Single-cell transcriptome analysis reveals subtype-specific clonal evolution and microenvironmental changes in liver metastasis of pancreatic adenocarcinoma and their clinical implications.

BACKGROUND: Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes. However, the precise characterization of diverse cell populations and their crosstalk associated with PDAC progression and metastasis is still challenging. METHODS: We performed single-cell RNA sequencing (scRNA-seq) of treatment-naïve primary PDAC samples with and without paired liver metastasis samples to understand the interplay between ITH and TME in the PDAC evolution and its clinical associations. RESULTS: scRNA-seq analysis revealed that even a small proportion (22%) of basal-like malignant ductal cells could lead to poor chemotherapy response and patient survival and that epithelial-mesenchymal transition programs were largely subtype-specific. The clonal homogeneity significantly increased with more prevalent and pronounced copy number gains of oncogenes, such as KRAS and ETV1, and losses of tumor suppressor genes, such as SMAD2 and MAP2K4, along PDAC progression and metastasis. Moreover, diverse immune cell populations, including naïve SELLhi regulatory T cells (Tregs) and activated TIGIThi Tregs, contributed to shaping immunosuppressive TMEs of PDAC through cellular interactions with malignant ductal cells in PDAC evolution. Importantly, the proportion of basal-like ductal cells negatively correlated with that of immunoreactive cell populations, such as cytotoxic T cells, but positively correlated with that of immunosuppressive cell populations, such as Tregs. CONCLUSION: We uncover that the proportion of basal-like subtype is a key determinant for chemotherapy response and patient outcome, and that PDAC clonally evolves with subtype-specific dosage changes of cancer-associated genes by forming immunosuppressive microenvironments in its progression and metastasis.

Establishment of a patient-specific avatar organoid model derived from EUS-guided fine-needle biopsy for timely clinical application in pancreatic ductal adenocarcinoma (with video).

BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) has the worst survival rate among tumors. At the time of diagnosis, more than 80% of PDACs are considered to be surgically unresectable, and there is an unmet need for treatment options in these inoperable PDACs. This study aimed to establish a patient-derived organoid (PDO) platform from EUS-guided fine-needle biopsy (EUS-FNB) collected at diagnosis and to determine its clinical applicability for the timely treatment of unresectable PDAC. METHODS: Patients with suspected PDAC were prospectively enrolled at the Samsung Medical Center from 2015 to 2019. PDAC tissues were acquired by means of EUS-FNB to establish PDAC PDOs, which were comprehensively analyzed for histology, genomic sequencing, and high-throughput screening (HTS) drug sensitivity test. RESULTS: PDAC PDOs were established with a success rate of 83.2% (94/113). It took approximately 3 weeks from acquiring minimal EUS-FNB specimens to generating sufficient PDAC PDOs for the simultaneous HTS drug sensitivity test and genomic sequencing. The high concordance between PDAC tissues and matched PDOs was confirmed, and whole-exome sequencing revealed the increased detection of genetic alterations in PDOs compared with EUS-FNB tissues. The HTS drug sensitivity test showed clinical correlation between the ex vivo PDO response and the actual chemotherapeutic response of the study patients in the real world (13 out of 15 cases). In addition, whole-transcriptome sequencing identified candidate genes associated with nab-paclitaxel resistance, such as ITGB7, ANPEP, and ST3GAL1. CONCLUSIONS: This PDAC PDO platform allows several therapeutic drugs to be tested within a short time window and opens the possibility for timely personalized medicine as a "patient avatar model" in clinical practice.

A nationwide real-world study for evaluation of effectiveness and safety of T-DM1 in patients with HER2-positive metastatic breast cancer in Korea (KCSG BR19-15).

