Publications by authors named "Brooke Smith"

76 Publications

Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size.

Brain 2019 09;142(9):2617-2630

GeneDx, Clinical Genomics, 207 Perry Parkway Gaithersburg, MD, USA.

The underpinnings of mild to moderate neurodevelopmental delay remain elusive, often leading to late diagnosis and interventions. Here, we present data on exome and genome sequencing as well as array analysis of 13 individuals that point to pathogenic, heterozygous, mostly de novo variants in WDFY3 (significant de novo enrichment P = 0.003) as a monogenic cause of mild and non-specific neurodevelopmental delay. Nine variants were protein-truncating and four missense. Overlapping symptoms included neurodevelopmental delay, intellectual disability, macrocephaly, and psychiatric disorders (autism spectrum disorders/attention deficit hyperactivity disorder). One proband presented with an opposing phenotype of microcephaly and the only missense-variant located in the PH-domain of WDFY3. Findings of this case are supported by previously published data, demonstrating that pathogenic PH-domain variants can lead to microcephaly via canonical Wnt-pathway upregulation. In a separate study, we reported that the autophagy scaffolding protein WDFY3 is required for cerebral cortical size regulation in mice, by controlling proper division of neural progenitors. Here, we show that proliferating cortical neural progenitors of human embryonic brains highly express WDFY3, further supporting a role for this molecule in the regulation of prenatal neurogenesis. We present data on Wnt-pathway dysregulation in Wdfy3-haploinsufficient mice, which display macrocephaly and deficits in motor coordination and associative learning, recapitulating the human phenotype. Consequently, we propose that in humans WDFY3 loss-of-function variants lead to macrocephaly via downregulation of the Wnt pathway. In summary, we present WDFY3 as a novel gene linked to mild to moderate neurodevelopmental delay and intellectual disability and conclude that variants putatively causing haploinsufficiency lead to macrocephaly, while an opposing pathomechanism due to variants in the PH-domain of WDFY3 leads to microcephaly.
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http://dx.doi.org/10.1093/brain/awz198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736092PMC
September 2019

TECHNICAL NOTE: A method for detection of differences in cook loss and tenderness of aged pork chops cooked to differing degrees of doneness using sous-vide.

J Anim Sci 2019 Jul;97(8):3348-3353

Department of Animal Sciences, University of Illinois, Urbana-Champaign, IL.

The objective was to determine the ability to detect differences in cook loss and Warner-Bratzler shear force (WBSF) values between chops aged for differing time periods and cooked to varying degrees of doneness with in a sous-vide style cooker. Loins from pigs (HCW = 96 kg) humanely slaughtered at the University of Illinois Meat Science Laboratory were separated between the 10th and 11th rib into anterior and posterior sections. The posterior section was cut into 6 separate 2.54-cm-thick chops. The middle 4 chops were randomly designated for aging of 3 d and cooked to 63 °C, aged 7 d and cooked to 63 °C, aged 14 d and cooked to 63 °C, or aged 14 d and cooked to 71 °C. Chops were cooked by placing them in a water bath with an immersion circulator set to the desired end-point temperature for 90 min. Cook loss was calculated for each chop by measuring initial and final weight, and accounting for packaging weight. Four cores measuring 1.25 cm in diameter were cut parallel to the muscle fibers from each chop and analyzed for WBSF. Data were analyzed using a 1-way ANOVA. Least squares means were separated using the probability of difference option in the MIXED procedure of SAS. Among chops cooked to 63 °C, chops aged 3 d has less (P < 0.01) cook loss than those aged 7 d, and chops aged 7 d had less (P < 0.01) cook loss than those aged 14 d. Among chops aged for 14 d, chops cooked to 71 °C had greater (P < 0.001) cook loss than chops cooked to 63 °C. Differences in tenderness were also detected between aging periods. Among chops cooked to 63 °C, chops aged 3 d required more (P = 0.02) force to shear than those aged 7 d, but chops aged 7 d did not differ (P = 0.15) from those aged 14 d. Chops aged 14 d and cooked to 71 °C required (P < 0.0001) more force than those aged 14 d and cooked to 63 °C. Overall, these data indicate that sous-vide is an acceptable cooking method for use in experiments as expected differences in cook loss and WBSF were detected in chops aged to differing time points or cooked to differed degrees of doneness.
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http://dx.doi.org/10.1093/jas/skz198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667237PMC
July 2019

Agglutinin-Like Sequence () Genes in the Species Complex: Blurring the Boundaries Between Gene Families That Encode Cell-Wall Proteins.

Front Microbiol 2019 26;10:781. Epub 2019 Apr 26.

Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, United States.

