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.

Profiling Chromosome Topological Features by Super-Resolution 3D Structured Illumination Microscopy.

Three-dimensional structured illumination microscopy (3D-SIM) and fluorescence in situ hybridization on three-dimensional preserved cells (3D-FISH) have proven to be robust and efficient methodologies for analyzing nuclear architecture and profiling the genome's topological features. These methods have allowed the simultaneous visualization and evaluation of several target structures at super-resolution. In this chapter, we focus on the application of 3D-SIM for the visualization of 3D-FISH preparations of chromosomes in interphase, known as Chromosome Territories (CTs). We provide a workflow and detailed guidelines for sample preparation, image acquisition, and image analysis to obtain quantitative measurements for profiling chromosome topological features. In parallel, we address a practical example of these protocols in the profiling of CTs 9 and 22 involved in the translocation t(9;22) in Chronic Myeloid Leukemia (CML). The profiling of chromosome topological features described in this chapter allowed us to characterize a large-scale topological disruption of CTs 9 and 22 that correlates directly with patients' response to treatment and as a possible potential change in the inheritance systems. These findings open new insights into how the genome structure is associated with the response to cancer treatments, highlighting the importance of microscopy in analyzing the topological features of the genome.

Reversion from basal histone H4 hypoacetylation at the replication fork increases DNA damage in FANCA deficient cells.

The FA/BRCA pathway safeguards DNA replication by repairing interstrand crosslinks (ICL) and maintaining replication fork stability. Chromatin structure, which is in part regulated by histones posttranslational modifications (PTMs), has a role in maintaining genomic integrity through stabilization of the DNA replication fork and promotion of DNA repair. An appropriate balance of PTMs, especially acetylation of histones H4 in nascent chromatin, is required to preserve a stable DNA replication fork. To evaluate the acetylation status of histone H4 at the replication fork of FANCA deficient cells, we compared histone acetylation status at the DNA replication fork of isogenic FANCA deficient and FANCA proficient cell lines by using accelerated native immunoprecipitation of nascent DNA (aniPOND) and in situ protein interactions in the replication fork (SIRF) assays. We found basal hypoacetylation of multiple residues of histone H4 in FA replication forks, together with increased levels of Histone Deacetylase 1 (HDAC1). Interestingly, high-dose short-term treatment with mitomycin C (MMC) had no effect over H4 acetylation abundance at the replication fork. However, chemical inhibition of histone deacetylases (HDAC) with Suberoylanilide hydroxamic acid (SAHA) induced acetylation of the FANCA deficient DNA replication forks to levels comparable to their isogenic control counterparts. This forced permanence of acetylation impacted FA cells homeostasis by inducing DNA damage and promoting G2 cell cycle arrest. Altogether, this caused reduced RAD51 foci formation and increased markers of replication stress, including phospho-RPA-S33. Hypoacetylation of the FANCA deficient replication fork, is part of the cellular phenotype, the perturbation of this feature by agents that prevent deacetylation, such as SAHA, have a deleterious effect over the delicate equilibrium they have reached to perdure despite a defective FA/BRCA pathway.

Descripción de las intervenciones broncoscópicas en estenosis traqueales posterior a infección por COVID-19 / Description of Bronchoscopic Interventions in Post-COVID Tracheal Stenosis

Introducción: La infección por SARS-CoV-2 puede presentar síndrome de distrés res-piratorio agudo con requerimiento de ventilación mecánica prolongada y retraso en la realización de traqueostomía. Esto trae como consecuencia un incremento en casos de estenosis traqueal y la necesidad de métodos menos invasivos para su abordaje. Métodos: Estudio descriptivo de corte transversal, desde marzo 2020 hasta diciem-bre 2021 en el Hospital Universitario Nacional de Colombia, en adultos con estenosis traqueal postintubación asociado SARS-CoV-2. Se realizó análisis univariado entre los grupos con infección o no por SARS-CoV-2 como control, y reintervención, grado de estenosis, uso de inyección intramucosa con dexametasona intratraqueal o múltiples estenosis como desenlaces de importancia. Se usó test exacto de Fisher, t Student y Man-Whitney según la naturaleza de variables. Se consideró p estadísticamente significativo menor a 0.05.Resultados: Se identificaron 26 pacientes, 20 tenían COVID-19 y 6 no. Se encontraron diferencias en edad (p=0,002), epilepsia (p=0,007) y estenosis múltiple (p= 0,04). En 85% de los casos se utilizó láser blue más dilatación con balón pulmonar, en 35% inyección intramucosa con dexametasona intratraqueal y reintervención en 35%, sin diferencias significativas entre grupos. Conclusiones: Se observó un incremento tres veces mayor de pacientes con estenosis múltiple en el grupo de infección por COVID-19, así mismo se encontró que el método más utilizado en este grupo para la recanalización fue el uso de láser blue más dilatación con balón pulmonar y la innovación en el uso de inyección intramucosa.

