Acquired therapeutic resistance is the major drawback to effective systemic therapies for cancers. Aggressive triple-negative breast cancers (TNBC) develop resistance to chemotherapies rapidly, ...whereas the underlying mechanisms are not completely understood. Here we show that genotoxic treatments significantly increased the expression of miR-181a in TNBC cells, which enhanced TNBC cell survival and metastasis upon Doxorubicin treatment. Consistently, high miR-181a level associated with poor disease free survival and overall survival after treatments in breast cancer patients. The upregulation of miR-181a was orchestrated by transcription factor STAT3 whose activation depended on NF-κB-mediated IL-6 induction in TNBC cells upon genotoxic treatment. Intriguingly, activated STAT3 not only directly bound to MIR181A1 promoter to drive transcription but also facilitated the recruitment of MSK1 to the same region where MSK1 promoted a local active chromatin state by phosphorylating histone H3. We further identified BAX as a direct functional target of miR-181a, whose suppression decreased apoptosis and increased invasion of TNBC cells upon Dox treatment. These results were further confirmed by evidence that suppression of miR-181a significantly enhanced therapeutic response and reduced lung metastasis in a TNBC orthotopic model. Collectively, our data suggested that miR-181a induction had a critical role in promoting therapeutic resistance and aggressive behavior of TNBC cells upon genotoxic treatment. Antagonizing miR-181a may serve as a promising strategy to sensitize TNBC cells to chemotherapy and mitigate metastasis.
In addition to the role in regulating leukocyte trafficking, chemokines recently have been shown to be involved in cancer growth and metastasis. Chemokine network in tumor neovascularity may be ...regulated by decoy receptors. Duffy antigen receptor for chemokines (DARC) is a specific decoy receptor binding with the angiogenic CC and CXC chemokines. To investigate the effects of DARC on the tumorigenesis and the metastasis potential of human breast cancer cells, human DARC cDNA was reintroduced into the MDA-MB-231 and MDA-MB-435HM cells which have a high capability of spontaneous pulmonary metastasis. We demonstrated that DARC overexpression induced inhibition of tumorigenesis and/or metastasis through interfering with the tumor angiogenesis in vivo. This inhibition is associated with decreasing CCL2 protein levels, and MVD and MMP-9 expression in xenograft tumors. In human breast cancer samples, we also demonstrated that low expression of the DARC protein is significantly associated with estrogen receptor (ER) status, MVD, lymph node metastasis, distant metastasis and poor survival. Our results suggest for the first time that DARC is a negative regulator of growth in breast cancer, mainly by sequestration of angiogenic chemokines and subsequent inhibition of tumor neovascularity.
Summary Objective The purposes of this study were to assess whether local anesthetics (LAs), such as ropivacaine and bupivacaine, could induce apoptosis of rabbit annulus fibrosus (AF) cells in vitro ...and further to explore the possible underlying mechanism. Methods Rabbit AF cells at second passage were treated with saline solution and various concentrations of LAs. Apoptosis of AF cells were examined by cell counting kit-8 (CCK-8), Annexin V assays, Hoechst 33342 staining, and Caspase-3, -9 activity assays. The expression of apoptosis-related markers was detected by real-time PCR (RT-PCR) and Western Blot. The JC-1 staining was used to evaluate the change of mitochondrial membrane potential (MMP). Moreover, the levels of reactive oxygen species (ROS) were determined with fluorescent probe DCFH-DA. Results The results of flow cytometry indicated that LAs could induce apoptosis of rabbit AF cells in a dose-dependent manner. Apoptosis was confirmed by cell morphology, condensed nuclei and activation of Caspase-3 and -9. In addition, the molecular data showed that LAs could significantly up-regulate the expression of Bax, accompanied by a significant down-regulation of Bcl-2 expression. Furthermore, we also observed that LAs resulted in alteration of MMP and accumulation of intracellular ROS in AF cells. Blockade of ROS production by N-acetyl- l -cysteine (NAC) inhibited LAs-induced apoptosis. Conclusions These findings suggest that LAs in clinically relevant concentrations could induce apoptosis of rabbit AF cells in vitro , and the mitochondrial pathway was, at least in part, involved in the LAs-mediated apoptosis. Further investigations focusing on the potential cytotoxicity of LAs on IVD cells are needed.
Nowadays, it is still questionable whether denatured collagen (DCol) can replace the native collagen (Col) as a bioactive protein in cartilage engineering. We sought to study the advantages of Col ...with a triple-helical structure in the collagen-based composite materials for cartilage engineering.
We presented new three-dimensional (3D) Col and DCol scaffolds with shape memory properties. The effects of Col and DCol scaffolds on rabbit chondrocytes' proliferation, adhesion, differentiation and interaction with matrix were investigated. Tissue compatibility was performed in a subcutaneous Sprague Dawley (SD) rat model. The repair ability of different scaffolds with chondrocytes for full-thickness articular cartilage defects in knee joints of New Zealand white rabbits were investigated.
