Search

Objective The Suzhou–Wuxi–Changzhou region is one of the most severely affected areas by land subsidence, both in China and globally. In the early 1970s, land subsidence occurred and resulted in the formation of ground fissures caused by differential subsidence, thus resulting in significant economic losses. In this century, the rate of ground subsidence has decreased, with some areas experiencing regional ground resilience. The unique developmental history of ground subsidence allows one to comprehensively interpret its evolutionary process and causal mechanisms. This study aims to unravel the life cycle and driving forces of land subsidence in the Suzhou–Wuxi–Changzhou region. Methods To achieve this, a multifaceted approach was employed, including long-term and large-scale monitoring of three-dimensional seepage, stress, and strain, complemented by physical experimental models and numerical simulations. An analysis was conducted to synthesize the macro-evolutionary patterns and causal mechanisms of land subsidence and the formation of ground fissures. Results and Conclusion The findings indicate that land subsidence in the Suzhou–Wuxi–Changzhou region exhibits distinct characteristics that evolve through five discernible stages: initiation, rapid development, deceleration, stagnation, and rebound. The development of land subsidence is intricately connected to groundwater extraction, with stratum deformation arising predominantly from the compaction and dewatering of aquifers and aquitards due to pumping. During the subsidence phase, primary aquifer sand and contiguous aquitards are identified as the primary contributors to subsidence. By dissecting the causal mechanisms of land subsidence and ground fissures, this study delineates the spatiotemporal evolution of the structural compression and rebound of strata under varying conditions of deep groundwater exploitation, restriction, and prohibition, along with their respective contributions to subsidence. Ground fissures, which act as a secondary geological hazard at certain stages of subsidence, exhibit a spatial distribution and occurrence time that are closely related to groundwater levels, land subsidence, bedrock undulations, and soil-layer structural disparities. The life cycle of ground fissures can be encapsulated by the mechanical processes of compression, tension, shearing, and rebound, which highlights the triggers and critical thresholds for fissure formation due to differential subsidence. An integrated “sky–air–ground” monitoring system that can perform full-section fiber-optic monitoring in geological boreholes and amalgamates diverse technical methods is established to obtain scientific and granular data support for land-subsidence control and prevention. Furthermore, an innovative finite-element coupling interface element method customized for regional and site-specific scales is developed. This method successfully simulates the mechanisms of stratum deformation as well as the genesis and propagation of ground fissures under complex three-dimensional geological conditions, thus facilitating the precise identification and management of subsidence and fissure prone areas. Significance This study highlights the government’s land subsidence control measures at various stages, which are characterized by technological innovations such as groundwater extraction restrictions and bans, thus setting a precedent for land subsidence management and groundwater resource stewardship in other provinces and cities across China.

The incidence and mortality rates of renal cell carcinoma (RCC) have been increasing annually due to obesity and environmental pollution. Although immunotherapy of RCC has been studied for decades, few comprehensive bibliometric analyses exist on the treatment. Therefore, the purpose of this bibliometric analysis was to identify scientific achievements of the global research on RCC immunotherapy from 2003 to 2022 and discuss research trends. Data were retrieved from the Clarivate Web of Science Core Collection using a set retrieval strategy. The Bibliometrics tool Cite Space 6.2 R2 (Chaomei Chen, Drexel University) was used to analyze 4,841 articles. The USA had the most publications (n = 1,864); Harvard University was identified as the leading institution (n = 264); and Dr. Toni K. Choueiri, was the most productive researcher in the field (n = 55). Keyword analysis showed that nivolumab, immune checkpoint inhibitors, tumor microenvironment, everolimus, cabozantinib, resistance, pembrolizumab and ipilimumab were the main hotspots and frontier directions of RCC. By analyzing the results of bibliometrics, national and international researchers can better understand the current research status of RCC immunotherapy and identify new directions for future research. However, the analysis also identified pockets of insularity, highlighting a need for greater collaboration and cooperation among researchers to advance the field of RCC immunotherapy.

Individuals with neurofibromatosis type 1 develop rat sarcoma virus (RAS)-mitogen-activated protein kinase-mitogen-activated and extracellular signal-regulated kinase (RAS-MAPK-MEK)-driven nerve tumors called neurofibromas. Although MEK inhibitors transiently reduce volumes of most plexiform neurofibromas in mouse models and in neurofibromatosis type 1 (NF1) patients, therapies that increase the efficacy of MEK inhibitors are needed. BI-3406 is a small molecule that prevents Son of Sevenless (SOS)1 interaction with Kirsten rat sarcoma viral oncoprotein (KRAS)-GDP, interfering with the RAS-MAPK cascade upstream of MEK. Single agent SOS1 inhibition had no significant effect in the DhhCre;Nf1 fl/fl mouse model of plexiform neurofibroma, but pharmacokinetics (PK)-driven combination of selumetinib with BI-3406 significantly improved tumor parameters. Tumor volumes and neurofibroma cell proliferation, reduced by MEK inhibition, were further reduced by the combination. Neurofibromas are rich in ionized calcium binding adaptor molecule 1 (Iba1)+ macrophages; combination treatment resulted in small and round macrophages, with altered cytokine expression indicative of altered activation. The significant effects of MEK inhibitor plus SOS1 inhibition in this preclinical study suggest potential clinical benefit of dual targeting of the RAS-MAPK pathway in neurofibromas. SIGNIFICANCE STATEMENT: Interfering with the RAS-mitogen-activated protein kinase (RAS-MAPK) cascade upstream of mitogen activated protein kinase kinase (MEK), together with MEK inhibition, augment effects of MEK inhibition on neurofibroma volume and tumor macrophages in a preclinical model system. This study emphasizes the critical role of the RAS-MAPK pathway in controlling tumor cell proliferation and the tumor microenvironment in benign neurofibromas.

