Biology subjects

Monette, S.

Publications and source records attributed to Monette, S..

7 recordsLinked to original sources

bioRxiv2025

The Spatial Atlas of Human Anatomy (SAHA): A Multimodal Subcellular-Resolution Reference Across Human Organs

The Spatial Atlas of Human Anatomy (SAHA) represents the first multimodal, subcellular- resolution reference of healthy adult human tissues across multiple organ systems. Integrating spatial transcriptomics, proteomics, and histological features across over 15 million cells from more than 100 donors, SAHA maps conserved and organ-specific cellular niches in gastrointestinal and immune tissues. High-resolution profiling using CosMx SMI, 10x Xenium, RNAscope, GeoMx DSP, and single-nucleus RNA-seq reveals spatially organized cell states, rare adaptive immune populations, and tissue-specific cell-cell interactions and ligand-receptor pairs. Comparative analyses with colorectal cancer and inflammatory bowel disease demonstrate the power of SAHA to detect disease-associated spatial disruptions, including crypt dedifferentiation, perineural invasion, and therapy-resistant immune remodeling. All data are openly accessible through a FAIR-compliant interactive portal to support exploration, benchmarking, and machine learning model training. Through SAHA, we provide a foundational framework for spatial diagnostics and next-generation precision medicine grounded in a comprehensive human tissue atlas, enabling the development of context-aware models that simulate tissue behavior, decode complex pathologies, and accelerate therapeutic innovation at unprecedented scale.

systems biology↗

bioRxiv2022

Assessing Mouse Kidney Parvovirus' Ability to Confound Research by Examining its Effects on Renally Excreted Chemotherapeutics and its Impact on Pathologic Endpoints in the Adenine Model of Chronic Kidney Disease

Mouse kidney parvovirus (MKPV) causes inclusion body nephropathy in severely immunocompromised mice and renal interstitial inflammation in immunocompetent mice. The purpose of this 2-part study was to determine the impact that MKPV may have on preclinical models as it relates to the pharmacokinetics of chemotherapeutics as well as its impact on the adenine diet model of chronic kidney disease. To assess the impact of MKPV on pharmacokinetics of 2 renally excreted chemotherapeutics commonly used in preclinical oncology studies, methotrexate and lenalidomide, blood and urine drug concentrations were measured in MKPV-infected or uninfected immunodeficient NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) and immunocompetent C57BL/6NCrl (B6) female mice. Differences in plasma pharmacokinetics were observed for methotrexate, but not for lenalidomide. Differences were most profound between uninfected NSG and B6 mice. The area under the curve (AUC) of methotrexate was 1.5-fold higher in uninfected NSG mice compared to infected NSG mice, 1.9-fold higher in infected B6 mice compared to uninfected B6 mice, and 4.3-fold higher in uninfected NSG mice compared to uninfected B6 mice. Renal clearance of both drugs was not impacted by MKPV infection but was generally lower in NSG mice. To assess the impact of MKPV on the adenine diet model of chronic kidney disease, MKPV-infected and uninfected B6 female mice were fed a 0.2% adenine diet and clinical and histopathologic features of disease were assessed over 8 weeks. Infection with MKPV did not have a significant impact on serum biomarkers of renal function such as BUN, creatinine, and SDMA; urine chemistry; or hemogram. However, infection did impact select histologic outcomes. MKPV-infected mice had significantly more foci of interstitial lymphoplasmacytic infiltrates than uninfected mice after 4 and 8 weeks of diet consumption, and significantly less interstitial fibrosis at week 8. Macrophage infiltrates and renal tubular injury, assessed using various immunohistochemical stains, were similar between groups. Together, these findings indicate that MKPV infection had minimal impact on the renal excretion of 2 chemotherapeutics and serum biomarkers of renal function. However, infection significantly impacted select histologic features of renal disease in the adenine diet model. While MKPV-free mice should be used in biomedical research, it is of the utmost importance in studies evaluating renal histology as an experimental outcome.

pathology↗

bioRxiv2022

Reemergence of the Murine Bacterial Pathogen Chlamydia muridarum in Laboratory Mouse Colonies

