Search

Background Docetaxel (DTX) exhibits antitumor effects against breast cancer by stabilizing microtubules and increasing the accumulation of reactive oxygen species (ROS). DTX extravasation during infusion often causes skin injury. The present study aimed to investigate the effects and mechanisms of icaritin (ICT) on DTX‐induced skin injury. Methods The effects of ICT on the viability and apoptosis of HaCaT cells were measured by SRB assay and flow cytometry, respectively. Endogenous LC3 puncta and microtubules were determined by immunofluorescence. The number of mitochondria was measured by MitoTracker orange staining. ROS were determined by dihydroethidium staining. The expression of markers of ROS and autophagy were measured by western blotting. Chloroquine, compound D, and tamoxifen were employed as the inhibitor for autophagy and AMPK, estrogen receptors (ERs) modulator, respectively. Results DTX inhibited the viability and decreased apoptosis of HaCaT cells, which can be rescued by ICT. ICT decreased microtubule bundles, increased the number of mitochondria, and attenuated ROS of HaCaT cells induced by DTX. ICT blocks autophagy and the autophagic flux. Compound C or tamoxifen diminished the protection effects of ICT on DTX‐treated HaCaT cells. Conclusion ICT alleviates DTX‐induced skin injury by suppressing ROS, reducing microtubule bundles, and blocking autophagy via ERs. Our study indicated that ICT may be a potential candidate for DTX‐induced skin injury., ICT alleviates DTX‐induced skin injury by alleviating the microtubule bundles, while the specific mechanism is unknown. At the same time, ICT, as an ER modulator, promotes the phosphorylation of the α subunit of AMPK to activate AMPK, thereby regulating the level of autophagy. ICT also reduces the level of ROS by acting as an ER modulator to reduce cell apoptosis.

Background. Probiotic supplements may be seen as a promising way to improve glucose metabolism. This study aimed to evaluate the effects of probiotic supplements on blood glucose, insulin resistance/sensitivity, and prevention of gestational diabetes mellitus (GDM) among pregnant women. Methods. Eleven electronic databases were searched from inception to May 2020. Two authors independently identified randomized controlled trials (RCTs), assessed the eligibility and quality of the included studies, and then extracted data. The primary outcomes were fasting plasma glucose (FPG), 1 h and 2 h plasma glucose after 75 g oral glucose tolerance test (OGTT), HbA1c, fasting plasma insulin, insulin resistance, and insulin sensitivity. Fixed and random effect models were used to pool the results. Results. A total of 20 RCTs involving 2972 participants were included according to the inclusion and exclusion criteria. The pooled results of this research showed that probiotic supplements could reduce the level of FPG (mean difference (MD) = −0.11; 95% CI = −0.15 to −0.04; P = 0.0007 ), serum insulin (MD = −1.68; 95% CI = −2.44 to −0.92; P < 0.00001 ), insulin resistance (MD = −0.36; 95% CI = −0.53 to −0.20; P < 0.00001 ), and insulin sensitivity (MD = −21.80; 95% CI = −31.92 to −11.67; P < 0.00001 ). Regarding the subgroup analysis of different pregnant women, the effects of probiotics on FPG, insulin, and insulin resistance were more obvious among GDM and healthy women than among overweight/obese women. Furthermore, the differences were not significant in HbA1c (MD = −0.05; 95% CI = −0.12 to 0.03; P = 0.23 ), 1 h OGTT (MD = −0.07; 95% CI = −0.25 to 0.10; P = 0.42 ), and 2 h OGTT (MD = −0.03; 95% CI = −0.17 to 0.12; P = 0.72 ). Conclusion. This review found that probiotic supplements had certain functions to reduce the level of FPG and improve insulin, insulin resistance, and insulin sensitivity, especially for GDM and healthy pregnant women.

Sonographic features are associated with pathological and immunohistochemical characteristics of triple-negative breast cancer (TNBC). To predict the biological property of TNBC, the performance using quantitative high-throughput sonographic feature analysis was compared with that using qualitative feature assessment. We retrospectively reviewed ultrasound images, clinical, pathological, and immunohistochemical (IHC) data of 252 female TNBC patients. All patients were subgrouped according to the histological grade, Ki67 expression level, and human epidermal growth factor receptor 2 (HER2) score. Qualitative sonographic feature assessment included shape, margin, posterior acoustic pattern, and calcification referring to the Breast Imaging Reporting and Data System (BI-RADS). Quantitative sonographic features were acquired based on the computer-aided radiomics analysis. Breast cancer masses were manually segmented from the surrounding breast tissues. For each ultrasound image, 1688 radiomics features of 7 feature classes were extracted. The principal component analysis (PCA), least absolute shrinkage and selection operator (LASSO), and support vector machine (SVM) were used to determine the high-throughput radiomics features that were highly correlated to biological properties. The performance using both quantitative and qualitative sonographic features to predict biological properties of TNBC was represented by the area under the receiver operating characteristic curve (AUC). In the qualitative assessment, regular tumor shape, no angular or spiculated margin, posterior acoustic enhancement, and no calcification were used as the independent sonographic features for TNBC. Using the combination of these four features to predict the histological grade, Ki67, HER2, axillary lymph node metastasis (ALNM), and lymphovascular invasion (LVI), the AUC was 0.673, 0.680, 0.651, 0.587, and 0.566, respectively. The number of high-throughput features that closely correlated with biological properties was 34 for histological grade (AUC 0.942), 27 for Ki67 (AUC 0.732), 25 for HER2 (AUC 0.730), 34 for ALNM (AUC 0.804), and 34 for LVI (AUC 0.795). High-throughput quantitative sonographic features are superior to traditional qualitative ultrasound features in predicting the biological behavior of TNBC. • Sonographic appearances of TNBCs showed a great variety in accordance with its biological and clinical characteristics. • Both qualitative and quantitative sonographic features of TNBCs are associated with tumor biological characteristics. • The quantitative high-throughput feature analysis is superior to two-dimensional sonographic feature assessment in predicting tumor biological property.

