Unravelling drivers of cutaneous squamous cell carcinoma in recessive dystrophic epidermolysis bullosa.

Epidermolysis bullosa (EB) is an umbrella term for a group of rare inherited skin disorders characterised by mucocutaneous fragility. Patients suffer from blisters and chronic wounds that arise spontaneously or following minor mechanical trauma, often resulting in inflammation, scarring and fibrosis due to poor healing. The recessive form of dystrophic EB (RDEB) has a particularly severe phenotype and is caused by mutations in the COL7A1 gene, encoding the collagen VII protein, which is responsible for adhering the epidermis and dermis together. One of the most feared and devastating complications of RDEB is the development of an aggressive form of cutaneous squamous cell carcinoma (cSCC), which is the main cause of mortality in this patient group. However, pathological drivers behind the development and progression of RDEB-associated cSCC (RDEB-cSCC) remain somewhat of an enigma, and the evidence to date points towards a complex process. Currently, there is no cure for RDEB-cSCC, and treatments primarily focus on prevention, symptom management and support. Therefore, there is an urgent need for a comprehensive understanding of this cancer's pathogenesis, with the aim of facilitating the discovery of drug targets. This review explores the current knowledge of RDEB-cSCC, emphasising the important role of the immune system, genetics, fibrosis, and the tumour-promoting microenvironment, all ultimately intricately interconnected.

A chain mediation model reveals the association between family sense of coherence and quality of life in caregivers of advanced cancer patients.

Caregivers of advanced cancer patients face challenges impacting their quality of life (QoL). While evidence suggests that family sense of coherence (FSOC) can enhance individual psychological well-being and reduce distress symptoms, the precise mechanism through which FSOC improves caregivers' QoL remains unclear. This study aimed to explore the relationships among FSOC, psychological resilience, psychological distress, and QoL in primary caregivers of advanced cancer patients. A cross-sectional observational study was undertaken from June 2020 to March 2021 across five tertiary hospitals in China. Instruments included a general characteristic questionnaire, the Family Sense of Coherence Scale, the Patient Health Questionnaire-4, the 10-item Connor-Davidson Resilience Scale, and the 8-item SF-8 health survey. Pearson's correlation and chain mediation analyses were performed using IBM SPSS (version 21) and PROCESS macro (version 3.4). Out of 290 valid questionnaires, results demonstrated that FSOC directly and positively influences caregivers' QoL. Psychological distress partially mediated the FSOC-QoL association, with paths "FSOC-psychological distress-QoL" and "FSOC-psychological resilience-psychological distress-QoL" contributing 43.08% and 6.72% of the total effect, respectively. Furthermore, this study distinguished physical and mental aspects of QoL, confirming both conform to the chain mediation model. FSOC impacts caregivers' QoL directly and indirectly through the mediation of psychological distress and the chain mediation effect of "psychological resilience-psychological distress". These insights enhance our understanding of the complex interplay between FSOC and QoL, underscoring the potential benefits of bolstering FSOC to strengthen caregiver resilience, alleviate distress, and ultimately elevate their QoL.

Regulatory microRNAs and phasiRNAs of paclitaxel biosynthesis in Taxus chinensis.

