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Interleukin-17 (IL-17) is an essential proinflammatory cytokine, which is mainly secreted by the CD4 helper T cells (Th17 cells) and subsets of innate lymphoid cells. IL-17A is associated with the pathogenesis of inflammatory diseases, including psoriasis, atopic dermatitis, hidradenitis suppurativa, alopecia areata, pityriasis rubra pilaris, pemphigus, and systemic sclerosis. Interleukin-23 (IL-23) plays a pivotal role in stimulating the production of IL-17 by activating the Th17 cells. The IL-23/IL-17 axis is an important pathway for targeted therapy for inflammatory diseases. Emerging evidence from clinical trials has shown that monoclonal antibodies against IL-23, IL-17, and tumor necrosis factor are effective in the treatment of patients with psoriasis, atopic dermatitis, hidradenitis suppurativa, pityriasis rubra pilaris, pemphigus, and systemic sclerosis. Here, we summarize the latest knowledge about the biology, signaling, and pathophysiological functions of the IL-23/IL-17 axis in inflammatory skin diseases. The currently available biologics targeting the axis is also discussed.

Numerical simulations of a 120 t/d sludge fluidized bed incinerator were performed using Computational Particle Fluid Dynamics (CPFD) method. The effects of secondary air on temperature distribution, gas distribution and pollutant emissions were investigated. The results show that the secondary air with a tangential arrangement significantly enhance flow field disturbance in the furnace compared with the original opposed arrangement. This can increase temperature and temperature distribution uniformity in the dilute phase region. The tangential arrangement facilitates vortex formation within the furnace, thereby accelerating gas-solid mixing and enhancing O 2 concentration uniformity in radial sections. Compared with the opposed arrangement, the tangential arrangement can promote the oxidation of CO and SO 2 while enabling effective reductive removal of NO. The computational results demonstrate that under the tangential arrangement, CO emissions at the furnace outlet decrease by 96.44%, with simultaneous reductions of 6.80% for NO and 53.42% for SO 2 , indicating significant improvements in comprehensive pollutant emissions control.

The first‐line therapy pattern transition of metastatic HER2‐positive gastric cancer is shifting. The KEYNOTE‐811 study demonstrated that the addition of immunotherapy to the standard treatment of HER2‐targeted therapy and chemotherapy showed good results in terms of PFS, especially in subgroup patients with PD‐L1 CPS≥1. In the future, the first‐line therapy pattern of metastatic HER2‐positive gastric cancer will be radically changed based on ongoing randomized controlled clinical trials. The first‐line therapy pattern transition of metastatic human epidermal growth factor receptor 2 (HER2)‐positive gastric cancer (GC) is shifting. The KEYNOTE‐811 study demonstrated that the addition of immunotherapy to the standard treatment of HER2‐targeted therapy and chemotherapy showed good results in terms of progression‐free survival, especially in subgroup patients with programmed cell death ligand 1 combined positive score ≥ 1. In the future, the first‐line therapy pattern of metastatic HER2‐positive GC will be radically changed based on ongoing randomized controlled clinical trials.

Background We previously found that (pro)renin receptor ((P)RR) augments Wnt3 protein without affecting Wnt3 gene transcription in colorectal cancer (CRC) cells, thus contributes to CRC initiation. The present study aims to investigate whether (P)RR further promotes CRC progression following oncogenesis and the related mechanisms. Notably, we deeply elaborate how (P)RR affects Wnt3 protein level and the key enzyme that mediates this process. Methods Immunohistochemistry, western blotting and immunofluorescence were performed to detect protein expression status. A kind of gastrointestinal epithelium-specific ATP6AP2 ((P)RR encoding gene) knock-in mice were generated using Crispr/Cas9 system. Results We found that increased (P)RR expression in primary CRC lesions is positively associated with higher Wnt3 protein level and disease progression. Progressive CRC presents less colocalization of Wnt3 and an E3 ubiquitin ligase NEDD4L in primary lesions than non-progressive CRC. In colon cancer cells, (P)RR dramatically inhibits the NEDD4L-mediated Wnt3 protein ubiquitination. ATP6AP2 knock-in mice show more diminished Wnt3-NEDD4L colocalization in their gut epithelium in comparison to wildtype mice. They also have abnormal gut bacterial flora distribution. Especially, Lachnospiraceae_NK4A136 and Bacteroides genus, which are generally protective against CRC, are suppressed in guts of ATP6AP2 knock-in mice. Conclusions Collectively, (P)RR promotes CRC progression through inhibiting the NEDD4L-mediated Wnt3 ubiquitination and modulating gut microbiota. 5Fh7m3ebJHKpa3LjUnmMxG Video Abstract

