Search

Introduction: Relapsing-Remitting Multiple Sclerosis manifests various motor symptoms including impairments in corticospinal tract integrity, whose symptoms can be assessed using transcranial magnetic stimulation. Several factors, such as exercise and interlimb coordination, can influence the plastic changes in corticospinal tract. Previous work in healthy and chronic stroke survivors showed that the greatest improvement in corticospinal plasticity occurred during in-phase bilateral exercises of the upper limbs. Altered corticospinal plasticity due to bilateral lesions in the central nervous system is common after Multiple Sclerosis, yet the effect of in-phase bilateral exercise on the bilateral corticospinal plasticity in this cohort remains unclear. Our aim was to investigate the effects of in-phase bilateral exercises on central motor conduction time, motor evoked potential amplitude and latency, motor threshold and clinical measures in people with Relapsing-Remitting Multiple Sclerosis., Methods: Five people were randomized and recruited in this single case concurrent multiple baseline design study. The intervention protocol lasted for 12 consecutive weeks (30-60 minutes /session x 3 sessions / week) and included in-phase bilateral upper limb movements, adapted to different sports activities and to functional motor training. To define the functional relation between the intervention and the results, we conducted a visual analysis. If a potential sizeable effect was observed, we subsequently performed a statistical analysis., Results: Results demonstrated bilateral reduction of the motor threshold alongside with improvement of all clinical measures, but not in any other corticospinal plasticity measures., Conclusion: Our preliminary findings suggest that in-phase bilateral exercise affects motor threshold in people with Relapsing-Remitting Multiple Sclerosis. Therefore, this measure could potentially serve as a proxy for detecting corticospinal plasticity in this cohort. However, future studies with larger sample sizes should validate and potentially establish the effect of in-phase bilateral exercise on the corticospinal plasticity and clinical measures in this cohort., Trial Registration: Clinical trial registration: ClinicalTrials.gov NCT05367947., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sokratous et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Relapsing-remitting Multiple Sclerosis is the most common demyelinating neurodegenerative disease and is characterized by periods of relapses and generation of various motor symptoms. These symptoms are associated with the corticospinal tract integrity, which is quantified by means of corticospinal plasticity which can be probed via transcranial magnetic stimulation and assessed with corticospinal excitability measures. Several factors, such as exercise and interlimb coordination, can influence corticospinal plasticity. Previous work in healthy and in chronic stroke survivors showed that the greatest improvement in corticospinal plasticity occurred during in-phase bilateral exercises of the upper limbs. During in-phase bilateral movement, both upper limbs are moving simultaneously, activating the same muscle groups and triggering the same brain region respectively. Altered corticospinal plasticity due to bilateral cortical lesions is common in MS, yet, the impact of these type of exercises in this cohort is unclear. The aim of this concurrent multiple baseline design study is to investigate the effects of in-phase bilateral exercises on corticospinal plasticity and on clinical measures using transcranial magnetic stimulation and standardized clinical assessment in five people with relapsing-remitting MS. The intervention protocol will last for 12 consecutive weeks (30-60 minutes /session x 3 sessions/week) and include in-phase bilateral movements of the upper limbs, adapted to different sports activities and to functional training. To define functional relation between the intervention and the results on corticospinal plasticity (central motor conduction time, resting motor threshold, motor evoked potential amplitude and latency) and on clinical measures (balance, gait, bilateral hand dexterity and strength, cognitive function), we will perform a visual analysis and if there is a potential sizeable effect, we will perform statistical analysis. A possible effect from our study, will introduce a proof-of-concept for this type of exercise that will be effective during disease progression. Trial registration: ClinicalTrials.gov NCT05367947., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sokratous et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Y-chromosome analysis provides valuable information regarding the migration patterns of male ancestors, ranging from the Paleolithic age to the modern humans. STR and SNP genotyping analysis provides data regarding the genetic and geographical ancestry of the populations studied. This study focused on the analysis of the Y-chromosome in Maronite Cypriots and Armenian Cypriots, who came to the island as a result of different historical events. The aim was to provide information on the paternal genetic ancestry of Maronites and Armenians of Cyprus and investigate any affinity with the Greek Cypriots and Turkish Cypriots of the island. Since there is limited information in the current literature, we proceeded and used 23 Y-chromosome STRs and 28 Y-chromosome SNPs to genotype 57 Maronite Cypriots and 56 Armenian Cypriots, which were then compared to data from 344 Greek Cypriots and 380 Turkish Cypriots. All samples were assigned to eight major Y-haplogroups but the most frequent haplogroup among all Cypriots is haplogroup J in the major subclade J2a-L559. The calculated pairwise genetic distances between the populations show that Armenian Cypriots are genetically closer to Greek and Turkish Cypriots compared to Maronite Cypriots. Median Joining Network analysis in 17 Y-STR haplotypes of all Cypriots assigned to J2a-L559, revealed that Cypriots share a common paternal ancestor, prior to the migration of the Armenians and Maronites to Cyprus, estimated in the Late Bronze Age and Early Iron Age., Competing Interests: The authors have declared that no competing interests exist.

