Javid Dar | King Saud University (original) (raw)

Papers by Javid Dar

Research paper thumbnail of Correction to: Screening and computational analysis of colorectal associated non-synonymous polymorphism in CTNNB1 gene in Pakistani population

BMC Medical Genetics, 2020

Following publication of the original article [1], the authors have flagged that the article has ... more Following publication of the original article [1], the authors have flagged that the article has published with an error in the order of the affiliations.

Research paper thumbnail of Taliban: A Bibliometric Investigation

Social Science Research Network, 2021

The primary objective of this study is to identify the global research output on Taliban during t... more The primary objective of this study is to identify the global research output on Taliban during the period of 25 years spanning from 1996-2020. Specific objectives are to analyze the distribution of literature, publication trends, authorship patterns, institutional productivity, collaboration networks, and prolific funding agencies. The data was harvested from the Web of Science Core Collection. A total of 614 records were retrieved on Taliban having 4416 total citations. The highest output was recorded in 2002, with a share of 7.83% to overall literature. The citation pattern depicted a fluctuating, the highest share being received in the year 2002 (14.47%), followed by the years 2010, 2004, and 2007 with the citation share of 11.03%, 10.67%, and 6.82% respectively. The results depict that among all the countries, the USA is topping the list, contributing almost 47.1% of the total research output followed by the United Kingdom, Pakistan, Australia, and Canada with the publication share of 16.78%, 6.19%, 6.03%, and 4.4% respectively.

Research paper thumbnail of The extracts of Berberis lycium and diabetes mellitus in alloxan monohydrate induced diabetic rats

Incidence of type II diabetes is rapidly increasing worldwide. In order to identify complementary... more Incidence of type II diabetes is rapidly increasing worldwide. In order to identify complementary or alternative approaches to existing medications, we studied anti-diabetic properties of Berberis lycium-a natural health product recommended for diabetes treatment in kashmir. The hypoglycemic activity of the aqueous and methanolic extracts of this plant at two dose levels of 250 and 500mg/kg b.wt in normal as well as in rats with Alloxan monohydrate induced diabetes was studied. The oral administration of aqueous and methanolic extract causes maximum fall of blood glucose level to 58.41% and 50.80% in diabetic rats respectively. The acute oral toxicity studies of the extracts revealed no toxic effects of the extracts. The extracts also lowered the levels of serum cholesterol, serum triglycerides, serum LDL, serum VLDL, serum SGOT, serum SGPT, and Serum ALP in diabetic rats. The histological studies depict that the extracts have a protective effect on the ß-cells of pancreas in diabet...

Research paper thumbnail of β-Catenin accumulation and S33F mutation of CTNNB1 gene in colorectal cancer in Saudi Arabia

Polish Journal of Pathology, 2016

Several risk factors associated with colorectal cancer (CRC) have been identified including β-cat... more Several risk factors associated with colorectal cancer (CRC) have been identified including β-catenin/CTNNB1 hotspot mutations. The levels of β-catenin within a cell are regulated via phosphorylation of the N terminus of β-catenin by GSK-3β. Thus far three serines (S33, 37, 45) and one threonine (T41) are considered to be the substrates for GSK-3β phosphorylation. In the present investigation an attempt was made to study the role of β-catenin mutations in exon-3 in 60 colorectal cancer patients from Kingdom of Saudi Arabia (KSA). The hot spot mutation region of β-catenin exon 3 was evaluated in matched tumor and normal tissues using PCR and direct sequencing. Sequencing of exon 3 of the CTNNB1 gene revealed an activating mutation (S33F) in one of the tumor samples as compared to the normal tissue from the same patient where there was no such mutation found. Immunohistochemical staining showed the accumulation of β-catenin protein both in cytoplasm and in the nuclei of cancer cells as compared to normal tissue.

Research paper thumbnail of Screening and computational analysis of colorectal associated non-synonymous polymorphism in CTNNB1 gene in Pakistani population

BMC Medical Genetics, 2019

BackgroundColorectal cancer (CRC) is categorized by alteration of vital pathways such as β-cateni... more BackgroundColorectal cancer (CRC) is categorized by alteration of vital pathways such as β-catenin(CTNNB1) mutations,WNTsignaling activation,tumor protein 53 (TP53) inactivation,BRAF, Adenomatous polyposis coli (APC) inactivation,KRAS, dysregulation of epithelial to mesenchymal transition (EMT) genes,MYCamplification, etc. In the present study an attempt was made to screenCTNNB1gene in colorectal cancer samples from Pakistani population and investigated the association ofCTNNB1gene mutations in the development of colorectal cancer.Methods200 colorectal tumors approximately of male and female patients with sporadic or familial colorectal tumors and normal tissues were included. DNA was extracted and amplified through polymerase chain reaction (PCR) and subjected to exome sequence analysis. Immunohistochemistry was done to study protein expression. Molecular dynamic (MD) simulations of CTNNB1WTand mutant S33F and T41A were performed to evaluate the stability, folding, conformational c...

Research paper thumbnail of RESEARCH ARTICLE Poly (A) Binding Protein Cytoplasmic 1 Is a Novel Co-Regulator of the Androgen Receptor

The androgen receptor (AR) is a member of the steroid receptor superfamily that regulates gene ex... more The androgen receptor (AR) is a member of the steroid receptor superfamily that regulates gene expression in a ligand-dependent manner. The NTD of the AR plays a key role in AR transactivation including androgen-independent activation of the AR in castration-resistant prostate cancer (CRPC) cells. We recently reported that amino acids (a.a.) 50-250 of the NTD are capable of modulating AR nucleocytoplasmic trafficking. To further explore the mechanism associated with a.a. 50-250, GFP pull-down assays were performed in C4-2 CRPC cells transfected with GFP tagged a.a. 50-250 of the AR. Mass spectrometry analy-sis of the pulled down proteins identified poly (A) binding protein cytoplasmic 1 (PABPC1) interaction with this region of the AR. In silicoanalysis of gene expression data revealed PABPC1 up-regulation in prostate cancer tissue specimens and this up-regulation corre-lates to increased disease recurrence. Co-immunoprecipitation assays confirmed the asso-ciation of PABPC1 with a.a....

