The Stress of Fungicides Changes the Expression of Clock Protein CmFRQ and the Morphology of Fruiting Bodies of Cordyceps militaris.

The physiological, biochemical, and morphological changes brought about by fungi in response to fungicides can undoubtedly bring diversity to fungi. Cordyceps militaris strains TN (mating type genes MAT1-1-1, MAT1-1-2, and MAT1-2-1) and CmFRQ-454 (mating type genes MAT1-1-1 and MAT1-1-2) were treated with non-lethal doses of fungicides amphotericin B, L-cysteine, terbinafine, and 5-fluorocytosine. The results showed that the treatment with amphotericin B, terbinafine, and 5-fluorocytosine promoted an increase in the relative content of clock protein CmFRQ (C. militaris FREQUENCY) in the mycelium of strain TN, while the high concentration of L-cysteine inhibited the expression of CmFRQ in strain TN. These four fungicides could reduce the relative contents of CmFRQ in the mycelium of strain CmFRQ454. The relative contents of CmFRQ in the mycelium of strain TN were increased after removing the four fungicides, but the relative contents of CmFRQ in the mycelium of strain CmFRQ454 were decreased after removing the four fungicides. This indicates that the effect of fungicides on CmFRQ on mycelium was still sustained after removing the stress of fungicides, and the operation of the circadian clock was changed. The fruiting bodies of C. militaris strain TN and CmFRQ-454 were still degenerated to varying degrees after removing amphotericin B, L-cysteine, and terbinafine. However, the fruiting bodies of strain TN after removing 5-fluorocytosine did not show significant degeneration; the fruiting bodies of strain CmFRQ-454 after removing 5-fluorocytosine obtained rejuvenation. These results indicate that the stress of fungicides could lead to the degeneration of fruiting bodies as well as the rejuvenation of fruiting bodies, resulting in the morphological diversity of C. militaris. The increase or decrease of the CmFRQ-454, the main component of the circadian clock, caused by the stress of fungicants, might lead to the differential degeneration of different mating-type strains of C. militaris.

Guiding the postoperative radioactive iodine-131 therapy for patients with papillary thyroid carcinoma according to the prognostic risk groups: a SEER-based study.

PURPOSE: The effectiveness of iodine-131(131I) therapy in patients with papillary thyroid cancer (PTC) of various stage is controversial. This study aimed to use prognostic risk groups to guide 131I therapy in patients with PTC after radical thyroidectomy. METHODS: Data of 53,484 patients with PTC after radical thyroidectomy were collected from the Epidemiology and End Results (SEER) database. Patients were divided into subgroups according to MACIS system and regional lymph node involvement. The prognostic role of 131I therapy was investigated by comparing Kaplan-Meier survival analysis and Cox proportional hazard models in different subgroups. RESULTS: Sex, age, tumor size, invasion, regional lymph node involvement, and distant metastasis was related to the survival of patients with PTC. If MACIS < 7, 131I treatment didn't affect the cancer-specific survival (CSS) rate. If MACIS ≥ 7, 131I therapy didn't work on CSS rate for patients with N0 or N1a < 5 status; 131I therapy had improved CSS rate for patients in the N1a ≥ 5 or N1b status. If patients with distant metastasis, invasion, or large tumor, 131I therapy didn't improve CSS rate for patients in N0 or N1a < 5 stage. CONCLUSION: After radical thyroidectomy, if MACIS < 7, patients with PTC could avoid 131I therapy. If MACIS ≥ 7, patients in the N0 or N1a < 5 could avoid 131I therapy; those in the N1a ≥ 5 or N1b stage should be given 131I therapy. Among them, all patients with distant metastasis should be given 131I therapy.

Lipid metabolic reprogramming in tumor microenvironment: from mechanisms to therapeutics.

Lipid metabolic reprogramming is an emerging hallmark of cancer. In order to sustain uncontrolled proliferation and survive in unfavorable environments that lack oxygen and nutrients, tumor cells undergo metabolic transformations to exploit various ways of acquiring lipid and increasing lipid oxidation. In addition, stromal cells and immune cells in the tumor microenvironment also undergo lipid metabolic reprogramming, which further affects tumor functional phenotypes and immune responses. Given that lipid metabolism plays a critical role in supporting cancer progression and remodeling the tumor microenvironment, targeting the lipid metabolism pathway could provide a novel approach to cancer treatment. This review seeks to: (1) clarify the overall landscape and mechanisms of lipid metabolic reprogramming in cancer, (2) summarize the lipid metabolic landscapes within stromal cells and immune cells in the tumor microenvironment, and clarify their roles in tumor progression, and (3) summarize potential therapeutic targets for lipid metabolism, and highlight the potential for combining such approaches with other anti-tumor therapies to provide new therapeutic opportunities for cancer patients.

