ABSTRACT
Myeloproliferative neoplasms (MPNs) transform to myelofibrosis (MF) and highly lethal acute myeloid leukemia (AML), although the actionable mechanisms driving progression remain elusive. Here, we elucidate the role of the high mobility group A1 (HMGA1) chromatin regulator as a novel driver of MPN progression. HMGA1 is upregulated in MPN, with highest levels after transformation to MF or AML. To define HMGA1 function, we disrupted gene expression via CRISPR/Cas9, short hairpin RNA, or genetic deletion in MPN models. HMGA1 depletion in JAK2V617F AML cell lines disrupts proliferation, clonogenicity, and leukemic engraftment. Surprisingly, loss of just a single Hmga1 allele prevents progression to MF in JAK2V617F mice, decreasing erythrocytosis, thrombocytosis, megakaryocyte hyperplasia, and expansion of stem and progenitors, while preventing splenomegaly and fibrosis within the spleen and BM. RNA-sequencing and chromatin immunoprecipitation sequencing revealed HMGA1 transcriptional networks and chromatin occupancy at genes that govern proliferation (E2F, G2M, mitotic spindle) and cell fate, including the GATA2 master regulatory gene. Silencing GATA2 recapitulates most phenotypes observed with HMGA1 depletion, whereas GATA2 re-expression partially rescues leukemogenesis. HMGA1 transactivates GATA2 through sequences near the developmental enhancer (+9.5), increasing chromatin accessibility and recruiting active histone marks. Further, HMGA1 transcriptional networks, including proliferation pathways and GATA2, are activated in human MF and MPN leukemic transformation. Importantly, HMGA1 depletion enhances responses to the JAK2 inhibitor, ruxolitinib, preventing MF and prolonging survival in murine models of JAK2V617F AML. These findings illuminate HMGA1 as a key epigenetic switch involved in MPN transformation and a promising therapeutic target to treat or prevent disease progression.
Subject(s)
GATA2 Transcription Factor , HMGA1a Protein , Leukemia, Myeloid, Acute , Myeloproliferative Disorders , Primary Myelofibrosis , Animals , Cell Proliferation , Chromatin/genetics , GATA2 Transcription Factor/genetics , Gene Regulatory Networks , HMGA1a Protein/genetics , HMGA1a Protein/metabolism , Janus Kinase 2/genetics , Janus Kinase 2/metabolism , Leukemia, Myeloid, Acute/genetics , Mice , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/metabolism , Primary Myelofibrosis/geneticsABSTRACT
This study presents a methodology for predicting the duration of surgical procedures using Machine Learning (ML). The methodology incorporates a new set of predictors emphasizing the significance of surgical team dynamics and composition, including experience, familiarity, social behavior, and gender diversity. By applying ML techniques to a comprehensive dataset of over 77,000 surgeries, we achieved a 24% improvement in the mean absolute error (MAE) over a model that mimics the current approach of the decision maker. Our results also underscore the critical role of surgeon experience and team composition dynamics in enhancing prediction accuracy. These advancements can lead to more efficient operational planning and resource allocation in hospitals, potentially reducing downtime in operating rooms and improving healthcare delivery.
ABSTRACT
BACKGROUND: On December 31, 2019, one of the most serious pandemics in recent times made its appearance. Certain health conditions, such as obesity and diabetes mellitus, have been described to be related to COVID-19 unfavorable outcomes. OBJECTIVE: To identify factors associated with mortality in patients with COVID-19. MATERIAL AND METHODS: Retrospective cohort of 998,639 patients. Patient sociodemographic and clinical characteristics were analyzed, with survivors being compared with the deceased individuals. Cox proportional hazards model was used to identify variables predictive of COVID-19-associated mortality. RESULTS: Among the deceased patients, men accounted for 64.3%, and women, for 35.7%, with the difference being statistically significant. Subjects older than 80 years had a 13-fold higher risk of dying from COVID-19 (95% CI = 12,469, 13,586), while chronic kidney disease entailed a risk 1.5 times higher (95% CI = 1,341, 1,798), and diabetes mellitus involved a risk 1.25 times higher (95% CI = 1.238,1.276). CONCLUSIONS: Age, sex, diabetes mellitus and obesity were found to be predictors of COVID-19 mortality. Further research related to chronic obstructive pulmonary disease, cardiovascular diseases, smoking and pregnancy is suggested.