Introduction: SARS-CoV-2 infection can lead to acute respiratory distress syndrome with a prolonged need for mechanical ventilation and delayed tracheostomy, resulting in an increase in cases of tracheal stenosis and the necessity for less invasive approaches.Methods: A descriptive cross-sectional study was conducted from March 2020 to December 2021 at the Hospital Universitario Nacional de Colombia, focusing on adults with post-intubation tracheal stenosis associated with SARS-CoV-2. Univariate analysis was performed between groups with or without SARS-CoV-2 infection as a control, considering reintervention, degree of stenosis, use of intratracheal steroids, or multiple stenoses as important outcomes. Fisher's exact test, Student's t-test, and Mann-Whit-ney test were employed based on the nature of variables. A p-value less than 0.05 was considered statistically significant.Results: A total of 26 patients were included, with 20 having COVID-19 and 6 without. Significant differences were found in age (p=0.002), epilepsy (p=0.007), and multiple stenosis (p=0.04). In 85% of cases, laser blue plus balloon pulmonary dilation was used, intratracheal dexamethasone in 35%, and reintervention in 35%, with no significant differences between groups.Conclusions: A threefold increase in subglottic stenosis was observed during the SARS-CoV-2 pandemic, with more instances of multiple stenosis and predominantly the use of laser blue plus balloon pulmonary dilation as a successful recanalization technique. There was a higher use of intratracheal dexamethasone in this group compared to oth-er pathologies causing tracheal stenosis.

Identificación de las características de los ganglios evaluados en el procedimiento EBUS y su relación con el diagnóstico de malignidad en instituto de alta complejidad en cáncer / Identification of the Characteristics of the Lymph Nodes Evaluated in the EBUS Procedure and their Relationship with the Diagnosis of Malignancy in a Highly Complex Cancer Institute

Introducción: La EBUS ha sido el foco de numerosos estudios destinados a evaluar su utilidad y rendimiento diagnóstico en diversas patologías. Objetivo principal: Identificación de las características ganglionares evaluadas en el procedimiento de Ultrasonido Endobronquial (EBUS) y su relación con el diagnóstico de malignidad en pacientes del Instituto Nacional del Cáncer de Colombia del 1 de enero de 2017 al 31 de marzo de 2021.Métodos: Estudio analítico observacional transversal. La recopilación de datos implicó un muestreo de casos consecutivos no probabilísticos entre individuos que cumplían los criterios de inclusión.Resultados: Un total de 75 pacientes fueron sometidos a EBUS. Se identificaron 6 características ecográficas de los ganglios de la biopsia asociadas a malignidad destacándose los ganglios mayores de 1 cm, márgenes mal definidos, ecogenicidad heterogénea, ausencia de una estructura hiliar central, presencia de signos de necrosis o coagulación y presencia de conglomerado ganglionar. Conclusión: Este estudio caracterizó la frecuencia de los hallazgos en la ultrasonografía endobronquial destacando algunas características ecográficas de los ganglios mediastínicos que podrían predecir patología maligna.

