Search

Abstract Patulin (PAT) is a common mycotoxin in moldy fruits that causes gastrointestinal injury if accidentally ingested. Some studies have reported the symptoms of intestinal injury caused by PAT. However, the effects of PAT on the gut microbiota and gut metabolism remain to be investigated, which is important for clarifying the toxicological mechanisms. Thus, C57/BL6J mice were gavaged once with 0, 1, 4, and 16 mg/kg body weight PAT, and the small intestinal and colonic contents were collected. The 16S rRNA sequencing and targeted and untargeted metabolomics were applied to assess the alterations in microbiota and metabolism, respectively. The results showed that Mycoplasma, Dubosiella, and Enterorhabdus were jointly affected by acute PAT exposure in the small intestinal and colonic contents. Some inflammation‐related bacteria, such as Mycoplasma in the small intestine and Mycoplasma, Alistipes, Eubacterium_coprostanoligenes_group, and Candidatus_saccharimona in the colon, increased with increasing doses of PAT. In metabolic results, amino acids decreased and bile acids elevated in both intestinal contents; lipids increased in the small intestinal contents but decreased in the colonic contents. PAT mainly affected host amino acid and lipid metabolism; it also downregulated microbial tryptophan metabolism and short‐chain fatty acid levels (mainly in the colon), which could be explained by the decrease of Bacteroides and Lactobacillus. These influences in microbial abundances and metabolic levels persisted after PAT and its products were cleared. These results fill a gap in the effects of PAT on the gut microbiota and provide a theoretical basis for elucidating the toxic mechanism of mycotoxins.

Abstract Ciprofol (also known as HSK3486) is a promising intravenous anesthetic candidate derived from propofol and independently developed by Haisco Pharmaceutical Group Co., Ltd. (Chengdu, China). Compared with propofol, ciprofol has the potential to reduce the dose required and the associated risks. Ciprofol is extensively metabolized in vivo, and its interaction with other concurrently administered drugs during clinical application is worthy of attention. Therefore, an open‐label, two‐stage sequential study was performed in healthy subjects who received either a single administration of ciprofol injection or ciprofol injection after oral administration of sodium divalproex. The aim of the study was to evaluate the effects of sodium divalproex on ciprofol with respect to pharmacokinetics, pharmacodynamics, and safety, thus providing a basis for the rational clinical use of ciprofol and sodium divalproex.

Abstract Background Anastomotic leak following radical gastrectomy poses a significant risk to patients. Despite previous studies, effective methods for diagnosing anastomotic leaks after gastric cancer surgery remain elusive. In this study, we aimed to assess the overall burden of anastomotic leaks and investigate diagnostic factors, particularly radiological signs on postoperative computed tomography (CT), that may facilitate early detection. Methods We included a total of 70 gastric cancer patients who underwent curative gastrectomy and underwent CT examination post‐surgery. Among them, 35 patients with anastomotic leak were matched with 35 patients without anastomotic leak. We compared the rates of various types of postoperative complications between the two groups and conducted univariate and multivariate analyses to identify predictive variables for postoperative diagnosis. Results Patients with anastomotic leaks experienced significantly longer postoperative hospital stays and higher overall expenditures (p

Abstract Purpose Bone marrow metastasis (BMM) is uncommon in breast cancer (BC), and early diagnosis is challenging. BMM lacks definitive treatment options and poses a great threat to the survival of patients. Herein, we investigated the clinical features, prognosis, and factors affecting the prognosis of BC patients with symptomatic BMM to help improve the understanding of this disease and provide effective diagnostic and treatment strategies. Methods Clinical data of 67 patients with BC and BMM were retrospectively analyzed for clinical characteristics, treatment, and prognosis of BMM. Univariate and multivariate analyses were performed to determine factors affecting overall survival following BMM (BMMOS). Results Among patients with BMM, 86.6% were diagnosed after bone metastasis (BM), while 13.4% were diagnosed simultaneously with BM. A total of 73.1%, 13.4%, and 13.4% of the patients had hormone receptor‐positive/human epidermal growth factor 2‐negative (HR+/HER2−) tumors, HER2+ tumors, and triple‐negative tumors, respectively. The most common symptoms of BMM were the coexistence of anemia and thrombocytopenia (26.9%), anemia (19.4%), and pancytopenia (17.9%). The median BMMOS was 7.6 months (95% CI, 3.9–11.3). Univariate and multivariate analyses showed that BMMOS was associated with platelet count

