Thermally tunable anti-ambipolar heterojunction devices.

Two-dimensional materials and their van der Waals heterostructures have emerged as a research focal point for constructing various innovative electronic devices due to their distinct photonic and electronic properties. Among them, anti-ambipolar devices, characterized by their unique nonlinear electrical behavior, have garnered attention as novel multifunctional components, positioning them as potential contenders for building multi-state logic devices. Utilizing the properties of few-layer As0.4P0.6 and PdSe2, we have constructed an anti-ambipolar heterojunction device. At 300 K, the device exhibits a peak voltage (Vpeak) of -3 V and a peak-to-valley ratio (PVR) close to 8 × 103, and the PVR can be modulated by bias voltage. Furthermore, by characterizing the anti-ambipolar attributes at different temperatures ranging from 80 K to 330 K, we have elucidated the thermally tunable feature of the device. At 330 K, a certain PVR (∼103) and a large Vpeak (∼-16 V) are obtained, while a PVR exceeding 108 has been achieved at 80 K. This temperature-related sensitivity empowers the device with significant potential and thermal tunability in various applications.

Fungal effectors: past, present, and future.

Fungal effector proteins function at the interfaces of diverse interactions between fungi and their plant and animal hosts, facilitating interactions that are pathogenic or mutualistic. Recent advancements in protein structure prediction have significantly accelerated the identification and functional predictions of these rapidly evolving effector proteins. This development enables scientists to generate testable hypotheses for functional validation using experimental approaches. Research frontiers in effector biology include understanding pathways through which effector proteins are secreted or translocated into host cells, their roles in manipulating host microbiomes, and their contribution to interacting with host immunity. Comparative effector repertoires among different fungal-host interactions can highlight unique adaptations, providing insights for the development of novel antifungal therapies and biocontrol strategies.

A rare case report of splenic infarction in a previously healthy teenager caused by acute infectious mononucleosis.

RATIONALE: Splenic infarction usually occurs in patients with underlying illnesses such as thromboembolic disorders and infiltrative hematologic diseases. Herein, we report a rare case of splenic infarction in a previously healthy boy diagnosed with infectious mononucleosis (IM). Splenic infarction is a rare complication of IM and its incidence is unknown. This case report summarizes the clinical characteristics, treatment options, and anticipated time for recovery from splenic infarction in IM. PATIENT CONCERN: A16-year-old boy presented to our clinic with complaints of fever, sore throat, and general sweakness for 7 days. The patient was diagnosed with IM due to an Epstein-Barr virus infection. Two days later, the patient developed severe abdominal pain in the left upper quadrant and returned to our ER for further evaluation. DIAGNOSIS: IM complicated with splenic infarction. INTERVENTIONS: Contrast-enhanced CT confirmed the diagnosis of splenic infarction. This patient was admitted for supportive treatment and close medical monitoring. Surgical. OUTCOMES: The patient recovered well with conservative treatment. LESSONS: IM is most often seen in adolescents and young adults. Splenic infarction is a rare complication of IM, particularly in patients who do not usually have any underlying predisposing medical conditions. Contrast-enhanced CT is the imaging modality of choice in suspected cases. Early recognition and treatment of splenic infarction in patients with IM can help prevent potentially life-threatening events. Patients should be advised to avoid sports that may precipitate splenic rupture. However it is still unknown when it is safe for patients to resume sports. In our case, 6 weeks after the splenic infarction, the patient generally felt well with complete resolution of objective symptoms and splenomegaly, and resumed sports without experiencing any adverse events.

Virulence of banana wilt-causing fungal pathogen Fusarium oxysporum tropical race 4 is mediated by nitric oxide biosynthesis and accessory genes.

