Inhibition of reactive oxygen species production accompanying alternatively activated microglia by risperidone in a mouse ketamine model of schizophrenia.

Recent studies have highlighted the potential involvement of reactive oxygen species (ROS) and microglia, a major source of ROS, in the pathophysiology of schizophrenia. In our study, we explored how the second-generation antipsychotic risperidone (RIS) affects ROS regulation and microglial activation in the hippocampus using a mouse ketamine (KET) model of schizophrenia. KET administration resulted in schizophrenia-like behaviors in male C57BL/6J mice, such as impaired prepulse inhibition (PPI) of the acoustic startle response and hyper-locomotion. These behaviors were mitigated by RIS. We found that the gene expression level of an enzyme responsible for ROS production (Nox2), which is primarily associated with activated microglia, was lower in KET/RIS-treated mice than in KET-treated mice. Conversely, the levels of antioxidant enzymes (Ho-1 and Gclc) were higher in KET/RIS-treated mice. The microglial density in the hippocampus was increased in KET-treated mice, which was counteracted by RIS. Hierarchical cluster analysis revealed three morphological subtypes of microglia. In control mice, most microglia were resting-ramified (type I, 89.7%). KET administration shifted the microglial composition to moderately ramified (type II, 44.4%) and hyper-ramified (type III, 25.0%). In KET/RIS-treated mice, type II decreased to 32.0%, while type III increased to 34.0%. An in vitro ROS assay showed that KET increased ROS production in dissociated hippocampal microglia, and this effect was mitigated by RIS. Furthermore, we discovered that a NOX2 inhibitor could counteract KET-induced behavioral deficits. These findings suggest that pharmacological inhibition of ROS production by RIS may play a crucial role in ameliorating schizophrenia-related symptoms. Moreover, modulating microglial activation to regulate ROS production has emerged as a novel avenue for developing innovative treatments for schizophrenia.

Utility of bronchoscopically obtained frozen cytology pellets for next-generation sequencing.

BACKGROUND: Next-generation sequencing (NGS) is essential for lung cancer treatment. It is important to collect sufficient tissue specimens, but sometimes we cannot obtain large enough samples for NGS analysis. We investigated the yield of NGS analysis by frozen cytology pellets using an Oncomine Comprehensive Assay or Oncomine Precision Assay. METHODS: We retrospectively enrolled patients with lung cancer who underwent bronchoscopy at Kobe University Hospital and were enrolled in the Lung Cancer Genomic Screening Project for Individualized Medicine. We investigated the amount of extracted DNA and RNA and determined the NGS success rates. We also compared the amount of DNA and RNA by bronchoscopy methods. To create the frozen cytology pellets, we first effectively collected the cells and then quickly centrifuged and cryopreserved them. RESULTS: A total of 132 patients were enrolled in this study between May 2016 and December 2022; of them, 75 were subjected to frozen cytology pellet examinations and 57 were subjected to frozen tissue examinations. The amount of DNA and RNA obtained by frozen cytology pellets was nearly equivalent to frozen tissues. Frozen cytology pellets collected by endobronchial ultrasound-guided transbronchial needle aspiration yielded significantly more DNA than those collected by transbronchial biopsy methods. (P < 0.01) In RNA content, cytology pellets were not inferior to frozen tissue. The success rate of NGS analysis with frozen cytology pellet specimens was comparable to the success rate of NGS analysis with frozen tissue specimens. CONCLUSIONS: Our study showed that frozen cytology pellets may have equivalent diagnostic value to frozen tissue for NGS analyses. Bronchial cytology specimens are usually used only for cytology, but NGS analysis is possible if enough cells are collected to create pellet specimens. In particular, the frozen cytology pellets obtained by endobronchial ultrasound-guided transbronchial needle aspiration yielded sufficient amounts of DNA. TRIAL REGISTRATION: This was registered with the University Medical Hospital Information Network in Japan (UMINCTR registration no. UMIN000052050).

