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PURPOSE Germline missense variants of unknown significance in cancer-related genes are increasingly being identified with the expanding use of next-generation sequencing. The ataxia telangiectasia–mutated ( ATM) gene on chromosome 11 has more than 1,000 germline missense variants of unknown significance and is a tumor suppressor. We aimed to determine if rare germline ATM variants are more frequent in chronic lymphocytic leukemia (CLL) compared with other hematologic malignancies and if they influence the clinical characteristics of CLL. METHODS We identified 3,128 patients (including 825 patients with CLL) in our hematologic malignancy clinic who had received clinical-grade sequencing of the entire coding region of ATM. We ascertained the comparative frequencies of germline ATM variants in categories of hematologic neoplasms, and, in patients with CLL, we determined whether these variants affected CLL-associated characteristics such as somatic 11q deletion. RESULTS Rare germline ATM variants are present in 24% of patients with CLL, significantly greater than that in patients with other lymphoid malignancies (16% prevalence), myeloid disease (15%), or no hematologic neoplasm (14%). Patients with CLL with germline ATM variants are younger at diagnosis and twice as likely to have 11q deletion. The ATM variant p.L2307F is present in 3% of patients with CLL, is associated with a three-fold increase in rates of somatic 11q deletion, and is a hypomorph in cell-based assays. CONCLUSION Germline ATM variants cluster within CLL and affect the phenotype of CLL that develops, implying that some of these variants (such as ATM p.L2307F) have functional significance and should not be ignored. Further studies are needed to determine whether these variants affect the response to therapy or account for some of the inherited risk of CLL.

Cancer immunotherapy is now the first-line treatment for many unresectable cancers. However, it remains far from a complete cure for all patients. Therefore, it is necessary to develop innovative methods for cancer immunotherapy, and immune cell therapy could be an option. Currently, several institutions are attempting to generate immune cells from induced pluripotent stem cells (iPSCs) for use in cancer immunotherapy. A method for generating dendritic cells (DCs) and macrophages (MPs) from iPSC has been established. iPSC-derived DCs (iPS-DCs) can activate T cells via antigen presentation, and iPSC-derived macrophages (iPS-MPs) attack cancer. Since iPSCs are used as the source, genetic modification is easy, and various immune functions, such as the production of anti-tumour cytokines, can be added. Furthermore, when iPS-DCs and iPS-MPs are immortalized, cost reduction through mass production is theoretically possible. In this review, the achievements of cancer research using iPS-DCs and iPS-MPs are summarized, and the prospects for the future are discussed.

Oxo- and hydroxo-bridged hexanuclear Ce(IV) clusters surrounded by 12 carboxylate ligands, Ce

Cobalt-catalyzed hydroalkynylation of alkynes, alkenes, and imines affords internal alkynes with various functional groups adjacent to the carbon–carbon triple bond moiety in an atom-economical manner. In addition, cross-coupling of in situ generated alkynylcobalt species from terminal alkynes, haloalkynes, and metal acetylides with (hetero)aromatic compounds and organic halides selectively provides various internal aryl- and alkylalkynes.1 Introduction2 Hydroalkynylation of Alkynes for 1,3-Enyne Synthesis3 Hydroalkynylation of Polar and Nonpolar Double Bonds4 Dehydrogenative Cross-Coupling Reaction Using Terminal Alkynes with Aromatic Compounds5 Cross-Coupling Reactions Using Haloalkynes as the Coupling Partners6 Cross-Coupling Reactions Using Metal Acetylides7 Conclusion

