Long-term outcome comparison for standard fractionation (>59 Gy) versus hyperfractionated (>45 Gy) radiotherapy plus concurrent chemotherapy for limited-stage small-cell lung cancer.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is commonly employed in limited-stage small-cell lung cancer (LS-SCLC); however, the optimal radiotherapy regimen is still unknown. This 3-institution analysis compares long-term disease control and survival outcomes for once- (QD) versus twice-daily (BID) radiotherapy at contemporary doses. METHODS AND MATERIALS: Data were collected for LS-SCLC patients treated with platinum-based CCRT and planned RT doses of >5940 cGy at >180 cGy QD or >4500 cGy at 150 cGy BID. Comparative outcome analyses were performed for treatment groups. RESULTS: From 2005 through 2014, 132 patients met inclusion criteria for analysis (80 QD, 52 BID). Treatment groups were well-balanced, excepting higher rate of advanced mediastinal staging, longer interval from biopsy to treatment initiation, and lower rate of prophylactic cranial irradiation for the QD group, as well as institutional practice variation. At median survivor follow-up of 33.5 months (range, 4.6-105.8), 80 patients experienced disease failure (44 QD, 36 BID), and 106 died (62 QD, 44 BID). No differences in disease control or survival were demonstrated between treatment groups. CONCLUSION: The present analysis did not detect a difference in disease control or survival outcomes for contemporary dose QD versus BID CCRT in LS-SCLC.

An In Vitro Model of Triple-Negative Breast Cancer.

We have characterized two highly tumorigenic and metastatic basal B TNBC cell lines, XtMCF and LmMCF, with the additional values of having the normal and early-stage counterparts of them. This model allows the study of the evolution of TNBC, and investigates molecular pathways at different stages of transformation and progression in a relatively constant genetic background. This constitutes an ideal model for developing targeted therapy in two important fields in cancer biology which are the epithelial mesenchymal transition (EMT) and cancer stem cells (CSC).

Rapamycin inhibits mTOR/p70S6K activation in CA3 region of the hippocampus of the rat and impairs long term memory.

The present study was aimed at establishing whether the mTOR pathway and its downstream effector p70S6K in CA3 pyramidal neurons are under the modulation of the cholinergic input to trigger the formation of long term memories, similar to what we demonstrated in CA1 hippocampus. We performed in vivo behavioral experiments using the step down inhibitory avoidance test in adult Wistar rats to evaluate memory formation under different conditions. We examined the effects of rapamycin, an inhibitor of mTORC1 formation, scopolamine, a muscarinic receptor antagonist or mecamylamine, a nicotinic receptor antagonist, on short and long term memory formation and on the functionality of the mTOR pathway. Acquisition was conducted 30min after i.c.v. injection of rapamycin. Recall testing was performed 1h, 4h or 24h after acquisition. We found that (1) mTOR and p70S6K activation in CA3 pyramidal neurons were involved in long term memory formation; (2) rapamycin significantly inhibited mTOR and of p70S6K activation at 4h, and long term memory impairment 24h after acquisition; (3) scopolamine impaired short but not long term memory, with an early increase of mTOR/p70S6K activation at 1h followed by stabilization at longer times; (4) mecamylamine and scopolamine co-administration impaired short term memory at 1h and 4h and reduced the scopolamine-induced increase of mTOR/p70S6K activation at 1h and 4h; (5) mecamylamine and scopolamine treatment did not impair long term memory formation; (6) unexpectedly, rapamycin increased mTORC2 activation in microglial cells. Our results demonstrate that in CA3 pyramidal neurons the mTOR/p70S6K pathway is under the modulation of the cholinergic system and is involved in long-term memory encoding, and are consistent with the hypothesis that the CA3 region of the hippocampus is involved in memory mechanisms based on rapid, one-trial object-place learning and recall. Furthermore, our results are in accordance with previous reports that selective molecular mechanisms underlie either short term memory, long term memory, or both. Furthermore, our discovery that administration of rapamycin increased the activation of mTORC2 in microglial cells supports a reappraisal of the beneficial/adverse effects of rapamycin administration.

