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Homeostasis is achieved by balancing cell survival and death. In cancer cells, especially those carrying driver mutations, the processes and signals that promote apoptosis are inhibited, facilitating the survival and proliferation of these dysregulated cells. Apoptosis induction is an important mechanism underlying the therapeutic efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for EGFR-mutated non-small cell lung cancer (NSCLC). However, the mechanisms by which EGFR-TKIs induce apoptosis have not been fully elucidated. A deeper understanding of the apoptotic pathways induced by EGFR-TKIs is essential for the developing novel strategies to overcome resistance to EGFR-TKIs or to enhance the initial efficacy through therapeutic synergistic combinations. Recently, therapeutic strategies targeting apoptosis have been developed for cancer. Here, we review the state of knowledge on EGFR-TKI-induced apoptotic pathways and discuss the therapeutic strategies for enhancing EGFR-TKI efficiency. We highlight the great progress achieved with third-generation EGFR-TKIs. In particular, combination therapies of EGFR-TKIs with anti-vascular endothelial growth factor/receptor inhibitors or chemotherapy have emerged as promising therapeutic strategies for patients with EGFR-mutated NSCLC. Nevertheless, further breakthroughs are needed to yield an appropriate standard care for patients with EGFR-mutated NSCLC, which requires gaining a deeper understanding of cancer cell dynamics in response to EGFR-TKIs.

Factors that may make endoscopic submucosal dissection (ESD) difficult for operators have been evaluated according to results based on the performance of experienced endoscopists. This study aimed to verify the predictors of difficult gastric ESD for ESD beginners. From January 2015 to December 2021, 466 superficial gastric neoplasms were treated with ESD at Showa University Hospital. Excluding 103 lesions that performed ESD by experts who experienced more than 80 ESDs, a total of 363 lesions were included. The lesions were divided into two groups according to the ESD performance experience of the operator: ESD beginner (EB; ESD experience≤30 cases) and ESD intermediate (EI; ESD experience 31-80 cases) groups. Relationships between difficult ESD (having at least one of the following: procedure time>60 min, incomplete resection, change of operator, and occurrence of severe complications) and clinicopathological findings of the lesion were analyzed. The complete resection rates and the difficult ESD rates in the EB and EI groups were 99.3%, 94.8%, and 61.2%, 50.7%, respectively. In the EB group, univariate analysis showed that difficult ESD rate was significantly higher in the non-lower third lesions, the lesser curvature lesions, and cancerous lesions. In the EI group, univariate analysis showed that difficult ESD rate was significantly higher in lesion with ≥20 mm size, lesser curvature lesions, lesions with ulcers, and submucosal cancers. Multivariate analysis showed that the lesser curvature location and cancerous histology in the EB group and ≥20 mm lesion size, the lesser curvature location and submucosal invasion in the EI group were independent predictors of difficult ESD. The lesser curvature location is recognized as independent ESD difficulty factor for both beginners and intermediates. Cases with lesions located in the lesser curvature should not be selected for gastric ESD training by beginners.

Ulcerative colitis (UC) predominantly affects the colon; upper gastrointestinal involvement (UGI) has been reported, but no established treatments exist. We report two cases of UC with concomitant UGI that showed positive responses to vedolizumab therapy. Case 1 involved a 29‐year‐old man who developed continuous inflammation extending from the stomach to the jejunum 1 month after an initial UC diagnosis. Intravenous prednisolone provided clinical remission; however, maintenance therapy with oral azathioprine was unsuccessful. Vedolizumab was initiated. Three months later, esophagogastroduodenoscopy (EGD) and colonoscopy confirmed the resolution of inflammation. Case 2 involved a 19‐year‐old man diagnosed with UGI via endoscopy while being evaluated for nausea and fever during UC treatment. 5‐aminosalicylic acid and prednisolone therapies were ineffective; therefore, vedolizumab was administered. Three months later, EGD confirmed mucosal healing. Both patients have maintained clinical remission for >2 years. To our knowledge, this is the first report of UC with UGI involvement that was successfully treated with vedolizumab. These findings suggest that vedolizumab is effective and safe for UGI treatment.

Fluorescence-based organic light-emitting diodes have continued to attract interest because of their long operational lifetimes, high colour purity of electroluminescence and potential to be manufactured at low cost in next-generation full-colour display and lighting applications. In fluorescent molecules, however, the exciton production efficiency is limited to 25% due to the deactivation of triplet excitons. Here we report fluorescence-based organic light-emitting diodes that realize external quantum efficiencies as high as 13.4–18% for blue, green, yellow and red emission, indicating that the exciton production efficiency reached nearly 100%. The high performance is enabled by utilization of thermally activated delayed fluorescence molecules as assistant dopants that permit efficient transfer of all electrically generated singlet and triplet excitons from the assistant dopants to the fluorescent emitters. Organic light-emitting diodes employing this exciton harvesting process provide freedom for the selection of emitters from a wide variety of conventional fluorescent molecules. Fluorescent organic light-emitting diodes hold promise for next-generation full-colour displays, but are currently limited by the internal electroluminescence quantum efficiency. Nakanotani et al. break this limit and demonstrate nearly 100% efficiency in a double-dopant system without a rare metal.

