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Auger decay of multiple excitons represents a significant obstacle to photonic applications of semiconductor quantum dots (QDs). This nonradiative process is particularly detrimental to the performance of QD-based electroluminescent and lasing devices. Here, we demonstrate that semiconductor quantum shells with an "inverted" QD geometry inhibit Auger recombination, allowing substantial improvements to their multiexciton characteristics. By promoting a spatial separation between multiple excitons, the quantum shell geometry leads to ultralong biexciton lifetimes (10 ns) and a large biexciton quantum yield. Furthermore, the architecture of quantum shells induces an exciton-exciton repulsion, which splits exciton and biexciton optical transitions, giving rise to an Auger-inactive single-exciton gain mode. In this regime, quantum shells exhibit the longest optical gain lifetime reported for colloidal QDs to date (6 ns), which makes this geometry an attractive candidate for the development of optically and electrically pumped gain media.

Study drug dosing

Supplementary Appendix

Supplementary Table from Mechanistic and Predictive Profiling of 5-Fluorouracil Resistance in Human Cancer Cells

Gene expression was analyzed in five pairs of 5-fluorouracil (5-FU) resistant and parental cancer cell lines on DNA microarrays. In unsupervised analysis, a prediction rule was built from the expression profiles of 29 genes, and 5-FU sensitivity class was predicted with 100% accuracy and high predictive strength. In supervised analysis of key 5-FU pathways, expression of 91 genes was associated with 5-FU sensitivity phenotype and segregated samples accordingly in hierarchical analysis. Key genes involved in 5-FU activation were significantly down-regulated (thymidine kinase, 2.9-fold; orotate phosphoribosyltransferase, 2.3-fold; uridine monophosphate kinase, 3.2-fold; pyrimidine nucleoside phosphorylase 3.6-fold) in resistant cells. Overexpression of thymidylate synthase and its adjacent gene, c-Yes, was detected in the resistant cell lines. The mRNA and protein overexpression of nuclear factor κB (NFκB) p65 and related antiapoptotic c-Flip gene was detected in resistant cells. The 5-FU-resistant cell lines also showed high NFκB DNA-binding activity. Cotransfection of NFκB p50 and p65 cDNA induced 5-FU resistance in MCF-7 cells. Both NFκB- and 5-FU-induced resistant cell lines manifested reduced expression of genes governing G1-S and S-phase transition. Expression of genes involved in DNA replication was also down-regulated in resistant cell lines. These findings were highly consistent with the slower growth rate, higher proportion of G1, and lower proportion of S-phase cells in the resistant cell lines. This phenotype may protect resistant cells from cell death induced by incorporation of 5-FU into DNA chains, by allowing time to repair 5-FU-induced damage. Our findings may provide novel targets for tackling 5-FU resistance.

Electrically coupled quantum dots (QDs) can support unique optoelectronic properties arising from the superposition of single-particle excited states. Experimental methods for integrating colloidal QDs within the same nano-object, however, have remained elusive to the rational design. Here, we demonstrate a chemical strategy that allows for the assembling of colloidal QDs into coupled composites, where proximal interactions give rise to unique optoelectronic behavior. The assembly method employing "adhesive" surfactants was used to fabricate both homogeneous (e.g., CdS-CdS, PbS-PbS, CdSe-CdSe) and heterogeneous (e.g., PbS-CdS, CdS-CdSe) nanoparticle assemblies, exhibiting quasi-one-dimensional exciton fine structure. In addition, tunable mixing of single-particle exciton states was achieved for dimer-like assemblies of CdSe/CdS core-shell nanocrystals. The nanoparticle assembly mechanism was explained within the viscoelastic interaction theory adapted for molten-surface colloids. We expect that the present work will provide the synthetic and theoretical foundation needed for building assemblies of many inorganic nanocrystals.

