Cancer SLC6A6-mediated taurine uptake transactivates immune checkpoint genes and induces exhaustion in CD8+ T cells.

Taurine is used to bolster immunity, but its effects on antitumor immunity are unclear. Here, we report that cancer-related taurine consumption causes T cell exhaustion and tumor progression. The taurine transporter SLC6A6 is correlated with aggressiveness and poor outcomes in multiple cancers. SLC6A6-mediated taurine uptake promotes the malignant behaviors of tumor cells but also increases the survival and effector function of CD8+ T cells. Tumor cells outcompete CD8+ T cells for taurine by overexpressing SLC6A6, which induces T cell death and malfunction, thereby fueling tumor progression. Mechanistically, taurine deficiency in CD8+ T cells increases ER stress, promoting ATF4 transcription in a PERK-JAK1-STAT3 signaling-dependent manner. Increased ATF4 transactivates multiple immune checkpoint genes and induces T cell exhaustion. In gastric cancer, we identify a chemotherapy-induced SP1-SLC6A6 regulatory axis. Our findings suggest that tumoral-SLC6A6-mediated taurine deficiency promotes immune evasion and that taurine supplementation reinvigorates exhausted CD8+ T cells and increases the efficacy of cancer therapies.

Recurrence and malignant transformation of laryngeal leukoplakia treated with CO2 laser: A systematic review and meta-analysis.

BACKGROUND: Laryngeal leukoplakia (LL) is a white lesion with high potential of recurrence and malignant transformation. Currently, CO2 laser has become the primary surgical treatment for LL, and the recurrence and malignant transformation rates after treatment vary widely. OBJECTIVE: We performed a systematic review and meta-analysis dedicated to evaluating the rates of recurrence and malignant transformation of LL lesions treated with CO2 laser and exploring relevant risk factors for recurrence or malignant transformation. METHODS: Literature searches were conducted on ProQuest, PubMed, Web of Science, Ovid Medline, Embase, and Cochrane databases. Some articles identified through hand searching were included. RESULTS: A total of 14 articles and 1462 patients were included in this review. Pooled results showed that the overall recurrence rate was 15%, and the malignant transformation rate was 3%. Subgroup analysis showed that the dysplasia grade was not a significant risk factor for the recurrence and malignant transformation of LL (P > .05). CONCLUSIONS: The results of this systematic review and meta-analysis suggest that the CO2 laser is a safe and effective surgical instrument for the excision of LL, which yields low rates of recurrence and malignant transformation. The risk factors relevant to recurrence or malignant transformation remain unclear and require further investigation.

Performance of an integrated sediment interceptor in removing phosphorus from agricultural drainage water.

Reducing phosphorus (P) loss from agricultural drainage water is challenging. In this study, we aimed to remove P from agricultural drainage water by developing an integrated sediment interceptor with adsorbent modules filled with Zr/Zn nanocomposite-modified ceramsite (ZMC-interceptor). The results of sequential chemical extraction and 31P NMR showed that the contents of H2O-P (1.15 % of total P), NaHCO3-Pi (10.48 % of total P), and ortho-P (orthophosphate, 90.6 % of total P) in the sediments of the ZMC-interceptors were higher than those in nearby field soils. The average enrichment ratios of particulate P (PP, >450 nm), medium-colloidal P (MCP, 220-450 nm), fine-colloidal P (FCP, 1-220 nm), and truly dissolved P (Truly DP, <1 nm) in the sediment over the field soil were 1.37, 1.21, 1.70, and 3.01, respectively. No significant differences were found in the sediment P-trapping function with and without ZMC integrated sediment interceptors. However, the ZMC-interceptors remarkably reduced total P (39.7 % for influent concentrations of 0.19-0.68 mg L-1) from agricultural drainage water compared to those unmodified ceramsite-interceptors (21.7 % for influent concentrations of 0.17-0.66 mg L-1) during the drainage 'window period' (June-August 2022). This was mainly due to the higher removal efficacies of MCP (19.7 %), FCP (23.3 %), and Truly DP (34.8 %) of the ZMC-interceptors. This study highlighted that the ZMC-interceptor not only trapped P in the sediment but also facilitated the removal of different-sized P fractionated from agricultural drainage water.

