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Greater Cairo (GC) is the seventh-largest metropolitan city globally. In recent decades, GC has witnessed massive urban expansion, which has yet to be empirically measured or characterized. This research seeks to explore the patterns of urban growth and changes in urban form in GC from 1973 to 2021 using remote sensing and geospatial metrics. Six Landsat images in 1973, 1984, 1992, 2003, 2013, and 2021 were used to explore urban growth in GC. Urban Land Density Function (ULDF), Landscape Expansion Index (LEI), and Fractal Dimension Index (FDI), were utilized to analyze various aspects of urban expansion. Additionally, the ratio of Land Consumption Rate (LCR) to Population Growth Rate (PGR) was calculated to assess the correlation between urban expansion and population changes. Our results reveal a substantial addition of 203 thousand hectares of urban areas over the last half-century. The ULDF highlights GC’s transformation from a condensed to a scattered urban landscape, particularly with the establishment of the New Administrative Capital in the vicinity. Edge expansion emerged as the principal type of urban growth throughout the research duration. The consistent increase in FDI from 1.44 in 1973 to 1.75 in 2021 signifies the fragmentation of the urban landscape. Moreover, the progressive rise in LCR from 0.023 in 1984 to 0.050 ​ha per person in 2021 suggests a steady expansion of low-density urban areas. Notably, the LCR-to-PGR ratio escalated from 0.878 in 1984 to 2.428 in 2021, indicating that urban expansion surpassed population growth. These results will help further understand the characteristics of GC’s urban expansion and may offer a scientific foundation for policymakers to reconsider the current horizontal expansion policy in GC.

STEAM has gained traction across informal and formal educational settings, but the connections between STEAM disciplines are not always obvious to youth. We argue that an explicit focus on how art and STEM overlap in the world, and how these overlaps connect personally to learner's interests and concerns, is a way to support the development of STEAM-related identities. We developed a "STEAM objects" pedagogical activity aimed at explicitly surfacing the ways that art and STEM are intertwined in everyday objects, as well as the ways that STEAM is connected to learners' own lives. We piloted the activity with educators, asking what they took up from the experience. Our results show how the educators made connections to land, historicity, their professions, function, aesthetics, and agency of materials during the activity. The STEAM objects served as boundary objects that illustrated the integrative nature of art and STEM in the world, as well as bridging important aspects of their lives and STEAM. We discuss the importance of recognizing and leveraging the multiplicities of meaning and ways of knowing, as well as implications for the classroom.

This study reports on crawling variability and differences in variability between infants with typical development (TD) and those with developmental delays. This longitudinal study included 0-year-old infants with no apparent dysfunction. The crawling movement in the video was coded objectively with reference to previous research. The infants were screened after 2 years of age, and the TD and suspected developmental delay (SDD) crawling codes were analysed and compared. Among TD infants, variation in hands-and-knees crawling decreased more in the group with belly-crawling experience than in the group without. However, this tendency was not observed in infants with SDD. Furthermore, TD infants showed more variable patterns of limb movement timing during belly-crawling than those with SDD. This study suggests variability during the entire crawling period. Moreover, exploration of an efficient diagonal gait was critical for crawling variability and subsequent development, which tends to be deficient in infants at risk of developmental delay.