Background/Aims: Although anti-tumor necrosis factor (TNF)-α agents are important therapeutic drugs for Crohn’s disease (CD), data regarding their long-term sustained effects are limited. Herein, we evaluated the long-term loss of response (LOR) to anti-TNF-α agents in patients with CD.Methods: This retrospective study included patients with CD who started treatment with infliximab or adalimumab as a first-line therapeutic approach. The cumulative event-free, retention, and surgery-free rates after the start of biological therapy were analyzed. Secondary LOR was analyzed in patients who achieved corticosteroid-free clinical remission after the start of biological therapy. Cox proportional hazards models were used to analyze the predictive factors of secondary LOR.Results: The cumulative event-free rates at 1, 2, 5, and 10 years were 83.3%, 75.1%, 37.4%, and 23.3%, respectively. The incidence of LOR was 10.6% per patient-year of follow-up. At 12–14 weeks after the start of biological therapy, the proportion of patients with a C-reactive protein to albumin (CRP/ALB) ratio ≥0.18 was significantly higher in patients with LOR (PP=0.009) and upper gastrointestinal tract inflammation (HR, 3.00; 95% CI, 1.26–7.13; P=0.013) were predictive factors of secondary LOR.Conclusions: Although anti-TNF-α agents contributed to long-term clinical remission of CD, the annual incidence of secondary LOR was 10.6%. The CRP/ALB ratio at 3 months after the start of biological therapy and upper gastrointestinal tract inflammation were identified as predictive factors of secondary LOR.

We investigated the molecular details of the role of protein tyrosine phosphatase (PTP)-PEST in cell migration. PTP-PEST knockout mouse embryonic fibroblasts (KO MEFs) and MEF cells expressing a dominant-negative mutant of PTP-PEST showed significant suppression of cell migration compared to MEF cells expressing wild-type PTP-PEST (WT MEFs). Moreover, MEF cells harbouring a constitutively active mutant of PTP-PEST (S39A MEFs) showed a marked decrease in cell migration. In addition, MEF cells with no PTP-PEST or little PTP activity rapidly adhered to fibronectin and made many focal adhesions compared to WT MEF cells. In contrast, S39A MEF cells showed weak adhesion to fibronectin and formed a few focal adhesions. Furthermore, investigating the subcellular localization showed that Ser39-phosphorylated PTP-PEST was favourably situated in the adherent area of the pseudopodia. Therefore, we propose that suppression of PTP-PEST enzyme activity due to Ser39-phosphorylation in pseudopodia and at the leading edge of migrating cells induces rapid and good adherence to the extracellular matrix. Thus, suppression of PTP activity by Ser39-phosphorylation is critical for cell migration. Three amino acid substitutions in human PTP-PEST have been previously reported to alter PTP activity. These amino acid substitutions in mouse PTP-PEST altered the migration of MEF cells in a positive correlation.

Background Sunlight contains ultraviolet B (UVB) radiation that triggers the production of vitamin D by skin. Vitamin D has widespread effects on brain function in both developing and adult brains. However, many people live at latitudes (about > 40 N or S) that do not receive enough UVB in winter to produce vitamin D. This exploratory study investigated the association between the age of onset of bipolar I disorder and the threshold for UVB sufficient for vitamin D production in a large global sample. Methods Data for 6972 patients with bipolar I disorder were obtained at 75 collection sites in 41 countries in both hemispheres. The best model to assess the relation between the threshold for UVB sufficient for vitamin D production and age of onset included 1 or more months below the threshold, family history of mood disorders, and birth cohort. All coefficients estimated at P ≤ 0.001. Results The 6972 patients had an onset in 582 locations in 70 countries, with a mean age of onset of 25.6 years. Of the onset locations, 34.0% had at least 1 month below the threshold for UVB sufficient for vitamin D production. The age of onset at locations with 1 or more months of less than or equal to the threshold for UVB was 1.66 years younger. Conclusion UVB and vitamin D may have an important influence on the development of bipolar disorder. Study limitations included a lack of data on patient vitamin D levels, lifestyles, or supplement use. More study of the impacts of UVB and vitamin D in bipolar disorder is needed to evaluate this supposition.

Blood pressure (BP) often rises before surgery. This study investigated whether BP elevation immediately before surgery was associated with adverse outcomes. Medical records of 11,732 patients (average age: 61 years; male: 47.4%) who underwent non-cardiac elective inpatient surgery under general anesthesia at Kagawa University Hospital between January 2011 and June 2019 were reviewed. Differences between the first BP values measured on the day before surgery and the first BP values in the operating room were defined as Δ systolic BP (ΔSBP) and Δ diastolic BP (ΔDBP). The relationships between ΔSBP/ΔDBP and 30-day mortality, 30-day readmission, and over-the-standard length of hospital stay (OSLOS) were assessed. OSLOS was defined as a hospital stay longer than mean+2 standard deviations and was calculated using the Japanese Diagnosis Procedure Combination data. In univariate analysis, the differences in ΔSBP and ΔDBP between the OSLOS and standard LOS groups were both 2 mmHg. In multivariate logistic regression analysis, only ΔDBP was associated with OSLOS. The adjusted odds ratio (95% confidence interval) for the largest quartile was 1.31 (1.02-1.69) (p

