Dasatinib promotes muscle differentiation and disrupts normal muscle regeneration.

Dasatinib is one of the second-generation tyrosine kinase inhibitors used to treat chronic myeloid leukemia and has a broad target spectrum, including KIT, PDGFR, and SRC family kinases. Due to its broad drug spectrum, dasatinib has been reported at the basic research level to improve athletic performance by eliminating senescent cell removal and to have an effect on muscle diseases such as Duchenne muscular dystrophy, but its effect on myoblasts has not been investigated. In this study, we evaluated the effects of dasatinib on skeletal muscle both under normal conditions and in the regenerating state. Dasatinib suppressed the proliferation and promoted the fusion of C2C12 myoblasts. During muscle regeneration, dasatinib increased the gene expressions of myogenic-related genes (Myod, Myog, and Mymx), and caused abnormally thin muscle fibers on the CTX-induced muscle injury mouse model. From these results, dasatinib changes the closely regulated gene expression pattern of myogenic regulatory factors during muscle differentiation and disrupts normal muscle regeneration. Our data suggest that when using dasatinib, its effects on skeletal muscle should be considered, particularly at regenerating stages.

Magnetic Rubber@Ni-Co layered double hydroxide derived from ZIF-67 template as nanostructured sorbent; application in determination of anticancer drugs in plasma samples.

In this study, a magnetic three-dimensional nano-composite based on Rubber-Fe3O4@Ni-Co Layered double hydroxide derived from ZIF-67 template was synthesized by a hydrothermal method. The proposed nano-composite was used as a sorbent for the enrichment of trace amounts of anti-cancer drugs (dasatinib and erlotinib hydrochloride) from plasma samples followed by determination using high-performance liquid chromatographic analysis (HPLC-UV). The synthesized nano-sorbent was characterized by X-ray diffraction, field emission scanning electron microscopy, Fourier transform infrared spectroscopy, vibrating-sample magnetometer, Brunauer-Emmett-Teller surface analysis, Barrett-Joyner-Halenda pore size analysis and energy dispersive X-ray spectroscopy. Under optimal experimental conditions, factors affecting on extraction efficiency such as pH, ionic strength, extraction temperature and time, desorption solvent and time, the limit of detection (LODs) and the limit of quantification (LOQs) were obtained as 0.6, 2 µg/L for both of dasatinib and erlotinib, respectively. Also, linear range of the method were 2-500 and 2-1000 µg/L for dasatinib and erlotinib, respectively. Relative standard deviations (RSD%) for the repeatability of extraction on sorbent to sorbent were obtained as 3.59, 1.97 %, and one sorbent reusability were investigated and relative standard deviation values were obtained 5.35, 3.30 % for dasatinib and erlotinib, respectively.

ASP210: a potent oligonucleotide-based inhibitor effective against TKI-resistant CML cells.

Clinical experience with tyrosine kinase inhibitors (TKIs) over the past two decades has shown that, despite the apparent therapeutic benefit, nearly 30% of patients with chronic myelogenous leukemia (CML) display primary resistance or intolerance to TKIs, and approximately 25% of those treated are forced to switch TKIs at least once during therapy due to acquired resistance. Safe and effective treatment modalities targeting leukemic clones that escape TKI therapy could hence be game changers in the professional management of these patients. Here, we aimed to investigate the efficacy of a novel therapeutic oligonucleotide of unconventional design, called ASP210, to reduce BCR-ABL1 mRNA levels in TKI-resistant CML cells, with the assumption of inducing their apoptosis. Imatinib- and dasatinib-resistant sublines of BCR-ABL1-positive MOLM-7 and CML-T1 cells were established and exposed to 0.25 and 2.5 µM ASP210 for 10 days. RT-qPCR showed a remarkable reduction of the target mRNA level by >99% after a single application. Cell viability was monitored daily by trypan blue staining. In response to the lack of driver oncoprotein BCR-ABL1, TKI-resistant CML cells underwent apoptosis regardless of the presence of the clinically relevant T315I mutation by day 5 after redosing with ASP210. The effect was selective for cancer cells, indicating a favorable safety profile for this therapeutic modality. Furthermore, the spontaneous uptake and high intracellular concentrations of ASP210 suggest its potential to be effective at relatively low doses. The present findings suggest that ASP210 is a promising therapeutic avenue for patients with CML who fail to respond to TKI therapy.NEW & NOTEWORTHY Effective treatment modalities targeting leukemic clones that escape tyrosine kinase inhibitor (TKI) therapy could be game changers in the professional management of patients displaying primary resistance, intolerance, or acquired resistance to TKIs. Although delivering authentic innovations today is more complex than ever, we developed a highly potent and safe oligonucleotide-based modality against BCR-ABL1 mRNA named ASP210 that effectively induces cell death in BCR-ABL1-positive TKI-resistant cells while sparing BCR-ABL1-negative healthy cells.