Research paper thumbnail of The Association of β-catenin Gene Mutations and Human Papillomavirus in Carcinoma of Esophagus in a High-risk Population of India

International journal of health sciences

Esophageal cancer (EC) is the sixth leading cause of death from cancer. In high-risk regions, squ... more Esophageal cancer (EC) is the sixth leading cause of death from cancer. In high-risk regions, squamous cell carcinoma is the most common type of EC, and its etiology remains poorly understood. It shows uneven geographical distribution in its occurrence, reflecting the influence of local environmental conditions, lifestyle and genetic predisposition in the development of the cancer. Kashmir, in the north of India, has been described as a high-risk area for esophageal squamous cell carcinoma (ESCC). In the present investigation an attempt was made to study the role of β-catenin mutations and human papillomavirus in 62 ESCC patients from Kashmir. METHODS: The hot spot mutation region of β-catenin exon 3 was evaluated in matched tumor and normal tissues using a combination of PCR-SSCP and direct sequencing. We used two different sets of consensus primers viz., GP5+ and GP6+; PGMY09 and PGMY11 in conjunction with reverse line blot assay to screen for human papillomavirus(HPV). RESULTS: N...

Research paper thumbnail of ral Annals of Clinical Microbiology and

Molecular epidemiology of clinical and carrier strains of methicillin resistant Staphylococcus au... more Molecular epidemiology of clinical and carrier strains of methicillin resistant Staphylococcus aureus (MRSA) in the hospital settings of north India

Research paper thumbnail of PC 04. Identification and characterization of a ligandregulated nuclear export signal in androgen receptor

Translational Andrology and Urology, 2012

Research paper thumbnail of Presence of RAS mutations but no role of BRAF and beta-catenin mutations together with human papilloma virus (HPV) in squamous cell carcinoma of esophagus in a high-risk population from Kashmir

Cancer Epidemiology and Prevention Biomarkers, 2006

B188 Worldwide esophageal cancer ranks among the ten most common cancers. Although, there is a ri... more B188 Worldwide esophageal cancer ranks among the ten most common cancers. Although, there is a rising entity of adenocarcinoma, the majority of carcinoma of the esophagus are squamous-cell carcinoma. It shows uneven geographical distribution in its occurrence, reflecting the influence of local environmental conditions, lifestyle and genetic predisposition in the development of the cancer. Kashmir valley, in the north of India, has been described as a high-risk area for esophageal squamous cell carcinoma (ESCC). In the present investigation an attempt was made to study polymorphisms in oncogenes viz., KRAS, NRAS, BRAF and beta-catenin in 47 ESCC patients from Kashmir valley. The hot spot mutation regions of KRAS, NRAS, BRAF and beta-catenin were analyzed in matched tumor and normal tissues using a combination of PCR-SSCP and direct sequencing. None of the tumors showed the presence of commonly reported mutations in either BRAF or beta-catenin but our analysis indicated the presence o...

Research paper thumbnail of Combined impact of polymorphism of folate metabolism genes; glutamate carboxypeptidase, methylene tetrahydrofolate reductase and methionine synthase reductase on breast cancer susceptibility in kashmiri women

International journal of health sciences, 2008

BACKGROUND Folate and methionine play a crucial role in DNA synthesis, repair and the epigenetic ... more BACKGROUND Folate and methionine play a crucial role in DNA synthesis, repair and the epigenetic profile of cell. Hence, the alterations in the folate metabolism can lead to aberrant proliferation leading to neoplasia. Most of the studies have associated polymorphisms in methylene tetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genes with reduced risk of cervical and colorectal cancer. However, the association with breast cancer is still controversial. Further, the involvement of Glutamate carboxypeptidase II (GCPII) polymorphism in cancer is not known. In the present study, we analyzed if the individual and combined effects of polymorphisms in folate pathway genes viz., MTHFR 677C > T, MTHFR 1298A > C, MTRR 66A > G and GCP II 1561 C>T, have any role in altering the susceptibility to breast cancer. METHODS The DNA of 35 female breast cancer patients and 33 healthy individuals, in the Kashmiri population from India, were analyzed using a PCR-RF...

Research paper thumbnail of The Association of Beta-catenin Gene Mutations and Human Papillomavirus in Carcinoma of Esophagus in a High-Risk Population of India

BACKGROUND Esophageal cancer (EC) is the sixth leading cause of death from cancer. In high-risk r... more BACKGROUND Esophageal cancer (EC) is the sixth leading cause of death from cancer. In high-risk regions, squamous cell carcinoma is the most common type of EC, and its etiology remains poorly understood. It shows uneven geographical distribution in its occurrence, reflecting the influence of local environmental conditions, lifestyle and genetic predisposition in the development of the cancer. Kashmir, in the north of India, has been described as a high-risk area for esophageal squamous cell carcinoma (ESCC). In the present investigation an attempt was made to study the role of β-catenin mutations and human papillomavirus in 62 ESCC patients from Kashmir. METHODS The hot spot mutation region of β-catenin exon 3 was evaluated in matched tumor and normal tissues using a combination of PCR-SSCP and direct sequencing. We used two different sets of consensus primers viz., GP5+ and GP6+; PGMY09 and PGMY11 in conjunction with reverse line blot assay to screen for human papillomavirus(HPV). ...

