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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 [...], * 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)

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 [...], 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 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 [...], 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 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 [...], 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.

Author(s): Michael C O'Donovan (corresponding author) [1]; Michael J Owen [1] Psychiatric disorders represent twenty-first-century medicine's greatest global challenge. They are the major cause worldwide of the nonfatal burden of [...], Recent genomic studies have revealed the highly polygenic nature of psychiatric disorders, including schizophrenia, bipolar disorder and major depressive disorder. Many of the individual genetic associations are shared across multiple disorders in a way that points to extensive biological pleiotropy and further challenges the biological validity of existing diagnostic approaches. Here we argue that the existence of risk alleles specific to a single diagnostic category is unlikely. We also highlight some of the important clinical repercussions of pleiotropy.

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 [...], 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.

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 [...], 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): 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] , [...], 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.

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 evidenced [...]