Search for Boosted Dark Matter in COSINE-100.

We search for energetic electron recoil signals induced by boosted dark matter (BDM) from the galactic center using the COSINE-100 array of NaI(Tl) crystal detectors at the Yangyang Underground Laboratory. The signal would be an excess of events with energies above 4 MeV over the well-understood background. Because no excess of events are observed in a 97.7 kg·yr exposure, we set limits on BDM interactions under a variety of hypotheses. Notably, we explored the dark photon parameter space, leading to competitive limits compared to direct dark photon search experiments, particularly for dark photon masses below 4 MeV and considering the invisible decay mode. Furthermore, by comparing our results with a previous BDM search conducted by the Super-Kamionkande experiment, we found that the COSINE-100 detector has advantages in searching for low-mass dark matter. This analysis demonstrates the potential of the COSINE-100 detector to search for MeV electron recoil signals produced by the dark sector particle interactions.

A quantum enhanced search for dark matter axions.

The manipulation of quantum states of light1 holds the potential to enhance searches for fundamental physics. Only recently has the maturation of quantum squeezing technology coincided with the emergence of fundamental physics searches that are limited by quantum uncertainty2,3. In particular, the quantum chromodynamics axion provides a possible solution to two of the greatest outstanding problems in fundamental physics: the strong-CP (charge-parity) problem of quantum chromodynamics4 and the unknown nature of dark matter5-7. In dark matter axion searches, quantum uncertainty manifests as a fundamental noise source, limiting the measurement of the quadrature observables used for detection. Few dark matter searches have approached this limit3,8, and until now none has exceeded it. Here we use vacuum squeezing to circumvent the quantum limit in a search for dark matter. By preparing a microwave-frequency electromagnetic field in a squeezed state and near-noiselessly reading out only the squeezed quadrature9, we double the search rate for axions over a mass range favoured by some recent theoretical projections10,11. We find no evidence of dark matter within the axion rest energy windows of 16.96-17.12 and 17.14-17.28 microelectronvolts. Breaking through the quantum limit invites an era of fundamental physics searches in which noise reduction techniques yield unbounded benefit compared with the diminishing returns of approaching the quantum limit.

Search for a Dark Matter-Induced Annual Modulation Signal in NaI(Tl) with the COSINE-100 Experiment.

We present new constraints on the dark matter-induced annual modulation signal using 1.7 years of COSINE-100 data with a total exposure of 97.7 kg yr. The COSINE-100 experiment, consisting of 106 kg of NaI(Tl) target material, is designed to carry out a model-independent test of DAMA/LIBRA's claim of WIMP discovery by searching for the same annual modulation signal using the same NaI(Tl) target. The crystal data show a 2.7 cpd/kg/keV background rate on average in the 2-6 keV energy region of interest. Using a χ-squared minimization method we observe best fit values for modulation amplitude and phase of 0.0092±0.0067 cpd/kg/keV and 127.2±45.9 d, respectively.

Low-Dose-Rate and High-Dose-Rate Brachytherapy for Localized Prostate Cancer in ABO-Incompatible Renal Transplant Recipients.

BACKGROUND: Brachytherapy is one of the standard treatments for localized prostate cancer (CaP). However, the feasibility of brachytherapy for renal transplant recipients (RTRs) is still uncertain. MATERIALS AND METHODS: Between August 2007 and March 2018, all patients who had undergone low-dose-rate (LDR) brachytherapy or high-dose-rate (HDR) brachytherapy for clinically localized CaP at our institution were retrospectively identified (n = 394). Of these patients, 3 had a history of renal transplantation. We reviewed all available clinical data retrospectively. RESULTS: All of the RTRs received ABO-incompatible renal grafts from their spouses and had stable renal graft function before the diagnosis of CaP. The median age at diagnosis of CaP was 65 years (range, 60-67 years). The median time between transplantation and brachytherapy was 7 years (range, 4-10 years). In all of the patients, clinical stage was cT1cN0M0. Two patients received 125I LDR-brachytherapy (dose, 145 Gy) and 1 patient was treated by 192Ir HDR brachytherapy (dose, 19 Gy in 2 fractions) combined with external beam radiation therapy of 39 Gy in 13 fractions. The median follow-up period after brachytherapy was 44 months (range, 34-50 months). During the follow-up period, none of the patients developed disease progression including biochemical recurrence or clinically significant adverse events associated with radiation therapy. CONCLUSIONS: LDR brachytherapy and HDR brachytherapy are safe and technically feasible in RTRs with CaP, and oncological outcomes in RTRs do not appear to be inferior to those of patients who did not receive renal transplant.

