How cancer cells remodel lipid metabolism: strategies targeting transcription factors

Reprogramming of lipid metabolism has received increasing recognition as a hallmark of cancer cells because lipid dysregulation and the alteration of related enzyme profiles are closely correlated with oncogenic signals and malignant phenotypes, such as metastasis and therapeutic resistance. In this review, we describe recent findings that support the importance of lipids, as well as the transcription factors involved in cancer lipid metabolism. With recent advances in transcription factor analysis, including computer-modeling techniques, transcription factors are emerging as central players in cancer biology. Considering the limited number and the crucial role of transcription factors associated with lipid rewiring in cancers, transcription factor targeting is a promising potential strategy for cancer therapy.This work was supported by National Research Foundation of Korea (No.2019R1A2C2083886, 2018R1A5A2025964)

Simultaneous electrochemical detection of both PSMA (+) and PSMA (-) prostate cancer cells using an RNA/peptide dual-aptamer probe

Using an RNA/peptide dual-aptamer probe, both PSMA (+) and PSMA (-) prostate cancer cells were simultaneously detected by electrochemical impedance spectroscopy. This approach can be applied as a general tool for early diagnosis of prostate cancer.CATALONA WJ, 1993, JAMA-J AM MED ASSOC, V270, P948Lupold SE, 2002, CANCER RES, V62, P4029Kue PF, 2002, INT J CANCER, V102, P572, DOI 10.1002/ijc.10734Drummond TG, 2003, NAT BIOTECHNOL, V21, P1192, DOI 10.1038/nbt873DARAIN F, 2004, BIOSENS BIOELECTRON, V20, P856Ban CG, 2004, NUCLEIC ACIDS RES, V32, DOI 10.1093/nar/gnh109Ghosh A, 2004, J CELL BIOCHEM, V91, P528, DOI 10.1002/jcb.10661LEVIN MA, 2005, J UROLOGY, V159, P475Rodriguez MC, 2005, CHEM COMMUN, P4267, DOI 10.1039/b506571bZitzmann S, 2005, CLIN CANCER RES, V11, P139Horninger W, 2001, CANCER-AM CANCER SOC, V91, P1667Lang SH, 2001, BRIT J CANCER, V85, P590Yamamoto T, 2001, UROLOGY, V58, P994Palecek E, 2002, CRIT REV ANAL CHEM, V32, P261Narain V, 2002, CANCER METAST REV, V21, P17Edwards S, 2005, BRIT J CANCER, V92, P376, DOI 10.1038/sj.bjc.6602261Postma R, 2005, EUR J CANCER, V41, P825, DOI 10.1016/j.ejca.2004.12.029Cahova-Kucharikova K, 2005, ANAL CHEM, V77, P2920Rahman MA, 2005, ANAL CHEM, V77, P4854, DOI 10.1021/ac050558vCho M, 2006, NUCLEIC ACIDS RES, V34, DOI 10.1093/nar/gkl364Farokhzad OC, 2006, P NATL ACAD SCI USA, V103, P6315, DOI 10.1073/pnas.0601755103Chu TC, 2006, CANCER RES, V66, P5989, DOI 10.1158/0008-5472.CAN-05-4583McNamara JO, 2006, NAT BIOTECHNOL, V24, P1005, DOI 10.1038/nbt1223Palecek E, 1998, BIOSENS BIOELECTRON, V13, P621Min K, 2008, BIOSENS BIOELECTRON, V23, P1819, DOI 10.1016/j.bios.2008.02.021CHO M, 2008, BMB REPORTS, V41, P119Kim D, 2007, J AM CHEM SOC, V129, P7661, DOI 10.1021/ja071471pMaalouf R, 2007, ANAL CHEM, V79, P4879, DOI 10.1021/ac070085nKRAHN MD, 1994, JAMA-J AM MED ASSOC, V272, P773

A Case of Disseminated and Fulminant Plasmacytomas That Developed during Bortezomib Treatment

