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bioRxiv2026

Entorhinal grid coding as a functional link between tau accumulation and episodic memory in human aging

Episodic memory decline is a common feature of cognitively normal aging, but its extent varies markedly across individuals. Although entorhinal tau pathology is thought to be a key contributor to episodic memory impairment, the neural mechanisms linking early tau accumulation to memory differences remain unclear. Grid-cell computations in the entorhinal cortex, which provide scaffolds for organizing experiences into episodic memories, offer one candidate mechanism. Here, we combined virtual-reality functional MRI, multivariate analysis, tau PET, and delayed word-list recall in cognitively normal older adults to test whether tau-related alterations in entorhinal coding are associated with worse episodic memory. Weaker left entorhinal grid-cell-like signal was associated with poorer memory performance, and individuals with higher left entorhinal tau burden showed weaker grid-cell-like signal. This association was specific to the canonical six-fold signal and was not explained by entorhinal volume, mean diffusivity, or intracortical myelination. A cross-sectional Bayesian mediation analysis further demonstrated that bilateral medial temporal tau burden is related to memory indirectly through left entorhinal grid-cell-like signal. Together, these findings provide evidence that entorhinal grid codes may constitute a functional pathway linking tau accumulation to memory variability in normal aging.

neuroscience↗

bioRxiv2026

MAPT regulates autophagic-lysosomal function and phagocytosis in human microglia

Tauopathies are characterized by the accumulation and spread of pathogenic tau aggregates throughout the brain, a process that is increasingly recognized to involve not only neurons but also microglia. However, whether pathogenic MAPT directly alters microglial degradative capacity remains poorly understood. Here, using isogenic human induced pluripotent stem cell-derived microglia carrying the pathogenic MAPT IVS10+16 mutation, we identify tau as a regulator of microglial lysosomal function. MAPT IVS10+16 microglia exhibited coordinated suppression of lysosomal and autophagic pathways, reduced lysosomal protease abundance and activity, and impaired autophagosome-lysosome fusion. Mutant microglia also showed reduced uptake of extracellular tau aggregates, reduced tau accumulation in acidic compartments, and a blunted lysosomal response to proteopathic stress. Conversely, genetic loss of MAPT increased lysosomal degradative capacity and accumulation of extracellular tau aggregates within acidic compartments, supporting a cell-intrinsic role for endogenous tau in regulating microglial degradative function. Pharmacologic enhancement of the autophagy lysosome pathway in MAPT IVS10+16 microglia increased proteolytic activity and improved tau handling. Together, these findings reveal a reciprocal relationship between tau and microglial lysosome function and identify degradative capacity as a modifiable component of the microglial response to tau pathology.

neuroscience↗

bioRxiv2026

m1A58 acts as a conformational checkpoint coupling human initiator tRNA maturation to translation initiation

tRNAs are characterized by extensive chemical modifications that influence tRNA fate. N1-methyladenosine at position 58 (m1A58) is a widespread core tRNA modification linked to physiological and pathological processes. However, how m1A58 coordinate tRNA folding and processing to ensure translational efficiency in mammalian cells remains largely unknown. Using acute dTAG-mediated degradation and CRISPR-Cas9 knockout, we identified initiator methionine tRNA (tRNAiMet) as selectively vulnerable to m1A58 loss, lacking the isodecoder buffering observed for most other tRNA isoacceptors. NMR analysis of the tRNAiMet showed that m1A58 stabilizes D/T-loop interactions, consistent with a maturation-competent conformation. In vitro processing assays further demonstrated that m1A58 promotes RNase P-mediated 5'-leader removal and RNase Z-mediated 3'-trailer cleavage, while La/SSB protects accumulated precursors. Disrupting this checkpoint impaired the assembly of the eIF2-containing 43S pre-initiation complex and global protein synthesis, which was substantially rescued by adding m1A58-modified tRNAiMet. Acute TRMT6 degradation elicited temporally coordinated gene-expression responses involving proteostasis, transport and signaling. Together, these findings establish m1A58 as a conformational checkpoint coupling human initiator-tRNA maturation to translation initiation and stress responses.

molecular biology↗

bioRxiv2026

Single nucleus RNA sequencing and spatial transcriptomics reveal unique functionalities of gray matter versus white matter oligodendrocytes in aging and Alzheimer's Disease