First Direct Search for Inelastic Boosted Dark Matter with COSINE-100.

A search for inelastic boosted dark matter (IBDM) using the COSINE-100 detector with 59.5 days of data is presented. This relativistic dark matter is theorized to interact with the target material through inelastic scattering with electrons, creating a heavier state that subsequently produces standard model particles, such as an electron-positron pair. In this study, we search for this electron-positron pair in coincidence with the initially scattered electron as a signature for an IBDM interaction. No excess over the predicted background event rate is observed. Therefore, we present limits on IBDM interactions under various hypotheses, one of which allows us to explore an area of the dark photon parameter space that has not yet been covered by other experiments. This is the first experimental search for IBDM using a terrestrial detector.

Background model for the NaI(Tl) crystals in COSINE-100.

The COSINE-100 dark matter search experiment is an array of NaI(Tl) crystal detectors located in the Yangyang Underground Laboratory (Y2L). To understand measured backgrounds in the NaI(Tl) crystals we have performed Monte Carlo simulations using the Geant4 toolkit and developed background models for each crystal that consider contributions from both internal and external sources, including cosmogenic nuclides. The background models are based on comparisons of measurement data with Monte Carlo simulations that are guided by a campaign of material assays and are used to evaluate backgrounds and identify their sources. The average background level for the six crystals (70 kg total mass) that are studied is 3.5 counts/day/keV/kg in the (2-6) keV energy interval. The dominant contributors in this energy region are found to be 210 Pb and 3 H.

Mode-selective optical packet switching in mode-division multiplexing networks.

A novel mode-selective optical packet switching, based on mode-multiplexers/demultiplexers and multi-port optical micro-electro-mechanical systems (MEMS) switches, has been proposed and experimentally demonstrated. The experimental demonstration was performed using the LP(01), LP(11a) and LP(11b) modes of a 30-km long mode-division multiplexed few-mode fiber link, utilizing 40 Gb/s, 16-QAM signals.

Involvement of high mobility group box 1 and the therapeutic effect of recombinant thrombomodulin in a mouse model of severe acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is accompanied by severe lung inflammation induced by various diseases. Despite the severity of the symptoms, therapeutic strategies have been ineffective. High mobility group box 1 (HMGB1), which was identified originally as a DNA binding protein, has been proposed as a mediator of acute lung injury. In addition to its anti-coagulant activity, recombinant thrombomodulin (rTM) possesses an ability to suppress the inflammatory response through neutralizing HMGB1. T regulatory (T(reg)) cells in the lungs are reported to modify innate immune responses during resolution of acute lung injury. In the present study, we investigated the therapeutic effect of rTM, and the contribution of T(reg) cells to this effect, in a mouse model of severe ARDS. C57BL/6 mice received sequential intratracheal administration of α-galactosylceramide (α-GalCer) and lipopolysaccharide (LPS), which resulted in the development of severe ARDS. HMGB1 levels in the lungs increased to a higher level in ARDS mice compared to those in mice treated with LPS alone. HMGB1 was expressed in the infiltrating neutrophils and macrophages in lungs. T(reg) cells were reduced significantly in the lungs of ARDS mice compared to those in mice treated with LPS alone. rTM administration prolonged the survival time and ameliorated the development of ARDS, which was associated with increased T(reg) cells and synthesis of interleukin (IL)-10 and transforming growth factor (TGF)-ß in the lungs. These results suggest that HMGB1 is involved in the development of severe ARDS and rTM shows therapeutic effects through promoting the accumulation of T(reg) cells at the inflammatory sites.

