MSH6-proficient crypt foci in MSH6 constitutional mismatch repair deficiency: reversion of a frameshifted coding microsatellite to its wild-type sequence.

The discovery of "mismatch repair deficient (MMRd)-crypt foci" in non-neoplastic intestinal mucosa in Lynch syndrome (LS) has significantly enhanced our understanding of how tumors and tumor immunity form and evolve in LS. In this study, we report the frequent presence of "mismatch repair proficient (MMRp)-crypt foci" in both non-neoplastic and neoplastic intestinal mucosa in a patient with constitutional MMR deficiency (CMMRD), who carried a germline MSH6 pathogenic variant (c.3261dupC) in trans with an MSH6 likely pathogenic variant (c.3724_3726del) and whose tissues were otherwise deficient in MMR globally. The MMRp-crypts occurred at a rate of 1.1/100 crypts in non-neoplastic intestinal mucosa and were readily discernible in adenomas > 1 cm. Sequencing analysis revealed normalization of the MSH6c.3261dupC variant in MMRp-adenoma crypts, indicating reverse frameshifting of the exon 5 C8 microsatellite. Interestingly but not surprisingly, the MMRp-adenoma crypts remained microsatellite-instability-high (MSI-H), and shared oncogenic APC mutations with the background MMRd-adenoma. Contrasting with MSH6-CMMRD, no PMS2-CMMRD individuals (0/5) harbored MMRp-crypts. In conclusion, our study documents distinct MMRp-crypts in MSH6-CMMRD, a phenomenon in keeping with MSH6 being a frequent target of MSI-H due to its coding microsatellite and suggesting that MSH6-CMMRD can potentially serve as a unique model system to further our understanding of MSH6's role in MSI-H tumor formation and evolution. Our findings also bear diagnostic implications; when using MMR immunohistochemistry as an ancillary tool in detecting CMMRD, awareness of these MMRp crypts can help avoid diagnostic pitfalls.

Characterisation of potential anti-inflammatory next-generation probiotics resistant to bisphenol A.

The world is witnessing an increasing incidence of chronic non-communicable diseases (NCDs), such as inflammatory bowel disease (IBD), a group of complex gastrointestinal disorders characterised by inflammation. It is believed that environmental factors, such as exposure to pollutants and endocrine-disrupting chemicals (i.e. bisphenol A [BPA]), are playing a role in IBD pathophysiology. New research suggests a potential treatment solution: next-generation probiotic (NGP) strains isolated from human gut microbiota that can biodegrade xenobiotics and thus possibly modulate IBD triggered by these xenobiotics. In this study, we hypothesised that specific BPA-tolerant bacteria would exhibit beneficial, anti-inflammatory properties that could counter the effects of BPA exposure and concomitantly reduce colitis severity. We observed that two such strains, Bacillus sp. AM1 and Paeniclostridium sp., exhibited potential anti-inflammatory properties in vitro and in vivo. First, these bacteria were able to decrease the secretion of interleukin (IL)-8 cytokines by HT-29 cells that had been exposed to the proinflammatory cytokine tumour necrosis factor (TNF)-α. Second, when treated with Bacillus sp. AM1 and Paeniclostridium sp. (this latter had a stronger reducing effect on inflammatory markers), mice with chemically induced colitis displayed lower levels of colon damage, monocyte chemotactic protein 1 (MCP-1), lipocalin-2 (LCN-2), and proinflammatory cytokines (IL-1ß and IL-6). Future research should clarify the underlying mechanisms at play and identify potential strategies for counteracting the systemic effects of IBD, including those exacerbated by BPA exposure. Our results suggest that one such strategy could be treatment with BPA-tolerant bacteria that possess anti-inflammatory properties.

Lung Structure and Longitudinal Change in Cardiac Structure and Function: The MESA COPD Study.

