Genetics of spontaneous cervical and coronary artery dissections.

Objectives: Spontaneous cervical artery dissections (SCeAD) and coronary artery dissections (SCoAD) are major causes of neurovascular and cardiovascular morbidity in young adults. Although multiple aspects of their etiology are still unknown, most consensuses are focused on the presence of constitutional genetic aspects and environmental triggers. Since recent evidence of genetic contribution points to a possible overlap between these conditions, we aimed to describe current information on SCeAD and SCoAD genetics and their potential shared pathological aspects. Materials and methods: A narrative review is presented. Publications in English and Spanish were queried using database search. The articles were evaluated by one team member in terms of inclusion criteria. After collecting, the articles were categorized based on scientific content. Results: Given that patients with SCeAD and SCoAD rarely present connective tissue disorders, other genetic loci are probably responsible for the increased susceptibility in some individuals. The common variant rs9349379 at PHACTR1 gene is associated with predisposition to pathologies of the arterial wall, likely mediated by variations in Endothelin-1 (ET-1) levels. The risk of arterial dissection may be increased for those who carry the rs9349379(A) allele, associated with lower expression levels of ET-1; however, the local effect of this vasomotor imbalance remains unclear. Sex differences seen in SCeAD and SCoAD support a role for sex hormones that could modulate risk, tilting the delicate balance and forcing vasodilator actions to prevail over vasoconstriction due to a reduction in ET-1 expression. Conclusions: New evidence points to a common gene variation that could explain dissection in both the cervical and coronary vasculatures. To further confirm the risk conferred by the rs9349379 variant, genome wide association studies are warranted, hopefully in larger and ethnically diverse populations.

Extracellular Cysteines Are Critical to Form Functional Cx46 Hemichannels.

Connexin (Cxs) hemichannels participate in several physiological and pathological processes, but the molecular mechanisms that control their gating remain elusive. We aimed at determining the role of extracellular cysteines (Cys) in the gating and function of Cx46 hemichannels. We studied Cx46 and mutated all of its extracellular Cys to alanine (Ala) (one at a time) and studied the effects of the Cys mutations on Cx46 expression, localization, and hemichannel activity. Wild-type Cx46 and Cys mutants were expressed at comparable levels, with similar cellular localization. However, functional experiments showed that hemichannels formed by the Cys mutants did not open either in response to membrane depolarization or removal of extracellular divalent cations. Molecular-dynamics simulations showed that Cys mutants may show a possible alteration in the electrostatic potential of the hemichannel pore and an altered disposition of important residues that could contribute to the selectivity and voltage dependency in the hemichannels. Replacement of extracellular Cys resulted in "permanently closed hemichannels", which is congruent with the inhibition of the Cx46 hemichannel by lipid peroxides, through the oxidation of extracellular Cys. These results point to the modification of extracellular Cys as potential targets for the treatment of Cx46-hemichannel associated pathologies, such as cataracts and cancer, and may shed light into the gating mechanisms of other Cx hemichannels.

Cervical Artery Dissection in Postpartum Women after Cesarean and Vaginal Delivery.

BACKGROUND AND AIMS: Cervical artery dissection (CAD) is an infrequent but potentially disabling and fatal disease, accounting for up to 25 % of strokes in young adults. Pregnancy-related hormonal changes and increased hemodynamic stress on artery walls during vaginal delivery have been associated to CAD. We aim to describe a series of women presenting CAD during postpartum (PP) after cesarean and vaginal delivery. METHODS: CAD women admitted to one hospital in Santiago, Chile, between July 2018 and October 2020 were included in a prospective cohort. Demographic, clinical and imaging data were registered for the PP group. RESULTS: Sixty-seven women were diagnosed with CAD, from which 10 were PP. Seven women had cesarean section and 3 had vaginal delivery. They presented CAD related symptoms after a median of 10.5 (IQR 5-15) days from delivery. All of them had headache as initial symptom, 9 presented cervical pain and 8 had a family history of stroke. Four patients presented preeclampsia during pregnancy. Acute treatment consisted mostly in antiplatelet agents and analgesics. None of these patients had a CAD related stroke. Demographic, clinical and imaging characteristics of these women with CAD during PP are described. CONCLUSIONS: This case series underpins the importance of clinical suspicion of CAD after delivery, highlighting the fact that CAD is not limited to women with vaginal delivery, thus alternative causes beyond acute hemodynamic stress could be involved. Further research is required to determine genetic components, along with deeper knowledge of modulating factors related to CAD in this setting.

NPC1 as a Modulator of Disease Severity and Viral Entry of SARSCoV- 2.

