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Article: Identification of Disease Risk DNA Variations is Shaping the Future of Precision Health.

Fakhouri, Walid D / Letra, Ariadne

2019 Volume 10, Issue 6

Abstract: In recent years, the knowledge generated by decoding the human genome has allowed groundbreaking genetic research to better understand genomic architecture and heritability in healthy and disease states. The vast amount of data generated over time and ... ...

Abstract	In recent years, the knowledge generated by decoding the human genome has allowed groundbreaking genetic research to better understand genomic architecture and heritability in healthy and disease states. The vast amount of data generated over time and yet to be generated provides the basis for translational research towards the development of preventive and therapeutic strategies for many conditions. In this special issue, we highlight the discoveries of disease-associated and protective DNA variations in common human diseases and developmental disorders.
MeSH term(s)	Alternative Splicing/genetics ; DNA/genetics ; Genetic Variation/genetics ; Genome, Human/genetics ; Genome-Wide Association Study ; Genomics ; Humans ; Precision Medicine
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2019-06-13
Publishing country	Switzerland
Document type	Editorial ; Introductory Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes10060450
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Article: Sequence-to-expression approach to identify etiological non-coding DNA variations in P53 and cMYC-driven diseases.

Kin, Katherine / Bhogale, Shounak / Zhu, Lisha / Thomas, Derrick / Bertol, Jessica / Zheng, W Jim / Sinha, Saurabh / Fakhouri, Walid D

Research square

2023

Abstract: Background and methods: Disease risk prediction based on DNA sequence and transcriptional profile can improve disease screening, prevention, and potential therapeutic approaches by revealing contributing genetic factors and altered regulatory networks. ... ...

Abstract	Background and methods: Disease risk prediction based on DNA sequence and transcriptional profile can improve disease screening, prevention, and potential therapeutic approaches by revealing contributing genetic factors and altered regulatory networks. Despite identifying many disease-associated DNA variants through genome-wide association studies, distinguishing deleterious non-coding DNA variations remains poor for most common diseases. We previously reported that non-coding variations disrupting cis-overlapping motifs (CisOMs) of opposing transcription factors significantly affect enhancer activity. We designed Results: Analyzing publicly available ChIP-seq data for P53 and cMYC in human embryonic stem cells and mouse embryonic cells showed that ~ 344-366 genomic regions are co-occupied by P53 and cMYC. We identified, on average, two CisOMs per region, suggesting that co-occupancy is evolutionarily conserved in vertebrates. Our data showed that treating U2OS cells with doxorubicin increased P53 protein level while reducing cMYC level. In contrast, no change in protein levels was observed in Raji cells. ChIP-seq analysis illustrated that 16-922 genomic regions were co-occupied by P53 and cMYC before and after treatment, and substitutions of cMYC signals by P53 were detected after doxorubicin treatment in U2OS. Around 187 expressed genes near co-occupied regions were altered at mRNA level according to RNA-seq data. We utilized a computational motif-matching approach to determine that changes in predicted P53 binding affinity by DNA variations in CisOMs of co-occupied elements significantly correlate with alterations in reporter gene expression. We performed a similar analysis using SNPs mapped in CisOMs for P53 and cMYC from ChIP-seq data in U2OS and Raji, and expression of target genes from the GTEx portal. Conclusions: We found a significant correlation between change in motif-predicted cMYC binding affinity by SNPs in CisOMs and altered gene expression. Our study brings us closer to developing a generally applicable approach to filter etiological non-coding variations associated with P53 and cMYC-dependent diseases.
Language	English
Publishing date	2023-07-12
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3037310/v1
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Article ; Online: Molecular mechanisms of TWIST1-regulated transcription in EMT and cancer metastasis.

Yu, Xiaobin / He, Tao / Tong, Zhangwei / Liao, Lan / Huang, Shixia / Fakhouri, Walid D / Edwards, Dean P / Xu, Jianming

EMBO reports

2023 Volume 24, Issue 11, Page(s) e56902

Abstract: TWIST1 induces epithelial-to-mesenchymal transition (EMT) to drive cancer metastasis. It is yet unclear what determines TWIST1 functions to activate or repress transcription. We found that the TWIST1 N-terminus antagonizes TWIST1-regulated gene ... ...

