Proteogenomic analysis of chemo-refractory high-grade serous ovarian cancer.

To improve the understanding of chemo-refractory high-grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and sensitive) HGSOCs, representing one discovery and two validation cohorts across two biospecimen types (formalin-fixed paraffin-embedded and frozen). We identified a 64-protein signature that predicts with high specificity a subset of HGSOCs refractory to initial platinum-based therapy and is validated in two independent patient cohorts. We detected significant association between lack of Ch17 loss of heterozygosity (LOH) and chemo-refractoriness. Based on pathway protein expression, we identified 5 clusters of HGSOC, which validated across two independent patient cohorts and patient-derived xenograft (PDX) models. These clusters may represent different mechanisms of refractoriness and implicate putative therapeutic vulnerabilities.

An ancestral mycobacterial effector promotes dissemination of infection.

The human pathogen Mycobacterium tuberculosis typically causes lung disease but can also disseminate to other tissues. We identified a M. tuberculosis (Mtb) outbreak presenting with unusually high rates of extrapulmonary dissemination and bone disease. We found that the causal strain carried an ancestral full-length version of the type VII-secreted effector EsxM rather than the truncated version present in other modern Mtb lineages. The ancestral EsxM variant exacerbated dissemination through enhancement of macrophage motility, increased egress of macrophages from established granulomas, and alterations in macrophage actin dynamics. Reconstitution of the ancestral version of EsxM in an attenuated modern strain of Mtb altered the migratory mode of infected macrophages, enhancing their motility. In a zebrafish model, full-length EsxM promoted bone disease. The presence of a derived nonsense variant in EsxM throughout the major Mtb lineages 2, 3, and 4 is consistent with a role for EsxM in regulating the extent of dissemination.

Subcutaneous Infliximab (CT-P13 SC) as Maintenance Therapy for Inflammatory Bowel Disease: Two Randomized Phase 3 Trials (LIBERTY).

BACKGROUND & AIMS: CT-P13 subcutaneous (SC), an SC formulation of the intravenous (IV) infliximab biosimilar CT-P13 IV, creates a unique exposure profile. The LIBERTY studies aimed to demonstrate superiority of CT-P13 SC vs placebo as maintenance therapy in patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Two randomized, placebo-controlled, double-blind studies were conducted in patients with moderately to severely active CD or UC and inadequate response or intolerance to corticosteroids and immunomodulators. All patients received open-label CT-P13 IV 5 mg/kg at weeks 0, 2, and 6. At week 10, clinical responders were randomized (2:1) to CT-P13 SC 120 mg or placebo every 2 weeks until week 54 (maintenance phase) using prefilled syringes. (Co-) primary end points were clinical remission and endoscopic response (CD) and clinical remission (UC) at week 54 (all-randomized population). RESULTS: Overall, 396 patients with CD and 548 patients with UC received induction treatment. At week 54 in the CD study, statistically significant higher proportions of CT-P13 SC-treated patients vs placebo-treated patients achieved clinical remission (62.3% vs 32.1%; P < .0001) and endoscopic response (51.1% vs 17.9%; P < .0001). In the UC study, clinical remission rates at week 54 were statistically significantly higher with CT-P13 SC vs placebo (43.2% vs 20.8%; P < .0001). Achievement of key secondary end points was significantly higher with CT-P13 SC vs placebo across both studies. CT-P13 SC was well tolerated, with no new safety signals identified. CONCLUSIONS: CT-P13 SC was more effective than placebo as maintenance therapy and was well tolerated in patients with moderately to severely active CD or UC who responded to CT-P13 IV induction. CLINICALTRIALS: gov, Numbers: NCT03945019 (CD) and NCT04205643 (UC).

Macrophage Epithelial Reprogramming Underlies Mycobacterial Granuloma Formation and Promotes Infection.

