Artificial Intelligence Literacy: Developing a Multi-institutional Infrastructure for AI Education.

RATIONALE AND OBJECTIVES: To evaluate the effectiveness of an artificial intelligence (AI) in radiology literacy course on participants from nine radiology residency programs in the Southeast and Mid-Atlantic United States. MATERIALS AND METHODS: A week-long AI in radiology course was developed and included participants from nine radiology residency programs in the Southeast and Mid-Atlantic United States. Ten 30 minutes lectures utilizing a remote learning format covered basic AI terms and methods, clinical applications of AI in radiology by four different subspecialties, and special topics lectures on the economics of AI, ethics of AI, algorithm bias, and medicolegal implications of AI in medicine. A proctored hands-on clinical AI session allowed participants to directly use an FDA cleared AI-assisted viewer and reporting system for advanced cancer. Pre- and post-course electronic surveys were distributed to assess participants' knowledge of AI terminology and applications and interest in AI education. RESULTS: There were an average of 75 participants each day of the course (range: 50-120). Nearly all participants reported a lack of sufficient exposure to AI in their radiology training (96.7%, 90/93). Mean participant score on the pre-course AI knowledge evaluation was 8.3/15, with a statistically significant increase to 10.1/15 on the post-course evaluation (p= 0.04). A majority of participants reported an interest in continued AI in radiology education in the future (78.6%, 22/28). CONCLUSION: A multi-institutional AI in radiology literacy course successfully improved AI education of participants, with the majority of participants reporting a continued interest in AI in radiology education in the future.

Oligonol prevented the relapse of dextran sulfate sodium-ulcerative colitis through enhancing NRF2-mediated antioxidative defense mechanism.

Repeated bouts of ulcerative colitis featured troublesome course of inflammatory bowel disease leading to fatal colitis-associated cancer, which is strongly associated with oxidative stress and sustained inflammation. Since oligonol, low molecular weighted polyphenol extracted from fruit lychee, showed antioxidative and anti-inflammatory actions, we hypothesized that oligonolcan prevent relapse of colitis. We compared oligonol with current gold standard therapeutics, sulfasalazine in preventive efficacy of relapse. First, dextran sulfate sodium (DSS)-induced colitis were made following pretreatment with oligonol, 10, 50, and 100 mg/kg for 7 days to measure therapeutic effect of oligonol and relapse model via repeated DSS administration was made following with either 50 mg/kg oligonol or 30 mg/kg sulfasalazine to explore relapse preventing action of oligonol in C57BL/6 mice. Detailed changes in colon were measured to explain molecular mechanisms. Pretreatment of 10, 50, 100 mg/kg oligonol (p.o.), significantly reduced DSS-induced colitis; total pathologic scores, colon length, and clinical symptom scores (P < 0.05). Oligonol pretreatment significantly decreased the levels of interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α) as well as nuclear factor-κB (NF-κB), c-Fos, and c-Jun in affected colon tissues, but the expression of heme oxygenase-1 (HO-1) and NADH: quinone oxidoreductase-1(NQO-1) as well as total antioxidant concentration (P < 0.005) was significantly increased with oligonol. A relapse model established with repeated DSS administration led to high mortality. However, oligonol significantly ameliorated exacerbations of colitis, while sulfasalazine did not (P < 0.01). Significantly decreased expressions of cyclooxygenase-2 (COX-2), TNF-α, and macrophages inhibition were relapse preventing actions of oligonal, but significant action of oligonol relevant to relapse prevention was either significantly increased expressions of NQO-1 or significantly preserved mucin (P < 0.05). Concerted anti-inflammatory, antioxidative, and host defense enhancing actions of oligonol can be applied during maintenance therapy of IBD to prevent relapse of IBD.

Incidence of psoriasiform diseases secondary to tumour necrosis factor antagonists in patients with inflammatory bowel disease: a nationwide population-based cohort study.

