The clinical effect of an electric massage chair on chemotherapy-induced nausea and vomiting in cancer patients: randomized phase II cross-over trial.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is a common adverse events in cancer patients and can negatively affect their quality of life (QoL). This study aimed to evaluate the clinical efficacy of an electric massage chair (EMC) for the treatment of CINV. METHODS: A randomized phase II cross-over trial was conducted on solid cancer patients who received moderate (MEC) to high emetogenic chemotherapy (HEC). The participants were randomly assigned to receive their first chemotherapy either on a standard bed (Group A) or in an EMC (Group B) during the infusion. The patients were then crossed over to the next cycle. CINV and QoL questionnaires were collected from the participants. RESULTS: A total of 59 patients completed the trial protocol and were included in the analysis, with 29 and 30 patients in Groups A and B, respectively. The mean INVR (Index of Nausea, Vomiting, and Retching) score in the 2nd day of the first cycle was higher in Group B (3.63 ± 5.35) than Group A (2.76 ± 4.78), but the difference was not statistically significant (p = 0.5367). The complete response rate showed little difference between the groups. Among the high-emetic risk subgroups, patients who received HEC (p = 0.04595), younger patients (p = 0.0108), and non-colorectal cancer patients (p = 0.0495) presented significantly lower CINV scores when EMC was applied. CONCLUSION: Overall, there was no significant difference in INVR scores between standard care and EMC. Applying EMC at the first chemotherapy infusion may help preserve QoL and reduce CINV in high-risk patients. TRIAL REGISTRATION: KCT0008200, 17/02/2023, Retrospectively registered.

Integrative multi-omics characterization reveals sex differences in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults, with limited treatment modalities and poor prognosis. Recent studies have highlighted the importance of considering sex differences in cancer incidence, prognosis, molecular disparities, and treatment outcomes across various tumor types, including colorectal adenocarcinoma, lung adenocarcinoma, and GBM. METHODS: We performed comprehensive analyses of large-scale multi-omics data (genomic, transcriptomic, and proteomic data) from TCGA, GLASS, and CPTAC to investigate the genetic and molecular determinants that contribute to the unique clinical properties of male and female GBM patients. RESULTS: Our results revealed several key differences, including enrichments of MGMT promoter methylation, which correlated with increased overall and post-recurrence survival and improved response to chemotherapy in female patients. Moreover, female GBM exhibited a higher degree of genomic instability, including aneuploidy and tumor mutational burden. Integrative proteomic and phosphor-proteomic characterization uncovered sex-specific protein abundance and phosphorylation activities, including EGFR activation in males and SPP1 hyperphosphorylation in female patients. Lastly, the identified sex-specific biomarkers demonstrated prognostic significance, suggesting their potential as therapeutic targets. CONCLUSIONS: Collectively, our study provides unprecedented insights into the fundamental modulators of tumor progression and clinical outcomes between male and female GBM patients and facilitates sex-specific treatment interventions. Highlights Female GBM patients were characterized by increased MGMT promoter methylation and favorable clinical outcomes compared to male patients. Female GBMs exhibited higher levels of genomic instability, including aneuploidy and TMB. Each sex-specific GBM is characterized by unique pathway dysregulations and molecular subtypes. EGFR activation is prevalent in male patients, while female patients are marked by SPP1 hyperphosphorylation.

Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults with limited treatment modalities and dismal prognosis. A thorough understanding of sex differences could facilitate personalized therapeutic strategies in GBM. In this study, we conducted a comprehensive multi-omics analysis from TCGA, CPTAC, and GLASS studies, revealing distinct molecular and clinical disparities between male and female GBM patients. We discovered that female GBM patients exhibited enrichments of MGMT promoter methylation and high genomic instability, including aneuploidy and TMB. While male GBMs were characterized by activation of EGFR protein and phosphorylation activities, female GBM patients demonstrated hyperphosphorylation of SPP1. Notably, these proteins demonstrated prognostic significance, highlighting their potential as therapeutic targets. Our findings provide unprecedented insights into the fundamental modulators of tumor progression and clinical outcomes in male and female GBM patients, offering valuable opportunities for sex-specific treatment interventions.

