RESUMEN
Renal cell carcinoma (RCC) is recognized as one of the three primary malignant tumors affecting the urinary system, posing a significant risk to human health and life. Despite advancements in understanding RCC, challenges persist in its diagnosis and treatment, particularly in early detection and diagnosis due to issues of low specificity and sensitivity. Consequently, there is an urgent need for the development of effective strategies to enhance diagnostic accuracy and treatment outcomes for RCC. In recent years, with the extensive research on materials for applications in the biomedical field, some materials have been identified as promising for clinical applications, e.g., in the diagnosis and treatment of many tumors, including RCC. Herein, we summarize the latest materials that are being studied and have been applied in the early diagnosis and treatment of RCC. While focusing on their adjuvant effects, we also discuss their technical principles and safety, thus highlighting the value and potential of their application. In addition, we also discuss the limitations of the application of these materials and possible future directions, providing new insights for improving RCC diagnosis and treatment.
RESUMEN
Ovarian cancer, ranking as the seventh most prevalent malignancy among women globally, faces significant challenges in diagnosis and therapeutic intervention. The difficulties in early detection are amplified by the limitations and inefficacies inherent in current screening methodologies, highlighting a pressing need for more efficacious diagnostic and treatment strategies. Phage display technology emerges as a pivotal innovation in this context, utilizing extensive phage-peptide libraries to identify ligands with specificity for cancer cell markers, thus enabling precision-targeted therapeutic strategies. This technology promises a paradigm shift in ovarian cancer management, concentrating on targeted drug delivery systems to improve treatment accuracy and efficacy while minimizing adverse effects. Through a meticulous review, this paper evaluates the revolutionary potential of phage display in enhancing ovarian cancer therapy, representing a significant advancement in combating this challenging disease. Phage display technology is heralded as an essential instrument for developing effective immunodiagnostic and therapeutic approaches in ovarian cancer, facilitating early detection, precision-targeted medication, and the implementation of customized treatment plans.
Asunto(s)
Técnicas de Visualización de Superficie Celular , Neoplasias Ováricas , Biblioteca de Péptidos , Femenino , Humanos , Neoplasias Ováricas/terapia , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/inmunología , Biomarcadores de Tumor , Animales , Inmunoterapia/métodosRESUMEN
In the advancement of Inflammatory Bowel Disease (IBD) treatment, existing therapeutic methods exhibit limitations; they do not offer a complete cure for IBD and can trigger adverse side effects. Consequently, the exploration of novel therapies and multifaceted treatment strategies provides patients with a broader range of options. Within the framework of IBD, gut microbiota plays a pivotal role in disease onset through diverse mechanisms. Bacteriophages, as natural microbial regulators, demonstrate remarkable specificity by accurately identifying and eliminating specific pathogens, thus holding therapeutic promise. Although clinical trials have affirmed the safety of phage therapy, its efficacy is prone to external influences during storage and transport, which may affect its infectivity and regulatory roles within the microbiota. Improving the stability and precise dosage control of bacteriophages-ensuring robustness in storage and transport, consistent dosing, and targeted delivery to infection sites-is crucial. This review thoroughly explores the latest developments in IBD treatment and its inherent challenges, focusing on the interaction between the microbiota and bacteriophages. It highlights bacteriophages' potential as microbiome modulators in IBD treatment, offering detailed insights into research on bacteriophage encapsulation and targeted delivery mechanisms. Particular attention is paid to the functionality of various carrier systems, especially regarding their protective properties and ability for colon-specific delivery. This review aims to provide a theoretical foundation for using bacteriophages as microbiome modulators in IBD treatment, paving the way for enhanced regulation of the intestinal microbiota.
