Publications

Publications

Gibson GE, Feldman HH, Zhang S, Flowers, SA, Luchsinger JA. Pharmacological thiamine levels as a therapeutic approach in Alzheimer’s disease. Front Med. 2022:9:1033272. doi: 10.3389/fmed.2022.1033272. Pubmed PMID: 36275801. pdf

Review of research that supports the use of thiamine in AD. This outlines the work that lead to our initial Benfotiamine trial (listed below).

McCann MS, Fernandez HR, Flowers SA, Maguire-Zeiss KA. Polychlorinated biphenyls induce oxidative stress and metabolic responses in astrocytes. NeuroToxicology. 2021 July 12;86:59-68. doi: 10.1016/j.neuro.2021.07.001. Pubmed PMID: 34265337. pdf

Analyses showing the impact of polychlorinated biphenyls on the metabolism of astrocytes using functional assays including Seahorse assays. This has implications for the importance of these compounds on neurodegenerative diseases such as Parkinson’s disease. This is work with the Maguire-Zeiss lab .

Yang FN, Bronshteyn M, Flowers SA, Dawson M, Kumar P, Rebeck GW, Turner RS, Moore DJ, Ellis RJ, Jiang X. Low CD4+ cell count nadir exacerbates the impacts of APOE ε4 on functional connectivity and memory in adults with HIV. AIDS. 2021 Apr 1;35(5):727-736. doi: 10.1097/QAD.0000000000002840. PubMed PMID: 33587445. pdf

Collaborative work with the Jiang lab looking at how APOE genotype impacts memory in HIV infected individuals, an aging population due to the success of cART. Individuals carrying an APOE4 allele had worse memory performance and reduced memory network functional connectivity. This was exacerbated in individuals with low CD4+ cell count nadir, a person’s lowest CD4+ cell count. This indicates that immunosuppression, along with APOE4 genotype, may be linked to memory disruption in HIV individuals.

Fernandez HR, Varma A, Flowers SA, Rebeck GW. Cancer Chemotherapy Related Cognitive Impairment and the Impact of the Alzheimer's Disease Risk Factor APOE. Cancers (Basel). 2020 Dec 19;12(12). doi: 10.3390/cancers12123842. Review. PubMed PMID: 33352780; PubMed Central PMCID: PMC7766535. pdf

A comprehensive review on cognitive decline associated with chemotherapy and the multifaceted way APOE4 exacerbates this decline in our increasing (thankfully) population of aging cancer survivors.

Flowers SA, Rebeck GW. APOE in the normal brain. Neurobiol Dis. 2020 Mar;136:104724. doi: 10.1016/j.nbd.2019.104724. Epub 2020 Jan 3. Review. PubMed PMID: 31911114; PubMed Central PMCID: PMC7002287. pdf

A review outlining the differences between the APOE2, APOE3 and APOE4 proteins and their impacts on the normal brain.

Flowers SA, Grant OC, Woods RJ, Rebeck GW. O-glycosylation on cerebrospinal fluid and plasma apolipoprotein E differs in the lipid-binding domain. Glycobiology. 2020 Jan 28;30(2):74-85. doi: 10.1093/glycob/cwz084. PubMed PMID: 31616924; PubMed Central PMCID: PMC7335482. pdf

An exciting, comprehensive O-glycan analysis of APOE by Dr. Flowers showing that APOE from the CSF holds different glycans (sugars) than the APOE in the blood and modeling the structure of these glycoproteins, and how they are arranged. These glycosylation differences may allow for the different binding roles APOE has in the brain compared to the periphery.

