Glycolysis inhibition induces anti-tumor central memory CD8+T cell differentiation upon combination with microwave ablation therapy.

Minimally invasive thermal therapy is a successful alternative treatment to surgery in solid tumors with high complete ablation rates, however, tumor recurrence remains a concern. Central memory CD8+ T cells (TCM) play important roles in protection from chronic infection and cancer. Here we find, by single-cell RNA analysis of human breast cancer samples, that although the memory phenotype of peripheral CD8+ T cells increases slightly after microwave ablation (MWA), the metabolism of peripheral CD8+ T cells remains unfavorable for memory phenotype. In mouse models, glycolysis inhibition by 2-deoxy-D-glucose (2DG) in combination with MWA results in long-term anti-tumor effect via enhancing differentiation of tumor-specific CD44hiCD62L+CD8+ TCM cells. Enhancement of CD8+ TCM cell differentiation determined by Stat-1, is dependent on the tumor-draining lymph nodes (TDLN) but takes place in peripheral blood, with metabolic remodeling of CD8+ T cells lasting the entire course of the the combination therapy. Importantly, in-vitro glycolysis inhibition in peripheral CD8+ T cells of patients with breast or liver tumors having been treated with MWA thrice leads to their differentiation into CD8+ TCM cells. Our work thus offers a potential strategy to avoid tumor recurrence following MWA therapy and lays down the proof-of-principle for future clinical trials.

1D Cu(I)-based chiral organic-inorganic hybrid material with second harmonic generation and circular polarized luminescence.

In recent years, organic-inorganic hybrid materials have demonstrated exceptional performance in nonlinear optics, attracting widespread attention. However, there are relatively few examples of coordination compounds synthesized with Cu as the metal center that exhibit excellent nonlinear optical properties. In this study, we successfully synthesized a pair of enantiomers named R/S-Cu2I2 by reacting chiral ligands with CuI. The crystal structure reveals a one-dimensional copper-iodide chain structure built by Cu2I2 clusters, and its ordered arrangement in space provides not only a strong second harmonic generation (SHG) signal (1.24 × KDP) but also a large birefringence (0.15@1064 nm). Under excitation at 395 nm, the crystals exhibit red fluorescence peaked at 675 nm. The CD spectra of R/S-Cu2I2 show a distinct mirror-symmetric Cotton effect, and their CPL signals are corresponding and opposite in the emission range, with a maximum glum of approximately ±2.5 × 10-3. Theoretical calculations using density functional theory were also carried out to enhance our understanding of the correlation between their structures and optical properties.

B Cells and IL-21-Producing Follicular Helper T Cells Cooperate to Determine the Dynamic Alterations of Premetastatic Tumor Draining Lymph Nodes of Breast Cancer.

Metastasis is the major cause of cancer-related death, and lymph node is the most common site of metastasis in breast cancer. However, the alterations that happen in tumor-draining lymph nodes (TDLNs) to form a premetastatic microenvironment are largely unknown. Here, we first report the dynamic changes in size and immune status of TDLNs before metastasis in breast cancer. With the progression of tumor, the TDLN is first enlarged and immune-activated at early stage that contains specific antitumor immunity against metastasis. The TDLN is then contracted and immunosuppressed at late stage before finally getting metastasized. Mechanistically, B and follicular helper T (Tfh) cells parallelly expand and contract to determine the size of TDLN. The activation status and specific antitumor immunity of CD8+ T cells in the TDLN are determined by interleukin-21 (IL-21) produced by Tfh cells, thus showing parallel changes. The turn from activated enlargement to suppressed contraction is due to the spontaneous contraction of germinal centers mediated by follicular regulatory T cells. On the basis of the B-Tfh-IL-21-CD8+ T cell axis, we prove that targeting the axis could activate TDLNs to resist metastasis. Together, our findings identify the dynamic alterations and regulatory mechanisms of premetastatic TDLNs of breast cancer and provide new strategies to inhibit lymph node metastasis.

Preoperative single-dose camrelizumab and/or microwave ablation in women with early-stage breast cancer: A window-of-opportunity trial.

