Assessment of TROP2, CEACAM5 and DLL3 in metastatic prostate cancer: Expression landscape and molecular correlates.

Therapeutic approaches targeting proteins on the surface of cancer cells have emerged as an important strategy for precision oncology. To capitalize on the potential impact of drugs targeting surface proteins, detailed knowledge about the expression patterns of the target proteins in tumor tissues is required. In castration-resistant prostate cancer (CRPC), agents targeting prostate-specific membrane antigen (PSMA) have demonstrated clinical activity. However, PSMA expression is lost in a significant number of CRPC tumors. The identification of additional cell surface targets is necessary to develop new therapeutic approaches. Here, we performed a comprehensive analysis of the expression heterogeneity and co-expression patterns of trophoblast cell-surface antigen 2 (TROP2), delta-like ligand 3 (DLL3), and carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) in CRPC samples from a rapid autopsy cohort. We show that DLL3 and CEACAM5 exhibit the highest expression in neuroendocrine prostate cancer (NEPC), while TROP2 is expressed across different CRPC molecular subtypes, except for NEPC. We further demonstrated that AR alterations were associated with higher expression of PSMA and TROP2. Conversely, PSMA and TROP2 expression was lower in RB1-altered tumors. In addition to genomic alterations, we show a tight correlation between epigenetic states, particularly histone H3 lysine 27 methylation (H3K27me3) at the transcriptional start site and gene body of TACSTD2 (encoding TROP2), DLL3, and CEACAM5, and their respective protein expression in CRPC patient-derived xenografts. Collectively, these findings provide insights into patterns and determinants of expression of TROP2, DLL3, and CEACAM5 with implications for the clinical development of cell surface targeting agents in CRPC.

Learning Curve of Robotic End-to-Side Microanastomoses.

BACKGROUND AND OBJECTIVES: Robotics are becoming increasingly widespread within various neurosurgical subspecialties, but data pertaining to their feasibility in vascular neurosurgery are limited. We present our novel attempt to evaluate the learning curve of a robotic platform for microvascular anastomoses. METHODS: One hundred and sixty one sutures were performed and assessed. Fourteen anastomoses (10 robotic [MUSA-2 Microsurgical system; Microsure] and 4 hand-sewn) were performed by the senior author on 1.5-mm caliber tubes and recorded with the Kinevo 900 (Zeiss) operative microscope. We separately compared interrupted sutures (from needle insertion until third knot) and running sutures (from needle insertion until loop pull-down). Average suture timing across all groups was compared using an unpaired Student's t test. Exponential smoothing (α = 0.2) was then applied to the robotic data sets for validation and a second set of t tests were performed. RESULTS: We compared 107 robotic sutures with 54 hand-sewn sutures. There was a significant difference between the average time/stitch for the robotic running sutures (n = 55) and the hand-sewn running sutures (n = 31) (31.2 seconds vs 48.3 seconds, respectively; P-value = .00052). Exponential smoothing (α = 0.2) reinforced these results (37.6 seconds vs 48.3 seconds; P-value = .014625). Average robotic running times surpassed hand-sewn by the second anastomosis (38.8 seconds vs 48.3 seconds) and continued to steadily decrease with subsequent stitches. The average of the robotic interrupted sutures (n = 52) was significantly longer than the hand-sewn (n = 23) (171.3 seconds vs 70 seconds; P = .000024). Exponential smoothing (α = 0.2) yielded similar results (196.7 seconds vs 70 seconds; P = .00001). However, average robotic interrupted times significantly decreased from the first to the final anastomosis (286 seconds vs 105.2 seconds; P = .003674). CONCLUSION: Our results indicate the learning curve for robotic microanastomoses is short and encouraging. The use of robotics warrants further study for potential use in cerebrovascular bypass procedures.

Venous Anatomy of the Central Nervous System.

Comprehensive understanding of venous anatomy is a key factor in the approach to a multitude of conditions. Moreover, the venous system has become the center of attention as a new frontier for treatment of diseases such as idiopathic intracranial hypertension (IIH), arteriovenous malformation (AVM), pulsatile tinnitus, hydrocephalus, and cerebrospinal fluid (CSF) venous fistulas. Its knowledge is ever more an essential requirement of the modern brain physician. In this article, the authors explore the descriptive and functional anatomy of the venous system of the CNS in 5 subsections: embryology, dural sinuses, cortical veins, deep veins, and spinal veins.

