TP53 disruptive mutation predicts platinum-based chemotherapy and PD-1/PD-L1 blockade response in urothelial carcinoma.

TP53 mutation is one of the most common genetic alterations in urothelial carcinoma (UrCa), and heterogeneity of TP53 mutants leads to heterogeneous clinical outcomes. This study aimed to investigate the clinical relevance of specific TP53 mutations in UrCa. In this study, a total of eight cohorts were enrolled, along with matched clinical annotation. TP53 mutations were classified as disruptive and nondisruptive according to the degree of disturbance of p53 protein function and structure. We evaluated the clinical significance of TP53 mutations in our local datasets and publicly available datasets. The co-occurring events of TP53 mutations in UrCa, along with their therapeutic indications, functional effects, and the tumor immune microenvironment, were also investigated. TP53 mutations were identified in 49.7% of the UrCa patients. Within this group, 25.1% of patients carried TP53Disruptive mutations, a genetic alteration correlated with a significantly poorer overall survival (OS) when compared to individuals with TP53Nondisruptive mutations and those with wild-type TP53. Significantly, patients with TP53Disruptive mutations exhibit an increased probability of responding favorably to PD-1/PD-L1 blockade and chemoimmunotherapy. Meanwhile, there was no noteworthy distinction in OS among patients with varying TP53 mutation status who underwent chemotherapy. Samples with TP53Disruptive mutations showed an enriched APOBEC- and POLE-related mutational signature, as well as an elevated tumor mutation burden. The sensitivity to immunotherapy in tumors carrying TP53Disruptive mutation may be attributed to the inflamed tumor microenvironment characterized by increased CD8+T cell infiltration and interferon-gamma signaling activation. In conclusion, UrCa patients with TP53Disruptive mutations have shown reduced survival rates, yet they may respond well to PD-1/PD-L1 blockade therapy and chemoimmunotherapy. By distinguishing specific TP53 mutations, we can improve risk stratification and offer personalized genomics-guided therapy to UrCa patients. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Integration of CD4+ T cells and molecular subtype predicts benefit from PD-L1 blockade in muscle-invasive bladder cancer.

Muscle-invasive bladder cancer (MIBC) is a disease characterized by molecular and clinical heterogeneity, posing challenges in selecting the most appropriate treatment in clinical settings. Considering the significant role of CD4+ T cells, there is an emerging need to integrate CD4+ T cells with molecular subtypes to refine classification. We conducted a comprehensive study involving 895 MIBC patients from four independent cohorts. The Zhongshan Hospital (ZSHS) and The Cancer Genome Atlas (TCGA) cohorts were included to investigate chemotherapeutic response. The IMvigor210 cohort was included to assess the immunotherapeutic response. NCT03179943 was used to evaluate the clinical response to a combination of immune checkpoint blockade (ICB) and chemotherapy. Additionally, we evaluated genomic characteristics and the immune microenvironment to gain deeper insights into the distinctive features of each subtype. We unveiled four immune-molecular subtypes, each exhibiting distinct clinical outcomes and molecular characteristics. These subtypes include luminal CD4+ Thigh, which demonstrated benefits from both immunotherapy and chemotherapy; luminal CD4+ Tlow, characterized by the highest level of fibroblast growth factor receptor 3 (FGFR3) mutation, thus indicating potential responsiveness to FGFR inhibitors; basal CD4+ Thigh, which could benefit from a combination of ICB and chemotherapy; and basal CD4+ Tlow, characterized by an immune suppression microenvironment and likely to benefit from transforming growth factor-ß (TGF-ß) inhibition. This immune-molecular classification offers new possibilities for optimizing therapeutic interventions in MIBC.

Integrating molecular subtype and CD8+ T cells infiltration to predict treatment response and survival in muscle-invasive bladder cancer.

BACKGROUND: Luminal and Basal are the primary intrinsic subtypes of muscle-invasive bladder cancer (MIBC). The presence of CD8+ T cells infiltration holds significant immunological relevance, potentially influencing the efficacy of antitumor responses. This study aims to synergize the influence of molecular subtypes and CD8+ T cells infiltration in MIBC. METHODS: This study included 889 patients with MIBC from Zhongshan Hospital, The Cancer Genome Atlas, IMvigor210 and NCT03179943 cohorts. We classified the patients into four distinct groups, based on the interplay of molecular subtypes and CD8+ T cells and probed into the clinical implications of these subgroups in MIBC. RESULTS: Among patients with Luminal-CD8+Thigh tumors, the confluence of elevated tumor mutational burden and PD-L1 expression correlated with a heightened potential for positive responses to immunotherapy. In contrast, patients featured by Luminal-CD8+Tlow displayed a proclivity for deriving clinical advantages from innovative targeted interventions. The Basal-CD8+Tlow subgroup exhibited the least favorable three-year overall survival outcome, whereas their Basal-CD8+Thigh counterparts exhibited a heightened responsiveness to chemotherapy. CONCLUSIONS: We emphasized the significant role of immune-molecular subtypes in shaping therapeutic approaches for MIBC. This insight establishes a foundation to refine the process of selecting subtype-specific treatments, thereby advancing personalized interventions for patients.