Gibson GE, Luchsinger JA, Cirio R, Chen H, Franchino-Elder J, Hirsch JA, Bettendorff L, Chen Z, Flowers SA, Gerber LM, Grandville T, Schupf N, Xu H, Stern Y, Habeck C, Jordan B, Fonzetti P. Benfotiamine and Cognitive Decline in Alzheimer's Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial. J Alzheimers Dis. 2020;78(3):989-1010. doi: 10.3233/JAD-200896. PubMed PMID: 33074237. pdf

A clinical trial Dr. Flowers has been involved in showing potential for the use of benfotiamine in the treatment of Alzheimer’s disease. Read more about the exciting work coming out of the Gibson Lab.

Flowers SA, Thomsson KA, Ali L, Huang S, Mthembu Y, Regmi SC, Holgersson J, Schmidt TA, Rolfson O, Björkman LI, Sundqvist M, Karlsson-Bengtsson A, Jay GD, Eisler T, Krawetz R, Karlsson NG. Decrease of core 2 O-glycans on synovial lubricin in osteoarthritis reduces galectin-3 mediated crosslinking. J Biol Chem. 2020 Nov 20;295(47):16023-16036. doi: 10.1074/jbc.RA120.012882. Epub 2020 Sep 14. PubMed PMID: 32928962; PubMed Central PMCID: PMC7681006. pdf

This paper shows how the glycosylation on the glycoprotein lubricin changes in osteoarthritis, the most common form of arthritis frequently afflicting the elderly. This protein is critical for healthy lubrication of the joint. It also outlines the glycosylation on the recombinant form of the protein, a potential therapeutic, created by Lubris BioPharma. This quantitative work was done using an MRM mass spectrometric method developed by Dr. Flowers for O-glycans.

Wenzel ED, Speidell A, Flowers SA, Wu C, Avdoshina V, Mocchetti I. Histone deacetylase 6 inhibition rescues axonal transport impairments and prevents the neurotoxicity of HIV-1 envelope protein gp120. Cell Death Dis. 2019 Sep 12;10(9):674. doi: 10.1038/s41419-019-1920-7. PubMed PMID: 31515470; PubMed Central PMCID: PMC6742654. pdf

Some really important and interesting work collaborating with the Mocchetti Lab which has implications for HIV associated neurocognitive disorders.

Lane CS, McManus K, Widdowson P, Flowers SA, Powell G, Anderson I, Campbell JL. Separation of Sialylated Glycan Isomers by Differential Mobility Spectrometry. Anal Chem. 2019 Aug 6;91(15):9916-9924. doi: 10.1021/acs.analchem.9b01595. Epub 2019 Jul 8. PubMed PMID: 31283185; PubMed Central PMCID: PMC6686149. pdf

Collaborative work with the mass spectrometry company Sciex showing how DMS is able to separate very similar sialylated isomers. Separating and defining the linkage of sialic acid isomers can be critical as this linkage changes the structure of the glycan impacting its function, sometimes quite dramatically.

Flowers SA, Lane CS, Karlsson NG. Deciphering Isomers with a Multiple Reaction Monitoring Method for the Complete Detectable O-Glycan Repertoire of the Candidate Therapeutic, Lubricin. Anal Chem. 2019 Aug 6;91(15):9819-9827. doi: 10.1021/acs.analchem.9b01485. Epub 2019 Jul 11. PubMed PMID: 31246420. pdf

This outlines an MRM method for all of the more than 20 different core 1 and core 2 O-glycans held by lubricin. The method is optimal for quantification but also allows easy identification of these common O-glycan structures, even differentiating isomers. By having easier methods to understand these structures and quantify differences, a broader range of scientists can analyze O-glycans and will expand our understanding of these prolific structures on protein function.

Flowers SA, Zieba A, Örnros J, Jin C, Rolfson O, Björkman LI, Eisler T, Kalamajski S, Kamali-Moghaddam M, Karlsson NG. Lubricin binds cartilage proteins, cartilage oligomeric matrix protein, fibronectin and collagen II at the cartilage surface. Sci Rep. 2017 Oct 13;7(1):13149. doi: 10.1038/s41598-017-13558-y. PubMed PMID: 29030641; PubMed Central PMCID: PMC5640667. pdf

Analysis of tissue samples identifying - using microscopy and binding assays - the interactions between lubricin and COMP, fibronectin and collagen II at the cartilage surface. This increases our understanding of how lubricin binds to cartilage creating the surface critical for joint lubrication that is lost in arthritis.