Objective The usefulness of leucine-rich alpha 2 glycoprotein (LRG) to evaluate Crohn’s disease (CD) activity differs among various intestinal lesions. We aimed to evaluate the association between endoscopic disease activity based on the Simple Endoscopic Score for Crohn’s Disease (SES-CD) and LRG level separately for small intestinal and colonic lesions. Methods We examined the correlation between LRG level and SES-CD and performed receiver operating characteristic (ROC) analysis to determine the LRG cutoff value in 141 patients who underwent endoscopy (total 235 measurements). Furthermore, the LRG cutoff value was analyzed by comparing small intestinal and colonic lesions. Results LRG levels were significantly higher in patients without mucosal healing than in those with mucosal healing (15.9 μg/mL vs 10.5 μg/mL, P Conclusion The optimal LRG cutoff value for evaluating mucosal healing in CD is 14.3 μg/mL. LRG is more useful than CRP for predicting mucosal healing in patients with type L1. The superiority of LRG to CRP differs between small intestinal and colonic lesions.

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder characterized by an accumulation of glycosaminoglycans (GAGs), including heparan sulfate, in the body. Major manifestations involve the central nerve system (CNS), skeletal deformation, and visceral manifestations. About 30% of MPS II is linked with an attenuated type of disease subtype with visceral involvement. In contrast, 70% of MPS II is associated with a severe type of disease subtype with CNS manifestations that are caused by the human iduronate-2-sulfatase (IDS)-Pro86Leu (P86L) mutation, a common missense mutation in MPS II. In this study, we reported a novel Ids-P88L MPS II mouse model, an analogous mutation to human IDS-P86L. In this mouse model, a significant impairment of IDS enzyme activity in the blood with a short lifespan was observed. Consistently, the IDS enzyme activity of the body, as assessed in the liver, kidney, spleen, lung, and heart, was significantly impaired. Conversely, the level of GAG was elevated in the body. A putative biomarker with unestablished nature termed UA-HNAc(1S) (late retention time), one of two UA-HNAc(1S) species with late retention time on reversed-phase separation,is a recently reported MPS II-specific biomarker derived from heparan sulfate with uncharacterized mechanism. Thus, we asked whether this biomarker might be elevated in our mouse model. We found a significant accumulation of this biomarker in the liver, suggesting that hepatic formation could be predominant. Finally, to examine whether gene therapy could enhance IDS enzyme activity in this model, the efficacy of the nuclease-mediated genome correction system was tested. We found a marginal elevation of IDS enzyme activity in the treated group, raising the possibility that the effect of gene correction could be assessed in this mouse model. In conclusion, we established a novel Ids-P88L MPS II mouse model that consistently recapitulates the previously reported phenotype in several mouse models.

In most colorectal cancers, Wnt/β-catenin signaling is activated by loss-of-function mutations in the adenomatous polyposis coli (APC) gene and plays a critical role in tumorigenesis. Tankyrases poly(ADP-ribosyl)ate and destabilize Axins, a negative regulator of β-catenin, and upregulate β-catenin signaling. Tankyrase inhibitors downregulate β-catenin and are expected to be promising therapeutics for colorectal cancer. However, colorectal cancer cells are not always sensitive to tankyrase inhibitors, and predictive biomarkers for the drug sensitivity remain elusive. Here we demonstrate that the short-form APC mutations predict the sensitivity of colorectal cancer cells to tankyrase inhibitors. By using well-established colorectal cancer cell lines, we found that tankyrase inhibitors downregulated β-catenin in the drug-sensitive, but not resistant, colorectal cancer cells. The drug-sensitive cells showed higher Tcf/LEF transcriptional activity than the resistant cells and possessed “short” truncated APCs lacking all seven β-catenin-binding 20-amino acid repeats (20-AARs). In contrast, the drug-resistant cells possessed “long” APC retaining two or more 20-AARs. Knockdown of the long APCs with two 20-AARs increased β-catenin, Tcf/LEF transcriptional activity and its target gene AXIN2 expression. Under these conditions, tankyrase inhibitors were able to downregulate β-catenin in the resistant cells. These results indicate that the long APCs are hypomorphic mutants, whereas they exert a dominant-negative effect on Axin-dependent β-catenin degradation caused by tankyrase inhibitors. Finally, we established 16 patient-derived colorectal cancer cells and confirmed that the tankyrase inhibitor–responsive cells harbor the short-form APC mutations. These observations exemplify the predictive importance of APC mutations, the most common genetic alteration in colorectal cancers, for molecular targeted therapeutics. Mol Cancer Ther; 16(4); 752–62. ©2017 AACR.