BACKGROUND: Lung structure and cardiac structure and function are associated cross-sectionally. The classic literature suggests relationships of airways disease to cor pulmonale and emphysema to reduced cardiac output (CO) but longitudinal data are lacking. METHODS: The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease (COPD) Study was a multi-center longitudinal COPD case-control study of participants 50-79 years with ≥10 pack-years smoking without clinical cardiovascular disease. Segmental airway wall area (WA) and percent emphysema were measured on computed tomography. Right and left ventricle (RV, LV) parameters were assessed on magnetic resonance imaging (MRI) in exams six years apart. Longitudinal and period cross-sectional associations were evaluated with mixed models adjusted for demographics, body size, and smoking. RESULTS: The 187 participants with repeated MRI were 67±7 years old; 42% had COPD; 22% currently smoked; and the race/ethnicity distribution was 54% white, 30% Black, 14% Hispanic, and 3% Asian. Greater WA at enrollment was associated with longitudinal increase in RV mass (3.5 g per 10mm2 WA, 95% CI: 1.1, 5.9). Greater percent emphysema was associated with stably lower LV end diastolic volume (-7.8 mL per 5% emphysema, 95% CI: -10.3, -3.0) and CO (-0.2 L·min-1 per 5% emphysema, 95% CI: -0.4, -0.1). CONCLUSION: Cardiac associations varied by lung structure over six years in this multi-ethnic study. Greater WA at enrollment was associated with longitudinal increases in RV mass; whereas greater percent emphysema was associated with stable decrements in LV filling and CO.

Sex-specific Genetic Determinants of Right Ventricular Structure and Function.

RATIONALE: While sex differences in right heart phenotypes have been observed, the molecular drivers remain unknown. OBJECTIVES: To provide biological insights into sex differences in the structure and function of the right ventricle (RV) using common genetic variation. METHODS: RV phenotypes were obtained from cardiac magnetic resonance imaging in 18,156 women and 16,171 men from the UK Biobank. Observational analyses and sex-stratified genome-wide association studies were performed. Candidate female-specific loci were evaluated against invasively measured cardiac performance in 479 female patients with idiopathic or heritable pulmonary arterial hypertension (PAH), recruited to the UK NIHR BioResource Rare Diseases study. MEASUREMENTS AND MAIN RESULTS: Sex was associated with differences in RV volumes and ejection fraction in models adjusting for left heart counterparts, blood pressure, lung function and sex hormone levels. Six genome-wide significant loci (13%) revealed heterogeneity of allelic effects between women and men, and significant sex-by-genotype interaction. These included two sex-specific candidate loci present in women only: a locus for RV ejection fraction in BMPR1A and a locus for RV end-systolic volume near DMRT2. Epigenetic data in RV tissue indicate that variation at the BMPR1A locus likely alters transcriptional regulation. In female patients with PAH, a variant located in the promoter of BMPR1A was significantly associated with cardiac index (effect size 0.16 l/min/m2), despite similar RV afterload. CONCLUSIONS: BMPR1A has emerged as a biologically plausible candidate gene for female-specific genetic determination of RV function, showing associations with cardiac performance under chronically increased afterload in female patients with PAH.

Outcomes of Distal Rectal Cancer Patients Who Did Not Qualify for Watch-and-Wait: Comparison of Intersphincteric Resection Versus Abdominoperineal Resection.

INTRODUCTION: Total mesorectal excision (TME) with intersphincteric resection and handsewn coloanal anastomosis (ISR-CAA) has been shown to be oncologically safe in patients with distal rectal cancer treated with preoperative chemoradiation. The introduction of the watch-and-wait (WW) strategy for rectal cancer patients with a clinical complete response to neoadjuvant therapy is changing the profile of patients undergoing TME surgery immediately following neoadjuvant treatment. The outcomes of ISR-CAA for patients with locally advanced rectal cancers not qualifying for WW have not been investigated. METHODS: We conducted a retrospective analysis comparing the outcomes of ISR-CAA and abdominoperineal resection (APR) in patients with distal rectal cancer treated with neoadjuvant therapy and not qualifying for WW, at a comprehensive cancer center with an established WW program. The primary outcome was local recurrence-free survival. RESULTS: Sixty-seven patients had ISR-CAA and 79 had APR. Median follow-up was 61.1 months. The two groups were similar in sex, tumor stage, grade, and distance from the anal verge, but patients in the APR group were older on average. An R0 resection was achieved in 94% of ISR-CAA patients and 91% of APR patients. Patients in the ISR-CAA group had a lower 5-year rate of local recurrence-free survival (79% vs. 93%; p = 0.038) compared with the APR group; however, 5-year disease-free survival did not differ significantly between groups (67% for ISR-CAA and 64% for APR; p = 0.19). CONCLUSIONS: The local recurrence rate after ISR-CAA may be higher than after APR for patients without a clinical complete response to neoadjuvant therapy requiring TME surgery.

