Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis.

Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer1-3. However, how such cycles affect the clonal composition of tissues, particularly in terms of cancer development, remains unknown. Here we show that in patients with ulcerative colitis, the inflamed intestine undergoes widespread remodelling by pervasive clones, many of which are positively selected by acquiring mutations that commonly involve the NFKBIZ, TRAF3IP2, ZC3H12A, PIGR and HNRNPF genes and are implicated in the downregulation of IL-17 and other pro-inflammatory signals. Mutational profiles vary substantially between colitis-associated cancer and non-dysplastic tissues in ulcerative colitis, which indicates that there are distinct mechanisms of positive selection in both tissues. In particular, mutations in NFKBIZ are highly prevalent in the epithelium of patients with ulcerative colitis but rarely found in both sporadic and colitis-associated cancer, indicating that NFKBIZ-mutant cells are selected against during colorectal carcinogenesis. In further support of this negative selection, we found that tumour formation was significantly attenuated in Nfkbiz-mutant mice and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells. Our results highlight common and discrete mechanisms of clonal selection in inflammatory tissues, which reveal unexpected cancer vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer.

Anti-integrin αvß6 autoantibodies are a potential biomarker for ulcerative colitis-like immune checkpoint inhibitor-induced colitis.

BACKGROUND: No specific biomarker for immune checkpoint inhibitor (ICI)-induced colitis has been established. Previously, we identified anti-integrin αvß6 autoantibodies in >90% of patients with ulcerative colitis (UC). Given that a subset of ICI-induced colitis is similar to UC, we aimed to clarify the relationship between such autoantibodies and ICI-induced colitis. METHODS: Serum anti-integrin αvß6 autoantibody levels were compared between 26 patients with ICI-induced colitis and 157 controls. Endoscopic images of ICI-induced colitis were centrally reviewed. Characteristics of anti-integrin αvß6 autoantibodies in the ICI-induced colitis patients were compared with those of UC patients. RESULTS: Anti-integrin αvß6 autoantibodies were found in 8/26 (30.8%) patients with ICI-induced colitis and 3/157 (1.9%) controls (P < 0.001). Patients with anti-integrin αvß6 autoantibodies had significantly more typical UC endoscopic features than those without the autoantibodies (P < 0.001). Anti-integrin αvß6 autoantibodies in ICI-induced colitis patients were associated with grade ≥3 colitis (P = 0.001) and steroid resistance (P = 0.005). Anti-integrin αvß6 autoantibody titers correlated with ICI-induced colitis disease activity. Anti-integrin αvß6 autoantibodies of ICI-induced colitis exhibited similar characteristics to those of UC. CONCLUSIONS: Anti-integrin αvß6 autoantibodies may serve as potential biomarkers for the diagnosis, classification, risk management, and monitoring the disease activity, of ICI-induced colitis.

Designing a muon scattering scanner for nuclear debris measurement.

Removal of fuel debris is planned to start at Unit 2 of the Fukushima Daiichi Nuclear Power Plant. During the removal, it is desirable to distinguish fuel debris from radioactive wastes and to sort the fuel debris accordingly to the amounts of nuclear material contained. Muon scattering tomography invented at Los Alamos in the early 2000s is highly sensitivity to high-atomic-number materials such as uranium. A muon scanner to sort the debris is designed and currently in production. One of the challenges is to operate the muon scanner in the presence of high γ-ray radiations from the debris: muon-event-identification electronics and a muon-tracking algorithm in the presence of high γ-ray radiations were developed.

Genetic characterization of 1210 Japanese pedigrees with inherited retinal diseases by whole-exome sequencing.

Inherited retinal diseases (IRDs) comprise a phenotypically and genetically heterogeneous group of ocular disorders that cause visual loss via progressive retinal degeneration. Here, we report the genetic characterization of 1210 IRD pedigrees enrolled through the Japan Eye Genetic Consortium and analyzed by whole exome sequencing. The most common phenotype was retinitis pigmentosa (RP, 43%), followed by macular dystrophy/cone- or cone-rod dystrophy (MD/CORD, 13%). In total, 67 causal genes were identified in 37% (448/1210) of the pedigrees. The first and second most frequently mutated genes were EYS and RP1, associated primarily with autosomal recessive (ar) RP, and RP and arMD/CORD, respectively. Examinations of variant frequency in total and by phenotype showed high accountability of a frequent EYS missense variant (c.2528G>A). In addition to the two known EYS founder mutations (c.4957dupA and c.8805C>G) of arRP, we observed a frequent RP1 variant (c.5797C>T) in patients with arMD/CORD.

Identification of an Anti-Integrin αvß6 Autoantibody in Patients With Ulcerative Colitis.

