Science translational medicine
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Protein replacement therapies for rare monogenic diseases have a higher probability of regulatory approval compared with biologics, small molecules, and grant-funded orphan drugs.
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Shock, sepsis, and multiorgan failure are associated with inflammation, morbidity, and high mortality. The underlying pathophysiological mechanism is unknown, but evidence suggests that pancreatic enzymes in the intestinal lumen autodigest the intestine and generate systemic inflammation. Blocking these enzymes in the intestine reduces inflammation and multiorgan dysfunction. ⋯ Animals treated with protease inhibitors also survived in larger numbers than untreated controls over a period of 12 weeks. Surviving animals recovered completely and returned to normal weight within 14 days after shock. The results suggest that the active and concentrated digestive enzymes in the lumen of the intestine play a central role in shock and multiorgan failure, which can be treated with protease inhibitors that are currently available for use in the clinic.
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Comment Letter
Comment on "chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model".
In a case study, the authors report an increase in phosphorylated neurofilament heavy chain, a marker of neuroaxonal damage, in the plasma of a blast-exposed patient immediately after injury. They suggest that this phosphoprotein may be a useful body fluid indicator of acute blast traumatic brain injury.
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Comment Letter
Comment on "chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model".
In their recent paper, Goldstein et al. show murine brain tau neuropathology after explosive blast with head rotation but do not present additional evidence that would delineate whether this neuropathology was principally caused by blast exposure alone or by blast exposure plus head rotational injury.
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Pulmonary lymphangioleiomyomatosis (LAM) is a rare genetic disease characterized by neoplastic growth of atypical smooth muscle-like LAM cells, destruction of lung parenchyma, obstruction of lymphatics, and formation of lung cysts, leading to spontaneous pneumothoraces (lung rupture and collapse) and progressive loss of pulmonary function. The disease is caused by mutational inactivation of the tumor suppressor gene tuberous sclerosis complex 1 (TSC1) or TSC2. By injecting TSC2-null cells into nude mice, we have developed a mouse model of LAM that is characterized by multiple random TSC2-null lung lesions, vascular endothelial growth factor-D expression, lymphangiogenesis, destruction of lung parenchyma, and decreased survival, similar to human LAM. ⋯ Treatment with simvastatin markedly inhibited MMP-2, MMP-3, and MMP-9 levels in lung and prevented alveolar destruction. The combination of rapamycin and simvastatin prevented both growth of TSC2-null lesions and lung destruction by inhibiting MMP-2, MMP-3, and MMP-9. Our findings demonstrate a mechanistic link between loss of TSC2 and alveolar destruction and suggest that treatment with rapamycin and simvastatin together could benefit patients with LAM by targeting cells with TSC2 dysfunction and preventing airspace enlargement.