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Background: Human epidermal growth factor receptor 2 (HER2)-targeted agents have significantly improved the outcomes of patients with HER2-positive breast cancer; however, a large proportion of patients still develop resistance to trastuzumab. In this study, we investigated the efficacy and safety of inetetamab, another anti-HER2 antibody, combined with pyrotinib and oral vinorelbine in patients with HER2-positive advanced breast cancer so as to provide new ideas for the treatment. Methods: In this prospective, single-arm, phase 2 trial, patients with HER2-positive advanced breast cancer with disease progression after trastuzumab were recruited. Patients received a combination of inetetamab (loading dose of 8 mg/kg and subsequent doses of 6 mg/kg intravenously once every 3 weeks), pyrotinib (400 mg orally once daily), and vinorelbine (60 mg/m2 orally once weekly) until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), overall survival (OS), disease control rate (DCR), and safety. Results: Between February 13, 2022 and December 25, 2022, 30 patients were screened and enrolled in this study. The median age of the patients at enrollment was 54 years, 12 patients (40.0 %) had hormone-receptor-positive disease and 23 patients (76.7 %) had visceral metastasis. The median PFS was 8.63 months (95 % confidence interval [CI] 4.15–13.12 months). The median OS was not reached. The ORR was 53.3 % (16/30) and the DCR was 96.7 % (29/30). The most common Grade III/IV adverse events were leukopenia (n = 5, 16.7 %), neutropenia (n = 4, 13.3 %), and diarrhea (n = 3, 10 %). No treatment-related serious adverse events or deaths occurred. Conclusions: The combination regimen of inetetamab, pyrotinib, and oral vinorelbine showed encouraging efficacy and favorable safety in patients with HER2-positive advanced breast cancer and could be considered as an alternative treatment option for the patients. Trial registration: No.NCT05823623; https://www.clinicaltrials.gov/.

The contents of selenomethionine (SeMet) and selenomethylcysteine (SeMC) in Selenium-Enriched black garlic extract (Se-BGE), a popular functional food in Asian countries, were 2.9 ± 0.6 μg/g and 12.2 ± 2.3 μg/g by PITC pre-column derivatization UPLC-MS method. Improved histological injury, significant extension of the median survival time, and attenuated serum levels of alanine aminotransferase, total bilirubin and SOD activity were observed in the acute liver failure (ALF) rats treated with Se-BGE (1.0 g/mL). 1HNMR-based metabonomics revealed that serum levels of lactate, pyruvate, betaine, choline, taurine, and glycine were restored, and 16S rDNA sequencing analysis showed that the composition and number of the intestinal flora were regressed to healthy levels in ALF rats treated by Se-BGE. Serum choline and betaine showed significant correlations with g_Lactobacillus and g_Escherichia. Our findings demonstrated that Se-BGE protects against LPS/D-GalN-induced ALF in rats, possibly due to antioxidation, metabolism, and intestinal flora regulations of Se-BGE.

Epigenetic therapies that cause genome-wide epigenetic alterations, could trigger local interplay between different histone marks, leading to a switch of transcriptional outcome and therapeutic responses of epigenetic treatment. However, in human cancers with diverse oncogenic activation, how oncogenic pathways cooperate with epigenetic modifiers to regulate the histone mark interplay is poorly understood. We herein discover that the hedgehog (Hh) pathway reprograms the histone methylation landscape in breast cancer, especially in triple-negative breast cancer (TNBC). This facilitates the histone acetylation caused by histone deacetylase (HDAC) inhibitors and gives rise to new therapeutic vulnerability of combination therapies. Specifically, overexpression of zinc finger protein of the cerebellum 1 (ZIC1) in breast cancer promotes Hh activation, facilitating the switch of H3K27 methylation (H3K27me) to acetylation (H3K27ac). The mutually exclusive relationship of H3K27me and H3K27ac allows their functional interplay at oncogenic gene locus and switches therapeutic outcomes. Using multiple in vivo breast cancer models including patient-derived TNBC xenograft, we show that Hh signaling-orchestrated H3K27me and H3K27ac interplay tailors combination epigenetic drugs in treating breast cancer. Together, this study reveals the new role of Hh signaling-regulated histone modifications interplay in responding to HDAC inhibitors and suggests new epigenetically-targeted therapeutic solutions for treating TNBC.

