhibits mitophagy by impeding Atg5-Atg12 formation. The self-antagonizing feature of PINK1/TUFm is critical for the robustness of mitophagy regulation, achieved by the unique kinetic parameters of p-S222-TUFm, p-S65-ubiquitin, and their common kinase PINK1. Our findings provide new mechanistic insights into mitophagy and mitophagy-associated disorders.

Palindromic probe-mediated strand displacement amplification for highly sensitive and selective microRNA imaging.

MicroRNAs (miRNAs) are involved in a variety of biological processes, and the accurate detection of miRNAs is of great importance for early diagnosis of various cancers. Herein, we have developed a highly sensitive method for the intracellular imaging of miRNAs based on a palindromic probe-induced strand displacement amplification (pSDA). The sensing element is a partly complementary hybrid consisting of two DNA components: one fluorescent dye-labeled signaling probe containing a palindromic sequence and loop-based target recognition site and one quencher moiety-attached locking probe. In the presence of target miRNA, the target species can hybridize with the loop site and release the terminal palindromic fragment, initiating the pSDA reaction. Thus, a considerable amount of fluorescent moieties are spatially separated from the quenchers, generating a dramatically enhanced fluorescence signal. As a result, the target miRNAs can be quantified down to 25 pM with the linear response range over four orders of magnitude. The detection specificity is high enough to eliminate the interference from nontarget miRNAs and other biospecies co-existing in samples, and thus the diseased cells are easily distinguished from healthy cells. Strikingly, the pSDA-based system possesses the desirable capability to discriminate tumor cells from healthy cells, indicating a promising diagnostic tool for the detection of cancers and other diseases in early stage.

Dosimetric and planning efficiency comparison for lung SBRT: CyberKnife vs VMAT vs knowledge-based VMAT.

This is the first study that compared treatment plan quality and planning efficiency for lung stereotactic body radiation therapy (SBRT) using CyberKnife (CK) Multiplan vs Varian Eclipse treatment planning systems, including volumetric modulated arc therapy (VMAT) and knowledge-based VMAT (KBP-VMAT). Thirteen lung SBRT patients treated with 50 to 55 Gy in 3 or 5 fractions were retrospectively included in this study. CK plans created with Multiplan V. 4.6.1 using 2 fixed circular cones were previously approved used for treatment. For the comparison, the computed tomography (CT) data sets and contours from the CK plans were used to generate VMAT and KBP-VMAT plans (University of California San Diego publicly-shared RapidPlan model) using Eclipse V. 13.7. Metrics used for the comparison of CK, VMAT, and KBP-VMAT plans included monitor units (MUs), conformity indices, dose heterogeneity, high-dose spillage, low-dose spillage, adjacent organs at risk (OAR) doses, and treatment planning time. One-way analysis of variance with post-hoc Tukey tests and paired t-tests were used to analyze the difference of these metrics corresponding to the different planning techniques. All of the 3 planning techniques achieved our clinical goals. With similar planning target volume (PTV) coverage, CK plans yielded the most MU (p< 0.001), the least dose homogeneity (p < 0.002), and the least D2cm dose (p < 0.001), while KBP-VMAT plans resulted in the most OAR sparing. No significant difference was found among other dosimetric metrics such as high-dose spillage, lung V20 and volume receiving 50% of the prescription dose. Compared to VMAT, KBP-VMAT improved OAR sparing (p < 0.05), but required significantly more MU (p < 0.001). KBP-VMAT was associated with the shortest planning time. Eclipse-based VMAT can achieve comparable plan quality for lung SBRT as CK, in a more efficient manner. RapidPlan can facilitate the planning process of KBP-VMAT, with potentially better OAR sparing but higher MU requirements. Further improvement for KBP-VMAT is likely achievable by developing site-specific patient models.

RU486 Metabolite Inhibits CCN1/Cyr61 Secretion by MDA-MB-231-Endothelial Adhesion.