ANTECEDENTES: El 31 de diciembre de 2019, se inició una de las pandemias más graves de los últimos tiempos. Se ha descrito que ciertas condiciones de salud, como la obesidad y la diabetes mellitus, están relacionadas con desenlaces desfavorables por COVID-19. OBJETIVO: Identificar factores asociados a mortalidad en pacientes con COVID-19. MATERIAL Y MÉTODOS: Cohorte retrospectiva de 998 639 pacientes. Se analizaron las características sociodemográficas y clínicas de los pacientes, y se compararon supervivientes con fallecidos. Se utilizó el modelo de riesgos proporcionales de Cox para la identificación de variables predictivas de defunción por COVID-19. RESULTADOS: Entre los fallecidos, los hombres representaron 64.3 % y las mujeres 35.7 %, diferencia que resultó estadísticamente significativa. Las personas con más de 80 años presentaron un riesgo 13 veces mayor de morir por COVID-19 (IC 95 % = 12.469,13.586) y la enfermedad renal crónica, un riesgo de 1.5 (IC 95 % = 1.341, 1.798); la diabetes mellitus tuvo un riesgo de 1.25 (IC 95 % = 1.238,1.276). CONCLUSIONES: La edad, el sexo, la diabetes mellitus y la obesidad resultaron ser entidades predictivas de muerte por COVID-19. Se sugiere más investigación relacionada con enfermedad pulmonar obstructiva crónica, enfermedades cardiovasculares, tabaquismo y embarazo.
Subject(s)
COVID-19 , Diabetes Mellitus , Obesity , Humans , COVID-19/mortality , COVID-19/epidemiology , Mexico/epidemiology , Female , Male , Retrospective Studies , Risk Factors , Aged , Middle Aged , Aged, 80 and over , Adult , Obesity/mortality , Obesity/epidemiology , Obesity/complications , Diabetes Mellitus/epidemiology , Diabetes Mellitus/mortality , Age Factors , Sex Factors , Young Adult , Proportional Hazards Models , Adolescent , Cohort Studies , Renal Insufficiency, Chronic/mortality , Renal Insufficiency, Chronic/epidemiologyABSTRACT
The formation of highly organized metal-DNA structures has significant implications in bioinorganic chemistry, molecular biology and material science due to their unique properties and potential applications. In this study, we report on the conversion of single-stranded polydeoxycytidine (dC15 ) into a Pd-DNA supramolecular structure using the [Pd(Aqa)] complex (Aqa=8-amino-4-hydroxyquinoline-2-carboxylic acid) through a self-assembly process. The resulting Pd-DNA assembly closely resembles a natural double helix, with continuous [Pd(Aqa)(C)] (C=cytosine) units serving as palladium-mediated base pairs, forming interbase hydrogen bonds and intrastrand stacking interactions. Notably, the design of the [Pd(Aqa)] complex favours the interaction with cytosine, distinguishing it from our previously reported [Pd(Cheld)] complex (Cheld=chelidamic acid). This finding opens possibilities for creating heteroleptic Pd-DNA hybrids where different complexes specifically bind to nucleobases. We confirmed the Pd-DNA supramolecular structural assembly and selective binding of the complexes using NMR spectroscopy, circular dichroism, mass spectrometry, isothermal titration calorimetry, and DFT calculations.
Subject(s)
DNA , Palladium , Base Pairing , Palladium/chemistry , DNA/chemistry , Cytosine/chemistryABSTRACT
The emergence of bovine spongiform encephalopathy (BSE) prions from atypical scrapie has been recently observed upon experimental transmission to rodent and swine models. This study aimed to assess whether the inoculation of atypical scrapie could induce BSE-like disease in cattle. Four calves were intracerebrally challenged with atypical scrapie. Animals were euthanized without clinical signs of prion disease and tested negative for PrPSc accumulation by immunohistochemistry and western blotting. However, an emergence of BSE-like prion seeding activity was detected during in vitro propagation of brain samples from the inoculated animals. These findings suggest that atypical scrapie may represent a potential source of BSE infection in cattle.
