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Article: The Role of the C-Clamp in Wnt-Related Colorectal Cancers.

Ravindranath, Aditi J / Cadigan, Ken M

2016 Volume 8, Issue 8

Abstract: T-cell Factor/Lymphoid Enhancer Factor (TCF/LEF) transcription factors are major regulators of Wnt targets, and the products of the TCF7 and TCF7L2 genes have both been implicated in the progression of colorectal cancer in animal models and humans. TCFs ... ...

Abstract	T-cell Factor/Lymphoid Enhancer Factor (TCF/LEF) transcription factors are major regulators of Wnt targets, and the products of the TCF7 and TCF7L2 genes have both been implicated in the progression of colorectal cancer in animal models and humans. TCFs recognize specific DNA sequences through their high mobility group (HMG) domains, but invertebrate TCFs and some isoforms of vertebrate TCF7 and TCF7L2 contain a second DNA binding domain known as the C-clamp. This review will cover the basic properties of C-clamps and their importance in Wnt signaling, using data from Drosophila, C. elegans, and mammalian cell culture. The connection between C-clamp containing TCFs and colorectal cancer will also be discussed.
Language	English
Publishing date	2016-08-03
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers8080074
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Article ; Online: The Increasing Economic Burden with Additional Steps of Pharmacotherapy in Major Depressive Disorder.

Arnaud, Alix / Suthoff, Ellison / Tavares, Rita M / Zhang, Xuan / Ravindranath, Aditi J

PharmacoEconomics

2021 Volume 39, Issue 6, Page(s) 691–706

Abstract: Objectives: Major depressive disorder (MDD) is a common and serious disorder with significant impact on patients and families. The goal of this retrospective cohort study was to determine the economic burden among patients with MDD stratified by number ... ...

Abstract	Objectives: Major depressive disorder (MDD) is a common and serious disorder with significant impact on patients and families. The goal of this retrospective cohort study was to determine the economic burden among patients with MDD stratified by number of treatment lines needed for episode resolution. Methods: Truven Health Analytics MarketScan Results: A total of 73,597 patients with MDD comprising the commercial (n = 66,459) and Medicare (n = 7138) populations met selection criteria. Patients who completed treatment for their episode with a single line of antidepressant had the lowest total adjusted direct costs (commercial $9975; Medicare $14,628) followed by those who completed with two lines (commercial $11,723; Medicare $15,526) and those treated with three or more lines of antidepressant regimens (commercial $21,259; Medicare $20,964). Patients who completed treatment with two lines as opposed to one incurred significantly higher direct costs (commercial +$1748, p < 0.0001; Medicare +$898, p = 0.0092). Patients who completed treatment with one line had the lowest employment-related costs compared to other groups. Conclusions: There was an increased economic burden associated with delay of episode resolution as early as the second line compared to the first line in MDD.
MeSH term(s)	Aged ; Cost of Illness ; Depressive Disorder, Major/drug therapy ; Health Care Costs ; Humans ; Medicare ; Retrospective Studies ; United States
Language	English
Publishing date	2021-04-28
Publishing country	New Zealand
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1100273-6
ISSN	1179-2027 ; 1170-7690
ISSN (online)	1179-2027
ISSN	1170-7690
DOI	10.1007/s40273-021-01021-w
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Article ; Online: Structure-function analysis of the C-clamp of TCF/Pangolin in Wnt/ß-catenin signaling.

Ravindranath, Aditi J / Ravindranath, Aditi / Cadigan, Ken M

PloS one

2014 Volume 9, Issue 1, Page(s) e86180

Abstract: The evolutionarily conserved Wnt/ß-catenin (Wnt/ß-cat) pathway plays an important role in animal development in metazoans. Many Wnt targets are regulated by members of the TCF/LEF1 (TCF) family of transcription factors. All TCFs contain a High Mobility ... ...

