Significance and implications of FHIT gene expression and promoter hypermethylation in acute lymphoblastic leukemia (ALL).

BACKGROUND: Fragile histidine triad (FHIT) has been documented to play a vital role in various cancers including acute lymphoblastic leukemia (ALL). Keeping in view the plausible role of FHIT gene, we aimed to examine DNA promoter hypermethylation and mRNA expression in ALL cases in Kashmir (North India). METHODS: A total of 66 cases of ALL were analyzed for FHIT mRNA expression and promoter methylation by qRT-PCR and Methylation Specific-PCR (MS-PCR) respectively. RESULTS: FHIT mRNA expression showed significantly decreased expression in ALL cases with mean fold change of 9.24 ± 5.44 as compared to healthy controls (p = 0.01). The pattern of FHIT deregulation in ALL cases differed significantly between decreased and increased expression (p < 0.0001). A threefold decreased expression was observed in 75% of ALL cases than healthy controls (- 3.58 ± 2.32). ALL patients with FHIT gene promoter hypermethylation presented significantly higher in 80% (53/66) of cases (p = 0.0005). The association of FHIT gene hypermethylation and its subsequent expression showed FHIT mRNA expression as significantly lower in ALL cases with hypermethylation (p = 0.0008). B-ALL cases exhibited a highly significant association between the methylation pattern and its mRNA expression (p = 0.000). In low range WBC group, a significant association was found between increased expression (26%) of the cases and methylated (4%)/unmethylated group 86% (p = 0.0006). CONCLUSION: The present study conclude that FHIT gene hypermethylation and its altered expression may be linked in the pathogenesis of ALL and provide an evidence for the role of FHIT in the development of ALL.

Novel DNA methylation biomarkers for early diagnosis of oral tongue squamous cell carcinoma (OTSCC).

Oral tongue squamous cell carcinoma (OTSCC) is the most common malignancy type among males across the world. However, analysis of molecular markers could be useful in detecting the early-stage OTSCC, which would allow optimal clinical treatments and prolong the survival rate of patients consequently. The study has the objective of detecting the role of salivary biomarkers based on gene promoter hypermethylation. Sample data from 45 OTSCC and normal groups were analyzed to exhibit the methylation levels of salivary biomarkers (TRH, FHIT, MGMT, p16, and RASSF1A). The specificity and sensitivity analysis of methylation biomarkers was conducted in addition to the receiver operating characteristic (ROC) curve for both early-stage and advanced OTSCC stages. Quantitative data findings showed the perfect sensitivity and specificity for TRH, MGMT, p16, and RASSF1A with 100%, and > 90%, respectively. In addition, the results indicated an inefficient area under curves (> 0.7) for these biomarkers to detect the OTSCC. There were no significant differences observed between TRH and FHIT and p16 and MGMT based on the Wilcoxon signed-rank test. The methylation statuses of genes TRH, RASSF1A, p16, and MGMT might become utilized as predictive biomarkers for clinical application in early diagnosis of OTSCC and noninvasive oral cancer screening.

Integrated analysis of FHIT gene alterations in cancer.

The Fragile Histidine Triad Diadenosine Triphosphatase (FHIT) gene is located in the Common Fragile Site FRA3B and encodes an enzyme that hydrolyzes the dinucleotide Ap3A. Although FHIT loss is one of the most frequent copy number alterations in cancer, its relevance for cancer initiation and progression remains unclear. FHIT is frequently lost in cancers from the digestive tract, which is compatible with being a cancer driver event in these tissues. However, FHIT loss could also be a passenger event due to the inherent fragility of the FRA3B locus. Moreover, the physiological relevance of FHIT enzymatic activity and the levels of Ap3A is largely unclear. We have conducted here a systematic pan-cancer analysis of FHIT status in connection with other mutations and phenotypic alterations, and we have critically discussed our findings in connection with the literature to provide an overall view of FHIT implications in cancer.

Expression of Tumor Suppressor FHIT Is Regulated by the LINC00173-SNAIL Axis in Human Lung Adenocarcinoma.

