RESUMEN
Head and Neck Squamous Cell Carcinoma (HNSCC) remains a significant health burden due to tumor heterogeneity and treatment resistance, emphasizing the need for improved biological understanding and tailored therapies. This study enrolled 31 HNSCC patients for the establishment of patient-derived tumor organoids (PDOs), which faithfully maintained genomic features and histopathological traits of primary tumors. Long-term culture preserved key characteristics, affirming PDOs as robust representative models. PDOs demonstrated predictive capability for cisplatin treatment responses, correlating ex vivo drug sensitivity with patient outcomes. Bulk and single-cell RNA sequencing unveiled molecular subtypes and intratumor heterogeneity (ITH) in PDOs, paralleling patient tumors. Notably, a hybrid epithelial-mesenchymal transition (hEMT)-like ITH program is associated with cisplatin resistance and poor patient survival. Functional analyses identified amphiregulin (AREG) as a potential regulator of the hybrid epithelial/mesenchymal state. Moreover, AREG contributes to cisplatin resistance via EGFR pathway activation, corroborated by clinical samples. In summary, HNSCC PDOs serve as reliable and versatile models, offer predictive insights into ITH programs and treatment responses, and uncover potential therapeutic targets for personalized medicine.
RESUMEN
Gastric cancer poses diverse treatment challenges due to its high tumor heterogeneity. Through the use of patient-derived tumor organoid (PDO) models, new research1 has identified genes and molecular signatures that are predictive of chemotherapeutic response, providing valuable insights for clinical management and translational advancements.
Asunto(s)
Organoides , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Organoides/patología , Organoides/efectos de los fármacos , Organoides/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
Upper aerodigestive squamous cell carcinoma (UASCC) is a common and aggressive malignancy with few effective therapeutic options. Here, we investigate amino acid metabolism in this cancer, surprisingly noting that UASCC exhibits the highest methionine level across all human cancers, driven by its transporter LAT1. We show that LAT1 is also expressed at the highest level in UASCC, transcriptionally activated by UASCC-specific promoter and enhancers, which are directly coregulated by SCC master regulators TP63/KLF5/SREBF1. Unexpectedly, unbiased bioinformatic screen identifies EZH2 as the most significant target downstream of the LAT1-methionine pathway, directly linking methionine metabolism to epigenomic reprogramming. Importantly, this cascade is indispensable for the survival and proliferation of UASCC patient-derived tumor organoids. In addition, LAT1 expression is closely associated with cellular sensitivity to inhibition of the LAT1-methionine-EZH2 axis. Notably, this unique LAT1-methionine-EZH2 cascade can be targeted effectively by either pharmacological approaches or dietary intervention in vivo. In summary, this work maps a unique mechanistic cross talk between epigenomic reprogramming with methionine metabolism, establishes its biological significance in the biology of UASCC, and identifies a unique tumor-specific vulnerability which can be exploited both pharmacologically and dietarily.
Asunto(s)
Carcinoma de Células Escamosas , Regulación Neoplásica de la Expresión Génica , Transportador de Aminoácidos Neutros Grandes 1 , Metionina , Metionina/metabolismo , Humanos , Transportador de Aminoácidos Neutros Grandes 1/metabolismo , Transportador de Aminoácidos Neutros Grandes 1/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Línea Celular Tumoral , Epigénesis Genética , Epigenómica/métodos , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Ratones , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Animales , Proliferación Celular , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Reprogramación Celular/genéticaRESUMEN
We measured the levels of High-Mobility Group Box 1 (HMGB1), Receptor for Advanced Glycation Endproducts (RAGE), T Helper 17 cells (Th17), Regulatory T cells (Treg), and related cytokines in the peripheral blood of patients with severe preeclampsia (SPE) complicated with acute heart failure (AHF) to explore the expression changes in these indicators. In total, 96 patients with SPE admitted to Gansu Provincial Maternity and Child-care Hospital between June 2020 and June 2022 were included in the study. The patients were divided into SPE+AHF (40 patients) and SPE (56 patients) groups based on whether they suffered from AHF. Additionally, 56 healthy pregnant women who either received prenatal examinations or were admitted to our hospital for delivery during the same period were selected as the healthy control group. An enzyme-linked immunosorbent assay was performed to detect the expression levels of HMGB1, RAGE, interleukin (IL)-17, IL-6, transforming growth factor ß (TGF-ß), IL-10, and NT-proBNP in plasma. Flow cytometry was employed to determine the percentages of Th17 and Treg cells. Compared to the healthy control group, the SPE+AHF and SPE groups had higher plasma levels of HMGB1 and RAGE expression, higher Th17 percentage and Th17/Treg ratio, and lower Treg percentage. Compared to the SPE group, the SPE+AHF group had higher plasma levels of HMGB1 and RAGE expression, higher Th17 percentage and Th17/Treg ratio, and lower Treg percentage (P < .05). In patients with SPE with AHF, plasma HMGB1 was positively correlated with RAGE, Th17, Th17/Treg, IL-17, and IL-6 and was negatively correlated with TGF-ß and IL-10 (P < .05). Our findings revealed that patients with SPE with AHF had elevated levels of HMGB1 and RAGE while exhibiting Th17/Treg immune imbalance, suggesting that the abnormal expression of these indicators may be involved in the pathogenesis of SPE with AHF.
