Comprehensive landscape and interference of clonal haematopoiesis mutations for liquid biopsy: A Chinese pan-cancer cohort

Tumour-derived DNA found in the plasma of cancer patients provides the probability to detect somatic mutations from circulating cell-free DNA (cfDNA) in plasma samples. However, clonal hematopoiesis (CH) mutations affect the accuracy of liquid biopsy for cancer diagnosis and treatment. Here, we integrated landscape of CH mutations in 11,725 pan-cancer patients of Chinese and explored effects of CH on liquid biopsies in real-world. We first identified 5933 CHs based on panel sequencing of matched DNA of white blood cell and cfDNA on 301 genes for 5100 patients, in which CH number of patients had positive correlation with their diagnosis age. We observed that canonical genes related to CH, including DNMT3A, TET2, ASXL1, TP53, ATM, CHEK2 and SF3B1, were dominant in the Chinese cohort and 13.29% of CH mutations only appeared in the Chinese cohort compared with the Western cohort. Analysis of CH gene distribution bias indicated that CH tended to appear in genes with functions of tyrosine kinase regulation, PI3K-Akt signalling and TP53 activity, suggesting unfavourable effects of CH mutations in cancer patients. We further confirmed effect of driver genes carried by CH on somatic mutations in liquid biopsy of cancer patients. Forty-eight actionable somatic mutations in 17 driver genes were considered CH genes in 92 patients (1.80%) of the Chinese cohort, implying potential impacts of CH on clinical decision-making. Taken together, this study exhibits strong evidence that gene mutations from CH interfere accuracy of liquid biopsies using cfDNA in cancer diagnosis and treatment in real-world.     

The emerging roles of NGS-based liquid biopsy in non-small cell lung cancer

The treatment paradigm of non-small cell lung cancer (NSCLC) has evolved into oncogene-directed precision medicine. Identifying actionable genomic alterations is the initial step towards precision medicine. An important scientific progress in molecular profiling of NSCLC over the past decade is the shift from the traditional piecemeal fashion to massively parallel sequencing with the use of next-generation sequencing (NGS). Another technical advance is the development of liquid biopsy with great potential in providing a dynamic and comprehensive genomic profiling of NSCLC in a minimally invasive manner. The integration of NGS with liquid biopsy has been demonstrated to play emerging roles in genomic profiling of NSCLC by increasing evidences. This review summarized the potential applications of NGS-based liquid biopsy in the diagnosis and treatment of NSCLC including identifying actionable genomic alterations, tracking spatiotemporal tumor evolution, dynamically monitoring response and resistance to targeted therapies, and diagnostic value in early-stage NSCLC, and discussed emerging challenges to overcome in order to facilitate clinical translation in future.     

肿瘤液态活检的研究进展及其临床应用

液态活检是一类新兴的病理检测手段,其研究内容包括肿瘤循环细胞、肿瘤循环DNA、外泌体等物质,其中的信息为肿瘤患者的个性化医疗提供有力的依据。它凭借无创、便捷等优势在临床应用中展现出广大前景。近年来,随着液态活检研究内容的扩大及其捕获与检测技术的发展,液态活检在临床中的应用日益广泛。本文旨在探讨近年来液态活检的主要研究对象、检测技术以及在临床应用中的发展前景与所面临的挑战,以期为肿瘤患者获得更佳的治疗,推动肿瘤精准医学的发展。     

The unique chemistry of benzoxaboroles: Current and emerging applications in biotechnology and therapeutic treatments

Benzoxaboroles have garnered much attention in recent years due to their diverse applications in bio-sensing technology, material science, and therapeutic intervention. Part of the reason arises from the benzoxaboroles’ unique chemical properties, especially in comparison to their acyclic boronic acid counterparts. Furthermore, the low bio-toxicity combined with the high target specificity associated with benzoxaboroles make them very attractive as therapeutic agents. Herein, we provide an updated summary on the current knowledge of the fundamental chemical reactivity of benzoxaboroles, followed by highlighting their major applications reported to date.     