Long non-coding RNAs (lncRNAs) play a critical role in a variety of human diseases such as cancer. Here, to elucidate a novel function of a lncRNA called LINC00173, we investigated its binding partner, target gene, and its regulatory mechanism in lung adenocarcinoma, including the A549 cell line and patients. In the A549 cell line, RNA immunoprecipitation (RIP) assays revealed that LINC00173 efficiently binds to SNAIL. RNA-seq and RT-qPCR analyses revealed that the expression of FHIT was decreased upon LINC00173 depletion, indicating that FHIT is a target gene of LINC00173. Overexpression of SNAIL suppressed and depletion of SNAIL increased the expression of FHIT, indicating that SNAIL negatively regulates FHIT. The downregulation of FHIT expression upon LINC00173 depletion was restored by additional SNAIL depletion, revealing a LINC00173-SNAIL-FHIT axis for FHIT regulation. Data from 501 patients with lung adenocarcinoma also support the existence of a LINC00173-SNAIL-FHIT axis, as FHIT expression correlated positively with LINC00173 (p = 1.75 × 10-6) and negatively with SNAIL (p = 7.00 × 10-5). Taken together, we propose that LINC00173 positively regulates FHIT gene expression by binding to SNAIL and inhibiting its function in human lung adenocarcinoma. Thus, this study sheds light on the LINC00173-SNAIL-FHIT axis, which may be a key mechanism for carcinogenesis and progression in human lung adenocarcinoma.

Investigation of the IL7Rα Gene Polymorphism rs6897932 and the Expression Levels of the CDH1, TTPAL, and FHIT Genes in Patients with Breast Cancer.

OBJECTIVE: The aim of this study was to determine the expression levels of CDH1, FHIT, and TTPAL genes and to determine the genotype and allele frequencies of the IL7Rα gene polymorphism rs6897932 in patients with breast cancer. METHODS: The expression levels of genes and the distribution of the IL7Rα gene polymorphism rs6897932 were analyzed by real-time polymerase chain reaction. RESULTS: No differences in genotype ratios or allele frequencies were observed between the 2 groups for the IL7Rα gene polymorphism rs6897932. The frequency of the IL7Rα rs6897932 T risk allele was found to be similar between breast cancer patients and controls. CDH1 messenger RNA (mRNA) levels decreased (0.714-fold and 0.834-fold, respectively), and TTPAL mRNA levels increased (2.675-fold [P < .05] and 1.169-fold, respectively) in tumor tissues and peripheral blood samples. FHIT mRNA levels decreased (0.559-fold) in tumor tissue samples and increased (2.21-fold) in peripheral blood samples. CONCLUSION: Our results are compatible with those reported in the literature. It can be suggested that the upregulation observed in the TTPAL gene might be a marker for breast cancer. The downregulation of CDH1 and FHIT gene expression has been validated in our study. An increase in the copy numbers of FHIT mRNA in blood samples and a decrease in the tumor samples can also be considered an abnormal condition.

Methylation Levels in the Promoter Region of FHIT and PIAS1 Genes Associated with Mastitis Resistance in Xinjiang Brown Cattle.

Mastitis causes serious economic losses in the dairy industry, but there are no effective treatments or preventive measures. In this study, the ZRANB3, PIAS1, ACTR3, LPCAT2, MGAT5, and SLC37A2 genes in Xinjiang brown cattle, which are associated with mastitis resistance, were identified using a GWAS. Pyrosequencing analysis showed that the promoter methylation levels of the FHIT and PIAS1 genes in the mastitis group were higher and lower, respectively, than those in the healthy group (65.97 ± 19.82% and 58.00 ± 23.52%). However, the methylation level of the PIAS1 gene promoter region in the mastitis group was lower than that in the healthy group (11.48 ± 4.12% and 12.17 ± 4.25%). Meanwhile, the methylation levels of CpG3, CpG5, CpG8, and CpG15 in the promoter region of the FHIT and PIAS1 genes in the mastitis group were significantly higher than those in the healthy group (p < 0.01), respectively. RT-qPCR showed that the expression levels of the FHIT and PIAS1 genes were significantly higher in the healthy group than those in the mastitis group (p < 0.01). Correlation analysis showed that the promoter methylation level of the FHIT gene was negatively correlated with its expression. Hence, increased methylation in the promoter of the FHIT gene reduces the mastitis resistance in Xinjiang brown cattle. Finally, this study provides a reference for the molecular-marker-assisted selection of mastitis resistance in dairy cattle.