Phase II study of nivolumab in patients with genetic alterations in DNA damage repair and response who progressed after standard treatment for metastatic solid cancers (KM-06).

BACKGROUND: Immune-modulating antibodies targeting programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) have demonstrated promising antitumor efficacy in various types of cancers, especially highly mutated ones. Genetic alterations in DNA damage response and repair (DDR) genes can lead to genetic instability, often accompanied by a high tumor mutation burden (TMB). However, few studies have validated the aberration of DDR genes as a predictive biomarker for response to immune-modulating antibodies. METHODS: The KM-06 open-label, multicenter, single-arm, phase II trial evaluated the safety and efficacy of nivolumab in refractory solid cancers with DDR gene mutations assessed by clinically targeted sequencing. Nivolumab (3 mg/kg) was administered every 2 weeks until disease progression, unacceptable toxicity, or for 24 months. The primary endpoint was the objective response rate (ORR) as per RECIST V.1.1 criteria. RESULTS: A total of 48 patients were enrolled in the study (median age 61, 58.3% male). The most common cancer type was colorectal cancer (41.7%), followed by prostate and biliary tract cancer (8.3% each). Eight patients achieved a partial response as their best overall response, resulting in an ORR of 17.8%. The disease control rate was 60.0%. The median progression-free survival was 2.9 months. Treatment-related adverse events of any grade and grade ≥3 occurred in 44 (91.7%) and 4 (8.3%) patients, respectively. Clinically targeted sequencing data inferred both TMB and microsatellite instability (MSI). Using a TMB cut-off of 12 mut/Mb, there were significant differences in overall survival (p=0.00035), progression-free survival (p=0.0061), and the best overall response (p=0.05). In the RNA sequencing analysis, nivolumab responders showed activation of the interleukin signaling pathway. Patients who experienced early progression presented high epithelial-mesenchymal transition signaling pathway activation. The responders exhibited a marked increase in PD-1-/Ki67+CD8 T cells at the early stage of treatment (C3D1) compared with non-responders (p=0.03). CONCLUSIONS: In this phase II trial, nivolumab demonstrated moderate efficacy and manageable toxicity in patients with solid cancer harboring DDR gene mutations. A high TMB (>12 mut/Mb) and MSI score (>2.5) determined through clinically target sequencing presented significant discriminatory power for the nivolumab response. TRIAL REGISTRATION NUMBER: NCT04761744.

Monitoring, exposure and risk assessment of formaldehyde in alcoholic beverages in Korea.

Formaldehyde occurs naturally in food and alcoholic beverages. Formaldehyde and alcoholic beverages can cause various health problems, including irritation of the eyes, nose, and throat, respiratory problems, and skin rashes. Alcoholic beverage samples (N = 236) were collected and analyzed for formaldehyde by liquid chromatography-tandem mass spectrometry. The highest average concentrations were detected in fruit wines (1.71 µg/g), followed by wines (1.15 µg/g), cheongju (0.95 µg/g), soju (0.85 µg/g), takju (0.64 µg/g) and beers (0.61 µg/g). We assessed the exposure and risk assessment to formaldehyde from alcoholic beverages based on the monitoring data for the general population and consumers in Korea using various schemes for point estimation. The daily intakes of formaldehyde for the general population and consumers were estimated to be 83 µg and 1202 µg, respectively. The mean hazard indexes (HI) for the general population and consumers in Korea were 0.009 and 0.132, respectively. On the other hand, the mean hazard indexes (HI) for the general population and consumers in Korea were 0.009 and 0.132, respectively. The exposure to formaldehyde in these alcoholic beverages for the Korean population was shown to be of low concern, but it is necessary to monitor the level of formaldehyde in alcoholic beverages and continuously conduct exposure assessment for consumers.