Correlation between connexin 43 expression in circulating tumor cells and biological characteristics of breast cancer.

Background: Connexin 43 (Cx43) has been closely linked to the occurrence and progression of breast cancer. Distant metastasis of breast cancer is aided by the epithelial-mesenchymal transition of circulating tumor cells (CTCs). However, the impact of Cx43 expression on CTCs and the extent of its role in the disease remain unclear. Methods: We determined CTCs in 156 patients, who had breast cancer with a disease course of two or more years. We also measured the expression of Cx43 in the CTCs. The CTCs were detected in the blood of 139 of these patients. These 139 patients were divided into two groups: the Cx43 group and the non-Cx43 group based on their Cx43 expression. Results: Overall, Cx43 expression was found in 83 of the 139 patients (59.7%, 83/139 cases). The two groups significantly differed in terms of the number of mixed biphenotypic type CTCs and the total number of CTCs (P < 0.05). There were significant correlations between Cx43 expression and Ki67 expression, tumor size, lymph node metastasis, and TNM stage (P < 0.05 for all). The data suggested that patients with Cx43 expression had a higher risk of distant metastasis and had later-stage disease. The difference in Cx43 expression between patients with and without epidermal growth factor receptor 2 (Her2) overexpression was statistically significant (P < 0.05). The difference in disease-free survival (DFS) between the two groups was statistically significant (P = 0.03), and the Cx43 group had a shorter duration of DFS. Univariate Cox regression analysis revealed that Cx43 expression, Her2 expression, and tumor size were significantly correlated with DFS (P = 0.03, 0.0023, and 0.01, respectively). Conclusion: Cx43 expression in the CTCs of patients with breast cancer is a cancer-promoting factor.

Histone acetyltransferase P300 deficiency promotes ferroptosis of vascular smooth muscle cells by activating the HIF-1α/HMOX1 axis.

BACKGROUND: E1A-associated 300-kDa protein (P300), an endogenous histone acetyltransferase, contributes to modifications of the chromatin landscape of genes involved in multiple cardiovascular diseases. Ferroptosis of vascular smooth muscle cells (VSMCs) is a novel pathological mechanism of aortic dissection. However, whether P300 regulates VSMC ferroptosis remains unknown. METHODS: Cystine deprivation (CD) and imidazole ketone erastin (IKE) were used to induce VSMC ferroptosis. Two different knockdown plasmids targeting P300 and A-485 (a specific inhibitor of P300) were used to investigate the function of P300 in the ferroptosis of human aortic smooth muscle cells (HASMCs). Cell counting kit-8, lactate dehydrogenase and flow cytometry with propidium iodide staining were performed to assess the cell viability and death under the treatment of CD and IKE. BODIPY-C11 assay, immunofluorescence staining of 4-hydroxynonenal and malondialdehyde assay were conducted to detect the level of lipid peroxidation. Furthermore, co-immunoprecipitation was utilized to explore the interaction between P300 and HIF-1α, HIF-1α and P53. RESULTS: Compared with normal control, the protein level of P300 was significantly decreased in HASMCs treated with CD and IKE, which was largely nullified by the ferroptosis inhibitor ferrostatin-1 but not by the autophagy inhibitor or apoptosis inhibitor. Knockdown of P300 by short-hairpin RNA or inhibition of P300 activity by A-485 promoted CD- and IKE-induced HASMC ferroptosis, as evidenced by a reduction in cell viability and aggravation of lipid peroxidation of HASMCs. Furthermore, we found that hypoxia-inducible factor-1α (HIF-1α)/heme oxygenase 1 (HMOX1) pathway was responsible for the impacts of P300 on ferroptosis of HASMCs. The results of co-immunoprecipitation demonstrated that P300 and P53 competitively bound HIF-1α to regulate the expression of HMOX1. Under normal conditions, P300 interacted with HIF-1α to inhibit HMOX1 expression, while reduced expression of P300 induced by ferroptosis inducers would favor HIF-1α binding to P53 to trigger HMOX1 overexpression. Furthermore, the aggravated effects of P300 knockdown on HASMC ferroptosis were largely nullified by HIF-1α knockdown or the HIF-1α inhibitor BAY87-2243. CONCLUSION: Thus, our results revealed that P300 deficiency or inactivation facilitated CD- and IKE-induced VSMC ferroptosis by activating the HIF-1α/HMOX1 axis, which may contribute to the development of diseases related to VSMC ferroptosis.