Device parameter to evaluate exciton energy transfer in organic whispering-gallery-mode microresonators and its dependence on the amplified spontaneous emission threshold.

Exciton energy transfer in organic whispering-gallery-mode (WGM) resonators and its effect on the amplified spontaneous emission (ASE) threshold have been investigated using the stilbene-based energy donor 4,4'-bis[(N-carbazole)styryl]biphenyl (BSB-Cz) and the coumarin-based energy acceptor 2,3,6,7-tetrahydro-1,1,7,7,-tetramethyl-1H,5H,11H-10-(2-benzothiazolyl)quinolizino[9,9a,1gh]coumarin (C545T). Using the stacked-layer structure of BSB-Cz/C545T/BSB-Cz, we fabricated bowl-shaped microresonators on silica microspheres with a total thickness of 250 nm fixing the thickness of the C545T layer to 1 nm. The ASE threshold depended on the thicknesses of the top and bottom BSB-Cz layers, which affect the magnitude of the energy transfer. To assess the relationship between the ASE threshold and energy transfer, we developed a device parameter to evaluate the magnitude of the energy transfer by formulating the rate equations. We found that ASE easily occurs under the condition that the C545T molecules become unable to accept energy from the BSB-Cz excitons owing to the high exciton density of C545T, and that the ASE threshold decreases with decreasing device parameter. The device parameter is useful for optimizing microresonator structures in multi-component organic WGM resonators that utilize energy transfer.

PSA-NCAM Colocalized with Cholecystokinin-Expressing Cells in the Hippocampus Is Involved in Mediating Antidepressant Efficacy.

The extracellular glycan polysialic acid linked to neural cell adhesion molecule (PSA-NCAM) is principally expressed in the developing brain and the adult neurogenic regions. Although colocalization of PSA-NCAM with cholecystokinin (CCK) was found in the adult brain, the role of PSA-NCAM remains unclear. In this study, we aimed to elucidate the functional significance of PSA-NCAM in the CA1 region of the male mouse hippocampus. Combined fluorescence in situ hybridization and immunohistochemistry showed that few vesicular glutamate transporter 3-negative/CCK-positive (VGluT3-/CCK+) cells were colocalized with PSA-NCAM, but most of the VGluT3+/CCK+ cells were colocalized with PSA-NCAM. The somata of PSA-NCAM+/CCK+ cells were highly innervated by serotonergic boutons than those of PSA-NCAM-/CCK+ cells. The expression ratios of 5-HT3A receptors and p11, a serotonin receptor-interacting protein, were higher in PSA-NCAM+/CCK+ cells than in PSA-NCAM-/CCK+ cells. Pharmacological digestion of PSA-NCAM impaired the efficacy of antidepressant fluoxetine (FLX), a selective serotonin reuptake inhibitor, but not the efficacy of benzodiazepine anxiolytic diazepam. A Western blot showed that restraint stress decreased the expressions of p11 and mature brain-derived neurotrophic factor (BDNF), and FLX increased them. Interestingly, the FLX-induced elevation of expression of p11, but not mature BDNF, was impaired by the digestion of PSA-NCAM. Quantitative reverse transcription-polymerase chain reaction showed that restraint stress reduced the expression of polysialyltransferase ST8Sia IV and FLX elevated it. Collectively, PSA-NCAM colocalized with VGluT3+/CCK+ cells in the CA1 region of the hippocampus may play a unique role in the regulation of antidepressant efficacy via the serotonergic pathway.SIGNIFICANCE STATEMENT Polysialic acid (PSA) is composed of eight or more α2,8-linked sialic acids. Here, we examined the functional significance of polysialic acid linked to the neural cell adhesion molecule (PSA-NCAM) in the adult mouse hippocampus. Few vesicular glutamate transporter 3-negative/cholecystokinin-positive (VGluT3-/CCK+) cells were colocalized with PSA-NCAM, but most of the VGluT3+/CCK+ cells were colocalized with PSA-NCAM. The expression ratios of 5-HT3A receptors and p11, a serotonin receptor-interacting protein, were higher in PSA-NCAM+/CCK+ cells than in PSA-NCAM-/CCK+ cells. The efficacy of antidepressants, but not anxiolytics, was impaired by the digestion of PSA-NCAM. The antidepressant-induced increase in p11 expression was inhibited following PSA-NCAM digestion. We hence hypothesize that PSA-NCAM colocalized with VGluT3+/CCK+ cells may play a unique role in regulating antidepressant efficacy.