Multimodal-based machine learning approach to classify features of internet gaming disorder and alcohol use disorder: A sensor-level and source-level resting-state electroencephalography activity and neuropsychological study.

OBJECTIVES: Addictions have recently been classified as substance use disorder (SUD) and behavioral addiction (BA), but the concept of BA is still debatable. Therefore, it is necessary to conduct further neuroscientific research to understand the mechanisms of BA to the same extent as SUD. The present study used machine learning (ML) algorithms to investigate the neuropsychological and neurophysiological aspects of addictions in individuals with internet gaming disorder (IGD) and alcohol use disorder (AUD). METHODS: We developed three models for distinguishing individuals with IGD from those with AUD, individuals with IGD from healthy controls (HCs), and individuals with AUD from HCs using ML algorithms, including L1-norm support vector machine, random forest, and L1-norm logistic regression (LR). Three distinct feature sets were used for model training: a unimodal-electroencephalography (EEG) feature set combined with sensor- and source-level feature; a unimodal-neuropsychological feature (NF) set included sex, age, depression, anxiety, impulsivity, and general cognitive function, and a multimodal (EEG + NF) feature set. RESULTS: The LR model with the multimodal feature set used for the classification of IGD and AUD outperformed the other models (accuracy: 0.712). The important features selected by the model highlighted that the IGD group had differential delta and beta source connectivity between right intrahemispheric regions and distinct sensor-level EEG activities. Among the NFs, sex and age were the important features for good model performance. CONCLUSIONS: Using ML techniques, we demonstrated the neurophysiological and neuropsychological similarities and differences between IGD (a BA) and AUD (a SUD).

Animal protein hydrolysate reduces visceral fat and inhibits insulin resistance and hepatic steatosis in aged mice.

BACKGROUND/OBJECTIVES: An increasing life expectancy in society has burdened healthcare systems substantially because of the rising prevalence of age-related metabolic diseases. This study compared the effects of animal protein hydrolysate (APH) and casein on metabolic diseases using aged mice. MATERIALS/METHODS: Eight-week-old and 50-week-old C57BL/6J mice were used as the non-aged (YC group) and aged controls (NC group), respectively. The aged mice were divided randomly into 3 groups (NC, low-APH [LP], and high-APH [HP] and fed each experimental diet for 12 weeks. In the LP and HP groups, casein in the AIN-93G diet was substituted with 16 kcal% and 24 kcal% APH, respectively. The mice were sacrificed when they were 63-week-old, and plasma and hepatic lipid, white adipose tissue weight, hepatic glucose, lipid, and antioxidant enzyme activities, immunohistochemistry staining, and mRNA expression related to the glucose metabolism on liver and muscle were analyzed. RESULTS: Supplementation of APH in aging mice resulted in a significant decrease in visceral fat (epididymal, perirenal, retroperitoneal, and mesenteric fat) compared to the negative control (NC) group. The intraperitoneal glucose tolerance test and area under the curve analysis revealed insulin resistance in the NC group, which was alleviated by APH supplementation. APH supplementation reduced hepatic gluconeogenesis and increased glucose utilization in the liver and muscle. Furthermore, APH supplementation improved hepatic steatosis by reducing the hepatic fatty acid and phosphatidate phosphatase activity while increasing the hepatic carnitine palmitoyltransferase activity. Furthermore, in the APH supplementation groups, the red blood cell (RBC) thiobarbituric acid reactive substances and hepatic H2O2 levels decreased, and the RBC glutathione, hepatic catalase, and glutathione peroxidase activities increased. CONCLUSIONS: APH supplementation reduced visceral fat accumulation and alleviated obesity-related metabolic diseases, including insulin resistance and hepatic steatosis, in aged mice. Therefore, high-quality animal protein APH that reduces the molecular weight and enhances the protein digestibility-corrected amino acid score has potential as a dietary supplement for healthy aging.

