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Radiation-induced enteritis is frequently observed following radiotherapy for cancer or occurs due to radiation exposure in a nuclear accident. The loss of the epithelial integrity leads to ‘leaky gut’, so recovery of damaged epithelium is an important strategy in therapeutic trials. Centella asiatica (CA), a traditional herbal medicine, is widely used for wound healing by protecting against endothelial damage. In this study, we investigated the radio-mitigating effect of CA, focusing on the crosstalk between endothelial and epithelial cells. CA treatment relieved radiation-induced endothelial dysfunction and mitigated radiation-induced enteritis. In particular, treatment of the conditioned media from CA-treated irradiated endothelial cells recovered radiation-induced epithelial barrier damage. We also determined that epidermal growth factor (EGF) is a critical factor secreted by CA-treated irradiated endothelial cells. Treatment with EGF effectively improved the radiation-induced epithelial barrier dysfunction. We also identified the therapeutic effects of CA-induced endothelial paracrine in a radiation-induced enteritis mouse model with epithelial barrier restoration. Otherwise, CA treatment did not show radioprotective effects on colorectal tumors in vivo. We showed therapeutic effects of CA on radiation-induced enteritis, with the recovery of endothelial and epithelial dysfunction. Thus, our findings suggest that CA is an effective radio-mitigator against radiation-induced enteritis.

Radiation-induced cutaneous ulcers are a challenging medical problem for patients receiving radiation therapy. The inhibition of cell senescence has been suggested as a prospective strategy to prevent radiation ulcers. However, there is no effective treatment for senescent cells in radiation ulcers. In this study, we investigated whether zileuton alleviated radiation-induced cutaneous ulcer by focusing on cell senescence. We demonstrate increased cell senescence and senescence-associated secretory phenotype (SASP) in irradiated dermal fibroblasts and skin tissue. The SASP secreted from senescent cells induces senescence in adjacent cells. In addition, 5-lipoxygenase (5-LO) expression increased in irradiated dermal fibroblasts and skin tissue, and SASP and cell senescence were regulated by 5-LO through p38 phosphorylation. Finally, the inhibition of 5-LO following treatment with zileuton inhibited SASP and mitigated radiation ulcers in animal models. Our results demonstrate that inhibition of SASP from senescent cells by zileuton can effectively mitigate radiation-induced cutaneous ulcers, indicating that inhibition of 5-LO might be a viable strategy for patients with this condition.

Radiotherapy or accidental exposure to high-dose radiation can cause severe damage to healthy organs. The gastrointestinal (GI) tract is a radiation-sensitive organ of the body. The intestinal barrier is the first line of defense in the GI tract, and consists of mucus secreted by goblet cells and a monolayer of epithelium. Intestinal stem cells (ISCs) help in barrier maintenance and intestinal function after injury by regulating efficient regeneration of the epithelium. The Wnt/β-catenin pathway plays a critical role in maintaining the intestinal epithelium and regulates ISC self-renewal. Metformin is the most widely used antidiabetic drug in clinical practice, and its anti-inflammatory, antioxidative, and antiapoptotic effects have also been widely studied. In this study, we investigated whether metformin alleviated radiation-induced enteropathy by focusing on its role in protecting the epithelial barrier. We found that metformin alleviated radiation-induced enteropathy, with increased villi length and crypt numbers, and restored the intestinal barrier function in the irradiated intestine. In a radiation-induced enteropathy mouse model, metformin treatment increased tight-junction expression in the epithelium and inhibited bacterial translocation to mesenteric lymph nodes. Metformin increased the number of ISCs from radiation toxicity and enhanced epithelial repair by activating Wnt/β-catenin signaling. These data suggested that metformin may be a potential therapeutic agent for radiation-induced enteropathy.

Radiation-induced gastrointestinal (GI) damage is one of the critical factors that serve as basis for the lethality of nuclear accidents or terrorism. Further, there are no Food and Drug Administration-approved agents available to mitigate radiation-induced intestinal injury. Although pravastatin (PS) has been shown to exhibit anti-inflammatory and epithelial reconstructive effects following radiation exposure using mouse and minipig models, the treatment failed to improve the survival rate of high-dose irradiated intestinal injury. Moreover, we previously found that metformin (MF), a common drug used for treating type 2 diabetes mellitus, has a mitigating effect on radiation-induced enteropathy by promoting stem cell properties. In this study, we investigated whether the combined administration of PS and MF could achieve therapeutic effects on acute radiation-induced intestinal injury in mouse and minipig models. We found that the combined treatment markedly increased the survival rate and attenuated histological damage in a radiation-induced intestinal injury mouse model, in addition to epithelial barrier recovery, anti-inflammatory effects, and improved epithelial proliferation with stem cell properties. Furthermore, in minipig models, combined treatment with PS and MF ameliorates gross pathological damage in abdominal organs and attenuated radiation-induced intestinal histological damage. Therefore, the combination of PS and MF effectively alleviated radiation-induced intestinal injury in the mouse and minipig models. We believe that the combined use of PS and MF is a promising therapeutic approach for treating radiation-induced intestinal injury.

Background Radiotherapy or accidental exposure to ionizing radiation causes severe damage of healthy intestinal tissues. Intestinal barrier function is highly sensitive to ionizing radiation, and loss of epithelial integrity results in mucosal inflammation, bacterial translocation, and endotoxemia. Few studies have of epithelial integrity as a therapeutic target to treat radiation toxicity. Here, we examined the effects of pravastatin (PS) and the molecular mechanisms underlying epithelial integrity on radiation-induced enteropathy. Methods The radio-mitigative effects of PS were evaluated in a minipig model by quantifying clinical symptoms, and performing histological and serological analyses and mRNA sequencing in intestinal tissues. To evaluate the role of intercellular junctions on radiation damage, we used tight junction regulator and metallothionein 2 (MT2) as treatments in a mouse model of radiation-induced enteropathy. Caco-2 monolayers were used to examine functional epithelial integrityand intercellular junction expression. Finding Using a minipig model of pharmaceutical oral bioavailability, we found that PS mitigated acute radiation-induced enteropathy. PS-treated irradiated minipigs had mild clinical symptoms, lower intestinal inflammation and endotoxin levels, and improved gastrointestinal integrity, compared with control group animals. The results of mRNA sequencing analysis indicated that PS treatment markedly influenced intercellular junctions by inhibiting p38 MAPK signaling in the irradiated intestinal epithelium. The PS-regulated gene MT2 improved the epithelial barrier via enhancement of intercellular junctions in radiation-induced enteropathy. Interpretation PS regulated epithelial integrity by modulating MT2 in radiation-damaged epithelial cells. These findings suggested that maintenance of epithelial integrity is a novel therapeutic target for treatment of radiation-induced gastrointestinal damage. Funding As stated in the Acknowledgments

Accurate dosimetry plays a key role in evaluating the radiation-induced health risks of radiation workers. The National Dose Registry in Korea contains the dose records of radiation workers in nuclear-related occupations since 1984. Thus, radiation doses for workers before 1984 are often sparse or missing. This study aimed to estimate the historical radiation dose before 1984 for radiation workers in Korea based on dose reconstruction models. The dose reconstruction models were derived from the nationwide self-administered questionnaire survey and the personal badge doses for workers in the cohort of the Korean Radiation Worker Study. The mean estimated annual doses between 1984 and 2016 from the dose reconstruction model were 4.67–0.6 mSv, which closely matched the reported doses of 4.51–0.43 mSv. The mean estimated annual doses between 1961 and 1983 based on the exposure scenarios developed by factors associated with radiation doses ranged from 11.08 to 4.82 mSv. The mean estimated annual doses of individuals in the cohort from 1961 to 1983 ranged from 11.15 to 4.88 mSv. Although caution needs to be exercised in the interpretation of these estimations due to uncertainty owed to the nature of extrapolation beyond the range of observed data, this study offers a sense of the radiation doses for workers during Korea’s early period of radiation-related activities, which can be a useful piece of information for radiation-induced health risk assessments.

