Publications by authors named "David Sedwick"

11 Publications

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Vascular dimorphism ensured by regulated proteoglycan dynamics favors rapid umbilical artery closure at birth.

Elife 2020 09 10;9. Epub 2020 Sep 10.

Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, United States.

The umbilical artery lumen closes rapidly at birth, preventing neonatal blood loss, whereas the umbilical vein remains patent longer. Here, analysis of umbilical cords from humans and other mammals identified differential arterial-venous proteoglycan dynamics as a determinant of these contrasting vascular responses. The umbilical artery, but not the vein, has an inner layer enriched in the hydrated proteoglycan aggrecan, external to which lie contraction-primed smooth muscle cells (SMC). At birth, SMC contraction drives inner layer buckling and centripetal displacement to occlude the arterial lumen, a mechanism revealed by biomechanical observations and confirmed by computational analyses. This vascular dimorphism arises from spatially regulated proteoglycan expression and breakdown. Mice lacking aggrecan or the metalloprotease ADAMTS1, which degrades proteoglycans, demonstrate their opposing roles in umbilical vascular dimorphism, including effects on SMC differentiation. Umbilical vessel dimorphism is conserved in mammals, suggesting that differential proteoglycan dynamics and inner layer buckling were positively selected during evolution.
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http://dx.doi.org/10.7554/eLife.60683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529456PMC
September 2020

Reply to Ashktorab et al.: Mutational landscape of colon cancers in African Americans.

Proc Natl Acad Sci U S A 2015 Jun 4;112(22):E2853. Epub 2015 May 4.

Case Comprehensive Cancer Center, and Department of Medicine, Case Medical Center, Case Western Reserve University, Cleveland, OH 44106; Department of Pathology.

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http://dx.doi.org/10.1073/pnas.1505059112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460466PMC
June 2015

Novel recurrently mutated genes in African American colon cancers.

Proc Natl Acad Sci U S A 2015 Jan 12;112(4):1149-54. Epub 2015 Jan 12.

Case Comprehensive Cancer Center, and Department of Medicine, Case Medical Center, Case Western Reserve University, Cleveland, OH 44106; Department of Pathology.

We used whole-exome and targeted sequencing to characterize somatic mutations in 103 colorectal cancers (CRC) from African Americans, identifying 20 new genes as significantly mutated in CRC. Resequencing 129 Caucasian derived CRCs confirmed a 15-gene set as a preferential target for mutations in African American CRCs. Two predominant genes, ephrin type A receptor 6 (EPHA6) and folliculin (FLCN), with mutations exclusive to African American CRCs, are by genetic and biological criteria highly likely African American CRC driver genes. These previously unsuspected differences in the mutational landscapes of CRCs arising among individuals of different ethnicities have potential to impact on broader disparities in cancer behaviors.
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http://dx.doi.org/10.1073/pnas.1417064112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313860PMC
January 2015

Gain of interaction with IRS1 by p110α-helical domain mutants is crucial for their oncogenic functions.

Cancer Cell 2013 May 2;23(5):583-93. Epub 2013 May 2.

Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.

PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase α, is frequently mutated in human cancers. Most of these mutations occur at two hot-spots: E545K and H1047R located in the helical domain and the kinase domain, respectively. Here, we report that p110α E545K, but not p110α H1047R, gains the ability to associate with IRS1 independent of the p85 regulatory subunit, thereby rewiring this oncogenic signaling pathway. Disruption of the IRS1-p110α E545K interaction destabilizes the p110α protein, reduces AKT phosphorylation, and slows xenograft tumor growth of a cancer cell line expressing p110α E545K. Moreover, a hydrocarbon-stapled peptide that disrupts this interaction inhibits the growth of tumors expressing p110α E545K.
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http://dx.doi.org/10.1016/j.ccr.2013.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671608PMC
May 2013

Cross-talk between phospho-STAT3 and PLCγ1 plays a critical role in colorectal tumorigenesis.

Mol Cancer Res 2011 Oct 12;9(10):1418-28. Epub 2011 Aug 12.

Department of Genetics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-7285, USA.

Hyperphosphorylation at the Y705 residue of signal transducer and activator of transcription 3 (STAT3) is implicated in tumorigenesis of leukemia and some solid tumors. However, its role in the development of colorectal cancer is not well defined. To rigorously test the impact of this phosphorylation on colorectal tumorigenesis, we engineered a STAT3 Y705F knock-in to interrupt STAT3 activity in HCT116 and RKO colorectal cancer cells. These STAT3 Y705F mutant cells fail to respond to cytokine stimulation and grow slower than parental cells. These mutant cells are also greatly diminished in their abilities to form colonies in culture, to exhibit anchorage-independent growth in soft agar, and to grow as xenografts in nude mice. These observations strongly support the premise that STAT3 Y705 phosphorylation is crucial in colorectal tumorigenesis. Although it is generally believed that STAT3 functions as a transcription factor, recent studies indicate that transcription-independent functions of STAT3 also play an important role in tumorigenesis. We show here that wild-type STAT3, but not STAT3 Y705F mutant protein, associates with phospholipase Cγ1 (PLCγ1). PLCγ1 is a central signal transducer of growth factor and cytokine signaling pathways that are involved in tumorigenesis. In STAT3 Y705F mutant colorectal cancer cells, PLCγ1 activity is reduced. Moreover, overexpression of a constitutively active form of PLCγ1 rescues the transformation defect of STAT3 Y705F mutant cells. In aggregate, our study identifies previously unknown cross-talk between STAT3 and the PLCγ signaling pathways that may play a critical role in colorectal tumorigenesis.
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http://dx.doi.org/10.1158/1541-7786.MCR-11-0147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3196678PMC
October 2011

