Side Chain Investigation of Imidazopyridazine as a Hinge Binder for Targeting Actionable Mutations of RET Kinase.

Actionable mutations of RET kinase have been identified as oncogenic drivers of solid tumors, including thyroid cancer, metastatic colorectal cancer, and nonsmall cell lung cancer. Although multikinase inhibitors and RET selective inhibitors are used to treat patients with RET alterations, there is insufficient research addressing certain issues: which actionable mutations arise from these therapies, how to improve the clinical response rate to RET inhibitors, and how to design new inhibitors to overcome drug resistance. Therefore, the development of sophisticated tool compounds is required to investigate the molecular mechanisms of actionable mutations and to develop breakthrough therapeutics for different RET alterations. Herein, we present our investigation into the side chains of imidazopyridazine hinge binders that are capable of inducing protein-ligand interaction patterns from the gatekeeper to the waterfront regions. Extending the substituents at the second and sixth positions enhanced the IC50 up to < 0.5 nM for diverse RET alterations.

A Novel Source/Drain Extension Scheme with Laser-Spike Annealing for Nanosheet Field-Effect Transistors in 3D ICs.

This study proposed a novel source/drain (S/D) extension scheme to increase the stress in nanosheet (NS) field-effect transistors (NSFETs) and investigated the scheme by using technology-computer-aided-design simulations. In three-dimensional integrated circuits, transistors in the bottom tier were exposed to subsequent processes; therefore, selective annealing, such as laser-spike annealing (LSA), should be applied. However, the application of the LSA process to NSFETs significantly decreased the on-state current (Ion) owing to diffusionless S/D dopants. Furthermore, the barrier height below the inner spacer was not lowered even under on-state bias conditions because ultra-shallow junctions between the NS and S/D were formed far from the gate metal. However, the proposed S/D extension scheme overcame these Ion reduction issues by adding an NS-channel-etching process before S/D formation. A larger S/D volume induced a larger stress in the NS channels; thus, the stress was boosted by over 25%. Additionally, an increase in carrier concentrations in the NS channels improved Ion. Therefore, Ion increased by approximately 21.7% (37.4%) in NFETs (PFETs) compared with NSFETs without the proposed scheme. Additionally, the RC delay was improved by 2.03% (9.27%) in NFETs (PFETs) compared with NSFETs using rapid thermal annealing. Therefore, the S/D extension scheme overcame the Ion reduction issues encountered in LSA and significantly enhanced the AC/DC performance.

H2 Plasma and PMA Effects on PEALD-Al2O3 Films with Different O2 Plasma Exposure Times for CIS Passivation Layers.

In this study, the electrical properties of Al2O3 film were analyzed and optimized to improve the properties of the passivation layer of CMOS image sensors (CISs). During Al2O3 deposition processing, the O2 plasma exposure time was adjusted, and H2 plasma treatment as well as post-metallization annealing (PMA) were performed as posttreatments. The flat-band voltage (Vfb) was significantly shifted (ΔVfb = 2.54 V) in the case of the Al2O3 film with a shorter O2 plasma exposure time; however, with a longer O2 plasma exposure time, Vfb was slightly shifted (ΔVfb = 0.61 V) owing to the reduction in the carbon impurity content. Additionally, the as-deposited Al2O3 sample with a shorter O2 plasma exposure time had a larger number of interface traps (interface trap density, Dit = 8.98 × 1013 eV-1·cm-2). However, Dit was reduced to 1.12 × 1012 eV-1·cm-2 by increasing the O2 plasma exposure time and further reduced after PMA. Consequently, we fabricated an Al2O3 film suitable for application as a CIS passivation layer with a reduced number of interface traps. However, the Al2O3 film with increased O2 plasma exposure time deteriorated owing to plasma damage after H2 plasma treatment, which is a method of reducing carbon impurity content. This deterioration was validated using the C-V hump and breakdown characteristics.

Pan-Src kinase inhibitor treatment attenuates diabetic kidney injury via inhibition of Fyn kinase-mediated endoplasmic reticulum stress.