Emedastine difumarate inhibits histamine-induced collagen synthesis in dermal fibroblasts.

BACKGROUND: Mast cell-derived histamine is known to act on dermal fibroblasts and contribute to formation of an intractable chronic allergic dermatitis. Although this fibrotic event may also occur in other organs such as the nasal mucosa, no direct evidence has been reported as to whether responsiveness to histamine by fibroblasts derived from different organs is of the same intensity. Furthermore, while type 1 histamine receptor (H1R) blockers have been shown to be effective for alleviation of the symptoms of allergic diseases, their ability to affect histamine-induced tissue remodeling has not yet been clarified. OBJECTIVE: Our aim was to study the effect of H1R-blockers on histamine-induced tissue remodeling. METHODS: A macroarray assay was used for a comprehensive analysis of histamine-induced gene expression by normal human fibroblasts. Fibroblasts derived from skin or nasal mucosa were cultured in the presence of various concentrations of histamine, and the synthesis of type 1 collagen was measured by means of semi-quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. To determine the effect of H1R blockers, diphenhydramine hydrochloride and emedastine difumarate were investigated in this assay. RESULTS: Histamine induced expression of various kinds of fibrogenic molecules in fibroblasts. Increased type 1 collagen expression was observed in fibroblasts treated with high-dose (0.1 mM to 1 microM) and low-dose (1 pM) histamine. This histamine-induced type 1 collagen synthesis was effectively diminished by emedastine difumarate. While organ specificity seems to be involved, emedastine difumarate is considered to be an effective drug for reversal of such histamine-induced remodeling in the skin. CONCLUSIONS: We found that the expression of fibroblast-derived genes is differentially regulated by different concentrations of histamine and that the robustness of the inhibitory action of H1R blockers is different for skin-derived and nasal mucosa-derived fibroblasts. We believe that our findings may contribute to a better understanding of the mechanisms of histamine-induced tissue remodeling and provide information useful for the management of refractory allergic dermatitis.

Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer.

Activation of Wnt signaling has been implicated in gastric tumorigenesis, although mutations in APC (adenomatous polyposis coli), CTNNB1 (beta-catenin) and AXIN are seen much less frequently in gastric cancer (GC) than in colorectal cancer. In the present study, we investigated the relationship between activation of Wnt signaling and changes in the expression of secreted frizzled-related protein (SFRP) family genes in GC. We frequently observed nuclear beta-catenin accumulation (13/15; 87%) and detected the active form of beta-catenin in most (12/16; 75%) GC cell lines. CpG methylation-dependent silencing of SFRP1, SFRP2 and SFRP5 was frequently seen among GC cell lines (SFRP1, 16/16, 100%; SFRP2, 16/16, 100%; SFRP5, 13/16, 81%) and primary GC specimens (SFRP1, 42/46, 91%; SFRP2, 44/46, 96%; SFRP5, 30/46, 65%), and treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine rapidly restored SFRP expression. Ectopic expression of SFRPs downregulated T-cell factor/lymphocyte enhancer factor transcriptional activity, suppressed cell growth and induced apoptosis in GC cells. Analysis of global expression revealed that overexpression of SFRP2 repressed Wnt target genes and induced changes in the expression of numerous genes related to proliferation, growth and apoptosis in GC cells. It thus appears that aberrant SFRP methylation is one of the major mechanisms by which Wnt signaling is activated in GC.

Absence of Bcl-2 and Fas/CD95/APO-1 predicts the response to immunotherapy in metastatic renal cell carcinoma.