Research paper thumbnail of Inhibition of Androgen Receptor Nuclear Localization and Castration Resistant Prostate Tumor Growth by Pyrroloimidazole-Based Small Molecules

Molecular cancer therapeutics, Oct 27, 2017

The androgen receptor (AR) is a ligand-dependent transcription factor that controls the expressio... more The androgen receptor (AR) is a ligand-dependent transcription factor that controls the expression of androgen-responsive genes. A key step in androgen action, which is amplified in castration resistant prostate cancer (CRPC), is AR nuclear translocation. Small molecules capable of inhibiting AR nuclear localization could be developed as novel therapeutics for CRPC. We developed a high throughput screen and identified two structurally-related pyrroloimidazoles that could block AR nuclear localization in CRPC cells. We show that these two small molecules, 3-(4-ethoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (EPPI) and 3-(4-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (CPPI) can inhibit the nuclear localization and transcriptional activity of AR and reduce the proliferation of AR-positive but not AR-negative prostate cancer cell lines. EPPI and CPPI did not inhibit nuclear localization of the glucocorticoid receptor or the estrogen receptor, suggesting they selectively ...

Research paper thumbnail of Inhibition of androgen receptor function and level in castration-resistant prostate cancer cells by 2-((isoxazol-4-ylmethyl)thio)-1-(4-phenylpiperazin-1-yl)ethanone

Endocrinology

The androgen receptor (AR) plays a critical role in the development of castration-resistant prost... more The androgen receptor (AR) plays a critical role in the development of castration-resistant prostate cancer (CRPC) as well as in the resistance to the second-generation AR antagonist enzalutamide and the selective inhibitor of cytochrome P450 17A1 (CYP17A1) abiraterone. Novel agents targeting AR may inhibit the growth of prostate cancer cells resistant to enzalutamide and/or abiraterone. Through a high-throughput/high-content screening of a 220,000-member small molecule library, we have previously identified 2-[(isoxazol-4-ylmethyl)thio]-1-(4-phenylpiperazin-1-yl)ethanone (IMTPPE) (SID 3712502) as a novel small molecule capable of inhibiting AR transcriptional activity and protein level in C4-2 prostate cancer cells. In this study, we show that IMTPPE inhibits ARtarget gene expression using real-time polymerase chain reaction, Western blot, and luciferase assays. IMTPPE inhibited proliferation of AR-positive, but not AR-negative, prostate cancer cells in culture. IMTPPE inhibited the transcriptional activity of a mutant AR lacking the ligand-binding domain (LBD), indicating that IMTPPE inhibition of AR is independent of the LBD. Furthermore, animal studies showed that IMTPPE inhibited the growth of 22Rv1 xenograft tumor, a model for enzalutamide-resistant prostate cancer. These findings suggest that IMTPPE is a potential lead compound for developing clinical candidates for the treatment of CRPC, including those resistant to enzalutamide. (Endocrinology 158: 3152-3161, 2017) A ndrogen deprivation therapy (ADT) is the standard treatment of patients with metastatic prostate cancer (1). However, ADT is not curative, and treated patients eventually develop castration-resistant prostate cancer (CRPC) (2, 3). CRPC is currently incurable, and it is predicted that in 2017 prostate cancer will be the third

Research paper thumbnail of Splicing factor Prp8 interacts with NES(AR) and regulates androgen receptor in prostate cancer cells

Molecular endocrinology (Baltimore, Md.), Jan 15, 2015

Androgen receptor (AR) plays a pivotal role in the development of primary as well as advanced cas... more Androgen receptor (AR) plays a pivotal role in the development of primary as well as advanced castration-resistant prostate cancer. Previous work in our lab identified a novel nuclear export signal (NES(AR)) in AR ligand binding domain essential for AR nucleocytoplasmic trafficking. By characterizing the localization of green fluorescence protein (GFP) tagged NES(AR), we designed and executed a yeast mutagenesis screen and isolated seven yeast mutants that failed to display the NES(AR) export function. One of those mutants was identified as the splicing factor Prp8. We further showed that Prp8 could regulate NES(AR) function using shRNA knockdown of Prp8 coupled with a rapamycin export assay in mammalian cells and knockdown of Prp8 could induce nuclear accumulation of GFP-tagged AR in PC3 cells. Prp8 expression was decreased in castration resistant LuCaP35 xenograft tumors as compared with androgen sensitive xenografts. Laser capture microdissection and quantitative PCR showed Prp8 ...

Research paper thumbnail of Acylated flavonol glycoside from Platanus orientalis

Fitoterapia, 2012

Background: Esophageal cancer (EC) is the sixth leading cause of death from cancer. In high-risk ... more Background: Esophageal cancer (EC) is the sixth leading cause of death from cancer. In high-risk regions, squamous cell carcinoma is the most common type of EC, and its etiology remains poorly understood. It shows uneven geographical distribution in its occurrence, reflecting the influence of local environmental conditions, lifestyle and genetic predisposition in the development of the cancer. Kashmir, in the north of India, has been described as a high-risk area for esophageal squamous cell carcinoma (ESCC). In the present investigation an attempt was made to study the role of -catenin mutations and human papillomavirus in 62 ESCC patients from Kashmir.

