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Mismatch negativity (MMN) has gained attention as a biomarker for psychosis and a translational intermediate phenotype in animal models of psychosis, including rodents and non-human primates. MMN has been linked to global functioning (Global Assessment of Functioning [GAF] score) and prognosis (psychosis onset or remission), suggesting that MMN reflects activities beyond auditory processing alone. This review examines the 45-year history of MMN from the perspective of psychiatric researchers and discusses current advances in computational and translational research on MMN, summarizing the current understanding of the MMN generation mechanism. We then address the essential question, "What do we observe through MMN?" Currently, we regard the relationship between global functioning in the real world and MMN as the key to answering this question. As a preliminary investigation, we analyzed the relationship between GAF as an objective variable and MMN, diagnosis, and basic epidemiological factors (age, sex, premorbid intelligence quotient) as explanatory variables (total n = 201, healthy controls: n = 41, patients with psychiatric disorders: n = 160) without assuming diagnostic categories. The relationship between functional outcomes and MMN was confirmed without a case-control design. Finally, we propose that new neurophysiological studies should acknowledge psychophysiological responses such as emotion, intention, and autonomic responses, as well as behavioral differences among participants beyond the dichotomy between healthy controls and patients. Measurements could be conducted in various settings from the participant's perspective. We discuss the potential for research investigating psychosis based on the interaction between individuals and the environment, using MMN as an illustrative model., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

KRAS G12C inhibitors sotorasib and adagrasib have been approved for the treatment of KRAS G12C -mutant non-small cell lung cancer (NSCLC). However, the efficacy of single-agent treatments is limited, presumably due to multiple resistance mechanisms. To overcome these therapeutic limitations, combination strategies that potentiate the antitumor efficacy of KRAS G12C inhibitors must be developed. Through unbiased high-throughput screening of 1395 kinase inhibitors, we identified adavosertib, a WEE1 inhibitor, as a promising combination partner of sotorasib. The combination of sotorasib and adavosertib exhibited synergistic antiproliferative activities both in vitro and in vivo, irrespective of TP53, STK11, and KEAP1 co-mutation profiles. WEE1 inhibition potentiated MCL-1-mediated apoptosis in sotorasib-treated cancer cells. Mechanistically, the combination downregulated MCL-1 protein levels by attenuating de novo translation and enhancing its degradation. WEE1 overexpression conferred resistance against sotorasib via MCL-1 upregulation. Moreover, cells that acquired sotorasib resistance profoundly upregulated both WEE1 and MCL-1 proteins, highlighting WEE1 as a crucial driver of sotorasib resistance. Importantly, WEE1 inhibition re-sensitized resistant cells to sotorasib treatment. The current findings demonstrate that combined inhibition of KRAS G12C and WEE1 not only exhibits synergistic antitumor efficacy but also overcomes resistance to KRAS G12C inhibitors, thus representing a novel therapeutic strategy for KRAS G12C -mutant NSCLC., Competing Interests: Declaration of competing interest A.H. reports grants or contracts from CIMIC Pharma Science, TOSOH, Chordia Thera, LSI medience, Chugai Pharmaceutical, Eli Lilly and Company, Sysmex, Healios, Konica Minolta, Boehringer Inhelheim, Eisai, Daiichi Sankyo, Astra Zeneca, Mitsubishi Tanabe Pharma, and Novartis Pharma. T.Y. reports grants or contracts from Novartis, AbbVie, Amgen, Daiichi-Sankyo, AstraZeneca, MSD, Chugai, Astellas, Medpace, Boehringer Ingelheim, BMS, Ono and Merck. Y.O. reports research funding from AstraZeneca, Chugai, Lilly, ONO, BMS, Pfizer, Taiho, Novartis, Takeda, Daiichi-Sankyo, Janssen; personal fees for expert testimony from AstraZeneca, Chugai, ONO, BMS, Celltrion, Amgen, Nippon Kayaku, Boehringer Ingelheim, AnHeart Therapeutics Inc., PharmaMar; personal fees as speakers from AstraZeneca, Chugai, Eli Lilly, ONO, BMS, Boehringer Ingelheim, Bayer, Pfizer, MSD, Taiho, Nippon Kayaku, Kyowa Hakko Kirin, Eisai, Daiichi-Sankyo, outside the submitted work. S.K. reports research support from Chugai Pharmaceutical. S.S.K. reports research support from Boehringer Ingelheim, MiRXES, Johnson&Johnson, and Taiho Therapeutics, as well as personal fees (honoraria) from AstraZeneca, Boehringer Ingelheim, Bristol Meyers Squibb, Chugai Pharmaceutical, and Takeda Pharmaceuticals, plus royalties from Life Technologies; all interests are outside the submitted work. A.O. was an employee of Takeda Pharmaceutical Company, Ltd. A.O. is a part-time employee of Astellas Pharma Inc. as a cross-appointment system. A.O. reported paid consulting or advisory roles for Ono Pharmaceutical Company Ltd., Craif Inc., and GEXVal Inc. out of this study. A.O. has received research funding from Takeda Pharmaceutical, Daiichi-Sankyo and Astellas Pharma companies out of this study., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Duplication of chromosome 15q11-13 has been reported to be one of the most frequent cytogenetic copy number variations in autism spectrum disorder (ASD), and a mouse model of paternal 15q11-13 duplication was generated, termed 15q dup mice. While previous studies have replicated some of the behavioral and brain structural phenotypes of ASD separately, the relationship between brain structure and behavior has rarely been examined. In this study, we performed behavioral experiments related to anxiety and social behaviors and magnetic resonance imaging (MRI) using the same set of 15q dup and wild-type mice. 15q dup mice showed increased anxiety and a tendency toward alterations in social behaviors, as reported previously, as well as variability in terms of sociability. MRI analysis revealed that a lower sociability index was correlated with a smaller gray matter volume in the right medial entorhinal cortex. These results may help to understand how variability in behavioral phenotypes of ASD arises even in individuals with the same genetic background and to determine the individual differences in neurodevelopmental trajectory correlated with specific brain structures that underlie these phenotypes., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is an autoimmune-demyelinating disease with an inflammatory pathology formed by self-reactive lymphocytes with activated glial cells. Progressive MS, characterized by resistance to medications, significantly differs from the non-progressive form in gut microbiome profiles. After confirming an increased abundance of "Tyzzerella nexilis" in various cohorts of progressive MS, we identified a distinct cluster of T. nexilis strains enriched in progressive MS based on long-read metagenomics. The distinct T. nexilis cluster is characterized by a large number of mobile genetic elements (MGEs) and a lack of defense systems against MGEs. Microbial genes for sulfate reduction and flagella formation with pathogenic implications are specific to this cluster. Moreover, these flagellar genes are encoded on MGEs. Mono-colonization with MGE-enriched T. nexilis made germ-free mice more susceptible to experimental autoimmune encephalomyelitis. These results indicate that the progression of MS may be promoted by MGE-enriched T. nexilis with potentially pathogenic properties., Competing Interests: Declaration of interests T.Y. served on the scientific advisory board of Biogen Japan, Ltd., and received support for research and clinical trials from Sanofi K.K., Chugai Pharmaceutical, Co., Ltd., UCB Japan Co., Ltd., Biogen Japan, Ltd., Chiome Bioscience, Inc., Novartis Pharma K.K., and Mebix, Inc., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Patient-derived xenograft (PDX) models, in which tumor tissues resected from cancer patients are transplanted into immunocompromised mice, have been recently considered the most reliable preclinical models that quite accurately stimulate the real-world characteristics and microenvironments of tumors in patients. The ethical uniqueness of the PDX model, which lies in the fact that it is a hybrid of living human tumor tissue and a carrier mouse, raises several ethical concerns. This study presents four ethical points for consideration and a model ethical governance policy for the implementation and use of PDX models for research. First, PDX models carrying living tumor tissues originating from individual patients with dignity must be treated ethically as materials and data in compliance with the principle of respect for persons. Second, although PDX models themselves are patentable and can be commercialized, it is a standard view, as represented by the Oviedo Convention by the Council of Europe, that those living tumor tissues carried by PDX models shall not give rise to financial gain since those tissues are human body parts; therefore, they should be treated according to a recent ethical approach with the custodianship model as the trust property of patients of origin and shall not be subjected directly to monetary transactions. Third, PDX models must be treated with due care in an ethical manner in line with experimental animal ethics. Finally, the implementation and use of PDX models for research purposes must comply with national and international regulations on both animal experimentation and human subject research. These four points should be carefully examined and properly institutionalized as an ethical governance policy in each institution that plans on utilizing or implementing PDX models for research., Competing Interests: None, (Copyright © Japan Medical Association.)

