Early detection and stratification of colorectal cancer using plasma cell-free DNA fragmentomic profiling.

Timely accurate and cost-efficient detection of colorectal cancer (CRC) is of great clinical importance. This study aims to establish prediction models for detecting CRC using plasma cell-free DNA (cfDNA) fragmentomic features. Whole-genome sequencing (WGS) was performed on cfDNA from 620 participants, including healthy individuals, patients with benign colorectal diseases and CRC patients. Using WGS data, three machine learning methods were compared to build prediction models for the stratification of CRC patients. The optimal model to discriminate CRC patients of all stages from healthy individuals achieved a sensitivity of 92.31% and a specificity of 91.14%, while the model to separate early-stage CRC patients (stage 0-II) from healthy individuals achieved a sensitivity of 88.8% and a specificity of 96.2%. Additionally, the cfDNA fragmentation profiles reflected disease-specific genomic alterations in CRC. Overall, this study suggests that cfDNA fragmentation profiles may potentially become a noninvasive approach for the detection and stratification of CRC.

Palladium-Catalyzed Ligand-Controlled Switchable Hetero-(5 + 3)/Enantioselective [2σ+2σ] Cycloadditions of Bicyclobutanes with Vinyl Oxiranes.

For nearly 60 years, significant research efforts have been focused on developing strategies for the cycloaddition of bicyclobutanes (BCBs). However, higher-order cycloaddition and catalytic asymmetric cycloaddition of BCBs have been long-standing formidable challenges. Here, we report Pd-catalyzed ligand-controlled, tunable cycloadditions for the divergent synthesis of bridged bicyclic frameworks. The dppb ligand facilitates the formal (5+3) cycloaddition of BCBs and vinyl oxiranes, yielding valuable eight-membered ethers with bridged bicyclic scaffolds in 100% regioselectivity. The Cy-DPEphos ligand promotes selective hetero-[2σ+2σ] cycloadditions to access pharmacologically important 2-oxabicyclo[3.1.1]heptane (O-BCHeps). Furthermore, the corresponding catalytic asymmetric synthesis of O-BCHeps with 94-99% ee has been achieved using chiral (S)-DTBM-Segphos, representing the first catalytic asymmetric cross-dimerization of two strained rings. The obtained O-BCHeps are promising bioisosteres for ortho-substituted benzenes.

A heterogeneous tumor immune microenvironment of uncommon epidermal growth factor receptor mutant non-small cell lung cancer.

Common epidermal growth factor receptor (EGFR) mutations are usually not considered for immunotherapy in non-small cell lung cancer (NSCLC) due to poor efficacy. However, whether uncommon EGFR mutations are suitable for immunotherapy has not been thoroughly studied. Thus, we explored the tumor immune microenvironment (TME) features in uncommon EGFR mutant NSCLC. In this study, a total of 41 patients with EGFR mutations were included, the majority (85.4%) of whom were stage I. Among them, 22 patients harbored common mutations, while 19 patients presented with uncommon mutations. Compared with common mutations, uncommon mutations exhibited more infiltrating T cells and fewer M2 macrophages, upregulated expression of antigen processing and a presentation pathway. Unsupervised clustering based on the mIF profile identified two classes with heterogeneous TME in uncommon mutations. Class 1 featured the absence of PD-1+ cytotoxic T cell infiltration, and class 2 displayed a hotter TME because of the downregulated expression of hypoxia (p < 0.001), oxidative phosphorylation (p = 0.009), and transforming growth factor beta signaling (p = 0.01) pathways as well as increased expression of CTLA4 (p = 0.001) and PDCD1 (p = 0.004). The association of CTLA4 and PDCD1 with TME profiles was validated in a TCGA lung adenocarcinoma cohort with uncommon EGFR mutations. Our study reveals the distinct and heterogeneous TME features in uncommon EGFR mutant NSCLC.

