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Current staging methods do not accurately predict the risk of disease recurrence and benefit of adjuvant chemotherapy for patients who have had surgery for stage II colon cancer. We postulated that expression patterns of multiple microRNAs (miRNAs) could, if combined into a single model, improve postoperative risk stratification and prediction of chemotherapy benefit for these patients. Using miRNA microarrays, we analysed 40 paired stage II colon cancer tumours and adjacent normal mucosa tissues, and identified 35 miRNAs that were differentially expressed between tumours and normal tissue. Using paraffin-embedded specimens from a further 138 patients with stage II colon cancer, we confirmed differential expression of these miRNAs using qRT-PCR. We then built a six-miRNA-based classifier using the LASSO Cox regression model, based on the association between the expression of every miRNA and the duration of individual patients' disease-free survival. We validated the prognostic and predictive accuracy of this classifier in both the internal testing group of 138 patients, and an external independent group of 460 patients. Using the LASSO model, we built a classifier based on the six miRNAs: miR-21-5p, miR-20a-5p, miR-103a-3p, miR-106b-5p, miR-143-5p, and miR-215. Using this tool, we were able to classify patients between those at high risk of disease progression (high-risk group), and those at low risk of disease progression (low-risk group). Disease-free survival was significantly different between these groups in every set of patients. In the initial training group of patients, 5-year disease-free survival was 89% (95% CI 77·3–94·4) for the low-risk group, and 60% (46·3–71·0) for the high-risk group (hazard ratio [HR] 4·24, 95% CI 2·13–8·47; p<0·0001). In the internal testing set of patients, 5-year disease-free survival was 85% (95% CI 74·3–91·8) for the low-risk group, and 57% (42·8–68·5) for the high-risk group (HR 3·63, 1·86–7·01; p<0·0001), and in the independent validation set of patients, was 85% (79·6–89·0) for the low-risk group and 54% (46·4–61·1) for the high-risk group (HR 3·70, 2·56–5·35; p<0·0001). The six-miRNA-based classifier was an independent prognostic factor for, and had better prognostic value than, clinicopathological risk factors and mismatch repair status. In an ad-hoc analysis, the patients in the high-risk group were found to have a favourable response to adjuvant chemotherapy (HR 1·69, 1·17–2·45; p=0·0054). We developed two nomograms for clinical use that integrated the six-miRNA-based classifier and four clinicopathological risk factors to predict which patients might benefit from adjuvant chemotherapy after surgery for stage II colon cancer. Our six-miRNA-based classifier is a reliable prognostic and predictive tool for disease recurrence in patients with stage II colon cancer, and might be able to predict which patients benefit from adjuvant chemotherapy. It might facilitate patient counselling and individualise management of patients with this disease. Natural Science Foundation of China.

Understanding the relationship between mineral occurrences and host granitic rocks can be controversial. The Zaozigou Au-Sb deposit (118 t Au, 0.12 Mt Sb), hosted in metasedimentary rocks and dacitic to granodioritic sills and dikes, is one such example of a large gold deposit argued to have formed from either magmatic or metamorphic hydrothermal processes. Two populations of monazite are identified within a mineralized dacite located along a major shear zone. Magmatic monazite commonly occurs within magmatic biotite and quartz phenocrysts and is characterized by uniform and high Th concentrations. It has a crystallization age of 238.3 ± 2.6 Ma, consistent with the zircon U-Pb age of 238.0 ± 1.8 Ma from the same dacite. Hydrothermal monazite is associated with sulfides and sericite, and has a 207Pb-corrected 206Pb/238U age of 211.1 ± 3.0 Ma. The amount of Th in hydrothermal monazite is widely variable. The low Th content of some monazite grains reflects direct precipitation from a metamorphic hydrothermal fluid. Furthermore, the elevated Th content in other hydrothermal monazite grains is likely due to the release of Th (and U) into hydrothermal fluids by dissolution of pre-existing Th-rich minerals in the country rock during ore-related alteration events. The magmatism, which overlaps Middle-Late Triassic terrane subduction-accretion in the West Qinling orogen, thus pre-dates the ore-forming event by about 30 m.y. The δ34S values of pyrite, arsenopyrite, stibnite, marcasite, and chalcopyrite from disseminated- and vein-type ores range from − 12.0 to − 5.5‰. Such negative values are distinct from those measured for other deposits in the northwestern part of the orogen that are genetically related to Triassic magmatism, including the Xiekeng-Jiangligou-Shuangpengxi Cu-Au-Fe-Mo skarn, Laodou reduced intrusion-related Au, and Gangcha epithermal Au ores. The Zaozigou deposit is best classified as an epizonal orogenic Au-Sb deposit. Our results demonstrate the usefulness of high-precision in situ geochronology on monazite for deciphering age relationships in ore deposits that have spatial associations with granitic rocks, thus aiding in the testing of the veracity of ore formation models.