The role of HPV11 E7 in modulating STING-dependent interferon ß response in recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a rare benign tumor caused mainly by the infection of the respiratory tract epithelial cells by the human papillomavirus (HPV) type 6/11. However, the specific mechanisms underlying the inhibition of the host's innate immune response by HPV remain unclear. For this purpose, we employed single-cell RNA sequencing to analyze the states of various immune cells in RRP samples post-HPV infection and utilized a cellular model of HPV infection to elucidate the mechanisms by which HPV evades the innate immune system in RRP. The results revealed distinct immune cell heterogeneity in RRP and demonstrated that HPV11 E7 can inhibit the phosphorylation of the stimulator of interferon genes protein, thereby circumventing the body's antiviral response. In vitro co-culture experiments demonstrated that stimulation of macrophages to produce interferon-beta induced the death of HPV-infected epithelial cells, also reducing HPV viral levels. In summary, our study preliminarily identifies the potential mechanisms by which HPV evades the host's antiviral immune response, as well as the latent antiviral functions exhibited by activated macrophages. This research serves as an initial exploration of antiviral immune evasion in RRP, laying a solid foundation for investigating immunotherapeutic approaches for the disease.IMPORTANCESurgical tumor reduction is the most common treatment for recurrent respiratory papillomatosis (RRP). One of the characteristics of RRP is its persistent recurrence, and multiple surgeries are usually required to control the symptoms. Recently, some adjuvant therapies have shown effectiveness, but none of them can completely clear human papillomavirus (HPV) infection, and thus, a localized antiviral immune response is significant for disease control; after all, HPV infection is limited to the epithelium. Inhibition of interferon-beta (IFN-ß) secretion by HPV11 E7 viral proteins in epithelial cells by affecting stimulator of interferon genes phosphorylation may account for the persistence of low-risk HPV replication in the RRP. Moreover, suppression of the IFN-I pathway in RRP cell types might provide clues regarding the hyporeactive function of local immune cells. However, activation of macrophage groups to produce IFN-ß can still destroy HPV-infected cells.

Microbially Induced Soil Colloidal Phosphorus Mobilization Under Anoxic Conditions.

Understanding the behavior of colloidal phosphorus (Pcoll) under anoxic conditions is pivotal for addressing soil phosphorus (P) mobilization and transport and its impact on nutrient cycling. Our study investigated Pcoll dynamics in acidic floodplain soil during a 30-day flooding event. The sudden oxic-to-anoxic shift led to a significant rise in pore-water Pcoll levels, which exceeded soluble P levels by more than 2.7-fold. Colloidal fractions transitioned from dispersed forms (<220 nm) to colloid-associated microaggregates (>220 nm), as confirmed by electron microscopy. The observed increase in colloidal sizes was paralleled by their heightened ability to form aggregates. Compared to sterile control conditions, anoxia prompted the transformation of initially dispersed colloids into larger particles through microbial activity. Curiously, the 16S rRNA and ITS microbial diversity analysis indicated that fungi were more strongly associated with anoxia-induced colloidal release than bacteria. These microbially induced shifts in Pcoll lead to its higher mobility and transport, with direct implications for P release from soil into floodwaters.

N6-methyladenosine reader hnRNPA2B1 recognizes and stabilizes NEAT1 to confer chemoresistance in gastric cancer.