Fusarium wilt of banana, caused by Fusarium oxysporum f. sp. cubense (Foc), is one of the most damaging plant diseases known. Foc race 1 (R1) decimated the Gros Michel-based banana (Musa acuminata) trade, and now Foc tropical race 4 (TR4) threatens global production of its replacement, the Cavendish banana. Here population genomics revealed that all Cavendish banana-infecting Foc race 4 strains share an evolutionary origin distinct from that of R1 strains. Although TR4 lacks accessory chromosomes, it contains accessory genes at the ends of some core chromosomes that are enriched for virulence and mitochondria-related functions. Meta-transcriptomics revealed the unique induction of the entire mitochondrion-localized nitric oxide (NO) biosynthesis pathway upon TR4 infection. Empirically, we confirmed the unique induction of a NO burst in TR4, suggesting that nitrosative pressure may contribute to virulence. Targeted mutagenesis demonstrated the functional importance of fungal NO production and the accessory gene SIX4 as virulence factors.

Paradoxical action of PP2A inhibition and its potential for therapeutic sensitization.

The protein phosphatase 2A (PP2A), a serine/threonine phosphatase, is recognized as a tumor suppressor involved in diverse cellular processes and essential for maintaining cell viability in vivo. However, endogenous inhibitors of PP2A such as cancerous inhibitor of PP2A (CIP2A) and endogenous nuclear protein inhibitor 2 of PP2A (SET) counteract the anticancer function of PP2A, promoting tumorigenesis, development, and drug resistance in tumors. Surprisingly though, contrary to conventional understanding, inhibition of the tumor suppressor gene PP2A with exogenous small molecule compounds can enhance the efficacy of cancer treatment and achieve superior tumor inhibition. Moreover, exogenous PP2A inhibitors resensitize cancers to treatment and provide novel therapeutic strategies for drug-resistant tumors, which warrant further investigation.

Stereotactic Radiosurgery for Intermediate (III) or High (IV-V) Spetzler-Martin Grade Arteriovenous Malformations: International Stereotactic Radiosurgery Society Practice Guideline.

BACKGROUND AND OBJECTIVES: Consensus guidelines do not exist to guide the role of stereotactic radiosurgery (SRS) in the management of patients with Spetzler-Martin Grade III-V arteriovenous malformations (AVMs). We sought to establish SRS practice guidelines for Grade III-V AVMs based on a critical systematic review of the published literature. METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant search of Medline, Embase, and Scopus, 1986 to 2023, for publications reporting post-SRS outcomes in ≥10 Grade III-V AVMs with the median follow-up ≥24 months was performed. Primary end points were AVM obliteration and post-SRS hemorrhage. Secondary end points included dosimetric variables, Spetzler-Martin parameters, and neurological outcome. RESULTS: : In total, 2463 abstracts were screened, 196 manuscripts were reviewed, and 9 met the strict inclusion criteria. The overall sample of 1634 AVMs consisted of 1431 Grade III (88%), 186 Grade IV (11%), and 11 Grade V lesions (1%). Total median post-SRS follow-up was 53 months for Grade III and 43 months for Grade IV-V AVMs (ranges, 2-290; 12-262). For Grade III AVMs, the crude obliteration rate was 72%, and among Grade IV-V lesions, the crude obliteration rate was 46%. Post-SRS hemorrhage was observed in 7% of Grade III compared with 17% of Grade IV-V lesions. Major permanent deficits or death from hemorrhage or radiation-induced complications occurred in 86 Grade III (6%) and 22 Grade IV-V AVMs (12%). CONCLUSION: Most patients with Spetzler-Martin Grade III AVMs have favorable SRS treatment outcomes; however, the obliteration rate for Grade IV-V AVMs is less than 50%. The available studies are heterogenous and lack nuanced, long-term, grade-specific outcomes.

Assessing the effectiveness of internet-based interventions for mental health outcomes: an umbrella review.