Natural History and Clinicopathological Associations of TRPC6-Associated Podocytopathy.

BACKGROUND: Understanding the genetic basis of human diseases has become integral to drug development and precision medicine. Recent advancements have enabled the identification of molecular pathways driving diseases, leading to targeted treatment strategies. The increasing investment in rare diseases by the biotech industry underscores the importance of genetic evidence in drug discovery and approval processes. Here we studied a monogenic Mendelian kidney disease, TRPC6-associated podocytopathy (TRPC6-AP), to present its natural history, genetic spectrum, and clinicopathological associations in a large cohort of patients with causal variants in TRPC6, in order to help define the specific features of disease and further facilitate drug development and clinical trials design. METHODS: the study involved 64 individuals from 39 families with TRPC6 causal missense variants. Clinical data, including age of onset, laboratory results, response to treatment, kidney biopsy findings, and genetic information, were collected from multiple centers nationally and internationally. Exome or targeted sequencing was performed and variant classification was based on strict criteria. Structural and functional analyses of TRPC6 variants were conducted to understand their impact on protein function. In depth re-analysis of light and electron microscopy specimens for 9 available kidney biopsies was conducted to identify pathological features and correlates of TRPC6-AP. RESULTS: Large-scale sequencing data did not support causality for TRPC6 protein-truncating variants. We identified 21 unique TRPC6 missense variants, clustering in three distinct regions of the protein, and with different effects on TRPC6 3D protein structure. Kidney biopsy analysis revealed FSGS patterns of injury in most cases, along with distinctive podocyte features including diffuse foot process effacement and swollen cell bodies. The majority of patients presented in adolescence or early adulthood but with ample variation (average 22, SD ± 14 years), with frequent progression to kidney failure but with variability in time between presentation and ESKD. CONCLUSIONS: This study provides insights into the genetic spectrum, clinicopathological associations, and natural history of TRPC6-AP.

Phenotypic traits related to methane emissions from Holstein dairy cows challenged by low or high forage proportion.

Limited literature is available identifying phenotypical traits related to enteric methane (CH4) production from dairy cows, despite its relevance in relation to breeding for animals with a low CH4 yield (g/kg DMI), and the derived consequences hereof. This study aimed to investigate the relationships between CH4 yield and different animal phenotypes when 16 2nd parity dairy cows, fitted with a ruminal cannula, were fed 2 diets differing in forage:concentrate ratio in a crossover design. The diets had either a low forage proportion (35% on DM basis, F35) or a high forage proportion (63% on DM basis, F63). Gas exchange was measured by means of indirect calorimetry. Spot samples of feces were collected, and indigestible NDF (INDF) was used as an internal marker to determine total-tract digestibility. In addition, ruminal evacuations, monitoring of chewing activity, determination of ruminal VFA concentration, analysis of relative abundance of methanogens, and measurement of liquid passage rate were performed. Statistical differences were analyzed by a linear mixed model with diet, days in milk, and period as fixed effects, and cow as random effect. The random cow estimates (RCE) were extracted from the model to get the Pearson correlations (r) between RCE of CH4 yield with RCE of all other variables measured, to identify possible phenotypes related to CH4 yield. Significant correlations were observed between RCE of CH4 yield and RCE of OM digestibility (r = 0.63) and ruminal concentration of valeric acid (r = -0.61), acetic acid (r = 0.54), ammonium (r = 0.55), and lactic acid (r = ‒0.53). Additionally, tendencies were observed for correlations between RCE of CH4 yield and RCE of H2 yield in g/kg DM (r = 0.47, P = 0.07), and ruminal isobutyric acid concentration (r = 0.43, P = 0.09). No correlations were observed between RCE of CH4 yield and RCE of ruminal pool sizes, milk data, urinary measurements, or chewing activity. Cows had a lower DMI and ECM, when they were fed F63 compared with F35. Cows fed F63 had higher NDF digestibility, CH4 emissions (g/d, g/kg of DMI, and g/kg of ECM), ruminal concentration of acetic acid, ruminal pH, degradation rate of digestible NDF (DNDF, %/h), and longer rumen retention time (h). Also, rumination and total chewing time (min/kg DMI) were higher for cows fed F63. The results in the present study emphasize the positive relation between cow's ability to digest OM and their CH4 emissions. The derived consequences of breeding for lower CH4 emission might be cows with lower ability to digest OM, but more studies are warranted for further documentation of this relationship.