Paclitaxel (trade name Taxol) is a rare diterpenoid with anticancer activity isolated from Taxus. At present, paclitaxel is mainly produced by the semi-synthetic method using extract of Taxus tissues as raw materials. The studies of regulatory mechanisms in paclitaxel biosynthesis would promote the production of paclitaxel through tissue/cell culture approaches. Here, we systematically identified 990 transcription factors (TFs), 460 microRNAs (miRNAs), and 160 phased small interfering RNAs (phasiRNAs) in Taxus chinensis to explore their interactions and potential roles in regulation of paclitaxel synthesis. The expression levels of enzyme genes in cone and root were higher than those in leaf and bark. Nearly all enzyme genes in the paclitaxel synthesis pathway were significantly up-regulated after jasmonate treatment, except for GGPPS and CoA Ligase. The expression level of enzyme genes located in the latter steps of the synthesis pathway was significantly higher in female barks than in male. Regulatory TFs were inferred through co-expression network analysis, resulting in the identification of TFs from diverse families including MYB and AP2. Genes with ADP binding and copper ion binding functions were overrepresented in targets of miRNA genes. The miRNA targets were mainly enriched with genes in plant hormone signal transduction, mRNA surveillance pathway, cell cycle and DNA replication. Genes in oxidoreductase activity, protein-disulfide reductase activity were enriched in targets of phasiRNAs. Regulatory networks were further constructed including components of enzyme genes, TFs, miRNAs, and phasiRNAs. The hierarchical regulation of paclitaxel production by miRNAs and phasiRNAs indicates a robust regulation at post-transcriptional level. Our study on transcriptional and posttranscriptional regulation of paclitaxel synthesis provides clues for enhancing paclitaxel production using synthetic biology technology.

Integrated multi-omics analysis and machine learning identify hub genes and potential mechanisms of resistance to immunotherapy in gastric cancer.

BACKGROUND: Patients with gastric cancer respond poorly to immunotherapy. There are still unknowns about the biomarkers associated with immunotherapy sensitivity and their underlying molecular mechanisms. METHODS: Gene expression data for gastric cancer were gathered from TCGA and GEO databases. DEGs associated with immunotherapy response came from ICBatlas. KEGG and GO analyses investigated pathways. Hub genes identification employed multiple machine algorithms. Associations between hub genes and signaling pathways, disease genes, immune cell infiltration, drug sensitivity, and prognostic predictions were explored via multi-omics analysis. Hub gene expression was validated through HPA and CCLE. Multiple algorithms pinpointed Cancer-Associated Fibroblasts genes (CAFs), with ten machine-learning methods generating CAFs scores for prognosis. Model gene expression was validated at the single-cell level using the TISCH database. RESULTS: We identified 201 upregulated and 935 downregulated DEGs. Three hub genes, namely CDH6, EGFLAM, and RASGRF2, were unveiled. These genes are implicated in diverse disease-related signaling pathways. Additionally, they exhibited significant correlations with disease-associated gene expression, immune cell infiltration, and drug sensitivity. Exploration of the HPA and CCLE databases exposed substantial expression variations across patients and cell lines for these genes. Subsequently, we identified CAFs-associated genes and established a robust prognostic model. The analysis in the TISCH database showed that the genes in this model were highly expressed in CAFs. CONCLUSIONS: The results unveil an association between CDH6, EGFLAM, and RASGRF2 and the immunotherapeutic response in gastric cancer. These genes hold potential as predictive biomarkers for gastric cancer immunotherapy resistance and prognostic assessment.

GLP-1 modulated the firing activity of nigral dopaminergic neurons in both normal and parkinsonian mice.

The spontaneous firing activity of nigral dopaminergic neurons is associated with some important roles including modulation of dopamine release, expression of tyrosine hydroxylase (TH), as well as neuronal survival. The decreased neuroactivity of nigral dopaminergic neurons has been revealed in Parkinson's disease. Central glucagon-like peptide-1 (GLP-1) functions as a neurotransmitter or neuromodulator to exert multiple brain functions. Although morphological studies revealed the expression of GLP-1 receptors (GLP-1Rs) in the substantia nigra pars compacta, the possible modulation of GLP-1 on spontaneous firing activity of nigral dopaminergic neurons is unknown. The present extracellular in vivo single unit recordings revealed that GLP-1R agonist exendin-4 significantly increased the spontaneous firing rate and decreased the firing regularity of partial nigral dopaminergic neurons of adult male C57BL/6 mice. Blockade of GLP-1Rs by exendin (9-39) decreased the firing rate of nigral dopaminergic neurons suggesting the involvement of endogenous GLP-1 in the modulation of firing activity. Furthermore, the PKA and the transient receptor potential canonical (TRPC) 4/5 channels are involved in activation of GLP-1Rs-induced excitatory effects of nigral dopaminergic neurons. Under parkinsonian state, both the exogenous and endogenous GLP-1 could still induce excitatory effects on the surviving nigral dopaminergic neurons. As the mild excitatory stimuli exert neuroprotective effects on nigral dopaminergic neurons, the present GLP-1-induced excitatory effects may partially contribute to its antiparkinsonian effects.