Chronic myeloid leukaemia with soft tissue mass formed by mature granulocytes.

Extramedullary lesions in patients with chronic myeloid leukaemia (CML) suggest progression to the blast phase because such lesions generally consist of immature granulocytes. We here report a case of an extramedullary mass formed by mature granulocytes during the chronic phase of CML. A 60-year-old woman who had discontinued treatment for CML with dasatinib of her own accord several years ago presented to our hospital with a complaint of right thigh pain. She had a mass on her right leg, which was located on her right thigh and was elastic, soft and fist-sized. Blood tests and the bone marrow findings were compatible with the chronic phase of CML, and a CT-guided needle biopsy showed an infiltrate containing numerous mature neutrophils and foam cells. The mass disappeared with dasatinib alone, without antibacterial agents or drainage.Although the detailed pathogenesis of mass formation with mature granulocytes in the chronic phase of CML has not been elucidated, the clinical course of the current case highlights the importance of prompt biopsy, pathological examination and the early initiation of appropriate treatment.

Irinotecan and temozolomide in combination with dasatinib and rapamycin versus irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma (RIST-rNB-2011): a multicentre, open-label, randomised, controlled, phase 2 trial.

BACKGROUND: Neuroblastoma is the most common extracranial solid tumour in children. Relapsed or refractory neuroblastoma is associated with a poor outcome. We assessed the combination of irinotecan-temozolomide and dasatinib-rapamycin (RIST) in patients with relapsed or refractory neuroblastoma. METHODS: The multicentre, open-label, randomised, controlled, phase 2, RIST-rNB-2011 trial recruited from 40 paediatric oncology centres in Germany and Austria. Patients aged 1-25 years with high-risk relapsed (defined as recurrence of all stage IV and MYCN amplification stages, after response to treatment) or refractory (progressive disease during primary treatment) neuroblastoma, with Lansky and Karnofsky performance status at least 50%, were assigned (1:1) to RIST (RIST group) or irinotecan-temozolomide (control group) by block randomisation, stratified by MYCN status. We compared RIST (oral rapamycin [loading 3 mg/m2 on day 1, maintenance 1 mg/m2 on days 2-4] and oral dasatinib [2 mg/kg per day] for 4 days with 3 days off, followed by intravenous irinotecan [50 mg/m2 per day] and oral temozolomide [150 mg/m2 per day] for 5 days with 2 days off; one course each of rapamycin-dasatinib and irinotecan-temozolomide for four cycles over 8 weeks, then two courses of rapamycin-dasatinib followed by one course of irinotecan-temozolomide for 12 weeks) with irinotecan-temozolomide alone (with identical dosing as experimental group). The primary endpoint of progression-free survival was analysed in all eligible patients who received at least one course of therapy. The safety population consisted of all patients who received at least one course of therapy and had at least one post-baseline safety assessment. This trial is registered at ClinicalTrials.gov, NCT01467986, and is closed to accrual. FINDINGS: Between Aug 26, 2013, and Sept 21, 2020, 129 patients were randomly assigned to the RIST group (n=63) or control group (n=66). Median age was 5·4 years (IQR 3·7-8·1). 