Exogenous putrescine plays a switch-like influence on the pH stress adaptability of biofilm-based activated sludge.

Microbial community adaptability to pH stress plays a crucial role in biofilm formation. This study aims to investigate the regulatory mechanisms of exogenous putrescine on pH stress, as well as enhance understanding and application for the technical measures and molecular mechanisms of biofilm regulation. Findings demonstrated that exogenous putrescine acted as a switch-like distributor affecting microorganism pH stress, thus promoting biofilm formation under acid conditions while inhibiting it under alkaline conditions. As pH decreases, the protonation degree of putrescine increases, making putrescine more readily adsorbed. Protonated exogenous putrescine could increase cell membrane permeability, facilitating its entry into the cell. Subsequently, putrescine consumed intracellular H+ by enhancing the glutamate-based acid resistance strategy and the γ-aminobutyric acid metabolic pathway to reduce acid stress on cells. Furthermore, putrescine stimulated ATPase expression, allowing for better utilization of energy in H+ transmembrane transport and enhancing oxidative phosphorylation activity. However, putrescine protonation was limited under alkaline conditions, and the intracellular H+ consumption further exacerbated alkali stress and inhibits cellular metabolic activity. Exogenous putrescine promoted the proportion of fungi and acidophilic bacteria under acidic stress and alkaliphilic bacteria under alkali stress while having a limited impact on fungi in alkaline biofilms. Increasing Bdellovibrio under alkali conditions with putrescine further aggravated the biofilm decomposition. This research shed light on the unclear relationship between exogenous putrescine, environmental pH, and pH stress adaptability of biofilm. By judiciously employing putrescine, biofilm formation could be controlled to meet the needs of engineering applications with different characteristics.IMPORTANCEThe objective of this study is to unravel the regulatory mechanism by which exogenous putrescine influences biofilm pH stress adaptability and understand the role of environmental pH in this intricate process. Our findings revealed that exogenous putrescine functioned as a switch-like distributor affecting the pH stress adaptability of biofilm-based activated sludge, which promoted energy utilization for growth and reproduction processes under acidic conditions while limiting biofilm development to conserve energy under alkaline conditions. This study not only clarified the previously ambiguous relationship between exogenous putrescine, environmental pH, and biofilm pH stress adaptability but also offered fresh insights into enhancing biofilm stability within extreme environments. Through the modulation of energy utilization, exerting control over biofilm growth and achieving more effective engineering goals could be possible.

The causality between systemic inflammatory regulators and chronic respiratory diseases: A bidirectional Mendelian-randomization study.

INTRODUCTION: Accumulative evidence suggests the associations between systemic inflammatory regulators and chronic respiratory diseases (CRDs). However, the intrinsic causation remains implicit. Therefore, this study aimed to examine causative associations by mendelian randomization (MR) and to identify valuable active factors. METHODS: Based on data from the GWAS database, we performed MR analyses of 41 serum cytokines from 8,293 Finnish and European descent cohorts from GBMI and UKBB for five major CRDs. We mainly applied inverse variance weighted regression, supplemented by MR-Egger regression, weighted median, maximum likelihood, weighted mode, and simple mode algorithms. Moreover, sensitivity analyses were conducted using Cochrane's Q test, MR-Egger intercept, MR-PRESSO Global test and MR-Steiger filtering. Eventually, the consistency of MR results was assessed by leave-one-out. RESULTS: Our results suggest that 12 genetically predicted systemic inflammatory regulators probably participate in the progression of CRDs, including four risk factors (IL-1RA, IL-4, MIP-1A, PDGF-BB) and one protective factor (IL-6) in IPF, two protective factors (SCF, SDF-1A) in COPD, and two protective factors (SCF, SDF-1A) in asthma, two protective factors (GROA, IL-2RA) were also included in asthma, whereas only one factor (HGF) was protective against bronchiectasis. Additionally, two protective factors (FGF-BASIC, G-CSF) were identified in sarcoidosis. Sensitivity analyses showed no horizontal pleiotropy and significant heterogeneity. Finally, based on the findings of inverse MR analysis, no inverse causal association was uncovered, confirming the robustness of results. CONCLUSION: Our study unearths potential associations between systemic inflammatory modulators and common CRDs, providing new insights for inflammation-mediated CRD prevention and therapeutic approaches.