BACKGROUND: Chemoresistance is a major cause of treatment failure in gastric cancer (GC). Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is an N6-methyladenosine (m6A)-binding protein involved in a variety of cancers. However, whether m6A modification and hnRNPA2B1 play a role in GC chemoresistance is largely unknown. In this study, we aimed to investigate the role of hnRNPA2B1 and the downstream mechanism in GC chemoresistance. METHODS: The expression of hnRNPA2B1 among public datasets were analyzed and validated by quantitative PCR (qPCR), Western blotting, immunofluorescence, and immunohistochemical staining. The biological functions of hnRNPA2B1 in GC chemoresistance were investigated both in vitro and in vivo. RNA sequencing, methylated RNA immunoprecipitation, RNA immunoprecipitation, and RNA stability assay were performed to assess the association between hnRNPA2B1 and the binding RNA. The role of hnRNPA2B1 in maintenance of GC stemness was evaluated by bioinformatic analysis, qPCR, Western blotting, immunofluorescence, and sphere formation assays. The expression patterns of hnRNPA2B1 and downstream regulators in GC specimens from patients who received adjuvant chemotherapy were analyzed by RNAscope and multiplex immunohistochemistry. RESULTS: Elevated expression of hnRNPA2B1 was found in GC cells and tissues, especially in multidrug-resistant (MDR) GC cell lines. The expression of hnRNPA2B1 was associated with poor outcomes of GC patients, especially in those who received 5-fluorouracil treatment. Silencing hnRNPA2B1 effectively sensitized GC cells to chemotherapy by inhibiting cell proliferation and inducing apoptosis both in vitro and in vivo. Mechanically, hnRNPA2B1 interacted with and stabilized long noncoding RNA NEAT1 in an m6A-dependent manner. Furthermore, hnRNPA2B1 and NEAT1 worked together to enhance the stemness properties of GC cells via Wnt/ß-catenin signaling pathway. In clinical specimens from GC patients subjected to chemotherapy, the expression levels of hnRNPA2B1, NEAT1, CD133, and CD44 were markedly elevated in non-responders compared with responders. CONCLUSION: Our findings indicated that hnRNPA2B1 interacts with and stabilizes lncRNA NEAT1, which contribute to the maintenance of stemness property via Wnt/ß-catenin pathway and exacerbate chemoresistance in GC.

Mitochondria-targeted photodynamic therapy triggers GSDME-mediated pyroptosis and sensitizes anti-PD-1 therapy in colorectal cancer.

BACKGROUND: The effectiveness of immune checkpoint inhibitors in colorectal cancer (CRC) is limited due to the low tumor neoantigen load and low immune infiltration in most microsatellite-stable (MSS) tumors. This study aimed to develop a mitochondria-targeted photodynamic therapy (PDT) approach to provoke host antitumor immunity of MSS-CRC and elucidate the underlying molecular mechanisms. METHODS: The role and mechanism of mitochondria-targeted PDT in inhibiting CRC progression and inducing pyroptosis were evaluated both in vitro and in vivo. The immune effects of PDT sensitization on PD-1 blockade were also assessed in CT26 and 4T1 tumor-bearing mouse models. RESULTS: Here, we report that PDT using IR700DX-6T, a photosensitizer targeting the mitochondrial translocation protein, may trigger an antitumor immune response initiated by pyroptosis in CRC. Mechanistically, IR700DX-6T-PDT produced reactive oxygen species on light irradiation and promoted downstream p38 phosphorylation and active caspase3 (CASP3)-mediated cleavage of gasdermin E (GSDME), subsequently inducing pyroptosis. Furthermore, IR700DX-6T-PDT enhanced the sensitivity of MSS-CRC cells to PD-1 blockade. Decitabine, a demethylation drug used to treat hematologic neoplasms, disrupted the abnormal methylation pattern of GSDME in tumor cells, enhanced the efficacy of IR700DX-6T-PDT, and elicited a potent antitumor immune response in combination with PD-1 blockade and IR700DX-6T-PDT. CONCLUSION: Our work provides clear a understanding of immunogenic cell death triggered by mitochondria-targeted PDT, offering a new approach for enhancing the efficacy of PD-1 blockade in CRC.

Fully Automated Identification of Lymph Node Metastases and Lymphovascular Invasion in Endometrial Cancer From Multi-Parametric MRI by Deep Learning.