Purpose: This study aimed to investigate clinical practices and factors related to the outcomes of T-DM1 use in patients with HER2-positive metastatic breast cancer (mBC). Methods: We included patients with HER2-positive mBC who received T-DM1 as a palliative therapy between August 2017 and December 2018. The safety and outcomes of T-DM1, including overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), were evaluated. A Cox proportional hazards model was used to estimate the hazard ratio and 95% confidence interval (CI) for mortality or progression to HER2-positive mBC. Results: In total, 824 patients were enrolled during the study period. The mean age of patients was 58 years, and 516 (62.6%) patients relapsed after curative treatment. Excluding a history of endocrine therapy, 341 (41.4%) patients previously received none or first-line chemotherapy, 179 (21.7%) received second-line therapy, and 303 (36.9%) received third-or later-line chemotherapy before T-DM1 therapy. During a median follow-up of 16.8 months, the ORR was 35%, the median PFS was 6.6 months, and the median OS was not reached. The clinical factors associated with the hazard of progression were age (<65 years), poor performance status (⩾2), advanced line of palliative chemotherapy (⩾2), prior pertuzumab use, and treatment duration of palliative trastuzumab (<10 months). Common grade 3-4 adverse events were thrombocytopenia (n = 107, 13.2%), neutropenia (n = 23, 2.8%), anemia (n = 21, 2.6%), and elevated liver enzyme (n = 20, 2.5%). Hypokalemia (⩽3.0 mmol/L) and any-grade bleeding events occurred in 25 (3.1%) and 94 (22.6%) patients, respectively. Conclusion: This is the first nationwide real-world study of T-DM1 use in patients with HER2-positive mBC in Korea. The effectiveness and toxicity profiles of T-DM1 in real-world practice were comparable to those in randomized trials. Moreover, patient factors and previous anti-HER2 therapy could predict the outcomes of T-DM1 therapy.

Improvement of Severe Colon Stricture after Rituximab Therapy for Concomitant Mucosa-associated Lymphoid Tissue Lymphoma in a Patient with Ulcerative Colitis.

Colorectal strictures are uncommon in patients with ulcerative colitis (UC). An extranodal marginal zone B-cell lymphoma of mucosa- associated lymphoid tissue (MALT) lymphoma is rarely involved in the colon but may be associated with inflammatory bowel diseases. A 41-year-old female with a six-year history of UC presented with a severe stricture of the sigmoid colon that prevented the passage of a colonoscope. A histological examination revealed non-specific inflammation and fibrosis without dysplasia or cancer. Despite conventional treatment, including mesalazine and azathioprine for one year after that visit, the stricture persisted. In addition, diffuse, edematous exudative inflammation and multiple shallow ulcers were observed in the distal rectum, revealing a MALT lymphoma testing positive for CD20, CD43, CD5, and Bcl-2, but negative for CD3, CD10, CD23, and cyclin-D1. Four weekly doses of rituximab were administered. Follow-up colonoscopy performed one month after treatment revealed slight improvement in the rectal lesion without remnant histological evidence of a MALT lymphoma. In addition, the stricture showed marked improvement, and the colonoscope could pass easily through the stricture site. This is the first case report on an improvement of a severe sigmoid colon stricture in a patient with UC after rituximab treatment for a concomitant rectal MALT lymphoma.

Extensive characterization of 28 complete chloroplast genomes of Hydrangea species: A perspective view of their organization and phylogenetic and evolutionary relationships.

The tribe Hydrangeeae displays a unique, distinctive disjunct distribution encompassing East Asia, North America and Hawaii. Despite its complex trait variations and polyphyletic nature, comprehensive phylogenomic and biogeographical studies on this tribe have been lacking. To address this gap, we sequenced and characterized 28 plastomes of Hydrangeeae. Our study highlights the highly conserved nature of Hydrangeaceae chloroplast (cp) genomes in terms of gene content and arrangement. Notably, synapomorphic characteristics of tandem repeats in the conserved domain of accD were observed in the Macrophyllae, Chinenses, and Dichroa sections within the Hydrangeeae tribe. Additionally, we found lower expression of accD in these sections using structure prediction and quantitative real-time PCR analysis. Phylogenomic analyses revealed the subdivision of the Hydrangeeae tribe into two clades with robust support values. Consistent with polyphyletic relationships, sect. Broussaisia was identified as the basal group in the tribe Hydrangeeae. Our study also provides insights into the phylogenetic relationships of Hydrangea petiolaris in the Jeju and Ulleung Island populations, suggesting the need for further studies with more samples and molecular data. Divergence time estimation and biogeographical analyses suggested that the common ancestors of the tribe Hydrangeeae likely originated from North America and East Asia during the Paleocene period via the Bering Land Bridge, potentially facilitating migration within the tribe between these regions. In conclusion, this study enhances our understanding of the evolutionary history and biogeography of the tribe Hydrangeeae, shedding light on the dispersal patterns and origins of this intriguing plant group with its unique disjunct distribution.

