Effect of X-ray tube on image quality and pancreatic ductal adenocarcinoma conspicuity in pancreatic protocol dual-energy CT.

AIM: To compare the radiation dose, image quality, and conspicuity of pancreatic ductal adenocarcinoma (PDAC) in pancreatic protocol dual-energy computed tomography (CT) between two X-ray tubes mounted in the same CT machine. MATERIAL AND METHODS: This retrospective study comprised 80 patients (median age, 73 years; 45 men) who underwent pancreatic protocol dual-energy CT from January 2019 to March 2022 using either old (Group A, n=41) or new (Group B, n=39) X-ray tubes mounted in the same CT machine. The imaging parameters were completely matched between the two groups, and CT data were reconstructed at 70 and 40 keV. The CT dose-index volume (CTDIvol); CT attenuation of the abdominal aorta, pancreas, and PDAC; background noise; and qualitative scores for the image noise, overall image quality, and PDAC conspicuity were compared between the two groups. RESULTS: The CTDIvol was lower in Group B than Group A (7.9 versus 9.2 mGy; p<0.001). The CT attenuation of all anatomical structures at 70 and 40 keV was comparable between the two groups (p=0.06-0.78). The background noise was lower in Group B than Group A (12 versus 14 HU at 70 keV, p=0.046; and 26 versus 30 HU at 40 keV, p<0.001). Qualitative scores for image noise and overall image quality at 70 and 40 keV and PDAC conspicuity at 40 keV were higher in Group B than Group A (p<0.001-0.045). CONCLUSION: The latest X-ray tube could reduce the radiation dose and improve image quality in pancreatic protocol dual-energy CT.

Not Only Hypoxia- but Radiation-Induced Epithelial-Mesenchymal Transition Is Modulated by Hypoxia-Inducible Factor 1 in A549 Lung Cancer Cells.

Hypoxia leads to post-treatment metastasis and recurrences of cancer via the epithelial-mesenchymal transition (EMT). Radiotherapy itself may also contribute to the acquisition of EMT phenotypes. Despite extensive studies on the EMT driven by either hypoxia or radiation stimuli, the molecular mechanisms characterizing these EMT events remain unclear. Thus, we aimed to evaluate the differences in the molecular pathways between hypoxia-induced EMT (Hypo-EMT) and radiation-induced EMT (R-EMT). Further, we investigated the therapeutic effects of HIF-1α inhibitor (LW6) on Hypo-EMT and R-EMT cells. A549 cells, lung adenocarcinoma cell line, acquired enhanced wound-healing activity under both hypoxia and irradiation. Localization of E-cadherin was altered from the cell membrane to the cytoplasm in both hypoxia and irradiated conditions. Of note, the expression levels of vimentin, one of the major EMT markers, was enhanced in irradiated cells, while it decreased under hypoxia condition. Importantly, LW6 significantly blocked EMT-related malignant phenotypes in both Hypo-EMT cells and R-EMT cells with concomitant re-location of E-cadherin onto the cell membrane. Moreover, LW6 deflected stress responsive signalling, JNK, activated sustainably under hypoxic condition, and the blockage of JNK impaired EMT phenotypes. Together, this work demonstrated the molecular events underlying Hypo-EMT and R-EMT, and highlighted HIF-1α as a therapeutic target not only in Hypo- EMT, but also in R-EMT.

A key-point based real-time tracking of lung tumor in x-ray image sequence by using difference of Gaussians filtering and optical flow.

