Publications by authors named "Min Jung Lee"

292 Publications

In small cell lung cancer patients treated with RRx-001, a downregulator of CD47, decreased expression of PD-L1 on circulating tumor cells significantly correlates with clinical benefit.

Transl Lung Cancer Res 2021 Jan;10(1):274-278

Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Background: Small cell lung cancer (SCLC) is the most aggressive lung tumor, characterized by a rapid doubling time and the development of widespread metastases, for which immune checkpoint inhibitors have been approved to overcome T cell anergy. In light of its dismal prognosis, and lack of curative options, new therapies for extensive-disease SCLC are desperately needed.

Methods: RRx-001 is a small molecule Myc inhibitor and down-regulates CD47 expression on tumor cells. We evaluated the programmed death-ligand 1 (PD-L1) status of circulating tumor cells (CTCs) pre and post RRx-001 treatment in a phase 2 clinical trial, called QUADRUPLE THREAT, where patients with previously treated SCLC received RRx-001 in combination with a platinum doublet. The trial was registered with ClinicalTrials.gov, number NCT02489903. Fourteen patients with SCLC were analyzed to investigate the association between clinical outcome and PD-L1 expression on CTCs pre and post RRx-001. The correlation between the binary clinical outcome (clinical benefit vs. progressive disease) and the change of PD-L1 expression on CTCs after RRx-001 was analyzed using a logistic regression adjusting for baseline PD-L1 expression.

Results: The logistic model McFadden goodness of fit score was 0.477. The logistic model analyzing the association between decreased PD-L1 expression on CTCs after RRx-001 and response to reintroduced platinum doublet had an approximate 92.8% accuracy in its prediction of clinical benefit. The estimated receiver operating characteristic (ROC) displayed a ROC area under the curve (AUC) of 0.93 (95% confidence interval, 0.78-0.99).

Conclusions: These results suggest that PD-L1 expression on CTCs decreased after RRx-001 was significantly correlated with response to reintroduced platinum-based doublet therapy. Monitoring PD-L1 expression on CTCs during RRx-001 treatment may serve as a biomarker to predict response to RRx-001-based cancer therapy.
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http://dx.doi.org/10.21037/tlcr-20-359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867783PMC
January 2021

A phase 1 study of entinostat in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1513, Pediatric Early Phase-Clinical Trial Network (PEP-CTN).

Pediatr Blood Cancer 2021 Apr 12;68(4):e28892. Epub 2021 Jan 12.

Department of Pediatrics, University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota.

Background: Entinostat is an oral small molecule inhibitor of class I histone deacetylases (HDAC), which has not previously been evaluated in pediatrics. We conducted a phase I trial to determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D), toxicity profile, pharmacokinetics (PK), and pharmacodynamics (PD) of entinostat in children with relapsed or refractory solid tumors including central nervous system (CNS) malignancies.

Methods: A rolling six dose escalation design evaluated two dose levels. Entinostat oral tablet formulation was administered once per week, four doses per 28-day cycle. PK and PD studies were performed.

Results: Twenty-one eligible patients' median (range) age was 14 years (6-20). Six subjects were treated at 3 mg/m dose level and 15 were treated in 4 mg/m dose level. The study included patients with CNS tumors (n = 12), sarcomas (n = 6), or other solid tumors (n = 3). Eight patients were not fully evaluable for toxicity due to progression of disease prior to receiving the required percentage of protocol therapy. No cycle one dose-limiting toxicity (DLT) was observed at either dose level. A three-fold higher area under the curve (AUC) was achieved in our cohort compared to adults using a similar dosing schedule. The PD studies showed increase in acetylated lysine in peripheral blood leukocytes at both doses.

Conclusions: Entinostat was well tolerated with no DLT observed. All patients experienced progression within the first two cycles, except one patient with ependymoma with stable disease. Based on PK and PD, the R2PD in pediatric patients with solid tumors is 4 mg/m orally administered once weekly.
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http://dx.doi.org/10.1002/pbc.28892DOI Listing
April 2021

A 2-year-old girl with periprocedural anaphylaxis.

Allergy Asthma Proc 2021 01;42(1):97-99

From the Division of Allergy and Immunology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas; and.

Periprocedural or perioperative anaphylaxis is rare, with an estimated incidence of 1 in 10,000 to 40,000 sedation cases. During such procedures, patients are often exposed to numerous medications, such as antimicrobials, neuromuscular blocking agents, sedative and/or hypnotics, and opioids. The most commonly implicated agents include antibiotics (in the United States) and neuromuscular blocking agents (in Europe). In this article, we explore the differential diagnosis and laboratory investigation of a case of periprocedural anaphylaxis.
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http://dx.doi.org/10.2500/aap.2021.42.200031DOI Listing
January 2021

Triglyceride Glucose-Waist Circumference Better Predicts Coronary Calcium Progression Compared with Other Indices of Insulin Resistance: A Longitudinal Observational Study.

J Clin Med 2020 Dec 29;10(1). Epub 2020 Dec 29.

Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.

The triglyceride glucose (TyG) index, a product of triglyceride and fasting glucose, is a reliable marker for insulin resistance. We aimed to investigate the association between the TyG-related markers and coronary artery calcification (CAC) progression. We enrolled 1145 asymptomatic participants who underwent repeated CAC score measurements during routine health examinations. Homeostasis model assessment of insulin resistance (HOMA-IR), TyG index, TyG-BMI (body mass index), and TyG-WC (waist circumference) were calculated. Progression of CAC was defined as (1) incident CAC in a CAC-free population, or an (2) increase of ≥2.5 units between the baseline and final square root of the CAC scores in participants with detectable CAC. According to the quartiles of parameters, we stratified the subjects into four groups. The prevalence of progression increased with the TyG-WC quartile (15.0%, 24.1%, 31.0%, and 32.2% for each of the groups; < 0.001). The multivariate-adjusted odds ratio (95% confidence interval) for CAC score progression was 1.66 (1.01-2.77) when the highest and lowest TyG-WC index quartiles were compared. Furthermore, the predictability of TyG-WC for CAC progression was better than the other indices in terms of the area under the curve. The TyG-WC index predicted CAC progression better than other indices and could be a potential marker of future coronary atherosclerosis.
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http://dx.doi.org/10.3390/jcm10010092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795085PMC
December 2020

Association Between Muscle Quality Measured by Abdominal Computed Tomography and Subclinical Coronary Atherosclerosis.

Arterioscler Thromb Vasc Biol 2020 Dec 24:ATVBAHA120315054. Epub 2020 Dec 24.