Integrated proteogenomic characterization of glioblastoma evolution.

The evolutionary trajectory of glioblastoma (GBM) is a multifaceted biological process that extends beyond genetic alterations alone. Here, we perform an integrative proteogenomic analysis of 123 longitudinal glioblastoma pairs and identify a highly proliferative cellular state at diagnosis and replacement by activation of neuronal transition and synaptogenic pathways in recurrent tumors. Proteomic and phosphoproteomic analyses reveal that the molecular transition to neuronal state at recurrence is marked by post-translational activation of the wingless-related integration site (WNT)/ planar cell polarity (PCP) signaling pathway and BRAF protein kinase. Consistently, multi-omic analysis of patient-derived xenograft (PDX) models mirror similar patterns of evolutionary trajectory. Inhibition of B-raf proto-oncogene (BRAF) kinase impairs both neuronal transition and migration capability of recurrent tumor cells, phenotypic hallmarks of post-therapy progression. Combinatorial treatment of temozolomide (TMZ) with BRAF inhibitor, vemurafenib, significantly extends the survival of PDX models. This study provides comprehensive insights into the biological mechanisms of glioblastoma evolution and treatment resistance, highlighting promising therapeutic strategies for clinical intervention.

Development of a Protocol for the Direct Breastfeeding of Premature Infants in Neonatal Intensive Care Units.

PURPOSE: This study aimed to develop a direct breastfeeding protocol for premature infants admitted to neonatal intensive care units (NICUs) and investigate its efficacy. BACKGROUND: Direct breastfeeding increases the amount and duration of breastfeeding. However, NICUs have low direct feeding rates owing to medical staff anxiety, lack of knowledge and experience, and fear of overwork. Accordingly, this study developed a protocol for direct breastfeeding in the NICU and evaluated its effect. METHODS: The protocol was developed through a literature review, expert validation, and preliminary investigation. Its application effects were identified using a nonexperimental, evidence-based research design targeting premature infants, their mothers, and NICU nurses. RESULTS: The protocol comprised 5 areas and 23 items. Application of the protocol resulted in continuous weight gain of the infants and increased self-efficacy in the mothers' direct breastfeeding ( t = 3.219, P = .004). Significant increases were noted in NICU nurses' direct breastfeeding activities ( t = 3.93, P < .001), breastfeeding rates in the NICU ( P = .037), and direct breastfeeding rates ( P = .007). CONCLUSIONS: Results underscore the value of an evidence-based protocol for improving breastfeeding rates in premature infants. This study highlights the need for continuous nursing education on protocol applications and human resource support.

Evaluation of Multiplex Rapid Antigen Tests for the Simultaneous Detection of SARS-CoV-2 and Influenza A/B Viruses.

Single-target rapid antigen tests (RATs) are commonly used to detect highly transmissible respiratory viruses (RVs), such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses. The simultaneous detection of RVs presenting overlapping symptoms is vital in making appropriate decisions about treatment, isolation, and resource utilization; however, few studies have evaluated multiplex RATs for SARS-CoV-2 and other RVs. We assessed the diagnostic performance of multiplex RATs targeting both the SARS-CoV-2 and influenza A/B viruses with the GenBody Influenza/COVID-19 Ag Triple, InstaView COVID-19/Flu Ag Combo (InstaView), STANDARDTM Q COVID-19 Ag Test, and STANDARDTM Q Influenza A/B Test kits using 974 nasopharyngeal swab samples. The cycle threshold values obtained from the real-time reverse transcription polymerase chain reaction results showed higher sensitivity (72.7-100%) when the values were below, rather than above, the cut-off values. The InstaView kit exhibited significantly higher positivity rates (80.21% for SARS-CoV-2, 61.75% for influenza A, and 46.15% for influenza B) and cut-off values (25.57 for SARS-CoV-2, 21.19 for influenza A, and 22.35 for influenza B) than the other two kits, and was able to detect SARS-CoV-2 Omicron subvariants. Therefore, the InstaView kit is the best choice for routine screening for both SARS-CoV-2 and influenza A/B in local communities.