Multiple myeloma is an incurable and slow growing plasma cell neoplasm. The introduction of new drugs has increased the number of treatment options. Bortezomib, the first-in-class proteasome inhibitor, has been shown to have a significant antitumor activity in the treatment of relapse/refractory patients with multiple myeloma. Additionally, plasmacytomas have shown significant response to bortezomib. In this case report, we describe a patient who developed disseminated and fulminant extramedullary plasmacytomas during combination chemotherapy treatment with bortezomib within a short period, after having shown clinical improvement

Kdm3b haploinsufficiency impairs the consolidation of cerebellum-dependent motor memory in mice

Histone modifications are a key mechanism underlying the epigenetic regulation of gene expression, which is critically involved in the consolidation of multiple forms of memory. However, the roles of histone modifications in cerebellum-dependent motor learning and memory are not well understood. To test whether changes in histone methylation are involved in cerebellar learning, we used heterozygous Kdm3b knockout (Kdm3b+/−) mice, which show reduced lysine 9 on histone 3 (H3K9) demethylase activity. H3K9 di-methylation is significantly increased selectively in the granule cell layer of the cerebellum of Kdm3b+/− mice. In the cerebellum-dependent optokinetic response (OKR) learning, Kdm3b+/− mice show deficits in memory consolidation, whereas they are normal in basal oculomotor performance and OKR acquisition. In addition, RNA-seq analyses revealed that the expression levels of several plasticity-related genes were altered in the mutant cerebellum. Our study suggests that active regulation of histone methylation is critical for the consolidation of cerebellar motor memory.This work was supported by grants to S.B.S. and Y.-S.L. (NRF2019R1A4A2001609), Y.-S.L. (NRF-2017M3C7A1026959), and S.J.K. (NRF2018R1A5A2025964) from the National Research Foundation of Korea

Urine myo-inositol as a novel prognostic biomarker for diabetic kidney disease: a targeted metabolomics study using nuclear magnetic resonance

Background As a leading cause of chronic kidney disease, clinical demand for noninvasive biomarkers of diabetic kidney disease (DKD) beyond proteinuria is increasing. Metabolomics is a popular method to identify mechanisms and biomarkers. We investigated urinary targeted metabolomics in DKD patients. Methods We conducted a targeted metabolomics study of 26 urinary metabolites in consecutive patients with DKD stage 1 to 5 (n = 208) and healthy controls (n = 26). The relationships between estimated glomerular filtration rate (eGFR) or urine protein-creatinine ratio (UPCR) and metabolites were evaluated. Multivariate Cox analysis was used to estimate relationships between urinary metabolites and the target outcome, end-stage renal disease (ESRD). C statistics and time-dependent receiver operating characteristics (ROC) were used to assess diagnostic validity. Results During a median 4.5 years of follow-up, 103 patients (44.0%) progressed to ESRD and 65 (27.8%) died. The median fold changes of nine metabolites belonged to monosaccharide and tricarboxylic acid (TCA) cycle metabolites tended to increase with DKD stage. Myo-inositol, choline, and citrates were correlated with eGFR and choline, while mannose and myo-inositol were correlated with UPCR. Elevated urinary monosaccharide and TCA cycle metabolites showed associations with increased morality and ESRD progression. The predictive power of ESRD progression was high, in the order of choline, myo-inositol, and citrate. Although urinary metabolites alone were less predictive than serum creatinine or UPCR, myo-inositol had additive effect with serum creatinine and UPCR. In time-dependent ROC, myo-inositol was more predictive than UPCR of 1-year ESRD progression prediction. Conclusion Myo-inositol can be used as an additive biomarker of ESRD progression in DKD

Efficacy and Tolerability of Peginterferon Alpha Plus Ribavirin in the Routine Daily Treatment of Chronic Hepatitis C Patients in Korea: A Multi-Center, Retrospective Observational Study

