Identification of novel pathogenic MSH2 mutation and new DNA repair genes variants: investigation of a Tunisian Lynch syndrome family with discordant twins.

BACKGROUND: Lynch syndrome (LS) is a highly penetrant inherited cancer predisposition syndrome, characterized by autosomal dominant inheritance and germline mutations in DNA mismatch repair genes. Despite several genetic variations that have been identified in various populations, the penetrance is highly variable and the reasons for this have not been fully elucidated. This study investigates whether, besides pathogenic mutations, environment and low penetrance genetic risk factors may result in phenotype modification in a Tunisian LS family. PATIENTS AND METHODS: A Tunisian family with strong colorectal cancer (CRC) history that fulfill the Amsterdam I criteria for the diagnosis of Lynch syndrome was proposed for oncogenetic counseling. The index case was a man, diagnosed at the age of 33 years with CRC. He has a monozygotic twin diagnosed at the age of 35 years with crohn disease. Forty-seven years-old was the onset age of his paternal uncle withCRC. An immunohistochemical (IHC) labeling for the four proteins (MLH1, MSH2, MSH6 and PMS2) of the MisMatchRepair (MMR) system was performed for the index case. A targeted sequencing of MSH2, MLH1 and a panel of 85 DNA repair genes was performed for the index case and for his unaffected father. RESULTS: The IHC results showed a loss of MSH2 but not MLH1, MSH6 and PMS2 proteins expression. Genomic DNA screening, by targeted DNA repair genes sequencing, revealed an MSH2 pathogenic mutation (c.1552C>T; p.Q518X), confirmed by Sanger sequencing. This mutation was suspected to be a causal mutation associated to the loss of MSH2 expression and it was found in first and second degree relatives. The index case has smoking and alcohol consumption habits. Moreover, he harbors extensive genetic variations in other DNA-repair genes not shared with his unaffected father. CONCLUSION: In our investigated Tunisian family, we confirmed the LS by IHC, molecular and in silico investigations. We identified a novel pathogenic mutation described for the first time in Tunisia. These results come enriching the previously reported pathogenic mutations in LS families. Our study brings new arguments to the interpretation of MMR expression pattern and highlights new risk modifiers genes eventually implicated in CRC. Twins discordance reported in this work underscore that disease penetrance could be influenced by both genetic background and environmental factors.

Mucosal human papillomavirus detection and TP53 immunohistochemical expression in non-melanoma skin cancer in Tunisian patients.

BACKGROUND: Several studies have reported the oncogenic role of human papillomavirus (HPV) in non-melanoma skin cancer (NMSC) carcinogenesis. Considering that HPV could affect tumor protein 53 (TP53) degradation via E6 oncoprotein, we evaluated the expression of TP53 according to HPV infection and E6 expression. METHODS: Biopsy specimens from 79 NMSCs (28 squamous cell carcinomas, 21 keratoacanthomas and 30 basal cell carcinomas) were enrolled. Nested PCR was used to detect mucosal HPV (mHPV) DNA. Genotyping was performed by reverse line hybridization. Expression of TP53 and E6 was evaluated by immunohistochemistry. RESULTS: mHPVs were detected in 34.2% (27/79) of NMSC, with 92.6% (25/27) of high-risk HPV (HR-HPV) types. HPV16-E6-positive expression was observed in all HPV16-positive samples. TP53 high expression was found in 51.4% (37/72) of specimens. In this group, 78.4% were HPV-negative (P = 0.014). TP53 expression was negative in 8/10 of HPV E6-positive specimens. Multivariate analysis showed that TP53 was associated with HPV infection independently of histopathologic type (P = 0.005). CONCLUSION: This study showed a high prevalence of mHPV in NMSC. Active infections assessed by E6 expression are associated with loss of p53 function, highlighting the involvement of mHPV in NMSC carcinogenesis.

Does acute aerobic exercise enhance selective attention, working memory, and problem-solving abilities in Alzheimer's patients? A sex-based comparative study.