Comparison of children with and without dyslexia using functional head impulse test and pediatric balance scale.

Purpose: The aim of this study is to compare functionality of vestibulo-ocular reflex (VOR) responses to evaluate the functional properties of the vestibular system and daily balance performance in children with dyslexia and children with normal development. Method: Fifteen participants diagnosed with dyslexia were included in the study group (SG), and 15 healthy participants were included in the control group (CG). All groups underwent Functional Head Impulse Test (f-HIT) and Pediatric Balance Scale (PBS). f-HIT was performed with at least 15 head impulses at 4000-5000-6000°/s2 randomly to the right and left in the plane of the horizontal semicircular canal (SCC). Statistical analysis was performed using descriptive statistics and the Mann-Whitney U test. Results: SG percentage values were obtained lower than CG percentage values. Comparisons between the two groups showed that there was a significant difference in all parameters (4000-5000-6000°/s2 and total) in the right-side stimulation, there was significant difference for 4,000 s2 and total correct answers in the left side. In addition, although there was no significant difference between the groups in terms of the PBS score, the SG scores were lower (p = 0.062). Conclusions: As a novel test, f-HIT, revealed the difference in functionality of vestibular performance in the dyslexia group. In the dyslexia group, f-HIT may be helpful in evaluating and monitoring the vestibular system.

An evaluation of the test-retest reliability of the functional head impulse test in healthy young adults.

AIM: To determine the test and retest reliability of the functional head impulse test (fHIT) in healthy young adults. MATERIALS AND METHODS: Thirty-three healthy participants (17 women, 16 men) aged 18-30 years were included in the study. Each participant underwent the fHIT twice, 1 week apart, by the same experienced clinician. Intraclass correlation coefficients (ICCs) were used to determine test-retest reliability. RESULTS: There was no statistically significant difference between the results of total percentage of correct answer (CA%) of the fHIT obtained in session 1 and session 2 measurements in the lateral, anterior, and posterior semicircular canals (SCCs) (p > 0.05). ICC values for test-retest reliability were found to range from 0.619 to 0.665 for the three semicircular canals (SCCs). CONCLUSION: The test-retest reliability of the fHIT device was moderate. Attention, cognition, and fatigue may be the factors reducing reliability. In the diagnosis, follow-up, and rehabilitation processes of vestibular diseases in clinics, changes in the fHIT CA% can be used to assess vestibulo-ocular reflex (VOR) functionality.

Acetylcholine promotes chronic stress-induced lung adenocarcinoma progression via α5-nAChR/FHIT pathway.

Chronic stress significantly elevates the expression levels of various neurotransmitters in the tumour microenvironment, thereby promoting the cell growth and metastasis of lung adenocarcinoma (LUAD). However, the role of chronic stress in the progression of LUAD remains unclear. In this study, we found that chronic restraint stress increases the levels of the neurotransmitter acetylcholine (ACh), and the α5-nicotinic acetylcholine receptor (α5-nAChR) and decreased fragile histidine triad (FHIT) expression in vivo. Crucially, the increased ACh levels promoted LUAD cell migration and invasion via modulation of the α5-nAChR/DNA methyltransferase 1 (DNMT1)/FHIT axis. In a chronic unpredictable stress (CUMS) mouse model, chronic stress promotes tumour development, accompanied by changes in α5-nAChR, DNMT1, FHIT, and vimentin. Together, these findings reveal a novel chronic stress-mediated LUAD signalling pathway: chronic stress enforces lung adenocarcinoma cell invasion and migration via the ACh/α5-nAChR/FHIT axis, which could be a potential therapeutic target for chronic stress-related LUAD.

Combinations of grape seed procyanidin extract and milk thistle silymarin extract against lung cancer - The role of MiR-663a and FHIT.

