Construction of Bi2WO6/g-C3N4 Z-Scheme Heterojunction and Its Enhanced Photocatalytic Degradation of Tetracycline with Persulfate under Solar Light.

Z-scheme heterojunction Bi2WO6/g-C3N4 was obtained by a novel hydrothermal process; its photocatalysis-persulfate (PDS) activation for tetracycline (TC) removal was explored under solar light (SL). The structure and photoelectrochemistry behavior of fabricated samples were well characterized by FT-IR, XRD, XPS, SEM-EDS, UV-vis DRS, Mott-Schottky, PL, photocurrent response, EIS and BET. The critical experimental factors in TC decomposition were investigated, including the Bi2WO6 doping ratio, catalyst dosage, TC concentration, PDS dose, pH, co-existing ion and humic acid (HA). The optimum test conditions were as follows: 0.4 g/L Bi2WO6/g-C3N4 (BC-3), 20 mg/L TC, 20 mg/L PDS and pH = 6.49, and the maximum removal efficiency of TC was 98.0% in 60 min. The decomposition rate in BC-3/SL/PDS system (0.0446 min-1) was 3.05 times higher than that of the g-C3N4/SL/PDS system (0.0146 min-1), which might be caused by the high-efficiency electron transfer inside the Z-scheme Bi2WO6/g-C3N4 heterojunction. Furthermore, the photogenerated hole (h+), superoxide (O2•-), sulfate radical (SO4•-) and singlet oxygen (1O2) were confirmed as the key oxidation factors in the BC-3/SL/PDS system for TC degradation by a free radical quenching experiment. Particularly, BC-3 possessed a wide application potential in actual antibiotic wastewater treatment for its superior catalytic performance that emerged in the experiment of co-existing components.

ACSL4: a double-edged sword target in multiple myeloma, promotes cell proliferation and sensitizes cell to ferroptosis.

Overactive fatty acid metabolism is usually found in hematological malignancies including multiple myeloma (MM), but the underlying mechanisms remain unclear. Here, we reveal that acyl-CoA synthetase long-chain family member 4 (ACSL4) is abnormally overexpressed in MM cell lines and MM patients compared to healthy donors. Knockdown of ACSL4 inhibited MM cell proliferation and reduced fatty acid levels possibly by regulating lipid metabolism genes including c-Myc and sterol regulatory element binding proteins (SREBPs). As a propellent in ferroptosis, ACSL4 also determines the sensitivity of MM cells to ferroptosis inducer RSL3. Knockdown of ACSL4 rendered MM cells resistance to ferroptosis. Our findings suggest that ACSL4 is a double-edged sword target in MM. Based on the high expression of ACSL4, ferroptosis induction represents a promising therapeutic strategy for MM.

FTO promotes multiple myeloma progression by posttranscriptional activation of HSF1 in an m6A-YTHDF2-dependent manner.

N6-methyladenosine (m6A), as the most pervasive internal modification of eukaryotic mRNA, plays a crucial role in various cancers, but its role in multiple myeloma (MM) pathogenesis has not yet been investigated. In this study, we revealed significantly decreased m6A methylation in plasma cells (PCs) from MM patients and showed that the abnormal m6A level resulted mainly from upregulation of the demethylase fat mass and obesity-associated protein (FTO). Gain- and loss-of-function studies demonstrated that FTO plays a tumor-promoting and pro-metastatic role in MM. Combined m6A and RNA sequencing (RNA-seq) and subsequent validation and functional studies identified heat shock factor 1 (HSF1) as a functional target of FTO-mediated m6A modification. FTO significantly promotes MM cell proliferation, migration, and invasion by targeting HSF1/HSPs in a YTHDF2-dependent manner. FTO inhibition, especially when combined with bortezomib (BTZ) treatment, synergistically inhibited myeloma bone tumor formation and extramedullary spread in NOD-Prkdcem26Cd52il2rgem26Cd22/Nju (NCG) mice. We demonstrated the functional importance of m6A demethylase FTO in MM progression, especially in promoting extramedullary myeloma (EMM) formation, and proposed the FTO-HSF1/HSP axis as a potential novel therapeutic target in MM.

Terbutaline attenuates LPS-induced injury of pulmonary microvascular endothelial cells by cAMP/Epac signaling.

