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.

Quistes y hamartomas biliares, no siempre son asintomáticos / Biliary cysts and hamartomas are not always asymptomatic

In daily clinical practice, we can find consultation reasons and exploratoryfindings that can guide us to a certain pathology. However, to avoid mistakes,we must remember that there are fewer common diseases, which could leadto an unexpected final diagnosis.Hepatic cystic lesions are usually found incidentally, having a wide differentialdiagnosis. Among them are biliary cysts and hamartomas, rare lesions, butwith not inconsiderable importance, as we will see in the case that is exposedbelow. (AU)

En la práctica clínica habitual nos podemos encontrar motivos de consulta yhallazgos exploratorios que nos pueden guiar a una determinada patología.Sin embargo, para no caer en errores, debemos recordar que existen enfermedades menos habituales, que podrían llevarnos a un diagnóstico finalinesperado.Las lesiones quísticas hepáticas se hallan generalmente de forma incidental, teniendo un amplio diagnóstico diferencial. Entre ellas se encuentranlos quistes y hamartomas biliares, lesiones poco frecuentes, pero con unaimportancia no desdeñable, como veremos en el caso que se expone a continuación. (AU)

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.

The promising role of new molecular biomarkers in prostate cancer: from coding and non-coding genes to artificial intelligence approaches.

BACKGROUND: Risk stratification or progression in prostate cancer is performed with the support of clinical-pathological data such as the sum of the Gleason score and serum levels PSA. For several decades, methods aimed at the early detection of prostate cancer have included the determination of PSA serum levels. The aim of this systematic review is to provide an overview about recent advances in the discovery of new molecular biomarkers through transcriptomics, genomics and artificial intelligence that are expected to improve clinical management of the prostate cancer patient. METHODS: An exhaustive search was conducted by Pubmed, Google Scholar and Connected Papers using keywords relating to the genetics, genomics and artificial intelligence in prostate cancer, it includes "biomarkers", "non-coding RNAs", "lncRNAs", "microRNAs", "repetitive sequence", "prognosis", "prediction", "whole-genome sequencing", "RNA-Seq", "transcriptome", "machine learning", and "deep learning". RESULTS: New advances, including the search for changes in novel biomarkers such as mRNAs, microRNAs, lncRNAs, and repetitive sequences, are expected to contribute to an earlier and accurate diagnosis for each patient in the context of precision medicine, thus improving the prognosis and quality of life of patients. We analyze several aspects that are relevant for prostate cancer including its new molecular markers associated with diagnosis, prognosis, and prediction to therapy and how bioinformatic approaches such as machine learning and deep learning can contribute to clinic. Furthermore, we also include current techniques that will allow an earlier diagnosis, such as Spatial Transcriptomics, Exome Sequencing, and Whole-Genome Sequencing. CONCLUSION: Transcriptomic and genomic analysis have contributed to generate knowledge in the field of prostate carcinogenesis, new information about coding and non-coding genes as biomarkers has emerged. Synergies created by the implementation of artificial intelligence to analyze and understand sequencing data have allowed the development of clinical strategies that facilitate decision-making and improve personalized management in prostate cancer.

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.

Transcriptome Analysis Identifies GATA3-AS1 as a Long Noncoding RNA Associated with Resistance to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer Patients.

Breast cancer is one of the leading causes of mortality in women worldwide, and neoadjuvant chemotherapy has emerged as an option for the management of locally advanced breast cancer. Extensive efforts have been made to identify new molecular markers to predict the response to neoadjuvant chemotherapy. Transcripts that do not encode proteins, termed long noncoding RNAs (lncRNAs), have been shown to display abnormal expression profiles in different types of cancer, but their role as biomarkers in response to neoadjuvant chemotherapy has not been extensively studied. Herein, lncRNA expression was profiled using RNA sequencing in biopsies from patients who subsequently showed either response or no response to treatment. GATA3-AS1 was overexpressed in the nonresponder group and was the most stable feature when performing selection in multiple random forest models. GATA3-AS1 was experimentally validated by quantitative RT-PCR in an extended group of 68 patients. Expression analysis confirmed that GATA3-AS1 is overexpressed primarily in patients who were nonresponsive to neoadjuvant chemotherapy, with a sensitivity of 92.9% and a specificity of 75.0%. The statistical model was based on luminal B-like patients and adjusted by menopausal status and phenotype (odds ratio, 37.49; 95% CI, 6.74-208.42; P = 0.001); GATA3-AS1 was established as an independent predictor of response. Thus, lncRNA GATA3-AS1 is proposed as a potential predictive biomarker of nonresponse to neoadjuvant chemotherapy.

Genetic epidemiology of BRCA1- and BRCA2-associated cancer across Latin America.

The prevalence and contribution of BRCA1/2 (BRCA) pathogenic variants (PVs) to the cancer burden in Latin America are not well understood. This study aims to address this disparity. BRCA analyses were performed on prospectively enrolled Latin American Clinical Cancer Genomics Community Research Network participants via a combination of methods: a Hispanic Mutation Panel (HISPANEL) on MassARRAY; semiconductor sequencing; and copy number variant (CNV) detection. BRCA PV probability was calculated using BRCAPRO. Among 1,627 participants (95.2% with cancer), we detected 236 (14.5%) BRCA PVs; 160 BRCA1 (31% CNVs); 76 BRCA2 PV frequency varied by country: 26% Brazil, 9% Colombia, 13% Peru, and 17% Mexico. Recurrent PVs (seen ≥3 times), some region-specific, represented 42.8% (101/236) of PVs. There was no ClinVar entry for 14% (17/125) of unique PVs, and 57% (111/196) of unique VUS. The area under the ROC curve for BRCAPRO was 0.76. In summary, we implemented a low-cost BRCA testing strategy and documented a significant burden of non-ClinVar reported BRCA PVs among Latin Americans. There are recurrent, population-specific PVs and CNVs, and we note that the BRCAPRO mutation probability model performs adequately. This study helps address the gap in our understanding of BRCA-associated cancer in Latin America.

