Alkylphenols disrupt estrogen homeostasis via diradical cross-coupling reactions: A novel pathway of endocrine disruption.

Estrogen, being an essential class of sex hormone, is an important target of endocrine disruption chemicals. It is well known that environmental disruptors could activate or inhibit estrogen receptors, acting as agonists or antagonists, and thus affect the circulating estrogen concentrations. Here, we report enzyme-mediated diradical cross-coupling reactions between alkylphenols (e.g., 2,4-di-tert-butylphenol [DBP], 4-nonylphenol [4-NP], and 4-tert-octylphenol [4-t-OP]) and estrogens (e.g., estradiol [E2]) that generate coupling metabolites and disrupt estrogen homeostasis. Among the phenolic xenobiotics, the screening of metabolic products revealed that alkylphenols had the highest reaction activities and generated coupling metabolites with high abundances (DBP-O-E2, 4-t-OP-O-E2, and 4-NP-O-E2). The coupling reactions were catalyzed by cytochrome P450 3A4 (CYP3A4) and verified by the detection of the coupling products in general populations. In vitro and in vivo exposures together with CYP3A4 inhibition demonstrated that cross-coupling reactions of phenols and E2 significantly reduced the normal levels of E2. We further established a unique spin-trapping-based high-throughput screening method to show the existence of diradicals in the coupling reaction. Density functional theory calculations revealed that spin aromatic delocalization was the fundamental cause of the high rebound barrier and sufficient lifetime of phenoxy radicals that enabled phenolic cross-coupling triggered by cytochrome P450. The identified mechanistic details for diradical cross-coupling reactions provide a novel pathway for phenolic chemicals to disrupt estrogen homeostasis.

Alpha lipoic acid ameliorates motor deficits by inhibiting ferroptosis in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease. Ferroptosis shares several features with PD pathophysiology, and anti-ferroptosis molecules are neuroprotective in PD animal models. As an antioxidant and iron chelating agent, alpha lipoic acid (ALA) has a neuroprotective effect on PD; however, the influence of ALA on ferroptosis in PD remains unclear. This study aimed to determine the mechanism of ALA in regulating ferroptosis in PD models. Results showed that ALA could ameliorate motor deficits in PD models and regulate iron metabolism by upregulating ferroportin (FPN) and ferritin heavy chain 1 (FTH1) and downregulating iron importer divalent metal transporter 1 (DMT1). Moreover, ALA decreased the accumulation of reactive oxygen species (ROS) and lipid peroxidation, rescued mitochondrial damage, and prevented ferroptosis effectively by inhibiting the downregulation of glutathione peroxidase 4 (GPX4) and cysteine/glutamate transporter (xCT) in PD. Mechanistic study indicated that the activation of SIRT1/NRF2 pathway was involved in the upregulation effect of GPX4 and FTH1. Thus, ALA ameliorates motor deficits in PD models by regulating iron metabolism and mitigating ferroptosis through the SIRT1/NRF2 signaling pathway.

Flap perfusion assessment with indocyanine green angiography in deep inferior epigastric perforator flap breast reconstruction: A systematic review and meta-analysis.

