- α2-Macroglobulin Is a Significant In Vivo Inhibitor of Activated Protein C and Low APC:α2M Levels Are Associated with Venous Thromboembolism. [Journal Article]
- THThromb Haemost 2018 Feb 15
- CONCLUSIONS: The APC:α2M assay reported here may be useful to help monitor the in vivo fate of APC in plasma. In addition, our results show that a low APC:α2M level is associated with increased VTE risk.
- α1-Antitrypsin Infusion for treatment of Steroid Resistant Acute Graft-versus-Host Disease. [Journal Article]
- BloodBlood 2018 Feb 02
- Corticosteroid resistance following acute GVHD (SR-aGVHD) results in high morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Current immunosuppressive therapies for SR...
Corticosteroid resistance following acute GVHD (SR-aGVHD) results in high morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Current immunosuppressive therapies for SR-aGVHD provide marginal effectiveness due to poor response or excessive toxicity, primarily from infection. Alpha-1 antitrypsin (AAT), a naturally abundant serine protease inhibitor, is capable of suppressing experimental GVHD by down-modulation of inflammation and increasing ratios of regulatory to effector T cells. In this prospective multicenter clinical study we sought to determine the safety and response rate of AAT administration in SR-aGVHD (NCT01700036). Forty patients at a median age of 59 years received intravenous AAT twice weekly for four weeks as first line treatment for SR-aGVHD. The primary endpoint was overall response rate (ORR), the proportion of SR-aGVHD in CR+PR by day 28 without addition of further immunosuppression. Treatment was well tolerated without drug related adverse events. A significant increase in serum levels of AAT was observed after treatment. The ORR and CR rate by day 28 was 65% and 35%, respectively, and included responses in all aGVHD target organs. At day 60, responses were sustained in 73% of patients without intervening immunosuppression. Infectious-mortality was 10% at 6 months and 2.5% within 30 days of last AAT infusion. Consistent with pre-clinical data, correlative samples showed an increase in ratio of activated Tregs to effector T cells after AAT treatment. These data suggest that AAT is safe, and may be potentially efficacious in treating SR-aGVHD.
- Mildly Elevated Liver Transaminase Levels: Causes and Evaluation. [Journal Article]
- AFAm Fam Physician 2017 Dec 01; 96(11):709-715
- Mild, asymptomatic elevations (less than five times the upper limit of normal) of alanine transaminase and aspartate transaminase levels are common in primary care. It is estimated that approximately...
Mild, asymptomatic elevations (less than five times the upper limit of normal) of alanine transaminase and aspartate transaminase levels are common in primary care. It is estimated that approximately 10% of the U.S. population has elevated transaminase levels. An approach based on the prevalence of diseases that cause asymptomatic transaminase elevations can help clinicians efficiently identify common and serious liver disease. The most common causes of elevated transaminase levels are nonalcoholic fatty liver disease and alcoholic liver disease. Uncommon causes include drug-induced liver injury, hepatitis B and C, and hereditary hemochromatosis. Rare causes include alpha1-antitrypsin deficiency, autoimmune hepatitis, and Wilson disease. Extrahepatic sources, such as thyroid disorders, celiac sprue, hemolysis, and muscle disorders, are also associated with mildly elevated transaminase levels. The initial evaluation should include an assessment for metabolic syndrome and insulin resistance (i.e., waist circumference, blood pressure, fasting lipid level, and fasting glucose or A1C level); a complete blood count with platelets; measurement of serum albumin, iron, total iron-binding capacity, and ferritin; and hepatitis C antibody and hepatitis B surface antigen testing. The nonalcoholic fatty liver disease fibrosis score and the alcoholic liver disease/nonalcoholic fatty liver disease index can be helpful in the evaluation of mildly elevated transaminase levels. If testing for common causes is consistent with nonalcoholic fatty liver disease and is otherwise unremarkable, a trial of lifestyle modification is appropriate. If the elevation persists, hepatic ultrasonography and further testing for uncommon causes should be considered.
- Role for Cela1 in Postnatal Lung Remodeling and AAT-deficient Emphysema. [Journal Article]
- AJAm J Respir Cell Mol Biol 2018 Feb 08
- CONCLUSIONS: Cela1 is important in physiologic and pathologic stretch-dependent remodeling processes in the postnatal lung. AAT is an important regulator of this process. Our findings provide proof-of-concept for the development of anti-Cela1 therapies to prevent and/or treat AAT-deficient emphysema.
- Association between α1-antitrypsin and bronchiectasis in patients with humoral immunodeficiency receiving gammaglobulin infusions. [Journal Article]
- AAAnn Allergy Asthma Immunol 2018; 120(2):200-206
- CONCLUSIONS: Median α1-antitrypsin levels and phenotype in subjects were associated with humoral immunodeficiency and their bronchiectasis status. Prospective studies might be necessary to determine possible benefits of augmentation therapy. This study supports the idea that what is considered a "normal or protective" α1-antitrypsin range might need to be refined for patients with humoral immunodeficiency on gammaglobulin therapy.