Introduction: The EBUS has been the focus of numerous studies aiming to evaluate its utility and diagnostic performance across various pathologies. Objective: Identification of the node characteristics evaluated in the Endobronchial Ultrasound (EBUS) procedure and their relationship with malignancy diagnosis in patients at the National Cancer Institute of Colombia from January 1st, 2017, to March 31st, 2021. Methods: Observational cross-sectional analytical study. Data collection involved non-probabilistic consecutive case sampling among individuals meeting the inclusion criteria.Results: A total of 75 patients underwent the EBUS procedure. Our findings revealed six predictors of malignancy based on sonographic features of biopsy nodes, including nodes larger than 1 cm, poorly defined margins, heterogeneous echogenicity, absence of a central hilar structure, presence of signs indicating necrosis or coagulation, and the presence of a ganglion conglomerate. Conclusions: This study showed that endobronchial ultrasonography has several sonographic characteristics at the time of evaluating mediastinal nodes that could predict malignant and benign pathology.

Role of TBX20 Truncating Variants in Dilated Cardiomyopathy and Left Ventricular Noncompaction.

BACKGROUND: Less than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. TBX20 has been linked to congenital heart defects; although an association with left ventricular noncompaction (LVNC) and DCM has been proposed, it is still considered a gene with limited evidence for these phenotypes. This study sought to investigate the association between the TBX20 truncating variant (TBX20tv) and DCM/LVNC. METHODS: TBX20 was sequenced by next-generation sequencing in 7463 unrelated probands with a diagnosis of DCM or LVNC, 22 773 probands of an internal comparison group (hypertrophic cardiomyopathy, channelopathies, or aortic diseases), and 124 098 external controls (individuals from the gnomAD database). Enrichment of TBX20tv in DCM/LVNC was calculated, cosegregation was determined in selected families, and clinical characteristics and outcomes were analyzed in carriers. RESULTS: TBX20tv was enriched in DCM/LVNC (24/7463; 0.32%) compared with internal (1/22 773; 0.004%) and external comparison groups (4/124 098; 0.003%), with odds ratios of 73.23 (95% CI, 9.90-541.45; P<0.0001) and 99.76 (95% CI, 34.60-287.62; P<0.0001), respectively. TBX20tv was cosegregated with DCM/LVNC phenotype in 21 families for a combined logarythm of the odds score of 4.53 (strong linkage). Among 57 individuals with TBX20tv (49.1% men; mean age, 35.9±20.8 years), 41 (71.9%) exhibited DCM/LVNC, of whom 14 (34.1%) had also congenital heart defects. After a median follow-up of 6.9 (95% CI, 25-75:3.6-14.5) years, 9.7% of patients with DCM/LVNC had end-stage heart failure events and 4.8% experienced malignant ventricular arrhythmias. CONCLUSIONS: TBX20tv is associated with DCM/LVNC; congenital heart defect is also present in around one-third of cases. TBX20tv-associated DCM/LVNC is characterized by a nonaggressive phenotype, with a low incidence of major cardiovascular events. TBX20 should be considered a definitive gene for DCM and LVNC and routinely included in genetic testing panels for these phenotypes.

Performance Evaluation of a Magnetic Resonance Imager with Evidence-Based Decision Making Tools.

Evidence-based decision-making tools were used to evaluate the performance of a 16-year-old 1.5T Magnetic Resonance Imager (MRI) that has been fully dedicated to clinical service in a public hospital in Mexico. The MRI age highlights the importance of regular performance evaluations to ensure that the equipment is still functioning optimally, even when the system went through an important software and hardware updated. The use of Multiple-Criteria Decision-Making is an effective method to evaluate the performance of complex systems like MR imagers. A technical global indicator was set, revealing that only 50% of available time has been used is interesting and could be further investigated to determine if there are any factors limiting the usage of the system. The good performance indicators in terms of productivity, availability, and technical aspects are encouraging and suggest that the updated software and hardware have had a positive impact on the overall performance of the system.Finally, the use of evidence-based decision-making tools to evaluate the performance of the MR imager was a successful approach and can serve as a model for other healthcare facilities to follow.Clinical Relevance- MRI is a non-invasive diagnostic test that uses a magnetic field and radiofrequency waves to obtain detailed images of internal structures of the body. Unlike X-rays and CT scans, which use ionizing radiation, MRI does not expose patients to harmful radiation, making it a safe option for diagnostic imaging. The use of MRI a valuable tool for characterizing lesions, detecting abnormalities, and monitoring disease progression and it is widely used in several medical fields, including neurology, oncology, and orthopedics, among others. Therefore, ensuring that the MRI system is working optimally is crucial for providing reliable and accurate results, which can lead to timely and appropriate treatment for patients.

