Biology subjects

Mehta, A. S.

Publications and source records attributed to Mehta, A. S..

8 recordsLinked to original sources

bioRxiv2026

Extracellular Matrix Proteomic Signatures Associate with Disease-Free Survival in Later Events of Ductal Carcinoma In Situ or Invasive Breast Cancer

BackgroundDuctal carcinoma in situ (DCIS) is a noninvasive breast lesion with variable risk of progression to invasive breast cancer (IBC). Current transcription and cell marker investigations suggest ECM decreases in later events but are limited in details of ECM proteomic composition, including post-translational modifications. We investigated whether the extracellular matrix (ECM) proteome alters with later breast events of DCIS or IBC. MethodsECM-targeted mass spectrometry imaging and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were applied to ten tissue microarrays from the Resource of Archival Human Breast Tissue cohort (RAHBT). Primary DCIS specimens (n=136) were analyzed in relation to later events of DCIS (n=40) or IBC(n=30), with a mean follow-up of 192.1 months 95% CI [179.1,205.1]. Statistical modeling, survival analyses, and exploratory machine learning approaches were used to identify ECM peptide signatures associated with later events. ResultsDistinct ECM peptide profiles were associated with later events of DCIS or IBC. Fifteen peptides derived from fibrillar collagens (COL1A1, COL1A2, COL3A1) and elastin, showed significantly reduced abundance in patients who developed IBC. Lower expression of specific collagen peptides associated with overall 19.9% 95% CI [17.92, 21.81] decreased disease-free survival for IBC. Lower expression of these peptides was significantly associated with reduced disease-free survival (age-adjusted hazard ratio [HR] = 2.45, 95% CI: 2.33-2.57; P < 0.05). Patient-matched samples of primary DCIS, later DCIS, and later invasive breast cancer further demonstrated reduction in ECM peptide detection. Exploratory predictive modeling from patient-matched samples achieved high performance (AUROC >0.98, accuracy >93%) in distinguishing primary from later events. Following prior work in the RAHBT cohort, reduction of certain collagen peptides was also observed in primary DCIS samples from higher risk patient groups. ConclusionsECM proteomic remodeling, particularly decreases of specific collagen domains, is strongly associated with later events of DCIS and IBC. These findings highlight ECM proteome as a critical regulator of breast cancer emergence with potential as a prognosticator of risk stratification to guide clinical management of DCIS.

pathology↗

bioRxiv2026

Histone methylation activity of KMT2D is required for proliferative control of the developing lung

KMT2D, the histone methyltransferase and core component of the COMPASS/MLL4 complex, has been implicated in developmental diseases such as Kabuki Syndrome, interstitial lung disease, and congenital diaphragmatic hernia, with clear links to pediatric pulmonary disorders. Despite this, the mechanism by which KMT2D governs lung development remains unclear. Knock-in mouse models rendering, KMT2D catalytically deactivated (KMT2DKI) and reducing H3K4 methylation, have demonstrated potential in defining KMT2Ds role in pulmonary development. Our examination of the lungs of KMT2DKI mice revealed increased cellular density and impaired sacculation indicated by reduced airspace chord length, thickening of intersaccular septa, and abnormal alveolar cell differentiation. KMT2DKI mice revealed narrowed Sox2+ conducting airways and epithelial differentiation defects characterized by reduced Cc10+ club cells. Accompanying the alveolar and airway hypoplasia, blood vessel luminal area was reduced. Conversely, KMT2DKI lungs had a significantly higher proportion of proliferating cells accompanied by a dramatic expansion in Pdgfr+ mesenchymal progenitor cells. Our findings therefore suggest that KMT2D-mediated H3K4 methylation is vital to normal lung development, and its impairment results in widespread pulmonary hypoplasia and potentially pulmonary hypertension.

