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Myocardial disease in the Boxer dog is characterized by 1 of 2 clinical presentations, dilated cardiomyopathy (DCM) characterized by ventricular systolic dysfunction, dilatation and tachyarrhythmias, and arrhythmogenic right ventricular cardiomyopathy (ARVC) characterized by ventricular tachyarrhythmias, syncope, and sudden death. Boxer ARVC has been associated with a deletion in the striatin gene in some families.We hypothesized that both presentations represent a single disease, and the development of DCM in the Boxer is associated with the striatin deletion.Thirty-three adult Boxer dogs with DCM, 29 adult Boxer dogs with the striatin deletion and ARVC, and 16 Boxers without cardiac disease.DNA samples were evaluated for the striatin deletion. Association of the deletion with the DCM phenotype was tested by a Fisher's exact test. T-tests were used to evaluate potential differences between the positive heterozygous and positive homozygous groups with DCM with regard to age, LVIDD, LVIDS, and FS%.Thirty of 33 dogs with DCM were positive for the striatin deletion. The striatin mutation and the homozygous genotype were strongly associated with the DCM phenotype (P

Background: CYP2D6 is the rate limiting enzyme responsible for the metabolic activation of tamoxifen (tam) to endoxifen. Compared to CYP2D6 poor metabolizers (PM), tam-treated CYP2D6 extensive metabolizers (EM) have higher endoxifen concentrations, more vasomotor symptoms (Goetz, MP J Clin Oncol 2005), and are more likely to discontinue tam (Rae, JM 2009. Pharmacogenomics J). Additionally, higher endoxifen concentrations are associated with a stepwise increase in tam side-effects (Lorizio, W Breast Cancer Res Treat 2012). The data regarding CYP2D6 genotype and recurrence is mixed. Venlafaxine is a weak CYP2D6 inhibitor not known to alter tam pharmacokinetics (PK) and commonly recommended for tam induced hot flashes. We conducted a multicenter pharmacological study to determine whether venlafaxine altered the PK of tam and to determine the distribution of CYP2D6 genotypes in this population Methods: Women taking tam for at least 4 weeks and for whom venlafaxine was recommended for the treatment of hot flashes were eligible. Blood samples were collected prior to and 8-16 weeks following initiation of venlafaxine for steady state tam and metabolites. Genotyping was performed for alleles associated with no (PM; *3, *4, *5,*6); reduced (intermediate, IM; *10, 17 and *41); and ultra-rapid (UM; *1x2) metabolism. Power calculations demonstrated that 17 patients with paired samples were required (two-sided alpha=0.05 t-test, 90% power) to detect a 25% change in endoxifen levels after at least 8 weeks of concurrent treatment. Results: 30 women (median age 48.5) initiated venlafaxine. CYP2D6 genotypes were within Hardy Weinberg Equilibrium (HWE). CYP2D6 UM allele frequency (6.7%) was higher while CYP2D6*4 (13.3%) was lower than expected compared to an unselected population (0.5 and 21% respectively; Sachse Am. J. Hum. Genet. 1997), resulting in the absence of CYP2D6 PM/PM. Mean (min/max) baseline endoxifen concentrations (8.73; 1.5-20.5 ng/ml) were correlated with CYP2D6 phenotype as follows: intermediate (EM/PM, PM/IM): 6.8 (1.5-11.2); extensive (EM/EM, EM/IM): 9.4 (1.5-20.5) and ultra-rapid (UM/EM: 11.0; 7.8-14) (r Background: CYP2D6 is the rate limiting enzyme responsible for the metabolic activation of tamoxifen (tam) to endoxifen. Compared to CYP2D6 poor metabolizers (PM), tam-treated CYP2D6 extensive metabolizers (EM) have higher endoxifen concentrations, more vasomotor symptoms (Goetz, MP J Clin Oncol 2005), and are more likely to discontinue tam (Rae, JM 2009. Pharmacogenomics J). Additionally, higher endoxifen concentrations are associated with a stepwise increase in tam side-effects (Lorizio, W Breast Cancer Res Treat 2012). The data regarding CYP2D6 genotype and recurrence is mixed. Venlafaxine is a weak CYP2D6 inhibitor not known to alter tam pharmacokinetics (PK) and commonly recommended for tam induced hot flashes. We conducted a multicenter pharmacological study to determine whether venlafaxine altered the PK of tam and to determine the distribution of CYP2D6 genotypes in this population Methods: Women taking tam for at least 4 weeks and for whom venlafaxine was recommended for the treatment of hot flashes were eligible. Blood samples were collected prior to and 8-16 weeks following initiation of