Cell-cell communication characteristics in breast cancer metastasis.

Breast cancer, a highly fatal disease due to its tendency to metastasize, is the most prevalent form of malignant tumors among women worldwide. Numerous studies indicate that breast cancer exhibits a unique predilection for metastasis to specific organs including the bone, liver, lung, and brain. However, different types of, The understanding of the heterogeneity of metastatic breast cancer has notably improved with the recent advances in high-throughput sequencing techniques. Focusing on the modification in the microenvironment of the metastatic organs and the crosstalk between tumor cells and in situ cells, noteworthy research points include the identification of two distinct modes of tumor growth in bone metastases, the influence of type II pneumocyte on lung metastases, the paradoxical role of Kupffer cells in liver metastases, and the breakthrough of the blood-brain barrier (BBB) breach in brain metastases. Overall, this review provides a comprehensive overview of the characteristics of breast cancer metastases, shedding light on the pivotal roles of immune and resident cells in the development of distinct metastatic foci.

Exosomal mRNA in plasma serves as a predictive marker for microvascular invasion in hepatocellular carcinoma.

BACKGROUND AND AIM: There is a pressing need for non-invasive preoperative prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC). This study investigates the potential of exosome-derived mRNA in plasma as a biomarker for diagnosing MVI. METHODS: Patients with suspected HCC undergoing hepatectomy were prospectively recruited for preoperative peripheral blood collection. Exosomal RNA profiling was conducted using RNA sequencing in the discovery cohort, followed by differential expression analysis to identify candidate targets. We employed multiplexed droplet digital PCR technology to efficiently validate them in a larger sample size cohort. RESULTS: A total of 131 HCC patients were ultimately enrolled, with 37 in the discovery cohort and 94 in the validation cohort. In the validation cohort, the expression levels of RSAD2, PRPSAP1, and HOXA2 were slightly elevated while CHMP4A showed a slight decrease in patients with MVI compared with those without MVI. These trends were consistent with the findings in the discovery cohort, although they did not reach statistical significance (P > 0.05). Notably, the expression level of exosomal PRPSAP1 in plasma was significantly higher in patients with more than 5 MVI than in those without MVI (0.147 vs 0.070, P = 0.035). CONCLUSION: This study unveils the potential of exosome-derived PRPSAP1 in plasma as a promising indicator for predicting MVI status preoperatively.

Characterization and Reactivity of Copper(II) and Copper(III) σ-Aryl Intermediates in Aminoquinoline-Directed C-H Functionalization.

Over the past decade, numerous reports have focused on the development and applications of Cu-mediated C-H functionalization reactions; however, to date, little is known about the Cu intermediates involved in these transformations. This paper details the observation and characterization of CuII and CuIII intermediates in aminoquinoline-directed C(sp2)-H functionalization of a fluoroarene substrate. An initial C(sp2)-H activation at CuII occurs at room temperature to afford an isolable anionic cyclometalated CuII complex. This complex undergoes single-electron oxidation with ferrocenium or AgI salts under mild conditions (5 min at room temperature) to afford C(sp2)-C(sp2) or C(sp2)-NO2 coupling products. Spectroscopic studies implicate the formation of a transient diamagnetic CuIII-σ-aryl intermediate that undergoes either (i) a second C(sp2)-H activation at CuIII followed by C-C bond-forming reductive elimination or (ii) reaction with a NO2- nucleophile and C(sp2)-NO2 coupling.

Precise nano-system-based drug delivery and synergistic therapy against androgen receptor-positive triple-negative breast cancer.

Targeting androgen receptor (AR) has shown great therapeutic potential in triple-negative breast cancer (TNBC), yet its efficacy remains unsatisfactory. Here, we aimed to identify promising targeted agents that synergize with enzalutamide, a second-generation AR inhibitor, in TNBC. By using a strategy for screening drug combinations based on the Sensitivity Index (SI), we found that MK-8776, a selective checkpoint kinase1 (CHK1) inhibitor, showed favorable synergism with enzalutamide in AR-positive TNBC. The combination of enzalutamide and MK-8776 was found to exert more significant anti-tumor effects in TNBC than the single application of enzalutamide or MK-8776, respectively. Furthermore, a nanoparticle-based on hyaluronic acid (HA)-modified hollow-manganese dioxide (HMnO2), named HMnE&M@H, was established to encapsulate and deliver enzalutamide and MK-8776. This HA-modified nanosystem managed targeted activation via pH/glutathione responsiveness. HMnE&M@H repressed tumor growth more obviously than the simple addition of enzalutamide and MK-8776 without a carrier. Collectively, our study elucidated the synergy of enzalutamide and MK-8776 in TNBC and developed a novel tumor-targeted nano drug delivery system HMnE&M@H, providing a potential therapeutic approach for the treatment of TNBC.

