Two-year outcomes of intravitreal brolucizumab for neovascular age-related macular degeneration: treat, extend, and stop-protocol.

PURPOSE: To investigate the real-world 2-year treatment outcomes of intravitreal brolucizumab (IVBr) for neovascular age-related macular degeneration (nAMD). METHODS: This multicenter, prospective, and interventional study included 53 eyes treated with brolucizumab from October 2020 to August 2021 at 3 institutions. A modified treat-and-extend (TAE) regimen with predefined discontinuation criteria was used. The mTAE regimen was discontinued if patients responded positively and achieved a treatment interval of 16 weeks twice with no sign of recurrence. The number of patients discontinuing TAE and the visual and anatomic changes at 1 and 2 years after the first IVBr were evaluated. RESULTS: Thirty-eight eyes from 38 patients (71%) completed the 2-year observation period and 7 eyes from 7 patients experienced intraocular inflammation (IOI). Of these 38 patients, 18 (47%) could discontinue the TAE at a median [interquartile range] of 13.1 [12.9-16.8] months after the first IVBr. Best-corrected visual acuity, central subfield retinal thickness, and central choroidal thickness were significantly improved compared with baseline at both 1 and 2 years after the first IVBr (all P < 0.001). An extension study revealed a 1-year recurrence rate of 5.6% (standard deviation, 5.4%) after TAE discontinuation. CONCLUSIONS: While IOI is a concern with brolucizumab, careful observation allows discontinuing the TAE regimen in patients treated with IVBr. Moreover, brolucizumab may reduce the risk of recurrence after treatment interruption. TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry ( http://www.umin.ac.jp/ ; R000050688 UMIN 000044374).

One-year visual and anatomical outcomes of intravitreal faricimab injection for neovascular age-related macular degeneration after prior brolucizumab treatment.

This single-center retrospective cohort study analyzed the 1-year real-world treatment outcomes of 63 consecutive eyes (of 60 patients) with neovascular age-related macular degeneration (nAMD) that were switched from intravitreal brolucizumab (IVBr) to intravitreal faricimab (IVF) and managed on a treat-and-extend regimen with discontinuation criteria. After the switch, patients opted to continue IVF, to switch back to IVBr, or receive photodynamic therapy (PDT). Thirty-eight patients continued IVF, 16 patients were switched back to IVBr, 2 patients received PDT, and 4 patients paused treatment. Best-corrected visual acuity (BCVA), central subfield thickness (CST), subfoveal choroidal thickness (sf-CT), and injection intervals were compared immediately before and 1 year after the initial IVF. Whereas there was no change in BCVA and CST; 0 [- 0.0969 to 0.125, P = 0.58], - 1.5 [- 27.8 to 13.5, P = 0.11] µm, respectively, sf-CT decreased significantly; - 19.5 [- 45.5 to 7.75, P = 0.015] µm. The patients switched back showed no significant change in sf-CT. The injection interval extended significantly in the IVF continuation and the switch-back group (2.0 and 3.0 weeks, respectively; [P = 0.0007 and 0.0078]) in eyes with a pre-switching interval of less than 12 weeks. Faricimab shows promise as a safe and effective alternative to brolucizumab for treating nAMD.

Scleritis following intravitreal brolucizumab injection: a case series.

BACKGROUND: This study reports the first cases of scleritis following intravitreal brolucizumab (IVBr) injection for nAMD, emphasizing the need to be aware of the possibility of scleritis following IVBr injections. CASE PRESENTATION: Case 1. A 74-year-old Japanese man with nAMD complained of conjunctivitis and decreased vision in the right eye 8 days after his eighth IVBr injection. Examination revealed scleritis without anterior inflammation. Topical 0.1% betamethasone and 0.3% gatifloxacin eye drops were started. The scleritis worsened in the following 2 weeks and became painful. He underwent sub-Tenon's capsule triamcinolone acetonide (STTA) injection. Two days later, he returned with a complaint of severe vision loss. Fundus examination revealed retinal artery occlusion, vasculitis, and vitreous opacity in the right eye. Vitreous surgery was performed. CASE 2: An 85-year-old Japanese woman with nAMD in the right eye complained of reddening of the eye 27 days after her fifth IVBr injection. Examination showed conjunctivitis and scleritis without anterior inflammation in the right eye. She was started on 0.1% fluorometholone and 0.5% levofloxacin hydrate eye drops. The scleritis worsened in the following 3 weeks. Her treatment was switched to 0.1% betamethasone eye drops. One month later, the scleritis had improved and a sixth IVBr injection was administered. There was no worsening of the scleritis at that time. However, 1 month after a seventh IVBr injection, she complained of severe hyperemia and decreased vision. Fundus examination revealed vitreous opacification. She underwent STTA, and the vitreous opacity improved in 24 days. Case 3. A 57-year-old Japanese man with nAMD complained of pain and decreased vision in the right eye 21 days after a fourth IVBr injection. Examination revealed scleritis with high intraocular pressure but no anterior chamber or fundus inflammation. STTA and topical eye drops were performed. One month later, scleritis improved but visual acuity didn't due to progression of nAMD. CONCLUSIONS: Intraocular inflammation following IVBr injection may progress to the posterior segment. Scleritis can occur after IVBr injection, and topical eye drops alone may not be sufficient for initial treatment. Clinicians should consider the possibility of scleritis in patients with worsening inflammation after IVBr injection.