Pembrolizumab is a major treatment for recurrent or advanced non-small-cell lung cancer (NSCLC). However, data on its use and pharmacokinetics (PK) in older patients are limited. This open-label, multicenter, observational study evaluated real-world data on the safety, efficacy, and PK of pembrolizumab in older patients with NSCLC. In 99 patients aged ≥75 years, PK was determined by liquid chromatography-mass spectrometry on pretreatment samples. Performance status (PS), geriatric assessment (GA), overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. The median age was 78 (75-87) years. PS was 2-3 in 14 patients. The median ORR, PFS, and OS were 47.5%, 8.0, and 20.5 months, respectively. Although PK and ORR were not significantly associated, patients with the lowest Cycle 1-trough quartile (Q1) experienced poorer PFS (Q1 vs. Q2-4; 3.4 vs. 11.8 months, P = 0.006) and OS (Q1 vs. Q2-4; 9.9 vs. 21.7 months, P = 0.005) than in other quartiles overall, and even in the PD-L1 ≥50% subset (PFS, Q1 vs. Q2-4; 4.1 vs. 14.7 months, P = 0.005; OS, Q1 vs. Q2-4; 9.4 vs. 22.1 months, P = 0.010). The Q1 subgroup was characterized by poor PS and lower albumin, and more frequent "weight loss ≥ 10%" on the GA. Pembrolizumab therapy had similar PK and efficaciousness in older as well as younger patients. In patients with PS ≥2, low albumin, and vulnerable GA, early increases in PK levels are less likely, potentially diminishing efficacy even when PD-L1 ≥50%., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Sleep is regulated by homeostatic processes, yet the biological basis of sleep pressure that accumulates during wakefulness, triggers sleep, and dissipates during sleep remains elusive. We explored a causal relationship between cellular synaptic strength and electroencephalography delta power indicating macro-level sleep pressure by developing a theoretical framework and a molecular tool to manipulate synaptic strength. The mathematical model predicted that increased synaptic strength promotes the neuronal "down state" and raises the delta power. Our molecular tool (synapse-targeted chemically induced translocation of Kalirin-7, SYNCit-K), which induces dendritic spine enlargement and synaptic potentiation through chemically induced translocation of protein Kalirin-7, demonstrated that synaptic potentiation of excitatory neurons in the prefrontal cortex (PFC) increases nonrapid eye movement sleep amounts and delta power. Thus, synaptic strength of PFC excitatory neurons dictates sleep pressure in mammals.