BACKGROUND: Indocyanine green angiography (ICG-A) has been widely applied for intraoperative flap assessment in DIEP flap breast reconstruction. However, the beneficial effect of ICG-A in DIEP flap breast reconstruction is still uncertain and no standardized protocol is available. This study aims to analyze the clinical outcome and comprehensively review protocols of this field. METHODS: A systematic review was conducted in MEDLINE, EMBASE, and Cochrane CENTRAL databases until September 15, 2022. Studies on the utility of intraoperative ICG-A in DIEP breast reconstruction were included. Data reporting reconstruction outcomes were extracted for pooled analysis. RESULTS: A total of 22 studies were enrolled in the review, among five studies with 1021 patients included in the meta-analysis. The protocols of ICG-A assessment of DIEP flap varied among studies. According to the pooled results, the incidence of postoperative fat necrosis was 10.89% (50 of 459 patients) with ICG-A and 21.53% (121 of 562 patients) with clinical judgment. The risk for postoperative fat necrosis was significantly lower in patients with intraoperative ICG-A than without (RR 0.47 95% CI 0.29-0.78, p = .004, I2 = 51%). Reoperation occurred in 5 of 48 patients (10.42%) in the ICG-A group and in 21 of 64 patients (32.82%) in the control group summarized from reports in two studies. The risk for reoperation was lower in the ICG-A group than in the control group (RR 0.41 95% CI 0.18-0.93, p = .03, I2 = 0%). Other complications, including flap loss, seroma, hematoma, dehiscence, mastectomy skin necrosis, and infection, were comparable between the two groups. Heterogeneities among studies were acceptable. No significant influence of specific studies was identified in sensitivity analysis. CONCLUSIONS: ICG-A is an accurate and reliable way to identify problematic perfusion of DIEP flaps during breast reconstruction. Protocols of ICG-A differed in current studies. Intraoperative ICG-A significantly decreases the rate of fat necrosis and reoperation in patients undergoing DIEP breast reconstruction. The synthesized results should be interpreted sensibly due to the sample size limitation. RCTs on the outcomes and high-quality studies for an optimized ICG-A protocol are still needed in the future.

TrDosePred: A deep learning dose prediction algorithm based on transformers for head and neck cancer radiotherapy.

BACKGROUND: Intensity-Modulated Radiation Therapy (IMRT) has been the standard of care for many types of tumors. However, treatment planning for IMRT is a time-consuming and labor-intensive process. PURPOSE: To alleviate this tedious planning process, a novel deep learning based dose prediction algorithm (TrDosePred) was developed for head and neck cancers. METHODS: The proposed TrDosePred, which generated the dose distribution from a contoured CT image, was a U-shape network constructed with a convolutional patch embedding and several local self-attention based transformers. Data augmentation and ensemble approach were used for further improvement. It was trained based on the dataset from Open Knowledge-Based Planning Challenge (OpenKBP). The performance of TrDosePred was evaluated with two mean absolute error (MAE) based scores utilized by OpenKBP challenge (i.e., Dose score and DVH score) and compared to the top three approaches of the challenge. In addition, several state-of-the-art methods were implemented and compared to TrDosePred. RESULTS: The TrDosePred ensemble achieved the dose score of 2.426 Gy and the DVH score of 1.592 Gy on the test dataset, ranking at 3rd and 9th respectively in the leaderboard on CodaLab as of writing. In terms of DVH metrics, on average, the relative MAE against the clinical plans was 2.25% for targets and 2.17% for organs at risk. CONCLUSIONS: A transformer-based framework TrDosePred was developed for dose prediction. The results showed a comparable or superior performance as compared to the previous state-of-the-art approaches, demonstrating the potential of transformer to boost the treatment planning procedures.

SIGIRR deficiency contributes to CD4 T cell abnormalities by facilitating the IL1/C/EBPß/TNF-α signaling axis in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a complex autoimmune disease with multiple etiological factors, among which aberrant memory CD4 T cells activation plays a key role in the initiation and perpetuation of the disease. SIGIRR (single immunoglobulin IL-1R-related receptor), a member of the IL-1 receptor (ILR) family, acts as a negative regulator of ILR and Toll-like receptor (TLR) downstream signaling pathways and inflammation. The aim of this study was to investigate the potential roles of SIGIRR on memory CD4 T cells in RA and the underlying cellular and molecular mechanisms. METHODS: Single-cell transcriptomics and bulk RNA sequencing data were integrated to predict SIGIRR gene distribution on different immune cell types of human PBMCs. Flow cytometry was employed to determine the differential expression of SIGIRR on memory CD4 T cells between the healthy and RA cohorts. A Spearman correlation study was used to determine the relationship between the percentage of SIGIRR+ memory CD4 T cells and RA disease activity. An AIA mouse model (antigen-induced arthritis) and CD4 T cells transfer experiments were performed to investigate the effect of SIGIRR deficiency on the development of arthritis in vivo. Overexpression of SIGIRR in memory CD4 T cells derived from human PBMCs or mouse spleens was utilized to confirm the roles of SIGIRR in the intracellular cytokine production of memory CD4 T cells. Immunoblots and RNA interference were employed to understand the molecular mechanism by which SIGIRR regulates TNF-α production in CD4 T cells. RESULTS: SIGIRR was preferentially distributed by human memory CD4 T cells, as revealed by single-cell RNA sequencing. SIGIRR expression was substantially reduced in RA patient-derived memory CD4 T cells, which was inversely associated with RA disease activity and related to enhanced TNF-α production. SIGIRR-deficient mice were more susceptible to antigen-induced arthritis (AIA), which was attributed to unleashed TNF-α production in memory CD4 T cells, confirmed by decreased TNF-α production resulting from ectopic expression of SIGIRR. Mechanistically, SIGIRR regulates the IL-1/C/EBPß/TNF-α signaling axis, as established by experimental evidence and cis-acting factor bioinformatics analysis. CONCLUSION: Taken together, SIGIRR deficiency in memory CD4 T cells in RA raises the possibility that receptor induction can target key abnormalities in T cells and represents a potentially novel strategy for immunomodulatory therapy.

