Madelung's Disease: Analysis of Clinical Characteristics, Fatty Mass Distribution, Comorbidities and Treatment of 54 Patients in China.

Purpose: Madelung's disease (MD) is a rare disease characterized by the deposition of unencapsulated fat masses on the face, neck, chest, back and other areas of patients. The aim of the study was to analyze the clinical characteristics, comorbidities and treatment of MD in Chinese populations. Patients and Methods: We retrospectively reviewed the medical records of 54 patients who were diagnosed with MD at the Affiliated Hospital of Qingdao University and Qingdao Municipal Hospital from January 2005 to February 2021 and collected the subjects' demographic information, clinical indicators, location of fat deposits, treatment, complications and prognostic data. Results: Among 54 MD patients in the study, only 1 (1.85%) was female, and the subjects had an average age of 56.65 ± 7.93 years. More than 70% of patients had a history of long-term smoking or/and alcohol abuse. In our study, type I accounted for approximately 61.11% of cases according to Donhauser's classification, and almost all patients had neck fat deposition. MD patients often have multiple comorbidities across several systems, such as the endocrine, digestive, circulatory, urinary, and neurological systems. Among these, endocrine system diseases were the most common comorbidities in our study, accounting for 81.48%. Notably, up to 20.37% of cases were complicated with cancer, especially digestive system tumors. More than 70% of the patients received surgical treatment, and nearly 40% experienced postoperative recurrence. Conclusion: Considering that MD patients often have comorbidities of multiple systems and that a small number of cases are even complicated by cancer, we recommend that clinicians comprehensively assess a patient's condition and complications, advocate that patients quit consuming alcohol and smoking as soon as possible, establish healthy dietary and living habits, and formulate individualized and comprehensive diagnosis and treatment plans.

A novel near-infrared fluorescent probe based on triphenylamine derivatives for the rapid and sensitive detection of heparin.

In this study, a positively charged near-infrared fluorescent probe (TPA-P+) was constructed by connecting a pyridine cation with triphenylamine and successfully used for the detection of heparin. The probe has the following characteristics: (1) TPA-P+ exhibited both AIE and TICT characteristics. (2) TPA-P+ could detect heparin by the introduction of a pyridine cation into TPA-P+, which increased the electrostatic interaction between the probe and heparin. (3) The probe has high sensitivity and good selectivity towards heparin and responds quickly. (4) Heparin detection using TPA-P+ was verified by protamine and was found to be reversible and effective. (5) The fluorescence intensity of TPA-P+ has good linearity with heparin concentration in the range of 0-16.0 µg mL-1 in human serum albumin.

Targeting USP22 with miR­30­5p to inhibit the hypoxia­induced expression of PD­L1 in lung adenocarcinoma cells.

Lung cancer is one of the most common forms of cancer and accounts for a significant proportion of all cancer­related deaths. Lung adenocarcinoma (LUAD) accounts for approximately 40% of all cases of lung cancer. In recent years, new developments in both the diagnosis and treatment of LUAD have been achieved. Unfortunately, the prognosis remains poor for patients with malignant LUAD. Hypoxia is a common characteristic of solid tumors and induce the immune evasion by increasing the expression of programmed cell death­ligand­1 (PD­L1) in the tumor. In this study, it was predicted that ubiquitin­specific peptidase 22 (USP22) is the direct target of the microRNA (miR)­30­5p family, including miR­30a­5p, miR­30b­5p, miR­30c­5p, miR­30d­5p and miR­30e­5p. Furthermore, the binding of USP22 with the miR­30­5p family was confirmed by luciferase assay. In addition, it was demonstrated that targeting USP22 via the miR­30­5p family inhibited the induction of PD­L1 expression in hypoxic conditions, thus preventing activated T cells from killing LUAD cells. Our results indicated that miR­30a­5p, miR­30b­5p, miR­30c­5p, miR­30d­5p and miR­30e­5p represent new targets for the treatment of LUAD.

