Pterostilbene alleviates MPTP-induced neurotoxicity by targeting neuroinflammation and oxidative stress.

Pterostilbene (PTE), a naturally occurring phenolic compound primarily found in blueberries, demonstrates neuroprotective properties. However, the role of PTE in Parkinson's disease (PD) remains unclear. This study aimed to investigate the neuroprotective role of PTE in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD animal model. Our findings demonstrate that administering PTE effectively reversed the diminished levels of dopamine in the striatum, thereby ameliorating motor impairments in the MPTP model. Moreover, PTE administration mitigated the loss of dopaminergic (DA) neurons and reduced the upregulation of α-synuclein (α-syn) induced by MPTP. Mechanistic analysis revealed that PTE administration inhibited the activation of microglia and astrocytes, as well as pro-inflammatory factors such as TNF-α and IL-1ß in the MPTP model. Additionally, PTE administration decreased MPTP-induced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), while increasing total antioxidant capacity (TAOC) and superoxide dismutase (SOD) activity, thereby attenuating oxidative stress. Collectively, these findings demonstrate that PTE exerts neuroprotective effects in the MPTP mouse model of PD by suppressing neuroinflammation and oxidative stress. Thus, PTE holds promise as a therapeutic agent for PD.

EZH2 mutation is associated with the development of visceral metastasis by enhancing proliferation and invasion and inhibiting apoptosis in breast cancer cells.

BACKGROUND: The prognosis of breast cancer patients with visceral metastasis (VM) is significantly worse than that of patients without VM. We aimed to evaluate EZH2 (enhancer of zeste homolog 2) mutation as a biomarker associated with VM. METHODS: Data from forty-nine patients with metastatic breast cancer (MBC) pathologically confirmed at our hospital between March 2016 and September 2018 were collected. Metastatic tissue samples were obtained via ultrasound-guided needle biopsy, and paired peripheral blood samples were also collected. Tissue and blood samples were subjected to targeted next-generation sequencing via a 247-gene panel. Stably transfected MDA-MB-231 cells expressing wild-type EZH2 (EZH2WT) or a mutant form of EZH2 (EZH2K515R) were generated. Cell proliferation, colony formation ability, migration and invasion abilities and apoptosis were assessed using CCK-8 assays, plate colony formation assays, Transwell chamber assays and flow cytometry. RESULTS: The incidence of EZH2 mutations in the VM subgroup was greater than that in the non-VM subgroup in the entire cohort (n = 49, 42.3% vs. 13.0%, p = 0.024) and in the triple-negative breast cancer (TNBC) subgroup (n = 20, 50.0% vs. 10.0%, p = 0.05). Patients carrying EZH2 mutations had a significantly greater risk of developing VM than did those in the non-EZH2 mutation group in the entire cohort (HR 2.9) and in the TNBC subgroup (HR 6.45). Multivariate analysis revealed that EZH2 mutation was an independent prognostic factor for VM (HR 2.99, p = 0.009) in the entire cohort and in the TNBC subgroup (HR 10.1, p = 0.006). Data from cBioPortal also showed that patients with EZH2 mutations had a significantly greater risk of developing VM (HR 3.1), and the time to develop VM was significantly earlier in the EZH2 mutation group (31.5 months vs. 109.7 months, p = 0.008). Multivariate analysis revealed that EZH2 mutation (HR 2.73, p = 0.026) was an independent factor for VM after breast cancer surgery. There was no correlation between EZH2 mutations and BRCA1/2 mutations. Most of the patients (81.8%) in our cohort who developed VM carried the "c.1544A > G (p.K515R)" mutation. Compared with EZH2WT MDA-MB-231 cells, EZH2K515R MDA-MB-231 cells had greater colony formation rates (p < 0.01), greater migration and invasion rates (p < 0.001), and lower apoptosis rates (p < 0.01). The proportion of S + G2/M phase cells in the EZH2K515R group was significantly greater than that in the EZH2WT group. CONCLUSIONS: EZH2 mutation is associated with VM development in breast cancer patients. The EZH2K515R mutation leads to VM and a poor prognosis by enhancing proliferation and invasion and inhibiting apoptosis in breast cancer cells.