Flowers SA, Kalamajski S, Ali L, Björkman LI, Raj JR, Aspberg A, Karlsson NG, Jin C. Cartilage oligomeric matrix protein forms protein complexes with synovial lubricin via non-covalent and covalent interactions. Osteoarthritis Cartilage. 2017 Sep;25(9):1496-1504. doi: 10.1016/j.joca.2017.03.016. Epub 2017 Apr 1. PubMed PMID: 28373131. pdf

Detailed MS analyses by Dr. Flowers characterizing the binding between lubricin and COMP, including identifying the location of the disulfide bonds between the two proteins.

Flowers SA, Zhou X, Wu J, Wang Y, Makambi K, Kallakury BV, Singer MS, Rosen SD, Davidson B, Goldman R. Expression of the extracellular sulfatase SULF2 is associated with squamous cell carcinoma of the head and neck. Oncotarget. 2016 Jul 12;7(28):43177-43187. doi: 10.18632/oncotarget.9506. PubMed PMID: 27223083; PubMed Central PMCID: PMC5190016. pdf

A tissue staining study showing differences in the expression of sulfatase SULF2 in head and neck cancer.

Chaudhury NM, Proctor GB, Karlsson NG, Carpenter GH, Flowers SA. Reduced Mucin-7 (Muc7) Sialylation and Altered Saliva Rheology in Sjögren's Syndrome Associated Oral Dryness. Mol Cell Proteomics. 2016 Mar;15(3):1048-59. doi: 10.1074/mcp.M115.052993. Epub 2015 Dec 2. PubMed PMID: 26631508; PubMed Central PMCID: PMC4813687. pdf

Sjogren’s Syndrome is an autoimmune disease that impacts salivary and lacrimal (tear) glands. This overlooked disease is often left undiagnosed for many years. This work associated the glycosylation on salivary protein Muc7, the physical properties of the saliva (basically how “stringy” it is), salivary flow, and how dry each patient felt their mouth was based on surveys. This showed that the feeling of dry mouth was associated with the glycosylation on Muc7, not how much saliva they had - and that it was the quality, not the quantity, of saliva that is important.

Zad M, Flowers SA, Bankvall M, Jontell M, Karlsson NG. Salivary mucin MUC7 oligosaccharides in patients with recurrent aphthous stomatitis. Clin Oral Investig. 2015 Nov;19(8):2147-52. doi: 10.1007/s00784-015-1495-3. Epub 2015 Jun 9. PubMed PMID: 26051835. pdf

A sibling study showing differences in the salivary MUC7 glycome in patients with RAS, a recurrent oral ulcerative condition.

Vitiazeva V, Kattla JJ, Flowers SA, Lindén SK, Premaratne P, Weijdegård B, Sundfeldt K, Karlsson NG. The O-Linked Glycome and Blood Group Antigens ABO on Mucin-Type Glycoproteins in Mucinous and Serous Epithelial Ovarian Tumors. PLoS One. 2015;10(6):e0130197. doi: 10.1371/journal.pone.0130197. eCollection 2015. PubMed PMID: 26075384; PubMed Central PMCID: PMC4468167. pdf

Comparison of the glycome of mucinous and serous ovarian tumors which differ in their malignancy and response to treatment.

Ali L, Flowers SA, Jin C, Bennet EP, Ekwall AK, Karlsson NG. The O-glycomap of lubricin, a novel mucin responsible for joint lubrication, identified by site-specific glycopeptide analysis. Mol Cell Proteomics. 2014 Dec;13(12):3396-409. doi: 10.1074/mcp.M114.040865. Epub 2014 Sep 3. PubMed PMID: 25187573; PubMed Central PMCID: PMC4256492. pdf

A detailed glycoproteomic analysis of the joint lubricating protein lubricin. Important work from the lab of Dr. Niclas Karlsson on Pathological Glycosylation.