Src family kinases (SFKs) have been implicated in the pathogenesis of kidney fibrosis. However, the specific mechanism by which SFKs contribute to the progression of diabetic kidney disease (DKD) remains unclear. Our preliminary transcriptome analysis suggested that SFK expression was increased in diabetic kidneys and that the expression of Fyn (a member of the SFKs), along with genes related to unfolded protein responses from the endoplasmic reticulum (ER) stress signaling pathway, was upregulated in the tubules of human diabetic kidneys. Thus, we examined whether SFK-induced ER stress is associated with DKD progression. Mouse proximal tubular (mProx24) cells were transfected with Fyn or Lyn siRNA and exposed to high glucose and palmitate (HG-Pal). Streptozotocin-induced diabetic rats were treated with KF-1607, a novel pan-Src kinase inhibitor (SKI) with low toxicity. The effect of KF-1607 was compared to that of losartan, a standard treatment for patients with DKD. Among the SFK family members, the Fyn and Lyn kinases were upregulated under diabetic stress. HG-Pal induced p70S6 kinase and JNK/CHOP signaling and promoted tubular injury. Fyn knockdown but not Lyn knockdown inhibited this detrimental signaling pathway. In addition, diabetic rats treated with KF-1607 showed improved kidney function and decreased ER stress, inflammation, and fibrosis compared with those treated with losartan. Collectively, these findings indicate that Fyn kinase is a specific member of the SFKs implicated in ER stress activation leading to proximal tubular injury in the diabetic milieu and that pan-SKI treatment attenuates kidney injury in diabetic rats. These data highlight Fyn kinase as a viable target for the development of therapeutic agents for DKD.

Characterization of HLA-A*33:03 epitopes via immunoprecipitation and LC-MS/MS.

Human leukocyte antigen (HLA) class I has more than 18,000 alleles, each of which binds to a set of unique peptides from the cellular degradome. Deciphering the interaction between antigenic peptides and HLA proteins is crucial for understanding immune responses in autoimmune diseases and cancer. In this study, we aimed to characterize the peptidome that binds to HLA-A*33:03, which is one of the most prevalent HLA-A alleles in the Northeast Asian population, but poorly studied. For this purpose, we analyzed the HLA-A*33:03 monoallelic B cell line using immunoprecipitation of HLA-A and peptide complexes, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In this study, we identified 5731 unique peptides that were associated with HLA A*33:03, and experimentally validated the affinity of 40 peptides for HLA-A*33:03 and their stability in HLA A*33:03-peptides complexes. To our knowledge, this study represents the largest dataset of peptides associated with HLA-A*33:03. Also, this is the first study in which HLA A*33:03-associated peptides were experimentally validated.

Effect of Neuromuscular Blockade on Intraoperative Respiratory Mechanics and Surgical Space Conditions during Robot-Assisted Radical Prostatectomy: A Prospective Randomized Controlled Trial.

The aim of this study was to investigate whether deep neuromuscular blockade (NMB) may affect intraoperative respiratory mechanics, surgical condition, and recovery profiles in patients undergoing robot-assisted radical prostatectomy (RARP). Patients were randomly assigned to the moderate or deep NMB groups. Pneumoperitoneum was maintained with carbon dioxide (CO2) insufflation at 15 mmHg during surgery. The primary outcome was peak inspiratory pressure (PIP) after CO2 insufflation. Mean airway pressure (Pmean) and dynamic lung compliance (Cdyn) were also recorded. The surgeon rated the surgical condition and surgical difficulty on a five-point scale (1 = extremely poor; 2 = poor; 3 = acceptable; 4 = good; 5 = optimal). Recovery profiles, such as pulmonary complications, pain scores, and recovery time, were recorded. We included 58 patients in this study. No significant differences were observed regarding intraoperative respiratory mechanics including PIP, Pmean and Cdyn, between the two groups. The number of patients with optimal surgical conditions was significantly higher in the deep than in the moderate NMB group (29 vs. 20, p = 0.014). We found no differences in recovery profiles. In conclusion, deep NMB had no significant effect on the intraoperative respiratory mechanics but resulted in optimal endoscopic surgical conditions during RARP compared with moderate NMB.

