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1.
Mol Ecol ; 33(1): e17194, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37933590

RESUMO

The focus of this study has been to understand the evolutionary relationships and taxonomy of a widely distributed parapatric species pair of wild silk moths in Europe: Saturnia pavonia and Saturnia pavoniella (Lepidoptera: Saturniidae). To address species delimitation in these parapatric taxa, target enrichment and mtDNA sequencing was employed alongside phylogenetic, admixture, introgression, and species delimitation analyses. The dataset included individuals from both species close to and farther away from the contact zone as well as two hybrids generated in the lab. Nuclear markers strongly supported both S. pavonia and S. pavoniella as two distinct species, with hybrids forming a sister group to S. pavoniella. However, the Maximum Likelihood (ML) tree generated from mtDNA sequencing data presented a different picture, showing both taxa to be phylogenetically intermixed. This inconsistency is likely attributable to mitonuclear discordance, which can arise from biological factors (e.g., introgressive hybridization and/or incomplete lineage sorting). Our analyses indicate that past introgressions have taken place, but that there is no evidence to suggest an ongoing admixture between the two species, demonstrating that the taxa have reached full postzygotic reproductive isolation and hence represent two distinct biological species. Finally, we discuss our results from an evolutionary point of view taking into consideration the past climatic oscillations that have likely shaped the present dynamics between the two species. Overall, our study demonstrates the effectiveness of the target enrichment approach in resolving shallow phylogenetic relationships under complex evolutionary circumstances and that this approach is useful in establishing robust and well-informed taxonomic delimitations involving parapatric taxa.


Assuntos
Mariposas , Animais , Filogenia , Mariposas/genética , Evolução Biológica , DNA Mitocondrial/genética , Mitocôndrias/genética
2.
BMC Med ; 21(1): 306, 2023 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-37580773

RESUMO

BACKGROUND: There is increasing interest in the use of liquid biopsies, but data on longitudinal analyses of circulating tumor DNA (ctDNA) remain relatively limited. Here, we report a longitudinal ctDNA analysis of MONALEESASIA, a phase Ib trial evaluating the efficacy and safety of ribociclib plus endocrine therapy (ET) in Asian patients with hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer. METHODS: MONALEESASIA enrolled premenopausal and postmenopausal Japanese and postmenopausal non-Japanese Asian patients. All patients received ribociclib with ET (letrozole, fulvestrant, or tamoxifen with goserelin). ctDNA was analyzed using a targeted next-generation sequencing panel of 572 cancer-related genes and correlated by best overall response (BOR). RESULTS: Five hundred seventy-four cell-free DNA samples from 87 patients were tested. The most frequently altered genes at baseline included PIK3CA (29%) and TP53 (22%). Treatment with ribociclib plus ET decreased ctDNA in most patients at the first on-treatment time point, regardless of dose or ET partner. Patients with partial response and stable disease had lower ctDNA at baseline that remained low until data cutoff if no progressive disease occurred. Most patients with progressive disease as the best response had higher ctDNA at baseline that remained high at the end of treatment. For patients with partial response and stable disease with subsequent progression, ctDNA increased towards the end of treatment in most patients, with a median lead time of 83 days (14-309 days). In some patients with BOR of partial response who experienced disease progression later, specific gene alterations and total ctDNA fraction increased; this was sometimes observed concurrently with the development of new lesions without a change in target lesion size. Patients with alterations in PIK3CA and TP53 at baseline had shorter median progression-free survival compared with patients with wild-type PIK3CA and TP53, 12.7 and 7.3 months vs 19.2 and 19.4 months, respectively (P = .016 and P = .0001, respectively). CONCLUSIONS: Higher ctDNA levels and PIK3CA and TP53 alterations detected at baseline were associated with inferior outcomes. On-treatment ctDNA levels were associated with different patterns based on BOR. Longitudinal tracking of ctDNA may be useful for monitoring tumor status and detection of alterations with treatment implications. TRIAL REGISTRATION: ClinicalTrials.gov NCT02333370 . Registered on January 7, 2015.