Sleep apnea is regarded as an important risk factor in the pathogenesis of Alzheimer disease (AD). Chronic intermittent hypoxia treatment (IHT) given during the sleep period of the circadian cycle in experimental animals is a well-established sleep apnea model. Here we report that transient IHT for 4 days on AD model mice causes Aβ overproduction 2 months after IHT presumably via upregulation of synaptic BACE1, side-by-side with tau hyperphosphorylation. These results suggest that even transient IHT may be sufficient to cause long-lasting changes in the molecules measured as AD biomarkers in the brain., Competing Interests: Declaration of Competing Interest The authors declare no further competing financial interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Electroconvulsive therapy (ECT) is one of the most effective psychiatric treatments but the underlying mechanisms are still unclear. In vivo human magnetic resonance imaging (MRI) studies have consistently reported ECT-induced transient hippocampal volume increases, and an animal model of ECT (electroconvulsive stimulation: ECS) was shown to increase neurogenesis. However, a causal relationship between neurogenesis and MRI-detectable hippocampal volume increases following ECT has not been verified. In this study, mice were randomly allocated into four groups, each undergoing a different number of ECS sessions (e.g., 0, 3, 6, 9). T2-weighted images were acquired using 11.7-tesla MRI. A whole brain voxel-based morphometry analysis was conducted to identify any ECS-induced brain volume changes. Additionally, a histological examination with super-resolution microscopy was conducted to investigate microstructural changes in the brain regions that showed volume changes following ECS. Furthermore, parallel experiments were performed on X-ray-irradiated mice to investigate the causal relationship between neurogenesis and ECS-related volume changes. As a result, we revealed for the first time that ECS induced MRI-detectable, dose-dependent hippocampal volume increase in mice. Furthermore, increased hippocampal volumes following ECS were seen even in mice lacking neurogenesis, suggesting that neurogenesis is not required for the increase. The comprehensive histological analyses identified an increase in excitatory synaptic density in the ventral CA1 as the major contributor to the observed hippocampal volume increase following ECS. Our findings demonstrate that modification of synaptic structures rather than neurogenesis may be the underlying biological mechanism of ECT/ECS-induced hippocampal volume increase., (© 2024. The Author(s).)

Despite widespread adoption of tissue clearing techniques in recent years, poor access to suitable light-sheet fluorescence microscopes remains a major obstacle for biomedical end-users. Here, we present descSPIM (desktop-equipped SPIM for cleared specimens), a low-cost ($20,000-50,000), low-expertise (one-day installation by a non-expert), yet practical do-it-yourself light-sheet microscope as a solution for this bottleneck. Even the most fundamental configuration of descSPIM enables multi-color imaging of whole mouse brains and a cancer cell line-derived xenograft tumor mass for the visualization of neurocircuitry, assessment of drug distribution, and pathological examination by false-colored hematoxylin and eosin staining in a three-dimensional manner. Academically open-sourced ( https://github.com/dbsb-juntendo/descSPIM ), descSPIM allows routine three-dimensional imaging of cleared samples in minutes. Thus, the dissemination of descSPIM will accelerate biomedical discoveries driven by tissue clearing technologies., (© 2024. The Author(s).)

The tau protein is a microtubule-associated protein that promotes microtubule stabilization. The phosphorylation of the tau protein has been linked to its dissociation from microtubules. Here, we examined the relationship between neuronal depolarization activity and tau protein phosphorylation by employing model systems in culture as well as in vivo. The KCl-evoked depolarization of cultured neurons has often been used to investigate the effects of neuronal activity. We found dephosphorylation at AT8 sites (S202, T205), T212, AT180 sites (T231, S235), and S396 in KCl-simulated cultured neurons. We also found that the KCl-induced tau protein dephosphorylation increases the level of the tau protein fractionated with stable microtubules. In an in vivo experiment, we demonstrated that the exposure of mice to a new environment activates protein phosphatase 1 in the mouse hippocampus and induces tau protein dephosphorylation. We also found an increased amount of the tau protein in a stable microtubule fraction, suggesting that the dephosphorylation of the tau protein may lead to its increased microtubule association in vivo. These results suggest that the association of microtubules with tau proteins may be regulated by the tau protein phosphorylation status affected by neuronal electrical activity.

E7820 and Indisulam (E7070) are sulfonamide molecular glues that modulate RNA splicing by degrading the splicing factor RBM39 via ternary complex formation with the E3 ligase adaptor DCAF15. To identify biomarkers of the antitumor efficacy of E7820, we treated patient-derived xenograft (PDX) mouse models established from 42 patients with solid tumors. The overall response rate was 38.1% (16 PDXs), and tumor regression was observed across various tumor types. Exome sequencing of the PDX genome revealed that loss-of-function mutations in genes of the homologous recombination repair (HRR) system, such as ATM, were significantly enriched in tumors that responded to E7820 (p = 4.5 × 10 3 ). Interestingly, E7820-mediated double-strand breaks in DNA were increased in tumors with BRCA2 dysfunction, and knockdown of BRCA1/2 transcripts or knockout of ATM, ATR, or BAP1 sensitized cancer cells to E7820. Transcriptomic analyses revealed that E7820 treatment resulted in the intron retention of mRNAs and decreased transcription, especially for HRR genes. This induced HRR malfunction probably leads to the synthetic lethality of tumor cells with homologous recombination deficiency (HRD). Furthermore, E7820, in combination with olaparib, exerted a synergistic effect, and E7820 was even effective in an olaparib-resistant cell line. In conclusion, HRD is a promising predictive biomarker of E7820 efficacy and has a high potential to improve the prognosis of patients with HRD-positive cancers., (© 2024. The Author(s).)

