TREM2 acts as a receptor for IL-34 to suppress acute myeloid leukemia in mice.

The bone marrow microenvironment supports leukocyte mobilization and differentiation and controls the development of leukemias, including acute myeloid leukemia (AML). Here, we found that the development of AML xenotransplants was suppressed in mice with osteoclasts tuberous sclerosis 1 (Tsc1) deletion. Tsc1-deficient osteoclasts released a high level of interleukin-34 (IL-34), which efficiently induced AML cell differentiation and prevented AML progression in various preclinical models. Conversely, AML development was accelerated in mice deficient in IL-34. Interestingly, IL-34 inhibited AML independent of its known receptors but bound directly to triggering receptor expressed on myeloid cells 2 (TREM2), a key hub of immune signals. TREM2-deficient AML cells and normal myeloid cells were resistant to IL-34 treatment. Mechanistically, IL-34-TREM2 binding rapidly phosphorylated Ras protein activator like 3 and inactivated extracellular signal-regulated protein kinase 1/2 signaling to prevent AML cell proliferation and stimulate differentiation. Furthermore, TREM2 was downregulated in patients with AML and associated with a poor prognosis. This study identified TREM2 as a novel receptor for IL-34, indicating a promising strategy for overcoming AML differentiation blockade in patients with AML.

Abemaciclib drives the therapeutic differentiation of acute myeloid leukaemia stem cells.

Self-renewal and differentiation arrest are two features of leukaemia stem cells (LSCs) responsible for the high relapse rate of acute myeloid leukaemia (AML). To screen drugs to overcome differentiation blockade for AML, we conducted screening of 2040 small molecules from a library of United States Food and Drug Administration-approved drugs and found that the cyclin-dependent kinase (CDK)4/6 inhibitor, abemaciclib, exerts high anti-leukaemic activity. Abemaciclib significantly suppressed proliferation and promoted the differentiation of LSCs in vitro. Abemaciclib also efficiently induced differentiation and impaired self-renewal of LSCs, thus reducing the leukaemic cell burden and improving survival in various preclinical animal models, including patient-derived xenografts. Importantly, abemaciclib strongly enhanced anti-tumour effects in combination with venetoclax, a B-cell lymphoma 2 (Bcl-2) inhibitor. This treatment combination led to a marked decrease in LSC-enriched populations and resulted in a synergistic anti-leukaemic effect. Target screening revealed that in addition to CDK4/6, abemaciclib bound to and inhibited CDK9, consequently attenuating the protein levels of global p-Ser2 RNA Polymerase II (Pol II) carboxy terminal domain (CTD), Myc, Bcl-2, and myeloid cell leukaemia-1 (Mcl-1), which was important for the anti-AML effect of abemaciclib. Collectively, these data provide a strong rationale for the clinical evaluation of abemaciclib to induce LSC differentiation and treat highly aggressive AML as well as other advanced haematological malignancies.

You Exude What You Eat: How Carbon-, Nitrogen-, and Sulfur-Rich Organic Substrates Shape Microbial Community Composition and the Dissolved Organic Matter Pool.

Phytoplankton is the major source of labile organic matter in the sunlit ocean, and they are therefore key players in most biogeochemical cycles. However, studies examining the heterotrophic bacterial cycling of specific phytoplankton-derived nitrogen (N)- and sulfur (S)-containing organic compounds are currently lacking at the molecular level. Therefore, the present study investigated how the addition of N-containing (glycine betaine [GBT]) and S-containing (dimethylsulfoniopropionate [DMSP]) organic compounds, as well as glucose, influenced the microbial production of new organic molecules and the microbial community composition. The chemical composition of microbial-produced dissolved organic matter (DOM) was analyzed by ultrahigh-resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) demonstrating that CHO-, CHON-, and CHOS-containing molecules were enriched in the glucose, GBT, and DMSP experiments, respectively. High-throughput sequencing showed that Alteromonadales was the dominant group in the glucose, while Rhodobacterales was the most abundant group in both the GBT and DMSP experiments. Cooccurrence network analysis furthermore indicated more complex linkages between the microbial community and organic molecules in the GBT compared with the other two experiments. Our results shed light on how different microbial communities respond to distinct organic compounds and mediate the cycling of ecologically relevant compounds. IMPORTANCE Nitrogen (N)- and sulfur (S)-containing compounds are normally considered part of the labile organic matter pool that fuels heterotrophic bacterial activity in the ocean. Both glycine betaine (GBT) and dimethylsulfoniopropionate (DMSP) are representative N- and S-containing organic compounds, respectively, that are important phytoplankton cellular compounds. The present study therefore examined how the microbial community and the organic matter they produce are influenced by the addition of carbohydrate-containing (glucose), N-containing (GBT), and S-containing (DMSP) organic compounds. The results demonstrate that when these carbon-, N-, and S-rich compounds are added separately, the organic molecules produced by the bacteria growing on them are enriched in the same elements. Similarly, the microbial community composition was also distinct when different compounds were added as the substrate. Overall, this study demonstrates how the microbial communities metabolize and transform different substrates thereby, expanding our understanding of the complexity of links between microbes and substrates in the ocean.

