14,019 results on '"DASATINIB"'
Search Results
152. TPX2 overexpression promotes sensitivity to dasatinib in breast cancer by activating YAP transcriptional signaling.
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Marugán, Carlos, Sanz‐Gómez, Natalia, Ortigosa, Beatriz, Monfort‐Vengut, Ana, Bertinetti, Cristina, Teijo, Ana, González, Marta, Alonso de la Vega, Alicia, Lallena, María José, Moreno‐Bueno, Gema, and de Cárcer, Guillermo
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Chromosomal instability (CIN) is a hallmark of cancer aggressiveness, providing genetic plasticity and tumor heterogeneity that allows the tumor to evolve and adapt to stress conditions. CIN is considered a cancer therapeutic biomarker because healthy cells do not exhibit CIN. Despite recent efforts to identify therapeutic strategies related to CIN, the results obtained have been very limited. CIN is characterized by a genetic signature where a collection of genes, mostly mitotic regulators, are overexpressed in CIN‐positive tumors, providing aggressiveness and poor prognosis. We attempted to identify new therapeutic strategies related to CIN genes by performing a drug screen, using cells that individually express CIN‐associated genes in an inducible manner. We find that the overexpression of targeting protein for Xklp2 (TPX2) enhances sensitivity to the proto‐oncogene c‐Src (SRC) inhibitor dasatinib due to activation of the Yes‐associated protein 1 (YAP) pathway. Furthermore, using breast cancer data from The Cancer Genome Atlas (TCGA) and a cohort of cancer‐derived patient samples, we find that both TPX2 overexpression and YAP activation are present in a significant percentage of cancer tumor samples and are associated with poor prognosis; therefore, they are putative biomarkers for selection for dasatinib therapy. [ABSTRACT FROM AUTHOR]
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- 2024
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153. Senolytic treatment fails to improve ovarian reserve or fertility in female mice.
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Garcia, Driele N., Hense, Jessica D., Zanini, Bianka M., Isola, Jose V. V., Prosczek, Juliane B., Ashiqueali, Sarah, Oliveira, Thais L., Mason, Jeffrey B., Schadock, Ines C., Barros, Carlos C., Stout, Michael B., Masternak, Michal M., and Schneider, Augusto
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OVARIAN reserve ,FERTILITY ,CHILDBEARING age ,LABORATORY mice ,DRUG efficacy - Abstract
Senescent cell number increases with age in different tissues, leading to greater senescent cell load, proinflammatory stress, and tissue dysfunction. In the current study, we tested the efficacy of senolytic drugs to reduce ovarian senescence and improve fertility in reproductive age female mice. In the first experiment, 1-month-old C57BL/6 female mice were treated every other week with D + Q (n = 24) or placebo (n = 24). At 3 and 6 months of age, female mice were mated with untreated males to evaluate pregnancy rate and litter size. In the second experiment, 6-month-old C57BL/6 female mice were treated monthly with D + Q (n = 30), fisetin (n = 30), or placebo (n = 30). Females were treated once a month until 11 months of age, then they were mated with untreated males for 30 days to evaluate pregnancy rate and litter size. In the first experiment, D + Q treatment did not affect pregnancy rate (P = 0.68), litter size (P = 0.58), or ovarian reserve (P > 0.05). Lipofuscin staining was lower in females treated with D + Q (P = 0.04), but expression of senescence genes in ovaries was similar. In the second experiment, D + Q or fisetin treatment also did not affect pregnancy rate (P = 0.37), litter size (P = 0.20), or ovarian reserve (P > 0.05). Lipofuscin staining (P = 0.008) and macrophage infiltration (P = 0.002) was lower in fisetin treated females. Overall, treatment with D + Q or fisetin did not affect ovarian reserve or fertility but did decrease some senescence markers in the ovary. [ABSTRACT FROM AUTHOR]
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- 2024
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154. Pazopanib-induced enteritis in a patient with renal cell carcinoma.
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Ariyoshi, Misa, Hayashi, Ryohei, Takasago, Takeshi, Yamashita, Ken, Hiyama, Yuichi, Yuge, Ryo, Urabe, Yuji, Ueno, Yoshitaka, Shimamoto, Fumio, and Oka, Shiro
- Abstract
A 69-year-old woman presented to our department with the chief complaint of diarrhea. She had undergone left nephrectomy for renal cancer 14 years earlier. Three years earlier, metastasis was detected in the left retroperitoneal cavity, and pazopanib administration was initiated. In the 29th month after the start of chemotherapy, the patient developed diarrhea, and on the 31st month, computed tomography showed thickening of the intestinal wall. Colonoscopy revealed white villi, intramucosal hemorrhage in the terminal ileum, and rough inflammatory mucosa with inflammatory polyps extending from the transverse to the sigmoid colon. Suspecting pazopanib-induced enteritis, we discontinued the medication, and the diarrhea resolved within 3 days. On the 21st day after discontinuation, colonoscopy revealed that the inflammatory polyps had shrunk, and the inflammatory findings had improved. Biopsy of the white villi of the ileum revealed histiocytes. The patient resumed treatment with pazopanib at 400 mg/day and developed soft stool on the 7th day after resumption. Compared with other tyrosine-kinase inhibitor-induced enteritis cases, this case showed less bleeding and more extensive inflammatory findings. There are similarities as well as differences from cases of previously reported pazopanib-induced enteritis. The mechanisms and characteristics of this disease require further investigation. [ABSTRACT FROM AUTHOR]
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- 2024
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155. The potential for senotherapy as a novel approach to extend life quality in veterinary medicine.
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Williams, Zoë J., Chow, Lyndah, Dow, Steven, and Pezzanite, Lynn M.
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VETERINARY medicine ,IMMUNOSENESCENCE ,CELLULAR aging ,QUALITY of life ,MATRIX metalloproteinases ,ANIMAL models in research ,PRESBYCUSIS - Abstract
Cellular senescence, a condition where cells undergo arrest and can assume an inflammatory phenotype, has been associated with initiation and perpetuation of inflammation driving multiple disease processes in rodent models and humans. Senescent cells secrete inflammatory cytokines, proteins, and matrix metalloproteinases, termed the senescence associated secretory phenotype (SASP), which accelerates the aging processes. In preclinical models, drug interventions termed "senotherapeutics" selectively clear senescent cells and represent a promising strategy to prevent or treatmultiple age-related conditions in humans and veterinary species. In this review, we summarize the current available literature describing in vitro evidence for senotheraputic activity, preclinical models of disease, ongoing human clinical trials, and potential clinical applications in veterinary medicine. These promising data to date provide further justification for future studies identifying the most active senotherapeutic combinations, dosages, and routes of administration for use in veterinary medicine. [ABSTRACT FROM AUTHOR]
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- 2024
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156. Long non-coding RNA PXN-AS1 promotes glutamine synthetase-mediated chronic myeloid leukemia BCR::ABL1-independent resistance to Imatinib via cell cycle signaling pathway.
