Drug-induced resistance evolution necessitates less aggressive treatment.

Increasing body of experimental evidence suggests that anticancer and antimicrobial therapies may themselves promote the acquisition of drug resistance by increasing mutability. The successful control of evolving populations requires that such biological costs of control are identified, quantified and included to the evolutionarily informed treatment protocol. Here we identify, characterise and exploit a trade-off between decreasing the target population size and generating a surplus of treatment-induced rescue mutations. We show that the probability of cure is maximized at an intermediate dosage, below the drug concentration yielding maximal population decay, suggesting that treatment outcomes may in some cases be substantially improved by less aggressive treatment strategies. We also provide a general analytical relationship that implicitly links growth rate, pharmacodynamics and dose-dependent mutation rate to an optimal control law. Our results highlight the important, but often neglected, role of fundamental eco-evolutionary costs of control. These costs can often lead to situations, where decreasing the cumulative drug dosage may be preferable even when the objective of the treatment is elimination, and not containment. Taken together, our results thus add to the ongoing criticism of the standard practice of administering aggressive, high-dose therapies and motivate further experimental and clinical investigation of the mutagenicity and other hidden collateral costs of therapies.

Inferring the dynamics of mutated hematopoietic stem and progenitor cells induced by IFNα in myeloproliferative neoplasms.

Classical BCR-ABL-negative myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells (HSCs) caused mainly by recurrent mutations in genes encoding JAK2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (MPL). Interferon α (IFNα) has demonstrated some efficacy in inducing molecular remission in MPNs. To determine factors that influence molecular response rate, we evaluated the long-term molecular efficacy of IFNα in patients with MPN by monitoring the fate of cells carrying driver mutations in a prospective observational and longitudinal study of 48 patients over more than 5 years. We measured the clonal architecture of early and late hematopoietic progenitors (84 845 measurements) and the global variant allele frequency in mature cells (409 measurements) several times per year. Using mathematical modeling and hierarchical Bayesian inference, we further inferred the dynamics of IFNα-targeted mutated HSCs. Our data support the hypothesis that IFNα targets JAK2V617F HSCs by inducing their exit from quiescence and differentiation into progenitors. Our observations indicate that treatment efficacy is higher in homozygous than heterozygous JAK2V617F HSCs and increases with high IFNα dose in heterozygous JAK2V617F HSCs. We also found that the molecular responses of CALRm HSCs to IFNα were heterogeneous, varying between type 1 and type 2 CALRm, and a high dose of IFNα correlates with worse outcomes. Our work indicates that the long-term molecular efficacy of IFNα implies an HSC exhaustion mechanism and depends on both the driver mutation type and IFNα dose.

Early Clinical Response in Community-acquired Bacterial Pneumonia: From Clinical Endpoint to Clinical Practice.

BACKGROUND: Early clinical response (ECR) is a new endpoint to determine whether a drug should be approved for community-acquired bacterial pneumonia in the United States. The Omadacycline for Pneumonia Treatment In the Community (OPTIC) phase III study demonstrated noninferiority of omadacycline to moxifloxacin using this endpoint. This study describes the performance of the ECR endpoint and clinical stability relative to a posttreatment evaluation (PTE) of clinical success. METHODS: ECR was defined as symptom improvement 72-120 hours after the first dose of study drug (ECR window), no use of rescue antibiotics, and patient survival. Clinical success at PTE was an investigator assessment of success. Clinical stability was defined based on vital sign stabilization, described in the American Thoracic Society and Infectious Diseases Society of America community-acquired pneumonia treatment guidelines. RESULTS: During the ECR window, ECR was achieved in 81.1% and 82.7% of omadacycline and moxifloxacin patients, respectively. Similar numbers of patients achieved clinical stability in each treatment group (omadacycline 74.6%, moxifloxacin 77.6%). The proportion of patients with improved symptoms who were considered clinically stable increased across the ECR window (69.2-77.6% for omadacycline; 68.0-79.7% for moxifloxacin). There was high concordance (>70%) and high positive predictive value (>90%) of ECR and clinical stability with overall clinical success at PTE. CONCLUSIONS: Omadacycline was noninferior to moxifloxacin, based on a new ECR endpoint. Clinical stability was similarly high when measured in the same time frame as ECR. Both ECR and clinical stability showed high concordance and high positive predictive value with clinical success at PTE. CLINICAL TRIALS REGISTRATION: NCT02531438.

Agricultural lands are hot-spots for annual runoff polluting the southern Great Barrier Reef lagoon.

The world's largest coral reef ecosystem, the Great Barrier Reef (GBR), continues to be degraded from land-based pollution. Information about the source of pollutants is critical for catchment management to improve GBR water quality. We report here on an 11-year source to sea study of pollutant delivery in runoff from the Fitzroy River Basin (FRB), the largest GBR catchment. An innovative technique that relates land use to pollutant generation is presented. Study results indicate that maximum pollutant concentrations at basin and sub-catchment scales are closely related to the percentage area of croplands receiving heavy rain. However, grazing lands contribute the majority of the long-term average annual load of most common pollutants. Findings suggest improved land management targets, rather than water quality targets should be implemented to reduce GBR pollution. This study provides a substantial contribution to the knowledge base for the targeted management of pollution 'hot-spots' to improve GBR water quality.

The discovery of the vinca alkaloids-chemotherapeutic agents against cancer

In folklore medicine, extracts of the leaves of the subtropical plant Catharanthus roseus (L.) G. Don (sometimes known as Madagascar periwinkle) were reputed to be useful in the treatment of diabetes. This review describes how attempts to verify the antidiabetic properties of the extracts led instead to the discovery and isolation of two complex indole alkaloids, vinblastine and vincristine, which are used in the clinical treatment of a variety of cancers. The two alkaloids, although structurally almost identical, nevertheless differ markedly in the type of tumors that they affect and in their toxic properties. These and related alkaloids have been the subject of many pharmacological and biochemical investigations both in vivo and in vitro in the search for improved cancer treatments. A model system used in these studies, a transplantable lymphoma in Noble strain rats designated Nb2 node, has serendipitously led to the development of a highly sensitive and specific bioassay for lactogenic hormones. (AU)