Introduction: Immunotherapy is becoming a promising approach for unresectable-hepatocellular carcinoma (HCC); the anti-tumor response is affected by the tumor microenvironment (TME). Although Wnt/β-catenin mutations are reported to cause non-inflamed phenotype, their role on TME remains controversial. We aimed to clarify the heterogeneity of immunophenotype in HCC with Wnt/β-catenin mutations. Methods: This study includes 152 resected HCCs; mutations in the catenin beta-1, adenomatous polyposis coli, or AXIN1, or AXIN2 genes were defined as Wnt/β-catenin mutations. With hierarchical cluster analyses, TME was classified into inflamed or non-inflamed classes based on the gene expressions associated with T-cell activation. Expression profiles of molecules related to cell differentiation and biliary-stem cell markers were compared between the TME classes to investigate whether differences in tumor traits were associated with TME. Results: Forty of 152 (26.3%) HCCs carried the Wnt/β-catenin mutations. Of these, 33 were classified as non-inflamed (33/40, 82.5%) and 7 as inflamed (7/40, 17.5%). Non-inflamed class was characterized by low number of CD3+, CD4+, and CD8+ cells on immunostaining, and high mRNA expressions of AXIN2 and GLUL, which are involved in the canonical Wnt/β-catenin signaling and hepatocyte differentiation, respectively. Non-inflamed tumors showed higher enhancement on the hepatobiliary-phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) compared to inflamed tumors. HCCs classified as inflamed class are revealed to have high numbers of CD3+, CD4+, and CD8+ tumor infiltrating lymphocytes on immunostaining. This class is associated with increased expression of anti-epithelial cell adhesion molecule and FOXM1 accompanied by upregulation of genes related to interferon-gamma signaling, dendritic cell migration, regulatory T cells, and myeloid-derived suppressor cell activation and recognized as low enhancement nodule on Gd-EOB-DTPA-enhanced MRI. Conclusion: Heterogeneity of tumor traits and TME was observed in HCC with Wnt/β-catenin mutation. The potential was indicated that tumor traits and TME are determined not only by the activation of the HNF4A but also by FOXM1, both of which are downstream transcription factor of the Wnt/β-catenin signaling pathway.

Abstract Liver fibrosis results from chronic liver injury triggered by factors such as viral infection, excess alcohol intake, and lipid accumulation. However, the mechanisms underlying liver fibrosis are not fully understood. Here, we demonstrate that the expression of fibroblast growth factor 18 (Fgf18) is elevated in mouse livers following the induction of chronic liver fibrosis models. Deletion of Fgf18 in hepatocytes attenuates liver fibrosis; conversely, overexpression of Fgf18 promotes liver fibrosis. Single-cell RNA sequencing reveals that overexpression of Fgf18 in hepatocytes results in an increase in the number of Lrat + hepatic stellate cells (HSCs), thereby inducing fibrosis. Mechanistically, FGF18 stimulates the proliferation of HSCs by inducing the expression of Ccnd1. Moreover, the expression of FGF18 is correlated with the expression of profibrotic genes, such as COL1A1 and ACTA2, in human liver biopsy samples. Thus, FGF18 promotes liver fibrosis and could serve as a therapeutic target to treat liver fibrosis.

Recombinant adeno-associated viruses (rAAVs) have emerged as one of the most promising gene therapy vectors that have been successfully used in pre-clinical models of heart disease. However, this has not translated well to humans due to species differences in rAAV transduction efficiency. As a result, the search for human cardiotropic capsids is a major contemporary challenge. We used a capsid-shuffled rAAV library to perform directed evolution in human iPSC-derived cardiomyocytes (hiPSC-CMs). Five candidates emerged, with four presenting high sequence identity to AAV6, while a fifth divergent variant was related to AAV3b. Functional analysis of the variants was performed in vitro using hiPSC-CMs, cardiac organoids, human cardiac slices, non-human primate and porcine cardiac slices, as well as mouse heart and liver in vivo. We showed that cell entry was not the best predictor of transgene expression efficiency. The novel variant rAAV.KK04 was the best-performing vector in human-based screening platforms, exceeding the benchmark rAAV6. None of the novel capsids demonstrate a significant transduction of liver in vivo. The range of experimental models used revealed the value of testing for tropism differences under the conditions of human specificity, bona fide, myocardium and cell type of interest.

In recent years, sports-related concussion (SRC) in soccer has been extensively researched worldwide. However, there have been no reports of large-scale SRC studies among soccer players in Japan. The purpose of this study is to investigate the epidemiology of SRC among university soccer players in Japan. This descriptive epidemiological study collected data on the history of SRC and details of SRC injuries during soccer. The participants were university male soccer players belonging to the Japan University Football Association. SRC rates were calculated per 1000 athlete-exposures (AEs). A total of 5953 students participated in this study. The SRC rate was 0.10/1000 AE during total activities. The SRC rate during competition (0.42/1000 AE) was higher than in practice (0.04/1000 AE). The most frequent mechanism of SRC was “head-to-head” (26.9%), followed by “head-to-ball” (24.2%). During competition, the most frequent mechanism was “head-to-head” (30.8%), followed by “head-to-ground” (23.8%), and “head-to-ball” (19.3%) followed, while in practice, it was “head-to-ball” (34.8%), followed by “head-to-ground” (23.8%), and “head-to-head” (17.2%). Thus, there was a difference in the mechanism of injury between competition and practice. In this study, among Japanese university soccer players, the SRC rate was to be approximately ten times higher in competition than in practice.