Colorectal cancer (CRC) is a recurring cancer that is often resistant to conventional therapies and therefore requires the development of molecular‐based therapeutic approaches. Dopamine receptor D2 (DRD2) is associated with the growth of many types of tumors, but its oncogenic role in CRC is unclear. Here, we observed that elevated DRD2 expression was associated with a poor survival rate among patients with CRC. Depletion of DRD2 suppressed CRC cell growth and motility by downregulating β‐catenin/ZEB signaling in vitro and in vivo, whereas overexpression of DRD2 promoted CRC cell progression. Inhibition of DRD2 by the antagonist pimozide inhibited tumor growth and lymph node metastasis in vivo and enhanced the cytotoxic effects of conventional agents in vitro. Taken together, our findings indicate that targeting the DRD2/β‐catenin/ZEB1 signaling axis is a potentially promising therapeutic strategy for patients with CRC., We provided targeting the DRD2/β‐catenin/ZEB1 signaling axis as a potentially promising therapeutic strategy for patients with CRC.

The current treatment strategy for patients with aggressive colorectal cancer has been hampered by resistance to radiotherapy and chemotherapy due to the existence of cancer stem-like cells (CSCs). Recent studies have shown that SOX2 expression plays an important role in the maintenance of CSC properties in colorectal cancer. In this study, we investigated the induction and regulatory role of SOX2 following the irradiation of radioresistant and radiosensitive colorectal cancer cells. We used FACS and western blotting to analyze SOX2 expression in cells. Among the markers of colorectal CSCs, the expression of CD44 increased upon irradiation in radioresistant cells. Further analysis revealed the retention of CSC properties with an upregulation of SOX2 as shown by enhanced resistance to radiation and metastatic potential in vitro. Interestingly, both the knockdown and overexpression of SOX2 led to increase in CD44+ population and induction of CSC properties in colorectal cancer following irradiation. Furthermore, selective genetic and pharmacological inhibition of the PI3K/AKT pathway, but not the MAPK pathway, attenuated SOX2-dependent CD44 expression and metastatic potential upon irradiation in vitro. Our findings suggested that SOX2 regulated by radiation-induced activation of PI3K/AKT pathway contributes to the induction of colorectal CSCs, thereby highlighting its potential as a therapeutic target.

Radiation-induced multiorgan dysfunction is thought to result primarily from damage to the endothelial system, leading to a systemic inflammatory response that is mediated by the recruitment of leukocytes. The Eph&ndash, ephrin signaling pathway in the vascular system participates in various disease developmental processes, including cancer and inflammation. In this study, we demonstrate that radiation exposure increased intestinal inflammation via endothelial dysfunction, caused by the radiation-induced activation of EphA2, an Eph receptor tyrosine kinase, and its ligand ephrinA1. Barrier dysfunction in endothelial and epithelial cells was aggravated by vascular endothelial&ndash, cadherin disruption and leukocyte adhesion in radiation-induced inflammation both in vitro and in vivo. Among all Eph receptors and their ligands, EphA2 and ephrinA1 were required for barrier destabilization and leukocyte adhesion. Knockdown of EphA2 in endothelial cells reduced radiation-induced endothelial dysfunction. Furthermore, pharmacological inhibition of EphA2&ndash, ephrinA1 by the tyrosine kinase inhibitor dasatinib attenuated the loss of vascular integrity and leukocyte adhesion in vitro. Mice administered dasatinib exhibited resistance to radiation injury characterized by reduced barrier leakage and decreased leukocyte infiltration into the intestine. Taken together, these data suggest that dasatinib therapy represents a potential approach for the protection of radiation-mediated intestinal damage by targeting the EphA2&ndash, ephrinA1 complex.

Background: It is difficult to distinguish parathyroid lesions (PLs) from thyroid lesions using fine needle aspiration cytology (FNAC) because of their proximity and their similar cytomorphological features. Methods: FNAC smears of 46 patients with pathologically proven PLs that were histologically diagnosed as parathyroid adenoma (PA, n = 35), parathyroid hyperplasia (PH, n = 3), atypical parathyroid adenoma (APA, n = 1), and parathyroid carcinoma (PC, n = 7) were retrospectively reviewed and analyzed. Results: Our initial cytological diagnoses indicated correct diagnoses in 31 of 46 PL patients (67%). The 15 erroneous diagnoses were 5 patients with non-specific benign disease (11%), 4 with nodular hyperplasia of the thyroid (9%), 5 with atypical cells (11%), and 1 with a metastatic papillary thyroid carcinoma (2%). Follicular pattern, papillary structures, colloid-like material, and macrophages, which often suggest thyroid lesions, were also present in some PLs. We found that branching capillaries along the papillary structures, stippled nuclear chromatin, and frequent occurrence of naked nuclei were useful for determining a parathyroid origin. Conclusions: It is important to be aware that PLs are frequently mistaken for thyroid lesions based on FNAC. The specific and unique characteristics of PLs identified here may be helpful in diagnosis.

Risk projection models estimating the lifetime cancer risk from radiation exposure are generally based on exposure dose, age at exposure, attained age, gender and study-population-specific factors such as baseline cancer risks and survival rates. Because such models have mostly been based on the Life Span Study cohort of Japanese atomic bomb survivors, the baseline risks and survival rates in the target population should be considered when applying the cancer risk. The survival function used in the risk projection models that are commonly used in the radiological protection field to estimate the cancer risk from medical or occupational exposure is based on all-cause mortality. Thus, it may not be accurate for estimating the lifetime risk of high-incidence but not life-threatening cancer with a long-term survival rate. Herein, we present the lifetime attributable risk (LAR) estimates of all solid cancers except thyroid cancer, thyroid cancer, and leukemia except chronic lymphocytic leukemia in South Korea for lifetime exposure to 1 mGy per year using the cancer-free survival function, as recently applied in the Fukushima health risk assessment by the World Health Organization. Compared with the estimates of LARs using an overall survival function solely based on all-cause mortality, the LARs of all solid cancers except thyroid cancer, and thyroid cancer evaluated using the cancer-free survival function, decreased by approximately 13% and 1% for men and 9% and 5% for women, respectively. The LAR of leukemia except chronic lymphocytic leukemia barely changed for either gender owing to the small absolute difference between its incidence and mortality. Given that many cancers have a high curative rate and low mortality rate, using a survival function solely based on all-cause mortality may cause an overestimation of the lifetime risk of cancer incidence. The lifetime fractional risk was robust against the choice of survival function.