Successful adhesion of circulating tumor cells (CTCs) to microvascular endothelium of distant metastatic tissue is the key starting step of metastatic cascade that could be effectively chemoprevented as we demonstrated previously. Here, we hypothesize that the hetero-adhesion may produce secretory biomarkers that may be important for both premetastatic diagnosis and chemoprevention. We show that co-incubation of triple-negative breast cancer (TNBC) cell line MDA-MB-231 with human pulmonary microvascular endothelial monolayers (HPMEC) secretes Cyr61 (CCN1), primarily from MDA-MB-231. However, addition of metapristone (RU486 metabolite) to the co-incubation system inhibits Cyr61 secretion probably via the Cyr61/integrin αvß1 signaling pathway without significant cytotoxicity on both MDA-MB-231 and HPMEC. Transfection of MDA-MB-231 with Cyr61-related recombinant plasmid or siRNA enhances or reduces Cyr61 expression, accordingly. The transfection significantly changes hetero-adhesion and migration of MDA-MB-231, and the changed bioactivities by overexpressed CYR61 could be antagonized by metapristone in vitro. Moreover, the circulating MDA-MB-231 develops lung metastasis in mice, which could be effectively prevented by oral metapristone without significant toxicity. The present study, for the first time, demonstrates that co-incubation of MDA-MB-231 with HPMEC secrets CYR61 probably via the CYR61/integrin αvß1 signaling pathway to promote adhesion-invasion of TNBC (early metastatic step). Metapristone, by interfering the adhesion-invasion process, prevents metastasis from happening.

Dosimetric comparison of deep-inspiration breath-hold and free-breathing treatment delivery techniques for left-sided breast cancer using 3D surface tracking.

INTRODUCTION: While radiation therapy has been shown to increase local control and overall survival for breast cancer, late cardiac toxicity remains a concern. Morbidity and mortality have been shown to increase proportionally to the mean heart dose. Deep inspiration breath-hold (DIBH) can reduce heart dose compared to free-breathing (FB) by increasing the heart-to-chest wall distance, especially in left-sided breast cancer. We present our clinical experience with DIBH in left breast and chest-wall irradiation using 3D optical surface tracking. MATERIALS & METHODS: 29 patients were treated with DIBH using a surface tracking system that provides a real time 3D surface image of the patient. Comparisons of maximum and mean heart dose, heart-chest wall separation, and the percentage of lung volume that receives 20 or more Gy (V20) between the DIBH and hypothetical FB treatment plans were conducted with the Student's t-test. Correlation coefficients were also calculated for heart-chest wall separation, heart volume, and lung volume. RESULTS: Comparing DIBH and FB plans showed a decrease in mean and maximum heart doses in all patients. Individual mean heart doses decreased by an average of 1.12 Gy, and the average mean heart dose for DIBH plans was significantly lower than corresponding FB plans (1.02 vs. 2.12 Gy; p < 0.0001). Maximum heart dose decreased by an average of 11.88 Gy and was significantly lower in DIBH versus FB plans (28.33 vs. 43.7 Gy; p = 0.0001). The average difference in heart to chest-wall separation between DIBH and FB images was 2.41 cm. DIBH left lung volume and measured increases in volume on inspiration inversely correlated with maximum heart dose (R = 0.39) and left lung V20 (R = 0.32). CONCLUSIONS: DIBH with 3D surface tracking can significantly benefit patients with left sided disease by limiting the mean and maximum heart dose. DIBH appears to viably reduce heart dose for left-breast cancer patients and thus potentially reduce long-term complications without prolonging treatment delivery.

S-Nitrosocaptopril prevents cancer metastasis in vivo by creating the hostile bloodstream microenvironment against circulating tumor cells.

A perfect microenvironment facilitates the activated circulating tumor cells (CTCs) to spark the adhesion-invasion-extravasation metastatic cascade in their premetastatic niche. Platelet-CTC interaction contributes to the progression of tumor malignancy by protecting CTCs from shear stress and immunological assault, aiding CTCs entrapment in the capillary bed, enabling CTCs to successfully exit the bloodstream and enter the tissue, inducing epithelial-mesenchymal-like transition (EMT), and assisting in the establishment of metastatic foci. To prevent the cascade from sparking, we show that, the multifunctional S-nitrosocaptopril (CapNO) acts on both CTCs and platelets to interrupt platelet/CTCs interplay and adhesion to endothelium, thus inhibiting CTC-based pulmonary metastasis in vivo. The activated platelets cloak cancer HT29 cells, resulting in HT29-exhibiting platelet biomarkers CD61 and P-selectin positive. CapNO inhibits both sialyl Lewisx (Slex) expression on HT29 and ADP-induced activation of platelets through P-selectin- and GPIIb/IIIa-dependent mechanisms, confirmed by the corresponding antibody assay. CapNO inhibits platelet- or interleukin (IL)-1ß-mediated adhesion between HT29 and endothelial cells, and micrometastatic formation in the lungs of immunocompetent syngeneic mouse models. CapNO have also shown the effects of vasodilation, anticoagulation, inhibition of matrix metalloproteinase-2 (MMP2) expression on cancer cells, and inhibition of cell adhesion molecules (CAMs) expression on vascular endothelium. Due to a series of the beneficial effects of CapNO, CTCs remain exposed to the hostile bloodstream environment and are vulnerable to death induced by shear stress and immune elimination. This new discovery provides a basis for CapNO used for cancer metastatic chemoprevention, and might suggest regulation of the CTCs bloodstream microenvironment as a new avenue for cancer metastatic prevention.