Recombinant humanized collagen type III with high antitumor activity inhibits breast cancer cells autophagy, proliferation, and migration through DDR1.

Breast cancer (BC) has become the most common cancer in the world and lacks safe and efficient treatment. The novel biomaterial recombinant humanized collagen type III (rhCOLIII) has been reported to have various biological functions, such as promoting skin extracellular matrix regeneration and improving the cell microenvironment, but its role in breast cancer is unclear. In this study, we first found that rhCOLIII inhibited the proliferation, migration, and invasion of breast cancer cells (BCCs) but had no effect on the survival of normal breast epithelial cells. In addition, rhCOLIII not only promoted apoptosis and dormancy of BCCs but also inhibited autophagy within BCCs. Subsequently, RNA-Seq analysis suggested that DDR1 may be a key target for rhCOLIII to exert antitumor effects, and we validated that inhibition of DDR1 eliminated the effects of rhCOLIII on the proliferation, migration, apoptosis, dormancy and autophagy of BCCs. Moreover, rhCOLIII treatment was found to reduce the tumorigenic activity of BCCs in animal experiments and to upregulate DDR1 protein expression while inhibiting autophagy at the tissue level. Therefore, rhCOLIII may serve as a potential treatment method for BC patients and is expected to improve the prognosis of patients.

Paeoniflorin Coordinates Macrophage Polarization and Mitigates Liver Inflammation and Fibrogenesis by Targeting the NF-[Formula: see text]B/HIF-1α Pathway in CCl4-Induced Liver Fibrosis.

Liver fibrosis is a disease largely driven by resident and recruited macrophages. The phenotypic switch of hepatic macrophages can be achieved by chemo-attractants and cytokines. During a screening of plants traditionally used to treat liver diseases in China, paeoniflorin was identified as a potential drug that affects the polarization of macrophages. The aim of this study was to evaluate the therapeutic effects of paeoniflorin in an animal model of liver fibrosis and explore its underlying mechanisms. Liver fibrosis was induced in Wistar rats via an intraperitoneal injection of CCl4. In addition, the RAW264.7 macrophages were cultured in the presence of CoCl2 to simulate a hypoxic microenvironment of fibrotic livers in vitro. The modeled rats were treated daily with either paeoniflorin (100, 150, and 200[Formula: see text]mg/kg) or YC-1 (2[Formula: see text]mg/kg) for 8 weeks. Hepatic function, inflammation and fibrosis, activation of hepatic stellate cells (HSC), and extracellular matrix (ECM) deposition were assessed in the in vivo and in vitro models. The expression levels of M1 and M2 macrophage markers and the NF-[Formula: see text]B/HIF-1[Formula: see text] pathway factors were measured using standard assays. Paeoniflorin significantly alleviated hepatic inflammation and fibrosis, as well as hepatocyte necrosis in the CCl4-induced fibrosis model. Furthermore, paeoniflorin also inhibited HSC activation and reduced ECM deposition both in vivo and in vitro. Mechanistically, paeoniflorin restrained M1 macrophage polarization and induced M2 polarization in the fibrotic liver tissues as well as in the RAW264.7 cells grown under hypoxic conditions by inactivating the NF-[Formula: see text]B/HIF-1[Formula: see text] signaling pathway. In conclusion, paeoniflorin exerts its anti-inflammatory and anti-fibrotic effects in the liver by coordinating macrophage polarization through the NF-[Formula: see text]B/HIF-1[Formula: see text] pathway.