Alteration of MDM2 by the Small Molecule YF438 Exerts Antitumor Effects in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) exhibits a high mortality rate and is the most aggressive subtype of breast cancer. As previous studies have shown that histone deacetylases (HDAC) may represent molecular targets for TNBC treatment, we screened a small library of synthetic molecules and identified a potent HDAC inhibitor (HDACi), YF438, which exerts effective anti-TNBC activity both in vitro and in vivo. Proteomic and biochemical studies revealed that YF438 significantly downregulated mouse double minute 2 homolog (MDM2) expression. In parallel, loss of MDM2 expression or blocking MDM2 E3 ligase activity rendered TNBC cells less sensitive to YF438 treatment, revealing an essential role of MDM2 E3 ligase activity in YF438-induced inhibition of TNBC. Mechanistically, YF438 disturbed the interaction between HDAC1 and MDM2, induced the dissociation of MDM2-MDMX, and subsequently increased MDM2 self-ubiquitination to accelerate its degradation, which ultimately inhibited growth and metastasis of TNBC cells. In addition, analysis of clinical tissue samples demonstrated high expression levels of MDM2 in TNBC, and MDM2 protein levels closely correlated with TNBC progression and metastasis. Collectively, these findings show that MDM2 plays an essential role in TNBC progression and targeting the HDAC1-MDM2-MDMX signaling axis with YF438 may provide a promising therapeutic option for TNBC. Furthermore, this novel underlying mechanism of a hydroxamate-based HDACi in altering MDM2 highlights the need for further development of HDACi for TNBC treatment. SIGNIFICANCE: This study uncovers the essential role of MDM2 in TNBC progression and suggests that targeting the HDAC1-MDM2-MDMX axis with a hydroxamate-based HDACi could be a promising therapeutic strategy for TNBC.

Resolvin D1 Protects Against Ischemia/Reperfusion-Induced Acute Kidney Injury by Increasing Treg Percentages via the ALX/FPR2 Pathway.

AIMS: To evaluate whether Resolvin D1 attenuates ischemia/reperfusion-induced (IRI) acute kidney injury (AKI) via affecting Tregs. MATERIALS AND METHODS: The IRI-AKI mouse model was established, and RvD1 was injected into the mouse tail vein. Further, the renal function, histological changes, injury markers and serum cytokines were detected at 24 and 72 h after IRI. Flow cytometry was used to categorize regulatory T cells (Tregs) in the spleen and kidney. Treg cells were stripped with the anti-CD25 antibody blocker PC61 to assess its role in the protective effect of RvD1 on IRI mice. CD4+ T cells were obtained from spleen monocytes by magnetic bead sorting and differentiated into induced Treg (iTreg) cells. The effect of RvD1 on iTreg cell differentiation was observed in vitro. In addition, neutralizing antibodies against the orphan receptor G-protein-coupled receptor 32 (anti-GPR32) and LXA4 receptor (anti-ALX/FPR2), both RvD1 receptor blockers, were used to evaluate the effect of RvD1 on iTreg cell differentiation. Boc-1, an ALX/FPR2 receptor inhibitor, was administered via the tail vein to observe its effects on the ameliorative efficacy of RvD1 in IRI-AKI mice in vivo. RESULTS: In vivo, RvD1 increased Treg percentages, alleviated renal tubular injury and reduced the serum levels of IFN-γ, TNF-α and IL-6 in IRI-AKI mice, while PC61 depleted the number of Tregs and reversed the protective effects of RvD1. In vitro, RvD1 induced the generation of iTregs. Importantly, preincubation with anti-ALX/FPR2 neutralizing antibodies but not with anti-GPR32 neutralizing antibodies, abrogated the enhancement activity of RvD1 on iTregs. In addition, in vivo blockade of the receptor ALX/FPR2 by Boc-1 reversed the beneficial effects of RvD1 on the splenic and kidney Treg percentages, renal tubular injury and serum IFN-γ, TNF-α, and IL-6 levels. CONCLUSION: Our study demonstrates that RvD1 protects against IRI-AKI by increasing the percentages of Tregs via the ALX/FPR2 pathway.

Cast nephropathy associated with monoclonal immunoglobulin M-secreting mucosa-associated lymphoid tissue B-cell lymphoma
.

The kidney is among the various anatomical sites involved in mucosa-associated lymphoid tissue (MALT) lymphoma. A variety of renal pathological types, including membranous glomerulopathy, membranoproliferative glomerulonephritis, crescentic IgA nephropathy, minimal change disease, and cryoglobulinemic glomerulopathy, have been reported in MALT lymphoma patients. However, cast nephropathy is extremely rare in MALT lymphoma. Herein, we describe the case of a patient with a history of MALT lymphoma of the stomach and small intestine 7 years before presenting with acute kidney failure 1 year after chemotherapy cessation. Monoclonal IgM-λ was detected in the serum, and kidney biopsy showed λ light chain deposition-based cast nephropathy. In addition, MALT recurrence was discovered in the stomach rather than intestinal tissue by gastrointestinal endoscope, and no lymphoplasmacytic infiltration was found in bone marrow. After 1 year of chemotherapy, renal function was partially restored, and the level of serum λ chain, serum IgM, and 24-hour urine protein all decreased. Our case illustrates that MALT lymphoma is prone to recurrence and grows slowly, moreover, with the characteristic of monoclonal immunoglobulin production and kidney infiltration.