A PD-L1 and VEGFR2 dual targeted peptide and its combination with irradiation for cancer immunotherapy.

Although the blockade of immune checkpoint PD-1/PD-L1 has achieved great success, the lack of tumor-infiltrating immune cells and PD-L1 expression in the tumor microenvironment results in a limited response in certain tumor types. Thus, rational and optimal combination strategies were urgently needed. The combination of PD-1/PD-L1 blockade and anti-angiogenic therapy has been reported to have great potential. Here, a chimeric peptide OGS was designed by conjugating the peptides OPBP-1 (8-12) and DA7R targeting PD-L1 and VEGFR2, respectively. OGS could bind to both human and mouse PD-L1 with high affinity and block the PD-1/PD-L1 interaction, and also inhibit the migration and tube formation of HUVEC cells in wound healing and tube formation assays. To further prolong the half-life of OGS, it was modified by coupling with peptide DSP which has a high binding affinity to both human serum albumin (HSA) and mouse serum albumin (MSA) to form the peptide DSPOGS. DSPOGS could not directly affect the viability, apoptosis, and cell cycle of tumor cells in vitro, while significantly inhibiting the tumor growth in the MC38 mouse model. DSPOGS could elicit a potent anti-tumor immune response and inhibit tumor angiogenesis, with the enhancement of tumor infiltrating CD8+ T cells and the IFN-γ secreting CD8+ T cells in the spleen and tumor-draining lymph node. Further, the combination of radiotherapy with DSPOGS could dramatically improve the therapeutic efficacy. Our study could provide a promising paradigm for the combination of immune checkpoint blockade, anti-angiogenesis, and radiotherapy.

Protective Effects and Mechanisms of Melatonin on Stress Myocardial Injury in Rats.

