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Previously, we reported the new pyrido-pyridazinone template as a feline sarcoma-related (FER) tyrosine kinase inhibitor. Representative compound 1 ( DS21360717 ) showed strong enzyme inhibitory activity (IC50 = 0.5 nM), however, its antitumor effect was insufficient, probably due to poor solubility and resultant low bioavailability (BA). In addition, the kinase selectivity was inadequate, which may result in certain safety risks. Here, we focused on derivatization of the unoptimized C-5 position to obtain promising FER inhibitors possessing strong antitumor effects and improved selectivity, referring to their X-ray crystal structure and the docking model with FES proto-oncogene tyrosine kinase as an FER surrogate. While establishing the synthetic route of the pyrido-pyridazinone scaffold, we obtained a desired compound via our derivatization. Our optimized compound 17c (DS08701581 ) showed the highest class cell-free and cell activities in this template, good oral BA, and improved kinase selectivity, resulting in significant tumor growth inhibition in the Ba/F3-FER tumor model without body weight loss., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Background: Advances in chemotherapy have increased clinical experience with conversion surgery for inoperable advanced gastric cancer. This report describes three patients with unresectable gastric cancer accompanied by multiple liver metastases. In all three patients, nivolumab resolved the liver metastases and subsequent conversion surgery achieved a pathological complete response., Case Presentation: In Case 1, a 68-year-old man with clinical Stage IVB gastric cancer and multiple liver metastases initiated first-line therapy with SOX plus nivolumab. The patient completed 13 cycles; however, only nivolumab was continued for 3 cycles because of adverse events. Distal gastrectomy and partial hepatic resection were performed because of a significant reduction in the size of the liver metastases as observed on magnetic resonance imaging (MRI). In Case 2, a 72-year-old man with clinical Stage IVB gastric cancer and multiple liver metastases initiated first-line therapy with SOX. Because of the subsequent emergence of new liver metastases, the patient transitioned to ramucirumab plus paclitaxel as second-line therapy. Third-line therapy with nivolumab was initiated because of side effects. MRI revealed necrosis within the liver metastasis, and the patient underwent proximal gastrectomy and partial hepatectomy. In Case 3, a 51-year-old woman with clinical Stage IVB gastric cancer accompanied by multiple metastases of the liver and para-aortic lymph nodes began first-line therapy with SOX plus nivolumab. The patient completed 10 cycles; however, only nivolumab was continued for 5 cycles because of adverse events. Computed tomography showed a significant decrease in the size of the para-aortic lymph nodes, while MRI indicated the presence of a singular liver metastasis. Distal gastrectomy and partial hepatic resection were subsequently performed. In all three cases, MRI revealed the presence of liver metastases; however, pathological examination showed no viable tumor cells., Conclusions: We herein present three cases in which chemotherapy, including nivolumab, elicited a response in patients with multiple unresectable liver metastases, ultimately culminating in R0 resection through conversion surgery. Although MRI showed liver metastases, pathological analysis revealed no cancer, underscoring the beneficial impact of chemotherapy., (© 2024. The Author(s).)

Background: L-ergothioneine (EGT), an antioxidative and anti-inflammatory amino acid, is abundant in various mushroom fruiting bodies. Meanwhile, the effects of EGT-containing mushrooms on human skin are unknown. This study investigated the effects of oral ingestion of a novel EGT-rich strain of Pleurotus species (hiratake) on skin conditions in humans., Methods: We conducted a 12-week, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate skin moisturizing functions and facial conditions in 80 healthy women who were randomly assigned to either a group that was supplemented with hiratake tablets containing 25 mg of EGT/day or a placebo group. Skin moisture content, transepidermal water loss (TEWL), and facial scores (VISIA scores) were measured at baseline, 8 weeks, and 12 weeks of supplementation., Results: At 8 weeks, the skin moisture content was significantly higher on the temple in the hiratake group than in the placebo group. The hiratake group also exhibited a significant increase in skin moisture content on the arm at 8 and 12 weeks compared with baseline. At 12 weeks, wrinkle and texture scores were significantly better in the hiratake group than in the placebo group, and plasma EGT concentrations in the hiratake group were 4.7-fold higher than baseline (from 3.4 to 15.9 μM). Furthermore, EGT concentrations in plasma were significantly correlated with improvements in skin moisture content and TEWL on the arm, implying that these skin moisturizing benefits could be partly attributed to EGT. A stratified analysis of participants with a low baseline plasma EGT concentration (< 3.3 μM) revealed that skin moisture content on the temple was significantly higher at 8 and 12 weeks, and skin moisture content on the arm at 12 weeks tended to be higher ( p = 0.074), in the hiratake group than in the placebo group. These findings suggested that oral ingestion of EGT-rich hiratake can improve skin moisturizing functions., Conclusion: EGT-rich hiratake may help maintain skin conditions in healthy women, and EGT may play a role in these beneficial effects., Competing Interests: MH, KM, JK were salaried employees of the Hokuto Corporation, which cultivated some of the mushrooms used in this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hanayama, Mori, Ishimoto, Kato and Kawai.)

Despite the development of various in vitro differentiation protocols for the efficient derivation of specific cell types, human induced pluripotent stem cell (hiPSC) lines have varing ability to differentiate into specific lineages. Therefore, surrogate markers for accurately predicting the differentiation propensity of hiPSC lines may facilitate cell-based therapeutic product development and manufacture. We attempted to identify marker genes that could predict the differentiation propensity of hiPSCs into neural stem/progenitor cells (NS/PCs). Using Spearman's rank correlation coefficients, we investigated genes in the undifferentiated state, the expression levels of which were significantly correlated with the neuronal differentiation propensity of several hiPSC lines. Among genes significantly correlated with NS/PC differentiation (P < 0.01), we identified ROR2 as a novel predictive marker. ROR2 expression in hiPSCs was negatively correlated with NS/PC differentiation tendency, regardless of the differentiation method, whereas its knockdown enhanced differentiation. ROR2 regulates NS/PC differentiation, suggesting that ROR2 is functionally essential for NS/PC differentiation. Selecting cell lines with relatively low ROR2 expression facilitated identification of hiPSCs that can differentiate into NS/PCs. Cells with ROR2 knockdown showed increased efficiency of differentiation into forebrain GABAergic neurons compared to controls. These findings suggest that ROR2 is a surrogate marker for selecting hiPSC lines appropriate for NS/PC and GABAergic neuronal differentiations., (© 2024. The Author(s).)

