A Molecular Characterization of the Allelic Expression of the BRCA1 Founder Δ9-12 Pathogenic Variant and Its Potential Clinical Relevance in Hereditary Cancer.

Hereditary breast and ovarian cancer (HBOC) syndrome is a genetic condition that increases the risk of breast cancer by 80% and that of ovarian cancer by 40%. The most common pathogenic variants (PVs) causing HBOC occur in the BRCA1 gene, with more than 3850 reported mutations in the gene sequence. The prevalence of specific PVs in BRCA1 has increased across populations due to the effect of founder mutations. Therefore, when a founder mutation is identified, it becomes key to improving cancer risk characterization and effective screening protocols. The only founder mutation described in the Mexican population is the deletion of exons 9 to 12 of BRCA1 (BRCA1Δ9-12), and its description focuses on the gene sequence, but no transcription profiles have been generated for individuals who carry this gene. In this study, we describe the transcription profiles of cancer patients and healthy individuals who were heterozygous for PV BRCA1Δ9-12 by analyzing the differential expression of both alleles compared with the homozygous BRCA1 control group using RT-qPCR, and we describe the isoforms produced by the BRCA1 wild-type and BRCA1Δ9-12 alleles using nanopore long-sequencing. Using the Kruskal-Wallis test, our results showed a similar transcript expression of the wild-type allele between the healthy heterozygous group and the homozygous BRCA1 control group. An association between the recurrence and increased expression of both alleles in HBOC patients was also observed. An analysis of the sequences indicated four wild-type isoforms with diagnostic potential for discerning individuals who carry the PV BRCA1Δ9-12 and identifying which of them has developed cancer.

Germline pathogenic variants in Mexican patients with hereditary triple-negative breast cancer.

OBJECTIVE: Describe the prevalence of breast cancer (BC)- associated germline pathogenic variants (PVs) among Mexican patients with triple-negative BC (TNBC). MATERIALS AND METHODS: The spectrum of PVs identified among patients with TNBC who were enrolled in a prospective registry and underwent genetic testing was analyzed. RESULTS: Of 387 patients with invasive TNBC and a median age at diagnosis of 39 years (range 21-72), 113 (29%) were carriers of PVs in BC-susceptibility genes: BRCA1 (79%), BRCA2 (15%), and other (6%: ATM, BRIP1, PALB2, PTEN, RAD51C, and TP53). PV carriers were younger at BC diagnosis (37 vs. 40 years, p=0.004) than non-carriers. CONCLUSION: A large proportion of TNBC in Mexican patients is associated with germline PVs, the vast majority in BRCA. The incremental yield of PVs in other BC-susceptibility genes was modest, and a stepwise approach starting with BRCA testing may be justified if it is more cost-effective than multigene panel testing.

Germline pathogenic variants in Mexican patients with hereditary triple-negative breast cancer / Variantes patóge nas de línea germinal en mexicanas con cáncer de mama triple negativo hereditario

Abstract: Objective: Describe the prevalence of breast cancer (BC)-associated germline pathogenic variants (PVs) among Mexican patients with triple-negative BC (TNBC). Materials and methods: The spectrum of PVs identified among patients with TNBC who were enrolled in a prospective registry and underwent genetic testing was analyzed. Results: Of 387 patients with invasive TNBC and a median age at diagnosis of 39 years (range 21-72), 113 (29%) were carriers of PVs in BC-susceptibility genes: BRCA1 (79%), BRCA2 (15%), and other (6%: ATM, BRIP1, PALB2, PTEN, RAD51C, and TP53). PV carriers were younger at BC diagnosis (37 vs. 40 years, p=0.004) than non-carriers. Conclusion: A large proportion of TNBC in Mexican patients is associated with germline PVs, the vast majority in BRCA. The incremental yield of PVs in other BC-susceptibility genes was modest, and a stepwise approach starting with BRCA testing may be justified if it is more cost-effective than multigene panel testing.

Resumen: Objetivo: Describir la prevalencia de variantes patógenas (VPs) germinales en genes asociados con cáncer de mama (CM) en pacientes mexicanos con CM triple negativo (CMTN). Material y métodos: Se analizó el espectro de VPs identificadas en pacientes con CMTN que fueron incluidos prospectivamente en un registro y se realizó un estudio genético. Resultados: Se analizó un total de 387 pacientes con una mediana de edad al diagnóstico de 39 años; 113 (29%) eran portadores de VPs en genes de susceptibilidad a CM: BRCA1 (79%), BRCA2(15%), y otros (6%: ATM, BRIP1, PALB2, PTEN, RAD51C y TP53). Los portadores de VPs eran más jóvenes al diagnóstico de CM (37 vs. 40 años, p=0.004). Conclusiones: Existe una alta prevalencia de VPs en pacientes mexicanos con CMTN y la mayoría se encuentra en genes BRCA. La realización de pruebas genéticas se puede optimizar mediante la adopción de un proceso escalonado para la detección de VPs.