Background/Purpose: The global coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in significant mortality, social disorder and economic hardships. We set out to understand why certain individuals could resolve the disease successfully without serious complications by immune profiling of PBMCs from convalescent COVID-19 patients (n = 14) with mild disease trajectory. Methods: We designed 7 peptides targeting the receptor binding region (RBD) of the spike protein of SARS-CoV-2, that encompass broad HLA class I / II alleles, with the aid of the Immune Epitope Database and Analysis Resource (IEDB) website. The RBD site was chosen as it was shown to be protective when neutralising antibodies against this region could negate binding of viral spike protein to host cell ACE-2 receptor. Convalescent COVID-19 patients enrolled in this study were screened and selected for positive antibody titre against the RBD region. PBMCs from convalescent COVID-19 patients were stimulated with/without the peptides for 72hrs and immune profiled (n = 70 markers across two panels) with the high dimensional single cell mass cytometry platform (CyToF). Results: Convalescent COVID-19 patients elicited a robust recall memory T follicular helper response (CD3 + CD4 + CD45RO + CXCR5 + Tigit + ;∗∗∗∗ p < 0.0001) demonstrating peptide efficacy. Unsupervised clustering (FlowSOM) of the CD4 T cell immune landscape reaffirmed increase in memory T follicular subsets and additionally CD4 + CD45RO + CXCR5 -subsets. Further gating of antigen specific memory cells (CD45RO + CD69 + ) revealed an increase in Tbet + CXCR3 + T effectors in both CD4 and CD8 compartments. Strikingly we detected a parallel increase in CD4 + Treg (CD25 + FoxP3 + ) CXCR3 + Tbet + CD45RO + CD152 + Tigit + expression. Conclusions: COVID-19 patients that successfully resolve the viral infection not only mount a robust T effector and follicular response but also in tandem a similar T regulatory profile.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor without curable therapy. Surgical resection remains the first choice of patients with GBM but tumors relapse rapidly even combined with conventional chemoradiotherapy. The mechanism of GBM rapid recurrence is poorly understood, which is largely due to the lack of an appropriate animal model, thus heavily impedes the improvement of postoperative therapy. Here we established a highly reproducible mouse GBM surgical model by using the syngeneic G422TN-GBM cells, which faithfully recapitulates the features of rapid recurrence of human GBM after surgery. Implanting 2 × 103–5 × 104 of G422TN-GBM cells in mouse cerebral cortex caused death in all animal within 23 days, while surgery was an effective therapy but not curable. After complete removal of visible tumors on day 5–9 of tumor growth, the tumors recurred macroscopically within 5 days accompanied by increasing infiltrative cancer foci. Mechanistically, the rapid recurrence of resected tumors was positively correlated to early Akt activation, which subsequently upregulated PD-L1/Vimentin and promoted proliferation/migration of cancer cells. In addition, environmental astrocytic activation with strong PD-L1 signal was prominent. Taken together, we provided a novel GBM surgical recurrence model for preclinical studies and suggested complicated recurring mechanisms involving in strong oncogenic signaling as well as immune inhibitory signals from both GBM cells and their neighboring astrocytes.

We aimed to assess the feeding pattern and influencing factors within six weeks postpartum on exclusive breastfeeding duration among Chinese mothers. This study was conducted using 2:1 matched case-control study. Cases and controls were matched for maternal age, parity and mode of birth. A total of 210 women were included. Approximately 67.9% of women stopped exclusive breastfeeding within the first six weeks postpartum. Maternal non-exclusive breastfeeding intention, lower maternal educational level, mother-infant skin to skin contact over one hour, unsatisfied breastfeeding self-evaluation and maternal unhealthy condition within the first six weeks were risk factors for creasing exclusive breastfeeding early.

Alzheimer’s disease (AD) is characterized by progressive synaptic dysfunction, neuronal death, and brain atrophy, with amyloid-β (Aβ) plaque deposits and hyperphosphorylated tau neurofibrillary tangle accumulation in the brain tissue, which all lead to loss of cognitive function. Pathogenic mutations in the well-known AD causal genes including APP, PSEN1, and PSEN2 impair a variety of pathways, including protein processing, axonal transport, and metabolic homeostasis. Here we identified a missense variant rs117916664 (c.896T>C, p.Asn299Ser [p.N299S]) of the acetyl-CoA acyltransferase 1 (ACAA1) gene in a Han Chinese AD family by whole-genome sequencing and validated its association with early-onset familial AD in an independent cohort. Further in vitro and in vivo evidence showed that ACAA1 p.N299S contributes to AD by disturbing its enzymatic activity, impairing lysosomal function, and aggravating the Aβ pathology and neuronal loss, which finally caused cognitive impairment in a murine model. Our findings reveal a fundamental role of peroxisome-mediated lysosomal dysfunction in AD pathogenesis.

Traumatic brain injury (TBI) is a common injury caused by external forces that lead to damaged brain function or pathological changes in the brain tissue. To explore the molecular mechanism and the hub genes of TBI, we downloaded gene expression profiles of the TBI model of rat and the sham control for the subsequent gene set enrichment analysis, pathway analysis and protein-protein interactions analysis. The results of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis indicated that multiple biological pathways, including immune response, inflammatory response and cellular response to interleukin-1, as well as signaling pathways, such as tumor necrosis factor signaling pathway, chemokine signaling pathway, cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway and nuclear factor kappa B signaling pathway were implicated in the TBI. In conclusion, this study provides insights into the molecular mechanism of TBI by screening the differentially expressed genes and hub genes that can be used as biomarkers and therapeutic targets.