Patellar non-eversion in primary TKA reduces the complication rate.

PURPOSE: This study was designed to evaluate the isolated benefits of patellar non-eversion in total knee arthroplasty (TKA). METHODS: This systematic review and meta-analysis was conducted following the PRISMA statement. A comprehensive search of the MEDLINE/PubMed, Cochrane Library, and Embase databases was performed in August 2014. Randomized controlled trials (RCTs) that considered the handling of the patella as the only variable were included in our review. Quality assessment of RCTs was performed according to the CONSORT statement. The meta-analysis was performed to pool the available data for some parameters. RESULTS: The searches of the MEDLINE/PubMed, Cochrane Library, and Embase databases yielded 10 RCTs, and five RCTs were selected for inclusion in the review. This results suggested that tourniquet time [mean difference (MD) = -5.69; 95% confidence interval (CI) -9.77 to -1.60], length of hospitalization (MD = 1.24; 95% CI 0.54-1.94) and the incidence of complications [odds ratio (OR) = 2.23; 95% CI 1.12-4.44] differed significantly between the eversion group and non-eversion group. No differences in postoperative pain, alignment, and the Insall-Salvati ratio were observed between the groups. CONCLUSION: The patellar non-eversion approach offers a shorter length of hospitalization and lower incidence of postoperative complications, but requires more operative time. The merits of patellar non-eversion for recovery of knee function remain controversial, and more high-quality RCTs are needed to draw clear conclusions. In general, avoidance of patellar eversion is recommended when exposing the knee joint for TKA.

Epidemiological and clinical characteristics of death from hemorrhagic fever with renal syndrome: a meta-analysis.

Introduction: Hemorrhagic fever with renal syndrome (HFRS) is an acute infectious disease comprising five stages: fever, hypotension, oliguria, diuresis (polyuria), and convalescence. Increased vascular permeability, coagulopathy, and renal injury are typical clinical features of HFRS, which has a case fatality rate of 1-15%. Despite this, a comprehensive meta-analyses of the clinical characteristics of patients who died from HFRS is lacking. Methods: Eleven Chinese- and English-language research databases were searched, including the China National Knowledge Infrastructure Database, Wanfang Database, SinoMed, VIP Database, PubMed, Embase, Scopus, Cochrane Library, Web of Science, Proquest, and Ovid, up to October 5, 2023. The search focused on clinical features of patients who died from HFRS. The extracted data were analyzed using STATA 14.0. Results: A total of 37 articles on 140,295 patients with laboratory-confirmed HFRS were included. Categorizing patients into those who died and those who survived, it was found that patients who died were older and more likely to smoke, have hypertension, and have diabetes. Significant differences were also observed in the clinical manifestations of multiple organ dysfunction syndrome, shock, occurrence of overlapping disease courses, cerebral edema, cerebral hemorrhage, toxic encephalopathy, convulsions, arrhythmias, heart failure, dyspnea, acute respiratory distress syndrome, pulmonary infection, liver damage, gastrointestinal bleeding, acute kidney injury, and urine protein levels. Compared to patients who survived, those who died were more likely to demonstrate elevated leukocyte count; decreased platelet count; increased lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase levels; prolonged activated partial thromboplastin time and prothrombin time; and low albumin and chloride levels and were more likely to use continuous renal therapy. Interestingly, patients who died received less dialysis and had shorter average length of hospital stay than those who survived. Conclusion: Older patients and those with histories of smoking, hypertension, diabetes, central nervous system damage, heart damage, liver damage, kidney damage, or multiorgan dysfunction were at a high risk of death. The results can be used to assess patients' clinical presentations and assist with prognostication.Systematic review registration:https://www.crd.york.ac.uk/prospero/, (CRD42023454553).