Oligodendrocyte (OL) dysfunction and white-matter (WM) vulnerability are increasingly recognized as important aspects of aging and Alzheimer's Disease (AD), yet human WM-focused, cellular-resolution transcriptomic data remain limited. Here, we profiled prefrontal WM from 48 brain donors spanning young adulthood and late-life with low versus high AD Neuropathologic Change (ADNC) using single-nucleus RNA sequencing followed by spatial transcriptomics (CosMx) in a subset of matched donors. We integrated aged WM OLs with a reference dorsolateral prefrontal cortex grey-matter (GM) OL dataset (SEA-AD) to define region- and pathology-associated OL programs. Across modalities, GM OLs exhibited a robust synapse/neurotransmitter-associated transcriptional signature relative to WM OLs, whereas this program was reduced with aging and attenuated in high ADNC GM. In contrast, WM OLs showed stronger immune-associated programs with aging and further enhancement in high ADNC, including cytokine/chemokine signaling and antigen presentation-related pathways. High ADNC WM OLs also displayed amplified proteostasis and stress-adaptation signatures, including selective upregulation of chaperone/heat shock genes and ferritin subunits, consistent with increased protein-folding demand and altered iron handling. To resolve OL state organization beyond static differential expression, we annotated OL sub-states using marker panels and inferred pseudotime-guided directional state-to-state flows within each tissue/condition stratum. This analysis identified a conserved newly formed differentiating (NFOL)/differentiating [->] lipid remodeling (APOE/ABCA1/LPL+) [->] Stress/ISR-reactive architecture, with a pronounced expansion of the Stress/ISR-reactive compartment and altered transition-associated pathway enrichment in high ADNC WM. Together, these data define WM-specific OL programs linked to aging and ADNC and nominate a stress/immune-enriched OL state landscape consistent with a putative senescence-like phenotype in diseased WM.

neuroscience↗

bioRxiv2026

A Metabolic Labeling Strategy for Tracking Protein Synthesis in Complex Biological Systems

Protein synthesis supports most biological processes. In the brain in particular, protein synthesis plays a critical role in physiological and pathological states. Here, we describe Tellurophene-Alkyne Cycloaddition-mediated Amino acid Tagging (TeACAT), a versatile strategy for fast, facile, and flexible tagging of newly synthesized proteins in mice. TeACAT is based on metabolic incorporation of the non-canonical amino acid TePhe into proteins by the endogenous protein synthesis machinery. Due to their high similarity, TePhe can efficiently replace canonical Phe without dietary or genetic manipulation. The subsequent bio-orthogonal reaction of TePhe with either fluorescent dyes or affinity handles enables both visualization and affinity enrichment of proteins synthesized during TePhe exposure. TeACAT is compatible with immunofluorescence for cell-type specific visualization of protein synthesis with subcellular resolution and can be used in conjunction with routine proteomics to identify and quantify newly synthesized proteins. Robust incorporation into the mouse proteome was observed on the scale of hours to days, allowing the interrogation of various biological processes. In summary, TeACAT enables the visualization and quantification of protein synthesis with minimal perturbation for biological discoveries.

molecular biology↗

bioRxiv2026

A patient-centric therapeutic paradigm uncouples prostate cancer suppression from systemic metabolic collapse

The clinical benefits of cancer therapies are often compromised by the tolerable adverse effects that impair systemic organismal health and may evolve into latent life threats. Here, we identified profound abiraterone-induced but androgen-independent metabolic perturbations in prostate cancer patients and developed Lifehug-9892 to balance tumor therapy with systemic metabolic homeostasis. By integrating population cohorts with high-resolution metabolomics, we demonstrate that abiraterone induces profound systemic lipidomic dysregulation, characterized by the massive, pathological accumulation of desmosterol. Abiraterone inhibits but stabilizes DHCR24, leading to a metabolic trap in patients showing elevated levels of both desmosterol and cholesterol. Desmosterol accumulation is highly lipotoxic, potently triggering endothelial cell senescence and necrosis, macrophage foam cell formation, murine atherosclerosis, and hepatic senescence. To mechanistically uncouple and therapeutically rescue this systemic metabolic collapse, Lifehug-9892 was rationally designed to selectively retain on-target CYP17A1 inhibition while completely sparing DHCR24 function. Lifehug-9892 maintains potent tumor-suppressive activity while fully preserving the desmosterol-cholesterol metabolic axis and preventing systemic cardiovascular and hepatic damage. Our study uncovers a critical mechanistic link between drug-induced metabolic dysregulation and organismal health in cancer patients, providing a biochemical framework for developing patient-centric targeted therapies that preserve host homeostasis.