This study identified occupational factors associated with radiation exposure in Korea. Survey data of 16 037 workers from 2016 to 2017, including lifestyle factors and occupational characteristics, were combined with the National Dose Registry. Higher average annual doses were observed in groups exhibiting health risk factors such as body mass index (BMI) and smoking. Average annual doses also differed according to occupational characteristics, including average daily working hours, use of radiation protection gear, calendar year of hiring and employment status. Moreover, the influence of different factors on radiation dose differed with occupations. In industrial radiography and nuclear power plants, average daily working hours were the most important factor determining worker radiation doses. In other occupations, such as education, industry and research, calendar year of hiring and duration of employment were the most important factors. This research indicates the need to consider the specific work procedures of occupations to determine exposure variations between or within facilities.

Background The skin is impacted by every form of external radiation therapy. However, effective therapeutic options for severe, acute radiation-induced skin reactions are limited. Although platelet-rich plasma (PRP) is known to improve cutaneous wound healing, its effects in the context of high-dose irradiation are still poorly understood. Methods We investigated the regenerative functions of PRP by subjecting the dorsal skin of mice to local irradiation (40 Gy) and exposing HaCaT cells to gamma rays (5 Gy). The cutaneous benefits of PRP were gauged by wound size, histologic features, immunostains, western blot, and transepithelial water loss (TEWL). To assess the molecular effects of PRP on keratinocytes of healing radiation-induced wounds, we evaluated AKT signaling. Results Heightened expression of keratin 14 (K14) was documented in irradiated HaCaT cells and skin tissue, although the healing capacity of injured HaCaT cells declined. By applying PRP, this capacity was restored via augmented AKT signaling. In our mouse model, PRP use achieved the following: (1) healing of desquamated skin, acutely injured by radiation; (2) activated AKT signaling, improving migration and proliferation of K14 cells; (3) greater expression of involucrin in keratin 10 cells and sebaceous glands; and (4) reduced TEWL, strengthening the cutaneous barrier function. Conclusions Our findings indicate that PRP enhances the functions of K14 cells via AKT signaling, accelerating the regeneration of irradiated skin. These wound-healing benefits may have merit in a clinical setting.

Aims The Notch signaling pathway is involved in normal development as well as tumorigenesis. However, it is unclear whether Notch activation is related to diverse clinicopathological factors in papillary thyroid carcinoma (PTC). Methods and Results We examined the relationship between clinicopathological factors and the expression of activated Notch1 and Hey1, which are indicators of Notch signaling pathway activation, in 109 PTC cases. Activated Notch1 showed strong, moderate, and weak expression in 23, 48, and 36 cases, respectively. Its expression was significantly related to histopathological variants (p=0.007), lymph node metastasis (p = 0.016), BRAF mutation (p = 0.036) and extent of surgery (p=0.014). Hey1 immunostaining could be divided into two groups: positive and negative, with 26 and 83 cases, respectively. Its expression was significantly related to histopathological variants (p=0.026), extrathyroidal extension (p = .005), BRAF mutation (p = .048), and recurrence or soft tissue metastasis (p = .000). Multivariate analysis revealed that tumor size (greater than 1 cm), Hey1 immunoreactivity, and the presence of lymph node metastasis were significantly associated with recurrence or soft tissue metastasis (OR = 7.38, 4.28, and 12.00, respectively). Conclusions Thus, we found that activation of Notch signaling was significantly correlated with clinicopathological parameters. Therefore, Notch signaling could be a useful prognostic marker in patients with PTC. This article is protected by copyright. All rights reserved.

Skin dermis includes various types of multipotent stromal cells (MSCs) and a subpopulation of dermal fibroblasts that exhibit the ability to differentiate. However, characterization of this dermal fibroblast subtype remains less understood. In this study, we isolated dermal cells from the skin of newborn C57/B6 mice and investigated their characteristics. Isolated murine dermal cells exhibited a fibroblast phenotype as judged by accepted criteria including a lack of MSC-related antigens and the differentiation potential of MSCs, and the positive expression of fibroblast markers. A comparative analysis demonstrated that CD73(-) CD105(+) but not CD73(-) CD105(-) dermal fibroblasts exhibited some of the functional properties of MSCs. Furthermore, the multipotent phenotype of CD73(-) CD105(+) cells was diminished by treatment of CD105 siRNA and shRNA, indicating that CD105 expression was critical for the retention of differentiation potential of those cells. Overall, these results suggest that CD73(-) CD105(+) cells are a distinct subset of dermal fibroblasts with multipotency and that their surface antigens could help to classify this subpopulation. These cells may contribute to the regeneration of damaged tissue.

Recurrence and chemoresistance in colorectal cancer remain important issues for patients treated with conventional therapeutics. Metformin and phenformin, previously used in the treatment of diabetes, have been shown to have anticancer effects in various cancers, including breast, lung and prostate cancers. However, their molecular mechanisms are still unclear. In this study, we examined the effects of these drugs in chemoresistant rectal cancer cell lines. We found that SW837 and SW1463 rectal cancer cells were more resistant to ionizing radiation and 5‐fluorouracil than HCT116 and LS513 colon cancer cells. In addition, metformin and phenformin increased the sensitivity of these cell lines by inhibiting cell proliferation, suppressing clonogenic ability and increasing apoptotic cell death in rectal cancer cells. Signal transducer and activator of transcription 3 and transforming growth factor‐β/Smad signaling pathways were more activated in rectal cancer cells, and inhibition of signal transducer and activator of transcription 3 expression using an inhibitor or siRNA sensitized rectal cancer cells to chemoresistant by inhibition of the expression of antiapoptotic proteins, such as X‐linked inhibitor of apoptosis, survivin and cellular inhibitor of apoptosis protein 1. Moreover, metformin and phenformin inhibited cell migration and invasion by suppression of transforming growth factor β receptor 2‐mediated Snail and Twist expression in rectal cancer cells. Therefore, metformin and phenformin may represent a novel strategy for the treatment of chemoresistant rectal cancer by targeting signal transducer and activator of transcription 3 and transforming growth factor‐β/Smad signaling.

Background The association between atopic diseases and inflammatory bowel diseases (IBD) still remains unclear. We conducted a nationwide population-based study to investigate the effect of atopic diseases on the development of IBD. Methods A total of 9,950,548 subjects who received medical check-up between 2009 and 2012 were included and followed up until 2017. The presence of any atopic disease including atopic dermatitis (AD), allergic rhinitis (AR), and asthma were evaluated. Patients who developed IBD including Crohn’s disease (CD) and ulcerative colitis (UC) were identified using the claims data from National Health Insurance. Results During a mean follow up of 7.3 years, 1,426 (0.014%) subjects developed CD and 5,916 (0.059%) subjects developed UC. The incidences of CD (per 100,000 person-years) were 4.088, 2.255, and 2.344 in patients with AD, AR, and asthma,, respectively. The incidences of UC were 11.926, 9.857, and 9.377 in patients with AD, AR, and asthma, respectively. Multivariable analysis revealed that the adjusted hazard ratios (aHR) for incident CD in patients with AD, AR, and asthma were 2.21, 1.33, and 1.59 (95% confidence interval (CI) 1.251–3.896, 1.152–1.532, and 1.186–2.123, respectively) compared with controls. The risk for incident UC in patients in AD, AR, and asthma were 1.51, 1.32, and 1.28 (95% CI 1.081–2.101, 1.235–1.416, and 1.110–1.484, respectively) compared with controls. Moreover, increase in the number of atopic diseases gradually increased the risk for CD and UC; CD showed aHR of 1.36 and 1.65 (95% CI 1.180–1.571 and 1.143–2.370), and UC showed aHR of 1.30 and 1.49 (95% CI 1.216–1.398 and 1.247-1.170) in one, and two or more atopic diseases, respectively. Conclusion Patients with any atopic diseases showed an increased risk for IBD, while an increase in the number of atopic diseases gradually increased the risk for IBD.