Incidence and analysis of intraoperative complications in femtosecond laser-assisted cataract surgery: a large-scale cohort study to establish the learning curve.

AIMS: To assess the safety of femtosecond laser-assisted cataract surgery (FLACS) based on surgical parameters and intraoperative complications analysis and to determine the length of the learning curve for FLACS. METHODS: A prospective consecutive cohort study was conducted on Chinese patients who underwent either FLACS (3289 cases) or contemporaneous conventional phacoemulsification cataract surgery (2130 cases). The laser group was divided into four subgroups in chronological order. We recorded intraoperative complication incidences and compared with surgical parameters between groups. Subgroup analysis was conducted to explore the learning curve of FLACS. RESULTS: The laser group had a 4.93% incidence of incomplete capsulotomies and a 1.22% incidence of anterior capsule tears. Subgroup analysis showed significant differences in 8 aspects between the first 250 cases (50 cases per surgeon) and the last 2539 cases, but only 2 aspects differed between the second 250 cases (50 cases per surgeon) and the last 2539 cases. There were no significant differences between the third 250 cases (50 cases per surgeon) and the last 2539 cases. CONCLUSIONS: The intraoperative complications of FLACS were reported, and the learning curve is associated with a significant reduction in the incidence of intraoperative complications. The length of the basic learning curve of FLACS is 100 cases, and the length of the advanced learning curve was 150 cases. This study demonstrated that FLACS is characterised by a relatively straightforward and secure operative technique.

A dynamic nomogram for predict individual risk of malignant brain edema after endovascular thrombectomy in acute ischemic stroke.

The aim of this study was to develop a dynamic nomogram combining clinical and imaging data to predict malignant brain edema (MBE) after endovascular thrombectomy (EVT) in patients with large vessel occlusion stroke (LVOS). We analyzed the data of LVOS patients receiving EVT at our center from October 2018 to February 2023, and divided a 7:3 ratio into the training cohort and internal validation cohort, and we also prospectively collected patients from another stroke center for external validation. MBE was defined as a midline shift or pineal gland shift > 5 mm, as determined by computed tomography (CT) scans obtained within 7 days after EVT. A nomogram was constructed using logistic regression analysis, and its receiver operating characteristic curve (ROC) and calibration were assessed in three cohorts. A total of 432 patients were enrolled in this study, with 247 in the training cohort, 100 in the internal validation cohort, and 85 in the external validation cohort. MBE occurred in 24% (59) in the training cohort, 16% (16) in the internal validation cohort and 14% (12) in the external validation cohort. After adjusting for various confounding factors, we constructed a nomogram including the clot burden score (CBS), baseline neutrophil count, core infarct volume on CTP before EVT, collateral index, and the number of retrieval attempts. The AUCs of the training cohorts were 0.891 (95% CI 0.840-0.942), the Hosmer-Lemeshow test showed good calibration of the nomogram (P = 0.879). And our nomogram performed well in both internal and external validation data. Our nomogram demonstrates promising potential in identifying patients at elevated risk of MBE following EVT for LVOS.

Azacitidine combined with venetoclax alleviates AML-MR with TP53 mutation in SDS: a case report and literature review.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive genetic disease, which is prone to transform into myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). TP53 mutation is a driving factor involved in the transformation of SDS into MDS/AML, and in the evolution of MDS to AML. Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only curable approach, however, challenge remains regarding the balance between efficacy and the high risk from treatment-related toxicity and mortality to achieve temporary disease control before transplantation to gain time and opportunities for transplantation. At present, pre-transplant bridging therapy has emerged as one of the important options with improved efficacy, reduced tumor burden, and less treatment-related toxicity. Here we reported azacitidine combined with venetoclax was used as pre-transplant bridging regimen in a TP53-mutant AML-MR case developed from SDS. He achieved complete remission with incomplete recovery and proceeded to Allo-HSCT. We hope to provide some evidence and insight for in-depth research and clinical treatment by presenting this case.