Mapping medically relevant RNA isoform diversity in the aged human frontal cortex with deep long-read RNA-seq.

Determining whether the RNA isoforms from medically relevant genes have distinct functions could facilitate direct targeting of RNA isoforms for disease treatment. Here, as a step toward this goal for neurological diseases, we sequenced 12 postmortem, aged human frontal cortices (6 Alzheimer disease cases and 6 controls; 50% female) using one Oxford Nanopore PromethION flow cell per sample. We identified 1,917 medically relevant genes expressing multiple isoforms in the frontal cortex where 1,018 had multiple isoforms with different protein-coding sequences. Of these 1,018 genes, 57 are implicated in brain-related diseases including major depression, schizophrenia, Parkinson's disease and Alzheimer disease. Our study also uncovered 53 new RNA isoforms in medically relevant genes, including several where the new isoform was one of the most highly expressed for that gene. We also reported on five mitochondrially encoded, spliced RNA isoforms. We found 99 differentially expressed RNA isoforms between cases with Alzheimer disease and controls.

What Environments Support Reading Growth Among Current Compared With Former Reading Intervention Recipients? A Multilevel Analysis of Students and Their Schools.

School context can shape relative intervention response in myriad ways due to factors, such as instructional quality, resource allocation, peer effects, and correlations between the school context and characteristics of enrolled students (e.g., higher-poverty students attending higher-poverty schools). In the current study, we used data from 16,000 Grade 3 students in a community-based supplemental reading intervention program to investigate the degree to which school context factors (percentage eligible for free/reduced-price lunch [FRPL], school-level achievement) relate to the differences in triannual reading fluency growth rates between students actively receiving supplemental intervention (active recipients) and those that formerly received intervention (and therefore only received general class instruction at this time; former recipients). Using Bayesian multilevel modeling, our findings indicate that school-level FRPL eligibility played a more prominent factor in growth rate differences between these two groups than school-level reading achievement. However, school-level reading achievement was much more strongly related to reading fluency differences between active and former intervention recipients at the beginning of the school year (when controlling for FRPL). Implications for investigating school-level heterogeneity in intervention response and sustainability are discussed.

Analysis Of Oklahoma Amputation Trends and Identification of Risk Factors to Target Areas For Limb Preservation Interventions.

BACKGROUND: Annual trends of lower extremity amputation due to end-stage chronic disease are on the rise in the United States. These amputations are leading to massive expenses for patients and the medical system. In Oklahoma, we have a high-risk population because access to care is low, the number of uninsured is high, cardiovascular health is poor, and our overall healthcare performance is ranked 50th in the country. But we know little about Oklahomans and their risk of limb loss. It is, therefore, imperative to look closely at this population to discover contemporary rates, trends, and state-specific risk factors for amputation due to diabetes and/or peripheral arterial disease (PAD). We hypothesize that state-specific groups will be identified as having the highest risk for limb loss and that contemporary trends in amputations are rising. To create implementable solutions to limb preservation, a baseline must be set. STUDY DESIGN: We conducted a 12-consecutive-year observational study using Oklahoma's hospital discharge data. Discharges among patients 20 years or older with a primary or secondary diagnosis of diabetes and/or PAD were included. Diagnoses and amputation procedures were identified using ICD-9 and ICD-10 codes. Amputation rates were calculated per 1,000 discharges. Trends in amputation rates were measured by annual percentage changes (APC). Prevalence ratios evaluated the differences in amputation rates across demographic groups. RESULTS: Over 5,000,000 discharges were identified from 2008-2019. Twenty-four percent had a diagnosis of diabetes and/or PAD. The overall amputation rate was 12 per thousand discharges for those with diabetes and/or PAD. Diabetes and/or PAD-related amputation rates increased from 8.1 to 16.2 (APC: 6.0, 95% CI:4.7-7.3). Most amputations were minor (59.5%), and though minor increased at a faster rate compared to major (minor amputation APC: 8.1, 95% CI: 6.7-9.6 vs. major amputation APC: 3.1, 95% CI:1.5-4.7), major amputations were notable in that they were significantly increasing. Amputation rates were the highest among males (16.7), American Indians (19.2), uninsured (21.2), non-married patients (12.7), and patients between 45 and 49 years of age (18.8), and calculated prevalence ratios for each were significant (p=0.001) when compared within their respective category. CONCLUSION: Amputation rates in Oklahoma have nearly doubled in 12 years, with both major and minor amputations significantly increasing. This study describes a worsening trend, underscoring that amputations due to chronic disease is an urgent statewide healthcare problem. We also present imperative examples of amputation healthcare disparities. By defining these state-specific areas and populations at risk, we have identified areas to pursue and improve care. These distinctive risk factors will help to frame a statewide limb preservation intervention.

