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131.
132.
Anthony W. Tolcher Razelle Kurzrock Vincente Valero Rene Gonzalez Rebecca S. Heist Antoinette R. Tan Julie Means-Powell Theresa L. Werner Carlos Becerra Chenxi Wang Cathrine Leonowens Shanker Kalyana-Sundaram Joseph F. Kleha Jennifer Gauvin Anthony M. DAmelio Catherine Ellis Nageatte Ibrahim Li Yan 《Cancer chemotherapy and pharmacology》2020,85(4):673-683
This study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK and/or AKT inhibition. This was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or BRAF-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5 mg once daily (QD) + uprosertib 50 mg QD. Adverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was < 5% (1 complete response, 5 partial responses). Continuous and intermittent dosing of trametinib in combination with uprosertib was not tolerated, and minimal clinical activity was observed in all schedules tested. 相似文献
133.
Voigt A Elgeti T Durmus T Idiz ME Butler C Beling M Schilling R Klingel K Kandolf R Stangl K Taupitz M Kivelitz D Wagner M 《European radiology》2011,21(5):925-935
Objective
To assess active myocardial inflammation by cardiovascular magnetic resonance (CMR) and endomyocardial biopsy (EMB) amongst adult patients with dilated cardiomyopathy (DCM).Methods
We evaluated 23 adults with chronic DCM, who had successfully undergone both CMR and EMB within 3.5?±?2.6?days. EMB was considered the gold standard. CMR assessment of myocardial inflammation used the following parameters as recommended by the recently published ??Lake Louise Criteria??: global myocardial oedema, global relative enhancement (RE), and late gadolinium enhancement (LGE). According to ??Lake Louise Criteria??, myocardial inflammation was diagnosed if two or more of the three above-mentioned parameters were positive.Results
Myocardial inflammation was confirmed by immunohistology in 12 patients (52.2%). Sensitivity, specificity, and diagnostic accuracy of CMR to detect immunohistologically confirmed myocardial inflammation were 75.0%, 72.7%, and 73.9%, respectively. Sensitivity, specificity, and diagnostic accuracy of the individual CMR parameters to detect myocardial inflammation were as follows: global myocardial oedema, 91.7%, 81.8%, and 87.0%, respectively; global RE, 58.3%, 63.6%, and 60.9%, respectively; LGE, 58.3%, 45.4%, and 52.2%, respectively.Conclusion
Global myocardial oedema was identified as a promising CMR parameter for assessment of myocardial inflammation in patients with DCM. In these patients, global myocardial oedema yielded superior diagnostic performance compared to ??Lake Louise Criteria??. 相似文献134.
135.
Robotic surgery is being used with increasing frequency in gynecologic oncology. To date, 44 cases were reported in the literature of radical hysterectomy performed with robotic surgery. When comparing robotic surgery with laparoscopy or laparotomy in performing a radical hysterectomy, the literature shows that robotic surgery offers an advantage over the other 2 surgical approaches with regard to operative time, blood loss, and length of hospitalization. Future studies are needed to further elucidate the equivalence or superiority of robotic surgery to laparoscopy or laparotomy in performing a radical hysterectomy. 相似文献
136.
Peroneus longus ligamentoplasty for chronic instability of the distal tibiofibular syndesmosis 总被引:11,自引:0,他引:11
Grass R Rammelt S Biewener A Zwipp H 《Foot & ankle international / American Orthopaedic Foot and Ankle Society [and] Swiss Foot and Ankle Society》2003,24(5):392-397
The distal tibiofibular syndesmosmotic ligament complex is important for dynamic stability and congruency of the ankle joint. Syndesmotic lesions in the ankle fracture-dislocations are well recognized and classified systematically. Chronic insufficiency of the syndesmosis leads to a lateral shift of the talus and under eversion stress permits a pathological rotation of the talus. There is also retroversion of the distal fibula representing a painful deformity. Little experience exists with surgical reconstruction of the syndesmosis. This article describes a new ligamentoplasty with a split peroneus longus tendon graft that mimics the normal anatomic conditions of the syndesmotic complex in 16 patients with symptomatic chronic syndesmotic insufficiency after pronation-external rotation and pronation abduction injuries to the ankle joint. Postoperatively, no infections or hematomas were seen. One patient had asymptomatic breakage of the syndesmosis screw; one patient had a 10 degree decrease of dorsiflexion at the ankle because of a partial anterior tibiofibular synostosis. Fifteen of 16 patients had pain relief at a mean follow-up period of 16.4 months (range, 13-29 months); all patients had relief of the chronic swelling of the ankle and the giving way. The mean Karlsson score at follow-up was 88 (range, 70-100) points. It may be concluded that peroneus longus ligamentoplasty in a preliminary series resulted in reliable ankle stability and considerable pain relief in patients with chronic syndesmotic instability. 相似文献
137.
