Abstract: Most drugs don't work optimally in most patients. The same drug can exert a significant overall therapeutic benefit in some patients while post a pronounced overall toxicity risk in others with the same disease. Pharmacogenomics has progressively received attention in the drug development process. But genetics is not the only factor that contributes to the differences that individual patients respond to drugs. Enter global systems biology. ... Read more

Abstract: In many areas of medicine risk prediction models are used to identify high-risk persons to receive treatment, with the goal of maximizing the ratio of benefits to harms. Thus there is considerable interest in evaluating markers to improve risk prediction. Many measures to evaluate a new marker for risk prediction are based solely on predictive accuracy including the odds ratio, change in the area under the receiver operating characteristic curve, and net reclassification improvement. However, predictive accuracy measures do not capture important clinical implications. Decision analysis comes to the rescue by including the ratio of the anticipated harm ("cost") of a false positive to the anticipated benefit of a true positive, which is transformed into a risk threshold (T) of indifference between treatment and no treatment. A decision-analytic measure of the "value" of a new marker is the number needed to test at a particular risk threshold, denoted NNTest(T), the minimum number of marker tests per true positive needed for risk prediction to be worthwhile. If NNTest(T) is acceptable given the invasiveness and adverse consequences of the test for the new marker, the new marker is recommended for inclusion in risk prediction. We provide a simple review of the derivation and computation of NNTest(T) from risk stratification tables and compare the minimum of NNTest(T), over risk thresholds, with measures of predictive accuracy in six studies. The results illustrate the advantages of this decision-analytic approach for evaluating a new marker for risk prediction. ... Read more

Abstract: Cervical cancer is the commonest cancer cause of death among women in developing countries and efforts to prevent the disease using newer approaches and HPV vaccination need to be explored. Detection of cervical cancer at an early stage is associated with excellent survival but most women in developing countries present with advanced and often untreatable disease, with very poor survival. The ratio between incidence and mortality from cervical cancer remains very high, largely due to lack of access to appropriate anti-cancer therapies in developing countries. In developed countries with functional screening programs, cervical cancer has been rendered a relatively rare disease. Ongoing efforts to refine the characteristics of screening tests continue, as does implementation of current HPV vaccines for the primary prevention of cervical cancer. ... Read more

Abstract: There have been numerous chemoprevention trials in the past 10 years, but the number of approved chemoprevention drugs is still quite small. This is likely due to a number of factors, but two consistent problems in the field of chemoprevention have been the lack of efficacy with or without unacceptable toxicity, and unexpected toxicity or fear of it associated with most of the approaches. This review intends to describe the types of chemoprevention as well as highlight recent successes and failures. We will also discuss potential solutions for the problems of limited efficacy and toxicity. ... Read more

Abstract: Gastrointestinal stromal tumors (GIST) are the most frequent sarcoma and were recognized as distinct molecular entities in 1998. Following the identification of driving molecular alterations in KIT, imatinib was rapidly introduced for the treatment of GIST, and became the paradigm of molecularly targeted therapies for solid tumors. While surgery was the only known effective treatment in 1998, two drugs are approved by the FDA and EMA in 2012 for the treatment of localized and advanced forms of this disease. Imatinib has been shown to provide a high level of clinical efficacy in patients with advanced GIST, a median progression-free survival (PFS) of 2 years and median overall survival close to 5 years, with 20% patients progression-free after 10 years of treatment. Imatinib has also been proven to improve overall survival and reduce the risk of relapse in localized GIST at high risk for relapse after resection. Sunitinib is indicated in advanced GIST after failure of imatinib, and provided a median PFS close to 6 months after imatinib failure. However, there is an important variability in the molecular and genetic characteristics that drive the pathogenesis of GIST, allowing thus for the identification of distinct molecular subtypes of GIST with different prognosis and sensitivity to the targeted treatments. Different strategies are now recommended in these different molecular subtypes of GIST which must be recognized as different entities regarding sensitivity to tyrosine kinase inhibitors and treatment decisions. This fragmentation of a yet recently recognized disease entity illustrates to strong trend of fragmentation in nosology of cancers, even in rare tumors such as GIST. For this aspect also, GIST is again a paradigmatic model for oncology, as many tumors with a higher prevalence will be fragmented in different molecular subsets and are going to become rare disease in the years to come. ... Read more

Abstract: Advances in clinical and basic sciences are raising the potential to use genetic and clinical biomarkers to identify a subgroup of patients who would most likely benefit from treatment, and to evaluate the benefit of treatment in that subgroup. To make full use of this potential, special clinical trial designs and analyses are needed. For identifying and evaluating a subgroup based on a single continuous biomarker, the most informative approach is the biomarker-analysis design, which is a randomized trial whose analysis involves estimation of the treatment benefit within patient groups defined with respect to various cutpoints or intervals of the biomarker. For identifying and evaluating a subgroup considering a range of possible markers, the adaptive signature design is recommended. In the adaptive signature design, participants are randomly split into training and test samples, a rule for creating the subgroup is formulated in the training sample, and treatment benefit is estimated in the test sample. The adaptive signature design can be usefully extended via the sliding-window subgroup plot that was originally developed for the biomarker-analysis design. ... Read more