Supplementary Material and Methods, Supplementary References, Supplementary Figure Legends

Supplementary Figure S1: Full scans of the immunoblots shown in Figs. 1C, 2A and 4A. Supplementary Figure S2: Basal expression of tankyrase, Axins, and β-catenin and intracellular localization of β-catenin in CRC cell lines used in this study. Supplementary Figure S3: Response of colorectal cancer SW480 cells to tankyrase inhibitors. Supplementary Figure S4: Depletion of long APC enhances β-catenin signaling and restores tankyrase inhibitor-mediated downregulation of the signal. Supplementary Figure S5: Long but not short APC represses Wnt/β-catenin signal and its knockdown sensitizes β-catenin to tankyrase inhibitor-mediated downregulation. Supplementary Figure S6: Schematic models for the differential effects of the "short" and "long" APC mutants on tankyrase inhibitor (TNKSi)-mediated downregulation of β-catenin. Supplementary Figure S7: APC mutations and sensitivity to tankyrase inhibitors of the patient-derived CRC cells. Supplementary Figure S8: Effects of a tankyrase inhibitor G007-LK on colony formation and β-catenin knockdown on proliferation of patient-derived CRC cells (PDCs).

Legends for Supplementary Figure S1-S8

Multiple regression analysis of tankyrase inhibitor sensitivities and genetic mutations in colorectal cancer cell lines

Supplementary Figure 1 shows morphology, growth and plasticity of the CD44-positive and -negative COLO-320DM cells. Supplementary Figure 2 shows that tankyrase inhibitors preferentially target CD44-positive COLO-320DM cells. Supplementary Figure 3 shows that tankyrase inhibitors decrease the CD44-positive cell populations in colorectal cancer cells. Supplementary Figure 4 shows that tankyrase inhibitors upregulate AMOTL1 to comparable levels in CD44-positive and -negative COLO-320DM cells. Supplementary Figure 5 shows c-KIT expression in colorectal cancer cell lines. Supplementary Figure 6 shows that c-KIT depletion inhibits proliferation of CD44-positive COLO-320DM cells. Supplementary Figure 7 shows difficulties in detecting c-KIT phosphorylation in colorectal cancer cells under the normal growth conditions. Supplementary Figure 8 shows c-KIT phosphorylation induced by stem cell factor in CD44-positive COLO-320DM cells and its downregulation by tankyrase inhibitors. Supplementary Figure 9 shows that c-KIT overexpression strengthens resistance of DLD-1 cells to tankyrase inhibitors. Supplementary Figure 10 shows that G007-LK does not significantly destabilize c-KIT protein in COLO-320DM cells. Supplementary Figure 11 shows negative effect of imatinib on CD44-positive cell populations in COLO-320DM and DLD-1 cells. Supplementary Figure 12 shows that AXIN2 knockdown blocks c-KIT downregulation in G007-LK-treated colorectal cancer cells. Supplementary Figure 13 shows that G007-LK does not affect the stability of c-KIT mRNA in COLO-320DM and DLD-1 cells. Supplementary Figure 14 shows that tankyrase inhibitors downregulate c-KIT promoter activity in an AXIN2-dependent manner in DLD-1 cells. Supplementary Figure 15 shows that tankyrase inhibitors do not significantly downregulate SP1 protein levels in COLO-320DM and DLD-1 cells. Supplementary Figure 16 shows that tankyrase inhibitors downregulate JNK phosphorylation levels in CD44-positive COLO-320DM cells. Supplementary Figure 17 shows that G007-LK upregulates AXIN2 and downregulates c-KIT in vivo. Supplementary Figure 18 shows that tankyrase inhibitors do not enhance the therapeutic efficacy of irinotecan on DLD-1 xenograft tumors in vivo.