Background The incidence of inflammatory bowel disease (IBD) is increasing in Asia. Numerous risk factors associated with IBD development have been investigated. This study aimed to demonstrate the risk factors of Crohn’s disease (CD) diagnosed in persons aged >40 years in South Korea and to specify any differences between age groups by using the National Health Insurance Service (NHIS) database. Methods Using the National Health Insurance Service (NHIS) database, a total of 14,060,821 persons aged >40 years who underwent national health screening in 2009 were followed up until December 2017. Patients with newly diagnosed CD were enrolled and compared with non-CD cohort. CD was identified according to the International Classification of Diseases 10th revision and the rare/intractable disease registration programme codes from the NHIS database. The mean follow-up periods were 7.39 years. Age and sex were adjusted for in the multivariate analysis model. Results During the follow-up, 1337 (1.33/100,000) patients developed CD. Men in the middle-aged group (40–64 years) had a higher risk than women (adjusted HR [aHR] 1.46, 95% CI 1.29–1.66); however, this difference tended to disappear as the age of onset increases. In the middle-aged group, patients with a history of smoking (adjusted hazard ratio [aHR] 1.29, 95% confidence interval [CI] 1.06–1.58) and anemia (aHR 1.99, 95% CI 1.67–2.36) had a significantly higher CD risk. In the elderly group (age, ³65 years), ex-smoking and anemia also increased the CD risk (aHR 1.58 [95% CI 1.16–2.18] and 1.91 [95% CI 1.53–2.38], respectively). Especially in the middle-aged group, those with chronic kidney disease (CKD) had a statistically elevated CD risk (aHR 1.38, 95% CI 1.06–1.79). Alcohol consumption and higher body mass index showed negative association trend with CD incidence in both of the age groups. (Middle-aged: aHR 0.76 [95%CI 0.65–0.87] and aHR 0.38 [95%CI 0.27–0.53], respectively) (elderly-group: aHR 0.57 [95%CI 0.42–0.77] and aHR 0.52 [95%CI 0.32-.83], respectively) For regular physical activity and dyslipidemia, negative correlation between CD incidences was proved only in the middle-aged group (aHR 0.85 [95%CI 0.74–0.96] and aHR 0. [95%CI 0.75 [95% CI 0.63–0.89], respectively). Conclusion This study demonstrated four risk factors (ex-smoking, anemia, CKD, and lower BMI) and three possible protective factors (alcohol consumption, physical activity, and dyslipidemia) for CD in Asians age >40 years. Individuals with potential risk factors need more cautious monitoring for CD.

Hyaluronic acid synthase 2 (HAS2) is suggested to play a critical role in malignancy and is abnormally expressed in many carcinomas. However, its role in colorectal cancer (CRC) malignancy and specific signaling mechanisms remain obscure. Here, we report that HAS2 was markedly increased in both CRC tissue and malignant CRC cell lines. Depletion of HAS2 in HCT116 and DLD1 cells, which express high levels of HAS2, critically increased sensitivity of radiation/oxaliplatin‐mediated apoptotic cell death. Moreover, downregulation of HAS2 suppressed migration, invasion and metastasis in nude mice. Conversely, ectopic overexpression of HAS2 in SW480 cells, which express low levels of HAS2, showed the opposite effect. Notably, HAS2 loss‐ and gain‐of‐function experiments revealed that it regulates CRC malignancy through TGF‐β expression and SMAD2/Snail downstream components. Collectively, our findings suggest that HAS2 contributes to malignant phenotypes of CRC, at least partly, through activation of the TGF‐β signaling pathway, and shed light on the novel mechanisms behind the constitutive activation of HAS2 signaling in CRC, thereby highlighting its potential as a therapeutic target.

Radiation-induced skin injury can be a serious cutaneous damage and have specific characteristics. Asymptomatic periods are classified as the latent stage. The skin barrier plays a critical role in the modulation of skin permeability and hydration and protects the body against a harsh external environment. However, an analysis on the skin barrier dysfunction against radiation exposure in the latent stage has not been conducted. Thus, we investigated whether skin barrier is impaired by irradiation in the latent stage and aimed to identify the molecules involved in skin barrier dysfunction. We analyzed skin barrier function and its components in SKH-1 mice that received 20 and 40 Gy local irradiation. Increased transepidermal water loss and skin pH were observed in the latent stage of the irradiated skin. Skin barrier components, such as structural proteins and lipid synthesis enzymes in keratinocyte, increased in the irradiated group. Interestingly, we noted sebaceous gland atrophy and increased serine protease and inflammatory cytokines in the irradiated skin during the latent period. This finding indicates that the main factor of skin barrier dysfunction in the latent stage of radiation-induced skin injury is sebaceous gland deficiency, which could be an intervention target for skin barrier impairment.

Although radiotherapy plays a crucial in the management of pelvic tumors, its toxicity on surrounding healthy tissues such as the small intestine, colon, and rectum is one of the major limitations associated with its use. In particular, proctitis is a major clinical complication of pelvic radiotherapy. Recent evidence suggests that endothelial injury significantly affects the initiation of radiation-induced inflammation. The damaged endothelial cells accelerate immune cell recruitment by activating the expression of endothelial adhesive molecules, which participate in the development of tissue damage. Pravastatin, a cholesterol lowering drug, exerts persistent anti-inflammatory and anti-thrombotic effects on irradiated endothelial cells and inhibits the interaction of leukocytes and damaged endothelial cells. Here, we aimed to investigate the effects of pravastatin on radiation-induced endothelial damage in human umbilical vein endothelial cell and a murine proctitis model. Pravastatin attenuated epithelial damage and inflammatory response in irradiated colorectal lesions. In particular, pravastatin improved radiation-induced endothelial damage by regulating thrombomodulin (TM) expression. In addition, exogenous TM inhibited leukocyte adhesion to the irradiated endothelial cells. Thus, pravastatin can inhibit endothelial damage by inducing TM, thereby alleviating radiation proctitis. Therefore, we suggest that pharmacological modulation of endothelial TM may limit intestinal inflammation after irradiation.

