A Non-Coding Variant in Modulates Enhancer Activity and Lysosomal Deacidification Linked to Lupus Susceptibility.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic basis. Despite the identification of several single nucleotide polymorphisms (SNPs) near the gene that are significantly associated with SLE across multiple populations, specific causal SNP(s) and molecular mechanisms responsible for disease susceptibility are unknown. To address this gap, we employed bioinformatics, expression quantitative trait loci (eQTLs), and 3D chromatin interaction analysis to nominate a likely functional variant, rs35907548, in an active intronic enhancer of .

A Non-Coding Variant in Modulates Enhancer Activity and Lysosomal Deacidification Linked to Lupus Susceptibility.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic basis. Despite the identification of several single nucleotide polymorphisms (SNPs) near the gene that are significantly associated with SLE across multiple populations, specific causal SNP(s) and molecular mechanisms responsible for disease susceptibility are unknown. To address this gap, we employed bioinformatics, expression quantitative trait loci (eQTLs), and 3D chromatin interaction analysis to nominate a likely functional variant, rs35907548, in an active intronic enhancer of .

Discovery and Functional Characterization of Two Regulatory Variants Underlying Lupus Susceptibility at 2p13.1.

Genome-wide association studies have identified 2p13.1 as a prominent susceptibility locus for systemic lupus erythematosus (SLE)—a complex, multisystem autoimmune disease. However, the identity of underlying causal variant (s) and molecular mechanisms for increasing disease susceptibility are poorly understood.

Idelalisib activates AKT via increased recruitment of PI3Kδ/PI3Kβ to BCR signalosome while reducing PDK1 in post-therapy CLL cells.

Idelalisib targets PI3Kδ in the BCR pathway generating only a partial response in CLL patients, indicating that the leukemic cells may have evolved escape signals. Indeed, we detected increased activation of AKT accompanied by upregulation of MYC/BCL2 in post-therapy CLL cells from patients treated with idelalisib/ofatumumab. To unravel the mechanism of increased AKT-activation, we studied the impact of idelalisib on a CLL-derived cell line, MEC1, as a model.

SIRT3 overexpression and epigenetic silencing of catalase regulate ROS accumulation in CLL cells activating AXL signaling axis.

Mitochondrial metabolism is the key source for abundant ROS in chronic lymphocytic leukemia (CLL) cells. Here, we detected significantly lower superoxide anion (O) levels with increased accumulation of hydrogen peroxide (HO) in CLL cells vs. normal B-cells.

Lupus Susceptibility Region Containing CDKN1B rs34330 Mechanistically Influences Expression and Function of Multiple Target Genes, Also Linked to Proliferation and Apoptosis.

Objective: In a recent genome-wide association study, a significant genetic association between rs34330 of CDKN1B and risk of systemic lupus erythematosus (SLE) in Han Chinese was identified. This study was undertaken to validate the reported association and elucidate the biochemical mechanisms underlying the effect of the variant.

Methods: We performed an allelic association analysis in patients with SLE, followed by a meta-analysis assessing genome-wide association data across 11 independent cohorts (n = 28,872).

Short-duration hyperoxia causes genotoxicity in mouse lungs: protection by volatile anesthetic isoflurane.

High concentrations of oxygen (hyperoxia) are routinely used during anesthesia, and supplemental oxygen is also administered in connection with several other clinical conditions. Although prolonged hyperoxia is known to cause acute lung injury (ALI), whether short-duration hyperoxia causes lung toxicity remains unknown. We exposed mice to room air (RA or 21% O) or 60% oxygen alone or in combination with 2% isoflurane for 2 h and determined the expression of oxidative stress marker genes, DNA damage and DNA repair genes, and expression of cell cycle regulatory proteins using quantitative PCR and Western analyses.

Remarkable difference in Al and Zn sensing properties of quinoline based isomers.