Internet-based interventions (IBIs) for behavioural health have been prevalent for over two decades, and a growing proportion of individuals with mental health concerns prefer these emerging digital alternatives. However, the effectiveness and acceptability of IBIs for various mental health disorders continue to be subject to scholarly debate. We performed an umbrella review of meta-analyses (MAs), conducting literature searches in PubMed, Web of Science, Embase, Cochrane and Ovid Medline from their inception to 17 January 2023. A total of 87 MAs, reporting on 1683 randomised controlled trials and 295 589 patients, were included. The results indicated that IBIs had a moderate effect on anxiety disorder (standardised mean difference (SMD)=0.53, 95% CI 0.44 to 0.62) and post-traumatic stress disorder (PTSD) (SMD=0.63, 95% CI 0.38 to 0.89). In contrast, the efficacy on depression (SMD=0.45, 95% CI 0.39 to 0.52), addiction (SMD=0.23, 95% CI 0.16 to 0.31), suicidal ideation (SMD=0.23, 95% CI 0.16 to 0.30), stress (SMD=0.41, 95% CI 0.33 to 0.48) and obsessive-compulsive disorder (SMD=0.47, 95% CI 0.22 to 0.73) was relatively small. However, no significant effects were observed for personality disorders (SMD=0.07, 95% CI -0.13 to 0.26). Our findings suggest a significant association between IBIs and improved mental health outcomes, with particular effectiveness noted in treating anxiety disorders and PTSD. However, it is noteworthy that the effectiveness of IBIs was impacted by high dropout rates during treatment. Furthermore, our results indicated that guided IBIs proved to be more effective than unguided ones, playing a positive role in reducing dropout rates and enhancing patient adherence rates. PROSPERO registration number: CRD42023417366.

Mapping the landscape: a bibliometric study of global chimeric antigen receptor T cell immunotherapy research.

The rise of immunotherapy provided new approaches to cancer treatment. We aimed to describe the contribution of chimeric antigen receptor T cell immunotherapy to future prospects. We analyzed 8035 articles from the Web of Science Core Collection with CiteSpace that covered with various aspects with countries, institutions, authors, co-cited authors, journals, keywords, and references. The USA was the most prolific country, with the University of Pennsylvania being the most published institution. Among individual authors, June Carl H published the most articles, while Maude SL was the most frequently co-cited author. "Blood" emerged as the most cited journal. Keyword clustering revealed six core themes: "Expression," "Chimeric Antigen Receptor," "Tumor Microenvironment," "Blinatumomab," "Multiple Myeloma," and "Cytokine Release Syndrome." In the process of researching the timeline chart of keywords and references, "Large B-cell lymphoma" was located on the right side of the timeline. In the keyword prominence analysis, we found that the keywords "biomarkers," "pd-1," "antibody drug conjugate," "BCMA," and "chimeric antigen" had high explosive intensity in the recent past. We found that in terms of related diseases, "large B-cell lymphoma" and "cytokine release syndrome" are still difficult problems in the future. In the study of therapeutic methods, "BCMA," "PD-1," "chimeric antigen," and "antibody drug conjugate" deserve more attention from researchers in the future.

Entry of ZSWIM4 to the nucleus is crucial for its inhibition of KIT and BMAL1 in gastrointestinal stromal tumors.

BACKGROUND: Zinc finger SWIM-type containing 4 (ZSWIM4) is a zinc finger protein with its function largely uncharacterized. In this study, we aimed to investigate the role of ZSWIM4 in gastrointestinal stromal tumors (GISTs). RESULTS: We found that ZSWIM4 expression is inhibited by the predominantly mutated protein KIT in GISTs, while conversely, ZSWIM4 inhibits KIT expression and downstream signaling. Consistent with the observation, ZSWIM4 inhibited GIST cell survival and proliferation in vitro. RNA sequencing of GISTs from KITV558A/WT mice and KITV558A/WT/ZSWIM4-/- mice showed that loss of ZSWIM4 expression increases the expression of circadian clock pathway member BMAL1 which contributes to GIST cell survival and proliferation. In addition, we found that KIT signaling increases the distribution of ZSWIM4 in the nucleus of GIST cells, and which is important for its inhibition of KIT and BMAL1. In agreement with the results in vitro, the in vivo studies showed that ZSWIM4 deficiency increases the tumorigenesis of GISTs in KITV558A/WT mice. CONCLUSIONS: Taken together, our results revealed that the entry of ZSWIM4 to the nucleus is important for its inhibition of KIT and BMAL1, ultimately attenuating GIST tumorigenesis. The results provide a novel insight in the understanding of signal transduction in GISTs and lay strong theoretical basis for the advancement of GIST treatment.