Prospective, comparative effectiveness trial of cow's milk elimination and swallowed fluticasone for pediatric eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease in which food antigens play a key role. Current therapeutic options are limited to long-term steroid medication and dietary elimination of multiple foods, each of which is challenging. Our objective was to compare single food elimination of cow's milk to swallowed fluticasone in pediatric EoE patients. This is a prospective, comparative effectiveness trial of newly diagnosed EoE patients (ages 2-18 years) treated with swallowed fluticasone (n = 24) or elimination of cow's milk (n = 20). The dual outcome measures of repeat esophageal biopsy (6-8 weeks) and change in Pediatric Quality of Life Inventor (PedsQL) EoE Module and Symptoms Scales were used to assess response to treatment. After 6-8 weeks of treatment, peak esophageal eosinophil counts decreased to below the threshold of 15 eosinophils/high-power field in 64% of patients treated with cow's milk elimination and 80% of patients treated with swallowed fluticasone (P = 0.4). Mean PedsQL EoE Module total scores (69 vs. 82; P < 0.005) and Total Symptoms scores (58 vs. 75; P = 0.001) showed significant improvement with cow's milk elimination. Among children treated with swallowed fluticasone, mean PedsQL EoE Module total scores (64 vs. 75; P < 0.05) and Total Symptoms scores (58 vs. 69; P < 0.01) were also significantly improved after 6-8 weeks of therapy. Removal of cow's milk from the diet is an effective single food elimination treatment for pediatric patients with EoE as assessed by statistically significant histologic and symptomatic improvement. Cow's milk elimination may be more desirable for EoE patients who do not want to take chronic, long-term steroid medications.

A trabecular plate-like phenotype is overrepresented in Chinese-American versus Caucasian women.

UNLABELLED: This study used extreme phenotype selection to define two trabecular bone phenotypes in a cohort of Chinese-American and Caucasian women. A trabecular plate-predominant phenotype is more common in Chinese-Americans while the rod-predominant phenotype is more typical of Caucasians. The robustness of these phenotypic associations with respect to lifestyle factors suggests that this trait may have a genetic basis and that these phenotypes can be utilized in future genetic studies. INTRODUCTION: Compared to Caucasians, Chinese-Americans have more plate-like trabecular bone when measured by individual trabecula segmentation (ITS). These findings suggest a phenotypic difference between the races, which may be amenable to genetic analysis. We sought to identify a single ITS plate trait to pursue in genetic studies by conducting an extreme phenotype selection strategy to numerically define two distinct phenotypes-plate-like and rod-like-and determine whether the selected phenotypic associations were independent of lifestyle factors in order to conduct future genetic studies. METHODS: A previously described cohort of 146 Chinese-American and Caucasian women with high-resolution peripheral quantitative computed tomography imaging and ITS analyses were studied with logistic regression and receiver operator characteristic analyses. RESULTS: The tibial plate-to-rod (TPR) ratio was the best ITS discriminator of race. Using extreme phenotypic selection, two TPR ratio phenotypes were defined numerically: plate-like as a TPR ratio value in the highest quartile (≥1.336) and rod-like as a TPR ratio value in the lowest quartile (≤0.621). Women with a plate-like phenotype were 25.7 times more likely (95 % CI 7.3-90.1) to be Chinese-American than women with rod-like morphology. After controlling for constitutional and lifestyle covariates, women in the highest vs. lowest TPR ratio quartile were 85.0 times more likely (95 % CI 12.7-568.0) to be Chinese-American. CONCLUSION: Using extreme phenotype selection, we defined a plate- and rod-like trabecular bone phenotype for the TPR ratio trait. The former phenotype is more common in Chinese-American women, while the latter is more typical of Caucasian women. The robustness of these phenotypic associations after controlling for differences in constitution and lifestyle suggest that the TPR ratio may have a genetic basis and that the extreme phenotypes defined in this analysis can be utilized for future studies.