An Analysis of the Demographics and Clinical Characteristics of Transgender and Intersex Populations in Korea: A Retrospective Study Using HIRA Database.

BACKGROUND: Transgender and intersex populations have long remained under-documented in South Korea, largely due to the absence of comprehensive epidemiological data. With increasing societal acknowledgment, there's an urgent need to understand the demographics and health challenges faced by these communities. METHODS: This retrospective, large-scale data study included people who received the F64 codes from the Korean Health Insurance Review & Assessment Service between January 2007 and December 2021. Demographics, gender-affirmative treatments, and psychiatric related medications were examined. RESULTS: Between 2007 and 2021, 8,602 patients were diagnosed with "gender identity disorder" and 45 with "intersex." A steadily increasing annual prevalence was observed, peaking at 986 cases in 2021. The majority (79.8%) were aged between 10 and 30. Nearly half (53.2%) exhibited mental and behavioral disorders. Two-thirds had been prescribed anxiolytics or sedatives either before or after diagnosis. Merely 12.1% received hormone therapy covered by health insurance. CONCLUSION: This is the first large-scale study highlighting the demographics and clinical characteristics of the transgender and intersex populations in Korea. The study reveals a consistent growth of these communities over the past 15 years, with a significant proportion under 30 years of age facing mental and behavioral challenges. Findings underscore the need for targeted healthcare interventions, early psychological support, and comprehensive insurance coverage tailored to the specific needs of these individuals in Korea.

In Situ Simultaneous Detection of Surface Protein and microRNA in Clustered Extracellular Vesicles from Cancer Cell Lines Using Flow Cytometry.

Extracellular vesicles (EVs) are becoming increasingly important in liquid biopsy for cancer because they contain multiple biomarkers, including proteins and RNAs, and circulate throughout the body. Cancer cell-derived EVs are highly heterogeneous, and multiplexed biomarker detection techniques are required to improve the accuracy of diagnosis. In addition, in situ EV biomarker detection increases the efficiency of the detection process because EVs are difficult to handle. In this study, in situ simultaneous detection of EV surface proteins, programmed cell death-ligand 1 (PD-L1), and internal miRNA-21 (miR-21) analyzed by conventional flow cytometry was developed for a breast cancer liquid biopsy. However, the majority of EVs were not recognized by flow cytometry for biomarker detection because the size of EVs was below the detectable size range of the flow cytometer. To solve this problem, the formation of EV clusters was induced by 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-polyethylene glycol-DSPE during biomarker detection. Consequently, both PD-L1 and miR-21 detection signals from cancer cell-derived EVs were drastically increased, making them distinguishable from normal cell-derived EVs. The in situ simultaneous cancer biomarker detection from EV clusters analyzed by flow cytometry contributes to an increase in the sensitivity and accuracy of the EV-based liquid biopsy for cancer.

The animal protein hydrolysate attenuates sarcopenia via the muscle-gut axis in aged mice.

Age-related muscle loss and dysfunction, sarcopenia, is a common condition that results in poor quality of life in the elderly. Protein supplementation is a potential strategy for preventing sarcopenia and increasing muscle synthesis, but the effectiveness of protein type and level in improving sarcopenia is not well understood. In this study, we compared animal protein hydrolysate (APH), which has a high protein digestibility-corrected amino acid score (PDCAAS) and low molecular weight, with casein as a control group to investigate the effects and mechanisms of sarcopenia improvement, with a particular focus on the gut-muscle axis. APH supplementation improved age-related declines in muscle mass, grip strength, hind leg thickness, muscle protein level, muscle fiber size, and myokine levels, compared to the control group. In particular, levels of plasma cortisol, muscle lipids, and muscle collagen were markedly reduced by APH supplements in the aged mice. Furthermore, APH efficiently recovered the concentration of total SCFAs including acetic, propionic, and isovaleric acids decreased in aged mice. Finally, APH induced changes in gut microbiota and increased production of SCFAs, which were positively correlated with muscle protein level and negatively correlated with pro-inflammatory cytokines. In conclusion, APH can help to inhibit age-related sarcopenia by increasing muscle synthesis, inhibiting muscle breakdown, and potentially modulating the gut-muscle axis.

