Combination of bazedoxifene with chemotherapy and SMAC-mimetics for the treatment of colorectal cancer.

Excessive STAT3 signalling via gp130, the shared receptor subunit for IL-6 and IL-11, contributes to disease progression and poor survival outcomes in patients with colorectal cancer. Here, we provide evidence that bazedoxifene inhibits tumour growth via direct interaction with the gp130 receptor to suppress IL-6 and IL-11-mediated STAT3 signalling. Additionally, bazedoxifene combined with chemotherapy synergistically reduced cell proliferation and induced apoptosis in patient-derived colon cancer organoids. We elucidated that the primary mechanism of anti-tumour activity conferred by bazedoxifene treatment occurs via pro-apoptotic responses in tumour cells. Co-treatment with bazedoxifene and the SMAC-mimetics, LCL161 or Birinapant, that target the IAP family of proteins, demonstrated increased apoptosis and reduced proliferation in colorectal cancer cells. Our findings provide evidence that bazedoxifene treatment could be combined with SMAC-mimetics and chemotherapy to enhance tumour cell apoptosis in colorectal cancer, where gp130 receptor signalling promotes tumour growth and progression.

A real-world observation on thrombopoietic agents for patients with cancer treatment-induced thrombocytopenia in China: A multicenter, cross-sectional study.

BACKGROUND: Studies on various thrombopoietic agents for cancer treatment-induced thrombocytopenia (CTIT) in China are lacking. This study aimed to provide detailed clinical profiles to understand the outcomes and safety of different CTIT treatment regimens. METHODS: In this retrospective, cross-sectional study, 1664 questionnaires were collected from 33 hospitals between March 1 and July 1, 2021. Patients aged >18 years were enrolled who were diagnosed with CTIT and treated with recombinant interleukin 11 (rhIL-11), recombinant thrombopoietin (rhTPO), or a thrombopoietin receptor agonist (TPO-RA). The outcomes, compliance, and safety of different treatments were analyzed. RESULTS: Among the 1437 analyzable cases, most patients were treated with either rhTPO alone (49.3%) or rhIL-11 alone (27.0%). The most common combination regimen used was rhTPO and rhIL-11 (10.9%). Platelet transfusions were received by 117 cases (8.1%). In multivariate analysis, rhTPO was associated with a significantly lower proportion of platelet recovery, platelet transfusion, and hospitalization due to chemotherapy-induced thrombocytopenia (CIT) than rhIL-11 alone. No significant difference was observed in the time taken to achieve a platelet count of >100 × 109/L and chemotherapy dose reduction due to CIT among the different thrombopoietic agents. The outcomes of thrombocytopenia in 170 patients who received targeted therapy and/or immunotherapy are also summarized. The results show that the proportion of platelet recovery was similar among the different thrombopoietic agents. No new safety signals related to thrombopoietic agents were observed in this study. A higher proportion of physicians preferred to continue treatment with TPO-RA alone than with rhTPO and rhIL-11. CONCLUSIONS: This survey provides an overview of CTIT and the application of various thrombopoietic agents throughout China. Comparison of monotherapy with rhIL-11, rhTPO, and TPO-RA requires further randomized clinical trials. The appropriate application for thrombopoietic agents should depend on the pretreatment of platelets, treatment variables, and risk of bleeding. PLAIN LANGUAGE SUMMARY: To provide an overview of the outcome of cancer treatment-induced thrombocytopenia in China, our cross-sectional study analyzed 1437 cases treated with different thrombopoietic agents. Most of the patients were treated with recombinant interleukin 11 (rhIL-11) and recombinant thrombopoietin (rhTPO). rhTPO was associated with a significantly lower proportion of platelet recovery and platelet transfusion compared with rhIL-11.

IL-11 ameliorates oxidative stress damage in neurons after spinal cord injury by activating the JAK/STAT signaling pathway.

