Vascular thiol isomerases (VTIs) encompass proteins such as protein disulfide isomerase (PDI), endoplasmic reticulum protein 5 (ERp5), ERp46, ERp57, ERp72, thioredoxin-related transmembrane protein 1 (TMX1), and TMX4, and play pivotal functions in platelet aggregation and formation of thrombosis. Investigating vascular thiol isomerases, their substrates implicated in thrombosis, the underlying regulatory mechanisms, and the development of inhibitors targeting these enzymes represents a rapidly advancing frontier within vascular biology. In this review, we summarize the structural characteristics and functional attributes of VTIs, describe the associations between these enzymes and thrombosis, and outline the progress in developing inhibitors of VTIs for potential antithrombotic therapeutic applications.
BACKGROUND:ALK gene rearrangements as oncogenic drivers have been described in many cancers, including inflammatory myofibroblastic sarcoma (IMS). The first-generation ALK inhibitor was limited in its ability to cross the blood-brain-barrier to treat brain metastasis. Drug-resistance invariably develops over time in ALK-rearranged tumors, which leads to disease progression. The newer generations of ALK inhibitors are designed to have higher potency in ALK inhibition and improved CNS penetration. CASE REPORT:We report a rare case of pulmonary IMS with ALK-1 gene rearrangement and multiple brain metastases as initial presentation. After the primary lung tumor and the larger brain metastases were resected, control of residual CNS disease and subsequent progression and CNS spread was achieved with favorable clinical response by all three generations of ALK inhibitors. CONCLUSIONS:ALK inhibitors may be an effective therapy for this rare and unusual form of ALK-1-rearranged cancer, even in the presence of multifocal CNS metastases with leptomeningeal involvement.
Abstract Current oral anticoagulants prescribed for the prevention of thrombosis suffer from severe hemorrhagic problems. Coagulation factor XIa (FXIa) has been confirmed as a safer antithrombotic target as intervention with FXIa causes lower hemorrhagic risks. In this study, by a high-throughput virtual screening, we identified Montelukast (MK), an oral antiasthmatic drug, as a potent and specific FXIa inhibitor (IC 50 = 0.17 µM). Compared with the two mostly prescribed anticoagulants (Warfarin and Apixaban), MK demonstrated comparable or even higher antithrombotic effects in three independent animal models. More importantly, in contrast to the severe hemorrhage caused by Warfarin or Apixaban, MK did not measurably increase blood loss in vivo . In addition, MK did not affect the hemostatic function in plasma from healthy individuals. In contrast, MK suppressed clot formation in clinical hypercoagulable plasma samples. This study provides a lead compound of anticoagulants targeting FXIa, and suggests the exploratory clinical researches on antithrombotic therapies using MK.
Abstract Progressive multifocal leukoencephalopathy ( PML ) is a rare, yet typically fatal complication of allogeneic stem cell transplantation. It is caused by reactivation of the John Cunningham ( JC ) virus in an immunocompromised host. This report describes an unfortunate case of PML in a recipient of an allogeneic stem cell transplant for acute myelogenous leukemia. The JC virus was undetectable in the patient's cerebrospinal fluid by polymerase chain reaction ( PCR ); however, a positive diagnosis was made after a brain biopsy. This and other published cases demonstrate that recipients of allogeneic stem cells can develop PML . Moreover, early diagnosis of the disease is often difficult and, as demonstrated in this case, screening with PCR does not appear to have strong diagnostic significance. With no effective treatment presently available, restoration of immune function is the only intervention that can affect prognosis. Further prospective studies are needed to understand the pathophysiology and treatment of this disease.
To investigate whether albumin can be substituted by mannitolum in cirrhotic patients with tense ascites treated by paracentesis.Sixty-eight patients admitted to this therapeutic procedure were randomly assigned to receive intravenous albumin (36 patients) and mannitolum (32 patients) infusion. In repeated large-volume paracentesis (3-6 L/day), intravenous albumin 20 g or intravenous 20% mannitolum 250 ml were added.In 24 and 48 hours after paracentesis the mean value of electrolytes, liver and renal functions and various indicators of systemic circulation either in Group 1 or in Group 2 cases were found without changes (P > 0.05). As compared with that before paracentesis, the diameter of spleen vein was increased significantly (P < 0.05). The complications occurring after paracentesis were similar in both groups.It was suggested that paracentesis with intravenous infusion of mannitolum is an effective and safe method in treating cirrhotic patients with tense ascites.
Introduction Contrast-induced acute nephropathy (CIN) in patients undergoing percutaneous coronary intervention (PCI) in the setting of acute coronary syndromes (ACS) is associated with adverse outcomes, including longer hospitalization and short and long-term mortality. Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are inflammatory markers that have been validated separately in prior studies as a predictor of CIN in patients with ACS who undergo a left heart catheterization. Our study aims to further investigate the role of NLR and PLR together as markers for predicting CIN in patients with ACS. Methods A retrospective chart review was performed on a total of 1,577 patients aged 18 - 90 who presented with ACS and underwent PCI between January 2011 to December 2015 at the Florida Hospital Orlando. Cut-off values used for a high PLR and NLR were PLR > 128 and NLR > 2.6. CIN was defined as an increased serum creatinine level by ≥ 0.5 mg/dL, or ≥ 25%, over the baseline value within 72 hours after contrast agent administration. Patients with end-stage renal disease (ESRD) were excluded. Results Of the 1,577 patients included in the study, 213 (13.51%) patients had CIN. On multivariate logistic regression analysis, high NLR showed an independent association with an elevated risk of CIN (OR 2.03, 95% CI: 1.403 - 3.176, P < 0.001). High PLR did not correlate with CIN (OR 0.831, 95% CI: 0.569 - 1.214, P = 0.339). Conclusion Elevated NLR is an independent predictor of CIN in patients with acute myocardial infarction (AMI) and may be used to improve on current risk prediction models.
Benign metastasizing leiomyoma is a very uncommon clinicopathologic entity with unknown molecular pathogenesis. We present a case of a 40-year-old woman who has a history of surgical resection of a large uterine leiomyoma and then subsequently presented with benign metastasizing leiomyomas to her lungs. Due to her tumor being estrogen receptor (ER) positive and progesterone receptor (PR) positive, she was empirically treated with anastrozole with sustained clinical benefit. Molecular studies with Foundation One testing showed low mutational burden and mutational variants in five known cancer genes. Our findings have important clinical and pathogenetic implication for metastasizing uterine leiomyoma.
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