The role of diet in renal cell carcinoma incidence: an umbrella review of meta-analyses of observational studies.

BACKGROUND: Evidence associating diet with the incidence of renal cell carcinoma (RCC) is inconclusive. We aimed to summarize evidence associating dietary factors with RCC incidence and assess the strength and validity of this evidence. METHODS: We conducted an umbrella review of systematic reviews or meta-analyses (SRoMAs) that assessed the association between diet and RCC incidence. Through April 2021, PubMed, Web of Science, Embase, The Cochrane Library, Scopus, and WCRF were searched. Two independent reviewers selected studies, extracted data, and appraised the quality of SRoMAs. According to credibility assessment criteria, evidence can be divided into five categories: convincing (class I), highly suggestive (class II), suggestive (class III), weak (class IV), and nonsignificant (class V). RESULTS: Twenty-nine meta-analyses were obtained after screening. After excluding 7 overlapping meta-analyses, 22 meta-analyses including 502 individual studies and 64 summary hazard ratios for RCC incidence were included: dietary patterns or dietary quality indices (n = 6), foods (n = 13), beverages (n = 4), alcohol (n = 7), macronutrients (n =15), and micronutrients (n =19). No meta-analyses had high methodological quality. Five meta-analyses exhibited small study effects; one meta-analysis showed evidence of excess significance bias. No dietary factors showed convincing or highly suggestive evidence of association with RCC in the overall analysis. Two protective factors had suggestive evidence (vegetables (0.74, 95% confidence interval 0.63 to 0.86) and vitamin C (0.77, 0.66 to 0.90)) in overall analysis. One protective factor had convincing evidence (moderate drinking (0.77, 0.70 to 0.84)) in Europe and North America and one protective factor had highly suggestive evidence (cruciferous vegetables (0.78, 0.70 to 0.86)) in North America. CONCLUSIONS: Although many meta-analyses have assessed associations between dietary factors and RCC, no high-quality evidence exists (classes I and II) in the overall analysis. Increased intake of vegetables and vitamin C is negatively associated with RCC risk. Moderate drinking might be beneficial for Europeans and North Americans, and cruciferous vegetables might be beneficial to North Americans, but the results should be interpreted with caution. More researches are needed in the future. TRIAL REGISTRATION: PROSPERO CRD42021246619.

Mechanical Forces Regulate Asymmetric Vascular Cell Alignment.

Mechanical forces between cells and their microenvironment critically regulate the asymmetric morphogenesis and physiological functions in vascular systems. Here, we investigated the asymmetric cell alignment and cellular forces simultaneously in micropatterned endothelial cell ring-shaped sheets and studied how the traction and intercellular forces are involved in the asymmetric vascular morphogenesis. Tuning the traction and intercellular forces using different topographic geometries of symmetric and asymmetric ring-shaped patterns regulated the vascular asymmetric morphogenesis in vitro. Moreover, pharmacologically suppressing the cell traction force and intercellular force disturbed the force-dependent asymmetric cell alignment. We further studied this phenomenon by modeling the vascular sheets with a mechanical force-propelled active particle model and confirmed that mechanical forces synergistically drive the asymmetric endothelial cell alignments in different tissue geometries. Further study using mouse diabetic aortic endothelial cells indicated that diseased endothelial cells exhibited abnormal cell alignments, traction, and intercellular forces, indicating the importance of mechanical forces in physiological vascular morphogenesis and functions. Overall, we have established a controllable micromechanical platform to study the force-dependent vascular asymmetric morphogenesis and thus provide a direct link between single-cell mechanical processes and collective behaviors in a multicellular environment.

The Interplay Between Cell-Cell and Cell-Matrix Forces Regulates Cell Migration Dynamics.

Cells in vivo encounter and exert forces as they interact with the extracellular matrix (ECM) and neighboring cells during migration. These mechanical forces play crucial roles in regulating cell migratory behaviors. Although a variety of studies have focused on describing single-cell or the collective cell migration behaviors, a fully mechanistic understanding of how the cell-cell (intercellular) and cell-ECM (extracellular) traction forces individually and cooperatively regulate single-cell migration and coordinate multicellular movement in a cellular monolayer is still lacking. Here, we developed an integrated experimental and analytical system to examine both the intercellular and extracellular traction forces acting on individual cells within an endothelial cell colony as well as their roles in guiding cell migratory behaviors (i.e., cell translation and rotation). Combined with force, multipole, and moment analysis, our results revealed that traction force dominates in regulating cell active translation, whereas intercellular force actively modulates cell rotation. Our findings advance the understanding of the intricacies of cell-cell and cell-ECM forces in regulating cellular migratory behaviors that occur during the monolayer development and may yield deeper insights into the single-cell dynamic behaviors during tissue development, embryogenesis, and wound healing.