BACKGROUND: Early and accurate identification of lymphatic node metastasis (LNM) and lymphatic vascular space invasion (LVSI) for endometrial cancer (EC) patients is important for treatment design, but difficult on multi-parametric MRI (mpMRI) images. PURPOSE: To develop a deep learning (DL) model to simultaneously identify of LNM and LVSI of EC from mpMRI images. STUDY TYPE: Retrospective. POPULATION: Six hundred twenty-one patients with histologically proven EC from two institutions, including 111 LNM-positive and 168 LVSI-positive, divided into training, internal, and external test cohorts of 398, 169, and 54 patients, respectively. FIELD STRENGTH/SEQUENCE: T2-weighted imaging (T2WI), contrast-enhanced T1WI (CE-T1WI), and diffusion-weighted imaging (DWI) were scanned with turbo spin-echo, gradient-echo, and two-dimensional echo-planar sequences, using either a 1.5 T or 3 T system. ASSESSMENT: EC lesions were manually delineated on T2WI by two radiologists and used to train an nnU-Net model for automatic segmentation. A multi-task DL model was developed to simultaneously identify LNM and LVSI positive status using the segmented EC lesion regions and T2WI, CE-T1WI, and DWI images as inputs. The performance of the model for LNM-positive diagnosis was compared with those of three radiologists in the external test cohort. STATISTICAL TESTS: Dice similarity coefficient (DSC) was used to evaluate segmentation results. Receiver Operating Characteristic (ROC) analysis was used to assess the performance of LNM and LVSI status identification. P value <0.05 was considered significant. RESULTS: EC lesion segmentation model achieved mean DSC values of 0.700 ± 0.25 and 0.693 ± 0.21 in the internal and external test cohorts, respectively. For LNM positive/LVSI positive identification, the proposed model achieved AUC values of 0.895/0.848, 0.806/0.795, and 0.804/0.728 in the training, internal, and external test cohorts, respectively, and better than those of three radiologists (AUC = 0.770/0.648/0.674). DATA CONCLUSION: The proposed model has potential to help clinicians to identify LNM and LVSI status of EC patients and improve treatment planning. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

MRI Plain Scan: A Tool in the Management of Cervical Cancer during Pregnancy.

OBJECTIVE: The purpose of this study was to assess the diagnostic value of magnetic resonance imaging (MRI) in staging and treatment of cervical cancer in pregnancy, and to evaluate the benefit of apparent diffusion coefficient (ADC) during neoadjuvant chemotherapy management. MATERIALS AND METHODS: This was a retrospective cohort study. Patients were divided into two groups according to the stage of cervical cancer. The mean term of pregnancy at the time of the diagnosis was the early second trimester (range 10-27 weeks) and the median age was 33 years (range 26-40 years). The abdominal and pelvic MRI images and clinical data of these patients were reviewed. Tumor size, local tumor spread, and nodal involvement were evaluated using an MRI dataset. The treatment and follow-up imaging were analyzed as well, and the ADC was measured before and after the chemotherapy. RESULTS: 16 patients with histopathologically confirmed cervical cancer during pregnancy were retrospectively enrolled. 7 patients were diagnosed with local cervical cancer (FIGO stage IAI) and designated as early stage group, as the lesion was invisible on MRI. In this group, pregnancies were allowed to continue until cesarean delivery (CD) at 38-41 weeks. The other 9 patients presenting with local or extensive cervical cancer (FIGO stage IB2-IIA2) were designated as the advanced-stage group. The lesion could be measured and analyzed on MRI. They were treated with neoadjuvant chemotherapy in pregnancy. Among them, 6 patients underwent TP regimen (paclitaxel 135~175 mg/m2 plus cisplatin 70~75 mg/m2), while 3 patients received TC regimen (paclitaxel 135~175 mg/m2 plus carboplatin AUC=5). NACT was performed for 1 to 2 courses before surgery. ADC demonstrated significant differences before and after chemotherapy administered during pregnancy (1.06 ± 0.12 sec/mm2 vs. 1.34 ± 0.21 sec/mm2). CONCLUSION: MRI has been found to be helpful in staging cervical cancer in pregnancy. Patients with stage IA confirmed by MRI can choose conservative treatment and continue the pregnancy until term birth. MRI can dynamically monitor the efficacy of chemotherapy for patients with stage IB and above during pregnancy. ADC value can have a potential role in the evaluation of chemotherapy efficacy.

Expert Consensus on the Diagnosis and Treatment of NRG1/2 Gene Fusion Solid Tumors.