Subject(s)
Cattle Diseases , Encephalopathy, Bovine Spongiform , Prion Diseases , Prions , Scrapie , Sheep Diseases , Swine Diseases , Sheep , Female , Cattle , Animals , Swine , Prion Diseases/veterinary , Brain/metabolismABSTRACT
MicroRNAs (miRs) have emerged as promising biomarkers for diagnosing and predicting the prognosis of liver injury. This study aimed to compare the performance of two Luminex platforms, MAGPIX and FLEXMAP 3D, utilizing the innovative Dynamic Chemical Labelling (DCL) technology for direct detection and analysis of miR-122-5p in serum samples from patients with liver injury. Serum samples were collected from four patients with liver injury and four healthy controls. The levels of miR-122-5p were measured using the DCL method on both MAGPIX and FLEXMAP 3D platforms. The performance evaluation included the limit of detection (LOD), intra-assay and inter-assay precision, as well as accuracy. The results demonstrated that both platforms exhibited high sensitivity and specificity in detecting miR-122-5p in serum samples from patients with liver injury. However, FLEXMAP 3D indicated a lower LOD compared to MAGPIX. The precision of miR-122-5p detection was similar between the two platforms. In conclusion, both MAGPIX and FLEXMAP 3D Luminex platforms, in conjunction with DCL reagents, proved to be reliable and sensitive tools for detecting miR-122-5p in serum samples from patients with liver injury. Although both platforms were effective, FLEXMAP 3D exhibited slightly better performance, suggesting its preference for miR detection in clinical settings. These findings offer valuable insights for selecting the appropriate Luminex platform for miR detection in patients with liver injury and beyond.
Subject(s)
MicroRNAs , Humans , Biomarkers , Prognosis , Limit of DetectionABSTRACT
Galectins, a family of endogenous glycan-binding proteins, play crucial roles in a broad range of physiological and pathological processes. Galectin-1 (Gal-1), a proto-type member of this family, is overexpressed in several cancers and plays critical roles in tumor-immune escape, angiogenesis and metastasis. Thus, generation of high-affinity Gal-1 inhibitors emerges as an attractive therapeutic approach for a wide range of neoplastic conditions. Small-molecule carbohydrate inhibitors based on lactose (Lac) and N-acetyllactosamine (LacNAc) structures have been tested showing different results. In this study, we evaluated Lac- and LacNAc-based compounds with specific chemical modifications at key positions as Gal-1 ligands by competitive solid-phase assays (SPA) and isothermal titration calorimetry (ITC). Both assays showed excellent correlation, highlighting that lactosides bearing bulky aromatic groups at the anomeric carbon and sulfate groups at the O3' position exhibited the highest binding affinities. To dissect the atomistic determinants for preferential affinity of the different tested Gal-1 ligands, molecular docking simulations were conducted and PRODIGY-LIG structure-based method was employed to predict binding affinity in protein-ligand complexes. Notably, calculated binding free energies derived from the molecular docking were in accordance with experimental values determined by SPA and ITC, showing excellent correlation between theoretical and experimental approaches. Moreover, this analysis showed that 3'-O-sulfate groups interact with residues of the Gal-1 subsite B, mainly with Asn33, while the ester groups of the aromatic anomeric group interact with Gly69 and Thr70 at Gal-1 subsite E, extending deeper into the pocket, which could account for the enhanced binding affinity. This study contributes to the rational design of highly optimized Gal-1 inhibitors to be further studied in cancer models and other pathologic conditions.
ABSTRACT
A mathematical concept, n-tuples are originally applied to medicinal chemistry, especially with the creation of scaffold diversity inspired by the hybridisation of different commercial drugs with cytarabine, a synthetic arabinonucleoside derived from two marine natural products, spongouridine and spongothymidine. The new methodology explores the virtual chemical-factorial combination of different commercial drugs (immunosuppressant, antibiotic, antiemetic, anti-inflammatory, and anticancer) with the anticancer drug cytarabine. Real chemical combinations were designed and synthesised for 8-duples, obtaining a small representative library of interesting organic molecules to be biologically tested as proof of concept. The synthesised library contains classical molecular properties regarding the Lipinski rules and/or beyond rules of five (bRo5) and is represented by the covalent combination of the anticancer drug cytarabine with ibuprofen, flurbiprofen, folic acid, sulfasalazine, ciprofloxacin, bortezomib, and methotrexate. The insertion of specific nomenclature could be implemented into artificial intelligence algorithms in order to enhance the efficiency of drug-hunting programs. The novel methodology has proven useful for the straightforward synthesis of most of the theoretically proposed duples and, in principle, could be extended to any other central drug.
