Faculty Bibliography
Searched for:
school:SOM
Department/Unit:Cell Biology
Total Results:
14089
Treatment of Segmental Bone Defects Biology and Treatment Options
Segmental bone defects (SBD) are difficult to treat, requiring a comprehensive understanding of the bone and soft tissue injury. Defect size, fracture characteristics, and local and systemic biology all help dictate treatment options. Bone grafting with autograft or allograft, Masquelet technique, and bone transport with external or internal fixation can all be used successfully in the correct patient. When deciding on the best treatment option and addressing any complications throughout the process, it is important to always keep in mind the three principles of bone healing: sterility, stability, and biology. The goal of this review is to present the history of treatment for critical SBD, including the indications and challenges that have been addressed and current and emerging treatment options.
PMID: 35234587
ISSN: 2328-5273
CID: 5190222
Multiple eruptive dermatofibromas in an adolescent with a history of pityriasis lichenoides et varioliformis acuta [Case Report]
PMCID:8816644
PMID: 35141383
ISSN: 2352-5126
CID: 5176102
Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility
Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings.
PMID: 35210625
ISSN: 1546-1718
CID: 5172442
PKM2 is essential for bladder cancer growth and maintenance
Pyruvate kinase M2 (PKM2) has been shown to promote tumorigenesis by facilitating the Warburg effect and enhancing the activities of oncoproteins. However, this paradigm has recently been challenged by studies in which the absence of PKM2 failed to inhibit and instead accelerated tumorigenesis in mouse models. These results seem inconsistent with the fact that most human tumors overexpress PKM2. To further elucidate the role of PKM2 in tumorigenesis, we investigated the effect of PKM2 knockout in oncogenic HRAS-driven urothelial carcinoma. While PKM2 ablation in mouse urothelial cells did not affect tumor initiation, it impaired the growth and maintenance of HRAS-driven tumors. Chemical inhibition of PKM2 recapitulated these effects. Both conditions substantially reduced complex formation of PKM2 with STAT3, their nuclear translocation, and HIF1α- and VEGF-related angiogenesis. The reduction in nuclear STAT3 in the absence of PKM2 also correlated with decreased autophagy and increased apoptosis. Time-controlled, inducible PKM2 overexpression in simple urothelial hyperplasia did not trigger tumorigenesis, while overexpression of PKM2, but not PKM1, in nodular urothelial hyperplasia with angiogenesis strongly accelerated tumorigenesis. Finally, in human patients, PKM2 was overexpressed in low-grade non-muscle invasive and high-grade muscle-invasive bladder cancer. Based on these data, PKM2 is not required for tumor initiation but is essential for tumor growth and maintenance by enhancing angiogenesis and metabolic addiction. The PKM2-STAT3-HIF1α/VEGF signaling axis may play a critical role in bladder cancer and may serve as an actionable therapeutic target.
PMID: 34903602
ISSN: 1538-7445
CID: 5109682
LPGAT1 controls the stearate/palmitate ratio of phosphatidylethanolamine and phosphatidylcholine in sn-1 specific remodeling
Most mammalian phospholipids contain a saturated fatty acid at the sn-1 carbon atom and an unsaturated fatty acid at the sn-2 carbon atom of the glycerol backbone group. While the sn-2 linked chains undergo extensive remodeling by deacylation and reacylation (Lands cycle), it is not known how the composition of saturated fatty acids is controlled at the sn-1 position. Here, we demonstrate that lysophosphatidylglycerol acyltransferase 1 (LPGAT1) is an sn-1 specific acyltransferase that controls the stearate/palmitate ratio of phosphatidylethanolamine (PE) and phosphatidylcholine. Bacterially expressed murine LPGAT1 transferred saturated acyl-CoAs specifically into the sn-1 position of lysophosphatidylethanolamine (LPE) rather than lysophosphatidylglycerol and preferred stearoyl-CoA over palmitoyl-CoA as the substrate. In addition, genetic ablation of LPGAT1 in mice abolished 1-LPE:stearoyl-CoA acyltransferase activity and caused a shift from stearate to palmitate species in PE, dimethyl-PE, and phosphatidylcholine. Lysophosphatidylglycerol acyltransferase 1 KO mice were leaner and had a shorter life span than their littermate controls. Finally, we show that total lipid synthesis was reduced in isolated hepatocytes of LPGAT1 knockout mice. Thus, we conclude that LPGAT1 is an sn-1 specific LPE acyltransferase that controls the stearate/palmitate homeostasis of PE and the metabolites of the PE methylation pathway and that LPGAT1 plays a central role in the regulation of lipid biosynthesis with implications for body fat content and longevity.