The impact of caregiver burden on quality of life in family caregivers of patients with advanced cancer: a moderated mediation analysis of the role of psychological distress and family resilience.

BACKGROUND: The caregiver burden frequently experienced by family members tending to advanced cancer patients significantly impacts their psychological well-being and quality of life (QoL). Although family resilience might function as a mitigating factor in this relationship, its specific role remains to be elucidated. This study aims to probe the mediating effect of psychological distress on the relationship between caregiver burden and QoL, as well as the moderating effect of family resilience. METHODS: A cross-sectional study was conducted between June 2020 and March 2021 in five tertiary hospitals in China. Data were collected on caregiver burden, family resilience, psychological distress (including anxiety and depression), and QoL. Moderated mediation analysis was performed. RESULTS: Data analysis included 290 caregivers. It confirmed the mediating role of psychological distress in the caregiver burden-QoL relationship (P < 0.001). Both overall family resilience and the specific dimension of family communication and problem-solving (FCPS) demonstrated significant moderating effects on the "psychological distress/anxiety-QoL" paths (P < 0.05). The utilization of social and economic resources (USER) significantly moderated the association between depression and QoL (P < 0.05). CONCLUSIONS: The study corroborates psychological distress's mediation between caregiver burden and QoL and family resilience's moderation between psychological distress and QoL. It underscores the need for minimizing psychological distress and bolstering family resilience among caregivers of advanced cancer patients. Accordingly, interventions should be tailored, inclusive of psychological assistance and promotion of family resilience, particularly focusing on FCPS and USER, to augment the caregivers' well-being and QoL.

Dbl family RhoGEFs in cancer: different roles and targeting strategies.

Small Ras homologous guanosine triphosphatase (Rho GTPase) family proteins are highly associated with tumorigenesis and development. As intrinsic exchange activity regulators of Rho GTPases, Rho guanine nucleotide exchange factors (RhoGEFs) have been demonstrated to be closely involved in tumor development and received increasing attention. They mainly contain two families: the diffuse B-cell lymphoma (Dbl) family and the dedicator of cytokinesis (Dock) family. More and more emphasis has been paid to the Dbl family members for their abnormally high expression in various cancers and their correlation to poor prognosis. In this review, the common and distinctive structures of Dbl family members are discussed, and their roles in cancer are summarized with a focus on Ect2, Tiam1/2, P-Rex1/2, Vav1/2/3, Trio, KALRN, and LARG. Significantly, the strategies targeting Dbl family RhoGEFs are highlighted as novel therapeutic opportunities for cancer.

RUNX transcription factors: biological functions and implications in cancer.

Runt-related transcription factors (RUNX) are a family of transcription factors that are essential for normal and malignant hematopoietic processes. Their most widely recognized role in malignancy is to promote the occurrence and development of acute myeloid leukemia. However, it is worth noting that during the last decade, studies of RUNX proteins in solid tumors have made considerable progress, suggesting that these proteins are directly involved in different stages of tumor development, including tumor initiation, progression, and invasion. RUNX proteins also play a role in tumor angiogenesis, the maintenance of tumor cell stemness, and resistance to antitumor drugs. These findings have led to the consideration of RUNX as a tumor biomarker. All RUNX proteins are involved in the occurrence and development of solid tumors, but the role of each RUNX protein in different tumors and the major signaling pathways involved are complicated by tumor heterogeneity and the interacting tumor microenvironment. Understanding how the dysregulation of RUNX in tumors affects normal biological processes is important to elucidate the molecular mechanisms by which RUNX affects malignant tumors.