Mycobacterium tuberculosis infection in humans triggers formation of granulomas, which are tightly organized immune cell aggregates that are the central structure of tuberculosis. Infected and uninfected macrophages interdigitate, assuming an altered, flattened appearance. Although pathologists have described these changes for over a century, the molecular and cellular programs underlying this transition are unclear. Here, using the zebrafish-Mycobacterium marinum model, we found that mycobacterial granuloma formation is accompanied by macrophage induction of canonical epithelial molecules and structures. We identified fundamental macrophage reprogramming events that parallel E-cadherin-dependent mesenchymal-epithelial transitions. Macrophage-specific disruption of E-cadherin function resulted in disordered granuloma formation, enhanced immune cell access, decreased bacterial burden, and increased host survival, suggesting that the granuloma can also serve a bacteria-protective role. Granuloma macrophages in humans with tuberculosis were similarly transformed. Thus, during mycobacterial infection, granuloma macrophages are broadly reprogrammed by epithelial modules, and this reprogramming alters the trajectory of infection and the associated immune response.

Catabolism of 2-keto-3-deoxy-galactonate and the production of its enantiomers.

2-Keto-3-deoxy-galactonate (KDGal) serves as a pivotal metabolic intermediate within both the fungal D-galacturonate pathway, which is integral to pectin catabolism, and the bacterial DeLey-Doudoroff pathway for D-galactose catabolism. The presence of KDGal enantiomers, L-KDGal and D-KDGal, varies across these pathways. Fungal pathways generate L-KDGal through the reduction and dehydration of D-galacturonate, whereas bacterial pathways produce D-KDGal through the oxidation and dehydration of D-galactose. Two distinct catabolic routes further metabolize KDGal: a nonphosphorolytic pathway that employs aldolase and a phosphorolytic pathway involving kinase and aldolase. Recent findings have revealed that L-KDGal, identified in the bacterial catabolism of 3,6-anhydro-L-galactose, a major component of red seaweeds, is also catabolized by Escherichia coli, which is traditionally known to be catabolized by specific fungal species, such as Trichoderma reesei. Furthermore, the potential industrial applications of KDGal and its derivatives, such as pyruvate and D- and L-glyceraldehyde, are underscored by their significant biological functions. This review comprehensively outlines the catabolism of L-KDGal and D-KDGal across different biological systems, highlights stereospecific methods for discriminating between enantiomers, and explores industrial application prospects for producing KDGal enantiomers. KEY POINTS: • KDGal is a metabolic intermediate in fungal and bacterial pathways • Stereospecific enzymes can be used to identify the enantiomeric nature of KDGal • KDGal can be used to induce pectin catabolism or produce functional materials.

Experiences of Generation Z Nurses Adapting to Work in a Tertiary Hospital: A Grounded Theory Study.

AIM: To investigate the adaptation process of Generation Z nurses at a tertiary hospital in Korea. DESIGN: This qualitative study using grounded theory. METHODS: The participants were 17 Generation Z nurses who were working at tertiary hospitals in Korea. Data were collected through in-depth interviews from September 2022 to July 2023. FINDINGS: Eight categories and 19 concepts were extracted. The core category was 'accepting deficient myself as a nurse in a vertical culture', which consisted of three phases: chaos, endeavouring to adapt and accepting myself. In the adaptation process at the tertiary hospital, most of the participants felt embarrassed by tasks. The most of them tended to stay away from stressors and endeavour to improve their competence. The participants who had familiarity and a sense of belonging and achievement tended to acknowledge themselves. CONCLUSIONS: This study provides help in suggesting the importance of a horizontal organisational culture to Generation Z nurses. Also, the support of senior nurses is needed to encourage Generation Z nurses to accept deficient themselves. IMPLICATIONS FOR THE PROFESSION: Generation Z nurses tended to feel confused by the vertical culture, uncertainty of work and daunting tasks; excessive criticism and rebuke seems to make Generation Z nurses feel a sense of shame. The family-centred culture of nursing organisations could cause conflicts for Generation Z nurses who tend to separate their personal lives from work. IMPACT: Generation Z nurses had no difficulty acquiring knowledge because they had the skills to search for the necessary information, but they experienced difficulty applying this knowledge in practice and becoming familiar with their role as a nurse. REPORT METHODS: We adhered to relevant EQUATOR guidelines of the Consolidated Criteria for Reporting Qualitative Research (COREQ). PATIENT OR PUBLIC INVOLVEMENT AND ENGAGEMENT: No patient or public involvement.

Effectiveness of electrocardiogram interpretation education program using mixed learning methods and webpage.