developmental biology↗

bioRxiv2025

Identification of sialic acid linkage profiles in primary liver cancers

Cholangiocarcinoma (CCA), also known as bile duct cancer, is the second most common form of primary liver cancer after hepatocellular carcinoma (HCC). Subtypes of CCA are diagnosed according to the anatomic location within the biliary tree, such as intrahepatic (iCCA) or extrahepatic (eCCA). Early diagnosis remains difficult due to the low sensitivity and specificity of current biomarkers. There has been significant interest in finding new biomarkers of CCA and much work has been performed to both discover and validate these new markers. In our previous work, we identified specific alterations in N-linked glycosylation that were associated with iCCA, which differed from non-malignant cholestasis disease and HCC. However, that analysis focused only on N-glycan structures devoid of sialic acid, as these N-glycan residues are not stable and were intentionally removed to minimize variability. Here, we explore the specificity of sialic acid residues in liver cancers, since sialic acid residues have been heavily linked to roles in tumor progression and metastasis by helping evade immunological surveillance. To circumvent the instability of sialic acid, we utilize a novel sialic acid stabilization method coupled with Matrix-Assisted Laser Desorption Ionization (MALDI) Imaging Mass Spectrometry (IMS) for detailed analysis of sialic acid linkages in iCCA tissue. We report a clear association between the linkages type of sialic acid residues with a HCC or CCA, including differentiation between CCA subtypes. Overall, we stabilize N-glycans with sialic acid residues to determine their linkages and elucidate their importance in different types of primary liver cancers and their subtypes by MALDI-IMS.

cancer biology↗

bioRxiv2025

Spatial Proteomics of the Normal Breast Collagen Stroma: Links to BI-RADS Categories and Body Mass Index

Collagen breast stroma is the basis of increased breast density and a well-established breast cancer risk factor, yet proteomic regulation of normal breast stroma remains poorly defined. This study reports spatial regulation of the collagen proteome in normal breast tissue sections annotated by clinical characteristics. Normal breast samples from the Susan G. Komen tissue bank included data on genetic ancestry (n=40 total; n=20 African ancestry; n=20 European ancestry), body-mass-index (BMI), age, and mammogram density by the Breast Imaging Reporting and Data System (BI-RADS). Multiplexed cell marker staining showed CD44 and COL1A1 markers modulated with BMI. Collagen fiber widths by second harmonic generation (SHG) showed potential contrasts in BMI categories by genetic ancestry. Targeted extracellular matrix proteomics mass spectrometry imaging showed collagen alpha-1(I) chain domain proteome was spatially heterogenous across the normal breast microenvironment with site specific post-translational modification of proline hydroxylation. Signatures computationally extracted from breast stroma reported that 47 collagen peptides distinguished BI-RADS categories (area under the receiver operating curve>0.7; p-value>0.05). Proteomic alterations were found between overweight to obese categories with strong positive associations to BMI by multivariate analysis. This study provides the first spatial analysis of the collagen proteome in normal breast within contexts of cellular markers and clinical characteristics.

cancer biology↗

bioRxiv2024

Decellularized biohybrid nerve promotes motor axon projections

Developing nerve grafts with intact mesostructures, superior conductivity, minimal immunogenicity, and improved tissue integration is essential for the treatment and restoration of neurological dysfunctions. A key factor is promoting directed axon growth into the grafts. To achieve this, we developed biohybrid nerves using decellularized rat sciatic nerve modified by in situ polymerization of poly(3,4-ethylenedioxythiophene) (PEDOT). We compared nine biohybrid nerves with varying polymerization conditions and cycles, selecting the best candidate through material characterization. Our results showed that a 1:1 ratio of FeCl3 oxidant to ethylenedioxythiophene (EDOT) monomer, cycled twice, provided superior conductivity (>0.2 mS/cm), mechanical alignment, intact mesostructures, and high compatibility with cells and blood. To test the biohybrid nerves effectiveness in promoting motor axon growth, we used human Spinal Cord Spheroids (hSCSs) from HUES 3 Hb9:GFP cells, with motor axons labeled with green fluorescent protein (GFP). Seeding hSCS onto one end of the conduit allowed motor axon outgrowth into the biohybrid nerve. Our construct effectively promoted directed motor axon growth, which improved significantly after seeding the grafts with Schwann cells. This study presents a promising approach for reconstructing axonal tracts in humans.