AIMS: Grape seed procyanidin extract (GSE), and milk thistle silymarin extract (MTE) contain structurally distinct polyphenols, and each agent has been shown to exert antineoplastic effects against lung cancer. We hypothesize that combinations of GSE and MTE will additively enhance their anticancer effects against lung cancer. MATERIALS AND METHODS: The anti-proliferative effects of GSE, MTE and combinations were evaluated in lung neoplastic cell lines. A dose range finding (DRF) study to determine safety, bioavailability and bioactivity, followed by human lung cancer xenograft efficacy studies were conducted in female nude mice with once daily gavage of leucoselect phytosome (LP), a standardized GSE, and/or siliphos, a standardized MTE. The roles of tumor suppressors miR-663a and its predicted target FHIT in mediating the additive, anti-proliferative effecs of GSE/MTE were also assessed. KEY FINDINGS: GSE with MTE additively inhibited lung preneoplastic and cancer cell proliferations. Mice tolerated all dosing regimens in the DRF study without signs of clinical toxicity nor histologic abnormalities in the lungs, livers and kidneys. Eight weeks of LP and siliphos additively inhibited lung tumor xenograft growth. Plasma GSE/metabolites and MTE/metabolites showed that the combinations did not decrease systemic bioavailabilities of each agent. GSE and MTE additively upregulated miR-663a and FHIT in lung cancer cell lines; transfection of antisense-miR-663a significantly abrogated the anti-proliferative effects of GSE/MTE, upregulation of FHIT mRNA and protein. LP and siliphos also additively increased miR-663a and FHIT protein in lung tumor xenografts. SIGNIFICANCE: Our findings support clinical translations of combinations of GSE and MTE against lung cancer.

The Rosetta Stone Hypothesis-Based Interaction of the Tumor Suppressor Proteins Nit1 and Fhit.

In previous studies, we have identified the tumor suppressor proteins Fhit (fragile histidine triad) and Nit1 (Nitrilase1) as interaction partners of ß-catenin both acting as repressors of the canonical Wnt pathway. Interestingly, in D. melanogaster and C. elegans these proteins are expressed as NitFhit fusion proteins. According to the Rosetta Stone hypothesis, if proteins are expressed as fusion proteins in one organism and as single proteins in others, the latter should interact physically and show common signaling function. Here, we tested this hypothesis and provide the first biochemical evidence for a direct association between Nit1 and Fhit. In addition, size exclusion chromatography of purified recombinant human Nit1 showed a tetrameric structure as also previously observed for the NitFhit Rosetta Stone fusion protein Nft-1 in C. elegans. Finally, in line with the Rosetta Stone hypothesis we identified Hsp60 and Ubc9 as other common interaction partners of Nit1 and Fhit. The interaction of Nit1 and Fhit may affect their enzymatic activities as well as interaction with other binding partners.

Transcriptomic FHITlow/pHER2high signature as a predictive factor of outcome and immunotherapy response in non-small cell lung cancer.

Introduction: In recent decades, the development of immunotherapy and targeted therapies has considerably improved the outcome of non-small cell lung cancer (NSCLC) patients. Despite these impressive clinical benefits, new biomarkers are needed for an accurate stratification of NSCLC patients and a more personalized management. We recently showed that the tumor suppressor fragile histidine triad (FHIT), frequently lost in NSCLC, controls HER2 receptor activity in lung tumor cells and that tumor cells from NSCLC patients harboring a FHITlow/pHER2high phenotype are sensitive to anti-HER2 drugs. Here, we sought to identify the transcriptomic signature of this phenotype and evaluate its clinical significance. Materials and methods: We performed RNA sequencing analysis on tumor cells isolated from NSCLC (n=12) according to FHIT/pHER2 status and a functional analysis of differentially regulated genes. We also investigated the FHITlow/pHER2high signature in The Cancer Genome Atlas (TCGA) lung adenocarcinoma (LUAD) (n=489) and lung squamous cell carcinoma (LUSC) (n=493) cohorts and used the tumor immune dysfunction and exclusion (TIDE) model to test the ability of this signature to predict response to immune checkpoint inhibitors (ICI). Results: We showed that up-regulated genes in FHITlow/pHER2high tumors were associated with cell proliferation, metabolism and metastasis, whereas down-regulated genes were related to immune response. The FHITlow/pHER2high signature was associated with the higher size of tumors, lymph node involvement, and late TNM stages in LUAD and LUSC cohorts. It was identified as an independent predictor of overall survival (OS) in LUAD cohort. FHITlow/pHER2high tumors were also predictive of poor response to ICI in both LUAD and LUSC cohorts. Conclusion: These data suggest that ICI might not be a relevant option for NSCLC patients with FHITlow/pHER2high tumors and that anti-HER2 targeted therapy could be a good therapeutic alternative for this molecular subclass with poorer prognosis.