PMID: 35131264
ISSN: 1083-351x
CID: 5175992
Artificial intelligence and deep learning to map immune cell types in inflamed human tissue
Biopsies of inflammatory tissue contain a complex network of interacting cells, orchestrating the immune or autoimmune response. While standard histological examination can identify relationships, it is clear that a great amount of data on each slide is not quantitated or categorized in standard microscopic examinations. To deal with the huge amount of data present in biopsy tissue in an unbiased and comprehensive way, we have developed a deep learning algorithm to identify immune cells in biopsies of inflammatory lesions. We focused on T follicular helper (Tfh) cell subsets and B cells in dermatomyositis biopsy images. We achieved strong performance on detection and classification of cells, including the rare Tfh cell subsets present in the tissue. This algorithm could be used to perform distance mapping between cell types in tissue, and could be easily adapted to other disease states.
PMID: 35131237
ISSN: 1872-7905
CID: 5175982
Emerging Concepts of Vascular Cell Clonal Expansion in Atherosclerosis
Clonal expansion is a process that can drive pathogenesis in human diseases, with atherosclerosis being a prominent example. Despite advances in understanding the etiology of atherosclerosis, clonality studies of vascular cells remain in an early stage. Recently, several paradigm-shifting preclinical studies have identified clonal expansion of progenitor cells in the vasculature in response to atherosclerosis. This review provides an overview of cell clonality in atherosclerotic progression, focusing particularly on smooth muscle cells and macrophages. We discuss key findings from the latest research that give insight into the mechanisms by which clonal expansion of vascular cells contributes to disease pathology. The further probing of these mechanisms will provide innovative directions for future progress in the understanding and therapy of atherosclerosis and its associated cardiovascular diseases.
PMID: 35109671
ISSN: 1524-4636
CID: 5153622
Gender disparities in editorial board of academic urology journals [Meeting Abstract]
Introduction & Objectives: Gender composition within surgical academic leadership, including academic medical journals, disproportionately favors men. Disparities in journal leadership may introduce bias due to the familiar nature of reviewing and accepting academic publications. Genderrepresentation among academic urological journals' editorial boards has not yet been assessed. We evaluated female representation on editorialboards of urologic journals across multiple countries.Materials & Methods: Urologic journal leadership appointees' names and position descriptions were collected (from what pool? Did you surveyevery academic urology journal in the world?). Probable gender was obtained using gender-api.com or through personal title, as available. Journaleditorial positions were aggregated into broad leadership categories. Journal characteristics were summarized by Scimago Journal quartile (3 year,algorithmic weighted citation ranking) and geographic area. Chi-square test and multivariate logistic regression analysis were performed to assessfemale gender representation (p<0.05 significant).