The fusion genes NRG1 and NRG2 , members of the epidermal growth factor (EGF) receptor family, have emerged as key drivers in cancer. Upon fusion, NRG1 retains its EGF-like active domain, binds to the ERBB ligand family, and triggers intracellular signaling cascades, promoting uncontrolled cell proliferation. The incidence of NRG1 gene fusion varies across cancer types, with lung cancer being the most prevalent at 0.19 to 0.27%. CD74 and SLC3A2 are the most frequently observed fusion partners. RNA-based next-generation sequencing is the primary method for detecting NRG1 and NRG2 gene fusions, whereas pERBB3 immunohistochemistry can serve as a rapid prescreening tool for identifying NRG1 -positive patients. Currently, there are no approved targeted drugs for NRG1 and NRG2 . Common treatment approaches involve pan-ERBB inhibitors, small molecule inhibitors targeting ERBB2 or ERBB3, and monoclonal antibodies. Given the current landscape of NRG1 and NRG2 in solid tumors, a consensus among diagnostic and treatment experts is proposed, and clinical trials hold promise for benefiting more patients with NRG1 and NRG2 gene fusion solid tumors.

Integrin ß4 Regulates Cell Migration of Lung Adenocarcinoma Through FAK Signaling.

The role of the integrin family in malignancy has received increasing attention. Many studies have confirmed that ITGB4 could activate multiple signal pathways and promote cell migration in various cancers. However, the regulatory role of integrin ß4 (ITGB4) in lung adenocarcinoma (LUAD) is still unclear. Examination of the expression or survival analysis of ITGB4 in cells, pathological samples, and bioinformatics lung adenocarcinoma databases showed ITGB4 was highly expressed in LUAD and significantly associated with poor prognosis. Small interfering RNA and plasmids were performed to investigate the effect of changes in ITGB4 expression on lung adenocarcinoma. Focal adhesion kinase (FAK) inhibitor defactinib was used to further explore the molecular mechanism of ITGB4. The results showed depletion of ITGB4 inhibited migration and activation of FAK signaling pathways in lung adenocarcinoma cells. Moreover, increased ITGB4 expression activated FAK signaling and promoted cell migration, which can be reversed by defactinib. In addition, ITGB4 could interact with FAK in lung adenocarcinoma cells. ITGB4 may promote cell migration of lung adenocarcinoma through FAK signaling pathway and has the potential to be a biomarker for lung adenocarcinoma.

Real-world outcomes of first-line maintenance therapy for recurrent or metastatic cervical cancer: A multi-center retrospective study.

BACKGROUND: Maintenance therapy (MT) for recurrent or metastatic cervical cancer remains non-standardized. This study assessed MT effectiveness using a comprehensive approach and identifies prognosis factors inpatients with recurrent or metastatic cervical cancer. METHODS: From January 2019 and December 2021, over 6000 patients from six Chinese institutions were retrospectively examined. Patients had recurrent/metastatic cervical cancer and underwent first-line chemotherapy with or without MT. We calculated overall and progression-free survival using Kaplan-Meier analysis, comparing via log-rank test, and conducted Cox regression for prognostic factors. RESULTS: Overall, 274 patients were stratified into an MT group (n = 77) and a non-MT group (n = 197). The 3-year OS rates were 52.5 % and 28.0 % for the MT and non-MT groups, respectively. The MT group had significantly enhanced median OS (37 vs. 21 months; HR, 0.43; 95 % CI, 0.30-0.61; P < 0.001) and PFS (21 vs. 14 months; HR, 0.65; 95 % CI, 0.47-0.90; P = 0.014) compared with the non-MT group. No significant differences in efficacy were observed among the various MT regimens, whether PD-1 monoclonal antibody, targeted therapeutic agents, or a combination of both. Extended PFS and OS were observed in patients receiving > 8 MT cycles. Multivariate analyses revealed that oligometastasis, MT, exclusive prior surgery (as opposed to combined surgery and radiotherapy), and extended interval before recurrence were independent OS predictors (P = 0.045, P < 0.001, P = 0.010, and P = 0.005, respectively); oligometastasis, concurrent radiotherapy, MT, and extended interval before recurrence were independent PFS predictors (P = 0.004, P = 0.007, P = 0.009, and P = 0.003). CONCLUSIONS: The MT integration markedly extended PFS and OS in patients diagnosed with recurrent or metastatic cervical cancer.

Novel 4-Aryl-4H-chromene derivative displayed excellent in vivo anti-glioblastoma efficacy as the microtubule-targeting agent.