IC50 values of colorectal cancer cell lines and colorectal cancer patient-derived cells

Supplementary Figure 1 shows analysis of TRIB1 expression in clinical prostate cancer specimens using Oncomine and cBioPortal database. Supplementary Figure 2 shows TRIB1 expression in prostate cancer cell lines and the effect of TRIB1 knockdown on the morphology of the prostate cancer cells. Supplementary Figure 3 shows TRIB1 knockdown in prostate cancer cell lines and the effect of TRIB1 overexpression on anchorage-independent cell growth. Supplementary Figure 4 shows that TRIB1 does not affect ERK phosphorylation or the C/EBP proteins. Supplementary Figure 5 shows subcellular localization of TRIB1, role of GRP78 in 2D and 3D cell survival, and regulation of GRP78 expression by TRIB1. Supplementary Figure 6 shows typical staining patterns of TRIB1 and the ER chaperone in human prostate cancer tissues. Supplementary Figure 7 shows analysis of the tumor-propagating cell population in patient-derived prostate cancer primary cultures.

OBJECTIVE: Circadian rhythm disruption is commonly observed in bipolar disorder (BD). Daylight is the most powerful signal to entrain the human circadian clock system. This exploratory study investigated if solar insolation at the onset location was associated with the polarity of the first episode of BD I. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area of the Earth.METHODS: Data from 7488 patients with BD I were collected at 75 sites in 42 countries. The first episode occurred at 591 onset locations in 67 countries at a wide range of latitudes in both hemispheres. Solar insolation values were obtained for every onset location, and the ratio of the minimum mean monthly insolation to the maximum mean monthly insolation was calculated. This ratio is largest near the equator (with little change in solar insolation over the year), and smallest near the poles (where winter insolation is very small compared to summer insolation). This ratio also applies to tropical locations which may have a cloudy wet and clear dry season, rather than winter and summer.RESULTS: The larger the change in solar insolation throughout the year (smaller the ratio between the minimum monthly and maximum monthly values), the greater the likelihood the first episode polarity was depression. Other associated variables were being female and increasing percentage of gross domestic product spent on country health expenditures. (All coefficients: P ≤ 0.001).CONCLUSION: Increased awareness and research into circadian dysfunction throughout the course of BD is warranted.

The purpose of this study was to examine the effect of pemafibrate (PEM) in primary biliary cholangitis (PBC) patients with dyslipidemia.Patients who were diagnosed with PBC between June 2018 and December 31, 2020 were included in the study if they also had dyslipidemia and their alkaline phosphatase (ALP) or gamma-glutamyl transferase (GGT) levels remained above the normal range despite taking 600 mg/day ursodeoxycholic acid (UDCA) for at least 6 months. Patients who were treated with UDCA alone were administered PEM as an add-on (PEM-add group), and patients who were treated with UDCA and bezafibrate (BEZ) for at least 6 months were given PEM instead of BEZ (PEM-switch group). Clinical parameters were compared in all patients, and the levels of ALP, GGT, the estimated glomerular filtration rate (eGFR), and creatinine (Cr) were compared between the PEM-add and PEM-switch groups. Improvement in cholangitis was also evaluated.In the PEM-add group, both ALP and GGT improved in 40 of 46 patients (87.0%). In the PEM-switch group, both ALP and GGT improved in 15 of 29 patients (51.7%). In the PEM-switch group, however, significant improvement was seen in eGFR and Cr.Administration of PEM is effective in PBC patients with dyslipidemia who are refractory to UDCA monotherapy. In patients using both UDCA and BEZ, there was an advantage in switching to PEM if they had renal damage; however, improvement of ALP and GGT occurred in about 50%.