Structural Transformations of Metal-Organic Cages through Tetrazine-Alkene Reactivity.

The assembly of metal-organic cages is governed by metal ion coordination preferences and the geometries of the typically rigid and planar precursor ligands. PdnL2n cages are among the most structurally diverse, with subtle differences in the metal-ligand coordination vectors resulting in drastically different assemblies, however almost all rely on rigid aromatic linkers to avoid the formation of intractable mixtures. Here we exploit the inverse electron-demand Diels-Alder (IEDDA) reaction between tetrazine linker groups and alkene reagents to trigger structural changes induced by post-assembly modification. The structure of the 1,4-dihydropyridazine produced by IEDDA (often an afterthought in click chemistry) is crucial; its two sp3 centers increase flexibility and nonplanarity, drastically changing the range of accessible coordination vectors. This triggers an initial Pd4L8 tetrahedral cage to transform into different Pd2L4 lantern cages, with both the transformation extent (thermodynamics) and rate (kinetics) dependent on the alkene dienophile selected. With cyclopentene, the unsymmetrical 1,4-dihydropyridazine ligands undergo integrative sorting in the solid state, with both head-to-tail orientation and enantiomer selection, leading to a single isomer from the 39 possible. This preference is rationalized through entropy, symmetry, and hydrogen bonding. Subsequent oxidation of the 1,4-dihydropyridazine to the aromatic pyridazine rigidifies the ligands, restoring planarity. The oxidized ligands no longer fit in the lantern structure, inducing further structural transformations into Pd4L8 tetrahedra and Pd3L6 double-walled triangles. The concept of controllable addition of limited additional flexibility and then its removal through well-defined reactivity we envisage being of great interest for structural transformations of any class of supramolecular architecture.

Long-read sequencing and de novo genome assembly data of Candida parapsilosis HMC1 and Rhodotorula mucilaginosa LBMH1012, two novel isolates with antifungal resistance signatures.

Candida parapsilosis and Rhodotorula mucilaginosa are opportunistic pathogens affecting mostly immunocompromised hosts. Both species have emerged as causes of invasive candidiasis and sepsis respectively. Here we present high-quality long-read genome assemblies for a strain of C. parapsilosis isolated from human breast milk, with multiple predicted signatures consistent with Candida Drug Resistance CDR1/CDR2 and Multi Drug Resistance MDR1-type genes, also for an environmental strain of R. mucilaginosa with multiresistance to azole antifungals. The genome sequencing was performed using the R9.4.1 flowcell with the MinION Mk1B sequencer (Oxford Nanopore Technologies, Oxford, UK). The draft genome of C. parapsilosis HMC1 was assembled from 85,745 long-reads and has 13,114,208 bp in length and comprises 10 contigs making it a highly contiguous assembly. The R. mucilaginosa LBMH1012 assembly has 23,636,156 bp in length and comprises 54 contigs. The genome completeness was estimated as 94.02 % and 91.40 % respectively using BUSCO. These data may be useful to explore the genetic diversity landscape in both species, infer potential causal genes for antifungal resistance and virulence, and represent an addition to the useful sequence space on emerging fungal pathogens.

Optimising recovery of DNA from minimally invasive sampling methods: Efficacy of buccal swabs, preservation strategy and DNA extraction approaches for amphibian studies.