Immunotherapy is the only available treatment for metastatic renal cell cancer (RCC), but the response rate is only about 20% and the treatment is occasionally associated with severe adverse effects. Thus, the selection of patients with a high susceptibility to immunotherapy is needed; however, there is no promising molecular marker that can predict the response to immunotherapy for RCC. This study was carried out to elucidate the potential role of apoptosis-related molecules Bcl-2 and Fas, as well as apoptotic and proliferating indexes (AI, PI) as predictors of the susceptibility of metastatic RCC to immunotherapy. Immunohistochemical examination of tumour tissues from 40 patients with metastatic RCC undergoing postoperative immunotherapy after radical nephrectomy was performed. Patients with progressive disease (PD) after immunotherapy presented with decreased survival (P=0.006). Progressive disease correlated with higher PI in the primary lesion (P=0.0087). All primary tumours of CR or PR patients were negative for Bcl-2, whereas among NC+PD patients, 40.6% were positive for Bcl-2 (P=0.0373). Patients in whom the primary tumours were both Bcl-2- and Fas-negative showed significantly better responses to immunotherapy in comparison with the remaining group (P=0.0022). The Bcl-2 and Fas status of the primary lesion may become useful criteria for the selection of patients with metastatic RCC for immunotherapy.

Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines.

Transcription factor 2 gene (TCF2) encodes hepatocyte nuclear factor 1beta (HNF1beta), a transcription factor associated with development and metabolism. Mutation of TCF2 has been observed in renal cell cancer, and by screening aberrantly methylated genes, we have now identified TCF2 as a target for epigenetic inactivation in ovarian cancer. TCF2 was methylated in 53% of ovarian cancer cell lines and 26% of primary ovarian cancers, resulting in loss of the gene's expression. TCF2 expression was restored by treating cells with a methyltransferase inhibitor, 5-aza-2'deoxycitidine (5-aza-dC). In addition, chromatin immunoprecipitation showed deacetylation of histone H3 in methylated cells and, when combined with 5-aza-dC, the histone deacetylase inhibitor trichostatin A synergistically induced TCF2 expression. Epigenetic inactivation of TCF2 was also seen in colorectal, gastric and pancreatic cell lines, suggesting general involvement of epigenetic inactivation of TCF2 in tumorigenesis. Restoration of TCF2 expression induced expression of HNF4alpha, a transcriptional target of HNF1beta, indicating that epigenetic silencing of TCF2 leads to alteration of the hepatocyte nuclear factor network in tumours. These results suggest that TCF2 is involved in the development of ovarian cancers and may represent a useful target for their detection and treatment.

Prognostic impact of FAS/CD95/APO-1 in urothelial cancers: decreased expression of Fas is associated with disease progression.

The death receptor Fas (Apo1/CD95) and Fas ligand (FasL) system is recognised as a major pathway for the induction of apoptosis in vivo, and antiapoptosis via its blockade plays a critical role in carcinogenesis and progression in several malignancies. However, the function of Fas-FasL system in urothelial cancer (UC) has not been elucidated. We therefore investigated the expression of Fas, FasL and Decoy receptor 3 for FasL (DcR3) in UC specimens and cell lines, and examined the cytotoxic effect of an anti-Fas-activating monoclonal antibody (mAb) in vitro. Immunohistochemical examinations of Fas-related molecules were performed on 123 UC and 30 normal urothelium surgical specimens. Normal urothelium showed Fas staining in the cell membrane and cytoplasm. In UC, less frequent Fas expression was significantly associated with a higher pathological grade (P < 0.0001), a more advanced stage (P = 0.023) and poorer prognosis (P = 0.010). Fas and the absence thereof were suggested to be crucial factors with which to select patients requiring more aggressive treatment. Moreover, low-dose anti-Fas-activating mAb sensitised resistant cells to adriamycin, and this synergistic effect could be applied in the development of new treatment strategy for UC patients with multidrug-resistant tumours.