Background The majority of clinical trials of first-line systemic treatments for hepatocellular carcinoma (HCC) used placebo or sorafenib as comparators, and there are limited data providing a cross comparison of treatments in this setting, especially for newly-approved immune checkpoint inhibitor and vascular endothelial growth factor inhibitor combination treatments. Aim To systematically review and compare response rates, survival outcomes, and safety of first-line systemic therapies for advanced hepatocellular carcinoma. Methods We searched PubMed, Science Direct, the Cochrane Database, Excerpta Medica Database, and abstracts from the American Society of Clinical Oncology 2020 annual congress. Eligible studies were randomized controlled trials of systemic therapy enrolling adults with advanced/unresectable HCC. Risk of bias was assessed with the Cochrane risk of bias tool for randomized controlled trials. A network meta-analysis was used to synthesize data and perform direct and indirect comparisons between treatments. P value, a frequentist analog to the surface under the cumulative ranking curve, was used to rank treatments. Results In total, 1398 articles were screened and 27 included. Treatments compared were atezolizumab plus bevacizumab, brivanib, donafenib, dovitinib, FOLFOX4, lenvatinib, linifanib, nintedanib, nivolumab, sorafenib, sunitinib, vandetanib, 11 sorafenib combination therapies, and three other combination therapies. For overall response rate, lenvatinib ranked 1/19, followed by atezolizumab plus bevacizumab and nivolumab. For progression-free survival (PFS), atezolizumab + bevacizumab was ranked 1/15, followed by lenvatinib. With the exception of atezolizumab + bevacizumab [hazard ratios (HR)PFS = 0.90; 95% confidence interval (CI): 0.64-1.25], the estimated HRs for PFS for all included treatments vs lenvatinib were > 1; however, the associated 95%CI passed through unity for bevacizumab plus erlotinib, linifanib, and FOLFOX4. For overall survival, atezolizumab plus bevacizumab was ranked 1/25, followed by vandetanib 100 mg/d and donafinib, with lenvatinib ranked 6/25. Atezolizumab + bevacizumab was associated with a lower risk of death vs lenvatinib (HRos = 0.63; 95%CI: 0.44-0.89), while the HR for overall survival for most other treatments vs lenvatinib had associated 95%CIs that passed through unity. Vandetanib 300 mg/d and 100 mg/d were ranked 1/13 and 2/13, respectively, for the lowest incidence of treatment terminations due to adverse events, followed by sorafenib (5/13), lenvatinib (10/13), and atezolizumab + bevacizumab (13/13). Conclusion There is not one single first-line treatment for advanced HCC associated with superior outcomes across all outcome measurements. Therefore, first-line systemic treatment should be selected based on individualized treatment goals.

Background Adding clomiphene citrate (CC) and/or letrozole (LE) to in vitro fertilization (IVF) cycles for mild ovarian stimulation is a general approach. Although lots of researches have demonstrated partial benefits of the strategy, all-around effects of oral medications remained deficient. This paper aims to assess whether an addition of oral medication will result in considerable outcomes on T-Gn (total dose of gonadotropin), Gn days, total retrieved ova, high quality embryos, blastocyst number, ovarian hyperstimulation syndrome (OHSS) rate, clinical pregnancy rate and cumulative pregnancy rate, even if it was not conventional mild/minimal stimulations. Results Participants were categorized to three diverse populations as high responders, normal responders and poor responders according to basal antral follicle count. T-Gn in patients treated with CC/LE distinctly decreased from 2496.96 IU/d to 1827.68 IU/d, from 2860.28 IU/d to 2119.99 IU/d, and from 3182.15 IU/d to 1802.84 IU/d, respectively. For high ovary responders and normal responders, the OHSS incidence rate also declined from 29.2 to 4.3% (P P = 0.090). Other, there was no statistical difference with respect to the T-retrieved ova (total retrieved ova), high quality embryos, cultured blastocyst and blastocyst number in high responders. For normal responders and poor ovary responders, T-Gn, Gn days, T-retrieved ova, high quality embryos, cultured blastocyst and blastocysts number in oral medications group all apparently decreased. Clinical pregnancy rate per fresh cycle of poor responders with prior oral medications was significantly decreased (25.7% vs. 50.8%, P = 0.005), and no significant differences in high responders and normal responders were expressed (52.5% vs. 44.2%, P = 0.310; 51.9% vs. 42.4%, P = 0.163) between two groups of participants. The numbers of cumulative pregnancy rates were lower in the conventional group compared to the add group for high (75.90% versus 81.03%, P = 0.279), normal (62.69% versus 71.36%, P = 0.016) and poor (39.74% versus 68.21%, P Conclusions The addition of CC/LE to the ovulation induction during IVF has certain efficacy in terms of low cost, low OHSS incidence. CC/LE deserves more recommendations as a responsible strategy in high responders due to advantageous pregnancy outcomes. For normal responders, the strategy needs to be considered with more comprehensive factors.

Introduction Perampanel is a highly selective and noncompetitive α‐amino‐3 ‐hydroxy‐5‐methyl‐4‐isoxazole propionate receptor (AMPAR) antagonist, which has been used as an orally administered antiepileptic drug in more than 55 countries. Recently, perampanel was shown to exert neuroprotective effects in hemorrhagic and ischemic stroke models via regulating blood–brain barrier (BBB) function. Aim Here, the protective effects of perampanel were investigated in an in vitro neurovascular unit (NVU) system established using a triple cell co‐culture model (neurons, astrocytes, and brain microvascular endothelial cells) and in an in vivo traumatic brain injury (TBI) model. Results Neurons in the NVU system exhibit a more mature morphological phenotype compared with neurons cultured alone, and the co‐culture system mimicked an impermeable barrier in vitro. Perampanel protects the NVU system against traumatic and excitotoxic injury, as evidenced by reduced lactate dehydrogenase (LDH) release and apoptotic rate. Treatment with perampanel attenuated lipid peroxidation and expression of inflammatory cytokines. In addition, perampanel increased Sirt3 protein expression, enhanced the activities of mitochondrial enzyme IDH2 and SOD2, and preserved BBB function in vitro. Knockdown of Sirt3 using specific siRNA (Si‐Sirt3) partially reserved the effects of perampanel on neuronal injury and BBB function. Treatment with perampanel in vivo attenuated brain edema, preserved neurological function, inhibited apoptosis and microglia activation after TBI. Furthermore, perampanel increased the expression of Sirt3 and preserved BBB function after TBI. The effect of perampanel on BBB function and brain edema was abolished by knockdown of Sirt3 in vivo. Conclusion Our results indicate that the noncompetitive AMPAR antagonist perampanel protects the NVU system and reduces brain damage after TBI via activating the Sirt3 cascades.

