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Purpose Exercise therapy (ET) is shown to improve toxicity and surrogates of survival for patients receiving chemotherapy. Current National Comprehensive Cancer Network (NCCN) guidelines lack recommendations for concurrent radiation therapy (RT) and ET. The main objective was to determine the impact of concurrent ET + RT with respect to (1) acceptability, feasibility, safety; and (2) to demonstrate how incorporating ET in cancer treatment can enhance patient-reported outcomes (PROs) and physical function—defined as strength or exercise capacity. Methods and Materials A PICOS/PRISMA selection protocol was used to search PubMed, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Cochrane Review for prospective randomized controlled trials evaluating concurrent ET + RT, including >10 patients and with 1 or more study arms. Acceptability, feasibility, and safety rates were calculated. PROs were assessed with study-specific metrics. Physical function was defined as improvements in strength or range of motion. Statistically significant improvement was defined by P Results Twenty-six of 693 screened studies including 1563 patients (831 receiving exercise, 732 controls) with localized breast cancer (67.1% of patients), prostate cancer (27.4%), head and neck cancers (2.8%), and spinal metastases (2.8%) were assessed. Objective 1: Among 3385 patients approached for ET, 1864 (55.1%) accepted the treatment; of those, 1563 patients (83.9%) completed the trials. Objective 2: Statistical improvements were noted in these PROs: quality of life (14 of 15 studies), fatigue (12 of 16 studies), mood/depression (9 of 13), and anxiety (6 of 7). Physical function improved statically in 16 of 16 studies. Conclusions Combination ET + RT is safe and well-tolerated with improvements in PROs and physical function. Additional studies are needed in patients with metastatic cancers to assess survival and to compare effectiveness of different exercise regimens.

Introduction This research evaluated a formal academic and career advisement program implemented in a doctor of pharmacy program, which included a “Meet Your Advisor” luncheon and required faculty advisement sessions with an assigned faculty member. Methods The advising experience of students from two cohorts of first-year pharmacy students who received the formal advisement program (referred to as advisement cohort 1 and advisement cohort 2) were compared to the experience of a cohort of second-year students who entered prior to the formal advisement program (referred to as the pre-advisement cohort). All students completed a survey with both quantitative and qualitative questions regarding the advisement program. Results Our research demonstrates that the formal advisement program was successful at ensuring that nearly all students receive personalized advisement. In the pre-advisement cohort 65% of students reported receiving individual advisement, while 94% of students in advisement cohort 1 reported individual advisement and 95% in advisement cohort 2. Advisement cohort 2 responded similarly to the pre-advisement cohort on many of the advisement scales, especially the developing understanding scales, which provided evidence that two years after making the advisement program mandatory, students were having similar experiences to the smaller group of students who self-selected to receive advisement. Conclusions A formal advisement program can be developed to include all students. Our research provides evidence that it may take time for the changes to be impactful and suggests the importance of faculty development.

Pancreatic cancer is a highly fatal malignancy for which surgery is currently considered to be the only curative treatment. However, less than a quarter of patients have disease amenable to definitive surgical resection. Local treatment with radiation therapy is a promising alternative to surgery for those patients with unresectable disease. However, conventional radiation techniques with computed tomography (CT)-guided therapy have yielded disappointing results due to the inability to deliver ablative doses of ionizing radiation, while sparing the radiosensitive adjacent organs at risk. Magnetic resonance-guided radiotherapy (MRgRT) has emerged as an alternative to CT-guided radiation treatment which allows for the delivery of higher doses of radiation with low toxicity to surrounding structures. Further study into the use of MRgRT and dose escalation for locally advanced unresectable pancreatic cancer is needed.

