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Triple-negative breast cancer (TNBC) is a highly aggressive disease and of poor prognosis. It is very important to identify novel biomarkers to predict therapeutic response and outcome of TNBC. We investigated the association between polymorphisms in PARP1 gene and clinicopathological characteristics or survival of 272 patients with stage I-III primary TNBC treated with anthracycline/taxane based adjuvant chemotherapy. We found that after adjusted by age, grade, tumor size, lymph node status and vascular invasion, rs7531668 TA genotype carriers had significantly better DFS rate than TT genotype carriers, the 5 y DFS was 79.3% and 69.2% ( P  = 0.046, HR 0.526 95% CI 0.280–0.990). In lymph node negative subgroup, DFS of rs6664761 CC genotype carriers was much better than TT genotype carriers ( P  = 0.016, HR 0.261 95% CI 0.088–0.778) and DFS of rs7531668 AA genotype carriers was shorter than TT genotype carriers ( P  = 0.015, HR 3.361 95% CI 1.259–8.969). In subgroup of age ≤ 50, rs6664761 TC genotype predicted favorable DFS than TT genotype ( P  = 0.042, HR 0.405 95% CI 0.170–0.967). Polymorphisms in PARP1 gene had no influence on treatment toxicities. After multivariate analysis, tumor size ( P  = 0.037, HR = 2.829, 95% CI: 1.063–7.525) and lymph node status ( P  < 0.001, HR = 9.943, 95% CI: 2.974–33.243) were demonstrated to be independent prognostic factors. Our results suggested that polymorphisms in PARP1 gene might predict the DFS of TNBC patients treated with anthracycline/taxane based adjuvant chemotherapy.

The accurate and nondestructive quantification of subgrade moisture content is a core demand for highway construction quality control and long-term performance maintenance. In order to study the response relationship between subgrade moisture content and ground-penetrating radar (GPR) signal eigenvalues, this study constructs the volumetric moisture content–dielectric constant relationship of Guangxi high-plasticity clay and carries out gprMax forward numerical simulations. Fourteen radar signal eigenvalues are extracted from preprocessed signals via time-domain waveform analysis, Hilbert transform analysis, and power spectral density analysis. Seven key eigenvalues are screened out through Pearson correlation coefficient-based dimensionality reduction. Three machine learning algorithms—artificial neural network (ANN), random forest (RF), and light gradient boosting machine (LightGBM)—are adopted to optimize the subgrade moisture-content inversion model, which is finally validated through indoor model box tests and field subgrade tests. The results show that: (1) The linear fitting formula is the most suitable for describing the volumetric moisture content–dielectric constant relationship of Guangxi clay, with a coefficient of determination (R2) of 0.979 and a mean absolute error (MAE) of 0.31. (2) The feature matrix after dimensionality reduction effectively alleviates the degradation of model generalization ability and interpretability. (3) The LightGBM model achieves the highest prediction accuracy for clay volumetric moisture content, with an R2 of 0.99926 and an MAE of 0.172%. (4) For gravimetric moisture-content inversion, the maximum relative error is 1.6% in the indoor model box test and 1.7% in the field test, both within the 2% tolerance of engineering requirements. This study verifies the feasibility of the proposed subgrade moisture-content identification method based on GPR signal eigenvalues. The proposed method provides an efficient technical path for the large-area and nondestructive detection of subgrade moisture and has promising application prospects in subgrade construction quality acceptance, daily maintenance monitoring and hidden disease early warning.

Ribosomal proteins (RPs) play important roles in modulating the MDM2-p53 pathway. However, less is known about the upstream regulators of the RPs. Here, we identify SPIN1 (Spindlin 1) as a novel binding partner of human RPL5/uL18 that is important for this pathway. SPIN1 ablation activates p53, suppresses cell growth, reduces clonogenic ability, and induces apoptosis of human cancer cells. Mechanistically, SPIN1 sequesters uL18 in the nucleolus, preventing it from interacting with MDM2, and thereby alleviating uL18-mediated inhibition of MDM2 ubiquitin ligase activity toward p53. SPIN1 deficiency increases ribosome-free uL18 and uL5 (human RPL11), which are required for SPIN1 depletion-induced p53 activation. Analysis of cancer genomic databases suggests that SPIN1 is highly expressed in several human cancers, and its overexpression is positively correlated with poor prognosis in cancer patients. Altogether, our findings reveal that the oncogenic property of SPIN1 may be attributed to its negative regulation of uL18, leading to p53 inactivation.