cancer biology↗

bioRxiv2026

Function-driven geometry directs human pilosebaceous unit development

Single-cell technologies have generated cell censuses of tissues, however, how tissue geometry reflects functional needs remains poorly characterized. The human pilosebaceous unit offers a tractable model, a prenatally-formed complex mini-organ combining hair and sebum production with a stem cell reservoir. Using histomorphology, spatial transcriptomics, and single-cell multiomics on the same human prenatal scalp skin samples (8-19 post-conception weeks), integrated and analyzed using machine learning approaches, we built a spatiotemporal map of pilosebaceous unit development. We demonstrate that epithelial-mesenchymal interactions coordinate cellular fate and organogenesis, using an in vitro hair-bearing skin organoid model to validate this tissue-patterning. In addition, we show sebaceous gland developmental programmes are overcome during tumor formation. Our large-scale multi-modal analysis provides a unique framework for understanding form and function of tissues with applications in tissue engineering and pathology.

developmental biology↗

bioRxiv2026

Comprehensive characterization of genomic, transcriptomic and epigenomic artifacts introduced in formalin-fixed, paraffin-embedded tissues.

Genomic, transcriptomic and epigenomic characterization has accelerated the discovery of clinically-relevant alterations in cancer, predominantly using fresh frozen (FF) specimens. However, clinical molecular pathology laboratories prefer formalin-fixed paraffin-embedded (FFPE) methods, known to introduce artifacts at the nucleic acid level, over fresh frozen methods. Extending the multi-platform analysis to FFPE specimens for comprehensive clinical molecular diagnosis requires a thorough understanding of the consequence of formalin-fixation. We present a detailed multi-platform characterization of FFPE preservation using paired FF specimens as the 'gold standard'. DNA and RNA were obtained from 38 patients across 6 cancer types using a FFPE optimized co-isolation. The impact of FFPE on exome sequencing was dependent on filtering, where a minimum coverage or supporting read filter can mitigate FFPE-specific false positives. Copy number alterations, MSI assessment, mutational signatures, and DNA methylation were comparable between FFPE and FF. FFPE biases in RNA expression can be overcome when using biology-relevant genes and we describe a novel consequence of FFPE on miRNA species diversity. Collectively, this data provides a broad view of FFPE artifact and offers best practices for overcome these biases.

bioinformatics↗

bioRxiv2026

Elevated hydrostatic pressure modulates endothelial junctional mechanotransduction through VE-cadherin remodelling and altered association with YAP1, EPS8: an endothelium-on-chip study