Abstract	TWIST1 induces epithelial-to-mesenchymal transition (EMT) to drive cancer metastasis. It is yet unclear what determines TWIST1 functions to activate or repress transcription. We found that the TWIST1 N-terminus antagonizes TWIST1-regulated gene expression, cancer growth and metastasis. TWIST1 interacts with both the NuRD complex and the NuA4/TIP60 complex (TIP60-Com) via its N-terminus. Non-acetylated TWIST1-K73/76 selectively interacts with and recruits NuRD to repress epithelial target gene transcription. Diacetylated TWIST1-acK73/76 binds BRD8, a component of TIP60-Com that also binds histone H4-acK5/8, to recruit TIP60-Com to activate mesenchymal target genes and MYC. Knockdown of BRD8 abolishes TWIST1 and TIP60-Com interaction and TIP60-Com recruitment to TWIST1-activated genes, resulting in decreasing TWIST1-activated target gene expression and cancer metastasis. Both TWIST1/NuRD and TWIST1/TIP60-Com complexes are required for TWIST1 to promote EMT, proliferation, and metastasis at full capacity. Therefore, the diacetylation status of TWIST1-K73/76 dictates whether TWIST1 interacts either with NuRD to repress epithelial genes, or with TIP60-Com to activate mesenchymal genes and MYC. Since BRD8 is essential for TWIST1-acK73/76 and TIP60-Com interaction, targeting BRD8 could be a means to inhibit TWIST1-activated gene expression.
MeSH term(s)	Humans ; Neoplasms/genetics ; Epithelial-Mesenchymal Transition/genetics ; Nuclear Proteins/genetics ; Twist-Related Protein 1/genetics
Chemical Substances	TWIST1 protein, human ; Nuclear Proteins ; Twist-Related Protein 1
Language	English
Publishing date	2023-09-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2020896-0
ISSN	1469-3178 ; 1469-221X
ISSN (online)	1469-3178
ISSN	1469-221X
DOI	10.15252/embr.202356902
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Article ; Online: An Insight into Acute Pericoronitis and the Need for an Evidence-Based Standard of Care.

Wehr, Chelsea / Cruz, Gianncarlo / Young, Simon / Fakhouri, Walid D

Dentistry journal

2019 Volume 7, Issue 3

Abstract: Background: ...

Abstract	Background:
Language	English
Publishing date	2019-09-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2681351-8
ISSN	2304-6767 ; 2304-6767
ISSN (online)	2304-6767
ISSN	2304-6767
DOI	10.3390/dj7030088
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Article ; Online: Surfactant Protein A and Microbiome Composition in Patients With Atraumatic Intraoral Lesions.

Adibi, Shawn / Seferovic, Davor / Tribble, Gena D / Alcorn, Joseph L / Fakhouri, Walid D

Frontiers in oral health

2021 Volume 2, Page(s) 663483

Abstract: Oral ulcers are lesions that occur due to disruption of epithelial integrity of the mucosa of the oral cavity. Intraoral ulcers are often associated with pain, redness, symptoms of discomfort, and blood hemorrhage. The etiology for many oral ulcers is ... ...

Abstract	Oral ulcers are lesions that occur due to disruption of epithelial integrity of the mucosa of the oral cavity. Intraoral ulcers are often associated with pain, redness, symptoms of discomfort, and blood hemorrhage. The etiology for many oral ulcers is local trauma, systemic health conditions, or medication; for other ulcers the cause is less clear. This pilot study aims to evaluate the salivary components and microbiome in patients with atraumatic pre-ulcerous and ulcerous oral lesions compared to control individuals, while considering three common risk factors for atraumatic ulcers, smoking, stress, and gender. This study uses matched age, sex, and ethnicity samples from healthy otherwise and oral lesion patients to investigate the changes in salivary surfactant protein A (SP-A) and examines the prevalence and diversity of the salivary oral microflora. The goal is to determine if there are factors in saliva that have the potential to be used as biomarkers for risk of developing atraumatic oral ulcers. Our data show that the average level of SP-A is significantly reduced in female smokers compared to non-smoker healthy females. The average level of SP-A in female oral lesion patients is reduced compared to controls. The microbiome composition is significantly affected by smoking and the level of SP-A. Comparing the control participants and oral lesion patients, there are 16 species of bacteria that are significantly different, and all of these bacteria are significantly affected by smoking and SP-A. LEfSe analysis identified five bacteria that may represent potential biomarkers. This preliminary study demonstrates the potential of the oral microbiome to act as a biomarker for oral ulcer risk and infers potential mechanistic links between risk factors and alterations in innate immune mechanisms such as SP-A levels.
Language	English
Publishing date	2021-04-22
Publishing country	Switzerland
Document type	Journal Article
ISSN	2673-4842
ISSN (online)	2673-4842
DOI	10.3389/froh.2021.663483
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Article: Mandibular Explant Assay for Investigating Extrinsic Stimuli on Bone and Cartilage Development.