Concepts of multi-level dynamical modelling: understanding mechanisms of squamous cell carcinoma development in Fanconi anemia.

Fanconi anemia (FA) is a rare disease (incidence of 1:300,000) primarily based on the inheritance of pathogenic variants in genes of the FA/BRCA (breast cancer) pathway. These variants ultimately reduce the functionality of different proteins involved in the repair of DNA interstrand crosslinks and DNA double-strand breaks. At birth, individuals with FA might present with typical malformations, particularly radial axis and renal malformations, as well as other physical abnormalities like skin pigmentation anomalies. During the first decade of life, FA mostly causes bone marrow failure due to reduced capacity and loss of the hematopoietic stem and progenitor cells. This often makes hematopoietic stem cell transplantation necessary, but this therapy increases the already intrinsic risk of developing squamous cell carcinoma (SCC) in early adult age. Due to the underlying genetic defect in FA, classical chemo-radiation-based treatment protocols cannot be applied. Therefore, detecting and treating the multi-step tumorigenesis process of SCC in an early stage, or even its progenitors, is the best option for prolonging the life of adult FA individuals. However, the small number of FA individuals makes classical evidence-based medicine approaches based on results from randomized clinical trials impossible. As an alternative, we introduce here the concept of multi-level dynamical modelling using large, longitudinally collected genome, proteome- and transcriptome-wide data sets from a small number of FA individuals. This mechanistic modelling approach is based on the "hallmarks of cancer in FA", which we derive from our unique database of the clinical history of over 750 FA individuals. Multi-omic data from healthy and diseased tissue samples of FA individuals are to be used for training constituent models of a multi-level tumorigenesis model, which will then be used to make experimentally testable predictions. In this way, mechanistic models facilitate not only a descriptive but also a functional understanding of SCC in FA. This approach will provide the basis for detecting signatures of SCCs at early stages and their precursors so they can be efficiently treated or even prevented, leading to a better prognosis and quality of life for the FA individual.

A Boolean network model of the double-strand break repair pathway choice.

Double strand break (DSB) repair is critical to maintaining the integrity of the genome. DSB repair deficiency underlies multiple pathologies, including cancer, chromosome instability syndromes, and, potentially, neurodevelopmental defects. DSB repair is mainly handled by two pathways: highly accurate homologous recombination (HR), which requires a sister chromatid for template-based repair, limited to S/G2 phases of the cell cycle, and canonical non-homologous end joining (c-NHEJ), available throughout the cell cycle in which minimum homology is sufficient for highly efficient yet error-prone repair. Some circumstances, such as cancer, require alternative highly mutagenic DSB repair pathways like microhomology-mediated end-joining (MMEJ) and single-strand annealing (SSA), which are triggered to attend to DNA damage. These non-canonical repair alternatives are emerging as prominent drivers of resistance in drug-based tumor therapies. Multiple DSB repair options require tight inter-pathway regulation to prevent unscheduled activities. In addition to this complexity, epigenetic modifications of the histones surrounding the DSB region are emerging as critical regulators of the DSB repair pathway choice. Modeling approaches to understanding DSBs repair pathway choice are advantageous to perform simulations and generate predictions on previously uncharacterized aspects of DSBs response. In this work, we present a Boolean network model of the DSB repair pathway choice that incorporates the knowledge, into a dynamic system, of the inter-pathways regulation involved in DSB repair, i.e., HR, c-NHEJ, SSA, and MMEJ. Our model recapitulates the well-characterized HR activity observed in wild-type cells in response to DSBs. It also recovers clinically relevant behaviors of BRCA1/FANCS mutants, and their corresponding drug resistance mechanisms ascribed to DNA repair gain-of-function pathogenic variants. Since epigenetic modifiers are dynamic and possible druggable targets, we incorporated them into our model to better characterize their involvement in DSB repair. Our model predicted that loss of the TIP60 complex and its corresponding histone acetylation activity leads to activation of SSA in response to DSBs. Our experimental validation showed that TIP60 effectively prevents activation of RAD52, a key SSA executor, and confirms the suitable use of Boolean network modeling for understanding DNA DSB repair.