We demonstrate that solution-phase semiconductor nanocrystals (NCs) undergo photoinduced rotation in an external electric field. Present measurements backed by theoretical calculations show that the rotation of colloidal NCs is driven by the excited-state dipole moment, which is counterbalanced by the solvent viscosity drag. Corresponding angular velocities range from 0.5°/ns for cubic CsPbBr3 NCs to 3°/ns for nanoparticles with a large photoinduced charge separation (CdSe/CdS core-shell and dot-in-a-rod NCs). Because of photoinduced rotation, solution-phase semiconductor NCs exhibited an order-of-magnitude increase in the spectral changes caused by the quantum confined Stark effect (QCSE), compared to solid NC assemblies. The enhanced QCSE of colloidal NCs reflected their global alignment in solution, which could be retained in a solid environment by slow crystallization. Overall, we expect that the demonstrated phenomenon of the colloidal nanocrystal rotation in an electric field will open up new avenues for developing electro-optical and voltage-sensitive applications.

Colloidal semiconductor nanocrystals (NCs) represent a promising class of nanomaterials for lasing applications. Currently, one of the key challenges facing the development of high-performance NC optical gain media lies in enhancing the lifetime of biexciton populations. This usually requires the employment of charge-delocalizing particle architectures, such as core/shell NCs, nanorods, and nanoplatelets. Here, we report on a two-dimensional nanoshell quantum dot (QD) morphology that enables a strong delocalization of photoinduced charges, leading to enhanced biexciton lifetimes and low lasing thresholds. A unique combination of a large exciton volume and a smoothed potential gradient across interfaces of the reported CdSbulk/CdSe/CdSshell (core/shell/shell) nanoshell QDs results in strong suppression of Auger processes, which was manifested in this work though the observation of stable amplified stimulated emission (ASE) at low pump fluences. An extensive charge delocalization in nanoshell QDs was confirmed by transient absorption measurements, showing that the presence of a bulk-size core in CdSbulk/CdSe/CdSshell QDs reduces exciton-exciton interactions. Overall, present findings demonstrate unique advantages of the nanoshell QD architecture as a promising optical gain medium in solid-state lighting and lasing applications.

The COVID-19 pandemic has brought with it a large number of challenges for healthcare professionals including intubation safety in out-of-theatre environments. An important aspect of this topic is the optimisation of a patient’s head and neck position prior to laryngoscopy which can be challenging when a pillow cannot be located. As a result, the authors compared how well the sniffing position (35o neck flexion and 15o head extension) could be reached using pillows or other novel head supports. The resulting data demonstrated that a 1-litre pressure bag and two 1-litre saline bags achieved the most accurate position.

Plasmonics is a rapidly developing field at the boundary of fundamental sciences and device engineering, which exploits the ability of metal nanostructures to concentrate electromagnetic radiation. The principal challenge lies in achieving an efficient conversion of the plasmon-concentrated field into some form of useful energy. To date, a substantial progress has been made within the scientific community in identifying the major pathways of the plasmon energy conversion. Strategies based on the hot electron injection and the near-field energy transfer have already shown promise in a number of proof-of-principle plasmonic architectures. Nevertheless, there are several fundamental questions that need to be addressed in the future to facilitate the transition of plasmonics to a variety of applications in both light amplification and optical detection. Of particular interest is a plasmon-induced resonance energy transfer (PIRET) process that couples the plasmon evanescent field to a semiconductor absorber via dipole-dipole interaction. This relatively unexplored mechanism has emerged as a promising light conversion strategy in the areas of photovoltaics and photocatalysis and represents the main focus of the present minireview. Along these lines, we highlight the key advances in this area and review some of the challenges associated with applications of the PIRET mechanism in nanostructured systems.

In the perioperative environment, communication, safety, and efficiency are paramount to ensure the effective delivery of patient care. Often overlooked, however, is the role that surgical instrumentation plays in these aspects of perioperative care. Through an analysis of the sterile processing environment at Massachusetts General Hospital (MGH), we identified a large amount of instrumentation being cycled unnecessarily throughout the system. This pattern was particularly notable for laparotomic equipment that is sent to almost all laparoscopic cases so that it is available in the event of conversion to laparotomy. Prompted by this analysis along with the high case volume and low conversion rate of laparoscopic cholecystectomies and appendectomies, we redesigned the laparotomic instrument supply chain for these procedures by placing all laparotomic conversion instruments on dedicated emergency case carts. In one month following implementation we avoided cycling nearly 15,000 pounds of unused instrumentation through the perioperative environment and have increased staff safety and communication among perioperative leadership. Objective to reduce the amount of unnecessary surgical instrumentation that is cycled through the perioperative environment.