Importance of early repair of isolated abdominal aortic dissecting aneurysm.

BACKGROUND: Since the available information on isolated abdominal aortic dissecting aneurysm (AADA) is mainly related to case reports or reports of small groups of patients, its natural history remains undetermined and there is no agreement on its optimal management. The purpose of this study is to define the features and pattern of development of this unusual entity as well as to propose criteria for treatment based on our own experience and previously published data. PATIENTS AND METHODS: We retrospectively evaluated the history of 6 patients diagnosed with AADA. The patients were 5 males and 1 female. The mean age was 71 +/- 8 years (range: 61-80 years), and the mean aneurysm diameter was 54 +/- 14 mm (range: 35-70 mm). All of these patients were hypertensive (100%). History of cerebrovascular accident, ischemic heart disease, peripheral arterial disease, or diabetes mellitus was present in 1 patient, respectively. Two patients developed mycotic AADA. RESULTS: Emergency operations had been performed in 3 cases, and scheduled surgical reconstruction in the remaining 3 cases. Operation consisted of aneurysmectomy and graft replacement of the diseased aortic segment in all cases. One patient treated in an emergency setting died subsequently of multisystem organ failure, but the others did well. CONCLUSION: Symptomatic patients or patients at good risk should undergo surgical repair earlier than in the case of abdominal aortic aneurysm without dissection (AAA). Dissection in addition to an AAA will further increase the weakness of the aortic wall and the possibility of aortic rupture will become higher.

The relationship between aberrant methylation and survival in non-small-cell lung cancers.

The present study examined the relationship between methylation of five genes (p16(INK4a), RASSF1A, APC, RARbeta and CDH13) and patient survival in 351 cases of surgically resected lung cancers. While there was no relationship between the other genes and survival, p16(INK4a) methylation was significantly related to unfavourable prognosis in lung adenocarcinomas.

Prognostic significance of metastatic lymph node size in patients with gastric cancer.

BACKGROUND: Patients with gastric cancer that has metastasized to the lymph nodes are a heterogeneous population with a variable prognosis. Stratification of these patients into prognostic groups is necessary for optimal adjuvant therapy. METHODS: The study comprised 715 patients who had undergone curative resection of a gastric neoplasm. Lymph nodes were sectioned, stained with haematoxylin and eosin, and the diameter of the largest metastatic lymph node (MLN) was measured. Patients with metastatic nodes were divided into groups n1 and n2 according to the size of the MLN. The cut-off level was set at 7 mm by a two-sample log rank test; patients in group n1 had a MLN size of 7 mm or less and those in group n2 had a MLN of 8 mm or more. RESULTS: Patients were stratified into significant prognostic groups by both the Union International Contra la Cancrum (UICC) node (N) stage and MLN size (n group). The UICC N-stage subcategories were further divided into prognostic groups according to MLN size (n group). On multivariate analysis the MLN size remained independently significant in terms of overall and disease-free survival rates, and the UICC N stage was not significant, independently of the n group. Node-positive patients with fewer than 15 lymph nodes removed at operation could also be stratified into prognostic groups by the n group. Stratification according to the TNM stage and by MLN size was superior to existing UICC TNM staging. CONCLUSION: This new method may help clinicians to design a more appropriate treatment strategy for patients with gastric cancer.

An epidemiological and clinical study of untreated patients with tinea pedis within a company in Japan.

In this study, we investigated epidemiological and clinical aspects of dermatophyte foot infections among employees of one dairy product company located in Kanagawa prefecture in central Japan. Sixty-nine of 377 subjects were reported having "athlete's foot" in response to a simple questionnaire. A subsequent mycological examination revealed 41 untreated patients with tinea pedis and/or tinea unguium (89% of subjects examined) and the overall prevalence was estimated at 18%. Comparing severity scores of five clinical symptoms (itching, erythema, vesicles/pustules, erosion/maceration, and scales) between those untreated patients within the subjects and another group of patients who spontaneously attended dermatological clinics to treat tinea pedis, itching, erythema, and total score were significantly higher in the latter group.