Assuntos
Neoplasias da Mama , Feminino , Humanos , Aminopiridinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Receptor ErbB-2/genética
3.
Exp Brain Res ; 234(7): 1893-1901, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26898313

RESUMO

The purpose of this study was to identify the influence of a high- and low-friction surface on the ability to maintain a steady downward force during an index finger pressing and moving task. Fifteen right-handed subjects (24-48 years) performed a static force pressing task and a hybrid pressing and moving task on the surface of an iPad mini while holding a steady 2-N force on high- and low-friction surfaces. Variability of force was quantified as the standard deviation (SD) of normal force (F z) and shear force (F xy) across friction conditions and tasks. The SD of F z was 227 % greater during the hybrid task as compared to the static task (p < .001) and was 19 % greater for the high- versus low-friction condition (p = .033). There were positive correlations between SD of F z and F xy during the hybrid force/motion tasks on the high- and low-friction conditions (r (2) = 0.5 and 0.86, respectively), suggesting significant associations between normal and shear forces for this hybrid task. The correlation between the SD of F z for static and hybrid tasks was r (2) = 0.44, indicating that the common practice of examining the control of static tasks may not sufficiently explain performance during hybrid tasks, at least for the young subjects tested in the current study. As activities of daily living frequently require hybrid force/motion tasks (e.g., writing, doing the dishes, and cleaning counters), the results of this study emphasize the need to study motor performance during hybrid tasks in addition to static force tasks.


Assuntos
Desempenho Psicomotor/fisiologia , Percepção do Tato/fisiologia , Percepção Visual/fisiologia , Adulto , Feminino , Fricção , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
4.
J Appl Biomech ; 32(6): 608-613, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27684301

RESUMO

In-vitro and invasive in-vivo studies have reported relatively independent motion in the medial and lateral forefoot segments during gait. However, most current surface-based models have not defined medial and lateral forefoot or midfoot segments. The purpose of the current study was to determine the reliability of a 7-segment foot model that includes medial and lateral midfoot and forefoot segments during walking gait. Three-dimensional positions of marker clusters located on the leg and 6 foot segments were tracked as 10 participants completed 5 walking trials. To examine the reliability of the foot model, coefficients of multiple correlation (CMC) were calculated across the trials for each participant. Three-dimensional stance time series and range of motion (ROM) during stance were also calculated for each functional articulation. CMCs for all of the functional articulations were ≥ 0.80. Overall, the rearfoot complex (leg-calcaneus segments) was the most reliable articulation and the medial midfoot complex (calcaneus-navicular segments) was the least reliable. With respect to ROM, reliability was greatest for plantarflexion/dorsiflexion and least for abduction/adduction. Further, the stance ROM and time-series patterns results between the current study and previous invasive in-vivo studies that have assessed actual bone motion were generally consistent.


Assuntos
Pé/fisiologia , Monitorização Ambulatorial/instrumentação , Caminhada/fisiologia , Fenômenos Biomecânicos , Feminino , Humanos , Masculino , Amplitude de Movimento Articular/fisiologia , Reprodutibilidade dos Testes , Adulto Jovem
5.
J Comput Assist Tomogr ; 37(1): 37-45, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23321831