A unique subtype of ramified microglia associated with synapses in the rat hippocampus.

To date, a number of studies have reported the heterogeneity of activated microglia. However, there is increasing evidence suggests that ramified, so-called resting, microglia may also be heterogeneous, and they may play diverse roles in normal brain homeostasis. Here, we found that both 5D4 keratan sulfate epitope-positive (5D4+ ) and 5D4-negative (5D4- ) microglia coexisted in the hippocampus of normal rats, while all microglia were negative for the 5D4 epitope in the hippocampus of normal mice. We thus aimed to determine the potential heterogeneity of microglia related to the 5D4 epitope in the normal rat hippocampus. The optical disector analysis showed that the densities of 5D4+ microglia were higher in the stratum oriens of the CA3 region than in other layers and regions. Although both 5D4+ and 5D4- microglia exhibited a ramified morphology, the three-dimensional reconstruction analysis showed that the node numbers, end numbers, and complexity of processes were higher in 5D4+ than in 5D4- microglia. The linear discriminant analysis showed that 5D4+ and 5D4- microglia can be classified into distinct morphometric subtypes. The ratios of contact between synaptic boutons and microglial processes were higher in 5D4+ than in 5D4- microglia. The gene expressions of pro-inflammatory cytokine interleukin-1ß and purinergic receptor P2Y12 (P2Y12 R) were higher in 5D4+ than in 5D4- microglia. Together, these results indicate that at least two different subtypes of ramified microglia coexist in the normal rat hippocampus and also suggest that 5D4+ microglia may represent a unique subtype associated with synapses.

Impulse measurement of laser induced ablation in a vacuum.

An impulse measurement system based on a simple pendulum is newly developed. The system has a resolution of 10-7 Ns for ablation events induced by a single laser at a pulse rate of 2 Hz or less. For ablation events at 10 Hz and above, the system can record the impulse as an average force. The impulse generated by a Nd:YAG pulse laser irradiating a 7075 aluminum alloy is investigated in vacuum. The impulse arises at 3 J/cm2 and the momentum coupling factor, Cm, plateaus at approximately 20 µNs/J over a range of 5 to 50 J/cm2 without producing a plasma shielding effect. Cm is characterized by only fluence independent of pulse width in the range of 10 to 20 ns. This result indicates that it should be feasible to deorbit a 150 kg abandoned satellite at an altitude of 1200 km using a chaser satellite equipped with a 100 W laser.

Increased Synthesis of Chondroitin Sulfate Proteoglycan Promotes Adult Hippocampal Neurogenesis in Response to Enriched Environment.