Mapping, cloning and genetic characterization of the region containing the Wilson disease gene.

Wilson disease (WD) is an autosomal recessive disorder of copper transport which map to chromosome 13q14.3. In pursuit of the WD gene, we developed yeast artificial chromosome and cosmid contigs, and microsatellite markers which span the WD gene region. Linkage disequilibrium and haplotype analysis of 115 WD families confined the disease locus to a single marker interval. A candidate cDNA clone was mapped to this interval which, as shown in the accompanying paper, is very likely the WD gene. Our haplotype and mutation analyses predict that approximately half of all WD mutations will be rare in the American and Russian populations.

Reentrant phase diagram of network fluids.

We introduce a microscopic model for particles with dissimilar patches which displays an unconventional "pinched" phase diagram, similar to the one predicted by Tlusty and Safran in the context of dipolar fluids [Science 290, 1328 (2000)]. The model-based on two types of patch interactions, which account, respectively, for chaining and branching of the self-assembled networks-is studied both numerically via Monte Carlo simulations and theoretically via first-order perturbation theory. The dense phase is rich in junctions, while the less-dense phase is rich in chain ends. The model provides a reference system for a deep understanding of the competition between condensation and self-assembly into equilibrium-polymer chains.

Kaposi's sarcoma-associated herpesvirus encodes a functional bcl-2 homologue.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a newly discovered herpesvirus etiologically associated with Kaposi's sarcoma (KS) and two lymphoproliferative disorders. We describe a KSHV vbcl-2 gene with homology to the proto-oncogene bcl-2. It is expressed in KS lesions and in cell lines derived from primary effusion lymphomas. Using yeast and human cells we demonstrate the ability of KSHV vBcl-2 protein to suppress Bax toxicity. We show that KSHV vBcl-2 heterodimerizes with human Bcl-2 in a yeast two-hybrid system. These results suggest that KSHV vBcl-2 plays an anti-apoptotic role in virus infected cells.

Re-entrant phase behaviour of network fluids: a patchy particle model with temperature-dependent valence.

We study a model consisting of particles with dissimilar bonding sites ("patches"), which exhibits self-assembly into chains connected by Y-junctions, and investigate its phase behaviour by both simulations and theory. We show that, as the energy cost ε(j) of forming Y-junctions increases, the extent of the liquid-vapour coexistence region at lower temperatures and densities is reduced. The phase diagram thus acquires a characteristic "pinched" shape in which the liquid branch density decreases as the temperature is lowered. To our knowledge, this is the first model in which the predicted topological phase transition between a fluid composed of short chains and a fluid rich in Y-junctions is actually observed. Above a certain threshold for ε(j), condensation ceases to exist because the entropy gain of forming Y-junctions can no longer offset their energy cost. We also show that the properties of these phase diagrams can be understood in terms of a temperature-dependent effective valence of the patchy particles.

Predicting Soybean Rust Incursions into the North American Continental Interior Using Crop Monitoring, Spore Trapping, and Aerobiological Modeling.

Between 2005 and 2009, millions of U.S. and Canadian soybean acres that would have received fungicide application remained untreated for soybean rust due to information disseminated through the Integrated Pest Management Pest Information Platform for Extension and Education (ipmPIPE), increasing North American producers' profits by hundreds of millions of dollars each year. The results of our analysis of Phakopsora pachyrhizi urediniospores in rain collections, aerobiology model output, and observations of soybean rust spread in 2007 and 2008 show a strong correspondence between spore collections and model predictions for the continental interior of North America, where soybean is an important crop. The analysis suggests that control practices based on up-to-date maps of soybean rust observations and associated commentary from Extension Specialists delivered by the ipmPIPE may have suppressed the number and strength of inoculum source areas in the southern states and retarded the northward progress of seasonal soybean rust incursions into continental North America. The analysis further indicates that spore trapping and aerobiological modeling can reduce our reliance on the costly Sentinel Plot Network while maintaining the effectiveness of the ipmPIPE system for soybean rust management.

