Diagnostic Assessment of Deep Learning Algorithms for Frozen Tissue Section Analysis in Women with Breast Cancer / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Assessing the metastasis status of the sentinel lymph nodes (SLNs) for hematoxylin and eosin–stained frozen tissue sections by pathologists is an essential but tedious and time-consuming task that contributes to accurate breast cancer staging. This study aimed to review a challenge competition (HeLP 2019) for the development of automated solutions for classifying the metastasis status of breast cancer patients. @*Materials and Methods@#A total of 524 digital slides were obtained from frozen SLN sections: 297 (56.7%) from Asan Medical Center (AMC) and 227 (43.4%) from Seoul National University Bundang Hospital (SNUBH), South Korea. The slides were divided into training, development, and validation sets, where the development set comprised slides from both institutions and training and validation set included slides from only AMC and SNUBH, respectively. The algorithms were assessed for area under the receiver operating characteristic curve (AUC) and measurement of the longest metastatic tumor diameter. The final total scores were calculated as the mean of the two metrics, and the three teams with AUC values greater than 0.500 were selected for review and analysis in this study. @*Results@#The top three teams showed AUC values of 0.891, 0.809, and 0.736 and major axis prediction scores of 0.525, 0.459, and 0.387 for the validation set. The major factor that lowered the diagnostic accuracy was micro-metastasis. @*Conclusion@#In this challenge competition, accurate deep learning algorithms were developed that can be helpful for making a diagnosis on intraoperative SLN biopsy. The clinical utility of this approach was evaluated by including an external validation set from SNUBH.

Joseph Needham’s ‘Motivations for Participation’ and ‘Major Roles’ in the International Scientific Commission on Bacterial Warfare during the Korean War / 의사학

This paper analyzes the motivations of the British biochemist Joseph Needham for participating in ‘the International Scientific Commission for the Investigation of the Facts Concerning Bacterial Warfare in Korea and China (ISC)’ and his major roles within it during the Korean War. Needham stayed in China for four years starting in 1942 as a scientific counselor and director of the British Scientific Mission in China, which enabled him to interact with many Chinese scientists and politicians. Surprisingly, during this period (1944), Needham conducted an investigation into the Japanese military’s use of bacterial warfare. Through his personal records, Needham repeatedly stated that his experience with bacterial warfare research in 1944 was one of the most important reasons for his participation in ISC activities. In addition, Needham secretly but very actively sought to recruit other investigators within Britain. Needham repeatedly tried to persuade fellow professors at Cambridge University, William Thorpe and Vincent Wigglesworth, to be included in the investigation team. Although Needham had doubts about his own expertise in investigative activities, he actively expressed his desire to become a member of the investigative team through various channels. Primary documents show that he actively and voluntarily led the investigation activities after joining the team in professional discussions, document analysis, and witness interrogations. Needham’s passion and sincerity demonstrated in internal meeting minutes dispel some misunderstandings that the investigation team’s activities were limited to passively approving Chinese data.

Relative infectivity of the SARS-CoV-2 Omicron variant in human alveolar cells

With the emergence of multiple highly transmissible SARS-CoV-2 variants during the recent pandemic, the comparison of their infectivity has become a substantially critical issue for public health. However, a direct assessment of these viral characteristics has been challenging due to the lack of appropriate experimental models and efficient methods. Here, we integrated human alveolar organoids and single-cell transcriptome sequencing techniques to facilitate the evaluation. In a proof-of-concept study using the assay with four highly transmissible SARS-CoV-2 variants, including GR (B.1.1.119), Alpha (B.1.1.7), Delta (B.1.617.2), and Omicron (BA.1), a rapid evaluation of the relative infectivity was possible. Our results demonstrate that the Omicron (BA.1) variant is 3-5-fold more infectious to human alveolar cells than the other SARS-CoV-2 variants at the early phase of infection. To our knowledge, this study provides the first direct measurement of the infectivity of the Omicron variant and new experimental procedures that can be applied for monitoring newly emerging viral variants.