We study the CP-odd and CP-even observables of the B mesons decaying into a baryon and antibaryon. We estimate these observables through the P03 model and chiral selection rule. The decay branching ratio of B+→pΛ‾ is calculated to be (2.31±0.69)×10−7, which is consistent with the current experiments. The effects of the B−B‾ oscillations are considered, which largely suppress the direct CP asymmetries in the Bs0 decays. We suggest the experiments to visit Bs0→Λ(→pπ−)Λ‾(→p‾π+), where the time-averaged CP-odd observables are estimated to be large. The direct CP asymmetries of B+→pΛ‾ and B0→pp‾ are found to be (26.2±7.9)% and (−3.1±0.9)% for a positive strong phase and (−36.9±11.1)% and (4.2±1.3)% for a negative strong phase, respectively.

The application of high-strength and high-toughness titanium alloy in armour protection is increasing with its excellent properties. However, there is little research on titanium alloy in explosion protection, especially the dynamic response process under localised explosion load and finite element simulation of the explosion resistance process of titanium alloy sheet. In this paper, the deformation and fracture failure features of the 1.6 mm thick Ti6Al4V titanium alloy sheet during the blast loading process were studied by combining LS-DYNA finite element simulation and air explosion experiments. The error of the overpressure peak value of explosion shock wave between the value obtained by improved theoretical empirical formula calculation of cylindrical charge and the value obtained by numerical simulation is only 0.2%. By studying the influence of explosive shape and air domain mesh size on the overpressure value in the process of detonation wave propagation, the Structured Arbitrary Lagrangian-Eulerian (S-ALE) algorithm was selected for finite element simulation. When the air domain mesh size is 1 mm, the tensile failure criterion was introduced into the finite element simulation process. The results show that the numerical simulation results of the full-scale model and the test results were consistent. The destruction morphology of the target showed severe asymmetry. Under 50 g TNT blast load, the 1.6 mm thick Ti6Al4V titanium alloy target was damaged seriously, and the central area of the target was completely torn. The failure features were mainly petal-shaped warping tearing cracks and localised plastic deformation. The tensile stress is the main stress mode of the target failure. Therefore, dynamic tensile strength should be used as one of the selection criteria for explosion-resistant titanium alloy sheets. The target failure mode is dominated by adiabatic shear fracture.

We study the Ξc−Ξc′ mixing effects in the semileptonic decays the doubly charm baryons of Ξcc. We focus on the ratio of R(θc)≡B(Ξcc→Ξc′e+νe)/B(Ξcc→Ξce+νe) and find that (R(θ0),R(−θ0))=(0.46±0.01,7.33±0.23) with θ0=0.137π, which are in sharp contrast to R(0)=2.15±0.11 without the mixing. The ratio is enhanced (suppressed) by a factor of four for a negative (positive) θc. In addition, the polarization asymmetries of Ξc(′) are found to be α(−θ0)=0.32(−0.76) and α(θ0)=−0.82(−0.38). As R and α are highly sensitive to θc and unaffected by the W-exchange contributions, they provide excellent opportunities to determine θc in the ongoing experiments.