9515 Background: Fianlimab and cemiplimab are two high-affinity, fully human, hinge-stabilized IgG4 monoclonal antibodies. In a Phase 1 dose escalation study, fianlimab combined with cemiplimab showed an acceptable safety profile and some clinical activity in pts with advanced malignancies. Here, we present safety and clinical activity data from two expansion cohorts of pts with advanced melanoma (anti–programmed cell death/ligand-1 [anti–PD-(L)1] naïve or experienced) who were treated with fianlimab + cemiplimab and had an opportunity for first on-treatment tumor assessment (cut-off date: Jan 4, 2021). Methods: Pts with advanced melanoma who had no prior anti–PD-(L)1 treatment (naïve) or prior anti–PD-(L)1 treatment within 3 months of screening (experienced) received fianlimab 1600 mg + cemiplimab 350 mg by IV infusion every 3 weeks. Tumor measurements were performed every 6 weeks for the first 24 weeks and subsequently every 9 weeks per RECIST v1.1. Results: 48 pts with advanced melanoma were treated with the combination therapy: 33 were anti–PD-(L)1 naïve and 15 were anti–PD-(L)1 experienced (median age: 69 years vs 59 years; male: 66.7% vs 46.7%; Caucasian: 87.9% vs 60%). The safety profile (including immune-related adverse events [AEs]) of fianlimab + cemiplimab combination therapy was similar to that of anti–PD-1 monotherapy with one exception. The rate of adrenal insufficiency, 8.3% (4/48) of pts, is similar to the rate previously observed with anti–PD-1 + anti–cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) combination therapy but higher than that observed with anti–PD-1 monotherapy. Grade ≥3 treatment-emergent AEs (TEAEs) occurred in 35.4% (17/48) of patients; Grade ≥3 serious TEAEs occurred in 22.9% (11/48) of patients; 8.3% (4/48) of patients discontinued treatment due to a TEAE. The most common TEAEs were fatigue (n = 15, 31.3%) and rash (n = 11, 22.9%). By investigator assessment, objective response rate (includes unconfirmed complete [CR] and partial responses [PR]) was 63.6% (3 CRs and 18 PRs) for anti–PD-(L)1 naïve pts and 13.3% (1 CR and 1 PR) for anti–PD-(L)1 experienced pts. Median progression-free survival and median duration of response for the anti–PD-(L)1 treatment naïve cohort have not been reached. Prognostic clinical markers and tumor biomarkers such as expression of LAG-3, PD-L1, and major histocompatibility complex II are being evaluated. Recruitment is ongoing. Conclusions: The safety profile of fianlimab + cemiplimab is similar to that observed with cemiplimab monotherapy and other anti–PD-1s, with the exception of higher rate of adrenal insufficiency. Fianlimab + cemiplimab combination has shown clinical activity for pts with advanced melanoma that is similar to anti–PD-1 + CTLA-4 combination therapy, but with lower demonstrated rates of TEAEs. Clinical trial information: NCT03005782.

Nanoshell quantum dots (QDs) represent a novel class of colloidal semiconductor nanocrystals (NCs), which supports tunable optoelectronic properties over the extended range of particle sizes. Traditionally, the ability to control the bandgap of colloidal semiconductor NCs is limited to small-size nanostructures, where photoinduced charges are confined by Coulomb interactions. A notorious drawback of such a restricted size range concerns the fact that assemblies of smaller nanoparticles tend to exhibit a greater density of interfacial and surface defects. This presents a potential problem for device applications of semiconductor NCs where the charge transport across nanoparticle films is important, as in the case of solar cells, field-effect transistors, and photoelectrochemical devices. The morphology of nanoshell QDs addresses this issue by enabling the quantum-confinement in the shell layer, where two-dimensional excitons can exist, regardless of the total particle size. Such a geometry exhibits one of the lowest surface-to-volume ratios among existing QD architectures and, therefore, could potentially lead to improved charge-transport and multi-exciton characteristics. The expected benefits of the nanoshell architecture were recently demonstrated by a number of reports on the CdSbulk/CdSe nanoshell model system, showing an improved photoconductivity of solids and increased lifetime of multi-exciton populations. Along these lines, this perspective will summarize the recent work on CdSbulk/CdSe nanoshell colloids and discuss the possibility of employing other nanoshell semiconductor combinations in light-harvesting and lasing applications.