BACKGROUND: There are increasing reports of paradoxical psoriasiform diseases secondary to anti-tumour necrosis factor (TNF) agents. AIMS: To determine the risks of paradoxical psoriasiform diseases secondary to anti-TNF agents in patients with inflammatory bowel disease (IBD). METHODS: A nationwide population study was performed using the Korea National Health Insurance Claim Data. A total of 50 502 patients with IBD were identified between 2007 and 2016. We compared 5428 patients who were treated with any anti-TNF agent for more than 6 months (anti-TNF group) and 10 856 matched controls who had never taken anti-TNF agents (control group). RESULTS: Incidence of psoriasis was significantly higher in the anti-TNF group (36.8 per 10 000 person-years) compared to the control group (14.5 per 10 000 person-years) (hazard ratio [HR] 2.357, 95% confidence interval [CI] 1.668-3.331). Palmoplantar pustulosis (HR 9.355, 95% CI 2.754-31.780) and psoriatic arthritis (HR 2.926, 95% CI 1.640-5.218) also showed higher risks in the anti-TNF group. In subgroup analyses, HRs for psoriasis by IBD subtype were 2.549 (95% CI 1.658-3.920) in Crohn's disease and 2.105 (95% CI 1.155-3.836) in ulcerative colitis. Interestingly, men and younger (10-39 years) patients have significantly higher risks of palmoplantar pustulosis (HR 19.682 [95% CI 3.867-100.169] and HR 14.318 [95% CI 2.915-70.315], respectively), whereas women and older (≥40 years) patients showed similar rates between the two groups. CONCLUSIONS: The risks of psoriasiform diseases are increased by anti-TNF agents in patients with IBD. Among psoriasiform diseases, the risk of palmoplantar pustulosis shows the biggest increase particularly in male and younger patients.

Do laryngoscopic findings reflect the characteristics of reflux in patients with laryngopharyngeal reflux?

OBJECTIVE: To analyse the association between 24-hour multichannel intraluminal impedance-pH (24-h MII-pH) parameters and each item of the reflux finding score (RFS) to determine whether the laryngoscopic findings of the RFS could reflect the characteristics of reflux in patients with laryngopharyngeal reflux (LPR). STUDY DESIGN: Prospective cohort study. SETTINGS: Tertiary care referral medical centre. PARTICIPANTS: Patients complaining of LPR symptoms were evaluated via a 24-hour MII-pH. Among them, 99 patients whose LPR was confirmed via 24-hour MII-pH were enrolled in this study. MAIN OUTCOME MEASURES: Correlations between RFS ratings and 24-hour MII-pH parameters were evaluated and compared between patients with or without each laryngoscopic finding used in the RFS. RESULTS: Subglottic oedema had a statistically significant positive correlation with number of non-acid LPR and non-acid full column reflux events. Ventricular obliteration and posterior commissure hypertrophy showed a significant correlation with non-acid exposure time and total reflux exposure time. We also found a significant correlation between granuloma/granulation score and number of acid LPR events. The numbers of non-acid LPR and full column reflux events in patients with subglottic oedema were significantly higher than those without subglottic oedema. CONCLUSION: Among the laryngoscopic findings used in the RFS, subglottic oedema is specific for non-acid reflux episodes, and granuloma/granulation is specific for acid reflux episodes.

Detection and classification of the breast abnormalities in digital mammograms via regional Convolutional Neural Network.

Automatic detection and classification of the masses in mammograms are still a big challenge and play a crucial role to assist radiologists for accurate diagnosis. In this paper, we propose a novel computer-aided diagnose (CAD) system based on one of the regional deep learning techniques: a ROI-based Convolutional Neural Network (CNN) which is called You Only Look Once (YOLO). Our proposed YOLO-based CAD system contains four main stages: mammograms preprocessing, feature extraction utilizing multi convolutional deep layers, mass detection with confidence model, and finally mass classification using fully connected neural network (FC-NN). A set of training mammograms with the information of ROI masses and their types are used to train YOLO. The trained YOLO-based CAD system detects the masses and classifies their types into benign or malignant. Our results show that the proposed YOLO-based CAD system detects the mass location with an overall accuracy of 96.33%. The system also distinguishes between benign and malignant lesions with an overall accuracy of 85.52%. Our proposed system seems to be feasible as a CAD system capable of detection and classification at the same time. It also overcomes some challenging breast cancer cases such as the mass existing in the pectoral muscles or dense regions.

Association between 24-hour combined multichannel intraluminal impedance-pH monitoring and symptoms or quality of life in patients with laryngopharyngeal reflux.