AIM: This study was conducted to develop an electrocardiogram education program that incorporates an HTML webpage and blended learning methods to enhance electrocardiogram interpretation skills. Through continual and efficient education, the program aims to assist nurses in providing appropriate care and treatment to patients. DESIGN: Pre-post design study. METHODS: We developed an electrocardiogram interpretation HTML webpage based on an electrocardiogram interpretation algorithm and implemented an 18-week (2023.5.15 ~ 2023.9.22) electrocardiogram education program, which included daily 5-minute training sessions. Twenty-seven ward nurses were provided with the URL ( https://ecgweb.github.io/ECGwebEN ) to the electrocardiogram interpretation HTML webpage and shared one electrocardiogram case daily for self-interpretation. Electrocardiogram interpretation performance and confidence were evaluated through questionnaires at three phases: before the program, after 6 weeks of basic electrocardiogram and arrhythmia education, and after 12 weeks of application of the electrocardiogram interpretation HTML webpage and case-based lecture education. The statistical tests used were repeated-measures ANOVA or the Wilcoxon signed-rank test. RESULTS: The average score for electrocardiogram interpretation performance before the electrocardiogram education program was 11.89(SD = 3.50), after 6 weeks of basic electrocardiogram and arrhythmia education it was 14.15(SD = 3.68), and after 12 weeks of application of the electrocardiogram interpretation HTML webpage and case-based lecture education, it was 15.56(SD = 3.04). This shows that electrocardiogram interpretation performance significantly improved over time (p < .001). Additionally, post-hoc analysis revealed significant differences in electrocardiogram interpretation performance at each stage, i.e., before, during, and after the application of an electrocardiogram education program. Furthermore, the electrocardiogram interpretation confidence questionnaire score (pre-Median 18, IQR = 5; post-Median 23, IQR = 3) was improved significantly after the completion of the 18-week education program (p < .001). CONCLUSIONS: Based on the results of this study, we believe that an electrocardiogram education program using HTML webpage, and a blended teaching method would be very beneficial for maintaining and improving electrocardiogram interpretation skills of clinical nurses. Such a program can help nurses interpret electrocardiograms more effectively and assist them in making important decisions in patient care.

Psychological separation, health locus of control, and transition readiness in adolescents and young adults with type I diabetes.

PURPOSE: The purpose of this study was to examine the effects of psychological separation and health locus of control on the health care transition readiness of adolescents and young adults (AYAs) with type 1 diabetes. METHODS: Data were collected between December 2020 and October 2021. One hundred twelve AYAs with type 1 diabetes treated at a tertiary hospital and under follow-up observation as well as AYAs with type 1 diabetes nationwide who were part of the type 1 diabetes internet community were enrolled. The Psychological Separation Inventory, the Multidimensional Health Locus of Control scale from C, and the Self-management and Transition to Adulthood with Therapeutics = Rx Questionnaire were used. RESULTS: Multiple regression analysis indicated that age (ß = 0.302, p = .001), hemoglobin A1c (HbA1c) (ß = -0.174, p = .040), conflictual separation (ß = 0.242, p = .005), functional separation (ß = 0.200, p = .045) and attitudinal separation (ß = -0.240 p = .015) were significantly associated with health management transition readiness; these predictors explained 27.6% of health care transition readiness (F = 8.062, p = .000). CONCLUSIONS: AYAs with type 1 diabetes can enhance readiness for health care transition by fostering psychological separation from parents, effectively managing blood glucose levels, and taking into account age-related factors during the preparation process. At this point, it is essential for healthcare professionals to guide parents in recognizing adolescents' psychological independence and facilitating their supportive role through the process of redefining their roles. PRACTICE IMPLICATIONS: Health care providers should promote psychological separation in AYAs. Additionally, taking into account the developmental characteristics of adolescence can facilitate a successful health care transition.

Divergent synthesis of two types of indolizines from pyridine-2-acetonitrile, (hetero)arylglyoxal, and TMSCN.