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Introduction: Cytokine release syndrome (CRS) is a life-threatening side effect of chimeric antigen receptor T (CAR-T) cell therapy. This study investigated whether serum inorganic phosphate (IP) and magnesium (Mg) levels are predictive markers of CRS development., Methods: This single-center retrospective cohort study enrolled 16 consecutive patients with diffuse large B-cell lymphoma who had received CAR-T cell therapy. Logistic regression models with generalized estimating equations were used to evaluate whether changes in IP and Mg levels from their baseline values were associated with the development of CRS within 48 hours., Results: Decreased IP and Mg levels from baseline (per 10% change) were associated with an increased CRS incidence (adjusted odds ratio 2.18 [95% confidence interval (CI), 1.31-3.62], 3.18 [95% CI, 1.57-6.44], respectively)., Conclusions: Changes in IP and Mg concentrations within 48 hours may be useful predictive markers of CRS onset., Competing Interests: The authors declare no conflict of interest. Disclosure forms provided by the authors are available on the website., (Copyright Ⓒ2023 Asia-Pacific Blood and Marrow Transplantation Group (APBMT).)

Competing Interests: Takeshi Ogura is an Editorial Board Member of the journal. This article was subject to the journal's standard procedures, with peer review handled independently of the editor and his research group.

Human multipotent mesenchymal stromal/stem cells (MSCs) have been utilized in cell therapy for various diseases and their clinical applications are expected to increase in the future. However, the variation in MSC-based product quality due to the MSC heterogeneity has resulted in significant constraints in the clinical utility of MSCs. Therefore, we hypothesized that it might be important to identify and ensure/enrich suitable cell subpopulations for therapies using MSC-based products. In this study, we aimed to identify functional cell subpopulations to predict the efficacy of angiogenic therapy using bone marrow-derived MSCs (BM-MSCs). To assess its angiogenic potency, we observed various levels of vascular endothelial growth factor (VEGF) secretion among 11 donor-derived BM-MSC lines under in vitro ischemic culture conditions. Next, by clarifying the heterogeneity of BM-MSCs using single-cell RNA-sequencing analysis, we identified a functional cell subpopulation that contributed to the overall VEGF production in BM-MSC lines under ischemic conditions. We also found that leucine-rich repeat-containing 75A (LRRC75A) was more highly expressed in this cell subpopulation than in the others. Importantly, knockdown of LRRC75A using small interfering RNA resulted in significant inhibition of VEGF secretion in ischemic BM-MSCs, indicating that LRRC75A regulates VEGF secretion under ischemic conditions. Therefore, LRRC75A may be a useful biomarker to identify cell subpopulations that contribute to the angiogenic effects of BM-MSCs. Our work provides evidence that a strategy based on single-cell transcriptome profiles is effective for identifying functional cell subpopulations in heterogeneous MSC-based products., (© The Author(s) 2023. Published by Oxford University Press.)

The Closterium peracerosum-strigosum-littorale complex (Closterium, Zygnematophyceae) has an isogamous mating system. Members of the Zygnematophyceae are the closest relatives to extant land plants and are distantly related to chlorophytic models, for which a genetic basis of mating type (MT) determination has been reported. We thus investigated MT determination in Closterium. We sequenced genomes representing the two MTs, mt+ and mt-, in Closterium and identified CpMinus1, a gene linked to the mt- phenotype. We analyzed its function using reverse genetics methods. CpMinus1 encodes a divergent RWP-RK domain-containing-like transcription factor and is specifically expressed during gamete differentiation. Introduction of CpMinus1 into an mt+ strain was sufficient to convert it to a phenotypically mt- strain, while CpMinus1-knockout mt- strains were phenotypically mt+. We propose that CpMinus1 is the major MT determinant that acts by evoking the mt- phenotype and suppressing the mt+ phenotype in heterothallic Closterium. CpMinus1 likely evolved independently in the Zygnematophyceae lineage, which lost an egg-sperm anisogamous mating system. mt- specific regions possibly constitute an MT locus flanked by common sequences that undergo some recombination., (© 2023 The Authors New Phytologist © 2023 New Phytologist Foundation.)

Background: Mushrooms are rich in dietary fiber, and fiber intake has been reported to increase the levels of short-chain fatty acids (SCFAs). It has also been reported that SCFAs promote immunoglobulin A (IgA) production, indicating involvement in systemic immunity., Objectives: The objective of this study was to evaluate the effects of mushroom consumption on the amount of intestinal IgA. We also aimed to comprehensively evaluate the gut microbiota and intestinal metabolome and to conduct an exploratory analysis of their relationship with IgA., Methods: Healthy adults ( n = 80) were enrolled in a parallel group trial. Participants consumed a diet with mushrooms or a placebo diet once daily for 4 weeks. Gut microbiota profiles were assessed by sequencing the bacterial 16S ribosomal RNA-encoding gene. Intestinal metabolome profiles were analyzed using capillary electrophoresis-time of flight mass spectrometry (CE-TOFMS)., Results: Mushroom consumption tended to increase IgA levels at 4 weeks of consumption compared to those in the control group ( p = 0.0807; Hedges' g = 0.480). The mushroom group had significantly higher levels of intestinal SCFAs, such as butyrate and propionate, than the control group ( p = 0.001 and 0.020; Hedges' g = 0.824 and 0.474, respectively). Correlation analysis between the changes in the amount of intestinal IgA and the baseline features of the intestinal environment showed that the increasing amount of intestinal IgA was positively correlated with the baseline levels of SCFAs (Spearman's R = 0.559 and 0.419 for butyrate and propionate, respectively)., Conclusion: Consumption of mushrooms significantly increased the intestinal SCFAs and IgA in some subjects. The increase in intestinal IgA levels was more prominent in subjects with higher SCFA levels at baseline. This finding provides evidence that mushroom alters the intestinal environment, but the intensity of the effect still depends on the baseline intestinal environment. This trial was registered at www.umin.ac.jp as UMIN000043979., Competing Interests: YN, TH, KK, and TK were employees of Metagen Inc. JK and KM were employees of HOKUTO Inc. SF was founder of Metagen Inc., (Copyright © 2023 Nishimoto, Kawai, Mori, Hartanto, Komatsu, Kudo and Fukuda.)