Identification of recurrent BRAF non-V600 mutations in intraductal carcinoma of the prostate in Chinese populations.

While BRAF alterations have been established as a driver in various solid malignancies, the characterization of BRAF alterations in prostate cancer (PCa) has not been thoroughly interrogated. By bioinformatics analysis, we first found that BRAF alterations were associated with advanced PCa and exhibited mutually exclusive pattern with ERG alteration across multiple cohorts. Of the most interest, recurrent non-V600 BRAF mutations were found in 3 of 21 (14.3 %) PCa patients demonstrating IDC-P morphology. Furthermore, experimental overexpression of BRAFK601E and BRAFL597R exhibited emergence of oncogenic phenotypes with intensified MAPK signaling in vitro, which could be targeted by MEK inhibitors. Comparison of the incidence of BRAF alterations in IDC-P between western and Chinese ancestry revealed an increased prevalence in the Chinese population. The BRAF mutation may represent important genetic alteration in a subset of IDC-P, highlighting the role of MAPK signaling pathway in this subtype of PCa. To the best of knowledge, this is the first description of non-V600 BRAF mutation in setting of IDC-P, which may in part explain the aggressive phenotype seen in IDC-P and could also bring more treatment options for PCa patients with IDC-P harboring such mutations.

MUC1 and MUC16: critical for immune modulation in cancer therapeutics.

The Mucin (MUC) family, a range of highly glycosylated macromolecules, is ubiquitously expressed in mammalian epithelial cells. Such molecules are pivotal in establishing protective mucosal barriers, serving as defenses against pathogenic assaults. Intriguingly, the aberrant expression of specific MUC proteins, notably Mucin 1 (MUC1) and Mucin 16 (MUC16), within tumor cells, is intimately associated with oncogenesis, proliferation, and metastasis. This association involves various mechanisms, including cellular proliferation, viability, apoptosis resistance, chemotherapeutic resilience, metabolic shifts, and immune surveillance evasion. Due to their distinctive biological roles and structural features in oncology, MUC proteins have attracted considerable attention as prospective targets and biomarkers in cancer therapy. The current review offers an exhaustive exploration of the roles of MUC1 and MUC16 in the context of cancer biomarkers, elucidating their critical contributions to the mechanisms of cellular signal transduction, regulation of immune responses, and the modulation of the tumor microenvironment. Additionally, the article evaluates the latest advances in therapeutic strategies targeting these mucins, focusing on innovations in immunotherapies and targeted drugs, aiming to enhance customization and accuracy in cancer treatments.

Research on different compound combinations of Realgar-Indigo naturalis formula to reverse acute promyelocytic leukemia arsenic resistance by regulating autophagy through mTOR pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: In China, the Chinese patent drug Realgar-Indigo naturalis Formula (RIF) is utilized for the therapy of acute promyelocytic leukemia (APL). Comprising four traditional Chinese herb-Realgar, Indigo naturalis, Salvia miltiorrhiza, and Pseudostellaria heterophylla-it notably includes tetra-arsenic tetra-sulfide, indirubin, tanshinone IIa, and total saponins of Radix Pseudostellariae as its primary active components. Due to its arsenic content, RIF distinctly contributes to the therapy for APL. However, the challenge of arsenic resistance in APL patients complicates the clinical use of arsenic agents. Interestingly, RIF demonstrates a high remission rate in APL patients, suggesting that its efficacy is not significantly compromised by arsenic resistance. Yet, the current state of research on RIF's ability to reverse arsenic resistance remains unclear. AIM OF THE STUDY: To investigate the mechanism of different combinations of the compound of RIF in reversing arsenic resistance in APL. MATERIALS AND METHODS: The present study utilized the arsenic-resistant HL60-PMLA216V-RARα cell line to investigate the effects of various RIF compounds, namely tetra-arsenic tetra-sulfide (A), indirubin (I), tanshinone IIa (T), and total saponins of Radix Pseudostellariae (S). The assessment of cell viability, observation of cell morphology, and evaluation of cell apoptosis were performed. Furthermore, the mitochondrial membrane potential, changes in the levels of PMLA216V-RARα, apoptosis-related factors, and the PI3K/AKT/mTOR pathway were examined, along with autophagy in all experimental groups. Meanwhile, we observed the changes about autophagy after blocking the PI3K or mTOR pathway. RESULTS: Tanshinone IIa, indirubin and total saponins of Radix Pseudostellariae could enhance the effect of tetra-arsenic tetra-sulfide down-regulating PMLA216V-RARα, and the mechanism was suggested to be related to inhibiting mTOR pathway to activate autophagy. CONCLUSIONS: We illustrated that the synergistic effect of different compound combinations of RIF can regulate autophagy through the mTOR pathway, enhance cell apoptosis, and degrade arsenic-resistant PMLA216V-RARα.