Chondroitin sulfate proteoglycan (CSPG) is a candidate regulator of embryonic neurogenesis. The aim of this study was to specify the functional significance of CSPG in adult hippocampal neurogenesis using male mice. Here, we showed that neural stem cells and neuronal progenitors in the dentate gyrus were covered in part by CSPG. Pharmacological depletion of CSPG in the dentate gyrus reduced the densities of neuronal progenitors and newborn granule cells. 3D reconstruction of newborn granule cells showed that their maturation was inhibited by CSPG digestion. The novel object recognition test revealed that CSPG digestion caused cognitive memory impairment. Western blot analysis showed that expression of ß-catenin in the dentate gyrus was decreased by CSPG digestion. The amount of CSPG in the dentate gyrus was increased by enriched environment (EE) and was decreased by forced swim stress. In addition, EE accelerated the recovery of CSPG expression in the dentate gyrus from the pharmacological depletion and promoted the restoration of granule cell production. Conversely, the densities of newborn granule cells were also decreased in mice that lacked chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGalNAcT1), a key enzyme for CSPG synthesis (T1KO mice). The capacity of EE to promote granule cell production and improve cognitive memory was impaired in T1KO mice. These findings indicate that CSPG is involved in the regulation of adult hippocampal neurogenesis and suggest that increased synthesis of CSPG by CSGalNacT1 may mediate promotion of granule cell production and improvement of cognitive memory in response to EE.SIGNIFICANCE STATEMENT Chondroitin sulfate proteoglycan (CSPG) is a candidate regulator of embryonic neurogenesis. Here, we specified the role of CSPG in adult neurogenesis in the mouse hippocampus. Digestion of CSPG in the dentate gyrus impaired granule cell production and cognitive memory. Enriched environment (EE) promoted the recovery of CSPG expression and granule cell production from the CSPG digestion. Additionally, adult neurogenesis was impaired in mice that lacked a key enzyme for CSPG synthesis (T1KO mice). The capacity of EE to promote granule cell production and cognitive memory was impaired in T1KO mice. Altogether, these findings indicate that CSPG underlies adult hippocampal neurogenesis and suggest that increased synthesis of CSPG may mediate promotion of granule cell production in response to EE.

Comparative morphometric analysis of microglia in the spinal cord of SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis.

It has long been recognized that reactive microglia undergo a series of phenotypic changes accompanying morphological transformation. However, the morphological classification of microglia has not yet been achieved. To address this issue, here we morphometrically analysed three-dimensionally reconstructed ionized calcium binding adaptor molecule 1-immunoreactive (Iba1(+) ) microglia in the ventral horn of the lumbar spinal cord of SOD1(G93A) transgenic mice, a model of amyotrophic lateral sclerosis. The hierarchical cluster analysis revealed that microglia were objectively divided into four groups: type S (named after surveillant microglia) and types R1, R2 and R3 (named after reactive microglia). For the purpose of comparative morphometry, we also analysed two pharmacological disease models using wild-type mice: 3,3'-iminodipropionitrile (IDPN)-induced axonopathy and lipopolysaccharide (LPS)-induced neuroinflammation. Type S microglia showed a typical ramified morphology of surveillant microglia, and were mostly observed in wild-type controls. Type R1 microglia were seen at the early stage of disease in SOD1(G93A) mice, and also frequently occurred in IDPN-treated mice. They exhibited small cell bodies with shorter and simple processes. Type R2 microglia were morphologically similar to type R1 microglia, but only transiently occurred in the middle stage of disease in SOD1(G93A) mice and in IDPN-treated mice. Type R3 microglia exhibited a bushy shape, and were observed in the end stage of disease in SOD1(G93A) mice and in LPS-treated mice. These findings indicate that microglia of SOD1(G93A) mice can be classified into four types, and also suggest that the phenotypic changes may be induced by the events related to axonopathy and neuroinflammation.

Enhanced Heat Stability of α-Chymotrypsin through Single-Enzyme Confinement in Attoliter Liposomes.

The entrapment of α-chymotrypsin (α-CT) within 70-140 nm liposomes formed from POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) leads to an unexpected and remarkable increase in the thermal stability of the enzyme. This finding is based on the observation that heating aqueous suspensions of α-CT-containing POPC liposomes to 80 °C for 30 minutes resulted in partial enzyme inactivation, whereas the same treatment of aqueous solutions of free α-CT inactivated the enzyme completely. The stabilizing effect of enzyme confinement in the attoliter volumes of the liposomes was found to increase with decreasing numbers of α-CT molecules per liposome. Single-enzyme confinement was particularly effective, as intermolecular interactions between heat-denatured α-CT molecules (causing irreversible inactivation) are not possible.

