Current Progress on the Influence Human Genetics Has on the Efficacy of Tyrosine Kinase Inhibitors Used to Treat Chronic Myeloid Leukemia.

The use of tyrosine kinase inhibitors (TKIs) has become the mainstay of treatment in patients suffering from chronic myeloid leukemia (CML), an adult leukemia caused by a reciprocal translocation between chromosomes 9 and 22, which creates an oncogene resulting in a myeloproliferative neoplasm. These drugs function by inhibiting the ATP-binding site on the fusion oncoprotein and subsequently halting proliferative activity. The goal of this work is to investigate the current state of research into genetic factors that influence the efficacy of four FDA-approved TKIs used to treat CML. This overview attempts to identify genetic criteria that could be considered when choosing one drug over the others and to identify where more research is needed. Our results suggest that the usual liver enzymes impacting patient response may not be a major factor affecting the efficacy of imatinib, nilotinib, and bosutinib, and yet, that is where most of the past research has focused. More research is warranted on the impact that human polymorphisms of the CYP enzymes have on dasatinib. The impact of polymorphisms in UGT1A1 should be investigated thoroughly in other TKIs, not only nilotinib. The role of influx and efflux transporters has been inconsistent thus far, possibly due to failures to account for the multiple proteins that can transport TKIs and the impact that tumors have on transporter expression. Because physicians cannot currently use a patient's genetic profile to better target their treatment with TKIs, it is critical that more research be conducted on auxiliary pathways or off-target binding effects to generate new leads for further study. Hopefully, new avenues of research will help explain treatment failures and improve patient outcomes.

Rapamycin vs TORin-1 or Gleevec vs Nilotinib: Simple chemical evolution that converts PAK1-blockers to TOR-blockers or vice versa?

Both PAK1 (RAC/CDC42-activating kinase 1) and TOR (Target of Rapamycin) are among the major oncogenic/ageing kinases. However, they play the opposite role in our immune system, namely immune system is suppressed by PAK1, while it requires TOR. Thus, PAK1-blockers, would be more effective for therapy of cancers, than TOR-blockers. Since 2015 when we discovered genetically that PDGF-induced melanogenesis depends on "PAK1", we are able to screening a series of PAK1-blockers as melanogenesis-inhibitors which could eventually promote longevity. Interestingly, rapamycin, the first TOR-inhibitor, promotes melanogenesis, clearly indicating that TOR suppresses melanogenesis. However, a new TOR-inhibitor called TORin-1 no longer suppresses immune system, and blocks melanogenesis in cell culture. These observations strongly indicate that TORin-1 acts as PAK1-blockers, instead of TOR-blockers, in vivo. Thus, it is most likely that melanogenesis in cell culture could enable us to discriminate PAK1-blockers from TORblockers.

The Cardiovascular Event Risk Associated with Tyrosine Kinase Inhibitors and the Lipid Profile in Patients with Chronic Myeloid Leukemia.

BACKGROUND: Second- and third-generation tyrosine kinase inhibitors (TKIs) are now available to treat chronic-phase chronic myeloid leukemia (CP-CML) in the first and second line. However, vascular adverse events (VAEs) have been reported for patients with CML treated with some TKIs. METHODS: We retrospectively evaluated the cumulative incidence (CI) and cardiovascular risk for 210 patients included in the Canarian Registry of CML. RESULT: With a mean follow up of 6 years, 19/210 (9.1%) patients developed VAEs, all of whom presented at least one cardiovascular risk factor at diagnosis. The mean time to VAE presentation was 54 months from the start of TKI treatment. We found a statistically significant difference between the CI for nilotinib-naïve vs. nilotinib-treated patients (p = 0.005), between dasatinib-naïve and dasatinib-treated patients (p = 0.039), and for patients who received three lines of treatment with first-line imatinib vs. first-line imatinib (p < 0.001). From the multivariable logistic regression analyses, the Framingham risk score (FRS) and patients with three lines of TKI with first-line imatinib were the only variables with statistically significant hazard ratios for VAE development. Significant increases in HDL-C and total cholesterol may also be predictive for VAE. CONCLUSIONS: In conclusion, it is important to estimate the cardiovascular risk at the diagnosis of CML as it can help determine whether a patient is likely to develop a VAE during TKI treatment.

