A gene signature for post-infectious chronic fatigue syndrome

Background: At present, there are no clinically reliable disease markers for chronic fatigue syndrome. DNA chip microarray technology provides a method for examining the differential expression of mRNA from a large number of genes. Our hypothesis was that a gene expression signature, generated by microarray assays, could help identify genes which are dysregulated in patients with post-infectious CFS and so help identify biomarkers for the condition. Methods: Human genome-wide Affymetrix GeneChip arrays (39,000 transcripts derived from 33,000 gene sequences) were used to compare the levels of gene expression in the peripheral blood mononuclear cells of male patients with post-infectious chronic fatigue (n = 8) and male healthy control subjects (n = 7). Results: Patients and healthy subjects differed significantly in the level of expression of 366 genes. Analysis of the differentially expressed genes indicated functional implications in immune modulation, oxidative stress and apoptosis. Prototype biomarkers were identified on the basis of differential levels of gene expression and possible biological significance Conclusion: Differential expression of key genes identified in this study offer an insight into the possible mechanism of chronic fatigue following infection. The representative biomarkers identified in this research appear promising as potential biomarkers for diagnosis and treatment

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

The Fourth International Symposium on the Intraductal Approach to Breast Cancer, Santa Barbara, California, 10–13 March 2005

Intraductal approaches encompass procedures and technologies that are designed to access and interrogate the ductal–alveolar systems of the human breast, and include nipple aspiration, ductal lavage, random periareolar fine needle aspiration, and ductoscopy. These approaches are being used to collect and analyze fluids and cells to develop methods for breast cancer detection and risk assessment; to introduce imaging technologies to explore the mammary tree for abnormalities; to administer therapeutic and/or preventive agents directly to the breast tissue; and to explore the biology of the normal mammary gland. The latest research findings in these areas, presented at The 4th International Symposium on the Intraductal Approach to Breast Cancer in 2005, are summarized in this report

Analysis of health related quality of life (HRQoL) of patients with clinically localized prostate cancer, one year after treatment with external beam radiotherapy (EBRT) alone versus EBRT and high dose rate brachytherapy (HDRBT)

<p>Abstract</p> <p>Purpose</p> <p>Prostate cancer is the leading form of cancer diagnosed among North American men. Most patients present with localized disease, which can be effectively treated with a variety of different modalities. These are associated with widely different acute and late effects, which can be both physical and psychological in nature. HRQoL concerns are therefore important for these patients for selecting between the different treatment options.</p> <p>Materials and methods</p> <p>One year after receiving radiotherapy for localised prostate cancer 117 patients with localized prostate cancer were invited to participate in a quality of life (QoL) self reported survey. 111 patients consented and participated in the survey, one year after completion of their treatment. 88 patients received EBRT and 23 received EBRT and HDRBT. QoL was compared in the two groups by using a modified version of Functional Assessment of Cancer Therapy-Prostate (FACT-P) survey instrument.</p> <p>Results</p> <p>One year after completion of treatment, there was no significant difference in overall QoL scores between the two groups of patients. For each component of the modified FACT-P survey, i.e. physical, social/family, emotional, and functional well-being; there were no statistically significant differences in the mean scores between the two groups.</p> <p>Conclusion</p> <p>In prostate cancer patients treated with EBRT alone versus combined EBRT and HDRBT, there was no significant difference in the QoL scores at one year post-treatment.</p

Societal Costs and Benefits of Treatment with Trastuzumab in Patients with Early HER2neu-Overexpressing Breast Cancer in Singapore

<p>Abstract</p> <p>Background</p> <p>Trastuzumab has revolutionized the way we treat early Her2Neu-positive breast cancer, as it significantly improves disease-free and overall survival. Little is known about the societal costs and benefits of treatment with trastuzumab in the adjuvant setting in Southeast Asia.</p> <p>Methods</p> <p>Societal costs (benefits) were estimated as the sum of direct and indirect costs minus benefits in the base case. Direct costs were derived from 4 treatment centers in Singapore (2 private and 2 public, comprising 60-70% of all patients with cancer seen in the island-nation); indirect costs were assessed as the loss of productivity caused by the disease or treatment. Benefits to society were based on extra years of productivity, as measured by GNI per capita, resulting from the quality adjusted life-years (QALYs) saved with the use of trastuzumab as determined in the models by Kurian, Liberato and Garrison.</p> <p>Results</p> <p>Incremental costs in Singapore, in 2005 US dollars, were $26,971.05. Average Cost per QALY was$19,174.59 (Median: $18,993.70). Costs (benefits) to society ranged from a cost of$79.42 to a benefit of $9,263.06, depending on the model used (Average benefit:$4,375.89, Median $3,944.03). Sensitivity analysis ranged from a cost of$10,685.00 to a Benefit of US$17,298.79</p> <p>Conclusions</p> <p>Treatment with adjuvant trastuzumab is likely to generate net societal economic benefits in Singapore. Nevertheless, the lower range of possible outcomes does not refute the possibility that treatment may actually generate costs. These costs however clearly fall within the usual range of acceptable cost-effectiveness.</p

Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism

Most inherited neurodegenerative disorders are incurable, and often only palliative treatment is available. Precision medicine has great potential to address this unmet clinical need. We explored this paradigm in dopamine transporter deficiency syndrome (DTDS), caused by biallelic loss-of-function mutations in SLC6A3, encoding the dopamine transporter (DAT). Patients present with early infantile hyperkinesia, severe progressive childhood parkinsonism, and raised cerebrospinal fluid dopamine metabolites. The absence of effective treatments and relentless disease course frequently leads to death in childhood. Using patient-derived induced pluripotent stem cells (iPSCs), we generated a midbrain dopaminergic (mDA) neuron model of DTDS that exhibited marked impairment of DAT activity, apoptotic neurodegeneration associated with TNFα-mediated inflammation, and dopamine toxicity. Partial restoration of DAT activity by the pharmacochaperone pifithrin-μ was mutation-specific. In contrast, lentiviral gene transfer of wild-type human SLC6A3 complementary DNA restored DAT activity and prevented neurodegeneration in all patient-derived mDA lines. To progress toward clinical translation, we used the knockout mouse model of DTDS that recapitulates human disease, exhibiting parkinsonism features, including tremor, bradykinesia, and premature death. Neonatal intracerebroventricular injection of human SLC6A3 using an adeno-associated virus (AAV) vector provided neuronal expression of human DAT, which ameliorated motor phenotype, life span, and neuronal survival in the substantia nigra and striatum, although off-target neurotoxic effects were seen at higher dosage. These were avoided with stereotactic delivery of AAV2.SLC6A3 gene therapy targeted to the midbrain of adult knockout mice, which rescued both motor phenotype and neurodegeneration, suggesting that targeted AAV gene therapy might be effective for patients with DTDS

Biomarkers of disease differentiation: HCV recurrence versus acute cellular rejection

The wound-healing process induced by chronic hepatitis C virus (HCV) infection triggers liver damage characterized by fibrosis development and finally cirrhosis. Liver Transplantation (LT) is the optimal surgical treatment for HCV-cirrhotic patients at end-stage liver disease. However, acute cellular rejection (ACR) and HCV recurrence disease represent two devastating complications post-LT. The accurate differential diagnosis between both conditions is critical for treatment choice, and similar histological features represent a challenge for pathologists. Moreover, the HCV recurrence disease severity is highly variable post-LT. HCV recurrence disease progression is characterized by an accelerated fibrogenesis process, and almost 30% of those patients develop cirrhosis at 5-years of follow-up. Whole-genome gene expression (WGE) analyses through well-defined oligonucleotide microarray platforms represent a powerful tool for the molecular characterization of biological process. In the present manuscript, the utility of microarray technology is applied for the ACR and HCV-recurrence biological characterization in post-LT liver biopsy samples. Moreover, WGE analysis was performed to identify predictive biomarkers of HCV recurrence severity in formalin-fixed paraffin-embedded liver biopsies prospectively collected

Advances of genomic science and systems biology in renal transplantation: a review

The diagnosis of rejection in kidney transplant patients is based on histologic classification of a graft biopsy. The current “gold standard” is the Banff 97 criteria; however, there are several limitations in classifying rejection based on biopsy samples. First, a biopsy involves an invasive procedure. Second, there is significant variance among blinded pathologists in the interpretation of a biopsy. And third, there is also variance between the histology and the molecular profiles of a biopsy. To increase the positive predictive value of classifiers of rejection, a Banff committee is developing criteria that integrate histologic and molecular data into a unified classifier that could diagnose and prognose rejection. To develop the most appropriate molecular criteria, there have been studies by multiple groups applying omics technologies in attempts to identify biomarkers of rejection. In this review, we discuss studies using genome-wide data sets of the transcriptome and proteome to investigate acute rejection, chronic allograft dysfunction, and tolerance. We also discuss studies which focus on genetic biomarkers in urine and peripheral blood, which will provide clinicians with minimally invasive methods for monitoring transplant patients. We also discuss emerging technologies, including whole-exome sequencing and RNA-Seq and new bioinformatic and systems biology approaches, which should increase the ability to develop both biomarkers and mechanistic understanding of the rejection process