Background/Aims: We aimed to evaluate the efficacy and safety of peginterferon plus ribavirin for chronic hepatitis C (CHC) patients under real life setting in Korea. Methods: We retrospectively analyzed the medical records of 758 CHC patients treated with peginterferon plus ribavirin between 2000 and 2008 from 14 university hospitals in the Gyeonggi-Incheon area in Korea. Results: Hepatitis C virus (HCV) genotype 1 was detected in 61.2% of patients, while genotype 2 was detected in 35.5%. Baseline HCV RNA level was >= 6x10(5) IU/mL in 51.6% of patients. The sustained virological response (SVR) rate was 59.6% regardless of genotype; 53.6% in genotype 1 and 71.4% in genotype 2/3. On multivariate analysis, male gender (p=0.011), early virological response (p<0.001), genotype 2/3 (p<0.001), HCV RNA <6x10(5) IU/mL (p=0.005) and adherence to the drug >80% of the planned dose (p<0.001) were associated with SVR. The rate of premature discontinuation was 35.7%. The main reason for withdrawal was intolerance to the drug due to common adverse events or cytopenia (48.2%). Conclusions: Our data suggest that the efficacy of peginterferon and ribavirin therapy in Koreans is better in Koreans than in Caucasians for the treatment of CHC, corroborating previous studies that have shown the superior therapeutic efficacy of this regimen in Asians.This study was supported by the Korean Association for the Study of the Liver in 2009

YH29407 with anti-PD-1 ameliorates anti-tumor effects via increased T cell functionality and antigen presenting machinery in the tumor microenvironment

Among cancer cells, indoleamine 2, 3-dioxygenase1 (IDO1) activity has been implicated in improving the proliferation and growth of cancer cells and suppressing immune cell activity. IDO1 is also responsible for the catabolism of tryptophan to kynurenine. Depletion of tryptophan and an increase in kynurenine exert important immunosuppressive functions by activating regulatory T cells and suppressing CD8+ T and natural killer (NK) cells. In this study, we compared the anti-tumor effects of YH29407, the best-in-class IDO1 inhibitor with improved pharmacodynamics and pharmacokinetics, with first and second-generation IDO1 inhibitors (epacadostat and BMS-986205, respectively). YH29407 treatment alone and anti-PD-1 (aPD-1) combination treatment induced significant tumor suppression compared with competing drugs. In particular, combination treatment showed the best anti-tumor effects, with most tumors reduced and complete responses. Our observations suggest that improved anti-tumor effects were caused by an increase in T cell infiltration and activity after YH29407 treatment. Notably, an immune depletion assay confirmed that YH29407 is closely related to CD8+ T cells. RNA-seq results showed that treatment with YH29407 increased the expression of genes involved in T cell function and antigen presentation in tumors expressing ZAP70, LCK, NFATC2, B2M, and MYD88 genes. Our results suggest that an IDO1 inhibitor, YH29407, has enhanced PK/PD compared to previous IDO1 inhibitors by causing a change in the population of CD8+ T cells including infiltrating T cells into the tumor. Ultimately, YH29407 overcame the limitations of the competing drugs and displayed potential as an immunotherapy strategy in combination with aPD-1

Hypothetical role of hypoxia-inducible factor-1 in adaptations to microgravity Papel hipotético del factor 1 inducible por hipoxia en las adaptaciones a la microgravedad

© 2019, Editorial Ciencias Medicas. All rights reserved.Maintaining health in microgravity and overcoming environmental hazards such as cosmic radiation are essential for long-term space flight. Recent studies have focused on the involvement of hypoxia-inducible factor (HIF)-1 in altered gravity using cell-based or in vivo mouse model systems. HIF-1alpha and its target downstream gene expression are differentially expressed in hypergravity and microgravity. Nevertheless, underlying molecular mechanism of HIF-1alpha involvement is still unclear. Herein, we analyzed the 2019 Science paper by Garrett-Bakelman and coauthors in which NASA performed multidimensional analyses of long-term human spaceflight in identical twin astronauts. Correlations were found between the expression of HIF-1alpha related cytokines and prolonged space flight. We hypothesize that HIF-1alpha is a molecular target for the development of therapeutics to prevent the detrimental effects of microgravity and cosmic radiation on astronauts during long-term space flight.N