A real-world study of the effectiveness and safety of apatinib-based regimens in metastatic triple-negative breast cancer.

PURPOSE: This investigation sought to examine the efficacy and safety of low-dose apatinib used alongside chemotherapy in the clinical management of patients with metastatic triple-negative breast cancer (TNBC) within a real-world setting, whilst comparing the outcomes with those treated solely with chemotherapy. METHODS: This case series study analyzed clinical data and treatment outcomes of 163 patients with metastatic TNBC who underwent rescue treatment at the Medical Oncology Department of Clinical Oncology, Fujian Cancer Hospital, School of Fujian Medical University, China, between October 2011 and January 2023. All the patients underwent rescue treatment with either chemotherapy alone or apatinib (250 mg/day) combined with chemotherapy. The study's primary outcome was progression-free survival (PFS), whereas the secondary outcomes included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety profiles. RESULTS: The study was designed to compare two groups [1]. Out of the 163 TNBC patients who participated in the study, 107 individuals (65.6%) received treatment based on chemotherapy, whereas 56 patients (34.4%) were given treatment based on a combination of low-dose apatinib (250 mg/day) and other treatments, including chemotherapy. After propensity score matching (PSM), the objective response rate (ORR) and disease control rate (DCR) of patients with advanced triple-negative breast cancer (TNBC) who received apatinib-based treatment were 50.0 and 90.0%, respectively, while they were 6.7 and 20.0%, respectively, for the chemotherapy-based group (P < 0.001). The group that received apatinib-based treatment showed superior results in both PFS and OS compared to the group that received chemotherapy. The median PFS and OS for the apatinib-based group were 7.8 and 20.3 months, respectively, while they were only 2.2 months and 9.0 months, respectively, for the chemotherapy-based group (P < 0.001) [2]. Patients who were administered combo therapies, including PD-1 inhibitors, were excluded. In total, 97 patients received chemotherapy alone, while 34 patients were treated with apatinib in combination with chemotherapy. After propensity score matching (PSM), the ORR and DCR for the total group who received combo therapies were 44.4 and 81.5%, respectively, while they were 11.1 and 22.2%, respectively, for the chemotherapy alone group (P < 0.001). The group receiving both apatinib and chemotherapy displayed notable advantages over the group solely receiving chemotherapy in regards to PFS and OS for the entirety of the population. The PFS was found to be 7.8 months in comparison to 2.1 months (P < 0.001) and the OS was 21.1 months in contrast to 9.0 months (P < 0.001). Apatinib combined with chemotherapy induced grade 3/4 hematological toxicities, including neutropenia (8.8%) and thrombocytopenia (2.9%). Additionally, non-hematological toxicities were commonly observed, such as Hand-foot syndrome (35.3%), proteinuria (26.5%), hypertension (61.8%), higher alanine aminotransferase levels (26.5%), and fatigue (35.3%). The most frequent non-hematological grade 3/4 toxicities were Hand-foot syndrome (2.9%) and hypertension (5.9%). The study did not report any fatal adverse effects. CONCLUSIONS: The combination of low-dose apatinib with chemotherapy has proven to be more effective than chemotherapy alone in treating metastatic triple-negative breast cancer (TNBC). Additionally, the occurrence of grade 3/4 non-hematologic toxicities was significantly lower compared to the recommended dose of apatinib.

Dietary factors and the risk of atopic dermatitis: a Mendelian randomisation study.

Previous studies have revealed an association between dietary factors and atopic dermatitis (AD). To explore whether there was a causal relationship between diet and AD, we performed Mendelian randomisation (MR) analysis. The dataset of twenty-one dietary factors was obtained from UK Biobank. The dataset for AD was obtained from the publicly available FinnGen consortium. The main research method was the inverse-variance weighting method, which was supplemented by MR‒Egger, weighted median and weighted mode. In addition, sensitivity analysis was performed to ensure the accuracy of the results. The study revealed that beef intake (OR = 0·351; 95 % CI 0·145, 0·847; P = 0·020) and white bread intake (OR = 0·141; 95 % CI 0·030, 0·656; P = 0·012) may be protective factors against AD. There were no causal relationships between AD and any other dietary intake factors. Sensitivity analysis showed that our results were reliable, and no heterogeneity or pleiotropy was found. Therefore, we believe that beef intake may be associated with a reduced risk of AD. Although white bread was significant in the IVW analysis, there was large uncertainty in the results given the wide 95 % CI. Other factors were not associated with AD in this study.