Studies in evolution, ecology and conservation are increasingly based on genetic and genomic data. With increased focus on molecular approaches, ethical concerns about destructive or more invasive techniques need to be considered, with a push for minimally invasive sampling to be optimised. Buccal swabs have been increasingly used to collect DNA in a number of taxa, including amphibians. However, DNA yield and purity from swabs are often low, limiting its use. In this study, we compare different types of swabs, preservation method and storage, and DNA extraction techniques in three case studies to assess the optimal approach for recovering DNA in anurans. Out of the five different types of swabs that we tested, Isohelix MS-02 and Rapidry swabs generated higher DNA yields than other swabs. When comparing storage buffers, ethanol is a better preservative than a non-alcoholic alternative. Dried samples resulted in similar or better final DNA yields compared to ethanol-fixed samples if kept cool. DNA extraction via a Qiagen™ DNeasy Blood and Tissue Kit and McHale's salting-out extraction method resulted in similar DNA yields but the Qiagen™ kit extracts contained less contamination. We also found that samples have better DNA recovery if they are frozen as soon as possible after collection. We provide recommendations for sample collection and extraction under different conditions, including budgetary considerations, size of individual animal sampled, access to cold storage facilities and DNA extraction methodology. Maximising efficacy of all of these factors for better DNA recovery will allow buccal swabs to be used for genetic and genomic studies in a range of vertebrates.

Association between low total serum testosterone and body mass index in Australian survivors of testicular cancer: a retrospective analysis.

BACKGROUND: Primary hypogonadism is a recognised complication in survivors of testicular cancer. However, secondary hypogonadism can result from other causes that suppress the hypothalamic-pituitary axis, including obesity, high dose glucocorticoids, chronic end organ failure, and diabetes. The aim of this study was to explore low total serum testosterone in Australian survivors of testicular cancer and examine associations with body mass index, age, and prior chemotherapy use. METHODS: Clinical data including height, weight, diagnosis, treatment, and hormonal evaluations during follow-up were extracted from the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group Chemocog study (2007-2012), accompanied by data from two Australian, high-volume testicular cancer centres included in the iTestis testicular cancer registry (2012-2019). Low testosterone was defined by a serum concentration of testosterone (T) < 10 nmol/L, and was classified as primary by a serum concentration of luteinising hormone (LH) > 8 IU/L, otherwise as secondary. RESULTS: Two hundred eighty-five individuals with either stage 1 or advanced testicular cancer were included. Of these, 105 (37%) were treated with orchidectomy and chemotherapy. Forty-nine (17%) met criteria for low testosterone during follow-up: 21 (43%) had primary and 27 (55%) had secondary low testosterone. Survivors of testicular cancer with higher body mass index were more likely to display low testosterone, both primary (p = 0.032) and secondary (p = 0.028). Our data did not show evidence of an association between older age or chemotherapy use and low testosterone in our cohort. CONCLUSIONS: Low total serum testosterone was common in survivors of testicular cancer, and associated with a higher body mass index prior to orchidectomy, suggesting that elevated body mass index may contribute to low testosterone in this population, and that body weight, diet, and exercise should be addressed in testicular cancer follow-up.

RéSUMé: CONTEXTE: L'hypogonadisme primaire est une complication reconnue chez les survivants d'un cancer du testicule. Cependant, l'hypogonadisme secondaire peut résulter d'autres causes qui suppriment l'axe hypothalamo-hypophysaire, notamment l'obésité, les glucocorticoïdes à forte dose, la défaillance chronique des organes cibles et le diabète. Le but de cette étude était d'explorer un faible taux de testostérone totale sérique chez les survivants australiens d'un cancer du testicule, et d'examiner les associations avec l'indice de masse corporelle, l'âge et l'utilisation antérieure d'une chimiothérapie. Les données cliniques, y compris la taille, le poids, le diagnostic, le traitement et les évaluations hormonales au cours du suivi, ont été extraites de l'étude Chemocog de l'Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group (2007­2012), accompagnées de données, provenant de deux centres australiens à fort volume de prise en charge de cancers du testicule, incluses dans le registre du cancer du testicule iTestis (2012­2019). Un taux faible de testostérone a été défini par une concentration sérique de testostérone (T) < 10 nmol/L, et a été classé comme primaire pour une concentration sérique d'hormone lutéinisante (LH) > 8 UI/L, sinon comme secondaire. RéSULTATS: Deux cent quatre-vingt-cinq personnes atteintes d'un cancer des testicules de stade 1 ou avancé ont été incluses. Parmi ceux-ci, 105 (37%) ont été traités par orchidectomie et chimiothérapie. Quarante-neuf (17%) répondaient aux critères d'un taux faible de testostérone au cours du suivi: 21 (43%) avaient un taux faible de testostérone primaire et 27 (55%) un faible taux secondaire. Les survivants d'un cancer du testicule avec un indice de masse corporelle plus élevé étaient plus susceptibles de présenter un taux faible de testostérone, à la fois primaire (p = 0,032) et secondaire (p = 0,028). Nos données n'ont pas montré de preuve d'une association entre un âge avancé ou l'utilisation de la chimiothérapie, et un taux faible de testostérone, dans notre cohorte. CONCLUSIONS: Un faible taux de testostérone sérique totale était fréquent chez les survivants d'un cancer du testicule, et associé à un indice de masse corporelle plus élevé avant l'orchidectomie; ceci suggère qu'un indice de masse corporelle élevé peut contribuer à un faible taux de testostérone dans cette population, et que le poids corporel, l'alimentation et l'exercice devraient être pris en compte dans le suivi du cancer du testicule.