Health Screening and Promotion Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea (M.J.L., H.-K.K., E.H.K., S.J.B., J.C.).

Objective: Low muscle mass was known to be associated with cardiovascular diseases. However, only few studies investigated the association between muscle quality and subclinical coronary atherosclerosis. Thus, we evaluated whether muscle quality measured by abdominal computed tomography is associated with the risk of coronary artery calcification. Approach and Results: We conducted a cross-sectional study on 4068 subjects without cardiovascular disease who underwent abdominal and coronary computed tomography between 2012 and 2013 during health examinations. The cross-sectional area of the skeletal muscle was measured at the L3 level (total abdominal muscle area, total abdominal muscle area) and segmented into normal attenuation muscle area, low attenuation muscle area, and intramuscular adipose tissue. We calculated the normal attenuation muscle area/total abdominal muscle area index, of which a higher value reflected a higher proportion of good quality muscle (normal attenuation muscle area) and a lower proportion of myosteatosis (low attenuation muscle area and intramuscular adipose tissue). In women, as the normal attenuation muscle area/total abdominal muscle area quartiles increased, the odds ratios (95% CIs) for significant coronary artery calcification (>100) consistently decreased (0.44 [0.24-0.80], 0.39 [0.19-0.81], 0.34 [0.12-0.98]; =0.003) after adjusting for cardiovascular risk factors including visceral fat area and insulin resistance. In men, the odds ratios in the Q2 group were significantly lower than those in the Q1, but the association was attenuated in Q3-4 after adjustment.

Conclusions: A higher proportion of good quality muscle was strongly associated with a lower prevalence of significant coronary artery calcification after adjustment, especially in women. Poor skeletal muscle quality may be an important risk factor for subclinical coronary atherosclerosis.
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http://dx.doi.org/10.1161/ATVBAHA.120.315054DOI Listing
December 2020

Gintonin mitigates experimental autoimmune encephalomyelitis by stabilization of Nrf2 signaling via stimulation of lysophosphatidic acid receptors.

Brain Behav Immun 2020 Dec 10. Epub 2020 Dec 10.

Department of Convergence Medical Science, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; Institute of Convergence Korean Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address:

Gintonin (GT), a glycolipoprotein fraction isolated from ginseng, exerts neuroprotective effects in models of neurodegenerative diseases such as Alzheimer's disease. However, the in vivo role of GT in multiple sclerosis (MS) has not been clearly resolved. We investigated the effect of GT in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), an animal model of MS. GT alleviated behavioral symptoms of EAE associated with reduced demyelination, diminished infiltration and activation of immune cells (microglia and macrophage), and decreased expression of inflammatory mediators in the spinal cord of the EAE group compared to that of the sham group. GT reduced the percentages of CD4/IFN-γ (Th1) and CD4/IL-17 (Th17) cells but increased the population of CD4/CD25/Foxp3 (Treg) cells in the spinal cord, in agreement with altered mRNA expression of IFN-γ, IL-17, and TGF-ß in the spinal cord in concordance with mitigated blood-brain barrier disruption. The underlying mechanism is related to inhibition of the ERK and p38 mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) pathways and the stabilization of nuclear factor erythroid 2-related factor 2 (Nrf2) via increased expression of lysophosphatidic acid receptor (LPAR) 1-3. Impressively, these beneficial effects of GT were completely neutralized by inhibiting LPARs with Ki16425, a LPAR1/3 antagonist. Our results strongly suggest that GT may be able to alleviate EAE due to its anti-inflammatory and antioxidant activities through LPARs. Therefore, GT is a potential therapeutic option for treating autoimmune disorders including MS.
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http://dx.doi.org/10.1016/j.bbi.2020.12.004DOI Listing
December 2020

Results from a biomarker study to accompany a phase II trial of RRx-001 with reintroduced platinum-based chemotherapy in relapsed small cell carcinoma.

Expert Opin Investig Drugs 2021 Feb 11;30(2):177-183. Epub 2021 Jan 11.

Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH) , Bethesda, MD, USA.

: In a Phase II study RRx-001 was combined with Etoposide platinum (EP) in previously platinum treated SCLC. We correlated expression of the M2 marker, CD206, on HLA-DR monocytes, a phenotype that correlates with a poor prognosis, with response to RRx-001. : Patients received 4 mg RRx-001 once weekly until progression followed by the start of EP (etoposide 100 mg/m IV on days 1-3 of a 21-day cycle and either cisplatin 80 mg/m IV on day 1 or carboplatin AUC 5-6 IV on day 1). Treatment continued until progression or intolerable toxicity. Peripheral blood was collected in Cell Preparation Tubes with sodium citrate from 14 patients for exploratory studies during screening and after therapy on Days 1, 8, and 15. Peripheral blood mononuclear cells (PBMCs) were isolated from blood by centrifugation and multiparameter flow cytometric analysis was performed. : CD206 expression on HLA-DR monocytes was associated with response to chemotherapy and overall survival. : During treatment with RRx-001, reduced expression of the protumorigenic M2 marker CD206 on peripheral monocytes positively correlated with increased response and survival.
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http://dx.doi.org/10.1080/13543784.2021.1863947DOI Listing
February 2021

Mast4 knockout shows the regulation of spermatogonial stem cell self-renewal via the FGF2/ERM pathway.

Cell Death Differ 2020 Nov 20. Epub 2020 Nov 20.

Division in Anatomy and Developmental Biology, Department of Oral Biology, Taste Research Center, Oral Science Research Center, BK21 FOUR Project, Yonsei University College of Dentistry, Seoul, 03722, Korea.

Spermatogenesis is an important cellular differentiation process that produces the male gametes and remains active throughout the individual's lifespan. Sertoli cell-only syndrome (SCO) refers to the dysfunction of the male reproductive system, including infertility. Accurate self-renewal of spermatogonial stem cells (SSCs) is essential to prevent SCO syndrome. This study investigated the role of microtubule-associated serine/threonine kinase family member 4 (MAST4) in spermatogenesis in mice. MAST4 was localized in Sertoli cells before puberty, providing a somatic niche for spermatogenesis in mice and MAST4 expression shifted to Leydig cells and spermatids throughout puberty. Mast4 knockout (KO) testes were reduced in size compared to wild-type testes, and germ cell depletion associated with an increase in apoptosis and subsequent loss of tubular structure were similar to the SCO phenotype. In addition, MAST4 phosphorylated the Ets-related molecule (ERM), specifically the serine 367 residue. The phosphorylation of ERM ultimately controls the transcription of ERM target genes related to SSC self-renewal. The expression of spermatogenesis-associated proteins was significantly decreased whereas Sertoli cell markers were increased in Mast4 KO testes, which was well-founded by RNA-sequencing analysis. Therefore, MAST4 is associated with the fibroblast growth factor 2 (FGF2)/ERM pathway and this association helps us explore the capacity of SSCs to maintain a vertebrate stem cell niche.
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http://dx.doi.org/10.1038/s41418-020-00670-2DOI Listing
November 2020

Entinostat plus Pembrolizumab in Patients with Metastatic NSCLC Previously Treated with Anti-PD-(L)1 Therapy.