Prion-based nanomaterials and their emerging applications

ABSTRACT

Protein misfolding and aggregation into highly ordered fibrillar structures have been traditionally associated with pathological processes. Nevertheless, nature has taken advantage of the particular properties of amyloids for functional purposes, like in the protection of organisms against environmental changing conditions. Over the last decades, these fibrillar structures have inspired the design of new nanomaterials with intriguing applications in biomedicine and nanotechnology such as tissue engineering, drug delivery, adhesive materials, biodegradable nanocomposites, nanowires or biosensors. Prion and prion-like proteins, which are considered a subclass of amyloids, are becoming ideal candidates for the design of new and tunable nanomaterials. In this review, we discuss the particular properties of this kind of proteins, and the current advances on the design of new materials based on prion sequences.     

Current and emerging commercial optical biosensors.

The field of commercial optical biosensors is rapidly evolving, with new systems and detection methods being developed each year. This review outlines the currently available biosensor hardware and highlights unique features of each platform. Affinity-based biosensor technology, with its high sensitivity, wide versatility and high throughput, is playing a significant role in basic research, pharmaceutical development, and the food and environmental sciences. Likewise, the increasing popularity of biosensors is prompting manufacturers to develop new instrumentation for dedicated applications. We provide a preview of some of the emerging commercial systems that are dedicated to drug discovery, proteomics, clinical diagnostics and routine biomolecular interaction analysis.     

Prognostic and immunological role of Fam20C in pan-cancer

Background: The family with sequence similarity 20-member C (Fam20C) kinase plays important roles in physiopathological process and is responsible for majority of the secreted phosphoproteome, including substrates associated with tumor cell migration. However, it remains unclear whether Fam20C plays a role in cancers. Here, we aimed to analyze the expression and prognostic value of Fam20C in pan-cancer and to gain insights into the association between Fam20C and immune infiltration.Methods: We analyzed Fam20C expression patterns and the associations between Fam20C expression levels and prognosis in pan-cancer via the ONCOMINE, TIMER (Tumor Immune Estimation Resource), PrognoScan, GEPIA (Gene Expression Profiling Interactive Analysis), and Kaplan–Meier Plotter databases. After that, GEPIA and TIMER databases were applied to investigate the relations between Fam20C expression and immune infiltration across different cancer types, especially BLCA (bladder urothelial carcinoma), LGG (brain lower grade glioma), and STAD (stomach adenocarcinoma).Results: Compared with adjacent normal tissues, Fam20C was widely expressed across many cancers. In general, Fam20C showed a detrimental role in pan-cancer, it was positively associated with poor survival of BLCA, LGG, and STAD patients. Specifically, based on TCGA (The Cancer Genome Atlas) database, a high expression level of Fam20C was associated with worse prognostic value in stages T2–T4 and stages N0–N2 in the cohort of STAD patients. Moreover, Fam20C expression had positive associations with immune infiltration, including CD4⁺ T cells, macrophages, neutrophils, and dendritic cells, and other diverse immune cells in BLCA, LGG, and STAD.Conclusion: Fam20C may serve as a promising prognostic biomarker in pan-cancer and has positive associations with immune infiltrates.     

Current and emerging vascularization strategies in skin tissue engineering

Vascularization is a key process in skin tissue engineering, determining the biological function of artificial skin implants. Hence, efficient vascularization strategies are a major prerequisite for the safe application of these implants in clinical practice. Current approaches include (i) modification of structural and physicochemical properties of dermal scaffolds, (ii) biological scaffold activation with growth factor-releasing systems or gene vectors, and (iii) generation of prevascularized skin substitutes by seeding scaffolds with vessel-forming cells. These conventional approaches may be further supplemented by emerging strategies, such as transplantation of adipose tissue-derived microvascular fragments, 3D bioprinting and microfluidics, miRNA modulation, cell sheet engineering, and fabrication of photosynthetic scaffolds. The successful translation of these vascularization strategies from bench to bedside may pave the way for a broad clinical implementation of skin tissue engineering.     

