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* Context.--Mutant KRAS is the main oncogenic driver in pancreatic ductal adenocarcinomas (PDACs). However, the clinical and phenotypic implications of harboring different mutant KRAS alleles remain poorly understood. Objective.--To characterize the potential morphologic and clinical outcome differences in PDACs harboring distinct mutant KRAS alleles. Design.--Cohort 1 consisted of 127 primary conventional PDACs with no neoadjuvant therapy, excluding colloid/ mucinous, adenosquamous, undifferentiated, and intraductal papillary mucinous neoplasm-associated carcinomas, for which an in-house 42-gene mutational panel had been performed. A morphologic classification system was devised wherein each tumor was assigned as conventional, papillary/ large duct (P+LD, defined as neoplastic glands with papillary structure and/or with length [greater than or equal to]0.5 mm), or poorly differentiated (when the aforementioned component was 60% or more of the tumor). Cohort 2 was a cohort of 88 PDACs in The Cancer Genome Atlas, which were similarly analyzed. Results.--In both cohorts, there was significant enrichment of P+LD morphology in PDACs with KRAS G12V and G12R compared with G12D. In the entire combined cohort, Kaplan-Meier analyses showed longer overall survival (OS) with KRAS G12R as compared with G12D (median OS of 1255 versus 682 days, P = .03) and in patients whose PDACs displayed P+LD morphology as compared with conventional morphology (median OS of 1175 versus 684 days, P = .04). In the adjuvant-only subset, KRAS G12R had the longest OS compared with G12D, G12V, and other alleles (median OS unreached/undefined versus 1009,1129, and 1222 days, respectively). Conclusions.--PDACs with different mutant KRAS alleles are associated with distinct morphologies and clinical outcomes, with KRAS G12R allele associated with P+LD morphology and longer OS when compared with G12D using Kaplan-Meier studies. (Arch Pathol Lab Med. 2024;148:1299-1309; doi: 10.5858/arpa.2023-0005-OA), Pancreatic cancer, the majority of which consists of pancreatic ductal adenocarcinomas (PDACs), is projected to become the second leading cause of cancer-related deaths by 2030. (1) Surgical resectability is the [...]

Prostate cancer is highly dependent on androgens and the androgen receptor (AR). Hormonal therapies inhibit gonadal testosterone production, block extragonadal androgen biosynthesis, or directly antagonize AR. Resistance to medical castration occurs as castration-resistant prostate cancer (CRPC) and is driven by reactivation of the androgen-AR axis. 3[beta]-hydroxysteroid dehydrogenase-1 (3[beta]HSD1) serves as the rate- limiting step for potent androgen synthesis from extragonadal precursors, thereby stimulating CRPC. Genetic evidence in men demonstrates the role of 3[beta]HSD1 in driving CRPC. In postmenopausal women, 3[beta]HSD1 is required for synthesis of aromatase substrates and plays an essential role in breast cancer. Therefore, 3[beta]HSD1 lies at a critical junction for the synthesis of androgens and estrogens, and this metabolic flux is regulated through germline-inherited mechanisms. We show that phosphorylation of tyrosine 344 (Y344) occurs and is required for 3[beta]HSD1 cellular activity and generation of [[DELTA].sup.4], 3-keto-substrates of 5[alpha]- reductase and aromatase, including in patient tissues. BMX directly interacts with 3[beta]HSD1 and is necessary for enzyme phosphorylation and androgen biosynthesis. In vivo blockade of 3[beta]HSD1 Y344 phosphorylation inhibits CRPC. These findings identify what we believe to be new hormonal therapy pharmacologic vulnerabilities for sex-steroid dependent cancers., Introduction Metastatic prostate cancer requires systemic therapy. Androgen deprivation therapy (ADT) with medical or surgical castration is the front-line treatment and is now frequently combined with other therapies; however, it [...]