Associations of ω-3, ω-6 polyunsaturated fatty acids intake and ω-6: ω-3 ratio with systemic immune and inflammatory biomarkers: NHANES 1999-2020.

Background: In recent years, diseases caused by abnormal immune-inflammatory responses have become increasingly severe. Dietary intervention involving omega-3 polyunsaturated fatty acids (ω-3 PUFAs) has emerged as a potential treatment. However, research investigating the relationship between ω-3, ω-6 PUFAs, and ω-6 to ω-3 ratio with inflammatory biomarkers remains controversial. Methods: To investigate the correlation between the intake of ω-3 and ω-6 PUFAs and the ratio of ω-6: ω-3 with biomarkers of inflammation, the National Health and Nutrition Examination Survey (NHANES) data (1999 to 2020) was utilized. The systemic immune-inflammation index (SII), platelet-lymphocyte ratio (PLR), neutrophil-lymphocyte ratio (NLR), and white blood cell (WBC) were selected as study subjects. Dietary data for ω-3 and ω-6 PUFAs were collected via two 24-h dietary recall interviews. SII index and other indicators were obtained from the blood routine data. The multiple linear regression and restricted cubic spline models were utilized to evaluate the association of ω-3, ω-6 PUFAs intake, and ω-6: ω-3 ratio to SII and secondary measures. Results: This study involved a total of 43,155 American adults. ω-3 and ω-6 PUFAs exhibited negative correlations with SII, PLR, NLR, and WBC. The correlation between ω-6: ω-3 ratio and SII, PLR, NLR, and WBC was not significant. Furthermore, the dose-response relationship showed that the relationship between the intake of ω-3 and ω-6 PUFAs and SII was an "L" pattern. Conclusion: Intake of dietary ω-3 and ω-6 PUFAs reduces the levels of several inflammatory biomarkers in the body and exerts immunomodulatory effects.

Repeat Single-Session Stereotactic Radiosurgery for Cerebral Arteriovenous Malformations: A Systematic Review, Meta-Analysis, and International Stereotactic Radiosurgery Society Practice Guidelines.

BACKGROUND AND OBJECTIVES: Repeat stereotactic radiosurgery (SRS) for residual arteriovenous malformations (AVMs) can be considered as a salvage approach after failure of initial SRS. There are no published guidelines regarding patient selection, timing, or SRS parameters to guide clinical practice. This systematic review aimed to review outcomes and complications from the published literature to inform practice recommendations provided on behalf of the International Stereotactic Radiosurgery Society. METHODS: We performed a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive search of MEDLINE, Scopus, Web of Science, and Embase was conducted. Fourteen studies with 925 patients met the inclusion criteria. Patients were treated between 1985 and 2022. All studies were retrospective, except for one prospective cohort. RESULTS: The median patient age at repeat SRS ranged from 32 to 60 years. Four studies (630 patients) reported detailed information on Spetzler-Martin grade at the time of repeat SRS; 12.54% of patients had Spetzler-Martin grade I AVMs (79/630 patients), 46.51% had grade II (293/630), 34.92% had grade III (220/630), 5.08% had grade IV (32/630), and 0.95% had grade V (6/630). The median prescription doses varied between 15 and 25 Gy (mean, 13.06-22.8 Gy). The pooled overall obliteration rate at the last follow-up after repeat SRS was 59% (95% CI 51%-67%) with a median follow-up between 21 and 50 months. The pooled hemorrhage incidence at the last follow-up was 5% (95% CI 4%-7%), and the pooled overall radiation-induced change incidence was 12% (95% CI 7%-20%). CONCLUSION: For an incompletely obliterated AVM, repeat radiosurgery after 3 to 5 years of follow-up from the first SRS provides a reasonable benefit to the risk profile. After repeat SRS, obliteration is achieved in the majority of patients. The risk of hemorrhage or radiation-induced change appears low, and International Stereotactic Radiosurgery Society recommendations are presented.

