Media Literacy Practices to Prevent Obesity and Eating Disorders in Youth.

PURPOSE OF REVIEW: Obesity and eating disorders share common issues related to media use and effects, especially in the USA. Current research increasingly demonstrates that media literacy can address this problem. This narrative review highlights current media literacy-based research for obesity and eating disorder prevention among youth. RECENT FINDINGS: Current research using media literacy techniques to prevent obesity indicates that these interventions improve nutrition outcomes, improve family communication about food, improve critical thinking about food advertisements, reduce sugar and fat intake, and reduce screen use for parents and youth. In addition, eating disorder research reveals that media literacy techniques lead to higher scores of body satisfaction and self-esteem, with lower scores of perfectionism, thinness, and ideal masculinity. There is a need for media literacy-based interventions to focus on family communication to prevent obesity and eating disorders. Furthermore, there should be more focus on identified levels of prevention and specific clinical outcomes.

Genetic mapping of sorghum resistance to an Illinois isolate of Colletotrichum sublineola.

Anthracnose leaf blight (ALB) is an economically important disease of sorghum [Sorghum bicolor (L.) Moench] caused by the fungal pathogen Colletotrichum sublineola Henn. ex Sacc. & Trotter. Although qualitative and quantitative resistance have been identified for ALB, the usefulness of resistance loci differs depending on the pathogen pathotype. Identifying resistance effective against unique pathogen pathotypes is critical to managing ALB, as the disease is managed primarily through the deployment of host resistance. We isolated C. sublineola from ALB-infected leaves collected in Illinois and found that the strain was a novel pathotype, as it produced a unique combination of virulence against a set of differential lines. Using this isolate, we inoculated 579 temperate-adapted sorghum conversion lines in 2019 and 2020. We then conducted a genome-wide association study (GWAS) and a metabolic pathway analysis using the Pathway Associated Study Tool (PAST). We identified 47 significant markers distributed across all chromosomes except chromosome 8. We identified 32 candidate genes based on physical proximity with significant markers, some of which have a known role in host defense. We identified 47 pathways associated with ALB resistance, indicating a role for secondary metabolism in defense to ALB. Our results are important to improve the understanding of the genetic basis of ALB resistance in sorghum and highlight the importance of developing durable resistance to ALB.

Investigation of electron-induced cross-linking of self-assembled monolayers by scanning tunneling microscopy.

Ultrathin membranes with subnanometer pores enabling molecular size-selective separation were generated on surfaces via electron-induced cross-linking of self-assembled monolayers (SAMs). The evolution of p-terphenylthiol (TPT) SAMs on Au(111) surfaces into cross-linked monolayers was observed with a scanning tunneling microscope. As the irradiation dose was increased, the cross-linked regions continued to grow and a large number of subnanometer voids appeared. Their equivalent diameter is 0.5 ± 0.2 nm and the areal density is ≈1.7 × 1017 m-2. Supported by classical molecular dynamics simulations, we propose that these voids may correspond to free volumes inside a cross-linked monolayer.

Identification of Loci That Confer Resistance to Bacterial and Fungal Diseases of Maize.

Crops are hosts to numerous plant pathogenic microorganisms. Maize has several major disease issues; thus, breeding multiple disease resistant (MDR) varieties is critical. While the genetic basis of resistance to multiple fungal pathogens has been studied in maize, less is known about the relationship between fungal and bacterial resistance. In this study, we evaluated a disease resistance introgression line (DRIL) population for the foliar disease Goss's bacterial wilt and blight (GW) and conducted quantitative trait locus (QTL) mapping. We identified a total of ten QTL across multiple environments. We then combined our GW data with data on four additional foliar diseases (northern corn leaf blight, southern corn leaf blight, gray leaf spot, and bacterial leaf streak) and conducted multivariate analysis to identify regions conferring resistance to multiple diseases. We identified 20 chromosomal bins with putative multiple disease effects. We examined the five chromosomal regions (bins 1.05, 3.04, 4.06, 8.03, and 9.02) with the strongest statistical support. By examining how each haplotype effected each disease, we identified several regions associated with increased resistance to multiple diseases and three regions associated with opposite effects for bacterial and fungal diseases. In summary, we identified several promising candidate regions for multiple disease resistance in maize and specific DRILs to expedite interrogation.