Synthesis of Novel Nilotinib Analogues and Biological Evaluation of Their Antiplatelet Activity and Functionality towards Cancer Cell Proliferation In Vitro.

Nilotinib, a second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia (CML), inhibits Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl-expressing cells, as well as other malignancies. In the present study, new nilotinib analogues were synthesized and fully characterized. A platelet aggregation assay was performed, and the expression of P-selectin and PAC-1, as well as the effect on the proliferation of healthy endothelial cells, were evaluated. The expression and antimetastatic effects of E-cadherin and N-cadherin were assessed. The analogues inhibited platelet aggregation in a statistically significant manner compared to nilotinib, while they exhibited a strong inhibitory effect on P-selectin and PAC-1 expression when activated by AA. All three analogues caused arrest in the mitosis phase of the HepG2 cell cycle, while analogue-1 exhibited the most potent apoptotic effect compared to nilotinib. Interestingly, none of them promoted apoptosis in HUVECs. All the analogues reduced the expression of E- and N-cadherin in different amounts, while the analogues-1 and -3 exhibited similar antimigratory effects on HepG2 cells. The results of this study reveal considerable potential to develop new tyrosine kinase inhibitors with improved antiplatelet and antitumor properties.

Hematopoietic cell kinase as a nexus for drug repurposing: implications for cancer and HIV therapy.

Hematopoietic cell kinase (HCK) has emerged as a potential target for therapeutic intervention in cancer and HIV infection because of its critical role in critical signaling pathways. Repurposing FDA-approved drugs offers an efficient strategy to identify new treatment options. Here, we address the need for novel therapies in cancer and HIV by investigating the potential of repurposed drugs against HCK. Our goal was to identify promising drug candidates with high binding affinities and specific interactions within the HCK binding pocket. We employed an integrated computational approach combining molecular docking and extensive molecular dynamics (MD) simulations. Initially, we analyzed the binding affinities and interaction patterns of a library of FDA-approved drugs sourced from DrugBank. After careful analysis, we focused on two compounds, Nilotinib and Radotinib, which exhibit exceptional binding affinities and specificity to the HCK binding pocket, including the active site. Additionally, we assessed the pharmacological properties of Nilotinib and Radotinib, making them attractive candidates for further drug development. Extensive all-atom MD simulations spanning 200 nanoseconds (ns) elucidated the conformational dynamics and stability of the HCK-Nilotinib and HCK-Radotinib complexes. These simulations demonstrate the robustness of these complexes over extended timescales. Our findings highlighted the potential of Nilotinib and Radotinib as promising candidates against HCK that offer valuable insights into their binding mechanisms. This computational approach provides a comprehensive understanding of drug interactions with HCK and sets the stage for future experimental validation and drug development endeavors.Communicated by Ramaswamy H. Sarma.

Nilotinib in combination with sunitinib renders MCL-1 for degradation and activates autophagy that overcomes sunitinib resistance in renal cell carcinoma.

PURPOSE: Sunitinib is a recommended drug for metastatic renal cell carcinoma (RCC). However, the therapeutic potential of sunitinib is impaired by toxicity and resistance. Therefore, we seek to explore a combinatorial strategy to improve sunitinib efficacy of low-toxicity dose for better clinical application. METHODS: We screen synergistic reagents of sunitinib from a compound library containing 1374 FDA-approved drugs by in vitro cell viability evaluation. The synergistically antiproliferative and proapoptotic effects were demonstrated on in vitro and in vivo models. The molecular mechanism was investigated by phosphoproteomics, co-immunoprecipitation, immunofluorescence and western-blot assays, etc. RESULTS: From the four-step screening, nilotinib stood out as a potential synergistic killer combined with sunitinib. Subsequent functional evaluation demonstrated that nilotinib and sunitinib synergistically inhibit RCC cell proliferation and promote apoptosis in vitro and in vivo. Mechanistically, nilotinib activates E3-ligase HUWE1 and in combination with sunitinib renders MCL-1 for degradation via proteasome pathway, resulting in the release of Beclin-1 from MCL-1/Beclin-1 complex. Subsequently, Beclin-1 induces complete autophagy flux to promote antitumor effect. CONCLUSION: Our findings revealed that a novel mechanism that nilotinib in combination with sunitinib overcomes sunitinib resistance in RCC. Therefore, this novel rational combination regimen provides a promising therapeutic avenue for metastatic RCC and rationale for evaluating this combination clinically.