BACKGROUND AND AIMS: Ulcerative colitis is the most frequent type of inflammatory bowel disease and is characterized by colonic epithelial cell damage. Although involvement of autoimmunity has been suggested in ulcerative colitis, specific autoantigens/antibodies have yet to be elucidated. METHODS: Using 23 recombinant integrin proteins, we performed enzyme-linked immunosorbent assays on sera from patients with ulcerative colitis and controls. Integrin expression and IgG binding in the colon tissues of patients with ulcerative colitis and controls were examined using immunofluorescence and coimmunoprecipitation, respectively. The blocking activity of autoantibodies was examined using solid-phase binding and cell adhesion assays. RESULTS: Screening revealed that patients with ulcerative colitis had IgG antibodies against integrin αvß6. In the training and validation groups, 103 of 112 (92.0%) patients with ulcerative colitis and only 8 of 155 (5.2%) controls had anti-integrin αvß6 antibodies (P < .001), resulting in a sensitivity of 92.0% and a specificity of 94.8% for diagnosing ulcerative colitis. Anti-integrin αvß6 antibody titers coincided with ulcerative colitis disease activity, and IgG1 was the major subclass. Patient IgG bound to the integrin αvß6 expressed on colonic epithelial cells. Moreover, IgG of patients with ulcerative colitis blocked integrin αvß6-fibronectin binding through an RGD (Arg-Gly-Asp) tripeptide motif and inhibited cell adhesion. CONCLUSIONS: A significant majority of patients with ulcerative colitis had autoantibodies against integrin αvß6, which may serve as a potential diagnostic biomarker with high sensitivity and specificity.

[Acute promyelocytic leukemia complicated with central nervous system involvement successfully treated with all-trans retinoic acid via nasogastric tube].

At initial diagnosis, central nervous system (CNS) involvement in acute promyelocytic leukemia (APL) is rare. Here, we report a case of newly diagnosed APL with CNS involvement that was successfully treated with all-trans retinoic acid (ATRA)-combined chemotherapy. A 64-year-old woman was referred to our hospital to evaluate a bleeding tendency, and she was diagnosed with APL. Induction chemotherapy with ATRA via a nasogastric tube was initiated under mechanical ventilation because of respiratory failure and disturbance of consciousness. Although her respiratory condition improved a few days after initiating treatment, the disturbance of consciousness remained. Brain magnetic resonance imaging showed mixed signals of tumor infiltration and acute cerebral infarction with a focus on the right cerebellum. The patient was diagnosed with CNS involvement of APL and acute cerebral infarction. Three months after the initiation of induction therapy, her consciousness improved along with the reduction in CNS involvement, and complete molecular remission was achieved. Thus, patients with APL can have CNS involvement at initial diagnosis. Administering ATRA via nasogastric tube can be a good therapeutic option in patients with difficulty swallowing due to disturbance of consciousness.

Sudden cardiac arrest associated with myxedema coma due to undiagnosed hypothyroidism: a case report.

BACKGROUND: Myxedema coma, which occurs due to hypothyroidism, is a rare and life-threatening condition. Some patients have hemodynamic dysfunction, which consequently leads to cardiac arrest. The rarity of this condition makes it difficult to determine the cause of cardiac arrest. It is important to diagnose myxedema coma based on clinical findings, including physical examination and laboratory parameters. We present a case of undiagnosed and untreated hypothyroidism that initially caused myxedema coma and then led to cardiac arrest. CASE PRESENTATION: A 56-year-old woman who had no medical history was transferred to our hospital for the management of return of spontaneous circulation due to sudden cardiac arrest. Findings of laboratory tests revealed that she had hypothyroidism. On physical examination, she was found to have a puffy face, thin eyebrows, and severe systemic non-pitting edema. Therefore, the patient was clinically diagnosed with myxedema coma, which was the cause of cardiac arrest. She was treated with thyroid hormone and hydrocortisone, resulting in improvement in her general condition, except for the neurological dysfunction. CONCLUSIONS: This case suggests that myxedema coma is caused by undiagnosed and untreated hypothyroidism, leading to sudden cardiac arrest. Our findings are useful in the differential diagnosis of hypothyroidism based on characteristic physical examination findings. Clinicians should be aware of the differential diagnosis of myxedema coma based on findings from physical examination and laboratory testing of thyroid function, and the treatment should be started immediately.

Theory and Algorithms for Shapelet-Based Multiple-Instance Learning.

We propose a new formulation of multiple-instance learning (MIL), in which a unit of data consists of a set of instances called a bag. The goal is to find a good classifier of bags based on the similarity with a "shapelet" (or pattern), where the similarity of a bag with a shapelet is the maximum similarity of instances in the bag. In previous work, some of the training instances have been chosen as shapelets with no theoretical justification. In our formulation, we use all possible, and thus infinitely many, shapelets, resulting in a richer class of classifiers. We show that the formulation is tractable, that is, it can be reduced through linear programming boosting (LPBoost) to difference of convex (DC) programs of finite (actually polynomial) size. Our theoretical result also gives justification to the heuristics of some previous work. The time complexity of the proposed algorithm highly depends on the size of the set of all instances in the training sample. To apply to the data containing a large number of instances, we also propose a heuristic option of the algorithm without the loss of the theoretical guarantee. Our empirical study demonstrates that our algorithm uniformly works for shapelet learning tasks on time-series classification and various MIL tasks with comparable accuracy to the existing methods. Moreover, we show that the proposed heuristics allow us to achieve the result in reasonable computational time.

