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Article ; Online: Potentially avoidable emergency department use by patients discharged to skilled nursing facilities.

Tian, Ye / Ayyappan, Vinay / Hemmert, Keith / Myers, Jennifer / Gitelman, Yevgeniy / Ryskina, Kira

2023 Volume 18, Issue 6, Page(s) 524–527

Abstract: One-third of patients discharged from hospitals to skilled nursing facilities (SNF) are sent back to the Emergency Department (ED) within 30 days. Little is known about those patients who are discharged from the ED directly back to SNF. We considered ... ...

Abstract	One-third of patients discharged from hospitals to skilled nursing facilities (SNF) are sent back to the Emergency Department (ED) within 30 days. Little is known about those patients who are discharged from the ED directly back to SNF. We considered these ED visits as potentially avoidable since they did not result in observation or hospitalization stay. Using a retrospective chart review of 1010 patients with ED visits within 14-days of discharge to SNF from University of Pennsylvania health system (UPHS) in 2020-2021, we identified 202 patients with potentially avoidable ED visits among medical and surgical patients. The most common reasons for these ED visits were mechanical falls (17.3%), postoperative problems (16.8%), and cardiac or pulmonary complaints (11.4%). Future interventions to decrease avoidable ED visits from SNFs should aim to provide access for SNF patients to receive timely outpatient lab and imaging services and postoperative follow-ups.
MeSH term(s)	Humans ; United States ; Patient Discharge ; Retrospective Studies ; Skilled Nursing Facilities ; Hospitalization ; Emergency Service, Hospital
Language	English
Publishing date	2023-04-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2233783-0
ISSN	1553-5606 ; 1553-5592
ISSN (online)	1553-5606
ISSN	1553-5592
DOI	10.1002/jhm.13111
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Article ; Online: Allelic correlation is a marker of trade-offs between barriers to transmission of expression variability and signal responsiveness in genetic networks.

Boe, Ryan H / Ayyappan, Vinay / Schuh, Lea / Raj, Arjun

Cell systems

2022 Volume 13, Issue 12, Page(s) 1016–1032.e6

Abstract: Genetic networks should respond to signals but prevent the transmission of spontaneous fluctuations. Limited data from mammalian cells suggest that noise transmission is uncommon, but systematic claims about noise transmission have been limited by the ... ...

Abstract	Genetic networks should respond to signals but prevent the transmission of spontaneous fluctuations. Limited data from mammalian cells suggest that noise transmission is uncommon, but systematic claims about noise transmission have been limited by the inability to directly measure it. Here, we build a mathematical framework modeling allelic correlation and noise transmission, showing that allelic correlation and noise transmission correspond across model parameters and network architectures. Limiting noise transmission comes with the trade-off of being unresponsive to signals, and within responsive regimes, there is a further trade-off between response time and basal noise transmission. Analysis of allele-specific single-cell RNA-sequencing data revealed that genes encoding upstream factors in signaling pathways and cell-type-specific factors have higher allelic correlation than downstream factors, suggesting they are more subject to regulation. Overall, our findings suggest that some noise transmission must result from signal responsiveness, but it can be minimized by trading off for a slower response. A record of this paper's transparent peer review process is included in the supplemental information.
MeSH term(s)	Animals ; Gene Regulatory Networks/genetics ; Alleles ; Signal Transduction/genetics ; Mammals
Language	English
Publishing date	2022-11-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2854138-8
ISSN	2405-4720 ; 2405-4712
ISSN (online)	2405-4720
ISSN	2405-4712
DOI	10.1016/j.cels.2022.10.008
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Article ; Online: Context-dependent roles for ubiquitous mitochondrial creatine kinase CKMT1 in breast cancer progression.

Ayyappan, Vinay / Jenkinson, Nicole M / Tressler, Caitlin M / Tan, Zheqiong / Cheng, Menglin / Shen, Xinyi Elaine / Guerrero, Alejandro / Sonkar, Kanchan / Cai, Ruoqing / Adelaja, Oluwatobi / Roy, Sujayita / Meeker, Alan / Argani, Pedram / Glunde, Kristine

Cell reports

2024 Volume 43, Issue 4, Page(s) 114121

Abstract: Metabolic reprogramming is a hallmark of cancer, enabling cancer cells to rapidly proliferate, invade, and metastasize. We show that creatine levels in metastatic breast cancer cell lines and secondary metastatic tumors are driven by the ubiquitous ... ...