The agglutinin-like sequence (Als) proteins are best-characterized in and known for their role in adhesion of the fungal cell to host and abiotic surfaces. sequences are often misassembled in whole-genome sequence data because each species has multiple loci that contain similar sequences, most notably tandem copies of highly conserved repeated sequences. The species complex includes , , and , three distinct but closely related species. Using publicly available genome resources, genome assemblies, and laboratory experimentation including Sanger sequencing, five genes were characterized in strain CDC317, three in strain 90-125, and four in strain ATCC 96143. The newly characterized genes shared similar features with the well-known family, but also displayed unique attributes such as novel short, imperfect repeat sequences that were found in other genes encoding fungal cell-wall proteins. Evidence of recombination between sequences and other genes was most obvious in , which had the 5' end of an gene and the repeated sequences and 3' end from the family. Together, these results blur the boundaries between the fungal cell-wall families that were defined in . TaqMan assays were used to quantify relative expression for each gene. Some measurements were complicated by the assay location within the gene. Considerable variation was noted in relative gene expression for isolates of the same species. Overall, however, there was a trend toward higher relative gene expression in saturated cultures rather than younger cultures. This work provides a complete description of the genes in the species complex and a toolkit that promotes further investigations into the role of the Als proteins in host-fungal interactions.
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http://dx.doi.org/10.3389/fmicb.2019.00781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499006PMC
April 2019

Effects of dietary soy isoflavones and soy protein source on response of weanling pigs to porcine reproductive and respiratory syndrome viral infection.

J Anim Sci 2019 Jul;97(7):2989-3006

Department of Animal Sciences, University of Illinois, Urbana, IL.

Porcine reproductive and respiratory syndrome virus (PRRSV) is the most prevalent disease of swine globally. Infection of weanling pigs with PRRSV leads to a complex immune response resulting in significant disease and decreased growth performance. Previous experimental evidence suggests that increasing concentrations of soybean meal in the diet of young pigs confer benefits in terms of growth performance and immune parameters. The objective of this experiment was to identify potential modes of action for this benefit, specifically the ability for soy-derived isoflavones (ISF) to confer immunological benefits to young pigs infected with PRRSV. Four dietary treatments differing in soy protein source (soy protein concentrate vs. enzyme-treated soybean meal) and ISF supplementation (none vs. 1,500 mg total ISF/kg) were fed; the control diet (CON) contained soy protein concentrate and no supplemental ISF. Weanling pigs (60 barrows, 21 d of age, 5.71 ± 0.44 kg) from a naturally Mycoplasma hyopneumoniae (Mh)-infected source herd were individually housed in disease containment chambers and provided ad libitum access to experimental diets for 7 d before receiving either a sham inoculation or a 9.28 × 103 50% tissue culture infective dose of PRRSV at 28 d of age (0 d postinoculation). A total of 5 experimental treatments included an uninfected group receiving the CON diet, plus four infected groups each receiving a different dietary treatment. Growth performance and rectal temperatures were recorded throughout the study, and blood was collected for quantification of serum PRRSV load, presence of anti-PRRSV antibodies, differential complete blood counts, cytokine concentrations, and T-cell immunophenotyping. Data were analyzed as a 2-way or 3-way ANOVA for all treatments including PRRSV-infected pigs, in addition to a single degree of freedom contrast to compare uninfected and infected pigs receiving the CON diet. PRRSV-infection reduced growth rate and efficiency compared with noninfected controls with minimal influences by ISF. Supplemental ISF reduced PRRSV-induced band neutrophilia and improved cytotoxic-to-helper T-cell ratios. These results suggest that ISF contribute to activation of adaptive immune system pathways and could benefit recovery from and clearance of PRRSV infections.
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http://dx.doi.org/10.1093/jas/skz135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606490PMC
July 2019

Effects of Acceptance and Commitment Therapy on Impulsive Decision-Making.

Behav Modif 2020 07 10;44(4):600-623. Epub 2019 Mar 10.

Utah State University, Logan, USA.

This study examined the transdiagnostic effect of acceptance and commitment therapy (ACT) on impulsive decision-making in a community sample. A total of 40 adults were randomized to eight individual sessions of ACT or an inactive control. Participants completed pre-, mid-, and post-assessments for psychological symptoms; overall behavior change; valued living; delay discounting; psychological flexibility; and distress tolerance. Data were analyzed with multilevel modeling of growth curves. Significant interaction effects of time and condition were observed for psychological flexibility, distress tolerance, psychological symptoms, and the obstruction subscale of valued living. No significant interaction effect was found for two delay discounting tasks nor the progress subscale of valued living. The ACT condition had a significantly larger reduction of problem behavior at post-assessment. The results support use of ACT as a transdiagnostic treatment for impulsive behaviors. The lack of change in delay discounting contrasts previous research.
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http://dx.doi.org/10.1177/0145445519833041DOI Listing
July 2020

Immunomodulatory effects of whole yeast cells and capsicum in weanling pigs challenged with pathogenic Escherichia coli1.

J Anim Sci 2019 Apr;97(4):1784-1795

Department of Animal Sciences, University of Illinois, Urbana, IL.