Abstract	The evolutionarily conserved Wnt/ß-catenin (Wnt/ß-cat) pathway plays an important role in animal development in metazoans. Many Wnt targets are regulated by members of the TCF/LEF1 (TCF) family of transcription factors. All TCFs contain a High Mobility Group (HMG) domain that bind specific DNA sequences. Invertebrate TCFs and some vertebrate TCF isoforms also contain another domain, called the C-clamp, which allows TCFs to recognize an additional DNA motif known as the Helper site. While the C-clamp has been shown to be important for regulating several Wnt reporter genes in cell culture, its physiological role in regulating Wnt targets is less clear. In addition, little is known about this domain, except that two of the four conserved cysteines are functionally important. Here, we carried out a systematic mutagenesis and functional analysis of the C-clamp from the Drosophila TCF/Pangolin (TCF/Pan) protein. We found that the C-clamp is a zinc-binding domain that is sufficient for binding to the Helper site. In addition to this DNA-binding activity, the C-clamp also inhibits the HMG domain from binding its cognate DNA site. Point mutations were identified that specifically affected DNA-binding or reduced the inhibitory effect. These mutants were characterized in TCF/Pan rescue assays. The specific DNA-binding activity of the C-clamp was essential for TCF/Pan function in cell culture and in patterning the embryonic epidermis of Drosophila, demonstrating the importance of this C-clamp activity in regulating Wnt target gene expression. In contrast, the inhibitory mutation had a subtle effect in cell culture and no effect on TCF/Pan activity in embryos. These results provide important information about the functional domains of the C-clamp, and highlight its importance for Wnt/ß-cat signaling in Drosophila.
MeSH term(s)	Animals ; Body Patterning ; Cells, Cultured ; DNA/metabolism ; Drosophila/chemistry ; Drosophila/embryology ; Drosophila/genetics ; Drosophila/metabolism ; Drosophila Proteins/chemistry ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Epidermis/embryology ; Mutagenesis ; Point Mutation ; Protein Structure, Tertiary ; Repressor Proteins/chemistry ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Wnt Proteins/metabolism ; Wnt Signaling Pathway ; Zinc/metabolism ; beta Catenin/metabolism
Chemical Substances	Drosophila Proteins ; Repressor Proteins ; Wnt Proteins ; beta Catenin ; pan protein, Drosophila ; DNA (9007-49-2) ; Zinc (J41CSQ7QDS)
Language	English
Publishing date	2014-01-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0086180
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Article ; Online: The Role of the C-Clamp in Wnt-Related Colorectal Cancers

Aditi J. Ravindranath / Ken M. Cadigan

Cancers, Vol 8, Iss 8, p

2016 Volume 74

Abstract	T-cell Factor/Lymphoid Enhancer Factor (TCF/LEF) transcription factors are major regulators of Wnt targets, and the products of the TCF7 and TCF7L2 genes have both been implicated in the progression of colorectal cancer in animal models and humans. TCFs recognize specific DNA sequences through their high mobility group (HMG) domains, but invertebrate TCFs and some isoforms of vertebrate TCF7 and TCF7L2 contain a second DNA binding domain known as the C-clamp. This review will cover the basic properties of C-clamps and their importance in Wnt signaling, using data from Drosophila, C. elegans, and mammalian cell culture. The connection between C-clamp containing TCFs and colorectal cancer will also be discussed.
Keywords	TCF/LEF ; C-clamp ; Wnt ; β-catenin ; colorectal cancer ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R
Language	English
Publishing date	2016-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Structure-function analysis of the C-clamp of TCF/Pangolin in Wnt/ß-catenin signaling.

