The Scar-Hidden Surgery on Gynecomastia: Experiences from a Single-Institutional Large Case Series.

BACKGROUND: To summarize the experiences on the mastoscopic subcutaneous mastectomy for gynecomastia by "nine-step method" based on the "5S" goal and standardize this operation. PATIENTS AND METHODS: Between January 1, 2002, and October 31, 2021, a total of 2035 breasts of 1082 male patients with gynecomastia, of which 129 patients with one side, were underwent mastoscopic subcutaneous mastectomy. The follow-up endpoint was 3 months after surgery. RESULTS: All patients were successfully completed the operation, and none of them was transferred to open operation. The operation time for unilateral breast was 12-28 min, and the average time was 17.7 ± 6.2 min. The amount of bleeding during unilateral operation was very small, about 5-10 ml. The total drainage volume was 5-50 ml after the operation, and the drainage tube was removed in 3-5 days. The epidermal necrosis occurred in 0.3% nipple. 0.2% chest wall had a little ecchymosis in the supero-medial region of the breast. All patients had the normal feeling of nipples and areola, the smoothing and symmetrical chest wall, and the natural contour. There was no recurrence during the follow-up period. CONCLUSIONS: The mastoscopic subcutaneous mastectomy for gynecomastia by "nine-step method" based on the "5S" goal has a short operation time, few surgical complications and good esthetics. It achieves the "5S" goals on the complete removal of glandular tissue (sweeping), small and scar-hidden incision are small (scarless), good symmetry of bilateral chest wall (symmetry), normal chest shape (shape), and smoothing chest wall (smoothing). LEVEL OF EVIDENCE III: The journal asks authors to assign a level of evidence to each article. For a complete description of Evidence-Based Medicine ratings, see the Table of Contents or the online Instructions for Authors at www.springer.com/00266 .

Upregulation of CD39 During Gout Attacks Promotes Spontaneous Remission of Acute Gouty Inflammation.

Gout is a self-limiting form of inflammatory arthropathy caused by the formation of urate crystals due to hyperuricemia. The resolution of gout involves the transition of proinflammatory M1-type macrophages to anti-inflammatory M2-type macrophages, as well as neutrophil-mediated extracellular trap (NET) formation. However, the underlying mechanisms of these changes are not clear. Studies have confirmed that high expression of CD39 on macrophages and neutrophils can trigger the polarization of macrophages from a proinflammatory state to an anti-inflammatory state. Recent studies have shown that the pathogenesis of gout involves extracellular ATP (eATP), and the synergistic effect of MSU and extracellular ATP can cause gout. CD39 is a kind of ATP hydrolysis enzyme that can degrade eATP, suggesting that CD39 may inhibit the aggravation of inflammation in gout and participate in the remission mechanism of gout. To confirm this hypothesis, using data mining and flow cytometry, we first found that CD39 expression was significantly upregulated on CD14 + monocytes and neutrophils in gout patients during the acute phase. Inhibition of CD39 by lentivirus or a CD39 inhibitor in acute gout models aggravated gouty arthritis and delayed gout remission. Apyrase, a functional analog of CD39, can significantly reduce the inflammatory response and promote gout remission in acute gout model mice. Our findings confirm that the upregulation of CD39 during gout flare-ups promotes spontaneous remission of acute gouty inflammation.

Targets and mechanisms of Xuebijing in the treatment of acute kidney injury associated with sepsis: a network pharmacology-based study.