Introduction: The present study aimed to evaluate the effect of acute aerobic exercise on certain cognitive functions known to be affected by Alzheimer's disease (AD), with a particular emphasis on sex differences. Methods: A total of 53 patients, with a mean age of 70.54 ± 0.88 years and moderate AD, voluntarily participated in the study. Participants were randomly assigned to two groups: the experimental group (EG), which participated in a 20-min moderate-intensity cycling session (60% of the individual maximum target heart rate recorded at the end of the 6-min walk test); and the control group (CG), which participated in a 20-min reading activity. Cognitive abilities were assessed before and after the physical exercise or reading session using the Stroop test for selective attention, the forward and backward digit span test for working memory, and the Tower of Hanoi task for problem-solving abilities. Results: At baseline, both groups had comparable cognitive performance (p > 0.05 in all tests). Regardless of sex, aerobic acute exercise improved attention in the Stroop test (p < 0.001), enhanced memory performance in both forward (p < 0.001) and backward (p < 0.001) conditions, and reduced the time required to solve the problem in the Tower of Hanoi task (p < 0.001). No significant differences were observed in the number of movements. In contrast, the CG did not significantly improve after the reading session for any of the cognitive tasks (p > 0.05). Consequently, the EG recorded greater performance improvements than the CG in most cognitive tasks tested (p < 0.0001) after the intervention session. Discussion: These findings demonstrate that, irrespective to sex, a single aerobic exercise session on an ergocycle can improve cognitive function in patients with moderate AD. The results suggest that acute aerobic exercise enhances cognitive function similarly in both female and male patients, indicating promising directions for inclusive therapeutic strategies.

Acute Effect of Simultaneous Exercise and Cognitive Tasks on Cognitive Functions in Elderly Individuals with Mild Cognitive Impairment.

The increasing prevalence of age-related cognitive decline, alongside the aging global population, underscores the urgent need for innovative and effective preventative strategies. While the advantages of combining physical and cognitive exercises have been recognized as a promising approach to address these socioeconomic challenges, the acute effects of such interventions on cognitive functions remain understudied. This study aimed to investigate whether simultaneous physical and cognitive exercise has a greater beneficial impact on the cognitive functions of older adults with mild cognitive impairment (MCI) than physical exercise alone or reading activities. A total of 44 MCI patients (75% females aged between 65 and 75 years) were randomly assigned to one of three groups: aerobic exercise alone (EG group, n = 15), aerobic combined with cognitive exercises (CEG group, n = 15), or a reading task for controls (CG group, n = 14). Attention, memory, and problem solving were assessed before and after the acute intervention using the Tower of Hanoi, Digit Span, and Stroop tasks, respectively. Statistical analysis revealed that both of the experimental interventions appeared to enhance cognitive function scores (p < 0.05), except for the number of moves in the Tower of Hanoi task, where no improvement was noted. In contrast, no significant differences in any cognitive performance measures were observed following the reading session. Notably, the CEG group exhibited a more pronounced positive impact, especially on working memory. This advantage was specifically evident in the digit span tasks, where significantly greater percentage gains were found in the CEG than in the CG (p = 0.02), while no significant difference existed between the EG and CG. Simultaneous combined exercise has proven to be a more effective method than aerobic physical exercise alone for improving cognitive function. The results of this study are recommended for inclusion in clinical practice guidelines to maintain the mental health of older adults, as simultaneous exercise seems to offer a time-efficient strategy to enhance cognitive performance in adults with MCI.

Effectiveness of Simultaneous Combined Intervention for Enhancing Cognitive Function in Patients with Moderate Alzheimer's Disease.