Aditi J Ravindranath / Ken M Cadigan

PLoS ONE, Vol 9, Iss 1, p e

2014 Volume 86180

Abstract	The evolutionarily conserved Wnt/ß-catenin (Wnt/ß-cat) pathway plays an important role in animal development in metazoans. Many Wnt targets are regulated by members of the TCF/LEF1 (TCF) family of transcription factors. All TCFs contain a High Mobility Group (HMG) domain that bind specific DNA sequences. Invertebrate TCFs and some vertebrate TCF isoforms also contain another domain, called the C-clamp, which allows TCFs to recognize an additional DNA motif known as the Helper site. While the C-clamp has been shown to be important for regulating several Wnt reporter genes in cell culture, its physiological role in regulating Wnt targets is less clear. In addition, little is known about this domain, except that two of the four conserved cysteines are functionally important. Here, we carried out a systematic mutagenesis and functional analysis of the C-clamp from the Drosophila TCF/Pangolin (TCF/Pan) protein. We found that the C-clamp is a zinc-binding domain that is sufficient for binding to the Helper site. In addition to this DNA-binding activity, the C-clamp also inhibits the HMG domain from binding its cognate DNA site. Point mutations were identified that specifically affected DNA-binding or reduced the inhibitory effect. These mutants were characterized in TCF/Pan rescue assays. The specific DNA-binding activity of the C-clamp was essential for TCF/Pan function in cell culture and in patterning the embryonic epidermis of Drosophila, demonstrating the importance of this C-clamp activity in regulating Wnt target gene expression. In contrast, the inhibitory mutation had a subtle effect in cell culture and no effect on TCF/Pan activity in embryos. These results provide important information about the functional domains of the C-clamp, and highlight its importance for Wnt/ß-cat signaling in Drosophila.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Cost Savings from Reduced Hospitalizations with Use of Home Noninvasive Ventilation for COPD.

Coughlin, Steven / Peyerl, Fred W / Munson, Sibyl H / Ravindranath, Aditi J / Lee-Chiong, Teofilo L

Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research

2017 Volume 20, Issue 3, Page(s) 379–387

Abstract: Background: Although evidence suggests significant clinical benefits of home noninvasive ventilation (NIV) for management of severe chronic obstructive pulmonary disease (COPD), economic analyses supporting the use of this technology are lacking.: ... ...

Abstract	Background: Although evidence suggests significant clinical benefits of home noninvasive ventilation (NIV) for management of severe chronic obstructive pulmonary disease (COPD), economic analyses supporting the use of this technology are lacking. Objectives: To evaluate the economic impact of adopting home NIV, as part of a multifaceted intervention program, for severe COPD. Methods: An economic model was developed to calculate savings associated with the use of Advanced NIV (averaged volume assured pressure support with autoexpiratory positive airway pressure; Trilogy100, Philips Respironics, Inc., Murrysville, PA) versus either no NIV or a respiratory assist device with bilevel pressure capacity in patients with severe COPD from two distinct perspectives: the hospital and the payer. The model examined hospital savings over 90 days and payer savings over 3 years. The number of patients with severe COPD eligible for home Advanced NIV was user-defined. Clinical and cost data were obtained from a quality improvement program and published reports. Scenario analyses calculated savings for hospitals and payers covering different COPD patient cohort sizes. Results: The hospital base case (250 patients) revealed cumulative savings of $402,981 and $449,101 over 30 and 90 days, respectively, for Advanced NIV versus both comparators. For the payer base case (100,000 patients), 3-year cumulative savings with Advanced NIV were $326 million versus no NIV and $1.04 billion versus respiratory assist device. Conclusions: This model concluded that adoption of home Advanced NIV with averaged volume assured pressure support with autoexpiratory positive airway pressure, as part of a multifaceted intervention program, presents an opportunity for hospitals to reduce COPD readmission-related costs and for payers to reduce costs associated with managing patients with severe COPD on the basis of reduced admissions.
MeSH term(s)	Cost-Benefit Analysis ; Health Care Costs ; Hospital Costs ; Hospitalization/economics ; Humans ; Models, Econometric ; Noninvasive Ventilation/economics ; Noninvasive Ventilation/methods ; Positive-Pressure Respiration/economics ; Positive-Pressure Respiration/methods ; Pulmonary Disease, Chronic Obstructive/economics ; Pulmonary Disease, Chronic Obstructive/mortality ; Pulmonary Disease, Chronic Obstructive/therapy ; Self Care/economics ; Self Care/methods
Language	English
Publishing date	2017-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	1471745-1
ISSN	1524-4733 ; 1098-3015
ISSN (online)	1524-4733
ISSN	1098-3015
DOI	10.1016/j.jval.2016.09.2401
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Article ; Online: Impact of Fluid Choice in Systemic Inflammatory Response Syndrome Patients on Hospital Cost Savings.