In this study, a series of novel 4-Aryl-4H-chromene derivatives (D1-D31) were designed and synthesized by integrating quinoline heterocycle to crolibulin template molecule based on the strategy of molecular hybridization. One of these compounds D19 displayed positive antiproliferative activity against U87 cancer cell line (IC50 = 0.90 ± 0.03 µM). Compound D19 was verified as the microtubule-targeting agent through downregulating tubulin related genes of U87 cells, destroying the cytoskeleton of tubulins and interacting with the colchicine-binding site to inhibit the polymerization of tubulins by transcriptome analysis, immune-fluorescence staining, microtubule dynamics and EBI competition assays as well as molecular docking simulations. Moreover, compound D19 induced G2/M phase arrest, resulted in cell apoptosis and inhibited the migration of U87 cells by flow cytometry analysis and wound healing assays. Significantly, compound D19 dose-dependently inhibited the tumor growth of orthotopic glioma xenografts model (GL261-Luc) and effectively prolonged the survival time of mice, which were extremely better than those of positive drug temozolomide (TMZ). Compound D19 exhibited potent in vivo antivascular activity as well as no observable toxicity. Furthermore, the results of in silico simulation studies and P-gp transwell assays verified the positive correlation between compound D19's Blood-Brain Barrier (BBB) permeability and its in vivo anti-GBM activity. Overall, compound D19 can be used as a promising anti-GBM lead compound for the treatment of glioblastoma.

The impact of chemical properties of the solid-liquid-adsorbate interfaces on the entropy-enthalpy compensation involved in adsorption.

Despite extensive studies on the thermodynamic mechanism governing molecular adsorption at the solid-water interface, a comprehensive understanding of the crucial role of interface properties in mediating the entropy-enthalpy compensation during adsorption is lacking, particularly at a quantitative level. Herein, we employed two types of surface models (hydroxyapatite and graphene) along with a series of amino acids to successfully elucidate how distinct interfacial features dictate the delicate balance between entropy and enthalpy variations. The adsorption of all amino acids on the hydroxyapatite surface is an enthalpy-dominated process, where the water-induced enthalpic component of the free energy and the surface-adsorbate electrostatic interaction term alternatively act as the driving force for adsorption in different regions of the surface. Although favorable interactions are observed between amino acids and the graphene surface, the entropy-enthalpy compensation exhibits dependence on the molecular size of the adsorbates. For small amino acids, favorable enthalpy changes predominantly determine their adsorption behavior; however, larger amino acids tend to bind more tightly with the graphene surface, which is thermodynamically dominated by the entropy variations despite the structural characteristics of amino acids. This study reveals specific entropy-enthalpy mechanisms underlying amino acid adsorption at the solid-liquid interface, providing guidance for surface design and synthesis of new biomolecules.

The Microscopic Morphology of Mouthparts and Their Sensilla in the Mycophagous Ladybeetle Illeis chinensis (Coleoptera: Coccinellidae).

The morphological diversity of insect mouthparts is closely related to changes in food sources and diets. Research into the structures of insect mouthparts may help to establish a fundamental basis for a better understanding of insect feeding mechanisms. In this study, we examined the fine morphology of the mouthparts of Illeis chinensis using scanning electron microscopy. We paid particular attention to the types, quantities, and distribution of sensilla on the mouthparts. Our results showed that the basic components of the mouthparts of I. chinensis are the same as those in other lady beetles, i.e., the labrum, mandible, maxillae, labium, and hypopharynx. We also found structural specialization indicating adaptation to fungal feeding. On the mouthparts, there are eight kinds of sensilla and two kinds of glandular structures, including sensilla chaetica, sensilla basiconica, sensilla styloconica, sensilla coeloconica, sensilla campaniformia, sensilla placodea, sensilla digitiformia, Böhm bristles, perforated plates, and cuticular pores. This is the first time that sensilla digitiformia has been reported in ladybirds. Finally, variations in mouthparts among ladybirds with differing diets, as well as the putative functions of each of the mouthparts and sensilla, were discussed. This research can provide a reference for understanding the functions of the mouthparts in ladybird feeding behavior and thereby contribute to the development of precise insect behavior regulation and management strategies.

UV irradiation enhanced removal of colloidal phosphorus in agricultural runoff.