RESUMO

PURPOSE: This study aimed to characterize the urinary tract stones in phantom and patients using single-source dual-energy computed tomography. MATERIALS AND METHODS: Twenty stones of pure crystalline composition (uric acid [UA], struvite, cystine, and calcium oxalate monohydrate) were assessed in a phantom and 11 patients (age 39-67 years) with urinary tract stones were evaluated. An initial low-dose unenhanced CT (tube potential, 120 kilovolts [peak]; milliampere range, 150-450; noise index, 26; section thickness, 5 mm) followed by a targeted dual-energy computed tomography acquisition on a single-source dual-energy computed tomography (Discovery CT 750 HDCT, GE) was performed. Uric acid and non-UA stones were defined using a 2-material decomposition (material density-iodine/water) algorithm. The stone effective atomic number (Zeff) was used to subclassify non-UA stones. The stone attenuation (Hounsfield unit) was also studied to determine its performance in predicting the composition. Ex vivo chemical analysis of the stone served as a criterion standard. RESULTS: Of the 59 verified stones (phantom, 20; patients, 39; mean size, 6 mm), there were 16 UA and 43 non-UA type. The material density images were 100% sensitive and accurate in detecting UA and non-UA stones. The Zeff accurately stratified struvite, cystine, and calcium (calcium oxalate monohydrate) stones in the phantom. In patients, Zeff identified 83% of calcium stones (n = 24), and in stones of mixed type, it resembled dominant composition. The Hounsfield unit measurements alone were 71% sensitive and 69% accurate in detecting the UA stones. CONCLUSIONS: Single-source dual-energy computed tomography can accurately predict UA and non-UA stone composition in vitro and in vivo. Substratification of non-UA stones of pure composition can be made in vitro and in vivo. In stones of mixed composition, the Zeff values reflect the dominant composition.


Assuntos
Cálculos Renais/química , Cálculos Renais/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Distribuição de Qui-Quadrado , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imagens de Fantasmas , Doses de Radiação , Interpretação de Imagem Radiográfica Assistida por Computador , Estudos Retrospectivos
6.
J Appl Biomech ; 28(5): 608-15, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23193068

RESUMO

The effect of time-to-boundary minima selection and stability limit definition was investigated during eyes open and eyes closed condition single-limb stance postural stability. Anteroposterior and mediolateral time-to-boundary were computed using the mean and standard deviation (SD) of all time-to-boundary minima during a trial, and the mean and SD of only the 10 absolute time-to-boundary minima. Time-to-boundary with rectangular, trapezoidal, and multisegmented polygon defined stability limits were also calculated. Spearman's rank correlation coefficient test results revealed significant medium-large correlations between anteroposterior and mediolateral time-to-boundary scores calculated using both the mean and SD of the 10 absolute time-to-boundary minima and of all the time-to-boundary minima. Friedman test results revealed significant mediolateral time-to-boundary differences between boundary shape definitions. Follow-up Wilcoxon signed rank test results revealed significant differences between the rectangular boundary shape and both the trapezoidal and multisegmented polygon shapes during the eyes open and eyes closed conditions when both the mean and the SD of the time-to-boundary minima were used to represent postural stability. Significant differences were also revealed between the trapezoidal and multisegmented polygon definitions during the eyes open condition when the SD of the time-to-boundary minima was used to represent postural stability. Based on these findings, the overall results (i.e., stable versus unstable participants or groups) of studies computing postural stability using different minima selection can be compared. With respect to boundary shape, the trapezoid or multisegmented polygon shapes may be more appropriate than the rectangular shape as they more closely represent the anatomical shape of the stance foot.


Assuntos
Perna (Membro)/fisiologia , Equilíbrio Postural/fisiologia , Adulto , Feminino , Pé/fisiologia , Humanos , Cinestesia/fisiologia , Análise e Desempenho de Tarefas , Tato/fisiologia , Visão Ocular , Adulto Jovem
7.
J Neurophysiol ; 106(1): 259-64, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21562196

