Is there still a place for conventional histopathology in the age of molecular medicine? Laurén classification, inflammatory infiltration and other current topics in gastric cancer diagnosis and prognosis.

Gastric cancer (GC) is the fifth most common cancer and the third cause of cancer-related deaths worldwide. In western countries, more than half of GC patients are diagnosed at advanced stages and 5-year survival rates range between 20-30%. The only curative treatment is surgery, and despite recent advances in oncological therapies, GC prognosis is still poor. The main prognostic tool for patient categorization and treatment selection is the TNM classification, but its limitations are being increasingly recognized. Early recurrences may occur in early-stage disease, and patients at the same stage show heterogeneous outcomes. Thus, there is a need to improve GC stratification and to identify new prognostic factors, which may allow us to select drug-susceptible populations, refine patient grouping for clinical trials and discover new therapeutic targets. Molecular classifications have been developed, but they have not been translated to the clinical practice. On the other hand, histological assessment is cheap and widely available, and it is still a mainstay in the era of molecular medicine. Furthermore, histological features are acquiring new roles as reflectors of the genotype-phenotype correlation, and their potential impact on patient management is currently being analyzed. The aim of this literature review is to provide a modern overview of the histological assessment of GC. In this study, we discuss recent topics on the histological diagnosis of GC, focusing on the current role of Laurén classification and the potential value of new histological features in GC, such as inflammatory infiltration and tumor budding.

Towards next generation therapies for cystic fibrosis: Folding, function and pharmacology of CFTR.

The treatment of cystic fibrosis (CF) has been transformed by orally-bioavailable small molecule modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), which restore function to CF mutants. However, CFTR modulators are not available to all people with CF and better modulators are required to prevent disease progression. Here, we review selectively recent advances in CFTR folding, function and pharmacology. We highlight ensemble and single-molecule studies of CFTR folding, which provide new insight into CFTR assembly, its perturbation by CF mutations and rescue by CFTR modulators. We discuss species-dependent differences in the action of the F508del-CFTR mutation on CFTR expression, stability and function, which might influence pharmacological studies of CFTR modulators in CF animal models. Finally, we illuminate the identification of combinations of two CFTR potentiators (termed co-potentiators), which restore therapeutically-relevant levels of CFTR activity to rare CF mutations. Thus, mechanistic studies of CFTR folding, function and pharmacology inform the development of highly effective CFTR modulators.

Alternative chloride transport pathways as pharmacological targets for the treatment of cystic fibrosis.

Cystic fibrosis is a hereditary disease that originates from mutations in the epithelial chloride channel CFTR. Whereas established therapies for the treatment of cystic fibrosis target CFTR to repair its function, alternative therapeutic strategies aim for the restoration of chloride transport by the activation of other chloride transport proteins such as TMEM16A or SLC26A9 or by the application of synthetic anionophores. TMEM16A is an anion-selective channel that is activated by the binding of Ca2+ from the cytoplasm. Pharmacological efforts aim for the increase of its open probability at resting Ca2+ concentrations. SLC26 is an uncoupled chloride transporter, which shuttles chloride across the membrane by an alternate-access mechanism. Its activation requires its mobilization from intracellular stores. Finally, anionophores are small synthetic molecules that bind chloride to form lipid-soluble complexes, which shuttle the anion across the membrane. All three approaches are currently pursued and have provided promising initial results.

Single-Molecule Sequencing: Towards Clinical Applications.

In the past several years, single-molecule sequencing platforms, such as those by Pacific Biosciences and Oxford Nanopore Technologies, have become available to researchers and are currently being tested for clinical applications. They offer exceptionally long reads that permit direct sequencing through regions of the genome inaccessible or difficult to analyze by short-read platforms. This includes disease-causing long repetitive elements, extreme GC content regions, and complex gene loci. Similarly, these platforms enable structural variation characterization at previously unparalleled resolution and direct detection of epigenetic marks in native DNA. Here, we review how these technologies are opening up new clinical avenues that are being applied to pathogenic microorganisms and viruses, constitutional disorders, pharmacogenomics, cancer, and more.

The Brave New World of Gene Editing and Molecular Medicine.

Gene therapy has long been a promise of molecular biology. So far, that promise has largely been unrealized. The advent of gene editing using technology adapted from bacteria may finally usher in the era of gene therapy.

Emerging Biomedical Applications of Enzyme-Like Catalytic Nanomaterials.