POLQ identifies a better response subset to immunotherapy in muscle-invasive bladder cancer with high PD-L1.

BACKGROUND: Though programmed cell death-ligand 1 (PD-L1) has been used in predicting the efficacy of immune checkpoint blockade (ICB), it is insufficient as a single biomarker. As a key effector of an intrinsically mutagenic microhomology-mediated end joining (MMEJ) pathway, DNA polymerase theta (POLQ) was overexpressed in various malignancies, whose expression might have an influence on genomic stability, therefore altering the sensitivity to chemotherapy and immunotherapy. METHODS: A total of 1304 patients with muscle-invasive bladder cancer (MIBC) from six independent cohorts were included in this study. The Zhongshan Hospital (ZSHS) cohort (n = 134), The Cancer Genome Atlas (TCGA) cohort (n = 391), and the Neo-cohort (n = 148) were included for the investigation of chemotherapeutic response. The IMvigor210 cohort (n = 234) and the UNC-108 cohort (n = 89) were used for the assessment of immunotherapeutic response. In addition, the relationship between POLQ and the immune microenvironment was assessed, and GSE32894 (n = 308) was used only for the evaluation of the immune microenvironment. RESULTS: We identified POLQhigh PD-L1high patients could benefit more from immunotherapy and platinum-based chemotherapy. Further analysis revealed that high POLQ expression was linked to chromosome instability and higher tumor mutational burden (TMB), which might elicit the production of neoantigens. Further, high POLQ expression was associated with an active tumor immune microenvironment with abundant infiltration of immune effector cells and molecules. CONCLUSIONS: The study demonstrated that high POLQ expression was correlated with chromosome instability and antitumor immune microenvironment in MIBC, and the combination of POLQ and PD-L1 could be used as a superior companion biomarker for predicting the efficacy of immunotherapy.

RAD51 Expression as a Biomarker to Predict Efficacy of Platinum-Based Chemotherapy and PD-L1 Blockade for Muscle-Invasive Bladder Cancer.

RAD51, a key recombinase that catalyzes homologous recombination (HR), is commonly overexpressed in multiple cancers. It is curial for DNA damage repair (DDR) to maintain genomic integrity which could further determine the therapeutic response. Herein, we attempt to explore the clinical value of RAD51 in therapeutic guidance in muscle-invasive bladder cancer (MIBC). In this retrospective study, a total of 823 patients with MIBC were included. Zhongshan hospital (ZSHS) cohort (n=134) and The Cancer Genome Atlas-Bladder Cancer (TCGA-BLCA) cohort (n=391) were included for the investigation of chemotherapeutic response. The IMvigor210 cohort (n=298) was utilized to interrogate the predictive efficacy of RAD51 status to programmed cell death ligand-1 (PD-L1) blockade. In addition, the association of RAD51 with genomic instability and tumor immune contexture was investigated. Patients with RAD51 overexpression were more likely to benefit from both platinum-based chemotherapy and immunotherapy rather than RAD51-low patients. The TMB high PD-L1 high RAD51 high subgroup possessed the best clinical benefits from PD-L1 blockade. RAD51-high tumors featured by genomic instability were correlated to highly inflamed and immunogenic contexture with activated immunotherapeutic pathway in MIBC. RAD51 could serve as a prognosticator for treatment response to platinum-based chemotherapy and PD-L1 inhibitor in MIBC patients. Besides, it could also improve the predictive efficacy of TMB and PD-L1.

Harnessing the power of traditional Chinese medicine monomers and compound prescriptions to boost cancer immunotherapy.

At present, cancer is the largest culprit that endangers human health. The current treatment options for cancer mainly include surgical resection, adjuvant radiotherapy and chemotherapy, but their therapeutic effects and long-term prognosis are unsatisfactory. Immunotherapy is an emerging therapy that has completely transformed the therapeutic landscape of advanced cancers, and has tried to occupy a place in the neoadjuvant therapy of resectable tumors. However, not all patients respond to immunotherapy due to the immunological and molecular features of the tumors. Traditional Chinese Medicine (TCM) provides a new perspective for cancer treatment and is considered to have the potential as promising anti-tumor drugs considering its immunoregulatory properties. This review concludes commonly used TCM monomers and compounds from the perspective of immune regulatory pathways, aiming to clearly introduce the basic mechanisms of TCM in boosting cancer immunotherapy and mechanisms of several common TCM. In addition, we also summarized closed and ongoing trials and presented prospects for future development. Due to the significant role of immunotherapy in the treatment of non-small cell lung cancer (NSCLC), TCM combined with immunotherapy should be emphasized in NSCLC.

