Tumors escape immunosurveillance by overexpressing the proteasome activator PSME3

The success of CD8+ T cell-based cancer immunotherapy emphasizes the importance of understanding the mechanisms of generation of MHC-I peptide ligands and the possible pathways of tumor cell escape from immunosurveillance. Recently, we showed that peptides generated in the nucleus during a pioneer round of mRNA translation (pioneer translation products, or PTPs) are an important source of tumor specific peptides which correlates with the aberrant splicing and transcription events associated with oncogenesis. Here we show that up-regulation of PSME3 proteasome activator in cancer cells results in increased destruction of PTP-derived peptides in the nucleus thus enabling cancer cell to subvert immunosurveillance. These findings unveil a previously unexpected role for PSME3 in antigen processing and identify PSME3 as a druggable target to improve the efficacy of cancer immunotherapy

The benefits and risks of bacille Calmette-Guérin vaccination among infants at high risk for both tuberculosis and severe combined immunodeficiency: assessment by Markov model

BACKGROUND: Bacille Calmette-Guérin (BCG) vaccine is given to Canadian Aboriginal neonates in selected communities. Severe reactions and deaths associated with BCG have been reported among infants born with immunodeficiency syndromes. The main objective of this study was to estimate threshold values for severe combined immunodeficiency (SCID) incidence, above which BCG is associated with greater risk than benefit. METHODS: A Markov model was developed to simulate the natural histories of tuberculosis (TB) and SCID in children from birth to 14 years. The annual risk of tuberculous infection (ARI) and SCID incidence were varied in analyses. The model compared a scenario of no vaccination to intervention with BCG. Appropriate variability and uncertainty analyses were conducted. Outcomes included TB incidence and quality-adjusted life years (QALYs). RESULTS: In sensitivity analyses, QALYs were lower among vaccinated infants if the ARI was 0.1% and the rate of SCID was higher than 4.2 per 100,000. Assuming an ARI of 1%, this threshold increased to 41 per 100,000. In uncertainty analyses (Monte Carlo simulations) which assumed an ARI of 0.1%, QALYs were not significantly increased by BCG unless SCID incidence is 0. With this ARI, QALYs were significantly decreased among vaccinated children if SCID incidence exceeds 23 per 100,000. BCG is associated with a significant increase in QALYs if the ARI is 1%, and SCID incidence is below 5 per 100,000. CONCLUSION: The possibility that Canadian Aboriginal children are at increased risk for SCID has serious implications for continued BCG use in this population. In this context, enhanced TB Control – including early detection and treatment of infection – may be a safer, more effective alternative

Causes of stigma and discrimination associated with tuberculosis in Nepal: a qualitative study

<p>Abstract</p> <p>Background</p> <p>Tuberculosis (TB) is a major cause of death. The condition is highly stigmatised, with considerable discrimination towards sufferers. Although there have been several studies assessing the extent of such discrimination, there is little published research explicitly investigating the causes of the stigma and discrimination associated with TB. The objectives of our research were therefore to take the first steps towards determining the causes of discrimination associated with TB.</p> <p>Methods</p> <p>Data collection was performed in Kathmandu, Nepal. Thirty four in-depth interviews were performed with TB patients, family members of patients, and members of the community.</p> <p>Results</p> <p>Causes of self-discrimination identified included fear of transmitting TB, and avoiding gossip and potential discrimination. Causes of discrimination by members of the general public included: fear of a perceived risk of infection; perceived links between TB and other causes of discrimination, particularly poverty and low caste; perceived links between TB and disreputable behaviour; and perceptions that TB was a divine punishment. Furthermore, some patients felt they were discriminated against by health workers</p> <p>Conclusion</p> <p>A comprehensive package of interventions, tailored to the local context, will be needed to address the multiple causes of discrimination identified: basic population-wide health education is unlikely to be effective.</p

Enzymatic Activities and DNA Substrate Specificity of Mycobacterium tuberculosis DNA Helicase XPB

XPB, also known as ERCC3 and RAD25, is a 3′→5′ DNA repair helicase belonging to the superfamily 2 of helicases. XPB is an essential core subunit of the eukaryotic basal transcription factor complex TFIIH. It has two well-established functions: in the context of damaged DNA, XPB facilitates nucleotide excision repair by unwinding double stranded DNA (dsDNA) surrounding a DNA lesion; while in the context of actively transcribing genes, XPB facilitates initiation of RNA polymerase II transcription at gene promoters. Human and other eukaryotic XPB homologs are relatively well characterized compared to conserved homologs found in mycobacteria and archaea. However, more insight into the function of bacterial helicases is central to understanding the mechanism of DNA metabolism and pathogenesis in general. Here, we characterized Mycobacterium tuberculosis XPB (Mtb XPB), a 3′→5′ DNA helicase with DNA-dependent ATPase activity. Mtb XPB efficiently catalyzed DNA unwinding in the presence of significant excess of enzyme. The unwinding activity was fueled by ATP or dATP in the presence of Mg2+/Mn2+. Consistent with the 3′→5′ polarity of this bacterial XPB helicase, the enzyme required a DNA substrate with a 3′ overhang of 15 nucleotides or more. Although Mtb XPB efficiently unwound DNA model substrates with a 3′ DNA tail, it was not active on substrates containing a 3′ RNA tail. We also found that Mtb XPB efficiently catalyzed ATP-independent annealing of complementary DNA strands. These observations significantly enhance our understanding of the biological roles of Mtb XPB

Variants of OTOF and PJVK Genes in Chinese Patients with Auditory Neuropathy Spectrum Disorder