Background Proteinuria has been identified as a sign of systemic endothelial dysfunction and chronic inflammation, and associated with the development of several systemic inflammatory diseases. However, the impact of proteinuria and its severity on the incidence of inflammatory bowel disease (IBD) has not been studied yet. The aim of this study was to determine the association between proteinuria measured by urine dipstick test and the development of IBD. Methods We conducted a nationwide population-based cohort study using claims data from the National Health Insurance (NHI) database, a mandatory health insurance programme covering about 97% of the Korean population. A total of 9,917,400 people aged 20 years or older who had undergone a national health examination conducted by NHI in 2009 were followed until 2017. The study population was classified into four groups, negative, trace, 1+, and ≥2+, depending on the degree of proteinuria measured by urine dipstick test. The primary endpoint was the newly diagnosed IBD, Crohn’s disease (CD) or ulcerative colitis (UC) during the follow-up period, which was detected by both ICD-10 (K50 and K51) and the rare intractable disease registration programme codes which provide co-payment reduction of up to 90% in South Korea. Results The incidence of CD significantly increased according to the degree of proteinuria (adjusted hazard ratio [aHR] with 95% confidence interval [CI], 1.01(0.703–1.451), 1.515(1.058–2.162), and 2.053(1.301–3.24) in trace, 1+, and ≥2+ dipstick groups, respectively) as compared with the dipstick-negative group. However, there was no significant difference in the incidence of UC among the degrees of proteinuria (aHR with 95% CI, 1.12(0.949–1.323), 0.947(0.764–1.174), 1.009(0.741–1.373 in trace, 1+, and ≥2+ dipstick groups, respectively). In subgroup analysis, dipstick-positive proteinuria independently increased the incidence of CD regardless of subgroups. However, in the development of UC, dipstick-positive proteinuria increased the risk of UC in those with diabetes mellitus (DM), but not in those without DM (aHR, 1.527 vs. 0.846; interaction p-value 0.004). Conclusion Proteinuria, measured by dipstick test, may be associated with the development of CD.

In order to conduct dose assessment of victims in criticality accidents, a method of fast neutron capture-activated (32)P measurement of hair in which samples are treated by a chemical and analytical procedure that takes 9 h and measurement is conducted by liquid scintillation counting is presented. To validate this measurement method, hair samples spiked with a (32)P reference source were measured and the results analysed and the optimal sample mass and detection efficiency were determined. To verify the correlation between (32)P-specific activity and absorbed dose for spectra with two neutron mean energies, samples collected from three normal individuals were irradiated at various neutron energies and irradiation times using the MC50 Cyclotron of the Korea Institute of Radiological and Medical Sciences. The (32)P-specific activity trend of the irradiated hair agreed well with the absorbed doses. Based on the results, dose conversion factors, which were 0.67 ± 0.15 and 0.59 ± 0.06 Gy (Bq g(-1))(-1) at neutron mean energies of 2.33 and 5.36 MeV, respectively, were calculated as a guide for medical treatment of criticality accident victims.

Purpose. Radiation-induced lung fibrosis (RILF) is a serious late complication of radiotherapy. In vitro studies have demonstrated that pentoxifylline (PTX) has suppressing effects in extracellular matrix production in fibroblasts, while the antifibrotic action of PTX alone using clinical dose is yet unexplored.Materials and Methods. We used micro-computed tomography (micro-CT) and histopathological analysis to evaluate the antifibrotic effects of PTX in a rat model of RILF.Results. Micro-CT findings showed that lung density, volume loss, and mediastinal shift are significantly increased at 16 weeks after irradiation. Simultaneously, histological analysis demonstrated thickening of alveolar walls, destruction of alveolar structures, and excessive collagen deposition in the irradiated lung. PTX treatment effectively attenuated the fibrotic changes based on both micro-CT and histopathological analyses. Western analysis also revealed increased levels of plasminogen activator inhibitor- (PAI-) 1 and fibronectin (FN) and PTX treatment reduced expression of PAI-1 and FN by restoring protein kinase A (PKA) phosphorylation but not TGF-β/Smad in both irradiated lung tissues and epithelial cells.Conclusions. Our results demonstrate the antifibrotic effect of PTX on radiation-induced lung fibrosis and its effect on modulation of PKA and PAI-1 expression as possible antifibrotic mechanisms.

Objective: To evaluate the cytological characteristics of each type of thymoma and introduce an algorithm to classify thymoma using fine needle aspiration biopsy (FNAB). Study Design: We retrospectively reviewed the cytological characteristics of 15 cases of thymoma with three thymic carcinoma (1 type A thymoma, 6 type AB thymomas and 8 type B thymomas), which were confirmed by histology. Three major and one minor cytomorphologic parameter were adopted for classification: (1) number of lymphocytes in the smear background; (2) nuclear characteristics of thymic cells; (3) lymphocytes and crush artifacts in thymic cell clusters, and (4) nuclear arrangement of thymic cells. Results: An abundant lymphocytic smear background indicated type B thymomas in 87.5% of cases, contrary to the few lymphocytes in the remaining thymic tumors excluding type B thymomas (90%). Thymic cells contained no vesicular nuclei and inconspicuous nucleoli in 85.7% of type A thymoma and type AB thymoma cases. Type AB thymomas and type B thymomas showed more prominent crush artifacts in cell clusters than type A thymoma and thymic carcinoma. Thymic cells of type B thymomas and thymic carcinoma were arranged without whirling architecture in clusters. The proposed algorithm demonstrated a predictive rate of 88.8% for thymoma classification. Conclusions: The stepwise classification of thymoma with FNAB may be useful in patients for whom an invasive diagnosis approach is not feasible.

Radiation-induced enteropathy remains a major complication after accidental or therapeutic exposure to ionizing radiation. Recent evidence suggests that intestinal microvascular damage significantly affects the development of radiation enteropathy. Mesenchymal stem cell (MSC) therapy is a promising tool to regenerate various tissues, including skin and intestine. Further, photobiomodulation (PBM), or low-level light therapy, can accelerate wound healing, especially by stimulating angiogenesis, and stem cells are particularly susceptible to PBM. Here, we explored the effect of PBM on the therapeutic potential of MSCs for the management of radiation enteropathy. In vitro, using human umbilical cord blood-derived MSCs, PBM increased proliferation and self-renewal. Intriguingly, the conditioned medium from MSCs treated with PBM attenuated irradiation-induced apoptosis and impaired tube formation in vascular endothelial cells, and these protective effects were associated with the upregulation of several angiogenic factors. In a mouse model of radiation-induced enteropathy, treatment with PBM-preconditioned MSCs alleviated mucosal destruction, improved crypt cell proliferation and epithelial barrier functions, and significantly attenuated the loss of microvascular endothelial cells in the irradiated intestinal mucosa. This treatment also significantly increased angiogenesis in the lamina propria. Together, we suggest that PBM enhances the angiogenic potential of MSCs, leading to improved therapeutic efficacy for the treatment of radiation-induced enteropathy.

The potential role of visceral adipose tissue (VAT) as a prognostic factor in patients with diffuse large B cell lymphoma (DLBCL) treated with frontline rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) immunochemotherapy was explored. Total adipose tissue and VAT were measured by analyzing positron emission tomography (PET)/computed tomography (CT) images obtained during the initial staging of patients with DLBCL. The VAT ratio was calculated as follows: VAT ratio = VAT area/total adipose tissue area. Body mass index (BMI), sex, and International Prognostic Index (IPI) were also incorporated as co-variates in the final model of multivariate Cox regression analysis for survival. A total of 156 patients with DLBCL, who were treated with frontline R-CHOP, were enrolled in our study. The median patient age was 61 years, and 81 patients were male (51.9 %). The median cycle of R-CHOP was six. The IPI risk group was a strong prognostic factor for progression-free survival (PFS) and overall survival (OS) (p < 0.001). Obese BMIs were an independent prognostic factor for PFS, but not for OS in multivariate analyses, compared to patients with normal BMIs (HR = 0.43, 95 % CI = 0.19-0.98, and p = 0.046 for PFS). A high VAT ratio (third tertile) was an independent adverse prognostic factor for PFS and OS in multivariate analyses (HR = 2.87 and 2.66, 95 % CI = 1.30-6.32 and 1.30-5.44, and p = 0.009 and 0.007 for PFS and OS, respectively). VAT ratio was an independent prognostic factor for patients with DLBCL treated with first-line R-CHOP; thus, additional large prospective studies are warranted.