This study aimed to clarify the differences between the previously reported mechanisms of sports-related concussion (SRC) injuries without a loss of consciousness in contact and collision sports and the mechanisms of SRC injuries in our cases. Based on two videos of SRC injuries occurring during a men’s rhythmic gymnastics competition (three people were injured), the risk of SRC occurrence was estimated from various parameters using a multibody analysis and eight brain injury evaluation criteria. In the present study, the three SRC impacts that occurred in men’s rhythmic gymnastics showed significant characteristics in duration compared to previously reported cases in the contact sports. This suggests that the occurrence of SRC may have been caused by a different type of impact from that which causes SRC in contact sports (e.g., tackling). In addition, calculation of the strain indicating the rate of brain deformation suggested a risk of nerve swelling in all cases involving type 2 axonal injuries. Therefore, when reexamining sports-related head injuries, it is important to recognize the characteristics and mechanisms of SRC that occur in each different sport, as well as the symptoms and course of SRC after injury.

This study aimed to investigate the significance of baseline measurements for amateur team athletes playing contact and collision team sports with a specific focus on the Sports Concussion Assessment Tool (SCAT) to improve concussion management. Symptoms of sports-related concussions (SRCs) can be diverse and long-lasting and include cognitive impairment, sleep disturbances, and vestibular dysfunction. Therefore, comprehensive baseline data are essential to preventing recurrent concussions and secondary injuries. This study was conducted during the 2023 off-season and evaluated the baseline condition of 65 male university rugby players using the SCAT5, which includes self-reported symptoms, and the modified Balance Error Scoring System (mBESS). The athletes were assessed for the presence or absence of SRC, and the mean values were compared using the Mann–Whitney U test. Among the participants, 35.38% (23/65) reported symptoms, with an average of 1.5 ± 2.8 symptoms per player and an average symptom score of 2.66 ± 5.93. In the mBESS, no errors were observed in the tandem stance test; however, 72.31% (47/65) made errors in the single-leg stance test on the non-dominant foot, with an average of 1.7 ± 1.5 errors. Many athletes self-reported symptoms and balance errors, even during asymptomatic periods before experiencing concussion, indicating unresolved issues. In the injury history survey, the baseline evaluations and injury histories of the participants classified into the SRC and non-SRC groups were compared. In the mBESS single-leg stance test (non-dominant foot), 84.21% (32/38) of the SRC group participants made errors, with an average score of 2.13 ± 1.52, whereas 55.55% (15/27) of the non-SRC group participants made errors, with an average score of 1.15 ± 1.35, showing a significant difference (p = 0.007). Additionally, significant differences were observed in the average number of ankle sprains (p = 0.027) and fractures (p = 0.048) between patients with and without a history of SRC. These findings indicate that athletes may have underlying issues even during normal periods before concussion. Moreover, the results highlighted the impact of previous concussions on motor control and injury risk. This underscores the importance of preseason baseline measurements using the SCAT to identify at-risk athletes and implement preventive measures. These findings align with the recommendations of the 6th International Conference on Concussion in Sport and suggest further refinement of concussion assessment tools.

Although genetic factors are involved in the etiology of autism spectrum disorder (ASD), the significance of genetic analysis in clinical settings is unclear. Forty-nine subjects diagnosed with non-syndromic ASD were analyzed by microarray comparative genomic hybridization (CGH) analysis, whole-exome sequencing (WES) analysis, and panel sequencing analysis for 52 common causative genes of ASD to detect inherited rare variants. Genetic analysis by microarray CGH and WES analyses showed conclusive results in about 10% of patients, however, many inherited variants detected by panel sequencing analysis were difficult to interpret and apply in clinical practice in the majority of patients. Further improvement of interpretation of many variants detected would be necessary for combined genetic tests to be used in clinical settings.

