[Predictive value of four items of new thrombus markers combined with conventional coagulation tests for thrombosis in antiphospholipid syndrome].

OBJECTIVE: To explore the predictive value of four items of new thrombus markers combined with conventional coagulation tests for thrombosis in antiphospholipid syndrome. METHODS: A total of 121 antiphospholipid syndrome (APS) patients who hospitalized at Peking University People's Hospital from March 2022 to January 2023 were selected and divided into thrombus group (50 cases) and nonthrombus group (71 cases) according to whether thrombosis occurred. The differences of laboratory characteristics including antiphospholipid antibodies were compared between the thrombotic and non-thrombotic groups. Chemiluminescent immunoassay was used to detect thrombomodulin (TM), thrombin-antithrombin complex (TAT), Plasmin-α2 plasmin inhibitor complex (PIC), and tissue plasminogen activator inhibitor complex (t-PAIC) in plasma from venous. The independent risk factors of thrombosis in patients with APS were determined using binary Logistic regression. Receiver operating characteristic (ROC) curve analysis was applied to evaluate the efficacy of each index on the prediction of thrombosis. RESULTS: Compared with the patients without thrombosis, the patients with thrombosis were older [49 (32, 64) years vs. 36 (32, 39) years, P < 0.05]. The percentages of male, smoking, hypertension, and global antiphospholipid syndrome score (GAPSS)≥10 in the patients with thrombosis were significantly higher than those in the patients without thrombosis (P < 0.05). The positive rates of anticardiolipin antibody (aCL) and lupus anticoagulant (LA) in the thrombotic group were significantly higher than those in the non-thrombotic group (P < 0.05), and the levels of prothrombin time, activated partial thromboplastin time, fibrinogen, fibrin degradation product in the thrombotic group were significantly higher than those in the non-thrombotic group (P < 0.05).Among the thrombosis group, venous thrombosis accounted for 19 (38.00%), including deep vein thrombosis (16, 84.21%) and pulmonary embolism accounted (5, 26.32%); Arterial thrombosis accounted for 35 (70.00%), including myocardial infarction (6, 17.14%) cerebral infarction (30, 85.71%). The patients in the thrombotic group had significantly greater TM levels than those in the non-thrombotic group (P < 0.05).There were no significant dif-ferences between the two groups in TAT (Z=-1.420, P=0.156), PIC (Z=-0.064, P=0.949), and t-PAIC (Z=-1.487, P=0.137). Univariate and binary Logistic regression analysis of relevant variables showed that advanced age [OR=1.126, P=0.002], elevated TM [OR=1.325, P=0.048], prolonged prothrombin time (PT) [OR=4.127, P=0.008] were independent risk factors for thrombosis in the patients with APS. ROC curve analysis of the above three independent risk factors showed that the combined detection of age, PT and TM had the highest Yoden index (0.727) and sensitivity (83.0%), with a specificity of 89.7%. CONCLUSION: TAT, PIC, TM, and t-PAIC may reflect thrombus formation from the coagulation system, fibrinolysis system, and endothelial system. The combined of age TM and PT is superior to the application of a single marker, which has diagnostic value for the early identification of APS thrombosis.

Microarray meta-analysis reveals comprehensive effects of 3,4,5-tricaffeolyquinic acid in cell differentiation and signaling.

Caffeoylquinic acids (CQA) are polyphenolic compounds found in fruits, vegetables, coffee, and spices that have exhibited several beneficial activities, including antioxidant, antibacterial, neuroprotective, anti-inflammatory, anticancer, antiviral, antidiabetic, and cardiovascular effects. A derivative, TCQA (3,4,5-Tri-O-caffeoylquinic acid), has also shown both neurogenic and pigment differentiation potential. A transcriptomic-based meta-analysis was conducted to explore potential biochemical processes and molecular targets of TCQA. This approach involved integrating data from various cell and tissue types, including human amniotic stem cells, human neural stem cells, human dermal papilla cells, and the brain cortex of aging model mice. It offered a comprehensive perspective on the significant gene regulations in response to TCQA treatment. The objective was to uncover the mechanism and novel targets of TCQA, facilitating a further understanding of its functions. New areas of interest found were TCQA's effect on adipogenesis, heart, and muscle tissue development. In addition, significantly enhanced biological activities found through meta-analysis included cell cycle, VEGFA-VEGFR2 pathway, and BMP signaling. Overall, a comprehensive functional and visual analysis using available biological databases uncovered the multi-target potential of this natural compound.

Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy.

Immune-responsive gene 1 (IRG1) encodes aconitate decarboxylase (ACOD1) that catalyzes the production of itaconic acids (ITAs). The anti-inflammatory function of IRG1/ITA has been established in multiple pathogen models, but very little is known in cancer. Here, we show that IRG1 is expressed in tumor-associated macrophages (TAMs) in both human and mouse tumors. Mechanistically, tumor cells induce Irg1 expression in macrophages by activating NF-κB pathway, and ITA produced by ACOD1 inhibits TET DNA dioxygenases to dampen the expression of inflammatory genes and the infiltration of CD8+ T cells into tumor sites. Deletion of Irg1 in mice suppresses the growth of multiple tumor types and enhances the efficacy of anti-PD-(L)1 immunotherapy. Our study provides a proof of concept that ACOD1 is a potential target for immune-oncology drugs and IRG1-deficient macrophages represent a potent cell therapy strategy for cancer treatment even in pancreatic tumors that are resistant to T cell-based immunotherapy.

Epigenetic regulation of cutaneous T-cell lymphoma is mediated by dysregulated lncRNA MALAT1 through modulation of tumor microenvironment.

Cutaneous T-Cell Lymphoma (CTCL) is a rare non-Hodgkin lymphoma marked by migration of T-lymphocytes to the skin. It has many subtypes some of which are aggressive with documented metastasis. We investigated a possible role of lncRNA MALAT1 in CTCL cells because of its documented involvement in cancer metastasis. A screening of MALAT1 in CTCL patients revealed its elevated levels in the patients, compared to healthy individuals. For our investigation, we employed HH and H9 CTCL cells and silenced MALAT1 to understand the MALAT1 mediated functions. Such silencing of MALAT1 resulted in reversal of EMT and inhibition of cancer stem cell phenotype, along with reduced cell growth and proliferation. EMT reversal was established through increased E-cadherin and reduced N-cadherin while inhibition of cancer stem cell phenotype was evident through reduced Sox2 and Nanog. CTCL patients had higher circulating levels of IL-6, IL-8, IL-10, TGFß, PGE2 and MMP7 which are factors released by tumor-associated macrophages in tumor microenvironment. MALAT1 sponged miR-124 as this tumor suppressive miRNA was de-repressed upon MALAT1 silencing. Moreover, downregulation of miR-124 attenuated MALAT1 silencing effects. Our study provides a rationale for further studies focused on an evaluation of MALAT1-miR-124 in CTCL progression.

From Ancient Medicine to Targeted Nanocarrier: A Sparganii Rhizoma-Derived Nanoparticle for Diagnostic Imaging and Endocrine Therapy in Cancer.

