Unmasking the pathological and therapeutic potential of histone deacetylases for liver cancer.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, currently ranking as one of the highest neoplastic-related mortalities in the world. Due to the difficulty in early diagnosis and lack of effective treatment options, the 5-year survival rate of HCC remains extremely low. Histone deacetylation is one of the most important epigenetic mechanisms, regulating cellular events such as differentiation, proliferation and cell cycle. Histone deacetylases (HDACs), the chief mediators of this epigenetic mechanism, are often aberrantly expressed in various tumours including HCC. Areas covered: This review focuses on the most up-to-date findings of HDACs and their associated molecular mechanisms in HCC onset and progression. In addition, a potential network between HDACs and non-coding RNAs including microRNAs and long noncoding RNAs underlying hepatocarcinogenesis is considered. Expert opinion: Unmasking the role of HDACs and their association with HCC pathogenesis could have implications for future personalized therapeutic and diagnostic targeting.

Antiviral activity of bone morphogenetic proteins and activins.

Understanding the control of viral infections is of broad importance. Chronic hepatitis C virus (HCV) infection causes decreased expression of the iron hormone hepcidin, which is regulated by hepatic bone morphogenetic protein (BMP)/SMAD signalling. We found that HCV infection and the BMP/SMAD pathway are mutually antagonistic. HCV blunted induction of hepcidin expression by BMP6, probably via tumour necrosis factor (TNF)-mediated downregulation of the BMP co-receptor haemojuvelin. In HCV-infected patients, disruption of the BMP6/hepcidin axis and genetic variation associated with the BMP/SMAD pathway predicted the outcome of infection, suggesting that BMP/SMAD activity influences antiviral immunity. Correspondingly, BMP6 regulated a gene repertoire reminiscent of type I interferon (IFN) signalling, including upregulating interferon regulatory factors (IRFs) and downregulating an inhibitor of IFN signalling, USP18. Moreover, in BMP-stimulated cells, SMAD1 occupied loci across the genome, similar to those bound by IRF1 in IFN-stimulated cells. Functionally, BMP6 enhanced the transcriptional and antiviral response to IFN, but BMP6 and related activin proteins also potently blocked HCV replication independently of IFN. Furthermore, BMP6 and activin A suppressed growth of HBV in cell culture, and activin A inhibited Zika virus replication alone and in combination with IFN. The data establish an unappreciated important role for BMPs and activins in cellular antiviral immunity, which acts independently of, and modulates, IFN.

Improved Early Postoperative Range of Motion in Total Knee Arthroplasty Using Tranexamic Acid: A Retrospective Analysis.

The use of tranexamic acid (TXA) in total knee arthroplasty (TKA) has become common practice. Recent literature has demonstrated a reduction in postoperative knee swelling and drain output while using TXA. Our purpose is to analyze the range of motion (ROM) following TKA in patients who received TXA compared with a control group. We hypothesize that patients treated with TXA will have improved early postoperative ROM when compared with controls. A retrospective chart review was performed for patients who underwent TKA from 2010 to 2012 performed by a single orthopaedic surgeon. Patients were stratified into three cohorts by route of TXA administration including intravenous (IV), topical, and a control group. Dependent variables analyzed included extension, flexion, and total arc ROM on each postoperative day (POD), average ROM across all three postoperative days, as well as pre-to-postoperative differences in ROM. Demographic data were recorded for each patient. A total of 174 patients were included for analysis, 75 controls and 99 receiving TXA. A significant difference was found between the treatment groups and the control for all variables (for each, p ≤ 0.002). There were no significant differences in ROM between the IV and topical TXA treatment groups (for each, p ≥ 0.558). A multivariate analysis demonstrated no significant difference between the groups in complication rate or demographic variables. The use of TXA may improve early postoperative ROM following TKA.