Sofalcone attenuates neurodegeneration in MPTP-induced mouse model of Parkinson's disease by inhibiting oxidative stress and neuroinflammation.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by oxidative stress and neuroinflammation. Sofalcone (SFC), a chalcone derivative known for its antioxidative and anti-inflammatory properties, is widely used clinically as a gastric mucosa protective agent. However, its therapeutic potential in PD remains to be fully explored. In this study, we investigated the neuroprotective effects of SFC in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. METHODS AND RESULTS: We found that SFC ameliorated MPTP-induced motor impairments in mice, as assessed by the rotarod and wire tests. Moreover, SFC administration prevented the loss of dopaminergic neurons and striatal degeneration induced by MPTP. Subsequent investigations revealed that SFC reversed MPTP-induced downregulation of NRF2, reduced elevated levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and increased total antioxidant capacity (TAOC). Furthermore, SFC suppressed MPTP-induced activation of microglia and astrocytes, downregulated the pro-inflammatory cytokine TNF-α, and upregulated the anti-inflammatory cytokine IL-4. Additionally, SFC ameliorated the MPTP-induced downregulation of phosphorylation of Akt at Ser473. CONCLUSIONS: This study provides evidence for the neuroprotective effects of SFC, highlighting its antioxidative and anti-inflammatory properties and its role in Akt activation in the PD model. These findings underscore SFC's potential as a promising therapeutic candidate for PD, warranting further clinical investigation.

Genetic insights into the gut microbiota and risk of facial skin aging: A Mendelian randomization study.

BACKGROUND: A growing number of experimental studies have shown an association between the gut microbiota (GM) and facial skin aging. However, the causal relationship between GM and facial skin aging remains unclear to date. METHODS: We conducted a two-sample Mendelian randomization (MR) analysis to investigate the potential causal relationship between GM and facial skin aging. MR analysis was mainly performed using the inverse-variance weighting (IVW) method, complemented by the weighted median (MW) method, MR-Egger regression, and weighted mode, and sensitivity analysis was used to test the reliability of MR analysis results. RESULTS: Eleven GM taxa associated with facial skin aging were identified by IVW method analysis, Family Victivallaceae (p = 0.010), Genus Eubacterium coprostanoligenes group (p = 0.038), and Genus Parasutterella (p = 0.011) were negatively associated with facial skin aging, while Phylum Verrucomicrobia (p = 0.034), Family Lactobacillaceae (p = 0.017) and its subgroups Genus Lactobacillus (p = 0.038), Genus Parabacteroides (p = 0.040), Genus Eggerthella (p = 0.049), Genus Family XIII UCG001 (p = 0.036), Genus Phascolarctobacterium (p = 0.027), and Genus Ruminococcaceae UCG005 (p = 0.012) were positively associated with facial skin aging. At Class and Order levels, we did not find a causal relationship between GM and facial skin aging. Results of sensitivity analyses did not show evidence of pleiotropy and heterogeneity. CONCLUSION: Our findings confirm the causal relationship between GM and facial skin aging, providing a new perspective on delaying facial aging.

Cost-effectiveness of utidelone and capecitabine versus monotherapy in anthracycline- and taxane-refractory metastatic breast cancer.