Factors Associated With Intraocular Inflammation in Neovascular Age-Related Macular Degeneration Patients Treated With Brolucizumab.

Purpose: To identify factors associated with intraocular inflammation (IOI) in patients with neovascular age-related macular degeneration (nAMD) treated with brolucizumab. Methods: In this prospective observational study, we collected aqueous humor samples from 96 eyes of 96 patients receiving treatment with brolucizumab; IOI subsequently developed in 19 eyes of 19 patients. To identify cytokines upregulated in eyes with subsequent development of IOI, we compared the aqueous humor cytokine levels between the IOI and non-IOI groups. We also collected plasma from 20 patients who developed IOI and 20 age- and sex-matched controls to identify differences in plasma biomarkers and the subfraction of CD4+ cells. Using stepwise variable selection and multivariate binary regression analysis, we developed an algorithm that accurately assessed the likelihood of IOI occurrence. Results: The IOI group showed elevated aqueous humor levels of P-selectin (584 vs. 324 pg/mL, P = 0.013), TNF-α (0.89 vs. 0.60 pg/mL, P = 0.018), and IL-1α (2.0 vs. 1.4 pg/mL, P = 0.035) compared with the non-IOI group. Serum MMP-9 concentrations were higher in the IOI group than the non-IOI group (18,310 vs. 13,450 pg/mL, P = 0.029). Furthermore, the percentage of Th2 cells was significantly decreased in the IOI compared with the non-IOI group (3.1% vs. 4.2%, P = 0.013). The receiver operating characteristic curves for the optimal models showed an area under the curve ranging from 0.71 to 0.89, indicating good performance. Conclusions: The combination of elevated concentrations of multiple aqueous humor cytokines and of serum MMP-9 and a lower number of plasma Th2 cells is associated with brolucizumab-related IOI in patients with nAMD.

One-year outcome of brolucizumab for neovascular age-related macular degeneration in Japanese patients.

A new anti-vascular endothelial growth factor agent, brolucizumab, was approved by the United States Food and Drug Administration in 2019. We evaluated whether brolucizumab reduces the treatment burden of neovascular age-related macular degeneration (nAMD) after switching by examining 1-year treatment outcomes in a real-world setting. This retrospective single-institution study included 107 consecutive eyes with nAMD treated with brolucizumab. Among these eyes, 30 with treatment-naïve nAMD and 77 treated with other anti-VEGF agents for more than a year were included. All eyes were managed using a treat and extend (TAE) or modified TAE regimen. The last injection intervals at 52 weeks were 12.9 and 12.1 weeks in the treatment-naïve and switch therapy groups, respectively. Among switch therapy group patients whose pre-switch injection intervals were shorter than 120 days (n = 62 eyes), the injection interval was significantly longer after the switch than before, with a mean difference of 2.7 weeks (P < 0.0001). Intraocular inflammation events occurred in 2 and 7 treatment-naïve and switch therapy patients, respectively. In conclusion, brolucizumab might reduce the treatment burden in patients who required the injection of other anti-VEGF agents with a 120-day interval or shorter, despite a relatively high discontinuation rate due to intraocular inflammation.

Visual and Anatomical Outcomes After Initial Intravitreal Faricimab Injection for Neovascular Age-Related Macular Degeneration in Patients with Prior Treatment History.

