Try a new search

Format these results:

Searched for:

school:SOM

Department/Unit:Cell Biology

Total Results:

14089


Transient Intermittent Hyperglycemia Accelerates Atherosclerosis by Promoting Myelopoiesis

Flynn, Michelle C; Kraakman, Michael J; Tikellis, Christos; Lee, Man Ks; Hanssen, Nordin Mj; Kammoun, Helene L; Pickering, Raelene; Dragoljevic, Dragana; Al-Sharea, Annas; Barrett, Tessa J; Hortle, Fiona; Byrne, Frances L; Olzomer, Ellen; McCarthy, Domenica A; Schalkwijk, Casper G; Forbes, Josephine M; Hoehn, Kyle; Makowski, Liza; Lancaster, Graeme I; El-Osta, Assam; Fisher, Edward A; Goldberg, Ira J; Cooper, Mark E; Nagareddy, Prabhakara R; Thomas, Merlin C; Murphy, Andrew J
Rationale: Treatment efficacy for diabetes is largely determined by assessment of HbA1c levels, which poorly reflects direct glucose variation. People with pre-diabetes and diabetes spend >50% of their time outside the optimal glucose range. These glucose variations, termed transient intermittent hyperglycemia (TIH) appear to be an independent risk-factor for cardiovascular disease (CVD) but the pathological basis for this association is unclear. Objective: To determine whether TIH per se promotes myelopoiesis to produce more monocytes and consequently adversely affects atherosclerosis. Methods and Results: To create a mouse model of TIH we administered 4 bolus doses of glucose at 2hr intervals intraperitoneally once to wild-type (WT) or once weekly to atherosclerotic prone mice. TIH accelerated atherogenesis without an increase in plasma cholesterol, seen in traditional models of diabetes. TIH promoted myelopoiesis in the bone marrow, resulting in increased circulating monocytes, particularly the inflammatory Ly6-Chi subset, and neutrophils. Hematopoietic-restricted deletion of S100a9, S100a8 or its cognate receptor Rage, prevented monocytosis. Mechanistically, glucose uptake via GLUT-1 and enhanced glycolysis in neutrophils promoted the production of S100A8/A9. Myeloid-restricted deletion of Slc2a1 (GLUT-1) or pharmacological inhibition of S100A8/A9 reduced TIH-induced myelopoiesis and atherosclerosis. Conclusions: Together, these data provide a mechanism as to how TIH, prevalent in people with impaired glucose metabolism, contributes to CVD. These findings provide a rationale for continual glucose control in these patients and may also suggest that strategies aimed at targeting the S100A8/A9-RAGE axis could represent a viable approach to protect the vulnerable blood vessels in diabetes.
PMID: 32564710
ISSN: 1524-4571
CID: 4514372

Collectively stabilizing and orienting posterior migratory forces disperses cell clusters in vivo

Lin, B; Luo, J; Lehmann, R
Individual cells detach from cohesive ensembles during development and can inappropriately separate in disease. Although much is known about how cells separate from epithelia, it remains unclear how cells disperse from clusters lacking apical-basal polarity, a hallmark of advanced epithelial cancers. Here, using live imaging of the developmental migration program of Drosophila primordial germ cells (PGCs), we show that cluster dispersal is accomplished by stabilizing and orienting migratory forces. PGCs utilize a G protein coupled receptor (GPCR), Tre1, to guide front-back migratory polarity radially from the cluster toward the endoderm. Posteriorly positioned myosin-dependent contractile forces pull on cell-cell contacts until cells release. Tre1 mutant cells migrate randomly with transient enrichment of the force machinery but fail to separate, indicating a temporal contractile force threshold for detachment. E-cadherin is retained on the cell surface during cell separation and augmenting cell-cell adhesion does not impede detachment. Notably, coordinated migration improves cluster dispersal efficiency by stabilizing cell-cell interfaces and facilitating symmetric pulling. We demonstrate that guidance of inherent migratory forces is sufficient to disperse cell clusters under physiological settings and present a paradigm for how such events could occur across development and disease.
PMCID:7479147
PMID: 32901019
ISSN: 2041-1723
CID: 4614672

