Targeted Demethylation of FOXP3-TSDR Enhances the Suppressive Capacity of STAT6-deficient Inducible T Regulatory Cells.

In vitro induced T regulatory cells (iTregs) are promising for addressing inflammation-driven diseases. However, current protocols for the generation and expansion of iTregs fail to induce extensive demethylation of the Treg-specific demethylated region (TSDR) within the FOXP3 gene, recognized as the master regulator for regulatory T cells (Tregs). This deficiency results in the rapid loss of Foxp3 expression and an unstable regulatory phenotype. Nevertheless, inhibition of STAT6 signaling effectively stabilizes Foxp3 expression in iTregs. Thus, this study aimed to develop a protocol combining epigenetic editing with STAT6 deficiency to improve iTregs' ability to maintain stable suppressive function and a functional phenotype. Our findings demonstrate that the combination of STAT6 deficiency (STAT6-/-) with targeted demethylation of the TSDR using a CRISPR-TET1 tool leads to extensive demethylation of FOXP3-TSDR. Demethylation in STAT6-/- iTregs was associated with enhanced expression of Foxp3 and suppressive markers such as CTLA-4, PD-1, IL-10, and TGF-ß. Furthermore, the edited STAT6-/- iTregs exhibited an increased capacity to suppress CD8+ and CD4+ lymphocytes and could more efficiently impair Th1-signature gene expression compared to conventional iTregs. In conclusion, the deactivation of STAT6 and TSDR-targeted demethylation via CRISPR-TET1 is sufficient to induce iTregs with heightened stability and increased suppressive capacity, offering potential applications against inflammatory and autoimmune diseases.

The exception to the rule? TORC1 triggers growth under low nutrient environments.

Eukaryotic cells' proliferation and growth are controlled by the target of rapamycin kinase (TOR). TOR usually activates in favorable energy and nutritional circumstances. This is challenged by recent research, suggesting that plant cells optimized for nutrient absorption in low nutritional conditions may activate the TOR pathway in a polarized manner.

A PTP1B-Cdk3 Signaling Axis Promotes Cell Cycle Progression of Human Glioblastoma Cells through an Rb-E2F Dependent Pathway.

PTP1B plays a key role in developing different types of cancer. However, the molecular mechanism underlying this effect is unclear. To identify molecular targets of PTP1B that mediate its role in tumorigenesis, we undertook a SILAC-based phosphoproteomic approach, which allowed us to identify Cdk3 as a novel PTP1B substrate. Substrate trapping experiments and docking studies revealed stable interactions between the PTP1B catalytic domain and Cdk3. In addition, we observed that PTP1B dephosphorylates Cdk3 at tyrosine residue 15 in vitro and interacts with it in human glioblastoma cells. Next, we found that pharmacological inhibition of PTP1B or its depletion with siRNA leads to cell cycle arrest with diminished activity of Cdk3, hypophosphorylation of Rb, and the downregulation of E2F target genes Cdk1, Cyclin A, and Cyclin E1. Finally, we observed that the expression of a constitutively active Cdk3 mutant bypasses the requirement of PTP1B for cell cycle progression and expression of E2F target genes. These data delineate a novel signaling pathway from PTP1B to Cdk3 required for efficient cell cycle progression in an Rb-E2F dependent manner in human GB cells.

New molecular components that regulates the transcriptional hub in root hairs: coupling environmental signals to endogenous hormones to coordinate growth.

Root hairs (RH) have become an important model system for studying plant growth and how plants modulate their growth in response to cell-intrinsic and environmental stimuli. Here, we will discuss recent advances in our understanding of the molecular mechanisms underlying the growth of Arabidopsis thaliana RH in the interface between responses to environmental cues (e.g. nutrients such as nitrates, phosphate and microorganism) and hormonal stimuli (e.g. auxin). RH growth is under the control of several transcription factors that are also under strong regulation at different levels. In this review we highlight recent new discoveries along these transcriptional pathways that may increase our capacity to enhance nutrient uptake by the roots in the context of abiotic stresses. We used text-mining capacities of the PlantConnectome database to generate the most updated view of RH growth in these complex biological contexts.