Introduction: This study validated real-world pharmacokinetic (PK) data using an established population PK (PopPK) model for atezolizumab in Japanese patients with NSCLC and explored the relationship between PK parameters, effectiveness, and adverse events (AEs) for the 1200 mg once every three weeks regimen., Methods: A subgroup of 262 of 1039 patients from J-TAIL consented to this exploratory research for PK evaluation of atezolizumab monotherapy for unresectable advanced/recurrent NSCLC (August 2018 to October 2019; 197 institutions). We evaluated plasma concentrations before the start of the third cycle of atezolizumab infusion classified into quartiles 1 to 4, their association with effectiveness, and the association between atezolizumab maximum plasma concentrations (C max ) calculated using the existing PopPK model and AEs of special interest (AESIs)., Results: Overall, 175 of 262 patients were included; baseline characteristics were similar to those of patients enrolled in J-TAIL (Eastern Cooperative Oncology Group performance status ≥ 2, 12.0%; age ≥ 75 y, 28.9%; atezolizumab as more than or equal to third-line treatment, 57.5%). Atezolizumab plasma concentrations were similar to previously reported data among Japanese/non-Japanese patients. The overall survival was significantly shorter in patients with lower atezolizumab plasma concentrations in Q1 versus Q2 to Q4, although progression-free survival remained the same. The PK data adequately fit the PopPK model, with the frequency of AESIs increasing as the calculated C max at cycle 1 increased., Conclusions: In real-world Japanese patients with unresectable advanced/recurrent NSCLC, PKs were similar to previous reports. Certain patient populations had shorter overall survival, and atezolizumab plasma concentrations in cycle 3 were lower in this population. Elevated C max at cycle 1 may be associated with an increased frequency of AESIs., Competing Interests: Dr. Yagishita has received grants or contracts from Nippon Boehringer Ingelheim and payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from LSI Medience in the past 36 months. Dr. Goto has received grants or contracts from 10.13039/100004325AstraZeneca and 10.13039/100004319Pfizer; grants for the institution from AbbVie, Eli Lilly, Bristol Myers Squibb, Ono, Novartis, Kyorin, Daiichi Sankyo, Novartis, and Preferred Network; payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Eli Lilly, Chugai, Taiho, Boehringer Ingelheim, Ono, Bristol Myers Squibb, Pfizer, Merck Sharp & Dohme, Novartis, Merck, and Thermo Fisher; has participated in data safety monitoring boards or advisory boards for AstraZeneca, Chugai, Boehringer Ingelheim, Eli Lilly, Taiho, Pfizer, Novartis, Guardant Health, Illumina, Daiichi Sankyo, Ono, Bristol Myers Squibb, and Merck Sharp & Dohme; and had a leadership or fiduciary role in Cancer Net Japan and JAMT in the past 36 months. Dr. Nishio has received payment or honoraria for lectures from Ono, Chugai, Taiho, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, AstraZeneca, Merck Sharp & Dohme, AbbVie, Takeda, Pfizer, Boehringer Ingelheim, Novartis, Nippon Kayaku, Merck, and Janssen in the past 36 months. Dr. Akamatsu has received grants or contracts from 10.13039/100002429Amgen, Eli Lilly, and 10.13039/100010795Chugai; payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Amgen, Ono, AstraZeneca, Pfizer, Boehringer Ingelheim, Takeda, Bristol Myers Squibb, Taiho, Chugai, Eli Lilly, Merck Sharp & Dohme, Nippon Kayaku, and Novartis; and has participated in data safety monitoring boards or advisory boards for Amgen and Janssen in the past 36 months. Dr. Hayashi has received grants or contracts from IQVIA Services, Syneos Health, EPS Corporation, Nippon Kayaku, Takeda, Merck Sharp & Dohme, Amgen, Taiho, Bristol Myers Squibb, Janssen, CMIC, Pfizer, Labcorp Drug Development, Kobayashi, Eisai, EP-CRSU, Shionogi, Otsuka, GlaxoSmithKline, Sanofi, Chugai, Nippon Boehringer Ingelheim, SRL Medisearch, PRA Health Sciences, Astellas Pharma, Ascent Development Services, Bayer Yakuhin, Parexel, Kissei, EPS Corporation, Daiichi Sankyo, Ono, PPD-SNBL, SymBio, Mebix, AstraZeneca, Mochida, Japan Clinical Research Operations, Eli Lilly, Novartis, Otsuka, and SRL; payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Ono, Daiichi Sankyo, AstraZeneca, Eli Lilly, Chugai Pharmaceutical, Merck Sharp & Dohme, Pfizer, Nippon Boehringer Ingelheim, Merck, 3H Clinical Trial, Novartis, Bristol Myers Squibb, Amgen, Sysmex Corporation, Takeda, and Guardant Health in the past 36 months. Dr. Miura has received payment or honoraria for lectures from Chugai, Taiho, Ono, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Boehringer Ingelheim, and Takeda in the past 36 months. Dr. Kagamu has received payment or honoraria for lectures from Chugai, Ono, AstraZeneca, and Bristol Myers Squibb in the past 36 months. Dr. Yoshino has received grants or contracts from AstraZeneca, Chugai, Daiichi Sankyo, and Taiho; consulting fees from 10.13039/100004325AstraZeneca, 10.13039/100010795Chugai, 10.13039/501100002736Covidien, and 10.13039/100004331Johnson & Johnson; and payment or honoraria for lectures from AstraZeneca, Chugai, Daiichi Sankyo, Eli Lilly, Covidien, Johnson & Johnson, Taiho, Amgen, Merck Sharp & Dohme, CSL Behring, KM Biologics, Intuitive Surgical, Shionogi, Tsumura, and Takeda in the past 36 months. Dr. Misumi has received honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Chugai, AstraZeneca, and Miyarisan in the past 36 months. Dr. Hata has received grants or contracts from Merck Sharp & Dohme, Taiho, Eli Lilly, Chugai, Boehringer Ingelheim, and AstraZeneca, and payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Eli Lilly, Merck Sharp & Dohme, Chugai, Pfizer, AstraZeneca, Boehringer Ingelheim, and Taiho in the past 36 months. Dr. Kijima has received grants or contracts from Chugai and payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Chugai in the past 36 months. Dr. Mitsudomi has received grants or contracts from Merck Sharp & Dohme, Ono, AstraZeneca, and Chugai; payment or honoraria for speaker’s bureau from Merck Sharp & Dohme, Ono, Bristol Myers Squibb, AstraZeneca, and Chugai; has participated in advisory boards for Merck Sharp & Dohme, Ono, Bristol Myers Squibb, AstraZeneca, and Chugai; and has been a President at IASLC in the past 36 months. The remaining authors declare no conflict of interest., (© 2024 The Authors.)