Abstract Background Anthracycline‐based chemotherapy (ABC) is one of the standard therapies against breast cancer. However, few guidelines are currently available to optimize the use of ABC. Therefore, the present analysis aimed at determining the profile and treatment patterns of ABC and the association of clinicopathological characteristics with ABC selection. Methods We retrospectively analyzed the data of a nation‐wide multicenter epidemiological study, which collected the medical records of breast cancer patients receiving chemotherapy in different settings from seven geographic regions in China (NCT03047889). Results In total, 3393 patients were included, with 2917 treated with ABC. Among them, 553 (89.8%), 2165 (81.7%), and 814 (25.7%) were subjected to ABC as neoadjuvant, adjuvant, and advanced chemotherapy, respectively. The most frequently used regimens were anthracycline‐taxane‐based combinations for neo‐ and adjuvant chemotherapy, along with taxanes and oral fluorouracils for the palliative stages. In the overall cohort, patients aged < 40 or 40‐65 (p < 0.001), in premenopause (p < 0.001), without comorbidities (p = 0.016), with invasive ductal carcinoma (p= 0.001), high lymph node involvement (p < 0.001), in the pTNM stage II, III, or IV versus stage I (p < 0.001), subjected to mastectomy (p < 0.001) or subjected to sentinel lymph node biopsy combined with axillary lymph node dissection (p = 0.044), or with a decreased disease‐free survival (p < 0.001) were more likely to be recommended to ABC. Conclusion Taken together, ABC remained the mainstay of breast cancer treatment, especially in neo and adjuvant therapy. ABC was mainly used as a combination therapy, and the correlation between influencing factors and ABC choice varied during different settings, indicating the preference and different perspectives of medication considered by medical oncologists regarding the use ABC in China.

Abstract Background Increasing studies have reported that oncogenes regulate components of the immune system, suggesting that this is a mechanism for tumorigenesis. Aurora kinase A (AURKA), a serine/threonine kinase, is involved in cell mitosis and is essential for tumor cell proliferation, metastasis, and drug resistance. However, the mechanism by which AURKA is involved in immune response regulation is unclear. Therefore, this study aimed to investigate the role of AURKA in immune regulation in triple‐negative breast cancer (TNBC). Methods Peripheral blood mononuclear cells (PBMCs) were co‐cultured with TNBC cells. The xCELLigence Real‐Time Cell Analyzer‐MP system was used to detect the killing efficiency of immune cells on TNBC cells. The expression of immune effector molecules was tested by quantitative real‐time polymerase chain reaction (qRT‐PCR) to evaluate immune function. Furthermore, to validate AURKA‐regulated immune response in vivo, 4T1 murine breast cancer cell line with AURKA overexpression or downregulation was engrafted into BALB/c mice. The distribution and proportion of immune cells in tumors were further evaluated by immunohistochemistry and flow cytometry. Results Downregulation of AURKA in TNBC cells increased immune response by activating CD8+ T cell proliferation and activity. Nuclear rather than cytoplasmic AURKA‐derived programmed death‐ligand 1 (PD‐L1) expression was independent of its kinase activity. Mechanistic investigations showed that nuclear AURKA increased PD‐L1 expression via an MYC‐dependent pathway. PD‐L1 overexpression mostly reversed AURKA silencing‐induced expression of immune effector molecules, including interleukin‐ (IL‐2), interferon‐γ (IFN‐γ), and perforin. Moreover, AURKA expression was negatively correlated with the enrichment and activity of tumor‐infiltrating CD8+ T cells in 4T1 engrafted BALB/c mouse model. Conclusions Nuclear AURKA elevated PD‐L1 expression via an MYC‐dependent pathway and contributed to immune evasion in TNBC. Therapies targeting nuclear AURKA may restore immune responses against tumors.

Summary Failed puberty is one of the main reasons for eliminating gilts from production herds. This is often caused by disorders of sex hormones. An increasing number of studies have suggested that the gut microbiota may regulate sex hormones and vice versa. Whether the gut microbiota is involved in the failure of oestrus in gilts remains unknown. We used 16S rRNA gene sequencing, network‐based microbiota analysis and prediction of functional capacity from 16S rRNA gene sequences to explore the shifts in the gut microbiota throughout a heat cycle in 22 eight‐month‐old gilts. We found that a module of co‐occurrence networks composed of Sphaerochaeta and Treponema, co‐occurred with oestrus during a heat cycle. The mcode score of this module reflecting the stability and importance in the network achieved the highest value at the oestrus stage. We then identified bacterial biosignatures associated with the failure to show puberty in 163 gilts. Prevotella, Treponema, Faecalibacterium, Oribacterium, Succinivibrio and Anaerovibrio were enriched in gilts showing normal heat cycles, while Lachnospiraceae, Ruminococcus, Coprococcus and Oscillospira had higher abundance in gilts failing to show puberty. Prediction of functional capacity of the gut microbiome identified a lesser abundance of the pathway ‘retinol metabolism’ in gilts that failed to undergo puberty. This pathway was also significantly associated with those bacterial taxa involved in failed puberty identified in this study (P

