Progress in research on B class CpG oligodeoxynucleotides in bacterial vaccines / 中国生物制品学杂志

@#CpG oligonucleotide(CpG ODN)is a synthetic oligodeoxynucleotide containing non-methylated CpG,which has broad application prospects in disease prevention and clinical treatment. Among them,B class CpG ODN is widely used in vaccine research because of its strong immune stimulation and some motifs have entered the clinical research stage. At the same time,the problem of bacterial resistance in clinical treatment has become increasingly serious,and the development of bacterial vaccine with B class CpG ODN as adjuvant has become a research hotspot. This paper reviewed the current research status and related progress of the existing B class CpG ODN 1826,2006,2007 and 1668 motifs in bacterial vaccines,with a view to providing a reference for the subsequent development and application of bacterial vaccines.

Cytotoxic Activities on Human Ovarian Cancer Cell Lines by Neolignans and Diarylnonanoids from the Seed of Myristica fragrans Houtt

Ovarian cancer is a primary global health concern, often diagnosed at advanced stages with limited treatment options and poor prognosis. Natural products have emerged as potential sources of safe and effective therapies. From the seeds of Myristica fragrans Houtt. (nutmeg), 24 compounds, including neolignans and diarylnonanoid derivatives, were isolated and structurally elucidated. The cytotoxic activities of these isolated metabolites against cisplatin-sensitive and resistant human ovarian cancer cell lines were evaluated. In particular, myrifragranone C (23) exhibited cytotoxicity against all test cancer cell lines A2780, TOV-112D, and SK-OV3 with IC50 values of 14.1, 16.9, and 33.4 μM, respectively. Furthermore, compound 23 induced the death of A2780 and SK-OV3 cancer cells via apoptosis. Western blotting revealed that compound 23 significantly increased the expression of cleaved caspase-3 and poly-ADP ribose polymerase and promoted apoptosis via the mitogenactivated protein kinase signaling pathway. Our findings may provide a preliminary understanding of the antiovarian cancer effect of the active compound myrifragranone C as a potential treatment using natural products.

Real World Characteristics and Clinical Outcomes of HER2-Mutant Non–Small Cell Lung Cancer Patients Detected by Next-Generation Sequencing / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#This study was conducted to investigate the clinical characteristics of patients with advanced non–small cell lung cancer (NSCLC) harboring human epidermal growth factor receptor 2 (HER2) mutations and to evaluate response to standard treatment and HER2-targeted agents. @*Materials and Methods@#Using tissue and/or blood next-generation sequencing, we identified 44 patients with NSCLC harboring HER2 mutations who were treated at Severance Hospital between December 2016 and February 2021. Clinical data, including patient characteristics, mutation status, incidence of metastasis for distant lesions, and response to chemotherapy, were retrospectively analyzed. @*Results@#The median age was 58 years, and 61% of the patients were female. Most patients (64%) were never-smokers. Adenocarcinoma was the most predominant subtype (98%). A total of 66% of the patients had extrathoracic metastatic lesions, and 32% had intracranial lesions at initial presentation. The median time to the development of brain metastasis was 15.6 months (range, 2.4 to 43.7). The most common type of HER2 mutation was 12 base pair in-frame insertion in exon 20, A775_G776insYVMA. Of the 44 patients, two had concomitant driver mutations, one with epidermal growth factor receptor (EGFR) mutation (V769M), and one with BRAF mutation (V600E). Patients treated with pemetrexed-based chemotherapy (75%) had an overall response rate (ORR) and progression-free survival (PFS) of 30% and 8.3 months (95% confidence interval [CI], 3.9 to 12.7), respectively. The ORR and PFS of HER2-targeted agent treated patients (14%) were 0.0% and 1.9 months (95% CI, 0.1 to 2.8), respectively. @*Conclusion@#Given its distinct characteristics and treatment responses, novel treatment strategies for HER2-mutant NSCLC should be developed promptly to improve survival outcomes of patients.