Abstract Background Induction or adjuvant therapies are not always beneficial for thoracic esophageal squamous cell carcinoma (ESCC) patients, and it is thus important to identify patients at high risk for postoperative ESCC recurrence. We investigated the usefulness of the total metabolic tumor volume (TMTV) for predicting the postoperative recurrence of thoracic ESCC. Methods We retrospectively analyzed the cases of 163 thoracic ESCC patients (135 men, 28 women; median age of 66 [range 34–82] years) treated at our hospital in 2007–2012. The TMTV was calculated from the fluorine-18 fluorodeoxyglucose (18F-FDG) uptake in the primary lesion and lymph node metastases. The optimal cut-off values for relapse and non-relapse were obtained by the time-dependent receiver operating curve analyses. Relapse-free survival (RFS) was evaluated by the Kaplan-Meier method, and between-subgroup differences in survival were analyzed by log-rank test. The prognostic significance of metabolic parameters and clinicopathological variables was assessed by a Cox proportional hazard regression analysis. The difference in the failure patterns after surgical resection was evaluated using the χ2-test. Results The optimal cut-off value of TMTV for discriminating relapse from non-relapse was 3.82. The patients with a TMTV ≥3.82 showed significantly worse prognoses than those with low values (p

Abstract Autism spectrum disorder (ASD) is a highly heritable, complex disorder in which rare variants contribute significantly to disease risk. Although many genes have been associated with ASD, there have been few genetic studies of ASD in the Japanese population. In whole exomes from a Japanese ASD sample of 309 cases and 299 controls, rare variants were associated with ASD within specific neurodevelopmental gene sets, including highly constrained genes, fragile X mental retardation protein target genes, and genes involved in synaptic function, with the strongest enrichment in trans-synaptic signaling (p = 4.4 × 10−4, Q-value = 0.06). In particular, we strengthen the evidence regarding the role of ABCA13, a synaptic function-related gene, in Japanese ASD. The overall results of this case-control exome study showed that rare variants related to synaptic function are associated with ASD susceptibility in the Japanese population.

Introduction: With the advent of effective systemic therapy, transarterial chemoembolization (TACE) is established as a highly effective locoregional treatment modality for carefully selected patients with hepatocellular carcinoma (HCC). This randomized controlled trial was conducted to clarify whether selective TACE with drug-eluting beads (DEB-TACE) loaded with epirubicin or selective conventional TACE (cTACE) with epirubicin-ethiodized oil might be more effective for obtaining complete response(CR) in patients with HCC. Methods: Between March 2016 and May 2019, Child-Pugh class A or B patients with unresectable HCC who were scheduled to receive selective TACE were randomly assigned at a 1:1 ratio to the DEB-TACE arm or the cTACE arm. The primary endpoint was the CR rate at 3 months, as evaluated according to the modified Response Evaluation Criteria in Solid Tumors by an independent review committee, and the secondary endpoints were the CR rate at 1 month and incidences of adverse events. Results: A total of 200 patients (DEB-TACE, 99 patients; cTACE, 101 patients) were enrolled in the study. The CR rates at 3 months and 1 month were significantly higher in the cTACE arm (75.2%, 84.2%) as compared with the DEB-TACE arm (27.6%, 35.7%). However, the frequencies of adverse events of any grade, including pyrexia (DEB-TACE vs. cTACE, 19.4% vs. 45.5%, p = 0.0001), fatigue (5.1% vs. 15.8%, p = 0.0194), malaise (11.1% vs. 25.7%, p = 0.0103), appetite loss (12.1% vs. 28.7%, p = 0.0048), abdominal pain (12.1% vs. 23.8%, p = 0.0423), increased serum bilirubin (22.2% vs. 48.5%, p = 0.0002), hypoalbuminemia (43.4% vs. 60.3%, p = 0.0154), increased serum aspartate aminotransferase (35.7% vs. 81.2%, p < 0.0001), and increased serum alanine aminotransferase (35.7% vs. 77.2%, p < 0.0001), were also significantly higher in the cTACE arm than in the DEB-TACE arm. Conclusions: Selective cTACE appeared to have higher CR rates for local tumor control as compared to selective DEB-TACE for HCC. However, the frequency of postembolization syndrome was also significantly higher in the cTACE group than in the DEB-TACE group. Thus, to achieve CR, cTACE may be selected over DEB-TACE in patients who can be expected to tolerate postembolization syndrome.