OBJECTIVE: To evaluate the association between the parameters of 24-hour multichannel intraluminal impedance (MII)-pH monitoring and the symptoms or quality of life (QoL) in laryngopharyngeal reflux (LPR) patients. DESIGN: Prospective cohort study without controls. SETTING: University teaching hospital. METHODS: Forty-five LPR patients were selected from subjects who underwent 24-hour MII-pH monitoring and were diagnosed with LPR from September 2014 to May 2015. Reflux Symptom Index (RSI), Health-related Quality of Life (HRQoL), Short Form 12 (SF-12) Survey questionnaires were surveyed. Spearman's correlation was used to analyse the association between the symptoms or QoL and 24-hour MII-pH monitoring. RESULTS: Most parameters in 24-hour MII-pH monitoring showed weak or no correlation with RSI, HRQoL and SF-12. Only number of non-acid reflux events that reached the larynx and pharynx (LPR-non-acid) and number of total reflux events that reached the larynx and pharynx (LPR-total) parameters showed strong correlation with heartburn in RSI (R = 0.520, P < 0.001, R = 0.478, P = 0.001, respectively). Multiple regression analysis showed that there was only one significant regression coefficient between LPR-non-acid and voice/hoarseness portion of HRQoL (b = 1.719, P = 0.022). CONCLUSION: Most parameters of 24-hour MII-pH monitoring did not reflect subjective symptoms or QoL in patients with LPR.

Who may benefit from robotic gastrectomy?: A subgroup analysis of multicenter prospective comparative study data on robotic versus laparoscopic gastrectomy.

AIMS: Robotic gastrectomy for gastric cancer has been proven to be a feasible and safe minimally invasive procedure. However, our previous multicenter prospective study indicated that robotic gastrectomy is not superior to laparoscopic gastrectomy. This study aimed to identify which subgroups of patients would benefit from robotic gastrectomy rather than from conventional laparoscopic gastrectomy. METHODS: A prospective multicenter comparative study comparing laparoscopic and robotic gastrectomy was previously conducted. We divided the patients into subgroups according to obesity, type of gastrectomy performed, and extent of lymph node dissection. Surgical outcomes were compared between the robotic and laparoscopic groups in each subgroup. RESULTS: A total of 434 patients were enrolled into the robotic (n = 223) and laparoscopic (n = 211) surgery groups. According to obesity and gastrectomy type, there was no difference in the estimated blood loss (EBL), number of retrieved lymph nodes, complication rate, open conversion rate, and the length of hospital stay between the robotic and laparoscopic groups. According to the extent of lymph node dissection, the robotic group showed a significantly lower EBL than did the laparoscopic group after D2 dissection (P = 0.021), while there was no difference in EBL in patients that did not undergo D2 dissection (P = 0.365). CONCLUSION: Patients with gastric cancer undergoing D2 lymph node dissection can benefit from less blood loss when a robotic surgery system is used.

Ten-Year Experience With Bowel Transplantation at Seoul St. Mary's Hospital.

A retrospective review of intestinal transplantation (ITx) at Seoul St. Mary's Hospital was made by collecting clinical data over the past 10 years. Fifteen consecutive cases from 2004 were analyzed. Five children and 10 adults (6 months to 69 years of age) were included. Primary diseases in adults included 4 mesenteric vessel thromboses, 2 strangulations, and 1 each of visceral myopathy, malignant gastrointestinal stromal tumor (GIST), mesenteric lymphangiectasis, and injury. Pediatric cases involved 2 Hirschsprung disease, 2 visceral myopathy, and 1 necrotizing enterocolitis. Three of 7 stomas were closed using a serial transverse enteroplasty procedure before transplantation. The ITx were performed using 3 living-donor Itx, 12 deceased-donor ITx, 14 isolated Itx, and 1 modified multivisceral transplantation. Daclizumab, basiliximab, alemtusumab, or basiliximab with rabbit antithymocyte globulin (rATG) was used for the induction; tacrolimus monotherapy was used as the basic maintenance immunosuppressant; and m-TOR inhibitor was used for renal dysfunction patients. Seven cases of acute cellular rejection were treated with rATG. Three cases of antibody-mediated rejection were treated with rituximab alone or with rituximab and bortezomib combination. There were 4 cases of early mortality within 6 months after Itx. Causes of death were declamping shock, cardiac tamponade with acute cellular rejection, dysmotility, and sepsis. Surgical complications consisted of 1 feeding jejunostomy displacement, and a minor leakage at a colo-colostomy site. One-year survival of the patient and graft was 73.33% (Kaplan-Meier survival curve). Although the total number of ITx is small, its social impact has been remarkable in changing the related laws and reimbursement policy in Korea.