ABSTRACT: Prolonged and intense stress can exceed the body's normal self-regulation and limited compensatory and repair capacity, resulting in pathological damage to the body. In this study, we established a rat stress myocardial injury (SMI) model to explore the protective effect of melatonin (MLT) on SMI and its possible mechanisms of action. Adult female Sprague Dawley (SD) rats were randomly divided into 5 groups: blank control group (NC), SMI group, MLT low-dose group, MLT medium-dose group, and MLT high-dose group, and 10 rats in each group were used to establish a SMI model by the water immersion restraint method. We observed the changes in body weight and tail vein glucose of each group. Serum levels of corticosterone (Cort), creatine kinase isoenzyme (CK-MB), and Troponin Ⅰ (Tn-Ⅰ) and activity of lactic acid dehydrogenase were measured by ELISA. Transcriptome sequencing was used to find differentially expressed genes in the control and model groups, and the results were verified by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). HE staining was used to visualize the pathological changes in the heart tissue of each group, and Western blot was used to study the differences in protein expression in the cardiomyocytes of each group to further corroborate the results. The body weight growth rate of rats in the SMI group was significantly lower than that of the NC group ( P < 0.01), and the body weight growth rate of rats in the MLT high-dose group was significantly higher than that of the SMI group ( P < 0.05) with no significant difference compared with the NC group rats. The mean blood glucose of rats in the SMI group was significantly higher compared with the NC group ( P < 0.001), while the mean blood glucose of rats in the MLT administration groups was dose-dependently reduced compared with the SMI group. By RNA-seq and bioinformatics tools such as KEGG and Gene ontology, we found that the circadian clock-related genes Ciart , Arnt1 , Per1 , and Dbp were significantly downregulated in the SMI group during water immersion stress, and differentially expressed genes were enriched in the p38MAPK signaling pathway and p53 signaling pathway. Moreover, genes related to inflammation and apoptosis were differentially expressed. ELISA results showed that Cort, CK-MB, and Tn-Ⅰ levels were significantly higher in the SMI group compared with the NC group ( P < 0.01) and melatonin reduced the levels of Cort, CK-MB, and Tn-Ⅰ and decreased lactic acid dehydrogenase activity in rat serum. HE staining results showed that melatonin could attenuate stress-generated myocardial injury. Western blot showed that melatonin reduced the expression of p38MAPK, p53, Bax, and caspase-3 and increased the expression of Bcl-2 protein in rat heart. Melatonin can inhibit myocardial injury caused by water immersion, and its mechanism of action may be related to the regulation of the expression of circadian clock genes such as Ciart , Arnt1 , Per1 , and Dbp ; the inhibition of the expression of proapoptotic proteins such as p38MAPK, p53, Bax, and caspase-3; and the increase of the expression of Bcl-2 antiapoptotic protein.

Analysis of Granulocyte-Macrophage Colony-Stimulating Factor-Producing T Helper Cells in a Mouse Model of Contact Hypersensitivity.

Parallel to traditional Th1/Th2/Th17/Treg lineages, granulocyte-macrophage colony-stimulating factor-producing T helper (Th-GM) cells have been identified as a distinct subset of T helper cells (GM-CSF+ IFN-γ- IL-17A- IL-22- effector CD4+ T cells) in human and mice. Contact hypersensitivity (CHS) is considered an excellent animal model for allergic contact dermatitis (ACD) in human, manifesting an intact T cell-mediated immune response. To provide a standardized and comprehensive assay to analyze the Th-GM cell subset in the T cell-dependent immune response in vivo, a murine CHS model was induced by sensitization/challenge with a reactive, low-molecular-weight, organic hapten, 2,4-dinitrofluorobenzene (DNFB). The Th-GM subset in effector CD4+ T cells generated upon immunization with the hapten was analyzed by flow cytometry. We found that Th-GM was mainly expanded in lesions and draining lymph nodes in the DNFB-induced CHS mouse model. This method can be applied to further study the biology of Th-GM cells and pharmacological research of therapeutic strategies centered on GM-CSF in various conditions, such as ACD.

Repositioning Azelnidipine as a Dual Inhibitor Targeting CD47/SIRPα and TIGIT/PVR Pathways for Cancer Immuno-Therapy.

Strategies boosting both innate and adaptive immunity have great application prospects in cancer immunotherapy. Antibodies dual blocking the innate checkpoint CD47 and adaptive checkpoint PD-L1 or TIGIT could achieve durable anti-tumor effects. However, a small molecule dual blockade of CD47/SIRPα and TIGIT/PVR pathways has not been investigated. Here, an elevated expression of CD47 and PVR was observed in tumor tissues and cell lines analyzed with the GEO datasets and by flow cytometry, respectively. Compounds approved by the FDA were screened with the software MOE by docking to the potential binding pockets of SIRPα and PVR identified with the corresponding structural analysis. The candidate compounds were screened by blocking and MST binding assays. Azelnidipine was found to dual block CD47/SIRPα and TIGIT/PVR pathways by co-targeting SIRPα and PVR. In vitro, azelnidipine could enhance the macrophage phagocytosis when co-cultured with tumor cells. In vivo, azelnidipine alone or combined with irradiation could significantly inhibit the growth of MC38 tumors. Azelnidipine also significantly inhibits the growth of CT26 tumors, by enhancing the infiltration and function of CD8+ T cell in tumor and systematic immune response in the tumor-draining lymph node and spleen in a CD8+ T cell dependent manner. Our research suggests that the anti-hypertensive drug azelnidipine could be repositioned for cancer immunotherapy.