Simple Summary: Unlike RECIST (version 1.1), which is the standard for assessing the treatment efficacy for solid tumors, tumor necrosis is considered a marker of the treatment effect in HCC. mRECIST, which considers tumor necrosis, and the Liver Cancer Treatment Direct Effectiveness Criteria (RECICL) are widely used. There are notable differences between one-dimensional and two-dimensional measurements in mRECIST and RECICL, and their practicality and usefulness are controversial. After fully understanding the characteristics and problems of each method, diagnostic imaging physicians must focus on the imaging modality and criteria that should be used to determine the effectiveness of the method. Furthermore, the inclusion of LI-RADS provides a standardized framework for evaluating HCC and supports consistent diagnostic and therapeutic decision-making. Given the availability of several drugs, predicting the efficacy of systemic chemotherapy for HCC is currently a clinical topic. However, the role of CT is limited. Recently, attempts have been made to detect Wnt/β-catenin mutation/activation in HCC using Gd-EOB-DTPA enhanced MRI (EOB-MRI), and future developments are expected in terms of predicting efficacy. For instance, regorafenib has demonstrated survival benefits in patients previously treated with sorafenib, as highlighted in a recent systematic review and meta-analysis. Additionally, atezolizumab combined with bevacizumab has emerged as a first-line treatment for unresectable hepatocellular carcinoma. The liver is supplied by a dual blood flow system consisting of the portal vein and hepatic artery. Imaging techniques for diagnosing hepatocellular carcinoma (HCC) have been developed along with blood flow imaging, which visualizes the amount of arterial and portal blood flow. The diagnosis of HCC differentiation is important for early-stage liver cancer screening and determination of treatment strategies. Dynamic computed tomography/magnetic resonance imaging (MRI) includes blood flow imaging and MRI with contrast-enhanced ultrasound and liver-specific contrast agents are used in combination. In addition, unlike the Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1), which is the standard for determining treatment efficacy for solid tumors in general, tumor necrosis is generally considered a treatment effect in HCC, and the modified RECIST and Liver Cancer Direct Effectiveness Criteria (RECICL) are widely used. Familiarity with the definitions, criteria, and potential challenges of the mRECIST and RECICL is essential for their effective application in clinical practice. This review integrates the latest advancements in systemic treatments and imaging techniques, including the role of LI-RADS and updates on molecular-targeted therapies such as regorafenib, supported by some systematic review and meta-analysis. [ABSTRACT FROM AUTHOR]

Programmed cell death, especially programmed necrosis such as necroptosis, ferroptosis, and pyroptosis, has attracted significant attention recently. Traditionally, necrosis was thought to occur accidentally without signaling pathways, but recent discoveries have revealed that molecular pathways regulate certain forms of necrosis, similar to apoptosis. Accumulating evidence indicates that programmed necrosis is involved in the development of various diseases, including myocardial ischemia–reperfusion injury (MIRI). MIRI occurs when blood flow and oxygen return to an ischemic area, causing excessive production of reactive oxygen species. While this reperfusion is critical for treating myocardial infarction, it inevitably causes cellular damage via oxidative stress. Furthermore, this cellular damage triggers multiple forms of cardiomyocyte death, which is the primary cause of inflammation, cardiac tissue remodeling, and ensuing heart failure. Therefore, understanding the molecular mechanisms of various forms of cell death in MIRI is crucial for therapeutic target discovery. Developing therapeutic strategies to inhibit multiple cell death pathways simultaneously could provide effective protection against MIRI. In this paper, we review the fundamental molecular pathways and MIRI-specific mechanisms of apoptosis, necroptosis, ferroptosis, and pyroptosis. Additionally, we suggest that the simultaneous suppression of multiple cell death pathways could be an effective therapy and identify potential therapeutic targets for implementing this strategy. [ABSTRACT FROM AUTHOR]