Facile Construction of CuFe-Based Metal Phosphides for Synergistic NOx -Reduction to NH3 and Zn-Nitrite Batteries in Electrochemical Cell.

The electrocatalytic nitrite/nitrate reduction reaction (eNO2RR/eNO3RR) offer a promising route for green ammonia production. The development of low cost, highly selective and long-lasting electrocatalysts for eNO2RR/eNO3RR is challenging. Herein, a method is presented for constructing Cu3P-Fe2P heterostructures on iron foam (CuFe-P/IF) that facilitates the effective conversion of NO2 - and NO3 - to NH3. At -0.1 and -0.2 V versus RHE (reversible hydrogen electrode), CuFe-P/IF achieves a Faradaic efficiency (FE) for NH3 production of 98.36% for eNO2RR and 72% for eNO3RR, while also demonstrating considerable stability across numerous cycles. The superior performance of CuFe-P/IF catalyst is due tothe rich Cu3P-Fe2P heterstuctures. Density functional theory calculations have shed light on the distinct roles that Cu3P and Fe2P play at different stages of the eNO2RR/eNO3RR processes. Fe2P is notably active in the early stages, engaging in the capture of NO2 -/NO3 -, O─H formation, and N─OH scission. Conversely, Cu3P becomes more dominant in the subsequent steps, which involve the formation of N─H bonds, elimination of OH* species, and desorption of the final products. Finally, a primary Zn-NO2 - battery is assembled using CuFe-P/IF as the cathode catalyst, which exhibits a power density of 4.34 mW cm-2 and an impressive NH3 FE of 96.59%.

Hepatic mitochondrial NAD + transporter SLC25A47 activates AMPKα mediating lipid metabolism and tumorigenesis.

BACKGROUND AIMS: SLC25A47 was initially identified as a mitochondrial HCC-downregulated carrier protein, but its physiological functions and transport substrates are unknown. We aimed to investigate the physiological role of SLC25A47 in hepatic metabolism. APPROACH RESULTS: In the treatment of hepatocytes with metformin, we found that metformin can transcriptionally activate the expression of Slc25a47 , which is required for AMP-activated protein kinase α (AMPKα) phosphorylation. Slc25a47 -deficient mice had increased hepatic lipid content, triglycerides, and cholesterol levels, and we found that Slc25a47 deficiency suppressed AMPKα phosphorylation and led to an increased accumulation of nuclear SREBPs, with elevated fatty acid and cholesterol biosynthetic activities. Conversely, when Slc25a47 was overexpressed in mouse liver, AMPKα was activated and resulted in the inhibition of lipogenesis. Moreover, using a diethylnitrosamine-induced mouse HCC model, we found that the deletion of Slc25a47 promoted HCC tumorigenesis and development through the activated mammalian target of rapamycin cascade. Employing homology modeling of SLC25A47 and virtual screening of the human metabolome database, we demonstrated that NAD + was an endogenous substrate for SLC25A47, and the activity of NAD + -dependent sirtuin 3 declined in Slc25a47 -deficient mice, followed by inactivation of AMPKα. CONCLUSIONS: Our findings reveal that SLC25A47, a hepatocyte-specific mitochondrial NAD + transporter, is one of the pharmacological targets of metformin and regulates lipid homeostasis through AMPKα, and may serve as a potential drug target for treating NAFLD and HCC.

A 15-Inflammation-Related Gene Signature Predicts the Prognosis of Patients With Pancreatic Ductal Adenocarcinoma.