A Media Literacy-Based Nutrition Program Fosters Parent-Child Food Marketing Discussions, Improves Home Food Environment, and Youth Consumption of Fruits and Vegetables.

Background: Media use is a known contributor to childhood obesity, but encouraging reductions in screen use only partially eliminates media influence. We tested a family-centered, media literacy-oriented intervention to empower parents and children 9-14 years to skillfully use media to reduce marketing influences, enhance nutrition knowledge, improve the selection of foods in the home environment, and improve fruit and vegetable consumption. Methods: A community-based, 6-U program included separate parent and youth (ages 9-14 years) sessions, each of which was followed by a session together in which skills from the individual sessions were reinforced. A pretest to posttest field test with control groups (N = 189, parent-child dyads) tested the intervention's efficacy. Results: Standardized mean differences from the multiple analysis of covariance tests showed that the intervention group demonstrated improvements on parents' use of nutrition labels (0.29), the ratio of healthy to unhealthy food in the home environment (0.25), youth's fruit (0.30) and vegetable (0.25) consumption, parent and youth media literacy skills, and family communication dynamics about food. The largest effects found were for negative parental mediation (0.48) and parents' report of child-initiated discussion (0.47). Consistent but weaker results were revealed for Latinx families. Conclusions: This family-centered approach helped family members practice using media together to make better nutrition decisions without depending on the ability of parents to limit media use. It successfully addressed the often-negative impact of the media on behaviors that increase obesity risk while also cultivating the potential for media to provide useful information that can lead to behaviors that decrease obesity risk.

Conserved defense responses between maize and sorghum to Exserohilum turcicum.

BACKGROUND: Exserohilum turcicum is an important pathogen of both sorghum and maize, causing sorghum leaf blight and northern corn leaf blight. Because the same pathogen can infect and cause major losses for two of the most important grain crops, it is an ideal pathosystem to study plant-pathogen evolution and investigate shared resistance mechanisms between the two plant species. To identify sorghum genes involved in the E. turcicum response, we conducted a genome-wide association study (GWAS). RESULTS: Using the sorghum conversion panel evaluated across three environments, we identified a total of 216 significant markers. Based on physical linkage with the significant markers, we detected a total of 113 unique candidate genes, some with known roles in plant defense. Also, we compared maize genes known to play a role in resistance to E. turcicum with the association mapping results and found evidence of genes conferring resistance in both crops, providing evidence of shared resistance between maize and sorghum. CONCLUSIONS: Using a genetics approach, we identified shared genetic regions conferring resistance to E. turcicum in both maize and sorghum. We identified several promising candidate genes for resistance to leaf blight in sorghum, including genes related to R-gene mediated resistance. We present significant advancements in the understanding of host resistance to E. turcicum, which is crucial to reduce losses due to this important pathogen.

Amplified cross-linking efficiency of self-assembled monolayers through targeted dissociative electron attachment for the production of carbon nanomembranes.