Research paper thumbnail of Genotypic diversity of the Killer Cell Immunoglobulin-like Receptors (KIR) and their HLA class I Ligands in a Saudi population

Genetics and Molecular Biology, 2016

Killer Cell Immunoglobulin-like Receptors (KIR) have been used as good markers for the study of g... more Killer Cell Immunoglobulin-like Receptors (KIR) have been used as good markers for the study of genetic predisposition in many diseases and in human genetic population dynamics. In this context, we have investigated the genetic diversity of KIR genes and their main HLA class I ligands in Saudi population and compared the data with other studies of neighboring populations. One hundred and fourteen randomly selected healthy Saudi subjects were genotyped for the presence or absence of 16 KIR genes and their HLA-C1, -C2, -Bw4Thr80 and Bw4Ile80 groups, using a PCR-SSP technique. The results show the occurrence of the framework genes (3DL2, 3DL3 and 2DL4) and the pseudogenes (2DP1 and 3DP1) at highest frequencies. All inhibitory KIR (iKIR) genes appeared at higher frequencies than activating genes (aKIR), except for 2DS4 with a frequency of 90.35%. A total of 55 different genotypes were observed appearing at different frequencies, where 12 are considered novel. Two haplotypes were characterized, AA and Bx (BB and AB), which were observed in 24.5% and 75.5% respectively of the studied group. The frequencies of iKIR + HLA associations were found to be much higher than aKIR + HLA. KIR genes frequencies in the Saudi population are comparable with other Middle Eastern and North African populations.

Research paper thumbnail of PCR array and protein array studies demonstrate that IL-1β (interleukin-1β) stimulates the expression and secretion of multiple cytokines and chemokines in human adipocytes

Archives of physiology and biochemistry, Jan 15, 2015

The role of IL-1β in regulating the expression and secretion of cytokines and chemokines by human... more The role of IL-1β in regulating the expression and secretion of cytokines and chemokines by human adipocytes was examined. Adipocytes were incubated with human IL-1β for 4 or 24 h. The expression of a panel of 84 cytokine/chemokine genes was probed using PCR arrays. IL-1β stimulated the expression of >30 cytokine/chemokine genes on the arrays; 15 showed >100-fold increases in mRNA at 4 or 24 h including CSF3, CXCL1, CXCL2, CXCL12 and IL8. CSF3 exhibited a 10 000-fold increase in mRNA at 4 h. ADIPOQ was among the genes whose expression was inhibited. Protein arrays were used to examine the secretion of cytokines/chemokines from adipocytes. IL-1β stimulated the secretion of multiple cytokines/chemokines including MCP-1, IL-8, IP-10, MIP-1α and MCP-4. The most responsive was IP-10, which exhibited a 5000-fold increase in secretion with IL-1β. IL-1β is likely to play a substantial role in stimulating the inflammatory response in human adipocytes in obesity.

Research paper thumbnail of PCR array and protein array studies demonstrate that IL-1 β (interleukin-1 β ) stimulates the expression and secretion of multiple cytokines and chemokines in human adipocytes

Archives of Physiology and Biochemistry, 2015

The role of IL-1β in regulating the expression and secretion of cytokines and chemokines by human... more The role of IL-1β in regulating the expression and secretion of cytokines and chemokines by human adipocytes was examined. Adipocytes were incubated with human IL-1β for 4 or 24 h. The expression of a panel of 84 cytokine/chemokine genes was probed using PCR arrays. IL-1β stimulated the expression of >30 cytokine/chemokine genes on the arrays; 15 showed >100-fold increases in mRNA at 4 or 24 h including CSF3, CXCL1, CXCL2, CXCL12 and IL8. CSF3 exhibited a 10 000-fold increase in mRNA at 4 h. ADIPOQ was among the genes whose expression was inhibited. Protein arrays were used to examine the secretion of cytokines/chemokines from adipocytes. IL-1β stimulated the secretion of multiple cytokines/chemokines including MCP-1, IL-8, IP-10, MIP-1α and MCP-4. The most responsive was IP-10, which exhibited a 5000-fold increase in secretion with IL-1β. IL-1β is likely to play a substantial role in stimulating the inflammatory response in human adipocytes in obesity.

Research paper thumbnail of The Relationship Between Killer Cell Immunoglobulin-Like Receptors and HLA-C Polymorphisms in Colorectal Cancer in a Saudi Population

Genetic Testing and Molecular Biomarkers, 2015

We performed an association study to evaluate the contribution of 16 killer cell immunoglobulin-l... more We performed an association study to evaluate the contribution of 16 killer cell immunoglobulin-like receptor (KIR) genotype polymorphisms and the HLA-C1 and -C2 ligands in the development of colorectal cancer (CRC) in Saudi Arabian patients. A total of 52 patients with different stages of malignant CRC as well as 70 healthy Saudi controls were enrolled at the King Khalid University Hospital. Our results showed that the frequency of the activating mutations KIR2DS1, 2DS2, 2DS3, 2DS5, and 3DS1 was significantly higher in CRC patients compared to controls. The 3DS1 gene contributed to the highest risk of CRC (odds ratio [OR] = 16.25, p < 0.0001), followed by 2DS1 (OR = 8.6; p < 0.0001). The distributions of HLA-C1 and -C2 ligands were not significantly different between patients and controls. Analyses of different combinations of KIR genes with their HLA-C1 and -C2 ligands show that the frequency of 2DL3 in the presence of its ligand, the allotype C1, was significantly more prevalent in patients compared to controls. In addition, 2DL2 and 2DL3 that were aggregated in combination with the ligand, HLA-C1, were found to be more highly associated mainly with the homozygote HLA-C1/C1 (p = 0.03; OR = 2.6). The activating mutations 2DS1 and 2DS2 when combined with their respective ligands, HLA-C2 and -C1, showed highly significant associations with CRC development. This study supports a key role for KIR gene mutations in the development of CRC, especially in association with their ligands.