Occupational and Psychological Factors Associated With Burnout in Night Shift Nurses

Objective@#Providing inpatient nursing care inevitably involves night shift work. However, night shift work nurses often face psychiatric health problems such as burnout. If night shift work is an essential work type for nurses, it is necessary to select personnel suitable for night shift work or establish improvement measures such as psychiatric intervention through psychiatric evaluation. The objective of this study was to identify factors that could be interventional among factors affecting burnout in shift-working nurses. @*Methods@#A total of 231 night shift female nurses participated in this study. A questionnaire survey was given to assess their general characteristics. To assess burnout, the Maslach Burnout Inventory–General Survey Korean version was adopted. In addition, several mental health scales were used to identify individual psychological characteristics. To identify variables associated with the presence of burnout, odds ratios were calculated using a logistic regression model taking three dimensions of burnout as a dependent variable after adjusting for psychological and occupational factors. @*Results@#High resilience was a significant preventive factor in the three dimensions of burnout. Regarding occupational factor, the longer the duration of employment, the higher depersonalization, but the professional efficacy was good. @*Conclusion@#Our results indicate that resilience and social support could be prevention factors for burnout. This study is meaningful in examining items that require active intervention and support for burnout targeting night shift nurses who are indispensable for patient care.

Primary Tumor Suppression and Systemic Immune Activation of Macrophages through the Sting Pathway in Metastatic Skin Tumor

Purpose@#Agonists of the stimulator of interferon genes (STING) play a key role in activating the STING pathway by promoting the production of cytokines. In this study, we investigated the antitumor effects and activation of the systemic immune response of treatment with DMXAA (5,6-dimethylxanthenone-4-acetic acid), a STING agonist, in EML4-ALK lung cancer and CT26 colon cancer. @*Materials and Methods@#The abscopal effects of DMXAA in the treatment of metastatic skin nodules were assessed. EML4-ALK lung cancer and CT26 colon cancer models were used to evaluate these effects after DMXAA treatment. To evaluate the expression of macrophages and T cells, we sacrificed the tumor-bearing mice after DMXAA treatment and obtained the formalin-fixed paraffin-embedded (FFPE) tissue and tumor cells. Immunohistochemistry and flow cytometry were performed to analyze the expression of each FFPE and tumor cell. @*Results@#We observed that highly infiltrating immune cells downstream of the STING pathway had increased levels of chemokines after DMXAA treatment. In addition, the levels of CD80 and CD86 in antigen-presenting cells were significantly increased after STING activation. Furthermore, innate immune activation altered the systemic T cell-mediated immune responses, induced proliferation of macrophages, inhibited tumor growth, and increased numbers of cytotoxic memory T cells. Tumor-specific lymphocytes also increased in number after treatment with DMXAA. @*Conclusion@#The abscopal effect of DMXAA treatment on the skin strongly reduced the spread of EML4-ALK lung cancer and CT26 colon cancer through the STING pathway and induced the presentation of antigens.

Laboratory information management system for COVID-19 non-clinical efficacy trial data / 한국실험동물학회지

Background@#As the number of large-scale studies involving multiple organizations producing data has steadily increased, an integrated system for a common interoperable format is needed. In response to the coronavirus disease 2019 (COVID-19) pandemic, a number of global efforts are underway to develop vaccines and therapeutics. We are therefore observing an explosion in the proliferation of COVID-19 data, and interoperability is highly requested in multiple institutions participating simultaneously in COVID-19 pandemic research. @*Results@#In this study, a laboratory information management system (LIMS) approach has been adopted to systemically manage various COVID-19 non-clinical trial data, including mortality, clinical signs, body weight, body temperature, organ weights, viral titer (viral replication and viral RNA), and multiorgan histopathology, from multiple institutions based on a web interface. The main aim of the implemented system is to integrate, standardize, and organize data collected from laboratories in multiple institutes for COVID-19 non-clinical efficacy testings. Six animal biosafety level 3 institutions proved the feasibility of our system. Substantial benefits were shown by maximizing collaborative high-quality non-clinical research. @*Conclusions@#This LIMS platform can be used for future outbreaks, leading to accelerated medical product development through the systematic management of extensive data from non-clinical animal studies.