Subject(s)
Antineoplastic Agents , Cytarabine , Cytarabine/pharmacology , Artificial Intelligence , Antineoplastic Agents/pharmacologyABSTRACT
Control of infections caused by carbapenem-resistant Klebsiella pneumoniae continues to be challenging. The success of this pathogen is favored by its ability to acquire antimicrobial resistance and to spread and persist in both the environment and in humans. The emergence of clinically important clones, such as sequence types 11, 15, 101, and 258, has been reported worldwide. However, the mechanisms promoting the dissemination of such high-risk clones are unknown. Unraveling the factors that play a role in the pathobiology and epidemicity of K. pneumoniae is therefore important for managing infections. To address this issue, we studied a carbapenem-resistant ST-15 K. pneumoniae isolate (Kp3380) that displayed a remarkable adherent phenotype with abundant pilus-like structures. Genome sequencing enabled us to identify a chaperone-usher pili system (Kpi) in Kp3380. Analysis of a large K. pneumoniae population from 32 European countries showed that the Kpi system is associated with the ST-15 clone. Phylogenetic analysis of the operon revealed that Kpi belongs to the little-characterized γ2-fimbrial clade. We demonstrate that Kpi contributes positively to the ability of K. pneumoniae to form biofilms and adhere to different host tissues. Moreover, the in vivo intestinal colonizing capacity of the Kpi-defective mutant was significantly reduced, as was its ability to infect Galleria mellonella The findings provide information about the pathobiology and epidemicity of Kpi+K. pneumoniae and indicate that the presence of Kpi may explain the success of the ST-15 clone. Disrupting bacterial adherence to the intestinal surface could potentially target gastrointestinal colonization.
Subject(s)
Fimbriae, Bacterial/genetics , Klebsiella pneumoniae/genetics , Molecular Chaperones/genetics , A549 Cells , Animals , Anti-Bacterial Agents , Bacterial Adhesion/drug effects , Bacterial Adhesion/genetics , Biofilms/drug effects , Biofilms/growth & development , Carbapenems/pharmacology , Cell Line , Disease Models, Animal , Drug Resistance, Multiple, Bacterial/genetics , Epithelial Cells/microbiology , Europe , Female , Gene Deletion , Genes, Bacterial/genetics , Humans , Klebsiella Infections , Klebsiella pneumoniae/cytology , Klebsiella pneumoniae/drug effects , Mice , Mice, Inbred BALB C , Multilocus Sequence Typing , Operon , PhylogenyABSTRACT
Oculocutaneous albinism (OCA) is a genetic disease caused by disorders in melanin synthesis or distribution. In this descriptive study conducted in a tertiary care pediatric hospital, patients with a clinical diagnosis of OCA and genetic study were retrospectively recruited and underwent dermatological and ophthalmological exam, including optical coherence tomography (OCT) and digital dermoscopy. Our findings revealed milder OCA phenotypic expression in individuals harboring single pathogenic mutations in conjunction with polymorphisms, as well as in those with mutations of uncertain significance. Regardless OCA subgroup, severe phenotypes of OCA were associated with a higher number of mutations/polymorphisms in melanin biosynthesis genes and paler dermoscopic patterns, such as vascular pattern, which was the most common pattern in our series.
Subject(s)
Albinism, Oculocutaneous , Melanins , Humans , Child , Melanins/genetics , Retrospective Studies , Mutation , Phenotype , Albinism, Oculocutaneous/genetics , Albinism, Oculocutaneous/diagnosis , Albinism, Oculocutaneous/pathologyABSTRACT
Galectins constitute a family of galactose-binding lectins overly expressed in the tumor microenvironment as well as in innate and adaptive immune cells, in inflammatory diseases. Lactose ((ß-D-galactopyranosyl)-(1â4)-ß-D-glucopyranose, Lac) and N-Acetyllactosamine (2-acetamido-2-deoxy-4-O-ß-D-galactopyranosyl-D-glucopyranose, LacNAc) have been widely exploited as ligands for a wide range of galectins, sometimes with modest selectivity. Even though several chemical modifications at single positions of the sugar rings have been applied to these ligands, very few examples combined the simultaneous modifications at key positions known to increase both affinity and selectivity. We report herein combined modifications at the anomeric position, C-2, and O-3' of each of the two sugars, resulting in a 3'-O-sulfated LacNAc analog having a Kd of 14.7 µM against human Gal-3 as measured by isothermal titration calorimetry (ITC). This represents a six-fold increase in affinity when compared to methyl ß-D-lactoside having a Kd of 91 µM. The three best compounds contained sulfate groups at the O-3' position of the galactoside moieties, which were perfectly in line with the observed highly cationic character of the human Gal-3 binding site shown by the co-crystal of one of the best candidates of the LacNAc series.