Does Attention Increase the Value of Choice Alternatives?

A growing recognition of the role of attention in decision-making has been driven by both the technology of eye tracking and the development of models that explicitly incorporate attention. One result of this convergence is the arresting claim that attention, by itself, can increase the perceived value of a decision alternative. In this review, we cover the origins of that claim, its empirical foundation, and the reasoning that supports it. The conclusion is that, to date, there is not sufficient evidence to support the claim. Alternative explanations for the extant evidentiary base are discussed, as is the balance between the bottom-up influence of empirical evidence and the top-down commitment to a conceptual framework.

A Recursive Partitioning Analysis Demonstrating Risk Subsets for 8-Year Biochemical Relapse After Margin-Positive Radical Prostatectomy Without Adjuvant Hormone or Radiation Therapy.

PURPOSE: The cohort of patients with locally advanced prostate cancer (PC) and positive surgical margin(s) at radical prostatectomy (RP) who would benefit from salvage or adjuvant treatment is unclear. This study examines the risk of prostate-specific antigen (PSA) relapse in a large population of men with PC after margin-positive RP. METHODS AND MATERIALS: Using a multi-institutional database, patients with clinically localized PC who underwent RP between 2002 and 2010 with recorded follow-up PSA were retrospectively selected. Patients were excluded for pathologic seminal vesicle or lymph node involvement, metastatic disease, pre-RP PSA ≥ 30, or adjuvant (nonsalvage) radiation therapy or hormone therapy. The primary endpoint was biochemical relapse free survival (bRFS), where PSA failure was defined as PSA > 0.10 ng/mL and rising, or at salvage intervention. The Kaplan-Meier method was employed for bRFS estimates; recursive partitioning analysis using cumulative or single maximal margin extent (ME) and Gleason grade (GG) at RP was applied to identify variables associated with bRFS. RESULTS: At median follow-up of 105 months, 210 patients with positive margins at RP were eligible for analysis, and 89 had experienced PSA relapse. Median age was 61 years (range, 43-76), and median pre-RP PSA 5.8 ng/mL (1.6-26.0). Recursive partitioning analysis yielded 5 discrete risk groups, with the lowest risk group (GG1, ≤ 2 mm ME) demonstrating a bRFS of 92% at 8 years compared with the highest risk group (GG3-5, ≥ 3 mm ME) of 11%. CONCLUSIONS: This retrospective study suggests that it may be possible to risk-stratify patients undergoing margin-positive RP using commonly acquired clinical and pathologic variables. Patients with low-grade tumors and minimally involved margins have a very low recurrence risk and may be able to forego postprostatectomy radiation. Meanwhile, those with higher grade and greater involvement could benefit from adjuvant or early salvage radiation therapy.

Estrogen and xenoestrogens in breast cancer.

There is growing concern that estrogenic environmental compounds that act as endocrine-disrupting chemicals might potentially have adverse effects on hormone-sensitive organs such as the breast. This concern is further fueled by evidence indicating that natural estrogens, specifically 17beta-estradiol, are important factors in the initiation and progression of breast cancer. We have developed an in vitro-in vivo model in which we have demonstrated the carcinogenicity of E2 in human breast epithelial cells MCF-10F. Hypermethylation of NRG1, STXBP6, BMP6, CSS3, SPRY1, and SNIP were found at different progression stages in this model. The use of this powerful and unique model has provided a tool for exploring whether bisphenol A and butyl benzyl phthalate have relevance in the initiation of breast cancer. These studies provide firsthand evidence that the natural estrogen 17beta-estradiol and xenoestrogenic substances like bisphenol A are able to induce neoplastic transformation in human breast epithelial cells.