Promising Blood Biomarkers for Clinical Use in Alzheimer’s Disease: A Focused Update

Alzheimer’s disease (AD) is the most-common cause of neurodegenerative dementia, and it is characterized by abnormal amyloid and tau accumulation, which indicates neurodegeneration. AD has mostly been diagnosed clinically. However, ligand-specific positron emission tomography (PET) imaging, such as amyloid PET, and cerebrospinal fluid (CSF) biomarkers are needed to accurately diagnose AD, since they supplement the shortcomings of clinical diagnoses. Using biomarkers that represent the pathology of AD is essential (particularly when disease-modifying treatment is available) to identify the corresponding pathology of targeted therapy and for monitoring the treatment response. Although imaging and CSF biomarkers are useful, their widespread use is restricted by their high cost and the discomfort during the lumbar puncture, respectively. Recent advances in AD blood biomarkers shed light on their future use for clinical purposes. The amyloid β (Aβ)42/Aβ40 ratio and the concentrations of phosphorylated tau at threonine 181 and at threonine 217, and of neurofilament light in the blood were found to represent the pathology of Aβ, tau, and neurodegeneration in the brain when using automatic electrochemiluminescence technologies, single-molecule arrays, immunoprecipitation coupled with mass spectrometry, etc. These blood biomarkers are imminently expected to be incorporated into clinical practice to predict, diagnose, and determine the stage of AD. In this review we focus on advancements in the measurement technologies for blood biomarkers and the promising biomarkers that are approaching clinical application.We also discuss the current limitations, the needed further investigations, and the perspectives on their use.

Normal Sonographic Anatomy of the Wrist and Hand

Tendon disorders commonly cause wrist and hand disability and curtail the performance of work-related tasks. Sonography allows for cost-effective, noninvasive, and dynamic evaluation of soft tissue structures, thus representing a valuable tool for ruling out musculoskeletal disorders of the wrist and hand. Because of the complexity of the wrist joint, sonographic training and familiarity with normal and variant anatomy are needed to avoid misdiagnosis and improper treatment. The purpose of this article is to demonstrate the structures representing normal findings during sonographic evaluations of the wrist and hand. The main reviews the gross anatomy and procedures that are recommended to assess the soft tissue structures of the wrist and hand, with particular emphasis given to tendons, nerves, and ligaments. In conclusion, sonography is effective in assessing the tendons of the hand and wrist and related disorders and represents a valuable tool for diagnosis.

Recommendations for the Use of Next-Generation Sequencing and the Molecular Tumor Board for Patients with Advanced Cancer: A Report from KSMO and KCSG Precision Medicine Networking Group / Journal of the Korean Cancer Association, 대한암학회지

Next-generation sequencing (NGS) is becoming essential in the fields of precision oncology. With implementation of NGS in daily clinic, the needs for continued education, facilitated interpretation of NGS results and optimal treatment delivery based on NGS results have been addressed. Molecular tumor board (MTB) is multidisciplinary approach to keep pace with the growing knowledge of complex molecular alterations in patients with advanced solid cancer. Although guidelines for NGS use and MTB have been developed in western countries, there is limitation for reflection of Korea’s public health environment and daily clinical practice. These recommendations provide a critical guidance from NGS panel testing to final treatment decision based on MTB discussion.

Anti-inflammatory and Cytotoxic Activities of Phenolic Compoundsfrom Broussonetia kazinoki

The phytochemical investigation of Broussonetia kazinoki roots led to the isolation of ten compounds, including six flavonoids (1–6), two lignans (7 and 8), and two coumarins (9 and 10) by comparing their 1H and 13C NMR spectra with reference values. To the best of our knowledge, compounds 9 and 10 were isolated from this plant for the first time. Among the ten isolates, compounds 2, 4, and 6 exhibited inhibitory effects against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophage RAW264.7 cells with IC50 values of 11.98, 10.16, and 24.06 μM, respectively. Furthermore, compounds 2, 4, and 6 reduced LPS-induced inducible nitric oxide synthase (iNOS) expression in a dose-dependent manner. Pre-incubation of cells with these compounds also significantly suppressed LPS-induced COX-2 protein expression. Compounds 2, 4, and 6 also showed cytotoxic activity against HL-60 cells with IC50 values ranging between 46.43 and 94.06 μM.