Exploring the causal relationship between immune cells and idiopathic pulmonary fibrosis: a bi-directional Mendelian randomization study.

BACKGROUND: The potential pathogenic mechanism of idiopathic pulmonary fibrosis is widely recognized to involve immune dysregulation. However, the current pool of studies has yet to establish a unanimous agreement regarding the correlation between various types of immune cells and IPF. METHODS: By conducting a two-sample Mendelian randomization analysis using publicly available genetic data, the study examined the causal relationship between IPF and 731 immune cells. To ensure the reliability of the results, combined sensitivity analyses and inverse Mendelian analyses were conducted. Moreover, within subgroups, multivariate Mendelian randomization analyses were utilized to investigate the autonomous causal connection between immune cell characteristics and IPF. RESULTS: After adjusting for false discovery rate, it was discovered that 20 immunophenotypes exhibited a significant association with IPF. After subgrouping for multivariate Mendelian randomization analysis, there were six immunophenotypes that remained significantly associated with IPF. These included CD33 + HLA DR + CD14dim (OR = 0.96, 95% CI 0.93-0.99, P = 0.033), HLA DR + NK (OR = 0.92, 95% CI 0.85-0.98, P = 0.017), CD39 + CD8 + T cell %T cell (OR = 0.93, 95% CI 0.88-0.99, P = 0.024), CD3 on activated & secreting Treg (OR = 0.91, 95% CI 0.84-0.98, P = 0.026), PDL-1 on CD14- CD16 + monocyte (OR = 0.89, 95% CI 0.84-0.95, P = 8 × 10-4), and CD45 on CD33 + HLA DR + CD14- (OR = 1.08, 95% CI 1.01-1.15, P = 0.011). CONCLUSION: Our study reveals a noteworthy association between IPF and various immune cells, providing valuable insights for clinical research and aiding the advancement of immunologically-based therapeutic strategies.

Unlocking the NIR-II AIEgen for High Brightness through Intramolecular Electrostatic Locking.

Fluorescent imaging and biosensing in the near-infrared-II (NIR-II) window holds great promise for non-invasive, radiation-free, and rapid-response clinical diagnosis. However, it's still challenging to develop bright NIR-II fluorophores. In this study, we report a new strategy to enhance the brightness of NIR-II aggregation-induced emission (AIE) fluorophores through intramolecular electrostatic locking. By introducing sulfur atoms into the side chains of the thiophene bridge in TSEH molecule, the molecular motion of the conjugated backbone can be locked through intramolecular interactions between the sulfur and nitrogen atoms. This leads to enhanced NIR-II fluorescent emission of TSEH in both solution and aggregation states. Notably, the encapsulated nanoparticles (NPs) of TSEH show enhanced brightness, which is 2.6-fold higher than TEH NPs with alkyl side chains. The in vivo experiments reveal the feasibility of TSEH NPs in vascular and tumor imaging with a high signal-to-background ratio and precise resection for tiny tumors. In addition, polystyrene nanospheres encapsulated with TSEH are utilized for antigen detection in lateral flow assays, showing a signal-to-noise ratio 1.9-fold higher than the TEH counterpart in detecting low-concentration antigens. This work highlights the potential for developing bright NIR-II fluorophores through intramolecular electrostatic locking and their potential applications in clinical diagnosis and biomedical research.

Stable, Bright, and Long-Fluorescence-Lifetime Dyes for Deep-Near-Infrared Bioimaging.

Near-infrared (NIR) fluorophores absorbing maximally in the region beyond 800 nm, i.e., deep-NIR spectral region, are actively sought for biomedical applications. Ideal dyes are bright, nontoxic, photostable, biocompatible, and easily derivatized to introduce functionalities (e.g., for bioconjugation or aqueous solubility). The rational design of such fluorophores remains a major challenge. Silicon-substituted rhodamines have been successful for bioimaging applications in the red spectral region. The longer-wavelength silicon-substituted congeners for the deep-NIR spectral region are unknown to date. We successfully prepared four silicon-substituted bis-benzannulated rhodamine dyes (ESi5a-ESi5d), with an efficient five-step cascade on a gram-scale. Because of the extensive overlapping of their HOMO-LUMO orbitals, ESi5a-ESi5d are highly absorbing (λabs ≈ 865 nm and ε > 105 cm-1 M-1). By restraining both the rotational freedom via annulation and the vibrational freedom via silicon-imparted strain, the fluorochromic scaffold of ESi5 is highly rigid, resulting in an unusually long fluorescence lifetime (τ > 700 ps in CH2Cl2) and a high fluorescence quantum yield (ϕ = 0.14 in CH2Cl2). Their half-lives toward photobleaching are 2 orders of magnitude longer than the current standard (ICG in serum). They are stable in the presence of biorelevant concentration of nucleophiles or reactive oxygen species. They are minimally toxic and readily metabolized. Upon tail vein injection of ESi5a (as an example), the vasculature of a nude mouse was imaged with a high signal-to-background ratio. ESi5 dyes have broad potentials for bioimaging in the deep-NIR spectral region.