Previously undescribed tetrahydroanthraquinones from Prismatomeris tetrandra (roxb.) K. Schum with antitumor cell proliferation activities.

To find structurally previously undescribed compounds with pharmacological effects from Prismatomeris tetrandra (Roxb.) K. Schum (Rubiaceae), thirteen undescribed tetrahydroanthraquinones (1⎼13) named prisconnatanones J⎼V and seven known anthraquinones (14⎼20) were isolated and characterized. The structures of these compounds were elucidated by detailed spectroscopic analyses, and their absolute configurations were established by modified Mosher's method and ECD calculations. The antitumor cell proliferative activities of prisconnatanones J⎼V were determined. Among them, prisconnatanones J possessed high antitumor cell proliferation in HGC27 cells (IC50, 0.792 µM) by blocking HGC27 cells in the S phase and significantly inducing apoptosis in HGC27 cells. Prisconnatanone J has no cytotoxicity to normal gastric cells line (GES-1) at 10 µM and showed a considerable selectivity for HGC27 cells. Prisconnatanone J can potentially inhibit tumor cell proliferation and should be further investigated.

Novel application of the ferroptosis-related genes risk model associated with disulfidptosis in hepatocellular carcinoma prognosis and immune infiltration.

Hepatocellular carcinoma (HCC) stands as the prevailing manifestation of primary liver cancer and continues to pose a formidable challenge to human well-being and longevity, owing to its elevated incidence and mortality rates. Nevertheless, the quest for reliable predictive biomarkers for HCC remains ongoing. Recent research has demonstrated a close correlation between ferroptosis and disulfidptosis, two cellular processes, and cancer prognosis, suggesting their potential as predictive factors for HCC. In this study, we employed a combination of bioinformatics algorithms and machine learning techniques, leveraging RNA sequencing data, mutation profiles, and clinical data from HCC samples in The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and the International Cancer Genome Consortium (ICGC) databases, to develop a risk prognosis model based on genes associated with ferroptosis and disulfidptosis. We conducted an unsupervised clustering analysis, calculating a risk score (RS) to predict the prognosis of HCC using these genes. Clustering analysis revealed two distinct HCC clusters, each characterized by significantly different prognostic and immune features. The median RS stratified HCC samples in the TCGA, GEO, and ICGC cohorts into high-and low-risk groups. Importantly, RS emerged as an independent prognostic factor in all three cohorts, with the high-risk group demonstrating poorer prognosis and a more active immunosuppressive microenvironment. Additionally, the high-risk group exhibited higher expression levels of tumor mutation burden (TMB), immune checkpoints (ICs), and human leukocyte antigen (HLA), suggesting a heightened responsiveness to immunotherapy. A cancer stem cell infiltration analysis revealed a higher similarity between tumor cells and stem cells in the high-risk group. Furthermore, drug sensitivity analysis highlighted significant differences in response to antitumor drugs between the two risk groups. In summary, our risk prognostic model, constructed based on ferroptosis-related genes associated with disulfidptosis, effectively predicts HCC prognosis. These findings hold potential implications for patient stratification and clinical decision-making, offering valuable theoretical insights in this field.