Clin Cancer Res 2021 Feb 17;27(4):1019-1028. Epub 2020 Nov 17.

Syndax Pharmaceuticals, Inc., Waltham, Massachusetts.

Purpose: New therapies are needed to treat immune checkpoint inhibitor-resistant non-small cell lung cancer (NSCLC) and identify biomarkers to personalize treatment. Epigenetic therapies, including histone deacetylase inhibitors, may synergize with programmed cell death-1 (PD-1) blockade to overcome resistance. We report outcomes in patients with anti-programmed cell death ligand-1 [PD-(L)1]-resistant/refractory NSCLC treated with pembrolizumab plus entinostat in ENCORE 601.

Patients And Methods: The expansion cohort of ENCORE 601 included patients with NSCLC who previously experienced disease progression with immune checkpoint inhibitors. The primary endpoint for the phase II expansion cohort is overall response rate (ORR); safety, tolerability, and exploratory endpoints are described.

Results: Of 76 treated patients, 71 were evaluable for efficacy. immune-regulated RECIST-assessed ORR was 9.2% [95% confidence interval (CI): 3.8-18.1], which did not meet the prespecified threshold for positivity. Median duration of response was 10.1 months (95% CI: 3.9-not estimable), progression-free survival (PFS) at 6 months was 22%, median PFS was 2.8 months (95% CI: 1.5-4.1), and median overall survival was 11.7 months (95% CI: 7.6-13.4). Benefit was enriched among patients with high levels of circulating classical monocytes at baseline. Baseline tumor PD-L1 expression and gene expression were not associated with benefit. Treatment-related grade ≥3 adverse events occurred in 41% of patients.

Conclusions: In anti-PD-(L)1-experienced patients with NSCLC, entinostat plus pembrolizumab did not achieve the primary response rate endpoint but provided a clinically meaningful benefit, with objective response in 9% of patients. No new toxicities, including immune-related adverse events, were seen for either drug. Future studies will continue to evaluate the association of monocyte levels and response.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887114PMC
February 2021

Korean Red Ginseng alleviates dehydroepiandrosterone-induced polycystic ovarian syndrome in rats via its antiinflammatory and antioxidant activities.

J Ginseng Res 2020 Nov 26;44(6):790-798. Epub 2019 Aug 26.

College of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea.

Background: Beneficial effects of Korean Red Ginseng (KRG) on polycystic ovarian syndrome (PCOS) remains unclear.

Methods: We examined whether pretreatment (daily from 2 hours before PCOS induction) with KRG extract in water (KRGE; 75 and 150 mg/kg/day, p.o.) could exert a favorable effect in a dehydroepiandrosterone (DHEA)-induced PCOS rat model.

Results: Pretreatment with KRGE significantly inhibited the elevation of body and ovary weights, the increase in number and size of ovarian cysts, and the elevation of serum testosterone and estradiol levels induced by DHEA. Pretreatment with KRGE also inhibited macrophage infiltration and enhanced mRNA expression levels of chemokines [interleukin (IL)-8, monocyte chemoattractant protein-1), proinflammatory cytokines (IL-1β, IL-6), and inducible nitric oxide synthase in ovaries induced by DHEA. It also prevented the reduction in mRNA expression of growth factors (epidermal growth factor, transforming growth factor-beta (EGF, TGF-β)) related to inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cell pathway and stimulation of the nuclear factor erythroid-derived 2-related factor 2 pathway. Interestingly, KRGE or representative ginsenosides (Rb1, Rg1, and Rg3(s)) inhibited the activity of inflammatory enzymes cyclooxygenase-2 and iNOS, cytosolic p-IkB, and nuclear p-nuclear factor kappa-light-chain-enhancer of activated B in lipopolysaccharide-induced RAW264.7 cells, whereas they increased nuclear factor erythroid-derived 2-related factor 2 nuclear translocation.

Conclusion: These results provide that KRGE could prevent DHEA-induced PCOS via antiinflammatory and antioxidant activities. Thus, KRGE may be used in preventive and therapeutic strategies for PCOS-like symptoms.
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http://dx.doi.org/10.1016/j.jgr.2019.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655494PMC
November 2020

Association between noninvasive assessment of liver fibrosis and coronary artery calcification progression in patients with nonalcoholic fatty liver disease.

Sci Rep 2020 10 27;10(1):18323. Epub 2020 Oct 27.

Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.

Advanced liver fibrosis and coronary artery calcification (CAC) progression has been reported to correlate with cardiovascular disease. This study investigated the association between noninvasive liver fibrosis score and CAC progression in patients with nonalcoholic fatty liver disease (NAFLD). We included 1173 asymptomatic adults with CAC scores from 2007-2013. CAC progression was defined as newly incident CAC or a ≥ 2.5-unit increase in the final CAC score square root. Liver fibrosis was assessed using fibrosis-4 index (FIB-4) score and NAFLD fibrosis score (NFS). A total of 293 (25.0%) subjects developed CAC. Mean baseline FIB-4 score was significantly higher in subjects with CAC. CAC progressed in 20.5% of subjects without NAFLD, 27.5% of those with NAFLD and low FIB-4 scores, and 35.9% of those with NAFLD and intermediate/high FIB-4 scores. On multivariate logistic regression analysis, the odds ratio for CAC progression was 1.70 (95% confidence interval, 1.12-2.58) for subjects with NAFLD plus intermediate/high FIB-4 scores versus those without NAFLD. In the sensitivity analysis, the odds ratio for CAC progression was 1.57 (95% confidence interval, 1.02-2.44) for subjects with NAFLD plus an intermediate/high NFS versus those without NAFLD. Advanced liver fibrosis stage assessed using noninvasive markers is associated with a higher risk of CAC progression in subjects with NAFLD.
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http://dx.doi.org/10.1038/s41598-020-75266-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591518PMC
October 2020

Phase 1 study of the HSP90 inhibitor onalespib in combination with AT7519, a pan-CDK inhibitor, in patients with advanced solid tumors.