BACKGROUND: Immune checkpoint blockade has shown low response rates for advanced breast cancer, and combination strategies are needed. Microwave ablation (MWA) may be a trigger of antitumor immunity. This window-of-opportunity trial (ClinicalTrials.gov: NCT04805736) was conducted to determine the safety and feasibility of preoperative camrelizumab (an anti-PD-1 antibody) combined with MWA in the treatment of early-stage breast cancer. METHODS: Sixty participants were randomized to preoperatively receive single-dose camrelizumab alone (n = 20), MWA alone (n = 20), or camrelizumab+MWA (n = 20). A random number table was used to allocate interventions. The primary outcome was the safety and feasibility of MWA combined with camrelizumab. FINDINGS: Camrelizumab and MWA were well tolerated alone and in combination without delays in prescheduled surgery. No treatment-related grade III/IV adverse events were observed. Different from in the single-dose camrelizumab or MWA group, participants showed stable counts of blood cells after combination therapy. After combination therapy, peripheral CD8+ T cells showed enhanced cytotoxic and effect-memory functions. Clonal expansional CD8+ T cells showed higher cytotoxic activity and effector memory- and tumor-specific signatures than emergent clones after combination therapy. Enhanced interactions between clonal expansional CD8+ T cells and monocytes were observed, suggesting that monocytes contributed to the enhanced functions of clonal expansional CD8+ T cells. Major histocompatibility complex (MHC) class I-related pathways and interferon signaling pathways were activated in monocytes by combination therapy. CONCLUSIONS: Camrelizumab combined with MWA was feasible for early-stage breast cancer. Peripheral CD8+ T cells were activated after combination therapy, dependent on monocytes with activated MHC class I pathways. FUNDING: This study was supported by the Natural Science Foundation of Jiangsu Province (BK20230017).

Typical Zollinger-Ellison syndrome-atypical location of gastrinoma and absence of hypergastrinemia: A case report and review of literature.

BACKGROUND: Zollinger-Ellison syndrome (ZES) results from hypersecretion of gastrin from pancreatic or duodenal neuroendocrine tumors, commonly referred to as gastrinomas. The high levels of gastrin lead to a typical presentation involving watery diarrhea and multiple ulcers in the duodenum. Here, we have presented the rare case of a patient with ZES and absence of hypergastrinemia as well as an atypical location of gastrinoma. CASE SUMMARY: A 72-year-old woman presented with the typical clinical manifestations of ZES, including upper abdominal pain, significant watery diarrhea, and acidic liquid vomitus. Surprisingly, however, she did not have an increased level of serum gastrin. In addition, there was no evidence of gastrinoma or any other ulcerogenic tumor. Esophagogastroduodenoscopy was conducted to examine the upper digestive tract. Revised diagnoses were considered, and an individualized treatment plan was developed. The patient responded to antacid medication while experiencing intermittent, recurring bouts of ZES. 18F-AlF-NOTA-octreotide positron emission tomography (18F-OC PET)/computed tomography (CT) helped locate the tumor. Postoperative pathology and immunohistochemistry results suggested that the tumor was a gastrinoma located at an unconventional site. CONCLUSION: This present case study demonstrates the possibility of ZES-like manifestation in patients with absence of hypergastrinemia. 18F-OC PET/CT is a relatively new imaging technique that can be applied for diagnosing even tiny gastrinomas that are atypical in terms of location.

Achieving gas pressure-dependent luminescence from an AIEgen-based metal-organic framework.

Materials exhibiting aggregation-induced emission (AIE) behaviour enable strong emission in solid state and can respond to various external stimuli, which may facilitate the development of materials for optical sensing, bioimaging or optoelectronic devices. Herein, we use an AIE luminogen 2',5'-diphenyl-[1,1':4',1"-terphenyl]-4,4"-dicarboxylic acid as the ligand to prepare an AIEgen-based MOF (metal-organic framework) named FJI-H31. FJI-H31 exhibits bright luminescence under ambient conditions (under air and at room temperature), but almost no emission is observed under vacuum. Our investigation shows that the emission intensity displays a smooth and reversible enhancement with increased gas pressure, which may be attributed to the restriction of intramolecular motion brought by structural deformation under pressure stimulus. Unlike most pressure-responsive MOFs, the luminescence reverts to its original state once gas pressure recovers. By virtue of its unique optical properties, a luminescent MOF with sensing ability of gas-pressure is realized.