venlafaxine for steady state tam and metabolites. Genotyping was performed for alleles associated with no (PM; *3, *4, *5,*6); reduced (intermediate, IM; *10, 17 and *41); and ultra-rapid (UM; *1x2) metabolism. Power calculations demonstrated that 17 patients with paired samples were required (two-sided alpha=0.05 t-test, 90% power) to detect a 25% change in endoxifen levels after at least 8 weeks of concurrent treatment. Results: 30 women (median age 48.5) initiated venlafaxine. CYP2D6 genotypes were within Hardy Weinberg Equilibrium (HWE). CYP2D6 UM allele frequency (6.7%) was higher while CYP2D6*4 (13.3%) was lower than expected compared to an unselected population (0.5 and 21% respectively; Sachse Am. J. Hum. Genet. 1997), resulting in the absence of CYP2D6 PM/PM. Mean (min/max) baseline endoxifen concentrations (8.73; 1.5-20.5 ng/ml) were correlated with CYP2D6 phenotype as follows: intermediate (EM/PM, PM/IM): 6.8 (1.5-11.2); extensive (EM/EM, EM/IM): 9.4 (1.5-20.5) and ultra-rapid (UM/EM: 11.0; 7.8-14) (r² = 0.35 p = 0.05). In patients with paired samples (n = 20), venlafaxine resulted in a 23% decrease in endoxifen (-2.06 ng/ml; 95% CI -0.69 to -3.04; p = 0.004), but not tam, NDMT, or 4HT concentrations. Following initiation of venlafaxine, CYP2D6 genotype was no longer associated with endoxifen concentrations (r² = 0.28 p = 0.23). For women with reduced CYP2D6 metabolism [EM/PM (n = 9) or PM/IM (n = 1)], venlafaxine lowered endoxifen concentrations (- 2.98 ng/ml) to a level (5.41 ng/ml) reported to be associated with a higher risk of recurrence in adjuvant tam treated patients (Madlensky, L Clin Pharmacol There 2011). Conclusions: In this study, women with tam-induced vasomotor symptoms requiring venlafaxine were comprised predominantly of CYP2D6 EM and UM metabolizers. Venlafaxine significantly decreased endoxifen concentrations. Although the optimal concentration of endoxifen is unknown, given prior data linking low endoxifen concentrations with recurrence, venlafaxine should be used with caution in tam treated patients. (Supported by R01CA133049) Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD10-08. = 0.35 p = 0.05). In patients with paired samples (n = 20), venlafaxine resulted in a 23% decrease in endoxifen (-2.06 ng/ml; 95% CI -0.69 to -3.04; p = 0.004), but not tam, NDMT, or 4HT concentrations. Following initiation of venlafaxine, CYP2D6 genotype was no longer associated with endoxifen concentrations (r² = 0.28 p = 0.23). For women with reduced CYP2D6 metabolism [EM/PM (n = 9) or PM/IM (n = 1)], venlafaxine lowered endoxifen concentrations (- 2.98 ng/ml) to a level (5.41 ng/ml) reported to be associated with a higher risk of recurrence in adjuvant tam treated patients (Madlensky, L Clin Pharmacol There 2011). Conclusions: In this study, women with tam-induced vasomotor symptoms requiring venlafaxine were comprised predominantly of CYP2D6 EM and UM metabolizers. Venlafaxine significantly decreased endoxifen concentrations. Although the optimal concentration of endoxifen is unknown, given prior data linking low endoxifen concentrations with recurrence, venlafaxine should be used with caution in tam treated patients. (Supported by R01CA133049) [ABSTRACT FROM AUTHOR]

Introduction: Adolescence represents a critical developmental period, with changes in emotional regulation capacities influencing physical and mental health. With less than 6% of Canadian youth currently meeting the 24-hour movement guidelines for physical activity, sleep and sedentary behaviour, there is an urgent need to understand the potential association between movement behaviours, physical literacy, emotional regulation and mental health during adolescence. Additionally, there is a need to better understand these associations among equity-deserving groups. We developed the Adolescents' Daily Lives (ADL) project to identify how, when, under what contexts and to whom to promote healthy engagement in movement behaviours to optimise youth mental health., Methods and Analysis: For the ADL project, we will employ a 14-day intensive longitudinal design to investigate the associations between physical literacy, movement behaviours, emotion regulation and mental health among a diverse sample of 120 adolescents (ages 13-17 years) living in the Greater Victoria Area, British Columbia, Canada. A comprehensive baseline survey and movement competence test, assessing physical and mental well-being, 24-hour movement behaviours (ie, physical activity, sleep