INTRODUCTION: The aim of this study was to investigate the safety and efficacy of a single injection of intravitreal faricimab (IVF) in patients with neovascular age-related macular degeneration (nAMD) who had a prior treatment history. METHODS: A retrospective analysis was conducted on a consecutive cohort of 80 eyes of 75 patients with nAMD who had a prior history of treatment with an injection of anti-vascular endothelial growth factor. Best-corrected visual acuity (BCVA), central subfield thickness (CST), and central choroidal thickness (CCT) were compared before the initial IVF injection and after a treatment interval matching the previous duration. RESULTS: Central choroidal thickness decreased significantly following the IVF injection, but there was no significant change in BCVA or CST. Mean (± standard deviation) BCVA changed from 0.34 ± 0.37 to 0.36 ± 0.40 (P = 0.29), CST changed from 242 ± 72 to 242 ± 82 µm (P = 0.99), and CCT changed from 189 ± 98 to 179 ± 97 µm (P < 0.0001). When the changes were evaluated according to the previous anti-VEGF agent administered, CCT was found to be significantly decreased by 8.7 ± 2.5 µm (P < 0.0001) in eyes previously treated with brolucizumab and by 13.1 ± 3.6 µm (P < 0.0001) in eyes previously treated with aflibercept. No adverse events were observed during the study period. CONCLUSION: Intravitreal faricimab injection is a safe and effective treatment for nAMD in terms of short-term outcomes. Further long-term study is necessary.

Tff2 defines transit-amplifying pancreatic acinar progenitors that lack regenerative potential and are protective against Kras-driven carcinogenesis.

While adult pancreatic stem cells are thought not to exist, it is now appreciated that the acinar compartment harbors progenitors, including tissue-repairing facultative progenitors (FPs). Here, we study a pancreatic acinar population marked by trefoil factor 2 (Tff2) expression. Long-term lineage tracing and single-cell RNA sequencing (scRNA-seq) analysis of Tff2-DTR-CreERT2-targeted cells defines a transit-amplifying progenitor (TAP) population that contributes to normal homeostasis. Following acute and chronic injury, Tff2+ cells, distinct from FPs, undergo depopulation but are eventually replenished. At baseline, oncogenic KrasG12D-targeted Tff2+ cells are resistant to PDAC initiation. However, KrasG12D activation in Tff2+ cells leads to survival and clonal expansion following pancreatitis and a cancer stem/progenitor cell-like state. Selective ablation of Tff2+ cells prior to KrasG12D activation in Mist1+ acinar or Dclk1+ FP cells results in enhanced tumorigenesis, which can be partially rescued by adenoviral Tff2 treatment. Together, Tff2 defines a pancreatic TAP population that protects against Kras-driven carcinogenesis.

Non-target GC-MS analyses of fecal VOCs in NASH-hepatocellular carcinoma model STAM mice.

The increased incidence of obesity in the global population has increased the risk of several chronic inflammation-related diseases, including non-alcoholic steatohepatitis (NASH)-hepatocellular carcinoma (HCC). The progression from NASH to HCC involves a virus-independent liver carcinogenic mechanism; however, we currently lack effective treatment and prevention strategies. Several reports have suggested that fecal volatile organic compounds (VOCs) are strongly associated with NASH-HCC; therefore, we explored the biomarkers involved in its pathogenesis and progression. Fecal samples collected from control and NASH-HCC model STAM mice were subjected to headspace autosampler gas chromatography-electron ionization-mass spectrometry. Non-target profiling analysis identified diacetyl (2,3-butandione) as a fecal VOC that characterizes STAM mice. Although fecal diacetyl levels were correlated with the HCC in STAM mice, diacetyl is known as a cytotoxic/tissue-damaging compound rather than genotoxic or mutagenic; therefore, we examined the effect of bioactivity associated with NASH progression. We observed that diacetyl induced several pro-inflammatory molecules, including tumor necrosis factor-α, cyclooxygenase-2, monocyte chemoattractant protein-1, and transforming growth factor-ß, in mouse macrophage RAW264.7 and Kupffer KPU5 cells. Additionally, we observed that diacetyl induced α-smooth muscle actin, one of the hallmarks of fibrosis, in an ex vivo cultured hepatic section, but not in in vitro hepatic stellate TWNT-1 cells. These results suggest that diacetyl would be a potential biomarker of fecal VOC in STAM mice, and its ability to trigger the macrophage-derived inflammation and fibrosis may partly contribute to NASH-HCC carcinogenesis.