In radiation therapy, for accurate radiation dose delivery to a target tumor and reduction of the extra exposure of normal tissues, real-time tumor tracking is typically an important technique in lung cancer treatment since lung tumors move with patients' respiration. To observe a tumor motion in real time, x-ray fluoroscopic devices can be employed, and various tracking techniques have been proposed to track tumors. However, development of a fast and accurate tracking method for clinical use is still a challenging task since the obscured image of the tumor can cause decreased tracking accuracy and can result in additional processing time for remedying the accuracy. In this study, a new key-point-based tumor tracking method, which is sufficiently fast and accurate, is presented. Given an x-ray image sequence, the proposed method employs a difference-of-Gaussians filtering technique to detect key points in the tumor region of the first frame which are robust against noise and outliers in the subsequent frames. In the subsequent frames, these key points are tracked using a fast optical flow technique, and tumor motion is estimated via their movement. To evaluate the performance, the proposed method has been tested on several clinical kV and MV x-ray image sequences. The experimental results showed that the average of the root mean square errors of tracking were [Formula: see text] and [Formula: see text] for kV and MV x-ray image sequences, respectively. This tracking performance was more accurate than previous tracking methods. In addition, the average processing times for each frame were [Formula: see text] and [Formula: see text] for kV and MV image sequences, respectively, and the proposed method was faster than previous methods as well as shorter than frame acquisition interval. Therefore, the proposed method has the potential for both highly accurate and fast tumor tracking in clinical applications.

Clinical results of accelerated hypofractionated radiotherapy for central-type small lung tumours.

PURPOSE: We evaluated the efficacy and toxicity of accelerated hypofractionated radiotherapy (ahypof-rt) for central-type small lung tumours. METHODS: Between November 2006 and January 2015, 40 patients with central-type small lung tumours underwent ahypof-rt delivered using 10 MV X-rays and a coplanar 3-field technique. The number of fractions ranged from 24 to 28, with a fraction size of 2.5-3 Gy. A total dose of 69-75 Gy to the isocentre of the planning target volume was administered to each patient. Cumulative survival and local control rates were calculated using the Kaplan-Meier method. RESULTS: The 27 men and 13 women enrolled in the study had a median age of 79 years (range: 60-87 years). The tumour stage was T1a in 9 patients, T1b in 17 patients, and T2a in 14 patients, with a median size of 26.5 cm (range: 11-49 cm). The median follow-up period was 23 months. A complete response was achieved in 3 patients (7.5%), and a partial response, in 17 patients (42.5%). The overall 2-year and 3-year local control rates were 87.3% and 81.8% respectively; the 2-year and 3-year overall survival rates were 78.9% and 66.7% respectively. Grade 3 pneumonitis occurred in 3 patients; no other severe adverse events (≥grade 3) were observed in any patient. CONCLUSIONS: Accelerated hypofractionated radiotherapy using a fraction size of 2.5-3 Gy was highly safe and can be a more effective treatment option than conventional radiotherapy for patients with central-type small lung tumours.

Intra-abdominal Pressure and Trunk Muscular Activities during Abdominal Bracing and Hollowing.

This study examined the difference in intra-abdominal pressure (IAP) between abdominal bracing and hollowing in relation to trunk muscular activities. IAP with a pressure transducer placed in the rectum and surface electromyograms for rectus abdominis, external oblique, internal oblique, and erector spinae during the 2 tasks were obtained in 7 young adult men. The difference between IAP at rest and its peak value (ΔIAPmax) showed high intra- and inter-day repeatability, and was significantly greater in abdominal bracing (116.4±15.0 mmHg) than in abdominal hollowing (9.9±4.5 mmHg). The trunk muscular activities at ΔIAPmax were significantly higher in abdominal bracing than in abdominal hollowing, and in the internal oblique than in the other 3 muscles. In both abdominal bracing and hollowing, the changes in IAP during the tasks were linearly correlated with those in trunk muscular activities, but the slope of the regression line for the relationship differed between the 2 tasks. The current results indicate that 1) abdominal bracing is an effective maneuver to elevate IAP compared with abdominal hollowing, and 2) in the 2 tasks, the changes in IAP are linked with those in trunk muscular activities, but the association is task-specific.

Preliminary results of proton-beam therapy for stage III non-small-cell lung cancer.