Patients with neurofibromatosis type 1 (NF1) are predisposed to develop neurofibromas, but the underlying molecular mechanisms of neurofibromagenesis are not fully understood. We showed dual genetic deletion of Runx1 and Runx3 in Schwann cells (SCs) and SC precursors delayed neurofibromagenesis and prolonged mouse survival. We identified peripheral myelin protein 22 (Pmp22/Gas3) related to neurofibroma initiation. Knockdown of Pmp22 with short hairpin RNAs increased Runx1fl/fl;Runx3fl/fl;Nf1fl/fl;DhhCre tumor-derived sphere numbers and enabled significantly more neurofibroma-like microlesions on transplantation. Conversely, overexpression of Pmp22 in mouse neurofibroma SCs decreased cell proliferation. Mechanistically, RUNX1/3 regulated alternative promoter usage and induced levels of protein expression of Pmp22 to control SC growth. Last, pharmacological inhibition of RUNX/core-binding factor β (CBFB) activity significantly reduced neurofibroma volume in vivo. Thus, we identified a signaling pathway involving RUNX1/3 suppression of Pmp22 in neurofibroma initiation and/or maintenance. Targeting disruption of RUNX/CBFB interaction might provide a novel therapy for patients with neurofibroma.

Plexiform neurofibroma is a major contributor to morbidity in patients with neurofibromatosis type I (NF1). Macrophages and mast cells infiltrate neurofibroma, and data from mouse models implicate these leukocytes in neurofibroma development. Antiinflammatory therapy targeting these cell populations has been suggested as a means to prevent neurofibroma development. Here, we compare gene expression in Nf1-mutant nerves, which invariably form neurofibroma, and show disruption of neuron-glial cell interactions and immune cell infiltration to mouse models, which rarely progresses to neurofibroma with or without disruption of neuron-glial cell interactions. We find that the chemokine Cxcl10 is uniquely upregulated in NF1 mice that invariably develop neurofibroma. Global deletion of the CXCL10 receptor Cxcr3 prevented neurofibroma development in these neurofibroma-prone mice, and an anti-Cxcr3 antibody somewhat reduced tumor numbers. Cxcr3 expression localized to T cells and DCs in both inflamed nerves and neurofibromas, and Cxcr3 expression was necessary to sustain elevated macrophage numbers in Nf1-mutant nerves. To our knowledge, these data support a heretofore-unappreciated role for T cells and DCs in neurofibroma initiation.

Introduction: Cardiovascular diseases (CVDs) are the leading causes of mortality and morbidity worldwide, making early diagnosis and effective treatment essential. As a promising and noninvasive research method, urine proteomics shows excellent potential to identify reliable urinary biomarkers that could enhance prediction, prevention, and prognosis in patients with CVD. Areas covered: This review summarizes recent advancements in urinary protein biomarker profiling using urine proteomic techniques to identify potential CVD biomarkers. Additionally, it highlights potential disease biomarkers for the early detection, risk stratification, and monitoring of CVD, including hypertension, atherosclerosis, coronary artery disease, angina, myocardial infarction, heart failure, preeclampsia, and vasculitis. A literature search was conducted through Pubmed, Scopus, Google Scholar, and Web of Science. The period is January 2009 to February 2024. Expert opinion: Over the past decade, urinary proteomics has been employed in CVD research, with the potential to facilitate the discovery of novel disease biomarkers and the exploration of prospective therapeutic targets. Proteomics-based multicenter cohort studies should be conducted in the future to gain deeper insights into the pathophysiological mechanisms of CVD, accelerate the identification of potential biomarkers for disease prediction, diagnosis, and treatment, and facilitate their clinical translation. [ABSTRACT FROM AUTHOR]

Polyploid plants often exhibit superior yield, stress resistance, and quality. In this study, homologous tetraploid wucai (Brassica campestris L.) was successfully obtained by spraying seedling growth points with colchicine. The morphological, cytological, and physiological characteristics of diploid and tetraploid wucai were analyzed, and transcriptomic sequencing was performed at three stages of development. Tetraploid seedings grew slowly but exhibited darker leaves, enlarged organs and cells, increased stomatal volume, decreased stomatal density, improved nutritional content, and enhanced photosynthesis. Differentially expressed genes (DEGs) identified in diploid and tetraploid plants at three stages of development were enriched in different pathways. Notably, DEGs identified in the tetraploid plants were specifically enriched in starch and sucrose metabolism, pentose and glucuronate interconversions, and ascorbate and aldarate metabolism. In addition, we found that the light green module was most relevant to ploidy, and DEGs in this module were significantly enriched in the glycolysis/gluconeogenesis and TCA cycle pathways. The differential expression of key glycolysis-associated genes at different developmental stages may be the driver of the observed differences between diploid and tetraploid wucai. This study lays a technical foundation for the development of polyploid wucai germplasm resources as well as the breeding of new varieties with improved quality, yield, and stress resistance. It also provides a good empirical reference for the genetic breeding of closely related Brassica species. [ABSTRACT FROM AUTHOR]