RESUMO

There is a controversy in the literature as to whether transfer of motor learning across the arms occurs because of an individual's cognitive awareness of the learned condition. The purpose of this study was to test whether the extent of interlimb transfer following adaptation to a novel visuomotor rotation with one arm, as well as the rate of learning acquired by the other arm, would vary depending on the subjects' awareness of the rotation condition. Awareness of the condition was varied by employing three experimental conditions. In one condition, visual rotation of the display up to 32° was gradually introduced to minimize the subjects' awareness of the rotation during targeted reaching movement. In another condition, the 32° rotation was abruptly introduced from the beginning of the adaptation session. Finally, the subjects were informed regarding the rotation prior to the adaptation session. After adaptation with the left arm under the three conditions, subjects performed reaching movement with the right arm under the same 32° rotation condition. Our results showed that the amount of initial transfer, and also the changes in performance with the right arm, did not vary significantly across the three conditions. This finding suggests that interlimb transfer of visuomotor adaptation does not occur based on an individual's awareness of the manipulation, but rather as a result of implicit generalization of the obtained visuomotor transformation across the arms.


Assuntos
Adaptação Fisiológica , Conscientização/fisiologia , Desempenho Psicomotor/fisiologia , Adolescente , Adulto , Braço/fisiologia , Feminino , Humanos , Masculino , Rotação , Percepção Visual/fisiologia , Adulto Jovem
8.
Arch Phys Med Rehabil ; 92(1): 76-82, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21187208

RESUMO

OBJECTIVE: To investigate the effectiveness of computing body-size-independent hip strength measures using muscle-specific allometric scaling and ratio standard normalization methods. DESIGN: Cross-sectional study. SETTING: University laboratory. PARTICIPANTS: A convenience sample of healthy participants (N=113; 42 men, 71 women). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Anthropometric measurements of the leg and thigh were obtained, and maximal hip strength was tested (medial and lateral rotation, abduction, adduction, flexion, extension). Strength was measured isometrically as force (kg) and then converted to torque (Nm). RESULTS: The allometric scaling analysis resulted in exponents for normalizing body mass (BM) in each muscle group assessed. In addition, a 6-muscle average exponent was also computed (bavg) for force (men, .554; women, .335) and torque (men, .792; women, .482). The nonsignificant results of the linear regression analysis revealed that normalizing hip strength to BM(bavg) (hip strength/BM(bavg)) effectively removed the influence of BM on force and torque. However, sex should be factored into analyses of allometric scaling because men have higher b-values than women for both force and torque. The linear regression analyses also demonstrated that force normalized to BM (P=.162-.895) and torque normalized to BM × Height (P=.146-.889) were body-size-independent measures. Force normalized to BM°·67 (P=.001-.191) and body mass index (BMI) (P=<.001-.066), and torque normalized to BM (P=.004-.415) and BMI (P<.001) were significantly related to BM and therefore were not body-size independent. CONCLUSIONS: Normalizing force and torque to BM(bavg) is the most effective method of removing body-size dependence and allowing comparisons of persons with differing body sizes.


Assuntos
Índice de Massa Corporal , Quadril/anatomia & histologia , Quadril/fisiologia , Contração Muscular/fisiologia , Força Muscular/fisiologia , Músculo Esquelético/anatomia & histologia , Músculo Esquelético/fisiologia , Adulto , Fenômenos Biomecânicos , Pesos e Medidas Corporais , Estudos Transversais , Feminino , Humanos , Extremidade Inferior/anatomia & histologia , Extremidade Inferior/fisiologia , Masculino , Dinamômetro de Força Muscular , Fatores Sexuais , Torque
9.
Genes (Basel) ; 12(12)2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34946956

RESUMO

We studied the evolutionary relationship of two widely distributed parapatric butterfly species, Melitaea athalia and Melitaea celadussa, using the ddRAD sequencing approach, as well as genital morphology and mtDNA data. M. athalia was retrieved as paraphyletic with respect to M. celadussa. Several cases of mito-nuclear discordance and morpho-genetic mismatch were found in the contact zone. A strongly diverged and marginally sympatric clade of M. athalia from the Balkans was revealed. An in-depth analysis of genomic structure detected high levels of admixture between M. athalia and M. celadussa at the contact zone, though not reaching the Balkan clade. The demographic modelling of populations supported the intermediate genetic make-up of European M. athalia populations with regards to M. celadussa and the Balkan clade. However, the dissimilarity matrix of genotype data (PCoA) suggested the Balkan lineage having a genetic component that is unrelated to the athalia-celadussa group. Although narrowly sympatric, almost no signs of gene flow were found between the main M. athalia group and the Balkan clade. We propose two possible scenarios on the historical evolution of our model taxa and the role of the last glacial maximum in shaping their current distribution. Finally, we discuss the complexities regarding the taxonomic delimitation of parapatric taxa.


