👤 Vahid Sheikhi

G-Quadruplexes (G4s) are noncanonical nucleic acid secondary structures enriched in genomic regions critical for transcription and replication. These dynamic scaffolds recruit G4-binding proteins (G4BPs), thereby regulating diverse cellular processes. However, the functional roles of G4BPs in the G4-bound state remain poorly defined. Here, we report the development of G4L-PROTACs-bifunctional small molecules that couple a G4 ligand with an E3 ligase recruiter to achieve selective proteasomal degradation of G4-bound G4BPs. Unlike RNAi or CRISPR-Cas9, which eliminate proteins irrespective of binding state, G4L-PROTACs enable depletion of G4BPs only when associated with G4s. Using model G4 motifs from telomeres and the NRAS 5' UTR, we demonstrated in vitro ternary complex formation. In cells, G4L-PROTAC treatment reduced endogenous levels of the G4-resolving helicase DHX36, resulting in a marked increase in intracellular G4 abundance, as shown by BG4 immunofluorescence. This phenotype highlights the ability of G4L-PROTACs to modulate the G4-protein equilibrium in living cells. Notably, G4L-PROTACs do not induce G4-mediated transcriptional silencing, underscoring their precision in modulating nucleic acid-protein interactions. This strategy offers a powerful platform for probing G4-G4BP functions and holds promise for therapeutic targeting of G4-associated proteins. Show less

Comprehensive molecular assessment of cancers could open up new horizons for novel therapies. Fibroblast growth factor receptor 1 (FGFR1) gene amplification has been previously demonstrated in non-small cell lung cancer (NSCLC) patients. The current study aimed to evaluate the prevalence of FGFR1 gene amplification and its association with clinical and demographic data in a group of NSCLC patients. The present study was performed on eighty-eight NSCLC patients who underwent bronchoscopy or surgery in Qaem Hospital, Mashhad, between 2010 and 2016. FGFR1 gene amplification was detected using real-time PCR assay on DNA extracted from paraffin-embedded tissue blocks of patients. Also, patients' clinical and demographic data, such as their survival, were evaluated. Statistical analysis was carried out using SPSS software. Seventeen (19.31%) out of eighty-eight patients with NSCLC presented FGFR1 gene amplification. Besides, we found a significant association between FGFR1 amplification and cigarette smoking (p-value= 0.01; OR: 4.08). Although cases with squamous cell carcinoma (SCC) showed a higher prevalence of FGFR1 amplification compared to adenocarcinoma patients, the difference was not statistically significant (p-value> 0.05). In addition, our findings showed no relationship between FGFR1 gene amplification and other clinical and demographic factors, including age, sex, grade, tumor operability, and survival. The frequency of FGFR1 amplification is estimated at 20% in the current study (26% in SCC versus 11% in adenocarcinoma; p-value= 0.07). Moreover, we found a direct association between FGFR1 amplification and cigarette smoking. However, no significant relationship with survival or other factors was observed. Show less

Apolipoprotein AIV has a role in chylomicrons and lipid secretion and catabolism. Also, Apo-AIV plays a role in the regulation of appetite and satiety. Previous studies on rats have shown that hyperthyroidism and hypothyroidism are associated with significant changes in Apo-AIV serum levels. There has been no research on serum Apo-AIV changes in hyper and hypothyroidism in humans. This case-control study was performed on new patients with hyper and hypothyroidism. Eighteen patients with hyperthyroidism and 18 patients with hypothyroidism enrolled in the study. After 12 weeks treatment blood samples were recruited. If euthyroidism was achieved, serum Apo-AIV level was measured. Eighteen euthyroid healthy individuals without thyroid disease were chosen as the control group from general population. Serum levels of Apo-AIV before treatment in hypothyroidism, hyperthyroidism and in the control group were 85.61, 110.66 and 33.51 mg/dL respectively (p<0.001), which was significantly higher in hyperthyroid patients than hypothyroidism and control group. In patients with hyperthyroidism there was a significant decrease in serum levels of Apo-AIV after treatment (p=0.044). However in hypothyroidism a non-significant elevation in serum levels of Apo-AIV was observed (p=0.403). Furthermore, serum levels of Apo-AIV after treatment were significantly higher in both hyperthyroidism and hypothyroidism in comparison to control group (p<0.001). The results of this study for the first time showed that the serum level of Apo-AIV is increased in patients with hyperthyroidism and is decreased in patients with hypothyroidism, and after treatment, there was a significant difference with the control group. Show less