and sedentary behaviours) and physical literacy, will be accompanied by daily diary surveys and accelerometer-based movement tracking (ie, Fitbit Inspire 3) to assess daily fluctuations in movement behaviour, emotional regulation and mood. Multivariate analyses, including multilevel modelling, multilevel structural equation modelling and Bayesian hierarchical continuous-time SEM, will be used to model the repeated measures data and understand the simultaneous variations in daily movement behaviours, emotion regulation and mental health., Ethics and Dissemination: The ADL project received ethical approval from the University of Victoria Behavioural Research Ethics Board (protocol #22-0262). Study participation is voluntary, and data collection will be anonymised to protect participant privacy and confidentiality. Research findings will be shared through academic publications and conference proceedings. Through knowledge mobilisation resources, cocreated with the youth community advisory board, relevant findings will be shared directly with the wider community of adolescents., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Inbred-hybrid breeding of diploid potatoes necessitates breeding lines that are self-compatible. One way of incorporating self-compatibility into incompatible cultivated potato ( Solanum tuberosum ) germplasm is to introduce the S-locus inhibitor gene ( Sli ), which functions as a dominant inhibitor of gametophytic self-incompatibility. To learn more about Sli diversity and function in wild species relatives of cultivated potato, we obtained Sli gene sequences that extended from the 5'UTR to the 3'UTR from 133 individuals from 22 wild species relatives of potato and eight diverse cultivated potato clones. DNA sequence alignment and phylogenetic trees based on genomic and protein sequences show that there are two highly conserved groups of Sli sequences. DNA sequences in one group contain the 533 bp insertion upstream of the start codon identified previously in self-compatible potato. The second group lacks the insertion. Three diploid and four polyploid individuals of wild species collected from geographically disjointed localities contained Sli with the 533 bp insertion. For most of the wild species clones examined, however, Sli did not have the insertion. Phylogenetic analysis indicated that Sli sequences with the insertion, in wild species and in cultivated clones, trace back to a single origin. Some diploid wild potatoes that have Sli with the insertion were self-incompatible and some wild potatoes that lack the insertion were self-compatible. Although there is evidence of positive selection for some codon positions in Sli , there is no evidence of diversifying selection at the gene level. In silico analysis of Sli protein structure did not support the hypothesis that amino acid changes from wild-type (no insertion) to insertion-type account for changes in protein function. Our study demonstrated that genetic factors besides the Sli gene must be important for conditioning a switch in the mating system from self-incompatible to self-compatible in wild potatoes., Competing Interests: The authors declare they have no conflict of interest., (© 2024 The Authors. Plant Direct published by John Wiley & Sons Ltd and American Society of Plant Biologists and the Society for Experimental Biology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Chronic kidney disease (CKD) leads to low serum concentrations of vitamin D metabolites. Thus, hypovitaminosis D associated with CKD might contribute to disease progression via increased concentration of renin angiotensin aldosterone system (RAAS) mediators., Objectives: To evaluate whether supplementation with calcifediol affects equilibrium concentrations of selected mediators of the RAAS. We hypothesized that vitamin D supplementation will decrease concentration of circulating RAAS mediators in dogs with CKD., Animals: Six client-owned adult dogs with IRIS Stage 2 and 3 CKD., Methods: Prospective study. Serum 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OH] 2 D), 24,25-dihydroxyvitamin D (24,25[OH] 2 D), RAAS mediators (angiotensin I/II/III/IV/1-5/1-7, and aldosterone), and surrogate angiotensin converting enzyme (ACE) activity (calculated by the ratio of angiotensin II to angiotensin I) were evaluated at baseline, after 3 months of calcifediol supplementation, and 2 months after discontinuing administration of supplement., Results: All serum