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Neuroblastoma is the most common paediatric solid tumour and prognosis remains poor for high-risk cases despite the use of multimodal treatment. Analysis of public drug sensitivity data showed neuroblastoma lines to be sensitive to indisulam, a molecular glue that selectively targets RNA splicing factor RBM39 for proteosomal degradation via DCAF15-E3-ubiquitin ligase. In neuroblastoma models, indisulam induces rapid loss of RBM39, accumulation of splicing errors and growth inhibition in a DCAF15-dependent manner. Integrative analysis of RNAseq and proteomics data highlight a distinct disruption to cell cycle and metabolism. Metabolic profiling demonstrates metabolome perturbations and mitochondrial dysfunction resulting from indisulam. Complete tumour regression without relapse was observed in both xenograft and the Th- MYCN transgenic model of neuroblastoma after indisulam treatment, with RBM39 loss, RNA splicing and metabolic changes confirmed in vivo. Our data show that dual-targeting of metabolism and RNA splicing with anticancer indisulam is a promising therapeutic approach for high-risk neuroblastoma. The prognosis of high-risk neuroblastoma is poor despite the availability of multimodal treatment. Here the authors show that high-risk neuroblastoma is sensitive to indisulam, a selective degrader of the splicing factor RBM39 through the dual targeting of RNA splicing and metabolism.

Anti-epidermal growth factor receptor (EGFR) therapy–associated cutaneous toxicity is a syndrome characterized by papulopustular rash, local inflammation, folliculitis, and microbial infection, resulting in a decrease in quality of life and dose interruption. However, no effective clinical intervention is available for this adverse effect. Here, we report the atrophy of dermal white adipose tissue (dWAT), a highly plastic adipose tissue with various skin-specific functions, correlates with rash occurrence and exacerbation in a murine model of EGFR inhibitor-induced rash. The reduction in dWAT is due to the inhibition of adipogenic differentiation by defects in peroxisome proliferator-activated receptor γ (PPARγ) signaling, and increased lipolysis by the induced expression of the lipolytic cytokine IL6. The activation of PPARγ by rosiglitazone maintains adipogenic differentiation and represses the transcription of IL6, eventually improving skin functions and ameliorating the severity of rash without altering the antitumor effects. Thus, activation of PPARγ represents a promising approach to ameliorate cutaneous toxicity in patients with cancer who receive anti-EGFR therapy.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Isoxazoline and isoxazole derivatives represent an important class of five-membered heterocycles, which play a pivotal role in drug discovery. In our previous study, we developed a series of isoxazole derivatives with an efficient method. In this study, we evaluated their effects on tumor cell growth. HCT116 cells were treated with isoxazole derivatives; an cholecystokinin octapeptide (CCK-8) assay was used to calculate the IC50 (half maximal inhibitory concentration) of each derivative. Compound SHU00238, which was obtained by the copper nitrate-mediated [2+2+1] cycloaddition reaction of olefinic azlactone with naphthalene-1,4-dione, has a lower IC50; we analyzed its inhibitory activity in further assays. Cell apoptosis was estimated by flow cytometry analysis in vitro. SHU00238 injection was used to treat tumor-bearing mice. We found that SHU00238 suppressed cell viability and promoted cell apoptosis in vitro. SHU00238 treatment significantly inhibited colonic tumor growth in vivo. Furthermore, we compared the miRNAs expression changes in HCT116 cells before and after SHU00238 treatment. MiRNA profiling revealed that SHU00238 treatment affected cell fate by regulating a set of miRNAs. In conclusion, SHU00238 impedes CRC tumor cell proliferation and promotes cell apoptosis by miRNAs regulation.