Research paper thumbnail of Correction to: Screening and computational analysis of colorectal associated non-synonymous polymorphism in CTNNB1 gene in Pakistani population

BMC Medical Genetics, 2020

Following publication of the original article [1], the authors have flagged that the article has ... more Following publication of the original article [1], the authors have flagged that the article has published with an error in the order of the affiliations.

Research paper thumbnail of Taliban: A Bibliometric Investigation

Social Science Research Network, 2021

The primary objective of this study is to identify the global research output on Taliban during t... more The primary objective of this study is to identify the global research output on Taliban during the period of 25 years spanning from 1996-2020. Specific objectives are to analyze the distribution of literature, publication trends, authorship patterns, institutional productivity, collaboration networks, and prolific funding agencies. The data was harvested from the Web of Science Core Collection. A total of 614 records were retrieved on Taliban having 4416 total citations. The highest output was recorded in 2002, with a share of 7.83% to overall literature. The citation pattern depicted a fluctuating, the highest share being received in the year 2002 (14.47%), followed by the years 2010, 2004, and 2007 with the citation share of 11.03%, 10.67%, and 6.82% respectively. The results depict that among all the countries, the USA is topping the list, contributing almost 47.1% of the total research output followed by the United Kingdom, Pakistan, Australia, and Canada with the publication share of 16.78%, 6.19%, 6.03%, and 4.4% respectively.

Research paper thumbnail of The extracts of Berberis lycium and diabetes mellitus in alloxan monohydrate induced diabetic rats

Incidence of type II diabetes is rapidly increasing worldwide. In order to identify complementary... more Incidence of type II diabetes is rapidly increasing worldwide. In order to identify complementary or alternative approaches to existing medications, we studied anti-diabetic properties of Berberis lycium-a natural health product recommended for diabetes treatment in kashmir. The hypoglycemic activity of the aqueous and methanolic extracts of this plant at two dose levels of 250 and 500mg/kg b.wt in normal as well as in rats with Alloxan monohydrate induced diabetes was studied. The oral administration of aqueous and methanolic extract causes maximum fall of blood glucose level to 58.41% and 50.80% in diabetic rats respectively. The acute oral toxicity studies of the extracts revealed no toxic effects of the extracts. The extracts also lowered the levels of serum cholesterol, serum triglycerides, serum LDL, serum VLDL, serum SGOT, serum SGPT, and Serum ALP in diabetic rats. The histological studies depict that the extracts have a protective effect on the ß-cells of pancreas in diabet...

Research paper thumbnail of β-Catenin accumulation and S33F mutation of CTNNB1 gene in colorectal cancer in Saudi Arabia

Polish Journal of Pathology, 2016

Several risk factors associated with colorectal cancer (CRC) have been identified including β-cat... more Several risk factors associated with colorectal cancer (CRC) have been identified including β-catenin/CTNNB1 hotspot mutations. The levels of β-catenin within a cell are regulated via phosphorylation of the N terminus of β-catenin by GSK-3β. Thus far three serines (S33, 37, 45) and one threonine (T41) are considered to be the substrates for GSK-3β phosphorylation. In the present investigation an attempt was made to study the role of β-catenin mutations in exon-3 in 60 colorectal cancer patients from Kingdom of Saudi Arabia (KSA). The hot spot mutation region of β-catenin exon 3 was evaluated in matched tumor and normal tissues using PCR and direct sequencing. Sequencing of exon 3 of the CTNNB1 gene revealed an activating mutation (S33F) in one of the tumor samples as compared to the normal tissue from the same patient where there was no such mutation found. Immunohistochemical staining showed the accumulation of β-catenin protein both in cytoplasm and in the nuclei of cancer cells as compared to normal tissue.

Research paper thumbnail of Screening and computational analysis of colorectal associated non-synonymous polymorphism in CTNNB1 gene in Pakistani population

BMC Medical Genetics, 2019

BackgroundColorectal cancer (CRC) is categorized by alteration of vital pathways such as β-cateni... more BackgroundColorectal cancer (CRC) is categorized by alteration of vital pathways such as β-catenin(CTNNB1) mutations,WNTsignaling activation,tumor protein 53 (TP53) inactivation,BRAF, Adenomatous polyposis coli (APC) inactivation,KRAS, dysregulation of epithelial to mesenchymal transition (EMT) genes,MYCamplification, etc. In the present study an attempt was made to screenCTNNB1gene in colorectal cancer samples from Pakistani population and investigated the association ofCTNNB1gene mutations in the development of colorectal cancer.Methods200 colorectal tumors approximately of male and female patients with sporadic or familial colorectal tumors and normal tissues were included. DNA was extracted and amplified through polymerase chain reaction (PCR) and subjected to exome sequence analysis. Immunohistochemistry was done to study protein expression. Molecular dynamic (MD) simulations of CTNNB1WTand mutant S33F and T41A were performed to evaluate the stability, folding, conformational c...

Research paper thumbnail of RESEARCH ARTICLE Poly (A) Binding Protein Cytoplasmic 1 Is a Novel Co-Regulator of the Androgen Receptor

The androgen receptor (AR) is a member of the steroid receptor superfamily that regulates gene ex... more The androgen receptor (AR) is a member of the steroid receptor superfamily that regulates gene expression in a ligand-dependent manner. The NTD of the AR plays a key role in AR transactivation including androgen-independent activation of the AR in castration-resistant prostate cancer (CRPC) cells. We recently reported that amino acids (a.a.) 50-250 of the NTD are capable of modulating AR nucleocytoplasmic trafficking. To further explore the mechanism associated with a.a. 50-250, GFP pull-down assays were performed in C4-2 CRPC cells transfected with GFP tagged a.a. 50-250 of the AR. Mass spectrometry analy-sis of the pulled down proteins identified poly (A) binding protein cytoplasmic 1 (PABPC1) interaction with this region of the AR. In silicoanalysis of gene expression data revealed PABPC1 up-regulation in prostate cancer tissue specimens and this up-regulation corre-lates to increased disease recurrence. Co-immunoprecipitation assays confirmed the asso-ciation of PABPC1 with a.a....