An experiment was conducted to evaluate growth performance, fecal bacterial counts, frequency of diarrhea, and clinical blood parameters in weanling pigs inoculated with enterotoxigenic Escherichia coli (ETEC) who were fed a whole yeast cell (WYC) product and capsicum, a plant essential oil. Weanling pigs (34 barrows and 30 gilts, 21 d of age, 5.90 ± 1.03 kg BW) were allotted to experimental treatments in a randomized complete block design based on litter, sex, and initial BW. Four pigs were individually housed within each containment chamber and assigned to 1 of 4 dietary treatments, which included a control diet without or with 0.2% WYC (CitriStim; ADM, Decatur, IL) or 10 ppm of capsicum (XTract 6933; Pancosma, Geneva, Switzerland), provided either alone or in combination. After receiving diets for 13 d, pigs were orally inoculated with F18+ ETEC and maintained on their assigned diets for an additional 10 d; a separate cohort of 12 pigs receiving the control diet was sham-inoculated using PBS. Body and feeder weights were recorded, and fecal swabs collected, on 0, 5, and 10 d postinoculation (DPI), with blood sampled at 0, 2, 7, and 10 DPI for isolation of peripheral blood mononuclear cells. Pigs challenged with ETEC and fed diets containing WYC or capsicum alone had a higher frequency of diarrhea when compared with pigs receiving diets without those compounds (P < 0.05). Total fecal bacterial counts in pigs fed the combination of additives were highest when compared with either additive alone (interaction, P = 0.03) at 10 DPI. Blood leukocyte counts were increased in challenged pigs receiving the combination of additives compared with all other challenged treatment groups (interaction, P = 0.04). The addition of WYC increased (main effect, P = 0.01) lymphocyte counts at 7 DPI. Proportions of CD8+ and CD4+CD8+ cells were lower in pigs fed the combination of additives compared with pigs fed either additive alone at 0 and 7 DPI. In conclusion, these data indicate that the combination of the 2 additives elicited higher ETEC shedding and circulating leukocyte counts, and reduced the proportions of cytotoxic and memory T-cells than either additive alone.
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http://dx.doi.org/10.1093/jas/skz063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447261PMC
April 2019

Adding acceptance and commitment therapy to exposure and response prevention for obsessive-compulsive disorder: A randomized controlled trial.

Behav Res Ther 2018 09 22;108:1-9. Epub 2018 Jun 22.

Florida State University, USA.

The objective of this study was to test whether treatment acceptability, exposure engagement, and completion rates could be increased by integrating acceptance and commitment therapy (ACT) with traditional exposure and response prevention (ERP). 58 adults (68% female) diagnosed with obsessive-compulsive disorder (OCD; M age = 27, 80% white) engaged in a multisite randomized controlled trial of 16 individual twice-weekly sessions of either ERP or ACT + ERP. Assessors unaware of treatment condition administered assessments of OCD, depression, psychological flexibility, and obsessional beliefs at pretreatment, posttreatment, and six-month follow-up. Treatment acceptability, credibility/expectancy, and exposure engagement were also assessed. Exposure engagement was high in both conditions and there were no significant differences in exposure engagement, treatment acceptability, or dropout rates between ACT + ERP and ERP. OCD symptoms, depression, psychological inflexibility, and obsessional beliefs decreased significantly at posttreatment and were maintained at follow-up in both conditions. No between-group differences in outcome were observed using intent to treat and predicted data from multilevel modeling. ACT + ERP and ERP were both highly effective treatments for OCD, and no differences were found in outcomes, processes of change, acceptability, or exposure engagement.
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http://dx.doi.org/10.1016/j.brat.2018.06.005DOI Listing
September 2018

The Influence of a Personal Values Intervention on Cold Pressor-Induced Distress Tolerance.

Behav Modif 2019 09 20;43(5):688-710. Epub 2018 Jun 20.

1 University of Nevada Reno, Reno, NV, USA.

Research has demonstrated that values and acceptance interventions can increase distress tolerance, but the individual contribution of each remains unclear. The current study examined the isolated effect of a values intervention on immersion time in a cold pressor. Participants randomized to Values ( = 18) and Control ( = 14) conditions completed two cold pressor tasks, separated by a 30-min values or control intervention. Immersion time increased 51.06 s for participants in the Values condition and decreased by 10.79 s for those in the Control condition. Increases in self-reported pain and distress predicted decreases in immersion time for Control, but not Values, participants. The best-fitting model accounted for 39% of the variance in immersion time change. Results suggest that a brief isolated values exercise can be used to improve distress tolerance despite increased perceptions of pain and distress, such that values alone may be sufficient to facilitate openness to difficult experiences.
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http://dx.doi.org/10.1177/0145445518782402DOI Listing
September 2019

Immunomodulatory potential of dietary soybean-derived isoflavones and saponins in pigs.

J Anim Sci 2018 Apr;96(4):1288-1304

Department of Animal Sciences, University of Illinois, Urbana, IL.