Bone Regeneration of Blood-derived Stem Cells within Dental Implants.

Peripheral blood (PB) is known as a source of mesenchymal stem cells (MSCs), as is bone marrow (BM), and is acquired easily. However, it is difficult to have enough MSCs, and their osteogenic capacity with dental implantations is scarce. Therefore, we characterized peripheral blood mesenchymal stem cells (PBMSCs) cultured on a bone marrow-derived mesenchymal stem cell (BMMSC) natural extracellular matrix (ECM) and demonstrated the osteogenic capability in an experimental chamber implant surgery model in rabbits. We isolated PBMSCs from rabbits by culturing on a natural ECM-coated plate during primary culture. We characterized the PBMSCs using a fluorescence-activated cell scanner, cell proliferation assay, and multiple differentiation assay and compared them with BMMSCs. We also analyzed the osteogenic potential of PBMSCs mixed with hydroxyapatite/tricalcium phosphate (HA/TCP) by transplanting them into immunocompromised mice. Then, the mixture was applied to the canals. After 3 and 6 wk, we analyzed new bone (NB) formation inside the chambers using histological and histomorphometric analyses. The PBMSCs had a similar rate of BrdU-positive cells to BMMSCs, positively expressing CD90 but negative for CD14. The PBMSCs also showed osteogenic, adipogenic, and chondrogenic ability in vitro and osteogenic ability in vivo. Histological and histomorphometric results illustrated that the PBMSC and BMMSC groups showed higher NB than the HA/TCP and defect groups in the upper and lower chambers at 6 wk and in the upper canal at 3 wk; however, there was no difference in NB among all groups in the lower canal at 3 wk. The PBMSCs have characteristics and bone regeneration ability similar to BMMSCs both in vitro and in vivo. ECM was effective for obtaining PBMSCs. Therefore, PBMSCs are a promising source for bone regeneration for clinical use.

Evaluation of a commercial orthopaedic metal artefact reduction tool in radiation therapy of patients with head and neck cancer.

OBJECTIVE: To assess the image quality and dosimetric effects of the Philips orthopaedic metal artefact reduction (OMAR) (Philips Healthcare System, Cleveland, OH) function for reducing metal artefacts on CT images of head and neck (H&N) patients. METHODS: 11 patients and a custom-built phantom with metal bead inserts (alumina, titanium, zirconia and chrome) were scanned. The image was reconstructed in two ways: with and without OMAR (OMAR and non-OMAR image). The mean and standard deviation values of CT Hounsfield unit (HU) for selected regions of interest of each case were investigated for both images. Volumetric modulated arc therapy plans were generated for all cases. Gamma analysis of each dose distribution pair in the patient (1%/1 mm criteria) and phantom (2%/2 mm and 3%/3 mm criteria) images was performed. The film measurements in phantom for two metal beads were conducted for evaluating the calculated dose on both OMAR and non-OMAR images. RESULTS: In the OMAR images, noise values were generally reduced, and the mean HU became closer to the reference value (measured from patients without metal implants) in both patient and phantom cases. Although dosimetric difference was insignificant for the eight closed-mouth patients (γ = 99.4 ± 0.5%), there was a large discrepancy in dosimetric calculation between OMAR and non-OMAR images for the three opened-mouth patients (γ = 91.1%, 94.8% and 96.6%). Moreover, the calculated dose on the OMAR image is closer to the real delivered dose on a radiochromic film than was the dose from the non-OMAR image. CONCLUSION: The OMAR algorithm increases the accuracy of CT HU and reduces the noise such that the entire radiation treatment planning process can be improved, especially for contouring and segmentation. ADVANCES IN KNOWLEDGE: OMAR reconstruction is appropriate for the radiotherapy planning process of H&N patients, particularly of patients who use a bite block.

Role of proton pump inhibitors in preventing hypergastrinemia-associated carcinogenesis and in antagonizing the trophic effect of gastrin.

