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The tumor microenvironment (TME) modulates therapeutic response and prognosis in patients with bladder cancer (BC). The roles of two phospholipase D (PLD) isoforms, PLD1 and PLD2 (hydrolysis of phosphatidylcholine to phosphatidic acid), in cancer cells have been well‐studied in numerous cancer types, but their roles in the TME remain unclear. We used a mouse BC Pld2‐KO carcinogenesis model and global transcriptomic analysis to reveal that PLD2 was significantly involved in BC progression through immunosuppressive pathways in the TME. We therefore focused on PLD2 and tumor‐associated macrophages (TAMs), which were increased in Pld2‐KO mice and further associated with poor prognoses in BC patients. In vitro, we found that Pld2‐KO mouse TAMs had significantly enhanced proliferation, correlating closely with increased interleukin‐1β (IL‐1β) production. These results indicate that PLD2 suppresses BC progression by regulation of IL‐1β secretion from TAMs in the TME, suggesting that PLD2 could serve as a potential therapeutic target for modifying the TME in BC. We reveal that phospholipase D2 (PLD2) knockout promotes bladder cancer progression through immunosuppressive modulation involving tumor‐associated macrophages (TAMs) in the tumor microenvironment. Notably, knockout of Pld2 increased TAMs and interleukin‐1β (IL‐1β) production, suggesting that PLD2 suppresses bladder cancer progression by regulating IL‐1β secretion from TAMs.

Detecting pediatric delirium in critically ill children is important. The Sophia Observation withdrawal Symptoms and Delirium scale (SOS-PD) is a tool for assessing both pediatric delirium and iatrogenic withdrawal symptoms and contains a question for parents to assist in detecting pediatric delirium. The aim was to translate the Japanese SOS-PD and to perform a cross-culture validation of the J-SOS-PD pediatric delirium dimension while confirming the accuracy of family assessments of pediatric delirium. The translation was undertaken with the internationally established forward- backward translation method. Pediatric delirium was simultaneously evaluated and compared between psychiatric diagnoses based on assessment by a pediatric intensivist and the Japanese version of the SOS-PD as evaluated by PICU researchers. We evaluated the criterion validity (sensitivity and specificity), cut-off point using a receiver operating characteristic (ROC) curve, and reliability with Cohen's κ coefficient and intraclass correlation coefficients (ICC). A total of 125 independent assessments were performed in 67 children with a median age of 15 (IQR 5, 54) months and with a pediatric delirium-positive rate of 30% based on psychiatric evaluation. Based on the ROC curve analysis, the cut-off point of 4 was the most appropriate within the original scale and the Japanese SOS-PD version showed high sensitivity (0.92, 95% CI 0.84-1.00) and specificity (0.97, 95% CI 0.94-1.00) at a cut-off point of 4 and high reliability within the researcher assessments (κ = 0.95). We also verified family assessments of pediatric delirium as showing high sensitivity (0.90) and specificity (0.89) over 36 assessments. The Japanese version of the SOS-PD shows a high accuracy similar to the original. Moreover, we revealed high accuracy in family perception of pediatric delirium that could promote family presence in PICU settings.

The East Asian region (China, Japan, and South Korea) is comprised of almost 1.5 billion people and recent industrialization has brought with it a pandemic of rising obesity, even in children. As these countries are rapidly aging and functioning at sub-replacement birthrates, the burgeoning costs of obesity-related care may threaten socialized healthcare systems and quality of life. However, a condition called metabolically healthy obesity (MHO) has been found to be without immediate cardiopulmonary or diabetic risk. Thus, maintenance of the MHO condition for the obese in East Asia could buffer the burden of long-term obesity care on medical systems and knowledge of the biochemical, genetic, and physiological milieu associated with it could also provide new targets for intervention. Diverse physiological, psychological, environmental, and social factors play a role in obesogenesis and the transition of MHO to a metabolically unhealthy obesity. This review will give a broad survey of the various causes of obesity and MHO, with special emphasis on the East Asian population and studies from that region.

Background In an increasingly globalized world, legal protocols related to health care that are both effective and culturally sensitive are paramount in providing excellent quality of care as well as protection for physicians tasked with decision making. Here, we analyze the current medicolegal status of brain death diagnosis with regard to end-of-life care in Japan, China, and South Korea from the perspectives of front-line health care workers. Main body Japan has legally wrestled with the concept of brain death for decades. An inability to declare brain death without consent from family coupled with cultural expectations of family involvement in medical care is mirrored in other Confucian-based cultures (China and South Korea) and may complicate care for patients from these countries when traveling or working overseas. Within Japan, China, and South Korea, medicolegal shortcomings in the diagnosis of brain death (and organ donation) act as a great source of stress for physicians and expose them to potential public and legal scorn. Here, we detail the medicolegal status of brain death diagnosis within Japan and compare it to China and South Korea to find common ground and elucidate the impact of legal ambiguity on health care workers. Conclusion The Confucian cultural foundation of multiple Asian countries raises common issues of family involvement with diagnosis and cultural considerations that must be met. Leveraging public education systems may increase awareness of brain death issues and lead to evolving laws that clarify such end-of-life issues while protecting physicians from sociocultural backlash.