Background: The evidence supporting the effectiveness of combined interventions in Alzheimer's disease (AD) patients remains inconclusive. Objective: The aim of this study was to evaluate the mid- and long-term effectiveness of physical training, alone or combined with cognitive games, on cognitive performance in patients with moderate AD. Methods: Seventy-nine AD patients (≈73% females, age of ≈70±1 years) were randomly divided into three groups: aerobic-based training (AT-group, n = 27), aerobic-based training plus cognitive games (ACT-group, n = 25), and a control group engaged in reading (CG, n = 26), two sessions per week. Cognitive performance was evaluated at the start, 4th week (W4), end of the 8th week (W8), and after a 4-week detraining period (W12), using problem-solving (Tower-of-Hanoi), selective attention (Stroop-test), and working memory (Digit-Span-test) assessments. Stress levels and quality of life were also evaluated.Results:: Aerobic and combined training induced a positive effect on all cognitive functions tested at W4 (except problem-solving) and W8 (all p < 0.001) with greater improvements in working-memory and problem-solving in ACT-group (p < 0.05). Depression levels also decreased significantly, and quality of life improved at W8 (p < 0.001) in both groups. After 4 weeks of detraining, the beneficial effect of AT and ACT was still observed. The CG did not show any significant improvements at all time points.Conclusions:: Physical and cognitive interventions appear effective for improving cognitive-functions, quality-of-life, and reducing depression in AD patients. Combined training emerges as a more effective strategy to mitigate AD progression. Further research is necessary to validate these results and explore their potential for preventing early cognitive decline.

BRAF V600E and Novel Somatic Mutations in Thyroid Cancer of Libyan Patients.

BACKGROUND: Thyroid cancer (TC) is a common endocrine malignancy that frequently harbours the oncogenic V600E BRAF mutation. This mutation has received considerable attention in recent years for its potential utility in the risk stratification and management of TC. This study aims to investigate BRAF mutational status in thyroid cancer of Libyan patients and their association with clinicopathological factors. METHODS: 44 thyroid tissue samples were analysed for mutations in exon 15 of the BRAF gene by performing polymerase chain reaction and Sanger sequencing. The results of BRAF mutation screening were correlated to clinical and pathological characteristics of the studied thyroid cancer patients. Statistical analyses were performed using SPSS. RESULTS: The BRAF exon 15 mutations were detected in 19 (43.2%) of the thyroid cancer cases. The V600E was the most frequent one found in 15/44 (34.1%) cases. We also detected 6 other variants in 7 patients (15.9%), the S616F, the W619R and the T599S. Three mutations were associated with V600E, the L584I, the D587Y and the synonymous L597L. None of these mutations were reported previously in thyroid cancers. No statistical association was found between BRAF mutations and clinicopathological factors except with papillary thyroid cancer type (p= 0,032). CONCLUSIONS: Novel BRAF mutations and V600E were frequently detected in thyroid cancer of Libyan patients; this suggests a potential role of these novel mutations in carcinogenesis and in anti-EGFR therapy resistance.

Acute Exercise and Cognitive Function in Alzheimer's Disease.

BACKGROUND: Many studies have shown the impact of acute aerobic exercises (AAE) on cognition in healthy adults or at a pre-dementia stage. Few studies, however, have explored the positive effects of AAE in moderate Alzheimer's disease (ADM) patients. OBJECTIVE: Evaluating the effect of AAE on cognitive functions in ADM patients. METHODS: Overall, 79 (age: 69.62±0.99) ADM patients were recruited. Participants were divided into three groups according to the task: aerobic exercises done alone or combined with cognitive games presented on a screen, and a control group who performed a reading task. The aerobic exercise protocol consisted of a 20-min cycling exercise of moderate intensity, corresponding to 60%of the individual target maximal heart rate recorded in a 6-minute walking test. The participants' cognition was monitored before and after the intervention using the Tower of Hanoi, Digit Span, and Stroop tasks. RESULTS: After the exercise, the participants' attention in both the physical and combined groups improved for the Stroop, the forward and backward Digit Span tasks, as well as the time taken to solve the Tower of Hanoi, although no significant differences were found in the number of moves taken in the latter. By contrast, the control group did not show any significant improvement for most of the cognitive tasks after the reading session. CONCLUSION: Current evidence suggests that AAE may help to improve cognitive functions in ADM patients. This improvement is enhanced when the exercise is combined with cognitive games. Safe and progressive types of exercises should be promoted among ADM patients.