Protein crowding in the inner mitochondrial membrane

Schlame, Michael
The inner membrane of mitochondria is known for its low lipid-to-protein ratio. Calculations based on the size and the concentration of the principal membrane components, suggest about half of the hydrophobic volume of the membrane is occupied by proteins. Such high degree of crowding is expected to strain the hydrophobic coupling between proteins and lipids unless stabilizing mechanisms are in place. Both protein supercomplexes and cardiolipin are likely to be critical for the integrity of the inner mitochondrial membrane because they reduce the energy penalty of crowding.
PMID: 32916174
ISSN: 1879-2650
CID: 4589672

Macrophage Subpopulation Dynamics Shift following Intravenous Infusion of Mesenchymal Stromal Cells

Kosaric, Nina; Srifa, Waracharee; Bonham, Clark A; Kiwanuka, Harriet; Chen, Kellen; Kuehlmann, Britta A; Maan, Zeshaan N; Noishiki, Chikage; Porteus, Matthew H; Longaker, Michael T; Gurtner, Geoffrey C
Intravenous infusion of mesenchymal stromal cells (MSCs) is thought to be a viable treatment for numerous disorders. Although the intrinsic immunosuppressive ability of MSCs has been credited for this therapeutic effect, their exact impact on endogenous tissue-resident cells following delivery has not been clearly characterized. Moreover, multiple studies have reported pulmonary sequestration of MSCs upon intravenous delivery. Despite substantial efforts to improve MSC homing, it remains unclear whether MSC migration to the site of injury is necessary to achieve a therapeutic effect. Using a murine excisional wound healing model, we offer an explanation of how sequestered MSCs improve healing through their systemic impact on macrophage subpopulations. We demonstrate that infusion of MSCs leads to pulmonary entrapment followed by rapid clearance, but also significantly accelerates wound closure. Using single-cell RNA sequencing of the wound, we show that following MSC delivery, innate immune cells, particularly macrophages, exhibit distinctive transcriptional changes. We identify the appearance of a pro-angiogenic CD9+ macrophage subpopulation, whose induction is mediated by several proteins secreted by MSCs, including COL6A1, PRG4, and TGFB3. Our findings suggest that MSCs do not need to act locally to induce broad changes in the immune system and ultimately treat disease.
PMID: 32531238
ISSN: 1525-0024
CID: 4478712

Structural basis for the reaction cycle of DASS dicarboxylate transporters

Sauer, David B; Trebesch, Noah; Marden, Jennifer J; Cocco, Nicolette; Song, Jinmei; Koide, Akiko; Koide, Shohei; Tajkhorshid, Emad; Wang, Da-Neng
Citrate, α-ketoglutarate and succinate are TCA cycle intermediates that also play essential roles in metabolic signaling and cellular regulation. These di- and tricarboxylates are imported into the cell by the divalent anion sodium symporter (DASS) family of plasma membrane transporters, which contains both cotransporters and exchangers. While DASS proteins transport substrates via an elevator mechanism, to date structures are only available for a single DASS cotransporter protein in a substrate-bound, inward-facing state. We report multiple cryo-EM and X-ray structures in four different states, including three hitherto unseen states, along with molecular dynamics simulations, of both a cotransporter and an exchanger. Comparison of these outward- and inward-facing structures reveal how the transport domain translates and rotates within the framework of the scaffold domain through the transport cycle. Additionally, we propose that DASS transporters ensure substrate coupling by a charge-compensation mechanism, and by structural changes upon substrate release.
PMID: 32869741
ISSN: 2050-084x
CID: 4583042

Epigenetic CRISPR screens identify Npm1 as a therapeutic vulnerability in non-small cell lung cancer