Chronic inflammation promotes the development of pancreatic ductal adenocarcinoma (PDAC) and PDAC-related inflammatory tumor microenvironment facilitates tumor growth and metastasis. Thus, we aimed to study the association between inflammatory response and prognosis in patients with PDAC. We conducted the whole transcriptomic sequencing using tissue samples collected from patients diagnosed with PDAC (n = 106) recruited from Shandong Cancer Hospital. We first constructed a prognostic signature using 15 inflammation-related genes in The Cancer Genome Atlas (TCGA) cohort (n = 177) and further validated it in an independent International Cancer Genome Consortium (ICGC) cohort (n = 90) and our in-house cohort. PDAC patients with a higher risk score had poorer overall survival (OS) (P < 0.001; HR, 3.02; 95% CI, 1.94-4.70). The association between the prognostic signature and OS remained significant in the multivariable Cox regression adjusting for age, sex, alcohol exposure, diabetes, and stage (P < 0.001; HR, 2.91; 95% CI, 1.73-4.89). This gene signature also robustly predicted prognosis in the ICGC cohort (P = 0.01; HR, 1.94; 95% CI, 1.14-3.30) and our cohort (P < 0.001; HR, 2.40; 95% CI, 1.45-3.97). Immune subtype C3 (inflammatory) was enriched and CD8+ T cells were higher in patients with a lower risk score (P < 0.05). Furthermore, PDAC patients with higher risk scores were more sensitive to chemotherapy, immunotherapy, and PARP inhibitors (P < 0.05). In sum, we identified a novel gene signature that was associated with inflammatory response for risk stratification, prognosis prediction, and therapy guidance in PDAC patients. Future studies are warranted to validate the clinical utility of the signature.

Positively Charged Silver and Gold Nanoparticles with Controllable Size Distribution for SERS Detection of Negatively Charged Molecules.

Surface-enhanced Raman spectroscopy (SERS) has been demonstrated as an ultrasensitive tool for various molecules. However, for the negatively charged molecules, the widely used SERS substrate [negatively charged Ag and Au nanoparticles (Ag or Au NPs (-)] showed either low sensitivity or poor stability. The best solution is to synthesize positively charged silver or gold nanoparticles [Ag or Au NPs (+)] with high stability and excellent SERS performance, which are currently unavailable. To this end, we revitalized the strategy of "charge reversal and seed growth". By selection of ascorbic acid as the reductant and surfactant, the surface charge of Ag or Au NP (-) seeds is adjusted to a balanced state, where the surface charge is negative enough to satisfy the stabilization of the NPs (-) but does not hinder the subsequent charge reversal. By optimization of the chain length and electric charge of polyamine molecules, the highly stable and size-controllable uniform Ag NPs (+) and Au NPs (+) were seed-growth synthesized with high reproducibility. More importantly, the SERS performance of both Ag NPs (+) and Au NPs (+) achieved the trace detection of negatively charged molecules at the level of 1 µg/L, demonstrating an improved SERS sensitivity of up to 3 orders of magnitude compared to the previously reported sensitivity. Promisingly, the introduction of polyamine-capped Ag NPs (+) and Au NPs (+) as SERS substrates with high stability (1 year shelf life) will significantly broaden the application of SERS.

Semirational Design Strategy To Enhance the Thermostability and Catalytic Activity of Cytochrome P450 105D7 for the Degradation of the Pharmaceutically Active Compounds: Diclofenac.

Pharmaceutically active compounds are an important category of emerging pollutants, and their biological transformation processes in the environment are crucial for understanding and evaluating the migration, transformation, and environmental fate of emerging pollutants. The cytochrome P450 105 enzyme family has been proven to play an important role in the degradation of exogenous environmental pollutants. However, its thermostability and catalytic activity still need to be improved to better adapt to complex environmental conditions. This work elucidates the key mechanisms and important residues of the degradation reaction through multiple computational strategies, establishes a mutation library, and obtains 21 single-point mutation designs. Experimental verification showed that 16 single mutants had enhanced thermostability, with the R89F and L197Y mutants showing the highest increases in thermostability at 135 and 119% relative to the wild-type enzyme, respectively. Additionally, as a result of the higher specific activity of D390Q, it was selected for combination mutagenesis, ultimately resulting in three combination mutants (R89F/L197Y, R89F/D390Q, and R89F/L197Y/D390Q) with enhanced thermostability and catalytic activity. This study provides a modification approach for constructing efficient enzyme variants through semirational design and can contribute to the development of control technologies for emerging pollutants.