Cancer Chemother Pharmacol 2020 Dec 23;86(6):815-827. Epub 2020 Oct 23.

Dana-Farber Cancer Institute, Boston, MA, USA.

Purpose: We conducted a phase 1 trial of the HSP90 inhibitor onalespib in combination with the CDK inhibitor AT7519, in patients with advanced solid tumors to determine the safety profile and maximally tolerated dose, pharmacokinetics, preliminary antitumor activity, and to assess the pharmacodynamic (PD) effects on HSP70 expression in patient-derived PBMCs and plasma.

Methods: This study followed a 3 + 3 trial design with 1 week of intravenous (IV) onalespib alone, followed by onalespib/AT7519 (IV) on days 1, 4, 8, and 11 of a 21-days cycle. PK and PD samples were collected at baseline, after onalespib alone, and following combination therapy.

Results: Twenty-eight patients were treated with the demonstration of downstream target engagement of HSP70 expression in plasma and PBMCs. The maximally tolerated dose was onalespib 80 mg/m IV + AT7519 21 mg/m IV. Most common drug-related adverse events included Grade 1/2 diarrhea (79%), fatigue (54%), mucositis (57%), nausea (46%), and vomiting (50%). Partial responses were seen in a palate adenocarcinoma and Sertoli-Leydig tumor; a colorectal and an endometrial cancer patient both remained on study for ten cycles with stable disease as the best response. There were no clinically relevant PK interactions for either drug.

Conclusions: Combined onalespib and AT7519 is tolerable, though below monotherapy RP2D. Promising preliminary clinical activity was seen. Further benefit may be seen with the incorporation of molecular signature pre-selection. Further biomarker development will require the assessment of the on-target impact on relevant client proteins in tumor tissue.
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http://dx.doi.org/10.1007/s00280-020-04176-zDOI Listing
December 2020

Antioxidant activity and calcium bioaccessibility of leaf hydrolysate, as a potential calcium supplement in food.

Food Sci Biotechnol 2020 Nov 5;29(11):1563-1571. Epub 2020 Sep 5.

Industrial Technology Research Group, Research and Development Division, World Institute of Kimchi, Nam-Gu, Gwangju, 61755 Republic of Korea.

leaf (ML) is rich in vitamins and minerals, specially abundant calcium, therefore it is widely used as a calcium supplement for food. This study aimed to investigate the antioxidant activity and calcium bioaccessibility of . leaf hydrolysate (MLH) as a calcium supplement for kimchi. MLH was prepared under three different proteases, two different protease contents, and three different incubation times. Total phenol content (TPC), total flavonoid content (TFC), and antioxidant activities were investigated. Cellular activity and calcium bioaccessibility were also investigated. The highest calcium level of MLH was observed in 3% Protamex treatment for 4 h. TPC, TFC, and antioxidant activities of MLH in Protamex and Alcalase treatments were higher than those in Flavourzyme treatment (< 0.05). Moreover, high cell viability and alkaline phosphatase activity were also observed in C2C12 cells. Kimchi containing MLH showed high calcium accessibility compared to kimchi alone. Taken together, the application of MLH could have potential as a calcium supplement for kimchi production.
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http://dx.doi.org/10.1007/s10068-020-00820-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561653PMC
November 2020

Evaluation of onion juices quality following heat-treatment and their application as a sugar substitute in Kimchi.

J Food Sci Technol 2020 Nov 21;57(11):4103-4110. Epub 2020 Apr 21.

World Institute of Kimchi, Gwangju, 61755 Republic of Korea.

This study was conducted to evaluate the quality of onion juices that had been heat-treated for different times as well as their use as a table sugar substitute in Kimchi. The onions were steamed at 100 ∘C for 30 min and boiled at 90 ∘C for 30, 60, and 120 min. The highest cycloalliin (0.76 mM), free-sugar (sucrose 1.66 g/L, glucose 8.62 g/L, and fructose 7.64 g/L), and malic acid (0.82 g/L) contents were observed in onion boiled at 90 ∘C for 120 min. The possibility of using heat-treated onion juices as an alternative to table sugar in Kimchi was evaluated by comparing the lactic acid bacteria count, pH, acidity, organic acid, and free-sugar in these juices with those in Kimchi prepared using table sugar (control). The total viable bacteria and lactic acid bacteria showed similar growth patterns as in the control. The average pH reduction and increase in titratable acidity (%) in all treated Kimchi samples during fermentation for 4 weeks were 1.18 ± 0.05 and 0.81 ± 0.06, respectively. Kimchi with onion juice heat-treated for 120 min (K120) had the most similar lactic acid and acetic acid contents to that in the control after fermentation for 4 weeks. The highest mannitol level after fermentation for 4 weeks was detected in K120, which showed better sensory qualities compared to the control.
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http://dx.doi.org/10.1007/s13197-020-04446-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520469PMC
November 2020

Cabozantinib plus docetaxel and prednisone in metastatic castration-resistant prostate cancer.

BJU Int 2020 Sep 24. Epub 2020 Sep 24.

Genitourinary Malignancies Branch, NCI, Bethesda, MD, USA.

Objective: To evaluate the safety and efficacy of cabozantinib combined with docetaxel.

Patients And Methods: This was a phase 1/2 multicentre study in patients with metastatic castration-resistant prostate cancer (mCRPC). Docetaxel (75 mg/m every 3 weeks with daily prednisone 10 mg) was combined with escalating doses of daily cabozantinib (20, 40 and 60 mg). Based on the results of the phase 1 study, the investigation was expanded into a randomized study of docetaxel with prednisone (hereafter 'docetaxel/prednisone') plus the maximum tolerated dose (MTD) of cabozantinib compared with docetaxel/prednisone alone.

Results: A total of 44 men with mCRPC were enrolled in this phase 1/2 trial. An MTD of 40 mg cabozantinib plus docetaxel/prednisone was determined. Dose-limiting toxicities were neutropenic fever and palmar-plantar erythrodysesthesia, and there was one death attributable to a thromboembolic event. In addition, grade 3 or 4 myelosuppression, hypophosphataemia and neuropathy were seen in three or more patients. In the phase 1 study, the median time to progression (TTP) and overall survival (OS) time were 13.6 and 16.3 months, respectively. In the phase 2 study, which was terminated early because of poor accrual, the median TTP and OS favoured the combination (n = 13) compared to docetaxel/prednisone alone (n = 12; 21.0 vs 6.6 months; P = 0.035 and 23.8 vs 15.6 months; P = 0.072, respectively).