BACKGROUND: Mutations in OTOF and PJVK genes cause DFNB9 and DFNB59 types of hearing loss, respectively. The patients carrying pathogenic mutations in either of these genes may show the typical phenotype of auditory neuropathy spectrum disorder (ANSD). The aim of the present study was to identify OTOF and PJVK mutations in sporadic ANSD patients. METHODS AND FINDINGS: A total of 76 unrelated Chinese non-syndromic ANSD patients were sequenced on the gene OTOF and PJVK exon by exon. Variants were valued in 105 controls with normal hearing to verify the carrying rate. We identified one pathogenic mutation (c.1194T>A) and three novel, possibly pathogenic, variants (c.3570+2T>C, c.4023+1 G>A, and c.1102G>A) in the OTOF gene, and one novel, possibly pathogenic, variant (c.548G>A) in PJVK. Moreover, we found three novel missense mutations within the exons of OTOF. CONCLUSIONS: As we identified 4 and 1 possible pathogenic variants of the OTOF gene and the PJVK gene, respectively, we believe that screening in these genes are important in sporadic ANSD patients. The pathogenicity of these novel mutations needs further study because of their single heterozygous nature. Knowledge on the mutation spectra of these genes in Chinese would be beneficial in understanding the genetic character of this worldwide disease

Standardized Treatment of Active Tuberculosis in Patients with Previous Treatment and/or with Mono-resistance to Isoniazid: A Systematic Review and Meta-analysis

Performing a systematic review of studies evaluating retreatment of tuberculosis or treatment of isoniazid mono-resistant infection, Dick Menzies and colleagues find a paucity of evidence to support the WHO-recommended regimen

Re-thinking global health sector efforts for HIV and tuberculosis epidemic control: promoting integration of programme activities within a strengthened health system

<p>Abstract</p> <p>Background</p> <p>The global financial crisis threatens global health, particularly exacerbating diseases of inequality, e.g. HIV/AIDS, and diseases of poverty, e.g. tuberculosis. The aim of this paper is to reconsider established practices and policies for HIV and tuberculosis epidemic control, aiming at delivering better results and value for money. This may be achieved by promoting greater integration of HIV and tuberculosis control programme activities within a strengthened health system.</p> <p>Discussion</p> <p>HIV and tuberculosis share many similarities in terms of their disease burden and the recommended stratagems for their control. HIV and tuberculosis programmes implement similar sorts of control activities, e.g. case finding and treatment, which depend for success on generic health system issues, including vital registration, drug procurement and supply, laboratory network, human resources, and financing. However, the current health system approach to HIV and tuberculosis control often involves separate specialised services. Despite some recent progress, collaboration between the programmes remains inadequate, progress in obtaining synergies has been slow, and results remain far below those needed to achieve universal access to key interventions. A fundamental re-think of the current strategic approach involves promoting integrated delivery of HIV and tuberculosis programme activities as part of strengthened general health services: epidemiological surveillance, programme monitoring and evaluation, community awareness of health-seeking behavior, risk behaviour modification, infection control, treatment scale-up (first-line treatment regimens), drug-resistance surveillance, containing and countering drug-resistance (second-line treatment regimens), research and development, global advocacy and global partnership. Health agencies should review policies and progress in HIV and tuberculosis epidemic control, learn mutual lessons for policy development and scaling up interventions, and identify ways of joint planning and joint funding of integrated delivery as part of strengthened health systems.</p> <p>Summary</p> <p>As both a danger and an opportunity, the global financial crisis may entail disaster or recovery for global health sector efforts for HIV and tuberculosis epidemic control. Review of policies and progress in control paves the way for identification of synergies between the two programmes, within strengthened health services. The silver lining in the global economic crisis could be better control of the HIV and tuberculosis epidemics, better overall health system performance and outcomes, and better value for money.</p

The DARE study of relapse prevention in depression: design for a phase 1/2 translational randomised controlled trial involving mindfulness-based cognitive therapy and supported self monitoring

<p>Abstract</p> <p>Background</p> <p>Depression is a common condition that typically has a relapsing course. Effective interventions targeting relapse have the potential to dramatically reduce the point prevalence of the condition. Mindfulness-based cognitive therapy (MBCT) is a group-based intervention that has shown efficacy in reducing depressive relapse. While trials of MBCT to date have met the core requirements of phase 1 translational research, there is a need now to move to phase 2 translational research - the application of MBCT within real-world settings with a view to informing policy and clinical practice. The aim of this trial is to examine the clinical impact and health economics of MBCT under real-world conditions and where efforts have been made to assess for and prevent resentful demoralization among the control group. Secondary aims of the project involve extending the phase 1 agenda to an examination of the effects of co-morbidity and mechanisms of action.</p> <p>Methods/Design</p> <p>This study is designed as a prospective, multi-site, single-blind, randomised controlled trial using a group comparison design between involving the intervention, MBCT, and a self-monitoring comparison condition, Depression Relapse Active Monitoring (DRAM). Follow-up is over 2 years. The design of the study indicates recruitment from primary and secondary care of 204 participants who have a history of 3 or more episodes of Major Depression but who are currently well. Measures assessing depressive relapse/recurrence, time to first clinical intervention, treatment expectancy and a range of secondary outcomes and process variables are included. A health economics evaluation will be undertaken to assess the incremental cost of MBCT.</p> <p>Discussion</p> <p>The results of this trial, including an examination of clinical, functional and health economic outcomes, will be used to assess the role that this treatment approach may have in recommendations for treatment of depression in Australia and elsewhere. If the findings are positive, we expect that this research will consolidate the evidence base to guide the decision to fund MBCT and to seek to promote its availability to those who have experienced at least 3 episodes of depression.</p> <p>Trial Registration</p> <p>Australian New Zealand Clinical Trials Registry: <a href="http://www.anzctr.org.au/ACTRN12607000166471.aspx">ACTRN12607000166471</a></p