The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism.

Arachidonic and adrenic acids in the membrane play key roles in ferroptosis. Here, we reveal that lipoprotein-associated phospholipase A2 (Lp-PLA2) controls intracellular phospholipid metabolism and contributes to ferroptosis resistance. A metabolic drug screen reveals that darapladib, an inhibitor of Lp-PLA2, synergistically induces ferroptosis in the presence of GPX4 inhibitors. We show that darapladib is able to enhance ferroptosis under lipoprotein-deficient or serum-free conditions. Furthermore, we find that Lp-PLA2 is located in the membrane and cytoplasm and suppresses ferroptosis, suggesting a critical role for intracellular Lp-PLA2. Lipidomic analyses show that darapladib treatment or deletion of PLA2G7, which encodes Lp-PLA2, generally enriches phosphatidylethanolamine species and reduces lysophosphatidylethanolamine species. Moreover, combination treatment of darapladib with the GPX4 inhibitor PACMA31 efficiently inhibits tumour growth in a xenograft model. Our study suggests that inhibition of Lp-PLA2 is a potential therapeutic strategy to enhance ferroptosis in cancer treatment.

FSP1 confers ferroptosis resistance in KEAP1 mutant non-small cell lung carcinoma in NRF2-dependent and -independent manner.

Ferroptosis, a type of cell death induced by lipid peroxidation, has emerged as a novel anti-cancer strategy. Cancer cells frequently acquire resistance to ferroptosis. However, the underlying mechanisms are poorly understood. To address this issue, we conducted a thorough investigation of the genomic and transcriptomic data derived from hundreds of human cancer cell lines and primary tissue samples, with a particular focus on non-small cell lung carcinoma (NSCLC). It was observed that mutations in Kelch-like ECH-associated protein 1 (KEAP1) and subsequent nuclear factor erythroid 2-related factor 2 (NRF2, also known as NFE2L2) activation are strongly associated with ferroptosis resistance in NSCLC. Additionally, AIFM2 gene, which encodes ferroptosis suppressor protein 1 (FSP1), was identified as the gene most significantly correlated with ferroptosis resistance, followed by multiple NRF2 targets. We found that inhibition of NRF2 alone was not sufficient to reduce FSP1 protein levels and promote ferroptosis, whereas FSP1 inhibition effectively sensitized KEAP1-mutant NSCLC cells to ferroptosis. Furthermore, we found that combined inhibition of FSP1 and NRF2 induced ferroptosis more intensely. Our findings imply that FSP1 is a crucial suppressor of ferroptosis whose expression is partially dependent on NRF2 and that synergistically targeting both FSP1 and NRF2 may be a promising strategy for overcoming ferroptosis resistance in cancer.

Ferric citrate and apo-transferrin enable erythroblast maturation with ß-globin from hemogenic endothelium.