Jiang, Jamie / Bertol, Jessica W / Fakhouri, Walid D

Bio-protocol

2018 Volume 7, Issue 23

Abstract: A major issue in developmental biology is to determine how embryonic tissues respond to molecular signals in a timely manner and given the position-restricted instructions during morphogenesis, of which Meckel's cartilage is a classical example. ... ...

Abstract	A major issue in developmental biology is to determine how embryonic tissues respond to molecular signals in a timely manner and given the position-restricted instructions during morphogenesis, of which Meckel's cartilage is a classical example. The
Language	English
Publishing date	2018-01-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2833269-6
ISSN	2331-8325
ISSN	2331-8325
DOI	10.21769/BioProtoc.2641
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Article ; Online: Conservation of Epithelial-to-Mesenchymal Transition Process in Neural Crest Cells and Metastatic Cancer.

Zhang, April / Aslam, Hira / Sharma, Neha / Warmflash, Aryeh / Fakhouri, Walid D

Cells, tissues, organs

2021 Volume 210, Issue 3, Page(s) 151–172

Abstract: Epithelial to mesenchymal transition (EMT) is a highly conserved cellular process in several species, from worms to humans. EMT plays a fundamental role in early embryogenesis, wound healing, and cancer metastasis. For neural crest cell (NCC) development, ...

Abstract	Epithelial to mesenchymal transition (EMT) is a highly conserved cellular process in several species, from worms to humans. EMT plays a fundamental role in early embryogenesis, wound healing, and cancer metastasis. For neural crest cell (NCC) development, EMT typically results in forming a migratory and potent cell population that generates a wide variety of cell and tissue, including cartilage, bone, connective tissue, endocrine cells, neurons, and glia amongst many others. The degree of conservation between the signaling pathways that regulate EMT during development and metastatic cancer (MC) has not been fully established, despite ample studies. This systematic review and meta-analysis dissects the major signaling pathways involved in EMT of NCC development and MC to unravel the similarities and differences. While the FGF, TGFβ/BMP, SHH, and NOTCH pathways have been rigorously investigated in both systems, the EGF, IGF, HIPPO, Factor Receptor Superfamily, and their intracellular signaling cascades need to be the focus of future NCC studies. In general, meta-analyses of the associated signaling pathways show a significant number of overlapping genes (particularly ligands, transcription regulators, and targeted cadherins) involved in each signaling pathway of both systems without stratification by body segments and cancer type. Lack of stratification makes it difficult to meaningfully evaluate the intracellular downstream effectors of each signaling pathway. Finally, pediatric neuroblastoma and melanoma are NCC-derived malignancies, which emphasize the importance of uncovering the EMT events that convert NCC into treatment-resistant malignant cells.
MeSH term(s)	Cell Movement ; Child ; Epithelial-Mesenchymal Transition ; Humans ; Neoplasms/genetics ; Neural Crest ; Transforming Growth Factor beta
Chemical Substances	Transforming Growth Factor beta
Language	English
Publishing date	2021-07-02
Publishing country	Switzerland
Document type	Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Systematic Review
ZDB-ID	1468141-9
ISSN	1422-6421 ; 1422-6405
ISSN (online)	1422-6421
ISSN	1422-6405
DOI	10.1159/000516466
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Article ; Online: Temperature Changes during Implant Osteotomy Preparations in Human Cadaver Tibiae Comparing MIS<sup>®</sup> Straight Drills with Densah<sup>®</sup> Burs.

Soldatos, Nikolaos / Pham, Huy / Fakhouri, Walid D / Ngo, Binh / Lampropoulos, Panagiotis / Tran, Tiffany / Weltman, Robin

Genes

2022 Volume 13, Issue 10

Abstract: 1) Background: Several studies showed a sustained temperature of 47 °C or 50 °C for one minute resulted in vascular stasis and bone resorption with only limited bone regrowth over a 3-4-week healing period. The purpose of the present study was to ... ...

