Obesity is a growing pandemic, and related health and economic costs are staggering. Pharmacotherapy, partnered with lifestyle modifications, forms the core of current strategies to reduce the burden ...of this disease and its sequelae. However, therapies targeting weight loss have a significant history of safety risks, including cardiovascular and psychiatric events. Here, evolving strategies for developing antiobesity therapies, including targets, mechanisms, and developmental status, are highlighted. Progress in this field is underscored by Belviq (lorcaserin) and Qsymia (phentermine/topiramate), the first agents in more than 10 years to achieve regulatory approval for chronic weight management in obese patients. On the horizon, novel insights into metabolism and energy homeostasis reveal guanosine 3′,5′‐cyclic monophosphate (cGMP) signaling circuits as emerging targets for antiobesity pharmacotherapy. These innovations in molecular discovery may elegantly align with practical off‐the‐shelf approaches, leveraging existing approved drugs that modulate cGMP levels for the management of obesity.
Clinical Pharmacology & Therapeutics (2013); 95 1, 53–66 advance online publication 13 November 2013. doi:10.1038/clpt.2013.204
Toxoplasma gondii chronically infects a quarter of the world’s population, and its recrudescence can cause life-threatening disease in immunocompromised individuals and recurrent ocular lesions in ...the immunocompetent. Acute-stage tachyzoites differentiate into chronic-stage bradyzoites, which form intracellular cysts resistant to immune clearance and existing therapies. The molecular basis of this differentiation is unknown, despite being efficiently triggered by stresses in culture. Through Cas9-mediated screening and single-cell profiling, we identify a Myb-like transcription factor (BFD1) necessary for differentiation in cell culture and in mice. BFD1 accumulates during stress and its synthetic expression is sufficient to drive differentiation. Consistent with its function as a transcription factor, BFD1 binds the promoters of many stage-specific genes and represents a counterpoint to the ApiAP2 factors that dominate our current view of parasite gene regulation. BFD1 provides a genetic switch to study and control Toxoplasma differentiation and will inform prevention and treatment of chronic infections.
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•BFD1 is a master regulator of chronic-stage differentiation in Toxoplasma gondii•ΔBFD1 parasites fail to differentiate in cell culture or form cysts in infected mice•Conditional expression of BFD1 is sufficient to induce differentiation•BFD1 binds transcriptional start sites of genes induced during chronic stages
A single parasite transcription factor drives the differentiation of Toxoplasma to a cyst-forming stage to sustain chronic infection.
Abstract
Factors such as shift work, poor diet, lack of physical activity, and irregular sleep patterns put men and women employed in high-stress occupations (e.g., firefighters, police officers) at ...risk for cardiometabolic diseases. Time-restricted feeding (TRF) is a new approach to combatting many of these diseases; it places an emphasis on when meals are consumed, rather than calorie content. By only manipulating the eating “window,” and without changing the food composition of the diet, research in rodent models has shown promising results that have health implications in people, such as obesity prevention, improved insulin sensitivity, and decreased oxidative stress, inflammation, and cholesterol synthesis. Human trials remain limited and the current data are mixed with regard to TRF and improving health. Present findings suggest the timing of the feeding-fasting window, with feeding taking place in the waking hours and fasting in the evening hours, might offer the greatest benefit for improving cardiometabolic markers. Although additional human trials are needed, TRF might reset and synchronize metabolic “clocks” found throughout the body that are disturbed with obesity, shift work, and frequent eating. Therefore, TRF might offer an effective feeding-fasting paradigm with significant clinical implications for the management and treatment of cardiometabolic diseases observed in individuals in high-stress occupations in the United States and in the US population in general. This review outlines the current rodent and human evidence in these areas and the efficacy of TRF for improving human health.
Distant metastasis accounts for 90% of deaths from colorectal cancer (CRC). Genomic heterogeneity has been reported in various solid malignancies, but remains largely under-explored in metastatic CRC ...tumors, especially in primary to metastatic tumor evolution.
We conducted high-depth whole-exome sequencing in multiple regions of matched primary and metastatic CRC tumors. Using a total of 28 tumor, normal, and lymph node tissues, we analyzed inter- and intra-individual heterogeneity, inferred the tumor subclonal architectures, and depicted the subclonal evolutionary routes from primary to metastatic tumors.
CRC has significant inter-individual but relatively limited intra-individual heterogeneity. Genomic landscapes were more similar within primary, metastatic, or lymph node tumors than across these types. Metastatic tumors exhibited less intratumor heterogeneity than primary tumors, indicating that single-region sequencing may be adequate to identify important metastasis mutations to guide treatment. Remarkably, all metastatic tumors inherited multiple genetically distinct subclones from primary tumors, supporting a possible polyclonal seeding mechanism for metastasis. Analysis of one patient with the trio samples of primary, metastatic, and lymph node tumors supported a mechanism of synchronous parallel dissemination from the primary to metastatic tumors that was not mediated through lymph nodes.