Novel Four-Way Variant Translocation, t(1;9;22;16)(q21;q34;q11.2;q24), in a Patient with Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) is characterized by the Philadelphia (Ph) chromosome resulting from the translocation of t(9;22)(q34;q11), producing the BCR::ABL1 fusion gene. Variant Ph chromosome translocations, involving rearrangements in chromosomes other than 9 and 22, occur in 5-10% of CML cases. Herein, we report a unique case of a 36-year-old male with a four-way variant Ph chromosome. Conventional chromosomal analysis performed on bone marrow aspirate samples showed 46, XY, t(1;9;22;16)(q21;q34;q11.2;q24). Nested RT-PCR of the BCR::ABL1 gene revealed a major BCR::ABL rearrangement. The treatment with nilotinib achieved a complete hematologic, cytogenetic, and molecular response after 12 months.

Second Treatment-Free Remission Attempt in Patients with Chronic Myeloid Leukemia.

Long-term survival outcomes of patients with chronic myeloid leukemia in the chronic phase are now similar to those of the general population, following the introduction of ABL1 tyrosine kinase inhibitors (TKIs). Approximately 40% to 80% of patients with chronic myeloid leukemia successfully achieved treatment-free remission after the first attempt of TKI discontinuation (TFR1), after achieving a durable deep molecular response. However, the possibility of achieving treatment-free remission after a second attempt of TKI discontinuation (TFR2) remains unclear. Therefore, we reviewed current TFR2 studies to clarify the feasibility of achieving TFR2. We identified 5 TFR2 clinical trials and 2 real-world reports. TFR2 attempt may be feasible after retreatment with imatinib, nilotinib, or dasatinib. Patients who have achieved MR4.0 or deeper durable molecular remission are eligible to enter the TFR2 phase. Imatinib is well tolerated and can be administered for consolidative treatment before the TFR2 attempt, whereas drug-related adverse effects of nilotinib or dasatinib affect their tolerability and might lead to discontinuation. Late onset relapse (> 1 year or > 2 year) was often reported, thus careful monitoring is needed.

Virtual Screening, Molecular Docking, and Dynamic Simulations Revealed TGF-ß1 Potential Inhibitors to Curtail Cervical Cancer Progression.

Cervical cancer is one of the main causes of cancer death in women globally, and its epidemiology is similar to that of a low-infectious venereal illness. Many sexual partners and early age at first intercourse have been demonstrated to have a significant influence on risk. TGF-ß1 is a multifunctional cytokine that is required for cervical carcinoma metastasis, tumor development, progression, and invasion. The TGF-ß1 signaling system plays a paradoxical function in cancer formation, suppressing early-stage tumor growth while increasing tumor progression and metastasis. Importantly, TGF-ß1 and TGF-ß receptor 1 (TGF-ßR1), two components of the TGF-ß signaling system, are substantially expressed in a range of cancers, including breast cancer, colon cancer, gastric cancer, and hepatocellular carcinoma. The current study aims to investigate possible inhibitors targeting TGF-ß1 using molecular docking and dynamic simulations. To target TGF-ß1, we used anti-cancer drugs and small molecules. MVD was utilized for virtual screening, and the highest scoring compound was then subjected to MD simulations using Schrodinger software package v2017-1 (Maestro v11.1) to identify the most favorable lead interactions against TGF-ß1. The Nilotinib compound has shown the least XP Gscore of -2.581 kcal/mol, 30ns MD simulations revealing that the Nilotinib- TGF-ß1 complex possesses the lowest energy of -77784.917 kcal/mol. Multiple parameters, including Root Mean Square Deviation, Root Mean Square Fluctuation, and Intermolecular Interactions, were used to analyze the simulation trajectory. Based on the results; we conclude that the ligand nilotinib appears to be a promising prospective TGF-ß1inhibitor for reducing TGF-ß1 expression ad halting cervical cancer progression.