- Probing the folding pathway of a consensus serpin using single tryptophan mutants. [Journal Article]
- SRSci Rep 2018 Feb 01; 8(1):2121
- Conserpin is an engineered protein that represents the consensus of a sequence alignment of eukaryotic serpins: protease inhibitors typified by a metastable native state and a structurally well-conse...
Conserpin is an engineered protein that represents the consensus of a sequence alignment of eukaryotic serpins: protease inhibitors typified by a metastable native state and a structurally well-conserved scaffold. Previously, this protein has been found to adopt a native inhibitory conformation, possess an atypical reversible folding pathway and exhibit pronounced resistance to inactivation. Here we have designed a version of conserpin, cAT, with the inhibitory specificity of α1-antitrypsin, and generated single-tryptophan variants to probe its folding pathway in more detail. cAT exhibited similar thermal stability to the parental protein, an inactivation associated with oligomerisation rather a transition to the latent conformation, and a native state with pronounced kinetic stability. The tryptophan variants reveal the unfolding intermediate ensemble to consist of an intact helix H, a distorted helix F and 'breach' region structurally similar to that of a mesophilic serpin intermediate. A combination of intrinsic fluorescence, circular dichroism, and analytical gel filtration provide insight into a highly cooperative folding pathway with concerted changes in secondary and tertiary structure, which minimises the accumulation of two directly-observed aggregation-prone intermediate species. This functional conserpin variant represents a basis for further studies of the relationship between structure and stability in the serpin superfamily.
- On the folding of a structurally complex protein to its metastable active state. [Journal Article]
- PNProc Natl Acad Sci U S A 2018 Jan 17
- For successful protease inhibition, the reactive center loop (RCL) of the two-domain serine protease inhibitor, α1-antitrypsin (α1-AT), needs to remain exposed in a metastable active conformation. Th...
For successful protease inhibition, the reactive center loop (RCL) of the two-domain serine protease inhibitor, α1-antitrypsin (α1-AT), needs to remain exposed in a metastable active conformation. The α1-AT RCL is sequestered in a β-sheet in the stable latent conformation. Thus, to be functional, α1-AT must always fold to a metastable conformation while avoiding folding to a stable conformation. We explore the structural basis of this choice using folding simulations of coarse-grained structure-based models of the two α1-AT conformations. Our simulations capture the key features of folding experiments performed on both conformations. The simulations also show that the free energy barrier to fold to the latent conformation is much larger than the barrier to fold to the active conformation. An entropically stabilized on-pathway intermediate lowers the barrier for folding to the active conformation. In this intermediate, the RCL is in an exposed configuration, and only one of the two α1-AT domains is folded. In contrast, early conversion of the RCL into a β-strand increases the coupling between the two α1-AT domains in the transition state and creates a larger barrier for folding to the latent conformation. Thus, unlike what happens in several proteins, where separate regions promote folding and function, the structure of the RCL, formed early during folding, determines both the conformational and the functional fate of α1-AT. Further, the short 12-residue RCL modulates the free energy barrier and the folding cooperativity of the large 370-residue α1-AT. Finally, we suggest experiments to test the predicted folding mechanism for the latent state.
- Geographical distribution of COPD prevalence in Europe, estimated by an inverse distance weighting interpolation technique. [Journal Article]
- IJInt J Chron Obstruct Pulmon Dis 2018; 13:57-67
- Existing data on COPD prevalence are limited or totally lacking in many regions of Europe. The geographic information system inverse distance weighted (IDW) interpolation technique has proved to be a...
Existing data on COPD prevalence are limited or totally lacking in many regions of Europe. The geographic information system inverse distance weighted (IDW) interpolation technique has proved to be an effective tool in spatial distribution estimation of epidemiological variables, when real data are few and widely separated. Therefore, in order to represent cartographically the prevalence of COPD in Europe, an IDW interpolation mapping was performed. The point prevalence data provided by 62 studies from 19 countries (21 from 5 Northern European countries, 11 from 3 Western European countries, 14 from 5 Central European countries, and 16 from 6 Southern European countries) were identified using validated spirometric criteria. Despite the lack of data in many areas (including all regions of the eastern part of the continent), the IDW mapping predicted the COPD prevalence in the whole territory, even in extensive areas lacking real data. Although the quality of the data obtained from some studies may have some limitations related to different confounding factors, this methodology may be a suitable tool for obtaining epidemiological estimates that can enable us to better address this major public health problem.
- Solid pseudopapillary tumour of the pancreas: clinicopathological analysis. [Journal Article]
- AJANZ J Surg 2018 Jan 08
- CONCLUSIONS: SPT is rare and affects mostly young women. An accurate diagnosis is important as the relative indolent behaviour can be managed with surgical resection even when large in size, bringing excellent long-term outcomes.
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- Surrogate Fecal Biomarkers in Inflammatory Bowel Disease: Rivals or Complementary Tools of Fecal Calprotectin? [Journal Article]
- IBInflamm Bowel Dis 2017 Dec 19; 24(1):78-92
- CONCLUSIONS: Several fecal biomarkers have the potential to become useful tools complementing FC in IBD diagnosis and monitoring. However, wide variability in their accuracy in assessment of intestinal inflammation suggests the need for further studies.