Abstract Background Overexpression of Aurora‐A (AURKA) is a feature of breast cancer and associates with adverse prognosis. The selective Aurora‐A inhibitor alisertib (MLN8237) has recently demonstrated promising antitumor responses as a single agent in various cancer types but its phase III clinical trial was reported as a failure since MLN8237 did not show an apparent effect in prolonging the survival of patients. Thus, identification of potential targets that could enhance the activity of MLN8237 would provide a rationale for drug combination to achieve better therapeutic outcome. Methods Here, we conducted a systematic synthetic lethality CRISPR/Cas9 screening of 507 kinases using MLN8237 in breast cancer cells and identified a number of targetable kinases that displayed synthetic lethality interactions with MLN8237. Then, we performed competitive growth assays, colony formation assays, cell viability assays, apoptosis assays, and xenograft murine model to evaluate the synergistic therapeutic effects of Haspin (GSG2) depletion or inhibition with MLN8237. For mechanistic studies, immunofluorescence was used to detect the state of microtubules and the localization of Aurora‐B and mitotic centromere‐associated kinesin (MCAK). Results Among the hits, we observed that Haspin depletion or inhibition marginally inhibited breast cancer cell growth but could substantially enhance the killing effects of MLN8237. Mechanistic studies showed that co‐treatment with Aurora‐A and Haspin inhibitors abolished the recruitment of Aurora‐B and mitotic centromere‐associated kinesin (MCAK) to centromeres which were associated with excessive microtubule depolymerization, kinetochore‐microtubule (KT‐MT) attachment failure, and severe mitotic catastrophe. We further showed that the combination of MLN8237 and the Haspin inhibitor CHR‐6494 synergistically reduced breast cancer cell viability and significantly inhibited both in vitro and in vivo tumor growth. Conclusions These findings establish Haspin as a synthetic lethal target and demonstrate CHR‐6494 as a potential combinational drug for promoting the therapeutic effects of MLN8237 on breast cancer.

Abstract The purpose of the study was to explore the microscopic and mesoscopic damage mechanisms of water‐bearing coal mass in the freeze‐thaw process with liquid nitrogen. For this purpose, by using a Zeiss microscope, a nonmetal ultrasonic velocity detector and a nuclear magnetic resonance (NMR) spectrometer, the changes in the structures of surface fractures and pores before and after coal masses with different moisture contents when subjected to freeze‐thaw treatment with liquid nitrogen (FTTLN) were tested. The result showed that under the freeze‐thaw effect of liquid nitrogen, the structures of surface fractures and internal pores of coal mass were both changed. Upon increasing the moisture content of the coal, the width of surface fractures increased; the surface fractures showed significant fractal characteristics: The higher the moisture content of the coal, the greater the rate of change of fractal dimension after FTTLN; the ultrasonic wave velocity in the coal mass gradually decreased after FTTLN, and the greater the moisture content, the more significant the decrease in ultrasonic wave velocity; under the freeze‐thaw effect of liquid nitrogen, the pore structure in the coal mass was transformed from micropores and small pores to mesopores and macropores and certain new micropores and small pores were generated. Upon increasing the moisture content of the coal mass, the peak area of micropores and small pores and their proportion decreased at first and then increased (reaching the minimum at 9.12% of moisture content); the peak area, peak area proportion, and porosity of mesopores and macropores always increased. The damage factor attained based on the width of fractures, longitudinal wave velocity, fractal dimension of surface fractures, and porosity was favorably correlated with the moisture content: With increasing moisture content, the coal mass became more severely damaged.

A novel method for synthetic aperture radar (SAR) three-dimensional (3D) sparse imaging based on a coprime linear array (CLA) is proposed. To reduce the geometric resolution loss caused by under-sampled sparse SAR, a jointed sparse imaging approach is used. In this scheme, the coprime sampled data of CLA is separately processed via the iterative reweight least-squares approach, and their recovered results are combined to cancel the false targets and grating-lobes to improve the imaging quality. Both simulated and experimented results demonstrate the effectiveness of the method. It shows that the exploiting of CLA and sparse recovery can significantly reduce the linear array antenna amount and the geometric resolution loss compared with the conventional uniform linear array SAR.