vitamin D metabolite concentrations increased significantly by month 3 (P < .001): 25(OH)D (median 250 ng/mL; range, 204-310), compared to baseline (median 43.2 ng/mL; range, 33.8-58.3 ng/mL); 1,25(OH) 2 D (median 66.1 pg/mL; range, 57.3-88.1 pg/mL) compared to baseline (median 35.2 pg/mL; range, 29.3-56.7 pg/mL); 24,25(OH) 2 D (median 68.4 ng/mL; range, 22.1-142.0 ng/mL) compared to baseline (median 14.4 ng/mL; range, 9.0-21.3 ng/mL). Calculated ACE activity was significantly lower at month 3 (median 0.5; range, 0.4-1.0) compared to baseline (median 0.7; range, 0.6-1.3; P = .01). There were no significant differences in any of the evaluated RAAS variables at any other time-point., Conclusions and Clinical Importance: Short-term calcifediol supplementation in this small group of CKD dogs appeared to decrease ACE activity., (© 2022 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background: The number of autistic individuals attending college or university is increasing, yet graduation rates are low as postsecondary environments often fail to support autistic students' individual needs. Peer mentorship programs are emerging as a promising approach for providing individualized, one-on-one support to meet this service gap for autistic postsecondary students. However, no literature has systematically described these programs., Methods: We conducted a systematic review that described existing peer mentorship programs for autistic students in postsecondary education as well as their effectiveness., Results: Our search of five databases found nine unique programs that were evaluated in 11 peer-reviewed articles. Programs reported positive outcomes in various domains, which included social skills, academic performance, and sense of belonging. The evidence for these programs was primarily qualitative, sample sizes were small, and there was considerable heterogeneity in the format, provision, and goals of these programs, as well as the evaluation methods used., Conclusions: Overall, the state of the research related to the efficacy of peer mentorship programs for autistic students remains in its infancy, and further research is needed to quantify effectiveness and enable program comparisons., Lay Summary: Why was this review done?: The number of autistic individuals attending college or university is increasing, yet graduation rates are low as most colleges and universities do not have the neccessary accommodations to support this population. Several peer mentorship programs now exist to provide individualized, one-on-one support for autistic students at college or university. What was the purpose of the review?: While several programs exist, it is unknown how effective these programs are in improving the academic experience for autistic students. What did the researchers do?: We systematically reviewed research describing existing peer mentorship programs for autistic university/college students and their effectiveness. Our search of five databases revealed nine unique programs that were evaluated in 11 peer-reviewed articles. What were the results of the review?: Most peer mentorship programs reported positive outcomes in various areas, including social skills, academic performance, and a sense of belonging. However, many of the studies were quite different in their approach and how they evaluated success, thus making it challenging to compare the programs with one another. What do these findings add to what was already known?: The findings from our systematic review highlight that only a few studies related to peer mentorship programs exist. We need more research to quantify the effectiveness of peer mentoring programs for autistic college/university students. What are potential weaknesses of this review?: There were evident inconsistencies between evaluation methods and types of measurement across studies, and studies often had a small number of participants, which limited our ability to make conclusions about the impact of such programs. How will these findings help autistic adults now or in the future?: This article provides a summary of the kinds of supports available to autistic adults within postsecondary settings, which may help autistic adults explore options for their own education. Advancing research in this area may improve the college/university experience for autistic adults in the future., Competing Interests: No competing financial interests exist., (Copyright 2021, Mary Ann Liebert, Inc., publishers.)