Harpertrioate A (1), an A,B,D-seco-limonoid with a rearranged ring B incorporating exocyclic C-30, was isolated from the EtOAc extract of Harrisonia perforata twigs. Its structure, including absolute configurations, was determined on the basis of spectroscopic data and X-ray crystallography. This compound exhibited biological activities against Alzheimer's disease by reducing Aβ42 and Aβ40 production and shifting APP processing toward nonamyloidogenic pathway. The effect of 1 on the Aβ production was comparable to that of gemfibrozil.

To investigate the effects of emodin on inflammation and autophagy in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and reveal its underlying mechanism. 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay was conducted to find the appropriate dose for emodin. RAW264.7 cells pretreated with different concentrations (0–50 μmol/L) of emodin or vehicle for 2 h prior to exposure to LPS for 16 h. Cell morphology was examined and propidium iodide staining was used to examine cell cycle. Expressions of inflammation-related proteins [nuclear factor-kappaB (NF-κ B) and I-kappaB (I κ B)α] and autophagy-related proteins [light chain (LC)3, P62/sequestosome 1, mammalian target of rapamycin (mTOR), and p-mTOR] were examined using Western blot analysis. Expression of inflammation-related cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 were detected by enzyme-linked immunosorbent assay. Autophagy was examined with LC3B fluorescence intensity and aggregation. The effect of emodin on autophagy was conducted with an autophagy inhibitor, 3-methyladenine (3-MA). The expression of NF-κ B in LPS-induced cells was significantly increased (P

Vascular endothelial growth factor (VEGF) had neuroprotective effects on dopaminergic (DA) neurons. In order to overcome the gastrointestinal digestion and bioaccessibility, VEGF was encapsulated with poly-lactic-co-glycolic acid nanospheres (NS) in order to prevent the VEGF degradation until its release. The caudal administration of VEGF and NS encapsulated VEGF at different doses (1.0, 10.0, and 100.0 ng/ml) on the rats with Parkinson's disease lesion was evaluated. Intravenous injected VEGF at the dose of 1 ng/ml displayed the strongest neuroprotective effect than other groups as well as the stereotaxic group. The NS encapsulated with VEGF can pass through blood-brain barrier and protect the DA neurons. There was no significant difference between intravenous injection method and stereotaxic method, while the first method is simpler and convenient. Injection of NS encapsulated with VEGF may become a valuable neurorescuing therapeutic approach for Parkinson's disease.

Transfusion of autologous blood is a timesaving, convenient, safe, and effective therapy from a clinical perspective, and often employed for the treatment of diabetic patients. Stabilization of HIF-1α has been widely reported to be a critical factor in the improvement of wound healing in diabetes. Therefore, our study reveals the roles of improved autologous blood in wound healing in diabetes, through autologous blood transfusion in a mouse model. Initially, BALB/c mice were subjected to streptozotocin for diabetic mouse model establishment. Diabetic mice were transfused with improved or standard autologous blood in perfusion culture system. Roles of improved autologous blood in mediating HIF-1α pathway were determined by measuring expression of VEGF, EGF, HIF-1α, and HSP-90. In order to assess the detailed regulatory mechanism of improved autologous blood in perspective of wound healing, cell proliferation, migration and cell cycle, fibroblasts isolated from diabetic mice were transfected with HIF-1α siRNA. Mice transfused with improved autologous blood exhibited increased levels of CD31 and α-SMA in skin tissues, and reduced TNF-α, IL-1β, and IL-6 levels, indicating that improved autologous blood promoted wound healing ability and reduced the release of inflammatory factors. Diabetic mice transfused with improved autologous blood presented activated HIF-1α pathway. The survival rate, proliferation, and migration of fibroblasts were elevated via activation of the HIF-1α pathway. Taken together, improved blood preservation solution could enhance the oxygen carrying capacity of red blood cells and wound healing in mice with diabetes, which is achieved through regulation of HIF-1α pathway.

Bladder cancer (BCa) is the fourth most common urological malignancy in the world, it has become the costliest cancer to manage due to its high rate of recurrence and lack of effective treatment modalities. As a natural byproduct of cellular metabolism, reactive oxygen species (ROS) have an important role in cell signaling and homeostasis. Although up-regulation of ROS is known to induce tumorigenesis, growing evidence suggests a number of agents that can selectively kill cancer cells through ROS induction. In particular, accumulation of ROS results in oxidative stress-induced apoptosis in cancer cells. So, ROS is a double-edged sword. A modest level of ROS is required for cancer cells to survive, whereas excessive levels kill them. This review summarizes the up-to-date findings of oxidative stress-regulated signaling pathways and transcription factors involved in the etiology and progression of BCa and explores the possible therapeutic implications of ROS regulators as therapeutic agents for BCa.