OBJECTIVE: Excess reactive oxygen species (ROS) generated by oxidative stress is a crucial factor affecting neuronal dysfunction after spinal cord injury (SCI). IL-11 has been reported to have antioxidative stress capacity. In the present study, we investigated the protective effect and mechanism of IL-11 against neuronal cell damage caused by oxidative imbalance. METHODS: We established a H2O2-induced oxidative stress injury model in PC12 cells and observed the effects of IL-11 on cellular activity, morphology, oxidase and antioxidant enzymes, and ROS release. Furthermore, the effect of IL-11 on apoptosis of PC12 cells was assessed by flow cytometry, a TUNEL assay and Western blotting. Transcriptome analysis and rescue experiments revealed the mechanism by which IL-11 protects neurons from oxidative stress damage. For the in vivo investigation, an adenovirus-mediated IL-11 overexpression SCI rat model was constructed to validate the beneficial effect of IL-11 against SCI. RESULTS: IL-11 significantly improved the viability and enhanced the antioxidant activity of H2O2-treated PC12 cells while reducing ROS release. In addition, IL-11 reduced H2O2-induced PC12 cell apoptosis. Transcriptome analysis revealed that the JAK/STAT pathway may be related to the antioxidant activity of IL-11. Treatment with a JAK/STAT inhibitor (Stattic) exacerbated the oxidative damage induced by H2O2 and attenuated the protective effects of IL-11. The results of in vivo studies showed that IL-11 prevented neuronal apoptosis due to oxidative imbalance and promoted the restoration of motor function in SCI rats by activating the JAK/STAT signaling pathway. CONCLUSION: IL-11 inhibited oxidative stress-induced neuronal apoptosis at least in part by activating the JAK/STAT signaling pathway and further promoted the recovery of motor function. These findings suggest that IL-11 may be an effective target for the treatment for SCI.

Renal Fibrosis Is Alleviated through Targeted Inhibition of IL-11-Induced Renal Tubular Epithelial-to-Mesenchymal Transition.

Renal fibrosis is a pathologic process that leads to irreversible renal failure without effective treatment. Epithelial-to-mesenchymal transition (EMT) plays a key role in this process. The current study found that aberrant expression of IL-11 is critically involved in tubular EMT. IL-11 and its receptor subunit alpha-1 (IL-11Rα1) were significantly induced in renal tubular epithelial cells (RTECs) in unilateral ureteral obstruction (UUO) kidneys, co-localized with transforming growth factor-ß1. IL-11 knockdown ameliorated UUO-induced renal fibrosis in vivo and transforming growth factor-ß1-induced EMT in vitro. IL-11 intervention directly induced the transdifferentiation of RTECs to the mesenchymal phenotype and increased the synthesis of profibrotic mediators. The EMT response induced by IL-11 was dependent on the sequential activation of STAT3 and extracellular signal-regulated kinase 1/2 signaling pathways and the up-regulation of metadherin in RTECs. Micheliolide (MCL) competitively inhibited the binding of IL-11 with IL-11Rα1, suppressing the activation of STAT3 and extracellular signal-regulated kinase 1/2-metadherin pathways, ultimately inhibiting renal tubular EMT and interstitial fibrosis induced by IL-11. In addition, treatment with dimethylaminomicheliolide, a pro-drug of MCL for in vivo use, significantly ameliorated renal fibrosis exacerbated by IL-11 in the UUO model. These findings suggest that IL-11 is a promising target in renal fibrosis and that MCL/dimethylaminomicheliolide exerts its antifibrotic effect by suppressing IL-11/IL-11Rα1 interaction and blocking its downstream effects.

[Consensus on the clinical diagnosis, treatment and prevention of cancer treatment-induced thrombocytopenia in China (2023 edition)].

Cancer treatment-induced thrombocytopenia (CTIT) is a common adverse event during anti-tumor treatment, of which incidence is related to tumor classification, regimens, course of chemotherapy, etc. CTIT may result in a series of events including bleeding, dose intensity reduction, chemotherapy delay, and in severe cases, even the need for platelet transfusion, ultimately affecting the implementation of treatment plan, increasing the cost of treatment, reducing treatment effect and quality of life, and leading to a poor prognosis. The treatment of CTIT should first identify the cause, assess the risk of bleeding, and then adopt treatment strategies according to the cause and severity of CTIT. The main treatments of CTIT include platelet transfusion, application of various types of platelet-producing drugs, and measures to reduce the additional loss of platelets. Among them, platelet-producing drugs mainly refer to platelet-stimulating factors, including recombinant human thrombopoietin (rhTPO), recombinant human interleukin 11(rhIL-11), and thrombopoietin receptor agonists (TPO-RAs). In addition, traditional Chinese medicine also has some assistance in raising platelets. Pharmacological prophylaxis in high-risk patients may help reduce the incidence and severity of CTIT. This consensus aims to support Chinese oncologists in the diagnosis and treatment of CTIT in China, reduce the risk of bleeding and improve the quality of life of patients.

Nanoparticle-Mediated RNA Therapy Attenuates Nonalcoholic Steatohepatitis and Related Fibrosis by Targeting Activated Hepatic Stellate Cells.

Chronic liver injury and inflammation triggered by metabolic abnormalities initiate the activation of hepatic stellate cells (HSCs), driving fibrosis and parenchymal dysfunction, culminating in disorders such as nonalcoholic steatohepatitis (NASH). Unfortunately, there are currently no approved drugs capable of effectively treating NASH due to the challenges in addressing fibrosis and restoring extracellular matrix (ECM) homeostasis. We discovered a significant up-regulation of interleukin-11 (IL-11) in fibrotic livers using two well-established murine models of NASH. To leverage this signaling pathway, we developed a nanoparticle (NP)-assisted RNA interfering approach that specifically targets activated HSCs (aHSCs), blocking IL-11/ERK signaling to regulate HSC transdifferentiation along with fibrotic remodeling. The most potent NP, designated NP-AEAA, showed enhanced accumulation in fibrotic livers with NASH and was primarily enriched in aHSCs. We further investigated the therapeutic efficacy of aHSC-targeting NP-AEAA encapsulating small interfering RNA (siRNA) against IL11 or its cognate receptor IL11ra1 (termed siIL11@NP-AEAA or siIL11ra1@NP-AEAA, respectively) for resolving fibrosis and NASH. Our results demonstrate that both siIL11@NP-AEAA and siIL11ra1@NP-AEAA effectively inhibit HSC activation and resolve fibrosis and inflammation in two well-established murine models of NASH. Notably, siIL11ra1@NP-AEAA exhibits a superior therapeutic effect over siIL11@NP-AEAA, in terms of reducing liver steatosis and fibrosis as well as recovering liver function. These results constitute a targeted nanoparticulate siRNA therapeutic approach against the IL-11 signaling pathway of aHSCs in the fibrotic liver, offering a promising therapeutic intervention for NASH and other diseases.

Efficacy of recombinant human interleukin-11 in preventing and treating oral mucositis after chemotherapy for patients with acute leukemia.

OBJECTIVE: This study aimed to investigate the clinical effects of recombinant human interleukin-11 (rhIL-11) gargle on preventing and treating oral mucositis (OM) after chemotherapy for acute leukemia. METHODS: This single-site, prospective, observer-blinded, nonrandomized controlled trial was conducted on 74 patients with acute leukemia, who were divided into the experimental and control groups. The patients in the experimental group were treated with IL-11 gargle, and those in the control group were treated with sodium bicarbonate gargle. We examined the time and severity of oral mucositis, severity and duration of associated pain, healing time of mucositis, effects of OM on eating, and levels of T-cell subset indicators before and after treatment to evaluate the effects of IL-11 treatment. RESULTS: The proportion of patients with severe OM was significantly lower in the experimental group than in the control group. Mucositis occurred later in the experimental group compared with the control group. The degree and duration of pain, ulcer healing time, and effects on eating were lower in the experimental group compared with the control group. Following treatment, the levels of all T-cell subset indicators improved in each of the two groups. However, the rate of improvement was significantly higher in the experimental group than in the control group. These differences were statistically significant (P < 0.05). CONCLUSIONS: IL-11 gargle reduced the severity of OM after chemotherapy for acute leukemia. Treatment with IL-11 relieved pain, promoted healing, and improved the curative effect of the condition, making it worthy of clinical promotion.

GPR84 potently inhibits osteoclastogenesis and alleviates osteolysis in bone metastasis of colorectal cancer.

The expression of GPR84 in bone marrow-derived monocytes/macrophages (BMMs) can inhibit osteoclast formation; however, its role in bone metastasis of colorectal cancer (CRC) is still unknown. To investigate the effects of GPR84 on bone metastasis of CRC, the murine CRC cell line MC-38 was injected into tibial bone marrow. We found that the expression of GPR84 in BMMs was gradually downregulated during bone metastasis of CRC, and the activation of GPR84 significantly prevented osteoclastogenesis in the tumor microenvironment. Mechanistically, the MAPK pathway mediated the effects of GPR84 on osteoclast formation. Moreover, we found that IL-11 at least partly inhibited the expression of GPR84 in the tumor microenvironment through the inactivation of STAT1. Additionally, activation of GPR84 could prevent osteolysis during bone metastasis of CRC. Our results suggest that CRC cells downregulate the expression of GPR84 in BMMs to promote osteoclastogenesis in an IL-11-dependent manner. Thus, GPR84 could be a potential therapeutic target to attenuate bone destruction induced by CRC metastasis.

