Overton E.T.,Washington University in St. Louis |
Kang M.,Harvard University |
Peters M.G.,University of California at San Francisco |
Umbleja T.,Harvard University |
And 8 more authors.
Vaccine | Year: 2010
HIV-infected persons are at risk for HBV co-infection which is associated with increased morbidity and mortality. Unfortunately, protective immunity following HBV vaccination in HIV-infected persons is poor. This randomized, phase II, open-label study aimed to evaluate efficacy and safety of 40mcg HBV vaccine with or without 250mcg GM-CSF administered at day 0, weeks 4 and 12. HIV-infected individuals ≥18 years of age, CD4 count ≥200cells/mm3, seronegative for HBV and HCV, and naïve to HBV vaccination were eligible. Primary endpoints were quantitative HBsAb titers and adverse events. The study enrolled 48 subjects. Median age and baseline CD4 were 41 years and 446cells/mm3, 37 were on ART, and 26 subjects had undetectable VL. Vaccination was well tolerated. Seven subjects in the GM-CSF arm reported transient grade ≥2 signs/symptoms (six grade 2, one grade 3), mostly aches and nausea. GM-CSF had no significant effect on VL or CD4. Four weeks after vaccination, 26 subjects (59%) developed a protective antibody response (HBsAb ≥10mIU/mL; 52% in the GM-CSF arm and 65% in the control arm) without improved Ab titer in the GM-CSF vs. control arm (median 11mIU/mL vs. 92mIU/mL, respectively). Response was more frequent in those with CD4 ≥350cells/mm3 (64%) than with CD4 <350cells/mm3 (50%), though not statistically significant. GM-CSF as an adjuvant did not improve the Ab titer or the development of protective immunity to HBV vaccination in those receiving an accelerated vaccine schedule. Given the common routes of transmission for HIV and HBV, additional HBV vaccine research is warranted. © 2010 Elsevier Ltd.
The Irritable Bowel Syndrome Outcome Study (IBSOS): Rationale and design of a randomized, placebo-controlled trial with 12month follow up of self- versus clinician-administered CBT for moderate to severe irritable bowel syndrome
Keefer L.,Northwestern University |
Jaccard J.,New York University |
Brenner D.,Northwestern University |
Bratten J.,Northwestern University |
And 3 more authors.
Contemporary Clinical Trials | Year: 2012
Irritable bowel syndrome is a common, oftentimes disabling, gastrointestinal disorder whose full range of symptoms has no satisfactory medical or dietary treatment. One of the few empirically validated treatments includes a specific psychological therapy called cognitive behavior therapy which, if available, is typically administered over several months by trained practitioners in tertiary care settings. There is an urgent need to develop more efficient versions of CBT that require minimal professional assistance but retain the efficacy profile of clinic based CBT. The Irritable Bowel Syndrome Outcome Study (IBSOS) is a multicenter, placebo-controlled randomized trial to evaluate whether a self-administered version of CBT is, at least as efficacious as standard CBT and more efficacious than an attention control in reducing core GI symptoms of IBS and its burden (e.g. distress, quality of life impairment, etc.) in moderately to severely affected IBS patients. Additional goals are to assess, at quarterly intervals, the durability of treatment response over a 12. month period; to identify clinically useful patient characteristics associated with outcome as a way of gaining an understanding of subgroups of participants for whom CBT is most beneficial; to identify theory-based change mechanisms (active ingredients) that explain how and why CBT works; and evaluate the economic costs and benefits of CBT. Between August 2010 when IBSOS began recruiting subjects and February 2012, the IBSOS randomized 171 of 480 patients. Findings have the potential to improve the health of IBS patients, reduce its social and economic costs, conserve scarce health care resources, and inform evidence-based practice guidelines. © 2012 Elsevier Inc.
