Antitumor activity in RAS-driven tumors by blocking AKT and MEK.

PURPOSE: KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. EXPERIMENTAL DESIGN: We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were defined as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily. RESULTS: Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical antitumor activity included RECIST 1.0-confirmed partial responses in non-small cell lung cancer and low-grade ovarian carcinoma. CONCLUSION: Responses in KRAS-mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS-driven human malignancies (Trial NCT number NCT01021748).The Drug Development Unit of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research is supported in part by a programme grant from Cancer Research UK (grant number: C347/A18077). Support was also provided by an Experimental Cancer Medicine Centre grant (no grant number) and the National Institute for Health Research Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research) (grant numbers: A46/CCR - CCR4057 & CCR4058).This is the accepted manuscript of a paper published in Clinical Cancer Research, February 15, 2015 21; 739, doi: 10.1158/1078-0432.CCR-14-190

Seismic Deployments and Experiments: PeruNet, GeoNet, and SeismoPhone.

In conjunction with Caltech and the Geophysical Institute of Peru, we installed our network of 49 seismic sites across steep and shallow subduction regions in Peru. Flat slab subduction is thought to have formed much of the major geology of the western United States some 100 million years ago. By examining such processes presently active in Central and South America we can piece together the history. The data from the Peruvian sites is delivered to UCLA every night and we have collected almost 1 year so far. In the GeoNet experiment, the science objective is to use a rapidly installable wirelessly linked seismic network to make near-real time unaliased observations in aftershock or volcanic zones. The immediate technical objective is to collaborate with Reftek to construct a new generation digital acquisition system (DAS) based on the CENS-developed LEAP (low-power energy aware processing) system and a newly developed low-power A/D converter from Texas Instruments. We also look into the possibility of using the cell phones for seismic data collection and research. Phones are increasingly being equipped with not only accelerometers, but also cameras, Global Positioning System (GPS) receivers and Internet connectivity. This makes them very attractive for use in data mining. We have tested a number of small USB accelerometers and a cell phone on a shake table and the results are encouraging

SEI 2: Embedded Wired and Wireless Seismic Networks for Structural Health Monitoring

A main thrust of the seismic application is the development of algorithms for performing high spatial resolution measurements and modeling of structures using wired and wireless arrays. The UCLA Factor building is a testbed for predictive numerical modeling, wireless network, and smart event-detection developments related to structural health monitoring. Waveform data from the 72-node array in the 17-story moment-resisting steel frame Factor building are used in comparison with finite element calculations for predictive behavior

A Low-Effort, Clinic-Wide Intervention Improves Attendance for HIV Primary Care

Data from 6 human immunodeficiency virus clinics showed improvements in clinic attendance after versus before a clinic-wide intervention (7% on short-term measure; 3% on longer-term measure). Several subgroups showed larger improvements: younger patients, new or reengaging patients, and patients with elevated viral loads. Background.  Retention in care for human immunodeficiency virus (HIV)–infected patients is a National HIV/AIDS Strategy priority. We hypothesized that retention could be improved with coordinated messages to encourage patients' clinic attendance. We report here the results of the first phase of the Centers for Disease Control and Prevention/Health Resources and Services Administration Retention in Care project. Methods.  Six HIV-specialty clinics participated in a cross-sectionally sampled pretest-posttest evaluation of brochures, posters, and messages that conveyed the importance of regular clinic attendance. 10 018 patients in 2008–2009 (preintervention period) and 11 039 patients in 2009–2010 (intervention period) were followed up for clinic attendance. Outcome variables were the percentage of patients who kept 2 consecutive primary care visits and the mean proportion of all primary care visits kept. Stratification variables were: new, reengaging, and active patients, HIV RNA viral load, CD4 cell count, age, sex, race or ethnicity, risk group, number of scheduled visits, and clinic site. Data were analyzed by multivariable log-binomial and linear models using generalized estimation equation methods. Results.  Clinic attendance for primary care was significantly higher in the intervention versus preintervention year. Overall relative improvement was 7.0% for keeping 2 consecutive visits and 3.0% for the mean proportion of all visits kept ( P  < .0001). Larger relative improvement for both outcomes was observed for new or reengaging patients, young patients and patients with elevated viral loads. Improved attendance among the new or reengaging patients was consistent across the 6 clinics, and less consistent across clinics for active patients. Conclusion.  Targeted messages on staying in care, which were delivered at minimal effort and cost, improved clinic attendance, especially for new or reengaging patients, young patients, and those with elevated viral loads

Combinatorial domain hunting: an effective approach for the identification of soluble protein domains adaptable to high-throughput applications

Exploitation of potential new targets for drug and vaccine development has an absolute requirement for multimilligram quantities of soluble protein. While recombinant expression of full-length proteins is frequently problematic, high-yield soluble expression of functional subconstructs is an effective alternative, so long as appropriate termini can be identified. Bioinformatics localizes domains, but doesn't predict boundaries with sufficient accuracy, so that subconstructs are typically found by trial and error. Combinatorial Domain Hunting (CDH) is a technology for discovering soluble, highly expressed constructs of target proteins. CDH combines unbiased, finely sampled gene-fragment libraries, with a screening protocol that provides "holistic" readout of solubility and yield for thousands of protein fragments. CDH is free of the "passenger solubilization" and out-of-frame translational start artifacts of fusion-protein systems, and hits are ready for scale-up expression. As a proof of principle, we applied CDH to p85alpha, successfully identifying soluble and highly expressed constructs encapsulating all the known globular domains, and immediately suitable for downstream applications

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified &gt;300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection