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Article ; Online: Exploring the molecular landscape of NNK-induced transformation: A comprehensive genome-wide CRISPR/Cas9 screening.

Dinh, Trang / Rahm, Mira / Wang, Zhenghe / McFarland, Christopher / Khalil, Athar

2023 Volume 11, Issue 4, Page(s) 101131

Language	English
Publishing date	2023-09-29
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2821806-1
ISSN	2352-3042 ; 2352-3042
ISSN (online)	2352-3042
ISSN	2352-3042
DOI	10.1016/j.gendis.2023.101131
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Article ; Online: The potential oncogenic role of the RAS-like GTP-binding gene RIT1 in glioblastoma.

Khalil, Athar / Nemer, Georges

Cancer biomarkers : section A of Disease markers

2021 Volume 29, Issue 4, Page(s) 509–519

Abstract: Glioblastoma is the most common type of malignant brain tumors and the most feared cancer among adults. The poor prognosis among patients affected with this type of cancer is associated with its high-invasiveness and the lack of successful therapies. A ... ...

Abstract	Glioblastoma is the most common type of malignant brain tumors and the most feared cancer among adults. The poor prognosis among patients affected with this type of cancer is associated with its high-invasiveness and the lack of successful therapies. A comprehensive understanding for the early molecular mechanisms in glioblastoma would definitely enhance the diagnosis and the treatment strategies. Deregulated expression of key genes that are known to be involved in early neurogenesis could be the instigator of brain tumorigenesis. Ras Like Without CAAX 1 (RIT1) gene that encodes an unusual "orphan" GTPase protein belongs to this category of critical genes that are known to be involved in controlling sequential proliferation and differentiation of adult hippocampal neural progenitor cells. In this study, we surveyed RIT1 gene expression by in-silico approaches to determine its spatio-temporal pattern in glioblastoma. Our results revealed a significant and progressive upregulation of RIT1 mRNA levels in various publicly available datasets. RIT1 expression ranked among the top upregulated genes in glioblastoma cohorts and it correlated with poor overall survival. Genetic and epigenetic analysis of RIT1 didn't reveal any significant aberration that could underlie its deregulated expression. Yet, our results highlighted the possibility of its activity to be transcriptionally controlled by STAT3, one of the main players in the onset of glioblastoma. In conclusion, our study presented for the first time a potential oncogenic role for RIT1 in glioblastoma. Knowing that the RAS superfamily of proteins has created an evolution in the cancer field, RIT1 should be added to this list through further investigations on its possible usage as a biomarker and therapeutic target in glioblastoma.
MeSH term(s)	Adult ; Brain Neoplasms/genetics ; Brain Neoplasms/metabolism ; Brain Neoplasms/pathology ; Cell Differentiation/physiology ; Gene Expression Profiling ; Glioblastoma/genetics ; Glioblastoma/metabolism ; Glioblastoma/pathology ; Humans ; RNA, Messenger/biosynthesis ; RNA, Messenger/genetics ; STAT3 Transcription Factor/genetics ; STAT3 Transcription Factor/metabolism ; Up-Regulation ; ras Proteins/genetics ; ras Proteins/metabolism
Chemical Substances	RNA, Messenger ; STAT3 Transcription Factor ; STAT3 protein, human ; RIT1 protein, human (EC 3.6.1.-) ; ras Proteins (EC 3.6.5.2)
Keywords	covid19
Language	English
Publishing date	2021-08-06
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2203517-5
ISSN	1875-8592 ; 1574-0153 ; 1875-8592
ISSN (online)	1875-8592 ; 1574-0153
ISSN	1875-8592
DOI	10.3233/CBM-191264
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Article: The Digenic Causality in Familial Hypercholesterolemia: Revising the Genotype-Phenotype Correlations of the Disease.

Kamar, Amina / Khalil, Athar / Nemer, Georges

Frontiers in genetics

2021 Volume 11, Page(s) 572045

Abstract: Genetically inherited defects in lipoprotein metabolism affect more than 10 million individuals around the globe with preponderance in some parts where consanguinity played a major role in establishing founder mutations. Mutations in four genes have been ...

Abstract	Genetically inherited defects in lipoprotein metabolism affect more than 10 million individuals around the globe with preponderance in some parts where consanguinity played a major role in establishing founder mutations. Mutations in four genes have been so far linked to the dominant and recessive form of the disease. Those players encode major proteins implicated in cholesterol regulation, namely, the low-density lipoprotein receptor (LDLR) and its associate protein 1 (LDLRAP1), the proprotein convertase substilin/kexin type 9 (PCSK9), and the apolipoprotein B (APOB). Single mutations or compound mutations in one of these genes are enough to account for a spectrum of mild to severe phenotypes. However, recently several reports have identified digenic mutations in familial cases that do not necessarily reflect a much severe phenotype. Yet, data in the literature supporting this notion are still lacking. Herein, we review all the reported cases of digenic mutations focusing on the biological impact of gene dosage and the potential protective effects of single-nucleotide polymorphisms linked to hypolipidemia. We also highlight the difficulty of establishing phenotype-genotype correlations in digenic familial hypercholesterolemia cases due to the complexity and heterogeneity of the phenotypes and the still faulty
Language	English
Publishing date	2021-01-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2020.572045
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Article: Unveiling immune checkpoint regulation: exploring the power of

Wang, Yuxiang / Khalil, Athar / Kamar, Amina / Du, Mengyan / Dinh, Trang / McFarland, Christopher / Wang, Zhenghe

Frontiers in genetics

2023 Volume 14, Page(s) 1304425

Abstract: Immune checkpoint inhibitors (ICIs) have revolutionized cancer immunotherapy by reinvigorating antitumor immune responses, but their efficacy remains limited in most patients. To address this challenge and optimize Immune check inhibitor treatment, ... ...

Abstract	Immune checkpoint inhibitors (ICIs) have revolutionized cancer immunotherapy by reinvigorating antitumor immune responses, but their efficacy remains limited in most patients. To address this challenge and optimize Immune check inhibitor treatment, understanding the underlying molecular intricacies involved is crucial. The emergence of CRISPR-Cas9 technology has empowered researchers to precisely investigate gene function and has introduced transformative shifts in identifying key genes for various physiological and pathological processes. CRISPR screenings, particularly
Language	English
Publishing date	2023-12-14
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2023.1304425
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Article ; Online: A Cautious Note on Thalidomide Usage in Cancer Treatment: Genetic Profiling of the TBX2 Sub-Family Gene Expression is Required.

Nemer, Georges / Khalil, Athar

Drug research

2019 Volume 69, Issue 9, Page(s) 512–518

Abstract: Thalidomide is still by excellence the mysterious drug that fascinated, blurred, misled, and changed the scientific community perspectives and policies. It was introduced in the 1950's as a sedative drug, then shortly withdrawn because of the devastating ...

Abstract	Thalidomide is still by excellence the mysterious drug that fascinated, blurred, misled, and changed the scientific community perspectives and policies. It was introduced in the 1950's as a sedative drug, then shortly withdrawn because of the devastating birth defects that affected tens of thousands throughout more than 40 countries. Back into the market in the mid 1990's and 2000's the drug is now being used to treat skin immune-related conditions and some cancers like multiple myeloma. Despite numerous beneficial effects which led to the development of new analogs, its direct mechanisms of action are still elusive. The identification of CRBN and TBX5 as potential direct ligands for this drug have opened the way to better understand its efficiency and its failure.We hereby review these mechanisms and provide evidence that could explain why thalidomide failed to make it as a drug of choice in lung cancer treatment. Linking the genetic signature of TBX2 subfamily in these tumors to their inability to respond properly to thalidomide raises concerns of worsening lung cancer patients' health if this drug is utilized.
MeSH term(s)	Animals ; Gene Expression/drug effects ; Humans ; Neoplasms/drug therapy ; Neoplasms/genetics ; T-Box Domain Proteins/genetics ; Thalidomide/pharmacology ; Thalidomide/therapeutic use
Chemical Substances	T-Box Domain Protein 2 ; T-Box Domain Proteins ; Thalidomide (4Z8R6ORS6L)
Language	English
Publishing date	2019-04-01
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	2703847-6
ISSN	2194-9387 ; 2194-9379
ISSN (online)	2194-9387
ISSN	2194-9379
DOI	10.1055/a-0873-3529
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Article: The Lebanese COVID-19 Cohort; A Challenge for the ABO Blood Group System.

Khalil, Athar / Feghali, Rita / Hassoun, Mahmoud

Frontiers in medicine

2020 Volume 7, Page(s) 585341

Abstract: A sudden outbreak of pneumonia caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has rapidly spread all over the world facilitating the declaration of the resultant disease as a pandemic on March 2020. Predisposing factors for ... ...

Abstract	A sudden outbreak of pneumonia caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has rapidly spread all over the world facilitating the declaration of the resultant disease as a pandemic on March 2020. Predisposing factors for acquiring COVID-19 and for developing a severe form of this disease were postulated to be related to the epidemiological, clinical, and genetic characteristics of the patients. Biological markers such as the ABO blood group system were amongst these factors that were proposed to be linked to the variability in the disease course and/or the prevalence of the infection among different groups. Herein, we conducted the first retrospective case-control study from the Middle East and North Africa that tackles the association between the blood group types and the susceptibility to, as well as the severity of, SARS-CoV-2 infection. Contrary to the most acknowledged hypothesis, our results challenged the significance of this association and questioned the role of the ABO blood group system in dictating the severity of this disease. For future similar studies, we endorsed analyzing larger cohorts among different populations and we encouraged implementing more rigorous approaches to diminish the potential confounding effect of some underlying comorbidities and genetic variants that are known to be associated with the ABO blood group system.
Language	English
Publishing date	2020-11-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2775999-4
ISSN	2296-858X
ISSN	2296-858X
DOI	10.3389/fmed.2020.585341
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Article ; Online: Novel genes linked to Class II Division 1 malocclusion with mandibular micrognathism.

El Chekie, Michelle R / Nemer, Georges / Khalil, Athar / Macari, Anthony T / Ghafari, Joseph G

American journal of orthodontics and dentofacial orthopedics : official publication of the American Association of Orthodontists, its constituent societies, and the American Board of Orthodontics

2022 Volume 163, Issue 5, Page(s) 667–676.e3

Abstract: Introduction: Mandibular micrognathism (MM) is an underdeveloped mandible resulting from complex interactions between genetic and environmental factors. Prior research focused mainly on the genetic determinants of mandibular retrognathism, not ... ...

Abstract	Introduction: Mandibular micrognathism (MM) is an underdeveloped mandible resulting from complex interactions between genetic and environmental factors. Prior research focused mainly on the genetic determinants of mandibular retrognathism, not necessarily reflecting micrognathism, thus supporting the need to study MM. This study aimed to explore the inheritance pattern and identify the candidate genes involved in the development and familial transmission of MM. Methods: Diagnosing probands with MM was based on clinical and lateral cephalometric data. The pedigrees were drawn for 11 identified families, 5 of whom accepted to undergo detailed data and biospecimen collection. These families included 15 MM and 13 non-MM subjects over 2-3 generations. The procedure involved the withdrawal of 5 mL of blood. Genomic DNA was isolated from blood cells to investigate protein-coding regions via whole exome sequencing. Standardized filtering steps were employed, and candidate genes were identified. Results: Most of the pedigrees suggested a Mendelian inheritance pattern and segregated in an autosomal-dominant manner. One of the families, which also underwent biospecimen, displayed an X-linked inheritance pattern of the trait. Genetic screening disclosed 8 potentially novel genes (GLUD2, ADGRG4, ARSH, TGIF1, FGFR3, ZNF181, INTS7, and WNT6). None of the recognized exonic regions were previously reported. Conclusions: Eight novel genes were identified in association with MM in the largest number of families reported to date. The genes were X-linked in 1 family, a finding previously not observed in mandibular genetics.
MeSH term(s)	Humans ; Micrognathism ; Malocclusion ; Phenotype ; Pedigree ; Mandible ; Malocclusion, Angle Class II ; Repressor Proteins ; Homeodomain Proteins
Chemical Substances	TGIF1 protein, human ; Repressor Proteins ; Homeodomain Proteins
Language	English
Publishing date	2022-12-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	356699-7
ISSN	1097-6752 ; 0889-5406 ; 0002-9416
ISSN (online)	1097-6752
ISSN	0889-5406 ; 0002-9416
DOI	10.1016/j.ajodo.2022.04.020
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Article ; Online: Mutational signatures in GATA3 transcription factor and its DNA binding domain that stimulate breast cancer and HDR syndrome.

El-Assaad, Atlal / Dawy, Zaher / Khalil, Athar / Nemer, Georges

Scientific reports

2021 Volume 11, Issue 1, Page(s) 22762

Abstract: Transcription factors (TFs) play important roles in many biochemical processes. Many human genetic disorders have been associated with mutations in the genes encoding these transcription factors, and so those mutations became targets for medications and ... ...

Abstract	Transcription factors (TFs) play important roles in many biochemical processes. Many human genetic disorders have been associated with mutations in the genes encoding these transcription factors, and so those mutations became targets for medications and drug design. In parallel, since many transcription factors act either as tumor suppressors or oncogenes, their mutations are mostly associated with cancer. In this perspective, we studied the GATA3 transcription factor when bound to DNA in a crystal structure and assessed the effect of different mutations encountered in patients with different diseases and phenotypes. We generated all missense mutants of GATA3 protein and DNA within the adjacent and the opposite GATA3:DNA complex models. We mutated every amino acid and studied the new binding of the complex after each mutation. Similarly, we did for every DNA base. We applied Poisson-Boltzmann electrostatic calculations feeding into free energy calculations. After analyzing our data, we identified amino acids and DNA bases keys for binding. Furthermore, we validated those findings against experimental genetic data. Our results are the first to propose in silico modeling for GATA:DNA bound complexes that could be used to score effects of missense mutations in other classes of transcription factors involved in common and genetic diseases.
MeSH term(s)	Binding Sites ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; DNA/genetics ; DNA/metabolism ; Female ; GATA3 Transcription Factor/genetics ; GATA3 Transcription Factor/metabolism ; Hearing Loss, Sensorineural/genetics ; Hearing Loss, Sensorineural/metabolism ; Hearing Loss, Sensorineural/pathology ; Humans ; Hypoparathyroidism/genetics ; Hypoparathyroidism/metabolism ; Hypoparathyroidism/pathology ; Mutation ; Nephrosis/genetics ; Nephrosis/metabolism ; Nephrosis/pathology
Chemical Substances	GATA3 Transcription Factor ; GATA3 protein, human ; DNA (9007-49-2)
Language	English
Publishing date	2021-11-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-01832-z
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Article ; Online: Thalidomide-Revisited: Are COVID-19 Patients Going to Be the Latest Victims of Yet Another Theoretical Drug-Repurposing?