Landscape of the Peripheral Immune Response Induced by Local Microwave Ablation in Patients with Breast Cancer.

Minimally invasive thermal therapies have been attempted in the treatment of breast cancer, and the immune response induced by these therapies has not been fully reported. A clinical trial is performed to determine the effect of microwave ablation (MWA) in the treatment of early-stage breast cancer. The authors perform single-cell RNA sequencing on peripheral blood mononuclear cells (PBMCs) from six patients before and after ablation. NK and CD8+ T cells are activated by MWA of breast cancer, with the increased inhibitory signature of CD8+ T cells but not dysfunctional. Enhanced co-stimulatory signature of CD4+ T cells is observed and increased frequency of ICOS+ CD4+ T cells after MWA is confirmed by flow cytometric analysis. After ablation, T-cell clones expand with increased T-cell receptor diversities. Activated antigen receptor-mediated signaling pathways are found in B cells. Enhanced interactions between B cells and CD4+ T cells are found, indicating that B cells are important antigen-presenting cells that initiate CD4+ T cells in MWA-induced immune response. Blockade of CTLA-4 or PD-1 of post-MWA PBMCs show higher T-cell activity than that of pre-MWA PBMCs. This study provide global characteristics of MWA-induced systemic immune response and pave a way for the identification of potential targets to improve the immune response.

White-Light Emission and Circularly Polarized Luminescence from a Chiral Copper(I) Coordination Polymer through Symmetry-Breaking Crystallization.

Achieving white-light emission, especially white circularly polarized luminescence (CPL) from a single-phase material is challenging. Herein, a pair of chiral CuI coordination polymers (1-M and 1-P) have been prepared by the asymmetrical assembly of achiral ligands and Cu2 I2 clusters. The compounds display dual emission bands and can be used as single-phase white-light phosphors, achieving a "warm"-white-light-emitting diode with an ultra-high color rendering index (CRI) of 93.4 and an appropriate correlated color temperature (CCT) of 3632 K. Meanwhile, corresponding CPL signals with maximum dissymmetry factor |glum |=8×10-3 have been observed. Hence, intrinsic white-light emission and CPL have been realized simultaneously in coordination polymers for the first time. This work gains insight into the nature of chiral assembly from achiral units and offers a prospect for the development of single-phase white-CPL materials.

Stepwise chemical oxidation to access ultrathin metal (oxy)-hydroxide nanosheets for the oxygen evolution reaction.

Incorporation of ultrathin nanosheets with dopants/defects shows great potential to enable metal (oxy)-hydroxide electrocatalysts with enhanced oxygen evolution reaction (OER) performance via the regulation of atomic structure and bonding arrangements. However, it remains challenging in synthesis especially for such dual control and at large scale. In this study, we present a stepwise chemical oxidation route, involving phase transition and reconstruction processes, to access ultrathin CoOOH nanosheets with a thickness of ca. 4 nm and abundant oxygen vacancies. Other transition metals were also doped into CoOOH nanosheets through this strategy. Among them, the optimized FeCoOOH nanosheets demonstrated an efficient OER activity with overpotential as low as 252 mV (current density: 10 mA cm-2) and excellent stability. A high and stable solar-to-hydrogen efficiency of 10.5% was acquired when FeCoOOH nanosheets were used as the anode in a constructed water splitting device driven by solar energy. This study offers a noble and facile strategy for potentially scalable preparation of atom-modulated ultrathin metal (oxy)-hydroxide nanosheets, and also demonstrates the OER applications.

Precision Breast-Conserving Surgery With Microwave Ablation Guidance: A Pilot Single-Center, Prospective Cohort Study.