Asunto(s)
Proteína HMGB1 , Preeclampsia , Femenino , Humanos , Embarazo , Citocinas , Productos Finales de Glicación Avanzada/metabolismo , Proteína HMGB1/metabolismo , Hipertensión/metabolismo , Interleucina-10/metabolismo , Interleucina-6 , Preeclampsia/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Linfocitos T Reguladores/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Squamous cell carcinomas (SCCs) are common and aggressive malignancies. Immune check point blockade (ICB) therapy using PD-1/PD-L1 antibodies has been approved in several types of advanced SCCs. However, low response rate and treatment resistance are common. Improving the efficacy of ICB therapy requires better understanding of the mechanism of immune evasion. Here, we identify that the SCC-master transcription factor TP63 suppresses interferon-γ (IFNγ) signaling. TP63 inhibition leads to increased CD8+ T cell infiltration and heighten tumor killing in in vivo syngeneic mouse model and ex vivo co-culture system, respectively. Moreover, expression of TP63 is negatively correlated with CD8+ T cell infiltration and activation in patients with SCC. Silencing of TP63 enhances the anti-tumor efficacy of PD-1 blockade by promoting CD8+ T cell infiltration and functionality. Mechanistically, TP63 and STAT1 mutually suppress each other to regulate the IFNγ signaling by co-occupying and co-regulating their own promoters and enhancers. Together, our findings elucidate a tumor-extrinsic function of TP63 in promoting immune evasion of SCC cells. Over-expression of TP63 may serve as a biomarker predicting the outcome of SCC patients treated with ICB therapy, and targeting TP63/STAT/IFNγ axis may enhance the efficacy of ICB therapy for this deadly cancer.
Asunto(s)
Carcinoma de Células Escamosas , Interferón gamma , Animales , Humanos , Ratones , Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Linfocitos T CD8-positivos , Línea Celular Tumoral , Inmunidad , Interferón gamma/metabolismo , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismo , Factores de Transcripción/metabolismo , Microambiente Tumoral , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Unlike most cancer types, the incidence of esophageal adenocarcinoma (EAC) has rapidly escalated in the western world over recent decades. Using whole genome bisulfite sequencing (WGBS), we identify the transcription factor (TF) FOXM1 as an important epigenetic regulator of EAC. FOXM1 plays a critical role in cellular proliferation and tumor growth in EAC patient-derived organoids and cell line models. We identify ERBB2 as an upstream regulator of the expression and transcriptional activity of FOXM1. Unexpectedly, gene set enrichment analysis (GSEA) unbiased screen reveals a prominent anti-correlation between FOXM1 and immune response pathways. Indeed, syngeneic mouse models show that FOXM1 inhibits the infiltration of CD8+ T cells into the tumor microenvironment. Consistently, FOXM1 suppresses CD8+ T cell chemotaxis in vitro and antigen-dependent CD8+ T cell killing. This study characterizes FOXM1 as a significant EAC-promoting TF and elucidates its novel function in regulating anti-tumor immune response.