We study the ratio of R=2Γ(Ξc0→Ξ−e+νe)/3Γ(Λc+→Λe+νe), which is found to be R=1(0.8) from the exact (broken) SU(3) flavor symmetry, in sharp contrast to the average value of Rav=0.59±0.10 from the ALICE collaboration and lattice QCD results. We propose to use the mixing of Ξc−Ξc′ to resolve the puzzle. From the mass spectra, we find that the mixing angle is |θc|=0.137(5)π, which suppresses Ξc→Ξe+νe about 20% model-independently, resulting in R≈0.6 with the SU(3) flavor breaking effect. We explicitly demonstrate that R=0.70±0.09 from the bag model, which is also consistent with Rav. To test the mixing mechanism, we recommend the experiments to measure the decays of Ξc→Ξ′(1530)e+νe, whose branching fractions are determined to be (4.4∼8.7)×10−3 and (1.3∼2.6)% for Ξc0 and Ξc+, respectively, but vanish without the mixing. In addition, nonvanishing values of B(Ξc+→Ξ′0(1530)π+) and B(Ξc+→Σ′+(1385)K‾0) will also be evidences of the mixing based on the Körner-Pati-Woo theorem, which are calculated as (3.8∼7.5)×10−3 and (6.6∼13)×10−4, respectively. We emphasize that θc is sizable and should be given serious considerations in future studies on the heavy baryon systems.

Background: Maternal Toxoplasma gondii (T. gondii) infection during pregnancy has been associated with various mental illnesses in the offspring. Ginsenoside Rh2 (GRh2) is a major bioactive compound obtained from ginseng that has an anti-T. gondii effect and attenuates microglial activation through toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway. GRh2 also alleviated tumor-associated or lipopolysaccharide-induced depression. However, the effects and potential mechanisms of GRh2 on depression-like behavior in mouse offspring caused by maternal T. gondii infection during pregnancy have not been investigated. Methods: We examined GRh2 effects on the depression-like behavior in mouse offspring, caused by maternal T. gondii infection during pregnancy, by measuring depression-like behaviors and assaying parameters at the neuronal and molecular level. Results: We showed that GRh2 significantly improved behavioral measures: sucrose consumption, forced swim time and tail suspended immobility time of their offspring. These corresponded with increased tissue concentrations of 5-hydroxytryptamine and dopamine, and attenuated indoleamine 2,3-dioxygenase or enhanced tyrosine hydroxylase expression in the prefrontal cortex. GRh2 ameliorated neuronal damage in the prefrontal cortex. Molecular docking results revealed that GRh2 binds strongly to both TLR4 and high mobility group box 1 (HMGB1). Conclusion: This study demonstrated that GRh2 ameliorated the depression-like behavior in mouse offspring of maternal T. gondii infection during pregnancy by attenuating the excessive activation of microglia and neuroinflammation through the HMGB1/TLR4/NF-κB signaling pathway. It suggests that GRh2 could be considered a potential therapy in preventing and treating psychiatric disorders in the offspring mice of mothers with prenatal exposure to T. gondii infection.

We study CP violation in b-baryon decays of Ξb−→Ξ−D with D=D0,D¯0 and Di(i=1,2). We find that these baryonic decay processes provide an ideal opportunity to measure the weak phase due to the absence of the relative strong phase. Explicitly, we relate ρ¯ and η¯ the CKM elements with the decay rate ratios of Ri=Γ(Ξb−→Ξ−Di)/Γ(Ξb−→Ξ−D0) without the charge conjugate states. As a complementary, we also examine the decay distributions of Λb→Λ(→pπ−)D. There are in total 32 decay observables, which can be parameterized by 9 real parameters, allowing the experiments to extract the angle γ≡arg⁡(−VudVub⁎/VcdVcb⁎) in the CKM unitarity triangle. In addition, the feasibilities of the experimental measurements are discussed. We find that ρ¯ and η¯ can be extracted at LHCb Run3 from Ξb−→Ξ−D, and a full analysis of Λb→Λ(→pπ−)D is available at LHCb Run4.