At present, non-point source pollution (NPSP) has overtaken point source as the most important source of water pollution in China. Ecological treatment projects (ETP) suitable for non-point source pollution have been widely recommended. However, China’s NPSP prevention system has not yet taken shape, the implementation and management levels are disorganized, and the long-term management and protection of NPSP-ETP remains an urgent problem. This paper focuses on the practical problems encountered in the promotion of ETP in China, and ways to solve these problems in the operation and maintenance process. First, problems encountered in the practice of NPSP-ETP in China are summarized as being caused by a lack of systematic regulation on operation and maintenance. Following this, promising countermeasures to solve these problems are proposed, including establishing an ecological treatment technology system, improving the technology selection assessment system, improving the assessment method in project operation, and establishing a systematic operation and maintenance process. Finally, a novel theory of Monitoring-Assessment-Repair (MAR) for ETP is proposed to solve the systematic bottlenecks in engineering operation and maintenance. Furthermore, the problem of clogging in infrastructure is discussed in detail, to illustrate the concrete operation of MAR theory. Overall, this study clarifies the issues in favor of a long-term mechanism of NPSP prevention in and beyond China.

The combination of PARP and NAMPT inhibitors (PARPi/NAMPTi) has been explored for the treatment of triple-negative breast cancer, Ewing sarcoma and high-grade serous carcinoma (HGSC). However, dose limiting toxicity has hampered NAMPTi in clinical trials. To maximise the therapeutic window, we set out to identify predictive genomic biomarkers. Bioinformatic analysis and screening of a panel of epithelial ovarian cancer (EOC) cell lines revealed that cells with RAS/PI3K pathway mutations are sensitive to the NAMPTi FK866. Combined exposure to olaparib and FK866 is associated with a reduction in nicotinamide mononucleotide (NMN) and the PARP substrate nicotinamide adenine dinucleotide (NAD + ), with coincident increases in ROS production, DNA damage and apoptosis induction. Caspase 3/7 activity is upregulated to a greater extent in RAS/PI3K mutant cell lines. Finally, the combination significantly reduces omental tumour weight and increases overall survival in mice injected with ID8 Trp53 -/- ;Pten -/- cells. This study highlights the potential of the PARPi/NAMPTi combination in RAS/PI3K pathway mutant EOC. RAS/PI3K pathway mutations sensitise epithelial ovarian cancer cells to NAMPT inhibition and increase the therapeutic window of a PARP and NAMPT inhibitor combination.

The potential impacts of dam building on resettled communities have been highlighted worldwide. This paper examines the impacts of the newly built Nuozhadu dam on the livelihoods of local communities following the implementation of China's new resettlement policies. Based on household-level data collected from the resettlement communities using semi-structured interviews and in-depth questionnaires, the pre-and post-dam differences in per capita land holdings, annual incomes, expenditures, and social capital of those resettled were analysed at a household level using the sustainable livelihoods framework. The results showed that significantly increased annual incomes and improved infrastructure occurred widely in the resettlement communities, although dam building led to significant losses of farmland and moderate impacts on social capital for the resettlers. Overall, the new resettlement policies have contributed significantly to bettering livelihoods of resettled people affected by dam building. This finding highlights the potential for improving the livelihoods of dam-induced resettlers in the ethnically diverse mountainous regions of southwest China.

Achieving controllable spin polarization and its reversal in symmetry-compensated magnets. Here we demonstrate, using symmetry analysis and a minimal tight-binding model, that uniaxial strain removes these constraints by inducing inequivalence between magnetic sublattices in two-dimensional (2D) system, driving an altermagnetic (AM) state into a fully compensated ferrimagnetic (fFIM) state and enabling fully spin polarization. Furthermore, strain along orthogonal directions gives rise to two energetically degenerate fFIM states with opposite spin polarization, enabling reversible spin switching. More importantly, the two symmetry-related fFIM states can be regarded as distinct ferroelastic variants, suggesting that this model or mechanism can be extended to ferroelastic fFIM systems. The generality of this mechanism is confirmed by combining spin-group analysis, first-principles calculations, and Boltzmann transport theory in representative candidates, including AM Mn\\(_2\\)SeO and ferroelastic fFIM V\\(_2\\)SO. Our results reveal a universal symmetry-driven framework for strain-controlled and -reversible fully spin-polarized transport and identify strain-engineered AM and ferroelastic fFIM systems as a promising platform for volatile and nonvolatile spintronic applications.