C1qa deficiency in mice increases susceptibility to mouse hepatitis virus A59 infection

Background@#Mouse hepatitis virus (MHV) A59 is a highly infectious pathogen and starts in the respiratory tract and progresses to systemic infection in laboratory mice. The complement system is an important part of the host immune response to viral infection. It is not clear the role of the classical complement pathway in MHV infection. @*Objectives@#The purpose of this study was to determine the importance of the classical pathway in coronavirus pathogenesis by comparing C1qa KO mice and wild-type mice. @*Methods@#We generated a C1qa KO mouse using CRISPR/Cas9 technology and compared the susceptibility to MHV A59 infection between C1qa KO and wild-type mice. Histopathological and immunohistochemical changes, viral loads, and chemokine expressions in both mice were measured. @*Results@#MHV A59-infected C1qa KO mice showed severe histopathological changes, such as hepatocellular necrosis and interstitial pneumonia, compared to MHV A59-infected wildtype mice. Virus copy numbers in the olfactory bulb, liver, and lungs of C1qa KO mice were significantly higher than those of wild-type mice. The increase in viral copy numbers in C1qa KO mice was consistent with the histopathologic changes in organs. These results indicate that C1qa deficiency enhances susceptibility to MHV A59 systemic infection in mice. In addition, this enhanced susceptibility effect is associated with dramatic elevations in spleen IFN-γ, MIP-1 α, and MCP-1 in C1qa KO mice. @*Conclusions@#These data suggest that C1qa deficiency enhances susceptibility to MHV A59 systemic infection, and activation of the classical complement pathway may be important for protecting the host against MHV A59 infection.

Asymmetric Amyloid-β Burden and Neurodegeneration in Late-Onset Alzheimer’s Disease Dementia

We report herein a 78-year-old woman with insidiously progressive cognitive impairment and asymmetric amyloid deposition and neurodegeneration. Brain magnetic resonance imaging revealed remarkable atrophy in the right-sided temporal lobe and hippocampus. Early dynamic 18F-flutemetamol brain amyloid positron-emission tomography images showed decreased uptake in the right temporoparietal regions. Delayed images revealed amyloid deposition which was most remarkable in the right frontotemporoparietal regions. Asymmetries of amyloid burden and neuronal dysfunction are positively correlated in Alzheimer’s disease in cortical regions with high amyloid load.

Longitudinal Observation of Early-Onset Alzheimer’s Disease Dementia with Positive CSF Biomarkers/Negative Amyloid-β Positron-Emission Tomography

We report a 61-year-old woman with clinical course for Alzheimer’s disease (AD) dementia and discordant amyloid-β positron-emission tomography (PET) and cerebrospinal fluid biomarkers. Brain magnetic resonance imaging revealed remarkable atrophy in the hippocampus. However, repeated delayed 18F-flutemetamol brain amyloid PET images with 1 year-interval revealed no amyloid deposition, whereas her CSF revealed low Aβ42, high total tau and p-tau181. This discordant amyloid-β PET and CSF biomarkers in this early-onset AD dementia might be associated with her low resilience or mixed pathology.

Impact of Intensivist and Nursing Staff on Critically Ill Patient Mortality: A Retrospective Analysis of the Korean NHIS Cohort Data, 2011–2015

Purpose@#Critical care medicine continues to evolve. However, critical care cases require increasing amount of medical resources.Intensive care unit (ICU) mortality significantly impacts the overall efficiency of healthcare resources within a system of limited medical resources. This study investigated the factors related to ICU mortality using long-term nationwide cohort data in South Korea. @*Materials and Methods@#This retrospective cohort study used data of 14905721 patients who submitted reimbursement claims to the Korean Health Insurance Service between January 1, 2011 and December 31, 2015. A total of 1498102 patients who were admitted to all ICU types, except neonatal and long-term acute care hospitals, were enrolled. @*Results@#Of the total 1498102 participants, 861397 (57.5%) were male and 636705 (42.5%) were female. The mean age at admission was 63.4±18.2 years; most of the subjects were aged over 60 years. During the 5-year period, in-hospital mortality rate was 12.9%.In Cox analysis, both in-hospital and 28-day mortality rates were significantly higher in male patients and those of lower socioeconomic status. As age increased and the number of nursing staff decreased, the mortality risk increased significantly by two or three times. The mortality risk was lower in patients admitted to an ICU of a tertiary university hospital and an ICU where intensivists worked. @*Conclusion@#The number of nursing staff and the presence of an intensivist in ICU were associated with the ICU mortality rate. Also, increasing the number of nursing staff and the presence of intensivist might reduce the mortality rate among ICU patients.