Bromodomain and extraterminal domain (BET) family proteins are epigenetic master regulators of gene expression via recognition of acetylated histones and recruitment of transcription factors and co‐activators to chromatin. Hence, BET family proteins have emerged as promising therapeutic targets in cancer. In this study, we examined the functional role of bromodomain containing 3 (BRD3), a BET family protein, in colorectal cancer (CRC). In vitro and vivo analyses using BRD3‐knockdown or BRD3‐overexpressing CRC cells showed that BRD3 suppressed tumor growth and cell cycle G1/S transition and induced p21 expression. Clinical analysis of CRC datasets from our hospital or The Cancer Genome Atlas revealed that BET family genes, including BRD3, were overexpressed in tumor tissues. In immunohistochemical analyses, BRD3 was observed mainly in the nucleus of CRC cells. According to single‐cell RNA sequencing in untreated CRC tissues, BRD3 was highly expressed in malignant epithelial cells, and cell cycle checkpoint‐related pathways were enriched in the epithelial cells with high BRD3 expression. Spatial transcriptomic and single‐cell RNA sequencing analyses of CRC tissues showed that BRD3 expression was positively associated with high p21 expression. Furthermore, overexpression of BRD3 combined with knockdown of, a driver gene in the BRD family, showed strong inhibition of CRC cells in vitro. In conclusion, we demonstrated a novel tumor suppressive role of BRD3 that inhibits tumor growth by cell cycle inhibition in part via induction of p21 expression. BRD3 activation might be a novel therapeutic approach for CRC. We conducted this study to obtain better insights into bromodomain containing 3 (BRD3), which is one of the bromodomain and extraterminal domain family proteins, epigenetic master regulators. Using biological analysis and bioinformatic analysis by single‐cell RNA sequencing and spatial transcriptomics, we demonstrated a novel tumor suppressive role of BRD3 that inhibits tumor growth by cell cycle inhibition in part via induction of p21 expression in colorectal cancer.

Adult T-cell leukemia/lymphoma (ATL) occurs after human T-cell leukemia virus type-1 (HTLV-1) infection with a long latency period exceeding several decades. This implies the presence of immune evasion mechanisms for HTLV-1-infected T cells. Although ATL cells have a CD4 + CD25 + phenotype similar to that of regulatory T cells (Tregs), they do not always possess the immunosuppressive functions of Tregs. Factors that impart effective immunosuppressive functions to HTLV-1-infected cells may exist. A previous study identified a new CD13 + Treg subpopulation with enhanced immunosuppressive activity. We, herein, describe the paired CD13 − (designated as MT-50.1) and CD13 + (MT-50.4) HTLV-1-infected T-cell lines with Treg-like phenotype, derived from the peripheral blood of a single patient with lymphoma-type ATL. The cell lines were found to be derived from HTLV-1-infected non-leukemic cells. MT-50.4 cells secreted higher levels of immunosuppressive cytokines, IL-10 and TGF-β, expressed higher levels of Foxp3, and showed stronger suppression of CD4 + CD25 − T cell proliferation than MT-50.1 cells. Furthermore, the CD13 inhibitor bestatin significantly attenuated MT-50.4 cell growth, while it did not for MT-50.1 cells. These findings suggest that CD13 expression may be involved in the increased Treg-like activity of MT-50.4 cells. Hence, MT-50.4 cells will be useful for in-depth studies of CD13 + Foxp3 + HTLV-1-infected cells.

Background Cancer-associated fibroblasts exhibit diversity and have several subtypes. The underlying relationship between the diversity of cancer-associated fibroblasts and their effect on gastric cancer progression remains unclear. In this study, mesenchymal stem cells were differentiated into cancer-associated fibroblasts with gastric cancer cell lines; clinical specimens were used to further investigate the impact of cancer-associated fibroblast diversity on cancer progression. Methods Nine gastric cancer cell lines (NUGC3, NUGC4, MKN7, MKN45, MKN74, FU97, OCUM1, NCI-N87, and KATOIII) were used to induce mesenchymal stem cell differentiation into cancer-associated fibroblasts. The cancer-associated fibroblasts were classified based on ACTA2 and PDPN expression. Cell function analysis was used to examine the impact of cancer-associated fibroblast subtypes on cancer cell phenotype. Tissue samples from 97gastric patients who underwent gastrectomy were used to examine the clinical significance of each subtype classified according to cancer-associated fibroblast expression. Results Co-culture of mesenchymal stem cells with nine gastric cancer cell lines revealed different subtypes of ACTA2 and PDPN expression in differentiated cancer-associated fibroblasts. Cancer-associated fibroblast subtypes with high ACTA2 plus PDPN expression levels significantly increased gastric cancer cell migration, invasion, and proliferation. The cancer-associated fibroblast subtype with ACTA2 plus PDPN expression was an independent prognostic factor along with lymph node metastasis for patients who had gastric cancer and were undergoing surgery. Conclusions Cancer-associated fibroblasts are educated by gastric cancer cells during the development of cancer-associated fibroblast diversity. Differentiated cancer-associated fibroblasts with distinct expression patterns could affect gastric cancer progression and enable prognostic stratification for gastric cancer.