Background. Primary dysmenorrhea (PD) is the commonest gynecological disorder in young women of reproductive age, and there is not always satisfactory relief of pain treated by common medications. Therefore, acupuncture has been used as an alternative therapy to relieve the symptoms of PD. In clinical practice, a penetrating method of acupuncture with long needle has been shown to be particularly effective for improving primary dysmenorrhea. This study was conducted to evaluate the effectiveness of this technique for pain relief in patients with primary dysmenorrhea as compared with a conventional pain medication. Methods. The present study is a perspective, randomized, ibuprofen-controlled trial. Sixty-two eligible participants were randomly assigned in a 1 : 1 ratio to receive either acupuncture treatment or ibuprofen administration. The treatment lasted for three menstrual cycles for both groups. The primary outcome was the intensity of menstrual pain measured by using the visual analogue scale at the completion of treatment. Secondary outcomes included the severity of symptoms associated with menstrual pain, responder rate, and safety of acupuncture treatment. The clinical outcomes were measured on each menstrual cycle at baseline, treatment course (3 cycles), and follow-up period. Results. Sixty-four patients of primary dysmenorrhea were recruited, and 62 subjects were included in the final analysis. At trial completion, acupuncture was shown to be associated with a significantly lower pain intensity and decreased symptom severity of primary dysmenorrhea as compared with ibuprofen (p

Density-driven free convection in porous media is highly affected by large-scale heterogeneity, typical of which are low- or high-permeability inclusions imbedded in homogeneous porous media. In this research, we applied the modified Elder problem to investigate the impact of low- or high-permeability inclusions on the migration of a dense, unstable salt plume. Sensitivity analyses were conducted in terms of the permeability contrast, the effective area (the area of the inclusion beneath the source zone), and the distance of the inclusion from the source zone, all of which were found to play a significant role in controlling the total mass flux released from the source into the media. Results show that (1) a high-permeability inclusion has stronger effects than low-permeability inclusion, due to significantly unbalanced solute distributions caused by accelerated solute transport, (2) the inclusion with a larger effective area has more potential to influence free convection, (3) free convection is more sensitive to the low-/high-permeability inclusion vertically closer to the source zone, and (4) free convection is more susceptible to the low-permeability inclusion horizontally closer to the source zone. For high-permeability inclusions, the inclusion horizontally closer to the source zone influences the transport process more significantly at the early stage, and conversely, the inclusion far from the source zone has a later impact. The results obtained could offer significant implications for understanding unstable density-driven flow and solute transport in porous media with structured heterogeneity.

This paper presents a diagnosis scheme based on a linear matrix inequality (LMI) algorithm for incipient faults in a nonlinear system class with unknown input disturbances. First, the nonlinear system is transformed into two subsystems, one of which is unrelated to the disturbances. Second, for the subsystem that is free from disturbances, a Luenberger observer is constructed; a sliding mode observer is then constructed for the subsystem which is subjected to disturbances, so that the effect of the unknown input disturbances is eliminated. Together, the entire system achieves both robustness to disturbances and sensitivity to incipient faults. Finally, the effectiveness and feasibility of the proposed method are verified through a numerical example using a single-link robotic arm.

Surface-plasmon-polariton (SPP) waveguides made of materials available in nature have, in general, been found to suffer from very high absorption loss when light confinement is beyond diffraction limit. In this paper, the possibility of combining both the conventional index-guiding and the SPP-guiding mechanisms together into one single waveguide is being explored. Such waveguides, expectedly, inherent the low-loss feature of all-dielectric waveguides as well as the superior mode field confinement possessed by SPP waveguides. By using experimentally ready materials, it is theoretically shown that compact metallodielectric waveguides can be designed with a ∼500×500 nm2 core size around the 1550 nm telecommunication wavelength. The examined waveguides can be interpreted as a gap SPP waveguide with an inner dielectric core. Compared to pure SPP waveguides, such hybrid waveguides have a comparable mode field size, but with significantly lower loss (∼0.05 dB/μm for either quasi-TE or quasi-TM operation). Therefore they can be potentially deployed for a range of integrated photonic applications.