Gastrin is the main hormone stimulating gastric acid secretion, but it exerts proliferative and anti-apoptotic actions on various cancer cell types, in addition to its well-known trophic effect on enterochromaffin-like cells. As treatment with proton pump inhibitors (PPIs) increases the biosynthesis and secretion of gastrin, it has been postulated that treatment with PPIs could increase the risk of cancer, especially in Barrett's esophagus, gastric carcinoids, and colorectal cancer (CRC). Some tumors produce gastrin of their own, which can act in an autocrine manner to promote tumor growth. In addition, gastrin is known to foster the tumor microenvironment. However, in spite of these potentially increased cancer risks due to PPI-induced hypergastrinemia, prospective, large-scale cohort studies did not show an increase in CRC prevalence. The question as to why the long-term use of PPIs was not associated with an increased cancer risk of CRC might be answered by the fact that the PPIs antagonized the trophic effects of hypergastrinemia. Furthermore, the blockade of proton pumps or potassium channels in cancer cells could limit the abnormal glycolytic energy metabolism of cancer cells. Apart from their suppressive effect on gastric acids, PPIs exert an anti-tumor effect through the selective induction of apoptosis as well as an anti-inflammatory effect, and they protect cells from developing chemo- or radiotherapeutic resistance. Moreover, the anti-carcinogenic actions of PPIs were augmented with PPI-induced hypergastrinemia. Together with their potential targeted killing of cancer stem cells, these effects demonstrate their potential anti-cancer actions.

Comparision of surgical outcomes of intraocular lens refixation and intraocular lens exchange with perfluorocarbon liquid and fibrin glue-assisted sutureless scleral fixation.

AIM: The purpose of this study was to compare the surgical outcomes of intraocular lens (IOL) refixation with intraocular lens exchange using perfluorocarbon liquid (PFCL) and fibrin glue-assisted sutureless scleral fixation surgery in patients with dislocation of the IOL. METHODS: Twenty-five eyes of 25 patients who underwent surgery for dislocated IOLs with PFCL and fibrin glue-assisted scleral fixation were studied; 13 eyes experienced IOL refixation (in-the-bag and out-of-the-bag), and 12 eyes experienced IOL exchange. Preoperative and postoperative clinical features from patient charts and 25 eyes with >6 months' follow-up information were reviewed and analyzed. RESULTS: At postoperative 6 months, best-corrected visual acuity (BCVA) and spherical equivalent of IOL refixation and exchange were significantly improved (P=0.042, P=0.001), and endothelial cell density was significantly decreased in the two groups with no significant difference between them. Surgically induced astigmatism of IOL refixation improved from 0.90±0.47 to 0.61±0.37 (P=0.012), and IOL exchange improved from 1.17±0.64 to 0.73±0.37 (P=0.037) at postoperative 6 months, with no significant difference between the two groups. Complications occurred in four eyes in the IOL refixation group and in three eyes in the IOL exchange group. CONCLUSION: PFCL and fibrin glue-assisted IOL sutureless scleral refixation or exchanged fixation was an effective surgical treatment for IOL dislocation. Also, because postoperative BCVA, surgical outcomes, and complications did not differ significantly between IOL refixation and exchange surgery, if IOL exchange surgery is not indicated, IOL refixation surgical techniques should be considered.

The effect of MLC speed and acceleration on the plan delivery accuracy of VMAT.

OBJECTIVE: To determine a new metric utilizing multileaf collimator (MLC) speeds and accelerations to predict plan delivery accuracy of volumetric modulated arc therapy (VMAT). METHODS: To verify VMAT delivery accuracy, gamma evaluations, analysis of mechanical parameter difference between plans and log files, and analysis of changes in dose-volumetric parameters between plans and plans reconstructed with log files were performed with 40 VMAT plans. The average proportion of leaf speeds ranging from l to h cm s(-1) (Sl-h and l-h = 0-0.4, 0.4-0.8, 0.8-1.2, 1.2-1.6 and 1.6-2.0), mean and standard deviation of MLC speeds were calculated for each VMAT plan. The same was carried out for accelerations in centimetre per second squared (Al-h and l-h = 0-4, 4-8, 8-12, 12-16 and 16-20). The correlations of those indicators to plan delivery accuracy were analysed with Spearman's correlation coefficient (rs). RESULTS: The S1.2-1.6 and mean acceleration of MLCs showed generally higher correlations to plan delivery accuracy than did others. The highest rs values were observed between S1.2-1.6 and global 1%/2 mm (rs = -0.698 with p < 0.001) as well as mean acceleration and global 1%/2 mm (rs = -0.650 with p < 0.001). As the proportion of MLC speeds and accelerations >0.4 and 4 cm s(-2) increased, the plan delivery accuracy of VMAT decreased. CONCLUSION: The variations in MLC speeds and accelerations showed considerable correlations to VMAT delivery accuracy. ADVANCES IN KNOWLEDGE: As the MLC speeds and accelerations increased, VMAT delivery accuracy reduced.