Inevitable human exposure to ionizing radiation from man-made sources has been increased with the proceeding of human civilization and consequently public concerns focus on the possible risk to human health. Moreover, Fukushima nuclear power plant accidents after the 2011 East-Japan earthquake and tsunami has brought the great fear and anxiety for the exposure of radiation at low levels, even much lower levels similar to natural background. Health effects of low dose radiation less than 100 mSv have been debated whether they are beneficial or detrimental because sample sizes were not large enough to allow epidemiological detection of excess effects and there was lack of consistency among the available experimental data. We have reviewed an extensive literature on the low dose radiation effects in both radiation biology and epidemiology, and highlighted some of the controversies therein. This article could provide a reasonable view of utilizing radiation for human life and responding to the public questions about radiation risk. In addition, it suggests the necessity of integrated studies of radiobiology and epidemiology at the national level in order to collect more systematic and profound information about health effects of low dose radiation., Graphical Abstract

To clarify the genetic background of ampullary neoplasm, we investigated the occurrence of microsatellite instability (MSI) in 64 samples of neoplasm of the ampulla of Vater. Eight out of 22 adenomas (34.6%), nine out of 32 carcinomas (28.1%) and one metastatic lesion (10.0%) showed MSI in 1-3 of the nine dinucleotide markers; those cases are categorized into microsatellite instability-low (MSI-L). The remaining samples were stable with respect to all of the tested markers. None of the samples showed a frameshift mutation in the poly A-tract of BAT-26 or transforming growth factor-beta type II receptor, which are frequently mutated in gastric or colorectal cancers showing microsatellite instability. To confirm our finding, we stained 93 ampullary neoplasms with antibodies against the mismatch repair proteins: hMLH1 and hMSH2. All tumors were found to express mismatch repair proteins. In contrast to gastric or colorectal cancers, MSI does not play an important role in the carcinogenesis of ampullary carcinoma.

IntroductionThe cancer risk of radiation exposure in the moderate-to-high dose range has been well established. However, the risk remains unclear at low-dose ranges with protracted low-dose rate exposure, which is typical of occupational exposure. Several epidemiological studies of Korean radiation workers have been conducted, but the data were analysed retrospectively in most cases. Moreover, groups with relatively high exposure, such as industrial radiographers, have been neglected. Therefore, we have launched a prospective cohort study of all Korean radiation workers to assess the health effects associated with occupational radiation exposure.Methods and analysisApproximately 42 000 Korean radiation workers registered with the Nuclear Safety and Security Commission from 2016 to 2017 are the initial target population of this study. Cohort participants are to be enrolled through a nationwide self-administered questionnaire survey between 24 May 2016 and 30 June 2017. As of 31 March 2017, 22 982 workers are enrolled in the study corresponding to a response rate of 75%. This enrolment will be continued at 5-year intervals to update information on existing study participants and recruit newly hired workers. Survey data will be linked with the national dose registry, the national cancer registry, the national vital statistics registry and national health insurance data via personal identification numbers. Age-specific and sex-specific standardised incidence and mortality ratios will be calculated for overall comparisons of cancer risk. For dose–response assessment, excess relative risk (per Gy) and excess absolute risk (per Gy) will be estimated with adjustments for birth year and potential confounders, such as lifestyle factors and socioeconomic status.Ethics and disseminationThis study has received ethical approval from the institutional review board of the Korea Institute of Radiological and Medical Sciences (IRB No. K-1603-002-034). All participants provided written informed consent prior to enrolment. The findings of the study will be disseminated through scientific peer-reviewed journals and be provided to the public, including radiation workers, via the study website (http://www.rhs.kr/) and onsite radiation safety education.

Curcumin, belonging to a class of natural phenol compounds, has been extensively studied due to its antioxidative, anticancer, anti-inflammatory, and antineurodegenerative effects. Recently, it has been shown to exert dual activities after irradiation, radioprotection, and radiosensitization. Here, we investigated the protective effect of curcumin against radiation damage usingD. melanogaster. Pretreatment with curcumin (100 μM) recovered the shortened lifespan caused by irradiation and increased eclosion rate. Flies subjected to high-dose irradiation showed a mutant phenotype of outstretched wings, whereas curcumin pretreatment reduced incidence of the mutant phenotype. Protein carbonylation and formation ofγH2Ax foci both increased following high-dose irradiation most likely due to generation of reactive oxygen species. Curcumin pretreatment reduced the amount of protein carbonylation as well as formation ofγH2Ax foci. Therefore, we suggest that curcumin acts as an oxidative stress reducer as well as an effective protective agent against radiation damage.

Given the shortage of pharmacogenetic studies on treatment response according to subtype of attention-deficit hyperactivity disorder (ADHD), we investigated the associations between the MspI and DraI polymorphisms of the alpha-2 A-adrenergic receptor gene (ADRA2A) and treatment response to methylphenidate according to subtype of ADHD.We enrolled 115 medication-naïve children with ADHD into an open label 8-week trial of methylphenidate. The participants were genotyped and evaluated using the Clinical -Global Impression (CGI), ADHD rating scale, and Continuous Performance Test (CPT) pre- and post-treatment.There was no statistically significant association between the MspI or DraI genotypes and the relative frequency of CGI-improvement (CGI-I) 1 or 2 status among any of the groups (all types of ADHD, ADHD-C, or ADHD-I). However, among the children with ADHD-C, those subjects with the C/C genotype at the ADRA2A DraI polymorphism tended to have a CGI-I 1 or 2 status post-treatment (OR=4.45, p=0.045).The results of this study do not support the association between the the MspI or DraI genotypes and treatment response to methylphenidate in ADHD. However, our results -suggest that subtypes might influence pharmacogenetic results in ADHD.·available online at http://www.thieme-connect.de/ejournals/toc/pharmaco.

Alpha-interferon (alpha-IFN) and gamma-interferon (gamma-IFN) are highly effective biologic agents in the treatment of chronic myelogenous leukemia (CML). 4-hydroperoxycyclophosphamide (4-HC) is the most commonly used chemotherapeutic drug when purging bone marrow contaminated with malignant cells. To investigate the efficacy of alpha-IFN, gamma-IFN and 4-HC as purging agents in CML patients, K562 cells, a human CML cell line, were treated in vitro with these drugs singly or in combination. The cytotoxic effect was evaluated by MTT assay. Data were analyzed for synergism by the median effect principle of Chou and Talalay. Using Southern blot analysis, the effect of purging on the suppression of bcr gene rearrangement was also evaluated. Alpha-IFN, gamma-IFN and 4-HC all showed good concentration-dependent cytotoxic effect. Median cytotoxic doses of alpha-IFN gamma-IFN and 4-HC were 0.03 microM 0.20 microM and 1.97 microM respectively, and molar ratios of median doses of alpha-IFN to 4-HC, gamma-IFN to 4-HC and alpha-IFN to gamma-IFN were 1:80, 1:10 and 1:8, respectively. The combination treatment of alpha-IFN and 4-HC, and gamma-IFN and 4-HC showed significant synergistic cytotoxic activities, but combination of alpha-IFN and gamma-IFN was antagonistic. Status of bcr gene rearrangements in K562 cells was not changed after the treatments. Our results appear to provide an efficient method for removing CML cells from the bone marrow of CML patients.