The COVID-19 plague is hitting mankind. Several viruses, including SARS-CoV-1, MERS-CoV, EBOV, and SARS-CoV-2, use the endocytic machinery to enter the cell. Genomic variants in NPC1, which encodes for the endo-lysosomal Niemann-Pick type C1 protein, restricts the host-range of viruses in bats and susceptibility to infections in humans. Lack of NPC1 and its pharmacological suppression inhibits many viral infections including SARS-CoV-1 and Type I Feline Coronavirus Infection. Antiviral effects of NPC1-inhibiting drugs for COVID-19 treatment should be explored.

Small molecule inhibitor screening identifified HSP90 inhibitor 17-AAG as potential therapeutic agent for gallbladder cancer.

Gallbladder cancer (GBC) is a lethal cancer with poor prognosis associated with high invasiveness and poor response to chemotherapy and radiotherapy. New therapeutic approaches are urgently needed in order to improve survival and response rates of GBC patients. We screened 130 small molecule inhibitors on a panel of seven GBC cell lines and identified the HSP90 inhibitor 17-AAG as one of the most potent inhibitory drugs across the different lines. We tested the antitumor efficacy of 17-AAG and geldanamycin (GA) in vitro and in a subcutaneous preclinical tumor model NOD-SCID mice. We also evaluated the expression of HSP90 by immunohistochemistry in human GBC tumors.In vitro assays showed that 17-AAG and GA significantly reduced the expression of HSP90 target proteins, including EGFR, AKT, phospho-AKT, Cyclin B1, phospho-ERK and Cyclin D1. These molecular changes were consistent with reduced cell viability and cell migration and promotion of G2/M cell cycle arrest and apoptosis observed in our in vitro studies.In vivo, 17-AAG showed efficacy in reducing subcutaneous tumors size, exhibiting a 69.6% reduction in tumor size in the treatment group compared to control mice (p < 0.05).The HSP90 immunohistochemical staining was seen in 182/209 cases of GBC (87%) and it was strongly expressed in 70 cases (33%), moderately in 58 cases (28%), and weakly in 54 cases (26%).Our pre-clinical observations strongly suggest that the inhibition of HSP90 function by HSP90 inhibitors is a promising therapeutic strategy for gallbladder cancer that may benefit from new HSP90 inhibitors currently in development.

VEGFA polymorphisms and cardiovascular anomalies in 22q11 microdeletion syndrome: a case-control and family-based study.

Microdeletion 22q11 in humans causes velocardiofacial and DiGeorge syndromes. Most patients share a common 3Mb deletion, but the clinical manifestations are very heterogeneous. Congenital heart disease is present in 50-80% of patients and is a significant cause of morbidity and mortality. The phenotypic variability suggests the presence of modifiers. Polymorphisms in the VEGFA gene, coding for the vascular endothelial growth factor A, have been associated with non-syndromic congenital heart disease, as well as with the presence of cardiovascular anomalies in patients with microdeletion 22q11. We evaluated the association of VEGFA polymorphisms c.-2578C>A (rs699947), c.-1154G>A (rs1570360) and c.-634C>G (rs2010963) with congenital heart disease in Chilean patients with microdeletion 22q11. The study was performed using case-control and family-based association designs. We evaluated 122 patients with microdeletion 22q11 and known anatomy of the heart and great vessels, and their parents. Half the patients had congenital heart disease. We obtained no evidence of association by either method of analysis. Our results provide further evidence of the incomplete penetrance of the cardiovascular phenotype of microdeletion 22ql 1, but do not support association between VEGFA promoter polymorphisms and the presence of congenital heart disease in Chilean patients with this syndrome.

VEGFA polymorphisms and cardiovascular anomalies in 22q11 microdeletion syndrome: a case-control and family-based study

Microdeletion 22q11 in humans causes velocardiofacial and DiGeorge syndromes. Most patients share a common 3Mb deletion, but the clinical manifestations are very heterogeneous. Congenital heart disease is present in 50-80 percent of patients and is a significant cause of morbidity and mortality. The phenotypic variability suggests the presence of modifiers. Polymorphisms in the VEGFA gene, coding for the vascular endothelial growth factor A, have been associated with non-syndromic congenital heart disease, as well as with the presence of cardiovascular anomalies in patients with microdeletion 22q11. We evaluated the association of VEGFA polymorphisms c.-2578C>A (rs699947), c.-1154G>A (rs1570360) and c.-634C>G (rs2010963) with congenital heart disease in Chilean patients with microdeletion 22q11. The study was performed using case-control and family-based association designs. We evaluated 122 patients with microdeletion 22q11 and known anatomy of the heart and great vessels, and their parents. Half the patients had congenital heart disease. We obtained no evidence of association by either method of analysis. Our results provide further evidence of the incomplete penetrance of the cardiovascular phenotype of microdeletion 22ql 1, but do not support association between VEGFA promoter polymorphisms and the presence of congenital heart disease in Chilean patients with this syndrome.