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.

Revealing the effects of static magnetic field on the anoxic/oxic sequencing batch reactor from the perspective of electron transport and microbial community shifts.

The effects of static magnetic field (SMF) on an anoxic/oxic sequencing batch reactor were investigated from the perspective of electron transport via determining the variations of reduced/oxidized nicotinamide adenine dinucleotide (NADH/NAD+) ratio, NADH concentration, electron transport system activity (ETSA), poly-ß-hydroxybutyrate (PHB), extracellular polymeric substances (EPS), as well as the gene expression under different conditions. Moreover, the shifts of microbial community were also analyzed. The application of SMF with an appropriate intensity significantly improved the performance of the process, the abundance of the anoxic denitrifiers, and the activity of the aerobic denitrifiers. The NADH content, as well as ETSA were also enhanced, therefore, the total nitrogen removal efficiency of the process was increased. However, the overhigh SMF intensity resulted in the change of microbial community, meanwhile, had negative effects on the metabolism of microorganisms. Selecting a proper intensity is crucial for the SMF-enhanced biological wastewater treatment process.

APOLLO: An accurate and independently validated prediction model of lower-grade gliomas overall survival and a comparative study of model performance.

BACKGROUND: Virtually few accurate and robust prediction models of lower-grade gliomas (LGG) survival exist that may aid physicians in making clinical decisions. We aimed to develop a prognostic prediction model of LGG by incorporating demographic, clinical and transcriptional biomarkers with either main effects or gene-gene interactions. METHODS: Based on gene expression profiles of 1,420 LGG patients from six independent cohorts comprising both European and Asian populations, we proposed a 3-D analysis strategy to develop and validate an Accurate Prediction mOdel of Lower-grade gLiomas Overall survival (APOLLO). We further conducted decision curve analysis to assess the net benefit (NB) of identifying true positives and the net reduction (NR) of unnecessary interventions. Finally, we compared the performance of APOLLO and the existing prediction models by the first systematic review. FINDINGS: APOLLO possessed an excellent discriminative ability to identify patients at high mortality risk. Compared to those with less than the 20th percentile of APOLLO risk score, patients with more than the 90th percentile of APOLLO risk score had significantly worse overall survival (HR=54·18, 95% CI: 34·73-84·52, P=2·66 × 10-69). Further, APOLLO can accurately predict both 36- and 60-month survival in six independent cohorts with a pooled AUC36-month=0·901 (95% CI: 0·879-0·923), AUC60-month=0·843 (95% CI: 0·815-0·871) and C-index=0·818 (95% CI: 0·800-0·835). Moreover, APOLLO offered an effective screening strategy for detecting LGG patients susceptible to death (NB36-month=0·166, NR36-month=40·1% and NB60-month=0·258, NR60-month=19·2%). The systematic comparisons revealed APOLLO outperformed the existing models in accuracy and robustness. INTERPRETATION: APOLLO has the demonstrated feasibility and utility of predicting LGG survival (http://bigdata.njmu.edu.cn/APOLLO). FUNDING: National Key Research and Development Program of China (2016YFE0204900); Natural Science Foundation of Jiangsu Province (BK20191354); National Natural Science Foundation of China (81973142 and 82103946); China Postdoctoral Science Foundation (2020M681671); National Institutes of Health (CA209414, CA249096, CA092824 and ES000002).

The complete mitochondrial genome of Indian Cuckoo Cuculus micropterus (Aves: Cuculiformes).

The Indian Cuckoo, Cuculus micropterus, belongs to the family Cuculidae. In this paper, we sequenced and analysized the complete mitochondrial genome of C. micropterus. The complete mitochondrial genome of C. micropterus is 17,541 bp in length, which was submitted to the NCBI database under the accession number MZ048030. It contains 13 protein-coding genes, 22 transfer RNA genes, two ribosome RNA genes, and one non-coding control region. The overall base composition of the mitochondrial DNA is 33.2% for A, 24.2% for T, 29.8% for C, and 12.8% for G, with a GC content of 42.6%. In order to explore the molecular phylogenetics evolution of Cuculidae, the nucleotide sequence data of 13 PCGs of C. micropterus and other 11 Cuculiformes were used for the phylogenetic analysis. The result shows that C. micropterus is closely related to Cuculus canorus bakeri. The study contributes to illuminating the taxonomic status of C. micropterus, and may facilitate further investigation of the evolution of Cuculidae.