HLA class II molecule HLA-DRA identifies immuno-hot tumors and predicts the therapeutic response to anti-PD-1 immunotherapy in NSCLC.

BACKGROUND: Immune checkpoint blockade (ICB) only works well for a certain subset of patients with non-small cell lung cancer (NSCLC). Therefore, biomarkers for patient stratification are desired, which can suggest the most beneficial treatment. METHODS: In this study, three datasets (GSE126044, GSE135222, and GSE136961) of immunotherapy from the Gene Expression Omnibus (GEO) database were analyzed, and seven intersected candidates were extracted as potential biomarkers for ICB followed by validation with The Cancer Genome Atlas (TCGA) dataset and the in-house cohort data. RESULTS: Among these candidates, we found that human leukocyte antigen-DR alpha (HLA-DRA) was downregulated in NSCLC tissues and both tumor and immune cells expressed HLA-DRA. In addition, HLA-DRA was associated with an inflamed tumor microenvironment (TME) and could predict the response to ICB in NSCLC. Moreover, we validated the predictive value of HLA-DRA in immunotherapy using an in-house cohort. Furthermore, HLA-DRA was related to the features of inflamed TME in not only NSCLC but also in most cancer types. CONCLUSION: Overall, HLA-DRA could be a promising biomarker for guiding ICB in NSCLC.

Rapid detection of airborne protein from Mycobacterium tuberculosis using a biosensor detection system.

Tuberculosis (TB), caused by infection with airborne Mycobacterium tuberculosis (MTB), seriously threatens human health and has become a public health problem of worldwide concern. To achieve effective control of TB, rapid and sensitive detection of MTB is particularly important. At present, the common detection methods for MTB cannot meet the requirements of speed, flexibility and portability simultaneously. In this work, a multichannel microfluidic chip was developed and packaged with an ultra-sensitive silicon nanowire field-effect-transistor biosensor. The fluid system was tested and optimized through simulation, and the best conditions were determined: the flow rate was 0.3 mL min-1 and the flow direction was perpendicular to a silicon nanowire. A one-way valve, a switching valve and a peristaltic pump were combined to establish a biosensor detection system to realize the automatic detection of TB samples. Then we systematically explained the factors affecting simulated exhaled breath condensate (SEBC) collection, and established and optimized the method for collection of SEBC from the perspective of collection volume and biological activity. The best collection conditions were determined for a 5 mm pipe diameter at 0 °C, and a sufficient sample volume was obtained in only 2 minutes for microfluidic detection. Then, the actual application value of the established collection method was further evaluated. Volunteers were recruited and this method was used to collect their exhaled breath condensate to analyze the collection effect. The system detected MTB in SEBC with good sensitivity (∼4 × 104 particles per mL). It is expected to be further integrated and miniaturized in the future to realize point-of-care testing.

Ultrafast Förster resonance energy transfer between tyrosine and tryptophan: potential contributions to protein-water dynamics measurements.

