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Abstract Background It is imperative to use a validated tool to measure and understand health behavior as it greatly impacts health status. It has been demonstrated that the Health Behavior Inventory - Short Form (HBI-SF) is valid in several countries. The purpose of this study was to translate the HBI-SF into Chinese and test its psychometric properties. Methods This study employed a two-phase methodology. The phase one entailed the cross-cultural adaptation of the HBI-SF, while the subsequent phase evaluated the psychometric properties of the scale. This evaluation encompassed classical test theory (CTT) and item response theory (IRT) tests to assess reliability and validity. It involved 1058 participants, of whom 1036 completed the questionnaire successfully. Out of these, 518 were analyzed for CTT, along with 518 for IRT. Results The S-CVI was found to be 0.935, while the I‐CVI ranged from 0.889 to 1.000. The results of the confirmatory factor analysis suggested the goodness-of-fit indices for the four-factor model was acceptable. Regarding the subscales, the average variance extracted (AVE) and Heterotrait-Monotrait Ratio of Correlations (HTMT) matrix also met the cutoff values (AVE > 0.5 and HTMI

The use of boundary elements in two-dimensional acoustic analysis is presented in this study, along with a detailed explanation of how to derive the final discrete equations from the fundamental fluctuation equations. In order to overcome the fictitious eigenfrequency problem that might arise during the examination of the external sound field, this work employs the Burton-Miller approach. Additionally, this work uses the Taylor expansion to extract the frequency-dependent component from the BEM function, which speeds up the computation and removes the frequency dependency of the system coefficient matrix. The effect of the radiated acoustic field generated by underwater structures’ on thin-walled structures such as submarines and ships is inspected in this work. Numerical examples verify the accuracy of the proposed method and the efficiency improvement.

Abstract How cells coordinate cell cycling with cell survival and death remains incompletely understood. Here, we show that cell cycle arrest has a potent suppressive effect on ferroptosis, a form of regulated cell death induced by overwhelming lipid peroxidation at cellular membranes. Mechanistically, cell cycle arrest induces diacylglycerol acyltransferase (DGAT)–dependent lipid droplet formation to sequester excessive polyunsaturated fatty acids (PUFAs) that accumulate in arrested cells in triacylglycerols (TAGs), resulting in ferroptosis suppression. Consequently, DGAT inhibition orchestrates a reshuffling of PUFAs from TAGs to phospholipids and re-sensitizes arrested cells to ferroptosis. We show that some slow-cycling antimitotic drug–resistant cancer cells, such as 5-fluorouracil–resistant cells, have accumulation of lipid droplets and that combined treatment with ferroptosis inducers and DGAT inhibitors effectively suppresses the growth of 5-fluorouracil–resistant tumors by inducing ferroptosis. Together, these results reveal a role for cell cycle arrest in driving ferroptosis resistance and suggest a ferroptosis-inducing therapeutic strategy to target slow-cycling therapy-resistant cancers.

Abstract The cystine transporter solute carrier family 7 member 11 (SLC7A11; also called xCT) protects cancer cells from oxidative stress and is overexpressed in many cancers. Here we report a surprising finding that, whereas moderate overexpression of SLC7A11 is beneficial for cancer cells treated with H2O2, a common oxidative stress inducer, its high overexpression dramatically increases H2O2-induced cell death. Mechanistically, high cystine uptake in cancer cells with high overexpression of SLC7A11 in combination with H2O2 treatment results in toxic buildup of intracellular cystine and other disulfide molecules, NADPH depletion, redox system collapse, and rapid cell death (likely disulfidptosis). We further show that high overexpression of SLC7A11 promotes tumor growth but suppresses tumor metastasis, likely because metastasizing cancer cells with high expression of SLC7A11 are particularly susceptible to oxidative stress. Our findings reveal that SLC7A11 expression level dictates cancer cells’ sensitivity to oxidative stress and suggests a context-dependent role for SLC7A11 in tumor biology.

KEAP1 mutations are frequently observed in NSCLC and lead to drug resistance. Here, the authors show that KEAP1 mutations in lung cancer cells leads to FSP1 upregulation through NRF2, resulting in ferroptosis resistance and radioresistance.