Chlamydia muridarum (Cm) was detected in mice from 2 colonies with lymphoplasmacytic pulmonary infiltrates using PCR and immunohistochemistry. This discovery was unexpected as Cm infection had not been reported in laboratory mice since the 1940s. A Cm specific PCR assay was developed and testing implemented for resident colonies from 8 vivaria from 3 academic institutions, 58 incoming mouse shipments from 39 academic institutions, and mice received from 55 commercial breeding colonies (4 vendors). To estimate Cms global prevalence in laboratory colonies, a database containing 11,387 metagenomic fecal microbiota samples from 120 institutions and a cohort of 900 diagnostic samples from 96 institutions were examined. Results indicate significant prevalence amongst academic institutions with Cm detected in 62.9% of soiled bedding sentinels from 3 institutions; 32.7% of incoming mouse shipments from 39 academic institutions; 14.2% of 120 institutions submitting microbiota samples; and 16.2% of the diagnostic sample cohort. All samples from commercial breeding colonies were negative. Additionally, naive NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice exposed to Cm shedding mice and their soiled bedding developed clinical disease 21 to 28 days following exposure. These mice had a moderate-to-severe histiocytic and neutrophilic bronchointerstitial pneumonia with respiratory epithelium demonstrating inclusions, chlamydial major outer membrane protein immunostaining, and hybridization with a Cm reference sequence (GenBank accession no. U68436). Cm was isolated on HeLa 229 cells from lungs, cecum, and feces of a Cm infected NSG mouse. The considerable prevalence of Cm is likely attributed to widespread global interinstitutional distribution of unique mouse strains and failure to recognize that some of these mice were from enzootically infected colonies. Given that experimental Cm colonization of mice results in a robust immune response and, on occasion, pathology, natural infection may confound experimental results. Therefore, Cm should be excluded and eradicated from endemically infected laboratory mouse colonies.

microbiology↗

bioRxiv2021

Caveolin-1 temporal modulation enhances trastuzumab and trastuzumab-drug conjugate efficacy in heterogeneous gastric cancer

Resistance mechanisms and heterogeneity in HER2-positive gastric cancers (GC) limit trastuzumab benefit in 32% of patients, and other targeted therapies have failed in clinical trials. Using genomic data from patient tissue, patient-derived xenografts (PDXs), partially humanized biological models, and HER2-targeted imaging we identified caveolin-1 (CAV1) as a complementary biomarker in GC selection for trastuzumab therapy. In retrospective analyses of samples from patients enrolled on trastuzumab trials, the CAV1-high profile was associated with low membrane HER2 density and reduced patient survival. We found a negative correlation between CAV1 tumoral protein levels - a major protein of cholesterol-rich membrane domains - and trastuzumab-drug conjugate TDM1 tumor uptake. Finally, CAV1 depletion using knockdown or pharmacologic approaches was shown to increase HER2-directed immunoPET uptake and TDM1 efficacy in GC with incomplete HER2 membranous reactivity. In support of these findings, background statin use in patients is associated with enhanced antibody efficacy. Together, this work provides mechanistic justification and clinical evidence that require prospective investigation of HER2-targeted therapies combined with statins to delay drug resistance in GC. SIGNIFICANCEThis study identifies how CAV1 protein expression and statin use relate to GC response in HER2-targeted imaging and therapeutic approaches. In addition, to support the synergy of CAV1 depletion with TDM1 observed in mouse models, we demonstrate that statin users had better clinical responses to antibody-based therapies in HER2+ GC.