A giant mucinous cystadenocarcinoma of the appendix: a case report and review of the literature.

BACKGROUND: Mucinous cystadenocarcinoma is the second most common etiology of appendiceal mucocele. We report a relatively rare case of a giant appendiceal mucocele caused by mucinous cystadenocarcinoma, which occupied the entire abdomen of an adult woman. CASE PRESENTATION: A 63-year-old woman presented with a chief complaint of abdominal distention. Imaging studies showed a giant cystic mass occupying her entire abdomen. Laparotomy confirmed a giant appendiceal mucocele, and the patient underwent ileocecal resection. A mucinous deposit was not found in her abdominal cavity, and the ovaries were grossly normal bilaterally. The pathological diagnosis was mucinous adenocarcinoma with a low-grade mucinous neoplasm that invaded the subserosa. Regional lymph node metastasis was not found. She has had recurrence-free survival for 5 years. CONCLUSIONS: The present case is the largest appendiceal cystadenocarcinoma ever reported. The optimal treatment of an appendiceal neoplasm requires further research based on consensus terminology of an appendiceal mucocele.

Coordinate and synergistic effects of extensive treadmill exercise and ovariectomy on articular cartilage degeneration.

BACKGROUND: Although osteoarthritis (OA) is a multifactorial disease, little has been reported regarding the cooperative interaction among these factors on cartilage metabolism. Here we examined the synergistic effect of ovariectomy (OVX) and excessive mechanical stress (forced running) on articular cartilage homeostasis in a mouse model resembling a human postmenopausal condition. METHODS: Mice were randomly divided into four groups, I: Sham, II: OVX, III: Sham and forced running (60 km in 6 weeks), and IV: OVX and forced running. Histological and immunohistochemical analyses were performed to evaluate the degeneration of articular cartilage and synovitis in the knee joint. Morphological changes of subchondral bone were analyzed by micro-CT. RESULTS: Micro-CT analyses showed significant loss of metaphyseal trabecular bone volume/tissue volume (BV/TV) after OVX as described previously. Forced running increased the trabecular BV/TV in all mice. In the epiphyseal region, no visible alteration in bone morphology or osteophyte formation was observed in any of the four groups. Histological analysis revealed that OVX or forced running respectively had subtle effects on cartilage degeneration. However, the combination of OVX and forced running synergistically enhanced synovitis and articular cartilage degeneration. Although morphological changes in chondrocytes were observed during OA initiation, no signs of bone marrow edema were observed in any of the four experimental groups. CONCLUSION: We report the coordinate and synergistic effects of extensive treadmill exercise and ovariectomy on articular cartilage degeneration. Since no surgical procedure was performed on the knee joint directly in this model, this model is useful in addressing the molecular pathogenesis of naturally occurring OA.

Number Frequency in L1 Differentially Affects Immediate Serial Recall of Numbers in L2 Between Beginning and Intermediate Learners.

A list number recall test in English (L2) was administered to both Japanese (L1) students with beginning-level English proficiency who attended evening high school and Japanese college students with intermediate-level English proficiency. The major findings were that, only for the high school group, the small numbers 1 and 2 in middle positions of lists were recalled better than the large numbers 8 and 9 and there was a significant correlation between number frequency in Japanese and recall performance. Equally intriguing was that in both groups for adjacent transposition errors, smaller numbers tended to appear in the first position and large numbers in the second; also, omission errors were commonly seen for larger numbers. These phenomena are interpreted as reflecting frequency and/or frequency-related effects. Briefly discussed were the bilingual short-term memory system, effects of number value, generality and implications of the findings, and weaknesses of the study.

S100A6 (calcyclin) is a novel marker of neural stem cells and astrocyte precursors in the subgranular zone of the adult mouse hippocampus.