INTRODUCTION: Negative margins in breast-conserving surgery (BCS) are essential for preventing recurrence. The aim of this study was to determine the use of preoperative microwave ablation (MWA) in the guidance of BCS for early-stage breast cancer and access whether MWA could influence the rates of positive resection margins. METHODS: From 2016 to 2018, 22 women with T1/T2 invasive breast cancer were enrolled for MWA prospectively in the guidance of BCS. US-guided MWA was performed under local anesthesia, followed by BCS and sentinel lymph node biopsy (SLNB) one week after ablation. Women who underwent palpation-guided BCS directly were included as control, and propensity score matching analysis was applied. RESULTS: MWA was performed in 22 patients. Of the 21 MWA cases with effect information, the mean tumor size in US was 20.9 ± 6.2 mm (6-37 mm). Compared with control group (BCS directly), a lower rate of positive/close margins was observed in MWA guidance group (P = 0.018), and MWA caused a higher rate of accurate surgery (the largest margin ≤ 3 cm and the smallest margin ≥ 1mm, P = 0.042). Of these 21 patients treated with MWA, 18 were candidates for SLNB. And sentinel lymph nodes were successfully identified in all cases, and no recurrence was found with a mean follow-up of 23 months. CONCLUSION: For patients with T1/T2 breast cancer, the application of preoperative MWA could guide BCS accurately without impairing SLNB. Clinical trials with long-term results are required to validate MWA in the guidance for breast cancer excision.

Phosphatidylserine-exposing tumor-derived microparticles exacerbate coagulation and cancer cell transendothelial migration in triple-negative breast cancer.

Background: Neoadjuvant chemotherapy is relevant to the formation of thromboembolism and secondary neoplasms in triple-negative breast cancer (TNBC). Chemotherapy-induced breast cancer cell-derived microparticles (BCMPs) may have important thrombogenic and pro-metastatic effects on platelets and endothelium, which may be related to the expression and distribution of phosphatidylserine (PS). However, investigating these interactions is challenging due to technical limitations. Methods: A study was conducted in 20 healthy individuals and 18 patients who had been recently diagnosed with TNBC and were undergoing neoadjuvant chemotherapy with doxorubicin and cyclophosphamide. BCMPs were isolated from patient blood samples and doxorubicin-treated breast cancer cell lines. Their structure and morphology were studied by electron microscopy and antigen levels were measured by fluorescence-activated cell sorting. In an inhibition assay, isolated BCMPs were pretreated with lactadherin or tissue factor antibodies. Platelets isolated from healthy subjects were treated with BCMPs and coagulation time, fibrin formation, and expression of intrinsic/extrinsic factor Xase (FXa) and thrombin were evaluated. The effects of BCMPs on endothelial thrombogenicity and integrity were assessed by confocal microscopy, electron microscopy, measurement of intrinsic/extrinsic FXa, prothrombinase assay, and transwell permeability assay. Results: Neoadjuvant chemotherapy significantly increased the expression of PS+ BCMPs in patient plasma. Its expression was associated with a rapid increase in procoagulant activity. Treatment with lactadherin, a PS-binding scavenging molecule, markedly reduced the adhesion of BCMPs and abolished their procoagulant activity, but this was not observed with tissue factor antibody treatment. Intravenous injection of BCMPs in mice induced a significant hypercoagulable state, reducing the extent of plasma fibrinogen and promoting the appearance of new thrombus. Cancer cells incubated with doxorubicin released large numbers of PS+ BCMPs, which stimulated and transformed endothelial cells into a procoagulant phenotype and increased the aggregation and activation of platelets. Moreover, cancer cells exploited this BCMP-induced endothelial leakiness and showed promoted metastasis. Pretreatment with lactadherin increased uptake of both PS+ BCMPs and cancer cells by endothelial cells and limited the transendothelial migration of cancer cells. Conclusion: Lactadherin, a biosensor that we developed, was used to study the extracellular vesicle distribution of PS, which revealed a novel PS+ BCMPs administrative axis that initiated a local coagulation cascade and facilitated metastatic colonization of circulating cancer cells.

Microwave ablation induces Th1-type immune response with activation of ICOS pathway in early-stage breast cancer.

