Biology subjects

Lee, H.-J.

Publications and source records attributed to Lee, H.-J..

46 records · Page 3Linked to original sources

bioRxiv2019

Induction of pancreatic tumor-selective ferroptosis through modulation of cystine import

Pancreatic ductal adenocarcinoma (PDA) is the third-leading cause of cancer mortality in the US and is highly resistant to classical, targeted, and immune therapies. We show that human PDA cells are dependent on the provision of exogenous cystine to avert a catastrophic accumulation of lipid reactive oxygen species (ROS) that, left unchecked, leads to ferroptotic cell death, both in vitro and in vivo. Using a dual-recombinase genetically engineered model, we found that acute deletion of Slc7a11 led to tumor-selective ferroptosis, tumor stabilizations/regressions, and extended overall survival. The mechanism of ferroptosis induction in PDA cells required the concerted depletion of both glutathione and coenzyme A, highlighting a novel branch of ferroptosis-relevant metabolism. Finally, we found that cystine depletion in vivo using the pre-IND agent cyst(e)inase phenocopied Slc7a11 deletion, inducing tumor-selective ferroptosis and disease stabilizations/regressions in the well-validated KPC model of PDA.\n\nOne Sentence SummaryGenetic and pharmacological targeting of cystine import induces pancreatic cancer-selective ferroptosis in vivo.

cancer biology↗

bioRxiv2019

A new formalism for perceptual classification with normative inference of internal criteria

Classification, one of the key ingredients for human cognition, entails establishing a criterion that splits a given feature space into mutually exclusive subspaces. In classification tasks performed in daily life, however, a criterion is often not provided explicitly but instead needs to be guessed from past samples of a feature space. For example, we judge todays temperature to be "cold" or "warm" by implicitly comparing it against a "typical" seasonal temperature. In such situations, establishing an optimal criterion is challenging for cognitive agents with bounded memory because it requires retrieving an entire set of past episodes with precision. As a computational account for how humans carry out this challenging operation, we developed a normative Bayesian model of classification (NBMC), in which Bayesian agents, whose working-memory precision decays as episodes elapse, continuously update their criterion as they perform a binary perceptual classification task on sequentially presented stimuli. We drew a set of specific implications regarding key properties of classification from the NBMC, and demonstrated the correspondence between the NBMC and human observers in classification behavior for each of those implications. Furthermore, in the functional magnetic resonance imaging responses acquired concurrently with behavioral data, we identified an ensemble of brain activities that coherently represent the latent variables, including the inferred criterion, of the NBMC. Given these results, we believe that the NBMC is worth being considered as a useful computational model that guides behavioral and neural studies on perceptual classification, especially for agents with bounded memory representation of past sensory events. Significant StatementAlthough classification--assigning events into mutually exclusive classes--requires a criterion, people often have to perform various classification tasks without explicit criteria. In such situations, forming a criterion based on past experience is quite challenging because peoples memory of past events deteriorates quickly over time. Here, we provided a computational model for how a memory-bounded yet normative agent infers the criterion from past episodes to maximally perform a binary perceptual classification task. This model successfully captured several key properties of human classification behavior, and the neural signals representing its latent variables were identified in the classifying human brains. By offering a rational account for memory-bonded agents classification, our model can guide future behavioral and neural studies on perceptual classification.

neuroscience↗

bioRxiv2019

Tissue of Origin Dictates GOT1 Dependence and Confers Synthetic Lethality to Radiotherapy

Metabolic programs in cancer cells are influenced by genotype and the tissue of origin. We have previously shown that central carbon metabolism is rewired in pancreatic ductal adenocarcinoma (PDA) to support proliferation through a glutamate oxaloacetate transaminase 1 (GOT1)-dependent pathway. Here we tested if tissue type impacted GOT1 dependence by comparing PDA and colorectal cancer (CRC) cell lines and tumor models of similar genotype. We found CRC to be insensitive to GOT1 inhibition, contrasting markedly with PDA, which exhibit profound growth inhibition upon GOT1 knockdown. Utilizing a combination of metabolomics strategies and computational modeling, we found that GOT1 inhibition disrupted glycolysis, nucleotide metabolism, and redox homeostasis in PDA but not CRC. These insights were leveraged in PDA, where we demonstrate that radiotherapy potently enhanced the effect of GOT1 inhibition on tumor growth. Taken together, these results illustrate the role of tissue type in dictating metabolic dependencies and provide new insights for targeting metabolism to treat PDA.

cancer biology↗

bioRxiv2019

NMDA receptor in vasopressin 1b neurons is not required for short-term social memory, object memory or aggression.