Background: This study aimed to assess the cost-effectiveness of combining utidelone with capecitabine, compared to capecitabine monotherapy, for the treatment of anthracycline- and taxane-refractory metastatic breast cancer within the Chinese healthcare system. Methods: A partitioned survival model was formulated based on patient characteristics from the NCT02253459 trial. Efficacy, safety, and health economics data were sourced from the trial and real-world clinical practices. We derived estimates for costs, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) for the two treatment strategies. Sensitivity and subgroup analyses were conducted to rigorously evaluate uncertainties' impact. Results: Over a 5-year span, the combination therapy manifested substantially higher costs than capecitabine monotherapy, with a differential of US$ 26,370.63. This combined approach conferred an additional 0.49 QALYs, resulting in an ICER of US$ 53,874.17/QALY. Utilizing the established willingness-to-pay threshold, the combination might not consistently be deemed cost-effective when juxtaposed against monotherapy. However, at an ICER of US$ 53,874.4/QALY, the probability of the combination being cost-effective increased to 48.97%. Subgroup analysis revealed that the combination was more cost-effective than capecitabine alone in specific patient groups, including those <60 years, patients with more than two chemotherapy rounds, patients lacking certain metastases, patients having limited metastatic sites, patients with an Eastern Cooperative Oncology Group status of 0, and patients with particular hormone receptor profiles. Conclusion: Although the combination of utidelone and capecitabine may not be an economically viable universal choice for anthracycline- and taxane-refractory metastatic breast cancer, it could be more cost-effective in specific patient subgroups than capecitabine monotherapy.

Plasma proteins and inflammatory dermatoses: proteome-wide Mendelian randomization and colocalization analyses.

Current genome-wide association studies (GWAS) of plasma proteomes provide additional possibilities for finding new drug targets for inflammatory dermatoses. We performed proteome-wide Mendelian randomization (MR) and colocalization analyses to identify novel potential drug targets for inflammatory dermatoses. We performed MR and colocalization analysis using genetic variation as instrumental variables to determine the causal relationship between circulating plasma proteins and inflammatory dermatoses. 5 plasma proteins were found to be causally associated with dermatitis eczematosa, SLE, urticaria and psoriasis using cis-pQTLs as instrumental variables, but not found in AD and LP. 19 candidate genes with high colocalization evidence were identified. These potential drug targets still require more research and rigorous validation in future trials.

Osteoclasts Link Dysregulated Peripheral Degradation Processes and Accelerated Progression in Alzheimer's Disease.

Background: The amyloid-ß (Aß) enhances the number and activity of blood monocyte-derived osteoclasts (OCs). Individuals with osteoporosis (OP) face an increased risk of developing dementia or Alzheimer's disease (AD). Despite this association, the contribution of bone-resorbing OCs to the progression of AD pathology remains unclear. Objective: Our objective was to investigate the potential impacts of OCs on the development of AD pathology. Methods: We conducted targeted analysis of publicly available whole blood transcriptomes from patients with AD to characterize the blood molecular signatures and pathways associated with hyperactive OCs. In addition, we used APP23 transgenic (APP23 TG) AD mouse model to assess the effects of OCs pharmacological blockade on AD pathology and behavior. Results: Patients with AD exhibited increased osteoclastogenesis signature in their blood cells, which appears to be positively correlated with dysfunction of peripheral clearance of Aß mediated by immune cells. Long-term anti-resorptive intervention with Alendronate inhibited OC activity in APP23 mice, leading to improvements in peripheral monocyte Aß-degrading enzyme expression, Aß-deposition, and memory decline. Conclusions: Our findings suggest that OCs have a disease-promoting role in the development and progression of AD, possibly linked to their modulation of peripheral immunity. These findings guide future research to further elucidate the connection between OP and AD pathogenesis, highlighting the potential benefits of preventing OP in alleviating cognitive burden.

[Analysis of Influencing Factors of Ozone Pollution Difference Between Chengdu and Chongqing in August 2022].

In August 2022, Chengdu and Chongqing showed significant differences in ozone (O3) pollution. Chengdu had O3 pollution days for 20 days, whereas Chongqing had no O3 pollution days. In this study, we analyzed the influencing factors of this difference from the emission level of precursors and meteorological conditions. The results showed that:① the total mixing ratio of 52 VOCs (volatile organic compounds) (including 26 alkanes, 16 aromatics, and 10 alkenes) in Chengdu (18.8×10-9) was 2.8 times that of Chongqing (6.6×10-9), and the total O3 formation potential (OFP) (51.2×10-9) was 2.0 times that of Chongqing (25.0×10-9). The·OH radical loss rate (L·OH) (3.9 s-1) was 1.7 times that of Chongqing (2.3 s-1). The top three OFP in Chengdu were ethylene, m/p-xylene, and isoprene, and those in Chongqing were isoprene, ethylene, and propylene. The contribution rate of alkenes to O3 in Chongqing was 60.7%, whereas the OFP of alkenes and aromatics in Chengdu were 1.6 times and 2.9 times that in Chongqing. In conclusion, the total mixing ratio of VOCs, atmospheric photochemical activity, and O3 formation potential of Chengdu were higher than those of Chongqing. ② Isoprene was ranked first place in L·OH in both Chengdu and Chongqing, indicating that the contribution of biogenic sources to O3 pollution in August was significant. However, the biogenic source emission activity was in response to temperature. From August 14 to 24, the high temperature in Chongqing (38.3℃) decreased biogenic source emission activity, whereas the temperature in Chengdu (34.9℃) increased the biogenic sources emission activity. ③ The horizontal and vertical atmospheric diffusion conditions of Chongqing were better than those of Chengdu, and Chengdu was affected by regional pollution transmission.