New type of tin(IV) complex based turn-on fluorescent chemosensor for fluoride ion recognition: elucidating the effect of molecular structure on sensing property.

A novel type of chemosensor based on tin(IV) complexes incorporating hydroxyquinoline derivatives has been designed and investigated for selectively detecting fluoride ions. Sn(meq)2Cl2 (meq = 2-methyl-8-quinolinol) (complex 1) exhibits a significant enhancement in luminescence upon the introduction of fluoride ions. This enhancement greatly surpasses that observed with Snq2Cl2 and Sn(dmqo)2Cl2 (q = 8-hydroxyquinnoline; dmqo = 5,7-dimethyl-8-quinolinol). Furthermore, complex 1 displays excellent sensitivity and selectivity for fluoride detection in comparison to halides and other anions. As a result, complex 1 serves as an outstanding turn-on fluorescent chemosensor, effectively sensing fluoride ions. The Benesi-Hilderbrand method and Job's plot confirmed that complex 1 associates with F- in a 1 : 2 binding stoichiometry. Also, complex 1 exhibited a large binding constant (pKb = 10.4 M-2) and a low detection limit (100 nM). To gain a deeper insight into the photophysical properties and the underlying mechanism governing the formation of the tin(IV) fluoride complex via halide exchange, we successfully synthesized partially fluorinated Sn(meq)2F0.67Cl1.33 (2) and fully fluorinated Sn(meq)2F2 (3), all of which were characterized through computational studies, thereby elucidating their photophysical properties. DFT studies reveal that converting Sn(meq)2Cl2 to Sn(meq)2F2, an endergonic process, leads to greater stability due to reducing steric hindrance about the metal center. Furthermore, the fluorinated complex significantly increases dipole moment, resulting in high affinity toward the F- ion.

Y Chromosome Loss and Implications for Oncology.

The Y chromosome has recognized functions in promoting male sex determination and regulating aspects of fertility. However, recent work has demonstrated important roles for the Y chromosome and Y-encoded genes in multiple domains of male health, including cancer. It is well-established that males experience shorter life spans than females, and this sex bias on overall mortality is ac-centuated in populations with longer life expectancy, in part related to elevated rates of cancer. The majority of human malignancies exhibit a sex bias with elevated frequencies in males. For many of these cancer types, the disparity has not been explained by environmental risk factors such as tobacco use. Notably, loss of the Y chromosome (LOY) detected in blood cells, termed mosaic LOY (mLOY) is a common event that is related to advancing age and is associated with a shortened lifespan. mLOY is linked to increased incidence and mortality across a range of malignancies. Further, tumors arising in different anatomic sites exhibit different frequencies of partial or complete Y chromosome loss. Causal oncogenic or tumor suppressive roles have been documented for several Y-encoded genes, such as KDM5D, that exert pleiotropic effects on cellular functions by virtue of genome-wide regulation of gene activity. In this review, we discuss aspects of the Y chromosome relevant to oncology. The recent completion of the entire human Y-chromosome sequence provides a reference map of Y-encoded genes and regulatory elements to enable causal molecular studies that may explain and exploit the marked disparity in male cancer risk and mortality.

Comprehensive Analysis of Post-Pipeline Endothelialization and Remodeling.

