the-stroke-preclinical-assessment-network-multi-laboratory-model

The Stroke Preclinical Assessment Network Multi-Laboratory Model of Thromboembolic Stroke with Thrombolysis: TE-MCAo

Current translational rodent stroke models induce middle cerebral artery occlusion (MCAo) using nylon filaments, injected emboli, intraluminal thrombin, ...

University of Iowa

Pancreatic cancer has dismally low mean survival rates worldwide. Only a few chemotherapeutic agents including gemcitabine have been shown to improve the survival of pancreatic cancer patients. Biochanin A, an isoflavone, is known to exert an anticancer effect on various cancer types. In this study, we examined the anticancer properties of biochanin A on pancreatic cancer cells. The effect of biochanin A on cellular survival, apoptosis, and proliferation was analyzed using MTT, flow cytometry, and colony formation assay. The effect of biochanin A on pancreatic cancer's mitogenic signaling was determined using western blot analysis. Migration assay and zymography were used to determine biochanin A's effect on pancreatic cancer progression. Biochanin A induced dose-dependent toxicity on pancreatic cancer cells (Panc1 and AsPC-1). It reduced colony formation ability of Panc1 cells and induced dose-dependent apoptosis. Activation of Akt and MAPK was inhibited. Furthermore, the migratory and invasive potential of the cancer cells was also reduced. The results suggest that biochanin A is effective in reducing pancreatic cancer cell survival by inhibiting their proliferation and inducing apoptosis. It affects mitogenic, migratory, and invasive processes involved in cancer progression. These findings may lead to novel approaches to treat pancreatic cancer using isoflavones in combination with other therapeutic drugs.

Biochanin A reduces pancreatic cancer survival and progression.

Laboratory tests are routinely used to test bonding properties of dental adhesives. Various aging methods that simulate the oral environment are used to complement these tests for assessment of adhesive bond durability. However, most of these methods challenge hydrolytic and mechanical stability of the adhesive- enamel/dentin interface, and not the biostability of dental adhesives. To compare resin-dentin microtensile bond strength (μTBS) after a 15-day Streptococcus mutans (SM) or Streptococcus sobrinus (SS) bacterial exposure to the 6-month water storage (WS) ISO 11405 type 3 test.

Dental adhesive microtensile bond strength following a biofilm-based in vitro aging model.

The objective of the study was to compare a dental student's practical ability to detect and stage radiographic caries per International Caries Detection and Assessment System (ICDAS), following a traditional lecture and a lecture containing an interactive session using an audience response system (ARS). Associations between the order of instructions and student performance were also evaluated.

Training in radiographic caries detection and staging using an interactive tool.

Mitochondrial calcium uniporter b (MCUb) is a negative regulator of the mitochondrial calcium uniporter (MCU) and is known to limit mitochondrial calcium ion (Ca) uptake. The role of MCUb in platelet function remains unclear.

Mitochondrial calcium uniporter b deletion inhibits platelet function and reduces susceptibility to arterial thrombosis.

Does dental treatment bring health to high-risk people with recurring disease?

Respiratory tract infections (RTIs) caused by bacteria or viruses are associated with stroke severity. Recent studies have revealed an imbalance in the von Willebrand factor (VWF)-ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) axis in patients with RTIs, including coronavirus disease 2019. We examined whether this imbalance contributes to RTI-mediated stroke severity. Wild-type (WT), Vwf-/-, or Adamts13-/- mice with respective littermate controls (Vwf+/+ or Adamts13+/+) were infected intranasally with sublethal doses of Staphylococcus aureus (on days 0, 2, and 5) or mouse-adapted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; on day 0) and subjected to transient (30 or 45 minutes) cerebral ischemia followed by reperfusion. In S aureus-infected mice, infarct volumes were assessed on day 2 and functional outcomes on weeks 1 and 4 after reperfusion. In SARS-CoV-2-infected mice, infarct volumes and functional outcomes (Bederson score) were assessed on day 1 after reperfusion. We demonstrated that S aureus or SARS-CoV-2 RTI was accompanied by an imbalance in the VWF-ADAMTS13 axis and an increase in plasma levels of interleukin-6, C-X-C motif chemokine ligand 1, and monocyte chemoattractant protein-1, which was associated with larger infarcts and worse functional outcomes (P < .05 vs mock infection). S aureus- or SARS-CoV-2-infected Vwf-/- mice exhibited reduced infarcts and improved functional outcomes, whereas infected Adamts13-/- mice displayed greater stroke severity (P < .05 vs control). In the models of RTI preceding stroke, VWF contributes to stroke severity, whereas ADAMTS13 is protective.

Imbalanced VWF-ADAMTS13 axis contributes to the detrimental impact of a preceding respiratory tract infection on stroke.

Past failures in translating stroke cerebroprotection provoked calls for a more rigorous methodological approach, leading to the stroke preclinical assessment network SPAN (Stroke Preclinical Assessment Network), where uric acid (UA) treatment exceeded a prespecified efficacy boundary for the primary functional outcome. Still, successful translation to humans requires confirmation of the effect of UA across key biological variables relevant to patients with stroke.

Uric Acid Stroke Cerebroprotection Transcended Sex, Age, and Comorbidities in a Multicenter Preclinical Trial.