The therapeutic properties of resminostat for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer with increases in new cases being reported annually. Histopathologists have identified hepatic steatosis as a characteristic of a broad range of chronic liver diseases that are associated with the onset and development of HCC. In this context, epigenetic modifications may serve as precancerous factors predisposing normal cells to the initiation of carcinogenesis. This study demonstrated that hepatic tumorigenesis and differentiated adipocytes may modulate both global histone deacetylase (HDAC) expression and specific class I HDAC genes in the tumour microenvironment. The novel class I HDAC inhibitor Resminostat was shown to reduce the proliferation of HCC cells along with its specificity in targeting class I HDACs and oncogenes. The combined effect of Resminostat with several pharmaceutical agents such as Sorafenib, Cisplatin and Doxorubicin was also demonstrated. The inhibition of heat shock protein 90 (HSP90) has been demonstrated as a potential therapeutic option for HCC. In line with this, the specific HSP90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) was selected and it was found that the combination of Resminostat and 17-AAG may provide a "smart" clinical strategy for HCC patients by targeting cellular communication within the tumour microenvironment. This study provides an insight into the use of Resminostat as an epigenetic based therapeutic for HCC along with other pharmaceutical options, in particular by targeting the cell-to-cell communication that occurs between hepatoma and adipocytes.

The Assessment of Blood Loss During Total Knee Arthroplasty When Comparing Intravenous vs Intracapsular Administration of Tranexamic Acid.

BACKGROUND: Administration of tranexamic acid topically and intravenously has demonstrated effectiveness in decreasing blood loss and transfusion rates. METHODS: We randomized 131 patients undergoing primary total knee arthroplasty to receive either intracapsular (69) or intravenous tranexamic acid (62). Postoperative blood loss was calculated using the formula derived by Nadler et al. The number of units transfused was recorded, as well as length of hospital stay. RESULTS: We found no statistically significant difference on calculated blood loss (postoperative day [POD] 1: 624 ± 326 vs 644 ± 292; P = .71, POD 2: 806 ± 368 vs 835 ± 319; P = .64, and POD 3: 1076 ± 419 vs 978 ± 343; P = .55). There was no difference in number of blood transfusions, length of stay, or complications. CONCLUSION: Intracapsular tranexamic acid is not inferior to intravenous tranexamic acid in decreasing blood loss and blood transfusion rate in primary total knee arthroplasty.

Long noncoding RNAs in liver cancer: what we know in 2014.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer with an estimated over half a million new cases diagnosed annually. Due to the difficulty in early diagnosis and lack of effective treatment options, HCC is currently ranked as the second highest neoplastic-related mortality in the world, with an extremely low 5-year survival rate of between 6 and 11%. Long noncoding RNAs (lncRNAs), are genes lacking protein coding ability, have recently emerged as pivotal participants in biological processes, often dysregulated in a range of cancers, including HCC. AREAS COVERED: In this review, we highlight the recent findings of lncRNAs in HCC pathogenesis, with particular attention on epigenetic events. In silico analysis was utilized to emphasize intrinsic linkages within the ncRNA families associated with hepatocarcinogenesis. EXPERT OPINION: While our understanding of lncRNAs in the onset and progression of HCC is still in its infancy, there is no doubt that understanding the activities of ncRNAs will certainly secure strong biomarkers and improve treatment options for HCC patients.

Greater trochanteric hip pain.

In the patient with lateral hip pain, there is a broad differential diagnosis, making appropriate evaluation and management challenging. Greater trochanteric pain syndrome is a term used to denote chronic lateral hip pain and encompasses several painful soft tissue diagnoses including coxa saltans, trochanteric bursitis, and gluteus minimus and medius tendon tears. An overview of these common causes is presented through a series of cases that encompass the anatomic associations, classic presentations, diagnostic tests, and management strategies unique to each disorder. By reviewing this information, we hope to provide clinicians with the tools to evaluate greater trochanteric pain syndrome efficiently and effectively.

Stop feeding cancer: pro-inflammatory role of visceral adiposity in liver cancer.