Asunto(s)
Adenocarcinoma , Linfocitos T CD8-positivos , Neoplasias Esofágicas , Proteína Forkhead Box M1 , Animales , Humanos , Ratones , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Proliferación Celular , Epigenómica , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/inmunología , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Regulación Neoplásica de la Expresión Génica , Inmunidad , Microambiente Tumoral/inmunologíaRESUMEN
BACKGROUND: Marine microalgae (phytoplankton) mediate almost half of the worldwide photosynthetic carbon dioxide fixation and therefore play a pivotal role in global carbon cycling, most prominently during massive phytoplankton blooms. Phytoplankton biomass consists of considerable proportions of polysaccharides, substantial parts of which are rapidly remineralized by heterotrophic bacteria. We analyzed the diversity, activity, and functional potential of such polysaccharide-degrading bacteria in different size fractions during a diverse spring phytoplankton bloom at Helgoland Roads (southern North Sea) at high temporal resolution using microscopic, physicochemical, biodiversity, metagenome, and metaproteome analyses. RESULTS: Prominent active 0.2-3 µm free-living clades comprised Aurantivirga, "Formosa", Cd. Prosiliicoccus, NS4, NS5, Amylibacter, Planktomarina, SAR11 Ia, SAR92, and SAR86, whereas BD1-7, Stappiaceae, Nitrincolaceae, Methylophagaceae, Sulfitobacter, NS9, Polaribacter, Lentimonas, CL500-3, Algibacter, and Glaciecola dominated 3-10 µm and > 10 µm particles. Particle-attached bacteria were more diverse and exhibited more dynamic adaptive shifts over time in terms of taxonomic composition and repertoires of encoded polysaccharide-targeting enzymes. In total, 305 species-level metagenome-assembled genomes were obtained, including 152 particle-attached bacteria, 100 of which were novel for the sampling site with 76 representing new species. Compared to free-living bacteria, they featured on average larger metagenome-assembled genomes with higher proportions of polysaccharide utilization loci. The latter were predicted to target a broader spectrum of polysaccharide substrates, ranging from readily soluble, simple structured storage polysaccharides (e.g., laminarin, α-glucans) to less soluble, complex structural, or secreted polysaccharides (e.g., xylans, cellulose, pectins). In particular, the potential to target poorly soluble or complex polysaccharides was more widespread among abundant and active particle-attached bacteria. CONCLUSIONS: Particle-attached bacteria represented only 1% of all bloom-associated bacteria, yet our data suggest that many abundant active clades played a pivotal gatekeeping role in the solubilization and subsequent degradation of numerous important classes of algal glycans. The high diversity of polysaccharide niches among the most active particle-attached clades therefore is a determining factor for the proportion of algal polysaccharides that can be rapidly remineralized during generally short-lived phytoplankton bloom events. Video Abstract.
Asunto(s)
Flavobacteriaceae , Microalgas , Fitoplancton/genética , Fitoplancton/metabolismo , Eutrofización , Polisacáridos/metabolismo , Flavobacteriaceae/metabolismo , Microalgas/metabolismoRESUMEN
Organoid culture systems are very powerful models that recapitulate in vivo organ development and disease pathogenesis, offering great promise in basic research, drug screening and precision medicine. However, the application of organoids derived from patients with cancer to immunotherapeutic research is a relatively untapped area. Esophageal cancer is one of the most lethal malignancies worldwide, including two major pathological subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma. ESCC shares many biological and genomic features with oral squamous cell cancers. Herein, we provide a versatile protocol for the establishment and maintenance of oral and esophageal organoid cultures derived from both murine and human samples. We describe culture conditions for organoids derived from normal tongue, esophagus and gastroesophageal junction, esophageal cancer and Barrett's esophagus. In addition, we establish an ex vivo model by co-culturing patient tumor-derived organoids and autologous CD8+ T lymphocytes to assess CD8+ T cell-mediated tumor killing. Our protocol can also be modified for organoid establishment from other squamous epithelia and carcinomas. The co-culture model can serve as a template for studies of other tumor-immune cell interactions and the efficacy of immune checkpoint blockade therapy.