The differential virulence of Fusarium strains causing corneal infections and plant diseases is associated with accessory chromosome composition.

Fusarium oxysporum is a cross-kingdom pathogen. While some strains cause disseminated fusariosis and blinding corneal infections in humans, others are responsible for devastating vascular wilt diseases in plants. To better understand the distinct adaptations of F. oxysporum to animal or plant hosts, we conducted a comparative phenotypic and genetic analysis of two strains: MRL8996 (isolated from a keratitis patient) and Fol4287 (isolated from a wilted tomato [Solanum lycopersicum]). In vivo infection of mouse corneas and tomato plants revealed that, while both strains cause symptoms in both hosts, MRL8996 caused more severe corneal ulceration and perforation in mice, whereas Fol4287 induced more pronounced wilting symptoms in tomato. In vitro assays using abiotic stress treatments revealed that the human pathogen MRL8996 was better adapted to elevated temperatures, whereas the plant pathogen Fol4287 was more tolerant of osmotic and cell wall stresses. Both strains displayed broad resistance to antifungal treatment, with MRL8996 exhibiting the paradoxical effect of increased tolerance to higher concentrations of the antifungal caspofungin. We identified a set of accessory chromosomes (ACs) and protein-encoding genes with distinct transposon profiles and functions, respectively, between MRL8996 and Fol4287. Interestingly, ACs from both genomes also encode proteins with shared functions, such as chromatin remodeling and post-translational protein modifications. Our phenotypic assays and comparative genomics analyses lay the foundation for future studies correlating genotype with phenotype and for developing targeted antifungals for agricultural and clinical uses.

Dosimetric characterization for GRID collimator-based spatially fractionated radiation therapy: Dosimetric parameter acquisition and machine interchangeability investigation.

PURPOSE: The purpose of this study is to characterize the dosimetric properties of a commercial brass GRID collimator for high energy photon beams including 15 and 10 MV. Then, the difference in dosimetric parameters of GRID beams among different energies and linacs was evaluated. METHOD: A water tank scanning system was used to acquire the dosimetric parameters, including the percentage depth dose (PDD), beam profiles, peak to valley dose ratios (PVDRs), and output factors (OFs). The profiles at various depths were measured at 100 cm source to surface distance (SSD), and field sizes of 10 × 10 cm2 and 20 × 20 cm2 on three linacs. The PVDRs and OFs were measured and compared with the treatment planning system (TPS) calculations. RESULTS: Compared with the open beam data, there were noticeable changes in PDDs of GRID fields across all the energies. The GRID fields demonstrated a maximal of 3 mm shift in dmax (Truebeam STX, 15MV, 10 × 10 cm2). The PVDR decreased as beam energy increases. The difference in PVDRs between Trilogy and Truebeam STx using 6MV and 15MV was 1.5% ± 4.0% and 2.1% ± 4.3%, respectively. However, two Truebeam linacs demonstrated less than 2% difference in PVDRs. The OF of the GRID field was dependent on the energy and field size. The measured PDDs, PVDRs, and OFs agreed with the TPS calculations within 3% difference. The TPS calculations agreed with the measurements when using 1 mm calculation resolution. CONCLUSION: The dosimetric characteristics of high-energy GRID fields, especially PVDR, significantly differ from those of low-energy GRID fields. Two Truebeam machines are interchangeable for GRID therapy, while a pronounced difference was observed between Truebeam and Trilogy. A series of empirical equations and reference look-up tables for GRID therapy can be generated to facilitate clinical applications.