SNS alleviates depression-like behaviors in CUMS mice by regluating dendritic spines via NCOA4-mediated ferritinophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Depression is one of the most common mood disturbances worldwide. The Si-ni-san formula (SNS) is a famous classic Traditional Chinese Medicine (TCM) widely used to treat depression for thousands of years in clinics. However, the mechanism underlying the therapeutic effect of SNS in improving depression-like behaviors following chronic unpredictable mild stress (CUMS) remains unknown. AIM OF THE STUDY: This study aimed to investigate whether SNS alleviates depression-like behaviors in CUMS mice by regulating dendritic spines via NCOA4-mediated ferritinophagy in vitro and in vivo. STUDY DESIGN AND METHODS: In vivo, mice were exposed to CUMS for 42 days, and SNS (4.9, 9.8, 19.6 g/kg/d), fluoxetine (10 mg/kg/d), 3-methyladenine (3-MA) (30 mg/kg/d), rapamycin(1 mg/kg/d), and deferoxamine (DFO) (200 mg/kg/d) were conducted once daily during the last 3 weeks of the CUMS procedure. In vitro, a depressive model was established by culture of SH-SY5Y cells with corticosterone, followed by treatment with different concentrations of freeze-dried SNS (0.001, 0.01, 0.1 mg/mL) and rapamycin (10 nM), NCOA4-overexpression, Si-NCOA4. After the behavioral test (open-field test (OFT), sucrose preference test (SPT), forced swimming test (FST) and tail suspension test (TST), dendritic spines, GluR2 protein expression, iron concentration, and ferritinophagy-related protein levels (P62, FTH, NCOA4, LC3-II/LC3-I) were tested in vitro and in vivo using immunohistochemistry, golgi staining, immunofluorescence, and Western blot assays. Finally, HEK-293T cells were transfected by si-NCOA4 or GluR2-and NCOA4-overexpression plasmid and treated with corticosterone(100 µM), freeze-dried SNS(0.01 mg/mL), rapamycin(25 nM), and 3-MA(5 mM). The binding amount of GluR2, NCOA4, and LC3 was assessed by the co-immunoprecipitation (CO-IP) assay. RESULTS: 3-MA, SNS, and DFO promoted depressive-like behaviors in CUMS mice during OFT, SPT, FST and TST, improved the amount of the total, thin, mushroom spine density and enhanced GluR2 protein expression in the hippocampus. Meanwhile, treatment with SNS decreased iron concentrations and inhibited NCOA4-mediated ferritinophagy activation in vitro and in vivo. Importantly, 3-MA and SNS could prevent the binding of GluR2, NCOA4 and LC3 in corticosterone-treated HEK-293T, and rapamycin reversed this phenomenon after treatment with SNS. CONCLUSION: SNS alleviates depression-like behaviors in CUMS mice by regulating dendritic spines via NCOA4-mediated ferritinophagy.

Safety and immunogenicity of the third (booster) dose of inactivated and recombinant protein SARS-CoV-2 vaccine for patients with endocrine-related cancer.

Background: Our study aimed to evaluate the safety and immunogenicity of the third (booster) dose of the COVID-19 vaccine for patients with endocrine-related cancers. Methods: This observational study involved 94 breast cancer patients, 92 thyroid cancer patients, and 123 healthy individuals who had received the third (booster) dose of the COVID-19 vaccine. Data on the adverse effects, serum anti-receptor binding domain (RBD)-immunoglobulin (Ig) G, and neutralizing antibodies (NAbs) were collected prospectively. Results: The serum anti-RBD-IgG and NAb titers were significantly lower for the patients with endocrine-related malignancies than for the healthy controls (3.01 [IQR: 1.11-6.70] vs. 4.19 [1.95-9.11], p = 0.001; 0.23 [0.11-0.52] vs. 0.41 [0.22-0.78], p = 0.001), and the seroconversion rates of anti-RBD-IgG and NAbs showed similar results. The serum antibody titers and seroconversion rates were significantly lower for patients aged ≥65 years with endocrine-related cancers, but there were no significant differences related to gender, vaccine type, or cancer type. Subgroup analysis showed that the antibody titers and seroconversion rates were significantly lower for patients with intermediate to advanced breast cancer, HR-/Her2+ breast cancer, and breast cancer undergoing treatment than for healthy controls. In contrast, breast cancer patients who completed their treatment and those who received endocrine therapy after completing their treatment were not significantly different from healthy controls. The NAbs titers and seroconversion rates were significantly lower for patients with primary thyroid cancer (0.19 [IQR: 0.10-0.46] vs. 0.41 [0.22-0.78], p = 0.003; 55.9 vs. 84.9%, p < 0.001); the seroconversion rates were significantly higher for the patients with combined Hashimoto's thyroiditis than for those without it. Multiple linear regression showed that patients aged ≥65 years who were receiving treatment were at risk of having lower antibody levels. Conclusion: The third (booster) dose of the COVID-19 vaccine is safe and well-tolerated. Our data support a third (booster) dose of the SARS-CoV-2 vaccine for breast and thyroid cancer patients. Breast cancer patients aged ≥65 years who are receiving treatment should be more protected, while thyroid cancer and breast cancer patients who have completed their treatment can be vaccinated like the general population.