Asunto(s)
Bacteriófagos , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Terapia de Fagos , Humanos , Terapia de Fagos/métodos , Enfermedades Inflamatorias del Intestino/terapia , Bacteriófagos/fisiología , AnimalesRESUMEN
Monocyte-derived tumor-associated macrophages (Mo-TAMs) intensively infiltrate diffuse gliomas with remarkable heterogeneity. Using single-cell transcriptomics, we chart a spatially resolved transcriptional landscape of Mo-TAMs across 51 patients with isocitrate dehydrogenase (IDH)-wild-type glioblastomas or IDH-mutant gliomas. We characterize a Mo-TAM subset that is localized to the peri-necrotic niche and skewed by hypoxic niche cues to acquire a hypoxia response signature. Hypoxia-TAM destabilizes endothelial adherens junctions by activating adrenomedullin paracrine signaling, thereby stimulating a hyperpermeable neovasculature that hampers drug delivery in glioblastoma xenografts. Accordingly, genetic ablation or pharmacological blockade of adrenomedullin produced by Hypoxia-TAM restores vascular integrity, improves intratumoral concentration of the anti-tumor agent dabrafenib, and achieves combinatorial therapeutic benefits. Increased proportion of Hypoxia-TAM or adrenomedullin expression is predictive of tumor vessel hyperpermeability and a worse prognosis of glioblastoma. Our findings highlight Mo-TAM diversity and spatial niche-steered Mo-TAM reprogramming in diffuse gliomas and indicate potential therapeutics targeting Hypoxia-TAM to normalize tumor vasculature.
Asunto(s)
Adrenomedulina , Neoplasias Encefálicas , Glioblastoma , Macrófagos Asociados a Tumores , Humanos , Glioblastoma/patología , Glioblastoma/tratamiento farmacológico , Glioblastoma/irrigación sanguínea , Glioblastoma/genética , Glioblastoma/metabolismo , Animales , Adrenomedulina/genética , Adrenomedulina/metabolismo , Ratones , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/irrigación sanguínea , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Macrófagos Asociados a Tumores/metabolismo , Neovascularización Patológica/genética , Microambiente Tumoral , Isocitrato Deshidrogenasa/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral , Macrófagos/metabolismo , Hipoxia de la CélulaRESUMEN
Cholera, a persistent global public health concern, continues to cause outbreaks in approximately 30 countries and territories this year. The imperative to safeguard water sources and food from Vibrio cholerae, the causative pathogen, remains urgent. The bacterium is mainly disseminated via ingestion of contaminated water or food. Despite the plate method's gold standard status for detection, its time-consuming nature, taking several days to provide results, remains a challenge. The emergence of novel virulence serotypes raises public health concerns, potentially compromising existing detection methods. Hence, exploiting Vibrio cholerae toxin testing holds promise due to its inherent stability. Immunobiosensors, leveraging antibody specificity and sensitivity, present formidable tools for detecting diverse small molecules, encompassing drugs, hormones, toxins, and environmental pollutants. This review explores cholera toxin detection, highlighting phage display-based nano immunosensors' potential. Engineered bacteriophages exhibit exceptional cholera toxin affinity, through specific antibody fragments or mimotopes, enabling precise quantification. This innovative approach promises to reshape cholera toxin detection, offering an alternative to animal-derived methods. Harnessing engineered bacteriophages aligns with ethical detection and emphasizes sensitivity and accuracy, a pivotal stride in the evolution of detection strategies. This review primarily introduces recent advancements in phage display-based nano immunosensors for cholera toxin, encompassing technical aspects, current challenges, and future prospects.
Asunto(s)
Bacteriófagos , Cólera , Vibrio cholerae , Humanos , Toxina del Cólera , Cólera/microbiología , AguaRESUMEN
BACKGROUND: Tumors of the gastrointestinal tract impose a substantial healthcare burden due to their prevalence and challenging prognosis. METHODS: We conducted a review of peer-reviewed scientific literature using reputable databases (PubMed, Scopus, Web of Science) with a focus on oncolytic virus therapy within the context of gastrointestinal tumors. Our search covered the period up to the study's completion in June 2023. INCLUSION AND EXCLUSION CRITERIA: This study includes articles from peer-reviewed scientific journals, written in English, that specifically address oncolytic virus therapy for gastrointestinal tumors, encompassing genetic engineering advances, combined therapeutic strategies, and safety and efficacy concerns. Excluded are articles not meeting these criteria or focusing on non-primary gastrointestinal metastatic tumors. RESULTS: Our review revealed the remarkable specificity of oncolytic viruses in targeting tumor cells and their potential to enhance anti-tumor immune responses. However, challenges related to safety and efficacy persist, underscoring the need for ongoing research and improvement. CONCLUSION: This study highlights the promising role of oncolytic virus therapy in enhancing gastrointestinal tumor treatments. Continued investigation and innovative combination therapies hold the key to reducing the burden of these tumors on patients and healthcare systems.