The role of Tcfap2c in tumorigenesis and cancer growth in an activated Neu model of mammary carcinogenesis.

TFAP2C/AP-2γ influences development of the mammary gland and regulates patterns of gene expression in luminal and HER2-amplified breast cancer. The roles of TFAP2C in mammary gland tumorigenesis and in pathways critical to cancer progression remain poorly understood. To gain greater insight into oncogenic mechanisms regulated by TFAP2C, we examined mammary tumorigenesis in MMTV-Neu transgenic female mice with or without conditional knockout (KO) of Tcfap2c, the mouse homolog of TFAP2C. Loss of Tcfap2c increased the latency of tumorigenesis and tumors that formed demonstrated reduced proliferative index and increased apoptosis. In addition, tumors formed in Tcfap2c KO animals had a significant reduction in Egfr levels without a change in the expression of the Neu oncogene. The MMneu-flAP2C cell line was established from tumor tissue derived from MMTV-Neu/Tcfap2c(L/L) control animals and parallel cell lines with and without expression of Tcfap2c were created by transduction with adenovirus-empty and adenovirus-Cre, respectively. KO of Tcfap2c in vitro reduced activated phosphorylated-Erk, decreased cell viability, repressed tumor growth and was associated with attenuation of Egfr expression. Chromatin immunoprecipitation and direct sequencing and expression analysis confirmed that Egfr was a Tcfap2c target gene in murine, as well as human, mammary carcinoma cells. Furthermore, decreased viability of mammary cancer cells was directly related to Egfr functional blockade. We conclude that TFAP2C regulates tumorigenesis, cell growth and survival in HER2-amplified breast cancer through transcriptional regulation of EGFR. The findings have important implications for targeting the EGFR pathway in breast cancer.

TFAP2C governs the luminal epithelial phenotype in mammary development and carcinogenesis.

Molecular subtypes of breast cancer are characterized by distinct patterns of gene expression that are predictive of outcome and response to therapy. The luminal breast cancer subtypes are defined by the expression of estrogen receptor-alpha (ERα)-associated genes, many of which are directly responsive to the transcription factor activator protein 2C (TFAP2C). TFAP2C participates in a gene regulatory network controlling cell growth and differentiation during ectodermal development and regulating ESR1/ERα and other luminal cell-associated genes in breast cancer. TFAP2C has been established as a prognostic factor in human breast cancer, however, its role in the establishment and maintenance of the luminal cell phenotype during carcinogenesis and mammary gland development have remained elusive. Herein, we demonstrate a critical role for TFAP2C in maintaining the luminal phenotype in human breast cancer and in influencing the luminal cell phenotype during normal mammary development. Knockdown of TFAP2C in luminal breast carcinoma cells induced epithelial-mesenchymal transition with morphological and phenotypic changes characterized by a loss of luminal-associated gene expression and a concomitant gain of basal-associated gene expression. Conditional knockout of the mouse homolog of TFAP2C, Tcfap2c, in mouse mammary epithelium driven by MMTV-Cre promoted aberrant growth of the mammary tree leading to a reduction in the CD24(hi)/CD49f(mid) luminal cell population and concomitant gain of the CD24(mid)/CD49f(hi) basal cell population at maturity. Our results establish TFAP2C as a key transcriptional regulator for maintaining the luminal phenotype in human breast carcinoma. Furthermore, Tcfap2c influences development of the luminal cell type during mammary development. The data suggest that TFAP2C has an important role in regulated luminal-specific genes and may be a viable therapeutic target in breast cancer.

New conformity indices based on the calculation of distances between the target volume and the volume of reference isodose.