Background: Nipple discharge cytology is a simple non-invasive method that may provide valuable information for detecting underlying malignancy. Several studies have investigated the diagnostic value of cytology in breast cancer patients with pathological nipple discharge, but the results have been highly variable. Herein we presented a systematic review and meta-analysis of published studies pertaining to the diagnostic capacity of nipple discharge cytology in patients with breast cancer. Methods: A systematic literature search was performed (Medline/PubMed, Embase, Cochrane Library databases, and Google Scholar) to identify studies that investigated the diagnostic capacity of cytology with regard to breast cancer in patients with pathologic nipple discharge. Two independent researchers identified articles that assessed the sensitivity and specificity of cytological evaluation for breast cancer detection in patients with pathologic nipple discharge published between January 2000 and October 2018. Articles were only included in the meta-analysis if they met predetermined criteria. The characteristics of each study and the data they yielded were summarized. Quality assessment of all articles included was performed using the Methodological Index for Non-randomized Studies Criteria (MINORS) and the Quality Assessment of Diagnostic Accuracy Study 2 (QUADAS-2). Heterogeneity was tested via Cochran Q test and the I2 statistic using Stata 12.0 and Meta-DiSc 1.4 software, and meta-analysis was performed. Results: A total of 286 articles were identified, of which 12 articles including a total of 1476 patients were deemed eligible for inclusion in the meta-analysis. A random-effects model assessing the capacity of nipple discharge cytology to predict breast cancer yielded pooled sensitivity 63% (95% confidence interval [CI]: 53%-72%), specificity 95% (95% CI: 87%-98%), positive likelihood ratio 12.35 (95% CI: 4.87-31.34), and negative likelihood ratio 0.39 (95% CI: 0.30-0.50). The diagnostic odds ratio was 31.88 (95% CI: 11.30-89.98). The area under the summary receiver operating characteristic curve was 0.79 (95% CI: 0.75-0.82). Conclusion: The current meta-analysis suggests that nipple discharge cytology is a useful diagnostic modality for detection of breast cancer in patients with pathological nipple discharge, with moderate sensitivity and high specificity. Key words: Breast carcinoma; Cytology; Diagnosis; Meta-analysis; Nipple discharge

Objective: To explore the underlying molecular mechanisms of cellular response to the challenge by 1-methyl-4-phenylpyridinium (MPP+)-induced apoptosis of PC12 cells, an in vitro cell model for Parkinson’s disease, and the effect of NF-κB activation on the protection of Parkinson’s disease by Isoflavone (I). Methods: PC12 cells were used to establish the cell model of Parkinson’s disease, and are divided into five groups: control group; MPP+ group; I (Isoflavone) + MPP+ group; I group; SN-50 + MPP+ group. The content of NF-κB in PC12 cells was determined by immunocytochemistry; The viability of PC12 cells after treated with cell-permeable NF-κB inhibitor SN-50 and cell viability were measured by MTT assay; the expression levels of NF-κB p65 in cytoplasm and nuclear fractions were evaluated by western blot analysis; the mRNA expression of NF-κB p65 was analyzed by in situ hybridization (ISH). Results: Compared with the control group, the protein of NF-κB p65 both in cytoplasm and in nuclei was significantly higher than in I + MPP+ and MPP+ groups; similarly, the mRNA expression level of NF-κB p65 gene was also significantly higher; moreover, the protein expression of NF-κB p65 was much lower in I group (P + group, the protein of NF-κB p65 was significantly lower in I + MPP+ group, the mRNA expression level of NF-κB p65 gene was also significantly lower, and the protein expression level of NF-κB p65 was much lower in I + MPP+ group (P + group (P > 0.05). Conclusion: NF-κB activation is essential to MPP+-induced apoptosis in PC12 cells; but Isoflavone can inhibit the cell damage to some extent to execute its protective function, which may be involved in nigral neurodegeneration in patients with Parkinson’s disease.

During the implantation of embryo, apoptosis is inevitable. These apoptotic cells (AC) are removed by efferocytosis, which fills the macrophage with a metabolite load nearly equal to the phagocyte itself. A timely question pertains to the interrelationship between efferocytosis metabolism and the immune behavior of decidual macrophages (dMΦs) and its effect on pregnancy outcome. Here we report a positive feedback of IL-33/ST2-AXL-efferocytosis leading to pregnancy failure through metabolic reprogramming of dMΦs. We compared the serum level of IL-33, sST2, along with IL-33, ST2, efferocytosis and metabolism of dMΦs from both normal gravidas and unexplained recurrent pregnancy loss (RPL) patients. And we revealed the disturbance of IL-33/ST2 axis, increased apoptotic cells and elevated efferocytosis of dMΦs from the patients with RPL. Afterwards the dMΦs swallowing so many apoptotic cells secreted more sST2 and less TGF-β, which polarized dMΦs towards M1 phenotype. Moreover, the elevated sST2 biased the efferocytosis metabolism of RPL dMΦs towards oxidative phosphorylation and exacerbated the disruption of IL-33/ST2 signaling pathway. The metabolic disorders also led to the dysfunction of efferocytosis, resulting in more uncleared apoptotic cells and the secondary necrosis occurred. We also screened efferocytotic molecule AXL regulated by IL-33/ST2. This positive feedback of IL-33/ST2-AXL-efferocytosis led to pregnancy failure. And the IL-33 knockout mice demonstrated poor pregnancy outcomes, and exogenous supplementation of mouse IL-33 could partially alleviate the fate of embryo losses. These findings highlight a new etiological mechanism whereby dMΦs leverage immunometabolism for the homeostasis of microenvironment at the maternal-fetal interface.

