RESUMO
Only one accelerometer is used in this paper for estimating the maximum inter-story drifts and time histories of the relative displacements of all stories of multi-degree-of-freedom (MDOF) shear structures under seismic excitation. The calculation based on the data of one sensor using a conventional method is unstable, and when modal coordinates are used, higher modes should be included, which is different from the estimation based on the responses recorded by many accelerometers. However, the parameters of the higher modes of structures are difficult to obtain from structures under small excitations. To overcome this difficulty, the recorded absolute acceleration is converted into the absolute displacement, and a state-space equation is formulated. Numerical simulations of a nine-story structure were conducted to check the applicability, robustness against environmental noise, and optimal installation location of the accelerometer of the proposed approach. In addition, the effects of the higher modes were analyzed in terms of the number of accelerometers and type of response. Finally, the proposed approach was validated in a simple experiment. The results indicate that it can accurately estimate the time histories of the relative displacements and maximum inter-story drifts of all floors when one accelerometer is used and just the first two modal parameters are incorporated in the model. Furthermore, the approach is robust against environmental noise.
Assuntos
Aceleração , AcelerometriaRESUMO
Climbing and descending stairs are demanding daily activities, and the monitoring of them may reveal the presence of musculoskeletal diseases at an early stage. A markerless system is needed to monitor such stair walking activity without mentally or physically disturbing the subject. Microsoft Kinect v2 has been used for gait monitoring, as it provides a markerless skeleton tracking function. However, few studies have used this device for stair walking monitoring, and the accuracy of its skeleton tracking function during stair walking has not been evaluated. Moreover, skeleton tracking is not likely to be suitable for estimating body joints during stair walking, as the form of the body is different from what it is when it walks on level surfaces. In this study, a new method of estimating the 3D position of the knee joint was devised that uses the depth data of Kinect v2. The accuracy of this method was compared with that of the skeleton tracking function of Kinect v2 by simultaneously measuring subjects with a 3D motion capture system. The depth data method was found to be more accurate than skeleton tracking. The mean error of the 3D Euclidian distance of the depth data method was 43.2 ± 27.5 mm, while that of the skeleton tracking was 50.4 ± 23.9 mm. This method indicates the possibility of stair walking monitoring for the early discovery of musculoskeletal diseases.
Assuntos
Articulação do Joelho , Fenômenos Biomecânicos , Marcha , Humanos , Amplitude de Movimento Articular , CaminhadaRESUMO
BACKGROUND: TAS-106 is a novel nucleoside analog that inhibits RNA polymerases I, II and II and has demonstrated robust antitumor activity in a wide range of models of human cancer in preclinical studies. This study was performed to principally evaluate the feasibility of administering TAS-106 as a bolus intravenous (IV) infusion every 3 weeks. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of TAS-106 as a single bolus IV infusion every 3 weeks. Plasma and urine sampling were performed during the first course to characterize the pharmacokinetic profile of TAS-106 and assess pharmacodynamic relationships. RESULTS: Thirty patients were treated with 66 courses of TAS-106 at eight dose levels ranging from 0.67-9.46 mg/m(2). A cumulative sensory peripheral neuropathy was the principal dose-limiting toxicity (DLT) of TAS-106 at the 6.31 mg/m(2) dose level, which was determined to be the maximum tolerated dose (MTD). Other mild-moderate drug-related toxicities include asthenia, anorexia, nausea, vomiting, myelosuppression, and dermatologic effects. Major objective antitumor responses were not observed. The pharmacokinetics of TAS-106 were dose-proportional. The terminal elimination half-life (t(1/2)) averaged 11.3 ± 3.3 h. Approximately 71% of TAS-106 was excreted in the urine as unchanged drug. Pharmacodynamic relationships were observed between neuropathy and: C(5min;) AUC(0-inf;) and dermatologic toxicity. CONCLUSIONS: The recommended phase II dose of TAS-106 is 4.21 mg/m(2). However, due to a cumulative drug-related peripheral sensory neuropathy that proved to be dose-limiting, further evaluation of this bolus every 21 day infusion schedule will not be pursued and instead, an alternate dosing schedule of TAS-106 administered as a continuous 24-hour infusion will be explored to decrease C(max) in efforts to minimize peripheral neuropathy and maximize antitumor activity.