Ultrafast Förster Resonance Energy Transfer (FRET) between Tyrosine (Tyr, Y) and Tryptophan (Trp, W) in the model peptides Trp-(Pro)n-Tyr (WPnY) has been investigated using a femtosecond up-conversion spectrophotofluorometer. The ultrafast energy transfer process (<100 ps) in short peptides (WY, WPY and WP2Y) has been resolved. In fact, this FRET rate is found to be mixed with the rates of solvent relaxation (SR), ultrafast population decay (QSSQ) and other lifetime components. To further dissect and analyze the FRET, a spectral working model is constructed, and the contribution of a FRET lifetime is separated by reconciling the shapes of decay associated spectra (DAS). Surprisingly, FRET efficiency did not decrease monotonically with the growth of the peptide chain (as expected) but increased first and then decreased. The highest FRET efficiency occurred in peptide WPY. The kinetic results have been accompanied with molecular dynamics simulations that reconcile and explain this strange phenomenon: due to the strong interaction between amino acids, the distance between the donor and receptor in peptide WPY is actually closest, resulting in the fastest FRET. In addition, the FRET lifetimes (τcal) were estimated within the molecular dynamics simulations, and they were consistent with the lifetimes (τexp) separated out by the experimental measurements and the DAS working model. This benchmark study has implications for both previous and future studies of protein ultrafast dynamics. The approach taken can be generalized for the study of proximate tyrosine and tryptophan in proteins and it suggests spectral strategies for extracting mixed rates in other complex FRET problems.

Thermally activated delayed fluorescence emitters with dual conformations for white organic light-emitting diodes: mechanism and molecular design.

Thermally activated delayed fluorescence (TADF) molecules with dual emission have great potential for use as single emitters in white organic light-emitting diodes (WOLEDs). In this paper, the light-emitting mechanisms of PTZ-TTR and PTZ-Ph-TTR with blue-orange dual emission are studied systematically. The near-planar and near-orthogonal conformations are responsible for the blue and orange emission, respectively. For PTZ-TTR, the near-orthogonal conformation is only generated by the transformation from the near-planar conformation, while the near-orthogonal conformation of PTZ-Ph-TTR can be generated by both excitation and transformation. This results in relatively strong orange emission in PTZ-Ph-TTR. In addition, the TADF mechanism is investigated, and two up-conversion pathways are revealed for both molecules. Based on the comparison of the photophysical properties of PTZ-TTR in toluene and the aggregation state, we find that aggregation could induce a smaller energy gap between the first singlet excited state and the first triplet excited state. Besides, the substitution effect of donors on light-emitting properties is studied, and the design rules for emitters with dual conformations and compensatory emission are proposed. Our theoretical results would favor the understanding of the light-emitting mechanism as well as the design of new-type TADF emitters for WOLEDs.

Stochastic processes shape microbial community assembly in biofilters: Hidden role of rare taxa.

Stochastic and deterministic processes are the major themes governing microbial community assembly; however, their roles in bioreactors are poorly understood. Herein, the mechanisms underlying microbial assembly and the effect of rare taxa were studied in biofilters. Phylogenetic tree analysis revealed differences in microbial communities at various stages. Null model analysis showed that stochastic processes shaped the community assembly, and deterministic processes emerged only in the inoculated activated sludge after domestication. This finding indicates the dominant role of stochastic factors (biofilm formation, accumulation, and aging). The Sloan neutral model corroborated the advantages of stochastic processes and mainly attributed these advantages to rare taxa. Cooccurrence networks revealed the importance of rare taxa, which accounted for more than 85% of the keystones. Overall, these results provide good foundations for understanding community assembly, especially the role of rare taxa, and offer theoretical support for future community design and reactor regulation.

The diagnostic potential role of thioredoxin reductase and TXNRD1 in early lung adenocarcinoma: A cohort study.

Background: Lung adenocarcinoma (LUAD) is the primary form of lung cancer, yet the reliable biomarkers for early diagnosis remain insufficient. Thioredoxin reductase (TrxR) is strongly linked to the occurrence, development, and drug resistance of lung cancer, making it a potential biomarker. However, further research is required to assess its diagnostic value in LUAD. Methods: A retrospective analysis was performed on patients who underwent pulmonary nodule resection at our center from 2018 to 2022. Clinical data, including preoperative TrxR levels, imaging, and laboratory characteristics, were identified as study variables. Two prediction models were constructed using multiple logistic regression, and their prediction performance was evaluated comprehensively. Besides, bioinformatics analyses of TrxR coding genes including differential expression, functional enrichment, immune infiltration, drug sensitivity, and single-cell landscape were performed based on TCGA database, which were subsequently validated by Human Protein Atlas. Results: A total of 506 eligible patients (72 benign lesions, 77 AISs, 185 MIAs and 172 IACs) were identified in the clinical cohort. Two TrxR-based models were developed, which were able to distinguish between benign and malignant pulmonary nodules, as well as pathological subtypes of LUAD, respectively. The models exhibited good predictive ability with all AUC values ranging from 0.7 to 0.9. Based on calibration curves and clinical decision analysis, the nomogram models showed high reliability. Functional analysis indicated that TXNRD1 primarily participated in cell cycle and lipid metabolism. Immune infiltration analysis showed that TXNRD1 has a strong association with immune cells and could impact immunotherapy. Then, we identified small molecular compounds that inhibit TXNRD1 and confirmed TXNRD1 expression by single-cell landscape and immunohistochemistry. Conclusion: This study validated the diagnostic value of TrxR and TXNRD1 in clinical cohorts and transcriptional data, respectively. TrxR and TXNRD1 could be used in the risk diagnosis of early LUAD and facilitate personalized treatment strategies.