Cytokine profiles in the aqueous humor following brolucizumab administration for exudative age-related macular degeneration.

PURPOSE: To identify the inflammatory cytokine profile in the aqueous humor (AH) of patients with intraocular inflammation (IOI) after intravitreal administration of brolucizumab (IVBr) for neovascular age-related macular degeneration. METHODS: Eight eyes from seven patients with IOI after initial IVBr (IVBrIOI +) were enrolled. Sixteen eyes from 16 patients without IOI after IVBr (IVBrIOI -) and aflibercept (IVA) were used as controls. AH samples were analyzed using a multiplex immunoassay. RESULTS: C-C motif chemokine ligand (CCL)2, C-X-C motif chemokine ligand (CXCL)1, CXCL10, CXCL13, interleukin (IL)-6, IL-8, IL-10, matrix metalloproteinase (MMP)-1, MMP-9, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), intercellular adhesion molecule (ICAM)-1, E-selectin, and P-selectin levels were significantly higher in IVBrIOI + than in IVBrIOI - and IVA. Vascular endothelial growth factor (VEGF) was significantly lower in IVBrIOI - compared to that in IVBrIOI + and IVA. In the IVBrIOI + group, there were significant correlations between CCL2, CXCL1, IL-6, IL-8, IL-10, G-CSF, GM-CSF, ICAM-1, and E-selectin, which also exhibited significant correlations in the IVBrIOI - group. CONCLUSION: The number of inflammatory cytokines increases during IOI, which is associated with type IV hypersensitivity and vascular inflammation. Some cytokines exhibit correlations even in non-inflamed eyes, indicating a subclinical response to IVBr.

Induction of antitoxic antibody and preventive effect against porcine edema disease by the pentameric Stx2eB subunit vaccine.

Porcine edema disease (ED) is an enterotoxaemia that frequently occurs in 4-12 week-old piglets and results in high mortality. ED is caused by Shiga toxin 2e (Stx2e), produced by host-adapted Shiga toxin-producing Escherichia coli (STEC) strains. We constructed a recombinant protein in which the B subunit of Stx2e (Stx2eB) was linked to Cartilage Oligomeric Matrix Protein (COMP)'s pentameric domain to enhance antigenicity to induce neutralizing antibodies against Stx2e. We evaluated the efficacy of this antigen as a vaccine on the farm where ED had occurred. The suckling piglets were divided into two groups. The pigs in the vaccinated group were intramuscularly immunized with the vaccine containing 30 µg/head of Stx2eB-COMP at 1 and 4 weeks of age. The control pigs were injected with saline instead of the vaccine. The neutralizing antibody titer to Stx2e, mortality, clinical score, and body weight was evaluated up to 11 weeks after the first vaccination. In the vaccinated group, the Stx2e neutralizing antibody was detected 3 weeks after the first vaccination, its titer increased during the following weeks. The antibody was not detected in the control group during the test period. The STEC gene was detected in both groups during the test period, but a typical ED was observed only in control pigs; the mortality and clinical score were significantly lower in the vaccinated group than in the control group. These data indicate that the pentameric B subunit vaccine is effective for preventing ED and offers a promising tool for pig health control.

HNF1B-driven three-dimensional chromatin structure for molecular classification in pancreatic cancers.

The molecular subtypes of pancreatic cancer (PC), either classical/progenitor-like or basal/squamous-like, are currently a major topic of research because of their direct association with clinical outcomes. Some transcription factors (TFs) have been reported to be associated with these subtypes. However, the mechanisms by which these molecular signatures of PCs are established remain unknown. Epigenetic regulatory processes, supported by dynamic changes in the chromatin structure, are essential for transcriptional profiles. Previously, we reported the importance of open chromatin profiles in the biological features and transcriptional status of PCs. Here, we aimed to analyze the relationships between three-dimensional (3D) genome structures and the molecular subtypes of human PCs using Hi-C analysis. We observed a correlation of the specific elements of 3D genome modules, including compartments, topologically associating domains, and enhancer-promoter loops, with the expression of related genes. We focused on HNF1B, a TF that is implicated in the progenitor subtype. Forced expression of HNF1B in squamous-type PC organoids induced the upregulation and downregulation of genes associated with progenitor and squamous subtypes, respectively. Long-range genomic interactions induced by HNF1B were accompanied by compartment modulation and H3K27ac redistribution. We also found that these HNF1B-induced changes in subtype-related gene expression required an intrinsically disordered region, suggesting a possible involvement of phase separation in compartment modulation. Thus, mapping of 3D structural changes induced by TFs, such as HNF1B, may become a useful resource for further understanding the molecular features of PCs.

