Research Spotlight

Gupta, S., Wang, L., Slifker, M.J., Cai, K.Q., Maclean, K.N., Wasek, B., Bottiglieri, T. and Kruger, W.D. (2021). “Analysis of differential neonatal lethality in cystathionine β-synthase deficient mouse models using metabolic profiling.” Faseb j 35(6): e21629.

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Cystathionine beta-synthase (CBS) is a key enzyme of the trans-sulfuration pathway that converts homocysteine to cystathionine. Loss of CBS activity due to mutation results in CBS deficiency, an inborn error of metabolism characterized by extreme elevation of plasma total homocysteine (tHcy). C57BL6 mice containing either a homozygous null mutation in the cystathionine β-synthase (Cbs(-/-) ) gene or an inactive human CBS protein (Tg-G307S Cbs(-/-) ) are born in mendelian numbers, but the vast majority die between 18 and 21 days of age due to liver failure. However, adult Cbs null mice that express a hypomorphic allele of human CBS as a transgene (Tg-I278T Cbs(-/-) ) show almost no neonatal lethality despite having serum tHcy levels similar to mice with no CBS activity. Here, we characterize liver and serum metabolites in neonatal Cbs(+/-) , Tg-G307S Cbs(-/-) , and Tg-I278T Cbs(-/-) mice at 6, 10, and 17 days of age to understand this difference. In serum, we observe similar elevations in tHcy in both Tg-G307S Cbs(-/-) and Tg-I278T Cbs(-/-) compared to control animals, but methionine is much more severely elevated in Tg-G307S Cbs(-/-) mice. Large scale metabolomic analysis of liver tissue confirms that both methionine and methionine-sulfoxide are significantly more elevated in Tg-G307S Cbs(-/-) animals, along with significant differences in several other metabolites including hexoses, amino acids, other amines, lipids, and carboxylic acids. Our data are consistent with a model that the neonatal lethality observed in CBS-null mice is driven by excess methionine resulting in increased stress on a variety of related pathways including the urea cycle, TCA cycle, gluconeogenesis, and phosphatidylcholine biosynthesis.

Creary, L.E., Sacchi, N., Mazzocco, M., Morris, G.P., Montero-Martin, G., Chong, W., Brown, C.J., Dinou, A., Stavropoulos-Giokas, C., Gorodezky, C., Narayan, S., Periathiruvadi, S., Thomas, R., De Santis, D., Pepperall, J., ElGhazali, G.E., Al Yafei, Z., Askar, M., Tyagi, S., Kanga, U., Marino, S.R., Planelles, D., Chang, C.J. and Fernández-Viña, M.A. (2021). “High-resolution HLA allele and haplotype frequencies in several unrelated populations determined by next generation sequencing: 17th International HLA and Immunogenetics Workshop joint report.” Hum Immunol May 22;S0198-8859(21)00109-9. [Epub ahead of print].

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The primary goal of the unrelated population HLA diversity (UPHD) component of the 17th International HLA and Immunogenetics Workshop was to characterize HLA alleles at maximum allelic-resolution in worldwide populations and re-evaluate patterns of HLA diversity across populations. The UPHD project included HLA genotype and sequence data, generated by various next-generation sequencing methods, from 4,240 individuals collated from 12 different countries. Population data included well-defined large datasets from the USA and smaller samples from Europe, Australia, and Western Asia. Allele and haplotype frequencies varied across populations from distant geographical regions. HLA genetic diversity estimated at 2- and 4-field allelic resolution revealed that diversity at the majority of loci, particularly for European-descent populations, was lower at the 2-field resolution. Several common alleles with identical protein sequences differing only by intronic substitutions were found in distinct haplotypes, revealing a more detailed characterization of linkage between variants within the HLA region. The examination of coding and non-coding nucleotide variation revealed many examples in which almost complete biunivocal relations between common alleles at different loci were observed resulting in higher linkage disequilibrium. Our reference data of HLA profiles characterized at maximum resolution from many populations is useful for anthropological studies, unrelated donor searches, transplantation, and disease association studies.E

Cooper, J.P., Storer, B.E., Granot, N., Gyurkocza, B., Sorror, M.L., Chauncey, T.R., Shizuru, J., Franke, G.N., Maris, M.B., Boyer, M., Bruno, B., Sahebi, F., Langston, A.A., Hari, P., Agura, E.D., Lykke Petersen, S., Maziarz, R.T., Bethge, W., Asch, J., Gutman, J.A., Olesen, G., Yeager, A.M., Hübel, K., Hogan, W.J., Maloney, D.G., Mielcarek, M., Martin, P.J., Flowers, M.E.D., Georges, G.E., Woolfrey, A.E., Deeg, J.H., Scott, B.L., McDonald, G.B., Storb, R. and Sandmaier, B.M. (2021). “Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades.” Haematologica 106(6): 1599-1607.

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We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010-2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010-2017. When outcomes from 2004 +/- 2009 and 2010-2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004-2009 and P <.0001 for 2010-2017), profression-free survival (P=.002 for 2004-2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades.

Agarwala, A., Quispe, R., Goldberg, A.C. and Michos, E.D. (2021). “Bempedoic Acid for Heterozygous Familial Hypercholesterolemia: From Bench to Bedside.” Drug Des Devel Ther 15: 1955-1963.

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Bempedoic acid is a first-in-class, oral, inhibitor of cholesterol biosynthesis that is approved for use in patients with atherosclerotic cardiovascular disease (ASCVD) and for primary prevention in individuals with heterozygous familial hypercholesterolemia (HeFH) by the United States Food and Drug Administration. Pooled data from the phase III clinical trials, CLEAR Harmony and CLEAR Wisdom, have demonstrated the safety and efficacy of bempedoic acid with regard to lowering of low-density lipoprotein cholesterol (LDL-C) in patients with HeFH as an adjunct or alternative to currently existing lipid-lowering therapies. CLEAR Outcomes is a cardiovascular outcomes trial that is currently underway that will provide additional insight as to where bempedoic acid will fit into treatment regimens among the non-statin lipid-lowering therapy options. Patients who might particularly benefit from bempedoic acid are those with HeFH and those unable to take adequate doses of statins or take any statin therapy altogether who need additional LDL-C lowering. In this review, we will discuss the profile of bempedoic acid from its design, development, and its place in therapy for the management of LDL-C for the purposes of ASCVD prevention

Yi, Y., Stenberg, W., Luo, W., Feng, J.Q. and Zhao, H. (2021). “Alveolar Bone Marrow Gli1+ Stem Cells Support Implant Osseointegration.” J Dent Res: 220345211013722.

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Osseointegration is the key issue for implant success. The in vivo properties of cell populations driving the osseointegration process have remained largely unknown. In the current study, using tissue clearing-based 3-dimensional imaging and transgenic mouse model-based lineage tracing methods, we identified Gli1+ cells within alveolar bone marrow and their progeny as the cell population participating in extraction socket healing and implant osseointegration. These Gli1(+) cells are surrounding blood vessels and do not express lineage differentiation markers. After tooth extraction and delayed placement of a dental implant, Gli1(+) cells were activated into proliferation, and their descendants contributed significantly to new bone formation. Ablation of Gli1(+) cells severely compromised the healing and osseointegration processes. Blockage of canonical Wnt signaling resulted in impaired recruitment of Gli1(+) cells and compromised bone healing surrounding implants. Collectively, these findings demonstrate that Gli1(+) cells surrounding alveolar bone marrow vasculature are stem cells supporting dental implant osseointegration. Canonical Wnt signal plays critical roles in regulating Gli1(+) stem cells.