Research paper thumbnail of The Association of β-catenin Gene Mutations and Human Papillomavirus in Carcinoma of Esophagus in a High-risk Population of India

International journal of health sciences

Esophageal cancer (EC) is the sixth leading cause of death from cancer. In high-risk regions, squ... more Esophageal cancer (EC) is the sixth leading cause of death from cancer. In high-risk regions, squamous cell carcinoma is the most common type of EC, and its etiology remains poorly understood. It shows uneven geographical distribution in its occurrence, reflecting the influence of local environmental conditions, lifestyle and genetic predisposition in the development of the cancer. Kashmir, in the north of India, has been described as a high-risk area for esophageal squamous cell carcinoma (ESCC). In the present investigation an attempt was made to study the role of β-catenin mutations and human papillomavirus in 62 ESCC patients from Kashmir. METHODS: The hot spot mutation region of β-catenin exon 3 was evaluated in matched tumor and normal tissues using a combination of PCR-SSCP and direct sequencing. We used two different sets of consensus primers viz., GP5+ and GP6+; PGMY09 and PGMY11 in conjunction with reverse line blot assay to screen for human papillomavirus(HPV). RESULTS: N...

Research paper thumbnail of ral Annals of Clinical Microbiology and

Molecular epidemiology of clinical and carrier strains of methicillin resistant Staphylococcus au... more Molecular epidemiology of clinical and carrier strains of methicillin resistant Staphylococcus aureus (MRSA) in the hospital settings of north India

Research paper thumbnail of PC 04. Identification and characterization of a ligandregulated nuclear export signal in androgen receptor

Translational Andrology and Urology, 2012

Research paper thumbnail of Presence of RAS mutations but no role of BRAF and beta-catenin mutations together with human papilloma virus (HPV) in squamous cell carcinoma of esophagus in a high-risk population from Kashmir

Cancer Epidemiology and Prevention Biomarkers, 2006

B188 Worldwide esophageal cancer ranks among the ten most common cancers. Although, there is a ri... more B188 Worldwide esophageal cancer ranks among the ten most common cancers. Although, there is a rising entity of adenocarcinoma, the majority of carcinoma of the esophagus are squamous-cell carcinoma. It shows uneven geographical distribution in its occurrence, reflecting the influence of local environmental conditions, lifestyle and genetic predisposition in the development of the cancer. Kashmir valley, in the north of India, has been described as a high-risk area for esophageal squamous cell carcinoma (ESCC). In the present investigation an attempt was made to study polymorphisms in oncogenes viz., KRAS, NRAS, BRAF and beta-catenin in 47 ESCC patients from Kashmir valley. The hot spot mutation regions of KRAS, NRAS, BRAF and beta-catenin were analyzed in matched tumor and normal tissues using a combination of PCR-SSCP and direct sequencing. None of the tumors showed the presence of commonly reported mutations in either BRAF or beta-catenin but our analysis indicated the presence o...

Research paper thumbnail of Combined impact of polymorphism of folate metabolism genes; glutamate carboxypeptidase, methylene tetrahydrofolate reductase and methionine synthase reductase on breast cancer susceptibility in kashmiri women

International journal of health sciences, 2008

BACKGROUND Folate and methionine play a crucial role in DNA synthesis, repair and the epigenetic ... more BACKGROUND Folate and methionine play a crucial role in DNA synthesis, repair and the epigenetic profile of cell. Hence, the alterations in the folate metabolism can lead to aberrant proliferation leading to neoplasia. Most of the studies have associated polymorphisms in methylene tetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genes with reduced risk of cervical and colorectal cancer. However, the association with breast cancer is still controversial. Further, the involvement of Glutamate carboxypeptidase II (GCPII) polymorphism in cancer is not known. In the present study, we analyzed if the individual and combined effects of polymorphisms in folate pathway genes viz., MTHFR 677C > T, MTHFR 1298A > C, MTRR 66A > G and GCP II 1561 C>T, have any role in altering the susceptibility to breast cancer. METHODS The DNA of 35 female breast cancer patients and 33 healthy individuals, in the Kashmiri population from India, were analyzed using a PCR-RF...

Research paper thumbnail of The Association of Beta-catenin Gene Mutations and Human Papillomavirus in Carcinoma of Esophagus in a High-Risk Population of India

BACKGROUND Esophageal cancer (EC) is the sixth leading cause of death from cancer. In high-risk r... more BACKGROUND Esophageal cancer (EC) is the sixth leading cause of death from cancer. In high-risk regions, squamous cell carcinoma is the most common type of EC, and its etiology remains poorly understood. It shows uneven geographical distribution in its occurrence, reflecting the influence of local environmental conditions, lifestyle and genetic predisposition in the development of the cancer. Kashmir, in the north of India, has been described as a high-risk area for esophageal squamous cell carcinoma (ESCC). In the present investigation an attempt was made to study the role of β-catenin mutations and human papillomavirus in 62 ESCC patients from Kashmir. METHODS The hot spot mutation region of β-catenin exon 3 was evaluated in matched tumor and normal tissues using a combination of PCR-SSCP and direct sequencing. We used two different sets of consensus primers viz., GP5+ and GP6+; PGMY09 and PGMY11 in conjunction with reverse line blot assay to screen for human papillomavirus(HPV). ...