Endothelial dysfunction is a hallmark of numerous vascular pathologies and is strongly influenced by mechanobiological forces within the vascular microenvironment. While the effects of shear stress have been extensively investigated, the mechanisms by which elevated hydrostatic pressure regulates endothelial junctional organisation remain sparsely investigated. Here, we employed a microfluidic platform to investigate the combined effects of low shear stress (1.4 dyne/cm2) and elevated hydrostatic pressure (~3972 Pa) on endothelial junctional dynamics. Elevated hydrostatic pressure induced marked remodelling of VE-cadherin junctions, characterised by formation of serrated, finger-like structures accompanied by increased YAP1 nuclear localisation and reduced YAP1-VE-cadherin cytoplasmic colocalisation compared to shear stress alone conditions. Further, elevated hydrostatic pressure also demonstrated an increase in cytoplasmic accumulation of EPS8, an actin adaptor protein, and increased cytoplasmic EPS8-VE-cadherin colocalisation. These observations were accompanied by functional changes marked by increased endothelial permeability, and enhanced THP-1 monocyte adhesion, thus suggesting activation of mechanosensitive pathways linked to dynamic junctional reorganisation. Inhibition of PI3K at elevated hydrostatic pressure exhibited a thin VE-cadherin patterning and increased cytoplasmic EPS8-VE-cadherin colocalisation, thus demonstrating a prominent role for PI3K signalling in regulating the junction organisation. Interestingly, Piezo-1 activation using Yoda1 produced context-dependent effects. Under shear stress alone, Yoda1 promoted YAP1 nuclear translocation, reduced YAP1-VE-cadherin colocalisation, increased endothelial permeability but strikingly did not impact THP-1 adhesion compared to shear stress alone conditions. In contrast, under elevated hydrostatic pressure conditions, Yoda1 significantly reduced both endothelial permeability and THP-1 adhesion while increasing YAP1-VE-cadherin colocalisation and decreasing YAP1 nuclear accumulation. Collectively, these findings identify a previously underappreciated elevated hydrostatic pressure-Piezo-1-PI3K signalling axis that regulates endothelial barrier integrity and pro-adhesive endothelial activation through coordinated regulation of VE-cadherin, YAP1, and EPS8. These results highlight elevated hydrostatic pressure as a unique mechanobiological stimulus, distinct from that of shear stress alone and provide novel insights into mechanisms underlying microvascular dysfunction.

bioengineering↗

bioRxiv2026

Differential expression of NEAT1 in the corneal endothelium increases susceptibility to oxidative stress in Fuchs Endothelial Corneal Dystrophy

Fuchs endothelial corneal dystrophy (FECD) is a disease of the corneal endothelium (CE) characterized by the loss of corneal endothelial cells (CECs) and guttae formation, ultimately resulting in corneal edema and vision loss. FECD primarily affects the central CE while sparing the peripheral CE, however the underlying mechanism contributing to the spatial differences remain unknown. Oxidative stress has been increasingly recognized as a key contributor to the pathogenesis of FECD, with CECs being particularly susceptible to damage from reactive oxygen species (ROS), high metabolic activity and ultraviolet induced DNA damage. The non-proliferative nature of CECs, along with the accumulation of oxidative damage can ultimately lead to CEC loss, a key feature of FECD. In this study, we induced oxidative stress with hydrogen peroxide (H2O2) on ex-vivo corneal specimens and observe increased cell death in the central region compared to the peripheral CE. To investigate these underlying differences, we performed bulk RNA sequencing (RNA-seq) on the central and peripheral regions of CE from FECD and normal cadaveric donors. Pathway analysis identified an enrichment of genes involved in collagen and extracellular matrix between the central and peripheral regions of CE in both normal and FECD, as well as between normal and FECD CE. Intriguingly, we identified the long non-coding RNA (lncRNA), NEAT1 as a top differentially expressed gene, with reduced expression in the central CE compared to the peripheral CE and lower expression in FECD compared with normal CE. Using corneal endothelial cell lines and ex-vivo specimens from FECD patients and normal cadavers, we found decreased NEAT1 expression levels in FECD and increased susceptibility to H2O2-induced oxidative stress. We observed that NEAT1 knockdown in normal and FECD cells exacerbated H2O2-mediated oxidative stress, and that NEAT1 overexpression protected FECD cells. We report in this study, a novel insight in the spatial differences in gene expression in the CE and identify reduced expression of NEAT1 in the central CE as a potential contributor to oxidative stress-related cell death in FECD. These findings provide novel insight into FECD pathogenesis and why FECD pathology preferentially affects the central CE. Antioxidants targeting NEAT1 signaling could be developed into novel therapeutics aimed at preventing FECD pathogenesis.

cell biology↗

bioRxiv2026

Predicting Cerebral Pericyte Contractility Across Experimental and Physiological Conditions: an in-silico framework