Transcription factor NAC1 activates expression of peptidase-encoding AtCEPs in roots to limit root hair growth.

Plant genomes encode a unique group of papain-type Cysteine EndoPeptidases (CysEPs) containing a KDEL endoplasmic reticulum (ER) retention signal (KDEL-CysEPs or CEPs). CEPs process the cell-wall scaffolding EXTENSIN (EXT) proteins that regulate de novo cell-wall formation and cell expansion. Since CEPs cleave EXTs and EXT-related proteins, acting as cell-wall-weakening agents, they may play a role in cell elongation. The Arabidopsis (Arabidopsis thaliana) genome encodes 3 CEPs (AtCPE1-AtCEP3). Here, we report that the genes encoding these 3 Arabidopsis CEPs are highly expressed in root-hair (RH) cell files. Single mutants have no evident abnormal RH phenotype, but atcep1-3 atcep3-2 and atcep1-3 atcep2-2 double mutants have longer RHs than wild-type (Wt) plants, suggesting that expression of AtCEPs in root trichoblasts restrains polar elongation of the RH. We provide evidence that the transcription factor NAC1 (petunia NAM and Arabidopsis ATAF1, ATAF2, and CUC2) activates AtCEPs expression in roots to limit RH growth. Chromatin immunoprecipitation indicates that NAC1 binds to the promoter of AtCEP1, AtCEP2, and, to a lower extent, AtCEP3 and may directly regulate their expression. Inducible NAC1 overexpression increases AtCEP1 and AtCEP2 transcript levels in roots and leads to reduced RH growth while the loss of function nac1-2 mutation reduces AtCEP1-AtCEP3 gene expression and enhances RH growth. Likewise, expression of a dominant chimeric NAC1-SRDX repressor construct leads to increased RH length. Finally, we show that RH cell walls in the atcep1-3 atcep3-2 double mutant have reduced levels of EXT deposition, suggesting that the defects in RH elongation are linked to alterations in EXT processing and accumulation. Our results support the involvement of AtCEPs in controlling RH polar growth through EXT processing and insolubilization at the cell wall.

Molecular transition of SARS-CoV-2 from critical patients during the first year of the COVID-19 pandemic in Mexico City.

Background: The SARS-CoV-2 virus has caused unprecedented mortality since its emergence in late 2019. The continuous evolution of the viral genome through the concerted action of mutational forces has produced distinct variants that became dominant, challenging human immunity and vaccine development. Aim and methods: In this work, through an integrative genomic approach, we describe the molecular transition of SARS-CoV-2 by analyzing the viral whole genome sequences from 50 critical COVID-19 patients recruited during the first year of the pandemic in Mexico City. Results: Our results revealed differential levels of the evolutionary forces across the genome and specific mutational processes that have shaped the first two epidemiological waves of the pandemic in Mexico. Through phylogenetic analyses, we observed a genomic transition in the circulating SARS-CoV-2 genomes from several lineages prevalent in the first wave to a dominance of the B.1.1.519 variant (defined by T478K, P681H, and T732A mutations in the spike protein) in the second wave. Conclusion: This work contributes to a better understanding of the evolutionary dynamics and selective pressures that act at the genomic level, the prediction of more accurate variants of clinical significance, and a better comprehension of the molecular mechanisms driving the evolution of SARS-CoV-2 to improve vaccine and drug development.

Understanding signaling pathways governing the polar development of root hairs in low-temperature, nutrient-deficient environments.