We investigated the interplay between genetics and oral peanut protein exposure in the determination of the immunological response to peanut using the targeted intervention in the LEAP clinical trial. We identified an association between peanut-specific IgG4 and HLA-DQA1*01:02 that was only observed in the presence of sustained oral peanut protein exposure. The association between IgG4 and HLA-DQA1*01:02 was driven by IgG4 specific for the Ara h 2 component. Once peanut consumption ceased, the association between IgG4-specific Ara h 2 and HLA-DQA1*01:02 was attenuated. The association was validated by observing expanded IgG4-specific epitopes in people who carried HLA-DQA1*01:02. Notably, we confirmed the previously reported associations with HLA-DQA1*01:02 and peanut allergy risk in the absence of oral peanut protein exposure. Interaction between HLA and presence or absence of exposure to peanut in an allergen- and epitope-specific manner implicates a mechanism of antigen recognition that is fundamental to driving immune responses related to allergy risk or protection., Introduction The interplay between an individual's genetics and exposure to particular environmental or therapeutic modulators influences mechanisms of disease, prognosis, and treatment. Clinical trials of food allergy tolerance, in which [...]

Apolipoprotein L1 (APOL1) risk alleles in donor kidneys associate with graft loss, but whether recipient risk allele expression affects transplant outcomes is unclear. To test whether recipient APOL1 risk alleles independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data on donors and recipients from 2 kidney transplant cohorts: Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation 01/17 (CTOT-01/17). We estimated genetic ancestry (quantified as the proportion of African ancestry, or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we noted that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with an increased risk of death-censored allograft loss (DCAL), independent of ancestry (HR = 2.14; P = 0.006), as well as within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with an increased risk of any T cell-mediated rejection (TCMR) event. These associations were validated in CTOT-01/17. Ex vivo studies of PMBCs revealed, unexpectedly, high expression levels of APOL1 in activated [CD4.sup.+]/[CD8.sup.+] T cells and NK cells. We detected enriched immune response gene pathways in risk allele carriers compared with noncarriers on the kidney transplant waitlist and among healthy controls. Our findings demonstrate an immunomodulatory role for recipient APOL1 risk alleles associated with TCMR and DCAL. We believe this finding has broader implications for immune-mediated injury to native kidneys., Introduction Patients with African ancestry have a significantly higher risk of non-Mendelian focal segmental glomerulosclerosis (FSGS) as well as end-stage renal disease (ESRD) (reviewed in ref. 1). Seminal work identified [...]

The mouse pancreas adopts a pre-inflammatory state in response to a chemical injury or the loss of one copy of the gene Nr5a2. This state might predispose mice, and possibly humans, to pancreatitis and pancreatic cancer. The mouse pancreas adopts a pre-inflammatory state in response to a chemical injury or the loss of one copy of the gene Nr5a2. This state might predispose mice, and possibly humans, to pancreatitis and pancreatic cancer., Author(s): L. Charles Murtaugh, Raymond J. MacDonald Author Affiliations: An inflammatory transcriptional switch Inflammation can initiate the repair of injured tissue, but, if it persists, can also be a fertile [...]