The visualization of distinct molecular species represents an important challenge of bio-imaging research. In past decades, the development of multicolor fluorescent (FL) labels has greatly improved our ability to track biological analytes, paving the way for important advances in understanding the cell dynamics. It remains challenging, however, to visualize a large number of different fluorephores simultaneously. Owing to a spectrally broad absorption of fluorescent dyes, only up to five color categories can be resolved at once. Here, we demonstrate a general strategy for distinguishing between multiple fluorescent targets in acquired microscopy images with improved accuracy. The present strategy is enabled through spectral shaping of the excitation light with an optical filter that uniquely attenuates the light absorption of each fluorophore in the investigated sample. The resulting emission changes, induced by such excitation modulation, are therefore target-specific and can be used for identifying various fluorescent species. The technique is demonstrated through an accurate identification of 8 different CdSe dyes with absorption maxima spanning the 520-620 spectral range. It is subsequently applied for accurate measurements of the pH balance in buffers emulating a metabolism of tumor cells.

Purpose: To compare long-term outcomes between men and women in a large cohort of clinical trial participants with early-stage colon cancer, specifically by examining whether the prognostic effect of sex varies based on age, stage of disease, and type of adjuvant therapy received. Methods: A pooled analysis of individual patient data from 33,345 patients with colon cancer enrolled in 24 phase III studies of various adjuvant systemic therapies was conducted. Chemotherapy consisted of (1) fluorouracil (5-FU), (2) 5-FU variations, (3) 5-FU plus oxaliplatin, (4) 5-FU plus irinotecan, or (5) oral fluoropyrimidine-based regimens. The primary endpoint was disease-free survival; secondary endpoints included overall survival and time to recurrence. Stratified Cox models were used to assess the effect of sex on outcomes. Multivariate models were used to assess adjusted effects and to explore the interaction among sex and other factors. Results: A total of 18,244 (55%) men and 15,101 (45%) women were included. In the entire cohort, the median age was 61 years; 91% (24,868) were white; 31% (10,347) and 69% (22,964) had stage I/II and III disease, respectively. Overall, men had inferior prognoses when compared with women for time to recurrence (hazard ratio [HR] 1.05 [95% CI, 1.01-1.09]) and other endpoints after adjusting for age, stage, and treatment. Sex was not a predictive factor of treatment efficacy (P for interaction between sex and treatment when adjusting for age and stage were .40, .67, and .77 for disease-free survival, overall survival, and time to recurrence, respectively). In exploratory analyses, worse outcomes in men were more prominent in the older patients when adjusting for stage and treatment (HR 1.08 in age ≤ 65 years vs. HR 1.18 in age > 65 years; interaction P = .016 for disease-free survival). The stage of disease and type of adjuvant regimen did not modify the prognostic value of sex. Conclusions: Sex is a modest independent prognostic marker for patients with early-stage colon cancer, particularly in older patients. © 2013 Elsevier Inc. All rights reserved.