CD47/SIRPα blocking peptide identification and synergistic effect with irradiation for cancer immunotherapy.

BACKGROUND: Immunotherapy has achieved remarkable advances via a variety of strategies against tumor cells that evade immune surveillance. As important innate immune cells, macrophages play important roles in maintaining homeostasis, preventing pathogen invasion, resisting tumor cells and promoting adaptive immune response. CD47 is found to be overexpressed on tumor cells and act as a don't eat me' signal, which contributes to immune evasion. Macrophages mediated phagocytosis via blockade CD47/SIRPα (signal regulatory protein alpha) interaction was proved to induce effective antitumor immune response. METHODS: A novel peptide pep-20, specifically targeting CD47 and blocking CD47/SIRPα interaction, was identified via high-throughput phage display library bio-panning. The capability to enhance the macrophage-mediated phagocytosis activities and antitumor effects of pep-20 were investigated. The mechanism of pep-20 to induce T-cell response was explored by ex vivo analysis and confirmed via macrophage depleting strategy. The structure-activity relationship and D-amino acid substitution of pep-20 were also studied. The antitumor effects and mechanism of a proteolysis resistant D-amino acid derivate pep-20-D12 combined with irradiation (IR) were also investigated. RESULTS: Pep-20 showed remarkable enhancement of macrophage-mediated phagocytosis to both solid and hematologic tumor cells in vitro, and inhibited tumor growth in immune-competent tumor-bearing mice. Furthermore, pep-20 promoted macrophages to mobilize the antitumor T-cell response with minimal toxicity. Furthermore, systemic administration of the derivate pep-20-D12 showed robust synergistic antitumor efficacy in combination with IR. CONCLUSION: In summary, these results demonstrated that CD47/SIRPα blocking peptides, pep-20 and its derivate, could serve as promising candidates to promote macrophages-mediated phagocytosis and immune response in cancer immunotherapy.

Repositioning liothyronine for cancer immunotherapy by blocking the interaction of immune checkpoint TIGIT/PVR.

BACKGROUND: Inhibitors targeting immune checkpoint were proved effective in cancer immunotherapy, such as PD-1/PD-L1 blockade. The novel immune checkpoint TIGIT/PVR plays critical roles in suppressing the anti-tumor effects of CD8+ T and NK cells, and dual blockade of TIGIT/PVR and PD-1/PD-L1 by antibody can elicit synergistic effects in tumor models and clinical trials. However, small molecules for TIGIT/PVR blockade have not been investigated. METHODS: The expression of PVR in tumors were analyzed by using TCGA, Oncomine and GEO database, and in cancer cell lines examined by flow cytometry. Natural product compounds were docked to PVR for virtual screening by using the software Molecular Operating Environment (MOE). Candidate compounds were further tested by biolayer interferometry-based binding assay, microscale thermophoresis assay and cell based blocking assay. The in vitro activity of the candidate compound was determined by MTT, peripheral blood mononuclear cells (PBMCs) activation assay and coculture assay. The anti-tumor effects and mechanism were also investigated by using MC38 tumor-bearing mice model and immune cell depletion tumor model. RESULTS: PVR was over-expressed in many tumor tissues and cancer cell lines, making it a promising therapeutic target. Through virtual screening, binding, and blocking assay, liothyronine was discovered to bind PVR and block the interaction of TIGIT/PVR. Liothyronine could enhance the function of CD4+ and CD8+ T cells in PBMCs. Besides, in the Jurkat-hTIGIT and CHOK1-hPVR coculture assay, liothyronine could reverse the IL-2 secretion inhibition resulted by TIGIT/PVR ligation. Although had no influence on the proliferation of tumor cells in vitro, liothyronine could significantly inhibit tumor growth when administrated in vivo, by enhancing CD8+ T cell infiltration and immune responses in the tumor bearing mice. The immune cell depletion model showed that the anti-tumor effects of liothyronine depends on CD4+ T cells, CD8+ T cells and NK cells. CONCLUSIONS: A small molecule liothyronine was discovered to serve as a potential candidate for cancer immunotherapy by blocking the immune checkpoint TIGIT/PVR. Video abstract.