Background The human embryo or foetus is susceptible to harmful effects of radiation, which include growth delay, malformations, impaired cognitive function, cancer and foetal demise. The purpose of this study is to describe pregnancy screening practices in radiation oncology, so that potential health effects may be avoided and areas of prevention may be identified. Methods An electronic survey was delivered to 6,304 members of the American Society for Radiation Oncology. The survey subjects were radiation oncologists who are currently practicing in the world. Chi-square tests and a multiple logistic regression model were used to analyse the data. All tests were two-sided and the statistical significance level used was 0.05. This study (STUDY00009765) was approved by an Institutional Review Board. Results A total of 434 responses from practicing radiation oncologists were received. Of these respondents, 69.1% were practicing in the United States. Of all respondents, 19.8% reported treating paediatric patients and 93.6% reported treating premenopausal patients. Despite 84.8% of radiation oncologists saying they would ‘strongly agree’ or ‘agree’ that one should screen for pregnancy prior to radiation therapy, 29.7% of respondents reported their department has no screening policy and 7.1% of respondents reported they do not screen for pregnancy. Having a departmental policy was associated with screening for pregnancy (p-value = 0.0005). Of all respondents, 93 reported treating a known pregnant patient. Of these 93 respondents, 76 reported intentionally treating and 17 reported accidentally treating a pregnant patient. Respondents who did not screen at time of simulation were significantly more likely to treat a pregnant patient than those who screened at time of simulation (p-value = 0.0459). Conclusions Heterogeneity exists among practicing radiation oncologists regarding pregnancy screening. Institutional policies should be clear and consistent. All members of the radiation oncology team should make every effort to minimise unintended radiation exposure to the embryo or foetus.

Background Endometrial hyperplasia is a precursor to endometrioid adenocarcinoma (EMC), the most common uterine cancer. The likelihood of progression to carcinoma may be evaluated by histologic subclassification of endometrial hyperplasia, although these subclasses are subjective and only modestly reproducible among pathologists. Patient care would be improved by a more objective test to predict the risk of cancer progression. Methods Next-generation sequencing was performed on archived endometrial biopsy specimens from a retrospective cohort of women with endometrial hyperplasia. Cases were considered to be either progressing if the patient subsequently developed EMC or resolving if the patient had a subsequent negative tissue sampling or no cancer during medium-term follow-up (32 patients: 15 progressing and 17 resolving). Somatic mutations in endometrial hyperplasia were assessed for enrichment in progressing cases versus resolving cases, with an emphasis on genes commonly mutated in EMC. Results Several mutations were more common in progressing hyperplasia than resolving hyperplasia, although significant overlap was observed between progressing and resolving cases. Mutations included those in PTEN, PIK3CA, and FGFR2, genes commonly mutated in EMC. Mutations in ARID1A and MYC were seen only in progressing hyperplasia, although these were uncommon; this limited diagnostic sensitivity. Progressing hyperplasia demonstrated an accumulation of mutations in oncogenic signaling pathways similarly to endometrial carcinoma. Conclusions Because of mutational differences between progressing and nonprogressing hyperplasia, mutational analysis may predict the risk of progression from endometrial hyperplasia to EMC.

Women with metastatic breast cancer desire interventions that would allow them to self‐manage symptoms, but which do not require additional clinic appointments. We used a community based participatory research approach to develop a tablet based supportive care intervention called Nurse AMIE to address this need. The intervention modules are drawn from published evidence based clinical guidelines from ASCO and NCCN, including physical activity, soothing music, mindfulness meditation, guided imagery, cognitive behavioral therapy, and psychoeducation. Preliminary results include 61% and 55% acceptability from clinicians and patients, respectively, as well as 86% feasibility, defined as using the tablet for at least 30 of the 90‐day intervention. These preliminary results warrant additional research, particularly given the potential for this intervention to address needs of rural and medically underserved patients.