Purpose: The purpose of the present study was first to apply the progressive optimization algorithm based automatic volumetric modulated arc therapy (POA-VMAT) technology to accelerate and improve the radiotherapy of cervicothoracic esophageal cancer (CTEC). We comprehensive analyze the feasibility, normal tissue complication probability (NTCP) and dosimetric results of POA-VMAT, manual based VMAT and step-shoot intensity-modulated radiation therapy (IMRT) plans in the treatment of CTEC. Methods: Sixty patients with CTEC with or without concomitant chemotherapy at our institution between 2017 and 2019 were retrospectively identified. The manual 7field-IMRT (7f-IMRT), Single-arc-VMAT and Double-arc-VMAT (Single-Arc/Double-Arc) plans were generated in all cases. The POA-VMAT was designed using the automatic dual-arc VMAT technology of Pinnacle3 9.10 planning system based on progressive optimization algorithm. Specially, it includes the selection of treatment techniques, the running of automated planning scripts, and the evaluation of the final radiotherapy regimen. Subsequently, quantitative evaluation of plans was performed by means of standard dose–volume histograms, homogeneity index (HI) and conformity index (CI). Results: Target dose conformity of the 7f-IMRT plan was inferior to all plans, whereas the Double-Arc plan was slightly inferior to the POA-VMAT but superior to the Single-Arc and 7f-IMRT plan. The HI for 7f-IMRT, Single-Arc, Double-Arc and POA-VMAT were 0.17 ± 0.08, 0.28 ± 0.06, 0.29 ± 0.06 and 0.28 ± 0.03, respectively. For the NTCP results, there was significant statistical difference among POA-VMAT, IMRT and VMAT plans. The total MU was reduced by 48.3% and 42.1% in Single-Arc and POA-VMAT plans compare to IMRT plans. Conclusions: By comprehensive consideration, POA-VMAT efficiently generate acceptable treatment plans for CTEC without dose escalation to OARs and overall superior to manual planning which is a good option for treating CTEC.

It has been corroborated that long noncoding RNA (lncRNA) played fundamental function in various human malignancies development including lung adenocarcinoma (lung ADC). In our study, LINC00520 roles in lung ADC tumorigenesis were explored. We found that LINC00520 level was elevated in lung ADC tissues and cell lines. Besides, the LINC00520 expression had a negative connection with miR-1252-5p level in lung ADC tissues. Additionally, our results demonstrated the reciprocal repression influence between LINC00520 and miR-1252-5p. Moreover, luciferase reporter assays, RIP (RNA-binding protein immunoprecipitation) and pull down assays revealed that miR-1252-5p regulated LINC00520 in RISC-dependent. Furthermore, knockdown of LINC00520 inhibited lung ADC cells proliferation, migration and invasion, while co-transfection with a miR-1252-5p inhibitor inverted these influences. Additionally, the findings also demonstrated that FOXR2 was a target of miR-1252-5p; thus, LINC00520 could regulate FOXR2 level. Moreover, LINC00520 silencing suppressed the tumor growth of lung ADC in vivo. In summary, our data indicated that LINC00520 may act as a ceRNA to modulated FOXR2 level by sponging miR-1252-5p, which might bring a potential and effective biomarker to lung ADC treatment.

White dwarf–main sequence (WDMS) binaries provide important laboratories for studying binary evolution and the formation of low-mass white dwarfs. In this work, we identify 654 reliable WDMS candidates with FGK-type companions from an initial set of 772 ultraviolet-excess sources, selected using stellar atmospheric parameters from LAMOST spectroscopy and subsequently refined with Gaia DR3 astrometry and photometry together with ultraviolet data from GALEX. Candidates were selected based on ultraviolet excess relative to the Gaia main-sequence (MS) locus and refined using isochrone constraints to exclude systems inconsistent with MS companions. Binary spectral energy distribution fitting yields effective temperatures and radii for both components, as well as distance and extinction estimates. The MS companions are dominated by G-type stars (∼52%), with comparable fractions of F- and K-type companions, and no A-type primaries. Using white-dwarf (WD) evolutionary cooling models, we find that the WD components are predominantly low-mass (MWD ∼ 0.2–0.4 M⊙), including a substantial population of extremely low-mass (<0.3 M⊙) WDs likely produced through binary interaction. The WDs are generally hot (∼1.5 × 104 K), consistent with the ultraviolet selection bias favoring luminous, large-radius WDs. Multiepoch LAMOST radial velocities show larger amplitudes than those of a comparison sample of MS stars, supporting the close-binary nature of these systems. Although subject to strong selection effects, the catalog offers a clean and well-characterized sample of FGK+WD binaries.