Twin target self-amplification-based DNA machine for highly sensitive detection of cancer-related gene.

The sensitive detection of cancer-related genes is of great significance for early diagnosis and treatment of human cancers, and previous isothermal amplification sensing systems were often based on the reuse of target DNA, the amplification of enzymatic products and the accumulation of reporting probes. However, no reporting probes are able to be transformed into target species and in turn initiate the signal of other probes. Herein we reported a simple, isothermal and highly sensitive homogeneous assay system for tumor suppressor p53 gene detection based on a new autonomous DNA machine, where the signaling probe, molecular beacon (MB), was able to execute the function similar to target DNA besides providing the common signal. In the presence of target p53 gene, the operation of DNA machine can be initiated, and cyclical nucleic acid strand-displacement polymerization (CNDP) and nicking/polymerization cyclical amplification (NPCA) occur, during which the MB was opened by target species and cleaved by restriction endonuclease. In turn, the cleaved fragments could activate the next signaling process as target DNA did. According to the functional similarity, the cleaved fragment was called twin target, and the corresponding fashion to amplify the signal was named twin target self-amplification. Utilizing this newly-proposed DNA machine, the target DNA could be detected down to 0.1 pM with a wide dynamic range (6 orders of magnitude) and single-base mismatched targets were discriminated, indicating a very high assay sensitivity and good specificity. In addition, the DNA machine was not only used to screen the p53 gene in complex biological matrix but also was capable of practically detecting genomic DNA p53 extracted from A549 cell line. This indicates that the proposed DNA machine holds the potential application in biomedical research and early clinical diagnosis.

A 3D-Printed Patient-Specific Phantom for External Beam Radiation Therapy of Prostate Cancer.

This paper presents the design evolution, fabrication, and testing of a novel patient and organ-specific, 3D printed phantom for external beam radiation therapy of prostate cancer. In contrast to those found in current practice, this phantom can be used to plan and validate treatment tailored to an individual patient. It contains a model of the prostate gland with a dominant intraprostatic lesion, seminal vesicles, urethra, ejaculatory duct, neurovascular bundles, rectal wall, and penile bulb generated from a series of combined T2-weighted/dynamic contrast-enhanced magnetic resonance images. The iterative process for designing the phantom based on user interaction and evaluation is described. Using the CyberKnife System at Boston Medical Center a treatment plan was successfully created and delivered. Dosage delivery results were validated through gamma index calculations based on radiochromic film measurements which yielded a 99.8% passing rate. This phantom is a demonstration of a methodology for incorporating high-contrast magnetic resonance imaging into computed-tomography-based radiotherapy treatment planning; moreover, it can be used to perform quality assurance.

Fetal QT Interval Estimation Using Sequential Hypothesis Testing.