Plants exposed to freezing and above-freezing low temperatures must employ a variety of strategies to minimize fitness loss. There is a considerable knowledge gap regarding how mild low temperatures (around 10 °C) affect plant growth and developmental processes, even though the majority of the molecular mechanisms that plants use to adapt to extremely low temperatures are well understood. Root hairs (RH) have become a useful model system for studying how plants regulate their growth in response to both cell-intrinsic cues and environmental inputs. Here, we'll focus on recent advances in the molecular mechanisms underpinning Arabidopsis thaliana RH growth at mild low temperatures and how these discoveries may influence our understanding of nutrient sensing mechanisms by the roots. This highlights how intricately linked mechanisms are necessary for plant development to take place under specific circumstances and to produce a coherent response, even at the level of a single RH cell.

STAT6 controls the stability and suppressive function of regulatory T cells.

Signal transducer and activator of transcription 6 (STAT6) promotes tumorigenesis by decreasing the Forkhead box P3+ (Foxp3+) cell frequency allowing for the infiltration of inflammatory cells during the early stages of colitis-associated cancer (CAC). In this study, we dissected the role of STAT6 in the generation of inducible in vitro regulatory T cells (iTregs) and peripheral in vivo Tregs (pTregs) under inflammatory conditions. In in vitro assays, when STAT6 was lacking, iTregs preserved a stable phenotype and expressed high levels of Foxp3 and CD25 during long expansion periods, even in the presence of IL-6. This effect was associated with increased in vitro suppressive ability, over-expression of programmed death-1 (PD-1), CTLA-4, and Foxp3, and decreased IFN-γ expression. Furthermore, iTregs developed during STAT6 deficiency showed a higher demethylation status for the FOXP3 Treg-specific demethylated region (TSDR), coupled with lower DNA methyltransferase 1 (DNMT1) mRNA expression, suggesting that STAT6 may lead to Foxp3 silencing. Using a mouse model of CAC, the STAT6-/- pTregs expressed a more activated phenotype at the intestine, had higher suppressive capacity, and expressed more significant levels of PD-1 and latency-associated peptide of TGF-ß (LAP) associated with their ability to attenuate tumor development. These data suggest that STAT6 signaling impairs the induction, stability, and suppressive capacity of Tregs developed in vitro or in vivo during gut inflammation.

Mexican Colorectal Cancer Research Consortium (MEX-CCRC): Etiology, Diagnosis/Prognosis, and Innovative Therapies.

In 2013, recognizing that Colorectal Cancer (CRC) is the second leading cause of death by cancer worldwide and that it was a neglected disease increasing rapidly in Mexico, the community of researchers at the Biomedicine Research Unit of the Facultad de Estudios Superiores Iztacala from the Universidad Nacional Autónoma de México (UNAM) established an intramural consortium that involves a multidisciplinary group of researchers, technicians, and postgraduate students to contribute to the understanding of this pathology in Mexico. This article is about the work developed by the Mexican Colorectal Cancer Research Consortium (MEX-CCRC): how the Consortium was created, its members, and its short- and long-term goals. Moreover, it is a narrative of the accomplishments of this project. Finally, we reflect on possible strategies against CRC in Mexico and contrast all the data presented with another international strategy to prevent and treat CRC. We believe that the Consortium's characteristics must be maintained to initiate a national strategy, and the reported data could be useful to establish future collaborations with other countries in Latin America and the world.

Failure to EGFR-TKI-based therapy and tumoural progression are promoted by MEOX2/GLI1-mediated epigenetic regulation of EGFR in the human lung cancer.