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Li, Yifei, Yuan, Shiyi, Zhou, Ying, Zhou, Jingwen, Zhang, Xuan, Zhang, Ping, Xiao, Wenrui, Zhang, Ying, Deng, Jianchuan, and Lou, Shifeng
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CHRONIC myeloid leukemia , *LINCRNA , *CELL cycle , *CELL communication , *CELLULAR signal transduction , *DASATINIB , *NILOTINIB , *CHRONIC leukemia - Abstract
Background: Chronic myeloid leukemia (CML) is a common hematological malignancy, and tyrosine kinase inhibitors (TKIs) represent the primary therapeutic approach for CML. Activation of metabolism signaling pathway has been connected with BCR::ABL1-independent TKIs resistance in CML cells. However, the specific mechanism by which metabolism signaling mediates this drug resistance remains unclear. Here, we identified one relationship between glutamine synthetase (GS) and BCR::ABL1-independent Imatinib resistance in CML cells. Methods: GS and PXN-AS1 in bone marrow samples of CML patients with Imatinib resistance (IR) were screened and detected by whole transcriptome sequencing. GS expression was upregulated using LVs and blocked using shRNAs respectively, then GS expression, Gln content, and cell cycle progression were respectively tested. The CML IR mice model were established by tail vein injection, prognosis of CML IR mice model were evaluated by Kaplan–Meier analysis, the ratio of spleen/body weight, HE staining, and IHC. PXN-AS1 level was blocked using shRNAs, and the effects of PXN-AS1 on CML IR cells in vitro and in vivo were tested the same as GS. Several RNA-RNA tools were used to predict the potential target microRNAs binding to both GS and PXN-AS1. RNA mimics and RNA inhibitors were used to explore the mechanism through which PXN-AS1 regulates miR-635 or miR-635 regulates GS. Results: GS was highly expressed in the bone marrow samples of CML patients with Imatinib resistance. In addition, the lncRNA PXN-AS1 was found to mediate GS expression and disorder cell cycle in CML IR cells via mTOR signaling pathway. PXN-AS1 regulated GS expression by binding to miR-635. Additionally, knockdown of PXN-AS1 attenuated BCR::ABL1-independent Imatinib resistance in CML cells via PXN-AS1/miR-635/GS/Gln/mTOR signaling pathway. Conclusions: Thus, PXN-AS1 promotes GS-mediated BCR::ABL1-independent Imatinib resistance in CML cells via cell cycle signaling pathway. [ABSTRACT FROM AUTHOR]
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- 2024
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157. Failure of senolytic treatment to prevent cognitive decline in a female rodent model of aging.
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Rani, Asha, Bean, Linda, Budamagunta, Vivekananda, Kumar, Ashok, and Foster, Thomas C.
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RODENTS ,ACCLIMATIZATION ,REPEATED measures design ,THERAPEUTICS ,PROMPTS (Psychology) ,DATA analysis ,T-test (Statistics) ,RESEARCH funding ,SEX distribution ,EPISODIC memory ,CELLULAR aging ,PILOT projects ,STATISTICAL sampling ,BODY weight ,KRUSKAL-Wallis Test ,ESTROGEN ,ANXIETY ,DESCRIPTIVE statistics ,MANN Whitney U Test ,BEHAVIOR ,NEUROSCIENCES ,RATS ,DASATINIB ,QUERCETIN ,ESTRADIOL ,AGING ,COGNITION disorders ,ANIMAL experimentation ,PSYCHOLOGICAL stress ,MEMORY ,ANALYSIS of variance ,STATISTICS ,ONE-way analysis of variance ,TREATMENT failure ,HIPPOCAMPUS (Brain) ,DISCRIMINATION (Sociology) ,SPACE perception ,COGNITIVE aging ,MEMORY disorders ,GRIP strength ,AVOIDANCE (Psychology) ,REPRODUCTION ,PHARMACODYNAMICS - Abstract
There are sex differences in vulnerability and resilience to the stressors of aging and subsequent age-related cognitive decline. Cellular senescence occurs as a response to damaging or stress-inducing stimuli. The response includes a state of irreversible growth arrest, the development of a senescence- associated secretory phenotype, and the release of pro-inflammatory cytokines associated with aging and age-related diseases. Senolytics are compounds designed to eliminate senescent cells. Our recent work indicates that senolytic treatment preserves cognitive function in aging male F344 rats. The current study examined the effect of senolytic treatment on cognitive function in aging female rats. Female F344 rats (12 months) were treated with dasatinib (1.2 mg/kg) + quercetin (12 mg/kg) or ABT-263 (12 mg/kg) or vehicle for 7 months. Examination of the estrus cycle indicated that females had undergone estropause during treatment. Senolytic treatment may have increased sex differences in behavioral stress responsivity, particularly for the initial training on the cued version of the watermaze. However, pre-training on the cue task reduced stress responsivity for subsequent spatial training and all groups learned the spatial discrimination. In contrast to preserved memory observed in senolytic-treated males, all older females exhibited impaired episodic memory relative to young (6-month) females. We suggest that the senolytic treatment may not have been able to compensate for the loss of estradiol, which can act on aging mechanisms for anxiety and memory independent of cellular senescence. [ABSTRACT FROM AUTHOR]
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- 2024
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158. Thiazole as an Indispensable Scaffold in Anti‐Leukemic Agents: A Semicentennial Review.
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Sharma, Shailendra, Das, Rudradip, Jadhav, Madhav, and Shard, Amit
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BONE marrow , *BONE marrow transplantation , *VITAMIN B1 , *THIAZOLES , *DASATINIB , *STRUCTURE-activity relationships , *THIAZOLE derivatives , *LYMPHATICS - Abstract
Leukemia affects the body's blood‐forming tissues, especially the bone marrow and lymphatic system. Leukemia incidence varies between communities and between pathological kinds. Many treatment modalities exist for leukemia, such as chemotherapy, targeted therapy, radiation therapy, bone marrow transplantation, immunotherapy, and the engineering of immune cells to fight leukemia. Leukemia might be treated with a variety of pharmaceuticals, the most popular of which are imatinib (Gleevec), dasatinib (Sprycel), nilotinib (Tasigna), obinutuzumab (Gazyva), venetoclax (Venclexta), and so on. Thiazole is one of the scaffolds that are actively explored in leukemia. Derivatives having the thiazole nucleus have been surfacing as potent candidates in the treatment of leukemia for quite sometime now, but a consolidated report accumulating all these ventures is absent. Numerous naturally occurring substances, including flavones, alkaloids, anabolic steroids, and vitamin B1 (thiamine), include the basic thiazole molecule. Thiazole derivatives have been researched for their possible therapeutic effects in the treatment of leukemia. Thus, this review comprising reports regarding the effect of different thiazole‐based species in leukemia is a timely effort to the best of our knowledge. This review covers the chronological development of antileukemic thiazole‐based molecules, their synthesis, biological activity, and structure–activity relationships. [ABSTRACT FROM AUTHOR]
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- 2024
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159. SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma.
