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Environmental DNA (eDNA) metabarcoding is an emerging tool for monitoring biological communities in aquatic ecosystems. The selection of bioinformatic pipelines significantly impacts the results of biodiversity assessments. However, there is currently no consensus on the appropriate bioinformatic pipelines for fish community analysis in eDNA metabarcoding. In this study, we compared three bioinformatic pipelines (Uparse, DADA2, and UNOISE3) using real and mock (constructed with 15/30 known fish) communities to investigate the differences in biological interpretation during the data analysis process in eDNA metabarcoding. Performance evaluation and diversity analyses revealed that the choice of bioinformatic pipeline could impact the biological results of metabarcoding experiments. Among the three pipelines, the operational taxonomic units (OTU)-based pipeline (Uparse) showed the best performance (sensitivity: 0.6250 ± 0.0166; compositional similarity: 0.4000 ± 0.0571), the highest richness (25-102) and minimal inter-group differences in alpha diversity. It suggested the OTU-based pipeline possessed superior capability in fish diversity monitoring compared to ASV/ZOTU-based pipeline. Additionally, the Bray-Curtis distance matrix achieved the highest discriminative effect in the PCoA (43.3%-53.89%) and inter-group analysis (P < 0.01), indicating it was better at distinguishing compositional differences or specific genera of fish community at different sampling sites than other distance matrices. These findings provide new insights into fish community monitoring through eDNA metabarcoding in estuarine environments.
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The existence of potential pathogens may lead to severe water pollution, disease transmission, and the risk of infectious diseases, posing threats to the stability of aquatic ecosystems and human health. In-depth research on the dynamic of potential pathogenic communities is of significant importance, it can provide crucial support for assessing the health status of aquatic ecosystems, maintaining ecological balance, promoting sustainable economic development, and safeguarding human health. Nevertheless, the current understanding of the distribution and geographic patterns of potential pathogens in coastal ecosystems remains rather limited. Here, we investigated the diversity, assembly, and co-occurrence network of potential pathogenic communities in two anthropogenic coastal regions, i.e., the eight mouths (EPR) and nearshore region (NSE), of the Pearl River Estuary (PRE) and a total of 11 potential pathogenic types were detected. The composition and diversity of potential pathogenic communities exhibited noteworthy distinctions between the EPR and NSE, with 6 shared potential pathogenic families. Additionally, in the NSE, a significant pattern of geographic decay was observed, whereas in the EPR, the pattern of geographic decay was not significant. Based on the Stegen null model, it was noted that undominant processes (53.36%/69.24%) and heterogeneous selection (27.35%/25.19%) dominated the assembly of potential pathogenic communities in EPR and NSE. Co-occurrence network analysis showed higher number of nodes, a lower average path length and graph diameter, as well as higher level of negative co-occurrences and modularity in EPR than those in NSE, indicating more complex and stable correlations between potential pathogens in EPR. These findings lay the groundwork for the effective management of potential pathogens, offering essential information for ecosystem conservation and public health considerations in the anthropogenic coastal regions.
Subject(s)
Environmental Monitoring , Estuaries , Environmental Monitoring/methods , Urbanization , Rivers/chemistry , Rivers/microbiology , Ecosystem , China , Humans , Water Pollution/statistics & numerical data , Water MicrobiologyABSTRACT
Vitamin B12 is a group of biologically active cobalamin compounds. In this study, we investigated the inhibitory effects of methylcobalamin (MeCbl) and hydroxocobalamin acetate (OHCbl Acetate) on protein tyrosine phosphatase 1B (PTP1B). MeCbl and OHCbl Acetate exhibited an IC50 of approximately 58.390 ± 2.811 µM and 8.998 ± 0.587 µM, respectively. The Ki values of MeCbl and OHCbl Acetate were 25.01 µM and 4.04 µM respectively. To elucidate the inhibition mechanism, we conducted a 500 ns Gaussian accelerated molecular dynamics (GaMD) simulation. Utilizing PCA and tICA, we constructed Markov state models (MSM) to examine secondary structure changes during motion. Our findings revealed that the α-helix at residues 37-42 remained the most stable in the PTP1B-OHCbl Acetate system. Furthermore, upon binding of OHCbl Acetate or MeCbl, the WPD loop of PTP1B moved inward to the active pocket, forming a closed conformation and potentially obstructs substrate entry. Protein-ligand interaction analysis and MM-PBSA showed that OHCbl Acetate exhibited lower binding free energy and engaged in more residue interactions with PTP1B. In summary, our study confirmed the substantial inhibitory activity of OHCbl Acetate against PTP1B, with its inhibitory potency notably surpassing that of MeCbl. We demonstrated potential molecular mechanisms of OHCbl Acetate inhibiting PTP1B.