Occurrence, source apportionment, and ecological risk of legacy and emerging per- and poly-fluoroalkyl substances (PFASs) in the Dahei river basin of a typical arid region in China.

Per- and poly-fluoroalkyl substances (PFASs) are artificial chemicals with broad commercial and industrial applications. Many studies about PFASs have been conducted in densely industrial and populated regions. However, fewer studies have focused on the PFASs' status in a typical arid region. Here, we investigated 30 legacy and emerging PFASs in surface water from the mainstream and tributaries of the Dahei River. Our results revealed that total PFASs concentrations (∑30PFASs) in water ranged from 3.13 to 289.1 ng/L (mean: 25.40 ng/L). Perfluorooctanoic acid (PFOA) had the highest mean concentration of 2.44 ng/L with a 100% detection frequency (DF), followed by perfluorohexanoic acid (PFHxA) (mean concentration: 1.34 ng/L, DF: 59.26%). Also, perfluorohexane sulfonate (DF: 44.44%), perfluorobutane sulfonate (DF: 88.89%), and perfluorooctane sulfonate (PFOS) (DF: 92.59%) had mean concentrations of 12.94, 2.00, and 1.05 ng/L, respectively. Source apportionment through ratio analysis and principal component analysis-multiple linear regression analysis showed that treated or untreated sewage, aqueous film-forming foam, degradation of precursors, and fluoropolymer production were the primary sources. The PFOS alternatives were more prevalent than those of PFOA. Conductivity, total phosphorus, and chlorophyll a positively correlated with Σ30PFASs and total perfluoroalkane sulfonates concentrations. Furthermore, ecological risk assessment showed that more attention should be paid to perfluorooctadecanoic acid, perfluorohexadecanoic acid, perfluorooctane sulfonate, perfluorohexane sulfonate, and (6:2 and 6:2/8:2) polyfluoroalkyl phosphate mono- and di-esters. The mass load of PFASs to the Yellow River was 1.28 kg/year due to the low annual runoff in the Dahei River in the arid region. This study provides baseline data for PFASs in the Dahei River that can aid in the development of effective management strategies for controlling PFASs pollution in typical arid regions in China.

The Role of Metabolomics and Microbiology in Urinary Tract Infection.

One of the common illnesses that affect women's physical and mental health is urinary tract infection (UTI). The disappointing results of empirical anti-infective treatment and the lengthy time required for urine bacterial culture are two issues. Antibiotic misuse is common, especially in females who experience recurrent UTI (rUTI). This leads to a higher prevalence of antibiotic resistance in the microorganisms that cause the infection. Antibiotic therapy will face major challenges in the future, prompting clinicians to update their practices. New testing techniques are making the potential association between the urogenital microbiota and UTIs increasingly apparent. Monitoring changes in female urinary tract (UT) microbiota, as well as metabolites, may be useful in exploring newer preventive treatments for UTIs. This review focuses on advances in urogenital microbiology and organismal metabolites relevant to the identification and handling of UTIs in an attempt to provide novel methods for the identification and management of infections of the UT. Particular attention is paid to the microbiota and metabolites in the patient's urine in relation to their role in supporting host health.

Assembly mechanism and stability of zooplankton communities affected by China's south-to-north water diversion project.