Background The death burden attributable to modifiable risk factors is key to colorectal cancer (CRC) prevention. This study aimed to assess the prevalence and regional distribution of attributable CRC death burden worldwide from 1990 to 2019. Methods We extracted data from the Global Burden of Disease Study in 2019 and assessed the mortality, age‐standardized death rate (ASDR), population attributable fractions, and time trend in CRC attributable to risk factors by geography, socio‐demographic index (SDI) quintile, age, and sex. Results Over the past 30 years, from high to low SDI region, the number of deaths increased by 46.56%, 103.55%, 249.64%, 231.89%, 163.11%, and the average annual percentage change (AAPC) for ASDR were −1.06%, −0.01%, 1.32%, 1.19%, and 0.65%, respectively. ASDR in males was 1.88 times than in females in 2019; ASDR in males showed an increasing trend (AAPC 0.07%), whereas ASDR in females showed a decreasing trend (AAPC −0.69%) compared to figures in 1990. In 2019, from high to low SDI region, the 15–49 age group accounted for 3%, 6%, 10%, 11%, and 15% of the total population; dietary and metabolic factors contributed 43.4% and 20.8% to CRC‐attributable death worldwide. From high to low SDI region, ASDRs caused by dietary and metabolic factors increased by −23.4%, −5.5%, 25.8%, 29.1%, 13.5%, and 1.4%, 33.3%, 100.8%, 128.4%, 77.7% respectively, compared to 1990. Conclusions The attributable CRC death burden gradually shifted from higher SDI to lower SDI regions. The limitation in males was more significant, and the gap is expected to be further expanded. In lower SDI regions, the death burden tended to affect younger people. The leading cause of CRC‐attributable deaths was the inadequate control of dietary and metabolic risk factors.

Current therapeutic approaches for colorectal cancer (CRC) face challenges such as recurrence and drug resistance. Ferroptosis, a novel form of cell death, is a promising therapeutic approach for CRC. SPOP plays an important biological role as a substrate-binding protein of the E3 ubiquitin ligase complex CRL3, but its therapeutic effects in CRC patients and its ability to modulate ferroptosis remain largely unknown. This study demonstrated that SPOP functions as a tumor suppressor in CRC and that SPOP inhibits the proliferation and metastasis of CRC cells and increases their sensitivity to ferroptosis. Transcriptome analysis suggested that Wnt signaling may be a potential target for the function of SPOP. Further data revealed that SPOP knockdown increased β-catenin protein levels, and the clinical data indicated that SPOP expression had the opposite effect on β-catenin protein levels. Molecular biology experiments suggest that SPOP promotes polyubiquitination and degradation of the K508 site of β-catenin. Interestingly, O-GlcNAcylation of SPOP reduces its protein stability and affects SPOP binding to β-catenin, and SPOP also promotes CRC ferroptosis by inhibiting the β-catenin/SLC7A11 axis. Combined treatment with the SPOP-targeted drug maprotiline and a ferroptosis inducer has synergistic antitumor efficacy in CRC cells and xenografts. Our study reveals the multifaceted function of SPOP in CRC, and the activation of SPOP may be a feasible strategy to increase the sensitivity of CRC to ferroptosis inducers.