Influence of germline BRCA genotype on the survival of patients with triple-negative breast cancer.

The presence of BRCA pathogenic variants (PVs) in triple-negative breast cancer (TNBC) is associated with a distinctive genomic profile that makes the tumor particularly susceptible to DNA-damaging treatments. However, patients with BRCA PVs can develop treatment resistance through the appearance of reversion mutations and restored BRCA expression. As copy-number variants (CNV) could be less susceptible to reversion mutations than point mutations, we hypothesize that carriers of BRCA CNVs may have improved survival after treatment compared to carriers of other BRCA PVs or BRCA wild-type. Women diagnosed with stage I-III TNBC at ≤50 years at a cancer center in Mexico City were screened for BRCA PVs using a recurrent PV assay (HISPANEL; 77% sensitivity). The recurrence-free (RFS) and overall survival (OS) were compared according to mutational status. Among 180 women, 17 (9%) were carriers of BRCA1 ex9-12del CNV and 26 (14%) of other BRCA PVs. RFS at ten years for the whole cohort was 79.2% (95% CI 72.3-84.6%), with no significant differences according to mutational status. 10-year OS for the entire cohort was 85.3% (95%CI: 78.7-90.0%), with BRCA CNV carriers demonstrating numerically superior OS rates other PV carriers and non-carriers (100% vs. 78.6% and 84.7%; log-rank p=0.037 and p=0.051, respectively). This study suggests that BRCA1 ex9-12del CNV carriers with TNBC may have a better OS, and supports the hypothesis that the genotype of BRCA PVs may influence survival by limiting treatment resistance mediated by reversion mutations among CNV carriers.

Cell therapy for spinal cord injury with olfactory ensheathing glia cells (OECs).

The prospects of achieving regeneration in the central nervous system (CNS) have changed, as most recent findings indicate that several species, including humans, can produce neurons in adulthood. Studies targeting this property may be considered as potential therapeutic strategies to respond to injury or the effects of demyelinating diseases in the CNS. While CNS trauma may interrupt the axonal tracts that connect neurons with their targets, some neurons remain alive, as seen in optic nerve and spinal cord (SC) injuries (SCIs). The devastating consequences of SCIs are due to the immediate and significant disruption of the ascending and descending spinal pathways, which result in varying degrees of motor and sensory impairment. Recent therapeutic studies for SCI have focused on cell transplantation in animal models, using cells capable of inducing axon regeneration like Schwann cells (SchCs), astrocytes, genetically modified fibroblasts and olfactory ensheathing glia cells (OECs). Nevertheless, and despite the improvements in such cell-based therapeutic strategies, there is still little information regarding the mechanisms underlying the success of transplantation and regarding any secondary effects. Therefore, further studies are needed to clarify these issues. In this review, we highlight the properties of OECs that make them suitable to achieve neuroplasticity/neuroregeneration in SCI. OECs can interact with the glial scar, stimulate angiogenesis, axon outgrowth and remyelination, improving functional outcomes following lesion. Furthermore, we present evidence of the utility of cell therapy with OECs to treat SCI, both from animal models and clinical studies performed on SCI patients, providing promising results for future treatments.

Combined Strategy for a Reliable Evaluation of Spinal Cord Injury Using an in vivo Model.

BACKGROUND: A complete neurological exam contributes in establishing spinal cord injury severity and its extent by identifying the damage to the sensory and motor pathways involved in order to address a more case-specific and precise pharmacological therapy. However, assessment of neurologic function in spinal cord injury models is usually reported by using sensory or motor tests independently. METHODS: A reliable integral method is needed to precisely evaluate location and severity of the injury at baseline and, in further assessments, to establish the degree of spontaneous recovery. A combination of sensation-based tests and motor-based tests was used to evaluate impaired neurologic function after spinal cord injury and the degree of spontaneous recovery, in different stages, on an in vivo model. RESULTS: Combined neurologic evaluation was useful to establish location and severity of the injury in all animals and also to detect degrees of spontaneous recovery at different stages after the injury. Comparisons of neurological function were assessed in time-days and groups between BBB motor score, latency maintenance of posture, locomotion and latency presentation of grooming before and after the injury. Our results suggest that a combined assessment strategy, including sensory and motor tests, can lead to better evaluation of spinal cord injury severity and location, and documentation of the extent of spontaneous recovery following SCI and identify specific motor and sensory pathway integrity. CONCLUSION: In conclusion, a combined assessment strategy provides a concise method for evaluating the impact of interventions in experimental models of SCI.

Germline mutations in NKX2-5, GATA4, and CRELD1 are rare in a Mexican sample of Down syndrome patients with endocardial cushion and septal heart defects.