Evidence of crosstalk between the Robo/Slit and Wnt signalling pathways is provided, and R-spondin signalling is shown to enhance canonical Wnt signalling and increase the proliferation of intestinal stem cells. Robo/Slit and Wnt signal tissue repair Jian-Guo Geng and colleagues have identified previously unrecognized crosstalk between the Robo–Slit and the Wnt signalling pathways. The authors studied how the Slit2 ligand and its receptor Robo1 influence intestinal crypt morphology and epithelial homeostasis. Reduction of Robo1 levels causes dramatic shortening of intestinal villi in the mouse intestine as well as a lower density of crypts, the niche occupied by intestinal stem cells. The authors provide evidence that Robo1 is a receptor for R-spondin 1, a secreted protein with known synergy for Wnt signalling. Combined with Slit2, R-spondin 1 signalling enhances canonical Wnt signalling and elevates the proliferation and lineage dynamics of intestinal stem cells. These findings indicate that Slit2 and R-spondin 1 cooperatively induce intestinal stem cells for intestinal homeostasis and repair, and significantly prolong overall survival following lethal doses of chemoradiotherapy. Cancer research has been rightly and successfully focused on prevention, early detection, and identification of specific molecular targets that distinguish the malignant cells from the neighbouring benign cells 1 . However, reducing lethal tissue injury caused by intensive chemoradiotherapy during treatment of late-stage metastatic cancers remains a key clinical challenge. Here we tested whether the induction of adult stem cells could repair chemoradiation-induced tissue injury and prolong overall survival in mice. We found that intestinal stem cells (ISCs) 2 expressed Slit2 and its single-span transmembrane cell-surface receptor roundabout 1 (Robo1) 3 , 4 . Partial genetic deletion of Robo1 decreased ISC numbers and caused villus hypotrophy, whereas a Slit2 transgene increased ISC numbers and triggered villus hypertrophy. During lethal dosages of chemoradiation, administering a short pulse of R-spondin 1 (Rspo1; a Wnt agonist) 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 plus Slit2 reduced ISC loss, mitigated gut impairment and protected animals from death, without concomitantly decreasing tumour sensitivity to chemotherapy. Therefore Rspo1 and Slit2 may act as therapeutic adjuvants to enhance host tolerance to aggressive chemoradiotherapy for eradicating metastatic cancers.

Obtaining reliable petrochronological and geochemical data from metamict zircon may be challenging. Metamict zircon and crystalline apatite from the Meiwu granodiorite and its microgranular enclaves from the Paleo-Tethys belt are examined to constrain their crystallization ages and the genetic mechanism of related skarn mineralization. The metamict zircon yields highly disturbed 206Pb/238U dates. Transmission electron microscopy shows that radiation damage forms nanoscale-banded damaged zones, leading to spurious dates. The coexisting apatite has not accumulated radiation damage, and apatite crystals from the granodiorite and its enclaves yield reasonably precise LA-ICPMS U–Pb Tera–Wasserburg concordia lower intercept dates of 240.2 ± 3.8 and 239.9 ± 4.0 Ma (2σ), with MSWDs of 1.0 and 2.1. Considering the fast cooling of the granite, the U–Pb dates effectively represent crystallization ages for these rocks. Compositional analysis shows that there are no Ce anomalies in apatite in either the granodiorite or enclave, indicating low oxygen fugacities. Apatite crystals from enclaves have weaker negative Eu anomalies, higher Sr, and lower HREE and Y contents than those in granodiorite. The compositions confirm enclaves as products of water-rich melts, resulting in amphibole fractionation and suppression of plagioclase crystallization. The hydrous magma induced production of hydrothermal-fluids that mobilized metals dispersed in dry magma and concentrated them into mineralization traps, which contributed to the formation of widespread skarns in Paleo-Tethys belt. This study demonstrates that apatite is effective in tracing the evolution of magmatic systems containing metamict zircon.