Liver cancer is the fifth most common cancer in the world with an estimated over half a million new cases diagnosed every year. Due to the difficulty in early diagnosis and lack of treatment options, the prevalence of liver cancer continues to climb with a 5-year survival rate of between 6% and 11%. Coinciding with the rise of liver cancer, the prevalence of obesity has rapidly increased over the past two decades. Evidence from epidemiological studies demonstrates a higher risk of hepatocellular carcinoma (HCC) in obese individuals. Obesity is recognised as a low-grade inflammatory disease, this is of particular relevance as inflammation has been proposed as the seventh hallmark of cancer development with abdominal visceral adiposity considered as an important source of pro-inflammatory stimuli. Emerging evidence points towards the direct role of visceral adipose tissue rather than generalised body fat in carcinogenesis. Cytokines such as IL-6 and TNF-α secreted from visceral adipose tissue have been demonstrated to induce a chronic inflammatory condition predisposing the liver to a protumourigenic milieu. This review focuses on excess visceral adiposity rather than simple obesity; particularly adipokines and their implications for chronic inflammation, lipid accumulation, insulin resistance, Endoplasmic Reticulum (ER) stress and angiogenesis. Evidence of molecular signalling pathways that may give rise to the onset and progression of HCC in this context are depicted. Delineation of the pro-inflammatory role of visceral adiposity in liver cancer and its targeting will provide better rational and therapeutic approaches for HCC prevention and elimination. The concept of a central role for metabolism in cancer is the culmination of an effort that began with one of the 20th century's leading biochemists and Nobel laureate of 1931, Otto Warburg.

MicroRNAs and liver cancer associated with iron overload: therapeutic targets unravelled.

Primary liver cancer is a global disease that is on the increase. Hepatocellular carcinoma (HCC) accounts for most primary liver cancers and has a notably low survival rate, largely attributable to late diagnosis, resistance to treatment, tumour recurrence and metastasis. MicroRNAs (miRNAs/miRs) are regulatory RNAs that modulate protein synthesis. miRNAs are involved in several biological and pathological processes including the development and progression of HCC. Given the poor outcomes with current HCC treatments, miRNAs represent an important new target for therapeutic intervention. Several studies have demonstrated their role in HCC development and progression. While many risk factors underlie the development of HCC, one process commonly altered is iron homeostasis. Iron overload occurs in several liver diseases associated with the development of HCC including Hepatitis C infection and the importance of miRNAs in iron homeostasis and hepatic iron overload is well characterised. Aberrant miRNA expression in hepatic fibrosis and injury response have been reported, as have dysregulated miRNA expression patterns affecting cell cycle progression, evasion of apoptosis, invasion and metastasis. In 2009, miR-26a delivery was shown to prevent HCC progression, highlighting its therapeutic potential. Several studies have since investigated the clinical potential of other miRNAs with one drug, Miravirsen, currently in phase II clinical trials. miRNAs also have potential as biomarkers for the diagnosis of HCC and to evaluate treatment efficacy. Ongoing studies and clinical trials suggest miRNA-based treatments and diagnostic methods will have novel clinical applications for HCC in the coming years, yielding improved HCC survival rates and patient outcomes.

Semitendinosus muscle fatty infiltration following tendon harvest in rabbits.

The hamstring tendon autograft is one of the most commonly used graft choices in Anterior cruciate ligament (ACL) reconstruction. There are conflicting results regarding postoperative hamstring strength deficits in patients who have had a hamstring graft. The semitendinosus tendon has been shown to regenerate after harvesting for ACL autograft, suggesting that the muscle has the potential to regain normal function. However, no studies have been performed to define the microstructural changes that occur in the semitendinosus muscle after tendon resection. In this study, we hypothesized that fatty infiltration of the semitendinosus muscle after tendon harvest in New Zealand White rabbits increases postoperatively and remains constant or increases during the first year of repair. The semitendinosus tendon was unilaterally detached and harvested from 15 rabbits. Five rabbits were sacrificed at 3-, 6-, and 12-month intervals, and the semitendinosus muscle-tendon units were analyzed. The contralateral unoperated limb served as the control. The gross tendon and muscle dimensions and histologic percentage of fatty infiltration were measured. We found no significant difference in fatty infiltration at any time point between the control muscle and test specimens and that there was no progression of fatty infiltration over time. If these results hold true in humans, natural repair of the hamstring muscle following tendon harvest during ACL autograft reconstruction is not inhibited by fatty infiltration.