Acute lung injury (ALI), characterized by an acute onset of severe hypoxemia, is a common and devastating syndrome usually triggered by lipopolysaccharide (LPS) infection from bacteria. This study is intended to explore whether terbutaline can alleviate LPS-induced human pulmonary microvascular endothelial cell (HPMVEC) injury through cAMP/Epac signaling. LPS was utilized to induce ALI in HPMVECs, and after exposure of LPS-induced HPMVECs to terbutaline, the cellular functions including cell viability and apoptosis were measured by cell counting kit-8 and terminal deoxynucleotidyl transferase dUTP nick-end labeling. The protein expression related to cAMP/Epac signaling, apoptosis, and that of tight junction and inflammatory factors were evaluated at the same time. The effects of terbutaline on cellular functions were confirmed again after the addition of antagonists of cAMP and Epac, respectively. The levels of both cAMP and Epac reduced by LPS was concentration-dependently increased by terbutaline. The apoptosis and endothelial cell permeability damage of LPS-induced HPMVECs were enhanced after the addition of KT-5720 and ESI-09. The beneficial effects of terbutaline on alleviating the inflammation and apoptosis in HPMVECs injured by LPS are mediated by cAMP/Epac signaling, and this evidence would demonstrate the potential of terbutaline in the treatment of ALI.

Identification of distinctive long noncoding RNA competitive interactions and a six-methylated-gene prognostic signature in acute myeloid leukemia with -5/del(5q) or -7/del(7q).

BACKGROUND: Acute myeloid leukemia (AML) with -5/del(5q) or -7/del(7q) has special clinical and biological characteristics, but its molecular mechanisms and risk stratification remain unknown. METHODS: The RNA sequencing and DNA methylation of 23 patients with -5/del(5q) or -7/del(7q) and 128 patients with other subtypes of acute myeloid leukemia were obtained from The Cancer Genome Atlas (TCGA). The regulatory mechanisms of competitive endogenous RNA (ceRNA) network and DNA methylation on gene expression were explored. To find robust and specific risk stratification for this AML subtype, a prognostic model was established and evaluated through four independent data sets. RESULTS: We identified 966 differentially expressed long noncoding RNA, 2274 differentially expressed genes, and 47 differentially expressed microRNAs, and constructed a ceRNA network. After the integrated analysis of differentially methylated and expressed genes, 19 genes showed the opposite trend between the methylation variation and gene expression. An six-methylated-gene prognostic signature which highly correlated with overall survival was established, and the performance was validated by leave-one-out cross validation method and permutation test. Furthermore, the excellent prognostic value of this model was supported by an independent cohort, while specificity of this model was validated by three independent data sets, suggesting it as a predictive classifier with high efficiency for distinguishing those with -5/del(5q) or -7/del(7q) from other AML subtypes. CONCLUSIONS: The ceRNA network may provide new ideas for the diagnosis and treatment for patients with -5/del(5q) or -7/del(7q).The six-methylated-gene prognostic signature was a robust, specific, and clinically practical risk stratification for the outcome of patients with AML having -5/del(5q) or -7/del(7q).

miR-221/222-Mediated Inhibition of Autophagy Promotes Dexamethasone Resistance in Multiple Myeloma.

Inherent or acquired resistance to chemotherapeutic drugs is still an obstacle for the treatment of multiple myeloma (MM). MicroRNA dysregulation is related to the development of chemoresistance in cancers. However, its role in chemoresistance of MM is largely unknown. Here we demonstrated that miR-221/222 were upregulated in plasma cells from patients with MM, especially those with relapsed or refractory disease. Moreover, expression levels of miR-221/222 were inversely correlated with dexamethasone (Dex) sensitivity of human MM cell lines. Importantly, we found that Dex induced pro-death autophagy in MM cells and the inhibition of autophagy significantly decreased Dex-induced cell death. Mechanistically, autophagy-related gene 12 (ATG12) was identified as a novel target gene of miR-221/222, and miR-221/222 overexpression inhibited autophagy by directly targeting ATG12 and the p27kip (p27)-mammalian target of rapamycin (mTOR) pathway. Indeed, Dex treatment decreased the expression of miR-221/222, thereby activating the ATG12/p27-mTOR autophagy-regulatory axis and inducing cell death in Dex-sensitive MM cells. Furthermore, both in vitro and in vivo results showed that the inhibitions of miR-221/222 increased the expression of ATG12 and p27 and functionally induced extended autophagy and cell death of MM cells. In conclusion, our findings demonstrated the crucial role of the miR-221/222-ATG12/p27-mTOR autophagy-regulatory axis in Dex resistance of MM, and they suggest potential prediction and treatment strategies for glucocorticoid resistance.