Osteoarthritis (OA), a common degenerative disease, is characterized by high disability and imposes substantial economic impacts on individuals and society. Current clinical treatments remain inadequate for effectively managing OA. Organoids, miniature 3D tissue structures from directed differentiation of stem or progenitor cells, mimic native organ structures and functions. They are useful for drug testing and serve as active grafts for organ repair. However, organoid construction requires extracellular matrix-like 3D scaffolds for cellular growth. Hydrogel microspheres, with tunable physical and chemical properties, show promise in cartilage tissue engineering by replicating the natural microenvironment. Building on prior work on SF-DNA dual-network hydrogels for cartilage regeneration, we developed a novel RGD-SF-DNA hydrogel microsphere (RSD-MS) via a microfluidic system by integrating photopolymerization with self-assembly techniques and then modified with Pep-RGDfKA. The RSD-MSs exhibited uniform size, porous surface, and optimal swelling and degradation properties. In vitro studies demonstrated that RSD-MSs enhanced bone marrow mesenchymal stem cells (BMSCs) proliferation, adhesion, and chondrogenic differentiation. Transcriptomic analysis showed RSD-MSs induced chondrogenesis mainly through integrin-mediated adhesion pathways and glycosaminoglycan biosynthesis. Moreover, in vivo studies showed that seeding BMSCs onto RSD-MSs to create cartilage organoid precursors (COPs) significantly enhanced cartilage regeneration. In conclusion, RSD-MS was an ideal candidate for the construction and long-term cultivation of cartilage organoids, offering an innovative strategy and material choice for cartilage regeneration and tissue engineering. [Display omitted] •RGD-SF-DNA hydrogel microspheres (RSD-MSs) were prepared through photopolymerization and self-assembly.•RSD-MSs up-regulated integrin-mediated cell adhesion and focal adhesion pathways.•Cartilage organoid precursors significantly enhanced cartilage regeneration.•RSD-MS emerged as an ideal candidate for the construction of cartilage organoids.

The Moebius topology (twisted, single-sided strip) is intriguing because of its structural elegance and distinct properties. Here we report the generation of block copolymer Moebius strips via a fast self-assembly of chiral block copolymer polystyrene- block -poly( D -lactide acid) (PS- b -PDLA) in tetrahydrofuran/water mixed solvents. The Moebius strip is formed by morphological evolution from large compound micelle (LCM) to spindle-like micelle (SLM) and then to toroid with a 180° twist along the ring. Mechanism insight reveals that a subtle balance of crystallization of PDLA and microphase separation between PS and PDLA chains dominates the formation of Moebius strips. An intriguing helix-helix transition occurs during the chiral transfer from microphase to assemblies, which is driven by relaxation of the internal stress within SLM related to orientated stretching of PS chains. Mesoporous chiral channels can be generated within Moebius strips after removal of PDLA, which are interesting in chiral recognition, separation and asymmetric catalysis. The Moebius topology is intriguing because of its structural elegance and distinct properties. Here the authors report block copolymer Moebius strips via a fast self-assembly of chiral block copolymer polystyrene- block -poly(D-lactide acid) in tetrahydrofuran/water mixed solvents.

Titanium and its alloys are the most widely applied orthopedic and dental implant materials due to their high biocompatibility, superior corrosion resistance, and outstanding mechanical properties. However, the lack of superior osseointegration remains the main obstacle to successful implantation. Previous traditional surface modification methods of titanium-based implants cannot fully meet the clinical needs of osseointegration. The construction of local drug delivery systems (e.g., antimicrobial drug delivery systems, anti-bone resorption drug delivery systems, etc.) on titanium-based implants has been proved to be an effective strategy to improve osseointegration. Meanwhile, these drug delivery systems can also be combined with traditional surface modification methods, such as anodic oxidation, acid etching, surface coating technology, etc., to achieve desirable and enhanced osseointegration. In this paper, we review the research progress of different local drug delivery systems using titanium-based implants and provide a theoretical basis for further research on drug delivery systems to promote bone–implant integration in the future.