The Role of Neural Signaling in the Pancreatic Cancer Microenvironment.

Pancreatic cancer is one of the most lethal malignant diseases. Various cells in the tumor microenvironment interact with tumor cells and orchestrate to support tumor progression. Several kinds of nerves are found in the tumor microenvironment, and each plays an essential role in tumor biology. Recent studies have shown that sympathetic, parasympathetic, and sensory neurons are found in the pancreatic cancer microenvironment. Neural signaling not only targets neural cells, but tumor cells and immune cells via neural receptors expressed on these cells, through which tumor growth, inflammation, and anti-tumor immunity are affected. Thus, these broad-range effects of neural signaling in the pancreatic cancer microenvironment may represent novel therapeutic targets. The modulation of neural signaling may be a therapeutic strategy targeting the whole tumor microenvironment. In this review, we describe the current understanding of the role of nerves in the tumor microenvironment of various cancers, with an emphasis on pancreatic cancer. We also discuss the underlying mechanisms and the possibility of therapeutic applications.

Adult enteric Dclk1-positive glial and neuronal cells reveal distinct responses to acute intestinal injury.

Intestinal ganglionic cells in the adult enteric nervous system (ENS) are continually exposed to stimuli from the surrounding microenvironment and need at times to respond to disturbed homeostasis following acute intestinal injury. The kinase DCLK1 and intestinal Dclk1-positive cells have been reported to contribute to intestinal regeneration. Although Dclk1-positive cells are present in adult enteric ganglia, their cellular identity and response to acute injury have not been investigated in detail. Here, we reveal the presence of distinct Dclk1-tdTom+/CD49b+ glial-like and Dclk1-tdTom+/CD49b- neuronal cell types in adult myenteric ganglia. These ganglionic cells demonstrate distinct patterns of tracing over time yet show a similar expansion in response to elevated serotonergic signaling. Interestingly, Dclk1-tdTom+ glial-like and neuronal cell types appear resistant to acute irradiation injury-mediated cell death. Moreover, Dclk1-tdTom+/CD49b+ glial-like cells show prominent changes in gene expression profiles induced by injury, in contrast to Dclk1-tdTom+/CD49b- neuronal cell types. Finally, subsets of Dclk1-tdTom+/CD49b+ glial-like cells demonstrate prominent overlap with Nestin and p75NTR and strong responses to elevated serotonergic signaling or acute injury. These findings, together with their role in early development and their neural crest-like gene expression signature, suggest the presence of reserve progenitor cells in the adult Dclk1 glial cell lineage.NEW & NOTEWORTHY The kinase DCLK1 identifies glial-like and neuronal cell types in adult murine enteric ganglia, which resist acute injury-mediated cell death yet differ in their cellular response to injury. Interestingly, Dclk1-labeled glial-like cells show prominent transcriptional changes in response to injury and harbor features reminiscent of previously described enteric neural precursor cells. Our data thus add to recently emerging evidence of reserve cellular plasticity in the adult enteric nervous system.

Interpretations of SARS-CoV-2 IgM and IgG antibody titers in the seroepidemiological study of asymptomatic healthy volunteers.

INTRODUCTION: The usefulness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody tests in asymptomatic individuals has not been well validated, although they have satisfied sensitivity and specificity in symptomatic patients. In this study, we investigated the significance of IgM and IgG antibody titers against SARS-CoV-2 in the serum of asymptomatic healthy subjects. METHODS: From June 2020, we recruited 10,039 participants to the project named the University of Tokyo COVID-19 Antibody Titer Survey (UT-CATS), and measured iFlash-SARS-CoV-2 IgM and IgG (YHLO IgM and IgG) titers in the collected serum. For the samples with increased IgM or IgG titers, we performed additional measurements using Elecsys Anti-SARS-CoV-2 Ig (Roche total Ig) and Architect SARS-CoV-2 IgG (Abbott IgG) and investigated the reactivity to N, S1, and receptor binding domain (RBD) proteins. RESULTS: After setting the cutoff value at 5 AU/mL, 61 (0.61%) were positive for YHLO IgM and 104 (1.04%) for YHLO IgG. Few samples with elevated YHLO IgM showed reactivity to S1 or RBD proteins, and IgG titers did not increase during the follow-up in any samples. The samples with elevated YHLO IgG consisted of two groups: one reacted to S1 or RBD proteins and the other did not, which was reflected in the results of Roche total Ig. CONCLUSIONS: In SARS-CoV-2 seroepidemiological studies of asymptomatic participants, sufficient attention should be given to the interpretation of the results of YHLO IgM and IgG, and the combined use of YHLO IgG and Roche total Ig might be more reliable.