A 4-microRNA signature for survival prognosis in pediatric and adolescent acute myeloid leukemia.

Acute myeloid leukemia (AML) is a hematologic malignancy with significant molecular heterogeneity. MicroRNAs (miRNAs) play a critical role in AML diagnosis, pathogenesis, and prognosis of AML. Little has been done to identify a miRNA signature in pediatric and adolescent patients for predicting overall survival. This study aims to identify a panel of miRNA signature that could predict the prognosis of all younger AML patients with all subtypes of AML by analyzing data from The Cancer Genome Atlas (TCGA). A total of 229 patients under 23 years with miRNA data and corresponding clinical data from TCGA database were enrolled in this study. Through conducting multivariate analysis in the training test, it was identified that the high expression of hsa-miR-509 and hsa-miR-542 were independent poor prognostic factors, whereas that of hsa-miR-146a and hsa-miR-3667 had a trend to be favorable factors. A 4-miRNA signature was constructed by these miRNAs considering the weight of each. In testing group and all 229 patients' cohort as well as 59 cytogenetically normal AML (CN-AML) patients' cohort, higher risk score was associated with shorter overall survival (OS). All results were confidential by using powerful statistical analysis. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis were carried out to further develop leukemia-relevant mechanisms supporting the model. The results indicate that the 4-miRNA-based signature is a reliable prognostic biomarker for pediatric and adolescent AML patients.

Myeloid-derived suppressor cells endow stem-like qualities to multiple myeloma cells by inducing piRNA-823 expression and DNMT3B activation.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) and cancer stem cells (CSCs) are two important cellular components in the tumor microenvironment, which may modify the cancer phenotype and affect patient survival. However, the crosstalk between MDSCs and multiple myeloma stem cells (MMSCs) are relatively poorly understood. METHODS: The frequencies of granulocytic-MDSCs (G-MDSCs) in MM patients were detected by flow cytometry and their association with the disease stage and patient survival were analyzed. RT-PCR, flow cytometry, western blot and sphere formation assays were performed to investigate the effects of G-MDSCs, piRNA-823 and DNA methylation on the maintenance of stemness in MM. Then a subcutaneous tumor mouse model was constructed to analyze tumor growth and angiogenesis after G-MDSCs induction and/or piRNA-823 knockdown in MM cells. RESULTS: Our clinical dataset validated the association between high G-MDSCs levels and poor overall survival in MM patients. In addition, for the first time we showed that G-MDSCs enhanced the side population, sphere formation and expression of CSCs core genes in MM cells. Moreover, the mechanism study showed that G-MDSCs triggered piRNA-823 expression, which then promoted DNA methylation and increased the tumorigenic potential of MM cells. Furthermore, silencing of piRNA-823 in MM cells reduced the stemness of MMSCs maintained by G-MDSCs, resulting in decreased tumor burden and angiogenesis in vivo. CONCLUSION: Altogether, these data established a cellular, molecular, and clinical network among G-MDSCs, piRNA-823, DNA methylation and CSCs core genes, suggesting a new anti-cancer strategy targeting both G-MDSCs and CSCs in MM microenvironment.

Rationally derived drug combinations with the novel Mcl-1 inhibitor EU-5346 in breast cancer.