Colloidal phosphorus (P) is an important P form in agricultural runoff and can threaten water quality. However, up to date, there are few effective approaches to mitigate colloidal P pollution. This study investigated the effect of ultraviolet (UV) irradiation on medium-colloidal (MC; 220 nm-450 nm) and fine-colloidal (FC; 3 kDa-220 nm) P in agricultural runoff. Under 24 h of UV irradiation, as the most abundant colloidal P fraction, concentration of total P (TP) in FC consistently decreased by 81.0%, while TP concentration in MC first increased by 74.4% after 3 h and then decreased with irradiation time. At the same time, particulate TP (>450 nm) concentration was found to be increased from 0 to 14.7 µM. However, there were no obvious variations in TP concentrations in FC and MC fractions under dark conditions. In FC fraction, with the decrease of TP, the corresponding concentrations of iron (Fe), aluminum (Al), silicon (Si) declined synchronously, and ferric iron/ferrous iron (Fe(III)/Fe(II)) ratio and organic matter (OM) concentration were reduced as well. These results suggested that P in FC fraction was gradually transformed into particulate P during photoreduction of Fe(III) and photodegradation of OM under UV irradiation. Our study helps to understand the mechanism of the phototransformation of colloidal P, and propose an UV irradiation-based approach to remove colloidal P in agricultural runoff.

A Deep Learning Pipeline Using Prior Knowledge for Automatic Evaluation of Placenta Accreta Spectrum Disorders With MRI.

BACKGROUND: The diagnosis of prenatal placenta accreta spectrum (PAS) with magnetic resonance imaging (MRI) is highly dependent on radiologists' experience. A deep learning (DL) method using the prior knowledge that PAS-related signs are generally found along the utero-placental borderline (UPB) may help radiologists, especially those with less experience, to mitigate this issue. PURPOSE: To develop a DL tool for antenatal diagnosis of PAS using T2-weighted MR images. STUDY TYPE: Retrospective. SUBJECTS: Five hundred and forty pregnant women with clinically suspected PAS disorders from two institutions, divided into training (409), internal test (103), and external test (28) datasets. FIELD STRENGTH/SEQUENCE: Sagittal T2-weighted fast spin echo sequence at 1.5 T and 3 T. ASSESSMENT: An nnU-Net was trained for placenta segmentation. The UPB straightening approach was used to extract the utero-placental boundary region. The UPB image was then fed into DenseNet-PAS for PAS diagnosis. DenseNet-PP learnt placental position information to improve the PAS diagnosis performance. Three radiologists with 8, 10, and 12 years of experience independently evaluated the images. Two radiologists marked the placenta tissue. Histopathological findings were the reference standard. STATISTICAL TESTS: Area under the curve (AUC) was used to evaluate the classification. Dice coefficient evaluated the segmentation between radiologists and the model performance. The Mann-Whitney U-test or the chi-squared test assessed the significance of differences. Decision curve analysis was used to determine clinical effectiveness. DeLong's test was used to compare AUCs. RESULTS: Of the 540 patients, 170 had PAS disorders confirmed by histopathology. The DL model using UPB images and placental position yielded the highest AUC of 0.860 and 0.897 in internal test and external test cohorts, respectively, significantly exceeding the performance of three radiologists (internal test AUC, 0.737-0.770). DATA CONCLUSION: By extracting the UPB image, this fully automatic DL pipeline achieved high accuracy and may assist radiologists in PAS diagnosis using MRI. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

The mechanism of lncRNA SNHG1 in osteogenic differentiation via miR-497-5p/ HIF1AN axis.