BACKGROUND: Despite great advances in the treatment of breast cancer, innovative approaches are still needed to reduce metastasis. As a minimally invasive local therapy (not standard therapy for breast cancer), microwave ablation (MWA) has been attempted to treat breast cancer, but the local effect and immune response induced by MWA have seldom been reported. METHODS: The clinical study was performed to determine the complete ablation rate of MWA for early-stage breast cancer. Secondary endpoints included safety and antitumor immune response. 35 subjects from this clinical study were enrolled in the current report, and the local effect was determined by pathological examinations or follow-up. To investigate MWA-induced immune response, patients treated with surgery (n=13) were enrolled as control, and blood samples were collected before and after MWA or surgery. The immune cell populations, serum cytokines, secretory immune checkpoint molecules, and T-cell receptor sequencing were analyzed. RESULTS: Of 35 enrolled patients, 32 (91.4%) showed complete ablation. Compared with surgery, MWA induced significantly increased levels of inducible co-stimulator (ICOS)+ activated CD4+ T cells and serum interferon gamma, indicating a shift in the Th1/Th2 balance toward Th1. The activated ICOS pathway was involved in the MWA-induced adaptive immune response. T-cell receptor sequencing revealed MWA of primary tumor activated T lymphocytes expansion and recognized some cancer-specific antigens. Moreover, CD4+ effector memory T-cell response was induced by MWA, and the immune response still existed after surgical resection of the ablated tumor. CONCLUSIONS: MWA may not only be a promising local therapy but also a trigger of antitumor immunity for breast cancer, opening new avenues for the treatment of breast cancer. Combinatorial strategy using additional agents which boost MWA-induced immune response could be considered as potential treatment for clinical study for early breast cancer therapy.

Construction of a Stable Lanthanide Metal-Organic Framework as a Luminescent Probe for Rapid Naked-Eye Recognition of Fe3+ and Acetone.

Four lanthanide metal-organic frameworks (Ln-MOFs), namely {[Me2NH2][LnL]·2H2O}n (Ln = Eu 1, Tb 2, Dy 3, Gd 4), have been constructed from a new tetradentate ligand 1-(3,5-dicarboxylatobenzyl)-3,5-pyrazole dicarboxylic acid (H4L). These isostructural Ln-MOFs, crystallizing in the monoclinic P21/c space group, feature a 3D structure with 7.5 Å × 9.8 Å channels along the b axis and the point symbol of {410.614.84} {45.6}2. The framework shows high air and hydrolytic stability, which can keep stable after exposed to humid air for 30 days or immersed in water for seven days. Four MOFs with different lanthanide ions (Eu3+, Tb3+, Dy3+, and Gd3+) ions exhibit red, green, yellow, and blue emissions, respectively. The Tb-MOF emitting bright green luminescence can selectively and rapidly (<40 s) detect Fe3+ in aqueous media via a fluorescence quenching effect. The detection shows excellent anti-inference ability toward many other cations and can be easily recognized by naked eyes. In addition, it can also be utilized as a rapid fluorescent sensor to detect acetone solvent as well as acetone vapor. Similar results of sensing experiments were observed from Eu-MOF. The sensing mechanism are further discussed.

Discontinuous moving shot technique for conformal thermal ablation in an ex vivo porcine liver model.

PURPOSE: We aimed to determine the ablation characteristics of discontinuous moving shot technique (DMST) in microwave ablation (MWA), radiofrequency ablation (RFA) and laser ablation (LA), and analyze the differences compared with fixed electrode technique (FET) in an ex vivo porcine liver model. METHODS: FET was defined as the ablation needle remaining fixed during ablation. In DMST, ablation needle moved backward for a fixed distance twice along the long axis during ablation. Four moving distances (0.5 cm, 0.75 cm, 1 cm and 2 cm) were used in DMST. Long-axis diameter (LAD) and short-axis diameter (SAD) of ablation zones were measured. The ratio of LAD/SAD was calculated. RESULTS: The shape and size of ablation zones were different between DMST and FET. Compared with FET, DMST could achieve greater LAD when the moving distance became long enough. In MWA with DMST, SAD decreased with the extension of moving distance and finally became smaller than the SAD in FET. While in LA and RFA, the change of moving distance did not affect SAD significantly. CONCLUSION: In MWA, RFA and LA, the characteristics of ablation zone of DMST were different from that of FET. This unique ablation technique may be suitable for conformal thermal ablation.

Comparison of Survival Outcomes Among Patients With Breast Cancer With Distant vs Ipsilateral Supraclavicular Lymph Node Metastases.