Asunto(s)
Neoplasias Gastrointestinales , Neoplasias , Viroterapia Oncolítica , Virus Oncolíticos , Humanos , Viroterapia Oncolítica/efectos adversos , Virus Oncolíticos/genética , Neoplasias/patología , Neoplasias Gastrointestinales/terapia , Ingeniería Genética , InmunoterapiaRESUMEN
Dyslipidemia and cognitive impairment are common among old adults and the occurrence of them rises exponentially with increasing age. Evidences of the relationships between serum lipids and cognitive impairment are inconsistent or equivocal among older adults. This study aimed to investigate the associations between lipid profiles and late-life cognitive impairment among oldest-old and centenarian adults. In this cross-sectional study, serum lipids were biochemically measured among 606 oldest-old adults and 653 centenarians, and cognitive function was evaluated using mini-mental state examination (MMSE). Multivariate linear and logistic regression analyses were performed to explore the associations between serum lipids and cognitive impairment. Results showed participants with cognitive impairment had lower total cholesterol (TC) levels compared with those without cognitive impairment (p < 0.05). TC levels were positively associated with MMSE (p < 0.05). Furthermore, a negative association was observed between TC levels and cognitive impairment (p for trend = 0.002). This negative association remained statistically significant after adjusting for confounders (p for trend = 0.028). These results suggested that older adults with higher TC levels were likely to have better cognitive function. Taking immoderate cholesterol-lowering drugs among older adults is questionable and requires investigation, and cognitive performance of old adults with lower TC levels deserves more attention.
RESUMEN
Pancreatic cancer is a devastating disease with a high mortality rate and a lack of effective therapies. The challenges associated with early detection and the highly aggressive nature of pancreatic cancer have limited treatment options, underscoring the urgent need for better disease-modifying therapies. Peptide-based biotherapeutics have become an attractive area of research due to their favorable properties such as high selectivity and affinity, chemical modifiability, good tissue permeability, and easy metabolism and excretion. Phage display, a powerful technique for identifying peptides with high affinity and specificity for their target molecules, has emerged as a key tool in the discovery of peptide-based drugs. Phage display technology involves the use of bacteriophages to express peptide libraries, which are then screened against a target of interest to identify peptides with desired properties. This approach has shown great promise in cancer diagnosis and treatment, with potential applications in targeting cancer cells and developing new therapies. In this comprehensive review, we provide an overview of the basic biology of phage vectors, the principles of phage library construction, and various methods for binding affinity assessment. We then describe the applications of phage display in pancreatic cancer therapy, targeted drug delivery, and early detection. Despite its promising potential, there are still challenges to be addressed, such as optimizing the selection process and improving the pharmacokinetic properties of phage-based drugs. Nevertheless, phage display represents a promising approach for the development of novel targeted therapies in pancreatic cancer and other tumors.
RESUMEN
This study was to explore epidemiological characteristics of malnutrition and factors associated with malnutrition in centenarians and oldest-old adults, so as to provide a reference for family members and government departments to take effective measures and promote healthy aging. Median age of all 1,654 participants was 100 (85, 102) years old, and prevalence of high malnutrition risk was 65.54% in all participants. Proportion of high-malnutrition risk was higher, and proportion of normal physical function was lower, in centenarians than those in oldest-old adults (p < 0.05 for all). Univariate and multivariate Poisson regression analyses showed that normal physical function was negatively associated with malnutrition risk in all participants, centenarians, and oldest-old adults (p < 0.05 for all). In conclusion, proportion of centenarians at malnutrition risk was significantly higher than that of oldest-old adults, and the independent factor associated with malnutrition in people aged over 80 years was physical function.
RESUMEN
Based on N-B bonds, a novel strategy was developed for improving the energetic performance of tetrazoles. By employing the amino neighboring group participation, the azolyl borane compound 7 was selectively constructed, which exhibited excellent stability in water and air. This strategy solved the acidity problem of tetrazole as well as increasing the heat of detonation and combustion by 25% and 36%, respectively. Through laser ignition experiments, it also improved the combustion performance of tetrazoles. In DSC experiments, thermal decomposition temperatures of N-B covalent compounds were elevated as well. In an electrostatic potential calculation and sensitivity test, N-B covalent compounds exhibited good sensitivity (IS > 40 J and FS > 360 N). Through TG-DSC-FTIR-MS and in situ IR experiments, decomposition products were investigated to determine the next optimization stage for heat of detonation. It offered a significant potential for development to incorporate the N-B bond into nitrogen-rich compounds.