Association of follicular fluid volume with membrane stretchability of human metaphase II oocytes following the gonadotropin-releasing hormone agonist protocol during intracytoplasmic sperm injection.

PURPOSE: The authors previously revealed the association of the follicular fluid (FF) volume with oolemma stretchability following the gonadotropin-releasing hormone (GnRH) antagonist protocol during intracytoplasmic sperm injection (ICSI). However, the impact of the GnRH agonist protocol on oolemma stretchability remains unclear. METHODS: Data that were obtained from 74 ICSI cycles were reviewed retrospectively. Controlled ovarian stimulation was performed in accordance with the short GnRH agonist protocol. Each follicle was individually aspirated and assigned to one of six groups, according to the FF volume. The oolemma stretchability during ICSI was evaluated by using a mechanical stimulus for oolemma penetration; that is, oolemma penetration with or without aspiration (high vs low stretchability, respectively). RESULTS: The incidence of low oolemma stretchability was significantly higher in the <1.0 mL group than that in the ≥1.0 mL group. The normal fertilization rate was significantly lower in the <1.0 mL group than that in the 2.0-<3.0 mL group. The rate of blastocyst development was lower in the <1.0 mL group than that in the 3.0-<4.0 mL group. CONCLUSION: The FF volume potentially was associated with metaphase II oolemma stretchability, fertilization, and blastocyst development.

Brassinolide-like activity of castasterone analogs with varied side chains against rice lamina inclination.

Brassinolide (BL) and castasterone (CS) are the representative members of brassinosteroid class of plant steroid hormone having plant growth promoting activity. In this study, eleven CS analogs bearing a variety of side chains were synthesized to determine the effect of the side chain structures on the BL-like activity. The plant hormonal activity was evaluated in a dwarf rice lamina inclination assay, and the potency was determined as the reciprocal logarithm of the 50% effective dose (ED50) from each dose-response curve. The reciprocal logarithm of ED50 (pED50) was decreased dramatically upon deletion of the C-28 methyl group of CS. The introduction of oxygen-containing groups such as hydroxy, methoxy, and ethoxycarbonyl was also unfavorable to the activity. The pED50 was influenced by the geometry of carbon-carbon double bond between C-24 and C-25 (cis and trans), but the introduction of a fluorine atom at the C-25 position of the double bond did not significantly change the activity. The binding free energy (ΔG) was calculated for all ligand-receptor binding interactions using molecular dynamics, resulting that ΔG is linearly correlated with the pED50.

Discovery of 3-Chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4-yl)phenyl][(2S)-piperidine-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide as a Potent Glycine Transporter 1 Inhibitor.

A novel glycine transporter 1 (GlyT1) inhibitor was designed by the superposition of different chemotypes to enhance its inhibitory activity. Starting from 2-chloro-N-{(S)-phenyl[(2S)-piperidin-2-yl]methyl}-3-(trifluoromethyl)benzamide (2, SSR504734), the introduction of heteroaromatic rings enabled an increase in the GlyT1 inhibitory activity. Subsequent optimization led to the identification of 3-chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4-yl)phenyl][(2S)-piperidine-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide (7w), which showed a powerful GlyT1 inhibitory activity (IC50=1.8 nM), good plasma exposure and a plasma to brain penetration in rats that was sufficient to evaluate the compound's pharmacological properties. Compound 7w showed significant effects in several rodent models for schizophrenia without causing any undesirable central nervous system side effects.

Identification of 1-Methyl-N-(propan-2-yl)-N-({2-[4-(trifluoromethoxy)phenyl]pyridin-4-yl}methyl)-1H-imidazole-4-carboxamide as a Potent and Orally Available Glycine Transporter 1 Inhibitor.

We previously identified 3-chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4-yl)phenyl][(2S)-piperidine-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide (5, TP0439150) as a potent and orally available glycine transporter 1 (GlyT1) inhibitor. In this article, we describe our identification of 1-methyl-N-(propan-2-yl)-N-({2-[4-(trifluoromethoxy)phenyl]pyridin-4-yl}methyl)-1H-imidazole-4-carboxamide (7n) as a structurally diverse back-up compound of 5, using central nervous system multiparameter optimization (CNS MPO) as a drug-likeness guideline. Compound 7n showed a higher CNS MPO score and different physicochemical properties as compared to 5. Compound 7n exhibited potent GlyT1 inhibitory activity, a favorable pharmacokinetics profile, and elicited an increase in the cerebrospinal fluid (CSF) concentration of glycine in rats.