Pegylated interferon-α induced hypoferremia is associated with the immediate response to treatment in hepatitis C.

UNLABELLED: Pegylated interferon-α (PEG-IFN-α) forms an integral part of the current treatment for hepatitis C virus (HCV) infection. PEG-IFN-α suppresses HCV production by augmenting the innate antiviral immune response. Recent studies have reported the induction of hepcidin, the iron regulatory hormone, by IFN-α in vitro. As hepcidin plays an important role in innate immunity, we hypothesized that this finding may be of clinical relevance to HCV and investigated the changes in iron homeostasis during the first 24 hours of treatment. Blood samples were obtained from HCV patients immediately prior to and 6, 12, and 24 hours following the first dose of PEG-IFN-α/ribavirin (RBV). Samples were analyzed for hepcidin, cytokine, iron levels, and HCV viral load, and hepcidin messenger RNA (mRNA) expression was quantified in peripheral blood mononuclear cells. Hepcidin induction by IFN-α was further analyzed in cell culture. In HCV patients a single dose of PEG-IFN-α/RBV resulted in a significant increase in serum hepcidin, peaking at 12 hours, coinciding with a 50% reduction in serum iron and transferrin saturation over the 24-hour period. Patients with a ≥ 2 log decline in HCV viral load over the first 24 hours had significantly lower SI and TS levels at 12 and 24 hours. Moreover, 24-hour SI levels were an independent predictor of the immediate HCV viral decline, an indicator of ultimate treatment outcome. In cell culture, a direct induction of hepcidin by IFN-α was seen, controlled by the STAT3 transcription factor. CONCLUSION: Hepcidin induction occurs following the initiation of PEG-IFN-α treatment for HCV, and is mediated by way of STAT3 signaling. The subsequent hypoferremia was greatest in those with the most significant decline in viral load, identifying systemic iron withdrawal as a marker of immediate interferon-α efficacy in HCV patients.

Early proteomic analysis may allow noninvasive identification of hepatitis C response to treatment with pegylated interferon α-2b and ribavirin.

BACKGROUND AND AIM: Chronic hepatitis C virus (HCV) infection represents a significant disease burden worldwide. Approximately 170 million people are chronically infected. HCV can lead to liver fibrosis, cirrhosis and hepatocellular carcinoma. Current standard treatment with pegylated interferon and ribavirin is suboptimal and up to 60% of patients fail to respond. Week 4 and 12 HCV RNA is used as a marker of response with nonresponders at 12 weeks discontinuing treatment. Earlier identification of nonresponders using novel biomarkers would be beneficial in preventing unnecessary toxicities and cost. This study profiled the proteomic response to treatment in HCV patients within the first 24 h using surface-enhanced laser desorption-ionization time-of-flight mass spectrometry (SELDI-TOF MS). METHODS: Serum from 25 HCV infected individuals during the initial 24 h of treatment was profiled using SELDI-TOF MS. Arrays were analyzed on the ProteinChip Reader and time-of-flight spectra were generated. Peak detection was performed by Biomarker Wizard software and analyzed using BioConductor packages. RESULTS: Significant differences were seen between the proteomic profiles of responders and nonresponders to treatment. Overall 70 peaks differentiated responders from nonresponders. A random forest classifier identified a panel of 20 peaks, which differentiated responders from nonresponders with 87.4% accuracy. The CM10 chip revealed 16 peaks identifying genotype 1 responders from nonresponders. CONCLUSION: This study identifies early proteomic spectra as potential predictors of HCV treatment response using SELDI-TOF MS. This illustrates the importance of early biomarkers in the prediction of response within the first 24 h, which may aid in tailoring HCV treatment regimens.