Abstract Spondyloepiphyseal dysplasia congenita (SEDC) is a multisystemic skeletal disorder caused by pathogenic variants in COL2A1. Here, we report the genotype-phenotype correlations in five Japanese patients with SEDC based on their clinical and radiological findings. All five patients had novel missense variants resulting in glycine substitutions (G474V, G543E, G567S, G594R, and G1170R). Genetic testing is important for early intervention for the extraskeletal complications of SEDC. Spondyloepiphyseal dysplasia congenita (SEDC) (OMIM#183900) is an autosomal dominant chondrodysplasia characterized by disproportionate short stature, abnormal epiphyses, flattened vertebral bodies (skeletal abnormalities), and extraskeletal features, including myopia, retinal degeneration with retinal detachment, and cleft palate. SEDC is caused by a heterozygous variant in the collagen II alpha 1 (COL2A1) gene.

Abstract Background Previous large-scale studies of de novo variants identified a number of genes associated with neurodevelopmental disorders (NDDs); however, it was also predicted that many NDD-associated genes await discovery. Such genes can be discovered by integrating copy number variants (CNVs), which have not been fully considered in previous studies, and increasing the sample size. Methods We first constructed a model estimating the rates of de novo CNVs per gene from several factors such as gene length and number of exons. Second, we compiled a comprehensive list of de novo single-nucleotide variants (SNVs) in 41,165 individuals and de novo CNVs in 3675 individuals with NDDs by aggregating our own and publicly available datasets, including denovo-db and the Deciphering Developmental Disorders study data. Third, summing up the de novo CNV rates that we estimated and SNV rates previously established, gene-based enrichment of de novo deleterious SNVs and CNVs were assessed in the 41,165 cases. Significantly enriched genes were further prioritized according to their similarity to known NDD genes using a deep learning model that considers functional characteristics (e.g., gene ontology and expression patterns). Results We identified a total of 380 genes achieving statistical significance (5% false discovery rate), including 31 genes affected by de novo CNVs. Of the 380 genes, 52 have not previously been reported as NDD genes, and the data of de novo CNVs contributed to the significance of three genes (GLTSCR1, MARK2, and UBR3). Among the 52 genes, we reasonably excluded 18 genes [a number almost identical to the theoretically expected false positives (i.e., 380 × 0.05 = 19)] given their constraints against deleterious variants and extracted 34 “plausible” candidate genes. Their validity as NDD genes was consistently supported by their similarity in function and gene expression patterns to known NDD genes. Quantifying the overall similarity using deep learning, we identified 11 high-confidence (> 90% true-positive probabilities) candidate genes: HDAC2, SUPT16H, HECTD4, CHD5, XPO1, GSK3B, NLGN2, ADGRB1, CTR9, BRD3, and MARK2. Conclusions We identified dozens of new candidates for NDD genes. Both the methods and the resources developed here will contribute to the further identification of novel NDD-associated genes.

Introduction Programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) signaling blockade is the most effective strategy for the treatment of immune evading hepatocellular carcinoma (HCC). While immune checkpoint inhibitor (ICI) has revolutionized the concept of cancer treatment, it has also led to unexpected tumor growth. Regulatory T cells express PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) receptors, which are proliferated and activated by antibody binding, and their ratio to CD8+ T cells is altered, which is one of the causes for hyper progressive disease (HPD). We examined the frequency of HPD in anti-PD-1/PD-L1 monotherapy and combination therapy with vascular endothelial growth factor (VEGF) antibody and anti-CTLA-4 antibodies. Methods This was a prospective and retrospective cohort study which enrolled 198 patients with unresectable HCC from January, 2015 to December, 2021 at the Kindai University Hospital. Fifty-eight patients received anti-PD-1/PD-L1 monotherapy, 119 patients combination with VEGF antibody, and 21 patients combination with anti-CTLA-4 antibody. We defined HPD as tumor growth rate (TGR) ratio ≥4, ΔTGR ≥40% and tumor growth kinetics ratio ≥4. Results The HPD rate was 10.3% (6/58) in anti-PD-1/PD-L1 monotherapy, 1.7% (2/119) in combination with VEGF antibody, and 4.8% (1/21) in combination with anti-CTLA-4 antibody (P=0.034). The odds ratio for HPD in the combined anti-CTLA-4 antibody group was 0.433 (95% CI: 0.05-3.83) when compared to the anti-PD-1/PD-L1 monotherapy group, and 2.93 (95% CI: 0.25-33.79) when compared to the combined VEGF antibody group. Conclusion The frequency of HPD in unresectable HCC compared to anti-PD-1/PD-L1 monotherapy was decreased with the combination with anti-VEGF antibody, and not increased with anti-CTLA-4 antibody. Anti-PD-1/PD-L1 combined with anti-CTLA-4 antibody is now available in real-world and needs to be further validated with accumulated clinical practice.