Conclusion: Despite the limited number of patients in this study, preliminary data suggest that cabozantinib can be safely added to docetaxel/prednisone with possible enhanced efficacy.
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http://dx.doi.org/10.1111/bju.15227DOI Listing
September 2020

Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors.

J Clin Oncol 2020 11 11;38(31):3672-3684. Epub 2020 Sep 11.

Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, and the Comprehensive Cancer Center, Columbus, OH.

Purpose: We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignances.

Patients And Methods: Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS).

Results: Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC.

Conclusion: CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.
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http://dx.doi.org/10.1200/JCO.20.01652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605393PMC
November 2020

Effects of combining two lactic acid bacteria as a starter culture on model kimchi fermentation.

Food Res Int 2020 10 28;136:109591. Epub 2020 Jul 28.

World Institute of Kimchi, Gwangju 61755, Republic of Korea. Electronic address:

This study aimed to establish a mixed starter culture to standardize the flavor of kimchi, a traditional Korean food. Leuconostoc mesenteroides and Lactobacillus sakei were selected for the culture based on their key roles in kimchi fermentation. The effects of various starter culture mixing ratios on the overall fermentation process were investigated. Fermentation was carried out at 15 °C for 72 h. In the microbial community analysis, a similar ratio to the initial mixed inoculated ratio was observed in the microbial environments. Treatment with high-rate L. mesenteroides inoculation, exhibiting hetero-fermentative characteristics, led to the production of mannitol (1393.11 mg/100 g), acetic acid (57.70 mg/kg), and lactic acid (1141.90 mg/kg), in addition to the induction of a rapid increase in the number of viable cells, thereby reducing the pH (pH 3.9). Conversely, treatment with high-rate L. sakei inoculation, exhibiting homo-fermentative characteristics, led to the production of less mannitol and acetic acid, with more lactic acid. Principal component analysis score plots showed a distinct difference in kimchi metabolites depending on the lactic acid bacteria (LAB) starter culture. Therefore, by using mixed LAB starter strains, this study demonstrated the value of various characteristics and standardized manufacturing of kimchi. LAB types and inoculation ratios greatly affected the types and concentration of metabolites in kimchi fermentation.
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http://dx.doi.org/10.1016/j.foodres.2020.109591DOI Listing
October 2020

Clinical outcomes of prexasertib monotherapy in recurrent wild-type high-grade serous ovarian cancer involve innate and adaptive immune responses.

J Immunother Cancer 2020 07;8(2)

Women's Malignancies Branch, National Cancer Institute, Bethesda, Maryland, USA.

Background: Preclinical data suggest cell cycle checkpoint blockade may induce an immunostimulatory tumor microenvironment. However, it remains elusive whether immunomodulation occurs in the clinical setting. To test this, we used blood and fresh tissue samples collected at baseline and post therapy from a phase II trial of the cell cycle checkpoint 1 inhibitor (CHK1i) prexasertib in recurrent ovarian cancer.

Methods: Paired blood samples and fresh core biopsies, taken before treatment was started at baseline (cycle 1 day 1 (C1D1)) and post second dose on day 15 of cycle 1 (C1D15), were collected. To evaluate changes in the immune responses after treatment, multiparametric flow cytometry for DNA damage markers and immune cell subsets was performed on paired blood samples. RNA sequencing (RNAseq) of paired core biopsies was also analyzed. Archival tissue immune microenvironment was evaluated with immunohistochemistry. All correlative study statistical analyses used two-sided significance with a cut-off of p=0.05.

Results: Flow cytometric analysis showed significantly increased γ-H2AX staining after CHK1i treatment, accompanied by increased monocyte populations, suggestive of an activated innate immune response (median 31.6% vs 45.6%, p=0.005). Increased expressions of immunocompetence marker HLA-DR (Human Leukocyte Antigen DR antigen) on monocytes and of a marker of STING (stimulator of interferon genes) pathway activation, in biopsies were associated with improved progression-free survival (PFS) (9.25 vs 3.5 months, p=0.019; 9 vs 3 months, p=0.003, respectively). Computational analysis of RNAseq data indicated increased infiltration of tumor niches by naïve B-cells and resting memory T-cells, suggestive of a possibly activated adaptive immune response, and greater T-reg infiltration after treatment correlated with worse PFS (9.25 vs 3.5 months, p=0.007). An immunosuppressive adaptive immune response, perhaps compensatory, was also observed on flow cytometry, including lymphodepletion of total peripheral CD4+ and CD8+T cells after CHK1i and an increase in the proportion of T-regs among these T-cells. Additionally, there was a trend of improved PFS with greater tumor-infiltrating lymphocytes (TILs) in archival tissues (13.7 months >30% TILs vs 5.5 months ≤30% TILs, p=0.05).

Conclusion: Our study demonstrates that a favorable clinical response in high-grade serous ovarian carcinoma patients treated with CHK1i is possibly associated with enhanced innate and adaptive immunity, requiring further mechanistic studies. It is supportive of current efforts for a clinical development strategy for therapeutic combinations with immunotherapy in ovarian cancer.
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http://dx.doi.org/10.1136/jitc-2019-000516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380948PMC
July 2020

POPs Case Report: A 2-year-old girl with periprocedural anaphylaxis.

Allergy Asthma Proc 2020 Jul 23. Epub 2020 Jul 23.

Periprocedural or perioperative anaphylaxis is rare, with an estimated incidence of 1 in 10,000 to 40,000 sedation cases.During such procedures, patients are often exposed to numerous medications, such as antimicrobials, neuromuscular blockingagents, sedative and/or hypnotics, and opioids. The most commonly implicated agents include antibiotics (in the UnitedStates) and neuromuscular blocking agents (in Europe). In this article, we explore the differential diagnosis and laboratoryinvestigation of a case of periprocedural anaphylaxis.
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http://dx.doi.org/10.2500/aap.2020.41.200031DOI Listing
July 2020

Cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma: an open-label, single-centre, phase 2 trial.

Lancet Oncol 2020 08 6;21(8):1099-1109. Epub 2020 Jul 6.

Developmental Therapeutics Branch, Magnuson Clinical Center, Bethesda, MD, USA.

Background: Cabozantinib is a multikinase inhibitor of MET, VEGFR, AXL, and RET, which also has an effect on the tumour immune microenvironment by decreasing regulatory T cells and myeloid-derived suppressor cells. In this study, we examined the activity of cabozantinib in patients with metastatic platinum-refractory urothelial carcinoma.