INTRODUCTION: Sepsis is a state of the systemic inflammatory response of the host induced by infection, frequently affecting numerous organs and producing varied degrees of damage. The most typical consequence of sepsis is sepsis-associated acute kidney injury(SA-AKI). Xuebijing is developed based on XueFuZhuYu Decoction. Five Chinese herbal extracts, including Carthami Flos, Radix Paeoniae Rubra, Chuanxiong Rhizoma, Radix Salviae, and Angelicae Sinensis Radix, make up the majority of the mixture. It has properties that are anti-inflammatory and anti-oxidative stress. Xuebijing is an effective medication for the treatment of SA-AKI, according to clinical research. But its pharmacological mechanism is still not completely understood. MATERIALS AND METHODS: First, the composition and target information of Carthami Flos, Radix Paeoniae Rubra, Chuanxiong Rhizoma, Radix Salviae, and Angelicae Sinensis Radix were collected from the TCMSP database, while the therapeutic targets of SA-AKI were exported from the gene card database. To do a GO and KEGG enrichment analysis, we first screened the key targets using a Venn diagram and Cytoscape 3.9.1. To assess the binding activity between the active component and the target, we lastly used molecular docking. RESULTS: For Xuebijing, a total of 59 active components and 267 corresponding targets were discovered, while for SA-AKI, a total of 1,276 targets were connected. There were 117 targets in all that was shared by goals for active ingredients and objectives for diseases. The TNF signaling pathway and the AGE-RAGE pathway were later found to be significant pathways for the therapeutic effects of Xuebijing by GO analysis and KEGG pathway analysis. Quercetin, luteolin, and kaempferol were shown to target and modulate CXCL8, CASP3, and TNF, respectively, according to molecular docking results. CONCLUSION: This study predicts the mechanism of action of the active ingredients of Xuebijing in the treatment of SA-AKI, which provides a basis for future applications of Xuebijing and studies targeting the mechanism.

IFN-beta and EIF2AK2 are potential biomarkers for interstitial lung disease in anti-MDA5 positive dermatomyositis.

OBJECTIVE: DM with positive anti-melanoma differentiation-related gene 5 (MDA5) antibody is an autoimmune disease with multiple complications. Interstitial lung diseases (ILDs) are significantly associated with DM and are particularly related to MDA5+ DM. This article aims to explore potential molecular mechanisms and develop new diagnostic biomarkers for MDA5+ DM-ILD. METHODS: The series matrix files of DM and non-specific interstitial pneumonia (NSIP) were downloaded from the Gene Expression Omnibus (GEO) database to identify the differentially expressed genes (DEGs). Gene set enrichment analysis (GSEA) was used to screen the common enriched pathways related to DM and NSIP. Next, the co-expressed differential expressed genes (co-DEGs) between MDA5+, MDA5- and NSIP groups were identified by Venn plots, and then selected for different enrichment analyses and protein-protein interaction (PPI) network construction. The mRNA expression levels of IFN-beta and EIF2AK2 were measured by RT-qPCR. The protein expression levels of IFN-beta were measured by ELISA. RESULTS: Using GSEA, the enriched pathway 'herpes simplex virus 1 infection' was both up-regulated in DM and NSIP. Enrichment analysis in MDA5+ DM, MDA5- DM and NSIP reported that the IFN-beta signalling pathway was an important influencing factor in the MDA5+ DM-ILD. We also identified that eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) was an important gene signature in the MDA5+ DM-ILD by PPI analysis. The expression levels of IFN-beta and EIF2AK2 were significantly increased in MDA5+ DM-ILD patients. CONCLUSIONS: IFN-beta and EIF2AK2 contributed to the pathogenesis of MDA5+ DM-ILD, which could be used as potential therapeutic targets.

P2X7R Mediates the Synergistic Effect of ATP and MSU Crystals to Induce Acute Gouty Arthritis.

Activation of the nod-like receptor protein 3 (NLRP3) inflammasome by monosodium urate (MSU) crystals has been identified as the molecular basis for the acute inflammatory response in gouty arthritis. However, MSU crystals alone are not sufficient to induce acute gouty arthritis (AGA). Adenosine triphosphate (ATP) is an endogenous signaling molecule involved in the NLRP3 inflammasome activation. We aimed to explore the role of ATP in MSU crystal-induced AGA development. In peripheral blood mononuclear cell-derived macrophages obtained from gout patients, we observed a synergistic effect of ATP on MSU crystal-induced IL-1ß release. Furthermore, in a rat model of spontaneous gout, we demonstrated that a synergistic effect of ATP and MSU crystals, but not MSU crystals alone, is essential for triggering AGA. Mechanistically, this synergistic effect is achieved through the purinergic receptor P2X7 (P2X7R). Blockade of P2X7R prevented AGA induction in rats after local injection of MSU crystals, and carrying the mutant hP2X7R gene contributed to the inhibition of NLRP3 inflammasome activation induced by costimulation of MSU crystals and ATP in vitro. Taken together, these results support the synergistic effect of ATP on MSU crystal-induced NLRP3 inflammasome activation facilitating inflammatory episodes in AGA. In this process, P2X7R plays a key regulatory role, suggesting targeting P2X7R to be an attractive therapeutic strategy for the treatment of AGA.