Efficacy of quadratus lumborum block for analgesia in adult participants undergoing hip surgery: A meta-analysis of randomized controlled trials.

STUDY OBJECTIVE: This study aimed to identify the benefits of quadratus lumborum block (QLB) in terms of postoperative analgesic effects in adult participants undergoing hip surgery. DESIGN: Meta-analysis of randomized controlled trials. SETTING: Previous randomized controlled trials that evaluated the analgesic effect of QLB compared to that of no block. PATIENTS: Nine studies including 616 participants. INTERVENTIONS: Participants in the treatment group received QLB, whereas those in the control group received no block. MEASUREMENTS: Outcomes were postoperative 24-h opioid consumption (primary), 12-h/24-h visual analog scale (VAS) or numeric rating scale (NRS) pain scores, postoperative nausea and vomiting (PONV), and satisfaction. The effect size was estimated using the standardized mean difference (SMD), mean difference (MD), or risk ratio (RR) with a 95% confidence interval (CI). We used the risk of bias tool (RoB 2) to assess the risk of bias of the included studies and the GRADE approach to determine the level of certainty of the evidence. MAIN RESULTS: Compared to no block, the QLB group has less opioid consumption (SMD -1.69, 95% CI -2.54 to -0.84; low level of certainty of the evidence). Estimated MD for morphine consumption was 24 mg. The QLB group had a lower 12-h VAS/NRS pain score (MD -1.16, 95% CI -1.82 to -0.51; moderate level of certainty of the evidence) and 24-h VAS/NRS pain score (MD -0.92, 95% CI -1.42 to -0.43; moderate level of certainty of the evidence). QLB decreased the incidence of PONV (RR 0.43, 95% CI 0.24 to 0.79; moderate level of certainty of the evidence) and increased participants' satisfaction (SMD 1.15, 95% CI 0.63 to 1.67; moderate level of certainty of the evidence). Estimated MD for satisfaction was 1.74 points of Likert scale. There were no significant adverse events associated with the QLB in any of the included trials. CONCLUSION: Our meta-analysis showed that QLB when compared to no block clinically decreased opioid requirements, reduced PONV, and improved participants' satisfaction. QLB also seems to be significantly superior to no block in terms of pain score, but its clinical importance remains unclear.

Src is essential for the endosomal delivery of the FGFR4 signaling complex in hepatocellular carcinoma.

BACKGROUND: Hepatocytes usually express fibroblast growth factor receptor 4 (FGFR4), but not its ligand, fibroblast growth factor 19 (FGF19). A subtype of hepatocellular carcinoma (HCC) expresses FGF19, which activates the FGFR4 signaling pathway that induces cell proliferation. FGFR4 inhibitors that target this mechanism are under clinical development for the treatment of HCCs with FGF19 amplification or FGFR4 overexpression. Src plays an essential role in the FGFR1 and FGFR2 signaling pathways. However, it is yet to be understood whether Src has any role in the FGF19-FGFR4 pathway in HCCs. In this study, we aimed to elucidate the role of Src in the FGF19-FGFR4 axis in HCC. METHODS: 3 HCC cell lines expressing both FGF19 and FGFR4 were selected. The expression of each protein was suppressed by siRNA treatment, and the activity-regulating relationship between FGFR4 and Src was investigated by westernblot. Co-immunoprecipitation was performed using the FGFR4 antibody to identify the endosomal complex formation and receptor endocytosis. The intracellular migration pathways of the endosomal complex were observed by immuno-fluorescence and nuclear co-immunoprecipitation. Dasatinib and BLU9931 were used for cytotoxicity comparison. RESULTS: FGFR4 modulates the activity of Src and Src modulates the expression of FGFR4, showing a mutual regulatory relationship. FGFR4 activated by FGF19 formed an endosomal complex with Src and STAT3 and moved to the nucleus. However, when Src was suppressed, the formation of the endosomal complex was not observed. FGFR4 was released from the complex transferred into the nucleus and the binding of Src and STAT3 was maintained. Dasatinib showed cytotoxic results comparable to BLU9931. The results of our study demonstrated that Src is essential for the nuclear transport of STAT3, as it induces the endosomal delivery of FGFR4 in FGF19-expressing HCC cell lines. CONCLUSIONS: We found that Src is essential for the endosomal delivery of the FGFR4 signaling complex in HCC. Our findings provide a scientific rationale for repurposing Src inhibitors for the treatment of HCCs in which the FGFR4 pathway is activated.