Red blood cell (RBC) generation from human pluripotent stem cells (PSCs) offers potential for innovative cell therapy in regenerative medicine as well as developmental studies. Ex vivo erythropoiesis from PSCs is currently limited by the low efficiency of functional RBCs with ß-globin expression in culture systems. During induction of ß-globin expression, the absence of a physiological microenvironment, such as a bone marrow niche, may impair cell maturation and lineage specification. Here, we describe a simple and reproducible culture system that can be used to generate erythroblasts with ß-globin expression. We prepared a two-dimensional defined culture with ferric citrate treatment based on definitive hemogenic endothelium (HE). Floating erythroblasts derived from HE cells were primarily CD45+CD71+CD235a+ cells, and their number increased remarkably upon Fe treatment. Upon maturation, the erythroblasts cultured in the presence of ferric citrate showed high transcriptional levels of ß-globin and enrichment of genes associated with heme synthesis and cell cycle regulation, indicating functionality. The rapid maturation of these erythroblasts into RBCs was observed when injected in vivo, suggesting the development of RBCs that were ready to grow. Hence, induction of ß-globin expression may be explained by the effects of ferric citrate that promote cell maturation by binding with soluble transferrin and entering the cells.Taken together, upon treatment with Fe, erythroblasts showed advanced maturity with a high transcription of ß-globin. These findings can help devise a stable protocol for the generation of clinically applicable RBCs.

Dry-milled flour rice 'Seolgaeng' harbors a mutated fructose-6-phosphate 2-kinase/fructose-2,6-bisphosphatase2.

'Seolgaeng', an opaque-endosperm rice (Oryza sativa) mutant, is used to prepare high-quality dry-milled rice flour. The mutation causing its opaque-endosperm phenotype was unknown. Map-based cloning identified a missense mutation in the gene FRUCTOSE-6-PHOSPHATE 2-KINASE/FRUCTOSE-2,6-BISPHOSPHATASE 2 (OsF2KP2) in Seolgaeng. Transfer DNA insertion and clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated nuclease 9 (Cas9)-induced f2kp2 mutants exhibited opaque endosperm. Rice harbors another F2KP gene, OsF2KP1. CRISPR/Cas9-induced double mutants of OsF2KP1 and OsF2KP2 (f2kp-d) possessed more opaque endosperm compared to f2kp2 single mutants, whereas the endosperm of the f2kp1 single mutant was normal. Grain hardness and damaged starch content were significantly reduced in f2kp2 mutants compared to the wild type and f2kp1. Amylose content was lower than normal in f2kp2 mutants but not f2kp1. Grain hardness and amylose content were much lower in f2kp-d than in f2kp2. Starch polymerization analysis revealed altered amylopectin structure in f2kp2 and f2kp-d mutants. F2KP activity was lower in f2kp2 and much lower in the double mutants when compared to the wild types, but f2kp1 showed no significant difference. In coleoptiles, hypoxia induced OsF2KP2 expression but downregulated OsF2KP1. These results suggest that OsF2KP2 functions as the main F2KP isoform in endosperm experiencing hypoxia, but OsF2KP1 may partially compensate for the absence of OsF2KP2. We propose that F2KP has a crucial role in inorganic pyrophosphate-utilizing energy metabolism for starch biosynthesis in rice endosperm.

An integrated view of lipid metabolism in ferroptosis revisited via lipidomic analysis.

Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. This process contributes to cellular and tissue damage in various human diseases, such as cardiovascular diseases, neurodegeneration, liver disease, and cancer. Although polyunsaturated fatty acids (PUFAs) in membrane phospholipids are preferentially oxidized, saturated/monounsaturated fatty acids (SFAs/MUFAs) also influence lipid peroxidation and ferroptosis. In this review, we first explain how cells differentially synthesize SFA/MUFAs and PUFAs and how they control fatty acid pools via fatty acid uptake and ß-oxidation, impacting ferroptosis. Furthermore, we discuss how fatty acids are stored in different lipids, such as diacyl or ether phospholipids with different head groups; triglycerides; and cholesterols. Moreover, we explain how these fatty acids are released from these molecules. In summary, we provide an integrated view of the diverse and dynamic metabolic processes in the context of ferroptosis by revisiting lipidomic studies. Thus, this review contributes to the development of therapeutic strategies for ferroptosis-related diseases.

Machine learning-based identification and related features of depression in patients with diabetes mellitus based on the Korea National Health and Nutrition Examination Survey: A cross-sectional study.