The Tumour Suppressor Fhit Protein Activates C-Raf Ubiquitination and Degradation in Human Melanoma Cells by Interacting with Hsp90.

Fhit protein expression is reduced in the majority of human tumors; moreover, its restoration both triggers apoptosis of cancer cells and suppresses tumor formation in a large number of preclinical models of cancers. In the following study, we observed that Fhit expression is significantly reduced in human melanoma cells, and their in vivo growth is blocked by a recombinant adenovirus carrying the FHIT gene. Importantly, we found here that Fhit physically interacts with Hsp90. Since Hsp90 is a chaperone with a crucial function in the conformational maturation and stabilization of C-Raf, we also investigated whether Fhit could interfere with the Hsp90/C-Raf protein complex in melanoma. Interestingly, the administration of the Hsp90 inhibitor 17-AAG, in combination with Fhit protein overexpression in melanoma cells, reacts synergistically to increase C-Raf ubiquitination and degradation. These data reveal Hsp90 as a novel interactor of Fhit and suggest that FHIT activity restoration could represent a helpful strategy for suppressing the oncogenic C-Raf pathway in the therapy of human melanoma.

Investigation of the expression levels of CDH1, FHIT, PTEN, and TTPAL genes in colorectal tumors.

BACKGROUND: The main aim of the study is to assess expression levels of CDH1, FHIT, PTEN, and TTPAL genes in tumors and peripheral bloods of colorectal cancer patients in staged I-IV. METHODS: Gene expression analysis of related genes were performed for tumor tissues and peripheral blood samples of 51 colorectal cancer patients and colon tissues and blood samples of 5 healthy individuals. The real-time-PCR reaction method was used for the analysis. RESULTS: Alteration of mRNA levels of related genes in tumor tissues of colorectal cancer cases was determined compared to control tissues. GAPDH and TBP were used for the normalization. While the mRNA levels of CDH1 decreased, the mRNA level of the FHIT and TTPAL genes increased in the tumor tissues. There was no PTEN gene expression difference in tumor tissues (total). The mRNA levels of the CDH1 and PTEN genes were increased while the mRNA levels of FHIT and TTPAL genes decreased in the blood (total). T he mRNA levels of the CDH1 gene decreased at each stage (I-IV) in the tumor tissues and increased at each stage (I-IV) in the blood. T he PTEN gene mRNA levels at each stage were controversial. The mRNA levels of the FHIT gene increased at stage I-II-III, decreased at stage IV in the tissues and decreased at each stage (I-IV) in the blood. The mRNA levels of TTPAL gene increased at each stage (I-IV) in the tissues and decreased at each stage (I-IV) in the blood.

Corrigendum: Overcome Chemoresistance: Biophysical and Structural Analysis of Synthetic FHIT-Derived Peptides.

[This corrects the article DOI: 10.3389/fmolb.2021.715263.].

System analysis of FHIT in LUAD and LUSC: The expression, prognosis, gene regulation network, and regulation targets.