Laplante, Suzanne / Makhija, Dilip U / Munson, Sibyl H / Khangulov, Victor S / Peyerl, Fred W / Paluszkiewicz, Scott M / Ravindranath, Aditi J / Schermer, Carol R

PharmacoEconomics - open

2018 Volume 2, Issue 3, Page(s) 325–335

Abstract: Background: There is growing evidence of the benefits of intravenous fluid therapy with balanced crystalloids over 0.9% 'normal' saline. This analysis evaluated the economic impact of increasing usage of a calcium-free balanced crystalloid solution (BAL) ...

Abstract	Background: There is growing evidence of the benefits of intravenous fluid therapy with balanced crystalloids over 0.9% 'normal' saline. This analysis evaluated the economic impact of increasing usage of a calcium-free balanced crystalloid solution (BAL) in patients with systemic inflammatory response syndrome (SIRS) on an annual hospital budget. Methods: An Excel Results: Base-case scenario analysis (300-bed hospital, 80% occupancy, current and year 5 BAL usage in 5 and 75% of SIRS patients, respectively, exponential year-over-year adoption) showed year 1 hospital savings of US$29,232 and cumulative 5-year savings of US$1.16M. Cumulative 5-year pharmacy savings were US$172,641. Scenario analyses demonstrated increasing cumulative 5-year savings with increasing hospital size, year 5 BAL usage in greater proportions of patients, and rapid/early BAL adoption. Conclusions: Increased BAL usage represents an opportunity for hospitals and pharmacy departments to reduce complication-related costs associated with managing SIRS patients. The model suggests that savings could be expected across a range of scenarios, likely benefiting hospitals of various sizes and with different adoption capabilities.
Language	English
Publishing date	2018-04-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2874287-4
ISSN	2509-4254 ; 2509-4262
ISSN (online)	2509-4254
ISSN	2509-4262
DOI	10.1007/s41669-017-0055-y
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Book ; Online: Mobilising climate finance to achieve food, land, and water system transformation

Marshall, Suzie / Chilambe, Pedro Anglaze / Cosgrove, Bethany Emma / Stapleton, James / Ravindranath, D. / Salfi, Laura / Mukherji, Aditi

2023

Keywords	climate change ; food systems ; water ; land ; finance
Language	English
Publishing date	2023-12-12T07:38:52Z
Publisher	CGIAR System Organization
Publishing country	fr
Document type	Book ; Online
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Article ; Online: Sex difference in evolution of cognitive decline: studies on mouse model and the Dominantly Inherited Alzheimer Network cohort.

Kommaddi, Reddy Peera / Verma, Aditi / Muniz-Terrera, Graciela / Tiwari, Vivek / Chithanathan, Keerthana / Diwakar, Latha / Gowaikar, Ruturaj / Karunakaran, Smitha / Malo, Palash Kumar / Graff-Radford, Neill R / Day, Gregory S / Laske, Christoph / Vöglein, Jonathan / Nübling, Georg / Ikeuchi, Takeshi / Kasuga, Kensaku / Ravindranath, Vijayalakshmi

Translational psychiatry

2023 Volume 13, Issue 1, Page(s) 123

Abstract: Women carry a higher burden of Alzheimer's disease (AD) compared to men, which is not accounted entirely by differences in lifespan. To identify the mechanisms underlying this effect, we investigated sex-specific differences in the progression of ... ...