Regulated cell death (RCD) contributes to reshaping the tumor immune microenvironment and participating in the progression of non-small cell lung cancer (NSCLC); however, related mechanisms have not been fully disclosed. Here, we identified 5 subclusters of NSCLC based on consensus clustering of 3429 RCD-associated genes in the TCGA database and depicted the genomic features and immune landscape of these clusters. Importantly, the clusters provided insights into recognizing tumor microenvironment (TME) and tumor responses to immunotherapy and chemotherapy. Further, we established and validated an RCD-Risk model based on RCD-associated genes, which strongly predicted the prognosis, TME, and immunotherapy outcomes in NSCLC patients. Notably, tissue microarray staining confirmed that the expression of LDLRAD3, a core gene in RCD-Risk model, correlated with poor survival. In conclusion, we developed a novel RCD classification system and RCD-Risk model of NSCLC, serving as a robust and promising predictor for prognosis and immunotherapy benefit of individual NSCLC patients.

The aging microenvironment serves important roles in cancers. However, most studies focus on circumscribed hot spots such as immunity and metabolism. Thus, it is well ignored that the aging microenvironment contributes to the proliferation of tumor. Herein, we established three prognosis-distinctive aging microenvironment subtypes, including AME1, AME2, and AME3, based on aging-related genes and characterized them with “Immune Exclusion,” “Immune Infiltration,” and “Immune Intermediate” features separately. AME2-subtype tumors were characterized by specific activation of immune cells and were most likely to be sensitive to immunotherapy. AME1-subtype tumors were characterized by inhibition of immune cells with high proportion of Catenin Beta 1 (CTNNB1) mutation, which was more likely to be insensitive to immunotherapy. Furthermore, we found that CTNNB1 may inhibit the expression of C-C Motif Chemokine Ligand 19 (CCL19), thus restraining immune cells and attenuating the sensitivity to immunotherapy. Finally, we also established a robust aging prognostic model to predict the prognosis of patients with hepatocellular carcinoma. Overall, this research promotes a comprehensive understanding about the aging microenvironment and immunity in hepatocellular carcinoma and may provide potential therapeutic targets for immunotherapy.

BackgroundRhino-orbito-cerebral mucormycosis (ROCM) is an acute, fulminant, opportunistic fungal infection that usually occurs in diabetes or immunocompromised patients. Amphotericin B combined with surgical debridement remains the standard treatment, although it is controversial due to its lager nephrotoxicity. Thus far, no studies have reported the treatment for ROCM-associated fungal endophthalmitis because the exact pathogenesis and transmission routes in ROCM remain unclear. Here, we reported a case of ROCM complicated with fungal endophthalmitis treated favorably with amphotericin B colloidal dispersion (ABCD) in combination with other antifungals and surgical debridement.Case PresentationA 34-year-old woman with diabetes was admitted to our hospital owing to right-sided headache for 8 days, blindness with swelling in the right eye for 5 days, and blindness in the left eye for 1 day. MRI showed that the patient had sphenoid sinus, sinuses, frontal lobe lesions, and proptosis of the right eye. Metagenomic sequencing revealed that the patient had Rhizopus oryzae infection. During hospitalization, the patient received intravenous ABCD, oral posaconazole, and topical amphotericin B and underwent surgical debridement. After 67 days of treatment, the patient’s condition was significantly improved, and limb muscle strength showed grade V. Rhizopus oryzae showed negative results, and conjunctival swelling decreased. Additionally, no nephrotoxicity occurred during treatment. After discharge, the patient’s treatment was transitioned to oral posaconazole and she was free of complaints during the 30-day follow-up without any additional treatment for ROCM.ConclusionTreatment with ABCD combined with other antifungal drugs and surgical debridement for ROCM complicated with fungal endophthalmitis showed remarkable efficacy and good safety. Hence, this regimen is a promising treatment strategy for this fatal disease.

Glutathione peroxidase 4 (GPX4) inhibits ferroptosis, but protein synthesis is inefficient and costly. Here, the authors reveal that cystine uptake promotes GPX4 synthesis by activating mTORC1 and show that cancer cells are sensitized to ferroptosis by mTORC1 inhibition.

