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The nonlinear behavior of spudcan foundation will lead to the decrease of the rotational stiffness of the spudcan, leading to the increase of the stress at the critical member of the offshore jack-up drilling platform. Secant rotational stiffness is used to represent the value of rotational stiffness of linear foundation model when the soil changes from elastic to elasto-plastic and then to plastic. In this paper, the “wished in-place” small strain finite element analysis (SSFE) analysis is used to simulate the load-displacement response of spudcans pre-embedded in the plastic soil, thus calculating the secant rotational stiffness of spudcans. New expressions of failure ratio and secant rotational stiffness are proposed with the coupling effect of horizontal force and moment taken into account.

Chemotherapy elicits tumor immune evasion with poorly characterized mechanisms. Here, we demonstrate that chemotherapy markedly enhances the expression levels of CD47 in osteosarcoma tissues, which are positively associated with patient mortality. We reveal that macrophages in response to chemotherapy secrete interleukin-18, which in turn upregulates expression of L-amino acid transporter 2 (LAT2) in tumor cells for substantially enhanced uptakes of leucine and glutamine, two potent stimulators of mTORC1. The increased levels of leucine and enhanced glutaminolysis activate mTORC1 and subsequent c-Myc-mediated transcription of CD47. Depletion of LAT2 or treatment of tumor cells with a LAT inhibitor downregulates CD47 with enhanced macrophage infiltration and phagocytosis of tumor cells, and sensitizes osteosarcoma to doxorubicin treatment in mice. These findings unveil a mutual regulation between macrophage and tumor cells that plays a critical role in tumor immune evasion and underscore the potential to intervene with the LAT2-mediated amino acid uptake for improving cancer therapies. Chemo-resistance and immune evasion are major challenges in osteosarcoma treatment. Here the authors show that doxorubicin promotes IL-18 secretion by tumor associated macrophages inducing LAT2-dependent CD47 upregulation in osteosarcoma cells, suggesting LAT2 inhibition as a therapeutic option in combination with doxorubicin.

Occurrence of Colorectal cancer (CRC) is relevant with gut microbiota. However, role of IRF3, a key signaling mediator in innate immune sensing, has been barely investigated in CRC. Here, we unexpectedly found that the IRF3 deficient mice are hyper-susceptible to the development of intestinal tumor in AOM/DSS and Apc min/+ models. Genetic ablation of IRF3 profoundly promotes the proliferation of intestinal epithelial cells via aberrantly activating Wnt signaling. Mechanically, IRF3 in resting state robustly associates with the active β-catenin in the cytoplasm, thus preventing its nuclear translocation and cell proliferation, which can be relieved upon microbe-induced activation of IRF3. In accordance, the survival of CRC is clinically correlated with the expression level of IRF3. Therefore, our study identifies IRF3 as a negative regulator of the Wnt/β-catenin pathway and a potential prognosis marker for Wnt-related tumorigenesis, and describes an intriguing link between gut microbiota and CRC via the IRF3-β-catenin axis. The alternative mechanisms of innate immunity in tumorigenesis of colorectal cancers are unclear. Here, the authors report a non-canonical function of IRF3, a mediator of innate immune signalling, in the suppression of colorectal tumorigenesis and this is via the inhibition of Wnt/β-catenin pathway.