PURPOSE: Recent studies have emphasized a key role for the anti-apoptotic Bcl-2 family member Mcl-1 in conferring tumor cell survival and drug resistance in breast cancer (BC). Mcl-1 inhibitors, such as the BH3-mimetic EU-5346, therefore represent an exciting new class of targeting agents and are a current focus of widespread cancer-drug development efforts. METHODS: ONCOMINE analysis was utilized to compare expression profiles of Bcl-2 family members across all major BC subgroups. Potential toxicities of EU-5346 were evaluated using iPS-generated cardiomyocytes, blood cells and astrocytes. The anti-BC cell activity of EU-5346-based therapies was evaluated using [3H]-thymidine uptake and spheroid-forming assays as well as immunoblotting and the Chou-Talalay method. Protein level-based activity of EU-5346, the specific anti-Bcl-2 inhibitor ABT-199 and the specific anti-Bcl-xL inhibitor WEHI-539 was verified in Mcl-1Δ/null versus Mcl-1wt/wt MEFs. RESULTS: We previously demonstrated significant anti-tumor activity of EU-5346 in all BC subtypes. Our present results go further and suggest that EU-5346 may induce limited adverse events such as cardiotoxicity, hematotoxicity, and neurotoxicity, frequently observed with other BH3 mimetics. As demonstrated by our mathematical scoring model, the prediction of EU-5643-induced IC50 not only relies on the protein level of Mcl-1 but also on Bak, Bim, and Noxa. Synergistic anti-BC activity of low-dose EU-5346 with the BH3 mimetics ABT-199 or WEHI-539 was observed only in those BC cells expressing Bcl-2 or Bcl-xL, respectively. Similarly, when combined with tamoxifen or trastuzumab, low-dose EU-5346 induced significant anti-BC activity in hormone receptor positive or Her2-positive BC cells, respectively. Finally, EU-5346 in combination with paclitaxel induced synergistic anti-BC activity in both paclitaxel-sensitive and paclitaxel-resistant TNBC cells. CONCLUSION: These data strongly support the further clinical development of EU-5346 to improve BC patient survival.

Clinical characteristics and prognosis of immunoglobulin D myeloma in the novel agent era.

Immunoglobulin D (IgD) myeloma is a rare subtype that used to lead to a poor outcome. To investigate the current clinical features, cytogenetic changes and survival of patients with IgD myeloma under novel treatments, we analysed 47 patients with IgD myeloma, 31 men and 16 women, with a median age of 54.5 years. We found that IgD myeloma was associated with higher frequencies of anaemia, renal failure, and hypercalcemia and higher levels of serum LDH compared with non-IgD myeloma. More than 90% of patients with IgD myeloma had at least one cytogenetic abnormality demonstrated by fluorescence in situ hybridisation (FISH). IGH translocations were the most common abnormalities, which were mainly caused by t(11;14). Moreover, 36.2% of patients were at the Revised International Staging System (RISS) stage III when diagnosed. Those patients had significantly shorter PFS and OS compared with patients at RISS stages I and II. In conclusion, IgD myeloma has specific clinical characteristics. The RISS grade was shown to be a simple and effective method to predict the prognosis of patients with IgD myeloma.

MicroRNA-324-5p regulates stemness, pathogenesis and sensitivity to bortezomib in multiple myeloma cells by targeting hedgehog signaling.

Chromosome 17p deletions are present in 10% of patients with newly diagnosed multiple myeloma (MM), and are associated with inferior prognosis. miR-324-5p is located on chromosome 17p, and shows diverse functions in different types of cancers. However, its role in MM is largely unknown. Here we found the expression of miR-324-5p was decreased in MM, especially in del(17p) MM. In contrast, the expression of hedgehog (Hh) signaling components was elevated, indicating a correlation between miR-324-5p and Hh signaling in MM. Hh signaling is important for the pathogenesis of MM and maintenance of MM stem cell compartment. Indeed, overexpression of miR-324-5p significantly decreased Hh signaling components Smo and Gli1, and functionally reduced cell growth, survival as well as stem cell compartment in MM. Moreover, miR-324-5p potentiated the anti-MM efficacy of bortezomib through regulating the activities of multidrug-resistance proteins and the expression of Bcl-2 family genes. Consistent results were obtained in vivo. Finally, miR-324-5p overcame the protective effect of bone marrow stromal cells on MM cells. Taken together, our data demonstrate that miR-324-5p is essential for MM pathogenesis and downregulation of miR-324-5p is a novel mechanism of Hh signaling activation in MM. Therefore, targeting miR-324-5p provides a potential therapeutic strategy for MM.

Prognostic and clinicopathological significance of long noncoding RNA HOXA11-AS expression in human solid tumors: a meta-analysis.