PCSK6 exacerbates Alzheimer's disease pathogenesis by promoting MT5-MMP maturation.

Proprotein convertase subtilisin/kexin type 6 (PCSK6) is a calcium-dependent serine proteinase that regulates the proteolytic activity of various precursor proteins and facilitates protein maturation. Dysregulation of PCSK6 expression or function has been implicated in several pathological processes including nervous system diseases. However, whether and how PCSK6 is involved in the pathogenesis of Alzheimer's disease (AD) remains unclear. In this study, we reported that the expression of PCSK6 was significantly increased in the brain tissues of postmortem AD patients and APP23/PS45 transgenic AD model mice, as well as N2AAPP cells. Genetic knockdown of PCSK6 reduced amyloidogenic processing of APP in N2AAPP cells by suppressing the activation of membrane-type 5-matrix metalloproteinase (MT5-MMP), referred to as η-secretase. We further found that PCSK6 cleaved and activated MT5-MMP by recognizing the RRRNKR sequence in its N-terminal propeptide domain in N2A cells. The mutation or knockout of this cleavage motif prevented PCSK6 from interacting with MT5-MMP and performing cleavage. Importantly, genetic knockdown of PCSK6 with adeno-associated virus (AAV) reduced Aß production and ameliorated hippocampal long-term potentiation (LTP) and long-term spatial learning and memory in APP23/PS45 transgenic mice. Taken together, these results demonstrate that genetic knockdown of PCSK6 effectively alleviate AD-related pathology and cognitive impairments by inactivating MT5-MMP, highlighting its potential as a novel therapeutic target for AD treatment.

Dihydroartemisinin promotes tau O-GlcNAcylation and improves cognitive function in hTau transgenic mice.

Tauopathy is a collective term for several neurodegenerative diseases characterized by the intracellular accumulation of hyperphosphorylated microtubule-associated protein Tau (P-tau). Our recent report has revealed the neuroprotective effect of dihydroartemisinin (DHA) on mice overexpressing human Tau (hTau) in the hippocampus by enhancing O-linked-N-Acetylglucosaminylation (O-GlcNAcylation) modification. However, whether DHA can improve synaptic and cognitive function in hTau transgenic mice by specifically promoting Tau O-GlcNAcylation is still unclear. Here, we introduced hTau transgenic mice, a more optimal tauopathy model, to study the effect of DHA on Tau O-GlcNAcylation. We reported that DHA treatment alleviated the deficits of hippocampal CA1 LTP and spatial learning and memory in the Barnes maze and context fear conditioning tests in hTau transgenic mice. Mechanically, we revealed that DHA exerted a significant protective effect by upregulating Tau O-GlcNAcylation and attenuating Tau hyperphosphorylation. Through molecular docking, we found a stable binding between DHA and O-GlcNAc transferase (OGT). We further reported that DHA treatment had no effect on the expression of OGT, but it promoted OGT nuclear export, thereby enhancing OGT-mediated Tau O-GlcNAcylation. Taken together, these results indicate that DHA exerts neuroprotective effect by promoting cytoplasmic translocation of OGT and rebuilding the balance of Tau O-GlcNAcylation/phosphorylation, enhancing O-GlcNAcylation of Tau, suggesting that DHA may be a potential therapeutic agent against tauopathy.