Risk of waning humoral responses after inactivated or subunit recombinant SARS-CoV-2 vaccination in patients with chronic diseases: Findings from a prospective observational study in China.

Heterogeneity of antibody responses has been reported in SARS-CoV-2 vaccination recipients with underlying diseases. We investigated the impact of the presence of comorbidities on the humoral response to SARS-CoV-2 vaccination in patients with chronic disease (PWCD) and assessed the effect of the number of comorbidities on the humoral response to vaccination. In this study, neutralizing antibodies (NAbs) and IgG antibodies against the receptor-binding domain (RBD-IgG) were monitored following a full-course vaccination. In total, 1400 PWCD (82.7%, inactivated vaccines; 17.3%, subunit recombinant vaccine) and 245 healthy controls (65.7% inactivated vaccines, 34.3% subunit recombinant vaccine) vaccinated with inactivated or subunit recombinant SARS-CoV-2 vaccines, were included. The seroconversion and antibody levels of the NAbs and RBD-IgG were different in the PWCD group compared with those in the control group. Chronic hepatitis B (odds ratio [OR]: 0.65; 95% confidence interval [CI]: 0.46-0.93), cancer (OR: 0.65; 95% CI: 0.42-0.99), and diabetes (OR: 0.50; 95% CI: 0.28-0.89) were associated with lower seroconversion of NAbs. Chronic kidney disease (OR: 0.29; 95% CI: 0.11-0.76), cancer (OR: 0.38; 95% CI: 0.23-0.62), and diabetes (OR: 0.37; 95% CI: 0.20-0.69) were associated with lower seroconversion of RBD-IgG. Only the presence of autoimmune disease showed significantly lower NAbs and RBD-IgG titers. Patients with most types of chronic diseases showed similar responses to the controls, but humoral responses were still significantly associated with the presence of ≥2 coexisting diseases. Our study suggested that humoral responses following SARS-CoV-2 vaccination are impaired in patients with certain chronic diseases.

[Corrigendum] miR­382 inhibits breast cancer progression and metastasis by affecting the M2 polarization of tumor­associated macrophages by targeting PGC­1α.

Subsequently to the publication of the above article, the authors have contacted the Editorial Office to explain that Fig. 7 was published containing an erroneously placed data panel. Specifically, the center panel of the images selected for the invasion assay experiments portrayed in Fig. 7A (i.e., the miR­382 experiment) was chosen incorrectly, and the authors have requested that this panel be replaced by the panel containing the data that was actually used for the statistical analysis shown in part (B). The revised version of Fig. 7, showing the correct data panel for the miR­382 experiment in the invasion assay images in part (A), is shown on the next page. The authors can confirm that the change made to this figure does not affect the overall conclusions reported in the study, and all the authors agree to the publication of this corrigendum. The authors are grateful to the Editor of International Journal of Oncology for allowing them the opportunity to publish this additional Corrigendum; furthermore, they apologize for any inconvenience caused to the readership of the Journal. [International Journal of Oncology 61: 126, 2022; DOI: 10.3892/ijo.2022.5416].

Assessment of the reliability and quality of breast cancer related videos on TikTok and Bilibili: cross-sectional study in China.