Subject(s)
Molecular Dynamics Simulation , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Vitamin B 12 , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Protein Tyrosine Phosphatase, Non-Receptor Type 1/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Vitamin B 12/chemistry , Vitamin B 12/analogs & derivatives , Vitamin B 12/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Molecular Docking Simulation , Protein Binding , Kinetics , Structure-Activity RelationshipABSTRACT
White organic light-emitting diodes (WOLEDs) hold vast prospects in the fields of next-generation displays and solid-state lighting. Ultrathin emitting layers (UEMLs) have become a research hotspot because of their unique advantage. On the basis of simplifying the device structure and preparation process, they can achieve electroluminescent performance comparable to that of doped devices. In this review, we first discuss the working principles and advantages of WOLEDs based on UEML architecture, which can achieve low cost and more flexibility by simplifying the device structure and preparation process. Subsequently, the successful applications of doping and non-doping technologies in fluorescent, phosphorescent, and hybrid WOLEDs combined with UEMLs are discussed, and the operation mechanisms of these WOLEDs are emphasized briefly. We firmly believe that this article will bring new hope for the development of UEML-based WOLEDs in the future.
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This publisher's note contains a correction to Opt. Lett.48, 5771 (2023)10.1364/OL.506371.
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Type 2 diabetes mellitus (T2DM) is marked by persistent hyperglycemia, insulin resistance, and pancreatic ß-cell dysfunction, imposing substantial health burdens and elevating the risk of systemic complications and cardiovascular diseases. While the pathogenesis of diabetes remains elusive, a cyclical relationship between insulin resistance and inflammation is acknowledged, wherein inflammation exacerbates insulin resistance, perpetuating a deleterious cycle. Consequently, anti-inflammatory interventions offer a therapeutic avenue for T2DM management. In this study, a herb called Baikal skullcap, renowned for its repertoire of bioactive compounds with anti-inflammatory potential, is posited as a promising source for novel T2DM therapeutic strategies. Our study probed the anti-diabetic properties of compounds from Baikal skullcap via network pharmacology, molecular docking, and cellular assays, concentrating on their dual modulatory effects on diabetes through Protein Tyrosine Phosphatase 1B (PTP1B) enzyme inhibition and anti-inflammatory actions. We identified the major compounds in Baikal skullcap using liquid chromatography-mass spectrometry (LC-MS), highlighting six flavonoids, including the well-studied baicalein, as potent inhibitors of PTP1B. Furthermore, cellular experiments revealed that baicalin and baicalein exhibited enhanced anti-inflammatory responses compared to the active constituents of licorice, a known anti-inflammatory agent in TCM. Our findings confirmed that baicalin and baicalein mitigate diabetes via two distinct pathways: PTP1B inhibition and anti-inflammatory effects. Additionally, we have identified six flavonoid molecules with substantial potential for drug development, thereby augmenting the T2DM pharmacotherapeutic arsenal and promoting the integration of herb-derived treatments into modern pharmacology.