New Obligations of Health Insurance Review and Assessment Service: Taking Full-fledged Action Against the COVID-19 Pandemic / 예방의학회지

In 2020, the coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented disruptions to global health systems. The Korea has taken full-fledged actions against this novel infectious disease, swiftly implementing a testing-tracing-treatment strategy. New obligations have therefore been given to the Health Insurance Review and Assessment Service (HIRA) to devote the utmost effort towards tackling this global health crisis. Thanks to the universal national health insurance and state-of-the-art information communications technology (ICT) of the Korea, HIRA has conducted far-reaching countermeasures to detect and treat cases early, prevent the spread of COVID-19, respond quickly to surging demand for the healthcare services, and translate evidence into policy. Three main factors have enabled HIRA to undertake pandemic control preemptively and systematically: nationwide data aggregated from all healthcare providers and patients, pre-existing ICT network systems, and real-time data exchanges. HIRA has maximized the use of data and pre-existing network systems to conduct rapid and responsive measures in a centralized way, both of which have been the most critical tactics and strategies used by the Korean healthcare system. In the face of new obligations, our promise is to strive for a more responsive and resilient health system during this prolonged crisis.

Compositional and Functional Changes in the Gut Microbiota in Irritable Bowel Syndrome Patients

Background/Aims@#This study aimed to characterize the changes in the gut microbiota of irritable bowel syndrome (IBS) patients and to investigate the consequent alterations in bacterial functions. @*Methods@#We performed 16S rRNA metagenomic sequencing and a phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) analyses using fecal samples from control (n=12) and diarrhea-dominant IBS patients (n=7). @*Results@#The samples were clustered by the principal coordinates analysis depending on the presence of IBS (p=0.003). In the IBS patients, the abundances of Acidaminococcaceae, Sutterellaceae, and Desulfovibrionaceae were significantly increased, while those of Enterococcaceae, Leuconostocaceae, Clostridiaceae, Peptostreptococcaceae, and Lachnospiraceae were significantly decreased. The PICRUSt results indicated that two orthologues involved in secondary bile acid biosynthesis were significantly decreased in IBS patients. Modules involved in multidrug resistance, lipopolysaccharide biosynthesis, the reductive citrate cycle, and the citrate cycle were significantly increased in the IBS patients. In contrast, modules involved in cationic antimicrobial peptide resistance, and some transport systems were more abundant in controls than in IBS patients. @*Conclusions@#Changes in the gut microbiota composition in IBS patients lead to alterations in bacterial functions, such as bile acid transformation and the induction of inflammation, which is a known pathophysiological mechanism of IBS.

Efficacy of Tegoprazan for Improving the Susceptibility of Antimicrobial Agents against Antibiotic-Resistant Helicobacter pylori

Background/Aims@#Favorable outcomes of potassium-competitive acid blocker (PCAB)-containing eradication therapy have been reported. In fact, tegoprazan, a recently developed PCAB, was presumed to show good eradication efficacy even for resistant Helicobacter pylori. We aimed to investigate the anti-H. pylori efficacy of tegoprazan compared with that of vonoprazan. @*Methods@#A total of 220 resistant clinical H. pylori isolates were utilized. The anti-H. pylori efficacy of PCABs was determined by evaluating the minimum inhibitory concentrations (MICs) of clarithromycin, fluoroquinolone, metronidazole, and amoxicillin in combination with vonoprazan or tegoprazan by the agar dilution method. The impact of the mutations responsible for resistance development, such as 23S rRNA, gyrA, rdxA, frxA, and pbp1 mutations, was also analyzed. @*Results@#H. pylori growth was significantly inhibited in a medium containing 1 μg/mL clarithromy-cin with tegoprazan (128 μg/mL). The MICs of clarithromycin (46.3%), fluoroquinolone (46.7%), metronidazole (55.6%), and amoxicillin (34.5%) against resistant H. pylori isolates improved after tegoprazan administration. Tegoprazan demonstrated more frequent susceptibility acquisitionwith metronidazole than with vonoprazan (20.6% vs 4.7%, p=0.014). However, there were nosignificant differences depending on the mutational status of each antimicrobial agent. @*Conclusions@#Tegoprazan administration may improve the susceptibility of antimicrobial-resistant H. pylori, independent of acid suppression.