Bacteria and other prokaryotes have been around for billions of years because they managed to develop successful evolutionary strategies for survival. For instance, they possess defense mechanisms that allow them to discriminate between self and non-self DNA in the event of a virus infection. These defense mechanisms are called restriction-modification systems and are based on the balance between the two enzymes M (methyltransferase) and R (restriction endonuclease). M tags endogenous DNA as self by methylating short specific DNA sequences—called restriction sites, and R recognizes unmethylated restriction sites as non-self and cleaves the DNA to render it harmless. It has been suspected that the discrimination mechanism of restriction-modification systems may be imperfect and that also bacteria may experience autoimmunity issues because the number of restriction sites in many bacterial genomes is lower than expected. On the upside of potential mistakes, occasional cleavage of self-DNA could promote DNA recombination and contribute to genetic variation in microbial populations, thus facilitating adaptive evolution. On the downside however, it might lead to cell death and thus impose a fitness cost on bacterial populations. Despite these potential implications, autoimmunity in bacteria has not been directly observed so far. Maros Pleska, a graduate student in the laboratory of C?lin Guet, an Assistant Professor at IST Austria, together with the teams of their colleagues Edo Kussell of New York University and Yuichi Wakamoto of Tokyo University, as well as IST Austria postdoc Tobias Bergmiller examine this scenario in their paper published on January 21, 2016, in Current Biology. The authors studied two different restriction-modification systems originating from the bacterium Escherichia coli, named EcoRI and EcoRV (pronounced as "eco R one" and "eco R five"). Pleska and his colleagues analyzed populations as well as single cells carrying these restriction-modification systems and found that EcoRI is indeed prone to erroneously cleave self DNA while EcoRV is not. These autoimmune events are very rare and easily masked by the majority of unaffected cells, which is why, up until now, detection of bacterial autoimmunity was a major experimental challenge. The authors managed to spot the rare events of bacterial autoimmunity and show that when they occur, the SOS response is triggered and specific proteins disengage to repair the damaged DNA. By comparing and counting nearly one hundred thousand bacterial colonies (see picture), the authors found out that under standard conditions, everything works just fine, but the ability to fix the damage is decreased in conditions where resources are scarce. But why are some restriction-modification systems more likely to cause autoimmunity than others? Guet and his team found that the probability of cleaving self DNA is higher for more efficient restriction-modification systems—in this case EcoRI. It almost seems as if these systems are overeager at times in their attempt to protect the cell from harm. The result suggests the existence of an evolutionary tradeoff between enhanced protection against exogenous DNA and increased autoimmunity. The autoimmunity work would not have been possible without the highly interdisciplinary team from Austria, Japan and USA, which was supported by a Young Investigator Human Frontier Science Grant to Guet, Kussell and Wakamoto that specifically supports high risk interdisciplinary projects, as well as a DOC OeAW Fellowship awarded to Pleska. More information: Maroš Pleška et al. Bacterial Autoimmunity Due to a Restriction-Modification System, Current Biology (2016). DOI: 10.1016/j.cub.2015.12.041
Azim Jr. H.A.,Luniversite Libre Of Bruxelles Ulb |
Metzger-Filho O.,Luniversite Libre Of Bruxelles Ulb |
De Azambuja E.,Luniversite Libre Of Bruxelles Ulb |
Loibl S.,Klinikum Offenbach |
And 4 more authors.