Subject(s)
Diabetes Mellitus, Type 2 , Flavanones , Insulin Resistance , Scutellaria baicalensis , Diabetes Mellitus, Type 2/drug therapy , Liquid Chromatography-Mass Spectrometry , Chromatography, Liquid , Molecular Docking Simulation , Tandem Mass Spectrometry , Flavonoids/pharmacology , Inflammation , Anti-Inflammatory Agents/pharmacologyABSTRACT
Dipeptidyl peptidase 4 (DPP4) inhibitors can effectively inhibit the activity of DPP4, increasing the concentrations of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which allows for them to effectively contribute to the reduction of blood sugar levels. Leu-Pro-Ala-Val-Thr-Ile-Arg (LPAVTIR) and Leu-Pro-Pro-Glu-His-Asp-Trp-Arg (LPPEHDWR) were the two peptides with the strongest inhibitory activity against DPP4 selected from silkworm pupa proteins. In this study, four systems were established: Apo (ligand-free DPP4), IPI (IPI-bound DPP4), LPAVTIR (LPAVTIR-bound DPP4), LPPEHDWR (LPPEHDWR-bound DPP4), and Gaussian accelerated molecular dynamic (GaMD) simulation was conducted to investigate the mechanism of action of two inhibitory peptides binding to DPP4. Our study revealed that the LPAVTIR peptide possessed a more stable structure and exhibited a tighter binding to the Ser630 active site in DPP4, thus exhibiting a favorable competitive inhibition effect. In contrast, the LPPEHDWR peptide caused the horizontal α-helix (residues 201-215) composed of Glu205 and Glu206 residues in DPP4 to disappear. The spatial arrangement of active sites Ser630 relative to Glu205 and Glu206 was disrupted, resulting in enzyme inactivation. Moreover, the size of the substrate channel and cavity volume was significantly reduced after the binding of the inhibitory peptide to the protein, which was an important factor in the inhibition of the enzyme activity. A similar effect was also found from IPI (our positive control). By stabilizing the active site of DPP4, the IPI peptide induced the disappearance of the horizontal α-helix and a notable reduction in the active cavity volume. In conclusion, our study provided a solid theoretical foundation for the inhibitory mechanisms of IPI, LPAVTIR, and LPPEHDWR on DPP4, offering valuable insights for advancing the development of drug targets for type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Humans , Dipeptidyl Peptidase 4 , Molecular Dynamics Simulation , Peptides/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/pharmacologyABSTRACT
A bimolecular excited system is considered as a promising candidate for developing white organic light-emitting diodes (WOLEDs) with reduced phosphorescent components. However, for actualizing high-performance WOLED, little attention has been paid to electromers compared to exciplexes. Herein, we construct the bimolecular excited system to prepare fluorescent WOLEDs by combining the electromer emission with the exciplex emission, achieving a maximum power efficiency of 11.8â lm/W with a color rendering index (CRI) of over 80. Furthermore, phosphorescent dopants are doped into an exciplex host to construct hybrid WOLEDs. The fabricated complementary-color and three-color devices achieve maximum efficiencies of 55.3â cd/A (46.8â lm/W) and 34.1â cd/A (26.8â lm/W), respectively. The spectral coverages of WOLEDs are broadened by the bimolecular excited system, and CRIs are further improved at high luminance. Our strategy may bring light to the future development of highly efficient WOLEDs with economy and sustainability.
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Interfacial exciplex has recently been adopted as an effective host to achieve phosphorescent organic light-emitting diodes (OLEDs) with high efficiencies and low driving voltages. However, a systematic understanding of exciton recombination behavior in either host of interfacial exciplex is still deficient. Herein, the strategic design rule of interfacial exciplex host is proposed to overcome the negative effects of direct trapping recombination by systematically investigating exciton recombination behavior in interfacial exciplex hosts. As a result, blue and orange phosphorescent devices acquire peak external quantum efficiencies of 23.5% and 29.2% with low turn-on voltages. These results provide a simple method to realize highly efficient OLEDs aiming for general lighting and display applications.