BACKGROUND: Fragile histidine triad (FHIT) is a strong tumor suppressor gene, and cells deficient in FHIT are prone to acquiring cancer-promoting mutations. Due to its location, deletions within FHIT are common in cancer. Over 50% of cancers show loss of FHIT expression. However, to date, expression levels, gene regulatory networks, prognostic value, and target prediction of FHIT in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) have not been fully reported. Therefore, systematic analysis of FHIT expression, gene regulatory network, prognostic value, and targeted prediction in patients with LUAD and LUSC has important guiding significance, providing new therapeutic targets and strategies for clinical treatment of lung cancer to further improve the therapeutic effect of lung cancer. METHODS: Multiple free online databases were used for the abovementioned analysis in this study, including cBioPortal, TRRUST, Human Protein Atlas, GeneMANIA, GEPIA, Metascape, UALCAN, LinkedOmics, and TIMER. RESULTS: FHIT was upregulated in patients with LUAD, and downregulated in patients with LUSC. Genetic alterations of FHIT were found in patients with LUAD (7%), and LUSC (10%). The promoter methylation of FHIT was lower in patients with LUAD and LUSC. FHIT expression significantly correlated with LUSC pathological stages. Furthermore, patients with LUAD and LUSC having low FHIT expression levels had a longer survival than those having high FHIT expression levels. FHIT and its neighboring genes (the 50 most frequently altered neighboring genes of FHIT) functioned in the regulation of protein kinase and DNA binding in patients with LUAD, as well as cell channels and membrane potential in patients with LUSC. Gene ontology enrichment analysis revealed that the functions of FHIT and its neighboring genes are mainly related to disordered domain-specific binding, protein kinase binding, and ion gated channel activity in patients with LUAD, as well as calcium ion binding and intracellular ligand-gated ion channel activity in patients with LUSC. Transcription factor targets of FHIT and its neighboring genes in patients with lung cancer were found: USF1, SOX6, USF2, SIRT1, VHL, LEF1, EZH2, TP53, HDAC1, ESR1, EGR1, YY1, MYC, RELA, NFKB1, and E2F1 in LUAD; and HDAC1, DNMT1, and E2F1 in LUSC. We further explored the FHIT-associated kinase (PRKCQ, AURKB and ATM in LUAD as well as PLK3 in LUSC) and FHIT-associated miRNA targets (MIR-188, MIR-323, and MIR-518A-2 in LUAD). Furthermore, the following genes had the strongest correlation with FHIT expression in patients with lung cancer: NICN1, HEMK1, and BDH2 in LUAD, and ZMAT1, TTC21A, and NICN1 in LUSC. FHIT expression was positively associated with immune cell infiltration (B cell) in patients with LUAD, as well as B cell, CD8 + T, CD4 + T cells, macrophages, and dendritic cells in patients with LUSC. Nevertheless, FHIT expression was negatively associated with CD8 + T cells and neutrophils in patients with LUAD. CONCLUSIONS: The expression, gene regulatory network, prognostic value and targeted prediction of FHIT in patients with LUAD and LUSC were systematically analyzed and revealed in this study, thereby laying a foundation for further research on the role of FHIT in LUAD and LUSC occurrence. This study provides new LUAD and LUSC therapeutic targets and prognostic biomarkers as a reference for fundamental and clinical research.

Oncogenic and tumor suppressor genes expression in myeloproliferative neoplasms: The hidden side of a complex pathology.

BACKGROUND: The present study aimed to explore the changes in the expressions of six tumor-related genes in myeloproliferative neoplasms (MPNs). The study population included 130 patients with MPNs (52 with chronic myeloid leukemia (CML), 49 with essential thrombocythemia (ET), 20 with polycythemia vera (PV), and 9 with primary myelofibrosis (PMF)) and 51 healthy individuals. METHODS: The expression profiling of six genes (ADAMTS18, CMTM5, CDKN2B, DCC, FHIT, and WNT5B) in the peripheral blood granulocyte cells was explored by real-time quantitative reverse transcription polymerase chain reaction. RESULTS: The patients with MPNs showed significant downregulation of CMTM5 (EFC = 0.66) and DCC (EFC = 0.65) genes in contrast to a non-significant upregulation of ADAMTS18, CDKN2B, FHIT, and WNT5B genes. Downregulation of DCC was consistent in all subtypes of MPN (EFC range: 0.591-0.860). However, CMTM5 had a 1.22-fold upregulation in PMF in contrast to downregulation in other MPN subtypes (EFC range: 0.599-0.775). The results revealed a significant downregulation in CMTM5 and DCC at below 60-years of age. Furthermore, female patients showed a clear-cut downregulation in both CMTM5 and DCC (EFC DCC: 0.436 and CMTM5: 0.570), while male patients presented a less prominent downregulation with a borderline p-value only in DCC (EFC: 0.69; p = 0.05). CONCLUSIONS: Chronic myeloid leukemia cases showed a significant upregulation of WNT5B, as a known oncogenesis gene. Two tumor suppressor genes, namely DCC and CMTM5, were downregulated in the patients with MPNs, especially in females and patients below 60 years of age.