Result(s): A total of 105 journals were reviewed with 5,991 total members: 877 (14.6%) female, 5,112 (85.3%) male and 2 (0.03%) non-binarypersons. Female representation significantly differed by leadership position, journal ranking, and geographic region. Editors-in-chief roles had thelowest female representation (48 females, 12.1%), while non-academic (32 females, 40.5%) and administrative (4 females, 80%) positions werehighest. Female representation, by journal ranking, was highest in Q1 (417 females, 19.4%) and lowest in Q3 (133 females, 8.9%) and by region,was highest in North American (323 females, 23.0%) and lowest in Asiatic region journals (55 females, 6.6%). On multivariate logistic regressionanalysis, Q1 journals had higher odds of female representation compared to Q2 and Q3. Additionally, compared to Western Europe, North Americanjournals had 78% higher odds and Asiatic journals had 50% lower odds of female representation (Fig 1).(Figure Presented)Conclusions: Female representation in urologic journal leadership is low across all journals, although trends in their proportion were identified by journal quartile and region. Addressing this gender imbalance may improve equal gender representation in journals and likely also improve female authored publication rates
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Result(s): A total of 105 journals were reviewed with 5,991 total members: 877 (14.6%) female, 5,112 (85.3%) male and 2 (0.03%) non-binarypersons. Female representation significantly differed by leadership position, journal ranking, and geographic region. Editors-in-chief roles had thelowest female representation (48 females, 12.1%), while non-academic (32 females, 40.5%) and administrative (4 females, 80%) positions werehighest. Female representation, by journal ranking, was highest in Q1 (417 females, 19.4%) and lowest in Q3 (133 females, 8.9%) and by region,was highest in North American (323 females, 23.0%) and lowest in Asiatic region journals (55 females, 6.6%). On multivariate logistic regressionanalysis, Q1 journals had higher odds of female representation compared to Q2 and Q3. Additionally, compared to Western Europe, North Americanjournals had 78% higher odds and Asiatic journals had 50% lower odds of female representation (Fig 1).(Figure Presented)Conclusions: Female representation in urologic journal leadership is low across all journals, although trends in their proportion were identified by journal quartile and region. Addressing this gender imbalance may improve equal gender representation in journals and likely also improve female authored publication rates
Copyright
EMBASE:2016657896
ISSN: 1873-7560
CID: 5173232
In vivo multimodal imaging of hyaluronan-mediated inflammatory response in articular cartilage
OBJECTIVE:One driving factor in the progression to posttraumatic osteoarthritis (PTOA) is the perpetuation of the inflammatory response to injury into chronic inflammation. Molecular imaging offers many opportunities to complement the sensitivity of current imaging modalities with molecular specificity. The goal of this study was to develop and characterize agents to image hyaluronan (HA)-mediated inflammatory signaling. DESIGN/METHODS:We developed optical (Cy5.5-P15-1) and magnetic resonance contrast agents (Gd-DOTA-P15-1) based in a hyaluronan-binding peptide (P15-1) that has shown anti-inflammatory effects on human chondrocytes, and validated them in vitro and in vivo in two animal models of PTOA. RESULTS:In vitro studies with a near infrared (NIR) Cy5.5-P15-1 imaging agent showed a fast and stable localization of Cy5.5-P15-1 on chondrocytes, but not in synovial cells. In vivo NIR showed significantly higher retention of imaging agent in PTOA knees between 12 and 72h (n=8, Cohen's d>2 after 24h). NIR fluorescence accumulation correlated with histologic severity in cartilage and meniscus (Ï between 0.37 and 0.57, p<0.001). By using in vivo magnetic resonance imaging with a Gd-DOTA-P15-1 contrast agent in 12 rats, we detected a significant decrease of T1 on injured knees in all cartilage plates at 48h (-15%, 95%-confidence interval (CI)=[-18%,-11%] []) while no change was observed in the controls (-2%, 95%-CI=[-5%,+1%]). CONCLUSIONS:This study provides the first in vivo evidence that hyaluronan-related inflammatory response in cartilage after injury is a common finding. Beyond P15-1, we have demonstrated that molecular imaging can provide a versatile technology to investigate and phenotype PTOA pathogenesis, as well as study therapeutic interventions.
PMID: 34774790
ISSN: 1522-9653
CID: 5048842
Rear traction forces drive adherent tissue migration in vivo
During animal embryogenesis, homeostasis and disease, tissues push and pull on their surroundings to move forward. Although the force-generating machinery is known, it is unknown how tissues exert physical stresses on their substrate to generate motion in vivo. Here, we identify the force transmission machinery, the substrate and the stresses that a tissue, the zebrafish posterior lateral line primordium, generates during its migration. We find that the primordium couples actin flow through integrins to the basement membrane for forward movement. Talin- and integrin-mediated coupling is required for efficient migration, and its loss is partially compensated for by increased actin flow. Using Embryogram, an approach to measure stresses in vivo, we show that the rear of the primordium exerts higher stresses than the front, which suggests that this tissue pushes itself forward with its back. This unexpected strategy probably also underlies the motion of other tissues in animals.
PMCID:8868490
PMID: 35165417
ISSN: 1476-4679
CID: 5167392