Methods: This study was an open-label, single-arm, three-cohort phase 2 trial done at the National Cancer Institute (Bethesda, MD, USA). Eligible patients were 18 years or older, had histologically confirmed urothelial carcinoma or rare genitourinary tract histologies, Karnofsky performance scale index of 60% or higher, and documented disease progression after at least one previous line of platinum-based chemotherapy (platinum-refractory). Cohort one included patients with metastatic urothelial carcinoma with measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Two additional cohorts that enrolled in parallel (patients with bone-only urothelial carcinoma metastases and patients with rare histologies of the genitourinary tract) were exploratory. Patients received cabozantinib 60 mg orally once daily in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate by RECIST in cohort one. Response was assessed in all patients who met the eligibility criteria and who received at least 8 weeks of therapy. All patients who received at least one dose of cabozantinib were included in the safety analysis. This completed study is registered with ClinicalTrials.gov, NCT01688999.

Findings: Between Sept 28, 2012, and Oct, 20, 2015, 68 patients were enrolled on the study (49 in cohort one, six in cohort two, and 13 in cohort three). All patients received at least one dose of cabozantinib. The median follow-up was 61·2 months (IQR 53·8-70·0) for the 57 patients evaluable for response. In the 42 evaluable patients in cohort one, there was one complete response and seven partial responses (objective response rate 19%, 95% CI 9-34). The most common grade 3-4 adverse events were fatigue (six [9%] patients), hypertension (five [7%]), proteinuria (four [6%]), and hypophosphataemia (four [6%]). There were no treatment-related deaths.

Interpretation: Cabozantinib has single-agent clinical activity in patients with heavily pretreated, platinum-refractory metastatic urothelial carcinoma with measurable disease and bone metastases and is generally well tolerated. Cabozantinib has innate and adaptive immunomodulatory properties providing a rationale for combining cabozantinib with immunotherapeutic strategies.

Funding: National Cancer Institute Intramural Program and the Cancer Therapy Evaluation Program.
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http://dx.doi.org/10.1016/S1470-2045(20)30202-3DOI Listing
August 2020

A Phase II Single Arm Pilot Study of the CHK1 Inhibitor Prexasertib (LY2606368) in BRCA Wild-Type, Advanced Triple-Negative Breast Cancer.

Oncologist 2020 12 24;25(12):1013-e1824. Epub 2020 Jun 24.

Women's Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Lessons Learned: Monotherapy with prexasertib demonstrated modest activity in BRCA wild-type, recurrent triple-negative breast cancer, highlighting the unmet need for combination treatment strategies. Neutropenia, anemia, and thrombocytopenia are common with the use of prexasertib but are manageable with supportive care measures. Prophylactic use of granulocyte colony stimulating factor should be considered to avoid dose reductions or treatment delays. Pharmacodynamic studies showed prexasertib treatment induced DNA damage in peripheral immune cells.

Background: Cell cycle checkpoint kinase 1 (CHK1) is a major G2/M cell cycle regulator in tumors with p53 dysfunction, such as triple-negative breast cancer (TNBC). We hypothesized the second-generation CHK1 inhibitor, prexasertib, would yield clinical activity in sporadic TNBC.

Methods: This single arm, phase II trial evaluated prexasertib at 105 mg/m IV every 2 weeks in patients with metastatic/recurrent TNBC. The primary endpoint was overall response rate (ORR).

Results: All nine patients enrolled were germline BRCA wild-type (BRCAwt) and had at least one prior treatment. One partial response (PR) was observed (ORR of 11.1%). Four patients experienced stable disease. The median progression-free survival (PFS) was 86 days (range 17 to 159 days). Grade 3/4 treatment-related adverse events included afebrile neutropenia (n = 8; 88.9%), anemia (n = 3; 33.3%), and thrombocytopenia (n = 1; 11.1%). Pharmacodynamic studies showed prexasertib treatment induced DNA damage in peripheral immune cells and demonstrated a decrease in activated/reinvigorated CD8 T cells; however, the one patient with a PR showed evidence of T-cell recovery.

Conclusion: Prexasertib monotherapy had modest clinical efficacy in BRCAwt TNBC. Further studies of prexasertib in combination with other agents are needed.
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http://dx.doi.org/10.1634/theoncologist.2020-0491DOI Listing
December 2020

Reference Data and T-Scores of Lumbar Skeletal Muscle Area and Its Skeletal Muscle Indices Measured by CT Scan in a Healthy Korean Population.

J Gerontol A Biol Sci Med Sci 2021 Jan;76(2):265-271

Health Screening and Promotion Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Background: Although computed tomography (CT) is considered the gold standard for investigating skeletal muscles, diagnostic cutoff points for sarcopenia have not been established. We therefore suggested clinically relevant diagnostic cutoff points for sarcopenia based on reference values of skeletal muscle area (SMA) measured by CT scan in a large-sized healthy Asian population.

Methods: This cross-sectional analysis included 11,845 subjects (7,314 men, 4,531 women) who underwent abdominal CT scans in South Korea. SMA including all muscles on the selected axial images of the L3 lumbar vertebrae level was demarcated using predetermined thresholds (-29 to +150 Hounsfield units). SMA indices (height-, weight-, and body mass index [BMI]-adjusted) were calculated.

Results: When T-score < -2.0 was used as the cutoff for defining sarcopenia, the sex-specific cutoff points of SMA, SMA/height2, SMA/weight, and SMA/BMI were 119.3 and 74.2 cm2, 39.8 and 28.4 cm2/m2, 1.65 and 1.38 cm2/kg, and 4.97 and 3.46 in men and women, respectively. In both sexes, the SMA/BMI values peaked in the 20s and decreased gradually. The SMA/BMI yielded the highest diagnostic rate of sarcopenia (4.2% in men, 8.7% in women), while SMA/height2 provided the lowest yield (2.8% in men, 1.0% in women).

Conclusions: This is the first study to report the reference values of SMA and skeletal muscle indices (SMIs) measured on CT scans and to suggest cutoff points for diagnosis of sarcopenia based on T-score in Asian subjects. BMI-adjusted index (SMA/BMI) was the best index of CT-measured SMA to reflect the age-related muscle changes and to maximize the diagnostic yield for sarcopenia.
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http://dx.doi.org/10.1093/gerona/glaa065DOI Listing
January 2021

Dynamic Imaging of LDH Inhibition in Tumors Reveals Rapid In Vivo Metabolic Rewiring and Vulnerability to Combination Therapy.