The determination of the negative ion yield of 2'-chloro-1,1'-biphenyl (2-Cl-BP), 2'-bromo-1,1'-biphenyl (2-Br-BP) and 2'-iodo-1,1'-biphenyl (2-I-BP) upon dissociative electron attachment (DEA) at an electron energy of 0 eV revealed cross section values that were more than ten times higher for iodide loss from 2-I-BP than for the other halogenides from the respective biphenyls (BPs). Comparison with dissociative ionization mass spectra shows that the ratio of the efficiency of electron impact ionization induced fragmentation of 2-I-BP, 2-Br-BP, and 2-Cl-BP amounts to approximately 1:0.7:0.6. Inspired by these results, self-assembled monolayers (SAMs) of the respective biphenyl-4-thiols, 2-Cl-BPT, 2-Br-BPT, 2-I-BPT as well as BPT, were grown on a Au(111) substrate and exposed to 50 eV electrons. The effect of electron irradiation was investigated by X-ray photoelectron spectroscopy (XPS), to determine whether the high relative DEA cross section for iodide loss from 2-I-BPT as compared to 2-Br-BP and 2-Cl-BP is reflected in the cross-linking efficiency of SAMs made from these materials. Such sensitization could reduce the electron dose needed for the cross-linking process and may thus lead to a significantly faster conversion of the respective SAMs into carbon nanomembranes (CNMs) without the need for an increased current density. XPS data support the notation that DEA sensitization may be used to achieve more efficient electron-induced cross-linking of SAMs, revealing more than ten times faster cross-linking of 2-I-BPT SAMs compared to those made from the other halogenated biphenyls or from native BPT at the same current density. Furthermore, the transfer of a freestanding membrane onto a TEM grid and the subsequent investigation by helium ion microscopy (HIM) verified the existence of a mechanically stable CNM created from 2-I-BPT after exposure to an electron dose as low as 1.8 mC/cm2. In contrast, SAMs made from BPT, 2-Cl-BPT and 2-Br-BPT did not form stable CNMs after a significantly higher electron dose of 9 mC/cm2.

Phase 2 study of tabalumab, a human anti-B-cell activating factor antibody, with bortezomib and dexamethasone in patients with previously treated multiple myeloma.

In this double-blind, Phase 2 study, 220 patients with relapsed/refractory multiple myeloma were randomly assigned 1:1:1 to receive placebo (N = 72), tabalumab 100 mg (N = 74), or tabalumab 300 mg (N = 74), each in combination with dexamethasone 20 mg and subcutaneous bortezomib 1·3 mg/m2 on a 21-day cycle. No significant intergroup differences were observed among primary (median progression-free survival [mPFS]) or secondary efficacy outcomes. The mPFS was 6·6, 7·5 and 7·6 months for the tabalumab 100, 300 mg and placebo groups, respectively (tabalumab 100 mg vs. placebo Hazard ratio (HR) [95% confidence interval (CI)] = 1·13 [0·80-1·59], P = 0·480; tabalumab 300 mg vs. placebo HR [95% CI] = 1·03 [0·72-1·45], P = 0·884). The most commonly-reported treatment-emergent adverse events were thrombocytopenia (37%), fatigue (37%), diarrhoea (35%) and constipation (32%). Across treatments, patients with low baseline BAFF (also termed TNFSF13B) expression (n = 162) had significantly longer mPFS than those with high BAFF expression (n = 55), using the 75th percentile cut-off point (mPFS [95% CI] = 8·3 [7·0-9·3] months vs. 5·8 [3·7-6·6] months; HR [95% CI] = 1·59 [1·11-2·29], P = 0·015). Although generally well tolerated, PFS was not improved during treatment with tabalumab compared to placebo. A higher dose of 300 mg tabalumab did not improve efficacy compared to the 100 mg dose. Nonetheless, BAFF appears to have some prognostic value in patients with multiple myeloma.

Impact of Patient and Lesion Complexity on Long-Term Outcomes Following Coronary Revascularization With New-Generation Drug-Eluting Stents.

Long-term clinical outcomes of new-generation drug-eluting stents in complex anatomic and clinical settings are not well defined. This study assessed the impact of patient and lesion complexity on 2-year outcomes after coronary revascularization with ultrathin strut biodegradable-polymer (BP) sirolimus-eluting stents (SES) versus durable-polymer (DP) everolimus-eluting stents (EES). In a prespecified analysis of the BIOSCIENCE randomized trial (NCT01443104), complex patients (911 of 2,119; 43%) were defined by the presence of acute ST-elevation myocardial infarction (MI); left ventricular ejection fraction ≤30%; renal dysfunction; insulin-treated diabetes; treatment of ostial lesion, bypass graft, unprotected left main lesion; or 3-vessel intervention. The primary end point was target lesion failure (TLF), a composite of cardiac death, target vessel MI, and clinically indicated target lesion revascularization. At 2 years, complex compared with simple patients had a greater risk of TLF (14.5% vs 7.4%, risk ratio 2.05, 95% confidence interval 1.56 to 2.69; p <0.001). The difference was sustained beyond 1 year on landmark analysis. Complex patients had higher rates of the patient-oriented composite end point of death, any MI, or any revascularization (23% vs 14.4%; p <0.001) as well as definite stent thrombosis (1.6% vs 0.4%, p = 0.006). There were no differences in TLF and patient-oriented composite end point between the BP-SES versus DP-EES, consistently among simple and complex patients. In conclusion, patient and lesion complexity had a durable adverse impact on clinical outcomes throughout 2 years of follow-up in this all-comers randomized trial. Safety and efficacy of new-generation BP-SES and DP-EES were comparable, irrespective of complexity status.