Competing Interests: None

Edible mushrooms are known to exert anti-inflammatory effects. In this study, the effects of ethanol extracts from edible mushrooms, such as Hericium erinaceus, and other edible mushrooms on inflammatory responses were investigated. Experiments were conducted using the inflammatory responses of human monocytes induced by lipopolysaccharide (LPS), a bacterial component, that provokes inflammation. Notably, we demonstrated that LPS mixed with ethanol and hot water extracts derived from edible mushrooms attenuated the production of inflammatory cytokines, such as interleukin (IL)-1β, -6, and -8, induced by LPS in human monocytic cell cultures. Moreover, we found that the ethanol extract of H. erinaceus contained ergosterol, which attenuated IL-8 production in LPS-stimulated cells. Subsequent component analysis of the ethanol extract of H. erinaceus revealed that ergosterol binds to lipid A to attenuate LPS-induced inflammation. Together, our findings suggest that ergosterol in ethanol extracts from edible mushrooms can prevent the induction of inflammation by binding to LPS., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hiroyuki Tada reports financial support was provided by Hokuto Foundation for Biological Sciences., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Aim: Bilateral stent deployment for malignant biliary obstruction (MHBO) can be achieved using side-by-side (SBS) or stent-in-stent (SIS) procedures. Compared with SBS techniques, the procedural steps of SIS are technically complex due to the necessity of introducing the delivery system into a contralateral biliary tract through the mesh of the SEMS. To overcome this issue, a novel uncovered SEMS, the HILZO Moving Cell Stent (MCS) has been released. The present study examined the technical feasibility of treating MHBO using bilateral deployment of this novel stent without dilating the mesh of the first stent to achieve insertion of the second stent within a single session, using a prospective, multicenter setting., Method: The primary outcome in the present study was the technical success rate. Technical success was defined as deployment of bilateral MCSs into two or more biliary tracts using SIS without a dilation device in a single-session., Results: A total of 27 patients with complications of MHBO were enrolled in this study. Bilateral SIS using two MCS was successfully performed in 23 patients without using dilation devices among 27 patients (initial technical success rate; 85.2%). Median time to recurrent biliary obstruction (TRBO) was 271 days. Stent dysfunction was observed in 12 patients (44.4%), and re-intervention was successfully performed in all patients without one patient who instead received best supportive care., Conclusions: The SIS technique using MCS without dilation of the mesh may be technically feasible and safe. In addition, this may be useful for re-intervention. Further comparative randomized trials are needed., (© 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Competing Interests: The authors declare that they have no conflict of interest.

A novel neutral diradical of π-extended phenalenyl derivative having three oxo-groups, tri-tert-butyl-1,4,7-trioxophenalenyl, and two types of the corresponding σ-dimers were investigated. Quantum chemical calculations showed that the neutral diradical is in triplet ground state having doubly degenerate singly occupied molecular orbitals. The neutral diradical undergoes a σ-dimerization, generating two types of σ-dimers immediately after the preparation. One of the σ-dimers, which was selectively generated in the crystalline state, was a close-shell dimer linked through double-σ-bonds on the phenalenyl skeleton with a long C-C bond length of 1.66 Å. The other σ-dimer, which existed only in the solution state, was a peroxy-linked open-shell dimer in which one σ-bond was formed between two oxygen atoms. Furthermore, the temperature-dependent 1 H NMR and ESR spectra revealed that these σ-dimers are in equilibrium in the solution state by the reversible σ-bond formation/cleavage via the neutral diradical as a key intermediate., (© 2022 Wiley-VCH GmbH.)

Competing Interests: The authors declare that they have no conflict of interest.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, in December 2019. Despite the recent introduction of vaccines against SARS-CoV-2, more effective vaccines and antiviral drugs must be developed. Here, we isolated five SARS-CoV-2 strains from four patients with coronavirus disease (COVID-19) and an asymptomatic individual using pharyngeal swabs, nasopharyngeal swabs, and sputum samples. Cytopathic effects in inoculated Vero cells were observed between days 3 and 7. SARS-CoV-2 infection was confirmed by quantitative reverse-transcription polymerase chain reaction (RT-qPCR) and next-generation sequencing. Phylogenetic analyses of the whole genome sequences showed that the virus isolates from the clinical samples belonged to the Wuhan and European lineages. These findings and the isolated viruses may contribute to the development of diagnostic tools, vaccines, and antiviral drugs for COVID-19.

Tri- tert -butylated 4,7-dihydroxyphenalenone was designed and synthesized from a corresponding 4,9-dimethoxyphenalenone derivative by regioselective deoxygenation/oxygenation. The 4,7-dihydroxyphenalenone derivative showed a chromic behavior accompanied by protonation and deprotonation, giving monocation and dianion species, respectively, and their C 3 symmetric electronic structures were elucidated by experimental and theoretical methods.