We investigated gene electrotransfer using electrical short-circuiting via a cell suspension droplet in dielectric oil. An aqueous droplet of a few microliters placed between a pair of electrodes can be deformed by an intense DC electric field depending on the electric field intensity. When a droplet containing suspended cells and plasmid DNA elongates during deformation and connects the electrodes, the resulting short circuit can cause successful gene electrotransfection into various mammalian cells. We also investigated the influence of the electroporation medium on membrane permeabilization and the mechanisms of gene electrotransfection using short-circuiting via an aqueous droplet. One aim of this study was to investigate the influence of the conductivity of electroporation medium on gene electrotransfer stimulated by short-circuiting. It was found that low-conductivity medium with plasmid DNA resulted in a significant decrease in cell viability compared to the high-conductivity medium with plasmid DNA. Therefore, we demonstrated the influence of exogenous DNA on membrane damage stimulated by droplet electroporation using a low-conductivity medium. Thus, electrical stimulation with the combination of plasmid DNA and the low-conductivity medium resulted in tremendous membrane damage. Linearized plasmid DNA stimulated more significant membrane damage than circular DNA. However, the size of linear DNA did not influence the efflux of small intracellular molecules.

Lentiviral vectors are a robust gene delivery tool for inducing transgene expression in a variety of cells. They are well suited to facilitate the testing of therapeutic candidate genes in vitro, due to relative ease of packaging and ability to transduce dividing and non-dividing cells. Our goal was to identify a gene that could be delivered to the heart to protect against cancer-therapy-induced cardiotoxicity. We sought to generate a lentivirus construct with a ubiquitous CMV promoter driving expression of B-cell lymphocyte/leukemia 2 gene (Bcl-2), a potent anti-apoptotic gene. Contrary to our aim, overexpression of Bcl-2 induced cell death in the producer HEK293T cells, resulting in failure to produce usable vector titre. This was circumvented by exchanging the CMV promoter to the cardiac-specific NCX1 promoter, leading to the successful production of a lentiviral vector which could induce cardioprotective expression of Bcl-2. In conclusion, reduced expression of Bcl-2 driven by a weaker promoter improved vector yield, and led to the production of functional cardioprotective Bcl-2 in primary cardiomyocytes.

Abstract An increasing body of evidence suggests that impaired synapse development and function are associated with schizophrenia; however, the underlying molecular pathophysiological mechanism of the disease remains largely unclear. We conducted a family-based study combined with molecular and cellular analysis using induced pluripotent stem cell (iPSC) technology. We generated iPSCs from patients with familial schizophrenia, differentiated these cells into neurons, and investigated the molecular and cellular phenotypes of the patient’s neurons. We identified multiple altered synaptic functions, including increased glutamatergic synaptic transmission, higher synaptic density, and altered splicing of dopamine D2 receptor mRNA in iPSC-derived neurons from patients. We also identified patients’ specific genetic mutations using whole-exome sequencing. Our findings support the notion that altered synaptic function may underlie the molecular and cellular pathophysiology of schizophrenia, and that multiple genetic factors cooperatively contribute to the development of schizophrenia.

Bacillus Calmette–Guerin (BCG) intravesical instillation therapy is the most effective adjuvant therapy for bladder cancer after transurethral resection of bladder tumor (TURBT). We present the first case to our knowledge with bladder and ureteral necrosis as a severe local side effect of it.