A robust time-delay selection criterion applied to convergent cross mapping.

This work presents a heuristic for the selection of a time delay based on optimizing the global maximum of mutual information in orthonormal coordinates for embedding a dynamical system. This criterion is demonstrated to be more robust compared to methods that utilize a local minimum, as the global maximum is guaranteed to exist in the proposed coordinate system for any dynamical system. By contrast, methods using local minima can be ill-posed as a local minimum can be difficult to identify in the presence of noise or may simply not exist. The performance of the global maximum and local minimum methods are compared in the context of causality detection using convergent cross mapping using both a noisy Lorenz system and experimental data from an oscillating plasma source. The proposed heuristic for time lag selection is shown to be more consistent in the presence of noise and closer to an optimal uniform time lag selection.

Nonconjugated Polyurethane Derivatives with Aggregation-Induced Luminochromism for Multicolor and White Photoluminescent Films.

A simple and effective strategy to obtain solid-state multicolor emitting materials is a particularly attractive topic. Nonconventional/nonconjugated polymers are receiving widespread attention because of their advantages of rich structural diversity, low cost, and good processability. However, it is difficult to control the molecular conformation or to obtain the crystal structure of amorphous molecules, which means it is a challenge to obtain nontraditional polymeric materials with multicolor emission. In this work, a polyurethane derivative (PUH) with red-shifted emission was synthesized by a simple one-pot polymerization reaction. By exploiting the aggregation-induced luminochromism of PUH, a series of plastic films with tunable emission from blue to orange, and white-light emission, was obtained by doping different amounts of PUH into poly(methyl methacrylate) (PMMA), thereby changing the aggregation degree of PUH. This work demonstrates the excellent promise of polyurethane derivatives for the simple fabrication of large-scale flexible luminescent films.

Modelling the continuum of macrophage phenotypes and their role in inflammation.

Macrophages are a type of white blood cell that play a significant role in determining the inflammatory response associated with a wide range of medical conditions. They are highly plastic, having the capacity to adopt numerous polarisation states or 'phenotypes' with disparate pro- or anti-inflammatory roles. Many previous studies divide macrophages into two categorisations: M1 macrophages are largely pro-inflammatory in nature, while M2 macrophages are largely restorative. However, there is a growing body of evidence that the M1 and M2 classifications represent the extremes of a much broader spectrum of phenotypes, and that intermediate phenotypes can play important roles in the progression or treatment of many medical conditions. In this article, we present a model of macrophage dynamics that includes a continuous description of phenotype, and hence incorporates intermediate phenotype configurations. We describe macrophage phenotype switching via nonlinear convective flux terms that scale with background levels of generic pro- and anti-inflammatory mediators. Through numerical simulation and bifurcation analysis, we unravel the model's resulting dynamics, paying close attention to the system's multistability and the extent to which key macrophage-mediator interactions provide bifurcations that act as switches between chronic states and restoration of health. We show that interactions that promote M1-like phenotypes generally result in a greater array of stable chronic states, while interactions that promote M2-like phenotypes can promote restoration of health. Additionally, our model admits oscillatory solutions reminiscent of relapsing-remitting conditions, with macrophages being largely polarised toward anti-inflammatory activity during remission, but with intermediate phenotypes playing a role in inflammatory flare-ups. We conclude by reflecting on our observations in the context of the ongoing pursuance of novel therapeutic interventions.