The zygnematophycean algae occupy an important phylogenetic position as the closest living relatives of land plants. Reverse genetics is quite useful for dissecting the functions of genes. However, this strategy requires genetic transformation, and there are only a few reports of successful transformation in zygnematophycean algae. Here, we established a simple and highly efficient transformation technique for the unicellular zygnematophycean alga Closterium peracerosum-strigosum-littorale complex using a square electric pulse-generating electroporator without the need for cell wall removal. Using this method, the transformation efficiency increased > 100-fold compared with our previous study using particle bombardment. We also succeeded in performing CRISPR/Cas9-based gene knockout using this new method. Our method requires only small amounts of labor, time and incubator space. Moreover, our technique could also be utilized to transform other charophycean algae with available genome information by optimizing the electric pulse conditions., (© 2021 The Authors. New Phytologist © 2021 New Phytologist Foundation.)

Recently, endoscopic ultrasound (EUS)-guided biliary drainage has been developed as an alternative biliary drainage technique for failed endoscopic retrograde cholangiopancreatography (ERCP) or inaccessible papilla. Among the various EUS-guided biliary drainage procedures, EUS-guided hepaticogastrostomy (HGS) can be performed in patients with surgically altered anatomy. More recently, various transluminal treatments have been described after EUS-HGS, such as antegrade stone removal. In patients with hepaticojejunostomy strictures, stone extraction into the intestine might be challenging even after performing hepaticojejunostomy stricture dilation using a balloon catheter. In such cases, transluminal stone removal is considered an alternative method. With transluminal stone removal, a small stone that escapes from the conventional basket or from a balloon catheter could migrate into the branch bile ducts. The novel spiral basket catheter available in Japan. The wires form a helix shape, wherein each wire is wound counterclockwise, and the winding pitch becomes gradually tighter from the proximal portion to the tip. As the winding pitch is smaller and the wires are in closer contact with the bile duct wall as compared with conventional basket catheter, small bile duct stones can be easily captured by simply pulling back the catheter while the basket is open. In addition, even during withdrawal inside the bile duct, a high retrieval performance is assured by the special design that maintains the opening width on the top end. Therefore, transluminal stone removal using this novel basket catheter might be clinically useful, although further prospective evaluation of a larger number of cases is needed., (© 2021 Japan Gastroenterological Endoscopy Society.)

Patients with triple-negative breast cancer have a poor prognosis as only a few efficient targeted therapies are available. Cancer cells are characterized by their unregulated proliferation and require large amounts of nucleotides to replicate their DNA. One-carbon metabolism contributes to purine and pyrimidine nucleotide synthesis by supplying one carbon atom. Although mitochondrial one-carbon metabolism has recently been focused on as an important target for cancer treatment, few specific inhibitors have been reported. In this study, we aimed to examine the effects of DS18561882 (DS18), a novel, orally active, specific inhibitor of methylenetetrahydrofolate dehydrogenase (MTHFD2), a mitochondrial enzyme involved in one-carbon metabolism. Treatment with DS18 led to a marked reduction in cancer-cell proliferation; however, it did not induce cell death. Combinatorial treatment with DS18 and inhibitors of checkpoint kinase 1 (Chk1), an activator of the S phase checkpoint pathway, efficiently induced apoptotic cell death in breast cancer cells and suppressed tumorigenesis in a triple-negative breast cancer patient-derived xenograft model. Mechanistically, MTHFD2 inhibition led to cell cycle arrest and slowed nucleotide synthesis. This finding suggests that DNA replication stress occurs due to nucleotide shortage and that the S-phase checkpoint pathway is activated, leading to cell-cycle arrest. Combinatorial treatment with both inhibitors released cell-cycle arrest, but induced accumulation of DNA double-strand breaks, leading to apoptotic cell death. Collectively, a combination of MTHFD2 and Chk1 inhibitors would be a rational treatment option for patients with triple-negative breast cancer., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Noriko Gotoh reports equipment, drugs, or supplies was provided by Daiichi Sankyo Co Ltd. Noriko Gotoh has patent #2014-244956 Japan pending to Licensee. no activities to declare., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Cynomolgus macaque (Macaca fascicularis) and common marmoset (Callithrix jacchus) have been widely used in human biomedical research. Long-standing primate genome assemblies used the human genome as a reference for ordering and orienting the assembled fragments into chromosomes. Here we performed de novo genome assembly of these two species without any human genome-based bias observed in the genome assemblies released earlier. We assembled PacBio long reads, and the resultant contigs were scaffolded with Hi-C data, which were further refined based on Hi-C contact maps and alternate de novo assemblies. The assemblies achieved scaffold N50 lengths of 149 Mb and 137 Mb for cynomolgus macaque and common marmoset, respectively. The high fidelity of our assembly is also ascertained by BAC-end concordance in common marmoset. Our assembly of cynomolgus macaque outperformed all the available assemblies of this species in terms of contiguity. The chromosome-scale genome assemblies produced in this study are valuable resources for non-human primate models and provide an important baseline in human biomedical research.