Integrative epigenetic and genetic pan-cancer somatic alteration portraits

Genetic and epigenetic alterations are required for carcinogenesis and the mutation burden across tumor types has been investigated. Here, we investigate epigenetic alterations with a novel measure of global DNA methylation dysregulation, the methylation dysregulation index (MDI), across 14 cancer types in The Cancer Genome Atlas (TCGA) database. DNA methylation data—obtained using Illumina HumanMethylation450 BeadChip—was accessed from TCGA. We calculated the MDI in 14 tumor types (n = 5,592 tumors), using adjacent normal tissues (n = 701) from each tumor site. Copy number alteration, and mutation burden were retrieved from cBioportal (n = 5,152). We tested the relation of subject MDI across tumors and with age, gender, tumor stage, estimated tumor purity, and copy number alterations for both overall MDI and genomic-context-specific MDI. We also investigated the top most dysregulated loci shared across tumor types. There was a broad range of extent in methylation dysregulation across tumor types (P < 2.2E-16). However, a consistent pattern of methylation dysregulation stratified by genomic context was observed across tumor types where the highest dysregulation occurred at non-CpG island regions. Considering other summary measures of somatic alteration, MDI was correlated with copy number alterations but not with mutation burden. Using the top dysregulated CpG sites in common across tumors, 4 classes of cancer types were observed, and the functional consequences of these alterations to gene expression were confirmed. This work identified the global DNA methylation dysregulation patterns across 14 cancer types showing a higher impact for the non-CpG island areas. The most dysregulated loci across cancer types identified common clusters across cancer types that may have implications for future treatment and prevention measures.     

Current and emerging methods for probing neuropeptide transmission

Neuropeptides comprise the most diverse category of neurochemicals in the brain, playing critical roles in a wide range of physiological and pathophysiological processes. Monitoring neuropeptides with high spatial and temporal resolution is essential for understanding how peptidergic transmission is regulated throughout the central nervous system. In this review, we provide an overview of current non-optical and optical approaches used to detect neuropeptides, including their design principles, intrinsic properties, and potential limitations. We also highlight the advantages of using G protein‒coupled receptor (GPCR) activation‒based (GRAB) sensors to monitor neuropeptides in vivo with high sensitivity, good specificity, and high spatiotemporal resolution. Finally, we present a promising outlook regarding the development and optimization of new GRAB neuropeptide sensors, as well as their potential applications.     

Current and emerging therapeutic strategies for Fanconi anemia

Fanconi Anemia (FA) is a rare disorder with incidence of 1in 350,000 births. It is characterized by progressive bone marrow failure leading to death of many patients in their childhood while development of cancer at later stages of life in some. The treatment of FA is still a medical challenge. Current treatments of FA include androgen administration, hematopoietic growth factors administration and hematopoietic stem cell transplantation (HSCT). Clinical gene therapy trials are still ongoing. The partial success of current therapies has renewed interest in the search for new treatments. Generation of patient-specific induced pluripotent stem (iPS) has shown promising results for cell and gene based therapy. Small molecule interventions have been observed to delay tumor onset in FA. Tumors deficient in FA pathway can be treated by profiling of DNA repair pathway through synthetic lethality mechanism. Targeting toll-like receptor 8 (TLR8) dependent TNFα overexpression is yet another upcoming therapeutic approach to treat FA patients. In conclusion, in the present scenario of treatments available for FA, a proper algorithm of treatment decisions must be followed for better management of FA patients and to ensure their increased survival. Innovative therapeutic approaches that can prevent both anemia and cancer should be developed for more effective treatment of FA.     

HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications

Reversible acetylation mediated by histone deacetylases (HDACs) influences a broad repertoire of physiological processes, many of which are aberrantly controlled in tumor cells. As HDAC inhibition prompts tumor cells to enter apoptosis, small-molecule HDAC inhibitors have been developed as a new class of mechanism-based anti-cancer agent, many of which have entered clinical trials. Although the clinical picture is evolving and the precise utility of HDAC inhibitors remains to be determined, it is noteworthy that certain tumor types undergo a favorable response, in particular hematological malignancies. Vorinostat and romidepsin have been approved for treating cutaneous T-cell lymphoma in patients with progressive, persistent or recurrent disease. Here, we discuss developments in our understanding of molecular events that underlie the anti-cancer effects of HDAC inhibitors and relate this information to the emerging clinical picture for the application of these inhibitors in the treatment of cancer.     

Functional DNA nanotechnology: emerging applications of DNAzymes and aptamers

In the past 25 years, DNA molecules have been utilized both as powerful synthetic building blocks to create nanoscale architectures and as versatile programmable templates for assembly of nanomaterials. In parallel, the functions of DNA molecules have been expanded from pure genetic information storage to catalytic functions like those of protein enzymes (DNAzymes) and specific binding functions like antibodies (aptamers). In the past few years, a new interdisciplinary field has emerged that aims to combine functional DNA biology with nanotechnology to generate more dynamic and controllable DNA-based nanostructures or DNA-templated nanomaterials that are responsive to chemical stimuli.     

LRRK2 correlates with macrophage infiltration in pan-cancer

Leucine-rich repeat kinase2 (LRRK2) influences the host immune responses and correlates with the pathogenesis of inflammation, cancer as well as Parkinson’ Disease. Herein, we explored the oncogenic role of LRRK2 at pan-cancer level and validated the analysis by single cell RNA-sequencing and in-vitro experiments. As a result, LRRK2 significantly correlated with the survival events. Specifically, LRRK2 increased the risk of Low-Grade Glioma whereas improved the survival probability of patients with Skin Cutaneous Melanoma. Gene set enrichment analysis demonstrated the involvement of LRRK2 in the host immune responses. Within the tumor microenvironment, LRRK2 was positively associated with the recruitment of macrophages. Furthermore, scRNA-seq and co-culture experiments demonstrated that LRRK2 deficiency impaired macrophage functions, and influenced the neoplastic progression in a cancer type-specific manner. Therefore, the present study provided a therapeutic strategy for LGG based on the interference with LRRK2 expression and activity to prevent macrophage recruitment and promote tumor eradication.     

Envisioning emerging frontiers on human gut microbiota and its applications

The human gut microbiota is involved in multiple health-influencing host interactions during the host’s entire life span. Microbes colonize the infant gut instantaneously after birth and subsequently the founding and interactive progress of this early gut microbiota is considered to be driven and modulated by different host- and microbe-associated forces. A rising number of studies propose that the composition of the human gut microbiota in the early stages of life impact on the human health conditions at later stages of life. This notion has powered research aimed at detailed investigations of the infant gut microbiota composition. Nevertheless, the molecular mechanisms supporting the gut microbiome functionality and the interaction of the early gut microbes with the human host remain largely unknown.     

Molecular beacons: nucleic acid hybridization and emerging applications.

Molecular beacons (MBs) are a novel class of nucleic acid probes that become fluorescent when bound to a complementary sequence. Because of this characteristic, coupled with the sequence specificity of nucleic acid hybridization and the sensitivity of fluorescence techniques, MBs are very useful probes for a variety of applications requiring the detection of DNA or RNA. We survey various applications of MBs, including the monitoring of DNA triplex formation, and describe recent developments in MB design that enhance their sensitivity.     

Human embryonic stem cells: emerging technologies and practical applications

Human embryonic stem cells possess the unique ability to differentiate into any adult cell type. Recent advances in the understanding of stem cell biology make new applications possible for stem cell based technology. Of note, it is now possible to reprogram terminally differentiated human somatic cells into pluripotent cells that are functionally equivalent to embryonic stem cells. These induced pluripotent cells may become the substrate for future disease models and cell-based therapies. In addition, novel techniques for genetic manipulation have increased the ease with which genes can be modified into stem cells. In this review, we describe these novel technologies as well as developments in the understanding of basic biology of stem cell pluripotency and differentiation.