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Phase I clinical trial of the Src inhibitor dasatinib with dacarbazine in metastatic melanoma.
BackgroundSrc inhibitors sensitise melanoma cells to chemotherapy in preclinical models. The combination of dasatinib and dacarbazine was tested in a phase I trial in melanoma.MethodsPatients had ECOG performance status 0-2 and normal organ function. Dacarbazine was administered on day 1 and dasatinib on day 2 through 19 of each 21-day cycle. Both were escalated from 50 mg b.i.d. of dasatinib and 800 mg m(-2) of dacarbazine. Available pre-treatment biopsies were sequenced for BRAF, NRAS, and C-Kit mutations.ResultsDose-limiting toxicity was reached at dasatinib 70 mg b.i.d./dacarbazine 1000 mg m(-2), and was predominantly haematological. In 29 patients receiving dasatinib 70 mg b.i.d., the objective response rate (ORR) was 13.8%, the clinical benefit rate (ORR+SD) was 72.4%, the 6-month progression-free survival (PFS) was 20.7%, and the 12-month overall survival (OS) was 34.5%. Two out of three patients who were wild type for BRAF, NRAS, and c-KIT mutations had confirmed partial responses, and one had a minor response.ConclusionThe recommended phase II dose is dasatinib 70 mg b.i.d with dacarbazine 800 mg m(-2). PFS and OS data for dasatinib at 70 mg b.i.d. with dacarbazine compared favourably with historical controls. Preliminary data support evaluating tumour mutation status further as a biomarker of response
Citrobacter rodentium induces rapid and unique metabolic and inflammatory responses in mice suffering from severe disease.
The mouse pathogen Citrobacter rodentium is used to model infections with enterohaemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC). Pathogenesis is commonly modelled in mice developing mild disease (e.g., C57BL/6). However, little is known about host responses in mice exhibiting severe colitis (e.g., C3H/HeN), which arguably provide a more clinically relevant model for human paediatric enteric infection. Infection of C3H/HeN mice with C. rodentium results in rapid colonic colonisation, coinciding with induction of key inflammatory signatures and colonic crypt hyperplasia. Infection also induces dramatic changes to bioenergetics in intestinal epithelial cells, with transition from oxidative phosphorylation (OXPHOS) to aerobic glycolysis and higher abundance of SGLT4, LDHA, and MCT4. Concomitantly, mitochondrial proteins involved in the TCA cycle and OXPHOS were in lower abundance. Similar to observations in C57BL/6 mice, we detected simultaneous activation of cholesterol biogenesis, import, and efflux. Distinctly, however, the pattern recognition receptors NLRP3 and ALPK1 were specifically induced in C3H/HeN. Using cell-based assays revealed that C. rodentium activates the ALPK1/TIFA axis, which is dependent on the ADP-heptose biosynthesis pathway but independent of the Type III secretion system. This study reveals for the first time the unfolding intestinal epithelial cells' responses during severe infectious colitis, which resemble EPEC human infections
The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network
Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.
Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientÅ› delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.
Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects
Quantum nondemolition measurement of mechanical motion quanta
The fields of opto- and electromechanics have facilitated numerous advances
in the areas of precision measurement and sensing, ultimately driving the
studies of mechanical systems into the quantum regime. To date, however, the
quantization of the mechanical motion and the associated quantum jumps between
phonon states remains elusive. For optomechanical systems, the coupling to the
environment was shown to preclude the detection of the mechanical mode
occupation, unless strong single photon optomechanical coupling is achieved.
Here, we propose and analyse an electromechanical setup, which allows to
overcome this limitation and resolve the energy levels of a mechanical
oscillator. We find that the heating of the membrane, caused by the interaction
with the environment and unwanted couplings, can be suppressed for carefully
designed electromechanical systems. The results suggest that phonon number
measurement is within reach for modern electromechanical setups.Comment: 8 pages, 5 figures plus 24 pages, 11 figures supplemental materia
Interactive Actor Analysis for Rural Water Management in The Netherlands
Recent developments in the policy sciences emphasize the social environment
in which decisions are made. The ‘network metaphor’ is often used to describe
the key role of interactions between interdependent actors involved in decision
making. These interactions take place in a policy arena drawn up by actors with an
interest in and control over decisions on the issues addressed. Interdependencies,
caused by the need for actors to increase their means of realizing objectives, are
the driving force behind these interactions. Dependency relations are of special
interest to water management and river basin management because of the fundamental
asymmetrical interdependencies that exist in river basins between upstream
and downstream stakeholders. Coleman’s linear system of action models decision
making process involving dependencies between multiple stakeholders as exchange
of control over issues, while interactions are required to negotiate exchanges of
control. We developed an interactive method for actor analysis based on Coleman’s
linear system of action and applied it to the national rural water management policy
domain in The Netherlands. The method is firmly rooted in mathematical sociology
and defies the criticism that methods for actor and stakeholder analysis do not specify
a theoretical basis explaining the causal relations between the variables analyzed and
policy change. With the application to the rural water management policy arena we
intended to increase our insight into the practical applicability of this analyticmethod
in an interactive workshop, the acceptability of the approach for the participating
actors, its contribution to the process of decision making and our understanding of
the rural water management policy arena in The Netherlands. We found that the
Association of Water Authorities, the Ministry of Public Works and the Ministry of
Agriculture are the most powerful actor in the policy domain, while governance and
cost and benefits of rural water management are the most salient issues. Progress
in policy development for rural water management is probably most promising for the issues governance, costs and benefits, safety and rural living conditions through
improved interaction between the Association of Water Authorities, the Ministry of
Agriculture and the Rural Credit Bank. Besides these analytic results the interactive
approach implemented increased the participants understanding of their dependency
on other actors in the rural water management policy domain and supported them
in developing a sound perspective on their dependency position. We concluded
that the method developed is acceptable to real-world policy decision makers, can
successfully be applied in an interactive setting, potentially contributes to the process
of decision making by increasing the participants understanding of their dependency
position, has the potential to delivers valuable advice for future decision-making and
increases our understanding of policy development for rural water management in
general
Do all patients in the phase I oncology trials need to be hospitalized? Domestic but outstanding issues for globalization of drug development in Japan
Climate impacts of energy technologies depend on emissions timing
Energy technologies emit greenhouse gases with differing radiative efficiencies and atmospheric lifetimes. Standard practice for evaluating technologies, which uses the global warming potential (GWP) to compare the integrated radiative forcing of emitted gases over a fixed time horizon, does not acknowledge the importance of a changing background climate relative to climate change mitigation targets. Here we demonstrate that the GWP misvalues the impact of CH[subscript 4]-emitting technologies as mid-century approaches, and we propose a new class of metrics to evaluate technologies based on their time of use. The instantaneous climate impact (ICI) compares gases in an expected radiative forcing stabilization year, and the cumulative climate impact (CCI) compares their time-integrated radiative forcing up to a stabilization year. Using these dynamic metrics, we quantify the climate impacts of technologies and show that high-CH[subscript 4]-emitting energy sources become less advantageous over time. The impact of natural gas for transportation, with CH[subscript 4] leakage, exceeds that of gasoline within 1–2 decades for a commonly cited 3 W m[superscript −2] stabilization target. The impact of algae biodiesel overtakes that of corn ethanol within 2–3 decades, where algae co-products are used to produce biogas and corn co-products are used for animal feed. The proposed metrics capture the changing importance of CH[subscript 4] emissions as a climate threshold is approached, thereby addressing a major shortcoming of the GWP for technology evaluation.New England University Transportation Center (DOT Grant DTRT07-G-0001
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