Antibiotic Delivery Strategies to Treat Skin Infections When Innate Antimicrobial Defense Fails.

The epidermal skin barrier protects the body from a host of daily challenges, providing protection against mechanical insults and the absorption of chemicals and xenobiotics. In addition to the physical barrier, the epidermis also presents an innate defense against microbial overgrowth. This is achieved through the presence of a diverse collection of microorganisms on the skin (the "microbiota") that maintain a delicate balance with the host and play a significant role in overall human health. When the skin is wounded, the local tissue with a compromised barrier can become colonized and ultimately infected if bacterial growth overcomes the host response. Wound infections present an immense burden in healthcare costs and decreased quality of life for patients, and treatment becomes increasingly important because of the negative impact that infection has on slowing the rate of wound healing. In this review, we discuss specific challenges of treating wound infections and the advances in drug delivery platforms and formulations that are under development to improve topical delivery of antimicrobial treatments.

Genetic architecture of the human tryptophan hydroxylase 2 Gene: existence of neural isoforms and relevance for major depression.

Impaired brain serotonin neurotransmission is a potential component of the diathesis of major depression. Tryptophan hydroxylase-2 (TPH2), is the rate limiting biosynthetic isoenzyme for serotonin that is preferentially expressed in the brain and a cause of impaired serotonin transmission. Here, we identify a novel TPH2 short isoform with truncated catalytic domain expressed in human brainstem, prefrontal cortex, hippocampus and amygdala. An exploratory study of 166 Caucasian subjects revealed association with major depression or suicide of a novel single nucleotide polymorphism (SNP) g.22879A>G located in exon 6 of this short isoform. This SNP and additional SNPs were discovered through a systematic characterization of the genetic architecture of the TPH2 gene for further genetic and functional investigations of its relationship to major depression and other psychopathology.

Is More Always Better? An Assessment of the Impact of Lymph Node Yield on Outcome for Clinically Localized Prostate Cancer with Low/Intermediate Risk Pathology (pT2-3a/pN0) Managed with Prostatectomy Alone.

The clinical impact of lymph node dissection extent remains undetermined in the contemporary setting, as reflected in care pattern variations. Despite some series demonstrating a direct relationship between number of lymph nodes identified and detection of nodal involvement, the correlation between lymph node yield and disease control or survival outcomes remains unclear. Patients with clinically localized prostate cancer, pre-RP PSA <30, and pT2-3a/N0 disease at RP were retrospectively identified from two databases for inclusion. Those who received pre- or post-RP radiotherapy or hormone therapy were excluded. Kaplan-Meier method was employed for survival probability estimation. Cox regression models were used to assess bRFS differences between subsets. From 2002 to 2010, 667 eligible patients were identified. The median age was 61 yrs. (range, 43-76), with median PSA 5.6 ng/dL (0.9-28.0). At RP, most patients had pT2c (64%) disease with Gleason Score (GS) ≤6 (43%) or 7 (48%); 218 (33%) patients had positive margins (M+). At median clinical and PSA follow-up of 96 and 87 months, respectively, 146 patients (22%) experienced PSA failure with an estimated bRFS of 81%/76% at 5/8 years. For patients who underwent LND, univariable analysis identified PSA (at diagnosis), higher GS (≥7, at biopsy or RP), intermediate/high risk stratification, M+ as adversely associated with bRFS (all p < 0.01). A higher number of LNs excised was not associated with improved bRFS for the entire cohort (HR = 0.97, p = 0.27), nor for any clinical risk stratum, biopsy GS, or RP GS subgroup. This study did not demonstrate an association between LN yield and bRFS in patients with clinically localized pT2-3a/pN0 prostate cancer managed with RP alone, either in the entire population or with substratification by clinical risk stratum or GS.

The goal of consistency as a cause of information distortion.