Mechanism of exosomes in the tumor microenvironment in the abscopal effect (Review).

Previously, the abscopal effect, which is an antitumor therapeutic effect on untreated tumor locations elsewhere in the body as a result of treatment of the targeted region, was rarely reported, and its mechanism remains unknown. Increasing evidence has shown that the immune system is implicated in the abscopal effect, and that combining immunotherapy and radiation can assist to improve its frequency. Understanding how different types of cells and cell­derived exosomes cause the abscopal effect in the tumor microenvironment (TME) is crucial to increasing the clinical occurrence of the abscopal effect in the TME.

Z1456467176 alleviates gouty arthritis by allosterically modulating P2X7R to inhibit NLRP3 inflammasome activation.

NLRP3 inflammasome activation is a central process in initiating gout flares. The unique conformational rearrangement of the P2X7 receptor (P2X7R) upon ATP binding is critical for the activation of the NLRP3 inflammasome. However, studies on allosteric modulation of P2X7R in gout treatment are limited. Here, we aimed to investigate the therapeutic implications of targeting P2X7R in gout by designing a P2X7R allosteric inhibitor and validating the inhibitory function on NLRP3 inflammasome activation. Through virtual screening, we identified Z1456467176 (N-{3-[(2-aminoethyl) sulfamoyl] phenyl}-2-methyl-3-[3-(trifluoromethyl) phenyl] propanamide hydrochloride) bound to the drug-binding pocket as a potential antagonist of P2X7R. In functional assays, ATP- or BzATP-induced P2X7R function was assessed in vitro in HEK-293T cells overexpressing hP2X7R (dye uptake assay) and macrophages (IL-1ß release assay). Z1456467176 exhibited a stable and significant P2X7R inhibitory effect. Importantly, in MSU crystal-induced gout, the presence and involvement of ATP were confirmed. Z1456467176 blocked ATP-induced activation of the NLRP3-caspase-1-IL-1ß pathway and exerted promising effects in reducing gouty joint inflammation in rats. In addition, molecular docking and molecular dynamics simulation studies showed that the P27XR protein conformation was remodeled by Z1456467176 binding. Collectively, our results provide a potent P2X7R allosteric inhibitor that facilitates the remission of MSU crystal-induced gout inflammation by inhibiting NLRP3 inflammasome activation, suggesting that allosteric inhibition of P2X7R represents a new direction in gout treatment.

17-Year Follow-up of Comparing Mastoscopic and Conventional Axillary Dissection in Breast Cancer: A Multicenter, Randomized Controlled Trial.