CYP1B1-RMDN2 Alzheimer's disease endophenotype locus identified for cerebral tau PET.

Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.

Apolipoproteins, lipids, lipid-lowering drugs and risk of amyotrophic lateral sclerosis and frontotemporal dementia: a meta-analysis and Mendelian randomisation study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have clinical, pathological and genetic overlapping. Lipid pathways are implicated in ALS. This study examined the effect of blood lipid levels on ALS, FTD risk, and survival in ALS. METHODS: A systematic review and meta-analysis of high and low-density lipoprotein cholesterol (HDL-c and LDL-c), total cholesterol, triglycerides, apolipoproteins B and A1 levels with ALS was performed. Two-sample Mendelian randomisation (MR) analysis sought the causal effects of these exposures on ALS, FTD, and survival in ALS. The effect of lipid-lowering drugs was also examined using genetic proxies for targets of lipid-lowering medications. RESULTS: Three cohort studies met the inclusion criteria for meta-analysis. Meta-analysis indicated an association between higher LDL-c (HRper mmol/L = 1.07, 95%CI:1.02-1.12; I 2 =18%) and lower HDL-c (HRper mmol/L = 0.83, 95%CI:0.74-0.94; I 2 =0%) with an increased risk of ALS. MR suggested causal effects of higher LDL-c (ORIVW = 1.085, 95%:CI 1.008-1.168, pFDR = 0.0406), total cholesterol (ORIVW = 1.081, 95%:CI 1.013-1.154, pFDR = 0.0458) and apolipoprotein B (ORIVW = 1.104, 95%:CI 1.041-1.171, pFDR = 0.0061) increasing ALS risk, and higher apolipoprotein B level increasing FTD risk (ORIVW = 1.424, 95%CI 1.072-1.829, pFDR = 0.0382). Reducing LDL-c through APOB inhibition was associated with lower ALS (ORIVW = 0.84, 95%CI 0.759-0.929, pFDR = 0.00275) and FTD risk (ORIVW = 0.581, 95%CI 0.387-0.874, pFDR = 0.0362). CONCLUSION: These data support the influence of LDL-c and total cholesterol on ALS risk and apolipoprotein B on the risk of ALS and FTD. Potential APOB inhibition might decrease the risk of sporadic ALS and FTD. Further work in monogenic forms of ALS and FTD is necessary to determine whether blood lipids influence penetrance and phenotype.

Survival of men with metastatic hormone-sensitive prostate cancer and adrenal-permissive HSD3B1 inheritance.

BACKGROUNDMetastatic hormone-sensitive prostate cancer (mHSPC) is androgen dependent, and its treatment includes androgen deprivation therapy (ADT) with gonadal testosterone suppression. Since 2014, overall survival (OS) has been prolonged with addition of other systemic therapies, such as adrenal androgen synthesis blockers, potent androgen receptor blockers, or docetaxel, to ADT. HSD3B1 encodes the rate-limiting enzyme for nongonadal androgen synthesis, 3ß-hydroxysteroid dehydrogenase-1, and has a common adrenal-permissive missense-encoding variant that confers increased synthesis of potent androgens from nongonadal precursor steroids and poorer prostate cancer outcomes.METHODSOur prespecified hypothesis was that poor outcome associated with inheritance of the adrenal-permissive HSD3B1 allele with ADT alone is reversed in patients with low-volume (LV) mHSPC with up-front ADT plus addition of androgen receptor (AR) antagonists to inhibit the effect of adrenal androgens. HSD3B1 genotype was obtained in 287 patients with LV disease treated with ADT + AR antagonist only in the phase III Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) trial and was associated with clinical outcomes.RESULTSPatients who inherited the adrenal-permissive HSD3B1 allele had more favorable 5-year clinical progression-free survival and OS when treated with ADT plus enzalutamide or ADT plus nonsteroidal antiandrogen compared with their counterparts who did not have adrenal-permissive HSD3B1 inheritance. HSD3B1 was also associated with OS after accounting for known clinical variables. Patients with both genotypes benefited from early enzalutamide.CONCLUSIONThese data demonstrated an inherited physiologic driver of prostate cancer mortality is associated with clinical outcomes and is potentially pharmacologically reversible.FUNDINGNational Cancer Institute, NIH; Department of Defense; Prostate Cancer Foundation, Australian National Health and Medical Research Council.