BACKGROUND: Recent studies have emphasized the important prognostic role of long noncoding RNAs (lncRNAs) in various types of cancers. Here we conducted a meta-analysis to investigate whether lncRNA HOXA11-AS can be served as a prognostic biomarker in human cancers. PATIENTS/METHODS: We systematically searched PubMed, Embase, ISI Web of Science, and SCOPUS for relevant studies, to investigate the prognostic significance of HOXA11-AS expression in cancer patients. Odds ratios (ORs) or hazards ratios (HRs) with corresponding 95% confidence intervals (CIs) are pooled to estimate the association between HOXA11-AS expression and clinicopathological parameters or survival of cancer patients. RESULTS: A total of eight eligible studies with 1320 cancer patients were enrolled in our meta-analysis. The results revealed that increased expression level of HOXA11-AS was significantly associated with clinicopathological parameters including more lymph node metastasis (OR = 2.06, 95% CI 1.31-3.25), advanced tumor stage (OR = 4.22, 95% CI 2.60-6.85), as well as poor tumor differentiation (OR = 2.49, 95 CI 1.47-4.20), but not correlated with age (p = 0.101) or gender (p = 0.845). In addition, cancer patients with high HOXA11-AS are prognosed to have shorter OS (pooled HR = 1.86, 95% CI 1.39-2.48) and PFS (pooled HR = 2.47, 95% CI 1.29-4.75). CONCLUSIONS: HOXA11-AS overexpression might be a convinced unfavorable prognostic factor that helps the clinical decision-making process.

Identification of long non-coding RNA competing interactions and biological pathways associated with prognosis in pediatric and adolescent cytogenetically normal acute myeloid leukemia.

BACKGROUND: LncRNAs can regulate miRNAs and mRNAs by sequestering and binding them. Indeed, many researchers have reported lncRNA mediated-competing endogenous RNAs (ceRNAs) could regulate the progression of solid tumors. However, the roles of ceRNA in acute myeloid leukemia (AML), especially in pediatric and adolescent AML, were not completely expounded. MATERIALS AND METHODS: 27 cytogenetically normal acute myeloid leukemia (CN-AML) patients under 18 years old with corresponding clinical data were selected from the cancer genome atlas (TCGA), which was a large sample sequencing database of RNA sequencing. We constructed a survival specific ceRNA network, and investigated its associations with patients' clinical information by analyzing the data from TCGA. RESULTS: We identified survival specific lncRNAs, miRNAs and mRNAs, and constructed a survival specific ceRNA network of CN-AML patients and a weighted correlation network. Furthermore, we identified 4 biological pathways associated with OS and selected the most enriched pathway 'Transcriptional misregulation in cancer' to verify that it could accurately predict younger CN-AML patients' prognosis to guide treatment. CONCLUSIONS: We successfully constructed a survival specific ceRNA network which could provide a new approach to lncRNA research in younger CN-AML. Importantly, we constructed a weighted correlation network to overcome the difficulty in biological interpretation of individual genes.

Prognostic role of neutrophil-to-lymphocyte ratio in diffuse large B cell lymphoma patients: an updated dose-response meta-analysis.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR), a biomarker for systematic inflammation, has been recently identified as a prognostic factor for various types of both solid and hematologic malignancies. Here we conducted an updated dose-response meta-analysis to investigate whether NLR can be served as a prognostic biomarker in diffuse large B cell lymphoma (DLBCL). METHODS: We systematically searched PubMed, Embase, ISI Web of Science and CNKI for relevant studies. Odds ratios or hazards ratios (HRs) with corresponding 95% confidence intervals (CIs) were pooled to estimate the association between NLR and clinicopathological parameters or survival of cancer patients. RESULTS: Eleven trials with 2515 DLBCL patients were included in the meta-analysis. The results revealed that elevated pretreatment NLR was significantly associated with elder age, advanced Ann Arbor stage, higher incidence rate of B symptoms and bone marrow involvement, and higher lactate dehydrogenase level, etc. Moreover, increased NLR also predicted poorer overall survival (HR 1.826, 95% CI 1.238-2.692) and progression-free survival/event-free survival (PFS/EFS) (HR 1.591, 95% CI 1.124-2.252). And two-stage dose-response meta-analysis revealed non-linear association between increased NLR and risk of mortality in DLBCL patients. CONCLUSION: DLBCL patients with higher NLR are more likely to have poorer prognosis than those with lower NLR.

Allogeneic stem-cell transplantation for multiple myeloma: a systematic review and meta-analysis from 2007 to 2017.