Phase 1 Study of Tabalumab, a Human Anti-B-Cell Activating Factor Antibody, and Bortezomib in Patients with Relapsed/Refractory Multiple Myeloma.

PURPOSE: Tabalumab, a human mAb that neutralizes B-cell-activating factor (BAFF), demonstrated antitumor activity in xenograft models of multiple myeloma. Here we report on a phase I study of relapsed/refractory multiple myeloma patients in which the primary objective was to identify a tolerable and potentially efficacious dose of tabalumab when combined with bortezomib. EXPERIMENTAL DESIGN: Forty-eight patients were enrolled; 20 to the dose-escalation cohort, and 28 to cohort expansion in which a dose of 100 mg of tabalumab was evaluated. All patients had received either prior bortezomib or an immunomodulatory drug; the median number of prior therapies was 3. Bortezomib was administered intravenously on days 1, 4, 8, and 11 of a 21-day schedule. Tabalumab was given every 21 days for 3 cycles, then every 42 days thereafter. RESULTS: The most common grade 3/4 toxicities included thrombocytopenia, neutropenia, pneumonia, and peripheral sensory neuropathy. There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. Pharmacokinetic data suggested serum exposure increased in a greater than dose-proportional manner up to a dose of 100 mg. Out of 46 evaluable patients, 20 had confirmed responses. The median time to progression (9 patients censored) was 4.8 months, and the median response duration (4 patients censored) was 7.2 months. CONCLUSIONS: A dose of 100 mg tabalumab in combination with bortezomib was well tolerated and active and is currently under further investigation. Clin Cancer Res; 22(23); 5688-95. ©2016 AACR.

The differential impact of plastic surgery subspecialties on the financial performance of an academic clinical practice.

BACKGROUND: In an academic center, plastic surgery provides multiple important and distinct services. Limited data exist on how each service affects a department clinically and financially. METHODS: All new patient consultations and surgical cases between 2004 and 2012 were reviewed. Conversion rates from consultation to surgery and relative value units were calculated. Professional and facility revenues, costs, and net income were ascertained. These measures were compared between different subspecialties. RESULTS: A total of 12,020 new patient consultations and 5741 surgical cases were reviewed. Total growth in consultations was greatest for breast reconstruction (396.8 percent), followed by aesthetic (83.8 percent), oncology (12.9 percent), general (-16.9 percent), and burn/trauma (-75.0 percent). The conversion rate from consultation to surgery was highest in breast reconstruction (57.0 ± 3.1 percent) and oncology (56.9 ± 6.6 percent), followed by burn/trauma (47.0 ± 6.8 percent), general (46.1 ± 3.5 percent), and aesthetic (37.0 ± 4.8 percent). Total growth in professional net income was greatest for breast reconstruction (1241.4 percent), followed by oncology (378.4 percent), general (159.7 percent), aesthetic (130.5 percent), and burn/trauma (-20.9 percent). Total growth in facility net income was greatest for breast reconstruction (7619.5 percent), followed by oncology (2648.0 percent), aesthetic (432.3 percent), general (283.3 percent), and burn/trauma (108.7 percent). CONCLUSIONS: Breast reconstruction exhibited the greatest growth in consultations, and oncologic consultations demonstrated the highest consultation-to-surgery conversion rate. The higher consultation volume and conversion rate associated with breast reconstruction resulted in greater financial gains for both the department and the hospital. These findings may be of utility in the development of academic plastic surgery programs.

A randomized, open-label clinical trial of tasisulam sodium versus paclitaxel as second-line treatment in patients with metastatic melanoma.