The clinical significance of fHIT in migraine patient without vertigo symptom.

OBJECTIVE: The aim of this study was to assess the functional head impulse test on migraine patients without vertigo. fHIT is a new vestibular test which evaluates the ability to see and read clearly during head movement as a functional measurement of the vestibulo-ocular reflex. MATERIALS AND METHODS: The study included 20 patients suffering from migraine without vertigo between the ages of 20 and 30-years-old who were diagnosed by a neurologist and 20 individuals with non-migraine headaches (control group), with similar demographic characteristics. The functional head impulse test was applied to both groups, and the migraine disability assessment test was applied to migraine patients. RESULTS: There was no statistically significant difference in the general fHIT results between the migraine group and the control group (p > 0.05). However, a statistically significant decrease was obtained in migraine patients in the left lateral (p = 0.018) and right posterior (p = 0.029) semicircular canals at 4000 Hz and the right anterior semicircular canal at 6000 Hz (p = 0.019). When compared by the degree of migraine disability assessment test, no significant difference in the fHIT results were observed (p > 0.05). CONCLUSION: The semicircular canals may be affected at high head acceleration (4000-6000 Hz) in migraine patients without a history of vertigo. It should be considered that fHIT results between 4000 and 6000 Hz in migraine patients without vertigo can be pathologic.

The relationship between functional head impulse test and age in healthy individuals.

BACKGROUND: fHIT is an easily applicable test battery that indirectly evaluates the vestibulo-ocular reflex (VOR) from a functional perspective. AIMS/OBJECTIVES: The aim of this study was to Individuals determine the correlation between age and the percentage of correct answers (%CA) obtained in the functional head impulse test (fHIT) in healthy individuals. MATERIAL AND METHODS: A total of 105 volunteers, 50 males and 55 females, between the ages of 18 and 70 years, participated in the study. A Beon Solution fHIT system (Zero Branco (TV), Italy) was used in the study. RESULTS: In our study, a decrease in the mean %CA was observed in all semicircular canals (SCCs) with increasing age. Between age and mean %CA, a significant negative moderate (-0.311) correlation was observed in lateral SCCs, and a significant negative low (-0.257) correlation was observed in posterior SCCs (p < 0.05). In anterior SCCs, there was no statistically significant relationship between age and mean %CA (p > 0.05). CONCLUSIONS: The present study performed in a healthy population will be helpful in terms of making comparisons in studies to be conducted in various vestibular diseases. It will also be a guide for identifying pathological consequences in vestibular diseases.

Overcome Chemoresistance: Biophysical and Structural Analysis of Synthetic FHIT-Derived Peptides.

The fragile histidine triad (FHIT) protein is a member of the large and ubiquitous histidine triad (HIT) family of proteins. On the basis of genetic evidence, it has been postulated that the FHIT protein may function as tumor suppressor, implying a role for the FHIT protein in carcinogenesis. Recently, Gaudio et al. reported that FHIT binds and delocalizes annexin A4 (ANXA4) from plasma membrane to cytosol in paclitaxel-resistant lung cancer cells, thus restoring their chemosensitivity to the drug. They also identified the smallest protein sequence of the FHIT still interacting with ANXA4, ranging from position 7 to 13: QHLIKPS. This short sequence of FHIT protein was not only able to bind ANXA4 but also to hold its target in the cytosol during paclitaxel treatment, thus avoiding ANXA4 translocation to the inner side of the cell membrane. Starting from these results, to obtain much information about structure requirements involved in the interaction of the peptide mentioned above, we synthetized a panel of seven peptides through an Ala-scan approach. In detail, to study the binding of FHIT derived peptides with ANXA4, we applied a combination of different biophysical techniques such as differential scanning fluorimetry (DSF), surface plasmon resonance (SPR), and microscale thermophoresis (MST). Circular dichroism (CD) and nuclear magnetic resonance (NMR) were used to determine the conformational structure of the lead peptide (7-13) and peptides generated from ala-scan technique. The application of different biophysical and structural techniques, integrated by a preliminary biological evaluation, allowed us to build a solid structure activity relationship on the synthesized peptides.