bioengineering↗

bioRxiv2023

Quantifying innervation facilitated by deep learning in wound healing

The peripheral nerves (PNs) innervate the dermis and epidermis, which have been suggested to play an important role in wound healing. Several methods to quantify skin innervation during wound healing have been reported. Those usually require multiple observers, are complex and labor-intensive, and noise/background associated with the Immunohistochemistry (IHC) images could cause quantification errors/user bias. In this study, we employed the state-of-the-art deep neural network, DnCNN, to perform pre-processing and effectively reduce the noise in the IHC images. Additionally, we utilized an automated image analysis tool, assisted by Matlab, to accurately determine the extent of skin innervation during various stages of wound healing. The 8mm wound is generated using a circular biopsy punch in the wild-type mouse. Skin samples were collected on days 3,7,10 and 15, and sections from paraffin-embedded tissues were stained against pan-neuronal marker- protein-gene-product 9.5 (PGP 9.5) antibody. On day 3 and day 7, negligible nerve fibers were present throughout the wound with few only on the lateral boundaries of the wound. On day 10, a slight increase in nerve fiber density appeared, which significantly increased on day 15. Importantly we found a positive correlation (R-2 = 0.933) between nerve fiber density and re-epithelization, suggesting an association between re-innervation and re-epithelization. These results established a quantitative time course of re-innervation in wound healing, and the automated image analysis method offers a novel and useful tool to facilitate the quantification of innervation in the skin and other tissues.

molecular biology↗

bioRxiv2022

Lyme Disease IgG N-linked Glycans Contrast the Canonical Inflammatory Signature

Lyme disease (LD) infection is caused by Borrelia burgdorferi sensu lato. Due to the limited presence of this pathogen in the bloodstream in humans, diagnosis of LD relies on seroconversion. Immunoglobulins produced in response to infection are differentially glycosylated to promote or inhibit downstream inflammatory responses by the immune system. IgG N-glycan responses to LD have not been characterized. In this study, we analyzed IgG N-glycans from cohorts of healthy controls, acute LD patient serum, and serum collected after acute LD patients completed a 2- to 3-week course of antibiotics and convalesced for 70-90 days. Results indicate that during the acute phase of Bb infection, IgG shifts its glycosylation profile to include structures that are not associated with the classic proinflammatory IgG N-glycan signature. This unexpected result is in direct contrast to what is reported for other inflammatory diseases. Furthermore, IgG N-glycans detected during acute LD infection discriminated between control, acute, and treated cohorts with a sensitivity of 75-100% and specificity of 94.7-100%. Author summaryThe causative agent of Lyme disease (LD), Borrelia burgdorferi sensu lato (Bb), is transmitted from an infected Ixodes tick into the human host dermis during the ticks blood meal. Currently, LD is the most prevalent vector-borne disease in the US, with an estimated 476,000 annual cases. LD diagnostics rely on patient seroconversion against Bb antigens, and these tests cannot distinguish between an acute patient compared to a patient previously treated for LD. With the goal of identifying novel biomarkers associated specifically with LD infections, we analyzed the glycoprotein Immunoglobulin G (IgG) N-glycan signatures from healthy control, acute LD, and a second time point composed of the same LD patients after antibiotic therapy. We found acute LD IgG N-glycan signatures were significantly different from the canonical pro-inflammatory profile associated with most inflammatory diseases. The dramatic shifts observed in the acute LD time point were further altered at the treated time point. IgG N-glycan signature data was employed to discriminate between acute LD and healthy controls. In addition, IgG N-glycan signatures distinguished patients who completed antibiotic therapy from the acute LD timepoint. Our study will contribute to the accurate and prompt treatment of LD patients and reveals a new research avenue of immune dysregulation associated with LD. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

immunology↗

bioRxiv2021

Novel newt regeneration genes regulate Wingless signaling to restore patterning in Drosophila eye

A fundamental process of regeneration, which varies among animals, recruits conserved signaling pathways to restore missing parts. Only a few animals like newts can repeatedly regenerate lost body parts throughout their lifespan that can be attributed to strategic regulation of conserved signaling pathways by newts regeneration tool-kit genes. Here we report use of genetically tractable Drosophila eye model to demonstrate the regeneration potential of a group of unique protein(s) from newt (Notophthalmus viridescens), which when ectopically expressed can significantly rescue missing photoreceptor cells in a Drosophila eye mutant. These newt proteins with signal peptides motifs exhibit non-cell-autonomous rescue properties and their regeneration potential even extends into later stages of fly development. Ectopic expression of these newt genes can rescue eye mutant phenotype by promoting cell proliferation and blocking cell death. These novel newt genes downregulate evolutionarily conserved Wingless (Wg)/Wnt signaling pathway to promote rescue. Modulation of Wg/Wnt signaling levels by using antagonists or agonists of Wg/Wnt signaling pathway in eye mutant background where newt gene(s) is ectopically expressed suggests that Wg signaling acts downstream of newt genes. Our data highlights the regeneration potential of novel newt proteins that regulate conserved pathways to trigger a robust regeneration response in Drosophila model with weak regeneration capability.

developmental biology↗