Water diversion can effectively alleviate water resource shortages and improve water environmental conditions, while also causing unknown ecological consequences, in particular, the assembly mechanism of zooplankton communities in the affected areas will become more complex after long-term water transfer. Taking Nansi Lake, the second largest impounded lake along the eastern route of China's South to North Water Diversion Project (SNWDP), as an example, the composition and diversity of zooplankton communities in the lake area and estuaries during the water diversion period (WDP) and non-water diversion period (NWDP) were studied. The potential assembly process of zooplankton communities was further explored, and the stability of communities in different regions during different periods was compared. The related results indicated that the changes in water quality conditions induced by water diversion had a relatively weak impact on the zooplankton communities. In the assembly mechanism of zooplankton communities, stochastic process played a more important role during both WDP or NWDP, and the proportion of deterministic process was relatively higher during NWDP, which may be related to the greater role of total nitrogen (TN) in the assembly of the zooplankton communities. The network analysis and cohesion calculation results showed that the stability of the zooplankton communities in the lake area sites was higher than that in the estuary sites, and the stability during NWDP was higher than that during WDP. In sum, the stability of zooplankton communities displayed a degree of change affected by water diversion activities, but the community assembly was not significantly influenced by the water quality fluctuations after about relatively long-term water diversion. This study provides an in-depth understanding of the ecological effects of water diversion on the biological communities in the affected lake, which is beneficial to the management and regulation of long-term water diversion projects.

Occurrence, source apportionment and ecological risk of bisphenol analogues in river sediments in areas with different land use patterns.

Bisphenol analogues (BPs) have gained increasing attention in recent years due to their ubiquitousness and potential endocrine disrupting properties in environments. However, little information is available on their spatiotemporal distribution, source apportionment and ecological risk in river sediments, especially the case in river basins with a high population density and those typical regions with agricultural-urban gradient, where land use patterns and intensity of human activity are varying. In this study, field investigations of BPs in the sediment of the entire Qinhuai River Basin, a typical agricultural-suburban agricultural-urban gradient area, were conducted before and after the flood period. Thirty-two sites were sampled for six types of BPs, resulted in no significant difference in the concentration of ΣBPs between the two periods, with ΣBPs ranging from 3.92 to 151 ng/g and 2.16-59.0 ng/g, respectively. Bisphenol A (BPA) was the main contributor. Whereas a multivariate analysis of variance (MANOVA) suggested that the composition structure of BPs had been influenced by water periods. The land use patterns had an impact on the distribution of ΣBPs in river sediments, which was more significant in after the flood period, with ΣBPs in urban rivers was 1.85 times, 3.44 times, and 3.08 times higher than the suburban rivers, agricultural rivers, and reservoirs, respectively. Yet land use types did not significantly alter the composition structure of BPs. The correlation analysis between BPs and the physicochemical properties of sediments showed a significant positive correlation between BPA and total organic carbon (TOC). The positive matrix factorization model (PMF) suggested that BPs in sediments of the basin might be influenced by industrial coatings, textiles, electronics and biopharmaceuticals, as well as urban wastewater or solid waste generated from daily life. The ecological risk assessment posed by BPA, based on the risk quotient, indicated that the ecological risk of BPA in sediments was low for three indicator benthic organisms: crustaceans, worms, and mollusks. However, the risk of BPA in river sediments varied among different land use patterns, with the risk ranking as follows: reservoirs < agricultural rivers < suburban rivers < urban rivers.

Objective Quantification Technique and Widely Targeted Metabolomics-Based Analysis of the Effects of Different Saccharidation Processes on Preserved French Plums.

Vacuum saccharification significantly affected the flavor and color of preserved French plums. However, the correlation between color, flavor, and metabolites remains unclear. Metabolites contribute significantly to enhancing the taste and overall quality of preserved French plums. This study aimed to investigate the distinctive metabolites in samples from various stages of the processing of preserved French plums. The PCF4 exhibited the highest appearance, overall taste, and chroma. Furthermore, utilizing UPLC and ESI-Q TRAP-MS/MS, a comprehensive examination of the metabolome in the processing of preserved French plums was conducted. A total of 1776 metabolites were analyzed. Using WGCNA, we explored metabolites associated with sensory features through 10 modules. Based on this, building the correlation of modules and objective quantification metrics yielded three key modules. After screening for 151 differentiated metabolites, amino acids, and their derivatives, phenolic acids, flavonoids, organic acids, and other groups were identified as key differentiators. The response of differential metabolites to stress influenced the taste and color properties of preserved prunes. Based on these analyses, six important metabolic pathways were identified. This study identified changes in the sensory properties of sugar-stained preserved prunes and their association with metabolite composition, providing a scientific basis for future work to improve the quality of prune processing.