BACKGROUND: Mesenchyme homeobox-2 (MEOX2)-mediated regulation of glioma-associated oncogene-1 (GLI1) has been associated with poor overall survival, conferring chemoresistance in lung cancer. However, the role of MEOX2/GLI1 in resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs)-based therapy remains unexplored in human lung cancer. METHODS: Functional assays using genetic silencing strategy by short hairpin RNAs, as well as cytotoxic (tetrazolium dye MTT) and clonogenic assays, were performed to evaluate MEOX2/GLI1-induced malignancy capacity in lung cancer cells. Further analysis performed includes western blot, qPCR and ChIP-qPCR assays to identify whether MEOX2/GLI1 promote EGFR/AKT/ERK activation, as well as EGFR overexpression through epigenetic mechanisms. Finally, preclinical tumour progression in vivo and progression-free disease interval analyses in patients treated with EGFR-TKI were included. RESULTS: Overexpressed MEOX2/GLI1 in both EGFR wild-type and EGFR/KRAS-mutated lung cancer cells were detected and involved in the activation/expression of EGFR/AKT/ERK biomarkers. In addition, MEOX2/GLI1 was shown to be involved in the increased proliferation of tumour cells and resistance capacity to cisplatin, EGFR-TKIs (erlotinib and AZD9291 'osimertinib'), AZD8542-SMO, and AZD6244-MEKK1/2. In addition, we identified that MEOX2/GLI1 promote lung tumour cells progression in vivo and are clinically associated with poorer progression-free disease intervals. Finally, both MEOX2 and GLI1 were detected to be epigenetically involved in EGFR expression by reducing both repressive markers polycomb-EZH2 and histone H3K27me3, but, particularly, increasing an activated histone profile H3K27Ac/H3K4me3 at EGFR-gene enhancer-promoter sequences that probably representing a novel EGFR-TKI-based therapy resistance mechanism. CONCLUSION: MEOX2/GLI1 promote resistance to cisplatin and EGFR-TKI-based therapy in lung cancer cells, modulating EGFR/AKT/ERK signalling pathway activation, as well as inducing an aberrant epigenetic modulation of the EGFR-gene expression in human lung cancer.

LncRNA SOX2-OT regulates AKT/ERK and SOX2/GLI-1 expression, hinders therapy, and worsens clinical prognosis in malignant lung diseases.

The involvement of LncRNA SOX2-overlapping transcript (SOX2-OT), SOX2, and GLI-1 transcription factors in cancer has been well documented. Nonetheless, it is still unknown whether co-expressed SOX2-OT/SOX2 or SOX2-OT/SOX2/GLI-1 axes are epigenetically/transcriptionally involved in terms of resistance to oncology therapy and in poorer clinical outcomes for patients with lung cancer. We evaluated the role of SOX2-OT/SOX2 and SOX2-OT/SOX2/GLI-1 axes using RT-qPCR, western blot, immunofluorescence analyses, gene silencing, cellular cytotoxic, and ChIP-qPCR assays on human cell lines, solid lung malignant tumors, and normal lung tissue. We detected that the SOX2-OT/SOX2/GLI-1 axis promotes resistance to tyrosine kinase inhibitor (TKI)-erlotinib and cisplatin-based therapy. Evidence from this study show that SOX2-OT modulates the expression/activation of EGFR-pathway members AKT/ERK. Further, both SOX2-OT and GLI-1 genes are epigenetically regulated at their promoter sequences, in an LncRNA SOX2-OT-dependent manner, mainly through modifying the enrichment of the activation histone mark H3K4me3/H3K27Ac, versus the repressive histone mark H3K9me3/H3K27me3. In addition, we identified that inhibition of SOX2-OT and reduced expression of SOX2/GLI-1 sensitizes lung cancer cells to EGFR/TKI-erlotinib or cisplatin-based treatment. Finally, we show that high co-expression of SOX2-OT/SOX2 transcripts and SOX2/GLI-1 proteins appears to correlate with a poor clinical prognosis and lung malignant phenotype. Collectively, these results present evidence that LncRNA SOX2-OT modulates an orchestrated resistance mechanism, promoting poor prognosis and human lung malignancy through genetic, epigenetic, and post-translational mechanisms.

[Balloon pulmonary angioplasty for the treatment of chronic thromboembolic pulmonary hypertension]. / Angioplastía con balón para el tratamiento de la hipertensión arterial pulmonar por enfermedad tromboembólica crónica. Resultados hemodinámicos y clínicos inmediatos.