Congenital heart defects (CHD) are found in ~50 % of Down syndrome (DS) patients. Genetic variants have been implicated, including CRELD1 mutations, but no previous study has examined the candidate genes, NKX2-5 and GATA4, in DS patients with secundum atrial defects (ASDII) and ventricular septal defects (VSD). Furthermore, CRELD1 mutations have not yet been studied in Mexican DS patients with atrioventricular septal defects (AVSD). Mexican DS patients (n = 148) with standard trisomy 21 were classified as follows: group I, normal heart; group II, VSD, ASDII, or both; and group III, AVSD. Mexican healthy controls (n = 113) were also included. Sequence analysis was performed on NKX2-5 and GATA4 in all three groups, and on CRELD1 in only group III. Statistical differences in the percentages of functional variants were analyzed by Fisher's exact test. Three non-synonymous variants in NKX2-5 were identified in the heterozygous state: a novel p.Pro5Ser was found in one DS patient without CHD; the p.Glu21Gln was found in one ASDII patient; and the p.Arg25Cys (R25C) was found in three patients (one from each DS study group). The p.Glu21Gln and R25C were also documented in 0.88 % of the controls. No significant difference was observed between the DS groups and healthy controls. Germline mutations in the NKX2-5, GATA4, and CRELD1 genes do not appear to be associated with CHD in Mexican DS patients. Our findings also support the notion that the R25C variant of NKX2-5 is a polymorphism, as it was not significantly different between our DS patients and controls.

Fusarium species (section Liseola) occurrence and natural incidence of beauvericin, fusaproliferin and fumonisins in maize hybrids harvested in Mexico.

Fusarium species can produce fumonisins (FBs), fusaric acid, beauvericin (BEA), fusaproliferin (FUS) and moniliformin. Data on the natural occurrence of FBs have been widely reported, but information on BEA and FUS in maize is limited. The aims of this study were to establish the occurrence of Fusarium species in different maize hybrids in Mexico, to determine the ability of Fusarium spp. isolates to produce BEA, FUS and FBs and their natural occurrence in maize. Twenty-eight samples corresponding to seven different maize hybrids were analyzed for mycobiota and natural mycotoxin contamination by LC. Fusarium verticillioides was the dominant species (44-80%) followed by F. subglutinans (13-37%) and F. proliferatum (2-16%). Beauvericin was detected in three different hybrids with levels ranging from 300 to 400 ng g(-1), while only one hybrid was contaminated with FUS (200 ng g(-1)). All samples were positive for FB1 and FB2 contamination showing levels up to 606 and 277 ng g(-1), respectively. All F. verticillioides isolates were able to produce FB1 (13.8-4,860 µg g(-1)) and some also produced FB2 and FUS. Beauvericin, FUS, FB1 and FB2 were produced by several isolates including F. proliferatum and F. subglutinans and co-production was observed. This is the first report on the co-occurrence of these toxins in maize samples from Mexico. The analysis of the presence of multiple mycotoxins in this substrate is necessary to understand the significance of these compounds in the human and animal food chains.

[Degree of trait anxiety in a sample of athletes of the Puerto Rican delegation to the XII Pan American Games held in Winnipeg '99]. / La medida de ansiedad rasgo en una muestra de atletas de la delegación de Puerto Rico a los XII Juegos Panamericanos en Winnipeg'99.

This study was conducted in an attempt to determine the degree of anxiety generated by athletes of the Puerto Rican delegation to the XII Pan American Games held in Winnipeng'99 to develop support programs that contribute to the enhancement of the athletes' mental skills and the development of sports, psychology, in particular. The sample consisted of 55 athletes that participated in the abovementioned Pan American Games. The athletes represented 16 sorts and made up 40% of the Puerto Rican athletes officially registered to participate. The Sport Competition Anxiety Test-Form A was used to detect trait anxiety during competition. An analysis of the variables was conducted utilizing t-tests to determine whether there were significant (p < or = 0.05) between the quantitative variables under study. The results indicated that the athletes of the Puerto Rican delegation that participated in the XII Pan American Games have a degree of trait anxiety that needs professional attention.

La medida de ansiedad rasgo en una muestra de atletas de la delegación de Puerto Rico a los XII Juegos Panamericanos en Winnipeg'99 / Degree of trait anxiety in a sample of athletes of the Puerto Rican delegation to the XII Pan American Games held in Winnipeg '99

This study was conducted in an attempt to determine the degree of anxiety generated by athletes of the Puerto Rican delegation to the XII Pan American Games held in Winnipeng'99 to develop support programs that contribute to the enhancement of the athletes' mental skills and the development of sports, psychology, in particular. The sample consisted of 55 athletes that participated in the abovementioned Pan American Games. The athletes represented 16 sorts and made up 40 of the Puerto Rican athletes officially registered to participate. The Sport Competition Anxiety Test-Form A was used to detect trait anxiety during competition. An analysis of the variables was conducted utilizing t-tests to determine whether there were significant (p < or = 0.05) between the quantitative variables under study. The results indicated that the athletes of the Puerto Rican delegation that participated in the XII Pan American Games have a degree of trait anxiety that needs professional attention.