BACKGROUND: Despite recent advances, multiple myeloma (MM) remains incurable. However, the appearance of allogeneic stem cell transplantation (allo-SCT) through graft-versus-myeloma effect provides a potential way to cure MM to some degree. This systematic review aimed to evaluate the outcome of patients receiving allo-SCT and identified a series of prognostic factors that may affect the outcome of allo-SCT. PATIENTS/METHODS: We systematically searched PubMed, Embase, and the Cochrane Library from 2007.01.01 to 2017.05.03 using the keywords 'allogeneic' and 'myeloma'. RESULTS: A total of 61 clinical trials involving 8698 adult patients were included. The pooled estimates (95% CI) for overall survival (OS) at 1, 2, 3 and 5 years were 70 (95% CI 56-84%), 62 (95% CI 53-71%), 52 (95% CI 44-61%), and 46 (95% CI 40-52%), respectively; for progression-free survival were 51 (95% CI 38-64%), 40 (95% CI 32-48%), 34 (95% CI 27-41%), and 27 (95% CI 23-31%), respectively; and for treatment-related mortality (TRM) were 18 (95% CI 14-21%), 21 (95% CI 17-25%), 20 (95% CI 13-26%), and 27 (95% CI 21-33%), respectively. Additionally, the pooled 100-day TRM was 12 (95% CI 5-18%). The incidences of grades II-IV acute graft-versus-host disease (GVHD) and chronic GVHD were 34 (95% CI 30-37%) and 51 (95% CI 46-56%), respectively. The incidences of relapse rate (RR) and death rate were 50 (95% CI 45-55%) and 51 (95% CI 45-57%), respectively. Importantly, disease progression was the most major cause of death (48%), followed by TRM (44%). The results failed to show an apparent benefit of allo-SCT for standard risk patients, compared with tandem auto-SCT. In contrast, all 14 trials in our study showed that patients with high cytogenetic risk after allo-SCT had similar OS and PFS compared to those with standard risk, suggesting that allo-SCT may overcome the adverse prognosis of high cytogenetic risk. CONCLUSION: Due to the lack of consistent survival benefit, allo-SCT should not be considered as a standard of care for newly diagnosed and relapsed standard-risk MM patients. However, for patients with high-risk MM who have a poor long-term prognosis, allo-SCT may be a strong consideration in their initial course of therapy or in first relapse after chemotherapy, when the risk of disease progression may outweigh the transplant-related risks. A large number of prospective randomized controlled trials were needed to prove the benefits of these therapeutic options.

Mcl-1 confers protection of Her2-positive breast cancer cells to hypoxia: therapeutic implications.

BACKGROUND: Molecular mechanisms leading to the adaptation of breast cancer (BC) cells to hypoxia are largely unknown. The anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) is frequently amplified in BC; and elevated Mcl-1 levels have been correlated with poor prognosis. Here we investigated the pathophysiologic role of Mcl-1 in Her2-positive BC cells under hypoxic conditions. METHODS: RNA interference and a novel small molecule inhibitor, EU-5346, were used to examine the role of Mcl-1 in Her2-positive BC cell lines and primary BC cells (sensitive or intrinsically resistant to Her2 inhibitors) under hypoxic conditions (using a hypoxic incubation chamber). Mechanisms-of-action were investigated by RT-PCR, mitochondrial isolation, as well as immunoprecipitation/blotting analysis, and microscopy. The specificity against Mcl-1 of the novel small molecule inhibitor EU5346 was verified in Mcl-1(Δ/null) versus Mcl-1(wt/wt) Murine Embryonic Fibroblasts (MEFs). Proliferation, survival, and spheroid formation were assessed in response to Mcl-1 and Her2 inhibition. RESULTS: We demonstrate for a strong correlation between high Mcl-1 protein levels and hypoxia, predominantly in Her2-positive BC cells. Surprisingly, genetic depletion of Mcl-1 decreased Her2 and Hif-1α levels followed by inhibition of BC cell survival. In contrast, Mcl-1 protein levels were not downregulated after genetic depletion of Her2 indicating a regulatory role of Mcl-1 upstream of Her2. Indeed, Mcl-1 and Her2 co-localize within the mitochondrial fraction and form a Mcl-1/Her2- protein complex. Similar to genetically targeting Mcl-1 the novel small molecule Mcl-1 inhibitor EU-5346 induced cell death and decreased spheroid formation in Her2-positive BC cells. Of interest, EU-5346 induced ubiquitination of Mcl-1- bound Her2 demonstrating a previously unknown role for Mcl-1 to stabilize Her2 protein levels. Importantly, targeting Mcl-1 was also active in Her2-positive BC cells resistant to Her2 inhibitors, including a brain-primed Her2-positive cell line. CONCLUSION: Our data demonstrate a critical role of Mcl-1 in Her2-positive BC cell survival under hypoxic conditions and provide the preclinical framework for the therapeutic use of novel Mcl-1- targeting agents to improve patient outcome in BC.