A 1-year survey on the chemical and physical properties of Douglas fir [Pseudotsuga menziesii (Mirbel) Franco] bark was conducted with the following objectives: 1) to document baseline chemical and physical properties of Douglas fir bark (DFB) that have relevance to production of container plants; 2) to determine the effect of DFB age on its chemical and physical properties; and 3) to document the consistency of those properties throughout the year. In June, August, October, and Dec. 2005, and February and May 2006, fresh and aged DFB samples were collected from two primary DFB suppliers (bark sources) for Oregon nurseries: source A offers a bark screened to 0.95 cm or less (fine) and source B screened to 2.2 cm or less (coarse). Samples were analyzed for pH, electrical conductivity (EC), essential plant macro- and micronutrients, bulk density, particle size distribution, and substrate moisture characteristic curves. Air space (AS), container capacity (CC), and solids were determined as a percent of container volume. Nonamended fresh and aged DFB contains appreciable extractable amounts of all measured plant macro- and micronutrients, except N. In general, the aging process reduced pH; and increased EC, and extractability of phosphorous, calcium, magnesium, boron, iron, and aluminum. Uniformity of DFB chemical properties throughout the year was affected by bark source and less so by age. In terms of physical properties, aged DFB had lower AS and higher CC compared with fresh DFB. Average differences in AS and CC between fresh and aged DFB within a source were 8% or less. Similar to chemical properties, uniformity of DFB physical properties was more affected by bark source than age.

Introduction: Microsurgical spermatic cord denervation (MSCD) is an effective surgical technique to manage chronic orchalgia, but it has not been readily adopted by Canadian urosurgeons. This paper reviews the early experience of a single urosurgeon in Canada.Methods: Nine consecutive testicular units underwent MSCD over a 24 month period. These patients underwent MSCD after ruling out reversible causes and after a successful diagnostic spermatic cord block.Results: Of these patients, 77% (7/9) had a complete resolution and 22% (2/9) had a partial resolution of their pain symptoms following MSCD. There were no failures or complications.Conclusions: MSCD is an effective, safe, and reproducible surgical technique that should be included in the treatment armamentarium for chronic orchalgia.

The bioavailability of a development candidate active pharmaceutical ingredient (API) was very low after oral dosing in dogs. In order to improve bioavailability, we sought to increase the dissolution rate of the solid form of the API. When traditional methods of forming salts and amorphous material failed to produce a viable solid form for continued development, we turned to the non-traditional approach of cocrystallization. A crystal engineering approach was used to design and execute a cocrystal screen of the API. Hydrogen bonding between the API and pharmaceutically acceptable carboxylic acids was identified as a viable synthon for associating multiple components in the solid state. A number of carboxylic acid guest molecules were tested for cocrystal formation with the API. A cocrystal containing the API and glutaric acid in a 1:1 molecular ratio was identified and the single crystal structure is reported. Physical characterization of the cocrystal showed that it is unique regarding thermal, spectroscopic, X-ray, and dissolution properties. The cocrystal solid is nonhygroscopic, and chemically and physically stable to thermal stress. Use of the cocrystal increased the aqueous dissolution rate by 18 times as compared to the homomeric crystalline form of the drug. Single dose dog exposure studies confirmed that the cocrystal increased plasma AUC values by three times at two different dose levels. APIs that are non-ionizable or demonstrate poor salt forming ability traditionally present few opportunities for creating crystalline solid forms with desired physical properties. Cocrystals are an additional class of crystalline solid that can provide options for improved properties. In this case, a crystalline molecular complex of glutaric acid and an API was identified and used to demonstrate an improvement in the oral bioavailability of the API in dogs.

Identifying the existence and orientation of buried drainage systems is necessary to incorporate the impact of these features in solute transport and hydrologic models. This study was conducted to determine if a cesium magnetometer survey could identify clay tile locations. A cesium magnetometer survey with a sampling interval of 10 cm along the survey transect and 50-cm spaced transects was used at the Oregon State University Research Dairy in an attempt to map clay tile orientation and location. A shaded-relief plot of the magnetic data from a 100- . 100-m portion of the Dairy successfully identified clay tile in the western part of the study area, but was unable to identify clay tile in the eastern part of the study area. Probing and trenching confirmed the existence of clay tile in both portions of the site. This case study has shown that cesium magnetometer surveys can locate clay tile with a spatial accuracy (horizontally) of .25 cm, and offers a new technique for non-invasive subsurface drainage pipe location. This study has also elucidated potential limitations in this method for identifying subsurface drainage pipe locations that may depend on soil type, management strategies, and soil magnetic properties.