Assuntos
Antineoplásicos/administração & dosagem , Citidina/análogos & derivados , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Neoplasias/tratamento farmacológico , RNA Polimerase III/antagonistas & inibidores , RNA Polimerase II/antagonistas & inibidores , RNA Polimerase I/antagonistas & inibidores , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Área Sob a Curva , Biotransformação , Citidina/administração & dosagem , Citidina/efeitos adversos , Citidina/farmacocinética , Esquema de Medicação , Inibidores Enzimáticos/efeitos adversos , Estudos de Viabilidade , Feminino , Meia-Vida , Humanos , Infusões Intravenosas , Estimativa de Kaplan-Meier , Masculino , Dose Máxima Tolerável , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Neoplasias/enzimologia , Neoplasias/genética , Neoplasias/patologia , RNA Polimerase I/metabolismo , RNA Polimerase II/metabolismo , RNA Polimerase III/metabolismo , Texas , Resultado do TratamentoRESUMO
TAS-102 is a novel formulation of the fluorinated pyrimidine analogue trifluorothymidine (FTD) with an inhibitor of thymidine phosphorylase. The purpose of this study was to determine the MTD and DLT for TAS-102 administered three times a day on days 1-5 and 8-12 every 4 weeks. Fifteen patients were enrolled with two patients experiencing dose-limiting fatigue and granulocytopenia at the first dose level (80 mg/m2/day). Granulocytopenia was the primary toxicity: 7 patients experienced grade 3 or 4 granulocytopenia with the first course. No responses were noted, but nine patients demonstrated prolonged stable disease in this heavily pretreated 5-FU refractory population.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Trifluridina/administração & dosagem , Uracila/análogos & derivados , Adenocarcinoma/tratamento farmacológico , Administração Oral , Adulto , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Combinação de Medicamentos , Feminino , Gastroenteropatias/induzido quimicamente , Doenças Hematológicas/induzido quimicamente , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Pirrolidinas , Timina , Trifluridina/efeitos adversos , Trifluridina/uso terapêutico , Uracila/administração & dosagem , Uracila/efeitos adversos , Uracila/uso terapêuticoRESUMO
This study proposes damage detection algorithms for multistory shear structures that only need the first two or three natural frequencies. The methods are able to determine the location and severity of damage on the basis of damage location indices (DLI) and damage quantification indices (DQI) consisting of the changes in the first few squared natural frequencies of the undamaged and damaged states. The damage is assumed to be represented by a reduction in stiffness. This stiffness reduction causes a shift in the natural frequencies of the structure. The uncertainty associated with system identification methods for obtaining natural frequencies is also carefully considered. The methods are accurate and cost-effective means only requiring the changes in the natural frequencies.