In CRC, metastatic tumors have different but less heterogeneous genomic landscapes than primary tumors. It is possible that CRC metastasis is, at least partly, mediated through a polyclonal seeding mechanism. These findings demonstrated the rationale and feasibility for identifying and targeting primary tumor-derived metastasis-potent subclones for the prediction, prevention, and treatment of CRC metastasis.
Success in pharmaceutical development led to a record 51 drugs approved in the past year, surpassing every previous year since 1950. Technology innovation enabled identification and exploitation of ...increasingly precise disease targets ensuring next generation diagnostic and therapeutic products for patient management. The expanding biopharmaceutical portfolio stands, however, in contradistinction to the unsustainable costs that reflect remarkable challenges of clinical development programs. This annual Therapeutic Innovations issue juxtaposes advances in translating molecular breakthroughs into transformative therapies with essential considerations for lowering attrition and improving the cost‐effectiveness of the drug‐development paradigm. Realizing the discovery‐translation‐application continuum mandates a congruent approval, adoption, and access triad.
Clinical Pharmacology & Therapeutics (CPT), the definitive and timely source for advances in human therapeutics, transcends the drug discovery, development, regulation, and utilization continuum to ...catalyze, evolve, and disseminate discipline‐transformative knowledge. Prioritized themes and multidisciplinary content drive the science and practice of clinical pharmacology, offering a trusted point of reference. An authoritative herald across global communities, CPT is a timeless information vehicle at the vanguard of discovery, translation, and application ushering therapeutic innovation into modern healthcare.
Clinical Pharmacology & Therapeutics (CPT) is an established voice of the discipline, a trusted source of new knowledge showcasing discovery, translation, and application of novel therapeutic ...paradigms to advance the management of patients and populations. Identifying, evaluating, prioritizing, and disseminating the best science along the discovery–development–regulatory–utilization continuum are responsibilities shared through peer review. To enhance the uniformity of this essential component of quality assurance and innovation, and maximize the value of the journal and its contents to authors, reviewers, and the readership, we review key concepts concerning peer review as it specifically relates to CPT.
Enabling omic technologies adopt a holistic view to produce unprecedented insights into the molecular underpinnings of health and disease, in part, by generating massive high‐dimensional biological ...data. Leveraging these systems‐level insights as an engine driving the healthcare evolution is maximized through integration with medical, demographic, and environmental datasets from individuals to populations. Big data analytics has accordingly emerged to add value to the technical aspects of storage, transfer, and analysis required for merging vast arrays of omic‐, clinical‐, and eco‐datasets. In turn, this new field at the interface of biology, medicine, and information science is systematically transforming modern therapeutics across discovery, development, regulation, and utilization.
Mini Abstract
This literature review summarized studies that evaluated the effects of epidural steroid injections (ESIs) on skeletal health. While evidence is limited, studies suggest that ESIs may ...cause bone loss. Better understanding of these skeletal consequences will help foster strategies to prevent bone loss in the growing population of patients receiving ESIs.
Purpose
Approximately nine million epidural steroid injections (ESIs) are administered annually in the United States to treat radicular back pain. ESIs often provide pain relief and functional improvement. While the overall incidence of adverse events resulting from ESIs is low, their effects on the skeleton are poorly understood. This is an important consideration given the profound skeletal impact of other forms of glucocorticoids.
Methods
Ovid MEDLINE and PubMed search results since 2010, including older, frequently referenced publications were reviewed.
Results
Systemic absorption of glucocorticoids occurs after ESI, which can cause hyperglycemia and endogenous cortisol suppression. The majority of studies investigating the skeletal effects of ESIs are retrospective. Several have found a relationship between low areal bone mineral density (BMD) by dual-energy x-ray absorptiometry and ESI exposure, but this finding is not uniform. Recently a dose-response relationship between ESI exposure and low spine volumetric BMD by computed tomography has been reported. Few studies have investigated the relationship between ESI exposure and fracture risk. Results of these studies are conflicting, and most have not been adequately powered to detect fracture outcomes.
Conclusions
While evidence is limited, studies suggest that ESIs may cause bone loss, particularly those investigating volumetric BMD. Larger doses appear to confer greater risk. Further prospective studies are needed to investigate the relationship between ESI and fracture risk. Better understanding of the skeletal consequences of ESIs will help foster strategies to prevent bone loss in the growing population of patients receiving this treatment.
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