Microbial communities exhibit distinct diversities and assembly mechanisms in rainwater and tap-water storage systems.

Roof-harvested rainwater stored for potable and nonpotable usages represent a clean and sustainable water supply resource. However, the microbial dynamics and mechanisms of community assembly in long-termed operated rainwater storage systems remain elusive. In this study, characteristics of microbial communities in different habitats were systematically compared within rainwater and tap-water simulated storage systems (SWSSs) constructed with different tank materials (PVC, stainless steel and cement). Distinct microbial communities were observed between rainwater and tap-water SWSSs for both water and biofilm samples (ANOSIM, p < 0.05), with lower diversity indexes noted in rainwater samples. Notably, a divergent potential pathogen profile was observed between rainwater and tap-water SWSSs, with higher relative abundances of potential pathogens noted in rainwater SWSSs. Moreover, tank materials had a notable impact on microbial communities in rainwater SWSSs (ANOSIM, p < 0.05), rather than tap-water SWSSs, illustrating the distinct interplay between water chemistry and engineering factors in shaping the SWSS microbiomes. Deterministic processes contributed predominantly to the microbial community assembly in cement rainwater SWSSs and all tap-water SWSSs, which might be ascribed to the high pH levels in cement rainwater SWSSs and low-nutrient levels in all tap-water SWSSs, respectively. However, microbial communities in the PVC and stainless-steel rainwater SWSSs were mainly driven by stochastic processes. Overall, the results provided insights to the distinct microbial assembly mechanisms and potential health risks in stored roof-harvested rainwater, highlighting the importance of developing tailored microbial management strategies for the storage and utilization of rainwater.

Recent Advances in Material Technology for Leukemia Treatments.

Leukemia is a widespread hematological malignancy characterized by an elevated white blood cell count in both the blood and the bone marrow. Despite notable advancements in leukemia intervention in the clinic, a large proportion of patients, especially acute leukemia patients, fail to achieve long-term remission or complete remission following treatment. Therefore, leukemia therapy necessitates optimization to meet the treatment requirements. In recent years, a multitude of materials have undergone rigorous study to serve as delivery vectors or direct intervention agents to bolster the effectiveness of leukemia therapy. These materials include liposomes, protein-based materials, polymeric materials, cell-derived materials, and inorganic materials. They possess unique characteristics and are applied in a broad array of therapeutic modalities, including chemotherapy, gene therapy, immunotherapy, radiotherapy, hematopoietic stem cell transplantation, and other evolving treatments. Here, an overview of these materials is presented, describing their physicochemical properties, their role in leukemia treatment, and the challenges they face in the context of clinical translation. This review inspires researchers to further develop various materials that can be used to augment the efficacy of multiple therapeutic modalities for novel applications in leukemia treatment.

Targeting PARP14 with lomitapide suppresses drug resistance through the activation of DRP1-induced mitophagy in multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy that remains incurable, primarily due to the high likelihood of relapse or development of resistance to current treatments. To explore and discover new medications capable of overcoming drug resistance in MM, we conducted cell viability inhibition screens of 1504 FDA-approved drugs. Lomitapide, a cholesterol-lowering agent, was found to exhibit effective inhibition on bortezomib-resistant MM cells in vitro and in vivo. Our data also indicated that lomitapide decreases the permeability of the mitochondrial outer membrane and induces mitochondrial dysfunction in MM cells. Next, lomitapide treatment upregulated DRP1 and PINK1 expression levels, coupled with the mitochondrial translocation of Parkin, leading to MM cell mitophagy. Excessive mitophagy caused mitochondrial damage and dysfunction induced by lomitapide. Meanwhile, PARP14 was identified as a direct target of lomitapide by SPR-HPLC-MS, and we showed that DRP1-induced mitophagy was crucial in the anti-MM activity mediated by PARP14. Furthermore, PARP14 is overexpressed in MM patients, implying that it is a novel therapeutic target in MM. Collectively, our results demonstrate that DRP1-mediated mitophagy induced by PARP14 may be the cause for mitochondrial dysfunction and damage in response to lomitapide treatment.