DNMT1 stability is regulated by proteins coordinating deubiquitination and acetylation-driven ubiquitination.

Sci Signal 2010 Nov 2;3(146):ra80. Epub 2010 Nov 2.

Department of Genetics, Case Western Reserve University, Cleveland, OH 44106, USA.

DNA methyltransferase 1 (DNMT1) is the primary enzyme that maintains DNA methylation. We describe a previously unknown mode of regulation of DNMT1 protein stability through the coordinated action of an array of DNMT1-associated proteins. DNMT1 was destabilized by acetylation by the acetyltransferase Tip60, which triggered ubiquitination by the E3 ligase UHRF1, thereby targeting DNMT1 for proteasomal degradation. In contrast, DNMT1 was stabilized by histone deacetylase 1 (HDAC1) and the deubiquitinase HAUSP (herpes virus-associated ubiquitin-specific protease). Analysis of the abundance of DNMT1 and Tip60, as well as the association between HAUSP and DNMT1, suggested that during the cell cycle the initiation of DNMT1 degradation was coordinated with the end of DNA replication and the need for DNMT activity. In human colon cancers, the abundance of DNMT1 correlated with that of HAUSP. HAUSP knockdown rendered colon cancer cells more sensitive to killing by HDAC inhibitors both in tissue culture and in tumor xenograft models. Thus, these studies provide a mechanism-based rationale for the development of HDAC and HAUSP inhibitors for combined use in cancer therapy.
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http://dx.doi.org/10.1126/scisignal.2001462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116231PMC
November 2010

DNA mismatch repair (MMR)-dependent 5-fluorouracil cytotoxicity and the potential for new therapeutic targets.

Br J Pharmacol 2009 Oct 23;158(3):679-92. Epub 2009 Sep 23.

Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.

The metabolism and efficacy of 5-fluorouracil (FUra) and other fluorinated pyrimidine (FP) derivatives have been intensively investigated for over fifty years. FUra and its antimetabolites can be incorporated at RNA- and DNA-levels, with RNA level incorporation provoking toxic responses in human normal tissue, and DNA-level antimetabolite formation and incorporation believed primarily responsible for tumour-selective responses. Attempts to direct FUra into DNA-level antimetabolites, based on mechanism-of-action studies, have led to gradual improvements in tumour therapy. These include the use of leukovorin to stabilize the inhibitory thymidylate synthase-5-fluoro-2'-deoxyuridine 5' monophoshate (FdUMP)-5,10-methylene tetrahydrofolate (5,10-CH(2)FH(4)) trimeric complex. FUra incorporated into DNA also contributes to antitumour activity in preclinical and clinical studies. This review examines our current state of knowledge regarding the mechanistic aspects of FUra:Gua lesion detection by DNA mismatch repair (MMR) machinery that ultimately results in lethality. MMR-dependent direct cell death signalling or futile cycle responses will be discussed. As 10-30% of sporadic colon and endometrial tumours display MMR defects as a result of human MutL homologue-1 (hMLH1) promoter hypermethylation, we discuss the use and manipulation of the hypomethylating agent, 5-fluorodeoxycytidine (FdCyd), and our ability to manipulate its metabolism using the cytidine or deoxycytidylate (dCMP) deaminase inhibitors, tetrahydrouridine or deoxytetrahydrouridine, respectively, as a method for re-expression of hMLH1 and re-sensitization of tumours to FP therapy.
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http://dx.doi.org/10.1111/j.1476-5381.2009.00423.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2765589PMC
October 2009

Novel boron-containing, nonclassical antifolates: synthesis and preliminary biological and structural evaluation.

J Med Chem 2007 Jul 15;50(14):3283-9. Epub 2007 Jun 15.

Drug Discovery Division, Southern Research Institute, Birmingham, Alabama 35205, USA.

