Browsing by Subject "cancer patients"

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    Fatigue and Sleep Disturbance in Arabic Cancer Patients After Completion of Therapy: Prevalence, Correlates, and Association With Quality of Life
    (Wolters Kluwer, 2021-09) Al Maqbali, Mohammed; Hughes, Ciara; Rankin, Jane; Dunwoody, Lynn; Hacker, Eileen; Gracey, Jackie; School of Nursing
    Background Fatigue and sleep disturbance are 2 of the most common and distressing cancer symptoms that negatively affect quality of life. Objective The aim of this study was to assess the prevalence of, and factors contributing to, fatigue and sleep disturbance in Arabic-speaking cancer patients in Oman after completion of their cancer treatment. Methods A cross-sectional and descriptive correlational design was used. Data were collected using the Pittsburgh Sleep Quality Index where a score of >5 indicated as poorer sleep, the Functional Assessment of Cancer Therapy–Fatigue a score of ≤34 indicating clinically significant fatigue, and the Functional Assessment of Cancer Therapy–General. Results Of the 369 patients who participated, 77.5% (n = 286) reported clinically significant fatigue, and 78% (n = 288) reported poor sleep. Fatigue (P < .05) was significantly associated with age, cancer site, months since diagnosis, type of treatment received, and comorbidity. Those experiencing fatigue and poor sleep had the lowest quality of life among the cancer patients studied. Conclusion Fatigue and sleep disturbance are significant problems for the Arabic patients diagnosed with cancer. Both fatigue and sleep disturbance should be routinely assessed in the case of such patients. Implications for Practice Routine assessments of fatigue and sleep disturbance are recommended so that appropriate interventions and treatment management plans can be introduced to reduce fatigue and improve sleep quality among patients with cancer.
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    MAPKs activation and mitochondrial depletion are associated with chemotherapy-related cachexia
    (Office of the Vice Chancellor for Research, 2016-04-08) Barreto, Rafael; Waning, David L.; Gao, Hongyu; Liu, Yunlong; Zimmers, Teresa A.; Bonetto, Andrea
    Background. Cachexia, defined by increased fatigue and loss of muscle function, results from muscle and fat depletion and affects the majority of cancer patients with no effective treatments. Previous studies suggest that chemotherapy itself may contribute to cachexia, although the mechanisms responsible for these derangements are not clear. The purpose of this study was to investigate the mechanism(s) associated with chemotherapyrelated effects on body composition and muscle function. Methods. Chemotherapy regimens routinely used for the therapy of solid tumors were tested in normal CD2F1 mice, followed by assessment of body composition and muscle strength. Mitochondrial activity in muscle sections was evaluated, and TEM imaging in EDL muscle was performed. To determine whether chemotherapy modulates signaling pathways associated with the regulation of muscle mass, Western blotting, qRT-PCR and RNASequencing were utilized. Results. Administration of Folfox (5-FU, leucovorin, oxaliplatin), Folfiri (5-FU, leucovorin, irinotecan) or Gemcitabine/Paclitaxel for up to 5 weeks to normal mice caused marked decreases in adipose tissue and skeletal muscle content, coherent with reduced muscle strength. Notably, ERK1/2/MAPK and p38/MAPK signaling pathways, as well as myostatin expression were significantly up-regulated. TEM analysis unveiled a marked depletion in muscle mitochondrial content and alterations of the sarcomeric structure consistent with loss of muscle structural proteins in the mice receiving chemotherapy. Moreover, the RNA-Sequencing analysis identified several markers associated with mitochondrial homeostasis, lipid metabolism and acute phase response that were significantly affected by Folfiri administration. Conclusions. Our findings suggest that chemotherapy promotes the activation of MAPK- and myostatindependent muscle atrophy and causes mitochondrial depletion and alterations of the sarcomeric units, likely playing a causative role in the occurrence of muscle loss and weakness. Future investigations will clarify whether pharmacologically increasing muscle mass or inhibiting MAPK activation reduces chemotherapy-related cachexia, thereby providing potential pharmacological targets to improve efficacy and tolerance of anticancer drugs.