Abstract	Metabolic reprogramming is a hallmark of cancer, enabling cancer cells to rapidly proliferate, invade, and metastasize. We show that creatine levels in metastatic breast cancer cell lines and secondary metastatic tumors are driven by the ubiquitous mitochondrial creatine kinase (CKMT1). We discover that, while CKMT1 is highly expressed in primary tumors and promotes cell viability, it is downregulated in metastasis. We further show that CKMT1 downregulation, as seen in breast cancer metastasis, drives up mitochondrial reactive oxygen species (ROS) levels. CKMT1 downregulation contributes to the migratory and invasive potential of cells by ROS-induced upregulation of adhesion and degradative factors, which can be reversed by antioxidant treatment. Our study thus reconciles conflicting evidence about the roles of metabolites in the creatine metabolic pathway in breast cancer progression and reveals that tight, context-dependent regulation of CKMT1 expression facilitates cell viability, cell migration, and cell invasion, which are hallmarks of metastatic spread.
MeSH term(s)	Humans ; Breast Neoplasms/pathology ; Breast Neoplasms/metabolism ; Breast Neoplasms/genetics ; Female ; Cell Movement ; Creatine Kinase, Mitochondrial Form/metabolism ; Reactive Oxygen Species/metabolism ; Mitochondria/metabolism ; Cell Line, Tumor ; Disease Progression ; Animals ; Neoplasm Invasiveness ; Mice ; Cell Survival ; Gene Expression Regulation, Neoplastic ; Neoplasm Metastasis ; Creatine Kinase
Chemical Substances	Creatine Kinase, Mitochondrial Form (EC 2.7.3.2) ; Reactive Oxygen Species ; CKMT1A protein, human (EC 2.7.3.2) ; Creatine Kinase (EC 2.7.3.2)
Language	English
Publishing date	2024-04-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2024.114121
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Article ; Online: Primary breast tumor induced extracellular matrix remodeling in premetastatic lungs.

Cai, Ruoqing / Tressler, Caitlin M / Cheng, Menglin / Sonkar, Kanchan / Tan, Zheqiong / Paidi, Santosh Kumar / Ayyappan, Vinay / Barman, Ishan / Glunde, Kristine

Scientific reports

2023 Volume 13, Issue 1, Page(s) 18566

Abstract: The premetastatic niche hypothesis proposes an active priming of the metastatic site by factors secreted from the primary tumor prior to the arrival of the first cancer cells. We investigated several extracellular matrix (ECM) structural proteins, ECM ... ...

Abstract	The premetastatic niche hypothesis proposes an active priming of the metastatic site by factors secreted from the primary tumor prior to the arrival of the first cancer cells. We investigated several extracellular matrix (ECM) structural proteins, ECM degrading enzymes, and ECM processing proteins involved in the ECM remodeling of the premetastatic niche. Our in vitro model consisted of lung fibroblasts, which were exposed to factors secreted by nonmalignant breast epithelial cells, nonmetastatic breast cancer cells, or metastatic breast cancer cells. We assessed ECM remodeling in vivo in premetastatic lungs of female mice growing orthotopic primary breast tumor xenografts, as compared to lungs of control mice without tumors. Premetastatic lungs contained significantly upregulated Collagen (Col) Col4A5, matrix metalloproteinases (MMPs) MMP9 and MMP14, and decreased levels of MMP13 and lysyl oxidase (LOX) as compared to control lungs. These in vivo findings were consistent with several of our in vitro cell culture findings, which showed elevated Col14A1, Col4A5, glypican-1 (GPC1) and decreased Col5A1 and Col15A1 for ECM structural proteins, increased MMP2, MMP3, and MMP14 for ECM degrading enzymes, and decreased LOX, LOXL2, and prolyl 4-hydroxylase alpha-1 (P4HA1) for ECM processing proteins in lung fibroblasts conditioned with metastatic breast cancer cell media as compared to control. Taken together, our data show that premetastatic priming of lungs by primary breast tumors resulted in significant ECM remodeling which could facilitate metastasis by increasing interstitial fibrillar collagens and ECM stiffness (Col14A1), disruptions of basement membranes (Col4A5), and formation of leaky blood vessels (MMP2, MMP3, MMP9, and MMP14) to promote metastasis.
MeSH term(s)	Humans ; Female ; Mice ; Animals ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; Matrix Metalloproteinase 14/metabolism ; Matrix Metalloproteinase 3/metabolism ; Lung/pathology ; Extracellular Matrix/metabolism ; Mammary Neoplasms, Animal/metabolism ; Extracellular Matrix Proteins/metabolism ; Breast Neoplasms/pathology
Chemical Substances	Matrix Metalloproteinase 2 (EC 3.4.24.24) ; Matrix Metalloproteinase 9 (EC 3.4.24.35) ; Matrix Metalloproteinase 14 (EC 3.4.24.80) ; Matrix Metalloproteinase 3 (EC 3.4.24.17) ; Extracellular Matrix Proteins
Language	English
Publishing date	2023-10-30
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-45832-7
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Article ; Online: Poly(ADP-ribose)-dependent ubiquitination and its clinical implications.