Cell Rep 2020 02;30(6):1798-1810.e4

Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address:

The reliance of many cancers on aerobic glycolysis has stimulated efforts to develop lactate dehydrogenase (LDH) inhibitors. However, despite significant efforts, LDH inhibitors (LDHi) with sufficient specificity and in vivo activity to determine whether LDH is a feasible drug target are lacking. We describe an LDHi with potent, on-target, in vivo activity. Using hyperpolarized magnetic resonance spectroscopic imaging (HP-MRSI), we demonstrate in vivo LDH inhibition in two glycolytic cancer models, MIA PaCa-2 and HT29, and we correlate depth and duration of LDH inhibition with direct anti-tumor activity. HP-MRSI also reveals a metabolic rewiring that occurs in vivo within 30 min of LDH inhibition, wherein pyruvate in a tumor is redirected toward mitochondrial metabolism. Using HP-MRSI, we show that inhibition of mitochondrial complex 1 rapidly redirects tumor pyruvate toward lactate. Inhibition of both mitochondrial complex 1 and LDH suppresses metabolic plasticity, causing metabolic quiescence in vitro and tumor growth inhibition in vivo.
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http://dx.doi.org/10.1016/j.celrep.2020.01.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039685PMC
February 2020

Imbalance of Gut , , and Determines the Natural Course of Atopic Dermatitis in Infant.

Allergy Asthma Immunol Res 2020 03;12(2):322-337

Department of Pediatrics, Childhood Asthma Atopy Center, Environmental Health Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: The roles of gut microbiota on the natural course of atopic dermatitis (AD) are not yet fully understood. We investigated whether the composition and function of gut microbiota and short-chain fatty acids (SCFAs) at 6 months of age could affect the natural course of AD up to 24 months in early childhood.

Methods: Fecal samples from 132 infants were analyzed using pyrosequencing, including 84 healthy controls, 22 transient AD and 26 persistent AD subjects from the Cohort for Childhood Origin of Asthma and Allergic Diseases (COCOA) birth cohort. The functional profile of the gut microbiome was analyzed by whole-metagenome sequencing. SCFAs were measured using gas chromatography-mass spectrometry.

Results: Low levels of and high amounts of were evident in transient AD cases, and low , and high were found in children with persistent AD. The relative abundance of positively correlated with scoring of AD (SCORAD) score, whereas that of negatively correlated with SCORAD score. The persistent AD group showed decreased gut microbial functional genes related to oxidative phosphorylation compared with healthy controls. Butyrate and valerate levels were lower in transient AD infants compared with healthy and persistent AD infants.

Conclusions: Compositions, functions and metabolites of the early gut microbiome are related to natural courses of AD in infants.
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http://dx.doi.org/10.4168/aair.2020.12.2.322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997289PMC
March 2020

Identification of ALDH6A1 as a Potential Molecular Signature in Hepatocellular Carcinoma via Quantitative Profiling of the Mitochondrial Proteome.

J Proteome Res 2020 04 10;19(4):1684-1695. Epub 2020 Mar 10.

Yonsei Proteome Research Center, Yonsei University, Seoul 03722, Republic of Korea.

Various liver diseases, including hepatocellular carcinoma (HCC), have been linked to mitochondrial dysfunction, reduction of reactive oxygen species (ROS), and elevation of nitric oxide (NO). In this study, we subjected the human liver mitochondrial proteome to extensive quantitative proteomic profiling analysis and molecular characterization to identify potential signatures indicative of cancer cell growth and progression. Sequential proteomic analysis identified 2452 mitochondrial proteins, of which 1464 and 2010 were classified as nontumor and tumor (HCC) mitochondrial proteins, respectively, with 1022 overlaps. Further metabolic mapping of the HCC mitochondrial proteins narrowed our biological characterization to four proteins, namely, ALDH4A1, LRPPRC, ATP5C1, and ALDH6A1. The latter protein, a mitochondrial methylmalonate semialdehyde dehydrogenase (ALDH6A1), was most strongly suppressed in HCC tumor regions (∼10-fold decrease) in contrast to LRPPRC (∼6-fold increase) and was predicted to be present in plasma. Accordingly, we selected ALDH6A1 for functional analysis and engineered Hep3B cells to overexpress this protein, called ALDH6A1-O/E cells. Since ALDH6A1 is predicted to be involved in mitochondrial respiration, we assessed changes in the levels of NO and ROS in the overexpressed cell lines. Surprisingly, in ALDH6A1-O/E cells, NO was decreased nearly 50% but ROS was increased at a similar level, while the former was restored by treatment with -nitroso--acetyl-penicillamine. The lactate levels were also decreased relative to control cells. Propidium iodide and Rhodamine-123 staining suggested that the decrease in NO and increase in ROS in ALDH6A1-O/E cells could be caused by depolarization of the mitochondrial membrane potential (ΔΨ). Taken together, our results suggest that hepatic neoplastic transformation appears to suppress the expression of ALDH6A1, which is accompanied by a respective increase and decrease in NO and ROS in cancer cells. Given the close link between ALDH6A1 suppression and abnormal cancer cell growth, this protein may serve as a potential molecular signature or biomarker of hepatocarcinogenesis and treatment responses.
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http://dx.doi.org/10.1021/acs.jproteome.9b00846DOI Listing
April 2020

Decitabine and Vorinostat with Chemotherapy in Relapsed Pediatric Acute Lymphoblastic Leukemia: A TACL Pilot Study.

Clin Cancer Res 2020 05 22;26(10):2297-2307. Epub 2020 Jan 22.

Division of Pediatric Oncology, Johns Hopkins University, Baltimore, Maryland.

Purpose: Treatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of drug resistance is a potential solution.

Patients And Methods: We report results investigating the epigenetic modulators decitabine and vorinostat with vincristine, dexamethasone, mitoxantrone, and PEG-asparaginase for pediatric patients with relapsed or refractory B-cell ALL (B-ALL). Twenty-three patients, median age 12 years (range, 1-21) were treated in this trial.

Results: The most common grade 3-4 toxicities included hypokalemia (65%), anemia (78%), febrile neutropenia (57%), hypophosphatemia (43%), leukopenia (61%), hyperbilirubinemia (39%), thrombocytopenia (87%), neutropenia (91%), and hypocalcemia (39%). Three subjects experienced dose-limiting toxicities, which included cholestasis, steatosis, and hyperbilirubinemia ( = 1); seizure, somnolence, and delirium ( = 1); and pneumonitis, hypoxia, and hyperbilirubinemia ( = 1). Infectious complications were common with 17 of 23 (74%) subjects experiencing grade ≥3 infections including invasive fungal infections in 35% (8/23). Nine subjects (39%) achieved a complete response (CR + CR without platelet recovery + CR without neutrophil recovery) and five had stable disease (22%). Nine (39%) subjects were not evaluable for response, primarily due to treatment-related toxicities. Correlative pharmacodynamics demonstrated potent modulation of epigenetic marks, and modulation of biologic pathways associated with functional antileukemic effects.