Cytochrome P450 enzyme 2D6 (CYP2D6) is an important member of the cytochrome P450 enzyme superfamily, with more than 100 CYP2D6 allelic variants being previously reported. The aim of this study was to assess the catalytic characteristics of 25 alleles (CYP2D6.1 and 24 CYP2D6 variants) and their effects on the metabolism of propafenone in vitro. Twenty-five CYP2D6 alleles were expressing in 21 Spodoptera frugiperda (Sf) insect cells, and each variant was evaluated using propafenone as the substrate. Reactions were performed at 37°C with 1-100 µmol/L propafenone for 30 min. After termination, the product 5-OH-propafenone was extracted and used for signal collection by ultra- performance liquid chromatography (UPLC). Compared with wild type CYP2D6.1, the intrinsic clearance ([V.sub.max] and [K.sub.m]) values of all variants were significantly altered. Three variants (CYP2D6.87, CYP2D6.90, CYP2D6.F219S) exhibited markedly increased intrinsic clearance values (129% to 165%), whereas 21 variants exhibited significantly decreased values (16% to 85%) due to increased [K.sub.m] and (or) decreased [V.sub.max] values. These results indicated that the majority of tested alleles had significantly altered catalytic activity towards propafenone hydroxylation in this expression system. Attention should be paid to subjects carrying these rare alleles when treated with propafenone. Key words: CYP2D6, variants, propafenone, metabolism, vitro. Le cytochrome P450 2D6 (CYP2D6) est un membre important de la superfamille des cytochromes P450, plus de 100 variants alleliques de CYP2D6 ayant deja ete rapportes. Le but de cette etude etait d'evaluer les caracteristiques catalytiques de 25 alleles (CYP2D6.1 et 24 variants de CYP2D6) et leurs effets sur le metabolisme de la propafenone in vitro. Vingt-cinq alleles CYP2D6 ont ete exprimes dans les cellules d'insecte Spodoptera frugiperda (Sf) 21 et chaque variant a ete evalue a l'aide de la propafenone comme substrat. Les reactions ont ete realisees a 37°C avec 1-100 µmol/L de propafenone pendant 30 min. A la fin, la 5-OH-propafenone a ete extraite et detectee par UPLC. Comparativement au CYP2D6.1, les valeurs de clairance intrinseque ([V.sub.max]/[K.sub.m]) de tous les variants etaient significativement modifiees. Trois variants (CYP2D6.87, CYP2D6.90 CYP2D6.F219S) presentaient des valeurs de clairance intrinseque fortement accrues (129 a 165 %), alors que 21 variants presentaient des valeurs significativement diminuees (16 a 85 %), a cause des valeurs de [K.sub.m] accrues et (ou) de [V.sub.max] diminuees. Ces resultats indiquaient que la majorite des alleles testes possedaient une activite catalytique significativement modifiee quant a l'hydroxylation de la propafenone dans ce systeme d'expression. Les sujets portant ces alleles rares devraient etre attentivement surveilles s'ils sont traites a la propafenone. [Traduit par la Redaction] Mots-cles: CYP2D6, variants, propafenone, metabolisme, vitro., Introduction Propafenone (PPF) is an antiarrhythmic agent widely used in the treatment of ventricular and supraventricular arrhythmias (Stoschitzky et al. 2015). It undergoes extensive first-pass metabolism by liver to form [...]

Sclerotinia sclerotiorum is a yield-limiting pathogen of several economically important crops, and it reproduces sexually by self-fertilization. Based on the presence of an inversion in the mating type locus, S. sclerotiorum can be grouped as inversion negative (Inv- MAT) and inversion positive (Inv+ MAT) isolates. This study was conducted to determine the prevalence of Inv- and Inv+ MAT S. sclerotiorum isolates across the United States. In total, 164 isolates from 16 hosts and 22 states were evaluated, including 87 isolates from North Dakota and northern Minnesota and 47 isolates from soybean. PCR screening was performed separately for Inv- and Inv+ MAT with specific primers. Of the two kinds of MAT homokaryons, Inv- MAT isolates were the most frequent (31.7%) and were identified in 15 states. Another 12.8% of isolates were Inv+ MAT, and were identified in 8 states. The majority (55.5%) of isolates screened were MAT heterokaryons, and these were identified from 18 states and 11 hosts. The implications of MAT heterokaryons for the biology and management of S. sclerotiorum are discussed. Key words: fungi, Sclerotinia sclerotiorum, mating type (MAT) alleles, MAT heterokaryon. Sclerotinia sclerotiorum est un pathogene qui limite le rendement de recoltes d'importance economique, et il se reproduit de maniere sexuee par autogamie. Selon la presence d'une inversion dans le locus du type sexuel, S. sclerotiorum peut se grouper en isolats negatifs pour l'inversion (Inv- MAT) et positifs pour l'inversion (Inv+ MAT). Cette etude a ete menee afin de determiner la prevalence des isolats de S. sclerotiorum Inv- MAT et Inv+ MAT a travers les Etats-Unis. Au total, 164 isolats provenant de 16 hotes et 22 etats ont ete evalues, y compris 87 isolats du Dakota du Nord et de la region nord du Minnesota, et 47 isolats provenant de la feve de soja. Un criblage par PCR a ete realise separement pour Inv- MAT et Inv+ MAT a l'aide d'amorces specifiques. Des deux types d'homocaryons MAT, les isolats Inv- MAT etaient les plus frequents (31,7 %) et ils ont ete identifies dans 15 etats. Les isolats Inv+ MAT formaient 12,8% de la population et ils ont ete identifies dans 8 etats. La majorite (55,5 %) des isolats cribles etaient des heterocaryons MAT et ils ont ete identifies dans 18 etats et sur 11 hotes. Les implications des heterocaryons MAT dans la biologie et la gestion de S. sclerotiorum sont discutees. [Traduit par la Redaction] Mots-cles : champignons, Sclerotinia sclerotiorum, alleles du type sexuel (MAT), heterocaryon MAT., Introduction Sclerotinia sclerotiorum is an ascomycete phytopathogen which attacks more than 400 plant species, including numerous economically important crops worldwide (Boland and Hall 1994). Sunflower, soybean, oilseed rape, dry bean, [...]