BACKGROUND: We conducted a preliminary retrospective evaluation of the efficacy and toxicity of proton-beam therapy (pbt) for stage iii non-small-cell lung cancer. METHODS: Between January 2009 and August 2013, 27 patients (26 men, 1 woman) with stage iii non-small-cell lung cancer underwent pbt. The relative biologic effectiveness value of the proton beam was defined as 1.1. The beam energy and spread-out Bragg peak were fine-tuned such that the 90% isodose volume of the prescribed dose encompassed the planning target volume. Of the 27 patients, 11 underwent neoadjuvant chemotherapy. Cumulative survival curves were calculated using the Kaplan-Meier method. Treatment toxicities were evaluated using version 4 of the Common Terminology Criteria for Adverse Events. RESULTS: Median age of the patients was 72 years (range: 57-91 years), and median follow-up was 15.4 months (range: 7.8-36.9 months). Clinical stage was iiia in 14 patients (52%) and iiib in 13 (48%). The median dose of pbt was 77 GyE (range: 66-86.4 GyE). The overall survival rate in the cohort was 92.3% at 1 year and 51.1% at 2 years. Locoregional failure occurred in 7 patients, and distant metastasis, in 10. In 2 patients, initial failure was both locoregional and distant. The 1-year and 2-year rates of local control were 68.1% and 36.4% respectively. The 1-year and 2-year rates of progression-free survival were 39.9% and 21.4% respectively. Two patients experienced grade 3 pneumonitis. CONCLUSIONS: For patients with stage iii non-small-cell lung cancer, pbt can be an effective and safe treatment option.

Cytogenetic dosimetry by micronucleus assay using peripheral blood cells is modified by thyroid hormones.

Cytokinesis-block micronucleus (CBMN) assay is a convenient and easy method of radiation biodosimetry that uses peripheral blood (PB) cells. However, for micronuclei (MN) frequency induced by ionising radiation, a dose-response relationship in abnormal condition, such as in cancer patients, has not been assessed. To clarify the difference between the dose-response curve generated by the CBMN assay in conditions when thyroid hormone levels were normal and during thyroid hormone withdrawal (THW) prior to (131)I treatment, 12 thyroid cancer patients who underwent thyroidectomy were studied. The collected PB mononuclear cells were exposed to 0.5-3.0 Gy X-ray irradiation. Under normal conditions, dose dependency and independency of MN frequency were observed in 92 % and 8 %, respectively. In contrast, during THW, the number of patients who showed dose independency significantly increased to 42 % in comparison with control. Furthermore, a higher concentration of serum thyroglobulin in dose-independent patients was observed. These results suggest that MN frequency in cytogenetic dosimetry is affected by thyroid hormones.

Applicability of ultrasound muscle thickness measurements for predicting fat-free mass in elderly population.

OBJECTIVE: This study aimed to examine the applicability of ultrasound muscle thickness (MT) measurements for predicting whole body fat-free mass (FFM) in elderly individuals. DESIGN AND SETTING: Cross-sectional study of 77 healthy elderly individuals. METHODS: MTs at nine sites of the body and FFM were determined using B-mode ultrasound and dual-energy x-ray absorptiometry (DXA), respectively, in 44 women and 33 men aged 52 to 78 yrs. Stepwise multiple regression analysis produced two equations for predicting DXA-based FFM with sex (dummy: woman = 0 and man = 1) and either MTs at the anterior and posterior of thigh and lower leg (Eq1) or the product of MT and limb length (MT×LL) at thigh anterior and posterior, lower leg posterior, and upper arm anterior (Eq2) as independent variables. RESULTS: The R2 and SEE for each of the two equations were 0.929 and 2.5 kg for Eq1 and 0.955 and 2.0 kg for Eq2. The estimated FFM from each of Eq1 (44.4 ± 8.9 kg) and Eq2 (44.4 ± 9.0 kg) did not significantly differ from that of the DXA-based FFM (44.4 ± 9.2 kg), without systematic error. However, the absolute value of the difference between the DXA-based and estimated FFM was significantly greater with Eq1 (2.0 ± 1.5 kg) than with Eq2 (1.5 ± 1.3 kg). CONCLUSION: The current results indicate that ultrasound MT measurement is useful to predict FFM in the elderly, and its accuracy is improved by using the product of MT and limb length as an independent variable.