Campbell MP, Nguyen-Khuong T, Hayes CA, Flowers SA, Alagesan K, Kolarich D, Packer NH, Karlsson NG. Validation of the curation pipeline of UniCarb-DB: building a global glycan reference MS/MS repository. Biochim Biophys Acta. 2014 Jan;1844(1 Pt A):108-16. doi: 10.1016/j.bbapap.2013.04.018. Epub 2013 Apr 25. PubMed PMID: 23624262. pdf

A publication about the UniCarb-DB resource, a database of glycan MS/MS spectra in which Dr. Flowers deposited many standard glycan spectra. This and other such resources are critical to keep pushing the glycosylation field forward.

Flowers SA, Ali L, Lane CS, Olin M, Karlsson NG. Selected reaction monitoring to differentiate and relatively quantitate isomers of sulfated and unsulfated core 1 O-glycans from salivary MUC7 protein in rheumatoid arthritis. Mol Cell Proteomics. 2013 Apr;12(4):921-31. doi: 10.1074/mcp.M113.028878. Epub 2013 Mar 1. PubMed PMID: 23457413; PubMed Central PMCID: PMC3617339. pdf

Quantitative mass spectrometric (SRM or MRM) analyses of RA patient saliva samples showing that this systemic autoimmune disease causes glycan changes in the saliva of RA patients compared to controls. This also showed how sulfated glycans in particular are impacted by our inflammatory health, that these glycans are important, and that this is a valid approach for their quantification.

Belli SI, Ferguson DJ, Katrib M, Slapetova I, Mai K, Slapeta J, Flowers SA, Miska KB, Tomley FM, Shirley MW, Wallach MG, Smith NC. Conservation of proteins involved in oocyst wall formation in Eimeria maxima, Eimeria tenella and Eimeria acervulina. Int J Parasitol. 2009 Aug;39(10):1063-70. doi: 10.1016/j.ijpara.2009.05.004. Epub 2009 May 25. PubMed PMID: 19477178; PubMed Central PMCID: PMC2726925. pdf

Work on conserved oocyst wall formation proteins across Eimeria species increased our understanding of the formation of this critical wall structure.

Belli SI, Walker RA, Flowers SA. Global protein expression analysis in apicomplexan parasites: current status. Proteomics. 2005 Mar;5(4):918-24. doi: 10.1002/pmic.200401161. Review. PubMed PMID: 15759314. pdf

A review outlining proteomic analyses in Apicomplexan parasites like Eimeria, Toxoplasma and Plasmodium.

Patents

Rebeck, GW, and Flowers, SA. APOE modifications and uses thereof. United States of America. Application No. 62/545,839. August 15, 2017. PCT/IB2018/056138, August 15, 2018.

Jin, C, Kalamajski, S, Karlsson, N, and Flowers SA Method for diagnosing arthritis or other joint degrading disease. Sweden. Application number SE1650230-4. 23 February 2016, International. Application number PCT/EP2017/054117. 23 February 2017.

Technical notes

Lane, CS, McManus, K, Widdowson, P, Flowers SA, Powell, G, Anderson, I, and Campbell, LJ. Differentiation of α2,3 and α2,6 sialic acid linked glycan isomers using SelexION® differential mobility spectrometry technology. SCIEX, 2019, RUO-MKT-02-6645-A. 1-3. pdf

Campbell, LJ, Lane, CS, Flowers, SA, Liu, C, and LeBlanc, YJC. Differential mobility spectrometry analysis of glycans and glycopeptides using SelexION technology. SCIEX, 2017, RUO-MKT-02-2811-A. 1-4. pdf