Heavy metal induced shifts in microbial community composition and interactions with dissolved organic matter in coastal sediments.

Heavy metals can impact the structure and function of coastal sediment. The dissolved organic matter (DOM) pool plays an important role in determining both the heavy metal toxicity and microbial community composition in coastal sediments. However, how heavy metals affect the interactions between microbial communities and DOM remains unclear. Here, we investigated the influence of heavy metals on the microbial community structure (including bacteria and archaea) and DOM composition in surface sediments of Beibu Gulf, China. Our results revealed firstly that chromium, zinc, cadmium, and lead were the heavy metals contributing to pollution in our studied area. Furthermore, the DOM chemical composition was distinctly different in the contaminated area from the uncontaminated area, characterized by a higher average O/C ratio and increased prevalence of carboxyl-rich alicyclic molecules (CRAM) and highly unsaturated compounds (HUC). This indicates that DOM in the contaminated area was more recalcitrant compared to the uncontaminated area. Except for differences in archaeal diversity between the two areas, there were no significant variations observed in the structure of archaea and bacteria, as well as the diversity of bacteria, across the two areas. Nevertheless, our co-occurrence network analysis revealed that the B2M28 and Euryarchaeota, dominating bacterial and archaeal groups in the contaminated area were strongly related to CRAM. The network analysis also unveiled correlations between active bacteria and elevated proportions of nitrogen-containing DOM molecules. In contrast, the archaea-DOM network exhibited strong associations with nitrogen- and sulfur-containing molecules. Collectively, these findings suggest that heavy metals indeed influence the interaction between microbial communities and DOM, potentially affecting the accumulation of recalcitrant compounds in coastal sediments.

Efficacy of a novel chelator BPCBG for removing uranium and protecting against uranium-induced renal cell damage in rats and HK-2 cells.

Chelation therapy is a known effective method to increase the excretion of U(VI) from the body. Until now, no any uranium chelator has been approved for emergency medical use worldwide. The present study aimed to evaluate the efficacy of new ligand BPCBG containing two catechol groups and two aminocarboxylic acid groups in decorporation of U(VI) and protection against acute U(VI) nephrotoxicity in rats, and further explored the detoxification mechanism of BPCBG for U(VI)-induced nephrotoxicity in HK-2 cells with comparison to DTPA-CaNa3. Chelating agents were administered at various times before or after injections of U(VI) in rats. The U(VI) levels in urine, kidneys and femurs were measured 24 h after U(VI) injections. Histopathological changes in the kidney and serum urea and creatinine and urine protein were examined. After treatment of U(VI)-exposed HK-2 cells with chelating agent, the intracellular U(VI) contents, formation of micronuclei, lactate dehydrogenase (LDH) activity and production of reactive oxygen species (ROS) were assessed. It was found that prompt, advanced or delayed injections of BPCBG effectively increased 24 h-urinary U(VI) excretion and decreased the levels of U(VI) in kidney and bone. Meanwhile, BPCBG injection obviously reduced the severity of the U(VI)-induced histological alterations in the kidney, which was in parallel with the amelioration noted in serum indicators, urea and creatinine, and urine protein of U(VI) nephrotoxicity. In U(VI)-exposed HK-2 cells, immediate and delayed treatment with BPCBG significantly decreased the formation of micronuclei and LDH release by inhibiting the cellular U(VI) intake, promoting the intracellular U(VI) release and inhibiting the production of intracellular ROS. Our data suggest that BPCBG is a novel bi-functional U(VI) decorporation agent with a better efficacy than DTPA-CaNa3.

Unraveling bacterial and eukaryotic communities in secondary water supply systems: Dynamics, assembly, and health implications.