Objective: Recent studies utilizing fetal magnetocardiography have demonstrated the efficacy of corrected QT interval (QTc) measurement for in utero diagnosis and prognosis of long QT syndrome, a leading cause of sudden death in early life. The objective of the study was to formulate and test a novel statistical estimation method to detect the end of the fetal T-wave and thereby improve the accuracy of fetal QT interval measurement. Methods: To detect the end of the T-wave, we apply a sequential composite hypothesis test to decide when the T-wave has returned to baseline. The method uses the generalized likelihood ratio test in conjunction with a low-rank spatiotemporal model that exploits the repetitive nature of cardiac signals. The unknown model parameters are determined using maximum likelihood estimation. Results: In realistic simulations, the detector was shown to be accurate to within 10 ms (95% prediction interval), even at noise-to-signal ratios as high as 6. When applied to real data from normal fetuses, the detector agreed well with measurements made by cardiologists ( 1.4 6.9 ms). Conclusions: The method was effective and practical. Detector performance was excellent despite the continual presence of strong maternal interference. Significance: This detector serves as a valuable adjunct to traditional measurement based on subjective assessment.Objective: Recent studies utilizing fetal magnetocardiography have demonstrated the efficacy of corrected QT interval (QTc) measurement for in utero diagnosis and prognosis of long QT syndrome, a leading cause of sudden death in early life. The objective of the study was to formulate and test a novel statistical estimation method to detect the end of the fetal T-wave and thereby improve the accuracy of fetal QT interval measurement. Methods: To detect the end of the T-wave, we apply a sequential composite hypothesis test to decide when the T-wave has returned to baseline. The method uses the generalized likelihood ratio test in conjunction with a low-rank spatiotemporal model that exploits the repetitive nature of cardiac signals. The unknown model parameters are determined using maximum likelihood estimation. Results: In realistic simulations, the detector was shown to be accurate to within 10 ms (95% prediction interval), even at noise-to-signal ratios as high as 6. When applied to real data from normal fetuses, the detector agreed well with measurements made by cardiologists ( 1.4 6.9 ms). Conclusions: The method was effective and practical. Detector performance was excellent despite the continual presence of strong maternal interference. Significance: This detector serves as a valuable adjunct to traditional measurement based on subjective assessment.

Promising Compounds From Murraya exotica for Cancer Metastasis Chemoprevention.

Most of the present anticancer drugs are highly cytotoxic and focus mainly on killing tumor cells rather than slowing the progress of cancer metastasis. Evidence has been reported that bridges the mechanisms of inflammation and tumor invasion. Therefore, we evaluated the potency in cancer metastasis chemoprevention of compounds and a coumarin extracted from Murraya exotica, which is known for its anti-inflammation bioactivity. By carrying out experiments in vitro, we found the root extracts more efficient than the leaf extracts in restraining cell migration of MDA-MB-231 cells, while leaf extracts presented slightly stronger inhibition of tumor cell adhesion at low concentrations. In addition, compared to root extracts, a novel coumarin identified previously from root extracts showed equal inhibition on cancer cell adhesion and less inhibition on cell migration. All extracts used in this study presented low cytotoxicity in vitro. Through comparison of the contents of leaf and root extracts from M exotica, several compounds are considered promising against cancer metastasis. This study evaluates the worth of further development of M exotica to find its effect on cancer metastasis chemoprevention.

Focal Hepatic Fluorodeoxyglucose Uptake Mimics Liver Metastasis Following External Beam Radiation for Gastroesophageal Cancers: A Case and Review of the Literature.

Patients with locally advanced gastroesophageal cancers frequently undergo concurrent chemotherapy and radiation (CRT). 18-fluorodeoxyglucose-positron emission tomography ((18)FDG-PET) in combination with computed tomography is used for disease staging and assessing response to therapy. (18)FDG-PET interpretation is subject to confounding influences including infectious/inflammatory conditions, serum glucose, and concurrent medications. Radiotherapy induces tissue damage, which may be associated with FDG-avidity; however, few reports have described the focal areas of hepatic uptake following concurrent chemoradiation (CRT). Distinguishing hepatic FDG uptake from disease progression represents an important clinical scenario. Here, we present two cases of unexpected FDG uptake in the liver after CRT and review the literature describing incidental liver uptake on FDG-PET.

Radiation dermatitis caused by a bolus effect from an abdominal compression device.