The status and roles of the 406th Medical General Laboratory of the U.S. Army, 1946-1953 / 의사학

In 1946, the U.S. Army established the 406th Medical General Laboratory as the central medical research institute for their new Asia-Pacific-occupied area. The primary mission of the 406th medical laboratory was to supplement the epidemiologic, sanitary, and diagnostic services available in other medical facilities and hospitals, and to investigate outbreaks of disease and conditions which affect or may affect the health of the people in the occupied area. At the time of its establishment, the 406th laboratory had considerable difficulties securing researchers, but it solved the related problems by actively cooperating with Japanese medical researchers and research institutes. According to the statistics in 1947, the 406th laboratory consisted of 46% of its total research personnel, Japanese researchers. The 406th medical laboratory’s professional research departments included the department of Pathology, Serology, Bacteriology, Medical Zoology, Chemistry, Virus and Ricketts, Entomology (established in 1949), and Epidemiology (established in 1951). All research departments played a central role in the Asia-Pacific region in their professional fields. For example, the department of Pathology functioned as the “histopathology center of all hospitals in Japan, Korea, and the Mariana-Bonin Command” under the provision of “Army Regulation 40-410,” and the department of Chemistry was called an “analytical chemistry laboratory for the Far East Command” because it performed various chemical experiments for many medical facilities in the area with insufficient research facilities.

Matrix Metalloproteinase-8 Inhibitor Ameliorates Inflammatory Responses and Behavioral Deficits in LRRK2 G2019S Parkinson’s Disease Model Mice

Parkinson’s disease (PD) is a neurodegenerative disorder that involves the loss of dopaminergic neurons in the substantia nigra (SN). Matrix metalloproteinases-8 (MMP-8), neutrophil collagenase, is a functional player in the progressive pathology of various inflammatory disorders. In this study, we administered an MMP-8 inhibitor (MMP-8i) in Leucine-rich repeat kinase 2 (LRRK2) G2019S transgenic mice, to determine the effects of MMP-8i on PD pathology. We observed a significant increase of ionized calcium- binding adapter molecule 1 (Iba1)-positive activated microglia in the striatum of LRRK2 G2019S mice compared to normal control mice, indicating enhanced neuro-inflammatory responses. The increased number of Iba1-positive activated microglia in LRRK2 G2019S PD mice was down-regulated by systemic administration of MMP-8i. Interestingly, this LRRK2 G2019S PD mice showed significantly reduced size of cell body area of tyrosine hydroxylase (TH) positive neurons in SN region and MMP-8i significantly recovered cellular atrophy shown in PD model indicating distinct neuro-protective effects of MMP-8i. Furthermore, MMP-8i administration markedly improved behavioral abnormalities of motor balancing coordination in rota-rod test in LRRK2 G2019S mice. These data suggest that MMP-8i attenuates the pathological symptoms of PD through anti-inflammatory processes.

Far-infrared rays enhance mitochondrial biogenesis and GLUT3 expression under low glucose conditions in rat skeletal muscle cells

Far-infrared rays (FIR) are known to have various effects on atoms and molecular structures within cells owing to their radiation and vibration frequencies. The present study examined the effects of FIR on gene expression related to glucose transport through microarray analysis in rat skeletal muscle cells, as well as on mitochondrial biogenesis, at high and low glucose conditions. FIR were emitted from a bio-active material coated fabric (BMCF). L6 cells were treated with 30% BMCF for 24 h in medium containing 25 or 5.5 mM glucose, and changes in the expression of glucose transporter genes were determined. The expression of GLUT3 (Slc2a3) increased 2.0-fold (p < 0.05) under 5.5 mM glucose and 30% BMCF. In addition, mitochondrial oxygen consumption and membrane potential (ΔΨm) increased 1.5- and 3.4-fold (p < 0.05 and p < 0.001), respectively, but no significant change in expression of Pgc-1a, a regulator of mitochondrial biogenesis, was observed in 24 h. To analyze the relationship between GLUT3 expression and mitochondrial biogenesis under FIR, GLUT3 was down-modulated by siRNA for 72 h. As a result, the ΔΨm of the GLUT3 siRNA-treated cells increased 3.0-fold (p < 0.001), whereas that of the control group increased 4.6-fold (p < 0.001). Moreover, Pgc-1a expression increased upon 30% BMCF treatment for 72 h; an effect that was more pronounced in the presence of GLUT3. These results suggest that FIR may hold therapeutic potential for improving glucose metabolism and mitochondrial function in metabolic diseases associated with insufficient glucose supply, such as type 2 diabetes.