In this review, the potential for use of soy-derived bioactive compounds as immunomodulatory feed additives in pigs is discussed. Soy is a major component of the modern U.S. swine diet in today's commercial industry, providing the bulk of dietary AA necessary for growth and production. However, soy use has generally been limited in early growth phases, during which the risks of immunological insult and disease are among the highest. Improvements of soybean processing and development of soy protein products with little to no antinutritional factors have made soy more appropriate for use in young pigs but additional processing may affect bioactive compound levels in the feed. The bioactive compounds of interest for this review are soy isoflavones and soy saponins. Soy isoflavones are flavonoid compounds with a range of biological activity including moderate estrogenic effects at low biological concentrations. Although estrogenic effects are of more interest in human medical research, isoflavones are also known for their anti-inflammatory, antioxidative properties at cellular levels, engaging several receptors and pathways including inhibition of NF-κB activation and inducible-nitric oxide synthase enzymes, thereby ascribing antiviral properties. Saponins, amphipathic glycoside compounds, also engage anti-inflammatory pathways, though their biological activity in pigs has not been well investigated and seem to mainly be observed on the mucous membrane in the gastrointestinal tract. Regarding use as an immunomodulatory feed additive, supplemental soy isoflavones have been shown to improve immunological status of pigs and produce mild improvements of growth performance under certain disease challenges including porcine reproductive and respiratory syndrome virus. Although more in vivo research in pigs is needed to fully understand biological activity of these compounds in the live animal, soy-derived bioactive compounds show great potential as a health promoting feed additive for the modern swine industry.
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http://dx.doi.org/10.1093/jas/sky036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140853PMC
April 2018

Persistence and relapse of reinforced behavioral variability.

J Exp Anal Behav 2018 01;109(1):210-237

Utah State University.

The present study examined persistence and relapse of reinforced behavioral variability in pigeons. Pigeons emitted four-response sequences across two keys. Sequences produced food according to a lag schedule, in which a response sequence was followed by food if it differed from a certain number of previous sequences. In Experiment 1, food was delivered for sequences that satisfied a lag schedule in both components of a multiple schedule. When reinforcement was removed for one component (i.e., extinction), levels of behavioral variability decreased for only that component. In Experiment 2, food was delivered for sequences satisfying a lag schedule in one component of a multiple schedule. In the other component, food was delivered at the same rate, but without the lag variability requirement (i.e., yoked). Following extinction, levels of behavioral variability returned to baseline for both components after response-independent food delivery (i.e., reinstatement). In Experiment 3, one group of pigeons responded on a lag variability schedule, and the other group responded on a lag repetition schedule. For both groups, levels of behavioral variability increased when alternative reinforcement was suspended (i.e., resurgence). In each experiment, we observed some evidence for extinction-induced response variability and for variability as an operant dimension of behavior.
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http://dx.doi.org/10.1002/jeab.309DOI Listing
January 2018

Prospective evaluation of the International Study Group for Liver Surgery definition of post hepatectomy liver failure after liver resection: an international multicentre study.

HPB (Oxford) 2018 05 26;20(5):462-469. Epub 2017 Dec 26.

Flinders Medical Centre and Flinders University of South Australia, Australia.

Background: The International Study Group for Liver Surgery (ISGLS) definition of post hepatectomy liver failure (PHLF) was developed to be consistent, widely applicable, and to include severity stratification. This international multicentre collaborative study aimed to prospectively validate the ISGLS definition of PHLF.

Methods: 11 HPB centres from 7 countries developed a standardised reporting form. Prospectively acquired anonymised data on liver resections performed between 01 July 2010 and 30 June 2011 was collected. A multivariate analysis was undertaken of clinically important variables.

Results: Of the 949 patients included, 86 (9%) met PHLF requirements. On multivariate analyses, age ≥70 years, pre-operative chemotherapy, steatosis, resection of >3 segments, vascular reconstruction and intraoperative blood loss >300 ml significantly increased the risk of PHLF. Receiver operator curve (ROC) analysis of INR and serum bilirubin relationship with PHLF demonstrated post-operative day 3 and 5 INR performed equally in predicting PHLF, and day 5 bilirubin was the strongest predictor of PHLF. Combining ISGLS grades B and C groups resulted in a high sensitivity for predicting mortality compared to the 50-50 rule and Peak bilirubin >7 mg/dl.

Conclusions: The ISGLS definition performed well in this prospective validation study, and may be the optimal definition for PHLF in future research to allow for comparability of data.
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http://dx.doi.org/10.1016/j.hpb.2017.11.007DOI Listing
May 2018

Liver resection for colorectal cancer metastases: a comparison of outcomes over time in South Australia.

HPB (Oxford) 2018 04 1;20(4):340-346. Epub 2017 Dec 1.

Department of HPB Surgery, Flinders Medical Centre, Bedford Park, SA 5045, Australia; Department of Surgery, Faculty of Medicine, Flinders University, Adelaide, SA 5001, Australia. Electronic address:

Background: The aim of the current study was to assess outcomes following liver resection in metastatic CRC (mCRC) in South Australia across two study periods (pre-2006 versus post-2006).