Nanomaterials have been developed for many biomedical applications, including medical imaging, drug delivery, and antimicrobial coatings. Intriguingly, nanoparticles can display 'enzyme-like' activity and have been explored as alternatives to natural enzymes in several industrial and energy-related applications. Recently, these catalytic nanomaterials with enzyme-mimetic properties have found new biomedical applications, from biofilm disruption to protection against neurodegeneration and tumor prevention. In this review we focus on recent in vivo studies demonstrating potential therapeutic uses of catalytic nanomaterials. We also provide insights about the relationships between catalytic activity, therapeutic efficacy, and biocompatibility that are critical for clinical translatability. Finally, we discuss current challenges and future directions for the use of these nanomaterials as novel platforms for the development of sustainable, affordable, and safe therapeutics.

[Conference Dr. Ignacio Chávez. Moving towards molecular medicine]. / Conferencia Dr. Ignacio Chávez: Caminando hacia una medicina molecular.

El solo nombre del Dr. Ignacio Chávez y la calidad académica de los que me han precedido me hacen sentir emocionado, consciente de que me encuentro sobre los hombros de grandes aportadores a nuestra medicina.

Diagnóstico molecular del cáncer de endometrio / Molecular diagnosis of endometrial cancer

Mediante caracterización molecular se han identificado una combinación de biomarcadores fuertemente relacionados con la presencia de cáncer de endometrio. Concretamente, se ha desarrollado un test de diagnóstico molecular asociado a un algoritmo matemático que, con el análisis de una simple muestra de aspirado endometrial, permite mejorar el diagnóstico precoz del cáncer de endometrio. Este test, llamado GynEC(R)-DX, se basa en la interpretación de cambios moleculares que preceden las alteraciones morfológicas asociadas al cáncer de endometrio. La aplicabilidad del test GynEC(R)-DX, rápido y fiable, mejora por sí mismo la precisión diagnóstica de las pruebas convencionales de biopsia por aspirado o dirigida por histeroscopia, minimizando la posibilidad de resultados no concluyentes, y aporta una información de alto valor en determinados perfiles clínicos, que refuerza la confianza en la toma de decisión terapéutica y en el proceso de despistaje del cáncer de endometrio. Consecuentemente, se reduce el tiempo y el coste medio del diagnóstico de cáncer, especialmente en 5 perfiles específicos de pacientes característicos: hemorragia uterina anormal de repetición, ecografía con línea endometrial irregular sin dictamen claro histológico, diagnóstico de pólipo endometrial, hiperplasia endometrial sin atipias y Síndrome de Lynch. En el presente trabajo se describe el momento de aplicación del diagnóstico molecular, adaptado al algoritmo diagnóstico de la SEGO, para cada uno de los citados perfiles de alto riesgo, así como las ventajas clínicas derivadas (AU)

Through molecular characterization, a combination of biomarkers strongly related to the presence of endometrial cancer has been identified. Specifically, a molecular diagnostic test associated with a mathematical algorithm has been developed which, with the analysis of a simple sample of endometrial aspirate, allows improving the early diagnosis of endometrial cancer. This test, called GynEC(R)-DX, is based on the interpretation of molecular changes that precede the morphological alterations associated with endometrial cancer. The applicability of this test, called GynEC(R)-DX, fast and reliable, improves by itself the diagnostic accuracy of conventional aspiration or hysteroscopy-guided biopsy tests, minimizing the possibility of inconclusive results, and provides high value information in certain clinical profiles, which reinforces confidence in therapeutic decision- making and in the endometrial cancer screening process. The combination of GynEC(R)-DX with histological analysis on endometrial aspirate increases efficacy, sensitivity and Negative Predictive Value. Consequently, time and average cost of cancer diagnosis is reduced, especially in 5 characteristic profiles of abnormal patients: recurrent abnormal uterine bleeding, ultrasound with irregular endometrial line without clear histological opinion, diagnosis of endometrial polyp, endometrial hyperplasia without atypia and Lynch Syndrome. The present work describes the application of endometrial cancer molecular diagnosis, adapted to the SEGO diagnostic algorithm, for the high risk profiles mentioned above, as well as the derived clinical advantages (AU)

Exploiting the potential of next-generation sequencing in genomic medicine.