RESUMEN
BACKGROUND: Glioblastoma (GBM) is the most common and lethal primary brain tumor characterized by extensive vascularization. Anti-angiogenic therapy for this cancer offers the possibility of universal efficacy. However, preclinical and clinical studies suggest that anti-VEGF drugs, such as Bevacizumab, actively promote tumor invasion, which ultimately leads to a therapy-resistant and recurrent phenotype of GBMs. Whether Bevacizumab can improve survival over chemotherapy alone remains debated. Herein, we emphasize the importance of small extracellular vesicles (sEVs) internalization by glioma stem cells (GSCs) in giving rise to the failure of anti-angiogenic therapy in the treatment of GBMs and discover a specific therapeutic target for this damaging disease. METHODS: To experimentally prove that hypoxia conditions promote the release of GBM cells-derived sEVs, which could be taken up by the surrounding GSCs, we used an ultracentrifugation strategy to isolate GBM-derived sEVs under hypoxic or normoxic conditions, performed bioinformatics analysis and multidimensional molecular biology experiments, and established a xenograft mouse model. RESULTS: The internalization of sEVs by GSCs was proven to promote tumor growth and angiogenesis through the pericyte-phenotype transition. Hypoxia-derived sEVs could efficiently deliver TGF-ß1 to GSCs, thus resulting in the activation of the TGF-ß signaling pathway and the consequent pericyte-phenotype transition. Specifically targeting GSC-derived pericytes using Ibrutinib can reverse the effects of GBM-derived sEVs and enhance the tumor-eradicating effects when combined with Bevacizumab. CONCLUSION: This present study provides a new interpretation of the failure of anti-angiogenic therapy in the non-operative treatment of GBMs and discovers a promising therapeutic target for this intractable disease.
Asunto(s)
Neoplasias Encefálicas , Vesículas Extracelulares , Glioblastoma , Glioma , Humanos , Animales , Ratones , Pericitos/metabolismo , Pericitos/patología , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Células Madre Neoplásicas/metabolismo , Glioma/patología , Glioblastoma/metabolismo , Hipoxia/metabolismo , Vesículas Extracelulares/metabolismo , Fenotipo , Neoplasias Encefálicas/patologíaRESUMEN
Fully actuated signal controls are becoming increasingly popular in modern urban environments, attempting to reduce congestion locally, synchronize flows, or prioritize specific types of vehicles. This trend is expected to grow as more vehicles are expected to communicate via Vehicle-to-Infrastructure (V2I) communication. The presented dataset contains cleaned observations from a fully actuated signal control system with priority for public transportation. Time series data of traffic signals that regulate vehicle, public transportation, bicycle, and pedestrian traffic flows are available, showing where a traffic signal operates in a red or green phase. Also, loop detector data representing the occupancy at several locations at an urban intersection in Zurich, Switzerland is available. The data of all traffic signals and loop detectors corresponds to January and February 2019 and has a resolution of 1 s. Recent advances in transportation science show novel approaches for signalized intersections, but most publications assess their methodology on self-collected or simulated data. Therefore, the presented dataset aims at facilitating the development, calibration, and validation of novel methodological developments for modeling, estimation, forecasting, and other tasks in traffic engineering. Furthermore, it can be used as a real-world benchmark dataset for objectively comparing different methodologies.