Abstract	(1) Background: Several studies showed a sustained temperature of 47 °C or 50 °C for one minute resulted in vascular stasis and bone resorption with only limited bone regrowth over a 3-4-week healing period. The purpose of the present study was to evaluate the temperature changes (ΔΤ) that occur during the preparation of dental implant osteotomies using MIS<sup>®</sup> straight drills versus Densah<sup>®</sup> burs in a clockwise (cutting) drilling protocol. (2) Methods: Two hundred forty (240) osteotomies of two different systems' drills were prepared at 6 mm depth at 800, 1000, and 1200 revolutions per minute (RPM), in fresh, unembalmed tibiae, obtained by a female cadaver. ΔΤ was calculated by subtracting the baseline temperature on the tibial surface, from the maximum temperature-inside the osteotomy (ΔT = T<sub>max</sub> - T<sub>base</sub>). The variables were evaluated both for their individual and for their synergistic effect on ΔΤ with the use of one-, two-, three- and four-way interactions; (3) Results: An independent and a three-way interaction (drill design, drill width, and RPM) was found in all three RPM for the Densah<sup>®</sup> burs and at 1000 RPM for the MIS<sup>®</sup> straight drills. As Densah<sup>®</sup> burs diameter increased, ΔΤ decreased. The aforementioned pattern was seen only at 1000 RPM for the MIS<sup>®</sup> straight drills. The usage of drills 20 times more than the implant manufacturers' recommendation did not significantly affect the ΔΤ. A stereoscopic examination of the specimens confirmed the findings. (4) Conclusions: The independent and synergistic effect of drills' diameter, design and RPM had a significant effect on ΔΤ in human tibiae, which never exceeded the critical threshold of 47 °C.
MeSH term(s)	Humans ; Female ; Temperature ; Dental Implants ; Osteotomy ; Tibia/surgery ; Cadaver
Chemical Substances	Dental Implants
Language	English
Publishing date	2022-09-24
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes13101716
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Article ; Online: Dose-response effect of Montelukast on post-extraction dental socket repair and skeletal phenotype of mice.

Ribeiro, Kim Henderson Carmo / da Silva, Raquel Barroso Parra / Roseno, Ana Carolyna Becher / Barreto, Ana Julia Moreno / Bacelar, Ana Carolina Zucon / Ervolino, Edilson / Duarte, Marco Antônio Húngaro / Fakhouri, Walid D / Chaves-Neto, Antonio Hernandes / Biguetti, Cláudia Cristina / Matsumoto, Mariza Akemi

Odontology

2023 Volume 111, Issue 4, Page(s) 891–903

Abstract: Bone metabolism and repair are directly regulated by arachidonic acid metabolites. At present, we analyzed the dose-response effects of a selective cysteinyl leukotriene receptor type-1 antagonist during bone repair after tooth extraction and on non- ... ...

Abstract	Bone metabolism and repair are directly regulated by arachidonic acid metabolites. At present, we analyzed the dose-response effects of a selective cysteinyl leukotriene receptor type-1 antagonist during bone repair after tooth extraction and on non-injured skeleton. Sixty-three 129 Sv/Ev male mice composed the groups: C-Control (saline solution); MTK2-2 mg/Kg of Montelukast (MTK) and MTK4-4 mg/Kg of MTK, daily administered by mouth throughout all experimental periods set at 7, 14, and 21 days post-operative. Dental sockets were analyzed by computed microtomography (microCT), histopathology, and immunohistochemistry. Femurs, L5 vertebra and organs were also removed for observation. Blood was collected for plasma bone and liver markers. Histopathology and microCT analysis revealed early socket repair of MTK2 and MTK4 animals, with significant increased BV/TV at days 14 and 21 compared to C. Higher plasma calcium was detected at days 7 and 21 in MTK4 in comparison to C, while phosphate was significantly increased in MTK2 in the same periods in comparison to C and MTK4. No significant differences were found regarding plasma ALP and TRAP, neither for local TRAP and Runx2 immunolabeling at the healing sockets. Organs did not present histological abnormalities. Increased AST levels have been detected in distinct groups and periods. In general, femur phenotype was improved in MTK treated animals. Collectively, MTK promoted early bone formation after tooth extraction and increased bone quality of femurs and vertebra in a time-dose-dependent manner, and should be considered as an alternative therapy when improved post-extraction socket repair or skeleton preservation is required.
MeSH term(s)	Male ; Mice ; Animals ; Tooth Socket/pathology ; Tooth Socket/surgery ; Wound Healing/physiology ; Tooth Extraction ; Acetates/pharmacology
Chemical Substances	montelukast (MHM278SD3E) ; Acetates
Language	English
Publishing date	2023-03-15
Publishing country	Japan
Document type	Journal Article
ZDB-ID	2092085-4
ISSN	1618-1255 ; 1618-1247
ISSN (online)	1618-1255
ISSN	1618-1247
DOI	10.1007/s10266-023-00800-5
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Article ; Online: Analysis of salivary flow rate, biochemical composition, and redox status in orchiectomized spontaneously hypertensive rats.