Feasibility and tolerability of eribulin-based chemotherapy versus other chemotherapy regimens for patients with metastatic triple-negative breast cancer: a single-centre retrospective study.

Background: Patients with Triple-negative breast cancer (TNBC) face a poor prognosis and limited therapeutic options. Current data on eribulin usage to treat TNBC is scarce. Therefore, we sought to compare the feasibility and tolerability of eribulin-based regimens with other chemotherapy regimens in patients with TNBC. Method: This retrospective study was conducted at Fujian Medical University Cancer Hospital and included 159 patients with TNBC enrolled between October 2011 and January 2023. Patients underwent treatment with eribulin-based and other chemotherapy regimens. The study's primary endpoints were progression-free survival (PFS) and overall survival (OS), while its secondary endpoint was objective response rate (ORR), disease control rate (DCR), and safety. Tumour response was assessed using RECIST V.1.1 criteria. Results: Of the 159 participants in the study, 42 individuals (26.4%) received treatment with eribulin, whereas 117 participants (73.6%) were administered alternative chemotherapy regimens, which included nab-paclitaxel-based therapy (n = 45) and platinum-based therapy (n = 51). The follow-up period for all patients ended on 31 December 2022, and the median follow-up time was 18.3 months (range:0.7-27.5). Following propensity score matching (PSM), eribulin-based treatment resulted in longer median progression-free survival compared to platinum-based (hazard ratio (HR) = 0.41, p = 0.006), nab-paclitaxel-based (hazard ratio = 0.36, p = 0.001) and other chemotherapy (HR = 0.39, p < 0.001). Also, eribulin induced a remarkable prolongation of the median overall survival duration in all three comparative groups. The group receiving eribulin treatment showed significantly reduced incidences of any grade of anaemia, peripheral neuropathy, nausea and vomiting, and hair loss compared to other chemotherapy groups. Conclusion: For the salvage treatment of advanced TNBC, treatment with eribulin produced longer median PFS and OS than other chemotherapy regimens, with a well-tolerated safety profile. Therefore, further investigation of eribulin-based treatment in larger randomized trials for patients with advanced TNBC is warranted.

Exosome proteomics study of the effects of traditional cigarettes and electronic cigarettes on human bronchial epithelial cells.

Electronic cigarette (e-Cig) has been promoted as a safer alternative to traditional cigarette (t-Cig) recently. However, there are limited scientific data on the potential health effects of e-Cig use. In this study, we evaluated the cytotoxicities of e-Cig and t-Cig condensate solutions (e-CigCS and t-CigCS) on human bronchial epithelial cells (16HBE cells) in vitro, and employed the exosome proteomic technique to systematically assess the effects of e-CigCS and t-CigCS on 16HBE cells. Cytotoxicity assay showed 16HBE cells were more sensitive to t-CigCS than e-CigCS. Proteomic analysis demonstrated that there are 431 differential expressed exosomal proteins (DEEPs) in test groups compared to the control air group (P-value<0.05) and t-CigCS has a greater influence than e-CigCS on exosomal protein expression. Bioinformatic analysis showed the DEEPs from the t-Cig group were significantly enriched in pathways in cancer while tobacco-flavored e-Cig (e-Cigt) and menthol-flavored e-Cig (e-Cigm) groups were not. Further validations of some DEEPs, such as NF-κB p65, Sulfiredoxin-1(SRXN1) and Thioredoxin-interacting protein (TXNIP), were carried out using immunoblot and Real-time PCR analysis, showing that t-Cig may have a greater influence than e-Cig on tumor development and metastasis. Taken together, the finding reported here strongly support our hypothesis that electronic cigarettes are significantly less toxic compared with traditional cigarette.

Lack of interferon regulatory factor 3 leads to anxiety/depression-like behaviors through disrupting the balance of neuronal excitation and inhibition in mice.