High Non-Cardiac Death Incidence Should Be a Limitation of Drug-Eluting Stents Implantation? Insights from Recent Randomized Data.

Despite the introduction of drug-eluting stents (DES) significantly improved the efficacy and safety of percutaneous coronary interventions (PCI), particularly in a high-risk group of patients, the gap between PCI with his competitor's coronary artery bypass surgery (CABG) and/or optimal medical treatment alone was not reduced. In this revision, we highlighted the fact that in recent years landmark randomized studies reported at mid and long-term follow-ups a high incidence of non-cardiac death, cancer incidence, or both in the DES group of patients. The overall incidence of non-cardiac death was significantly higher in the DES vs. the comparator arm: 5.5% and 3.8%, respectively, p = 0.000018, and non-cardiac death appears to be more divergent between DES vs. the comparator at the extended follow-up to expenses of the last one. One of these trials reported five times greater cancer incidence in the DES arm at late follow-up, 5% vs. 0.7% p < 0.0018. We review the potential reason for these unexpected findings, although we can discard that DES biology could be involved in it. Until all these issues are resolved, we propose that DES implantation should be tailored accorded patient age, life expectancy, and lesion complexity.

Evaluación de resultados en una serie de pacientes con trasplante cardiaco: experiencia en el Instituto Nacional de Cardiología

Exponemos la experiencia del Instituto Nacional de Cardiología de una serie de casos de pacientes sometidos a trasplante cardiaco entre mayo de 2016 y junio 2022. Se realizaron 14 trasplantes, 13 fueron del sexo masculino. La edad osciló entre 19 y 62 años. Las etiologías fueron cardiopatías de tipo idiopática en 57% y valvular en 21%. El 50% se trasplantó en INTERMACS 4 (Interagency Registry for Mechanically Assisted Circulatory Support), 21% INTERMACS 3 y solo 28% en INTERMACS 2. Tres pacientes se trasplantaron con asistencia circulatoria tipo membrana circulación extracorpórea. Las complicaciones más frecuentes fueron las infecciosas. La mortalidad hospitalaria fue 35,7%. Hubo un fallecido en el seguimiento tras 5 años de trasplante.

We present the experience of the National Institute of Cardiology of a series of cases of patients undergoing heart transplantation between May 2016 and June 2022. Fourteen transplants were performed, 13 of the patients were male. The age ranged between 19 and 62 years. The etiologies were idiopathic heart disease in 57% and valvular heart disease in 21%. Fifty percent was transplanted in INTERMACS 4 (Interagency Registry for Mechanically Assisted Circulatory Support), 21% in INTERMACS 3 and only 28% in INTERMACS 2. Three patients were transplanted with membrane type extracorporeal circulation circulatory support. The most frequent complications were infectious. Hospital mortality was 35.7%. There was one patient who died during follow-up after 5 years of transplantation.

Inherited bone marrow failure syndromes: phenotype as a tool for early diagnostic suspicion at a major reference center in Mexico.

Introduction: The inherited bone marrow failure syndromes (IBMFSs) are a group of rare disorders characterized by bone marrow failure (BMF), physical abnormalities, and an increased risk of neoplasia. The National Institute of Pediatrics (INP) is a major medical institution in Mexico, where patients with BMF receive a complete approach that includes paraclinical tests. Readily recognizable features, such as the hematological and distinctive physical phenotypes, identified by clinical dysmorphologists, remain crucial for the diagnosis and management of these patients, particularly in circumstances where next-generation sequencing (NGS) is not easily available. Here, we describe a group of Mexican patients with a high clinical suspicion of an IBMFS. Methods: We performed a systematic retrospective analysis of the medical records of patients who had a high IBMFS suspicion at our institution from January 2018 to July 2021. An initial assessment included first ruling out acquired causes of BMF by the Hematology Department and referral of the patient to the Department of Human Genetics for physical examination to search for specific phenotypes suggesting an IBMFS. Patients with high suspicion of having an IBMFS were classified into two main groups: 1) specific IBMFS, including dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), Shwachman-Diamond syndrome (SDS), thrombocytopenia with absent radii (TAR), and severe congenital neutropenia (SCN); 2) undefined IBMFS (UI). Results: We established a high suspicion of having an IBMFS in 48 patients. At initial evaluation, the most common hematologic features were bicytopenia (20%) and aplastic anemia (16%); three patients received hematopoietic stem cell transplantation. Among patients with a suspicion of an IBMFS, the most common physical abnormality was minor craniofacial features in 83% of patients and neurodevelopmental disorders in 52%. The specific suspicions that we built were DBA (31%), SDS (18%), DC (14%), TAR (4%), and SCN (4%), whereas 27% of cases remained as undefined IBMFS. SDS, TAR, and SCN were more commonly suspected at an earlier age (<1 year), followed by DBA (2 years) and DC (5 years). Conclusions: Thorough examination of reported clinical data allowed us to highly suspect a specific IBMFS in approximately 70% of patients; however, an important number of patients remained with suspicion of an undefined IBMFS. Implementation of NGS and telomere length measurement are forthcoming measures to improve IBMFS diagnosis in Mexico.