Alpha-Lipoic Acid Mediates Clearance of Iron Accumulation by Regulating Iron Metabolism in a Parkinson's Disease Model Induced by 6-OHDA.

The disruption of neuronal iron homeostasis and oxidative stress are related to the pathogenesis of Parkinson's disease (PD). Alpha-lipoic acid (ALA) is a naturally occurring enzyme cofactor with antioxidant and iron chelator properties and has many known effects. ALA has neuroprotective effects on PD. However, its underlying mechanism remains unclear. In the present study, we established PD models induced by 6-hydroxydopamine (6-OHDA) to explore the neuroprotective ability of ALA and its underlying mechanism in vivo and in vitro. Our results showed that ALA could provide significant protection from 6-OHDA-induced cell damage in vitro by decreasing the levels of intracellular reactive oxygen species and iron. ALA significantly promoted the survival of the dopaminergic neuron in the 6-OHDA-induced PD rat model and remarkably ameliorated motor deficits by dramatically inhibiting the decrease in tyrosine hydroxylase expression and superoxide dismutase activity in the substantia nigra. Interestingly, ALA attenuated 6-OHDA-induced iron accumulation both in vivo and in vitro by antagonizing the 6-OHDA-induced upregulation of iron regulatory protein 2 and divalent metal transporter 1. These results indicated that the neuroprotective mechanism of ALA against neurological injury induced by 6-OHDA may be related to the regulation of iron homeostasis and reduced oxidative stress levels. Therefore, ALA may provide neuroprotective therapy for PD and other diseases related to iron metabolism disorder.

Physical dosimetry reconstructions of significant radiation exposure at an industrial accelerator facility in Tianjin (China).

The goal of this thesis is to estimate the physical radiation doses for two victims who were accidently exposed to an industrial electron beam at an industrial accelerator facility on 7 July 7 2016 in Tianjin, China. On the basis of the radiation source parameters, irradiation situation and irradiation time, physical dose reconstruction was carried out at the accident site by using a Bottle-Manikin-Absorption (BOMAB) phantom and an Alderson Radiation Therapy (ART) phantom. With thermoluminscent dosimeters (TLDs), skin estimation was conducted for the feet, calves, upper arms, left side of the body and neck, and the mean dose was estimated to be 14.1 ± 5.6 Gy. The foot and leg skin received the highest dose, which was >16.3 Gy. In addition, the mean dose estimated for the eye lens was 0.18 ± 0.07 Gy. The organ effective dose estimated and the total organs effective dose estimated were 0.46-4.94 mSv and 0.21 Sv, respectively. In the course of the accident, the damage caused by the electron radiation field to the exposed person was mainly to the skin, and the contributions to other radiation-sensitive organs were small. The damage to the organs other than the skin was mainly caused by the X-rays generated by the bremsstrahlung of the electron beam from the environment or the human body.

[Alpha-lipoic acid inhibits the expression of α-synuclein in PC12 cells induced by 6-hydroxydopamine and its mechanism].