The pivotal role of lncRNAs in osteoporosis progression and development necessitates a comprehensive exploration of the functional and precise molecular mechanisms underlying lncRNA SNHG1's regulation of osteoblast differentiation and calcification. The study involved inducing BMSCs cells to differentiate into osteoblasts, followed by transfections of miR-497-5p inhibitors, pcDNA3.1-SNHG1, sh-HIF1AN, miR-497-5p mimics, and respective negative controls into BMSCs. Quantitative PCR (qPCR) was employed to assess the expression of SNHG1 and miR-497-5p. Western Blotting was conducted to measure the levels of short stature-related transcription factor 2 (RUNX2), osteopontin (OPN), osteocalcin (OCN), and HIF1AN. Alkaline phosphatase (ALP) activity was determined using appropriate assay kits. Calcium nodule staining was performed through Alizarin red staining. Dual luciferase reporter gene assays were executed to validate the interaction between SNHG1 and miR-497-5p, as well as HIF1AN. Throughout osteogenic differentiation, there was a down-regulation of SNHG1 and HIF1AN, in contrast to an elevation in miR-497-5p levels. Direct interactions between miR-497-5p and both SNHG1 and HIF1AN were observed. Notably, SNHG1 exhibited the ability to modulate HIF1AN by influencing miR-497-5p, thereby inhibiting osteogenic differentiation. Functioning as a competitive endogenous RNA, lncRNA SNHG1 exerts an inhibitory influence on osteogenic differentiation via the miR-497-5p/HIF1AN axis. This highlights the potential for lncRNA SNHG1 to emerge as a promising therapeutic target for osteoporosis. The study's findings pave the way for a novel target strategy in the future treatment of osteoporosis.

Synergistic antitumor efficacy of gemcitabine and cisplatin to induce ferroptosis in pancreatic ductal adenocarcinoma via Sp1-SAT1-polyamine metabolism pathway.

PURPOSE: The combination of cisplatin and gemcitabine-based chemotherapy has been recommended as a preferred regimen for pancreatic ductal adenocarcinoma (PDAC) patients with germline-based mutations. However, the underlying mechanism remains poorly elucidated. Therefore, our study aimed to explore the mechanistic basis of the cell-killing activity of gemcitabine plus cisplatin and identify potential therapeutic targets. METHODS: First, we explored the synergistic cytotoxic effects of gemcitabine and cisplatin on PDAC through in vitro and in vivo experiments. Then, we investigated ferroptosis-related biomarkers, to assess the impact of the combination therapy on ferroptosis. Using bioinformatics methods, we identified SAT1 as a potential key mediator of ferroptosis induced by gemcitabine and cisplatin. We tested the polyamine levels in PDAC cells by LC-MS after overexpressed or knocked down SAT1, and explored the role of polyamines in ferroptosis using exogenous supplementation. Finally, we explored the regulatory effect of Sp1 on SAT1 through ChIP-qPCR and dual-luciferase reporter assay. RESULTS: Gemcitabine plus cisplatin enhanced cell death and induced ferroptosis in PDAC. This combination upregulated SAT1 transcription by inhibiting Sp1. SAT1 activation promoted the catabolism of spermine and spermidine, leading to iron accumulation and lipid peroxide generation, ultimately resulting in ferroptosis. CONCLUSIONS: In summary, our findings suggested the gemcitabine and cisplatin combination therapy induced ferroptosis in a GSH-independent manner in PDAC. The combined treatment inhibited Sp1 and upregulated SAT1 transcription, leading to the breakdown of spermine and spermidine. Therefore, targeting SAT1-induced polyamine metabolism may represent a promising therapeutic strategy for PDAC.

Reprogramming and multi-lineage transdifferentiation attenuate the tumorigenicity of colorectal cancer cells.

Significant advances have been made in reprogramming various somatic cells into induced pluripotent stem cells (iPSCs) and in multi-lineage differentiation (transdifferentiation) into different tissues. These manipulable transdifferentiating techniques may be applied in cancer therapy. Limited works have been reported that cancer cell malignancy can be switched to benign phenotypes through reprogramming techniques. Here, we reported that two colorectal cancer (CRC) cell lines (DLD1, HT29) could be reprogrammed into iPSCs (D-iPSCs, H-iPSCs). D- and H-iPSCs showed reduced tumorigenesis. Furthermore, we successfully induced D- and H-iPSCs differentiation into terminally differentiated cell types such as cardiomyocyte, neuron, and adipocyte-like cells. Impressively, the differentiated cells exhibited further attenuated tumorigenesis in vitro and in vivo. RNA-Seq further indicated that epigenetic changes occurred after reprogramming and transdifferentiation that caused reduced tumorigenicity. Overall, our study indicated that CRC cells can be reprogrammed and further differentiated into terminally differentiated lineages with attenuation of their malignancy in vitro and in vivo. The current work sheds light on a potential multi-lineage differentiation therapeutic strategy for colorectal cancer.