Lu-177 PSMA vs Comparator Treatments and Survival in Metastatic Castration-Resistant Prostate Cancer.

Importance: Observed treatment effects on overall survival (OS) differed substantially in the first 2 randomized clinical trials of lutetium Lu 177 vipivotide tetraxetan (Lu-177) prostate-specific membrane antigen (PSMA) in metastatic castration-resistant prostate cancer. Objective: To investigate factors associated with the observed difference in treatment effects on OS, including differences in the risk of crossover from randomized treatment after disease progression. Design, Setting, and Participants: This comparative effectiveness study used individual participant data from 2 randomized clinical trials, TheraP (A Randomised Phase 2 Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer [ANZUP Protocol 1603]) (n = 200), recruited from February 2018 to September 2019 in Australia, and published data from VISION (An International, Prospective, Open Label, Multicenter, Randomized Phase 3 Study of 177Lu-PSMA-617 in the Treatment of Patients With Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer) (n = 831), recruited from June 2018 to October 2019 in North America and Europe. Individual participant data for OS were reconstructed from VISION using the published survival curves. Data were analyzed February 6, 2018, to December 31, 2021, for TheraP and June 4, 2018, to January 27, 2021, for VISION. Interventions: TheraP randomized participants to receive treatment with Lu-177 PSMA or cabazitaxel. VISION randomized participants to receive treatment with or without Lu-177 PSMA in addition to physicians' choice of protocol-permitted treatments (PPT; approved hormonal treatments [such as abiraterone and enzalutamide], bisphosphonates, radiotherapy, denosumab, or glucocorticoids), excluding cabazitaxel. Main Outcomes and Measures: Patient characteristics, treatment protocols, and OS outcomes of the 2 trials were compared. Estimates of the effect on OS from TheraP were adjusted for crossover from randomly assigned treatment using a rank-preserving structural failure time model (RPSFTM) and inverse probability of censoring weights (IPCW) methods. Results: The 200 participants in TheraP and 831 participants in VISION were similar in age (median [range], 72 [49-86] vs 71 [40-94] years). Improved OS was observed in the comparator treatment group (cabazitaxel) in TheraP compared with VISION (PPT) (hazard ratio [HR], 0.53 [95% CI, 0.39-0.71]). The Lu-177 PSMA treatment groups in TheraP and VISION had similar OS (HR, 0.92 [95% CI, 0.70-1.19]). In TheraP, 20 of 101 participants in the cabazitaxel group crossed over to Lu-177 PSMA, while 32 of 99 participants in the Lu-177 PSMA arm crossed over to cabazitaxel. No statistically significant differences in OS between the Lu-177 PSMA and cabazitaxel groups of TheraP were observed after controlling for crossover to cabazitaxel: RPSFTM HR, 0.97 (95% CI, 0.60-1.58); IPCW HR, 0.92 (95% CI, 0.65-1.32); RPSFTM HR, 0.97 (95% CI, 0.60-1.58) and IPCW HR, 0.82 (95% CI, 0.54-1.24) for crossover to Lu-177 PSMA; RPSFTM HR, 0.96 (95% CI, 0.53-1.74) and IPCW HR, 0.82 (95% CI, 0.53-1.27) for crossover to either Lu-177 PSMA or cabazitaxel. Conclusions and Relevance: Findings of this secondary analysis of the TheraP and VISION randomized clinical trials suggest that the choice of comparator treatments (ie, cabazitaxel vs PPT) may explain the difference in the observed effect of Lu-177 PSMA on OS between the 2 trials. Causal inference methods such as RPSFTM and IPCW may help rule out crossover as a plausible explanation.