Importance: There is a lack of studies exploring whether the survival of patients with distant lymph node metastases (DLNM) is different from that of patients with ipsilateral supraclavicular lymph node metastases (ISLM) and other stage IV breast cancer. Objective: To assess the survival of patients with DLNM from breast cancer vs ISLM and other stage IV breast cancer. Design, Setting, and Participants: This cohort study included 2033 patients diagnosed with breast cancer between January 1, 2010, and December 31, 2014, from the Surveillance, Epidemiology and End Results registries database. Three groups of patients were included: (1) patients with ISLM without any distant metastasis, (2) patients with DLNM, and (3) patients with distant metastases (DLNM excluded). Patients younger than 18 years or older than 100 years were excluded. The data were analyzed in February 2020. Exposures: Surgery for primary tumor, surgery for distant lymph nodes, and radiotherapy. Main Outcomes and Measures: Overall survival (OS) and breast cancer-specific survival (BCSS). Results: Of the 2033 women (mean [SD] age, 62.03 [14.62] years [range, 23.00-99.00 years]; 1510 White participants [74.3%]) with breast cancer included in the study, 346 patients (17.0%) had DLNM, 212 (10.4%) had ISLM, and 1475 (72.6%) had distant metastases (DLNM excluded). The 3-year BCSS rates were 63.24% for ISLM, 64.54% for DLNM, and 41.20% for distant metastases. The 3-year OS rates were 53.46% for ISLM, 62.67% for DLNM, and 38.21% for distant metastases. Compared with patients with ISLM, patients with DLNM showed similar BCSS (hazard ratio [HR], 0.81; 95% CI, 0.52-1.25; P = .34) and OS (HR, 0.73; 95% CI, 0.51-1.05; P = .09), whereas patients with distant metastases showed significantly poorer BCSS (HR, 1.99; 95% CI, 1.43-2.78; P < .001) and OS (HR, 1.79; 95% CI, 1.35-2.38; P < .001). Of the 346 patients with DLNM, primary surgery (HR, 0.21; 95% CI, 0.12-0.39; P < .001) and radiotherapy (HR, 0.46; 95% CI, 0.25-0.87; P = .02) were significantly associated with improved OS. Conclusions and Relevance: The results of this cohort study suggest that DLNM of breast cancer, with similar survival to N3c disease (indicating metastases to the ipsilateral supraclavicular lymph nodes), might be a regional disease, and reassessment of the role of lymph node metastases in breast cancer may be necessary. Given these findings, aggressive locoregional therapies for this disease are recommended, although future studies are still needed to confirm these results.

Microwave ablation of primary breast cancer inhibits metastatic progression in model mice via activation of natural killer cells.

Surgery is essential for controlling the symptoms and complications of stage IV breast cancer. However, locoregional treatment of primary tumors often results in distant progression, including lung metastasis, the most common type of visceral metastasis. As a minimally invasive thermal therapy, microwave ablation (MWA) has been attempted in the treatment of breast cancer, but the innate immune response after MWA has not yet been reported. Using two murine models of stage IV breast cancer, we found that MWA of primary breast cancer inhibited the progression of lung metastasis and improved survival. NK cells were activated after MWA of the primary tumor and exhibited enhanced cytotoxic functions, and the cytotoxic pathways of NK cells were activated. Depletion experiments showed that NK cells but not CD4+ or CD8+ T cells played a pivotal role in prolonging survival. Then, we found that compared with surgery or control treatment, MWA of the primary tumor induced completely different NK-cell-related cytokine profiles. Macrophages were activated after MWA of the primary tumor and produced IL-15 that activated NK cells to inhibit the progression of metastasis. In addition, MWA of human breast cancer stimulated an autologous NK-cell response. These results demonstrate that MWA of the primary tumor in metastatic breast cancer inhibits metastatic progression via the macrophage/IL-15/NK-cell axis. MWA of the primary tumor may be a promising treatment strategy for de novo stage IV breast cancer, although further substantiation is essential for clinical testing.

Neutrophil extracellular traps enhance procoagulant activity and thrombotic tendency in patients with obstructive jaundice.