Entangled photon pair generation in an integrated SiC platform.

Entanglement plays a vital role in quantum information processing. Owing to its unique material properties, silicon carbide recently emerged as a promising candidate for the scalable implementation of advanced quantum information processing capabilities. To date, however, only entanglement of nuclear spins has been reported in silicon carbide, while an entangled photon source, whether it is based on bulk or chip-scale technologies, has remained elusive. Here, we report the demonstration of an entangled photon source in an integrated silicon carbide platform for the first time. Specifically, strongly correlated photon pairs are efficiently generated at the telecom C-band wavelength through implementing spontaneous four-wave mixing in a compact microring resonator in the 4H-silicon-carbide-on-insulator platform. The maximum coincidence-to-accidental ratio exceeds 600 at a pump power of 0.17 mW, corresponding to a pair generation rate of (9 ± 1) × 103 pairs/s. Energy-time entanglement is created and verified for such signal-idler photon pairs, with the two-photon interference fringes exhibiting a visibility larger than 99%. The heralded single-photon properties are also measured, with the heralded g(2)(0) on the order of 10-3, demonstrating the SiC platform as a prospective fully integrated, complementary metal-oxide-semiconductor compatible single-photon source for quantum applications.

Characteristics and prediction of agricultural ecological efficiency for coordination between economy and environment.

Agricultural ecological efficiency is an important tool with which to measure the coordination of the sustainable development of agricultural economies and ecological environments. In this paper, a super-efficiency slacks-based measures model was used to measure the agricultural ecological efficiency in Hebei Province. The characteristics of spatial and temporal evolution patterns were explored using a spatial Markov transfer matrix. The results showed that (i) based on measurements, the agricultural ecological efficiency in Hebei Province showed regional differences in four regions (eastern, northern, central and southern Hebei) and 141 counties; (ii) from the perspective of evolutionary characteristics of agricultural ecological efficiency, the overall development of in Hebei Province was good, with more concentrated spatial distribution and more obvious direction, while the type of transfer of agricultural ecological efficiency in Hebei Province showed strong stability that was significantly affected by geographical neighborhood conditions and the club convergence phenomenon; (iii) from the perspective of the long-term evolutionary trend of agricultural ecological efficiency, the areas adjacent to counties with low efficiency had limited potential for improvement, and the areas adjacent to counties with high grade had great potential. However, it was difficult to achieve large-scale improvement in agricultural ecological efficiency in Hebei Province, whether the impact of geospatial backgrounds was considered or not.

Advancements and future directions in positron emission tomography-guided radiotherapy: a narrative review.

BACKGROUND AND OBJECTIVE: Positron emission tomography (PET) imaging has been useful in delineating tumor volumes and allowing for improved radiation treatment. The field of PET-guided radiotherapy is rapidly growing and will have significant impact on radiotherapy delivery in the future. This narrative review provides an overview of the current state of PET-guided radiotherapy as well as the future directions of the field. METHODS: For this narrative review, PubMed was searched for articles from 2010-2023. A total of 18 keywords or phrases were searched to provide an overview of PET-guided radiotherapy, radiotracers, the role of PET-guided radiotherapy in oligometastatic disease, and biology-guided radiotherapy (BgRT). The first 300 results for each keyword were searched and relevant articles were extracted. The references of these articles were also reviewed for relevant articles. KEY CONTENT AND FINDINGS: In radiotherapy, 18F-2-fluoro-2-deoxy-D-glucose (F-FDG or FDG) is the major radiotracer for PET and when combined with computed tomography (CT) scan allows for anatomic visualization of metabolically active malignancy. Novel radiotracers are being explored to delineate certain cell types and numerous tumor metrics including metabolism, hypoxia, vascularity, and cellular proliferation. This molecular and functional imaging will provide improved tumor characterization. Through these radiotracers, radiation plans can employ dose painting by creating different dose levels based upon specific risk factors of the target volume. Additionally, biologic imaging during radiotherapy can allow for adaptation of the radiation plan based on response to treatment. Dose painting and adaptive radiotherapy should improve the therapeutic ratio through more selective dose delivery. The novel PET-linear accelerator hopes to combine these techniques and more by using radiotracers to deliver BgRT. The areas of radiotracer uptake will serve as fiducials to guide radiotherapy to themselves. This technique may prove promising in the growing area of oligometastatic radiation treatment. CONCLUSIONS: Significant challenges exist for the future of PET-guided radiotherapy. However, with the advancements being made, PET imaging is set to change the delivery of radiotherapy.