Introduction: Immune checkpoint inhibitors (ICIs) are promising agents for the treatment of hepatocellular carcinoma (HCC). However, the establishment of noninvasive measure that could predict the response to ICIs is challenging. This study aimed to evaluate tumor responses to ICIs using the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI), which was shown to reflect Wnt/β-catenin activating mutation. Methods: A total of 68 intrahepatic HCC nodules from 18 patients with unresectable HCC and Child-Pugh class A liver function who received anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) monotherapy were enrolled in this study. All patients had viable intrahepatic lesions evaluable using the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI within the 6 months prior to the treatment. The relative enhancement ratio was calculated, and the time to nodular progression (TTnP) defined as 20% or more increase in each nodule was compared between higher or hypo-enhancement HCC nodules. Then, the progression-free survival (PFS) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) were compared between patients with and without HCC nodules with higher enhancement on hepatobiliary phase images. Results: The median PFS was 2.7 (95% confidence interval [CI]: 1.4–4.0) months in patients with HCC nodules with higher enhancement (n = 8) and 5.8 (95% CI: 0.0–18.9) months in patients with hypointense HCC nodules (n = 10) (p = 0.007). The median TTnP of HCC nodules with higher enhancement (n = 23) was 1.97 (95% CI: 1.86–2.07) months and that of hypointense HCC nodules (n = 45) was not reached (p = 0.003). The ORR was 12.5% (1/8) versus 30.0% (3/10); the disease control rate was 37.5% (3/8) versus 70.0% (7/10), respectively, in patients with or without higher enhancement intrahepatic HCC nodules. Conclusion: The TTnP on HCC nodules with higher enhancement and the median PFS in patients who carried higher enhancement intrahepatic HCC nodules were significantly shorter than those in hypointense HCC nodules with anti-PD-1/PD-L1 monotherapy. The intensity of the nodule on the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI is a promising imaging biomarker for predicting unfavorable response with anti-PD-1/PD-L1 monotherapy in patients with HCC.

Objective(s): To assess respiratory-gated (RG) positron emission tomography (PET) acquisition for patients with liver metastases during delayed PET/computed tomography (CT) scanning with fluorine-18-fluorodeoxyglucose (18F-FDG).Methods: Nineteen patients with liver metastases who had undergone early whole-body 18F-FDG PET/CT scans without the RG technique and delayed scans with the RG technique were retrospectively selected. The maximum standardized uptake value (SUVmax) of 41 liver lesions and the tumor-to-liver uptake ratios (TLRs) for these same lesions were compared among three data sets: early non-respiratory-gated (early non-RG) images, delayed non-respiratory-gated (delayed non-RG) images, and delayed respiratory-gated (delayed RG) images. In the delayed non-RG and delayed RG images, the improvements in the TLR, relative to the early non-RG images, were assessed according to lesion size.Results: For liver lesions, the SUVmax of early non-RG, delayed non-RG, and delayed RG images were 6.58±2.34, 7.69±3.08, and 9.47±3.73, respectively. There were significant differences among the three images (P10 mm in size; in the delayed non-RG images, the difference in the TLR improvement for the same lesion categories was 6%.Conclusion: Delayed RG imaging improves the TLR, compared with early non-RG and delayed non-RG imaging, especially for small lesions. RG PET acquisition may be a promising protocol for assessing liver metastases on delayed PET/CT scans.

STEAM has gained traction across informal and formal educational settings, but the connections between STEAM disciplines are not always obvious to youth. We argue that an explicit focus on how art and STEM overlap in the world, and how these overlaps connect personally to learner's interests and concerns, is a way to support the development of STEAM-related identities. We developed a "STEAM objects" pedagogical activity aimed at explicitly surfacing the ways that art and STEM are intertwined in everyday objects, as well as the ways that STEAM is connected to learners' own lives. We piloted the activity with educators, asking what they took up from the experience. Our results show how the educators made connections to land, historicity, their professions, function, aesthetics, and agency of materials during the activity. The STEAM objects served as boundary objects that illustrated the integrative nature of art and STEM in the world, as well as bridging important aspects of their lives and STEAM. We discuss the importance of recognizing and leveraging the multiplicities of meaning and ways of knowing, as well as implications for the classroom. [ABSTRACT FROM AUTHOR]