RESUMEN
We have been interested in the development of rubisco-based biomimetic systems for reversible CO2 capture from air. Our design of the chemical CO2 capture and release (CCR) system is informed by the understanding of the binding of the activator CO2 (A CO2 ) in rubisco (ribulose-1,5-bisphosphate carboxylase/oxygenase). The active site consists of the tetrapeptide sequence Lys-Asp-Asp-Glu (or KDDE) and the Lys sidechain amine is responsible for the CO2 capture reaction. We are studying the structural chemistry and the thermodynamics of CO2 capture based on the tetrapeptide CH3 CO-KDDE-NH2 ("KDDE") in aqueous solution to develop rubisco mimetic CCR systems. Here, we report the results of 1 H NMR and 13 C NMR analyses of CO2 capture by butylamine and by KDDE. The carbamylation of butylamine was studied to develop the NMR method and with the protocol established, we were able to quantify the oligopeptide carbamylation at much lower concentration. We performed a pH profile in the multi equilibrium system and measured amine species and carbamic acid/carbamate species by the integration of 1 H NMR signals as a function of pH in the range 8≤pH≤11. The determination of ΔG1 (R) for the reaction R-NH2 +CO2 â â ${ \mathbin{{\stackrel{\textstyle\rightarrow} { {\smash{\leftarrow}\vphantom{_{\vbox to.5ex{\vss}}}} } }} }$ R-NH-COOH requires the solution of a multi-equilibrium equation system, which accounts for the dissociation constants K2 and K3 controlling carbonate and bicarbonate concentrations, the acid dissociation constant K4 of the conjugated acid of the amine, and the acid dissociation constant K5 of the alkylcarbamic acid. We show how the multi-equilibrium equation system can be solved with the measurements of the daughter/parent ratio X, the knowledge of the pH values, and the initial concentrations [HCO3 - ]0 and [R-NH2 ]0 . For the reaction energies of the carbamylations of butylamine and KDDE, our best values are ΔG1 (Bu)=-1.57â kcal/mol and ΔG1 (KDDE)=-1.17â kcal/mol. Both CO2 capture reactions are modestly exergonic and thereby ensure reversibility in an energy-efficient manner. These results validate the hypothesis that KDDE-type oligopeptides may serve as reversible CCR systems in aqueous solution and guide designs for their improvement.
RESUMEN
Immune checkpoint inhibitors (ICIs) have been an encouraging treatment method in non-small cell lung cancer (NSCLC). However, bone and liver metastases are considered to restrain immunotherapy efficacy. Since serum alkaline phosphatase (ALP) is associated with bone and liver metastases, it was investigated whether serum ALP could be a novel biomarker to predict the efficacy of ICIs treatment. In the present study, 143 patients with NSCLC receiving ICIs treatment were retrospectively analyzed. The objective response rate (ORR) was compared between the ALP high and low groups, bone metastasis and non-bone metastasis groups, and liver metastasis or non-liver metastasis groups. The associations between clinical characteristics, including ALP level, bone or liver metastasis and median progression-free survival (mPFS) time were analyzed by univariate and multivariate Cox regression analysis. It was found that bone metastasis was associated with a lower ORR (24 vs. 43%; P<0.05) and shorter mPFS (10.2 vs. 17.3 months; P=0.010) in patients with NSCLC receiving ICIs. Liver metastasis was associated with lower ORR (22 vs. 38%; P<0.05), but not with mPFS (P=0.119). The ALP level was higher in patients with bone or liver metastasis than in those without (119.6 or 103.6 vs. 83.3 U/l, respectively; P<0.05). Higher ALP levels were also associated with bone or liver metastasis, lower ORR (20 vs. 39%; P<0.05) and shorter mPFS (8.5 vs. 15.4 months; P=0.009). Cox regression analysis demonstrated that ALP was an independent prognostic indicator of mPFS (hazard ratio, 1.856; 95% confidence interval, 1.030-3.343; P=0.040). In conclusion, pretreatment levels of serum ALP might be a predictive indicator of clinical outcome in patients with NSCLC after ICIs treatment.
RESUMEN
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease harboring significant microenvironment heterogeneity, especially for the macrophages. Tumor-associated macrophages (TAMs) orchestrate PDAC malignancy, but their dynamics during disease progression remains poorly understood. There is a pressing need to identify the molecular mechanism underlying tumor-macrophage interactions and thus design novel therapeutic strategies. METHODS: Herein, we developed an insilico computational method incorporating bulk and single-cell transcriptome profiling to characterize macrophage heterogeneity. CellPhoneDB algorithm was applied to infer macrophage-tumor interaction networks, whereas pseudotime trajectory for dissecting cell evolution and dynamics. RESULTS: We demonstrated myeloid compartment was an interactive hub of tumor microenvironment (TME) essential for PDAC progression. Dimensionality reduction classified seven clusters within the myeloid cells wherein five subsets of macrophages were characterized by diverse cell states and functionality. Remarkably, tissue-resident macrophages and inflammatory monocyte were identified as potential sources of TAMs. Further, we uncovered several ligand-receptor pairs lining tumor cells and macrophages. Among them, HBEGF-CD44, HBEGF-EGFR, LGALS9-CD44, LGALS9-MET, and GRN-EGFR were correlated with worse overall survival. Notably, as in vitro experiments indicated, TAM-derived HBEGF promoted proliferation and invasion of the pancreatic cancer cell line. CONCLUSION: Together, our work deciphered a comprehensive single-cell atlas of the macrophage compartment of PDAC and provided novel macrophage-tumor interaction features with potential value in developing targeted immunotherapies and molecular diagnostics for predicting patient outcome.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/genética , Macrófagos , Comunicación Celular/genética , Receptores ErbB , Microambiente Tumoral/genética , Neoplasias PancreáticasRESUMEN