Toxicities and Quality of Life during Cancer Treatment in Advanced Solid Tumors.

The purpose of the study was to identify subgroups of advanced cancer patients who experienced grade 3-4 toxicities as reported by their oncologists as well as identify the demographic, clinical, and treatment symptom characteristics as well as QoL outcomes associated with distinct profiles of each patient. A prospective, multicenter, observational study was conducted with advanced cancer patients of 15 different hospitals across Spain. After three months of systemic cancer treatment, participants completed questionnaires that evaluated psychological distress (BSI-18), quality of life (EORTC QLQ-C30) and fatigue (FAS). The most common tumor sites for the 557 cancer patients with a mean age of 65 years were bronchopulmonary, digestive, and pancreas. Overall, 19% of patients experienced high-grade toxicities (grade 3-4) during treatment. Patients with recurrent advanced cancer, with non-adenocarcinoma cancer, undergoing chemotherapy, and a showing deteriorated baseline status (ECOG > 1) were more likely to experience higher toxicity. Patients who experienced grade 3-4 toxicities during cancer treatment had their treatment suspended in 59% of the cases. Additionally, 87% of the patients had a dose adjustment or a cycle delayed in their treatment due to a high risk of dying during treatment. Future research should focus on identifying interventions to reduce high-grade toxicities and improve quality of life in cancer patients.

Decreased GCF DEL-1 and increased GCF neutrophils with increasing probing pocket depth.

PURPOSE: Developmental endothelial locus-1 (DEL-1) plays a role in regulating neutrophil migration within the periodontium. The objective of this study was to evaluate the levels of DEL-1 in saliva and gingival crevicular fluid (GCF), as well as the number of neutrophils in patients with periodontitis. METHODS: Forty systemically healthy, non-smoking periodontitis patients participated in this study. Clinical periodontal parameters, including the plaque index, probing pocket depth (PPD), clinical attachment level, bleeding on probing, modified sulcular bleeding index, and marginal bone level, were measured. Levels of DEL-1, interleukin (IL)-1ß, IL-6, and IL-8 in unstimulated saliva samples, as well as DEL-1 in the GCF of 3 teeth from each participant, were assessed. Neutrophil counts in oral rinse and GCF samples were recorded. Spearman correlation coefficients were used to examine the correlation between protein levels, clinical parameters, and neutrophil quantities. Participants were divided into 2 age groups (those under 50 years and those 50 years or older) in order to investigate potential age-related differences. RESULTS: DEL-1 levels in the GCF showed a negative relationship with PPD (sum). Neutrophils in oral rinse samples were positively correlated with PPD, IL-8, and IL-1ß levels. Neutrophils in GCF exhibited a positive correlation with PPD (sum). Salivary DEL-1 levels showed correlations with IL-8 and IL-1ß, but not with the clinical parameters of periodontitis. CONCLUSIONS: The negative relationship observed between PPD and GCF DEL-1 levels is consistent with the proposed protective role of DEL-1.

Clinicians' and Advanced Cancer Patients' Estimates of Treatment Efficacy and Toxicity in Oncologic Treatment.