de Oliveira, Ana Carolina Fujimori / Brito, Victor Gustavo Balera / Ramos, Guilherme Henrique Alves Dos Santos / Werlang, Matheus Lima Cypriano / Fiais, Gabriela Alice / Dornelles, Rita Cássia Menegati / Antoniali, Cristina / Nakamune, Ana Cláudiade Melo Stevanato / Fakhouri, Walid D / Chaves-Neto, Antonio Hernandes

Archives of oral biology

2023 Volume 152, Page(s) 105732

Abstract: Objective: This study aimed to analyze the salivary flow rate, biochemical composition, and redox status in orchiectomized spontaneously hypertensive rats (SHR) compared to normotensive Wistar rats.: Design: Thirty-two young adult male SHR and Wistar ...

Abstract	Objective: This study aimed to analyze the salivary flow rate, biochemical composition, and redox status in orchiectomized spontaneously hypertensive rats (SHR) compared to normotensive Wistar rats. Design: Thirty-two young adult male SHR and Wistar (3-months-old) rats were randomly distributed into four groups; either castrated bilaterally (ORX) or underwent fictitious surgery (SHAM) as Wistar-SHAM, Wistar-ORX, SHR-SHAM, and SHR-ORX. Two months beyond castration, pilocarpine-induced salivary secretion was collected from 5-month-old rats to analyze salivary flow rate, pH, buffer capacity, total protein, amylase, calcium, phosphate, sodium, potassium, chloride, thiobarbituric acid reactive substances (TBARs), carbonyl protein, nitrite, and total antioxidant capacity. Results: The salivary flow rate was higher in the Wistar-ORX compared to the Wistar-SHAM group, while remaining similar between the SHR-SHAM and SHR-ORX groups. ORX did not affect pH and salivary buffer capacity in both strains. However, salivary total protein and amylase were significantly reduced in the Wistar-ORX and SHR-ORX compared to the respective SHAM groups. In both ORX groups, salivary total antioxidant capacity and carbonylated protein were increased, while lipid oxidative damage (TBARs) and nitrite concentration were higher only in the Wistar-ORX than in the Wistar-SHAM group. In the Wistar-ORX and SHR-ORX, the salivary calcium, phosphate, and chloride were increased while no change was detected in the SHAM groups. Only salivary buffering capacity, calcium, and chloride in the SHR-ORX adjusted to values similar to Wistar-SHAM group. Conclusion: Hypertensive phenotype mitigated the orchiectomy-induced salivary dysfunction, since the disturbances were restricted to alterations in the salivary biochemical composition and redox state.
MeSH term(s)	Rats ; Male ; Animals ; Rats, Inbred SHR ; Rats, Wistar ; Antioxidants ; Calcium ; Thiobarbituric Acid Reactive Substances ; Nitrites ; Chlorides ; Oxidation-Reduction ; Proteins ; Amylases
Chemical Substances	Antioxidants ; Calcium (SY7Q814VUP) ; Thiobarbituric Acid Reactive Substances ; Nitrites ; Chlorides ; Proteins ; Amylases (EC 3.2.1.-)
Language	English
Publishing date	2023-05-19
Publishing country	England
Document type	Journal Article
ZDB-ID	80227-x
ISSN	1879-1506 ; 0003-9969
ISSN (online)	1879-1506
ISSN	0003-9969
DOI	10.1016/j.archoralbio.2023.105732
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