Background: As the most common malignant tumor in the world, breast cancer also brings a huge disease burden to China. Ordinary people are increasingly inclined to use the Internet, especially video social platforms, as a source of health information. Educating the public to obtain correct information is important to reduce the incidence of breast cancer and improve the prognosis. However, the quality and reliability of breast cancer-related video content have not been fully studied. Objective: This study aims to evaluate the quality of the information of breast cancer-related videos on TikTok and Bilibili video sharing platforms and factors related to video quality. Methods: We collected the top 100 videos about breast cancer on TikTok and Bilibili, respectively. Categorize videos according to video source and video content. Video quality and reliability were assessed using Global Quality Score (GQS) and modified DISCERN (mDISCERN) tools. We also analyzed the correlation between video quality and video likes, comments, saves, and shares. Results: Although the quality and reliability of Bilibili's breast cancer videos were higher than TikTok (p = 0.002 and p = 0.001, respectively), the video quality of both video sharing platforms was not satisfactory, with a median GQS scores of 2.00 and 3.00 and mDISCERN scores of 1.00 and 2.00, respectively. In general, the quality and reliability of videos released by medical practitioners were higher than those of non-medical practitioners, and the quality and reliability of videos covering disease-related knowledge were higher than those of news reports (all p < 0.001). Among medical practitioners, the quality of videos uploaded by doctors in breast disease was significantly lower than that of doctors in other areas (p < 0.05). There was a significant positive correlation between video quality and duration (r = 0.240, p < 0.001), a weak negative correlation between video quality and likes (r = 0.191, p < 0.01), video quality and comments (r = 0.256, p < 0.001), video reliability and likes (r = 0.198, p < 0.001), video reliability and comments (r = 0.243, p < 0.01). Conclusion: Our study shows that the quality and reliability of breast cancer-related videos on TikTok and Bilibili are poor, and the overall quality is unsatisfactory. But videos uploaded by medical practitioners covering disease knowledge, prevention and treatment are of higher quality. Medical practitioners are encouraged to publish more high-quality videos, while video social platforms should formulate relevant policies to censor and supervise health education videos, so as to enable the public to obtain reliable health information.

In vivo micro-computed tomography imaging in liver tumor study of mice using Fenestra VC and Fenestra HDVC.

Contrast agents are used to enhance the visibility of rodent organs during in vivo micro-computed tomography imaging. Specifically, this non-invasive technique can study liver tumor growth and progression in small animals. Fenestra VC and the novel Fenestra HDVC were compared for enhancement in the liver of healthy and tumor-bearing mice, and the images were compared for their ability to define the tumor border, volume and quantity of tumors. Fenestra VC and Fenestra HDVC were injected into healthy eight-week-old female mice (C57BL/6) via the tail vein then imaged at seven different time points. The experimental results showed that 0.005 mL/g of Fenestra HDVC resulted in the same enhancement for all eight organs as 0.01 mL/g of Fenestra VC across all time points. For the tumor study, B16F10 tumors were surgically introduced into ten eight-week-old female mice (C57BL/6) then imaged in vivo over a 3 day period. Ex vivo micro-CT images of the excised livers were also obtained. The tumor volume and quantity were measured in each image, and the tumour progression observed over 3 days. We showed Fenestra HDVC is effective for in vivo imaging in rodents because the optimal enhancement level in organs is maintained at a reduced injection volume.

Clinical Features and Prognosis Analysis of Hormone Receptor-Positive, HER2-Negative Breast Cancer with Differential Expression Levels of Estrogen and Progesterone Receptors: A 10-Year Retrospective Study.

Background: Estrogen and progesterone receptor status can predict breast cancer patient prognosis and treatment sensitivity, but research on low ER and PR levels and expression balance remains limited. Methods: From January 2010 to October 2016, 283 ER+/PR+/HER2-breast cancer patients who met the inclusion criteria were enrolled and divided into the H group (ER > 10%, N = 261) and the L group (1% ≤ ER ≤ 10%, N = 22). Groups were further divided into the HH group (ER > 10%/PR > 20%, N = 201), the HL group (ER > 10%/ER 1% ≤ PR ≤ 20% PR, N = 60), the LH group (1% ≤ ER ≤ 10%/PR > 20%, N = 5), and the LL group (1% ≤ ER ≤ 10%/1% ≤ PR ≤ 20%, N = 17). The LH group was excluded due to its small size, leaving the clinical and prognostic characteristics of 2 large groups and 3 subgroups to be analyzed. Results: L group patients had significantly more stage N2 axillary lymph nodes than H group patients (31.8% vs. 9.2%, P = 0.007). Age (P = 0.011), menopause status (P = 0.001), and tumor size (P = 0.024) were significantly different in the HL vs. HH and LL groups. Five-year DFS (94.6% vs. 77.0%, P < 0.001) and 5-year OS (97.2% vs. 85.8%, P = 0.001) rates significantly differed between HH and HL. No significant differences in 5-year DFS (77.0% vs. 81.9%, P = 0.564) or 5-year OS (85.8% vs. 87.8%, P = 0.729) rates were observed between HL and LL; the OS rates of HL and LL were similar. Conclusion: In the group of ER+/PR+/HER2-patients, there was no significant prognostic difference between ER-low positive and ER-high positive groups, but low PR expression was significantly associated with a worse prognosis. The role of ER and PR balance in breast cancer progression and individualized treatment requires further investigation.