Brainstem manifestations in neuromyelitis optica: a multicenter study of 258 patients.

BACKGROUND: Neuromyelitis optica (NMO) is a severe autoimmune disease of the central nervous system characterized by spinal cord and optic nerve involvement. Brainstem manifestations have recently been described. OBJECTIVE: To evaluate the time of occurrence, the frequency and the characteristics of brainstem symptoms in a cohort of patients with NMO according to the ethnic background and the serologic status for anti-aquaporin-4 antibodies (AQP4-abs). METHODS: We performed a multicenter study of 258 patients with NMO according to the 2006 Wingerchuk criteria and we evaluated prospectively the frequency, the date of onset and the duration of various brainstem signs in this population. RESULTS: Brainstem signs were observed in 81 patients (31.4%). The most frequently observed signs were vomiting (33.1%), hiccups (22.3%), oculomotor dysfunction (19.8%), pruritus (12.4%), followed by hearing loss (2.5%), facial palsy (2.5%), vertigo or vestibular ataxia (1.7%), trigeminal neuralgia (2.5%) and other cranial nerve signs (3.3%). They were inaugural in 44 patients (54.3%). The prevalence was higher in the non-Caucasian population (36.6%) than in the Caucasian population (26%) (p<0.05) and was higher in AQP4-ab-seropositive patients (32.7%) than in seronegative patients (26%) (not significant). CONCLUSIONS: This study confirms the high frequency of brainstem symptoms in NMO with a majority of vomiting and hiccups. The prevalence of these manifestations was higher in the non Caucasian population.

Effect of short-term maximal voluntary co-contraction training on neuromuscular function.

The present study aimed to examine the effect of short-term training utilizing voluntary co-contraction with maximal efforts. 23 healthy young men (training group: TG, n = 13; control group: CG, n = 10) participated in this study. TG conducted a 4-week training program (3 days/week), which consisted of 4 s simultaneous maximal voluntary contractions of elbow flexors and extensors at 90° of the elbow joint, followed by 4 s muscle relaxation (10 repetitions/set, 5 sets/day). Before and after the intervention, maximal voluntary isometric and isokinetic torques and the muscle thicknesses of the elbow flexors and extensors were determined. The electromyograms (EMGs) of the 2 muscle groups during isometric maximal voluntary contraction (MVC) were also recorded. After the intervention, CG did not show any significant changes in all measured variables. In TG, significant increases were found in the agonist EMG activities during MVC, and maximal isometric and isokinetic torques of the elbow flexors and extensors, without significant changes in the muscle thicknesses and involuntary coactivation levels during MVC. The current results indicate that the training mode with maximal voluntary co-contraction is effective for improving the force-generating capabilities of the exercising muscles, without any increases in the level of involuntary coactivation during MVC.

Influence of pregnancy on neuromyelitis optica spectrum disorder.

OBJECTIVE: To investigate the influence of pregnancy on patients with neuromyelitis optica spectrum disorder (NMOSD). METHODS: A total of 190 women with NMOSD were enrolled from 7 referral hospitals in 4 countries. We reviewed medical records and used a structured questionnaire to investigate gravidity, parity, and the number of relapses during the 2 years before pregnancy, during each trimester of pregnancy, during the first and second trimesters after delivery, and for 6 months thereafter. The annualized relapse rate (ARR) was calculated for each period. RESULTS: Of the 190 women with NMOSD, 40 patients experienced 54 informative pregnancies, and all of them were seropositive for aquaporin-4 antibody. Fourteen patients developed the first symptoms of NMOSD either during the pregnancy (3 patients) or within a year after delivery or abortion (8 and 3 patients, respectively). Twenty-six patients experienced 40 pregnancies after the onset of NMOSD (26 deliveries and 14 abortions [1 spontaneous and 13 elective]). There was one preterm delivery with birth defects and no stillbirths. The ARR during pregnancy did not differ from that before pregnancy, but it increased significantly during the first and second trimesters after delivery (5.3 and 3.7 times, respectively). Moreover, 77% of the deliveries were associated with postpartum relapses. CONCLUSION: The significantly increased relapse rate and numerous cases of NMOSD onset after pregnancy suggest that delivery adversely affects the course of NMOSD. Prospective studies are needed to confirm our findings.