BACKGROUND AND PURPOSE: Successful post-flow-diverter endoluminal reconstruction is widely believed to require endothelial overgrowth of the aneurysmal inflow zone. However, endothelialization/neointimal overgrowth is a complex process, over which we currently have very limited influence. Less emphasized is vascular remodeling of the target arterial segment, the dynamic response of the vessel to flow-diverter implantation. This process is distinct from flow modifications in covered branches. It appears that basic angiographic methods allow simple and useful observations. The purpose of this article was to quantitatively evaluate observable postimplantation changes in target vessels following deployment of Pipeline endoluminal constructs. MATERIALS AND METHODS: One hundred consecutive adults with unruptured, previously untreated, nondissecting aneurysms treated with the Pipeline Embolization Device with Shield Technology and the availability of follow-up conventional angiography were studied with 2D DSA imaging. Target vessel size; Pipeline Embolization Device diameter; endothelial thickness; and various demographic, antiplatelet, and device-related parameters were recorded and analyzed. RESULTS: The thickness of neointimal overgrowth (mean, 0.3 [SD, 0.1] mm; range, 0.1-0.7 mm) is inversely correlated with age and is independent of vessel size, smoking status, sex, and degree of platelet inhibition. The decrease in lumen diameter caused by neointimal overgrowth, however, appears counteracted by outward remodeling (dilation) of the target arterial segment. This leads to an increase in the diameter with a corresponding decrease in length (foreshortening) of the implanted Pipeline Embolization Device. This physiologic remodeling process affects optimally implanted devices and is not a consequence of stretching, device migration, vasospasm, and so forth. A direct, linear, statistically significant relationship exists between the degree of observed outward remodeling and the diameter of the implanted Pipeline Embolization Device relative to the target vessel. Overall, remodeled arterial diameters were reduced by 15% (SD, 10%) relative to baseline and followed a normal distribution. Clinically relevant stenosis was not observed. CONCLUSIONS: Vessel healing involves both outward remodeling and neointimal overgrowth. Judicial oversizing could be useful in specific settings to counter the reduction in lumen diameter due to postimplant neointimal overgrowth; however, this overszing needs to be balanced against the decrease in metal coverage accompanying the use of oversized devices. Similar analysis for other devices is essential.

Single Cell Analysis of Treatment-Resistant Prostate Cancer: Implications of Cell State Changes for Cell Surface Antigen Targeted Therapies.

Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)--a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis (TMA) on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated, but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer (SCLC) subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to novel antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types.

Androgen receptor splice variants drive castration-resistant prostate cancer metastasis by activating distinct transcriptional programs.

One critical mechanism through which prostate cancer (PCa) adapts to treatments targeting androgen receptor (AR) signaling is the emergence of ligand-binding domain-truncated and constitutively active AR splice variants, particularly AR-V7. While AR-V7 has been intensively studied, its ability to activate distinct biological functions compared to the full-length AR (AR-FL), and its role in regulating the metastatic progression of castration-resistant PCa (CRPC), remains unclear. Our study found that, under castrated conditions, AR-V7 strongly induced osteoblastic bone lesions, a response not observed with AR-FL overexpression. Through combined ChIP-seq, ATAC-seq, and RNA-seq analyses, we demonstrated that AR-V7 uniquely accesses the androgen-responsive elements in compact chromatin regions, activating a distinct transcription program. This program was highly enriched for genes involved in epithelial-mesenchymal transition and metastasis. Notably, we discovered that SOX9, a critical metastasis driver gene, was a direct target and downstream effector of AR-V7. Its protein expression was dramatically upregulated in AR-V7-induced bone lesions. Moreover, we found that Ser81 phosphorylation enhanced AR-V7's pro-metastasis function by selectively altering its specific transcription program. Blocking this phosphorylation with CDK9 inhibitors impaired the AR-V7-mediated metastasis program. Overall, our study has provided molecular insights into the role of AR splice variants in driving the metastatic progression of CRPC.

Development and Characterisation of a New Patient-Derived Xenograft Model of AR-Negative Metastatic Castration-Resistant Prostate Cancer.

As the treatment landscape for prostate cancer gradually evolves, the frequency of treatment-induced neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC) that is deficient for androgen receptor (AR) and neuroendocrine (NE) markers has increased. These prostate cancer subtypes are typically refractory to AR-directed therapies and exhibit poor clinical outcomes. Only a small range of NEPC/DNPC models exist, limiting our molecular understanding of this disease and hindering our ability to perform preclinical trials exploring novel therapies to treat NEPC/DNPC that are urgently needed in the clinic. Here, we report the development of the CU-PC01 PDX model that represents AR-negative mCRPC with PTEN/RB/PSMA loss and CTNN1B/TP53/BRCA2 genetic variants. The CU-PC01 model lacks classic NE markers, with only focal and/or weak expression of chromogranin A, INSM1 and CD56. Collectively, these findings are most consistent with a DNPC phenotype. Ex vivo and in vivo preclinical studies revealed that CU-PC01 PDX tumours are resistant to mCRPC standard-of-care treatments enzalutamide and docetaxel, mirroring the donor patient's treatment response. Furthermore, short-term CU-PC01 tumour explant cultures indicate this model is initially sensitive to PARP inhibition with olaparib. Thus, the CU-PC01 PDX model provides a valuable opportunity to study AR-negative mCRPC biology and to discover new treatment avenues for this hard-to-treat disease.