Objective The risk of osteochondral fracture (OCF) after patellar dislocation has been shown to be related to patellofemoral anatomy, but its relationship to patellar morphology remains unknown. The aim of this study was to investigate the associations between patellar morphology and the risk of OCF after patellar dislocation. Methods A total of 140 patients with patellar dislocation between January 2018 and June 2023 were enrolled in this study and divided into two groups. Sixty‐five patellar dislocation patients with OCF were included in the OCF group, while 75 patellar dislocation patients without OCF were included in the non‐OCF group. Computed tomography was used to compare measurements of patellar morphology including Wiberg classification, patellar width and thickness, Wiberg angle, Wiberg index, facet ratio, lateral patellar facet angle, and patellar tilt angle. A logistic regression model was performed to evaluate the correlations between patellar morphology and the risk of OCF after patellar dislocation. Receiver operating characteristic curves were used to calculate the area under the curve (AUC) and determine the diagnostic values of patellar morphology for OCF after patellar dislocation. Subgroup analyses for gender and age were conducted to compare the differences in patellar morphology of PD patients. Results Wiberg angle was significantly lower in the OCF group (p = 0.017), while Wiberg index (p = 0.002) and facet ratio (p = 0.023) were significantly higher in the OCF group. According to the results of logistic regression analysis, Wiberg angle (odds ratio [OR] = 0.96, p = 0.022) and Wiberg index (OR = 1.105, p = 0.032) were the final relevant factors for the occurrence of OCF after patellar dislocation. The AUC was 0.622 (95% confidence interval [CI]: 0.529–0.714) for Wiberg angle, 0.65 (95% CI: 0.558–0.742) for Wiberg index, and 0.702 (95% CI: 0.615–0.788) for the combination of Wiberg angle plus Wiberg index. Conclusion Wiberg angle and Wiberg index were independent risk factors for the occurrence of osteochondral fracture after patellar dislocation. Moreover, Wiberg angle, Wiberg index, and the combination of Wiberg angle plus Wiberg index had good predictive diagnostic value for the occurrence of OCF after patellar dislocation.

Abstract Monoamine oxidases (MAOs) are a class of flavin enzymes that are mainly present in the outer membrane of mitochondria and play a crucial role in maintaining the homeostasis of monoamine neurotransmitters in the central nervous system. Furthermore, expression of MAOs is associated with the functions of peripheral organs. Dysfunction of MAOs is relevant in a variety of diseases such as neurodegenerative diseases, heart failure, metabolic disorders, and cancers. Monoamine oxidases have two isoenzymes, namely, monoamine oxidase A (MAO‐A) and monoamine oxidase B (MAO‐B). Therefore, the development of reliable and specific methods to detect these two isoenzymes is of great significance for the in‐depth understanding of their functions in biological systems, and for further promoting the clinical diagnosis and treatment of MAO‐related diseases. This review mainly focuses on the advances in small molecular probes for the specific imaging of MAO‐A and MAO‐B, including radiolabeled probes, fluorescent probes, and a 19F magnetic resonance imaging probe. In addition, applications of these probes for detecting MAO expression levels in cells, tissues, animal models, and patients are described. Finally, the challenges and perspectives of developing novel MAO imaging probes are also highlighted.

Abstract Patients with glycogen storage disease type Ib (GSD‐Ib) frequently have inflammatory bowel disease (IBD). however, the underlying etiology remains unclear. Herein, this study finds that digestive symptoms are commonly observed in patients with GSD‐Ib, presenting as single or multiple scattered deep round ulcers, inflammatory pseudo‐polyps, obstructions, and strictures, which differ substantially from those in typical IBD. Distinct microbiota profiling and single‐cell clustering of colonic mucosae in patients with GSD are conducted. Heterogeneous oral pathogenic enteric outgrowth induced by GSD is a potent inducer of gut microbiota immaturity and colonic macrophage accumulation. Specifically, a unique population of macrophages with high CCL4L2 expression is identified in response to pathogenic bacteria in the intestine. Hyper‐activation of the CCL4L2‐VSIR axis leads to increased expression of AGR2 and ZG16 in epithelial cells, which mediates the unique progression of IBD in GSD‐Ib. Collectively, the microbiota‐driven pathomechanism of IBD is demonstrated in GSD‐Ib and revealed the active role of the CCL4L2‐VSIR axis in the interaction between the microbiota and colonic mucosal immunity. Thus, targeting gut dysbiosis and/or the CCL4L2‐VISR axis may represent a potential therapy for GSD‐associated IBD.