Secondary water supply systems (SWSSs) are crucial water supply infrastructures for high-rise buildings in metropolitan cities. In recent years, they have garnered public attention due to increased microbial risks. However, our understanding of SWSS microbial ecology, particularly concerning the composition of eukaryotes and the underlying mechanisms driving microbial dynamics and assembly in SWSSs, remains elusive. Herein, we conducted a comprehensive investigation on both eukaryotes and bacteria along the water transportation pathway and across various microbial habitats (water, biofilm, and sediment) in SWSSs. Sequencing results revealed that eukaryotes within SWSSs predominantly consist of protists (average abundance: 31.23%) and metazoans (20.91%), while amoebae accounted for 4.71% of the total. During water transportation from the distribution mains to taps, both bacterial and eukaryotic communities exhibited significant community shifts, and higher degrees of variation were observed for eukaryotic community among different locations within SWSSs. The normalized stochasticity ratio (NST) analysis demonstrated that bacterial community assembly was governed by stochastic processes, while eukaryotic community assembly was primarily shaped by deterministic processes. Within SWSS tanks, bacterial communities significantly varied across water, biofilm, and sediment, whereas eukaryotic communities showed minor differences among these habitats. The co-occurrence networks analysis revealed that tank biofilm and sediment harbored more eukaryote-bacterium linkages than water, suggesting biofilm and sediment might be hotspots for inter-kingdom interactions. We also applied FEAST analysis to track the source of tap water microbiota, results of which showed that household-tap bacteria mainly originated from tank water. In contrast, tank biofilm was identified as the primary microbial source to eukaryotes in household tap water. Additionally, engineering factors such as tank materials significantly affected amoeba community, and the SWSS configuration was found to influence Legionella and Mycobacterium abundances in SWSSs. Overall, results of our study shed light on the microbial ecology in SWSS and provide insights into SWSS management and health risk control.

Knockdown of MEF2D inhibits the development and progression of B-cell acute lymphoblastic leukemia.

Background: Myocyte enhancer factor 2D (MEF2D) is involved in the progression of various malignant tumors. However, its impact on B-cell acute lymphoblastic leukemia (B-ALL) has not been elucidated. Methods: In this study, the expression level of MEF2D in B-ALL patients was validated through the Gene Expression Omnibus (GEO) database and clinical specimens. MEF2D-knockdown B-ALL cell lines were constructed by lentivirus transfection, and the effects of MEF2D on the viability, apoptosis, cycle progression, and drug sensitivity of B-ALL cells were verified by Cell Counting Kit-8 (CCK-8) and flow cytometry (FCM). The effect of MEF2D on the proliferation of B-ALL cells in vivo was verified via the construction of a xenograft mouse model. The mechanism of MEF2D regulating B-ALL cells was explored by RNA sequencing analysis, quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemical (IHC). Results: In this study, overexpression of MEF2D was observed in B-ALL patients and was remarkably correlated to disease progression in ALL patients. The knockdown of MEF2D expression suppressed cell viability, induced cell apoptosis, blockaded cell cycle progression, enhanced drug sensitivity of B-ALL cells in vitro, and reduced the tumor load in vivo. Furthermore, mechanistic studies revealed that MEF2D knockdown downregulated the expression of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway. Conclusions: Our research demonstrated that MEF2D was markedly expressed in B-ALL. MEF2D knockdown inhibited cancer progression of B-ALL both in vitro and in vivo, which may be related to the downregulation of the PI3K-AKT signaling pathway. The data suggest that MEF2D plays a vital role in the process of tumorigenesis and may be a potential novel target for B-ALL therapy.

Antihepatoma peptide, scolopentide, derived from the centipede scolopendra subspinipes mutilans.