BACKGROUND & AIMS: Patients with obstructive jaundice (OJ) are considered to be prothrombotic with increased risk of thromboembolism complications. The role of neutrophil extracellular traps (NETs) in procoagulant activity (PCA) and thrombosis risk in patients with OJ is unclear. In this study, we investigated NETs formation in OJ patients and the role of elevated unconjugated bilirubin (UCB) in inducing NETs, resulting in enhanced PCA and endothelial injury. METHODS: NETs of OJ patients and healthy controls were measured. NETs PCA was assessed via coagulation time (CT), fibrin formation and purified coagulation complex production assays. Visualization of NETs and mitochondrial reactive oxygen species (MitoROS) were performed with a fluorescence microscope. We further used confocal microscopy to quantify the exposure of phosphatidylserine (PS), fibrin strands and FVa/Xa on Human umbilical vein endothelial cells (HUVECs). RESULTS: Assessment of NETs components levels revealed greater NETs production in OJ patients than in healthy controls. Importantly, OJ-NETs were responsible for enhanced PCA. UCB induced NETs formation via MitoROS accumulation and mitochondrial mobilization. HUVECs cocultured with OJ NETs lost their cell-cell junctions and consequently converted to a procoagulant phenotype. The PCA was attenuated by using DNase I alone or in combination with lactadherin. CONCLUSIONS: Our results suggest that UCB-induced NETs play a prominent role in promoting the hypercoagulable and prothrombotic state in OJ patients. The increased MitoROS accumulation in neutrophils initiated NETosis. NETs are promising targets for indicating or improving coagulation disorders in OJ patients.

Endothelial damage and a thin intercellular fibrin network promote haemorrhage in acute promyelocytic leukaemia.

BACKGROUND: The role of vascular endothelium in acute promyelocytic leukaemia (APL) remains unknown. We aimed to investigate the mechanisms by which APL cells interact with endothelial cells (ECs) and to further explore how the endothelium affects bleeding as well as therapeutic interventions. METHOD: APL cells and an original APL cell line, NB4 cells, were used for experiments. The effects of leukaemic cells on ECs were analyzed in vitro and in vivo. Moreover, the endothelial barrier function and procoagulant activity were detected. An APL mouse model was established for in vivo studies. FINDINGS: APL cells interacted with ECs via ICAM-1 and VCAM-1 receptors to disrupt endothelial integrity. This binding activated MLCK signaling, resulting in the trans-endothelial passage of protein and red blood cells (RBCs). Combined treatment with asiatic acid or anti-adhesion receptor antibody inhibited the response of ECs to APL cells, thereby preventing APL-associated haemorrhage in vitro and in vivo. Activated ECs exhibited a procoagulant phenotype after phosphatidylserine exposure. Plasma from APL patients formed a thin fibrin network between procoagulant ECs, and this intercellular fibrin decreased the passage of albumin and RBCs. Ex vivo addition of fibrinogen further enhanced this barrier function in a dose-dependent manner. INTERPRETATION: Endothelial damage induced by leukaemic cell adherence promotes haemorrhaging in APL. Stabilization of ECs, decreasing adhesion receptor expression, and increasing fibrinogen transfusion levels may be a new therapeutic avenue to alleviate this fatal bleeding complication. FUNDING: National Science Foundation of China (81670128, 81873433).

Boosting water oxidation activity by tuning the proton transfer process of cobalt phosphonates in neutral solution.

Water oxidation is a vital step in both natural and artificial photosynthetic processes. However, the effect of second coordination sphere for efficient oxygen evolution electrocatalysts has rarely been studied, becoming a bottleneck in many energy-related issues. In this article, the cobalt phosphonate (NH3C6H4NH3)Co2(hedpH)2·H2O (Co-PDA) displayed decent electrocatalytic water oxidation activity in 50 mM PBS solution (pH 7.0), comparable to the activity of state-of-the-art IrO2. Moreover, it exhibited a 160 mV lower onset potential and 6 times higher TOF than those of the counterpart, (NH4)2Co2(hedpH)2 (Co-NH4+), which existed with the same Co active center, while surrounded by different ligands. The related mechanistic studydemonstrates that the ligand in Co-PDA would benefit the proton-coupled electron transfer (PCET) processes and the formation of high valence state Co(iv).

Constructing multi-cluster copper(i) halides using conformationally flexible ligands.

Three unprecedented multi-cluster copper(i) halides (MCCHs) have been assembled using conformationally flexible ligands. Further explorations demonstrate that the conformational compliance of the ligands may be the key to trap and stabilize the various copper(i)-halide clusters in one system, which opens a new way for the construction of multi-Cu(i)-cluster complexes. Moreover, the MCCHs show distinctive temperature-dependent photoluminescence.