BACKGROUND: Tasisulam sodium (hereafter referred to as tasisulam) is a novel, highly albumin-bound agent that demonstrated activity in a phase 2 melanoma study. METHODS: In this open-label phase 3 study, patients with AJCC stage IV melanoma received tasisulam (targeting an albumin-corrected exposure of 1200-6400 h (hour).µg/mL on day 1) or paclitaxel (80 mg/m(2) on days 1, 8, and 15) every 28 days as second-line treatment. RESULTS: The study was placed on clinical hold after randomization of 336 patients when a safety review indicated an imbalance of possibly drug-related deaths in the tasisulam arm. Efficacy results for tasisulam versus paclitaxel revealed a response rate of 3.0% versus 4.8%, a median progression-free survival of 1.94 months versus 2.14 months (P = .048), and a median overall survival of 6.77 months versus 9.36 months (P = .121). The most common drug-related grade ≥3 laboratory toxicities (graded according to Common Terminology for Adverse Events [version 3.0]) were thrombocytopenia (18.9%) for patients treated with tasisulam and neutropenia/leukopenia (8.7%) among those receiving paclitaxel. There were 13 possibly related deaths reported to occur on the study, with the majority occurring during cycle 2 in the setting of grade 4 myelosuppression, all in the tasisulam arm. Investigation of the unexpectedly high rate of hematologic toxicity revealed a subset of patients with low tasisulam clearance, leading to drug accumulation and high albumin-corrected exposure in cycle 2. CONCLUSIONS: Although the study was stopped early because of safety issues in the tasisulam arm, tasisulam was considered unlikely to be superior to paclitaxel, and paclitaxel activity in the second-line treatment of melanoma was much lower than expected. The toxicity imbalance was attributed to an unexpectedly low tasisulam clearance in a subset of patients, underscoring the importance of pharmacokinetic monitoring of compounds with complex dosing, even in late-phase studies.

Evaluating and utilizing probability of study success in clinical development.

BACKGROUND: Drug development has become increasingly costly, lengthy, and risky. The call for better decision making in research and development has never been stronger. Analytic tools that utilize available data can inform decision makers of the risks and benefits of various decisions, which could lead to better and more informed decisions. PURPOSE: Through some real oncology examples, we will demonstrate how using available data to analytically evaluate probability of study success (PrSS) can lead to better decisions in clinical development. METHODS: The predictive power, or average conditional power, is used to quantify the PrSS. To calculate the probability, we follow a general two-step process: (1) use Bayesian modeling and appropriate assumptions to synthesize relevant data to derive the distribution of treatment effect and (2) evaluate the PrSS analytically or via trial simulation. RESULTS: We applied the procedure to several compounds in our oncology pipeline. The analysis informed decision making where PrSS was an important factor to consider. LIMITATIONS: When modeling the treatment effect, we made certain assumptions, including how two drugs work together and exchangeable treatment effects across studies. Those assumptions are reasonable for our specific situations but may not generalize well. CONCLUSIONS: From our experience, PrSS based on available data can help decision making in drug development, particularly the Go/No-Go decision after the proof of concept trial is completed. When applicable, we recommend this evaluation be regularly done in addition to the routine data analysis for clinical trials.

Meta-analysis comparing efficacy and safety of first generation drug-eluting stents to bare-metal stents in patients with diabetes mellitus undergoing primary percutaneous coronary intervention.