Association of Nilotinib With Cardiovascular Diseases in Patients With Chronic Myelogenous Leukemia: A National Population-Based Cohort Study.

BACKGROUND: Tyrosine kinase inhibitor (TKI) treatment has been identified to be a risk factor for metabolic syndrome and cardiovascular diseases (CVDs) in patients diagnosed with chronic myeloid leukemia (CML). However, the specific contribution of post-TKI metabolic syndrome and the individual TKIs, including imatinib, nilotinib, and dasatinib, contribute to the development of CVDs remains unclear. METHODS: We conducted a nationwide database to investigate the incidence of post-TKI metabolic syndrome, including diabetes, hyperlipidemia, and hypertension, as well as their association with CVDs. To compare the risk of post-TKI comorbidities and CVDs among TKIs, we utilized the incidence rate ratio (IRR), and subdistribution hazard ratio (SHR) calculated from multiple Fine-Gray models. RESULTS: A total of 1211 patients without diabetes, 1235 patients without hyperlipidemia, and 1074 patients without hypertension were enrolled in the study. The incidence rate of post-TKI diabetes and hyperlipidemia was the highest in patients treated with nilotinib compared to imatinib and dasatinib (IRRs ≥ 3.15, Ps ≤ .047). After adjusting for confounders, nilotinib remained a significant risk factor for post-TKI diabetes and hyperlipidemia at an SHR of 3.83 (P < .001) and 5.15 (P < .001), respectively. Regarding the occurrence of CVDs, patients treated with nilotinib were more likely to develop CVDs than those treated with imatinib in non-hyperlipidemic group (IRR = 3.21, P = .020). Pre-existing and post-TKI hyperlipidemia were found to have a stronger association with CVDs, with SHR values of 5.81 (P = .034) and 13.21 (P = .001), respectively. CONCLUSION: The findings of this study indicate that nilotinib treatment is associated with increased risks of diabetes and hyperlipidemia, with hyperlipidemia being the most significant risk for CVDs. Therefore, we recommend that CML patients receiving nilotinib should undergo screening for diabetes and hyperlipidemia prior to initiating TKI treatment. Additionally, regular monitoring of lipid profiles during TKI therapy and implementing effective management strategies to control hyperlipidemia are crucial.

Nilotinib exhibits less toxicity than imatinib and influences the immune state by modulating iNOS, p-p38 and p-JNK in LPS/IFN gamma-activated macrophages.

In this study, we aimed to analyze the effects of first and second-generation Bcr-Abl tyrosine kinase inhibitors, imatinib and nilotinib on LPS/IFN gamma activated RAW 264.7 macrophages. Our data revealed that imatinib was less effective on nitrite levels and more toxic on macrophages compared to nilotinib. Therefore, we further analysed the effect of nilotinib on various inflammatory markers including iNOS, COX-2, NFkB, IL-6, p-ERK, p-p38 and p-JNK in LPS/IFN gamma activated RAW264.7 macrophages. Spectrophotometric viability test and Griess assay,western blot, RT-PCR and luciferase reporter assays were used to analyze the biological activity of nilotinib. Our findings revealed that nilotinib decreases nitrite levels, iNOS mRNA, iNOS and p-p38 protein expressions significantly whereas induces IL-6 mRNA and p-JNK protein expressions at particular doses. We did not find significant effect of nilotinib on COX-2, p-ERK and nuclear p65 proteins and NFkB transcriptional activity. In addition, the binding mode of nilotinib to iNOS protein was predicted by molecular docking. According to the docking analyses, nilotinib exhibited hydrophobic interactions between MET349, ALA191, VAL346, PHE363, TYR367, MET368, CYS194, TRP366 residues at the binding pocket and the molecule as well as van der Waals interactions at specific residues. In conclusion, our results reveal that, in addition to its anticancer activity, nilotinib can exhibit immune modulatory effects on macrophages through its effects on iNOS, IL-6, p-p38 and p-JNK.