Subject(s)
Galectin 3 , Lactose , Humans , Galectin 3/chemistry , Galectin 3/pharmacology , Galectins/chemistry , Lactose/chemistry , LigandsABSTRACT
Cardiac troponin is a regulatory protein complex located on the sarcomere that regulates the engagement of myosin on actin filaments. Low-molecular weight modulators of troponin that bind allosterically with the calcium ion have the potential to improve cardiac contractility in patients with reduced cardiac function. Here we propose an approach to the rational design of troponin modulators through the combined use of solution nuclear magnetic resonance and isothermal titration calorimetry methods. In contrast to traditional approaches limited to calcium and activator-bound troponin structures, here we analyzed the structural and thermodynamic impact of an activator in the context of the troponin functional cycle. This led us to propose a rationale for developing an efficacious troponin activator.
Subject(s)
Calcium , Myocardium , Actins/metabolism , Calcium/metabolism , Humans , Myocardial Contraction/physiology , Myocardium/metabolism , Thermodynamics , Tropomyosin/metabolism , Troponin/chemistryABSTRACT
A code is defined by the nature of the symbols, which are used to generate information-storing combinations (e. g. oligo- and polymers). Like nucleic acids and proteins, oligo- and polysaccharides are ubiquitous, and they are a biochemical platform for establishing molecular messages. Of note, the letters of the sugar code system (third alphabet of life) excel in coding capacity by making an unsurpassed versatility for isomer (code word) formation possible by variability in anomery and linkage position of the glycosidic bond, ring size and branching. The enzymatic machinery for glycan biosynthesis (writers) realizes this enormous potential for building a large vocabulary. It includes possibilities for dynamic editing/erasing as known from nucleic acids and proteins. Matching the glycome diversity, a large panel of sugar receptors (lectins) has developed based on more than a dozen folds. Lectins 'read' the glycan-encoded information. Hydrogen/coordination bonding and ionic pairing together with stacking and C-H/π-interactions as well as modes of spatial glycan presentation underlie the selectivity and specificity of glycan-lectin recognition. Modular design of lectins together with glycan display and the nature of the cognate glycoconjugate account for the large number of post-binding events. They give an entry to the glycan vocabulary its functional, often context-dependent meaning(s), hereby building the dictionary of the sugar code.
Subject(s)
Nucleic Acids , Sugars , Carbohydrates/chemistry , Lectins/metabolism , Polysaccharides/chemistryABSTRACT
BACKGROUND: Systemic sclerosis (SSc) is an autoimmune chronic rheumatic disease with a high mortality rate, which continues to be a challenge for clinicians today. AIM: To assess changes in mortality trends in the Spanish SSc population between 1980 and 2019, taking into account the independent effects of sex, age, time period and birth cohort. METHODS: SSc death records and mid-year population data were collected from the National Statistics Institute. Age-standardized mortality rates were calculated for the overall population and for each sex (male, female) and age group (5-year groups). Significant changes in mortality trends were identified by joinpoint regressions. An age-period-cohort (APC) analysis and potential years of life lost (PYLL) analysis were performed to identify the burden of SSc. RESULTS: Age-standardized mortality rates due to SSc increased from 1.87 (95% CI 1.00-3.02) per 1 000 000 inhabitants between 1980 and 1984, to 2.47 (95% CI 1.74-3.02) per 1 000 000 inhabitants between 2015 and 2019. The relative risk of mortality fell in all groups in cohorts born after 1990. The PYLL rates showed a gradual rise for both sexes. CONCLUSION: There was an increase in overall SSc mortality in Spain during the 39 years evaluated, although there was a progressive drop for men.