Two positional isomers, 4-methyl-2-((quinolin-6-ylimino)methyl)phenol (6-QMP) and 4-methyl-2-((quinolin-2-ylimino)methyl)phenol (2-QMP), have been synthesized to compare their fluorescence sensing properties. 6-QMP and 2-QMP have been synthesized by Schiff-base condensation between 2-hydroxy-5-methylbenzaldehyde and the respective amine (6-aminoquinoline for 6-QMP and 2-aminoquinoline for 2-QMP) under mild conditions. These compounds have been characterized by standard methods.

SNP rs1049430 in the 3'-UTR of SH3GL2 regulates its expression: Clinical and prognostic implications in head and neck squamous cell carcinoma.

Single nucleotide polymorphisms (SNPs) in the 3'-UTR region are emerging cis-regulatory factors associated with the occurrences of several human diseases. SH3GL2, which is located at chromosome 9p21-22, is associated with hyperplastic/mildly dysplastic lesions of the head and neck and has a long 3'-UTR with multiple SNPs. The aim of the present study was to determine the susceptible allele(s) in the 3'-UTR SNPs of SH3GL2 in head and neck squamous cell carcinoma (HNSCC).

Frequent inactivation of SLIT2 and ROBO1 signaling in head and neck lesions: clinical and prognostic implications.

Objective: The protein SLIT2 and its receptor ROBO1 regulate different cellular processes, such as proliferation, apoptosis, and migration. In this study our aim is to understand the alterations of these genes during development of head and neck squamous cell carcinoma (HNSCC).

Materials And Methods: First, molecular alterations of the genes were analyzed in 30 dysplastic lesions, 128 primary HNSCC samples, and 1 HNSCC cell line.

Reduction of proliferation and induction of apoptosis are associated with shrinkage of head and neck squamous cell carcinoma due to neoadjuvant chemotherapy.

Background: Neoadjuvant chemotherapy (NACT) is a treatment modality whereby chemotherapy is used as the initial treatment of HNSCC in patients presenting with advanced cancer that cannot be treated by other means. It leads to shrinkage of tumours to an operable size without significant compromise to essential oro-facial organs of the patients. The molecular mechanisms behind shrinkage due to NACT is not well elucidated.

Overexpression of EGFR in head and neck squamous cell carcinoma is associated with inactivation of SH3GL2 and CDC25A genes.

The aim of this study is to understand the mechanism of EGFR overexpression in head and neck squamous cell carcinoma (HNSCC). For this reason, expression/mutation of EGFR were analyzed in 30 dysplastic head and neck lesions and 148 HNSCC samples of Indian patients along with 3 HNSCC cell lines. In addition, deletion/methylation/mutation/expression of SH3GL2 (associated with EGFR degradation) and CDC25A (associated with dephosphorylation of EGFR) were analyzed in the same set of samples.

Inactivation of 9q22.3 tumor suppressor genes predict outcome for patients with head and neck squamous cell carcinoma.

Aim: This study examined the prognostic significance of candidate tumor suppressor genes (TSGs) PHD finger protein-2 (PHF2), Fanconi anaemia complementation group C (FANCC) and human homologue of Drosophila patched gene (PTCH1), in head and neck squamous cell carcinoma (HNSCC) treated primarily with surgery, or surgery followed by adjuvant radiotherapy.

Patients And Methods: Eighty-four patients with HNSCC were followed-up for recurrence/death for up to five years after diagnosis. Molecular alterations (deletion/methylation) of TSGs and human papilloma virus (HPV) status were determined in previous studies of our group.

Comprehensive SNP scan of DNA repair and DNA damage response genes reveal multiple susceptibility loci conferring risk to tobacco associated leukoplakia and oral cancer.

Polymorphic variants of DNA repair and damage response genes play major role in carcinogenesis. These variants are suspected as predisposition factors to Oral Squamous Cell Carcinoma (OSCC). For identification of susceptible variants affecting OSCC development in Indian population, the "maximally informative" method of SNP selection from HapMap data to non-HapMap populations was applied.