James Cassidy looks at what has changed in terms of the Data Protection Act and what practice managers should be doing to ensure compliance

With a 3-fold increase in the number of cancer survivors noted since the 1970s, there are now over 28 million cancer survivors worldwide. Accordingly, there is a heightened awareness of long-term toxicities and the impact on quality of life following treatment in cancer survivors. This review will address the increasing importance and challenge of chemotherapy-induced neurotoxicity, with a focus on neuropathy associated with the treatment of breast cancer, colorectal cancer, testicular cancer, and hematological cancers. An overview of the diagnosis, symptomatology, and pathophysiology of chemotherapy-induced peripheral neuropathy will be provided, with a critical analysis of assessment strategies, neuroprotective approaches, and potential treatments. The review will concentrate on neuropathy associated with taxanes, platinum compounds, vinca alkaloids, thalidomide, and bortezomib, providing clinical information specific to these chemotherapies.

A mechanism is investigated by which surface-exposed fractures could be a source of aquifer salinization in low-permeability fractured formations under arid conditions. It is hypothesized that evaporation of pore water within surface-exposed fractures is enhanced by convective air circulation within those fractures that vents moisture to the atmosphere. This evaporation also simultaneously enhances lateral movement of pore water from the adjacent matrix towards the fracture surface, permitting dissolved solutes to precipitate on the surface and form a crust. The salt crust can then dissolve during infiltration events and be flushed downward to the aquifer. Theoretical analysis shows that convective venting is expected during cool nights when atmospheric air is denser than the fracture air. Laboratory experiments support the hypothesis of rapid salt-crust formation in the presence of convectively moving air across a fracture face. A numerical model is developed and used to quantify the buildup of salt on a fracture face.

The buccal delivery of the nonsteroidal antiinflammatory drug, diclofenac sodium (Voltaren), from a prototype hydrogel was studied in man in a randomized crossover design of buccal delivery and i.v. infusion. After a 30-min delay, plasma levels of diclofenac increased to near steady-state levels of 100 ng/ml by 3 hr. With each subject serving as his own control, the i.v. infusion data facilitated the calculation of a mean steady-state flux of diclofenac sodium of 2.1 ± 0.6 mg/cm2-hr across human buccal mucosa and a time lag of 1.0 ± 0.5 hr. The large flux of this ionized species indicates that the traditional lipoidal model of buccal permeation based on the partition coefficient is inadequate.

Acquired chemoresistance is one of the obstacles for success of 5-fluorouracil (5-FU)-based cancer chemotherapy. Some molecular mechanisms of acquired 5-FU resistance are still unknown. We have recently demonstrated down-regulation of a group of cell cycle related genes in acquired 5-FU resistant human cancer cell lines. In this study, the bivariate distribution of propidium iodide versus BrdU in acquired 5-FU resistant colon (H630R10) and breast (T47DFU2.5) cancer cell lines was compared with their parental cell lines using flow cytometric analysis. The resistant cell lines showed significantly lower labelling index (T47DFU2.5) and cell cycle delay in G1 and G1/S boundary and prolonged DNA synthesis time (H630R10). Both resistant cell lines demonstrated significantly prolonged potential doubling time (Tpot). The protein expression levels of some G1 and S phase transition-related genes were also analysed by Western blot. CDK2 protein and Thr-160 phosphorylated CDK2 were remarkably reduced in the resistant cell lines. Cyclin D3 and cyclin A were also decreased in the resistant cells. Total pRB expression was unaltered but hypophosphorylation of pRB (Ser780, Ser795 and Ser807/811) was detected in the resistant cancer cells. Our data suggest that there may be a slow down in cell cycle traverse preventing incorporation of 5-FU metabolites into DNA and also providing cancer cells with sufficient time to correct the mis-incorporated nucleotides. The cell cycle perturbation may be involved in acquired 5-FU resistance.