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Luk, Iris S., Bridgwater, Caroline M., Yu, Angela, Boila, Liberalis D., Yáñez-Bartolomé, Mariana, Lampano, Aaron E., Hulahan, Taylor S., Boukhali, Myriam, Kathiresan, Meena, Macarulla, Teresa, Kenerson, Heidi L., Yamamoto, Naomi, Sokolov, David, Engstrom, Ian A., Sullivan, Lucas B., Lampe, Paul D., Cooper, Jonathan A., Yeung, Raymond S., Tian, Tian V., and Haas, Wilhelm
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DASATINIB ,CHOLANGIOCARCINOMA ,ISOCITRATE dehydrogenase ,RIBOSOMAL proteins ,BILE ducts ,CELL size - Abstract
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. Editor's summary: In intrahepatic cholangiocarcinoma (ICC), mutations in the genes encoding isocitrate dehydrogenase (IDH) lead to dependence on SRC kinase and sensitivity to dasatinib, but the underlying mechanisms are unclear. Here, Luk and colleagues identified that SRC activates p70 S6 kinase (S6K) and ribosomal protein S6 signaling independent of the mTORC1 complex. In IDH-mutant ICC, dasatinib treatment reduced S6K and S6 activity, and resistance to dasatinib was mediated by increased phosphorylation of S6. Combining dasatinib with the S6K/AKT inhibitor M2698 resulted in increased cell death in vitro and resulted in better tumor growth inhibition and survival than individual treatment in mice bearing patient-derived xenografts, suggesting a combination therapy that may be beneficial for patients with IDH-mutant ICC. —Melissa L. Norton [ABSTRACT FROM AUTHOR]
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- 2024
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160. NK92 cells and peripheral blood NK cells respond oppositely upon dasatinib treatment.
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Li, Fengqi, Wang, Zhongyi, Zheng, Dongpeng, Pang, Zhaojun, Feng, Chunjing, Ma, Yue, Yang, Ce, Li, Xueren, Peng, Shouchun, Liu, Zichuan, and Mu, Xin
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KILLER cells , *BLOOD cells , *DASATINIB , *CHRONIC myeloid leukemia , *ACUTE myeloid leukemia , *CHRONIC leukemia - Abstract
Natural killer (NK) cell is a valuable tool for immunotherapy in cancer treatment, both the cultured cell line NK92 and primary NK cells are widely studied and used in research and clinical trials. Clinical observations witnessed the improvement of patients' NK cells in terms of cell counts and cytotoxic activity upon dasatinib treatment, an approved drug for chronic myeloid leukaemia and Ph+ acute lymphocytic leukaemia. Several studies supported the clinical observations, yet others argued a detrimental effect of dasatinib on NK cells. Due to the complex conditions in different studies, the definite influence of dasatinib on NK92 and primary NK cells remains to be settled. Here, we used a well‐defined in vitro system to evaluate the effects of dasatinib on NK92 cells and peripheral blood (PB)‐NK cells. By co‐culturing NK cells with dasatinib to test the cell counts and target cell‐killing activities, we surprisingly found that the chemical influenced oppositely on these two types of NK cells. While dasatinib suppressed NK92 cell proliferation and cytotoxic activity, it improved PB‐NK‐killing tumour cells. RNA sequencing analysis further supported this finding, uncovering several proliferating and cytotoxic pathways responding invertedly between them. Our results highlighted an intrinsic difference between NK92 and PB‐NK cells and may build clues to understand how dasatinib interacts with NK cells in vivo. [ABSTRACT FROM AUTHOR]
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- 2024
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161. Downregulated SPESP1‐driven fibroblast senescence decreases wound healing in aged mice.
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Zhong, Yun, Zhou, Lei, Guo, Yi, Wang, Fan, He, Fanping, Cheng, Yufan, Meng, Xin, Xie, Hongfu, Zhang, Yiya, and Li, Ji
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QUERCETIN , *SKIN aging , *AGING , *DASATINIB , *LIQUID chromatography-mass spectrometry , *HEALING , *WOUND healing - Abstract
Background: Human dermal fibroblasts (HDFs) are essential in the processes of skin ageing and wound healing. However, the underlying mechanism of HDFs in skin healing of the elderly has not been well defined. This study aims to elucidate the mechanisms of HDFs senescence and how senescent HDFs affect wound healing in aged skin. Methods: The expression and function of sperm equatorial segment protein 1 (SPESP1) in skin ageing were evaluated via in vivo and in vitro experiments. To delve into the potential molecular mechanisms by which SPESP1 influences skin ageing, a combination of techniques was employed, including proteomics, RNA sequencing, immunoprecipitation, chromatin immunoprecipitation and liquid chromatography‐mass spectrometry analyses. Clearance of senescent cells by dasatinib plus quercetin (D+Q) was investigated to explore the role of SPESP1‐induced senescent HDFs in wound healing. Results: Here, we define the critical role of SPESP1 in ameliorating HDFs senescence and retarding the skin ageing process. Mechanistic studies demonstrate that SPESP1 directly binds to methyl‐binding protein, leading to Decorin demethylation and subsequently upregulation of its expression. Moreover, SPESP1 knockdown delays wound healing in young mice and SPESP1 overexpression induces wound healing in old mice. Notably, pharmacogenetic clearance of senescent cells by D+Q improved wound healing in SPESP1 knockdown skin. Conclusions: Taken together, these findings reveal the critical role of SPESP1 in skin ageing and wound healing, expecting to facilitate the development of anti‐ageing strategies and improve wound healing in the elderly. [ABSTRACT FROM AUTHOR]
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- 2024
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162. Electrospun nanofibers synthesized from polymers incorporated with bioactive compounds for wound healing.
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Palani, Naveen, Vijayakumar, Pradeshwaran, Monisha, P., Ayyadurai, Saravanakumar, and Rajadesingu, Suriyaprakash
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WOUND healing , *BIOPOLYMERS , *BIOACTIVE compounds , *TARGETED drug delivery , *CHRONIC wounds & injuries , *NANOFIBERS , *POLYCAPROLACTONE , *DASATINIB - Abstract
The development of innovative wound dressing materials is crucial for effective wound care. It's an active area of research driven by a better understanding of chronic wound pathogenesis. Addressing wound care properly is a clinical challenge, but there is a growing demand for advancements in this field. The synergy of medicinal plants and nanotechnology offers a promising approach to expedite the healing process for both acute and chronic wounds by facilitating the appropriate progression through various healing phases. Metal nanoparticles play an increasingly pivotal role in promoting efficient wound healing and preventing secondary bacterial infections. Their small size and high surface area facilitate enhanced biological interaction and penetration at the wound site. Specifically designed for topical drug delivery, these nanoparticles enable the sustained release of therapeutic molecules, such as growth factors and antibiotics. This targeted approach ensures optimal cell-to-cell interactions, proliferation, and vascularization, fostering effective and controlled wound healing. Nanoscale scaffolds have significant attention due to their attractive properties, including delivery capacity, high porosity and high surface area. They mimic the Extracellular matrix (ECM) and hence biocompatible. In response to the alarming rise of antibiotic-resistant, biohybrid nanofibrous wound dressings are gradually replacing conventional antibiotic delivery systems. This emerging class of wound dressings comprises biopolymeric nanofibers with inherent antibacterial properties, nature-derived compounds, and biofunctional agents. Nanotechnology, diminutive nanomaterials, nanoscaffolds, nanofibers, and biomaterials are harnessed for targeted drug delivery aimed at wound healing. This review article discusses the effects of nanofibrous scaffolds loaded with nanoparticles on wound healing, including biological (in vivo and in vitro) and mechanical outcomes. [ABSTRACT FROM AUTHOR]
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- 2024
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163. Mutation analysis of BCR-ABL1 kinase domain in chronic myeloid leukemia patients with tyrosine kinase inhibitors resistance: a Malaysian cohort study.