Asunto(s)
Adenocarcinoma , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Animales , Ratones , OrganoidesRESUMEN
Aprotic lithium-oxygen (Li-O2) batteries are considered to be a promising alternative option to lithium-ion batteries for high gravimetric energy storage devices. However, the sluggish electrochemical kinetics, the passivation, and the structural damage to the cathode caused by the solid discharge products have greatly hindered the practical application of Li-O2 batteries. Herein, the nonsolid-state discharge products of the off-stoichiometric Li1-xO2 in the electrolyte solutions are achieved by iridium (Ir) single-atom-based porous organic polymers (termed as Ir/AP-POP) as a homogeneous, soluble electrocatalyst for Li-O2 batteries. In particular, the numerous atomic active sites act as the main nucleation sites of O2-related discharge reactions, which are favorable to interacting with O2-/LiO2 intermediates in the electrolyte solutions, owing to the highly similar lattice-matching effect between the in situ-formed Ir3Li and LiO2, achieving a nonsolid LiO2 as the final discharge product in the electrolyte solutions for Li-O2 batteries. Consequently, the Li-O2 battery with a soluble Ir/AP-POP electrocatalyst exhibits an ultrahigh discharge capacity of 12.8 mAh, an ultralow overpotential of 0.03 V, and a long cyclic life of 700 h with the carbon cloth cathode. The manipulation of nonsolid discharge products in aprotic Li-O2 batteries breaks the traditional growth mode of Li2O2, bringing Li-O2 batteries closer to being a viable technology.
RESUMEN
Master transcription factors such as TP63 establish super-enhancers (SEs) to drive core transcriptional networks in cancer cells, yet the spatiotemporal regulation of SEs within the nucleus remains unknown. The nuclear pore complex (NPC) may tether SEs to the nuclear pore where RNA export rates are maximal. Here, we report that NUP153, a component of the NPC, anchors SEs to the NPC and enhances TP63 expression by maximizing mRNA export. This anchoring is mediated through protein-protein interaction between the intrinsically disordered regions (IDRs) of NUP153 and the coactivator BRD4. Silencing of NUP153 excludes SEs from the nuclear periphery, decreases TP63 expression, impairs cellular growth, and induces epidermal differentiation of squamous cell carcinoma. Overall, this work reveals the critical roles of NUP153 IDRs in the regulation of SE localization, thus providing insights into a new layer of gene regulation at the epigenomic and spatial level.
RESUMEN
Background Improper settings of outdoor smoking points in public places may increase the risk of secondhand smoke exposure among the population. Conducting research on air pollution in and around smoking spots and related influencing factors can provide valuable insights for optimizing the setting of outdoor smoking points. Objective To investigate the influence of the number of smokers at outdoor smoking points and the distance on the diffusion characteristics of surrounding air pollutants, in order to optimize the setting of outdoor smoking points. Methods Surrounding the exhibition halls in the China International Import Expo (CIIE), two outdoor smoking points were randomly selected, one on the first floor (ground level) and the other on the second floor (16 m above ground), respectively. At 0, 3, 6, and 9 m from the smoking points in the same direction, validated portable air pollutant monitors were used to measure the real-time fine particulate matter (PM2.5) and carbon dioxide (CO2) concentrations for consecutive 5 d during the exhibition, as well as the environmental meteorological factors at 0 m with weather meters including wind speed, wind direction, and air pressure. An open outdoor atmospheric background sampling point was selected on each of the two floors to carry out parallel sampling. Simultaneously, the number of smokers at each smoking point were double recorded per minute. The relationships between the number of smokers, distance from the smoking points, and ambient PM2.5 and CO2 concentrations were evaluated by generalized additive regression models for time-series data after adjustment of confounders such as temperature, relative humidity, and wind speed. Results The median numbers of smokers at smoking points on the first and second floors were 6 [interquartile range (IQR): 3, 9] and 9 (IQR: 6, 13), respectively. Windless (wind speed <0.6 m·s−1) occupied most of the time (85.9%) at both locations. The average concentration of ambient PM2.5 at the smoking points (0 m) [mean ± standard deviation, (106±114) μg·m−3] was 4.2 times higher than that of the atmospheric background [(25±7) μg·m−3], the PM2.5 concentration showed a gradient decline with the increase of distance from the smoking points, and the average PM2.5 concentration at 9 m points [(35±22) μg·m−3] was close to the background level (1.4 times higher). The maximum concentration of CO2 [(628±23) μmol·mol−1] was observed at 0 m, and its average value was 1.3 times higher than that of the atmospheric background [(481±40) μmol·mol−1], and there was no gradient decrease in CO2 concentration with increasing distance at 0, 3, 6, and 9 m points. The regression analyses showed that, taking smoking point as the reference, every 3 m increase in distance was associated with a decrease of ambient PM2.5 by 24.6 [95% confidence interval (95%CI): 23.5, 25.8] μg·m−3 (23.2%) and CO2 by 54.1 (95%CI: 53.1, 55.1) μmol·mol−1 (8.6%). Every one extra smoker at the smoking point was associated with an average increase of PM2.5 and CO2 by 2.0 (95%CI: 1.7, 2.8) μg·m−3 and 1.0 (95%CI: 0.7,1.2) μmol·mol−1, respectively. The sensitivity analysis indicated that, under windless conditions, the concentrations of PM2.5 and CO2 at the smoking points were even higher but the decreasing and dispersion characteristics remained consistent. Conclusion Outdoor smoking points could significantly increase the PM2.5 concentrations in the surrounding air and the risks of secondhand smoke exposure, despite of the noticeable decreasing trend with increasing distance. Considering the inevitable poor dispersion conditions such as windless and light wind, outdoor smoking points are recommended to be set at least 9 m or farther away from non-smoking areas.