American Association of Physicists in Medicine (AAPM) Task Group 176 evaluated the dosimetric effects caused by couch tops and immobilization devices. The report analyzed the extensive physics-based literature on couch tops, stereotactic body radiation therapy (SBRT) frames, and body immobilization bags, while noting the scarcity of clinical reports of skin toxicity because of external devices. Here, we present a clinical case report of grade 1 abdominal skin toxicity owing to an abdominal compression device. We discuss the dosimetric implications of the utilized treatment plan as well as post hoc alternative plans and quantify differences in attenuation and skin dose/build-up between the device, a lower-density alternative device, and an open field. The description of the case includes a 66-year-old male with HER2 amplified poorly differentiated distal esophageal adenocarcinoma treated with neoadjuvant chemo-radiation and the use of an abdominal compression device. Radiation was delivered using volumetric modulated arc therapy (VMAT) with 2 arcs using abdominal compression and image guidance. The total dose was 50.4Gy delivered over 40 elapsed days. With 2 fractions remaining, the patient developed dermatitis in the area of the compression device. The original treatment plan did not include a contour of the device. Alternative post hoc treatment plans were generated, one to contour the device and a second with anterior avoidance. In conclusion, replanning with the device contoured revealed the bolus effect. The skin dose increased from 27 to 36Gy. planned target volume (PTV) coverage at 45Gy was reduced to 76.5% from 95.8%. The second VMAT treatment plan with an anterior avoidance sector and more oblique beam angles maintained PTV coverage and spared the anterior wall, however at the expense of substantially increased dose to lung. This case report provides an important reminder of the bolus effect from external devices such as abdominal compression. Special consideration must be given to contour and/or avoiding beam entrance to the device, and to the use of such devices in patients who may have heightened radiosensitivity, such as those who are human immunodeficiency virus (HIV)-positive.

Pharmacoproteomic analysis reveals that metapristone (RU486 metabolite) intervenes E-cadherin and vimentin to realize cancer metastasis chemoprevention.

Metapristone is the most predominant biological active metabolite of mifepristone, and being developed as a novel cancer metastasis chemopreventive agent by us. Despite its prominent metastasis chemopreventive effect, the underlying mechanism remains elusive. Our study, for the first time, demonstrated that metapristone had the ability to prevent breast cancer cells from migration, invasion, and interfere with their adhesion to endothelial cells. To explore the underlying mechanism of metapristone, we employed the iTRAQ technique to assess the effect of metapristone on MDA-MB-231 cells. In total, 5,145 proteins were identified, of which, 311 proteins showed significant differences in metapristone-treated cells compared to the control group (P-value < 0.05). Bioinformatic analysis showed many differentially expressed proteins (DEPs) functionally associated with post-translational modification, chaperones, translation, transcription, replication, signal transduction, etc. Importantly, many of the DEPs, such as E-cadherin, vimentin, TGF-ß receptor I/II, smad2/3, ß-catenin, caveolin, and dystroglycan were associated with TGF-ß and Wnt signaling pathways, which were also linked to epithelial-to-mesenchymal transition (EMT) process. Further validation of the epithelial marker "E-caderin" and mesenchymal marker "vimetin" were carried out using immunoblot and immunofluorescence. These results have revealed a novel mechanism that metapristone-mediated metastasis chemoprevention is through intervening the EMT-related signaling pathways.

Thirty-day rat toxicity study reveals reversible liver toxicity of mifepristone (RU486) and metapristone.

OBJECTIVE: Mifepristone (RU486) is an oral first-line contraceptive used by hundreds of millions of women, and recently it was tested for anticancer activity in both genders worldwide. We are developing metapristone (the N-monodemethyl RU486) as a potential metastasis chemopreventive. The present acute and 30-d subacute toxicity study aimed at examining and compared in parallel the potential toxicity of the two drugs. METHODS: The single-dose acute toxicity and 30-d subacute toxicity studies were conducted in mice and rats, respectively, by gavaging metapristone or mifepristone at various doses. Blood samples and organs were collected for blood chemistry, hematology and histology analyses. RESULTS: Oral mifepristone (3000 mg/kg) caused 30% and 40% death in female and male mice, respectively, within 15 h post-dosing. In comparison, the same dose of metapristone produced 30% acute death in males only. Thirty-day oral administration of the two drugs to rats (12.5, 50 and 200 mg/kg/day) caused reversible hepatotoxicity that only occurred at 200 mg/kg/day group, evidenced by the elevated liver enzyme activity and liver organ weight. CONCLUSION: The present study, for the first time, reveals reversible hepatotoxicity in rats caused by the 30-d consecutive administration at the high dose, and warns the potential hepatotoxicity caused by long-term administrations of high doses of mifepristone or metapristone in clinical trials but not by the acute single abortion doses.