To investigate the incidence of radiotherapy-related acute and late toxicities among patients with pro-inflammatory comorbidities.PICOS/PRISMA/MOOSE methods were used to identify studies on PubMed and MEDLINE, 1970-2018. The following were extracted: location, cancer, sample size, age, follow-up duration, medical contraindication, treatment, and toxicity. A weighted random effects model with the DerSimonian and Laird method was used in the meta-analysis. The primary endpoint was the grade ≥ 3 acute toxicity, and the secondary endpoint was late toxicity.There were 1137 articles screened and 18 included, assessing 621 patients. Among the 18 articles, 10 had collagen vascular disease (n = 417) and 8 had inflammatory bowel disease (n = 204). Median follow-up was 52.8 months. 457 patients received radiotherapy alone, and 153 received concurrent chemo-radiotherapy. The random effects estimate for incidence of grade ≥ 3 toxicity in collagen vascular disease patients (95% confidence interval) was 11.7% (5.4-19.6%) and 6.1% (1.4-12.6%) for acute and late toxicities, respectively. Incidence of grade ≥ 3 toxicity in inflammatory bowel disease patients was 14.0% (7.1-22.4%) and 10.2% (3.2-19.7%) for acute and late toxicities, respectively. Average grade 4 toxicity across both diseases was 1.5% and 4.5% for acute and late toxicities, respectively. Average grade 5 toxicity across both diseases was negligible (1%).Patients with historically accepted contraindications to radiation therapy have a 10-15% risk of any grade ≥ 3 toxicity,5% risk of grade 4 toxicity, and1% risk for grade 5 toxicity, suggesting that collagen vascular disease and inflammatory bowel disease are not absolute contraindications to radiotherapy.

Background and purpose To investigate the incidence of radiotherapy-related acute and late toxicities among patients with pro-inflammatory comorbidities. Material and methods PICOS/PRISMA/MOOSE methods were used to identify studies on PubMed and MEDLINE, 1970–2018. The following were extracted: location, cancer, sample size, age, follow-up duration, medical contraindication, treatment, and toxicity. A weighted random effects model with the DerSimonian and Laird method was used in the meta-analysis. The primary endpoint was the grade ≥ 3 acute toxicity, and the secondary endpoint was late toxicity. Results There were 1137 articles screened and 18 included, assessing 621 patients. Among the 18 articles, 10 had collagen vascular disease (n = 417) and 8 had inflammatory bowel disease (n = 204). Median follow-up was 52.8 months. 457 patients received radiotherapy alone, and 153 received concurrent chemo-radiotherapy. The random effects estimate for incidence of grade ≥ 3 toxicity in collagen vascular disease patients (95% confidence interval) was 11.7% (5.4–19.6%) and 6.1% (1.4–12.6%) for acute and late toxicities, respectively. Incidence of grade ≥ 3 toxicity in inflammatory bowel disease patients was 14.0% (7.1–22.4%) and 10.2% (3.2–19.7%) for acute and late toxicities, respectively. Average grade 4 toxicity across both diseases was 1.5% and 4.5% for acute and late toxicities, respectively. Average grade 5 toxicity across both diseases was negligible ( Conclusions Patients with historically accepted contraindications to radiation therapy have a 10–15% risk of any grade ≥ 3 toxicity

Systematic mapping of protein-protein interactions, or 'interactome' mapping, was initiated in model organisms, starting with defined biological processes and then expanding to the scale of the proteome. Although far from complete, such maps have revealed global topological and dynamic features of interactome networks that relate to known biological properties, suggesting that a human interactome map will provide insight into development and disease mechanisms at a systems level. Here we describe an initial version of a proteome-scale map of human binary protein-protein interactions. Using a stringent, high-throughput yeast two-hybrid system, we tested pairwise interactions among the products of approximately 8,100 currently available Gateway-cloned open reading frames and detected approximately 2,800 interactions. This data set, called CCSB-HI1, has a verification rate of approximately 78% as revealed by an independent co-affinity purification assay, and correlates significantly with other biological attributes. The CCSB-HI1 data set increases by approximately 70% the set of available binary interactions within the tested space and reveals more than 300 new connections to over 100 disease-associated proteins. This work represents an important step towards a systematic and comprehensive human interactome project.