Sweet syndrome is a neutrophilic dermatosis that could be associated with malignancy, especially hematologic malignancy. Few studies have systematically elaborated on this disorder and its features related with hematologic malignancy. This study aimed to describe the clinicopathological characteristics, treatment, and outcome of Sweet syndrome and to evaluate patient characteristics associated with hematologic malignancy. We retrospectively reviewed patients with Sweet syndrome at the Department of Dermatology, the First Affiliated Hospital of Zhejiang University from October 2010 to February 2019. The study included 37 patients (16 men and 21 women), with a mean age of 53 years. Ten patients (27%) were classified as having malignancy-associated Sweet syndrome: nine with a hematologic malignancy including acute myeloid leukemia (4/9, 44%), myelodysplastic syndrome (4/9, 44%), and multiple myeloma (1/9, 11%) and one with a solid tumor diagnosed with liver carcinoma. The mean hemoglobin and platelet levels ( = 0.007 and = 0.013, respectively), were significantly lower in patients with hematologic malignancy than in those with Sweet syndrome only. No significant difference in histopathology was found between patients with and without hematologic malignancy. Systemic corticosteroids were the most frequently used treatment (24/37, 65%). Higher mortality was found in patients with hematologic malignancy. It is important to assess Sweet syndrome patients who have laboratory evidence of lower hemoglobin and platelet levels for a hematologic malignancy.

Objective: In some patients with adenomatous polyposis, an identifiable pathogenic variant of known associated genes cannot befound. Researchers have studied this for decades; however, few new genes have been identified. Methods: Adenomatous polyposis coli (APC) negative polyposis patients were identified through next-generation sequencingand multiplex ligation-dependent probe amplification. Then, whole-exome sequencing (WES) was used to determine candidategenes harboring pathogenic variants. Functional experiments were performed to explore their effects. Subsequently, using Sangersequencing, we found other polyposis patients carrying variants of the DUOX2 gene, encoding dual oxidase 2, and analyzed them. Results: From 88 patients with suspected familial adenomatous polyposis, 25 unrelated APC negative polyposis patients wereidentified. Based on the WES results of 3 patients and 2 healthy relatives from a family, the germline nonsense variant (c.1588A>T;p.K530X) of the DUOX2 gene was speculated to play a decisive role in the pedigree in relation to adenomatous polyposis. Duringfunctional experiments, we observed that the truncated protein, hDuox2 K530, was overexpressed in the adenoma in a carrier of theDUOX2 nonsense variant, causing abnormal cell proliferation through endoplasmic reticulum (ER) retention. In addition, we foundtwo unrelated APC negative patients carrying DUOX2 missense variants (c.3329G>A, p.R1110Q; c.4027C>T, p.L1343F). Given theresults of the in silico analysis, these two missense variants might exert a negative influence on the function of hDuox2. Conclusions: To our knowledge, this is the first study that reports the possible association of DUOX2 germline variants withadenomatous polyposis. With an autosomal dominant inheritance, it causes ER retention, inducing an unfolded protein response.

The overall goal of this research was to develop the Vis/BC-BiOI/PMS system, integrating multiple advanced oxidation technologies, to effectively treat Enrofloxacin (ENR), a typical antibiotic pollutant known for its resistance to degradation. The modified biochar underwent thorough characterization, including analysis of its structure, morphology, surface material composition, and other properties. Adsorption experiments revealed that the Biochar (BC) component exhibited the most robust adsorption removal rate, reaching 15%, followed by Bismuth Iodide Oxide loaded Biochar (BC-BiOI) (9%) and Bismuth Iodide Oxide (BiOI) (2%). The control experiment was separately conducted under dark or visible light conditions, demonstrating that photocatalysis primarily contributed to ENR degradation. The subsequent degradation kinetics also showed this point. The pathway and mechanism of ENR degradation in the Vis/BC-BiOI/PMS system were extensively analyzed. The contribution of each active substance was determined through free radical quenching tests and Electron Paramagnetic Resonance (EPR) spectra. The results indicated that ·OH and SO4−· played dominant roles in the early stages of ENR degradation, while 1O2 became the primary contributor in the later stages, with 1O2 > ·OH > SO4−·. In addition, the toxicity and applicability of the Vis/BC-BiOI/PMS system were evaluated. This study demonstrates the effectiveness and feasibility of the Vis/BC-BiOI/PMS system in treating ENR wastewater.