BACKGROUND: Balloon pulmonary angioplasty (BPA) is a therapeutic alternative for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). AIM: To report the initial experience with the "refined BPA technique" with the use of intravascular images. PATIENTS AND METHODS: Between June 2015 and June 2016 we selected fourteen patients with CTEPH who were considered candidates for BPA. Lesions targeted for treatment were further analyzed using intravascular imaging with optical frequency domain imaging (OFDI). We report the immediate hemodynamic results and four weeks of follow-up of the first eight patients of this series. RESULTS: We performed 16 BPA in eight patients aged 61 ± 14 years (88% women). Mean pulmonary artery pressure (PAPm) was 48.6 ± 5.8 mmHg. Success was achieved in seven patients (88%). A mean of 2.3 segments per patient were intervened in 11 sessions (1.6 sessions/ patient). Only one patient developed lung reperfusion injury. No mortality was associated with the procedure. After the last BPA session, PAPm decreased to 37.4 ± 8.6 mmHg (p=0.02). Pulmonary vascular resistance (RVP) decreased from 858,6 ± 377,0 at baseline to 516,6 ± 323,3 Dynes/sec/cm-5 (p<0.01) and the cardiac index increased from 2.4±0.6 at baseline to 2.8±0.3 L/min/m2 (p=0.01). At 4 weeks after the last BPA, WHO functional class improved from 3.3±0.5 to 2.5±0.5 (p<0,01) and six minutes walking distance from 331±92 to 451±149 m (p=0.01). CONCLUSIONS: BPA guided by OFDI for the treatment of inoperable CTEPH patients is a safe alternative with excellent immediate hemodynamic and clinical results.

Epigenetics in non-small cell lung carcinomas.

OBJECTIVE: To perform a systematic review of the main epigenetic aberrations involved in non-small cell lung carcinomas' (NSCLC) diagnosis, progression, and therapeutics. MATERIALS AND METHODS: We performed a systematic review of the scientific literature on lung cancer epigenetics, focusing on NSCLC. RESULTS: Several advances in the molecular study of classical epigenetic mechanisms and massive studies of lung cancer epigenome have contributed relevant new evidence revealing that various molecular complexes are functionally influencing genetic-epigenetic and transcriptional mechanisms that promote lung tumorigenesis (initiation, promotion, and progression), and are also involved in NSCLC therapyresistance mechanisms. CONCLUSIONS: Several epigenetic complexes and mechanisms must be analyzed and considered for the design of new and efficient therapies, which could be fundamental to develop an integrated knowledge to achieve a comprehensive lung cancer personalized medicine.

OBJETIVO: Realizar una revisión sistemática y estructurada de las principales aberraciones epigenéticas involucradas en el diagnóstico, progresión y terapia del cáncer pulmonar de células no pequeñas (CPCNP). MATERIAL Y MÉTODOS: Revisión sistemática de literatura científica sobre epigenética del cáncer pulmonar del grupo CPCNP. RESULTADOS: El estudio de los diversos mecanismos epigenéticos y su impronta epigenética en el epigenoma del cáncer pulmonar han arrojado nuevas evidencias a nivel biológico, biomédico y médico-clínico del impacto que los mecanismos epigenéticotranscripcionales promueven de manera activa y reversible sobre los procesos de tumorigénesis, progresión histopatológica y mecanismos de resistencia a la terapia oncológica pulmonar. CONCLUSIONES: Deben analizarse diferentes complejos y mecanismos epigenéticos para el estudio y diseño de esquemas nuevos y eficaces de terapia epigenética, los cuales podrían ser fundamentales para desarrollar un conocimiento integral en el desarrollo de la medicina personalizada en el cáncer pulmonar del grupo CPCNP.

