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Study drug dosing

Overall survival (Kaplan-Meier Method) by PIK3CA and NRAS status

Progression-free survival (Kaplan-Meier Method) by PIK3CA and NRAS status

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.

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.

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.

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.

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.

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.