Distribution pattern of tumor infiltrating lymphocytes and tumor microenvironment composition as prognostic indicators in anorectal malignant melanoma.

Anorectal malignant melanoma (ARMM) is a rare disease with poor prognosis. Determining ARMM prognosis precisely is difficult due to the lack of proper assessment techniques. Immunotherapy has proven effective against cutaneous malignant melanoma and may show efficacy in ARMM. Herein, we assessed the immune profile of ARMM to identify possible prognostic biomarkers. Twenty-two ARMM formalin-fixed and paraffin-embedded samples were evaluated using an nCounter® PanCancer Immune Profiling Panel. Validation was performed through immunohistochemical staining for CD3, CD8, Foxp3, CD68, CD163, and PD-L1. RNA analysis revealed significantly decreased scores for pathways involved in cell regulation and function, as well as chemokines, in recurrent patients compared to nonrecurrent patients. In cell-type profiling, the recurrent cases displayed significantly low tumor infiltrating lymphocyte (TIL) scores. Recurrence/death prediction models were defined using logistic regression and showed significantly lower scores in recurrent and deceased patients (all, P < 0.001) compared to those in nonrecurrent and surviving patients. The high total TIL and tumor-associated macrophage (TAM) groups had significantly better overall survival outcomes compared to the low total TIL and TAM groups (P = 0.007 and P = 0.035, respectively). In addition, the presence of CD3 + TILs in the invasion front was an independent favorable prognostic indicator (P = 0.003, hazard ratio = 0.21, 95% confidential interval, 0.01-0.41). Patients with inflamed or brisk-infiltration type tumors also had a significantly better overall survival than that of patients with immune-desert/excluded and absent/non-brisk type tumors (P = 0.03 and P = 0.0023, respectively). In conclusion, TILs have a strong prognostic value in ARMM, and the quantification of TILs and an analysis of the TIL phenotype and infiltration pattern during pathological diagnosis are essential to guide treatment strategies and accurate prognosis in ARMM.

KF-1607, a Novel Pan Src Kinase Inhibitor, Attenuates Obstruction-Induced Tubulointerstitial Fibrosis in Mice.

Src family kinases (SFKs), an important group of non-receptor tyrosine kinases, are suggested to be excessively activated during various types of tissue fibrosis. The present study investigated the effect of KF-1607, an orally active and a newly synthesized Src kinase inhibitor (SKI) with proposed low toxicity, in preventing the progression of renal interstitial fibrosis. Unilateral ureteral obstruction (UUO) surgery was performed in 6-week-old male C57BL/6 mice to induce renal interstitial fibrosis. Either KF-1607 (30 mg/kg, oral gavage) or PP2 (2 mg/kg, intraperitoneal injection), a common experimental SKI, was administered to mice for seven days, started one day prior to surgery. UUO injury-induced SFK expression, including Src, Fyn, and Lyn kinase. SFK inhibition by KF-1607 prevented the progression of tubular injury in UUO mice, as indicated by decreases in albuminuria, urinary KIM-1 excretion, and kidney NGAL protein expression. Renal tubulointerstitial fibrosis was attenuated in response to KF-1607, as shown by decreases in α-SMA, collagen I and IV protein expression, along with reduced Masson's trichrome and collagen-I staining in kidneys. KF-1607 also inhibited inflammation in the UUO kidney, as exhibited by reductions in F4/80 positive-staining and protein expression of p-NFκB and ICAM. Importantly, the observed effects of KF-1607 were similar to those of PP2. A new pan Src kinase inhibitor, KF-1607, is a potential pharmaceutical agent to prevent the progression of renal interstitial fibrosis.

A Nine-Gene Signature for Predicting the Response to Preoperative Chemoradiotherapy in Patients with Locally Advanced Rectal Cancer.

