Tumor protein 53 mutation (TP53mut) is one of the most important driver events facilitating tumorigenesis, which could induce a series of chain reactions to promote tumor malignant transformation. However, the malignancy progression patterns under TP53 mutation remain less known. Clarifying the molecular landscapes of TP53mut tumors will help us understand the process of tumor development and aid precise treatment. Here, we distilled genetic and epigenetic features altered in TP53mut cancers for cluster-of-clusters analysis. Using integrated classification, we derived 5 different subtypes of TP53mut patients. These subtypes have distinct features in genomic alteration, clinical relevance, microenvironment dysregulation, and potential therapeutics. Among the 5 subtypes, COCA3 was identified as the subtype with worst prognosis, causing an immunosuppressive microenvironment and immunotherapeutic resistance. Further drug efficacy research highlighted olaparib as the most promising therapeutic agents for COCA3 tumors. Importantly, the therapeutic efficacy of olaparib in COCA3 and immunotherapy in non-COCA3 tumors was validated via in vivo experimentation. Our study explored the important molecular events and developed a subtype classification system with distinct targeted therapy strategies for different subtypes of TP53mut tumors. These multiomics classification systems provide a valuable resource that significantly expands the knowledge of TP53mut tumors and may eventually benefit in clinical practice.
In many metazoans, germ cells are separated from somatic lineages early in development and maintain their identity throughout life. Here, we show that a Polycomb group (PcG) component, Enhancer of Zeste [E(z)], a histone transferase that generates trimethylation at lysine 27 of histone H3, maintains germline identity in Drosophila adult testes. We find excessive early-stage somatic gonadal cells in E(z) mutant testes, which originate from both overproliferative cyst stem cells and germ cells turning on an early-stage somatic cell marker. Using complementary lineage-tracing experiments in E(z) mutant testes, a portion of excessive early-stage somatic gonadal cells are found to originate from early-stage germ cells, including germline stem cells. Moreover, knocking down E(z) specifically in somatic cells caused this change, which suggests a non-cell autonomous role of E(z) to antagonize somatic identity in germ cells.
Gardenia blue (GB) is a natural blue pigment that possesses high stability. The hydrolysis of geniposide with β-glucosidases (Bgls) is a pivotal stage in the formation of GB. For the first time, BglY442 was identified uniquely as a Bgl in glycoside hydrolyzing family 1 (GH1) from hot-spring sediment metagenomic data. The maximum activity of BglY442 was exhibited at a temperature of 75 ℃ and a pH of 6.0. Furthermore, it exhibited a maximum specific activity of 235 U/mg when assessed with p-nitrophenyl β-D-glucopyranoside (pNPG) under optimum conditions.In addition, BglY442 exhibited remarkable thermostability, as it maintained 50% of its activity following incubation at 70 ℃ for 36 h. Furthermore, the activity of BglY442 increased more than four times when the reaction system contained 2 M glucose or xylose with pNPG as a substrate. The investigation of kinetic parameters revealed that Km was 0.75 mM and Kcat was 35.94 s-1. Molecular docking analysis indicated that the enzyme had a similar catalytic mechanism to reported GH1 Bgls.BglY442 was subjected to produce GB with geniposide and Arg or Met under optimum conditions. The OD590nm of GB was detected to be 1.06 after 24 h with the addition of Arg, and 1.6 after 36 h with the addition of Met. BglY442 demonstrated promising capabilities for the production of GB by the one-step method. Given its notable thermal stability and glucose tolerance, BglY442 exhibits considerable potential as a Bgl for various biotechnological applications.
The treatment options for cancer of unknown primary (CUP) are challenging due to the lack of knowledge about the primary sites, often resulting in a poor prognosis. The emerging next-generation sequencing (NGS) technique has provided a reliable approach to facilitate tumor primary site prediction and targetable gene alteration identification for CUP patients. In this report, we described a 63-year-old female patient who experienced recurrent CUP. NGS-based genetic profiling results revealed a pathogenic germline BRCA1 R71K mutation. Accordingly, the patient received the poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor olaparib treatment and demonstrated a favorable response to this treatment. Our case suggests that NGS holds great promise for providing improved diagnosis and treatment options to patients with CUP, warranting further clinical investigation.
Background: Recessive mutations in ETFDH gene have been associated with Multiple Acyl-CoA dehydrogenase deficiency (MADD). The late-onset MADD is often muscle involved, presenting with lipid storage myopathy (LSM). The symptoms of LSM were heterogeneous and definite diagnosis of this disease depends on the pathology and gene test.Methods: Neurological examination, muscle biopsy, and MRI examinations were performed in a patient with a novel missense ETFDH mutation.Results: We describe a patient with lipid storage myopathy complicated with skin damage. In addition, the next generation revealed a novel missense mutation (c.970G > T, p.Val324Leu) in exon 8, which was predicted to be a disease-causing mutation by Mutation-taster, and destroy the function of the protein by Sift.Conclusion: These findings expand the known mutational spectrum of ETFDH and phenotype of MADD.
Vaccinium duclouxii is an endemic species in China, which is distributed in Sichuan and Yunnan province of China. The chloroplast (cp) genome of V. duclouxii is 168,953 bp in size containing 123 unique genes, including 8 rRNA genes, 38 tRNA genes, and 77 protein-coding genes (PCGs). Phylogenetic analysis exhibited that V. duclouxii and V. macrocarpon were most related to Arbutus unedo.
Abstract Background Emerging evidence has underscored infiltrating immune cells in the tumor microenvironment (TME) of non‐small cell lung cancer (NSCLC). Owing to screening programs, the prevalence of early‐stage NSCLC is growing, but its high recurrence risk and poor survival impose an increasing demand for further understanding the TME. Methods Tissue and plasma samples from 33 resectable stage IA NSCLC patients were collected from the surgery and subject to histological and genomic analyses. The distribution of CD8+ T cells, tumor‐associated macrophages (TAMs, M1 polarization and M2 polarization), and natural killer (NK) cells (CD56dim and CD56bright) was analyzed. The impact of clinical characteristics and immunotherapy‐related biomarkers on immune cell infiltration were also investigated. Results Using multiplex immunohistochemistry (mIHC), we found a significantly higher M1 polarization proportion of total TAMs in tumor parenchyma than in other tissues, while other immune cells remained stable. Patients under 50 showed higher infiltrating CD8+ T cell density and M1 ratio in tumor tissues. Tumors carrying RAS‐MAPK mutations were associated with significantly increased infiltration of CD8+ T cells. We also identified significantly higher infiltration of CD8+ T cells and enrichment of CD56bright NK cells in high tumor mutation burden (TMB) and high programmed cell death ligand 1 (PD‐L1) samples, respectively. Conclusions Our study highlighted the heterogeneity and dynamics of infiltrating immune cells in stage IA NSCLC TME, featured by M1 TAM enrichment in tumor parenchyma. Age, driver mutation type, TMB, and PD‐L1 level were found to associate with immune cell infiltration in the TME, shedding light on immunotherapy development.
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