Objectives: To understand the role of the community environment on intergenerational continuity in adverse childhood experiences (ACEs) among a rural White sample., Methods: Parents in 12 counties in rural Iowa reported retrospectively on their own ACEs in 1989. We measured their child's ACEs retrospectively and prospectively across adolescence (n = 451 families). We measured structural and social process-related measures of community environment (i.e., community socioeconomic status, parents' perception of community services, perceived community social cohesion, and neighborhood alcohol vendor density) on multiple occasions during the child's adolescence., Results: The 4 measures of community environment were all correlated with the child's ACEs, but only alcohol vendor density predicted ACEs after inclusion of covariates. Intergenerational continuity in ACEs was moderated by both social cohesion (b = -0.11; SE = 0.04) and alcohol vendor density (b = -0.11; SE = 0.05)., Conclusions: Efforts to increase community social cohesion and manage alcohol vendor density may assist families in breaking the cycle of maltreatment across generations.

Orchids are the most diverse family of angiosperms, with over 25 000 species,more than mammals, birds and reptiles combined. Tests of hypotheses to account for such diversity have been stymied by the lack of a fully resolved broad-scale phylogeny. Here,we provide such a phylogeny, based on 75 chloroplast genes for 39 species representing all orchid subfamilies and 16 of 17 tribes, time-calibrated against 17 angiosperm fossils. Asupermatrix analysis places an additional 144 species based on three plastid genes. Orchids appear to have arisen roughly 112 million years ago (Mya); the subfamilies Orchidoideae and Epidendroideae diverged from each other at the end of the Cretaceous; and the eight tribes and three previously unplaced subtribes of the upper epidendroids diverged rapidly from each other between 37.9 and 30.8 Mya. Orchids appear to have undergone one significant acceleration of net species diversification in the orchidoids, and two accelerations and one deceleration in the upper epidendroids. Consistent with theory, such accelerations were correlated with the evolution of pollinia, the epiphytic habit, CAM photosynthesis, tropical distribution (especially in extensive cordilleras),and pollination via Lepidoptera or euglossine bees. Deceit pollination appears to have elevated the number of orchid species by one-half but not via acceleration of the rate of net diversification. The highest rate of net species diversification within the orchids (0.382 sp sp(-1) My(-1)) is 6.8 times that at the Asparagales crown.

An 8-week-old male domestic shorthair was presented to the Internal Medicine Service at North Carolina State University for regurgitation. Radiographic diagnosis of generalized esophageal dilation and failure of esophageal peristalsis were compatible with diagnosis of congenital megaesophagus. Endoscopic examination of the esophagus revealed a fibrous stricture just orad to the lower esophageal sphincter. Conservative management to increase the body condition and size of the kitten consisted of feeding through a gastrostomy tube, during which time the esophagus regained normal peristaltic function, the stricture orifice widened in size and successful balloon dilatation of the stricture was performed. Esophageal endoscopy should be considered to rule out a stricture near the lower esophageal sphincter in kittens with radiographic findings suggestive of congenital megaesophagus. Management of such kittens by means of gastrostomy tube feeding may be associated with a return of normal esophageal motility and widening of the esophageal stricture, and facilitate subsequent success of interventional dilation of the esophageal stricture., (© ISFM and AAFP 2014.)