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Immunotherapy is considered a major breakthrough in the treatment of small cell lung cancer (SCLC), although its anti-tumor efficacy is limited. With a high degree of malignancy and high heterogeneity, SCLC is difficult to treat in the clinic. A new combination strategy is urgently needed to further improve the efficacy of immunotherapy in patients with SCLC. By immunofluorescence, 100 SCLC patients in a local cohort were classified into the SCLC-A (high ASCL1 expression; n = 36), SCLC-N (high NEUROD1 expression; n = 32), SCLC-P (high POU2F3 expression; n = 14), and SCLC-Y (high YAP1 expression; n = 18) subtypes. Each SCLC molecular subtype represented different prognoses, tumor microenvironment traits, and immunotherapy sensitivities. Analysis of both the local and public cohorts suggested that the SCLC-Y subtype exhibited the worst clinical outcome (p < 0.05) when compared with other subtypes. SCLC with high YAP1 expression was characterized by high PD-L1 expression, high stromal score, T-cell functional impairment, and a close relationship with immune-related pathways. YAP1 upregulated PD-L1 expression and suppressed T cell activation, thus leading to immune evasion. In in vitro experiments, blockade of YAP1 promoted cancer cell apoptosis, immune cell proliferation, T-cell activation, and cytotoxic T-cell infiltration, thus further potentiating the efficacy of immunotherapy in patients with the SCLC-Y subtype.
Subject(s)
Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Small Cell Lung Carcinoma/genetics , B7-H1 Antigen , Immunosuppression Therapy , Immunotherapy , Lung Neoplasms/genetics , Tumor MicroenvironmentABSTRACT
To comprehensively elucidate the ecology of the bacterial community and antibiotic resistance genes (ARGs) in urbanised coastal ecosystems, this study investigated the variations of bacterial community and five common types of ARGs, the impacting factors and assembly of bacterial community, as well as their co-occurrence relationships in two ecosystems of the Pearl River Estuary (PRE). The bacterial community composition and structure of the nearshore ecosystem (NSE) and the eight mouths of the PRE (EPR) markedly differed, with 38 phyla shared between these two ecosystems. The abundances of 10 ARGs and bacterial community diversity were significantly higher in the EPR than NSE. Moreover, 67.82% and 27.82% of the variation in the bacterial community was explained by spatial (44.42%/8.63%) and environmental (23.40%/19.19%) variables in the NSE and EPR, respectively. Significant distance-decay patterns were observed, and distinct stochastic processes (undominated processes or dispersal limitation) dominated bacterial community assembly in the NSE and EPR. Furthermore, co-occurrence patterns showed significant positive correlations between 48/182 ASVs belonging to 6/15 bacterial phyla and 8/11 ARGs in the NSE/EPR, with six common dominant hosts. These results clarify the drivers and mechanism shaping the bacterial community, providing further proof for potential ARG bacterial hosts in urbanised estuarine ecosystems.
Subject(s)
Anti-Bacterial Agents , Ecosystem , Anti-Bacterial Agents/pharmacology , Genes, Bacterial , Rivers/microbiology , Estuaries , Bacteria/genetics , Drug Resistance, Microbial/genetics , ChinaABSTRACT
Introduction: Immune checkpoint inhibitors (ICIs) have demonstrated promising efficacy as monotherapy in patients with pulmonary sarcomatoid carcinoma (PSC). We performed the current multi-institutional, real-world study to assess the efficacy of ICIs plus chemotherapy in patients with PSC. Methods: All consecutive patients with locally advanced or metastatic PSC from three centers treated with ICIs between January 2018 and July 2021 were enrolled. Programmed death ligand 1 (PD-L1) expression was stained and evaluated using immunohistochemical with 22C3. Single-cell RNA sequencing (scRNA-seq) was performed in two patients with PSC and two patients with adenocarcinoma to understand the cell-type-specific transcriptome landscape of cancer cells and tumor microenvironment (TME) of PSC. Results: A cohort of 42 PSC patients was identified. In the overall population, the objective response rate (ORR) was 73.8%, median progression-free survival (mPFS) was 10.3 months and median overall survival was not reached and 2-year survival rate was 51.2%. For 34 treatment-naïve patients who received first-line ICIs plus chemotherapy, the ORR was 70.6%, mPFS was 10.3 months and 2-year survival rate was 57.8%. In patients with PD-L1 tumor proportion score (TPS) < 1%, 1-49%, and ⩾50%, the ORR was 33.3%, 72.7%, and 85.7% and mPFS was 6.0, 6.7, and 10.3 months, respectively. Notably, two patients with transformed PSC from lung adenocarcinoma after epidermal growth factor receptor-tyrosine kinase inhibitor treatment also responded well to ICIs plus chemotherapy. scRNA-seq revealed immune-cell-inflamed TME, lower intratumoral heterogeneity, and activated immune response pathway in PSC. Conclusions: Our study demonstrated remarkable efficacy of ICIs plus chemotherapy as first-line therapy for patient with locally advanced or metastatic PSC.