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    MECHANISM OF ORLISTAT HYDROLYSIS BY FATTY ACID SYNTHASE THIOESTERASE
    (Office of the Vice Chancellor for Research, 2012-04-13) Liu, Jing-Yuan; Zhang, Jian-Ting
    Fatty acid synthase (FASN) is the sole protein capable of de novo synthesis of free fatty acids. The fatty acid synthesis cycle begins with the condensa-tion of acetyl-CoA and malonyl-CoA, and continues with the elongation of the fatty acid chain, which is tethered to an acyl carrier protein domain (ACP), via a repeating cycle. At the end of elongation, the thioesterase (TE) domain of FASN cleaves the bond between the fatty acid and ACP, releasing the fatty acid. FASN has been found to be over-expressed in a wide variety of human cancers, and this over-expression is correlated to a higher meta-static potential and poorer prognosis in cancer patients. Orlistat, an FDA ap-proved drug for obesity treatment, is a compound found to reversibly inhibit FASN TE by covalently binding to the active site serine within the TE domain. In crystal structure studies, a hydrolyzed form of orlistat can also be ob-served in the active site of TE, demonstrating that orlistat is not a stable in-hibitor of FASN. In this study, we examined the mechanism of orlistat hy-drolysis within the TE domain of FASN using molecular dynamics simula-tions. We found that the hexanoyl tail of orlistat is capable of shifting while covalently bound to the active site serine, and that this shift is accompanied by the destabilization of a hydrogen bond that exists between a hydroxyl moiety of orlistat and the active site histidine, allowing a catalytic water molecule to enter the active site with the proper orientation for catalysis of the covalent bond between orlistat and serine. These findings suggest that the hexanoyl tail of orlistat plays an important role in its hydrolysis and may guide the future design of new inhibitors that target the TE domain of FASN with greater endurance for potential use in the treatment of cancer.
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    Simultaneous Quantification of Vincristine and Its Major M1 Metabolite from Dried Blood Spot Samples of Kenyan Pediatric Cancer Patients by UPLC-MS/MS
    (Elsevier, 2021-09) Agu, Lorita; Skiles, Jodi L.; Masters, Andrea R.; Renbarger, Jamie L.; Chow, Diana S-L; Pediatrics, School of Medicine
    Vincristine (VCR) is an integral part of chemotherapy regimens in the US and in developing countries. There is a paucity of information about its disposition and optimal therapeutic dosing. VCR is preferentially metabolized to its major M1 metabolite by the polymorphic CYP3A5 enzyme, which may be clinically significant as CYP3A5 expression varies across populations. Thus, it is important to monitor both VCR and M1 and characterize their dispositions. A previously developed HPLC-MS/MS method for VCR quantification was not sensitive enough to quantify the M1 metabolite beyond 1 hr. post VCR dose (not published). Establishing a highly sensitive assay is a pre-requisite to simultaneously quantify and monitor VCR and M1, which will enable characterization of drug exposure and dispositions of both analytes in a pediatric cancer population. The addition of formic acid during the extraction process enhanced M1 extraction from DBS samples. A sensitive, accurate, and precise UPLC-MS/MS assay method for the simultaneous quantification of VCR and M1 from human dried blood spots (DBS) was developed and validated. Chromatographic separation was performed on Inertsil ODS-3 C18 column (5 μm, 3.0 x 150 mm). A gradient elution of mobile phase A (methanol-0.2% formic acid in water, 20:80 v/v) and mobile phase B (methanol-0.2% formic acid in water, 80:20 v/v) was used with a flow rate of 0.4 mL/min and a total run time of 5 min. The analytes were ionized by electrospray ionization in the positive ion mode. The linearity range for both analytes in DBS were 0.6-100 ng/ml for VCR and 0.4-100 ng/ml for M1. The intra- and inter-day accuracies for VCR and M1 were 93.10-117.17% and 95.88-111.21%, respectively. While their intra- and inter-day precisions were 1.05 to 10.11% and 5.78 to 8.91%, respectively. The extraction recovery of VCR from DBS paper was 35.3 – 39.4% and 10.4 – 13.4% for M1, with no carryover observed for both analytes. This is the first analytical method to report the simultaneous quantification of VCR and M1 from human DBS. For the first time, concentrations of M1 from DBS patient samples were obtained beyond 1 -h post VCR dose. The developed method was successfully employed to monitor both compounds and perform pharmacokinetic analysis in a population of Kenyan pediatric cancer patients.