Li, Fei; Ng, Wai-Lung; Luster, Troy A; Hu, Hai; Sviderskiy, Vladislav O; Dowling, Catríona M; Hollinshead, Kate E R; Zouitine, Paula; Zhang, Hua; Huang, Qingyuan; Ranieri, Michela; Wang, Wei; Fang, Zhaoyuan; Chen, Ting; Deng, Jiehui; Zhao, Kai; So, Hon-Cheong; Khodadadi-Jamayran, Alireza; Xu, Mousheng; Karatza, Angeliki; Pyon, Val; Li, Shuai; Pan, Yuanwang; Labbe, Kristen; Almonte, Christina; Poirier, John T; Miller, George; Possemato, Richard; Qi, Jun; Wong, Kwok-Kin
Despite advancements in treatment options, the overall cure and survival rates for non-small cell lung cancers (NSCLC) remain low. While small-molecule inhibitors of epigenetic regulators have recently emerged as promising cancer therapeutics, their application in patients with NSCLC is limited. To exploit epigenetic regulators as novel therapeutic targets in NSCLC, we performed pooled epigenome-wide CRISPR knockout screens in vitro and in vivo and identified the histone chaperone nucleophosmin 1 (NPM1) as a potential therapeutic target. Genetic ablation of Npm1 significantly attenuated tumor progression in vitro and in vivo. Furthermore, KRAS-mutant cancer cells were more addicted to NPM1 expression. Genetic ablation of Npm1 rewired the balance of metabolism in cancer cells from predominant aerobic glycolysis to oxidative phosphorylation and reduced the population of tumor-propagating cells. Overall, our results support NPM1 as a therapeutic vulnerability in NSCLC.
PMID: 32646968
ISSN: 1538-7445
CID: 4518022

Epigenetic silencing of the ubiquitin ligase subunit FBXL7 impairs c-SRC degradation and promotes epithelial-to-mesenchymal transition and metastasis

Moro, Loredana; Simoneschi, Daniele; Kurz, Emma; Arbini, Arnaldo A; Jang, Shaowen; Guaragnella, Nicoletta; Giannattasio, Sergio; Wang, Wei; Chen, Yu-An; Pires, Geoffrey; Dang, Andrew; Hernandez, Elizabeth; Kapur, Payal; Mishra, Ankita; Tsirigos, Aristotelis; Miller, George; Hsieh, Jer-Tsong; Pagano, Michele
Epigenetic plasticity is a pivotal factor that drives metastasis. Here, we show that the promoter of the gene that encodes the ubiquitin ligase subunit FBXL7 is hypermethylated in advanced prostate and pancreatic cancers, correlating with decreased FBXL7 mRNA and protein levels. Low FBXL7 mRNA levels are predictive of poor survival in patients with pancreatic and prostatic cancers. FBXL7 mediates the ubiquitylation and proteasomal degradation of active c-SRC after its phosphorylation at Ser 104. The DNA-demethylating agent decitabine recovers FBXL7 expression and limits epithelial-to-mesenchymal transition and cell invasion in a c-SRC-dependent manner. In vivo, FBXL7-depleted cancer cells form tumours with a high metastatic burden. Silencing of c-SRC or treatment with the c-SRC inhibitor dasatinib together with FBXL7 depletion prevents metastases. Furthermore, decitabine reduces metastases derived from prostate and pancreatic cancer cells in a FBXL7-dependent manner. Collectively, this research implicates FBXL7 as a metastasis-suppressor gene and suggests therapeutic strategies to counteract metastatic dissemination of pancreatic and prostatic cancer cells.
PMID: 32839549
ISSN: 1476-4679
CID: 4574162