The one-leg stance is frequently used in balance training and rehabilitation programs for various balance disorders. There are some typical one-leg stance postures in Tai Chi (TC) and yoga, which are normally used for improving balance. However, the mechanism is poorly understood. Besides, the differences of one-leg stance postures between TC and yoga in training balance are still unknown. Therefore, the aim of the present study was to investigate cortical activation and rambling and trembling trajectories to elucidate the possible mechanism of improving one-leg stance balance, and compare the postural demands during one-leg stance postures between TC and yoga. Thirty-two healthy young individuals were recruited to perform two TC one-leg stance postures, i.e., right heel kick (RHK) and left lower body and stand on one leg (LSOL), two yoga postures, i.e., one-leg balance and Tree, and normal one-leg standing (OLS). Brain activation in the primary motor cortex, supplementary motor area (SMA), and dorsolateral prefrontal cortex (DLPFC) was measured using functional near-infrared spectroscopy. The center of pressure was simultaneously recorded using a force platform and decomposed into rambling and trembling components. One-way repeated-measures analysis of variance was used for the main effects. The relative concentration changes of oxygenated hemoglobin (ΔHbO) in SMA were significantly higher during RHK, LSOL, and Tree than that during OLS (p < 0.001). RHK (p < 0.001), LSOL (p = 0.003), and Tree (p = 0.006) all showed significantly larger root mean square rambling (RmRMS) than that during OLS in the medial–lateral direction. The right DLPFC activation was significantly greater during the RHK than that during the Tree (p = 0.023), OLB (p < 0.001), and OLS (p = 0.013) postures. In conclusion, the RHK, LSOL, and Tree could be used as training movements for people with impaired balance. Furthermore, the RHK in TC may provide more cognitive training in postural control than Tree and OLB in yoga. Knowledge from this study could be used and implemented in training one-leg stance balance.

Sodium-glucose cotransporter 2(SGLT2) inhibitors show prominent renal protective effect in diabetic kidney disease (DKD), anti-inflammatory effect being one of its key mechanisms. Over-activation of the complement system, a crucial part of innate immunity, plays an important role in DKD. We aimed to investigate the effect of SGLT2 inhibitors on alleviating complement over-activation in DKD. Db/db mice were randomly divided into two groups, with 7 mice in each group treated with dapagliflozin and vehicle respectively, and 7 mice in m/m mice group. Laboratory and renal pathological parameters were evaluated. Mouse proximal tubular epithelial cells (MPTECs) were cultured and treated with high glucose. Dapagliflozin and dimethyloxallyl glycine (DMOG) were added as conditional treatment. Dapagliflozin-treated db/db mice showed significantly lower urinary albumin than vehicle-treated ones. Besides typical glomerular and tubulointerstitial injury, both C3b and membrane attack complex (MAC) depositions were significantly attenuated in dapagliflozin-treated db/db mice. The expression of complement receptor type 1-related protein y (Crry), a key complement regulator which inhibits complement over-activation, was significantly upregulated by dapagliflozin. Dapagliflozin-mediated Crry upregulation was associated with inhibition of HIF-1α accumulation under high glucose. When HIF-1α expression was stabilized by DMOG, the protective effect of dapagliflozin via upregulating Crry was blocked. In conclusion, dapagliflozin could attenuate complement over-activation in diabetic mice via upregulating Crry, which is associated with the suppression of HIF-1α accumulation in MPTECs.

Future HIV-1 curative therapies require a thorough understanding of the distribution of genetically-intact HIV-1 within T-cell subsets during antiretroviral therapy (ART) and the cellular mechanisms that maintain this reservoir. Therefore, we sequenced near-full-length HIV-1 genomes and identified genetically-intact and genetically-defective genomes from resting naive, stem-cell memory, central memory, transitional memory, effector memory, and terminally-differentiated CD4+ T-cells with known cellular half-lives from 11 participants on ART. We find that a higher infection frequency with any HIV-1 genome was significantly associated with a shorter cellular half-life, such as transitional and effector memory cells. A similar enrichment of genetically-intact provirus was observed in these cells with relatively shorter half-lives. We found that effector memory and terminally-differentiated cells also had significantly higher levels of expansions of genetically-identical sequences, while only transitional and effector memory cells contained genetically-intact proviruses that were part of a cluster of identical sequences. Expansions of identical sequences were used to infer cellular proliferation from clonal expansion. Altogether, this indicates that specific cellular mechanisms such as short half-life and proliferative potential contribute to the persistence of genetically-intact HIV-1. IMPORTANCE The design of future HIV-1 curative therapies requires a more thorough understanding of the distribution of genetically-intact HIV-1 within T-cell subsets as well as the cellular mechanisms that maintain this reservoir. These genetically-intact and presumably replication-competent proviruses make up the latent HIV-1 reservoir. Our investigations into the possible cellular mechanisms maintaining the HIV-1 reservoir in different T-cell subsets have revealed a link between the half-lives of T-cells and the level of proviruses they contain. Taken together, we believe our study shows that more differentiated and proliferative cells, such as transitional and effector memory T-cells, contain the highest levels of genetically-intact proviruses, and the rapid turnover rate of these cells contributes to the expansion of genetically-intact proviruses within them. Therefore, our study delivers an in-depth assessment of the cellular mechanisms, such as cellular proliferation and half-life, that contribute to and maintain the latent HIV-1 reservoir.

Background: The aims of this study were to determine the prevalence and characteristics of infections as well as the use of antimicrobials among hemodialysis outpatients. Methods: We used the dialysis event surveillance protocol to conduct a prospective study in 2019. Results: Totally 180 outpatients who received maintenance hemodialysis were included in the cohort study. The total number of dialysis events was 53 in 38 patients. Among the collected events, 42 (79.25%) events used intravenous antimicrobial treatments; five (9.43%) had positive blood cultures; and six (11.32%) had pus, redness, or swelling at the access site. Type of vascular access was an influencing factor for infection among hemodialysis outpatients. Blood flow rate on dialysis was another factor influencing infection events, the risk of infection increased in patients who had lower blood flow rate. Additional analysis showed that lower blood flow rate was also observed as adverse impact in patients who used central lines, but not in those with fistulas. And Erythropoietin use was higher in the infection group. Conclusions: Patients who used central lines, and especially patients both with central lines and low blood flow rate, were more vulnerable to infection. Using Erythropoietin was another risk factor for infection in hemodialysis outpatients.