124 patients (78 [63%] male and 46 [37%] female) were included in the efficacy analysis. At a median follow-up of 72 months (IQR 31-88), the median progression-free survival was 11 months (95% CI 7-17) in the RIST group and 5 months (2-8) in the control group (hazard ratio 0·62, one-sided 90% CI 0·81; p=0·019). Median progression-free survival in patients with amplified MYCN (n=48) was 6 months (95% CI 4-24) in the RIST group versus 2 months (2-5) in the control group (HR 0·45 [95% CI 0·24-0·84], p=0·012); median progression-free survival in patients without amplified MYCN (n=76) was 14 months (95% CI 9-7) in the RIST group versus 8 months (4-15) in the control group (HR 0·84 [95% CI 0·51-1·38], p=0·49). The most common grade 3 or worse adverse events were neutropenia (54 [81%] of 67 patients given RIST vs 49 [82%] of 60 patients given control), thrombocytopenia (45 [67%] vs 41 [68%]), and anaemia (39 [58%] vs 38 [63%]). Nine serious treatment-related adverse events were reported (five patients given control and four patients given RIST). There were no treatment-related deaths in the control group and one in the RIST group (multiorgan failure). INTERPRETATION: RIST-rNB-2011 demonstrated that targeting of MYCN-amplified relapsed or refractory neuroblastoma with a pathway-directed metronomic combination of a multkinase inhibitor and an mTOR inhibitor can improve progression-free survival and overall survival. This exclusive efficacy in MYCN-amplified, relapsed neuroblastoma warrants further investigation in the first-line setting. FUNDING: Deutsche Krebshilfe.

[Treatment status of tyrosine kinase inhibitor for newly-diagnosed chronic myeloid leukemia: a domestic multi-centre retrospective real-world study].

Objective: To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China. Methods: Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed. Results: 6 893 patients in CP (n=6 453, 93.6%) or AP (n=440, 6.4%) receiving initial imatinib (n=4 906, 71.2%), nilotinib (n=1 157, 16.8%), dasatinib (n=298, 4.3%) or flumatinib (n=532, 7.2%) -therapy. With the median follow-up of 43 (IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance (n=1 055, 15.3%), intolerance (n=248, 3.6%), pursuit of better efficacy (n=168, 2.4%), economic or other reasons (n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph(+) ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph(+) ACA, poorer TFS; Ph(+) ACA, poorer OS. Conclusion: At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.

An association between Dasatinib, elevated left atrial pressure and pleural effusion.

BACKGROUND: Tyrosine kinase inhibitors (TKI), such as Dasatinib, are effective in the treatment of chronic myeloid leukemia (CML) but associated with development of pleural effusions (PE). The relationship between haemodynamic parameters identified on transthoracic echocardiogram (TTE) such as elevated estimated left atrial pressure (LAP), and PE development is unknown. This study aims to describe associations between Dasatinib, elevated LAP and PE. METHODS: This was a retrospective study of 71 CML patients who underwent TTE during treatment with various TKIs. Descriptive analysis was performed to identify associations between TKI use, PE and elevated LAP on TTE. Multivariate logistic regression was performed to identify predictors of elevated LAP. RESULTS: There were 36 patients treated with Dasatinib, 15 Nilotinib, and 20 Imatinib. Those treated with Dasatinib had higher rates of elevated LAP (44% vs 7% Nilotinib vs 10% Imatinib, p < 0.01) and PE (39% vs 7% vs 0%, p < 0.01). In the 15 patients who developed PE, 14 (93%) patients were treated with Dasatinib. Patients with PE had higher rates of elevated LAP (67% vs 16%, p < 0.01). Nineteen (26.8%) patients in the entire cohort had elevated LAP. After multivariate adjustment, Dasatinib (OR 33.50, 95% CI = 4.99-224.73, p < 0.01) and age (OR 1.12, 95% CI = 1.04-1.20, p < 0.01) were associated with elevated LAP. CONCLUSIONS: Among patients with CML, there was an association between Dasatinib use, PE and elevated LAP on TTE. These findings are hypothesis generating and further studies are required to evaluate the utility of elevated LAP on TTE as a novel marker for prediction and surveillance of PE.

SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive bile duct malignancy that frequently exhibits isocitrate dehydrogenase (IDH1/IDH2) mutations. Mutant IDH (IDHm) ICC is dependent on SRC kinase for growth and survival and is hypersensitive to inhibition by dasatinib, but the molecular mechanism underlying this sensitivity is unclear. We found that dasatinib reduced p70 S6 kinase (S6K) and ribosomal protein S6 (S6), leading to substantial reductions in cell size and de novo protein synthesis. Using an unbiased phosphoproteomic screen, we identified membrane-associated guanylate kinase, WW, and PDZ domain containing 1 (MAGI1) as an SRC substrate in IDHm ICC. Biochemical and functional assays further showed that SRC inhibits a latent tumor-suppressing function of the MAGI1-protein phosphatase 2A (PP2A) complex to activate S6K/S6 signaling in IDHm ICC. Inhibiting SRC led to activation and increased access of PP2A to dephosphorylate S6K, resulting in cell death. Evidence from patient tissue and cell line models revealed that both intrinsic and extrinsic resistance to dasatinib is due to increased phospho-S6 (pS6). To block pS6, we paired dasatinib with the S6K/AKT inhibitor M2698, which led to a marked reduction in pS6 in IDHm ICC cell lines and patient-derived organoids in vitro and substantial growth inhibition in ICC patient-derived xenografts in vivo. Together, these results elucidated the mechanism of action of dasatinib in IDHm ICC, revealed a signaling complex regulating S6K phosphorylation independent of mTOR, suggested markers for dasatinib sensitivity, and described a combination therapy for IDHm ICC that may be actionable in the clinic.

Targeting pathological cells with senolytic drugs reduces seizures in neurodevelopmental mTOR-related epilepsy.

Cortical malformations such as focal cortical dysplasia type II (FCDII) are associated with pediatric drug-resistant epilepsy that necessitates neurosurgery. FCDII results from somatic mosaicism due to post-zygotic mutations in genes of the PI3K-AKT-mTOR pathway, which produce a subset of dysmorphic cells clustered within healthy brain tissue. Here we show a correlation between epileptiform activity in acute cortical slices obtained from human surgical FCDII brain tissues and the density of dysmorphic neurons. We uncovered multiple signatures of cellular senescence in these pathological cells, including p53/p16 expression, SASP expression and senescence-associated ß-galactosidase activity. We also show that administration of senolytic drugs (dasatinib/quercetin) decreases the load of senescent cells and reduces seizure frequency in an MtorS2215F FCDII preclinical mouse model, providing proof of concept that senotherapy may be a useful approach to control seizures. These findings pave the way for therapeutic strategies selectively targeting mutated senescent cells in FCDII brain tissue.

Senolytic combination of dasatinib and quercetin attenuates renal damage in diabetic kidney disease.