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Objective: The aim of the study is to investigate the potential role of keratoconus (KC) in the diagnosis of keratoconus (KC). Methods: GSE151631 and GSE77938 were downloaded from the comprehensive gene expression database (GEO). By using the random forest model (RF), support vector machine model (SVM), and generalized linear model (GLM), important immune-related genes were identified as biomarkers for KC diagnosis. Results: Through the LASSO, RFE, and RF algorithms and comparing the three sets of DEGs, a total of 8 overlapping DEGs were obtained. We took 8 DEGs as the final optimal combination of DEGs: AREG, BBC3, DUSP2, map3k8, Smad7, CDKN1A, JUN, and LIF. Conclusion: Abnormal cell proliferation, apoptosis, and autophagy defects are related to KC, which may be the etiology and potential target of KC.
Subject(s)
Keratoconus , Algorithms , Biomarkers , Humans , Keratoconus/diagnosis , Keratoconus/genetics , Linear Models , Support Vector MachineABSTRACT
The role of government support in sustainable urban development has always been a research topic of scholars, but research focusing on the relationship between government innovation support and urban green sustainable development is still relatively rare. This article uses China's innovative city pilot policy (ICPP) to represent the innovation support provided by the government and address the interaction mechanism and the spatial spillover effect of China's innovative city pilot policy (ICPP), green technology innovation (GTI), and green sustainable development performance (GSDP) with the support of the mediating effect model and the spatial econometric model. Based on panel data of 24 cities in the Yangtze River Delta urban agglomeration from 2001 to 2020, this paper establishes an evaluation index system of green sustainable development performance (GSDP), measuring with the SBM directional distance function based on the undesired output. This paper adopts the spatial difference-in-difference model (SDID) to study the impact mechanism of the ICPP on the GSDP in the Yangtze River Delta. The results show that (i) there is a positive spatial spillover effect of GSDP in the urban agglomeration of the Yangtze River Delta urban agglomeration; (ii) ICPP has a significantly positive effect on GSDP, as verified by several robustness checks; (iii) green technology innovation plays a partial mediating effect in the relationship of the ICPP and GSDP.
Subject(s)
Sustainable Development , Urbanization , China , Cities , Economic Development , Government , RiversABSTRACT
Background: The hemoglobin (Hgb)/red cell distribution width (RDW) ratio (HRR) is a simple prognostic marker for small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), but no data are available for pulmonary large cell neuroendocrine carcinoma (PLCNEC). This study aimed to assess the potential prognostic role of preoperative HRR in PLCNEC. Methods: This single-center retrospective study included patients with PLCNEC who underwent surgery at Shanghai Pulmonary Hospital from January 2012 to August 2016. The follow-up was censored in August 2020. The participants were grouped as low/high HRR according to their optimal value calculated using a receiver operating characteristic (ROC) curve. Univariable and multivariable Cox analysis were performed to identify the risk factors for overall survival (OS). Results: A total of 80 patients with PLCNEC were included. The optimal cutoff values were 0.969 for HRR. Compared with the high HRR group, the low HRR group had a lower mean Hgb (12.1 vs. 14.1 g/dL, P<0.001), lower mean albumin-globulin ratio (AGR) (1.4 vs. 1.6, P=0.017), and higher median RDW (14.5% vs. 12.9%, P<0.001). The median OS was 30.0 months [95% confidence interval (CI): 13.4 to 46.5 months]. Participants in the low HRR group exhibited a poorer OS than those with high HRR (20.3 months, 95% CI: 14.5 to 26.1 months vs. not reached, P<0.001). The multivariable analysis showed that low HRR was significantly associated with poor OS [hazard ratio (HR) =3.16, 95% CI: 1.69 to 5.93, P<0.001]. Conclusions: Low HRR is associated with poor OS in patients with PLCNEC and can be used as an inexpensive prognostic factor in patients undergoing PLCNEC resection.
