Circulating Tumor DNA–Based Genotyping and Monitoring for Predicting Disease Relapses of Patients with Peripheral T-Cell Lymphomas / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Plasma circulating tumor DNA (ctDNA) could reflect the genetic alterations present in tumor tissues. However, there is little information about the clinical relevance of cell-free DNA genotyping in peripheral T-cell lymphoma (PTCL). @*Materials and Methods@#After targeted sequencing plasma cell-free DNA of patients with various subtypes of PTCL (n=94), we analyzed the mutation profiles of plasma ctDNA samples and their predictive value of dynamic ctDNA monitoring for treatment outcomes. @*Results@#Plasma ctDNA mutations were detected in 53 patients (56%, 53/94), and the detection rate of somatic mutations was highest in angioimmunoblastic T-cell lymphoma (24/31, 77%) and PTCL, not otherwise specified (18/29, 62.1%). Somatic mutations were detected in 51 of 66 genes that were sequenced, including the following top 10 ranked genes: RHOA, CREBBP, KMT2D, TP53, IDH2, ALK, MEF2B, SOCS1, CARD11, and KRAS. In the longitudinal assessment of ctDNA mutation, the difference in ctDNA mutation volume after treatment showed a significant correlation with disease relapse or progression. Thus, a ≥ 1.5-log decrease in genome equivalent (GE) between baseline and the end of treatment showed a significant association with better survival outcomes than a < 1.5-log decrease in GE. @*Conclusion@#Our results suggest the clinical relevance of plasma ctDNA analysis in patients with PTCL. However, our findings should be validated by a subsequent study with a larger study population and using a broader gene panel.

Targeted Liquid Biopsy Using Irradiation to Facilitate the Release of Cell-Free DNA from a Spatially Aimed Tumor Tissue / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#We investigated the feasibility of using an anatomically localized, target-enriched liquid biopsy (TLB) in mouse models of lung cancer. @*Materials and Methods@#After irradiating xenograft mouse with human lung cancer cell lines, H1299 (NRAS proto-oncogene, GTPase [NRAS] Q61K) and HCC827 (epidermal growth factor receptor [EGFR] E746-750del), circulating (cell-free) tumor DNA (ctDNA) levels were monitored with quantitative polymerase chain reaction on human long interspersed nuclear element-1 and cell line-specific mutations. We checked dose-dependency at 6, 12, or 18 Gy to each tumor-bearing mouse leg using 6-MV photon beams. We also analyzed ctDNA of lung cancer patients by LiquidSCAN, a targeted deep sequencing to validated the clinical performances of TLB method. @*Results@#Irradiation could enhance the detection sensitivity of NRAS Q61K in the plasma sample of H1299-xenograft mouse to 4.5- fold. While cell-free DNA (cfDNA) level was not changed at 6 Gy, ctDNA level was increased upon irradiation. Using double-xenograft mouse with H1299 and HCC827, ctDNA polymerase chain reaction analysis with local irradiation in each region could specify mutation type matched to transplanted cell types, proposing an anatomically localized, TLB. Furthermore, when we performed targeted deep sequencing of cfDNA to monitor ctDNA level in 11 patients with lung cancer who underwent radiotherapy, the average ctDNA level was increased within a week after the start of radiotherapy. @*Conclusion@#TLB using irradiation could temporarily amplify ctDNA release in xenograft mouse and lung cancer patients, which enables us to develop theragnostic method for cancer patients with accurate ctDNA detection.

Plasma Circulating Tumor DNA in Patients with Primary Central Nervous System Lymphoma / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Analysis of circulating tumor DNA (ctDNA) in blood could allow noninvasive genetic analysis of primary tumors. Although there have been unmet needs for noninvasive methods in patients with primary central nervous system lymphoma (PCNSL), it is still not determined whether plasma ctDNA analysis could be useful for patients with PCNSL. @*Materials and Methods@#Targeted deep sequencing of 54 genes was performed in cell-free DNA isolated from plasma samples collected pretreatment, during treatment, and at the end of treatment in 42 consecutively diagnosed PCNSL patients between January 2017 and December 2018. @*Results@#Targeted sequencing of plasma cell-free DNA detected somatic mutations representing ctDNA in 11 cases (11/41, 27%). The detection of ctDNA was not related to the concentration of cell-free DNA or tumor volume. The mutation profiles of these 11 cases varied between patients. The most frequently mutated gene was PIM1 (4/11, 36.4%), whereas KMT2D, PIK3CA, and MYD88 were each observed in three patients (3/11, 27%). The mutations of 13 genes were concordantly found in primary tumor tissue and plasma ctDNA, giving a detection sensitivity of 45%. During the serial tracking of seven patients with complete response, the disappearance of ctDNA mutations was found in four patients, whereas three patients had detected ctDNA mutation at the end of treatment. @*Conclusion@#The plasma ctDNA mutation analysis still has limited value for surveillance and predicting treatment outcomes of PCNSL because the detection efficiency was lower than other systemic lymphomas. Thus, analytical platforms should be improved to overcome anatomical hurdles associated with PCNSL.

