Phenylboronic ester-modified polymeric nanoparticles for promoting TRP2 peptide antigen delivery in cancer immunotherapy

The tremendous development of peptide-based cancer vaccine has attracted incremental interest as a powerful approach in cancer management, prevention and treatment. As successful as tumor vaccine has been, major challenges associated with achieving efficient immune response against cancer are (1) drainage to and retention in lymph nodes; (2) uptake by dendritic cells (DCs); (3) activation of DCs. In order to overcome these barriers, here we construct PBE-modified TRP2 nanovaccine, which comprises TRP2 peptide tumor antigen and diblock copolymer PEG-b-PAsp grafted with phenylboronic ester (PBE). We confirmed that this TRP2 nanovaccine can be effectively trapped into lymph node, uptake by dendritic cells and induce DC maturation, relying on increased negative charge, ROS response and pH response. Consistently, this vehicle loaded with TRP2 peptide could boost the strongest T cell immune response against melanoma in vivo and potentiate antitumor efficacy both in tumor prevention and tumor treatment without any exogenous adjuvant. Furthermore, the TRP2 nanovaccine can suppress the tumor growth and prolong animal survival time, which may result from its synergistic effect of inhibiting tumor immunosuppression and increasing cytotoxic lymphocyte (CTL) response. Hence this type of PBE-modified nanovaccine would be widely used as a simple, safe and robust platform to deliver other antigen in cancer immunotherapy

MiR-23a Regulates Skin Langerhans Cell Phagocytosis and Inflammation-Induced Langerhans Cell Repopulation

Langerhans cells (LCs) are skin-resident macrophage that act similarly to dendritic cells for controlling adaptive immunity and immune tolerance in the skin, and they are key players in the development of numerous skin diseases. While TGF-β and related downstream signaling pathways are known to control numerous aspects of LC biology, little is known about the epigenetic signals that coordinate cell signaling during LC ontogeny, maintenance, and function. Our previous studies in a total miRNA deletion mouse model showed that miRNAs are critically involved in embryonic LC development and postnatal LC homeostasis; however, the specific miRNA(s) that regulate LCs remain unknown. miR-23a is the first member of the miR-23a-27a-24-2 cluster, a direct downstream target of PU.1 and TGF-b, which regulate the determination of myeloid versus lymphoid fates. Therefore, we used a myeloid-specific miR-23a deletion mouse model to explore whether and how miR-23a affects LC ontogeny and function in the skin. We observed the indispensable role of miR-23a in LC antigen uptake and inflammation-induced LC epidermal repopulation; however, embryonic LC development and postnatal homeostasis were not affected by cells lacking miR23a. Our results suggest that miR-23a controls LC phagocytosis by targeting molecules that regulate efferocytosis and endocytosis, whereas miR-23a promotes homeostasis in bone marrow-derived LCs that repopulate the skin after inflammatory insult by targeting Fas and Bcl-2 family proapoptotic molecules. Collectively, the context-dependent regulatory role of miR-23a in LCs represents an extra-epigenetic layer that incorporates TGF-b- and PU.1-mediated regulation during steady-state and inflammation-induced repopulation

Scaling-up Strategy as an Appropriate Approach for Sustainable New Town Development? Lessons from Wujin, Changzhou, China

China has achieved rapid urbanization and unprecedented economic booming over the past three decades. Numerous cities and towns dreamed of cloning the miracles of Shenzhen and Pudong, Shanghai, in terms of their international development. However, inappropriate development strategies have meant that the majority of fast expanding urban suburbs or newly developed towns suffer a high ratio of vacant dwellings in real estate markets and a massive loss of farmland. The frequent exposure of these empty cities to mass media or the public has urged urban governments to impose fiscal austerity. These unexpected and negative consequences of urban development have explicit conflicts with sustainability. This paper aims to provide a political economy view of these unsustainable outcomes of new development. To achieve this, the processes and agendas of new city or town planning in Wujin District, Changzhou City, are analyzed and evaluated from the perspective of scale theory. Extensive interviews conducted with local politicians at different levels, planners, real estate agents and local residents facilitate the interpretation of these processes and agendas. It is argued that the legends of Shenzhen and Pudong, Shanghai originate from a modified neoliberal capitalism intervention at the right time and place, with which other peer cities are not comparable. It is concluded that the scaling-up strategy is not appropriate for the local new town development of Wujin, which has led to unsustainable outcomes—empty cities and towns—and created important lessons for the sustainable development of Chinese cities