Unlike the joints, ocular involvement with juvenile rheumatoid arthritis is most often asymptomatic; yet, the inflammation can cause serious morbidity with loss of vision. Scheduled slit-lamp examinations by an ophthalmologist at specific intervals can detect ocular disease early, and prompt treatment can prevent vision loss.

Analysis of tumour markers is helping to predict individual patient response to chemotherapy. However, the difficulties in obtaining metastatic disease samples has led to a reliance on assessment of primary tumour, with little data on its predictive ability. This study assessed thymidylate synthase (TS), a target for the commonly used drug 5FU, in 42 paired primary colorectal tumour and lymph node metastasis. High TS staining was seen in 63% of primary colon tumour cells and 81% of the secondary lymph node. Primary tumour did not have significant predictive power for secondary tumour samples (kappa=0.125; p=0.38). There was no significant relationship between TS staining and expression of G1/S cell cycle proteins p21, p27, p53, cyclin D1, proliferating cell nuclear antigen (PCNA) and retinoblastoma protein (Rb) (p0.05 in all cases). Discordance in TS protein levels between primary and secondary tumours demonstrates the danger of predicting outcome after chemotherapy in metastatic colorectal cancer from the primary tumour.

3520 Background: EOTR has been suggested as a potential surrogate for overall survival (OS) in patients (pts) with mCRC and allows early assessment of treatment efficacy, facilitating adaptive trial design. We assessed at the individual patient level, the correlation between EOTR (complete or partial response) at 6, 8 and 12 weeks (wk), OS and progression free survival (PFS) in pts with mCRC treated with 1stline chemotherapy with or without a targeted agent as a first step in a surrogacy demonstration. Methods: IPD from 13,949 pts enrolled on 15 randomized Phase III trials in 1st line mCRC were used; 8 trials included targeted (anti-angiogenic and anti-EGFR) agents. EOTR prognostic value was assessed by landmark analyses using Cox models stratified by treatment assignment. P-values st line treatment was a strong and independent predictor of both OS and PFS in patient with mCRC and warrants further consideration as a potential endpoint for future trials, particularly randomized phase II trials.

Voles are well-known crop pests, especially when peak populations are present, but their role in soil fertility and impacts on agricultural sustainability are not well understood. Five months after the abrupt disappearance of a peak in a gray-tailed vole (Microtus canicaudus) population, we examined burrow structure, determined concentrations of trace elements, carbon and nitrogen in the soil immediately surrounding vole burrows, and compared soil chemical properties to a depth of 90 cm between areas with prior vole activity and areas of no activity. Vole tunneling activity was confined to the top 10 cm of the soil profile and was coincident with the majority of root biomass. Soil NH 4 +, NO 3 -, extractable organic carbon, and soil organic matter were greater below vole tunnels than above; however, due to small sample sizes, differences were not significant. There were no differences in trace elements with respect to position around vole tunnels. Vole activity was associated with increased soil nitrate concentrations and decreased soil pH to a depth of 90 cm, indicating that nitrification might be enhanced by vole activity, and that this effect continues after vole populations crash. Greater inorganic nitrogen could have long-term effects on ecosystem productivity. The effects voles have on soil processes that influence carbon and nutrient cycle requires further investigation.

Adenosine and the synthetic adenosine agonists 2-chloroadenosine and N 6 -(L-2-phenylisopropyl)-adenosine were tested for effects on hormone secretion from the rat isolated perfused pancreas. These nucleosides, at concentrations of 5 μM, markedly potentiated both phases of arginine-induced glucagon release; the two synthetic agonists were more effective than adenosine. In the absence of arginine, each of the nucleosides induced a transient burst of glucagon. In contrast, adenosine and both synthetic agonists inhibited arginine-induced insulin secretion to varying degrees and caused only negligible insulin release when perfused without arginine. The adenosine antagonist 8-( p -sulfophenyl)-theophylline prevented the actions of adenosine on hormone release from the pancreas. Our data suggest that adenosine potentiation of arginine-induced glucagon release may be mediated via adenosine receptors on alpha cell membranes; such a mechanism could provide an important endogenous control over glucagon secretion.