Several concerns have emerged regarding the higher risk for stent thrombosis (ST) after drug-eluting stent (DES) implantation, especially in the setting of ST-segment elevation myocardial infarction (STEMI). Few data have been reported so far in patients with diabetes mellitus, which is associated with high rates of target vessel revascularization after bare-metal stent (BMS) implantation but also higher rates of ST after DES implantation. Therefore, the aim of this study was to perform a meta-analysis of individual patients' data to evaluate the long-term safety and effectiveness of DES compared with BMS in patients with diabetes who undergo primary percutaneous coronary intervention for STEMI. Published reports were scanned by formal searches of electronic databases (MEDLINE and CENTRAL). All completed randomized trials of DES for STEMI were examined. No language restrictions were enforced. Individual patients' data were obtained from 11 of 13 trials, including a total of 972 patients with diabetes (616 [63.4%] randomized to DES and 356 [36.6%] to BMS). At long-term follow-up (median 1,095 days, interquartile range 1,087 to 1,460), DES significantly reduced the occurrence of target vessel revascularization (hazard ratio 0.42, 95% confidence interval 0.29 to 0.59, p <0.0001), without any significant difference in terms of mortality, late reinfarction, and ST (>1 year) with DES. In conclusion, this meta-analysis, based on individual patients' data from 11 randomized trials, showed that among patients with diabetes with STEMIs who undergo primary percutaneous coronary intervention, sirolimus-eluting stents and paclitaxel-eluting stents, compared with BMS, are associated with a significant reduction in target vessel revascularization at long-term follow-up, without any apparent concern in terms of mortality, despite the trend toward higher rates of reinfarction and ST.

A phase II study of tasisulam sodium (LY573636 sodium) as second-line or third-line treatment for patients with unresectable or metastatic soft tissue sarcoma.

BACKGROUND: Tasisulam sodium (hereafter tasisulam), a novel anticancer agent, is being studied in a broad range of tumors. The primary objective of this phase II study was to determine progression-free survival (PFS) in patients with 1 or 2 prior chemotherapy regimens for unresectable/metastatic soft tissue sarcoma (STS). Secondary objectives included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), pharmacokinetics, and safety. METHODS: Tasisulam was administered intravenously on day 1 of 21-day cycles according to a lean body weight-based dosing algorithm targeting a peak plasma concentration (C(max)) of 420 µg/mL; a 360-µg/mL dose level was also explored. RESULTS: The median age of patients treated at 420 µg/mL was 58.3 years (range, 18.6-80.4; n = 63). Median PFS was 2.64 months (90 % CI, 1.41-3.38), with a 6-month PFS rate of 11 % (90 % CI, 4-17). Median OS was 8.71 months (90 % CI, 7.39-16.23); ORR, 3.2 %; and CBR, 46.0 % (stable disease, n = 27; partial response/confirmed, n = 2 [angiosarcoma and leiomyosarcoma]; partial response/unconfirmed, n = 1 [desmoplastic small round cell tumor]). The most frequent drug-related grade 3/4 toxicities in patients treated at 420 µg/mL were thrombocytopenia (27.0 %) and neutropenia (22.2 %). Incidences of grade 4 thrombocytopenia and/or neutropenia were 20.6 % in patients treated at 420 µg/mL and 15.8 % in those treated at 360 µg/mL (n = 38). CONCLUSIONS: Tasisulam at a target C(max) of 420 µg/mL on day 1 of 21-day cycles demonstrated modest activity as second-/third-line treatment in patients with STS. Grade 4 hematologic toxicity posed some challenges in these heavily pre-treated patients. Tasisulam dosing continues to be refined.

A randomised, double-blind, phase II study of two doses of pemetrexed in the treatment of platinum-resistant, epithelial ovarian or primary peritoneal cancer.

PURPOSE: We conducted a randomised phase II study to assess the safety and efficacy of standard versus high-dose pemetrexed in platinum-resistant epithelial ovarian cancer (PR-EOC). The expression of ten genes was also examined as potential biomarkers of pemetrexed/platinum activity. PATIENTS AND METHODS: Patients received pemetrexed 500mg/m(2) (Pem500) or 900mg/m(2) (Pem900) on day 1 of each 21-d cycle. Responses were defined per RECIST for measurable disease or by Gynaecologic Cancer Intergroup (GCIG) CA-125 criteria for non-measurable disease. RESULTS: Of 102 patients randomised, 98 were evaluable for toxicity (47 Pem500, 51 Pem900) and 91 were evaluable for efficacy (43 Pem500, 48 Pem900) of whom 68 had measurable disease and 23 had CA-125-defined disease. The overall RR was 9.3% (95% CI: 2.6-22.1%) on Pem500 and 10.4% (95% CI: 3.5-22.7%) on Pem900. The median progression-free survival (PFS) was 2.8 months on both arms, and the median survival was 11.9 and 10.3 months, respectively. Lower mRNA expression of excision repair cross-complementation group 1 (ERCC1) and reduced folate carrier 1 (RFC1) were associated with longer PFS and time to treatment failure, respectively. Grade 3/4 toxicities, including fatigue, nausea and vomiting, were numerically greater on Pem900. Pemetrexed-related SAEs occurred in 17% and 28% of Pem500 and Pem900 patients, respectively. CONCLUSIONS: Pemetrexed has activity in PR-EOC equivalent to other agents in platinum-resistant disease; however, Pem500 has the preferable toxicity profile. ERCC1 and RFC1 may merit examination as predictive biomarkers in PR-EOC.