AIM To investigate a suitable long-term culture system and optimal cryopreservation of intestinal organoid to improve organoid-based therapy by acquiring large numbers of cells. METHODS Crypts were isolated from jejunum of C57BL/6 mouse. Two hundred crypts were cultured in organoid medium with either epidermal growth factor/Noggin/R-spondin1 (ENR) or ENR/CHIR99021/VPA (ENR-CV). For subculture, organoids cultured on day 7 were passaged using enzyme-free cell dissociation buffer (STEMCELL Technologies). The passage was performed once per week until indicated passage. For cryopreservation, undissociated and dissociated organoids were resuspended in freezing medium with or without Rho kinase inhibitor subjected to different treatment times. The characteristics of intestinal organoids upon extended passage and freeze-thaw were analyzed using EdU staining, methyl thiazolyl tetrazolium assay, qPCR and time-lapse live cell imaging. RESULTS We established a three-dimensional culture system for murine small intestinal organoids using ENR and ENR-CV media. Both conditions yielded organoids with a crypt-villus architecture exhibiting Lgr5+ cells and differentiated intestinal epithelial cells as shown by morphological and biochemical analysis. However, during extended passage (more than 3 mo), a comparative analysis revealed that continuous passaging under ENR-CV conditions, but not ENR conditions induced phenotypic changes as observed by morphological transition, reduced numbers of Lgr5+ cells and inconsistent expression of markers for differentiated intestinal epithelial cell types. We also found that recovery of long-term cryopreserved organoids was significantly affected by the organoid state, i.e., whether dissociation was applied, and the timing of treatment with the Rho-kinase inhibitor Y-27632. Furthermore, the retention of typical morphological characteristics of intestinal organoids such as the crypt-villus structure from freeze-thawed cells was observed by live cell imaging. CONCLUSION The maintenance of the characteristics of intestinal organoids upon extended passage is mediated by ENR condition, but not ENR-CV condition. Identified long-term cryopreservation may contribute to the establishment of standardized cryopreservation protocols for intestinal organoids for use in clinical applications.

To determine whether previously reported abnormalities in fibrinolytic activity and plasma lipoprotein (a) levels could reflect obesity rather than diabetes per se, plasma concentrations of tissue-type plasminogen activator (t-PA), type 1 plasminogen activator inhibitor (PAI-1), and lipoprotein (a) (Lp (a)) were investigated in sixty-four type 2 diabetic patients (56.1 +/- 9.5 years; body mass index, 24.6 +/- 3.3 kg/m2) and thirty-two control subjects (57.9 +/- 8.9 years; body mass index, 24.6 +/- 3.4 kg/m2). Both the plasma t-PA and PAI-1 antigen levels were similar between the diabetic group (10.6 +/- 3.8 ng/ml; 27.7 +/- 11.6 ng/ml) and the control group (12.2 +/- 3.5 ng/ml; 27.7 +/- 9.6 ng/ml). The PAI-1 levels were evenly distributed from 5.93 to 52.7 ng/ml in diabetic patients. The difference of Lp (a) levels between the two groups was negligible (the diabetic group, median 11 mg/dl (range 0-72 mg/dl); the control group, median 13 mg/dl (range 0-55 mg/dl)). Significant correlations between PAI-1 levels and body mass index (BMI) were observed in both groups. In the diabetic group, PAI-1 levels also correlated with fasting C-peptide levels (r = 0.54, P < 0.01) and serum triglyceride levels (r = 0.28, P < 0.05). However, we could not find a significant association between either t-PA or PAI-1 levels and Lp (a) levels in the diabetic and control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinicopathological features of four cases of oncocytic adrenocortical carcinomas were studied. All tumors were large, circumscribed tumors with average size and weight of 11.5 cm and 586 g, respectively. The cut surfaces were yellow or brown and tan with areas of hemorrhage, necrosis, fibrosis, myxoid and cystic change. The tumor cells were exclusively oncocytic with a diffuse or compact and solid arrangement. Nuclear atypia was identified but mitosis was rare. Capsular invasion was identified in all tumors and vascular invasion was identified in one tumor. All tumors were immunoreactive for vimentin and inhibins. Immunoreactivity for pancytokeratin, synaptophysin and S-100 protein was variable and focal. All tumors had low proliferative indices, of less than 1%, and were negative for p53 protein. Ultrastructurally, the cytoplasm of tumor cells showed numerous mitochondria in a compact arrangement. Oncocytic adrenocortical carcinomas showed a similar sex ratio, slightly older mean age, similar left predilection, slightly smaller size and lighter weight compared with the conventional carcinomas. We suggest that most oncocytic adrenocortical carcinomas might be low-grade malignancies with less aggressive histological features compared with conventional carcinomas. However, they should be excised completely because of the likelihood of recurrence and metastasis during the follow-up period.

Aim: Recent trends in treatment strategy for early gastric cancer (EGC) are towards minimal surgical procedures, such as endoscopic mucosal resection and laparoscopic partial resection. There is a possibility of incomplete removal of regional lymph nodes in minimal procedures, which may subsequently decrease the chance of a cure. Therefore, it is essential to be able to predict lymph node status and to make careful selection of candidates for mucosal resection. Methods and results: We studied the relationship between lymph node status and various pathological parameters including macroscopic appearance, location, size, differentiation, presence of ulceration, vascularity, presence of gastritis cystica profunda-like glandular proliferation, disruption of the muscularis mucosae and invasion into the muscularis mucosae, using age- and sex-matched samples of 40 node-positive and 80 node-negative tumours to define the characteristics of intramucosal EGCs. Histological differentiation (P

Induced pluripotent stem cells (iPSC) are specially manipulated cells from somatic cells by the introduction of four factors that are reprogrammed. The properties of iPSC are similar to embryonic stem cells (ESC) characteristic of self-renewal and pluripotency. The technology of reprogramming somatic cells to iPSC enables the generation of patient-specific cells that can be used as powerful tools for drug screening, in vitro models for human disease and autologous transplantation. The iPSC technology provides a priceless resource for regenerative medicine but there are still changing obstacles over the safety of iPSC in avoiding induction of tumorigenicity and maintaining high purity of re-differentiated cells from iPSC to produce more functional cells for cell therapy. A variety of methods to overcome the limitation of iPSC application applied in the clinical setting have been developed. In this review, we summarize the recent progress in iPSC generation and differentiation techniques to facilitate clinical application of iPSC with future potential in regenerative medicine.

Objective To provide improved identification of small cell carcinoma (SMCC) and reevaluate the significance of cervical cytologic smears in its diagnosis. Study design Analyses of histocytologic morphology and clinical data were performed by reviewing clinical records, histopathology and cervical cytology smears from 18 SMCC cases of the uterine cervix (including one recurrent case and three SMCC cases with adenocarcinoma) between 1986 and 2001. Results Most cases showed minimal cytoplasm, finely stippled ("salt and pepper") chromatin, prominent nuclear molding and smearing effect. Cytologic smears diagnosed or suggested 79% of SMCC cases before histologic confirmation. Of the cases, 89% displayed moderate to high cellularity. The tumor cells were arranged mostly in clusters of varying sizes with no typical architectural pattern. In addition, the tumors often exhibited very pleomorphic cells and recognizable nucleoli. Conclusion Cytologic features of SMCC cells are characteristics enough for specific diagnosis or at least an early indication of it. Timely detection by cervical cytologic smears will allow clinicians to initiate prompt treatment of these aggressive tumors.