RESUMO
BACKGROUND: The nucleoside 3'-c-ethynylcytidine (TAS-106) was designed to inhibit RNA synthesis which occurs throughout the cell cycle except for the M phase. TAS-106 is incorporated into cells, is rapidly phosphorylated to a monophosphate form, and is preferentially distributed into malignant cells. Preclinical studies showed that TAS-106 has a wide antitumor spectrum against human cancer xenografts. This phase I study was conducted in order to determine the recommended phase II dose of TAS-106 administered once per week for three consecutive weeks, every 28 days in patients with solid tumors. PATIENTS AND METHODS: Patients were enrolled in cohorts of three, starting at 0.22 mg/m(2)/dose. Patients received at least two doses in order to be evaluable in each dose cohort. Dose escalation was stopped if two or more patients experienced dose limiting toxicity at any dose level. RESULTS: In 20 evaluable patients, TAS-106 was given at the following dose levels (mg/m(2)/dose): 0.22 (3 pts), 0.33 (3 pts), 0.66 (3 pts), 0.99 (1 pt), 1.32 (3 pts), 2.64 (3 pts) and 3.96 (1 pt). Three additional patients were evaluated at 2.64 mg/m(2)/dose for further characterization of toxicity and safety. A total of 16 patients completed courses 1 and 2. All 21 patients enrolled experienced at least one adverse event. The AE attributed to the study drug was grade 2 peripheral neuropathy characterized by peripheral sensory neuropathy, numbness, tremor, pain, and hyperesthesia involving the fingers, hands, toes, and feet. CONCLUSION: Due to neurotoxicity the MTD was the 2.64 mg/m(2)/dose for the study schedule. No suggested phase II dose was determined. However, at the 1.32 mg/m(2)/dose level, no patients experienced DLTs during course 1 or 2. This could be further studied to determine its viability as a potential phase II dosage.
Assuntos
Antineoplásicos/administração & dosagem , Citidina/análogos & derivados , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Citidina/administração & dosagem , Citidina/efeitos adversos , Citidina/farmacocinética , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
1-(3-C-ethynyl-beta-d-ribo-pentofuranosyl)cytosine (ECyd) is a ribose-modified nucleoside analog of cytidine with potent anticancer activity in several cancers. The main antitumor mechanism of this promising RNA-directed nucleoside anti-metabolite is efficient blockade of RNA synthesis in cancer cells. Here, we examined the therapeutic potential of this RNA-directed anti-metabolite in in vitro models of nasopharyngeal cancer (NPC). In a panel of 6 NPC cell lines, ECyd effectively inhibited cellular proliferation at nM concentrations (IC(50): approximately 13-44nM). Moreover, cisplatin-resistant NPC cells were highly sensitive to ECyd (at nM concentration). The ECyd-mediated growth inhibition was associated with G(2)/M cell cycle arrest, PARP cleavage (a hallmark of apoptosis) and Bcl-2 downregulation, indicating induction of apoptosis by ECyd in NPC cells. Unexpectedly, ECyd-induced significant downregulation of TIGAR, a newly described dual regulator of apoptosis and glycolysis. More importantly, this novel action of ECyd on TIGAR was accompanied by marked depletion of NADPH, the major reducing power critically required for cell proliferation and survival. We hypothesized that ECyd-induced TIGAR downregulation was crucially involved in the antitumor activity of ECyd. Indeed, overexpression of TIGAR was able to rescue NPC cells from ECyd-induced growth inhibition, demonstrating a novel mechanistic action of ECyd on TIGAR. We demonstrated for the first time that an RNA-directed nucleoside analog, ECyd, exerts its antitumor activity via downregulation of a novel regulator of apoptosis, TIGAR. Moreover, ECyd may represent a novel therapy for NPC.