Conclusions: Despite encouraging response rates and pharmacodynamics, the combination of decitabine and vorinostat on this intensive chemotherapy backbone was determined not feasible in B-ALL due to the high incidence of significant infectious toxicities. This study is registered at http://www.clinicaltrials.gov as NCT01483690.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477726PMC
May 2020

Developing a preoperative serum metabolome-based recurrence-predicting nomogram for patients with resected pancreatic ductal adenocarcinoma.

Sci Rep 2019 12 9;9(1):18634. Epub 2019 Dec 9.

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.

We investigated the potential application of preoperative serum metabolomes in predicting recurrence in patients with resected pancreatic cancer. From November 2012 to June 2014, patients who underwent potentially curative pancreatectomy for pancreatic ductal adenocarcinoma were examined. Among 57 patients, 32 were men; 42 had pancreatic head cancers. The 57 patients could be clearly categorized into two main clusters using 178 preoperative serum metabolomes. Patients within cluster 2 showed earlier tumor recurrence, compared with those within cluster 1 (p = 0.034). A nomogram was developed for predicting the probability of early disease-free survival in patients with resected pancreatic cancer. Preoperative cancer antigen (CA) 19-9 levels and serum metabolomes PC.aa.C38_4, PC.ae.C42_5, and PC.ae.C38_6 were the most powerful preoperative clinical variables with which to predict 6-month and 1-year cancer recurrence-free survival after radical pancreatectomy, with a Harrell's concordance index of 0.823 (95% CI: 0.750-0.891) and integrated area under the curve of 0.816 (95% CI: 0.736-0.893). Patients with resected pancreatic cancer could be categorized according to their different metabolomes to predict early cancer recurrence. Preoperative detectable parameters, serum CA 19-9, PC.aa.C38_4, PC.ae.C42_5, and PC.ae.C38_6 were the most powerful predictors of early recurrence of pancreatic cancer.
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http://dx.doi.org/10.1038/s41598-019-55016-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901525PMC
December 2019

Phase I/II Study of the Mesothelin-targeted Immunotoxin LMB-100 with Nab-Paclitaxel for Patients with Advanced Pancreatic Adenocarcinoma.

Clin Cancer Res 2020 02 2;26(4):828-836. Epub 2019 Dec 2.

Laboratory of Molecular Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.

Purpose: LMB-100 is a recombinant immunotoxin (iTox) consisting of a mesothelin-binding Fab for targeting and a modified exotoxin A payload. Preclinical studies showed that combining taxanes with iTox results in synergistic antitumor activity. The objectives of this phase I/II study were to determine the MTD of LMB-100 when administered with nanoalbumin bound (nab)-paclitaxel to patients with previously treated advanced pancreatic adenocarcinoma and to assess the objective response rate.

Patients And Methods: Patients ( = 20) received fixed-dose nab-paclitaxel (125 mg/m on days 1 and 8) with LMB-100 (65 or 100 μg/kg on days 1, 3, and 5) in 21-day cycles for 1-3 cycles.

Results: Fourteen patients were treated on the dose escalation and an additional six in the phase II expansion. MTD of 65 μg/kg was established for the combination. Dose-limiting toxicity resulting from capillary leak syndrome (CLS) was seen in two of five patients treated at 100 μg/kg and one of six evaluable phase I patients receiving the MTD. Severity of CLS was associated with increases in apoptotic circulating endothelial cells. LMB-100 exposure was unaffected by anti-LMB-100 antibody formation in five of 13 patients during cycle 2. Seven of 17 evaluable patients experienced >50% decrease in CA 19-9, including three with previous exposure to nab-paclitaxel. One patient developed an objective partial response. Patients with biomarker responses had higher tumor mesothelin expression.

Conclusions: Although clinical activity was observed, the combination was not well tolerated and alternative drug combinations with LMB-100 will be pursued.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2586DOI Listing
February 2020

Determining the clinical significance of co-colonization of vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus in the intestinal tracts of patients in intensive care units: a case-control study.

Ann Clin Microbiol Antimicrob 2019 Oct 10;18(1):28. Epub 2019 Oct 10.

Division of Infectious Diseases, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Inchon-ro 73, Seongbuk-gu, Seoul, 02841, Republic of Korea.

Background: The emergence of vancomycin-resistant Staphylococcus aureus (VRSA) has become a global concern for public health. The proximity of vancomycin-resistant enterococcus (VRE) and methicillin-resistant S. aureus (MRSA) is considered to be one of the foremost risk factors for the development of VRSA. This study aimed to determine the incidence, risk factors, and clinical outcomes of intestinal co-colonization with VRE and MRSA.

Methods: A case-control study was conducted in 52-bed intensive care units (ICUs) of a university-affiliated hospital from September 2012 to October 2017. Active surveillance using rectal cultures for VRE were conducted at ICU admission and on a weekly basis. Weekly surveillance cultures for detection of rectal MRSA were also conducted in patients with VRE carriage. Patients with intestinal co-colonization of VRE and MRSA were compared with randomly selected control patients with VRE colonization alone (1:1). Vancomycin minimum inhibitory concentrations (MICs) for MRSA isolates were determined by the Etest.

Results: Of the 4679 consecutive patients, 195 cases and 924 controls were detected. The median monthly incidence and duration of intestinal co-colonization with VRE and MRSA were 2.3/1000 patient-days and 7 days, respectively. The frequency of both MRSA infections and mortality attributable to MRSA were higher in the case group than in the control group: 56.9% vs. 44.1% (P = 0.011) and 8.2% vs. 1.0% (P = 0.002), respectively. Independent risk factors for intestinal co-colonization were enteral tube feeding (odds ratio [OR], 2.09; 95% confidence interval [CI] 1.32-3.32), metabolic diseases (OR, 1.75; 95% CI 1.05-2.93), male gender (OR, 1.62; 95% CI 1.06-2.50), and Charlson comorbidity index < 3 (OR, 3.61; 95% CI 1.88-6.94). All MRSA isolates from case patients were susceptible to vancomycin (MIC ≤ 2 mg/L).

Conclusions: Our study indicates that intestinal co-colonization of VRE and MRSA occurs commonly among patients in the ICU with MRSA endemicity, which might be associated with poor clinical outcomes.
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http://dx.doi.org/10.1186/s12941-019-0327-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785887PMC
October 2019