Methods: The South Australian (SA) Clinical Registry for mCRC maintains data prospectively on all patients in SA with mCRC diagnosed from 01 February 2006. This data was linked with a prospectively collated database on liver resections for mCRC from 01/01/1992 to 01/02/2006. The primary end point was overall survival.

Results: 757 patients underwent liver resection for mCRC. Liver resection was performed on 286 patients pre-2006 and 471 patients post-2006. The median age of the study population was 62 years, and this was similar across both eras. Overall survival was significantly better in the post-2006 era (hazard ratio HR = 0.45, p = 0.001). Complications (59% pre-2006 versus 23% post-2006) and transfusion rates (34% pre-2006 versus 2% post-2006) were significantly higher in the pre-2006 era. Repeat liver resection rates were significantly higher in the post-2006 era (1% pre-2006 versus 10% post-2006).

Conclusions: Outcomes following liver resection for mCRC have improved over time, with significantly better overall survival in the post-2006 era compared to pre-2006.
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http://dx.doi.org/10.1016/j.hpb.2017.10.005DOI Listing
April 2018

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer.

Nature 2017 11 8;551(7681):512-516. Epub 2017 Nov 8.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8 T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies.
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http://dx.doi.org/10.1038/nature24462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145146PMC
November 2017

Effects of differential rates of alternative reinforcement on resurgence of human behavior.

J Exp Anal Behav 2017 01;107(1):191-202

Utah State University.

Despite the success of exposure-based psychotherapies in anxiety treatment, relapse remains problematic. Resurgence, the return of previously eliminated behavior following the elimination of an alternative source of reinforcement, is a promising model of operant relapse. Nonhuman resurgence research has shown that higher rates of alternative reinforcement result in faster, more comprehensive suppression of target behavior, but also in greater resurgence when alternative reinforcement is eliminated. This study investigated rich and lean rates of alternative reinforcement on response suppression and resurgence in typically developing humans. In Phase 1, three groups (Rich, n = 18; Lean, n = 18; Control, n = 10) acquired the target response. In Phase 2, target responding was extinguished and alternative reinforcement delivered on RI 1 s, RI 3 s, and extinction schedules, respectively. Resurgence was assessed during Phase 3 under extinction conditions for all groups. Target responding was suppressed most thoroughly in Rich and partially in Lean. Target responding resurged in the Rich and Lean groups, but not in the Control group. Between groups, resurgence was more pronounced in the Rich group than the Lean and Control groups. Clinical implications of these findings, including care on the part of clinicians when identifying alternative sources of reinforcement, are discussed.
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http://dx.doi.org/10.1002/jeab.241DOI Listing
January 2017

Avoiding bile duct injury in cholecystectomy through anatomical appreciation.

ANZ J Surg 2016 Jul;86(7-8):533

Department of Surgery, Flinders Medical Centre, Royal Adelaide Hospital, Adelaide, South Australia, Australia.

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http://dx.doi.org/10.1111/ans.13581DOI Listing
July 2016

Whole exome sequencing reveals de novo pathogenic variants in KAT6A as a cause of a neurodevelopmental disorder.

Am J Med Genet A 2016 07 2;170(7):1791-8. Epub 2016 May 2.

GeneDx, Gaithersburg, Maryland.

Neurodevelopmental disorders (NDD) are common, with 1-3% of general population being affected, but the etiology is unknown in most individuals. Clinical whole-exome sequencing (WES) has proven to be a powerful tool for the identification of pathogenic variants leading to Mendelian disorders, among which NDD represent a significant percentage. Performing WES with a trio-approach has proven to be extremely effective in identifying de novo pathogenic variants as a common cause of NDD. Here we report six unrelated individuals with a common phenotype consisting of NDD with severe speech delay, hypotonia, and facial dysmorphism. These patients underwent WES with a trio approach and de novo heterozygous predicted pathogenic novel variants in the KAT6A gene were identified. The KAT6A gene encodes a histone acetyltransfrease protein and it has long been known for its structural involvement in acute myeloid leukemia; however, it has not previously been associated with any congenital disorder. In animal models the KAT6A ortholog is involved in transcriptional regulation during development. Given the similar findings in animal models and our patient's phenotypes, we hypothesize that KAT6A could play a role in development of the brain, face, and heart in humans. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37670DOI Listing
July 2016

CHD8 intragenic deletion associated with autism spectrum disorder.

Eur J Med Genet 2016 Apr 26;59(4):189-94. Epub 2016 Feb 26.

Greenwood Genetic Center, Greenwood, SC, 29646, USA.

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders that are highly heritable. De novo genomic alterations are considered an important cause of autism spectrum disorders. Recent research has shown that de novo loss-of-function mutations in the chromodomain helicase DNA-binding protein 8 (CHD8) gene are associated with an increased risk of ASD. We describe a single case of an intragenic deletion of exons 26-28 in the CHD8 gene in a patient with autism and global developmental delay. Our clinical case supports the hypothesis that CHD8 may play a central role in neuronal cell development and ASD risk.
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http://dx.doi.org/10.1016/j.ejmg.2016.02.010DOI Listing
April 2016

Genomic analyses identify molecular subtypes of pancreatic cancer.