Renal cell carcinoma (RCC) features altered lipid metabolism and accumulated polyunsaturated fatty acids (PUFAs). Elongation of very long–chain fatty acid (ELOVL) family enzymes catalyze fatty acid elongation, and ELOVL5 is indispensable for PUFAs elongation, but its role in RCC progression remains unclear. Here, we show that higher levels of ELOVL5 correlate with poor RCC clinical prognosis. Liquid chromatography/electrospray ionization‐tandem mass spectrometry analysis showed decreases in ELOVL5 end products (arachidonic acid and eicosapentaenoic acid) under CRISPR/Cas9‐mediated knockout of ELOVL5 while supplementation with these fatty acids partially reversed the cellular proliferation and invasion effects of ELOVL5 knockout. Regarding cellular proliferation and invasion, CRISPR/Cas9‐mediated knockout of ELOVL5 suppressed the formation of lipid droplets and induced apoptosis via endoplasmic reticulum stress while suppressing renal cancer cell proliferation and in vivo tumor growth. Furthermore, CRISPR/Cas9‐mediated knockout of ELOVL5 inhibited AKT Ser473 phosphorylation and suppressed renal cancer cell invasion through chemokine (C‐C motif) ligand‐2 downregulation by AKT‐mTOR‐STAT3 signaling. Collectively, these results suggest that ELOVL5‐mediated fatty acid elongation promotes not only cellular proliferation but also invasion in RCC. Elevated ELOVL5 expression is associated with poor renal cancer clinical prognosis. ELOVL5 promotes cellular proliferation by inhibiting apoptosis. ELOVL5 promotes cellular invasion via the AKT‐mTOR‐STAT3‐CCL2 signaling pathway.

Epilepsy affects approximately 70 million people globally, with around 20-30% of these individuals experiencing drug-resistant epilepsy in which seizures remain uncontrolled despite prolonged treatment with anti-seizure medications (ASMs). Such refractory epilepsy significantly impairs quality of life, often necessitating surgical resection of the epileptic focus when ASMs fail. Accurate localization of the epileptic focus is crucial for successful surgery and typically requires invasive intracranial monitoring through subdural electrodes (SDE) or stereotactic electroencephalography (SEEG). Despite their effectiveness, the invasiveness of these methods poses significant risks. In response to these challenges, the EP-01 device has been developed to measure intracranial electroencephalogram (EEG) via the cerebral veins, offering a less invasive alternative. The Endovascular EEG Device Prospective Multicenter Single-arm clinical trial to confirm efficacy and safety performance on patients with Intractable Epilepsy (EPSILON IE) trial aims to evaluate the efficacy and safety of EP-01 in diagnosing the lateralization of epileptic foci in patients with focal epilepsy. The hypothesis is that EP-01, when equipped with multiple endovascular EEG electrodes, can accurately diagnose lateralization, reducing the need for more invasive procedures like SDE and SEEG. This multicenter, prospective, single-arm validation clinical trial is set to take place from March 2024 to August 2025, with follow-up extending to August 2026. The study will enroll 37 patients with refractory focal epilepsy across several Japanese medical institutions. Eligibility criteria include age 15-70 years and a vascular anatomy that allows the EP-01 to be guided into cerebral veins close to the epileptic focus. The EP-01 device will be inserted via the jugular veins, with electrodes positioned in target cerebral veins to record intracranial EEG data. The primary endpoint is the percentage agreement in lateralization diagnosis between EP-01 and conventional intracranial electrodes. Secondary endpoints include the diagnostic performance of EP-01, safety assessments, and seizure outcomes one year after resection surgery. Participants will undergo a screening period of 30 days, followed by the clinical trial period of up to two weeks, during which EP-01 will be inserted and monitored. A post-observation period of one week will follow device removal to assess potential adverse events. Data collection will involve EEG recordings, imaging studies, and safety evaluations, with results analyzed to determine the efficacy and safety of the device compared to traditional methods. This trial aims to provide critical data on the potential for EP-01 to serve as a less-invasive, effective alternative for diagnosing epileptic focus lateralization, potentially reducing the need for traditional invasive monitoring methods.