Vivelo, Christina A / Ayyappan, Vinay / Leung, Anthony K L

Biochemical pharmacology

2019 Volume 167, Page(s) 3–12

Abstract: ADP-ribosylation-the addition of one or multiple ADP-ribose units onto proteins-is a therapeutically important post-translational modification implicated in cancer, neurodegeneration, and infectious diseases. The protein modification regulates a broad ... ...

Abstract	ADP-ribosylation-the addition of one or multiple ADP-ribose units onto proteins-is a therapeutically important post-translational modification implicated in cancer, neurodegeneration, and infectious diseases. The protein modification regulates a broad range of biological processes, including DNA repair, transcription, RNA metabolism, and the structural integrity of nonmembranous structures. The polymeric form of ADP-ribose, poly(ADP-ribose), was recently identified as a signal for triggering protein degradation through the ubiquitin-proteasome system. Using informatics analyses, we found that these ubiquitinated substrates tend to be low abundance proteins, which may serve as rate-limiting factors within signaling networks or metabolic processes. In this review, we summarize the current literature on poly(ADP-ribose)-dependent ubiquitination (PARdU) regarding its biological mechanisms, substrates, and relevance to diseases.
MeSH term(s)	Animals ; DNA Repair/physiology ; Humans ; Poly Adenosine Diphosphate Ribose/chemistry ; Poly Adenosine Diphosphate Ribose/metabolism ; Protein Structure, Secondary ; Ubiquitination/physiology
Chemical Substances	Poly Adenosine Diphosphate Ribose (26656-46-2)
Language	English
Publishing date	2019-05-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2019.05.006
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Article ; Online: Primary breast tumor induced extracellular matrix remodeling in premetastatic lungs

Ruoqing Cai / Caitlin M. Tressler / Menglin Cheng / Kanchan Sonkar / Zheqiong Tan / Santosh Kumar Paidi / Vinay Ayyappan / Ishan Barman / Kristine Glunde

Scientific Reports, Vol 13, Iss 1, Pp 1-

2023 Volume 12

Abstract: Abstract The premetastatic niche hypothesis proposes an active priming of the metastatic site by factors secreted from the primary tumor prior to the arrival of the first cancer cells. We investigated several extracellular matrix (ECM) structural ... ...