Why, during a decision between new alternatives, do people bias their evaluations of information to support a tentatively preferred option? The authors test the following 3 decision process goals as the potential drivers of such distortion of information: (a) to reduce the effort of evaluating new information, (b) to increase the separation between alternatives, and (c) to achieve consistency between old and new units of information. Two methods, the nonconscious priming of each goal and assessing the ambient activation levels of multiple goals, reveal that the goal of consistency drives information distortion. Results suggest the potential value of combining these methods in studying the dynamics of multiple, simultaneously active goals.

Effects of cartilage rings on airflow and particle deposition in the trachea and main bronchi.

In most computational fluid dynamic (CFD) analysis of the human lung, it has been assumed that the trachea and branches of the lung have smooth walls. In order to determine if this is a valid assumption, the effects of cartilage rings on airflow and particle deposition in the lungs was determined through conducting simulations with two CFD packages, Fluent and CFX. A smooth walled model and a ringed model of the trachea and main bronchi were created based on idealized models with realistic characteristics. Turbulent velocity profiles were implemented at the inlet of the trachea to account for the laryngeal jet at 15, 30 and 60 lpm's, while random and uniform distributions of particles were injected into the airways. Deposition of particles through sedimentation and impaction were recorded and compared for each model at each flow rate. The results of this work show that the effects of cartilage rings increase with the size of particles and flow rate.

Bayesian Revision vs. Information Distortion.

The rational status of the Bayesian calculus for revising likelihoods is compromised by the common but still unfamiliar phenomenon of information distortion. This bias is the distortion in the evaluation of a new datum toward favoring the currently preferred option in a decision or judgment. While the Bayesian calculus requires the independent combination of the prior probability and a new datum, information distortion invalidates such independence (because the prior influences the datum). Although widespread, information distortion has not generally been recognized. First, individuals are not aware when they themselves commit this bias. In addition, it is often hidden in more obvious suboptimal phenomena. Finally, the Bayesian calculus is usually explained only with undistortable data like colored balls drawn randomly. Partly because information distortion is unrecognized by the individuals exhibiting it, no way has been devised for eliminating it. Partial reduction is possible in some situations such as presenting all data simultaneously rather than sequentially with revision after each datum. The potential dangers of information distortion are illustrated for three professional revision tasks: forecasting, predicting consumer choices from internet data, and statistical inference from experimental results. The optimality of the Bayesian calculus competes with people's natural desire that their belief systems remain coherent in the face of new data. Information distortion provides this coherence by biasing those data toward greater agreement with the currently preferred position-but at the cost of Bayesian optimality.

Photoallergic Contact Dermatitis to Sunscreens Containing Oxybenzone in La Plata, Argentina. / Dermatitis por contacto fotoalérgica a protectores solares con oxibenzona en La Plata, Argentina.

BACKGROUND: Photoallergic contact dermatitis (PACD) to oxybenzone was reported for the first time in 1980. Oxybenzone is the most common photoallergen in the United States and Canada and the fourth most common .in Europe. There are no studies or data on the prevalence of oxybenzone PACD in Argentina. OBJECTIVE: To determine the proportion of photosensitive patients with PACD to oxybenzone. METHODS: We conducted a descriptive cross-sectional study of 35 patients with photosensitivity reactions confirmed by photopatch testing at the Research Center of Hospital Público San Martín in La Plata, Argentina, in 2015 and 2016. RESULTS: PACD was identified in 6 patients (17.14%). Five of these (14.28%) had at least one positive reaction to oxybenzone in the photopatch test; 4 had a reaction at irradiated sites only (5 J/cm2 UVA) and one had a reaction at both irradiated and nonirradiated sites. CONCLUSIONS: PACD to sunscreens containing oxybenzone is common and is probably underdiagnosed due to a lack of confirmation by photopatch tests or other diagnostic tools. Sensitization rates vary according to region and are influenced by sunscreen ingredients and variations in the use of sunscreen products, cosmetics, and topical drugs.