California tiger salamanders (Ambystoma californiense) exhibit an obligate metamorphic life history strategy in which aquatic larvae metamorphose into terrestrial juveniles early each summer. However, we have recently documented two occurrences of populations containing large gilled California tiger salamander larvae during the winter months. Large gilled larvae could be the result of genetic admixture between California tiger salamanders and an introduced congener, the barred tiger salamander (Ambystoma tigrinum mavortium), but the population occurrences we observed are located outside the presumed extent of the A. californiense/A. t. mavortium-hybrid swarm. We used single nucleotide polymorphisms (SNPs) to investigate the possibility the genomes of these atypical larvae have been introgressed by 'superinvasive' loci that have escaped from the established hybrid swarm. We also discuss the possibility the overwintering larval phenotypes may be the result of increased prevalence of large, fishless, semipermanent ponds, or of a combination of both introgression and habitat modification., INTRODUCTION When confronted with variation in environmental conditions, some salamander species are able to respond with phenotypic plasticity in life history strategies by altering the timing or rate of their [...]

Inherited alleles account for most of the genetic risk for schizophrenia. However, new (de novo) mutations, in the form of large chromosomal copy number changes, occur in a small fraction of cases and disproportionally disrupt genes encoding postsynaptic proteins. Here we show that small de novo mutations, affecting one or a few nucleotides, are overrepresented among glutamatergic postsynaptic proteins comprising activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-d-aspartate receptor (NMDAR) complexes. Mutations are additionally enriched in proteins that interact with these complexes to modulate synaptic strength, namely proteins regulating actin filament dynamics and those whose messenger RNAs are targets of fragile X mental retardation protein (FMRP). Genes affected by mutations in schizophrenia overlap those mutated in autism and intellectual disability, as do mutation-enriched synaptic pathways. Aligning our findings with a parallel case-control study, we demonstrate reproducible insights into aetiological mechanisms for schizophrenia and reveal pathophysiology shared with other neurodevelopmental disorders. The authors report the largest family-trio exome sequencing study of schizophrenia to date; mutations are overrepresented in genes for glutamatergic synaptic proteins and also genes mutated in autism and intellectual disability, providing insights into aetiological mechanisms and pathopshyisology shared with other neurodevelopmental disorders. Pathogenic mechanisms in schizophrenia Two major sequencing studies of the exome -- the protein-coding portion of the genome -- in schizophrenia sufferers and their relatives are published in this issue of Nature. Together they provide strong pointers to specific pathogenic mechanisms that disrupt the glutamatergic synapses in schizophrenia. In particular, mutations that influence the action of the scaffold protein ARC (activity-regulated cytoskeleton-associated protein) are prominently involved, as are mutations in targets of the fragile X mental retardation protein (FMRP). Defects in FMRP have previously been shown to be associated with autism spectrum disorders., Author(s): Menachem Fromer [sup.1] [sup.2] , Andrew J. Pocklington [sup.3] , David H. Kavanagh [sup.3] , Hywel J. Williams [sup.3] , Sarah Dwyer [sup.3] , Padhraig Gormley [sup.4] [sup.5] , [...]