BACKGROUND: Senolytic combination of dasatinib and quercetin (DQ) is the most studied senolytics drugs used to treat various age-related diseases. However, its protective activity against diabetic kidney disease (DKD) and underlying mechanisms are uncertain. PURPOSE: To investigate the functions and potential mechanisms of the senolytics DQ on DKD. METHODS: Diabetic db/db mice were administrated DQ or transfected with over-expressed PPARα or shPPARα vector. The positive control group was administered irbesartan. Renal function and fibrotic changes in kidney tissue were tested. Single-cell RNA-seq (scRNA-seq) was conducted to analyze the differential transcriptome between the diabetic and control mice. Molecular docking simulation was used to assess the combination of DQ and potential factors. Moreover, tubular epithelial cells under high-glucose (HG) conditions were incubated with DQ and transfected with or without over-expressed PPARα/siPPARα vector. RESULTS: DQ significantly improved renal function, histopathological and fibrotic changes, alleviated lipid deposition, and increased ATP levels in mice with DKD. DQ reduced multiple fatty acid oxidation (FAO) pathway-related proteins and up-regulated PPARα in db/db mice. Overexpression of PPARα upregulated the expression of PPARα-targeting downstream FAO pathway-related proteins, restored renal function, and inhibited renal fibrosis in vitro and in vivo. Moreover, molecular docking and dynamics simulation analyses indicated the nephroprotective effect of DQ via binding to PPARα. Knockdown of PPARα reversed the effect of DQ on the FAO pathway and impaired the protective effect of DQ during DKD. CONCLUSION: For the first time, DQ was found to exert a renal protective effect by binding to PPARα and attenuating renal damage through the promotion of FAO in DKD.

Multiaction Pt(IV) Prodrugs Releasing Cisplatin and Dasatinib Are Potent Anticancer and Anti-Invasive Agents Displaying Synergism between the Two Drugs.

Herein, we describe the general design, synthesis, characterization, and biological activity of new multitargeting Pt(IV) prodrugs that combine antitumor cisplatin and dasatinib, a potent inhibitor of Src kinase. These prodrugs exhibit impressive antiproliferative and anti-invasive activities in tumor cell lines in both two-dimensional (2D) monolayers of cell cultures and three-dimensional (3D) spheroids. We show that the cisplatin moiety and dasatinib in the investigated Pt(IV) complexes are both involved in the mechanism of action in MCF7 breast cancer cells and act synergistically. Thus, combining dasatinib and cisplatin into one molecule, compared to using individual components in a mix, may bring several advantages, such as significantly higher activity in cancer cell lines and higher selectivity for tumor cells. Most importantly, Pt(IV)-dasatinib complexes hold significant promise for potential anticancer therapies by targeting epithelial-mesenchymal transition, thus preventing the spread and metastasis of tumors, a value unachievable by a simple combination of both individual components.

A physiologically-based pharmacokinetic precision dosing approach to manage dasatinib drug-drug interactions.

Dasatinib, a second-generation tyrosine kinase inhibitor, is approved for treating chronic myeloid and acute lymphoblastic leukemia. As a sensitive cytochrome P450 (CYP) 3A4 substrate and weak base with strong pH-sensitive solubility, dasatinib is susceptible to enzyme-mediated drug-drug interactions (DDIs) with CYP3A4 perpetrators and pH-dependent DDIs with acid-reducing agents. This work aimed to develop a whole-body physiologically-based pharmacokinetic (PBPK) model of dasatinib to describe and predict enzyme-mediated and pH-dependent DDIs, to evaluate the impact of strong and moderate CYP3A4 inhibitors and inducers on dasatinib exposure and to support optimized dasatinib dosing. Overall, 63 plasma profiles from perorally administered dasatinib in healthy volunteers and cancer patients were used for model development. The model accurately described and predicted plasma profiles with geometric mean fold errors (GMFEs) for area under the concentration-time curve from the first to the last timepoint of measurement (AUClast) and maximum plasma concentration (Cmax) of 1.27 and 1.29, respectively. Regarding the DDI studies used for model development, all (8/8) predicted AUClast and Cmax ratios were within twofold of observed ratios. Application of the PBPK model for dose adaptations within various DDIs revealed dasatinib dose reductions of 50%-80% for strong and 0%-70% for moderate CYP3A4 inhibitors and a 2.3-3.1-fold increase of the daily dasatinib dose for CYP3A4 inducers to match the exposure of dasatinib administered alone. The developed model can be further employed to personalize dasatinib therapy, thereby help coping with clinical challenges resulting from DDIs and patient-related factors, such as elevated gastric pH.