OBJECTIVE: Menstrual lifespan (ML) is an important biological characteristic for women. Rare evidence has established the associations between menopause age (MI), geriatric depression and healthy longevity. This study aimed to address these associations in Chinese oldest-old and centenarian women, and explore their related factors in order to provide strategy support for healthy aging. METHODS: The China Hainan Centenarian Cohort Study provides a population-based sample in Hainan, China. A total of 723 women including 318 centenarian women and 405 oldest-old women aged 80-99 years were included in this study. Data on demographic information were collected using a structured questionnaire. Physical examination and blood samples were obtained following standard procedure. Geriatric Depression Scale (GDS-15) was used to evaluate depressive symptoms for all participants. RESULTS: The proportions of participants with depression and longevity were 19.78 % (143 older adults) and 43.98 % (318 older adults), respectively. After adjusting for a wide range of other covariates in multiple logistic regression analyses, ML was positively and significantly associated with depression and longevity [Exp(ß) 1.076 and 1.121; P < 0.05 for all]. In multiple linear regression analyses, there were significantly positive associations of ML with GDS-15 (ß = 0.061) and age (ß = 0.238, p < 0.05 for all) after adjusting for all covariates. CONCLUSIONS: This study provides epidemiological evidence that menstrual lifespan has positive associations with geriatric depression and healthy longevity in Chinese oldest-old and centenarian women. Future researches should focus on the effects of intervening MI on psychological health and successful longevity.
Asunto(s)
Centenarios , Depresión , Longevidad , Menstruación , Anciano , Anciano de 80 o más Años , Femenino , Humanos , China/epidemiología , Estudios de Cohortes , Depresión/epidemiología , Pueblos del Este de AsiaRESUMEN
Stroke poses a critical global health challenge, leading to substantial morbidity and mortality. Existing treatments often miss vital timeframes and encounter limitations due to adverse effects, prompting the pursuit of innovative approaches to restore compromised brain function. This review explores the potential of filamentous phages in enhancing stroke recovery. Initially antimicrobial-centric, bacteriophage therapy has evolved into a regenerative solution. We explore the diverse role of filamentous phages in post-stroke neurological restoration, emphasizing their ability to integrate peptides into phage coat proteins, thereby facilitating recovery. Experimental evidence supports their efficacy in alleviating post-stroke complications, immune modulation, and tissue regeneration. However, rigorous clinical validation is essential to address challenges like dosing and administration routes. Additionally, genetic modification enhances their potential as injectable biomaterials for complex brain tissue issues. This review emphasizes innovative strategies and the capacity of filamentous phages to contribute to enhanced stroke recovery, as opposed to serving as standalone treatment, particularly in addressing stroke-induced brain tissue damage.
Asunto(s)
Bacteriófagos , Inovirus , Inovirus/genéticaRESUMEN
The crystal structure of l-phenylalanyl l-phenylalanine (Phe-Phe, FF, a.k.a. diphenylalanine) is not merely noncentrosymmetric, but it is highly dipole parallel aligned. It is for this reason that FF is a nonlinear optical (NLO) material and exhibits strong second harmonic generation (SHG). Enhancement of the SHG response by ortho fluorination was demonstrated. Crystallization is nontrivial, and learning about the zwitterion structures in solution is important for the rational improvement of the crystallization process. Here, we present an NMR study of di-fluorinated FF (Phe(2-F)-Phe(2-F)) and mono-fluorinated FF isomers (Phe(2-F)-Phe and Phe-Phe(2-F)). The dipeptides were prepared by solid-phase synthesis and purified by high-performance liquid chromatography (HPLC). Their 1H and 13C NMR spectra were recorded in partially deuterated water (10% D2O), and two-dimensional (2D) NMR techniques were employed for signal assignments. The unambiguous assignments are reported of all chemical shifts for the aliphatic H and C atoms and of the C atoms of the carboxylate, the amide carbonyl, the CF carbons, and of every arene C atom in each phenyl ring. The dipeptides are trans amides and intramolecular hydrogen bonding between the ammonium group and the amide carbonyl restricts the H3N-CH-C(O) geometry. We explored the rotational profile of the diphenylalanines as a function of the τ = â (C-N-C-CO2) dihedral angle at the SMD(B3LYP/6-31G*) level without and with specific hydration and report the associated Karplus curves J(θ) vs θ = â (H-N-C-H). The rotational profiles show a maximum of three stationary structures, and relative conformer stabilities of the free diphenylalanines show that the conformation found in the crystal M1 is the least stable among the three, M3 > M2 â« M1. Specific water solvation makes all of the difference and adds a large competitive advantage to the water-bridged ion pair M1a. In fact, M1a becomes the most stable and dominant conformation for the parent diphenylalanine and mono1 F-FF and M1a becomes competitive with M3c for mono2 F-FF and di F-FF. Implications are discussed regarding the importance of the conformational preorganization of diphenylalanines in solution and the facility for their crystallization.