Hitomi Kashima, Satohiro Matsumoto, Shu Kojima, Yudai Koito, Takaya Miura, Takehiro Ishii, Hirosato Mashima Department of Gastroenterology, Jichi Medical University Saitama Medical Center, Saitama, JapanCorrespondence: Satohiro MatsumotoDepartment of Gastroenterology, Jichi Medical University Saitama Medical Center, 1-847 Amanuma, Omiya, Saitama, Saitama, 330-8503, Japan, Tel +81 48 647 2111, Fax +81 48 648 5188, Email s.w.himananon@ac.auone-net.jpAbstract: A 55-year-old man presented with recurrent ulcers and an enterocutaneous fistula at the anastomotic site after surgery for an ileovesical fistula and was diagnosed with intestinal Behçet’s disease after undergoing surgery for enterocutaneous fistulae twice. The patient was transferred to our hospital because of recurrent enterocutaneous fistulae. He had a history of recurrent oral aphthous ulcers, folliculitis, and epididymitis and met the diagnostic/classification criteria for incomplete Behçet’s disease and thus was diagnosed as having intestinal Behçet’s disease. Remission induction therapy with steroids was administered for an ileal ulcer and an enterocutaneous fistula, and adalimumab was initiated for maintenance therapy. The fistula was closed, and the clinical course was favorable. Two months after initiating adalimumab, a subcutaneous abscess was detected at the site of the enterocutaneous fistula scar, and relapse of intestinal Behçet’s disease was suspected. Steroids were re-administered for remission induction, followed by maintenance therapy, for which adalimumab was switched to infliximab. No relapse was detected after steroid withdrawal. No therapeutic strategies have been established for intestinal Behçet’s disease. Moreover, there have been very few reports on therapeutic strategies and postoperative maintenance therapy for enterocutaneous fistulae. We thus consider this case valuable.Keywords: intestinal Behçet’s disease, adalimumab, infliximab, enterocutaneous fistulae

Programmable Logic Controllers (PLCs) are essential components for enabling remote monitoring and automated control in industrial control systems. Recently PLCs are often utilized in a modernized power grid system for implementing an additional layer of automated control, such as operation of circuit breakers under specific conditions. Thus, in order to create a software-based smart grid testbed (or ‘cyber range’ for cyber security experiments); emulation of the PLC is imperative. OpenPLC is a software widely used for emulating PLCs, but unfortunately it does not support IEC 61850 standard, which is the globally adopted standard for substation automation in smart power grid systems. Thus, in this paper, the enhancement of OpenPLC to support IEC 61850 protocol and information models is discussed. The performance of the implementation has been validated to corroborate its application for use cases in the smart grid paradigm. Subsequently, the implementation is demonstrated in a smart grid cyber range to evaluate the impacts of attacks and thereby, the effectiveness of security measures and robustness of PLC control logic. The implementation, named ‘OpenPLC61850’, is made available as an open-source project for the wider research and industry community.

Amyloid fibril formation of cytochrome c is spatially and temporally controlled by the optical trapping method, identifying that the structural change in the region containing Ala83 is essential for the amyloid fibril formation.

Climate change is increasing the frequency and the intensity of weather events, leading to large-scale disruptions to critical infrastructure systems. The high level of interdependence among these systems further aggravates the extent of disruptions. To mitigate these impacts, models and methods are needed to support rapid decision-making for optimal resource allocation in the aftermath of a disruption and to substantiate investment decisions for the structural reconfiguration of these systems. In this paper, we leverage infrastructure simulation models and Machine Learning (ML) algorithms to develop resilience prediction models. First, we employ an interdependent infrastructure simulation model to generate infrastructure disruption and recovery scenarios and compute the resilience value for each scenario. The infrastructure-, disruption-, and recovery-related attributes are recorded for each scenario and ML algorithms are employed on the synthetic dataset to develop accurate resilience prediction models. The results of the prediction models are analyzed and possible design strategies suggested based on the resilience enhancement attributes. The proposed methodology can support infrastructure agencies in the resource-allocation process for pre- and post-disaster interventions., IEEE Access, 10, ISSN:2169-3536

Chromium-catalyzed olefination of arylaldehydes with haloforms was achieved using 2,3,5,6-tetramethyl