Mix and Shake: A Mild Way to Drug-Loaded Lysozyme Nanoparticles.

Biocompatible nanoparticles as drug carriers can improve the therapeutic efficiency of hydrophobic drugs. However, the synthesis of biocompatible and biodegradable polymeric nanoparticles can be time-consuming and often involves toxic solvents. Here, a simple method for protein-based stable drug-loaded particles with a narrow polydispersity is introduced. In this process, lysozyme is mixed with hydrophobic drugs (curcumin, ellipticine, and dasatinib) and fructose to prepare lysozyme-based drug particles of around 150 nm in size. Fructose is mixed with the drug to generate nanoparticles that serve as templates for the lysozyme coating. The effect of lysozyme on the physicochemical properties of these nanoparticles is studied by transmission electron microscopy (TEM) and scattering techniques (e.g., dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS)). We observed that lysozyme significantly stabilized the curcumin fructose particles for 7 days. Moreover, additional drugs, such as ellipticine and dasatinib, can be loaded to form dual-drug particles with narrow polydispersity and spherical morphology. The results also reveal that lysozyme dual ellipticine/dasatinib curcumin particles enhance the cytotoxicity and uptake on MCF-7 cells, RAW 264.7 cells, and U-87 MG cells due to the larger and rigid hydrophobic core. In summary, lysozyme in combination with fructose and curcumin can serve as a powerful combination to form protein-based stable particles for the delivery of hydrophobic drugs.

Co-assembly of cisplatin and dasatinib in hyaluronan nanogel to combat triple negative breast cancer with reduced side effects.

Treatment for triple negative breast cancer (TNBC) remains a huge challenge due to the lack of targeted therapeutics and tumor heterogenicity. Cisplatin (Cis) have demonstrated favorable therapeutic response in TNBC and thus is used together with various kinase inhibitors to fight the heterogenicity of TNBC. The combination of Cis with SRC inhibitor dasatinib (DAS) has shown encouraging anti-TNBC efficacy although the additive toxicity was commonly observed. To overcome the severe side effects of this Cis involved therapy, here we co-encapsulated Cis and DAS into a self-assembled hyaluronan (HA) nanogel (designated as HA/Cis/DAS (HCD) nanogel) to afford the TNBC targeted delivery by using the 4T1 mouse model. The acquired HCD nanogel was around 181 nm in aqueous solution, demonstrating the pharmacological activities of both Cis and DAS. Taking advantages of HA's targeting capability towards CD44 that is overexpressed on many TNBC cells, the HCD could well maintain the anticancer efficacy of the Cis and DAS combination, significantly increase the maximum tolerated dose and relieve the renal toxicity in vivo. The current HCD nanogel provides a potent strategy to improve the therapeutic outcome of Cis and DAS combination and thus representing a new targeted treatment option for TNBC.

Combination of Dasatinib and Quercetin alleviates heat stress-induced cognitive deficits in aged and young adult male mice.

OBJECTIVE: Dasatinib and quercetin (D & Q) have demonstrated promise in improving aged-related pathophysiological dysfunctions in humans and mice. Herein we aimed to ascertain whether the heat stress (HS)-induced cognitive deficits in aged or even young adult male mice can be reduced by D & Q therapy. METHODS: Before the onset of HS, animals were pre-treated with D & Q or placebo for 3 consecutive days every 2 weeks over a 10-week period. Cognitive function, intestinal barrier permeability, and blood-brain barrier permeability were assessed. RESULTS: Compared to the non-HS young adult male mice, the HS young adult male mice or the aged male mice had significantly lesser extents of the exacerbated stress reactions, intestinal barrier disruption, endotoxemia, systemic inflammation and oxidative stress, blood-brain barrier disruption, hippocampal inflammation and oxidative stress, and cognitive deficits evaluated at 7 days post-HS. All the cognitive deficits and other syndromes that occurred in young adult HS mice or in aged HS mice were significantly attenuated by D & Q therapy (P < 0.01). Compared to the young adult HS mice, the aged HS mice had significantly (P < 0.01) higher severity of cognitive deficits and other related syndromes. CONCLUSIONS: First, our data show that aged male mice are more vulnerable to HS-induced cognitive deficits than those of the young adult male mice. Second, we demonstrate that a combination of D and Q therapy attenuates cognitive deficits in heat stressed aged or young adult male mice via broad normalization of the brain-gut-endotoxin axis function.