TGFß pathway is required for viable gestation of Fanconi anemia embryos.

Overexpression of the TGFß pathway impairs the proliferation of the hematopoietic stem and progenitor cells (HSPCs) pool in Fanconi anemia (FA). TGFß promotes the expression of NHEJ genes, known to function in a low-fidelity DNA repair pathway, and pharmacological inhibition of TGFß signaling rescues FA HSPCs. Here, we demonstrate that genetic disruption of Smad3, a transducer of the canonical TGFß pathway, modifies the phenotype of FA mouse models deficient for Fancd2. We observed that the TGFß and NHEJ pathway genes are overexpressed during the embryogenesis of Fancd2-/- mice and that the Fancd2-/-Smad3-/- double knockout (DKO) mice undergo high levels of embryonic lethality due to loss of the TGFß-NHEJ axis. Fancd2-deficient embryos acquire extensive genomic instability during gestation which is not reversed by Smad3 inactivation. Strikingly, the few DKO survivors have activated the non-canonical TGFß-ERK pathway, ensuring expression of NHEJ genes during embryogenesis and improved survival. Activation of the TGFß-NHEJ axis was critical for the survival of the few Fancd2-/-Smad3-/- DKO newborn mice but had detrimental consequences for these surviving mice, such as enhanced genomic instability and ineffective hematopoiesis.

Fanconi anemia and dyskeratosis congenita/telomere biology disorders: Two inherited bone marrow failure syndromes with genomic instability.

Inherited bone marrow failure syndromes (IBMFS) are a complex and heterogeneous group of genetic diseases. To date, at least 13 IBMFS have been characterized. Their pathophysiology is associated with germline pathogenic variants in genes that affect hematopoiesis. A couple of these diseases also have genomic instability, Fanconi anemia due to DNA damage repair deficiency and dyskeratosis congenita/telomere biology disorders as a result of an alteration in telomere maintenance. Patients can have extramedullary manifestations, including cancer and functional or structural physical abnormalities. Furthermore, the phenotypic spectrum varies from cryptic features to patients with significantly evident manifestations. These diseases require a high index of suspicion and should be considered in any patient with abnormal hematopoiesis, even if extramedullary manifestations are not evident. This review describes the disrupted cellular processes that lead to the affected maintenance of the genome structure, contrasting the dysmorphological and oncological phenotypes of Fanconi anemia and dyskeratosis congenita/telomere biology disorders. Through a dysmorphological analysis, we describe the phenotypic features that allow to make the differential diagnosis and the early identification of patients, even before the onset of hematological or oncological manifestations. From the oncological perspective, we analyzed the spectrum and risks of cancers in patients and carriers.

Resultados de un registro prospectivo de pacientes con desórdenes hipertensivos del embarazo en un centro de la Ciudad de Buenos Aires / Results of a Prospective Registry of Patients with Hypertensive Disorders of Pregnancy in a Center of the City of Buenos Aires