MNX1-HNF1B Axis Is Indispensable for Intraductal Papillary Mucinous Neoplasm Lineages.

BACKGROUND & AIMS: Chromatin architecture governs cell lineages by regulating the specific gene expression; however, its role in the diversity of cancer development remains unknown. Among pancreatic cancers, pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMN) with an associated invasive carcinoma (IPMNinv) arise from 2 distinct precursors, and their fundamental differences remain obscure. Here, we aimed to assess the difference of chromatin architecture regulating the transcriptional signatures or biological features in pancreatic cancers. METHODS: We established 28 human organoids from distinct subtypes of pancreatic tumors, including IPMN, IPMNinv, and PDAC. We performed exome sequencing (seq), RNA-seq, assay for transposase-accessible chromatin-seq, chromatin immunoprecipitation-seq, high-throughput chromosome conformation capture, and phenotypic analyses with short hairpin RNA or clustered regularly interspaced short palindromic repeats interference. RESULTS: Established organoids successfully reproduced the histology of primary tumors. IPMN and IPMNinv organoids harbored GNAS, RNF43, or KLF4 mutations and showed the distinct expression profiles compared with PDAC. Chromatin accessibility profiles revealed the gain of stomach-specific open regions in IPMN and the pattern of diverse gastrointestinal tissues in IPMNinv. In contrast, PDAC presented an impressive loss of accessible regions compared with normal pancreatic ducts. Transcription factor footprint analysis and functional assays identified that MNX1 and HNF1B were biologically indispensable for IPMN lineages. The upregulation of MNX1 was specifically marked in the human IPMN lineage tissues. The MNX1-HNF1B axis governed a set of genes, including MYC, SOX9, and OLFM4, which are known to be essential for gastrointestinal stem cells. High-throughput chromosome conformation capture analysis suggested the HNF1B target genes to be 3-dimensionally connected in the genome of IPMNinv. CONCLUSIONS: Our organoid analyses identified the MNX1-HNF1B axis to be biologically significant in IPMN lineages.

Bio-inspired asymmetric aldehyde arylations catalyzed by rhodium-cyclodextrin self-inclusion complexes.

Transition-metal catalysts are powerful tools for carbon-carbon bond-forming reactions that are difficult to achieve using native enzymes. Enzymes that exhibit inherent selectivities and reactivities through host-guest interactions have inspired widespread interest in incorporating enzymatic behavior into transition-metal catalytic systems that highly efficiently produce enantiopure compounds. Nevertheless, bio-inspired transition-metal catalysts that are highly enantioselective and reactive have rarely been reported. In this study, we applied γ-cyclodextrin-imidazolium salts to the rhodium-catalyzed asymmetric arylations of aldehydes. The method exhibits wide substrate scope and the corresponding arylcarbinols are obtained in excellent yields under optimized conditions, with enantiomeric excesses of up to 96% observed. Kinetic and competition experiments revealed that self-inclusion of the Rh complex contributes to the high enantioselectivity and reactivity achieved by this catalytic system. Thus, this bio-inspired self-inclusion strategy is promising for the development of highly enantioselective and reactive transition-metal catalysts for asymmetric carbon-carbon bond formation.

Sodium channel mutations (T929I and F1534S) found in pyrethroid-resistant strains of the cigarette beetle, Lasioderma serricorne (Coleoptera: Anobiidae).

RNA-seq data analysis of cigarette beetle (Lasioderma serricorne) strains having different sensitivities to pyrethroids identified sodium channel mutations in strains showing pyrethroid resistance: the T929I and F1534S mutations. These results suggest that reduced sensitivity of the sodium channel confers the pyrethroid resistance of L. serricorne. Results also showed that the F1534S mutation mostly occurred concurrently with the T929I mutation. The functional relation between both mutations for pyrethroid resistance is discussed.