S100A6 (calcyclin), an EF-hand calcium binding protein, is considered to play various roles in the brain, for example, cell proliferation and differentiation, calcium homeostasis, and neuronal degeneration. In addition to some limbic nuclei, S100A6 is distributed in the rostral migratory stream, one of the major neurogenic niches of the adult brain. However, the potential involvement of S100A6 in adult neurogenesis remains unclear. In this study, we aimed to elucidate the role of S100A6 in the other major neurogenic niche, the subgranular zone of the dentate gyrus in the adult mouse hippocampus. Immunofluorescent multiple labeling showed that S100A6 was highly expressed in neural stem cells labeled by sex determining region Y-box 2, brain lipid-binding protein protein and glial fibrillary acidic protein. S100A6+ cells often extended a long process typical of radial glial morphology. In addition, S100A6 was found in some S100ß+ astrocyte lineage cells. Interestingly, proliferating cell nuclear antigen was detected in a fraction of S100A6+/S100ß+ cells. These cells were considered to be lineage-restricted astrocyte precursors maintaining mitotic potential. On the other hand, S100A6 was rarely seen in neural lineage cells labeled by T-box brain protein 2, doublecortin, calretinin and calbindin D28K. Cell fate-tracing experiment using BrdU showed that the majority of newly generated immature astrocytes were immunoreactive for S100A6, while mature astrocytes lacked S100A6 immunoreactivity. Administration of S100 protein inhibitor, trifluoperazine, caused a reduction in production of S100ß+ astrocyte lineage cells, but had no impact on neurogenesis. Overall, our data provide the first evidence that S100A6 is a specific marker of neural stem cells and astrocyte precursors, and may be especially important for generation of astrocytes in the adult hippocampus.

Age-related differences in oligodendrogenesis across the dorsal-ventral axis of the mouse hippocampus.

Oligodendrocyte precursor cells (OPCs) continue to divide and generate new oligodendrocytes (OLs) in the healthy adult brain. Although recent studies have indicated that adult oligodendrogenesis may be vital for the maintenance of normal brain function, the significance of adult oligodendrogenesis in brain aging remains unclear. In this study, we report a stereological estimation of age-related oligodendrogenesis changes in the mouse hippocampus: the dorsal subdivision is related to learning and memory, while the ventral subdivision is involved in emotional behaviors. To identify OPCs and OLs, we used a set of molecular markers, OL lineage transcription factor (Olig2) and platelet-derived growth factor receptor-alpha (PDGFαR). Intracellular dye injection shows that PDGFαR+/Olig2+ cells and PDGFαR-/Olig2+ cells can be defined as OPCs and OLs, respectively. In the dorsal Ammon's horn, the numbers of OPCs decreased with age, while those of OLs remained unchanged during aging. In the ventral Ammon's horn, the numbers of OPCs and OLs generally decreased with age. Bromodeoxyuridine (BrdU) fate-tracing analysis revealed that the numbers of BrdU+ mitotic OPCs in the Ammon's horn remained unchanged during aging in both the dorsal and ventral subdivisions. Unexpectedly, the numbers of BrdU+ newly generated OLs increased with age in the dorsal Ammon's horn, but remained unchanged in the ventral Ammon's horn. Together, the numbers of OLs in the dorsal Ammon's horn may be maintained during aging by increased survival of adult born OLs, while the numbers of OLs in the ventral Ammon's horn may be reduced with age due to the lack of such compensatory mechanisms. These observations provide new insight into the involvement of adult oligodendrogenesis in age-related changes in the structure and function of the hippocampus.

[Treatment progress of large-size puncta and clinical investigation of the extrusion rate and other complications associated with large-size punctal plugs].