Breast Cancer Research and Treatment | Year: 2012
Only few case reports describe the pregnancy course and outcome of breast cancer patients, who were under treatment with trastuzumab at the time of conception or who have completed trastuzumab therapy before becoming pregnant. The HERA trial is a large phase III randomized clinical trial in which patients with early HER2-positive breast cancer were randomized to receive 1 or 2 years of trastuzumab or observation following completion of primary chemotherapy. To examine the effect of trastuzumab on pregnancy outcome, we report all pregnancy events that occurred until March 2010 in patients enrolled in the study. For the sake of this analysis, patients were assigned to three groups: (1) pregnancy occurring during and up to 3 months after trastuzumab exposure (group 1); (2) pregnancy occurring >3 months of last trastuzumab dose (group 2); and (3) pregnancy occurring in patients without prior exposure to trastuzumab (group 3). Sixteen, 45 and 9 pregnancies took place in groups 1, 2, and 3, respectively. 25 and 16% of patients in groups 1 and 2 experienced spontaneous abortion, the former being higher than figures reported in the general population. However, short-term fetal outcome appeared normal across the three groups. Only 2 congenital anomalies were reported, one in group 2 and one in group 3. No congenital anomalies were reported in those exposed to trastuzumab in utero. This is the first report from a large randomized trial assessing the effect of trastuzumab on pregnancy course and outcome. Based on our results, trastuzumab does not appear to affect fetal outcome in patients who manage to complete their pregnancy. We are currently initiating a collaboration to collect similar data from the other large adjuvant trastuzumab trials to confirm these findings. © 2012 Springer Science+Business Media, LLC.
The world of epigenetics – where molecular ‘switches’ attached to DNA turn genes on and off – has just got bigger with the discovery by a team of scientists from the University of Cambridge of a new type of epigenetic modification. Published in the journal Nature Structural and Molecular Biology, the discovery suggests that many more DNA modifications than previously thought may exist in human, mouse and other vertebrates. DNA is made up of four ‘bases’: molecules known as adenine, cytosine, guanine and thymine – the A, C, G and T letters. Strings of these letters form genes, which provide the code for essential proteins, and other regions of DNA, some of which can regulate these genes. Epigenetics (epi - the Greek prefix meaning ‘on top of’) is the study of how genes are switched on or off. It is thought to be one explanation for how our environment and behavior, such as our diet or smoking habit, can affect our DNA and how these changes may even be passed down to our children and grandchildren. Epigenetics has so far focused mainly on studying proteins called histones that bind to DNA. Such histones can be modified, which can result in genes being switched on or of. In addition to histone modifications, genes are also known to be regulated by a form of epigenetic modification that directly affects one base of the DNA, namely the base C. More than 60 years ago, scientists discovered that C can be modified directly through a process known as methylation, whereby small molecules of carbon and hydrogen attach to this base and act like switches to turn genes on and off, or to ‘dim’ their activity. Around 75 million (one in ten) of the Cs in the human genome are methylated. Now, researchers at the Wellcome Trust-Cancer Research UK Gurdon Institute and the Medical Research Council Cancer Unit at the University of Cambridge have identified and characterized a new form of direct modification – methylation of the base A – in several species, including frogs, mouse and humans. Methylation of A appears to be far less common that C methylation, occurring on around 1,700 As in the genome, but is spread across the entire genome. However, it does not appear to occur on sections of our genes known as exons, which provide the code for proteins. “These newly-discovered modifiers only seem to appear in low abundance across the genome, but that does not necessarily mean they are unimportant,” said Dr. Magdalena Koziol from the Gurdon Institute. “At the moment, we don’t know exactly what they actually do, but it could be that even in small numbers they have a big impact on our DNA, gene regulation and ultimately human health.” More than two years ago, Dr. Koziol made the discovery while studying modifications of RNA. There are 66 known RNA modifications in the cells of complex organisms. Using an antibody that identifies a specific RNA modification, Dr. Koziol looked to see if the analogous modification was also present on DNA, and discovered that this was indeed the case. Researchers at the MRC Cancer Unit then confirmed that this modification was to DNA, rather than from any RNA contaminating the sample. “It’s possible that we struck lucky with this modifier,” said Dr. Koziol, “but we believe it is more likely that there are many more modifications that directly regulate our DNA. This could open up the field of epigenetics.” The research was funded by the Biotechnology and Biological Sciences Research Council, Human Frontier Science Program, Isaac Newton Trust, Wellcome Trust, Cancer Research UK and the Medical Research Council.