Ring Contraction of Saturated Cyclic Amines and Rearrangement of Acyclic Amines Through Their Corresponding Hydroxylamines.

Compared to modifications at the molecular periphery, skeletal adjustments present greater challenges. Within this context, skeletal rearrangement technology stands out for its significant advantages in rapidly achieving structural diversity. Yet, the development of this technology for ring contraction of saturated cyclic amines remains exceedingly rare. While most existing methods rely on specific substitution patterns to achieve ring contraction, there is a persistent demand for a more general strategy for substitution-free cyclic amines. To address this issue, we report a B(C6F5)3-catalyzed skeletal rearrangement of hydroxylamines with hydrosilanes. This methodology, when combined with the N-hydroxylation of amines, enables the regioselective ring contraction of cyclic amines and proves equally effective for rapid reorganization of acyclic amine skeletons. By this, the direct scaffold hopping of drug molecules and the strategic deletion of carbon atoms are achieved in a mild manner. Based on mechanistic experiments and density functional theory calculations, a possible mechanism for this process is proposed.

Switching between the [2π+2σ] and Hetero-[4π+2σ] Cycloaddition Reactivity of Bicyclobutanes with Lewis Acid Catalysts Enables the Synthesis of Spirocycles and Bridged Heterocycles.

The exploration of the complex chemical diversity of bicyclo[n.1.1]alkanes and their use as benzene bioisosteres has garnered significant attention over the past two decades. Regiodivergent syntheses of thiabicyclo[4.1.1]octanes (S-BCOs) and highly substituted bicyclo[2.1.1]hexanes (BCHs) using a Lewis acid-catalyzed formal cycloaddition of bicyclobutanes (BCBs) and 3-benzylideneindoline-2-thione derivatives have been established. The first hetero-(4+3) cycloaddition of BCBs, catalyzed by Zn(OTf)2, was achieved with a broad substrate scope under mild conditions. In contrast, the less electrophilic BCB ester undergoes a Sc(OTf)3-catalyzed [2π+2σ] reaction with 1,1,2-trisubstituted alkenes, yielding BCHs with a spirocyclic quaternary carbon center. Control experiments and preliminary theoretical calculations suggest that the diastereoselective [2π+2σ] product formation may involve a concerted cycloaddition between a zwitterionic intermediate and E-1,1,2-trisubstituted alkenes. Additionally, the hetero-(4+3) cycloaddition may involve a concerted nucleophilic ring-opening mechanism.

Divergent Synthesis of Sulfur-Containing Bridged Cyclobutanes by Lewis Acid Catalyzed Formal Cycloadditions of Pyridinium 1,4-Zwitterionic Thiolates and Bicyclobutanes.

Bridged cyclobutanes and sulfur heterocycles are currently under intense investigation as building blocks for pharmaceutical drug design. Two formal cycloaddition modes involving bicyclobutanes (BCBs) and pyridinium 1,4-zwitterionic thiolate derivatives were described to rapidly expand the chemical space of sulfur-containing bridged cyclobutanes. By using Ni(ClO4)2 as the catalyst, an uncommon higher-order (5+3) cycloaddition of BCBs with quinolinium 1,4-zwitterionic thiolate was achieved with broad substrate scope under mild reaction conditions. Furthermore, the first Lewis acid-catalyzed asymmetric polar (5+3) cycloaddition of BCB with pyridazinium 1,4-zwitterionic thiolate was accomplished. In contrast, pyridinium 1,4-zwitterionic thiolates undergo an Sc(OTf)3-catalyzed formal (3+3) reaction with BCBs to generate thia-norpinene products, which represent the initial instance of synthesizing 2-thiabicyclo[3.1.1]heptanes (thia-BCHeps) from BCBs. Moreover, we have successfully used this (3+3) protocol to rapidly prepare thia-BCHeps-substituted analogues of the bioactive molecule Pitofenone. Density functional theory (DFT) computations imply that kinetic factors govern the (5+3) cycloaddition reaction between BCB and quinolinium 1,4-zwitterionic thiolate, whereas the (3+3) reaction involving pyridinium 1,4-zwitterionic thiolates is under thermodynamic control.