Asunto(s)
Neoplasias , Transcriptoma , Humanos , Biología , Neoplasias/genética , Perfilación de la Expresión GénicaRESUMEN
ARID1A, a member of the chromatin remodeling SWI/SNF complex, is frequently lost in many cancer types, including esophageal adenocarcinoma (EAC). Here, we study the impact of ARID1A deficiency on the anti-tumor immune response in EAC. We find that EAC tumors with ARID1A mutations are associated with enhanced tumor-infiltrating CD8+ T cell levels. ARID1A-deficient EAC cells exhibit heightened IFN response signaling and promote CD8+ T cell recruitment and cytolytic activity. Moreover, we demonstrate that ARID1A regulates fatty acid metabolism genes in EAC, showing that fatty acid metabolism could also regulate CD8+ T cell recruitment and CD8+ T cell cytolytic activity in EAC cells. These results suggest that ARID1A deficiency shapes both tumor immunity and lipid metabolism in EAC, with significant implications for immune checkpoint blockade therapy in EAC.
RESUMEN
A novel Gram-stain-negative, aerobic, non-motile, rod-shaped and orange-colored bacterium, designated as strain C305T, was isolated from marine sediment of the coast area of Weihai, China. Strain C305T growth occurs at 4-40 °C (optimally at 30-33 °C), pH 6.0-9.0 (optimally at pH 8.0) and with 0.5-10.0% (w/v) NaCl (optimum 1.5-3.0%). No growth is observed without NaCl. The major cellular fatty acids of strain C305T were identified as iso-C15:0, iso-C15:1G and iso-C17:0 3-OH. The major respiratory quinone was found to be MK-6, and the DNA G + C content was determined to be 35.5 mol%. The predominant polar lipids were mainly phosphatidylethanolamines (PE), unidentified aminophospholipids (APL), andunidentified lipid (L2). Phylogenetic analysis based on 16S rRNA gene sequences revealed that C305T was a member of the genus Brumimicrobium and had a 16S rRNA gene sequence similarity values of 96.9-98.0% with recognized Brumimicrobium species. On the basis of the phylogenetic and phenotypic evidences, strain C305T represents a novel species of the genus Brumimicrobium, for which the name Brumimicrobium oceani sp. nov. is proposed. The type strain is C305T (= KCTC 62371 T = MCCC 1H00297T).