F-box and WD repeat domain-containing 5 (FBXW5), with WD40 repeats, can bind to the PPxY sequence of the large tumor suppressor kinases 1/2 (LATS1/2) kinase domain, resulting in ubiquitination. Ubiquitination and the subsequent degradation of LATS1/2 abrogate the Hippo pathway and worsen gastric cancer (GC). However, the effects and molecular mechanisms of FBXW5 in GC remain unexplored. To elucidate the clinical significance of FBXW5, immunohistochemistry was conducted to reveal the positive correlation between FBXW5 expression and lymph node metastasis ( p  < 0.001) and TNM stage (training cohort: p  = 0.018; validation cohort: p  = 0.001). Further, patients with high FBXW5 expression were found to have poor prognosis (training cohort: log-rank p  = 0.020; validation cohort: log-rank p  = 0.025). Cell experiments revealed the promoting effects of FBXW5 on the proliferation, invasion, metastasis, and chemoresistance of GC cells. Blocking LATS1-YAP1 leads to the loss of FBXW5-mediated regulation of the Hippo pathway and partial functions. Further, co-immunoprecipitation and in vivo ubiquitination assays revealed the interaction between FBXW5 and LATS1, which promoted the ubiquitination and degradation of LATS1. Based on mouse xenograft assays, FBXW5 silencing attenuated the growth of subcutaneous tumor xenografts. Altogether, FBXW5 was found to inactivate the Hippo signaling pathway by enhancing LATS1 ubiquitination and degradation, which promoted the invasion, metastasis, and drug resistance of GC cells.

Methamphetamine (Meth), a psychostimulant drug of the amphetamine type, is widely abused and highly neurotoxic. Meth exposure leads to neuronal necroptosis, and the mitochondrial dysfunction may be involved. However, the underlying mechanisms remain poorly understood. Here, we found that Meth significantly elicited the formation of the RIPK1–RIPK3–MLKL necrosome complex. Intriguingly, the activated MLKL (p-MLKL) translocated to the mitochondrial membrane and displayed pore-forming activity, manifesting as the penetration of MLKL in the cell membranes of the mitochondria, which caused decreased mitochondrial membrane potential, ATP generation, and mitochondrial DNA (mtDNA) and increased mitochondrial ROS (mtROS) generation, which finalized neuronal necroptosis. Notably, MLKL activation and translocation seem to depend on the RIPK1–RIPK3 axis since these adverse effects can be substantially ameliorated by disruption of the necrosome complex formation by the necroptotic inhibitor 1 (Nec-1), which also markedly impeded the MLKL mitochondrial membrane translocation. Finally, to delineate the effects of pore formation-associated ROS generation, specific blockage of mtROS retarded the Meth-induced neuronal necroptosis. In conclusion, our study reveals for the first time that MLKL mitochondrial membrane translocation may be involved in Meth-induced neuronal necroptosis. Therefore, impeding MLKL translocation might provide a novel therapeutic strategy for Meth-induced neurotoxicity.

Blocking the interaction between PD-1 and its ligands is a promising treatment strategy for advanced hepatocellular carcinoma. This study aimed to assess the antitumour activity and safety of the anti-PD-1 inhibitor camrelizumab in pretreated patients with advanced hepatocellular carcinoma. This is a multicentre, open-label, parallel-group, randomised, phase 2 trial done at 13 study sites in China. Eligible patients were aged 18 years and older with a histological or cytological diagnosis of advanced hepatocellular carcinoma, had progressed on or were intolerant to previous systemic treatment, and had an Eastern Cooperative Oncology Group performance score of 0–1. Patients were randomly assigned (1:1) to receive camrelizumab 3 mg/kg intravenously every 2 or 3 weeks, via a centralised interactive web-response system using block randomisation (block size of four). The primary endpoints were objective response (per blinded independent central review) and 6-month overall survival, in all randomly assigned patients who had at least one dose of study treatment. Safety was analysed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02989922, and follow-up is ongoing, but enrolment is closed. Between Nov 15, 2016, and Nov 16, 2017, 303 patients were screened for eligibility, of whom 220 eligible patients were randomly assigned and among whom 217 received camrelizumab (109 patients were given treatment every 2 weeks and 108 every 3 weeks). Median follow-up was 12·5 months (IQR 5·7–15·5). Objective response was reported in 32 (14·7%; 95% CI 10·3–20·2) of 217 patients. The overall survival probability at 6 months was 74·4% (95% CI 68·0–79·7)]. Grade 3 or 4 treatment-related adverse events occurred in 47 (22%) of 217 patients; the most common were increased aspartate aminotransferase (ten [5%]) and decreased neutrophil count (seven [3%]). Two deaths were judged by the investigators to be potentially treatment-related (one due to liver dysfunction and one due to multiple organ failure). Camrelizumab showed antitumour activity in pretreated Chinese patients with advanced hepatocellular carcinoma, with manageable toxicities, and might represent a new treatment option for these patients. Jiangsu Hengrui Medicine.