BACKGROUND: Centipedes have been used to treat tumors for hundreds of years in China. However, current studies focus on antimicrobial and anticoagulation agents rather than tumors. The molecular identities of antihepatoma bioactive components in centipedes have not yet been extensively investigated. It is a challenge to isolate and characterize the effective components of centipedes due to limited peptide purification technologies for animal-derived medicines. AIM: To purify, characterize, and synthesize the bioactive components with the strongest antihepatoma activity from centipedes and determine the antihepatoma mechanism. METHODS: An antihepatoma peptide (scolopentide) was isolated and identified from the centipede scolopendra subspinipes mutilans using a combination of enzymatic hydrolysis, a Sephadex G-25 column, and two steps of high-performance liquid chromatography (HPLC). Additionally, the CCK8 assay was used to select the extracted fraction with the strongest antihepatoma activity. The molecular weight of the extracted scolopentide was characterized by quadrupole time of flight mass spectrometry (QTOF MS), and the sequence was matched by using the Mascot search engine. Based on the sequence and molecular weight, scolopentide was synthesized using solid-phase peptide synthesis methods. The synthetic scolopentide was confirmed by MS and HPLC. The antineoplastic effect of extracted scolopentide was confirmed by CCK8 assay and morphological changes again in vitro. The antihepatoma effect of synthetic scolopentide was assessed by the CCK8 assay and Hoechst staining in vitro and tumor volume and tumor weight in vivo. In the tumor xenograft experiments, qualified model mice (male 5-week-old BALB/c nude mice) were randomly divided into 2 groups (n = 6): The scolopentide group (0.15 mL/d, via intraperitoneal injection of synthetic scolopentide, 500 mg/kg/d) and the vehicle group (0.15 mL/d, via intraperitoneal injection of normal saline). The mice were euthanized by cervical dislocation after 14 d of continuous treatment. Mechanistically, flow cytometry was conducted to evaluate the apoptosis rate of HepG2 cells after treatment with extracted scolopentide in vitro. A Hoechst staining assay was also used to observe apoptosis in HepG2 cells after treatment with synthetic scolopentide in vitro. CCK8 assays and morphological changes were used to compare the cytotoxicity of synthetic scolopentide to liver cancer cells and normal liver cells in vitro. Molecular docking was performed to clarify whether scolopentide tightly bound to death receptor 4 (DR4) and DR5. qRT-PCR was used to measure the mRNA expression of DR4, DR5, fas-associated death domain protein (FADD), Caspase-8, Caspase-3, cytochrome c (Cyto-C), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), x-chromosome linked inhibitor-of-apoptosis protein and Cellular fas-associated death domain-like interleukin-1ß converting enzyme inhibitory protein in hepatocarcinoma subcutaneous xenograft tumors from mice. Western blot assays were used to measure the protein expression of DR4, DR5, FADD, Caspase-8, Caspase-3, and Cyto-C in the tumor tissues. The reactive oxygen species (ROS) of tumor tissues were tested. RESULTS: In the process of purification, characterization and synthesis of scolopentide, the optimal enzymatic hydrolysis conditions (extract ratio: 5.86%, IC50: 0.310 mg/mL) were as follows: Trypsin at 0.1 g (300 U/g, centipede-trypsin ratio of 20:1), enzymolysis temperature of 46 °C, and enzymolysis time of 4 h, which was superior to freeze-thawing with liquid nitrogen (IC50: 3.07 mg/mL). A peptide with the strongest antihepatoma activity (scolopentide) was further purified through a Sephadex G-25 column (obtained A2) and two steps of HPLC (obtained B5 and C3). The molecular weight of the extracted scolopentide was 1018.997 Da, and the peptide sequence was RAQNHYCK, as characterized by QTOF MS and Mascot. Scolopentide was synthesized in vitro with a qualified molecular weight (1018.8 Da) and purity (98.014%), which was characterized by MS and HPLC. Extracted scolopentide still had an antineoplastic effect in vitro, which inhibited the proliferation of Eca-109 (IC50: 76.27 µg/mL), HepG2 (IC50: 22.06 µg/mL), and A549 (IC50: 35.13 µg/mL) cells, especially HepG2 cells. Synthetic scolopentide inhibited the proliferation of HepG2 cells (treated 6, 12, and 24 h) in a concentration-dependent manner in vitro, and the inhibitory effects were the strongest at 12 h (IC50: 208.11 µg/mL). Synthetic scolopentide also inhibited the tumor volume (Vehicle vs Scolopentide, P = 0.0003) and weight (Vehicle vs Scolopentide, P = 0.0022) in the tumor xenograft experiment. Mechanistically, flow cytometry suggested that the apoptosis ratios of HepG2 cells after treatment with extracted scolopentide were 5.01% (0 µg/mL), 12.13% (10 µg/mL), 16.52% (20 µg/mL), and 23.20% (40 µg/mL). Hoechst staining revealed apoptosis in HepG2 cells after treatment with synthetic scolopentide in vitro. The CCK8 assay and morphological changes indicated that synthetic scolopentide was cytotoxic and was significantly stronger in HepG2 cells than in L02 cells. Molecular docking suggested that scolopentide tightly bound to DR4 and DR5, and the binding free energies were-10.4 kcal/mol and-7.1 kcal/mol, respectively. In subcutaneous xenograft tumors from mice, quantitative real-time polymerase chain reaction and western blotting suggested that scolopentide activated DR4 and DR5 and induced apoptosis in SMMC-7721 Liver cancer cells by promoting the expression of FADD, caspase-8 and caspase-3 through a mitochondria-independent pathway. CONCLUSION: Scolopentide, an antihepatoma peptide purified from centipedes, may inspire new antihepatoma agents. Scolopentide activates DR4 and DR5 and induces apoptosis in liver cancer cells through a mitochondria-independent pathway.