Abstract	Abstract The premetastatic niche hypothesis proposes an active priming of the metastatic site by factors secreted from the primary tumor prior to the arrival of the first cancer cells. We investigated several extracellular matrix (ECM) structural proteins, ECM degrading enzymes, and ECM processing proteins involved in the ECM remodeling of the premetastatic niche. Our in vitro model consisted of lung fibroblasts, which were exposed to factors secreted by nonmalignant breast epithelial cells, nonmetastatic breast cancer cells, or metastatic breast cancer cells. We assessed ECM remodeling in vivo in premetastatic lungs of female mice growing orthotopic primary breast tumor xenografts, as compared to lungs of control mice without tumors. Premetastatic lungs contained significantly upregulated Collagen (Col) Col4A5, matrix metalloproteinases (MMPs) MMP9 and MMP14, and decreased levels of MMP13 and lysyl oxidase (LOX) as compared to control lungs. These in vivo findings were consistent with several of our in vitro cell culture findings, which showed elevated Col14A1, Col4A5, glypican-1 (GPC1) and decreased Col5A1 and Col15A1 for ECM structural proteins, increased MMP2, MMP3, and MMP14 for ECM degrading enzymes, and decreased LOX, LOXL2, and prolyl 4-hydroxylase alpha-1 (P4HA1) for ECM processing proteins in lung fibroblasts conditioned with metastatic breast cancer cell media as compared to control. Taken together, our data show that premetastatic priming of lungs by primary breast tumors resulted in significant ECM remodeling which could facilitate metastasis by increasing interstitial fibrillar collagens and ECM stiffness (Col14A1), disruptions of basement membranes (Col4A5), and formation of leaky blood vessels (MMP2, MMP3, MMP9, and MMP14) to promote metastasis.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2023-10-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A multimodal pipeline using NMR spectroscopy and MALDI-TOF mass spectrometry imaging from the same tissue sample.

Tressler, Caitlin M / Ayyappan, Vinay / Nakuchima, Sofia / Yang, Ethan / Sonkar, Kanchan / Tan, Zheqiong / Glunde, Kristine

NMR in biomedicine

2022 Volume 36, Issue 4, Page(s) e4770

Abstract: NMR spectroscopy and matrix assisted laser desorption ionization mass spectrometry imaging (MALDI MSI) are both commonly used to detect large numbers of metabolites and lipids in metabolomic and lipidomic studies. We have demonstrated a new workflow, ... ...

Abstract	NMR spectroscopy and matrix assisted laser desorption ionization mass spectrometry imaging (MALDI MSI) are both commonly used to detect large numbers of metabolites and lipids in metabolomic and lipidomic studies. We have demonstrated a new workflow, highlighting the benefits of both techniques to obtain metabolomic and lipidomic data, which has realized for the first time the combination of these two complementary and powerful technologies. NMR spectroscopy is frequently used to obtain quantitative metabolite information from cells and tissues. Lipid detection is also possible with NMR spectroscopy, with changes being visible across entire classes of molecules. Meanwhile, MALDI MSI provides relative measures of metabolite and lipid concentrations, mapping spatial information of many specific metabolite and lipid molecules across cells or tissues. We have used these two complementary techniques in combination to obtain metabolomic and lipidomic measurements from triple-negative human breast cancer cells and tumor xenograft models. We have emphasized critical experimental procedures that ensured the success of achieving NMR spectroscopy and MALDI MSI in a combined workflow from the same sample. Our data show that several phospholipid metabolite species were differentially distributed in viable and necrotic regions of breast tumor xenografts. This study emphasizes the power of combined NMR spectroscopy-MALDI imaging to advance metabolomic and lipidomic studies.
MeSH term(s)	Humans ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods ; Metabolomics ; Lipidomics ; Phospholipids
Chemical Substances	Phospholipids
Language	English
Publishing date	2022-06-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1000976-0
ISSN	1099-1492 ; 0952-3480
ISSN (online)	1099-1492
ISSN	0952-3480
DOI	10.1002/nbm.4770
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Article ; Online: Imaging tumor lactate is feasible for identifying intermediate-risk prostate cancer patients with postsurgical biochemical recurrence.

Sushentsev, Nikita / Hamm, Gregory / Richings, Jack / McLean, Mary A / Menih, Ines Horvat / Ayyappan, Vinay / Mills, Ian G / Warren, Anne Y / Gnanapragasam, Vincent J / Barry, Simon T / Goodwin, Richard J A / Gallagher, Ferdia A / Barrett, Tristan

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 49, Page(s) e2312261120

Abstract: While radical prostatectomy remains the mainstay of prostate cancer (PCa) treatment, 20 to 40% of patients develop postsurgical biochemical recurrence (BCR). A particularly challenging clinical cohort includes patients with intermediate-risk disease ... ...