Matrix Metalloproteinase-8 Inhibitor Ameliorates Inflammatory Responses and Behavioral Deficits in LRRK2 G2019S Parkinson’s Disease Model Mice

Parkinson’s disease (PD) is a neurodegenerative disorder that involves the loss of dopaminergic neurons in the substantia nigra (SN). Matrix metalloproteinases-8 (MMP-8), neutrophil collagenase, is a functional player in the progressive pathology of various inflammatory disorders. In this study, we administered an MMP-8 inhibitor (MMP-8i) in Leucine-rich repeat kinase 2 (LRRK2) G2019S transgenic mice, to determine the effects of MMP-8i on PD pathology. We observed a significant increase of ionized calcium- binding adapter molecule 1 (Iba1)-positive activated microglia in the striatum of LRRK2 G2019S mice compared to normal control mice, indicating enhanced neuro-inflammatory responses. The increased number of Iba1-positive activated microglia in LRRK2 G2019S PD mice was down-regulated by systemic administration of MMP-8i. Interestingly, this LRRK2 G2019S PD mice showed significantly reduced size of cell body area of tyrosine hydroxylase (TH) positive neurons in SN region and MMP-8i significantly recovered cellular atrophy shown in PD model indicating distinct neuro-protective effects of MMP-8i. Furthermore, MMP-8i administration markedly improved behavioral abnormalities of motor balancing coordination in rota-rod test in LRRK2 G2019S mice. These data suggest that MMP-8i attenuates the pathological symptoms of PD through anti-inflammatory processes.

Far-infrared rays enhance mitochondrial biogenesis and GLUT3 expression under low glucose conditions in rat skeletal muscle cells

Far-infrared rays (FIR) are known to have various effects on atoms and molecular structures within cells owing to their radiation and vibration frequencies. The present study examined the effects of FIR on gene expression related to glucose transport through microarray analysis in rat skeletal muscle cells, as well as on mitochondrial biogenesis, at high and low glucose conditions. FIR were emitted from a bio-active material coated fabric (BMCF). L6 cells were treated with 30% BMCF for 24 h in medium containing 25 or 5.5 mM glucose, and changes in the expression of glucose transporter genes were determined. The expression of GLUT3 (Slc2a3) increased 2.0-fold (p < 0.05) under 5.5 mM glucose and 30% BMCF. In addition, mitochondrial oxygen consumption and membrane potential (ΔΨm) increased 1.5- and 3.4-fold (p < 0.05 and p < 0.001), respectively, but no significant change in expression of Pgc-1a, a regulator of mitochondrial biogenesis, was observed in 24 h. To analyze the relationship between GLUT3 expression and mitochondrial biogenesis under FIR, GLUT3 was down-modulated by siRNA for 72 h. As a result, the ΔΨm of the GLUT3 siRNA-treated cells increased 3.0-fold (p < 0.001), whereas that of the control group increased 4.6-fold (p < 0.001). Moreover, Pgc-1a expression increased upon 30% BMCF treatment for 72 h; an effect that was more pronounced in the presence of GLUT3. These results suggest that FIR may hold therapeutic potential for improving glucose metabolism and mitochondrial function in metabolic diseases associated with insufficient glucose supply, such as type 2 diabetes.