Discovery of novel, potent, selective and orally bioavailable HPK1 inhibitor for enhancing the efficacy of anti-PD-L1 antibody.

Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase in the MAP4K family, is expressed predominantly in immune cells, and has been identified as a negative regulator of immune signaling. Accumulating evidences demonstrated that loss of HPK1 kinase function effectively enhances anti-tumor responses. In this study, we disclose the medicinal chemistry campaigns to discovery potent, selective, and orally active HPK1 inhibitors, starting from our previous work based on rigidification strategy. Systematically structure-activity relationship (SAR) exploration led to the identification of F03 (HMC-B17). The representative compound, HMC-B17, showed the potent HPK1 inhibition with an IC50 value of 1.39 nM and favorable selectivity against TCR-related kinases. In addition, the HMC-B17 effectively enhanced the IL-2 secretion in Jurkat cells (EC50 = 11.56 nM). Strikingly, immune-reverse effects and improved immune response in vivo were observed after HMC-B17 treatment. Furthermore, HMC-B17 combined with anti-PD-L1 antibody demonstrated a synergistic antitumor efficacy with TGI% value of 71.24 % in CT26 model. Collectively, our findings suggest that HMC-B17 could be a valuable lead compound to develop a safe and potent HPK1 inhibitor for further cancer immunotherapy.

Multiregion sampling of de novo metastatic prostate cancer reveals complex polyclonality and augments clinical genotyping.

De novo metastatic prostate cancer is highly aggressive, but the paucity of routinely collected tissue has hindered genomic stratification and precision oncology. Here, we leveraged a rare study of surgical intervention in 43 de novo metastatic prostate cancers to assess somatic genotypes across 607 synchronous primary and metastatic tissue regions plus circulating tumor DNA. Intra-prostate heterogeneity was pervasive and impacted clinically relevant genes, resulting in discordant genotypes between select primary restricted regions and synchronous metastases. Additional complexity was driven by polyclonal metastatic seeding from phylogenetically related primary populations. When simulating clinical practice relying on a single tissue region, genomic heterogeneity plus variable tumor fraction across samples caused inaccurate genotyping of dominant disease; however, pooling extracted DNA from multiple biopsy cores before sequencing can rescue misassigned somatic genotypes. Our results define the relationship between synchronous treatment-sensitive primary and metastatic lesions in men with de novo metastatic prostate cancer and provide a framework for implementing genomics-guided patient management.

Integrated Bulk and Single-cell RNA Sequencing Data Constructs and Validates a Prognostic Model for Non-small Cell Lung Cancer.

Background: Most of the current research on prognostic model construction for non-small cell lung cancer (NSCLC) only involves in bulk RNA-seq data without integration of single-cell RNA-seq (scRNA-seq) data. Besides, most of the prognostic models are constructed by predictive genes, ignoring other predictive variables such as clinical features. Methods: We obtained scRNA-seq data from GEO database and bulk RNA-seq data from TCGA database. We construct a prognostic model through the Least Absolute Shrinkage and Selection Operator (LASSO) and Cox regression. Furthermore, we performed ESTIMATE, CIBERSORT, immune checkpoint-related analyses and compared drug sensitivity using pRRophetic method judged by IC50 between different risk groups. Results: 14 tumor-related genes were extracted for model construction. The AUC for 1-, 3-, and 5 years overall survival prediction in TCGA and three validation cohorts were almost higher than 0.65, some of which were even higher than 0.7, even 0.8. Besides, calibration curves suggested no departure between model prediction and perfect fit. Additionally, immune-related and drug sensitivity results revealed potential targets and strategies for treatment, which can provide clinical guidance. Conclusion: We integrated traditional bulk RNA-seq and scRNA-seq data, along with predictive clinical features to develop a prognostic model for patients with NSCLC. According to the constructed model, patients in different groups can follow precise and individual therapeutic schedules based on immune characteristics as well as drug sensitivity.