The purpose of the study was to compare curability expectations between clinicians and patients and examine the influence of sociodemographic and clinical variables on these expectations and satisfaction within the clinician-patient relationship. This prospective study, conducted from February 2020 to May 2023, involved 986 advanced cancer patients. The patients completed questionnaires assessing treatment efficacy and toxicity predictions and the Scale to Assess the Therapeutic Relationship (STAR). Seventy-four percent of advanced cancer patients had an inaccurate perception of treatment curability. Clinicians perceived male patients with lung or digestive cancer without adenocarcinoma at locally advanced stages, with fewer comorbidities and better functional status (ECOG), as having higher curability expectations. Clinicians tended to have more realistic expectations than patients, since they had to consider the presence of treatment's side effects, while patients underestimated the possibility of experiencing these adverse effects. Patients who had more favorable expectations regarding survival and quality of life were found to be more satisfied with the care provided by their oncologists. It is crucial for patients to understand the treatment goals and establish realistic expectations in order to actively participate in decision-making and achieve a better quality of life at the end of life.

Clinical and life style factors related to the nighttime blood pressure, nighttime dipping and their phenotypes in Korean hypertensive patients.

BACKGROUND: Non-dipping or reverse dipping patterns are known to be associated with adverse cardiovascular prognosis among the general population and clinical cohort. Few large sized studies have explored factors including sleep duration and sleep quality related to nighttime blood pressure (BP) and nocturnal dipping patterns. METHODS: Among 5,360 patients enrolled  in Korean multicenter nationwide prospective Registry of ambulatory BP monitoring (KORABP), 981 subjects with complete data on sleep duration, sleep quality assessed using a 4-point Likert scale, and clinical variables were included in the analysis. Phenotypes of nighttime BP pattern were categorized as extreme dipper, dipper, non-dipper, and reverse dipper. Hypertension was defined as a 24-h ambulatory BPs were 130/80 mmHg or higher. RESULTS: Among 981 subjects, 221 were normotensive, 359 were untreated hypertensive, and 401 were treated hypertensive. Age of the participants were 53.87 ± 14.02 years and 47.1% were female. In overall patients, sleep duration was 431.99 ± 107.61 min, and one to four points of sleep quality were observed in 15.5%, 30.0%, 30.4%, and 24.2%, respectively. Of the 760 hypertensive patients, extreme dipper, dipper, non-dipper, and reverse dipper were observed in 58 (7.63%), 277 (36.45%), 325 (42.76%), and 100 (13.16%), respectively. In multiple linear regression analysis, sleep duration (ß = 0.0105, p < 0.001) and sleep quality (ß = -0.8093, p < 0.001) were associated with nighttime systolic BP and sleep quality was associated with extent of nighttime systolic BP dipping (ß = 0.7622, p < 0.001) in hypertensive patients. In addition, sleep quality showed positive association with dipper pattern (odds ratio [OR] = 1.16, 95% confidence interval [CI] = 1.03-1.30) and showed negative association with reverse dipper pattern (OR = 0.73, 95% CI = 0.62-0.86) in multiple logistic regression analyses. CONCLUSION: When adjusted covariates, less sleep duration and poor sleep quality were positively associated with nighttime systolic BP. Additionally, sleep quality was the independent associated factor for dipper and reverse dipper phenotypes. The study also found that male sex, low estimated glomerular filtration rate, high ambulatory BP, low office BP, and poor sleep quality were associated with blunted nighttime SBP dipping.

The Role of Financial Difficulties as a Mediator between Physical Symptoms and Depression in Advanced Cancer Patients.

Financial difficulties experienced by cancer patients negatively impact the mental health of the patients. The objective of this study was to examine the mediating role of financial difficulties between physical symptoms and depression in patients with advanced cancer. A prospective, cross-sectional design was adopted in the study. The data were collected from 861 participants with advanced cancer in 15 different tertiary hospitals in Spain. The participants' socio-demographic characteristics were collected using a standardized self-report form. Hierarchical linear regression models were used to explore the mediating role of financial difficulties. In the results, 24% of patients reported a high level of financial difficulties. Physical symptoms were positively associated with financial difficulties and depression (ß = 0.46 and ß = 0.43, respectively), and financial difficulties was positively associated with depression (ß = 0.26). Additionally, financial difficulties played a role in explaining the relationship between physical symptoms and depression, showing a standardized regression coefficient of 0.43 which decreased to 0.39 after the financial difficulties were controlled. Healthcare professionals should consider the importance of providing financial resources and emotional support to help patients and their families cope with the financial burden associated with cancer treatment and its symptoms.