Precise control of pre-mRNA splicing is critical for transcriptome integrity, and its disruption is increasingly recognised as a vulnerability in cancer. Here, we identify a functional interplay between two key splicing regulators, RBM39 and serine/arginine protein kinase 1 (SRPK1), and show that dual targeting of these factors severely compromises splicing fidelity in high-risk neuroblastoma. We use the molecular glue indisulam to degrade RBM39 and repurpose the clinical ALK inhibitor alectinib which potently inhibits SRPK1. Co-treatment with indisulam and alectinib inhibited cell proliferation, induced apoptosis, and caused G2/M arrest in multiple cancer cell lines, including MYCN-amplified neuroblastoma. RNA sequencing revealed enhanced splicing defects preferentially in DNA repair and genome maintenance related genes following combination treatment, leading to R-loop accumulation and increased DNA damage. In the Th-MYCN/ALKF1174L neuroblastoma mouse model, combination therapy induced complete tumour regression and significantly improved survival rates compared with monotherapies. These findings demonstrate that combining indisulam and alectinib is a promising approach to treat aggressive malignancies such as high-risk neuroblastoma, exploiting the previously untapped polypharmacology of alectinib as a clinical RNA splicing inhibitor and supporting the therapeutic value of co-targeting interdependent splicing factors for synergistic benefit.

The occurrence of lightning-induced forest fires during a time period is count data featuring over-dispersion （i.e., variance is larger than mean） and a high frequency of zero counts. In this study, we used six generalized linear models to examine the relationship between the occurrence of lightning-induced forest fires and meteorological factors in the Northern Daxing＇an Mountains of China. The six models included Poisson, negative binomial （NB）, zero- inflated Poisson （ZIP）, zero-inflated negative binomial （ZINB）, Poisson hurdle （PH）, and negative binomial hurdle （NBH） models. Goodness-of-fit was compared and tested among the six models using Akaike information criterion （AIC）, sum of squared errors, likelihood ratio test, and Vuong test. The predictive performance of the models was assessed and compared using independent validation data by the data-splitting method. Based on the model AIC, the ZINB model best fitted the fire occurrence data, followed by （in order of smaller AIC） NBH, ZIP, NB, PH, and Poisson models. The ZINB model was also best for pre- dicting either zero counts or positive counts （〉1）. The two Hurdle models （PH and NBH） were better than ZIP, Poisson, and NB models for predicting positive counts, but worse than these three models for predicting zero counts. Thus, the ZINB model was the first choice for modeling the occurrence of lightning-induced forest fires in this study, which implied that the excessive zero counts of lightning- induced fires came from both structure and sampling zeros.

The combination of PARP and NAMPT inhibitors (PARPi/NAMPTi) has been explored for the treatment of TNBC, Ewing Sarcoma and high grade serous carcinoma (HGSC). However, dose limiting toxicity has hampered NAMPTi in clinical trials. To maximise the therapeutic window, we set out to identify predictive genomic biomarkers. Bioinformatic analysis and screening of a panel of epithelial ovarian cancer (EOC) cell lines revealed that cells with RAS/PI3K pathway mutations were sensitive to the NAMPTi FK866. Activity of olaparib and FK866 was associated with a reduction in nicotinamide mononucleotide (NMN) and the PARP substrate nicotinamide adenine dinucleotide (NAD+), with coincident increases in ROS production, DNA damage and apoptosis induction. Caspase 3/7 activity was upregulated to a greater extent in RAS/PI3K mutant cell lines. Finally, the combination significantly reduced omental tumour weight and increased overall survival in mice injected with ID8 Trp53-/-;Pten-/- cells. This study highlights the potential of the PARPi/NAMPTi combination in RAS/PI3K pathway mutant EOC.