Solitary fibrous tumours of the lower gingiva: a case report.

Solitary fibrous tumours (SFTs) are rare lesions in the oral cavity. Typically they arise in the pleura. We report a lesion occurring in the lower anterior gingiva. In histochemical examination, the spindle-shaped, neoplastic cells stained strongly for CD34 antigen and vimentin, but did not stain for desmin, smooth-muscle actin, muscle actin and S-100 protein. The expression of CD34 antigen and vimentin were useful for the differential diagnosis.

Prognostic significance of ultrasound derived intratumoral peak systolic velocity in epithelial ovarian cancer.

OBJECTIVE: To evaluate the prognostic significance of ultrasound derived intratumoral peak systolic velocity in epithelial ovarian cancer. DESIGN: Color Doppler imaging and pulsed Doppler spectral analysis were used in the investigation of 49 patients with epithelial ovarian cancer (19 serous, 15 mucinous, eight endometrioid, four clear cell and three Brenner cell) immediately before laparotomy. Twenty-two were stage I, six were stage II, 17 were stage III and four were stage IV. Sections of malignant tumors were analyzed for the cellular expression of thymidine phosphorylase and the intratumoral density of microvessels by immunohistochemistry using antibodies to thymidine phosphorylase and factor VIII-related antigen, respectively. Moreover, the apoptotic index was evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling method. Intratumoral peak systolic velocity was tested for correlation with patients' age at diagnosis, stage of disease, presence of a residual tumor, histological subtype and grade, thymidine phosphorylase expression, apoptotic index, microvessel count and patient survival. RESULTS: Histological grade (P = 0.025), thymidine phosphorylase expression (P = 0.044), apoptotic index (P = 0.039) and microvessel count (P = 0.014) were all significantly associated with peak systolic velocity. Stage of disease (P = 0.002), presence of residual disease (P = 0.0002) and peak systolic velocity (P = 0.041) were found by univariate Cox regression analysis to be significantly associated with a poor prognosis. Multivariate Cox regression analysis revealed that stage of disease (P = 0.006) and peak systolic velocity (P = 0.008) are independent prognostic factors. CONCLUSIONS: Intratumoral peak systolic velocity could be a preoperatively pertinent prognostic predictor of survival in patients with epithelial ovarian cancer.

[Surgical results for aortic involvement in Marfan syndrome].

From 1991 through 2001, 21 Marfan patients underwent aortic operations in our hospital. They received a total of 36 aortic operations, 31 by ourselves including 4 non-elective operations and 2 operations before 1991. Extent of replacement was Bentall + total arch (4), Bentall (8), valve sparing aortic root (reimplantation) (2), re-anastomosis + coronary aortic bypass grafting (CABG) after Bentall (1), ascending + total arch (3), ascending (1), total arch (1), total thoracoabdominal (10), thoracoabdominal (1), descending thoracic (2), distal arch (1), abdominal (2). Multiple operations were required in 11 patients (2 operations in 7, 3 operations in 4). Eight reoperations in 6 patients were for adjacent lesion, 5 reoperations were for remote lesion, and 2 others were for complication of Bentall (initial operation elsewhere). Among the 8 reoperations for adjacent lesion, 3 were scheduled operation (2 with elephant trunk), 4 were for residual dissection, and 1 was for annulo-aortic ectasia (AAE). Total aortic replacement was achieved in 4 and subtotal replacement excluding the root in 2. There was no hospital mortality. Paraparesis occurred in 1 who died 4.7 years after operation. The remaining patients are currently alive. No other aortic event occurred. Aortic reoperation-free survival was 83% at 5 year and 28% at 10 year.