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Seman, Zahidah Abu, Ahid, Fadly, Kamaluddin, Nor Rizan, Sahid, Ermi Neiza Mohd, Esa, Ezalia, Said, Siti Shahrum Muhamed, Azman, Norazlina, Mat, Wan Khairull Dhalila Wan, Abdullah, Julia, Ali, Nurul Aqilah, Khalid, Mohd Khairul Nizam Mohd, and Yusoff, Yuslina Mat
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CHRONIC myeloid leukemia , *NUCLEOTIDE sequencing , *PROTEIN-tyrosine kinase inhibitors , *GENETIC mutation , *DASATINIB , *COHORT analysis , *MEDICAL protocols - Abstract
Objective: Mutational analysis of BCR::ABL1 kinase domain (KD) is a crucial component of clinical decision algorithms for chronic myeloid leukemia (CML) patients with failure or warning responses to tyrosine kinase inhibitor (TKI) therapy. This study aimed to detect BCR::ABL1 KD mutations in CML patients with treatment resistance and assess the concordance between NGS (next generation sequencing) and Sanger sequencing (SS) in detecting these mutations. Results: In total, 12 different BCR::ABL1 KD mutations were identified by SS in 22.6% (19/84) of patients who were resistant to TKI treatment. Interestingly, NGS analysis of the same patient group revealed an additional four different BCR::ABL1 KD mutations in 27.4% (23/84) of patients. These mutations are M244V, A344V, E355A, and E459K with variant read frequency below 15%. No mutation was detected in 18 patients with optimal response to TKI therapy. Resistance to TKIs is associated with the acquisition of additional mutations in BCR::ABL1 KD after treatment with TKIs. Additionally, the use of NGS is advised for accurately determining the mutation status of BCR::ABL1 KD, particularly in cases where the allele frequency is low, and for identifying mutations across multiple exons simultaneously. Therefore, the utilization of NGS as a diagnostic platform for this test is very promising to guide therapeutic decision-making. [ABSTRACT FROM AUTHOR]
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- 2024
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164. High Level of CD8 + PD-1 + Cells in Patients with Chronic Myeloid Leukemia Who Experienced Loss of MMR after Imatinib Discontinuation.
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Kwaśnik, Paulina, Zaleska, Joanna, Link-Lenczowska, Dorota, Zawada, Magdalena, Wysogląd, Hubert, Ochrem, Bogdan, Bober, Grażyna, Wasilewska, Ewa, Hus, Iwona, Szarejko, Monika, Prejzner, Witold, Grzybowska-Izydorczyk, Olga, Klonowska-Szymczyk, Agnieszka, Mędraś, Ewa, Kiełbus, Michał, Sacha, Tomasz, and Giannopoulos, Krzysztof
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CHRONIC myeloid leukemia , *IMATINIB , *DASATINIB , *PROGRAMMED cell death 1 receptors , *CD8 antigen , *BIOMARKERS , *PROTEIN-tyrosine kinase inhibitors - Abstract
Treatment-free remission (TFR) is achieved in approximately half of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors. The mechanisms responsible for TFR maintenance remain elusive. This study aimed to identify immune markers responsible for the control of residual CML cells early in the TFR (at 3 months), which may be the key to achieving long-term TFR and relapse-free survival (RFS) after discontinuation of imatinib. Our study included 63 CML patients after imatinib discontinuation, in whom comprehensive analysis of changes in the immune system was performed by flow cytometry, and changes in the BCR::ABL1 transcript levels were assessed by RQ-PCR and ddPCR. We demonstrated a significant increase in the percentage of CD8+PD-1+ cells in patients losing TFR. The level of CD8+PD-1+ cells is inversely related to the duration of treatment and incidence of deep molecular response (DMR) before discontinuation. Analysis of the ROC curve showed that the percentage of CD8+PD-1+ cells may be a significant factor in early molecular recurrence. Interestingly, at 3 months of TFR, patients with the e13a2 transcript had a significantly higher proportion of the PD-1-expressing immune cells compared to patients with the e14a2. Our results suggest the important involvement of CD8+PD-1+ cells in the success of TFR and may help in identifying a group of patients who could successfully discontinue imatinib. [ABSTRACT FROM AUTHOR]
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- 2024
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165. Surufatinib combined with photodynamic therapy induces ferroptosis to inhibit cholangiocarcinoma in vitro and in tumor models.
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Yun-Peng Huang, Yong-Xiang Wang, Hui Zhou, Zhong-Tao Liu, Zi-Jian Zhang, Li Xiong, Heng Zou, and Yu Wen
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PHOTODYNAMIC therapy ,CHOLANGIOCARCINOMA ,GLUTATHIONE peroxidase ,REACTIVE oxygen species ,HYDROGEN peroxide ,DASATINIB ,OVERALL survival - Abstract
The curative effect of single therapy for advanced cholangiocarcinoma (CCA) is poor, thus investigating combined treatment strategies holds promise for improving prognosis. Surufatinib (SUR) is a novel multikinase inhibitor that has been confirmed to prolong survival of patients with advanced CCA. Photodynamic therapy (PDT) can also ablate advanced CCA and relieve biliary obstruction. In this study, we explored the anti-CCA effect of SUR combined with PDT, and explored the underlying mechanism. We found that SUR could effectively inhibit the abilities of proliferation, migration and metastasis in CCA cells (HUCCT-1, RBE). The ability of SUR to inhibit CCA was also confirmed by the HUCCT-1 cell xenograft model in Balb/c nude mice and CCA patient-derived organoids. SUR combined with PDT can significantly enhance the inhibitory effect on CCA, and can be alleviated by two ferroptosis inhibitors (Ferrostatin-1, Deferoxamine). By detecting the level of reactive oxygen species, lipid peroxides, malondialdehyde and glutathione, we further confirmed that SUR combined with PDT can inhibit CCA cells by inducing ferroptosis. Glutathione peroxidase 4 (GPX4) belongs to the glutathione peroxidase family and is mainly responsible for the metabolism of intracellular hydrogen peroxide. GPX4 inhibits ferroptosis by reducing cytotoxic lipid peroxides (L-OOH) to the corresponding alcohols (L-OH). Acyl-CoA synthetase long-chain family member 4 (ACSL4) is a member of the long-chain fatty acid coenzyme a synthetase family and is mainly involved in the biosynthesis and catabolism of fatty acids. ACSL4 induces ferroptosis by promoting the accumulation of lipid peroxides. Both SUR and PDT can induce ferroptosis by promoting ACSL4 and inhibiting GPX4. The regulation effect is found to be more significant in combined treatment group. In conclusion, SUR combined with PDT exerted an anti-CCA effect by inducing ferroptosis. Combination therapy provides a new idea for the clinical treatment of CCA. [ABSTRACT FROM AUTHOR]
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- 2024
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166. JAK2 as Predictor of Therapeutic Response in Patients with Chronic Myeloid Leukemia Treated with Imatinib.
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Wijaya, Indra, Bashari, Muhammad H., Reniarti, Lelani, Rahmawati, Anita, and Roesli, Rully M. A.