Physiologically Based Pharmacokinetic Modeling of Nilotinib for Drug-Drug Interactions, Pediatric Patients, and Pregnancy and Lactation.

Nilotinib is a second-generation BCR-ABL tyrosine kinase inhibitor for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia in both adult and pediatric patients. The pharmacokinetics (PK) of nilotinib in specific populations such as pregnant and lactating people remain poorly understood. Therefore, the objectives of the current study were to develop a physiologically based pharmacokinetic (PBPK) model to predict nilotinib PK in virtual drug-drug interaction (DDI) studies, as well as in pediatric, pregnant, and lactating populations. The nilotinib PBPK model was built in PK-Sim, which is part of the free and open-source software Open Systems Pharmacology. The observed clinical data for the validation of the nilotinib models were obtained from the literature. The model reasonably predicted nilotinib concentrations in the adult population; the DDIs between nilotinib and rifampin or ketoconazole in the adult population; and the PK in the pediatric, pregnant, and lactating populations, although in the latter 2 populations plasma concentrations were slightly underestimated. The ratio of predicted versus observed PK parameters for the adult model ranged from 0.71 to 1.11 for area under the concentration-time curve and 0.55 to 0.95 for maximum concentration. For the DDI, the predicted area under the concentration-time curve ratio and maximum concentration ratio fell within the Guest criterion. The current study demonstrated the utility of using PBPK modeling to understand the mechanistic basis of PK differences between adults and specific populations, such as pediatrics, and pregnant and lactating individuals, indicating that this technology can potentially inform or optimize dosing conditions in specific populations.

The new Systematic Coronary Risk Evaluation (SCORE2 and SCORE2-OP) estimates the risk of arterial occlusive events in chronic myeloid leukemia patients treated with nilotinib or ponatinib.

Patients with chronic myeloid leukemia (CML) treated with nilotinib or ponatinib may experience arterial occlusive events (AOEs). It is currently recommended to thoroughly assess cardiovascular risk factors before treating CML. We identified 455 consecutive CML adult patients, 335 treated with nilotinib and 120 with ponatinib; 380 patients without previous cardiovascular diseases or diabetes were stratified according to the Systematic Coronary Risk Evaluation (SCORE2) and SCORE2-Older Persons (SCORE2-OP). This updated algorithm from the European Society of Cardiology (ESC) estimates a 10-year risk of fatal and non-fatal cardiovascular diseases. It is based on sex, age, smoking habits, systolic blood pressure, non-high-density lipoprotein cholesterol, and European geographical region of cardiovascular risk. The SCORE2/SCORE2-OP algorithm translated more patients (50.2%) to the high-very high cardiovascular risk category than the previous SCORE (25.3%). Patients with a high to very high SCORE2/SCORE2-OP risk showed a significantly higher incidence rate of AOEs (69.2% vs. 46.5%, p < 0.001). The older SCORE was less specific in estimating AOEs in patients classified as low-intermediate risk (69.8 vs. 54.2%). In multivariate analysis, no associations were found between AOEs and gender, age, and type or dose of tyrosine kinase inhibitor. Only the SCORE2/SCORE2-OP risk was confirmed as a significant predictive factor (p = 0.028; hazard ratio = 2.2; 95% confidence interval = 1.1-4.5). Patients with AOEs required, in most cases, imaging diagnostic tests, additional drugs, and sometimes invasive procedures, increasing access to visits and hospital management. This real-life study suggested that the SCORE2 and SCORE2-OP charts could help identify cardiovascular fragility in CML patients providing them with more attention and a proper TKI selection.

Identification of common genes and pathways underlying imatinib and nilotinib treatment in CML: a Bioinformatics Study.