The pancreatic clock is a key determinant of pancreatic fibrosis progression and exocrine dysfunction.

Chronic pancreatitis (CP) is characterized by progressive fibrosis and exocrine dysregulation, which have long been considered irreversible. As a peripheral oscillator, the pancreas harbors autonomous and self-sustained timekeeping systems in both its endocrine and exocrine compartments, although the role of the latter remains poorly understood. By using different models of CP established in mice with dysfunctional pancreatic clocks, we found that the local clock played an important role in CP pathology, and genetic or external disruption of the pancreatic clock exacerbated fibrogenesis and exocrine insufficiency. Mechanistically, an impaired retinoic acid receptor-related orphan receptor A (Rora)/nuclear receptor subfamily 1, group D, member 1 (Nr1d1)/aryl hydrocarbon receptor nuclear translocator-like (Arntl or Bmal1) loop, called the circadian stabilizing loop, resulted in the deficiency of pancreatic Bmal1, which was responsible for controlling the fibrogenic properties of pancreatic stellate cells (PSCs) and for rewiring the function of acinar cells in a clock-TGF signaling-IL-11/IL-11RA axis-dependent manner. During PSC activation, the antagonistic interaction between Nr1d1 and Rora was unbalanced in response to the loss of cytoplasmic retinoid-containing lipid droplets. Patients with CP also exhibited reduced production of endogenous melatonin. Enhancing the clock through pharmacological restoration of the circadian stabilizing loop using a combination of melatonin and the Rora agonist SR1078 attenuated intrapancreatic pathological changes in mouse models of CP. Collectively, this study identified a protective role of the pancreatic clock against pancreatic fibrosis and exocrine dysfunction. Pancreatic clock-targeted therapy may represent a potential strategy to treat CP.

Protective mechanisms of Zanthoxylum bungeanum essential oil on DSS-induced ulcerative colitis in mice based on a colonic mucosal transcriptomic approach.

The ameliorative effects on ulcerative colitis (UC) as well as the related mechanisms of the essential oil derived from the edible herb Zanthoxylum bungeanum Maxim (ZBEO) have been demonstrated herein. Based on GC-MS analysis, 45 volatile compounds in ZBEO were determined for its quality control. In vitro studies showed that after pretreatment with ZBEO, the disordered expression levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) and an anti-inflammatory cytokine (IL-10) on colon epithelial NCM460 cells induced by lipopolysaccharide (LPS) could be reversed. Additionally, oral administration of ZBEO significantly alleviated colitis in dextran sulfate sodium (DSS)-induced UC mice, including body weight loss, colon length shortening, disease activity index and colonic pathological damage. Furthermore, to uncover the anti-UC mechanisms of ZBEO, analysis of transcriptomes by next-generation sequencing technology was performed to explore the RNA genetic variation on colon tissues. Based on GO analysis and KEGG pathway analysis, a series of genetic pathways involved in the protective role of ZBEO against UC were determined. As a result, ZBEO treatment could decrease the expression of VCAM-1, TLR8, IL-1ß and IL-11 mRNA as verified by qRT-PCR, which are involved in these potential genetic pathways. In conclusion, ZBEO administration would be a medicinal or dietary supplementation strategy for ulcerative colitis treatment.

IL-11Rα-targeted nanostrategy empowers chemotherapy of relapsed and patient-derived osteosarcoma.

Osteosarcoma (OS) is a rare but frequently lethal bone malignancy in children and adolescents. The adjuvant chemotherapy with doxorubicin (Dox) and cisplatin remains a mainstream clinical practice though it affords only limited clinical benefits due to low tumor deposition, dose-limiting toxicity and high rate of relapse/metastasis. Here, taking advantage of high IL-11Rα expression in the OS patients, we installed IL-11Rα specific peptide (sequence: cyclic CGRRAGGSC) onto redox-responsive polymersomes encapsulating Dox (IL11-PDox) to boost the specificity and anti-OS efficacy of chemotherapy. Of note, IL-11Rα peptide at a density of 20% greatly augmented the internalization, apoptotic activity, and migration inhibition of Dox in IL-11Rα-overexpressing 143B OS cells. The active targeting effect of IL11-PDox was supported in orthotopic and relapsed 143B OS models, as shown by striking repression of tumor growth and lung metastasis, and substantial survival benefits over free Dox control. We further verified that IL11-PDox could effectively inhibit patient-derived OS xenografts. IL-11Rα-targeted nanodelivery of chemotherapeutics provides a potential therapeutic strategy for advanced osteosarcoma.