Short-term safety and immunogenicity of inactivated and peptide-based SARS-CoV-2 vaccines in patients with endocrine-related cancer.

Background: The aim of this study was to explore the short-term safety and immunogenicity of inactivated and peptide-based SARS-CoV-2 vaccines in patients with endocrine-related cancer (ER). Methods: Eighty-eight patients with ER cancer and 82 healthy controls who had completed a full course of inactivated or peptide-based SARS-CoV-2 vaccines were recruited. Adverse events (AEs) were recorded. Responses to receptor-binding domain IgG antibody (anti-RBD-IgG), neutralizing antibodies (NAbs) and RBD+ memory B cells (MBCs) were evaluated. Results: Approximately 26.14% (23/88) of patients with ER cancer reported AEs within 7 days, which was comparable to that reported by healthy controls (24.39%, 20/82). Both the overall seroprevalence of anti-RBD-IgG and NAbs was obviously lower in the cancer group (70.45% vs. 86.59%, P < 0.05; 69.32% vs. 82.93%, P < 0.05, respectively). Anti-RBD-IgG and NAbs titers exhibited similar results, and dropped gradually over time. Patients with ongoing treatment had an attenuated immune response, especially in patients receiving active chemotherapy. The frequency of overall RBD+ MBCs was similar between the two groups, but the percentage of active MBCs was remarkably reduced in patients with ER cancer. Unlike antibody titers, MBCs responses were relatively constant over time. Conclusion: Inactivated and peptide-based COVID-19 vaccines were well tolerated, but with lower immunogenicity for ER cancer patients. More intensive antibody monitoring and timely booster immunization is recommended for patients with ER cancer presenting disordered subpopulations of RBD+ MBCs.

miR­382 inhibits breast cancer progression and metastasis by affecting the M2 polarization of tumor­associated macrophages by targeting PGC­1α.

Macrophages are principal immune cells with a high plasticity in the human body that can differentiate under different conditions in the tumor microenvironment to adopt two polarized phenotypes with opposite functions. Therefore, converting macrophages from the immunosuppressive phenotype (M2) to the inflammatory phenotype (M1) is considered a promising therapeutic strategy for cancer. However, the molecular mechanisms underlying this conversion process have not yet been completely elucidated. In recent years, microRNAs (miRNAs or miRs) have been shown to play key roles in regulating macrophage polarization through their ability to modulate gene expression. In the present study, it was found that miR­382 expression was significantly downregulated in tumor­associated macrophages (TAMs) and M2­polarized macrophages in breast cancer. In vitro, macrophage polarization toward the M2 phenotype and M2­type cytokine release were inhibited by transfection with miR­382­overexpressing lentivirus. Similarly, the overexpression of miR­382 inhibited the ability of TAMs to promote the malignant behaviors of breast cancer cells. In addition, peroxisome proliferator­activated receptor γ coactivator­1α (PGC­1α) was identified as the downstream target of miR­382 and it was found that PGC­1α affected macrophage polarization by altering the metabolic status. The ectopic expression of PGC­1α restored the phenotype and cytokine secretion of miR­382­overexpressing macrophages. Furthermore, PGC­1α expression reversed the miR­382­induced changes in the metabolic state of TAMs and the effects of TAMs on breast cancer cells. Of note, the in vivo growth and metastasis of 4T1 cells were inhibited by miR­382­overexpressing TAMs. Taken together, the results of the present study suggest that miR­382 may alter the metabolic status of macrophages by targeting PGC­1α, thereby decreasing the proportion of TAMs with the M2 phenotype, and inhibiting the progression and metastasis of breast cancer.

Characterization of Migratory Cells From Bioengineered Bovine Cartilage in a 3D Co-culture Model.