Molecular determinants of efficacy for 5-FU-based treatments in advanced colorectal cancer: mRNA expression for 18 chemotherapy-related genes.

5-Fluorouracil (5-FU)-based regimens remain a cornerstone in the treatment of colorectal cancer (CRC). However, the attendant toxicity prevents these regimens from reaching maximum therapeutic potential. In this retrospective analysis, we examined the pretreatment expression of 18 genes in archival tumor bank samples from patients with advanced CRC to determine if one or more of the selected genes showed promise as either a prognostic or predictive marker of 5-FU-based treatment outcomes. One hundred and forty-four CRC patient samples (collected from 1983 to 2004) were analyzed via real-time PCR for gene expression. Univariate analyses were used to correlate gene expression with efficacy and time-to-event variables. Low thymidine phosphorylase (TP), dihydrofolate reductase, dihydropyrimidine dehydrogenase (DPD), excision repair cross-complementing 1 (ERCC1) and thymidylate synthase gene expression were associated with better time-to-progression in the entire population. Low TP, DPD and ERCC1 expression were independently associated with improved overall survival. Low TP gene expression was also predictive of response. This study suggests that TP gene expression in particular is a predictive as well as a prognostic biomarker for advanced CRC patients. Gene panels assessing pretreatment TP, DPD, ERCC1, dihydrofolate reductase and thymidylate synthase gene expression may help improve the therapeutic potential of 5-FU- or other novel antifolate-based regimens. Further analysis of the prognostic or predictive value of these genes in prospective trials in CRC patients seems warranted.

Seed dispersal and establishment of endangered plants on Oceanic Islands: the Janzen-Connell model, and the use of ecological analogues.

BACKGROUND: The Janzen-Connell model states that plant-specific natural enemies may have a disproportionately large negative effect on progeny close to maternal trees. The majority of experimental and theoretical studies addressing the Janzen-Connell model have explored how it can explain existing patterns of species diversity in tropical mainland areas. Very few studies have investigated how the model's predictions apply to isolated oceanic islands, or to the conservation management of endangered plants. Here, we provide the first experimental investigation of the predictions of the Janzen-Connell model on an oceanic island, in a conservation context. In addition, we experimentally evaluate the use of ecological analogue animals to resurrect the functional component of extinct frugivores that could have dispersed seeds away from maternal trees. METHODOLOGY/PRINCIPAL FINDINGS: In Mauritius, we investigated seed germination and seedling survival patterns of the critically endangered endemic plant Syzygium mamillatum (Myrtaceae) in relation to proximity to maternal trees. We found strong negative effects of proximity to maternal trees on growth and survival of seedlings. We successfully used giant Aldabran tortoises as ecological analogues for extinct Mauritian frugivores. Effects of gut-passage were negative at the seed germination stage, but seedlings from gut-passed seeds grew taller, had more leaves, and suffered less damage from natural enemies than any of the other seedlings. CONCLUSIONS/SIGNIFICANCE: We provide the first experimental evidence of a distance-dependent Janzen-Connell effect on an oceanic island. Our results potentially have serious implications for the conservation management of rare plant species on oceanic islands, which harbour a disproportionately large fraction of the world's endemic and endangered plants. Furthermore, in contrast to recent controversy about the use of non-indigenous extant megafauna for re-wilding projects in North America and elsewhere, we argue that Mauritius and other oceanic islands are ideal study systems in which to empirically explore the use of ecological analogue species in restoration ecology.