Imatinib (IMA) and nilotinib are the first and second generations of BCR-ABL tyrosine kinase inhibitors, which widely applied in chronic myeloid leukemia (CML) treatment. Here we aimed to provide new targets for CML treatment by transcriptome analysis. Microarray data GSE19567 was downloaded and analyzed from Gene Expression Omnibus (GEO) to identify common genes, which are downregulated or upregulated in K562-imatinib and K562-nilotinib treated cells. The differentially expressed genes (DEGs) were assessed, and STRING and Cytoscape were used to create the protein-protein interaction (PPI) network. In imatinib and nilotinib treated groups' comparison, there were common 626 upregulated and 268 downregulated genes, which were differentially expressed. The GO analysis represented the enrichment of DEGs in iron ion binding, protein tyrosine kinase activity, transcription factor activity, ATP binding, sequence-specific DNA binding, cytokine activity, the mitochondrion, sequence-specific DNA binding, plasma membrane and cell-cell adherens junction. KEGG pathway analysis revealed that downregulated DEGs were associated with pathways including microRNAs in cancer and PI3K-Akt signaling pathway. Furthermore, upregulated DEGs were involved in hematopoietic cell lineage, lysosome and chemical carcinogenesis. Among the upregulated genes, MYH9, MYH14, MYL10, MYL7, MYL5, RXRA, CYP1A1, FECH, AKR1C3, ALAD, CAT, CITED2, CPT1A, CYP3A5, CYP3A7, FABP1, HBD, HMBS and PPOX genes were found as hub genes. Moreover, 20 downregulated genes, YARS, AARS, SARS, GARS, CARS, IARS, RRP79, CEBPB, RRP12, UTP14A, PNO1, CCND1, DDX10, MYC, WDR43, CEBPG, DDIT3, VEGFA, PIM1 and TRIB3 were identified as hub genes. These genes have the potential to become target genes for diagnosis and therapy of CML patients.

Computational Design, Synthesis, and Bioevaluation of 2-(Pyrimidin-4-yl)oxazole-4-carboxamide Derivatives: Dual Inhibition of EGFRWT and EGFRT790M with ADMET Profiling.

The ongoing research in cancer treatment underscores the significance of dual epidermal growth factor receptor (EGFR) kinase inhibitors targeting both mutant and wild-type variants. In this study, employing in silico fragment-based drug design (FBDD) and computational analysis, we have successfully developed a novel chemical series of 2-(pyrimidin-4-yl)oxazole-4-carboxamide (16a-j) derivatives designed as dual EGFR kinase inhibitors. A comparative in vitro anticancer profile of the newly synthesized compounds (16a-j) was tested against a panel of five human cancer cell lines like prostate cancer (PC3 & DU-145), lung cancer (A549), human liver cancer (HEPG2), and breast cancer (MDA-MB-468) by employing MTT method. In this experiment a well-known anticancer agent, Etoposide was used as positive control. Most of the derivatives demonstrated significant cytotoxicity, ranging from excellent to moderate levels. The IC50 values for the synthesized compounds observed between 0.10 ± 0.052 to 9.83 ± 5.96 µM, while the positive control exhibited a range of 1.97 ± 0.45 µM to 3.08 ± 0.135 µM. These results indicate that the synthesized compounds demonstrate higher cytotoxic potency in comparison to the reference compound. Furthermore, all these compounds underwent screening against normal Vero cell lines to assess their cytotoxicity. In each case, the observed cytotoxicity values (IC50) were higher than 22 µM, affirming the compounds selectivity for cancer cell lines. Among the compounds investigated, three compounds (16a, 16e, and 16i) exhibited notable cytotoxicity, while two compounds (16g and 16h) demonstrated exceptional cytotoxicity. The selectivity index of the tested compounds indicates a pronounced preference for targeting cancer cell lines over normal cells. Furthermore, all the compounds 16a-j underwent assessment for their EGFR kinase inhibitory activity against both EGFRWT and mutated EGFRT790M. The results unveiled the potential eligibility of this new series of compounds as effective EGFR inhibitors. Moreover, compound 16h underwent additional testing for cell cycle analysis, revealing its capability to arrest the cell cycle in the G2/M phase and induce apoptosis at the IC50 concentration.

Remodeling of the liver fibrosis microenvironment based on nilotinib-loaded multicatalytic nanozymes with boosted antifibrogenic activity.