Nerve block is usually performed before surgery because it inhibits reflection of the skin incision and reduces the amount of intraoperative anesthetic used. We hypothesized that performing rectus sheath block (RSB) after surgery would result in a longer duration of the analgesic effects and have a subtle influence on sleep time after surgery but that it would not decrease the perioperative cytokine levels of patients undergoing gynecological surgery. A randomized, double-blinded, controlled trial was conducted from October 2015 to June 2016. Seventy-seven patients undergoing elective transabdominal gynecological surgery were randomly assigned to the following two groups: a general anesthesia group who received 0.5% ropivacaine hydrochloride RSB preoperatively and saline RSB postoperatively, and another group who received the opposite sequence. The objective of the trial was to evaluate the postoperative pain, sleep and changes in cytokine levels of patients during the postoperative 48 h. A total of 61 female patients (mean age: 50 years; range: 24–65 years) were included in the final study sample. There was no significant difference in the pain, consumption of oxycodone, or time to first administration of patient-controlled intravenous analgesia between the two groups. The postoperative sleep stages N2 and N3 were increased by 52.9 and 29.1 min per patient, respectively, in the preoperative RSB group compared with those in the postoperative group. The preoperative IL-6 concentration in the preoperative RSB group was lower than that in the same group at the end of surgery and 24 h postoperatively. We concluded that preoperative RSB might preserve postoperative sleep by inhibiting the increase of IL-6 without shortening the analgesia time compared with postoperative RSB in female patients undergoing elective midline incision transabdominal gynecological surgery. ClinicalTrials.gov , NCT02477098 , registered on 15 June 2015.

To investigate post-traumatic growth induced by COVID-19 pandemic in certain Yunnan residents and to analyze its influencing factors. A total of 581 permanent residents of Yunnan province completed the electronic questionnaire from 18 April 2020 to 26 April 2020. Logistic regression analysis showed that the educational levels, self-perceived health status, family history of infectious diseases, family history of infectious diseases, personality and frequency of going through COVID-19 related news were influencing factors of PTG (P

Following the publication of the above article, the authors have realized that Fig. 2 was published with an incorrect data panel: Essentially, Fig. 2D was erroneously selected from the representative images of the Fig. 1C data group during figure compilation. The authors were able to locate their original data, and the corrected version of Fig. 2, featuring the corrected data panel for Fig. 2D, is shown below. All the authors agree with this Corrigendum, and are grateful to the Editor of Molecular Medicine Reports for allowing them to publish it. The authors also regret that this inadvertent error was included in the paper, even though it did not substantially alter any of the major conclusions reported in the study, and apologize to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 11: 1160‑1166, 2014; DOI: 10.3892/mmr.2014.2783].

The gestational weight gain (GWG) range of Chinese women with gestational diabetes mellitus (GDM) still remains unclear. Our objective was to identify the ranges of GWG in Chinese women with GDM, and to investigate the associations between pre-pregnancy body mass index (BMI), GWG and maternal-infant adverse outcomes. GDM Women delivering singleton from 2013 to 2018 in a tertiary public hospital were collected. Logistic regression analysis was used to assess the joint effects of pre-pregnancy BMI and GWG on maternal-infant adverse outcomes. Finally, 14,578 women were collected. The ranges of GWG of Chinese women with GDM in the underweight, normal weight, overweight and obese groups were 5.95-21.95kg, 4.23-21.83kg, 0.88-21.12kg and-1.76-19.95kg, respectively. The risks of large for gestational age (LGA), macrosomia and cesarean delivery were significantly increased with the increase of pre-pregnancy BMI. Furthermore, the risks of LGA, macrosomia and cesarean delivery were significantly higher in normal weight group with GWG higher than the National Academy of Medicine’s (NAM) recommendation. Similarly, in overweight group with GWG higher than NAM recommendation, the risks of LGA were significantly higher, while, the risks of macrosomia were significantly lower. In conclusion, the ranges of GWG in GDM women were different with NAM recommendation.

Ethnopharmacological relevance Eucommia ulmoides (E. ulmoides) leaves are included in the Chinese Pharmacopoeia, and are traditionally used to treat hypertension, obesity, diabetes, and other diseases. Numerous pharmacological studies have shown that E. ulmoides has a good effect on lowering blood lipids and can improve obesity and nonalcoholic fatty liver. Aim To study the mechanism of E. ulmoides leaves in regulating nonalcoholic fatty liver disease by combining prediction and validation. Methods Using network pharmacology, and molecular docking to predict E. ulmoides in regulating the action mechanism and potential active ingredients of nonalcoholic fatty liver, large hole adsorption resin enrichment active sites, in vitro experiments were performed to verify its fat-lowering effect and mechanism. Results The major components of E. ulmoides leaves exhibited good combination with lipid metabolism-regulating core proteins, particularly flavonoids. EUL 50 significantly reduced lipid accumulation, and increased PPARγ. Compared with the control group, the autophagy level increased after the administration of EUL 50. PPARγ decreased significantly after the addition of chloroquine (CQ, autophagy inhibitor). Conclusion The active ingredients in E. ulmoides leaves regulating nonalcoholic fatty liver disease are mainly flavonoids and phenolics. EUL 50 may play a role in lowering lipids by regulating PPARγ expression through inducing autophagy.