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The interface exciplex system is a promising technology for reaching organic light-emitting diodes (OLEDs) with low turn-on voltages, high efficiencies and long lifetimes due to its unique virtue of barrier-free charge transport, well-confined recombination region, and thermally activated delayed fluorescence characteristics. In this review, we firstly illustrate the mechanism frameworks and superiorities of the interface exciplex system. We then summarize the primary applications of interface exciplex systems fabricated by doping and doping-free technologies. The operation mechanisms of these OLEDs are emphasized briefly. In addition, various novel strategies for further improving the performances of interface exciplex-based devices are demonstrated. We believe this review will give a promising perspective and attract researchers to further develop this technology in the future.
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Lung cancer is the top reason for cancer-related deaths worldwide. The 5-year overall survival rate of lung cancer is approximately 20 % due to the delayed diagnosis and low response rate to regular treatments. Microbiota, both host-microbiota and alien pathogenic microbiota, have been investigated to be involved in a complicated and contradictory relationship with lung cancer initiation, treatments, and prognosis. Disorders of certain host-microbiota and pathogen infection are associated with the risk of lung cancers based on epidemiological evidence, and antibiotics (ATBs) could dramatically impair anti-cancer treatment efficacy, including chemotherapy and immunotherapy. Moreover, probiotics and microbe-mediated drugs are potential approaches to enhance regular anti-tumor treatments. Therefore, the knowledge of the complex dual effect of microbes on lung cancer is beneficial to take their essence and remove their dross. This review offers insight into the current trends and advancements in microbiota or microbial components related to lung cancer.
Subject(s)
Lung Neoplasms , Microbiota , Probiotics , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/etiology , Immunotherapy , Probiotics/therapeutic use , PrognosisABSTRACT
DNA damage response and repair (DDR) gene alterations increase tumor-infiltrating lymphocytes, genomic instability, and tumor mutational burden (TMB). Whether DDR-related alterations relate to therapeutic response and prognosis in lung cancer lacking oncogenic drivers remains unknown. Pretherapeutic cancer samples of 122 patients [86 non-small cell lung cancer and 36 small cell lung cancer (SCLC)] harboring no EGFR/ALK alterations were collected. Through whole-exome sequencing, we outlined DDR mutational landscape and determined relationships between DDR gene alterations and TMB or intratumoral heterogeneity. Then, we evaluated the impacts of DDR gene alterations on therapeutic response and prognosis and established a DDR-based model for prognosis prediction. In addition, we investigated somatic interactions of DDR genes and immunomodulatory genes, immune expression patterns, immune microenvironment, and immune infiltration characteristics between DDR-deficient and DDR-proficient samples. Samples from cBioportal datasets were utilized for verification. We found that deleterious DDR gene alterations were closely associated with higher TMB than proficient-types (p < 0.001). DDR mechanisms attach great importance to the determination of patients' prognosis after chemotherapy, and alterations of base excision repair pathway in adenocarcinoma, nucleotide excision repair in squamous carcinoma, and homologous recombination pathway in SCLC tend to associate with worse progression-free survival to first-line chemotherapy (all p < 0.05). A predictive nomogram model was constructed incorporating DDR-related alterations, clinical stage, and smoking status, with the area under curve values of 0.692-0.789 for 1- and 2-year receiver operating characteristic curves in training and testing cohorts. Furthermore, DDR-altered tumors contained enhanced frequencies of alterations in various genes of human leukocyte antigen (HLA) class I pathway including TAP1 and TAP2 than DDR-proficient samples. DDR-deficient types had lower expressions of STING1 (p = 0.01), CD28 (p = 0.020), HLA-DRB6 (p = 0.014) in adenocarcinoma, lower TNFRSF4 (p = 0.017), and TGFB1 expressions (p = 0.033) in squamous carcinoma, and higher CD40 (p = 0.012) and TNFRSF14 expressions (p = 0.022) in SCLC. DDR alteration enhanced activated mast cells in adenocarcinoma (p = 0.044) and M2 macrophage in squamous carcinoma (p = 0.004) than DDR-proficient types. Collectively, DDR gene alterations in lung cancer without oncogenic drivers are positively associated with high TMB. Specific DDR gene alterations tend to associate with worse progression-free survival to initial chemotherapy.