Disrupting the balance of neuronal excitation and inhibition (E/I) is an important pathogenic mechanism of anxiety and depression. Interferon regulatory factor 3 (IRF3) plays a key role in the innate immune response, and activation of IRF3 triggers the expression of type I interferons and downstream interferon-stimulated genes, which are associated with anxiety and depression. However, whether IRF3 participates in the pathogenesis of anxiety/depression by regulating E/I balance remains poorly understood. Here, we reported that global knockout (KO) of IRF3 (IRF3-/-) significantly increased anxiety/depression-like behaviors, but did not affect normal spatial learning and memory. Compared with wild type (WT) control mice, the E/I balance was disrupted, as reflected by enhanced glutamatergic transmission and decreased GABAergic transmission in the neurons of hippocampal CA1 and medial prefrontal cortex (mPFC) in IRF3-KO mice. Importantly, genetic rescue of IRF3 expression by adeno-associated virus (AAV) was sufficient to alleviate anxiety/depression-like behaviors and restore the neuronal E/I balance in IRF3-KO mice. Taken together, our results indicate that IRF3 is critical in maintaining neuronal E/I balance, thereby playing an essential role in ensuring emotional stability.

The Efficacy and Safety of Inetetamab and Pyrotinib in Combination with Vinorelbine for Second-line Therapy and Beyond in HER2-positive Metastatic Breast Cancer: A Single-institution Clinical Experience.

BACKGROUND AND OBJECTIVE: This study aimed to observe the efficacy and safety of inetetamab and pyrotinib in combination with vinorelbine in second-line therapy and beyond in HER2-positive metastatic breast cancer (MBC). METHODS: Patients with HER2-positive MBC admitted to our hospital from January 2016 to December 2021 were selected. For patients who could not receive antibody‒drug conjugates (ADCs) during second-line (2nd-line) or third-line and beyond (≥3rd-line) anti-HER2 therapy, inetetamab + pyrotinib + vinorelbine was used for treatment until unacceptable adverse events occurred or the disease progressed, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 every 2 cycles. The progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), and adverse reactions were recorded. Multivariate Cox regression analysis was performed to explore the prognostic factors influencing the curative effect. RESULTS: Overall, 52 patients were included; 13 patients received 2nd-line treatment, and 39 patients received ≥3rd-line treatment. The median PFS (mPFS) for all patients treated with inetetamab + pyrotinib + vinorelbine was 7 months. The mPFS of the 2nd-line subgroup was significantly better than that of the ≥3rd-line subgroup (17 vs. 5 months, P = 0.001). The mPFS of the subgroups that received trastuzumab (H) or trastuzumab and pertuzumab (HP) only was significantly better than that of the H or HP and tyrosine kinase inhibitor (TKI) subgroups (8 vs. 5 months, P = 0.030). The mPFS of the HER2 resistance subgroup was better than that of the HER2 refractoriness subgroup (14 vs. 7 months, P = 0.025). Cox regression analysis showed that the treatment line (2nd-line more so than ≥3rd-line) was an independent prognostic factor for PFS. In addition, the ORR and CBR of 2nd-line patients were significantly higher than those of ≥3rd-line patients (69.2% vs. 30.8% and 92.3% vs. 64.1%, respectively). The most common hematological toxicities were leukopenia and neutropenia, and the most common nonhematological toxicity was diarrhea. CONCLUSION: Inetetamab and pyrotinib in combination with vinorelbine have good efficacy in ≥2ndline treatment of HER2-positive MBC with controllable toxicity, and the combination is a new treatment option, especially for patients who cannot use ADCs in 2nd-line treatment.

Tumor mutational burden in non-immunotherapy patients with heavily pretreated metastatic breast cancer: long-term outcomes from a single institution.

Patients with heavily pretreated (≥3rd-line treatment) metastatic breast cancer (MBC) had poor outcomes and lack prognostic biomarkers. Tumor mutational burden (TMB) was a prognostic biomarker for immunotherapy, but is not well defined in non-immunotherapy. Forty-nine heavily pretreated MBC not received immunotherapy were enrolled between March 2016 and September 2018. TMB of metastatic tumor tissue was evaluated by targeted next-generation sequencing of a 247-genes panel. CBRs (clinical benefit rates) were 47.7% (9 months), 36.2% (12 months) in high TMB patients, higher than 16.1% (9 months), 8.1% (12 months) in low TMB patients, respectively. After a median follow-up of 38 months, patients with high TMB had a longer mPFS (median progress-free survival) compared to low TMB patients in 3rd-line treatment group (13.5 versus 7 months, HR 0.32, p = 0.019) but not in >3rd-line treatment group. Cox regression showed TMB and line of treatment were the two independent prognostic factors for prolonged mPFS in heavily pretreated MBC, with a HR of 0.34 (p = 0.009) for high TMB and 0.37 (p = 0.013) for 3rd-line treatment. In luminal subtype, mPFS was longer with endocrine therapy (ET) alone than with endocrine therapy + chemotherapy (ET + CT) in high TMB cohort (p = 0.037) but shorter mPFS with ET alone than with ET + CT in low TMB cohort (p = 0.047). High TMB and line of treatment are two independent prognostic factors for prolonged mPFS in heavily pretreated MBC patients. TMB may be a predictive biomarker of efficacy with ET alone or ET + CT in luminal subtype.