RESUMEN Introducción: Los desórdenes hipertensivos del embarazo (DHE) complican el 10% de los embarazos. Son la principal causa de mortalidad materna, y requieren un equipo multidisciplinario para su abordaje. Objetivos: Cuantificar prevalencia y definir características y evolución de los DHE en un centro con un programa dedicado para su abordaje. Material y métodos: Registro continuo y prospectivo desde noviembre 2019 hasta julio 2021 que incluyó todas las pacientes con DHE (Hipertensión arterial crónica - HTAC, hipertensión gestacional - HTg, preeclampsia precoz - PEp, preeclampsia tardía - PEt, preeclampsia sobreimpuesta - PESI, y eclampsia) y que cumplieran los criterios de inclusión. Se excluyeron las pacientes sin cobertura médica que impidiera su seguimiento ambulatorio a largo plazo en la institución. Se evaluaron características basales y evolución, tratamiento y persistencia de HTA luego del puerperio. Se analizó la incidencia de retardo en el crecimiento intrauterino (RCIU), parto pretérmino, mortalidad materna y muerte neonatal dentro de los primeros 28 días de vida. Resultados: Se realizaron 5825 partos/cesáreas y se incluyeron 152 pacientes que cumplieron criterios de inclusión, con HTg (37,5%), PEp (19,7%), PEt (38,8%), PESI (3,3%)), eclampsia (0,6%). Edad media 36,4 ± 5,6 años. El 38,1% recibió aspirina. Los antihipertensivos más utilizados fueron labetalol (65,8%) y enalapril (44,1 %) en el embarazo y el puerperio respectivamente. No hubo mortalidad materna, y la neonatal fue 3,6%. La persistencia de HTA fue del 20,0% Conclusión: La preeclampsia tardía fue el DHE más frecuente en la población analizada. Más de la mitad de las pacientes que desarrollaron DHE no recibían tratamiento preventivo con aspirina, evidenciándose un déficit en la identificación de la población de riesgo. Una de cada 5 pacientes con DHE quedó con hipertensión arterial crónica luego del puerperio.

ABSTRACT Background: Hypertensive disorders of pregnancy (HDP) complicate 10% of pregnancies. They are the main cause of maternal mortality and require a multidisciplinary team to address them. Objectives: The aim of this study was to quantify the prevalence and define the characteristics and outcome of HDP in a center with a program focused on its management. Methods: This was a continuous and prospective registry from November 2019 to July 2021 that included all patients with HDP [chronic hypertension (CHT), gestational hypertension (GHT), early-onset preeclampsia (EPE), late preeclampsia (LPE), superimposed preeclampsia (SIPE) and eclampsia] who met the inclusion criteria. Patients without medical coverage that prevented long-term outpatient follow-up at the institution were excluded. Baseline characteristics and evolution, treatment and persistent HT after puerperium were evaluated. The incidence of intrauterine growth retardation (IUGR), preterm delivery, maternal mortality and neonatal death within the first 28 days of life was analyzed. Results: Among a total f 5825 deliveries/caesarean sections, 152 patients with GHT (37.5%), EPE (19.7%), LPE (38.8%), SIPE (3.3%), and eclampsia (0.6%) who met the inclusion criteria were included in the study. Mean age was 36.4±5.6 years. Aspirin was administered to 38.1% of patients. The most commonly used antihypertensive drugs were labetalol (65.8%) and enalapril (44.1%) during pregnancy and puerperium, respectively. There was no maternal mortality, and neonatal mortality was 3.6%. Persistent HT was 20.0%. Conclusion: Late preeclampsia was the most frequent HDP in the population analyzed. More than half of the patients who developed HDP did not receive preventive treatment with aspirin, showing a deficit in the identification of the population at risk. One in 5 HDP patients remained with CHTN after puerperium.

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America.

Objectives: Venetoclax combinations are a new standard for patients with acute myeloid leukemia (AML). We aimed to evaluate the safety and efficacy of these combinations in a period of accelerated approval in Latin-America.Methods: This observational study evaluated adults with acute myeloid leukemia who received venetoclax-based therapy in 11 public or private centers in Mexico and Peru for both newly diagnosed or relapsed and refractory AML.Results: Fifty patients were included; 28 with newly diagnosed (ND) AML and 22 with relapsed/refractory (RR) disease. ND patients were older (64 vs. 40 years; p < 0.001) with a lower functional capacity (ECOG ≥2 64.3% vs 9%; p < 0.001). Venetoclax was frequently combined with azacytidine (60%) and prophylactic azoles (82%) with a median maximum dose of 200 mg (range, 100-600 mg). Hematologic toxicities were common. Complete response rates including patients with incomplete hematopoietic recovery were 78.6% in ND and 45.5% in RR patients, with a median overall survival of 9.6 (95% CI 3.7-15.5) and 8 months (95% CI 4.8-11.2).Discussion: Our study showed a preferred use of venetoclax plus azacytidine over cyatrabine. Patients in the first-line setting were similar to those in the landmark studies, while most patients with relapsed disease had received prior intensive therapies. Responses were favorable, with a median survival in agreement to other reports, albeit shorter than that observed in the randomized phase-3 trials.Conclusion: Venetoclax-based therapy in AML was effective despite dose reductions and prophylactic antifungals in two middle-income countries outside of a clinical trial setting.