The Slit family of guidance cues binds to Roundabout （Robo） receptors and modulates cell migration. We report here that ectopic expression of Slit2 and Robol or recombinant Slit2 treatment of Robol-expressing colorectal epithelial carcinoma cells recruited an ubiquitin ligase Hakai for E-cadherin （E-cad） ubiquitination and lysosomal degradation, epithelial-mesenchymal transition （EMT）, and tumor growth and liver metastasis, which were rescued by knockdown of Hakai. In contrast, knockdown of endogenous Robol or specific blockade of Slit2 binding to Robol prevented E-cad degradation and reversed EMT, resulting in diminished tumor growth and liver metastasis. Ectopic expression of Robol also triggered a malignant transformation in Slit2-positive human embryonic kidney 293 cells. Importantly, the expression of Slit2 and Robol was significantly associated with an increased metastatic risk and poorer overall survival in colorectal carcinoma patients. We conclude that engagement of Robol by Slit2 induces malignant transformation through Hakai-mediated E-cad ubiquitination and lysosomal degradation during colorectal epithelial cell carcinogenesis.

Islet transplantation is a promising approach for the treatment of type 1 diabetes (T1D). Currently, clinical islet transplantation is limited by allo - and autoimmunity that may cause partial or complete loss of islet function within a short period of time, and long-term immunosuppression is required to prevent rejection. Encapsulation into semipermeable biomaterials provides a strategy that allows nutrients, oxygen and secreted hormones to diffuse through the membrane while blocking immune cells and the like out of the capsule, allowing long-term graft survival and avoiding long-term use of immunosuppression. In recent years, a variety of engineering strategies have been developed to improve the composition and properties of encapsulation materials and to explore the clinical practicality of islet cell transplantation from different sources. In particular, the encapsulation of porcine islet and the co-encapsulation of islet cells with other by-standing cells or active ingredients for promoting long-term functionality, attracted significant research efforts. Hydrogels have been widely used for cell encapsulation as well as other therapeutic applications including tissue engineering, cell carriers or drug delivery. Here, we review the current status of various hydrogel biomaterials, natural and synthetic, with particular focus on islet transplantation applications. Natural hydrophilic polymers include polysaccharides (starch, cellulose, alginic acid, hyaluronic acid, chitosan) and peptides (collagen, poly-L-lysine, poly-L-glutamic acid). Synthetic hydrophilic polymers include alcohol, acrylic acid and their derivatives [poly (acrylic acid), poly (methacrylic acid), poly(acrylamide)]. By understanding the advantages and disadvantages of materials from different sources and types, appropriate materials and encapsuling methods can be designed and selected as needed to improve the efficacy and duration of islet. Islet capsule transplantation is emerging as a promising future treatment for T1D.

The ideal tissue engineering scaffold should facilitate rapid cell infiltration and provide an optimal immune microenvironment during interactions with the host. Electrospinning can produce two-dimensional (2D) membranes mimicking the extracellular matrix. However, their dense structure hinders cell penetration, and their thin form restricts scaffold utility. In this study, latticed hydrogels were three-dimensional (3D) printed onto electrospun membranes. This technique allowed for layer-by-layer assembly of the membranes into 3D scaffolds, which maintained their resilience impressively under both dry and wet conditions. We assessed the cellular and host responses of these 3D nanofiber scaffolds by comparing random membranes and mesh-like membranes with three different mesh sizes (250, 500, and 750 μm). It was found that scaffolds with a mesh size of 500 μm were superior for M2 macrophage phenotype polarization, vascularization, and matrix deposition. Furthermore, it was confirmed by subsequent experiments such as RNA sequencing that the mesh-like topology may promote polarization to the M2 phenotype by affecting the PI3K/AKT pathway. In conclusion, our work offers a novel method for transforming 2D nanofiber membranes into 3D scaffolds. This method boasts flexibility, allowing for the use of varied electrospun membranes and hydrogels in terms of structure and composition. It has vast potential in tissue repair and regeneration.