In recent years, endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) has been performed as an important salvage option for failed endoscopic retrograde cholangiopancreatography for biliary drainage. However, technical issues, such as puncture site (bile duct of segment 3 [B3] or bile duct of segment 2 [B2]), dilation method, stent selection, and procedural safety, need to be resolved for the optimization of EUS-HGS. The present study was to compare the safety, difficulty, and technical and functional success between biliary access via B2 and B3 during EUS-HGS.We conducted a retrospective investigation of 161 consecutive EUS-HGS cases across a total of 6 facilities, including those at our hospital. The patients were divided into two groups according to the successful drainage route: the puncture to B2 (P-B2) or the puncture to B3 (P-B3). We compared the technical and functional success rates, technical difficulty, and adverse events between the two groups. We also conducted a subgroup analysis to show the factors related to the procedure time.There were 92 cases in the P-B2 group and 69 cases in the P-B3 group. There were no significant differences in the technical success, functional success, or adverse events between the groups; however, the procedure time was significantly shorter in P-B2 cases than in P-B3 cases. The multivariate analysis showed that the puncture site was the only factor related to the procedure time.Based on these findings, P-B2 appears useful and safe. P-B2 is as effective as P-B3 and was able to be performed in a shorter period of time. The B2 approach can be considered a useful option for EUS-HGS.

Electrical substations are becoming more prone to cyber-attacks due to increasing digitalization. Prevailing defense measures based on cyber rules are often inadequate to detect attacks that use legitimate-looking measurements. In this work, we design and implement a bad data detection solution for electrical substations called ResiGate, that effectively combines a physics-based approach and a machine-learning-based approach to provide substantial speed-up in high-throughput substation communication scenarios, while still maintaining high detection accuracy and confidence. While many existing physics-based schemes are designed for deployment in control centers (due to their high computational requirement), ResiGate is designed as a security appliance that can be deployed on low-cost industrial computers at the edge of the smart grid so that it can detect local substation-level attacks in a timely manner. A key challenge for this is to continuously run the computationally demanding physics-based analysis to monitor the measurement data frequently transmitted in a typical substation. To provide high throughput without sacrificing accuracy, ResiGate uses machine learning to effectively filter out most of the non-suspicious (normal) data and thereby reducing the overall computational load, allowing efficient performance even with a high volume of network traffic. We implement ResiGate on a low-cost industrial computer and our experiments confirm that ResiGate can detect attacks with zero error while sustaining a high throughput.

Cyber-physical systems (CPSs) are monitored and controlled by a computing andcommunicating core. This cyber layer enables better management of the controlledsubsystem, but it also introduces threats to the security and protection of CPSs, asdemonstrated by recent cyberattacks. The resulting governance and policy emphasison cybersecurity is reflected in the academia by a vast body of literature. In this arti-cle, we systematize existing knowledge on CPS analysis. Specifically, we focus onthe quantitative assessment of CPSs before and after the occurrence of a disruption.Through the systematic analysis of the models and methods adopted in the literature,we develop a CPS resilience assessment framework consisting of three steps, namely,(1) CPS description, (2) disruption scenario identification, and (3) resilience strategyselection. For each step of the framework, we suggest established methods for CPSanalysis and suggest four criteria for method selection. The framework proposes a stan-dardized workflow to assess the resilience of CPSs before and after the occurrence of adisruption. The application of the proposed framework is exemplified with reference toa power substation and associated communication network.The case study shows thatthe proposed framework supports resilience decision making by quantifying the effectsof the implementation of resilience strategies., Risk Analysis, ISSN:0272-4332, ISSN:1539-6924

Intravascular large B-cell lymphoma (IVLBCL) is a subtype of B-cell lymphoma, characterized by lymphoma cell proliferation within small blood vessels. We herein describe a rare case with long spinal cord lesions caused by venous congestive myelopathy associated with IVLBCL. An 81-year-old man presented with paraplegia of the lower limbs and sensory disturbances. Magnetic resonance imaging revealed intramedullary longitudinal T2-hyperintensity lesions in the thoracic cords. The patient died three months after disease onset, and a neuropathological analysis revealed predominantly atypical B-lymphocytes located sparsely in the veins of the spinal cord. IVLBCL should be considered in the differential diagnoses of long spinal cord lesions.

Nucleic acid aptamers are innovative and promising candidates to block the hallmark event in the prion diseases, that is the conversion of prion protein (PrP) into an abnormal form; however, they need chemical modifications for effective therapeutic activity. This communication reports on the development and biophysical characterization of a small library of chemically modified G-quadruplex-forming aptamers targeting the cellular PrP and the evaluation of their anti-prion activity. The results show the possibility of enhancing anti-prion aptamer properties through straightforward modifications.