BAP1-related signature predicts benefits from immunotherapy over VEGFR/mTOR inhibitors in ccRCC: a retrospective analysis of JAVELIN Renal 101 and checkmate-009/010/025 trials.

BACKGROUND: In patients with advanced clear cell renal cell carcinoma, despite the undoubted benefits from immune checkpoint inhibitor (ICI)-based therapies over monotherapies of angiogenic/mTOR inhibitors in the intention-to-treat population, approximately a quarter of the patients can scarcely gain advantage from ICIs, prompting the search for predictive biomarkers for patient selection. METHODS: Clinical and multi-omic data of 2428 ccRCC patients were obtained from The Cancer Genome Atlas (TCGA, n = 537), JAVELIN Renal 101 (avelumab plus axitinib vs. sunitinib, n = 885), and CheckMate-009/010/025 (nivolumab vs. everolimus, n = 1006). RESULTS: BAP1 mutations were associated with large progression-free survival (PFS) benefits from ICI-based immunotherapies over sunitinib/everolimus (pooled estimate of interaction HR = 0.71, 95% CI 0.51-0.99, P = 0.045). Using the top 20 BAP1 mutation-associated differentially expressed genes (DEGs) generated from the TCGA cohort, we developed the BAP1-score, negatively correlated with angiogenesis and positively correlated with multiple immune-related signatures concerning immune cell infiltration, antigen presentation, B/T cell receptor, interleukin, programmed death-1, and interferon. A high BAP1-score indicated remarkable PFS benefits from ICI-based immunotherapies over angiogenic/mTOR inhibitors (avelumab plus axitinib vs. sunitinib: HR = 0.55, 95% CI 0.43-0.70, P < 0.001; nivolumab vs. everolimus: HR = 0.72, 95% CI 0.52-1.00, P = 0.045), while these benefits were negligible in the low BAP1-score subgroup (HR = 1.16 and 1.02, respectively). CONCLUSION: In advanced ccRCCs, the BAP1-score is a biologically and clinically significant predictor of immune microenvironment and the clinical benefits from ICI-based immunotherapies over angiogenic/mTOR inhibitors, demonstrating its potential utility in optimizing the personalized therapeutic strategies in patients with advanced ccRCC.

Tumor immune contexture predicts recurrence after prostatectomy and efficacy of androgen deprivation and immunotherapy in prostate cancer.

BACKGROUND: Prostate cancer is one of the most common cancers in men with notable interpatient heterogeneity. Implications of the immune microenvironment in predicting the biochemical recurrence-free survival (BCRFS) after radical prostatectomy and the efficacy of systemic therapies in prostate cancer remain ambiguous. METHODS: The tumor immune contexture score (TICS) involving eight immune contexture-related signatures was developed using seven cohorts of 1120 patients treated with radical prostatectomy (training: GSE46602, GSE54460, GSE70769, and GSE94767; validation: GSE70768, DKFZ2018, and TCGA). The association between the TICS and treatment efficacy was investigated in GSE111177 (androgen deprivation therapy [ADT]) and EGAS00001004050 (ipilimumab). RESULTS: A high TICS was associated with prolonged BCRFS after radical prostatectomy in the training (HR = 0.32, 95% CI 0.24-0.45, P < 0.001) and the validation cohorts (HR = 0.45, 95% CI 0.32-0.62, P < 0.001). The TICS showed stable prognostic power independent of tumor stage, surgical margin, pre-treatment prostatic specific antigen (PSA), and Gleason score (multivariable HR = 0.50, 95% CI 0.39-0.63, P < 0.001). Adding the TICS into the prognostic model constructed using clinicopathological features significantly improved its 1/2/3/4/5-year area under curve (P < 0.05). A low TICS was associated with high homologous recombination deficiency scores, abnormally activated pathways concerning DNA replication, cell cycle, steroid hormone biosynthesis, and drug metabolism, and fewer tumor-infiltrating immune cells (P < 0.05). The patients with a high TICS had favorable BCRFS with ADT (HR = 0.25, 95% CI 0.06-0.99, P = 0.034) or ipilimumab monotherapy (HR = 0.23, 95% CI 0.06-0.81, P = 0.012). CONCLUSIONS: Our study delineates the associations of tumor immune contexture with molecular features, recurrence after radical prostatectomy, and the efficacy of ADT and immunotherapy. The TICS may improve the existing risk stratification systems and serve as a patient-selection tool for ADT and immunotherapy in prostate cancer.