Robust three-dimensional expansion of human adult alveolar stem cells and SARS-CoV-2 infection

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), which is the cause of a present global pandemic, infects human lung alveolar cells (hACs). Characterising the pathogenesis is crucial for developing vaccines and therapeutics. However, the lack of models mirroring the cellular physiology and pathology of hACs limits the study. Here, we develop a feeder-free, long-term three-dimensional (3D) culture technique for human alveolar type 2 (hAT2) cells, and investigate infection response to SARS-CoV-2. By imaging-based analysis and single-cell transcriptome profiling, we reveal rapid viral replication and the increased expression of interferon-associated genes and pro-inflammatory genes in infected hAT2 cells, indicating robust endogenous innate immune response. Further tracing of viral mutations acquired during transmission identifies full infection of individual cells effectively from a single viral entry. Our study provides deep insights into the pathogenesis of SARS-CoV-2, and the application of long-term 3D hAT2 cultures as models for respiratory diseases.

Research Trends and Prospects of Medical Anthropology: Concepts and Their Intersection with History of Medicine / 의사학

This study explores the history of research in Medical Anthropology by examining key concepts in the field with a focus on their relevance with findings from the field of History of Medicine. The concepts discussed in this paper are Medical Pluralism, Social Suffering, Biopolitics, and Care. Since concepts internalize the ethnographic gaze, what this paper aims is to trace the development of the gaze on a historical axis. Although concepts come from a specific historical period, they are by no means exclusive to it, as they are revisited again and again through various discourses. In other words, the insight that the previous meaning of a concept has grasped is instilled into the revisited concept. In this way, concepts engage in historical communication, create intersections with the interests of History of Medicine. By discussing these intersections with each concept, this paper suggests the complementary roles of the two fields and their approach to historical events and phenomena.

Research Trends and Prospects of Medical Anthropology: Concepts and Their Intersection with History of Medicine / 의사학

This study explores the history of research in Medical Anthropology by examining key concepts in the field with a focus on their relevance with findings from the field of History of Medicine. The concepts discussed in this paper are Medical Pluralism, Social Suffering, Biopolitics, and Care. Since concepts internalize the ethnographic gaze, what this paper aims is to trace the development of the gaze on a historical axis. Although concepts come from a specific historical period, they are by no means exclusive to it, as they are revisited again and again through various discourses. In other words, the insight that the previous meaning of a concept has grasped is instilled into the revisited concept. In this way, concepts engage in historical communication, create intersections with the interests of History of Medicine. By discussing these intersections with each concept, this paper suggests the complementary roles of the two fields and their approach to historical events and phenomena.

Dorsolateral septum somatostatin interneurons gate mobility to calibrate context-specific behavioral fear responses.

Adaptive fear responses to external threats rely upon efficient relay of computations underlying contextual encoding to subcortical circuits. Brain-wide analysis of highly coactivated ensembles following contextual fear discrimination identified the dorsolateral septum (DLS) as a relay of the dentate gyrus-CA3 circuit. Retrograde monosynaptic tracing and electrophysiological whole-cell recordings demonstrated that DLS somatostatin-expressing interneurons (SST-INs) receive direct CA3 inputs. Longitudinal in vivo calcium imaging of DLS SST-INs in awake, behaving mice identified a stable population of footshock-responsive SST-INs during contextual conditioning whose activity tracked and predicted non-freezing epochs during subsequent recall in the training context but not in a similar, neutral context or open field. Optogenetic attenuation or stimulation of DLS SST-INs bidirectionally modulated conditioned fear responses and recruited proximal and distal subcortical targets. Together, these observations suggest a role for a potentially hard-wired DLS SST-IN subpopulation as arbiters of mobility that calibrate context-appropriate behavioral fear responses.