A randomized, double-blind, phase II study of two doses of pemetrexed as first-line chemotherapy for advanced breast cancer.

PURPOSE: Pemetrexed has shown varied response rates in advanced breast cancer. This randomized, double-blind, phase II study was conducted to assess the efficacy and safety of two doses of pemetrexed in a homogeneous population. A secondary objective was to identify molecular biomarkers correlating with response and toxicity. EXPERIMENTAL DESIGN: Patients with newly diagnosed metastatic breast cancer or locally recurrent breast cancer received 600 mg/m(2) (P600 arm) or 900 mg/m(2) (P900 arm) of pemetrexed on day 1 of a 21-day cycle. All patients received folic acid and vitamin B(12) supplementation. RESULTS: The P600 (47 patients) and P900 (45 patients) arms had response rates of 17.0% (95% confidence interval, 7.7-30.8%) and 15.6% (95% confidence interval, 6.5-29.5%) with approximately 50% stable disease per arm, median progression-free survival of 4.2 and 4.1 months, and median times to tumor progression of 4.2 and 4.6 months, respectively. Both arms exhibited minimal toxicity (grade 3/4 neutropenia <20%, leukopenia <9%, and other toxicities <5%). Tumor samples from 49 patients were assessed for the expression levels of 12 pemetrexed-related genes. Folylpolyglutamate synthetase and thymidine phosphorylase correlated with efficacy. Best response rates and median time to tumor progression for high versus low thymidine phosphorylase expression were 27.6% versus 6.3% (P = 0.023) and 5.4 versus 1.9 months (P = 0.076), and for folylpolyglutamate synthetase were 37.5% versus 10.0% (P = 0.115) and 8.6 versus 3.0 months (P = 0.019), respectively. gamma-Glutamyl hydrolase expression correlated with grade 3/4 toxicities: 78.6% for high versus 27.3% for low gamma-glutamyl hydrolase (P = 0.024). CONCLUSION: The two pemetrexed doses yielded similar efficacy and safety profiles. Exploratory biomarker analysis identified efficacy and toxicity correlations and warrants further evaluation.

A randomized phase II trial of pemetrexed plus irinotecan (ALIRI) versus leucovorin-modulated 5-FU plus irinotecan (FOLFIRI) in first-line treatment of locally advanced or metastatic colorectal cancer.

BACKGROUND: This multicenter, randomized trial compared overall response rate between pemetrexed plus irinotecan (ALIRI) and leucovorin-modulated 5-fluorouracil plus irinotecan (FOLFIRI) in patients with advanced colorectal cancer. Secondary objectives included overall and progression-free survival, duration of response, toxicities, and biomarkers. PATIENTS AND METHODS: ALIRI patients received pemetrexed 500 mg/m(2) and irinotecan 350 mg/m(2) with vitamin supplementation on day 1 of each 21-day cycle. FOLFIRI patients received irinotecan 180 mg/m(2) on days 1, 15, 29; on days 1, 2, 15, 16, 29, 30, patients received leucovorin 200 mg/m(2), bolus 5-fluorouracil 400 mg/m(2), and 5-fluorouracil 600 mg/m(2) as 22-hour infusion. RESULTS: Of 132 patients randomly assigned, 130 patients (64 = ALIRI, 66 = FOLFIRI) received > or =1 dose of treatment. Response rates (ALIRI = 20.0%, FOLFIRI = 33.3%) were not significantly different between arms (p = 0.095). Progression-free survival was 5.7 months for ALIRI and 7.7 months for FOLFIRI (p < 0.001). Neutropenia, fatigue, diarrhea, nausea, and vomiting were the major toxicities. There were 5 drug-related deaths (ALIRI = 4, FOLFIRI = 1). Biomarker analysis failed to reveal that any of the 18 preselected genes were clearly associated with tumor response. CONCLUSIONS: Neither efficacy nor safety improved on the ALIRI arm compared to the FOLFIRI arm. Progression-free survival on FOLFIRI was significantly longer compared to ALIRI. Potential biomarkers capable of predicting response to either regimen in advanced or metastatic colorectal carcinoma need further characterization.