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Colorectal cancer (CRC) at advanced stages is rarely curable, underscoring the importance of exploring the mechanism of CRC progression and invasion. NOD-like receptor family member NLRP12 was shown to suppress colorectal tumorigenesis, but the precise mechanism was unknown. Here, we demonstrate that invasive adenocarcinoma development in Nlrp12-deficient mice is associated with elevated expression of genes involved in proliferation, matrix degradation, and epithelialmesenchymal transition. Signaling pathway analysis revealed higher activation of the Wnt/[beta]-catenin pathway, but not NF-[kappa]B and MAPK pathways, in the Nlrp12-deficient tumors. Using Nlrp12-conditional knockout mice, we revealed that NLRP12 downregulates [beta]-catenin activation in intestinal epithelial cells, thereby suppressing colorectal tumorigenesis. Consistent with this, Nlrp12-deficient intestinal organoids and CRC cells showed increased proliferation, accompanied by higher activation of [beta]-catenin in vitro. With proteomic studies, we identified STK38 as an interacting partner of NLRP12 involved in the inhibition of phosphorylation of GSK3[beta], leading to the degradation of [beta]-catenin. Consistently, the expression of NLRP12 was significantly reduced, while p-GSK3[beta] and [beta]-catenin were upregulated in mouse and human colorectal tumor tissues. In summary, NLRP12 is a potent negative regulator of the Wnt/[beta]-catenin pathway, and the NLRP12/STK38/GSK3[beta] signaling axis could be a promising therapeutic target for CRC., Introduction With more than 1.2 million newly diagnosed cases per year, colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-related death worldwide (1). [...]

Stromal cells in adult bone marrow that express leptin receptor (LEPR) are a critical source of growth factors, including stem cell factor (SCF), for the maintenance of haematopoietic stem cells and early restricted progenitors.sup.1-6. LEPR.sup.+ cells are heterogeneous, including skeletal stem cells and osteogenic and adipogenic progenitors.sup.7-12, although few markers have been available to distinguish these subsets or to compare their functions. Here we show that expression of an osteogenic growth factor, osteolectin.sup.13,14, distinguishes peri-arteriolar LEPR.sup.+ cells poised to undergo osteogenesis from peri-sinusoidal LEPR.sup.+ cells poised to undergo adipogenesis (but retaining osteogenic potential). Peri-arteriolar LEPR.sup.+osteolectin.sup.+ cells are rapidly dividing, short-lived osteogenic progenitors that increase in number after fracture and are depleted during ageing. Deletion of Scf from adult osteolectin.sup.+ cells did not affect the maintenance of haematopoietic stem cells or most restricted progenitors but depleted common lymphoid progenitors, impairing lymphopoiesis, bacterial clearance, and survival after acute bacterial infection. Peri-arteriolar osteolectin.sup.+ cell maintenance required mechanical stimulation. Voluntary running increased, whereas hindlimb unloading decreased, the frequencies of peri-arteriolar osteolectin.sup.+ cells and common lymphoid progenitors. Deletion of the mechanosensitive ion channel PIEZO1 from osteolectin.sup.+ cells depleted osteolectin.sup.+ cells and common lymphoid progenitors. These results show that a peri-arteriolar niche for osteogenesis and lymphopoiesis in bone marrow is maintained by mechanical stimulation and depleted during ageing. A peri-arteriolar niche in the bone marrow for osteogenesis and lymphopoiesis is maintained by mechanical stimulation and is depleted during ageing., Author(s): Bo Shen [sup.1] , Alpaslan Tasdogan [sup.1] , Jessalyn M. Ubellacker [sup.1] , Jingzhu Zhang [sup.1] , Elena D. Nosyreva [sup.2] , Liming Du [sup.1] , Malea M. Murphy [...]