RESUMEN
Background: Malignant pleural mesothelioma (MPM) is a rare and intractable disease exhibiting a remarkable intratumoral heterogeneity and dismal prognosis. Although immunotherapy has reshaped the therapeutic strategies for MPM, patients react with discrepant responsiveness. Methods: Herein, we recruited 333 MPM patients from 5 various cohorts and developed an in-silico classification system using unsupervised Non-negative Matrix Factorization and Nearest Template Prediction algorithms. The genomic alterations, immune signatures, and patient outcomes were systemically analyzed across the external TCGA-MESO samples. Machine learning-based integrated methodology was applied to identify a gene classifier for clinical application. Results: The gene expression profiling-based classification algorithm identified immune-related subtypes for MPMs. In comparison with the non-immune subtype, we validated the existence of abundant immunocytes in the immune subtype. Immune-suppressed MPMs were enriched with stroma fraction, myeloid components, and immunosuppressive tumor-associated macrophages (TAMs) as well exhibited increased TGF-ß signature that informs worse clinical outcomes and reduced efficacy of anti-PD-1 treatment. The immune-activated MPMs harbored the highest lymphocyte infiltration, growing TCR and BCR diversity, and presented the pan-cancer immune phenotype of IFN-γ dominant, which confers these tumors with better drug response when undergoing immune checkpoint inhibitor (ICI) treatment. Genetically, BAP1 mutation was most commonly found in patients of immune-activated MPMs and was associated with a favorable outcome in a subtype-specific pattern. Finally, a robust 12-gene classifier was generated to classify MPMs with high accuracy, holding promise value in predicting patient survival. Conclusions: We demonstrate that the novel classification system can be exploited to guide the identification of diverse immune subtypes, providing critical biological insights into the mechanisms driving tumor heterogeneity and responsible for cancer-related patient prognoses.
RESUMEN
Glioma progression is accompanied with increased tumor tissue stiffness, yet the underlying mechanisms are unclear. Herein, we employed atomic force microscopy analysis to show that tissue stiffness was higher in isocitrate dehydrogenase (IDH)-wild type gliomas than IDH-mutant gliomas. Bioinformatic analyses revealed that tissue inhibitor of metalloproteinase-1 (TIMP1) was one of the preferentially upregulated genes in IDH-wild type gliomas as compared to IDH-mutant gliomas, and its higher expression indicated worse prognosis of glioma patients. TIMP1 intensity determined by immunofluorescence staining on glioma tissues positively correlated with glioma tissue stiffness. Mechanistically, TIMP1 expression was positively correlated with the gene expression of two predominant extracellular matrix components, tenascin C and fibronectin, both of which were also highly expressed in IDH-wild type gliomas. By introducing IDH1-R132H-containing vectors into human IDH1-wild type glioma cells to obtain an IDH1-mutant cell line, we found that IDH1 mutation increased the TIMP1 promoter methylation through methylation-specific PCR. More importantly, IDH1-R132H mutation decreased both the expression of TIMP1, fibronectin, tenascin C, and the tumor tissue stiffness in IDH1-mutant glioma xenografts in contrast to IDH1-wild type counterparts. Moreover, TIMP1 knockdown in IDH-wild type glioma cells inhibited the expression of tenascin C and fibronectin, and decreased tissue stiffness in intracranial glioma xenografts. Conclusively, we revealed an IDH mutation status-mediated mechanism in regulating glioma tissue stiffness through modulating TIMP1 and downstream extracellular matrix components.