The Caenorhabditis elegans genome sequence, released in December 1998, was nearly complete and highly accurate, with an error rate estimated at 1/30,000 (The C. elegans Sequencing Consortium 1998). The finished sequence was eventually released in November 2002, comprising 100,258,171 bp in six contiguous segments corresponding to the six C. elegans chromosomes (J. Sulston, pers com; http://elegans.swmed.edu/Announcements/genome_complete.html). Although the technology required for rapid and accurate whole-genome sequencing is mature, the gene prediction tools currently available to identify protein-encoding open reading frames (ORFs) and to define their exon/intron structures still need improvements. For exon prediction in mammalian genomes, these tools have an overall sensitivity and specificity of only 60% (Burset and Guigo 1996), and ∼40% for the 5′ and 3′ gene boundaries specifically (Korf et al. 2001). Predicted genes can be truncated, extended, split, or merged (see Reboul et al. 2001), relative to their actual “observed” exon/intron structure. Using GeneFinder, a gene prediction tool developed for C. elegans (http://ftp.genome.washington.edu/cgi-bin/genefinder_req.pl), a total of 19,477 ORFs were annotated in Wormbase release WS9 (August 1999; http://www.Wormbase.org; Stein et al. 2001). Approximately 50% of these ORFs were predicted ab initio, without experimental support. The C. elegans ORFeome project was launched to test the accuracy of these gene predictions, while simultaneously creating a resource of cloned full-length predicted ORFs to be used in various functional genomics and reverse proteomics studies (Reboul et al. 2001, 2003). ORFs were PCR-amplified between their 5′- and 3′-ends, and cloned using the Gateway recombinational cloning system (Hartley et al. 2000; Walhout et al. 2000a,b). PCR amplification was performed on a highly representative cDNA library using gene-specific primer pairs for each of the 19,477 ORFs based on WS9 predictions. Gateway tails attached to all primers allowed the cloning of the ORFs into the pDONR201 vector, resulting in a total of 11,984 (61.5% of the ORFs) Entry clones in the first version of the ORFeome (version v1.1; Supplemental Table 1). The C. elegans ORFeome version 1.1a (v1.1a) represents a consolidated set of 10,623 ORFs cloned in-frame, 11.4% (1361 out of 11,984) of all cloned ORFs in version 1 were cloned outof-frame because of mispredicted gene boundaries (v1.1b). This first version of the worm ORFeome contributed significantly to the reannotation of C. elegans gene structure. The alignment of OSTs (ORF Sequence Tags) to the corresponding predicted gene sequences allowed the improvement of C. elegans annotations by correcting the internal gene structure of 20% of v1.1a cloned ORFs. In addition, OSTs provided experimental verification for 45% of the set of “untouched” ORFs, that is, not detected yet by any mRNA or EST. For each gene, ORFeome v1.1a contains cloned pools that result from mixing ∼50 to ∼1000 Escherichia coli transformants for each Entry clone. Thus, such Entry pools might contain multiple splice variants and alleles corresponding to PCR misincorporations. We are in the process of generating a new resource, ORFeome v2 (Reboul et al. 2003), in which we isolate individual wild-type clones for all detected splice variants of ORFs cloned in v1.1a. We will shortly initiate similar attempts for the ORFs cloned in the ORFeome version 3 described below. The difficulties inherent in identifying ORFs within metazoan genomes and predicting their correct structure are not specific to C. elegans. Genome annotation initiatives in the model organisms Arabidopsis thaliana (Yamada et al. 2003) and Drosophila melanogaster (Hild et al. 2003) have also shown limited accuracy. The accuracy of current gene prediction algorithms is also a major issue for the human genome. High numbers of splice variants and lower signal-to-noise ratios caused by longer introns and intergenic regions render human genome annotations even more difficult than for the model systems experimentally validated so far. Hence, both in model organisms and in human, functional genomic and reverse proteomics studies, which require the use of large sets of full-length ORFs, are hampered by inaccuracies in gene prediction, limiting the usefulness of sequenced genomes. Since the release of Wormbase WS9 in 1999, continuous efforts to reannotate the C. elegans genome have occurred. Reannotations are mainly based on new experimental data, such as mRNAs and ESTs (the EMBL nucleotide sequence database [http://www.ebi.ac.uk/embl/] and the Y. Kohara DNA databank [DDBJ, http://www.ddbj.nig.ac.jp/]), as well as splice-leader sequences (Blumenthal et al. 2002). Furthermore, more refined ab initio approaches have allowed the reprediction of genes for which no confirmatory experimental data are yet available. To experimentally validate these new predictions, improve gene annotation, and generate a more complete C. elegans ORFeome resource, we attempted to clone the 4232 ORFs originally missed in v1.1a and that have been either repredicted or newly predicted between the release of WS9 and that of WS100 (May 2003).