Activation of the AKT/cyclin D1/Cdk4 survival signaling pathway in radioresistant cancer stem cells.

Radioresistance, which is a major cause of failure of radiotherapy (RT), is proposed as one of the intrinsic characteristics of cancer stem cells (CSCs) whose unique DNA damage response (DDR), efficient DNA repair and resistance to apoptosis are thought to confer the phenotype. We have isolated surviving CSCs by exposure to long-term fractionated radiation for 82 days from HepG2 and A172 cells (82FR-31NR cells). 82FR-31NR cells exhibited CSC properties, such as high expression of CSC marker CD133 and the ABC transporters (MDR1 and BCRP1), and high tumorigenic potential after transplantation into nude mice. The advantage of our isolated CSCs is that they can proliferate in as the same growth medium as that of parental cells without loss of CSC properties. Therefore, we can analyze DDR of non-stem cells and CSCs without any influences caused by different culture conditions. 82FR-31NR cells showed efficient DNA repair of radiation-induced DNA damage and radioresistance with activation of the AKT/cyclin D1 survival signaling pathway. In contrast, DNA damage persisted for a long time after irradiation in parental cells compared with isolated CSCs. Persisted DNA damage induced apoptosis in parental cells without activation of the AKT/cyclin D1 pathway. Therefore, inhibition of the AKT/cyclin D1 pathway by an AKT inhibitor, API-2, or cyclin D1 siRNA resulted in a loss of efficient DNA repair and radiosensitization of 82FR-31NR cells. Furthermore, knockdown of Cdk4 by its siRNA or a Cdk4 inhibitor was sufficient to suppress radioresistance of CSCs. In this study, we present a newly discovered DDR regarding the AKT/cyclin D1/Cdk4 pathway in response to radiation in CSCs. Combination of fractionated RT and reagents targeting the AKT/cyclin D1/Cdk4 pathway to eradicate CSCs would be effective therapeutic modality.

SU-D-BRA-02: An Extended Time-Variant Seasonal Autoregressive Model-Based Prediction for Irregular Breathing Motion Tracking.

PURPOSE: Real-time tumor position/shape measurement and dynamic beam tracking techniques allow accurate and continuous irradiation to moving tumor, but there can be a delay of several hundred milliseconds between observation and irradiation. A time-variant seasonal autoregressive (TVSAR) model has been proposed for compensating the delay by predicting respiratory tumor motion with sub-millimeter accuracy for a second latency. This is the-state-of-the-art model for almost regular breathing prediction so far. In this study, we propose an extended prediction method based on TVSAR to be usable for various breathing patterns, by predicting the residual component obtained from conventional TVSAR. METHODS: An essential core of the method is to take into account the residual component that is not predictable by only TVSAR. The residual component involves baseline shift, amplitude variation, and so on. In this study, the time series of the residual obtained for every new sample are predicted by using autoregressive (AR) model. The order and parameters of the AR model is adaptively determined for each residual component by using an information criterion. Eleven data sets of 3-D lung tumor motion, observed at Georgetown University Hospital by using Cyberknife Synchrony system, were used for evaluation of the prediction performance. RESULTS: Experimental results indicated that the proposed method is superior to those of conventional and the state-of-the-art methods for 0 to 1 s ahead prediction. The average prediction error of the proposed method was 0.920 plus/minus 0.348 mm for 0.5 s forward prediction. CONCLUSION: We have developed the new prediction method based on TVSAR model with adaptive residual prediction. The new method can predict various respiratory motions including not only regular but also a variety of irregular breathing patterns and thus can compensate the bad effect of the delay in dynamic irradiation system for moving tumor tracking. A part of this work has been financially supported by Varian Medical Systems Inc., Palo Alto, CA and Japan Society for the Promotion of Science (JSPS), Japan.