INTRODUCTION: Longer follow-up was necessary to determine the exact value of mastoscopic axillary lymph node dissection (MALND). METHODS: From January 1, 2003, to December 31, 2005, 1027 patients with breast cancer were randomly assigned to two groups: MALND and CALND (conventional axillary lymph node dissection); 996 eligible patients were enrolled. RESULTS: The final cohort of 996 patients was followed for an average of 198 months. Events other than death differed significantly between the two cohorts (p = 0.0311; 46.3% in MALND and 53.2% in CALND, respectively). The sum of events other than death and deaths from other causes was much higher in the CALND (59.6%) than MALND (53.4%) group (p = 0.0494). The 17-year disease-free survival DFS rates were 36.7% for the MALND and 33.6% for the CALND group, respectively. There was a significant difference between the groups (p = 0.0306). Overall survival (OS) rates were 53.2% after MALND and 46.0% after CALND (p = 0.0119). MALND patients had much less axillary pain (p = 0.0000), numbness or paresthesia (p = 0.0000), arm mobility (p = 0.0000) and arm swelling on the operated side (p = 0.0000). Aesthetic appearance of the axilla was much better in the MALND than CALND group (p = 0.0000) at an average follow-up of 17 years. CONCLUSIONS: The use of MALND in breast cancer surgery not only decreases the relapse and arm complications but also improves long-term survival of patients. Therefore, MALND should be one of the preferred approaches for breast cancer surgery when ALND is needed. TRIAL REGISTRATION INFORMATION: The comparison of long-term outcomes of mastoscopic and conventional axillary lymph node dissection in breast cancer: a multicenter randomized control trial. ChiCTR-TRC-11001477, CHiCTR. First registration 08/14/2011.

Dual-specificity phosphatase 8 (DUSP8) induces drug resistance in breast cancer by regulating MAPK pathways.

The aim of the study was to explore the role and molecular mechanism of dual-specificity phosphatase 8 (DUSP8) in the drug resistance of trastuzumab in breast cancer. Real-time PCR and western blot detected the difference in expression of DUSP8 between breast cancer tissue/cells and trastuzumab-resistant tissues/cells. Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of DUSP8 in breast cancer. si-DUSP8 or dusp8 overexpression vector was transiently transfected, and the effects of si-DUSP8 on apoptosis, cell viability and cell migration of drug-resistant cell lines were investigated by flow cytometry, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) and Transwell assays, and its regulation mechanism finally explored. The results showed that the expression of DUSP8 in breast cancer tissues and cells was significantly higher than in matched non-tumor tissues and cells. DUSP8 was significantly upregulated in non-responsive patients compared with patients who responded to trastuzumab. ROC analysis showed that the area under the curve was 0.732, and the diagnostic sensitivity and specificity were 64.86% and 75.76%. DUSP8 knockdown promotes apoptosis and reduces trastuzumab resistance in BT474/TR and SKBR3/TR cells by inhibiting cell migration and cell viability. Knockdown of DUSP8 increased the expression of p-p38 and p-ERK, and the regulation of DUSP8 in chemotherapy resistance of breast cancer cells may be realized by mediating mitogen-activated protein kinase (MAPK)-related signaling pathways. In conclusion, knockdown of DUSP8 expression in trastuzumab-resistant cells can inhibit cell migration and proliferation, and leads to decreased drug resistance by activating MAPK signaling pathway in trastuzumab-resistant cells.

Circular RNA circPTK2 modulates migration and invasion via miR-136/NFIB signaling on triple-negative breast cancer cells in vitro.

OBJECTIVE AND BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive breast type of cancer with poor prognosis and high mortality rates. CircRNAs have been widely investigated, due to their crucial role in cancer progression. We aimed to elucidate the function of circPTK2 (has_circ_0003221) in TNBC and explore the mechanism in progression of TNBC. METHODS: qPCR was performed to validate the expression of circPTK2 and related mRNA in TNBC tissue and cell lines. CCK-8, EdU, Transwell assay were conducted to detect the proliferation, migration and invasion of circPTK2 and miR-136 on TNBC cells. RIP and dual-luciferase reporter assay were used to confirm the interaction among circPTK2, miR-136 and NFIB. Si-circPTK2, mimic and inhibitor of miR-136 were transfected in TNBC cells to confirm the mechanism of circPTK2 and miR-136 in TNBC cells. RESULTS: CircPTK2 were downregulated in TNBC tissues and cell lines. CircPTK2 significantly promoted the proliferation, migration, and invasion of TNBC cells. CircPTK2 was confirmed to be a sponge of miR-136, and directly regulated NFBI and AKT/PI3K pathway. A rescue assay validated circPTK2/miR-136/NFIB axis in TNBC cells. CONCLUSION: CircPTK2 promoted TNBC progression and development. circPTK2/miR-136/NFIB might be an effective biomarker for TNBC.