This study delves into the mechanical properties of various rock types found in glutenite reservoirs in the Ma'nan area of the Xinjiang oilfield. It bridges a knowledge gap by exploring the mechanical deformation and failure patterns among different glutenite types. Employing porosity-permeability tests, ultrasonic wave velocity measurements, and triaxial compression tests, this research scrutinizes physical parameters, mechanical properties, deformation, and failure modes of dolomitic sandstone, calcareous coarse sandstone, calcareous fine siltstone, and glutenite. Results highlight a porosity increase from dolomitic sandstone to glutenite, with calcareous coarse sandstone having the lowest permeability and glutenite the highest. Shear wave velocity is greater in dolomitic sandstone and calcareous coarse sandstone compared to calcareous fine siltstone, while longitudinal wave velocity is higher in dolomitic sandstone than in glutenite. Deformation behavior varies: dolomitic sandstone is primarily elastic, and calcareous sandstone and glutenite show elastoplastic characteristics. Dolomitic sandstone boasts the highest compressive strength, elastic modulus, and Poisson's ratio. Calcareous fine siltstone's compressive strength and elastic modulus fall below dolomitic sandstone, while the Poisson's ratio of calcareous coarse sandstone is three-quarters that of dolomitic sandstone. Main failure modes observed are shear failure in dolomitic sandstone, calcareous coarse sandstone, and glutenite, and axial splitting failure in calcareous fine siltstone. Microscopic analyses, including environmental scanning electron microscopy and mineral composition, shed light on the mechanical differences among the rocks. In sum, this research yields crucial insights into the mechanical traits of glutenite reservoir rocks, essential for optimizing hydraulic fracturing strategies in such reservoirs. [ABSTRACT FROM AUTHOR]

Background: Low‐grade appendiceal mucinous neoplasms (LAMN) are very rare, accounting for approximately 0.2%–0.5% of gastrointestinal tumors. We conducted a multicenter retrospective study to explore the impact of different surgical procedures combined with HIPEC on the short‐term outcomes and long‐term survival of patients. Methods: We retrospectively analyzed the clinicopathological data of 91 LAMN perforation patients from 9 teaching hospitals over a 10‐year period, and divided them into HIPEC group and non‐HIPEC group based on whether or not underwent HIPEC. Results: Of the 91 patients with LAMN, 52 were in the HIPEC group and 39 in the non‐HIPEC group. The Kaplan‐Meier method predicted that 52 patients in the HIPEC group had 5‐ and 10‐year overall survival rates of 82.7% and 76.9%, respectively, compared with predicted survival rates of 51.3% and 46.2% for the 39 patients in the non‐HIPEC group, with a statistically significant difference between the two groups (χ2 = 10.622, p = 0.001; χ2 = 10.995, p = 0.001). Compared to the 5‐year and 10‐year relapse‐free survival rates of 75.0% and 65.4% in the HIPEC group, respectively, the 5‐year and 10‐year relapse‐free survival rates of 48.7% and 46.2% in the non‐HIPEC group were significant different between the two outcomes (χ2 = 8.063, p = 0.005; χ2 = 6.775, p = 0.009). The incidence of postoperative electrolyte disturbances and hypoalbuminemia was significantly higher in the HIPEC group than in the non‐HIPEC group (p = 0.023; p = 0.044). Conclusions: This study shows that surgery combined with HIPEC can significantly improve 5‐year and 10‐year overall survival rates and relapse‐free survival rates of LAMN perforation patients, without affecting their short‐term clinical outcomes. [ABSTRACT FROM AUTHOR]

Hamaker constants are characteristic material properties that determine the magnitude of the nonlinear van der Waals force between atoms, molecules and nanoscale aggregates of atoms. This paper explores the novel possibility of using Harmonic Balance based non-linear system identification methods to extract from the nonlinear vibration spectrum of resonant atomic force silicon microcantilevers, the Hamaker constants between a few atoms at the tip of the microcantilever and graphite, gold and silicon carbide samples. First, the nonlinear dynamics of a diving board microcantilever coupled to the samples through van der Waals force potentials are investigated through a discretized model of the system. Next, the feasibility of using Harmonic Balance based nonlinear system identification techniques are demonstrated using simulations of the discretized model. Finally the method is implemented on an AFM system. The results indicate that the proposed method provides a novel alternative way to measure Hamaker constants and the measured results are within the range of known experimental data. [DOI: 10.1115/1.1760560]