Subject(s)
Scleroderma, Systemic , Humans , Male , Female , Spain/epidemiology , Cohort StudiesABSTRACT
OBJECTIVE: To analyse mortality rate trends in Spain for oral cavity and oropharyngeal cancer (OCOPC) from 1979 to 2018, evaluating differences between oral cavity cancer (OCC) and oropharyngeal cancer (OPC). MATERIALS AND METHODS: Death certificates and mid-year population data were collected from the Spanish National Statistics Institute. Age-standardized mortality rates were calculated using the direct method. Joinpoint regressions were used to identify significant changes in mortality trends. Independent effects of age, period and cohort (APC) were estimated. RESULTS: A total of 52,057 deaths were registered from OCOPC, 38,988 from OCC and 13,069 from OPC between 1979 and 2018. While OCC mortality rates declined, OCOPC rates increased slightly and OPC significantly. OCC and OPC mortality reached their highest values between 1979 and 1992, when OCC rates began to decrease in males and OPC levelled off until 2018. Lip cancer suffered the highest drop. APC models showed a mortality increase in males and females from 40 to 45 and 50 to 55 years of age, respectively. CONCLUSIONS: Favourable OCC mortality trends was plausibly influenced by decreased tobacco/alcohol consumption, while OPC rise was probably associated with increased human papillomavirus infection. The importance of closely monitoring these cancers by age group, sex and location, and continuing with preventive measures against known risk factors, is highlighted.
Subject(s)
Mouth Neoplasms , Oropharyngeal Neoplasms , Papillomavirus Infections , Female , Humans , Incidence , Male , Oropharyngeal Neoplasms/epidemiology , Papillomavirus Infections/epidemiology , Spain/epidemiologyABSTRACT
Glycan-lectin recognition is assumed to elicit its broad range of (patho)physiological functions via a combination of specific contact formation with generation of complexes of distinct signal-triggering topology on biomembranes. Faced with the challenge to understand why evolution has led to three particular modes of modular architecture for adhesion/growth-regulatory galectins in vertebrates, here we introduce protein engineering to enable design switches. The impact of changes is measured in assays on cell growth and on bridging fully synthetic nanovesicles (glycodendrimersomes) with a chemically programmable surface. Using the example of homodimeric galectin-1 and monomeric galectin-3, the mutual design conversion caused qualitative differences, i.e., from bridging effector to antagonist/from antagonist to growth inhibitor and vice versa. In addition to attaining proof-of-principle evidence for the hypothesis that chimera-type galectin-3 design makes functional antagonism possible, we underscore the value of versatile surface programming with a derivative of the pan-galectin ligand lactose. Aggregation assays with N,N'-diacetyllactosamine establishing a parasite-like surface signature revealed marked selectivity among the family of galectins and bridging potency of homodimers. These findings provide fundamental insights into design-functionality relationships of galectins. Moreover, our strategy generates the tools to identify biofunctional lattice formation on biomembranes and galectin-reagents with therapeutic potential.
Subject(s)
Galectin 1/chemistry , Galectin 3/chemistry , Glycoconjugates/chemistry , Polysaccharides/chemistry , Amino Sugars/chemistry , Amino Sugars/metabolism , Binding Sites , Blood Proteins , Cell Adhesion/genetics , Cell Proliferation/genetics , Galectin 1/genetics , Galectin 3/genetics , Galectins , Humans , Lactose/chemistry , Ligands , Nanoparticles/chemistry , Polysaccharides/geneticsABSTRACT
Human galectin-3 (hGal-3) is involved in a variety of biological processes and is implicated in wide range of diseases. As a result, targeting hGal-3 for clinical applications has become an intense area of research. As a step towards the development of novel hGal-3 inhibitors, we describe a study of the binding of two Se-containing hGal-3 inhibitors, specifically that of di(ß-D-galactopyranosyl)selenide (SeDG), in which two galactose rings are linked by one Se atom and a di(ß-D-galactopyranosyl)diselenide (DSeDG) analogue with a diseleno bond between the two sugar units. The binding affinities of these derivatives to hGal-3 were determined by 15N-1H HSQC NMR spectroscopy and fluorescence anisotropy titrations in solution, indicating a slight decrease in the strength of interaction for SeDG compared to thiodigalactoside (TDG), a well-known inhibitor of hGal-3, while DSeDG displayed a much weaker interaction strength. NMR and FA measurements showed that both seleno derivatives bind to the canonical S face site of hGal-3 and stack against the conserved W181 residue also confirmed by X-ray crystallography, revealing canonical properties of the interaction. The interaction with DSeDG revealed two distinct binding modes in the crystal structure which are in fast exchange on the NMR time scale in solution, explaining a weaker interaction with hGal-3 than SeDG. Using molecular dynamics simulations, we have found that energetic contributions to the binding enthalpies mainly differ in the electrostatic interactions and in polar solvation terms and are responsible for weaker binding of DSeDG compared to SeDG. Selenium-containing carbohydrate inhibitors of hGal-3 showing canonical binding modes offer the potential of becoming novel hydrolytically stable scaffolds for a new class of hGal-3 inhibitors.