Text and Practice in East Asian Medicine: The Structure of East Asian Medical Knowledge Examined by Donguibogam Currents in Contemporary South Korea / 의사학

How do classical texts, such as Hwangdi Neijing and Shanghanlun, continuously play significant roles in medical practices in the history of East Asian medicine? Although this is a significant question in interpreting the position of written texts in the medical history and even for understanding the structure of East Asian medical knowledge, it has been conspicuously underexamined in the studies of East Asian medicine. In order to explore this underrepresented question, this study focuses on currents of tradition in contemporary South Korea. Drawing on anthropological fieldwork at three Donguibogam (Treasured Mirror of Eastern Medicine) currents, it delves into the interaction of text and practice in East Asian medicine. Even though all three currents (Hyun-dong, Byeong-in, Hyung-sang) are based on Donguibogam, their ways of reading the text and organizing clinical practices are diverse. Each current sets up a keyword, such as pulse diagnosis, cause of disease, and appearance-image, and attempts to penetrate the entire Donguibogam through the keyword. This means that the classical medical text is open to plural approaches. This study found that there is a visible gap between a medical text and the reader of the text in East Asia. Masters and currents of tradition are the actors who fill up the gap, continuously interpreting and reinterpreting classical texts, and guiding medical practices of new readers. Adding the history of practice to the body of literature that have focused on the history of written texts, this study will contribute to the history of East Asian medicine.

HDAC Inhibition by Valproic Acid Induces Neuroprotection and Improvement of PD-like Behaviors in LRRK2 R1441G Transgenic Mice

Parkinson’s disease (PD) is one of the late-onset neurodegenerative movement disorder. Major pathological markers of PD include progressive loss of dopaminergic neurons, Lewy body formation, genetic mutations, and environmental factors. Epigenetic regulation of specific gene expression via impaired histone acetylation is associated with neuronal dysfunction in various neurodegenerative diseases. In this study, we hypothesized that histone deacetylase (HDAC) inhibitor, valproic acid (VPA), can improve motor function by enhancing cell survival in PD genetic model mice with LRRK2 R1441G mutation. To address this question, we administered VPA in LRRK2 R1441G transgenic mice to determine whether VPA affects 1) histone acetylation and HDAC expression, 2) dopaminergic neuron survival, 3) inflammatory responses, 4) motor or non-motor symptoms. As results, VPA administration increased histone acetylation level and the number of tyrosine hydroxylase (TH) positive neurons in substantia nigra of LRRK2 R1441G mice. VPA reduced iba-1 positive activated microglia and the mRNA levels of pro-inflammatory marker genes in LRRK2 R1441G mice. In addition, VPA induced the improvement of PD-like motor and non-motor behavior in LRRK2 R1441G mice. These data suggest that the inhibition of HDAC can be further studied as potential future therapeutics for PD.

A contribution to the fauna of raspy crickets (orthoptera: gryllacrididae: gryllacridinae) in Korea.

The little known raspy cricket subfamily Gryllacridinae is reviewed for Korea. Three species are confirmed through material examination and are taxonomically considered as follows: Eugryllacris japonica (Matsumura et Shiraki, 1908) comb. nov. is transferred from Prosopogryllacris japonica (Matsumura et Shiraki, 1908), Nippancistroger testaceus (Matsumura et Shiraki, 1908) has a newly proposed junior synonym Nippancistroger koreanus Storozhenko & Paik, 2003 syn. nov., and Metriogryllacris tigris sp. nov. is newly described from the far southern Yeoseo-do Island. 

Probiotic dietary supplementation in a dog with chronic kidney disease / 동물의과학연구지

A 7-year-old spayed female English Cocker Spaniel dog presented with polyuria (PU), polydipsia (PD), intermittent vomiting, and weight loss. Physical examination revealed pale, tacky mucous membranes and severe emaciation. Hematological and biochemical examinations revealed moderate normocytic normochromic non-regenerative anemia and moderate azotemia. Abdominal ultrasonography demonstrated bilaterally small lumpy-bumpy kidneys with hyperechoic parenchyma as well as loss of renal corticomedullary junction. Based on clinical history and examinations, the dog was diagnosed with chronic kidney disease (CKD). The dog was treated with supportive care including fluid therapy, phosphate-binding agent, and histamine H2-receptor antagonist. Darbepoetin Alfa was administered to control renal secondary non-regenerative anemia. Prescribed diet with low-protein and low-phosphorus was fed to alleviate CKD signs. Further, dietary probiotics were supplemented. This case demonstrates that oral probiotic supplementation helped reduce blood urea-nitrogen (BUN) levels. This case indicates that dietary probiotics can be a potential alternative therapeutic agent for management of renal failure.