Liver fibrosis is a reversible pathological process caused by chronic liver damage and a major risk factor for hepatocellular carcinoma (HCC). Hepatic stellate cell (HSC) activation is considered the main target for liver fibrosis therapy. However, the efficiency of this strategy is limited due to the complex microenvironment of liver fibrosis, including excessive extracellular matrix (ECM) deposition and hypoxia-induced imbalanced ECM metabolism. Herein, nilotinib (NIL)-loaded hyaluronic acid (HA)-coated Ag@Pt nanotriangular nanozymes (APNH NTs) were developed to inhibit HSCs activation and remodel the microenvironment of liver fibrosis. APNH NTs efficiently eliminated intrahepatic reactive oxygen species (ROS) due to their inherent superoxide dismutase (SOD) and catalase (CAT) activities, thereby downregulating the expression of NADPH oxidase-4 (NOX-4) and inhibiting HSCs activation. Simultaneously, the oxygen produced by the APNH NTs further alleviated the hypoxic microenvironment. Importantly, the released NIL promoted collagen depletion by suppressing the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), thus synergistically remodeling the microenvironment of liver fibrosis. Notably, an in vivo study in CCl4-induced mice revealed that APNH NTs exhibited significant antifibrogenic effects without obvious long-term toxicity. Taken together, the data from this work suggest that treatment with the synthesized APNH NTs provides an enlightening strategy for remodeling the microenvironment of liver fibrosis with boosted antifibrogenic activity.

Low-Intensity and Chemo-Free Treatments in Ph+ ALL: Progression-Free Survival Based on Indirect Comparisons.

In Philadelphia chromosome-positive B-cell (Ph+) acute lymphoblastic leukemia (LLA), growing evidence has accumulated regarding the efficacy of low-intensity and chemo-free regimens. Our objective was to analyze all recent trials evaluating these treatments and to compare them in terms of efficacy. We applied the Shiny method, an artificial intelligence technique, to analyze Kaplan-Meier curves and reconstruct patient-level data. Reconstructed patient data were then evaluated through standard survival statistics and subjected to indirect head-to-head treatment comparisons. The endpoint was progression-free survival (PFS). Based on 432 reconstructed patients, eight trials were analyzed. The survival data from these trials were pooled into three types of treatments: (i) treatments based on tyrosine kinase inhibitors (TKIs) combined with reduced-intensity chemotherapy (denoted as TKICHE); (ii) TKIs associated with steroids with no chemotherapy (TKISTE); (iii) chemotherapy-free combinations of blinatumomab plus TKIs (TKIBLI). According to the Shiny method, the three PFS curves were reported in a single Kaplan-Meier graph and subjected to survival statistics. In terms of PFS, TKIBLI ranked first, TKICHE second, and TKISTE third; the differences between these three regimens were statistically significant. This multi-treatment Kaplan-Meier graph, generated through the Shiny method, summarized the current evidence on these treatments in both qualitative and quantitative terms.

18 months follow-up of deep molecular response 4.5 (MR4.5) with nilotinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia: a prospective, multi-center study in China.

Introduction: Early stable deep molecular response (DMR) to nilotinib is associated with goal of treatment-free remission (TFR) in patients with chronic-phase chronic myeloid leukemia (CML-CP). It is important to early distinguish between patients who can achieve a DMR and those who are fit for TFR. Methods: We performed a multicenter study to explore the early cumulative MR4.5 rate at 18 months with nilotinib in patients with newly diagnosed CML-CP (ND-CML-CP) in China. Of the 29 institutes, 106 patients with ND-CML-CP received nilotinib (300 mg BID). Results and discussion: The cumulative MR4.5 rate of nilotinib treatment at 18 months was 69.8% (74/106). The cumulative MMR and MR4.0 rates for nilotinib at 18 months were 94.3% (100/106) and 84.9% (90/106), respectively. Patients with an ultra-early molecular response (u-EMR) at 6 weeks were not significantly different in obtaining DMR or MMR by 24 months compared with those without u-EMR (p = 0.7584 and p = 0.9543, respectively). Our study demonstrated that nilotinib treatment in patients with ND-CML-CP contributed to obtain high early MR4.5.