Epigenetics in non-small cell lung carcinomas / Epigenetica en carcinomas pulmonares de células no pequeñas

Abstract: Objective: To perform a systematic review of the main epigenetic aberrations involved in non-small cell lung carcinomas' (NSCLC) diagnosis, progression, and therapeutics. Materials and methods: We performed a systematic review of the scientific literature on lung cancer epigenetics, focusing on NSCLC. Results: Several advances in the molecular study of classical epigenetic mechanisms and massive studies of lung cancer epigenome have contributed relevant new evidence revealing that various molecular complexes are functionally influencing genetic-epigenetic and transcriptional mechanisms that promote lung tumorigenesis (initiation, promotion, and progression), and are also involved in NSCLC therapy-resistance mechanisms. Conclusion: Several epigenetic complexes and mechanisms must be analyzed and considered for the design of new and efficient therapies, which could be fundamental to develop an integrated knowledge to achieve a comprehensive lung cancer personalized medicine.

Resumen: Objetivo: Realizar una revisión sistemática y estructurada de las principales aberraciones epigenéticas involucradas en el diagnóstico, progresión y terapia del cáncer pulmonar de células no pequeñas (CPCNP). Material y métodos: Revisión sistemática de literatura científica sobre epigenética del cáncer pulmonar del grupo CPCNP. Resultados: El estudio de los diversos mecanismos epigenéticos y su impronta epigenética en el epigenoma del cáncer pulmonar han arrojado nuevas evidencias a nivel biológico, biomédico y médico-clínico del impacto que los mecanismos epigenético-transcripcionales promueven de manera activa y reversible sobre los procesos de tumorigénesis, progresión histopatológica y mecanismos de resistencia a la terapia oncológica pulmonar. Conclusión: Deben analizarse diferentes complejos y mecanismos epigenéticos para el estudio y diseño de esquemas nuevos y eficaces de terapia epigenética, los cuales podrían ser fundamentales para desarrollar un conocimiento integral en el desarrollo de la medicina personalizada en el cáncer pulmonar del grupo CPCNP.

Angioplastía con balón para el tratamiento de la hipertensión arterial pulmonar por enfermedad tromboembólica crónica. Resultados hemodinámicos y clínicos inmediatos / Balloon pulmonary angioplasty for the treatment of chronic thromboembolic pulmonary hypertension

Background: Balloon pulmonary angioplasty (BPA) is a therapeutic alternative for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Aim: To report the initial experience with the "refined BPA technique" with the use of intravascular images. Patients and Methods: Between June 2015 and June 2016 we selected fourteen patients with CTEPH who were considered candidates for BPA. Lesions targeted for treatment were further analyzed using intravascular imaging with optical frequency domain imaging (OFDI). We report the immediate hemodynamic results and four weeks of follow-up of the first eight patients of this series. Results: We performed 16 BPA in eight patients aged 61 ± 14 years (88% women). Mean pulmonary artery pressure (PAPm) was 48.6 ± 5.8 mmHg. Success was achieved in seven patients (88%). A mean of 2.3 segments per patient were intervened in 11 sessions (1.6 sessions/ patient). Only one patient developed lung reperfusion injury. No mortality was associated with the procedure. After the last BPA session, PAPm decreased to 37.4 ± 8.6 mmHg (p=0.02). Pulmonary vascular resistance (RVP) decreased from 858,6 ± 377,0 at baseline to 516,6 ± 323,3 Dynes/sec/cm−5 (p<0.01) and the cardiac index increased from 2.4±0.6 at baseline to 2.8±0.3 L/min/m2 (p=0.01). At 4 weeks after the last BPA, WHO functional class improved from 3.3±0.5 to 2.5±0.5 (p<0,01) and six minutes walking distance from 331±92 to 451±149 m (p=0.01). Conclusions: BPA guided by OFDI for the treatment of inoperable CTEPH patients is a safe alternative with excellent immediate hemodynamic and clinical results.

Epigenomic study identifies a novel mesenchyme homeobox2-GLI1 transcription axis involved in cancer drug resistance, overall survival and therapy prognosis in lung cancer patients.