Cross-institutional data sharing for cohort discovery is critical to enabling future research. While particularly useful in rare diseases, the ability to target enrollment and to determine if an institution has a sufficient number of patients is valuable in all research, particularly in the initiation of projects and collaborations. An optimal technology solution would work with any source database with minimal resource investment for deployment and would meet all necessary security and confidentiality requirements of participating organizations. We describe a platform-neutral reference implementation to meet these requirements: the Federated Aggregate Cohort Estimator (FACE). FACE was developed and implemented through a collaboration of The University of Alabama at Birmingham (UAB), The Ohio State University (OSU), the University of Massachusetts Medical School (UMMS), and the Denver Health and Hospital Authority (DHHA) a clinical affiliate of the Colorado Clinical and Translational Sciences Institute. The reference implementation of FACE federated diverse SQL data sources and an i2b2 instance to estimate combined research subject availability from three institutions. It used easily-deployed virtual machines and addressed privacy and security concerns for data sharing., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Myocardial disease in the Boxer dog is characterized by 1 of 2 clinical presentations, dilated cardiomyopathy (DCM) characterized by ventricular systolic dysfunction, dilatation and tachyarrhythmias, and arrhythmogenic right ventricular cardiomyopathy (ARVC) characterized by ventricular tachyarrhythmias, syncope, and sudden death. Boxer ARVC has been associated with a deletion in the striatin gene in some families., Hypothesis/objectives: We hypothesized that both presentations represent a single disease, and the development of DCM in the Boxer is associated with the striatin deletion., Animals: Thirty-three adult Boxer dogs with DCM, 29 adult Boxer dogs with the striatin deletion and ARVC, and 16 Boxers without cardiac disease., Methods: DNA samples were evaluated for the striatin deletion. Association of the deletion with the DCM phenotype was tested by a Fisher's exact test. T-tests were used to evaluate potential differences between the positive heterozygous and positive homozygous groups with DCM with regard to age, LVIDD, LVIDS, and FS%., Results: Thirty of 33 dogs with DCM were positive for the striatin deletion. The striatin mutation and the homozygous genotype were strongly associated with the DCM phenotype (P < .001 and P = .005). There was no statistical difference between the heterozygous and homozygous groups with regard to age and echocardiographic measurements., Conclusions and Clinical Importance: This study demonstrates an association between DCM in the Boxer dog and the striatin mutation, particularly with the homozygous genotype. The observation that 3/33 dogs developed DCM and lacked the striatin mutation suggests that there is at least 1 other cause of DCM in the Boxer dog., (Copyright © 2013 by the American College of Veterinary Internal Medicine.)

Previous studies based on DNA restriction-site and sequence variation have shown that the Hawaiian lobeliads are monophyletic and that the two largest genera, Cyanea and Clermontia, diverged from each other ca. 9.7 Mya. Sequence divergence among species of Clermontia is quite limited, however, and extensive hybridization is suspected, which has interfered with production of a well-resolved molecular phylogeny for the genus. Clermontia is of considerable interest because several species posses petal-like sepals, raising the question of whether such a homeotic mutation has arisen once or several times. In addition, morphological and molecular studies have implied different patterns of inter-island dispersal within the genus. Here we use nuclear ISSRs (inter-simple sequence repeat polymorphisms) and five plastid non-coding sequences to derive biparental and maternal phylogenies for Clermontia. Our findings imply that (1) Clermontia is not monophyletic, with Cl. pyrularia nested within Cyanea and apparently an intergeneric hybrid; (2) the earliest divergent clades within Clermontia are native to Kauài, then Òahu, then Maui, supporting the progression rule of dispersal down the chain toward progressively younger islands, although that rule is violated in later-evolving taxa in the ISSR tree; (3) almost no sequence divergence among several Clermontia species in 4.5 kb of rapidly evolving plastid DNA; (4) several apparent cases of hybridization/introgression or incomplete lineage sorting (i.e., Cl. oblongifolia, peleana, persicifolia, pyrularia, samuelii, tuberculata), based on extensive conflict between the ISSR and plastid phylogenies; and (5) two origins and two losses of petaloid sepals, or--perhaps more plausibly--a single origin and two losses of this homeotic mutation, with its introgression into Cl. persicifolia. Our phylogenies are better resolved and geographically more informative than others based on ITS and 5S-NTS sequences and nuclear SNPs, but agree with them in supporting Clermontia's origin on Kauài or some older island and dispersal down the chain subsequently.