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CHRONIC myeloid leukemia , *DASATINIB , *IMATINIB , *PROTEIN-tyrosine kinase inhibitors , *MYELOPROLIFERATIVE neoplasms , *BLOOD cell count , *BLOOD testing , *GENE expression - Abstract
Background. Chronic myeloid leukemia (CML) or chronic granulocytic leukemia is a myeloproliferative neoplasm indicated by the presence of the Philadelphia (Ph+) chromosome. First-line tyrosine kinase inhibitor, imatinib, is the gold standard for treatment. However, there has been known unresponsiveness to treatment, especially due to the involvement of other genes, such as the Janus kinase 2 (JAK2) gene. This study aimed to evaluate the relationships between JAK2 levels and complete hematological response (CHR), as well as early molecular response (EMR) after 3 months of imatinib treatment in patients with chronic phase CML. Methods. Patients with Ph+ CML in the chronic phase (n = 40; mean age, 40 ± 11 years) were recruited to complete assessments consisting of clinical examination and blood test, including evaluation of complete blood counts and the JAK2 levels, at baseline and following 3 months of therapy with imatinib (at an oral dose of 400 mg per day). Subjects were divided into two groups according to the presence of CHR and EMR. Results. JAK2 gene levels, phosphorylated, and total JAK2 proteins at baseline were significantly lower in the group with the presence of CHR and EMR. In addition, baseline JAK2 levels, including JAK2 gene expression, phosphorylated, and total JAK2 proteins, were negatively correlated with the presence of CHR and EMR. Conclusions. Based on these findings, JAK2 levels may be a potential indicator for evaluating treatment response on imatinib due to its role in the pathophysiology of CML. [ABSTRACT FROM AUTHOR]
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- 2024
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167. BZ-97: A Promising Compound Against Trypanosoma cruzi.
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Botacio, Milixza M., Alves-Rosa, Maria F., Escala, Nerea, Ng, Michele, Coronado, Lorena M., Carrasco, Jafeth, Dorta, Doriana, Pineda, Laura, del Olmo, Esther, Correa, Ricardo, and Spadafora, Carmenza
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TRYPANOSOMA cruzi , *CHAGAS' disease , *NEGLECTED diseases , *LEAD compounds , *FLUORIMETRY , *SYNTHETIC products , *AMILORIDE , *DASATINIB - Abstract
Chagas Disease has been considered "the most neglected among the neglected diseases." Only two very toxic drugs developed in the 1960s have been approved to control the disease in its acute phase and are infective in the chronic stage of the illness. It is imperative to find new molecules that can act against the causative parasite, Trypanosoma cruzi. BZ-97 is a synthetic product derived from the benzimidazole scaffold. It was tested against other human parasites, showing the best activity (IC50 = 0.76 μM) towards T. cruzi intracellular stages. The effects of BZ-97 on epimastigotes of the Y strain were analyzed. Signs of changes in the parasite homeostasis were evident by acidocalcisomes alkalinization, calcium mobilization, changes in their morphology and some signs of apoptotic events with a lack of ROS production, which is a crucial advantage over the behavior of the reference drug, benznidazole. Acidocalcisomes alkalinization was evidenced through fluorescence microscopy analysis and the use of 5-[N-ethyl-N-isopropyl] amiloride (EIPA), an inhibitor of the TcNHE pump, confirmed the involvement of this proton pump in the BZ-97-mediated acidocalcisome alkalinization. BZ-97 is presented as a potential lead compound against T. cruzi that is worthy of further studies in the future. [ABSTRACT FROM AUTHOR]
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- 2024
- Full Text
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168. Kinetics of molecular recurrence after tyrosine kinase inhibitor cessation in chronic phase chronic myelogenous leukaemia patients.
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Alcazer, Vincent, Morisset, Stéphane, Rea, Delphine, Legros, Laurence, Dulucq, Stéphanie, Hayette, Sandrine, Cayuela, Jean‐Michel, Huguet, Françoise, Mahon, François‐Xavier, Etienne, Gabriel, and Nicolini, Franck E.
- Subjects
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PROTEIN-tyrosine kinase inhibitors , *MOLECULAR kinetics , *NILOTINIB , *DASATINIB , *CHRONIC leukemia , *CHRONIC myeloid leukemia - Abstract
This article examines the relapse rates in chronic myelogenous leukemia (CML) patients after stopping tyrosine kinase inhibitor (TKI) treatment. The study found that relapse occurred faster in patients who had previously received the first-generation TKI imatinib compared to second-generation TKIs dasatinib or nilotinib. The study used standardized definitions of response and resistance and included patients from multiple centers. The findings suggest that the choice of TKI may affect the rate of relapse after treatment discontinuation. However, more research is needed to validate these findings in larger studies and clinical trials. [Extracted from the article]
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- 2024
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169. RP-LC Method Development and Validation for Dasatinib Forced Degradation Study: Isolation and Structural Characterization by NMR and HRMS.
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Kavitapu, Dasameswara Rao, Murty, Jayanti Naga Sri Rama Chandra, Maruthapillai, Arthanareeswari, Senadi, Gopal C, and Mahapatra, Sudarshan
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- *
REVERSE phase liquid chromatography , *DASATINIB , *TANDEM mass spectrometry , *FOURIER transform infrared spectroscopy , *NUCLEAR magnetic resonance spectroscopy , *CHEMICAL formulas , *GRADIENT elution (Chromatography) - Abstract
A reverse phase high-performance liquid chromatography (HPLC) method has been developed for the quantification of a typical drug Dasatinib (DST) and its related impurities in pharmaceuticals. Kinetex C18 (4.6 × 150 mm, 5 μm) column was used in the chromatographic separations, using buffer (1.36 g of KH2PO4 in 1000 mL of water, pH = 7.8; adjusted with diluted KOH solution) with solvent as acetonitrile and mode of elution as the gradient. The flow rate is 0.9 mL/min, column oven temperature as 45°C and the overall gradient run time as 65 min. The developed method was found to produce symmetric and good separation between the process-related and degradation impurities. Method optimization is achieved with photodiode array at 305 nm over the concentration range of 0.5 mg/mL and degradation studies were carried out under acidic, alkaline, oxidative, photolytic and thermal conditions to demonstrate the stability indicating capability of the method. Two major impurities were found in forced degradation studies in the HPLC analysis, the unknown, acid degradants were enriched and isolated by preparative HPLC, then characterized through high-resolution mass spectrometry, nuclear magnetic resonance spectroscopy and Fourier transform infrared spectroscopy. The unknown acid degradation impurity was showing Exact Mass of 521.11, molecular formula C22H25Cl2N7O2S and its chemical name as 2-(5-chloro-6-(4-(2-hydroxyethyl) piperazin-1-yl)-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl) thiazole-5-carboxamide. Another impurity (oxidative degradant) found as known DST N-oxide Impurity-L and its chemical name as 4-(6-((5-((2-chloro-6-methylphenyl) carbamoyl) thiazol-2-yl) amino)-2-methylpyrimidin-4-yl)-1-(2-hydroxyethyl) piperazine 1-oxide. The analytical HPLC method was further validated as per ICH guidelines. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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170. Simultaneous Quantitation of Anlotinib and Osimertinib by Isotope-Labeled UHPLC–MS/MS in Human Plasma: Application in NSCLC Patients.