cAMP is a universal second messenger regulated by various upstream pathways including Ca 2+ and G-protein-coupled receptors (GPCRs). To decipher in vivo cAMP dynamics, we rationally designed cAMPinG1, a sensitive genetically encoded green cAMP indicator that outperformed its predecessors in both dynamic range and cAMP affinity. Two-photon cAMPinG1 imaging detected cAMP transients in the somata and dendritic spines of neurons in the mouse visual cortex on the order of tens of seconds. In addition, multicolor imaging with a sensitive red Ca 2+ indicator RCaMP3 allowed simultaneous measurement of population patterns in Ca 2+ and cAMP in hundreds of neurons. We found Ca 2+ -related cAMP responses that represented specific information, such as direction selectivity in vision and locomotion, as well as GPCR-related cAMP responses. Overall, our multicolor suite will facilitate analysis of the interaction between the Ca 2+ , GPCR and cAMP signaling at single-cell resolution both in vitro and in vivo., (© 2024. The Author(s).)

Background: Patients with cancer, particularly those undergoing chemotherapy, are at risk from the low immunogenicity of Coronavirus Disease 19 (COVID-19) vaccines., Methods: This prospective study assessed the seroconversion rate of COVID-19 vaccines among patients with cancer and hospital staff. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific IgG (S-IgG) concentrations were evaluated before the first vaccination, and 1-3 and 4-6 months after the second vaccination. The primary endpoint was the seroconversion rate measured 1-3 months after the second vaccine., Results: In total, 590 patients and 183 healthy hospital staff were analyzed. At 1-3 months after the second vaccination, the S-IgG antibody concentration exceeded the cut-off value (20 BAU/mL) in 96.1% (567/590) of the patients with cancer and 100% (183/183) of the healthy controls (p = 0.0024). At 4-6 months after the second vaccination, the S-IgG antibody concentration exceeded the cut-off value (20 BAU/ml for S-IgG) in 93.1% (461/495) of the patients with cancer and 100% (170/170) of the healthy controls (p < 0.0001). Old age, being male, and low lymphocyte count were related to low SARS-CoV-2 S-IgG levels 1-3 months after the second vaccination among patients, while body mass index, smoking history, and serum albumin level were not. Patients undergoing platinum combination therapy and alkylating agent among cytotoxic drugs, and PARP inhibitor, mTOR inhibitor, and BCR-ABL inhibitor exhibited a low S-IgG antibody concentration compared to the no treatment group., Conclusions: COVID-19 vaccine immunogenicity was reduced among patients with cancer, especially under several treatment regimens., (© 2024. The Author(s).)

The progressive ratio (PR) lever-press task serves as a benchmark for assessing goal-oriented motivation. However, a well-recognized limitation of the PR task is that only a single data point, known as the breakpoint, is obtained from an entire session as a barometer of motivation. Because the breakpoint is defined as the final ratio of responses achieved in a PR session, variations in choice behavior during the PR task cannot be captured. We addressed this limitation by constructing four reinforcement learning models: a simple Q-learning model, an asymmetric model with two learning rates, a perseverance model with choice traces, and a perseverance model without learning. These models incorporated three behavioral choices: reinforced and non-reinforced lever presses and void magazine nosepokes, because we noticed that male mice performed frequent magazine nosepokes during PR tasks. The best model was the perseverance model, which predicted a gradual reduction in amplitudes of reward prediction errors (RPEs) upon void magazine nosepokes. We confirmed the prediction experimentally with fiber photometry of extracellular dopamine (DA) dynamics in the ventral striatum of male mice using a fluorescent protein (genetically encoded GPCR activation-based DA sensor: GRAB DA2m ). We verified application of the model by acute intraperitoneal injection of low-dose methamphetamine (METH) before a PR task, which increased the frequency of magazine nosepokes during the PR session without changing the breakpoint. The perseverance model captured behavioral modulation as a result of increased initial action values, which are customarily set to zero and disregarded in reinforcement learning analysis. Our findings suggest that the perseverance model reveals the effects of psychoactive drugs on choice behaviors during PR tasks., Competing Interests: The 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 Ihara, Shikano, Kato, Yagishita, Tanaka and Takata.)

Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) is a subset of ALL that demonstrated a high treatment failure rate. One of the hallmarks of Ph-like ALL is PDGFRB gene fusion, with fusion partner proteins often harboring dimerization domains and enhancing the kinase activity of PDGFRB. We determined a novel oncogenic PDGFRB fusion gene, NRIP1::PDGFRB, from a pediatric patient with ALL, encoding a protein with the carboxy-terminal kinase domain of PDGFRB, without the partner peptide. We confirmed the oncogenic potential of NRIP1::PDGFRB in vitro and the efficacy of all ABL1-specific inhibitor generations, including imatinib, dasatinib, nilotinib, and ponatinib, in suppressing this potential. PDGFRB activation mechanism may include juxtamembrane domain truncation in the predicted peptide. In conclusion, we determined a novel fusion gene pattern in Ph-like ALL., (© 2023. The Author(s).)

Background: Delta-like ligand 3 (DLL3) is a therapeutic target in small-cell lung cancer (SCLC). However, how DLL3 expression status affects the tumor microenvironment (TME) and clinical outcomes in SCLC remains unclear., Methods: This retrospective study included patients with postoperative limited-stage (LS)-SCLC and extensive-stage (ES)-SCLC treated with platinum and etoposide (PE) plus anti-programmed cell death ligand 1 (PD-L1) antibody. We investigated the relationship of DLL3 expression with TME, mutation status, tumor neoantigens, and immunochemotherapy., Results: In the LS-SCLC cohort (n = 59), whole-exome sequencing revealed that DLL3 High cases had significantly more neoantigens (P = 0.004) and a significantly higher rate of the signature SBS4 associated with smoking (P = 0.02) than DLL3 Low cases. Transcriptome analysis in the LS-SCLC cohort revealed that DLL3 High cases had significantly suppressed immune-related pathways and dendritic cell (DC) function. SCLC with DLL3 High had significantly lower proportions of T cells, macrophages, and DCs than those with DLL3 Low . In the ES-SCLC cohort (n = 30), the progression-free survival associated with PE plus anti-PD-L1 antibody was significantly worse in DLL3 High cases than in DLL3 Low cases (4.7 vs. 7.4 months, P = 0.01)., Conclusions: Although SCLC with DLL3 High had a higher neoantigen load, these tumors were resistant to immunochemotherapy due to suppressed tumor immunity by inhibiting antigen-presenting functions., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