The vasopressin 1b receptor (Avpr1b) plays an important role in social behaviors including aggression, social learning and memory. Genetic removal of Avpr1b from mouse models results in deficits in aggression and short-term social recognition in adults. Avpr1b gene expression is highly enriched in the pyramidal neurons of the hippocampal cornu ammonis 2 (CA2) region. Activity of the hippocampal CA2 has been shown to be required for normal short-term social recognition and aggressive behaviors. Vasopressin acts to enhance synaptic responses of CA2 neurons through a NMDA-receptor dependent mechanism. Genetic removal of the obligatory subunit of the NMDA receptor (Grin1) within distinct hippocampal regions impairs non-social learning and memory. However, the question of a direct role for NMDA receptor activity in Avpr1b neurons to modulate social behavior remains unclear. To answer this question, we first created a novel transgenic mouse line with Cre recombinase knocked into the Avpr1b coding region to genetically target Avpr1b neurons. We confirmed this line has dense Cre expression throughout the dorsal and ventral CA2 regions of the hippocampus, along with scattered expression within the caudate-putamen and olfactory bulb. Conditional removal of the NMDA receptor was achieved by crossing our line to an available floxed Grin1 line. The resulting mice were measured on a battery of social and memory behavioral tests. Surprisingly, we did not observe any differences between Avpr1b-Grin1 knockout mice and their wildtype siblings. We conclude that mice without typical NMDA receptor function in Avpr1b neurons can develop normal aggression as well as short-term social and object memory performance.\n\nSignificance StatementActivity of neurons that express vasopressin 1b receptor are essential for aggressive and social recognition behaviors. We created a novel transgenic mouse to allow selective targeting of vasopressin 1b neurons. Our studies indicate that NMDA receptor expression in vasopressin 1b neurons (including most CA2 neurons) are not required for development of the typical expression of aggression or recognition memory. Thus, CA2 neurons may have a unique way of incorporating novel stimuli into memory that deserves further investigation.

neuroscience↗

bioRxiv2019

Meta-analysis of targeted metabolomics data from heterogeneous biological samples provides insights into metabolite dynamics

IntroductionMass spectrometry-based metabolomics coupled to liquid chromatography, or LC-MS metabolomics, has become the most popular tool for global metabolite abundance profiling to study metabolism. However, the physicochemical complexity of metabolites poses a major challenge for reliable measurements of metabolite abundance. One way to address the issue is to use multiple chromatographic methods to capture a greater range of molecular diversity. We previously developed a tandem mass spectrometry-based label-free targeted metabolomics analysis framework coupled to two distinct chromatographic methods, reversed-phase liquid chromatography (RPLC) and hydrophilic interaction liquid chromatography (HILIC), with dynamic multiple reaction monitoring (dMRM) for simultaneous detection of over 200 metabolites to study core metabolic pathways. ObjectivesWe aim to analyze a large-scale heterogeneous data compendium generated from our LC-MS/MS platform with both RPLC and HILIC methods to systematically assess measurement quality in biological replicate groups and to gain insights into metabolite dynamics across different biological conditions. MethodsOur metabolomics framework was applied in a wide range of experimental systems including cancer cell lines, tumors, extracellular media, primary cells, immune cells, organoids, organs (e.g. pancreata), tissues, and sera from human and mice. We also developed computational and statistical analysis pipelines, which include hierarchical clustering, replicate-group CV analysis, correlation analysis, and case-control paired analysis. ResultsWe generated a compendium of 42 heterogeneous deidentified datasets with 635 samples using both RPLC and HILIC methods. There exist signature metabolites that correspond to heterogeneous phenotypes, involved in several metabolic pathways. The RPLC method shows overall better reproducibility than the HILIC method for most metabolites including polar amino acids. Correlation analysis reveals high confidence metabolites irrespective of experimental systems such as methionine, phenylalanine, and taurine. We also identify homocystine, reduced glutathione, and phosphoenolpyruvic acid as highly dynamic metabolites across all case-control paired samples. ConclusionsOur study is expected to serve as a resource and a reference point for a systematic analysis of label-free LC-MS/MS targeted metabolomics data in both RPLC and HILIC methods with dMRM.