Herein we describe the divergent synthesis of two types of indolizines via construction of the pyrrole moiety from pyridine-2-acetonitriles, arylglyoxals, and TMSCN. While one-pot three-component coupling provided 2-aryl-3-aminoindolizines via an unusual fragmentation process, a sequential two-step assembly protocol with these starting materials allowed efficient access to a wide range of new 2-acyl-3-aminoindolizines through an aldol condensation-Michael addition-cycloisomerization process. The subsequent manipulation of 2-acyl-3-aminoindolizines enabled direct access to novel polycyclic N-fused heteroaromatic skeletons.

Production of Ethyl-agarobioside, a Novel Skin Moisturizer, by Mimicking the Alcoholysis from the Japanese Sake-Brewing Process.

Agarobiose (AB; d-galactose-ß-1,4-AHG), produced by one-step acid hydrolysis of agarose of red seaweed, is considered a promising cosmetic ingredient due to its skin-moisturizing activity. In this study, the use of AB as a cosmetic ingredient was found to be hampered due to its instability at high temperature and alkaline pH. Therefore, to increase the chemical stability of AB, we devised a novel process to synthesize ethyl-agarobioside (ethyl-AB) from the acid-catalyzed alcoholysis of agarose. This process mimics the generation of ethyl α-glucoside and glyceryl α-glucoside by alcoholysis in the presence of ethanol and glycerol during the traditional Japanese sake-brewing process. Ethyl-AB also showed in vitro skin-moisturizing activity similar to that of AB, but showed higher thermal and pH stability than AB. This is the first report of ethyl-AB, a novel compound produced from red seaweed, as a functional cosmetic ingredient with high chemical stability.

Effects of Familial Relationships on School Adjustment of Adolescents and Young Adults With Congenital Heart Disease.

BACKGROUND: As more than 85% of patients with congenital heart disease (CHD) have grown to adulthood through improvement in treatment and surgery, the difficulties they experience are expanding into areas related to daily life. Accordingly, adjustment to school in adolescents and young adults (AYAs) with CHD is of increasing interest and is influenced by familial factors. OBJECTIVE: This was a cross-sectional descriptive study to examine the effects of parental positive emotional expressiveness and sibling relationships on school adjustment of AYAs with CHD. METHODS: In this study, a self-reported questionnaire survey was used to collect the data. The participants were 104 AYAs with CHD aged 13 to 21 years who were attending school and had siblings. RESULTS: Maternal positive emotional expressiveness ( r = 0.584, P < .01), paternal positive emotional expressiveness ( r = 0.584, P < .01), and sibling warmth/closeness ( r = 0.478, P < .01) were significantly correlated with school adjustment. However, the results of multiple regression analysis showed that only maternal positive emotional expressiveness (ß = 0.459, P < .05) and sibling warmth/closeness (ß = 0.236, P < .05) were significantly associated with school adjustment. CONCLUSIONS: Adolescents and young adults with CHD who reported higher maternal positive emotional expressiveness and sibling warmth/closeness exhibited better school adjustment. Findings suggest that intervention programs to increase parental positive expressiveness and enhance warmth/closeness of sibling relationships may contribute to improving school adjustment.

Demonstration of the Yonsei-Social Play Evaluation Tool Keyforms for Occupational Therapy Practice.

Play is regarded as a child's primary occupation and provides valuable information about the child's abilities. Thus, informative assessment tools of play skills are critical for establishing play-related treatment goals in occupational therapy. The objective of this study is to present a practical method for occupational therapists to develop intervention goals using the Yonsei-Social Play Evaluation Tool (Y-SPET) keyforms. Parent responses (n = 310) for preschool children (three to six years old) who did not have a medical diagnosis were examined. The Rasch measurement model was used to create keyforms for the Y-SPET. All children's raw scores were converted into individual Rasch-calibrated logit scores and standard errors were estimated to establish logically attainable treatment goals. Results showed use of the keyforms could logically identify the intervention goals of the children's social play. This suggests that the Y-SPET keyforms are helpful for assessing the level of children's social play and establishing practical treatment goals.

Reversing BCG-mediated autophagy inhibition and mycobacterial survival to improve vaccine efficacy.