Preoperative chemoradiotherapy (PCRT) and subsequent surgery is the standard multimodal treatment for locally advanced rectal cancer (LARC), albeit PCRT response varies among the individuals. This creates a dire necessity to identify a predictive model to forecast treatment response outcomes and identify patients who would benefit from PCRT. In this study, we performed a gene expression study using formalin-fixed paraffin-embedded (FFPE) tumor biopsy samples from 156 LARC patients (training cohort n = 60; validation cohort n = 96); we identified the nine-gene signature (FGFR3, GNA11, H3F3A, IL12A, IL1R1, IL2RB, NKD1, SGK2, and SPRY2) that distinctively differentiated responders from non-responders in the training cohort (accuracy = 86.9%, specificity = 84.8%, sensitivity = 81.5%) as well as in an independent validation cohort (accuracy = 81.0%, specificity = 79.4%, sensitivity = 82.3%). The signature was independent of all pathological and clinical features and was robust in predicting PCRT response. It is readily applicable to the clinical setting using FFPE samples and Food and Drug Administration (FDA) approved hardware and reagents. Predicting the response to PCRT may aid in tailored therapies for respective responders to PCRT and improve the oncologic outcomes for LARC patients.

Data on the stability of Prx1-associated snRNAs and mRNAs.

This data set is related to the research article entitled "Peroxiredoxin 1 post-transcriptionally regulates snoRNA expression" (Kim et al., 2019). It demonstrates that peroxiredoxin 1 (Prx1) increases the stability of Prx1-associated small nuclear RNAs (snRNAs) and mRNAs. We overexpressed Prx1 in SNU484 and HeLa cells, which were then treated with Actinomycin D (ActD) to inhibit transcription. After that, we measured the levels of Prx1-associated snRNAs and mRNAs using qPCR analysis.

Peroxiredoxin 1 post-transcriptionally regulates snoRNA expression.

Peroxiredoxin 1 (Prx1) is a member of the Prx family that detoxifies various peroxide substrates through conserved catalytic cysteine residues with the use of reducing equivalents. In addition to this well-known role of Prx1, we have previously demonstrated that Prx1 also has RNA-binding properties, but its function as an RNA-binding protein (RBP) remains unknown. To characterize the role of Prx1 as an RBP, we pulled down Prx1-RNA complexes and sequenced the target RNAs of Prx1. Through sequencing and further validation studies, we revealed that Prx1 binds to a specific subset of small nucleolar RNAs (snoRNAs) and regulates these molecules at the post-transcriptional level. We also found that active cysteine residues provide a structural and functional link between these two distinct functions of Prx1 (i.e., ROS scavenging and RNA-binding activities). Prx1 functions as a snoRNA-binding protein in its reduced state, and post-transcriptionally regulates the expression of a set of snoRNAs. However, when the active cysteine residues are oxidized, Prx1 loses its activity as a snoRNA-binding protein. This study is the first report describing the novel role of Prx1 as a post-transcriptional regulator of snoRNAs.

FGF19-FGFR4 Signaling in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the sixth most common type of cancer, with an increasing mortality rate. Aberrant expression of fibroblast growth factor 19-fibroblast growth factor receptor 4 (FGF19-FGFR4) is reported to be an oncogenic-driver pathway for HCC patients. Thus, the FGF19-FGFR4 signaling pathway is a promising target for the treatment of HCC. Several pan-FGFR (1-4) and FGFR4-specific inhibitors are in different phases of clinical trials. In this review, we summarize the information, recent developments, binding modes, selectivity, and clinical trial phases of different available FGFR4/pan-FGF inhibitors. We also discuss future perspectives and highlight the points that should be addressed to improve the efficacy of these inhibitors.

Characterization of Hepatocellular Carcinoma Patients with FGF19 Amplification Assessed by Fluorescence in situ Hybridization: A Large Cohort Study.