- Author
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Liu, Yao, Lin, Zhong, Luo, Wenji, Pei, Xiaofeng, She, Ziyue, Sha, Zhou, Guan, Yanping, Ming, Dandan, and Liang, Jiabi
- Subjects
- *
OSIMERTINIB , *ANLOTINIB , *PROTEIN-tyrosine kinase inhibitors , *LIQUID chromatography-mass spectrometry , *DASATINIB , *NON-small-cell lung carcinoma - Abstract
Anlotinib and osimertinib are a class of tyrosine kinase inhibitors for the treatment of malignant tumor. The combination of anlotinib and osimertinib is currently used for treating non-small cell lung cancer (NSCLC) patients. This study aimed to develop a simple and rapid isotope-labeled UHPLC–MS/MS method for the simultaneous determination of anlotinib and osimertinib in human plasma. The analytes were extracted by protein precipitation with acetonitrile and were then separated on a Shim-pack GIST C18 column. The detection was performed on Shimadzu 8050 triple quadruple mass spectrometer in the positive electrospray ionization mode with multiple reaction monitoring. The precursor-to-product ion transitions were m/z 408.10→ 339.75, 500.25→ 72.20 and 413.50 → 344.50 for anlotinib, osimertinib and D5-anlotinib, respectively. Validation is based on US Food and Drug Administration guidelines. The linearity ranges were 0.5–100 ng/mL for anlotinib and were 1–500 ng/mL for osimertinib with the correlation coefficients (r 2) ≥ 0.99. Accuracy and precision, matrix effect, extraction recovery and stability of anlotinib and osimertinib were acceptable after validation. The UHPLC–MS/MS method was successfully validated and was applied to monitor the concentration of anlotinib and osimertinib in NSCLC patients. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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171. Polymeric Amorphous Solid Dispersions of Dasatinib: Formulation and Ecotoxicological Assessment.
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Sokač, Katarina, Miloloža, Martina, Kučić Grgić, Dajana, and Žižek, Krunoslav
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- *
AMORPHOUS substances , *DASATINIB , *LEMNA minor , *DUCKWEEDS , *VIBRIO fischeri , *ANTINEOPLASTIC agents , *CHLORELLA vulgaris , *DUNALIELLA - Abstract
Dasatinib (DAS), a potent anticancer drug, has been subjected to formulation enhancements due to challenges such as significant first-pass metabolism, poor absorption, and limited oral bioavailability. To improve its release profile, DAS was embedded in a matrix of the hydrophilic polymer polyvinylpyrrolidone (PVP). Drug amorphization was induced in a planetary ball mill by solvent-free co-grinding, facilitating mechanochemical activation. This process resulted in the formation of amorphous solid dispersions (ASDs). The ASD capsules exhibited a notable enhancement in the release rate of DAS compared to capsules containing the initial drug. Given that anticancer drugs often undergo limited metabolism in the body with unchanged excretion, the ecotoxicological effect of the native form of DAS was investigated as well, considering its potential accumulation in the environment. The highest ecotoxicological effect was observed on the bacteria Vibrio fischeri, while other test organisms (bacteria Pseudomonas putida, microalgae Chlorella sp., and duckweed Lemna minor) exhibited negligible effects. The enhanced drug release not only contributes to improved oral absorption but also has the potential to reduce the proportion of DAS that enters the environment through human excretion. This comprehensive approach highlights the significance of integrating advances in drug development while considering its environmental implications. [ABSTRACT FROM AUTHOR]
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- 2024
- Full Text
- View/download PDF
172. Progress in the Use of Hydrogels for Antioxidant Delivery in Skin Wounds.
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Maeso, Lidia, Antezana, Pablo Edmundo, Hvozda Arana, Ailen Gala, Evelson, Pablo Andrés, Orive, Gorka, and Desimone, Martín Federico
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- *
SKIN injuries , *CHRONIC wounds & injuries , *WOUND healing , *WOUND care , *HYDROGELS , *TISSUES , *SKIN , *DASATINIB - Abstract
The skin is the largest organ of the body, and it acts as a protective barrier against external factors. Chronic wounds affect millions of people worldwide and are associated with significant morbidity and reduced quality of life. One of the main factors involved in delayed wound healing is oxidative injury, which is triggered by the overproduction of reactive oxygen species. Oxidative stress has been implicated in the pathogenesis of chronic wounds, where it is known to impair wound healing by causing damage to cellular components, delaying the inflammatory phase of healing, and inhibiting the formation of new blood vessels. Thereby, the treatment of chronic wounds requires a multidisciplinary approach that addresses the underlying causes of the wound, provides optimal wound care, and promotes wound healing. Among the promising approaches to taking care of chronic wounds, antioxidants are gaining interest since they offer multiple benefits related to skin health. Therefore, in this review, we will highlight the latest advances in the use of natural polymers with antioxidants to generate tissue regeneration microenvironments for skin wound healing. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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173. 尼洛替尼与达沙替尼二线治疗慢性髓性白血病的成本效用分析.
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马 玲, 赵燕鸿, 刘 佳, and 屠文莲
- Abstract
Objective To evaluate the cost-effectiveness of nilotinib versus dasatinib in the second-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase. Methods Establish a Markov model for cost-effectiveness analysis, including four health states: chronic phase (CP),accelerated phase ( AP), blast phase ( BP), and death. Clinical parameters related to progression-free survival rates, disease progression rates, overall survival rates, etc. for treatment with nilotinib and dasatinib are derived from previously published studies and expert opinions, while health state utility values are sourced from the literature. Using Treeage software, the incremental cost-effectiveness ratio (ICER) was used as an evaluation metric to assess the total output and total costs of the two schemes of nilotinib and dasatinib, and model stability is evaluated through univariate and probabilistic sensitivity analyses. Results Compared with using dasatinib for treatment, the ICER for using nilotinib treatment is 182 487.71 yuan per QALY, which is less than 3 times the national per capita GDP in 2021. Sensitivity analysis showed that the main influencing parameters are the discount rate, dasatinib price, and nilotinib price,and the model results are stable. Conclusion Nilotinib has a cost-utility advantage over dasatinib in the treatment of Ph+CML-CP patients who are resistant or intolerent to imatinib. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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174. METHOD DEVELOPMENT AND VALIDATION FOR QUANTIFICATION OF IMATINIB MESYLATE SPIKED IN VITRO SALIVA BY LC-MS/MS.