A DNA Damage Response Related Signature to Predict Prognosis in Patients with Acute Myeloid Leukemia.

The prognosis of acute myeloid leukemia (AML) is disappointing in most subtypes and varies widely. DNA damage response (DDR) is associated with prognosis and immunotherapy in multiple cancers. Here, we identify a signature of eight DDR-related genes associated with overall survival, which stratifies AML patients into high- and low-risk groups. Patients in low-risk group were more likely to respond to sorafenib. The signature could be an independent prognostic predictor for patients treated with ADE and ADE plus gemtuzumab ozogamicin. Therefore, this DDR prognostic signature might be applied to prognostic stratification and treatment selection in AML patients, which warrants further studies.

Deciphering a cell death-associated signature for predicting prognosis and response to immunotherapy in lung squamous cell carcinoma.

BACKGROUND: Lung squamous cell carcinoma (LUSC) is a subtype of non-small cell carcinoma, accounting for about 30% of all lung cancers. Yet, the evaluation of prognostic outcome and therapy response of patients with LUSC remains to be resolved. This study aimed to explore the prognostic value of cell death pathways and develop a cell death-associated signature for predicting prognosis and guiding treatment in LUSC. METHODS: Transcriptome profiles and corresponding clinical information of LUSC patients were gathered from The Cancer Genome Atlas (TCGA-LUSC, n = 493) and Gene Expression Omnibus database (GSE74777, n = 107). The cell death-related genes including autophagy (n = 348), apoptosis (n = 163), and necrosis (n = 166) were retrieved from the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology databases. In the training cohort (TCGA-LUSC), LASSO Cox regression was used to construct four prognostic signatures of respective autophagy, apoptosis, and necrosis pathway and genes of three pathways. After comparing the four signatures, the cell death index (CDI), the signature of combined genes, was further validated in the GSE74777 dataset. We also investigated the clinical significance of the CDI signature in predicting the immunotherapeutic response of LUSC patients. RESULTS: The CDI signature was significantly associated with the overall survival of LUSC patients in the training cohort (HR, 2.13; 95% CI, 1.62‒2.82; P < 0.001) and in the validation cohort (HR, 1.94; 95% CI, 1.01‒3.72; P = 0.04). The differentially expressed genes between the high- and low-risk groups contained cell death-associated cytokines and were enriched in immune-associated pathways. We also found a higher infiltration of naive CD4+ T cells, monocytes, activated dendritic cells, neutrophils, and lower infiltration of plasma cells and resting memory CD4+ T cells in the high-risk group. Tumor stemness indices, mRNAsi and mDNAsi, were both negatively correlated with the risk score of the CDI. Moreover, LUSC patients in the low-risk group are more likely to respond to immunotherapy than those in the high-risk group (P = 0.002). CONCLUSIONS: This study revealed a reliable cell death-associated signature (CDI) that closely correlated with prognosis and the tumor microenvironment in LUSC, which may assist in predicting the prognosis and response to immunotherapy for patients with LUSC.