Myocardial infarction accelerates breast cancer via innate immune reprogramming

Koelwyn, Graeme J; Newman, Alexandra A C; Afonso, Milessa S; van Solingen, Coen; Corr, Emma M; Brown, Emily J; Albers, Kathleen B; Yamaguchi, Naoko; Narke, Deven; Schlegel, Martin; Sharma, Monika; Shanley, Lianne C; Barrett, Tessa J; Rahman, Karishma; Mezzano, Valeria; Fisher, Edward A; Park, David S; Newman, Jonathan D; Quail, Daniela F; Nelson, Erik R; Caan, Bette J; Jones, Lee W; Moore, Kathryn J
Disruption of systemic homeostasis by either chronic or acute stressors, such as obesity1 or surgery2, alters cancer pathogenesis. Patients with cancer, particularly those with breast cancer, can be at increased risk of cardiovascular disease due to treatment toxicity and changes in lifestyle behaviors3-5. While elevated risk and incidence of cardiovascular events in breast cancer is well established, whether such events impact cancer pathogenesis is not known. Here we show that myocardial infarction (MI) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6Chi monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in both the circulation and tumor. In parallel, MI increased circulating Ly6Chi monocyte levels and recruitment to tumors and depletion of these cells abrogated MI-induced tumor growth. Furthermore, patients with early-stage breast cancer who experienced cardiovascular events after cancer diagnosis had increased risk of recurrence and cancer-specific death. These preclinical and clinical results demonstrate that MI induces alterations in systemic homeostasis, triggering cross-disease communication that accelerates breast cancer.
PMID: 32661390
ISSN: 1546-170x
CID: 4528032

Modification of a Validated Risk Stratification Tool to Characterize Geriatric Hip Fracture Outcomes and Optimize Care in a Post-COVID-19 World

Konda, Sanjit R; Ranson, Rachel A; Solasz, Sara J; Dedhia, Nicket; Lott, Ariana; Bird, Mackenzie L; Landes, Emma K; Aggarwal, Vinay K; Bosco, Joseph A; Furgiuele, David L; Gould, Jason; Lyon, Thomas R; McLaurin, Toni M; Tejwani, Nirmal C; Zuckerman, Joseph D; Leucht, Philipp; Ganta, Abhishek; Egol, Kenneth A
OBJECTIVES:(1) To demonstrate how a risk assessment tool modified to account for the COVID-19 virus during the current global pandemic is able to provide risk assessment for low-energy geriatric hip fracture patients. (2) To provide a treatment algorithm for care of COVID-19 positive/suspected hip fractures patients that accounts for their increased risk of morbidity and mortality. SETTING:One academic medical center including 4 Level 1 trauma centers, 1 university-based tertiary care referral hospital, and 1 orthopaedic specialty hospital. PATIENTS/PARTICIPANTS:One thousand two hundred seventy-eight patients treated for hip fractures between October 2014 and April 2020, including 136 patients treated during the COVID-19 pandemic between February 1, 2020 and April 15, 2020. INTERVENTION:The Score for Trauma Triage in the Geriatric and Middle-Aged ORIGINAL (STTGMAORIGINAL) score was modified by adding COVID-19 virus as a risk factor for mortality to create the STTGMACOVID score. Patients were stratified into quartiles to demonstrate differences in risk distribution between the scores. MAIN OUTCOME MEASUREMENTS:Inpatient and 30-day mortality, major, and minor complications. RESULTS:Both STTGMA score and COVID-19 positive/suspected status are independent predictors of inpatient mortality, confirming their use in risk assessment models for geriatric hip fracture patients. Compared with STTGMAORIGINAL, where COVID-19 patients are haphazardly distributed among the risk groups and COVID-19 inpatient and 30 days mortalities comprise 50% deaths in the minimal-risk and low-risk cohorts, the STTGMACOVID tool is able to triage 100% of COVID-19 patients and 100% of COVID-19 inpatient and 30 days mortalities into the highest risk quartile, where it was demonstrated that these patients have a 55% rate of pneumonia, a 35% rate of acute respiratory distress syndrome, a 22% rate of inpatient mortality, and a 35% rate of 30 days mortality. COVID-19 patients who are symptomatic on presentation to the emergency department and undergo surgical fixation have a 30% inpatient mortality rate compared with 12.5% for patients who are initially asymptomatic but later develop symptoms. CONCLUSION:The STTGMA tool can be modified for specific disease processes, in this case to account for the COVID-19 virus and provide a robust risk stratification tool that accounts for a heretofore unknown risk factor. COVID-19 positive/suspected status portends a poor outcome in this susceptible trauma population and should be included in risk assessment models. These patients should be considered a high risk for perioperative morbidity and mortality. Patients with COVID-19 symptoms on presentation should have surgery deferred until symptoms improve or resolve and should be reassessed for surgical treatment versus definitive nonoperative treatment with palliative care and/or hospice care. LEVEL OF EVIDENCE:Prognostic Level III. See Instructions for Authors for a complete description of Levels of Evidence.
PMID: 32815845
ISSN: 1531-2291
CID: 4574902