Challenges in QCD matter physics - The Compressed Baryonic Matter experiment at FAIR

Substantial experimental and theoretical efforts worldwide are devoted to explore the phase diagram of strongly interacting matter. At LHC and top RHIC energies, QCD matter is studied at very high temperatures and nearly vanishing net-baryon densities. There is evidence that a Quark-Gluon-Plasma (QGP) was created at experiments at RHIC and LHC. The transition from the QGP back to the hadron gas is found to be a smooth cross over. For larger net-baryon densities and lower temperatures, it is expected that the QCD phase diagram exhibits a rich structure, such as a first-order phase transition between hadronic and partonic matter which terminates in a critical point, or exotic phases like quarkyonic matter. The discovery of these landmarks would be a breakthrough in our understanding of the strong interaction and is therefore in the focus of various high-energy heavy-ion research programs. The Compressed Baryonic Matter (CBM) experiment at FAIR will play a unique role in the exploration of the QCD phase diagram in the region of high net-baryon densities, because it is designed to run at unprecedented interaction rates. High-rate operation is the key prerequisite for high-precision measurements of multi-differential observables and of rare diagnostic probes which are sensitive to the dense phase of the nuclear fireball. The goal of the CBM experiment at SIS100 (sqrt(s_NN) = 2.7 - 4.9 GeV) is to discover fundamental properties of QCD matter: the phase structure at large baryon-chemical potentials (mu_B > 500 MeV), effects of chiral symmetry, and the equation-of-state at high density as it is expected to occur in the core of neutron stars. In this article, we review the motivation for and the physics programme of CBM, including activities before the start of data taking in 2022, in the context of the worldwide efforts to explore high-density QCD matter.Comment: 15 pages, 11 figures. Published in European Physical Journal

YB-1 as an Oncoprotein: Functions, Regulation, Post-Translational Modifications, and Targeted Therapy

Y box binding protein 1 (YB-1) is a protein with a highly conserved cold shock domain (CSD) that also belongs to the family of DNA- and RNA-binding proteins. YB-1 is present in both the nucleus and cytoplasm and plays versatile roles in gene transcription, RNA splicing, DNA damage repair, cell cycle progression, and immunity. Cumulative evidence suggests that YB-1 promotes the progression of multiple tumor types and serves as a potential tumor biomarker and therapeutic target. This review comprehensively summarizes the emerging functions, mechanisms, and regulation of YB-1 in cancers, and further discusses targeted strategies

Comprehensive analysis of circulating cell-free RNAs in blood for diagnosing non-small cell lung cancer

Early screening and detection of non-small cell lung cancer (NSCLC) is crucial due to the significantly low survival rate in advanced stages. Blood-based liquid biopsy is non-invasive test to assistant disease diagnosis, while cell-free RNA is one of the promising biomarkers in blood. However, the disease related signatures have not been explored completely for most cell-free RNA transcriptome sequencing (cfRNA-Seq) datasets. To address this gap, we developed a comprehensive cfRNA-Seq pipeline for data analysis and constructed a machine learning model to facilitate noninvasive early diagnosis of NSCLC. The results of our study have demonstrated the identification of differential mRNA, lncRNAs and miRNAs from cfRNA-Seq, which have exhibited significant association with development and progression of lung cancer. The classifier based on gene expression signatures achieved an impressive area under the curve (AUC) of up to 0.9, indicating high specificity and sensitivity in both cross-validation and independent test. Furthermore, the analysis of T cell and B cell immune repertoire extracted from cfRNA-Seq have provided insights into the immune status of cancer patients, while the microbiome analysis has revealed distinct bacterial and viral profiles between NSCLC and normal samples. In our future work, we aim to validate the existence of cancer associated T cell receptors (TCR)/B cell receptors (BCR) and microorganisms, and subsequently integrate all identified signatures into diagnostic model to improve the prediction accuracy. This study not only provided a comprehensive analysis pipeline for cfRNA-Seq dataset but also highlights the potential of cfRNAs as promising biomarkers and models for early NSCLC diagnosis, emphasizing their importance in clinical settings