bioinformatics↗

bioRxiv2018

Macrophage Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer

Pancreatic Ductal Adenocarcinoma (PDA) is characterized by abundant infiltration of tumor associated macrophages (TAMs). TAMs have been reported to drive resistance to gemcitabine, the front-line chemotherapy in PDA, though the mechanism of this resistance remains unclear. Profiling metabolite exchange, we demonstrate macrophages programmed by PDA cells release a spectrum of pyrimidine species. These include deoxycytidine, which inhibits gemcitabine through molecular competition at the level of drug uptake and metabolism. Accordingly, genetic or pharmacological depletion of TAMs in murine models of PDA sensitizes these tumors to gemcitabine. Consistent with this, patients with low macrophage burden demonstrate superior response to gemcitabine treatment. Additionally, we report pyrimidine release is a general function of anti-inflammatory myeloid cells, suggesting an unknown physiological role of pyrimidine exchange by immune cells.

cancer biology↗

bioRxiv2018

Pasakbumin A controls the growth of Mycobacterium tuberculosis by enhancing the autophagy and production of antibacterial mediators in mouse macrophages

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb) and remains a major health problem worldwide. Thus, there is an urgent need to identify new and more effective drugs to treat emerging multidrug-resistant TB (MDR-TB) and to reduce the side effects of anti-TB drugs, such as liver toxicity and other detrimental changes. In this study, to develop a novel candidate drug for effective TB treatment with few side effects in the host, we selected pasakbumin A isolated from Eurycoma longifolia (E. longifolia) Jack, which protected host cells against Mtb infection-induced death. Pasakbumin A significantly inhibited intracellular Mtb growth by inducing autophagy via the ERK1/2-mediated signaling pathway in Mtb-infected macrophages. We further investigated whether pasakbumin A could be used as a potential adjuvant for TB treatment. Treatment with pasakbumin A and the anti-TB drug rifampicin (RMP) potently suppressed intracellular Mtb killing by promoting autophagy as well as TNF- production via the ERK1/2- and NF-{kappa}B-mediated signaling pathways in Mtb-infected cells. Our results suggest that pasakbumin A could be developed as a novel anti-TB drug or host-directed therapeutic (HDT) strategy to protect against host cell death and improve host defense mechanisms against Mtb infection in macrophages.

immunology↗

bioRxiv2018

Socioeconomic status associated with carpal tunnel syndrome: A retrospective nationwide 11-year population-based cohort study in South Korea

ImportanceThere have only been a few large-scale studies that have included a risk factor analysis for CTS. No prior study has investigated the relationship between the occurrence of CTS and stratified socioeconomic status, which is closely related to a persons type of job.\n\nObjectiveTo confirm the known risk factors for CTS and also to determine the correlation between stratified socioeconomic status and the occurrence of CTS.\n\nDesignWe conducted this study using a retrospective cohort model based on the combined databases of the Korean National Health Insurance System from 2003-2013, a database compiled using information from a national periodic health-screening program that is used for reimbursement claims.\n\nSettingThe setting was a population-based retrospective cohort study.\n\nParticipantsFirst, we randomly sampled 514,795 patients who represented 10% of the 5,147,950 people who took part in periodic health screenings from 2002-2003. Existing CTS patients were excluded from this group. Therefore, this study finally included 512,942 participants and followed their medical records from 2003-2013.\n\nMain Outcomes and MeasuresDesired outcomes were the incidence rate of CTS and the hazard ratios according to stratified socioeconomic status.\n\nResultsA correlation analysis showed that CTS was more likely to occur in patients from a lower socioeconomic status.\n\nConclusions and RelevanceCTS was associated with people of a lower socioeconomic status who work in simple but repetitive manual labor jobs. We believe that the results of our study will be helpful to determine the pathophysiology of CTS and to set up a new industrial health policy for this condition.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSWhat is the relationship between stratified socioeconomic status and the incidence of carpal tunnel syndrome (CTS)?\n\nFindingsIn this retrospective population-based cohort study that included 512,942 participants sampled from the Korean National Health Insurance System(KNHIS) database, the incidence rate and hazard ratios for CTS tended to increase with lower socioeconomic status.\n\nImplicationsLow socioeconomic status was identified as a risk factor for the incidence of CTS.