The Differential Effect of Senolytics on SASP Cytokine Secretion and Regulation of EMT by CAFs.

The tumor microenvironment (TME) plays an essential role in tumor progression and in modulating tumor response to anticancer therapy. Cellular senescence leads to a switch in the cell secretome, characterized by the senescence-associated secretory phenotype (SASP), which may regulate tumorigenesis. Senolytic therapy is considered a novel anticancer strategy that eliminates the deleterious effects of senescent cells in the TME. Here, we show that two different types of senolytic drugs, despite efficiently depleting senescent cells, have opposite effects on cancer-associated fibroblasts (CAFs) and their ability to regulate epithelial-mesenchymal transition (EMT). We found that senolytic drugs, navitoclax and the combination of dasatinib/quercetin, reduced the number of spontaneously senescent and TNF-induced senescent CAFs. Despite the depletion of senescent cells, the combination of dasatinib/quercetin versus navitoclax increased the secretion of the SASP pro-inflammatory cytokine IL-6. This differential effect correlated with the promotion of enhanced migration and EMT in MC38 colorectal cancer cells. Our results demonstrate that some senolytics may have side effects unrelated to their senolytic activity and may promote tumorigenesis. We argue for more careful and extensive studies of the effects of senolytics on various aspects of tumor progression and tumor resistance to therapy before the senolytic strategy is implemented in the clinic.

Enhancement of NETosis by ACE2-cross-reactive anti-SARS-CoV-2 RBD antibodies in patients with COVID-19.

BACKGROUND: High levels of neutrophil extracellular trap (NET) formation or NETosis and autoantibodies are related to poor prognosis and disease severity of COVID-19 patients. Human angiotensin-converting enzyme 2 (ACE2) cross-reactive anti-severe acute respiratory syndrome coronavirus 2 spike protein receptor-binding domain (SARS-CoV-2 RBD) antibodies (CR Abs) have been reported as one of the sources of anti-ACE2 autoantibodies. However, the pathological implications of CR Abs in NET formation remain unknown. METHODS: In this study, we first assessed the presence of CR Abs in the sera of COVID-19 patients with different severity by serological analysis. Sera and purified IgG from CR Abs positive COVID-19 patients as well as a mouse monoclonal Ab (mAb 127) that can recognize both ACE2 and the RBD were tested for their influence on NETosis and the possible mechanisms involved were studied. RESULTS: An association between CR Abs levels and the severity of COVID-19 in 120 patients was found. The CR Abs-positive sera and IgG from severe COVID-19 patients and mAb 127 significantly activated human leukocytes and triggered NETosis, in the presence of RBD. This NETosis, triggered by the coexistence of CR Abs and RBD, activated thrombus-related cells but was abolished when the interaction between CR Abs and ACE2 or Fc receptors was disrupted. We also revealed that CR Abs-induced NETosis was suppressed in the presence of recombinant ACE2 or the Src family kinase inhibitor, dasatinib. Furthermore, we found that COVID-19 vaccination not only reduced COVID-19 severity but also prevented the production of CR Abs after SARS-CoV-2 infection. CONCLUSIONS: Our findings provide possible pathogenic effects of CR Abs in exacerbating COVID-19 by enhancing NETosis, highlighting ACE2 and dasatinib as potential treatments, and supporting the benefit of vaccination in reducing disease severity and CR Abs production in COVID-19 patients.