OBJECTIVE: To present conformity indices (CIs) based on the distance differences between the target volume (TV) and the volume of reference isodose (VRI). METHODS: The points on the three-dimensional surfaces of the TV and the VRI were generated. Then, the averaged distances between the points on the TV and the VRI were calculated (CIdistance). The performance of the presented CIs were evaluated by analysing six situations, which were a perfect match, an expansion and a reduction of the distance from the centroid to the VRI compared with the distance from the centroid to the TV by 10%, a lateral shift of the VRI by 3 cm, a rotation of the VRI by 45° and a spherical-shaped VRI having the same volume as the TV. The presented CIs were applied to the clinical prostate and head and neck (H&N) plans. RESULTS: For the perfect match, CIdistance was 0 with 0 as the standard deviation (SD). When expanding and reducing, CIdistance was 10 and -10 with SDs <1.3, respectively. With shifting and rotating of the VRI, the CIdistance was almost 0 with SDs >11. The average value of the CIdistance in the prostate and H&N plans was 0.13 ± 7.44 and 6.04 ± 23.27, respectively. CONCLUSION: The performance of the CIdistance was equal or better than those of the conventional CIs. ADVANCES IN KNOWLEDGE: The evaluation of target conformity by the distances between the surface of the TV and the VRI could be more accurate than evaluation with volume information.

Development of an applicator for eye lens dosimetry during radiotherapy.

OBJECTIVE: To develop an applicator for in vivo measurements of lens dose during radiotherapy. METHODS: A contact lens-shaped applicator made of acrylic was developed for in vivo measurements of lens dose. This lens applicator allows the insertion of commercially available metal oxide semiconductor field effect transistors (MOSFETs) dosemeters. CT images of an anthropomorphic phantom with and without the applicator were acquired. Ten volumetric modulated arc therapy plans each for the brain and the head and neck cancer were generated and delivered to an anthropomorphic phantom. The differences between the measured and the calculated doses at the lens applicator, as well as the differences between the measured and the calculated doses at the surface of the eyelid were acquired. RESULTS: The average difference between the measured and the calculated doses with the applicator was 3.1 ± 1.8 cGy with a micro MOSFET and 2.8 ± 1.3 cGy with a standard MOSFET. The average difference without the lens applicator was 4.8 ± 5.2 cGy with the micro MOSFET and 5.7 ± 6.5 cGy with the standard MOSFET. The maximum difference with the micro MOSFET was 10.5 cGy with the applicator and 21.1 cGy without the applicator. For the standard MOSFET, it was 6.8 cGy with the applicator and 27.6 cGy without the applicator. CONCLUSION: The lens applicator allowed reduction of the differences between the calculated and the measured doses during in vivo measurement for the lens compared with in vivo measurement at the surface of the eyelid. ADVANCES IN KNOWLEDGE: By using an applicator for in vivo dosimetry of the eye lens, it was possible to reduce the measurement uncertainty.

Aberrant expression of Wnt family contributes to the pathogenesis of diabetes-induced erectile dysfunction.

Diabetic erectile dysfunction (ED) has multiple causative factors, such as endothelial and smooth muscle dysfunction and cavernous fibrosis. Wnt signalling is essential for normal embryonic development and for tissue homeostasis in adults. Aberrant activation of Wnt family members has been implicated in tissue fibrosis and in angiogenesis. In this study, we investigated the differential expression of Wnts in the penises of mice with streptozotocin-induced diabetic ED. We also examined the effect of transforming growth factor-ß1 (TGF-ß1) on the expression of Wnts in primary cultured fibroblasts isolated from human tunica albuginea. Among the mouse and human Wnts tested, 16 mouse Wnts and 14 human Wnts were detected in the corpus cavernosum tissue of normal mice and in fibroblasts derived from human tunica albuginea respectively. We observed up-regulation of Wnt10b (known to be involved in tissue fibrosis) and down-regulation of Wnt16 (known to be involved in vasculogenesis and hematopoiesis), both in the diabetic condition in vivo and with treatment of fibroblasts with TGF-ß1 in vitro. Wnt10b was mainly expressed in fibroblasts and Wnt16 was colocalized with smooth muscle cells in the corpus cavernosum tissue. Cavernous TGF-ß1 protein expression and the degree of cavernous fibrosis determined by the ratio of collagen to smooth muscle content were significantly higher in diabetic mice than in controls. Cavernous endothelial content was significantly decreased by the diabetic condition. Overexpression of Wnt16 with plasmid vector accelerated tube formation in primary cultured mouse cavernous endothelial cells. However, down-regulation of Wnt10b with small interfering RNA did not decrease the production of extracellular matrix protein in human fibroblasts. This is the first report demonstrating the differential expression of Wnts in diabetic mouse penis. Aberrant Wnt expression might contribute to the pathogenesis of ED.