Hospital-acquired pneumonia after lung resection surgery is associated with characteristic cytokine gene expression.

BACKGROUND: Infection in humans has been linked with altered cytokine gene transcription. It is unclear whether this phenomenon is a consequence of an established disease process or precedes the infective process. The primary end point of this study was to determine whether hospital-acquired pneumonia (HAP) was associated with differential gene expression of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and IL-23p19. The secondary end point was to identify whether alteration in gene expression preceded the clinical onset of infection. METHODS: Sixty consecutive patients undergoing elective thoracic surgery were recruited. HAP was diagnosed as per National Nosocomial Infection Surveillance guidelines. Messenger RNA (mRNA) and protein levels were analyzed preoperatively and 24 h and 5 days postoperatively. RESULTS: Forty-one patients had an uncomplicated recovery. Nineteen patients developed HAP. IL-6, IL-10, IL-12p35, IL-23p19, IL-27p28, TNF-α, and IFN-γ mRNA and protein levels of IL-6, IL-23, and IFN-γ in peripheral blood leukocytes were analyzed before surgery and 24 h and 5 days postsurgery. IL-23p19 mRNA levels were reduced in the pneumonia group (median, 4.19; 10th-90th centile range, 3.90-4.71) compared with the nonpneumonia group (4.50; 3.85-5.32) day 1 postsurgery (P=02). IFN-γ mRNA levels were reduced in the pneumonia group (2.48; 1.20-3.20) compared with nonpneumonia group (2.81; 2.10-3.26) (P=03) day 5 postsurgery. Results are expressed as log to base 10 copy numbers of cytokine mRNA per 10 million ß-actin mRNA copy numbers. All values are given as median and 10th to 90th centile range. CONCLUSIONS: Cytokine gene expression is altered immediately following surgery in patients with postoperative HAP.

Targeting oxidative stress in cancer.

IMPORTANCE OF THE FIELD: Reactive oxygen species (ROS) occur as natural by-products of oxygen metabolism and have important cellular functions. Normally, the cell is able to maintain an adequate balance between the formation and removal of ROS either via anti-oxidants or through the use specific enzymatic pathways. However, if this balance is disturbed, oxidative stress may occur in the cell, a situation linked to the pathogenesis of many diseases, including cancer. AREAS COVERED IN THIS REVIEW: HDACs are important regulators of many oxidative stress pathways including those involved with both sensing and coordinating the cellular response to oxidative stress. In particular aberrant regulation of these pathways by histone deacetylases may play critical roles in cancer progression. WHAT THE READER WILL GAIN: In this review we discuss the notion that targeting HDACs may be a useful therapeutic avenue in the treatment of oxidative stress in cancer, using chronic obstructive pulmonary disease (COPD), NSCLC and hepatocellular carcinoma (HCC) as examples to illustrate this possibility. TAKE HOME MESSAGE: Epigenetic mechanisms may be an important new therapeutic avenue for targeting oxidative stress in cancer.

Early viral and peripheral blood mononuclear cell responses to pegylated interferon and ribavirin treatment: the first 24 h.