Several homeobox-related gene (HOX) transcription factors such as mesenchyme HOX-2 (MEOX2) have previously been associated with cancer drug resistance, malignant progression and/or clinical prognostic responses in lung cancer patients; however, the mechanisms involved in these responses have yet to be elucidated. Here, an epigenomic strategy was implemented to identify novel MEOX2 gene promoter transcription targets and propose a new molecular mechanism underlying lung cancer drug resistance and poor clinical prognosis. Chromatin immunoprecipitation (ChIP) assays derived from non-small cell lung carcinomas (NSCLC) hybridized on gene promoter tiling arrays and bioinformatics analyses were performed, and quantitative, functional and clinical validation were also carried out. We statistically identified a common profile consisting of 78 gene promoter targets, including Hedgehog-GLI1 gene promoter sequences (FDR≤0.1 and FDR≤0.2). The GLI-1 gene promoter region from -2,192 to -109 was occupied by MEOX2, accompanied by transcriptionally active RNA Pol II and was epigenetically linked to the active histones H3K27Ac and H3K4me3; these associations were quantitatively validated. Moreover, siRNA genetic silencing assays identified a MEOX2-GLI1 axis involved in cellular cytotoxic resistance to cisplatinum in a dose-dependent manner, as well as cellular migration and proliferation. Finally, Kaplan-Maier survival analyses identified significant MEOX2-dependent GLI-1 protein expression associated with clinical progression and poorer overall survival using an independent cohort of NSCLC patients undergoing platinum-based oncological therapy with both epidermal growth factor receptor (EGFR)-non-mutated and EGFR-mutated status. In conclusion, this is the first study to investigate epigenome-wide MEOX2-transcription factor occupation identifying a novel overexpressed MEOX2-GLI1 axis and its clinical association with platinum-based cancer drug resistance and EGFR-tyrosine kinase inhibitor (TKI)-based therapy responses in NSCLC patients.

The Hedgehog-GLI pathway in embryonic development and cancer: implications for pulmonary oncology therapy.

Transcriptional regulation and epigenetic mechanisms closely control gene expression through diverse physiological and pathophysiological processes. These include the development of germ layers and post-natal epithelial cell-tissue differentiation, as well as, involved with the induction, promotion and/or progression of human malignancies. Diverse studies have shed light on the molecular similarities and differences involved in the stages of embryological epithelial development and dedifferentiation processes in malignant tumors of epithelial origin, of which many focus on lung carcinomas. In lung cancer, several transcriptional, epigenetic and genetic aberrations have been described to partly arise from environmental risk factors, but ethnic genetic predisposition factors may also play a role. The classification of the molecular hallmarks of cancer has been essential to study and achieve a comprehensive view of the interaction networks between cell signaling pathways and functional roles of the transcriptional and epigenetic regulatory mechanisms. This has in turn increased understanding on how these molecular networks are involved in embryo-layers and malignant diseases development. Ultimately, a major biomedicine goal is to achieve a thorough understanding of their roles as diagnostic, prognostic and treatment response indicators in lung oncological patients. Recently, several notable cell-signaling pathways have been studied based on their contribution to promoting and/or regulating the engagement of different cancer hallmarks, among them genome instability, exacerbated proliferative signaling, replicative immortality, tumor invasion-metastasis, inflammation, and immune-surveillance evasion mechanisms. Of these, the Hedgehog-GLI (Hh) cell-signaling pathway has been identified as a main molecular contribution into several of the abovementioned functional embryo-malignancy processes. Nonetheless, the systematic study of the regulatory epigenetic and transcriptional mechanisms has remained mostly unexplored, which could identify the interaction networks between specific biomarkers and/or new therapeutic targets in malignant tumor progression and resistance to lung oncologic therapy. In the present work, we aimed to revise the most important up-to-date experimental and clinical findings in biology, embryology and cancer research regarding the Hh pathway. We explore the potential control of the transcriptional-epigenetic programming versus reprogramming mechanisms associated with its Hh-GLI cell signaling pathway members. Last, we present a summary of this information to systematically integrate the Hh signaling pathway to identify and propose novel compound strategies or better oncological therapeutic schemes for lung cancer patients.