Research paper thumbnail of Inhibition of Androgen Receptor Nuclear Localization and Castration Resistant Prostate Tumor Growth by Pyrroloimidazole-Based Small Molecules

Molecular cancer therapeutics, Oct 27, 2017

The androgen receptor (AR) is a ligand-dependent transcription factor that controls the expressio... more The androgen receptor (AR) is a ligand-dependent transcription factor that controls the expression of androgen-responsive genes. A key step in androgen action, which is amplified in castration resistant prostate cancer (CRPC), is AR nuclear translocation. Small molecules capable of inhibiting AR nuclear localization could be developed as novel therapeutics for CRPC. We developed a high throughput screen and identified two structurally-related pyrroloimidazoles that could block AR nuclear localization in CRPC cells. We show that these two small molecules, 3-(4-ethoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (EPPI) and 3-(4-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (CPPI) can inhibit the nuclear localization and transcriptional activity of AR and reduce the proliferation of AR-positive but not AR-negative prostate cancer cell lines. EPPI and CPPI did not inhibit nuclear localization of the glucocorticoid receptor or the estrogen receptor, suggesting they selectively ...

Research paper thumbnail of Inhibition of androgen receptor function and level in castration-resistant prostate cancer cells by 2-((isoxazol-4-ylmethyl)thio)-1-(4-phenylpiperazin-1-yl)ethanone

Endocrinology

The androgen receptor (AR) plays a critical role in the development of castration-resistant prost... more The androgen receptor (AR) plays a critical role in the development of castration-resistant prostate cancer (CRPC) as well as in the resistance to the second-generation AR antagonist enzalutamide and the selective inhibitor of cytochrome P450 17A1 (CYP17A1) abiraterone. Novel agents targeting AR may inhibit the growth of prostate cancer cells resistant to enzalutamide and/or abiraterone. Through a high-throughput/high-content screening of a 220,000-member small molecule library, we have previously identified 2-[(isoxazol-4-ylmethyl)thio]-1-(4-phenylpiperazin-1-yl)ethanone (IMTPPE) (SID 3712502) as a novel small molecule capable of inhibiting AR transcriptional activity and protein level in C4-2 prostate cancer cells. In this study, we show that IMTPPE inhibits ARtarget gene expression using real-time polymerase chain reaction, Western blot, and luciferase assays. IMTPPE inhibited proliferation of AR-positive, but not AR-negative, prostate cancer cells in culture. IMTPPE inhibited the transcriptional activity of a mutant AR lacking the ligand-binding domain (LBD), indicating that IMTPPE inhibition of AR is independent of the LBD. Furthermore, animal studies showed that IMTPPE inhibited the growth of 22Rv1 xenograft tumor, a model for enzalutamide-resistant prostate cancer. These findings suggest that IMTPPE is a potential lead compound for developing clinical candidates for the treatment of CRPC, including those resistant to enzalutamide. (Endocrinology 158: 3152-3161, 2017) A ndrogen deprivation therapy (ADT) is the standard treatment of patients with metastatic prostate cancer (1). However, ADT is not curative, and treated patients eventually develop castration-resistant prostate cancer (CRPC) (2, 3). CRPC is currently incurable, and it is predicted that in 2017 prostate cancer will be the third

Research paper thumbnail of Splicing factor Prp8 interacts with NES(AR) and regulates androgen receptor in prostate cancer cells

Molecular endocrinology (Baltimore, Md.), Jan 15, 2015

Androgen receptor (AR) plays a pivotal role in the development of primary as well as advanced cas... more Androgen receptor (AR) plays a pivotal role in the development of primary as well as advanced castration-resistant prostate cancer. Previous work in our lab identified a novel nuclear export signal (NES(AR)) in AR ligand binding domain essential for AR nucleocytoplasmic trafficking. By characterizing the localization of green fluorescence protein (GFP) tagged NES(AR), we designed and executed a yeast mutagenesis screen and isolated seven yeast mutants that failed to display the NES(AR) export function. One of those mutants was identified as the splicing factor Prp8. We further showed that Prp8 could regulate NES(AR) function using shRNA knockdown of Prp8 coupled with a rapamycin export assay in mammalian cells and knockdown of Prp8 could induce nuclear accumulation of GFP-tagged AR in PC3 cells. Prp8 expression was decreased in castration resistant LuCaP35 xenograft tumors as compared with androgen sensitive xenografts. Laser capture microdissection and quantitative PCR showed Prp8 ...

Research paper thumbnail of Acylated flavonol glycoside from Platanus orientalis

Fitoterapia, 2012

Background: Esophageal cancer (EC) is the sixth leading cause of death from cancer. In high-risk ... more Background: Esophageal cancer (EC) is the sixth leading cause of death from cancer. In high-risk regions, squamous cell carcinoma is the most common type of EC, and its etiology remains poorly understood. It shows uneven geographical distribution in its occurrence, reflecting the influence of local environmental conditions, lifestyle and genetic predisposition in the development of the cancer. Kashmir, in the north of India, has been described as a high-risk area for esophageal squamous cell carcinoma (ESCC). In the present investigation an attempt was made to study the role of -catenin mutations and human papillomavirus in 62 ESCC patients from Kashmir.