Awareness of intratumoral bacteria and their potential application in cancer treatment

Abstract Hitherto, the recognition of the microbiota role in tumorigenesis and clinical studies mostly focused on the intestinal flora. In contrast to the gut microbiome, microorganisms resident in tumor tissue are in close contact with cancer cells and therefore have the potential to have similar or even different functional patterns to the gut flora. Some investigations have shown intratumoral bacteria, which might come from commensal microbiota in mucosal areas including the gastrointestinal tract and oral cavity, or from nearby normal tissues. The existence, origin, and interactions of intratumoral bacteria with the tumor microenvironment all contribute to intratumoral microorganism heterogeneity. Intratumoral bacteria have a significant role in tumor formation. They can contribute to cancer at the genetic level by secreting poisons that directly damage DNA and also intimately related to immune system response at the systemic level. Intratumoral bacteria have an impact on chemotherapy and immunotherapy in cancer. Importantly, various properties of bacteria such as targeting and ease of modification make them powerful candidates for precision therapy, and combining microbial therapies with other therapies is expected to improve the effectiveness of cancer treatment. In this review, we mainly described the heterogeneity and potential sources of intratumoral bacteria, overviewed the important mechanisms by which they were involved in tumor progression, and summarized their potential value in oncology therapy. At last, we highlight the problems of research in this field, and look forward to a new wave of studies using the various applications of intratumoral microorganisms in cancer therapy

YB-1 as an Oncoprotein: Functions, Regulation, Post-Translational Modifications, and Targeted Therapy

Y box binding protein 1 (YB-1) is a protein with a highly conserved cold shock domain (CSD) that also belongs to the family of DNA- and RNA-binding proteins. YB-1 is present in both the nucleus and cytoplasm and plays versatile roles in gene transcription, RNA splicing, DNA damage repair, cell cycle progression, and immunity. Cumulative evidence suggests that YB-1 promotes the progression of multiple tumor types and serves as a potential tumor biomarker and therapeutic target. This review comprehensively summarizes the emerging functions, mechanisms, and regulation of YB-1 in cancers, and further discusses targeted strategies

Fluid activity and hydrocarbon accumulation period of Sinian Dengying Formation in northern Guizhou, South China

By taken the Sinian Dengying Formation in Northern Guizhou as an example, based on the data from homogenization temperature, salinity and density of fluid inclusions, and combined with the restoration of burial history and thermal history, this paper investigates hydrocarbonaceous fluid activity periods and restores the process of hydrocarbon accumulation and destruction. Four periods of hydrocarbonaceous fluid activity periods occurred in the research region, and they correspond to the homogenization temperature of fluid inclusions of 87.1–111.4 °C, 126.1–163.0 °C, 166.9–225.1 °C and 95.3–116.4 °C respectively, reflecting two stages of hydrocarbon charge, one stage of gas accumulation and gas reservoir destruction activity in Dengying Formation reservoir. Comprehensive analysis on observation of thin sections, cathodoluminescence and oxygen isotope show that, Dengying Formation reservoir developed six generations of cements, four stages of dolomite, and had four stages of dissolution, the organic acids from fluid activities in different buried environment produced multiphase dissolution on residual pores and fillings of the ancient karst. Dengying Formation in Northern Guizhou occurred three periods of petroleum accumulation which are, in order, Middle-Late Caledonian (470–428 Ma), Indo-Chinese epoch (252–228 Ma), Early Yanshanian period (177–145 Ma), and the ideal depth for the preservation of natural gas accumulation in Dengying Formation in Northern Guizhou is about 3 600 m. Key words: Sinian Dengying Formation, hydrocarbon accumulation period, fluid inclusion, fluid activity, dolomitizatio