Coordinated regulation of XPA stability by ATR and HERC2 during nucleotide excision repair.

ATR (ATM and Rad3-related) is an essential regulator of the nucleotide excision repair (NER) mechanism. For NER activation, ATR phosphorylates XPA, the rate-limiting factor in the NER pathway. However, the role of XPA phosphorylation at serine 196 by ATR has been elusive. Here we show that ATR-mediated XPA phosphorylation enhances XPA stability by inhibiting HERC2-mediated ubiquitination and subsequent degradation. We analyzed stabilization of XPA with substitutions of Ser 196 either to aspartate (S196D), a phosphomimetic mutation, or to alanine (S196A), a phosphodeficient mutation. Upon ultraviolet damage, ATR facilitated HERC2 dissociation from the XPA complex to induce XPA stabilization. However, this regulation was abrogated in S196A-complemented XPA-deficient cells due to persistent association of HERC2 with this XPA complex, resulting in enhanced ubiquitination of S196A. Conversely, the S196D substitution showed delayed degradation kinetics compared with the wild-type and less binding with HERC2, resulting in reduced ubiquitination of S196D. We also found that XPA phosphorylation enhanced the chromatin retention of XPA, the interaction with its binding partners following DNA damage. Taken together, our study presents a novel control mechanism in the NER pathway by regulating the steady-state level of XPA through posttranslational modifications by which ATR-mediated phosphorylation induces XPA stabilization by antagonizing HERC2-catalyzed XPA ubiquitination.

Gastrin promotes intestinal polyposis through cholecystokinin-B receptor-mediated proliferative signaling and fostering tumor microenvironment.

Increased serum gastrin concentrations in patients with colorectal cancer suggested the tumorigenic trophic effect of gastrin. Detailed and global molecular mechanisms explaining trophic effect of gastrin had not been revealed. In the current study, intestinal polyposis of APC(Min/⁺) mice was compared between phosphate buffered saline (PBS) injected and gastrin (10 µg/kg, thrice per week) injected group. Total number of intestinal polyposis was counted and immunohistochemical staining with F4/80 and CD3 was done. MTT assay, cell cycle analysis, and Western blot for cyclin D1, CDK4, and ß-catenin were performed in Raw 264.7 and HCT116 cells before and after gastrin administration. Experiments were repeated with YM022 or transfection with si-cholecystokinin-B receptor (CCK-B-R). Intraperitoneal gastrin significantly increased intestinal polyposis in APC(Min/⁺) mice (P<0.005), in which significant increases in macrophage were noted on F4/80 immunohistochemical staining (Plt;0.05) as well as Ki-67 staining (Plt;0.05) after gastrin. On comparative cytokine array, gastrin increased interleukin-1ß (IL-1ß), interleukin 3Rß (IL-3Rß), stromal cell-derived factor-1α (SDF-1α), thymus and activation-regulated chemokine (TARC), and thymus-derived chemotactic agent 3 (TCA-3) in macrophage cells, which was further confirmed with real time polymerase chain reaction (RT-PCR) analysis (P<0.05). In addition to increased inflammatory cytokines, gastrin increased macrophage proliferation accompanied with increased cyclin D1 and CDK4. Targeted for HCT116 cells, gastrin significantly increased proliferation as well as increases in synthetic phase of cell cycle. YM022 as gastrin antagonist significantly abolished the trophic actions of gastrin (P<0.05). HCT116 cells transfected with siCCK-B-R, gastrin did not increase either cell cycle or ß-catenin in spite of gastrin administration. Conclusively, gastrin promoted intestinal polyposis through either direct gastrin receptor-mediated proliferative signaling or fostering tumor microenvironment such as macrophage activation.