Amivantamab (JNJ-61186372), an EGFR-MET bispecific antibody, in combination with lazertinib, a 3rd-generation tyrosine kinase inhibitor (TKI), in advanced EGFR NSCLC [Meeting Abstract]

Cho, B C; Lee, K H; Cho, E K; Kim, D -W; Lee, J -S; Han, J -Y; Kim, S -W; Spira, A; Haura, E B; Sabari, J K; Sanborn, R E; Bauml, J M; Gomez, J E; Lorenzini, P; Infante, J R; Xie, J; Haddish-Berhane, N; Thayu, M; Knoblauch, R E; Park, K
Background: In preclinical studies, the combination of amivantamab (EGFR-MET bispecific antibody) with lazertinib demonstrates synergistic inhibition of tumor growth. We present the safety and early efficacy results of patients receiving amivantamab in combination with lazertinib in the phase 1 CHRYSALIS study (NCT02609776).
Method(s): Patients with EGFR Exon 19 deletion or L858R mutation non-small cell lung cancer (NSCLC) were enrolled in this 2-part study. To identify the recommended phase 2 combination dose (RP2CD), Part 1 enrolled patients without restriction on prior therapy to evaluate escalating dose cohorts of amivantamab (700-1050 mg, iv once weekly for 28 days; biweekly thereafter) in combination with standard monotherapy dosing of lazertinib (240 mg oral daily). The ongoing Part 2 dose expansion Cohort E is evaluating preliminary efficacy, without biomarker selection, in patients progressing on osimertinib. Response was assessed by investigator per RECIST v1.1.
Result(s): As of 17 March 2020, 71 patients received the combination: median age was 61 y (36-79), median prior lines was 1 (0-9). In Part 1, the RP2CD was the maximally assessed doses of 1050 mg (1400 mg, >=80 kg) amivantamab + 240 mg lazertinib. Interim safety profile includes rash (78%), infusion related reaction (61%), paronychia (42%), stomatitis (31%), pruritus (24%), and diarrhea (14%). Majority of treatment-related AEs were grade 1-2, with grade >=3 reported in 7%. As of 30 April 2020, in 23 Part 1 patients with measurable disease, the overall response rate (ORR) was 43.5% (95% CI, 23.2-65.5) with 10 partial responses (PRs), and 9 patients with stable disease (SD); median treatment duration was 8.2 months (0.5-10.7), with 13 patients still ongoing. In the post-osimertinib expansion Cohort E, early antitumor activity is being observed in 14/20 response-evaluable patients with 1 complete response, 7 PRs (2 pending confirmation), and 6 SD with tumor shrinkage.
Conclusion(s): Amivantamab can be combined safely with lazertinib at their respective full monotherapy doses. Encouraging preliminary activity was observed in osimertinib-relapsed disease: updated data will be presented. Clinical trial identification: NCT02609776; submitted November 18, 2015. Editorial acknowledgement: Medical writing support was provided by Tracy T. Cao, PhD (Janssen Global Services, LLC) and funded by Janssen Global Services, LLC. Legal entity responsible for the study: Janssen R&D.
