Prostate-specific membrane antigen (PSMA)-mediated laminin proteolysis generates a pro-angiogenic peptide

Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase expressed in a number of tissues. PSMA participates in various biological functions depending on the substrate available in the particular tissue; in the brain, PSMA cleaves the abundant neuropeptide N-acetyl-aspartyl-glutamate to regulate release of key neurotransmitters, while intestinal PSMA cleaves polyglutamated peptides to supply dietary folate. PSMA expression is also progressively upregulated in prostate cancer where it correlates with tumor progression as well as in tumor vasculature, where it regulates angiogenesis. The previous research determined that PSMA cleavage of small peptides generated via matrix metalloprotease-mediated proteolysis of the extracellular matrix protein laminin potently activated endothelial cells, integrin signaling and angiogenesis, although the specific peptide substrates were not identified. Herein, using enzymatic analyses and LC/MS, we unequivocally demonstrate that several laminin-derived peptides containing carboxy-terminal glutamate moieties (LQE, IEE, LNE) are bona fide substrates for PSMA. Subsequently, the peptide products were tested for their effects on angiogenesis in various models. We report that LQ, the dipeptide product of PSMA cleavage of LQE, efficiently activates endothelial cells in vitro and enhances angiogenesis in vivo. Importantly, LQE is not cleaved by an inactive PSMA enzyme containing an active site mutation (E424S). Endothelial cell activation by LQ was dependent on integrin beta-1-induced activation of focal adhesion kinase. These results characterize a novel PSMA substrate, provide a functional rationale for the upregulation of PSMA in cancer cells and tumor vasculature and suggest that inhibition of PSMA could lead to the development of new angiogenic therapies.     

Electrocardiographic prediction of the site of lesion in the anterior descending artery in acute myocardial infarction

INTRODUCTION AND OBJECTIVES: The goal of this study was to analyze the value of electrocardiography in predicting the site of the lesion in the left anterior descending coronary artery, in relation to the first septal and the first diagonal branches, in patients with acute anterior myocardial infarction. METHOD: Ninety consecutive patients who were admitted to the coronary unit with acute anterior myocardial infarction from July 1998 to May 2000 were studied retrospectively. The electrocardiographic changes were analyzed and correlated with the site of the lesion in the anterior descending artery, as determined by coronary angiography. RESULTS: The most useful parameters in predicting the site of the lesion in the left anterior descending coronary artery in acute anterior myocardial infarction are: 1) For lesions proximal to the first septal branch, ST-segment elevation in aVR (p < 0.001) and the absence of Q wave in V4-V6 (p = 0.01). 2) For lesions proximal to the first diagonal branch, abnormal Q wave in aVL (p = 0.01) and ST depression in III (p = 0.05). 3) For lesions proximal to both the first septal and first diagonal branches, ST elevation in aVR (p < 0.001), abnormal Q wave in aVL (p = 0.02), and absence of Q wave in V4-V6 (p = 0.01). 4) For lesions distal to both the first septal and first diagonal branches, abnormal Q wave in V4-V6 (p = 0.001) and absence of ST depression in III (p < 0.001). CONCLUSIONS: In acute anterior myocardial infarction, electrocardiography is useful for predicting the site of the lesion in the left anterior descending coronary artery in relation to the first septal and the first diagonal branches.     

Supra and infratentorial massive strokes in previously healthy young patients with SARS-CoV-2. The role of neurosurgery

The coronavirus disease 2019 (COVID-19) has amazed by its distinct forms of presentation and severity.COVID-19 patients can develop large-scale ischemic strokes in previously healthy patients without risk factors, especially in patients who develop an acute respiratory distress syndrome (SARS-CoV-2).We hypothesize that ischemic events are usually the result of the combined process of a pro-inflammatory and pro-coagulant state plus vascular endothelial dysfunction probably potentiated by hypoxia, hemodynamic instability, and immobilization, as reported in other cases.To the best of our knowledge, we report the first case of partial obstruction of a vertebral artery in a patient with COVID-19.Decompressive surgery remains a life-saving maneuver in these patients (as in other non-COVID-19 strokes) and requires further investigation.     

Hereditary Spastic Paraplegia Type 43 (SPG43) is Caused by Mutation in C19orf12

We report here the genetic basis for a form of progressive hereditary spastic paraplegia (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous missense variant (c.187G>C; p.Ala63Pro) in C19orf12, a gene recently implicated in neurodegeneration with brain iron accumulation (NBIA). The same mutation was subsequently also found in a Brazilian family with features of NBIA, and we identified another NBIA patient with a three‐nucleotide deletion (c.197_199del; p.Gly66del). Haplotype analysis revealed that the p.Ala63Pro mutations have a common origin, but MRI scans showed no brain iron deposition in the Malian SPG43 subjects. Heterologous expression of these SPG43 and NBIA variants resulted in similar alterations in the subcellular distribution of C19orf12. The SPG43 and NBIA variants reported here as well as the most common C19orf12 missense mutation reported in NBIA patients are found within a highly conserved, extended hydrophobic domain in C19orf12, underscoring the functional importance of this domain.     

Analysis of LMNB1 Duplications in Autosomal Dominant Leukodystrophy Provides Insights into Duplication Mechanisms and Allele‐Specific Expression

Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication‐based mechanisms such fork stalling and template switching or microhomology‐mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients’ fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele‐specific LMNB1 expression levels.     

Weaning from mechanical ventilation: a cross-sectional study of reference values and the discriminative validity of aging

[Purpose] To evaluate pre-extubation variables and check the discriminative validity of age as well as its correlation with weaning failure in elderly patients. [Subjects and Methods] Two hundred thirty-nine consecutive patients (48% female) who were on mechanical ventilation and had undergone orotracheal intubation were divided into four subgroups according to their age: <59 years, 60–69 years, 70–79 years, and >80 years old. The expiratory volume (V_E), respiratory frequency (f), tidal volume (V_T), and respiratory frequency/tidal volume ratio (f/V_T) were used to examine differences in weaning parameters between the four subgroups, and age was correlated with weaning failure. [Results] The rate of weaning failure was 27.8% in patients aged >80 years and 22.1% in patients aged <60 years old. Elderly patients presented higher f/V_T and f values and lower V_T values. The areas under the receiver operating characteristic curves for f/V_T ratio were smaller than those published previously. [Conclusion] Our results indicate that aging influences weaning criteria without causing an increase in weaning failure.Key words: Weaning, Mechanical ventilation, Aging