Assuntos
Borboletas/classificação , Núcleo Celular/genética , DNA Mitocondrial/genética , Genômica/métodos , Animais , Península Balcânica , Borboletas/anatomia & histologia , Borboletas/genética , Evolução Molecular , Fluxo Gênico , Especiação Genética , Mitocôndrias/genética , Filogenia , Análise de Sequência de DNA , Simpatria
10.
Arch Rehabil Res Clin Transl ; 2(4): 100080, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33543103

RESUMO

OBJECTIVE: To determine classes of motor performance based on community deployable motor impairment and functional tests in a heterogeneous adult population. DESIGN: Sixteen tests of limb-specific and whole-body measures of motor impairment and function were obtained. Linear regression analysis was used to dichotomize performance on each test as falling within or outside the age- and sex-predicted values. Latent class analysis was used to determine 3 classes of motor performance. The chi-square test of association and the Fisher exact test were used for categorical variables, and analysis of variance and the Kruskal-Wallis test were used for continuous variables to evaluate the relationship between demographic characteristics and latent classes. SETTING: General community. PARTICIPANTS: Individuals (N=118; 50 men) participated in the study. Quota sampling was used to recruit individuals who self-identified as healthy (n=44) or currently living with a preexisting chronic health condition, including arthritis (n=19), multiple sclerosis (n=18), Parkinson disease (n=17), stroke (n=18), or low functioning (n=2). INTERVENTION: Not applicable. MAIN OUTCOME MEASURE: Latent classes of motor performance. RESULTS: Across the entire sample, 3 latent classes of motor performance were determined that clustered individuals with motor performance falling: (1) within predicted values on most of the tests (expected class), (2) outside predicted values on some of the tests (moderate class), and (3) outside predicted values on most of the tests (severe class).The ability to distinguish between the respective classes based on the percent chance of falling outside predicted values was achieved using the following community deployable motor performance tests: 10-meter walk test (22%, 80%, and 100%), 6-minute walk test (14.5%, 37.5%, and 100%), grooved pegboard test (23%, 38%, and 100%), and modified physical performance test (3%, 54%, and 96%). CONCLUSIONS: In this heterogeneous group of adults, we found 3 distinct classes of motor performance, with the sample clustering into an expected test score group, a moderate test score deficiency group, and a severed test score deficiency group. Based on the motor performance tests, we established that community deployable, easily administered testing could accurately predict the established clusters of motor performance.

11.
Oncogenesis ; 8(3): 15, 2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30796200

RESUMO

Several therapeutic options are available for metastatic RCC, but responses are almost never complete, and resistance to therapy develops in the vast majority of patients. Consequently, novel treatments are needed to combat resistance to current therapies and to improve patient outcomes. We have applied integrated transcriptome and proteome analyses to identify cathepsin B (CTSB), a cysteine proteinase of the papain family, as one of the most highly upregulated gene products in established human RCC xenograft models of resistance to vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI). We used established RCC models to test the significance of CTSB in the progression of renal cancer. Our evaluation of CTSB showed that stable CTSB knockdown suppressed RCC growth in vitro and in vivo. Stable over-overexpression of wild-type CTSB (CTSBwt/hi), but not of an CTSB active site mutant (CTSBN298A), rescued cell growth in CTSB knockdown cells and abolished the efficacy of VEGFR TKI treatment. Genome-wide transcriptome profiling of CTSB knockdown cells demonstrated significant effects on multiple metabolic and stem cell-related pathways, with ALDHA1A (ALDH1) as one of the most significantly downregulated genes. Importantly, survival analysis across 16 major TCGA cancers revealed that CTSB overexpression is associated with low rates of three and five year patient survival rates (P = 2.5e-08, HR = 1.4). These data strongly support a contribution of CTSB activity to RCC cell growth and tumorigenicity. They further highlight the promise of CTSB inhibition in development of novel combination therapies designed to improve efficacy of current TKI treatments of metastatic RCC.