OBJECTIVES: This study explored gene expression differences in predicting response to pegylated interferon (IFN-PEG) and ribavirin (RBV) in hepatitis C infection. Current treatment for hepatitis C virus (HCV) with IFN-PEG alpha-2a/b and RBV is an expensive regimen with frequent significant side-effects where less than 60% of patients ultimately achieve a sustained virological response. Responders and nonresponders may not be identified for up to 6 months post-treatment. This dichotomy may be because of differences in the molecular genetic response. METHODS: Peripheral blood mononuclear cell samples were obtained from a cohort of 31 infected individuals within the first 24 h of treatment and the extracted RNA was hybridized to genome expression microarrays. Hepatitis C viral kinetics was also examined in these patients. The ability of differentially regulated genes to predict response to therapy was assessed with treatment outcome. RESULTS: Distinct patterns of gene expression distinguished responders from nonresponders to HCV treatment. The ultimate response to treatment with IFN-PEG and RBV was observed within the first 24 h of treatment by a greater drop in viral load (mean HCV RNA decline of 1.92+/-1.26 log10 IU/ml) in responders compared with nonresponders (P<0.007). Induced genes achieved maximal response within 12 h of therapy which coincided with a rapid decline in HCV RNA between 12 and 24 h. This study revealed that peripheral blood mononuclear cell metallothionein 2A, CCRL2, tumour necrosis factor-alpha-induced protein 6 (TNFAIP6) and IFN-induced protein with tetratricopeptide repeats 2 expression predicted viral treatment response to therapy verified by quantitative real time polymerase chain reaction. CONCLUSION: This study has identified a noninvasive gene microarray pattern and a set of verified genes to be predictive of hepatitis C patient response to IFN-PEG and RBV treatment within the first 24 h. The potential of this noninvasive diagnostic approach and identified genes as biomarkers of response to treatment warrants further investigation.

Defective bone morphogenic protein signaling underlies hepcidin deficiency in HFE hereditary hemochromatosis.

UNLABELLED: Hereditary hemochromatosis (HH) is a common inherited iron overload disorder. The vast majority of patients carry the missense Cys282Tyr mutation of the HFE gene. Hepcidin, the central regulator of iron homeostasis, is deficient in HH, leading to unchecked iron absorption and subsequent iron overload. The bone morphogenic protein (BMP)/small mothers against decapentaplegic (Smad) signaling cascade is central to the regulation of hepcidin. Recent data from HH mice models indicate that this pathway may be defective in the absence of the HFE protein. Hepatic BMP/Smad signaling has not been characterized in a human HFE-HH cohort to date. Hepatic expression of BMP/Smad-related genes was examined in 20 HFE-HH males with significant iron overload, and compared to seven male HFE wild-type controls using quantitative real-time reverse transcription polymerase chain reaction. Hepatic expression of BMP6 was appropriately elevated in HFE-HH compared to controls (P = 0.02), likely related to iron overload. Despite this, no increased expression of the BMP target genes hepcidin and Id1 was observed, and diminished phosphorylation of Smad1/Smad5/Smad8 protein relative to iron burden was found upon immunohistochemical analysis, suggesting that impaired BMP signaling occurs in HFE-HH. Furthermore, Smad6 and Smad7, inhibitors of BMP signaling, were up-regulated in HFE-HH compared to controls (P = 0.001 and P = 0.018, respectively). CONCLUSION: New data arising from this study suggest that impaired BMP signaling underlies the hepcidin deficiency of HFE-HH. Moreover, the inhibitory Smads, Smad6, and Smad7 are identified as potential disruptors of this signal and, hence, contributors to the pathogenesis of this disease.

Variant in CD209 promoter is associated with severity of liver disease in chronic hepatitis C virus infection.

CD209, a c-type lectin expressed by dendritic cells (DCs), acts as a pathogen recognition receptor. A single nucleotide polymorphism (SNP) in the promoter region of CD209 (-336 A/G; rs4804803) affects transcription and is associated with the severity of tuberculosis and dengue fever. Because CD209 binds hepatitis C virus (HCV) glycoprotein-E2, we investigated this SNP in the context of chronic HCV infection. A total of 131 Irish women who had received HCV-contaminated anti-D-immunoglobulin and 79 healthy control subjects were genotyped. We found no association between rs4804803 and the risk of HCV chronicity. However, of those with chronic infection, possession of at least one g-allele was associated with more advanced liver disease, with significantly higher liver fibrosis scores and levels of alanine transaminase (ALT) observed. We conclude that rs4804803, an SNP in the CD209 promoter, contributes to severity of liver disease in chronic HCV infection.