Enhanced tumor immunotherapy by polyfunctional CD19-CAR T cells engineered to secrete anti-CD47 single-chain variable fragment.

A high recurrence rate of non-Hodgkin's lymphoma (NHL) following chimeric antigen receptor T (CAR T) cell treatment remains a bottleneck, and immunosuppressive tumor microenvironment (TME) compromising CAR T cell efficacy in NHL is the primary cause of relapse. Accordingly, modifying the structure of CAR T cells to attenuate the inhibitory effect of TME thus reducing recurrence rate is a valuable research topic. CD47 has been proved to be a promising therapeutic target and is crucial in regulating macrophage function. Herein, we engineered CD19-CAR T cells to secrete an anti-CD47 single-chain variable fragment (scFv) and validated their function in enhancing antitumor efficacy, regulating T cells differentiation, modifying phagocytosis and polarization of macrophages by in vitro and in vivo researches. The efficacy was analogous or preferable to the combination of CAR T cells and CD47 antibody. Of note, anti-CD47 scFv secreting CAR T cells exert a more potent immune response following specific antigen stimulation compared with parental CAR T cells, characterized by more efficient degranulation and cytokine production with polyfunctionality. Furthermore, locally delivering anti-CD47 by CAR T cells potentially limits toxicities relevant to systemic antibody treatment. Collectively, our research provides a more effective and safer CAR T cell transformation method for enhancing tumor immunotherapy.

Histone acetylation by HBO1 (KAT7) activates Wnt/ß-catenin signaling to promote leukemogenesis in B-cell acute lymphoblastic leukemia.

B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematological disorder with a dismal prognosis. The dysregulation of histone acetylation is of great significance in the pathogenesis and progression of B-ALL. Regarded as a fundamental acetyltransferase gene, the role of HBO1 (lysine acetyltransferase 7/KAT7) in B-ALL has not been investigated. Herein, we found that HBO1 expression was elevated in human B-ALL cells and associated with poor disease-free survival. Strikingly, HBO1 knockdown inhibited viability, proliferation, and G1-S cycle progression in B-ALL cells, while provoking apoptosis. In contrast, ectopic overexpression of HBO1 enhanced cell viability and proliferation but inhibited apoptotic activation. The results of in vivo experiments also certificated the inhibitory effect of HBO1 knockdown on tumor growth. Mechanistically, HBO1 acetylated histone H3K14, H4K8, and H4K12, followed by upregulating CTNNB1 expression, resulting in activation of the Wnt/ß-catenin signaling pathway. Moreover, a novel small molecule inhibitor of HBO1, WM-3835, potently inhibited the progression of B-ALL. Our data identified HBO1 as an efficacious regulator of CTNNB1 with therapeutic potential in B-ALL.

Low doses of IFN-γ maintain self-renewal of leukemia stem cells in acute myeloid leukemia.