Reduced expression of LIMD1 in ulcerative oral epithelium associated with tobacco and areca nut.

Purpose: The aim of this study was to cast light on initiating molecular events associated with the development of premalignant oral lesions induced by tobacco and/or areca nut.

Method: Immunohistochemical analyses of cell cycle regulatory proteins (LIMD1, RBSP3, p16, RB, phosphorylated RB, p53), EGFR and SH3GL2 (EGFR associated protein) were performed with inflammatory/ ulcerative epithelium and adjacent hyperplastic/mild dysplastic lesions.

Results: No change in expression of the proteins was seen in inflammatory epithelium.

Association of FANCC and PTCH1 with the development of early dysplastic lesions of the head and neck.

Background: Alteration of chromosome 9q22.3 region is an early and frequent event in head and neck squamous cell carcinoma (HNSCC). The aim of this study was to understand the association of candidate tumor suppressor genes PHF2, FANCC, PTCH1, and XPA located in this region in the development of HNSCC.

Frequent alterations of the candidate genes hMLH1, ITGA9 and RBSP3 in early dysplastic lesions of head and neck: clinical and prognostic significance.

To understand the association between candidate tumor suppressor genes (TSGs) human mismatch repair protein homologue 1 (hMLH1), AP20 region gene 1 (APRG1), integrin alpha RLC (ITGA9), RB1 serine phosphates from human chromosome 3 (RBSP3) at chromosomal 3p22.3 region and development of head and neck squamous cell carcinoma (HNSCC), alterations (deletion/promoter methylation/expression) of these genes were analyzed in 65 dysplastic lesions and 84 HNSCC samples. Clinicopathological correlations were made with alterations of the genes.

LIMD1 is more frequently altered than RB1 in head and neck squamous cell carcinoma: clinical and prognostic implications.

Introduction: To understand the role of two interacting proteins LIMD1 and pRB in development of head and neck squamous cell carcinoma (HNSCC), alterations of these genes were analyzed in 25 dysplastic head and neck lesions, 58 primary HNSCC samples and two HNSCC cell lines.

Methods: Deletions of LIMD1 and RB1 were analyzed along with mutation and promoter methylation analysis of LIMD1. The genotyping of LIMD1 linked microsatellite marker, hmlimD1, was done to find out any risk allele.

Alterations of ROBO1/DUTT1 and ROBO2 loci in early dysplastic lesions of head and neck: clinical and prognostic implications.

Deletion of chromosomal 3p12.3 was suggested to be associated with dysplastic lesions of head and neck. This region harbors two candidate tumor suppressors ROBO1/DUTT1, ROBO2 and two non-coding RNAs (ncRNAs) located at intron 2 of ROBO1/DUTT1.

SH3GL2 and CDKN2A/2B loci are independently altered in early dysplastic lesions of head and neck: correlation with HPV infection and tobacco habit.

To understand the association of candidate tumour suppressor genes SH3GL2, p16(INK4a), p14(ARF), and p15(INK4b) in the pathogenesis of head and neck squamous cell carcinoma (HNSCC), we studied the deletion, mutation, and methylation of these genes in 61 dysplastic lesions and 94 HNSCC samples. In mild dysplasia, SH3GL2, p16(INK4a), and p14(ARF) showed a higher frequency of overall alterations (60-70%) than in p15(INK4b) (40%). However, in subsequent stages of tumour progression, the alteration frequency of these genes did not change significantly.

Alterations of 3p21.31 tumor suppressor genes in head and neck squamous cell carcinoma: Correlation with progression and prognosis.

The aim of our study was to analyze the alterations of some candidate tumor suppressor genes (TSGs) viz. LIMD1, LTF, CDC25A, SCOTIN, RASSF1A and CACNA2D2 located in the chromosomal region 3p21.31 associated with the development of early dysplastic lesions of head and neck.