Lycium barbarum polysaccharide reverses drug resistance in oxaliplatin-resistant colon cancer cells by inhibiting PI3K/AKT-dependent phosphomannose isomerase.

Objective: Here, we aimed to explore the effect of LBP in combination with Oxaliplatin (OXA) on reversing drug resistance in colon cancer cells through in vitro and in vivo experiments. We also aimed to explore the possible mechanism underlying this effect. Finally, we aimed to determine potential targets of Lycium barbarum polysaccharide (LBP) in colon cancer (CC) through network pharmacology and molecular docking. Methods: The invasion ability of colon cancer cells was assessed using the invasion assay. The migration ability of these cells was assessed using the migration assay and wound healing assay. Cell cycle analysis was carried out using flow cytometry. The expression levels of phosphomannose isomerase (PMI) and ATP-binding cassette transport protein of G2 (ABCG2) proteins were determined using immunofluorescence and western blotting. The expression levels of phosphatidylinositol3-kinase (PI3K), protein kinase B (AKT), B-cell lymphoma 2 (Bcl-2), and BCL2-Associated X (Bax) were determined using western blotting. Forty BALB/c nude mice purchased from Weitong Lihua, Beijing, for the in vivo analyses. The mice were randomly divided into eight groups. They were administered HCT116 and HCT116-OXR cells to prepare colon cancer xenograft models and then treated with PBS, LBP (50 mg/kg), OXA (10 mg/kg), or LBP + OXA (50 mg/kg + 10 mg/kg). The tumor weight and volume of treated model mice were measured, and organ toxicity was evaluated using hematoxylin and eosin staining. The expression levels of PMI, ABCG2, PI3K, and AKT proteins were then assessed using immunohistochemistry. Moreover, PMI and ABCG2 expression levels were analyzed using immunofluorescence and western blotting. The active components and possible targets of LBP in colon cancer were explored using in silico analysis. GeneCards was used to identify CC targets, and an online Venn analysis tool was used to determine intersection targets between these and LBP active components. The PPI network for intersection target protein interactions and the PPI network for interactions between the intersection target proteins and PMI was built using STRING and Cytoscape. To obtain putative targets of LBP in CC, we performed GO function enrichment and KEGG pathway enrichment analyses. Results: Compared with the HCT116-OXR blank treatment group, both invasion and migration abilities of HCT116-OXR cells were inhibited in the LBP + OXA (2.5 mg/mL LBP, 10 µΜ OXA) group (p < 0.05). Cells in the LBP + OXA (2.5 mg/mL LBP, 10 µΜ OXA) group were found to arrest in the G1 phase of the cell cycle. Knockdown of PMI was found to downregulate PI3K, AKT, and Bcl-2 (p < 0.05), while it was found to upregulate Bax (p < 0.05). After treatment with L. barbarum polysaccharide, 40 colon cancer subcutaneous tumor models showed a decrease in tumor size. There was no difference in the liver index after LBP treatment (p > 0.05). However, the spleen index decreased in the OXA and LBP + OXA groups (p < 0.05), possibly as a side effect of oxaliplatin. Immunohistochemistry, immunofluorescence, and western blotting showed that LBP + OXA treatment decreased PMI and ABCG2 expression levels (p < 0.05). Moreover, immunohistochemistry showed that LBP + OXA treatment decreased the expression levels of PI3K and AKT (p < 0.05). Network pharmacology analysis revealed 45 active LBP components, including carotenoids, phenylpropanoids, quercetin, xanthophylls, and other polyphenols. It also revealed 146 therapeutic targets of LBP, including AKT, SRC, EGFR, HRAS, STAT3, and MAPK3. KEGG pathway enrichment analysis showed that the LBP target proteins were enriched in pathways, including cancer-related signaling pathways, PI3K/AKT signaling pathway, and IL-17 signaling pathways. Finally, molecular docking experiments revealed that the active LBP components bind well with ABCG2 and PMI. conclusion: Our in vitro experiments showed that PMI knockdown downregulated PI3K, AKT, and Bcl-2 and upregulated Bax. This finding confirms that PMI plays a role in drug resistance by regulating the PI3K/AKT pathway and lays a foundation to study the mechanism underlying the reversal of colon cancer cell drug resistance by the combination of LBP and OXA. Our in vivo experiments showed that LBP combined with oxaliplatin could inhibit tumor growth. LBP showed no hepatic or splenic toxicity. LBP combined with oxaliplatin could downregulate the expression levels of PMI, ABCG2, PI3K, and AKT; it may thus have positive significance for the treatment of advanced metastatic colon cancer. Our network pharmacology analysis revealed the core targets of LBP in the treatment of CC as well as the pathways they are enriched in. It further verified the results of our in vitro and in vivo experiments, showing the involvement of multi-component, multi-target, and multi-pathway synergism in the drug-reversing effect of LBP in CC. Overall, the findings of the present study provide new avenues for the future clinical treatment of CC.