Background The tumor microenvironment (TME) has received an increasing amount of attention. CXC chemokines can regulate immune cell transport and tumor cell activity to exert anti-tumor immunity. However, studies on the expression and prognosis of CXC chemokines in cervical cancer (CC) are more limited. Methods The study investigated the role of CXC chemokines in TME of CC by using public databases. Moreover, quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) of CXC chemokines were performed to further verify. Results The transcriptional levels of CXCL1/3/5/6/8/9/10/11/13/16/17 in CC tissues were significantly elevated while the transcriptional levels of CXCL12/14 were significantly reduced. We reached a consistent conclusion that the expression of CXCL9/10/11/13 was verified by quantitative real-time PCR and immunohistochemistry. Moreover, CC patients with low transcriptional levels of CXCL1/2/3/4/5/8 were significantly associated with longer overall survival (OS). The CCL family was related to CXC chemokines neighboring alteration. RELA, NFKB1, LCK and PAK2 were the key transcription factors and kinase targets of CXC chemokines, respectively. We also found there were significant correlations between the expression of CXCL9/10/11 and the infiltration of immune cells (CD8+ T cell, CD4+ T cell, neutrophils and dendritic cells). Conclusions In brief, we conducted a comprehensive analysis of CXC chemokines via clinical data and some online public databases. Our results may provide a new idea for the selection of immunotherapeutic targets and prognostic biomarkers for cervical cancer.

Spinal cord ischemia–reperfusion injury (SCII) is still a serious problem, and the mechanism is not fully elaborated. In the rat SCII model, qRT-PCR was applied to explore the altered expression of miR-9 (miR-9a-5p) after SCII. The biological function of miR-9 and its potential target genes based on bioinformatics analysis and experiment validation in SCII were explored next. Before the surgical procedure of SCII, miR-9 mimic and inhibitor were intrathecally infused. miR-9 mimic improved neurological function. In addition, miR-9 mimic reduced blood-spinal cord barrier (BSCB) disruption, inhibited apoptosis and decreased the expression of IL-6 and IL-1β after SCII. Gene Ontology (GO) analysis demonstrated that the potential target genes of miR-9 were notably enriched in several biological processes, such as “central nervous system development”, “regulation of growth” and “response to cytokine”. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the potential target genes of miR-9 were significantly enriched in several signaling pathways, including “Notch signaling pathway”, “MAPK signaling pathway”, “Focal adhesion” and “Prolactin signaling pathway”. We further found that the protein expression of MAP2K3 and Notch2 were upregulated after SCII while miR-9 mimic reduced the increase of MAP2K3 and Notch2 protein. miR-9 mimic or MAP2K3 inhibitor reduced the release of IL-6 and IL-1β. miR-9 mimic or si-Notch2 reduced the increase of cleaved-caspase3. Moreover, MAP2K3 inhibitor and si-Notch2 reversed the effects of miR-9 inhibitor. In conclusion, overexpression of miR-9 improves neurological outcomes after SCII and might inhibit BSCB disruption, neuroinflammation, and apoptosis through MAP2K3-, or Notch2-mediated signaling pathway in SCII.

Purpose: Calcitonin gene-related peptide monoclonal antibodies (CGRPmAbs) are new agents approved by the US Food and Drug Administration for preventive treatment of chronic migraine. Comparison between CGRPmAbs and previously approved Botulinum neurotoxin A (BoNT-A) will inform optimal preventive treatment of chronic migraine, but head-to-head trials are lacking. We therefore aimed to perform adjusted indirect comparison between CGRPmAbs and BoNT-A through a meta-analysis.Methods: OVID MEDLINE, EMBASE and the Cochrane central register of controlled trials, clinical registries, and government websites were searched from inception to September 2019. Randomized controlled trials comparing CGRPmAbs or BoNT-A with placebo in the preventive treatment of chronic migraine were included. The primary outcomes were headache days and migraine days measured at week 12. Data were synthesized by using a frequentist approach; and the treatments were ranked by P-score.Results: We included 10 trials (n = 4,678) after screening 1049 candidates. Six trials were with low risk of bias. Fremanezumab had an effect similar to BoNT-A in the reduction of headache days at week 12 (standard mean difference [SMD] 0.08, 95%CI -0.55 to -0.7). Galcanezumab reduced more migraine days than BoNT-A at week 12 (SMD, -0.94, 95%CI −1.24 to −0.63); fremanezumab showed similar findings (SMD, −0.55, 95%CI −0.85 to −0.24). Galcanezumab and fremanezumab had better effect in mitigating headache impact at week 12. CGRPmAbs and BoNT-A had similar adverse event rate.Conclusion: CGRPmAbs and BoNT-A had similar effect in the preventive treatment of chronic migraine. BoNT-A might be preferentially selected owing to its cost-effectiveness profiles. Further studies with direct comparison of the two treatments are warranted.

With an increasing understanding of hepatitis B, the antiviral indications have been broadening gradually. To evaluate the effectiveness of tenofovir alafenamide (TAF) in chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) and detectable hepatitis B virus (HBV) DNA, those who are ineligible for broader antiviral criteria from the Chinese CHB prevention guide (2019).A total of 117 patients were recruited and their data were collected from paper or electronic medical records. HBV DNA and liver function were measured at baseline and throughout the 24-week follow-up. The effectiveness endpoint was complete virological response. The safety endpoint was the first occurrence of any clinical adverse event during the treatment.Among the 117 patients, 45 had normal ALT as well as detectable HBV DNA and they were not recommended for antiviral therapy according to Chinese Guidelines (2019). After TAF antiviral therapy, the rates of patients who achieved HBV DNA20 IU/mL at 4, 12 and 24 weeks were 77.1%, 96.7% and 96.8% respectively. Among them, the undetectable rates of HBV DNA in patients with low baseline viral load at 4, 12 and 24 weeks were 92.3%, 100% and 100%, while the rates of those with high baseline viral load were 68.2%, 94.1% and 94.4%. Compared with 71.4%, 94.4% and 94.7% in the high baseline group, the undetectable rates of HBV DNA at 4, 12 and 24 weeks in the low baseline liver stiffness group were 85.7%, 100% and 100%. There was no statistical significance among the above groups.CHB patients who had normal ALT and detectable HBV DNA and did not meet "CHB prevention guide (2019)", could achieve complete virological response in 24 weeks after antiviral treatment by TAF.