Abstract	Women carry a higher burden of Alzheimer's disease (AD) compared to men, which is not accounted entirely by differences in lifespan. To identify the mechanisms underlying this effect, we investigated sex-specific differences in the progression of familial AD in humans and in APPswe/PS1ΔE9 mice. Activity dependent protein translation and associative learning and memory deficits were examined in APPswe/PS1ΔE9 mice and wild-type mice. As a human comparator group, progression of cognitive dysfunction was assessed in mutation carriers and non-carriers from DIAN (Dominantly Inherited Alzheimer Network) cohort. Female APPswe/PS1ΔE9 mice did not show recall deficits after contextual fear conditioning until 8 months of age. Further, activity dependent protein translation and Akt1-mTOR signaling at the synapse were impaired in male but not in female mice until 8 months of age. Ovariectomized APPswe/PS1ΔE9 mice displayed recall deficits at 4 months of age and these were sustained until 8 months of age. Moreover, activity dependent protein translation was also impaired in 4 months old ovariectomized APPswe/PS1ΔE9 mice compared with sham female APPswe/PS1ΔE9 mice. Progression of memory impairment differed between men and women in the DIAN cohort as analyzed using linear mixed effects model, wherein men showed steeper cognitive decline irrespective of the age of entry in the study, while women showed significantly greater performance and slower decline in immediate recall (LOGIMEM) and delayed recall (MEMUNITS) than men. However, when the performance of men and women in several cognitive tasks (such as Wechsler's logical memory) are compared with the estimated year from expected symptom onset (EYO) we found no significant differences between men and women. We conclude that in familial AD patients and mouse models, females are protected, and the onset of disease is delayed as long as estrogen levels are intact.
MeSH term(s)	Humans ; Female ; Male ; Mice ; Animals ; Infant ; Alzheimer Disease/metabolism ; Mice, Transgenic ; Sex Characteristics ; Cognitive Dysfunction/genetics ; Fear ; Memory Disorders ; Disease Models, Animal ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Peptides/metabolism
Chemical Substances	Amyloid beta-Protein Precursor ; Amyloid beta-Peptides
Language	English
Publishing date	2023-04-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-023-02411-8
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Article ; Online: Distinct DNA binding sites contribute to the TCF transcriptional switch in C. elegans and Drosophila.

Bhambhani, Chandan / Ravindranath, Aditi J / Mentink, Remco A / Chang, Mikyung V / Betist, Marco C / Yang, Yaxuan X / Koushika, Sandhya P / Korswagen, Hendrik C / Cadigan, Ken M

PLoS genetics

2014 Volume 10, Issue 2, Page(s) e1004133

Abstract: Regulation of gene expression by signaling pathways often occurs through a transcriptional switch, where the transcription factor responsible for signal-dependent gene activation represses the same targets in the absence of signaling. T-cell factors ( ... ...

Abstract	Regulation of gene expression by signaling pathways often occurs through a transcriptional switch, where the transcription factor responsible for signal-dependent gene activation represses the same targets in the absence of signaling. T-cell factors (TCFs) are transcription factors in the Wnt/ß-catenin pathway, which control numerous cell fate specification events in metazoans. The TCF transcriptional switch is mediated by many co-regulators that contribute to repression or activation of Wnt target genes. It is typically assumed that DNA recognition by TCFs is important for target gene location, but plays no role in the actual switch. TCF/Pangolin (the fly TCF) and some vertebrate TCF isoforms bind DNA through two distinct domains, a High Mobility Group (HMG) domain and a C-clamp, which recognize DNA motifs known as HMG and Helper sites, respectively. Here, we demonstrate that POP-1 (the C. elegans TCF) also activates target genes through HMG and Helper site interactions. Helper sites enhanced the ability of a synthetic enhancer to detect Wnt/ß-catenin signaling in several tissues and revealed an unsuspected role for POP-1 in regulating the C. elegans defecation cycle. Searching for HMG-Helper site clusters allowed the identification of a new POP-1 target gene active in the head muscles and gut. While Helper sites and the C-clamp are essential for activation of worm and fly Wnt targets, they are dispensable for TCF-dependent repression of targets in the absence of Wnt signaling. These data suggest that a fundamental change in TCF-DNA binding contributes to the transcriptional switch that occurs upon Wnt stimulation.
MeSH term(s)	Animals ; Binding Sites ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/metabolism ; Caenorhabditis elegans Proteins/genetics ; Caenorhabditis elegans Proteins/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Drosophila/genetics ; Drosophila/metabolism ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Gene Expression Regulation ; HMG-Box Domains/genetics ; High Mobility Group Proteins/genetics ; High Mobility Group Proteins/metabolism ; Nucleotide Motifs/genetics ; Protein Binding ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Signal Transduction/genetics ; Wnt Signaling Pathway/genetics
Chemical Substances	Caenorhabditis elegans Proteins ; DNA-Binding Proteins ; Drosophila Proteins ; High Mobility Group Proteins ; Repressor Proteins ; pan protein, Drosophila ; pop-1 protein, C elegans
Language	English
Publishing date	2014-02-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1004133
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