The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive., Competing Interests: The authors have declared that no competing interests exist.

Ninety-four common genetic variants are confirmed to be associated with breast cancer. This study tested the hypothesis that breast cancer susceptibility variants may also be associated with chemotherapy-induced toxicity through shared mechanistic pathways such as DNA damage response, an association that, to our knowledge, has not been previously investigated. The study included breast cancer patients who received neoadjuvant/adjuvant chemotherapy from the Pharmacogenetic SNPs (PGSNPS) study. For each patient, a breast cancer polygenic risk score was created from the 94 breast cancer risk variants, all of which were genotyped or successfully imputed in PGSNPS. Logistic regression was performed to test the association with two clinically important toxicities: taxane- related neuropathy (n = 1279) and chemotherapy-induced neutropenia (n = 1676). This study was well powered (≥96%) to detect associations between polygenic risk score and chemotherapy toxicity. Patients with high breast cancer risk scores experienced less neutropenia compared to those with low risk scores (adjusted p-value = 0.06). Exploratory functional pathway analysis was performed and no functional pathways driving this trend were identified. Polygenic risk was not associated with taxane neuropathy (adjusted p-value = 0.48). These results suggest that breast cancer patients with high genetic risk of breast cancer, conferred by common variants, can safely receive standard chemotherapy without increased risk of taxane-related sensory neuropathy or chemotherapy-induced neutropenia and may experience less neutropenia. As neutropenia has previously been associated with improved survival and may reflect drug efficacy, these patients may be less likely to benefit from standard chemotherapy treatment.

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.

Genome-wide association studies (GWAS), conducted mostly in European or Asian descendants, have identified approximately 67 genetic susceptibility loci for breast cancer. Given the large differences in genetic architecture between the African-ancestry genome and genomes of Asians and Europeans, it is important to investigate these loci in African-ancestry populations. We evaluated index SNPs in all 67 breast cancer susceptibility loci identified to date in our study including up to 3,300 African-American women (1,231 cases and 2,069 controls), recruited in the Southern Community Cohort Study (SCCS) and the Nashville Breast Health Study (NBHS). Seven SNPs were statistically significant (P ≤ 0.05) with the risk of overall breast cancer in the same direction as previously reported: rs10069690 (5p15/TERT), rs999737 (14q24/RAD51L1), rs13387042 (2q35/TNP1), rs1219648 (10q26/FGFR2), rs8170 (19p13/BABAM1), rs17817449 (16q12/FTO), and rs13329835 (16q23/DYL2). A marginally significant association (P<0.10) was found for three additional SNPs: rs1045485 (2q33/CASP8), rs4849887 (2q14/INHBB), and rs4808801 (19p13/ELL). Three additional SNPs, including rs1011970 (9p21/CDKN2A/2B), rs941764 (14q32/CCDC88C), and rs17529111 (6q14/FAM46A), showed a significant association in analyses conducted by breast cancer subtype. The risk of breast cancer was elevated with an increasing number of risk variants, as measured by quintile of the genetic risk score, from 1.00 (reference), to 1.75 (1.30-2.37), 1.56 (1.15-2.11), 2.02 (1.50-2.74) and 2.63 (1.96-3.52), respectively, (P = 7.8 × 10(-10)). Results from this study highlight the need for large genetic studies in AAs to identify risk variants impacting this population.

Genetic variation at the TERT-CLPTM1L locus at 5p15.33 is associated with susceptibility to several cancers, including epithelial ovarian cancer (EOC). We have carried out fine-mapping of this region in EOC which implicates an association with a single nucleotide polymorphism (SNP) within the TERT promoter. We demonstrate that the minor alleles at rs2736109, and at an additional TERT promoter SNP, rs2736108, are associated with decreased breast cancer risk, and that the combination of both SNPs substantially reduces TERT promoter activity.