Pharmacologic inhibition of PARP is the primary therapeutic strategy for BRCA mutant ovarian cancer. However, most of patients carry wild-type BRCA1/2 with no significant clinical benefits from PARP inhibitors, calling for the needs to further understanding and developing new strategy when employing PARP inhibitors to treat ovarian cancer. Here, we show that ferroptosis, a form of regulated cell death driven by iron-dependent phospholipid peroxidation, is partly responsible for the efficacy of PARP inhibitor olaparib. Mechanistically, pharmacological inhibition or genetic deletion of PARP downregulates the expression of cystine transporter SLC7A11 in a p53-dependent manner. Consequently, decreased glutathione biosynthesis caused by SLC7A11 repression promotes lipid peroxidation and ferroptosis. Furthermore, ferroptosis perturbation results in significant resistance to olaparib without affecting DNA damage response, while boosting ferroptosis by ferroptosis inducers (FINs) synergistically sensitizes BRCA-proficient ovarian cancer cells and xenografts to PARP inhibitor. Together, our results reveal a previously unappreciated mechanism coupling ferroptosis to PARP inhibition and suggest the combination of PARP inhibitor and FINs in the treatment of BRCA-proficient ovarian cancer.

Summary: Metabolic reprogramming in cancer cells can create metabolic liabilities. KEAP1-mutant lung cancer is refractory to most current therapies. Here we show that KEAP1 deficiency promotes glucose dependency in lung cancer cells, and KEAP1-mutant/deficient lung cancer cells are more vulnerable to glucose deprivation than their WT counterparts. Mechanistically, KEAP1 inactivation in lung cancer cells induces constitutive activation of NRF2 transcription factor and aberrant expression of NRF2 target cystine transporter SLC7A11; under glucose limitation, high cystine uptake in KEAP1-inactivated lung cancer cells stimulates toxic intracellular disulfide buildup, NADPH depletion, and cell death, which can be rescued by genetic ablation of NRF2-SLC7A11 axis or treatments inhibiting disulfide accumulation. Finally, we show that KEAP1-inactivated lung cancer cells or xenograft tumors are sensitive to glucose transporter inhibitor. Together, our results reveal that KEAP1 deficiency induces glucose dependency in lung cancer cells and uncover a therapeutically relevant metabolic liability.

Ferroptosis is a cell death mechanism triggered by lipid peroxidation. Our recent study linked cyst(e)ine availability with glutathione peroxidase 4 (GPX4) protein synthesis and ferroptosis mitigation via a Rag-mechanistic target of rapamycin complex 1 (mTORC1) axis, and proposed that co-targeting mTORC1 and ferroptosis is a promising strategy for cancer therapy.

Abstract Immune checkpoints blockades have shown promising clinical effects in various malignancies, but the overall response rate is low. Here, the immune features are comprehensively characterized in >10 000 cancer patients from The Cancer Genome Atlas and significantly positive correlations are observed between targets of Sunitinib and inhibitory immune checkpoints and suppressive immune cells. It is further confirmed that Sunitinib treatment increases the antitumor immunity in a phase III trial. Mechanistically, it is discovered that Sunitinib regulates the stability of tumor PD‐L1 via p62, that p62 can bind to PD‐L1 and specifically promote its translocation into autophagic lysosome for degradation. Preclinically, Sunitinib shows a synergistic antitumor effect with cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) monoclonal antibody (mAb) in melanoma and nonsmall cell lung cancer (NSCLC) immune competent mice by promoting the tumor‐infiltrating lymphocytes activity. Clinically, a higher PD‐L1 level but a lower p62 level in the tumor region of responders as compared to those of nonresponders among anti‐PD‐1‐treated NSCLC patients is observed. Taken together, by utilizing rigorous computational analysis, functional characterization in vitro and in vivo, and neoadjuvent clinical trial, a novel molecular mechanism is revealed regarding the regulation of PD‐L1 via p62, thus providing a novel therapeutic strategy by the combination treatment of CTLA‐4 with Sunitinib.