Abstract	While radical prostatectomy remains the mainstay of prostate cancer (PCa) treatment, 20 to 40% of patients develop postsurgical biochemical recurrence (BCR). A particularly challenging clinical cohort includes patients with intermediate-risk disease whose risk stratification would benefit from advanced approaches that complement standard-of-care diagnostic tools. Here, we show that imaging tumor lactate using hyperpolarized
MeSH term(s)	Male ; Humans ; Prostate-Specific Antigen/analysis ; Lactic Acid ; Prospective Studies ; Prostatic Neoplasms/diagnostic imaging ; Prostatic Neoplasms/surgery ; Prostate/pathology ; Prostatectomy/methods ; Neoplasm Recurrence, Local/diagnostic imaging ; Neoplasm Recurrence, Local/pathology ; Retrospective Studies
Chemical Substances	Prostate-Specific Antigen (EC 3.4.21.77) ; Lactic Acid (33X04XA5AT)
Language	English
Publishing date	2023-11-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2312261120
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Article ; Online: Unlabeled aspirin as an activatable theranostic MRI agent for breast cancer.

Pavuluri, KowsalyaDevi / Yang, Ethan / Ayyappan, Vinay / Sonkar, Kanchan / Tan, Zheqiong / Tressler, Caitlin M / Bo, Shaowei / Bibic, Adnan / Glunde, Kristine / McMahon, Michael T

Theranostics

2022 Volume 12, Issue 4, Page(s) 1937–1951

Abstract: Rationale: ...

Abstract	Rationale:
MeSH term(s)	Animals ; Aspirin ; Breast Neoplasms/diagnostic imaging ; Breast Neoplasms/drug therapy ; Contrast Media ; Dinoprostone ; Female ; Humans ; Magnetic Resonance Imaging/methods ; Mice ; Theranostic Nanomedicine
Chemical Substances	Contrast Media ; Dinoprostone (K7Q1JQR04M) ; Aspirin (R16CO5Y76E)
Language	English
Publishing date	2022-01-24
Publishing country	Australia
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2592097-2
ISSN	1838-7640 ; 1838-7640
ISSN (online)	1838-7640
ISSN	1838-7640
DOI	10.7150/thno.53147
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Article ; Online: Identification and Staging of B-Cell Acute Lymphoblastic Leukemia Using Quantitative Phase Imaging and Machine Learning.

Ayyappan, Vinay / Chang, Alex / Zhang, Chi / Paidi, Santosh Kumar / Bordett, Rosalie / Liang, Tiffany / Barman, Ishan / Pandey, Rishikesh

ACS sensors

2020 Volume 5, Issue 10, Page(s) 3281–3289

Abstract: Identification and classification of leukemia cells in a rapid and label-free fashion is clinically challenging and thus presents a prime arena for implementing new diagnostic tools. Quantitative phase imaging, which maps optical path length delays ... ...

Abstract	Identification and classification of leukemia cells in a rapid and label-free fashion is clinically challenging and thus presents a prime arena for implementing new diagnostic tools. Quantitative phase imaging, which maps optical path length delays introduced by the specimen, has been demonstrated to discern cellular phenotypes based on differential morphological attributes. Rapid acquisition capability and the availability of label-free images with high information content have enabled researchers to use machine learning (ML) to reveal latent features. We developed a set of ML classifiers, including convolutional neural networks, to discern healthy B cells from lymphoblasts and classify stages of B cell acute lymphoblastic leukemia. Here, we show that the average dry mass and volume of normal B cells are lower than those of cancerous cells and that these morphologic parameters increase further alongside disease progression. We find that the relaxed training requirements of a ML approach are conducive to the classification of cell type, with minimal space, training time, and memory requirements. Our findings pave the way for a larger study on clinical samples of acute lymphoblastic leukemia, with the overarching goal of its broader use in hematopathology, where the prospect of objective diagnoses with minimal sample preparation remains highly desirable.
MeSH term(s)	B-Lymphocytes ; Diagnostic Imaging ; Humans ; Machine Learning ; Neural Networks, Computer ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis
Language	English
Publishing date	2020-10-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-3694
ISSN (online)	2379-3694
DOI	10.1021/acssensors.0c01811
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