Direct comparison of an automated oscillometric device with an electronic auscultatory device for epidemiologic survey to evaluate the prevalence of hypertension.

Mercury-free sphygmomanometers are gradually replacing the traditional sphygmomanometers in clinical settings and epidemiological surveys for measuring blood pressure (BP) due to mercury toxicity. No direct comparative studies have evaluated BP differences and statistical errors of automated oscillometric devices (ODs) against electronic auscultatory devices (ADs) for epidemiologic surveys. Herein, we evaluated the validity of ODs for the Korea National Health and Nutrition Examination Survey (KNHANES) using the Universal Standard for BP device validation through a direct comparison with ADs as the reference standard. Four trained observers performed validation on 278 volunteers aged ≥ 19 years with a standardized BP measurement protocol. Agreement between the BP measurements recorded with an OD against those recorded with an AD was assessed by Lin's concordance correlation coefficient (CCC) and Bland-Altman's limits of agreement. To evaluate the agreement for BP classification, weighted kappa values were estimated. To explore the factors associated with BP measurement differences between the 2 devices, multiple linear regression analysis was performed. The average BP differences (OD-AD) were 2.6 ±â€…6.2 mm Hg for systolic BP (SBP) and -5.1 ±â€…5.6 mm Hg for diastolic BP (DBP). Lin's CCCs were 0.927 and 0.768 for the overall SBP and DBP, respectively. The cumulative percentage of absolute errors ≤10 mm Hg was 88.1% for SBP and 81.3% for DBP. The weighted kappa value for the Joint National Committee 7 BP classification was 0.75 (95% confidence interval: 0.68-0.81). An OD overestimated the prevalence of SBP (0.3%, P = .0222) and underestimated the prevalence of DBP (1.8%, P < .0001). Multivariate analysis to identify the risk factors for BP difference revealed the arm circumference (AC) to be negatively associated with BP difference. Male sex was positively associated, while age was negatively associated with SBP difference. OD-DBP was positively associated with DBP difference and negatively associated for DBP absolute error. ODs met the accuracy requirements of the Universal Standard criteria against ADs for SBP but not for DBP. Thus, the DBP values may be underestimated by ODs in the KNHANES.

Protocol for construction and characterization of direct electron transfer-based enzyme-electrode using gold binding peptide as molecular binder.

Here, we present a protocol for constructing direct electron transfer (DET)-based enzyme-electrodes using gold-binding peptide (GBP). We describe fusion of four GBPs to flavin adenine dinucleotide (FAD)-dependent glucose dehydrogenase gamma-alpha complex (GDHγα), as model oxidoreductase, to generate four GDHγα variants. We then detail the measurements of catalytic and bioelectrochemical properties of these GDHγα variants on electrode together with surface morphology of GDHγα variants immobilized on gold surface. This protocol is useful for construction and validation of enzyme-based electrocatalytic system. For complete details on the use and execution of this protocol, please refer to Lee et al. (2021).

Clinical significance of circulating tumor cells after chemotherapy in unresectable pancreatic ductal adenocarcinoma.

Circulating tumor cells (CTCs) have emerged as liquid biopsy biomarker providing non-invasive assessment of cancer progression and biology. We investigated whether longitudinal analysis of CTCs could monitor disease progression, response to chemotherapy, and survival in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). A total of 52 patients with PDAC were prospectively enrolled in this study. Peripheral blood samples were serially collected at the time of diagnosis and after chemotherapy with clinical assessments. CTCs were isolated through a centrifugal microfluidic disc, enumerated with immunostaining against Epithelial cell adhesion molecule (EpCAM), Cytokeratin (CK), Plectin-1 and CD45, and identified by an automated imaging system. One or more CTCs were detected in 84.62% patients with unresectable PDAC at the time of diagnosis. CTC numbers were not statistically different across tumor sizes, location and metastatic sites. The absolute number of CTCs after chemotherapy was inversely related to overall survival (OS), and the decreased number of CTCs after chemotherapy was significantly associated with longer OS in patients with PDAC. Identifying CTCs and monitoring CTC changes after chemotherapy could be a useful prognostic marker for survival in patients with unresectable PDACs.