Pericytes (PCs) have recently emerged as critical regulators of cerebral blood flow (CBF) and represent a promising therapeutic target for various cerebrovascular pathologies. Given the complex array of biochemical and mechanical stimuli these cells integrate, a multiscale modeling framework is essential to quantify the impact of selective interventions on pericyte contractile machinery and blood flow restoration. Here, we introduce a computational framework to evaluate capillary pericyte responses across diverse experimental interventions and conditions (ex vivo and in vivo). To capture pharmacological modulation of the contractile apparatus, we developed a homogeneous intracellular model that incorporates key properties of robust control systems. In this framework, vascular tone generation depends strictly on intracellular calcium concentration (Ca2+), which emerges from a complex electrochemical equilibrium established by transmembrane ion (Na+, K+, Cl-) gradients, luminal mechanical forces, and external ligand concentrations. The resulting fraction of phosphorylated cross-bridges generates contractility, which is integrated into the strain energy function governing the constitutive behavior of the vascular wall. The model was successfully validated across four distinct experimental and pharmacological interventions (including pinacidil, high external K+, U46619, and nimodipine), demonstrating close agreement with observed ex vivo and in vivo vascular responses. By establishing a quantitative bridge between pericyte electrophysiology and microvascular mechanics, this framework provides a valuable foundation for evaluating targeted therapeutic strategies to alleviate tissue ischemia in stroke and vascular dementia.

systems biology↗

bioRxiv2026

Cross-species analysis links cell-cell communication rewiring to NOTCH2 during serous endometrial carcinogenesis

Cell-cell interactions shape the fate of mutant cells during cancer initiation but how these interactions evolve during progression to pathologically recognizable lesions remain poorly understood. Here, we investigated cell-cell communication during serous endometrial carcinoma (SEC; also known as uterine serous carcinoma) development using a lineage-traceable mouse model and cross-species analyses of the mouse and human neoplastic endometrium. In mice, the early, pre-dysplastic stage was marked by a global decrease in inferred cell-cell interactions, followed by extensive communication network rewiring during neoplastic progression. Pathway-specific analysis revealed a similar pattern for NOTCH signaling, with NOTCH2 emerging as the dominant NOTCH receptor in Trp53/Rb1-mutant immature epithelial cells. Functionally, NOTCH2 promoted the outgrowth of more proliferative mutant organoids. Cross-species transcriptomic analysis identified conserved immature epithelial states in mouse and human neoplastic endometrial epithelium. In human tissues, NOTCH2 was overexpressed in serous endometrial intraepithelial carcinoma, a precursor of SEC, and in overt SEC. Furthermore, elevated NOTCH2 expression was associated with poor patient survival. These findings link cell-cell communication rewiring during experimental SEC development to conserved neoplastic epithelial states and identify NOTCH2 as an early marker and a potential target of disease interception.

cancer biology↗

bioRxiv2026

Cardiomyocyte prohibitin ablation reprograms cardiac metabolism revealing a pathogenic role for mTORC1 in dilated cardiomyopathy

Maintaining cardiac structure and function throughout the lifespan requires a delicate balance in carbon allocation between energetic and biosynthetic processes. At the nexus of this balance are prohibitins-1 and -2 (PHB1, 2) which form a ring-like complex in mitochondrial and plasma membranes responsible for coordinating cellular growth, metabolism and autophagy. Here we describe how ablation of the PHB complex in cardiomyocytes of adult mice (cPHB1KO) causes unrestrained mechanistic target of rapamycin complex 1 (mTORC1) activity and a Warburg-like reprogramming of glucose metabolism in heart toward enhanced de novo amino acid biosynthesis. These changes are accompanied by disruptions in mitochondrial Ca2+ handling and impaired autophagy, leading to severe dilated cardiomyopathy and mortality within 12 weeks. Using pharmacological and nutritional approaches, we further show that mTORC1 inhibition attenuates pathologic cardiac remodeling only in female cPHB1KO mice. Our findings illustrate novel mechanisms linking the PHB complex with altered carbon flux and pathogenesis of cardiomyopathy.

cell biology↗

bioRxiv2026

Cardiomyocyte-specific loss of Smyd5 leads to a robust activation of inflammatory signaling and heart failure in mice.