The greater the reward expectations are, the more different the brain's physiological response will be. Although it is well-documented that better-than-expected outcomes are encoded quantitatively via midbrain dopaminergic (DA) activity, it has been less addressed experimentally whether worse-than-expected outcomes are expressed quantitatively as well. We show that larger reward expectations upon unexpected reward omissions are associated with the preceding slower rise and following larger decrease (DA dip) in the DA concentration at the ventral striatum of mice. We set up a lever press task on a fixed ratio (FR) schedule requiring five lever presses as an effort for a food reward (FR5). The mice occasionally checked the food magazine without a reward before completing the task. The percentage of this premature magazine entry (PME) increased as the number of lever presses approached five, showing rising expectations with increasing proximity to task completion, and hence greater reward expectations. Fibre photometry of extracellular DA dynamics in the ventral striatum using a fluorescent protein (genetically encoded GPCR activation-based DA sensor: GRAB DA2m ) revealed that the slow increase and fast decrease in DA levels around PMEs were correlated with the PME percentage, demonstrating a monotonic relationship between the DA dip amplitude and degree of expectations. Computational modelling of the lever press task implementing temporal difference errors and state transitions replicated the observed correlation between the PME frequency and DA dip amplitude in the FR5 task. Taken together, these findings indicate that the DA dip amplitude represents the degree of reward expectations monotonically, which may guide behavioural adjustment., (© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background/aim: Fucoxanthin (Fx), a dietary marine xanthophyll, exerts potent anticancer effects in various colorectal cancer (CRC) animal models. However, therapeutic effects of Fx in human cancer tissues remain unclear. A patient-derived xenograft (PDX) mouse model transplanted with cancer tissues from patients is widely accepted as the best preclinical model for evaluating the anticancer potential of drug candidates., Materials and Methods: Herein, we investigated the anticancer effects of Fx in PDX mice transplanted with cancer tissues derived from a patient with CRC (CRC-PDX) using LC-MS/MS- and western blot-based proteome analysis., Results: The tumor in the patient with CRC was a primary adenocarcinoma (T3N0M0, stage II) showing mutations of certain genes that were tumor protein p53 (TP53), AT-rich interaction domain 1A (ARID1A), neuroblastoma RAS viral oncogene homolog (NRAS), and PMS1 homolog 2 (PMS2). Administration of Fx significantly suppressed the tumor growth (0.6-fold) and tended to induce differentiation in CRC-PDX mice. Fx up-regulated glycanated-decorin (Gc-DCN) expression, and down-regulated Kinetochore-associated protein DSN1 homolog (DSN1), phospho(p) focal adhesion kinase (pFAK)(Tyr 397 ), pPaxillin(Tyr 31 ), and c-MYC involved in growth, adhesion, and/or cell cycle, in the tumors of CRC-PDX mice than in control mice. Alterations in the five proteins were consistent with those in human CRC HT-29 and HCT116 cells treated with fucoxanthinol (FxOH, a major metabolite of Fx)., Conclusion: Fx suppresses development of human-like CRC tissues, especially through growth, adhesion, and cell cycle signals., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Most cervical adenocarcinomas are associated with human papillomavirus (HPV). Gastric-type cervical adenocarcinoma (GAS), an HPV-independent adenocarcinoma, shows an aggressive clinical feature, resulting in a poor prognosis. Resistance to chemotherapy poses a difficulty in managing patients with metastatic GAS. We aimed to establish patient-derived xenografts (PDXs) of tumors from two patients with GAS and evaluated protein biomarkers for drug development using immunohistochemistry., Methods: Two PDXs were established 78 and 48 days after transplanting the patient's tumor tissues into immunodeficient mice, respectively. PDX and patient's tumor samples were stained for HER2, HER3, PMS2, MSH6, PanTrk, and ARID1A to evaluate biomarkers for therapeutic targets. In addition, whole exome sequencing and RNA sequencing were performed on available samples., Results: The pathological findings in morphological features and immunohistochemical profiles from the established PDXs were similar to those from the patients' surgical tumor specimens. HER3 was overexpressed in the patient's tumors, and the corresponding PDX tumors and HER2 was weakly stained in both types of tumor samples. In all PDX and patient tumor samples, PMS2, MSH6, and ARID1A were retained, and PanTrk was not expressed. In addition, a total of 10 samples, including tumor tissue samples from 8 other GAS patients, were evaluated for HER3 expression scores, all of which were 2 + or higher., Conclusions: In summary, we evaluated biomarkers for therapeutic targets using newly established PDX models of GAS. Frequent HER3 overexpression and HER2 expression in GAS tumors suggest the possibility of new treatments for patients with GAS by targeting HER3 and HER2., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yuki Kojima, Hiroshi Yoshida, Toshihiro Okuya, Hitomi S. Okuma, Kazuki Sudo, Maki Tanioka, Tatsunori Shimoi, Kenji Tamura, Yasuhito Tanase, Masaya Uno, Mitsuya Ishikawa, Motoko Arakaki, Shigehiro Yagishita and Tomoyasu Kato have no conflict interest to disclose; Tadaaki Nishikawa received research funds from Takeda Pharmaceutical Company, Eisai, AstraZeneca, outside the submitted work; Emi Noguchi received research funds from Pfizer, Taiho, Eli Lilly, AstraZeneca, Chugai, Eisai, outside the submitted work; Hitoshi Ichikawa received research funds from Chugai Pharma, Eisai, Healios, Ono Pharmaceutical, outside the submitted work; Akinobu Hamada received research funds from Shimadzu Corporation, Daiichi Sankyo Company, Chugai Pharmaceutical, AstraZeneca, outside the submitted work; Yasuhiro Fujiwara received research funds from AstraZeneca, Chugai, Daiichi Sankyo, Bristol-Myers, SRL, Santen, outside the submitted work; Kan Yonemori received research funds from Pfizer, AstraZeneca, Eisai, Takeda Pharmaceutical Company, Chugai, Ono Pharmaceutical Company, Novartis, Daiichi Sankyo, outside the submitted work., (© 2023 The Author(s).)

By nature, humans are " tojisha (participating subjects/player-witnesses)" who encounter an unpredictable real world. An important characteristic of the relationship between the individual brain and the world is that it creates a loop of interaction and mutual formation. However, cognitive sciences have traditionally been based on a model that treats the world as a given constant. We propose incorporating the interaction loop into this model to create "world-informed neuroscience (WIN)". Based on co-productive research with people with minority characteristics that do not match the world, we hypothesize that the tojisha and the world interact in a two-dimensional way of rule-based and story-based. By defining the cognitive process of becoming tojisha in this way, it is possible to contribute to the various issues of the real world and diversity and inclusion through the integration of the humanities and sciences. The critical role of the brain dopamine system as a basis for brain-world interaction and the importance of research on urbanicity and adolescent development as examples of the application of WIN were discussed. The promotion of these studies will require bidirectional translation between human population science and animal cognitive neuroscience. We propose that the social model of disability should be incorporated into cognitive sciences, and that disability-informed innovation is needed to identify how social factors are involved in mismatches that are difficult to visualize. To promote WIN to ultimately contribute to a diverse and inclusive society, co-production of research from the initial stage of research design should be a baseline requirement., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist 3,4-dihydroxy-L-phenylalanine (L-DOPA) to treat Parkinson's disease (L-DOPA-induced dyskinesia [LID]) or dopamine antagonists to treat schizophrenia (tardive dyskinesia [TD]). However, it remains unknown why distinct types of medications for distinct neuropsychiatric disorders induce similar involuntary movements. Here, we search for a shared structural footprint using magnetic resonance imaging-based macroscopic screening and super-resolution microscopy-based microscopic identification. We identify the enlarged axon terminals of striatal medium spiny neurons in LID and TD model mice. Striatal overexpression of the vesicular gamma-aminobutyric acid transporter (VGAT) is necessary and sufficient for modeling these structural changes; VGAT levels gate the functional and behavioral alterations in dyskinesia models. Our findings indicate that lowered type 2 dopamine receptor signaling with repetitive dopamine fluctuations is a common cause of VGAT overexpression and late-onset dyskinesia formation and that reducing dopamine fluctuation rescues dyskinesia pathology via VGAT downregulation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Loquat (Eriobotrya japonica) leaves contain many bioactive components such as ursolic acid (UA) and amygdalin. We investigated the effects of loquat leaf powder and methanol extract in human neuroglioma H4 cells stably expressing the Swedish-type APP695 (APP NL -H4 cells) and C57BL/6 J mice. Surprisingly, the extract greatly enhanced cellular amyloid-beta peptide (Aβ) 42 productions in APP NL -H4 cells. Administration of leaf powder increased Aβ42 levels after 3 months and decreased levels after 12 months compared to control mice. Leaf powder had no effect on working memory after 3 months, but improved working memory after 12 months. Administration of UA decreased Aβ42 and P-tau levels and improved working memory after 12 months, similar to the administration of leave powder for 12 months. Amygdalin enhanced cellular Aβ42 production in APP NL -H4 cells, which was the same as the extract. Three-month administration of amygdalin increased Aβ42 levels slightly but did not significantly increase them, which is similar to the trend observed with the administration of leaf powder for 3 months. UA was likely the main compound contained in loquat leaves responsible for the decrease in intracerebral Aβ42 and P-tau levels. Also, amygdalin might be one of the compounds responsible for the transiently increased intracerebral Aβ42 levels., (© 2023. Springer Nature Limited.)