A prospective interventional study of recombinant human interleukin-11 mouthwash in chemotherapy-induced oral mucositis.

BACKGROUND: This prospective interventional study aimed to evaluate and analyse the efficacy of rhIL-11 mouthwash compared to Kangfuxin fluid in treatment and blank control in prevention of oral mucositis (OM) in patients receiving chemotherapy. MATERIALS AND METHODS: In total, 50 patients in the treatment group and 62 patients in the prevention group were included. Subsequently, each group was divided into an experimental group and a control group. In the treatment group, the experimental patients received recombinant human interleukin-11 (rhIL-11) mouthwash, whereas the control group received Kangfuxin fluid. In the prevention group, experimental patients still received rhIL-11 mouthwash based on routine oral care, whereas the control group only received routine oral care. Meanwhile, we observed and recorded the efficacy in the treatment group, and the occurrence and grades of OM in the prevention group. RESULTS: Through statistical analysis, the results showed that on the seventh day of treatment, the experimental group showed more improvement compared to the control group, and it was statistically significant (p = 0.032). The average healing time in the experimental group (3.59 ± 1.927 days) was shorter than that in the control group (4.96 ± 2.421 days; p = 0.031). In the prevention group, we observed the incidence of oral mucositis. No significant differences were found in the occurrence and grades of OM in the experimental and control groups (p = 0.175). CONCLUSION: Our preliminary results indicate that rhIL-11 mouthwash may be a superior option to treat OM, especially in severe cases, compared to Kangfuxin fluid. However, there is no advantage in prevention.

[Correlation between Serum miR-34a Level and Thrombocytopenia after Chemotherapy in Patients with Diffuse Large B-Cell Lymphoma].

OBJECTIVE: To analyze the relationship between serum miR-34a level and thrombocytopenia after chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL). METHODS: A total of 69 eligible DLBCL patients who received chemotherapy in our hospital from January 2018 to January 2020 were prospectively included as the research subjects, all patients received R-CHOP 21 regimen (rituximab + cyclophosphamide + adriamycin + vincristine + prednisone) for chemotherapy, 3 weeks was 1 cycle, and 2 cycles of chemotherapy were used. The patients were divided into a reduction group and a non reduction group according to whether there was thrombocytopenia after chemotherapy, the general data and laboratory indexes of the two groups were investigated and compared, the relationship between serum miR-34a before chemotherapy and thrombocytopenia after chemotherapy in patients was analyzed. RESULTS: Among the 69 DLBCL patients, 36 patients developed thrombocytopenia after 2 cycles of R-CHOP 21 regimen for chemotherapy, the incidence was 52.17%; the level of serum IL-11 and the relative expression of miR-34a mRNA in the reduction group were significantly lower than the non reduction group (P<0.05), compared other data between groups, there was no statistical significant difference (P>0.05); after Logistic regression analysis, the results showed that the level of serum IL-11 and the relative expression of miR-34a mRNA were related to thrombocytopenia after chemotherapy in DLBCL patients, low expression of each index may be a risk factor of thrombocytopenia after chemotherapy in DLBCL patients (OR>1, P<0.05); ROC curve was drawn, and the results showed that the AUC of serum IL-11 level and miR-34a mRNA relative expression before chemotherapy alone and in combination predicted the risk of thrombocytopenia after chemotherapy in DLBCL patients were all >0.80, and the predictive value was ideal, when the cut-off value of serum IL-11 level before chemotherapy was 42.094 pg/ml, and the cut-off value of miR-34a mRNA relative expression was 3.894, the combined prediction value was the best. CONCLUSION: The relative expression of miR-34a mRNA is associated with thrombocytopenia after chemotherapy in DLBCL patients, which may be a risk factor for thrombocytopenia in patients after chemotherapy, has certain value in predicting the risk of thrombocytopenia of patients after chemotherapy.