Novel chemical stimulation for geothermal reservoirs by chelating agent driven selective mineral dissolution in fractured rocks.

Improving geothermal systems through hydraulic stimulation to create highly permeable fractured rocks can induce seismicity. Therefore, the technique must be applied at a moderate intensity; this has led to concerns of insufficient permeability enhancement. Adding chemical stimulation can mitigate these issues, but traditional methods using strong mineral acids have challenges in terms of achieving mineral dissolution over long distances and highly variable fluid chemistry. Here, we demonstrate a novel chemical stimulation method for improving the permeability of rock fractures using a chelating agent that substantially enhances the dissolution rate of specific minerals to create voids that are sustained under crustal stress without the challenges associated with the traditional methods. Applying this agent to fractured granite samples under confining stress at 200 °C in conjunction with 20 wt% aqueous solutions of sodium salts of environmentally friendly chelating agents (N-(2-hydroxyethyl)ethylenediamine-N, N', N'-triacetic acid and N, N-bis(carboxymethyl)-L-glutamic acid) at pH 4 was assessed. A significant permeability enhancement of up to approximately sixfold was observed within 2 h, primarily due to the formation of voids based on the selective dissolution of biotite. These results demonstrate a new approach for chemical stimulation.

Kamishoyosan potentiates pentobarbital-induced sleep in socially isolated, ovariectomized mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Sleep disorders are among the most common symptoms in both peri- and post-menopausal women. Kamishoyosan (KSS) is a Kampo medicine prescribed for the treatment of sleep disorders in menopausal women in Japan. However, its precise mechanism of action remains unclear. AIM OF THE STUDY: In the present study, we developed a new animal model of menopausal sleep disorders by inducing social isolation stress in ovariectomized mice. Using pentobarbital-induced sleeping time as an index, we aimed to investigate the effects of KSS and involvement of the benzodiazepine receptors. MATERIALS AND METHODS: Eight-week-old, female ddY mice were ovariectomized or subjected to a sham operation (control) and housed in social isolation or groups for 9 weeks. The animals were divided into four groups, group-housed sham-operated, isolated sham-operated, group-housed ovariectomized, and socially isolated ovariectomized. Pentobarbital (50 mg/kg) was administered intraperitoneally (i.p.). Sleeping time was considered the period between the loss of righting reflex and its return (up to 180 min). KSS was administered orally (p.o.) 60 min before the test. Diazepam and flumazenil were administered i.p. 30 and 45 min before the test, respectively. On the day after administration, the mice were euthanized, and their uteri were weighed. RESULTS: Socially isolated, ovariectomized mice had shorter sleeping times than mice in all other groups. In mice with intact ovaries, diazepam (1 mg/kg, i.p.) considerably prolonged the pentobarbital-induced sleeping time, but KSS (30-1000 mg/kg, p.o.) did not. However, KSS (100 mg/kg, p.o.) significantly prolonged the pentobarbital-induced sleeping time in socially isolated ovariectomized mice. The prolongation of sleeping time mediated by KSS was reversed by flumazenil (3 mg/kg, i.p.). CONCLUSIONS: KSS potentiated pentobarbital-induced sleep in socially isolated, ovariectomized mice, and the benzodiazepine receptors are possibly involved in its pharmacological mechanism. These findings suggest that KSS is beneficial for the treatment of menopausal sleep disorders.

Ibudilast suppresses oxaliplatin-induced mechanical allodynia and neurodegeneration in rats.

Oxaliplatin is a key drug used in the management of solid tumors, such as colorectal cancer; however, it causes peripheral neuropathy. In this study, we investigated the effect of ibudilast, a phosphodiesterase inhibitor, on oxaliplatin-induced mechanical allodynia and histological changes in rats. Ibudilast (7.5 mg/kg, i.p., 5 times per week) reduced mechanical allodynia and histological changes induced by oxaliplatin (4 mg/kg, i.p., twice a week). In contrast, ibudilast (0.01-10 µM) had no effect on oxaliplatin-induced tumor cytotoxicity in murine colon adenocarcinoma 26 cells. These findings suggest that ibudilast could be useful for preventing oxaliplatin-induced peripheral neuropathy in clinical settings.