Funding(s): Janssen R&D. Disclosure: B.C. Cho: Advisory/Consultancy: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Yuhan, Pfizer, Lilly, Janssen, Takeda, MSD, Ono Pharmaceuticals; Speaker Bureau/Expert testimony: Novartis; Licensing/Royalties: Champions Oncology; Shareholder/Stockholder/Stock options: Theravance, Gencurix, Bridgebio Therapeutics, Novartis, Bayer, AstraZeneca, Mogam Biotechnology Research Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, MSD; Research grant/Funding (self): Novartis, Bayer, AstraZeneca, Mogam Biotechnology Research Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, MSD. K.H. Lee: Advisory/Consultancy: Bristol-Myers Squibb, MSD, AstraZeneca; Honoraria (self): Bristol-Myers Squibb, MSD, AstraZeneca. D-W. Kim: Travel/Accommodation/Expenses: Daiichi Sankyo, Amgen; Research grant/Funding (institution): Alpha Biopharma, AstraZeneca/MedImmune, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Boehringer Ingelheim. J-Y. Han: Advisory/Consultancy: MSD Oncology, AstraZeneca, Bristol-Myers Squibb, Lilly, Novartis, Takeda, Pfizer; Honoraria (self): Roche, AstraZeneca, Bristol-Myers Squibb, MSD, Takeda; Research grant/Funding (self): Roche, Pfizer, Ono Pharmaceutical, Takeda. A. Spira: Advisory/Consultancy, AstraZeneca/MedImmune consulting applies to my institution: Array BioPharma, Incyte, Amgen, Novartis, AstraZeneca/MedImmune; Shareholder/Stockholder/Stock options: Lilly; Honoraria (self): CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen; Research grant/Funding (institution): Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, LAM Therapeutics, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol-Myers Squibb, Loxo, Arch Therap; Research grant/Funding (self): LAM Therapeutics. E.B. Haura: Advisory/Consultancy: Janssen; Travel/Accommodation/Expenses: Bristol-Myers Squibb, Roche, Janssen; Research grant/Funding (institution): Janssen, Novartis, Revolution Medicines, AstraZeneca, Genentech; Research grant/Funding (self): FORMA Therapeutics, Incyte. J.K. Sabari: Advisory/Consultancy: AstraZeneca. R.E. Sanborn: Advisory/Consultancy: Amgen, Seattle Genetics, Peregrine Pharmaceuticals, ARIAD, Genentech/Roche, AstraZeneca, Celldex, AbbVie, Takeda; Travel/Accommodation/Expenses: Five Prime Therapeutics, Janssen, AstraZeneca; Honoraria (self): AstraZeneca; Research grant/Funding (institution): Bristol-Myers Squibb, MedImmune; Research grant/Funding (self): Merck. J.M. Bauml: Advisory/Consultancy: Bristol-Myers Squibb, Merck, AstraZeneca, Genentech, Celgene, Boehringer Ingelheim, Guardant Health, Takeda, Novartis, Janssen, Ayala Pharmaceuticals, Regeneron; Research grant/Funding (institution): Merck, Carevive Systems, Novartis, Incyte, Bayer, Janssen, AstraZeneca, Takeda, Amgen. J.E. Gomez: Speaker Bureau/Expert testimony: Bristol-Myers Squibb, Atara, AstraZeneca. P. Lorenzini, J.R. Infante, J. Xie, N. Haddish-Berhane, M. Thayu, R.E. Knoblauch: Full/Part-time employment: Janssen; Shareholder/Stockholder/Stock options: Johnson & Johnson. K. Park: Advisory/Consultancy: AstraZeneca, Boehringer Ingelheim, Lilly, Hanmi, Novartis, Ono Pharmaceutical, Roche, Bristol-Myers Squibb, MSD, Blueprint Medicines, Amgen, Merck KGaA, Loxo, AbbVie, Daiichi Sankyo; Speaker Bureau/Expert testimony: Boehringer Ingelheim, AZD; Research grant/Funding (self): AstraZeneca, MSD Oncology. All other authors have declared no conflicts of interest.
Copyright
EMBASE:2007889324
ISSN: 1569-8041
CID: 4624172