Abstract: Rotaviruses (RVs) are a large genetically diverse population of segmented double-stranded (ds) RNA viruses that are important causes of gastroenteritis in many animal species. The human RVs are responsible for the deaths of nearly 450,000 infants and young children each year, most occurring in developing countries. Recent large-scale sequencing efforts have revealed that the genomes of human RVs typically consist of phylogenetically linked constellations of eleven dsRNA segments. The presence of such preferred constellations indicate that the human RV genes have co-evolved to produce protein sets that work optimally together to support virus replication. Two of the viral genes encode virion outer capsid proteins (VP7 and VP4) whose antigenic properties define the G/P type of the virus. From year-to-year and place-to-place, the G/P type of human RVs associated with disease can fluctuate dramatically, phenomena that can be associated with the presence and behavior of genetically distinct RV clades. The recent introduction of two live attenuated RV vaccines (RotaTeq^TM and Rotarix^TM) into the childhood vaccination programs of various countries has been highly effective in reducing the incidence of RV diarrheal disease. Whether the widespread use of these vaccines will introduce selective pressures on human RVs, triggering genetic and antigenic changes that undermine the effectiveness of vaccinations programs, is uncertain and will require continued surveillance of human RVs. ... Read more

Abstract: We are in the midst of a resurgence of Clostridium difficile infection (CDI) in North America and Europe for which morbidity and mortality are higher than ever seen. C. difficile has risen in frequency to become the most common healthcare-associated infection pathogen, exceeding methicillin-resistant Staphylococcus aureus in many hospitals. Protection against CDI is thought to be mediated first by the normal bacterial microbiota, supplemented by an adaptive immune antibody response directed primarily at C. difficile toxins. Treatment of CDI is with antimicrobials that also further disrupt the protective bacterial microbiota leaving the patient susceptible to recurrent CDI. In addition, patients most susceptible to CDI, the advanced elderly, may already have a limited immune response and fail to increase their adaptive immune response with infection. The importance of both of these protective modalities has been demonstrated by 1) the success of fecal microbiota to restore "colonization resistance" for patients with multiple recurrences of CDI, and 2) the marked reduction in CDI recurrences with the use of intravenous monoclonal antibodies directed against toxin A and toxin B as an adjunct to antimicrobial treatment. Anti-toxin vaccines, passive monoclonal anti-toxin antibodies, and non-toxigenic C. difficile (to restore colonization resistance) are already undergoing patient clinical trials. The opportunity to prevent CDI is compelling and future research should focus on understanding the critical elements of the microbiota needed to restore colonization resistance and on development of novel immunologic strategies that include systemic and mucosal vaccines and passive immune modulators. ... Read more

Abstract: Drug transporters mediate the movement of endobiotics and xenobiotics across biological membranes in multiple organs and in most tissues. As such, they are involved in physiology, development of disease, drug pharmacokinetics, and ultimately the clinical response to a myriad of medications. Genetic variants in transporters cause population-specific differences in drug transport and are responsible for considerable inter-individual variation in physiology and pharmacotherapy. The purpose of this review is to provide a broad overview of how inherited variants in transporters are associated with disease etiology, disease state, and the pharmacological treatment of diseases. Given that there are thousands of published papers related to the interplay between transporter genetics and medicine, this review will provide examples that exemplify the broader focus of the literature. ... Read more

Abstract: Vaccine-preventable diseases are still responsible for the deaths of more than 1 million children under the age of 5 years annually, mostly in developing countries. A substantial number of these deaths are due to pneumococcal bacteria and infections with rotavirus. Important issues faced by the WHO, governments, vaccine manufacturers, and international organizations such as UNICEF and the Global Alliance for Vaccines and Immunization (GAVI) are the cost-effective introduction of these life-saving vaccines in resource-poor countries where there is a considerable disease burden, and achieving high rates of completion of vaccination schedules remains elusive. Problems with vaccine coverage and vaccine delivery in these regions are significant, as in some cases large proportions of the target population do not receive adequate vaccination. Consequently, there is a need to develop more effective vaccination strategies that can provide adequate protection with reduced schedules. To date, emphasis has been placed on identifying novel vaccine antigens and adjuvants that induce stronger protective immune responses, as well as developing mucosally-administered vaccines. These approaches would have enormous benefits in allowing safe administration of vaccines in remote areas and may overcome the necessity for multiple doses. In this regard, the use of probiotic bacteria as novel mucosal adjuvants to enhance existing vaccine specific-immune responses offers an exciting new approach. In this review, we discuss the evidence for the role of probiotics in enhancing vaccine responses and provide justification for further investigation into their clinical effects and mechanisms of action. ... Read more