Nature 2016 Mar 24;531(7592):47-52. Epub 2016 Feb 24.

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
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http://dx.doi.org/10.1038/nature16965DOI Listing
March 2016

Distribution and pathological features of pancreatic, ampullary, biliary and duodenal cancers resected with pancreaticoduodenectomy.

World J Surg Oncol 2015 Feb 28;13:85. Epub 2015 Feb 28.

HPB Surgery Unit, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia.

Background: Pancreatic cancer (PC) has the worst survival of all periampullary cancers. This may relate to histopathological differences between pancreatic cancers and other periampullary cancers. Our aim was to examine the distribution and histopathologic features of pancreatic, ampullary, biliary and duodenal cancers resected with a pancreaticoduodenectomy (PD) and to examine local trends of periampullary cancers resected with a PD.

Methods: A retrospective review of PD between January 2000 and December 2012 at a public metropolitan database was performed. The institutional ethics committee approved this study.

Results: There were 142 PDs during the study period, of which 70 cases were pre-2010 and 72 post-2010, corresponding to a recent increase in the number of cases. Of the 142 cases, 116 were for periampullary cancers. There were also proportionately more PD for PC (26/60, 43% pre-2010 vs 39/56, 70% post-2010, P = 0.005). There were 65/116 (56%) pancreatic, 29/116 (25%), ampullary, 17/116 (15%) biliary and 5/116 (4%) duodenal cancers. Nodal involvement occurred more frequently in PC (78%) compared to ampullary (59%), biliary (47%) and duodenal cancers (20%), P = 0.002. Perineural invasion was also more frequent in PC (74%) compared to ampullary (34%), biliary (59%) and duodenal cancers (20%), P = 0.002. Microvascular invasion was seen in 57% pancreatic, 38% ampullary, 41% biliary and 20% duodenal cancers, P = 0.222. Overall, clear margins (R0) were achieved in fewer PC 41/65 (63%) compared to ampullary 27/29 (93%; P = 0.003) and biliary cancers 16/17 (94%; P = 0.014).

Conclusions: This study highlights that almost half of PD was performed for cancers other than PC, mainly ampullary and biliary cancers. The volume of PD has increased in recent years with an increased proportion being for PC. PC had higher rates of nodal and perineural invasion compared to ampullary, biliary and duodenal cancers.
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http://dx.doi.org/10.1186/s12957-015-0498-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348158PMC
February 2015

Joint Aspiration for Acute Hemarthrosis in Children Receiving Factor VIII Prophylaxis for Severe Hemophilia: 11-year Safety Data.

J Rheumatol 2015 May 1;42(5):885-90. Epub 2015 Mar 1.

From the School of Paediatrics and Child Health, and Faculty of Medicine, University of Western Australia; Department of Haematology, Princess Margaret Hospital for Children, Subiaco, Australia.P.J. Manners, MBBS, FRACP, School of Paediatrics and Child Health, University of Western Australia; P. Price, MBBS, FRACP, Department of Haematology, Princess Margaret Hospital for Children; D. Buurman, BSc; B. Lewin, BSc; B. Smith, BSc, Faculty of Medicine, University of Western Australia; C.H. Cole, MBBS, FRACP, FRCPA, School of Paediatrics and Child Health, University of Western Australia, and Department of Haematology, Princess Margaret Hospital for Children.

Objective: The aims of this study were (1) to document the prevalence of acute hemarthrosis in a cohort of 46 boys with severe hemophilia A receiving full primary prophylaxis in Western Australia (WA), and (2) to investigate the safety of the WA protocol over 11 years for management of hemarthrosis.

Methods: Case review. The WA protocol involves a pediatric rheumatologist washing out all acute hemarthrosis of large joints promptly and then instilling intraarticular (IA) corticosteroids.

Results: This study showed that joint bleeds occurred in 22 boys of 46 (47.8%). In over 11 years, 84 washouts were performed on 32 joints in 22 boys. No adverse events occurred. Fifteen of 22 boys had normal joints with a Hemophilic Joint Health Score = 0. Fifteen boys who had had all hemarthrosis washed out had clinically normal joints (100%). Seven boys had sustained joint damage prior to full instigation of the protocol, each having had documented hemarthrosis without aspiration. Parents needed to understand that joint bleeds constituted an emergency.

Conclusion: Of our cohort, 47.8% of patients with severe hemophilia receiving prophylaxis developed joint bleeding. The WA protocol is safe. There is evidence suggesting joint outcomes of hemophilic patients having hemarthrosis despite factor VIII prophylaxis may be much improved if there is access to a center using a procedure similar to the WA protocol.
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http://dx.doi.org/10.3899/jrheum.141236DOI Listing
May 2015

Oestrogen hormone receptors in focal nodular hyperplasia.

HPB (Oxford) 2015 Jun 28;17(6):502-7. Epub 2015 Feb 28.