Kevin T. Love Kerry P. Mahon Christopher G. Levins Kathryn A. Whitehead William Querbes J. Robert Dorkin June Qin William Cantley Liu Liang Qin Timothy Racie Maria Frank-Kamenetsky Ka Ning Yip Rene Alvarez Dinah W. Y. Sah Antonin de Fougerolles Kevin Fitzgerald Victor Koteliansky Akin Akinc Robert Langer Daniel G. Anderson 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(5):1864-1869
Significant effort has been applied to discover and develop vehicles which can guide small interfering RNAs (siRNA) through the many barriers guarding the interior of target cells. While studies have demonstrated the potential of gene silencing in vivo, improvements in delivery efficacy are required to fulfill the broadest potential of RNA interference therapeutics. Through the combinatorial synthesis and screening of a different class of materials, a formulation has been identified that enables siRNA-directed liver gene silencing in mice at doses below 0.01 mg/kg. This formulation was also shown to specifically inhibit expression of five hepatic genes simultaneously, after a single injection. The potential of this formulation was further validated in nonhuman primates, where high levels of knockdown of the clinically relevant gene transthyretin was observed at doses as low as 0.03 mg/kg. To our knowledge, this formulation facilitates gene silencing at orders-of-magnitude lower doses than required by any previously described siRNA liver delivery system. 相似文献
138.
Rene Ratschmann Milen Minkov Ana Kis Christina Hung Tony Rupar Adolf Mühl Brian Fowler Ebba Nexo Olaf A. Bodamer 《Molecular genetics and metabolism》2009,98(3):285-288
Transcobalamin II deficiency (# MIM 275350) is a rare, recessively inherited disorder of cobalamin transport that leads to intracellular cobalamin depletion with secondary impairment of methionine synthetase and methyl-malonyl CoA mutase activities. Affected individuals may suffer from long-term neurological sequelae if therapy with intramuscular hydroxocobalamin is not initiated promptly. We report two sisters with complete absence of transcobalamin due to homozygosity for a novel mutation (c.insC110) in the TCN2 gene that leads to a premature stop codon and non-functional protein. The older sister, now 4.5 years old, presented at 6 weeks of age with pancytopenia, protein losing enteropathy and a rapidly declining clinical course. Prompt therapy with 1 mg hydroxocobalamin/day led to full recovery within days. Her now 1.5 year old sister was diagnosed shortly after birth and was started on hydroxocobalamin prior to onset of clinical symptoms. Interestingly, urinary methylmalonic acid excretion was increased significantly during the first days of life suggesting that functional cobalamin deficiency is present also during fetal life, although not giving rise to clinical symptoms until well after birth. 相似文献
139.
Francesco S. Celi Marina Zemskova Joyce D. Linderman Nabeel I. Babar Monica C. Skarulis Gyorgy Csako Robert Wesley Rene Costello Scott R. Penzak Frank Pucino 《Clinical endocrinology》2010,72(5):709-715
Context The substitution of liothyronine (L‐T3) for levothyroxine (L‐T4) is commonly employed during thyroid hormone (TH) withdrawal in preparation for diagnostic and therapeutic interventions on thyroid cancer patients. Presently, only limited data are available on the L‐T3 for L‐T4 therapeutic substitution. Objective To characterize the pharmcodynamic equivalence of L‐T3 and L‐T4. Design Randomized, double‐blind, cross‐over intervention study. Setting NIH clinical center. Patients Ten thyroidectomized patients. Interventions Study participants were treated with L‐T3 or L‐T4 with a target TSH ≥ 0·5 ≤ 1·5 mU/l for at least 30 days before undergoing inpatient testing. Following testing, subjects crossed‐over according to the same scheme. Main outcome measures Area under the serum concentration–time curve of TSH from 0 to 60 min (AUC0–60) and peak TSH serum concentration (Cmax) following thyrotropin‐releasing hormone (TRH) stimulation test, total L‐T4 and L‐T3 dose (mcg/kg), and L‐T4/L‐T3 ratio. Results No difference was observed for time 0 TSH values between L‐T3 and L‐T4 replacement phases (1·48 ± 0·77 vs. 1·21 ± 0·62 mU/l, P = 0·293) at average daily doses of 40·3 ± 11·3 mcg L‐T3 and 115·2 ± 38·5 mcg L‐T4, L‐T3: L‐T4 ratio 0·36 ± 0·06. TRH stimulation test resulted in similar L‐T3 vs. L‐T4 TSH responses with AUC0–60 of 326·1 (95% CI 232·6–457·1) and 247·1 (95% CI 153·8–397·1) mU* min/l (P = 0·285); and Cmax of 6·83 (95% CI 4·88–9·55) and 5·23 (95% CI 3·31–8·3) mU/l (P = 0·383). Conclusions This is the first study addressing the equivalency between L‐T3 and L‐T4 therapy measured by baseline and TRH‐stimulated TSH. The therapeutic substitution of L‐T3 for L‐T4 was achieved at approximately 1:3 ratio. 相似文献
140.
A web-based simulation of a longitudinal clinic used in a 4-week ambulatory rotation: a cohort study