Psychometric properties of the Spanish version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30).

PURPOSE: The aim of this study was to analyze the internal structure of the EORTC QLQ-C30, to examine the validity and normative data for cancer patients. METHOD: Exploratory and Confirmatory factor analyses were conducted to explore the scale's dimensionality and test for strong measurement invariance across sex and tumor site. All the analyses were based on a multicenter cohort of 931 patients who completed the Brief Symptom Inventory (BSI-18) and the EORTC QLQ-C30. RESULTS: Our findings indicate that the EORTC QLQ-C30 has acceptable psychometric properties and an internal structure that is well accounted for a bifactor model: a general factor that evaluates quality of life and a group factor that would analyze physical health that would be defined by physical function, role function, and fatigue. The result of the multi-group CFA revealed a strong invariance according to sex, tumor, and over time. Reliability of the EORTC exceeding 0.86 and the simple sum of the items of the scale was a good indicator of oncology patients' quality of life. Both factors correlate closely with depression, anxiety, and psychological distress and are sensitive to change, especially the quality of life, with a significant decrease in the post-test. CONCLUSION: The Spanish version of the EORTC QLQ-C30 proved to be a valid, reliable instrument to appraise quality of life in cancer patients. The normative data collected from this study may be useful for the early detection of initial symptoms of deterioration of quality of life in oncology patients.

The clinical outcomes of second-line chemotherapy in patients with advanced pancreatic cancer: a retrospective study.

BACKGRUOUND: Despite recent advances in first-line chemotherapy for advanced pancreatic cancer, standard treatment after the failure of initial chemotherapy has not been established. Hence, we aimed to retrospectively analyze the clinical characteristics and outcomes of second-line chemotherapy in patients with advanced pancreatic cancer. METHODS: We reviewed the clinical data of patients with advanced pancreatic cancer who underwent palliative chemotherapy at Kosin University Gospel Hospital between January 2013 and October 2020. RESULTS: Among 366 patients with advanced pancreatic cancer who had received palliative chemotherapy, 104 (28.4%) underwent at least one cycle of second-line chemotherapy. The median age of the patients at the time of initiating second-line treatment was 62 years (interquartile range, 57-62 years), and 58.7% (61 patients) of them were male. The common second-line chemotherapy regimens were 5-fluorouracil (FU) plus leucovorin, irinotecan, and oxaliplatin (33 patients, 31.7%); gemcitabine/nab-paclitaxel (29, 27.9%), gemcitabine±erlotinib (13, 12.5%); and oxaliplatin and 5-FU/leucovorin (12, 11.5%). The median overall survival (OS) and progression-free survival were 6.4 months (95% confidence interval [CI], 4.5-8.6 months) and 4.5 months (95% CI, 2.7-6.3 months), respectively. In a multivariate analysis, poor performance status (PS) (hazard ratio [HR], 2.247; p=0.021), metastatic disease (HR, 2.745; p=0.011), and elevated carcinoembryonic antigen (CEA) levels (HR, 1.939; p=0.030) at the beginning of second-line chemotherapy were associated with poor OS. CONCLUSION: The survival outcome of second-line chemotherapy for advanced pancreatic cancer remains poor. However, PS, disease extent (locally advanced or metastatic), and CEA level may help determine patients who could benefit from second-line treatment.