[The Effect and Safety of Flumatinib in Patients with Chronic Myelogenous Leukemia Failed First-and Second-line Treatment].

OBJECTIVE: To analyze the efficacy and safety of flumatinib, a second-generation tyrosine kinase inhibitor (TKI) independently developed in China, in patients with chronic myelogenous leukemia in chronic phase (CML-CP) who falied first-line and second-line treatment. METHODS: The clinical data of 30 CML-CP patients treated with flumatinib in Lianyungang First People's Hospital from January 2020 to September 2022 were collected retrospectively. Among them, 15 patients who received imatinib first-line treatment but failed treatment were included in the second-line group, and the other 15 patients who failed second-line treatment with nilotinib or dasatinib were included in the third-line group. The hematological and molecular responses of the patients in the two groups at 3, 6 and 12 months of treatment, and the event-free survival (EFS) and adverse reactions of patients at the end of follow-up were statistical analyzed. RESULTS: At 3, 6, and 12 months of treatment, 10, 11, and 12 patients in the second line group achieved major molecular response (MMR), which was higher than that of 3, 4, and 5 patients in the third line group (P =0.010, P =0.011, P =0.010). At 3 months of treatment, 12 and 13 patients achieved complete hematological response (CHR) and early molecular response (EMR) in the second-line group, which was higher than that of 9 and 13 patients in the third-line group, but the difference between the two groups was not statistically significant (P =0.232, P =1.000); At 6 and 12 months of treatment, 6 and 7 patients in the second-line group achieved MR4.5, which were higher than of 3 and 2 cases in the third-line group, but the difference was not statistically significant (P =0.427, P =0.713). The hematological adverse reactions of patients in the second-line group during treatment the period were mainly grade 1-2 thrombocytopenia and anemia, and no grade 3-4 of adverse reactions occurred. In the third-line group, there were 2 cases of grade 1-2 thrombocytopenia, grade 1-2 anemia and white blood cell 3 cases were reduced each, 1 case of grade 3-4 anemia, 2 cases of grade 3-4 neutropenia. The non-hematological adverse reactions in the second-line group were rash (2 cases), headache (1 case), diarrhea (1 case), fatigue (1 case), limb pain (1 case). There were 1 cases of diarrhea, 1 cases of nausea, and 1 cases of edema in the third-line group. There was no statistical significance in hematological and non-hematological adverse reactions between the two groups of patients (P >0.05). At the end of follow-up, the EFS rate of patients in the second-line group was higher than that in the third-line group (100% vs 93.3%), but the difference was not statistically significant (P =0.317). CONCLUSION: The second-generation TKI flumatinib independently developed in China, has good curative effect and safety for CML-CP patients who failed first-line and second-line treatment.

[Discontinuation of tyrosine kinase inhibitors before epiphyseal closure leading to improved short stature in pediatric chronic myelogenous leukemia].

A 3-year-old boy was referred to our hospital with splenomegaly. Blood tests revealed hyperleukocytosis and bone marrow examination showed major BCR::ABL1 fusion, leading to the diagnosis of chronic myelogenous leukemia (CML). Due to intolerance, the tyrosine kinase inhibitor (TKI) was changed from imatinib to dasatinib to nilotinib. The patient achieved molecular remission but became markedly short in stature, measuring 129.3 cm (height standard deviation score [SDS] -3.3) at the age of 12. TKI therapy was discontinued at age 12 years and 10 months, which was 9 years and 8 months after the start of TKI and 1 year and 6 months after achievement of MR4.0, as discontinuation before epiphyseal closure would not improve short stature. At 2 years and 6 months after discontinuation, the patient's height improved to 156.1 cm (SDS-2.0) without relapse. Growth suppression by TKIs is a problem in the management of pediatric CML. This case illustrates how improvement in severe short stature can be achieved by discontinuing TKI therapy before epiphyseal closure.