Recapitulation of Neuropsychiatric Behavioral Features in Mice Using Acute Low-dose MK-801 Administration

Despite some innate limitations, animal models are a potent investigative tool when used to model specific symptoms of a disorder. For example, MK-801, an N-methyl-D-aspartate receptor antagonist, is used as a pharmacological tool to induce symptoms found in some neuropsychiatric disorders. However, a close examination of literature suggests that the application window of MK-801 doses is relatively narrow between individual behavioral paradigms, necessitating careful characterization of the evoked behavioral aberrations and the doses used to induce them. Moreover, variation in behaviors depending on the animal strain, gender of the subject, and the timing of administration is observed, making it difficult to compare the behavioral characteristics reported in different studies. We aim to characterize the behavioral aberrations induced by different doses of MK-801 in CD-1 mice and create a ready reference for future studies. We used CD-1 mice to recapitulate behavioral impairments resulting from acute administration of MK-801. In 0.1 mg kg⁻¹, we observed diminished spontaneous alteration during the Y-maze test, while 0.12 mg kg⁻¹ resulted in hyperlocomotion and social deficit. Mice treated with 0.2 and 0.3 mg kg⁻¹ of MK-801 demonstrated a decreased self-grooming. Finally, all doses significantly impaired cliff avoidance behaviors suggesting increased impulsivity. These results affirm that MK-801 can effectively model various symptoms of different neuropsychiatric disorders in a dose-dependent manner. The observed sensitivity against spatial-memory impairment and impulsive behaviors at low concentration of MK-801 suggest that MK801 may modulate cognitive function and impulsivity in even lower concentration before it can modulate other behavioral domains.

Sex-specific Behavioral Features of Rodent Models of Autism Spectrum Disorder

Sex is an important factor in understanding the clinical presentation, management, and developmental trajectory of children with neuropsychiatric disorders. While much is known about the clinical and neurobehavioral profiles of males with neuropsychiatric disorders, surprisingly little is known about females in this respect. Animal models may provide detailed mechanistic information about sex differences in autism spectrum disorder (ASD) in terms of manifestation, disease progression, and development of therapeutic options. This review aims to widen our understanding of the role of sex in autism spectrum disorder, by summarizing and comparing behavioral characteristics of animal models. Our current understanding of how differences emerge in boys and girls with neuropsychiatric disorders is limited: Information derived from animal studies will stimulate future research on the role of biological maturation rates, sex hormones, sex-selective protective (or aggravating) factors and psychosocial factors, which are essential to devise sex precision medicine and to improve diagnostic accuracy. Moreover, there is a strong need of novel strategies to elucidate the major mechanisms leading to sex-specific autism features, as well as novel models or methods to examine these sex differences.

Molecular imaging of membrane proteins and microfilaments using atomic force microscopy

Atomic force microscopy (AFM) is an emerging technique for a variety of uses involving the analysis of cells. AFM is widely applied to obtain information about both cellular structural and subcellular events. In particular, a variety of investigations into membrane proteins and microfilaments were performed with AFM. Here, we introduce applications of AFM to molecular imaging of membrane proteins, and various approaches for observation and identification of intracellular microfilaments at the molecular level. These approaches can contribute to many applications of AFM in cell imaging.