A set of currently known alleles increasing the risk for coronary artery disease, cancer, and type 2 diabetes as identified by genome-wide association studies was tested for compatibility with human longevity. Here, we show that nonagenarian siblings from long-lived families and singletons older than 85 y of age from the general population carry the same number of disease risk alleles as young controls. Longevity in this study population is not compromised by the cumulative effect of this set of risk alleles for common disease. association | aging SNP doi/ 10.1073/pnas.1003540107

We present an allele-specific copy number analysis of the in vivo breast cancer genome. We describe a unique bioinformatics approach, ASCAT (allele-specific copy number analysis of tumors), to accurately dissect the allele-specific copy number of solid tumors, simultaneously estimating and adjusting for both tumor ploidy and nonaberrant cell admixture. This allows calculation of 'ASCAT profiles' (genome-wide allele-specific copy-number profiles) from which gains, losses, copy number-neutral events, and loss of heterozygosity (LOH) can accurately be determined. In an early-stage breast carcinoma series, we observe aneuploidy (>2.7n) in 45% of the cases and an average nonaberrant cell admixture of 49%. By aggregation of ASCAT profiles across our series, we obtain genomic frequency distributions of gains and losses, as well as genome-wide views of LOH and copy number-neutral events in breast cancer. In addition, the ASCAT profiles reveal differences in aberrant tumor cell fraction, ploidy, gains, losses, LOH, and copy number-neutral events between the five previously identified molecular breast cancer subtypes. Basal-like breast carcinomas have a significantly higher frequency of LOH compared with other subtypes, and their ASCAT profiles show large-scale loss of genomic material during tumor development, followed by a whole-genome duplication, resulting in neartriploid genomes. Finally, from the ASCAT profiles, we construct a genome-wide map of allelic skewness in breast cancer, indicating loci where one allele is preferentially lost, whereas the other allele is preferentially gained. We hypothesize that these alternative alleles have a different influence on breast carcinoma development. breast carcinoma | single-nucleotide polymorphism arrays | bioinformatics | cancer doi/ 10.1073/pnas.1009843107

Abstract Vitamins D and K are lipid-phase nutrients that are pleiotropic--endowed with versatile homeostatic capacities at the organ, tissue, and cellular levels. Their metabolic and physiologic roles overlap considerably, as [...]

The evolutionarily highly conserved neuropeptide oxytocin is a key mediator of social and emotional behavior in mammals, including humans. A common variant (rs53576) in the oxytocin receptor gene (OXTR) has been implicated in social-behavioral phenotypes, such as maternal sensitivity and empathy, and with neuropsychiatric disorders associated with social impairment, but the intermediate neural mechanisms are unknown. Here, we used multimodal neuroimaging in a large sample of healthy human subjects to identify structural and functional alterations in OXTR risk allele carriers and their link to temperament. Activation and interregional coupling of the amygdala during the processing of emotionally salient social cues was significantly affected by genotype. In addition, evidence for structural alterations in key oxytocinergic regions emerged, particularly in the hypothalamus. These neural characteristics predicted lower levels of reward dependence, specifically in male risk allele carriers. Our findings identify sex-dependent mechanisms impacting the structure and function of hypothalamic-limbic circuits that are of potential clinical and translational significance. imaging genetics | neuroimaging | social behavior | prosocial neuropeptides | autism doi/ 10.1073/pnas.1003296107

Chronic beryllium disease (CBD) is a fibrotic lung disorder caused by beryllium (Be) exposure and is characterized by granulomatous inflammation and the accumulation of Be-responsive CD[4.sup.+] T cells in the lung. Genetic susceptibility to CBD has been associated with certain alleles of the MHCII molecule HLA-DP, especially HLA-DPB1*0201 and other alleles that contain a glutamic acid residue at position 69 of the [beta]-chain ([beta]Glu69). The HLA-DP alleles that can present Be to T cells match those implicated in the genetic susceptibility, suggesting that the HLA contribution to disease is based on the ability of those molecules to bind and present Be to T cells. The structure of HLA-DP2 and its interaction with Be are unknown. Here, we present the HLA-DP2 structure with its antigen-binding groove occupied by a self-peptide derived from the HLA-DR [alpha]-chain. The most striking feature of the structure is an unusual solvent exposed acidic pocket formed between the peptide backbone and the HLA-DP2 [beta]-chain [alpha]-helix and containing three glutamic acids from the [beta]-chain, including [beta]Glu69. In the crystal packing, this pocket has been filled with the guanidinium group of an arginine from a neighboring molecule. This positively charged moiety forms an extensive H-bond/salt bridge network with the three glutamic acids, offering a plausible model for how Be-containing complexes might occupy this site. This idea is strengthened by the demonstration that mutation of any of the three glutamic acids in this pocket results in Ioss of the ability of DP2 to present Be to T cells. antigen presentation | lung disease | metal hypersensitivity doi/ 10.1073/pnas.1001772107