BACKGROUND: FGF19 amplification is a relatively novel type of genetic aberration that has been proposed to be a driver of hepatocarcinogenesis. Selective inhibitors of FGFR4, a receptor of FGF19, have been developed as targeted therapies for hepatocellular carcinoma (HCC). Despite the role of FGF19 in mediating HCC progression, the clinicopathological characterization of patients exhibiting FGF19 amplification remains unclear. Immunohistochemical staining is the simplest and most widely used method of identifying aberrations in the FGF19 gene, although its specificity is very low. METHODS: This study investigated the prognostic significance of FGF19 amplification in a large cohort of 989 HCC patients using fluorescence in situ hybridization (FISH), which has a high degree of specificity. In addition, FISH data from formalin-fixed, paraffin-embedded sections were compared with copy number variation (CNV) data obtained from fresh frozen sections to validate the use of FISH as a diagnostic tool. RESULTS: FGF19 amplifications were detected by FISH in 51 (5.15%) of the 989 patients, and were independently associated with poor survival and a higher risk of tumor recurrence, as well as with poor prognostic factors such as a high α-fetoprotein level, hepatitis B or C virus infection, a large tumor size, microvascular invasion, and necrosis. In addition, FGF19 amplification was associated with TP53 mutation, and was mutually exclusive with CTNNB1 mutation. The results of the FISH and CNV analyses exhibited a significant concordance rate of 96% (κ = 0.618, p < 0.001). CONCLUSIONS: These data indicate that FGF19 amplification represents a unique molecular subtype associated with poor prognostic characteristics, which supports the hypothesis that the FGF19-FGFR4 signaling pathway plays an important role in hepatocarcinogenesis. We have also demonstrated that FISH is a viable alternative to CNV analysis, offering a number of advantages in the clinical setting.

Author Correction: Landscape of somatic mutations in 560 breast cancer whole-genome sequences.

In the Methods section of this Article, 'greater than' should have been 'less than' in the sentence 'Putative regions of clustered rearrangements were identified as having an average inter-rearrangement distance that was at least 10 times greater than the whole-genome average for the individual sample. '. The Article has not been corrected.

Increased genomic damage and vitamin B status in inflammatory bowel disease patients: A case-control, prospective, pilot study.

Vitamin B deficiency in patients with inflammatory bowel disease (IBD) is well-documented; however, few studies have explored genomic damage in patients with IBD using the cytokinesis-block micronucleus cytome (CBMN-Cyt) assay. This study investigated the frequency of micronuclei (MNi) using the CBMN-Cyt assay and the level of vitamin B in patients with IBD. This prospective study was conducted in 15 patients with ulcerative colitis, 15 patients with Crohn's disease, and 30 healthy controls from one tertiary hospital. Serum vitamin B and homocysteine levels were measured, and the MNi status was analyzed using the CBMN-Cyt assay. The patients with IBD showed significantly lower serum pyridoxine levels and significantly higher homocysteine levels than controls. The frequencies of binucleated cells (BNCs) with MNi, nucleoplasmic bridges (NPBs), and nuclear buds (Nbuds) were 8.5 [5.8-13.5], 1.0 [0.0-1.9], and 5.4 [4.3-7.4] for the IBD group, and 5.9 [4.8-7.7], 0.2 [0.0-1.0], and 3.5 [2.9-5.4] for the control group (P = 0.011, P = 0.010, and P = 0.002), respectively. This study suggests that patients with IBD have increased frequencies of MNi and decreased levels of pyridoxine than healthy controls.

FGFR1 expression defines clinically distinct subtypes in pancreatic cancer.