Given the global shortage of child psychiatrists and barriers to specialized care, remote assessment is a promising alternative for diagnosing and managing attention-deficit/hyperactivity disorder (ADHD). However, only a few studies have validated the accuracy and acceptability of these remote methods. This study aimed to test the agreement between remote and face-to-face assessments. Patients aged between 6 and 17 years with confirmed Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnoses of ADHD or autism spectrum disorder (ASD) were recruited from multiple institutions. In a randomized order, participants underwent 2 evaluations, face-to-face and remotely, with distinct evaluators administering the ADHD Rating Scale-IV (ADHD-RS-IV). Intraclass correlation coefficient (ICC) was used to assess the reliability of face-to-face and remote assessments. The participants included 74 Japanese children aged between 6 and 16 years who were primarily diagnosed with ADHD (43/74, 58%) or ASD (31/74, 42%). A total of 22 (30%) children were diagnosed with both conditions. The ADHD-RS-IV ICCs between face-to-face and remote assessments showed \"substantial\" agreement in the total ADHD-RS-IV score (ICC=0.769, 95% CI 0.654-0.849; P<.001) according to the Landis and Koch criteria. The ICC in patients with ADHD showed \"almost perfect\" agreement (ICC=0.816, 95% CI 0.683-0.897; P<.001), whereas in patients with ASD, it showed \"substantial\" agreement (ICC=0.674, 95% CI 0.420-0.831; P<.001), indicating the high reliability of both methods across both conditions. Our study validated the feasibility and reliability of remote ADHD testing, which has potential benefits such as reduced hospital visits and time-saving effects. Our results highlight the potential of telemedicine in resource-limited areas, clinical trials, and treatment evaluations, necessitating further studies to explore its broader application. UMIN Clinical Trials Registry UMIN000039860; http://tinyurl.com/yp34x6kh.

In this paper, we present a 3-USR-type 6-degree-of-freedom (6-DOF) parallel mechanism characterized by an expansive workspace. This mechanism consists of three coupling chains, each comprising a universal pair (U), a spherical pair (S), and a rotational pair (R), in sequence from the stationary base. To achieve a large workspace, the three stationary universal pairs are designated as active pairs, with their rotational axes intersecting at a single point, thereby creating a hemispherical workspace akin to that of a serial mechanism. To implement the active universal pair within a parallel mechanism, we replaced the spherical 5-link mechanism, which originally featured two stationary active rotational pairs, with stationary active universal pairs, and conducted an inverse kinematics analysis. Subsequently, we assessed the expansive workspace of the spherical 5-link mechanism, a key factor influencing the working area of the 3-USR-type 6-DOF parallel mechanism, by examining its motion transmissibility. Based on this evaluation, we designed two compact mechanisms that provide a large workspace and allow for the configuration of all three rotational axes to intersect at a single point. We experimentally investigated the relationship between motion transmissibility and rigidity for these two types of spherical 5-link mechanisms, demonstrating that motion transmissibility can serve as an indicator of rigidity. Finally, a prototype of the 3-USR mechanism was fabricated.

Protein dynamics play a crucial role in various physiological functions, including enzyme catalysis. To explore conformational changes during enzyme catalysis, we conduct mix-and-inject serial crystallography, an advanced technique to capture time-resolved protein structures in real time, using the microcrystals of bacterial copper amine oxidase containing a protein-derived quinone cofactor. Within 50 ms of mixing the microcrystals (<4 μm) with a preferred substrate (2-phenylethylamine) under anaerobic conditions (reductive half-reaction), we observe domain movements associated with substrate binding and formation of a metastable reaction intermediate, a product Schiff-base of the quinone cofactor. At 100–1000 ms after mixing, conformational transition from aminoresorcinol to the semiquinone radical forms of the reduced cofactor progresses gradually, likely depending on the replacement of the product aldehyde by the next-cycle amine substrate that triggers the cofactor conformational change. Overall, this study provides structural insight into enzyme catalysis accompanying the active-site conformational changes that are hardly scrutinized by studies in solution. Protein motion is essential for biological processes like enzyme function. Here the authors report the time-resolved protein structures captured during catalysis of copper amine oxidase using mix-and-inject serial femtosecond X-ray crystallography.