Successful Treatment of Imatinib-Induced DRESS Syndrome Using Reslizumab without Cessation of Imatinib: A Case Report.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous adverse drug reaction; reported cases are sometimes imatinib mesylate induced. The main treatment is the withdrawal of the causative drug, and most cases with imatinib-induced DRESS syndrome required withdrawal of imatinib. However, in such cases involving anticancer drugs, this may compromise cancer treatment. Herein, we report a patient with imatinib-induced DRESS syndrome that was successfully treated with reslizumab while continuing imatinib treatment. A 65-year-old female presented with facial edema and generalized skin rash after being given 400 mg imatinib 2 weeks ago for metastatic gastrointestinal stromal tumor. After stopping imatinib, the clinical symptoms improved. Imatinib desensitization was performed, and it was administered again. However, the clinical symptoms reappeared more severely 2 months after restart of imatinib, and the peripheral absolute eosinophil count increased to 1,690/µL. A diagnosis of imatinib-induced DRESS syndrome was made, based on the Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) criteria. Imatinib desensitization was repeated, but the clinical symptoms reappeared, and the peripheral eosinophilia persisted. We administered reslizumab, an interleukin-5 monoclonal antibody, without cessation of imatinib. The absolute eosinophil count decreased immediately, and the clinical symptoms improved gradually. After 2 weeks, the clinical symptoms reappeared mildly, but after administering reslizumab again, these disappeared completely. Reslizumab can be considered in the management of DRESS syndrome in cases wherein the causative medication needs to be continued.

Impact of a screening protocol for blood pressure level for hypertension in the Korean community health survey.

PURPOSE: A community program is an efficient model for improving the management of chronic diseases such as hypertension, diabetes, and dyslipidemia. A specific blood pressure (BP) measurement protocol was developed for community settings in which BP was measured by the interviewer at the interviewee's home. MATERIALS AND METHODS: In the 2018 Korean Community Health Survey, BP was measured twice at a five-minute interval after a five-minute resting period at the beginning of the survey. In 2019, BP was measured at the end of the survey after a two-minute rest and was obtained as three measurements at one-minute intervals. As factors related to BP level, stressful stimuli within 30 min before BP measurement such as smoking, caffeine, and/or exercise; duration of rest; and survey year were analysed. RESULTS: The mean age of participants was 55.2 years, and females accounted for 55.4% of the participants (n = 399,838). Stressful stimuli were observed in 21.9% of the participants in 2018 (n = 188,440) and 11.3% in 2019 (n = 211,398). Duration of rest was 0 min (2.1%), two minutes (55.0%), and five minutes (47.9%). When adjusted for age, sex, body mass index, antihypertensive medication, the arm of measurement, survey year (beta= -4.092), stressful stimuli (beta = 0.834), and resting time (beta = -1.296 per one minute of rest) were significant factors for mean systolic BP. A two-minute rest was not a significant factor in mean BP. The differences in adjusted mean systolic BPs were significant for rest times of five minutes vs. two minutes (3.1 mmHg, p < 0.0001), for stressful stimuli (0.8 mmHg, p < 0.0001), and for survey year (127.8 ± 0.2 mmHg vs. 122.2 ± 0.3 mmHg for 2018 vs. 2019, p < 0.0001). CONCLUSION: For the community-based home visit survey, avoidance of stressful stimuli, five-minute rest, and allocation of BP measurement in the last part of the survey was useful for obtaining a stable BP level.

The sulfur formation system mediating extracellular cysteine-cystine recycling in Fervidobacterium islandicum AW-1 is associated with keratin degradation.

Most extremophilic anaerobes possess a sulfur formation (Suf) system for Fe-S cluster biogenesis. In addition to its essential role in redox chemistry and stress responses of Fe-S cluster proteins, the Suf system may play an important role in keratin degradation by Fervidobacterium islandicum AW-1. Comparative genomics of the order Thermotogales revealed that the feather-degrading F. islandicum AW-1 has a complete Suf-like machinery (SufCBDSU) that is highly expressed in cells grown on native feathers in the absence of elemental sulfur (S0 ). On the other hand, F. islandicum AW-1 exhibited a significant retardation in the Suf system-mediated keratin degradation in the presence of S0 . Detailed differential expression analysis of sulfur assimilation machineries unveiled the mechanism by which an efficient sulfur delivery from persulfurated SufS to SufU is achieved during keratinolysis under sulfur starvation. Indeed, addition of SufS-SufU to cell extracts containing keratinolytic proteases accelerated keratin decomposition in vitro under reducing conditions. Remarkably, mass spectrometric analysis of extracellular and intracellular levels of amino acids suggested that redox homeostasis within cells coupled to extracellular cysteine and cystine recycling might be a prerequisite for keratinolysis. Taken together, these results suggest that the Suf-like machinery including the SufS-SufU complex may contribute to sulfur availability for an extracellular reducing environment as well as intracellular redox homeostasis through cysteine released from keratin hydrolysate under starvation conditions.