Hepatobiliary Unit, Royal Adelaide Hospital, Adelaide, SA, Australia.

Background: The role of hormones in focal nodular hyperplasia (FNH) has been investigated with conflicting results.

Objective: The aim of this study was to evaluate oestrogen and progesterone receptor immunohistochemical expression in FNH and surrounding normal liver (control material).

Methods: Biopsy materials from FNH and control tissue were investigated using an immunostainer. Receptor expression was graded as the proportion score (percentage of nuclear staining) and oestrogen receptor intensity score.

Results: Study material included tissue from 11 resected FNH lesions and two core biopsies in 13 patients (two male). Twelve samples showed oestrogen receptor expression. The percentage of nuclear oestrogen receptor staining was <33% in eight FNH biopsies, 34-66% in two FNH biopsies, and >67% in both core biopsies. The better staining in core biopsies relates to limitations of the staining technique imposed by the fibrous nature of larger resected FNH. Control samples from surrounding tissue were available for nine of the resected specimens and all showed oestrogen receptor expression. Progesterone receptor expression was negligible in FNH and control samples.

Conclusions: By contrast with previous studies, the majority of FNH and surrounding liver in this cohort demonstrated oestrogen receptor nuclear staining. The implications of this for continued oral contraceptive use in women of reproductive age with FNH remain uncertain given the lack of consistent reported growth response to oestrogen stimulation or withdrawal.
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http://dx.doi.org/10.1111/hpb.12387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4430780PMC
June 2015

Whole genomes redefine the mutational landscape of pancreatic cancer.

Nature 2015 Feb;518(7540):495-501

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.
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http://dx.doi.org/10.1038/nature14169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523082PMC
February 2015

Prospective evaluation of the International Study Group for Liver Surgery definition of bile leak after a liver resection and the role of routine operative drainage: an international multicentre study.

HPB (Oxford) 2015 Jan 24;17(1):46-51. Epub 2014 Jul 24.

Flinders Medical Centre, Bedford Park, SA, Australia; Flinders University of South Australia, Bedford Park, SA, Australia.

Background: The International Study Group for Liver Surgery (ISGLS) proposed a definition for bile leak after liver surgery. A multicentre international prospective study was designed to evaluate this definition.

Methods: Data collected prospectively from 949 consecutive patients on specific datasheets from 11 international centres were collated centrally.

Results: Bile leak occurred in 69 (7.3%) of patients, with 31 (3.3%), 32 (3.4%) and 6 (0.6%) classified as grade A, B and C, respectively. The grading system of severity correlated with the Dindo complication classification system (P < 0.001). Hospital length of stay was increased when bile leak occurred, from a median of 7 to 15 days (P < 0.001), as was intensive care stay (P < 0.001), and both correlated with increased severity grading of bile leak (P < 0.001). 96% of bile leaks occurred in patients with intra-operative drains. Drain placement did not prevent subsequent intervention in the bile leak group with a 5-15 times greater risk of intervention required in this group (P < 0.001).

Conclusion: The ISGLS definition of bile leak after liver surgery appears robust and intra-operative drain usage did not prevent the need for subsequent drain placement.
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http://dx.doi.org/10.1111/hpb.12322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266440PMC
January 2015

Anticoagulation policy after venous resection with a pancreatectomy: a systematic review.

HPB (Oxford) 2014 Aug 18;16(8):691-8. Epub 2013 Dec 18.

HPB Department, Flinders Medical Centre, Adelaide, SA, Australia; Department of Surgery, The University of Sydney, Sydney Medical School, Nepean, Penrith, NSW, Australia.

Background: Portal vein (PV) resection is used increasingly in pancreatic resections. There is no agreed policy regarding anticoagulation.

Methods: A systematic review was performed to compare studies with an anticoagulation policy (AC+) to no anticoagulation policy (AC-) after venous resection.

Results: There were eight AC+ studies (n = 266) and five AC- studies (n = 95). The AC+ studies included aspirin, clopidogrel, heparin or warfarin. Only 50% of patients in the AC+ group received anticoagulation. There were more prosthetic grafts in the AC+ group (30 versus 2, Fisher's exact P < 0.001). The overall morbidity and mortality was similar in both groups. Early PV thrombosis (EPVT) was similar in the AC+ group and the AC- group (7%, versus 3%, Fisher's exact P = 0.270) and was associated with a high mortality (8/20, 40%). When prosthetic grafts were excluded there was no difference in the incidence of EPVT between both groups (1% vs 2%, Fisher's exact test P = 0.621).

Conclusion: There is significant heterogeneity in the use of anticoagulation after PV resection. Overall morbidity, mortality and EPVT in both groups were similar. EPVT has a high associated mortality. While we have been unable to demonstrate a benefit for anticoagulation, the incidence of EPVT is low in the absence of prosthetic grafts.
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http://dx.doi.org/10.1111/hpb.12205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113250PMC
August 2014

Bouveret's syndrome: gastric outlet obstruction caused by a gallstone.