Fanconi Anemia Patients from an Indigenous Community in Mexico Carry a New Founder Pathogenic Variant in FANCG.

Fanconi anemia (FA) is a rare genetic disorder caused by pathogenic variants (PV) in at least 22 genes, which cooperate in the Fanconi anemia/Breast Cancer (FA/BRCA) pathway to maintain genome stability. PV in FANCA, FANCC, and FANCG account for most cases (~90%). This study evaluated the chromosomal, molecular, and physical phenotypic findings of a novel founder FANCG PV, identified in three patients with FA from the Mixe community of Oaxaca, Mexico. All patients presented chromosomal instability and a homozygous PV, FANCG: c.511-3_511-2delCA, identified by next-generation sequencing analysis. Bioinformatic predictions suggest that this deletion disrupts a splice acceptor site promoting the exon 5 skipping. Analysis of Cytoscan 750 K arrays for haplotyping and global ancestry supported the Mexican origin and founder effect of the variant, reaffirming the high frequency of founder PV in FANCG. The degree of bone marrow failure and physical findings (described through the acronyms VACTERL-H and PHENOS) were used to depict the phenotype of the patients. Despite having a similar frequency of chromosomal aberrations and genetic constitution, the phenotype showed a wide spectrum of severity. The identification of a founder PV could help for a systematic and accurate genetic screening of patients with FA suspicion in this population.

Prenatal diagnosis of Greig Cephalopolysyndactyly Syndrome. When to suspect it.

Greig Cephalopolysyndactyly Syndrome (GCPS) is a very rare multiple congenital anomaly with an estimated incidence of 1-9:1,000,000 in newborns with principal findings of macrocephaly, ocular hypertelorism, and polysyndactyly (preaxial or mixed preaxial and postaxial). Very few cases of prenatal diagnoses have been reported. The postnatal diagnosis is based on clinical findings and family background. GLI3, the only gene associated with this anomaly, is altered in more than 75% of cases. Deletions over 1 Mb and involving other genes yield severe clinical cases, which are known collectively as Greig Cephalopolysyndactyly-contiguous gene Syndrome. We report a case in which, despite early polydactyly findings on week 16, the diagnosis was established during the third trimester of pregnancy due to the late presentation of other anomalies corresponding to this syndrome.

Large-scale topological disruption of chromosome territories 9 and 22 is associated with nonresponse to treatment in CML.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm defined by the presence of t(9;22) translocation whose origin has been associated with the tridimensional genome organization. This rearrangement leads to the fusion of BCR and ABL1 genes giving rise to a chimeric protein with constitutive kinase activity. Imatinib, a tyrosine kinase inhibitor (TKI), is used as a first-line treatment for CML, though ~40% of CML patients do not respond. Here, using structured illumination microscopy (SIM) and 3D reconstruction, we studied the 3D organization patterns of the ABL1 and BCR genes, and their chromosome territories (CTs) CT9 and CT22, in CD34+ cells from CML patients that responded or not to TKI. We found that TKI resistance in CML is associated with high levels of structural disruption of CT9 and CT22 in CD34+ cells, increased CT volumes (especially for CT22), intermingling between CT9 and CT22, and an open-chromatin epigenetic mark in CT22. Altogether our results suggest that large-scale disruption of CT9 and CT22 correlates with the clinical response of CML patients, which could be translated into a potential prognostic marker of response to treatment in this disease and provide novel insights into the mechanisms underlying resistance to TKI in CML.