Hydrological alteration drives chemistry of dissolved organic matter in the largest freshwater lake of China (Poyang Lake).

As the largest reactive organic carbon pool, dissolved organic matter (DOM) plays an important role in various biogeochemical processes in lake ecosystems. Recently, climate change-induced extreme events (e.g., floods and droughts) have significantly modified the hydrological patterns of lakes worldwide, and regulated the quality and quantity of DOM. However, the responses of DOM chemistry to hydrological alteration in lakes remain poorly understood. Here we investigated the influences of hydrological alteration on sources, composition, and characteristics of DOM in Poyang Lake, the largest freshwater lake in China, using a combination of bulk chemical, optical and Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) techniques. Results show various sources of DOM (autochthonous, allochthonous, and anthropogenic inputs) and significant variations in DOM chemistry across four hydrological periods (the retreating, dry, rising, and flooding periods) in Poyang Lake. During the retreating, rising, and flooding periods, DOM was characterized by higher aromaticity, humification degree, and recalcitrance, and exhibited pronounced allochthonous signatures. In contrast, DOM contained more S-containing molecules and aliphatic compounds during the dry period, displaying relatively stronger autochthonous features. Terrestrial inputs and the lignin-CHOS formation process are likely the primary underlying mechanisms shaping the differences in DOM chemistry in Poyang Lake. Our research demonstrates the significant impacts of hydrological alteration on DOM dynamics, and provides an improved understanding of DOM biogeochemical cycles and carbon cycling in large aquatic systems under global climate change.

Microphysiological Systems for Cancer Immunotherapy Research and Development.

Cancer immunotherapy focuses on the use of patients' adaptive immune systems to combat cancer. In the past decade, FDA has approved many immunotherapy products for cancer patients who suffer from primary tumors, tumor relapse, and metastases. However, these immunotherapies still show resistance in many patients and often lead to inconsistent responses in patients due to variations in tumor genetic mutations and tumor immune microenvironment. Microfluidics-based organ-on-a-chip technologies or microphysiological systems have opened new ways that can provide relatively fast screening for personalized immunotherapy and help researchers and clinicians understand tumor-immune interactions in a patient-specific manner. They also have the potential to overcome the limitations of traditional drug screening and testing, given the models provide a more realistic 3D microenvironment with better controllability, reproducibility, and physiological relevance. This review focuses on the cutting-edge microphysiological organ-on-a-chip devices developed in recent years for studying cancer immunity and testing cancer immunotherapeutic agents, as well as some of the largest challenges of translating this technology to clinical applications in immunotherapy and personalized medicine.

A 3D Human Lymphatic Vessel-on-Chip Reveals the Roles of Interstitial Flow and VEGF-A/C for Lymphatic Sprouting and Discontinuous Junction Formation.

Introduction: Lymphatic vessels (LVs) maintain fluid homeostasis by draining excess interstitial fluid, which is accomplished by two distinct LVs: initial LVs and collecting LVs. The interstitial fluid is first drained into the initial LVs through permeable "button-like" lymphatic endothelial cell (LEC) junctions. Next, the drained fluid ("lymph") transports to lymph nodes through the collecting LVs with less permeable "zipper-like" junctions that minimize loss of lymph. Despite the significance of LEC junctions in lymphatic drainage and transport, it remains unclear how luminal or interstitial flow affects LEC junctions in vascular endothelial growth factors A and C (VEGF-A and VEGF-C) conditions. Moreover, it remains unclear how these flow and growth factor conditions impact lymphatic sprouting. Methods: We developed a 3D human lymphatic vessel-on-chip that can generate four different flow conditions (no flow, luminal flow, interstitial flow, both luminal and interstitial flow) to allow an engineered, rudimentary LV to experience those flows and respond to them in VEGF-A/C. Results: We examined LEC junction discontinuities, lymphatic sprouting, LEC junction thicknesses, and cell contractility-dependent vessel diameters in the four different flow conditions in VEGF-A/C. We discovered that interstitial flow in VEGF-C generates discontinuous LEC junctions that may be similar to the button-like junctions with no lymphatic sprouting. However, interstitial flow or both luminal and interstitial flow stimulated lymphatic sprouting in VEGF-A, maintaining zipper-like LEC junctions. LEC junction thickness and cell contractility-dependent vessel diameters were not changed by those conditions. Conclusions: In this study, we provide an engineered lymphatic vessel platform that can generate four different flow regimes and reveal the roles of interstitial flow and VEGF-A/C for lymphatic sprouting and discontinuous junction formation. Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-023-00780-0.

Spatial distribution pattern and correlation of dominant species in the arbor layer at a 25 hm2 forest plot in Lushan Mountain, China.