Conventional therapies for acute myeloid leukemia (AML) often fail to eliminate the disease-initiating leukemia stem cell (LSC) population, leading to disease relapse. Interferon-γ (IFN-γ) is a known inflammatory cytokine that promotes antitumor responses. Here, we found that low serum IFN-γ levels correlated with a higher percentage of LSCs and greater relapse incidence in AML patients. Furthermore, IFNGR1 was overexpressed in relapsed patients with AML and associated with a poor prognosis. We showed that high doses (5-10 µg/day) of IFN-γ exerted an anti-AML effect, while low doses (0.01-0.05 µg/day) of IFN-γ accelerated AML development and supported LSC self-renewal in patient-derived AML-LSCs and in an LSC-enriched MLL-AF9-driven mouse model. Importantly, targeting the IFN-γ receptor IFNGR1 by using lentiviral shRNAs or neutralizing antibodies induced AML differentiation and delayed leukemogenesis in vitro and in mice. Overall, we uncovered essential roles for IFN-γ and IFNGR1 in AML stemness and showed that targeting IFNGR1 is a strategy to decrease stemness and increase differentiation in relapsed AML patients.

Combination effects of chronic cadmium exposure and gamma-irradiation on the genotoxicity and cytotoxicity of peripheral blood lymphocytes and bone marrow cells in rats.

This work investigated the effects of chronic cadmium (Cd) exposure combined with γ-ray irradiation on the cytotoxicity and genotoxicity of peripheral blood cells and bone marrow cells in rats. Results showed that when the rats were exposed to low dose (LD) Cd of 0.1mg CdCl2/(kgd) for 8 and 12 weeks, the Cd concentration in blood reached to 135-140 µg/L and no toxic effects on peripheral blood lymphocytes, white blood cells (WBC) and granulocyte-monocyte (GM) progenitor cells were observed except polychromatic erythrocytes (PCE) of bone marrow. Moreover, this chronic LD Cd exposure significantly decreased irradiation-induced micronucleus (MN) formation and hypoxanthine-guanine phosphoribosyl transferase (hprt) mutation in lymphocytes and PCE, while the combination of LD Cd exposure and irradiation induced the additive metallothionein (MT) protein expression in bone marrow cells. When the rats were exposed to a high dose (HD) Cd of 0.5mg CdCl/2(kgd) for 8 and 12 weeks, the blood Cd level approached to 458-613 µg/L and an inflammatory response was induced, meanwhile, MN formation and hprt mutation were markedly increased, and the ratio of PCE/NCE (normochromatic erythrocyte) was significantly decreased. Furthermore, when the rats were exposed to HD Cd plus 2 Gy irradiation, additive toxic effects on MN formation, hprt mutation, PCE damage and GM progenitor cell proliferation were observed, while this combination treatment resulted in an obvious reduction of MT protein compared to HD Cd group. In conclusion, chronic exposure to LD Cd induced the adaptive response to irradiation in the genotoxicity of peripheral blood lymphocytes and PCE of bone marrow by the up-regulation of Cd-induced MT protein, but the combination of HD Cd exposure and irradiation generated the additive effects on the cytotoxicity and genotoxicity in peripheral blood lymphocytes and bone marrow cells.

Tegaserod maleate exhibits antileukemic activity by targeting TRPM8.

To identify therapeutic targets in acute myeloid leukemia (AML), we conducted growth inhibition screens of 2040 small molecules from a library of FDA-approved drugs using a panel of 12 AML cell lines. Tegaserod maleate, a 5-hydroxytryptamine 4 receptor partial agonist, elicits strong anti-AML effects in vitro and in vivo by targeting transient receptor potential melastatin subtype 8 (TRPM8), which plays critical roles in several important processes. However, the role of TRPM8 remains incompletely described in AML, whose treatment is based mostly on antimitotic chemotherapy. Here, we report an unexpected role of TRPM8 in leukemogenesis. Strikingly, TRPM8 knockout inhibits AML cell survival/proliferation by promoting apoptosis. Mechanistically, TRPM8 exerts its oncogenic effect by regulating the ERK-CREB/c-Fos signaling axis. Hyperactivation of ERK signaling can be reversed by TRPM8 inhibition. Importantly, TRPM8 is overexpressed in AML patients, indicating that it is a new prognostic factor in AML. Collectively, our work demonstrates the anti-AML effects of tegaserod maleate via targeting TRPM8 and indicates that TRPM8 is a regulator of leukemogenesis with therapeutic potential in AML.