BACKGROUND: Autophagy is an important mechanism for promoting Mycobacterium clearance from macrophages. Pathogenic and non-pathogenic mycobacterium can activate the mTOR pathway while simultaneously inducing autophagy. M. tuberculosis and M. bovis BCG inhibit autophagy and favor intracellular bacteria survival. RESULTS: We observed that pre-infection of live or heat-killed BCG could prevent autophagy induced by pharmacological activators or M. smegmatis, a strong autophagy-inducing mycobacterium. BCG-derived lipids are responsible for autophagy inhibition. However, post-infection with BCG could not stop the autophagy initiated by M. smegmatis, which increases further autophagy induction and mycobacteria clearance. Coinfection with BCG and heat killed M. smegmatis enhanced antigen specific CD4+ T cell responses and reduced mycobacterial survival. CONCLUSION: These results suggest that autophagy-inducing M. smegmatis could be used to promote better innate and consequential adaptive immune responses, improving BCG vaccine efficacy.

Metabolic discrimination of synovial fluid between rheumatoid arthritis and osteoarthritis using gas chromatography/time-of-flight mass spectrometry.

INTRODUCTION: Rheumatoid arthritis (RA) and osteoarthritis (OA) are clinicopathologically different. OBJECTIVES: We aimed to assess the feasibility of metabolomics in differentiating the metabolite profiles of synovial fluid between RA and OA using gas chromatography/time-of-flight mass spectrometry. METHODS: We first compared the global metabolomic changes in the synovial fluid of 19 patients with RA and OA. Partial least squares-discriminant, hierarchical clustering, and univariate analyses were performed to distinguish metabolites of RA and OA. These findings were then validated using synovial fluid samples from another set of 15 patients with RA and OA. RESULTS: We identified 121 metabolites in the synovial fluid of the first 19 samples. The score plot of PLS-DA showed a clear separation between RA and OA. Twenty-eight crucial metabolites, including hypoxanthine, xanthine, adenosine, citrulline, histidine, and tryptophan, were identified to be capable of distinguishing RA metabolism from that of OA; these were found to be associated with purine and amino acid metabolism. CONCLUSION: Our results demonstrated that metabolite profiling of synovial fluid could clearly discriminate between RA and OA, suggesting that metabolomics may be a feasible tool to assist in the diagnosis and advance the comprehension of pathological processes for diseases.

Dieckol Isolated from Eisenia bicyclis Ameliorates Wrinkling and Improves Skin Hydration via MAPK/AP-1 and TGF-ß/Smad Signaling Pathways in UVB-Irradiated Hairless Mice.

Repetitive exposure to ultraviolet B (UVB) is one of the main causes of skin photoaging. We previously reported that dieckol isolated from Eisenia bicyclis extract has potential anti-photoaging effects in UVB-irradiated Hs68 cells. Here, we aimed to evaluate the anti-photoaging activity of dieckol in a UVB-irradiated hairless mouse model. In this study, hairless mice were exposed to UVB for eight weeks. At the same time, dieckol at two doses (5 or 10 mg/kg) was administered orally three times a week. We found that dieckol suppressed UVB-induced collagen degradation and matrix metalloproteinases (MMPs)-1, -3, and -9 expression by regulating transforming growth factor beta (TGF-ß)/Smad2/3 and mitogen-activated protein kinases (MAPKs)/activator protein-1 (AP-1) signaling. In addition, dieckol rescued the production of hyaluronic acid (HA) and effectively restored the mRNA expression of hyaluronan synthase (HAS)-1/-2 and hyaluronidase (HYAL)-1/-2 in UVB-irradiated hairless mice. We observed a significant reduction in transepidermal water loss (TEWL), epidermal/dermal thickness, and wrinkle formation in hairless mice administered dieckol. Based on these results, we suggest that dieckol, due to its anti-photoaging role, may be used as a nutricosmetic ingredient for improving skin health.

Diastereoselective Synthesis of Densely Functionalized 3a,8a-Dihydro-8H-furo[3,2-a]pyrrolizines through One-Pot Three-Component Assembly.

A new domino mode of assembly was discovered from the one-pot three-component reactions of pyrrole derivatives, active methylene compounds (malononitrile, methyl cyanoacetate, or ethyl cyanoacetate), and sodium cyanide in the presence of piperidinium acetate in EtOH at room temperature, leading to a novel tricyclic skeleton in excellent yield under mild and eco-friendly conditions. This well-choreographed domino process enabled formation of multiple bonds (three C-C and one C-O) for consecutive construction of two rings (pyrrolidine and dihydrofuran) in a diastereoselective manner.