PURPOSE: One complication of punctal plug occlusion (PPO) is enlargement of the punctum. The purpose of the present study was to investigate large-size (over 1.0 mm) puncta after punctal plug extrusion. SUBJECTS AND METHODS: This study involved the treatment progress of 74 large-size (over 1.0 mm) puncta in 55 eyes of 46 patients who underwent PPO. The extrusion rate and other complications of the total 133 punctal plugs used for those puncta were investigated. RESULTS: Of the 74 puncta, 33 (44%) achieved occlusion by PPO alone, 20 (27%) achieved perfect occlusion of granulation, and 21 (29%) required surgical punctal occlusion. Although larger or longer punctal plug sizes have been used for PPO, the average elapsed time until extrusion was 143.5 +/- 217.0 (mean +/- SD) days, and the time until 50% of the plugs were extruded was 50 days. No significant extrusion rate was found among the punctal plugs, and there was 0% migration rate. Granulation was observed in 20.3% of the plugs, yet no soft whitish material was seen around the plugs. CONCLUSION: The findings of this study show that large-size puncta can successfully be occluded for a fixed period of time following PPO.

Oscillating latent dynamics in robot systems during walking and reaching.

Sensorimotor control of complex, dynamic systems such as humanoids or quadrupedal robots is notoriously difficult. While artificial systems traditionally employ hierarchical optimisation approaches or black-box policies, recent results in systems neuroscience suggest that complex behaviours such as locomotion and reaching are correlated with limit cycles in the primate motor cortex. A recent result suggests that, when applied to a learned latent space, oscillating patterns of activation can be used to control locomotion in a physical robot. While reminiscent of limit cycles observed in primate motor cortex, these dynamics are unsurprising given the cyclic nature of the robot's behaviour (walking). In this preliminary investigation, we consider how a similar approach extends to a less obviously cyclic behaviour (reaching). This has been explored in prior work using computational simulations. But simulations necessarily make simplifying assumptions that do not necessarily correspond to reality, so do not trivially transfer to real robot platforms. Our primary contribution is to demonstrate that we can infer and control real robot states in a learnt representation using oscillatory dynamics during reaching tasks. We further show that the learned latent representation encodes interpretable movements in the robot's workspace. Compared to robot locomotion, the dynamics that we observe for reaching are not fully cyclic, as they do not begin and end at the same position of latent space. However, they do begin to trace out the shape of a cycle, and, by construction, they are driven by the same underlying oscillatory mechanics.

Impact of concurrent medications on the outcome of immunotherapy in non-small cell lung carcinoma.

BACKGROUND: There have been reports on the impact of concurrent drugs on the outcome of immunotherapy for non-small cell lung carcinoma (NSCLC). However, the effect of some drugs, such as antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs), has not been clarified in patients with NSCLC. In the present study, we aimed to assess the association between concurrent drugs and the outcomes of immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy for patients with advanced NSCLC. METHODS: We retrospectively assessed patients with advanced NSCLC who underwent ICI treatment between September 2017 and December 2021 at Kobe University Hospital. We evaluated the data regarding the use of antibiotics within 30 days before ICI initiation, as well as the use of proton pump inhibitors (PPIs) and NSAIDs during ICI initiation. RESULTS: A total of 127 patients were assessed, among whom 28 (22.0%) patients received antibiotics, 39 (30.7%) PPIs, and 36 (28.3%) NSAIDs. No significant differences were observed between the patients with and without antibiotic use. However, patients using NSAIDs had significantly worse objective response rates (ORR) and progression-free survival (PFS) with ICI alone or in combination with chemotherapy compared to those who did not (ORR, 47.2% vs. 67.0%; p = 0.045. PFS, 6.3 months vs. 10.8 months; p = 0.02). Patients using PPIs demonstrated a worse ORR of ICI in combination with chemotherapy compared to those who did not (ORR, 45.2% vs. 72.6%; p = 0.013). CONCLUSIONS: The unnecessary use of NSAIDs along with immunotherapy should be discouraged.

Mechanism of action of adapalene for treating EGFR-TKI-induced skin disorder.