Advancement in early detection modalities will greatly improve the overall prognoses of pancreatic ductal adenocarcinoma (PDAC). For this purpose, we report a novel class of tumor‐specific probes for positron emission tomography (PET) based on targeting cell surface glycans. The PDAC‐targeting ability of rBC2LCN lectin, combined with fluorine‐18 (18F) ([18F]FB‐rBC2LCN), resulted in reproducible, high‐contrast PET imaging of tumors in a PDAC xenograft mouse model. [18F]N‐succinimidyl‐4‐fluorobenzoate ([18F]SFB) was conjugated to rBC2LCN, and [18F]FB‐rBC2LCN was successfully prepared with a radiochemical purity >95%. Cell binding and uptake revealed that [18F]FB‐rBC2LCN binds to H‐type‐3‐positive Capan‐1 pancreatic cancer cells. As early as 60 min after [18F]FB‐rBC2LCN (0.34 ± 0.15 MBq) injection into the tail vein of nude mice subcutaneously bearing Capan‐1 tumors, tumor uptake was high (6.6 ± 1.8 %ID/g), and the uptake increased over time (8.8 ± 1.9 %ID/g and 11 ± 3.2 %ID/g at 150 and 240 min after injection, respectively). Tumor‐to‐muscle ratios increased over time, up to 19 ± 1.8 at 360 min. High‐contrast PET imaging of tumors relative to background muscle was also achieved as early as 60 min after injection of [18F]FB‐rBC2LCN (0.66 ± 0.12 MBq) and continued to increase up to 240 min. Our 18F‐labeled rBC2LCN lectin warrants further clinical development to improve the accuracy and sensitivity of early‐stage pancreatic cancer detection. In this study, we generated an engineered, 18F‐labeled rBC2LCN lectin, [18F]FB‐rBC2LCN, to target cell surface glycans differentially upregulated in pancreatic cancer. In our pancreatic cancer cell xenograft model, [18F]FB‐rBC2LCN reproducibly yielded high‐contrast positron emission tomography (PET) imaging of tumors. Our 18F‐labeled rBC2LCN lectin warrants further clinical development to improve the accuracy and sensitivity of early‐stage detection of pancreatic cancer.

Background Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating side effect of taxane-based chemotherapy in breast cancer patients. Previous findings suggest that compression therapy may be a safe and effective preventive strategy against CIPN. However, patient-reported comfort and usability aspects of such therapy remain underexplored. This sub-analysis aimed to evaluate patient-reported discomfort and pressure associated with compression therapy and explore potential usability barriers to compliance. Methods This sub-analysis of a Phase I single-arm, open-label trial focused on patient-reported outcomes related to the subjective experience of compression therapy using double-layered surgical gloves and stockings during taxane administration. Parameters such as discomfort, pressure, pain, and itch in hands and feet were collected via questionnaires from 10 patients receiving neoadjuvant or adjuvant chemotherapy. Post hoc univariable analyses were conducted to explore potential factors associated with discomfort scores. Results Most patients reported minimal discomfort (mean hand discomfort score: 1.8; mean foot discomfort score: 2.2) and no pain in hands or feet during therapy. Mean perceived pressure scores were generally rated as “slight” to “mild,” though higher in calves (3.0) than toes (2.6) or fingertips (2.8). No statistically significant associations were identified between discomfort scores and other reported factors, though a positive trend between pain and discomfort was observed. Free-text responses highlighted that application and removal of double-layer compression garments posed greater challenges than physical discomfort itself. Conclusions Compression therapy using standard gloves and stockings appears tolerable and feasible for CIPN prevention. However, ease of application rather than discomfort may be the primary barrier to patient compliance. Future designs should prioritize usability and fit to ensure sustained adherence, especially in clinical settings. Trial registration jRCTs032210221, registered on 4 August 2021.

Squalene, a natural triterpene with antioxidant, anti-inflammatory, and immunostimulatory properties, holds promise for cancer therapy. Here, we examined a previously developed, diethylene glycol derivative of squalene (SQ-diEG) and investigated its in vivo anti-carcinogenic effects in bladder cancer. C57BL/6 mice were treated with 0.025% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) to induce bladder cancer, with SQ-diEG or PBS (control) administered orally from Week 0. SQ-diEG significantly reduced bladder cancer incidence to 3.7% after 8 weeks, compared to 21.4% in controls (p = 0.025). Transcriptomic analysis indicated that SQ-diEG may exert anti-carcinogenic effects by reducing ROS-mediated DNA damage, enhancing the immune microenvironment, and modulating cholesterol biosynthesis via SQLE downregulation. In vitro, SQ-diEG inhibited proliferation and induced apoptosis in bladder cancer cell lines. This study is the first to demonstrate that SQ-diEG significantly reduces bladder cancer in a BBN mouse model, highlighting potential for therapeutic development. Further research is needed to elucidate the mechanisms and long-term efficacy of SQ-diEG.

Surgical intervention creates reactive oxygen species through diverse molecular mechanisms, including direct stimulation of immune-mediated inflammation necessary for wound healing. However, dysregulation of redox homeostasis in surgical patients overwhelms the endogenous defense system, slowing the healing process and damaging organs. We broadly surveyed reactive oxygen species that result from surgical interventions and the endogenous and/or exogenous antioxidants that control them. This study assimilates current reports on surgical sources of reactive oxygen and nitrogen species along with literature reports on the effects of endogenous and exogenous antioxidants in human, animal, and clinical settings. Although exogenous antioxidants are generally beneficial, endogenous antioxidant systems account for over 80% of total activity, varying based on patient age, sex, and health or co-morbidity status, especially in smokers, the diabetic, and the obese. Supplementation of exogenous compounds for support in surgical patients is thus theoretically beneficial, but a lack of persuasive clinical evidence has left this potential patient support strategy without clear guidelines. A more thorough understanding of the mechanisms of exogenous antioxidants in patients with compromised health statuses and pharmacokinetic profiling may increase the utility of such support in both the operating and recovery rooms.