Blast disease is a devastating fungal disease of rice, one of the world's staple foods. Race-specific resistance to blast disease has usually not been durable. Here, we report the cloning of a previously unknown type of gene that confers non--race-specific resistance and its successful use in breeding. Pi21 encodes a proline-rich protein that includes a putative heavy metal--binding domain and putative protein-protein interaction motifs. Wild-type Pi21 appears to slow the plant's defense responses, which may support optimization of defense mechanisms. Deletions in its proline-rich motif inhibit this slowing. Pi21 is separable from a closely linked gene conferring poor flavor. The resistant pi21 allele, which is found in some strains of japonica rice, could improve blast resistance of rice worldwide.

Bovine leukocyte antigen DRB3 alleles from Holstein x Zebu crossbred dairy cows (n = 409) were analyzed using the PCR-RFLP technique. Exon II of DRB3 was amplified using locus-specific primers (HLO30/HLO32), followed by digestion with 3 restriction enzymes (RsaI, BstyI, and HaeIII). Forty alleles were found with frequency ranging from 0.005 to 0.139. The most frequently detected alleles of Holstein x Zebu were DRB3*16, *51, *23, *11, *8, and *1, accounting for 61.12% of the alleles in the population. Detection of candidate alleles for clinical mastitis occurrence was performed by logistic regression. It was found that percentage of Holstein fraction in crossbred cows had a nonsignificant effect (P > 0.05). However, parity had a significant effect on mastitis occurrence. In addition, DRB3*1 and *52 were the most associated with the occurrence of clinical mastitis, whereas *15, *51, and *22 were associated with resistance in crossbred populations. This is the first report of association of DRB3* 15 and *51 with mastitis resistance. The association was validated by examining the candidate alleles in another commercial population. Highly susceptible (n = 43) and resistant (n = 42) groups of Holstein x Zebu cows were investigated. The result confirmed that DRB3*1 and *52 could be considered as susceptibility alleles, whereas *15, *51, and *22 could be considered as resistant alleles in Holstein x Zebu raised under tropical conditions. In addition, allele effects on 305-d milk production were estimated by BLUP. It was shown that most alleles associated with high clinical mastitis occurrence were related to increased milk yield. This study revealed that allele DRB3*10 had the greatest effect on increasing milk yield with moderate resistance to clinical mastitis, which could be used as a potential marker for selection in dairy genetic evaluation. Key words: bovine leukocyte antigen DRB3 allele, candidate marker, clinical mastitis, Holstein x Zebu

Pendred syndrome is an autosomal recessive disorder characterized by sensorineural hearing loss, with malformations of the inner ear, ranging from enlarged vestibular aqueduct (EVA) to Mondini malformation, and deficient iodide organification in the thyroid gland. Nonsyndromic EVA (ns-EVA) is a separate type of sensorineural hearing loss showing normal thyroid function. Both Pendred syndrome and ns-EVA seem to be linked to the malfunction of pendrin (SLC26A4), a membrane transporter able to exchange anions between the cytosol and extracellular fluid. In the past, the pathogenicity of SLC26A4 missense mutations were assumed if the mutations fulfilled two criteria: low incidence of the mutation in the control population and substitution of evolutionary conserved amino acids. Here we show that these criteria are insufficient to make meaningful predictions about the effect of these SLC26A4 variants on the pendrin-induced ion transport. Furthermore, we functionally characterized 10 missense mutations within the SLC26A4 ORF, and consistently found that on the protein level, an addition or omission of a proline or a charged amino acid in the SLC26A4 sequence is detrimental to its function. These types of changes may be adequate for predicting SLC26A4 functionality in the absence of direct functional tests. ion transport physiology | genotype--phenotype correlation