Genomic Correlates of Prostate-Specific Membrane Antigen Expression and Response to 177Lu-PSMA-617: A Retrospective Multicenter Cohort Study.

PURPOSE: While 177Lu-PSMA-617 (LuPSMA) is an effective therapy for many patients with metastatic castration-resistant prostate cancer (mCRPC), biomarkers associated with outcomes are not well defined. We hypothesized that prostate cancer mutational profile may associate with clinical activity of LuPSMA. We devised a study to evaluate associations between mCRPC mutational profile with LuPSMA clinical outcomes. METHODS: This was a multicenter retrospective analysis of patients with mCRPC with next-generation sequencing (NGS) who received LuPSMA. PSA50 response (ie, ≥50% decline in prostate-specific antigen [PSA]) rate, PSA progression free survival (PSA PFS), and overall survival (OS) were compared between genetically defined subgroups. RESULTS: One hundred twenty-six patients with NGS results who received at least one cycle of LuPSMA were identified. The median age was 73 (IQR, 68-78) years, 124 (98.4%) received ≥1 prior androgen receptor-signaling inhibitor, and 121 (96%) received ≥1 taxane-based chemotherapy regimen. Fifty-eight (46%) patients with a DNA damage repair gene mutation (DNA damage response group) and 59 (46.8%) with a mutation in TP53, RB1, or PTEN tumor suppressor genes (TSG group) were identified. After adjusting for relevant confounders, the presence of ≥1 TSG mutation was associated with shorter PSA PFS (hazard ratio [HR], 1.93 [95% CI, 1.05 to 3.54]; P = .034) and OS (HR, 2.65 [95% CI, 1.15 to 6.11]; P = .023). There was improved OS favoring the DNA damage response group (HR, 0.37 [95% CI, 0.14 to 0.97]; P = .044) on multivariable analysis. Univariate analysis of patients with ATM mutations had significantly higher rates of PSA50 response, PSA PFS, and OS. CONCLUSION: Outcomes on LuPSMA varied on the basis of mutational profile. Prospective studies to define the clinical activity of LuPSMA in predefined genomic subgroups are justified.

Limbic-predominant age-related TDP-43 encephalopathy (LATE-NC): Co-pathologies and genetic risk factors provide clues about pathogenesis.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is detectable at autopsy in more than one-third of people beyond age 85 years and is robustly associated with dementia independent of other pathologies. Although LATE-NC has a large impact on public health, there remain uncertainties about the underlying biologic mechanisms. Here, we review the literature from human studies that may shed light on pathogenetic mechanisms. It is increasingly clear that certain combinations of pathologic changes tend to coexist in aging brains. Although "pure" LATE-NC is not rare, LATE-NC often coexists in the same brains with Alzheimer disease neuropathologic change, brain arteriolosclerosis, hippocampal sclerosis of aging, and/or age-related tau astrogliopathy (ARTAG). The patterns of pathologic comorbidities provide circumstantial evidence of mechanistic interactions ("synergies") between the pathologies, and also suggest common upstream influences. As to primary mediators of vulnerability to neuropathologic changes, genetics may play key roles. Genes associated with LATE-NC include TMEM106B, GRN, APOE, SORL1, ABCC9, and others. Although the anatomic distribution of TDP-43 pathology defines the condition, important cofactors for LATE-NC may include Tau pathology, endolysosomal pathways, and blood-brain barrier dysfunction. A review of the human phenomenology offers insights into disease-driving mechanisms, and may provide clues for diagnostic and therapeutic targets.

Defining the challenges and opportunities for using patient-derived models in prostate cancer research.