Eisenia bicyclis Extract Repairs UVB-Induced Skin Photoaging In Vitro and In Vivo: Photoprotective Effects.

Chronic exposure to ultraviolet B (UVB) is a major cause of skin aging. The aim of the present study was to determine the photoprotective effect of a 30% ethanol extract of Eisenia bicyclis (Kjellman) Setchell (EEB) against UVB-induced skin aging. By treating human dermal fibroblasts (Hs68) with EEB after UVB irradiation, we found that EEB had a cytoprotective effect. EEB treatment significantly decreased UVB-induced matrix metalloproteinase-1 (MMP-1) production by suppressing the activation of mitogen-activated protein kinase (MAPK)/activator protein 1 (AP-1) signaling and enhancing the protein expression of tissue inhibitors of metalloproteinases (TIMPs). EEB was also found to recover the UVB-induced degradation of pro-collagen by upregulating Smad signaling. Moreover, EEB increased the mRNA expression of filaggrin, involucrin, and loricrin in UVB-irradiated human epidermal keratinocytes (HaCaT). EEB decreased UVB-induced reactive oxygen species (ROS) generation by upregulating glutathione peroxidase 1 (GPx1) and heme oxygenase-1 (HO-1) expression via nuclear factor erythroid-2-related factor 2 (Nrf2) activation in Hs68 cells. In a UVB-induced HR-1 hairless mouse model, the oral administration of EEB mitigated photoaging lesions including wrinkle formation, skin thickness, and skin dryness by downregulating MMP-1 production and upregulating the expression of pro-collagen type I alpha 1 chain (pro-COL1A1). Collectively, our findings revealed that EEB prevents UVB-induced skin damage by regulating MMP-1 and pro-collagen type I production through MAPK/AP-1 and Smad pathways.

Factor analysis of the Korean version of the Illness Cognition Questionnaire for adolescents with chronic illness.

AIM: The purpose of this study was to examine the reliability and validity of the Korean version of the Illness Cognition Questionnaire. METHODS: A total of 237 adolescent Participants ages 13-20 years were collected from two hospitals for purposes of the study. The participants were diagnosed with blood cancer, congenital heart disease, paediatric rheumatoid arthritis, multiple sclerosis and diabetes mellitus. RESULTS: The Illness Cognition Questionnaire is composed of three subscales and 18 items. Exploratory factor analysis and confirmatory factor analysis were performed for all 18 items. The data used in the exploratory factor analysis were obtained from 126 adolescents with blood cancer. The data used for confirmatory factor analysis were obtained from 111 adolescents who had chronic diseases. The three-factor model of 18 items showed general fitness close to the standard but not a very good fit. CONCLUSIONS: This study indicated that the Korean version of the Illness Cognition Questionnaire is reasonable to use for Korean adolescents with chronic illness. The authors recommend that the meaning of Item 10 be clarified from 'I have learned to accept the limitations imposed by my illness' to 'I have learned to positively accept the limitations imposed by my illness'.

Strong σ-Hole Activation on Icosahedral Carborane Derivatives for a Directional Halide Recognition.

Crystal engineering based on σ-hole interactions is an emerging approach for realization of new materials with higher complexity. Neutral inorganic clusters derived from 1,2-dicarba-closo-dodecaborane, substituted with -SeMe, -TeMe, and -I moieties on both skeletal carbon vertices are experimentally demonstrated herein as outstanding chalcogen- and halogen-bond donors. In particular, these new molecules strongly interact with halide anions in the solid-state. The halide ions are coordinated by one or two donor groups (µ1 - and µ2 -coordinations), to stabilize a discrete monomer or dimer motifs to 1D supramolecular zig-zag chains. Crucially, the observed chalcogen bond and halogen bond interactions feature remarkably short distances and high directionality. Electrostatic potential calculations further demonstrate the efficiency of the carborane derivatives, with Vs,max being similar or even superior to that of reference organic halogen-bond donors, such as iodopentafluorobenzene.