Little is known about the value of adding concurrent chemotherapy (CC) to radiotherapy for stage II nasopharyngeal carcinoma (NPC) with undetectable (0 copies/mL) pretreatment Epstein-Barr Virus (EBV) DNA in the intensity-modulated radiotherapy (IMRT) era. To address this question, the present study retrospectively reviewed 514 patients with newly diagnosed stage II NPC and undetectable pretreatment EBV DNA from Sun Yat-sen University Cancer Center between March 2008 and October 2016. Clinical characteristics and survival outcomes between concurrent chemoradiotherapy (CCRT) and IMRT alone groups were compared. Propensity score matching analysis was conducted to control for confounding factors. Although CCRT group had significantly higher proportions of stage N1 disease than IMRT alone group before matching (85% vs. 61%, p 0.05). The five-year OS (96.9% vs. 98.2%, p = 0.302), DFS (92.0% vs. 95.2%, p = 0.777), DMFS (95.2% vs. 97.6%, p = 0.896), and LRFS (97.3% vs. 97.6%, p = 0.328) rates remain comparable for both CCRT and RT alone groups. Additionally, subgroup analysis still failed to observe any significant survival benefit for the addition of CC to IMRT for N1 disease (P>0.05 for all). Our results indicated that IMRT alone appeared to achieve comparable survival to CCRT for stage II NPC with undetectable pretreatment EBV DNA.

PURPOSE: To assess the effect of adding neoadjuvant chemotherapy (NACT) to concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and undetectable pretreatment Epstein-Barr virus (pEBV) DNA. MATERIALS AND METHODS: We enrolled 639 NPC patients with stage II to IVB and undetectable pEBV DNA to receive CCRT with or without NACT. Radiotherapy was 2.0 to 2.27 Gy per fraction with five daily fractions per week for 6 to 7 weeks to the primary tumor and 62 to 70 Gy to the involved neck area. NACT was cisplatin (80-100 mg/m2 day 1) and 5-fluorouracil (800-1000 mg/m2, 120-hour continuous intravenous infusion) every 3 weeks for two or three cycles. CCRT was cisplatin (80-100 mg/m2 day 1) every 3 weeks for three cycles. RESULTS: For all patients, the 5-year overall survival (OS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and progression-free survival (PFS) rates were 91.9%, 92.2%, 95.0%, and 86.4%, respectively. There was no significant difference in OS (5-year OS 90.8% [NACT + CCRT group] vs 92.7% [CCRT alone]; hazard ratio [HR] 1.24; P = .486), LRFS (HR 1.13, 95% confidence interval [CI] 0.59-2.14, P = .715), DMFS (HR 0.78, 95% CI 0.34-1.78, P = .554), or PFS (HR 1.21, 95% CI 0.75-1.95, P = .472). CONCLUSION: CCRT with or without NACT produced a good treatment outcome in patients with locoregionally advanced NPC and undetectable pEBV DNA, but NACT before CCRT did not significantly improve survival rates.

Two novel diamond lattice structures (Dfcc and Dhex) and the typical face-centered cubic (FCC) and body-centered cubic (BCC) lattice structures are manufactured by selective laser melting (SLM), and the effects of cell topology and relative density on the dynamic behavior of these structures are studied through a combination of experimental tests and numerical simulation. It is observed that in Dfcc and Dhex, failure initiates at the connection points between rods in the middle of the structure, causing a sudden drop of the measured stress value. However in FCC and BCC, failure initiates in the face-truss junction. Generally, the FCC and BCC are dominated by stretching and bending of the rods respectively, whereas the Dfcc and Dhex are a mixture of the two deformation modes. The results show that the mechanical properties of the lattice structures with different relative density can be described by a power law function. Moreover, for the lattice structures with the same rod diameter of 0.8 mm, FCC out-performs other structures in terms of specific strength, specific modulus and energy absorption. This gives evidence that lattice structures with the stretching-dominated deformation mode are more likely to exhibit better mechanical properties under dynamic loading. Keywords: Lattice structures, Mechanical properties, Failure analysis, Energy absorption