Two boron-containing, ortho-icosahedral carborane lipophilic antifolates were synthesized, and the crystal structures of their ternary complexes with human dihydrofolate reductase (DHFR) and dihydronicotinamide adenine dinucleotide phosphate were determined. The compounds were screened for activity against DHFR from six sources (human, rat liver, Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and Lactobacillus casei) and showed good to modest activity against these enzymes. The compounds were also tested for antibacterial activity against L. casei, M. tuberculosis H37Ra, and three M. avium strains and for cytotoxic activity against seven different human tumor cell lines. Antibacterial and cytotoxic activity was modest, with one sample, the closo-carborane 4, showing about 10-fold greater activity. The less toxic nido-carborane 2 was also tested as a candidate for boron neutron capture therapy, but showed poor tumor retention and low selectivity ratios for boron distribution in tumor tissue versus normal tissue.
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http://dx.doi.org/10.1021/jm0701977DOI Listing
July 2007

On systems and control approaches to therapeutic gain.

BMC Cancer 2006 Apr 25;6:104. Epub 2006 Apr 25.

Department of Epidemiology and Biostatistics Case Western Reserve University, Cleveland, Ohio 44106, USA.

Background: Mathematical models of cancer relevant processes are being developed at an increasing rate. Conceptual frameworks are needed to support new treatment designs based on such models.

Methods: A modern control perspective is used to formulate two therapeutic gain strategies.

Results: Two conceptually distinct therapeutic gain strategies are provided. The first is direct in that its goal is to kill cancer cells more so than normal cells, the second is indirect in that its goal is to achieve implicit therapeutic gains by transferring states of cancer cells of non-curable cases to a target state defined by the cancer cells of curable cases. The direct strategy requires models that connect anti-cancer agents to an endpoint that is modulated by the cause of the cancer and that correlates with cell death. It is an abstraction of a strategy for treating mismatch repair (MMR) deficient cancers with iodinated uridine (IUdR); IU-DNA correlates with radiation induced cell killing and MMR modulates the relationship between IUdR and IU-DNA because loss of MMR decreases the removal of IU from the DNA. The second strategy is indirect. It assumes that non-curable patient outcomes will improve if the states of their malignant cells are first transferred toward a state that is similar to that of a curable patient. This strategy is difficult to employ because it requires a model that relates drugs to determinants of differences in patient survival times. It is an abstraction of a strategy for treating BCR-ABL pro-B cell childhood leukemia patients using curable cases as the guides.

Conclusion: Cancer therapeutic gain problem formulations define the purpose, and thus the scope, of cancer process modeling. Their abstractions facilitate considerations of alternative treatment strategies and support syntheses of learning experiences across different cancers.
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http://dx.doi.org/10.1186/1471-2407-6-104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1484487PMC
April 2006

A role for DNA mismatch repair in sensing and responding to fluoropyrimidine damage.

Oncogene 2003 Oct;22(47):7376-88

Laboratory of Molecular Stress Responses, Department of Radiation Oncology, Case Western Reserve University, Biomedical Research Building 326-East, 2109 Adelbert Road, Cleveland, OH 44106-4942, USA.

The phenomenon of damage tolerance, whereby cells incur DNA lesions that are nonlethal, largely ignored, but highly mutagenic, appears to play a key role in carcinogenesis. Typically, these lesions are generated by alkylation of DNA or incorporation of base analogues. This tolerance is usually a result of the loss of specific DNA repair processes, most often DNA mismatch repair (MMR). The availability of genetically matched MMR-deficient and -corrected cell systems allows dissection of the consequences of this unrepaired damage in carcinogenesis as well as the elucidation of cell cycle checkpoint responses and cell death consequences. Recent data indicate that MMR plays an important role in detecting damage caused by fluorinated pyrimidines (FPs) and represents a repair system that is probably not the primary system for detecting damage caused by these agents, but may be an important system for correcting key mutagenic lesions that could initiate carcinogenesis. In fact, clinical studies have shown that there is no benefit of FP-based adjuvant chemotherapy in colon cancer patients exhibiting microsatellite instability, a hallmark of MMR deficiency. MMR-mediated damage tolerance and futile cycle repair processes are discussed, as well as possible strategies using FPs to exploit these systems for improved anticancer therapy.
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http://dx.doi.org/10.1038/sj.onc.1206941DOI Listing
October 2003

Mismatch repair and drug responses in cancer.

Drug Resist Updat 1999 Oct;2(5):295-306

Department of Medicine, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, OH

Defects in mismatch repair contribute to development of approximately 15% of colon cancers and to origination of endometrial, gastric and other cancers. Tumors with defects in mismatch repair exhibit marked resistance to alkylators and a variety of anticancer agents that modify DNA to create substrates for the mismatch repair system. These altered drug responses appear to derive from requirements for mismatch repair proteins in signalling apoptosis, altered cell cycle checkpoint behaviour and/or loss of mismatch repair dependent toxicity arising from futile repair cycling. Altered repair mechanisms for mismatched substrates in mismatch repair defective tumors provide both challenges for development of tumor-phenotype-screening methodologies to assure appropriate therapy is administered for these cancers and foci for development of new therapy approaches that capitalize on modified drug responses in mismatch repair- defective cells. Copyright 1999 Harcourt Publishers Ltd.
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http://dx.doi.org/10.1054/drup.1999.0099DOI Listing
October 1999
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