ATP-binding cassette transporter C4 (ABCC4) is associated with multidrug resistance and the regulation of cell signalling. Some prostaglandins (PGs), including: PGE 2 , PGF 2α , PGE 3 , and PGF 3α are known substrates of ABCC4, and are released from some types of cells to exert their biological effects. In the present study, we demonstrate that PGD 2 is a novel substrate of ABCC4 using a transport assay based on inside-out membrane vesicles prepared from ABCC4-overexpressing cells. Then, we used two types of cell lines with confirmed ABCC4 mRNA and PGD 2 release capacity (human mast cell lines HMC-1 cells and human rhabdomyosarcoma cell lines TE671 cells) to evaluate the contribution of ABCC4. The extracellular levels of PGD 2 were unchanged following addition of a selective ABCC4 inhibitor in TE671 cells. Pharmacological inhibition and knockdown of ABCC4 significantly reduced the extracellular levels of PGD 2 by at least 53% in HMC-1 cells. Moreover, the extracellular levels of PGD 2 decreased by at least 20% using the selective ABCC4 inhibitor in the other mast cell line RBL-2H3 cells. Therefore, our results suggest that ABCC4 functions as a PGD 2 exporter in HMC-1 cells., Competing Interests: Declaration Competing of Interest Additional Information, Competing financial interests: The authors declare no competing financial interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Study Design: Retrospective clinical series., Objective: To investigate the prognostic factors for the improvement of drop foot caused by degenerative lumbar disease after surgery., Summary of Background Data: Drop foot may be caused by lumbar spinal diseases and may affect daily life. There are limited data regarding predictors of drop foot, especially surgical timing., Methods: We retrospectively reviewed data from 87 patients with drop foot. Prognostic factors and precise timing of surgery affecting drop foot improvement were examined by multivariate logistic regression analysis., Results: Forty patients (46.0%) recovered from drop foot after surgery. Age [odds ratio (OR)=0.93; 95% confidence interval (CI), 0.87-0.98; P=0.01], preoperative anterior tibialis muscle strength (OR=12.0; 95% CI, 2.41-59.9; P=0.002), and duration of drop foot before surgery (OR=3.59; 95% CI, 1.09-11.8; P=0.04) were significant prognostic factors. Two months was the most appropriate cutoff for surgery after appearance of symptoms., Conclusions: Age, preoperative tibialis anterior muscle strength, and duration of drop foot were statistically significant prognostic factors of recovery from drop foot. Surgery within 2 months after the onset of drop foot may improve postoperative outcome.

Maltobionic acid is known to have an inhibitory effect on the differentiation of osteoclasts, and it has also been reported in an intervention trial that ingestion of corn syrup solids containing maltobionic acid maintained and increased the bone density of postmenopausal women. However, there is no information on whether maltobionic acid improves bone metabolism in humans. Therefore, we evaluated the influence of corn syrup solids containing maltobionic acid (maltobionic acid calcium salt) on bone resorption markers in healthy Japanese women. Forty-one individuals were selected from 68 participants and assigned to two groups: 21 individuals in the test food antecedent group and 20 individuals in the placebo food antecedent group; individuals in the first group ingested 4 g of corn syrup solids containing maltobionic acid, and subjects in the second group ingested 4 g of placebo (hydrous crystalline maltose and calcium carbonate) for 4 weeks. Bone resorption marker levels (DPD and u-NTx) were evaluated by urinalysis. Forty subjects completed the study, and no adverse events related to the test food were observed. Fourteen subjects were excluded prior to the efficacy analysis because of conflict with the control criteria; the remaining 33 subjects were analyzed. Consumption of corn syrup solids containing maltobionic acid was maintained; DPD and u-NTx values were improved ( p  < .05). These results indicate that corn syrup solids containing maltobionic acid might contribute to suppress bone resorption and improve bone metabolism in postmenstrual women. (UMIN-CTR ID: UMIN000034257; Foundation: San-ei Sucrochemical Co., Ltd.)., Competing Interests: Daiki Suehiro and Ken Fukami are employees of San‐ei Sucrochemical Co., Ltd. San‐ei Sucrochemical Co., Ltd. is the supplier of a food product containing maltobionic acid. Ayaka Nishio, Jyunya Kawai, and Motoko Ohnishi have no conflict of interest to declare., (© 2020 The Authors. Food Science & Nutrition published by Wiley Periodicals, Inc.)

Purpose: The aim of this study was to evaluate the efficacy of decompression surgery alone for patients with intolerable low back pain., Methods: We retrospectively identified 222 patients who underwent spinal decompression without fusion surgery who had substantial preoperative low back pain (preoperative numerical rating scale score ≥ 5). Their clinical outcomes were assessed using the numerical rating scale and the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) preoperatively and at 3 months and 1 year after surgery., Results: At 3 months and 1 year after surgery compared with baseline, there was a significant improvement in the overall mean numerical rating scale scores for low back pain (baseline = 6.8, 3 months = 2.1, 1 year = 2.7), leg pain (6.8, 2.1, 2.7), and leg numbness (6.4, 2.9, 3.2) (P < 0.05). The efficacy rate assessed by JOABPEQ was 68.1% for pain-related disorders, 47.0% for lumbar spine dysfunction, 63.3% for walking ability, 48.2% for social life dysfunction, and 21.6% for psychological disorders. When patients were classified into three groups depending on their degree of leg pain (mild, moderate, and severe), there was no significant difference in the efficacy rate between the three groups., Conclusion: Decompression surgery can improve low back pain, regardless of the degree of preoperative leg pain, but the average score for LBP and leg pain slightly worsened between 3 months and 1 year after surgery. These slides can be retrieved under Electronic Supplementary Material.

Background: Calcaneal insufficiency fracture (IF) following total knee arthroplasty (TKA) is a rare disorder. This study aimed to examine the prevalence and clinical findings of calcaneal IF following TKA., Methods: We retrospectively reviewed 3,585 consecutive patients undergoing primary TKA between 2012 and 2017 in four hospitals. Calcaneal IF following TKA was diagnosed by plain radiography or magnetic resonance imaging. First, we investigated the prevalence and clinical findings of calcaneal IF following TKA. Second, we classified calcaneal IF into three types based on its location: type 1, fracture by traction force around the Achilles tendon insertion; type 2, compression fracture around the posterior subtalar joint; and type 3, fracture by ground reaction force at the bottom of the calcaneus. Finally, we compared the clinical findings between calcaneal IF with and without TKA., Results: Calcaneal IF following TKA was seen in 17 (0.5%) of the 3,585 patients undergoing primary TKA. All patients were female, with a mean age of 76.5 ± 5.9 years, relatively high body mass index (BMI), and osteoporosis. All fractures achieved bone union with conservative treatment. Type 1 fractures were the most common. Calcaneal IFs following TKA were significantly shorter in height and the patients had higher BMI than those without TKA. The locations of calcaneal IF following TKA varied, while only type 1 calcaneal IFs were seen in cases without TKA. However, there were no significant differences with regard to the bone union period or malunion between the two groups., Conclusions: Calcaneal IF should be suspected in patients presenting with ipsilateral foot pain following TKA, particularly in female patients with a relatively high BMI and osteoporosis. Calcaneal IF can be classified into three types based on the fracture location. These variations in calcaneal IF may be due to differences in conditions and changes in mechanical loading of the lower extremity and bone quality following TKA., (Copyright © 2019. Published by Elsevier Ltd.)