To examine the role of Rb1 in gastrointestinal (GI) tumors, we generated mice with an [Apc.sup.1638N] allele, [Rb.sup.tm2brn] floxed alleles, and a villin-cre transgene (RBVCA). These animals had exon 19 deleted from Rb1 throughout the GI tract. We have shown previously that Rb1 deficiency is insufficient for GI tumor initiation, with inactivation of an Apc allele capable of overcoming the insufficiency. In this study we demonstrate that RBVCA mice have reduced median survival because of an increase in tumor incidence and multiplicity in the cecum and the proximal colon. Large intestinal tumors are predominantly adenomas, whereas the tumors of the small intestine are a mixture of adenomas and adenocarcinomas. We find truncation mutations to the second Apc allele in tumors of both the large and small intestine. Expression profiles of duodenal and cecal tumors relative to each other show unique gene subsets up and down regulated. Substantial expression patterns compare to human colorectal cancer, including recapitulation of embryonic genes. Our results indicate that Rb1 has significant influence over tumor location in the GI tract, and that both cecal and duodenal tumors initiate through inactivation of Apc. Expression profile analysis indicates the two tumor types differentially regulate distinct sets of genes that are over-expressed in a majority of human colorectal carcinomas. cancer | mouse | conditional | colorectal | retinoblastoma

DISC1 is a strong candidate susceptibility gene for schizophrenia, bipolar disorder, and depression. Using a mouse strain carrying an endogenous Disc1 orthologue engineered to model the putative effects of the disease-associated chromosomal translocation we demonstrate that impaired Disc1 function results in region-specific morphological alterations, including alterations in the organization of newly born and mature neurons of the dentate gyrus. Field recordings at CA3/CA1 synapses revealed a deficit in short-term plasticity. Using a battery of cognitive tests we found a selective impairment in working memory (WM), which may relate to deficits in WM and executive function observed in individuals with schizophrenia. Our results implicate malfunction of neural circuits within the hippocampus and medial prefrontal cortex and selective deficits in WM as contributing to the genetic risk conferred by this gene. bipolar disorder | gene | mouse model | working memory | adult neurogenesis

Byline: S. J. M. Weatherby (1), W. Thomson (2), L. Pepper (2), R. Donn (2), J. Worthington (2), C. L. A. Mann (1), M. B. Davies (2), A. A. Fryer (3), M. D. Boggild (3), C. A. Young (3), P. W. Jones (4), R. C. Strange (1), W. E. R. Ollier (2), C. P. Hawkins (1) Keywords: Key words Multiple sclerosis; HLA; Disability; Susceptibility Abstract: The association between susceptibility to multiple sclerosis (MS) and the class II MHC allele HLA-DRB1*15 is well established although a possible relationship between this allele and outcome in MS is less clear. HLA-DRB1 typing was performed on 375 unrelated white patients with clinically definite MS and on 367 healthy controls. Putative associations of the gene with outcome were examined by dividing patients into two groups: those with an EDSS of 0--5.5 (mild/moderate disease) and those with an EDSS of 6--10 (severe disease). In order to minimise the effects of disease variability patients with a disease duration of at least 10 years or 15 years were examined. As subsidiary HLA-DRB1*03 and HLA-DRB1*04 associations have been previously reported, the effect of these alleles was also examined. As expected, HLA-DRB1*15 was found more frequently in patients than in controls (P &lt 0.000001). HLA-DRB1*15 positive patients had a significantly earlier age at onset than HLA-DRB1*15 negative patients. No significant associations were noted between HLA-DRB1*15 and outcome in the total patient group or in patients with a disease duration of 10 years or longer. In patients with a disease duration of at least 15 years HLA-DRB1*15 negative status was associated with a worse prognosis, although this did not remain significant after correction for multiple testing. It is thus likely that the contribution of HLA in MS is primarily towards onset and initial triggering mechanisms rather than influencing disease progression, chronicity and severity Author Affiliation: (1) Keele Multiple Sclerosis Research Group, Postgraduate Medical School, Royal Infirmary, Stoke-on-Trent, UK, GB (2) ARC Epidemiology Unit, University Medical School, Manchester, UK, GB (3) Walton Centre for Neurology and Neurosurgery, Liverpool, UK, GB (4) Department of Statistics, Keele University, Stoke-on-Trent, UK, GB Article note: Received: 10 March 2000, Received in revised form: 25 October 2000, Accepted: 5 November 2000