Asunto(s)
Flavobacteriaceae , Agua de Mar , Agua de Mar/microbiología , Filogenia , ARN Ribosómico 16S/genética , Cloruro de Sodio , Lagos , ADN Bacteriano/genética , Técnicas de Tipificación Bacteriana , Análisis de Secuencia de ADN , Vitamina K 2/química , Ácidos Grasos/análisisRESUMEN
Inner Mongolia autonomous region of China and Mongolia are the primary regions where Chinese and Mongolian medicine and its medicinal plant resources are distributed. In this study, 133 families, 586 genera, and 1 497 species of medicinal plants in Inner Mongolia as well as 62 families, 261 genera, and 467 species of medicinal plants in Mongolia were collected through field investigation, specimen collection and identification, and literature research. And the species, geographic distribution, and influencing factors of the above medicinal plants were analyzed. The results revealed that there were more plant species utilized for medicinal reasons in Inner Mongolia than in Mongolia. Hotspots emerged in Hulunbuir, Chifeng, and Tongliao of Inner Mongolia, while there were several hotspots in Eastern province, Sukhbaatar province, Gobi Altai province, Bayankhongor province, Middle Gobi province, Kobdo province, South Gobi province, and Central province of Mongolia. The interplay of elevation and climate made a non-significant overall contribution to the diversity of plant types in Inner Mongolia and Mongolia. The contribution of each factor increased significantly when the vegetation types of Inner Mongolia and Mongolia were broadly divided into forest, grassland and desert. Thus, the distribution of medicinal plant resources and vegetation cover were jointly influenced by a variety of natural factors such as topography, climate and interactions between species, and these factors contributed to and constrained each other. This study provided reference for sustainable development and rational exploitation of medicinal plant resources in future.
Asunto(s)
Plantas Medicinales , Humanos , Mongolia , Clima , Medicina Tradicional Mongoliana , ChinaRESUMEN
A novel bacterial strain, N1Y112T, was isolated from coastal sediment collected in Weihai, PR China. This Gram-stain-negative, facultatively anaerobic, motile rod-shaped bacterium exhibited the ability to oxidize thiosulphate to sulphate and reduce nitrate to ammonia through its Sox system and nitrate reduction pathway, respectively. The strain grew at 20-35 °C (optimum, 28 °C), pH 6.0-10.0 (optimum, pH 7.5) and in the presence of 1.0-5.0â% (w/v) NaCl (optimum, 3.0â%). Major fatty acids present in the strain included summed feature 8 (comprising C18â:â1 ω7c and/or C18â:â1 ω6c), summed feature 3 (comprising C16â:â1 ω7c and/or C16â:â1 ω6c) and C16â:â0. Its polar lipid profile consisted of one phosphatidylethanolamine, two unknown aminolipids, one aminophosphoglycolipid, one diphosphatidylglycerol, one phosphatidylglycerol, two unknown phospholipids and two unknown lipids. Strain N1Y112T contained ubiquinone-7 and ubiquinone-8 as isoprenoid quinones, with a genomic G+C content of 50.6âmol%. Based on phylogenetic analysis, strain N1Y112T clustered with Pontibacterium granulatum JCM 30316T being its closest relative at 97.1â% 16S rRNA gene sequence similarity. The average nucleotide identity and digital DNA-DNA hybridization values were 77.1 and 20.7â%, respectively, which suggest significant differences between genomes of N1Y112T and P. granulatum JCM 30316T. Based on the findings from its phenotypic, genotypic and phylogenetic analyses, N1Y112T is considered to represent a novel species of the genus Pontibacterium, for which the name Pontibacterium sinense sp. nov. is proposed. The type strain is N1Y112T (=KCTC 72927T=MCCC 1H00429T).
Asunto(s)
Nitratos , Ubiquinona , Tiosulfatos , Filogenia , ARN Ribosómico 16S/genética , Composición de Base , Ácidos Grasos/química , Análisis de Secuencia de ADN , ADN Bacteriano/genética , Técnicas de Tipificación Bacteriana , Bacterias , Oxidación-ReducciónRESUMEN
BACKGROUND: As one of the most common malignancies, esophageal cancer has two subtypes, squamous cell carcinoma and adenocarcinoma, arising from distinct cells-of-origin. Distinguishing cell-type-specific molecular features from cancer-specific characteristics is challenging. RESULTS: We analyze whole-genome bisulfite sequencing data on 45 esophageal tumor and nonmalignant samples from both subtypes. We develop a novel sequence-aware method to identify large partially methylated domains (PMDs), revealing profound heterogeneity at both methylation level and genomic distribution of PMDs across tumor samples. We identify subtype-specific PMDs that are associated with repressive transcription, chromatin B compartments and high somatic mutation rate. While genomic locations of these PMDs are pre-established in normal cells, the degree of loss is significantly higher in tumors. We find that cell-type-specific deposition of H3K36me2 may underlie genomic distribution of PMDs. At a smaller genomic scale, both cell-type- and cancer-specific differentially methylated regions (DMRs) are identified for each subtype. Using binding motif analysis within these DMRs, we show that a cell-type-specific transcription factor HNF4A maintains the binding sites that it generates in normal cells, while establishing new binding sites cooperatively with novel partners such as FOSL1 in esophageal adenocarcinoma. Finally, leveraging pan-tissue single-cell and pan-cancer epigenomic datasets, we demonstrate that a substantial fraction of cell-type-specific PMDs and DMRs identified here in esophageal cancer are actually markers that co-occur in other cancers originating from related cell types. CONCLUSIONS: These findings advance our understanding of DNA methylation dynamics at various genomic scales in normal and malignant states, providing novel mechanistic insights into cell-type- and cancer-specific epigenetic regulations.