Inhaled siRNA nanoparticles targeting IL11 inhibit lung fibrosis and improve pulmonary function post-bleomycin challenge.

Interleukin-11 (IL-11) is a profibrotic cytokine essential for the differentiation of fibroblasts into collagen-secreting, actin alpha 2, smooth muscle-positive (ACTA2+) myofibroblasts, driving processes underlying the pathogenesis of idiopathic pulmonary fibrosis (IPF). Here, we developed an inhalable and mucus-penetrative nanoparticle (NP) system incorporating siRNA against IL11 (siIL11@PPGC NPs) and investigated therapeutic potential for the treatment of IPF. NPs are formulated through self-assembly of a biodegradable PLGA-PEG diblock copolymer and a self-created cationic lipid-like molecule G0-C14 to enable efficient transmucosal delivery of siIL11. Noninvasive aerosol inhalation hindered fibroblast differentiation and reduced ECM deposition via inhibition of ERK and SMAD2. Furthermore, siIL11@PPGC NPs significantly diminished fibrosis development and improved pulmonary function in a mouse model of bleomycin-induced pulmonary fibrosis without inducing systemic toxicity. This work presents a versatile NP platform for the locally inhaled delivery of siRNA therapeutics and exhibits promising clinical potential in the treatment of numerous respiratory diseases, including IPF.

[Analysis of immune inflammation-related proteins in serum of patients with rheumatoid arthritis and the regulatory effect of Xinfeng Capsule on cytokines].

Objective To screen and verify the expression profile of immune inflammatory key proteins in patients with rheumatoid arthritis (RA), and to explore the intervention effect of Xinfeng Capsule (XFC) on it. Methods The differential expressions of key proteins in serum of RA patients and healthy controls were screened by the RayBiotech antibody microarray. The correlation between differential proteins and laboratory indexes [rheumatoid factor (RF), hypersensitive C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), and anti-cyclic citrullinated peptide (ACCP) antibody] was analyzed by Pearson correlation. Eighty RA patients were randomly divided into XFC group and leflunomide (LEF) group, 40 cases in each group. After 4 weeks of treatment, the clinical efficacy, laboratory indexes, self-perception of patient [Self-rating Anxiety Scale (SAS), Self-rating Depression Scale (SDS), short form health survey questionnaire (SF-36)] and the changes of differential proteins were observed. Results Compared with healthy controls, in the RA group there were 24 up-regulated proteins and 9 down-regulated proteins, and IL-2, IL-5, IL-11, IL-17, tumor necrosis factor-ß (TNF-ß), and cytotoxic T lymphocyte-associated protein 4 (CTLA4) expressions were up-regulated, while IL-8, programmed death 1-ligand 2 (PD-L2) and macrophage surface marker CD86 expressions were down-regulated, among which IL-11, IL-17, and PD-L2 were with the most significant difference expressed. IL-11 was positively correlated with hs-CRP (r=0.2412) and ESR (r=0.3799), and IL-17 was positively correlated with hs-CRP (r=0.4667). After treatment, the apparent efficiency of XFC group [62.50% (25/40)] was significantly higher than that of LEF group [25.0% (10/40)]; SAS and SDS were decreased, while PF, VT, and SF were significantly increased in both groups, but there was no significant difference between the two; hs-CRP, ESR, RF, and anti-CCP were significantly decreased in both groups with the XFC group being significantly better in reducing hs-CRP, ESR, and RF compared with the LEF group; IL-11 and IL-17 were significantly decreased, while PD-L2 was significantly increased in both groups with the XFC group being significantly better in reducing IL-11, IL-17, and raising PD-L2 compared with the LEF group. Conclusion In serum of RA patients the expressions of IL-11 and IL-17 are significantly increased, and the expression of PD-L2 is significantly decreased. Patients' health improves with the XFC redressing the imbalance of the expressions of IL-11, IL-17, and PD-L2.

A Neutralizing IL-11 Antibody Improves Renal Function and Increases Lifespan in a Mouse Model of Alport Syndrome.