Liver cancer remains a significant public health issue in China, exhibiting high incidence, mortality, and burden. Understanding its temporal trends and projections is essential for designing targeted prevention and treatment strategies. This study analyzes long-term trends in liver cancer incidence, prevalence, mortality, and burden from 1990 to 2021, assessing age, period, and cohort effects, and projecting future trends. Data on liver cancer incidence, prevalence, mortality, disability-adjusted life years (DALYs), years lived with disability (YLDs), and years of life lost (YLLs) were analyzed from 1990 to 2021. Joinpoint regression analysis, age-period-cohort (APC) analysis, and BAPC modeling were applied to examine trends and project future trends. Decomposition analysis examined contributions of aging, epidemiological changes, and population growth. The study also compared China’s liver cancer trends with global data. From 1990 to 2021, China experienced a decrease in age-standardized rates for liver cancer incidence, prevalence, mortality, and burden. Notably, Age-standardized incidence rates (ASIR) exhibited a decline after 2016, with a significant reduction in the male population. In 2021, there were 196,637 new cases of liver cancer in China, with a higher burden in males. ASIR were 14.34 per 100,000 for males and 4.89 per 100,000 for females. Mortality also followed a declining trend, with a notable decrease in age-standardized mortality rates. The age-standardized mortality rate (ASMR) for males was 12.4 per 100,000, significantly higher than for females (4.57 per 100,000) in 2021. Additionally, the age-standardized prevalence rate (ASPR) was 20.0 for males and 6.64 for females, with 265,539 total cases. The burden, measured by DALYs, YLDs, and YLLs, also showed a notable decline in age-standardized rates and significant gender disparities. Despite this, the absolute number of cases, deaths, and DALYs has continued to rise due to population growth and aging, with males bearing a significantly higher burden than females. The study also highlights the impact of aging, population growth, and epidemiological changes on liver cancer incidence and mortality in China. Projections for 2030 suggest a continued decrease in liver cancer incidence, especially among females, reflecting the effectiveness of public health interventions and medical advancements. However, gender disparities remain significant, and further efforts are needed to reduce the overall liver cancer burden, with an emphasis on early detection and prevention strategies.

Gasdermin (GSDM) family proteins mediate tumor pyroptosis and impact cancer progression, but other than that, their involvement in the tumor immune microenvironment remains largely unknown. Here, we show that activation of GSDMD in human tumor specimens mainly occurs in tumor-infiltrating leukocytes. Significantly, GSDMD deficiency or its inactivation in CD4+ T cells disabled CD8+ T cell-mediated antitumor immunity and caused tumor outgrowth in mice. Further study uncovered that, via inducing IL-2 production, GSDMD was required for CD4+ T cells to provide help to CD8+ T cell function. Mechanistically, GSDMD was cleaved by TCR stimulation-activated caspase-8 to form GSDMD-N pores, which enhanced Ca2+ influx for IL-2 induction. Moreover, GSDMD activation and function were conserved in human CD4+ T cells and associated with favorable prognosis and improved response to anti-PD-1 immunotherapy in colonic and pancreatic cancer. We believe this study identifies a new nonpyroptotic role of GSDMD in tumor immunity, proposing GSDMD as a potential target for cancer immunotherapy.

As central cells involved in osteoimmunology, bone niche macrophages possess diverse functions, and their differentiation fate regulates bone homeostasis. Elucidation of the underlying mechanism involved in macrophage differentiation is important for developing new therapeutic targets for osteoporosis. Here, we show that knocking out Raf kinase inhibitor protein (RKIP), either globally or in macrophages, results in dramatically increased bone mass in mice due to synergistic inhibition of bone resorption and promotion of bone formation. Mechanistically, RKIP knockout inhibits differentiation of macrophages into osteoclasts and promotes their differentiation towards pro-angiogenic subclusters, which enhances formation of H-type vessels. RKIP enhances osteoclastogenesis by interacting with ARHGAP to suppress CDC42 inactivation. Intranuclear RKIP suppresses angiogenic genes expression by bridging the association between HIF-1α and VHL to reduce the protein stability of HIF-1α in macrophages. Furthermore, RKIP deletion or inhibitor rescues ovariectomy (OVX)-induced bone loss in vivo. Collectively, this study provides insights into the different roles of extranuclear or intranuclear RKIP in regulating differentiation of bone niche macrophages and could inform potential therapies for bone homeostasis-related diseases. Differentiation of bone niche macrophages regulates bone homeostasis. Here the authors show that Raf kinase inhibitor protein RKIP regulates differentiation of bone niche macrophages to mediate osteoclastogenesis and H-type vessel formation.