Antisense oligonucleotide (ASO) has the potential to induce off-target effects due to complementary binding between the ASO and unintended RNA with a sequence similar to the target RNA. Conventional animal studies cannot be used to assess toxicity induced by off-target effects because of differences in the genome sequence between humans and other animals. Consequently, the assessment of off-target effects with in silico analysis using a human RNA database and/or in vitro expression analysis using human cells has been proposed. Our previous study showed that the number of complementary regions of ASOs with mismatches in the human RNA sequences increases dramatically as the number of tolerated mismatches increases. However, to what extent the expression of genes with mismatches is affected by off-target effects at the cellular level is not clear. In this study, we evaluated off-target effects of gapmer ASOs, which cleave the target RNA in an RNase H-dependent manner, by introducing the ASO into human cells and performing microarray analysis. Our data indicate that gapmer ASOs induce off-target effects depending on the degree of complementarity between the ASO and off-target candidate genes. Based on our results, we also propose a scheme for the assessment of off-target effects of gapmer ASOs., (© 2019 The Authors. Genes to Cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

The increasing number of patients suffering from allergic diseases is a global health problem. Grifola frondosa is an edible mushroom consumed as a health food in Asia, and has recently been reported to have anti-allergic effects. We previously reported that G. frondosa extract (GFE) and its active components, ergosterol and its derivatives, inhibited the antigen-induced activation of RBL-2H3 cells. Here, we demonstrated that GFE and ergosterol also had an inhibitory effect on the degranulation of bone marrow-derived mast cells (BMMCs) and alleviated anaphylactic cutaneous responses in mice. Using an air pouch-type allergic inflammation mouse model, we confirmed that oral administration of GFE and ergosterol suppressed the degranulation of mast cells in vivo . Our findings suggest that G. frondosa , including ergosterol as its active component, reduces type I allergic reactions by suppressing mast cell degranulation in mice, and might be a novel functional food that prevents allergic diseases.

We report the discovery of a potent and isozyme-selective MTHFD2 inhibitor, DS18561882 ( 2 ). Through investigation of the substituents on our tricyclic coumarin scaffold (1,2,3,4-tetrahydrochromeno[3,4- c ]pyridin-5-one), MTHFD2 inhibitory activity was shown to be elevated by incorporating an amine moiety at the 8-position and a methyl group at the 7-position of the initial lead 1 . X-ray structure analysis revealed that a key interaction for enhanced potency was salt bridge formation between the amine moiety and the diphosphate linker of an NAD + cofactor. Furthermore, ortho-substituted sulfonamide in place of benzoic acid of 1 significantly improved cell permeability and cell-based growth inhibition against a human breast cancer cell line. The thus-optimized DS18561882 showed the strongest cell-based activity (GI 50 = 140 nM) in the class, a good oral pharmacokinetic profile, and thereby tumor growth inhibition in a mouse xenograft model upon oral administration.

A 76-year-old woman presented with temporary right back pain and renal dysfunction. She had undergone ileal ureter interposition for right ureteral resection due to retroperitoneal liposarcoma about forty years ago. Abdominal computed tomographic (CT) scan showed right hydronephrosis and a stenosis in the middle of the ileal ureter. The symptoms were relieved, and the patient was followed. Six months later, however, a contrast enhanced lesion was newly observed at the stenosis of the ileal ureter, and nineteen months later, right ovarian tumor and peritoneal dissemination were subsequently observed. Aiming at diagnosis and cytoreduction, right nephroureterectomy and bilateral oophorectomy were performed. Histopathological findings of the resected tumors showed common characteristics of infiltrating and proliferating adenocarcinoma. Immunohistochemistry findings showed that Cytokeratin 7 and Cytokeratin 20 stained positive. On the other hand, Mucin 2 and Special AT-rich sequence-binding protein 2 were not found. The histopathological diagnosis was metastatic mucinous adenocarcinoma of the ovary with ileal ureter and a wide peritoneal dissemination. The patient rejected adjuvant chemotherapy and a new lesion was found in the pelvic fourmonths afterthe surgery.

A man in his 60s was referred to our hospital for further examination of left hydronephrosis and renal dysfunction. An enhanced abdominal computed tomographic scan showed that the patient had chronic abdominal aortic dissection and a non-enhancing retroperitoneal soft tissue occupying the front of the abdominal aorta as well as the bilateral common iliac arteries. The left ureter was compressed by the soft tissue at the fourth lumbar level. No tumor markers were significantly elevated and idiopathic retroperitoneal fibrosis was suspected to be the cause. Before starting treatment, however, right hydronephrosis was newly observed. We placed bilateral ureteral stents and reviewed our diagnosis. Elevated serum IgG4 and accumulation of 18F-fluorodeoxyglucose in the soft tissue were the points at issue. To determine the diagnosis, we performed open wedge biopsy. Histopathological findings showed mainly fibrous connective tissue with lymphocytic infiltration, which was positive for CD10, CD20, and bcl-2. These findings indicated follicular lymphoma. Induction chemotherapy was performed with 6 cycles of rituximab/cyclophosphamide/vincristine/prednisolone. The soft tissue tumor shrank markedly and the patient has been free from bilateral ureteral stents.