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OBJECTIVE: To accurately evaluate tumor heterogeneity, make multidimensional diagnosis according to the causes and phenotypes of tumor heterogeneity, and assist in the individualized treatment of tumors. BACKGROUND: Tumor heterogeneity is one of the most essential characteristics of malignant tumors. In tumor recurrence, development, and evolution, tumor heterogeneity can lead to the formation of different cell groups with other molecular characteristics. Tumor heterogeneity can be characterized by the uneven distribution of tumor cell subsets of other genes between and within the disease site (spatial heterogeneity) or the time change of cancer cell molecular composition (temporal heterogeneity). The discovery of tumor targeting drugs has dramatically promoted tumor therapy. However, the existence of heterogeneity seriously affects the effect of tumor treatment and the prognosis of patients. METHODS: The literature discussing tumor heterogeneity and its resistance to tumor therapy was broadly searched to analyze tumor heterogeneity as well as the challenges and solutions for gene detection and tumor drug therapy. CONCLUSIONS: Tumor heterogeneity is affected by many factors consist of internal cell factors and cell microenvironment. Tumor heterogeneity greatly hinders effective and individualized tumor treatment. Understanding the fickle of tumors in multiple dimensions and flexibly using a variety of detection methods to capture the changes of tumors can help to improve the design of diagnosis and treatment plans for cancer and benefit millions of patients.
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BACKGROUND: Interventional bronchoscopy exhibits substantial effects for patients with malignant airway obstruction (MAO), while little information is available regarding the potential prognostic factors for these patients. METHODS: Between October 31, 2016, and July 31, 2019, a total of 150 patients undergoing interventional bronchoscopy and histologically-confirmed MAO were collected, in which 112 eligible participants formed the cohort for survival study. External validation cohort from another independent institution comprised 33 MAO patients with therapeutic bronchoscopy. The least absolute shrinkage and selection operator regression (LASSO) was applied to the model development dataset for selecting features correlated with MAO survival for inclusion in the Cox regression from which we elaborated the risk score system. A nomogram algorithm was also utilized. RESULTS: In our study, we observed a significant decline of stenosis rate after interventional bronchoscopy from 71.7%±2.1% to 36.6%±2.7% (P<0.001) and interventional bronchoscopy dilated airway effectively. Patients in our study undergoing interventional bronchoscopy had a median survival time of 614.000 days (95% CI: 269.876-958.124). Patients receiving distinct therapeutic methods of interventional bronchoscopy had different prognosis (P=0.022), and patients receiving treatment of electrocoagulation in combination with stenting and electrosurgical snare had worse survival than those receiving other options. Multivariate Cox analysis revealed that nonsmoking status, adenoid cystic carcinoma, and low preoperative stenosis length, as independent predictive factors for better overall survival (OS) of MAO patients. Then, the nomogram based on Cox regression and risk score system based on results from LASSO regression were elaborated respectively. Importantly, this risk score system was proved to have better performance than the nomogram and other single biomarkers such as traditional staging system (area under the curve 0.855 vs. 0.392-0.739). Survival curves showed that patients with the higher risk-score had poorer prognosis than those with lower risk-score (third quantile of OS: 126.000 days, 95% CI: 73.588-178.412 vs. 532.000 days, 95% CI: 0.000-1,110.372; P<0.001). CONCLUSIONS: Nonsmoking status, adenoid cystic carcinoma, and low preoperative stenosis length, were independent predictive factors for better OS of MAO patients. We proposed a nomogram and risk score system for survival prediction of MAO patients undergoing interventional bronchoscopy with good performance.