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.

Neuroglial Cell Cryopreservation in Appropriate Inductive Conditions.

An ability to store cells (if they cannot be used fresh) reduces cell wastage, thereby increasing the supply of transplantable material. Cell storage is also valuable in scientific research, allowing material to be archived and experiments to be repeated from the same tissue source and facilitating research collaboration by allowing stored samples to be distributed. Cryopreservation is currently considered the most promising and successful, long-term biological conservation method. Its use has led to optimizing survival, improving protocols and stem cell and neuroglia viability, thereby assuring its future use in neuroregeneration and restoration regarding cell therapy. The success of conservation processes in ensuring cell viability depends on aspects such as the characteristics, cells' cryobiological behavior, isolation methodologies, cell freezing, the use and choice of cryoprotectants and such aspects' influence on intra- and extra-cellular dynamics. This review deals with cells' cryobiological behavior, cryopreservation and cryoprotectants, emphasizing on stem cell and neuroglial populations as therapeutic target regarding nervous system diseases.

Approaches of the Transcriptomic Analysis in Astrocytes: Potential Pharmacological Targets.

Astrocytes are important glial cells involved in the ionic regulation of the extracellular fluid in the Central Nervous System (CNS), the formation of the blood brain barrier (BBB) and the support to neurons for the maintenance of the Krebs cycle intermediaries. Even though these cells are known to be important for the brain functioning, several of their functions and their development have not been fully elucidated. In this context, identifying the algorithms used for their analysis plays a pivotal role in the development of new strategies in the study of astrocytes. The main objective of this review is to summarize the techniques that have helped to obtain transcriptomic data in astrocytes and the new algorithms that were used to perform the analysis of experimental data, elucidating new studies in which these had been used. We also highlight the current transcriptomics approaches targeting astrocytes function as a possible target for pharmacological interventions.

Ultrastructural analysis of olfactory ensheathing cells derived from olfactory bulb and nerve of neonatal and juvenile rats.

Olfactory nerve derived and olfactory bulb derived olfactory ensheathing cells (OECs) have the ability to promote axonal regeneration and remyelination, both of which are essential in a successful cell transplant. Thus, morphological identification of OECs is a key aspect to develop an applicable cell therapy for injuries to the nervous system. However, there is no clear definition regarding which developmental stage or anatomical origin of OECs is more adequate for neural repair. In the present study, an ultrastructural comparison was made between OECs recovered from primary cultures of olfactory nerve and bulb in two developmental stages. The most notorious difference between cells obtained from olfactory nerve and bulb was the presence of indented nuclei in bulb derived OECs, suggesting a greater ability for possible chemotaxis. In neonatal OECs abundant mitochondria, lipid vacuoles, and smooth endoplasmic reticulum were detected, suggesting an active lipid metabolism, probably involved in synthesis of myelin. Our results suggest that neonatal OECs obtained from olfactory bulb have microscopic properties that could make them more suitable for neural repair.

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.

Intravenous ribavirin for respiratory syncytial viral infections in pediatric hematopoietic SCT recipients.

Respiratory syncytial virus (RSV) is a potential cause of serious morbidity and even mortality among children undergoing hematopoietic SCT (HSCT). Contrary to the available information regarding the aerosolized formulation of ribavirin, there is a paucity of published studies using i.v. ribavirin in adults, and very few single reports on pediatric patients. Aerosolized drug administration has been limited by potential toxicity and special air-flow requirements. In this regard, i.v. ribavirin could prevent these disadvantages, but its efficacy and safety remain controversial in the pediatric HSCT setting. The present study describes the outcome of six pediatric patients undergoing HSCT with nine episodes of proven RSV. Four episodes corresponded to lower respiratory tract infection (LRTI) and five presented with upper respiratory tract infection (URTI). All LRTI patients showed favorable clinical responses, with 100% survival and no progression to LRTI in the remaining five URTI. No side effects were documented during ribavirin administration. We conclude that ribavirin was well tolerated intravenously, without associated side effects, and was effective in the treatment of RSV in this limited number of pediatric HSCT patients. The role and efficacy of i.v. ribavirin needs to be further clarified by prospective controlled trials in pediatric populations.

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.

Structural evolution: mechanism of olefin insertion in hydroformylation reaction.

Hydroformylation is the transformation of an alkene to an aldehyde via the addition of both hydrogen and carbon monoxide. The final aldehyde has one more carbon atom than the precursor alkene. Two isomeric products can result. The regiochemistry of the hydroformylation reaction is believed to be controlled by the olefin insertion step. A reaction mechanism is usually studied by finding the reactants, products, intermediates, and transition states. Alternatively, a chemical reaction can be studied from the redistribution of the electron density along the reaction path connecting the stationary points. The aim of this work is to describe the reaction mechanism of the insertion process by the structural evolution defined by the changes in the electron density during the reaction.

[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.