Alterations in the immune landscape characterized by inflammatory activation and immune escape within 12 h after trauma.

BACKGROUND: Trauma is statistically a significant cause of mortality among patients across countries. Nevertheless, the precise correlation between genetic diagnostic markers and the intricate mechanism of trauma remains indistinct. METHODS: Our study exclusively centered on trauma patients and selected three trauma-related datasets from the Gene Expression Omnibus (GEO) database, all of which had blood samples collected within post-traumatic 12 h. Differential gene screening, the WGCNA and Cytoscape software were employed to analyze the two datasets, with a particular emphasis on the top 100 genes selected based on MCC algorithm scores. A logistic diagnostic model was constructed by analyzing the intersection genes in the third dataset, leading to the identification of diagnostic biomarkers with high efficiency. The global immune landscape of these patients was extensively investigated using a multidimensional approach. Meanwhile, the underlying pathological and physiological mechanisms associated with early trauma status are summarized by integrating existing literature. RESULTS: Out of these two GEO datasets, 21 overlapping genes were identified and incorporated into in the logistic diagnostic model constructed in the GSE36809 dataset. A panel of 9 genes was uncovered as a diagnostic biomarker, and their expression and correlation were subsequently verified. Additionally, by virtue of various algorithms, the findings revealed an upregulation of neutrophil expression and a downregulation of CD8+ T cell expression, indicating characteristic early trauma-induced inflammation activation and immune suppression. The correlation observed between the feature genes and immune cells serves to validate the exceptional diagnostic capability of these 9 genes in identifying trauma status and their promising potential for patients who could benefit from targeted immune interventions. Drawing from these findings, the discussion section offers insights into the underlying pathological and physiological mechanisms at play. CONCLUSION: Our research has discovered a novel diagnostic biomarker and unveiled its association with post-traumatic immune alterations. This breakthrough enables accurate and timely diagnosis of early trauma, facilitating the implementation of appropriate healthcare interventions.

Decoding the influence of low temperature on biofilm development: The hidden roles of c-di-GMP.

Biofilms are widely used and play important roles in biological processes. Low temperature of wastewater inhibits the development of biofilms derived from wastewater activated sludge. However, the specific mechanism of temperature on biofilm development is still unclear. This study explored the mechanism of temperature on biofilm development and found a feasible method to enhance biofilm development at low temperature. The amount of biofilm development decreased by approximately 66 % and 55 % at 4 °C and 15 °C, respectively, as compared to 28 °C. The cyclic dimeric guanosine monophosphate (c-di-GMP) concentration also decreased at low temperature and was positively correlated with extracellular polymeric substance (EPS) content, formation, and adhesion strength. Microbial community results showed that low temperature inhibited the normal survival of most microorganisms, but promoted the growth of some psychrophile bacteria like Sporosarcina, Caldilineaceae, Gemmataceae, Anaerolineaceae and Acidobacteriota. Further analysis of functional genes demonstrated that the abundance of functional genes related to the synthesis of c-di-GMP (K18968, K18967 and K13590) decreased at low temperature. Subsequently, the addition of exogenous spermidine increased the level of intracellular c-di-GMP and alleviated the inhibition effect of low temperature on biofilm development. Therefore, the possible mechanism of low temperature on biofilm development could be the inhibition of the microorganism activity and reduction of the communication level between cells, which is the closely related to the EPS content, formation, and adhesion strength. The enhancement of c-di-GMP level through the exogenous addition of spermidine provides an alternative strategy to enhance biofilm development at low temperatures. The results of this study enhance the understanding of the influence of temperature on biofilm development and provide possible strategies for enhancing biofilm development at low temperatures.