Patients with diabetes mellitus (DM) are twice as likely as nondiabetic individuals to develop depression, which is a prevalent but often undiagnosed psychiatric comorbidity. Patients with DM who are depressed have poor glycemic control, worse quality of life, increased risk of diabetic complications, and higher mortality rate. The present study aimed to develop machine learning (ML) models that identify depression in patients with DM, determine the best performing model by evaluating multiple ML algorithms, and investigate features related to depression. We developed six ML models, including random forest, K-nearest neighbor, support vector machine (SVM), Adaptive Boosting, light gradient-boosting machine, and Extreme Gradient Boosting, based on the Korea National Health and Nutrition Examination Survey. The results showed that the SVM model performed well, with a cross-validated area under the receiver operating characteristic curve of 0.835 (95% confidence interval [CI] = 0.730-0.901). Thirteen features were related to depression in patients with DM. Permutation feature importance showed that the most important feature was subjective health status, followed by level of general stress awareness; stress recognition rate; average monthly income; triglyceride (mg/dL) level; activity restriction status; European quality of life (EuroQoL): usual activity and lying in a sickbed in the past 1 month; EuroQoL: pain / discomfort, self-care, and physical discomfort in the last 2 weeks; and EuroQoL: mobility and chewing problems. The current findings may offer clinicians a better understanding of the relationship between DM and depression using ML approaches and may be an initial step toward developing a more predictive model for the early detection of depressive symptoms in patients with DM.

FLT4 as a marker for predicting prognostic risk of refractory acute myeloid leukemia.

Treating patients with refractory acute myeloid leukemia (AML) remains challenging. Currently there is no effective treatment for refractory AML. Increasing evidence has demonstrated that refractory/relapsed AML is associated with leukemic blasts which can confer resistance to anticancer drugs. We have previously reported that high expression of Fms-related tyrosine kinase 4 (FLT4) is associated with increased cancer activity in AML. However, the functional role of FLT4 in leukemic blasts remains unknown. Here, we explored the significance of FLT4 expression in leukemic blasts of refractory patients and mechanisms involved in the survival of AML blasts. Inhibition or absence of FLT4 in AML blasts suppressed homing to bone marrow of immunocompromised mice and blocked engraftment of AML blasts. Moreover, FLT4 inhibition by MAZ51, an antagonist, effectively reduced the number of leukemic cell-derived colony-forming units and increased apoptosis of blasts derived from refractory patients when it was co-treated with cytosine arabinoside under vascular endothelial growth factor C, its ligand. AML patients who expressed high cytosolic FLT4 were linked to an AML-refractory status by internalization mechanism. In conclusion, FLT4 has a biological function in leukemogenesis and refractoriness. This novel insight will be useful for targeted therapy and prognostic stratification of AML.

Generation of Red Blood Cells from Human Pluripotent Stem Cells-An Update.

Red blood cell (RBC) transfusion is a lifesaving medical procedure that can treat patients with anemia and hemoglobin disorders. However, the shortage of blood supply and risks of transfusion-transmitted infection and immune incompatibility present a challenge for transfusion. The in vitro generation of RBCs or erythrocytes holds great promise for transfusion medicine and novel cell-based therapies. While hematopoietic stem cells and progenitors derived from peripheral blood, cord blood, and bone marrow can give rise to erythrocytes, the use of human pluripotent stem cells (hPSCs) has also provided an important opportunity to obtain erythrocytes. These hPSCs include both human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). As hESCs carry ethical and political controversies, hiPSCs can be a more universal source for RBC generation. In this review, we first discuss the key concepts and mechanisms of erythropoiesis. Thereafter, we summarize different methodologies to differentiate hPSCs into erythrocytes with an emphasis on the key features of human definitive erythroid lineage cells. Finally, we address the current limitations and future directions of clinical applications using hiPSC-derived erythrocytes.