The traditional Chinese medicine Sparganii Rhizoma has a long history in the treatment of gynecological diseases. In our previous work, we found that an extract of Sparganii Rhizoma had antitumor activity, attributed to the aluminum-rich polysaccharide, "SpaTA", which we isolated. SpaTA can selectively regulate the estrogen receptor, but its mechanism of antitumor activity is poorly understood. In the present study, we found that SpaTA naturally exists as a nanoparticle with a regular physical morphology. SpaTA induced apoptosis in human breast cancer cells mainly through interaction with estrogen receptors, ERα and GPR30, followed by activation of the PI3K/Akt and MEK/ERK pathways. Notably, cells also adjusted their cytoskeletal plasticity in response to SpaTA, which inhibited cell motility by suppressing focal adhesion and cytoskeleton reorganization via FAK. On the basis of these antitumor effects, we further modified SpaTA by conjugating it with the near-infrared dye, ICG, and loading the particles with the TGFß inhibitor, LY2157299, to form the tumor-targeting nanomedicine, "SpaTAX". The application of SpaTAX to breast cancer models enables a dual use regimen: a single dose for fluorescence imaging of the tumor site, where SpaTAX accumulates due to the enhanced permeability and retention effect, and a multidose for antitumor treatment through estrogen receptor- and TGFß-related signaling pathways. The synergetic roles of estrogen receptors and TGFß pathways are responsible for SpaTAX-induced reinforced suppression on tumor growth. Finally, we assessed the biosafety of the formulation and found that SpaTAX is highly tolerable and may therefore be considered safe for future clinical theranostic application. Altogether, our results demonstrated a superior tumor targeting ability of SpaTA both in diagnostic imaging and endocrine therapy and also proved SpaTA as a promising nanocarrier with a high therapeutic capacity and a favorable modification potential.

Management and outcomes of pregnant patients with central nervous system hemangioblastoma.

The study aims to assess the management and maternal and fetal outcomes of pregnancies complicated by central nervous system (CNS) hemangioblastoma. Twenty-four female patients with CNS hemangioblastoma, who were pregnant in a tumor-burden status, were identified. Their medical charts, treatments, and follow-up materials were carefully reviewed. Of the included 24 CNS patients with hemangioblastoma (14 intracranial and 10 spinal hemangioblastomas), 5 patients (20.8%) were diagnosed with Von Hippel-Lindau disease (VHL). The median age of these patients at admission was 27.5 years. Intracranial hypertension was a common presenting symptom for patients with intracranial hemangioblastoma and was observed in 85.7% (12/14) of cases; the other 10 patients with spinal hemangioblastomas all suffered from paresthesia. Overall, 66.7% (16/24) of patients with CNS hemangioblastoma went through the gestational course with conventional observation; 16.6% (4/24) of patients accepted a ventriculo-peritoneal shunt (VPS) to delay the tumor resection; and 16.7% (4/24) of patients needed urgent tumor resection even when symptomatic treatments were given. Variable symptom improvement was seen when patients had follow-up visits at a median of 32.5 months. No maternal death or tumor recurrence was identified. For the fetal prognoses, one (4.2%) pregnancy ended in a spontaneous miscarriage and for (16.7%) pregnancies were interrupted; the other 19 (79.2%) live births were in good status without any congenital malformations. Symptomatic treatment was the first choice for pregnant patients with CNS hemangioblastoma. When needed, urgent tumor resection could be safely achieved with careful maternal and fetal monitoring. Both maternal and fetal prognoses were favorable during follow-up.

SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer.

Peroxisomes account for ~35% of total H2O2 generation in mammalian tissues. Peroxisomal ACOX1 (acyl-CoA oxidase 1) is the first and rate-limiting enzyme in fatty acid ß-oxidation and a major producer of H2O2 ACOX1 dysfunction is linked to peroxisomal disorders and hepatocarcinogenesis. Here, we show that the deacetylase sirtuin 5 (SIRT5) is present in peroxisomes and that ACOX1 is a physiological substrate of SIRT5. Mechanistically, SIRT5-mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation in both cultured cells and mouse livers. Deletion of SIRT5 increases H2O2 production and oxidative DNA damage, which can be alleviated by ACOX1 knockdown. We show that SIRT5 downregulation is associated with increased succinylation and activity of ACOX1 and oxidative DNA damage response in hepatocellular carcinoma (HCC). Our study reveals a novel role of SIRT5 in inhibiting peroxisome-induced oxidative stress, in liver protection, and in suppressing HCC development.