Development of a Baseline Checklist for CTD Risk Assessment / 대한산업의학회지

Today, CTDs (Cumulative Trauma Disorders) are one of major hazards in the US and European Industries disrupting work schedules, productivity and increasing workers compensation costs. The increase in injuries and their associated costs has led companies to form committees and implement programs to address this problem. Therefore, it is important that quantitative analysis tools help identify and assess industrial tasks that pose risk to workers. However, the process of quantifying risk in upper limb tasks is still in its infancy stage and calls for better measurement techniques are not going unheard. As the first work of quantification, baseline CTD checklist for risk assessment was developed in this study. It was mainly based on previous literature regarding CTDs. The checklist was unique in that its expected user was industrial hygienist who did not have much ergonomic background and in that it was targeted to Korean workers in various types of industries. As the first application of the checklist, some jobs in two industries (VDT, heavy Industry) were evaluated, and compared with the medical data. Eighteen out of thirty items in the checklist was univariately significant (p<0.05) on the results of medical examinations. The correlation between medical data and total risk score from the checklist was 0.62. The feasibility of its use by an industrial hygienist was also checked by comparing with the results by an ergonomist. Their correlation (on the basis of Kendall's tau-b) in terms of total risk score was 0.74. The checklist in this study shows reasonably good performance for the first trial. Further research will have to include continuous refinement and validation for many more industries and many more jobs.

Cumulative Trauma Disorders Among Shipyard Workers and Application of Baseline Checklist for Risk Assessment / 대한산업의학회지

Cumulative trauma disorders were surveyed in a cross-sectional study of 100 male ship yard workers and 43 male office workers. And baseline checklist for risk assessment of cumulative trauma disorders was applicated in a ship making process. Cases of cumulative trauma disorders were defined using physical examinations and electronic diagnostic methods. Data on demographics, individual factors (medical condition), work organization and psychosocial aspects of work were obtained by questionnaire. Association between the above factors and cumulative trauma disorders were assessed by multiple logistic regression models. 29(29 %) participants of male shipyard workers and 4(9.2 %) study subjects of male office workers met our case definitions for cumulative trauma disorders. The myofascial pain syndrome of neck muscles(12 % of participants) and carpal tunnel syndrome(5 % of participants) were the major two medical conditions in shipyard workers. The odds of male shipyard workers for cumulative trauma disorders to male office workers was 3.15 after adjustment of age(95 % C.I. :2.25-5.44). And the variables such as duration of present job, HIVD condition, and surges in workload were associated at least one of the cumulative trauma disorders in the final models (p<0.05) . This study indicates that work related upper extremity musculoskeletal disorders are relatively common among shipyard workers, and shows that the psychosocial factors is not likely to be related to the occur rences of these disorders in heavy workers. Also we developed baseline checklist for risk assessment of cumulative trauma disorders. The checklist was unique in that its expected users were industrial hygienists and occupational healthing nurses who did not have much ergonomic background and in that it was targeted to Korean workers in various types. As the first application of the checklist, shipyard workers were evaluated.

Cumulative Trauma Disorders Among Shipyard Workers and Application of Baseline Checklist for Risk Assessment / 대한산업의학회지

Cumulative trauma disorders were surveyed in a cross-sectional study of 100 male ship yard workers and 43 male office workers. And baseline checklist for risk assessment of cumulative trauma disorders was applicated in a ship making process. Cases of cumulative trauma disorders were defined using physical examinations and electronic diagnostic methods. Data on demographics, individual factors (medical condition), work organization and psychosocial aspects of work were obtained by questionnaire. Association between the above factors and cumulative trauma disorders were assessed by multiple logistic regression models. 29(29 %) participants of male shipyard workers and 4(9.2 %) study subjects of male office workers met our case definitions for cumulative trauma disorders. The myofascial pain syndrome of neck muscles(12 % of participants) and carpal tunnel syndrome(5 % of participants) were the major two medical conditions in shipyard workers. The odds of male shipyard workers for cumulative trauma disorders to male office workers was 3.15 after adjustment of age(95 % C.I. :2.25-5.44). And the variables such as duration of present job, HIVD condition, and surges in workload were associated at least one of the cumulative trauma disorders in the final models (p<0.05) . This study indicates that work related upper extremity musculoskeletal disorders are relatively common among shipyard workers, and shows that the psychosocial factors is not likely to be related to the occur rences of these disorders in heavy workers. Also we developed baseline checklist for risk assessment of cumulative trauma disorders. The checklist was unique in that its expected users were industrial hygienists and occupational healthing nurses who did not have much ergonomic background and in that it was targeted to Korean workers in various types. As the first application of the checklist, shipyard workers were evaluated.