Objective To investigate the effects of α-lipoic acid (α-LA) on the expression of α-synuclein(α-syn)in cellular models of Parkinson's disease (PD) induced by 6-hydroxydopamine (6-OHDA) and its mechanism. Methods PC12 cells were induced by 6-OHDA to establish the cellular models of PD, which was treated with α-LA. Cell viability was detected using MTT assay. The contents of intracellular iron and malondialdehyde (MDA) were detected by colorimetry.The level of intracellular reactive oxygen species (ROS) was detected by 2, 7-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. Western blot analysis was performed to detect the level of α-syn protein. Results Compared with the normal control group, the cell viability of the model group was significantly decreased, the contents of intracellular iron and MDA and the level of ROS were significantly increased, and the expression level of α-syn was significantly increased; compared with the model group, the cell viability of the α-LA treat group was significantly increased, the contents of intracellular iron and MDA and the level of ROS were significantly decreased, and the expression level of α-syn was significantly decreased. Conclusion α-LA can inhibit the overexpression of α-syn and attenuate the damage of PC12 cells induced by 6-OHDA, which may be related to the decrease of contents of intracellular iron and oxidative stress level by α-LA.

Treatment and prognosis of fetal lymphangioma.

OBJECTIVE: To investigate the treatment and prognosis of fetal lymphangioma and factors that inform treatment selection. STUDY DESIGN: Retrospective analysis of 79 patients with fetal lymphangioma treated at our hospital. Treatment methods included medical termination (death in-utero), expectant treatment, surgery, and interventional sclerotherapy (including ex utero intrapartum treatment, EXIT). Methods of treatment were selected according to the location and size of the lymphangioma. RESULTS: Among the 133,322 fetuses, in 130,202 pregnant women, examined at our hospital, a lymphangioma was identified in 79. The lymphangioma was confirmed by ultrasound, magnetic resonance imaging and post-natal computed tomography, as appropriate, and pathological results obtained postoperatively or on autopsy. Septation of the mass was identified in 66 of the 79 cases (83.54%). With regard to location, the lymphangioma was located in the neck in 50 fetuses (63.29%). Interventional sclerotherapy, using bleomycin, was performed in 22 neonates, of which 3 underwent ex utero intrapartum treatment (EXIT), due to evidence of airway or esophageal obstruction, 16 underwent expectant management and 7 surgical treatment. Medical termination of the pregnancy was performed in 32 cases, and 2 fetuses died in-utero. Of the 16 cases of expectant treatment, the lesions retrogressed during the intra-uterine period in 7 cases, before the post-natal age of 6 months in 4 neonates, and before the age of 2 years in 3 neonates, with no change in the size of the lymphangioma identified in 2 cases. Of the 7 neonates who were treated surgically, relapse occurred in 1 case, which required re-operation. CONCLUSIONS: Several treatment options for lymphangioma are available, with treatment selection being based on the location and size of the lymphangioma.

Fetal Lymphangioma: Prenatal diagnosis on ultrasound, treatment, and prognosis.

OBJECTIVE: To investigate the characteristics of fetal lymphangioma, including their location, imaging features, prenatal and differential diagnoses, treatment, and prognosis. STUDY DESIGN: Imaging data of 79 patients with fetal lymphangioma treated at our hospital were obtained. Imaging modalities included prenatal and post-natal magnetic resonance imaging (MRI), prenatal and post-natal color Doppler ultrasound, and post-natal contrast-enhanced computed tomography (CT). Modalities of delivery and treatment were selected according to the location and size of lymphangioma. RESULTS: Among the 133,322 fetuses of 130,202 pregnant women examined at our hospital, 5 fetuses were misdiagnosed and the diagnosis was missed in 5 fetuses prenatally. Finally, 79 had lymphangioma, confirmed by ultrasound, MRI, post-natal CT, and pathological results obtained postoperatively or on autopsy. The diagnostic coincidence rate of lymphangioma was 88.1% (74/84 cases). Of the 79 fetuses with a lymphangioma, septation of the mass was identified in 66 cases (83.54%), with no evidence of septation in the remaining 13 fetuses (16.46%). With regard to location, the lymphangioma was located in the neck in 50 fetuses (63.29%). Interventional sclerotherapy, using bleomycin, was performed in 22 neonates, of which 3 underwent ex utero intrapartum treatment (EXIT) due to evidence of airway or esophageal obstruction (16 patients underwent expectant management; 7 surgical operation). Thirty-two fetuses underwent medical termination and 2 fetuses died in-utero. Of the 16 patients who had expectant treatment, the lesions retroregressed during the intra-uterine period in 7 fetuses, before the post-natal age of 6 months in 4 neonates, and before the age of 2 years in 3 neonates. Of the 7 neonates who were treated surgically, relapse occurred in 1 case, which required re-operation. CONCLUSIONS: Prenatal ultrasound provides a clear differential diagnosis of fetal lymphangioma. Interventional therapy should be the first-choice treatment for neonates with a lymphangioma confirmed postnatally.