BACKGROUND: Alport syndrome is a genetic disorder characterized by a defective glomerular basement membrane, tubulointerstitial fibrosis, inflammation, and progressive renal failure. IL-11 was recently implicated in fibrotic kidney disease, but its role in Alport syndrome is unknown. METHODS: We determined IL-11 expression by molecular analyses and in an Alport syndrome mouse model. We assessed the effects of a neutralizing IL-11 antibody (×203) versus an IgG control in Col4a3-/- mice (lacking the gene encoding a type IV collagen component) on renal tubule damage, function, fibrosis, and inflammation. Effects of ×203, the IgG control, an angiotensin-converting enzyme (ACE) inhibitor (ramipril), or ramipril+X203 on lifespan were also studied. RESULTS: In Col4a3-/- mice, as kidney failure advanced, renal IL-11 levels increased, and IL-11 expression localized to tubular epithelial cells. The IL-11 receptor (IL-11RA1) is expressed in tubular epithelial cells and podocytes and is upregulated in tubular epithelial cells of Col4a3-/- mice. Administration of ×203 reduced albuminuria, improved renal function, and preserved podocyte numbers and levels of key podocyte proteins that are reduced in Col4a3-/- mice; these effects were accompanied by reduced fibrosis and inflammation, attenuation of epithelial-to-mesenchymal transition, and increased expression of regenerative markers. X203 attenuated pathogenic ERK and STAT3 pathways, which were activated in Col4a3-/- mice. The median lifespan of Col4a3-/- mice was prolonged 22% by ramipril, 44% with ×203, and 99% with ramipril+X203. CONCLUSIONS: In an Alport syndrome mouse model, renal IL-11 is upregulated, and neutralization of IL-11 reduces epithelial-to-mesenchymal transition, fibrosis, and inflammation while improving renal function. Anti-IL-11 combined with ACE inhibition synergistically extends lifespan. This suggests that a therapeutic approach targeting IL-11 holds promise for progressive kidney disease in Alport syndrome.

Correlation between Serum miR-34a Level and Thrombocytopenia after Chemotherapy in Patients with Diffuse Large B-Cell Lymphoma / 中国实验血液学杂志

OBJECTIVE@#To analyze the relationship between serum miR-34a level and thrombocytopenia after chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL).@*METHODS@#A total of 69 eligible DLBCL patients who received chemotherapy in our hospital from January 2018 to January 2020 were prospectively included as the research subjects, all patients received R-CHOP 21 regimen (rituximab + cyclophosphamide + adriamycin + vincristine + prednisone) for chemotherapy, 3 weeks was 1 cycle, and 2 cycles of chemotherapy were used. The patients were divided into a reduction group and a non reduction group according to whether there was thrombocytopenia after chemotherapy, the general data and laboratory indexes of the two groups were investigated and compared, the relationship between serum miR-34a before chemotherapy and thrombocytopenia after chemotherapy in patients was analyzed.@*RESULTS@#Among the 69 DLBCL patients, 36 patients developed thrombocytopenia after 2 cycles of R-CHOP 21 regimen for chemotherapy, the incidence was 52.17%; the level of serum IL-11 and the relative expression of miR-34a mRNA in the reduction group were significantly lower than the non reduction group (P<0.05), compared other data between groups, there was no statistical significant difference (P>0.05); after Logistic regression analysis, the results showed that the level of serum IL-11 and the relative expression of miR-34a mRNA were related to thrombocytopenia after chemotherapy in DLBCL patients, low expression of each index may be a risk factor of thrombocytopenia after chemotherapy in DLBCL patients (OR>1, P<0.05); ROC curve was drawn, and the results showed that the AUC of serum IL-11 level and miR-34a mRNA relative expression before chemotherapy alone and in combination predicted the risk of thrombocytopenia after chemotherapy in DLBCL patients were all >0.80, and the predictive value was ideal, when the cut-off value of serum IL-11 level before chemotherapy was 42.094 pg/ml, and the cut-off value of miR-34a mRNA relative expression was 3.894, the combined prediction value was the best.@*CONCLUSION@#The relative expression of miR-34a mRNA is associated with thrombocytopenia after chemotherapy in DLBCL patients, which may be a risk factor for thrombocytopenia in patients after chemotherapy, has certain value in predicting the risk of thrombocytopenia of patients after chemotherapy.

Estrogen receptor variant ERα46 and insulin receptor drive in primary breast cancer cells growth effects and interleukin 11 induction prompting the motility of cancer-associated fibroblasts.