Histone code and long non-coding RNAs (lncRNAs) aberrations in lung cancer: implications in the therapy response.

Respiratory diseases hold several genome, epigenome, and transcriptional aberrations as a cause of the accumulated damage promoted by, among others, environmental risk factors. Such aberrations can also come about as an adaptive response when faced with therapeutic oncological drugs. In epigenetic terms, aberrations in DNA methylation patterns, histone code marks balance, and/or chromatin-remodeling complexes recruitment, among Polycomb Repressive Complex-2 (PRC2) versus Trithorax (TRX) Activator Complex, have been proposed to be affected by several previously characterized functional long non-coding RNAs (lncRNAs). Such molecules are involved in modulating and/or controlling lung cancer epigenome and genome expression, as well as in malignancy and clinical progression in lung cancer. Several recent reports have described diverse epigenetic modifications in lung cancer cells and solid tumors, among others genomic DNA methylation and post-translational modifications (PTMs) on histone tails, as well as lncRNAs patterns and levels of expression. However, few systematic approaches have attempted to demonstrate a biological function and clinical association, aiming to improve therapeutic decisions in basic research and lung clinical oncology. A widely used example is the lncRNA HOTAIR and its functional histone mark H3K27me3, which is directly associated to the PRC2; however, few systematic pieces of solid evidence have been experimentally performed, conducted and/or validated to predict lung oncological therapeutic efficacy. Recent evidence suggests that chromatin-remodeling complexes accompanied by lncRNAs profiles are involved in several comprehensive lung carcinoma clinical parameters, including histopathology progression, prognosis, and/or responsiveness to unique or combined oncological therapies. The present manuscript offers a systematic revision of the current knowledge about the major epigenetic aberrations represented by changes in histone PTMs and lncRNAs expression levels and patterns in human lung carcinomas in cancer drug-based treatments, as an important comprehensive knowledge focusing on better oncological therapies. In addition, a new future direction must be refocusing on several gene target therapies, mainly on pharmaceutical EGFR-TKIs compounds, widely applied in lung cancer, currently the leading cause of death by malignant diseases.

Válvula aórtica cuadricúspide: caso clínico y discusión / Ouadricuspid aortic valve

The quadricuspid aortic valve is a rare congenital anomaly, usually presenting as an isolated malformation causing aortic regurgitation in the faith or sixth decades of life. The first reported cases were found at autopsy or became evident by surgical findings. However, the emergence of new imaging modalities currently allows an earlier diagnosis, including in asymptomatic patients. Hereby the case of a 60-year-old woman with quadricuspid aortic valve diagnosed by echocardiography is presented. A brief discussion of the disease is included.

[Survival of patients with pulmonary arterial hypertension after the advent of specific pulmonary vasodilator therapies]. / Sobrevida a mediano plazo en los pacientes con hipertensión arterial pulmonar en la era de terapias vasodilatadoras específicas del territorio vascular pulmonar.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare and progressive disease. Long-term survival remains poor despite of advances in specific vasodilator therapy. AIM: To describe the survival rate in a cohort of PAH patients in two referral centers in Chile. PATIENTS AND METHODS: One hundred fifteen patients aged 43 ± 15.6 years (85% females) with PAH qualified for this study. Their median pulmonary artery pressure was 55.4 ± 14 mmHg and their six minutes walking capacity was 368 ± 119 m. They were followed for 58 ± 0.4 months and their actual survival rates were compared with the estimated survival using the equation proposed by the French registry of PAH. RESULTS: One, two and three year survival rates were 97, 94 and 89%, respectively. The observed survival rates were greater than the estimated survival. CONCLUSIONS: The improvement in survival rates observed in this cohort of patients is similar to what has been described in literature.