12.
Acad Radiol ; 15(8): 1058-68, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18620126

RESUMO

RATIONALE AND OBJECTIVES: The purpose of this retrospective study was to compare the maximum intensity projection (MIP) images generated at a multidetector computed tomography (MDCT) scanner console using advanced tools at a three-dimensional (3D) workstation for assessment of pancreatic tumor resectability. MATERIALS AND METHODS: Institutional review board approval and informed consent wavier were obtained for this retrospective study. The intraoperative findings were used as reference standard. Two radiologists assessed console MIPs that were created using computed tomographic (CT) data sets of 30 patients (17 men and 13 women; age range, 35-79 years; mean age, 58 years) operated for pancreatic tumors. Semi-automated MIP images were created on a separate MDCT console. Two blinded radiologist (R1, R2) and surgeons (S1, S2) evaluated the image data independently for vascular involvement and tumor resectability. The image quality and diagnostic confidence for MIPs were graded on a 5-point scale (1 = poor, 2 = suboptimal, 3 = intermediate, 4 = good; 5 = excellent) and comparison was made with 3D workstation image scores. RESULTS: The findings revealed greater than 90% sensitivity, specificity, and accuracy for detecting involvement of peripancreatic vessels by pancreatic tumor with an excellent interobserver agreement (kappa = 0.87-1.00). The findings of console-generated MIPs were same as the findings of 3D workstation images. The mean of image quality and diagnostic confidence grading for console MIPs by assessors were 4.4 and 4.2, respectively. The average time to generate simple MIPs at the console was 3.4 minutes (range, 2.3-4.4) compared to 26 minutes (range, 18-33) to create images at the 3D workstation. CONCLUSION: Semi-automated MIPs generated from an MDCT scanner console is an excellent alternative to 3D workstation images for assessing resectability of pancreatic tumor based on vascular involvement. Console MIPs can be quickly generated during the time of scan and thus can improve CT workflow.


Assuntos
Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/cirurgia , Tomografia Computadorizada por Raios X/instrumentação , Adulto , Idoso , Feminino , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Estudos Retrospectivos , Sensibilidade e Especificidade , Fatores de Tempo
13.
Plant Divers ; 39(5): 263-272, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30159519

RESUMO

Rattans, or canes, are one of the most important non-timber forest products supporting the livelihood of many forest-dwelling communities in South and North-eastern India. Due to increased demand for rattan products, rattans have been extracted indiscriminately from the Western Ghats, a 1600-km mountain chain running parallel to the west coast of India. Extensive harvesting, loss of habitat and poor regeneration has resulted in dwindling rattan populations, necessitating an urgent attempt to conserve existing rattan resources. In this study, using niche-modelling tools, an attempt has been made to identify areas of high species richness of rattans in the Western Ghats, one of the mega-diversity regions of the world. We have also developed conservation values for 21 economically important and endemic rattans of the Western Ghats. We identified at least two to three sites of extremely high species richness outside the existing protected area network that should be prioritized for in situ conservation. This study emphasizes the need to develop strategies for the long-term conservation of rattans in the Western Ghats, India.