cancer biology↗

bioRxiv2021

Radiation Exposure of the Base of the Heart Accelerates Coronary Atherosclerosis

Clinical studies have identified cardiac exposure as an independent predictor for cardiovascular mortality in patients treated with radiation therapy (RT) for thoracic malignancies. Although the mechanisms are not completely understood, the available evidence indicate that direct injury to the coronary arteries endothelium is implicated. In these studies we tested the hypothesis that different areas of the heart are more sensitive to the effects of RT on the formation of atherosclerotic plaque in apolipoprotein E deficient (ApoE-/-) mice, a well validated model of atherosclerosis. MethodsApoE-/- mice on a high fat diet (HFD) received 16Gy cardiac irradiation targeted to the whole or partial (apical or basal) region of the heart at 9 weeks or 16 weeks of age. Atherosclerotic lesions and inflammatory changes in the hearts as compared to control unirradiated mice were assessed eight weeks following radiation. ResultsAfter either basal or whole heart RT at 9 weeks of age the number of subendocardial atherosclerotic lesions at the heart base was higher as compared to unirradiated mice. Irradiation of the apex did not increase the number of subendocardial atherosclerotic lesions in any region. After basal RT at 16 weeks of age the number of coronary and subendocardial atherosclerotic lesions was higher as compared to controls. Neither apical or whole heart RT had an impact on the development or acceleration of lesions in the basal region of the hearts of 16 week old mice, thus demonstrating the adverse impact of basal irradiation. Infiltration of inflammatory cells (CD45+ and CD3+) and enhanced expression of endothelial adhesion molecules (CD31), were differentially and locally regulated based upon the site of irradiation. In support of a role of eicosanoid mediators for base or whole heart atherogenic irradiation effects, apex irradiation eicosanoid mediators are not clearly atherogenic, in contrast to eicosanoid mediators detected in serum after base heart irradiation. These results indicate that the base of the heart is significantly more prone to the development of atherosclerotic lesions in the coronary arteries post-RT. ConclusionOur results indicate that the base of the heart is more susuceptible to development of RT-induced atherosclerotic lesions and therefore avoidance from RT direct exposure to this area may reduce the risk for atherosclerotic disease in patients undergoing RT.

cancer biology↗

bioRxiv2021

Chaphamaparvovirus Antigen and Nucleic Acids are not Detected in Kidney Tissues from Cats with Chronic Renal Disease or Immunosuppressive Diseases

Mouse Kidney Parvovirus (MKPV) was recently recognized as the cause of murine inclusion body nephropathy, a disease reported for over 40 years in laboratory mice. Immunodeficient mice are persistently infected with MKPV, leading to chronic renal disease, morbidity and mortality whereas immunocompetent mice seroconvert with mild renal pathology. Given the high incidence of MKPV infection in wild mice in the New York City area, the first goal of this study was to evaluate the possibility of MKPV involvement in feline chronic kidney disease (CKD) from the same geographic region. As MKPV and related parvoviruses recently described in other animal species appear to have a tropism for kidney tissue, the second goal was to investigate the possible role of a virus of this group, other than MKPV, in the development of feline CKD, Presence of MKPV and related viruses was investigated in feline renal samples using PCR, RNA in situ hybridization (ISH) and immunohistochemistry (IHC). Cats were divided into three groups: normal (N=25), CKD (N=25) and immune suppressed (N=25). None of the kidney tissues from any of the 75 cats revealed the presence of MKPV DNA, RNA or antigen expression. Nor was "fechavirus" detected using PCR in renal tissue from cats with chronic kidney disease. We conclude that MKPV is an unlikely cause or contributor to feline CKD.

pathology↗

bioRxiv2019

MKPV (aka MuCPV) and related chapparvoviruses are nephro-tropic and encode novel accessory proteins p15 and NS2

Mouse kidney parvovirus (MKPV) is a member of the provisional Chapparvovirus genus that causes renal disease in immune-compromised mice, with a disease course reminiscent of polyomavirus-associated nephropathy in immune-suppressed kidney transplant patients. Here we map four MKPV transcripts, created by alternative splicing, to a common transcription initiation region, and use mass spectrometry to identify \"p10\" and \"p15\" as novel chapparvovirus accessory proteins produced in MKPV-infected kidneys. p15 and a splicing-dependent putative accessory protein NS2 are conserved in all near-complete tetrapod chapparvovirus genomes currently available (from mammals, birds and a reptile). In contrast, p10 may be encoded only by viruses with >60% amino acid identity to MKPV. We show that MKPV is kidney-tropic and that the bat chapparvovirus DrPV-1 and a non-human primate chapparvovirus, CKPV, are also found in the kidneys of their hosts. We propose, therefore, that chapparvoviruses with >60% VP1 amino acid identity to MKPV be classified into a genus dubbed Nephroparvovirus, which is consistent with nomenclature for the genus Erythroparvovirus.

microbiology↗