Tumor-associated macrophages (TAMs) have been correlated with increased angiogenesis and poor prognosis in breast cancer. However, the precise role of TAMs in tamoxifen resistance remains unclear. We used immunohistochemical method to examine the expression of epidermal growth factor receptor (EGFR) and CD163+ macrophages in 100 breast cancer tissues. The clinical and biological features of 100 patients were estrogen receptor (ER)-positive and human epidermal growth factor receptor 2(Her-2)-negative tumors. The tamoxifen resistant tissues (n = 48) were the surgical excision samples from patients who developed recurrence or metastasis at the time of adjuvant tamoxifen treatment. The tamoxifen resistant tissues were contrast to tamoxifen sensitive tissues (n = 52). Positive staining for EGFR and CD163+ macrophages were observed in 21 samples (43.8 %) and in 26 samples (54.2 %) respectively in tamoxifen resistance group, which were higher than that of tamoxifen sensitive group (P = 0.001 and P = 0.000279 respectively). Significant positive correlations were found between the expression of EGFR and CD163+ macrophages (r = 0.567, P < 0.01). CD163+ macrophages were positively correlated with tumor size, lymph node metastasis and obesity. Obesity was also related to tamoxifen resistance (P < 0.05). The patients with higher density of CD163+ macrophages infiltration suffered from shorter time to develop recurrence or metastasis (P < 0.05). TAMs may be associated with tamoxifen resistance. Further studies are needed to investigate the potential mechanism between TAMs and tamoxifen resistance.
Clinical success of cancer radiotherapy is usually impeded by a combination of two factors, i.e., insufficient DNA damage and rapid DNA repair during and after treatment, respectively. Existing strategies for optimizing the radiotherapeutic efficacy often focus on only one facet of the issue, which may fail to function in the long term trials. Herein, we report a DNA-dual-targeting approach for enhanced cancer radiotherapy using a hierarchical multiplexing nanodroplet, which can simultaneously promote DNA lesion formation and prevent subsequent DNA damage repair. Specifically, the ultrasmall gold nanoparticles encapsulated in the liquid nanodroplets can concentrate the radiation energy and induce dramatic DNA damage as evidenced by the enhanced formation of γ-H2AX foci as well as in vivo tumor growth inhibition. Additionally, the ultrasound-triggered burst release of oxygen may relieve tumor hypoxia and fix the DNA radical intermediates produced by ionizing radiation, prevent DNA repair, and eventually result in cancer death. Finally, the nanodroplet platform is compatible with fluorescence, ultrasound, and magnetic resonance imaging techniques, allowing for real-time in vivo imaging-guided precision radiotherapy in an EMT-6 tumor model with significantly enhanced treatment efficacy. Our DNA-dual-targeting design of simultaneously enhancing DNA damage and preventing DNA repair presents an innovative strategy to effective cancer radiotherapy.
The Jagged1-Notch pathway showed elevated expression in AI-resistant breast cancer cells, resulting in macrophage differentiation towards M2 TAMs and there contributing to the acquisition of AI resistance.
The objective of this study is to expound the CT features of COVID-19 patients whose throat swab samples were negative for two consecutive nucleic acid tests after treatment. We retrospectively reviewed 46 COVID-19 patients with two consecutive negative RT-PCR tests after treatment. The cases were divided into moderate group and severe/critical group according to disease severity. Clinical and CT scanning data were collected. CT signs of pulmonary lesions and the score of lung involvement were expounded. Thirty-nine moderate cases and seven severe/critical cases were included. Residual pulmonary lesions were visible in CT images. Moderate patients showed peripheral lesions while severe/critical cases exhibited both central and peripheral lesions with all lobes involvement. Mixed ground glass opacity (GGO) and pulmonary consolidation were noted. A larger proportion of severe patients showed reticular pulmonary interstitium thickening. Air bronchogram, pleural effusion, vascular enlargement, bronchial wall thickening, bronchiectasis, pleural thickening and pleural adhesion were more frequently observed in severe/critical group. The severe/critical group showed higher CT score. Pulmonary lesions persisted even after twice consecutive negative nucleic acid tests. We strongly recommended regular follow-up of CT scans after nucleic acid tests conversion. Evaluation of complete remission should base on chest CT. Coronavirus Disease-2019 (COVID-19) is an acute infectious disease mainly involving the respiratory system 1. The highly contagious disease is caused by a novel coronavirus currently termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1. So far to April 9, 2020, 1,479,748 cases of COVID-19 patients and 87,444 deaths are reported. It is a huge strike to human health and draws much attention from countries all over the world. At present, etiological examinations, including reverse transcription-polymerase chain reaction (RT-PCR) and gene sequencing of sputum, throat swab and lower respiratory tract secretion, are the gold standard for diagnosis of COVID-19 2. Nucleic acid tests are widely recognized as the primary criteria of discharge after treatment. However, it remains unclear whether damage to the lung have been completely restored when the nucleic acid tests are negative after treatment. Explanation of this issue is essential for determining the timing of treatment termination and isolation release. Chest computed tomography (CT) provides us a powerful noninvasive mean for the diagnosis and monitoring for COVID-19. Ground glass opacity (GGO) and consolidative opacity involving bilateral and peripheral lung were CT hallmarks of COVID-19 pneumonia 3-8. It has been reported that CT manifestations vary with the course of disease 8. However, post-treatment patterns of CT images after nucleic acid tests conversion have not yet been described, which are paramount for not only understanding the pathophysiology but also developing management strategies. In the present study, we assessed chest CT images...