Advances in nano-immunotherapy for hematological malignancies.

Hematological malignancies (HMs) encompass a diverse group of blood neoplasms with significant morbidity and mortality. Immunotherapy has emerged as a validated and crucial treatment modality for patients with HMs. Despite notable advancements having been made in understanding and implementing immunotherapy for HMs over the past decade, several challenges persist. These challenges include immune-related adverse effects, the precise biodistribution and elimination of therapeutic antigens in vivo, immune tolerance of tumors, and immune evasion by tumor cells within the tumor microenvironment (TME). Nanotechnology, with its capacity to manipulate material properties at the nanometer scale, has the potential to tackle these obstacles and revolutionize treatment outcomes by improving various aspects such as drug targeting and stability. The convergence of nanotechnology and immunotherapy has given rise to nano-immunotherapy, a specialized branch of anti-tumor therapy. Nanotechnology has found applications in chimeric antigen receptor T cell (CAR-T) therapy, cancer vaccines, immune checkpoint inhibitors, and other immunotherapeutic strategies for HMs. In this review, we delineate recent developments and discuss current challenges in the field of nano-immunotherapy for HMs, offering novel insights into the potential of nanotechnology-based therapeutic approaches for these diseases.

Platelet RNA sequencing reveals profile of caffeic acid affecting hemostasis in mice.

Background: Caffeic acid (CA) is a naturally occurring phenolic compound with diverse pharmacologic properties. CA plays a crucial role in hemostasis by increasing platelet count. However, the mechanism by which CA regulates platelets to promote hemostasis remains unclear. Objectives: We aim to identify the potential target pathways and genes by which CA regulates platelets to promote hemostasis. Methods: We performed RNA sequencing (RNA-seq) analysis of mouse platelet pools in both the CA-gavaged group and phosphate-buffered saline-gavaged group. Results: The 12,934 expressed transcripts had been annotated after platelet RNA-seq. Compared with the phosphate-buffered saline group, 987 differentially expressed genes (DEGs) were identified, of which 466 were downregulated and 521 were upregulated in CA group. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Reactome gene set enrichment analysis demonstrated that upregulated DEGs were enriched in the pathways of hemostasis, platelet activation, signaling, aggregation, and degranulation. Moreover, Kyoto Encyclopedia of Genes and Genomes and Reactome gene set enrichment analysis revealed that 5 of the 25 cosignificantly upregulated DEGs were essential in CA-mediated platelet regulation to promote hemostasis. Conclusion: Our findings of platelet RNA-seq analysis demonstrate that CA regulates the gene expression of hemostasis and platelet activation-related pathways to increase platelet count and promote hemostasis. It will also provide reference molecular resources for future research on the function and mechanism by which CA regulates platelets to promote hemostasis.

Associations of blood pressure in the third trimester and risk of venous thromboembolism postpartum.

Studies on the associations of blood pressure (BP) and the risk of venous thromboembolism (VTE) had been performed neither among pregnant women nor in Chinese population. This study included participants of pregnant women from a retrospective multicenter cohort, between May 2020 and April 2023. Systolic BP (SBP) and diastolic BP (DBP) of the participants were measured in the third trimester. The incidences of VTE (including deep venous thrombosis and/or pulmonary embolism) at 42 days postpartum were followed. With regards to SBP, pregnant women in the Q1 (≤114 mmHg), Q2 (115-122 mmHg), and Q4 group (≥131 mmHg) had increased risk of VTE than those in Q3 group (123-130 mmHg), with ORs 4.48 [1.69, 11.85], 3.52 [1.30, 9.59], and 3.17 [1.12, 8.99], respectively. Compared with pregnant women with the Q4 of DBP (≥85 mmHg), women of Q1 (≤71 mmHg) were found to have elevated risk of VTE (OR 2.73 [1.25, 5.96]). A one standard deviation decrease of DBP (9 mmHg) was related with 37% elevated risk of VTE (OR 1.37 [1.05, 1.79]). This study demonstrated a U-shaped association of SBP in the third trimester and VTE postpartum and inverse association of DBP in the third trimester and VTE postpartum.