14.
Oncotarget ; 8(49): 84743-84760, 2017 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-29156680

RESUMO

PURPOSE: Papillary thyroid carcinoma (PTC) is the most frequent endocrine tumor. BRAFV600E represents the PTC hallmark and is targeted with selective inhibitors (e.g. vemurafenib). Although there have been promising results in clinical trials using these inhibitors, most patients develop resistance and progress. Tumor clonal diversity is proposed as one mechanism underlying drug resistance. Here we have investigated mechanisms of primary and secondary resistance to vemurafenib in BRAFWT/V600E-positive PTC patient-derived cells with P16-/- (CDKN2A-/-). EXPERIMENTAL DESIGN: Following treatment with vemurafenib, we expanded a sub-population of cells with primary resistance and characterized them genetically and cytogenetically. We have used exome sequencing, metaphase chromosome analysis, FISH and oligonucleotide SNP-microarray assays to assess clonal evolution of vemurafenib-resistant cells. Furthermore, we have validated our findings by networks and pathways analyses using PTC clinical samples. RESULTS: Vemurafenib-resistant cells grow similarly to naïve cells but are refractory to apoptosis upon treatment with vemurafenib, and accumulate in G2-M phase. We find that vemurafenib-resistant cells show amplification of chromosome 5 and de novo mutations in the RBM (RNA-binding motifs) genes family (i.e. RBMX, RBM10). RBMX knockdown in naïve-cells contributes to tetraploidization, including expansion of clones with chromosome 5 aberrations (e.g. isochromosome 5p). RBMX elicits gene regulatory networks with chromosome 5q cancer-associated genes and pathways for G2-M and DNA damage-response checkpoint regulation in BRAFWT/V600E-PTC. Importantly, combined therapy with vemurafenib plus palbociclib (inhibitor of CDK4/6, mimicking P16 functions) synergistically induces stronger apoptosis than single agents in resistant-cells and in anaplastic thyroid tumor cells harboring the heterozygous BRAFWT/V600E mutation. CONCLUSIONS: Critically, our findings suggest for the first time that targeting BRAFWT/V600E and CDK4/6 represents a novel therapeutic strategy to treat vemurafenib-resistant or vemurafenib-naïve radioiodine-refractory BRAFWT/V600E-PTC. This combined therapy could prevent selection and expansion of aggressive PTC cell sub-clones with intrinsic resistance, targeting tumor cells either with primary or secondary resistance to BRAFV600E inhibitor.

15.
J Athl Train ; 49(2): 173-80, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24568226

RESUMO

CONTEXT: Identification of impaired balance as a risk factor for lower extremity injury regardless of injury history has led to subsequent investigation of variables that may adversely affect balance in healthy individuals. OBJECTIVES: To investigate the relationship among core and lower extremity muscle function, foot posture, and balance. DESIGN: Descriptive laboratory study. SETTING: Musculoskeletal injury biomechanics laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 108 individuals (40 men, 68 women; age = 22.8 ± 4.7 years, height = 168.5 ± 10.4 cm, mass = 69.9 ± 13.3 kg) participated in the study. MAIN OUTCOME MEASURE(S): Core endurance was assessed during 1 time-to-failure trial, and isometric hip and ankle strength were assessed using a handheld dynamometer and isokinetic dynamometer, respectively. Foot structure was quantified using the digital photographic measurement method. Single-limb-stance time to boundary was assessed using a force plate during an eyes-closed condition. Hierarchical multiple regression analyses were performed to predict balance using lower extremity strength, foot posture, and core endurance. RESULTS: Foot posture (ß = -0.22, P = .03) and ankle-inversion strength (ß = -0.29, P = .006) predicted mediolateral balance. Increasing arch posture and ankle-inversion strength were associated with decreased mediolateral single-limb-stance balance. CONCLUSIONS: Increasing arch height was associated with decreased mediolateral control of single-limb stance. The relationship between time to boundary and injury risk, however, has not been explored. Therefore, the relationship between increasing arch height and injury due to postural instability cannot be determined from this study. If authors of future prospective studies identify a relationship between decreased time to boundary and increased injury risk, foot structure may be an important variable to assess during preparticipation physical examinations. The relationship between increasing ankle-inversion strength and decreased balance may require additional study to further elucidate the relationship between ankle strength and balance.