Photosensitizer-Amplified Antimicrobial Materials for Broad-Spectrum Ablation of Resistant Pathogens in Ocular Infections.

The emergence of multidrug resistant (MDR) pathogens and the scarcity of new potent antibiotics and antifungals are one of the biggest threats to human health. Antimicrobial photodynamic therapy (aPDT) combines light and photosensitizers to kill drug-resistant pathogens; however, there are limited materials that can effectively ablate different classes of infective pathogens. In the present work, a new class of benzodiazole-paired materials is designed as highly potent PDT agents with broad-spectrum antimicrobial activity upon illumination with nontoxic light. The results mechanistically demonstrate that the energy transfer and electron transfer between nonphotosensitive and photosensitive benzodiazole moieties embedded within pathogen-binding peptide sequences result in increased singlet oxygen generation and enhanced phototoxicity. Chemical optimization renders PEP3 as a novel PDT agent with remarkable activity against MDR bacteria and fungi as well as pathogens at different stages of development (e.g., biofilms, spores, and fungal hyphae), which also prove effective in an ex vivo porcine model of microbial keratitis. The chemical modularity of this strategy and its general compatibility with peptide-based targeting agents will accelerate the design of highly photosensitive materials for antimicrobial PDT.

A method establishment and application for biofilm quorum quenching activity assay.

The existence of quorum sensing (QS) and quorum quenching (QQ) plays important roles in biofilm formation. However, direct detection of QS ability is difficult due to the low concentrations of signal molecules inside the biofilm. Therefore, QQ activity is typically used to indicate the attribution of QS/QQ to the biofilm. Nevertheless, current detection methods of QQ activity based on biosensors present undesirable operability and accuracy. In this study, the 96-well plate assay based on a specific biosensor, Agrobacterium tumefaciens A136, and a colorimetric substance, X-gal was established. The reliable fitting results were obtained by standardizing the composition of the A136 X-gal assay solution and optimizing the operating conditions. This method improved the accuracy of QQ activity detection and reduced time and cost consumption. Finally, the 96-well plate assay was successfully applied to detect the QQ activities of biofilm samples and explore possible environmental influencing factors. In general, this study provided a new strategy for understanding the QQ effect in biofilm systems.

Untangling the web of intratumor microbiota in lung cancer.

Microbes are pivotal in contemporary cancer research, influencing various biological behaviors in cancer. The previous notion that the lung was sterile has been destabilized by the discovery of microbiota in the lower airway and lung, even within tumor tissues. Advances of biotechnology enable the association between intratumor microbiota and lung cancer to be revealed. Nonetheless, the origin and tumorigenicity of intratumor microbiota in lung cancer still remain implicit. Additionally, accumulating evidence indicates that intratumor microbiota might serve as an emerging biomarker for cancer diagnosis, prognosis, and even a therapeutic target across multiple cancer types, including lung cancer. However, research on intratumor microbiota's role in lung cancer is still nascent and warrants more profound exploration. Herein, this paper provides an extensive review of recent advancements in the following fields, including 1) established and emerging biotechnologies utilized to study intratumor microbiota in lung cancer, 2) causation between intratumor microbiota and lung cancer from the perspectives of translocation, cancerogenesis and metastasis, 3) potential application of intratumor microbiota as a novel biomarker for lung cancer diagnosis and prognosis, and 4) promising lung cancer therapies via regulating intratumor microbiota. Moreover, this review addresses the limitations, challenges, and future prospects of studies focused on intratumor microbiota in lung cancer.

The role of lipid metabolic reprogramming in tumor microenvironment.

Metabolic reprogramming is one of the most important hallmarks of malignant tumors. Specifically, lipid metabolic reprogramming has marked impacts on cancer progression and therapeutic response by remodeling the tumor microenvironment (TME). In the past few decades, immunotherapy has revolutionized the treatment landscape for advanced cancers. Lipid metabolic reprogramming plays pivotal role in regulating the immune microenvironment and response to cancer immunotherapy. Here, we systematically reviewed the characteristics, mechanism, and role of lipid metabolic reprogramming in tumor and immune cells in the TME, appraised the effects of various cell death modes (specifically ferroptosis) on lipid metabolism, and summarized the antitumor therapies targeting lipid metabolism. Overall, lipid metabolic reprogramming has profound effects on cancer immunotherapy by regulating the immune microenvironment; therefore, targeting lipid metabolic reprogramming may lead to the development of innovative clinical applications including sensitizing immunotherapy.