Background: Cardiomyocytes respond to stress by undergoing hypertrophic growth driven by dynamic changes in gene expression. Epigenetic mechanisms, including histone methylation, play critical roles in regulating these transcriptional programs, yet the enzymes controlling these modifications during cardiac disease remain largely unknown. The SMYD family of histone methyltransferases regulates gene expression in multiple biological contexts, but the function of SMYD5 in the mammalian heart has never been investigated. Methods: SMYD5 expression was assessed in human heart failure samples and in a mouse model of cardiac hypertrophy. To define its functional role in vivo, we generated inducible cardiomyocyte-specific Smyd5 knockout mice and characterized their cardiac phenotype using molecular, histological, and functional analyses. Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) was performed to examine histone H4 lysine 20 trimethylation (H4K20me3) at the Il-6 promoter. Results: SMYD5 expression was altered in diseased human and mouse hearts. Under basal conditions, cardiomyocyte-specific deletion of Smyd5 resulted in baseline structural cardiac remodeling and transcriptional signatures characteristic of pathological stress. Smyd5-deficient hearts exhibited marked inflammatory activation resembling a cytokine storm with immune cell infiltration and heart failure. Notably, Smyd5 knockout mice displayed a 100-fold increase in Il-6 expression, accompanied by a global reduction in H4K20me3. ChIP-qPCR analysis of the Il-6 promoter, together with loss- and gain-of-function analysis of SMYD5, supports a direct epigenetic role of SMYD5 in regulating Il-6 expression through H4K20me3 in cardiomyocytes. Conclusions: SMYD5 is a previously unrecognized epigenetic regulator of cardiac homeostasis that restrains inflammatory signaling in cardiomyocytes under normal conditions. Loss of Smyd5 disrupts H4K20me3, leading to derepression of Il-6 in cardiomyocytes and a robust inflammatory response characterized by immune cell recruitment and fibrosis, accompanied by rapid progression of cardiac remodeling and heart failure. These findings identify SMYD5 as a critical regulator of intrinsic cardiomyocyte inflammatory signaling and reveal a novel chromatin-based mechanism contributing to inflammatory cardiomyopathies.

molecular biology↗

bioRxiv2014

Notorious Novel Avian Influenza Viruses H10N8 and H7N9 in China in 2013 Co-originated from H9N2

In 2013, two new avian influenza viruses (AIVs) H7N9 and H10N8 emerged in China caused worldwide concerns. Previous studies have studied their originations independently; this study is the first time to investigate their co-originating characteristics. Gene segments of assorted subtype influenza A viruses, as well as H10N8 and H7N9, were collected from public database. 26 With the help of series software, small and large-scale phylogenetic trees, mean evolutionary rates, and divergence years were obtained successionally. The results demonstrated the two AIVs co-originated from H9N2, and shared a spectrum of mutations in common on many key sites related to pathogenic, tropism and epidemiological characteristics. For a long time, H9N2 viruses had been circulated in eastern and southern China; poultry was the stable and lasting maintenance reservoir. High carrying rate of AIVs H9N2 in poultry had an extremely high risk of co-infections with other influenza viruses, which increased the risk of virus reassortment. It implied that novel AIVs reassortants based on H9N2 might appear and prevail at any time in China; therefore, surveillance of H9N2 AIVs should be given a high priority.

Pathology↗

bioRxiv2015

Mutual predators: A descriptive cross-sectional study to identify prevalence and co-relation of Hepatitis C Virus and Human Immunodeficiency Virus type-1 coinfection

BackgroundCoinfection, bacterial or viral origin, in HIV infected individuals remains to be the only leading cause of deaths. This study was designed to analyze received plasma samples and plasma samples of referred patients for HIV testing to detect HIV and HCV mono and co-infection by real time PCR and finding co-relation of viral load of both viruses. Highlight and magnify the hidden coinfection, prior to seroconversion, of HIV type-1 and Hepatitis C Virus in received samples.\n\nMethodsAnalyses were based on randomly selected 78 patients stored plasmas. Plasma samples were tested for both, HIV-type 1 and HCV viral RNA by real time PCR. Statistical formulas were used to identify men and the inter quartile range of patients age. The data were analyzed by IBM SPSS Statistics 21 (SPSS Inc., Chicago, IL). Study variables include gender, age and viral loads of HIV type-1 and HCV. Pearson correlation was used to evaluate any correlation in study variables.\n\nResultPrevalence of HCV was 10.3%, HIV-type 1 was 19.2% and their co-infection was 37.2 percent. Thirty three percent individuals had no infection of both viruses. Gender based distribution showed that 74.4% (58/78) sample population was male. The mono-infection and co-infection was higher in males (39.7%) and highest viral load too. There was a positive correlation (CI= 95%) between the two variables; HIV and HCV viral loads, as r = 0.736, n=29, p= 0.001.\n\nConclusionPrevalence of HIV type-1 and HCV mono-infection and co-infection was higher among males as compared to females. Increased viral load was also evident among male co-infected individuals. This study proved the emergence of HCV coinfection in HIV infected individuals, and a need for on time diagnosis and treatment.