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Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) plays a key role in one-carbon (1C) metabolism in human mitochondria, and its high expression correlates with poor survival of patients with various types of cancer. An isozyme-selective MTHFD2 inhibitor is highly attractive for potential use in cancer treatment. Herein, we disclose a novel isozyme-selective MTHFD2 inhibitor DS44960156, with a tricyclic coumarin scaffold, which was initially discovered via high-throughput screening (HTS) and improved using structure-based drug design (SBDD). DS44960156 would offer a good starting point for further optimization based on the following features: (1) unprecedented selectivity (>18-fold) for MTHFD2 over MTHFD1, (2) a molecular weight of less than 400, and (3) good ligand efficiency (LE)., Competing Interests: The authors declare no competing financial interest.

While formaldehyde (HCHO) was likely generated in Earth's prebiotic atmosphere by ultraviolet light, electrical discharge, and/or volcano-created lightning, HCHO could not have accumulated in substantial amounts in prebiotic environments, including those needed for prebiotic processes that generate nucleosidic carbohydrates. HCHO at high concentrations in alkaline solutions self-reacts in the Cannizzaro reaction to give methanol and formate, neither having prebiotic value. Here, we explore the possibility that volcanic sulfur dioxide (SO 2 ) might have generated a reservoir for Hadean HCHO by a reversible reaction with HCHO to give hydroxymethanesulfonate (HMS). We show that salts of HMS are stable as solids at 90°C and do not react with themselves in solution, even at high (>8 M) concentrations. This makes them effective stores of HCHO, since the reverse reaction slowly delivers HCHO back into an environment where it can participate in prebiotically useful reactions. Specifically, we show that in alkaline borate solutions, HCHO derived from HMS allows formation of borate-stabilized carbohydrates as effectively as free HCHO, without losing material to Cannizzaro products. Further, we show that SO 2 can perform similar roles for glycolaldehyde and glyceraldehyde, two intrinsically unstable carbohydrates that are needed by various models as precursors for RNA building blocks. Zircons from the Hadean show that the Hadean mantle likely provided volcanic SO 2 at rates at least as great as the rates of atmospheric HCHO generation, making the formation of Hadean HMS essentially unavoidable. Thus, hydroxymethylsulfonate adducts of formaldehyde, glycolaldehyde, and glyceraldehyde, including the less soluble barium, strontium, and calcium salts, are likely candidates for prebiotically useful organic minerals on early Earth.

Selection of human induced pluripotent stem cell (hiPSC) lines with high cardiac differentiation potential is important for regenerative therapy and drug screening. We aimed to identify biomarkers for predicting cardiac differentiation potential of hiPSC lines by comparing the gene expression profiles of six undifferentiated hiPSC lines with different cardiac differentiation capabilities. We used three platforms of gene expression analysis, namely, cap analysis of gene expression (CAGE), mRNA array, and microRNA array to efficiently screen biomarkers related to cardiac differentiation of hiPSCs. Statistical analysis revealed candidate biomarker genes with significant correlation between the gene expression levels in the undifferentiated hiPSCs and their cardiac differentiation potential. Of the candidate genes, PF4 was validated as a biomarker expressed in undifferentiated hiPSCs with high potential for cardiac differentiation in 13 additional hiPSC lines. Our observations suggest that PF4 may be a useful biomarker for selecting hiPSC lines appropriate for the generation of cardiomyocytes.

Titan is the largest moon of Saturn and possesses a dense atmosphere composed of nitrogen and methane. Various types of organic compounds (hydrocarbons, nitriles, etc.) have been found on Titan, which were generated by reactions taking place in its atmosphere. These reactions are considered to provide crucial evidence for chemical reactions which may have occurred in the atmosphere of primitive Earth. Cassini discovered several lakes of liquid methane and ethane on Titan's surface; in addition, the presence of ammonia water in its sub-surface was implied. In order to simulate the chemical reactions in Titan's atmosphere, gas mixtures of nitrogen and methane have been exposed to plasma discharges to synthesize complex organic matters. In this study, we focused on the formation of nucleic acid bases and related compounds recovered from synthesized Titan tholins. The five nucleic acid bases that terrestrial life uses (adenine, cytosine, thymine, guanine, and uracil) have already been reported to be present in synthesized Titan tholins. Purines and pyrimidines, including the five aforementioned nucleic acid bases, were extracted from synthesized Titan tholins and analyzed by HPLC and LC/MS. As a result, the pyrimidine bases of isocytosine and 2, 4-diaminopyrimidine were detected together with the terrestrial nucleic acid bases of adenine, uracil, and cytosine. The results obtained in conjunction with those from previous studies show that some nucleic acid bases and related pyrimidine bases are found in synthesized Titan tholins, suggesting that chemical evolutions toward xenogenetic systems could occur in Titan's environment., (Copyright © 2018 The Committee on Space Research (COSPAR). Published by Elsevier Ltd. All rights reserved.)

An unnatural terpenoid scaffold containing a bicyclo[5.4.0]undecane moiety, as well as a salvialane skeleton based on an intramolecular C-C bond formation strategy were synthesized. Such a strategy was made possible by the removal of strained E-olefin conformations of the humulene skeleton. Some compounds were identified to show PPARα antagonist activity.

Grifola frondosa is an edible mushroom consumed as a health food and/or traditional medicine in Asia. However, the anti-allergic effects of G. frondosa are not yet understood. In this study, we demonstrated the effects of G. frondosa extract (GFE) on IgE-mediated allergic responses, using antigen-stimulated RBL-2H3 cells. Three active compounds: ergosterol, 6β-methoxyergosta-7,22-dien-3β,5α-diol (MEDD), and 6-oxoergosta-7,22-dien-3β-ol (6-OXO) were isolated from GFE and shown to inhibit the antigen-induced release of β-hexosaminidase and histamine. Among the three active components, we focused on ergosterol because of its high content in GFE. Ergosterol inhibited the aggregation of high-affinity IgE receptor (FcεRI), which is the first step in the activation of mast cells and antigen-induced tyrosine phosphorylation. Furthermore, ergosterol suppressed antigen-increased IL-4 and TNF-α mRNA. Taken together, our findings suggest that G. frondosa, including ergosterol and its derivatives as active components, has the potential to be a novel functional food that prevents type I allergies.