To explore the spatial pattern of zonal tree species in the subtropical subalpine mountain area on Lushan Mountain, a 25 hm2 forest plot was established in Yangtianping area of Lushan Mountain following the technical specification of CTFS in 2021. We classified these species into evergreen conifer species, deciduous broad-leaved species and evergreen broad-leaved species based on their leaf shape and deciduous or not to analyze the spatial pattern of dominant species of different types by spatial point pattern method. The results showed that Pinus taiwanensis, Cornus kousa subsp. chinensis, Platycarya strobilacea, Castanea henryi, Quercus serrata, Cornus controversa, Eurya muricata, Litsea elongata, and Eurya hebeclados were dominant species. Among these species, P. taiwanensis was the constructive one. The spatial pattern of dominant species was clustered at a certain scale, and gradually became to randomly distribution with the increases of scales. Evergreen conifer species was independent with deci-duous broad-leaved species and evergreen broad-leaved species at small scales, but was negatively correlated with them at large scales. Deciduous broad-leaved species and evergreen broad-leaved species were obviously negatively correlated with each other. Deciduous broad-leaved species were positively correlated or independent with each other at small scales, but were negatively correlated with each other at large scales. Evergreen broad-leaved species were positively correlated at small scales, independent at medium scales, and negatively correlated with each other at large scales.

Genome Assembly and Population Resequencing Reveal the Geographical Divergence of Shanmei (Rubus corchorifolius).

Rubus corchorifolius (Shanmei or mountain berry, 2n = 14) is widely distributed in China, and its fruits possess high nutritional and medicinal values. Here, we reported a high-quality chromosome-scale genome assembly of Shanmei, with contig size of 215.69 Mb and 26,696 genes. Genome comparison among Rosaceae species showed that Shanmei and Fupenzi (Rubus chingii Hu) were most closely related, followed by blackberry (Rubus occidentalis), and that environmental adaptation-related genes were expanded in the Shanmei genome. Further resequencing of 101 samples of Shanmei collected from four regions in the provinces of Yunnan, Hunan, Jiangxi, and Sichuan in China revealed that among these samples, the Hunan population of Shanmei possessed the highest diversity and represented the more ancestral population. Moreover, the Yunnan population underwent strong selection based on the nucleotide diversity, linkage disequilibrium, and historical effective population size analyses. Furthermore, genes from candidate genomic regions that showed strong divergence were significantly enriched in the flavonoid biosynthesis and plant hormone signal transduction pathways, indicating the genetic basis of adaptation of Shanmei to the local environment. The high-quality assembled genome and the variome dataset of Shanmei provide valuable resources for breeding applications and for elucidating the genome evolution and ecological adaptation of Rubus species.

Organ-on-a-Chip: A New Paradigm for Drug Development.

The pharmaceutical industry has been desperately searching for efficient drug discovery methods. Organ-on-a-Chip, a cutting-edge technology that can emulate the physiological environment and functionality of human organs on a chip for disease modeling and drug testing, shows great potential for revolutionizing the drug development pipeline. However, successful translation of this novel engineering platform into routine pharmacological and medical scenarios remains to be realized. In this review, we discuss how the Organ-on-a-Chip technology can have critical roles in different preclinical stages of drug development and highlight the current challenges in translation and commercialization of this technology for the pharmacological and medical end-users. Moreover, this review sheds light on the future developmental trends and need for a next-generation Organ-on-a-Chip platform to bridge the gap between animal studies and clinical trials for the pharmaceutical industry.

Dissecting the immunosuppressive tumor microenvironments in Glioblastoma-on-a-Chip for optimized PD-1 immunotherapy.

Programmed cell death protein-1 (PD-1) checkpoint immunotherapy efficacy remains unpredictable in glioblastoma (GBM) patients due to the genetic heterogeneity and immunosuppressive tumor microenvironments. Here, we report a microfluidics-based, patient-specific 'GBM-on-a-Chip' microphysiological system to dissect the heterogeneity of immunosuppressive tumor microenvironments and optimize anti-PD-1 immunotherapy for different GBM subtypes. Our clinical and experimental analyses demonstrated that molecularly distinct GBM subtypes have distinct epigenetic and immune signatures that may lead to different immunosuppressive mechanisms. The real-time analysis in GBM-on-a-Chip showed that mesenchymal GBM niche attracted low number of allogeneic CD154+CD8+ T-cells but abundant CD163+ tumor-associated macrophages (TAMs), and expressed elevated PD-1/PD-L1 immune checkpoints and TGF-ß1, IL-10, and CSF-1 cytokines compared to proneural GBM. To enhance PD-1 inhibitor nivolumab efficacy, we co-administered a CSF-1R inhibitor BLZ945 to ablate CD163+ M2-TAMs and strengthened CD154+CD8+ T-cell functionality and GBM apoptosis on-chip. Our ex vivo patient-specific GBM-on-a-Chip provides an avenue for a personalized screening of immunotherapies for GBM patients.