The results indicated that the Col scaffolds (with concentration 1.6wt% and 0.8wt%, respectively) promoted the proliferation, adhesion and redifferentiation of chondrocytes, as well as chondrocyte–matrix interaction, to a greater degree than the DCol scaffolds. In the animal experiment, the Col scaffolds filled in the defect hole significantly maintained chondrocytes function, promoted cartilage and subchondral bone regeneration, compared with the DCol scaffolds, and the scaffolds loaded with chondrocytes were better than the cell-free scaffolds, especially in the case of the Col scaffolds (1.6 wt%).
Taken together, these insights suggest that the better proliferation, adhesion and redifferentiation of chondrocytes in Col scaffolds with the triple-helical structure may contribute to the greater cartilage repair ability. Col scaffolds may be more appropriate for repairing cartilage defects than DCol scaffolds, and DCol cannot as an alternative when using collagen-based materials for cartilage engineering applications.
To identify more therapeutic targets and clarify the detailed mechanisms of Pseudomonas aeruginosa-mannose-sensitive hemagglutinin (PA-MSHA) on breast cancer cells both in vitro and in vivo. PA-MSHA ...was administered to epidermal growth factor receptor (EGFR)-positive human breast cancer cell lines MDA-MB-231HM and MDA-MB-468 in vitro and to mice bearing tumor xenografts. The mannose cocultured test was used to detect the effect of mannose on PA-MSHA-induced cell proliferation, cell cycle arrest, apoptosis, and EGFR pathway signaling. We found that cells stimulated with PA-MSHA exhibited a downregulation of EGFR signaling. The addition of mannose partially inhibited the PA-MSHA-stimulated cell anti-proliferative effect, cell apoptosis, cell cycle arrest, activation of apoptosis-associated caspases, and even downregulation of the EGFR signaling pathway. In vivo, PA-MSHA treatment significantly suppressed mammary tumorigenesis in xenografts in mice and decreased lung metastasis in MDA-MB-231HM cell-transplanted mice. Tumor sample analyses confirmed inhibition of the EGFR pathway in the PA-MSHA-treated mice. In conclusion, this study showed that the involvement of the mannose-mediated EGFR pathway has a critical function in the preclinical rationale for the development of PA-MSHA for the treatment of human breast cancer. It also suggests the potentially beneficial use of PA-MSHA in adjuvant therapy for breast tumors with EGFR overexpression.
Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected ...patients.
We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death.
The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission.
During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.).
Abstract Aims The purpose of this study was to evaluate the treatment outcomes and prognostic factors in patients with occult breast cancer (OBC). Methods We retrospectively analyzed 95 patients with ...OBC who were treated at our facility between January 1998 and June 2010. Of the 95 patients, 64 underwent mastectomy plus axillary lymph node dissection (ALND) with or without post-mastectomy radiation (Mast + ALND group), 13 underwent ALND followed by ipsilateral breast radiotherapy (BR + ALND group) and the remaining 18 were treated with ALND (ALND group). Results Patients who underwent Mast + ALND or BR + ALND had significantly improved rates of locoregional recurrence-free survival (LRFS) and recurrence/metastasis-free survival (RFS) than patients who only underwent ALND ( p < 0.05). There were no significant differences in the LRFS ( p = 0.718), RFS ( p = 0.935) and breast cancer-specific survival (BCSS) ( p = 0.991) rates between the patients who underwent Mast + ALND compared with those who received BR + ALND. Multivariate analysis revealed that patients with four or more involved lymph nodes had significantly worse outcomes ( p = 0.042, HR = 4.63, 95% CI = 1.66–32.47 for BCSS and p = 0.038, HR = 3.62, 95% CI = 1.08–20.77 for RFS). Conclusions Patients with OBC who received ALND and subsequent breast radiotherapy had similar outcomes to patients who underwent mastectomy. The presence of four or more involved lymph nodes may independently predict poor outcomes of OBC.