INTRODUCTION: The review highlights the impact of next-generation sequencing (NGS) on genomic medicine and the consequences of the progression from a single-gene panel technology to a whole exome sequencing approach. AREAS COVERED: We brought together literature-based evidences, personal unpublished data and clinical experience to provide a critical overview of the impact of NGS on our daily clinical practice. Expert commentary: NGS has changed the role of clinical geneticist and has broadened the view accomplishing a transition from a monogenic Mendelian perspective to an oligogenic approach to disorders. Thus, it is a compelling new expertise which combines clinical evaluation with big omics data interpretation and moves forward to phenotype re-evaluation in light of data analysis. We introduced the term, 'exotyping', to highlight this holistic approach. Further, the review discusses the impact that the combination of genetic reprogramming and transcriptome analysis will have on the discovery of evidence-based therapies.

Glycolytic activity in breast cancer using 18F-FDG PET/CT as prognostic predictor: A molecular phenotype approach / Actividad glicolítica en el cancer de mama mediante 18F-FDG PET/TC como predictor pronóstico: aproximación del fenotipo molecular

Aim. To explore the relationship between basal 18F-FDG uptake in breast tumors and survival in patients with breast cancer (BC) using a molecular phenotype approach. Material and Methods. This prospective and multicentre study included 193 women diagnosed with BC. All patients underwent an 18F-FDG PET/CT prior to treatment. Maximum standardized uptake value (SUVmax) in tumor (T), lymph nodes (N), and the N/T index was obtained in all the cases. Metabolic stage was established. As regards biological prognostic parameters, tumors were classified into molecular sub-types and risk categories. Overall survival (OS) and disease free survival (DFS) were obtained. An analysis was performed on the relationship between semi-quantitative metabolic parameters with molecular phenotypes and risk categories. The effect of molecular sub-type and risk categories in prognosis was analyzed using Kaplan-Meier and univariate and multivariate tests. Results. Statistical differences were found in both SUVT and SUVN, according to the molecular sub-types and risk classifications, with higher semi-quantitative values in more biologically aggressive tumors. No statistical differences were observed with respect to the N/T index. Kaplan–Meier analysis revealed that risk categories were significantly related to DFS and OS. In the multivariate analysis, metabolic stage and risk phenotype showed a significant association with DFS. Conclusion. High-risk phenotype category showed a worst prognosis with respect to the other categories with higher SUVmax in primary tumor and lymph nodes (AU)

Objetivo. Analizar la relación entre la captación basal de 18F-FDG en tumores mamarios y la supervivencia en pacientes con cancer de mama (CM) bajo la aproximación del fenotipo molecular. Material y métodos. Este estudio prospectivo y multicentrico incluyó 193 mujeres diagnosticadas de CM. Todas las pacientes fueron sometidas a una 18F-FDG PET/TC previa al tratamiento. Se obtuvo el SUVmax en el tumor (T), ganglios linfáticos (N) así como el índice N/T en todos los casos. Además se determinó el estadio metabólico. Atendiendo a los factores biológicos pronósticos, los tumores fueron clasificados en subtipos moleculares y categorias de riesgo. Se obtuvo tanto la supervivencia global (SG) como la supervivencia libre de enfermedad (SLE). Se estudió la relación entre los parámetros metabólicos semicuantitativos con los fenotipos moleculares y las categorías de riesgo. Se analizó el efecto del subtipo molecular y las categorías de riesgo en el pronóstico mediante análisis de Kaplan–Meier y test uni y multivariantes. Resultados. Se encontraron diferencias estadísticamente significativas en tanto el SUVT como el SUVN, deacuerdo a los fenotipos moleculares y las categorías de riesgo, con valores mayores en los tumores biológicamente más agresivos. No se observaron diferencias con respecto al índice N/T. El análisis de Kaplan–Meier reveló que las categorías de riesgo se relacionaron de forma significativa con la SG y SLE. En el análisis multivariante, el estadio metabólico y la categoría de riesgo mostraron asociación significativa con la SLE. Conclusion. La categoría de alto riesgo manifestó un peor pronóstico con respecto a las otras categorías, con mayores valores de SUVmax tanto en el tumor primario como en ganglios linfáticos (AU)

Molecular medicine - To be or not to be.

Molecular medicine is founded on the synergy between Chemistry, Physics, Biology and Medicine, with the ambitious goal of tackling diseases from a molecular perspective. This Review aims at retracing a personal outlook of the birth and development of molecular medicine, as well as at highlighting some of the most urgent challenges linked to aging and represented by incurable neurodegenerative diseases caused by protein misfolding. Furthermore, we emphasize the emerging role of the retromer dysfunctions and improper protein sorting in Alzheimer's disease and other important neurological disordered.