Immunosuppressive Drug Measurement by Liquid Chromatography Coupled to Tandem Mass Spectrometry: Interlaboratory Comparison in the Korean Clinical Laboratories

Background@#Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) is increasingly used for immunosuppressive drug tests. However, most LC-MS/MS tests are laboratory-developed and their agreement is unknown in different Korean laboratories.This interlaboratory comparison study evaluated test reproducibility and identified potential error sources. @*Methods@#Test samples containing three concentrations of tacrolimus, sirolimus, everolimus, cyclosporine, and mycophenolic acid were prepared by pooling surplus samples from patients undergoing routine therapeutic drug monitoring and tested in duplicate in the participating 10 clinical laboratories. Reconstitution and storage experiments were conducted for the commonly used commercial calibrator set. The robust estimators of reproducibility parameters were calculated. Spearman’s rank correlation coefficient (rho, ρ) was used to evaluate the correlation between drugs. Multiple linear regression was used to determine whether the experimental conditions alter the calibration curves. @*Results@#The reproducibility coefficient of variation exceeded 10% only for sirolimus concentrations 1 and 2 (10.8% and 12.5%, respectively) and everolimus concentrations 1 and 2 (12.3% and 11.4%, respectively). The percent difference values showed weak correlations between sirolimus and everolimus (ρ = 0.334, P = 0.175). The everolimus calibration curve slope was significantly altered after reconstitution following prolonged 5°C storage (P = 0.015 for 14 days; P = 0.025 for 28 days); the expected differences at 6 ng/mL were 0.598% for 14 days and 0.384% for 28 days. @*Conclusions@#LC-MS/MS test reproducibility for immunosuppressive drugs seems to be good in the Korean clinical laboratories. Continuous efforts are required to achieve test standardization and harmonization, especially for sirolimus and everolimus.

Evaluation of the Barricor Tube in 28 Routine Chemical Tests and Its Impact on Turnaround Time in an Outpatient Clinic

Background@#We recently introduced the Barricor (BD, Franklin Lakes, NJ, USA) plasma separation tube, which uses a mechanical separator instead of a gel. We evaluated the effects of using the Barricor tube in a stat (statin) laboratory on the results and turnaround time (TAT) of routine chemical tests. We verified the impact of Barricor tube on reducing TAT and providing results similar to those obtained using serum separator tubes (SSTs). @*Methods@#We collected venous blood samples from 166 outpatients in Barricor tubes and SSTs and measured 28 routine analytes using an AU5800 instrument (Beckman Coulter, Brea, CA, USA). TAT indexes were compared before and after using Barricor tube. @*Results@#Mean percent differences were 60 minutes decreased from 7.84% to 2.66%, which was approximately one-third of that for SST. The reduction in TAT was attributable to a decrease in centrifugation time. Incomplete clotting and repeated centrifugation, which occurred frequently when using SST, also decreased after using the Barricor tubes. @*Conclusions@#The Barricor tube is an alternative to SST for routine chemical tests in institutions aiming to reduce TAT, with clinically allowable differences in test results.

Treatment of rocuronium-induced anaphylaxis using sugammadex - A case report -

Background@#Perioperative anaphylaxis is a life-threatening clinical condition characterized by severe respiratory and cardiovascular manifestations. Neuromuscular blocking agents are the most common cause of anaphylaxis during anesthesia. Case: We report a case of rocuronium-induced anaphylaxis treated with sugammadex. A 75–year-old woman was scheduled to undergo spinal surgery. She had no history of allergies. After the injection of rocuronium, she developed hypotension and tachycardia, and skin rashes and urticaria appeared. The patient received sugammadex to delay the operation, and her vital signs were stabilized. On the 76th postoperative day, we performed intradermal tests for rocuronium, propofol, and cefazolin. Diluted rocuronium alone induced 14 mm of flare and 8 mm of wheal within 5 min, both of which disappeared within 15 min after the intradermal injection. @*Conclusions@#Sugammadex is a useful rocuronium antagonist that can be used to treat rocuronium-induced anaphylaxis.