P368 Serological response to the 23-valent pneumococcal polysaccharide vaccine in patients with Crohn’s disease: preliminary results of a prospective, multicentre study C.K. Lee1 *, H.-S. Kim2, H.-J. Kim1, W. Moon3, K.M. Lee4, J.-S. Koo5, G.S. Seo6, S.J. Park7, B.D. Ye8, C.H. Choi9, S.-A. Jung10, Y.S. Kim11, J.P. Im12, E.S. Kim13, S.N. Hong14. 1Kyung Hee University, South Korea, 2Yonsei University Wonju College of Medicine, South Korea, 3Kosin University, South Korea, 4The Catholic University of Korea, South Korea, 5Korea University, South Korea, 6Wonkwang University, South Korea, 7Yonsei University, South Korea, 8University of Ulsan, South Korea, 9Chung-Ang University, South Korea, 10Ewha Womans University, South Korea, 11Inje University, South Korea, 12Seoul National University, South Korea, 13Keimyung University, South Korea, 14Konkuk University, South Korea

Background: Approximately 30% of patients with relapsing, extensive ulcerative colitis (UC) require surgery. Pouchitis develops in about 50% of the UC patients undergoing colectomy. Finding simple risk factors predisposing to colectomy and the development of postoperative pouchitis could help to optimize therapy or indicate surgery in time in patients with UC. The aim of the present study was to evaluate the frequency of colectomy and postoperative pouchitis and to determine predictive factors of colectomy and pouchitis in our UC patients. Methods: Using our IBD database, we evaluated every hospital admissions of UC patients with acute exacerbation requiring intravenous corticosteroid treatment between 1998 and 2009. Inflammatory laboratory parameters were assessed at every hospitalization of patients undergoing colectomy and in those who avoided surgery. Clinical and demographic data were also compared and statistically analyzed between the two groups. Demographic, clinical and therapeutic parameters were compared between patients who did and did not develop pouchitis after colectomy and between those with pouchitis responding or being refractory to the conservative therapy. Results: The records of 182 UC patients with a total of 276 hospitalizations because of severe relapse of UC were reviewed. 46 patients underwent colectomy. Pancolitis, low hematocrit level and the need for blood transfusion were significantly more common in the colectomy group (p = 0.004 and p = 0.002). The number of hospitalization, disease duration, and a lower body mass index value also proved to predispose to surgery (p = 0.004, p = 0.049 and p = 0.027). 35 of the 46 colectomized patients underwent ileal pouchanal anastomosis procedure. 40% of these patients developed pouchitis. Frequent hospital admissions before colectomy, the presence of extraintestinal manifestations and non smoking status were characteristic for refractory pouchitis. Conclusions: Our results suggest that severe UC patients with pancolitis, anemia, longer disease duration and frequent hospital admissions have a higher likelihood of requiring colectomy. The development of pouchitis seems to be predisposed by frequent hospital admissions before colectomy. Severe, refractory pouchitis was significantly more common in nonsmokers and in patients with extraintestinal manifestations.

Purpose: To investigate time sampling and its interpolation effect on cerebral perfusion measurements for proving the possibility of low‐radiation‐dose CT examination than usual. Method and Materials: Immediately after non‐enhanced transverse scanning of a patient's brain, contrast material‐enhanced scanning was performed every 1 second for 40 seconds at a single‐slice level. Uniform time sampling was executed from 1/2 to 1/7 rate of total time series, respectively. Thirty tissue concentration time‐course data were collected, and arterial input curve data were fitted by gamma‐variate function. The sinc function was introduced for interpolation.Deconvolution analysis based on singular value decomposition was performed for quantification of CBF. The lowest singular value corresponding to the minimum difference between residue and its exponential curve‐fitted function was considered as the optimal threshold value. The CBF values were calculated from the maximum of the scaled residue function. The perfusion values through time sampling and interpolation were compared with the original perfusion values by independent samples t‐test. Results: The CBF values without interpolation were underestimated with a decrease of sampling rate, and with interpolation had a tendency fluctuated around the original CBF values. The CBV values through time sampling were not statistically different from the original CBV values regardless of the existence of interpolation. The MTT values without interpolation were overestimated with a decrease of sampling rate, and with interpolation had a tendency fluctuated inversely to CBF change around the original MTT. Time sampling without interpolation was statistically possible up to 1/2 sampling rate, and with interpolation up to 1/5 sampling rate. Conclusion: The perfusion values through time sampling with interpolation are acceptable up to some less sampling rate, and more accurate than without interpolation. This study will help in selecting reasonable image acquisition time interval for low‐radiation‐dose CT examination. Conflict of Interest: Young Investigator Competition.

Adenovirus pneumonia, while common in infancy and childhood, is rarely documented but may be fatal in the neonatal period. In regard to the serious outcome and no responsiveness to common anti-viral agents, adenovirus infection should be considered in the differential diagnosis of pneumonia in neonates. We report three cases of fatal neonatal adenovirus pneumonia, all of which were diagnosed by postmortem examination. Two patients were born by cesarean section at 35 or 36 weeks of gestation, and the other was a 5100 gm postmature baby born by vaginal delivery at 43 weeks of gestation. Respiratory insufficiency was detected just after birth or in the immediate postnatal period, and was associated with lethargy and chest X-ray findings of pneumonic infiltration. The postmortem findings of these patients were remarkably consistent and characterized by predominant lung involvement. The lungs showed diffuse massive consolidation with scattered patchy hemorrhage, and histologically revealed multifocal necrotizing alveolitis and/or bronchiolitis, often with hemorrhage. Alveolar lining cells and desquamated cells contained numerous smudge ells and many cells with characteristic inclusion bodies. Electron microscopy revealed that these inclusion bodies consisted of arrays of icosahedral particles of adenovirus. It is unusual that one of the patients, who was born by cesarean section without any evidence of prenatal infection, developed adenoviral pneumonia; this indicates that infection may occur in the immediate postnatal period as well as during passage of the birth canal.

Twenty-two placentas were investigated for the presence and patterns of inflammation by extensive examination, and divided into four groups: 1) term vaginal delivery [group I; n=6]; 2) term cesarean section delivery [group II; n=5]; 3) preterm vaginal delivery [group III; n=4], and 4) preterm cesarean section delivery [group IV; n=7]. In group I, all had deciduitis, and choriodeciduitis/ chorionitis was present in two cases (33.3%). In group II, four cases (80%) showed deciduitis and/or choriodeciduitis/chorionitis; three of these had intact membranes. In group III, three cases (75%) showed deciduitis, and two had chorionitis. In group IV, three cases (42.9%) showed no evidence of inflammation, three had deciduitis and one had deciduitis/chorioamnionitis. In all groups, membranitis was more severe, confined to the inner and mid segments in general, and deciduitis, choriodeciduitis/chorionitis and chorioamnionitis tended to overlap. The study newly demonstrates major characteristics of placental inflammation: higher prevalence and severity of inflammation in the inner segments of membrane and at the periphery of the placenta. Taking this histotopography into account, it is desirable to take sections from the placental margin, and the current concept of placental inflammation as a surrogate marker of intrauterine infection should be reevaluated.