Patient risk assessments for caries and periodontitis are hourly activities for dentists. The present study tested a caries and periodontitis risk assessment format based on managing the person using a critical thinking emulation model including levels of patient capacity and disease management. Additionally, we explored factors in student analysis contributing to the designation of higher/lower-risk determinants for caries and periodontitis.

An Emulation Model Combining Caries and Periodontitis Risk Assessment With Student Performance Report: An Exploratory Project.

Little is known about the role of metabolic regulatory mechanisms in the pathobiology of deep vein thrombosis (DVT). Recent studies have demonstrated the involvement of the metabolic enzyme pyruvate kinase M2 (PKM2) in platelet function; however, whether platelet PKM2 contributes to DVT has not been investigated yet. Using platelet-specific PKM2-/- (PKM2Plt-KO) or wild-type (WT) mice orally administered ML265 (a small molecule that limits PKM2 dimers by stabilizing PKM2 tetramers), we found reduced thrombus burden at 48 h post-surgery in the inferior vena cava (IVC) stenosis model compared with littermate controls. This reduction was associated with lower levels of CitH3, a marker of neutrophil extracellular traps (NETs), in the harvested thrombi and improved IVC wall contraction and relaxation responses (assessed by myography). Mechanistically, thrombin-stimulated platelets from PKM2Plt-KO mice or ML265-pretreated platelets from WT mice showed reduced SNAP23 phosphorylation and diminished PF4 release (a marker of α-granule exocytosis). The releasate collected from thrombin-stimulated platelets was less effective at inducing NETosis, compared to respective controls. Utilizing ML265-pretreated human whole blood perfused over a tissue factor-coated surface at a venous shear rate, we found that the area covered by platelet-leukocyte aggregates was profoundly reduced compared to vehicle control. Consistent with murine data, human platelets pretreated with ML265 and stimulated with thrombin exhibited decreased PF4 release and generated releasates that were less potent in inducing NETosis. These findings reveal for the first time that targeting PKM2 genetically or pharmacologically reduces SNAP23-mediated α-granule exocytosis in platelets, platelet releasate-induced NETosis, and susceptibility to DVT.

Pyruvate kinase M2 promotes venous thrombosis by enhancing SNAP23-mediated platelet exocytosis and consequent NETosis.

Ehlers-Danlos syndrome (EDS) is a group of connective tissue disorders characterized by joint hypermobility, skin hyperelasticity, perivascular tissue fragility, easy bruising, and increased bleeding risk. Abnormal bleeding in EDS ranges from mild ecchymoses to life-threatening hemorrhage. Platelet function abnormalities have been reported in people with EDS, but the broad nature and extent of these defects remain poorly defined. Herein, we evaluated blood samples from people with the hypermobile, classical, classical-like, and vascular types of EDS and utilized a Col5a1+/- mouse model of classical EDS to characterize the extent of platelet dysfunction. Our findings suggest that platelet dysfunction in EDS is an outcome of reduced integrin αIIbβ3 activation resulting from decreased phosphorylation of talin-1, leading to defects in aggregation and spreading. The observed platelet dysfunction was associated with reduced expression of the platelet surface receptors GPVI and PAR1 and impaired downstream signaling. Col5a1+/- mice demonstrated increased tail bleeding time, reproduced the signaling defects observed in platelets from people with EDS, and exhibited decreased susceptibility to FeCl3-induced carotid artery thrombosis. Collectively, our data indicate that platelet dysfunction in EDS is likely contributing to hemorrhagic complications.

Article	Year
Biochanin A reduces pancreatic cancer survival and progression. Anti-cancer drugs\| PubMed ID: 24201306	2014
Dental adhesive microtensile bond strength following a biofilm-based in vitro aging model. Journal of applied oral science : revista FOB\| PubMed ID: 32609185	2020
Training in radiographic caries detection and staging using an interactive tool. European journal of dental education : official journal of the Association for Dental Education in Europe\| PubMed ID: 34939265	2022
Mitochondrial calcium uniporter b deletion inhibits platelet function and reduces susceptibility to arterial thrombosis. Journal of thrombosis and haemostasis : JTH\| PubMed ID: 37061131	2023
Does dental treatment bring health to high-risk people with recurring disease? Journal of dental education\| PubMed ID: 39473036	2025
Imbalanced VWF-ADAMTS13 axis contributes to the detrimental impact of a preceding respiratory tract infection on stroke. Blood advances\| PubMed ID: 39787593	2025
Uric Acid Stroke Cerebroprotection Transcended Sex, Age, and Comorbidities in a Multicenter Preclinical Trial. Stroke\| PubMed ID: 40091742	2025
An Emulation Model Combining Caries and Periodontitis Risk Assessment With Student Performance Report: An Exploratory Project. Clinical and experimental dental research\| PubMed ID: 40304296	2025
Pyruvate kinase M2 promotes venous thrombosis by enhancing SNAP23-mediated platelet exocytosis and consequent NETosis. Blood advances\| PubMed ID: 41118613	2025
Platelet defects in patients and mice with Ehlers-Danlos syndrome. Blood\| PubMed ID: 41284637	2025

Aditi Jain

Biography

JoVE Journal Publications

Other Publications