Role of Myc Proto-Oncogene as a Transcriptional Hub to Regulate the Expression of Regeneration-Associated Genes following Preconditioning Peripheral Nerve Injury.

Preconditioning peripheral nerve injury enhances the intrinsic growth capacity of DRGs sensory axons by inducing transcriptional upregulation of the regeneration-associated genes (RAGs). However, it is still unclear how preconditioning injury leads to the orchestrated induction of many RAGs. The present study identified Myc proto-oncogene as a transcriptional hub gene to regulate the expression of a distinct subset of RAGs in DRGs following the preconditioning injury. We demonstrated that c-MYC bound to the promoters of certain RAGs, such as Jun, Atf3, and Sprr1a, and that Myc upregulation following SNI preceded that of the RAGs bound by c-MYC. Marked DNA methylation of the Myc exon 3 sequences was implicated in the early transcriptional activation and accompanied by open histone marks. Myc deletion led to a decrease in the injury-induced expression of a distinct subset of RAGs, which were highly overlapped with the list of RAGs that were upregulated by Myc overexpression. Following dorsal hemisection spinal cord injury in female rats, Myc overexpression in DRGs significantly prevented the retraction of the sensory axons in a manner dependent on its downstream RAG, June Our results suggest that Myc plays a critical role in axon regeneration via its transcriptional activity to regulate the expression of a spectrum of downstream RAGs and subsequent effector molecules. Identification of more upstream hub transcription factors and the epigenetic mechanisms specific for individual hub transcription factors would advance our understanding of how the preconditioning injury induces orchestrated upregulation of RAGs.

Metabolomic biomarkers in midtrimester maternal plasma can accurately predict the development of preeclampsia.

Early identification of patients at risk of developing preeclampsia (PE) would allow providers to tailor their prenatal management and adopt preventive strategies, such as low-dose aspirin. Nevertheless, no mid-trimester biomarkers have as yet been proven useful for prediction of PE. This study investigates the ability of metabolomic biomarkers in mid-trimester maternal plasma to predict PE. A case-control study was conducted including 33 pregnant women with mid-trimester maternal plasma (gestational age [GA], 16-24 weeks) who subsequently developed PE and 66 GA-matched controls with normal outcomes (mid-trimester cohort). Plasma samples were comprehensively profiled for primary metabolic and lipidomic signatures based on gas chromatography time-of-flight mass spectrometry (GC-TOF MS) and liquid chromatography Orbitrap mass spectrometry (LC-Orbitrap MS). A potential biomarker panel was computed based on binary logistic regression and evaluated using receiver operating characteristic (ROC) analysis. To evaluate whether this panel can be also used in late pregnancy, a retrospective cohort study was conducted using plasma collected from women who delivered in the late preterm period because of PE (n = 13) or other causes (n = 21) (at-delivery cohort). Metabolomic biomarkers were compared according to the indication for delivery. Performance of the metabolomic panel to identify patients with PE was compared also to a commonly used standard, the plasma soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio. In the mid-trimester cohort, a total of 329 metabolites were identified and semi-quantified in maternal plasma using GC-TOF MS and LC-Orbitrap-MS. Binary logistic regression analysis proposed a mid-trimester biomarker panel for the prediction of PE with five metabolites (SM C28:1, SM C30:1, LysoPC C19:0, LysoPE C20:0, propane-1,3-diol). This metabolomic model predicted PE better than PlGF (AUC [95% CI]: 0.868 [0.844-0.891] vs 0.604 [0.485-0.723]) and sFlt-1/PlGF ratio. Analysis of plasma from the at-delivery cohort confirmed the ability of this biomarker panel to distinguish PE from non-PE, with comparable discrimination power to that of the sFlt-1/PlGF ratio. In conclusion, an integrative metabolomic biomarker panel in mid-trimester maternal plasma can accurately predict the development of PE and showed good discriminatory power in patients with PE at delivery.