[Characteristics and Source Apportionment of Ambient VOCs in Lhasa].

Due to the high altitude of plateau cities and strong ultraviolet radiation, the sources and fates of volatile organic compounds show unique characteristics. In this study, the atmospheric volatile organic compound (VOCs) samples were collected at two urban sites and one background site using tank sampling in Lhasa in 2019, and then the composition, concentration, and sources were characterized. The results showed that the average φ(VOCs) in Lhasa was 49.83×10-9, of which the proportion of alkanes was the highest (61%), followed by OVOCs (12%), halogenated hydrocarbons (9%), olefin (9%), aromatic hydrocarbons (5%), and alkynes (4%). The respective contributions of VOCs sources at urban sites, such as Barkhor Street and Radiation Station in Lhasa, were as follows:combustion (64% and 48%) > traffic emission (17% and 31%) > industrial emission (14% and 14%) > solvents and coatings (3% and 3%) ≈plant+background (2% and 4%). The contribution of combustion was large mostly due to local incense burning (especially at Barkhor Street) and heating emissions. Traffic emissions contributed about one third to the VOCs at Radiation Station, which is related to its proximity to the transportation hub and the storage and logistics center upwind. Industrial emissions have a regional impact on ambient VOCs. Under the synergistic influence of meteorology and emissions, VOCs concentration, composition characteristics, and source contribution showed obvious seasonal variations and site differences in the Lhasa area.

Drug self-delivery nanorods enhance photodynamic therapy of triple-negative breast cancer by inhibiting oxidative phosphorylation.

Photodynamic therapy (PDT) shows very high potential for the clinical treatment of triple-negative breast cancer. However, the efficacy of PDT is significantly weakened by tumor hypoxia, the relatively high intracellular glutathione levels and the active proliferation of cancer cells. To address these issues, we developed a novel drug self-delivery nanorod (defined as AINRs) through the hydrophobic interaction among the mitochondrial complex III inhibitor (atovaquone, ATO), the photosensitizer (indocyanine green, ICG) and the dispersion stabilizer (distearoyl phosphoethanolamine-polyethylene glycol 2000, DSPE-PEG 2000). The AINRs showed a rod-like morphology with a mean diameter of 120.6 ± 5.4 nm, a zeta potential of -26.35 ± 1.63 mV and a significantly high drug loading rate of 93.48%. The results of in vitro cell experiments involving triple-negative breast cancer cell lines (4T1 cells and MDA-MB-231 cells) indicated that the AINRs could effectively block the oxidative phosphorylation of cancer cells through the inhibition of mitochondrial complex III, which results in the reduction of endogenous oxygen consumption and the decrease of the intracellular ATP level. The reduction of ATP content further inhibited the glutathione synthesis and arrested the cell cycle at the S-phase, which results in enhanced in vitro PDT efficacy of ICG. The results of in vivo antitumor activity in 4T1-bearing mice showed that the tumor growth inhibition rate of the AINRs with near-infrared laser irradiation (NIR) was greater than 90%, whereas the tumor growth inhibition rates of the AINRs without NIR, ICG with NIR and doxorubicin (3 mg/kg) were only 31.68%, 61.15% and 24.59%, respectively. In addition, the results of safety studies, including body weights, biochemical indicators and H&E staining images of the main organs demonstrated the security of the AINRs. In summary, this study showed that the oxidative phosphorylation inhibition of triple-negative breast cancer was a safe and effective method to enhance its PDT efficacy.