BACKGROUND: Skin disorders are the most common side effect associated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. It is important to manage skin lesions. Adapalene has been used to treat skin lesions caused by EGFR-TKIs in some cases. The aim of this study was to investigate the functional mechanism of adapalene in erlotinib-induced skin disorder. METHODS: To analyze the effect of adapalene on skin rash, afatinib and adapalene were administered to mice. The relationship between the concentration of adapalene and skin disorders was also examined by analyzing AQP3 expression. A skin lesion model was experimentally established in human skin keratinocytes (HaCaT) by using erlotinib with TNF-α and IL-1ß. We used qRT-PCR to analyze chemokine-induced inflammation and western blotting to analyze the effects of adapalene on the NF-κB signaling pathway. Antimicrobial peptides and adhesion factors were also examined using qRT-PCR. RESULTS: Mice administered 0.01% adapalene had less skin inflammation than mice treated with afatinib alone. The expression level of AQP3 decreased in an adapalene concentration-dependent manner. The mRNA levels of proinflammatory cytokines such as CCL2 and CCL27 in HaCaT cells were significantly reduced by adapalene. The expression of an antimicrobial peptide, hBD3, was upregulated after adapalene treatment. Adhesion factors, such as E-cadherin, were significantly downregulated by EGFR-TKI and significantly upregulated by adapalene treatment. Western blot analysis suggested that erlotinib-induced phosphorylation of p65 was decreased by adapalene. CONCLUSION: We suggest that adapalene may be a possible treatment option for skin disorders induced by EGFR-TKIs.

Human YKL39 (chitinase 3-like protein 2), an osteoarthritis-associated gene, enhances proliferation and type II collagen expression in ATDC5 cells.

Human YKL39 (chitinase 3-like protein 2/CHI3L2) is a secreted 39kDa protein produced by articular chondrocytes and synoviocytes. Recent studies showed that hYKL-39 expression is increased in osteoarthritic articular chondrocytes suggesting the involvement of hYKL-39 in the progression of osteoarthritis (OA). However little is known regarding the molecular function of hYKL-39 in joint homeostasis. Sequence analyses indicated that hYKL-39 has significant identity with the human chitotorisidase family molecules, although it is considered that hYKL-39 has no enzymatic activity since it lacks putative chitinase catalytic motif. In this study, to examine the molecular function of hYKL-39 in chondrocytes, we overexpressed hYKL-39 in ATDC5 cells. Here we report that hYKL-39 enhances colony forming activity, cell proliferation, and type II collagen expression in these cells. These data suggest that hYKL-39 is a novel growth and differentiation factor involved in cartilage homeostasis.

New BDH-TTP/[M(III)(C5O5)3]3- (M = Fe, Ga) isostructural molecular metals.

Two new isostructural molecular metals-(BDH-TTP)(6)[M(III)(C(5)O(5))(3)]·CH(2)Cl(2) (BDH-TTP = 2,5-bis(1,3-dithiolan-2-ylidene)-1,3,4,6-tetrathiapentalene, where M = Fe (1) and Ga (2))-have been prepared and fully characterized. Compound 1 is a molecular conductor showing paramagnetic behavior, which is due to the presence of isolated [Fe(C(5)O(5))(3)](3-) complexes with high-spin S = (5)/(2) Fe(III) metal ions. The conductivity originates from the BDH-TTP organic donors arranged in a κ-type molecular packing. At 4 kbar, compound 1 behaves as a metal down to ∼100 K, showing high conductivity (∼10 S cm(-1)) at room temperature. When applying a pressure higher than 7 kbar, the metal-insulator (M-I) transition is suppressed and the compound retains the metallic state down to low temperatures (2 K). For 1, ESR signals have been interpreted as being caused by the fine structure splitting of the high-spin (S = 5/2) state of Fe(III) in the distorted octahedral crystal field from the ligands. At 4 kbar, the isostructural compound 2 behaves as a metal down to ∼100 K, although it is noteworthy that the M-I transition is not suppressed, even at pressures of 15 kbar. For 2, only the signal assigned to delocalized π-electrons has been observed in the ESR measurements.