The Second-to-Fourth Digit Ratio in Cryptorchidism: A Case-Control Study

PURPOSE: The homeobox (Hox) genes a and d controlling limb and genital development influence the digit ratio and the fetal production of testicular androgen, which may result in testicular descent in boys. To assess whether the digit ratio reflects disease status, we investigated the second and fourth finger lengths in children with cryptorchidism, in children with hydrocele as a disease control, and in healthy controls (boys and girls). MATERIALS AND METHODS: One hundred ninety-six children (46 with cryptorchidism, 50 with hydrocele, 50 healthy boys, and 50 healthy girls) who were 6 to 23 months of age were prospectively enrolled. Digit lengths were measured by 2 investigators, and the mean value was recorded. RESULTS: The second-to-fourth digit ratios (2D:4Ds) of the left hand in the cryptorchidism group, hydrocele group, healthy boys, and healthy girls were 0.958, 0.956, 0.950, and 0.956, respectively. The 2D:4D values of the right hand were 0.946, 0.945, 0.952, and 0.969, respectively. The right and left 2D:4D ratios were not significantly different among groups. The 2D:4D of both hands was not related to age, weight, or height. CONCLUSIONS: According to these results, the 2D:4D was not significantly different in boys with cryptorchidism than in boys with hydrocele or in healthy controls (boys and girls) and failed to reflect disease conditions in the infant period.

Inhibitory effects of Capsicum annuum L. water extracts on lipoprotein lipase activity in 3T3-L1 cells

Obesity, an intractable metabolic disease, currently has no medical treatment without side effects, so studies have been actively carried out to find natural compounds that have anti-obesity activity with minimum side effects. In this study, the anti-obesity effects of water extracts of seven Capsicum annuum L. varieties being Putgochu (Pca), Oyee gochu (Oca), Kwari putgochu (Kca), Green pepper (Gca), Yellow paprika (Yca), Red paprika (Rca) and Cheongyang gochu (Cca), were examined through the evaluation of lipoprotein lipase (LPL) mRNA expression level in 3T3-L1 cells (mouse pre-adipocytes). After capsaicin elimination by chloroform defatting, freeze-dried powder of Cca was treated to 3T3-L1 cells and anti-obesity effects were examined by determining the LPL mRNA level using the RT-PCR method. Of the primary fractions, only proven fractions underwent secondary and tertiary refractionating to determine anti-obesity effects. From seven different Capsicum annuum L., there was a significant decrease of the LPL mRNA expression level of 50.9% in Cca treatment compared to the control group. A significant decrease of the LPL mRNA expression level was shown in primary fractions (Fr) 5 (36.2% decrease) and 6 (30.5% decrease) of the Cca water extracts. Due to the impurities checked by UPLC chromatography, Fr 5 and 6 were refractionated to determine the LPL mRNA expression level. Treatment of Fr 6-6 (35.8% decrease) and Fr 5-6 (35.3% decrease) showed a significant decrease in the LPL mRNA expression level. When analyzed using UPLC, major compounds of Fr 6-6 and Fr 5-6 were very similar. Subsequently, we refractionated Fr 6-6 and Fr 5-6 to isolate the major peak for structure elucidation. Treatment of Fr 5-6-1 (26.6% decrease) and Fr 6-6-1 (29.7% decrease) showed a significant decrease in the LPL mRNA expression level. Consequently, the fractions may have a possibility to ameliorate obesity through the decrease of the LPL mRNA expression level.

Erratum: Funding Acknowledgment

The funding acknowledgment in this article was omitted as published.

Erratum: Funding Acknowledgment

The funding acknowledgment in this article was omitted as published.