Establishment and validation of nomograms for predicting survival of lung invasive adenocarcinoma based on the level of pathological differentiation: a SEER cohort-based analysis.

Background: The pathological differentiation of invasive adenocarcinoma (IAC) has been linked closely with epidemiological characteristics and clinical prognosis. However, the current models cannot accurately predict IAC outcomes and the role of pathological differentiation is confused. This study aimed to establish differentiation-specific nomograms to explore the effect of IAC pathological differentiation on overall survival (OS) and cancer-specific survival (CSS). Methods: The data of eligible IAC patients between 1975 and 2019 were collected from the Surveillance, Epidemiology, and End Results (SEER) database, and randomly divided in a ratio of 7:3 into a training cohort and a validation cohort. The associations between pathological differentiation and other clinical characteristics were evaluated using chi-squared test. The OS and CSS analyses were performed using the Kaplan-Meier estimator, and the log-rank test was used for nonparametric group comparisons. Multivariate survival analysis was performed using a Cox proportional hazards regression model. The discrimination, calibration, and clinical performance of nomograms were assessed by area under receiver operating characteristic curve (AUC), calibration plots, and decision curve analysis (DCA). Results: A total of 4,418 IAC patients (1,001 high-differentiation, 1,866 moderate-differentiation, and 1,551 low-differentiation) were identified. Seven risk factors [age, sex, race, tumor-node-metastasis (TNM) stage, tumor size, marital status, and surgery] were screened to construct differentiation-specific nomograms. Subgroup analyses showed that disparate pathological differentiation played distinct roles in prognosis, especially in patients with older age, white race, and higher TNM stage. The AUC of nomograms for OS and CSS in the training cohort were 0.817 and 0.835, while in the validation cohort were 0.784 and 0.813. The calibration curves showed good conformity between the prediction of the nomograms and the actual observations. DCA results indicated that these nomogram models could be used as a supplement to the prediction of the TNM stage. Conclusions: Pathological differentiation should be considered as an independent risk factor for OS and CSS of IAC. Differentiation-specific nomogram models with good discrimination and calibration capacity were developed in the study to predict the OS and CSS in 1-, 3- and 5-year, which could be used predict prognosis and select appropriate treatment options.

The multi-omics analysis identifies a novel cuproptosis-anoikis-related gene signature in prognosis and immune infiltration characterization of lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) has emerged as one of the most aggressive lethal cancers. Anoikis serves as programmed apoptosis initiated by the detachment of cells from the extracel-lular matrix. Cuproptosis is distinct from traditional cell death modalities. The above two modes are both closely related to tumor progression, prognosis, and treatment. However, whether they have synergistic effects in LUAD deserves further investigation. Methods: The anoikis-related prognostic genes (ANRGs) co-expressed with cuproptosis-associated genes (CAGs) were screened using correlation analysis, analysis of variance, least absolute shrinkage, and selection operator (LASSO), and COX regression followed by functional analysis, and then LUAD risk score model was constructed. Using consensus clustering, the relationship between different subtypes and clinicopathological features, immune infiltration characteristics, and somatic mutations was analyzed. A nomogram was developed by incorporating clinical information, which provided a prediction of the survival of patients. Finally, a comprehensive analysis of ANRGs was performed and verified by the HPA database. Results: A total of 27 ANRGs associated with cuproptosis were obtained. On this basis, three distinct ANRGs subtypes were identified, and the differences between clinical prognosis and immune infiltration were observed. A risk score model has been constructed by incorporating seven ANRGs signatures (EIF2AK3, IKZF3, ITGAV, OGT, PLK1, TRAF2, XRCC5). A highly reliable nomogram was developed to help formulate treatment strategies based on risk score and the clinicopathological features of LUAD. The seven-gene signature was turned out to be strongly linked to immune cells and validated in single-cell data. Immunohistochemistry proved that all of them are highly expressed in LUAD tissues. Conclusion: This study reveals the potential relationship between cuproptosis-related ANRGs and clinicopathological features, tumor microenvironment (TME), and mutation characteristics, which can be applied for predicting the prognosis of LUAD and help develop individualized treatment strategies.