Umbilical cord mesenchymal stem cell-derived exosomes inhibits fibrosis in human endometrial stromal cells via miR-140-3p/FOXP1/Smad axis.

Endometrial fibrosis is the histologic appearance of intrauterine adhesion (IUA). Emerging evidences demonstrated umbilical cord mesenchymal stem cell-derived exosomes (UCMSC-exo) could alleviate endometrial fibrosis. But the specific mechanism is not clear. In this study, we explored the effect of UCMSC-exo on endometrial fibrosis, and investigated the possible role of miR-140-3p/FOXP1/Smad axis in anti-fibrotic properties of UCMSC-exo. UCMSC-exo were isolated and identified. Transforming growth factor-ß (TGF-ß) was used to induce human endometrial stromal cell (HESC) fibrosis. Dual luciferase assay was performed to verify the relationship between miR-140-3p and FOXP1. The expressions of fibrotic markers, SIP1, and p-Smad2/p-Smad3 in HESCs stimulated with UCMSC-exo were detected by western blot. In addition, the effects of miR-140-3p mimic, miR-140-3p inhibitor and FOXP1 over-expression on endometrial fibrosis were assessed. The isolated UCMSC-exo had a typical cup-shaped morphology and could be internalized into HESCs. The expressions of fibrotic markers were significantly increased by TGF-ß, which was reversed by UCMSC-exo. MiR-140-3p in UCMSC-exo ameliorated TGf-ß-induced HESCs fibrosis. FOXP1 was identified as the direct target of miR-140-3p, which could inversely regulate miR-140-3p's function on HESCs fibrosis. Furthermore, we demonstrated that miR-140-3p in UCMSC-exo regulated Smad signal pathway to exert the anti-fibrotic effect in HESCs. The anti-fibrotic effect of UCMSC-derived exosomes against HESC fibrosis was at least partially achieved by miR-140-3p/FOXP1/Smad axis.