Background: Risk factors for predicting pneumonitis during durvalumab consolidation after chemoradiotherapy (CRT) in locally advanced non-small cell lung cancer (LA-NSCLC) are still lacking. Extracellular vesicles (EVs) play a crucial role in intercellular communication and are potential diagnostic tools for various diseases., Methods: We retrospectively collected predurvalumab treatment serum samples from patients treated with durvalumab for LA-NSCLC, isolated EVs using anti-CD9 and anti-CD63 antibodies, and performed proteomic analyses. We examined EV proteins that could predict the development of symptomatic pneumonitis (SP) during durvalumab treatment. Potential EV-protein biomarkers were validated in an independent cohort., Results: In the discovery cohort, 73 patients were included, 49 with asymptomatic pneumonitis (AP) and 24 with SP. Of the 5797 proteins detected in circulating EVs, 33 were significantly elevated (fold change [FC] > 1.5, p < 0.05) in the SP group, indicating enrichment of the nuclear factor kappa B (NF-κB) pathway. Patients with high levels of EV-RELA, an NF-κB subunit, had a higher incidence of SP than those with low levels of EV-RELA (53.8% vs. 13.4%, p = 0.0017). In the receiver operating characteristic analysis, EV-RELA demonstrated a higher area under the curve (AUC) than lung V20 (0.76 vs. 0.62) and was identified as an independent risk factor in the multivariate logistic regression analysis (p = 0.008, odds ratio 7.72). Moreover, high EV-RELA was also a predictor of SP in the validation cohort comprising 43 patients (AUC of 0.80)., Conclusions: Circulating EV-RELA may be a predictive marker for symptomatic pneumonitis in patients with LA-NSCLC treated with durvalumab., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Purpose: Uterine carcinosarcoma (UCS), a subtype of endometrial carcinoma, is a rare and aggressive cancer with a poor prognosis. High clinical efficacy of trastuzumab deruxtecan (T-DXd) in HER2-expressing UCS was recently reported in a phase II trial (STATICE trial). We performed a co-clinical study of T-DXd using patient-derived xenograft (PDX) models of participants in the STATICE trial., Experimental Design: Tumor specimens were resected during primary surgery or biopsied at recurrence from patients with UCS and transplanted into immunodeficient mice. Seven UCS-PDXs from six patients were established and HER2, estrogen receptor (ER), and p53 expression in PDX and the original tumor was assessed. Drug efficacy tests were performed using six of the seven PDXs. Of the six UCS-PDXs tested, two were derived from patients enrolled in the STATICE trial., Results: The histopathological characteristics of the six PDXs were well-conserved from the original tumors. HER2 expression was 1+ in all PDXs, and ER and p53 expression was almost similar to that in the original tumors. Remarkable tumor shrinkage after T-DXd administration was observed in four of the six PDXs (67%), comparable with the response rate (70%) of HER2 1+ patients in the STATICE trial. Two patients enrolled in the STATICE trial showed partial response as the best response, and the clinical effect was well-replicated with marked tumor shrinkage., Conclusions: We successfully performed a co-clinical study of T-DXd in HER2-expressing UCS, along with the STATICE trial. Our PDX models can predict clinical efficacy and serve as an effective preclinical evaluation platform., (©2023 American Association for Cancer Research.)

Although circulating tumour DNA (ctDNA)-based next-generation sequencing (NGS) is a less invasive method for assessing ESR1 mutations that are essential mechanisms of endocrine therapy resistance in patients with oestrogen receptor-positive breast cancer, adequate amounts of DNA are required to assess polyclonal ESR1 mutations. By combining a peptide nucleic acid and locked nucleic acid polymerase chain reaction (PNA-LNA PCR) clamping assay, we have developed a novel detection system to screen for polyclonal ESR1 mutations in ctDNA. A validation assay was prospectively performed on clinical samples and compared with the NGS results. The PNA-LNA PCR clamp assay was validated using six and four blood samples in which ESR1 mutations were detected by NGS and no mutations were detected, respectively. The PNA-LNA assay results were comparable with those of NGS. We prospectively assessed the concordance between the PNA-LNA PCR clamp method and NGS. Using the PNA-LNA PCR clamp method, ESR1 mutations were detected in 5 out of 18 samples, including those in which mutations were not detected by NGS due to small amounts of ctDNA. The PNA-LNA PCR clamping method is a highly sensitive and minimally invasive assay for polyclonal ESR1 mutation detection in the ctDNA of patients with breast cancer.