Asunto(s)
Adenocarcinoma , Carcinoma de Células Escamosas , Neoplasias Esofágicas , Humanos , Epigénesis Genética , Neoplasias Esofágicas/genética , Adenocarcinoma/genética , Carcinoma de Células Escamosas/genética , CromatinaRESUMEN
A transdermal drug delivery system (TDDS) is one of the most attractive approaches and is popular due to high patient compliance, low risk and ease of applicability. To formulate a bioadhesive gel with Ropivacaine-loaded nanoparticles for enhancement of the local anaesthesia. The ionotropic gelation method was used to formulate nanoparticles and characterized for particle size, zeta potential, PDI, drug loading and surface morphology. The optimized nanoparticulate formulation was further used in the development of bioadhesive gel and characterized for clarity, pH, bioadhesive strength, drug content, viscosity, ex-vivo skin permeation and in vivo Tail Flick test on a rat model. Among nanoparticle formulations, NP4 formulation was found to be the ideal formulation based on Physico chemical parameters. The F6 bioadhesive gel was considered optimised amongst all the formulations. The F6 gel showed an excellent skin permeation profile over 14 hr as compared to other formulations. This formulation showed maximum anesthetic effect compared to other formulations as observed in the tail flick test. F6 formulation containing RPV nanoparticles showed 3.32 folds increase in anesthetic activity as compared to the control gel. Bioadhesive transdermal gel containing RPV nanoparticles would be a potential alternative strategy for improving the anesthetic effect.
RESUMEN
The rising prevalence of metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM) poses a major challenge to global health. Existing therapeutic approaches have limitations, and there is a need for new, safe, and less invasive treatments. Interventional metabolic therapy is a new addition to the treatment arsenal for metabolic disorders. This review focuses on two interventional techniques: bariatric arterial embolization (BAE) and endovascular denervation (EDN). BAE involves embolizing specific arteries feeding ghrelin-producing cells to suppress appetite and promote weight loss. EDN targets nerves that regulate metabolic organs to improve glycemic control in T2DM patients. We describe the current state of these techniques, their mechanisms of action, and the available safety and effectiveness data. We also propose a new territory called "Interventional Metabology" to encompass these and other interventional approaches to treating metabolic disorders.
Asunto(s)
Cirugía Bariátrica , Bariatria , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/terapia , Obesidad/metabolismo , Pérdida de Peso , DesnervaciónRESUMEN
BACKGROUND: The comparative impact of histologic variants and grade has not been well described. METHODS: Salivary cancer histologies were profiled using hospital and population-based cancer registries. Multivariable models were employed to assess relationships between histology, grade, and survival. RESULTS: On univariate analysis, histologic variants exhibited a wide spectrum of mortality risk (5-year overall survival (OS): 86% (acinic cell carcinoma), 78% (mucoepidermoid carcinoma), 72% (adenoid cystic carcinoma), 64% (carcinoma ex-pleomorphic adenoma), 52% (adenocarcinoma NOS), and 47% (salivary duct carcinoma) (p < 0.001). However, on multivariable analysis these differences largely vanished. Worsening grade corresponded with deteriorating survival (5-year OS: 89% [low-grade], 81% [intermediate-grade], 45% [high-grade]; p < 0.001), which was upheld on multivariable analysis and propensity score matching. Recursive partitioning analysis generated TNM + G schema (c-index 0.75) superior to the existing system (c-index 0.73). CONCLUSION: Grade represents a primary determinant of salivary cancer prognosis. Integrating grade into stage strengthens current staging systems.