Khalil, Athar / Kamar, Amina / Nemer, Georges

Frontiers in immunology

2020 Volume 11, Page(s) 1248

Abstract: The coronavirus disease 2019 (COVID-19) pandemic is a worldwide threatening health issue. The progression of this viral infection occurs in the airways of the lungs with an exaggerated inflammatory response referred to as the "cytokine storm" that can ... ...

Abstract	The coronavirus disease 2019 (COVID-19) pandemic is a worldwide threatening health issue. The progression of this viral infection occurs in the airways of the lungs with an exaggerated inflammatory response referred to as the "cytokine storm" that can lead to lethal lung injuries. In the absence of an effective anti-viral molecule and until the formulation of a successful vaccine, anti-inflammatory drugs might offer a complementary tool for controlling the associated complications of COVID-19 and thus decreasing the subsequent fatalities. Drug repurposing for several molecules has emerged as a rapid temporary solution for COVID-19. Among these drugs is Thalidomide; a historically emblematic controversial molecule that harbors an FDA approval for treating erythema nodosum leprosum (ENL) and multiple myeloma (MM). Based on just one-case report that presented positive outcomes in a patient treated amongst others with Thalidomide, two clinical trials on the efficacy and safety of Thalidomide in treating severe respiratory complications in COVID-19 patients were registered. Yet, the absence of substantial evidence on Thalidomide usage in that context along with the discontinued studies on the efficiency of this drug in similar pulmonary diseases, might cause a significant obstacle for carrying out further clinical evaluations. Herein, we will discuss the theoretical effectiveness of Thalidomide in attenuating inflammatory complications that are encountered in COVID-19 patients while pinpointing the lack of the needed evidences to move forward with this drug.
MeSH term(s)	Animals ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Antiviral Agents/therapeutic use ; COVID-19 ; Coronavirus Infections/complications ; Coronavirus Infections/drug therapy ; Coronavirus Infections/immunology ; Disease Progression ; Drug Repositioning ; Humans ; Inflammation/drug therapy ; Inflammation/etiology ; Pandemics ; Pneumonia, Viral/complications ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/immunology ; Thalidomide/therapeutic use ; COVID-19 Drug Treatment
Chemical Substances	Anti-Inflammatory Agents, Non-Steroidal ; Antiviral Agents ; Thalidomide (4Z8R6ORS6L)
Keywords	covid19
Language	English
Publishing date	2020-05-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.01248
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Article ; Online: The Lebanese COVID-19 Cohort; A Challenge for the ABO Blood Group System

Athar Khalil / Rita Feghali / Mahmoud Hassoun

Frontiers in Medicine, Vol

2020 Volume 7

Abstract	A sudden outbreak of pneumonia caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has rapidly spread all over the world facilitating the declaration of the resultant disease as a pandemic on March 2020. Predisposing factors for acquiring COVID-19 and for developing a severe form of this disease were postulated to be related to the epidemiological, clinical, and genetic characteristics of the patients. Biological markers such as the ABO blood group system were amongst these factors that were proposed to be linked to the variability in the disease course and/or the prevalence of the infection among different groups. Herein, we conducted the first retrospective case-control study from the Middle East and North Africa that tackles the association between the blood group types and the susceptibility to, as well as the severity of, SARS-CoV-2 infection. Contrary to the most acknowledged hypothesis, our results challenged the significance of this association and questioned the role of the ABO blood group system in dictating the severity of this disease. For future similar studies, we endorsed analyzing larger cohorts among different populations and we encouraged implementing more rigorous approaches to diminish the potential confounding effect of some underlying comorbidities and genetic variants that are known to be associated with the ABO blood group system.
Keywords	COVID-19 ; ABO ; SARS–CoV-2 ; infection predisposition ; MENA (Middle East and North Africa) ; Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2020-11-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
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