SU-E-J-135: 3-D Fourier-Based Volumetric Registration for Estimating Intra-Fractional Lung Tumor Motion.

PURPOSE: To develop a three-dimensional (3-D) volumetric registration algorithm to estimate the intra-fractional lung tumor motion between respiratory phases for improving the accuracy of radiotherapy treatment. METHODS: The 3-D thoracic CT volumes (512×512×160 voxels, with dimensions 0.97×0.97×2.5 mm3 ) in different respiratory phases were acquired on a General Electric Optima T580 scanner in cine mode. As a preprocess, a bicubic interpolation was used to interpolate the original 3-D volumes along the cephalo-caudal axis to volumes of size 512×512×400 voxels, with dimensions 0.97×0.97×1 mm3 . In each respiratory phase, a sub-volume covering the tumor was roughly specified manually. A 3-D phase correlation of two sub-volumes was computed by using the 3-D inverse Fourier transformation of the normalized cross power spectrum of two sub-volumes. The 3-D displacements along three axes were estimated by finding the location of the highest peak in the 3-D phase correlation. RESULTS: Experiments were conducted on an artificial 4-D CT data set and three clinical 4-D CT data sets. Experimental results shown that the proposed algorithm was capable of estimating the tumor motion between respiratory phases with a high-accuracy (mean square error <1 mm). CONCLUSIONS: This work extended the conventional image registration techniques from 2-D to 3-D for tumor motion estimation. This work indicates a potential for significant accuracy improvement in radiotherapy treatment planning. The high-accurate 3-D tumor motion information provides a reliable basis for expanding a clinical target volume (CTV) to a planning target volume (PTV) to incorporate the intra-fractional tumor motion.

Body mass-based exercise in middle-aged and older women.

The present study examined whether the degree to which muscle strength is improved by a body mass-based home exercise program in middle-aged and older women depends on the force-generating capabilities of the muscles prior to the intervention. 75 women (53-76 years) voluntarily participated in a circuit training program consisting of 5 exercises (16 repetitions/exercise, 2 or 3 circuits/day) using only body mass as resistance for 3 months. The subjects performed the training program 6 days a week in their own home and once a week in a local gym. Before and after intervention, isometric torques during maximal voluntary knee extension (KET) and plantar flexion (PFT) were determined and expressed relative to body mass (KET/BM and PFT/BM, respectively). KET/BM and PFT/BM increased significantly after intervention, and their relative changes were negatively correlated to the absolute values before intervention. Most of the subjects whose KET/BM and PFT/BM values before intervention were greater than 2.8 Nm/kg and 1.7 Nm/kg, respectively, did not show increases in strength after intervention. Thus, although body mass-based exercise at home is effective in improving lower limb strength in middle-aged and older women, the magnitude of the improvement is influenced by the force-generating capability before intervention.

Pain in neuromyelitis optica and its effect on quality of life: a cross-sectional study.