Bovine respiratory disease complex (BRDC) involves multiple pathogens, shows diverse lung lesions, and is a major concern in calves. Pathogens from 160 lung samples of dead cattle from 81 cattle ...farms in Northeast China from 2016 to 2021 were collected to characterize the molecular epidemiology and risk factors of BRDC and to assess the major pathogens involved in bovine suppurative or caseous necrotizing pneumonia. The BRDC was diagnosed by autopsy, pathogen isolation, PCR, or reverse transcription-PCR detection, and gene sequencing. More than 18 species of pathogens, including 491 strains of respiratory pathogens, were detected. The positivity rate of bacteria in the 160 lung samples was 31.77%, including Trueperella pyogenes (9.37%), Pasteurella multocida (8.35%), Histophilus somni (4.48%), Mannheimia haemolytica (2.44%), and other bacteria (7.13%). The positivity rate of Mycoplasma spp. was 38.9%, including M. bovis (7.74%), M. dispar (11.61%), M. bovirhinis (7.94%), M. alkalescens (6.11%), M. arginini (0.81%), and undetermined species (4.68%). Six species of viruses were detected with a positivity rate of 29.33%, including bovine herpesvirus-1 (BoHV-1; 13.25%), bovine respiratory syncytial virus (BRSV; 5.50%), bovine viral diarrhea virus (BVDV; 4.89%), bovine parainfluenza virus type-3 (BPIV-3; 4.28%), bovine parainfluenza virus type-5 (1.22%), and bovine coronavirus (2.24%). Mixed infections among bacteria (73.75%), viruses (50%), and M. bovis (23.75%) were the major features of BRDC in these cattle herds. The risk analysis for multi-pathogen co-infection indicated that BoHV-1 and H. somni; BVDV and M. bovis, P. multocida, T. pyogenes, or Mann. haemolytica; BPIV-3 and M. bovis; BRSV and M. bovis, P. multocida, or T. pyogenes; P. multocida and T. pyogenes; and M. bovis and T. pyogenes or H. somni showed co-infection trends. A survey on molecular epidemiology indicated that the occurrence rate of currently prevalent pathogens in BRDC was 46.15% (6/13) for BoHV-1.2b and 53.85% (7/13) for BoHV-1.2c, 53.3% (8/15) for BVDV-1b and 46.7% (7/15) for BVDV-1d, 29.41% (5/17) for BPIV-3a and 70.59% (12/17) for BPIV-3c, 100% (2/2) for BRSV gene subgroup IX, 91.67% (33/36) for P. multocida serotype A, and 8.33% (3/36) for P. multocida serotype D. Our research discovered new subgenotypes for BoHV-1.2c, BRSV gene subgroup IX, and P. multocida serotype D in China's cattle herds. In the BRDC cases, bovine suppurative or caseous necrotizing pneumonia was highly related to BVDV odds ratio (OR) = 4.18; 95% confidence interval (95% CI): 1.6–10.7, M. bovis (OR = 2.35; 95% CI: 1.1–4.9), H. somni (OR = 8.2; 95% CI: 2.6–25.5), and T. pyogenes (OR = 13.92; 95% CI: 5.8–33.3). The risk factor analysis found that dairy calves <3 mo and beef calves >3 mo (OR = 5.39; 95% CI: 2.7–10.7) were more susceptible to BRDC. Beef cattle were more susceptible to bovine suppurative or caseous necrotizing pneumonia than dairy cattle (OR = 2.32; 95% CI: 1.2–4.4). These epidemiological data and the new pathogen subgenotypes will be helpful in formulating strategies of control and prevention, developing new vaccines, improving clinical differential diagnosis by necropsy, predicting the most likely pathogen, and justifying antimicrobial use.
The cross section for the process e^{+}e^{-}→π^{+}π^{-}J/ψ is measured precisely at center-of-mass energies from 3.77 to 4.60 GeV using 9 fb^{-1} of data collected with the BESIII detector operating ...at the BEPCII storage ring. Two resonant structures are observed in a fit to the cross section. The first resonance has a mass of (4222.0±3.1±1.4) MeV/c^{2} and a width of (44.1±4.3±2.0) MeV, while the second one has a mass of (4320.0±10.4±7.0) MeV/c^{2} and a width of (101.4_{-19.7}^{+25.3}±10.2) MeV, where the first errors are statistical and second ones are systematic. The first resonance agrees with the Y(4260) resonance reported by previous experiments. The precision of its resonant parameters is improved significantly. The second resonance is observed in e^{+}e^{-}→π^{+}π^{-}J/ψ for the first time. The statistical significance of this resonance is estimated to be larger than 7.6σ. The mass and width of the second resonance agree with the Y(4360) resonance reported by the BABAR and Belle experiments within errors. Finally, the Y(4008) resonance previously observed by the Belle experiment is not confirmed in the description of the BESIII data.
Solute atoms segregation to the interfaces, such as grain boundary or twin boundary, often plays a critical role in modulating the properties of a metallic alloy. Deformation induced segregation to ...the interfaces has been a subject of significant research, since this is one of the key issues to fully understand the deformation mechanism and microstructure evolution in service of engineering materials. By means of the high-resolution aberration-corrected scanning transmission electron microscopy (STEM), we report the investigations of segregations to symmetrical boundaries, kink boundary (KB) and twin boundary (TB), in the Mg-Zn-Y alloys containing long period stacking ordered (LPSO) phases subjected to a compression at room temperature. We found that Zn atoms preferentially segregate to the deformation-induced symmetrical KBs in the LPSO structures and sandwiched Mg layers, while only a small amount of Y atoms concentrate at KB in LPSO structure. These enriched atoms may be in a random distribution, form nanoscale clusters or in a periodic pattern. Furthermore, solute atoms would rather decorate the segment of coherent TBs than enrich the overlapped TBs. Based on the direct atomic observations, the segregation mechanisms to the featured microstructures are proposed.
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