Assuntos
Pé/fisiologia , Extremidade Inferior/fisiologia , Músculo Esquelético/fisiologia , Postura/fisiologia , Adulto , Tornozelo/fisiologia , Índice de Massa Corporal , Feminino , Humanos , Masculino , Força Muscular/fisiologia , Pronação/fisiologia , Adulto Jovem
16.
J Appl Biomech ; 26(4): 444-53, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21245504

RESUMO

The increased number of women participating in sports has led to a higher knee injury rate in women compared with men. Among these injuries, those occurring to the ACL are commonly observed during landing maneuvers. The purpose of this study was to determine gender differences in landing strategies during unilateral and bilateral landings. Sixteen male and 17 female recreational athletes were recruited to perform unilateral and bilateral landings from a raised platform, scaled to match their individual jumping abilities. Three-dimensional kinematics and kinetics of the dominant leg were calculated during the landing phase and reported as initial ground contact angle, ranges of motion (ROM) and peak moments. Lower extremity energy absorption was also calculated for the duration of the landing phase. Results showed that gender differences were only observed in sagittal plane hip and knee ROM, potentially due to the use of a relative drop height versus the commonly used absolute drop height. Unilateral landings were characterized by significant differences in hip and knee kinematics that have been linked to increased injury risk and would best be classified as "stiff" landings. The ankle musculature was used more for impact absorption during unilateral landing, which required increased joint extension at touchdown and may increase injury risk during an unbalanced landing. In addition, there was only an 11% increase in total energy absorption during unilateral landings, suggesting that there was a substantial amount of passive energy transfer during unilateral landings.


Assuntos
Articulação do Tornozelo/fisiologia , Lesões do Ligamento Cruzado Anterior , Desempenho Atlético/fisiologia , Articulação do Quadril/fisiologia , Traumatismos do Joelho/fisiopatologia , Articulação do Joelho/fisiologia , Caracteres Sexuais , Adulto , Fenômenos Biomecânicos , Feminino , Humanos , Masculino , Amplitude de Movimento Articular
17.
Radiology ; 244(2): 583-90, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17641376

RESUMO

Institutional Review Board approval was obtained and informed consent was waived for this HIPAA-compliant study. The aim of this study was to retrospectively compare the accuracy of semiautomated maximum intensity projection (MIP) images created at a 16-section multidetector CT console with three-dimensional (3D)-workstation-generated images for the definition of renal donor anatomy, with intraoperative findings as a reference standard. In examining 40 renal donors (21 men and 19 women; age range, 24-56 years; mean age, 40.4 years), the sensitivity and accuracy for mapping donor anatomy by two readers were greater than 95%, interobserver agreement was excellent (kappa = 0.89-1.00). The 95% confidence interval for sensitivity was also calculated. Simple MIPs compared well with 3D-workstation images. MIPs from a predesigned protocol on the scanner console were generated more quickly than similar images from 3D workstations; postprocessing demands (eg, for renal donors) can be quickly fulfilled at the scanner console itself. The average time to generate simple MIPs at the console was 3.4 minutes (range, 1.7-4.4 minutes), and 22.3 minutes (range, 15-30 minutes) to create images at the 3D workstation.


Assuntos
Transplante de Fígado , Fígado/diagnóstico por imagem , Doadores Vivos , Intensificação de Imagem Radiográfica/métodos , Tomografia Computadorizada por Raios X/métodos , Interface Usuário-Computador , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nefrectomia , Interpretação de Imagem Radiográfica Assistida por Computador , Sistemas de Informação em Radiologia , Estudos Retrospectivos , Sensibilidade e Especificidade
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