BACKGROUND: The clinical significance of fibroblast growth factor receptor 1 (FGFR1) protein expression in pancreatic cancer is largely unknown. In this study, we aimed investigate the clinical significance of FGFR1 expression in pancreatic cancer. METHODS: First, we investigated the relationship between FGFR pathway gene expression and clinicopathological data in three pancreatic cancer cohorts containing 313 cases. Subsequently, to confirm the findings from the discovery cohorts, we performed immunohistochemistry (IHC) of FGFR1 protein in a validation cohort of 205 pancreatic cancer cases. RESULTS: In discovery cohort 1, FGFR1 and Klotho beta (KLB) overexpression was associated with low tumor stage (P < 0.05), low tumor grade (P < 0.05), and better overall survival. Multivariate analysis predicted FGFR1 (P < 0.05) as a prognostic factor for better overall survival. In discovery cohorts 2 and 3, only FGFR1 overexpression was associated with better overall survival (P < 0.05). In the validation cohort, there were 15.7% and 61% strong and weak/moderate FGFR1-positive cases, respectively. FGFR1-positive cases showed better overall survival than FGFR1-negative cases (P < 0.05). Furthermore, multivariate analysis revealed FGFR1 positivity as an independent prognostic factor for better overall survival in pancreatic cancer patients (hazard ratio 0.677, 95% confidence interval 0.471-0.972, P = 0.035). CONCLUSIONS: FGFR1 expression, as estimated by IHC, may be used to define clinically distinct subtypes in pancreatic cancer. Moreover, FGFR1-based subclassification of pancreatic cancer may lead to new therapeutic approaches for the FGFR1-positive subtype.

Genomics of drug sensitivity in bladder cancer: an integrated resource for pharmacogenomic analysis in bladder cancer.

BACKGROUND: Bladder cancer has numerous genomic features that are potentially actionable by targeted agents. Nevertheless, both pre-clinical and clinical research using molecular targeted agents have been very limited in bladder cancer. RESULTS: We created the Genomics of Drug Sensitivity in Bladder Cancer (GDBC) database, an integrated database (DB) to facilitate the genomic understanding of bladder cancer in relation to drug sensitivity, in order to promote potential therapeutic applications of targeted agents in bladder cancer treatment. The GDBC database contains two separate datasets: 1) in-house drug sensitivity data, in which 13 targeted agents were tested against 10 bladder cancer cell lines; 2) data extracted and integrated from public databases, including the Cancer Therapeutics Research Portal, Cancer Cell Line Encyclopedia, Genomics of Drug Sensitivity in Cancer, Kyoto Encyclopedia of Genes and Genomes, and the Cancer Gene Census databases, as well as bladder cancer genomics data and synthetic lethality/synthetic dosage lethality connections. CONCLUSIONS: GDBC is an integrated DB of genomics and drug sensitivity data with a specific focus on bladder cancer. With a user-friendly web-interface, GDBC helps users generate genomics-based hypotheses that can be tested experimentally using drugs and cell lines included in GDBC.

The clinical implications of G1-G6 transcriptomic signature and 5-gene score in Korean patients with hepatocellular carcinoma.

BACKGROUND: Efforts have been made to classify Hepatocellular Carcinoma (HCC) at surgically curable stages because molecular classification, which is prognostically informative, can accurately identify patients in need of additional early therapeutic interventions. Recently, HCC classification based French studies on the expression of 16 genes and 5 genes were proposed. In 16-gene classification, transcriptomic signatures (G1-G6) were used to classify HCC patients into clinical, genomic and pathway-specific subgroups. In 5-gene score classification, the good or poor prognosis of HCC patients was predicted. The patient's cohort in these studies was mainly from Caucasian and African populations. Here, we aimed to validate G1-G6 and 5-gene score signatures in 205 Korean HCC patients since genomic profiles of Korean patients are distinct from other regions. METHODS: Integrated analyses using whole-exome sequencing, copy number variation and clinical data was performed against these two signatures to find statistical correlations. Kaplan-Meier, univariate and multivariate COX regression analysis were performed for Disease-Specific Survival (DSS) and Recurrence-Free Survival (RFS). RESULTS: The G2 and G3 subgroups of transcriptomic signature were significantly associated with TP53 mutations while G5 and G6 subgroups were significantly associated with CTNNB1 mutations which is in concordance with original French studies. Similarly, the poor prognosis group of 5-gene score showed shorter DSS (p = 0.045) and early RFS (p = 0.023) as well as a significant association with microvascular invasion, tumor size (> 5 cm), elevated AFP levels, and RB1 mutations. However, the 5-gene score was not an independent prognostic factor for survival. CONCLUSION: The G1-G6 and 5-gene signatures showed significant concordance between genetic profiles of Korean HCC patients and patients in original French studies. Thus, G1-G6 and 5-gene score signatures can be targeted as potential therapeutic biomarkers against HCC patients worldwide.