BACKGROUND: Chondrocyte migration in native cartilage is limited and has been implicated as one of the reasons for the poor integration of native implants. Through use of an in vitro integration model, it has previously been shown that cells from bioengineered cartilage can migrate into the native host cartilage during integration. Platelet-rich plasma (PRP) treatment further enhanced integration of bioengineered cartilage to native cartilage in vitro. However, it is not known how PRP treatment of the bioengineered construct promotes this. HYPOTHESIS: PRP supports cell migration from bioengineered cartilage and these migratory cells have the ability to accumulate cartilage-like matrix. STUDY DESIGN: Controlled laboratory study. METHODS: Osteochondral-like constructs were generated by culturing primary bovine chondrocytes on the top surface of a porous bone substitute biomaterial composed of calcium polyphosphate. After 1 week in culture, the constructs were submerged in PRP and placed adjacent, but 2 mm distant, to a native bovine osteochondral plug in a co-culture model for 2 weeks. Cell migration was monitored using phase-contrast imaging. Cell phenotype was determined by evaluating the gene expression of matrix metalloprotease 13 (MMP-13), Ki67, and cartilage matrix molecules using quantitative polymerase chain reaction. When tissue formed, it was assessed by histology, immunohistochemistry, and quantification of matrix content. RESULTS: PRP treatment resulted in the formation of a fiber network connecting the bioengineered cartilage and native osteochondral plug. Cells from both the bioengineered cartilage and the native osteochondral tissue migrated onto the PRP fibers and formed a tissue bridge after 2 weeks of culture. Migratory cells on the tissue bridge expressed higher levels of collagen types II and I (COL2, COL1), Ki67 and MMP-13 mRNA compared with nonmigratory cells in the bioengineered cartilage. Ki67 and MMP-13-positive cells were found on the edges of the tissue bridge. The tissue bridge accumulated COL1 and COL2 and aggrecan and contained comparable collagen and glycosaminoglycan content to the bioengineered cartilage matrix. The tissue bridge did not reliably develop in the absence of cells from the native osteochondral plug. CONCLUSION: Bioengineered cartilage formed by bovine chondrocytes contains cells that can migrate on PRP fibers and form cartilaginous tissue. CLINICAL RELEVANCE: Migratory cells from bioengineered cartilage may promote cartilage integration. Further studies are required to determine the role of migratory cells in integration in vivo.

Kinsenoside alleviates inflammation and fibrosis in experimental NASH mice by suppressing the NF-κB/NLRP3 signaling pathway.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) has replaced viral hepatitis as the main driver of the rising morbidity and mortality associated with cirrhosis and liver cancer worldwide, while no FDA-approved therapies are currently known. Kinsenoside (KD), naturally isolated from Anoectochilus roxburghii, possesses multiple biological activities, including lipolysis, anti-inflammation, and hepatoprotection. However, the effects of KD on NASH remain unclear. PURPOSE: This study aimed to explore the roles of KD in NASH and its engaged mechanisms. METHODS: Two typical animal models of NASH, mice fed a methionine-choline-deficient (MCD) diet (representing non-obese NASH) and mice fed a high-fat and -fructose diet (HFFD) (representing obese NASH), were used to investigate the effect of KD on NASH in vivo. Transcriptome sequencing was performed to elucidate the underlying mechanisms of KD. Lipopolysaccharide (LPS)-stimulated THP-1 cells and transforming growth factor ß1 (TGF-ß1)-activated LX-2 cells were applied to further explore the effects and mechanisms of KD in vitro. RESULTS: The intragastric administration of KD remarkably alleviated MCD/HFFD-induced murine NASH almost in a dose-dependent manner. Specifically, KD reduced lipid accumulation, inflammation, and fibrosis in the liver of NASH mice. KD ameliorated alanine aminotransferase (ALT), aspartate aminotransferase (AST), superoxide dismutase (SOD), and malondialdehyde (MDA) abnormalities. In addition, it decreased the level of serum proinflammatory factors (IL-12p70, IL-6, TNF-α, MCP-1, IFN-γ) and the hepatic expression of typical fibrosis-related molecules (α-SMA, Col-I, TIMP-1). Mechanically, KD attenuated the MCD/HFFD-induced NASH through the inhibition of the NF-κB/NLRP3 signaling pathway. Consistently, KD reduced inflammation stimulated by LPS in THP-1 cells via suppressing the NF-κB/NLRP3 pathway. Furthermore, it prevented the activation of LX-2 cells directly, by inhibiting the proliferation stimulated by TGF-ß1, and indirectly, by inactivating the NLRP3 inflammasome in macrophages. CONCLUSION: For the first time, the practical improvement of NASH by KD was revealed. Our study found that KD exerted its alleviative effects on NASH through the inhibition of the NF-κB/NLRP3 signaling pathway. Given its hepatoprotective and nontoxic properties, KD has the potential to be a novel and effective drug to treat NASH.