OBJECTIVE: To assess the features of pain and its impact on the health-related quality of life (HRQOL) in neuromyelitis optica (NMO). METHODS: We analyzed 37 patients with NMO or NMO spectrum disorders seen at the Department of Neurology, Tohoku University Hospital, Sendai, Japan, during the period from November 2008 to February 2009. A total of 35 of them were aquaporin-4 antibody-positive. We used Short Form Brief Pain Inventory (BPI) to assess pain and Short Form 36-item (SF-36) health survey to evaluate the HRQOL. Fifty-one patients with multiple sclerosis (MS) were also studied for comparison. RESULTS: Pain in NMO (83.8%) was far more common than in MS (47.1%). The Pain Severity Index score in BPI was significantly higher in NMO than in MS, and patients' daily life assessed by BPI was highly interfered by pain in NMO as compared with MS. Pain involving the trunk and both legs was much more frequent in NMO than in MS. SF-36 scores in NMO were lower than MS, especially in bodily pain. CONCLUSION: Our study showed that pain in NMO is more frequent and severe than in MS and that pain has a grave impact on NMO patients' daily life and HRQOL. Therapy to relieve pain is expected to improve their HRQOL.

Thoracic mass in a cynomolgus macaque (Macaca fascicularis).

A male cynomolgus macaque at the age of 3 years and 11 months suffered sudden cardiac arrest during a surgical operation. This animal had been clinically asymptomatic for 6 months from the acclimatization period to death. At necropsy, a white mass approximately 5 cm in diameter was found at the base of the heart. Histopathologically, the mass consisted of a granuloma with a number of multinucleated giant cells and multiple necrotic foci. Fungal hyphae characterized by parallel cell walls, distinct septa, and branching were observed in the lesion. The granuloma extended into the thoracic lymph nodes and the subepicardium of the left atrium, compressed the bronchioli, and was separated from the pulmonary parenchyma by a thick fibrous layer. The hyphal morphology and results of polymerase chain reaction assays demonstrated that the pathogen was Aspergillus sp.

Acquired radioresistance of human tumor cells by DNA-PK/AKT/GSK3beta-mediated cyclin D1 overexpression.

Recurrence is frequently associated with the acquisition of radioresistance by tumors and resulting failures in radiotherapy. We report, in this study, that long-term fractionated radiation (FR) exposures conferred radioresistance to the human tumor cells, HepG2 and HeLa with cyclin D1 overexpression. A positive feedback loop was responsible for the cyclin D1 overexpression in which constitutively active AKT was involved. AKT is known to inactivate glycogen synthase kinase-3beta (GSK3beta), which is essential for the proteasomal degradation of cyclin D1. The resulting cyclin D1 overexpression led to the forced progression of S-phase with the induction of DNA double strand breaks. Cyclin D1-dependent DNA damage activated DNA-dependent protein kinase (DNA-PK), which in turn activated AKT and inactivated GSK3beta, thus completing a positive feedback loop of cyclin D1 overproduction. Cyclin D1 overexpression led to the activation of DNA damage response (DDR) consisted of ataxia telangiectasia mutated (ATM)- and Chk1-dependent DNA damage checkpoint and homologous recombination repair (HRR). Long-term FR cells repaired radiation-induced DNA damage faster than non-FR cells. Thus, acquired radioresistance of long-term FR cells was the result of alterations in DDR mediated by cyclin D1 overexpression. Inhibition of the AKT/GSK3beta/cyclin D1/Cdk4 pathway by the AKT inhibitor, Cdk4 inhibitor or cyclin D1 targeting small interfering RNA (siRNA) suppressed the radioresistance. Present observations give a mechanistic insight for acquired radioresistance of tumor cells by cyclin D1 overexpression, and provide novel therapeutic targets for recurrent radioresistant tumors.

A pathological study of sepsis associated with sarcoptic mange in raccoon dogs (Nyctereutes procyonoides) in Japan.

The pathological findings in Japanese raccoon dogs with sarcoptic mange infection associated with death from sepsis are described. Microscopical lesions of the skin were consistent with those described previously in wildlife populations with Sarcoptes infection, but secondary lesions were also present in the lungs, heart, kidneys, liver, spleen and brain of these animals. This infection was therefore very similar to "crusted scabies" or "Norwegian scabies" in man and was characterized by severe pathology and high mortality, with deaths frequently occurring due to sepsis.