ANZ J Surg 2013 Dec;83(12):996-7

Flinders University Department of Surgery, Flinders Medical Centre, Bedford Park, South Australia, Australia.

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http://dx.doi.org/10.1111/ans.12227DOI Listing
December 2013

A case of pancreatic cancer in the setting of autoimmune pancreatitis with nondiagnostic serum markers.

Case Rep Surg 2013 28;2013:809023. Epub 2013 May 28.

Hepatobiliary Unit, Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000, Australia.

Background. Autoimmune pancreatitis (AIP) often mimics pancreatic cancer. The diagnosis of both conditions is difficult preoperatively let alone when they coexist. Several reports have been published describing pancreatic cancer in the setting of AIP. Case Report. The case of a 53-year-old man who presented with abdominal pain, jaundice, and radiological features of autoimmune pancreatitis, with a "sausage-shaped" pancreas and bulky pancreatic head with portal vein impingement, is presented. He had a normal serum IgG4 and only mildly elevated Ca-19.9. Initial endoscopic ultrasound-(EUS-) guided fine-needle aspiration (FNA) of the pancreas revealed an inflammatory sclerosing process only. A repeat EUS guided biopsy following biliary decompression demonstrated both malignancy and features of autoimmune pancreatitis. At laparotomy, a uniformly hard, bulky pancreas was found with no sonographically definable mass. A total pancreatectomy with portal vein resection and reconstruction was performed. Histology revealed adenosquamous carcinoma of the pancreatic head and autoimmune pancreatitis and squamous metaplasia in the remaining pancreas. Conclusion. This case highlights the diagnostic and management difficulties in a patient with pancreatic cancer in the setting of serum IgG4-negative, Type 2 AIP.
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http://dx.doi.org/10.1155/2013/809023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679691PMC
June 2013

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

Nature 2012 Nov 24;491(7424):399-405. Epub 2012 Oct 24.

The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.
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http://dx.doi.org/10.1038/nature11547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530898PMC
November 2012

RON is not a prognostic marker for resectable pancreatic cancer.

BMC Cancer 2012 Sep 7;12:395. Epub 2012 Sep 7.

Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.

Background: The receptor tyrosine kinase RON exhibits increased expression during pancreatic cancer progression and promotes migration, invasion and gemcitabine resistance of pancreatic cancer cells in experimental models. However, the prognostic significance of RON expression in pancreatic cancer is unknown.

Methods: RON expression was characterized in several large cohorts, including a prospective study, totaling 492 pancreatic cancer patients and relationships with patient outcome and clinico-pathologic variables were assessed.

Results: RON expression was associated with outcome in a training set, but this was not recapitulated in the validation set, nor was there any association with therapeutic responsiveness in the validation set or the prospective study.

Conclusions: Although RON is implicated in pancreatic cancer progression in experimental models, and may constitute a therapeutic target, RON expression is not associated with prognosis or therapeutic responsiveness in resected pancreatic cancer.
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http://dx.doi.org/10.1186/1471-2407-12-395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532183PMC
September 2012

Cirrhosis and microvascular invasion predict outcomes in hepatocellular carcinoma.

ANZ J Surg 2013 May 3;83(5):331-5. Epub 2012 Sep 3.

Hepatopancreatobiliary Unit and South Australian Liver Transplant Unit, Flinders Medical Centre, Adelaide, South Australia, Australia.

Background: Liver resection (LR) and liver transplantation (LT) are two modalities offering potential for cure in patients with hepatocellular carcinoma (HCC). The objective of this study was to evaluate the long-term survival of patients with HCC treated with LT and LR and to analyse variables influencing these outcomes.

Methods: Patients referred to the South Australian Liver Transplant Unit and Hepatopancreatobiliary Unit at Flinders Medical Centre from January 1992 to September 2009 with a diagnosis of HCC who underwent LT or LR were included in the study. Histopathological parameters analysed included size, number and grade of tumour, microscopic vascular invasion and presence or absence of cirrhosis in remnant liver.

Results: Eighty-five patients with a median age of 58 years (range 26-85 years) underwent LT or LR. Median follow-up was 40 months in both groups. Overall, 5-year actuarial survival for all patients with HCC in both groups was 55%. LR patients were significantly older (P < 0.001) than LT patients. Their tumours were larger (P < 001) and more often solitary (P < 0.001) compared with the LT group. In multivariate analysis, age >60 (P < 0.02), histopathological evidence of vascular invasion (P < 0.02) and presence of cirrhosis (P < 0.02) were associated with a significantly reduced survival. Patients without vascular invasion and cirrhosis had an actuarial 5-year survival >70%.

Conclusions: Our study indicates that LT (within University of California, San Francisco criteria) and LR can lead to acceptable long-term survival outcomes in patients with HCC. Microscopic vascular invasion and cirrhosis were the most significant prognostic factors impacting on survival.
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http://dx.doi.org/10.1111/j.1445-2197.2012.06196.xDOI Listing
May 2013
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