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Remidicherla, Swetha Sri, Chakravarthi, Guntupalli, S., Pravallika, Reddy, Alavala Rajasekhar, and Rao, G. S. N. Koteswara
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IMATINIB , *CHRONIC myeloid leukemia , *DRUG monitoring , *PROTEIN-tyrosine kinase inhibitors , *LIQUID chromatography-mass spectrometry , *CHRONIC leukemia , *VORICONAZOLE , *DASATINIB - Abstract
A novel, sensible, rapid, reliable and economical analytical hyphenated LC-MS/MS method has been developed as a key for the safety surveillance in chronic leukemia patients, and as a part of therapeutic drug monitoring of imatinib mesylate in human saliva. Imatinib mesylate or imatinib methane sulfonate is a tyrosine kinase inhibitor, apoptosis inducer and also known to be an anticoronaviral agent. Imatinib mesylate is a monomesylate salt of imatinib used for the treatment of gastrointestinal tumors and chronic myelogenous leukemia, and also in other complex malignancies. The lmax of imatinib mesylate was observed at 258 nm by UV spectrometry, establishing a very good linearity along with sensitivity. The detection limit (LOD) =0.2925 µg mL-1 and quantitation limit (LOQ)= 0.8977 µg mL-1 were obtained from the linear concentrations taken in the range of 2-12 µg mL-1. The correlation coefficient (r2) found was 0.999. The method validation parameters according to ICH Q2 (R1) were performed. The developed method described here, UPLC-MS/MS, was found to be novel, sensitive and rapid with improved results when successfully tested for human saliva samples without significant differences in the steady state imatinib mesylate concentrations. Current method could overcome the safety issues during therapeutic drug monitoring and pharmacokinetic behavior of the drug when tested clinically. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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175. 达沙替尼致重度肺动脉高压1例并文献分析.
- Author
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杨 翠 and 汪 哲
- Abstract
Copyright of Practical Pharmacy & Clinical Remedies is the property of Editorial Department of Practical Pharmacy & Clinical Remedies and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2024
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176. Dasatinib in Treating Patients With Locally Advanced or Metastatic Mucosal Melanoma, Acral Melanoma, or Vulvovaginal Melanoma That Cannot Be Removed By Surgery
- Author
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National Cancer Institute (NCI)
- Published
- 2023
177. Dasatinib and Crizotinib in Advanced Cancer
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Pfizer
- Published
- 2023
178. Study of Dasatinib vs Imatinib in Patients With Chronic Myeloid Leukemia (CML) Who Did Not Have Favorable Response to Imatinib (DASCERN)
- Author
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ICON Clinical Research, PPD DEVELOPMENT, LP, Molecular MD, MultiPharma, Q2 Solutions, Donald E. Morisky, MD Anderson Symptom Inventory (MDASI-CML), OBiS, Inc, and Steering Committee
- Published
- 2023
179. Dasatinib Holiday for Improved Tolerability (DasaHIT)
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Prof. Dr. med. Andreas Hochhaus, Director of the Clinic of Internal Medicine II
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- 2023
180. Frontline Asciminib Combination in Chronic Phase CML (CMLXI)
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Ludwig-Maximilians - University of Munich, Novartis Pharmaceuticals, and Thomas Ernst, PD Dr. med., Principal Investigator
- Published
- 2023
181. Continuing Treatment for Subjects Who Have Participated on a Prior Protocol Investigating Dasatinib
- Published
- 2023
182. Dasatinib in Imatinib Resistant/Intolerant Chinese CML (Chronic and Advanced Phase) Subjects
- Published
- 2023
183. Psma Intensity Can be Altered by Androgen and Phospho-SrC Obstruction (PICASSO)
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Anthony Joshua, FRACP, Head of Medical Oncology, The Kinghorn Cancer Centre
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- 2023
184. A Pivotal Study of HQP1351 in Patients With Chronic Myeloid Leukemia in Chronic Phase
- Author
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HealthQuest Pharma Inc.
- Published
- 2023
185. Opposite Effects of Src Family Kinases on YAP and ERK Activation in Pancreatic Cancer Cells: Implications for Targeted Therapy
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Sinnett-Smith, James, Anwar, Tarique, Reed, Elaine F, Teper, Yaroslav, Eibl, Guido, and Rozengurt, Enrique
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biological Sciences ,Biotechnology ,Pancreatic Cancer ,Orphan Drug ,Cancer ,Digestive Diseases ,Rare Diseases ,Animals ,Mice ,Carcinoma ,Pancreatic Ductal ,Cell Line ,Tumor ,Dasatinib ,Insulins ,Mice ,Nude ,Mitogen-Activated Protein Kinase Kinases ,Pancreatic Neoplasms ,Phosphorylation ,Prospective Studies ,Protein Kinase Inhibitors ,src-Family Kinases ,Humans ,YAP-Signaling Proteins ,Pharmacology and Pharmaceutical Sciences ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains an aggressive disease that is expected to become the second cause of cancer fatalities during the next decade. As therapeutic options are limited, novel targets, and agents for therapeutic intervention are urgently needed. Previously, we identified potent positive crosstalk between insulin/IGF-1 receptors and G protein-coupled (GPCR) signaling systems leading to mitogenic signaling in PDAC cells. Here, we show that a combination of insulin and the GPCR agonist neurotensin induced rapid activation of Src family of tyrosine kinases (SFK) within PANC-1 cells, as shown by FAK phosphorylation at Tyr576/577 and Tyr861, sensitive biomarkers of SFK activity within intact cells and Src416 autophosphorylation. Crucially, SFKs promoted YAP nuclear localization and phosphorylation at Tyr357, as shown by using the SFK inhibitors dasatinib, saracatinib, the preferential YES1 inhibitor CH6953755, siRNA-mediated knockdown of YES1, and transfection of epitogue-tagged YAP mutants in PANC-1 and Mia PaCa-2 cancer cells, models of the aggressive squamous subtype of PDAC. Surprisingly, our results also demonstrate that exposure to SFK inhibitors, including dasatinib or knockdown of YES and Src induces ERK overactivation in PDAC cells. Dasatinib-induced ERK activation was completely abolished by exposure to the FDA-approved MEK inhibitor trametinib. A combination of dasatinib and trametinib potently and synergistically inhibited colony formation by PDAC cells and suppressed the growth of Mia PaCa-2 cells xenografted into the flank of nude mice. The results provide rationale for considering a combination(s) of FDA-approved SFK (dasatinib) and MEK (e.g., trametinib) inhibitors in prospective clinical trials for the treatment of PDAC.
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- 2022
186. Targeting HER2-positive breast cancer cells by a combination of dasatinib and BMS-202: Insight into the molecular pathways
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Hadeel Kheraldine, Ishita Gupta, Farhan Sachal Cyprian, Semir Vranic, Halema F. Al-Farsi, Maysaloun Merhi, Said Dermime, and Ala-Eddin Al Moustafa
- Subjects
Dasatinib ,PD-1/PD-L1 ,HER2-positive breast cancer ,EMT ,Invasion ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
Abstract Background Recent investigations have reported the benefits of using a tyrosine kinase inhibitor, dasatinib (DA), as well as programmed death-ligand 1 (PD-L1) inhibitors in the management of several solid tumors, including breast cancer. Nevertheless, the outcome of the combination of these inhibitors on HER2-positive breast cancer is not explored yet. Methods Herein, we investigated the impact of DA and PD-L1 inhibitor (BMS-202) combination on HER2-positive breast cancer cell lines, SKBR3 and ZR75. Results Our data reveal that the combination significantly inhibits cell viability of both cancer cell lines as compared to monotreatment. Moreover, the combination inhibits epithelial-mesenchymal transition (EMT) progression and reduces cancer cell invasion by restoring E-cadherin and β-catenin expressions and loss of vimentin, major biomarkers of EMT. Additionally, the combination reduces the colony formation of both cell lines in comparison with their matched control. Also, the combination considerably inhibits the angiogenesis of the chorioallantoic membrane model compared with monotreatment. Molecular pathway analysis of treated cells shows that this combination blocks HER2, AKT, β-catenin, and JNK1/2/3 activities. Conclusion Our findings implicate that a combination of DA and BMS-202 could have a significant impact on the management of HER2-positive breast cancer.