A phase I trial of ABT-888 (veliparib), a PARP inhibitor, in combination with topotecan, a topoisomerase I-targeted agent, was carried out to determine maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of the combination in patients with refractory solid tumors and lymphomas. Varying schedules and doses of intravenous topotecan in combination with ABT-888 (10 mg) administered orally twice a day (BID) were evaluated. Plasma and urine pharmacokinetics were assessed and levels of poly(ADP-ribose) (PAR) and the DNA damage marker γH2AX were measured in tumor and peripheral blood mononuclear cells (PBMC). Twenty-four patients were enrolled. Significant myelosuppression limited the ability to coadminister ABT-888 with standard doses of topotecan, necessitating dose reductions. Preclinical studies using athymic mice carrying human tumor xenografts also informed schedule changes. The MTD was established as topotecan 0.6 mg/m²/d and ABT-888 10 mg BID on days one to five of 21-day cycles. Topotecan did not alter the pharmacokinetics of ABT-888. A more than 75% reduction in PAR levels was observed in 3 paired tumor biopsy samples; a greater than 50% reduction was observed in PBMCs from 19 of 23 patients with measurable levels. Increases in γH2AX response in circulating tumor cells (CTC) and PBMCs were observed in patients receiving ABT-888 with topotecan. We show a mechanistic interaction of a PARP inhibitor, ABT-888, with a topoisomerase I inhibitor, topotecan, in PBMCs, tumor, and CTCs. Results of this trial reveal that PARP inhibition can modulate the capacity to repair topoisomerase I-mediated DNA damage in the clinic., (©2011 AACR.)

Background: Screening tests for Trisomy 21 (T21), also known as Down syndrome, are routinely performed for the majority of pregnant women. However, current tests rely on either evaluating non-specific markers, which lead to false negative and false positive results, or on invasive tests, which while highly accurate, are expensive and carry a risk of fetal loss. We outline a novel, rapid, highly sensitive, and targeted approach to non-invasively detect fetal T21 using maternal plasma DNA., Methods and Findings: Highly heterozygous tandem Single Nucleotide Polymorphism (SNP) sequences on chromosome 21 were analyzed using High-Fidelity PCR and Cycling Temperature Capillary Electrophoresis (CTCE). This approach was used to blindly analyze plasma DNA obtained from peripheral blood from 40 high risk pregnant women, in adherence to a Medical College of Wisconsin Institutional Review Board approved protocol. Tandem SNP sequences were informative when the mother was heterozygous and a third paternal haplotype was present, permitting a quantitative comparison between the maternally inherited haplotype and the paternally inherited haplotype to infer fetal chromosomal dosage by calculating a Haplotype Ratio (HR). 27 subjects were assessable; 13 subjects were not informative due to either low DNA yield or were not informative at the tandem SNP sequences examined. All results were confirmed by a procedure (amniocentesis/CVS) or at postnatal follow-up. Twenty subjects were identified as carrying a disomy 21 fetus (with two copies of chromosome 21) and seven subjects were identified as carrying a T21 fetus. The sensitivity and the specificity of the assay was 100% when HR values lying between 3/5 and 5/3 were used as a threshold for normal subjects., Conclusions: In summary, a targeted approach, based on calculation of Haplotype Ratios from tandem SNP sequences combined with a sensitive and quantitative DNA measurement technology can be used to accurately detect fetal T21 in maternal plasma when sufficient fetal DNA is present in maternal plasma.