Research paper thumbnail of Genotypic diversity of the Killer Cell Immunoglobulin-like Receptors (KIR) and their HLA class I Ligands in a Saudi population

Genetics and Molecular Biology, 2016

Killer Cell Immunoglobulin-like Receptors (KIR) have been used as good markers for the study of g... more Killer Cell Immunoglobulin-like Receptors (KIR) have been used as good markers for the study of genetic predisposition in many diseases and in human genetic population dynamics. In this context, we have investigated the genetic diversity of KIR genes and their main HLA class I ligands in Saudi population and compared the data with other studies of neighboring populations. One hundred and fourteen randomly selected healthy Saudi subjects were genotyped for the presence or absence of 16 KIR genes and their HLA-C1, -C2, -Bw4Thr80 and Bw4Ile80 groups, using a PCR-SSP technique. The results show the occurrence of the framework genes (3DL2, 3DL3 and 2DL4) and the pseudogenes (2DP1 and 3DP1) at highest frequencies. All inhibitory KIR (iKIR) genes appeared at higher frequencies than activating genes (aKIR), except for 2DS4 with a frequency of 90.35%. A total of 55 different genotypes were observed appearing at different frequencies, where 12 are considered novel. Two haplotypes were characterized, AA and Bx (BB and AB), which were observed in 24.5% and 75.5% respectively of the studied group. The frequencies of iKIR + HLA associations were found to be much higher than aKIR + HLA. KIR genes frequencies in the Saudi population are comparable with other Middle Eastern and North African populations.

Research paper thumbnail of PCR array and protein array studies demonstrate that IL-1β (interleukin-1β) stimulates the expression and secretion of multiple cytokines and chemokines in human adipocytes

Archives of physiology and biochemistry, Jan 15, 2015

The role of IL-1β in regulating the expression and secretion of cytokines and chemokines by human... more The role of IL-1β in regulating the expression and secretion of cytokines and chemokines by human adipocytes was examined. Adipocytes were incubated with human IL-1β for 4 or 24 h. The expression of a panel of 84 cytokine/chemokine genes was probed using PCR arrays. IL-1β stimulated the expression of >30 cytokine/chemokine genes on the arrays; 15 showed >100-fold increases in mRNA at 4 or 24 h including CSF3, CXCL1, CXCL2, CXCL12 and IL8. CSF3 exhibited a 10 000-fold increase in mRNA at 4 h. ADIPOQ was among the genes whose expression was inhibited. Protein arrays were used to examine the secretion of cytokines/chemokines from adipocytes. IL-1β stimulated the secretion of multiple cytokines/chemokines including MCP-1, IL-8, IP-10, MIP-1α and MCP-4. The most responsive was IP-10, which exhibited a 5000-fold increase in secretion with IL-1β. IL-1β is likely to play a substantial role in stimulating the inflammatory response in human adipocytes in obesity.

Research paper thumbnail of PCR array and protein array studies demonstrate that IL-1 β (interleukin-1 β ) stimulates the expression and secretion of multiple cytokines and chemokines in human adipocytes

Archives of Physiology and Biochemistry, 2015

The role of IL-1β in regulating the expression and secretion of cytokines and chemokines by human... more The role of IL-1β in regulating the expression and secretion of cytokines and chemokines by human adipocytes was examined. Adipocytes were incubated with human IL-1β for 4 or 24 h. The expression of a panel of 84 cytokine/chemokine genes was probed using PCR arrays. IL-1β stimulated the expression of >30 cytokine/chemokine genes on the arrays; 15 showed >100-fold increases in mRNA at 4 or 24 h including CSF3, CXCL1, CXCL2, CXCL12 and IL8. CSF3 exhibited a 10 000-fold increase in mRNA at 4 h. ADIPOQ was among the genes whose expression was inhibited. Protein arrays were used to examine the secretion of cytokines/chemokines from adipocytes. IL-1β stimulated the secretion of multiple cytokines/chemokines including MCP-1, IL-8, IP-10, MIP-1α and MCP-4. The most responsive was IP-10, which exhibited a 5000-fold increase in secretion with IL-1β. IL-1β is likely to play a substantial role in stimulating the inflammatory response in human adipocytes in obesity.

Research paper thumbnail of The Relationship Between Killer Cell Immunoglobulin-Like Receptors and HLA-C Polymorphisms in Colorectal Cancer in a Saudi Population

Genetic Testing and Molecular Biomarkers, 2015

We performed an association study to evaluate the contribution of 16 killer cell immunoglobulin-l... more We performed an association study to evaluate the contribution of 16 killer cell immunoglobulin-like receptor (KIR) genotype polymorphisms and the HLA-C1 and -C2 ligands in the development of colorectal cancer (CRC) in Saudi Arabian patients. A total of 52 patients with different stages of malignant CRC as well as 70 healthy Saudi controls were enrolled at the King Khalid University Hospital. Our results showed that the frequency of the activating mutations KIR2DS1, 2DS2, 2DS3, 2DS5, and 3DS1 was significantly higher in CRC patients compared to controls. The 3DS1 gene contributed to the highest risk of CRC (odds ratio [OR] = 16.25, p < 0.0001), followed by 2DS1 (OR = 8.6; p < 0.0001). The distributions of HLA-C1 and -C2 ligands were not significantly different between patients and controls. Analyses of different combinations of KIR genes with their HLA-C1 and -C2 ligands show that the frequency of 2DL3 in the presence of its ligand, the allotype C1, was significantly more prevalent in patients compared to controls. In addition, 2DL2 and 2DL3 that were aggregated in combination with the ligand, HLA-C1, were found to be more highly associated mainly with the homozygote HLA-C1/C1 (p = 0.03; OR = 2.6). The activating mutations 2DS1 and 2DS2 when combined with their respective ligands, HLA-C2 and -C1, showed highly significant associations with CRC development. This study supports a key role for KIR gene mutations in the development of CRC, especially in association with their ligands.