[Mechanism of α-lipoic acid promoting iron efflux in substantia nigra cells of Parkinson's disease rats].

Objective To observe the effect of α-lipoic acid (α-LA) on the expressions of iron regulatory protein 2 (IRP2) and ferroportin1 (FP1) in substantia nigra of rats with Parkinson's disease (PD) and explore the mechanism by which α-LA regulates iron efflux in substantia nigra cells of PD rat models. Methods Sixty healthy male SD rats were randomly divided into a sham group (n=15) and a model group (n=45). To establish the PD model, the rats of the model group were injected with 6-hydroxydopamine (6-OHDA) into their right striatum by the stereotactic technique, and the sham operation group was injected with the same dose of normal saline. Four weeks later, 30 model rats were randomly picked and divided into a PD model group (n=15) and a PD treatment group (n=15). The PD treatment group was intraperitoneally injected with α-LA (50 mg/kg) daily for 2 weeks, and the PD model group was given the same dose of saline. After 14 days of treatment, the left forelimb use rate was tested by cylinder test. The right middle cerebral substantia nigra was taken from each group, and the expression and distribution of tyrosine hydroxylase (TH) was detected by immunohistochemical staining; the number of iron positive cells was determined by Prussian blue staining; and the levels of IRP2 and FP1 were examined by Western blotting. Results Compared with the sham operation group, the left forelimb use rate of the PD model group was significantly reduced. The number of TH positive cells significantly decreased, and the number of iron positive cells in the substantia nigra significantly increased. The level of IRP2 significantly increased, and the level of FP1 decreased remarkably. Compared with PD model group, the left forelimb use rate of the PD treatment group was significantly raised. The number of TH positive cells was significantly elevated, and the number of iron positive cells in the substantia nigra was significantly reduced. The IRP2 level decreased and the FP1 level increased. Conclusion By decreasing the IRP2 level and via the IRP2/IRE pathway, α-LA can increase FP1 level, promote the outflow of iron ions from cells, and reduce iron deposition in the substantia nigra of PD model rats, thereby alleviating brain injury in PD rats induced by 6-OHDA.

Huge fetal hepatic Hemangioma: prenatal diagnosis on ultrasound and prognosis.

BACKGROUND: Although huge fetal hepatic hemangiomas are rare, they can cause fatal complications. The purpose of this study is to describe the imaging features and prognosis of these tumors. METHODS: Imaging data were collected for 6 patients with huge fetal hepatic hemangiomas treated at our hospital. Imaging modalities included prenatal magnetic resonance imaging and ultrasound and postnatal color Doppler ultrasound and contrast-enhanced computed tomography (CT). RESULTS: Among the 93,562 fetuses of 92,126 pregnant women examined at our hospital, 6 had huge hepatic hemangiomas (incidence rate, 0.64/10,000), as confirmed via postnatal color Doppler imaging and contrast-enhanced CT. Five fetuses had solitary lesions, whereas 1 (fetus 2) had multiple lesions. Four fetuses had lesions in the right liver lobe and 1 had a lesion in the left liver lobe, and 1 (fetus 2) had lesions in both lobes. All lesions showed centripetal enhancement on postnatal contrast-enhanced CT, which was more intense peripherally. Following postnatal treatment with oral propranolol, with or without dexamethasone or interventional therapy with the medical sclerosant pingyangmycin, all lesions decreased in size, with calcification plaques appearing 6 months after treatment. CONCLUSIONS: Huge hepatic hemangiomas have typical ultrasonographic features and can be diagnosed prenatally. Treatment with propranolol, with or without dexamethasone, may result in a favorable prognosis.