Two cytidine analogues, gemcitabine (dFdC) and 1-beta-d-arabinofuranosylcytosine (AraC), show significant therapeutic effect in a variety of cancers. However, response to these drugs varies widely. Evidence from tumor biopsy samples shows that expression levels for genes involved in the cytidine transport, metabolism, and bioactivation pathway contribute to this variation in response. In the present study, we set out to test the hypothesis that variation in gene expression both within and outside of this "pathway" might influence sensitivity to gemcitabine and AraC. Specifically, Affymetrix U133 Plus 2.0 GeneChip and cytotoxicity assays were performed to obtain basal mRNA expression and IC(50) values for both drugs in 197 ethnically defined Human Variation Panel lymphoblastoid cell lines. Genes with a high degree of association with IC(50) values were involved mainly in cell death, cancer, cell cycle, and nucleic acid metabolism pathways. We validated selected significant genes by performing real-time quantitative reverse transcription-PCR and selected two representative candidates, NT5C3 (within the pathway) and FKBP5 (outside of the pathway), for functional validation. Those studies showed that down-regulation of NT5C3 and FKBP5 altered tumor cell sensitivity to both drugs. Our results suggest that cell-based model system studies, when combined with complementary functional characterization, may help to identify biomarkers for response to chemotherapy with these cytidine analogues.

Landrace potato cultivars are native to two areas in South America: the high Andes from eastern Venezuela to northern Argentina and the lowlands of south-central Chile. Potato first appeared outside of South America in Europe in 1567 and rapidly diffused worldwide. Two competing hypotheses suggested the origin of the "European" potato from the Andes or from lowland Chile, but the Andean origin has been widely accepted over the last 60 years. All modern potato cultivars predominantly have Chilean germplasm, explained as originating from breeding with Chilean landraces subsequent to the late blight epidemics beginning in 1845 in the UK. The Andean origin has been questioned recently through examination of landraces in India and the Canary Islands, but this evidence is inferential. Through a plastid DNA deletion marker from historical herbarium specimens, we report that the Andean potato predominated in the 1700s, but the Chilean potato was introduced into Europe as early as 1811 and became predominant long before the late blight epidemics in the UK. Our results provide the first direct evidence of these events and change the history of introduction of the European potato. They shed new light on the value of past breeding efforts to recreate the European potato from Andean forms and highlight the value of herbarium specimens in investigating origins of crop plants.

Purpose: To determine the recommended phase 2 dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the heat shock protein (Hsp) 90 inhibitor, 17-allylaminogeldanamycin (17-AAG)., Experimental Design: 17-AAG was administered as a 60-min infusion, on days 1, 4, 8, and 11 of a 21-day cycle at dose levels of 150, 200, 270, and 360 mg/m(2)/dose. Pharmacokinetic studies and evaluations for Hsp72 and Akt levels in peripheral blood mononuclear cells were done during the first course of therapy., Results: Seventeen patients (7 males), median 7 years of age (range, 1-19 years), were enrolled using a standard dose escalation scheme. No DLTs were observed. Although there were no objective responses, three patients remain on therapy at 6+, 7+, and 9+ months with stable disease. One patient with hepatoblastoma had a reduction in alpha-fetoprotein and stable disease over three cycles. At 270 mg/m(2)/dose, the C(max) and areas under the plasma concentration-time curves of 17-AAG were 5,303 +/- 1,591 ng/mL and 13,656 +/- 4,757 ng/mL h, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.24 +/- 0.80 h. Induction of Hsp72, a surrogate marker for inhibition of Hsp90, was detected at the 270 mg/m(2) dose level., Conclusions: Drug exposures consistent with those required for anticancer activity in preclinical models were achieved without DLT. Evidence for drug-induced modulation of Hsp90 systemically was also detected. The recommended phase II dose of 17-AAG is 360 mg/m(2)/d. Non-DMSO-containing formulations may improve acceptance of this drug by children and their families.