A woman in her 50s was admitted to our hospital with fever and lower abdominal swelling. Abdominal CT/MRI examinations revealed irregular thickening of the transverse colon wall, which was attached to a subcutaneous abscess. An abdominal wall mass, a patent urachus, and a tumor in the 5th segment of the liver were also noted. Colonoscopy revealed type 2 advanced transverse colon cancer. The solitary, sessile tumor was observed at the apex of the bladder under cystoscopy, suggesting the formation of the urachal carcinoma. Transcutaneous liver biopsy obtained from the liver tumor indicated adenocarcinoma, which was morphologically different from the existing transverse colon cancer. Right hemicolectomy with resection of the umbilicus, abdominal wall, urachus, and part of the bladder wall was performed. Diagnosis of the transverse colon cancer invading the abdominal wall and bladder was confirmed by histopathological examination. Hepatectomy was performed in the next surgery, and the tumor was histopathologically diagnosed as an intrahepatic cholangiocarcinoma. Both the transverse colon cancer and the intrahepatic cholangiocarcinoma were radically resected. Radical surgical diagnostic resection may be valuable in cases of multicentric cancers of unknown primary origin, if radical resection of each individual tumor is required.

Aims: The clinical significance of papillary muscle hypertrophy and its electrocardiography (ECG) findings has not been fully elucidated. This study aimed to investigate the relationship between ECG findings and papillary muscle hypertrophy and to confirm the importance of papillary muscle measurements on transthoracic echocardiography (TTE)., Methods and Results: Of the 237 consecutive patients who showed left ventricular hypertrophy (LVH) pattern on a 12-lead ECG, TTE data were available for 101 patients. The patients were divided into the two groups according to the presence (ECG-LVH [strain pos] group, n = 60) or absence (ECG-LVH [strain neg] group, n = 41) of LV strain pattern (study 1). The prevalence of papillary muscle hypertrophy using TTE was significantly higher in the ECG-LVH (strain neg) group than in the ECG-LVH (strain pos) group (P = .0002). Of the 42 cases with papillary muscle hypertrophy, 5 cases (12%) showed isolated papillary muscle hypertrophy with normal geometry. ECG data were prospectively analyzed for 36 patients who were diagnosed with papillary muscle hypertrophy by TTE (study 2). The prevalence of LV strain pattern was significantly higher in patients with LV wall hypertrophy than in those without LV wall hypertrophy (P = .04). Of the 25 cases with papillary muscle hypertrophy, 6 cases (24%) showed normal geometry and 4 cases (16%) showed ECG abnormality., Conclusions: Isolated papillary muscle hypertrophy can cause ECG abnormalities such as LV high voltage and LV strain pattern. Particular attention must be paid to the papillary muscle during echocardiographic examinations., (© 2017, Wiley Periodicals, Inc.)

Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci associated with a given trait, and help to identify underlying biological processes. Using cap analysis of gene expression (CAGE) profiles of promoter- and enhancer-derived RNAs across 1824 human samples, we have analysed coexpression of RNAs originating from trait-associated regulatory regions using a novel quantitative method (network density analysis; NDA). For most traits studied, phenotype-associated variants in regulatory regions were linked to tightly-coexpressed networks that are likely to share important functional characteristics. Coexpression provides a new signal, independent of phenotype association, to enable fine mapping of causative variants. The NDA coexpression approach identifies new genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. NDA strongly implicates particular cell types and tissues in disease pathogenesis. For example, distinct groupings of disease-associated regulatory regions implicate two distinct biological processes in the pathogenesis of ulcerative colitis; a further two separate processes are implicated in Crohn's disease. Thus, our functional analysis of genetic predisposition to disease defines new distinct disease endotypes. We predict that patients with a preponderance of susceptibility variants in each group are likely to respond differently to pharmacological therapy. Together, these findings enable a deeper biological understanding of the causal basis of complex traits.

We report a case of triple negative spindle cell carcinoma of the breast, responsive to irinotecan chemotherapy. A 49-year old woman who had a tumor in the chest wall with a skin ulcer visited our hospital. After being diagnosed with triple negative spindle cell carcinoma of the breast, she underwent surgery, adjuvant chemotherapy, and radiation at the other hospital. Fourteen months after the surgery, she developed an ipsilateral breast tumor as a result of local recurrence. Since eribulin and paclitaxel plus bevacizumab chemotherapies were not effective, she was transferred to our hospital, and we administered irinotecan as third-line chemotherapy. Skin lesions and effusion were reduced and her quality of life improved for 4 months.

Background: Mitral annular disjunction is a structural abnormality of the mitral annulus fibrosus and is pathologically defined by a separation between the atrial wall-mitral valve junction and the left ventricular attachment. Mitral annular disjunction can cause hypermobility of the mitral valve apparatus and is often associated with mitral valve prolapse (MVP). The aim of this study was to investigate the frequency and characteristics of mitral annular disjunction in the patients referred to an echocardiography laboratory and to compare these with previously reported pathological data., Methods and Results: We retrospectively studied 1439 patients (mean age 65 ± 17 years, 58% male) referred to our echocardiography laboratory from 6 January 2014 to 31 March 2014. The echocardiographic parameters were compared between the patients with and without mitral annular disjunction. There were 125 cases (8.7%) with mitral annular disjunction, of which 15 (12%) also had MVP. The number of MVP patients in the group with mitral annular disjunction was significantly larger than in the group without mitral annular disjunction (p < 0.0001). The grade of mitral regurgitation was not significantly different between the two groups., Conclusions: Mitral annular disjunction was detected not only in patients with a myxomatous mitral valve but also in normal cases. The number of MVPs was significantly larger in patients with mitral annular disjunction than patients without mitral annular disjunction. Further investigation is needed to clarify the clinical significance of the mitral annular disjunction detected by routine echocardiography.