A Novel Liver Cancer-Selective Histone Deacetylase Inhibitor Is Effective against Hepatocellular Carcinoma and Induces Durable Responses with Immunotherapy.

Hepatocellular carcinoma (HCC) progression is facilitated by gene-silencing chromatin histone hypoacetylation due to histone deacetylase (HDAC) activation. However, inhibiting HDACs-an effective treatment for lymphomas-has shown limited success in solid tumors. We report the discovery of a class of HDAC inhibitors (HDACi) that demonstrates exquisite selective cytotoxicity against human HCC cells.

A Novel Liver Cancer-Selective Histone Deacetylase Inhibitor Is Effective Against Hepatocellular Carcinoma and Induces Durable Responses with Immunotherapy.

Hepatocellular cancer (HCC) progression is facilitated by gene-silencing chromatin histone hypoacetylation due to histone deacetylases (HDACs) activation. However, inhibiting HDACs, an effective treatment for lymphomas, has shown limited success in solid tumors. We report the discovery of a class of HDAC inhibitors (HDACi) that demonstrates exquisite selective cytotoxicity against human HCC cells.

Discovery of 5'-Substituted 5-Fluoro-2'-deoxyuridine Monophosphate Analogs: A Novel Class of Thymidylate Synthase Inhibitors.

5-Fluorouracil and 5-fluorouracil-based prodrugs have been used clinically for decades to treat cancer. Their anticancer effects are most prominently ascribed to inhibition of thymidylate synthase (TS) by metabolite 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP). However, 5-fluorouracil and FdUMP are subject to numerous unfavorable metabolic events that can drive undesired systemic toxicity.

Liver-Targeting Class I Selective Histone Deacetylase Inhibitors Potently Suppress Hepatocellular Tumor Growth as Standalone Agents.

Dysfunctions in epigenetic regulation play critical roles in tumor development and progression. Histone deacetylases (HDACs) and histone acetyl transferase (HAT) are functionally opposing epigenetic regulators, which control the expression status of tumor suppressor genes. Upregulation of HDAC activities, which results in silencing of tumor suppressor genes and uncontrolled proliferation, predominates in malignant tumors.

Molecular characteristics and markers of advanced clear cell renal cell carcinoma: Pitfalls due to intratumoral heterogeneity and identification of genetic alterations associated with metastasis.

Objectives: To identify clear cell renal cell carcinoma-related gene mutations potentially associated with aggressive disease, sarcomatoid differentiation or poor prognosis.

Methods: We carried out genomic analysis of 217 tumor foci from 25 patients with conventional clear cell renal cell carcinoma (14 patients), clear cell renal cell carcinoma with sarcomatoid differentiation (six patients) and non-clear cell renal cell carcinoma (five patients). Each tumor nodule on the tissue block that corresponded to the same focus on the slide was separated from the normal parenchyma and other histologically distinct areas of tumor.

The JNK inhibitor AS602801 Synergizes with Enzalutamide to Kill Prostate Cancer Cells In Vitro and In Vivo and Inhibit Androgen Receptor Expression.

In our previous study, we observed that androgen deprivation therapy (ADT) may induce a compensatory increase in MAPK or JNK signaling. Here, we tested the effects of the MEK inhibitors PD0325901 and GSK1120212, ERK1/2 inhibitor GDC-0994, and the JNK inhibitor AS602801 alone and in combination with the AR inhibitor enzalutamide (ENZ) in androgen-sensitive LNCaP cells and androgen-resistant C4-2 and 22Rv1 cells. Enzalutamide combined with AS602801 synergistically killed LNCaP, C4-2, and 22Rv1 cells, and decreased migration and invasion of LNCaP and C4-2 cells.

Discovery and mechanisms of host defense to oncogenesis: targeting the β-defensin-1 peptide as a natural tumor inhibitor.

Human beta-defensin-1 (hBD-1) is one of a number of small cationic host-defense peptides. Besides its well-known broad-spectrum antimicrobial function, hBD-1 has recently been identified as a chromosome 8p tumor-suppressor gene. The role of hBD-1 in modulating the host immune response to oncogenesis, associated with cell signaling and potential therapeutic applications, has become increasingly appreciated over time.

Preoperative Metabolic Signatures of Prostate Cancer Recurrence Following Radical Prostatectomy.

Technological advances in mass spectrometry (MS), liquid chromatography (LC) separations, nuclear magnetic resonance (NMR) spectroscopy, and big data analytics have made possible studying metabolism at an "omics" or systems level. Here, we applied a multiplatform (NMR + LC-MS) metabolomics approach to the study of preoperative metabolic alterations associated with prostate cancer recurrence. Thus far, predicting which patients will recur even after radical prostatectomy has not been possible.

Identification of the Transcription Factor Relationships Associated with Androgen Deprivation Therapy Response and Metastatic Progression in Prostate Cancer.

Background: Patients with locally advanced or recurrent prostate cancer typically undergo androgen deprivation therapy (ADT), but the benefits are often short-lived and the responses variable. ADT failure results in castration-resistant prostate cancer (CRPC), which inevitably leads to metastasis. We hypothesized that differences in tumor transcriptional programs may reflect differential responses to ADT and subsequent metastasis.

Comparative Cost Analysis: Teleurology vs Conventional Face-to-Face Clinics.

Objective: To compare costs associated with teleurology vs face-to-face clinic visits for initial outpatient hematuria evaluation.