Among the prognostic and predictive biomarkers of breast cancer (BC), the role of estrogen receptor (ER)α wild-type has been acknowledged, although the action of certain ERα splice variants has not been elucidated. Insulin/insulin receptor (IR) axis has also been involved in the progression and metastasis of BC. For instance, hyperinsulinemia, which is often associated with obesity and type 2 diabetes, may be a risk factor for BC. Similarly, an aberrant expression of IR or its hyperactivation may correlate with aggressive BC phenotypes. In the present study, we have shown that a novel naturally immortalized BC cell line (named BCAHC-1) is characterized by a unique expression of 46 kDa ERα splice variant (ERα46) along with IR. Moreover, we have shown that a multifaceted crosstalk between ERα46 and IR occurs in BCAHC-1 cells upon estrogen and insulin exposure for growth and pulmonary metastasis. Through high-throughput RNA sequencing analysis, we have also found that the cytokine interleukin-11 (IL11) is the main factor linking BCAHC-1 cells to breast cancer-associated fibroblasts (CAFs). In particular, we have found that IL11 induced by estrogens and insulin in BCAHC-1 cells regulates pro-tumorigenic genes of the "extracellular matrix organization" signaling pathway, such as ICAM-1 and ITGA5, and promotes both migratory and invasive features in breast CAFs. Overall, our results may open a new scientific avenue to identify additional prognostic and therapeutic targets in BC.

Immunogenicity and toxicokinetics assessment of the mono-PEGylated recombinant human interleukin-11 in cynomolgus monkeys.

AIM: Protein therapeutics have potential to elicit immune responses resulting in undesirable anti-drug antibodies (ADA) that might affect product efficacy and patient safety, and should be assessed in animals before applying the treatment to humans. In this paper, we aim to assess the immunogenicity and toxicokinetics of the mono-PEGylated recombinant human interleukin-11 (rhIL-11), a novel protein therapeutic for the treatment of chemotherapy-induced thrombocytopenia, in repeated administration to cynomolgus monkeys. MAIN METHODS: Enzyme-linked immunosorbent assay (ELISA) methods were developed to measure ADA responses and plasma PEGylated IL-11 (PEG-IL11) concentration in monkeys. Assay parameters of immunogenicity and toxicokinetics methods were evaluated during validation in accordance with regulatory guidelines. We also employed cell-based assays to test the neutralizing activity of ADA provoked in monkeys. KEY FINDINGS: The results showed that weak immunogenicity occurred in some monkeys after receiving repeated dose of 0.1-0.3 mg/kg by subcutaneous administration and disappeared after the recovery period. More pronounced immunogenicity occurred at high dose of 0.9 mg/kg, with a higher positive rate and titer, and some ADAs had neutralizing activity, but it can be greatly reduced after recovery. Such ADAs generated in monkeys may be accounted for the plasma toxicokinetics changes of PEG-IL11 and a minor reduction in systemic exposure. SIGNIFICANCE: These methods have been successfully applied to immunogenicity and toxicokinetic studies of PEG-IL11 in repeated dose toxicity following subcutaneous administration to monkeys, and could be successfully used in clinical trials after some modifications.

Efficacy and safety of recombinant human interleukin-11 in the treatment of acute leukaemia patients with chemotherapy-induced thrombocytopenia: A systematic review and meta-analysis.

RATIONALE, AIMS, AND OBJECTIVES: Current meta-analysis was conducted aiming to assess the efficacy and safety of recombinant human interleukin-11 (rhIL-11) in the treatment of acute leukaemia (AL) patients with chemotherapy-induced thrombocytopenia (CIT). METHODS: We searched PubMed, Embase, Chinese National Knowledge Infrastructure database (CNKI), Cochrane Library, and Wan Fang Database on 4 July 2018. RESULTS: Ten randomized controlled trials (RCTs) and two observational studies were included, which involved 754 AL patients with CIT. Pooled analysis demonstrated that rhIL-11 was beneficial on CIT: recovery time of platelet count to 50 × 109 /L [weight mean difference (WMD) = -4.19 days; 95% CI: -5.01, -3.37], recovery time of platelet count to 100 × 109 /L (WMD = -4.45 days; 95% CI: -4.85, -4.06), platelet transfusion volume (WMD = -6.14 U; 95% CI: -9.20, -3.09), and the rate of haemorrhage (RR = 0.46; 95% CI: 0.36 to 0.61). Most adverse events associated with rhIL-11 were mild to moderate. CONCLUSION: Our findings suggest that rhIL-11 is effective and safe in the treatment of CIT in patients with AL.