Pathology↗

bioRxiv2015

Mass spectrometry-based quantitation of Her2 in gastroesophageal tumor tissue: Comparison to IHC and FISH

BackgroundTrastuzumab showed survival benefit for Her2-positive gastroesophageal cancers (GEC). Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) currently determine eligibility for trastuzumab-based therapy. However, both assays are low throughput with various limitations.\n\nMethodsWe developed a selected reaction monitoring mass spectrometric (SRM-MS) assay and quantified levels (amol/ug) of Her2-SRM in cell lines (n=27) and GEC tissues (n=139). We compared Her2-SRM expression with IHC/FISH, seeking to determine optimal SRM expression cut-offs to identify HER2 amplification.\n\nResultsAfter demonstrating assay development, precision, and stability, Her2-SRM measurement was observed to be highly concordant with HER2/CEP17 ratio, particularly in a multivariate regression model adjusted for SRM-expression of Met, Egfr, Her3, and HER2-heterogeneity covariates, and their interactions (cell lines r2=0.9842; FFPE r2=0.7643). In GEC tissues, Her2-SRM was detected in 71.2% of cases, and 12.3% were identified as HER2+. ROC curves demonstrated HER2-SRM levels to have high specificity (100%) at an upper-level cut-off of >750 amol/g and sensitivity (75%) at lower-level cut-off of <450 amol/ug. We observed an equivocal-zone between 450-750 amol/ug, analogous to IHC2+, but less frequent (9-16% of cases versus 36-41%).\n\nSignificanceCompared to IHC, SRM-MS provided more objective and quantitative Her2 expression with excellent HER2/CEP17 FISH correlation and fewer equivocal cases. Along with the multiplex capability for other relevant oncoproteins, these results demonstrated a refined HER2 expression assay for clinical application.

Pathology↗

bioRxiv2015

PIK3CA Mutational Analysis in Formalin-Fixed, Paraffin-Embedded Archival Tissues of Urothelial Carcinoma of Urinary Bladder

ObjectiveUrothelial carcinoma of the urinary bladder is the fourth most common cancer in males in the United States. In addition to mutations in FGFR3, TP53, AKT1, TSC1, and PTEN genes, mutations in PIK3CA have been also described in urothelial carcinomas, preferentially in low-grade tumors. Mutations in PIK3CA also has been shown to have implications for prognosis, surveillance and therapeutic response. Thus, determining the PIK3CA status in urothelial carcinomas could potentially improved the clinical management of patients with bladder cancer. Herein, we evaluated the presence of PIK3CA mutations in exons 1, 9, and 20 in 21 urothelial carcinomas of the urinary bladder.\n\nMethodsPatients were treated by radical cystectomy without neoadjuvant chemotherapy. Representative tissue blocks (1 for each case) were selected. We used a pinpoint DNA extraction technique from formalin-fixed, paraffin-embedded and mutational analysis using the polymerase chain reaction (PCR) assay coupled with sequencing of targeted exons. Patients included 15 men and 6 women, with a median age of 68 years (range, 42 to 76 years), with 3 noninvasive and 18 invasive urothelial carcinomas. Noninvasive carcinomas included 1 case each of low-grade papillary urothelial carcinoma, high-grade papillary urothelial carcinoma, and urothelial carcinoma in situ (CIS). Invasive tumors included 3 pT1, 5 pT2, 6 pT3, and 4 pT4 urothelial carcinomas.\n\nResultsWe did not find mutations in the analyzed exons of the PIK3CA gene, in any of the 21 urothelial carcinomas. The preponderance of invasive high-grade and high-stage tumors could explain the absence of identifiable mutations in our cohort.\n\nConclusionsPIK3CA mutations as prognosti-cators of outcome or predictors of therapeutic response await further evaluation.

Pathology↗