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

 Pheochromocytoma and paraganglioma (PHEO/PGL) are rare neuroendocrine tumors which may cause potentially life-threatening complications, with about a third of cases found to harbor specific gene mutations. Thus, early diagnosis, treatment, and meticulous monitoring are of utmost importance. Because of low incidence of succinate dehydrogenase complex subunit A ()-related metastatic PHEO/PGL, currently there exists insufficient clinical information, especially with regards to its diagnostic and treatment characteristics.  Ten patients with -related metastatic PHEO/PGL were followed-up prospectively and/or retrospectively between January 2010-July 2018. They underwent biochemical tests ( = 10), I-MIBG ( = 9) scintigraphy, and multiple whole-body positron emission tomography/computed tomography (PET/CT) scans with Ga-DOTATATE ( = 10), F-FDG ( = 10), and F-FDOPA ( = 6).  Our findings suggest that these tumors can occur early and at extra-adrenal locations, behave aggressively, and have a tendency to develop metastatic disease within a short period of time. None of our patients had a family history of PHEO/PGL, making them appear sporadic. Nine out of 10 patients showed abnormal PHEO/PGL-specific biochemical markers with predominantly noradrenergic and/or dopaminergic phenotype, suggesting their utility in diagnosing and monitoring the disease. Per patient detection rates of Ga-DOTATATE ( = 10/10), F-FDG ( = 10/10), F-FDOPA ( = 5/6) PET/CT, and I-MIBG ( = 7/9) scintigraphy were 100, 100, 83.33, and 77.77%, respectively. Five out of 7 I-MIBG positive patients had minimal I-MIBG avidity or detected very few lesions compared to widespread metastatic disease on F-FDG PET/CT, implying that diagnosis and treatment with I-MIBG is not a good option. Ga-DOTATATE PET/CT was found to be superior or equal to F-FDG PET/CT in 7 out of 10 patients and hence, is recommended for evaluation and follow-up of these patients. All 7 out of 7 patients who received conventional therapies (chemotherapy, somatostatin analog therapy, radiation therapy, I-MIBG, peptide receptor radionuclide therapy) in addition to surgery showed disease progression.  In our cohort of patients, -related metastatic PHEO/PGL followed a disease-course similar to that of -related metastatic PHEO/PGL, showing highly aggressive behavior, similar imaging and biochemical phenotypes, and suboptimal response to conventional therapies. Therefore, we recommend careful surveillance of the affected patients and a search for effective therapies.

Clinical, Diagnostic, and Treatment Characteristics of -Related Metastatic Pheochromocytoma and Paraganglioma.

Targeted radionuclide therapies (TRT) using I-metaiodobenzylguanidine (I-MIBG) and peptide receptor radionuclide therapy (Lu or Y) represent several of the therapeutic options in the management of metastatic/inoperable pheochromocytoma/paraganglioma. Recently, high-specific-activity-I-MIBG therapy was approved by the FDA and both Lu-DOTATATE and I-MIBG therapy were recommended by the National Comprehensive Cancer Network guidelines for the treatment of metastatic pheochromocytoma/paraganglioma. However, a clinical dilemma often arises in the selection of TRT, especially when a patient can be treated with either type of therapy based on eligibility by MIBG and somatostatin receptor imaging. To address this problem, we assembled a group of international experts, including oncologists, endocrinologists, and nuclear medicine physicians, with substantial experience in treating neuroendocrine tumors with TRTs to develop consensus and provide expert recommendations and perspectives on how to select between these two therapeutic options for metastatic/inoperable pheochromocytoma/paraganglioma. This article aims to summarize the survival outcomes of the available TRTs; discuss personalized treatment strategies based on functional imaging scans; address practical issues, including regulatory approvals; and compare toxicities and risk factors across treatments. Furthermore, it discusses the emerging TRTs.

High-Specific-Activity-I-MIBG versus Lu-DOTATATE Targeted Radionuclide Therapy for Metastatic Pheochromocytoma and Paraganglioma.

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.

 This study explores the design of substituted tetrahydroquinoline (THQ) derivatives and their synthesis as possible inhibitors of mTOR inhibitors for targeted cancer therapy.  Inspired by the structural characteristics of known mTOR inhibitors, eight novel derivatives were synthesized, characterized using mass spectroscopy, H, and C NMR, and evaluated for anticancer activity.  Computational studies, including molecular docking and molecular dynamics (MD) simulations, highlighted the derivative's strong binding interaction and stability within the mTOR active site. Assays for in vitro cytotoxicity showed strong and specific anticancer action against cell lines of triple-negative breast cancer, lung cancer, and breast cancer while causing negligible impact on healthy cells.  Compound  emerged as the most promising candidate, displaying exceptional activity against A549 cells (IC = 0.033 µM) and inducing apoptosis in a dose-dependent manner, surpassing standard agents, like Everolimus and 5-flurouracil. Structure-activity relationship analysis revealed that incorporating trifluoromethyl and morpholine moieties significantly enhanced selectivity and potency. MD simulations further validated these findings, confirming stable protein-ligand interactions and favorable dynamics over a 100-ns simulation period. Collectively, this study underscores the therapeutic potential of THQ derivatives, particularly compound , as promising mTOR inhibitors with potential applications in lung cancer treatment.

Morpholine-Substituted Tetrahydroquinoline Derivatives as Potential mTOR Inhibitors: Synthesis, Computational Insights, and Cellular Analysis.

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.

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
Clinical, Diagnostic, and Treatment Characteristics of -Related Metastatic Pheochromocytoma and Paraganglioma. Frontiers in oncology\| PubMed ID: 30854332	2019
High-Specific-Activity-I-MIBG versus Lu-DOTATATE Targeted Radionuclide Therapy for Metastatic Pheochromocytoma and Paraganglioma. Clinical cancer research : an official journal of the American Association for Cancer Research\| PubMed ID: 33685867	2021
Imbalanced VWF-ADAMTS13 axis contributes to the detrimental impact of a preceding respiratory tract infection on stroke. Blood advances\| PubMed ID: 39787593	2025
Morpholine-Substituted Tetrahydroquinoline Derivatives as Potential mTOR Inhibitors: Synthesis, Computational Insights, and Cellular Analysis. Cancers\| PubMed ID: 40075606	2025
Uric Acid Stroke Cerebroprotection Transcended Sex, Age, and Comorbidities in a Multicenter Preclinical Trial. Stroke\| PubMed ID: 40091742	2025
Platelet defects in patients and mice with Ehlers-Danlos syndrome. Blood\| PubMed ID: 41284637	2025

Abhishek Jha

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