epidemiology↗

bioRxiv2018

Validation of known risk factors associated with carpal tunnel syndrome: A retrospective nationwide 11-year population-based cohort study in South Korea

Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the relationship between the previously known risk factors and occurrence of carpal tunnel syndrome (CTS)?\n\nFindingsIn this retrospective population-based cohort study that included 512,942 participants sampled from the Korean National Health Insurance System database, we determined the following known risk factors were related to the occurrence of CTS: the age of 40s, female, being overweight, diabetes, rheumatoid arthritis, gout, and Raynauds syndrome. However, ESRD, hypothyroidism and smoking were not correlated with CTS occurrence.\n\nImplicationsWe identified the age of 40s, female, overweight, diabetes, rheumatoid arthritis, gout, and Raynauds syndrome as risk factors for the occurrence of CTS.\n\nAbstractO_ST_ABSImportanceC_ST_ABSThere have been few large-scale studies that have included a risk factor analysis for CTS. No prior study has investigated and validated the relationship between the occurrence of CTS and known risk factors using nationwide health care database.\n\nObjectiveTo confirm the actual risk factors for CTS out of various known risk factors\n\nDesignWe conducted this study using a retrospective cohort model based on the combined two databases of the Korean National Health Insurance System; the national periodic health screening program database from 2002-2003 and health insurance database of reimbursement claims from 2003 through 2013.\n\nSettingA population-based retrospective cohort study.\n\nParticipantsFirst, we randomly sampled 514,795 patients who represented 10% of the 5,147,950 people who took part in periodic health screenings in 2002-2003. Existing CTS patients were excluded from this group. Therefore, this study finally included 512,942 participants and followed up their medical records from 2003-2013.\n\nMain Outcomes and MeasuresDesired outcomes were the incidence rate of CTS in patients with various risk factors and the hazard ratios of risk factors affecting the diseases occurrence.\n\nResultsThe incidence of CTS was highest in patients in the age of 40s, in the moderate obesity group, in females, and in patients with diabetes mellitus (DM). The hazard ratio analysis revealed that the following risk factors were strongly related to the occurrence of CTS: age of 40s, female, obesity, DM, rheumatoid arthritis, gout, and Raynauds syndrome. However, ESRD, hypothyroidism and smoking were not correlated with CTS occurrence.\n\nConclusions and RelevanceIn our large-scale cohort study, risk factors such as being in ones 40s, obesity, being female, suffering from DM, and rheumatoid arthritis were reaffirmed as those of CTS occurrence.

epidemiology↗

bioRxiv2018

Risk factors associated with Parkinson’s disease: An 11-year population-based South Korean study

ObjectiveTo validate various known risk factors of Parkinsonism and to establish basic information to formulate public health policy by using a 10-year follow-up cohort model.\n\nMethodsThis population based nation-wide study was performed using the National Health Insurance Database of reimbursement claims of the Health Insurance Review and Assessment Service of South Korea data on regular health check-ups in 2003 and 2004, with 10 years follow-up.\n\nResultsWe identified 7,746 patients with Parkinsonism. Old age, hypertension, diabetes, depression, anxiety, taking statin medication, high body mass index, non-smoking, non-alcohol drinking, and low socioeconomic status were each associated with an increase in the risk of Parkinsonism (fully adjusted Cox proportional hazards model: hazard ratio (HR) 1.259, 95% confidence interval (CI) 1.194-1.328 for hypertension, HR 1.255, 95% CI 1.186-1.329 for diabetes, HR 1.554, 95% CI 1.664-1.965 for depression, HR 1.808, 95% CI 1.462-1.652 for anxiety, and HR 1.157, 95% CI 1.072-1.250 for taking statin medication).\n\nConclusionsIn our study, old age, depression, anxiety, and a non-smoker status were found to be risk factors of Parkinsonism, in agreement with previous studies. However, sex, hypertension, diabetes, taking statin medication, non-drinking of Alcohol, and lower socioeconomic status have not been described as risk factors in previous studies and need further verification in future studies.

epidemiology↗