Materials And Methods: The analysis included 3 cost domains: transportation, clinic operations, and patient time. Transportation cost was based on standard government travel reimbursement.

Discovery of a Fluorinated Enigmol Analog with Enhanced in Vivo Pharmacokinetic and Anti-Tumor Properties.

The orally bioavailable 1-deoxy-sphingosine analog, Enigmol, has demonstrated anticancer activity in numerous in vivo settings. However, as no Enigmol analog with enhanced potency in vitro has been identified, a new strategy to improve efficacy in vivo by increasing tumor uptake was adopted. Herein, synthesis and biological evaluation of two novel fluorinated Enigmol analogs, CF3-Enigmol and CF2-Enigmol, are reported.

Perlecan/HSPG2 and matrilysin/MMP-7 as indices of tissue invasion: tissue localization and circulating perlecan fragments in a cohort of 288 radical prostatectomy patients.

Prostate cancer (PCa) cells use matrix metalloproteinases (MMPs) to degrade tissue during invasion. Perlecan/HSPG2 is degraded at basement membranes, in reactive stroma and in bone marrow during metastasis. We previously showed MMP-7 efficiently degrades perlecan.

A mitochondrial DNA mutation influences the apoptotic effect of statins on prostate cancer.

Background: Statins, 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are currently the most widely used cholesterol-lowering drugs. Previous epidemiological studies have suggested that there may be be an association between statin use and decreased risk of prostate cancer progression. Both inherited and somatic mutations of the mitochondrial genome are linked to prostate cancer.

Mitochondrial DNA mutations in prostate cancer bone metastases.

Prostate cancer is the most common non-skin cancer in men. Those with local or regional disease often have good long-term prognosis, but patients with metastatic disease face high morbidity and mortality. The vast majority of cases with distant spread have some degree of bony involvement.

Bone metastasis in prostate cancer: Recurring mitochondrial DNA mutation reveals selective pressure exerted by the bone microenvironment.

Background: Cancer progression and metastasis occur such that cells with acquired mutations enhancing growth and survival (or inhibiting cell death) increase in number, a concept that has been recognized as analogous to Darwinian evolution of species since Peter C. Nowell's description in 1976. Selective forces include those intrinsic to the host (including metastatic site) as well as those resulting from anti-cancer therapies.

Targeting L1 cell adhesion molecule expression using liposome-encapsulated siRNA suppresses prostate cancer bone metastasis and growth.

The L1 cell adhesion molecule (L1CAM) has been implicated in tumor progression of many types of cancers, but its role in prostate cancer and its application in targeted gene therapy have not been investigated. Herein, we demonstrated that the L1CAM was expressed in androgen-insensitive and highly metastatic human prostate cancer cell lines. The correlation between L1CAM expression and prostate cancer metastasis was also validated in serum samples of prostate cancer patients.

Incidence and clinical characteristics of lower urinary tract symptoms as a presenting symptom for patients with newly diagnosed bladder cancer.

Purpose: The incidence of lower urinary tract symptoms (LUTS) as the sole presenting symptom for bladder cancer has traditionally been reported to be low. The objective of this study was to evaluate the prevalence and clinical characteristics of newly diagnosed bladder cancer patients who presented with LUTS in the absence of gross or microscopic hematuria.

Materials And Methods: We queried our database of bladder cancer patients at the Atlanta Veteran's Affairs Medical Center (AVAMC) to identify patients who presented solely with LUTS and were subsequently diagnosed with bladder cancer.

Aquaporin-1 protein levels elevated in fresh urine of renal cell carcinoma patients: potential use for screening and classification of incidental renal lesions.

Introduction And Objectives: There are over 65,000 new cases of renal cell carcinoma (RCC) each year, yet there is no effective clinical screening test for RCC. A single report claimed no overlap between urine levels of aquaporin-1 (AQP1) in patients with and without RCC (Mayo Clin Proc. 85:413, 2010).

Global transcriptome analysis of formalin-fixed prostate cancer specimens identifies biomarkers of disease recurrence.

Prostate cancer remains the second leading cause of cancer death in American men and there is an unmet need for biomarkers to identify patients with aggressive disease. In an effort to identify biomarkers of recurrence, we performed global RNA sequencing on 106 formalin-fixed, paraffin-embedded prostatectomy samples from 100 patients at three independent sites, defining a 24-gene signature panel. The 24 genes in this panel function in cell-cycle progression, angiogenesis, hypoxia, apoptosis, PI3K signaling, steroid metabolism, translation, chromatin modification, and transcription.

von Hippel-Lindau exonic methylation analysis using MALDI-TOF mass spectrometry.

Purpose: Aberrant promoter methylation turns off gene expression and is involved in human malignancy. Studies show that first exon methylation has a tighter association with gene silencing compared to promoter methylation or gene mutation. However, to our knowledge the clinical importance of exonic methylation in renal cell carcinoma is unknown.

Formalin disinfection of biopsy needle minimizes the risk of sepsis following prostate biopsy.

Purpose: We describe a simple and effective method to reduce the risk of infection after prostate biopsy.

Materials And Methods: A total of 1,642 consecutive prostate biopsy procedures during a 4-year period (2008 to 2012) were included in the study. Inclusion criteria consisted of pre-biopsy negative urine culture, bisacodyl enema and fluoroquinolone antibiotics (3 days).