BACKGROUND: There are relatively few widely used models of prostate cancer compared to other common malignancies. This impedes translational prostate cancer research because the range of models does not reflect the diversity of disease seen in clinical practice. In response to this challenge, research laboratories around the world have been developing new patient-derived models of prostate cancer, including xenografts, organoids, and tumor explants. METHODS: In May 2023, we held a workshop at the Monash University Prato Campus for researchers with expertise in establishing and using a variety of patient-derived models of prostate cancer. This review summarizes our collective ideas on how patient-derived models are currently being used, the common challenges, and future opportunities for maximizing their usefulness in prostate cancer research. RESULTS: An increasing number of patient-derived models for prostate cancer are being developed. Despite their individual limitations and varying success rates, these models are valuable resources for exploring new concepts in prostate cancer biology and for preclinical testing of potential treatments. Here we focus on the need for larger collections of models that represent the changing treatment landscape of prostate cancer, robust readouts for preclinical testing, improved in vitro culture conditions, and integration of the tumor microenvironment. Additional priorities include ensuring model reproducibility, standardization, and replication, and streamlining the exchange of models and data sets among research groups. CONCLUSIONS: There are several opportunities to maximize the impact of patient-derived models on prostate cancer research. We must develop large, diverse and accessible cohorts of models and more sophisticated methods for emulating the intricacy of patient tumors. In this way, we can use the samples that are generously donated by patients to advance the outcomes of patients in the future.

Sex-Biased Expression and Response of microRNAs in Neurological Diseases and Neurotrauma.

Neurological diseases and neurotrauma manifest significant sex differences in prevalence, progression, outcome, and therapeutic responses. Genetic predisposition, sex hormones, inflammation, and environmental exposures are among many physiological and pathological factors that impact the sex disparity in neurological diseases. MicroRNAs (miRNAs) are a powerful class of gene expression regulator that are extensively involved in mediating biological pathways. Emerging evidence demonstrates that miRNAs play a crucial role in the sex dimorphism observed in various human diseases, including neurological diseases. Understanding the sex differences in miRNA expression and response is believed to have important implications for assessing the risk of neurological disease, defining therapeutic intervention strategies, and advancing both basic research and clinical investigations. However, there is limited research exploring the extent to which miRNAs contribute to the sex disparities observed in various neurological diseases. Here, we review the current state of knowledge related to the sexual dimorphism in miRNAs in neurological diseases and neurotrauma research. We also discuss how sex chromosomes may contribute to the miRNA sexual dimorphism phenomenon. We attempt to emphasize the significance of sexual dimorphism in miRNA biology in human diseases and to advocate a gender/sex-balanced science.

Genetic associations with dementia-related proteinopathy: Application of item response theory.

INTRODUCTION: Although dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete. METHODS: We applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aß, tau, α-synuclein, and TDP-43. RESULTS: Final included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP-43-, Aß/Tau-, and α-synuclein-related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP-43 pathology; and GBA for α-synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility. DISCUSSION: A novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies. HIGHLIGHTS: Latent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors.

Unraveling the Global Proteome and Phosphoproteome of Prostate Cancer Patient-Derived Xenografts.

Resistance to androgen-deprivation therapies leads to metastatic castration-resistant prostate cancer (mCRPC) of adenocarcinoma (AdCa) origin that can transform into emergent aggressive variant prostate cancer (AVPC), which has neuroendocrine (NE)-like features. In this work, we used LuCaP patient-derived xenograft (PDX) tumors, clinically relevant models that reflect and retain key features of the tumor from advanced prostate cancer patients. Here we performed proteome and phosphoproteome characterization of 48 LuCaP PDX tumors and identified over 94,000 peptides and 9,700 phosphopeptides corresponding to 7,738 proteins. We compared 15 NE versus 33 AdCa samples, which included six different PDX tumors for each group in biological replicates, and identified 309 unique proteins and 476 unique phosphopeptides that were significantly altered and corresponded to proteins that are known to distinguish these two phenotypes. Assessment of concordance from PDX tumor-matched protein and mRNA revealed increased dissonance in transcriptionally regulated proteins in NE and metabolite interconversion enzymes in AdCa. IMPLICATIONS: Overall, our study highlights the importance of protein-based identification when compared with RNA and provides a rich resource of new and feasible targets for clinical assay development and in understanding the underlying biology of these tumors.