Apoptosis of the Tracheal Epithelium Can Increase the Number of Recipient Bone Marrow-Derived Myofibroblasts in Allografts and Exacerbate Obliterative Bronchiolitis After Tracheal Transplantation in Mice.

BACKGROUND: The long-term outcome of lung transplantation is impeded by the development of obliterative bronchiolitis (OB). We sought to investigate the relationship between the apoptosis of tracheal epithelial cells and bone marrow-derived myofibroblasts in the process of OB. METHODS: The mouse orthotopic tracheal transplant model was established. The allografts and syngrafts were harvested at 1, 2, 3, and 4 weeks after tracheal transplant. The percentage of tracheal lumen occlusion was assayed via histology and morphometry. Immunofluorescence staining was used to detect the apoptotic epithelial cells and recipient-derived myofibroblasts. The expression of SDF-1α and TGF-ß and the infiltrations of CD4 and CD8 T cells in the grafts were detected using immunohistochemical staining. RESULTS: We found that there were more apoptotic epithelia in the allograft group than in the syngraft group and that the level of tracheal lumen occlusion was higher at different time points. Moreover, the increase in the apoptosis of the tracheal epithelium occurred earlier than that of occlusion of the tracheal lumen. There were more myofibroblasts derived from the recipient's bone marrow and more CD4 and CD8 T cells in the allografts. The expression of SDF-1α and TGF-ß was higher in the epithelium from allografts than in those of the syngrafts. CONCLUSIONS: Our study indicated that the apoptotic tracheal epithelia in the OB model might increase the amount of myofibroblasts derived from the recipient's bone marrow. Therapeutic methods aimed at preventing apoptosis of the tracheal epithelium may improve the outcome of lung transplantation.

Surgical Treatment of Enormous Recurrent Dermatofibrosarcoma Protuberans.

A patient with enormous recurrent dermatofibrosarcoma protuberans underwent modified three-dimensional histology surgery. Frozen-section examination was used to identify the margins. The patient had a normal postoperative course.

OM85-BV induced the productions of IL-1ß, IL-6, and TNF-α via TLR4- and TLR2-mediated ERK1/2/NF-κB pathway in RAW264.7 cells.

Broncho-Vaxom (OM85-BV) is an extract mixture from 8 strains of Gram(+) and Gram(-) bacteria and plays an important role in anti-infection immune response by regulating macrophage activity and cytokine productions. However, the mechanism by which OM85-BV enhances the cytokine expression is still obscure. In this study, we evaluated the effects of OM85-BV on the productions of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α (TNF-α) in RAW264.7 murine macrophages. Exposure of RAW264.7 cells to 100 µg/mL OM85-BV upregulated the expression of IL-1ß, IL-6, and TNF-α at the mRNA and protein levels in a time- and dose-dependent manner. In addition, OM85-BV induced extracellular signal-regulated kinase (ERK) 1/2 and nuclear factor-kappa B (NF-κB) phosphorylation. Pretreatment with U0126 or Bay11-7082, respectively, could decrease IL-1ß, IL-6, and TNF-α productions induced by OM85-BV. Application of Toll-like receptor (TLR) 4 or TLR2 small-interfering RNA (siRNA) into RAW264.7 cells could inhibit the productions of cytokines and ERK1/2 and NF-κB phosphorylation induced by OM85-BV. Consistent with this, downregulating either myeloid differentiation factor 88 (MyD88) or TRIF-related adaptor molecule (TRAM) gene with MyD88-siRNA or TRAM-siRNA separately could reduce the productions of cytokines and ERK1/2 and NF-κB phosphorylation induced by OM85-BV. Our study demonstrated that the productions of IL-1ß, IL-6, and TNF-α induced by OM85-BV in RAW264.7 cells were through TLR4 and TLR2 signaling pathway-mediated activation of ERK1/2 and NF-κB.