Subject(s)
Blood Proteins/chemistry , Galectin 3 , Galectins/chemistry , Crystallography, X-Ray , Galactose , Galectin 3/metabolism , Galectins/metabolism , Humans , Protein BindingABSTRACT
BACKGROUND: Oral cavity cancer (OCC) and oropharyngeal cancer (OPC) are two common malignancies whose mortality is worryingly increasing worldwide. However, few studies have estimated the mortality trends for these cancers in the coming years. This study analysed the mortality rates for OCC and OPC observed between 1980 and 2019 to generate a predictive model for the next 25 years in Spain. METHODS: Mid-year population data and death certificates for the period 1980-2019 were obtained from the Spanish National Institute of Statistics. The Nordpred program (Norwegian Cancer Registry, Oslo, Norway) was used to calculate adjusted mortality rates as well as estimated mortality projections with an age-period-cohort model for the period 2020-2044. RESULTS: The specific mortality rate per 100,000 inhabitants for OCC decreased from 2.36 (1980-1984) to 2.17 (2015-2019) and is expected to decline to 1.68 (2040-2044), particularly in males. For OPC, mortality rates rose from 0.67 (1980-1984) to 1.23 (2015-2019) and are projected to drop to 0.71 (2040-2044). In the group of females > 65 years predictions showed rising mortality rates for both OCC and OPC. The predictive model projects more deaths in females than in males for OCC in the period 2040-2044, while deaths for OPC will decrease in males and gradually increase in females. CONCLUSIONS: Although OCC mortality rates have been found to decrease in males in the last observed decades, there is still room to improve them in females > 65 years in the future by promoting campaigns against smoking and alcohol consumption. OPC mortality will become a growing health problem. Vaccination campaigns for the prevention of human papillomavirus-associated cancers may have a long-term impact on the mortality of these cancers, which should be evaluated in upcoming studies. CLINICAL RELEVANCE: Our findings highlighted the importance of closely monitoring OCC and OPC mortality rates in the coming years by age group and sex, and the need to continue preventive measures against the main known risk factors, such as tobacco, alcohol, and human papillomavirus infection.
Subject(s)
Mouth Neoplasms , Oropharyngeal Neoplasms , Female , Humans , Incidence , Male , Mouth Neoplasms/pathology , Spain/epidemiologyABSTRACT
Glycan-lectin recognition is vital to processes that impact human health, including viral infections. Proceeding from crystallographical evidence of case studies on adeno-, corona-, and rotaviral spike proteins, the relationship of these adhesins to mammalian galectins was examined by computational similarity assessments. Intrafamily diversity among human galectins was in the range of that to these viral surface proteins. Our findings are offered to inspire the consideration of lectin-based approaches to thwart infection by present and future viral threats, also mentioning possible implications for vaccine development.
Subject(s)
Galectins , Polysaccharides , Spike Glycoprotein, Coronavirus , Animals , Coronaviridae , HumansABSTRACT
Functional pairing between cellular glycoconjugates and tissue lectins like galectins has wide (patho)physiological significance. Their study is facilitated by nonhydrolysable derivatives of the natural O-glycans, such as S- and Se-glycosides. The latter enable extensive analyses by specific 77 Se NMR spectroscopy, but still remain underexplored. By using the example of selenodigalactoside (SeDG) and the human galectin-1 and -3, we have evaluated diverse 77 Se NMR detection methods and propose selective 1 H,77 Se heteronuclear Hartmann-Hahn transfer for efficient use in competitive NMR screening against a selenoglycoside spy ligand. By fluorescence anisotropy, circular dichroism, and isothermal titration calorimetry (ITC), we show that the affinity and thermodynamics of SeDG binding by galectins are similar to thiodigalactoside (TDG) and N-acetyllactosamine (LacNAc), confirming that Se substitution has no major impact. ITC data in D2 O versus H2 O are similar for TDG and LacNAc binding by both galectins, but a solvent effect, indicating solvent rearrangement at the binding site, is hinted at for SeDG and clearly observed for LacNAc dimers with extended chain length.