Various factors play key roles in maintaining intestine homeostasis. Disruption of the balance may lead to inflammatory bowel diseases and even colorectal cancer (CRC). Loss or gain of function of many key proteins can result in dysregulated intestinal homeostasis. Our research demonstrated that neural precursor cells expressed developmentally downregulated 4-like protein (NEDD4L, or NEDD4-2), a type of HECT family E3 ubiquitin ligase, played an important role in maintaining intestinal homeostasis. NEDD4L expression was significantly inhibited in intestinal epithelial cells (IECs) of patients with Crohn's disease, ulcerative colitis, and CRC. Global KO of NEDD4L or its deficiency in IECs exacerbated colitis induced by dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS) and CRC induced by azoxymethane and DSS. Mechanistically, NEDD4L deficiency in IECs inhibited expression of the key ferroptosis regulator glutathione peroxidase 4 (GPX4) by reducing the protein expression of solute carrier family 3 member 2 (SLC3A2) without affecting its gene expression, ultimately promoting DSS-induced IEC ferroptosis. Importantly, ferroptosis inhibitors reduced the susceptibility of NEDD4L-deficient mice to colitis and colitis-associated CRC. Thus, NEDD4L is an important regulator in IEC ferroptosis, maintaining intestinal homeostasis, making it a potential clinical target for diagnosing and treating IBDs.

Background The randomized, dose-optimization, open-label ReDOS study in US patients with metastatic colorectal cancer (CRC) showed that, compared with a standard dosing approach, initiating regorafenib at 80 mg/day and escalating to 160 mg/day depending on tolerability increased the proportion of patients reaching their third treatment cycle and reduced the incidence of adverse events without compromising efficacy. Subsequently, the ReDOS dose-escalation strategy was included as an alternative regorafenib dosing option in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines. A retrospective analysis was conducted using a US claims database to assess whether inclusion of this dose-escalation strategy in NCCN Guidelines has influenced the use of flexible dosing in routine US clinical practice, and to describe clinical outcomes pre- and post-inclusion in NCCN Guidelines. Methods Patients with CRC in the Optum’s de-identified Clinformatics® Data Mart database initiating regorafenib for the first time between January 2016 and June 2020 were stratified based on whether they initiated regorafenib pre- or post-inclusion of ReDOS in NCCN Guidelines, and in two groups: flexible dosing (< 160 mg/day; < 84 tablets in the first treatment cycle) and standard dosing (160 mg/day; ≥ 84 tablets in the first treatment cycle). The primary endpoints were the proportion of patients who initiated their third treatment cycle and the mean number of treatment cycles per group. Results 703 patients initiated regorafenib during the study period, of whom 310 (44%) initiated before and 393 (56%) initiated after inclusion of ReDOS in NCCN Guidelines. After inclusion in the guidelines, the proportion of patients who received flexible dosing increased from 21% ( n  = 66/310) to 45% ( n  = 178/393), the proportion who received standard dosing decreased from 79% ( n  = 244/310) to 55% ( n  = 215/393), the proportion who initiated their third treatment cycle increased from 36% ( n  = 113/310) to 46% ( n  = 179/393), and the mean (standard deviation) number of treatment cycles increased from 2.6 (2.9) to 3.2 (3.1). Conclusions Following inclusion of ReDOS in NCCN Guidelines, real-world data suggest that US clinicians have markedly increased use of flexible dosing in clinical practice, potentially maximizing clinical benefits and safety outcomes for patients with metastatic CRC receiving regorafenib.

Interleukin 17 (IL-17) is a key inflammatory cytokine that plays a critical role in tissue inflammation and autoimmune diseases. However, its signaling remains poorly understood. In this study, we identified serine/threonine kinase 24 (Stk24) as a positive modulator of IL-17-mediated signaling and inflammation. Stk24 deficiency or knockdown markedly inhibited IL-17-induced phosphorylation of NF-κB and impaired IL-17-induced chemokines and cytokines expression. Stk24 overexpression greatly enhanced IL-17-induced NF-κB activation and expression of chemokines and cytokines in a kinase activity-independent manner. The IL-17-induced inflammatory response was significantly reduced in Stk24-deficient mice. In addition, the severity of experimental autoimmune encephalomyelitis was markedly reduced in mice with a deficiency of Stk24 in non-hematopoietic cells. We further demonstrated that Stk24 directly interacts with TAK1 and IKKβ and promotes the formation of TAK1/IKK complexes, leading to enhanced IKKβ/NF-κB activation and downstream cytokines and chemokines induction. Collectively, our findings suggest that Stk24 plays an important role in controlling IL-17-triggered inflammation and autoimmune diseases and provides new insight into the therapeutic targets of IL-17-mediated inflammatory disease.