Although the precise mechanisms involved in intestinal barrier dysfunction induced by proinflammatory cytokines are incompletely understood, pharmacological restoration of barrier function is very important to the management of intestinal disease. This study was aimed to investigate the protective role of HIF-1α inhibitor oligomycin against intestinal epithelial barrier dysfunction induced by proinflammatory cytokines IFN-γ and TNF-α, and the underlying mechanisms. To induce barrier dysfunction, Caco-2 monolayers were treated with IFN-γ and TNF-α simultaneously. The cytokinestreated Caco-2 monolayers in the absence and in the presence of oligomycin were used for physiological, morphological, and biochemical analyses. The results showed that at the concentration of blocking HIF-1α activation, oligomycin significantly ameliorated TER reduction and paracellular permeability increase in Caco-2 monolayers challenged with IFN-γ and TNF-α. Oligomycin also largely attenuated the IFN-γ and TNF-α-related relocalization of tight junction proteins ZO-1 and occludin. Western blot analysis revealed that oligomycin abolished the increases of both MLC phosphorylation and MLCK protein expression induced by IFN-γ and TNF-α challenge. Quantitative RT-PCR analysis showed that oligomycin inhibited the IFN-γ and TNF-α-induced up-regulation of MLCK mRNA. It is concluded that oligomycin is able to attenuate intestinal epithelial barrier dysfunction induced by proinflammatory cytokines IFN-γ and TNF-α. The mechanism by which oligomycin protects intestinal barrier function may, at least in part, be attributed to block the up-regulated MLCK transcription and protein expression induced by IFN-γ and TNF-α.
Background: Therapeutically immunosuppressed transplant recipients exhibit attenuated responses to COVID-19 vaccines. To better understand the immune alterations that determined poor vaccine response, we correlated quantities of circulating T and B cell subsets at baseline with longitudinal serologic responses to SARS-CoV-2 mRNA vaccination in heart and lung transplant recipients. Methods: Samples at baseline and at approximately 8 and 30 days after each vaccine dose for 22 heart and lung transplant recipients with no history of COVID-19, four heart and lung transplant recipients with prior COVID-19 infection, and 12 healthy controls undergoing vaccination were analyzed. Anti-spike protein receptor binding domain (RBD) IgG and pseudovirus neutralization activity were measured. Proportions of B and T cell subsets at baseline were comprehensively quantitated. Results: At 8-30 days post vaccination, healthy controls displayed robust anti-RBD IgG responses, whereas heart and lung transplant recipients showed minimally increased responses. A parallel absence of activity was observed in pseudovirus neutralization. In contrast, three of four (75%) transplant recipients with prior COVID-19 infection displayed robust responses at levels comparable to controls. Baseline levels of activated PD-1+ HLA-DR+ CXCR5- CD4+ T cells (also known as T peripheral helper [TPH] cells) and CD4+ T cells strongly predicted the ability to mount a response. Conclusions: Immunosuppressed patients have defective vaccine responses but can be induced to generate neutralizing antibodies after SARS-CoV-2 infection. Strong correlations of vaccine responsiveness with baseline TPH and CD4+ T cell numbers highlights a role for T helper activity in B cell differentiation into antibody secreting cells during vaccine response.
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