Assuntos
Citidina/análogos & derivados , Regulação para Baixo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Nasofaríngeas/patologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Citidina/farmacologia , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Peptídeos e Proteínas de Sinalização Intracelular/genética , NADP/metabolismo , Neoplasias Nasofaríngeas/tratamento farmacológico , Monoéster Fosfórico HidrolasesRESUMO
This study was designed to determine the safety and optimal dosing of TAS-102, a novel oral combination of alphaalphaalpha-trifluorothymidine (FTD) and an inhibitor of thymidine phoshorylase, in patients with solid tumors. Patients who met the eligibility criteria were treated with one of two different TAS-102 regimens: once per day on either days 1-5 and 8-12 every 4 weeks (schedule A) or days 1-5 every 3 weeks (schedule B). The primary objectives were the determination of the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose. Pharmacokinetic analysis was conducted during courses 1 and 2. Sixty-three patients received a total of 172 courses of therapy with the median number of courses delivered on both schedules being 2. DLTs were observed in three patients on schedule A, 70 mg/m(2)/day (1) and 110 mg/m(2)/day (2); and in five patients on schedule B, 120 mg/m(2)/day (1), 170 mg/m(2)/day (2), 180 mg/m(2)/day (2). Granulocytopenia was the DLT in seven of the eight cases. The most frequent toxicities were nausea, fatigue, granulocytopenia, anemia, diarrhea, and abdominal pain. Twelve patients, 6 on schedule A and 6 on schedule B, were treated at the recommended phase II dose, with good tolerance. No objective responses were seen in this heavily pretreated, 5-FU-refractory population. The pharmacokinetic parameters of FTD are a T (max) of 0.53 to 3.15 h, t (1/2) of 1.46 to 4.20 h, volume of distribution of 0.0526 to 0.483 l/kg, and clearance of 0.0194 to 0.197 1/h/kg. The recommended phase II doses for TAS-102 are 100 mg/m(2)/day on schedule A and 160 mg/m(2)/day on schedule B. Future development of TAS-102 should focus upon multiple daily dosing schedules.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Pirrolidinas , Timina , Trifluridina/administração & dosagem , Trifluridina/efeitos adversos , Trifluridina/farmacocinética , Uracila/administração & dosagem , Uracila/efeitos adversos , Uracila/farmacocinética , Uracila/uso terapêuticoRESUMO
BACKGROUND: The purpose of the current study was to determine the maximum tolerated dose, dose-limiting toxicities, pharmacokinetic profile, and recommended Phase II dose of oral administration of TAS-102, a novel nucleoside formed by the combination of alpha,alpha,alpha-trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI: 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione). METHODS: Eligible patients had advanced solid tumors, adequate organ function, and had not received anticancer therapy in the preceding 4 weeks. TAS-102 was administered orally once daily for 14 days, followed by a 1-week rest, repeated every 3 weeks. The initial dose of TAS-102 administered was 100 mg/m2/day. The first 2 patients treated at that dose experienced substantial toxicity and, therefore, lower dose levels of TAS-102 were subsequently explored. RESULTS: Fourteen patients were enrolled; all patients were evaluable for toxicity assessment and 12 were evaluable for response. The initial dose explored was 100 mg/m2/day, based on a preclinical monkey model. However, the first 2 patients experienced bone marrow suppression of Grade 3 or 4 in course 1. The protocol was amended to study the next cohort of patients at 50 mg/m2/day. At this dose level no Grade 3 or 4 toxicities were observed in course 1. In the subsequent dose level (60 mg/m2/day), 3 of 6 patients experienced Grade 3 or 4 granulocytopenia as dose-limiting toxicity. Three additional patients for a total of 6 were enrolled at 50 mg/m2/day without occurrence of dose-limiting toxicity. Thus, 50 mg/m2/day was declared the maximum tolerated dose for this schedule. CONCLUSIONS: The authors' study showed that 50 mg/m2/day was a tolerable dose of the novel antimetabolite FTD in combination with an inhibitor of its inactivating enzyme TP, and this is the recommended Phase II dose. Evaluation of this daily dose in malignancies for which fluoropyrimidines have failed is needed.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Administração Oral , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Área Sob a Curva , Astenia/induzido quimicamente , Relação Dose-Resposta a Droga , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias/metabolismo , Pirrolidinas , Timina , Resultado do Tratamento , Trifluridina/sangue , Trifluridina/farmacocinética , Uracila/farmacocinética , Uracila/uso terapêuticoRESUMO
A new response control strategy is proposed for tall buildings. The proposed control strategy takes the advantage of the mega-structure configuration which is an efficient structural system for a super tall building and does not require any additional mass. The sub-structures contained in the mega-structure serve as energy absorbers. The difficulties to augment supplemental damping into a tall building associated with the high rigidity of the structural system and the bending deformation are naturally resolved under the current control strategy. A numerical study is perfomed to demonstrate the feasibility of the strategy.(AU)