A small sample of children in western Kenya, studied first in infancy and again at age five, was tested in order to ascertain whether mother-holding in infancy continued to predict affective and cognitive outcomes at age 12, as had been the case at age five. Results indicated that (1) positive affective outcomes at age 12 were associated with frequency of mother-holding, but with no other measure of care in infancy; (2) cognitive performance at age 12 was unrelated to mother-holding in infancy; and (3) for most of the affective measures, though notfor the cognitive measures, performance at age 12 was related to earlier test performance at age five. Discussion centered on plausible bases for thefindings as well as on methodological concerns that raise threats to the interpretation.

The overall goals of this study were to test single vs. multiple cognitive deficit models of dyslexia (reading disability) at the level of individual cases and to determine the clinical utility of these models for prediction and diagnosis of dyslexia. To accomplish these goals, we tested five cognitive models of dyslexia: two single-deficit models, two multiple-deficit models, and one hybrid model in two large population-based samples, one cross-sectional (Colorado Learning Disability Research Center—CLDRC) and one longitudinal (International longitudinal Twin Study—ILTS). The cognitive deficits included in these cognitive models were in phonological awareness, language skill, and processing speed and/ or naming speed. To determine whether an individual case fit one of these models, we used two methods: 1) the presence or absence of the predicted cognitive deficits, and 2) whether the individual’s level of reading skill best fit the regression equation with the relevant cognitive predictors (i.e. whether their reading skill was proportional to those cognitive predictors.) We found that roughly equal proportions of cases met both tests of model fit for the multiple deficit models (30–36%) and single deficit models (24–28%); hence, the hybrid model provided the best overall fit to the data. The remaining roughly 40% of cases in each sample lacked the deficit or deficits that corresponded with their best fitting regression model. We discuss the clinical implications of these results for both diagnosis of school age children and preschool prediction of children at risk for dyslexia.

L-DOPA-2,3-dioxygenase from Streptomyces lincolnensis is a single-domain type I extradiol dioxygenase of the vicinal oxygen chelate superfamily and catalyzes the second step in the metabolism of tyrosine to the propylhygric acid moiety of the antibiotic, lincomycin. S. lincolnensis L-DOPA-2,3-dioxygenase was overexpressed, purified and reconstituted with Fe(II). The activity of L-DOPA-2,3-dioxygenase was kinetically characterized with L-DOPA (K(M)=38 microM, k(cat)=4.2 min(-1)) and additional catecholic substrates including dopamine, 3,4-dihydroxyhydrocinnamic acid, catechol and D-DOPA. 3,4-Dihydroxyphenylacetic acid was characterized as a competitive inhibitor of the enzyme (K(i) =2.2 mM). Site-directed mutagenesis and its effects on enzymatic activity were used to identify His14 and His70 as iron ligands.

Differential regulation of gene expression is essential for cell fate specification in metazoans. Characterizing the transcriptional activity of gene promoters, in time and in space, is therefore a critical step toward understanding complex biological systems. Here we present an in vivo spatiotemporal analysis for approximately 900 predicted C. elegans promoters (approximately 5% of the predicted protein-coding genes), each driving the expression of green fluorescent protein (GFP). Using a flow-cytometer adapted for nematode profiling, we generated 'chronograms', two-dimensional representations of fluorescence intensity along the body axis and throughout development from early larvae to adults. Automated comparison and clustering of the obtained in vivo expression patterns show that genes coexpressed in space and time tend to belong to common functional categories. Moreover, integration of this data set with C. elegans protein-protein interactome data sets enables prediction of anatomical and temporal interaction territories between protein partners.