- Published
- 2024
- Full Text
- View/download PDF
187. Ascites does not accompany pleural effusion developing under dasatinib therapy in patients with CML-CP
- Author
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Küçükyurt Selin, Eşkazan Tuğçe, Ayer Mesut, Kılıçkıran Avcı Burçak, Hatemi İbrahim, and Eşkazan Ahmet Emre
- Subjects
ascites ,chronic myeloid leukemia ,chronic-phase chronic myeloid leukemia (cml-cp) ,dasatinib ,pleural effusion ,Medicine ,Specialties of internal medicine ,RC581-951 - Abstract
Pleural effusion (PE) is the most frequent pulmonary complication of dasatinib, a tyrosine kinase inhibitor (TKI). Concurrent pericardial effusions have been reported in about one-third of the cases. In this study, we aimed to investigate ascites generation in chronic-phase chronic myeloid leukemia (CML-CP) patients developing PE under dasatinib.
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- 2024
- Full Text
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188. PI3K/AKT and STAT3 pathways mediate the neuroprotective effect of dasatinib from acute cerebral injury in endotoxemic mice
- Author
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Ammar Rasoul Mohammad, Ekhlas Sabah Hassan, and Sahar Abdulrudha Majeed
- Subjects
clp ,dasatinib ,endotoxemia ,sepsis. ,Pharmacy and materia medica ,RS1-441 - Abstract
Background and purpose: Sepsis induces brain dysfunction and there is still a requirement for an unemployed viable restorative approach. This study aimed to investigate the role of dasatinib in the modulation of proinflammatory mediators, attenuating neuroinflammatory response, and it's signaling pathway during endotoxemia. Experimental approach: Twenty-four adult male Swiss-albino mice were randomized into four groups: sham (undergo laparotomy without cecal ligation and puncture, sepsis (laparotomy with cecal ligation and puncture), vehicle-dimethyl sulfoxide, dasatinib (20 mg/kg/day) intraperitoneally. Brain tissue used for assessment of interleukin (IL)-6, IL-1β, tumor necrosis factor-alpha (TNF-α), IL-10, Toll-like receptor 4 (TLR4), protein kinase B (AKT), phosphoinositide 3-kinases (PI3K), signal transducer and activator of transcription 3 (STAT3), and histopathological examination. Findings/Results: Brain tissue levels of TNF-α, IL-6, and IL1 β were higher in the sepsis group than in the sham and vehicle groups. The dasatinib group had considerably lower tissue levels of these markers and significantly higher tissue values of IL-10 than the sepsis and vehicle groups. The sham group had much lower tissue values of TLR4, AKT, STAT3, and PI3k than in sepsis and vehicle groups. Furthermore, tissue levels of these markers in the dasatinib group were considerably lower than those in the sepsis and vehicle groups. Histopathology demonstrated that dasatinib might considerably reduce brain damage and the intensity of neuroinflammation when compared to sepsis and vehicle groups that showed extensive brain inflammation and damage. Conclusion and implication: Dasatinib attenuated endotoxemia-induced acute brain damage in mice via modulating effects on TLR4, PI3K, AKT, and STAT3 downstream signaling pathways.
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- 2024
- Full Text
- View/download PDF
189. IGFBP7: From Senescence Biomarker to a Vaccine for Heart Failure.
- Author
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Aboumsallem, Joseph Pierre and de Boer, Rudolf A.
- Subjects
- *
INSULIN-like growth factor-binding proteins , *VASCULAR endothelial growth factors , *SOMATOMEDIN , *VASCULAR endothelial cells , *CELLULAR aging , *DASATINIB , *VENTRICULAR ejection fraction - Abstract
IGFBP7 has been identified as a potential biomarker for predicting and diagnosing heart failure. It is linked to cellular senescence and tissue aging. A recent study highlights IGFBP7 as an endothelial biomarker and a key protein in heart failure. The study suggests that IGFBP7 originating from endothelial cells adversely influences cardiomyocyte metabolism. Further research is needed to understand the exact interaction between IGFBP7 and other factors in heart failure. Two studies conducted on mice show promising results in targeting IGFBP7 as a treatment for heart failure. However, more research is needed to assess the long-term effects and potential sex differences in treatment response. [Extracted from the article]
- Published
- 2024
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190. Dasatinib Followed by Stem Cell Transplant in Treating Older Patients With Newly Diagnosed Acute Lymphoblastic Leukemia
- Published
- 2023
191. Dasatinib In Combination With Trastuzumab And Paclitaxel In First Line Treatment Of Her2-Positive MBC Patients
- Author
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Bristol-Myers Squibb
- Published
- 2023
192. Apatinib Mesylate Versus Standard Second-line TKI in the Treatment of Advanced GIST
- Author
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Suzhou Suncadia Biopharmaceuticals Co., Ltd.
- Published
- 2023
193. The Life After Stopping Tyrosine Kinase Inhibitors Study (The LAST Study)
- Author
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University of Chicago, University of California, San Francisco, University of Utah, Dana-Farber Cancer Institute, Emory University, Barbara Ann Karmanos Cancer Institute, Duke Cancer Institute, Fred Hutchinson Cancer Center, Memorial Sloan Kettering Cancer Center, Weill Medical College of Cornell University, H. Lee Moffitt Cancer Center and Research Institute, and Ehab L Atallah, Professor (Principal Investigator)
- Published
- 2023
194. Dasatinib and Quercetin to Treat Fibrotic Non-alcoholic Fatty Liver Disease
- Author
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Max Nieuwdorp, Prof. dr.
- Published
- 2023
195. Study to Investigate Outcome of Individualized Treatment in Patients With Metastatic Colorectal Cancer (EVIDENT)
- Author
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Tormod Kyrre Guren, MD, Principal Investigator
- Published
- 2023
196. Senolytic Therapy to Modulate Progression of Alzheimer's Disease (SToMP-AD)
- Author
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Mayo Clinic and Mitzi Gonzales, PhD, Associate Professor
- Published
- 2023
197. Combination Chemotherapy and Dasatinib in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
- Published
- 2023
198. Precision Dosing of Tyrosine Kinase Inhibitors in CML Patients
- Published
- 2023
199. Nanoformulation of dasatinib cannot overcome therapy resistance of pancreatic cancer cells with low LYN kinase expression
- Author
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Kaul, Marilyn, Sanin, Ahmed Y., Shi, Wenjie, Janiak, Christoph, and Kahlert, Ulf D.
- Published
- 2024
- Full Text
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200. PDIA2 is associated with the prognosis of prostate cancer, and downregulation of PDIA2 delays the progression of prostate cancer cells
- Author
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Zhou, Qiang, Ge, Yue, Ma, Sheng, Xiong, Zezhong, Wang, Yanan, Li, Le, Li, Ling, Chao, Zheng, Zhang, Junbiao, Li, Tengfei, Wu, Zixi, Gao, Yuan, Qu, Guanyu, Dong, Haoxiao, Wang, Zhihua, Jing, Wang, and Chen, Guojun
- Published
- 2024
- Full Text
- View/download PDF
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